Abstract
An asymmetric synthesis of (-)-6,7-dideoxysqualestatin H5 is reported. Key features of the synthesis include the following: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a β-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalyzed cyclic carbonyl ylide formation-cycloaddition by co-generation of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalyzed Csp3-Csp2 cross-electrophile coupling between tricarboxylate core and unsaturated side chain to complete the natural product.
Highlights
(1, Scheme 1), the zaragozic acids/squalestatins have been the focus of considerable interest ever since reports of their isolation appeared in the early 1990s.1 Potent mammalian squalene synthase inhibition originally propelled these natural products into the limelight as lead structures for cholesterollowering therapeutics.[2]
We report the advancement of this chemistry to a synthesis of (−)-6,7dideoxysqualestatin H5 (2).[11]
Seebach reported that the limited stability of the lithium enolate of tartrate acetonide 11 restricted feasible alkylation to reactive halides (∼85:15 drs),[15] we have found that n-alkyl iodides can be successfully induced to react under prolonged reaction times at low temperature and with improved diastereoselectivity
Summary
Letter desired regio- and stereochemical induction for squalestatin synthesis, as anticipated from our previous model study.[9]. A total synthesis of the natural product (−)-6,7dideoxysqualestatin H5 (2) was completed starting from the bulk chemical isoprenol (12); the 16-step sequence compares favorably with Martin’s previous 14- and 17-step routes.8c Noteworthy features include improvement in alkylation scope and stereochemical efficiency from the enolate of a commercially available tartrate acetonide 11, leading to a new entry to the β-hydroxy-α-ketoester motif in an asymmetric manner. A late-stage ester and alcohol functional group-tolerant Ni-catalyzed Mn-mediated Csp3−Csp[2] crosselectrophile coupling involving equimolar quantities of the halide partners and occurring at room temperature with geometrical integrity at the internal alkenyl halide demonstrates the utility of this emerging technology in complex natural product synthesis.
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