Synthesis, conformational analysis, and biological evaluation of heteroaromatic taxanes

Article abstract of DOI:10.1021/jo951961c

The asymmetric syntheses of heteroaromatic 3-[(tert-butyldimethylsilyl)oxy]-2-azetidinones 12-16 via chiral ester enolate-imine cyclocondensation chemistry are described. The azetidinones contain heteroaromatic moieties which, in certain cases, contribute

Full text of DOI:10.1021/jo951961c

2664
J . Org. Chem. 1996, 61, 2664-2676
Syn th esis, Con for m a tion a l An a lysis, a n d Biologica l Eva lu a tion of
Heter oa r om a tic Ta xa n es
Gunda I. Georg,* Geraldine C. B. Harriman, Michael Hepperle, J amie S. Clowers, and
David G. Vander Velde
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045
Richard H. Himes
Department of Biochemistry, University of Kansas, Lawrence, Kansas 66045
Received November 3, 1995X
The asymmetric syntheses of heteroaromatic 3-[(tert-butyldimethylsilyl)oxy]-2-azetidinones 12-
16 via chiral ester enolate-imine cyclocondensation chemistry are described. The azetidinones
contain heteroaromatic moieties which, in certain cases, contribute to a decrease in enantioselectivity
due to possible alternate coordinations in the transition states. The (3R,4S)-3-[(tert-butyldimeth-
ylsilyl)oxy]-4-heteroaryl-2-azetidinones were subsequently converted to the heteroaromatic taxanes
31-36 and 43-45. Conformational analyses of the 3′-(2-pyridyl) analogue 31 and 3′-(2-furyl)
analogue 43 indicate they have solution conformational preferences virtually identical to paclitaxel
and docetaxel. Heteroaromatic N-acyl paclitaxel analogues 47-51 were prepared from N-
debenzoylpaclitaxel via Schotten-Baumann acylation. The majority of the 14 analogues displayed
good to excellent activity in a microtubule assembly assay in comparison to paclitaxel. The
analogues were also tested for cytotoxicity against B16 melanoma cells. 3′-Dephenyl-3′-(2-pyridyl)-
paclitaxel (31), 3′-dephenyl-3′-(2-furyl)paclitaxel (34), N-BOC-3′-dephenyl-3′-(2-furyl)paclitaxel (43),
3′-dephenyl-3′-(2-furyl)-N-(hexanoyl)paclitaxel (44), and N-debenzoyl-N-(3-furoyl)paclitaxel (51) were
found to be more cytotoxic than paclitaxel against this cell line. 3′-Dephenyl-3′-(4-pyridyl)paclitaxel
(33) and N-debenzoyl-N-(2-furoyl)paclitaxel (50) displayed cytotoxicity against B16 melanoma cells
similar to paclitaxel.
The antitumor agent paclitaxel (Figure 1, 1) was
isolated in 1971 from the bark of the pacific yew.1
Paclitaxel’s utility for the treatment of cisplatin refrac-
tory ovarian cancer, metastatic breast cancer, head and
neck cancer, and lung cancer2 as well as its complex
structure have made it an exciting target for synthetic3-5
and semisynthetic studies.6-8 Paclitaxel also possesses
a unique mechanism of action in which this agent
promotes the polymerization and subsequent stabiliza-
tion of cellular microtubules.9,10 Intense studies on the
paclitaxel framework and its diterpene moiety have been
F igu r e 1. Paclitaxel (1).
X Abstract published in Advance ACS Abstracts, April 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.
performed to attempt to identify the paclitaxel
pharmacophore.7,8,11-14
(2) For review: 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; Vol. 583; pp 31-57.
Structure-activity relationship studies have shown
that the C13 N-benzoyl-3′-phenylisoserine side chain of
paclitaxel is crucial for the molecule to elicit its biological
activity.1 Also of importance is the stereochemistry at
the C2′ and C3′ stereogenic centers, with the most active
diastereoisomer being that which is found in the natural
product.15 In our continuing studies on the asymmetric
(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.
(4) 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.
(5) Nicolaou, K. C.; Yang, Z.; Liu, J . J .; Ueno, H.; Nantermet, P. G.;
Guy, R. K.; Claiborne, C. F.; Renaud, J .; Couladouros, E. A.; Paul-
vannan, K.; Sorensen, E. J . Nature 1994, 367, 630-634.
(6) For review: Kingston, D. G. I.; Molinero, A. A.; Rimoldi, J . M.
In Progress in the Chemistry of Organic Natural Products; Herz, W.,
Kirby, G. W., Moore, R. E., Steglich, W., Tamm, C., Eds.; Springer:
New York, 1993; Vol. 61; pp 1-206.
(10) For review: J ordan, M. A.; Wilson, L. In Taxane Anticancer
Agents: Basic Science and Current Status; Georg, G. I., Chen, T., C.,
Ojima, I., Vyas, D. M., Eds.; ACS Symposium Series No. 583; American
Chemical Society: Washington, DC, 1995; Vol. 583; pp 138-153.
(11) Czaplinski, K.-H. A.; Grunewald, G. L. Bioorg. Med. Chem. Lett.
1994, 4, 2211-2216.
(12) For review: Gue´nard, D.; Gue´ritte-Voegelein, F.; Potier, P. Acc.
Chem. Res. 1993, 26, 160-167.
(13) For review: Hepperle, M.; Georg, G. I. Drugs Future 1994, 19,
573-584.
(14) For review: Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.;
Clowers, J . S.; Harriman, G. C. B.; Hepperle, M.; Park, H. In Taxol®
Science and Applications; Suffness, M., Ed.; CRC: Boca Raton, FL,
1995; pp 317-375.
(15) Gue´ritte-Voegelein, F.; Gue´nard, D.; Lavelle, F.; Le Goff, M.-
T.; Mangatal, L.; Potier, P. J . Med. Chem. 1991, 34, 992-998.
(7) For review: 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: Wash-
ington, DC, 1995.
(8) For review: Taxol® Science and Applications; Suffness, M., Ed.;
CRC: Boca Raton, FL, 1995, pp 426.
(9) For review: Horwitz, S. B. Trends Pharm. Sci. 1992, 13, 134-
136.
0022-3263/96/1961-2664$12.00/0 © 1996 American Chemical Society

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2665
Sch em e 1
F igu r e 2. Proposed mechanism for the formation of cis-â-
lactams in the ester enolate-imine cyclocondensation reaction.
synthesis of â-amino acids and their conversion to the
phenylisoserine moiety of paclitaxel,16-21 we now report
on the asymmetric synthesis of a series of cis-3-[(tert-
bu t yldim et h ylsilyl)oxy]-4-h et er oa r om a t ic-2-a zet i-
dinones and their application to the synthesis of novel
taxanes.22 Conformational analyses of two representa-
tive heteroaromatic analogues indicated that they have
solution conformational preferences virtually identical to
paclitaxel and docetaxel. We are also detailing the
synthesis and biological evaluation of novel N-debenzoyl-
N-heteroaroylpaclitaxel analogues from N-debenzoyl-
paclitaxel via Schotten-Baumann acylation.
enolates and (E)-imines react to form cis products while
(Z)-enolates and (E)-imines (not shown) typically react
to form mixtures of cis and trans products.25
We have shown that paclitaxel’s N-benzoyl-3-phenyl-
isoserine side chain, an R-hydroxy â-amino acid, can be
derived through this chemistry.17,21 The R-hydroxyl moi-
ety of the starting glycolate affords a handle to control
enolate geometry,29-31 and the use of trimethylsilyl
imines afford (E)-aza-aldehyde equivalents.25,32 We herein
fully report on our chemistry leading to the synthesis of
optically active cis-3-[(tert-butyldimethylsilyl)oxy]-4-
pyridyl- and cis-3-[(tert-butyldimethylsilyl)oxy]-4-furyl-
2-azetidinones which were further transformed into
heterocyclic taxanes.22
The asymmetric syntheses of the targeted 4-heteroaryl-
2-azetidinone intermediates were initiated by the syn-
thesis of the appropriately functionalized chiral glycolate
6 (Scheme 1), which is utilized in the asymmetric ester
enolate-imine cyclocondensation.17 Acylation of Oppol-
zer’s chiral auxiliary33 2 was accomplished with chloro-
acetyl chloride and (N,N-dimethylamino)pyridine (Scheme
1). Nucleophilic displacement of the halide of 3 with
sodium formate gave 4 quantitatively. Treatment of 4
with methanolic HCl afforded the free carbinol 5 in
quantitative yield. The free hydroxyl group was then
protected as the tert-butyldimethylsilyl ether 6.
Ch em istr y a n d Discu ssion
The chiral ester enolate-imine cyclocondensation reac-
tion has proven to be a useful approach to the asymmetric
synthesis of functionalized 2-azetidinones and â-amino
acids.23-28 Remote stereocontrol in this reaction can be
invoked by a chiral alcohol moiety of an achiral ester,
which can afford excellent stereoselectivity (Figure 2).
This chemistry also results in the recovery of the intact
chiral auxiliary as the final cyclization, after the genera-
tion of the stereogenic centers, results in displacement
of the auxiliary. The ester enolate-imine cycloconden-
sation reaction proves to be quite versatile for the
synthesis of cis-2-azetidinones via control of the imine
and enolate geometries which can be rationalized through
a six-membered chairlike transition state (Figure 2). (E)-
(16) Georg, G. I.; Akgu¨n, E.; Mashava, P. M.; Milstead, M.; Ping,
H.; Wu, Z.; Vander Velde, D.; Takusagawa, F. Tetrahedron Lett. 1992,
33, 2111-2114.
The addition of a bulky protecting group to the R-posi-
tion of the ester functionality allows for the selective
formation of the (E)-enolate as intramolecular coordina-
tion by the counterion to the lone electron pairs of the
ether oxygen is prevented by the steric demand of the
protecting group.29-31 The sterically demanding TBS
functionality is also important to achieve high enantio-
selectivity in the â-lactam formation.17 Deprotonation of
the chiral ester 6 with LDA at -78 °C was followed by
the addition of heterocyclic imines 7-11 (Scheme 2).
The imines were synthesized following chemistry
developed by Hart34 and used as crude products since
(17) Georg, G. I.; Cheruvallath, Z. S.; Harriman, G. C. B.; Hepperle,
M.; Park, H. Bioorg. Med. Chem. Lett. 1993, 3, 2467-2470.
(18) Georg, G. I.; Cheruvallath, Z. S.; Himes, R. H.; Mejillano, M.
R. Bioorg. Med. Chem. Lett. 1992, 2, 295-298.
(19) Georg, G. I.; Wu, Z. Tetrahedron Lett. 1994, 35, 381-384.
(20) For review: Georg, G. I.; Harriman, G. C. B.; Vander Velde, D.
G.; Boge, T. C.; Cheruvallath, Z. S.; Datta, A.; Hepperle, M.; Park, H.;
Himes, R. H.; J ayasinghe, L. 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 217-232.
(21) Ojima, I.; Habus, I.; Zhao, M.; Georg, G. I.; J ayasinghe, L. R.
J . Org. Chem. 1991, 56, 1681-1683.
(22) Georg, G. I.; Harriman, G. C. B.; Hepperle, M.; Himes, R. H.
Bioorg. Med. Chem. Lett. 1994, 4, 1381-1384.
(23) Gluchowski, C.; Cooper, L.; Bergbreiter, D. E.; Newcomb, M.
J . Org. Chem. 1980, 45, 3413-3416.
(24) Georg, G. I. Tetrahedron Lett. 1984, 25, 3779-3782.
(25) Ha, D.-C.; Hart, D. J .; Yang, T.-K. J . Am. Chem. Soc. 1984,
106, 4819-4825.
(29) Hattori, K.; Yamamoto, H. J . Org. Chem. 1993, 58, 5301-5303.
(30) Barrish, J . C.; Lee, h. L.; Baggiolini, E. G.; Uskovic, M. R. J .
Org. Chem. 1987, 52, 1372-1375.
(26) For review: Hart, D. J .; Ha, D.-C. Chem. Rev. 1989, 89, 1447-
(31) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J . J . Org. Chem. 1983,
48, 5221-5228.
1465.
(27) For review: Brown, M. J . Heterocycles 1989, 29, 2225-2244.
(28) Hart, D. J .; Lee, C.-S.; Pirkle, W. H.; Hyon, M. H.; Tsipours, A.
J . Am. Chem. Soc. 1986, 108, 6054-6056.
(32) Colvin, E. W.; McGarry, D.; Nugent, M. J . Tetrahedron 1988,
44, 4157-4172.
(33) For review: Oppolzer, W. Tetrahedron 1987, 43, 1969-2004.

2666 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
Sch em e 2
F igu r e 3. Coordinated transition states leading to cis prod-
ucts.
observed with the 4-pyridyl, as the lone electron pair in
this compound is not oriented properly for coordination.
Also supporting this hypothesis is the formation of the
trans isomer of 15, which presumably forms through an
open transition state.
A multiple coordinated polymeric system could be an
alternate cause for the decreases in enantioselectivity,
but the fact that the 4-pyridyl-2-azetidinone, which has
an additional coordination site, is formed in excellent
enantiomeric purity seems to disfavor this alternate
hypothesis.
Ta ble 1. Op tica l Rota tion s, En a n tiom er ic Excesses (ee),
HP LC Reten tion Tim es, a n d F low Ra tes (DIACEL
CHIRACEL OD-H Ch ir a l Colu m n ) of Azetid in on es 12-16
in Com p a r ison to cis-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-
p h en yl-2-a zetid in on e (R ) p h en yl)
The absolute stereochemistry of azetidinones 12-16
was assigned by comparing the signs of their optical
rotations to the known 4-phenyl analogue, (3R,4S)-3-
[(tert-butyldimethylsilyl)oxy]-4-phenyl-2-azetidinone (Table
1).21 It is of interest to note that the retention times of
the major and minor enantiomer of the 2-azetidinones
on the chiral HPLC column varied (Table 1). In the case
of the 2-pyridyl- and 3-pyridylazetidinones 12 and 13,
the minor enantiomer had the longer retention time,
whereas the other analogues showed longer retention
times for the major isomer.
Azetidinones 12-16 were converted to their electro-
philic imides 17-21 via acylation with benzoyl chloride
and catalytic amounts of DMAP (Scheme 2). N-Benzoyl-
2-azetidinones 17-21 were then reacted with the sodium
alkoxide35 of 7-O-(triethylsilyl)baccatin III (25) to afford
the disilyltaxanes 26-30 (Scheme 3).
Due to the poor enantioselectivity in the synthesis of
azetidinones 13 and 16, compounds 27 and 30 were
isolated as a 2:1 and 3:1 mixture of diastereomers,
respectively. However, in the synthesis of 3′-(2-pyridyl)-
taxane 26 from â-lactam 12 (44% ee), the reaction
proceeded with kinetic resolution to afford a single
stereoisomer. Interestingly, reaction of N-benzoyl-2-
azetidinone 19 with 7-O-(triethylsilyl)baccatin III re-
sulted in the formation of the desired product 28a and
an elimination side product 28b (Scheme 4).
optical
tR of major tR of minor
rotation ee enantiomer enantiomer flow rate
[R]D
R
(%)
(min)
(min)
(mL/min)
phenyl
+56
+86
+26
+96
+30
+21
93
44
31
95
92
36
20.7
22.3
24.2
23.0
18.7
13.8
19.2
30.7
35.8
14.0
17.2
12.0
0.7
1.4
1.3
1.3
1.0
1.4
2-pyridyl (12)
3-pyridyl (13)
4-pyridyl (14)
2-furyl (15)a
3-furyl (16)
a
Cis isomer.
attempts to purify them by vacuum distillation led to
intense polymerization. The syntheses of the 4-hetero-
aryl-2-azetidinones 12-16 were accomplished in good
yields (Scheme 2) but with varying asymmetric induction
(Table 1).
â-Lactams 14 and 15 were produced in excellent
enantiomeric excesses (92 and 95%, respectively). The
remainder of the 2-azetidinones were isolated in good
yields but low ee’s, and surprisingly, azetidinone 15 was
isolated in a 14:1 cis:trans ratio.35 The heteroaryl sub-
stituents on 12, 13, 15, and 16 are functionalities that
contain additional accessible coordination sites. The lone
pairs of electrons available for coordination of the 2-furyl,
3-furyl, 2-pyridyl, and 3-pyridyl moieties are situated
such that chelation36,37 possibly occurs with the lithium
counterion in the ester enolate-imine cyclocondensation
transition state (Figure 3, 22a and 22b).
This additional coordination could strain and disrupt
the transition state by enhancing a disfavorable 1,3-
diaxial interaction with the chiral auxiliary or by sig-
nificantly distorting the ordered transition state (Figure
3), allowing for the cyclocondensation to also occur
through a competing open transition state where facial
selectivity is compromised. This phenomenon is not
The enamide 28b, generated under base catalysis, may
have been a product of deprotonation of the C3′ amide
functionality (28c, Scheme 4) which could then in turn
have catalyzed the intramolecular deprotonation of H3′
and initiated the antiperiplanar elimination cascade
which led to the formation of the energetically favored
highly conjugated enamide 28b. One also cannot rule
out the possibility of direct deprotonation at C3′ (28a ,
Scheme 4), although no C3-epimerized products were
detected. The formation of the enamide 28b is evident
by 1H NMR by the loss of the signal of the (tert-
butyldimethylsilyl)oxy functionality. In addition, the 1H
NMR of the enamide is devoid of a doublet resonance at
5.70 ppm which corresponds to the 3′-phenylisoserine
proton. The new olefinic 2′ side chain proton is now
(34) Hart, D. J .; Kanai, K.; Thomas, D. G.; Yang, T.-K. J . Org. Chem.
1983, 48, 289-294.
(35) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.
M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
(36) Boger, D. L.; Honda, T. Tetrahedron Lett. 1993, 34, 1567-1570.
(37) Gribble, G. W.; J ohnson, D. A. Tetrahedron Lett. 1987, 28,
5259-5262.
1
deshielded; the H NMR resonance shifts from 4.71 ppm
to 5.44 ppm, and the multiplicity changes from a doublet
to a singlet. The amide proton of 28b, intensely involved

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2667
Sch em e 3
Sch em e 4
etaxel analogue 43. Following along the same synthetic
route with the exception of the acylating agents used,
heteroaromatic side chain analogues 44 and 45 were
assembled. For the synthesis of the furyl analogue of
taxol C 44, the acylating agent was caproyl chloride, and
for the synthesis of furyl taxane 45 the acylating agent
was decanoyl chloride. Base-mediated coupling and
fluoride-assisted deprotection produced the target com-
pounds 44 and 45.
in a six-membered hydrogen bond with the C1′ carbonyl
oxygen, resonates at 11.72 ppm. The Z-configuration at
the double bond was assigned through NOE studies in
which irradiation at H2′ (5.44 ppm) results in an NOE
enhancement at the pyridyl protons and irradiation at
the amide proton at 11.72 ppm causes NOE enhancement
of the ortho benzamide protons only. It was found that
the ratios of enamide 28b to desired product 28a (60%:
20%) could be altered to disfavor the production of the
enamide by limiting the quantity of base utilized in the
reaction. A decreased amount of NaH (10 equiv) pro-
duced the 4-pyridyltaxane 28a in 80% yield and enamide
28b in 10%. The protected heterocyclic taxanes 26-30
were then converted to their corresponding free taxanes
31-36 via fluoride-mediated deprotection (Schemes 3 and
4).
Biological evaluation of these heteroaromatic taxanes
revealed that the 3′-(2-furyl)paclitaxel analogues 34 was
about three times more cytotoxic against B16 melanoma
cells than paclitaxel (Table 3). We therefore decided to
prepare analogues of 34, in the hope to increase its
potency even further. Since docetaxel and taxol C were
reported to be more cytotoxic than paclitaxel,15,38 we
prepared the corresponding 3′-furyl analogues 43 and 44
(Scheme 5). In addition, we prepared N-decanoyl ana-
logue 45 to test whether an increase in lipophilicity might
increase cytotoxicity in this series of compounds.
The synthesis of taxanes 43-45 started with the
acylation of 2-azetidinone 15 (Scheme 5). The first step
in the synthesis of analogue 43 was the formation of the
N-tert-butoxycarbonyl derivative of 15 to form 37 in high
yield. The activated 2-azetidinone was then treated with
the sodium alkoxide of 7-O-(triethylsilyl)baccatin III to
give protected taxane 40. Desilylation promoted by
pyridinium hydrofluoride afforded heteroaromatic doc-
Previously, we39 and others40-42 have noted that in
polar solvents, a “hydrophobically collapsed” conforma-
tion of paclitaxel and docetaxel becomes populated in
which the 2-benzoyl, 3′-phenyl, and 4-acetyl groups are
proximate. The size of J 2′,3′ also increases in polar
solvents, indicating increasing population of rotamers
with a large torsion angle. A recent X-ray structure of
paclitaxel shows these same features.43 In the case of
the 3′-heterocycle analogues, the aromatic rings show
chemical shift changes (Table 2) and new NOE’s in
DMSO/water analogous to those seen for paclitaxel and
docetaxel, showing the presence of this same conforma-
tion (Figures 4 and 5). Since the protons on the pyridyl
ring are now nonequivalent, it is possible to ascertain
that, in 31, the pyridyl nitrogen prefers to face “up” away
from the 4-acetyl and the interior of the hydrophobic
cluster (Figure 4). The 3′′-pyridyl proton has the largest
NOE’s to the 4-acetyl methyl, which is “down;” also, the
6′′-pyridyl proton has a small NOE to the 14-proton
assigned as â by its large NOE to H13, which is “up.”
The 4′′-pyridyl proton lacks this NOE. The 5′′-pyridyl
proton (corresponding to para for the 3′-phenyl) shows
the largest NOE’s to the 2-benzoyl ring, with those from
4′′ and 6′′ being of approximately equal size. The NOE’s
involving 2′, 3′, and the 4-acetyl to the 2-benzoyl and 3′-
(2′′-pyridyl) groups are also illustrated in Figure 4.
Although there are some overlapping peaks in the
(39) Vander Velde, D. G.; Georg, G. I.; Grunewald, G. L.; Gunn, K.;
Mitscher, L. A. J . Am. Chem. Soc. 1993, 115, 11650-11651.
(40) Williams, H. J .; Scott, A. I.; Dieden, R. A.; Swindell, C. S.;
Chirlian, L. E.; Francl, M. M.; Heerding, J . M.; Krauss, N. E.
Tetrahedron 1993, 49, 6545-6560.
(41) Nicolaou, K. C.; Guy, R. K.; Pitsinos, E. N.; Wrasidlo, W. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1583-1587.
(42) Paloma, L. G.; Guy, R. K.; Wrasidlo, W.; Nicolaou, K. C. Chem.
Biol. 1994, 1, 107-112.
(38) Ma, W.; Park, G. L.; Gomez, G. A.; Nieder, M. H.; Adams, T.
L.; Aynsley, J . S.; Sahai, O. P.; Smith, R. J .; Stahlhut, R. W.; Hylands,
P. J .; Bitsch, F.; Shackleton, C. J . Nat. Prod. 1994, 57, 116-122.
(43) Mastropaolo, D.; Camerman, A.; Luo, Y.; Brayer, G. D.; Cam-
erman, N. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6920-6924.

2668 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
Sch em e 5
spectrum, there are no unambiguous NOE’s to the
N-benzoyl group from any of these others. This is
consistent with our earlier observation that there are no
NOE’s of this type in paclitaxel or docetaxel39 and
molecular dynamics results indicating this group has no
preferred orientation in solution.40
debenzoylpaclitaxel (46, Scheme 6).45,46 This intermedi-
ate can be derived through removal of the N-BOC or the
N-CBZ group of N-BOC- or N-CBZ-N-debenzoylpacli-
taxel.45,46 Acylation of this intermediate under Schotten-
Baumann conditions47 with the appropriate hetero-
aromatic acid chlorides afforded taxanes 47-51.
Analogue 43 appears to have the same “up” orientation
of the heteroatom, away from the 4-acetyl (Figure 5).
Furyl proton 3′′ has a significantly stronger NOE to the
4-acetyl whereas the 4′′ proton on the furyl ring has a
significantly stronger NOE to the 2-benzoyl ortho proton.
Additional NOE’s between these rings are expected from
this conformer, but because of overlap between the 5′′-
furyl and 2-benzoyl meta protons, they cannot be ob-
served. The 3′′ and 4′′ protons of the furan ring, which
are coincidentally isochronous in CDCl3, show a separa-
tion of about 0.2 ppm in DMSO/water. This chemical
shift change evidently results from the new proximity to
the 2-benzoyl ring in the polar solvent. In the CDCl3
spectra of compounds 15 (free NH) and 20, to which a
benzoyl group has been added adjacent to the 2-furyl ring,
virtually identical shift changes are observed.
Biologica l Eva lu a tion
The heteroaromatic taxanes were evaluated for their
ability to promote assembly of tubulin into microtubules
and for their cytotoxicity against B16 melanoma cells
(Table 3). The majority of the heteroaromatic analogues,
with the exception of 36, 45, 47, and 49, displayed a
better or similar ability to promote polymerization of
microtubules than the parent paclitaxel (1). The evalu-
ation of the 3′-heteroaryl analogues 31-35 revealed that
the 2-pyridyl and the 2-furyl analogues 31 and 34 were
more cytotoxic against B16 melanoma cell cells than
paclitaxel. Although the 3-pyridyl and the 3-furyl ana-
logues 32 and 35 were quite active in the tubulin
assembly assay, their cytotoxicity against B16 melanoma
cells was reduced in comparison to paclitaxel. Their
diminished cytotoxicity may be partly due to the fact that
they were tested as diastereomeric mixtures. It is
interesting to note that the 4-pyridyl analogue 33 has
These compounds thus display solution conformational
preferences like all other active taxanes with 3′-aromatic
substituents which have been reported to date.20 How-
ever, we have noted that highly active 3′-cyclohexyl
analogs do not adopt this conformation.20,44
(45) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Harriman, G. C.
B.; Hepperle, M.; Park, H.; Himes, R. H. Bioorg. Med. Chem. Lett. 1994,
4, 1825-1830.
The syntheses of the N-acyl heterocyclic taxanes 47-
51 were achieved through a common intermediate, N-
(46) Dasgupta, D.; Park, H.; Harriman, G. C. B.; Georg, G. I.; Himes,
R. H. J . Med. Chem. 1994, 37, 2976-2980.
(47) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Harriman, G. C.
B.; Hepperle, M.; Park, H.; Himes, R. H. Bioorg. Med. Chem. Lett. 1994,
4, 335-338.
(44) Boge, T. C.; Himes, R. H.; Vander Velde, D. G.; Georg, G. I. J .
Med. Chem. 1994, 37, 3337-3343.

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2669

2670 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
F igu r e 5. Structure of 43 and tile plots of low-temperature
NOESY spectra of 43 taken in DMSO/D2O, illustrating cor-
relations between the 2-benzoyl, 4-acetyl, and side chain
protons. The NOE’s indicate that a conformation like the one
pictured (derived from a recent X-ray structure of paclitaxel)43
is significantly populated in polar solvents. The 5′′- and
2-benzoyl meta signals overlap. The 2′ signal was lost under
the HOD line and is not shown. The spectrum also shows some
doubled signals (most notably 3′) owing to slow cis-trans
isomerism around the BOC group.
F igu r e 4. Structure of 31 and tile plots of low-temperature
NOESY spectra of 31 taken in DMSO/D2O, illustrating cor-
relations between the 2-benzoyl, 4-acetyl, and side chain
protons. The NOE’s indicate that a conformation like the one
pictured (derived from a recent X-ray structure of paclitaxel)43
is significantly populated in polar solvents. The 4′′- and 3′-
benzamide ortho signals overlap. The intense 18-methyl signal
appears just upfield of 14â, producing some NOE’s visible in
the figure.
microtubule assembly assay compared to paclitaxel and
compound 34 but was about twice as cytotoxic as pacli-
taxel. The N-decanoylpaclitaxel analogue 45 displayed
reduced activity in both assays compared to paclitaxel,
indicating that introduction of an N-decanoyl side chain
is detrimental to activity.
In the N-heteroaroyl series, the two furoyl analogues
50 and 51 displayed very good cytotoxicity. Taxane 51
showed approximately 2-fold greater activity than pacli-
taxel in both assays. Analogue 50 was slightly more
active in the microtubule assembly assay and as cytotoxic
as paclitaxel against B16 melanoma cell proliferation.
None of the pyridinecarboxylic acid derivatives 47-49
demonstrated significant activity to inhibit B16 mela-
noma cell proliferation. The picolinoyl analogue 47 was
about five times less active than taxol and the two other
analogues 48 and 49 showed greatly decreased toxicity.
In summary, the most cytotoxic analogues prepared
in this study were the 3′-(2-pyridyl) analogue 31, the 3′-
cytotoxicity comparable to paclitaxel. These results
indicate that cellular uptake and/or metabolic fate may
be influenced by the exact spatial orientation of the
heteroatom in the 3′-aryl moiety of the 3-arylisoserine
side chain. The enamide 36 proved to be virtually
inactive in both assays. This is not surprising as taxanes
devoid of the 2′-hydroxyl or taxanes with protected 2′-
hydroxyl positions exhibit poor biological activities.15,48
Replacement of the N-benzoyl group in 34 with a BOC
group provided docetaxel analogue 43, a compound that
was approximately five times more potent in the micro-
tubule assembly assay than paclitaxel and 34. However,
no further improvement of cytotoxicity against B16
melanoma was seen due to the introduction of the N-BOC
group. The cytotoxicity of 43 was similar to 34. The
N-hexanoyl analogue 44 showed reduced activity in the
(48) Kant, J .; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina,
V. Bioorg. Med. Chem. Lett. 1993, 3, 2471-2474.

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2671
Ta ble 3. Biologica l Eva lu a tion of Heter oa r yl Ta xa n es
microtubule assemblya
ED50/ED50(paclitaxel)
B16 melanomab
ED50/ED50(paclitaxel)
compd no.
compd name
1
31
32c
33
34
35d
36
43
44
45
47
48
49
50
51
paclitaxel
3′-dephenyl-3′-(2-pyridyl)paclitaxel
3′-dephenyl-3′-(3-pyridyl)paclitaxel
3′-dephenyl-3′-(4-pyridyl)paclitaxel
3′-dephenyl-3′-(2-furyl)paclitaxel
3′-dephenyl-3′-(3-furyl)paclitaxel
baccatin III 13-O-[(Z)-3-amino-N-benzoyl-3-(4-pyridyl)acrylate]
N-BOC-N-debenzoyl-3′-dephenyl-3′-(2-furyl)paclitaxel
N-debenzoyl-3′-dephenyl-3′-(2-furyl)-N-(hexanoyl)paclitaxel
N-debenzoyl-3′-dephenyl-3′-(2-furyl)-N-(decanoyl)paclitaxel
N-debenzoyl-N-(picolinoyl)paclitaxel
N-debenzoyl-N-(nicotinoyl)paclitaxel
N-debenzoyl-N-(isonicotinoyl)paclitaxel
N-debenzoyl-N-(2-furoyl)paclitaxel
1
1
0.8
27
1.3
0.3
0.7
0.5
0.4
0.9
0.9
14
0.20
1.6
2.1
3.5
0.6
2.0
0.8
0.4
3.3
>36
0.41
0.50
2.6
4.6
26
>36
1.0
0.5
N-debenzoyl-N-(3-furoyl)paclitaxel
a
ED50 is the concentration which causes polymerization of 50% of the tubulin present in 15 min at 37 °C. b ED50 refers to the concentration
which produces 50% inhibition of proliferation after 40 h incubation. c Assayed as a 2:1 diastereomeric mixture. Assayed as a 3:1
d
diastereomeric mixture.
All spectra in DMSO/D2O were acquired on a Bruker AM-
500 operating at 500.14 MHz for 1H. 1D and COSY spectra
were acquired at room temperature; phase sensitive (TPPI)
Sch em e 6
1
NOESY spectra were acquired in a dedicated H probe at -20
°C in 75% DMSO/25% D2O with a taxane concentration of 2-5
mg/mL. Typical NOESY conditions were as follows: sweep
width 4000 Hz, 2K data points in t2, 2 s delay, 0.26 s
acquisition time with sequential quadrature sampling, tmix 200
ms, 256 blocks with four dummy scans and 80 scans per block.
2D files were transferred to a Silicon Graphics Indigo work-
station for processing and plotting using Felix 2.30 (Biosym,
San Diego, CA). A 1024 point squared sinebell window
function was used prior to transforming the data taken in t2;
the t1 data was linear predicted to 512 points, multiplied by a
512 point squared sinebell window, and zero-filled to 1K points
prior to transformation to give a final matrix size of 1K × 1K
complex points. All crosspeaks were of the same sign as the
diagonal; only positive contours are presented in the figures
as there were no negative features except t1 streaks.
2-O -(C h lo r o a c e t y l)-10-(d ic y c lo h e x y ls u lfa m o y l)-D -
isobor n eol (3). To a cold (0 °C) stirring solution of 10-
(dicyclohexylsulfamoyl)-D-isoborneol (2.50 g, 6.30 mmol) in
anhydrous THF (20 mL) were added DMAP (0.880 g, 2.52
mmol) and over a period of 2 min dropwise chloroacetyl
chloride (0.753 mL, 9.45 mmol). The ice bath was removed,
and the solution was refluxed for 18 h. Since TLC (20%
EtOAc/hexane) indicated remaining starting material, the
reaction was cooled to rt, additional chloroacetyl chloride (0.251
mL, 3.15 mmol) was added, and stirring at reflux temperature
was continued until the disappearance of the starting material
by TLC (20% EtOAc/hexane). The reaction was then cooled
to rt, carefully quenched with a saturated solution of NaHCO3
(20 mL), extracted with ether, and dried over anhydrous
MgSO4. Isobornyl chloroacetate (3) was isolated in quantita-
tive yield as white crystals after purification by silica gel flash
chromatography eluting with 20% EtOAc/hexane: mp 136 °C;
[R]D -38 (c ) 0.59, CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.87
(s, 3H), 0.99 (s, 3H), 1.03-2.02 (m, 27H), 2.94 (qab, J ) 189.3,
13.2 Hz, 2H), 3.18-3.28 (m, 2H), 4.04 (s, 2H), 5.03 (dd, J )
8.4, 3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.4, 20.8, 25.7,
26.9, 27.4, 30.7, 33.1, 33.4, 39.6, 41.5, 44.9, 49.6, 50.1, 54.1,
57.9, 80.6, 166.0. Anal. Calcd for C24H40ClNO4S: C, 60.86;
H, 8.52; N, 2.96. Found: C, 60.48; H, 8.49; N, 2.58.
(4-pyridyl) analogue 33, the 3′-(2-furyl) analogues 34, 43,
and 44, and the N-(2-furoyl) and N-(3-furoyl) derivatives
50 and 51, all of which displayed either better or similar
cytotoxic activity against B16 melanoma cells compared
to paclitaxel. Thus, the replacement of the 3′-phenyl and
the N-benzoyl moiety of paclitaxel by select hetero-
aromatic moieties provided highly cytotoxic novel pacli-
taxel analogues.
Exp er im en ta l P r oced u r es
Gen er a l. For general synthetic procedures, see refs 49 and
50. All starting materials and reagents are commercially
available with the exception of 3-furoyl chloride and picolinoyl
chloride which were prepared from the corresponding com-
mercially available acids by treatment with cyanuric chloride.51
HPLC analyses for the determination of the enantiomeric
excesses of the described 2-azetidinones were performed on a
Waters Model 481 LC spectrometer detector set at 254 nm
equipped with a Waters 740 Data Module integrator using a
chiral column (DIACEL CHIRACEL OD-H) utilizing a 20:1
hexane/2-propanol mobile phase with a flow rate of 0.7-1.4
mL/min (Table 1). For a description of the biological assays,
see refs 52 and 53.
10-(Dicycloh exylsu lfa m oyl)-2-O-[(for m yloxy)a cetyl]-D-
isobor n eol (4). To a solution of 3 (2.99 g, 6.31 mmol) in
toluene (20 mL) were added sodium formate (0.858 g, 12.6
mmol) and tetrabutylammonium bromide (0.010 g, 0.032
mmol). The reaction was heated to reflux for 12 h or until
the disappearance of 3 by TLC (25% EtOAc/hexane). After
(49) Georg, G. I.; Cheruvallath, Z. S.; Himes, R. H.; Mejillano, M.
R.; Burke, C. T. J . Med. Chem. 1992, 35, 4230-4237.
(50) Georg, G. I.; He, P.; Kant, J .; Wu, Z. J . Org. Chem. 1993, 58,
5771-5778.
(51) Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1979, 3037-
3040.
(52) Sengupta, S.; Boge, T. C.; Georg, G. I.; Himes, R. H. Biochem-
istry 1995, 36, 11889-11894.
(53) Ali, S. M.; Hoemann, M. Z.; Aube´, J .; Mitscher, L. A.; Georg,
G. I.; McCall, R.; J ayasinghe, L. R. J . Med. Chem. 1995, 38, 3821-
3828.

2672 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
being cooled to rt the suspension was filtered, and the filtrate
was diluted with water, extracted with ether, and dried over
anhydrous MgSO4. (Formyloxy)acetate 4 was isolated as white
crystals in quantitative yield after purification by silica gel
flash chromatography eluting with 25% EtOAc/hexane: mp
170 °C; [R]D -38 (c ) 0.88, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 0.86 (s, 3H), 0.94 (s, 3H), 1.00-2.02 (m, 27H), 2.90 (qab, J )
161.4, 13.2 Hz, 2H), 3.18-3.28 (m, 2H), 4.66 (qab, J ) 22.2,
15.3 Hz, 2H), 5.05 (dd, J ) 7.8, 2.7 Hz, 1H), 8.10 (s, 1H); 13C
NMR (75 MHz, CDCl3) δ 20.4, 20.8, 25.6, 26.9, 27.4, 30.7, 33.2,
39.6, 44.9, 49.6, 50.0, 54.2, 57.9, 80.2, 160.2, 165.9. Anal. Calcd
for C25H41NO6S: C, 62.08; H, 8.55; N, 2.90. Found: C, 61.68;
H, 8.90; N, 2.50.
10-(Dicycloh e xylsu lfa m oyl)-2-O-(h yd r oxya ce t yl)-D-
isobor n eol (5). (Formyloxy)acetate 4 (3.05 g, 6.31 mmol) was
dissolved in MeOH (20 mL) and after addition of five drops of
concentrated HCl stirred for 10 min. The volatiles were
removed under reduced pressure, and glycolate 5 was isolated
in quantitative yield as white crystals after purification by
silica gel flash chromatography eluting with 20% EtOAc/
hexane: mp 165 °C; [R]D -45 (c ) 0.65, CHCl3); 1H NMR (300
MHz, CDCl3) δ 0.86 (s, 3H), 0.95 (s, 3H), 1.00-2.05 (m, 27H),
2.47 (br s, 1H), 2.90 (qab, J ) 156.9, 13.5 Hz, 2H), 3.15-3.26
(m, 2H), 4.10 (dd, J ) 5.7, 3.0 Hz, 2H), 5.06 (dd, J ) 7.8, 2.7
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.4, 20.8, 25.6, 26.9,
27.4, 30.7, 33.2, 33.3, 39.8, 44.9, 49.6, 50.0, 54.2, 58.0, 61.2,
80.2, 172.3. Anal. Calcd for C24H41NO5S: C, 63.26; H, 9.08;
N, 3.08. Found: C, 62.88; H, 8.83; N, 2.90.
2-O-[[(ter t-Bu tyld im eth ylsilyl)oxy]a cetyl]-10-(d icyclo-
h exylsu lfa m oyl)-D-isobor n eol (6). To a stirring solution of
5 (2.88 g, 6.31 mmol) in methylene chloride (20 mL) under
argon were added triethylamine (1.756 mL, 12.62 mmol),
DMAP (0.003 g, 0.03 mmol), and tert-butyldimethylsilyl chlo-
ride (1.143 g, 7.570 mmol). This mixture was stirred for 2 h
at rt, quenched with water (30 mL), extracted with methylene
chloride, and subsequently dried over anhydrous MgSO4.
Compound 6 was isolated in 98% yield as white crystals after
purification by silica gel flash chromatography eluting with
10% EtOAc/hexane: mp 112 °C; [R]D -37 (c ) 0.83, CHCl3);
1H NMR (300 MHz, CDCl3) δ 0.71 (s, 3H), 0.87 (s, 3H), 0.85
(s, 3H), 0.88 (s, 9H), 0.95 (s, 3H), 1.02-2.02 (m, 27H), 2.89
(qab, J ) 170.7, 13.2 Hz, 2H), 3.14-3.24 (m, 2H), 4.19 (s, 2H),
4.97 (dd, J ) 8.7, 2.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
-5.2, -4.8, 18.8, 20.5, 20.8, 25.6, 26.2, 27.4, 30.6, 33.2, 33.4,
40.0, 44.9, 49.5, 49.9, 54.1, 58.0, 79.4, 170.7. Anal. Calcd for
C30H55NO5SSi: C, 63.23; H, 9.74; N, 2.46. Found: C, 63.00;
H, 0.10; N, 2.30.
(-78 °C) stirred solution of diisopropylamine (0.32 mL, 2.25
mmol) in anhydrous THF (1 mL) was added 2.5 M n-
butyllithium (0.78 mL, 1.95 mmol) dropwise. The reaction was
stirred at -78 °C for 0.5 h. Ester 6 (0.92 mg, 1.62 mmol) in
THF (2 mL) was then added to the cold LDA solution dropwise.
The reaction was stirred at -78 °C for 2 h. Imine (2.25 mmol)
in THF (2 mL) was added dropwise to the cold enolate solution.
The reaction was stirred at -78 °C for 3 h and then rt
overnight. The reaction was quenched by the addition of a
saturated aqueous NH4Cl solution (1 mL). The reaction
mixture was extracted with ether (3 × 20 mL) and subse-
quently dried over anhydrous MgSO4.
(3R,4S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-(2-p yr id yl)-
2-a zetid in on e (12). Azetidinone 12 was isolated as a viscous
colorless oil in 59% yield and 44% ee after purification by silica
gel flash chromatography eluting with EtOAc: [R]D +86 (c )
2.5, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ -0.20 (s, 3H), -0.01
(s, 3H), 0.56 (s, 9H), 4.91 (d, J ) 4.8 Hz, 1H), 5.07 (q, J ) 4.8,
2.9 Hz, 1H), 7.13-7.17 (m, 1H), 7.36 (br s, 1H), 7.39 (d, J )
7.9 Hz, 1H), 7.64 (dt, J ) 7.8, 1.6 Hz, 1H), 8.48 (d, J ) 3.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ -5.6, -5.1, 17.6, 25.1, 60.1,
79.8, 122.2, 122.6, 135.9, 148.6, 156.9, 170.0. Anal. Calcd for
C14H22N2O2Si: C, 60.39; H, 7.96; N, 10.06. Found: C, 60.43;
H, 8.32; N, 9.85.
(3R,4S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-(3-p yr id yl)-
2-a zetid in on e (13). Azetidinone 13 was isolated in 58% yield
and 31% ee as a white powder after purification by silica gel
flash chromatography eluting with EtOAc: mp 76-78 °C; [R]D
+26 (c ) 1.6, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ -0.15 (s,
3H), -0.03 (s, 3H), 0.62 (s, 9H), 4.83 (d, J ) 4.5 Hz, 1H), 5.07
(q, J ) 4.6, 2.8 Hz, 1H), 7.00 (br s, 1H), 7.29 (ps t, J ) 7.4 Hz,
1H), 7.67 (dd, J ) 7.9, 1.7 Hz, 1H), 8.49 (s, 1H), 8.51 (m, 1H);
13C NMR (75 MHz, CDCl3) δ -5.6, -5.0, 17.6, 25.1, 56.6, 79.4,
122.8, 132.3, 135.6, 149.1, 169.7. Anal. Calcd for C14H22N2O2-
Si: C, 60.39; H, 7.96; N, 10.06. Found: C, 60.79; H, 8.10; N,
9.80.
(3R,4S)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-4-(4-p yr id yl)-
2-a zetid in on e (14). Azetidinone 14 was isolated in 74% yield
and 95% ee as a white powder after purification by silica gel
flash chromatography eluting with EtOAc: mp 174-176 °C;
[R]D +96 (c ) 1.2, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ -0.11
(s, 3H), -0.04 (s, 3H), 0.62 (s, 9H), 4.79 (d, J ) 4.8 Hz, 1H),
5.09 (dd, J ) 4.8, 2.9 Hz, 1H), 6.80-6.88 (br s, 1H), 7.21 (d, J
) 6.0 Hz, 2H), 8.57 (d, J ) 5.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ -5.4, -4.9, 17.7, 26.2, 58.0, 79.8, 122.7, 145.7, 149.4,
169.3. Anal. Calcd for C14H22N2O2Si: C, 60.39; H, 7.96; N,
10.06. Found: C, 60.21; H, 8.00; N, 9.82.
Gen er a l P r oced u r e for t h e Syn t h esis of Ald im in es
7-11. To a cold (0 °C) solution of hexamethyldisilazane (4.0
mmoles) in anhydrous THF under an argon atmosphere was
added 2.5 M n-butyllithium (3.6 mmoles) dropwise. The
reaction was stirred at 0 °C for 0.5 h. The reaction was cooled
further to -78 °C, and a THF solution of aldehyde (4.0 mmol
in 2 mL THF) was added dropwise to the lithiated HMDS. The
reaction was stirred at -78 °C for 0.5 h and then warmed to
rt. Excess solvent was removed under reduced pressure at
35 °C. The imines were utilized crude in the ester enolate-
imine cyclocondensation reactions.
(3R,4R)-3-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-(2-fu r yl)-2-
a zetid in on e (15a ). Azetidinone 15a was isolated as a white
solid in 86% yield and 92% ee, along with 6% of the corre-
sponding trans isomer 15b (15:1, cis:trans), after purification
by silica gel flash chromatography eluting with 25% EtOAc/
1
hexane: mp 78 °C; [R]D +30 (c ) 0.9, CHCl3); H NMR (300
MHz, CDCl3) δ -0.20 (s, 3H), 0.50 (s, 3H), 0.76 (s, 9H), 4.80
(d, J ) 4.5 Hz, 1H), 5.05 (dd, J ) 4.5, 2.4 Hz, 1H), 6.04 (br s,
1H), 6.36 (m, 2H), 7.39 (d, J ) 0.9 Hz, 1H). Anal. Calcd for
C13H21NO3Si: C, 58.40; H, 7.92; N, 5.24. Found: C, 58.12; H,
8.20; N, 5.01.
N-(Tr im eth ylsilyl)p icolin a ld im in e (7): 1H NMR (300
MHz, CDCl3) δ 0.30 (s, 9H), 7.32 (ddd, J ) 7.4, 4.9, 1.4 Hz,
1H), 7.74 (dt, J ) 7.9, 2 Hz, 1H), 7.99 (dd, J ) 4.8, 1.1 Hz,
1H), 8.65 (dd, J ) 4.9, 1.1 Hz, 1H), 9.02 (s, 1H).
t r a n s-3-[(t er t -Bu t yld im e t h ylsilyl)oxy]-4-(2-fu r yl)-2-
a zetid in on e (15b): yellow oil; [R]D +44.7 (c ) 1.33, CHCl3);
1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3H), 0.07 (s, 3H), 0.84
(s, 9H), 4.47 (d, J ) 1.8 Hz, 1H), 4.85 (t, J ) 1.8 Hz, 1H), 6.31-
6.36 (m, 2H), 7.39 (d, J ) 1.2 Hz, 1H).
(3R,4S)-3-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-(3-fu r yl)-2-
a zetid in on e (16). Azetidinone 16 was isolated as a white
solid in 55% yield and 36% ee after purification by silica gel
flash chromatography eluting with 25% EtOAc/hexane: mp
N-(Tr im eth ylsilyl)n icotin a ld im in e (8): 1H NMR (300
MHz, CDCl3) δ 0.25 (s, 9H), 7.36 (q, J ) 7.8, 4.8 Hz, 1H), 8.16
(dt, J ) 6.0, 1.8 Hz, 1H), 8.67 (dd, J ) 4.9, 1.7 Hz, 1H), 8.93
(d, J ) 1.9 Hz, 1H), 8.99 (s, 1H).
N-(Tr im eth ylsilyl)ison icotin a ld im in e (9): 1H NMR (300
MHz, CDCl3) δ 0.27 (s, 9H), 7.65 (d, J ) 6.0 Hz, 2H), 8.73 (d,
J ) 5.9 Hz, 2H), 8.94 (s, 1H).
116 °C; [R]D
+21 (c ) 0.95, CHCl3); 1H NMR (300 MHz, CDCl3)
δ -0.05 (s, 3H), 0.90 (s, 3H), 0.78 (s, 9H), 4.72 (d, J ) 4.5 Hz,
1H), 5.00 (dd, J ) 4.5, 2.4 Hz, 1H), 6.13 (br s, 1H), 6.43 (d, J
N-(Tr im eth ylsilyl)-2-fu r a ld im in e (10): 1H NMR (300
MHz, CDCl3) δ 0.25 (s, 9H), 6.50 (dd, J ) 3.3, 1.8 Hz, 1H),
6.82 (dd, J ) 3.3, 0.6 Hz, 1H), 7.51-7.52 (m, 1H), 8.75 (s, 1H).
N-(Tr im eth ylsilyl)-3-fu r a ld im in e (11): 1H NMR (300
MHz, CDCl3) δ 0.20 (s, 9H), 6.81 (d, J ) 1.5 Hz, 1H), 7.38 (s,
1H), 7.76 (s, 1H), 8.87 (s, 1H).
) 0.9 Hz, 1H), 7.39-7.41 (m, 2H). Anal. Calcd for C13H21
NO3Si: C, 58.40; H, 7.92; N, 5.24. Found: C, 58.46; H, 8.32;
N, 5.04.
-
Gen er a l P r oced u r e for th e Syn th esis of N-Ben zoyl-2-
a zetid in on es 17-21. To a cold (0 °C) stirred solution of
â-lactam (50 mg, 0.18 mmol), triethylamine (1 mL, excess),
and DMAP (2 mg, catalytic) in anhydrous CH2Cl2 was added
Gen er a l P r oced u r e for th e Syn th esis of (3R,4S)-4-Ar yl-
3-[(ter t-bu tyld im eth ylsilyl)oxy]-2-a zetid in on es. To a cold

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2673
benzoyl chloride (0.03 mL, 0.27 mmol) dropwise. The reaction
mixture was stirred at 0 °C for 15 min, quenched with brine,
extracted with CH2Cl2 (3 × 15 mL), and dried over anhydrous
MgSO4.
yield after purification by silica gel flash chromatography
eluting with 25% EtOAc/hexane: 1H NMR (300 MHz, CDCl3)
δ 0.52-0.60 (m, 6H), 0.91 (t, J ) 7.8 Hz, 9H), 1.02 (s, 3H),
1.19 (s, 3H), 1.59 (s, 3H), 1.84 (s, 3H), 2.19 (s, 3H), 2.30 (s,
3H), 3.87 (d, J ) 7.2 Hz, 1H), 4.21 (qab, J ) 49.2, 8.1 Hz, 2H),
4.48 (dd, J ) 10.5, 6.6 Hz, 1H), 4.82 (t, J ) 7.8 Hz, 1H), 4.94
(d, J ) 7.8 Hz, 1H), 5.62 (d, J ) 6.9 Hz, 1H), 6.44 (s, 1H), 7.46
(t, J ) 7.2 Hz, 2H), 7.59 (t, J ) 7.2 Hz, 1H), 8.09 (t, J ) 7.2
Hz, 2H).
(3R,4S)-1-Ben zoyl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-4-(2-
p yr id yl)-2-a zet id in on e (17). N-Benzoyl-2-azetidinone 17
was isolated as a colorless oil in 85% yield after purification
via silica gel flash chromatography eluting with 25% EtOAc/
hexane: [R]D +98.0 (c ) 1.33, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ -0.08 (s, 3H), 0.10 (s, 3H), 0.65 (s, 9H), 5.21 (d, J )
6.3 Hz, 1H), 5.55 (d, J ) 6.2 Hz, 1H), 7.23 (dd, J ) 7.3, 4.9 Hz,
1H), 7.32 (d, J ) 7.8 Hz, 1H), 7.49 (t, J ) 7.2 Hz, 2H), 7.61 (t,
J ) 7.3 Hz, 1H), 7.68 (dt, J ) 7.7, 1.7 Hz, 1H), 8.07 (d, J ) 7.3
Hz, 2H), 8.61 (d, J ) 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ -5.1, -4.5, 18.2, 25.6, 62.0, 76.9, 122.2, 123.3, 128.6, 130.3,
132.3, 133.8, 136.5, 149.7, 154.6, 165.2, 166.8; HRMS m/ z
calcd or C21H26N2O3Si (M+ + H) 382.1713, found 382.1708.
(3R,4S)-1-Ben zoyl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-4-(3-
p yr id yl)-2-a zetid in on e (18). N-Benzoyl-2-azetidinone 18
was isolated in 79% yield as a colorless glass after purification
by silica gel flash chromatography eluting with 20% EtOAc/
hexane: [R]D +92 (c ) 0.68, CH2Cl2); 1H NMR (300 MHz,
CDCl3) δ -0.090 (s, 3H), -0.093 (s, 3H), 0.69 (s, 9H), 5.16 (d,
J ) 5.9 Hz, 1H), 5.43 (d, J ) 6.2 Hz, 1H), 7.31 (dd, J ) 8.0,
4.8 Hz, 1H), 7.48 (t, J ) 8.2 Hz, 2H), 7.59 (t, J ) 8.3 Hz, 1H),
7.68 (d, J ) 7.9 Hz, 1H), 8.02 (d, J ) 8.3 Hz, 2H), 8.58 (d, J )
4.8 Hz, 1H), 8.65 (s, 1H,); 13C NMR (75 MHz, CDCl3) δ -5.5,
-5.0, 17.8, 25.2, 58.3, 76.2, 123.0, 126.2, 128.2, 128.3, 129.7,
129.8, 131.5, 133.6, 135.5, 149.4, 164.4, 166.1; EI HRMS m/ z
calcd for C21H26N2O3Si (M+ + H) 382.1713, found 382.1712.
(3R,4S)-1-Ben zoyl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-4-(4-
p yr id yl)-2-a zet id in on e (19). N-Benzoyl-2-azetidinone 19
was isolated in 52% yield as a light yellow oil after purification
by silica gel flash chromatography eluting with 20% EtOAc/
Gen er a l P r oced u r e for th e Acyla tion of 7-O-(Tr ieth -
ylsilyl)ba cca tin III w ith Sod iu m Hyd r id e a s th e Ba se.
To a cold (0 °C) stirred solution of 24 (0.20 mg, 0.029 mmol)
and â-lactam (0.038 mmol) in anhydrous THF (1 mL) was
added NaH (47 mg, 1.45 mmol, 60% dispersion) at once. The
reaction was stirred at 0 °C for 0.5 h and then warmed to 30
°C. The reaction was stirred at 30 °C for 3 h or until the
disappearance of 24 was evident by TLC (35% EtOAc/hexane).
The reaction mixture was cooled back down to 0 °C and
carefully quenched by the dropwise addition of acetic acid (1
mL). The reaction mixture was extracted with ether and
subsequently dried over anhydrous MgSO4. Pure coupled
products 26-30 were obtained via silica gel flash chromatog-
raphy.
2-O-(ter t-Bu tyldim eth ylsilyl)-3′-deph en yl-3′-(2-pyr idyl)-
7-O-(tr ieth ylsilyl)p a clita xel (26). Taxane 26 was isolated
as a white powder in 86% yield after purification through silica
gel flash chromatography eluting with 50% EtOAc/hexane: 1H
NMR (300 MHz, CDCl3) δ -0.32 (s, 3H), 0.05 (s, 3H), 0.57-
0.62 (m, 6H), 0.74 (s, 9H), 0.93 (t, J ) 7.7 Hz, 9H), 1.17 (s,
3H), 1.22 (s, 3H), 1.64 (s, 3H), 1.70 (s, 3H,), 1.83-1.98 (m, 1H),
2.10-2.22 (m, 1H), 2.17 (s, 3H), 2.35-2.48 (m, 1H), 2.50-2.59
(m, 1H), 2.61 (s, 3H), 3.85 (d, J ) 7.2 Hz, 1H), 4.25 (qab, J )
37.6, 8.3 Hz, 2H), 4.49 (dd, J ) 10.6, 6.45 Hz, 1H), 4.96 (d, J
) 8.1 Hz, 1H), 5.30 (d, J ) 1.9 Hz, 1H), 5.68-5.75 (m, 2H),
6.24 (t, J ) 9.8 Hz, 1H), 6.47 (s, 1H), 7.20-7.32 (m, 4H), 7.42-
7.61 (m, 7H), 7.67 (dt, J ) 7.7, 1.7 Hz, 1H).
2-O-(ter t-Bu tyldim eth ylsilyl)-3′-deph en yl-3′-(3-pyr idyl)-
7-O-(tr ieth ylsilyl)p a clita xel (27). Taxane 27 was isolated
as a 2:1 diastereomeric mixture in 74% yield after purification
by silica gel flash chromatography eluting with 30% EtOAc/
hexane: 1H NMR (300 MHz, CDCl3) δ -0.22 and -0.18 (s,
3H), -0.01 and 0.05 (s, 3H), 0.55-0.70 (m, 6H), 0.85 and 0.88
(s, 9H), 0.59-1.00 (m, 9H), 1.20 (s, 3H), 1.25 and 1.29 (s, 3H),
1.72 and 1.82 (s, 3H), 1.88-2.00 (m, 1H), 2.08 and 2.13 (s, 3H),
2.10-2.25 (m, 1H), 2.18 and 2.20 (s, 3H), 2.30-2.48 (m, 1H),
2.32 and 2.59 (s, 3H), 2.50-2.61 (m, 1H), 3.86 and 3.90 (d, J
) 7.4 Hz, 1H), 4.29 and 4.27 (qab, J ) 40.4, 8.3 Hz, 2H), 4.47-
4.53 (m, 1H), 4.55 and 4.67 (d, J ) 1.6 Hz, 1H), 4.88 (b d, J )
7.4 Hz, 1H), 5.70-5.79 (m, 2H), 6.25 and 6.28 (t, J ) 9.3 Hz,
1H), 6.48 and 6.49 (s, 1H), 7.15 (d, J ) 9.0 Hz, 1H), 7.30-7.88
(m, 10H), 8.10 and 8.17 (d, J ) 7.6 Hz, 2H), 8.61 (d, J ) 4.4
Hz, 1H), 8.68 and 8.80 (d, J ) 2.0 Hz, 1H).
2-O-(ter t-Bu tyldim eth ylsilyl)-3′-deph en yl-3′-(4-pyr idyl)-
7-O-(tr ieth ylsilyl)p a clita xel (28a ). Taxane 28a was isolated
in 60% yield as a white powder along with 20% of elimination
product 28b after purification via silica gel flash chromatog-
raphy eluting with 50% EtOAc/hexane: 1H NMR (300 MHz,
CDCl3) δ -0.25 (s, 3H), 0.04 (s, 3H), 0.58-0.62 (m, 2H), 0.79
(s, 9H), 0.89-0.96 (m, 3H), 1.18 (s, 3H), 1.22 (s, 3H), 1.71 (s,
3H), 1.88-1.96 (m, 1H), 2.02-2.14 (m, 1H), 2.05 (s, 3H), 2.18
(s, 3H), 2.31-2.41 (m, 1H), 2.51-2.58 (m, 1H), 2.55 (s, 3H),
3.83 (d, J ) 6.8 Hz, 1H), 4.26 (qab, J ) 36.5, 8.7 Hz, 2H), 4.48
(dd, J ) 10.4, 6.4 Hz, 1H), 4.71 (d, J ) 1.9 Hz, 1H), 4.95 (dd,
J ) 7.6, 1.9 Hz, 1H), 5.69-5.73 (m, 2H), 6.28 (t, J ) 8.4 Hz,
1H), 6.45 (s, 1H), 7.07 (d, J ) 8.5 Hz, 1H), 7.30 (d, J ) 6.0 Hz,
2H), 7.40-7.63 (m, 6H), 7.74 (d, J ) 7.1 Hz, 2H), 8.13 (d, J )
7.0 Hz, 2H), 8.66 (d, J ) 6.0 Hz, 2H).
1
hexane: [R]D +88.9 (c ) 0.875, CH2Cl2); H NMR (300 MHz,
CDCl3) δ -0.05 (s, 3H), 0.10 (s, 3H), 0.69 (s, 9H), 5.17 (d, J )
6.2 Hz, 1H), 5.39 (d, J ) 6.2 Hz, 1H), 7.26 (dd, J ) 4.5, 1.6 Hz,
2H), 7.51 (t, J ) 7.3 Hz, 2H), 7.63 (tt, J ) 7.4, 1.3 Hz, 1H),
8.06 (dd, J ) 7.1, 1.5 Hz, 2H), 8.62 (dd, J ) 4.4, 1.5 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ -5.4, -4.9, 17.8, 25.2, 59.4, 76.2,
122.7, 128.3, 129.9, 131.4, 133.7, 143.1, 149.6, 164.2, 166.1;
EI HRMS m/ z calcd for C21H26N2O3Si (M+ + H) 382.1713,
found 382.1712.
(3R,4R)-1-Ben zoyl-3-[(ter t-b u t yld im et h ylsilyl)oxy]-4-
(2-fu r yl)-2-a zetid in on e (20). N-Benzoyl-2-azetidinone 20
was isolated as a transparent oil in 86% yield after purification
by silica gel flash chromatography eluting with 10% EtOAc/
hexane: [R]D +82 (c ) 0.61, CHCl3); 1H NMR (300 MHz,
CDCl3) δ -0.05 (s, 3H), 0.12 (s, 3H), 0.80 (s, 9H), 5.11 (d, J )
6.0 Hz, 1H), 5.43 (d, J ) 6.0 Hz, 1H), 6.36 (dd, J ) 3.3, 1.8 Hz,
1H), 6.42 (d, J ) 3.3 Hz, 1H), 7.41-7.48 (m, 3H), 7.54-7.60
(m, 1H), 7.97-8.00 (m, 2H). Anal. Calcd for C20H25NO4Si: C,
64.66; H, 6.79; N, 3.77. Found: C, 64.56; H, 6.81; N, 3.60.
(3R,4S)-1-Ben zoyl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-4-(3-
fu r yl)-2-a zetid in on e (21). N-Benzoyl-2-azetidinone 21 was
isolated as a transparent oil in 88% yield after purification by
silica gel flash chromatography eluting with 10% EtOAc/
hexane: [R]D +27 (c ) 0.76, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 0.02 (s, 3H), 0.15 (s, 3H), 0.85 (s, 9H), 5.10 (d, J )
6.3 Hz, 1H), 5.37 (d, J ) 6.0 Hz, 1H), 6.49 (s, 1H), 7.39-7.47
(m, 3H), 7.54-7.59 (m, 2H), 7.95 (d, J ) 8.1 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ -5.0, -4.3, 18.0, 26.2, 54.5, 76.8, 110.4,
118.9, 127.8, 130.0, 134.1, 142.2, 143.2, 165.4, 166.6. Anal.
Calcd for C20H25NO4Si: C, 64.66; H, 6.79; N, 3.77. Found: C,
64.60; H, 6.89; N, 3.50.
7-O-(Tr ieth ylsilyl)ba cca tin III (25).54 To a stirring solu-
tion of baccatin III (0.150 g, 0.256 mmol) in pyridine (10 mL)
was added dropwise at 0 °C triethylsilyl chloride (0.857 mL,
5.12 mmol). The reaction mixture was stirred at rt for 12 h,
quenched with water and extracted with methylene chloride
(3 × 50 mL). The combined organic layer was washed with 1
N HCl (3 × 10 mL) and brine (3 × 10 mL), dried over
anhydrous MgSO4, and concentrated under reduced pressure.
Protected baccatin III 25 was isolated as a white solid in 71%
7-O-(Tr iet h ylsilyl)b a cca t in III 13-O-[(Z)-3-a m in o-N-
1
ben zoyl-3-(4-p yr id yl)a cr yla te] (28b): H NMR (300 MHz,
CDCl3) δ 0.59 (q, J ) 6.9 Hz, 6H), 0.88-0.95 (m, 9H), 1.21 (s,
3H), 1.25 (s, 3H), 1.69 (s, 3H), 1.81-1.92 (m, 1H), 2.10-2.38
(m, 2H), 2.11 (s, 3H), 2.18 (s, 3H), 2.33 (s, 3H), 2.46-2.60 (m,
1H), 3.85 (d, J ) 6.8 Hz, 1H), 4.23 (qab, J ) 50.0, 8.3 Hz, 2H),
4.48 (dd, J ) 10.3, 6.8 Hz, 1H), 4.96 (d, J ) 8.8 Hz, 1H), 5.44
(s, 1H), 5.68 (d, J ) 6.8 Hz, 1H), 6.20 (b t, J ) 7.9 Hz, 1H),
6.47 (s, 1H), 7.33-7.61 (m, 8H), 7.97 (d, J ) 7.1 Hz, 1H), 8.07
(54) 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.

2674 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
(d, J ) 7.3 Hz, 1H), 8.71 (b d, J ) 4.4 Hz, 1H), 11.72 (s, 1H);
MS m/ z calcd for C52H62O12Si (M+ + H) 951, found 951.
2-O-(ter t-Bu tyld im eth ylsilyl)-3′-d ep h en yl-3′-(2-fu r yl)-
7-O-(tr ieth ylsilyl)p a clita xel (29). Protected taxane 29 was
isolated as an amorphous solid in 80% yield: 1H NMR (300
MHz, CDCl3) δ -0.19 (s, 3H), 0.08 (s, 3H), 0.50-0.61 (m, 6H),
0.81 (s, 9H), 0.91 (t, J ) 7.7 Hz, 9H), 1.15 (s, 3H), 1.22 (s, 3H),
1.68 (s, 3H), 1.84-1.94 (m, 1H), 2.02 (s, 3H), 2.10-2.19 (m,
2H), 2.15 (s, 3H), 2.36-2.44 (m, 1H), 2.53 (s, 3H), 3.83 (d, J )
6.9 Hz, 1H), 4.29 (qab, J ) 37.2, 8.4 Hz, 2H), 4.46 (dd, J )
10.5, 6.6 Hz, 1H), 4.86 (d, J ) 1.8 Hz, 1H), 4.94 (d, J ) 8.1 Hz,
1H), 5.68 (d, J ) 6.9 Hz, 1H), 5.79 (d, J ) 9.3 Hz, 1H), 6.17-
6.22 (m, 2H), 6.34-6.35 (m, 1H), 6.44 (s, 1H), 6.89 (d, J ) 9.0
Hz, 1H), 7.39-7.61 (m, 7H), 7.71-7.73 (m, 2H), 8.16 (d, J )
7.2 Hz, 2H).
2-O-(ter t-Bu tyld im eth ylsilyl)-3′-d ep h en yl-3′-(3-fu r yl)-
7-O-(tr ieth ylsilyl)p a clita xel (30). Silylated taxane 30 was
isolated in 72% yield as a 3:1 inseparable mixture of dia-
stereomers after purification by silica gel flash chromatogra-
phy eluting with 25% EtOAc/hexane: 1H NMR (300 MHz,
CDCl3) δ -0.04 and -0.01 (s, 3H), 0.08 and 0.10 (s, 3H), 0.50-
0.66 (m, 6H), 0.86-0.97 (m, 9H), 0.88 and 0.92 (s, 9H), 1.16
(s, 3H), 1.21 and 1.25 (s, 3H), 1.67 and 1.68 (s, 3H), 1.84-2.06
(m, 1H), 1.99 (s, 3H), 2.14 and 2.16 (s, 3H), 2.25-2.41 (m, 2H),
2.48 (s, 3H), 2.48-2.58 (m, 1H), 3.82 (d, J ) 6.9 Hz, 1H), 4.23
and 4.25 (qab, J ) 34.2, 8.4 Hz, 2H), 4.43-4.48 (m, 1H), 4.53
and 4.60 (d, J ) 2.1 Hz, 1H), 4.93 (b d, J ) 8.1 Hz, 1H), 5.64-
5.70 (m, 2H), 6.13 and 6.20 (t, J ) 9.0 Hz, 1H), 6.38 (s, 1H),
6.43 and 6.45 (s, 1H), 6.82 and 7.00 (d, J ) 9.0 Hz, 1H), 7.35-
7.62 (m, 8H), 7.69 and 7.75 (d, J ) 6.9 Hz, 2H), 8.05 and 8.11
(d, J ) 7.2 Hz, 2H).
133.2, 128.7, 129.1, 130.0, 130.1, 132.2, 133.2, 133.4, 133.8,
134.1, 135.2, 141.5, 148.6, 149.4, 166.9, 167.0, 170.4, 171.1,
172.1, 203.5; FAB HRMS m/ z calcd for C46H51N2O14 (M+
+
H) 855.3340, found 855.3356.
3′-Dep h en yl-3′-(4-p yr id yl)p a clita xel (33). Taxane 33
was isolated in 89% yield after purification via silica gel flash
chromatography eluting with 2% MeOH/CH2Cl2: [R]D -40 (c
) 0.6, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 1.11 (s, 3H), 1.19
(s, 3H), 1.65 (s, 3H), 1.76 (s, 3H), 1.80-1.89 (m, 1H), 2.12-
2.32 (m, 2H), 2.20 (s, 3H), 2.37 (s, 3H), 2.46-2.58 (m, 1H), 3.76
(d, J ) 6.8 Hz, 1H), 4.22 (qab, J ) 48, 8.3 Hz, 2H), 4.35 (dd, J
) 10.7, 6.8 Hz, 1H), 4.79 (d, J ) 2.2 Hz, 1H), 4.91 (dd, J )
7.8, 1.5 Hz, 1H), 5.63 (d, J ) 7.0 Hz, 1H), 5.79 (d, J ) 9.3 Hz,
1H), 6.19-6.23 (m, 2H), 7.19 (d, J ) 9.1 Hz, 1H), 7.35-7.60
(m, 8H), 7.73 (d, J ) 7.2 Hz, 2H), 8.09 (d, J ) 7.3 Hz, 2H),
8.57 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 9.6, 14.9, 20.8,
21.7, 22.6, 26.9, 29.7, 35.6, 36.7, 43.2, 45.7, 54.0, 58.6, 72.2,
72.4, 72.6, 74.8, 75.5, 79.0, 81.3, 84.3, 122.3, 127.1, 128.7, 128.8,
129.1, 130.2, 132.3, 133.0, 133.5, 133.8, 141.5, 148.1, 149.6,
167.96, 167.01, 170.5, 171.2, 171.9, 203.5; FAB HRMS m/ z
calcd for C46H51N2O13 (M+ + H) 855.3335, found 855.3340.
3′-Dep h en yl-3′-(2-fu r yl)p a clita xel (34). Taxane 34 was
isolated as a white solid in 79% yield after purification by silica
gel flash chromatography eluting with 50% EtOAc/hexane:
[R]D -42 (c ) 0.21, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.14
(s, 3H), 1.23 (s, 3H,), 1.68 (s, 3H,), 1.81-1.92 (m, 1H), 1.85 (s,
3H), 2.23 (s, 3H), 2.31-2.46 (m, 2H), 2.42 (s, 3H), 2.44-2.68
(m, 1H), 3.47 (d, J ) 5.4 Hz, 1H), 3.81 (d, J ) 6.9 Hz, 1H),
4.25 (qab, J ) 34.8, 8.4 Hz, 2H), 4.37-4.44 (m, 1H), 4.81 (d, J
) 2.1 Hz, 1H), 4.95 (d, J ) 7.8 Hz, 1H), 5.67 (d, J ) 7.2 Hz,
1H), 5.87 (dd, J ) 9.3, 2.4 Hz, 1H), 6.23 (b t, J ) 9.0 Hz, 1H),
6.26 (s, 1H), 6.39 (d, J ) 0.9 Hz, 2H), 6.84 (d, J ) 9.3 Hz, 1H),
7.37-7.62 (m, 7H), 7.73 (d, J ) 7.5 Hz, 2H), 8.14 (d, J ) 7.5
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 10.0, 15.3, 21.3, 22.2,
23.0, 27.3, 36.0, 43.6, 46.0, 50.6, 59.1, 72.2, 72.6, 72.9, 75.4,
76.0, 76.8, 79.4, 81.5, 84.9, 108.4, 111.2, 127.5, 129.1, 129.7,
130.7, 132.7, 133.8, 134.2, 142.7, 143.3, 151.2, 167.4, 170.9,
171.8, 172.8, 204.1; FAB HRMS m/ z calcd for C45H49NO15Na
(M+ + Na) 866.3000, found 866.3030.
Gen er a l P r oced u r e for th e Dep r otection of Ta xa n es
31-35. Silylated taxanes (20 mg, 0.019 mmol) in anhydrous
pyridine (1 mL) were placed in a nalgene reaction vessel. To
the solution was added pyridinium HF (0.25 mL, excess). The
reaction vessel was then sealed and allowed to stir at rt for 3
h. The reaction mixture was carefully quenched by pouring
the reaction mixture into a saturated NaHCO3 solution,
extracted with EtOAc (3 × 10 mL), and dried over anhydrous
MgSO4.
3′-Dep h en yl-3′-(3-fu r yl)p a clita xel (35). The mixture of
the two diastereomers of deprotected taxane 33 was isolated
as a white solid in 59% yield after purification by silica gel
flash chromatography eluting with 50% EtOAc/hexane: 1H
NMR (300 MHz, CDCl3) δ 1.14 (s, 3H), 1.23 (s, 3H,), 1.68 (s,
3H), 1.83 (s, 3H), 1.86-1.92 (m, 1H), 2.03 (s, 1H), 2.22 (s, 3H),
2.34-2.39 (m, 2H), 2.38 (s, 3H), 2.49-2.62 (m, 1H), 3.57 (d, J
) 4.8 Hz, 1H), 3.80 (d, J ) 7.2 Hz, 1H), 4.25 (qab, J ) 34.8, 8.4
Hz, 2H), 4.36-4.43 (m, 1H), 4.59 and 4.67 (d, J ) 1.5 Hz, 1H),
4.94 (d, J ) 7.5 Hz, 1H), 5.67 (d, J ) 7.2 Hz, 1H), 5.72 (dd, J
) 9.0, 1.5 Hz, 1H), 6.14-6.29 (m, 1H), 6.27 and 6.29 (s, 1H),
6.51 and 6.58 (t, J ) 0.9 Hz, 1H), 6.66 and 6.71 (d, J ) 9.0 Hz,
1H), 7.35-7.72 (m, 10H), 8.04 and 8.13 (d, J ) 7.2 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 10.0, 15.3, 22.0, 22.2, 22.9, 27.3,
36.1, 43.8, 46.1, 48.5, 59.2, 72.7, 72.8, 73.1, 75.4, 76.0, 76.8,
77.0, 79.4, 81.7, 84.8, 110.0, 110.1, 123.4, 127.4, 129.1, 129.7,
130.4, 130.6, 132.4, 133.8, 139.2, 140.9, 142.3, 144.1, 167.2,
167.3, 170.9, 171.5, 173.1, 204.1; FAB HRMS m/ z calcd for
C45H49NO15Li (M+ + Li) 850.3262, found 850.3288.
3′-Dep h en yl-3′-(2-p yr id yl)p a clita xel (31). Taxane 31
was isolated as a white powder in 90% yield after purification
by silica gel flash chromatography eluting with 50% EtOAc/
1
hexane: [R]D -30.2 (c ) 0.215, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 1.13 (s, 3H), 1.23 (s, 3H), 1.68 (s, 3H), 1.83-1.94 (m,
1H), 1.84 (s, 3H), 2.20-2.36 (m, 2H), 2.24 (s, 3H), 2.48 (s, 3H),
2.50-2.62 (m, 1H), 3.83 (d, J ) 6.6 Hz, 1H), 4.24 (qab, J )
44.9, 8.3 Hz, 2H), 4.44 (dd, J ) 14.0, 3.4 Hz, 1H), 4.82 (d, J )
3.3 Hz, 1H), 4.99 (d, J ) 7.5 Hz, 1H), 5.67 (d, J ) 6.8 Hz, 1H),
5.92 (dd, J ) 9.4, 2.9 Hz, 1H), 6.19 (b t, J ) 8.4 Hz, 1H), 6.28
(s, 1H), 7.30 (dd, J ) 7.6, 5.3 Hz, 1H), 7.43-7.64 (m, 8H), 7.71-
7.78 (m, 2H), 7.86 (d, J ) 7.4 Hz, 2H), 8.10 (d, J ) 7.3 Hz,
2H), 8.53 (b d, J ) 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
9.5, 14.8, 20.8, 21.8, 22.2, 26.7, 29.7, 35.6, 35.7, 43.1, 45.7, 54.6,
58.6, 71.2, 72.2, 73.5, 75.0, 75.6, 76.4, 79.3, 80.8, 84.4, 122.5,
123.3, 127.1, 128.7, 128.7, 129.1, 130.1, 132.1, 132.8, 133.7,
137.9, 142.5, 148.2, 167.1, 170.6, 171.3, 173.3, 203.8; FAB
HRMS m/ z calcd for C46H51N2O14 (M+ + H) 855.3340, found
855.3369.
Ba cca t in III 13-O-[(Z)-3-Am in o-N-b en zoyl-3-(4-p yr i-
d yl)a cr yla te] (36). Enamide 36 was isolated quantitatively
by silica gel flash chromatography eluting with 80% EtOAc/
hexane. Taxane 36 was isolated in a 10:1 Z:E mixture. Major
isomer: 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 3H), 1.26 (s,
3H), 1.67 (s, 3H), 1.82-1.91 (m, 1H), 1.96 (s, 3H), 2.20-2.37
(m, 2H), 2.23 (s, 3H), 2.31 (s, 3H), 2.50-2.65 (m, 1H), 3.83 (d,
J ) 6.9 Hz, 1H), 4.22 (qab, J ) 49, 8.4 Hz, 2H), 4.44 (dd, J )
10.8, 6.3 Hz, 1H), 4.96 (d, J ) 8.7 Hz, 1H), 5.42 (s, 1H), 5.66
(d, J ) 6.9 Hz, 1H), 6.23 (t, J ) 9.6 Hz, 1H), 6.30 (s, 1H), 7.36
(d, J ) 4.6 Hz, 2H), 7.46-7.61 (m, 5H), 7.77 (t, J ) 7.5 Hz,
1H), 7.97 (d, J ) 7.2 Hz, 2H), 8.07 (d, J ) 7.4, 2H,), 8.69-8.78
(br s, 2H), 11.72 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 9.5, 15.3,
20.8, 21.5, 22.7, 26.8, 29.7, 35.6, 35.9, 43.1, 46.3, 58.7, 59.2,
70.4, 72.2, 74.9, 75.6, 76.4, 79.3, 80.8, 81.1, 84.3, 101.1, 121.3,
127.0, 127.8, 128.7, 129.1, 129.2, 130.0, 133.2, 133.8, 142.4,
149.7, 154.4, 164.9, 166.7, 167.9, 171.2, 171.9, 203.6; FAB
HRMS m/ z calcd for C46H49N2O13 (M+ + H) 837.3235, found
837.3249.
3′-Dep h en yl-3′-(3-p yr id yl)p a clita xel (32). Taxane 32 (an
inseparable 2:1 mixture of diastereomers) was isolated in 90%
yield after purification by silica gel flash chromatography
eluting with EtOAc: 1H NMR (300 MHz, CDCl3) δ 1.15 (s, 3H),
1.23 (s, 3H), 1.69 (s, 3H), 1.78 (s, 3H), 1.81-1.91 (m, 1H), 2.03
(s, 1H), 2.24 (s, 3H), 2.27-2.36 (m, 2H), 2.41 (s, 3H), 2.49-
2.64 (m, 1H), 3.79 and 3.85 (d, J ) 6.8 Hz, 1H), 4.25 and 4.21
(qab, J ) 36.1, 8.3 Hz, 2H), 4.38 and 4.46 (dd, J ) 11.1, 7.1 Hz,
1H), 4.68 and 4.78 (d, J ) 2.4 Hz, 1H), 4.95 and 4.97 (d, J )
7.8 Hz, 1H), 5.67 (d, J ) 6.8 Hz, 1H), 5.81 and 5.85 (dd, J )
2.4, 8.7 Hz, 1H), 6.21-6.31 (m, 2H), 7.10 and 7.14 (d, J ) 8.9
Hz, 1H), 7.33-7.65 (m, 8H), 7.60 and 7.61 (t, J ) 7.4 Hz, 1H),
7.72 and 7.73 (d, J ) 7.2 Hz, 2H), 7.85-7.93 (m, 1H), 8.04
and 8.13 (d, J ) 7.2 Hz, 2H), 8.57-8.60 (m, 1H), 8.76 and 8.88
(d, J ) 2.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 9.49, 9.54,
14.9, 20.78, 20.83, 21.6, 22.6, 26.9, 29.7, 35.6, 35.7, 43.2, 45.7,
52.9, 58.6, 72.2, 72.5, 72.8, 74.8, 75.5, 76.5, 78.9, 81.3, 84.3,
123.7, 127.0, 127.1, 128.7, 128.8, 129.1, 130.0, 130.1, 132.2,

Synthesis of Heteroaromatic Taxanes
J . Org. Chem., Vol. 61, No. 8, 1996 2675
(3R,4R)-1-(ter t-Bu toxyca r bon yl)-3-[(ter t-bu tyld im eth -
ylsilyl)oxy]-4-(2-fu r yl)-2-a zetid in on e (37). To a stirring
solution of (3R,4S)-3-[(tert-butyldimethylsilyl)oxy]-4-(2-furyl)-
2-azetidinone (15, 0.426 g, 0.160 mmol) in THF (10 mL) were
added at rt triethylamine (0.111 mL, 0.800 mmol), DMAP
(0.004 g, 0.03 mmol), and (BOC)2O (0.110 mL, 0.480 mmol).
After being stirred for 10 min, the reaction mixture was diluted
with ether, quenched with water, extracted with ether (3 ×
20 mL), washed with brine, dried over anhydrous MgSO4, and
evaporated under reduced pressure. 2-Azetidinone 37 was
isolated as a white solid in 96% yield after purification by silica
gel flash chromatography eluting with 5% EtOAc/hexane: mp
saturated ammonium chloride solution (5 mL), extracted with
ether, dried over anhydrous MgSO4, and evaporated under
reduced pressure.
2′-O-(ter t-Bu tyldim eth ylsilyl)-N-deben zoyl-3′-deph en yl-
3′-(2-fu r yl)-N-h exa n oyl-7-O-(tr ieth ylsilyl)p a clita xel (41).
Protected taxane 41 was prepared according to the general
procedure by coupling of protected baccatin III 25 (0.036 g,
0.051 mmol) with 38 (0.037 g, 0.10 mmol) and isolated as a
transparent oil in 46% yield after purification by silica gel flash
chromatography eluting with 25% EtOAc/hexane: 1H NMR
(300 MHz, CDCl3) δ -0.16 (s, 3H), 0.01 (s, 3H), 0.51-0.59 (m,
6H), 0.79 (s, 9H), 0.79-0.93 (m, 12H), 1.20 (s, 3H), 1.22-1.25
(m, 7H), 1.54-1.68 (m, 2H), 1.68 (s, 3H), 1.84-1.93 (m, 2H),
2.10-2.24 (m, 2H), 2.16 (s, 3H), 2.32-2.41 (m, 2H), 2.48 (s,
3H), 2.48-2.56 (m, 1H), 3.82 (d, J ) 6.9 Hz, 1H), 4.24 (qab, J
) 34.8, 8.4 Hz, 2H), 4.45 (dd, J ) 10.5, 6.6 Hz, 1H), 4.76 (d, J
) 1.8 Hz, 1H), 4.93 (d, J ) 8.1 Hz, 1H), 5.62-5.70 (m, 2H),
6.12-6.22 (m, 3H), 6.34 (dd, J ) 3.3, 1.8 Hz, 1H), 6.44 (s, 1H),
7.36 (d, J ) 1.2 Hz, 1H), 7.47 (t, J ) 7.8 Hz, 2H), 7.57 (t, J )
7.2 Hz, 1H), 8.07-8.10 (m, 2H).
1
51-52 °C; [R]D +53.6 (c ) 1.09, CHCl3); H NMR (300 MHz,
CDCl3) δ -0.06 (s, 3H), 0.08 (s, 3H), 0.78 (s, 9H), 1.41 (s, 9H),
5.01 (d, J ) 5.7 Hz, 1H), 5.07 (d, J ) 5.7 Hz, 1H), 5.36 (d, J )
1.2 Hz, 2H), 7.40 (t, J ) 3.0, 1.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -4.6, -4.6, 18.3, 25.7, 27.9, 28.3, 56.3, 83.9, 110.1,
110.9, 143.1, 148.1, 148.4, 166.0. Anal. Calcd for C18H29NO5-
Si: C, 58.83; H, 7.96; N, 3.81. Found: C, 58.68; H, 8.10; N,
4.00.
(3R,4R)-3-[(ter t-Bu t yld im et h ylsilyl)oxy]-4-(2-fu r yl)-1-
h exa n oyl-2-a zetid in on e (38). 2-Azetidinone 38 was pre-
pared according to the general procedure by acylation of 15
(0.040 g, 0.15 mmol) with hexanoyl chloride (0.032 mL, 0.22
mmol) and isolated as a transparent oil in 90% yield after
purification by silica gel flash chromatography eluting with
2′-O-(ter t-Bu tyldim eth ylsilyl)-N-deben zoyl-N-decan oyl-
3′-d ep h en yl-3′-(2-fu r yl)-7-O-(tr ieth ylsilyl)p a clita xel (42).
Protected taxane 42 was prepared according to the general
procedure from protected baccatin III (0.035 g, 0.050 mmol)
and 39 (0.042 g, 0.10 mmol) and isolated as a transparent oil
in 48% yield after purification by silica gel flash chromatog-
raphy eluting with 25% EtOAc/hexane: 1H NMR (300 MHz,
CDCl3) δ -0.16 (s, 3H), 0.01 (s, 3H), 0.51-0.59 (m, 6H), 0.79
(s, 9H), 0.81-0.94 (m, 12H), 1.15-1.30 (m, 18H), 1.50-1.60
(m, 2H), 1.68 (s, 3H), 1.81-1.94 (m, 1H), 2.00 (s, 3H), 2.07-
2.23 (m, 2H), 2.16 (s, 3H), 2.31-2.41 (m, 2H), 2.47-2.58 (m,
1H), 2.47 (s, 3H), 3.82 (d, J ) 6.9 Hz, 1H), 4.23 (qab, J ) 33.6,
8.1 Hz, 2H), 4.45 (dd, J ) 10.5, 6.9 Hz, 1H), 4.75 (d, J ) 1.8
Hz, 1H), 4.93 (d, J ) 8.1 Hz, 1H), 5.61-5.70 (m, 2H), 6.12-
6.21 (m, 3H), 6.33 (dd, J ) 3.3, 1.8 Hz, 1H), 6.44 (s, 1H), 7.34
(bs, 1H), 7.47 (t, J ) 7.2 Hz, 2H), 7.57 (t, J ) 7.2 Hz, 1H), 8.09
(d, J ) 6.9 Hz, 2H).
N-(ter t-Bu t oxyca r b on yl)-N-d eben zoyl-3′-d ep h en yl-3′-
(2-fu r yl)p a clita xel (43). Bis-silylated taxane 40 (0.040 g,
0.038 mmol) was deprotected according to the general proce-
dure, and taxane 43 was isolated as a white solid in 81% yield
after purification by silica gel flash chromatography eluting
with 50% EtOAc/hexane: mp 155-158 °C; [R]D -79 (c ) 0.67,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.13 (s, 3H), 1.24 (s, 3H),
1.33 (s, 9H), 1.66 (s, 3H), 1.82-1.91 (m, 1H), 1.87 (s, 3H), 2.23
(s, 3H), 2.28-2.39 (m, 2H), 2.39 (s, 3H), 2.48-2.58 (m, 1H),
3.80 (d, J ) 7.2 Hz, 1H), 4.22 (qab, J ) 42.3, 8.4 Hz, 2H), 4.41
(dd, J ) 10.8, 6.6 Hz, 1H), 4.70 (d, J ) 1.8 Hz, 1H), 4.94 (d, J
) 7.8 Hz, 1H), 5.23-5.34 (m, 2H,), 5.66 (d, J ) 6.9 Hz, 1H),
6.22 (t, J ) 9.0, 1H), 6.29-6.31 (m, 2H), 6.35-6.37 (m, 1H),
7.40 (d, J ) 0.9 Hz, 1H), 7.47 (t, J ) 7.5 Hz, 2H), 7.59 (t, J )
7.5 Hz, 1H), 8.09 (d, J ) 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 9.9, 15.3, 21.3, 22.2, 22.9, 23.0, 27.1, 28.5, 35.8, 35.9,
36.0, 43.6, 46.1, 52.1, 59.0, 72.2, 72.6, 72.9, 75.4, 75.5, 76.0,
79.4, 80.9, 81.4, 81.5, 81.6, 84.9, 107.9, 111.1, 129.5, 129.8,
130.7, 134.8, 135.0, 142.4, 142.7, 142.9, 151.9, 155.8, 167.6,
171.0, 171.5, 171.8, 173.2, 202.3; FAB HRMS m/ z calcd for
C43H53NO16Li 846.3524, found 846.3547.
1
5% EtOAc/hexane: [R]D +42 (c ) 1.1, CHCl3); H NMR (300
MHz, CDCl3) δ -0.08 (s, 3H), 0.10 (s, 3H), 0.75 (s, 9H), 0.86
(t, J ) 6.9 Hz, 3H), 1.25-1.33 (m, 4H), 1.59-1.66 (m, 2H),
2.62-2.81 (m, 2H), 5.05 (d, J ) 5.7 Hz, 1H), 5.16 (d, J ) 5.7
Hz, 1H), 6.33 (s, 2H), 7.37 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ -5.0, -4.6, 14.3, 18.3, 22.7, 24.1, 25.7, 31.6, 37.2, 55.0, 77.0,
110.2, 110.9, 143.2, 147.9, 166.4, 177.7; HRMS m/ z calcd for
C19H32NO4Si 366.2100, found 366.2108.
(3R,4R)-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-1-d eca n oyl-4-
(2-fu r yl)-2-a zetid in on e (39). 2-Azetidinone 39 was prepared
according to the general procedure by acylation of 15 (0.040
g, 0.15 mmol) with decanoyl chloride (0.047 mL, 0.22 mmol)
and isolated as a transparent oil in 94% yield after purification
by silica gel flash chromatography eluting with 5% EtOAc/
hexane: [R]D +28.5 (c ) 1.05, CHCl3); 1H NMR (300 MHz,
CDCl3) δ -0.08 (s, 3H), 0.10 (s, 3H), 0.73 (s, 9H), 0.85 (t, J )
7.2 Hz, 3H), 1.23-1.33 (m, 12H), 1.58-1.68 (m, 2H), 2.61-
2.81 (m, 2H), 5.05 (d, 5.7 Hz, 1H), 5.16 (d, 5.7 Hz, 1H), 6.31-
6.34 (m, 2H), 7.37 (t, J ) 1.5 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ -5.0, -4.6, 14.5, 18.3, 23.1, 24.5, 25.7, 29.4, 29.6,
29.7, 29.8, 32.3, 37.2, 55.0, 71.4, 77.0, 110.2, 110.9, 143.2, 147.9,
166.4, 171.7; HRMS m/ z calcd for C23H40NO4Si 422.2726,
found 422.2748.
N-(ter t-Bu toxyca r bon yl)-2′-O-(ter t-bu tyld im eth ylsilyl)-
N-d eben zoyl-3′-d ep h en yl-3′-(2-fu r yl)-7-O-(t r iet h ylsilyl)-
p a clita xel (40). Protected taxane 40 was prepared according
to the general procedure (NaH as the base) by coupling of
protected baccatin III 25 (0.036 g, 0.051 mmol) with 37 (0.028
g, 0.076 mmol) and isolated as a transparent solid in 78% yield
after purification by silica gel flash chromatography eluting
with 5% EtOAc/hexane: mp 132 °C; [R]D -41.4 (c ) 1.01,
1
CHCl3); H NMR (300 MHz, CDCl3) δ -0.16 (s, 3H), 0.03 (s,
3H), 0.52-0.60 (m, 6H), 0.77 (s, 9H), 0.91 (t, J ) 7.8 Hz, 9H),
1.19 (s, 3H), 1.22 (s, 3H), 1.32 (s, 9H), 1.68 (s, 3H), 1.85-1.94
(m, 1H), 2.01 (s, 3H), 2.16 (s, 3H), 2.30-2.43 (m, 2H), 2.45-
N-Deben zoyl-3′-d ep h en yl-3′-(2-fu r yl)-N-h exa n oylp a cli-
ta xel (44). Bis-silylated taxane 41 (0.020 g, 0.019 mmol) was
deprotected according to the general procedure, and taxane
44 was isolated as an amorphous solid in 64% yield after
purification by silica gel flash chromatography eluting with
50% EtOAc/hexane: mp 136-139 °C; [R]D -42 (c ) 0.23,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 0.81-0.85 (m, 3H), 1.15
(s, 3H), 1.21-1.25 (m, 7H,), 1.67 (s, 3H), 1.83-1.92 (m, 1H),
1.86 (s, 3H), 2.16-2.23 (m, 2H), 2.23 (s, 3H), 2.28-2.44 (m,
4H), 2.37 (s, 3H), 2.49-2.59 (m, 1H), 3.33 (d, J ) 5.1 Hz, 1H),
3.80 (d, J ) 6.9 Hz, 1H), 4.24 (qab, J ) 33.3, 8.7 Hz, 2H), 4.37-
4.44 (m, 1H), 4.71 (d, J ) 1.8 Hz, 1H), 4.94 (dd, J ) 9.3, 1.8
Hz, 1H), 5.64-5.68 (m, 2H), 6.08 (d, J ) 9.3 Hz, 1H), 6.21 (t,
J ) 9.0 Hz, 1H), 6.28 (s, 1H), 6.31 (d, J ) 3.3 Hz, 1H), 6.38
(dd, J ) 3.3, 1.8 Hz, 1H), 7.41 (d, J ) 1.2 Hz, 1H), 7.48 (t, J )
7.2 Hz, 2H), 7.59 (t, J ) 7.2 Hz, 1H), 8.10 (d, J ) 7.5 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 9.6, 13.8, 14.9, 20.9, 21.9, 22.3,
22.5, 25.3, 26.8, 29.7, 31.2, 35.6, 36.4, 43.2, 45.6, 49.7, 58.6,
71.6, 72.2, 72.5, 75.0, 75.6, 76.5, 78.9, 81.1, 84.4, 107.7, 110.7,
2.62 (m, 1H), 2.48 (s, 3H), 3.84 (d, J ) 6.9 Hz, 1H), 4.23 (qab
,
J ) 38.1, 8.4 Hz, 2H), 4.46 (dd, J ) 10.5, 6.9 Hz, 1H), 4.73 (d,
J ) 1.5 Hz, 1H), 4.93 (d, J ) 8.4 Hz, 1H), 5.22-5.36 (m, 2H),
5.67 (d, J ) 6.9 Hz, 1H), 6.20-6.26 (m, 2H), 6.32-6.34 (m,
1H), 6.45 (s, 1H), 7.35 (s, 1H), 7.46 (t, J ) 7.8 Hz, 2H), 7.55 (t,
J ) 7.2 Hz, 1H), 8.09 (d, J ) 7.2 Hz, 2H).
Gen er a l P r oced u r e for t h e Sod iu m Bis(t r im et h yl-
silyl)a m id e-P r om oted Acyla tion of 7-O-(Tr ieth ylsilyl)-
ba cca tin III for th e F or m a tion of Com p ou n d s 41 a n d 42.
To a cold (-41 °C) solution of 7-O-(triethylsilyl)baccatin III
(0.025 g, 0.036 mmol) and N-acyl-2-azetidinone (0.054 mmol)
in anhydrous THF (1 mL) was added dropwise a 1 M THF
solution of sodium bis(trimethylsilyl)amide (0.54 mL). The
reaction was stirred at -41 °C for 10 min or until the
disappearance of 24 by TLC (35% EtOAc/hexane), warmed to
0 °C, carefully quenched by the dropwise addition of a

2676 J . Org. Chem., Vol. 61, No. 8, 1996
Georg et al.
128.7, 129.1, 130.2, 133.2, 133.7, 142.0, 142.6, 150.9, 167.0,
170.3, 171.3, 172.4, 173.1, 203.7; FAB HRMS m/ z calcd for
C44H56NO15 838.3650, found 838.3669.
1H), 5.76 (dd, J ) 9.0, 2.4 Hz, 1H), 6.22 (t, J ) 8.7 Hz, 1H),
6.25 (s, 1H), 7.19 (d, J ) 8.7 Hz, 1H), 7.32-7.63 (m, 10H),
8.11 (d, J ) 7.5 Hz, 2H), 8.68 (d, J ) 5.7 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 9.5, 14.1, 14.9, 20.9, 21.7, 22.7, 26.9, 29.2,
29.7, 31.9, 35.5, 43.2, 45.6, 54.9, 58.6, 72.2, 72.5, 72.9, 74.9,
75.5, 76.5, 79.1, 81.2, 84.4, 120.8, 127.0, 128.6, 128.7, 129.1,
129.2, 130.2, 133.4, 133.8, 137.4, 141.0, 141.7, 150.7, 165.0,
167.0, 170.4, 171.3, 172.5, 203.5; FAB HRMS m/ z calcd for
N-Deben zoyl-N-d eca n oyl-3′-d ep h en yl-3′-(2-fu r yl)p a cli-
ta xel (45). Bis-silylated taxane 42 (0.025 g, 0.022 mmol) was
deprotected according to the general procedure and taxane 45
was isolated as a white solid in 69% yield after purification
by silica gel flash chromatography eluting with 50% EtOAc/
hexane: mp 116-118 °C; [R]D -88 (c ) 0.28, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 0.85 (t, J ) 6.6 Hz, 3H), 1.14-1.25
(m, 18H), 1.67 (s, 3H), 1.80-1.92 (m, 1H), 1.86 (s, 3H), 2.15-
2.23 (m, 2H), 2.23 (s, 3H), 2.27-2.45 (m, 4H), 2.37 (s, 3H),
2.49-2.58 (m, 1H), 3.36 (d, J ) 5.1 Hz, 1H), 3.79 (d, J ) 6.9
Hz, 1H), 4.23 (qab, J ) 33.0, 8.4 Hz, 2H), 4.37-4.43 (m, 1H),
4.71 (d, J ) 2.4 Hz, 1H), 4.93 (d, J ) 8.1 Hz, 1H), 5.64-5.68
(m, 2H), 6.09 (d, J ) 9.3 Hz, 1H), 6.20 (t, J ) 9.0 Hz, 1H),
6.28 (s, 1H), 6.31 (d, J ) 3.0 Hz, 1H), 6.37 (dd, J ) 3.0, 1.8
Hz, 1H), 7.41 (b s, 1H), 7.48 (t, J ) 7.2 Hz, 2H), 7.59 (t, J )
7.5 Hz, 1H), 8.00 (d, J ) 7.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 10.0, 14.5, 15.2, 21.2, 22.3, 22.9, 23.0, 26.1, 27.2, 29.6,
29.7, 32.2, 36.0, 36.9, 43.6, 46.1, 50.1, 59.1, 72.1, 72.9, 75.4,
76.0, 79.4, 81.5, 84.9, 108.1, 111.2, 129.6, 130.6, 133.7, 134.1,
143.0, 151.4, 152.3, 154.0, 167.4, 170.7, 172.8, 173.3, 189.6,
204.1; FAB HRMS m/ z calcd for C48H64NO15 894.4276, found
894.4305.
C
46H51N2O14 (M+ + H) 855.3340, found 855.3343.
N-Deb en zoyl-N-(2-fu r oyl)p a clit a xel (50). Taxane 50
was isolated as a white solid in 69% yield after purification
by silica gel flash chromatography eluting with 30% EtOAc/
hexane: [R]D -30 (c ) 0.7, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.12 (s, 3H), 1.22 (s, 3H), 1.68 (s, 3H), 1.75-1.92 (m, 1H),
1.79 (s, 3H), 2.20-2.38 (m, 2H), 2.24 (s, 3H), 2.39 (s, 3H), 2.44-
2.49 (m, 1H), 3.53 (d, J ) 5.3 Hz, 1H), 3.78 (d, J ) 6.3 Hz,
1H), 4.23 (qab, J ) 33.0, 8.4 Hz, 2H), 4.35-4.43 (m, 1H), 4.75
(dd, J ) 5.1, 2.7 Hz, 1H), 4.93 (d, J ) 8.1 Hz, 1H), 5.65 (d, J
) 6.9 Hz, 1H), 5.72 (dd, J ) 9.0, 2.1 Hz, 1H), 6.19-6.27 (m,
1H), 6.25 (s, 1H), 6.46 (dd, J ) 3.6, 1.8 Hz, 1H), 7.01 (d, J )
3.6 Hz, 1H), 7.13 (d, J ) 9.3 Hz, 1H), 7.33-7.62 (m, 9H), 8.12
(d, J ) 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 10.0, 15.2,
21.2, 22.2, 23.0, 27.3, 36.0, 36.1, 43.6, 46.1, 54.8, 59.1, 72.6,
72.7, 73.8, 75.4, 76.0, 79.5, 81.6, 84.8, 112.7, 115.6, 127.4, 128.8,
129.1, 129.4, 129.6, 130.6, 133.6, 134.2, 138.9, 142.8, 144.4,
158.4, 167.1, 170.3, 172.0, 203.1; FAB HRMS m/ z calcd for
C45H49NO15Na (M+ + Na) 866.3000, found 866.3019.
Gen er a l Sch otten -Ba u m a n n Acyla tion P r oced u r e for
th e Syn th esis of 47-51. To a stirring solution of 46 (20 mg,
0.033 mmol) in EtOAc (1 mL) and saturated NaHCO3 solution
(1 mL) was added acid chloride (1.5 equiv). The reaction
mixture was vigorously stirred at rt for 15 min. The organic
layer was separated and dried over anhydrous MgSO4.
N-Deben zoyl-N-(p icolin oyl)p a clita xel (47). Taxane 47
was isolated as a white powder in 90% yield after purification
by silica gel flash chromatography eluting with 50% EtOAc/
N-Deb en zoyl-N-(3-fu r oyl)p a clit a xel (51). Taxane 51
was isolated as a white solid in 71% yield after purification
by silica gel flash chromatography eluting with 30% EtOAc/
hexane: [R]D -30 (c ) 0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.21 (s, 3H), 1.22 (s, 3H), 1.66 (s, 3H), 1.77-1.90 (m, 1H),
1.77 (s, 3H), 2.18-2.32 (m, 2H), 2.22 (s, 3H), 2.35 (s, 3H), 2.49-
2.58 (m, 1H), 3.68 (br s, 1H), 3.77 (d, J ) 6.9 Hz, 1H), 4.22
(qab, J ) 32.4, 8.4 Hz, 2H), 4.35-4.40 (m, 1H), 4.75 (br s, 1H),
4.92 (d, J ) 7.8 Hz, 1H), 5.64 (d, J ) 7.2 Hz, 1H), 5.72 (dd, J
) 9.0, 2.7 Hz, 1H), 6.18-6.25 (m, 1H), 6.25 (s, 1H), 6.56-6.57
(m, 1H), 6.66 (d, J ) 8.7 Hz, 1H), 7.29-7.63 (m, 9H), 7.86 (br
s, 1H), 8.11 (d, J ) 7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
10.1, 14.9, 21.3, 23.1, 36.0, 43.6, 46.6, 47.0, 55.0, 59.0, 71.7,
73.6, 75.3, 76.5, 79.5, 81.6, 83.9, 122.2, 126.4, 128.1, 128.4,
129.5, 129.6, 130.2, 131.3, 133.6, 138.3, 142.4, 144.4, 145.5,
147.0, 162.6, 167.4, 170.8, 171.7, 173.0, 204.0; FAB HRMS m/ z
calcd for C45H50NO15 (M+ + H) 844.3180, found 844.3197.
1
hexane: [R]D -30.2 (c ) 0.215, CH2Cl2); H NMR (300 MHz,
CDCl3) δ 1.13 (s, 3H), 1.23 (s, 3H), 1.68 (s, 3H), 1.83-1.94 (m,
1H), 1.84 (s, 3H), 2.20-2.36 (m, 2H), 2.24 (s, 3H), 2.48 (s, 3H),
2.50-2.62 (m, 1H), 3.83 (d, J ) 6.6 Hz, 1H), 4.24 (qab, J )
44.9, 8.3 Hz, 2H), 4.44 (dd, J ) 14.0, 3.4 Hz, 1H), 4.82 (d, J )
3.3 Hz, 1H), 4.99 (d, J ) 7.5 Hz, 1H), 5.67 (d, J ) 6.8 Hz, 1H),
5.92 (dd, J ) 9.4, 2.9 Hz, 1H), 6.19 (b t, J ) 8.4 Hz, 1H), 6.28
(s, 1H), 7.30 (dd, J ) 7.6, 5.3 Hz, 1H), 7.43-7.64 (m, 8H), 7.71-
7.78 (m, 2H), 7.86 (d, J ) 7.4 Hz, 2H), 8.10 (d, J ) 7.3 Hz,
2H), 8.53 (b d, J ) 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ
9.5, 14.8, 20.8, 21.8, 22.2, 26.7, 29.7, 35.6, 35.7, 43.1, 45.7, 54.6,
58.6, 71.2, 72.2, 73.5, 75.0, 75.6, 76.4, 79.3, 80.8, 84.4, 122.5,
123.3, 127.1, 128.7, 128.7, 129.1, 130.1, 132.1, 132.8, 133.7,
137.9, 142.5, 148.2, 167.1, 170.6, 171.3, 173.3, 203.8; FAB
HRMS m/ z calcd for C46H51N2O14 (M+ + H) 855.3340, found
855.3369.
N-Deben zoyl-N-(n icotin oyl)p a clita xel (48). Taxane 48
was isolated in 79% yield as a colorless glass after purification
by silica gel flash chromatography eluting with 2% MeOH/
CH2Cl2: [R]D -30 (c ) 0.3, CH2Cl2); 1H NMR (300 MHz, CDCl3)
δ 1.13 (s, 3H), 1.23 (s, 3H), 1.67 (s, 3H), 1.80 (s, 3H), 1.81-
1.94 (m, 1H), 2.10-2.32 (m, 2H), 2.24 (s, 3H), 2.40 (s, 3H),
2.46-2.60 (m, 1H), 3.77 (d, J ) 6.9 Hz, 1H), 4.24 (qab, J )
36.0, 8.0 Hz, 2H), 4.39 (dd, J ) 10.9, 6.7 Hz, 1H), 4.81 (d, J )
3.5 Hz, 1H), 4.93 (dd, J ) 9.1, 1.5 Hz, 1H), 5.65 (d, J ) 7.2 Hz,
1H), 5.78 (dd, J ) 8.0, 3.0 Hz, 1H), 6.22 (t, J ) 7.9 Hz, 1H),
6.25 (s, 1H), 7.32-7.65 (m, 9H), 7.95 (br s, 1H), 8.12 (d, J )
8.5 Hz, 2H), 8.31 (d, J ) 7.0 Hz, 1H), 8.71-8.78 (m, 1H), 9.36-
9.39 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 9.6, 14.2, 14.9, 20.9,
21.9, 22.7, 26.9, 29.7, 31.9, 35.6, 43.2, 45.6, 55.2, 58.6, 72.2,
72.3, 73.1, 74.9, 75.5, 77.2, 79.1, 81.2, 84.4, 127.1, 128.5, 128.7,
129.1, 129.15, 130.2, 133.3, 133.8, 137.6, 141.8, 164.7, 167.0,
170.4, 171.3, 172.6, 178.6, 203.2; FAB HRMS m/ z calcd for
C46H51N2O14 (M+ + H) 855.3340, found 855.3339.
Ackn owledgm en t. Financial support for this project
is acknowledged from the National Institutes of Health
(NCI). We also gratefully acknowledge the Marion
Merrell Dow Scientific Education Partnership for a
postdoctoral fellowship to G.C.B.H. and the Kansas
Health Foundation for a postdoctoral fellowship to
G.C.B.H. and a predoctoral fellowship to M.H. Pacli-
taxel was provided to us by the National Cancer
Institute.
Su p p or tin g In for m a tion Ava ila ble: Proton NMR spectra
are provided for 10, 11, 17-19, 26, 27, 28a , 29-31, 31
expansion, 32-34, 34 expansion in DMSO/D2O, 35, 36, 38-
43, 43 COSY, 43 COSY expansion, and 44-51. Carbon NMR
spectra are provided for 17-19, 26, 29-31, 31 expansion, 32-
35, 35 expansion, 36, 38, 38 expansion, 39, 39 expansion, 43-
45, 45 expansion, 47-51, and 51 expansion. HPLC analyses
are provided for 34, 35, 43-45, 50, and 51 (70 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.
N-Deben zoyl-N-(ison icotin oyl)p a clita xel (49). Taxane
49 was isolated as a white powder in 92% yield after purifica-
tion by silica gel flash chromatography eluting with 2%
MeOH/CH2Cl2: [R]D -43 (c ) 0.21, CH2Cl2); 1H NMR (300
MHz, CDCl3) δ 1.13 (s, 3H), 1.22 (s, 3H), 1.67 (s, 3H), 1.76 (s,
3H), 1.83-1.93 (m, 1H), 2.17-2.31 (m, 2H), 2.22 (s, 3H), 2.36
(s, 3H), 2.47-2.58 (m, 1H), 3.77 (d, J ) 6.9 Hz, 1H), 4.23 (qab
,
J ) 35.4, 8.4 Hz, 2H), 4.37 (dd, J ) 10.8, 6.6 Hz, 1H), 4.78 (d,
J ) 2.4 Hz, 1H), 4.92 (d, J ) 7.8 Hz, 1H), 5.65 (d, J ) 6.9 Hz,
J O951961C