Total Synthesis of the Polyene-Polyol Macrolide RK-397, Featuring Cross-Couplings of Alkynylepoxide Modules

Burova, Svetlana A.; McDonald, Frank E.

doi:10.1021/ja039618+

Cited by 89 publications

(37 citation statements)

References 30 publications

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“…Reactions were carried out in accord with safe laboratory practices (26). New compounds were characterized by 1 H NMR, 13 C NMR, and IR spectroscopy and by MS or elemental analysis.…”

Section: Methodsmentioning

confidence: 99%

“…We set out to develop a unified synthetic strategy that is flexible enough to be applied to any member of the class. Polyene macrolides are of interest to synthetic chemists (13)(14)(15), and we recently reported the synthesis of the rimocidin aglycone (16). Herein is described a generalization of the strategy that is illustrated with syntheses of nystatin and candidin polyols and of the protected candidin aglycon 34.…”

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confidence: 99%

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A unified approach to polyene macrolides: Synthesis of candidin and nystatin polyols

Kadota

Packard

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Polyene macrolide antibiotics are naturally occurring antifungal agents. Members of this class include amphotericin B, which has been used widely to treat systemic fungal infections. A general synthetic strategy has been devised to prepare polyol chains associated with the polyene macrolides. Cyanohydrin acetonide alkylations were used to assemble the carbon skeleton, and a simple modification of the strategy allowed an advanced intermediate to be converted to either the candidin polyol or the nystatin polyol. The candidin polyol was further elaborated to a protected candidin aglycone. This strategy will be applicable to other members of the polyene macrolide natural products.T he mycosamine-containing polyene macrolides are clinically important antifungal agents. Amphotericin B (1) is the most prominent member of this class (2, 3) which includes rimocidin (1) (4), nystatin (2) (5), candidin (3) (6), and others (7). The synthesis of amphotericin B has been the subject of extensive investigation (8)(9)(10)(11)(12). In general, the antifungal activity of these polyenes has been attributed to their assembly into ion channels in the presence of sterol-containing membranes (2, 3). A flexible synthetic route into these compounds would allow the structural basis of this interesting self-assembly phenomenon to be explored systematically.An obvious stereochemical relationship exists between these polyene macrolides (Fig. 1). The substitution and configuration of the hemiacetal ring and of the adjacent stereogenic centers are conserved throughout the members of the class. We set out to develop a unified synthetic strategy that is flexible enough to be applied to any member of the class. Polyene macrolides are of interest to synthetic chemists (13-15), and we recently reported the synthesis of the rimocidin aglycone (16). Herein is described a generalization of the strategy that is illustrated with syntheses of nystatin and candidin polyols and of the protected candidin aglycon 34.The hemiacetal ring found in each of these polyenes would arise from the protected segment 4, where the C13 ketone is masked as a cyanohydrin. The cyanohydrin group enables the key bond disconnection between cyanohydrin acetonide 6 and alkylating agent 5, which incorporates all the stereogenic centers in the hemiacetal ring. The R group in 4 would include part or all of the remaining polyol chain. Cyanohydrins are well established as acyl anion equivalents (17, 18), as are dithiane anions (19-22). However, cyanohydrin acetonides have several important advantages over simple cyanohydrins or dithianes. We have shown that they alkylate to give the axial nitrile (e.g., 4) with high diastereoselectivity (23-25), rather than the mixtures commonly found with simple cyanohydrins. They are also easier to deprotonate than dithianes, the anions are excellent nucleophiles, and they can be deprotected under very mild conditions (25). These features make a cyanohydrin acetonide disconnection a very powerful strategy for convergent synthesis. Materials and Meth...

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“…Reactions were carried out in accord with safe laboratory practices (26). New compounds were characterized by 1 H NMR, 13 C NMR, and IR spectroscopy and by MS or elemental analysis.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

A unified approach to polyene macrolides: Synthesis of candidin and nystatin polyols

Kadota

Packard

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the aldol addition reaction has found widespread application in the synthesis of linear acyclic polyol structures, it is certainly not the only method available. Other transformations, such as allylations, [3] alkylations of 4-cyano-1,3-dioxanes, [4] and nucleophilic epoxide-opening reactions of epoxyalkynols, [5] have also been developed as viable alternatives to the aldol reaction.…”

Section: Introductionmentioning

confidence: 99%

Catalytic, Enantioselective, Vinylogous Aldol Reactions

Denmark¹,

Heemstra²,

Beutner³

2005

Angew Chem Int Ed

447

149

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In 1935, R. C. Fuson formulated the principle of vinylogy to explain how the influence of a functional group may be felt at a distant point in the molecule when this position is connected by conjugated double-bond linkages to the group. In polar reactions, this concept allows the extension of the electrophilic or nucleophilic character of a functional group through the pi system of a carbon-carbon double bond. This vinylogous extension has been applied to the aldol reaction by employing "extended" dienol ethers derived from gamma-enolizable alpha,beta-unsaturated carbonyl compounds. Since 1994, several methods for the catalytic, enantioselective, vinylogous aldol reaction have appeared, with which varying degrees of regio- (site), enantio-, and diastereoselectivity can be attained. In this Review, the current scope and limitations of this transformation, as well as its application in natural product synthesis, are discussed.

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“…For the synthesis of the key intermediate 16 two building blocks were required: 1) the Grignard reagent 17, [14] available from (3R,7R)-hexahydrofarnesol 18, [15] and 2) the allyl epoxide 19, which was accessible from commercially available (R)-epichlorohydrin. [16] The reaction between 17 and 19, catalyzed by lithium cuprate, [17][18] gave the alcohol 16 in 80 % yield and 97 % de (diastereomeric excess), determined on the corresponding p-nitrobenzoate. Unlike in cases of tertiary alcohols [14] the Mitsunobu reaction between the non-activated 16 and the phenol 14 proceeded readily and gave the phenol ether 20 in 60 % yield with complete inversion of configuration.…”

Section: Synthesis Of Nor-a-tocopherolmentioning

confidence: 99%

Asymmetric Synthesis and Biological Activity of nor‐α‐Tocopherol, a New Vitamin E Analogue

et al. 2010

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Total Synthesis of the Polyene-Polyol Macrolide RK-397, Featuring Cross-Couplings of Alkynylepoxide Modules

Cited by 89 publications

References 30 publications

A unified approach to polyene macrolides: Synthesis of candidin and nystatin polyols

A unified approach to polyene macrolides: Synthesis of candidin and nystatin polyols

Catalytic, Enantioselective, Vinylogous Aldol Reactions

Asymmetric Synthesis and Biological Activity of nor‐α‐Tocopherol, a New Vitamin E Analogue

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