Efficient Asymmetric Synthesis of Long‐Chain Polyketides Containing up to Ten Contiguous Stereogenic Centres by Double Chain Elongation

Abstract

The 2,3-anti-3,4-syn-stereotriad (1Z,2S,3R,4S)-1-ethylidene-2,4-dimethyl-3-[(1S)-1-phenylethoxy]-5-oxopent-1-yl isobutyrate {(-)-8, obtained in a one-pot operation from the trimethylsilyl (Z)-enol ether derived from pentan-3-one and (1E,3Z)-1[(1S)-phenylethoxy]-2-methylpenta-1,3-dien-3-yl isobutyrate through SO 2 umpolung} contains an ethyl ketone moiety that undergoes diastereoselective cross-aldol reactions with acetaldehyde. After subsequent reductions, various diastereomeric stereohexads (polypropionate fragments containing six contiguous stereogenic centres) in which the

Polypropionate Synthesis via Substrate‐Controlled Stereoselective Aldol Couplings of Chiral Fragments

“…In contrast to the selective formation of the 1,3-syn-1,1 -syn adduct syn-9ss from addition of i-PrCHO to syn-(Z)-8a [M = B or Ti(IV)] (Scheme 6.6), the analogous lithium enolates syn-(Z)-8a [ML n = Li] gave the 1,3-anti-1,1 -syn adduct syn-9as with low to moderate diastereoselectivity depending on the protecting group at C4 [47,48] (Scheme 6.7). Similar results were observed with related lithium (Z)-enolates [41,43,45]. In all cases, the 1,1 -syn adducts were predominant as expected for …”

“…Similar reactions of (E)-enol dicyclohexylborinates syn-(E)-8 or anti-(E)-8 [ML n = B(c-Hex) 2 ] produced the corresponding 1,3-syn-1,1 -anti adducts syn-9sa and anti-9sa, respectively, with excellent selectivities [39]. Other researchers have reported comparable results using related substrates [40] including those with benzyl-type protecting groups at C4 [41][42][43] and in reactions with enals [22c, 44]. Low (e.g., 1,3-syn/1,3-anti adducts, 2 : 1) [45] or even reverse diastereoface selectivities (e.g., 1,3-anti/1,3-syn adducts, >12 : 1) [46] have been observed with a few closely related enolates that incorporate a cyclic protecting group on a β,δ-diol moiety.…”

“…Interestingly, the BF 3 ·OEt 2 -promoted Mukaiyama reaction of i-PrCHO with syn-(Z)-8 [ML n = SiMe 3 ] also resulted in highly diastereoselective addition to the enolate to produce 1,3-anti adducts (1,3-anti/1,3-syn adducts, 19 : 1) but with poorly selective relative topicity (syn-9as/syn-9aa, 1.5 : 1) [25]. Similar enolate diastereoface selectivity has been reported in a number of related examples [43,49,50] often with more selective relative topicity (1,1 -syn/1,1 -anti adducts, up to 6 : 1). In analogy to syn-(E)-8a [ML n = B(c-Hex) 2 ], reaction of syn-(E)-8a [M = Li] with i-PrCHO gave the 1,3-syn-1,1 -anti adduct syn-9sa preferentially but with much lower enolate diastereoface selectivity (1,3-syn/1,3-anti adducts, <4 : 1) and less selective relative topicity (1,1 -anti/1,1 -syn adducts, about 5 : 1) [48] (Scheme 6.7).…”

Exploiting Hidden Symmetry in Natural Products: Total Syntheses of Amphidinolides C and F

“…Removal of the benzoate ester in presence of the pivaloate (Piv) moiety was problematic. Fortunately, we found that treatment with modulated methyl lithium (MeLi•LiBr) 34 provided conditions that selectively cleaved the benzoate moiety to reveal the in situ enolate 37 which was protonated with aqueous ammonium chloride to provide the common intermediate 20 . A small amount of the pivaloate deprotected product (≈10%) was observed under these conditions; however, use of MeLi instead of MeLi•LiBr led to significantly larger amount of depivaloated product.…”

Stereodivergent routes in organic synthesis: marine natural products, lactones, other natural products, heterocycles and unnatural compounds

“…Polypropionates contain alternatively methyl-and hydroxy-substituents in alkyl chains are found in several natural products. 122 Vogel and co-workers 123 have reported diastereodivergent routes to long-chain polyketides. Thus, starting from (1Z,2S,3R,4S)-1-ethylidene-2.4-dimethyl-3-[(1S)-1-phenylethoxy-5oxohept-1-yl] isobutyrate, an anti,syn-stereotriad ?NO ENTIENDO, REVISAR FRASE?, by an aldol reaction with acetaldehyde using Peterson's method gave, after borate oxidation, mainly the corresponding anti-aldol (Scheme 78).…”