1. A cascade strategy enables a total synthesis of (-)-gephyrotoxin
Shuyu Chu, Stephen Wallace, Martin D Smith Angew Chem Int Ed Engl. 2014 Dec 8;53(50):13826-9. doi: 10.1002/anie.201409038. Epub 2014 Oct 16.
A concise and efficient synthesis of (-)-gephyrotoxin from L-pyroglutaminol has been realized. The key step in this approach is a diastereoselective intramolecular enamine/Michael cascade reaction that forms two rings and two stereocenters and generates a stable tricyclic iminium cation. A hydroxy-directed reduction of this intermediate plays a key role in establishing the required cis-decahydroquinoline ring system, enabling the total synthesis of (-)-gephyrotoxin in nine steps and 14% overall yield. The absolute configuration of the synthetic material was confirmed by single-crystal X-ray diffraction and is consistent with the structure originally proposed for material isolated from the natural source.
2. Lithium Enolates Derived from Pyroglutaminol: Mechanism and Stereoselectivity of an Azaaldol Addition
Michael J Houghton, Christopher J Huck, Stephen W Wright, David B Collum J Am Chem Soc. 2016 Aug 17;138(32):10276-83. doi: 10.1021/jacs.6b05481. Epub 2016 Aug 8.
A lithium enolate derived from an acetonide-protected pyroglutaminol undergoes a highly selective azaaldol addition with (E)-N-phenyl-1-[2-(trifluoromethyl)phenyl]methanimine. The selectivity is sensitive to tetrahydrofuran (THF) concentration, temperature, and the presence of excess lithium diisopropylamide base. Rate studies show that the observable tetrasolvated dimeric enolate undergoes reversible deaggregation, with the reaction proceeding via a disolvated-monomer-based transition structure. Limited stereochemical erosion stems from the intervention of a trisolvated-monomer-based pathway, which is suppressed at low THF concentrations and elevated temperature. Endofacial selectivity observed with excess lithium diisopropylamide (LDA) is traced to an intermediate dianion formed by subsequent lithiation of the monomeric azaaldol adduct, which is characterized as both a dilithio form and a trilithio dianion-LDA mixed aggregate.
3. Total synthesis of (-)-stemoamide
Staffan Torssell, Emil Wanngren, Peter Somfai J Org Chem. 2007 May 25;72(11):4246-9. doi: 10.1021/jo070498o. Epub 2007 Apr 24.
A stereocontrolled total synthesis of (-)-stemoamide (1) is presented. The synthesis starts from commercially available (S)-pyroglutaminol (4). A chemoselective iodoboration of 5 was used to access key intermediate 3. The beta,gamma-unsaturated azepine derivative 2 was obtained via a Pd(0)-catalyzed sp(2)-sp(3) Negishi cross-coupling using a Reformatsky nucleophile followed by a ring-closing metathesis reaction. The required C8-C9 trans-stereochemistry of 1 was accessed through a stereoselective bromolactonization/1,4-reduction sequence.
