Enoates 1,4-reduction

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

Enones and enoates undergo 1,2-reduction [115, 191]. Lipshutz et al. reported the effective protection of carbonyl functions by the triisopropylsilyl acyl silane group (TIPS), which allowed the selective conversion of alkenes or alkynes to the corresponding zirconocene complexes [24]. The aldehyde could subsequently be regenerated by desilylation with TBAF [186]. 

Motherwell and Whitehead et al. reported a similar intramolecular reductive aldol reaction of aldehyde-enoate derivatives. The cyclization of 6-oxo-ester 23 was catalyzed by RhCl(PPh3)3 (1 mol%) with Et3SiH (210 mol%) as terminal reductant (Scheme 9) [17,18]. The cyclization proceeded at 50 °C for 18 h to give the aldol product 24 in 81% yield with ds-selectivity (cis trans =... 

Scheme 9 Rh-catalyzed intramolecular reductive aldol reaction of 6-oxo-hex-2-enoates...

Enoate Reductase in Reduction of Triply Substituted Double Bonds... 

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. 

The organosilane reduction of pentafluorophenyl acrylate in the presence of an imine was shown to lead to /1-lactams in good yields (Eq. 295)476 The conversion of an ethyl ynoate into an E-ethyl enoate in high yield is shown in Eq. 296 477... 

Copper-mediated conjugate reductions of enones and enoates were reported in 1988 by Stryker and co-workers (188). Stryker and Mahoney (189) showed that the reaction could be made catalytic in copper under an atmosphere of hydrogen gas however, under these conditions, overreduction was observed. In 1998, Lipshutz... 

The actual synthesis (Scheme 21) started with the stereoselective alkylation of Myers hydroxy-amide 131 [40] followed by reductive removal of the auxiliary to give 132 in high yield and enantioselectivity. Wittig olefination furnished enoate 133, which was then elaborated into the (E)-l-acetoxy-diene 129 using... 

Although unhindered enones and enoates work well, attempted 1,4-reduction of acrylonitrile afforded a-silylated product 9 (Scheme 5.4). Presumably this unexpected product results from a 1,4-reduction/a-anion trapping by the PhMe2SiCl present in solution. Curiously, there was no mention of any similar quenching of intermediate enolates on either carbon or oxygen when unsaturated ketones or esters were involved. 

Another approach to preparing enantiomerically pure carboxylic acids and related compounds is via enanhoselective reduction of conjugated double bonds using NAD(P)H-dependent enoate reductases (EREDs EC 1.3.1.X), members of the so-called Old Yellow Enzyme family [44]. EREDs are ubiquitous in nature and their catalytic mechanism is well documented [45]. They contain a catalytic flavin cofactor and a stoichiometric nicotinamide cofactor which must be regenerated (Scheme 6.23). 

Synthesis of Boc-Phei/ [(Z)-CF=CH]Gly-OEt (64) utilizing organocopper-mediated reduction of y,y-difluoro-ot, -enoates... 

A Rh-catalyzed Reformatsky reaction of chiral imine (24) led to the stereoselective preparation of the a,a-difluoro-jS-amino acid (25). 25 was converted to difluor-oalkene (26), and subsequently L-Val-i/r[(Z)CF=CH]Gly derivative (23) in greater than 82% for both steps. The samarium diiodide-mediated reductive transformation of the y,y-difluoro-a, S-enoates proceeded via successive two-electron transfers to form a dienolate species which upon kinetically controlled trapping with fert-BuOH formed 23 (Scheme 6). 

Recently, the synthesis of functionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-a, S-enoates (37) (Scheme 7) was reported [73] (Scheme 26). 

A. Otaka, J. Watanabe, A. Yukimasa, Y. Sasaki, H. Watanabe, T. Kinoshita, S. Oishi, H. Tamamura, N. Fujii, Sml2-mediated reduction of y,y-difluoro-a,/ -enoates with... 

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