Asymmetric synthesis diastereoselective hydrogenation

Asymmetric synthesis is a method for direct synthesis of optically active amino acids and finding efficient catalysts is a great target for researchers. Many exceUent reviews have been pubHshed (72). Asymmetric syntheses are classified as either enantioselective or diastereoselective reactions. Asymmetric hydrogenation has been appHed for practical manufacturing of l-DOPA and t-phenylalanine, but conventional methods have not been exceeded because of the short life of catalysts. An example of an enantio selective reaction, asymmetric hydrogenation of a-acetamidoacryHc acid derivatives, eg, Z-2-acetamidocinnamic acid [55065-02-6] (6), is shown below and in Table 4 (73). 

Another possibility to increase the diastereoselectivity in an asymmetric synthesis can arise from different thermodynamic stabilities of the diasteieoisomeric products. If the thermodynamic stabilities of these are different enough, then, under conditions of equilibrium, a complete conversion of the less stable into the more stable can be achieved. For example, the diastereoselective hydrogenation of naphthalene derivates over Pd/C catalyst leads to a mixture of dihydronaphtalenes in which the cA-isomer predominates. The conversion of this isomer into the tram occurs by changing the properties of the reaction medium, namely by equilibration with a base. For such a purpose, NaOMe in IHF can be used [263], Generally, such an increase in stability in the six-membered rings can result from a rearrangement of the substituents from an axial to an equatorial position. 

R)-(-)-2,2-Diphenylcyclopentanol (1) is a highly effective chiral auxiliary in asymmetric synthesis. Hydrogenation of chiral 0-acetamidocrotonates derived from this alcohol has afforded the corresponding 0-amido esters with high diastereoselectivity (96% de).6 In addition, (R)-1 has been used as a chiral auxiliary in Mn(lll)-based oxidative free-radical cyclizations to provide diastereomerically enriched cycloalkanones (60% de).7 Our interest in (R)-(-)-2,2-diphenylcyclopentanol is its utility as a chiral auxiliary in Lewis acid-promoted, asymmetric nitroalkene [4+2] cycloadditions. The 2-(acetoxy)vinyl ether derived from alcohol (R)-1 is useful for the asymmetric synthesis of 3-hydroxy-4-substituted pyrrolidines from nitroalkenes (96% ee).8 In a similar fashion, a number of enantiomerically enriched (71-97% ee) N-protected, 3-substituted pyrrolidines have been prepared in two steps from 2-substituted 1-nitroalkenes and (R)-2,2-diphenyl-1-ethenoxycyclopentane (2) (see Table).9... 

Applications in Total Synthesis. Two recent examples of directed hydrogenations employing (1) in the total synthesis of complex molecules are illustrated. In eq I a simultaneous diastereoselective reduction of the trisuhstituted alkene and the a,p-unsaturated ester afforded the illustrated advanced intermediate in the asymmetric total synthesis of ionomycin. In addition, a two-directional application has been utilized in an asymmetric synthesis FK-506 (eq 2). ... 

The reports in the organic sections of this review are now considered. Irradiation of valerophenone is well known to yield both acetophenone and cyclobutanols by a Norrish Type II process but Zepp et al. report that the latter product (cis trans ratio 2.4 1) is more efficient in aqueous systems than hydrocarbons. Such ketones as 1 readily undergo the Type II process in the solid phase and from a detailed study involving the use of chiral auxiliaries as counter ions of its carboxylate derivative, Leibovitch et al. conclude that the ionic chiral auxiliary approach is a viable general method for asymmetric synthesis. Crystals of the ketone 2 are apparently photostable at room temperature but when finely ground or at elevated temperatures intramolecular hydrogen abstraction and formation of the benzocyclobutene 3 occurs (Ito et al), and the same workers also note that irradiation of S-4 at 4 °C in the solid state and at 34% conversion gives the SS product 5 with a diastereoselectivity of 99%. 

Since the discovery and development of highly efficient Rh catalysts with chiral diphosphites and phosphine-phosphites in the 1990s, the enantioselectivity of asymmetric hydroformylation has reached the equivalent level to that of asymmetric hydrogenation for several substrates. Nevertheless, there still exist substrates that require even further development of more efficient chiral ligands, catalyst systems, and reaction conditions. Diastereoselective hydroformylation is expected to find many applications in the total synthesis of complex natural products as well as the syntheses of biologically active compounds of medicinal and agrochemical interests in the near future. Advances in asymmetric hydrocarboxylation has been much slower than that of asymmetric hydroformylation in spite of its high potential in the syntheses of fine chemicals. 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

Diastereoselective reduction of the chiral silyloxy ynone A with (RJt)-43 and 2-propanol predominantly gives (7R,9R)-B (Scheme 1.88) [328]. The chirality of the C9 position is controlled by the BINAP-Ru catalyzed asymmetric hydrogenation. The chiral product is a key intermediate in the synthesis of taurospongin A, a potent inhibitor of DNA polymerase 3 and HIV reverse transcriptase. 

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. 

Initially, /-menthyl 2-cyano-3-methyI-2-pentenoate, and /-menthyl and r/-bornyl cy-clopentylidenecyanoacetateswere epoxidized with hydrogen peroxide in the presence of sodium tungstate. Some asymmetric induction was achieved, but the degree of diastereoselectivity was not estimated26. In the final step of the synthesis of the antibiotic phosphonomycin, (Z)-propenylphosphonic acid was epoxidized under Weitz-Scheffer conditions and 92% optically pure phosphonomycin (+ )-x-phenethylammonium-c -epoxypropylphosphonate crystallized from the reaction mixture. It is unclear whether an asymmetric induction occurs during the epoxidation step and to what extent27. 

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