Expedient Enantioselective Synthesis of Cermizine D

Abstract

An efficient enantioselective synthesis of cermizine D has been developed that exploits the use of a common intermediate to access over 85% of the carbon backbone. Key steps include an organocatalyzed heteroatom Michael addition, a diastereoselective alkylation with α-iodomethyl phenyl sulfide, a conjugate addition to a vinyl sulfone species and a sulfone coupling / desulfurization sequence to join the two major subunits.

A concise synthesis of the Lycopodium alkaloid cermizine D

“…5 Recently, in 2012, a second synthesis of (+)-1 including two different approaches, a cuprate addition strategy and a PhSCH2I alkylation pathway, 10 and 16 steps respectively, was published by Carter and collaborators. 6 From these syntheses, the absolute stereochemistry of natural cermizine D can be assigned as (-)-1.…”

Toward a Unified Approach for the Lycopodines: Synthesis of 10-Hydroxylycopodine, Deacetylpaniculine, and Paniculine

“…1 The lycopodine and lycodine sub-families have attracted considerable attention from numerous laboratories 2 including our own. 3 Interestingly, despite these efforts, there are wide sections of the lycopodium alkaloids that remain unexplored (e.g. compounds 2–5 in Figure 1).…”

“…Sulfone 6 in turn could be constructed via a tandem sulfone migration followed by intramolecular Mannich cyclization of imine 8 – a process first developed for our total synthesis of lycopodine ( 1 ). 3b–c The imine 8 would be derived from keto sulfone 9 . The key C 7 –C 12 linkage could be accessed via a diastereoselective intramolecular Michael addition.…”

“…The key C 7 –C 12 linkage could be accessed via a diastereoselective intramolecular Michael addition. The proposed strategy builds on our prior work in the total synthesis of 1 ; 3b–c however, the presence of the additional stereochemistry and functionality at C 10 complicates the approach. While natural products 2–4 represent the only known lycopodium alkaloids containing oxygenation at the C 10 position, this functionality could provide an important handle for accessing compounds possessing an additional C-C bond at this position (e.g.…”

“…Compound 13 is available in enantioenriched form in 3 steps from 1-bromo-3-butene via sulfone incorporation, epoxidation and Jacobsen hydrolytic kinetic resolution. 7 Acetonide formation under standard conditions followed by sulfone ester coupling with ester 11 3b–c cleanly provided the coupled material 14 . Next, cross metathesis with 3-penten-2-one and Hoveyda-Grubbs 2 nd generation catalyst ( 15 ) produced the enone 10 .…”