An efficient semisynthesis of 7-deoxypaclitaxel from taxine

Article abstract of DOI:10.1039/a803990i

Highly cytotoxic 7-deoxypaclitaxel analogues are obtained by a semisynthesis starting from taxine - the most abundant naturally occurring taxane diterpene fraction.

Full text of DOI:10.1039/a803990i

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An efficient semisynthesis of 7-deoxypaclitaxel from taxine
Radomir Matovic´a and Radomir N. Saicˆic´*b†
a ICTM, Center for Chemistry, Njegoseva 12, Belgrade, YU-11000 Yugoslavia
b Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 158, Belgrade, YU-11001 Yugoslavia
Highly cytotoxic 7-deoxypaclitaxel analogues are obtained
by a semisynthesis starting from taxine—the most abundant
naturally occurring taxane diterpene fraction.
We first re-examined the possibility of exploiting the
favourable arrangement of functional groups in the major
constituent of taxine, i.e. taxine B 2a (Scheme 2). Quaterniza-
tion of the crude taxine,7a followed by DBU induced elimina-
tion under anhydrous conditions, afforded a mixture of 9- and
10-acetyl-5-cinnamoyltaxicine I (4 and 5), which could be
separated by a flash chromatography on a SiO2 column, and
were isolated in yields of 1 and 1.7 g kg21 of needles,
respectively. The former could be isomerised into the required
10-acetyl derivative 5 by treatment with methanolic KOAc
(43% yield at 70% conversion, without optimisation), to afford
a total of 2 g of 10-acetyl-5-cinnamoyltaxicine I 5 per 1 kg of
dry leaves.
With the suitable starting compound 5 in hand, the synthesis
of 7-deoxybaccatin III proceeded as displayed in Scheme 3.
Treatment of 5 with phosgene, followed by hydrolytic work-up,
furnished the cyclic carbonate 6 (90%), which was further
oxidised to diketone 7 (Dess–Martin periodinane, 80%), thus
establishing the final functionalization of the ‘upper’ part of the
molecule. The elaboration of the oxetane ring was envisaged to
proceed via triol 10.7a For that purpose a method for selective
removal of the cinnamoyl chain was needed, as the simultane-
ous cleavage of the C-10 acetate would require additional
protective steps. To achieve this, allylic cinnamate 7 was
oxidised with OsO4/NMO, as it was anticipated that intra-
molecular hydrogen bonding in 8 should activate the dihydrox-
yphenylpropionate ester towards hydrolysis under very mild
conditions. Although some concern existed about the ster-
eochemical outcome of the osmylation, to our pleasure the
reaction proceeded in quantitative yield, and with complete
stereoselectivity. This structural change brought about the
expected modification in the reactivity profile of 8, as indicated
by its proclivity towards spontaneous migration of the ester side
chain from O-5 to O-20 on standing in solution at room
temperature; treatment of 8 with K2CO3 or NaHCO3 in MeOH–
H2O at 0 °C induced very rapid hydrolysis of the dihydrox-
ypropanoate ester, but the hydrolysis of the C-10 acetate also
Owing to its great potential in the successful treatment of many
types of cancer, unusual mode of antimitotic action, and
complex molecular architecture, paclitaxel has attracted enor-
mous interest from the scientific community.1 Paclitaxel is
currently produced via extraction from the bark of the Pacific
yew, Taxus brevifolia, or by semisynthesis from 10-deace-
tylbaccatin III, which is in turn isolated, most notably, from the
leaves of the European yew, Taxus baccata.2 However,
10-deacetylbaccatin III is not the most abundant secondary
metabolite of the yew tree: its variable content in the needles of
Taxus baccata ranges from 0.05 to 1 g per kg of leaves.3 In
contrast, a mixture of alkaloids collectively referred to as
‘Taxine’ 2 can be obtained by a simple extraction procedure in
yields of 7–12 g kg21 4
, the two major constituents of this
fraction (ca. 35%) being taxine B 2a and isotaxine B 2b;5
therefore, the development of the procedure that would allow
for the efficient use of this starting material for the preparation
of biologically active paclitaxel analogues would be of
considerable interest.
Earlier reports on 7-deoxypaclitaxel 1, obtained by radical
deoxygenation of paclitaxel, or baccatin derivative, showed this
compound to be of comparable, or even superior, cytotoxic
activity with respect to paclitaxel,6 and, given the structural
congruence with taxine B, indicated it as a semisynthetic target.
The possibility of such a synthetic transformation was investi-
gated by several groups.7 As the preparative separation of taxine
alkaloids is difficult, the crude taxine mixture was hydrolysed in
order to obtain a well-defined starting material, i.e. tetraol 3.
However, the differentiation between hydroxy groups in tetraol
3 required extensive use of protective groups, leading to long
synthetic sequences, and lowering considerably the overall
yield.8 We endeavoured to develop an efficient procedure for
the conversion of taxine into 7-deoxypaclitaxel derivatives
(Scheme 1). The accomplishment of this task was expected not
only to give access to large amounts of 7-deoxypaclitaxel
analogues, but also to provide additional information on the
reactivity of the taxane system, as well as derivatives suitable
for further SAR studies.
R4O
AcO
OR3
OH
i, v, iv
O
O
O
N
O
R1
H
R2O
HO
H
AcO
AcO
Ph
O
HO
Ph
O
18
BzHN
Ph
O
10
9
O
O
11
12
19
2
17
5
15
7
O
16
O
13
1
8
i–iv
OH
6
14
2
3
vi, iv
4
HO
O
O
5
H
H
HO
HO
BzO
O
O
OH
OH
AcO20
HO
OAc
OH
1
O
O
R4O
O
O
OR3
2a R1 = OH, R2 = R3 = H, R4 = Ac
HO
HO
H
H
HO
taxine B
HO
O
Ph
O
Ph
O
b R1 = OH, R2 = R4 = H, R3 = Ac
4
3
N
O
isotaxine B
c R1 = H or OH, R2, R3, R4 = H, Ac
R1
H
R2O
Scheme 2 Reagents and conditions: i, MeI, THF, room temp., 5 h; ii,
K2CO3, H2O, EtOH, room temp., 3 h; iii, NaOMe, MeOH, 0 °C, 16 h; iv,
column chromatography on SiO2; v, DBU, CHCl3, room temp., 1.5 h; vi,
10% KOAc in MeOH, room temp., 3 h
O
Ph
other minor isomers
2
Scheme 1
Chem. Commun., 1998
1745

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AcO
AcO
O
AcO
OH
BzNH
Ph
O
OH
OPMP
O
O
i
O
i, ii
O
BzN
Ph
17 +
O
O
90%
O
75%
OH
HO
H
O
O
Ph
HO
HO
Ph
O
COOH
O
BzO
5
6
AcO
O
1
ii 80%
Scheme 4 Reagents and conditions: i, DCC, DMAP (cat.), room temp., 3 h;
ii, 5% TsOH in MeOH, room temp., 1 h
AcO
AcO
O
O
iii
O
O
100%
O
OH
Ph
O
The described chemistry offers an efficient pathway for the
preparation of new paclitaxel derivatives, and points to the
naturally abundant taxane diterpene fraction—taxine—as a
valuable starting material for further semisynthetic studies.
O
O
O
O
O
O
Ph
HO
O
OH
OH
O
8
7
AcO
iv
80%
Notes and References
O
O
OH
Ph
† E-mail: rsaicic@chem.bg.ac.yu
O
MeO
+
1 Taxol®: Science and Applications, ed. M. Suffness, CRC Press, Boca
Raton, 1995, and references cited therein. Isolation and structure
elucidation: M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon and A. T.
McPhail, J. Am. Chem. Soc., 1971, 93, 2325. Total syntheses: K. C.
Nicolaou, H. Ueno, J.-J. Liu, P. G. Nantermet, Z. Yang, J. Renaud, K.
Paulvannan and R. Chadha, J. Am. Chem. Soc., 1995, 117, 653; R. A.
Holton, H.-B. Kim, C. Somoza, F. Liang, R. J. Biediger, P. D. Boatman,
M. Shindo, C. C. Smith, S. Kim, H. Nadizadeh, Y. Suzuki, C. Tao, P.
Vu, S. Tang, P. Zhang, K. K. Murthi, L. N. Gentile and J. H. Liu, J. Am.
Chem. Soc., 1994, 116, 1599; S. J. Danishefsky, J. J. Masters, W. B.
Young, J. T. Link, L. B. Snyder, T. V. Magee, D. K. Jung, R. C. A.
Isaacs, W. G. Bornmann, C. A. Alaimo, C. A. Coburn and M. J. Di
Grandi, J. Am. Chem. Soc., 1996, 118, 2843; P. A. Wender, N. F.
Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, J. B. Houze, N. E.
Krauss, D. Lae, D. G. Marquess, P. L. McGrane, W. Meng, M. G.
Natchus, A. J. Shuker, J. C. Sutton and R. E. Taylor, J. Am. Chem. Soc.,
1997, 119, 2757
O
O
OH
OR2
OR1
O
HO
9
10 R1 = R2 = H
v
80%
11 R1 = TBDMS, R2 = H
12 R1 = TBDMS, R2 = Ms
13 R1 = H, R2 = Ms
HNBz
O
vi
vii
87%
91%
Ph
MeO
OH
viii 82%
AcO
O
AcO
O
O
x
HO
O
BzO
70%
O
AcO
16
2 J.-N. Denis, A. E. Greene, D. Guenard, F. Gueritte-Voegelein, L.
Mangatal and P. Potier, J. Am. Chem. Soc., 1998, 110, 5917
3 G. Chauviere, D. Guenard, F. Picot, V. Senilh and P. Potier, C. R.
Seances Acad. Sci., Ser. 2, 1981, 293, 501; K. M. Witherup, S. A. Look,
M. W. Stasko, T. J. Ghiorzi, G. M. Mushik and G. M. Cragg, J. Nat.
Prod., 1990, 53, 1249; see also ref. 2.
O
O
xi 83%
RO
O
O
AcO
O
14 R = H
15 R = OAc
ix 60%
HO
4 H. Lucas, Arch. Pharm., 1856, 14, 438; G. Appendino, in Alkaloids:
Chemical and Biological Perspectives, ed., S. W. Pelletier, Pergamon,
Oxford, 1996, vol. 11, p. 237; L. H. D. Jenniskens, E. L. M. van
Rosendaal, T. A. van Beek, P. H. G. Wiegerinck and H. W. Scheeren,
J. Nat. Prod., 1996, 59, 117; for an alternative isolation procedure, see
ref. 7(a).
HO
H
BzO
O
AcO
17
Scheme 3 Reagents and conditions: i, COCl2 (20 equiv.), CH2Cl2, 0 °C, 20
min; then Et2O, H2O, imidazole (cat.), 0 °C, 20 min; ii, Dess–Martin
periodinane (2 equiv.), CH2Cl2, TFA (cat.), room temp., 12 h; iii, OsO4
(cat.), NMO, THF, H2O, room temp., 4 h; iv, 10% KOAc in MeOH, reflux,
30 min; v, TBDMSCl, imidazole, DMF, room temp., 3 h; vi, MsCl, Py, 0 °C
to room temp., 24 h; vii, 7% HF in MeCN, room temp., 7 h; viii, Pri2NEt (7
equiv.), toluene, reflux, 30 h; ix, Ac2O (7 equiv.), DMAP (14 equiv.),
CH2Cl2, room temp., 4 h; x, PhLi (10 equiv.), THF, 278 °C, 0.5 h; then
Ac2O, DMAP, CH2Cl2, room temp., 1 h; xi, NaBH4 (excess), MeOH, room
temp., 3 h
5 L. Ettouati, A. Ahond, C. Poupat and P. Potier, J. Nat. Prod., 1991, 54,
1455; in some specimens of Taxus baccata a content of taxine as high
as 17 g kg21 was found, 10 g being taxine B; the authors are grateful to
Dr A. Ahond and Dr C. Poupat for this personal communication.
6 A. G. Chaudhary, J. M. Rimoldi and D. G. I. Kingston, J. Org. Chem.,
1993, 58, 3798; S.-H. Chen, S. Huang, J. Kant, C. Fairchild, J. Wei and
V. Farina, J. Org. Chem., 1993, 58, 5028; V. Farina, S.-H. Chen, D. R.
Langley, M. D. Wittman, J. Kant and D. Vyas, Eur. Pat. Appl., EP
590,267/6 apr, 1994 (Chem. Abstr., 1994, 121, 205747n).
7 (a) L. Ettouati, A. Ahond, C. Poupat and P. Potier, Tetrahedron, 1991,
47, 9823; (b) P. H. G. Wiegerinck, L. Fluks, J. B. Hammink, S. J. E.
Mulders, F. M. H. de Groot, H. L. M. van Rosendaal and H. W. Sheeren,
J. Org. Chem., 1996, 61, 7092; (c) I. Fenoglio, G. M. Nano, D. G. V.
Velde and G. Appendino, Tetrahedron Lett., 1996, 37, 3203; (d) H.
Poujol, A. A. Mourabit, A. Ahond, C. Poupat and P. Potier,
Tetrahedron, 1997, 53, 12 575 and references cited therein.
8 While this work was in progress, the first semisynthesis of 7-deox-
ybaccatin from 3 was reported, in 15 steps and 1.7% overall yield, see
ref. 7(d).
occurred under these conditions. Eventually, refluxing 8 with
methanolic KOAc afforded the desired triol 10 in 80% yield.
Optically pure (2S,3R)-(-)-methyl 2,3-dihydroxy-3-phenylpro-
panoate 9 was isolated as the side product of this reaction, and
further converted into the paclitaxel side chain according to a
previously published procedure.9 The transformation of the key
intermediate 10 into 7-deoxybaccatin III 17 was accomplished
by applying a modified methodology previously developed in
total syntheses of paclitaxel.1,7a In this way, starting from
cinnamoyltaxicine I 5, 7-deoxybaccatin III was obtained in
11.5% overall yield (unoptimized).10
9 J.-N. Denis, A. Correa and A. E. Greene, J. Org. Chem., 1990, 55,
1957
10 Spectral data identical to those reported in ref. 7(d).
11 A. M. Kanazawa, J.-N. Denis and A. E. Greene, Chem. Commun., 1994,
2591
12 1H NMR data identical to those reported in ref. 6.
7-Deoxybaccatin is a direct precursor of paclitaxel ana-
logues: esterification of 17 with acid 18,11 followed by acidic
hydrolysis (TsOH in MeOH) afforded 7-deoxypaclitaxel 1 in
75% yield (Scheme 4).12
Received in Glasgow, UK, 28th May 1998; 8/03990I
1746
Chem. Commun., 1998