Asymmetric synthesis of carboxylic acids

MEYERS Asymmetric synthesis Chsal oxazoles in asymmetric synthesis of carboxylic acids, aldehydes, chual dihydrona(Aithalenes. 

Alkylations of acyclic enolates containing a collection of chiral auxiliary groups have been used successfully for the asymmetric synthesis of carboxylic acids. The chiral, nonracemic substrates that have been used include amides, imides, esters, imine derivatives of glycinates and acyl derivatives of chiral transition metals. In these systems either extraannular or chelate-enforced intraannular chirality transfer may control the sense of the alkylation step. 

The results of asymmetric hydrocarboxylation of aliphatic alkenes are compiled in Table 11 and rarely exceed 20% ee. Thus, with the catalytic systems used up to now, this method is not yet conveniently applicable to the asymmetric synthesis of carboxylic acids. The new catalytic systems used for hydrocarboxylation of styrenes and heterofuuctionalized alkenes may give better results, if applied to these substrates. 

The Evans oxazolidinone methodology is quite versatile and quite apart from its use in aldol reactions (section 5.3.3) lends itself well to the asymmetric synthesis of carboxylic acids substituted in the a-position with oxygen, nitrogen, and carbon.ti l The auxiliary shown is derived from (+)-norephedrine and the opposite enantiomers of the products are available from the valine-derived auxiliary. 

The asymmetric synthesis of carboxylic acids and their related esters is performed using olefins, carbon monoxide, and water or alcohols (represented as R OH in Scheme 3.2) in the presence of a chiral palladium catalyst. Considering that these chiral carboxylic acids are usually obtained from the oxidation of chiral aldehydes... 

Schdllkopf and cowoikers have pioneered the development of anions of another type of masked carboxylic acid derivative, i.e. bislactim ethers such as (159), derived from (5)-valine and glycine or alanine, for the asymmetric synthesis of amino acids. As shown in Scheme 78, compounds such as... 

Enamides can also be used as precursors for the asymmetric synthesis of amino acids via hydroformylation. Thus, asymmetric branched hydroformylation of vinylsuccinimide and vinylphthalimide upon further oxidation leads to, V-protccted amino carboxylic acids such as alanine. Branched products are obtained with high regioselectivities and good to high optical yields of up to 96% (see Table 7)125. 

Detailed experimental procedure D. W. Goheen, W. R. Vaughan, Org. Syn. coll. vol. 4, 594 (1963). Application to the synthesis of carboxylic acids T. Satoh etal, Bull. Chem. Soc. Japan 66, 2339 (1993). Applications to asymmetric synthesis idem etal,... 

The oxidation of aldehydes (alkanals) and ketones (alkanones) has been reviewed extensively [1-3], and there are compilations based on reagent types [4-8] and oxidation methods for most functionalized compounds including those having carbonyl groups. Books [9, 10] and comprehensive review articles [11-16] on carboxylic acids and their derivatives also provide important background information on the oxidation of carbonyl compounds. This account will focus exclusively on the synthesis of carboxylic acid derivatives. After a brief summary of the well-estabHshed methods, new directions in oxidative transformations of carbonyl compounds will be described. Among these, in particular, catalytic [17, 18] and asymmetric versions will be emphasized. 

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. 

The Rh2(DOSP)4 catalysts (6b) of Davies have proven to be remarkably effective for highly enantioselective cydopropanation reactions of aryl- and vinyl-diazoacetates [2]. The discovery that enantiocontrol could be enhanced when reactions were performed in pentane [35] added advantages that could be attributed to the solvent-directed orientation of chiral attachments of the ligand carboxylates [59]. In addition to the synthesis of (+)-sertraline (1) [6], the uses of this methodology have been extended to the construction of cyclopropane amino acids (Eq. 3) [35], the synthesis of tricyclic systems such as 22 (Eq. 4) [60], and, as an example of tandem cyclopropanation-Cope rearrangement, an efficient asymmetric synthesis of epi-tremulane 23 (Eq. 5) [61]. 

The asymmetric synthesis of / -branched carboxylic acid derivatives was accomplished by conjugate addition of mixed organoaluminum reagents to optically active Arabinose-derived c -unsaturated A-acyloxazolidinones (Scheme 47). Efficient stereocontrol was achieved using different optically active bicyclic oxazolidinones, yielding (.R)- or ( -configured / -branched carboxylic acid derivatives.136a... 

The previous section discussed chelation enforced intra-annular chirality transfer in the asymmetric synthesis of substituted carbonyl compounds. These compounds can be used as building blocks in the asymmetric synthesis of important chiral ligands or biologically active natural compounds. Asymmetric synthesis of chiral quaternary carbon centers has been of significant interest because several types of natural products with bioactivity possess a quaternary stereocenter, so the synthesis of such compounds raises the challenge of enantiomer construction. This applies especially to the asymmetric synthesis of amino group-substituted carboxylic acids with quaternary chiral centers. 

Efforts have been made to apply r 3-allyltitanium chemistry to the asymmetric synthesis of homoallylic alcohols and carboxylic acids. The synthesis and reactions of chiral r 3 -allyl-titanocenes with planar chirality, or containing Cp ligands with chiral substituents, have been reported [6c,15,30—32]. The enantiofacial selectivity in the allyltitanation reactions has been examined for the complexes 12 [15], 13 [30], 14 [31], 15, 16, and 17 [32] depicted in Figure 13.2. 

Stoodley developed an asymmetric synthesis of (5A)-2,3,4,5-tetrahydropyridazine-3-carboxylic acid (see Section 8.01.6.4). The ring construction was achieved via cycloaddition of dienes 295 bearing a tetraacetyl /3-D-glucopyranosyl moiety for chiral induction with azodicarboxylates (Equation 73) <1999J(P1)2591>. 

The alkylation of metalated imines, hydrazones, 4,5-dihydrooxazoles, 4,5-dihydroisoxazoles, 5,6-dihydro-4/7-1,2-oxazines and 2,5-dialkoxy-3,6-dihydropyrazines (i.e., azaenolates) is a commonly used method in asymmetric synthesis of enantiomerically enriched aldehydes, ketones, spiroacetals, amines, /J-oxo esters, carboxylic acids, lactones, 1,3-amino alcohols, /(-hydroxy ketones and amino acids. 

Subsequently, the asymmetric synthesis of stereospecifically monodeu-terated 1-aminocyclopropane-l-carboxylic acids (IS, 2R) and (IS, 2S) has also been achieved by a modification of the above route (89JOC270). The essential step involves an intramolecular alkylation on a lactim ether anion (Scheme 64). 

There are many routes available for the synthesis of aziridine 2-carboxylic acids, however there are few reactions which yield enantiomerically pure products. These compounds (especially those with cis-stereochemistry) are especially useful for the synthesis of bioactive molecules556. There is thus significant effort in this area of synthesis557,558, but most methods are lengthy multistep procedures. Recently, a simple, one-pot procedure, utilizing imines, has been developed for the asymmetric synthesis of c/s-N-substituted aziridine-2-carboxylic acids via a Darzens-type reaction (equation 154)559. 

The catalytic and chiral efficiency of (S,S)-le was also appreciated in the asymmetric synthesis of isoquinoline derivatives, which are important conformationally constrained a-amino acids. Treatment of 2 with a,a -dibromo-o-xylene under liquid-liquid phase-transfer conditions in the presence of (S,S)-le showed complete consumption ofthe starting Schiffbase. Imine hydrolysis and subsequent treatment with an excess amount of NaHCOs facilitated intramolecular ring closure to give 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butyl ester 38 in 82% yield with 98% ee. A variety of l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives possessing different aromatic substituents, such as 39 and 40, can be conveniently prepared in a similar manner, with excellent enantioselectivity (Scheme 5.20) [25]. 

A recent screening of various chiral carboxylic acids has allowed the selection of galacturonic derivative 12 as a very efficient control in the stereochemical course of some Passerini reactions (Scheme 1.5). Although the de seems to be strongly dependent on the isocyanide employed, this result suggests the possibility of employing carboxylic acids as easily removable chiral auxiliaries in the asymmetric synthesis of biologically important mandelamides [16]. 

In the eburnamine-vincamine sub-group, Takano etal. have given details99" of their synthesis of ( )-eburnamine.99i Other synthetic work reported includes further preparations of ( )-vincamone (eburnamonine)100" and ethyl apovin-caminate,100 and a modification of Szantay s route to vincamine which was intended to result in an asymmetric synthesis of vincamine-5-carboxylic acid, since L-tryptophan was used as starting material. Unfortunately, racemization of C-5 occurred during the synthesis, so the final product was an ester of ( )-vincamine-5-carboxylic acid.101... 

Fukumasa, M. Furuhashi, K. Umezawa, J. Takahashi, O. Hirai, T. Asymmetric synthesis of a-methyl carboxylic acid derivatives. Stereochemistry in acidic ring opening of epoxides. Tetrahedron Lett. 1991, 32, 1059-1062. 

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