Hydroformylation polyketide synthesis

The approach to polyketide synthesis described in Scheme 5.2 requires the relatively nontrivial synthesis of acid-sensitive enol acetals 1. An alternative can be envisioned wherein hemiacetals derived from homoallylic alcohols and aldehydes undergo dia-stereoselective oxymercuration. Transmetallation to rhodium could then intercept the hydroformylation pathway and lead to formylation to produce aldehydes 2. This proposal has been reduced to practice as shown in Scheme 5.6. For example, Yb(OTf)3-cata-lyzed oxymercuration of the illustrated homoallyhc alcohol provided organomercurial 14 [6]. Rhodium(l)-catalyzed hydroformylation of 14 proved successful, giving aldehyde 15, but was highly dependent on the use of exactly 0.5 equiv of DABCO as an additive [7]. Several other amines and diamines were examined with variation of the stoichiometry and none proved nearly as effective in promoting the reaction. This remarkable effect has been ascribed to the facilitation of transmetallation by formation of a 2 1 R-HgCl DABCO complex and the unique properties of DABCO when both amines are complexed/protonated. 

Common substructural motifs in polyketide natural products are six-membered ring lactones, lactols, and tetrahydropyrans. It was recognized by Wuts and co-workers that hydroformylation of readily available homoaUyhc alcohols would provide a direct and efficient entry into these ring systems. Such an approach was employed in a synthesis of Prelog-Djerassi lactone (Scheme 5.11) [13]. 

Aldehyde 11a, produced by diastereoselective hydroformylation (R=Me Scheme 5.4), has been employed in the synthesis of polyketide fragment 40, a key building block for the synthesis of bafilomycin Ai (Scheme 5.16) [21]. 

Ethylene provides a good example of a petrochemical feedstock for the synthesis of lipids and polyketides. It can be oligomerized to provide a variety of alkenes into which functionalization can be introduced by hydration, oxidation, hydroformylation, and so on. Of course, telomerization can be used to provide functionalized materials directly. 

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