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Sulfenic acid anions are increasingly being recognized as valuable entities for the construction of sulfur containing organic compounds. These compounds are of interest because of the growing recognition for their role in biological systems, because several aspects of their alkylation chemistry remain unexplored and since preparing sulfinyl compounds from sulfenates is counter to the paradigms of sulfur oxidation and nucleophilic attack at sulfur. Recent work by Madec¹ clearly shows sulfenate value for the formation of enantioenriched aryl sulfoxides. Any synthetic protocol for sulfenates must work within the limitations of their stability. Specifically, sulfenates are generally not isolable, but must be created from the appropriate precursor and then reacted in the same vessel.  One of the viable methods for accessing sulfenates involves their release from beta-sulfinyl acrylates. In our group, this is achieved by treating the beta-sulfinyl acrylates with cyclohexanethiolate to effect a stereospecific addition-elimination reaction, releasing sulfenate anion.² The beta-sulfinyl acrylates are generally prepared from a conjugate addition/oxidation sequence. However we have developed a protocol for selected E-beta-sulfinyl acrylates by utilizing a new reagent, cesium 2-Z-carbomethoxyethenethiolate.³

This strategy is most applicable for targeted sulfenates that are base sensitive. As such we have been investigating the chemistry of a protected cysteinesulfenate derivative (2). Our addition elimination chemistry proceeds with minimal perturbation of the sensitive a-proton that normally makes amino acid chemistry difficult. Under this plan, cysteine derivative 1 was required for cysteinesulfenate liberation. During the first period of PRF funding, two different syntheses of 1 were fully evaluated. Analogs of 1 have previously been prepared by Aversa,⁴ by way of sulfenic acid capture. That method is viable, but time consuming, and several intermediates in the sequence are thermally sensitive. The alternative route of conjugate addition of thiol to methyl propiolate followed by oxidation has been fully optimized and compound 1 can be formed in 75% (2 g scale) or 60% (8 g scale) yield in one afternoon!

The sulfenate (2) was then generated via thiolate treatment and captured with a selection of electrophiles including several substituted benzyl bromides affording diastereomeric sulfoxides (3, Scheme 1). All possible products were prepared by conventional means and these compounds were used as identification and calibration standards. Chiral HPLC analysis was used to establish the diastereomeric ratio. Yields ranged from 52-99% and diastereomeric ratios range from 89:11 to 95:5 (14 examples), with the R-configuration assigned to the sulfinyl group.⁵ In the burgeoning field of sulfenate chemistry these diastereoselectivities are quite good. Compounds 4 and 5, protected analogs of naturally occurring constituents of garlic were also obtained by this chemistry. Finally, on a one gram scale, the yields tend to be much higher than recently reported.⁵

An interesting feature of the cysteine sulfenate chemistry is the stereochemistry of alkylation in the presence of 12-crown-4 (12-c-4), a crown ether well known for its affinity for lithium cations. The introduction of 12-c-4 mildly attenuates the observed dr values, indicating a) that lithium is important to the stereoinduction process and b) how strongly the cysteinesulfenate holds the lithium. The latter is particularly intriguing since 12-c-4 is well known for its strength to coordinate lithium, but sulfenate 2 appears to be competitive or even stronger.

It has been proposed that the benzylic sulfoxides diastereoselectively formed by this sulfenate chemistry are good candidates for intramolecular cyclization chemistry targeting 7- or 8-membered sulfur/nitrogen heterocycles. A number of reactions of 3 (X = o-Br) have been evaluated, but the substrate decomposes under the thermal activation required for the cyclization. Acid mediated removal of the Boc group was achieved without perturbation of the sulfenyl group, but cyclization attempts of those substrates did not proceed. Reduced forms of compounds 3 are under investigation.

Marcus Verdu, an MSc candidate since Jan. 2007, Dr. Suneel P. Singh, a pdf since late March 2008 have performed the chemistry outlined above. Marcus has completed his MSc while garnering substantial instrumental skills (NMR, HPLC, ReactIR) and project management skills. He has secured employment as an analytical chemist at Testmark Laboratories, a highly accredited, ISO/IEC 17025 certified privately own analysis company. Dr. Singh will be continuing his appointment, working on cyclizations of some substrates herein, but also moving to phospholipid and amino acid synthesis under other funding.

Under this PRF grant we have also been probing the stereoinduction of alkylation using chiral electrophiles. Specifically, the reaction of sulfenate 6 and an iodide derived from phenylalanine has been tested as a model system. Optimization studies are almost complete, with yields reaching 87% with a good dr of 89:11 observed (Scheme 2). Several other sulfenates and electrophiles are due to be evaluated. This chemistry is ongoing as a major component of the research of PhD candidate Stefan Soderman who has received a graduate scholarship through the Canadian funding agency NSERC.

Finally for Adrian Schwan, this funding has permitted a deeper analysis of sulfenate chemistry from which have arisen a number of new directions. Many of the ideas will form the basis of other grant proposals for funding from other sources.

References Cited

1. Maitro, G.; Vogel, S.; Sadaoui, M.; Prestat, G.; Madec, D.; Poli, G. Org. Lett.  2007, 9, 5493.

2. O'Donnell, J.S.; Schwan, A.L. Tetrahedron Lett.  2003, 44, 6293.

3. O'Donnell, J. S.; Singh, S. P.; Metcalf, T. A.; Schwan, A. L. Eur. J. Org. Chem. 2009, 547.

4. Aversa, M.C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P.  J. Org. Chem. 2005, 70,1986.

5. Schwan, A.L.; Verdu, M.J.; Singh, S.P.; O'Donnell j.S.; Ahmadi A.N. J. Org. Chem., 2009, 74, 6851.