LETTER
3063
Regio- and Enantioselective Ring-Opening of Epoxides with HMDST: A Straightforward Access to 1,2-Mercaptoalcohols AAlessandro c es to1,2-Mercaptoalcoh ls Degl’Innocenti,*a Antonella Capperucci,*a Arianna Cerreti,a,b Salvatore Pollicino,b Serena Scapecchi,c Irene Malesci,a Giulio Castagnolia a
Dipartimento di Chimica Organica, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy Dipartimento di Chimica Organica, ‘A. Mangini’, viale Risorgimento 4, 40136 Bologna, Italy c Dipartimento di Scienze Farmaceutiche, Università di Firenze, via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy Fax +39(055)4573585; E-mail:
[email protected] Received 14 September 2005 b
Abstract: TBAF-catalyzed reaction of a range of substituted epoxides with hexamethyldisilathiane smoothly affords a direct and simple access to b-mercaptoalcohols in a highly regio- and stereoselective way. Key words: epoxides, thiosilane, 1,2-mercaptoalcohols, enantioselectivity, regioselectivity
Ring-opening of epoxides with various nucleophiles is an important and useful synthetic transformation providing an easy access to a large number of functionalized intermediates, useful in the synthesis of more complex organic structures.1 In this context, reactions with thio nucleophiles play an important role2 affording hydroxythio derivatives as useful building blocks in organic chemistry, particularly in the pharmaceutical and natural products field.3 In fact, ring-opening of 1,2-oxiranes with thiols yields b-hydroxy thioethers, which can be used in the synthesis of leukotrienes,4 HIV-1 protease inhibitors,3e and MMP inhibitors.3d Such ring-openings are promoted either by Lewis acids [Zn(II) halides,5 LiClO4,2d Ln(III) complexes,2b Ti(iPrO)4,2i,6 COCl2,1g BF3·OEt2,7 Sn(II) salts,8 InCl32j] or by basic catalysts (alumina,9 quaternary ammonium salts,2c,e,10 including TBAF, and amines11) and afford bhydroxy sulfides in good yields with high regiochemical control. Stereoselective ring-opening of chiral epoxides is often achieved and catalytic asymmetric oxirane ring-openings are usually obtained through the use of chiral metal complexes, leading to desymmetrization of meso-epoxides and the introduction of two contiguous stereogenic centers.2h Thiosilanes, a class of compounds which couple in the same structure a powerful oxygenophile (SiR3) and a strong nucleophile (RS group), have also been used as nucleophiles in reactions with oxiranes in place of thiols.4c,5,10b,11,12 Aliphatic and aromatic organothiosilanes, including amino acid and glutathione derivatives,
SYNLETT 2005, No. 20, pp 3063–306619.12 05 Advanced online publication: 28.11.2005 DOI: 10.1055/s-2005-921922; Art ID: G29005ST © Georg Thieme Verlag Stuttgart · New York
have been used, thus affording the corresponding functionalized b-hydroxy thioethers with high regio- and stereocontrol, under suitable catalytic conditions. Nonetheless, among the reactions of sulfur nucleophiles with epoxides, to the best of our knowledge there are a few methods which allow a direct access to b-mercaptoalcohols, which indeed represent very interesting intermediates in the synthesis of various biologically important compounds. Some procedures involve reactions of H2S,13 NaBH2S3,2a and thiourea.14 In connection with this, it is worth mentioning the ringopening of epoxides induced by silane thiols, such as Ph3SiSH11 and i-Pr3SiSH (HSTIPS),15 which behave as monoprotected H2S, but are easier to handle and afford the desired b-hydroxy thiols in high yields. In the case of Ph3SiSH, ring-opening of epoxides proved to be not always regiospecific, the isomeric distribution being dependent on the stoichiometric ratio of Et3N, while the use of HSTIPS led in a regiospecific way to the corresponding b-trialkylsilyloxy mercaptans; therefore a deprotection step must be employed to access the free hydroxy compounds. Moreover, some of the methods often involve extended reaction times, undesirable side reactions, or poor regioselectivity. During the course of our research on the evaluation of the reactivity of bis(trimethylsilyl)sulfide (hexamethyldisilathiane, HMDST) as a versatile thionating agent affording thiocarbonyl derivatives directly16 we wondered whether HMDST could behave as an efficient sulfur nucleophile in the ring-opening reaction of epoxides, taking into consideration that it may be regarded as the synthetic equivalent of H2S, but would be much easier to handle and to measure. Thus, treatment of 2-methyloxirane 1a with HMDST at room temperature in the presence of a catalytic amount of TBAF (0.2 equiv) led smoothly to uncover a simple access to 1-mercaptopropan-2-ol 17 (2a; Scheme 1), arising from clean regioselective attack of the thio nucleophile on the less hindered side of the oxirane, no trace of the other regioisomer was detected.
3064 O
+ (TMS)2S Me
LETTER
A. Degl’Innocenti et al. TBAF THF/r.t.
1a
RO Me
Direct Synthesis of b-Mercaptoalcohols
Table 1 SH
Entry Epoxide
1,2-Mercaptoalcohol
Yield (%)a
1
HO
65b
2a, 3a 2a: R = H (0.2 equiv TBAF) 3a: R = TMS (0.1 equiv TBAF)
O Me
Scheme 1 2
Such behavior discloses a potentially useful straightforward access to 1,2-mercaptoalcohols. In order to evaluate the generality of such methodology, a series of substituted epoxides was reacted under the same conditions (Table 1). The reactivity proved general, leading to the synthesis of substituted 1,2-mercaptoalcohols bearing aromatic, aliphatic, and vinylic moieties. This reaction appears quite interesting, in so far as it is operationally simple and represents a direct access to b-hydroxy mercaptans under very mild conditions with a catalytic amount of TBAF. All the reactions occur with very good yields of monosubstituted epoxides, while for 1,2-substituted oxiranes, as already pointed out by other authors,11 the yields tend to decrease. It is interesting to underline that the process is generally highly regioselective, only one isomer being observed in the crude. Only in the case of styrene oxide and isopropyl glycidyl ether were the corresponding regioisomers detected (Table 1, entries 2, 3). Concerning the amount of TBAF, it must be considered that in most cases the addition of a catalytic amount (0.2– 0.3 equiv) of the ammonium salt afforded the b-hydroxy thiol as the sole product (Table 1, entries 1, 2, 4, 7–9), while smaller amounts of TBAF led to the isolation of the silyl ether.17 On the contrary, treatment of epoxides 1c, 1e, and 1f with 0.2 equivalents of TBAF led to the isolation of b-trimethylsilyloxy thiols as the major compounds. Simple addition in the same flask of an additional 0.2 equivalents of TBAF smoothly afforded the desired bmercaptoalcohols 2c, 2e, and 2f in good yields. Due to the mildness of the experimental conditions, this methodology can be applied also to very useful, but labile compounds such as glycidol derivatives, which represent important structures in different fields.3d,7,10b,18 Protected glycidols 1c and 1d were opened in good yields and the protective moieties were not removed under the reaction conditions (Table 1, entries 3 and 4). Moreover, epichlorohydrin (1e) reacts smoothly with HMDST (Table 1, entry 5). In this case the reaction must be run at –15 °C, at room temperature an exothermic reaction occurs leading to a complex mixture of products. The oxirane is again regioselectively opened at the less hindered carbon, and nucleophilic attack occurs exclusively on the epoxide, the halide being preserved on the side chain. Contrary to that reported by others,5 it is interesting to note that under the present conditions, ring-opening of Synlett 2005, No. 20, 3063–3066
Me
1a
© Thieme Stuttgart · New York
SH
2a O
95c
HO
Ph
Ph
1b
SH
2b
3
72d,e
HO
O i-PrO
i-PrOCH2
1c
SH
2c 4
87
HO
O AllO
AllOCH2
1d
SH
2d
5
O
40f
HO
Cl ClCH2
1e
SH
2e 6
CH2=CH
1f 7
80g
HO
O
SH
2f O
Me
Me
1g
HO
SH
Me
Me
55h
2g
8
90h
OH O SH
1h
2h
9
O
HO O
O O
1i
50
SH O
O
O
O
O
2i
a
Refers to isolated products whose spectroscopic data are consistent with the assigned structure. b By using 10% of TBAF 2-(trimethylsilyloxy)propane-1-thiol (3a) was isolated in 72% yield.16, c Yield of regioisomer isolated: 4.6%. d Yield of regioisomer recovered: 2.5%. e Silyl ether was obtained with TBAF (0.3 equiv) in 90% yield. f Silyl ether was obtained with TBAF (0.3 equiv) in 70% yield. g Yield of silyl ether recovered: 18%. h Racemic.
butadiene mono-oxide 1f leads to the clean formation of vinyl-substituted b-hydroxy thiol 2f, together with the corresponding silyl ether (Table 1, entry 6). No 1,4-adduct is observed, the mercaptoalcohol thus obtained arises from the regioselective attack of the nucleophile on the less substituted carbon of the epoxide. The D-mannitol epoxide was also reacted to afford 1,2mercaptoalcohol diacetonide 2i, together with unreacted starting oxirane (Table 1, entry 9).
LETTER
Access to 1,2-Mercaptoalcohols
This mild and selective procedure may be usefully applied also to chiral molecules. When enantiopure epoxides are reacted under the same conditions, optically active b-hydroxy thiols were regioselectively formed (Table 2). Besides glycidol derivatives (Table 2, entries 2 and 3), pyrrolidine-substituted b-hydroxy thiol 2n was of particular interest (Table 2, entry 4) as a useful reagent for the synthesis of 1,3-oxathiolane-derivatives, which have been recently demonstrated as important molecules in the pharmacological field.19 Table 2
Enantioselective Synthesis of 1,2-Mercaptoalcohols
Entry Epoxide
1,2-Mercaptoalcohol Yield (%)a [a]D20,b
1
HO
O Ph
Ph
R-(–)-1b O
84
–5
65
–9
86d
+25
SH HO
O MeOCH2
S-(+)-1l
SH
R-(–)-2l
3
O Bn
–5820
R-(–)-2b
2 Me
95c
HO
O
R-(+)-1m 4
O
N Cbz
1S,2S-(+)-1n
BnOCH2
SH
S-(–)-2m HO
N Cbz
SH
1S,2S-(+)-2n
a Refers to isolated products whose spectroscopic data are consistent with the assigned structure. b Optical rotation: c 1, THF. c Yield of regioisomer isolated: 4.6%. d Traces (3%) of silyl ether were evidenced.
In conclusion, we have devised a general and efficient ring-opening of oxiranes by HMDST, which behaves as an effective synthetic equivalent of H2S, leading directly to b-mercaptoalcohols, interesting starting materials of more complex molecules. The reactions occur with high regio- and stereoselectivity and are operationally simple with short reaction times. The mildness of this procedure should be useful in the synthesis of sensitive substrates, which preclude the use of strong reaction conditions.
Acknowledgment Financial support by the National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’ (MURST, Roma) is gratefully acknowledged. Ente Cassa di Risparmio di Firenze is acknowledged for granting a 400-MHz NMR spectrometer.
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References (1) Inter alia: (a) Lidy, W.; Sundermeyer, W. Tetrahedron Lett. 1973, 1449. (b) Mullis, J. C.; Weber, W. P. J. Org. Chem. 1982, 47, 2873. (c) Guddenheim, T. L. J. Am. Chem. Soc. 1982, 104, 5849. (d) Gassman, P. G.; Gremban, R. S. Tetrahedron Lett. 1984, 25, 3259. (e) Behrens, C. H.; Sharpless, K. B. J. Org. Chem. 1985, 50, 5696. (f) Yamashita, H. Bull. Chem. Soc. Jpn. 1988, 61, 1213. (g) Iqbal, J.; Pandey, A.; Shukla, A.; Srivastava, R. R.; Tripathi, S. Tetrahedron 1990, 46, 6423; and references cited therein. (h) Kesavan, V.; Bonnet-Delpon, D.; Bégué, J.-P. Tetrahedron Lett. 2000, 41, 2895; and references cited therein. (2) Inter alia: (a) Lalancette, J. M.; Frêche, A. Can. J. Chem. 1971, 49, 4047. (b) Vougioukas, A. E.; Kagan, H. B. Tetrahedron Lett. 1987, 28, 6065. (c) Nishikubo, T.; Iizawa, T.; Shimojo, M.; Kato, T.; Shiina, A. J. Org. Chem. 1990, 55, 2536. (d) Chini, M.; Crotti, P.; Giovani, E.; Macchia, F.; Pineschi, M. Synlett 1992, 303. (e) Albanese, D.; Landini, D.; Penso, M. Synthesis 1994, 34. (f) Chou, W.-C.; Chen, L.; Fang, J.-M.; Wong, C.-H. J. Am. Chem. Soc. 1994, 116, 6191. (g) Iida, T.; Yamamoto, Y.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1997, 119, 4783. (h) Wu, M. H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 5252. (i) Wu, J.; Hou, X.-L.; Dai, L.-X.; Xia, L.-J.; Tang, M.-H. Tetrahedron: Asymmetry 1998, 9, 3431. (j) Yadav, J. S.; Reddy, B. V.; Baishya, G. Chem. Lett. 2002, 906. (k) Friguelli, F.; Pizzo, F.; Tortoioli, S.; Vaccaro, L. Tetrahedron Lett. 2003, 44, 6785. (l) Movassagh, B.; Sobhani, S.; Kheirdoush, F.; Fadaei, Z. Synth. Commun. 2003, 33, 3103. (m) Heimgartner, H.; Fu, C.; Blagoev, M.; Linden, A. Phosphorus, Sulfur Silicon Relat. Elem. 2005, 180, 1309. (3) (a) Luly, J. R.; Yi, N.; Soderquist, J.; Stein, H.; Cohen, J.; Perun, T. J.; Plattner, J. J. J. Med. Chem. 1987, 30, 1609. (b) Meffre, P.; Vo Quang, L.; Vo Quang, Y.; Le Goffic, F. Tetrahedron Lett. 1990, 31, 2291. (c) Scholz, D.; Billich, A.; Charpiot, B.; Ettmayer, P.; Lehr, P.; Roaenwirth, B.; Schreiner, E.; Gstach, H. J. Med. Chem. 1994, 37, 3079. (d) Paulvannan, K.; Chen, T. Synlett 1999, 1371. (e) Mühlman, A.; Classon, B.; Hallberg, A.; Samuelsson, B. J. Med. Chem. 2001, 44, 3402. (4) (a) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammarstrom, S. J. Am. Chem. Soc. 1980, 102, 1436. (b) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.; Mioskowski, C.; Samuelsson, B.; Hammarstrom, S. J. Am. Chem. Soc. 1980, 102, 3663. (c) Rokach, J.; Girard, Y.; Guindon, Y.; Atkinson, J. G.; Larue, M.; Young, R. N.; Masson, P.; Holme, G. Tetrahedron Lett. 1980, 21, 1485. (5) Guindon, Y.; Young, R. N.; Frenette, R. Synth. Commun. 1981, 11, 391. (6) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560. (7) Guivisdalsky, P. N.; Bittman, R. J. Am. Chem. Soc. 1989, 111, 3077. (8) Hashiyama, T.; Inoue, H.; Takeda, M.; Aoe, K.; Kotera, K.; Konda, M. J. Chem. Soc., Perkin Trans. 1 1985, 421. (9) Posner, G. H.; Rogers, D. Z. J. Am. Chem. Soc. 1977, 79, 8208. (10) (a) Iizawa, T.; Goto, A.; Nishikubo, T. Bull. Chem. Soc. Jpn. 1989, 62, 597. (b) Tanabe, Y.; Mori, K.; Yoshida, Y. J. Chem. Soc., Perkin Trans. 1 1997, 671. (c) Pirrung, M. C.; Tumey, L. N.; Raetz, C. R.; Jackman, J. E.; Snahalatha, K.; McClerren, A. L.; Fierke, C. A.; Gantt, S. L.; Rusche, K. M. J. Med. Chem. 2002, 45, 4359. (11) Brittain, J.; Gareau, Y. Tetrahedron Lett. 1993, 34, 3363.
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(12) (a) Abel, E. W.; Walker, D. J. J. Chem. Soc. A 1968, 2338. (b) Trost, B. M.; Scanlan, T. S. Tetrahedron Lett. 1986, 27, 4141. (13) (a) Steger, B. N. U. S. Patent 4564710, 1986; Chem. Abstr. 1986, 105, 45235. (b) Morishiri, H.; Shimakawa, K.; Ryu, A.; Kawato, N.; Kobayashi, S. Jpn. Kokai Tokkyo Koho JP 2003155269, 2003; Chem. Abstr. 2004, 138, 385064. (14) Bordwell, F. G.; Anderson, H. M. J. Am. Chem. Soc. 1953, 75, 4959. (15) Justo de Pomar, J. C.; Soderquist, J. A. Tetrahedron Lett. 1998, 39, 4409. (16) Degl’Innocenti, A.; Capperucci, A.; Castagnoli, G.; Malesci, I. Synlett 2005, 1965. (17) Typical Procedure: A solution of 2-methyloxirane (1a, 100 mg, 1.72 mmol) and HMDST (470 mL, 2.24 mmol, 398 mg) in THF (0.1 mL) was treated at r.t. with TBAF (1 M in THF; 450 mL, 0.45 mmol) under an inert atmosphere. The mixture became bright green and after 5 min pale yellow. The reaction was carried out for 30 min and the progress of the reaction monitored by TLC. After addition of citric acid (50% aq solution; 0.5 mL) the mixture was stirred for 5 min, then diluted with Et2O. The organic phase was then washed with citric acid (20% aq solution), extracted with Et2O, and dried over Na2SO4. Evaporation of the solvent afforded 106
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LETTER mg of 1-mercaptopropan-2-ol (2a; 65%), which was pure enough to be used without further purification. 1H NMR (200 MHz, CDCl3): d = 1.25 (3 H, d, J = 6.0 Hz), 1.43 (1 H, app t, J = 8.7 Hz), 2.32 (1 H, br s), 2.44–2.56 (1 H, m), 2.60– 2.71 (1 H, m), 3.71–3.84 (1 H, m). 13C NMR (50 MHz, CDCl3): d = 21.7, 33.2, 68.4. MS: m/z (%) = 92 (0.08), 91 (0.25), 75 (11), 45 (100). Following the above procedure, oxirane 1a and HMDST were treated with a solution of TBAF (225 mL, 0.22 mmol)to give cleanly 2-(trimethylsilyloxy)propane-1-thiol (3a; 203 mg, 72% yield). 1H NMR (200 MHz, CDCl3): d = 0.14 (9 H, s), 1.22 (3 H, d, J = 6.0 Hz), 1.46 (1 H, dd, J = 9.0 Hz, J = 8.8 Hz), 2.43–2.59 (2 H, m), 3.84 (1 H, app sextet). 13C NMR (50 MHz, CDCl3): d = 0.2, 22.5, 33.3, 70.0. MS: m/z (%) = 164 (0.6), 149 (10), 117 (66), 91 (15), 75 (53), 73 (100). (18) (a) Hanson, R. M. Chem. Rev. 1991, 91, 437. (b) Kim, M.J.; Choi, Y. K. J. Org. Chem. 1992, 57, 1605. (19) Dei, S.; Bellucci, C.; Buccioni, M.; Ferraroni, M.; Gualtieri, F.; Guandalini, L.; Manetti, D.; Matucci, R.; Romanelli, M. N.; Scapecchi, S.; Teodori, E. Bioorg. Med. Chem. 2003, 11, 3153. (20) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. J. Org. Chem. 1997, 62, 4376.
