Synthesis of Each Enantiomer of Rocaglamide by Means of a Palladium(0)‐Catalyzed Nazarov‐Type Cyclization

Abstract

A recently reported Pd(0)-catalyzed asymmetric Nazarov-type cyclization has been successfully applied in the key step of the first catalytic asymmetric total synthesis of (-)-rocaglamide (natural) and (+)-rocaglamide. The stereochemistry at the C3 position that controls the stereochemistry of all other stereocenters is determined in the cyclization step. This versatile and modular synthesis proceeds from simple reagents.

The Evolution of the Total Synthesis of Rocaglamide

“…Although Schemes – define a serviceable synthesis of racemic rocaglamide, the approach was problematic at two points for reasons that only became clear during the execution of the asymmetric series. We prepared enantiomerically enriched 6 (89:11 e.r.) and carried it through the reactions of Scheme to form 17 .…”

“…Diketoester 34 was exposed to Pd 0 and phosphoramidite 37 to provide chiro ‐ 6 in 70 % yield and in 89:11 e.r. as described in earlier work . There were two restrictions placed on the choice of protecting group for the C3a alcohol.…”

“…In a recent communication, we described the first catalytic asymmetric synthesis of (+)‐ and (−)‐rocaglamide (Figure ) . The key step was a Pd 0 ‐catalyzed Nazarov‐type cyclization .…”

Recent Advances in the Synthesis of Flavaglines, a Family of Potent Bioactive Natural Compounds Originating from Traditional Chinese Medicine

“…In 2015, Tius and co‐workers reported a new synthesis of flavaglines. It was also based on a Nazarov reaction, but their strategy used a different disconnection from that used by Frontier and Magnus . The preparation of dienone 82 employed a selective deprotonation of 80 with TMPMgCl · LiCl (TMP = 2,2,6,6‐tetramethylpiperidyl) and its condensation with acid chloride 81 .…”

Sulfoxide‐Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)‐Isopaucifloral F, (+)‐Quadrangularin A, and (+)‐Pallidol

“…[9] Another elegant approach is the Nazarov cyclization. [10][11][12] Flynn and coworkers, implemented Evans oxazolidinonest oc ontrol the Nazarov cyc-lization, which resultedi na ne nantioselective synthesis of 1 with notable success. [12b] However,t he multiple steps towards the enone substrates and removalo ft he auxiliary may deteriorate the overall efficiency.W ee nvisioned am ore practical and efficient alternative involving the C2-substituted enantiomerically pure methyl para-tolyl sulfoxide auxiliary within a,b-unsaturated carbonyl compounds as substrates (10 a, Figure 2).…”