Asymmetric nitrogen nucleophile

During our investigations on asymmetric C—C bond formation reactions via conjugate addition of SAMP hydrazones to various a,(3-unsaturated Michael acceptors, it occurred to us to use the chiral hydrazine auxiliary S AM P as a nitrogen nucleophile and a chiral equivalent of ammonia in aza-Michael additions. Thus, we developed diastereo- and enantioselective 1,4-additions for the synthesis of P-amino acids and P-aminosulfonates [14, 15]. 

Reaction with Nitrogen Nucleophiles. The acid-catalyzed reaction of primary, secondary, and tertiary amines with ethyleneimine yields asymmetrically substituted ethylenediamines (71). Steric effects dominate basicity in the relative reactivity of various amines in the ring-opening reaction with ethyleneimine (72). The use of carbon dioxide as catalyst in the aminoethylation of aliphatic amines, for which a patent application has been filed (73), has two advantages. First, the corrosive salts produced when mineral acids are used as catalysts (74,75) are no longer formed, and second, the reaction proceeds with good yields under atmospheric pressure. 

Asymmetric cycloaddition of 2-vinyloxiranes to carbodiimides proceeds in the presence of Pd2(dba)3-CHC13 and TolBINAP as the chiral ligand in THF at room temperature to yield 4-vinyl-l,3-oxazolidin-2-imines with up to 95% ee [74] (Eq. 8A.50). The enantio-determining step is assumed to be the nucleophilic attack of a nitrogen nucleophile on a 7i-allylpalladium intermediate. Reactions of 2-vinyloxiranes with isocyanates using the same catalyst system afford 4-vinyl-l,3-oxazolidin-2-ones with low enantioselectivity. 

Scheme 8E.28. Asymmetric alkylation of vinyl epoxide with nitrogen nucleophile.

An asymmetric version of a Michael addition with nitrogen nucleophiles can be also realized with simple short-chain peptides as catalysts. This has been demonstrated by Miller et al. for the addition of an azide to a,/(-unsaturated carbonyl compounds [16]. In the presence of the tripeptide 9 as a catalyst (2.5 mol-%) the products 10 have been formed in excellent yields and with up to 85% ee (Scheme 7). In addition, this reaction represents an attractive access to /(-amino acids. 

Reactions with Nitrogen Nucleophiles. The palladium(O)-catalyzed asymmetric desymmetrization of cw-3,5-dibenzoyloxy-1-cyclopentene, with 6-chloropurine and 2-amino-6-chloropurine as nucleophiles, has been utilized in the synthesis of (-)-carbovir and (—)-neplanocin. In these examples, the diphenylethanediamine and the anthracenyldiamine based ligands were found to be superior to the standard ligand. 

Later work has shown that a dynamic kinetic asymmetric transformation could be obtained if the acetates were converted into carbonate groups. With the tetra(2,2,2-trichloroethyl) carbonate derivative, reactions with carbon and nitrogen nucleophiles gave exclusively the monosubstituted products in high yield (61-95%) and excellent enantiomeric excesses (95-99%). However, car-boxylate nucleophiles afforded the disubstituted products in high yield and enantiomeric excess (eq 7). This allowed an efficient synthesis of D-myo-inositol-l,4,5-trisphosphate to be devised. 

Although a vast amount of research has been devoted to the asymmetric 7i-allylic subshtuhon of acyclic esters (e.g. 1,3-diphenylpropenyl esters) with carbon and nitrogen nucleophiles, studies on the catalytic asymmehic subshtuhon of cyclic... 

Reactions of chiral allylic boranes with carbonyl compounds Reactions of chiral allyl boranes with imines Asymmetric Addition of Carbon Nucleophiles to Ketones Addition of alkyl lithiums to ketones Asymmetric epoxidation with chiral sulfur ylids Asymmetric Nucleophilic Attack by Chiral Alcohols Deracemisation of arylpropionic acids Deracemisation of a-halo acids Asymmetric Conjugate Addition of Nitrogen Nucleophiles An asymmetric synthesis of thienamycin Asymmetric Protonation... 

Sharpless asymmetric epoxidation (chapter 27) of the allylic alcohol 148 with cumyl hydroperoxide and (+)-di-isopropyl tartrate (DIPT) gave the epoxide 149 in excellent yield and enantiomeric purity. The other enantiomer could be made simply by using the other enantiomer of DIPT. The problem is now how to react the epoxide regiospecifically with a nitrogen nucleophile ... 

The application of chiral sulfoxides to the asymmetric synthesis of biologically active compounds has recently been reviewed [3]. Conjugate addition to chiral vinyl sulfoxides has been used by several research groups to achieve the enantioselective synthesis of natural products. For example, intramolecular asymmetric conjugate addition of a nitrogen nucleophile to a chiral vinyl sulfoxide (Scheme 3) was studied by Pyne and applied to the enantioselective synthesis of (-R)-carnegine and other alkaloid systems (Scheme 3) [10]. 

Ma has developed a three-component allene carboamination reaction for the stereoselective synthesis of 2,5-as-disubstituted pyrrolidine derivatives [54]. A representative transformation involving allene 58, 4-iodoanisole, and imine 59 that generates 60 in 90% yield is shown below (Eq. (1.28)). The reaction is believed to proceed through the intermediate Jt-allylpalladium complex 62, which is formed by carbopalladation of the alkene to give 61 followed by addition of the malonate anion to the activated imine. Intramolecular capture of the allylpalladium moiety by the pendant nitrogen nucleophile affords the pyrrolidine product. A related asymmetric synthesis of pyrazolidines that employs azodicarboxylates as one of the electrophilic components has also been reported [55]. The pyrazolidine products are obtained with up to 84% ee when chiral bis oxazolines are employed as ligands. 

More recently, Enders et al. disclosed a facile access to tetracyclic double annulated indole derivatives 175, which basically relies on the chemistry of the acidic 2-substituted indole and its nitrogen nucleophilicity. Indeed, the employed quadruple cascade is initiated by the asymmetric aza-Michael-type A-alkylation of indole-2-methylene malono-nitrile derivative 174 to o,p-unsaturated aldehydes 95 under iminium activation (Scheme 2.57). The next weU-known enamine-iminium-enamine sequence, which practically is realized with an intramolecular Michael addition followed by a further intermolecular Michael and aldol reactions, gives access to the titled tetracyclic indole scaffold 175 with A-fused 5-membered rings annulated to cyclohexanes in both diastereo- and enantioselectivity [83]. 

The final synthesis we will consider uses asymmetric catalysis to establish absolute stereochemistry. Thus, treatment of cyclohexenone (172) with dimethylzinc and catalytic Cu(I) in the presence of chiral ligand 173 proceeded with good asymmetric induction. Alkylation of the intermediate enolate using allyl acetate in the presence of Pd(0) provided 174 with 96% ee. This ketone was reduced to provide a mixture of alcohols which were separated and converted to 171 by degrading the allylic side chain to a carboxyl group, and displacing the alcohol with a nitrogen nucleophile. 

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