A new method for the synthesis of normal and medium ring silylated unsaturated thiolactones

Article abstract of DOI:10.1055/s-1999-6182

Enolizable ω-carboxy acylsilanes are converted via (Z)ω-carboxy-α- silyl enethiols into unsaturated silylated thiolactones having a ring size in the range from five to ten.

Full text of DOI:10.1055/s-1999-6182

486
LETTER
A New Method for the Synthesis of Normal and Medium Ring Silylated
Unsaturated Thiolactones
Bianca F. Bonini,* Mauro Comes-Franchini, Mariafrancesca Fochi, Germana Mazzanti, Alfredo Ricci
Dipartimento di Chimica Organica “A.Mangini”, Università di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
Fax +39 (0) 51 6443654; E-mail: bonini@ms.fci.unibo.it
Received 15 December 1998
In the past we developed10b,11 a generally applicable meth-
od for the synthesis of acylsilanes, based on the nucleo-
philic silylation of an acid chloride with
bis(dimethylphenylsilyl)lithium cyano cuprate12 at -78°C.
Following this procedure, starting from commercially
available acyl dichlorides and one equivalent of bis(dime-
thylphenylsilyl)lithium cyano cuprate, we prepared ω-
carboxy acylsilanes 113 in moderate yields (Table), due to
the competitive formation of the bis(acyl)silanes 4, ob-
tained in yields ranging from 10% to 13%.
Abstract: Enolizable w-carboxy acylsilanes are converted via (Z)-
w-carboxy-a-silyl enethiols into unsaturated silylated thiolactones
having a ring size in the range from five to ten.
Key words:
enethiols, thiolactones, polyphosphate esters
w-carboxy acylsilanes,
(Z)-w-carboxy-a-silyl
Thiolactones present a particular interest due to the bio-
logical activity associated with a number of derivatives
such as thiolactomycin,1 thiotetromycin,1 thiocoumarins2
and a2-macroglobulin.3 Moreover, the resolution of the
crucial problem concerning the alkylation of b-4 and g-thi-
olactones,5 has considerably increased their utility in syn-
thesis. Despite the importance of this class of compounds,
relatively little attention has been given to their prepara-
tion. A general approach to g- and d-thiolactones has been
developed starting from bismetallated derivatives of thio-
O
O
O
SMe
SiMe2Ph
( )n
PhMe2Si
SiMe2Ph
MeO
4
5
acids and carbonyl compounds.6 The thioaldeyde Diels- We have already reported that acylsilanes, containing a
Alder approach provides an access to unsaturated δ- hydrogen atom a to the carbonyl group, can be trans-
thiolactones7 and the reaction of S-(4-alkenyl)-dithiocar- formed stereoselectively into (Z)-a-silyl enethiols14 by
bonates with tri-n-butyltin hydride affords g-thiolac- thionation at low temperature with hydrogen sulfide and
tones.8 More recently, it has been reported9 that w-halo hydrogen chloride followed by neutralization of the ether-
acid chlorides give a sulfur transfer reaction, mediated by eal solution with solid sodium hydrogencarbonate. With
benzyltriethylammonium tetrathiomolybdate, leading to this procedure15 compounds 1 were transformed into (Z)-
saturated thiolactones. However, this method does not w-carboxy-a-silyl enethiols 2 in very good yields (Table).
give satisfactory yields especially in the case of macrocy- The (Z)-stereochemistry has been assigned to enethiols 2
cles (ring size ≥ 12) and the synthesis of mesocycles (ring by n.O.e. experiments performed on methyl 5-[dimeth-
size in the range 8 to 11) has not been reported.
yl(phenyl)silyl]-5-(methylsulfanyl)-4-pentenoate 5,16 ob-
tained from 2b by reaction with MeI and K2CO3 in
acetone.
In connection with our ongoing interest in the chemistry
of enolizable thioacylsilanes as a source of sulfur hetero-
cycles,10 we pursued a new method for the preparation of The cyclization can be performed by using polyphosphate
unsaturated silylated thiolactones 3, starting from acyl ester (PPE) as a condensation reagent, very easily pre-
dichlorides via acylsilanes 1 and (Z)-w-carboxy-a-silyl pared from phosphorus pentoxide and ether.17 The con-
enethiols 2 (Scheme 1).
densation, carried out18 both at room temperature and at
40°C, gave the better yields in thiolactones 3 under the lat-
ter condition (Table) probably due to the shorter time re-
quired for the reaction.
O
O
O
O
ii
i
( )n
Cl
Cl
( )n
1a-e
HO
SiMe2Ph
O
The best yields were obtained in the synthesis of d- and e-
thiolactones (Table, entries 2 and 3). Starting from 3-me-
thyl glutaryl chloride also the methyl substituted thiolac-
tone 6 could be obtained, working at 40°C, in 85% yield.20
a n = 2
b n = 3
c n = 4
d n = 5
e n = 7
O
iii
SiMe2Ph
()n-1
S
( )n-1
HO
SH
SiMe2Ph
2b-e
3b-e
Scheme 1 i) (PhMe2Si)2CuCNLi2, THF, -78°C, 1h; ii) H2S/HCl,
Et2O, -20°C, then solid NaHCO3, r.t.; iii) PPE, CHCl3, r.t. or 40°C.
Synlett 1999, No. 4, 486–488 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Method for the Synthesis of Normal and Medium Ring Silylated Unsaturated Thiolactones
487
O
S
8
The sequence of the events and a mechanistic explanation
for the formation of 8 are still under investigation.
In conclusion, this protocol can be successfully applied
not only to the synthesis of unsaturated silylated thiolac-
tones having a ring size of six and seven, but also to the
synthesis of medium ring thiolactones with a ring sizes in
the range 8 to 11 and to the synthesis of thiolactones bear-
ing a substituent. Further optimization of the reaction con-
ditions for the synthesis of acylsilanes 1 and the extension
of this strategy towards the synthesis of macrocycles are
currently under way.
O
S
Me
SiMe2Ph
6
It is known that medium ring compounds are much more
difficult to synthesize by cyclization methods than other
cyclic compounds including macrocycles.21 Also in our
case the cyclization to eight-and ten-membered rings (Ta-
ble, entries 4 and 5, respectively), gave to some extent
lower yields under the conditions employed.22 The reac-
tion leading to the 8-membered ring, performed at room
temperature, gave the competitive formation of a dimeric
product, to whom structure 7 has been assigned on the ba-
sis of its spectral data.23 The formation of a dimeric prod-
uct is in agreement with other results obtained during the
synthesis of 2-silyl-thiacyclooct-2-ene10c and of medium
rings in general,24 and can be rationalized through a
dimerization of 2d followed by an intramolecular cycliza-
tion to a sixteen-membered ring 7 (Scheme 2).
Acknowledgement
Financial support of this work by the Ministero dell’Università e
della Ricerca Scientifica e Tecnologica (MURST ex 60%), Italy, is
gratefully acknowledged.
References and Notes
(1) Wang, C.L.J.; Salvino, J.M. Tetrahedron Lett. 1984, 25, 5243.
(2) Panetta, J.A.; Rapoport, H. J. Org. Chem. 1982, 47, 2626.
(3) (a) Khan, S.A.; Erickson, B.W. J. Am. Chem. Soc. 1984, 106,
798. (b) Araujo, H.C.; Mahajan, J.R. Synthesis 1978, 228.
(4) (a) Carter, S.D.; Stoodley, R.J. J. Chem. Soc., Chem. Com-
mun. 1977, 92. (b) Carter, S.D.; Kaura, A.C.; Stoodley, R.J. J.
Chem. Soc., Perkin Trans. 1 1980, 388. (c) Al-Zaidi, S.M.R.;
Crilley, M.M.L.; Stoodley, R.J. J. Chem. Soc., Perkin Trans.
1 1983, 2259.
(5) Lucast, D.H.; Wemple, J. Synthesis 1976, 724.
(6) Sarpeshkar, A.M.; Gossick, G.J.; Wemple, J. Tetrahedron
Lett. 1979, 703.
(7) Vedejs, E.; Stults, J.S. J. Org. Chem. 1988, 53, 2226.
(8) Crich, D. Tetrahedron Lett. 1988, 29, 5805.
(9) Bhar, D.; Chandrasekaran, S. Tetrahedron 1997, 53, 11835.
(10) (a) Bonini, B.F.; Comes-Franchini, M.; Mazzanti, G.; Ricci,
A.; Rosa-Fauzza, L.; Zani, P. Tetrahedron Lett. 1994, 35,
9227. (b) Bonini, B.F.; Comes-Franchini, M.; Fochi, M.; Maz-
zanti, G.; Ricci, A. Tetrahedron 1996, 52, 4803. (c) Bonini,
B.F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci,
A. Tetrahedron 1997, 53, 7897.
O
O
PhMe2Si
HS
PhMe2Si
( )4
S
( )4
S
2d
HO
( )
S
( )
4
SiMe2Ph
4
SiMe2Ph
O
O
7
Scheme 2
The synthesis of the 5-membered ring thiolactone 3a
proved to be difficult. In fact the w-carboxy acylsilane 1a,
deriving from succinyl dichoride was obtained in very
poor yield (Table, entry 1), besides a large amount of suc-
cinic acid and some degradation products. Moreover, the
thionation did not afford the expected enethiol 2a but the
thiolactone 825 arising probably from a direct cyclization
of 2a, followed by desilylation and migration of the dou-
ble bond in the a,b-position.
(11) Bonini, B.F.; Busi, F.; de Laet, R.C.; Mazzanti, G.; Thuring,
J.W.J.F.; Zani, P.; Zwanenburg, B. J. Chem. Soc., Perkin
Trans. 1 1993, 1011.
(12) Fleming, I.; Newton, T.W.; Roessler, F. J. Chem. Soc., Perkin
Trans. 1 1981, 2527.
(13) General procedure for the preparation of 1: bis(dimethyl phe-
nylsilyl)copper-cyano cuprate (5.0 mmol) was added slowly
at -78 °C under argon to a solution of acyl dichloride (5.0
mmol) in anhydrous THF (5 mL) via cannula. The mixture
was stirred at -78 °C for 1 h, then was allowed to warm to 0 °C
and was stirred for 1 h at 0 °C. The mixture was quenched with
saturated aqueous ammonium chloride and extracted with
diethyl ether. The organic layer was dried and concentrated
under reduced pressure. Column chromatography on silica gel
(light petroleum-diethyl ether 5:1 and 1:1 as eluent) gave, as
the higher Rf fraction, a product arising from the silylcuprate,
Synlett 1999, No. 4, 486–488 ISSN 0936-5214 © Thieme Stuttgart · New York

488
B. F. Bonini et al.
LETTER
as the second Rf fraction bis(acyl)silane 4 as a yellow oil and
as the lower Rf fraction the ω-carboxy acylsilane 1 as a yellow
oil.
CH2), 5.92 (1H, m, vinylic H), 7.3-7.65 (5H, m, ArH), 9.0
(1H, bs, OH); 13C-NMR (50.28 MHz, CDCl3) d, ppm: -3.36
(SiMe2), 25.41, 32.69 (CH2), 127.90, 129.49, 134.06, 136.93
(3ArCH + vinylic CH), 133.2, 137.2 (ArC + vinylic C),
179.07 (COOH); MS (m/z): 266 (M+), 248 (M+-H2O), 233
(248-CH3), 135 (SiMe2Ph).
(14) (a) Bonini, B.F.; Comes-Franchini, M.; Fochi, M.; Mazzanti,
G.; Peri, F.; Ricci, A. J. Chem. Soc., Perkin Trans. 1 1996,
2803. (b) Bonini, B.F.; Comes-Franchini, M.; Fochi, M.; Maz-
zanti, G.; Ricci, A. J. Chem. Soc., Perkin Trans. 1 1997, 3211.
(15) General procedure for the preparation of 2: hydrogen chlori-
de and hydrogen sulfide were bubbled into a solution of the w-
carboxy acylsilane 1 (1.0 mmol) in anhydrous diethyl ether
(50 mL) at -20 °C, until the starting acylsilane had disappeared
(TLC with 1:1 light petroleum-diethyl ether as eluent). The
mixture was allowed to warm to room temperature and solid
sodium hydrogen carbonate was added to the solution until the
evolution of carbon dioxide ceased (10 g), then the reaction
was left overnight. The crude, filtered and concentrated under
reduced pressure, gave the (Z)-w-carboxy-a-silyl enethiol 2 in
a pure form.
(16) 5: To a solution of 2b (1 mmol) in acetone (5 mL), solid oven-
dried K2CO3 (1.5 mmol) and the methyl iodide (2.5 mmol)
were added. The mixture was stirred at room temperature for
3h then quenched with water and extracted with diethyl ether.
The organic layer was dried and concentrated. Column chro-
matography on silica gel (light petroleum-ethyl acetate 15:1 as
eluent) gave the title product in 65% yield as an oil. I.R. (CCl4)
3b: I.R. (CCl4) nmax, cm-1: 1680 (COS), 1430 (SiPh), 1250
(SiMe2), 1130 (SiPh); 1H-NMR (200 MHz, CDCl3) d, ppm:
0.48 (6H, s, SiMe2), 2.55 (4H, m, 2CH2), 6.38 (1H, m, vinylic
H), 7.35-7.45 (3H, m, ArH), 7.50-7.65 (2H, m, ArH); 13C-
NMR (50.28 MHz, CDCl3) d, ppm: -3.37 (SiMe2), 25.53,
38.02 (CH2), 127.94, 129.69, 132.75, 133.95 (3ArCH + vinyl-
ic CH), 134.88, 135.48 (ArC + vinylic C), 200.33 (COS); MS
(m/z): 248 (M+) 233 (M+- CH3), 215 (M+- SH), 191 (M+-
C3H5O), 171 (M+-C6H5), 135(SiMe2Ph).
3d: I.R. (CCl4) nmax, cm-1: 1675 (COS), 1430 (SiPh), 1250
(SiMe2) 1110 (SiPh); 1H-NMR (300 MHz, CDCl3) d, ppm:
0.44 (6H, s, SiMe2), 1.65 (4H, m, 2CH2), 2.25 (2H, m, CH2),
2.48 (2H, t, CH2), 6.57 (1H, t, J 7.2 Hz, vinylic H), 7.30-7.40
(3H, m, ArH), 7.50-7.65 (2H, m, ArH); 13C-NMR (75.4 MHz,
CDCl3) d, ppm: -3.79 (SiMe2), 24.53, 24.88, 29.74, 38.97
(CH2), 127.91, 129.55, 134.00 (ArCH), 150.96 (vinylic CH),
132.83, 135.73 (ArC + vinylic C), 205.48 (COS); MS (m/z):
276 (M+) 261 (M+- CH3), 247 (M+- COH), 135 (SiMe2Ph).
4b: I.R. (CCl4) nmax, cm-1: 1640 (COSiMe2Ph), 1430 (SiPh),
1240 (SiMe2), 1110 (SiPh); 1H-NMR (300 MHz, CDCl3) d,
ppm: 0.5 (6H, s, SiMe2), 1.65 (2H, m, CH2), 2.5 (4H, t, J 7.1
Hz, 2CH2), 7.3-7.6 (5H, m, ArH); 13C-NMR (75.4 MHz,
CDCl3) d, ppm: -4.17 (SiMe2), 15.44 (CH2), 48.34
n
max, cm-1: 1740 (COOMe), 1430 (SiPh), 1260 (SiMe2), 1110
(SiPh); 1H-NMR (200 MHz, CDCl3) d, ppm: 0.42 (6H, s,
SiMe2), 2.0 (3H, s, SMe), 2.45 (2H, t, J 7.5 Hz, CH2), 2.7 (2H,
m, CH2), 3.68 (3H, s, OCH3), 6.15 (1H, t, J 6.0 Hz, vinylic
CH), 7.30-7.60 (5H, m, ArH); 13C-NMR (50.28 MHz, CDCl3)
d, ppm: -2.12 (SiMe2), 17.61 (SCH3), 25.89, 33.20 (CH2),
51.43 (OCH3), 127.77, 129.14, 133.90 (ArCH), 145.19 (viny-
lic CH), 133.02, 138.1 (ArC + vinylic C), 173.29 (COOCH3);
MS (m/z): 294 (M+), 247 (M+-SCH3), 135 (SiMe2Ph). Irradia-
tion of the dimethylsilyl signal at 0.62 ppm produced a signi-
ficant increase (15%) of the intensity of the signal of the
vinylic proton at 6.18 ppm.
(CH2COSiMe2Ph), 128.81, 130.53, 134.60 (ArCH), 129.48
(ArC), 245.71 (COSiMe2Ph); MS (m/z): 368 (M+), 233 (M+-
SiMe2Ph), 163 (COSiMe2Ph), 135 (SiMe2Ph).
(20) 6: oil; I.R. (CCl4) nmax, cm-1: 1690 (COS), 1430 (SiPh), 1250
(SiMe2), 1130 (SiPh); 1H-NMR (300 MHz, CDCl3) d, ppm:
0.48 (6H, s, SiMe2), 1.15 (3H, d, J 7.1 Hz, CH3), 2.35 (1H, dd,
J1 15.18, J2 11.25 Hz, Ha-CH2), 2.61 (1H, dd, J1 15.48, J2 4.27
Hz, Hb-CH2), 2.75 (1H, m, CH), 6.22 (1H, d, J 3.7 Hz, vinylic
H), 7.35-7.45 (3H, m, ArH), 7.50-7.65 (2H, m, ArH); 13C-
NMR (75.4 MHz, CDCl3) d, ppm: -1.98 (SiMe2), 19.52 (CH3),
31.96 (CH), 45.75 (CH2), 127.93, 129.75, 132.05 (ArCH),
123.61, 135.83 (ArC + vinylic C), 139.53 (vinylic CH),
200.03 (COS); MS (m/z): 262 (M+) 247 (M+- CH3), 215 (M+-
SH), 205 (M+- C3H5O), 185 (M+-C6H5), 135(SiMe2Ph).
(21) Rousseau, G. Tetrahedron 1995, 51, 2777.
(17) Pollmann W.; Schramm, G. Biochem. Biophys. Acta 1964, 80,
1.
(18) General procedure for the preparation of 3: a mixture of (Z)-
w-carboxy-a-silyl enethiol 3 (0.5 mmol) and PPE (1 mL) in
CHCl3 (8 mL) was stirred at room temperature for 12h or at
40°C for 2h. The reaction mixture was treated with saturated
aqueous ammonium chloride and extracted with chloroform.
The organic layer was dried with sodium sulfate and concen-
trated under reduced pressure. Column chromatography on si-
lica gel (light petroleum-ethyl acetate 10:1 as eluent) gave the
title product as a yellow oil.
(22) In the attempt of improving the yields of mesocycles, we per-
formed the cyclization in high dilution conditions, by adding
slowly products 2d and 2e to a solution of the polyphosphate
ester in CHCl3, but the reactions failed and we isolated only
undesired products among which were the ethyl esters of 2d
and 2e.
(19) All new compounds gave spectroscopic data in agreement
with the assigned structures. Selected data for 1, 2, 3, 4:
1b: I.R. (CCl4) nmax, cm-1: 3520 (OH), 1710 (COOH), 1645
(COSiMe2Ph), 1430 (SiPh), 1260 (SiMe2), 1110 (SiPh); 1H-
NMR (300 MHz, CDCl3) d, ppm: 0.50 (6H, s, SiMe2), 1.5 (2H,
m, CH2), 2.2 (2H, t, J 7.3 Hz, CH2), 2.6 (2H, t, J 7.3 Hz, CH2),
7.4-7.8 (5H, m, ArH); 13C-NMR (50.28 MHz, CDCl3) d, ppm:
-4.33 (SiMe2), 17.67 (CH2), 33.52 (CH2COOH), 47.81
(CH2COSiMe2Ph), 128.56, 130.52, 134.65 (ArCH), 129.86
(ArC), 179.71 (COOH), 245.62 (COSiMe2Ph); MS (m/z): 250
(M+), 233 (M+-H2O), 205 (M+-COOH), 163 (COSiMe2Ph),
135 (SiMe2Ph), 115 (M+-SiMe2Ph).
(23) 7: p.f. = 133-134°C (from methanol); I.R.(CCl4) nmax, cm-1:
1700 (COS), 1430 (SiPh), 1250 (SiMe2) 1110 (SiPh); 1H-
NMR (300 MHz, CDCl3) d, ppm: 0.34 (6H, s, SiMe2), 1.35
(2H, m, CH2), 1.62 (2H, m, CH2), 2.18 (2H, m, CH2), 2.50
(2H, t, J 7.0 Hz, CH2), 6.52 (1H, t, J 7.26 Hz, vinylic H), 7.30-
7.40 (3H, m, ArH), 7.50-7.65 (2H, m, ArH); 13C-NMR (75.4
MHz, CDCl3) d, ppm: -3.03 (SiMe2), 24.57, 27.36, 30.72,
42.97 (CH2), 127.68, 129.17, 134.14 (ArCH), 155.49 (vinylic
CH), 134.05, 137.23 (ArC + vinylic C), 197.23 (COS); MS
(m/z): 552 (M+) 537 (M+- CH3), 135 (SiMe2Ph).
2b: I.R. (CCl4) nmax, cm-1: 3540 (OH), 1720 (COOH), 1430
(SiPh), 1260 (SiMe2), 1110 (SiPh); 1H-NMR (200 MHz,
CDCl3) d, ppm: 0.42 (6H, s, SiMe2), 2.52 (5H, m, SH + 2
(24) Casadei, M. A.; Galli, G.; Mandolini, L. J. Org. Chem. 1981,
46, 3127.
(25) Dowd, P.; Weber, W. J. Org. Chem. 1982, 47, 4777.
Synlett 1999, No. 4, 486–488 ISSN 0936-5214 © Thieme Stuttgart · New York