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  • Title: [Development of highly stereoselective reactions utilizing heteroatoms--asymmetric synthesis of alpha-substituted serines].
    Author: Sano S.
    Journal: Yakugaku Zasshi; 2000 Jan; 120(1):28-41. PubMed ID: 10655780.
    Abstract:
    This article reviews the efficient methods for diastereoselective and enantioselective syntheses of alpha-substituted serines. A newly designed bislactim ether, ethyl (5S)- or (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate, was treated with base or Lewis acid-tertiary amine to generate an enolate or enaminate (imine anion, metalloenamine). Alkylation or aldol-type reaction with the resultant enolate or enaminate proceeded in a highly diastereoselective manner to give the corresponding alkylated or aldol products, respectively. Reduction of these products with diisobutylaluminum hydride (DIBAL) followed by hydrolysis with hydrochloric acid afforded the desirable alpha-substituted serines. The enantioselective aldol-type reaction of an achiral bislactim ether, ethyl 3,6-diethoxy-2,5-dihydro-2-pyrazinecarboxylate, was also investigated by employing Sn(OSO2CF3)2-triethylamine in the presence of an external chiral ligand, (--)-sparteine. Not only a stoichiometric amount, but also a catalytic amount of (--)-sparteine promoted the highly enantioselective aldol-type reactions. Interestingly, the stereoselective outcome of the Sn(II)-mediated reaction differed from that of the Mg(II)-mediated one in the aldol-type reaction of the bislactim ethers with aliphatic aldehydes. On the other hand, chemoenzymatic synthesis of enantiomerically pure alpha-substituted serines must also be a convenient and useful procedure. Porcine liver esterase (PLE) or rabbit liver esterase (RLE) catalyzed hydrolysis of the pro-S ester group of diethyl alpha-alkyl-alpha-(benzyloxycarbonylamino)malonates to afford (R)-ethyl alpha-alkyl-alpha-(benzyloxycarbonylamino)malonates each in excellent enantiomeric excess. Enantiodivergent reductions of these acid esters readily proceeded to furnish both the corresponding enantiomeric alpha-substituted serines. Finally, the application of these methodologies mentioned above to a total synthesis of ISP-I (a potent immunosuppressive principle in the Isaria sinclairii metabolite) is described. Asymmetric total synthesis of ISP-I has been achieved in a highly stereoselective manner by utilizing the Mg(II)-promoted aldol-type reaction with ethyl (5R)-3,6-diethoxy-2,5-dihydro-5-isopropyl-2-pyrazinecarboxylate and Schlosser modification of the Wittig reaction.
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