Polyol, 1,3-skipped

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Leighton and coworkers [217] have also used this approach to develop efficient strategies for the synthesis of polyketide-derived natural products [218]. A main motif of these compounds is a skipped polyol structure, as in 6/2-94 this can easily be prepared by a novel Rh-catalyzed domino reaction of a diallylsilyl ether in the presence of CO, followed by a Tamao oxidation [219]. Thus, reaction of, for example, the silane 6/2-93, which is readily prepared from the corresponding ho-... 

The natural products Mycoticin A (22, R = H) and B (22, R = Me) belong to the skipped-polyol-polyene class of antibiotics. Our analytical interest here is to use this very complex molecular structure to demonstrate some of the tools employed, mainly for the elucidation of the polyene part of the molecule. This family of polyene macrolide class was discovered in 195045 with the finding of Nystatin (23), which is produced by the Streptomyces bacteria. The exact structure was elucidated only in 1970 by Chong and Rickards46 and, in 1971, Nystatin Ai (23) and A2 (not shown in this review) were separated. 

The tandem silylformylation/allylsilylation reaction is particularly well suited to the synthesis of skipped polyol motifs such as are found in the oxopolyene macroHdes. The synthesis of protected triol 43 (an intermediate in the mycoticin A formal synthesis described above see Scheme 5.18) relied on an application of this methodology. Thus, homoallylic alcohol 76 was transformed into triol 77 in 55% overall yield and >10 1 diastereoselectivity (Scheme 5.27) [23]. Selective protection of the triol to give 43... 

Carreira and co-workers have also extended the scope of aldehydes that may be utilized in catalytic addition reactions to include stannylpropenal 108 as a substrate (Table 8B2.12, Entry 7). The adduct produced from the aldol addition of 105 is isolated with 92% ee and serves as a useful building block, as it is amenable for further synthetic elaboration (Scheme 8B2.9). Thus, vinylstannane 109 is a substrate for Stille cross-coupling reactions to give a diverse family of protected acetoacetate adducts 110. Following deprotection of the masked keto ester, the corresponding hydroxy keto ester 111 may be converted to either the syn or anti skipped polyols 112 or 113. A recent total synthesis of macrolactin A by Carreira and co-workers utilizes aldol... 

TTie nonracemic secondary ethers (58) and (60) rearrange with over 90% retention of stereochemistry at the migrating center (equations 16 and 17). A lithium-bridged diradical species (63 Scheme 2) is postulated to account for the observed diastereoselectivity. Recombination of the radical pair must occur more rapidly than inversion of the radical center, judging from the high degree of retention observed with (58) and (60). A two-directional application of this rearrangement was used to prepare the syn-skipped polyols (66) and (68 Scheme 3). 

Scialdone, M.A., and Johnson, C.R., Building blocks for skipped polyols, syn-1,3-Acetonides by chemoenzymatic synthesis from cycloheptatriene. Tetrahedron Lett., 36, 43, 1995. 

The stereoselective reduction of / -hydroxy ketones provides a general, reliable approach for the synthesis of 1,3-diols, or skipped polyols. Methods that afford complementary stereochemical outcome with the formation of both 1,3-syn and 1,3-anti diols have been developed (Scheme 2.15). 

The power of Noyori s Ru -BINAP system in ketone reductions has been amply demonstrated in numerous complex molecule syntheses. Schreiber, for example, has disclosed a route to the macrolide antibiotic mycoticin A (221, Scheme 2.27) [139] that relies on a strategy involving two-directional chain synthesis [140]. Catalytic asymmetric reduction of diketone 216 affords the C2-symmetric diol 217. Conversion of 217 into bis(ketoester) 218 then allows double ketone reduction to furnish 219, which was subsequently elaborated into the skipped polyol chain 220 of mycoticin A (221). 

The Sharpless asymmetric epoxidation reaction has been utilized widely in total syntheses. Nicolaou investigated the combination of a Sharpless asymmetric epoxidation with a regioselective reduction of the resulting epoxide in an iterative manner as a general means to synthesize 1,3-skipped polyols [80]. The strategy was put into practice in the total synthesis of the antifungal agent amphotericin B (64, Scheme 9.7) [81]. 

C9 fragment of the lichen marcolactone (+)-aspicillin [143]. A FraA-mediated stereoselective addition also served as the key step in the synthesis of the noncarbohydrate, skipped polyol C9-C16 fragment 82 of the macrolide antibiotic pentamycin [144,145],... 

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