Use of a palladium(II)-catalyzed oxidative kinetic resolution in synthetic efforts toward bielschowskysin

Abstract

Progress toward the cyclobutane core of bielshowskysin is reported. The core was thought to arise from a cyclopropane intermediate via a furan-mediated cyclopropane fragmentation, followed by a 1,4-Michael addition. The synthesis of the cyclopropane intermediate utilizes a Suzuki coupling reaction, an esterification with 2-diazoacetoacetic acid, and a copper catalyzed cyclopropanation. An alcohol intermediate within the synthetic route was obtained in high enantiopurity via a highly selective palladium(II)-catalyzed oxidative kinetic resolution (OKR).

Recent developments in non-enzymatic catalytic oxidative kinetic resolution of secondary alcohols

“…31 In 2013, Stoltz et al reported the synthesis of a key intermediate in the synthesis of the naturally occurring anti-cancer agent bielschowskysin based on a palladium-catalysed oxidative kinetic resolution performed under oxygen atmosphere. 32 As shown in Scheme 12, the treatment of a racemic functionalised secondary alcohol by a combination of 5 mol % of Pd(nbd)Cl 2 and 20 mol% of (À)-sparteine in toluene at 80 C led to the almost enantiopure (3R,5S)-alcohol (>95% ee) with a high selectivity factor (s ¼ 23) along with the corresponding (3S)-ketone in 57% conversion.…”

Synthetic Applications and Methodological Developments of Donor−Acceptor Cyclopropanes and Related Compounds

“…[17] Isolated in 2004 from a Caribbean coral, 26 was found to possesses potent anticancer activity. [18] The simplified scaffold of 27 was chosen as a model system.…”

“…The Stoltz laboratory continued to investigate the strategy of cyclopropane fragmentation en route to larger carbocyclic rings in their approach toward the total synthesis of bielschowskysin ( 26 , Scheme 6). [17] Isolated in 2004 from a Caribbean coral, 26 was found to possesses potent anticancer activity. [18] The simplified scaffold of 27 was chosen as a model system.…”

An Approach Toward the Bridged 14‐Membered Carbon Macrocycle of Bielschowskysin

“…Hexacyclic natural product 1 is arguably one of the most complex furanocembranoids known to date, as it features an unprecedented cis ‐fused tricyclo[9.3.0.0 2,10 ]tetradecane ring system and 11 stereogenic centers . Numerous groups including our own have communicated efforts towards the total synthesis of bielschowskysin . Although the synthesis of the natural product has not been accomplished yet, our contribution relying on non‐photochemical and photochemical strategies resulted in several advanced intermediates containing the crucial stereogenic center, the cyclobutane moiety, and fully substituted southern as well as northern hemispheres of the target molecule , .…”