Chiral bioactive compounds

The protected dipeptide Z-His-Phe-NH2 is a precursor for cyclo[-His-Phe-], which is known as a catalyst for addition of cyanide to aldehydes, with high enantiomeric excess.f l Such optically active cyanohydrins are valuable starting materials for the synthesis of a variety of chiral, bioactive compounds.The easy scale-up (to mole scale) of the suspension-to-sus-pension conversion approach has been demonstrated by the thermolysin-catalyzed synthesis of Z-His-Phe-NH2.[ ]... 

Over the past few years, an impressive array of epoxide hydrolases has been identified from microbial sources. Due to the fact that they can be easily employed as whole-cell preparations or crude cell-free extracts in sufficient amounts by fermentation, they are just being recognized as highly versatile biocatalysts for the preparation of enantiopure epoxides and vicinal diols. The future will certainly bring an increasing number of useful applications of these systems to the asymmetric synthesis of chiral bioactive compounds. As for all enzymes, the enantioselectivity of... 

IV. UTILIZATION OF OPTICALLY ACTIVE p-HYDROXY ACIDS FOR THE SYNTHESIS OF CHIRAL BIOACTIVE COMPOUNDS... 

In this section, chiral building blocks derived from some optically active p-hydroxy acids and their use in the synthesis of chiral bioactive compounds (including their precursors) are reviewed. 

Biooxidation of cyclobutanones is a particularly useful transformation, as the corresponding chiral butyrolactones represent highly valuable building blocks for a large variety of natural products as well as bioactive compounds [165]. 

Both chiral lactones and ketones have been utilized in asymmetric synthesis of bioactive compounds like lipoic acid [175[ and natural products like various insect pheromones [176[. 

Enantioenriched alcohols and amines are valuable building blocks for the synthesis of bioactive compounds. While some of them are available from nature s chiral pool , the large majority is accessible only by asymmetric synthesis or resolution of a racemic mixture. Similarly to DMAP, 64b is readily acylated by acetic anhydride to form a positively charged planar chiral acylpyridinium species [64b-Ac] (Fig. 43). The latter preferentially reacts with one enantiomer of a racemic alcohol by acyl-transfer thereby regenerating the free catalyst. For this type of reaction, the CsPhs-derivatives 64b/d have been found superior. 

Fig. 32.28 Examples of bioactive compounds and chiral diphosphines obtainable by BlNAP-Ru-catalyzed hydrogenation via dynamic kinetic resolution.

Therefore, the chiral cyanohydrins are valuable and versatile synthons as their single hydroxyl asymmetric centre is accompanied by at least one other chemical functionality. Thus with careful functional group protection, differential and selective chemical transformations can be performed. Such synthetic techniques lead to production of interesting bioactive compounds and natural products. These products include intermediates of j3-blockers 15 1117], j3-hydroxy-a-amino acids 16 [118],chiral crown ethers 17 [lll],coriolic acid 18 [120], sphingosines 19 [121], and bronchodilators such as salbutamol 20 [122] (Fig. 3). 

Enantiomerically pure 3-amino alcohols which are important intermediates for many bioactive compounds can be directly synthesized by the ARO reaction of readily accessible racemic and meso epoxides with appropriate amines. Indeed, some simple and multifunctional p-amino alcohols have been obtained using this strategy by the promotion of chiral BINOL [30-32,88,89], salen [35,52], bipyridine [33,40,90-94] and proline-A,JV-dioxide based metal complexes [95]. However, none of these systems demonstrated the recyclability of the precious chiral catalyst. 

Neonepetalactone, 61 (Fig. 1.2.3), a bioactive compound found to be quite attractive to cats [41], was isolated in 1965 from the leaves and galls of Actinidia polygama by T. Sakan et al. and its absolute configuration was determined in 1980 [41b]. As some syntheses of the racemic mixture or ex-chiral-pool syntheses had already been reported, we realized that our SAMP/RAMP hydrazone methodology would make it possible to develop a very short asymmetric synthesis of this bioactive 8-lactone. 

The stereoselective hydrogenation of a-monosubstituted (3-keto carboxylates and phosphonates through dynamic kinetic resolution has been applied to the synthesis of a wide variety of useful bioactive compounds as well as some chiral diphosphines (Figure 1.16) [lc,20,162b,c,179,243,246,250,252], The stereogenic center determined by the BINAP-Ru... 

Epoxide is an important intermediate for various bioactive compounds, so the demand for the chiral epoxide is increasing. Epoxide hydrolase can hydrolyze epoxide enantioselectively (Figure 20).21 For example, Aspergillus niger was used for the hydrolysis of carvone epoxide (Figure 20(a)).2 11 In the reaction of styrene oxide, the... 

Asymmetric Pummerer rearrangement is a very attractive reaction as previously described. In particular, the reactions induced by SKA work well, and may be synthetically exploited in many cases. The results described here demonstrate that the stereoselective a-deprotonation of the sulfoxide is a prerequisite process for asymmetric induction in the Pummerer reaction. Since many kinds of synthetic and enzymatic preparative methods of optically pure sulfoxides have been developed, the present Pummerer-type reaction will be applicable to many other chiral sulfoxides with one a-substituent, chiral vinylsulfoxides and chiral co-carbamoylsulfox-ides, thus leading to enantioselective syntheses of many new bioactive compounds in the near future. 

The development of enantioselective chemical processes is critical to the preparation of enantiomerically pure bioactive compounds. Roughly 75% of small molecule pharmaceuticals are marketed in enantiomerically pure form [1], Enantioselective chemical processes require the use of chiral media that drive chemical reactions kinetically to produce one of two enantiomers selectively. Many such enantioselective... 

Chiral organofluorine compounds containing a fluorine atom bonded directly to a stereogenic center have been used in a variety of research investigations, including mechanistic studies of enzymes and intermediates in the asymmetric synthesis of bioactive compounds. The development of effechve methodologies for the... 

Carbonyl-selective asymmetric hydrogenation of simple 2-cyclohexenone is still difficult. The optical yield obtained with [Ir(OCH3)(cod)]2-DIOP is only 25%, while the carbonyl-selectivity is 95% at 65% conversion (Scheme 23) [80]. Hydrogenation of 2,4,4-trimethyl-2-cyclohexenone with a Ru(II)-TolBINAP-4-KOH catalyst system under 8 atm of hydrogen at 0 °C gives 2,4,4-trimethyl-2-cy-clohexenol quantitatively in 96% ee [81, 82]. Notably, the combination of (R)-TolBINAP and (S,S)-4 matched well to give the S alcohol with a high ee. The chiral allylic alcohol is the key intermediate in the synthesis of carotenoid-derived odorants and other bioactive compounds [83]. 

---