Semisynthesis of some 7-deoxypaclitaxel analogs from taxine B

Article abstract of DOI:10.1021/jo960438a

Taxine B (3), isolated from the dried needles of Taxus baccata, was converted into six novel 7-deoxypaclitaxel analogs, 20, 21a,b, and 23-25, that have structural changes at C1, C2, and C4. A method for the introduction of the benzoyl function at C2, via a benzylidene acetal at C1-C2, will be revealed. All compounds showed very little or no measurable cytotoxic activity against some well-characterized human tumor cell lines, probably due to the nonacylated hydroxyl group at C4.

Full text of DOI:10.1021/jo960438a

7092
J . Org. Chem. 1996, 61, 7092-7100
Sem isyn th esis of Som e 7-Deoxyp a clita xel An a logs fr om Ta xin e B
Peter H. G. Wiegerinck, Lizette Fluks, J eannet B. Hammink, Suzanne J . E. Mulders,
Franciscus M. H. de Groot, Hendrik L. M. van Rozendaal, and Hans W. Scheeren*
Department of Organic Chemistry, University of Nijmegen, NSR-Center,
Toernooiveld, 6525 ED Nijmegen, The Netherlands
Received March 4, 1996X
Taxine B (3), isolated from the dried needles of Taxus baccata, was converted into six novel
7-deoxypaclitaxel analogs, 20, 21a ,b, and 23-25, that have structural changes at C1, C2, and C4.
A method for the introduction of the benzoyl function at C2, via a benzylidene acetal at C1-C2,
will be revealed. All compounds showed very little or no measurable cytotoxic activity against
some well-characterized human tumor cell lines, probably due to the nonacylated hydroxyl group
at C4.
Ch a r t 1
The diterpenoid paclitaxel (1) (Chart 1), first isolated
by Wani and Wall1 from the bark of the western yew
Taxus brevifolia, is a new and very promising antitumor
compound.2 The structural complexity of (1), and its
unique mechanism of action,3 have stimulated extensive
research toward the synthesis of paclitaxel as well as the
synthesis of new analogs. Until recently, the synthesis
of paclitaxel has been achieved both by semisynthesis,4
starting from 10-deacetylbaccatin III (2) (Chart 1), and
by total synthesis.5
The synthesis of analogs for structure-activity rela-
tionship (SAR) studies have mostly been accomplished
by structurally modifying paclitaxel itself.6 In several
cases, precursors, such as baccatin III,7 brevifoliol,8 13-
acetyl-9-dihydrobacatin III,9 and 14-â-hydroxy-10-des-
acetylbaccatin,10 isolated from the needles of different
Taxus species, were used.
* To whom correspondence should be addressed. Phone: 31-24-
3652331. Fax: 31-243652929. E-mail: J SCH@SCI.KUN.NL.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J . Am. Chem. Soc. 1971, 93, 2325-2327.
(2) (a) Rowinsky, E. K.; Cazenave, L. A; Donhower, R. C. J . Natl.
Cancer Inst. 1990, 82, 1247-1258. (b) Holmes, F. A.; Kudelka, A. P.;
Kavanagh, J . J .; Huber, M. H.; Ajani, J . A.; Valero, V. In Taxane
Anticancer Agents, Basic Science and Current Status; Georg, G. I.,
Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series No.
583; American Chemical Society: Washington, DC, 1995; pp 31-57.
(3) (a) Horwitz, S. B. Trends Pharmacol. Sci. 1992, 13, 134-136.
(b) Schiff, P. B.; Fant, J .; Horwitz, S. B. Nature 1979, 277, 665-667.
(4) (a) Denis, J .-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein,
F.; Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
(b) Denis, J .-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Pilard, J . European Patent 1989, EP 0336840A1.
(5) (a) Holton, R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R.
J .; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.;
Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile,
L. N.; Liu, J . H. J . Am. Chem. Soc. 1994, 116, 1597-1598. (b) Holton,
R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J .; Boatman, P.
D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.; Tao,
C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J . H.
J . Am. Chem. Soc. 1994, 116, 1599-1600. (c) Nicolaou, K. C.; Yang,
Z.; Liu, J . J .; Ueno, H.; Nantermet, P. G.; Guy, R. K.; Cialborne, C. F.;
Renaud, J .; Couladouros, E. A.; Paulvannan, K.; Sorensen, E. J . Nature
1994, 367, 630-634.
(6) (a) Georg, G. I.; Ali, S. M.; Boge, T. C.; Datta, A.; Falborg, L.
Tetrahedron Lett. 1994, 35, 8931-8934. (b) Roth, G. P.; Marshall, D.
R.; Chen, S.-H. Tetrahedron Lett. 1995, 36, 1609-1612. (c) Georg, G.
I.; Ali, S. M.; Boge, T. C.; Datta, A.; Falborg, L.; Park, H. Bioorg. Med.
Chem. Lett. 1995, 5, 259-264.
Taxine B (3), the most abundant precursor present in
the needles of Taxus baccata L. (Chart 1), has had little
attention paid to it as a precursor for either the synthesis
of paclitaxel or for the synthesis of its analogs. To our
knowledge, only one investigation11 to date has been
carried out using taxine B as a starting material. This
synthesis, however, did not lead to analogs that possessed
the necessary â-amino acid side chain. A retrosynthetic
analysis showed that the synthesis of paclitaxel itself
from taxine B would require more than 20 steps. The
introduction of the 7-hydroxyl group, in particular, was
expected to be difficult. We concentrated our efforts on
the synthesis of 7-deoxypaclitaxel analogs, when in in
vitro assays it was shown that the 7-hydroxyl group had
practically no effect on activity.12
From SAR studies it is known that the oxetane ring,13
the paclitaxel side chain,14 and the hydroxyl group15 at
(9) (a) Klein, L. Tetrahedron Lett. 1993, 34, 2047-2050. (b) Klein,
L.; Li, L.; Maring, C. J .; Yeung, C. M.; Thomas, S. A.; Grampovnik, D.
J .; Plattner, J . J . J . Med. Chem. 1995, 38, 1482-1492.
(10) Kant, I.; Farina, V.; Fairchild, C.; Kadow, J . F.; Langley, D. R.;
Long, B. H.; Rose, W. C.; Vyas, D. M. Bioorg. Med. Chem. Lett. 1994,
4, 1565-1570.
(7) (a) Chen, S.-H.; Wei, J .-M.; Farina, V. Tetrahedron Lett. 1993,
34, 3205-3206. (b) Chen, S.-H.; Farina, V.; Wei, J .-M.; Long, B.;
Fairchild, C.; Mamber, S. W.; Kadow, J . F.; Vyas, D.; Doyle, T. W.
Bioorg. Med. Chem. Lett. 1994, 4, 479-482. (c) Georg, G. I.; Cheru-
vallath, Z. S.; Vander Velde, D. G. Tetrahedron Lett. 1995, 36, 1783-
1786.
(11) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823-9838.
(12) (a) Ringel, I.; Horwitz, S. B. J . Pharm. Exp. Ther. 1987, 242,
692-698. (b) Kingston, D. G. I.; Samaranayake, G.; Ivey, C. A. J . Nat.
Prod. 1990, 53, 1-12. (c) Chaudhary, A. G.; Rimoldi, J . M.; Kingston,
D. G. I. J . Org. Chem. 1993, 58, 3798-3799. (d) Chen, S.; Huang, S.;
Kant, J .; Fairchild, C.; Wei, J .; Farina, V. J . Org. Chem. 1993, 58,
5028-5029.
(8) Georg, G. I.; Cheruvallath, Z. S.; Vander Velde, D.; Ye, Q.-M.;
Mitscher, L. A. Bioorg. Med. Chem. Lett. 1993, 3, 1349-1350.
S0022-3263(96)00438-0 CCC: $12.00 © 1996 American Chemical Society

Semisynthesis of Some 7-Deoxypaclitaxel Analogs
J . Org. Chem., Vol. 61, No. 20, 1996 7093
C2′ are important for cytotoxic activity and that the
functional groups at the upper side of paclitaxel, positions
C7,12 C9,9,16 and C10,9,12b,16 are of less importance for
cytotoxic activity. The bottom side of paclitaxel, positions
C1, C2, and C4, was a black box at the start of our
research. In this paper, we present the synthesis of some
7-deoxypaclitaxel analogs (20, 21a ,b, and 23-25) with
structural changes at C1, C2, and C4. At positions C9
and C10, all the analogs have either free hydroxyl groups
or hydroxyl groups protected by an isopropylidene func-
tionality. The introduction of the C2-benzoate function-
ality was not possible by earlier described methods.
Therefore, a method has been developed to introduce the
benzoate group via oxidation of the benzylidene acetal.
intermediates 14 was carried out analogously to an
approach of Ettouati et al.11 for 14b, although we have
made some modifications to the synthetic route. After
these ammonium salts were collected by filtration, tri-
methylammonium iodide was eliminated by K2CO3 to
give a mixture of 5a -f. In the next step, the acetyl
groups were removed with 1.2 equiv of sodium methoxide
to give a mixture of 6a ,b. Selective introduction of the
acetonide bridge at 6a ,b using acetone and CuSO4 yielded
a mixture of 7a ,b. At this stage the first purification by
chromatography was carried out. Separation of 7a and
7b was unsuccessful, however. The yield of 7a ,b was
55% starting from 5a -f. Treatment of the mixture of
7a ,b with dihydropyran, acetone, or the dimethyl acetal
of benzaldehyde, respectively, yielded 8a , 8b,20 and 8c,
respectively, mixed with 7b. At this stage it was possible
to separate compound 7b (14%), which itself is an
interesting precursor for the synthesis of 1-deoxypacli-
taxel analogs,21 from compounds 8a ,b,c (82, 73, and 85%)
by chromatography. In order to discriminate between
the OH groups at C1, C2, C9, and C10, the tetrahydro-
pyranyl-protected compound 8a was prepared. We ex-
pected that the tetrahydropyranyl groups could be re-
moved independently from the isopropylidene functionality
as well as from each other. The benzylidene functionality
(8c) was selected because it is possible to convert it into
a benzoyl group by oxidation.22
Resu lts
Crude taxine B can easily be isolated, without chro-
matographic steps, from the needles of the European yew,
Taxus baccata L., in yields of 12 g per kg of dried leaves,
by an extraction method based on procedures described
by Lucas and Graf.17 The yield of 10-deacetylbaccatin
III, the precursor used in the synthesis of paclitaxel, from
these needles is at least five times less.18 Crude taxine
B, therefore, seemed to be an excellent precursor for the
synthesis of 7-deoxypaclitaxel analogs.
A closer investigation of isolated crude taxine B
showed19 that it was a mixture of several compounds,
40% of which had a taxane skeleton (4a -f). No further
purification was necessary, however, because the com-
pounds with the taxane skeleton were easily separated
from the other compounds by crystallization as am-
monium salts after reaction with methyl iodide. The
complete conversions of the crude taxine B mixture 4a -f
into the protected 7-deoxypaclitaxel derivatives 15a -c
are presented in Scheme 1. The preparation of the
Since all the hydroxyl groups were protected as acetals,
it was possible to remove the cinnamoyl side chain11 with
20 N NaOH, yielding compounds 9a ,b,c (95, 93, and
76%). Conversion of the allylic alcohol function into an
oxetane ring was achieved by established methods.11,23
Dihydroxylation with osmium tetraoxide gave 10a ,b ,c
(75, 87, and 55%). Protection of the primary alcohol with
tert-butyldimethylsilyl chloride and mesylation of the
secondary alcohol gave 11a ,b,c (85, 81, and 77%). From
compound 11a we followed two routes to compound 14a .
The first route (11a via 12a to 14a ) had already been
worked out by Ettouati et al.11 in the preparation of
compound 14b from 11b. Removal of the tert-butyldi-
methylsilyl group with Bu4N+ -F, followed by ring closure
with Bu4N+ -OAc, yielded 12a (75%). Reduction of the
carbonyl at C13 with DIBALH gave the R-isomer 14a
(37% from 11a ; the â-isomer was isolated in 11% yield).
In order to find a more selective reduction of the carbonyl
group at C13 by a different route (11a via 13a to 14a )
this carbonyl of 11a was first reduced by DIBALH. Use
of models and calculations24 indicated that the mesyl
functionality at C5 is able to shield the back side of the
(13) (a) Kingston, D. G. I.; Magri, N. F.; J itrangsri, C. Stud. Org.
Chem. (Amstedam) 1986, 26, 219-235. (b) Samaranayake, G.; Magri,
N. F.; J itrangsri, C.; Kingston, D. G. I. J . Org. Chem. 1991, 56, 5114-
5119. (c) Chordia, M. D.; Chaudhary, A. G.; Kingston, D. G. I.; J iang,
Y. Q.; Hamel, E. Tetrahedron Lett. 1994, 35, 6843-6846.
(14) Parness, J .; Kingston, D. G. I.; Powell, R. G.; Harracksingh,
C.; Horwitz, S. B. Biochem. Biophys. Res. Commun. 1982, 105, 1082-
1089.
(15) (a) Mellado, W.; Magri, N. F.; Kingston, D. G. I.; Garcia-Arenas,
R.; Orr, G. A.; Horwitz, S. B. Biochem. Biophys. Res. Commun. 1984,
124, 329-336. (b) Magri, N. F.; Kingston, D. G. I. J . Nat. Prod. 1988,
51, 298-306. (c) Kant, J .; Huang, S.; Wong, H.; Fairchild, C.; Vyas,
D.; Farina, V. Bioorg. Med. Chem. Lett. 1993, 3, 2471-2474.
(16) (a) Horwitz, S. B.; Lothstein, L.; Manfredi, J . J .; Mellado, W.;
Parness, J .; Roy, S. N.; Schiff, P. B., Sorbara, L.; Zeheb, R. Ann. N. Y.
Acad. Sci. 1986, 466, 733-739. (b) Chen, S.; Fairchild, C.; Mamber, S.
W.; Farina, V. J . Org. Chem. 1993, 58, 2927-2928. (c) Klein, L. L.;
Yeung, C. M.; Li, L.; Plattner, J . L. Tetrahedron Lett. 1994, 35, 4707-
4710. (d) Datta, A.; Vander Velde, D. G.; Georg, G. I. Tetrahedron Lett.
1995, 36, 1985-1988. (e) Kant, J .; O’Keeffe, W. S.; Chen, S.; Farina,
V.; Fairchild, C.; J ohnston, K.; Kadow, J . F.; Long, B. H.; Vyas, D.
Tetrahedron Lett. 1994, 35, 5543-5546. (f) Rao, K. V.; Bhakuni, R. S.;
J ohnson, J .; Oruganti, R. S. J . Med. Chem. 1995, 38, 3411-3414.
(17) (a) Lucas, H. Arch. Pharm. 1856, 85, 145-149. (b) Graf, E.;
Bertholdt, H. Pharm. Zentralhalle Dtschl. 1957, 96, 385. (c) Graf, E.
Arch. Pharm. 1958, 291, 443-449.
(18) (a) Crude taxine B, which is isolated in 12 g per kg of dried
leaves, contains about 40% (5 g) of the compounds 4a -f. Denis et al.
claim to isolate 10-deacetylbaccatin III, the precursor applied in the
synthesis of paclitaxel, in yields of ca. 1 g per kg of fresh leaves.4
Mostly, much lower yields, however, are reported in the literature.18b
Furthermore, the isolation of the taxines is much less labor intensive
and also less expensive. No organic solvents are required in the initial
extraction procedure and no chromatographic steps are needed for the
purification. (b) ElSohly, H. N.; Croom, E. M.; Kopycki, W. J .; J oshi,
A. S.; ElSohli, M. A.; McChesney, J . D. Phytochem. An. 1995, 6, 149-
156.
(20) Compounds 8b-14b were prepared as reported by Ettouati et
al. The 1H-NMR spectra of 8b-14b were in agreement with those in
the literature; also, see ref 12.
(21) (a) Compound 7b was difficult to purify. Therefore, the C2-OH
of 7b was protected with trimethylsilyl chloride. This silylated
compound was then fully characterized; see also the supporting
information. (b) In a similar way as described for 8a -c in this paper,
compound 7b can be converted into 1,7-dideoxypaclitaxel analogs (to
be published).
(22) (a) Hosokawa, T.; Imada, Y.; Murahashi, S.-I. J . Chem. Soc.,
Chem. Commun. 1983, 1245-1246. (b) Kloosterman, M.; Slaghek, T.;
Hermans, J . P. G.; Boom van, J . H. Recl: J . R. Neth. Chem. Soc. 1984,
103, 335-341. (c) Han, O.; Liu, H.-W. Tetrahedro Lett. 1987, 28, 1073-
1076. (d) Sato, K.-I.; Igarashi, T.; Yanagisawa, Y.; Kawauchi, N.;
Hashimoto, H.; Yoshimura, J . Chem. Lett. 1988, 1699-1702. (e) Ziegler,
F. E.; Tung, J . S. J . Org. Chem. 1991, 56, 6530-6537. (f) Murahashi,
S.-I.; Oda, Y.; Naota, T. Chem. Lett. 1992, 2237-2240. (g) Bhat, S.;
Ramesha, A. R.; Chandrasekaran, S. Synlett 1995, 329-330.
(23) (a) Berkowitz, W. F.; Amarasekara, A. S. Tetratehdron Lett.
1985, 26, 3663-3664. (b) Berkowitz, W. F.; Amarasekara, A. S.;
Perumattam, J . J . J . Org. Chem. 1987, 52, 1119-1124. (c) Lin, J .;
Nikaido, M. M.; Clark, G. J . Org. Chem. 1987, 52, 3745-3752.
(19) J enniskens, L. H. D.; Rozendaal van, E. L. M.; Beek van, T. A.;
Wiegerinck, P. H. G.; Scheeren, H. W. J . Nat. Prod. 1996, 59, 117-
123.

7094 J . Org. Chem., Vol. 61, No. 20, 1996
Wiegerinck et al.
Sch em e 1
carbonyl at C13. The attack of a hydride, therefore, can
only take place from the front side. Indeed, only the
R-isomer, 13a , was formed; the â-isomer was not de-
tected. Unfortunately, 13a was isolated in only 45%
yield. From the remaining 55%, about 30% was lost as
a result of column chromatography. The other 25%
consisted of several products that were not further
identified. The reduction was not studied further at this
stage although it may be optimized by using other
(leaving) groups instead of the mesyl functionality.
Desilylation with Bu4N+ -F followed by treatment with
(24) mm+-calculations were carried out with the computer program
and CS Chem3D Pro (version 3.2).

Semisynthesis of Some 7-Deoxypaclitaxel Analogs
J . Org. Chem., Vol. 61, No. 20, 1996 7095
Sch em e 2
Sch em e 3
tion of the benzoyl group, we tried several reducing
agents including BH3-THF, NaBH4, LiBH4, and K-
selectride. The best results were obtained after reduction
with BH3-THF, although in this case concomitant reduc-
tion of the C11-C12 double bond could not be avoided.
The obtained yield of 18, therefore, was only 21%.
Coupling of 18 with the paclitaxel side chain by the
method described above yielded 19 (80%).
Deprotection of the 7-deoxypaclitaxel analogs 15a -c
and 19 was performed by acid hydrolysis. Treatment of
15a with a 2/2/1 mixture of H2O/HOAc/THF provided 20
(76%), as shown in Scheme 3. Using a 2/4/1 mixture at
40 °C, the isopropylidene functionality at C9,C10 of 15a
and 15b, respectively, was also hydrolyzed, yielding 21a
(63%) and 21b (66%). Unfortunately, it was not possible
to remove the THP group at C2 of compound 21a or to
remove the isopropylidene functionality at C1,C2 of
compound 21b without destruction of other parts of the
molecule. Recently, analogous problems with the hy-
drolysis of the isopropylidene functionality of a related
taxane compound have been reported by Nicolaou et al.26
Compound 23 was isolated in 68% yield after depro-
tection of compound 15c with a 2/4/1 mixture of H2O/
HOAc/THF at 40 °C, as shown in Scheme 4. Deprotection
of compound 15c with a 2/2/1 mixture of H2O/HOAc/THF
at room temperature gave 22 in 73% yield.
Bu4N+ -OAC yielded 14a (36% from 11a ). The yield of
14a , therefore, was about the same for both routes,
although purification by column chromatography after
each step appeared to be much more difficult for route
2, probably due to the early reduction step that yielded
too many side products. For this reason, compounds 14b
(24%) and 14c (29%) were synthesized from 11b and 11c,
respectively, by the first route. Coupling of compounds
14a ,b,c with the oxazinone side chain, according to the
protocol described by Holton,25 gave the protected analogs
of 7-deoxypaclitaxel, 15a ,b,c (89%, 66%, and 70%).
Due to the surprising acid stability of an acetal
protecting functionality at C2, it is not possible to
introduce the necessary benzoate group at C2 via
benzoylation of an OH group at the C2 position. Taking
this into account, we rationalized that the benzoate group
may be selectively introduced at C2 via oxidation of a
benzylidene acetal at C1, C2. For the oxidation of the
benzylidene functionality to a benzoyl group we tried
several methods.22 Best results were obtained when the
benzylidene functionality at C1,C2 of 22 was oxidized by
t-BuOOH in the presence of a catalytic amount of Pd-
(OAc)2 to yield compound 24 (28%), with a 55% recovery
of compound 22.
Protected analog 19 was synthesized as depicted in
Scheme 2. Starting from compound 12a , the hydroxyl
groups at C1 and C2 were first deprotected, after which
the benzoate group was introduced at C2. It appeared,
however, not to be possible to hydrolyze both THP groups.
Only the THP group at C1 was hydrolyzed, yielding 16
(89%), as became clear after the free hydroxyl group was
benzoylated with benzoyl chloride in pyridine, yielding
17 (96%). The 400 MHz 1H-NMR spectrum of compound
17 showed no downfield shift of the proton at C2 as would
be expected if the benzoate group is attached to C2 (4.14
ppm in 16 and 4.15 ppm in 17). In order to achieve
selective reduction of the C13 carbonyl and avoid reduc-
(26) Nicolaou, K. C.; Guy, R. K. Angew. Chem. 1995, 107, 2247-
2259.
(25) Holton, R. A. European Patent 1991, EP 0428376A1.

7096 J . Org. Chem., Vol. 61, No. 20, 1996
Wiegerinck et al.
Sch em e 4
Sch em e 5
assigned at C4 and the R-configuration at C5 because of
the NOE contact between CH3(19) and H(20â).
Biologica l Eva lu a tion
All the compounds 20, 21a ,b, and 23-25 showed no
or very slight in vitro cytotoxicity against seven well-
characterized human tumor cell lines.28 This lack of
activity was first attributed to the missing benzoate
group at C2, an assumption in agreement with SAR
studies6c,7a,b,29 in which it was shown that the benzoate
functionality at C2 is necessary for activity.
In compounds 21a and 23 we hoped that the THP
group and the benzylidene acetal functionality could be
a substitute for the benzoate group at C2, due to the two
acetal oxygens, which are in about the same position as
the two oxygens of the benzoate group. Compound 25
could demonstrate that a benzoyl group at this position
does not have the same important influence on the
activity as this functionality has on C2. Also, no cyto-
toxicity was found for compound 24, which has a benzoate
group at C2.
Acid hydrolysis of compound 19 to give 25 (Scheme 5)
appeared to be rather difficult. In a 4/2/1 mixture of
AcOH/H2O/THF at 50 °C, the isopropylidene functionality
was not hydrolyzed. It was necessary to use a 12/2/1
mixture of AcOH/H2O/THF at 50 °C. Under these
conditions the paclitaxel side chain was split off for 32%.
Nevertheless, we were able to isolate 25 in 61% yield.
Recent SAR studies on paclitaxel analogs with sub-
stituent variations at C4 have shown that the substituent
at C4 is very important for cytotoxic activity.9b,13c,30 We
suppose, therefore, that the lack of activity seen in the
compounds presented here is probably due to the missing
acetate group at C4.
Str u ctu r e Deter m in a tion of Com p ou n d 23
The structure of 23 is presumed to be as drawn in
Scheme 4. The configurations at C4, C5, C13, and C4′
(for numbering see 23, Scheme 4) were confirmed by NOE
difference experiments. The following NOE contacts
were found: H(2)-H(9); H(2)-CH3(17); H(2)-CH3(19);
H(2)-H(4′); H(9)-CH3(19); H(13)-H(14â); H(13)-CH3-
(16); H(14â)-CH3(16), and CH3(19)-H(20â). The con-
figuration at C13 must be the S-configuration, as no NOE
contact is possible between H(13) and CH3(16) in the case
of the R-configuration.27 The configuration at C4′ must
also be the S-configuration because of the NOE contact
between H(4′) and H(2). In the R-configuration these
protons are in the trans-position; such a NOE contact,
therefore, is not possible. The S-configuration was
(28) (a) The determination of the cytotoxicity was carried out by H.
J . Kolker, J . Verweij, G. Stoter, and J . H. M. Schellens, from the
laboratory of Experimental Chemotherapy and Pharmacology, Depart-
ment of Medical Oncology. Rotterdam Cancer Institute (Dr. Daniel den
Hoed Kliniek). (b) For details of the in vitro assay, see: Kepers, Y. P.;
Pizao, P. E.; Peters, G. J .; Van Ark-Otte, J .; Winograd, B.; Pinedo, H.
M. Eur. J . Cancer 1991, 27, 897-900. (c) The seven human tumor cell
lines used for the cytotoxity tests were as follows: MCF7, breast cancer;
EVSA-T, breast cancer; WIDR, colon cancer; IGROV, ovarian cancer;
M19 MEL, melanoma; A498, renal cancer; H226, nonsmall cell lung
cancer.
(29) (a) Chaudhary, A. G.; Gharpure, M. M.; Rimoldi, J . M.; Chordia,
M. D.; Gunatilaka, A. A. L.; Kingston, D. G. I.; Grover, S.; Lin, C. M.;
Hamel, E. J . Am. Chem. Soc. 1994, 116, 4097-4098. (b) Nicolaou, K.
C.; Renaud, J .; Nantermet, P. G.; Couladouros, E. A.; Guy, E. A.;
Wrasidlo, W. J . Am. Chem. Soc. 1995, 117, 2409-2420.
(27) Hoemann, M. Z.; Vander Velde, D.; Aube´, J .; Georg, G. I.;
J ayasinghe, L. R. J . Org. Chem. 1995, 60, 2918-2921.

Semisynthesis of Some 7-Deoxypaclitaxel Analogs
J . Org. Chem., Vol. 61, No. 20, 1996 7097
Cl2 (75 mL) was slowly added dihydropyran (2.3 g, 27 mmol)
in CH2Cl2 (10 mL) at rt. After 1 d the reaction mixture was
washed with saturated NaHCO3 solution and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography (EtOAc/hexane 2/5), yielding 7b21 (0.68 g,
1.3 mmol, 14%) and 8a (5.4 g, 7.7 mmol, 82%): mp 66 °C; 1H-
NMR (400 MHz, CDCl3) δ 7.73 (m,2H), 7.41 (m, 3H), 7.61 (d,
J ) 15.9 Hz, 1H), 6.33 (d, J ) 15.9 Hz, 1H), 5.58 (bs, 1H),
5.33 (s, 1H), 5.27 (bs, 1H), 4.91 (m, 1H), 4.90 (d, J ) 9.2 Hz,
1H), 4.56 (m, 1H), 4.26 (d, J ) 9.2 Hz, 1H), 4.14 (d, J ) 5.6
Hz, 1H), 3.85 (m, 1H), 3.73 (m, 1H), 3.49 (m, 1H), 3.39 (m,
1H), 3.09 (d, J ) 5.6 Hz, 1H), 2.67 (s, 2H), 2.12 (s, 3H), 1.59
(s, 3H), 1.50 (s, 3H), 1.44 (s, 3H), 1.36 (s, 3H), 1.10 (s, 3H);
FAB-MS 705 [M + H]+. Anal. Calcd for C42H56O9: C, 71.57;
H, 8.01. Found: C, 71.91; H, 7.95.
Our future synthetic program is directed toward
7-deoxypaclitaxel analogs that possess a benzoate group
at C2 as well as an acetate group at C4. Furthermore,
the conversion of compound 7b into 1,7-dideoxypaclitaxel
analogs is now in progress.21b
Exp er im en ta l Section
Chemical shift values are reported as δ-values relative to
TMS as internal standard; deuteriochloroform was used as
solvent. Mass spectra were obtained with a double-focusing
spectrometer. Melting points are uncorrected.
Compounds 8b-14b were prepared as reported by Ettouati
et al.11 The 1H-NMR spectra of 8b-14b were in agreement
with those reported in the literature.11
1,2-O-Ben zylid en e-9,10-O-(p r op a n e-2,2-d iyl)-5r-cin n -
a m oylta xicin -I (8c). The same procedure was followed as
for 8a . Instead of dihydropyran, the dimethyl acetal of
benzaldehyde (2.8 mL, 18.6 mmol) was added. Compound 8c
was isolated in 85% yield (4.98 g, 7.98 mmol, 85%): mp 108-
110 °C; FAB-MS 625 [M + H]+, 647 [M + Na]+. Anal. Calcd
for C39H44O7: C, 74.98; H, 7.10. Found: C, 74.63; H, 7.23.
Hyd r olysis of 8a t o 9a . To a solution of 8a (5.4 g, 7.7
mmol) in dry THF (60 mL) was added 20 N NaOH (aq) (25
mL). The reaction mixture was stirred at reflux temperature
for 2 d. The reaction mixture was subsequently diluted with
water (50 mL) and extracted twice with CH2Cl2 (150 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography (EtOAc/hexane 1/1), yielding 9a (4.20 g,
Extr a ction P r oced u r e for Cr u d e Ta xin e B. Dried
leaves (17 kg) of T. baccata were soaked in an aqueous solution
of H2SO4 (100 L, 0.5% v/v) for 3 days. The sulfuric acid
solution was separated from the leaves and extracted (in
portions of 20 L) with diethyl ether (3 L) in a continuous
extraction apparatus for 1 d, in order to remove the major part
of the undesirable neutral organic compounds. The sulfuric
acid solution was brought to pH 9 by addition of aqueous
ammonia. This solution was extracted twice with diethyl ether
(3 L) in a continuous extraction apparatus for 1 d. The
combined ether layers were dried over Na2SO4 and concen-
trated in vacuo, yielding crude taxine (150-200 g from 17 kg,
depending on the quality of the leaves) as a light yellow
amorphous powder.
P r ep a r a tion of th e Mixtu r e of 5a -f. To a solution of
crude taxine B (containing 40% of 4a -f) (25.0 g, 42.9 mmol)
in ether (150 mL) was added methyl iodide (12.5 mL). After
1 d the pale yellow amorphous iodide salt of 4a -f was
collected, washed with ether, and dried (13.4 g, 18.3 mmol). A
solution of this salt (13.4 g) in ethanol (50 mL) was added to
a solution of K2CO3 (15.0 g) in water (750 mL). The reaction
mixture was stirred for 2 h. The precipitated mixture of 5a -f
was collected, washed with water, and dried (9.50 g, 17.7
mmol).
P r ep a r a tion of th e Mixtu r e of 5r-Cin n a m oylta xicin -I
(6a ) a n d 5r-Cin n a m oylta xicin -II (6b). A solution of sodium
methoxide prepared from 0.49 g of sodium (0.021 mol), in
methanol (550 mL) was cooled to 0 °C under an argon
atmosphere. After addition of 5a -f (9.50 g, 17.7 mmol), the
mixture was stirred for 16 h at 0 °C. The reaction mixture
was subsequently acidified with glacial acetic acid and con-
centrated, and water (500 mL) was added. This solution was
extracted twice with ether (200 mL). The combined ether
layers were washed with saturated NaHCO3 solution, dried
over Na2SO4, and concentrated in vacuo, yielding a mixture
of 6a ,b (7.45 g, 15.0 mmol, 85%).
P r ep a r a tion of th e Mixtu r e of 9,10-O-(P r op a n e-2,2-
d iyl)-5r-cin n a m oylta xicin -I (7a ) a n d 9,10-O-(P r op a n e-
2,2-d iyl)-5r-cin n a m oylta xicin -II (7b). To a suspension of
anhydrous CuSO4 (35 g, 0.22 mol) in dry acetone (750 mL)
was added the mixture of 6a,b (7.45 g, 15.0 mmol) and a
catalytic amount of p-toluenesulfonic acid were added. After
2 d at rt the solution was filtered. The filtrate was concen-
trated in vacuo. The residue was purified by chromatography
(EtOAc/hexane 2/5) to give a mixture of 7a and 7b (5.23 g, 9.80
mmol, 65%).
1
7.32 mmol, 95%): mp 66-69 °C; H-NMR (400 MHz, CDCl3)
δ 5.47 (bs, 1H), 5.09 (bs, 1H), 4.91 (d, J ) 9.2 Hz, 1H), 4.89
(m, 1H), 4.58, (m, 1H), 4.22 (d, J ) 9.2 Hz, 1H), 4.17 (bs, 1H),
4.10 (d, J ) 5.4 Hz, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 3.50 (m,
1H), 3.40 (m, 1H), 3.23 (d, J ) 5.4 Hz, 1H), 2.60 (bs, 2H), 2.06
(s, 3H), 1.58 (s, 3H), 1.49 (s, 3H), 1.45 (s, 3H), 1.32 (s, 3H),
1.05 (s, 3H); CIMS, 574 [M]+. Anal. Calcd for C33H50O8: C,
68.95; H, 8.79. Found: C, 69.17; H, 8.63.
Hyd r olysis of 8c to 9c. The same procedure was followed
as for 9a , using 8c (4.98 g, 7.98 mmol). Compound 9c was
isolated in 76% yield (3.00 g, 6.07 mmol): mp 180 °C; FAB-
MS 495 [M + H]+. Anal. Calcd for C30H38O6: C, 72.85; H,
7.74. Found: C, 72.51; H, 8.00.
Dih yd r oxyla tion of 9a to 10a . To a solution of 9a (4.20
g, 7.32 mmol) in THF/H2O (80/40 mL) were added N-methyl-
morpholine N-oxide monohydrate (900 mg, 6.70 mmol) and a
solution of OsO4 (2.5% in t-BuOH, 6.4 mL). The reaction
mixture rapidly turned red. After 20 h, Florisil (2.0 g), water
(26 mL), and Na2O4S2 (256 mg) were added. The mixture was
stirred for an additional 10 min and then filtered. The filtrate
was diluted with a saturated solution of NH4Cl in water (100
mL) and extracted twice with EtOAc (150 mL). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by chroma-
tography (EtOAc), yielding 10a (3.33 g, 5.48 mmol, 75%): mp
72 °C; 1H-NMR (400 MHz, CDCl3) δ 4.97 (m, 1H), 4.81 (d, J )
9.3 Hz, 1H), 4.55, (m, 1H), 4.15 (d, J ) 9.3 Hz, 1H), 4.09 (d, J
) 4.9 Hz, 1H), 4.04 (bs, 1H), 3.87 (m, 1H), 3.82 (bs, 1H), 3.77
(m, 1H), 3.59 (bs, 1H), 3.50 (m, 1H), 3.42 (m, 1H), 3.23 (d, J )
19.3 Hz, 1H), 2.65 (d, J ) 4.9 Hz, 1H), 2.62 (d, J ) 19.3 Hz,
1H), 2.03 (s, 3H), 1.56 (s, 3H), 1.46 (s, 3H), 1.43 (s, 3H), 1.34
(s, 3H), 1.08 (s, 3H); FAB-MS 524 [M - THP + H]+. Anal.
Calcd for C33H52O10: C, 65.11; H, 8.61. Found: C, 64.72; H,
8.28.
Dih yd r oxyla tion of 9c to 10c. The same procedure was
followed as for 10a , using 9c (3.00 g, 6.07 mmol). Compound
10c was isolated in 55% yield (1.77 g, 3.35 mmol): mp 133
°C; FAB-MS 551 [M + Na]+. Anal. Calcd for C30H40O8‚H2O:
C, 65.90; H, 7.75. Found: C, 66.26; H, 7.57.
Silyla tion a n d Mesyla tion of 10a to 11a . A solution of
imidazole (5.10 g, 74.8 mmol) and TBDMSCl (4.64 g, 30.9
mmol) in DMF (30 mL) was stirred for 15 min. Compound
10a (3.33 g, 5.48 mmol) was subsequently added. After 3 h
the reaction mixture was diluted with a solution of 10% citric
acid in water (200 mL) and extracted twice with EtOAc (100
mL). The combined organic layers were washed with brine,
1,2-Di(tetr a h yd r op yr a n -2-yl)-9,10-O-(p r op a n e-2,2-d iyl)-
5r-cin n a m oylta xicin -I (8a ). To a solution of 7a ,b (5.0 g, 9.4
mmol) and p-toluenesulfonic acid (10 mg, 0.05 mmol) in CH2-
(30) (a) Neidigh, K. A.; Gharpure, M. M.; Rimoldi, J . M.; Kingston,
D. G. I.; J iang, Y.Q.; Hamel, E. Tetrahedron Lett. 1994, 35, 6839-
6842. (b) Chen, S.; Kadow, J . F.; Farina, V. Fairchild, C. R.; J ohnston,
K. A. J . Org. Chem. 1994, 59, 6156-6158. (c) Klein, L. L.; Li, L.; Yeung,
C. M.; Maring, C. J .; Thomas, S. A.; Grampovnik, D. J .; Plattner, J . J .
In Taxane Anticancer Agents, Basic Science and Current Status; Georg,
G. I., Chen, T. T., Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series
No. 583; American Chemical Society: Washington, DC, 1995; 276-
287. (d) Chen, S.-H.; Wei, J .-M.; Long, B. H.; Fairchild, C. A.; Carboni,
J .; Mamber, S. W.; Rose, W. C.; J ohnston, K.; Casazza, A. M.; Kadow,
J . F.; Farina, V.; Vyas, D. M.; Doyle, T. W. Bioorg. Med. Chem. Lett.
1995, 5, 2741-2746.

7098 J . Org. Chem., Vol. 61, No. 20, 1996
Wiegerinck et al.
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by chromatography (EtOAc/hexane 2/5), yielding
the silylated compound (3.78 g, 5.23 mmol, 95%): mp 52 °C;
FAB-MS 746 [M + Na]+. Anal. Calcd for C39H66O10Si‚H2O:
C, 63.20; H, 9.27. Found: C, 63.56; H, 8.95.
solution of DIBALH in CH2Cl2 (2.0 mL, 1 M, 2.0 mmol) was
added. The reaction mixture was stirred at 0 °C for 3 h, after
which time a solution of 10% citric acid in water (20 mL) was
carefully added. The water layer was extracted twice with
CH2Cl2 (50 mL). The combined organic layers were washed
with saturated NaHCO3 solution and with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography (EtOAc/hexane 2/5), yielding 13a (0.47 g,
0.59 mmol, 45%): mp 49 °C; 1H-NMR (400 MHz, CDCl3) δ 4.88
(m, 2H), 4.74 (d, J ) 9.4 Hz, 1H), 4.58 (m, 1H), 4.43 (m, 1H),
4.26 (d, J ) 10.5 Hz, 1H), 4.02 (d, J ) 9.4 Hz, 1H), 3.86 (m,
2H), 3.74 (m, 1H), 3.63 (d, J ) 10.5 Hz, 1H), 3.51 (m, 1H),
3.47 (s, 1H), 3.39 (m, 1H), 3.06 (s, 3H), 2.69 (d, J ) 4.0 Hz,
1H), 2.41 (bd, J ) 6.3 Hz, 2H), 2.06 (s, 3H), 1.59 (s, 3H), 1.46
(s, 3H), 1.43 (s, 3H), 1.40 (s, 3H), 1.06 (s, 3H), 0.91 (s, 9H),
To a solution of the silylated compound (3.78 g, 5.23 mmol)
in pyridine (50 mL) at 0 °C was added MsCl (2.5 mL). The
reaction mixture was stirred for 20 h at rt, after which time
CH2Cl2 (150 mL) was added. The mixture was washed with
a solution of 10% citric acid in water (75 mL) and with
saturated NaHCO3 solution, dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by chromatography
(EtOAc/hexane 2/5), yielding 11a (3.70 g, 4.63 mmol, 89%):
mp 57 °C; 1H-NMR (400 MHz, CDCl3) δ 4.94 (m, 1H), 4.86
(bs, 1H), 4.80 (d, J ) 9.3 Hz, 1H), 4.57 (m, 1H), 4.18 (d, J )
9.3 Hz, 1H), 4.12 (d, J ) 10.4 Hz, 1H), 4.02 (d, J ) 4.1 Hz,
1H), 3.86 (m, 1H), 3.74 (m, 1H), 3.66 (d, J ) 10.4 Hz, 1H),
3.51 (m, 1H), 3.47 (d, J ) 19.4 Hz, 1H), 3.38 (m, 1H), 2.94 (s,
3H), 2.56 (d, J ) 19.4 Hz, 1H), 2.51 (d, J ) 4.1 Hz, 1H), 2.07
(s, 3H), 1.55 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H),
1.08 (s, 3H), 0.90 (s, 9H), 0.08 (s, 6H); FAB-MS 823 [M + Na]+.
Anal. Calcd for C40H68O12SiS: C, 59.97; H, 8.56; S, 4.00.
Found: C, 60.14; H, 8.47; S, 2.69.31
Silyla tion a n d Mesyla tion of 10c to 11c. The same
procedure was followed as for 11a , using 10c (1.77 g, 3.35
mmol). The silylated compound was isolated in 93% (2.03 g,
3.16 mmol) yield: mp 61 °C; FAB-MS, 665 [M + Na]+. Anal.
Calcd for C36H54O8Si: C, 67.26; H, 8.47. Found: C, 67.07; H,
8.83.
Compound 11c was isolated in 83% yield (1.91 g, 2.65
mmol): mp 199 °C; FAB-MS 743 [M + Na]+. Anal. Calcd for
C37H56O10SiS: C, 61.64; H, 7.83; S, 4.45. Found: C, 61.35; H,
8.09; S, 4.47.
0.08 (s, 6H); FAB-MS: 825 [M + Na]+. Anal. Calcd for C40H70
-
O12SiS: C, 59.82; H, 8.53; S, 3.99. Found: C, 59.74; H, 8.78;
S, 3.56.
2-Deben zoyl-1,2-(d itetr a h yd r op yr a n -2-yl)-4-d ea cetyl-
7-d eoxy-10-d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-9(R)-d ih y-
d r oba cca tin III (14a ) (Rou te 1). The same procedure was
followed as for 13a (route 2), using 12a (2.04 g, 3.46 mmol).
Compound 14a was isolated in 49% yield (1.02 g, 1.72 mmol):
1
mp 50 °C; H-NMR (400 MHz, CDCl3): δ 4.91 (m, 1H), 4.79
(dd, J ) 8.0, 3.6 Hz, 1H), 4.65 (d, J ) 8.9 Hz, 1H), 4.62 (d, J
) 8.0 Hz, 1H), 4.54 (m, 1H), 4.49 (d, J ) 8.0 Hz, 1H), 4.41 (m,
1H), 4.10 (d, J ) 8.9 Hz, 1H), 3.98 (d, J ) 4.4 Hz, 1H), 3.91
(m, 1H), 3.79 (m, 1H), 3.73 (s, 1H), 3.50 (m, 1H), 3.41 (m, 1H),
2.43 (dd, J ) 16.0, 9.8 Hz, 1H), 2.16 (m, 2H), 2.00 (m, 2H),
1.93 (s, 3H), 1.63 (s, 3H), 1.49 (s, 3H), 1.46 (s, 3H), 1.42 (s,
3H), 1.13 (s, 3H); FAB-MS 615 [M + Na]+. Anal. Calcd for
C33H52O9‚H2O: C, 64.89; H, 8.91. Found: C, 65.25; H, 8.83.
2-Deben zoyl-1,2-(d itetr a h yd r op yr a n -2-yl)-4-d ea cetyl-
7-d eoxy-10-d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-9(R)-d ih y-
d r oba cca tin III (14a ) (Rou te 2). The same procedure was
followed as for 12a (route 1), using 13a (0.47 g, 0.59 mmol).
The desilylated compound was not further purified.
Con str u ction of th e Oxeta n e Rin g: 11a to 12a (Rou te
1). To a solution of 11a (3.70 g, 4.63 mmol) in THF (75 mL)
was added tetrabutylammonium fluoride (1.8 g, 6.9 mmol). The
reaction mixture was stirred for 1 h at rt, after which time
EtOAc (150 mL) was added. The organic layer was washed
with saturated NaHCO3 solution, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by chroma-
tography (EtOAc/hexane 1/1), yielding the desilylated com-
pound (3.10 g, 4.52 mmol, 98%); mp 89 °C; FAB-MS, 687 [M
+ H]+, 709 [M + Na]+. Anal. Calcd for C34H54O12S: C, 59.46;
H, 7.92; S, 4.67. Found: C, 59.35; H, 7.88; S, 3.31.31
To a solution of the desilylated compound (3.10 g, 4.52
mmol) in butanone (75 mL) was added tetrabutylammonium
acetate (12.0 g, 39.9 mmol). The reaction mixture was stirred
at reflux temperature for 17 h. The mixture was diluted with
EtOAc (100 mL) and washed with a saturated solution of NH4-
Cl in water. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by chroma-
tography (EtOAc/hexane 2/5), yielding 12a (2.04 g, 3.46 mmol,
Compound 14a was isolated in 79% yield (0.28 g, 0.47
1
mmol): mp 49 °C; H-NMR (400 MHz, CDCl3) was the same
as for 14a in route 1.
2-Deben zoyl-1,2-O-ben zylid en e-4-d ea cetyl-7-d eoxy-10-
d ea cet yl-9,10-O-(p r op a n e-2,2-d iyl)-9(R)-d ih yd r ob a cca -
tin III (14c) (Rou te 1). The same procedure was followed
as for 13a (route 2), using 12c (0.85 g, 1.7 mmol). Compound
14c was isolated in 46% yield (0.40 g, 0.78 mmol): mp 105-
108 °C; FAB-MS 535 [M + Na]+. Anal. Calcd for C30H40O7:
C, 70.29; H, 7.86. Found: C, 70.27; H, 8.00.
2-Deben zoyl-1,2-(d itetr a h yd r op yr a n -2-yl)-4-d ea cetyl-
7-d eoxy-10-d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-2′-(eth oxy-
eth yl)-9(R)-d ih yd r op a clita xel (15a ). To a solution of 14a
(1.02 g, 1.72 mmol) in toluene (50 mL) were added DMAP (210
mg, 1.72 mmol), pyridine (1 mL) and modified paclitaxel
sidechain25 (2.75 g, 7.99 mmol). The reaction mixture was
stirred for 12 h at rt, after which time the reaction mixture
was diluted with EtOAc (200 mL). This mixture was washed
with a solution of 10% CuSO4 in water (50 mL). The organic
layer was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by chromatography (EtOAc/hexane 2/5),
yielding 15a (1.41 g, 1.51 mmol, 89%): mp 63 °C; 1H-NMR
(400 MHz, CDCl3) δ 7.76 (m, 2H), 7.48 (m, 5H), 7.33 (m, 3H),
7.08 (d, J ) 10.3 Hz, 1H), 6.12 (d, J ) 10.3 Hz, 1H), 5.88 (m,
1H), 4.95 (m, 1H), 4.79 (m, 1H), 4.61 (m, 3H), 4.47 (m, 3H),
4.18 (m, 2H), 3.94 (bs, 1H), 3.78 (m, 1H), 3.63 (m, 1H), 3.47
(m, 1H), 3.28 (m, 2H), 3.08-2.95 (dq, J ) 7.03 Hz, 1H), 2.24
(m, 3H), 2.06 (m, 3H), 1.86 (s, 3H), 1.63 (s, 3H), 1.52 (s, 3H),
1.46 (s, 3H), 1.43 (s, 3H), 1.26 (d, J ) 4.2 Hz, 3H), 1.19 (s,
3H), 0.92-0.85 (dt, J ) 7.03 Hz, 3H); FAB-MS, 955 [M + Na]+.
Anal. Calcd for C53H73NO13‚0.5H2O: C, 67.62; H, 7.94; N, 1.49.
Found: C, 67.47; H, 7.58; N, 1.90.
1
77%): mp 65 °C; H-NMR (400 MHz, CDCl3) δ 4.94 (m, 1H),
4.86 (bs, 1H), 4.80 (d, J ) 9.3 Hz, 1H), 4.57 (m, 1H), 4.18 (d,
J ) 9.3 Hz, 1H), 4.12 (d, J ) 10.4 Hz, 1H), 4.02 (d, J ) 4.1 Hz,
1H), 3.86 (m, 1H), 3.74 (m, 1H), 3.66 (d, J ) 10.4 Hz, 1H),
3.51 (m, 1H), 3.47 (d, J ) 19.4 Hz, 1H), 3.38 (m, 1H), 2.94 (s,
3H), 2.56 (d, J ) 19.4 Hz, 1H), 2.51 (d, J ) 4.1 Hz, 1H), 2.07
(s, 3H), 1.55 (s, 3H), 1.47 (s, 3H), 1.43 (s, 3H), 1.34 (s, 3H),
1.08 (s, 3H); FAB-MS 591 [M + H]+, 613 [M + Na]+. Anal.
Calcd for C33H50O9: C, 67.09; H, 8.53. Found: C, 67.04; H,
8.47.
Con str u ction of th e Oxeta n e Rin g: 11c to 12c (Rou te
1). The same procedure was followed as for 12a , using 11c
(1.91 g, 2.65 mmol). The desilylated compound was isolated
in 98% yield (1.60 g, 2.64 mmol): mp 116-120 °C; FAB-MS
629 [M + Na]+. Anal. Calcd for C31H42O10S: C, 61.37; H, 6.98;
S, 5.28. Found: C, 61.06; H, 7.08; S, 4.63.31
Compound 12c was isolated in 64% yield (0.85 g, 1.7
mmol): mp 109 °C; FAB-MS 533 [M + Na]+. Anal. Calcd for
C30H38O7‚H2O: C, 68.15; H, 7.64. Found: C, 67.80; H, 7.59.
Red u ction of 11a to 13a (r ou te 2). To a solution of 11a
(1.00 g, 1.25 mmol) in CH2Cl2 (10 mL) at -10 °C was added a
2-D e b e n zo y l-1,2-a c e t o n id e -4-d e a c e t y l-7-d e o x y -10-
d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-2′-(eth oxyeth yl)-9(R)-
d ih yd r op a clita xel (15b). The same procedure was followed
as for 15a , using 14b (0.49 g, 1.1 mmol). Compound 15b was
isolated in 66% yield (0.58 g, 0.72 mmol): mp 65 °C; FAB-MS
(31) This compound was not obtained completely pure and was used
as such in the next step.
804 [M + H]+, 826 [M + Na]+. Anal. Calcd for C46H61
-

Semisynthesis of Some 7-Deoxypaclitaxel Analogs
J . Org. Chem., Vol. 61, No. 20, 1996 7099
NO11‚H2O: C, 67.20; H, 7.74; N, 1.70. Found: C, 67.53; H,
7.70; N, 1.98.
3H), 1.37 (dd, J ) 5.5 Hz, 3H), 1.26 (s, 3H), 1.19 (s, 3H), 0.92
(dt, J ) 7.0 Hz, 3H); FAB-MS, 974 [M + Na]+. Anal. Calcd
for C55H69NO13‚H2O: C, 68.08; H, 7.39; N, 1.44. Found: C,
67.83; H, 7.13; N, 1.44.
2-Deben zoyl-1,2-O-ben zylid en e-4-d ea cetyl-7-d eoxy-10-
d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-2′-(eth oxyeth yl)-9(R)-
d ih yd r op a clita xel (15c). The same procedure was followed
as for 15a , using 14c (0.40 g, 0.78 mmol). Compound 15c was
isolated in 70% yield (0.47 g, 0.55 mmol): mp 73 °C; FAB-MS
874 [M + Na]+. Anal. Calcd for C50H61N O11‚H2O: C, 69.01;
H, 7.31; N, 1.61. Found: C, 68.94; H, 6.92; N, 1.90.
Hyd r olysis of 12a to 16. Compound 12a (1.00 g, 1.69
mmol) was dissolved in a mixture of HOAc/H2O/THF (68/34/
17 mL). After being stirred for 24 h at rt, the mixture was
diluted with EtOAc (100 mL). The organic layer was washed
with saturated NaHCO3 solution (75 mL) and with brine. The
organic layer was dried over Na2SO4 and concentrated in
vacuo. The residue was purified by chromatography (EtOAc/
hexane 1/1), yielding 16 (770 mg, 1.52 mmol, 89%); mp 67 °C;
1H-NMR (400 MHz, CDCl3) δ 4.94 (t, J ) 5.1 Hz, 1H), 4.96
(dd, J ) 8.5, 2.2 Hz, 1H), 4.67 (d, J ) 9.4 Hz, 1H), 4.61 (d, J
) 8.1 Hz, 1H), 4.37 (d, J ) 8.1 Hz, 1H), 4.26 (d, J ) 9.4 Hz,
1H), 4.14 (d, J ) 5.4 Hz, 1H), 3.67 (m, 2), 3.07 (s, 1H), 3.05 (d,
J ) 19.2 Hz, 1H), 2.59 (d, J ) 19.2 Hz, 1H), 2.02 (m, 3H), 1.93
(s, 3H), 1.81 (d, J ) 5.3 Hz, 1H), 1.62 (s, 3H), 1.58 (s, 3H),
1.49 (s, 3H), 1.45 (s, 3H), 1.33 (s, 3H); FAB-MS 529 [M + Na]+.
Anal. Calcd for C28H42O8: C, 66.38; H, 8.36. Found: C, 66.79;
H, 8.46.
Ben zoyla tion of 16 to 17. To a solution of 16 (0.77 g, 1.5
mmol) in EtOAc (10 mL) were added triethylamine (0.62 mL,
4.4 mmol), DMAP (1.16 g, 9.51 mmol), and benzoyl chloride
(0.32 mL, 2.8 mmol). After the mixture was stirred for 24 h
at rt, EtOAc (50 mL) was added. The mixture was washed
with a 10% citric acid solution in water (50 mL) and with brine,
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by chromatography (EtOAc/hexane 2/5), yielding
17 (891 mg, 1.46 mmol, 96%): mp 184 °C; 1H-NMR (400 MHz,
CDCl3) δ 8.04 (dd, J ) 7.4, 1.2 Hz, 2H), 7.57 (t, J ) 7.4 Hz,
1H), 7.45 (t, J ) 7.6 Hz, 2H), 4.97 (t, J ) 5.1 Hz, 1H), 4.78
(dd, J ) 8.4, 2.1 Hz, 1H), 4.67 (d, J ) 9.4 Hz, 1H), 4.58 (d, J
) 8.1 Hz, 1H), 4.34 (m, 3H), 4.25 (d, J ) 9.4 Hz, 1H), 4.14 (d,
J ) 5.4 Hz, 1H), 3.05 (d, J ) 19.2 Hz, 1H), 2.90 (s, 1H), 2.60
(d, J ) 19.2 Hz, 1H), 2.02 (m, 3H), 1.93 (s, 3H), 1.82 (d, J )
5.5 Hz, 1H), 1.58 (s, 3H), 1.55 (s, 3H), 1.49 (s, 3H), 1.45 (s,
3H), 1.33 (s, 3H); FAB-MS 611 [M + H]+, 633 [M + Na]+. Anal.
Calcd for C35H46O9: C, 68.83; H, 7.59. Found: C, 69.01; H,
7.26.
2-De b e n zoyl-2-(t e t r a h yd r op yr a n -2-yl)-4-d e a ce t yl-7-
d eoxy-10-d ea cet yl-9,10-O-(p r op a n e-2,2-d iyl)-9(R)-d ih y-
d r op a clita xel (20). Compound 15a (0.25 g, 0.27 mmol) was
dissolved in HOAc/THF/H2O (8/4/8 mL). After 20 h at rt the
reaction mixture was diluted with EtOAc (50 mL). The organic
layer was washed with saturated NaHCO3 solution (20 mL),
dried over Na2SO4, and concentrated in vacuo. The residue
was purified by chromatography (EtOAc/hexane 1/1), yielding
20 (159 mg, 0.205 mmol, 76%): mp 115 °C; 1H-NMR (400 MHz,
CDCl3) δ 7.72 (d, J ) 7.4 Hz, 2H), 7.58 (d, J ) 7.5 Hz, 2H),
7.40 (m, 6H), 7.03 (d, J ) 9.5 Hz, 1H), 5.98 (bd, J ) 10.0 Hz,
1H), 5.95 (m, 1H), 4.92 (bd, J ) 7.4 Hz, 1H); 4.86 (t, J ) 4.7
Hz, 1H), 4.60 (m, 3H), 4.49 (d, J ) 8.0 Hz, 1H), 4.25 (s, 1H),
4.15 (d, J ) 9.5 Hz, 1H), 3.98 (d, J ) 5.3 Hz, 1H), 3.59 (bs,
1H), 3.53 (t, J ) 5.5 Hz, 2H), 2.39 (dd, J ) 15.9, 3.7 Hz, 1H),
2.23 (m, 2H), 2.07 (d, J ) 5.3 Hz, 1H), 2.00 (m, 3H), 1.73 (s,
3H), 1.55 (s, 3H), 1.53 (s, 3H), 1.46 (s, 3H), 1.42 (s, 3H), 1.46
(s, 3H); FAB-MS 776 [M + H]+, 798 [M + Na]+. Anal. Calcd
for C44H57NO11‚H2O: C, 66.55; H, 7.49; N, 1.76. Found: C,
66.51; H, 7.40; N, 1.73.
2-De b e n zoyl-2-(t e t r a h yd r op yr a n -2-yl)-4-d e a ce t yl-7-
d eoxy-10-d ea cetyl-9(R)-d ih yd r op a clita xel (21a ). Com-
pound 15a (0.20 g, 0.21 mmol) was dissolved in HOAc/THF/
H2O (12/3/6 mL). The reaction mixture was stirred for 24 h
at 40 °C. The reaction mixture was diluted with EtOAc (50
mL). The organic layer was washed with saturated NaHCO3
solution (20 mL), dried over Na2SO4, and concentrated in
vacuo. The residue was purified by chromatography (EtOAc/
hexane 7/3), yielding 21a (97 mg, 0.13 mmol, 63%): mp 198
°C; 1H-NMR (400 MHz, CDCl3) δ 7.74 (d, J ) 7.3 Hz, 2H), 7.56
(d, J ) 7.6 Hz, 2H), 7.40 (m, 6H), 7.09 (d, J ) 9.5 Hz, 1H),
5.97 (bd, J ) 9.4 Hz, 1H), 5.89 (m, 1H), 4.91 (dd, J ) 8.8, 2.1
Hz, 1H), 4.86 (t, J ) 5.3 Hz, 1H), 4.62 (m, 3H), 4.48 (d, J )
8.0 Hz, 1H), 4.15 (bs, 1H), 3.97 (d, J ) 9.5 Hz, 1H), 3.93 (d, J
) 5.4 Hz, 1H), 3.70 (bs, 1H), 3.54 (t, J ) 5.5 Hz, 2), 2.75 (bs,
1H), 2.50 (bs, 1H), 2.36 (dd, J ) 15.8, 3.5 Hz, 1H), 2.27 (d, J
) 5.3 Hz, 1H), 2.22 (dd, J ) 15.7, 6.3 Hz, 1H), 2.00 (m, 5H),
1.67 (s, 3H), 1.55 (s, 3H), 1.48 (s, 3H), 1.16 (s, 3H); FAB-MS
736 [M + H]+, 758 [M + Na]+. Anal. Calcd for C41H53
-
NO11‚H2O: C, 65.32; H, 7.35; N, 1.86. Found: C, 65.02; H,
7.40; N, 1.80.
2-Deben zoyl-1,2-a ceton id e-4-d ea cetyl-7-d eoxy-9-d ih y-
d r o-10-d ea cetylp a clita xel (21b). The same procedure was
followed as for 21a , using 15b (0.20 g, 0.25 mmol). Compound
21b was isolated in 66% yield (114 mg, 0.165 mmol): mp 150
°C; FAB-MS 692 [M + H]+, 714 [M + Na]+. Anal. Calcd for
C39H49NO10‚1.5H2O: C, 65.15; H, 7.31; N, 1.95. Found: C,
65.29; H, 7.22; N, 1.92.
1-Be n zoyl-2-d e b e n zoyl-2-(t e t r a h yd r op yr a n -2-yl)-4-
d ea cetyl-7-d eoxy-10-d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-
9(R)-d ih yd r oba cca tin III (18). To a solution of 17 (0.89 g,
1.5 mmol) in dry THF (20 mL) was added BH3‚THF (20 mL, 1
M in THF, 20 mmol). After 3 h at rt, EtOAc (50 mL) was
added. The mixture was washed with a 10% citric acid
solution in water (50 mL) and with saturated NaHCO3
solution, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by chromatography (EtOAc/hexane 1/1),
yielding 18 (192 mg, 0.314 mmol, 21%): mp 127 °C; 1H-NMR
(400 MHz, CDCl3) δ 8.05 (d, J ) 7.4 Hz, 2H), 7.56 (t, J ) 7.3
Hz, 1H), 7.45 (t, J ) 7.7 Hz, 2H), 4.91 (t, J ) 5.1 Hz, 1H), 4.80
(dd, J ) 10.0, 5.1 Hz, 1H), 4.62 (d, J ) 9.4 Hz, 1H), 4.61 (d, J
) 8.1 Hz, 1H), 4.36 (m, 4H), 4.09 (d, J ) 9.4 Hz, 1H), 3.98 (d,
J ) 5.4 Hz, 1H), 3.26 (s, 1H), 2.44 (d, J ) 16.0 Hz, 1H), 2.14
(m, 2H), 2.03 (m, 3H), 1.93 (s, 3H), 1.49 (s, 3H), 1.48 (s, 3H),
1.45 (s, 3H), 1.42 (s, 3H), 1.13 (s, 3H); FAB-MS 635 [M + Na]+.
Anal. Calcd for C35H48O9‚H2O: C, 66.63; H, 8.01. Found: C,
66.31; H, 7.96.
1-Be n zoyl-2-d e b e n zoyl-2-(t e t r a h yd r op yr a n -2-yl)-4-
d ea cetyl-7-d eoxy-10-d ea cetyl-9,10-O-(p r op a n e-2,2-d iyl)-
2′-(et h oxyet h yl)-9(R)-d ih yd r op a clit a xel (19). The same
procedure was followed as for 15a , using 18 (0.19 g, 0.31
mmol). Compound 19 was isolated in 80% yield (240 mg, 0.252
mmol): mp 141 °C; 1H-NMR (400 MHz, CDCl3) δ 8.01 (d, J )
7.7 Hz, 2H), 7.83 (d, J ) 7.2 Hz, 2H), 7.75 (m, 2H), 7.40 (m,
9H), 7.07 (d, J ) 9.6 Hz, 1H), 6.13 (d, J ) 9.7 Hz, 1H), 5.85
(m, 1H), 4.94 (bd, J ) 5.5 Hz, 1H), 4.81 (m, 1H5), 4.65 (d, J )
9.5 Hz, 1H), 4.59 (d, J ) 7.9 Hz, 1H), 4.48 (m, 2H), 4.19 (m,
4H), 3.96 (d, J ) 5.3 Hz, 1H), 3.25-2.98 (m, 2H), 2.25 (m, 2H),
2.05 (m, 4H), 1.88 (s, 3H), 1.52 (s, 3H), 1.47 (s, 3H), 1.44 (s,
2-Deben zoyl-1,2-O-ben zylid en e-4-d ea cetyl-7-d eoxy-10-
d ea cet yl-9,10-O-(p r op a n e-2,2-d iyl)-9(R)-d ih yd r op a cli-
ta xel (22). Compound 15c (0.20 g, 0.24 mmol) was dissolved
in HOAc/THF/H2O (8/4/8 mL). After 2 h at rt the reaction
mixture was diluted with EtOAc (50 mL). The organic layer
was washed with saturated NaHCO3 solution (20 mL), dried
over Na2SO4, and concentrated in vacuo. The residue was
purified by chromatography (EtOAc/hexane 1/1), yielding 22
1
(136 mg, 0.175 mmol, 73%): mp 99 °C; H-NMR (400 MHz,
CDCl3): δ 7.71-7.15 (m, 15H), 7.10 (d, J ) 7.9 Hz, 1H), 5.95
(bd, J ) 9.2 Hz, 1H), 5.90 (m, 1H), 5.74 (s, 1H), 4.90 (dd, J )
6.7 Hz, J ) 1.8 Hz, 1H), 4.67 (d, J ) 8.1 Hz, 1H), 4.62 (bs,
1H), 4.59 (d, J ) 9.5 Hz, 1H), 4.44 (d, J ) 8.2 Hz, 1H), 4.25 (d,
J ) 5.2 Hz, 1H), 4.21 (d, J ) 9.5 Hz, 1H), 3.91 (s, 1H), 3.75
(bs, 1H), 2.45 (m, 2H), 2.24 (m, 2H), 2.20 (d, J )5.2 Hz, 1H),
1.67 (s, 3H), 1.63 (s, 3H), 1.59 (s, 3H), 1.49 (s, 3H), 1.43 (s,
3H), 1.23 (s, 3H); FAB-MS 802 [M + Na]+. Anal. Calcd for
C46H53N O10‚0.5H2O: C, 70.03; H, 6.89; N, 1.78. Found: C,
69.93; H, 6.54; N, 2.13.
2-Deb en zoyl-1,2-O-b en zylid en e)-4-d ea cet yl-7-d eoxy-
10-d ea cetyl-9(R)-d ih yd r op a clita xel (23). The same pro-
cedure was followed as for 21a , using 15c (0.10 g, 0.12 mmol).
Compound 23 was isolated in 68% yield (60 mg, 0.081 mmol):
mp 144 °C; FAB-MS 740 [M + H]+, 762 [M + Na]+. Anal.

7100 J . Org. Chem., Vol. 61, No. 20, 1996
Wiegerinck et al.
Calcd for C43H49N O10‚H2O: C, 68.14; H, 6.80; N, 1.85.
Found: C, 67.81; H, 6.57; N, 2.15.
washed with saturated NaHCO3 solution (20 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified
by chromatography (EtOAc/hexane 1/1), yielding 25 (61 mg,
4-Dea cet yl-7-d eoxy-10-d ea cet yl-9,10-O-(p r op a n e-2,2-
d iyl)-9(R)-d ih yd r op a clita xel (24). To a solution of 22 (0.10
g, 0.13 mmol) in toluene (5 mL) were added a solution of
t-BuOOH in decane (26 µL, 5.0-6.0M) and Pd(OAc)2 (2.4 mg,
0.011 mmol). The reaction mixture was stirred at 50 °C for
24 h. The reaction mixture was diluted with EtOAc (20 mL)
and filtered over Hyflo. The filtrate was washed with water
and brine. The organic layer was dried over Na2SO4 and
concentrated in vacuo. The residue was purified by chroma-
tography (EtOAc/hexane 1/1), yielding 24 (29 mg, 0.036 mmol,
28%): mp 125-128 °C; 1H-NMR (400 MHz, CDCl3) δ 8.23 (d,
J ) 7.5 Hz, 2H), 7.78 (d, J ) 7.3 Hz, 2H), 7.60 (d, J ) 7.4 Hz,
2H), 7.42 (m, 9H), 7.07 (d, J ) 9.6 Hz, 1H), 6.16 (d, J ) 9.5
Hz, 1H), 6.01 (m, 1H), 5.87 (d, J ) 5.2 Hz, 1H), 4.89 (dd, J )
6.7, 1.8 Hz, 1H), 4.70 (d, J ) 9.5 Hz, 1H), 4.67 (bs, 1H), 4.40
(d, J ) 9.6 Hz, 1H), 4.34 (d, J ) 7.9 Hz, 1H), 4.19 (d, J ) 7.9
Hz, 1H), 3.41 (bs, 1H), 2.91 (dd, J ) 15.7, 3.6 Hz, 1H), 2.55 (d,
J ) 5.2 Hz, 1H), 2.30 (dd, J ) 15.7, 6.4 Hz, 1H), 2.05 (m, 4H),
1.90 (s, 1H), 1.85 (s, 3H), 1.53 (s, 3H), 1.52 (s, 3H), 1.46 (s,
3H), 1.43 (s, 3H16), 1.19 (s, 3H); FAB-MS 796 [M + H]+, 818
[M + Na]+. Anal. Calcd for C46H53NO11‚1.5H2O: C, 67.08;
H, 6.85; N, 1.78. Found: C, 66.77; H, 6.67; N, 2.00.
1
0.073 mmol, 61%): mp 122 °C; H-NMR (400 MHz, CDCl3) δ
8.02 (dd, J ) 7.8, 1.4 Hz, 2H), 7.73 (dd, J ) 7.8, 1.6 Hz, 2H),
7.55 (m, 3H), 7.37 (m, 8H), 7.05 (d, J ) 9.5 Hz, 1H), 6.02 (bd,
J ) 9.5 Hz, 1H), 5.88 (m, 1H), 4.91 (dd, J ) 8.9, 2.3 Hz, 1H),
4.86 (t, J ) 5.6 Hz, 1H), 4.62 (m, 3H), 4.44 (d, J ) 7.9 Hz,
1H), 4.24 (m, 2H), 4.09 (s, 1H), 3.98 (d, J ) 9.4 Hz, 1H), 3.93
(d, J ) 5.5 Hz, 1H), 3.70 (bs, 1H), 2.66 (bs, 1H), 2.35-1.99 (m,
8H), 1.68 (s, 3H), 1.58 (s, 3H), 1.48 (s, 3H), 1.16 (s, 3H); FAB-
MS, 840 [M + H]+, 862 [M + Na]+. Anal. Calcd for C48H57
-
NO12: C, 68.62; H, 6.85; N, 1.67. Found: C, 68.38; H, 7.05;
N, 1.41.
Ack n ow led gm en t. We would like to thank Phar-
machemie BV and the Dutch Cancer Foundation, Ned-
erlandse Kankerbestrijding Koningin Wilhelmina Fonds,
for their financial support.
1
Su p p or tin g In for m a tion Ava ila ble: 400 MHz H-NMR
spectral data for compounds 8b,c, 9b,c, 10b,c, 11b,c, 12b,c,
14b,c, 15b,c, 21b, and 23. All analytical data of 2-TMS-[7b]
(4 pages). This material is contained in libraries on microfiche;
it immediately follows this article in the microfilm version of
the journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1-Be n zoyl-2-d e b e n zoyl-2-(t e t r a h yd r op yr a n -2-yl)-4-
deacetyl-7-deoxy-10-deacetyl-9(R)-dih ydr opaclitaxel (25).
Compound 19 (0.10 g, 0.12 mmol) was dissolved in HOAc/THF/
H2O (36/3/6 mL). After 24 h at 50 °C, the reaction mixture
was diluted with EtOAc (50 mL). The organic layer was
J O960438A