Julian D. Smith

The total synthesis of swinholide A. Part 4: Synthesis of swinholide A and isoswinholide A from the protected monomeric seco acid, pre-swinholide A

Abstract Swinholide A and isoswinholide A were synthesised in 7 steps from the fully protected seco acid 4 . Key steps include: ( i) bimolecular acylation, 7 + 10 → 12 , ( ii ) selective hydrolysis of the methyl ester, 16 → 17 , and ( iii ) regioselective macrolactonisation. 17 → 18 . The monomeric lactone analogues 2 and 5 were prepared by regioselective macrolactonisation of the seco acid 6 , where the ring size was controlled by variation of the reaction conditions.

Anticonvulsant activity of glycine-site NMDA antagonists. 2. trans 2-carboxy-4-substituted tetrahydroquinolines.

Abstract Anticonvulsant activity has been optimized in a series of glycine-site NMDA antagonists based on 2-carboxy tetrahydroquinoline, leading to the benzylamine 7 (L-690,590), its methyl ester prodrug 13 (L-691,470) and the phenylalanine 8 (L-696,833) which have ED 50 values of 39, 31.5 and 29 mg/kg (i.p.) respectively in the DBA/2 mouse audiogenic seizure model. Correlations between in vivo and in vitro activities suggest that systemic anticonvulsant action of glycine antagonists depends on both brain penetration as well as ‘access’ to receptors within the brain.

The total synthesis of swinholide A. Part 3: A stereocontrolled synthesis of (−)-pre-swinholide A.

Two coupling strategies for (−)-pre-swinholide A were devised based on the analysis in Scheme 1. In the first route, a boron-mediated aldol reaction between the ethyl ketone 19 and the aldehyde 3 was used to construct the C15-C16 bond with moderate diastereoselectivity. In the second route, a Mukaiyama aldol reaction between the methyl ketone 54 and the aldehyde 4 introduced the C18-C19 bond with complete stereocontrol.

Studies in marine macrolide synthesis: Asymmetric synthesis of C1-C15/C16 subunits of swinholide A and scytophycin C.

The aldehyde 8, a C1-C15 subunit of swinholide A, was prepared in 10 steps (14.5% yield, 78% ds) by starting with the asymmetric aldol reaction, 15 + 17 → 18. Conversion into the corresponding ethyl ketone 9 provides a C1-C15 subunit of scytophycin C.

Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists

Abstract 3-Substituted-2-quinoloners ( 6–8 ) have been identified as glycine-site N-methyl-D-aspartate receptor antagonists. It is proposed that the α-phenyl lactam unit in the potent 4-hydroxy-3-phenyl derivatives ( 7d and 8b , L-701,315) may act as a glycine bioisostere in receptor recognition.