Enamines stereoselectivity

The condensation of aldehydes or ketones with secondary amines leads to "encunines via N-hemiacetals and immonium hydroxides, when the water is removed. In these conjugated systems electron density and nudeophilicity are largely transferred from the nitrogen to the a-carbon atom, and thus enamines are useful electroneutral d -reagents (G.A. Cook, 1969 S.F. Dyke, 1973). A bulky heterocyclic substituent supports regio- and stereoselective reactions. 

Thermal and photochemical electrocyclic reactions are particularly useful in the synthesis of alkaloids (W. Oppolzer, 1973,1978 B K. Wiesner, 1968). A high degree of regio- and stereoselectivity can be reached, if cyclic olefin or enamine components are used in ene reactions or photochemical [2 + 2]cycloadditions. 

Cyanoallene, when treated with the morpholine enamine of cyclohexanone, undergoes a 1,3-cycloaddition reaction to form 72 (89). The reaction between cyanoallene and diendiamine 73a produces di-1,2-cycloaddition adduct 73 (i 9). The 4a-azonioanthracene ion (73b) readily undergoes a 1,4-cycloaddition reaction with nucleophilic dienophiles such as enamines (89a). The cycloaddition is stereoselective so that the a- and... 

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. 

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. 

The intramolecular cyclization of enolate of l-tryptophyl-3-((3-ketobutyl) pyridinium bromide (160) afforded enamine 161, which undergoes stereoselective acid cyclization with cone. HCl to give the pentacyclic ketone 162 (Catalytic hydrogenation of 162 led to (d,l)-pseudoyohimbone (163) (76JA3645). Again, H3-H15 were found to have the tmns configuration in 162. 

This was ihe first investigation of stereoselective formation of geometric isomers of tertiary amines. The authors suggested most enamine systems should be subject to considerable stereochemical control. 

The isomerization of an allylic amine to an enamine by means of a formal 1,3-hydrogen shift constitutes a relatively small structural change. However, this transformation could be extremely valuable if it could be rendered stereoselective. In important early studies, Otsuka and Tani showed that a chiral cobalt catalyst, prepared in situ from a Co(ii) salt, a chiral phosphine, and diisobutylaluminum hydride (Dibal-H), can bring about the conversion of certain pro-chiral olefins to chiral, isomeric olefins by double bond migra-... 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

The stereoselectivity of the addition of an enamine to an iminium salt is not significantly influenced by its anion. Therefore, iminium chlorides 2a can also be used. Indeed, they are the reagents of choice on large scale syntheses. Compared to iminium chlorides 2a the corresponding tctrachloroaluminates 2b are clearly less hygroscopic and for that reason particularly easy to handle 1. 

High stereoselectivity is also observed in the addition of an enamine using 2-methoxymethylpyrrolidine as the amine.327... 

A key step in the synthesis in Scheme 13.11 was a cycloaddition between an electron-rich ynamine and the electron-poor enone. The cyclobutane ring was then opened in a process that corresponds to retrosynthetic step 10-IIa 10-IIIa in Scheme 13.10. The crucial step for stereochemical control occurs in Step B. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate. 

The cyclobutane ring was then cleaved by hydrolysis of the enamine and ring opening of the resulting (3-diketone. The relative configuration of the chiral centers is unaffected by subsequent transformations, so the overall sequence is stereoselective. Another key step in this synthesis is Step D, which corresponds to the transformation 10-IIa => 10-la in the retrosynthesis. A protected cyanohydrin was used as a nucleophilic acyl anion equivalent in this step. The final steps of the synthesis in Scheme 13.11 employed the C(2) carbonyl group to introduce the carboxy group and the C(l)-C(2) double bond. 

Enamines are reduced to amines in good yields with Et3SiH/TFA.529 533 This reagent combination causes a variety of indoles to undergo stereoselective cis... 

The intermolecular ruthenium enyne Alder-ene reaction has been extended to the stereoselective preparation of enamines (Equation (26)).39 The yields obtained for this reaction were high with allylacetamides, -benzamides,... 

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). 

The reaction of 1,2-propadienyl p-tolyl sulfoxide with tert-butylamine gave a (Z)-enamine, indicating that the C=C bond migrated from the /3,y-position to the apposition [95]. The stereoselectivity may be explained by the intramolecular hydrogen bonding in (Z)-184. 

The chiral furan 120, prepared from 119, underwent a Diels-Alder reaction with racemic 110b (4equiv.) at -100 °C. Kinetic resolution of the allenic diester efficiently occurred to afford the oxabicydic enamine adduct 121 stereoselectively [100], The adduct was transformed to (+)-cydophellitol. 

For a synthesis of leurosidine (56), 15,20-dihydrocatharanthine iV-oxide (57) was subjected to coupling with vindoline (3) under the modified Polo-novski conditions. The initial adduct, imonium salt 58, was converted to the enamine 59 in base. Oxidation of this product with osmium tetrox-ide proceeded chemo- and stereoselectively, without reaction of the... 

Scheme 13.10. The stereoselectivity of this step results from preferential protonation of the enamine from the less hindered side of the bicyclic intermediate.

One of the most widely applied cycloaddition techniques for the preparation of thietanes is the reaction of sulfenes with enamines. The stereochemistry of these reactions has been extensively investigated by Truce and Rach. Whether the mechanism is a two-step or a concerted process, both in accordance with the stereoselective formation of the cis form in Scheme 1, is still unresolved. The special orientation of the 1,4-dipolar intermediate 64, in which the charged phenyl and dimethylamino moieties are in proximity, enforces the cis geometry of the resulting thietane dioxide. In the concerted mode of reaction, formation of the orthogonal oriented unsaturated system, 65 should also yield the cis cycloadduct. 

The stereoselective or stereospecific formation of these compounds and their interaction with butyllithium was studied with the help of NMR. Paquette and Freeman first applied asymmetric induction to the synthesis of four-membered rings, especially with the sulfene-enamine 2 -F 2 cycloaddition. The in situ generation of sulfene 68 by dehydrochlorination with butyllithium of the sulfonyl chloride allowed the formation of cycloadduct 69 in 88 % yield. In a variation, the sulfene may be generated by base-induced... 

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