The synthesis of optically active carboxylic acids

Before 1967 the preparation of 2-alkyl-and 2,2-dialkyl-acetic acids was achieved by the classical and important malonic ester route (Section 5.11.6 above). An 

The most important development of this useful procedure has been the incorporation of an optically active amino alcohol, to provide a chiral adjuvant (or auxiliary), in the resulting oxazoline. The amino alcohol employed was (1S,2S)- 

7Va s-(4S,5S)-2-ethyI-4-hydroxyinethyl-5-phenyl-2-oxazoIine. A mixture of 126.5g (0.76mol) of (1 S,2S)-( +)-2-amino-1 -phenylpropane-1,3-diol (1) and 160g (0.91 mol) of triethyl orthopropanoate in 550 ml of 1,2-dichloroethane is heated under reflux for 7 hours. The solvent is removed leaving an oil (159 g) which crystallises on standing. This is treated with 70 ml of ether and cooled in a dry-ipe-acetone bath and the partially purified product collected by filtration. The crystalline material is dissolved in ether (c. 600 ml), treated with charcoal, filtered, concentrated to about 300 ml and cooled to — 78 °C. The recrystallised material is filtered and washed with a small amount (15— 20 ml) of precooled (— 78 °C) ether. The yield of product is 106.9 g (69%), m.p. 68-69 °C, Mil, -135.1° (c 10.4 in CHC13). 

(1) This amino alcohol may be recrystallised by dissolving 1 part in 1 part of methanol and adding 2 parts of ethyl acetate and cooling. The pure material has m.p. 112-113 °C, [a]ii9 26.6° (c 10.0 in MeOH). 

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The synthesis of optically active carboxylic acids (Expt 5.137). 

Compounds 137 and 138 are thus synthons for carboxylic acids this is another indirect method for the a alkylation of a carboxylic acid, representing an alternative to the malonic ester synthesis (10-104) and to 10-106 and 10-109. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent. Note that, unlike 132, 137 can be alkylated even if R is alkyl. However, the C=N bond of 137 and 138 cannot be effectively reduced, so that aldehyde synthesis is not feasible here. ... 

Further evidence for the formation of intermediate compounds in catalytic reactions is afforded by the observation (a) that optically active camphor is formed from optically inactive (racemic) camphor carboxylic acid in the presence of the d- or /-forms of quinine, quinidine or nicotine and (6) that optically active bases, e.g., quinidine, catalyze the synthesis of optically active mandelonitrile from benzaldehyde and hydrocyanic acid.10 These results hardly admit of any other interpretation than the intermittent production of a catalyst-reactant compound. 

In the synthesis of optically active 2-phenylalkanoic acids (244), a derivative of (S)-phenylalanine was used as a chiral auxiliary 2441. The carboxylic acids (244) were obtained in optical yields of up to 53 %. 

The asymmetric synthesis of enantiomerically pure primary amines has received considerable attention in recent years due to applications of the chiral amines, either as chiral auxiliaries for the synthesis of optically active molecules [33] or as a deri-vatizing agent for the resolution of racemic carboxylic acids [34], Hydroboration -amination is also a convenient synthetic route to epimerically clean amine derivatives in a simple one-stage reaction. Interestingly, rrans-2-phenylcyclopentylamine (cypenamine), which is an antidepressant [35], can be obtained as a pure isomer in good yields by the hydroboration of 1-methylcyclopentene [7,10,36] (Scheme 13). 

The synthesis of optically active TIQ-1-carboxylic acids has recently been accomplished by the chemical reactions shown in Fig. 26. Carboxylic acids 99 and 100, after esterification and reaction of the methyl esters with optically active I-phenylethyl isocyanates, gave ureas 101 and 102, respectively, which were separated from their diastereoisomers by chromatography (33,218). Ureas 101 and 102, on treatment with base or on... 

Alkynylepoxides [123,142,143 Eq. (68) 142] and alkynyl propiolactones [Eq. (69) 144] afforded allenyl-alcohols or allenyl-carboxylic acids. Diastereoselective ring opening of alkynylepoxides has been studied [143,145]. The use of optically active propargyl substrates enables the synthesis of optically active allenes [Eq. (70) 146] [10,140,145-147]. A subtle change of the reaction medium may drastically change the degree of chirality transfer, which has been systematically examined [145]. 

Reactions exhibiting diastereofacial selectivity, which occur when the imine or the enolate contains an endogenous stereocenter or a chiral auxiliary, have important applications for the synthesis of optically active 3-l ctams and 3-amino carboxylic acid derivatives. Early work by Furukawa et al. has demonstrated the viability of preparing optically active 3-amino acids from chiral imines. For example, the Schiff base derived from (5)-a-methylbenzylamine (110) reacts with Reformatsky reagent (111) to give, after hydrolysis and removal of the chiral auxiliary, 3-amino-2,2-dimethyl-3-phenylpropionic acid (112) in 33% ee (Scheme 21). Similar Reformatsky reactions have been performed using (-)-menthyl esters but the enantiomeric excess values are lower. ... 

Dieckmann cyclization of (21a) gave, depending upon conditions, either (21b) or (21c) predominantly. These compounds were transformed into the thiophens (21d) and (21e). The acid-catalysed reaction of (22) with hydrogen sulphide at -35 °C leads via the enethiol to ethyl 2,5-dimethyl thiophen-3-carboxylate as the main product. The monoacetals of substituted succinaldehyde (23), which are conveniently prepared through hydro-formylation of a -unsaturated aldehyde acetals with trans-bis(triphenyl-phosphine)carbonyl chlororhodium(i) as catalyst, have been used for the synthesis of optically active 3-substituted thiophens (from optically active a/3-unsaturated aldehyde acetals) through the acid-catalysed reaction with... 

Aziridine carboxylates are chiral intermediates for the synthesis of -lactams and amino acids [200]. The use of enantioselective ester hydrolysis in the synthesis of optically active A -unsubstituted and A-substituted aziridine carboxylate by Candida cylindraceae lipase has been demonstrated by Bucciareli et al. [199]. Racemic methyl aziridine-2-car-boxylate and 2,3-dicarboxylate 110 were used as substrates both for enzymatic hydrolysis and for the synthesis of AAchloro, iV-acyl and A-sulfonyl derivatives (Fig. 38). The reaction yield of 35-45% (theoretical maximum yield is 50%) and the e.e. s of 90-98% were obtained depending on substrate used in the reaction mixture. 

In this chapter, we review the production methods for optically active -hydroxy-carboxylic acids (esters), and chiral building blocks derived from optically active 3-hydroxy acids and their use in the synthesis of optically active bioactive compounds. 

A cursory inspection of key intermediate 8 (see Scheme 1) reveals that it possesses both vicinal and remote stereochemical relationships. To cope with the stereochemical challenge posed by this intermediate and to enhance overall efficiency, a convergent approach featuring the union of optically active intermediates 18 and 19 was adopted. Scheme 5a illustrates the synthesis of intermediate 18. Thus, oxidative cleavage of the trisubstituted olefin of (/ )-citronellic acid benzyl ester (28) with ozone, followed by oxidative workup with Jones reagent, affords a carboxylic acid which can be oxidatively decarboxylated to 29 with lead tetraacetate and copper(n) acetate. Saponification of the benzyl ester in 29 with potassium hydroxide provides an unsaturated carboxylic acid which undergoes smooth conversion to trans iodolactone 30 on treatment with iodine in acetonitrile at -15 °C (89% yield from 29).24 The diastereoselectivity of the thermodynamically controlled iodolacto-nization reaction is approximately 20 1 in favor of the more stable trans iodolactone 30. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

Various molecules were considered for studying the influence of the five-mem-bered ring conformations, and of the bulkiness of the ring substituents on the dia-stereomeric excess of the aminated products. Optically active (+)-ephedrine 89a and (—)-pseudo-ephedrine 89b were chosen as the chiral amino alcohols because of their relatively low cost and in view of the excellent results obtained in the similar asymmetric synthesis of a-amino carboxylic acids [13]. 

An enantioselective synthesis of TIQ-1-carboxylic acids 91a,b has recently been reported (279). Hydrolysis of the optically active methyl ether enantiomer of hydantoin 103 was accomplished by 20% sodium hydroxide in refluxing methyl cellosolve and led to the dimethyl ether analog of 91a, which was used to establish the absolute configuration of the products. Amino acids 91a,b have also been prepared by chemical resolution of the N,0-benzylated acid 108 with optically active 1-phenylethylamines. Catalytic debenzylation of enantiomer 109a gave... 

An important use of enantiomerically pure homoenolate equivalents is the synthesis of other a-amino acids from serine. Natural (5)-(+)-serine 54 is protected on both its amino and carboxyl groups and the OH group turned into a leaving group 55. Displacement with iodide gives the starting material 56 with no loss of optical activity.14... 

Further uses of Novozyme 435 have been described in recent patent applications filed by the Mitsubishi Gas Chemical Company and comprise processes for the production of optically active secondary alcohols (Scheme 33) [98] and the manufacture of optically active chroman-2-carboxylic acids (Scheme 34) [99]. In the first case the resolution of racemic 4-isopropyloxy-2-butanol (rac-108) by Novo 435 was an important step toward (R)-(+)-4-(isopropyloxy)-2-bu-tanol ((R)-108) via acetate 109. Compound R)-10S can be used for the synthesis of liquid crystal materials. 

In a synthesis of optically active 11-deoxy-PGEi, Abraham [141] prepared the cyclopropane derivative (133) by ozonolysis of the methyl ester of (-)-2-vinylcyclopropane-l,l-dicarboxylic acid and elaboration of the resulting aldehyde, and then effected a condensation with trimethyl heptane-1,1,7-tri-carboxylate to give, after hydrolysis, the cyclopentanone (134) which afforded 1 l-deoxy-PGE and its C-IS epimers on alkali treatment. 

Oxirans.—A simple four-stage preparation of (5)-propylene oxide from ethyl L-( —)-maleate has been described (Scheme 2). This work is of importance for the synthesis of nonactin carboxylic acid. Another synthesis of optically-active propylene oxide involves the cyclization of OL-propylene chlorohydrin with a variety of bases in the presence of a cobalt complex the highest optical purity was 27%. Wynberg and co-workers have shown that the base-catalysed epoxidation of electron-poor alkenes is subject to catalytic asymmetric induction hydrogen peroxide and t-butyl hydroperoxide were used as oxidants in the presence of quaternary... 

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