Amidation stereoselectivity

Matoishi, K. Sano, A. Imai, N. Yamazaki, T. Yokoyama, M. Sugai, T. Ohta, H. Rhodococcus rhodochrous IFO 15564-mediated hydrolysis of alicyclic nitriles and amides stereoselectivity and use for kinetic resolution and asymmetri-zation. Tetrahedron Asymmetry 1998, 9, 1097-1102. 

If alkyl groups are attached to the ylide carbon atom, cis-olefins are formed at low temperatures with stereoselectivity up to 98Vo. Sodium bis(trimethylsilyl)amide is a recommended base for this purpose. Electron withdrawing groups at the ylide carbon atom give rise to trans-stereoselectivity. If the carbon atom is connected with a polyene, mixtures of cis- and rrans-alkenes are formed. The trans-olefin is also stereoseiectively produced when phosphonate diester a-carbanions are used, because the elimination of a phosphate ester anion is slow (W.S. Wadsworth, 1977). 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

Af-Fluorobis(trifluoromethanesulfonyl)imide is also effective in the mono-fluonnation of ester and amide enolates, and of neutral dicarbonyl compounds. Excellent stereoselectivity is observed [48, 80, 81] (equations 39-41)... 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

Uneyama et al. have shown that enantiopure trifluoromethyloxirane (193) can be lithiated and stereoselectively trapped with a variety of electrophiles to give substituted trifluoromethyloxiranes such as 195 (Scheme 5.46) [70] the use of a Weinreb amide as the electrophile is unusual. 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

A very simple and elegant alternative to the use of ion-exchange columns or extraction to separate the mixture of D-amino add amide and the L-amino add has been elaborated. Addition of one equivalent of benzaldehyde (with respect to die D-amino add amide) to the enzymic hydrolysate results in the formation of a Schiff base with die D-amino add amide, which is insoluble in water and, therefore, can be easily separated. Add hydrolysis (H2SQ4, HX, HNO3, etc.) results in the formation of die D-amino add (without racemizadon). Alternatively the D-amino add amide can be hydrolysed by cell-preparations of Rhodococcus erythropolis. This biocatalyst lacks stereoselectivity. This option is very useful for amino adds which are highly soluble in die neutralised reaction mixture obtained after acid hydrolysis of the amide. 

L-Amino adds could be produced from D,L-aminonitriles with 50% conversion using Pseudomonas putida and Brembacterium sp respectively, the remainder being the corresponding D-amino add amide. However, this does not prove the presence of a stereoselective nitrilase. It is more likely that the nitrile hydratase converts the D,L-nitrile into the D,L-amino add amide, where upon a L-spedfic amidase converts the amide further into 50% L-amino add and 50% D-amino add amide. In this respect the method has no real advantage over the process of using a stereospecific L-aminopeptidase (vide supra). 

A similar dependence of the stereoselectivity on the solvent and reaction temperature was found with the x-oxo amides 9 derived from phenylglyoxylic acid (R = C6H5) and 2-oxopropanoic acid (R = CH3) with amine F (Table 23)15. Thus, the highest selectivity was observed under chelation-controlled conditions in the presence of the Lewis acid titanium(IV) chloride. 

Chiral amides of 2-(tributylstannylmethyl)-2-propenoic acid show useful stereoselectivity in their Lewis acid induced reactions with aldehydes, and the products have been converted into optically active a-methylenelactones95. 

Chiral amide and imide enolates are amongst the most effective reagents providing. yv -3-hy-droxycarboxylic acids in both high simple diastereoselectivity and induced stereoselectivity, e.g., the amides 1 and 2, and especially, the imides 3 and 4 (derived from (S(-valine and (l/ ,2S)-norephedrine, respectively)93 and the C2-symmetric amide 594 are highly effective systems ... 

Thus, jyn-adducts arise predominantly, as expected, according to the Zimmerman-Traxier model. Provided that either boron or zirconium is the enolate-metal atom, high syn selectivity is achieved. The total amount of anti-adducts is lower than 2% in the case of amides 1 and 2, and it approaches zero when the other reagents arc used94 . The induced stereoselectivities are impressive for the amides and remarkable in the case of the imides. 

In contrast to the low stereoselections realized in the above syntheses utilizing imines of various chiral aldehydes79-8 1, an almost complete stereoselectivity is reported for the Ugi reaction of 2,3 4,5-bis-O-isopropylidenearabinose with ammonia, acetic acid and cyclohexyl isocyanide giving the 2-acetamino-2-deoxyglueono amides as the exclusive products84. 

A variety of Michael donors such as ketones, esters, thioesters, amides, lactones and lactams may be used and in all of these cases the problems of stereoselectivity apply. 

A further improvement utilizes the compatibility of hindered lithium dialkylamides with TMSC1 at —78 °C. Deprotonation of ketones and esters with lithium dialkylamides in the presence of TMSC1 leads to enhanced selectivity (3) for the kinetically generated enolate. Lithium t-octyl-t-butyl-amide (4) appears to be superior to LDA for the regioselective generation of enolates and in the stereoselective formation of (E) enolates. 

Thus unsubstituted (R=H) and substituted (R = alkyl) non-stabilized diyiides 1 react with phenylisocyanate and dicyclohexylcarbodiimide (R NCX), leading to the formation of new monoylide type intermediates. These last ones react in situ with carbonyl compounds through a Wittig type reaction leading respectively to a,)8-unsaturated amides 2 and amidines 3, with a high E stereoselectivity, the double bond being di- or tri-substituted [48,49]. By a similar reactional pathway, diyiides also react with carbonic acid derivatives, with the synthesis as final products of -a,/l-unsaturated esters 4 and acids 5 [50]. 

Scheme 4 Stereoselective synthesis of (f )-2-hydroxy acid amides and (7 )-2-hydroxy acids hy hydrolysis of (f )-cyanohydrins.

The Z-selectivity seems to be associated primarily with reduced basicity of the amide anion. It is postulated that the shift to Z-stereoselectivity is the result of a looser TS, in which the steric effects of the chair TS are reduced. 

Many of the compounds used have additional functional groups, including ester, amide, ether, and acetal. These groups may be involved in coordination to samarium and thereby influence the stereoselectivity of the reaction. 

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