Chemoenzymatic methods

Hu S, Tat D, Martinez C, Yazbeck D, Tao J (2005) An efficient and practical chemoenzymatic method for preparing optically active secondary amines. Org Lett 7 4329-4331... 

P-Adrenergic-blocking agents, such as propranolol, have been synthesized by different chemoenzymatic methods where the key step to introduce the chirality is an enzymatic acylation or a hydrolysis process. The main reason to prepare these amino alcohols in optically pure form is due to the fact that the activity of these pharmaceuticals resides in the (S)-enantiomer. In Scheme 10.1 we have represented a chemoenzymatic approach that has been carried out for the preparation of this dmg where the key step is the resolution of the key intermediate 1-chloro-... 

Racemization via 1) HBr/AcOH and 2) KOH/MeOH Scheme 10.3 Two different preparations of (S)-ibuprofen by chemoenzymatic methods. 

Buffer pH 7.0, 27"C Scheme 10.7 Production of gabapentin by chemoenzymatic methods. 

An important breakthrough was made very recently in this area. A chemoenzymatic method developed by Turner has allowed the cyclic deracemization of tertiary amines [80]. Enantiopure tertiary amines cannot be obtained via DKR. One of the variants obtained by directed evolution of the monoamine oxidase from Aspergillus niger showed high activity and enantioselectivity toward cyclic tertiary amines (Scheme 5.40). 

Banwell MG, Edwards AJ, Harfoot GJ, Jolliffe KA, McLeod MD, McRae KJ, Stewart SG, Vogtle M (2003) Chemoenzymatic Methods for the Enantioselective Preparation of Sesquiterpenoid Natural Products from Aromatic Precursors. Pure Appl Chem 75 223... 

In vitro glycorandomization (TVG) is a chemoenzymatic method that uses substrate-flexible anomeric sugar kinases and Ntfs to convert diverse sugars into their NDP-activated forms [21], The ability to enhance the promiscuity of these two... 

Due to the structural complexity of carbohydrates, preparation of structurally well-defined carbohydrates with broad diversity is a key issue for glycan array development. Because it is difficult to obtain sufficient quantities of glycans from natural sources, chemical or chemoenzymatic methods or even pure enzymatic methods have been used to address this deficiency. The recent advances in carbohydrate syntheses that are described in other chapters of this book have greatly reduced the labor for glycan preparation. 

A number of functional sialyl Lewis mimetics have been synthesized. Their activities in vitro are equal or even better than those of the tetrasac-charide itself. To overcome synthetic problems, efficient stereoselective glycosylations as well as new chemoenzymatic methods for C-C bond formations had to be developed. The substitution of neuraminic acid by (5)-phenyl- and (5)-cyclohexyl lactic acid, as less flexible glycol acid residues, turned out to be very successful [10]. Also, a phosphate and a sulfate group, respectively, mimic neuraminic acid without loss of activity [11]. (5)-Cyclohexyl lactic acid-mimetic 2 shows a more than ten-fold efficacy compared with sialyl Lewis, whereas the corresponding (/ )-isomer 3 is almost inactive [10]. The deviating orientation of the carboxylic acid functionality compared to the bioactive sialyl Lewis conformation leads to the examined loss of activity. It was shown by transfer-NOE measurements of the corresponding E-selectin complexes that the coordinates of the bioactive conformation of sialyl Lewis and of compound 2 are similar. Con.se-quently structure 2 should bind to E-selectin in the same manner as that of sialyl Lewis [ 10a, b]. 

C2- and D2-symmetric dioxatetraaza 18-membered macrocycles such as 14 and 15 have been prepared by a chemoenzymatic method involving ( )-fraiw-diaminocyclohexane as starting material (eq 26). Good enantiomeric discrimination was observed with tetraprotonated species (/ ,/ )-14 and the D-enantiomer of N-acetyl aspartate. 

A simple, divergent, asymmetric synthesis of the four stereoisomers of the 3-amino-2,3,6-trideoxy-L-hexose family was proposed by Dai and coworkers [222], which is based on the Katsuki-Sharpless asymmetric epoxidation of allylic alcohols (Scheme 13.115). Recently, A-trifluoroacetyl-L-daunosamine, A-trifluoroacetyl-L-acosamine, A-benzoyl-D-acosamine and A-benzoyl-D-nistosamine were derived from methyl sorbate via the methyl 4,5-epoxy-( -hex-2-enoates obtained via a chemoenzymatic method [223]. 

Covalent inhibitors were synthesized by Withers and coworkers.148 149 The use of 3F-sialyl fluoride 136 as donor substrate allowed identification of the covalent mechanism for TcTS. Fluoride 136 completely inactivates the enzyme, but only at concentrations as high as 20 mM, and separation of excess inactivator caused recovery of the activity.148 Since the 3D structure of TcTS showed that the donor site is more spacious and hydrophobic than in a human sialidase, derivatives at C-9 of the fluoride 136 were synthesized by a chemoenzymatic method and tested as inhibitors (Fig. 10).149 Inhibition was analyzed with trifluoromethylumbelliferyl sialic acid for measuring hydrolase activity, however, as the site is the same for... 

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