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Available online at www.sciencedirect.com

Tetrahedron 64 (2008) 2683e2723 www.elsevier.com/locate/tet

Tetrahedron report number 828

Synthesis of six-membered oxygenated heterocycles through carboneoxygen bond-forming reactions Igor Larrosa a, Pedro Romea b,*, Fe`lix Urpı´ b,* b

a School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK Departament de Quı´mica Orga`nica, Universitat de Barcelona, Martı´ i Franque´s 1e11, 08028 Barcelona, Catalonia, Spain

Received 12 November 2007

Contents 1. 2. 3. 4. 5.

Introduction and scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2684 SN2-Mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2684 SN1-Mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2685 Epoxide-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2686 Alkene-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2690 5.1. Stoichiometric cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2691 5.1.1. Mercury-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2691 5.1.2. Halo-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2692 5.1.3. Seleno-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2693 5.2. Catalytic cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694 5.2.1. Palladium-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694 5.2.1.1. Catalysis by Pd(0) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2694 5.2.1.2. Catalysis by Pd(II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2695 5.2.2. Other metal-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2699 5.3. Acid-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2699 6. Allene-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2700 7. Alkyne-mediated cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2700 8. Other metal-promoted cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2704 8.1. Cyclizations of 4-alkynols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2704 8.2. Cyclizations of diazo compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2706 8.3. Intramolecular etherification of aryl and vinyl halides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2709 9. Intramolecular conjugate additions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2710 9.1. 6-exo Ring closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2710 9.2. 6-endo Ring closures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2713 10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717 References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2717 Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2723

* Corresponding authors. Tel.: þ34 93 4039106 (P.R.); tel.: þ34 93 4021247 (F.U.). E-mail addresses: [email protected] (P. Romea), [email protected] (F. Urpı´). 0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.11.092

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2684

O

OMe O

N

O

O

N

H N

O

R1 R2

O

O

OMe O

O

OMe

MeO

O

O

Br

O

O OH

O

O N O

OH

2a phorboxazole A, R1 = OH, R2 = H 2b phorboxazole B, R1 = H, R2 = OH

1 leucascandrolide A

Figure 1.

1. Introduction and scope Six-membered oxygenated heterocycles, or pyrans, are probably one of the most common structural motifs spread across natural products, from simple glucose to structurally complex metabolites such as leucascandrolide A (1),1 phorboxazole A (2a) and B (2b),2e4 and the even more elaborated architectures present in palytoxin, maitotoxin, and other marine natural products (Fig. 1).5 Due to the remarkably rich array of functionalities and chiral centers that these heterocycles can incorporate, their stereoselective preparation has become a continuous challenge for organic synthesis practitioners.6e10 They can be synthesized by means of five-membered ring expansions (e.g., BaeyereVilliger oxidation of cyclopentanones11), cycloaddition processes (e.g., Hetero-DielseAlder reactions12), or intramolecular cyclizations.13 Classical examples of these cyclizations are the lactonisation of d-hydroxy acids or the thermodynamically favorable conversion of d-hydroxy aldehydes into the corresponding hemiacetals, which, in turn, can be easily modified (e.g., C-glycosidation reactions14) to provide other pyran-based structures. In addition to these processes, there is a set of important methodologies based on the cyclization of an oxygenated precursor that affords pyran structures in a highly efficient and straightforward manner. Considering the crucial ring-forming step (or the parallel transform in the retrosynthetic sense), the cyclization methodologies can be classified into three types, represented in Figure 2. Type 1 gathers those methodologies based on O1eC2 bond formation15 (or disconnection in the retrosynthetic sense), which encompass SN2- and SN1-mediated cyclizations, metalpromoted processes, and Michael-like reactions. Likewise, Type 2 and 3 methodologies affect C2eC3 and C3eC4 bond formation, respectively, which include Prins sequences, PetasiseFerrier rearrangements, or ring-closing metathesis reactions.

4 3

O

2

O

2

3

O

1

Type 1

Type 2

Figure 2.

Type 3

The aim of this report is to highlight Type 1 methodologies addressed to the stereoselective construction of di- and tetrahydropyrans and their application to the synthesis of natural products, with special attention being paid to the most recent contributions.

2. SN2-Mediated cyclizations Transformations based on an SN2-mediated cyclization of a hydroxy precursor represent the simplest strategy leading to di- and tetrahydropyran. They only require a suitable combination of base (B: tertiary amine, alkoxide, hydride; see Scheme 1) and leaving group (X: sulfonate, halide; see Scheme 1) to promote a 6-exo-tet process16 with inversion of the configuration at the CeX center in accordance with the pattern dictated by the Williamson reaction (see path A in Scheme 1). Thus, the stereochemistry of the resulting tetrahydropyran relies exclusively on the configuration of the acyclic precursor. path B

path A B OH

O

X

X

OH

–H O

Scheme 1.

With regard to the reactivity of such systems, cyclizations that involve leaving groups placed on a primary position take place smoothly,17 whereas those located on a secondary position often require a more accurate control of the reaction conditions.18 Even in such a challenging situation, this strategy enjoys an interesting synthetic potentiality, as has been clearly proved in the successful construction of tetrahydropyrans embedded in leucascandrolide A (1),1f and phorboxazole A (2a)2d and B (2b).3b Noteworthy, either 2,6-cis-tetrahydropyran (see 4 and 8 in Scheme 2) or 2,6-trans-tetrahydropyran (see 6 and 10 in Scheme 2) is obtained by simple application of the same experimental conditions. Thus, both stereochemistries

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 7

S S

OH

OTs

7

S

NaH

S

PhH, 90 °C

3

O 3

75%

OPMB

2685

11

OPMB

3

4

TBSO

7

OTBDPS

OTs OMe O 15

11

1

7

O

OPMB 5

1) HF·pyr, pyr

OMe O

15

3

OTBS

OTBDPS 2) NaH, PhH, 60 °C

3

OH

OPMB

73%

6

OH OPiv

11

1) MsCl, Et3N 2) TsOH, MeOH

15

O

O

15

3) NaH, PhMe,

N

O

11

O

O

OPiv

N

72%

PMBO

PMBO

7

8 OTBDPS

OTBDPS 15

O

2a

15

11

O N

PMBO

O

9

N

TsO

PhH,

5

5

PMBO

89%

HO

10

PivO

11

O

O

NaH

9

9

OPiv

Scheme 2.

are available, depending on the configuration of the reacting center. Remarkably, an SN2-mediated cyclization has also been used for the assemblage of C5eC9 tetrahydropyran of phorboxazole A (2a) in the final stages of the synthesis.2h Thereby, alcohol 11 is easily converted into its mesylate 12, the silicon protecting group at C5 is selectively removed and the simple exposure of the resulting hydroxy mesylate 13 to Et3N affords the desired 2,6-trans-tetrahydropyran 14 in an excellent yield (Scheme 3).

3. SN1-Mediated cyclizations In contrast to the above-mentioned methodologies, SN1mediated cyclizations take advantage of the stability of allylic and benzylic carbocations to drain the process represented in Scheme 1 along path B.19,20 Now, the planarity of the carbocationic intermediate does not exert any control on the configuration of the new stereocenter and the stereochemical outcome of the cyclization relies on the stereogenic elements of the substrate and the experimental conditions.

O OTBDPS

N O Br

OMe

O

MeO

O

OPMB

OR1

OR2 5

N

O

OMe OTBDPS MsCl, Et3N, 99% PPTS cat., MeOH, 98%

11

R1:

H

TES

O

OMe

MeO

9

O O

O

OTBDPS

N

13 R1: Ms R2: H

OPMB

O 5

N

OMe OTBDPS

14

Scheme 3.

Et3N MeCN,

O

12 R1: Ms R2: TES

Br 2a

OTBDPS R2:

OTBDPS

86%

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2686 TBSO

TBSO

OTBS

Cl

TBSO

OTBS

HO

OTBS

OTBS

OTBS

12b

OTBS OTBS

Cl

Cl

Cl

OTBS

12b

12b

O

H

45% dr 5:1

H

H 15

H

16

17

Scheme 4.

Thereby, cyclization of benzylic allylic alcohol 15 during an aqueous work-up is supposed to proceed through cationic intermediate 16, which undergoes ring closure followed by the release of the silicon protecting group (Scheme 4).19d The stereochemistry of the major diastereomer 17 arises from the preferential attack of the OTBS oxygen from the opposite side of C12b methyl. Better results are typically obtained for 2,6-cis-tetrahydropyrans, which are usually the most stable diastereomers. For instance, construction of the C22eC26 2,6-cis-tetrahydropyran of phorboxazole A (2a) has been achieved through an intramolecular SN1-mediated cyclization of alcohol 18, as shown in Scheme 5. Actually, the stereochemical outcome of this transformation is consistent with the internal capture of a transoid allylic cation at C26 by the C22 b-methoxymethyl ether and dealkylation of the resulting oxonium species.2d,21 Propargylic carbocations can also participate in these cyclizations, since they are easily generated by treatment of Co2(CO)6ealkynol complexes with either Brønsted or Lewis acid22 and are stable enough to be intramolecularly trapped by oxygenated nucleophiles. Indeed, ring closure of diol 20 affords tetrahydropyrans 21 in excellent overall yield (Scheme 6).23 Remarkably, the thermodynamically more stable 2,3trans derivative is increasingly obtained with long reaction times or higher temperatures. Furthermore, epoxides can also act as nucleophiles and, in particular, precursors containing a protected epoxy alcohol moiety participate in highly regio- and stereoselective

cyclizations. For instance, treatment of carbonates 22a or b (Scheme 7) with BF3$OEt2 followed by protecting group transformations furnishes 2,6-cis-tetrahydropyran 23a or b as a sole diastereomer through a putative propargylic carbocation,24 which has provided a new entry to a formal synthesis of (þ)-muconin 24.25 4. Epoxide-mediated cyclizations Since the seminal studies on the intramolecular epoxide opening carried out by Nicolaou et al.26 established the structural criteria required for the regio- and stereocontrolled synthesis of six-membered oxygenated heterocycles overriding the competitive formation of the corresponding five- or seven-membered counterparts, acid-catalyzed cyclizations of hydroxy epoxides have become a common approach to the stereoselective construction of tetrahydropyrans.27 The regioselectivity of the cyclization for g-hydroxy epoxides greatly depends on the geometry of the epoxide. Indeed, cis-epoxides reliably afford the 5-exo ring closure probably because these systems do not easily assume the planar arrangements necessary for maximum stabilization in the transition states leading to six-membered rings (Eq. 1 in Scheme 8). On the other hand, trans-epoxides enable the desired 6-endo process provided that a p-orbital adjacent to the epoxide unit activates the CeO bond close to it and stabilizes the developing positive charge in the transition state (Eq. 2 in Scheme 8). In both cases, these cyclizations are accompanied OPMB

OMOM 22

N R

OH

22

26

OTES

O

OPMB Tf2O, pyr

N

CH2Cl2, –20 °C

O

O

55%

18

2a

OTES

26

R

19

Scheme 5.

H

OBn

1) BF3·OEt2, CH2Cl2, T, t

Co2(CO)6

HO HO

C5H11 20

O

T (°C) t (h) trans-cis Yield (%) 0.33 2.5 18

10:1 1.2:1 9.9:1

OBn

+

2) CAN, acetone, 0 °C

20 –20 –20

H

OBn

94 70 87

Scheme 6.

H

21-trans

O C5H11

H

21-cis

C5H11

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 TMS

Co2(CO)6

OH

O

2687

O

OBoc 22a

OBoc

OH

Co2(CO)6

TMS

BF3·OEt2, CH2Cl2 –20 °C, 4 h t-BuO O O

22b

BF3·OEt2, CH2Cl2 rt, 3 h O

TMS

O

(CO)6Co2

(CO)6Co2

Ot-Bu

TMS

(CO) 6Co2

OH (CO)6Co2 TMS

O

O

O

OH

O

TMS

OBoc

OH 1) CAN, acetone, rt, 30 min 55% 2) K2CO3, MeOH, rt, 6 h 3) CH2(OMe)2, CSA, rt , 3 h

1) Ac2O, CH2Cl2, rt, 30 min 70% 2) CAN, acetone, rt, 10 min OAc O

OBoc

O

23a

O

23b

O

O O

O

O n-C12H25 OH

OH

OH

(+)-muconin 24

Scheme 7.

5-exo

HO R

H

O

favored

6-endo

O R

OH

HO R

cis epoxide

5-exo

HO R

H

O

favored R: CH2X

O R

trans epoxide

H

(1) H

HO

7-endo

R HO

O

6-exo

O R

favored

(3)

HO

OH

R

H

O

cis epoxide 6-endo

OH

H

favored R: CH=CH2

HO R

H

H

(2) H

O

Scheme 8.

by inversion of the stereochemistry at the carbon undergoing nucleophilic attack. A similar analysis was performed for d-hydroxy epoxides. In these systems, cis-epoxides exhibit low selectivity for the 7-endo ring closure irrespective of the R substituent, preferentially forming the corresponding tetrahydropyran (Eq. 3 in Scheme 9). Conversely, the R substituent plays a crucial role in the case of trans-epoxides. As expected on kinetic grounds, any saturated substituent favors the 6-exo process and yields almost exclusively the six-membered ring, whereas, once again, a p-orbital close to the epoxide directs the attack to the allylic position and produces the oxepane ring (Eq. 4 in Scheme 9). These models account for most of the synthetic approaches found across the most recent literature.28 For instance, construction of the bicyclic ether core of (þ)-sorangicin A (25

HO R H

7-endo O

favored R: CH=CH2

O R

6-exo favored OH

R: CH2X

(4)

HO R

H

O

trans epoxide

Scheme 9.

in Scheme 10) illustrates some of the aforementioned trends. Exposure of epoxide 26 to aqueous acid produces tetrahydropyran 27 through a 6-exo ring closure (see Eq. 4 in Scheme 9), without observing alternative 7-endo or even 5-endo cyclizations. Furthermore, 27 can be easily converted into epoxy alcohol 28, which is subjected to an acid-mediated cyclization that follows a 5-exo pathway (see Eq. 1 in Scheme 8). Interestingly, three steps can be combined in a one-pot, three-step sequence that delivers the bicyclic ether 29 in a 62% overall yield.29,30 Similarly, a parallel set of experimental conditions based on the use of a Lewis acid (Ti(i-PrO)4 activation in hot benzene) have been devised for the assemblage of the C22eC26 2,6-cistetrahydropyran 31 from 30 in a route to phorboxazole A (2a) (Scheme 11).2c

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2688

6-exo

HO

O

O HO

OH OH

O

5-endo

O

Ph

Ph

H3O

26

OH

OH

O

O

O

O O

Ph

H3O

OH

Ph

O HO

6-endo

HOOC

29

OTs

27

7-endo

1) 10% HCl, rt, 18 h 62% 2) 10% NaOH, rt 3) 10% HCl, rt, 4 h

(+)-sorangicin A 25

O HO

OTs

OH

5-exo

O

28

Scheme 10.

6-exo

22

PMBO

OH

26

HO

O Ti(i-PrO)4

22

O 30

HO

PhH,

26

OPMB

2a

OH

76%

31

Scheme 11.

As pointed out in Scheme 8, alkenes adjacent to epoxides override the common bias favoring the 5-exo ring-closure mode. This is the behavior observed in the intramolecular cyclization of a,b-unsaturated epoxide 33, which permits the regio- and stereoselective preparation of a densely substituted C8eC12 tetrahydropyran directed toward the synthesis of brevenal (32 in Scheme 12).31 Indeed, removal of the PMB group on 33 triggers a 6-endo cyclization to a tetrahydropyran, which is subsequently converted into TES ether 34.32 Occasionally, these methodologies are combined in a synthetic sequence. For instance, the tristetrahydropyran substructure of diol 35, an advanced intermediate toward the synthesis of thyrsiferol and venustatriol (36a and 36b, respectively, in Scheme 13), has been regio- and stereoselectively prepared through three intramolecular cyclizations of g- and d-hydroxy epoxides.33 The first acid-catalyzed ring closure of hydroxy epoxide 37 proceeds quantitatively to form 38 with complete 6-exo regioselectivity,y and no competitive 7-endo cyclization is observed. Next, the construction of tetrahydropyran B takes advantage of the allylic character of a trans-epoxide. Indeed, cyclization of hydroxy diepoxide 39 affords the desired sixmembered heterocycle 40 under very mild conditions with excellent 6-endo regioselectivity. Eventually, Ti(i-PrO)4 activation of hydroxy epoxide 41 produces the third ring in 58% yield. In spite of these accomplishments, it was soon realized that new methodologies able to switch 5-exo to 6-endo processes irrespective of the substituent R (see Eqs. 1 and 2 in Scheme

y Actually ring closure to tetrahydropyran A is carried out on a 1:1 epimeric mixture of 3-bromo derivatives. Interestingly, the experimental conditions provide a highly efficient kinetic resolution and just hydroxy epoxide 37 undergoes the desired cyclization.

8) were highly desirable. In this context, it has been recently reported that epoxide openings triggered by bulky silyl triflates in nitromethane yield the desired tetrahydropyrans regioselectively.34 In addition to these observations, the regioselective tenet summarized in Scheme 8 favoring 5-exo over 6-endo ring closures of g-hydroxy epoxides has recently been challenged in vanadium-catalyzed mediated processes.35 As outlined in Scheme 14, the asymmetric oxidation of unsaturated a-hydroxy esters followed by an epoxidation/cyclization sequence using the same chiral catalyst provide regio- (6-endo/ 5-exo ratio ca. 4:1) and stereoselectively (dr>88:12, ee>95%) 2,5-trans-tetrahydropyrans in 20e35% yield (the highest theoretical yield is 50%). Hence, this process is divided into two steps. The first step involves the oxidative resolution (acetone/O2) of a racemic mixture of a-hydroxy esters (R1, R2sH) using a vanadium catalyst prepared from VO(i-PrO)3 and the chiral Schiff base 42. Once the alcohol has been chemo- and stereoselectively oxidized, change of solvent and oxidant to CHCl3/t-BuOOH promotes a stereoselective epoxidation followed by a fast cyclization of the resultant hydroxy epoxide. The mechanistic model that accounts for the stereochemical outcome of the overall process emphasizes the coordination of the ester carbonyl to the metal. Such a coordination places the ester in the pseudoaxial position, which allows an efficient p-facial discrimination of the carbonecarbon double bond. Finally, the resultant short-lived epoxide undergoes a backside attack of the hydroxyl to the corresponding 2,5-trans tetrahydropyran.36 The pursuit for regioselective 6-endo cyclizations has found its own Holy Grail in the synthesis of fused polycyclic ethers, a family of marine metabolites with remarkable biological activity.9 As partly suggested by the name, their molecular architectures contain large and highly rigid polycyclic frameworks of all fused six- to nine-membered oxygenated rings in a welldefined stereochemical arrangement, as shown in Figure 3.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2689 H

12

O OPMB

8

TBDPSO

33

OTES

1) DDQ, CH2Cl2-H2O, rt 8

TBDPSO

2) TESOTf, 2,6-lut, CH2Cl2, 0 °C

H

89% Me H H O

brevenal 32

H O 12 Me

H OH

OHC

H

O

O

Me

34

6-endo 8

12

OH Me

H O

O H H

Me

Scheme 12.

The synthesis of these large and complex structures has raised much interest in strategies rooted on biogenetic grounds. Unfortunately, the biosynthesis of these metabolites is not well understood and current working hypotheses are rather speculative. In this context, the CaneeCelmereWestley model, originally proposed for the synthesis of polyether antibiotics,37 has inspired most of those hypotheses, which envisage that the fused polycyclic ether frameworks might arise from the cyclization of a polyepoxide precursor through a cascade of SN2 ring openings.38 Therefore, any biomimetic strategy must be able to provide a synthetic route to a chiral

polyepoxide with the structural elements to allow for the regio- and stereoselective 6-endo ring closures required for the fused tetrahydropyran arrays. Otherwise, alternative pathways based on 5-exo cyclizations leading to tetrahydrofurans would predominate (Scheme 15).39 In this context, a biomimetic approach takes advantage of endo-selective cyclizations of methoxymethyl epoxy alcohols controlled by chelation with a suitable Lewis acid. Indeed, the asymmetric epoxidation of polyene 43 leads to 44 in 56% isolated yield, and removal of the silicon protecting group provides quantitatively triepoxide alcohol 45 (Scheme 16). Then, R

O C

B O

O A

35

R : OH HO R:

OH thyrsiferol, 36a

O

HO

Br

venustatriol, 36b

O

R:

H OH H OH

O 40 mol% CSA

Br HO

OAc

O A

Et2O,rt, 0.5 h

37

OH OAc

Br

100%

38

OH B O

O A

1 equiv PPTS

OTBS

CHCl3, rt, 5 min

O 40

Br

O B OH

O A Br

70%

OTBS O

39

OH

OH O A

B O

0.9 equiv Ti(i-PrO)4

OH

58%

41

Br

O A

PhMe, 70–80 °C, 3 h

O

B O

O C

OH

35

Br

Scheme 13.

O R1

RO R2

OH

10 mol% VO(i-PrO)3, 11 mol% 42 O2 acetone, 30 °C, 30–48 h

R2

t-BuO

O

R1

5 2

CO2R

2,5-trans-tetrahydropyran

R1 R2

OH

HO R1 O R2

O RO

20–35% t-BuO dr > 88:12 ee > 95%

HO [V] O

R2 OR

Scheme 14.

R1

10 mol% VO(i-PrO)3, 11 mol% 42 t-BuOOH, CHCl3, rt, 24–72 h O O [V] O H

OR

t-Bu t-Bu

N

H

OH

OH t-Bu

42

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2690

A different strategy employs epoxysilanes as starting materials for the cyclizations. It takes advantage of trimethylsilyl groups to achieve highly regioselective openings of the epoxides, and, immediately after the ring closure, the silicon group is removed by fluoride-promoted protodesilylation.42 As outlined in Scheme 18, this approach allows for the straightforward conversion of triepoxysilane 49 into the large tetrahydropyran array 50. Indeed, chiral epoxide 49, prepared from a reagent-controlled Shi epoxidation (dr 90:10), undergoes a cascade of ring openings mediated by a Brønsted base and a fluoride source in a hydroxylic solvent. Finally, the resultant alcohol is acylated to furnish 50 in 20% overall yield.

cis R1 trans O

R3

R2

O

trans

()

n

R4

O

n = 1, 2, 3, or 4 R1, R2, R3, R4 : H, Me

Figure 3.

a cascade cyclization catalyzed by La(OTf)3 proceeds in a stepwise mechanism to afford the desired tricyclic ether 46 in 9% yield.40 Lewis acid-mediated endo oxacyclization of polyepoxides affords cis- or trans-fused polyethers depending on the nature of the terminal nucleophile. The rationale for such dependence relies on the mechanism depicted in Scheme 17. Initially, Lewis acid activation of a first epoxide triggers the generation of a bridged onium intermediate, which can evolve through a tight ion pair to a tertiary carbocation. Therefore, the terminal nucleophile may intercept different species. It has been proposed that the cis-fused products arise by trapping of an intermediate close to the carbocation, whereas the trans-fused derivatives are mainly obtained with a better nucleophile (i.e., a tertiary carbamate) by adding to an intermediate structurally close to the epoxonium ion. This is the case for dimethylcarbamate epoxide 47 prepared through stereoselective Sharpless and Shi epoxidations of the corresponding alkenes. Then, BF3$OEt2-promoted oxacyclization of 47 produces the desired polyether 48 in 31% isolated yield.41

Closely related to the epoxide-mediated cyclizations, there is an important number of methodologies based on the intramolecular attack of an oxygenated nucleophile on an olefin activated by electrophiles. The most common precursors are d-hydroxy alkenes, which afford the corresponding pyrans through highly regioselective 6-exo ring closures (Scheme 19). The rationale for these cyclizations assumes the reversible formation of a p-complex, which can proceed either directly to the corresponding heterocycle by reaction with the nucleophile or indirectly by first collapsing to an onium intermediate before undergoing nucleophilic attack.43 In any case, cyclization involves the attack of the oxygenated nucleophile on the opposite face of the electrophile. Therefore, the success of this strategy mostly relies on the stereocontrolled electrophilic addition to the alkene. These cyclizations can be classified as stoichiometric or catalytic, according to the amount of electrophile engaged in the process. The stoichiometric electrophile-induced cyclizations routinely involve mercury(II) salts and iodo or seleno reagents as activators of the carbonecarbon double bond. Otherwise, palladium chemistry dominates the catalytic counterparts, although other metals are being increasingly employed.

O

O

5-exo ring closure O

5. Alkene-mediated cyclizations

O Nu

Nu

O

O

6-endo ring closure

O

Nu

O

Nu

Scheme 15.

O MeO

O

MeO

OR

O

H

O 46

MeO

, Oxone

H

H OMe

R O

9%

HO

44

O

H OMe

R

R: H

O Me

Me O

OMe La

O

La

Scheme 16.

R: TBDPS

45 H O

OMe

O

1.1 equiv La(OTf)3 0.3 equiv La2O3 5.5 equiv H2O CH2Cl2, rt

OR

TBAF, THF 100%

OMe

O

O MeO

R: TBDPS

O

MeO

O

MeCN, (MeO)2CH2, 0 °C 56%

43

H

O

O

MeO

MeO HO

O

H

O

R

O O H

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 O

O R

O

O

BF3

O

R

O R

2691

O

O

O BF3

O O

O

R

O O

O

R

BF3

O

O

tertiary carbocation H

R

O

H

O

O

Me cis-fused

O O

BF3

R

O O

O

Me trans-fused

BF3

O

H O

Me2N

O

O

O

0.01 M BF3·OEt2 CH2Cl2, 20 °C

O O

O

31%

47

BF3

epoxonium ion

ion pair

O

O

O

BF3

O

Me

Me H 48

OH

O

Scheme 17.

5.1. Stoichiometric cyclizations

of 54 with n-Bu3SnH effects the desired demercuriation to 55 in excellent yield. The intramolecular oxymercuriation has also been applied to the assemblage of the C22eC26 tetrahydropyran of phorboxazole B (2b). As shown in Scheme 21, treatment of diol 56 with Hg(OAc)2 followed by reaction of the resultant organomercuriate with iodine furnishes a 5:1 mixture of the 2,6cis-tetrahydropyran 57-cis and the corresponding 2,6-trans isomer. Then, chromatographic purification of the mixture permits the isolation of the desired 57-cis in 71% yield. Given that the success of such a strategy relies on the pfacial discrimination of an alkene, any methodology able to fulfill this requirement should allow for a complete stereochemical control. In this context, mercury(II)-mediated electrophilic ring-opening reactions of d-hydroxy cyclopropylcarbinol derivatives represent an appealing entry into the asymmetric synthesis of tetrahydropyrans. In this approach, the cyclopropane unit plays the role of an activated olefin. These highly diastereoselective processes usually occur with anchimeric assistance by the closest alcohol and subsequent nucleophilic backside

5.1.1. Mercury-mediated cyclizations The electrophiles employed in these processes are mercury(II) salts and the resultant carbonemercury bonds are usually reduced with NaBH4 or n-Bu3SnH.44 The course of these intramolecular oxymercuriations depends on the stability of the cationic intermediates and, with the exception of one example,45 they are substrate-controlled processes that usually lead to the thermodynamically more stable tetrahydropyran. Thus, the hydroxy alkene must contain the structural elements required to achieve the desired p-facial discrimination of the carbonecarbon double bond. This is the case for the d-hydroxy alkene 52, an intermediate in the total synthesis of the antibiotic X-206 (51 in Scheme 20).44a Indeed, steric and conformational arguments would be responsible for the outstanding stereocontrolled electrophilic addition of Hg(OAc)2 to the olefin in such a way that the resulting onium intermediate 53 is suitably prepared for the intramolecular cyclization leading to 2,6-cis-tetrahydropyran 54 quantitatively. Eventually, treatment

O TMS

HO

TMS O

H

H 1) Cs2CO3, CsF, MeOH,

O TMS

H

O

2) Ac2O, DMAP, pyr, CH2Cl2

AcO

20%

O

H

H

H

49

H

O

H

O

H

H

O

50

Scheme 18.

E +E OH

6-exo –H

OH complex

E 6-exo OH onium intermediate

Scheme 19.

–H

O

E

–E

O

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2692

OBOM

7

3

OH COXc

H HgOAc NaCl aq. H OH OBOM H R 99% 53

Hg(OAc)2

R

CH2Cl2, rt

XcCO H

52 O

OBOM 3

O COXc

7

R X

54 X: HgCl 55 X: H

OH 3

7

HO

O

O

OH

O

OH OH

O OH

O

n-Bu3SnH PhMe 94%

O OH

X-206 51

Scheme 20.

attack of the d-OH, which causes an inversion in the configuration of the reacting center (Scheme 22). Hence, the stereochemical outcome of these cyclizations mostly depends upon the configuration of the cyclopropane ring.46 This strategy has been applied to the construction of the C3e C7 tetrahydropyran of zincophorin (58 in Scheme 23).47 The cyclopropane ring of the advanced intermediate 59 is installed at the beginning of the synthesis by means of the catalytic asymmetric cyclopropanation of an allylic diazoacetate. Then, simple treatment of 59 with Hg(OCOCF3)2 followed by aqueous work-up cleanly produces 2,6-trans-tetrahydropyran 60. In turn, this organomercuric bromide is subjected to a reductive demercuriation, which eventually provides 61 in 85% yield and 93:7 dr. 5.1.2. Halo-mediated cyclizations Halo-mediated cyclizations are similar to the processes based on mercury(II) salts. Most of the intramolecular haloetherification reactions take advantage of the use of iodine or N-iodosuccinimide (NIS),48e50 reagents mild enough to be used on structurally complex substrates. For instance, NIS-mediated iodoetherification plays a crucial role in the assemblage of the G-ring of azaspiracid-1 (62 in Scheme 24), a prominent member of a family of marine metabolites responsible for human poisoning resulting from the consumption of tainted shellfish. Initially reported in 1998, azaspiracids were shrouded in structural ambiguity that partially arises from

the complex and intricate array of sensitive functional groups embedded in their structure and, only in 2004, have Nicolaou et al. reported the correct structure of azaspiracid-1 after considerable synthetic work. It is, then, not surprising that the endeavors applied to the construction of such challenging compounds have spurred the development of new strategies (see also Schemes 57 and 91). As represented in Scheme 24, the intramolecular iodoetherification of the structurally complex alcohol 63 affords iodoether 64, which is reduced with an excess of n-Bu3SnH in toluene to remove the superfluous iodine at C29. Thus, the highly advanced intermediate 65 is obtained through this two-step sequence in 53% yield. Iodoetherification on substrates containing an allylic alcohol turns out to be highly dependent on conformational issues. Indeed, diol 66a undergoes a facile cyclization to 2,6-cis-tetrahydropyran 67a, while the diastereomer 66b fails to give the expected bicyclic system 67b (Scheme 25).48e The rationale for such different behavior relies on the conformational analysis of the allylic moiety. Cyclizations in which the nucleophile is in the R group proceed rapidly (or slowly) through the favored p-complex 68a (or the disfavored p-complex 68b) when CeOH (or CeH) eclipses the carbonecarbon double bond. This is the situation for 66a (or 66b). Thus, cyclization of 66b requires a more reactive iodinating agent such as bis(sym-collidine)2IPF6, prepared in situ from bis(sym-collidine)2AgPF6 and iodine in CH2Cl2. This reagent converts 66b into the desired tetrahydropyran 67b in 80% yield. I

22

O

22

OH

1) Hg(OAc)2, PhMe, 0 °C, 8 h

26

2) I2, rt, 12 h

OH

O

O 2b OH

26

O O

71%

57-cis

56

Scheme 21.

reductive demercuriation

HgX2 HO

OH

HO

OH

–HX

Hg X

O

OH HgX

X

Scheme 22.

O

OH

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

CO2Me H N O N Rh Rh N NOO

O

O

N2

O 0.1% Rh2[5R-MEPY]4

O

O

CH2Cl2,

Rh2[5R-MEPY]4

91% ee > 95%

O

O

1) Hg(OCOCF3)2, CH2Cl2, rt

BzO

2693

O

BzO

2) KBr aq.

OH

O H

R 60 R: HgBr

59

n-Bu3SnH, PhMe-THF –60 °C to rt

61 R: H

OH

O

OH OH OH 7

3

HO

85% dr 93:7

O OH

zincophorin 58

Scheme 23.

A conceptually different approach to electrophile-induced cyclizations takes advantage of the nucleophilicity of the carbonyl oxygen of a ketone. As outlined in Scheme 26, if the carbonyl of a d-alkenyl ketone could trap the p-complex obtained by treatment of the olefin with an electrophile, then the resultant oxocarbenium intermediate would easily lead to the corresponding acetal. This idea has been put into practice for the stereoselective construction of the C1eC5 ring of a new antitumor agent, FR-901464 (69 in Scheme 27). With this target in mind, the NBS-mediated cyclizations of two d-alkenyl ketones, 70 and 71, have been tested and, in both cases, a sole diastereomer has been isolated in good yield.51a Unfortunately, none of the resultant C4eC5 stereochemistries in 72 and 73 match with that in FR-901464 and its final total synthesis has recently been achieved following an alternative strategy.51b Despite this failure, the key concept of this methodology maintains a high appeal, as has been proved in a parallel process in the arena of alkynols, which has been commented further upon.52,53

TeocN OTBS AcO

O

O

H HO

O

O NIS, NaHCO3 THF, 0 °C, 12 h

OH TeocN

62%

H

OTBS O 64

O

H

O

63

AcO

O O

O

O

O H

O

29

O

X: I

X

O OH

cat. Et3B, n-Bu3SnH-PhMe 1:2, 0 °C, 20 min 86% 65

X: H NH I

A O

HO O

B O

O

D O

C

azaspiracid-1 62

O OH H OH

H H O O G H O

5.1.3. Seleno-mediated cyclizations Cyclizations based on selenium reagents are not as common as the mercury(II)- or halo-mediated methodologies.54,55 Moreover, and contrary to these methods, the stereochemical

F

Scheme 24.

HO

H O

H O HO

MeCN 0 °C to rt, 2.5 h

O

HO

I2, NaHCO3

OH

R

H

O I

67a

H O

MeCN

R

H

O

HO

I2, NaHCO3

H I2 OH

O

O < 5%

(collidine)2AgPF6, I2, CH2Cl2, rt, 2.5 h 80%

Scheme 25.

H H OH R favored complex 68a

H

O I

H O HO

66b

I2

H O HO

66a HO

H O

70%

I2 H

O

H O HO

67b

R HO

H

H

I2 disfavored complex 68b

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2694

O

R

O

E

R

E

E

O

R

R1OH

E

O

OR1 R

–H

Scheme 26.

O

NBS MeOH, MeCN

TESO O

70

O

O

NBS

71

5 O

OMe

TESO 4 O

59%

MeOH, THF

TESO

Br

Br

5 O

72 OMe

TESO 4 O

47%

73

AcO

O

O

O

5

N H

1

OH

HO FR-901464 69

O

Scheme 27.

outcome of the selenoetherification reactions mostly relies on the coordination of electrophiles such as phenylselenyl chloride (PhSeCl) or N-phenylselenophthalimide (NPSP) with the olefin, which is then followed by the ring-closure step. Therefore, the stereoselectivity of these cyclizations reflects the kinetic selectivity for the formation of the onium intermediate, which may give access to 2,6-trans-tetrahydropyrans. This is the trend observed for hydroxy alkene 74. As shown in Scheme 28, 2,6-trans-tetrahydropyran 75-trans is only obtained through a selenium-mediated cyclization, whereas 75-cis results from the other methods.50 A more selective reagent has been used for the assemblage of the C11eC15 2,6-trans-tetrahydropyran of leucascandrolide A (1) from diol 76 (Scheme 29).1d Unexpectedly, iodine-based electrophiles show little diastereoselectivity, but this is dramatically improved by the use of selenium reagents. Remarkably, the bulky 2,4,6-triisopropylphenylselenyl bromide (TIPPSeBr)z affords 2,6-trans-tetrahydropyran 77 in 74% yield and good diastereomeric ratio (dr 88:12). Eventually, a tin-free radical reduction of 77 provides the desired advanced intermediate 78 in 85% yield. 5.2. Catalytic cyclizations 5.2.1. Palladium-mediated cyclizations In spite of the achievements mentioned above, the use and removal of stoichiometric amounts of often toxic elements have fueled research into alternative activators of olefins that allow the desired intramolecular cyclizations under mild conditions and in a catalytic fashion. In this context, catalytic methodologies based on the activation of olefins are dominated by the palladium chemistry, which has achieved prominent levels of maturity.13e,56 In this arena, the construction of heterocycles can proceed through carbonecarbon or carbone heteroatom bond formation, depending upon the nucleophile involved in the ring-closure step. In particular, the synthesis

z

TIPPSeBr is prepared in situ from (TIPPSe)2 and bromine.

of pyrans relies on the intramolecular cyclization of hydroxy alkenes, which implies the suitable activation of the olefin with a palladium catalyst and the subsequent intramolecular attack by the alcohol. Since the reactivity of palladium catalysts is dominated by their oxidation states, Pd(0) and Pd(II) complexes are considered independently. Indeed, Pd(0) complexes are fairly nucleophilic and the cyclizations of d-hydroxy alkenes leading to pyrans progress via the p-allylpalladium cations (TsujieTrost reaction). Otherwise, parallel processes involving Pd(II) complexes take advantage of their electrophilic character and commonly proceed through the fast and reversible formation of p-complexes with the carbonecarbon double bond, which next undergo an intramolecular attack by the nucleophile. 5.2.1.1. Catalysis by Pd(0). Palladium(0) complexes catalyze the cyclizations of d-hydroxy alkenes containing allylic leaving groups (X: OAc, OCO2R, OPO(OR)2, OAr, Cl, Br). As shown in Scheme 30, the initial p-complex evolves through a h3-complex to a p-allyl cation, a highly reactive intermediate that undergoes intramolecular attack of the hydroxyl to provide the corresponding pyran. The regioselectivity of this cyclization is rarely a problem, since 6-exo ring closures are more favored than their competitive 8-endo counterparts. From a stereochemical point of view, substrate-controlled cyclizations usually proceed with retention of configuration at the reacting center. Coordination of the palladium to the carbonecarbon double bond occurs on the less-hindered face opposite to the leaving group and the nucleophile adds to the cationic p-allylpalladium complex on the opposite face to the metal. Thus, a net retention of the stereochemistry is observed.57 Studies on the assemblage of the tetrahydropyran moiety embedded in zampanolide (79 in Scheme 31) have demonstrated how highly diastereoselective this strategy can be. Indeed, Pd(0)-mediated cyclizations of both 80a and 80b afford, respectively, 2,6-cis- and 2,6-trans-tetrahydropyrans 81 as a single diastereomer in good yields under very mild conditions.58 Palladium(0) catalysts also offer the opportunity for enantioselective cyclizations. Trost et al. have proved that

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 OMe

2695

OMe OBn

OBn +

X

HO

X

O

OTBDPS

O

OTBDPS

Conditions cis-trans Yield (%) Hg(OAc)2, Br2, THF, rt 100:0 71 NBS, DMF, rt 100:0 77 2.3:1 NIS, CH2Cl2, rt NPSP, CSA, CH2Cl2, rt 1:1.8 87

74

OMe OBn

Conditions

OTBDPS 75-trans

75-cis X: Br, I, or SePh

Scheme 28.

OTBS OH OH O OH

CH2Cl2, –78 °C, 2 h

O

O

1

OH O

15

O

74% dr 88:12

CO2Me

OTBS

11

TIPPSeBr, DTBMP

CO2Me

X OH

O 76

O

77

X: TIPPSe

78

X: H

MeO

TBS OMe

, AIBN, hexane, 85%

Scheme 29.

generated by mixing Pd2(dba)3$CHCl3, chiral diphosphine 83, and Et3N in CH2Cl2 at 0  C provides the tetrahydropyran 84 in 80% yield and 94% ee (Scheme 32). Furthermore, the stereocontrol imparted by the catalyst is absolute on the more elaborated chiral substrate 85, and the tetrahydropyran 86-trans or the isomer 86-cis is exclusively formed by switching the configuration of 83.61 High stereochemical control has also been observed in d-hydroxy alkenes containing other allylic leaving groups (Scheme 33). For instance, Pd(0)-catalyzed cyclization of carbonate 87 affords the tetrahydropyran 88 in high diastereomeric ratio, whereas 90 is obtained with complete stereocontrol from ester 89 in 96% yield.62,63

PdL2 Pd(0)L2

X

X

OH

OH X

PdL2

PdL2X

OH

OH 3-complex

-allyl cation –HX

O

–Pd(0)L2 PdL2

O

Scheme 30.

5.2.1.2. Catalysis by Pd(II). As previously mentioned, palladium(II) catalysts exhibit an electrophilic character that accounts for the formation of p-complexes with carbone carbon double bonds, which easily undergo the addition of nucleophiles. In this manner, the Pd(II)-mediated intramolecular cyclization of hydroxy alkenes provides a straightforward

intramolecular asymmetric allylic alkylations59 of hydroxy alkenes can be highly enantioselective, with the nucleophilic addition of the alcohol to the p-allylic cation being the enantio-determining step of the process.60 As a case study, treatment of the hydroxy alkene 82 with a palladium catalyst

BnO

BnO OCO2Et

OBn

OBn 5 mol% Pd(PPh3)4

HO

O

THF, rt

80a

O

71%

BnO

81-cis

HO

O

N H

O

O

BnO OCO2Et

O OBn

OBn 5 mol% Pd(PPh3)4

HO

O

zampanolide 79

THF, rt

80b

68%

81-trans

Scheme 31.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2696 DMPS O

DMPS

2 mol% Pd2(dba)3·CHCl3 6 mol% 83 Et3N

Ar

Ar: 4-NO2Ph

80%

O

O NH HN

CH2Cl2, 0 °C

OH

83

O

PPh2 Ph2P

ee 94%

82

84 TMS 2 mol% Pd2(dba)3·CHCl3, 6 mol% 83, Et3N

TMS O Pr

O

OH

O

Pr

CH2Cl2, 0 °C

Ar

60% dr > 97:3

Ar: 4-NO2Ph

O O

TMS

O 86-trans

2 mol% Pd2(dba)3·CHCl3, 6 mol% ent-83, Et3N

85

Pr

CH2Cl2, 0 °C 58% dr > 97:3

O

O

O

86-cis

Scheme 32.

EtO2CO

OBn

87

Cbz N

OH

O 89

H

OBn Pd(0) THF, rt

HO

Pd(II)

O

ligand

dr

PPh3 83 ent-83

3:2 1:2 10:1

δ

R 88

1.3 mol% Pd2(dba)3·CHCl3 Cbz 5.3 mol% ent-83 N OAc THF, rt O 96%

H

PdII

R

1,3-axial interactions

O

PdII

2,6-cis

PdII

R HO

R

O

PdII

2,6-trans

Scheme 35.

O 90

unfavorable axial interactions are developed on the way to 2,6-trans isomers. The success of such a strategy is intimately related to the regioselectivity of the b-hydride elimination step. Studies on this issue have proved that it is highly solvent dependent, DMSO being the best choice,68 but, in spite of these accomplishments, these cyclizations have been scarcely applied to the synthesis of natural products.69 This limitation has been overcome through the introduction of a hydroxy group at the allylic position.70 As represented in Scheme 36, the key feature of this process entails the coordination of the allylic alcohol, a0 -OH, to the metal. Then, the initial Pdep-complex is selectively formed on the same face of the double bond as the a0 -OH. This complex determines the approach of the dOH to the reacting center (syn attack) and, consequently, the stereochemical outcome of the cyclization. Eventually, the resultant s-complex undergoes a selective Pd(II) elimination leading to a new olefinic bond. Hence, the overall sequence may be considered as a Pd-mediated SN20 process that can proceed without any oxidant. In this context, a chiral starting material can give access to disubstituted tetrahydropyrans stereoselectively (Scheme 37).

entry to oxygenated heterocycles. The regioselectivity of such cyclizations is commonly determined by the ring size, which facilitates the acquisition of pyrans from d-hydroxy alkenes through a 6-exo ring closure (Scheme 34).64e66 The nucleophilic attack of the hydroxyl on the corresponding p-complex usually occurs anti to the metal to produce a s-alkylpalladium(II) intermediate, which next undertakes a b-hydride elimination. Importantly, Pd(0) is produced in the final step and, consequently, a mild re-oxidant to transform Pd(0) back into Pd(II) without affecting the substrates or products is required to obtain a process catalytic in palladium; otherwise, the process must be carried out using stoichiometric amounts of the Pd(II) complex.67 The rationale for the stereochemical outcome of these cyclizations usually hinges on the relative steric demands of the reversibly formed palladium intermediates.65 Attention is then focused on the steric interactions engaged in the alternative approaches outlined in Scheme 35. Hence, 2,6-cis arrangements are often preferred, especially in the case where all the substituents are placed in equatorial positions or clearly

Pd(II)LnX2

OH Pd(II)

Scheme 33.

OH

R HO

PdIILnX2 OH

–Pd(0)Ln –HX

O

PdIILnX

-alkylpalladium

-complex

Scheme 34.

–HX

O

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 α

α

δ α'

PdCl2 OH α'

OH

α

δ

δ

Pd Cl O Cl H

ClPd

O

OH HO

α' Pd

π-complexes

Cl

O

–HCl

H

2697

–Pd(OH)Cl

O

HO

Cl

σ-complex

Scheme 36.

Indeed, chiral diols 91a,b afford 2,6-cis- or 2,6-trans-tetrahydropyrans 92 as a single isomer in excellent yields, depending upon the configuration of the allylic stereocenter, a0 , with perfect 1,3-chirality transfer. According to the mechanistic guidelines presented in Scheme 37, the p-face selectivity observed in these cyclizations can be rationalized by considering conformations on the a0 -stereocenter, so that the most favored approaches avoid 1,3-allylic strain.71 This strategy has been successfully applied to the construction of pyran rings embedded in the structure of laulimalide (93 in Scheme 38). Moreover, it has been subjected to the Pd(0)-mediated methodology described in Section 5.2.1 for the synthesis of the C23eC27 dihydropyran 95. Both the Pd complexes catalyze the 6-exo-like cyclization of 94 to 95 as a sole isomer in good-to-excellent yields. Furthermore, the 6-endo-trig cyclization of 96 occurs through a syn-SN20 process to give exclusively the desired 2,6-trans-dihydropyran 97 in 60% yield.70a As shown in Scheme 34, the Pd-mediated intramolecular addition of a hydroxyl group to an alkene leads to a s10 mol% PdCl2(MeCN)2

S

OH R

alkylpalladium(II) intermediate. This intermediate can then be trapped by CO and the resultant acylpalladium species is easily converted into the corresponding methyl ester (Scheme 39). Thus, the overall process is a 1,2-alkoxycarbonylation that avoids any b-elimination. In the case of chiral centers, the insertion of CO into the carbonepalladium bond usually retains the configuration that arises from the cyclization step, and so pyran-containing ester groups can be stereoselectively obtained as a result of these transformations.72,73 This methodology has been applied to the synthesis of leucascandrolide A (1)1a and phorboxazole A (2a).2g As shown in Scheme 40, the intramolecular alkoxycarbonylation of diol 98 in 1:1 MeOHePhCN (the use of benzonitrile facilitates a cleaner and more efficient process) provides the desired 2,6-cis-tetrahydropyran 99 in 75% yield and dr >10:1. Noteworthy is the fact that the cyclization is highly selective and the two alcohols and two alkenes in 98 are completely differentiated, which simplifies the protecting-group strategy. Furthermore, the C22eC26 tetrahydropyran (101) of 2a is prepared in high yield through the Pd(OAc)2-mediated HO

HO

THF, 0 °C

H H

H

O

HO

72%

minimisation of 1,3-allylic strain

91a

H OH

10 mol% PdCl2(MeCN)2

S

OH S

HO 91b

92-cis

THF, 0 °C

H

OH O

H 79%

minimisation of 1,3-allylic strain

92-trans

Scheme 37. Note: Pd atoms have been omitted for clarity.

via Pd(0)-carbonate R: CO2Me

20 mol% Pd2(dba)3, neocuproine O

PhMe, 80 °C

O

23

O O

23

59%

O

OR

10 mol% PdCl2(MeCN)2

27

OPMB

OH

27

OPMB

THF, 0 °C

OH O

OBz 15 mol% PdCl2(MeCN)2, benzoquinone

OH 9

OBz 9

5

97

96

Scheme 38.

O 27

OPMB

60% OH

O

O

O

THF, –5 °C

5

23

95

via Pd(II)-hydroxyl R: H

OPMB

OH

O

89%

94

laulimalide 93

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2698

O

CO O

PdIILnX

O

MeOH PdIILnX –Pd(0)Ln –HX

O

O

OMe

-alkylpalladium

Scheme 39.

cyclization of hydroxy alkene 100, although 2.5 equiv of the Pd(II) reagent is needed for complete conversion because of its reduction by CO during the course of the reaction (acetonitrile is used to minimize such deactivation).74 In turn, the parallel ring closure of 102 has been carried out in the presence of a large excess of p-benzoquinone to afford 2,6-cis-tetrahydropyran 103 in 58% isolated yield. The s-alkylpalladium(II) intermediates can also be trapped through a Heck reaction. This possibility is nicely illustrated by a palladium-catalyzed sequence along the synthesis of a-tocopherol (104 in Scheme 41).75 Indeed, the reaction of 105

O

CO (1 atm) 10 mol% PdCl2, 4 equiv CuCl2,

OTBDPS

7

OH OH

75%

98

26

O

dr > 10:1

MeOH-MeCN 1:1, rt, 3 d

OTIPS

86%

O

CO2Me 99 CO2Me 22

O N

OTIPS

26

O

100

101

O

2a

O CO (1 atm) 10 mol% PdCl2(MeCN)2

OTBDPS

15

N

Cl

1

OH O 3

CO (1 atm) 2.5 equiv Pd(OAc)2

22

HO

OTBDPS

7

MeOH-PhCN 1:1, rt, 2 h

3

N

with methyl acrylate in the presence of catalytic amounts of Pd(OCOCF3)2, the chiral ligand 106, and p-benzoquinone affords chroman 107 with 96% ee in 84% yield. This twostep sequence is assumed to proceed via the enantioselective oxypalladation of 105. The resultant s-alkylpalladium complex then undergoes a Heck reaction with methyl acrylate and, finally, a b-hydride elimination delivers the desired product. A conceptually different strategy to the synthesis of 2,3-dihydro-4H-pyranones such as 109aec takes advantage of the reactivity of enones. As represented in Scheme 42, it relies on the oxidative cyclization of b-hydroxy enones 108aec with PdCl2. Thus, this methodology represents a new approach to the enantioselective assemblage of these useful intermediates, based on a 6-endo ring closure of a Pd(II)ep-complex followed by a completely regioselective b-hydride elimination, without affecting the integrity of the existing stereocenters.76

Cl

N

5.5 equiv benzoquinone MeOH-MeCN 1:1, rt, 1 d

HO 11

102

58%

OTBDPS

15

O 11

103

CO2Me

Scheme 40.

MeO

PdLn(OCOCF3)2

MeO

oxypalladation

OH

O

PdLn(OCOCF3)

105

H2C=CHCO2Me 10 mol% Pd(OCOCF3)2 40 mol% 106 p-benzoquinone CH2Cl2, rt, 3.5 d

O 84%

96% ee

MeO

O O

OMe

-HPdLn(OCOCF3) OMe

-hydride elimination

insertion

MeO

O O

107

MeO

OMe PdLn(OCOCF3)

O

O

N

N

O

-tocopherol

106

104

Scheme 41.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 OH O Ph

OH O

OH O

Ph 108a

Bn

δ

Ph 108b

112

108c

Ph

Ph

Ph

109b

109c

61%

74%

50%

87%

5.2.2. Other metal-mediated cyclizations Besides palladium chemistry, there is a handful of emerging catalytic methodologies for the cyclization of d- and g-hydroxy alkenes, based on the activation of the olefin by other metals, e.g., platinum,78 tin,79 silver,80 or cerium81 (Scheme 44). The mechanism that accounts for such processes involves the electrophilic activation of olefin according to the guidelines illustrated in Scheme 19. The regioselectivity is well defined for d-hydroxy alkenes, whereas ring closure of g-hydroxy alkenes 114 and 116 is apparently ruled by the Markovnikov tenet, in which the stabilization provided by substituents of the olefin seems to support the formation of tetrahydropyrans over their tetrahydrofuran counterparts. Synthetically, the scope of these approaches is still limited and they cannot compete with the performance of palladium catalysts, but they offer new avenues to the construction of tetrahydropyrans and constitute a promising area of research. Remarkably, gold catalysts can participate in a cascade sequence that presumably involves a 6-exo ring closure of a hydroxy enone intermediate through a metal activation of the carbonecarbon double bond.82 Indeed, treatment of homopropargylic ether

Me N Me 111

H

OTIPS

N H O

OMe

5 mol% Ph3PAuCl 5 mol% AgSbF6

O

OH wet CH2Cl2, 35 °C, 2 d

HO 118

97%

O

HO

119

O

OH

120

OH

Scheme 45.

5.3. Acid-mediated cyclizations Acid-mediated cyclizations of hydroxy alkenes represent a particular class of processes, as they are promoted by stoichiometric or catalytic amounts of Brønsted acids. Although the mechanistic issues of these cyclizations are rather speculative, their regioselectivity is usually controlled by the Markovnikov tenet and most of them involve strong Brønsted acids. Actually, they are commonly carried out in the presence of large quantities of these reagents. This is the situation observed during the synthesis of platensimycin (121 in Scheme 46),83 in which treatment of a 2:1 mixture of diastereomers 122a and 122b with TFA (TFAeCH2Cl2 2:1) gives the cage-like structure 123 in 87% yield, based on the isomer 122a present in the mixture. Interestingly, the undesired diastereomer 122b is recovered unchanged.84 It also occurs that these cyclizations can be carried out under catalytic conditions.79,85 For instance, the ring closure of hydroxy vinylsilanes such as 124 to 125 using a catalytic amount of Brønsted acids has been thoroughly studied H

H

117

118 with Ph3PAuCleAgSbF6 in wet CH2Cl2 gives the enone intermediate 119 that cyclizes to 2,6-cis-tetrahydropyran 120 in excellent yield (Scheme 45).

A related cyclization involving a 6-endo ring closure of an a,b-unsaturated ketone has been used to build the dihydropyranyl enone unit of several Alstonia alkaloids, such as alstophylline (110 in Scheme 43).77 Although the detailed mechanism is not clear, the process is believed to involve the formation of a Pdep-complex on 111, removal of the silyl group, and nucleophilic attack of the deprotected alcohol on the palladium complex. Finally, b-hydride elimination provides 110, while the Pd(0) is re-oxidized to Pd(II) by t-BuOOH.

H

Ph

Scheme 44.

Scheme 42.

MeO

O

5 mol% AgOTf Cl2CHCHCl2, 83 °C, 15 h

O

109a

Ph

115

77% OH

O

O

113

MeNO2, Δ, 1 h

116 O

O

O

5 mol% Sn(OTf)4

114 γ

Ph

Bn

60% OH Ph

O2, 10 mol% PdCl2,10 mol% CuCl,10 mol% Na2HPO4 DME, 50 °C

O

0.5 mol% [PtCl2(H2C=CH2)]2 1 mol% P(4-CF3Ph)3

OH

Cl2CHCHCl2, 70 °C, 24 h

γ

O

2699

8 mol% Na2PdCl4 NaOAc, t-BuOOH 1:3:3 AcOH-H2O-dioxane 80 °C, 6 h 55%

Scheme 43.

MeO Me N Me alstophylline 110

H

H O

N H O

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2700

6. Allene-mediated cyclizations

O

O

TFA-CH2Cl2 2:1

H

0 °C, 1.5 h

OH 122a O

O

87%

123

HO

OH O H

HOOC

O

N OH H

122b

O

platensimycin 121

Scheme 46.

(Scheme 47). A plausible mechanism for this cyclization involves the formation of a b-silylcarbenium ion intermediate by protonation of the sp2-carbon a to the silyl group and the subsequent intramolecular attack of the hydroxy oxygen on the cationic center.86 OH

DMPS

7. Alkyne-mediated cyclizations

O

5 mol% TsOH

DMPS

CHCl3, 60 °C, 4 d 124

86%

Allenes containing a nucleophile can undergo intramolecular cyclizations on treatment with transition metal catalysts.89 In particular, gold-catalyzed cycloisomerization of b- or d-hydroxyallene gives access to six-membered oxygenated heterocycles in a straightforward manner. As occurs for alkenes (see Scheme 19), the initial coordination of the gold catalyst to one of the terminal double bonds of a b-hydroxyallene such as 132 gives rise to the formation of an intermediate, which, upon nucleophilic attack of the oxygen, is converted into a s-gold complex through a 6-endo-trig ring closure (Scheme 49). Subsequent protodemetallation of this complex furnishes the corresponding dihydropyran 133.90 Likewise, d-hydroxyallene 134 undergoes a 6-exo-trig hydroalkoxylation to form the corresponding 2-alkenyl tetrahydropyran derivative 135 in excellent yield.91 Remarkably, gold-mediated hydroalkoxylation of 134 in the presence of the chiral diphosphine 136 affords 135 in 96% yield and 88% ee.92

125

Scheme 47.

Eventually, Lewis acids can also be involved in the intramolecular hydroxyalkoxylation of unactivated olefins, leading to tetrahydropyrans. These processes presumably proceed through the formation of a Lewis acideOH complex that enhances the acidity of the hydroxyl proton.86,87 Furthermore, polycyclic compounds such as ()-caparrapi oxide and (þ)-8epicaparrapi oxide (126 and 127, respectively, in Scheme 48) have been obtained from hydroxy alkene 128 in the presence of stoichiometric amounts of chiral LBA (Lewis acid-assisted chiral Brønsted Acid) complexes 129 and ent-129. Indeed, the asymmetric ring closure of 128 induced by 129 gives an 81:19 mixture of 130 (>99% ee) and 131 (21% ee), whereas the parallel cyclization induced by ent-129 provides a 14:86 mixture of 130 (27% ee) and 131 (98% ee). Eventually, optically pure 130 and 131 are isolated in 74 and 73% yield by column chromatography.88

A conceptually related set of approaches based on the electrophilic activation of carbonecarbon triple bonds have also proved to be a highly efficient entry into the synthesis of six-membered oxygenated heterocycles.93 Indeed, the catalytic metal-mediated intramolecular cyclizations of precursors containing alkynes and different oxygenated nucleophiles can be exploited for the construction of a wide array of oxygencontaining heterocycles. Surprisingly, the simplest strategy based on the use of hydroxy alkynes had been scarcely applied to date, but recent reports on the cyclization of 4- and 5-alkynol have established the synthetic potential of such an approach. In this context, palladium94,95 and iridium96 complexes catalyze the 6-endodig ring closure of 2-alkynylbenzyl alcohols with internal triple bonds to the corresponding isochromenes in good yields. The mechanism for this transformation is outlined in Scheme 50. As for alkenes or allenes, initial coordination of the metal to the carbonecarbon triple bond enhances its electrophilicity and facilitates the attack of the hydroxyl. Then, a protodemetallation step renders the cyclic enol ether and regenerates the catalytic species. OCOBn

OCOBn

OH

128

O

O

2 equiv 129 CH2Cl2-PrCl 1:1 –80 °C, 2 d 74% dr 81:19 > 99% ee

Ar

H

H 130

OCOBn

(–)-Caparrapi oxide 126

O SnCl4 OH OMe Ar: 2-FPh 129

CH2Cl2-PrCl 1:1 –80 °C, 2 d 73% dr 86:14 98% ee

Scheme 48.

O

O

2 equiv ent-129 H

131

H (+)-8-Epicaparrapi oxide 127

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 5 mol% Ph3PAuCl 5 mol% AgBF4

β

Bu

PhMe, rt, 1 d

HO

LnAu

Bu

HO

5 mol% Au[P(t-Bu)2(o-biphenyl)]Cl 5 mol% AgOTs LnAu PhMe, rt, 5 min

Bu

O H

6-endo-trig

Ph Ph HO

LnAu

Bu

132

2701

O

32% 133

Ph Ph HO 6-exo-trig

δ

98% O

2.5 mol% Au2[136]Cl2, 5 mol% AgOTs

134

PhMe, –20 °C, 18 h

136 MeO MeO

135

PAr2 PAr2

96% 88% ee

Ar: 3,5-(t-Bu)2-4-MeOPh

Scheme 49.

6-endo-dig O

H R

OH

MLn

R

OH

LnM

O –MLn

LnM

R

R H

O H 5-exo-dig

O

–MLn

R LnM

R H

Scheme 50.

As shown in Scheme 50, an alternative pathway involving a 5-exo-dig ring closure threatens the success of such methodology. A comprehensive analysis of the regioselectivity of this cyclization for palladium catalysts has revealed that the 6-endo-dig is favored over the 5-exo-dig mode by alkyl, rather than aryl, substitution on the triple bond, low solvent polarity (dioxane), high temperatures (80e100  C), and dilute conditions.94,97 Keeping these limitations in mind, both palladium(II) and iridium(III) catalysts provide a good entry into isochromenes 138a,b from 2-alkynylbenzyl alcohols 137a,b (Scheme 51). Working in the 4-alkynol arena, a tandem palladium(II)catalyzed reaction offers an appealing entry into the synthesis of dihydropyrans.98 As represented in Scheme 52, the palladium-catalyzed addition of a terminal alkyne to a hydroxy OH

2 mol% PdI2, 4 mol% KI

O

dioxane, 80 °C, 3 h 137a

Bu

63%

Bu 138a

PPh3 H Ir O O PPh3

4 mol% OH

O

CHCl3, 80 °C, 2 h 137b

Pr

77%

Scheme 51.

Pr 138b

ynoate initially affords a conjugated adduct, which undergoes a 6-endo-dig cyclization. Remarkably, the resultant dihydropyran contains an exocyclic carbonecarbon double bond with a well-defined geometry (for an outstanding application of this palladium-based tandem synthesis and a related ruthenium process, see Scheme 89). Furthermore, a palladium(II)-catalyzed 6-endo-dig cyclization of b-hydroxy ynones, similar to that outlined in Scheme 42, has recently been disclosed.99 Differently, the s-alkenylpalladium intermediate obtained in this reaction undergoes insertion of ethyl acrylate to form trisubstituted dihydropyranones featuring an alkenyl substituent a to the carbonyl (Scheme 53). Thus, the overall process entails a cascade Wackere Heck reaction that involves the chemoselective coupling of two electron-deficient reactants. This WackereHeck sequence does not affect the stereochemical integrity of the starting b-hydroxy ynones 139a,b and affords the corresponding dihydropyranones 140a,b in good yields. Otherwise, 5-alkynols with a terminal triple bond undergo completely regioselective 6-exo-dig ring closures to exocyclic enol ethers in the presence of palladium,100 iridium,101 platinum,102 or gold102,103 catalysts (Scheme 54). Their mechanism is also based on the electrophilic activation of the alkyne according to the guidelines previously described, but, differently, the competitive 7-endo-dig pathway is never observed. Interestingly, the resultant cyclic enol ethers can be the starting point for further transformations. For instance, treatment of

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2702 CO2R1 H

CO2R1

10 mol% Pd(OAc)2 4 mol% TDMPP

+

R2

R

PhH, rt, 2–3.5 d

R

HO

OH

CO2R1

R2

R

50–60%

R2

O

R: alkyl, Ph R1: Me, Et R2: alkyl

Scheme 52.

PdLnX2

2

R3

R2

R1

R2

PdLnX2

R

R1

O

O

O

OH O

OH

–HX

R3

R1

2

CO2Et R

PdLnX O

CO2Et

R1

R3

Wacker

R3

O

Heck

O OH O

CO2Et

Ph

20 equiv H2C=CHCO2Et, O2 10 mol% [PdCl2(CH3CN)2] Cu(OAc)2·H2O, PPh3, 20 mol% LiBr DME, 20 h, 65 °C

Ph

139a

OH O 139b

Ph

Ph

O

47%

140a

O CO2Et

Ph Ph

47% de > 99%

140b

O

Scheme 53.

H O

H MLn

H O

H MLn

6-exo-dig

H O

O –MLn

143a R: THP 143b R: TBS

OH

Scheme 54.

144a R: THP 144b R: TBS

O O 145

O

+ O

O R

H

143a 143b 144a 144b

30:1 20:1 9:1 3.7:1

75 83 60 58

146

Scheme 91), the assemblage of the AeD rings starting from alkynol 147 relies on the addition of the C6 hydroxy group across the C10eC11 alkyne followed by the engagement of the C13 ketal exocyclic oxygen atom to form the desired spiroketal.107 Remarkably, treatment of 147 with catalytic amounts of AuCl and PPTS furnishes 148 in 75% yield. A closely related methodology takes advantage of the hydroxyl-like character of hemiacetals. Yamamoto et al. have reported that the simultaneous activation of a carbonyl and OR1

2 mol% MLn

Alkynol145:146Yield (%)

Scheme 56.

H

R

OR

1) 1 mol% [PtCl2(CH2=CH2)], Et2O, rt, 30 min 2) 5 mol% CSA, MeCN-H2O, rt, 4 h 3) MgSO4, rt, 5 h

alkynols 141 (Scheme 55) with platinum or gold catalysts leads to the enol ethers, which undergo a Prins-type cyclization through an oxocarbenium intermediate that eventually affords the eight-membered carbocycles 142 as a sole diastereomer in excellent yields, irrespective of the catalyst.102 Internal alkynols can also participate in highly regioselective cycloisomerizations, provided that the resultant enol ethers are satisfactorily trapped by other nucleophiles. For instance, platinum(II)-catalyzed hydroxyalkoxylation of alkynols 143a,b and 144a,b deliver selectively spiroketal 145 through initial 6-exo-dig or 6-endo-dig ring-closure modes, respectively (Scheme 56).104e106 A similar gold-catalyzed 6-exo-dig cyclization plays a crucial role in the synthesis of the trioxadispiroketal of azaspiracids (62 in Scheme 24). As represented in Scheme 57 (see also H O

HO

RO

MLn

O R

R

R1OH O 88–96%

141

MLn: PtCl2(cod), PtCl4, AuCl3 R: Me, Bu, i-Pr, t-Bu, allyl R1OH: solvent (MeOH, EtOH, MeCOOH, EtCOOH)

Scheme 55.

R

O 142

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

PMBO

OH 6 10

MeO

O

MeO

H OTBDPS

11

O

O

147

75% B O

O C

D O

PMBO

O

O

Me

OTBDPS Me

O

OTBDPS O

+H

148

H

H

PMBO

–H , –Me2O

O

Au

8 mol% AuCl, PPTS MeOH, rt, 20 min A O OPMB

2703

–Au

O

OTBDPS O

H

62

Scheme 57.

R

SnBu3

5 mol% Pd(OAc)2, 2 equiv R1OH, benzoquinone

O

R O

dioxane, rt, 0.5–1 h 74–90%

149 H R: alkyl, aryl

150

R : Me, Et, i-Pr

–Pd(OAc)2 R

R

(AcO)2Pd

PdOAc R

R1OH O H

Pd(OAc)2

OH

151

OTMS

AcOH

Pd(OAc)2

O

79%

OR1

1

Ph

BF3·OEt2

Ph BF3·OEt2

Ph O

85%

Ph

O

–AcOH

1

OR1

OR

152

O

Scheme 58.

a carbonecarbon triple bond by palladium(II) catalysts allows the construction of cyclic alkenyl ethers from acetylenic aldehydes. Indeed, cyclization of 2-alkynylbenzaldehydes 149 proceeds smoothly in the presence of Pd(OAc)2 to provide acetals 150 in high yields (Scheme 58).108 The authors propose a mechanism in which the palladium catalyst initially acts as a Lewis acid, promoting the formation of the corresponding hemiacetal. Then, coordination of the metal to the alkyne facilitates the anti attack of the hydroxyl from the side opposite to the metal via a 6-endo-dig pathway.x The resultant vinylpalladium intermediate is subsequently protonated to afford the final alkenyl acetal with complete regioselectivity. Noteworthy is the fact that the high reactivity of the benzylic acetal in 150 (R: Ph, R1: Me) makes possible the introduction of carbon nucleophiles via HosomieSakurai allylation and Mukaiyama aldol reactions to afford 151 and 152 in high yields.109 Other oxygenated nucleophiles such as carboxylic acid derivatives and carbonyls have also been utilized in this type of cyclization.93a,110 A step forward in this area relies on the electrophilic activation of the carbonecarbon triple bond of

x It is worth pointing out that the aromatic ring is crucial to the observed regioselectivity. The reaction of the equivalent carbon-tethered acetylenic aldehydes, 4-alkynals, mainly yields the corresponding five-membered acetals through 5-exo-dig cyclizations.

2-alkynylbenzaldehydes and related systems. Now, the nucleophilic attack of the carbonyl oxygen on the electronically deficient alkyne produces a 2-benzopyrylium-like intermediate, which can undergo further transformations that ultimately offer a rich assortment of structures.111e114 This methodology has been applied to the synthesis of ()S-15183a (153 in Scheme 59), a member of the azaphilones, a family of natural products containing a highly oxygenated bicyclic core and a quaternary stereocenter.115 The reported synthesis takes advantage of a gold-mediated cycloisomerization of 2-alkynylbenzaldehyde 154 followed by oxidation of the resultant 2-benzopyrylium salt. As outlined in Scheme 59, a plausible mechanism for this transformation entails the coordination of the gold catalyst to the triple bond followed by cyclization and protodemetallation to furnish the 2-benzopyrylium salt. Eventually, oxidation of this salt affords in 84% overall yield the desired oxygenated heterocycle 155 as a racemic mixture. Having developed a straightforward route to the bicyclic core, attention was focused on the asymmetric oxidation of the benzopyrylium salt. However, all attempts were unsuccessful and a new strategy, based on the initial oxidation of the aromatic ring, was disclosed. Remarkably, the Cu2[()-sparteine]2O2-mediated enantioselective oxidative dearomatization of 154 provides a hydroxy derivative, which undergoes the desired cycloisomerization under very mild conditions to afford ()-155 in 98% ee and 84% overall yield (Scheme 60). It is

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2704 R HO

1) 5 mol% Au(OAc)3

O OH

O

2) IBX, 5 mol% TBAI, rt HO

84%

H

154

R

O

ClCH2CH2Cl–TFA 10:1, rt

RCOCl O

CH2Cl2, rt 61%

O

RCOO

(±)-155

R: –(CH2)6Me

AuLn

R

O

i-Pr2NEt, DMAP

O

(±)-S-15183a (±)-153

oxidation R

LnAu HO

LnAu

H

HO

R O

O OH

H

HO

TFA

R O

–AuLn

OH

OH

CF3COO

Scheme 59.

O2, 2.2 equiv Cu(MeCN)PF6

154

R

2.4 equiv (–)-sparteine i-Pr2NEt, DMAP

O

CH2Cl2, –78 to –10 °C

KH2PO4–K2HPO4 buffer pH 7.2

R

O O

MeCN, rt HO

O

HO

OH

84%

98% ee

O (–)-155

Scheme 60.

worth emphasizing that the 6-endo-dig ring closure is carried out without any metal at pH 7.2.116,117 Other systems available for this chemistry are 4-propargyl1,3-cyclopentanediones 156 represented in Scheme 61. Metalmediated cyclization of these 1,3-diketones admits catalysts based on palladium,118 platinum, tungsten, and mercury.119 Noteworthy is the fact that the platinum-mediated catalysis of terminal and substituted alkynes affords exclusively the bicycles 157 in high yields at room temperature. These 6-endo-dig cyclizations are supposed to proceed under kinetic control by coordination of the catalyst to the triple bond. Then, the alkyneemetal complex undergoes anti attack of the carbonyl oxygen and the resultant vinylplatinum intermediate is protonated to afford the oxabicycle 157. Since related 1,3-cyclohexadienones are prone to 5-exo-dig ring closures, the excellent regioselectivity observed for 156 is presumably due to subtle intrinsic strain on the way to the exo- or endo-bicyclic systems. As well as these catalytic processes, there are some stoichiometric metal-free methodologies based on the iodinemediated electrophilic activation of the substituted carbone carbon triple bond of 2-alkynylbenzaldehydes that allow for the highly efficient construction of six-membered oxygenated O

R

O

THF–dioxane 2:1 156

O

O

R

R

O

rt, 24–72 h R: H, Me

PtCl2

HO

10 mol% PtCl2

157

76–85%

–PtCl2 O

6-endo-dig

R

HO PtCl2

PtCl2

Scheme 61.

heterocycles120,121 and other carbocycles.122 For instance, addition of the iodonium ion generated from Ipyr2BF4/HBF4 to the triple bond of 2-alkynylbenzaldehydes 149 leads to an iodobenzopyrylium salt, which, in turn, reacts with nucleophiles and offers a straight and useful access to highly elaborated oxygenated heterocycles 158e161 (Scheme 62).120 Importantly, most of these transformations can be carried out following a procedure based on the use of iodine.121 8. Other metal-promoted cyclizations In addition to the methodologies just described, metals can also catalyze other cyclizations that require the in situ generation of transition metalecarbenoid species. Such transformations encompass the cycloisomerization of 4-alkynols via metal vinylidene complexes and the intramolecular addition of oxygenated nucleophiles to metal carbenes obtained from diazo precursors. This chapter also takes into account a less studied transformation: the intramolecular etherification of aryl and vinyl halides catalyzed by palladium and copper. 8.1. Cyclizations of 4-alkynols The transition metal-mediated isomerization of hydroxy alkynes containing a terminal carbonecarbon triple bond represents a highly valuable route for preparing 3,4-dihydro-2Hpyrans (see Eq. 5 in Scheme 63).123 Unlike the methodologies previously discussed, these processes proceed through a metal vinylidene intermediate that undergoes intramolecular attack by an alcohol. Thus, the key element of such cyclizations relies on providing metal vinylidene intermediates reactive enough to sustain a catalytic process. These species arise from the initial

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

I

158

Ph

MeOH

2705

O

OMe I

63% TMS

Ph Ipyr2BF4, HBF4

R O

159

OTMS

CH2Cl2, 0 °C to rt R

O

42%

I O

Ph

H

55%

H

PhNMe2

R: alkyl, aryl, alkenyl

I

O

Ph

O

Ph

45%

149

160

I Ph

O NMe2

161

Scheme 62.

OH

H

MLn

MLn

HO

O

OH

(5)

H

OH

MLn

H alkynol R O

N2

R O

3,4-dihydro-2H-pyran

-complex

O

MLn

(6)

–N2 diazo precursor

H

MLn

metal vinylidene

MLn

vinylidene intermediate

O

O MLn

metal carbene

MLn

O

MLn

or

tetrahydropyran –MLn

Scheme 63.

–MLn O

O

coordination of a metal to a terminal alkyne (Scheme 64). Then, the resultant p-complex undergoes either a 1,2-hydrogen migration over the triple bond or an oxidative addition of the C(sp)eH bond to the metal center and subsequent 1,3-shift of the hydride to the alkyne ligand.124,125 The a-carbon in the Cb]Ca]MLn moiety exhibits electrophilic properties and undertakes additions of nucleophiles that eventually lead to formal anti-Markovnikov products. Importantly, the intramolecular attack of the hydroxyl on the Ca-center of the vinylidene intermediate derived from 4alkynols must override a competitive pathway arising from the simple addition to the activated p-complex (Scheme 65). Thus, the structural elements on the substrate, the catalyst, and the reaction conditions have to be carefully chosen to avoid such a 5-exo-dig ring closure. These conditions are rather stringent and few metals form vinylidene intermediates that are able to take part in catalytic sequences. To date, this limited group includes rhodium,126 ruthenium,127 and mostly, tungsten complexes.123,128 Ruthenium(II) complexes [CpRuCl(PR3)3] catalyze the highly selective synthesis of lactones and cyclic enol ethers,

Scheme 65.

depending on the phosphine and the amount of N-hydroxysuccinimide employed (Scheme 66).127a Indeed, electron-rich arylphosphines such as P(4-MeOPh)3 and a large excess of N-hydroxysuccinimide produce six-membered lactones, whereas electron-poor arylphosphines such as P(4-FPh)3 and small amounts of the sodium salt of N-hydroxysuccinimide provide the corresponding dihydropyrans. Unfortunately, none of these conditions can be applied to substrates bearing oxygenated substituents at the propargylic position. Despite this limitation, the efficiency of ruthenium(II) catalysts has been proved for the assemblage of structurally complex fused polyethers such as 163e166 from 162.127b Tungsten-like chemistry has attracted much attention.123 The most common tungsten complex used for the cycloisomerization of 4-alkynols is W(CO)6, which is photochemically activated in situ to generate the true catalytic species, presumably W(CO)5.129,130 The cyclization is routinely carried out 1,2-hydride shift

R

MLn •

HO

H

H

MLn

MLn R

R H

-complex

R

oxidative addition

Scheme 64.

H MLn

MLn H 1,3-hydride shift

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2706

10 mol% CpRuCl[P(4-MeOPh)3]3 40 mol% P(4-MeOPh)3, 30 mol% Bu4NPF6 OH N O , 2 equiv NaHCO3

6 equiv O

H BnO

DMF, 85 °C, 20 h 60%

BnO

H

H

O

O

163

O

BnO

O

BnO

5 mol% CpRuCl[P(4-FPh)3]3 20 mol% P(4-FPh)3, 15 mol% Bu4NPF6

H

OH 162

ONa N

0.5 equiv O

H

O

BnO

DMF, 85 °C, 26 h 70%

BnO

O

H

H

O

164 H

H

O

BnO BnO

H

O

H

H

O

as previously

BnO

H

O

BnO

H

H

65%

166

H

O

OH

H

H

165

Scheme 66.

with 5e25 mol % W(CO)6 and an excess of a tertiary amine (DABCO often gives better results than Et3N) in THF or toluene under constant irradiation at 350 nm. Remarkably, these tungsten-based catalysts tolerate substituents at the propargylic position and are compatible with a wide variety of functional groups such as alcohols, ethers, amides, and carbamates.131 This methodology has been successfully applied to the construction of the trisaccharide component of digitoxin (167 in Scheme 67). Thereby, iterative alkynol cycloisomerization based on W(CO)6 constitutes the most important feature of the synthetic sequence that provides glycal 171 and eventually allows for the total synthesis of digitoxin.132 In addition to W(CO)6, a preformed THF$W(CO)5 complex has been employed.133,134 Moreover, a recent communication has disclosed a new catalytic system that does not require photochemical activation, based on (methoxymethylcarbene)pentacarbonyl tungsten (172 in Scheme 68).135 The optimal

H

O

H

TBSO TBSO

O

8.2. Cyclizations of diazo compounds Metal carbenes are easily obtained from diazo compounds in the presence of copper and rhodium complexes. The accepted mechanism for this transformation combines the Lewis acid character of the metal complex and the basic properties of the carbon center of the diazo precursor. Hence, formation of an acidebase adduct is followed by back donation of electron density from the metal with concomitant loss of nitrogen, thus producing the metal carbene (Scheme 69).136,137

25 mol% W(CO)6 DABCO

OH

THF, h , 65 °C

O TBS

results are obtained with 25 mol % of oxacarbene 172 in the presence of 10 equiv of Et3N by simple warming to 40  C in THF. This experimental procedure has been successfully applied to the synthesis of the altromycin disaccharide 173 via 174 and 175.

H

96%

H

TBSO TBSO

O

HO HO

H

H O

O

O

O

O TBS

169

168

H

H

O

O TBS

H

1) 25 mol% W(CO)6, DABCO THF, h , 65 °C

O H O TBSO

2) Ac2O, Et3N, CH2Cl2

O

HO

81% O

171

HO O

H

O O TBS

H O

HO HO

O

O HO

O

O

H O

H

HO

Scheme 67.

OH

digitoxin 167

H O

OH H O TBSO

170

H

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 CO

OMe MeO Et3N +

(Et3N)W(CO)5

W(CO)5 172

HO

H

O

O

CbzHN

O

25 mol% 172 10 equiv Et3N

Et3N + W(CO)6

h

O O

THF, 40 °C, 12 h CbzHN 83% OMOM

OTIPS

174

2707

O

O

O

Me2N 175

OMOM OTIPS

OMOM 173

OMe

Scheme 68.

R1

N2

MLn

N2

R1

R2 diazo compound

R2

R1

MLn

–N2

MLn

R2 metal carbene

Scheme 69.

Stabilized diazo compounds, particularly a-diazo ketones or esters, are suitable precursors for metal carbenes that exhibit electrophilic properties at the carbon center, which allow them to undergo attack of nucleophiles with the eventual release of the metal. In particular, catalytic conversion of the diazo groups into the corresponding metal carbenes followed by intramolecular reaction with alcohols, ethers, or carbonyls affords a wide variety of oxygenated heterocycles (see Eq. 6 in Scheme 63). As the reacting roles are clearly defined, the regioselectivity of such cyclization is not at all troublesome and the only concern lies in the configuration of the resultant stereocenters. The use of alcohols as the nucleophilic source for these cyclizations has been seldom exploited for the synthesis of pyran-like structures. Probably, more synthetic applications are lacking because the mechanism of the process is not fully understood. Studies on the insertion of metal carbenes into a polar OeH bond suggest that this transformation proceeds through a concerted pathway, as for parallel reactions with nonpolar CeH or SieH bonds (Scheme 70).136,138 However, evidence supporting a stepwise mechanism has also been reported.139 The latter model entails the formation of an oxonium ylide, either free or associated to the metal, followed by a rapid [1,2]-hydrogen shift. This methodology has been applied to the synthesis of 2-deoxy-b-KDO (176 in Scheme 71). Metalecarbene ring

O H O

H

concerted insertion

MLn –MLn

O

MLn H O

H

H O

MLn

–MLn stepwise insertion associated oxonium ylide

free oxonium ylide

Scheme 70.

closure of the polyoxygenated a-diazo ester 177 produces 2,6-trans tetrahydropyran 179a as the sole diastereomer in almost quantitative yield when the reaction is carried out with Rh2(OAc)4 in benzene at room temperature.140 Otherwise, a 4:1 mixture of epimers 179a and 179b is obtained when benzene is replaced by chloroform or wet benzene. The rationale for this behavior assumes that the intramolecular attack proceeds on two alternative chair-like conformations 178a and 178b, the population of which is strongly solvent dependent.141 Ethers can also react with metal carbenes via an oxonium ylide intermediate to give six-membered oxygenated heterocycles. Although it is still unclear whether an associated or free oxonium ylide is the true intermediate for such transformation, it is generally accepted that these species can evolve through a [1,2]- or [2,3]-shift for allyl ethers (Scheme 72). Irrespective of the pathway, copper catalysts usually provide better results than their rhodium counterparts, presumably because they favor ylide formation over competitive CeH bond insertion. In this context, copper-catalyzed cyclizations of a-diazo ketones containing an allyl ether have already been applied to the synthesis of natural products.142,143 As an example, stereoselective oxonium ylide [2,3]-rearrangements have been used in an iterative approach for the construction of fused polyethers.142 As shown in Scheme 73, treatment of allyl a-diazo ketone 180 with Cu(tfacac)2 provides the bicyclic compound 181 in 80% yield and excellent diastereomeric ratio. Epimerization of 181 to the more stable equatorial isomer needed for eventual iteration and reduction of the resulting mixture delivers the alcohol 182 in 86% yield. Then, further functional-group manipulations afford the a-diazo ketone 183, ready for a new cyclizationeepimerizationereduction sequence leading via 184 to polyether 185. The use of carbonyls as oxygenated nucleophiles for the intramolecular addition to metal carbenes has received much attention. Attack of the oxygen atom of the C]O bond on a metal carbene produces a transient carbonyl ylide that can participate in 1,3-dipolar cycloadditions (Scheme 74). Thus, ring closure based on the nucleophilic addition of a carbonyl to a metal carbene represents the first step in a cascade sequence that gives access to structurally complex bicyclic systems. In this context, rhodium complexes afford higher yields than the copper adducts, because they enable diazo decomposition under milder conditions. Thus, cyclization

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2708

Rh2(OAc)4

O CO2Et R

OH

O

PhH, rt 15 min

R O

OH

OH

O

HO

RhLn 96%

R

H

O

H

O

HO

H

O

H

CO2H

176

O

CO2Et

OH

R O

HO

2-deoxy- -KDO

O

RhLn O

CO2Et 179a

178a

177

O

R:

O

CO2Et

N2

O

R

H

O

H

CO2Et 179b

178b

Scheme 71.

R O

MLn

R O

MLn

R O

O

MLn

O

MLn

O

O

[1,2]–shift

deals with an intramolecular version of such a cascade sequence from a-diazo ketone 190, in which a simple olefin acts as dipolarophile to obtain diastereoselectively the tricyclic adduct 191 in 73% yield.148 Surprisingly, the synthetic material shows a higher specific rotation than the samples obtained from natural sources, which suggests that polygalolide A might be biosynthesized through a poorly stereoselective pathway.150

R

O

[2,3]–shift

Scheme 72.

H

O

O

H

N2

5 mol% Cu(tfacac)2 CH2Cl2, reflux

O

H

80%

O

dr 30:1

180

H

O

H

O

H

O

1) DBU O

H

2) LiAlH4

O

86%

H

OH

H 1) DBU 2) LiAlH4

O

O

86%

185

H

O

H

H

OH

H

181

H

O

182

O

H 5 mol% Cu(tfacac)2 CH2Cl2, reflux

O

80%

184

O

H

O

H

H

O O

N2

183

Scheme 73.

R

O

MLn

cyclization

R

O

MLn

R

carbonyl ylide

O

A B

R

A B O

1,3-dipolar cycloaddition

Scheme 74.

methodologies that take advantage of the carbonyl ylide reactivity currently employ rhodium(II) catalysts.144e146 The power of the carbonyl ylide cycloaddition methodology for the rapid assemblage of bicyclic systems has been proved in the stereoselective synthesis of structurally complex natural products such as zaragozic acid C147 and polygalolide A148 (186 and 187, respectively, in Fig. 4).149 The first example entails the intermolecular trapping of the carbonyl ylide intermediate from a-diazo ester 188 with 3-butyn-2-one to construct the cycloadduct 189 as a single diastereomer in 72% yield (Scheme 75).147 The second example

Since the cycloaddition step can be faster than metal decomplexation from the carbonyl ylide, enantioselective tandem sequences can also be achieved by positioning chiral ligands on the rhodium catalyst.151 This approach has been applied to the synthesis of pseudolaric acid A (192 in Scheme 76).152 Indeed, a substrate-controlled cascade from the a-diazo ketone 193 in the presence of achiral rhodium catalysts is found to favor the formation of the oxatricycle 194a, whereas a chiral Rh2[(S)-bptv]4 catalyst smoothly delivers a mixture containing the desired diastereomer 194b as the major component in 82% overall yield. Moreover, the stereochemical outcome of these transformations can also rely on chiral Lewis acids affecting the cycloaddition step. Although the scope of these transformations is sometimes narrow, significant levels of enantioselectivity have been reported for the reaction of carbonyl ylides arising from a-diazo ketones 195 with substrates able to form chelates with chiral Pyboxelanthanide triflate catalysts (Scheme 77).153

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2709 O

O Ph

O

MeO

OH

H O

OAc HO

HOOC O HOOC O HO COOH

zaragozic acid C 186

O

Ph polygalolide A 187

O O

Figure 4.

O N2

O

OMOM OTBDPS

t-BuO2C TMSO CO2t-Bu

5 mol% Rh2(OAc)4 3 equiv HC CCOMe

O

R1

R1

PhH, reflux, 1 h

R1:

COMe R1 1 R

R2

O

TMSO

188

N2

COMe

OTBDPS R2:

CO2t-Bu

72%

OTBDPS

O

5 mol% Rh2(OAc)4

O

O O

OPMB

OTBDPS

OTBDPS

PMBO

O

PhCF3, 100 °C, 5 min

O

TMSO

186

189

(CH2)2OMOM

OPMB

O

R2 O

O

187

O

OTBDPS

73% O

190

191

Scheme 75.

OPMB Rh2(OAc)4 N2 PMBO

O

O

O

O

iPr H

O

N O

CH2Cl2, 0 °C

H

O

O

61%

O

Rh

Rh

dr 3:1

O OPMB

Rh2[(S)-bptv]4

194a

O O O

O

3 mol% Rh2[(S)-bptv]4 PhCF3, –40 °C

193

82% dr 1.6:1

H

O

O HOOC

O O

194b

pseudolaric acid A

OAc 192

Scheme 76.

8.3. Intramolecular etherification of aryl and vinyl halides Although the coupling of oxygenated nucleophiles with aryl halides is a long-established method for the preparation of aryl ethers, the harsh reaction conditions commonly required to effect this transformation have restricted its synthetic scope. Indeed, there are relatively few examples for the construction of oxygen heterocycles through the intramolecular etherification of aryl halides. This lack of synthetic methodologies was covered a few years ago by a procedure based on intramolecular palladiumcatalyzed carboneoxygen bond formation.154 The reaction proceeds under mild conditions using bulky and electron-rich o-biarylphosphines in the presence of weak bases. Remarkably, the choice of the phosphine turns out to be crucial, since its steric bulk accelerates the reductive elimination step and minimizes the competitive b-hydride elimination pathway (Scheme 78). Aryl chlorides and bromides are suitable substrates for this transformation. Then, primary as well as secondary substrates

can be cyclized in the presence of bulky dialkylphosphinobiaryl ligands such as 203a and 203b (Scheme 79). Moreover, aryl bromides in which the hydroxyl-bearing chain contains stereocenters and additional functional groups such as amines, amides, or esters also afford the corresponding heterocycles in high yields without erosion of the optical purity. The potential of this transformation has been proved in the synthesis of several heterocyclic compounds with different biological activities.154a,155 For instance, the intramolecular palladium-mediated etherification of the aryl bromide 204 generates the chroman ring 205, which is easily transformed into (S)-equol (206), a metabolite with a high estrogenic activity (Scheme 80).155d In spite of the success of this palladium-catalyzed cyclization, the pursuit of easy-to-handle reagents and easier procedures is fueling the development of new methodologies. A recent report on a copper-catalyzed intramolecular coupling of vinyl bromides is a good example of this emerging chemistry.156 As illustrated in Scheme 81, the vinyl bromide 207 is

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2710

MeO

BnOCH2CHO 10 mol% 196-Sc(OTf)3

O

O MeCOCO2Bn, 10 mol% TFA 10 mol% 196-Sc(OTf)3

O O

OR

2 mol% Rh2(OAc)4

O N2

199 * 96% exo/endo 12:88 ee (endo) 91%

MeO

CH2Cl2, –25 °C OR

CO2Bn

O

98% exo/endo 93:7 O ee (exo) 94%

200 *

O O

O

CH2Cl2

O

N

O

MeO

O

10 mol% 197-Yb(OTf)3

195

O

94% 201 * exo/endo 82:18 O ee (exo) 96%

O O

O

N N

N

O

O

R2

N

R1 R1 196 R1: i-Pr R2: H 197 R1: Ph R2: H 198 R1: Ph R2: Ph

p-BrPhCH2O

O

O N

O

CH2Cl2, –10 °C

R2

OBn

O

CH2Cl2, –10 °C

20 mol% 198-Yb(OTf)3

O

O N

O

CH2Cl2, rt

O

60% 202 *exo/endo > 1:99 ee (endo) 96%

*absolute configuration has not been determined

Scheme 77.

reductive elimination OH X

Pd(0)Ln

OH PdXLn

O

O PdLn

base

O H

X: Cl, Br

-hydride elimination and reductive elimination

Scheme 78.

easily transformed into the tetrahydropyran 208 in the presence of a copper(I) salt and 1,10-phenanthroline. 9. Intramolecular conjugate additions The venerable Michael reaction has found a fertile field of application in the synthesis of six-membered oxygenated heterocycles. As outlined in Scheme 82, intramolecular nucleophilic attack of an alcohol on the electronically deficient C(sp2) or C(sp) center of a,b-unsaturated systems proceeds smoothly through exo and endo ring-closure modes to provide the corresponding pyrans. 9.1. 6-exo Ring closures The most common procedure for the synthesis of tetrahydropyrans based on the Michael reaction involves 6-exo-trig cyclizations of a,b-unsaturated hydroxy ketones or esters (see Eq. 7

in Scheme 82). These transformations are usually carried out in the presence of stoichiometric, or even catalytic, amounts of base under thermodynamic control, which implies that the configuration of the new stereocenter can be predicted from conformational analysis of the resultant heterocycle. Therefore, considering that the most stable conformer of saturated sixmembered heterocycles adopts the chair form as a rule, it is in general anticipated that these cyclizations mainly provide 2,6-cis-disubstituted tetrahydropyrans.157 As represented in Scheme 83, this methodology has been largely applied to the synthesis of leucascandrolide A (1),1d,g,j phorboxazole A (2a),2c spongistatin 1 (209), and other natural products.158,159 However, careful optimization of the experimental conditions enables the acquisition of the kinetically favored 2,6trans diastereomers.160,161 Thereby, cyclization of hydroxy ester 210 affords either 211-cis or 211-trans tetrahydropyran under basic conditions (Scheme 84).160b The all-equatorial 211-cis diastereomer is assumed to be the most stable isomer

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

P(t-Bu)2

203a

P(t-Bu)2

203b

2–3 mol% Pd(OAc) 2 2.5–3.5 mol% 203 1.5 equiv Cs2CO3

R OH

PhMe, 50 °C, 24 h

X X: Cl, Br

R: H, Me

O

R

72–85%

Scheme 79.

MeO

Br

Ar

2.5 mol% Pd(OAc)2 2.5 mol% 203a 1.5 equiv Cs2CO3

OH

PhMe, 50 °C, 22 h

204 Ar: 4-MeOPh

Ar O

MeO

205

46% OH pyr·HCl

(S)-equol 206

HO

150 °C, 28 h

O

66%

Scheme 80.

10 mol% CuI 20 mol% 1,10-phenanthroline 2 equiv Cs2CO3

Ph

Br OH 207

PhMe, , 20 h 60%

Ph

O 208

Scheme 81.

6-exo cyclizations 6-exo-trig OH

EWG

EWG

O

(7)

6-endo cyclizations O

O 6-endo-dig

(8)

OH

O

O

O 6-endo-trig

OH EWG OH

(9) O EWG

6-endo-trig

(10) O

Scheme 82.

and is predominantly obtained at room temperature and long reaction times. Otherwise, low temperatures and shorter reaction times supply 211-trans in good diastereomeric ratios. The synthesis of (þ)-SCH-351448 (212 in Scheme 85) takes advantage of analogous procedures.162 Indeed, treatment

2711

of a,b-unsaturated ester 213 with a catalytic amount of base under equilibrating conditions (THF, 0  C) provides the more stable 2,6-cis-disubstituted tetrahydropyran 214-cis, whereas low temperatures favor the cyclization to the 2,6trans derivative 214-trans. Similarly, assemblage of the 2,6cis-tetrahydropyran 216-cis from a,b-unsaturated ester 215 is carried out at 35  C, because the 2,6-trans isomer 216-trans predominates when the reaction is conducted at 78  C. Furthermore, the stereochemical outcome of oxa-Michael cyclizations on a,b-unsaturated esters containing an additional hydroxy group at the allylic position is strongly influenced by the protecting group and the alkene geometry.163e166 In this manner, kinetically controlled cyclization in aprotic basic conditions of a,b-unsaturated esters 217 affords 2,3-cis- or 2,3-trans-disubstituted tetrahydropyrans 218, depending on the geometry of the carbonecarbon double bond. As shown in Scheme 86, tetrahydropyran 218-trans is almost exclusively obtained from the (Z)-ester 217-Z, whereas the 218-cis isomer is prepared in high diastereomeric ratios from (E)-ester 217-E. In both cases, NaH provides good results, but potassium bases such as KHMDS are the most convenient regarding both stereoselectivity and rate.164a,b It has also been shown that (E)-a,b-unsaturated ester 219 cyclizes quantitatively to 2,3-cis-2,6-cis-tetrahydropyran 220 (Scheme 87), whereas (Z)-a,b-unsaturated ester 221 provides 2,3-trans-2,6-trans-tetrahydropyran 222a, which can be equilibrated to the thermodynamically more stable 2,3cis-2,6-cis 222b.167,168 Theoretical calculations on the intramolecular Michael addition on all these systems emphasize the important role of the cation, the conformational analysis of the a,b-unsaturated esters, and the reversibility of the process for the stereochemical outcome of such cyclizations. One of the most appealing features of Michael-mediated cyclizations is that they can participate in cascade sequences.169,170 This is the case for the double-cascade cyclization triggered by a 6-exo-trig oxa-Michael addition on the advanced intermediate 224 en route to tetronasin 1 (223 in Scheme 88). Indeed, treatment of 224 with KHMDS in toluene at 0  C gives exclusively the 2,6-cis-disubstituted tetrahydropyran 225 in an impressive 67% yield.171 Moreover, a new route to 2,6-cis-tetrahydropyrans based on a tandem alkyneeenone coupling and a Michael addition has recently been disclosed.172 As illustrated in Scheme 89, the eneeyne coupling of b,g-unsaturated ketone 226 and TMSprotected homopropargylic alcohol 227 presumably provides a hydroxy enone, which undergoes a Michael-like cyclization to afford the C11eC15 2,6-cis-disubstituted tetrahydropyran 228 in good yield and diastereomeric ratio.173 Mechanistically, the preference for the 2,6-cis diastereomer seems to arise from a late transition state, in which the relative stabilities would play a significant role. This ruthenium-based sequence is combined with a palladium-catalyzed dihydropyran synthesis previously reported (see Scheme 52). In this case, coupling of terminal alkyne 229 with hydroxy ynoate 230 in the presence of palladium(II) catalysts delivers the C19eC23 dihydropyran 231 in 55% yield. Both processes cover key transformations

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2712

OTBS OH OH

O

OTBS

10 mol% t-BuOK

CO2Et TBSO

80% dr 9:1

1

OH O

O

THF, 0 °C, 10 min

CO2Et TBSO OTIPS

OTIPS 1.1 equiv NaHMDS THF, –78 °C, 1 h

OH

O N

CO2Et

Boc

O

PMBO

O

PMBO

N

87%

OPMB

O

PMB OPMB O

HO

AcO

OMe

O O

OH

O

2) KOH, MeOH rt, 24 h 86%

O

Boc

1) AcOH, THF–H2O rt, 48 h

O

2a

CO2Et

O

O

O O

AcO

OPMB

dr > 95:5

HO

OH

spongistatin 1 209

O

O HO

O O

Cl

H

OH

OH OH

Scheme 83.

OH S S

OH

OH 2.2 equiv NaH

O O

OMe

211-trans

1 equiv NaH

S

THF –78 to 0 °C 2.5 h 78% dr 81:19

S

OH MeO 210

S

THF –40 °C to rt 7h O 61% dr 98:2

O

S

OMe

O

211-cis

Scheme 84.

10 mol% t-BuOK

10 mol% t-BuOK O

O

THF, –78 °C, 20 min

CO2Bn

86% dr 13:1

214-trans

OH O

THF, 0 °C, 10 min

CO2Bn

90%

214-cis

CO2Me

60 mol% t-BuOK OH

THF, –78 °C

216-trans

CO2Me

80%

215

216-cis CO2H

OH O

O NaO2C

OH O

O

O

O

O

THF, from –78 to –35 °C

CO2Me

74% dr 12.5:1

O

CO2Bn

213 60 mol% t-BuOK

O

O

OH O

O

HO

(+)-SCH-351448, 212

Scheme 85.

for the total synthesis of 232, a ring-expanded analogue of bryostatin 1. Ring closure of the putative intermediate represented in Scheme 89 is believed to be catalyzed by the ruthenium Lewis acid. Indeed, Michael-mediated cyclizations can also proceed under Brønsted acid conditions.174 Although poorly exploited,

this sort of reaction has been applied to 6-exo-trig cyclizations on a,b-unsaturated ketones for the synthesis of complex natural products. For instance, deprotection of 1,3-diol in 233 in acetic acid triggers the formation of 2,6-trans-tetrahydropyran 234 in excellent yield and moderate diastereoselectivity (Scheme 90);175 reaction of lactol 235 with a stabilized

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 H

OBz OH

O CO2Me

217-E

H

OBz CO2Me

OBz

+

OBz

CO2Me

O

H

2713

218-trans 2,3-trans-tetrahydropyran

218-cis 2,3-cis-tetrahydropyran

CO2Me

OH

H

Ester

Base

Solvent

T (ºC)

dr (cis-trans)

217-E 217-E 217-Z 217-Z

KHMDS NaH KHMDS NaH

PhMe THF PhMe THF

–78 –78 0 0

9:1 9:1 1:20 1:11

217-Z

Scheme 86.

CO2R1 OH

PGO

t-BuOK

THF, 0 °C

OPG PG: TBDPS

OH

CO2R2

3 OPG

OPG

t-BuOK

PGO

6 O 2

PhMe-t-BuOH, rt

Ph

Ph

CO2R2

t-BuOK

6 O 2

PGO

PhMe, 0 °C

CO2R2

3 OPG

100% dr 95:5

2,3-trans-2,6-trans 222a

221

R2: O

R1: O

3 OPG

76% dr > 98:2

PG: TBDPS

CO2R1

2,3-cis-2,6-cis 220

100% dr > 95:5 219

PGO

6 O 2

PGO

2,3-cis-2,6-cis 222b

Scheme 87.

Intramolecular Hetero Michael Addition (DIHMA) based on a 6-exo-dig cyclization followed by a stereoselective 6-exotrig ring closure.179 In this manner, the acid-mediated double intramolecular oxa-Michael addition on dihydroxy ynone 240 gives the bicyclic ketal 241 as a single diastereomer in excellent yield (Scheme 91).180 Similarly, treatment of ynone 242 with TBAF promotes silyl ether cleavage and addition of the corresponding oxygen atoms upon C28 to provide in high yield the targeted FG-ring system 243 present in azaspiracids.181

phosphorane provides enone 236, which is cyclized by treatment with CSA to furnish 2,6-cis-tetrahydropyran 237 as the sole diastereomer in 73% yield over two steps176 and, eventually, removal of isopropylidene acetal and silicon protecting groups in the advanced intermediate 238 en route to bryostatins with HF leads to the C1eC16 fragment 239 containing two 2,6-cis-tetrahydropyrans.177,178 As well as all of these cyclizations, a 6-exo-dig ring-closure mode based on a Michael reaction is, in fact, possible. However, there is no clear example in the literature, because the enone generated in this cyclization process usually undergoes a second Michael addition, as can be appreciated in the synthesis of azaspiracids (62 in Scheme 24, see also Scheme 57). In this case, the retrosynthetic analysis of the C27eC40 domain followed by Forsyth et al. relies on a formal Double

EtO2C

HO

9.2. 6-endo Ring closures Contrary to the Michael-mediated 6-exo-dig cyclizations, parallel 6-endo-dig processes have been identified as a useful

O

MeO2C

OMe 224 KHMDS PhMe, 0 °C, 30 min HO EtO2C H

O

OMe

CO2Me

O OMe

O 225

H

O

H

67% single diastereomer

Scheme 88.

ONa

H O O

O

tetronasin 1 223

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2714

TBDPSO

O O

TBDPSO

TMS

O O

+

10 mol% [CpRu(MeCN)3]PF6

11

O

acetone, rt, 40 h O

56% dr 9:1

PMBO

OH

O O

+

MeO MeO2C

OTBS

1) 4 mol% Pd(OAc)2 4 mol% TDMPP Ph, rt, 1 d

19 O 23

CO2Me

O

O

15

OH (H2C)3

O

O OH H O

CO2Me

55%

230

OAc

11

O

2) 8 mol% Pd(OCOCF3)2 2d

H

OPMB 228

PMBO

227

226

O

15

OPMB

OTBS

229

TMS

OH O

OH PMBO

R

TMS

231

19

O

23

analogue of bryostatin 1 AcO 232

OH CO2Me

Scheme 89.

O

SEMO

O

SEM O O

O

OSEM OH

AcOH SEMO

OBn

THF– H2O, rt, 19 h

O

95% dr: 2.5:1

234

233

OBn

O O BnO

OH

OH

OBn

BnO

235

OBn

CH2Cl2, rt, 1 h

BnO

73%

236

OBn MeO

OBn OBn O

O

1) 56% HF, MeCN, rt, 24 h

O

O

237

TMS

TBSO

H

O

10 mol% CSA

OBn

O

O

2) HC(OMe)3, MeOH, cat PPTS, rt, 3 h

OTBS

OH

34% 238

239

OH OBn

Scheme 90.

tool to gain access to pyranones (see Eq. 8 in Scheme 82). In particular, 6-endo-dig cyclizations of o-alkynoylphenols provide an appealing entry into the synthesis of the heterocyclic structures present in many natural products. The O O

O

TBDPSO

selectivity of these reactions turns out to be highly dependent upon the experimental conditions. Indeed, base-catalyzed cyclization of o-alkynoylphenols can proceed through a 5-exo-dig or 6-endo-dig pathway to afford, respectively, 1) 10 mol% CSA CH2Cl2-MeOH 5:1, rt, 3.5 h

OTBDPS

2) 10 mol% TsOH PhH, rt, 4 h

240

O

O

O

2 41

90% 6-exo-trig

6-exo-dig

O

OTBDPS

O HO

OH OH

O

TBDPSO OTBS

Boc N

Boc H O

OTBS

TBAF THF, rt

242

O

85%

Scheme 91.

N O

O O

H 243

O

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

benzofuranones or benzopyranones. According to the experimental results, theoretical calculations on a model ketone shown in Scheme 92 have revealed that the transition states for both processes are very close in energy. Nevertheless, the 6-endo-dig product is thermodynamically favored and can be obtained under equilibrating conditions in the absence of proton donors.182 This approach has been successfully applied to the synthesis of several members of a family of antibiotics containing an anthrapyran core.183,184 As represented in Scheme 93, basic treatment of ynone 244 under aprotic conditions promotes a highly selective 6-endo-dig cyclization to the tetracyclic compound 245 that is further elaborated into the antibiotic AH-1763 IIa (246).184a Alternatively, this type of cyclization can also be carried out under acidic conditions, but the mechanism is still unclear.185 Overshadowed by 6-exo-trig cyclizations, the related 6endo-trig ring-closure mode (see Eq. 9 in Scheme 82) had traditionally attracted not much attention. However, the increasing interest in the asymmetric synthesis of di- and tetrahydropyranones has modified this situation, since this type of cyclization emerges as an appealing alternative to the hetero-

O

OH O

H

6-endo-dig

O

O

B

H O

O

DielseAlder reaction. Initial reports on 6-endo-trig cyclizations of a,b-unsaturated ketones are due to Paterson and Osborne.186 In particular, the aldol adducts obtained through stereoselective reactions from b-chloro vinyl ketones undergo Lewis acid-mediated cyclizations that eventually give dihydropyranones.187 Application of this methodology to methyl ketone 247 and 3-benzoyloxypropanal supplies aldol 248, which is easily converted into the desired dihydropyranone 249 (Scheme 94). Further recrystallization provides an enantiomerically pure material that has been employed for the total synthesis of swinholide A,188a scytophycin C,188b and, more recently, laulimalide (93 in Scheme 38).188c Aldol adducts lacking the b-chlorine atom can also take part in these cyclizations to afford the tetrahydropyranones. A comprehensive survey of the ability of Brønsted and Lewis acids as well as palladium(II) complexes to enhance the electrophilicity of enones 250 has identified Amberlyst-15, Al(ClO4)3$9H2O, and [Pd(MeCN)4](BF4)2 as suitable catalysts to carry out the desired 6-endo-trig cyclization (250a,b to 251a,b) under mild conditions (Scheme 95).76b,189 As anticipated for a thermodynamically controlled reaction, Amberlyst-15 affords the all-equatorial products after extended reaction times. Interestingly, the palladium-mediated cyclizations are irreversible and give access to the other isomers in excellent diastereomeric ratios. Another aldol reaction is at the center of a different methodology. Aldol compounds arising from b-keto esters can participate in an acid-mediated Knoevenagel condensation that generates a highly reactive a,b-unsaturated keto ester, which undergoes a 6-endo-trig cyclization based on a reversible oxa-Michael addition. Finally, decarboxylation of the resultant system provides the 2,6-cis-disubstituted tetrahydropyranones.190,191 This methodology has been applied to the preparation of ()-centrolobine (252 in Scheme 96). The reported sequence takes advantage of a Mukaiyama aldol reaction to

O

5-exo-dig

O

O

O

O

Scheme 92.

OBn

O

O

OBn

OH

O O

2715

O

OH

O

OH O

Cs2CO3

O

O

O

acetone, rt, 30 min O

71%

244

O

O

245

AH-1763 IIa 246

Scheme 93.

O Cl 247

(+)-Ipc2BCl i-Pr2NEt Et2O, 0 °C 1h

O Cl

BIpc2 –78 to –20 °C 20 h 56%

O

BzO laulimalide 93

O

OHC(CH2)2OBz Cl

OH OBz

248

80% ee

TMSOTf, i-Pr2NEt CH2Cl2, –78 °C to rt, 1.5 h

249

61% (upgrade to >98% ee by recrystallization)

O

Scheme 94.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723

2716

8 mol% [Pd(MeCN)4](BF4)2

OH O Ph

M O

Ph H

HO

CH2Cl2, rt, 3 h

O Ph

78% dr 96:4

H H

O

251a

250a

M

8 mol% [Pd(MeCN)4](BF4)2

OH O Ph

CH2Cl2, rt, 3 h

H HO

OH Ph

250b

O Ph

75% dr 97:3

O

251b

H

Scheme 95.

OMe OTMS

O 1) 1 equiv Yb(OTf)3 CH2Cl2, –78 °C, 3 h

TMSO +

2) 2 equiv TFA 4-MeOPhCHO rt, 5 h OTBS

OHC

MeO2C HO MeO

OH

60% O

MeO2C O

O

MeO

OH

MeO

OH 253

(±)-centrolobine 252

Scheme 96.

OH O

O Ot-Bu

Ar

255

O

1) 10 mol% 254a PhMe, –25 °C, 24–38 h 2) 50 mol% TsOH 80 °C, 10–50 h 65–94% 88–94% ee

O

N

S

Ar

H

BnO

256a

N H

N H

Ar

254a

N N

OH O

O H

O

1) 20 mol% 254b 5 mol% piperidinium acetate Ot-Bu PhMe, 4 Å MS, rt, 2 d 2) 30 mol% TsOH 257 PhMe, 80 °C, 9 h Ph

77%

O

O

Ph

flindersiachromanone

80% ee

OMe

S Ar

N H

N H

H N

254b

256b

Scheme 97.

install the first appendage of the tetrahydropyran. Then, addition of anisaldehyde and TFA to the reaction mixture affords the tetrahydropyranone 253 and further functional-group manipulations deliver ()-centrolobine.192 Closely connected to this methodology, it has recently been discovered that the chiral thiourea-based catalysts 254, shown in Scheme 97, activate a-alkylidene-b-keto esters 255 and trigger intramolecular conjugate additions of phenol to the corresponding flavanones 256. Remarkably, a one-pot reaction involving the simple b-keto ester 257, hydrocinnamaldehyde, piperidinium acetate, and chiral thiourea 254b in the presence of molecular sieves in toluene at room temperature followed by decarboxylation affords the natural product, flindersiachromanone 256b, in 80% ee and 77% overall yield.193,194 Although 2,6-cis-disubstituted tetrahydropyranones are usually the most stable diastereomers, other elements in the

structure can alter this situation. For instance, thermodynamically controlled transannular conjugate addition on a,b-unsaturated ketone 258 affords 2,6-trans-disubstituted tetrahydropyranone 259, used as an advanced intermediate in a formal total synthesis of ()-apicularen A (260 in Scheme 98). Interestingly, exposure of epimer 258-epi to identical conditions yields the same tetrahydropyranone 259.195 In contrast to the above examples, some 6-endo-trig cyclizations match the model reaction represented by Eq. 10 in Scheme 82.196 For instance, chiral dienyl sulfoxides 261 have been identified as suitable precursors of dihydropyrans. This process is based on a highly stereoselective conjugated addition (the examples shown in Scheme 99 afford a single diastereomer) followed by subsequent transformations of the resultant allylic sulfoxides 262.197 Interestingly, this methodology accepts additional stereocenters and other substituents on the double bond of the dienyl sulfoxide.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 OMe O H O

2717

OMe O H O

OMe O H O Amberlyst-15

Amberlyst-15 HO

O

CDCl3, reflux, 18 h 90% selectivity > 10:1

258 O

HO

CDCl3, reflux, 23 h 78% selectivity > 10:1

259 O

OH O H O

O N H

O

OH

258-epi O

(–)- apicularen A 260

Scheme 98. O S

H p-Tol

OH R 261a R: Ph 261b R: Bu

LDA THF, –78 °C to rt 3–4 h

O S

p-Tol

10 equiv P(OMe)3 MeOH, 50 °C 4d

O

R H 262a 84% 262b 94%

HO O

Ph

263a 50%

Scheme 99.

10. Conclusions As this report proves, the apparently simple construction of pyrans through CeO bond formation is surprising, with an extremely varied array of methodologies ranging from the venerable SN2- or Michael-based cyclizations to the more recent transition metal-catalyzed reactions. The scope and synthetic efficiency of such ring-forming methodologies have already been established along with the total synthesis of a large number of structurally complex natural products, but, in spite of these outstanding achievements, the increasing demand for more selective processes to gain access in a straightforward manner to six-membered oxygenated heterocycles is fueling the development of new concepts and methodologies. Remarkable examples are the recent developments in epoxide-mediated cyclizations that allow selective formation of the pyrans over the more favored furans or the spectacular simultaneous construction of up to three fused tetrahydropyran units in a cascade sequence. Moreover, emerging methodologies such as platinum- or gold-catalyzed cyclizations of hydroxy alkenes, allenes, and alkynes will undoubtedly play a major role in further developments in this field.

2.

3.

Acknowledgements We are grateful for the financial support from the Spanish Ministerio de Ciencia y Tecnologı´a (Grant CTQ2006-13249/ BQU), the Generalitat de Catalunya (2005SGR00584), and the Universitat de Barcelona (ACES-UB2006). References and notes 1. For total syntheses of leucascandrolide A, see: (a) Hornberger, K. R.; Hamblett, C. L.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 12894e

4.

5. 6.

12895; (b) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc. 2001, 123, 8420e8421; (c) Wipf, P.; Reeves, J. T. Chem. Commun. 2002, 2066e2067; (d) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274e9283; (e) Paterson, I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343e347; (f) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed. 2003, 42, 3934e3938; (g) Crimmins, M. T.; Siliphaivanh, P. Org. Lett. 2003, 5, 4641e4644; (h) Wang, Y.; Janjic, J.; Kozmin, S. A. Pure Appl. Chem. 2005, 77, 1161e1169; (i) Su, Q.; Dakin, L. A.; Panek, J. S. J. Org. Chem. 2007, 72, 2e24; (j) Ferrie´, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2007, 9, 2461e2464; (k) Van Orden, L. J.; Patterson, B. D.; Rychnovsky, S. D. J. Org. Chem. 2007, 72, 5784e 5793. For total syntheses of phorboxazole A, see: (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597e5598; (b) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942e10953; (c) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan, D. S.; Plowright, A. T.; Tornos, J. A.; Ye, T. Org. Biomol. Chem. 2003, 1, 4173e4208; (d) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12058e12063; (e) Smith, A. B., III; Razler, T. M.; Ciavarri, J. P.; Hirose, T.; Ishikawa, T. Org. Lett. 2005, 7, 4399e 4402; (f) Wang, B.; Forsyth, C. J. Org. Lett. 2006, 8, 5223e5226; (g) White, J. D.; Kuntiyong, P.; Lee, T. H. Org. Lett. 2006, 8, 6029e6042; (h) White, J. D.; Lee, T. H.; Kuntiyong, P. Org. Lett. 2006, 8, 6043e 6046. For total syntheses of phorboxazole B, see: (a) Evans, D. A.; Fitch, D. M.; Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033e 10046; (b) Li, D.-R.; Zhang, D.-H.; Sun, C.-Y.; Zhang, J.-W.; Yang, L.; Chen, J.; Liu, B.; Su, C.; Zhou, W.-S.; Lin, G.-Q. Chem.dEur. J. 2006, 12, 1185e1204; (c) Lucas, B. S.; Gopalsamuthiram, V.; Burke, S. D. Angew. Chem., Int. Ed. 2007, 46, 769e772. For a review on the synthesis of phorboxazoles, see: Haustedt, L. O.; Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem., Int. Ed. 2003, 42, 2711e2716. (a) Kishi, Y. Pure Appl. Chem. 1998, 70, 339e344; (b) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1e48 and references therein. For reviews on the synthesis of tetrahydropyrans, see: (a) Boivin, T. L. B. Tetrahedron 1987, 43, 3309e3362; (b) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2002, 2301e2323; (c) Clarke, P. A.; Santos, S. Eur. J. Org. Chem. 2006, 2045e2053; (d) Tang, Y.; Oppenheimer, J.; Song, Z.; You, L.; Zhang, X.; Hsung, R. P. Tetrahedron 2006, 62, 10785e10813.

2718

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7. For the stereoselective preparation of pyrans in the context of the synthesis of polyether ionophore antibiotics, see: Faul, M. M.; Huff, B. E. Chem. Rev. 2000, 100, 2407e2473. 8. For the stereoselective preparation of pyrans in the context of the synthesis of marine macrolides, see: Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237e4313. 9. For the stereoselective preparation of pyrans in the context of the synthesis of polycyclic ethers, see: (a) Nakata, T. Chem. Rev. 2005, 105, 4314e 4347; (b) Inoue, M. Chem. Rev. 2005, 105, 4379e4405. 10. For the stereoselective preparation of spirans, see: Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. Rev. 2005, 105, 4406e4440. 11. For a BaeyereVilliger oxidation of a cyclopentanone en route to phorboxazoles, see: Misske, A. M.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 4315e4324. 12. For HDA cycloadditions en route to 1 and 2, see Refs. 1e,2a,b. 13. For the synthesis of pyrans in the context of comprehensive reactivity reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127e2198; (b) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199e2238; (c) Barluenga, J.; Santamarı´a, J.; Toma´s, M. Chem. Rev. 2004, 104, 2259e2283; (d) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285e2309; (e) Muzart, J. Tetrahedron 2005, 61, 5955e6008. 14. For C-glycosidation transformations en route to 1 and 2, see Refs. 1a,e,3a. 15. We have systematically adopted along the review the heterocyclic nomenclature (and not the carbohydrate-like one), which assigns number 1 to the oxygen atom. 16. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734e736. 17. (a) Smith, A. B., III; Zhu, W.; Shirakami, S.; Sfouggatakis, C.; Doughty, V. A.; Bennett, C. S.; Sakamoto, Y. Org. Lett. 2003, 5, 761e764; (b) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7, 937e 939. 18. (a) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1997, 62, 5672e5673; (b) Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003, 59, 8613e8622; (d) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 5509e5512; (e) Chakraborty, T. K.; Reddy, V. R. Tetrahedron Lett. 2006, 47, 2099e2102. 19. (a) Bolster, M. G.; Jansen, B. J. M.; de Groot, A. Tetrahedron 2002, 58, 5275e5285; (b) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Minakawa, N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W. H. J. Am. Chem. Soc. 2003, 125, 8228e8237; (c) Pichlmair, S.; Marques, M. M. B.; Green, M. P.; Martin, H. J.; Mulzer, J. Org. Lett. 2003, 5, 4657e4659; (d) Hua, D. H.; Huang, X.; Chen, Y.; Battina, S. K.; Tamura, M.; Noh, S. K.; Koo, S. I.; Namatame, I.; Tomoda, H.; Perchellet, E. M.; Perchellet, J.-M. J. Org. Chem. 2004, 69, 6065e6078; (e) Prasad, K.; Anbarasan, P. Tetrahedron 2007, 63, 1089e1092; (f) Zhou, J.; Snider, B. B. Org. Lett. 2007, 9, 2071e2074. 20. Occasionally, an SN20 mechanism can also be proposed to rationalize this type of cyclizations, see: (a) Ravn, M. M.; Peters, R. J.; Coates, R. M.; Croteau, R. J. Am. Chem. Soc. 2002, 124, 6998e7006; (b) Kang, Y.; Mei, Y.; Du, Y.; Jin, Z. Org. Lett. 2003, 5, 4481e4484. 21. Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J. T. Angew. Chem., Int. Ed. 2003, 42, 1258e1262. 22. For a recent account on the Nicholas reaction, see: Dı´az, D. D.; Betancort, J. M.; Martı´n, V. S. Synlett 2007, 343e359. 23. Betancort, J. M.; Martı´n, T.; Palazo´n, J. M.; Martı´n, V. S. J. Org. Chem. 2003, 68, 3216e3224; See also: Dı´az, D.; Martı´n, T.; Martı´n, V. S. Org. Lett. 2001, 3, 3289e3291. 24. Criso´stomo, F. R. P.; Martı´n, T.; Martı´n, V. S. Org. Lett. 2004, 6, 565e 568. 25. Criso´stomo, F. R. P.; Carrillo, R.; Leo´n, L. G.; Martı´n, T.; Padro´n, J. M.; Martı´n, V. S. J. Org. Chem. 2006, 71, 2339e2345. 26. (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330e5334; (b) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5335e5340. 27. For theoretical studies on the acid-mediated epoxy alcohol cyclizations, see: (a) Na, J.; Houk, K. N.; Shevlin, C. G.; Janda, K. D.; Lerner, R. A. J. Am. Chem. Soc. 1993, 115, 8453e8454; (b) Na, J.; Houk, K. N. J. Am. Chem. Soc. 1996, 118, 9204e9205.

28. Conformational restrictions on the substrate may alter the model reactions described in Schemes 7 and 8. For an example, see: Nicolaou, K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129, 429e440 and references therein. 29. Crimmins, M. T.; Haley, M. W. Org. Lett. 2006, 8, 4223e4225. 30. For other 6-exo cyclizations, see: (a) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem. 2001, 66, 1885e1893; (b) Williams, D. R.; Ihle, D. C.; Plummer, S. V. Org. Lett. 2001, 3, 1383e1386; (c) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004, 69, 1993e1998; (d) Chang, S.-K.; Paquette, L. A. Synlett 2005, 2915e2918; (e) Kadota, I.; Abe, T.; Sato, Y.; Kabuto, C.; Yamamoto, Y. Tetrahedron Lett. 2006, 47, 6545e6548; (f) Takahashi, S.; Hongo, Y.; Ogawa, N.; Koshino, H.; Nakata, T. J. Org. Chem. 2006, 71, 6305e6308; (g) Takizawa, A.; Fujiwara, K.; Doi, E.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2006, 62, 7408e7435; (h) Bedore, M. W.; Chang, S.-K.; Paquette, L. A. Org. Lett. 2007, 9, 513e516. 31. Fuwa, H.; Ebine, M.; Bourdelais, A. J.; Baden, D. G.; Sasaki, M. J. Am. Chem. Soc. 2006, 128, 16989e16999. 32. For other 6-endo cyclizations, see: (a) Mukai, C.; Sugimoto, Y.-i.; Ikeda, Y.; Hanaoka, M. Tetrahedron 1998, 54, 823e850; (b) Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le Brazidec, J.-Y.; Hirama, M. Tetrahedron 2002, 58, 6493e6512; (c) Sato, K.; Sasaki, M. Angew. Chem., Int. Ed. 2007, 46, 2518e2522; (d) Shangguan, N.; Kiren, S.; Williams, L. J. Org. Lett. 2007, 9, 1093e1096. 33. McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593e595. 34. (a) Morimoto, Y.; Nishikawa, Y.; Ueba, C.; Tanaka, T. Angew. Chem., Int. Ed. 2006, 45, 810e812; (b) Morimoto, Y.; Yata, H.; Nishikawa, Y. Angew. Chem., Int. Ed. 2007, 46, 6481e6484. 35. Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 2096e2099. 36. For a comprehensive analysis of such processes in the context of functionalized tetrahydrofurans, see: Hartung, J.; Drees, S.; Greb, M.; Schimdt, P.; Svoboda, I.; Fuess, H.; Murso, A.; Stalke, D. Eur. J. Org. Chem. 2003, 2388e2408. 37. Cane, D. E.; Celmer, W. D.; Westley, J. W. J. Am. Chem. Soc. 1983, 105, 3594e3600. 38. (a) Fujiwara, K.; Murai, A. Bull. Chem. Soc. Jpn. 2004, 77, 2129e2146; (b) Valentine, J. C.; McDonald, F. E. Synlett 2006, 1816e1828; (c) Gallimore, A. R.; Spencer, J. B. Angew. Chem., Int. Ed. 2006, 45, 4406e4413. 39. The efficiency of such strategy has been proved in the synthesis of a Cs-symmetric diastereomer of glabrescol, a polyether containing five contiguous tetrahydrofuran rings, see: Xiong, Z.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 4831e4832. 40. Tokiwano, T.; Fujiwara, K.; Murai, A. Synlett 2000, 335e338. 41. Bravo, F.; McDonald, F. E.; Neiwert, W. A.; Do, B.; Hardcastle, K. I. Org. Lett. 2003, 5, 2123e2126. 42. Simpson, G. L.; Heffron, T. P.; Merino, E.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1056e1057. 43. Chamberlin, A. R.; Mulholland, R. L.; Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 672e677. 44. For mercury(II)-mediated cyclizations, see: (a) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988, 110, 2506e2526; (b) de Koning, C. B.; Green, I. R.; Michael, J. P.; Oliveira, J. R. Tetrahedron 2001, 57, 9623e9634; (c) Liu, B.; Zhou, W.-S. Tetrahedron Lett. 2003, 44, 4933e4935; (d) Takao, H.; Wakabayashi, A.; Takahashi, K.; Imagawa, H.; Sugihara, T.; Nishizawa, M. Tetrahedron Lett. 2004, 45, 1079e 1082; (e) Petri, A. F.; Bayer, A.; Maier, M. E. Angew. Chem., Int. Ed. 2004, 43, 5821e5823; (f) Nicolaou, K. C.; Pihko, P. M.; Bernal, F.; Frederick, M. O.; Qian, W.; Uesaka, N.; Diedrichs, N.; Hinrichs, J.; Koftis, T. V.; Loizidou, E.; Petrovic, G.; Rodriquez, M.; Sarlah, D.; Zou, N. J. Am. Chem. Soc. 2006, 128, 2244e2257. 45. The cyclization of g-hydroxy-cis-alkenes promoted by mercury(II) salts and chiral bisoxazolines as ligands affords 2-substituted tetrahydrofurans. Application of this methodology to just a d-hydroxy-cis-alkene provides the corresponding tetrahydropyran in excellent ee, see: Kang, S. H.; Kim, M. J. Am. Chem. Soc. 2003, 125, 4684e4685. 46. Meyer, C.; Blanchard, N.; Defosseux, M.; Cossy, J. Acc. Chem. Res. 2003, 36, 766e772.

I. Larrosa et al. / Tetrahedron 64 (2008) 2683e2723 47. Defosseux, M.; Blanchard, N.; Meyer, C.; Cossy, J. J. Org. Chem. 2004, 69, 4626e4647. 48. (a) Schultz, A. G.; Guzi, T. J.; Larsson, E.; Rahm, R.; Thakkar, K.; Bidlack, J. M. J. Org. Chem. 1998, 63, 7795e7804; (b) Bernard, N.; Chemla, F.; Ferreira, F.; Mostefai, N.; Normant, J.-F. Chem.dEur. J. 2002, 8, 3139e3147; (c) Van der Weghe, P.; Aoun, D.; Boiteau, J.-G.; Eustache, J. Org. Lett. 2002, 4, 4105e4108; (d) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H.-w.; Jun, H.-S.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew. Chem., Int. Ed. 2003, 42, 4779e4782; (e) Gao, X.; Snider, B. B. J. Org. Chem. 2004, 69, 5517e5527; (f) Dı´ez, D.; Nu´~ nez, M. G.; Moro, R. F.; Lumeras, W.; Marcos, I. S.; Basabe, P.; Urones, J. G. Synlett 2006, 939e941; (g) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Tang, W.; Frederick, M. O.; Chen, D. Y.-K.; Li, Y.; Ling, T.; Yamada, Y. M. A. J. Am. Chem. Soc. 2006, 128, 2859e2872. 49. For a recent example on the classical iodolactonization process leading to a six-membered lactone, see: Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125, 7822e7824. 50. For other halo-mediated cyclizations, see: Zhong, H. M.; Sohn, J.-H.; Rawal, V. H. J. Org. Chem. 2007, 72, 386e397. 51. (a) Albert, B. J.; Koide, K. Org. Lett. 2004, 6, 3655e3658; (b) Albert, B. J.; Sivaramakrishnan, A.; Naka, T.; Koide, K. J. Am. Chem. Soc. 2006, 128, 2792e2793. 52. For a related iodoetherification involving a ketone, see: Clarke, P. A.; Grist, M.; Ebden, M.; Wilson, C.; Blake, A. J. Tetrahedron 2005, 61, 353e363. 53. For other cyclizations involving oxygenated nucleophiles different than alcohols or carboxylic acids, see: (a) Liu, K.; Taylor, R. E.; Kartika, R. Org. Lett. 2006, 8, 5393e5395; (b) Braddock, D. C. Org. Lett. 2006, 8, 6055e6058. 54. For a review on selenocyclizations, see: Petragnani, N.; Stefani, H. A.; Valduga, C. J. Tetrahedron 2001, 57, 1411e1448. 55. (a) See Refs. 1d, 19d, 50, 51; (b) Iwasaki, K.; Nakatani, M.; Inoue, M.; Katoh, T. Tetrahedron 2003, 59, 8763e8773. 56. For a comprehensive overview, see: Tsuji, J. Palladium Reagents and Catalysts. New Perspectives for the 21st Century; John Wiley and Sons: Chichester, UK, 2004. 57. The stereoselectivity of the process can be eroded if p-facial selectivity is not enough effective or the equilibration of diastereomeric complexes via pesep mechanism is faster than the nucleophilic addition. 58. Hansen, E. C.; Lee, D. Tetrahedron Lett. 2004, 45, 7151e7155. 59. For reviews on stereoselective allylic alkylations, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395e422; (b) Trost, B. M. Acc. Chem. Res. 1996, 29, 355e364; (c) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921e2943. 60. Trost, B. M.; Machacek, M. R.; Faulk, B. D. J. Am. Chem. Soc. 2006, 128, 6745e6754. 61. For further applications of this methodology, see: Trost, B. M.; Machacek, M. R.; Tsui, H. C. J. Am. Chem. Soc. 2005, 127, 7014e7024. 62. Campbell, J. E.; Englund, E. E.; Burke, S. D. Org. Lett. 2002, 4, 2273e 2275. 63. For other Pd(0)-mediated cyclizations, see: (a) Lucas, B. S.; Burke, S. D. Org. Lett. 2003, 5, 3915e3918; (b) Zacuto, M. J.; Leighton, J. L. Org. Lett. 2005, 7, 5525e5527. 64. The alternative 7-endo ring closures leading to oxepanes have never been observed. 65. The intramolecular cyclization of g-hydroxy alkenes could afford the corresponding six-membered oxygenated heterocycles through a 6-endo ring closure. However, the five-membered oxygenated counterparts are usually obtained, with the exception of those substrates containing E-disubstituted olefins. See: (a) Semmelhack, M. F.; Bodurow, C. J. Am. Chem. Soc. 1984, 106, 1496e1498; (b) Semmelhack, M. F.; Zhang, N. J. Org. Chem. 1989, 54, 4483e4485; (c) McCormick, M.; Monahan, R., III; Soria, J.; Goldsmith, D.; Liotta, D. J. Org. Chem. 1989, 54, 4485e4487. 66. The regioselectivity of Pd(II)-mediated intramolecular cyclizations of o-allylic phenols seems to be largely dependent of palladium(II) salts. The use of PdCl2 appears to afford six-membered heterocycles, whereas

67.

68. 69.

70.

71.

72. 73.

74. 75. 76.

77. 78. 79. 80. 81. 82. 83.

84.

85.

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the five-membered counterparts are preferred with Pd(OAc)2. See: Hosokawa, T.; Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49e54. Hegedus, S. L. Organometallic in Synthesis: A Manual; Schlosser, M., Ed.; John Wiley and Sons: Chichester, UK, 2002; Chapter 10, pp 1123e1217. Semmelhack, M. F.; Kim, C. R. K.; Dobler, W.; Meier, M. Tetrahedron Lett. 1989, 30, 4925e4928. For other Pd(II)-mediated cyclizations, see: (a) Semmelhack, M. F.; Epa, W. R.; Cheung, A. W.-H.; Gu, Y.; Kim, C.; Zhang, N.; Lew, W. J. Am. Chem. Soc. 1994, 116, 7455e7456; (b) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907e2908; (c) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892e2895; (d) Koh, J. H.; Mascarenhas, C.; Gagne´, M. R. Tetrahedron 2004, 60, 7405e7410. (a) Uenishi, J.; Ohmi, M. Angew. Chem., Int. Ed. 2005, 44, 2756e2760; (b) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006, 71, 4530e4537; See also: (c) Miyazawa, M.; Hirose, Y.; Narantsetseg, M.; Yokoyama, H.; Yamaguchi, S.; Hirai, Y. Tetrahedron Lett. 2004, 45, 2883e2886. This analysis has been expanded to the corresponding Z isomers. Under the same conditions, (2S,3Z,8S) isomer also affords 92-cis as a single product in 76% yield. However, cyclization of (2R,3Z,8S) isomer turns out to be less stereoselective and more stringent conditions are required. Semmelhack, M. F.; Kim, C.; Zhang, N.; Bodurow, C.; Sanner, M.; Dobler, W.; Meier, M. Pure Appl. Chem. 1990, 62, 2035e2040. For an analysis on the influence of stereochemistry on the intramolecular Pd(II)-mediated alkoxycarbonylation, see: Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.; Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org. Chem. 2005, 70, 5449e5460. White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3, 4003e 4006. Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F. Angew. Chem., Int. Ed. 2005, 44, 257e259. (a) Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91e94; (b) Baker-Glenn, C.; Hodnett, N.; Reiter, M.; Ropp, S.; Ancliff, R.; Gouverneur, V. J. Am. Chem. Soc. 2005, 127, 1481e1486; (c) Reiter, M.; Turner, H.; Mills-Webb, R.; Gouverneur, V. J. Org. Chem. 2005, 70, 8478e8485; (d) Han, S. B.; Krische, M. J. Org. Lett. 2006, 8, 5657e5660. Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501e3504. Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536e9537. Coulombel, L.; Favier, I.; Du~nach, E. Chem. Commun. 2005, 2286e 2288. Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553e 4556. Marotta, E.; Foresti, E.; Marcelli, T.; Peri, F.; Righi, P.; Scardovi, N.; Rosini, G. Org. Lett. 2002, 4, 4451e4453. Jung, H. H.; Floreancig, P. E. Org. Lett. 2006, 8, 1949e1951. (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J. Angew. Chem., Int. Ed. 2006, 45, 7086e7090; (b) Zou, Y.; Chen, C.-H.; Taylor, C. D.; Foxman, B. M.; Snider, B. B. Org. Lett. 2007, 9, 1825e1828; (c) Kaliappan, K. P.; Ravikumar, V. Org. Lett. 2007, 9, 2417e2419; (d) Nicolaou, K. C.; Edmonds, D. J.; Li, A.; Tria, G. S. Angew. Chem., Int. Ed. 2007, 46, 1e5; (e) Nicolaou, K. C.; Tang, Y.; Wang, J. Chem. Commun. 2007, 1922e1923. For other examples on the Brønsted acid-mediated cyclization of hydroxy alkenes, see: (a) Nicolaides, D. N.; Gautam, D. R.; Litinas, K. E.; Papamehael, T. J. Chem. Soc., Perkin Trans. 1 2002, 1455e 1460; (b) Linares-Palomino, P. J.; Salido, S.; Altarejos, J.; Sa´nchez, A. Tetrahedron Lett. 2003, 44, 6651e6655; (c) Neighbors, J. D.; Beutler, J. A.; Wiemer, D. F. J. Org. Chem. 2005, 70, 925e931; (d) Alvarez-Manzaneda, E. J.; Chahboun, R.; Pe´rez, I. B.; Cabrera, E.; Alvarez, E.; Alvarez-Manzaneda, R. Org. Lett. 2005, 7, 1477e1480; (e) Gru¨tter, C.; Alonso, E.; Chougnet, A.; Woggon, W.-D. Angew. Chem., Int. Ed. 2006, 45, 1126e1130. Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179e4182.

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167. Strand, D.; Norrby, P.-O.; Rein, T. J. Org. Chem. 2006, 71, 1879e1891. 168. The opposite bias has been observed for the cyclization of hydroxy esters containing an epoxide at the allylic position. see: Harvey, J. E.; Raw, S. A.; Taylor, R. J. K. Org. Lett. 2004, 6, 2611e2614. 169. The thermodynamically controlled addition of benzaldehyde to 5-hydroxy-2,3-unsaturated esters or amides in the presence of catalytic amounts of base might be mentioned as a good example of this concept. Indeed, it relies on the initial formation of a metal hemiacetal that subsequently undergoes an intramolecular nucleophilic attack to the conjugated position to provide benzylidene protected 1,3-syn diols. Thus, although the target of such process is not the assemblage of a pyranlike heterocycles, it illustrates the potential of oxa-Michael addition in cascade sequences. see: (a) Evans, D. A.; Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446e2453; (b) Ahmed, Md. M.; Mortensen, M. S.; O’Doherty, G. A. J. Org. Chem. 2006, 71, 7741e7746; (c) Evans, D. A.; Nagorny, P.; Reynolds, D. J.; McRae, K. J. Angew. Chem., Int. Ed. 2007, 46, 541e544. 170. Nicolaou, K. C.; Lim, Y. H.; Papageorgiou, C. D.; Piper, J. L. Angew. Chem., Int. Ed. 2005, 44, 7917e7921. 171. Ley, S. V.; Brown, D. S.; Clase, J. A.; Fairbanks, A. J.; Lennon, I. C.; Osborn, H. M. I.; Stokes, E. S. E.; Wadsworth, D. J. J. Chem. Soc., Perkin Trans. 1 1998, 2259e2276. 172. Trost, B. M.; Yang, H.; Wuitschik, G. Org. Lett. 2005, 7, 4761e4764. 173. Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S. J. Am. Chem. Soc. 2007, 129, 2206e2207. 174. Most of these cyclizations involve protic acids. For a Lewis acid-mediated 6-exo-trig assemblage of 2,6-cis-tetrahydropyran from silyloxy enones, see: Evans, P. A.; Andrews, W. J. Tetrahedron Lett. 2005, 46, 5625e5627. 175. Paterson, I.; Keown, L. E. Tetrahedron Lett. 1997, 38, 5727e5730. 176. Nicolaou, K. C.; Bunnage, M. E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Wallace, P. A.; Chu, X.-J.; Agrios, K. A.; Gunzner, J. L.; Yang, Z. Chem.dEur. J. 1999, 5, 599e617. 177. O’Brien, M.; Taylor, N. H.; Thomas, E. J. Tetrahedron Lett. 2002, 43, 5491e5494. 178. For other examples, see: (a) Paterson, I.; Luckhurst, C. A. Tetrahedron Lett. 2003, 44, 3749e3754; (b) Chandrasekhar, S.; Shyamsunder, T.; Prakash, S. J.; Prabhakar, A.; Jagadeesh, B. Tetrahedron Lett. 2006, 47, 47e49; (c) Liu, J.; Yang, J. H.; Ko, C.; Hsung, R. P. Tetrahedron Lett. 2006, 47, 6121e6123; (d) See Refs. 157c and 160c. 179. Nguyen, S.; Xu, J.; Forsyth, C. J. Tetrahedron 2006, 62, 5338e5346. 180. Aiguade, J.; Hao, J.; Forsyth, C. J. Org. Lett. 2001, 3, 979e982. 181. (a) Forsyth, C. J.; Hao, J.; Aiguade, J. Angew. Chem., Int. Ed. 2001, 40, 3663e3667; (b) Forsyth, C. J.; Xu, J.; Nguyen, S. T.; Samdal, I. A.; Briggs, L. R.; Rundberget, T.; Sandvik, M.; Miles, C. O. J. Am. Chem. Soc. 2006, 128, 15114e15116.

182. Nakatani, K.; Okamoto, A.; Yamanuki, M.; Saito, I. J. Org. Chem. 1994, 59, 4360e4361. 183. Nakatani, K.; Okamoto, A.; Matsuno, T.; Saito, I. J. Am. Chem. Soc. 1998, 120, 11219e11225. 184. (a) Tietze, L. F.; Gericke, K. M.; Singidi, R. R. Angew. Chem., Int. Ed. 2006, 45, 6990e6993; (b) Tietze, L. F.; Singidi, R. R.; Gericke, K. M. Org. Lett. 2006, 8, 5873e5876. 185. (a) Sakamoto, K.; Honda, E.; Ono, N.; Uno, H. Tetrahedron Lett. 2000, 41, 1819e1823; (b) Uno, H.; Sakamoto, K.; Honda, E.; Fukuhara, K.; Ono, N.; Tanaka, J.; Sakanaka, M. J. Chem. Soc., Perkin Trans. 1 2001, 229e238. 186. Paterson, I.; Osborne, S. Tetrahedron Lett. 1990, 31, 2213e2216. 187. For other intramolecular conjugate addition/elimination processes, see: (a) Miao, H.; Yang, Z. Org. Lett. 2000, 2, 1765e1768; (b) Nicolaou, K. C.; Xu, H.; Wartmann, M. Angew. Chem., Int. Ed. 2005, 44, 756e 761; (c) Gao, B.; Yu, Z.; Fu, Z.; Feng, X. Tetrahedron Lett. 2006, 47, 1537e1539; (d) Hjelmgaard, T.; Søtofte, I.; Tanner, D. J. Org. Chem. 2005, 70, 5688e5697; (e) See also Ref. 32c. 188. (a) Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413e 9436; (b) Paterson, I.; Watson, C.; Yeung, K.-S.; Wallace, P. A.; Ward, R. A. J. Org. Chem. 1997, 62, 452e453; (c) Paterson, I.; De Savi, C.; Tudge, M. Org. Lett. 2001, 3, 3149e3152. 189. Reiter, M.; Turner, H.; Gouverneur, V. Chem.dEur. J. 2006, 12, 7190e 7203. 190. (a) Clarke, P. A.; Martin, W. H. C. Org. Lett. 2002, 4, 4527e4529; (b) Sabitha, G.; Reddy, G. S. K. K.; Rajkumar, M.; Yadav, J. S.; Ramakrishna, K. V. S.; Kunwar, A. C. Tetrahedron Lett. 2003, 44, 7455e7457; (c) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061e1063; (d) Clarke, P. A.; Martin, W. H. C.; Hargreaves, J. M.; Wilson, C.; Blake, A. J. Org. Biomol. Chem. 2005, 3, 3551e3563. 191. For a similar procedure, see: DiVirgilio, E. S.; Dugan, E. C.; Mulrooney, C. A.; Kozlowski, M. C. Org. Lett. 2007, 9, 385e388. 192. Clarke, P. A.; Martin, W. H. C. Tetrahedron 2005, 61, 5433e5438. 193. Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 3830e3831. 194. For a related process, see: Chemler, J. A.; Yan, Y.; Leonard, E.; Koffas, M. A. G. Org. Lett. 2007, 9, 1855e1858. 195. Hilli, F.; White, J. M.; Rizzacasa, M. A. Org. Lett. 2004, 6, 1289e1292. 196. (a) Jones, D. N.; Khan, M. A.; Mirza, S. M. Tetrahedron 1999, 55, 9933e9946; (b) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3, 3385e3387; (c) Kaye, P. T.; Nocanda, X. W. J. Chem. Soc., Perkin Trans. 1 2002, 1318e1323; (d) Kaye, P. T.; Musa, M. A.; Nocanda, X. W.; Robinson, R. S. Org. Biomol. Chem. 2003, 1, 1133e1138. 197. Ferna´ndez de la Pradilla, R.; Tortosa, M. Org. Lett. 2004, 6, 2157e2160.

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Biographical sketch

Igor Larrosa graduated from the University of Barcelona in 1999. In 2004, he completed his Ph.D. under the supervision of Dr. Fe`lix Urpı´ and Dr. Pedro Romea in the area of asymmetric C-glycosidation reactions and natural product synthesis. Subsequently, he became a postdoctoral research associate in Professor Anthony G. M. Barrett’s group at Imperial College London, where he carried out research on methodology development and its applications to natural product synthesis. In 2007, he was appointed as a lecturer at Queen Mary, University of London.

Pedro Romea completed his B.Sc. in Chemistry in 1984 at the University of Barcelona. That year, he joined the group of Professor Jaume Vilarrasa, at the University of Barcelona and received his Master’s Degree in 1985, and he followed Ph.D. studies in the same group from 1987 to 1991. Then, he joined the group of Professor Ian Paterson at the University of Cambridge (UK), where he participated in the total synthesis of oleandolide. Back to the University of Barcelona, he became Associate Professor in 1993. His research interests have focused on the development of new synthetic methodologies and their application to the stereoselective synthesis of naturally occurring molecular structures.

Fe`lix Urpı´ received his B.Sc. in Chemistry in 1980 at the University of Barcelona. In 1981, he joined the group of Professor Jaume Vilarrasa, at the University of Barcelona and received his Master’s Degree in 1981 and Ph.D. in 1988, where he was an Assistant Professor. He then worked as an NATO postdoctoral research associate in titanium enolate chemistry with Professor David A. Evans, at Harvard University at Boston. He moved back to the University of Barcelona and became Associate Professor in 1991. His research interests have focused on the development of new synthetic methodologies and their application to the stereoselective synthesis of naturally occurring molecular structures.