Enantioselective synthesis blocks

Many methods have been reported for the enantioselective synthesis of the remaining PG building block, the (J )-4-hydroxy-cyclopent-2-enone. For example, the racemate can be kinetically resolved as shown in Scheme 7-28. (iS )-BINAP-Ru(II) dicarboxylate complex 93 is an excellent catalyst for the enantioselective kinetic resolution of the racemic hydroxy enone (an allylic alcohol). By controlling the reaction conditions, the C C double bond in one enantiomer, the (S )-isomer, will be prone to hydrogenation, leaving the slow reacting enantiomer intact and thus accomplishing the kinetic resolution.20... 

Baeza, A., Casa, J., Najera, C., Sansano, J.M. and Saa, J.M., Enantioselective synthesis of O-methoxycarbonyl cyanohydrins chiral building blocks generated by bifunctional catalysis with BINOLAM-AICI. Eur. J. Org. Chem., 2006, 1949. 

The cyclopropane aldehyde 156 was identified as a versatile chiral building block for the enantioselective synthesis of 4,5 disubstituted y-butyrolactones of type 158 or 159. Both enantiomers of 156 can be easily obtained in a highly diastereo- and enantioselective manner from fixran-2-carboxylic ester 154 using an asymmetric copper-catalyzed cyclopropanation as the key step followed by an ozonolysis of the remaining double bond (Scheme 25) [63]. Addition of... 

This approach sets the stage for an enantiotopos-differentiating olefin metathesis which would allow the enantioselective synthesis of 258. However, the realization of such an approach has not yet been successful [132]. The second building block (259) containing the A ring was synthesized diastereoselectively by a diastereoface-differentiating intramolecular Heck-Mizoroki reaction of the enantiomerically enriched furan 260 [120]. 

Merck-Schuchardt, Chiralica — Reagents, catalysts and building blocks for enantioselective synthesis Resolving Agents, E Merck Co., Germany, 1985. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

The mild cleavage conditions with NEt3 HF, which do not cause epimerization at centers a to the carbonyl group, are essential for an enantioselective synthesis of y-oxoesters using optically active catalysts 641 in the cyclopropanation step. Up to 50 % ee have been obtained so far 65). Improvements should be possible, if the trans/cis-ratio of the siloxycyclopropane can be increased. Formylesters of type 99 are promising building blocks for further transformations (e.g. synthesis of y-butyrolactones). 

Catalyst 36 was also used for the enantioselective synthesis of functionalized tetrahydropyrans, important building blocks in several biologically active molecules (Scheme 29) [78]. The enantioselectivity of such a reaction was significantly improved by using a ruthenium iodide complex 37. This halogen effect has been previously observed in the ring-closing metathesis (vide supra) [52]. 

Addition of the lithium anion of chloromethylphosphonate to sulfinimine 126 gave a-chloro-P-aminophosphonates 195 in a ratio of 59 41 and 98% total yield.104 The diastereomeric products can be separated and each converted to the corresponding aziridine-2-phosphonates 196, new building chiral blocks for the enantioselective synthesis of a-aminophosphonates 197 and azirinyl phosphonates 198.104... 

Cyanohydrins are versatile building blocks that are used in both the pharmaceutical and agrochemical industries [2-9]. Consequently their enantioselective synthesis has attracted considerable attention (Scheme 5.1). Their preparation by the addition of HCN to an aldehyde or a ketone is 100% atom efficient. It is, however, an equilibrium reaction. The racemic addition of HCN is base-catalyzed, thus the enantioselective, enzymatic cyanide addition should be performed under mildly acidic conditions to suppress the undesired background reaction. While the formation of cyanohydrins from aldehydes proceeds readily, the equilibrium for ketones lies on the side of the starting materials. The latter reaction can therefore only be performed successfully by either bio- or chemo-cat-... 

Recently it was described that site directed mutagenesis has led to a Prunus amygdalus HNL that can be employed for the preparation of (R)-2-hydroxy-4-phe-nylbutyronitrile with excellent enantioselectivity (ee>96%). This is a chiral building block for the enantioselective synthesis of ACE inhibitors such as ena-lapril (Scheme 5.4) [13]. 

Cyanohydrins are versatile and important building blocks in organic synthesis [20]. Consequently, their enantioselective synthesis has attracted considerable attention... 

Terminal epoxides of high enantiopurity are among the most important chiral building blocks in enantioselective synthesis, because they are easily opened through nucleophilic substitution reactions. Furthermore, this procedure can be scaled to industrial levels with low catalyst loading. Chiral metal salen complexes have also been successfully applied to the asymmetric hydroxylation of C H bonds, asymmetric oxidation of sulfides, asymmetric aziridination of alkenes, and the asymmetric alkylation of keto esters to name a few. 

M. J. Taschner and D. J. Block, The enzymatic Baeyer-Villiger oxidation Enantioselective synthesis of lactones from mesomeric cyclohexanones, ). Am. Chem. Soc., 110 6892 (1988). 

Enders, D, Jegelka, U, l,3-Dioxan-5-one as C3-building block for the diastereo- and enantioselective synthesis of C5- to Cg-deoxy sugars using the SAMP-/RAMP-hydrazone method. Tetrahedron Lett., 34, 2453-2456, 1993. 

Asymmetric transfer hydrogenation with a chiral ruthenium complex is an alternative option for preparation of substituted phenethyl alcohols, which are important building blocks for the agricultural fungicide, (S)-MA20565 [47]. In the enantioselective synthesis of antidepressant sertraline (50), different chiral secondary alcohols have been proposed as pivotal intermediates (Scheme 14). Reduction of the keto ester 46 catdyzed by oxazaborolidine 45 provides chiral intermediate 47 in 90% ee [48]. Alternatively, reductive fragmentation of C2-symmetric oxa-tricyclic alkene 48 with DIBAL catalyzed by a BINAP-Ni complex generates a novel intermediate 49 in 88 % yield with 91% ee [49]. 

Enantioselective synthesis involves chemical modification via (section 9.2.1) introduction of a chiral center into achiral fluorinated building blocks, (9.2.2) chiral transposition, (9.2.3) introduction of fluorine functionality into nonfluorinated chiral building blocks, (9.2.4) modification of chiral fluorinated building blocks, and (9.2.5) enzymatic resolution of racemic fluorinated building blocks. The following sections summarize these five categories. 

Chemicals Enantioselective hydrolysis Enantioselective synthesis Chiral building blocks Specialty chemicals... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of pharmacologically important molecules and natural products. The enantioselective synthesis of these compounds initially involved the chiral auxiUary-based asymmetric allylation of imines [41a, 4lb, 41c], and it is just recently that a few enantioselective variants have been reported. Although still in the regime of stoichiometric asymmetric synthesis, the first methods described below merit discussion for their synthetic utility and for establishing the groundwork for future development. 

Enantioselective Synthesis. Wiley-VCH, Weinheim, 1997. (b). J Gawrowski, K Gawrowski. Tartaric and Malic Acids in Synthesis A Source Book of Building Blocks, Ligands, Auxiliaries, and Resolving Agents. Wiley, New York, 1999. 

In the last decade, optically pure cyanohydrins (a-hydroxynitriles) have become a versatile source for the synthesis of a variety of chiral building blocks. Diverse methods for the enantioselective synthesis of cyanohydrins have been published and reviewed111. Besides enzyme catalyzed methods, hydrocyanation or silylcyanation of aldehydes or ketones controlled by chiral metal complexes or cyclic dipeptides, as well as diastereoselective hydrocyanation of chiral carbonyl compounds, have been applied with moderate success. 

Scheme 1 The use of HheC for the enantioselective synthesis of (S)-4-cyano-3-hydroxybutanoate methylester, a key building block for statins.

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