Stereochemistry and Asymmetric Hydrogenation

Of at least as great importance to the chemistry of PX3 compounds as the electronic factors are steric factors.6 Indeed these may be more important or even dominant in determining the stereochemistries and structures of compounds Steric factors also affect rates and equilibria of dissociation reactions and the stereochemistry of phosphine ligands is the prime factor in many highly selective catalytic reactions of phosphine complexes, such as hydroformylation and asymmetric hydrogenation. 

Asymmetric syntheses of warfarin <96TL8321> and the axially chiral bicoumarin, isokotanin A <96TL3015> have been reported. The former is based on a Rh-catalysed asymmetric hydrogenation of a 3-(a,P-unsaturated ketone) substituted coumarin, whilst the key steps of the latter are an asymmetric Ullmann coupling and a selective demethylation. The stereochemistry of the fused dihydrocoumarin resulting from Li/NHs reduction of... 

Related catalytic enantioselective processes Although great progress has been achieved in the area of metal-catalyzed hydrogenation reactions [124], examples of catalytic asymmetric hydrogenations of tetrasubstituted alkenes are rare. One other example, reported by Pfaltz and co-workers, is depicted in Eq. 6.26 (81 % ee, absolute stereochemistry of the product not determined) [125],... 

Two-step asymmetric hydrogenation of (3-diketones shows that the overall stereochemistry is determined by the catalyst and by the chirality of the intermediate hydroxy ketone. Thus partial hydrogenation of acetylacetone (2) catalyzed by Ru-... 

Reaction Conditions versus Selectivity. [Rh(binap)(CH30H)2]C104 is an excellent chiral catalyst for asymmetric hydrogenation (13, 16). Scheme 5 relates the double bond geometry of the starting materials, the configuration of the BINAP ligand, and the stereochemistry of the products. The optical yield and the sense of asymmetric induction are... 

Asymmetric hydrogenation. Procbiral u,/ -unsaturated acids and their derivatives can be hydrogenated with high stereoselectivity by rhodium complexes with 1, such as (BPPM)Rh(COD)Cl and (BPPM)Rh(COD)+ClCV, in which COD = 1,5-eyclooctadiene. The stereoselectivity is dependent in part on the hydrogen pressure, ami the effect can be attenuated by addition of triethylamine, which also increases Ihc optical yield. The stereoselectivity is markedly controlled by the stereochemistry of the double bond.1... 

A diastereoselective Mukaiyama aldol lactonization between thiopyridylsilylketene acetals and aldehydes was used to form the /3-lactone ring in the total synthesis of (-)-panclicin D <1997T16471>. Noyori asymmetric hydrogenation was a key step in a total synthesis of panclicins A-E and was used to establish the stereocenter in aldehyde 140, which in turn directed the stereochemistry of subsequent reactions <1998J(P1)1373>. The /3-lactone ring was then formed by a [2+2] cycloaddition reaction of 140 with alkyl(trimethylsilyl)ketenes and a Lewis acid catalyst. 

Optical yields as high as 56% (but more typically 10-20%) have been recorded by Solodar (41) in the direct asymmetric hydrogenation of ketones with [Rh(COD)(ACMP)2] + BF4. 8 Catalyst turnover ratios of over 1000 were observed. It was found that the stereochemistry was quite dependent on the choice of solvent and its water content. For example, the hydrogenation of 2-octanone in ethanol gave the (+)-S-carbinol with 1.6% ee in N, Af-dimethyl-formamide (DMF) the i -carbinol was observed in 5.1% ee, and in acetic acid the R-carbinol was observed in 12.0% ee. In varying the water content of the isobutyric acid solvent in the hydrogenation of 2-octanone from 0.1 to 8%, the optical yield dropped from 13.9 to 5.3%. 

Figure 9.3 Catalytic cycles for the asymmetric hydrogenation of a-acetamido methyl acrylate (or cinamate). For clarity the detailed structure of the organic substrate is not shown. In 9.21 and 9.22 for ease of identification the carbon atom to which the metal hydride is transferred is marked by an arrow and the hydride is circled. Note that, excepting the chelating chiral phosphine, the stereochemistries around the rhodium in the left- and right-hand cycles have mirror-image relationships.

Transfer of hydrogen to NAD or NADP creates a new asymmetric center at C-4 of the pyridine ring. The hydrogen atoms appear on both sides of the plane of the ring the sides have been designated170 the A and B sides of the molecule, and the hydrogen atoms as HA and Hb. The absolute stereochemistry has been elucidated,171,172 and Ha has been found to correspond to the pro-fi hydrogen atom. 

Ohta, T., Takaya, H., Noyori, R. Stereochemistry and mechanism of the asymmetric hydrogenation of unsaturated carboxylic acids catalyzed by BINAP-ruthenium(ll) dicarboxylate complexes. Tetrahedron Lett. 1990, 31,7189-7192. 

Hydroxyalkylphosphonates have been prepared by reduction of the corresponding ketones. These include phosphonomalate esters by highly diastereose-lective reduction of 3-phosphonopyruvates with NHs.BHa and both 2-hydroxyalkyl-phosphonates, e.g. 178, and thiophosphonates by asymmetric hydrogenation using chiral ruthenium catalysts. An enantioselective synthesis, from 179, of both enantiomers of phosphonothrixin 180 and their absolute stereochemistry have been reported.The epoxide 179 was prepared from 2-methy -3-hydroxymethyl-1,3-butadiene via a Sharpless epoxidation. 

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