Protecting medicinal chemistry

Aminoalcohols are an important class of compounds in medicinal chemistry because many drugs contain this structure. For their resolution, there are two possibilities acylation of amino function or an enzymatic transesterification with vinyl esters through the hydroxyl group. However, the amino or hydroxyl group must be protected, because if the starting material is the free aminoalcohol, the O- and N-acylation can take place, and in addition, there are migrations obtaining... 

At the beginning of the project, we had studied the introduction of the pMB group to 4 as a nitrogen protecting group, as used in the Medicinal Chemistry route. There was a classical regioselectivity problem, O- versus N-alkylation. Under the Medicinal Chemistry conditions, the desired N-alkylated product 5 was mainly formed, but around 10-12% of the corresponding O-alkylated product 16 was also... 

Obviously, there are two ways to prepare Efavirenz from the pMB protected chiral amino alcohol 50 (i) creation of the benzoxazinone first then removal of the pMB group or (ii) removal of the pMB first then formation of benzoxazinone. Preparation of the benzoxazinone was demonstrated by Medicinal Chemistry from the amino-alcohol with CDI. 

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

In the original Medicinal Chemistry route, protection of the phenolic OH with a benzoate was carried out prior to N-methylation. In order to simplify the process, the direct N-methylation of hydroxypyrimidinone 3 was investigated. To our delight, methylation of 3 gave a mixture of the desired N-methyl product 31 and the undesired O-methyl by-product 32 as a 70 30 mixture (Scheme 6.7 path b). Surprisingly, methyl ethers 28-30 were not observed at all (Scheme 6.7 path a). 

Thiolactomycin (16) is another natural product that reversibly inhibits E. coli FabF, FabB, and FabH with respective ICso s of 6, 25 and 110 (iM. Unlike cerulenin, it binds the malonyl-ACP site of the enzyme [27]. Despite modest double-digit MICs on . coli, S. aureus, Serratia marces-cens, and Mycobacterium tuberculosis, 16 has generated quite some interest due to its good in vivo protection against an oral or intramuscular S. marcescens urinary tract infection model where it displayed rapid tissue distribution [28]. Despite several medicinal chemistry efforts, thiolactomycin has proven difficult to optimize due to some strict functional group requirements for its SAR [29]. 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

The creation of a peptide bond is a very important reaction in medicinal chemistry and there are many ways to synthesize DKPs. It is very important to prevent the formation of the wrong peptide bond. When two different amino acids are reacted with each other, it can give rise to four different products. It is therefore vital to protect the amino terminal of one and the carboxyl group of the other amino acid. 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

Dihydrooxazoles continue to occupy an important place in organic synthesis and medicinal chemistry as they have found use as versatile synthetic intermediates, protecting groups/pro-drugs for carboxylic acids, and chiral auxiliaries in asymmetric synthesis. There are several protocols in the literature for the transformations of functional groups such as acids, esters, nitriles, hydroxyl amides, aldehydes, and alkenes to 2-oxazolines. Newer additions to these methods feature greater ease of synthesis and milder conditions. 

The example in Scheme 60 provides a nice illustration of the efficient synthesis of a 1,2-dithiolane analogue of leucine, of interest in medicinal chemistry due to the biological activity of the heterocyclic ring. Thus, the stereo-controlled synthesis of N- and C-protected derivative of (A)-amino-3-(l,2-dithiolan-4-yl)propionic acid 326 and its reduced 1,2-dithiolic form from /< /t-butyl (A)-A - /t-butoxycarbonylpyroglutamate 322 as a precursor were reported <20020L1139>. 

Han, B. and Zhang, J.T. (2004) Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2. Current Medicinal Chemistry. Anticancer Agents, 4 (1), 31—42. 

Frank Weisenborn In Dr. Biel s discussion of the rational approach, I still don t think anyone has really said how it is or put it all together. I think it is a mixture of rationality and hope in that in many fields of medicinal chemistry we look for the sophisticated organic chemist to build a new heterocyclic molecule because we want to build a broad protection in terms of a patentable area, and then we look for an experienced medicinal chemist to attach the appropriate side chains. It is a... 

Soialeau, M. Legal aspects of product protection—What a medicinal chemist should know about patent protection, Chapter 41 in The Practice of Medicinal Chemistry, C. G. Wermuth (ed.). Academic Press, San Diego, 1996. 

The Fukuyama amine synthesis has seen wide application in the context of natural product synthesis. Complex polyamine natural products that highlight the orthogonal nature of the nosyl protecting group, such as lipogrammistin-A12 and various spider toxins,13 have been efficiently synthesized. This protocol has also been used in the context of medicinal chemistry,14 glucosylamines,15 and blasticidin amino acids.16... 

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