Stereogenic center formation esters

The Morita-Baylis-Hillman (MBH) reaction is the formation of a-methylene-/ -hydroxycarbonyl compounds X by addition of aldehydes IX to a,/ -unsaturated carbonyl compounds VIII, for example vinyl ketones, acrylonitriles or acrylic esters (Scheme 6.58) [143-148]. For the reaction to occur the presence of catalytically active nucleophiles ( Nu , Scheme 6.58) is required. It is now commonly accepted that the MBH reaction is initiated by addition of the catalytically active nucleophile to the enone/enoate VIII. The resulting enolate adds to the aldehyde IX, establishing the new stereogenic center at the aldehydic carbonyl carbon atom. Formation of the product X is completed by proton transfer from the a-position of the carbonyl moiety to the alcoholate oxygen atom with concomitant elimination of the nucleophile. Thus Nu is available for the next catalytic cycle. 

The stereogenic center at C20 is introduced by enantioselective enzymatic hydrolysis of MOM-protected malonic acid dimethyl ester derivative 60 (Scheme 10) with pig liver esterase (PLE). The asymmetric compound 61 is obtained in 90 % yield and 98 % ee. Amide formation with Mu-... 

The formation of the soIute-CSP diastereomeric complexes in these CSPs usually requires the insertion of an aromatic moiety on the solute into the chirality of the optically active polymer. Thus, the solutes should contain an aromatic moiety near or at the stereogenic center. Enantiomeric molecules containing the necessary aromatic moiety and one of the following functionalities have been resolved on these CSPs alcohol, amide, ester, ether, and ketone (9-11). 

The key step in the enantioselective synthesis of a polycyclic target is the establishment of the first cyclic stereogenic center. Further construction can then be chrected by that initial center. This principle is nicely illustrated by a synthesis of (+)-estrone methyl ether (145), reported by Taber (Scheme 8). The specifically designed naphthylbomyl ester (141) is used to direct C—insertion selectively toward one of the two diastereotopic C—H bonds. The new ternary center so created then directs the formation of the adjacent quaternary center in the course of the alkylation. Finally, the chiral skew in the product cy-clopentanone (144) directs the relative and absolute course of the intramolecular cycloaddition, to give the steroid carbon skeleton. 

As a part of ongoing efforts to synthesize a potent, orally active anti-platelet agent, xemilofiban 1 [1], development of an efficient chemoenzymatic process for 2, the chiral yS-amino acid ester synthon (Fig. 1) was proposed. The scheme emphasized the creation of the stereogenic center as the key step. In parallel with the enzymatic approach, chemical synthesis of the / -amino acid ester synthon emphasized formation of a chiral imine, nucleophilic addition of the Reformatsky reagent, and oxidative removal of the chiral auxiliary. This chapter describes a selective amida-tion/amide hydrolysis using the enzyme Penicillin G amidohydrolase from E. coli to synthesize (R)- and (S)-enantiomers of ethyl 3-amino-5-(trimethylsilyl)-4-pen-tynoate in an optically pure form. The design of the experimental approach was applied in order to optimize the critical reaction parameters to control the stereoselectivity of the enzyme Penicillin G amidohydrolase. 

The formation of the lactones exhibits a preference for the hms-product in relation to the ester-bearing carbon atom. If the radical center is prostereogenic. the cyclization generates two new stereogenic centers with excellent trans selectivity. 

In order to limit the size of this chapter, a-amino acids will be the emphasis. The major problem for the synthesis of unnatural amino acids revolves around control of the stereogenic center, especially when large-scale synthesis is required. Inspection of the structure of an a-amino acid (1) allows a number of potential disconnections and approaches (Figure 9.1). The desired stereogenic center can be obtained by a resolution of a racemic mixture either in a kinetic or dynamic manner (route a). The reagent to achieve the separation can be chemical, biological, or a combination of the two. To achieve a dynamic resolution, only one substituent can be present (i.e., R = H). Resolutions are often achieved by formation or transformation of just one enantiomer of a derivative, such as an ester (route b) or amide (route c). 

The construction of the alkenyl side chain and the control of the C9, CIO and Cll stereogenic centers was achieved from (5)-(+)-methyl 3-hydroxy-2-methylpropionate 1. (Scheme 21) This compound was transformed to aldehyde 99 in three steps. Bis(2,2,2)trifluoroethyl)[(methoxycabonyl)methyl]-phosphonate [23] was employed for the selective formation of the cA-a, 3-unsaturated ester 100. From this Z-unsaturated ester 100, the three consecutive asymmetric units were constructed via epoxide 101 (m-CPBA), which was selectively opened by lithium dimethylcuprate to produce 102. After deprotection-protection, the alcohol 102 was converted to the phosphonium iodide 103 via a tosylate intermediate(Scheme 21). 

New innovations incorporated in the sequences shown in Eqs. (25) and (26) are an improved method for Barton ester formation by the use of a thiouronium derivative of Barton s reagent 42 [41] and new auxiliary groups 43 bearing a tertiary C-6 substituent, which can be prepared in either enantiomeric form. These new auxiliaries give product as a mixture of diastereomers in a ratio of 7 1 to 10 1. The fact that both enantiomers of 43 are available permits one to dial in the configuration of each stereogenic center produced in a complex product. 

Another example presented by this group involved the reduction of ( )-3-hydroxy-5-phenyl-2-pentanone with Sml2 in the presence of ethyl crotonate to afford jjn-y-lactone in excellent yield and diastereoselectivity at three contiguous stereocenters (Scheme 6) [19, 20], Cram cyclic model K was used to explain the selectivity in the formation of the first new stereogenic center. Subsequent coordination of the ethyl crotonate ester group to the Sm" was responsible for the facial selectivity during the formation of the second center [20]. 

Formation of the acetal-tethered triene 34 was achieved by selective nucleophilic displacement of the secondary alkyl bromide in 35 with hydroxydiene 36. Subsequent thermolysis at 145 °C for 70 h resulted in completely regiospecific cycloaddition with the formation of two out of the possible four diastereoisomers 37 and 38 in a 2.5-3 1 ratio (Scheme 10-11). The presence of a stereogenic center in the tether provides the source of stereocontrol - the products derive from exo and endo T. S.s in which the bromomethyl group in the tether occupies a pseudo-equatorial position (Scheme 10-11). Small differences in non-bonding interactions between the tether and pyruvate ester most probably account for the slight exo. selectivity. The separated major product was further elaborated, and finally the tether was cleaved under reductive conditions to provide the advanced cyclohexene intermediate 39. 

---