Development of a Large-Scale Asymmetric Process for tert-Butanesulfinamide

Abstract

Process development for a scalable and green synthesis of chiral tert-butanesulfinamide (TBSA) on a multikilogram scale is reported. The process is based on the identification of a chiral sulfinyl transfer agent, benzo [1,3]oxathiozin-2-one, that contains active and differentiated S−N and S−O bonds, allowing the synthesis to proceed under mild reaction conditions. This method is practical and overcomes the disadvantages of earlier methods deploying harsh reaction conditions and hazardous and toxic reagents.

Diastereoselective Synthesis of Chiral Oxathiazine 2‐Oxide Scaffolds as Sulfinyl Transfer Agents

“…More recently, Han and Senanayake proposed a more efficient oxathiozinone sulfinyl‐transfer agent ( VI , Scheme 1) for the stereoselective synthesis of t BSA and of the bulkier triisopropylphenylsulfinamide (TIPPSA) [9] . This practical and efficient methodology was later applied by the same authors to the stereoselective kilogram‐scale preparation of t BSA [10] …”

“…Using scaffold 8 bA (entry 1), results comparable to the ones reported by Senanayake using the transfer agent deriving from V (Scheme 1, X = Cl) were obtained (mean yield and ee on 3 batches for the last step: 93%, 93%; overall tBSA yield starting from 6: 40%). [10] While phenyl substituent gave a slightly lower enantiomeric excess, although with a very good yield (entry we were very pleased to find that the allyl group (entry 3) gave comparable results to the original methyl substituent, opening the possibility of further functionalizations, for example by cross-metathesis. In all cases, the precursors 6 b were recovered in almost quantitative yields, after purification by flash-chromatography, further confirming the efficiency of the protocol.…”

“…With the desired chiral precursors 6 in our hands, we studied their conversion into the corresponding oxathiazine 2-oxide scaffolds 7 and their efficiency as stereoselective sulfinyl transfer agents in the preparation of enantiomerically enriched tBSA, using the same protocols recently reported by Han and Senanayake (Scheme 3). [9,10] Scaffolds 7 were prepared by reaction with thionyl chloride and pyridine in THF at À 15 °C, in good to high yields. Except for 7 aA, which can be isolated and purified by flash-chromatography on silica as a stable white solid, all other oxathiazine 2-oxides are unstable and easily hydrolyze back to the precursors 6 if prolonged reaction times are used, as well as during the work-up stage and during purification by flash-chromatography on silica.…”

“…Again, the relative stereochemistry of the major diastereoisomer of oxathiazine 2-oxides 7 was tentatively assigned in accordance with the work of Han and Senanayake. [10] Ring-opening of oxathiazine 2-oxides was thus tested using tBuMgCl in THF at À 40 °C and the results obtained are reported in Table 2.…”

Syntheses and Transformations of Sulfinamides

“…Toluenesulfonyl methamphetamine had proven to be a very versatile intermediate for the synthesis of various sulfinamides. Recently Senanayake and co-workers 28 also reported a method for synthesis of enantioenriched sulfinamides using chiral oxathiozin- Senanayake and colleagues further optimized the above method and reported a method for asymmetric synthesis of enantioenriched sulfinamides using quinine as a chiral auxiliary (Scheme 11). 29 The chiral auxiliary agent quinine is easily available and inexpensive in this method.…”