Polyether antibiotic synthesis

Several groups of workers have been occupied with the synthesis of spiro-ketals and polyoxa-polyspiro-alkanes. The hetero Diels-Alder reaction between furanoid or pyranoid exocyclic vinyl ethers and acrolein established the spiro-ketal systems (76) and (77). Oxidative ring-contraction led to 1,6-dioxaspiro-alkane carboxylic acids (Scheme 9), which are useful subunits for polyether antibiotic synthesis. Phillips and his co-workers have tackled the problem using... 

It would be difficult to overestimate the role that the polyether antibiotics have played in the development of organic synthesis, particularly in the area of acyclic stereocontrol. These molecules have inspired many spectacular achievements in organic synthesis, achievements that have dramatically expanded the power and scope of the science. In fact, it would not be inaccurate to attribute much of our understanding about the factors controlling acyclic stereoselectivity for such fundamental processes as hydroboration,5 epox-... 

Similar 5-exo cyclization procedures have been widely utilized by Evans in his total syntheses of complex natural compounds, such as the synthesis of ionomycin [12a] and polyether antibiotic X-206 [12b]. A 5-exo cyclization of a y-epoxy alcohol has also been observed under basic conditions [12c]. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

Functionalization of various substrates to produce oxygenated compounds with high selectivity is a permanent challenge in metal-catalyzed organic synthesis. Most of these products present interesting biological properties. For instance polyether antibiotics contain often a furan or a pyran ring [1]. Simi-... 

Highly substituted 2,3-dihydrofurans 44 (Scheme 1.3.18) would make particularly interesting starting materials for the asymmetric synthesis of tetrahydrofu-rans, structural motifs which can be found in many important natural products, including polyether antibiotics, lignans, and nucleosides [30]. Not only the activated double bond but also the vinylic silyl group of 44 should allow useful synthetic transformations. 

Total Synthesis of Polyether Antibiotics Y. Kishi and T. Nakata, Kagaku Sosetsu, 1981, 31, 243-260. 

The advent of the polyether antibiotics with the challenging aspect of stereocontrolled construction of the substituted tetrahydrofuran units has greatly extended the chemistry of this oxygen heterocycle. The nonactins (194), lasalocid A (195) and monensin (196) are among the ionophores for which syntheses have been achieved. Detailed reviews on synthesis of reduced furans are available (65HOU(6/3)l, 80H(14)1825). 

An improved procedure for cyclopalladation-carbonylation (of e.g. 320) relies on the addition of CuCl and LiCl to the standard PdCl2-CuCl2 mixture. This indicates that both the Cu2+ and Cu+ are required in sufficient concentrations to keep up the cascade of the catalytic cycle. This method is superior to the Hg(II)-mediated cyclization followed by transmetallation with Pd in CO/MeOH197. For application in the synthesis of polyether antibiotics, see elsewhere435. 

The masked tetrahydroxyketone 28 (Fig. 7) which can theoretically give isomers 29 and 30, was found to yield isomer 29 exclusively (26). The structure of 29 was proven by X-ray analysis. Similarly, dibromodihydroxyketone 31 can give either isomer 32 or 33. Upon cyclization, isomer 32 was the product formed (27) and its structure was also established by X-ray (28). The recently reported total synthesis of ionophore A-23187 (29), a polyether antibiotic whih possesses the 1,7-dioxaspiro[5.5]undecane skeleton having a conformation equivalent to 29 and 32 confirms these results. 

In his synthesis of the polyether antibiotic X-506, Evans4 needed the triol 20 with two of the OH groups protected. He added an allyl group as a nucleophile to open the epoxide 17 at the less hindered end and then protected the two OH groups as an acetal 19 before the third was introduced by ozonolysis and reduction. These two examples emphasise the versatility of the allyl group. 

The hydroboration/oxidation depicted below was used in the initial stages of the first synthesis of the polyether antibiotic lysocellin. Explain carefully the chemical and stereochemical outcome of the transformation. 

Allylic alcohols may also be formed from their corresponding halides by reaction with either peracids222 or potassium superoxide and a crown ether223. This latter methodology has been used in the synthesis of a polyether antibiotic, containing an allylic alcohol and a spiroacetal, where other methods have failed223. During allylic halide conversion, allylic... 

Tetr 39 2323 (1983) (Recent Advances in the Preparation and Synthetic Applications of Oxiranes) 43 3309 (1987) (Synthetic Routes to Tetrahydrofiiran, Tetrahydropyran, and Spiroketal Units of Polyether Antibiotics and a Survey of Spiroketals of Other Natural Products) 50 8885 (1994) (Chemical and Biological Synthesis of Chiral Epoxides)... 

The high diastereoselectivity attending the spirocyclisation of ketene dithioacetals provides an effective means for controlling the stereochemistry of a methyl substituent at the a-position on a 6-lactone ring,244 The method was applied to the synthesis of the polyether antibiotic Salinomycin [Scheme 2.120].242 Condensation of the methyl ketone 120 1 with the lithiated l,3-dithian-2-yl-phospho-nic acid diethyl ester 120.2 gave the ketene dithioacetal 1203 in 76% yield. After hydrolysis of the two benzoate ester groups, cyclisation of diol 120.4 was... 

Triphenylsilyl ethers are similar in lability to TMS ethers toward basic hydrolysis but they are about 400 times more stable than TMS ethers towards acid hydrolysis. A triphenylsilyl ether group played an important strategic role in the finale of a synthesis of the polyether antibiotic Lonomycin A [Scheme 4.96],154 Model studies of the directed aldol reaction by which the lithium enolate 96.1... 

During a synthesis of the polyether antibiotic X-206. Evans and co-workers503 accomplished the protection of a hindered secondary alcohol with benzyl bro momethyl ether (BOMBr) in the presence of proton sponge [l,8-bis(dimethyl-amino )naphthalene], without racemising the two stereogenic centres adjacent to the ketone function [Scheme 4.281],... 

Synthesis of tetrahydrofuran, tetrahydropyran, and spiroketal units of polyether antibiotics 87T3309. 

Bromoetherification, the addition of the elements of Br and OR to a double bond, is a common method for constructing rings containing oxygen atoms. This reaction has been used in the synthesis of the polyether antibiotic monensin (Problem 21.40). Draw a stepwise mechanism for the following intramolecular bromoetherification reaction. 

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