Peter Szeto

Cyclic sulfamidates as versatile lactam precursors. An evaluation of synthetic strategies towards (−)-aphanorphine

A full account of studies which led to the efficient asymmetric synthesis of (-)-aphanorphine is reported. Two routes to the key cyclic sulfamidate intermediate are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (, and ) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) alpha-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of . These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of in 12 steps from anisaldehyde.

Reactivity of cyclic sulfamidates towards sulfur-stabilised enolates. Stereocontrolled synthesis of functionalised lactams

A structurally representative series of 1,2- and 1,3-cyclic sulfamidates react with enolates derived from methyl alpha-phenylthioacetate 9b to give 5- and 6-substituted alpha-phenylthio lactams 20-24. These products provide, via the corresponding sulfoxides, an entry to alpha,beta-unsaturated lactams e.g. 12, 27, 29 and their alpha-phenylthio analogues e.g. 26 and 30. With the enantiomerically pure 1,2-cyclic sulfamidates 10, 15 and 17, these reactions all proceed with no detectable loss of stereochemical integrity.

A Short and Efficient Synthesis of Neodysiherbaine A by Using Catalytic Oxidative Cyclization

(1) is a potent convulsant and a highly selective agonist for kainate (KA) and a-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptors. Considering its size, 1 has proven to be a challenging synthetic target and was first synthesized by Sakai et al. in 26 steps. Since the original report, 1 has also been synthesized by Sasaki and co-workers (23 steps) and Hatakeyama and co-workers (21 steps). The most efficient synthesis reported to date was completed by Lygo et al. in 15 steps starting from diacetyl-l-arabinal. However, all of these syntheses are lengthy and involve an oxidation/reduction sequence in order to accomplish hydroxy inversion on the sugar moiety. As part of a program of research aimed at developing new catalytic methods for the formation of heterocycles, we chose 1 as a target upon which to test some recently developed methodology. Our retrosynthesis of this molecule began with the disconnection of the central tetrahydrofuran (THF) ring back to the hydroxy alkene 2 as shown in Scheme 1. We suspected that 2 would be an interesting precursor for our recently developed transition-metal-catalyzed oxidative cyclization. This reaction would enable the direct formation of the heterocyclic ring and also set the correct stereochemistry at the quaternary C-4 center. Further disconnection of 2 reveals that the amino acid side chain could be installed by the Negishi coupling of a serine-derived organozinc reagent 3 with a vinyl halide that is attached to the sugar portion. Finally, we envisaged that the vinyl halide precursor for the Negishi coupling could be installed by the addition of an allylderived nucleophile to the anomeric center of the ribose sugar system 4 (note that the stereoselectivity of this addition would need to be syn to the existing stereogenic centers on the ribose to give the desired natural product stereochemistry at C-6). We anticipated that Woerpel and co-workers recent work relating to the stereoselective addition of nucleophiles to oxocarbenium ions derived from pyranose sugar systems, could be usefully employed here. Our synthesis began with commercially available b-dribose tetraacetate 4 (which can also be readily prepared in one step from d-ribose in 58% yield, if desired). This compound was treated with a Lewis acid (presumably forming an intermediate oxocarbenium ion) and the commercially available bromoallylsilane nucleophile 5 (Scheme 2). This reaction resulted in the installation of the bromoallyl group at the C-1 position of the sugar with syn selectivity; under the optimized conditions (Scheme 2, entry 5) we could isolate diastereoisomer 6 in 53% yield. This selectivity may be rationalized by using a model proposed by Lucero and Woerpel. Assuming an SN1 mechanism, nucleophilic addition of the bromoallyl group can occur (axially) onto two conformers of an oxocarbenium ion, such that the product is formed via a chairlike transition structure. In this case, it is likely that transition structure B is destabilized by 1,3-diaxial interactions of the acetate groups, resulting in transition structure A being favored (Scheme 2). Scheme 1. Retrosynthetic analysis of ( )-neodysiherbaine A. PG =protecting group, L = ligand.

Reactivity of cyclic sulfamidates towards phosphonate-stabilised enolates: synthesis and applications of α-phosphono lactams

Five and six ring a-phosphono lactams 14-20 are available by reaction of 1,2- and 1,3-cyclic sulfamidates respectively with enolates derived from ethyl dialkylphosphonoacetates 3 and 4. Subsequent Wadsworth-Emmons olefination provides the enantiomerically pure exo-alkylidene variants e.g. 25, which is efficiently converted to vinyl triflate 29 (> 98% ee). Suzuki coupling of 29 to a range of aryl and vinyl boronic acids leads to a structurally diverse range of pyrrolidinones exemplified by 30 and 34. The degree of epimerisation at the base-sensitive C(5) stereocentre during the Suzuki coupling of 29 is shown to be dependent on both the nature of the aryl boronic acid and the reaction conditions used.