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Enantiospecific Heteroatom-Tethered 1,6-Enyne Cycloisomerizations

Headshot of Haofan Ji, Asian man wearing glasses and a white shirt
Haofan Ji
Graduate Student, Department of Chemistry
University of Georgia
iSTEM-2 Building, Room 1218
Organic Seminar

Cycloisomerizations of 1,n-enynes catalyzed by electrophilic p-acid metal complexes provide a powerful method of carbon–carbon bond formation, and a unique platform for studying reactivity and mechanism.1  Our previous report on the total synthesis of (±)-gelsenicine took advantage of a cycloisomerization/rearrangement strategy to access the central bridging bicyclic structure of the compound.2  Continuing our interest in the gelsenicine total synthesis and enyne cycloisomerization, we describe two strategies to formulate our strategy toward an asymmetric variant of our route.

Diagram of Two strategies toward the enantioselective formal total synthesis of (+)-gelsenicine

In developing our asymmetric synthetic strategy based on chirality transfer, we demonstrated enantiospecific cycloisomerizations of chiral ethereal 1,6-enynes (Figure 1).  The utilization of this strategy afforded 86% ee as the best result.  Separately, chiral bisphosphine-gold-catalyzed cycloisomerizations were pursued.  The DTBM-SEGPHOS(AuCl)2 provided a key synthetic intermediate in high enantiopurity (97% ee).3  As the following steps are diastereoselective, this outcome signified a formal enenatioselective total synthesis of (+) gelsenicine.

Illustration of Enantiospecific cycloisomerizations with N-tethered enynes.

Applying the enantiospecific cycloisomerization to N-tethered enynes became of interest.  The best result in the current scope catalyzed by JohnPhosAu(MeCN)SbF6 could reach nearly enantiopure (Scheme 1).  With further investigation on N-tethered enynes, this strategy could benefit heterocycle synthesis.



1. For reviews on enyne cycloisomerization, see: (a) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208-3221. (b) Fürstner, A. Acc. Chem. Res. 2014, 47, 925-938. (c) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028-9072.

2. Newcomb, E. T.; Knutson, P. C.; Pedersen, B. A.; Ferreira, E. M. J. Am. Chem. Soc. 2016, 138, 108-111.

3. Knutson, P. C.; Ji, H.; Harrington, C. M.; Ke, Y.-T.; Ferreira, E. M. Org. Lett. 2022, 24, 4971-4976.




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