173433-56-2Relevant articles and documents
ALPHA-SUBSTITUTED α,β-UNSATURATED E- OR Z-ALDEHYDES, USE THEREOF, AND PROCESSES FOR THEIR PREPARATION α,β
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Page/Page column 16, (2009/03/07)
This invention relates to novel alpha-substituted α,β-unsaturated E- or Z-aldehydes, or isomer mixture thereof, of the formula (I) in which R1 and R2 may be identical or different and are each H or a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms and R3 and R4 may be identical or different and are each a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms, and R5 may be identical or different and is H or a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms, to the use thereof, and to processes for their preparation. The invention further relates to the preparation of further intermediates for pharmaceuticals and to the preparation of the pharmaceuticals.
PROCESS FOR PREPARING (R OR S)-2-ALKYL-3-HETEROCYCLYL-1-PROPANOLS
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Page/Page column 57-59; 61, (2008/12/06)
Compounds of the formula (I) in which R'1, R'2,R'3 and Het are each defined as specified in the description are obtainable in high yields by a stereoselective addition of R'3-substituted propionic esters onto R'1- and R'2-substituted unsaturated, bicyclic heterocyclylaldehydes of the formula R-CHO to give corresponding 3-(R)-3-hydroxy-2-R'3-propionic esters. Conversion of the OH group to a leaving group, a subsequent regioselective elimination to give 3-(R)-2-R'3-propenoic esters, followed by: 1) hydrolysis to the corresponding 3-(R)-2-R'3-propenoic acids, their enantioselective hydrogenation to corresponding chiral 3-(R)-2-R'3-propenoic acids and their reduction, or 2) hydrolysis to the corresponding 3-(R)-2-R'3-propenoic acids, their reduction to corresponding 3-(R)-2-R'3-allylalcohols and their enantioselective hydrogenation, or 3) reduction to corresponding 3-(R)-2-R'3-allylalcohols and their enantioselective hydrogenation, where R is formula (II) and the enantioselective hydrogenations are performed with metal complexes which have, as ligands, ferrocene-1,1'-diphosphines which have, in the 1-position, a ferrocene-substituted secondary phosphine group and, in the1'-position, a secondary phosphine group.
The nonchiral bislactim diethoxy ether as a highly stereo-inducing synthon for sterically hindered, γ-branched α-amino acids: A practical, large-scale route to an intermediate of the novel renin inhibitor aliskiren
Goeschke, Richard,Stutz, Stefan,Heinzelmann, Walter,Maibaum, Juergen
, p. 2848 - 2870 (2007/10/03)
The diastereoselective synthesis of the sterically hindered, γ-branched α-amino acid derivative (2S,4S)-24a and its N-[(tert-butoxy)carbonyl](Boc)-protected alcohol (2S,4S)-19, both key intermediates of a novel class of nonpeptide renin inhibitors such as aliskiren (1), is described. Initially, the analogous methyl ester (2S,4S)-17 was obtained by alkylation of the chiral Schoellkopf dihydropyrazine (R)-12a with the dialkoxy-substituted alkyl bromide (R)-11a, which proceeded with explicitly high diastereofacial selectivity (ds > 98%) to give (2S,SR,2′S)-13a (Scheme 4), followed by mild acid hydrolysis and N-Boc protection (Scheme 5). Conversely, the complete lack of stereocontrol and poor yields for the reaction of (R)-11a with the enantiomeric (S)-12b suggested, in addition to the anticipated shielding effect by the iPr group at C(2) of the auxiliary, steric repulsion between the MeO-C(6) and the bulky residues of (R)-11a in the proposed transition state, which would strongly disfavor both the Si and Re attack of the electrophile (see Fig.). Based on this rationale, alkylation of the readily accessible achiral diethoxy-dihydropyrazine 21 with (R)-11a was found to provide a 95:5 mixture of diastereoisomers (2S,2′S)-22a and (2R,2′S)-23a in high yield (Scheme 6), which afforded in two steps and after recrystallization enantiomerically pure (2S,4S)-24a. Similarly, the stereochemical course for the alkylation reactions of the related alkyl bromides (S)-28a and (R)-28b with both (R)-12a and (S)-12b as well as with the achiral 21 was investigated (Schemes 7-9). The precursor bromides (R)-11a, (S)-11b, (R)-28a, and (S)-28b were efficiently synthesized via the diastereoselective alkylation of the Evans 3-isovaleroyloxazolidin-2-ones (R)-7a and (S)-7b either with bromide 6 or with benzyl chloromethyl ether, and subsequent standard transformations (Schemes 3 and 7). A practical and economical protocol of the preparation of (2S,4S)-24a on a multi-100-g scale is given. This is the first report of the application of an achiral dihydropyrazine, i.e., in form of 21, as a highly stereo-inducing synthon providing rapid access to a N-protected γ-branched α-amino acid with (2S) absolute configuration.
