MOJ Bioorganic & Organic Chemistry Review Article Open Access Application of chiral sulfoxides in asymmetric synthesis Abstract Volume 2 Issue 2 - 2018 Chiral sulfoxides are used as a toolbox for the synthesis of enantiomeric/diastereomeric compounds, which are used as precursors for the pharmaceutically/chemically Ganapathy Subramanian Sankaran,1 important molecules. The current review focuses on applying these chiral sulfoxides Srinivasan Arumugan,2 Sivaraman towards the synthesis of the compounds having stereogenic center. In general, the 3 stereogenic center induced by the sulfoxide is able to direct the stereochemistry of Balasubramaniam 1University of Massachusetts Medical School, USA further transformation necessary to complete the total synthesis of bioactive molecules. 2Department of Science and Humanity (Chemistry), Karunya The nature of the reactive conformation of the sulfoxide is strongly dependent on the Institute of Technology and Sciences, India nature of the substituents at C-α and/or C-β. 3Indian Institute of Technology Madras, Chennai, India Correspondence: Sivaraman Balasubramaniam, Senior Research Scientist, Indian Institute of Technology Madras, Chennai, India, Tel +9177 1880 5113, Email [email protected] Received: March 07, 2018 | Published: March 29, 2018 Introduction occurred in a further oxidation step of one of the sulfinyl enantiomer to sulfone.13 The titanium-binaphthol complex catalyzes not only the Over the last three decades, the sulfinyl group has received asymmetric oxidation but also the kinetic resolution process. considerable attention in asymmetric synthesis1‒5 as a chiral tool. The sulfinyl group is widely used as to bring about numerous asymmetric transformations. The effectiveness of the sulfoxide in diastereoselective auxiliary-induced reactions is mainly due to the steric and stereo electronic differences existing between the substituents on the stereogenic sulfur atom: a lone electron pair, oxygen, and two different carbon ligands, which are able to differentiate the diastereotopic faces of a proximal or even remote reaction center. Besides the high configurational stability of the sulfinyl group,6,7 the existence of several efficient methods to obtain Figure 1 Asymmetric oxidation of the thioethers. homochiral sulfoxide as well as their synthetic versatility has led to a substantial growth of the use of these chiral starting materials in the synthesis of enantiomerically enriched compounds and in the total synthesis of numerous biologically active natural products. An overview on the synthesis of homochiral sulfoxides Asymmetric oxidation of the thioethers A variety of methods are available to obtain optically active Figure 2 Catalytic approach to enantiomerically pure alkyl aryl sulfoxides sulfoxides, these include optical resolution, asymmetric oxidation using a combination of 3,5-diiodo Schiff. and asymmetric synthesis. The first example of asymmetric oxidation of sulfides to sulfoxides were independently reported by Pitchen More general are the application of the stoichiometric chiral et al.8 and Di Furia et al.9 using a modified Sharp less epoxidation oxidizing reagents described by Davis et al.14,15 The enantiopure i t (camphorsulfonyl)oxaziridines and their 8,8-dichloro derivatives reagent [Ti(O Pr)4/(+)-DET/ BuOOH]. Further development of this methedology10,11 showed an increase in the optical purity of the available in both antipodal form, afforded sulfoxides with ee up to resulting sulfoxide by replacing the tert-butylhydroperoxide with 96%. cumenehydroperoxide. Dargo et al.16 came up with a catalytic approach to enantiomerically The use of (R)-(+)-binaphthol12 instead of DET (Figure 1) as pure alkyl aryl sulfoxides using a combination of 3,5-diiodo Schiff chiral ligand improved the modest ee (60-70%) achieved in the base ligands and [VO(acac)2] as the catalyst in the presence of H2O2 as transformation of some methyl aryl sulfides into sulfoxides to 96% oxidant (Figure 2). This combination proved to be effective affording ee by taking advantage of the kinetic resolution process which sulfoxides possessing high ee and in high yields. Both enantiomers Submit Manuscript | http://medcraveonline.com MOJ Biorg Org Chem. 2018;2(2):93–101. 93 © 2018 Sankaran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and build upon your work non-commercially. Copyright: Application of chiral sulfoxides in asymmetric synthesis ©2018 Sankaran et al. 94 of the ligand can be easily prepared on multi gram scale and can be Methyl carbinol: One of the great advantages of sulfoxides is stored for prolonged periods without any loss of optical purity. allowing the asymmetric induction step to be carried out at the very last part of the synthesis via this stereoselective β-keto sulfoxide Nucleophilic substitution on chiral sulfur derivatives reduction. A convergent synthesis of dimethyl ether (S)-6,23 a The most widely used approach to enantiomerically pure sulfoxides precursor of zearalenone, a naturally occurring macrolide with is the Anderson synthesis17,18 based on the nucleophilic substitution anabolic and uterotropic properties has been described (Figure 5). on diastereomerically pure (S S)-menthyl p-toluenesulfinate19 with The enantiomerically pure hydroxy sulfoxide 4 derived from glutaric Grignard reagents which occurs with full inversion of configuration anhydride was transformed to the silyl ether of methyl carbinol 5 at sulfur (Figure 3). The classical method has been extensively via silyl ether protection and subsequent desulfurization, which was used to prepare p-tolyl alkyl or aryl sulfoxides. The usefulness of further elaborated to the natural product. this method is mainly due to the accessibility of the sulfinylating agent, obtained as mixture of sulfur epimers through esterification of p-toluenesulfinyl chloride. This originally described procedure to obtain enantiomerically pure sulfoxide was further improved and scaled up by equilibrating the epimeric sufinate in the presence of HCl to displace the equilibrium by precipitation of the (S,S) diastereomer in acetone being thus isolating it in 80% yield. Figure 5 Methyl carbinol. The anomeric effect was used to advantage in the highly stereo- selective cyclization of dihydroxy disulfoxide 8, accessible with both the S and R configuration at both the hydroxylic centers depending on the reduction method utilized in its obtention from the diketone 7. Upon treatment in acidic medium, compound 8 evolved into a spi- roketal derivative whose desulfurization afforded compound 9, pre- Figure 3 Nucleophilic substitution on chiral sulfur derivatives. sent in the rectal glandular secretion of certain species of fruit flies 24 Reactions exploiting sulfur chirality (Figure 6). The enantiomer could be synthesized from the dihydroxy disulfoxide resulting from reduction with DIBAL/ZnCl2. As a chiral auxiliary in the diastereoselective reduction of β-ketosulfoxides Acyclic β-keto sulfoxides are readily available by the reaction of α-sulfinyl anion with an ester.20,21 The main contribution to the synthesis of optically active secondary carbinols from β-keto sulfoxide is due to Carreno et al.22 The Stereochemical outcome in the reduction of the β-keto sulfoxide can be controlled by the configuration of the sulfoxide, the reducing agent and the absence or presence of a Lewis acid. The reduction of β-keto sulfoxide (R ) 1 with DIBAL gave (R ,S)-carbinol Figure 6 Enantiomer could be synthesized from the dihydroxy disulfoxide S S resulting from reduction with DIBAL/ZnCl . 2 via intramolecular hydride transfer through a six-membered cyclic 2 transition state (I), while the reduction with LiAlH4 or DIBAL in the 1,2-Diols: The protocol transforming β-hydroxy sulfoxides into presence of ZnCl2 as a Lewis acid give the epimer at the hydroxy terminal 1,2-diols via the Pummerer rearrangement followed by center (RS, R)-carbinol 3 which is rationalized by a conformationally desulfurization or LAH reduction of the resulting hemi-thioketal, rigid six-membered cyclic transition state (II) involving chelation of has been utilized in the synthesis of several polyhydroxylated the Lewis acid to the sulfinyl and carbonyl oxygen (Figure 4). This natural products. As a showcase, enantiomerically pure β-hydroxy methodology has been employed in enantioselective synthesis of unsaturated sulfoxide 10 was transformed to the triol derivative 11 methyl carbinol, 1,2-diols and epoxides which are used as the key by dihydroxylation. Compound 11 was further converted to L-penta- intermediates in the total synthesis of natural products. O-acetylarabinitol 12 by applying the above strategy (Figure 7).25,26 Figure 7 1,2-Diols. Epoxides: β-Hydroxy sulfoxides can also be easily transformed into chiral epoxides giving access to a variety of natural products. Figure 4 As a chiral auxiliary in the diastereoselective reduction of The asymmetric synthesis of juvenile hormone II 13 was based on β-ketosulfoxides. Citation: Sankaran GS, Arumugan S, Balasubramaniam S. Application of chiral sulfoxides in asymmetric synthesis. MOJ Biorg Org Chem. 2018;2(2):93–101. DOI: 10.15406/mojboc.2018.02.00062 Copyright: Application of chiral sulfoxides in asymmetric synthesis ©2018 Sankaran et al. 95 the diastereoselective alkylation and carbonyl reduction of β-keto Reactions of sulfinyl carbanions sulfoxide 14.27 Alkylation of 14 produced a (9:1) mixture of (R, R ) s 1,2-Addition to carbonyl: Although