Diastereo‐ and Enantioselective Synthesis of anti‐1,3‐Mercapto Alcohols from α,β‐Unsaturated Ketones via Tandem Michael Addition—MPV Reduction.

Abstract

Diastereoselective syntheses Diastereoselective syntheses O 0031Diastereo-and Enantioselective Synthesis of anti-1,3-Mercapto Alcohols from α,β-Unsaturated Ketones via Tandem Michael Addition-MPV Reduction. -The addition of chiral bicyclic mercapto alcohol (I) to unsaturated ketones (II) results in the formation of anti-sulfides (III) via the diastereoselective construction of two stereogenic centers. Transformation of products (III) to the target mercapto alcohols (V) is performed via reduction of the carbonyl group, and a Wagner-Meerwein rearrangement/thiol exchange reaction under acidic conditions using BF 3 ·OEt 2 /dodecanethiol. This transformation fails for substrates (IIIh) and (IIIi) containing a phenyl group adjacent to the carbonyl group. In these cases, the transformation is performed via rearrangement of O-Mom-protected sulfides (VII) to vinyl sulfides (VIII). These intermediates are converted to mercapto alcohols (X) either via reductive ozonolysis followed by hydrolysis, or via thiol exchange reaction using dodecanethiol/Bu 2 BOTf. -(OZEKI, M.; NISHIDE, K.; TERAOKA, F.; NODE*, M.; Tetrahedron: Asymmetry 15 (2004) 5, 895-907; Kyoto Pharm. Univ., Misasagi, Yamashina, Kyoto 607, Japan; Eng.) -Klein

Influence of the Stereochemistry on the Sensory Properties of 4-Mercapto-2-heptanol and Its Acetyl-Derivatives

“…HPLC of 3 on a normal phase silica column resulted in a separation sufficient for preparative isolation of the diastereoisomers. As shown in Table , the NMR data of the first eluted diastereoisomer were in excellent agreement with the data reported for anti -configured (2 S ,4 S )-4-mercapto-2-heptanol . Therefore, the diastereoisomer eluted first from the HPLC column constitutes the pair of anti -configured (2 S ,4 S )- and (2 R ,4 R )-enantiomers.…”

“…Capillary gas chromatographic analysis of 3 using heptakis(2,3-di- O -acetyl-6- O - tert -butyl dimethylsilyl)-β-cyclodextrin as chiral stationary phase enabled the separation of the four stereoisomers (Figure B). The assignment of the order of elution was based on a two-step procedure: (i) separation of the two diastereoisomers via HPLC and comparison of the NMR data to those reported for anti -(2 S ,4 S )-4-mercapto-2-heptanol, the product obtained from 3-hepten-2-one utilizing tandem Michael addition-Meerwein-Ponndorf-Verley reduction, and (ii) preparation of the (4 S )-configured stereoisomer via lipase-catalyzed resolution of 4-acetylthio-2-heptanone 2 and subsequent reduction of the remaining substrate with lithium aluminum hydride. , …”

“…The assignment of the order of elution was based on a two-step procedure: (i) separation of the two diastereoisomers via HPLC and comparison of the NMR data to those reported for anti-(2S,4S)-4-mercapto-2-heptanol, the product obtained from 3-hepten-2-one utilizing tandem Michael addition-MeerweinPonndorf-Verley reduction, and (ii) preparation of the (4S)-configured stereoisomer via lipase-catalyzed resolution of 4-acetylthio-2-heptanone 2 and subsequent reduction of the remaining substrate with lithium aluminum hydride. 22,30 Step (i). HPLC of 3 on a normal phase silica column resulted in a separation sufficient for preparative isolation of the diastereoisomers.…”

“…As shown in Table 1, the NMR data of the first eluted diastereoisomer were in excellent agreement with the data reported for anti-configured (2S,4S)-4-mercapto-2-heptanol. 30 Therefore, the diastereoisomer eluted first from the HPLC column constitutes the pair of anti-configured (2S,4S)-and (2R,4R)-enantiomers. Reinvestigation by GC showed that this HPLC fraction corresponded to the first eluted peak in the capillary gas chromatogram (Figure 2A) and to the first pair of stereoisomers separated on the chiral stationary phase ( Figure 2B).…”

Analysis and Sensory Evaluation of the Stereoisomers of a Homologous Series (C5–C10) of 4-Mercapto-2-alkanols

“…Chromatographic, mass spectrometric, and NMR data were in agreement with those previously reported. 7,21,22,24,26 Enzyme-Catalyzed Kinetic Resolution of Racemic 4-Acetylthio-2-alkanones. In analogy to the method described by Wakabayashi et al, 17,18 5 mmol of synthesized 4-acetylthio-2-alkanone (0.80 g of 7, 0.87 g of 8, 0.94 g of 9, 1.01 g of 10, 1.08 g of 11, and 1.15 g of 12, respectively) were dissolved in 50 mL of potassium phosphate buffer (50 mM, pH 7.4).…”