Enantioselective imine additions

Zr-Catalyzed Enantioselective Cyanide Additions to Imines (Strecker Reactions)... 

Scheme 6.22. Zr-catalyzed enantioselective cyanide addition to imines in the presence of Bu3SnCN.

Chiral amines, ArCH(R)NH2, can be prepared by addition of a dialkylzinc to A-(diphenylphosphinoyl)imines, ArCH=N—P(=0)Ph2, using a suitable auxiliary, followed by acid hydrolysis to cleave the phosphorus moiety. A series of 2-azanorbornylmethanols (65) give ee% up to 92%, and they also induce some enantioselectivity in additions to benzaldehyde. A highly organized transition state with two zincs is proposed one coordinates the nitrogens of substrate and catalyst and the other coordinates the oxygens. 

To date, hydrogen bond catalysis has been successfully utilized to facilitate enantioselective Michael additions, Baylis-Hillman reactions, Diels-Alder cycloadditions, and additions of 7i-nucleophiles to imines. 

In enantioselective enamine catalysis, the enamine can control the approach of the electrophile either by the steric bulk of the enamine or by directing the electrophile with an activating group. As can be readily observed with relatively unreactive electrophiles, such as aldehydes, ketones or imines, additional assistance for catalysis can be provided by suitably positioned hydrogen bond donors and/or other acids (Scheme 6) [46]. 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

Enantioselective nucleophilic addition to imines has been carried out with a planar-chiral Lewis acid based on a 1,2-azaborolyl framework. 64 ... 

Lewis acid and the oxygen atom of the phosphane oxide, respectively. With this catalyst system, N-allyl- and N-benzhydrylimines generally gave lower enantioselectivities. The addition of phenol was found to have a beneficial effect on the reaction rates. The JandaJEL -supported bifunctional catalyst of 14 has also been shown by Shibasaki and co-workers to promote the Strecker-type reaction of aromatic and a,/ -unsaturated imines in excellent yields with 83-87% ee in the presence of tert-butanol (110%) [11]. The reactivity of the Janda/EL catalyst was comparable to the homogeneous analogue 14, and the catalyst could be recycled at least four times. 

Although in some cases, copper catalysis has little effect on the stereochemistry, some asymmetric induction by chiral copper catalysts such as copper(i) complexes of aminotropone iminates (8) [79] or the chiral arylthiocopper compound (9) [80] has been achieved. Chiral zinc(n) complexes (8) also promote enantioselective conjugate addition [81]. 

Enantioselective Copjugate Additions. The use of chiral imines for the enantioselective conjugate addition of carbonyl compounds to a,p-unsaturated systems is well established, mostly with imines derived from a-methylbenzylamine. Recently, (1) has been used to effect the Michael addition of a 4-piperidone to acrylonitrile and methyl acrylate (eq 2) ... 

The reaction is somewhat selective for the cis-diastereomer. The use of chiral additives in this reaction leads to aziridines enantioselectively. " Imines can be formed by the reaction of an aldehyde and an amine, and subsequent treatment with Me3SiI and butyllithium gives an aziridine. " A-Tosyl imines react with diazoalkenes to form A-tosyl aziridines, with good cis-selectivity " and modest enantioselectivity in the presence of a chiral copper catalyst, " but excellent enantioselectivity with a chiral rhodium catalyst. . It is noted that A-tosyl aziridines are formed by the... 

Ricci, Pettersen, and coworkers reported that P-isocupreidine (P-ICD) derived from quinidine (69,20 mol%) promotes the enantioselective decarboxylative addition of the malonic half thioesters 70 to the imines 71 to afford the protected P-amino thioesters 72, which act as precursors for the preparation of P-amino acids [32] (Scheme 8.23). However, only low to moderate ee values (4—79% ee) were obtained. 

Aminals, compounds having two amino groups bound to the same carbon atom, are represented in many medicinal agents having versatile therapeutic action, such as proteinase inhibitors and neurotensins. Antilla and coworkers developed an en antioselective synthesis of protected aminals from the amidation reaction of N Boc imines with a series of sulfonamides catalyzed by chiral phosphoric acids (Scheme 3.54a) [111]. In this novel enantioselective transformation, phosphoric acid 9 exhibited excellent catalytic activity and enantioselectivity in addition to N Boc aromatic imines. The enantioenriched aminal products were stable upon storage neither decomposition nor racemization was observed in solution over several days. The same research group reported the enantioselective amidation reaction of N Boc aromatic imines with phthalimide or its derivatives (Scheme 3.54b) [112]. 

The vinylogous Mannich reaction of 2 silyloxy furans and imines may also be catalyzed through chiral Brpnsted acids, as shown by Akiyama et al. [10]. Previously, Akiyama [11] and Terada [12] had independently discovered that 3,3 substituted BINOL based phosphoric acids were excellent Bronsted acids for a broad range of mainly imine addition reactions via protonation of the imines and in situ formation of chiral iminium contact ion pairs. Using the slightly modified phosphoric acid 28 as catalyst carrying additional iodine substituents in the 6,6 positions, the y amino substituted butenolides 27 were obtained in excellent enantioselectivity and variable diastereoselectivity (Table 5.4). 

The reactions of N arylidenediphenylphosphinamides with hexafluoroisopropyl acrylate (HFIPA) to give the corresponding aza MBH adducts in moderate to excellent yields with good enantiomeric excesses was also reported by Hatakeya ma [20] (Scheme 13.11). In contrast to the corresponding aldehydes, imines show the opposite enantioselectivity, and Hatakeyama and coworkers indicated that H bonding was responsible for the reversal in enantioselectivity. Michael addition... 

The second report of catalytic enantioselective organolithium additions to the imine group came in 1991 from the laboratories of Itsuno and co-workers [23aj. These researchers studied the addition of -BuLi to AT-(trimethylsilyl)benzalde-hyde imine 5a in the presence of chiral modifiers such as alcohols, diols, and amino alcohols (<1 g of imine, ca. 0.13 M). The chiral ligands used were easily prepared according to literature procedures. The enantiomerically enriched primary amine 6 was obtained in 27-90% yield after appropriate workup, depending on the nature of the chiral ligand and the reaction solvent (Scheme 4). 

The first prominent catalytic asymmetric addition of an organolithium reagent was realized in the reaction of 1-naphthyllithinmwith l-fluoro-2-naphthy-laldehyde imine in the presence of the chiral diether 1 to afford chiral binaphthyls in over 82% ee (Scheme 2). Merely a catalytic amount of 1 (5 mol %) is required to effect the reaction, in which an enantioselective conjugate addition-elimination mechanism is operative [18]. 

Another approach to the synthesis of p hydroxy-a-amino acids is by aldol reaction of imines derived from amino adds. The benzophenone imine of glycine (7.102) undergoes highly enantioselective aldol addition with a range of aliphatic aldehydes, including (7.71) xmder phase-transfer conditions in the presence of the bromide salt of phase-transfer catalyst (7.103). A similar transformation is catalysed, in low to moderate ee, by the bimetallic catalysts developed by Shibasaki and CO workers. ... 

Lateral Lithiation. An enantioselective synthesis of tetrahydroisoquinolin-l-ones via a BuLi/(—)-sparteine-mediated lateral metalation-imine addition sequence proceeds with highest yields and induction in toluene/ether mixtures (eq 46). ... 

The enantioselective alkyne-imine addition has been achieved using a copper(i)-bis(oxazoline) compound in [G4GiIm]N(GF3S02)2 (Scheme 46). ... 

Binaphthol-derived chiral phosphoric acid catalysts (137 or 157-162) have been applied to enantioselective radical addition reactions of alkyl iodides to imines (155) and provided chiral amines (156) in good enan-tioselectivities (73-84% ee) (Scheme 42). " ... 

The chiral, proline-derived a-aminoalcohol ligand (606) was applied to the enantioselective, nucleophilic addition of trimethylsilylacetylene (605) to aromatic, heteroaromatic and aliphatic A-(diphenylphosphinoyl)imines (603) to give optically active propargylic phosphinoamides (605) in good yields (up to 92%) and enantioselectivities (up to 95%) (Scheme 150). ° ... 

Scheme 4.42 89a-catalyzed enantioselective Michael addition of a glycine imine to... 

The same trend as with imine was observed for the enantioselective diethylzine addition to benzaldehyde and the best results (94% yield and 90% ee) were also obtained with PS(Ephed)s [143],... 

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