Drug synthesis chiral building blocks

Aldol reactions enjoy great recognition as a useful tool for the synthesis of building blocks in natural product and drug synthesis [42, 182]. The stereochemistry of the stereogenic centers formed can be controlled by various means. Besides chiral auxiliaries, catalytic methods with chiral Lewis acids, organocatalysts, or catalytic antibodies were established for stereochemical control [183-187]. 

Benzofuran-based structures are used as important chiral building blocks in the synthesis of biologically active compounds. Several 2-substitued benzofuran drugs are available nowadays such as Amiodarone (cardiac and anti-arrythmic) and Benziodarone (coronary vasodilator), adding to that they can be used in inhibiting HIV-1 reverse transcriptase or acting as antiaging compounds. 

Despite their low cost and abundant availability, the applications of monoterpenes as chiral synthons or building blocks for synthesis of chiral fine chemicals on an industrial scale have lagged far behind amino acids and carbohydrates. Most of the work in this area is related to multi-step total synthesis of complex natural products in laboratory scale. With the structures of new drug candidates in the research and development pipeline of pharmaceutical companies getting bigger and more complicated, the application of more sophisticated chiral building blocks such as the terpenes will... 

The development of methodologies for the production of chiral building blocks is of crucial importance, as such enantiomerically pure molecules are required as key intermediates in the synthesis of drugs. Due to the... 

Chiral alcohols are useful starting materials for the synthesis of various biologically active compounds. The need for enantiomerically pure drugs and agrochemicals has increased in recent years [13]. Derivatives of enantiopure 1-phenylethanol are important chiral building blocks, which can be used as synthetic intermediates for the production of pharmaceuticals, fine-chemicals agrochemicals, and natural products. In particular (R)-1-phenylethanol is in widespread use as an ophthalmic preservative, an inhibitor of cholesterol intestinal adsorption, a solvatochromic dye, a fragrance, and so on. 

These results have led to an interesting industrial apphcation for the synthesis of the j5-blockers Metoprolol and Atenolol. Thus, epoxidation of the prochiral allyl ethers by several bacteria, including the P. oleovorans strain mentioned above, led to the corresponding (S)-epoxides which showed excellent enantiomeric purities (Fig. 3). Further on, these chirons (i.e. chiral building blocks) were transformed into the corresponding (S)-enantiomers of the drugs developed by the Shell and Gist-Brocades companies [44]. Refinement of this approach... 

Biocatalyzed in water synthesis of chiral building blocks for the preparation of anti-cancer drugs A green approach 13COC1132. 

An a-acetoxysulfide shown in Scheme 3.16 was used as central chiral building block for the s)mthesis of Lamivudine, a highly promising drug candidate for the treatment of HIV and HBV infections. Due to the different toxicities of the two enantiomers, an enantioselective route was required. Furthermore, applicability to large-scale synthesis and absence of any unwanted enantiomers were important issues particularly in view of the possible drug application. 

Examples of the use of these chiral building blocks in the synthesis of drugs and natural products abound in the literature. They include the synthesis of grahamimycin the macrocyclic component of the antibiotic elaiophylin, fungicides norpyrenophorin, pyrenophorin and vermiculin, phorcantholide I and J, which are defensive secretions of the eucarypt longicorn beetle,citronellol and a pheromone of the western corn rootworm. Clearly the monomeric chiral derivatives of PHB have a role to play in enantiomer-specific synthesis. 

Another auxiliary that proved to be useful as a base for enolate alkylations is cis-l-amino-2-indanol 37 developed by researchers at Merck, Sharp, and Dhome. Both enantiomers of the amino alcohol are commercially available in bulk. The alkylation method was elaborated for a synthesis of indinavir, the orally active HIV protease inhibitor that emerged as a major drug for treatment of AIDS. Thus, N-acylated Af,0-acetal 38 was converted into the lithium enolate and subsequently treated with allyl bromide to give the alkene 39 in excellent chemical yield and diastereoselectivity. The conversion into indinavir reveals that the amino alcohol 37 functions both as auxiliary and chiral building block (Scheme 4.8) [26]. 

Hoyos, P, Pace, V., and Alcantara, A. R. (2013). Biocatalyzed on water synthesis of chiral building blocks for the preparation of anti-cancer drugs A greener approach. Curr. Org. Chem., 17,1132-1157. 

Trost has utilized the same class of chiral ligands for the conversion of butadiene oxide (54) into a number of useful chiral building blocks, such as 57 (Scheme 14.11) [67, 68]. In the course of reaction optimization studies, naphthyl-substituted ligand 56 proved optimal and led to the formation of 57 in 96% ee (>99% ee after recrystallization). A powerful illustration of the synthetic utility of such optically active building blocks involved the synthesis of several medicinally important agents, including the tuberculostatic drug ethambutol (58) [68]. 

This type of reaction forming unnatural L-amino acids uses enzymes from the metabolism of proteinogenic amino acids which additionally have an unexpectedly versatile substrate specificity by also accepting highly sterically hindered a-keto acids. L-Tle and L-Npg are of growing importance because of their extended use as building blocks in pharmaceutical drugs and as chiral auxiliaries in asymmetric synthesis [114]. 

Due to the nitrile and hydroxyl functionality, enantiomerically pure cyanohydrins are useful building blocks for synthesis of chiral drugs and having enzymes available that make either the (R)- or (S)-enantiomer is very versatile. Scheme 4.12A illustrates the selectivity and substrate scope of Prunus amygdalus R-HNL and Hevea brasiliensis S-HNL. For most aldehyde and ketone substrates tested, high e.e.s can be reached [51a, 52]. 

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