Semisynthesis of D-ring-modified taxoids: Thietane derivatives from taxine B

Article abstract of DOI:10.1016/S0040-4039(00)00727-9

The semisynthesis of 7-deoxobaccatin III derivatives, in which the oxygen atom in ring D is substituted for a sulfur atom, is presented; the starting material is the natural taxine B and isotaxine B extracted from the needles of Taxus baccata. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00727-9

Tetrahedron Letters 41 (2000) 4891±4894
Semisynthesis of D-ring-modi®ed taxoids:
thietane derivatives from taxine B
Christophe Payre, Ali Al Mourabit, Ludovic Merckle, Alain Ahond,
Christiane Poupat* and Pierre Potier
Institut de Chimie des Substances Naturelles du CNRS, 91198 Gif-sur-Yvette cedex, France
Received 18 February 2000; accepted 4 May 2000
Abstract
The semisynthesis of 7-deoxobaccatin III derivatives, in which the oxygen atom in ring D is substituted
for a sulfur atom, is presented; the starting material is the natural taxine B and isotaxine B extracted from
the needles of Taxus baccata. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 7-deoxothiabaccatin III; thietane; protected taxicine I; taxine B.
Since the anticancer activity of paclitaxel 1 and docetaxel 2 is known, various studies of the
chemistry and structure±activity relationships have been developed. The oxetane ring is considered
as essential for biological activity but its precise role is not yet so clear.1 3
Only a few analogues in which the oxygen atom in ring D is substituted by another heteroatom
(N, S, Se) have been described4 6 in the paclitaxel or docetaxel series. Recently, Kingston's
group described the preparation of a thiapaclitaxel from paclitaxel.6 We present the synthesis of
`7-deoxothiabaccatin' derivatives from natural taxine B 3 and isotaxine B 4. This starting material
had already been used in the ®rst synthesis of the oxetane D-ring,7 and in the semisynthesis of
deoxopaclitaxel and 7-deoxydocetaxel derivatives.8 11
* Corresponding author. Tel: 33 1 69 82 30 23; fax: 33 1 69 07 72 47; e-mail: Christiane.Poupat@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00727-9

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Prepared in 3 steps from taxine B and isotaxine B,7 the starting material is the 5-cinnamoyl-
taxicine I 5 (Scheme 1). Before the solvolysis of the cinnamoyl ester, the hydroxyles of 5 had to be
protected: the protection±deprotection steps remain hard to manage. Three possibilities were
explored: 1,2,9,10-di-O-isopropylidene, 1,2-O-benzylidene-9,10-O-isopropylidene and 1,2,9,10-di-
O-benzylidene.
Scheme 1. Reagents and conditions: (a) Me2C(OMe)2, PTSA, THF, rt, 5 h, 64%; (b) NaOH 20N, THF, 60ꢀC, 36 h,
90% 6; (c) Me2C(OMe)2, PTSA, THF, rt, 3.5 h, 84%; (d) Ph CH(OMe)2, PTSA, THF, 60ꢀC, 7.5 h, 80%; (e) NaOH
20N, THF, 60ꢀC, 22 h, 86% 7; (f) Ph CH(OMe)2, PTSA, THF, 60ꢀC, 2.5 h, 54%; (g) NaOH 20N, THF, 60ꢀC, 30 h,
90% 8A+8B
After solvolysis of the cinnamoyl ester, 6, 7, 8A, 8B were obtained in good yields,12,13 the latter
two being easily separated by preparative TLC.
Various methods for preparation of the thietane heterocycle have been reported. After preliminary
experiments, we chose the direct access via 5-hydroxy-4,20-epoxide derivatives. Our strategy was
inspired by the Ohuchida et al. synthesis14,15 of a thromboxane A2 sulfur analogue: a derivative
doubly substituted by the mesylate and thioacetate groups is prepared and the mesylate undergoes
a nucleophilic substitution by an in situ native sul®de.
Epoxidation of the 4,(20) double bond and mesylation of the C-5 hydroxyle provided 9, 10,
11A, 11B and 12, 13, 14A+14B, successively (Scheme 2).
Scheme 2. Reagents and conditions: (a) mCPBA, CH2Cl2, 0ꢀC, 0.5 h, 98% 9, 98% 10, 96% 11A+11B; (b) MsCl,
C5H5N, 0ꢀC, 0.5 h, 74% 12, 73% 13, 78% 14A+14B; (c) AcSH, NaH, DMF, 5 h, 60ꢀC, 60% 15, 66% 16, 80%
17A+17B; (d) MeONa, MeOH, 60ꢀC, 1 h, 85% 18, 86% 19, 77% 20A+20B

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Attempts to transform the 4 (20)-epoxide into a thietane by using Na2S, Li2S (prepared in situ)
or Ph3SiSH were unsuccessful, but the treatment of 12 by thioacetic acid and NaH provided
compound 15 (60% yield), while 13 and 14A+14B provided 16 and 17A+17B, respectively (66 and
80% yields).
The cyclisation of the intermediates 15, 16 and 17A+17B was carried out by treatment with
NaOMe in MeOH (60ꢀC, 1 h): the thietane derivatives 18,16 19,17 20A+20B18 were obtained with
85, 86 and 77% yields, respectively. The compounds 20A+20B could be separated by preparative
TLC; 20B in solution was spontaneously oxidised by air oxygen to sulfoxide 21B.19
It is worthy of note that several attempts to acetylate the C-4 hydroxyl group of the compounds
18 and 19 failed while the derivatives 20A+20B could be acetylated (Ac2O, DMAP, pyridine) to
22A+22B20 in 30% yield (Scheme 3).
Scheme 3.
These favourable results incited us to follow this way with other substituents or protective
groups in positions 1, 2, 9 and 10 which would be more appropriate to provide the paclitaxel or
docetaxel substitution pattern in these positions: these studies are in progress.
References
1. Kingston, D. G. I.; Molinero, A. A.; Rimoldi, J. M. Prog. Chem. Org. Natl. Prod. 1991, 61, 1±188.
2. Chen, S. H.; Farina, V. In The Chemistry and Pharmacology of Taxol and its Derivatives; Farina,V., Ed.; Elsevier:
New York, 1995; pp. 165±223.
3. Guenard, D.; Gueritte-Voegelin, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160±167.
4. Fenoglio, I.; Nano, G. M.; Vander Velde, D. G.; Appendino, G. Tetrahedron Lett. 1996, 37, 3203±3206.
5. Marder-Karsenti, R.; Dubois, J.; Bricard, L.; Guenard, D.; Gueritte-Voegelein, F. J. Org. Chem. 1997, 62, 6631±
6637.
6. Gunatilaka, A. A. L.; Ramdayal, F. D.; Sarragiotto, M. H.; Kingston, D. G. I.; Sackett, D. L.; Hamel, E. J. Org.
Chem. 1999, 64, 2694±2703.
7. Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991, 47, 9823±9838.
8. Wiegerinck, P. H. G.; Fluks, L.; Hamminck, J. B.; Mulders, S. J. E.; De Groot, F. M. H.; Van Rozendaal,
H. L. M.; Scheeren, H. W. J. Org. Chem. 1996, 61, 7092±7100.
9. Beusker, P. H.; Braamer, L.; Scheeren, J. W.; Van Rozendaal, H. L. M. Herba Polonica 1998, XLIV, 243±246.
10. Poujol, H.; Ahond, A.; Al Mourabit, A.; Chiaroni, A.; Poupat, C.; Riche, C.; Potier, P. Tetrahedron 1997, 53,
5169±5184.
11. Poujol, H.; Al Mourabit, A.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1997, 53, 12575±12594.
12. Payre, C. DEA, University of Paris-sud, Orsay, 1996.

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13. Merckle, L. DEA, University of Paris-sud, Orsay, 1998.
14. Ohuchida, S.; Hamanaka, N.; Hayashi, M. Tetrahedron Lett. 1981, 22, 1349±1352.
15. Ohuchida, S.; Hamanaka, N.; Hayashi, M. Tetrahedron Lett. 1981, 22, 5301±5302.
16. Data for 18: C26H38O6S (M=478). Amorphous. Rf: 0.6 (heptane:AcOEt, 7:3), [ꢀ]D +211 (c 0.18, CHCl3). IR
(CHCl3): 1679 cm^1 (CO). SM IC (T=190ꢀC, isobutane): 479 (MH)+. 1H NMR (300 MHz) ꢁ: 1.31 (s, 3H, Me-17),
1.36, 1.44, 1.45, 1.50 (4s, 4Â3H, 4 Me-isopropylidene), 1.54 (s, 3H, Me-19), 1.56 (s, 3H, Me-16), 1.62 (d, J=5 Hz,
1H, H-3), 1.93 (s, 3H, Me-18), 2.24 (m, 2H, H-6), 2.63 (d, J=19.5 Hz, 1H, H-14), 2.96 (dd, J=11 and 1 Hz, 1H,
H-20), 3.23 (t ep., 1H, H-5), 3.25 (d, J=19.5 Hz, 1H, H-14), 3.76 (d, J=11 Hz, H-20), 4.17 (d, J=5 Hz, 1H, H-2),
4.25 (d, J=9 Hz, 1H, H-9), 4.65 (d, J=9 Hz, 1H, H-10), ( H-7 probably at: 1.20 and 1.98 ppm). 13C NMR (75 MHz)
ꢁ: 14.15 (C-18), 18.70 (C-19), 19.90 (C-16), 26.20, 26.80, 27.10 (3ÂCH3-isopropylidene), 27.95 (CH3-isopropylidene
and C-7), 30.30 (C-6), 33.55 (C-17), 40.20 (C-20), 44.60 (C-14), 48.25 (C-5), 48.55 (C-3), 75.55 (C-10), 76.55 (C-2),
81.75 (C-9), 106.80, 107.70 (2ÂCq-isopropylidene), 141.23 (C-11), 152.37 (C-12), 199.94 (C-13). SM HR (IC):
C26H39O6S, calculated: 479.2467; obtained: 479.2432.
17. Data for 19: C30H38O6S (M=526). Amorphous. Rf: 0.7 (heptane:AcOEt, 5:5), [ꢀ]D +151 (c 0.23, CHCl3). IR
1
(CHCl3): 1679 cm^1 (CO). SM FAB (thioglycerol+NaCl): 549 (MNa)+. H NMR (250 MHz) ꢁ: 1.22, 1.37, 1.45,
1.51, 1.57, 1.66 (6s, 6Â3H, 6Me), 1.84 (d, J=5 Hz, 1H, H-3), 1.94 (s, 3H, Me-18), 2.28 (m, 2H, H-6), 2.67 (d,
J=19 Hz, 1H, H-14), 2.97 (dd, J=11 and 1Hz, 1H, H-20a), 3.19 (t ep., 1H, H-5), 3.41 (d, J=19 Hz, 1H, H-14),
3.90 (d, J=11 Hz, 1H, H-20), 4.29 (d, J=5 Hz, 1H, H-2), 4.31 (d, J=1 Hz, 1H, H-9), 4.69 (d, J=9 Hz, 1H, H-10),
5.84 (s, 1H, H-benzylidene), 7.4 (m, 5H, H-Ph). SM HR (IC): C30H39O6S, calculated: 527.2466; obtained:
527.2429.
18. The two epimers 20A and 20B (ratio 3:2) were separated by preparative TLC: three migrations in
cyclohexane:AcOEt, 7:3. Data for 20A: C34H38O6S (M=574). Amorphous. Rf: 0.65 (heptane:AcOEt, 5:5); [ꢀ]D
+165 (c 0.29, CHCl3). UV [lmax nm (")]: 276 (6800). IR (CHCl3): 1681cm^1 (CO). SM IC (T=190ꢀC, isobutane):
631 (M+57)+, 575 (MH)+. 1H NMR (200 MHz) ꢁ: 1.42, 1.69, 1.74 (3s, 3Â3H, 3Me), 1.81 (d, J=5 Hz, 1H, H-3), 1.93
(s, 3H, Me-18), 2.31 (m, 2H, H-6), 2.69 (d, J=19 Hz, 1H, H-14), 3.00 (dd, J=11 and 2 Hz, 1H, H-20), 3.21 (t,
J=8 Hz, 1H, H-5), 3.31 (s, 1H, OH), 3.41 (d, J=19 Hz, 1H, H-14), 3.92 (d, J=11 Hz, 1H, H-20), 4.33 (d, J=5
Hz, 1H, H-2), 4.53 (d, J=10 Hz, 1H, H-9), 4.86 (d, J=10 Hz, 1H, H-10), 5.88 (s, 1H, H-benzylidene-1,2), 6.15 (s,
1H, H-benzylidene-9,10), 7.42 (m, 5H, H-Ph), 7.44 (m, 5H, H-Ph). 13C NMR (75 MHz) ꢁ: 14.50 (C-18), 28.40 (C-
7), 30.80 (C-6), 40.60 (C-20), 42.35 (C-15), 45.55 (C-14), 48.90 (C-3), 49.60 (C-5), 75.85 (C-10), 80.05 (C-2), 81.40
(C-4), 84.35 (C-9), 84.85 (C-1), 102.90 (CH-benzylidene-9,10), 103.20 (CH-benzylidene-1,2), 126.55 (4ÂC-Ph),
128.75 (4ÂC-Ph), 129.65 (2ÂC-Ph), 137.85 (2ÂC ipso Ph), 142.10 (C-12), 153.20 (C-11), 200.15 (C-13). Data for
20B: C34H38O6S (M=574). Amorphous. Rf: 0.62 (heptane:AcOEt, 5:5); [ꢀ]D +145 (c 0.29, CHCl3). UV [lmax nm
(")]: 273 (10200). IR: 3553 (OH), 1680 cm^1 (CO). SM IC (T=200ꢀC, isobutane): 631 (M+57)+, 575 (MH)+. H
1
NMR (250 MHz) ꢁ: 1.20±1.29 (m, 1H, H-7 or H-6), 1.36, 1.52, 1.66 (3s, 3Â3H, 3Me), 1.78 (d, J=5 Hz, 1H, H-3),
2.01 (s, 3H, Me-18), 2.09±2.14 (m, 1H, H-7 or H-6), 2.30±2.38 (m, 2H, H-6 or H-7), 2.68 (d, J=19 Hz, 1H, H-14),
2.98 (d, J=11.5 Hz, 1H, H-20), 3.22 (dd, J=8.5 and 7.9 Hz, 1H, H-5), 3.30 (s, 1H, OH), 3.41 (d, J=19 Hz, 1H,
H-14), 3.90 (d, J=11.5 Hz, 1H, H-20), 4.28 (d, J=5 Hz, 1H, H-2), 4.43 (d, J=9.5 Hz, 1H, H-9), 4.88 (d, J=9.5
Hz, 1H, H-10), 5.81 (s, 1H, H-benzylidene-1,2), 6.11 (s, 1H, H-benzylidene-9,10), 7.37±7.53 (m, 10H, H-Ph). SM
HR (IC): C34H39O6S, calculated: 575.2467; obtained: 575.2434.
19. Data for 21B: C34H38O7S (M=590). Amorphous. Rf: 0.12 (heptane:AcOEt, 5:5); [ꢀ]D+100 (c 0.33; CHCl3). SM IC
(T=210ꢀC, isobutane): 591 (MH)+. H NMR (400 MHz) ꢁ: 1.37, 1.52, 1.59 (3s, 3Â3H, 3Me), 1.94 (d, J=5 Hz,
1
1H, H-3), 2.01 (s, 3H, Me-18), 2.34 (m, 2H, H-6), 2.63 (d, J=19 Hz, 1H, H-14), 3.02 (dd, J=15 and 5 Hz, 1H, H-20),
3.16 (m, 1H, H-5), 3.52 (d, J=19 Hz, 1H, H-14), 4.08 (d, J=15 Hz, 1H, H-20), 4.12 (s, 1H, OH), 4.27 (d, J=5 Hz,
1H, H-2), 4.42 (d, J=10 Hz, 1H, H-9), 4.88 (d, J=10 Hz, 1H, H-10), 5.81 (s, 1H, H-benzylidene-1,2), 6.10 (s, 1H,
H-benzylidene-9,10), 7.40 (m, 5H, H-Ph), 7.43 (m, 5H, H-Ph).
20. Data for 22A+22B: C36H40O7S (M=616). Amorphous. Rf: 0.70 (heptane:AcOEt, 5:5). SM FAB
(thioglycerol+NaCl): 579 (M-AcOH+Na)+. 1H NMR (300 MHz) ꢁ: 1.26/1.30, 1.52/1.73, 1.81/1.82 (3s, 3Â3H,
3Me), 1.97/2.04 (s, 3H, Me-18), 2.06 (s, 3H, Me-CO), 2.51 (s, 2H, H-14), 2.86/2.88 (d, J=5 Hz, 1H, H-3), 3.43/
3.46 (d, J=12.5 Hz, 1H, H-20), 3.76/3.78 (d, J=12.5 Hz, 1H, H-20), 3.98±4.03 (m, 1H, H-5), 4.28/4.32 (d, J=5 Hz,
1H, H-2), 4.48/4.56 (d, J=9.5 Hz, 1H, H-9), 4.91/4.93 (d, J=9.5 Hz, 1H, H-10), 5.85/5.91 (s, 1H, H-benzylidene-1,2),
6.11/6.15 (s, 1H, H-benzylidene-9,10), 7.39±7.50 (m, 10H, H-Ph). SM HR (IC): C36H41O7S, calculated: 617.2572;
obtained: 617.2584.