Azlactones asymmetric hydrogenation

Monsanto s commercial route to the Parkinson s drug, L-DOPA (3,4-dihydroxyphenylalanine), utilizes an Erlenmeyer azlactone prepared from vanillin. The pioneering research in catalytic asymmetric hydrogenation by William Knowles as exemplified by his reduction of 24 to 25 in 95% ee with the DiPAMP diphosphine ligand was recognized with a Nobel Prize in Chemistry in 2001. ... 

Azlactones 12 were obtained from hippuric acid (11, R2=phenyl) in higher purity and in better yield than those from N-acetylglycine (11, R2=methyl). The question as to which of the aldehydes, vanillin (10, Rj= acetyl) or veratrumaldehyde (10, R3 = methyl), should be chosen was decided by the availability of the latter at a relatively low price from Italy. By asymmetric hydrogenation applying [Rh(Ph-/ -glup)(cod)]BF4 (see formula 15, cod=ds,ds-cydoocta-l,5-diene, A =tetrafluoroborate) all acid substrates led to higher enantioselectivities than their esters (Tab. 1) [12]. 

N-acyldehydrodipeptides were readily prepared either by the condensation of N -acyldehydro-a-amino acids with a-amino acid esters or by the reaction of the azlactones of dehydro-a-amino acid with a-amino acid esters (eq. 1). Asymmetric hydrogenation of the N-acyldehydrodipeptides thus obtained (eq. 2) was carried out by using rhodium complexes with a variety of chiral diphosphines such as -Br-Phenyl-CAPP (3), Ph-CAPP (3), (-)BPPM (4), (+)BPPM (4), (-)DIOP ( ), (+)DIOP ( ), diPAMP (6), Chiraphos (7), Prophos (S), BPPFA (9) and CBZ-Phe-PPM (Fig. 1)(10). The chiral catalysts were prepared in situ from chiral diphosphine ligand with [Rh(NBD)2l -CIO4 (NBD = norbomadiene). Typical results are summarized in Tables I-V. 

The scope of the method was later extended to indoHnes [121] however, as the previous optimized conditions failed to afford any acylated product, a fine-tuning of both the nucleophilic catalyst and the acyl donor appeared to be necessary. After intensive screening, the use of a bulkier cyclopentadienyl-derived catalyst such as 113 in conjunction with 0-acetylated azlactone 111 led to a more effective catalytic system, allowing the resolution of various indo lines with useful levels of selectivity ranging from s = 9.5 to 31 (Scheme 41.45). Most importantly, 2,3-disubstituted indolines, which are usually difficult to obtain in high ee by other methods such as the asymmetric hydrogenation of indoles, were also shown to be suitable substrates. 

Glaser, R., and M. Twaik Structural Requirements in Chiral Diphosphine-Rhodium Complexes. II. NMR-Determination of E-Z-Geometry in Prochiral Substrates Used in Asymmetric Hydrogenation Reactions. a-Acetamidocinnamic Acids, Esters and Parent Azlactones. Tetrahedron Letters 1976, 1219. 

Scheme 6.89 Proposed mechanistic picture for the asymmetric alcoholytic DKR of racemic aziactones promoted by bifunctional (thio)urea catalysts 64, 77, and 78 (A) hydrogen-bonded azlactone-64 complex supported by NMR methods (B).

The approach exploiting a chiral centre that is already in the synthon is effective in a number of cases. The chiral moiety in the synthon diverts a reaction at a nearby prochiral centre in favour of one enantiomer (asymmetric induction). An excellent example of the latter is the Schollkopf method (4 in Scheme 6.3, see also 5 in Scheme 6.7) hydrogenation of azlactones (3 in Scheme 6.3) using a homogeneous chiral catalyst is one route illustrating the former approach. Use of chiral five-membered heterocyclic compounds (e.g., 6 and 7) offers an alternative successful approach to asymmetric amino-acid synthesis. 

Newly designed chiral tetraaminophosphonium salt 184 possessing an organic anion cooperatively catalyzes asymmetric Mannich-type reaction of azlactones (182) with N-sulfonyl imines (183) (Scheme 28.20). The basic carboxylate anion deprotonates the active methine proton of the azlactone (182) to form the corresponding chiral phosphonium enolate with a defined hydrogen bonding network (ion pair), and then highly stereoselective bond formation proceeds [92]. 

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