A Flexible Asymmetric Synthesis of 1,2-anti tert-Butylsulfanyl Amines

Abstract

A flexible diastereo- and enantioselective synthesis of various 1,2-anti tert-butylsulfanyl amines 5a-e is described. As starting material SAMP-hydrazone (S)-2 was obtained from 2-(bromomethyl)-1,3-dioxolane (1) in a three-step procedure. α-Alkylation with various electrophiles, followed by 1,2-addition to the C-N double bond and removal of the auxiliary by cleavage of the N-N-bond results in the title compounds in excellent diastereomeric and enantiomeric excesses (de, ee ≥ 96%).

asymmetric synthesis - hydrazones - nucleophilic 1,2-addition - α-alkylation - sulfanyl amines/thioether amines

References

1a Petra DGI. Kamer PCJ. Spek AL. Schoemaker HE. van Leeuwen PWNM. J. Org. Chem.  2000,  65:  3010 

1b Anderson JC. Hareding M. J. Chem. Soc., Chem. Commun.  1998,  393 

2a Berkessel A. Bats JW. Bolte M. Neumann T. Seidel L. Chem. Ber.  1997,  130:  891 

2b Sheldrick WS. Exner R. J. Organomet. Chem.  1990,  386:  375 

3a Catalytic Asymmetric Synthesis   Ojima I. VCH Publishers; New York: 1993. 

3b Brunner H. Zettlmeier W. Handbook of Enantioselective Catalysis   VCH Publishers; New York: 1993. 

3c Noyori R. Asymmetric Catalysis in Organic Chemistry   Wiley; New York: 1994. 

4 Poelert MA. Hof RP. Peper NCMW. Kellogg RM. Heterocycles  1994,  37:  461 

5a Benati L. Montevecchi PC. Spagnolo P. Tetrahedron  1986,  42:  1145 

5b Egli M. Hoesch L. Dreiding AS. Helv. Chim. Acta  1985,  68:  220 

5c Bewick A. Coe DE. Mellor JM. Owton WM. J. Chem. Perkin Trans. 1  1985,  1033 

5d Trost BM. Shibata T. J. Am. Chem. Soc.  1982,  104:  3225 

6 Lucchini V. Modena G. Pasquato L. J. Chem. Soc., Chem. Commun.  1994,  1565 

7a Enders D. Eichenauer H. Tetrahedron Lett.  1977,  18:  191 

7b Enders D. Reinhold U. Tetrahedron: Asymmetry  1997,  8:  1895 

8 Enders D. Lochtman R. Meiers M. Müller S. Lazny R. Synlett  1998,  1182 

For examples see:

9a Enders D. Thiebes C. Synlett  2000,  1745 

9b Enders D. Kirchhoff JH. Synthesis  2000,  2099 

9c

Enders, D.; Kallfass, U.; Nolte, B. Synlett 2002, in press.

10 Enders D. Schäfer T. Piva O. Zamponi A. Tetrahedron  1994,  50:  3349 

11

General Procedure for the α-Alkylation of Sulfanyl Aldehyde SAMP-Hydrazone 2. To a solution of 1.05 equiv LDA (freshly prepared from n-butyllithium and diisopropylamine) in dry THF (2 mL/mmol) 1 equiv of 2 was slowly added at 0 °C. After stirring at this temperature for 5 h, 1.1 equiv of alkyhalide was added at -100 °C. The solution was stirred for 1 h and then allowed to warm up to room temperature within 15 h. The reaction mixture was quenched with saturated aqueous NH₄Cl solution. The aqueous portion was extracted with Et₂O and the combined organic layers were washed with brine, dried (MgSO₄) and concentrated in vacuo. Flash column chromatography of the residue on silica gel eluting with pentane-Et₂O (7:1) gave the α-alkylated hydrazones 3 as colourless oils. [13]

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Typical Procedure of 1,2-Addition to Sulfanyl Aldehyde SAMP-Hydrazones, N , N -Cleavage and Cbz-Protection of the Amino Group. 3 equiv of CeCl₃·7H₂O were dehydrated for 2 h at 130 °C in vacuo and then suspended in dry THF (3 mL/mmol) under sonification until the CeCl₃ was finely dispersed over the flask followed by stirring overnight at r.t. After cooling to -78 °C, 3 equiv of organolithium were added and stirred for 2 h at this temperature. The resulting yellow suspension was then added to a solution of 1 equiv hydrazone 3 in dry THF (4mL/mmol) at -100 °C. The solution was stirred for 5-15 h (TLC control) and allowed to warm up to -30 °C. The reaction mixture was quenched with saturated aqueous NaHCO₃ solution and the aqueous portion was extracted with Et₂O. The combined organic layers were washed with brine, dried (MgSO₄) and concentrated in vacuo. The resulting crude hydrazines 4 were directly used in the following step. After dissolving in dry THF (10 mL/mmol), 12 equiv BH₃·THF-complex were added and the solution was refluxed for 4 h. For hydrolysis methanol (ca. 0.5 mL/mmol BH₃·THF-complex) was added and the solution concentrated in vacuo. The residue was dissolved in methanol (10 mL/mmol) and refluxed for 2 h. The mixture was concentrated in vacuo and the crude amine either purified by flash column chromatography on silica gel eluting with pentane-Et₂O (1:1) or subsequently converted to the benzylcarbamate. 1 Equiv of the crude product was dissolved in CH₂Cl₂-H₂O (2:1) (10 mL/mmol) and 2.7 equiv K₂CO₃ and 2.5 equiv CbzCl were added and refluxed for 3 d. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were washed with brine, dried (MgSO₄) and concentrated in vacuo. Flash column chromatography of the residue on silica gel eluting with pentane-Et₂O (15:1) gave the desired products 5 as colourless oils. [13]

13

All new compounds showed suitable spectroscopic data (NMR, MS, IR) and correct elemental analyses or high-resolution mass spectra.