Enantio-enriched -amino

Palladium-catalyzed carboalkoxylation of imidoyl iodides 6 provides benzyl [9] and even te/t-butyl[10] esters 7. Asymmetric hydrogenation of the imino moiety of imono esters 7 in a Pd(OCOCF3)2 / (7 )-BINAP / CF3CH2OH system gives enantio-enriched amino esters 8 in 85-91% ee (see Scheme 9.2) [11].The enantioselectivity achieved by the hydrogenation was much better than that by Corey s hydride reduction [12] and was employed for the syntheses of enantiomerically pure A-Boc-(3,(3-difluoroproline benzyl ester 9 (see Scheme 9.3)[13] and enantiomerically enriched A-Boc-P -difluoroglutamic acid benzyl ester [13]. 

A recent development of this approach by Jeajean et al. is a synthesis of highly enantio enriched amino acids from the oxazolidinone 26, as illustrated in Eq. (1) for the preparation of 27 with drs of 96 4 [21]. 

Scheme 4.34 Application of PEG-supported ligand (56) for the synthesis of enantio-enriched a-amino acids.

Tomoyasu, T. Tomooka, K. Nakai, T. Asymmetric synthesis of enantio-enriched acyclic a-amino alkylstannanes and rearrangement behavior of carbanions thereof. Tetrahedron Lett. 2003, 44,1239-1242. 

For diaryl amino alcohols as enantio-enriched oxazaborolidine precursors, see (a) Itsuno, S. Ito, K. Hirao, A. Nakahama, S J. Chem. Soc., Cham. Commun. 

Preparative Methods substituted 2,3-methanoamino acids are difficult to prepare. Unfortunately, most of the reported syntheses give racemic materials whereas stereochemically pure compounds are required for studies of cyclopropane-based peptidomimetics. The only 2,3-methanologs of protein amino acids prepared in optically active form are ( )- and (Z)-cyclo-Phe and -Tyr, all four stereoisomers of cyc/o-Met, (Z)-cyclo-Arg and (25,35)-(Z)-cyc/o-Trp, although several routes to enantio-enriched 2,3-methanologs of simple nonproteogenic amino acids have been reported. " The most practical synthesis of the title compound is that based on a diastereoselective, rhodium-catalyzed cyclopropanation reaction. ... 

Noyori asymmetric hydrogenation Formation of enantio-enriched carboxylic acids, alcohols and amino acids from unsaturated carboxylic acids, allylic alcohols and enamides, respectively. 316... 

Asymmetric dihydroxylation of trifluoromethylalkenes is also useful for construction of enantio-enriched trifluoromethylated diols usable for trifluoromethylated amino acids with chiral hydroxyl group. Thus, Sharpless AD reaction of 16 provides diol 17 with excellent enantioselectivity. Regioselective and stereospecific replacement of the sulfonate moiety in 18 with azide ion enables the introduction of nitrogen functionality. A series of well-known chemical transformation of 19 leads to 4,4,4-trifluorothreonine 20 (see Scheme 9.6) [16]. Dehydroxylative-hydrogenation of 21 by radical reaction via thiocarbonate and subsequent chemical transformation synthesize enantio-enriched (S)-2-amino-4,4,4-trifluoro-butanoic acid 22 [16]. Both enantiomers of 20 and 22 were prepared in a similar manner from (2R,3S)-diol of 17. 

Oxazolidine 130 is a masked aldimine bearing a chiral N-(2-hydroxy-l-phenyl)ethyl moiety and is readily available from (R)-phenylglycinol. Mannich reaction of 130 with Reformatsky reagent of ethyl bromodifluoroacetate produces difluorolactam 131 in high diastereoselectivity, which is then transformed to enantio-enriched (S)-3-amino-2,2-difluoro-3-phenylpropanoic acid 133 (see Scheme 9.28) [55]. 

Nakai and coworkers have reported that a mixture of diastereomeric tin precursors 28 can be used to provide highly enantio enriched products, as shown for the conversion of 28 to 29 (Scheme 8). Furthermore, reduction of 29 is diastere-oselective to afford (following chiral auxiliary removal) enantio enriched (3-amino alcohols, 30 [22]. In another report, Nakai has described the conversion of the diastereomeric organolithium intermediates from tin-lithium exchange of 28 to copper species which can be used for 1,4 additions to a, 3-unsaturated aldehydes... 

Peters applied the cooperative activation by a soft bimetallic catalyst 220, a hard Br0nsted acid, and a hard Bronsted base to the formation of highly enantio-enriched, diastereomerically pure masked a-amino acids 225 bearing adjacent tetrasubstituted and tertiary carbon stereocenters on the basis of a domino azlactone formation/Michael addition reaction starting from N-benzoylated amino acids 221 and a,P-unsaturated ketones 180 (Scheme 11.47). Since the activated catalyst was stable toward acetic anhydride, the in situ formation of azlactones 223 could be achieved through O-acylation with acetic anhydride of N-benzoylated amino acids... 

As an extension of this work, a total synthesis of sulfobacin A, a von Willebrand factor receptor antagonist, was reported by the same group, in 2004. The key steps of this short route to sulfobacin A involved ruthenium-catalysed asymmetric hydrogenation reactions of a /i-ketoester and a /J-keto-a-amino ester hydrochloride to afford, respectively, the corresponding enantiomerically pure S-hydroxy ester and the enantio-enriched anti -hydroxy-a-amino ester hydrochloride through DKRs (Scheme 2.15). 

A -Phosphinoyl and A -thiophosphinoyl ketimines, Ph-C(Me)=N-P(=X)Ph2 (X = O and S), have been hydrophosphonylated in high yield and ee using a copper(I) catalyst liganded with a chiral diphosphino ethane. In the case of the sulfur substrates, facile differentiated removal of the t/imphosphinoyl group affords a-amino phosphonic acid derivatives, Ph- C(Me)(NH2)-P(=0)(0Et)2, that is, phosphonic acid analogues of enantio-enriched a,a-disubstituted a-amino acids. The reaction also accommodates alkyl, cycloalkyl and alkenyl substituents in place of the phenyl. 

N-heterocyclic carbene catalysis has become one of the major categories in orga-nocatalysis. Azolium salts are ready deprotonated by weak bases to generate a carbene, which then adds to an aldehyde to form an acyl anion equivalent, generally called the Breslow intermediate. The reactive acyl anion attacks an electrophile to promote the various transformations such as benzoin, Stetter, and redox reactions [107]. Recently, an interesting approach for NHC-catalyzed generation of an enol/enolate intermediate was reported. Enantio-enriched (i-amino acid derivatives (217) are formed by the reaction between the a-aryloxyaldehyde 214 and N-tosyl-imines (215) in the presence of phenyalanine-derived azoUum salt 216 as a pre-catalyst and aryl phenoxide as a base (Scheme 28.28) [108]. 

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