Design and Synthesis of Chiral Oxathiozinone Scaffolds: Efficient Synthesis of Hindered Enantiopure Sulfinamides and Sulfinyl Ketimines

Abstract

Ist das S‐O? Die im Titel bezeichneten Molekülgerüste verfügen über eine hoch aktive und ausreichend differenzierte S‐O‐Bindung für die effiziente Synthese enantiomerenreiner Sulfinamide. Die beschriebene Methode ist praktisch und umweltverträglich und könnte als Grundlage für ein ökonomisches kommerzielles Verfahren zur Herstellung sperriger Sulfinamide dienen.

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

“…Finally, we also tried the ring opening of 7 bA using 2‐mesitylmagnesium bromide, but in this case, we were able to isolate only the corresponding symmetrical sulfoxide, even when the reaction was carried out at −78 °C or using a two‐fold excess of 7 bA . This last result was not completely unexpected, since the symmetrical sulfoxide was obtained also by Senanayake as the major product when using the more sterically hindered 1,3,5‐triisopropylphenylmagnesium bromide [9] …”

“…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.…”

“…The capability of unsubstituted phenol to act as a potential leaving group was demonstrated by the same authors using the addition of LiHMDS to the corresponding structurally simpler phenylsulfinate ester. [9] Apparently, the presence of a supplementary aminoalkyl substituent on the aromatic ring of the sulfinate esters 8 is either enough to make it an unsuitable leaving group, or it actively participates in the organometallic addition by chelating LiHMDS and promoting a different reaction pathway with respect to the unsubstituted phenol.…”

“…More recently, Han and Senanayake proposed a more efficient oxathiozinone sulfinyl-transfer agent (VI, Scheme 1) for the stereoselective synthesis of tBSA 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 tBSA. [10] The precursor (V) to the chiral oxathiozinone scaffold (VI) was prepared starting from an acetylated phenol (I) by Fries' rearrangement to give the ketone II, followed by a reductive amination with ammonia and borane to give the racemic amine IV, that is resolved using tartaric acid affording both enantiomers in high optical yield.…”

DMAP‐Catalysed Sulfinylation of Diacetone‐D‐Glucose: Improved Method for the Synthesis of Enantiopure tert‐Butyl Sulfoxides and tert‐Butanesulfinamides

“…But these conditions are harsh, and there is the additional drawback that large amounts of hazardous NH 2 Li/NH 3 must be handled and disposed of. During the course of our work, Senanayake reported a phenol‐based tert ‐butanesulfinylating agent that is able to smoothly give the sulfinamide intermediate 42. We found that the addition of LiHMDS to ( R S )‐DAG‐ tert ‐butanesulfinate ester 2 R S in THF at 0 °C, followed by treatment with methanol and silica, gave the desired enantiopure ( R S )‐ tert ‐butanesulfinamide ( 17 R S ) in 92 % yield (Scheme ).…”