Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (−)‐Elisabethadione

Abstract

A new, highly efficient Lewis base catalyst for a practical enantio‐ and diastereoselective crotylation of unsaturated aldehydes with E‐ and Z‐crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (−)‐elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy‐Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.

Asymmetric Total Synthesis of (−)‐Erogorgiaene and Its C‐11 Epimer and Investigation of Their Antimycobacterial Activity

“…Catalytic methods for highly enantio‐ and diastereoselective crotylation of unsaturated aldehydes mediated by chiral Lewis bases have been reported from this laboratory and by others . Therefore, the initial studies for assessing the feasibility of this sequence focused on the stereochemical course of the AOC rearrangement and subsequent transformations.…”

“…Therefore, the initial studies for assessing the feasibility of this sequence focused on the stereochemical course of the AOC rearrangement and subsequent transformations. The model experiments were carried out with alcohols syn ‐ 9 a and anti ‐ 14 , which were conveniently synthesised in diastereomerically pure form by crotylation of α‐methylcinnamaldehyde 11 a with Z ‐crotyltrichlorosilane 10 or its E ‐isomer 13 , respectively (Scheme ). The enolate resulting from the rearrangement was protonated with MeOH at −78 °C and the intermediate aldehyde, without isolation, was subjected to Wittig alkenylation to furnish 15 a .…”

“…It is also pertinent to note that to produce the same C‐4 enantiomer of 17/17′ , alcohols syn ‐ 9 a and anti ‐ 14 should come from the opposite enantiomeric series (Scheme and Scheme ). As a consequence, to enable efficient transfer of chirality in the asymmetric variant of the AOC, it is a prerequisite to employ diastereomerically pure 9 a , because asymmetric crotylation is usually face‐selective and affords syn and anti isomers ( 9 and 14 ) with the same absolute configuration of the alcohol …”

“…Furthermore, E ‐configuration of the double bond in 17 (and 15 a ) is crucial for achieving 1,4‐ trans tetralin structure 16 a in the subsequent cationic cyclisation (Scheme , cf. Figure ), as Z ‐alkene 18 appears to favour formation of the respective 1,4‐ cis tetralin …”

“…Recently, we reported the enantioselective synthesis of (−)‐elisabethadione 3 , in which the key stereochemistry defining steps included: 1) catalytic asymmetric crotylation, 2) anionic oxy‐Cope rearrangement (AOC), and 3) cationic cyclisation . Herein, we present extension of this strategy to a wider range of serrulatane diterpenes with a detailed insight into the stereochemistry of the AOC.…”