Enantioselective azidation

Despite these significant results in azide additions, only limited success has been obtained in enantioselective addition of other sp2-hybridized nitrogen-centered nucleophiles to meso-epoxides. Bartoli et al. demonstrated that aniline was a... 

Subsequent to the development of the (salen)Cr-catalyzed desymmetrization of meso-epoxides with azide (Scheme 7.3), Jacobsen discovered that the analogous (salen)Co(n) complex 6 promoted the enantioselective addition of benzoic acids to meso-epoxides to afford valuable monoprotected C2-symmetric diols (Scheme 7.15) [26], Under the reaction conditions, complex 6 served as a precatalyst for the (salen) Co(iii)-OBz complex, which was fonned in situ by aerobic oxidation. While the enantioselectivity was moderate for certain substrates, the high crystallinity of the products allowed access to enantiopure materials by simple recrystallization. 

A novel approach to azabicyclic ring systems, based on an epoxide-initiated electrophilic cyclization of an alkyl azide, has been developed by Baskaran. A new stereo- and enantioselective synthesis of the 5-hydroxymethyl azabicyclic framework 91a, present in (+)- and (-)-indolizidines 167B and 209D, for example, was... 

In contrast to the synthesis of carbocyclic rings, the Cope rearrangement has been used sparsely for generating azepinones. Recently, the enantioselectivity of the conversion of 2-aza-divinylcyclopropane 286 has been investigated. The synthesis started from the optically active cyclopropanecarboxylic acid (90% ee), which had been converted into the isocyanate 286 by initial azidation to 285 and a consecutive Curtius rearrangement. Furthermore, the conditions of the iso-... 

Investigations into the mechanism of this reaction revealed several interesting facts (61). Compelling evidence was presented that a discreet Cu nitrenoid was involved in the catalytic cycle. Photolysis of a solution of tosyl azide and styrene in the presence of the catalyst afforded aziridine with the same enantioselectivity as obtained from the PhI=NTs reaction, Eq. 69. Since photolysis of tosyl azide is known to extrude dinitrogen and form the free nitrene, the authors argue that this is indicative of a common Cu-nitrenoid intermediate in this reaction. 

However, the two syntheses of Tamiflu, involving two potentially hazardous azide-containing intermediates, need further improvements. A recently published short and enantioselective pathway starting from acrylic acid and 1,3-butadiene looks promising [47]. 

Nugent, W. A. (1992) Chiral Lewis acid catalysis Enantioselective addition of azide to meso-epoxides., J. Am. Chem. Soc, 114 2768-2769. 

Cha and co-workers (54) described an enantioselective total synthesis of (—)-slaframine (269) based on an intramolecular cycloaddition of an azide (Scheme 9.54). On reaction with NaN3 in DMF at 60 °C followed by intramolecular... 

Two enantioselective syntheses of (+)-biotin (293) from L-cysteine were reported based upon the intramolecular 1,3-dipolar cycloadditions of carbamoyl azides 289 and 291 by Deroose and De Clercq (58) (Scheme 9.58). Thermolysis of the carbamoyl azides 289 and 291 gave the triazolines 290 and 292, respectively. Both 290 and 292 were converted into (+)-biotin (293) in several steps. 

The Dendrobatid poison arrow frogs of Central and South America exude a potent mixture of alkaloids from their skins. It was originally thought that the frogs biosynthesized these alkaloids, but it has since been shown that they are of dietary origin. The skin exudate of the Colombian frog Minyobates bombetes causes severe locomotor difficulties, muscle spasms and convulsions upon injection in mice. The major component of the alkaloid mixture is 251F3. Jeff Aube of the University of Kansas recently described (J. Am. Chem. Soc. 2004,126,5475) the enantioselective total synthesis of 3. The key step in the synthesis was the cyclization of the keto azide 2. 

The synthesis uses Evans chemistry to introduce enantioselectively an azide group, which is then reduced to the a-amino group (Scheme 16). Note that in all cases, the phosphinyl group is protected as its sulfide during the synthesis to avoid complication (oxidation) observed with the phosphine. The phosphine sulfide is compatible with Fmoc- and Boc-peptide synthesis conditions. The free phosphine can later be regenerated by treating the sulfide with Raney nickel in MeOH (as shown in Scheme 15) or by methylation followed by treatment with HMPTJ50 This reduction was even applied successfully to sulfide-protected phosphine peptides still attached to the solid support.151 ... 

Miller and co-workers, as part of their program in connection to the development of polypeptides as practical and readily modular chiral catalysts and new screening protocols for combinatorial synthesis, have been able to achieve efficient catalytic enantioselective conjugate additions of azides to acyclic enones [15]. As the example in Eq. (5) illustrates, the resulting 3-azidocarbonyls can be easily modified to afford N-containing heterocycles. 

Evans et al. proposed that an imino-copper species in the 3+ oxidation state (Cu3+=NTs) should be the key intermediate in copper-catalyzed aziridinations [75b]. This proposal was supported by Jacobsen s study on the dependence of enantioselectivity on the nitrene precursors and/or the substrate structures with two iminoiodoarenes, PhI=NTs and 2,3,4-Me3-6-(r-Bu)C6HI=NTs), in the presence of CuPF6-33a complex and four olefins [80b]. This study disclosed that enantioselectivity did not depend on the iminoiodoarene, but on the olefins used, that is, the finding excludes the possibility that a Cu-Arl=NTs adduct is a key intermediate. It has also been observed that the photochemical aziridination with tosyl azide (TsN3) catalyzed... 

Chiral epoxyoxazolidines (39) undergo regio selective ling opening by sodium azide to products (40).35 Further appropriate manipulations of functional groups lead to chiral /1-ammo alcohols, which are intermediates for the enantioselective synthesis of bioactive products related to taxol. 

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