Asymmetric Synthesis of a Chiral Building Block for Cyclopentanoids:  A Novel Enantioselective Synthesis of Preclavulone A

Abstract

A new asymmetric approach to the hydroxylactone (+)-(3aR,4R,6aS)-4-(hydroxymethyl)-3a,4-dihydro-3H-cyclopenta[b]furan-2(6aH)-one (1), a key synthetic building block for cis-1,2-disubstituted five-membered ring derivatives (i.e., isoprostanes, jasmonates, and clavulones), has been described. A remarkable control of the absolute and relative configuration of the three stereocenters was achieved. Thus, the use of the Trost's asymmetric allylic alkylation strategy secured highly enantioenriched (R)-3-(nitromethyl)cyclopent-1-ene (13), which was smoothly converted to (R)-cyclopent-2-enecarboxylic acid (15) in excellent yield and high enantiomeric purity (>98% ee). 6-exo-trig atom-transfer radical cyclizations of ((R)-cyclopent-2-enyl)methyl 2-iodoacetate (12) produced exclusively the desired cis-fused delta-lactone (4aR,7aR)-hexahydro-5-iodocyclopenta[c]pyran-3(1H)-one (11), which was subsequently elaborated to hydroxylactone 1 through a stereocontrolled Pd(II)-mediated lactonization reaction. En route to preclavulone A, a putative elusive intermediate in the biosynthesis of clavulones, the synthetic utility of compound 1 was demonstrated. The key feature in this synthesis was the installation of the lower side chain via the Knochel organozinc sp3-sp C-C coupling protocol.

Synthesis of Chiral Cyclopentenones

“…The same research group has also demonstrated the insertion of the ω side chain by means of a one-pot/two-step Knochel organozinc sp 3 −sp C−C coupling protocol (Scheme 312). 597 Iodolactone 1314 was prepared by a 6-exo-trig atom-transfer radical cyclization with a strong preference for the formation of the cis-fused δ-lactone ring, whereas enantioselective formation of (+)-1294 was secured using the Trost asymmetric ligand in a Pd-induced lactonization (asymmetric allylic alkylation) of the corresponding sodium carboxylate. The ω side chain was installed using the sp 3 −sp C−C coupling based on Knochel organozinc chemistry through the coupling of the functionalized copper−zinc reagent with 1-bromoalkyne.…”

“…The α-chain was then attached, forming 1-ethoxyethyl ether (OEE)-protected olefin 1305 via a protected Weinreb This powerful and versatile strategy was also used by Vidari et al to achieve the first truly enantioselective synthesis of (8R,12R)-preclavulone A (Scheme 311). 596 The starting alkyl sulfone 1312 was prepared by Mitsunobu condensation of hydroxylactone (−)-1294, which is available in multigram amounts using an enantioselective organometallic approach 597 with bis(phenylsulfonyl) methane. The highly stereoselective Julia−Kocienski coupling of the lithio derivative of phenylsulfone with hexanal furnished stereodefined Z olefin 1313 in four steps in 76% yield.…”

Carbon–Carbon Bond Forming Reactions Mediated by Organozinc Reagents

“…Presumably, the reaction mechanism consists of a two-step sequence involving carbocupration of the alkyne followed by β-elimination of copper halide [115]. Regardless of this, the transformation is of synthetic utility Scheme 4.25 Cross-coupling of zinc-copper reagents and 1-haloalkynes [117].…”

“…as illustrated by its application in the context of the preparation of polyfunctional acetylenic ethers [116] and products of biological interest such as pheromones [115] and prostaglandins [117].…”

A New Approach to the Synthesis of Chiral Blocks for Cyclopentanoids

“…Let us note in this respect that syntheses of chiral lactone (+)-9 and its use for the synthesis of prostaglandin precursors and next of preclavulon A, isoprostanes, neuprostanes, etc. have been reported by Zanoni and Vidari [17][18][19][20].Tietze reports the labor-intensive chemoenzymatic synthesis of compound (+)-9 and (-)-9 [21], and his group used enantiomerically pure (+)-9 for synthesis of spinosyn A analogues [22]. For homologization of the γ-lactone fragment in δ-lactone compounds, 2 were tested in a thermal ring-opening reaction with the cyanide ion.…”