Asymmetric Synthesis of Nitrogen Heterocycles

The reaction chemistiy of aziridines is underdeveloped. This is particularly surprising because aziridines are easily prepared in high enantiomeric purity. Arlette Solladie-Cavallo of the Universite L. Pasteur, Strasbourg, reports J. Org. Chem. 2004, 69, 1409) that addition of the pulegone-derived sulfonium ylide 6 to an aldehyde tosylimine. such as 7 proceeds to give the N-tosyl aziridine 8 in high ee and with good diastereocontrol. The sulfide precursor to 6 is recovered in almost quantitiative yield. N-Tosyl aziridines such as 8 are readily opened both by carbon and by heteroatom nucleophiles. 

Amino acids continue to be useful starting materials for the preparation of enantiomerically-pure heterocycles. Henk Hiemstr a of the University of Amsterdam and Floris Rutjes of the Univer sity of Nijmegen report (J. Am. Chem. Soc. 2004, 126,4100) that cyclization of the allyl silane 9 followed by ring-closing metathesis leads to the highly-functionalized quinolizidine 11. 

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Waldmann H. Amino Add Esters Versatile Chiral Auxiliary Groups for the Asymmetric Synthesis of Nitrogen Heterocycles Synlett 1995 133-141... 

Gwilherm Evano was born in 1977 in Paris he studied chemistry at the Ecole Normale Superieure in Paris and received his Ph.D. from Universite Pierre et Marie Curie in 2002 under the supervision of Professors Francois Couty and Claude Agami. After postdoctoral study with Professor James S. Panek at Boston University, he became assistant professor at the University of Versailles in 2004. His research interests concern the field of asymmetric synthesis of nitrogen heterocycles as well as their reactivity and the total synthesis of natural products. 

At that time, as now, the enantiomers of many chiral amines were obtained as natural products or by synthesis from naturally occurring amines, a-amino acids and alkaloids, while others were only prepared by introduction of an amino group by appropriate reactions into substances from the chiral pool carbohydrates, hydroxy acids, terpenes and alkaloids. In this connection, a recent review10 outlines the preparation of chiral aziridines from enantiomerically pure starting materials from natural or synthetic sources and the use of these aziridines in stereoselective transformations. Another report11 gives the use of the enantiomers of the a-amino acid esters for the asymmetric synthesis of nitrogen heterocyclic compounds. 

B-2005MI65 R. Pedrosa, C. Andres, and J. Nieto in New Methods for the Asymmetric Synthesis of Nitrogen Heterocycles ,... 

Waldmann, H. Amino acid esters versatile chiral auxiliary groups for the asymmetric synthesis of nitrogen heterocycles. Synlett 1995,133-141. 

Royer J (2009) Asymmetric synthesis of nitrogen heterocycles. Wiley-VCH VerlagGmbH Co. KGaA, Weinheim... 

G. Lesma, A. Sacchetti, A. Silvani, and B. Danieli, New Methods for the Asymmetric Synthesis of Nitrogen Containing Heterocycles, J. L. Vicario et al., Eds., Research Signpost, Trivandrum, India, 2005. 

As an extension of this chemistry, 7V-sulfinyl aziridine 188, prepared from (/ )-187, was utilized in the asymmetric synthesis of protein kinase C inhibitor D-e/yf/iro-sphingosine 189" and in the first enantioselective synthesis of the marine cytotoxic antibiotic (/ )-(-)-dysidazirine (190).100 This latter result constitutes the first general method for preparing nonracemic 2//-azirines, the smallest of the unsaturated nitrogen heterocycles.100,101... 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

Bicyclic 5-5 systems with one ring junction nitrogen atom and no extra heteroatoms were not covered in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I). Pyrrolizines <84AHC(37)i, 87Sio>, pyrrolizidines <88H(27)1465> and the asymmetric synthesis of pyrrolizidines <90H(30)l23l> have been reviewed. 

Metal rf-inline complexes with various transition metals [1-10] and lanthanides [11,12] are well known in the literature. Early transition metal if-imine complexes have attracted attention as a-amino carbanion equivalents. Zirconium rf-imine complexes, or zirconaaziridines (the names describe different resonance structures), are readily accessible and have been applied in organic synthesis in view of the umpolung [13] of their carbons whereas imines readily react with nucleophiles, zirconaaziridines undergo the insertion of electrophilic reagents. Accessible compounds include heterocycles and nitrogen-containing products such as allylic amines, diamines, amino alcohols, amino amides, amino am-idines, and amino acid esters. Asymmetric syntheses of allylic amines and a-amino acid esters have even been carried out. The mechanism of such transformations has implications not only for imine complexes, but also for the related aldehyde and ketone complexes [14-16]. The synthesis and properties of zirconaaziridines and their applications toward organic transformations will be discussed in this chapter. 

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