Diastereoselective hydrogenations of unsymmetrically substituted aromatics

Abstract

Attempts to induce enantioselectivity in the catalytic hydrogenation of unsymmetrically substituted aromatics using covalently bound, well known chiral auxiliaries are described. Marked differences in stereoselectivity and rate of hydrogenolysis are noted as a function of the auxihary used. Enantioselectivities obtained in the resulting cyclohexyl derivatives are rather poor. o 1995 Wiey-Liss, hc.KEY WORDS: prochirality, rhodium, chn-a1 auxiliaries, (-)-menthol, L-prohe, chiral cyclohexane derivativesHighly substituted chiral cyclohexyl moieties frequently constitute essential parts of biologically very active compounds like FK 506 (a potent immunosuppressor, Fig. 1)'"~~ and rapamycin (an antifungal agent) and in the synthesis of trichotecenes2 and GABA antagonist^.^The classical ways to such fragments are asymmetric Diels-Alder reactions4 or strategies applying the "chiral pool" concept,' some using enzymatic methods. We succeeded in using the most simple approach (Fig. 2): hydrogenation of appropriately substituted aromatic compounds (e. g., vanillic acid)7 and enzymatic resolution of the enantiomers with the help of enzymes8 shortens the preparation from 10 (the average of the reported syntheses) to 4 steps.From a theoretical point of view, unsymmetrically substituted aromatics can be regarded as prochiral entities (Fig. 3). Hansong in his original paper regarding prochirality, although not explicitly mentioning aromatics, implicitly included them: "It may be desirable in the future to define. . . planar prochirality. . . . It remains to be determined which combination of symmetry elements, i.e. which point groups, are compatible with prochxality. " If one is able to exploit this property, enantioselective hydrogenations of appropriately substituted benzene rings should be possible.In principle, four ways to such selective transformations can be envisaged: Here we report on our attempts regarding the second route. MATERIALS AND METHODSMelting points were determined with a Buchi apparatus and are uncorrected. Optical rotations were measured w i t h a 0 1995 Wiley-Liss, Inc.JASCO DIP-370 polarimeter. NMR spectra were recorded on a Varian Gemini instrument (199.98 MHz for 'H and 50.29 MHz for 13C). Chemical shifts are in ppm relative to TMS as internal standard. For the analysis of the product mixture of the hydrogenation of 6a GLC was used DAN1 8500, column DB-1701, 1 = 30 cm. No internal standard was used. Reactions were monitored by TLC using Merck silica gel 60 F, , plates. Purification of the products was performed on Merck silica gel 60. All reagents and solvents were obtained from commercial suppliers and used without further purification.The Rh catalysts were donated by Johnson Matthep. '' Hydrog e n a t i o n~~~ were done in a Berghoff autoclave, 250 ml, m a . 150 bar. 4-Acetoxy-3-methoxybenzoic Acid (2)Vanillic acid, 10.0 g (59.4 mmol), was dissolved in 100 ml CH,CI, and 12.0 ml (148.7 mmol) pyridine and 8.4 ml (89.2 mmol) acetic anhydride added. The mixture was heated under reflux for 3 days....

Enantiospecific equilibrium adsorption and chemistry of d‐/l‐proline mixtures on chiral and achiral Cu surfaces

“…[25][26][27][28][29][30] The rigidity of Pro has been employed in metal-catalyzed diastereoselective hydrogenation reactions to produce enantiopure hydrogenated products. [31][32][33][34] In these reaction schemes, Pro is used as a chiral auxiliary which forms an intermediate compound with the organic reactant. Given the rigidity and chirality of Pro, this intermediate then adsorbs on the metal catalyst surface in single enantiomer conformation which in turn causes the hydrogenation reaction to yield an enantiomeric excess in the organic product.…”

Formation of Bioinorganic Complexes by the Corrosive Adsorption of (S)-Proline on Ni/Au(111)

“…In this study, we chose to investigate the structurally similar amino acid ( S )-proline (Figure A) in order to probe the effect of removing the carbonyl group from the pyrrolidone ring on the ability of proline to form metal–organic structures. ( S )-Proline is of additional interest as it is used widely in chiral organic synthesis, for example in the hydrogenation of α,β-unsaturated ketones such as isophorone and in the hydrogenation of substituted aromatic compounds such as unsymmetrically substituted aromatics . The adsorption of proline has been reported on Cu(110), , TiO 2 (110), , Pd(111), and Au(111) surfaces.…”

Asymmetric Hydrogenation of Pyridines: Enantioselective Synthesis of Nipecotic Acid Derivatives

“…[2][3][4] However, asymmetric hydrogenation of an aromatic ring, one of the most readily available unsaturated compounds, has received little attention and is generally regarded as the greatest challenge in the asymmetric hydrogenation field. [5][6][7][8] Some positive results have been reported recently concerning the asymmetric hydrogenation of polycyclic heteroaromatic compounds, [9,10] such as 2-substituted quinolines [11][12][13] and indoles. [14][15][16][17][18] Some promising results have been reported in the preparation of optically active 2-piperazine derivatives by the reduction of tetrahydropyrazines derived from pyrazines.…”