Aziridine phosphonates

The Darzens condensation reaction has been used with a wide variety of enolate equivalents that have been covered elsewhere. A recent application of this important reaction was appljed toward the asymmetric synthesis of aziridine phosphonates by Davis and coworkers.In this application, a THF solution of sulfinimine 34 (0.37 mmol, >98% ee) and iodophosphonate 35 (0.74 mmol) was treated with LiHMDS (0.74 mmol) at -78 °C to give aziridine 36 in 75% yield. Treatment of 36 with MeMgBr removed the sulfinyl group to provide aziridine 37 in 72% yield. 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

Acyl halides Halopyrimidine s Aldehydes Aliphatic esters Aziridines Phosphonate esters... 

Amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols, and nonsteroidal anti-inflammatory drugs (NSAIDs). 

Davis has also employed a similar procedure for the synthesis of aziridine-2-phosphonoates, involving the addition of N-(2,4,6-trimethylphenylsulfinyl)imine to anions of diethyl a-halomethyl phosphonates (Scheme 1.29) [53, 54], Aziridines... 

The substrate scope is limited, as electron-withdrawing groups (X = p-N02 or p-CF3) on the aromatic substituent are not tolerated. However, this route does provide valuable intermediates to unnatural a-amino phosphonic acid analogues and the sulfimine can readily be oxidized to the corresponding sulfonamide, thereby providing an activated aziridine for further manipulation, or it can easily be removed by treatment with a Grignard reagent. 

The chemistry of aziridine-2-carboxylates and phosphonates has been discussed in part in several reviews covering the literature through 1999 [1-3], This chapter is intended to give an overview of asymmetric syntheses using chiral nonracemic aziridine-2-carboxylates and -phosphonates with particular emphasis on their applications as chiral building blocks in asymmetric synthesis since 2000. Some overlap with earlier reviews is necessary for the sake of continuity. 

Preparation of Aziridine-2-carbo>cflates and Aziridine-2-phosphonates I 75... 

Methodology for the cyclization of a-hydroxy-P-amino phosphonates has also been developed and employed in synthesis of aziridine-2-phosphonates [79, 80]. Mesyla-tion of a-hydroxy-P-amino phosphonates 89 (Scheme 3.29), for example, gave a-mesyloxy-P-amino phosphonates 90. Treatment of 90 with K2CO3 afforded azir-idine-2-phosphonates 91 in 93-95% yield [79]. 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

Reduction of azirine-2-phosphonates 99 (Scheme 3.32) with NaBH4 in ethanol exclusively gave ris-aziridine-2-phosphonates 100 in 81-82 % yield [86, 87]. A Diels-Alder reaction between azirine-2-phosphonate 101 and trans-piperylene 102... 

Scheme 3.33) afforded the bicyclic aziridine-2-phosphonate 103 in 89% yield [83]. 

Swern oxidation of N-unsubstituted aziridine-2-phosphonates resulted in the formation of both 2H-azirine-2-phosphonates and 2H-azirine-3-phosphonates [81, 83]. Treatment of ds-aziridine-2-phosphonate 226 (Scheme 3.84) with DM SO/ (COCl)2/Et3N afforded azirine-phosphonates 227 and 228, with the former predominating [81]. Under similar conditions, however, trans-aziridine-2-phospho-... 

Aziridine 2-ohosphonates/Azirinvl phosphonates) Davis, F. A. McCoull, W. Tetrahedron Lett. 1999, 40, 249. 

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