A-Hydrazino acids

The third group4 used (1R,2S)-N methylephedrine as the chiral auxiliary. Thus the derived silylketene acetal (6) reacts with 1 in the presence of TiCl4 to give 7 in 45-70% yield with —90% stereoselectivity. The products are converted by TFA and LiOH to (R)-a-hydrazino acids (8), which are obtained in 5=98% ee after one crystallization. 

A corollary to the above argument is that enantioselectivities depend on alkene geometry. Indeed, isomeric enolsilanes provide enantiomeric products. Because obtaining enolsilanes such as 344 in high isomeric purity is difficult, enantioselectivities with these nucleophiles are reflective, Eqs. 214 and 215. Pyrrole-derived enolsilanes are accessible in very high isomeric purity (>99 1) thus providing a convenient solution to this problem. Their use in the catalytic amination reaction provides access to a-hydrazino acid derivatives in high enantioselectivity. 

Scheme 17 Chemical Structures of a Piperazic Acid (Piz) Residue and an a-Hydrazino Acid...

In the late 1980s various asymmetric procedures for the synthesis a-hydrazino acids, based on the electrophilic amination of an enolate bearing a chiral auxiliary by a dialkylazodi-carboxylate, have appeared in the literature (Table 1)J55 68 72i The a-hydrazino acid is recovered in high yield after cleavage of the chiral auxiliary and acidolysis of the Boc groups in 63. The D-enantiomer is obtained with 65, A and the L-enantiomer with 66,[551 67,169 71 and 68.[70] A chiral auxiliary is not required for hydrazinating chiral (i-hydroxyesters.172 ... 

Table 1 Asymmetric Synthesis of a-Hydrazino Acid Derivatives Using a Chiral Auxiliary 55-68-71 ...

The conversion of urea to hydrazine using hypochlorite is known as Shestakov rearrangement.1731 It has been used to obtain a-hydrazino acids from a-amino acid derived hydantoic acids, with chiral retention but in a moderate yield (about 20-40%), using NaOCI.174,751 The use of KOC1, instead of NaOCl, greatly increases the yield of Shestakov rearrangement (Scheme 19).176-781... 

Scheme 19 Synthesis of an a-Hydrazino Acid by Shestakov Rearrangement 781...

Scheme 22 N -Coupling of N(l-Protected a-Hydrazino Acid Derivatives1971...

The amidoxy, or ip[C0-NH-0], link 6 (R1 = H) results from N-acylation of an a-aminoxy acid. a-Aminoxy acids have been isolated from natural sources and some of them present antibacterial properties as such, or when coupled to an a-amino acid, as in malioxamycin H-L-Vali )[C0-NH-0]D-Asp-0Hj115 117l The a-aminoxy acids are homologous to the a-hy-drazino acids with the advantage that there is no problem of regioselectivity for N-acylation. Despite the easy preparation of a-aminoxy acids,1118-1201 the number of (amidoxy) peptides reported in the literature is rather limited, with no examples of solid-phase synthesis. Recently, it has been observed that the a-aminoxy and a-hydrazino acid units induce quite similar local folded structures.1 21-123 ... 

V-Phthalimidoaziridines may be obtained by reaction of alkenes with 7V-aminophthali-mide which has been treated with lead tetraacetate (equation 152)550-554. These compounds are useful in the synthesis of a-hydrazino acid derivatives which are inhibitors of amino acid metabolising enzymes. 

This synthesis of 1 is noteworthy for its seminal demonstration of the utility of tandem electrophilic hydrazination-nucleophilic cyclisation9 for preparing functionalised homochiral cyclic a hydrazino acids.10 It highlights, yet again, the great utility of functionalised glyceraldehyde synthons for the installation of remote hydroxy stereocentres in natural product target molecules. 

In summary, a-hydrazino acids and natural and unnatural a-amino acids could be obtained in both the R and S configurations by this practical method. 

Classical methods for removal of the chiral oxazolidinone moiety such as benzyl alcohol transesterification, caused some epimerization at the newly aminated center. The use of anhydrous LiSH (1 equiv., THF, 20 °C, 10 min) was successful and the cleavage occurred without sensible epimerisation. Treatment of the resulting reaction mixture with THF/CH3C03H (1 1 mixture, 40% in H20) gave the carboxylic acids 44 in 76-85 % yields. Compounds 44 were hydrogenolyzed under classical conditions (H2, Pd/C) to the free a-hydrazino acids which were converted to the a-amino acids 45 by subsequent cleavage of the N-N bond in the presence of Ra-ney-Ni (500 psi, 10% aqueous AcOH) with 80-95 % yield (Scheme 23). 

The reactions of electrophilic animation displayed little if any stereoselectivity (Table 3.10, entries 1 to 6). The chromatographic separation of the diastereomers was generally quite difficult. The menthyl and bomyl carbamate moieties in products 99a and 99b proved to be very stable and difficult to remove, even with prolonged reflux in 6 M HC1 or concentrated HBr, and the corresponding a-hydrazino acids could not be obtained in reasonable yield. However, the isobomyl 99c analogues were readily hydrolyzed. 

Achiral oxazolidinones 106 were aminated at -78 °C using the standard procedure. Only one diastereomer could be detected for the products using H NMR spectroscopy, and X-ray crystallographic analysis of 107 (R = Me) showed that the new stereogenic center had the (S) absolute configuration (Scheme 49). Attempts to remove the binaphthyl moiety to produce the optically pure free a-hydrazino acid have been unsuccessful. 

Scheme 13.10 Synthesis of a-hydrazino acids from a-amino acids.

The a tz-adduct 15 is generally the major one (compare theazidation reaction, Section 7.1.1.1.). After separation from the minor adduct 16 by chromatography, the different ester groups are saponified, giving /i-hydroxy-a-hydrazino acids 17 in reasonably good yields. The hydrochlorides of 17 can be reduced to the corresponding a-amino acids 18. The optical purity of these amino acids is directly related to the optical purity of the esters 1419. 

Detailed procedures for the formation of the /I-hydroxy-a-hydrazino acids 17 and the /Miydroxy-a-amino acids 18 are described earlier in this section. 

A two-step hydrolysis of crude 2 with trifluoroacetic acid and lithium hydroxide gives the optically pure a-hydrazino acids 3 (ee >98 %). Reduction with hydrogen on platinum(II) oxide reduces 3 to the a-amino acids 4 in high yields. Alternatively, 2 can also be reduced with metal hydrides (LiAIH4/Et20) to, V-inethylcphedrinc and /i-hydrazino alcohols 5. After transformation into the Mosher ester [with (- )-(S)-methoxy-4-(tri fluoromcthyljphenylacctyl chloride], 5 (R = CH3) shows a diastereomeric ratio d.r. [(2,S,2, S )/(2,S, 2 7f)] >95 5. 

Chiral hydrazines can be transformed to a-amino acids and amines by cleavage of the N-N bond. Conversion to a-hydrazino acids by hydrolysis of the esters or into hydrazines by deacylation is likewise possible. ... 

Related Reagents. The synthesis of chiral diazenedicarboxylates as potential chiral electrophilic aminating agents has received little attention. A series of chiral bomyl, isobomyl and menthyl diazenedicarboxylates has been reported and their reaction with achiral enolates of esters and N,N-dimethyl amides afforded a-hydrazino acid derivatives with little or no selectivity. Incorporation of a chiral azodicarboxamide unit into a chiral bridging binaphthyl moiety afforded a-hydrazino acid derivatives with high stereoselectivity in reactions with achiral oxazolidinone anions. ... 

Azodicarboxylate esters are the reagents of choice for electrophilic N-amino amination leading to hydrazine derivatives. Besides Grignard reagents and alkyl or aryl lithium compounds,enolates and silyl enol ethersderived from ketones have been aminated by this method. In particular, di-r-butyl azodicarboxylate has been reacted with a variety of chiral enolates (Scheme I9)i03->o and chiral silyl ketene acetds (Schemes 20 and to afford a-hydrazino acid derivatives with high dia-... 

Evans, D. A., Britton, T. C., Dellaria, J. F., Jr. The asymmetric synthesis of a-amino and a-hydrazino acid derivatives via the stereoselective amination of chiral enolates with azodicarboxylate esters. Tetrahedron 1988, 44, 5525-5540. 

Indeed, we quickly affirmed that the cationic Et-DuPHOS-Rh catalysts allowed smooth reduction of the A -benzoylhydrazones 32 in up to 97% ee (Scheme 15)[34]. Analogous rhodium catalysts based on known chiral diphosphines such as BDPP, BINAP, CHIRAPHOS, DIOP, and Ph P-Glup reduced A-benzoylhy-dra/ones with low relative rates and low enantioselectivites (highest 23% ee. 75% conversion over 48 hr with BINAP-Rh). This process provides simple access to a-arylhydrazines (33, R = aromatic or heteroaromatic ring) and a-hydrazino acids (33, R = CO2Me) with high enantiomeric excesses. 

In situ generated allenyltitanium complexes of type 47 are aminated by azodicarboxylic esters and the products may be degraded to a-hydrazino acids (Eq. 59).360 High a-symmetric induction is achieved only when R is a methyl group when it is n-butyl or isobutyl, the enantiomeric excess in the product decreases to 55% and 27%, respectively. 

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