Merck amino acid synthesis

H- % ee after recrystallization Figure 1.6 Merck -amino acid synthesis. 

Compound 45 (6.45 g, 0.81 mmol) was treated TFA (50 mL), as described in the synthesis of 42, and the product converted into the HQ salt. The HC1 salt and 37 (2.12 g, 0.88 mmol) were dissolved in a mixture of CHCl/TFE (3 1,150 mL), and HODhbt (0.14 g, 0.88 mmol) was then dissolved in the soln. EDC (free base, 0.16mL, 0.88mmol) was added dropwise to the soln with stirring at —10°C, and the mixture allowed to react for 3 h at rt. The product was precipitated by adding an excess of MeCN, the precipitate collected by filtration, washed successively with H20 and MeOH, and purified by dissolving in a small volume of CHCl/TFE (3 1) followed by precipitation with EtOAc yield 7.88 g (96%) TLC (Merck Kieselgel 60F-254) Rf 0.41 (CHCl3/80% aq AcOH/TFE 6 1 1). Formation of the desired product 46 was confirmed by amino acid analysis. 

The enantioselective synthesis of the jS-amino acid ester shown in Figure 1.6 has recently been reported by Kubryk and Hansen (Merck) where good ees were obtained by asymmetric hydrogenation. Using an in-situ reaction with diBoc-anhydride to protect the amine group a crystalline product was obtained that was recrystallized to the required 99 % + ee purity very easily. 

In the past decade many new examples have been described, mostly for amino acid derivatives using (substituted) benzaldehyde as a racemization catalyst. In Scheme 7.7 an application of this procedure on multi-kilogram scale from Merck Co is described for the asymmetric transformation of a benzodiazepinone in the synthesis of the CCK antagonist, L-364,718 (10),36 More recently, the Merck group also applied this method to other bendiazepinones.37... 

Merck has used a diastereoselective double RCM in the synthesis of NK-1 receptor antagonists (Scheme 28.3).33 Previously reported studies by the same group showed that amino acid-derived tetraene 12 smoothly underwent ring closure in a diastereoselective fashion to give the corresponding spirocyclic compounds 13 in excellent diastereoselectivity.34 An extension of this work to the tetraene system derived from phenylglycine gave the desired spirocycle in 86% yield and 70% ds. 

The original intention of Leuchs and Fischer was to use NCAs in peptide synthesis, but the high reactivity of these reagents and their tendency to ohgomerize dampened the enthusiasm of most laboratories for these self-activated amino acids. Based on some successes in the early 1950s,workers at Merck developed conditions where controlled-sequence peptides could be synthesized in aqueous media.f l The crowning achievement involved the use of NCAs in the synthesis of ribonuclease A by the Merck group in 1969. 

Fig. 2.7 Ligands with broad scope and versatility, (a) A concise synthesis of a non-proteinogenic amino acid developed and scaled by Dowpharma using a DuPHOS catalyst [38], (b) Merck route to c/s-aminoindanol, a key building block made via salen-catalyzed epoxidation for onwards usage, for example in the synthesis of the anti-H IV compound indinavir [39].

The first successful efforts in enzyme total synthesis involved ribonuclease in the late 1960s and were disclosed in simultaneous publications by Merrifield and Gutte at the Rockefeller [200] and Denkwalter and co-workers at Merck [45, 46, 201-203]. The Rockefeller group s bovine ribonuclease A (RNase A) synthesis utilized automated, stepwise Boc/Bzl chemistry to assemble the 124 amino acid sequence. Following conversion to the S-sulfonate derivative and purification by ion-exchange and gel chromatography, the material was reduced to the firee sulf-hydryl form and air oxidized to form the four disulfide bonds. Upon further purification the protein was shown to be identical to the native enzyme by paper... 

Merck has discovered a more efficient catalytic synthesis for sitagliptin, a chiral (3-amino acid derivative that is the active ingredient in their new treatment for type 2 diabetes, Januvia . This revolutionary synthesis creates 220 pounds less waste for each pound of sitagliptin manufactured, and increases the overall yield by nearly 50%. Over the lifetime of Januvia , Merck expects to eliminate the formation of at least 330 million pounds of waste, including nearly 110 million pounds of aqueous waste. 

Finally, the integration of combinatorial chemistry with other drug discovery tools is occurring. The identification of hydroxyethylamine-based inhibitors of cathepsin D by Ellman (libraries 1.14a,b and 1.15), and the penultimate derivation of selective MMP-3 inhibitors from a library of N-carboxyalkyl amino acid by researchers at DuPont Merck (library 1.23), represent two illustrations of the successful merger of structure-based ligand design and library synthesis. The recent introduction of S AR by NMR methodology for lead discovery has also been used in conjunction with a combinatorial library (library 4.12). 

The amino acid 114 (Scheme 2.18) was developed by Merck Research Laboratories as a potential lead for the treatment of hypertension, congestive heart failure, and renal diseases.The main challenge encountered in obtaining preparative quantities of 114 involved the installation of three contiguous stereocenters on the cyclopentane ring. To address this difficulty, a strategy was developed in which the Ar stereocenter was secured prior to formation of the cyclopentane ring. ° As depicted in Scheme 2.18, the synthesis of 114 initiated with the reaction of /cr/-butyl ester 110 (available from 2,6-dibromopyridine) with (5,5)-pseudoephedrine 111 to provide the Michael acceptor 112. 

The first total synthesis of an enzyme, ribonuclease A, was reported in 1969 [7]. In this work, accomplished almost simultaneously by research groups at Rockefeller University and at Merck and Company, 19 amino acids were assembled into the protein that has 124 units in a definite sequence (Figure 15.2). In one technique, each amino acid was added in sequence after the first, valine, was fully bound to an insoluble substrate. To do this, 369 chemical reactions requiring 11,931 steps were carried out in an automated apparatus. A three-dimensional picture of the enzyme illustrates the formation of helical and sheetlike portions (Figure 15.3). Much can be learned about protein behavior and conformation by studying simpler molecules, such as synthetic polypeptides, which are polymers of a single a-amino acid. 

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