Chiral a-amino acetals

Using the chiral a-amino acetal 1-120 ion and two different N-nucleophiles 1-122 and 1-123, the pyrrolidines 1-124 and 1-125, respectively, are obtained in good di-... 

Scheme 27 Addition of nitronates, enolates and silyl ketene acetals to chiral a-amino imines and iminium ions...

The aldol reaction between a chiral a-amino aldehyde 16 and an acetate derived enolate 17 creates a new stereogenic center and two possible diastereomers. Several different methods for the synthesis of statine derivatives following an aldol reaction have been reported most of them lead to a mixture of the (35,45)- and (3/ ,45)-diastereomers 18 (Scheme 3), which have to be separated by laborious chromatographic methods.[17 211 Two distinct approaches for stereochemical control have been used substrate control and reagent control. 

Since the allyl function represents a latent carboxy unit, diastereomerically pure homoallylic alcohols syn-21 or anti-21, obtained by condensation of allylic metals 26 with chiral a-amino aldehydes or acetals (Scheme 6), have been used to prepare the corresponding y-amino-p-hydroxy acids (Scheme 7). 

TiCU-mediated addition of silyl enol ether (95) to chiral a-amino aldehyde (94) was reported to proceed with good chelation control, albeit in poor yield (equation 28). Effective chelation control was also reported in the TiCU-mediated reactions of chiral a-alkoxy and p-alkoxy acyl cyanides (96) and (97) with silyl enol ether (95 equations 29 and SO). Reaction of acyl cyanide (97) with the ( )-silyl enol ether (93) gave a single stereoisomer as a result of complete chelation control and syn simple stereoselection (equation 31). Additions of silyl enol ethers and silyl ketene acetals to (-)-menthyl phenyl-glyoxylate and pyruvate were reported to proceed with moderate facial selectivity the best result (84 16) is shown in equation (32). ... 

A catalytic and enantioselective alkylation of Af,0-acetals, protected by the SES group, is an interesting method to prepare various chiral a-amino esters from a common precursor, the SES hydroxyglycine (21), which is easier to form and more resistant to hydrolysis than the corresponding imine (eq 21). A first equivalent of enol silyl ether reacts with iV,0-acetal (21) to form the imine intermediate in situ. Eventually, a second equivalent of enol silyl ether is necessary to perform the alkylation of the Cu(I) SES imine complex. 

Muralidharan KR, MokhaUalati MK, Pridgen LN. Enantioselective synthesis of a-amino acetals (aldehydes) via nucleophilic 1,2-addition to chiral 1,3-oxazolidines. Tetrahedron Lett. 1994 35 7489-7492. 

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Chiral cyclic /V,D-acetals of glyoxal and their use for preparation of a-amino acids 98SL449. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Hepatite Virus NS3/4A having the pyrrolidine-5,5-trans-lactam skeleton [83], starting from (R)- and (S)-methionine, respectively. The key step is the addition of the proper silyl ketene acetal to an iminium ion, e.g., that generated by treatment of the intermediate 177 with boron trifluoride, which provided the adduct 178 with better diastereoselectivity than other Lewis acids. Inhibitors of hepatitis C virus NS3/4A were efficiently prepared by a similar route from (S)-methionine [83]. The addition of indole to a chiral (z-amino iminium ion was a completely diastereoselective step in a reported synthesis of tilivalline, a natural molecule which displays strong cytotoxicity towards mouse leukemia L 1210 [84]. 

General procedures for the synthesis of the imidazole core have been published in 2000. Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles 64 from aldehydes 62 and 1,2-dicarbonyl compounds 63 in the presence of ammonium acetate and alumina has been reported <00TL5031>. V-protected a-amino glyoxals 65 were utilized as potential chiral educts for the synthesis of amino acid-derived imidazoles 66 <00TL1275>. 

Another chiral auxiliary for controlling the absolute stereochemistry in Mukaiyama aldol reactions of chiral silyl ketene acetals has been derived from TV-methyl ephedrine.18 This has been successfully applied to the enantioselec-tive synthesis of various natural products19 such as a-methyl-/ -hydroxy esters (ee 91-94%),18,20 a-methyl-/Miydroxy aldehydes (91% ee),21 a-hydrazino and a-amino acids (78-91% ee),22 a-methyl-d-oxoesters (72-75% ee),20b cis- and trans-l1-lactams (70-96% ee),23 and carbapenem antibiotics.24... 

Using the same principle as that described for l,3-dioxolan-4-ones, it is possible to a-alkylate 2-amino acids without racemization76,78. An A. O-acetal is formed from an (7 )-amino acid 1, e.g., with trimethylacetaldehyde (R2 = -Bu) the l,3-oxazolidin-5-ones 2 and 3 are furnished with a defined diastereoselectivity, which is the first stage in the process of self-reproduction of chirality 82. Formation of the enolate 4 from 2 and attack of an electrophile in the second step gives the product 6 with retention of configuration in the a-position, and 7 with inversion of configuration, again with a defined diastereoselectivity. Hydrolysis yields the a-alkylated amino acids 10 and 11. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

Aldol condensation of a-amino silyl ketene acetals (l).10 2-Dibenzylami-noketene trimethylsilyl acetals (1) react with aldehydes premixed with TiCl4 to give a-amino-p-hydroxy carboxylic esters (2) with moderate to high syn-selectivity. Surprisingly, TiCl4-catalyzed reaction of 1 with a chiral a-alkoxy aldehyde proceeds with low asymmetric induction. 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

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