Chiral synthons

PLE catalyzes the hydrolysis of a wide range of meso-diesters (Table 2). This reaction is interesting from both theoretical and practical standpoints. Indeed, the analysis of a large range of kinetic data provided sufficient information to create a detailed active site model of PLE (31). From a practical standpoint, selective hydrolysis of y j (9-cyclo-I,2-dicarboxylates leads to chiral synthons that are valuable intermediates for the synthesis of a variety of natural products. 

The two oxidoreductase systems most frequentiy used for preparation of chiral synthons include baker s yeast and horse hver alcohol dehydrogenase (HLAD). The use of baker s yeast has been recendy reviewed in great detail (6,163) and therefore will not be coveted here. The emphasis here is on dehydrogenase-catalyzed oxidation and reduction of alcohols, ketones, and keto acid, oxidations at unsaturated carbon, and Bayer-Vidiger oxidations. 

The enantioselective synthesis of the V-benzyl-substituted /3-lactam 274a (NR2 = PhCH2NH), a precursor for carbapenem antibiotics, was described starting from the chiral synthon 5(R)-menthyloxy-2(5//)-furanone 170 (Scheme 71)... 

The term biotransformation or biocatalysis is used for processes in which a starting material (precursor) is converted into the desired product in just one step. This can be done by use either of whole cells or of (partially) purified enzymes. Product examples range from bulk chemicals (such as acrylamide) to fine chemicals and chiral synthons (chiral amines or alcohols, for example). There are several books and reviews dealing with the use of bio transformations either at laboratory or at industrial scales [1, 10-13]. 

S)-a-substituted P-bromo-a-hydroxy acids (S)-4 are very important chiral synthon for medicinally important compounds, such as potential new hypoglycemia active alkylglycidic acids (ref. 1) and anti-ulcer active misoprost (ref. 2). 

This method is very simple and convenient, therefore it can be widely utilized to the synthesis of the medicinally important compounds which have this chiral synthon (ref. 7). 

Ph2P(NH2)NP(NH2)Ph2]+Cl, 19, which is prepared by the reaction of Ph2PCl3 and ammonia (136). This synthon has a preformed N-P-N-P-N unit and can be readily cyclized to a six or higher membered ring upon reaction with an appropriate reagent (137). An important application of the use of the Bezman s salt approach has been the synthesis of metallocyclophosphazenes of the type 20, which contain an early transition metal in the framework of the cyclophosphazene skeleton [Fig. 15(A)] (138). A modification of the Bezman s salt to design a chiral synthon allowed the synthesis of an optically pure cyclophosphazene (139). 

The usefulness of the carbonyl reductase from Candida magnoliae as an enzyme catalyst in the synthesis of chiral alcohol intermediates has been demonstrated by carrying out the reduction of several ketones on a preparative scale [56]. The isolated yields and enantiomeric excess of the product alcohols are summarized in Table 7.1, from which it can be seen that these chiral alcohols were obtained in essentially optically pure forms in excellent yields. These chiral alcohols are important intermediates in the synthesis of pharmaceuticals and agrichemicals. For example, optically active 2-hydroxy-3-methylbutyrate is an important chiral synthon... 

Amidjojo, M. and Weuster-Botz, D. (2005) Asymmetric synthesis of the chiral synthon ethyl (S)-4-chloro-3-hydroxybutanoate using Lactobacillus kefir. Tetrahedron Asymmetry, 16 (4), 899-901. 

Enoate reductase reduces a,/3-unsaturated carboxylate ions in an NADPH-dependent reaction to saturated carboxylated anions. Useful chiral synthons can be conveniently prepared by the asymmetric reduction of a triply substituted C—C bond by the action of enoate reductase, when the double bond is activated with strongly polarizing groups [22]. Enoate reductases are not commercially available as isolated enzymes therefore, microorganisms such as baker s yeast or Clostridium sp. containing enoate reductase are used to carry out the reduction reaction. 

After completing the enantioselective total synthesis of (+)-18,19-dihydro-antirhine [(+)-14](i40), Kametani et al. reported (394) the synthesis of (—)-antirhine [(-)-ll] by using (3S)-[3-hydroxy-( )-prop-l-enyl]cyclopentanone as a chiral synthon. 

Racemic dihydrocorynantheol (21) has been prepared by Danieli ef al. (395). The levorotatory antipode of dihydrocorynantheol [(—)-21] at the same time has been synthesized by Kametani et al. (396) via the chiral synthon 215 utilized previously (140) for the synthesis of (+)-18,19-dihydroantirhine. 

Chiralsil-val, 6 96-97 Chiral smectic C liquid crystals, 15 106-107 Chiral stationary phases, 6 79-82 Chiral supramolecular clusters, 24 61 Chiral synthons, 11 5 Chiral titanium complexes, 25 98—99 Chirobiotic phases, for chiral separations, 6 90-91... 

Sugars as chiral synthons in the preparation of fine chemicals 232... 

This chapter has discussed the transition metal-catalyzed synthesis of allenes. Because allenes have attracted considerable attention as useful synthons for synthetic organic chemistry, effective synthetic methods for their preparation are desirable. Some recent reports have demonstrated the potential usefulness of optically active axially chiral allenes as chiral synthons however, methods for supplying the enantiomerically enriched allenes are still limited. Apparently, transition metal-catalyzed reactions can provide solutions to these problems. From the economics point of view, the enantioselective synthesis of axially chiral allenes from achiral precursors using catalytic amounts of chiral transition metal catalysts is especially attractive. Considering these facts, further novel metal-catalyzed reactions for the preparation of allenes will certainly be developed in the future. 

The ready availability of the selectively protected 2,4,5-trihydroxypentanoic acid derivatives of defined stereochemistry, such as (2S,4S)-2,4,5-trihydroxypentanoic acid 4,5-acetonide methyl ester described here, coupled with Mitsunobu inversion,3 7 provide chiral synthons with the promise of broad utility. 

Stereospecific syntheses of the eight stereoisomers [94] used a variation of the methodology developed in Mori s previous synthesis of the stereoisomers of 6,10,13-trimethyltetradecanol (see Scheme 5) [91], using chiral synthons derived from commercially available enantiomers of citronellol and methyl 3-hydroxy-2-methylpropanoate, and the iterative series of steps outlined in Scheme 13A for one of the stereoisomers [94]. A key step involved moving the... 

Another approach to (R)-(-)-phoracantholide I (245) used a ring enlargement of cyclohexanone (255) which had been alkylated with chiral synthon 256 (Scheme 14) [206]. Thus, compound 257 was prepared in 35% yield on a 7-g scale by alkylation of cyclohexanone with chiral 256. Cyclization with Am-berlyst A-15 provided enol ether 258 that was directly submitted to ruthenium tetroxide oxidation to give oxolactone 259 in a 47% yield. Reduction of the latter with catecholborane via its tosylhydrazone afforded (R)-(-)-phoracan-tholide I (245) in 31% yield. 

K. Adachi, S. Kobayashi, M. Ohno, Chiral Synthons by Enantioselective Hydrolysis of meso-Diesters with Pig Liver Esterase Substrate-Stereoselectivity Relationships , Chi-mia 1986, 40, 311-314. 

Alphand, V., Archelas, A. andFurstoss, R., Microbial transformations 16. One-step synthesis of a pivotal prostaglandin chiral synthon via a highly enantioselective microbiological Baeyer-Villiger-type reaction. Tetrahedron Lett., 1989, 30, 3663. 

Cyclohexadienones 61 and 64 are readily available from monoprotected hydro-quinones or para-substituted phenols, respectively. Conjugate additions to these symmetrical dienones result in desymmetrization of the prochiral dienone moieties, providing access to multifunctional chiral synthons in two steps from the aromatic precursors (Scheme 7.17) [72]. 

J )-Mandelic acid 3 is a useful chiral synthon for the production of pharmaceuticals such as semi-synthetic penecillins, cephalosporins and antiobesity agents and many methods have been reported for the preparation of the optically pure material. A method to deracemize the racemate which is readily available on a large scale was developed by Ohta et al. using a combination of two biotransformations. The method consists of enantioselective oxidation of (S)-... 

Keywoids Chiral synthon. Chiral building blocks. Stereospecific synthesis. Stereoselective degradation. Microbial transformation. 

Stereochemical impurities present in drug substances or drug products can arise from a number of different sources. Armstrong et al. performed an extensive study in the 1990s focusing on enantiomeric impurities in chiral synthons... 

Compounds 29, 34, 39, and 40 constitute chiral synthons suitable for use in stereospecific aninocyclitol synthesis. Thus, 40 or other, appropriately N protected derivatives of 39 may be employed for stereospecific substitution at OH-6 alternatively, after temporary protection of OH-6 followed by removal of the acetal, the molecule should be amenable to manipulation at OH-4. In 9 and 4, the two unequal nitrogenous functions may be reduced stepwise to amino groups, thus offering possibilities for stereospecific introduction of an N-substituent at either position. In order to demonstrate that such a strategy is feasible, reaction sequences leading to the enantiomers of mono-N-methyl-2-deoxystreptamine were performed, as illustrated in Figure 5. 

Furthermore, yeast treatment of the a-acetoxy ketone 53, bearing two oxygen substituents ( ) at a and affords the carbinol 54 in 20 % yield, somewhat less than 10 % of the (2R) diastereoisomer, and 70 % of recovered starting material. From the carbinol 54, crystalline 55 is obtained, which may be converted through suitable manipulation of the protecting groups and ozonolysis, into A-deoxy-D-talo-hexose 56. The minor diastereoisomer similarly affords A-deoxy-D-xylo-hexose 57. Thus, in the yeast treatment of 53, as the results of the enzymic kinetic resolution, the (2S, 4S, 5R) diol 55, a carbohydrate-like chiral synthon, is accessible out of eight possible isomers. 

Similar carbohydrate-like chiral synthons are obtained by yeast reduction of the -acetoxyketones 58 and 59 ( ), bearing in 1,6 and 1,5 relationship, respectively, two masked carbonyl functions accessible chemoselectively with different reagents. The mode of reduction of 58 and 59 is, however, opposite. Whereas yeast treatment of 58 affords... 

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