Synthesis of macrocycles by intramolecular ketophosphonate reactions. Stereoselective construction of the "left-wing" of carbomycin B and a synthesis of dl-muscone from oleic acid

Nicolaou, K. C.; Seitz, Steven P.; Pavia, Michael R.; Petasis, Nicos A.

doi:10.1021/jo01336a069

Cited by 110 publications

(35 citation statements)

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“…Deprotection and oxidation of the C1 benzyl ether gave acid 32, which was coupled with alcohol 30 under Yamaguchi conditions (38). Macrolide formation was realized by using K 2 CO 3 and 18-crown-6 in PhCH 3 at 23°C (39,40). Higher temperatures led to partial epimerization at C16, and LiCl͞DBU conditions (41) led to decomposition.…”

Section: Resultsmentioning

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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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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Section: Resultsmentioning

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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“…Reaction of alcohol 20 with PBr 3 afforded the corresponding allylic bromide, [16] which was directly used in the next step without any further purification due to its instability. First, of the different attempts used to remove the secondary TBS ether by using standard methods, [17] only the action of HF·pyridine complex [18] in THF at 40 8C cleanly afforded the monodeprotected derivative 22 in 79 % yield. To complete the synthesis of kopeolin (1), we needed to simultaneously remove both TBS protecting groups.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, coupling of the potassium salt of umbelliferone and the crude allylic bromide in acetone yielded coumarin derivative 21 in 70 % yield over two steps. Fortunately, after extensive screening of several deprotection conditions, desilylation was accomplished with KF in the presence of [18]crown-6 in DMSO at 125 8C. The use of several fluorine sources (TBAF, aq.…”

Section: Resultsmentioning

confidence: 99%

Enantioselective Syntheses of the Proposed Structures of Kopeolin and Kopeolone

Miquet

Vanthuyne

Brémond

et al. 2013

Chemistry A European J

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The first total syntheses of the proposed structures of kopeolin (1) and kopeolone (3) have been achieved from a common enantiopure chiral building block obtained by a chemoenzymatic enantioconvergent methodology. The syntheses feature two key steps: a one-pot reduction/diastereoselective protonation followed by a highly diastereoselective addition of an organocerate. The synthetic structures were fully characterized and all stereocenters were confirmed. The results show that the two previously reported structures were not assigned correctly, and suggest an initial structural misassignment during the isolation of the natural products. Thus, two revised structures, 1' for kopeolin and 3' for kopeolone, are proposed.

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“…This strategy had been previously developed and deployed by us11 and by others,12 but this application remains to this day one of the most, if not the most, demanding tests of this macrocyclization technique. Pleasantly, the yellow-colored ketophosphonate 1 9 was converted into red/orange-colored 38-membered macrocycle 20 in 70% yield upon exposure to mildly basic conditions.…”

Section: Amphotericin Bmentioning

confidence: 99%

From nature to the laboratory and into the clinic

Nicolaou

Chen

Dalby

2009

Bioorganic & Medicinal Chemistry

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Natural products possess a broad diversity of structure and function, and they provide inspiration for chemistry, biology, and medicine. In this review article, we highlight and place in context our laboratory's total syntheses of, and related studies on, complex secondary metabolites that were clinically important drugs, or have since been developed into useful medicines, namely amphotericin B (1, Figure 1), calicheamicin γ 1 I (2), rapamycin (3), Taxol® (4), the epothilones [e.g. epothilones A (5) and B (6)], and vancomycin (7). We also briefly highlight our research with other selected inspirational natural products possessing interesting biological activities [i.e. dynemicin A (8, Figure 2), uncialamycin (9), eleutherobin (10), sarcodictyin A (11), azaspiracid-1 (12), thiostrepton (13), abyssomicin C (14), platensimycin (15), platencin (16), and palmerolide A (17)].

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Synthesis of macrocycles by intramolecular ketophosphonate reactions. Stereoselective construction of the "left-wing" of carbomycin B and a synthesis of dl-muscone from oleic acid

Abstract: Aus Ölsäuremethylester erhält man durch Ozonolyse den Aldehydester (Ia), der in die Derivate (Ib)‐(Id) übergeführt wird.

Cited by 110 publications

References 1 publication

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

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

Enantioselective Syntheses of the Proposed Structures of Kopeolin and Kopeolone

From nature to the laboratory and into the clinic

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