On the origin of siphonariid polypropionates: total synthesis of baconipyrone A, baconipyrone C, and siphonarin B via their putative common precursor.

The hypothesis that siphonariid polypropionates originate from nonenzymatic processes on acyclic biosynthetic precursors was tested by examining the properties of the putative common precursor for the S. zelandica decapropionates siphonarin B, caloundrin B, baconipyrone A, and baconipyrone C, i.e., (4S,5S,6S,8RS,10S,11S,12R,14R)-14-(6-ethyl-3,5-dimethyl-4-oxo-4H-pyran-2-yl)-5,11-dihydroxy-4,6,8,10,12-pentamethylpentadecane-3,7,9,13-tetraone. The first synthesis of such a precursor was achieved in an efficient and fully enantioselective manner using a thiopyran-based strategy for polypropionate synthesis. This putative precursor, a complex mixture of ring-chain and keto-enol tautomers, was kinetically stable and isomerized exceedingly slowly to the thermodynamically more stable siphonarin B. In the presence of imidazole, the mixture reached apparent equilibrium within several hours giving siphonarin B as the predominant component (ca. 70%), thereby constituting its enantioselective total synthesis. In the presence of alumina, both siphonarin B and the dihydroxytetraone precursor underwent retro-Claisen rearrangements (via a hemiacetal tautomer) to give baconipyrones A and C among other products. This is the first total synthesis of baconipyrone A and "biomimetic" synthesis of baconipyrone C. Control experiments suggested that baconipyrone A was produced in an unprecedented cascade process where the intermediate enol(ate) of the retro-Claisen rearrangement was directly engaged in aldol cyclization while baconipyrone C resulted from simple ketonization of the enol(ate). These experiments provide the first unambiguous demonstration that the baconipyrones are plausible isolation artifacts and suggest they are most likely derived from siphonarins rather than an "acyclic" precursor. Caloundrin B was not detected among the products from any of the isomerization experiments, suggesting the possibility that it is an unstable biosynthetic product.

Synthetic studies on siphonariid polypropionates: synthesis and isomerization of the caloundrin B trioxaadamantane ring system.

(1R,3R,5R,7R,8S,9R,10S)-3,5-Diethyl-8,9,10-trimethyl-2,4,6-trioxatricyclo[3.3.1.1(3,7)]decan-1-ol (II), a model of the trioxaadamantane ring system embedded in caloundrin B, was prepared by isomerization of the thermodynamically unstable (9S)-diastereomer (I) in the presence of imidazole. Alternatively, isomerization of I with HF.py or DBU gave the hemiacetal III or its retro-Claisen ester IV, respectively, which represent structural motifs present in the closely related siphonariid polypropionates siphonarin B and baconipyrone C.

Thiopyran route to polypropionates: exploiting and overcoming double stereodifferentiation and mutual kinetic enantioselection in aldol couplings of chiral fragments.

The aldol reaction of tetrahydro-4H-thiopyranone with 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (I) gives four possible diastereomeric adducts (II). Aldol reactions of I with each of the diastereomers of II and their corresponding methoxymethyl ethers III via the Ti enolates were investigated. Using racemic reactants, reactions with II proceeded with high levels of mutual kinetic enantioselection (MKE) and double stereodifferentiation (DS) to give one of the eight possible bisaldol adducts. Similar reactions of III proceeded with low levels of MKE and DS and gave two bisaldol adducts, one from each of the possible combinations of enantiomeric reactants. By extension, 11 of the 20 possible diastereomers of the bisaldol adduct could be obtained selectively. These adducts are useful for polypropionate synthesis.

Thiopyran route to polypropionates: an efficient synthesis of serricornin.

The synthesis of serricornin [(4S,6S,7S)-7-hydroxy-4,6-dimethylnonan-3-one], a sex pheromone produced by the female cigarette beetle (Lasioderma serricorne F.), in seven steps from readily available racemic 1,4-dioxa-8-thiaspiro[4.5]decane-6-carboxaldehyde (6) is described. The key steps include enantioselective aldol reaction of 6 with tetrahydrothiopyran-4-one catalyzed by 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole to fabricate the tetrapropionate skeleton, stereoselective Li(s)Bu(3)BH reduction of the resulting aldol adduct, Barton-McCombie deoxygenation, and Raney nickel desulfurization.