Amide asymmetric addition

The first example of asymmetric rhodium-catalyzed 1,4-addition of organoboron reagents to enones was described in 1998 by Hayashi and Miyaura. Significant progress has been made in the past few years. This asymmetric addition reaction can be carried out in aqueous solvent for a broad range of substrates, such as a,/ -unsaturated ketones, esters, amides, phosphonates, nitroalkenes. The enantioselectivity is always very high (in most cases over 90% ee). This asymmetric transformation provides the best method for the enantioselective introduction of aryl and alkenyl groups to the / -position of these electron-deficient olefins. 

In 2001, Miyaura and Sakuma reported the asymmetric addition of arylboronic acids to a,/3-unsaturated amides in the presence of the Rh(acac)(C2H4)2/(V)-BINAP catalyst (acac = acetylacetonate Scheme 36).112 The... 

This kind of asymmetric addition was also applicable for a,/3-unsaturated ester and amide, which gave the corresponding /2-phenylation products with good selectivity (Scheme 59). 

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides. In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed. In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine. Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above. 

Asymmetric addition to a chiral a-keto amide. The Lewis acid-catalyzed addition of allyltrimethylsilane to a chiral a-keto amide (1) derived from methyl (S)-prolinate proceeds with good to high diastereoselectivity, probably because of chelation with the ester group of 1. SnBrj, SnCU. and TiCU are the most effective catalysts. 

Asymmetric addition to chiral oxazolines. The chiral 1-oxazolinylnaphthalene 2, obtained by the reaction of (-I- )-l with a-naphthy.amide, reacts with an organolithium to form an intermediate enolatc that is trapped on me opptisite face by an electrophile to give 3 as a mixture of diastereomers in the ratio s3 17. The major product results from attack of the organolithium at the p-facc. The dia tercomers arc separable by flash chro-... 

The cinchona alkaloids are particularly valuable ligands in asymmetric addition of diethylzinc to a N-diphenyl phosphinoylimine (228) leading to enantiomerically enriched (R)- and (S)-N-(l-phenylpropyl-diphenylphosphinic amide) (229). Cinchonine and cinchonidine were found to be the pseudo-enantiomeric pair which gave the adduct in highest enantiomeric excess (up to 93% ee) (Scheme 62)." ... 

Asymmetric addition of Grignard reagents to oiy -unsaturated amides, In... 

Kobayashi et al. developed catalytic asymmetric 1,4-additions using chiral calcium species prepared from calcium isopropoxide and chiral bisoxazoline ligands 39, 166 and 168. They found that calcium pyBOX catalysts could effectively mediate catalytic asymmetric additions of 1,3-dicarbonyl compounds 4 to nitroalkenes 86, N-Boc-imines 138 or unsaturated amides 49 giving products 165,167 and 170, respectively. Neutral coordinative ligands worked well in these reactions, giving a noticeably faster rate of reaction... 

A copper-catalyzed asymmetric addition of diorganozinc reagents to N-phosphi-noylimines has been developed for the synthesis of chiral a,a,a-trifluoromethyl-amides (249). Ketimines (250), generated in situ from the corresponding hemiaminals, led to the chiral amides in high yields and excellent enantiocontrol (Scheme 101). ... 

The rhodium-catalyzed addition of aryl- and 1-alkenylboronic acids tooc, unsaiurated ketones, aldehydes, esters, and amides gave the conjugate 1,4-addition products in high yidds. The ifaodium(I) complexes also catalyzed the 1,2-addition of organoboronic acids to aldehydes or N-sulfonyl aldimines. The dficiency of protocol was demonstrated in the asymmetric addition reactions of organoboronic acids in the presoice of a rhodium(acacV BINAP complex. 

The answer suggests the Michael-type asymmetric addition of an enantiopure amine or its more reactive anion to enone to 23b. The authors used a lithium amide reagent for the addition to obtain the key chiral intermediate 23c (Scheme 3.9) [14]. The selected (S)-configuration of the phenyl ethylamino unit in the chiral amide anion induces the (7 )-configuration in the precursor of —)- R)-sitagliptin. 

This review describes recent progress in asymmetric addition reactions of soft Cu (l)-conjugated carbon nucleophiles in the presence of protic functional groups, mainly focusing on chemoselectivity. Protic functimial groups of amides, hydroxy... 

All of the above mentioned W,X-acetalizations are based on the well-established ability of phosphoric acids and their derivatives to catalyze asymmetric additions of nucleophiles to imines. Imines are readily activated by Brpnsted acids due to their relatively high basicity, and the intermediate iminium ion possesses strong hydrogen bonding to the chiral anion (Scheme 7). This makes the ion pair reasonably well organized enabling an efficient enantiocontrol. The crucial step in the direct N,N- and 77,0-acetalizations of aldehydes is the intramolecular asymmetric addition to an iminium ion intermediate, which is formed after the condensation of the amide or amine moiety with the aldehyde (Scheme 7). 

Abraham, E., Brock, E.A., Candela-Lena, J.I., Davies. S.G., Georgiou, M., Nicholson, R.L., Perkins, J.H., Roberts, P.M., Russell, A.J., Sanchez-Femandez, E.M., Scott, P.M., Smith, A.D., and Thomson, J. E. (2008) Asymmetric synthesis of N,0,0,0-tetra-acetyl o-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylUne via lithium amide conjugate addition. Org. Biomol. Chem., 6,1665—1673. 

Oniy diastereomer Yamamoto s asymmetric addition of amide cuprate [6]... 

A-Acido imines (R R"C = N —X=0) like /V-acyl (X = CR) /V-sulfonyl [X = S(R)=0]2-7 or /V-diphenylphosphinoylimines [X = P(C6H5)2]3 are masked inline derivatives of ammonia. Compared to the imines themselves these activated derivatives are better electrophiles showing less tendency to undergo undesired deprotonation rather than addition of organometal-lics1812 The apparent advantages of these compounds have been exploited for asymmetric syntheses of amines, amides, amino acids and /J-lactams1-8 I6. 

Substantially high diastereoselectivity was accomplished by the conjugate addition of Grignard reagents to the amide 1 derived from 1-ephedrine32. The reagent attacked from the Re-face of the double bond, as shown in 2, via a chelated intermediate. Low asymmetric induction was observed when butyllithium was used instead of butylmagnesium bromide. 

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