Enamine reduction, stereoselective

The chemical reduction of enamines by hydride again depends upon the prior generation of an imonium salt (111,225). Thus an equivalent of acid, such as perchloric acid, must be added to the enamine in reductions with lithium aluminum hydride. Studies of the steric course (537) of lithium aluminum hydride reductions of imonium salts indicate less stereoselectivity in comparison with the analogous carbonyl compounds, where an equatorial alcohol usually predominates in the reduction products of six-membered ring ketones. 

Stereoselective reduction to the appropriate tetrahydro derivatives is observed in the case of the reaction of heteroannelated dihydroazines (R5and R6 are Het, X is N, for example, compounds 346, 348 and 350) with sodium borohydride [174, 295, 296, 297] or with hydrogen in the presence of Pd on A1203 under 3,000 Torr [298] (Scheme 3.93). Reduction of the enamines 346 and... 

For the structural optimization of the tricyclic triazolium salt 119 the cw-tricyclic lactam 126 was chosen as the precursor for the synthesis of the tetracyclic triazolium salt 127. The diastereo- and enantiopure y-lactam 126 was synthesized following a procedure reported by Ennis et al. (Scheme 32) (Ennis et al. 1996 Nieman and Ennis 2000). a-Tetralone (124) was a-alkylated with ethyl bromoacetate and subsequently hydrolyzed to the corresponding carboxylic acid. Condensation with (R)-phenylglycinol yielded the lactam 125 as a single stereoisomer. Stereoselective reduction, dehydration of the alcohol, and acid-catalyzed enamine hydrolysis provided the cis-tricyclic lactam 126. The one-pot procedure that had previously been successful in the synthe-... 

Enamines are hydrogenated over Pt catalysts and on Pd-on-carbon. A completely stereoselective reduction of lactone 6 is achieved over Rh. ... 

Stereoselective reduction of 6-keto-compounds in the morphine, codeine, and morphinan series to 6-a- and 6-/S-hydroxy-compounds by formamidine-sulphinic acid has been reported. Dihydrocodeinone pyrrolidine enamine (141) has been shown to react with 2,4-dinitrofluorobenzene in the presence of potassium hydroxide to give the aci-nitro-salt (142), accessible also directly from dihydrocodeinone and m-dinitrobenzene in alkali. 

While much effort has been concentrated on the stereoselective reduction of p-ketosulfoxides (Section 4.1), relatively little attention has been paid to the analogous reactions of P-iminosulfoxides or the corresponding enamine tautomers as an approach to chiral P-aminosulfoxides. 

Greater stereoselectivity for the formation of equatorial amines has been found in the reduction of enamines with formic acid or formamides (553-559). The selective formation of 3-a-amino-5- -steroids by this method and of 3- 3-amino-5- 3-steroids by catalytic reduction (5<50) of the corresponding enamines is of interest. 

Dihydrocorynantheine was obtained via similar steps from normal cyanoacetic ester 319 (172). Stereoselective transformation of the alio cyanoacetic ester 315 to the normal stereoisomer 319 was achieved by utilizing a unique epimerization reaction of the corresponding quinolizidine-enamine system (174). Oxidation of alio cyanoacetic ester 315 with lead tetraacetate in acetic acid medium, followed by treatment with base, yielded the cis-disubstituted enamine 317, which slowly isomerized to the trans isomer 318. It has been proved that this reversible eipmerization process occurs at C-15. The ratio of trans/cis enamines (318/317) is about 9 1. The sodium borohydride reduction of 318 furnished the desired cyanoacetic ester derivative 319 with normal stereo arrangement. The details of the C-15 epimerization mechanism are discussed by B rczai-Beke etal. (174). 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

P,y-Diamino analogues 49 of statine are prepared stereoselectively starting from the O-methyl hydroxamate derivative of N-protected statine. The reaction sequence involves the formation of a p-lactam intermediate obtained by internal cyclization under Mitsunobu conditions.184 Alternatively, direct amination of either a p-oxo ester 31 followed by reduction of the resulting enamine 50, 85 or by reduction of the corresponding ,p-unsaturated ester, 88 gives an enantiomeric mixture of the corresponding unprotected p-amine, which is protected by a carbamate prior to chromatographic separation (Scheme 20). 

Other current investigations concerning cycloadditions of nitrosoalkenes are directed towards employment of more complex dienophiles, e. g. NjM-bis-tri-methylsilyl enamines [380, 381] or 2,5-dihydrooxepines [382]. Furthermore, interest focuses on exploring the scope of subsequent reactions of the cycloadducts, such as stereoselective halogenation [383], ds-dihydroxylation [384] and numerous reductive [385] as well as acid or transition metal induced [386] transformations of 5,6-dihydro-4H-l,2-oxazines. 

Under these conditions the stereoselectivity is higher, as the attack of the reagent occurs equatorially, leading to axial amines (72-92%). A comparison with the results of reduction of 4-f-butylcyclohexanone shows a complete inversion of stereoselectivity (16-27% of equatorial attack). Reductions of 2-alkylcyclohexanone enamines also proceed with high stereoselectivity, leading predominantly to the cis amines in the six-membered ring derivatives (66-96%), and almost exclusively in the case of the five-membered enamines (95-98%) (Scheme 84). The A1,3 strain112 in fact would shift the conformational equilibrium towards the axial (or pseudo xial) orientation of the substituent. 

In contrast, lack of stereoselectivity was found in the reduction of a heterocyclic enamine with NaBH4 (and H2/Pt02), as four isomers were formed. Three of them were isolated130 (Scheme 95). 

Selection of test items so that they are as dissimilar a possible to each other is accomplished by choosing items which are projected far from each other and on the periphery of the plot. Such designs are useful for answering the question of whether or not the properties have an influence. A maximum spread design wa used to determine whether modification of the solvent would increase the endo/exo stereoselectivity in the reduction of an enamine from camphor. The answer was negative [17 a],... 

Nilsson, L., Rappe, C. Alkylation of enamines. A convenient route to 1,4-dicarbonyl compounds. Acta Chem. Scand. 1976, B30,1000-1002. Schubert, S., Renaud, P., Carrupt, P. A., Schenk, K. Stereoselectivity of the radical reductive alkylation of enamines importance of the allylic 1,3-strain model. Helv. Chim. Acta 1993, 76, 2473-2489. 

The reduction of the morpholine enamine from camphor by the reaction with formic acid was discussed in Chapter 5. In the example below, this reaction was applied to the reduction of the corresponding pyrrolidine enamine. The reaction was conducted without any solvent present, i.e. by adding formic acid dropwise to the hot enamine, and afforded an almost quantitative conversion to the corresponding bornyl pyrrolidine. However, the reaction was not stereoselective and a mixture of endo and exo isomers was formed. The proportions were endo isomer (85 %), exo isomer (15 %). This was regarded as a promising result. 

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