Direct Chemical Synthesis of Chiral Methanol of 98% ee and Its Conversion to [²H₁,³H]Methyl Tosylate and [²H₁,³H-Methyl]Methionine

Abstract

This paper describes the synthesis of chiral methanols [(R)- and (S)-CHDTOH] in a total of 12 steps starting from (chloromethyl)dimethylphenylsilane. The metalated carbamates derived from (dimethylphenylsilyl)methanol and secondary amines were borylated at low temperatures (-78 or -94 degrees C) using borates derived from tert-butyl alcohol and (+)-pinane-2,3-diol or (R,R)-1,2-dicyclohexylethane-1,2-diol to give diastereomeric boronates (dr 1:1 to 5:1). The carbamoyloxy group could be replaced smoothly with inversion of configuration by an isotope of hydrogen using LiAlH(D)4 [or LiBEt3H(D,T)]. If the individual diastereomeric boronates were reduced with LiAlD4 and oxidized with H2O2/NaHCO3, monodeuterated (dimethylphenylsilyl)methanols of ee > 98% resulted. The absolute configurations of the boronates were based on a single-crystal X-ray structure analysis. Brook rearrangement of the enantiomers of (dimethylphenylsilyl)-[(2)H1,(3)H]methanol prepared similarly furnished the chiral methanols which were isolated as 3,5-dinitrobenzoates in 81% and 90% yield, respectively. For determination of the enantiomeric excesses (98%), the methyl groups were transferred to the nitrogen of (S)-2-methylpiperidine and (3)H{(1)H} NMR spectra were recorded. The Brook rearrangement is a stereospecific process following a retentive course. The chiral methanols were also transformed into methyl tosylates used to prepare [(2)H1,(3)H-methyl]methionines in high overall yields (>80%).

A sensitive mass spectrum assay to characterize engineered methionine adenosyltransferases with S-alkyl methionine analogues as substrates

“…In addition, bulkier SAAM 6 , 7 and 8 were also synthesized given that the corresponding SAM analogues have been reported as SAM surrogates for multiple native or engineered methyltransferases [17, 19–21]. Briefly, the treatment of methionine with benzyl chloride in concentrated HCl furnished S -benzyl- L -homocysteine [29]. Its benzyl moiety was then removed by sodium metal in liquid ammonia.…”

“…S -Benzyl- L -homocysteine and S -allyl- L -homocysteine (SAAM 3 ) were prepared as reported previously [28]. To prepare SAAM 4 – 8 (Scheme 1), S -benzyl- L -homocysteine (255 mg, 1 mmol) [29] was placed in a round-bottom flask connected to an ammonia cylinder and dissolved in approximately 20 mL condensed liquid ammonia in a dry ice-ethanol bath. Sodium metal (50 mg, 2.2 mmol) was then added gradually to afford a dark blue solution.…”

“…Here the residues adjacent to S -methyl moiety of the substrate methionine are constructed and highlighted upon comparing human MATI/II (Blue, PDB 2OBV and 2P02) and E. coli MAT (black in the bracket) as reported previously [29]. …”

On the Configurational Stability of Chiral Heteroatom‐Substituted [D1]Methylpalladium Complexes as Intermediates of Stille and Suzuki–Miyaura Cross‐Coupling Reactions

“…An alternative to (tributylstannyl)[D 1 ]methanol as a synthetic equivalent of chiral CHDOH is boronate ( S )-[D 1 ] 18 ,[24] which is more easily accessible than the former compound (Scheme 6). To study the feasibility of the given sequence, we tested the Suzuki–Miyaura reaction[25] for transferring the [(dimethylphenyl)silyl]methyl group in non-deuterated and deuterated form from boronates 18 and ( S )-[D 1 ] 18 , respectively.…”

Boronate Derivatives of Functionally Diverse Catechols: Stability Studies

“…Gas chromatography-mass spectroscopy (GC-MS), of cyclic boronates is valuable and thus relatively highly volatile derivatives of a great variety of the less volatile polar multifunctional compounds, including many of biological importance [ 17 , 18 , 19 , 20 ], may be analyzed. Structural information which can be acquired for specific ions, associated with the MS fragmentation of the new functionality, the identification of these, and of other ions containing boron was facilitated by the characteristic isotope ratio of boron (B 11 :B 10 , 4:1) [ 21 ]; Aryl and heteroaryl boronates are very important intermediates in organic synthesis that have been deployed in many useful transformations [ 22 , 23 , 24 ] and for the determination of absolute configuration [ 25 ]. The rigidity of the cyclic boronate derivatives of corresponding 1,2- or 1,3-diols, requiring relatively fixed conformations, is used in nuclear magnetic resonance (NMR) studies of carbohydrate concentrations and the position of their functional groups [ 26 ].…”