Synthetic Studies toward the Total Synthesis of Swinholide. 1. Stereoselective Construction of the C₁₉−C₃₅ Subunit

Abstract

The development of an approach directed at the total synthesis of the complex cytotoxic marine macrodiolide swinholide is described. The present study focuses on the development of a synthetic route for the preparation of the C 19 -C 35 segment of the structure, which is composed of a trisubstituted pyran moiety with a contrathermodynamic anti arrangement of the C 2 and C 6 pyran substituents (swinholide C 27 and C 31 ) which is joined by an ethano linker to an acyclic array containing five contiguous stereocenters. The pyran subunit was constructed using a stereoselective allylation of a β-alkoxy aldehyde with 1,3-asymmetric induction and a second stereoselective allylation to prepare the C-glycosidic type of linkage. Use of the Hafner-Duthaler reagent was investigated as a potential means of constructing the anti vicinal hydroxyl-methyl relationships found in the C 19 -C 24 segment but was found not to be practical in this instance. The Evans bis propionate methodology was used to introduce a four-carbon unit, and a Mukaiyama aldol was used for chain extension to incorporate the remaining two carbons and two stereocenters of this segment. Attempted use of the Hanessian benzylidene acetal fragmentation reaction in this sequence was thwarted by neighboring group participation of an oxazolidinone in one case and an unexpected regiochemical outcome in another. The approach developed affords the C 19 -C 35 substructure in 18 steps overall from ethyl acetoacetate and in adequate quantities (10% overall yield) to support the projected total synthesis.

Stereochemistry of Nucleophilic Substitution Reactions Depending upon Substituent: Evidence for Electrostatic Stabilization of Pseudoaxial Conformers of Oxocarbenium Ions by Heteroatom Substituents

“…As was observed in the C-4 systems, reactions of oxocarbenium ions substituted at C-3 with alkyl or alkoxy groups demonstrate divergent diastereoselectivity. Nucleophilic substitution on methyl-substituted acetal 24a provided the 1,3-trans product 26a with high selectivity, and the benzyloxy-substituted analogue 24b provided 1,3-cis product 25b with high selectivity (eq 8). The results can be explained by considering that a C-3 methyl-substituted cation favors the pseudoequatorial conformer 27 , while a benzyloxy-substituted cation prefers the pseudoaxial conformer 28 because of an electrostatic attraction between the cationic carbon 19,26 and the heteroatom substituent (Scheme ) .…”

“…Disubstituted Systems. While the experiments described here have focused on the influence of a single substituent on selectivity, oxocarbenium ions with several substituents should react with selectivities resulting from the aggregated influences of the substituents . An experiment was designed to measure the relative importance of the conformational preference of the oxocarbenium ion (the ground-state effect) and destabilizing steric interactions that emerge upon approach of the nucleophile (the transition-state effect).…”

Enantioselective Alcohol C–H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis

“… − Similarly, the C19–C27 stereo­heptet of rifa­mycin S , and the C19–C25 stereo­quintet of scyto­phycin C , (Figure ) could be assembled in a fraction of the steps previously required, representing formal syntheses of these compounds . Finally, using diol double crotyl­ation in combination with site-selective diol allyl­ation, a stereo­polyad common to the swin­holides − and numerous other type I polyketides, ,, including salini­ketal, reidi­spongi­olide, and premisa­kinolide, could be prepared in a relatively short number of steps, constituting a formal synthesis of the latter (Scheme ). …”

Stereoselective Synthesis of 1,3-Diols

“…This is exemplified by the enantioselective synthesis of b-hydroxyketones, 220 which is a vast field of ongoing research, or the application of [3+2] annulation to the stereoselective synthesis of five-membered-ring heterocycles, precursors of 1, Other methods might be restricted to special features of reagents or substrates, like the anti to syn transformation, observed by Keck and Lundquist, of benzylidene acetal 165 with N-bromosuccinimide due to neighboring-group participation of an oxazolidinone (Scheme 99). 222 Scheme 99 Transformation (anti to syn) of benzylidene acetal 165. 222…”