Diastereoselectivity of the hydrogenation

The total synthesis of pentacyclic alkaloid (-)-haliclonadiamine was accomplished by D.F. Taber and co-workers. The Noyori asymmetric hydrogenation was used to prepare a bicyclic 3-hydroxy ester intermediate in enantiopure form from a racemic bicyclic P-keto ester via kinetic resolution. It was found that the hydrogenation only took place in the presence of added HCI and by optimizing the amount of HCI added, the proportion of the total reduced ketone could be controlled. About 87% of the "matched" ketone was reduced, while the other P-keto ester enantiomer was not significantly converted to the reduced product. Interestingly, the diastereoselectivity of the hydrogenation depended on the nature of the added acid with HCI, the trans diastereomer was the major product, while with AcOH the cis diastereomer was dominant. 

It was found that a variety of radical precursors could be added, and that the specific electronic and steric effects exerted on the resulting radical effected the diastereoselectivity of the hydrogen atom transfer. Increasing the size of R group appeared to increase the selectivity of the trap. For instance, reaction with t-butyl radical and tributyltin hydride gave the highest selectivity, >98 2 (70% yield), for the trans product (77). Reactions with electron-deficient radicals suffered from low yields and decreased selectivity. Results also indicate that reactions with tributyltin hydride produced higher selectivities but lower yields than those per-... 

The diastereoselectivity of the hydrogenation of pinene monoterpenoids and related systems depends on the location of the double bond. The endocyclic double bond in a-pinene (5) is reduced from the less hindered face yielding pinane (6) in a 93 7 (cis/trans) ratio56. 

The convergent synthesis of these compounds is rather simple. On the one side, the required a-keto ester may be synthesised from diethyl oxalate by a Grignard reaction. On the other side, alanine or trifluoroacetyllysine is coupled with proline via the oxazolidine-2,5-dione (the so-called Leuchs anhydride ). The two halves are combined by reductive amination. The diastereoselectivity of the hydrogenation is dependent on the choice of catalyst. With Raney nickel, the diastereoselectivity lies in case of enalapril at 87 13 and for Iisinoprii at 95 5 in favour of the desired diastereomers. In the case of Iisinoprii, there follows a final hydrolysis of the ester and amide function. The active material is ultimately purified by crystallisation. 

In a more complex elaboration of the hydrogen atom abstraction/nucleo-philic cyclization route to tetrahydrofurans (Scheme 20), a carbohydrate-based N-alkoxy phthalimide was converted to a spirocyclic acetal in excellent yield and diastereoselectivity (Scheme 33) [136]. In this cyclization, nucleophilic attack takes place from the endo face of the trioxabicyclo [3.3.0] octane... 

C, C double and triple bonds C=C double bonds can be stereoselectively hydrogenated with cis or trans addition of the hydrogen atoms. 2,3-Diphenylindenone underwent a selective cis addition in 0.25 M sulfuric acid, while a trans addition was found at higher pH values (Fig. 59) [321]. For the corresponding methyl-phenyl- and dimethylindenone, the diastereoselectivity was low. 

Benzamido allylic acetates 242 and 243 undergo palladium-catalyzed cychza-tion to oxazolines. Excellent yields and very high diastereoselectivity is observed for the conversion of several acyclic primary and secondary benzamido aUyhc acetates to tran -5-vinyl substituted oxazolines 244. The diastereoselectivity of the reaction is determined by the the steric interactions between the R group and the hydrogen of the 7i-allylpalladium complex in the transition state, trans-Oxazolines are obtained since transition state A is favored over transition state B (Scheme 8.66). 

A study of the alkylation of the trimethylsilyl enol ether of octahydro-1 (2//)-naphthalenone reveals that the diastereoselectivity of the reaction is similar to that of the methylation of the corresponding lithium enolate (see Section 1.1.1.3.1.1.2 1.)89. Lewis acid cataly2ed phenyl-thioalkylations of the type indicated (i.e., 3 -> 4) have been used for a-alkylations of several cyclic and acyclic ketones, as well as aldehydes89. The easy removal of the phenylthio group by catalytic hydrogenation completes this convenient procedure for a-alkylation of carbonyl compounds89. 

The asymmetric hydrogenation of the phenylhydrazone of methyl-N-(3,3-dimethyl-2-oxobutanoyl)-(S)-valinate (83) was investigated using palladium catalysts105). The absolute configuration of the newly formed t-leucine moiety in (84) was found to be (S). The diastereoselectivity in the hydrogenation step was shown to be as high as 56%. 

An interesting sidelight is that when the methyl group at position 3 of the bislactim ether is replaced by hydrogen, the diastereoselectivity of the alkylation drops to 90-95% (83T2085). The product obtained on acid hydrolysis is an a-unsubstituted amino acid ester (194) (Scheme 60). 

Catalytic hydrogenation of PGA-homoallylamines simultaneously reduced the double bond and removed the chiral auxiliary in one step. Some typical examples of enantiomerically pure (R)-aminobutanes 12 obtained are shown in Scheme 25.6. The nonoptimized yields varied between 49% and 88% with ee values of 94% to >98%. The high enantiomeric excesses of these chiral amines are in agreement with the equally high diastereoselectivity of the allylation reaction and lack of racemization of the phenylglycine amide moiety in any of the steps. Enantiomerically pure chiral (f )-a-propylpiperonylamine 12c is an important building block of the human leukocyte elastase inhibitor L-694,458 (13).28... 

The exchange of the hydrogen in benzaldehyde by a methoxy group completely inverted the diastereoselectivity in the photocycloaddition with furan. Further modification of the oc-substituent in the benzoyl substrates disclosed a distinct dependence of the exo/endo ratio on the size of this substituent. The photocycloaddition of acetophenone with furan gave only one product, whereas a 77 23 mixture of diastereoisomers resulted from the addition of benzoyl cyanide. Increasing the size of the aryl group from... 

Hydrogen bonding is a possible reason also for the diastereoselectivity of the [2+2] photocycloaddition of benzophenone also in case of acyclic chiral allylic alcohols 142 (Sch. 49). These substrates afforded only one regioisomer of the diastereomeric threo, erythro oxetanes 143 and preferentially the threo isomer [144]. The diastereoselectivity was remarkably reduced in the presence of a protic solvent (methanol as a competitive intermolecular hydrogen bonding substrate) and totally disappeared in case of the silylated substrate [145]. 

Gallium-mediated allylation of aldehydes or ketones in water gives the corresponding homoallyl alcohols in high yields without the assistance of either acids or sonication. The diastereoselectivity of the allylation of 2,3-dihydroxy-propanal depends on the solvent. When the reaction is carried out in water, the dominant product is the yy/z-isomer. In contrast, the anti-isomer is dominant when THF is employed. The yy/z-isomer may be regarded as the chelation-controlled product, due to the hydrogen bond between the two hydroxy groups. The aqueous environment favors... 

The control of the diastereoselectivity of the allylic ene reaction could extended to alkenes 205 substituted by a removable chiral auxiliary. Here ag the best de are obtained when hydrogen bonds can be developed between substrate and 1C>2 (Scheme 55) [124]. 

The model in Scheme 11 explains the regioselectivity, enantioselectivity and diastereoselectivity of the reaction. In the radical cyclisation step the endo radical 28 is formed exclusively due to the high stability of the resulting benzyl radical. The approach of the alkyl radical in the complex 27 (+)-12 occurs from the sterically unhindered re face whereas the attack of the radical from the si face is blocked by the tetrahydronaphthalene shield. For the same reason the hydrogen abstraction step in the complex 28 (+)-12 takes place at the same face to form product trans-29 predominantly with high enantioselectivity. 

Interesting is the excellent diastereoselectivity of the sequence where the R, acyl-R, and R substituents are exclusively placed in a syn-syn arrangement, whereas with a substituent R" other than hydrogen, epimers are formed with... 

The diastereoselectivity of the peracid epoxidation of open chain allylic alcohols (Table 8) under standard conditions is excellently reproduced by a force-field analysis (see Section 4.5.1.1.1.), as long as undirected transition states (without internal hydrogen bonding) cannot compete in the formation of either diastereomer. Two principle transition state con-formers (conformers 1 and IV of Figure 1) can contribute to each diastercomeric transition state. 

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