(1R,5R)-2H-1,5-Benzodithiepin-3(4H)-one 1,5-Dioxide

[183595-53-1]  · C9H8O3S2  · (228.29)

(chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols)

Alternate Name: 2H-1,5-benzodithiepin-3(4H)-one, 1,5-dioxide, (1R-trans)-; (1R,5R)-1,5-benzodithiepan-3-one 1,5-dioxide.

Physical Data: colorless prisms, mp 195.0-196.0°C (decomposes) (from hexane/EtOAc), [a]D25-100.3 (c 0.29, CHCl3).

Solubility: soluble in MeOH, acetone, EtOAc, THF, CH2Cl2, and CHCl3.

Form Supplied in: colorless powder; not commercially available.

Analysis of Reagent Purity: 1H and 13C NMR; elemental analysis.

Preparative Methods: the title reagent can be prepared from commercially available (1,2-benzenedithiol1 and 1,3-dichloroacetone. After condensation of these reagents in the presence of DMAP, the resulting 1,5-benzodithepan-3-one is enantioselectively oxidized to the (R)-monosulfoxide by modified Sharpless oxidation [cumene hydroperoxide, Ti(O-i-Pr)4] in the presence of (+)-diethyl tartrate as a chiral ligand.2,3 Subsequent dry ozonation4 of the (R)-monosulfoxide affords (1R,5R)-bis-sulfoxide 1, having >98% optical purity. Alternative use of (-)-diethyl tartrate in the modified Sharpless oxidation makes possible convenient access to enantiomeric (1S,5S)-1.5,6

Purification: purification is performed by column chromatography. Since unpurified (1R,5R)-bis-sulfoxide 1 is only slightly soluble in the eluent, the following procedure is convenient. The crude material is dissolved in EtOAc and mixed with silica gel (ca. 5 g silica gel per 1 g of crude reagent). After solvent evaporation, the silica gel residue containing 1 is added to the top of the column and eluted with hexane-EtOAc (2:1).

Handling, Storage, and Precautions: the reagent can be stored for at least 1 month at room temperature without loss of its chemical and optical purities.

Introduction

(1R,5R)-2H-1,5-Benzodithiepin-3(4H)-one 1,5-dioxide (C2-symmetric bis-sulfoxide 1) has been used as a chiral auxiliary for asymmetric desymmetrization of cyclic meso-1,2-diols via diastereoselective acetal cleavage reaction. The procedure consists of three steps (eq 1), that is, acetalization (step 1), acetal cleavage reaction followed by benzylation (step 2), and hydrolysis of the vinyl ether (step 3). Due to the C2-symmetry of 1, the chiral auxiliary gives only one product in step 1. In addition, no regio- or geometric isomers of the enol ether are formed in step 2. This reagent can be recovered by acid-promoted hydrolysis and reused.

Acetal Formation Involving C2-Symmetric bis-Sulfoxide and meso-1,2-Diols (Step 1)

Acetalization of meso-1,2-diols with this reagent should be conducted with TMSOTf and 2,6-lutidine in dichloromethane below 4°C.7 Higher temperatures and prolonged reaction times cause undesirable racemization and decomposition of the reagent. When the reactivity of meso-1,2-diols with the chiral auxiliary is low, acetalization using the mono-TMS ether of meso-diols and TMSOTf is recommended.8

Diastereoselective Acetal Fission Followed by Benzylation (Step 2)

Upon treatment with KHMDS and 18-crown-6 in THF at -78°C, the acetal from the (R,R)-bis-sulfoxide is rapidly converted into the alkoxide having the (1S,2R) configuration. The counter cation of the base is very important for high selectivity. Diastereoselectivity was seen to increase in the order LiHMDS (8% de) <NaHMDS (90% de) <KHMDS (>96% de).

Hydrolysis of the Vinyl Ether and Reagent Recovery (Step 3)

The resulting vinyl ether can be hydrolyzed with 10% HCl in acetone at room temperature. The chiral auxiliary is recovered without loss of optical purity and is reusable.

Desymmetrization of Functionalized meso-1,2-diols

Using this methodology, various cyclic meso-1,2-diols can be desymmetrized with very high (>96% ee) and predictable selectivity. The enantiomers are obtained through use of an appropriate chiral auxiliary. Bis-sulfoxide 1 has been applied to the desymmetrization of a poly-oxygenated meso-diol containing five stereogenic centers (eq 2).

However, the same chiral auxiliary is not suited to the desymmetrization of acyclic meso-diols since the acetalization step is sluggish. Nonetheless, an acyclic meso-diol such as erythritol can be desymmetrized by prior protection of the terminal primary hydroxyl groups as an o-xylyl ether (eq 3).

Desymmetrization by means of this methodology was successfully applied to a synthesis of key intermediates for mosin B,9 aspicilin,10 gala-quercitol,11 and allosamizoline.8

Related Reagents.

(1S,5S)-2H-1,5-benzodithiepin-3(4H)-one 1,5-dioxide.


1. Giolando, D. M.; Kirschbaum, K., Synthesis 1992, 451.
2. Di Furia, F.; Modena, G.; Seraglia, R., Synthesis 1984, 325.
3. Zhao, S. H.; Samuel, O.; Kagan, H. B., Tetrahedron 1987, 43, 5135.
4. Cohen, Z.; Keinan, E.; Mazur, Y.; Varkony, T. H., J. Org. Chem. 1975, 40, 2141.
5. Maezaki, N.; Sakamoto, A.; Nagahashi, N.; Soejima, M.; Li, Y. X; Imamura, T.; Kojima, N.; Ohishi, H.; Sakaguchi, K.; Iwata, C.; Tanaka, T., J. Org. Chem. 2000, 65, 3284.
6. Maezaki, N.; Sakamoto, A.; Soejima, M.; Sakamoto, I.; Li, Y. X.; Tanaka, T.; Ohishi, H.; Sakaguchi, K.; Iwata, C., Tetrahedron: Asymmetry 1996, 7, 2787.
7. Matsuda, F.; Terashima, S., Tetrahedron 1988, 44, 4721.
8. Maezaki, N.; Sakamoto, A.; Tanaka, T.; Iwata, C., Tetrahedron: Asymmetry 1998, 9, 179.
9. Maezaki, N.; Kojima, N.; Sakamoto, A.; Iwata, C.; Tanaka, T., Org. Lett. 2001, 3, 429.
10. Maezaki, N.; Li, Y. X.; Ohkubo, K.; Goda, S.; Iwata, C.; Tanaka, T., Tetrahedron 2000, 56, 4405.
11. Maezaki, N.; Nagahashi, N.; Yoshigami, R.; Iwata, C.; Tanaka, T., Tetrahedron Lett. 1999, 40, 3781.

Naoyoshi Maezaki & Tetsuaki Tanaka

Osaka University, Suita, Japan



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