Totalsynthese von natülichem α‐Tocopherol. 5. Mitteilung. Asymmetrische Alkylierung und asymmetrische Epoxidierung als Methoden zur Einführung der (R)‐Konfiguration an C(2) des Chroman‐Systems

Abstract

Based on the reductive, stereospecific ring closure of (2R,4R,8'R)-a -'Tocopherylquinone' or corresponding analogues with a short, functionalized side chain (B, Scheme 1 ) to 1 resp. the chroman system of 1 (C), two different approaches for the introduction of the required tertiary methyl-substituted alcohol structure in the side chain of the aromatic precursors (A, Scheme 1 ) were developed. The first approach uses asymmetric alkylation in three different versions featuring a ) diastereoselective steering with chiral auxiliaries I-IV (Scheme 2) attached as esters to a-keto acids, b ) intermediate transfer of chirality in an ester enolate (from 18, Scheme 4 ) derived from an optically active a -hydroxyacid, c) enantioselective alkylation of phytenal (20) and subsequent ring closure with chirality transfer (Schemes 5-7). The second approach is based on the asymmetric epoxidation of ~-metallylalcohol (Sharpless epoxidation), the corresponding epoxyalcohol being converted in situ to the (S)-or (R)-chlorodiol (S)-and (R)-29, respectively, for isolation (Schemes 8 and 9 ) . Nucleophilic epoxide opening with a (3R,7R)-3,7,11-trimethyldodecyl (Cy;*) and an ArCH, unit in appropriate sequence is used to assemble the C-framework of the target molecule via corresponding epoxide intermediates from either chlorodiol. Combined with the use of the methoxymethyl-ether function for protection of the hydroquinone system, the epoxide approach provides a short route to 1 (Scheme 10). Einleitung

Enantiocomplementary Chemoenzymatic Asymmetric Synthesis of (R)‐ and (S)‐Chromanemethanol

“…113–114 °C), R f = 0.63 (toluene/EtOAc, 10:1). The NMR spectroscopic data are in accordance with the literature 11 . 1 H NMR: δ = 3.66 (s, 6 H), 2.20 (s, 12 H) ppm.…”

“…The regioselective C–C coupling between the epoxide ( R )‐ or ( S )‐ 3 and the aromatic moiety 7 was achieved by nucleophilic attack of the (soft) benzylic lithium species of 7 (obtained by deprotonation using n BuLi) on the less hindered carbon atom of the oxirane ring system 11. To minimise undesired double‐coupling of two epoxides onto one molecule of dimethoxydurol ( 7 ), an excess of 2 molar equivalents of the aromatic component was used.…”

“…The solvent was removed under vacuum and the solid obtained was recrystallised from CH 2 Cl 2 /EtOH and dried in a desiccator over CaCl 2 to give 7 as white crystals (3.9 g, 20 mmol, 85 % yield), m.p. 113–116 °C (ref 11. 113–114 °C), R f = 0.63 (toluene/EtOAc, 10:1).…”

Katalysierte asymmetrische Arylierungen

“…Hier wurde das Zinkreagens aus Zinkdichlorid und Phenylmagnesiumbromid in situ gebildet 91. Zur chiralen Modifizierung wurde N , N ‐Dibutylnorephedrin 110 im Überschuss verwendet, wodurch enantiomerenangereicherte Produkte mit bis zu 82 % ee erhalten werden konnten 92. Überraschenderweise war die Seitenselektivität in dieser Reaktion genau umgekehrt zu der, die bei den eng verwandten Dialkylzinkadditionen resultierte.…”

Origin of Enantioselectivities in Chiral β-Amino Alcohol Catalyzed Asymmetric Additions of Organozinc Reagents to Benzaldehyde: PM3 Transition State Modeling

“…Besides β-amino alcohol camphor derivatives, a huge variety of other ligands and catalysts has been developed and applied for this type of reaction, e.g., Soai's proline ligands, Seebach's titanium tetraaryl-1,3-dioxolane-4,5-dimethanolates (TADDOLs), Corey's 11 and Soai's 14 ephedrine derivatives, and Bolm's bipyridines . Organozinc additions to aldehydes promoted by chiral auxiliaries have been employed in the syntheses of an α-tocopherol precurser and an insecticide 2 (a) PM3 transition structure 4-syn .…”