Selective and Practical Oxidation of Sulfides to Diastereopure Sulfoxides: A Combined Experimental and Computational Investigation. Issue 1 (4th January 2013)

• Record Type: Journal Article
• Authors: Bottoni, Andrea; Calvaresi, Matteo; Ciogli, Alessia; Cosimelli, Barbara; Mazzeo, Giuseppe; Pisani, Laura; Severi, Elda; Spinelli, Domenico; Superchi, Stefano
• Is Part Of: Advanced synthesis & catalysis. Volume 355:Issue 1(2013)
• Page Start: 191
• Page End: 202
• Publication Date: 2013-01-04
• Subjects: Catalysis -- Periodicals; Organic compounds -- Synthesis -- Periodicals; Chemistry -- Periodicals; Chemistry, Technical -- Periodicals; Chemistry -- Periodicals; Catalysis -- Periodicals; Technology, Pharmaceutical -- Periodicals; 547.2
• DOI: 10.1002/adsc.201200459
• Languages: English
• ISSNs: 1615-4150

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>We describe an effective oxidation of diltiazem (DTZ)‐like molecules (a class of prochiral sulfides with potential pharmacological properties) using <italic>m</italic>‐chloroperbenzoic acid (MCPBA) as oxidant either in dichloromethane or methanol. An excellent diastereomeric excess of one sulfoxide has been observed "<italic>in the absence of any chiral auxiliary</italic>". The stereochemistry of the two diastereomeric sulfoxides has been determined by TDDFT simulations of the experimental <italic>electronic circular dichroism</italic> (ECD) spectra. A computational DFT study of the reaction mechanism shows that the attack of MCPBA on the two sulfide enantiotopic faces affords two preliminary complexes <bold>M1</bold> and <bold>M1′. M1</bold> is more stable than <bold>M1′</bold> by 3.3 and 3.5 kcal mol<sup>−1</sup> in dichloromethane and methanol, respectively, and after equilibration its population must be dominant. Two diastereomeric pathways originate from <bold>M1</bold> and <bold>M1′</bold> and give two diastereomeric sulfoxides with <italic>R</italic> and <italic>S</italic> configurations at the new chiral sulfur, respectively. Since <bold>TS</bold> (the transition state originating from <bold>M1</bold>) is more stable than <bold>TS′</bold> (the energy gap is 0.7 kcal mol<sup>−1</sup> in dichloromethane or methanol), following the Curtin–Hammett principle, the favoured path is the <italic>pro</italic>‐<italic>R</italic> channel (<bold>M1</bold>→<bold>TS→M2</bold>) affording the (<italic>R<sub>c</sub>, R<sub>s</sub></italic>)‐<bold>2a′</bold> product species in agreement with the observed diastereoselectivity. The <bold>M1</bold>–<bold>M1′</bold> and <bold>TS</bold>–<bold>TS′</bold> energy gaps are actually determined by the difference in the hydrogen bond network that features the two species even if the approaching orientation of the two molecules is governed by the interactions between the π systems of oxidant and substrate aromatic rings. The diastereomeric ratio computed on the basis of the energy difference between <bold>TS</bold> and <bold>TS′</bold> (0.7 kcal mol<sup>−1</sup>) is 63:37, which must be compared to the experimental value 9:1. When we consider free energy differences (2.4 kcal mol<sup>−1</sup> in vacuum and 2.9 kcal mol<sup>−1</sup> in solution) this theoretical ratio becomes 85:15 and 89:11, respectively, in excellent agreement with the experimental value 9:1.</p> </abstract>