A novel bicyclic orthoester as a chiral auxiliary: Application to the synthesis of α-hydroxy acids (original) (raw)
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A synthetic strategy has been devised for the preparation of chiral β-keto sulfoxides (actually, α-vinylsulfinyl ketones) starting from the readily available C-6 substituted 2,3-dihydro-1,4-oxathiines. The procedure, which is characterized by high yields and excellent enantiomeric excesses, represents an improvement in preparation methods for chiral β-keto sulfoxides. Chiral β-keto sulfoxides have been extensively investigated and are commonly used in the synthesis of natural products and biologically active compounds. 1 Acyclic β-keto sulfoxides are generally prepared according to a procedure based on the reaction of α-sulfinyl anions with esters, as described by Corey. 2 Usually (+)-(R)-methyl p-tolyl sulfoxide, prepared by reaction of magnesium methyl iodide on a suitable chiral sulfinate ester, is converted by lithium diethylamide into its corresponding sulfinyl anion and the latter is then coupled with an ester. 3 Other methods include Claisen-type condensation of the optically active sulfinate ester with ketone enolate anions, 4 as well as the reaction of α-sulfinyl anions with cyclohexanones for the synthesis of chiral β-sulfinyl cyclohexanones. We wish to report in this paper a new procedure for the synthesis of chiral acyclic β-keto sulfoxides starting from chiral cyclic sulfoxides that in turn are prepared, with both R and S configurations, from C-6 substituted 2,3-dihydro-1,4-oxathiines. These starting compounds can be easily obtained from methyl ketones via their 1,3-oxathiolanes (overall yield range 85-92%), according to a procedure we have previously reported. The oxidation at the sulfur atom in the oxathiine ring is then performed under modified Sharpless conditions, 7,8 using cumene hydroperoxide (CHP) and Ti IV isopropoxide in the presence of either L-(+) or D-(−) diethyl tartrate, in dry methylene chloride at −18°C, as shown in Scheme 1. The molar ratio of substrate and reagents is reported in . Other oxidation systems and substrate:reagent ratios were also tested, as shown in , although the results were definitely less satisfactory, in terms of both chemical yield and e.e.
The syntheses of new chiral cyclic 1,2-diacetals from (2R, 3R)-(+)-tartaric acid are described. C 2 -symmetrical diamines were prepared via direct amidation of the tartrate or from the corresponding bismesylate via reaction with sodium azide. For C 1 -symmetrical compounds, the Appel reaction was used to form the key intermediate, a monochlorocarbinol, from the diol. Some of the new chiral compounds, produced in good to high yields, may be potentially useful as asymmetric organocatalysts or as nitrogen and sulfur chelating ligands for asymmetric metal catalyzed reactions. Thus, a bis-N-methylmethanamine derivative, used in substoichiometric amounts, was found to catalyze the enantioselective addition of cyclohexanone to (E)-β-nitrostyrene with high diastereoselectivity (syn / anti = 92:8), albeit giving moderate optical purity (syn: 30 %).
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(2S,3R) 77mo-3-hydroxy-omitlk haa bun synthixd e!Eciently using a highly stemxhh-II of the chiral Z-oleb 7 prepared from D-serine. g-Hydroq-~aminoacids are an important class of compounds, due to their presence in nature as primary metabolites themselves (threonine, serine, 4hydroxyproline) and as components of more complex natural compounds (e.g. cyclic peptides', MeBmt in cyclospori&, 341ydroxyhomotyrosine in echinocandin K?). Moreover, they have been used as intermediates in the synthesis of important natural products4 like g-lactams and ami110p01~0ls~. In this context procl avaminic acid 1 has recently been recognised as the biosynthetic precursor of clavmanic acid 2, a potent inhibitor of many bacterial g-k&mases6.
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tioselectivity. Notably, the alkylation products of a-ketoesters bear both a quaternary stereocenter and an ester group, hence they are suitable precursors for the synthesis of many valuable complex compounds. Although the use of chiral auxiliaries to promote diastereoselective additions of or-A C H T U N G T R E N N U N G ganometallic reagents to enantiopure a-ketoesters has been widely studied, [6] scarce examples of catalytic asymmetric additions with a chiral ligand have been reported. [7] The first catalyst used to this end was Kozlowskis titanium-salen complex, [7a] which affords the Et 2 Zn addition products in good yields, although with moderate enantioselectivities (up to 78 % enantiomeric excess (ee)). Since then, approximately five different kinds of ligand have been employed for catalytic alkylation of a-ketoesters, [7b-f] two of which have been reported to achieve high enantioselectivities (> 90 % ee). Shibasaki et al. reported a privileged prolinol-derived ligand, which promoted addition of Me 2 Zn to a-ketoesters with enantioselectivities ranging from 59-96 % ee. [7b] In 2005, Hoveyda and Snapper disclosed an aluminum-catalyzed enantioselective addition of Et 2 Zn and Me 2 Zn to a-ketoesters that permitted the isolation of products with notable enantioselectivity (56-95 % ee). [7c] Recently, we have shown that chiral decahydro-4aH-pyrrolo[2,1-b,1,3]benzoxazin-3-ol ligands promote asymmetric addition of diethylzinc and arylzinc derivatives to aldehydes with excellent enantioselectivities under mild conditions, even at very low ligand loadings (0.2 mol %). [8] Based on these results, herein we describe the asymmetric addition of dimethylzinc to aromatic, heteroaromatic, and aliphatic a-ketoesters promoted by enantiopure perhydro-1,3-benzoxazine-based ligands. Additionally, we further exploited the versatility of the resulting hydroxyesters for the synthesis of complex valuable products, such as oxazolidinediones or azidoalcohols, which are important building blocks for biologically active compounds. Abstract: A highly efficient enantioselective addition of Me 2 Zn to a-ketoesters, assisted by a chiral perhydro-1,3-benzoxazine ligand, is described. This novel catalytic system offers homogeneous elevated enantioselectivities in the preparation of a-hydroxyesters that bear a quaternary stereocenter, with a minor dependence on electronic and steric effects when aromatic, heteroaromatic, or aliphatic a-keto-
Asymmetric synthesis of malic acid-type synthons VIA chiral norephedrine-derived oxazolidines
Tetrahedron, 1990
Polyoxygenated C, synthons 5-7 am synthesized in enantiomerically pure form starting from ephedrine derived oxazolidines 2,4 and 13. The l&benzylate addition to 2 and 4, the key step in the synthesis of 5 and 6, proceeds cleanly with almost complete diastereoface selection. The key steps in the synthesis of target 7 are the nucleophilic epoxidation of aldehyde 13 and the lithium dimethyl cuprate epoxide opening, both of which proceed with high regio and stereocontrol. This route compares favorably with synthesis from malic acid, in that both enantiomers of ephedrine are available cheaply and it provides three differentiated oxygenated positions directly. Malic acid has been extensively used as a C, chiron for the enantiospecific synthesis of several classes of compounds.' The naturally occurring (S) enantiomer is, in fact, a cheap source of chiiality in a highly functional&d environment, its two carboxyl groups representing convenient synthetic handles for elongation.