Amino optically active derivatives

Volume 64 of our series consists of six chapters covering an exciting range of topics in contemporary heterocyclic chemistry. M. TiSler and P. Kolar (Ljubljana, Slovenia) review applications of various amino acids in the synthesis of chiral heterocycles which have become of great importance as synthons for the preparation of a variety of optically active derivatives. 

Any kind of C-Mannich base has been actually allowed to react with a variety of amines, including aminoalcohols and amino acids. Cyclic amines, - including optically active derivatives, - and amides arc also employed as are a number of aromatic heterocycles. 

The lithium enolate derived from (2S//5)-l-tert-butoxycarbonyl-2-tcrt-butyl-3-methyl-4-imida-zolinone [(S)-l or (7J)-1], an optically active derivative of glycine, is stercosclectively attacked by electrophiles from the less hindered side. Alkylation of (S)-l yields the (S,S)-isomer which can be hydrolyzed to the (S)-amino acid. If, however, the (S.S)-isomer is again deprotonated then reprotonated, complete inversion (>92%) gives the (S,7J)-isomer, which consequently yields the (TJ)-amino acid on hydrolysis110 1106. 

Fisher carbenes easily react with an amine to give the aminocarbene, and the aminocarbene reacts with carbon monoxide under light irradiation to give an aminoester as shown in eq. (13.47) [79]. If the optically active oxazolidine derivatives are used as the aminocarbene, by photolytic carbonylation the above synthesis of amino acid ester gives an optically active derivative as shown in eq. (13.48) [79]. 

Compounds 33b, 34 with the amino group attached to the spiropyrrolidine or cyclopropyl-substituted pyrrolidine fragment proved to exhibit broad spectrum of antibacterial activity (Scheme 18) [124-129]. Aminomethyl substituted pyrrolidines and their heterocyclic derivatives were incorporated into position 7 of fluoroquinolone [130-132]. Optically active derivatives of 7-(3-hydroxypyrro-lidin-l-yl)-6-fluoroquinolones have been shown to be promising antibacterials [133-135]. 

Heterocycles of high enantiomeric purity are used to prepare other optically active compounds for example, to obtain chiral amino acids some optically active derivatives of hydantoin or aziridine have been employed [68]. 

Synthetic utility of stereoselective alkylations in natural product chemistry is exemplified by the preparation of optically active 2-arylglycine esters (38). Chirally specific a-amino acids with methoxyaryl groups attached to the a-carbon were prepared by reaction of the dimethyl ether of a chiral bis-lactam derivative with methoxy arenes. Using SnCl as the Lewis acid, enantioselectivities ranging from 65 to 95% were obtained. 

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Figure A8.9 Procedure for the preparation of optically active a-disubstituted amino acids through stereoselective enzymatic cydisation of the N-carbamoyl derivatives.

The optically active oxazolidinone derivative 3, readily obtainable from serine (see Appendix), is alkylated to give predominantly the cw-product98. The auxiliary is removed by acid hydrolysis to give the 2-amino alcohol. 

Optically active five- or six-membered cyclic A -acyliminium ions of this type are generated from the a-inethoxy derivatives, easily obtainable through anodic methoxylation of intermediates that are prepared via ex-chiral-pool syntheses from certain natural amino acids. Reaction of 5-substituted five-membered cyclic A -acyliminium ions with various nucleophiles leads to the predominant formation of cw-products with moderate selectivity. The trans-selective reaction with alkyl copper reagents appears to be an exception. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

A variety of chiral amides as well as oxazolidones388 and imidazolidones389,390 may easily be prepared from amino alcohols that are derived from amino acids391 392. The addition of the lithium enolates of these amides under kinetically controlled conditions to a,/i-unsaturated esters yields optically active pentanedioates. Both syn- and //-5-amino-5-oxopcntanoates may be obtained with good diastereomeric ratios192. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

With optically active formamide-derived aminocarbene complexes high enantioselectivity was observed in most cases (Table 5). This chemistry was used in the synthesis of 1-carbacephalathin and 3-ANA precursors (Eq. 9) [48], as well as the synthesis of a,a -disubstituted amino acids (Scheme 1) [49]. 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

In 1995, and regrettably missed in last year s review, Klotgen and Wiirthwein described the formation of the 4,5-dihydroazepine derivatives 2 by lithium induced cyclisation of the triene 1, followed by acylation <95TL7065>. This work has now been extended to the preparation of a number of l-acyl-2,3-dihydroazepines 4 from 3 <96T14801>. The formation of the intermediate anion and its subsequent cyclisation was followed by NMR spectroscopy and the stereochemistry of the final product elucidated by x-ray spectroscopy. The synthesis of optically active 2//-azepines 6 from amino acids has been described <96T10883>. The key step is the cyclisation of the amino acid derived alkene 5 with TFA. These azepines isomerise to the thermodynamically more stable 3//-azepines 7 in solution. 

The synthesis of the CG525155 (a neutral endopeptidase inhibitor) required a Pd catalyzed Tsuji-Trost reaction as the key step following the strategy described by Johnson. Starting from the optically active allenyl amino acid methylester 91 (synthesized in several steps from 90), the seco-derivative 92 as the crucial precursor was generated in several steps in high yield. The Pd (0)... 

These catalysts were first tested as resin-bound derivatives via HTS, first with metals and then without. Three libraries of chiral molecules, based on three different enantiomerically pure diamines, bulky salicylidene moities and optically active ii-amino acids were used for structure optimisation (Scheme 37 TBSCN = fBuMe2SiCN) [152]. 

The Jacobsen group has also shown that the recycling of the resin-bounded catalyst can be successfully performed [152,154]. Moreover, they have developed an efficient method for the hydrolysis of the aminonitrile into the corresponding amino acid. This method was apphed for the commercial production of optically active K-amino acids at Rhodia ChiRex (e.g. tert-leucine) the catalyst was immobihsed on a resin support (4 mol %, 10 cycles) and the intermediate hydrocyanation adduct was trapped by simply replacing TFAA with HCOOH/AC2O, for example. Highly crystalhne formamide derivatives were thus obtained in excellent yields (97-98% per cycle) with very high enantioselectivities (92-93% per cycle) [158]. 

Among other carba-sugar derivatives, the most important compounds are amino carba-sugars having an amino group at C-1. They are known as validamine, valiolamine, hydroxyvalidamine, and valienamine, and are found in validamycin antibiotics as unique components they have been synthesized in dl forms and also in optically active forms. 

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