Synthesis and Evaluation of Enantiopure 6-Thiabicyclo[3.2.1]octanes for Asymmetric Epoxidation of Benzaldehyde

Abstract

A one-step synthesis of 6-thiabicyclo[3.2.1]octan-3-one from carvone is reported. Chiral sulfides were subsequently elaborated in a few steps and used as competent sulfonium ylide promoters for the asymmetric epoxidation of aldehydes. Their odourant characteristics are also described.

Key words

sulfur - ylides - epoxidations - catalysis - asymmetric

References and Notes

• For recent reviews on sulfide in enantioselective catalysis, see:
• 1a Pellissier H. Tetrahedron  2007,  63:  1297 
• 1b Mellah M. Voituriez A. Schulz E. Chem. Rev.  2007,  107:  5133 
• 1c McGarrigle EM. Myers EL. Illa O. Shaw MA. Riches SL. Aggarwal VK. Chem. Rev.  2007,  107:  5841 
• 1d McGarrigle EM. Aggarwal VK. Enantioselective Organocatalysis: Reactions and Experimental Procedures   Dalko PI. Wiley-VCH; Weinheim: 2007.  Chap. 10.
• 1e Seayad J. List B. Org. Biomol. Chem.  2005,  3:  719 
• For recent reviews on chiral odorants, see:
• 2a Goeke A. Sulfur Rep.  2002,  23:  243 
• 2b Brenna E. Fuganti C. Serra S. Tetrahedron: Asymmetry  2003,  14:  1 
• 2c Bentley R. Chem. Rev.  2006,  106:  4099 
• 3a Demole E. Enggist P. Ohloff G. Helv. Chim. Acta  1982,  65:  1785 
• 3b Lehmann D. Dietrich A. Hener U. Mosandl A. Phytochem. Anal.  1995,  6:  255 ; and references cited therein
• 4a Weitkamp AW. J. Am. Chem. Soc.  1959,  81:  3437 
• 4b Moore CG. Porter M. Tetrahedron  1959,  6:  10 
• 4c Bertaina C. Cozzolino F. Fellous R. George G. Rouvier E. Parfums Cosmét. Arômes  1986,  71:  69 
• 4d Janes JF. Marr IM. Unwin N. Banthorpe DV. Yusuf A. Flavour Frag. J.  1993,  8:  289 
• 5a Hargreaves M. McDougall R. Rabari L. Z. Naturforsch., B: Anorg. Chem. Org. Chem.  1978,  33:  1535 
• 5b Krein EB. Aizenshtat Z. J. Org. Chem.  1993,  58:  6103 
• 5c Sirazieva EV. Startseva VA. Nikitina LE. Sofronov AV. Artemova NP. Fedyunina IV. Chem. Nat. Compd.  2007,  43:  52 
• 6a Review on polysulfane: Steudel R. Chem. Rev.  2007,  102:  3905 
• 6b Recent paper: Aebisher D. Brzostowska EM. Mahendran A. Greer A. J. Org. Chem.  2007,  72:  2951 ; and references cited therein
• For recent reviews, see:
• 7a Aggarwal VK. Richardson J. Chem. Commun.  2003,  2644 
• 7b Aggarwal VK. Winn CL. Acc. Chem. Res.  2004,  37:  611 ; see also ref. 1c
• 10a Ranu BC. Mandal T. Synlett  2007,  925 
• 10b Lou F.-W. Xu J.-M. Liu B.-K. Wu Q. Pan Q. Lin X.-F. Tetrahedron Lett.  2007,  48:  2815 
• 10c Weïwer M. Coulombel L. Duñach E. Chem. Commun.  2006,  332 ; and references cited therein
• 11 Yan T.-H. Tsai C.-C. Chien C.-T. Cho C.-C. Huang P.-C. Org. Lett.  2004,  6:  4961 
• For selected recent examples, see:
• 16a Winn CL. Bellenie BR. Goodman JM. Tetrahedron Lett.  2002,  43:  5427 
• 16b Aggarwal VK. Alonso E. Bae I. Hynd G. Lydon KM. Palmer MJ. Patel M. Porcelloni M. Richardson J. Stenson RA. Studley JR. Vasse J.-L. Winn CL. J. Am. Chem. Soc.  2003,  125:  10926 
• 16c Deng X.-M. Cai J. Ye S. Sun X.-L. Liao W.-W. Li K. Tang Y. Wu Y.-D. Dai LX. J. Am. Chem. Soc.  2006,  128:  9730 
• 16d Davoust M. Brière J.-F. Jaffrès P.-A. Metzner P. J. Org. Chem.  2005,  70:  4166 ; and references cited therein
• 17a Silva MA. Bellenie BR. Goodman JM. Org. Lett.  2004,  61:  2559 
• 17b Edwards DR. Montoya-Peleaz P. Crudden CM. Org. Lett.  2007,  9:  5481 
• 17c

  For exhaustive studies on sulfonium ylide mechanism, see also ref. 1c, 7a.

• 20 Jaubert J.-N. Tapiero C. Dore J.-C. Perfum. Flav.  1995,  20:  1 

8

The aqueous solutions of (NH₄)₂S (20% or 50%) are commercially available from Aldrich.

9

Synthesis of 4,7,7-Trimethyl-6-thia-1,5-bicyclo[3.2.1]octan-3-one (5) A 50% aq solution of diammonium sulfide (20 mL, 146.8 mmol) was added dropwise to a mixture of TBAB (1.544 g, 4.8 mmol) and elemental sulfur (4.689 g, 146.2 mmol). The solution was stirred for 5 min. Then, THF (9 mL) was added and carvone (15 mL, 93.8 mmol) was slowly introduced. The obtained red solution was vigorously stirred at r.t. for 3-4 d (until carvone disappeared on TLC). The solution was diluted in H₂O (100 mL), and the product was extracted with Et₂O (3 × 50 mL). The combined organic layers were washed with a sat. aq solution of NH₄Cl (15 mL), a sat. aq solution of K₂CO₃ (15 mL) and brine (15 mL). The organic layer was dried over MgSO₄, filtrated, and concentrated in vacuo. The obtained oil was purified by flash column chromatography (heptane-EtOAc, 5:1) to afford an inseparable mixture of diastereomers as an oil which crystallised as a yellow powder (59%, 86:14 eq/ax). Trituration in i-PrOH facilitated the crystallisation without changing the diastereomeric ratio. This is a stable compound, which could be stored for at least a year in the fridge. Melting point and optical rotation of the 86:14 mixture of diastereomers are given for indication: mp 65-67 °C (lit^5b 67-68 °C for the pure equatorial compound 5), [α]_D ²⁰ +116 (c 1.0, CHCl₃). ¹H NMR (250 MHz, CDCl₃):
δ = 1.08 (d, J = 6.5 Hz, 3 H, eq), 1.19 (d, J = 7.5 Hz, 3 H, ax), 1.38 (s, 3 H, eq), 1.43 (s, 3 H, ax), 1.44 (s, 3 H, eq + ax), 2.27-2.43 (m, 3 H, eq + ax), 2.62-2.71 (m, 3 H, eq + ax), 3.47 (br s, 1 H, eq + ax). ¹³C NMR (63 MHz, CDCl₃):
δ (eq) = 209.1, 54.8, 52.5, 52.1, 49.6, 44.9, 41.1, 34.0, 27.1, 13.7; δ (ax) = 212.6, 54.3, 49.9, 48.9, 42.1, 33.9, 33.8, 24.5, 17.4. IR (neat): 2951, 1698. HRMS: m/z calcd for C₁₀H₁₇OS [M + H]⁺: 185.1000; found: 185.1007. GC-MS: 2 peaks with the same mass(184). Enantioselective GC was performed on a CYDEX-B chiral capillary column (25 m × 0.22 mm), 10 psi at 130 °C; t _R (enantiomers of the major epimer 5) = 47.7 and 49.5.

12

4,7,7-Trimethyl-3-methylene-6-thiabi-cyclo[3.2.1]octane (7)
Obtained as a mixture of epimers (58 mg, 95:5 eq/ax) after column-chromatography purification (pentane-Et₂O, 30:1); colourless liquid. ¹H NMR (250 MHz, CDCl₃): δ = 1.02 (d, J = 6.5 Hz, 3 H, eq), 1.15 (d, J = 7.3 Hz, 3 H, ax), 1.39 (s, 3 H, eq + ax), 1.43 (s, 3 H, eq), 1.50 (s, 3 H, ax), 1.98-2.22 (m, 3 H, eq + ax), 2.44-2.54 (m, 3 H, eq + ax), 3.47 (br s, 1 H, eq + ax), 4.80-4.90 (m, 2 H, eq + ax). ¹³C NMR (63 MHz, CDCl₃): δ (main equatorial isomer) = 148.3, 112.8, 54.9, 53.8, 48.2, 42.6, 42.4, 38.5, 34.4, 25.5, 17.3. IR (neat): 1641, 1455, 886. HRMS: m/z calcd for C₁₁H₁₈S [M]⁺: 182.1129; found: 182.1126.

13

4,7,7-Trimethyl-3-phenyl-6-thiabicyclo[3.2.1]octan-3-ol (8)
A small sample was purified on column chromatography (heptane-Et₂O, 30:1) for analytical purposes. Only one diastereomer is seen by NMR. White solid; mp 116-118 °C. ¹H NMR (250 MHz, CDCl₃): δ = 0.77 (d, J = 6.9 Hz, 3 H), 1.51 (s, 3 H), 1.72 (s, 3 H) 2.05 (dd, J = 4.5, 15.2 Hz, 1 H), 2.15 (d, J = 12.0 Hz, 1 H), 2.19-2.26 (m, 1 H), 2.27-2.38 (m, 2 H), 2.58-2.67 (m, 1 H), 3.46 (br d, J = 7.1 Hz, 1 H), 5.20 (s, 1 H, OH), 7.16-7.35 (m, 3 H), 7.46-7.50 (m, 2 H). ¹³C NMR (63 MHz, CDCl₃): δ = 148.2, 127.9, 126.3, 125.4, 75.9, 55.2, 53.4, 49.5, 46.1, 44.4, 41.7, 35.0, 27.3, 14.3.
IR (neat): 3369, 2929, 1492, 1448, 1382. MS (EI): m/z (%) = 262 (46), 244 (80).

14

4,7,7-Trimethyl-3-phenyl-6-thiabicyclo[3.2.1]oct-2-ene (9)
Obtained as a mixture of epimers (191 mg, 80:20 eq/ax) after column-chromatography purification (heptane-Et₂O, 50:1). Yellow oil. ¹H NMR (250 MHz, CDCl₃): δ = 0.64 (d, J = 6.4 Hz, 3 H, ax), 0.91 (d, J = 7.2 Hz, 3 H, eq), 1.44 (s, 3 H, ax), 1.47 (s, 3 H, eq), 1.49 (s, 3 H, eq), 1.51 (s, 3 H, ax), 2.19-2.27 (m, 1 H, eq + ax), 2.31-2.44 (m, 1 H, eq + ax), 2.45-2.55 (m, 1 H, eq + ax), 3.15-3.23 (m, 1 H, eq + ax), 3.58 (t, J = 4.4 Hz, 1 H, eq + ax), 5.27-5.37 (m, 1 H, ax), 5.82 (br d, J = 6.6 Hz, 1 H, eq), 7.18-7.28 (m, 5 H, eq + ax). ¹³C NMR (63 MHz, CDCl₃): δ (eq) = 141.9, 141.4, 128.4, 128.2, 126.8, 126.8, 60.5, 53.6, 48.4, 39.9, 38.8, 33.4, 27.6, 17.3; δ (ax) = 143.6, 128.3, 128.1, 127.1, 127.0, 54.8, 48.8, 48.1, 47.0, 35.0, 33.0, 25.9, 13.5; one sp² signal is overlapping with one equatorial signal. IR (neat): 2927, 1777, 1599, 1453. HRMS: m/z calcd for C₁₆H₂₁S [M + H]⁺: 245.1364; found: 245.1360.

15

3-Methoxy-4,7,7-trimethyl-6-thiabi-cyclo[3.2.1]octane (11)
Obtained as a mixture of epimers (379 mg, 98:2 eq/ax) after column-chromatography purification (heptane-Et₂O, 20:1). Colourless oil. ¹H NMR (400 MHz, CDCl₃): δ (main equatorial isomer) = 0.99 (d, J = 6.9 Hz, 3 H), 1.43 (s, 3 H), 1.52 (s, 3 H), 1.54-1.59 (m, 1 H), 1.83-1.86 (m, 1 H), 1.96-1.99 (m, 1 H), 2.13-2.08 (m, 1 H), 2.25-2.30 (m, 1 H), 2.45-2.50 (m, 1 H), 3.14-3.16 (m, 1 H), 3.21 (t, J = 5.8 Hz, 1 H), 3.29 (s, 3 H). ¹³C NMR (63 MHz, CDCl₃): δ (eq) = 78.4, 57.7, 53.5, 51.7, 47.0, 42.1, 41.8, 35.5, 30.5, 26.9, 16.3. IR (neat): 2923, 1459, 1115, 1091. HRMS: m/z calcd for C₁₁H₂₁OS [M + H]⁺: 201.1313; found: 201.1316.

18

The determination of odour concentration was carried out at IAP-SENTIC company (France) by dynamic olfactometry according to the European standard EN13725 with trained 4 or 6 sensory assessors. Sample preparation: 10-20 mg of compounds were solubilised in 2 g of abs. EtOH (solution 1) and diluted 100 times (solution 2). Then, 25 µL of either solution 1 or 2 were injected within 10 l of air and analysed.

19

The odorant factor is defined as the maximum volume (m³) in which 1 g of compound could be detected (by the nose of assessors). The odorant factor of limonene-thiol 3 (from Sigma Aldrich - CAS 71159-90-5) was evaluated to 11·10⁶ by the method described in ref. 18.