S_N1‐Type Substitution Reactions of N‐Protected β‐Hydroxytyrosine Esters: Stereoselective Synthesis of β‐Aryl and β‐Alkyltyrosines

Abstract

The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N-dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman's catalyst delivered the unprotected β-hydroxytyrosine esters, which were further N-protected as N,N-phthaloyl (Phth) and N-fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel-Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH(2)) gave preferentially syn-products but the anti-selectivity increased when going from NHFmoc over NPhth to NBn(2). If the ester substituent was varied the syn-preference increased in the order Me < Et < iPr. The reactions were shown to be fully stereoconvergent and proceeded under kinetic product control. A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N-unprotected isopropyl ester, which gave Friedel-Crafts alkylation products with good syn-selectivity (anti/syn=21:79 to 7:93), and for the N,N-dibenzyl-protected methyl ester, which led preferentially to anti-products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)(3) -catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti-selectivitiy (anti/syn≥95:5).

α‐Aziridinyl Carbenium Ion Intermediate and Stereoselective Dehydroxylative Diarylation of Aziridin‐2‐yl Carboxaldehyde

“…Bach et al reported syn-or anti-selective reactions depending on the N-substitution of amines (Scheme 1a). [10] Hanessian et al demonstrated synselective reactions starting from syn-alcohols with nitro or azido groups (Scheme 1b). [11] For tetralin systems, Lautens et al reported a highly anti-selective arylation mediated by AlCl 3 (Scheme 1c).…”

“…Bach et al . reported syn ‐ or anti ‐selective reactions depending on the N ‐substitution of amines (Scheme 1a) [10] . Hanessian et al .…”

Stereodivergent entry to β-branched β-trifluoromethyl α-amino acid derivatives by sequential catalytic asymmetric reactions

“… 1 The stereocontrolled preparation of these compounds has been tackled and realised with different (catalytic) methods. 2–7 A non-comprehensive list of examples includes enantioselective conjugate additions and alkylations of glycinate imines, 2 palladium catalysed β-C(sp 3 )–H alkylation and arylation of AAs, 3 aziridine ring-opening, 4 an engineered tryptophan synthase, 5 multi-enzymatic β-methylation of AAs, 6 and catalytic asymmetric hydrogenation of α,β-dehydro-amino acids (DHAAs), in its implementation with tetra-substituted substrates. 7 This latter approach ( Scheme 1(a) ) has disclosed diastereo- and enantioselective entries to various classes of β-branched AAs, including 7 d less common yet relevant β-trifluoromethyl AA derivatives.…”

Syntheses of Chroman-2-ones and α-Amino Acids through a Diastereoselective Domino Reaction

“…Different approaches have been established to reach this objective. Representative examples include Armstrong’s ring opening of aziridines, Bach’s diastereoselective S N 1 reactions on phenylalanine derivatives, Chen, Yu, Daugulis, and Corey’s palladium-catalyzed C–H functionalization of alanine derivatives, Liu and Hruby’s alkylations with a chiral auxiliary, Leighton’s aza-Darzens/ring opening reactions, Molinaro’s hydrogenation of tetrasubstituted olefin, Chen’s chiral catalyst applied to nitroacrylates, Hou’s alkylation of glycine derivatives, etc. These methods may require directing ligands, expensive chiral auxiliaries, metallic catalysts, or protecting groups.…”