Enantioselective synthesis aziridines

Enantioselective synthesis and transformations of oxirane and aziridine derivatives 99PAC423. 

Saito has recently reported high yields and enantioselectivities in aziridine synthesis through reactions between aryl- or vinyl-substituted N-sulfonyl imines and aryl bromides in the presence of base and mediated by a chiral sulfide 122 (Scheme 1.41) [66]. Aryl substituents with electron-withdrawing and -donating groups gave modest transxis selectivities (around 3 1) with high enantioselectiv-... 

Sn2 Reactions with epoxides and aziridines are also synthetically useful. An example of epoxide cleavage with an organocopper reagent with sp carbon moieties is the enantioselective synthesis of (3S, 4S)-4-methyl-3-heptanol (53), an elm bark beetle (Scolytus multistriatus) pheromone [42]. The chiral epoxy oxazolidine 51 [43], prepared from (R)-phenylglycinol, reacted with a propylmagnesium bromide-derived cuprate at —70 °C to afford the oxazolidine 52 in 74% yield (Scheme 9.12). Compound 52 was converted into the target molecular 53 by conventional procedures. 

Lewis acid-promoted [3+2] cycloadditions of aziridines and epoxides proceeding via carbon-carbon bond cleavage of three-membered ring heterocycles are demonstrated for the first time. This proposal details plans for extending these initial results into a general synthetic method for the enantioselective synthesis of structurally diverse pyrrolidine- and tetrahydrofuran-containing organic compounds. Expected outcomes of the proposed work will include... 

From haloaziridine, homologation 160 Opening 92,193 Synthesis, enantioselective 92 Aziridine aldehyde to amino ester 115... 

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... 

Addition of the lithium anion of chloromethylphosphonate to sulfinimine 126 gave a-chloro-P-aminophosphonates 195 in a ratio of 59 41 and 98% total yield.104 The diastereomeric products can be separated and each converted to the corresponding aziridine-2-phosphonates 196, new building chiral blocks for the enantioselective synthesis of a-aminophosphonates 197 and azirinyl phosphonates 198.104... 

A novel Pd-catalyzed asymmetric annulation was reported between 5-bromopyrrole-2-carboxylate esters and vinyl aziridines <07OL2357>. The resulting pyrrolopiperazinones such as 58 served as key intermediates in the enantioselective synthesis of longamide B and a number of other pyrrole alkaloids. 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

Salto, T., Sakairi, M., Akiba, D. Enantioselective synthesis of aziridines from imines and alkyl halides using a camphor-derived chiral sulfide mediator via the imino Corey-Chaykovsky reaction. Tetrahedron Lett. 2001,42, 5451-5454. 

Yamamoto and coworkers reported the synthesis of Brpnsted acids of chiral borate anions 4.34 and 4.35 made or derived from enantiopure BINOL (1,L binaphthalenyl2,2 -diol). The Bis(binaphthol)borate anion BNB (4.34) is configurationally stable and was used as chiral counter anion with some Cu(l) complexes to promote enantioselective asymmetric aziridination of styrene by Andtsen and coworkers (Scheme 4.4). ... 

The sulfoniutn ylide-mediated epoxidation procedure developed by Aggarwal (see Section 4.8) has been adapted to the enantioselective synthesis of aziridines from imines bearing electron withdrawing groups on nitrogen. The... 

Enantioselective synthesis of brefeldin A was achieved by utilizing [3 + 2] cycloaddition of 263 with the chiral butenolide 268 to provide 269 as a key reaction [99]. Less basic triisopropyl phosphite was used as a suitable ligand. Functionalized piperidine 271 was prepared in an enantiomerically pure form by [3 + 3] cycloaddition of enantiomerically pure aziridine 270 with 263 and the total synthesis of (—)-pseudoconhydrine has been achieved [100]. 

It is well known that alkyl azides also behave as 1,3-dipoles in intramolecular thermal cycloaddition reactions. The formation of two carbon-nitrogen bonds leads to triazolines, which are usually not stable. They decompose after the loss of nitrogen to aziridines, diazo compounds, and heterocyclic imines. There are a limited number of examples reported in which the triazoline was isolated [15]. The dipolar cycloaddition methodology has been extremely useful for the synthesis of many natural products with interesting biological activities [16], In recent years, the cycloaddition approach has allowed many successful syntheses of complex molecules which would be difficult to obtain by different routes. For instance, Cha and co-workers developed a general approach to functionalized indolizidine and pyrrolizidine alkaloids such as (-i-)-crotanecine [17] and (-)-slaframine [18]. The key step of the enantioselective synthesis of (-)-swainsonine (41), starting from 36, involves the construction of the bicyclic imine 38 by an intramolecular 1,3-dipolar cycloaddition of an azide derived from tosylate 36, as shown in Scheme 6 [ 19). 

Enantioselective organocatalytic a-heterofimctionalization of active methines to give versatile intermediates for the synthesis of natural products and pharmaceuticals (2002 to mid-2011) 12RCA385. Enantioselective synthesis of natural epoxyquinoids 13COS2. Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis 12CRV1681. 

Scheme 4.22 Enantioselective synthesis of 4,5-dihydropyrroles via domino ring opening/ cyclization of N-activated aziridines with malononitrile.

The memory of chirality concept has been employed in a strategy for the synthesis of chiral a,/ -diamino- and a-amino-/ -hydroxy ester derivatives via asymmetric imino-aldol and aldol reactions, starting from protected aminoesters. The route can 0 be extended to the enantioselective synthesis of aziridines. 

SCHEME 17.13. Enantioselective synthesis of (—)-indolizidines 209B 57 and 209D 58 by an aza-[2,3]-Wittig rearrangement ring expansion of aziridine 55. 

Ghorai MK, Shukla D, Das K. Enantioselective synthesis of morpholines and their homologues via S v2-type ring opening of aziridines and azetidines with haloalcohols. J. Org. Chem. 2009 74(18) 7013-7022. 

Ghorai MK, Nanaji Y, Yadav AK. Ring opening/C-iV cyclization of activated aziridines with carbon nucleophiles highly diastereo- and enantioselective synthesis of tetrahydroquinolines. Org. Lett. 2011 13(16) 4256 4259. 

Lewis acids such as zinc triflate[16] and BF3[17] have been used to effect the reaction of indole with jV-proiected aziridine-2-carboxylate esters. These alkylations by aziridines constitute a potential method for the enantioselective introduction of tryptophan side-chains in a single step. (See Chapter 13 for other methods of synthesis of tryptophans.)... 

Synthesis of aziridines by treatment of carbenes with imines was reported by Jacobsen [56]. A metallocarbene 104 derived from ethyl diazoacetate and copper fluorophosphate was treated with N-arylaldimines to form aziridines with reasonable diastereoselectivities (>10 1 in favor of cis) but with low enantioselectivities (about 44% ee). This was shown to result from a competitive achiral reaction path-... 

In 2003, Bonini et al. reported a new synthesis of ferrocenyloxazolines based on an iodide-mediated ring expansion of A-ferrocenoyl-aziridine-2-carboxylic esters. The thus-formed ligands were successfully employed as palladium chelates for the test reaction, since they allowed the product to be formed in quantitative yields and good to high enantioselectivities (Scheme 1.69). According to the results, it seemed that the additional chiral centre present in the oxazoline backbone of these ligands did not play a major role for the asymmetric induction and the activity of the corresponding catalysts. 

Since the discovery of the CBS catalyst system, many chiral //-amino alcohols have been prepared for the synthesis of new oxazoborolidine catalysts. Compounds 95 and 96 have been prepared93 from L-cysteine. Aziridine carbi-nols 97a and 97b have been prepared94 from L-serine and L-threonine, respectively. When applied in the catalytic borane reduction of prochiral ketones, good to excellent enantioselectivity can be attained (Schemes 6-42 and 6-43). 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

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