Regiospecific synthesis of cepanolide, a cancer chemoprotective micronutrient found in green onions

Article abstract of DOI:10.1016/j.tetlet.2012.04.007

The naturally occurring γ-hydroxy-β-sulfanylbutenolide cepanolide and a range of new analogues were synthesized in concise, regiospecific manner through the combined use of 2-silyloxyfuran oxyfunctionalization and tandem thio-Michael addition/elimination.

Full text of DOI:10.1016/j.tetlet.2012.04.007

Tetrahedron Letters 53 (2012) 3027–3029
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regiospecific synthesis of cepanolide, a cancer chemoprotective
micronutrient found in green onions
⇑
John Boukouvalas , Vincent Albert
Département de Chimie, Pavillon Alexandre-Vachon, Université Laval, 1045 Avenue de la Médecine, Quebec City, Quebec, Canada G1V 0A6
a r t i c l e i n f o
a b s t r a c t
Article history:
The naturally occurring c-hydroxy-b-sulfanylbutenolide cepanolide and a range of new analogues were
synthesized in concise, regiospecific manner through the combined use of 2-silyloxyfuran oxyfunctional-
ization and tandem thio-Michael addition/elimination.
Received 22 March 2012
Accepted 2 April 2012
Available online 9 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dimethyldioxirane
Butenolide
Furan
Organosulfur compound
Thio-Michael addition
Compelling evidence from epidemiologic studies indicates that
individuals who consume copious amounts of Allium vegetables
(e.g., onions and garlic) reduce their susceptibility to cancer at a
variety of organ sites.1 The protective effects of Alliums have been
largely attributed to their content of organosulfur compounds
(OSCs), as exemplified by diallyl sulfide (DAS) and diallyl disulfide
(DADS, Fig. 1).2 Indeed, both DAS and DADS have been shown to
confer protection against chemical-induced carcinogenesis in ani-
mal models.3 A major mechanism by which OSCs are believed to
inhibit carcinogenesis involves upregulation of phase II detoxifying
enzymes, such as quinone reductase (QR) and glutathione S-trans-
ferase (GST).4 Thus, phase II enzyme induction has emerged as a
promising strategy for cancer chemoprevention.5
of doubling GST activity at higher concentrations.6 The combina-
tion of potentially useful biological properties, low natural abun-
dance (0.0006% of dry onion weight) and unusual structure,
renders 1 an attractive target for synthesis. Additionally, the favor-
able physicochemical properties of 1 (MW 188, CLogP 0.80) make it
an excellent starting point for structural optimization through ana-
logue synthesis.7
Recently, the groups of Paul and Ordónez synthesized 1 along
with its isomer 2 by two related pathways (5–6 steps) that ulti-
mately involve borohydride reduction of anhydride 3 (Scheme 1).8
Notwithstanding the modest regioselectivity of this reaction, the
identity of the major isomer (1) was unambiguously established
In 2007, Xiao and Parkin reported the discovery of a new QR-
inducer from Allium cepa (green onion) that we now name cepan-
olide (1, Fig. 1).6 In murine hepatoma cells, cepanolide increased
O
O
S
QR activity up to 6-fold (CD = 15.6
l
g/mL) and was also capable
O
O
R
O
O
3
S
OH
S
R = H or Me
DAS
0 °C
O
NaBH
S
O
4
S
S
O
OH
S
cepanolide (1)
DADS
O
O
+
Figure 1. Structures of Allium OSCs.
(70 : 30)
O
OH
1
2
⇑
Corresponding author. Tel.: +1 418 656 5473; fax: +1 418 656 7916.
E-mail address: john.boukouvalas@chm.ulaval.ca (J. Boukouvalas).
Scheme 1. Previous synthesis of cepanolide.8
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.007

3028
J. Boukouvalas, V. Albert / Tetrahedron Letters 53 (2012) 3027–3029
Table 1
-
RS
X
Synthesis of cepanolide analogues
OH
OH
O
RS
X
OH
OH
O
O
Br
RS
RSH, Et N
3
O
-
CH Cl , rt
O
B
O
2
2
12-16 h
O
O
7
8-14
-
X
-
Entry
1
Product
Yielda (%)
OH
O
OH
X
RS
S
O
O
O
92
C
A
O
O
8
Scheme 2. Our synthetic strategy.
OH
S
O
2
3
84
82
Br
O
9
Br
Br
TIPSOTf
Et3N
AgOCOCF3
Br
O
O
OH
CF3CH2OH,
90%
Δ
S
6
CO2H
4
5
O
OTIPS
O
89%
O
10
O O
OH
O
94%
S
+
H O
then
3
4
5
89
83
11
O
OH
O
OH
O
S
Br
n-PrSH, Et3N
CH2Cl2
OH
S
1
O
7
O
87%
O
Scheme 3. Regiospecific synthesis of cepanolide (1).
12
O
OH
S
by X-ray analysis,8 thereby also confirming the originally proposed
structure of cepanolide.
We now describe a distinctly different synthetic approach that
is inherently regiospecific and amenable to analogue production.
As outlined in Scheme 2, cepanolide and its analogues (cf. A) would
derive from unprotected hydroxybutenolide B by means of tandem
O
6
7
91
84
MeO
Cl
O
13
OH
S
O
thio-Michael addition/elimination. Although related reactions of c-
alkoxy-b-halobutenolides have been described in the literature,9
little is known on the behavior of the corresponding hydroxybute-
nolides toward thiolates.10 Nonetheless, we felt that the compara-
tively high acidity of alkyl thiols (pKa 10–11) should alleviate the
need of protecting the hydroxyl group of B, which would in turn
derive from C by the application of our oxyfunctionalization
method.11,12
O
14
a
Isolated yield after column chromatography.
n-PrSH/Et3N in dichoromethane at room temperature. In this man-
ner, analytically pure cepanolide (1) was obtained in 87% yield
after flash chromatography (Scheme 3).18 Prompted by the effi-
ciency of this process, its scope and preparative value were further
investigated by the synthesis of a small library of unnatural cepan-
olide analogues (Table 1).19 Remarkably, yields were excellent
across the whole range of alkyl, allyl, benzyl and aryl thiols tried,
including the highly hindered t-BuSH (entry 2).
In conclusion, a regiospecific synthesis of the naturally occur-
ring phase II enzyme inducer cepanolide has been achieved in four
steps and 66% overall yield from commercially available 2,2-dibro-
mo-1-methylcyclopropanecarboxylic acid. The inherent flexibility
The synthesis began from commercially available or easily pre-
pared13 2,2-dibromo-1-methylcyclopropanecarboxylic acid (4,
Scheme 3). Acid 4 was converted to bromobutenolide 5 with high
efficiency using the operationally simple procedure of Sydnes.14,15
Silylation of 5 with TIPSOTf/Et3N in dichloromethane (1 h, 0 °C)
afforded 2-silyloxyfuran 6 in an unoptimized yield of 89% after
flash chromatography.16 Sequential treatment of 6 with an acetone
solution of dimethyldioxirane and a few drops of water/Amberlyst
15,11 provided the desired hydroxybutenolide 7 in excellent
yield.17 This highly crystalline building block could be stored at
room temperature for several months without any signs of
decomposition.
of this route along with a new protocol for constructing c-hydro-
xy-b-sulfanylbutenolides were further demonstrated by the expe-
dient preparation of a range of unnatural cepanolide analogues.
With unfettered synthetic access to such densely functionalized
OSCs, the stage is now set for more thorough biological evaluation
in vitro and in vivo.
With easy access to 7, the displacement of bromide ion by thio-
late was briefly examined. Among the conditions tried, the sim-
plest and most effective consisted in the use of a slight excess of

J. Boukouvalas, V. Albert / Tetrahedron Letters 53 (2012) 3027–3029
3029
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9808; (g) Boukouvalas, J.; Côté, S.; Ndzi, B. Tetrahedron Lett. 2007, 48, 105–107;
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Acknowledgments
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada (NSERC), the Department of Education of Québec
(FQRNT program), and the FQRNT Centre in Green Chemistry and
Catalysis (CGCC) for financial support. We also thank the
Georges-Élie-Amyot Foundation of Laval University for a graduate
scholarship to V.A.
16. The silica gel was pretreated with Et3N/hexanes before use. Data for
silyloxyfuran 6: colorless oil, Rf 0.62 (hexanes); IR (NaCl, film): 2946, 2869,
1647, 1531, 1464, 1412, 1374, 1265, 1091, 1027, 927, 883, 848, 681 cmÀ1 1H
;
NMR (400 MHz, CDCl3) d 6.84 (s, 1H), 1.82 (s, 3H), 1.28–1.19 (m, 3H), 1.08 (d,
References and notes
J = 7.2 Hz, 18H); 13C NMR (100 MHz, CDCl3) d 152.6, 128.8, 104.7, 93.4, 17.7,
12.5, 7.6; HRMS (ESI): Calcd for
332.0807.
17. Data for hydroxybutenolide 7: white solid (mp 90–92 °C), Rf 0.37 (40% EtOAc/
C14H25O2BrSi (m/z): 332.0831, Found:
1. (a) Galeone, C.; Pelucchi, C.; Levi, F.; Negri, E.; Franceschi, S.; Talamini, R.;
Giacosa, A.; La Vecchia, C. Am. J. Clin. Nutr. 2006, 84, 1027–1032; (b) Grant, W. B.
Eur. Urol. 2004, 45, 271–279; (c) Izzo, A. A.; Capasso, R.; Capasso, F. Br. J. Cancer
2004, 91, 194; (d) Zhou, Y.; Zhuang, W.; Hu, W.; Liu, G.-J.; Wu, T.-X.; Wu, X.-T.
Gastroenterology 2011, 141, 80–89.
hexanes); IR (NaCl, film): 3244, 2922, 1733, 1653, 1456, 1331, 1280, 1176,
1117, 1062, 950, 839, 750 cmÀ1 1H NMR (400 MHz, CDCl3) d 6.00 (s, 1H), 4.81
;
(br s, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3) d 169.9, 141.3, 132.2, 98.0,
10.4; HRMS (ESI): Calcd for C5H5O3Br (m/z): 191.9427, Found: 191.9422.
18. Synthesis of cepanolide (1): To a solution of hydroxybutenolide 7 (30.3 mg,
2. Scherer, C.; Jacob, C.; Dicato, M.; Diederich, M. Phytochem. Rev. 2009, 8, 349–
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1661–1665; (e) Iciek, M.; Marcinek, J.; Mleczko, U.; Włodek, L. Eur. J. Pharmacol.
2007, 569, 1–7.
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Castro, D. J.; Gonzalez, F. J.; Williams, D. E.; Huang, Y.; Kong, A.-N. T.; Doloff, J.
C.; Ma, J.; Waxman, D. J.; Scott, E. E. Drug Metab. Dispos. 2010, 38, 539–544.
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Hattotuwagama, C.; Churcher, I. Angew. Chem., Int. Ed. 2012, 51, 1114–1122.
8. Borikar, S. P.; Paul, V.; Puranik, V. G.; Sathe, V. T.; Lagunas-Rivera, S.; Ordónez,
M. Synthesis 2011, 1595–1598.
9. (a) Fariña, F.; Martín, M. V.; Sánchez, F.; Maestro, M. C.; Martín, M. R. Synthesis
1983, 397–398; (b) Martín, M. R.; Mateo, A. I. Tetrahedron: Asymmetry 1994, 5,
1385–1392; (c) Chen, Q.; Geng, Z.; Huang, B. Tetrahedron: Asymmetry 1995, 6,
401–404; (d) Wei, M.-X.; Feng, L.; Li, X.-Q.; Zhou, X.-Z.; Shao, Z.-H. Eur. J. Med.
Chem. 2009, 44, 3340–3344.
10. For the reaction of thiols with mucochloric acid, see: (a) Kurbangalieva, A. R.;
Devyatova, N. F.; Bogdanov, A. V.; Berdnikov, E. A.; Mannafov, T. G.; Krivolapov,
D. B.; Litvinov, I. A.; Chmutova, G. A. Phosphorus, Sulfur Silicon Relat. Elem. 2007,
182, 607–630; (b) Kurbangalieva, A. R.; Lodochnikova, O. A.; Devyatova, N. F.;
Berdnikov, E. A.; Gnezdilov, O. I.; Litvinov, I. A.; Chmutova, G. A. Tetrahedron
2010, 66, 9945–9953.
0.157 mmol) in dichloromethane (0.5 mL), 1-propanethiol (23
lL, 0.251 mmol,
1.6 equiv) and triethylamine (46 L, 0.330 mmol, 2.1 equiv) were successively
l
added at rt. After stirring for 15 h at rt, the volatiles were evaporated under
reduced pressure. Flash chromatography on silica gel (25% EtOAc in hexanes)
afforded 1 as a white solid (25.8 mg, 87% yield); mp 65–69 °C, Rf 0.30 (30%
EtOAc/hexanes); IR (NaCl, film): 3296, 2969, 2918, 1734, 1626, 1457, 1281,
1142, 1072, 961, 864, 750 cmÀ1 1H NMR (400 MHz, CDCl3) d 6.05 (s, 1H), 3.72
;
(br s, 1H), 3.08 (t, J = 8.0 Hz, 2H), 1.85 (s, 3H), 1.77–1.67 (m, 2H), 1.05 (t,
J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 170.7, 157.5, 123.2, 96.4, 32.6,
23.7, 13.4, 9.4; HRMS (ESI): Calcd for C8H12O3S (m/z): 188.0515, Found:
188.0507; Anal. Calcd for C8H12O3S: C, 51.04; H, 6.43; S, 17.03. Found: C, 50.91;
H, 6.60; S, 16.93.
19. Data for cepanolide analogues (8–14): Compound 8: mp 66–68 °C, IR (NaCl,
film): 3343, 2958, 2925, 2871, 1732, 1622, 1468, 1295, 1153, 1065, 957, 864,
751, 631 cmÀ1 1H NMR (400 MHz, CDCl3) d 6.07 (s, 1H), 3.11 (t, J = 8.0 Hz, 2H),
;
1.82 (s, 3H), 1.76–1.69 (m, 1H), 1.58–1.53 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d 171.2, 158.0, 122.8, 96.7, 39.0, 28.8, 27.6, 22.4, 9.4;
HRMS (ESI): Calcd for C10H16O3S (m/z): 216.0835, Found: 216.0820. Compound
9: mp 94–97 °C, IR (NaCl, film): 3271, 2994, 2967, 2926, 2865, 1758, 1732,
1628, 1459, 1368, 1345, 1295, 1162, 1124, 1061, 1044, 956, 848 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d 6.15 (s, 1H), 4.18 (br s, 1H), 1.94 (s, 3H), 1.49 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 171.2, 155.1, 133.6, 98.3, 49.9, 32.7, 10.5; HRMS (ESI):
Calcd for C9H14O3S (m/z): 202.0669, Found: 202.0664. Compound 10: mp 77–
79 °C, IR (NaCl, film): 3340, 3086, 2979, 2923, 2858, 1756, 1622, 1434, 1343,
1297, 1152, 1128, 1064, 1044, 958, 863, 751, 633 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d 6.12 (s, 1H), 5.94–5.85 (m, 1H), 5.34 (d, J = 16.8 Hz, 1H), 5.23 (d,
J = 10.0 Hz, 1H), 3.88 (dd, J = 14.4, 8.0 Hz, 1H), 3.63 (dd, J = 14.4, 5.8 Hz, 1H),
1.83 (s, 3H); 13C NMR (100 MHz, CDCl3) d 171.2, 157.2, 133.3, 123.7, 119.3,
96.6, 33.6, 9.4; HRMS (ESI): Calcd for C8H10O3S (m/z): 186.0332, Found:
186.0351. Compound 11: mp 110–113 °C, IR (NaCl, film): 3331, 2923, 2853,
1732, 1622, 1455, 1295, 1153, 1127, 1068, 958, 751, 706 cmÀ1 1H NMR
;
(400 MHz, CDCl3) d 7.39-7.28 (m, 5H), 5.98 (s, 1H), 4.34 (s, 2H), 1.81 (s, 3H); 13
C
11. Boukouvalas, J.; Lachance, N. Synlett 1998, 31–32.
NMR (100 MHz, CDCl3) d 170.6, 156.7, 136.1, 129.2, 129.0, 128.3, 123.7, 96.5,
35.1, 9.4; HRMS (ESI): Calcd for C12H12O3S (m/z): 236.0515, Found: 236.0507.
Compound 12: mp 96–99 °C, IR (NaCl, film): 3336, 2963, 2868, 1733, 1622,
12. For a variety of synthetic applications, see: (a) Boukouvalas, J.; Cheng, Y.-X.;
Robichaud, J. J. Org. Chem. 1998, 63, 228–229; (b) Boukouvalas, J.; Cheng, Y.-X.
Tetrahedron Lett. 1998, 39, 7025–7026; (c) Marcos, I. S.; Pedrero, A. B.; Sexmero,
M. J.; Diez, D.; García, N.; Escola, M. A.; Basabe, P.; Conde, A.; Moro, R. F.;
Urones, J. G. Synthesis 2005, 3301–3310; (d) Boukouvalas, J.; Wang, J.-X.;
Marion, O.; Ndzi, B. J. Org. Chem. 2006, 71, 6670–6673; (e) Boukouvalas, J.;
Robichaud, J.; Maltais, F. Synlett 2006, 2480–2482; (f) Boukouvalas, J.; Xiao, Y.;
Cheng, Y.-X.; Loach, R. P. Synlett 2007, 3198–3200; (g) Boukouvalas, J.; Loach, R.
P. J. Org. Chem. 2008, 73, 8109–8112; (h) Boukouvalas, J.; McCann, L. C.
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P.; Ouellet, E. Tetrahedron Lett. 2011, 52, 5047–5050.
1464, 1292, 1151, 1065, 960, 752 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.37 (d,
;
J = 8.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.02 (s, 1H), 4.93 (br s, 1H), 4.33 (s, 2H),
1.80 (s, 3H), 1.31 (s, 9H); 13C NMR (100 MHz, CDCl3) d 171.4, 157.8, 151.3,
133.0, 128.7, 126.1, 122.8, 96.8, 34.8, 34.7, 31.5, 9.4; HRMS (ESI): Calcd for
C
16H20O3S (m/z): 292.1152, Found: 292.1133. Compound 13: mp 66–68 °C, IR
(NaCl, film): 3364, 2925, 2853, 1732, 1626, 1592, 1495, 1291, 1251, 1175,
1152, 1029, 955, 831, 711, 640 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.51 (d,
J = 9.2 Hz, 2H), 6.91 (d, J = 9.2 Hz, 2H), 5.65 (s, 1H), 3.83 (s, 3H), 1.77 (s, 3H); 13
;
C
NMR (100 MHz, CDCl3) d 171.0, 161.3, 157.6, 137.3, 123.3, 117.6, 115.2, 96.4,
55.7, 9.3; HRMS (ESI): Calcd for C12H12O4S (m/z): 252.0475, Found: 252.0456.
Compound 14: mp 136–138 °C, IR (NaCl, film): 3378, 3098, 2924, 2863, 1742,
1627, 1479, 1430, 1333, 1289, 1153, 1133, 1091, 1060, 1039, 1010, 956,
13. Acid
4 can be prepared on a 20-gram scale from inexpensive methyl
methacrylate by dibromocarbene addition and ester hydrolysis: (a) Al-
Dulayymi, A.; Li, X.; Neuenschwander, M. Helv. Chim. Acta 2000, 83, 1633–
1644; see also (b) Baird, M. S.; Licence, P.; Tverezovsky, V. V.; Bolesov, I. G.;
Clegg, W. Tetrahedron 1999, 55, 2773–2784.
821 cmÀ1 1H NMR (400 MHz, CDCl3)
; d 7.52 (d, J = 8.8 Hz, 2H), 7.38 (d,
J = 8.8 Hz, 2H), 5.71 (s, 1H), 3.41 (br s, 1H), 1.83 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 170.5, 155.5, 136.7, 136.4, 130.0, 126.1, 125.5, 96.2, 9.6; HRMS (ESI):
Calcd for C11H9O3ClS (m/z): 255.9971, Found: 255.9961.
14. Svendsen, J. S.; Sydnes, L. K. Acta Chem. Scand. 1990, 44, 202–204.
15. For the use of 5 and related building blocks in the synthesis of substituted
butenolides, see: (a) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M.