Chiral /3-amino acid derivatives

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. 

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

In 1988 Kunz and Pfrengle introduced the preparation of chiral amino acid derivatives by the U-4CR in the presence of 2,3,4,6-tetra-6)-pivaloyl- 3-D-galacto-pyranosylamine, 57, in the presence of ZnCl2-etherate as catalyst. They obtained excellent stereoselectivity and high yields of their products. One of the disadvantages of such U-4CRs is that only formic acid can be used as the acid component, and the auxiliary group of the products can only be removed by half-concentrated hot methanolic HCl. 

Hayashi et al.74 described a process of kinetic resolution in the coupling of Grignard reagents R Mgx (having a chiral center at the point of attachment to the metal) with various alkenyl halides under the influence of chiral phosphine-nickel complexes. Chiral amino acid derivatives (35) were used as ligands. 

The bacteriostatic gliotoxin was prepared206 by a total synthesis involving an asymmetric Michael-addition. A chiral amino acid derivative served as chiral auxiliary in the key step. 

Chiral organomagnesium amides form an efficient method to realize enantioselective conjugate addition. Sibi and Asano have reported the Michael addition of cr-bound magnesium reagents derived from bisoxazolines to enamidomalonates (equation 41). The enantioselectivity of the addition is discussed in Section El. This method allows the preparation of chiral -amino acid derivatives. ... 

A commercially packed h.p.l.c. column (25 cm x 4.6 mm) of y-aminopropyl silanised silica [e.g. 5/mi Spherisorb (Regis Chemical Co.), or 7/im Zorbax (Dupont Co.), or 10 /im Lithosorb (Merck), or 5 m irregular (J. T. Baker Chemical Co.)] was sequentially treated, at a pumping rate of 2 ml/min, with the following solutions 2 ml of triethylamine in 40 ml of dry tetrahydrofuran, 2g of (R)-JV-(3,5-dinitrobenzoyl)phenylglycine in 40 ml of dry tetrahydrofuran, 20 ml of dry tetrahydrofuran, and finally 10 per cent propan-2-ol in hexane, until the base line stabilises. The chiral amino acid derivative (which is available from Aldrich Chemical Co.) becomes ionically bonded to the amino residues on the stationary phase. 

More recently, Benaglia and coworkers reported that the allylation reaction of a-iminoesters proceeded to give the homoallyl alcohols with moderate enantioselectivities (Scheme 9.4).9 The chiral diimine that has a chiral 1,2-cyclohexyldiamine framework was used as the ligand. The reaction of a-iminoesters and allyltributyltin in the presence of AgOTf and diimine ligand proceeded to afford chiral amino acid derivatives with moderate enantioselectivities. 

Alder reactions, 1,3-dipolar cycloadditions (Jen et al. 2000), and conjugate additions of electron rich aromatic and heteroaromatic compounds can be catalyzed using chiral amino acid derived imidazolidinones as catalysts (Scheme 17 Eqs. 35-38 Paras and MacMillan 2001, 2002 Austin and MacMillan 2002 Brown et al. 2003b). In addition, highly enantioselective epoxidations (Marigo et al. 2005b) and cyclopropana-tions (Kunz and MacMillan 2005) have recently been developed. 

Asymmetric Hydrogenation. Rhodium complexes of the type Rh(diene)(diphos )+, where diphos is a chiral bidentate diphosphine ligand, are catalyst precursors for the asymmetric hydrogenation of certain prochiral olefins (15). Asymmetric hydrogenation of a-acylaminoacrylates, for example, affords chiral amino acid derivatives, some of which have medicinal utility such as L-DOPA. 

L = chiral amino acid derivatives Muller, P. Ghanem, A. Org. Lett. 2004,6,4347. 

There are three main types of chiral GC stationary phases (1) chiral amino acid derivatives [8-10] (2) chiral metal coordination compounds [11] and (3) cyclodextrin derivatives [12-14]. The cyclodextrin phases have proven to be the most versatile for gas chromatography. 

Bis(trichloromethyl)carbonate (Iriphosgene) [53] is successfully utilized in the sequential synthesis of carbamates and unsymmetrical ureas also bearing chiral amino acid derivatives, without having to purify the intermediates [507]. 

The same authors have made use of a similar reaction sequence to prepare / ,/ -methylserine esters (3) from ketones (R R CO) and the lithio derivative of dihydropyrazine (4). Once again the dihydropyrazine is prepared from a chiral amino-acid (2 moles L-alanine). Alternatively, if alkyl halides are reacted with the lithio derivative of (4) then chiral homologues of L-valine are obtained. In a related application, the chiral amino-acid derivative L-AT-ethoxycarbonyl-... 

The detection of D-amino acids is carried out by enantioselective HPLC or GC of chiral amino acid derivatives. In a frequently applied method, the derivatives are produced in a precolumn by reaction with o-phthalaldehyde and a chiral thiol (cf. 1.2.4.2.4). Alternatively, the amino acids can be transformed into trifluoroacetylamino acid-2-(R,S)-butylesters. Their GC separation is shown in Fig. 1.3. 

This is the first example of a highly enantioselective reaction induced by chirality resulting from deuterium substitution of amino acids. In addition, chirally deuterated primary alcohols [52] and chiral amino acid derivatives with partially deuterated substituent such as monodeuterated methyl group (—CDH2) can induce the chirality in asymmetric autocatalysis [53]. 

An important early example of the combinational use of a chiral amino catalyst and chiral Bronsted acid was presented by list et al. in 2006. They found that the valine ester phosphate salt formed by chiral BlNOL-derived Br0nsted acid 77 and chiral amino acid-derived primary amine 78 was effective for the transfer hydrogenation of various a,p-imsaturated ketones 74 with commercially available Hantzsch ester 75 to give saturated ketones 76 in excellent enantioselectivities (Scheme 43.15) [26]. 

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