An Efficient Formal Synthesis of (−)-Clavosolide A Featuring a “Mismatched” Stereoselective Oxocarbenium Reduction

Abstract

The enantioselective formal synthesis of the polyketide marine natural product (-)-clavosolide A is presented. The construction of the β-Cglycoside subunit is highlighted by a one-pot oxocarbenium cation formation/reduction sequence. Yamaguchi dimerization afforded the diolide aglycon in 18 steps (longest linear sequence).

Tandem Allylboration–Prins Reaction for the Rapid Construction of Substituted Tetrahydropyrans: Application to the Total Synthesis of (−)‐Clavosolide A

“…We then envisaged incorporation of the cyclopropyl unit through a lithiation–borylation reaction between carbamate 3 and boronic ester 4 . Whilst substrate‐controlled cyclopropanation of allylic alcohols is well established and has previously been employed in the synthesis of (−)‐clavosolide A,,– unfortunately it gives the undesired diastereoisomer and therefore requires additional steps for correction. The carbamate bearing the THP core 3 could potentially be assembled by a three‐component allylboration–Prins reaction from boronic ester ( R )‐ 6 a and aldehyde 7 a .…”

“…Creating increasingly efficient syntheses of common structural motifs found in Nature is al ong-running objective in organic synthesis.F or example,s ubstituted pyrans are frequently encountered in the family of polyketide natural products. [1] Clavosolide A [2,3] is ac ontemporary example, whose correct structure was established following total syntheses by Willis, [3a] Lee [3b] and Smith [3c] (Figure 1). This molecule has been prepared by avariety of strategies and the tetrasubstituted tetrahydropyran (THP) core alone has been constructed in !…”

“…6steps. [3] In some cases additional steps were employed to construct THPs with high structural complexity towards the end of the synthesis.…”

Synthesis of natural products by intramolecular Michael addition

“…More importantly, the newly built chiral center which would be C4 in the final product was constructed by the induction from the C6 chirality. With the cis-dioxane (88) in hand, the reduction, oxidation and Wittig reaction were subsequently carried out to form the (E)-enone derivative (90). To deprotect the diol and induce the intramolecular oxy-Michael addition, TFA was used in this key step and only the 2,6-cis tetrahydropyran was claimed to be obtained.…”

“…84 For the synthesis of the allylic ester (223), the Recently, Jennings' group reported a formal synthesis of (-)-clavosolide A featuring a stereoselective oxocarbenium reduction giving access to the tetrahydropyran core. 90 The synthetic approach began with the synthesis of the cyclopropanyl amide by a route similar to Smith's route (Scheme 76). The resulting diol (250) was then protected as its acetonide and ozonolysis converted the double bond to an aldehyde (251) which underwent Evans' aldol reaction.…”