Efficient conversion of cephalomannine to paclitaxel and 3'-N-acyl-3'-N-debenzoylpaclitaxel analogs

Full text of DOI:10.1021/jo9700639

J . Org. Chem. 1997, 62, 3775-3778
3775
in that it has an N-tigloyl group rather than an N-benzoyl
Efficien t Con ver sion of Cep h a lom a n n in e to
P a clita xel a n d
group on the side chain.8 Cephalomannine is difficult to
3′-N-Acyl-3′-N-d eben zoylp a clita xel An a logs
A. A. Leslie Gunatilaka, Mahendra D. Chordia, and
David G. I. Kingston*
Department of Chemistry, Virginia Polytechnic Institute and
State University, Blacksburg, Virginia 24061-0212
Received J anuary 13, 1997
The clinically important anticancer drug paclitaxel
(Taxol) (1)1 was, until recently, available only by a
complex and expensive isolation process from Taxus
brevifolia bark, which is a nonrenewable and relatively
scarce resource. This dependence on bark as the source
of a drug required in ever increasing amounts focused
both public and scientific interest on the discovery of
alternate sources,2 and several approaches to the produc-
tion of paclitaxel have been investigated. Total synthesis
is the most fundamental approach to this problem, and
to date four total syntheses of paclitaxel have been
reported,3 but regrettably none of these syntheses is as
yet suitable for large-scale production. Other approaches
have included plant tissue culture and fungal culture,4
but the major current commercial production method is
that of partial synthesis from 10-deacetylbaccatin III,5
which is available in reasonable yield from the needles
of Taxus baccata and other Taxus species.6
separate from paclitaxel, but it does represent a poten-
tially valuable additional source of this compound, espe-
cially since it can occur in Taxus species in amounts that
exceed those of paclitaxel.9 One possible approach to the
required conversion of cephalomannine to paclitaxel is
by the known chemistry of separation from paclitaxel
followed by cleavage of the side chain to produce baccatin
III,10 followed by protection at C-7, acylation at C-13 with
the paclitaxel side chain, and deprotection.5 This pro-
cedure is a lengthy one, and we thus sought an alternate
approach that would provide the desired conversion more
efficiently. Ideally this conversion would be effective
either on purified cephalomannine or on a mixture of
paclitaxel and cephalomannine, thus avoiding the dif-
ficult separation of the two compounds. We now report
the efficient achievement of such a conversion.
Conceptually, the direct conversion of cephalomannine
(2) to paclitaxel (1) involves a transamidation reaction,
or selective removal of the N-tigloyl group followed by
N-benzoylation. The presence of various reactive groups
in cephalomannine such as its ester and oxetane func-
tions precluded the use of vigorous conditions for the
removal of the N-tigloyl group and even prevented the
use of reagents which are selective for amide cleavage.
Thus Meerwein’s reagent, which normally will form
imino ethers from amides in the presence of esters,11 gave
only oxetane ring-opened products with paclitaxel12 and
would presumably give the same type of reaction with
cephalomannine. Similarly, selective hydrolysis of 2′-O,7-
O,3′-N-tris(tert-butoxycarbonyl)paclitaxel gave no N-de-
benzoyl product, yielding instead the 2-debenzoyl analog
and thus opening up a route to the synthesis of such
analogs.13 This reaction on cephalomannine would also
presumably give the same 2-O-debenzoyl product rather
Although the partial synthesis of paclitaxel from 10-
deacetylbaccatin III has alleviated the immediate pacli-
taxel supply problem, paclitaxel is still being obtained
by direct isolation from T. brevifolia bark and the needles
of various Taxus species.7 This process yields not only
paclitaxel (1) but also the closely related compound
cephalomannine (2), which differs from paclitaxel only
(1) (a) 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; ACS Symposium Series 583; Georg, G. I., Chen,
T. T., Ojima, I., Vyas, D. M., Eds.; American Chemical Society:
Washington, DC, 1994; pp 31-57. (b) Arbuck, S. G.; Blaylock, B. A. In
Taxol: Science and Applications; Suffness, M., Ed.; CRC Press, Inc.:
Boca Raton, FL, 1995; pp 379-415. (c) McGuire, W. P., Rowinsky, E.
K., Eds. Paclitaxel in Cancer Treatment; Marcel Dekker, Inc.: New
York, Basel, Hong Kong, 1995; Vol. 8, pp 1-349.
(2) (a) Borman, S. Chem. Eng. News 1991, Sept. 2, 11-18. (b)
Edgington, S. M. Bio/ Technology 1991, 9, 933-938. (c) Chase, M. Wall
Street J . 1991, 217 (69), 1.
(3) Holton, R. A.; Somoza, C.; Kim, H. B.; 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, 1599-1600.
(b) Nicolaou, K. C.; Yang, Z.; Veno, H.; Nantermet, P. G.; Guy, R. K.;
Claiborne, C. F.; Renaud, J .; Couladouros, E. A.; Paulvannan, K.;
Sorensen, E. J . Nature 1994, 367, 630-634. (c) Danishefsky, S. J .;
Nasters, J . J .; Young, W. B.; Link, J . T.; Snyder, L. B.; Magee, T. V.;
J ung, D. K.; Laals, R. C. A.; Boshmann, W. G.; Alaimo, C. A.; Coburn,
C. A.; Di Grandi, J . J . Am. Chem. Soc. 1996, 118, 2843-2859. (d)
Wender, P. A.; Glass, T. E.; Krauss, N. E.; Mu¨hlebach, M.; Peschke,
B.; Rawlins, D. B. J . Org. Chem. 1996, 61, 7662-7663.
(4) (a) Stierle, A.; Strobel, G.; Stierle, D. Science 1993, 260, 214-
216. (b) Gibson, D. M.; Ketchum, R. E. B.; Hirasuna, T. J .; Shuler, M.
L. In Taxol: Science and Applications; Suffness, M., Ed.; CRC Press,
Inc.: Boca Raton, FL, 1995; pp 71-95.
(5) Holton, R. A.; Biediger, R. J .; Boatman, P. D. In Taxol: Science
and Applications; Suffness, M., Ed.; CRC Press, Inc.: Boca Raton, FL,
1995; pp 97-121.
(8) Miller, R. W.; Powell, R. G.; Smith, C. R., J r.; Arnold, E.; Clardy,
J . J . Org. Chem. 1981, 46, 1469-1474.
(9) (a) Vidensek, N.; Lim, P.; Campbell, A.; Carlson, C. J . Nat. Prod.
1990, 53, 1609-1610. (b) Wheeler, N. C.; J ech, K.; Masters, S.; Brobst,
S. W.; Alvarado, A. B.; Hoover, A. J . J . Nat. Prod. 1992, 55, 432-440.
(c) Kelsey, R. G.; Vance, N. C. J . Nat. Prod. 1992, 55, 912-917. (d)
Witherup, K. M.; Look, S. A.; Stasko, M. W.; Ghiorzi, T. J .; Muschik,
G. M. J . Nat. Prod. 1990, 53, 1249-1255.
(10) (a) Magri, N. F.; Kingston, D. G. I.; J itrangsri, C.; Piccariello,
T. J . Org. Chem. 1986, 51, 3239-3242. (b) Zheng, Q. Y.; Darbie, L. G.;
Murray, C. K. Abstracts, 208th ACS National Meeting, August 21-
25; American Chemical Society: Washington, DC, 1994; MEDI 63.
Murray, C. K.; Beckvermit, J . T. 208th ACS National Meeting, August
21-25; American Chemical Society: Washington, DC, 1994; MEDI 64,
p O3.
(11) Chen, F. M. F.; Benoiton, N. L. Can. J . Chem. 1977, 55, 1433-
1435.
(6) Denis, J .-N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein, F.;
Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
(7) Paclitaxel is being produced commercially by isolation from
Taxus sp. by several companies, including Hauser Chemical Research,
Inc., Boulder, CO; NaPro BioTherapeutics, Inc., Boulder, CO; and Yew
Tree Pharmaceuticals B.V., Schipholpoort, The Netherlands.
(12) Samaranayake, G.; Magri, N. F.; J itrangsri, C.; Kingston, D.
G. I. J . Org. Chem. 1991, 56, 5114-5119.
(13) Kingston, D. G. I. In Taxane Anticancer Agents: Basic Science
and Current Status; ACS Symposium Series 583; Georg, G. I., Chen,
T. T., Ojima, I., Vyas, D. M., Ed.; American Chemical Society:
Washington, DC, 1995; pp 203-216.
S0022-3263(97)00063-7 CCC: $14.00 © 1997 American Chemical Society

3776 J . Org. Chem., Vol. 62, No. 11, 1997
Notes
Sch em e 1a
a
Key: (a) OsO4 (catalytic), t-BuOOH, Et4NOAc, acetone, 0 °C, 1 h; (b) NaIO4, H2O, rt 1 h; (c) O3, CH2Cl2, -78 °C, 30 min, then -78
°C, 15 min; (d) ArCOOH, DCC, 4-PP, EtOAc, rt, 2-4 h; (e) o-phenylenediamine, p-TsOH, dry C6H6, reflux, 12-18 h.
than the 3′-N-detigloyl derivative. Devising a selective
and direct conversion of cephalomannine to paclitaxel
was thus not a trivial undertaking.
event, the diastereomeric mixture of cephalomanninediols
(3) could be oxidized to the ketoamide 4 in 93% yield by
treatment with sodium periodate in methanol. In an
alternative approach, the ketoamide 4 could be obtained
directly from cephalomannine in 97% yield by ozonolysis.
Treatment of the ketoamide 4 with o-phenylenediamine
and a catalytic quantity of p-toluenesulfonic acid in
refluxing benzene did not yield the quinoxaline 5 but
instead gave the free amine 6, albeit in low yield. The
low yield was most probably due to difficulties in workup
of the basic product, and so a strategy was devised to
circumvent this difficulty. The ketoamide 4 was first
converted to its 2′-O-benzoyl derivative 8a in 92% yield
by selective acylation with benzoic acid under standard
DCC/DMAP conditions. The 2′-O-benzoate 8a was then
treated with o-phenylenediamine and p-toluenesulfonic
acid in refluxing benzene to achieve a direct transforma-
tion to paclitaxel (1) in one pot; the yield proved to be a
very satisfactory 91%. The conversion presumably pro-
ceeds through the free quinoxaline 5b and thence to the
O-benzoylamino alcohol 9a , which then undergoes in-
tramolecular O f N transacylation to give 1.
As noted above, paclitaxel and cephalomannine have
similar chromatographic properties and are difficult to
separate from each other. In earlier work, we devised a
practical method for the separation of paclitaxel from
cephalomannine which took advantage of the fact that
the 11,12-double bond of both compounds is very unre-
active14 while the double bond of the tigloyl group has a
normal reactivity. Selective osmylation of the side chain
of cephalomannine to give the diol mixture 3 can thus
readily be achieved, and diols 3 can be easily separated
from paclitaxel by flash chromatography.15 The avail-
ability of the diol mixture 3 prompted us to investigate
its conversion to paclitaxel.
Our synthetic strategy was based on the observation
that oxidation of the diol mixture 3 or direct ozonolysis
of cephalomannine16 readily yields the ketoamide 4. It
seemed reasonable to assume that 4 would react readily
with o-phenylenediamine to give the 2-aminoquinoxaline
5a and that this would then undergo acid hydrolysis to
give the amino alcohol 6 and the quinoxalinone 7. The
facile hydrolysis of 2-aminoquinoxalines has been known
for over 100 years; as an example, hydrolysis of 2,3-
diaminoquinoxaline with hydrochloric acid gives 3-amino-
2-quinoxalinone under relatively mild conditions.17 In the
This sequence of steps thus provides a simple and high-
yield process for the conversion of cephalomannine (2) to
paclitaxel (1). If the ozonolysis route is selected, the
overall yield is 81%. The route via the diol 3 has a lower
overall yield of 73% assuming a yield of 94% for the
conversion of cephalomannine to its diol,15 but it has the
advantage of simultaneously providing a simple method
for the separation of paclitaxel from cephalomannine.
(14) Kingston, D. G. I. Pharmacol. Ther. 1991, 52, 1-34.
(15) Kingston, D. G. I.; Gunatilaka, A. A. L.; Ivey, C. A. J . Nat. Prod.
1992, 55, 259-261.
Having achieved the goal of a simple conversion of
cephalomannine to paclitaxel, we next investigated the
generality of the reaction by using it to prepare three
paclitaxel analogs in which the 3′-N-benzoyl group was
(16) (a) J itrangsri, C. Approaches to the Synthesis of Modified
Taxols. Ph.D. Dissertation, Virginia Polytechnic Institute and State
University, Blacksburg, VA, 1986; pp 145-159. (b) Beckvermit, J . T.;
Anziano, D. J .; Murray, C. K. J . Org. Chem. 1996, 612, 9038-9040.
(17) Bladin, J . A. Chem. Ber. 1885, 18, 666-674.

Notes
J . Org. Chem., Vol. 62, No. 11, 1997 3777
Ta ble 1. Biologica l Eva lu a tion of 10b-d
cytotoxicity to P-388 murine leukemiaa
no.
compd name
ED50
ED50/ED50(paclitaxel)
1
paclitaxel
0.0029
0.013
0.074
0.13
1.0
4.5
25.0
45.0
10b
10c
10d
N-debenzoyl-N-(o-chlorobenzoyl)paclitaxel
N-debenzoyl-N-(o-bromobenzoyl)paclitaxel
N-debenzoyl-N-(o-nitrobenzoyl)paclitaxel
a
ED50 refers to the concentration which produces 50% inhibition of proliferation after 48 h incubation.
J ) 6.9, 1H), 6.18 (t, J ) 7.0, 1H), 6.27 (s, 1H), 7.28-7.65 (m,
8H), 7.80 (d, J ) 9.3, 1H), 8.12 (d, J ) 7.0, 2H); 13C NMR δ
9.53, 14.83, 20.81, 21.65, 22.54, 24.48, 26.80, 35.48, 35.59, 43.14,
45.65, 54.93, 58.48, 72.07, 73.30, 74.83, 75.49, 76.42, 76.68, 78.98,
81.14, 84.31, 126.98, 128.60, 128.89, 128.94, 129.43, 130.12,
133.18, 133.74, 137.08, 141.73, 159.62, 166.92, 170.35, 171.16,
171.92, 196.30, 203.47; HRFABMS calcd for C43H50NO15 [M +
H]+ m/ z 820.3102, found 820.3137.
replaced with an o-substituted benzoyl group. The three
analogs 10b-d were prepared by the procedure described
above but substituting o-chloro-, o-bromo-, or o-nitroben-
zoic acid for the benzoic acid of the original process to
give the 2′-O-aroyl derivatives 8b-d . Treatment of 8b-d
with o-phenylenediamine as described above gave the
paclitaxel analogs 10b-d in good yield.
The cytotoxicities of the 3′-N-aroyl analogs 10b-d were
determined in the P-388 murine lymphocytic leukemia
system; the results are shown in Table 1.18 All three
analogs were less cytotoxic than paclitaxel in this bioas-
say, suggesting that an ortho substitution on the 3′-N-
benzoyl group is deleterious to the cytotoxicity of pacli-
taxel.
Ozon olysis of Cep h a lom a n n in e (2) to th e Ketoa m id e 4.
A solution of cephalomannine (166.2 mg, 2.0 mmol) in dry CH2-
Cl2 (15 mL) was cooled to -78 °C, and ozone was passed through
the solution for 30 min during which the color of the solution
changed from colorless to pinkish blue. The solution was allowed
to stir at -78 °C for an additional 15 min, after which nitrogen
was purged through the solution for 10 min. Evaporation under
reduced pressure afforded a crude material. Purification by
column chromatography over silica gel (hexane:EtOAc, 1:1)
afforded 4 (158.0 mg, 97%) identical with the sample obtained
above.
Exp er im en ta l Section
Gen er a l Meth od s. All chemicals were procured from Aldrich
Chemical Co. and used without further purification. All anhy-
drous reactions were performed in oven-dried glassware under
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 2′-O-Ar oyl
Der iva tives 8a -d . The aromatic carboxylic acid (0.043 mmol,
1.2 equiv), dicyclohexylcarbodiimide (11.1 mg, 0.054 mmol), and
pyrrolidinopyridine (2.0 mg; catalytic) were dissolved in dry
EtOAc (2 mL) and stirred at room temperature for 10 min. To
this mixture was added 4 (30.0 mg, 0.036 mmol), and the
mixture was stirred at room temperature for 2-4 h (TLC
control). The mixture was then filtered through a bed of silica
gel and Celite. Evaporation of the filtrate under reduced
pressure afforded the crude product which on purification by
preparative TLC (silica gel; hexane:EtOAc, 1:1) yielded the
corresponding 2′-O-aroyl derivatives 8a -d as amorphous solids
in 79-91% yields.
Com p ou n d 8a : 1H NMR δ 1.14 (s, 3H), 1.25 (s, 3H), 1.64 (s,
3H), 1.85 (s, 3H), 1.95-2.05 (m, 1H), 2.18-2.24 (m, 1H), 2.20,
2.35, and 2.38 (s, 3H each), 2.46-2.58 (m, 2H), 3.78 (d, J ) 6.8,
1H), 4.15 (d, J ) 8.6, 1H), 4.25 (d, J ) 8.6, 1H), 4.44 (m, 1H),
4.95 (br d, J ) 7.5, 1H), 5.55 (d, J ) 3.4, 1H), 5.64 (d, J ) 6.8,
1H), 5.70 (dd, J ) 3.4, 8.8, 1H), 6.20 (t, J ) 7.0, 1H), 6.23 (s,
1H), 7.25-7.62 (m, 11H), 7.80 (d, J ) 8.8, 1H), 8.00, 8.10 (d, J
) 7.0, 2H each); 13C NMR δ 9.59, 14.81, 20.80, 22.16, 22.54,
24.41, 26.80, 35.35, 35.43, 43.14, 45.52, 53.30, 58.42, 71.99, 72.05,
74.56, 75.11, 76.35, 79.35, 80.98, 84.43, 126.73, 128.32, 128.66,
128.72, 128.97, 129.18, 129.21, 129.90, 130.16, 132.69, 133.72,
134.00, 135.88, 142.76, 159.53, 165.44, 167.03, 167.78, 169.63,
171.25, 196.12, 203.75; HRFABMS calcd for C50H54NO16 [M +
H]+ m/ z 924.3364, found 924.3391.
Com p ou n d 8b: 1H NMR δ 1.14 (s, 3H), 1.25 (s, 3H), 1.67 (s,
3H), 1.8-2.4 (m, 3H), 1.94 (s, 3H), 2.22 (s, 3H), 2.32 (m, 1H),
2.38 (s, 3H), 2.39 (s, 3H), 2.4-2.6 (m, 2H), 3.81 (d, J ) 6.8, 1H),
4.19 (d, J ) 8.6, 1H), 4.30 (d, J ) 8.6, 1H), 4.45 (m, 1H), 4.97
(br d, J ) 7.4, 1H), 5.64 (d, J ) 3.4, 1H), 5.70 (d, J ) 6.8, 1H),
5.75 (dd, J ) 2.9, 8.8, 1H), 6.29 (s, 1H), 6.29 (t, 1H), 7.30-7.90
(m, 13H), 8.13 (d, J ) 7.0, 2H).
Com p ou n d 8c: 1H NMR δ 1.14 (s, 3H), 1.26 (s, 3H), 1.67 (s,
3H), 1.95 (s, 3H), 2.0-2.4 (m, 3H), 2.22 (s, 3H), 2.32 (m, 1H),
2.39 (s, 3H), 2.41 (s, 3H), 2.50 (d, J ) 2.0, 1H), 2.50-2.65 (m,
1H), 3.81 (d, J ) 6.8, 1H), 4.19 (d, J ) 8.6, 1H), 4.30 (d, J ) 8.6,
1H), 4.45 (m, 1H), 4.97 (br d, J ) 7.4, 1H), 5.64 (d, J ) 3.4),
5.70 (d, 1H, J ) 6.8), 5.75 (dd, J ) 2.9, 8.8, 1H), 6.29 (s, 1H),
6.29 (t, J ) 7.0, 1H), 7.30-7.80 (m, 13H), 8.13 (d, J ) 7.0, 2H).
a
positive pressure of argon. Solvents used in anhydrous
reactions were freshly distilled over appropriate dehydrating
agents. All reactions were monitored by TLC (silica gel, GF),
analyzed with UV light, and developed with vanillin/H2SO4
spray. 1H NMR spectra were obtained at 270 or 400 MHz, and
13C NMR spectra were obtained at 100.57 MHz. All NMR
spectra were recorded in CDCl3 using solvent (δC 77.0 ppm) or
residual CHCl3 (δH 7.24 ppm) as internal standards. Coupling
constants are reported in hertz (Hz). 1H and 13C NMR spectra
were assigned primarily by comparison of chemical shifts and
coupling constants with those of related compounds. Some 1H
NMR spectra showed the presence of traces of ethyl acetate;
paclitaxel and its derivative retain ethyl acetate very tightly,
and it cannot be removed completely even on prolonged treat-
ment in vacuo at 38 °C. Exact mass measurements were
performed at the Nebraska Center for Mass Spectrometry.
Dih yd r oxyla tion of Cep h a lom a n n in e (2) in a Mixtu r e
of P a clita xel (1) a n d 2. A crude mixture (1.0 g, ca. 80% pure;
1
ratio of 1:2, ca. 80:20 by H NMR) of 1 and 2 in acetone (10 mL;
HPLC grade) was treated with Et4NOAc‚4H2O (80 mg), tBuOOH
(70% in H2O, 300 µL), and OsO4 (2.5% in tBuOH, 300 µL,
catalytic) at 0 °C. Purification of the crude product (900 mg) as
described previously15 afforded pure paclitaxel (1a ) (570 mg) and
a diastereomeric mixture of cephalomanninediols 3 (150 mg),
having spectral properties identical with those previously re-
ported.15
Oxid a tion of Cep h a lom a n n in ed iols 3 to th e Ketoa m id e
4. To a solution of cephalomanninediols (3) (140 mg, 0.16 mmol)
in a mixture of MeOH (4.0 mL) and water (1.0 mL) was added
NaIO4 (55 mg, 0.25 mmol). The reaction mixture was stirred
at 25 °C for 3 h, after which MeOH was evaporated and the
product extracted with EtOAc. The organic layer was washed
successively with water and brine and dried over Na2SO4.
Concentration under reduced pressure gave pure ketoamide 4
(120 mg, 93%) as an amorphous solid which resisted crystal-
lization. Compound 4: 1H NMR (CDCl3) δ 1.15 (s, 3H), 1.24 (s,
3H), 1.67 (s, 3H), 1.80 (s, 3H), 1.80-1.90 (m, 1H), 2.20-2.40 (m,
1H), 2.24 (s, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 2.44-2.60 (m, 2H),
3.50 (br s, 1H), (m, 2H, 6-H), 3.79 (d, J ) 6.9, 1H), 4.18 (d, J )
8.5, 1H), 4.30 (d, J ) 8.5, 1H), 4.37 (m, 1H), 4.66 (d, J ) 2.8,
1H), 4.94 (d, J ) 7.6, 1H), 5.48 (dd, J ) 2.8, 9.3, 1H), 5.66 (d,
Com p ou n d 8d : 1H NMR δ 1.13 (s, 3H), 1.24 (s, 3H), 1.66 (s,
3H), 1.8-2.0 (m, 1H), 1.93 (s, 3H), 2.1-2.4 (m, 2H), 2.22 (s, 3H),
2.32 (m, 1H), 2.39 (s, 3H), 2.4-2.6 (m, 1H), 2.40 (s, 3H), 2.50 (d,
J ) 2.0, 1H), 2.53 (m, 2H), 3.80 (d, J ) 6.8, 1H), 4.17 (d, J )
8.2, 1H), 4.31 (d, J ) 8.2, 1H), 4.44 (m, 1H), 4.97 (br d, J ) 7.9,
(18) Cytotoxicities were determined by Dr. W. Lichter, University
of Miami, using established NCI protocols.

3778 J . Org. Chem., Vol. 62, No. 11, 1997
Notes
1H), 5.63 (m, 3H), 6.20 (t, J ) 7.0, 1H), 6.28 (s, 1H), 7.32-7.98
(m, 13H), 8.13 (d, J ) 7.3, 2H).
4.45 (m, 1H), 4.77 (br d, J ) 1.2, 1H), 4.95 (d, J ) 7.8, 1H), 5.68
(d, J ) 7.0, 1H), 5.79 (dd, J ) 1.2, 9.0, 1H), 6.28 (m, 1H), 6.28
(s, 1H), 6.84 (d, J ) 9.0, 1H), 7.24-7.60 (m, 12H), 8.10 (d, J )
8.5, 2H); FABMS m/ z [M + H]+ calcd for C47H50O14NBr [M +
H]+ 934 and 932, found 934 and 932.
Com p ou n d 10d : 1H NMR δ 1.15 (s, 3H), 1.30 (s, 3H), 1.68
(s, 3H), 1.8-1.9 (m, 1H), 1.85 (s, 3H), 2.24 (s, 3H), 2.3-2.4 (m,
1H), 2.36 (s, 3H), 2.4-2.6 (m, 2H), 2.45 (br s, 1H), 2.50 (m, 2H),
3.48 (br s, 1H), 3.80 (d, J ) 7.0, 1H), 4.21 (d, J ) 8.0, 1H), 4.28
(d, J ) 8.0, 1H), 4.46 (m, 1H), 4.83 (br s, 1H), 4.95 (d, J ) 7.8,
1H), 5.68 (d, J ) 7.0, 1H), 5.82 (br d, J ) 9.0, 1H), 6.29 (s, 1H),
6.42 (t, J ) 7.0, 1H), 6.71 (d, J ) 9.0, 1H), 7.40-7.65 (m, 11H),
8.01 (d, J ) 8.0, 1H), 8.08 (d, J ) 8.5, 2H, o-H of 2-benzoyl);
HRFABMS m/ z [M + H]+ calcd for C47H51O16N2 899.3238, found
899.3212.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of 3′-N-Ar oyl
Der iva tives 1 a n d 10b-d . To a solution of 2′-O-aroyl com-
pound 8a -d (0.025 mmol) in dry benzene (5 mL) were added
activated molecular sieves (4 Å, 3 balls), o-phenylenediamine
(27.0 mg, 0.25 mmol), and p-toluenesulfonic acid (2.0 mg;
catalytic). The mixture was then refluxed on an oil bath for 12-
18 h (TLC control). The color changed from yellow orange to
dark red. The mixture was allowed to cool to room temperature,
diluted with EtOAc (10 mL), and washed successively with dilute
HCl (1 N) followed by water and brine. The organic layer was
dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The crude products obtained were purified by pre-
parative TLC (silica gel; hexane:EtOAc, 1:1) to yield the corre-
sponding 3′-N-aroyl analogs 10b-d , as amorphous solids in 70-
91% yields.
Ack n ow led gm en t. This work was supported by a
grant from the National Cancer Institute, Grant No.
RO1 CA55131, and this support is gratefully acknowl-
edged. A gift of crude paclitaxel-containing fractions
from T. brevifolia by Dr. K. Snader, NCI, is also
gratefully acknowledged.
P a clita xel (1). Paclitaxel was obtained from 8a in 91% yield.
Spectral data (1H and 13C NMR and LRFABMS) were identical
with those reported for paclitaxel.13
Com p ou n d 10b: 1H NMR δ 1.14 (s, 3H), 1.25 (s, 3H), 1.67
(s, 3H), 1.8-1.9 (m, 1H), 1.82 (s, 3H), 2.23 (s, 3H), 2.35-2.4 (m,
1H), 2.38 (s, 3H), 2.48 (br s, 1H), 2.5-2.65 (m, 1H), 3.50 (br s,
1H), 3.80 (d, J ) 7.0, 1H), 4.19 (d, J ) 8.0, 1H), 4.29 (d, J ) 8.0,
1H), 4.44 (m, 1H), 4.76 (br s, 1H), 4.95 (d, J ) 7.8, 1H), 5.67 (d,
J ) 7.0, 1H), 5.80 (br d, J ) 9.0, 1H), 6.23 (t, J ) 7.0, 1H), 6.28
(s, 1H), 7.10 (d, J ) 9.0, 1H), 7.24-7.60 (m, 12H), 8.11 (d, J )
8.5, 2H); HRFABMS m/ z [M + H]+ calcd for C47H51O14NCl
888.2998, found 888.2976.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra and a listing of NMR peak assignments of compounds
4, 8a -d , and 10b-d (11 pages). This material is contained
in libraries on microfiche, 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.
Com p ou n d 10c: 1H NMR δ 1.14 (s, 3H), 1.26 (s, 3H), 1.68 (s,
3H), 1.8-1.9 (1H, m), 1.83 (s, 3H), 2.2-2.4 (m, 1H), 2.24 (s, 3H),
2.37 (s, 3H), 2.47 (br s, 1H), 2.47-2.6 (m, 2H), 3.48 (br s, 1H),
3.80 (d, J ) 7.0, 1H), 4.19 (d, J ) 8.0, 1H), 4.29 (d, J ) 8.0, 1H),
J O9700639