Natural polypropionate

Hydroxy-8-lactone such as 209 constitutes the structural motif of natural polypropionates and an intermediate in the step-by-step biosynthesis of these compounds. As shown in Scheme 22.34, 209 is readily obtained by diaster-eoselective reduction of ketone 202, followed by ozonolysis of its enol ester moiety. ... 

Rodriguez, J., Riguera, R., and Debitus, C. (1992a) The natural polypropionate-derived esters of the mollusc Onchidium sp. J. Org. Chem., 57, 4624-4632. 

This highly convergent synthesis amply demonstrates the utility of Evans s asymmetric aldol and alkylation methodology for the synthesis of polypropionate-derived natural products. By virtue of the molecular complexity and pronounced lability of cytovaricin, this synthesis ranks among the most outstanding synthetic achievements in the macrolide field. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

Tridachiahydropyrone belongs to the family of marine polypropionates [69]. Efforts towards its total synthesis have recently led to a revision of the structure with the new proposal 2-147 [70]. The construction of the highly substituted cyclohex-enone moiety 2-146 which could be incorporated into this natural product [71] has been described by Perkins and coworkers (Scheme 2.33) [70, 72]. The conjugate addition/ Dieckmann-type cydization utilizing organocopper species as Michael donors afforded the enantiopure 2-145 in 68% yield. A further methylation of the (3-ketoester moiety in 2-145 followed by an elimination led to the desired cydohex-enone 2-146. 

The addition of an enolsilane to an aldehyde, commonly referred to as the Mukaiyama aldol reaction, is readily promoted by Lewis acids and has been the subject of intense interest in the field of chiral Lewis acid catalysis. Copper-based Lewis acids have been applied to this process in an attempt to generate polyacetate and polypropionate synthons for natural product synthesis. Although the considerable Lewis acidity of many of these complexes is more than sufficient to activate a broad range of aldehydes, high selectivities have been observed predominantly with substrates capable of two-point coordination to the metal. Of these, benzy-loxyacetaldehyde and pyruvate esters have been most successful. 

In 1997 (-)-callystatin A (Fig. 1.2.2), a potent cytotoxic polyketide, was isolated from the marine sponge Callyspongia truncata and structurally elucidated by Ko-bayashi et al. [20] shortly afterward its absolute configuration was confirmed by the same authors by total synthesis [21]. The structure of (-)-callystatin A shows a polypropionate chain and a lactone ring connected to each other by two diene systems separated by two sp carbon atoms (Fig. 1.2.2). Since this arrangement is structurally related to several antitumor antibiotics and due to the fact that only very small amounts can be isolated from natural sources, callistatin A has been... 

Brecknell, D. D., Collett, L., Davies-Coleman, M. T., Jones, D. D., and Garson, M. J., New noncontiguous polypropionates from marine molluscs a comment on their natural product status, Tetrahedron, 56, 2497, 2000. 

Yamamoto has also investigated the use of 1 and 2 with racemic aldehydes such as 5 in a series of addition reactions (Eq. (8.2)). The chiral enolate participates in aldol additions to afford a mixture of anti- and yn-products 6 and 7 in which the aldehyde facial selectivity has been determined in large part by the overriding bias of the auxiliary. Thus the process offers great promise for the construction of stereochemically complex, densely functionalized fragments common in numerous polypropionate-derived natural products. 

Aldol reactions using chiral auxiliaries are popular as the stereochemical outcome is usually highly predictable and, as such, they provide a reliable method for the incorporation of adjacent stereocenters. The oxazolidinone-based imides 36 and (ent)-36 are the most commonly employed, and these lead to syn aldol products with high levels of stereocontrol [20]. The reaction can be extended to include a variety of a-heteroatom functionality as in 37 (Scheme 9-13) [21]. Numerous examples of the use of these auxiliaries in the synthesis of polypropionate natural products have been reported. Many related auxiliaries are also available and the camphor-based sultam 38 is notable [22]. 

Rutamydns. Rutamycins A (137) and B (138) are 26-membered macrolide antibiotics isolated from Streptomyces cultures (Scheme 9-43). They are closely related to the oligomycin family of natural products and more distantly to the 22-membered cytovaricin. Each of these macrocycles consists of a highly functionalized spiroacetal unit bridged by a polypropionate-derived chain. In the rutamycins, the asymmetric aldol reaction could be envisaged to play a key role in assembling the spiroacetal portion and the C4-C]4 polypropionate sector with various strategic disconnections possible. 

The reaction of carbonyl compounds and allylmetal reagents is an important transformation in organic synthesis. Advances in stereoselective carbonyl allylation reactions have been spurred by interest in the synthesis of polypropionate-derived natural products, carbohydrates and other polyhydroxylated compounds. These reactions are ideally suited for the construction of stereochemically rich acyclic skeletons. Additionally, cyclic polyether-containing natural products, among others, have inspired chemists to investigate ring-closing allylation reactions. This review will focus on recent developments in the allylation reaction, with special emphasis on its application towards the synthesis of natural products. 

Panek and co-workers have demonstrated that crotylsilanes 217 and 343 react with a variety of electrophiles including aldehydes, a, ff-unsaturated ketones, acetals and imines under appropriate activation conditions (usually Lewis acidic) to form homoallylic ethers [149, 261], homoallylic alcohols [58, 150, 151], tetrahy-drofurans [262, 263], cyclopentanes [264], pyrrolidines and homoallylic amines [265] with high levels of enantio- and diastereoselectivity [12]. This review will focus on the reactions of crotylsilanes 217 with Lewis acid-activated acetals and aldehydes, and the application of these reactions to the synthesis of polypropionate natural products [266-271]. 

Stereochemical problems associated with the synthesis of polypropionate-derived natural products. 

Marshall s chiral allenylmetal reagents have been utilized in double asymmetric reactions with chiral aldehydes for the synthesis of polypropionate natural products. All four dipropionate diastereomers are accessible from the reactions of chiral allenylmetal reagents with a-chiraI-y5-alkoxy aldehydes 97 (153, 158, 276, 277]. The BF3-OEt2-catalyzed addition of allylstannane (l )-218a to aldehyde 97a occurs in high yield and diastereoselectivity to give the xyn.syn-dipropionate 395, presumably through either the synclinal or antiperiplanar Felkin transition states 396 and 397 (Eq. (11.31)). 

Allyl epoxides are produced by the acclaimed Sharpless asymmetric epoxidation reaction [75], and are important intermediates and products. For example, an allyl epoxide is a vital part of the structure of amphidinolides, a series of unique macrolides isolated from dinoflagellates (Amphidinium sp.). Amphidinolide H (AmpH) is a potent cytotoxic 26-membered macrolide with potent cytotoxicity for several carcinoma cell lines [76]. An allyl epoxide is involved in the total synthesis of prostaglandin A2 with a cuprate reagent [77]. Allyl epoxides derived from Sharpless chemistry are a practical method for construction of polypropionate structures by Lewis acid-induced rearrangement [78,79]. Other allyl epoxides such as l,2-epoxy-3-methyl-3-butanol are useful organic intermediates for the production of a-hydroxyketones, which are used for the synthesis of various natural... 

Several naturally-occurring pyranone-based polypropionates have been synthesised from pyran-4-ones <05CC1687, 05OL641, 05OL819, 05OL2837> and an enantiopure cyclohexadiene-fused pyran-4-one analogous to one of these has been synthesised <050L407>. An enantioselective synthesis of (-t-)-candelalide has been described... 

We have already collected some powerful tools for use in stereocontrolled aldol reactions, but we have not finished. We shall see now in Paterson s synthesis of (+)-discodermolide, how reagent control is used not to enhance the intrinsic substrate selectivity, but to overturn it. The aldol reaction is undoubtedly one of the most powerful ways of making carbon-carbon bonds and nature thinks so too. There are numerous natural products that are replete with 1,3 related oxygen functionality. Many of these are acetate or propionate-derived in nature. The methods detailed above developed from studies into the syntheses of these natural products. The manipulations of chiral ethyl ketones of this kind are of particular interest when it comes to natural products that are polypropionate-derived. 

Stereoselective anti-aldol reactions. As part of a synthesis of polypropionate natural products, Evans et al. have studied the stereoselectivity of the reaction of isobutyraldehyde with the chiral /3-kctoimide la, which has been shown to undergo syn-sclectivc aldol reactions.4 Surprisingly, the (E)-boron cnolatc, generated in ether from dicyclohexylchloroborane and ethyldimcthylaminc, reacts with isobutyraldehyde to give the anti, am/-aldol 2 and the syn, anri-aldol 2 in the ratio 84 16. Similar diastereoselectivity obtains with the reaction of the isomeric /3-kctoimide lb. 

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