A new synthesis of the Glyoxalase-I inhibitor COTC

Article abstract of DOI:10.1016/S0040-4039(00)00103-9

A stereoselective, chiral synthesis of the glyoxalase I inhibitor 2- crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone 1 (COTC) from a simple derivative of (-)-quinic acid is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00103-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2031–2034
A new synthesis of the glyoxalase-I inhibitor COTC
C. Frederick M. Huntley, Harold B. Wood † and Bruce Ganem ∗
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA
Received 4 December 1999; revised 12 January 2000; accepted 13 January 2000
Abstract
A stereoselective, chiral synthesis of the glyoxalase I inhibitor 2-crotonyloxymethyl-(4R,5R,6R)-4,5,6-
trihydroxycyclohex-2-enone 1 (COTC) from a simple derivative of (−)-quinic acid is described. © 2000 Elsevier
Science Ltd. All rights reserved.
The metabolic detoxification of reactive α-ketoaldehydes into benign α-hydroxyacids is achieved
by the glyoxalase I/II enzyme system in conjunction with reduced glutathione. Although the catalytic
mechanism of glyoxalase I (lactoylglutathione lyase, EC 4.4.1.5) has not been fully elucidated,1 it
has been suggested that inhibitors of this enzyme might serve as potential tumor-selective anticancer
agents.2,3 Of notable interest in that connection is the glyoxalase I inhibitor 2-crotonyloxymethyl-
(4R,5R,6R)-4,5,6-trihydroxycyclohex-2-enone 1 (COTC, shown below), which was first isolated from
the culture broth of Streptomyces griseosporeus by Umezawa and co-workers.4 Besides exhibiting
selective cytotoxic activity,5 COTC is also cancerostatic, and enhances the potency of other anticancer
agents.6 With its unusual structure and promising biological profile, COTC has attracted the attention of
synthetic chemists. To date, four successful enantioselective syntheses have been reported.7–10 Starting
from a readily available derivative of (−)-quinic acid, an 8-step synthesis of 1 is disclosed that features
a regioselective epoxide opening under oxidative conditions. Also of interest is a regioselective tin-
mediated monooxidation of a bis-allylic diol uncovered during the synthesis.
Starting from the known cyclohexylidene acetal 2 of (−)-methyl quinate,11 the all-cis-
trihydroxycyclohexene ring framework of 1 was assembled as shown in Scheme 1. The bis-triflate of 2
∗
†
Corresponding author.
Current address: Merck & Company, PO Box 2000, Rahway, NJ 07065, USA.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00103-9
tetl 16382

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spontaneously formed 3 upon stirring at rt. When treated with cesium acetate, 3 afforded diene 4 in good
yield,12 which, without purification, underwent face-selective addition of Br+ affording bromoformate
ester 5. Reduction of both ester groups in 5 furnished bromodiol 6,13 which was smoothly transformed
to epoxide 714 in the presence of lithium hexamethyldisilazide.
Scheme 1. Reagents: (a) Tf2O (2.2 equiv.), pyr, CH2Cl2; (b) CsOAc, DMF; (c) NBS–H2O, DMF; (d) DIBAL-H, ben-
zene–toluene; (e) LiN(TMS)2, THF, −78°C
Initial attempts to carry out the oxidative opening of epoxide 7 to 9 using DMSO in the presence of
either boron trifluoride etherate15 or triflic acid16 led instead to triol 8,17 the product of direct trans-
opening of the oxirane ring (Scheme 2). Recognizing that the bis-allylic diol grouping in 8 might form a
cyclic stannylene, and that such stannylenes have been reported to undergo selective oxidations,18 diol 8
was treated with (Bu3Sn)2O and Br2. After aqueous workup, the desired dihydroxyketone 9 was obtained
in 51% yield.19
Several lines of evidence suggested that in the reaction of 7 with DMSO, the fragmentation of the
resulting oxysulfonium salt using triethylamine was slow. Ultimately, the desired transformation of 7
directly to dihydroxyenone 9 was achieved using methanesulfonic acid/DMSO, followed by an excess
of Et3N at rt. In the process of confirming the structure of 9, its cyclohexylidene acetal group was
hydrolyzed to afford the known natural product KD16-U1, 10, a metabolite of Streptomyces filipensis.20
All spectroscopic and chiroptical data for compound 10, which has been prepared by other groups,7,10
matched the values reported in the literature. However, the melting point of several samples of 10
prepared in our laboratory was higher (mp 131–132°C) than that reported for natural or synthetic samples
(mp 114°C) under identical crystallization conditions. To resolve this discrepancy, we obtained a sample
1
of natural 10,10 whose H NMR spectrum was identical with synthetic (−)-10. After recrystallization
from ethyl acetate, natural 10 gave mp 130–131°C, undepressed when admixed with synthetic (−) 10. As
further independent confirmation, the structures of synthetic (−)-9 and (−)-10 prepared in our laboratory
were confirmed by single crystal X-ray diffraction analysis.
The primary hydroxyl group in diol 9 was selectively crotonylated to afford 11.21 Deprotection of the
acetal furnished (−)-COTC 1 in eight steps and 7.4% overall yield from 2.

2033
Scheme 2. Reagents: (f) BF3–OEt2, DMSO; (g) (Bu3Sn)2O, Br2 (1.5 equiv. ea), CH2Cl2; (h) CH3SO3H, DMSO, rt, 1.5 h; then
Et3N, rt, 5 min; (i) 1:1 TFA:H2O; (j) crotonic anhydride, DCC, DMAP, THF
Acknowledgements
We thank the National Institutes of Health (GM 24054) for financial assistance, and Professor K.
Tatsuta, Waseda University, for providing a sample of natural KD16-U1. Support of the Cornell NMR
Facility has been provided by the NSF (CHE 7904825; PGM 8018643) and NIH (RR02002).
References
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4. Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa, H.; Yoshioka, O.; Oguchi, N.; Takahashi, Y.; Matsuda, A. J. Antibiot.
1975, 28, 737–742.
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1975, 28, 743–748.
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7. Mirza, S.; Molleyres, L.-P.; Vasella, A. Helv. Chim. Acta 1985, 68, 988–996.
8. Takayama, H.; Hayashi, K.; Koizumi, T. Tetrahedron Lett. 1986, 27, 5509–5512.
9. Shing, T. K. M.; Tang, Y. Tetrahedron 1990, 46, 6575–6584.
10. Tatsuta, K.; Yasuda, S.; Araki, N.; Takahashi, M.; Kamiya, Y. Tetrahedron Lett. 1998, 39, 401–402.
11. Ulibarri, G.; Nadler, W.; Skrydstrup, T.; Audrain, H.; Chiaroni, A.; Riche, C.; Grierson, D. S. J. Org. Chem. 1995, 60,
2753–2761.
12. Kruizinga, W. H.; Strijtveen, B.; Kellogg, R. M. J. Org. Chem. 1981, 46, 4321–4323.
25
13. Compound 6: Rf 0.25 (1:1 EtOAc:hexanes); mp 98–100°C; [α]D −63° (c=1.02, MeOH); 1H NMR (300 MHz, CDCl3) δ
5.82 (m, 1H, J=1.07 Hz), δ 4.63 (m, 1H, J=1.07, 9.44 Hz), δ 4.45 (t, 1H, J=6.98, 5.38, 11.56 Hz), δ 4.30 (t, 1H, J=6.98,
10.74 Hz), δ 4.22 (m, 3H, J=6.98 Hz), δ 3.27 (d, 1H, J=7.52 Hz), δ 2.52 (t, 1H, J=6.45, 12.08 Hz), δ 1.74–1.27 (br m, 10H);
13C NMR (300 MHz, CDCl3) δ 140.7, 121.1, 112.0, 76.9, 71.9, 70.6, 64.2, 53.6, 38.2, 35.7, 25.0, 24.1, 23.8; IR (film) 3400,
2950, 2900, 1450 cm−1; EIMS m/z 320 (M+1, 48%), 95 (100%).
25
14. Compound 7: Rf 0.22 (1:1 EtOAc:hexanes); mp 89–90°C; [α]D −34° (c=1.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ
6.02 (m, 1H, J=1.61, 2.15 Hz), δ 4.60 (dt, 1H, J=1.07, 5.90 Hz), δ 4.38 (dd, 1H, J=2.15, 5.37 Hz), δ 4.31 (s, 2H), δ 3.65 (m,

2034
1H, J=2.15, 1.61 Hz), δ 3.42 (dd, 1H, J=1.61, 2.15 Hz), δ 1.79–1.18 (br m, 10H); 13C NMR (300 MHz, CDCl3) δ 142.0,
122.9, 108.9, 72.8, 70.1, 64.8, 56.6, 50.8, 37.2, 34.8, 25.4, 24.1; IR (film) 3400, 2950, 2900, 1450 cm−1; EIMS m/z 238 (M,
58%), 55 (100%).
15. Cohen, T.; Tsuji, T. J. Org. Chem. 1961, 26, 1681.
16. Trost, B. M.; Fray, M. J. Tetrahedron Lett. 1988, 29, 2163–2166.
25
17. Compound 8: Rf 0.31 (95:5 EtOAc:MeOH); mp 128–129°C; [α]D −44° (c=1.26, MeOH); 1H NMR (300 MHz, CDCl3)
δ 5.64 (m, 1H, J=1.07, 1.61 Hz), δ 4.67 (m, 1H, J=1.61, 2.15, 3.76 Hz), δ 4.50 (m, 2H, J=3.22, 7.52 Hz), δ 4.25 (q, 2H,
J=12.89 Hz), δ 3.68 (dd, 1H, J=3.22, 8.05 Hz), δ 2.34 (br s, 3H), δ 1.64–1.30 (br m, 10H); 13C NMR (300 MHz, CDCl3) δ
139.0, 124.5, 110.6, 75.7, 73.8, 73.1, 70.0, 64.2, 37.4, 36.0, 25.2, 24.3, 23.9; IR (film) 3350, 2950, 2850, cm−1; EIMS m/z
256 (M, 49%), 111 (100%).
18. Ueno, Y.; Okawara, M. Tetrahedron Lett. 1976, 4597–4600.
25
19. Compound 9: Rf 0.33 (4:1 EtOAc:hexanes); mp 155–156°C; [α]D −94° (c=0.83, MeOH); 1H NMR (300 MHz, CDCl3) δ
6.60 (s, 1H), δ 4.87 (t, 2H, J=2.15, 2.68 Hz), δ 4.43 (d, 1H, J=2.69 Hz), δ 4.33 (s, 2H), δ 1.70–1.20 (br m, 10H); 13C NMR
(300 MHz, CDCl3) δ 197.8, 141.3, 135.7, 112.4, 77.6, 73.2, 72.0, 60.4, 37.6, 36.5, 25.1, 24.1, 23.9; IR (film) 3400, 2950,
2850, 1700, 1450 cm−1; EIMS m/z 254 (M, 33%), 55 (100%).
20. Tatsuta, K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H.; Naganawa, H. J. Antibiot. 1974, 27, 579–586.
25
21. Compound 11: Rf 0.42 (1:1 EtOAc:hexanes); [α]D −22° (c=0.36, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.99 (m, 1H,
J=6.99, 7.51, 1.08 Hz), δ 6.58 (s, 1H), δ 5.85 (dd, 1H, J=1.61, 15.58 Hz), δ 4.92–4.75 (m, 4H), δ 4.43 (d, 1H, J=2.68 Hz),
δ 1.87 (dd, 3H, J=1.61, 6.98 Hz), δ 1.75–1.08 (br m, 10H); 13C NMR (300 MHz, CDCl3) δ 196.1, 166.0, 146.2, 142.3,
132.2, 122.2, 112.5, 77.6, 73.1, 71.8, 60.1, 37.5, 36.5, 25.1, 24.1, 23.9, 18.4; IR (film) 2950, 2850, 1725, 1700, 1650 cm−1
;
EIMS m/z 322 (M, 41%), 69 (100%).