Pyrrolidine derivatives from/.-serine

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

Corey s earlier synthesis22 uses a related strategy from serine involving a Seebach-style relay chiral centre and two stereoselective aldol reactions. The aldol reaction with /-PrCHO is carried out first and the pyrrolidine ring assembled later with the second aldol reaction. Serine 137 is converted to the cyclic t-BuCHO derivative 138. An aldol reaction with the enolate of 138 and /-PrCHO gives mostly the wanted aldol 139. The aldehyde adds to the face opposite to the /-butyl group. 

The methyl group on the pyrrolidine nitrogen of nicotine is derivable from methionine, where it is transferred as such (397, 398), from choline, which is probably first oxidized to betaine (399, 400), from formaldehyde (401), from glycine and from glycolic acid, of which the a-carbon is transferred (402, 403), and from serine (402) and from glycolic acid (403), from both of which the /3-carbon is transferred. 

Two differently JV-acyl protected derivatives of (S)-serinal 197, readily available from D-glucosamine, have been subjected to aldolizations with DHAP aldolases to furnish the corresponding 5-aminoketoses 196/198 [220,235], The latter compounds are interesting in their own right or as further potential precursors for pyrrolidine-type azasugars. 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Like most other aspects of the luzopeptin effort, deblocking of hard-won dipeptides 106 and 107 turned out to be a delicate proposition. In derivatives of proline and pipecolinic acid, the serine segment had been extricated from its protective webbing by A-deacetylation with pyrrolidine in aeetonitrile and Kunieda cleavage of the oxazolone. However, reaction of 106 with pyrrolidine furnished 109 (30%) as the sole identifiable compound. Evidently, pyrrolidine was basic enough to promote p-elimination of acetate and subsequent Michael-type addition to intermediate 108, a significant fraction of which may have been lost to polymerization. Other amines, such as ethylamine, diethylamine. 

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