Stereoselectivity drug synthesis

Bhisutthibhan, J., Pan, X.-O., Hossler, P.A., Walker, D.J., Yowell, C.A., Carlton, J., Dame, J.B., and Meshnick, S.R. The plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin, /. Biol. Chem., 273,16192,1998. 21. Avery, M.A., Chong, W.K.M., and Jennings-White, C. Stereoselective total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L., /. Am. Chem. Soc., 114,974,1992. Avery, M.A., Bonk, J.D., and Bupp, J. Radiolabeled antimalarials synthesis of 14C-artemisinin, /. Labelled Comp. Radiopharm., 38, 263, 1996. 

The great majority of natural molecules contain chiral centers and are optically active. This is the case because living systems and their extracts as enzymes are able to produce completely stereoselective asymmetrical synthesis or transformations. This led Pasteur to say that life is asymmetrical — at the molecular level. The majority of food and drug molecules of physiological activity are chiral. 

Enantiomerically enriched, tertiary alcohols could also be constructed by addition of Al(2-thienyl)3(THF), mediated by the same catalyst system [93]. Several aryl,methyl ketones and an enone could frequently be transformed in almost quantitative yields and with ee s exceeding 90%. Again, 2-methoxyacetophenone furnished only a moderate ee of 45%, and unfortunately, alkyl,methyl ketones (alkyl = nPr, Pr, nBu) were transformed all in 96% yield but with less than 17% ee. Conducting the reactions in toluene led to better results than in THF, and the optimized conditions allowed the stereoselective total synthesis of the anticholinergic/spasmolytic drug tiemonium iodide (50) in 84% yield over three steps from 48 (Scheme 9). 

Unfortunately, this reaction has not yet reached its fid potential for the stereoselective total synthesis of natural products. It is easy to recognize that piperazic acid derivatives 201 could develop from an azo Diels-Alder reaction. These nonproteinogenic cyclic a-hydrazino acids are widely found in depsipeptide natural products like the antimycobacteria lydiamycins 202 isolated from the fermentation broth of Streptomyces lycidus or in cdazapril 203 an angiotensin-converting enzyme inhibitor used as an antihypertensive drug by Hoffman-Laroche (Scheme 41.43). ... 

This chapter has introduced the aldol and related allylation reactions of carbonyl compounds, the allylation of imine compounds, and Mannich-type reactions. Double asymmetric synthesis creates two chiral centers in one step and is regarded as one of the most efficient synthetic strategies in organic synthesis. The aldol and related reactions discussed in this chapter are very important reactions in organic synthesis because the reaction products constitute the backbone of many important antibiotics, anticancer drugs, and other bioactive molecules. Indeed, study of the aldol reaction is still actively pursued in order to improve reaction conditions, enhance stereoselectivity, and widen the scope of applicability of this type of reaction. 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

Nonorganic and organometallic catalysts are also used to channel the reactions toward the chiral synthesis pathway. The drug called levodopa, (5)-3,4-dihydroxyalanine, is an effective drug against Parkinson s disease. It is stereoselectively manufactured using catalysts such as rhodium or ruthenium complexes. 

The synthesis of PS chiral analogues of biophosphates via P compounds required as therapeutic continues to attract attention. It is apparent that future perspectives in this fascinating area will focus on finding easy access to chiral P compounds other than the separation of diastereoisomers and improvements in the stereoselective coupling procedures. So far research efforts in synthesis of new drugs with a phosphorus backbone has paid insufficient attention to cost and difficulties of large scale production [110]. This chapter illustrated the trends with a series of selected examples. 

Recently, another interesting application of nitrilases has been demonstrated for the synthesis of pregabalin-the API of the neurophatic pain drug Lyrica. In this approach, the key step is the resolution of racemic isobutylsuccinonitrile (Scheme 10.8) [18], the process takes place with total regio- and stereoselectivity, and the (S)-acid is obtained and the (R)-substrate can be recycled under basic conditions. To improve the biocatalytic step, directed evolution was applied using the electronic polymerase chain reaction and in the first round of evolution a single C236S mutation led to a mutant with 3-fold increase in activity [19]. 

---