Synthesis and biological evaluation of C-13 amide-linked paclitaxel (Taxol) analogs

Article abstract of DOI:10.1021/jo952067o

Several C-13 amidopaclitaxel analogs have been synthesized during the course of our structure-activity relationship study at the C-13 position. These include 4-deacetyl-13-amidopaclitaxel (4), 13-amidopaclitaxel 4-(methyl carbonate) derivatives (5a,b), and 13-amidopaclitaxel (6). None of these novel C-13 amidopaclitaxel analogs retain any activity in the tubulin polymerization assay or the in vitro cytotoxicity assay.

Full text of DOI:10.1021/jo952067o

J . Org. Chem. 1996, 61, 2065-2070
2065
Syn th esis a n d Biologica l Eva lu a tion of C-13 Am id e-Lin k ed
P a clita xel (Ta xol†) An a logs
Shu-Hui Chen,*,¶ Vittorio Farina,‡ Dolatrai M. Vyas, and Terrence W. Doyle¶
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06492-7660
Byron H. Long and Craig Fairchild
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New J ersey 08543
Received November 22, 1995X
Several C-13 amidopaclitaxel analogs have been synthesized during the course of our structure-
activity relationship study at the C-13 position. These include 4-deacetyl-13-amidopaclitaxel (4),
13-amidopaclitaxel 4-(methyl carbonate) derivatives (5a ,b), and 13-amidopaclitaxel (6). None of
these novel C-13 amidopaclitaxel analogs retain any activity in the tubulin polymerization assay
or the in vitro cytotoxicity assay.
Paclitaxel (Taxol) (1), the structurally unique diterpe-
noid1 marketed by Bristol-Myers Squibb, is one of the
most exciting antitumor drugs available today. Its
current indications (refractory ovarian and metastatic
breast cancer) may soon be expanded to include lung and
head-neck cancers.2 The clinical importance of this
drug, coupled with its structural complexity1 and novel
mechanism of action,3 has stimulated intensive research
activities toward its total synthesis4 and structure-
activity relationship (SAR) studies.5
In 1990, we launched systematic SAR investigations
in search of analogs possessing improved biological
profiles. As a result of such efforts, we have reported on
a wide variety of paclitaxel analogs modified at the C-2,6
C-4,7 C-6,8 C-7,9 and C-1010 positions.
In addition to our core SAR modifications, we were also
interested in the side-chain SAR.11 Despite the fact that
a large number of paclitaxel side-chain analogs have been
prepared, including the C-13 acetic acid, crotonic acid,
lactic acid derivatives,12 and the C-13-epi-paclitaxel,13
modifications of the C-13 ester linkage itself, such as
replacement of the C-13 oxygen moiety with other het-
eroatoms, have not yet been reported. We thought that
the exchange of the C-13 phenylisoserine moiety with the
amide linkage could in principle alter the side-chain
conformation.14 This may in turn have considerable
impact on the drug’s overall performance. With these
considerations in mind, we decided to embark on the
syntheses of a novel series of C-13 amide-linked paclitaxel
analogs. One of our goals was to devise a method for
the preparation of such C-13 amido-carrying analogs,
such as the C-4-deacetyl derivative 4, the C-4 methyl
carbonate 5, and the C-13 amidopaclitaxel 6 itself, and
to evaluate their biological profile. Herein we report the
details of our investigations.
† Taxol is a registered trademark of Bristol-Myers Squibb Company.
‡ Current address: Department of Process Research, Boehringer
Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT
06877.
¶
Current address: OncoRx Inc., 4 Science Park, New Haven, CT
06511.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J . Am. Chem. Soc. 1971, 93, 2325. (b) Appendino, G. In The
Chemistry and Pharmacology of Taxol and Its Derivatives; Farina, V.,
Ed.; Elsevier: Amsterdam, 1995; p 7 and 55.
(2) (a) Paclitaxel (Taxol) was approved for the treatment ovarian
and breast cancer in 1992 and 1994, respectively. (b) Rowinsky, E. K.;
Donehower, R. C. New Engl. J . Med. 1995, 332, 1004.
(3) (a) Schiff, P. B.; Fant, J .; Horwitz, S. B. Nature 1979, 277, 665.
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J .; Boatman, 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, 1599. (b) Nicolaou,
K. C.; Yang, Z.; Liu, J . J .; Ueno, H.; Nantermet, P. G.; Guy, R. K.;
Claiborne, C. F.; Renaud, J .; Couladouros, E. A.; Paulvannan, K.;
Sorensen, E. J . Nature 1994, 367, 630. (c) Masters, J . J .; Link, J . T.;
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1991, 52, 1. (b) Suffness, M. Annu. Rep. Med. Chem. 1993, 28, 305. (c)
Georg, G. I. Ali, S. M.; Zygmunt, J .; J ayasinghe, L. R. Expert. Opin.
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34, 3205. (b) Chen, S. H.; Farina, V.; Wei, J . M.; Long, B.; Fairchild,
C.; Mamber, S. W.; Kadow, J . F.; Vyas, D.; Doyle, T. W. Bioorg. Med.
Chem. Lett. 1994, 4, 479.
One obvious strategy for the synthesis of C-13 ami-
dopaclitaxel analogs utilized the known coupling reaction
between a C-13 amino-bearing baccatin III and the
paclitaxel side-chain â-lactam15 according to the method
of Holton16a or Ojima.16b We further envisioned that C-13
aminobaccatin derivative might be obtained from the
direct functionalization of baccatin III via either reductive
(11) Kant, J .; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina,
V. Bioorg. Med. Chem. Lett. 1993, 3, 2471.
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Proc. Natl. Acad. Sci. U.S.A. 1984, 81, 4090. (b) Gue´ritte-Voegelein,
F.; Gue´nard, D.; Lavelle, F.; Le Goff, M.-T.; Mangatal, L.; Potier, P. J .
Med. Chem. 1991, 34, 992. (c) Swindell, C. S.; Krauss, N. E.; Horwitz,
S. B.; Ringel, I. J . Med. Chem. 1991, 34, 1176.
(7) (a) Chen, S. H.; Kadow, J . F.; Farina, V.; et al. J . Org. Chem.
1994, 59, 6156. (b) Chen, S. H.; Fairchild, C.; Long, B. H. J . Med. Chem.
1995, 38, 2263. (c) Chen, S. H.; Wei, J . M.; Long, B. H.; et al. Bioorg.
Med. Chem. Lett. 1995, 5, 2741.
(13) Hoemann, M. Z.; Vander Velde, D.; Aube´, J .; et al. J . Org. Chem.
1995, 60, 2918.
(14) Vander Velde, D.; Georg, G. I.; Grunewald, G. L.; Gunn, C. W.;
Mitscher, L. A. J . Am. Chem. Soc. 1993, 115, 11650.
(8) Chen, S. H.; Huang, S.; Roth, G. P. Tetrahedron Lett. 1995, 36,
8933.
(9) Chen, S. H.; Kant, J .; Mamber, S. W.; et al. Bioorg. Med. Chem.
Lett. 1994, 4, 2223 and the references cited therein.
(10) (a) Chen, S. H.; Fairchild, C.; Mamber, S. W.; Farina, V. J . Org.
Chem. 1993, 58, 2927. (b) Kant, J .; O’Keeffe, W. S.; Chen, S. H.; et al.
Tetrahedron Lett. 1994, 35, 5543.
(15) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.
M.; Brigaud, T. Tetrahedron 1992, 48, 6985.
(16) (a) Holton, R. A. Abstracts of Papers, 203rd National Meeting
of the American Chemical Society, San Francisco, Spring 1992;
American Chemical Society: Washington, DC, 1992; Abstract ORGN
0355. (b) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.;
Kuduk, S. Tetrahedron Lett. 1993, 34, 4149.
0022-3263/96/1961-2065$12.00/0 © 1996 American Chemical Society

2066 J . Org. Chem., Vol. 61, No. 6, 1996
Chen et al.
two steps from the C-13 carbinol 10 in ∼35% overall
yield. In this case, the hydroxyl group in 10 was first
brominated with CBr4/PPh3,20 affording 2:1 (â/R) mixtures
of the two C-13 bromobaccatin derivatives without ox-
etane opening. Gently heating of a DMF solution of the
resulting C-13 bromobaccatins with sodium azide pro-
vided only the 13R-azido-bearing baccatin 12 with the
desired stereochemistry at C-13.
Having made the desired C-13 azidobaccatin 12, we
next turned our attention to the C-4 reacylation and
subsequent reduction of the azido moiety at C-13. Sur-
prisingly, the C-4 hydroxyl moiety in 12 was found to be
rather resistant to various acylation conditions. For
example, treating 12 with LiHMDS/AcCl afforded only
small amounts (<5%) of the desired product 14. At-
tempted acylation of 12 with DCC and acetic acid or
acetic anhydride at room temperature also failed to
provide the desired product. However, treatment of 12
with LiHMDS and methyl chloroformate in anhydrous
THF provided the desired C4 methyl carbonate derivative
15 in low yield (20-45%). After many unsuccessful
attempts, it was later found that heating a toluene
solution of 12 with a large excess (15-20 equiv) of acetic
anhydride and DMAP at 80 °C led to the formation of
the desired C-4 acetylated-13-azido baccatin 18 (22%)
along with similar amount of the A-ring contraction
product 17 (20%). The C-1 protecting group (DMS) was
lost under these harsh conditions (Scheme 2).
Surprisingly again, treatment of the C-13 azido moiety
by either standard palladium-catalyzed hydrogenolysis22
and triphenylphosphine or tributylphosphine23 failed to
effect the desired reduction. After some experimentation,
it was found that gently heating a triethylamine solution
of 12 and PhSeH24 at 60 °C provided the desired 13R-
amino-bearing baccatin 13 in 86% yield. The C-13 azido
moieties in 15 and 18 were reduced in an analogous
manner and provided the desired C-13 amino-bearing
baccatins 16 (80%) and 19 (58%), respectively, as shown
in Scheme 2.
The paclitaxel side chain was readily attached to the
C-13 aminobaccatin 13 via Holton’s protocol16a using
â-lactam 2015 as the side-chain source and afforded a 53%
yield of the adduct 21. This intermediate was further
desilylated to provide the desired 13-amido-4-deacetylpa-
clitaxel 4 in 71% yield (see Scheme 3).
A similar coupling reaction was attempted with the
C-13-aminobaccatin 16. Disappointingly, no desired
coupling product was formed. The lack of reactivity
observed here with the free amine 16 was likely due to
the intramolecular hydrogen bonding between the C-13
amino moiety and the C-4 carbonate group. In view of
this difficulty, we then decided to attempt an alternative
method which employed oxazolines 22a /22b as the side-
chain sources.25 Successful applications of the similar
DCC/DMAP-mediated side-chain coupling reactions were
recently reported by Kingston and by scientists from
Bristol-Myers Squibb.25b Indeed, treatment of a toluene
solution of the C-13 aminobaccatin 16 and the side-chain
carboxylic acid 22a or 22b with DCC and DMAP resulted
F igu r e 1.
amination17 or a sequence of double Mitsunobu reactions
with net retention at C-13.18 Much to our disappoint-
ment, heating an ethanol solution of 13-keto-7-TES
baccatin III and hydroxylamine only led to the removal
of the acetoxy moiety at C-10. Furthermore, 7-TES-
baccatin III was found to be inert under standard
Mitsunobu conditions.19 The lack of reactivity of the C-13
hydroxyl moiety in this case was possibly due to its
intramolecular hydrogen bonding to the C-4 acetoxy
group. More vigorous conditions were therefore tried.
20
Attempts to brominate C-13 with CBr4/PPh3 resulted
in oxetane opening. We have already shown that this
opening reaction occurs with anchimeric participation of
the C-4 acetoxy moiety. Bearing this in mind, it was
concluded that in order to modify the C-13 position the
intramolecular hydrogen bonding between the C-13
carbinol and the C-4 acetoxy moiety had to be removed.21
Thus, an alternative strategy was devised consisting of
(i) chemoselective removal of the C-4 acetoxy group in
baccatin III, (ii) introduction of an amine/azide function-
ality at the C-13 with retention of configuration, and (iii)
reacylation of the C-4 hydroxyl moiety.
Scheme 1 summarizes the synthetic route leading to
the preparation of the C-13 azidobaccatin derivative 12.
Treatment of 7-TES-baccatin 7 with two silylation re-
agents sequentially (TMSCl, DMSCl) afforded fully sily-
lated baccatin 8 in 87% yield. When this material was
treated with 4 equiv of Red-Al in THF at 0 °C, the C-13
desilylated C-4 deacetylbaccatin 10 was isolated, after
workup with sodium tartaric acid saturated solution, as
the major product in 50-60% yield. Small amounts of
the C-10 deacetyl product 9 were also obtained. We also
noted that the trimethylsilyl group at C-13 was removed
during the aqueous workup prior to the more labile C-1
dimethylsilane (DMS). We immediately recognized that
compound 10 would be an ideal substrate on which to
study the C-13 modification and the C-4 reacylation.
Indeed, the reactivity of the allylic hydroxyl group at
C-13 in 10 was improved after the removal of the C-4
acetoxy group. For example, when compound 10 was
treated with aza-Mitsunobu reagents,19c the C-13â azi-
dobaccatin derivative 11 was obtained in 35% yield. The
C-13 R-azidobaccatin derivative 12 was also prepared in
(17) Hartung, W. H.; Beaujon, J . H.; Cocolas, G. Organic Syntheses;
Wiley: New York, 1973; Collect. Vol. 5, p 376.
(18) Cf. Chen, S. H.; Danishefsky, S. J . Tetrahedron Lett. 1990, 31,
2229.
(22) Rylander, P. N. In Hydrogenation Methods; Academic Press:
London, 1985; p 168.
(23) (a) J ung, M. E.; Lyster, M. A. J . Org. Chem. 1977, 42, 3761. (b)
Kratzer, B.; Schmidt, R. R. Tetrahedron Lett. 1993, 34, 1761.
(24) Myers, A. G.; Gin, D. Y.; Rogers, D. H. J . Am. Chem. Soc. 1993,
115, 2036.
(25) (a) Kingston, D. G. I.; Chaudhary, A. G.; Gunatilaka, A. A. L.;
Middleton, M. L. Tetrahedron Lett. 1994, 35, 4483. (b) Poss, M. A.;
Moniot, J . L.; Trifunovich, I. D.; et al. PCT Patent WO94/14787.
(19) (a) Cf. Mitsunobu, O. Synthesis 1981, 1. (b) For a recent review,
see: Hughes, D. L. Org. React. 1993, 335. (c) Lal, B.; Pramanik, B. N.;
Manhas, M. S.; Bose, A. K. Tetrahedron Lett. 1977, 18, 1977.
(20) See: Castro, B. C. R. Org. React. 1983, 29.
(21) Removal of the C-4 acetoxy would also remove the anchimeric
assistance of this group toward the oxetane and therefore prevent ring
opening.

C-13 Amide-Linked Paclitaxel (Taxol) Analogs
J . Org. Chem., Vol. 61, No. 6, 1996 2067
Sch em e 1
Sch em e 4a
a
Conditions: (i) TMSCl/imidazole/DMF/0 °C, then DMSCl/
imidazole/0 °C, 87%; (ii) Red-Al/THF/0 °C, 15% of 9 plus 58% of
10; (iii) DEAD/PPh3/(BnO)2P(O)N3/THF, rt, 35%; (iv) CBr4/PPh3/
CH2Cl2/0 °C, 50%; (v) NaN3/DMF/rt to 40 °C, 63%.
a
Conditions: (i) DCC/DMAP/toluene/rt/22a , 92% of 23a ; (ii)
DCC/DMAP/toluene/rt/22b, 68% of 23b; (iii) 1 N HCl/THF +
MeOH/5 °C, then NaHCO3/rt, 61% of 5a ; or 39% of 5b; or 50% of
6; (iv) DCC/DMAP/toluene/rt/22a , 100%.
Sch em e 2a
Ta ble 1. Resu lts of Biologica l Eva lu a tion of C-13
Am id op a clita xel An a logs 1-6
tubulin
IC50 (nM)b
HCT-116
compd
polym. ratioa
1 (Paclitaxel)
6
2
4
1.0
>200
200
2.4
>100
>58
>96
2.0
60
0.41
3
5a
5b
>200
>200
54
82
a
This ratio indicates the potency of an analog relative to
b
paclitaxel. IC50 measures the drug concentration required for the
inhibition of 50% cell proliferation after a 72 h incubation.
coupling of the C-13 aminobaccatin 19 and the carboxylic
acid 22a followed by subsequent oxazoline hydrolysis and
deprotection at C-7 (see Scheme 4).
Compounds 4, 5(a ,b), and 6 were evaluated in a
tubulin polymerization assay12c and an in vitro cytotox-
icity assay against a human colon cancer cell line (HCT-
116).26 The results are summarized in Table 1. Two C-4
paclitaxel analogs, 2 and 3, were synthesized7c using the
methodology disclosed recently,7 as reference compounds
for their C-13 amide counterparts 4 and 5, respectively.
As can be seen in Table 1, the two C-4 deacetyl deriva-
tives, the C-4-deacetylpaclitaxel (2) and its C-13 amido
congener 4, were devoid of any activity. This observation
confirms that the presence of a C-4 acyl group is essential
for biological activity.7 Surprisingly, unlike the bioactive
C-4 methyl carbonate 3, its C-13 amido conterpart 5a was
also found to be inactive in both the tubulin polymeri-
zation assay and the cytotoxicity assay. Similar results
were also obtained with the 3′-furyl-bearing C-13 amido
analog 5b and with the C-13 amidopaclitaxel 6. These
results clearly indicate that replacement of the C-13 ester
linkage with the corresponding amide is detrimental to
activity.
a
Conditions: (i) LHMDS/THF/0 °C, AcCl/0 °C, <5% of 14; (ii)
LHMDS/THF/0 °C, then MeOC(O)Cl, 28%; (iii) PhSeH/Et3N/60 °C,
86% of 13; 80% of 16; 58% of 19; (iv) Ac2O/DMAP/toluene/80 °C,
20% of 17 plus 22% of 18.
Sch em e 3a
a
Conditions: (i) LHMDS/THF/-40 °C, then 20, 53%; (ii) Pyr/
48% HF/CH3CN, 71%.
in the formation of the desired adducts 23a and 23b in
92% and 68% yields, respectively. Finally, acidic hy-
drolysis of the oxazoline moiety followed by side-chain
benzoyl migration (from 2′-O to 3′-N) and desilylation (at
C-1 and C-7) furnished the desired products 5a (61%) and
5b (39%). Following the same sequence, the C-13 ami-
dopaclitaxel 6 was obtained in 50% overall yield via
In summary, we have succeeded in the preparation of
a novel series of C-13 amido-containing paclitaxel ana-
logs. None of these analogs (4, 5a , 5b, 6) was found to
be bioactive in vitro. Further study aimed at determining
(26) Scudiero, D. A.; Shoemaker, R. H.; Paull, K. D.; Monks, A.;
Tierney, S.; Nofziger, T. H.; Currens, M. J .; Seniff, D.; Boyd, M. R.
Cancer Res. 1988, 48, 4827.
(27) (a) Dubois, J .; Gue´nard, D.; Gue´ritte-Voegelein, F.; Guedira,
N.; Potier, P.; Gillet, B.; Beloeil, J .-C. Tetrahedron 1993, 49, 6533. (b)
Williams, H. J .; Scott, A. I.; Dieden, R. A. Tetrahedron 1993, 49, 6545.

2068 J . Org. Chem., Vol. 61, No. 6, 1996
Chen et al.
δ 201.2, 169.2, 164.6, 139.4, 137.4, 133.5, 129.8, 129.6, 128.6,
87.0, 84.8, 80.9, 75.7, 74.4, 73.7, 72.2, 62.4, 58.3, 50.0, 42.7,
37.0, 33.9, 31.5, 20.8, 19.1, 19.0, 9.7, 6.6, 5.1, 1.1, 0.1. HRMS:
calcd for C37H56N3O9Si2 (MH+) 742.3555, found 742.3515.
the cause(s) for the lack of activity of analogs (4-6) is in
progress, and the result of this investigation will be
reported in due time.
P r ep a r a tion of Com p ou n d 12. A dichloromethane solu-
tion of 10 (219 mg, 0.306 mmol) was treated at 0 °C with
triphenylphosphine (96.2 mg, 0.367 mmol), followed by carbon
tetrachloride (121.6 mg, 0.367 mmol). The reaction mixture
was stirred at 0 °C for 1 h. The solvent was then removed,
and the residue was chromatographed (20-40% EtOAc/hex-
ane) to afford 120 mg (50%) of a mixture of the two (a and b)
C-13 bromobaccatin derivatives along with 44 mg (20%) of
starting material 10. These two intermediates were dissolved
in dry DMF (1.5 mL) and treated with sodium azide (100 mg,
1.54 mmol). The reaction mixture was stirred at 40 °C for 2
h. The reaction mixture was then diluted with EtOAc (50 mL)
and washed with water (3 × 5 mL). The organic layer was
dried and concd in vacuo. The residue was chromatographed
(20% EtOAc/hexane) to afford 60 mg (63%) of the desired C-13
azido-bearing baccatin derivative 12.
Exp er im en ta l Section
P r ep a r a tion of Com p ou n d (8). 7-TES-baccatin III 7
(3.00 g, 4.286 mmol) was dissolved in dry DMF (17 mL). To
this solution at 0 °C was added imidazole (874.3 mg, 12.86
mmol), followed by TMSCl (1.63 mL, 12.86 mmol). After
stirring at 0 °C for 1.5 h, the reaction mixture was diluted
with EtOAc (300 mL) and washed with water (3 × 20 mL)
and then brine (30 mL). The organic layer was dried and concd
in vacuo. The resulting material was then dissolved in dry
DMF (20 mL) and treated at 0 °C with imidazole (816 mg,
12.00 mmol), followed by chlorodimethylsilane (1.135 g, 12.00
mmol). The reaction mixture was stirred for 1 h at 0 °C and
then diluted with EtOAc (200 mL). The organic layer was
washed with water and brine. Upon silica gel chromatography
(10% ethyl acetate in hexane), 3.197 g (90%) of the desired
product 8 was obtained.
1H NMR (300 MHz, CDCl3): δ 8.09-8.06 (m, 2H), 7.59-
7.43 (m, 3H), 6.43 (s, 1H), 5.70 (d, J ) 6.9 Hz, 1H), 4.92 (d, J
) 7.7 Hz,1H), 4.86 (m, 1H), 4.50 (m, 1H), 4.43 (dd, J ) 6.6 Hz,
J ′ ) 10.5 Hz, 1H), 4.20 (ABq, J ) 8.2 Hz, 2H), 3.78 (d, J ) 6.9
Hz, 1H), 2.50-0.16 (m, 46H, includes singlets at 2.26, 2.16,
2.07, 1.65, 1.18, 1.05, 3H each, 0.18, 9H), 0.05 (d, J ) 2.7 Hz,
3H), -0.28 (d, J ) 2.7 Hz, 3H). 13C NMR (75 MHz, CDCl3):
δ 202.1, 169.8, 169.2, 165.2, 144.4, 133.1, 131.6, 130.2, 130.0,
128.3, 84.1, 81.7, 80.8, 76.4, 75.6, 75.5, 72.1, 68.3, 58.2, 46.6,
43.9, 38.8, 37.1, 27.3, 22.5, 21.7, 20.8, 14.8, 9.9, 6.6, 5.1.
HRMS: calcd for C42H67O11Si3 (MH+) 831.3991, found 831.4001.
P r ep a r a tion of Com p ou n d s 9 a n d 10. To a THF solution
(8.8 mL) of 8 (439 mg, 0.529 mmol) was added at 0 °C Red-Al
(0.514 mL, 60%, 2.645 mmol). The reaction was stirred
vigorously for 40 min. At this time, a saturated sodium
tartrate solution (4 mL) was slowly added. After 5-10 min,
the reaction mixture was extracted with EtOAc (2 × 50 mL).
The organic layer was washed with brine and then dried and
concd in vacuo. The residue was chromatographed (40% ethyl
acetate in hexanes) to afford 53 mg (15%) of 9 along with 220
mg (58%) of the desired product 10.
1H NMR (300 MHz, CDCl3) of 9: δ 8.04-8.01 (m, 2H), 7.54-
7.34 (m, 3H), 5.54 (d, J ) 5.6 Hz, 1H), 5.16 (s, 1H), 4.70 (m,
2H), 4.54 (m, 2H), 4.35 (d, J ) 8.3 Hz, 1H), 4.29 (s, 1H), 4.06
(d, J ) 8.1 Hz, 1H), 4.00 (d, J ) 8.7 Hz, 1H), 3.91 (dd, J ) 5.6
Hz, J ′ ) 11.6 Hz, 1H), 3.66 (d, J ) 5.6 Hz, 1H), 2.72-0.32 (m,
31H, includes singlets at 2.05, 1.58, 1.03, 0.97, 3H each), -0.01
(d, J ) 1.8 Hz, 3H), -0.35 (d, J ) 1.9 Hz, 3H). MS: calcd for
C35H54O9Si2 (M+) 674, found 674.
1H NMR (300 MHz, CDCl3) of 10: δ 8.05-8.02 (m, 2H),
7.56-7.37 (m, 3H), 6.43 (s, 1H), 5.62 (d, J ) 5.8 Hz, 1H), 4.70
(dd, J ) 4.5 Hz, J ′ ) 9.7 Hz, 1H), 4.58 (m, 1H), 4.22 (ABq, J
) 8.5 Hz, 2H), 4.05 (m, 1H), 3.64 (m, 2H), 2.80-0.50 (m, 34H,
includes singlets at 2.18, 6H, 1.55, 1.16, 0.95, 3H each), 0.03
(d, J ) 2.7 Hz,3H), -0.31 (d, J ) 2.7 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 201.7, 169.3, 164.9, 142.5, 135.2, 133.3, 130.0,
129.8, 128.4, 88.3, 80.5, 80.2, 75.9, 73.7, 72.0, 68.9, 58.8, 50.2,
43.0, 37.3, 37.1, 29.7, 20.8, 18.9, 16.8, 9.8, 6.6, 5.1. HRMS:
calcd for C37H57O10Si2 (MH+) 717.3490, found 717.3505.
P r ep a r a tion of Com p ou n d 11. To a THF solution (1.2
mL) of 10 (50 mg, 0.070 mmol) were added DEAD (0.013 mL,
0.084 mmol) and triphenylphosphine (22.0 mg, 0.084 mmol)
followed by diphenylphosphosphoryl azide (0.018 mL, 0.084
mmol). The reaction was stirred at room temperature for 1.5
h. The solvent was removed, and the residue was chromato-
graphed (10-20% EtOAc/hexanes) to afford 18 mg (35%) of
C-13 â-azido-bearing baccatin 11.
1H NMR (300 MHz, CDCl3) of 12: δ 8.08-8.05 (m, 2H),
7.58-7.41 (m, 3H), 6.37 (s, 1H), 5.61 (d, J ) 6.0 Hz, 1H), 4.75
(dd, J ) 3.7 Hz, J ′ ) 9.7 Hz, 1H), 4.58 (m, 2H), 4.19 (ABq, J
) 8.0 Hz, 2H), 3.98 (dd, J ) 6.1 Hz, J ′ ) 11.5 Hz, 1H), 3.11 (d,
J ) 6.0 Hz, 1H), 2.94 (dd, J ) 4.7 Hz, J ′ ) 15.5 Hz, 1H), 2.57
(dd, J ) 10.4 Hz, J ′ ) 15.2 Hz, 1H), 2.38 (m, 1H), 2.21 (s, 3H),
2.17 (s, 3H), 1.94 (m, 1H), 1.56 (s, 3H), 1.18 (s, 3H), 0.99 (s,
3H), 0.88 (m, 9H), 0.53 (m, 6H), 0.04 (d, J ) 2.7 Hz, 3H), -0.31
(d, J ) 2.7 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 201.5, 169.5,
165.1, 138.5, 136.9, 133.4, 130.2, 129.9, 128.5, 87.8, 80.7, 80.0,
75.5, 75.1, 74.1, 72.6, 61.9, 58.9, 51.7, 43.5, 37.4, 34.7, 28.7,
20.9, 19.5, 17.4, 9.8, 6.7, 5.2, 0.7, 0.1. HRMS: calcd for
C
37H56N3O9Si2 (MH+) 742.3555, found 742.2383.
P r ep a r a tion of Com p ou n d 14. A THF solution (2.5 mL)
of 12 (95 mg, 0.128 mmol) was treated at 0 °C with LHMDS
(0.166 mL, 1 M, 0.166 mmol) for 30 min. At this time, acetyl
chloride (0.014 mL, 0.192 mmol) was added, and the resulting
reaction mixture was stirred at 0 °C for 1 h. After the reaction
was quenched with NH4Cl saturated solution (2 mL), the
reaction mixture was extracted with EtOAc (50 mL). The
organic layer was washed with water and brine and then dried
and concd in vacuo. The residue was chromatographed (10-
20% EtOAc/hexane) to provide only a trace amount (<5%) of
the desired product 14. Large amounts of the starting
material 12 (71 mg, 75%) were recovered.
1H NMR (300 MHz, CDCl3): δ 8.11-8.08 (m, 2H), 7.63-
7.46 (m, 3H), 6.42 (s, 1H), 5.70 (d, J ) 7.0 Hz, 1H), 4.92 (d, J
) 7.8 Hz, 1H), 4.76 (m, 1H), 4.57 (m, 1H), 4.43 (dd, J ) 6.7
Hz, J ′ ) 10.5 Hz, 1H), 4.21 (ABq, J ) 8.2 Hz, 2H), 3.69 (d, J
) 6.9 Hz, 1H), 2.58-0.50 (m, 37H, includes singlets at 2.34,
2.22, 2.19, 1.67, 1.20, 1.07, 3H each), 0.08 (d, J ) 2.7 Hz, 3H),
-0.26 (d, J ) 2.7 Hz, 3H). MS: calcd for C39H57N3O10Si2 (M+)
783, found 783.
P r ep a r a tion of Com p ou n d 15. A THF solution (4.7 mL)
of 12 (209.5 mg, 0.283 mmol) was treated at 0 °C with LHMDS
(0.368 mL, 1 M, 0.368 mmol). After 30 min at that temper-
ature, methyl chloroformate (0.033 mL, 0.425 mmol) was
added. After stirring for 1 h at 0 °C, the reaction was
quenched with an NH4Cl-saturated solution (2 mL), and then
the solution was extracted with EtOAc (75 mL). The organic
layer was washed with water and brine and then dried and
concd in vacuo. The resulting residue was chromatographed
(10-20% EtOAc/hexane) to afford 62.6 mg (28%) of the desired
product 15 along with 100 mg (48%) of the recovered starting
material 12.
1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 2H), 7.59-
7.45 (m, 3H), 6.42 (s, 1H), 5.71 (d, J ) 6.8 Hz, 1H), 4.96 (d, J
) 9.4 Hz, 1H), 4.78 (m, 1H), 4.56 (m, 1H), 4.39 (dd, J ) 6.5
Hz, J ′ ) 10.4 Hz, 1H), 4.20 (ABq, J ) 8.4 Hz, 2H), 3.93 (s,
3H), 3.69 (d, J ) 6.8 Hz, 1H), 2.56-0.52 (m, 34H, includes
singlets at 2.21, 2.18, 1.66, 1.20, 1.06, 3H each), 0.07 (d, J )
2.7 Hz, 3H), -0.28 (d, J ) 2.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 201.4, 169.2, 165.2, 153.7, 139.5, 134.6, 133.3, 130.1,
129.9, 128.5, 83.7, 82.2, 81.7, 76.0, 75.3, 74.7, 72.1, 60.5, 58.3,
1H NMR (300 MHz, CDCl3): δ 8.02-7.98 (m, 2H), 7.58-
7.43 (m, 3H), 6.38 (s, 1H), 5.65 (d, J ) 5.5 Hz, 1H), 4.66 (m,
2H), 4.19 (ABq, J ) 8.4 Hz, 2H), 4.16 (dd, J ) 4.8 Hz, J ′ ) 9.8
Hz, 1H), 3.93 (m, 1H), 3.06 (dd, J ) 9.8 Hz, J ′ ) 14.5 Hz, 1H),
3.00 (d, J ) 6.4 Hz, 1H), 2.40-0.48 (m, 33H, includes singlets
at 2.18, 2.12, 1.54, 1.13, 1.09, 3H each), 0.05 (d, J ) 2.8 Hz,
3H), -0.29 (d, J ) 2.8 Hz, 3H). 13C NMR (75 MHz, CDCl3):

C-13 Amide-Linked Paclitaxel (Taxol) Analogs
J . Org. Chem., Vol. 61, No. 6, 1996 2069
54.4, 47.0, 43.7, 37.0, 35.2, 27.2, 20.9, 20.8, 16.1, 9.8, 6.6, 5.1.
HRMS: calcd for C39H58N3O11Si2 (MH+) 800.3610, found
800.3601.
P r ep a r a tion of Com p ou n d 13. Compound 12 (60.0 mg,
0.081 mmol) was dissolved in triethylamine (1 mL). To this
solution at room temperature was added PhSeH (0.034 mL,
0.324 mmol). The reaction mixture was then heated at 60 °C
for 3 h. The reaction mixture was then cooled to room
temperature and chromatographed (30-100% EtOAc/hexane)
to provide 49.8 mg (86%) of the desired product 13.
LHMDS (0.079 mL, 1M, 0.079 mmol), followed by a THF
solution (0.5 mL) of â-lactam 20 (27.5 mg, 0.0723 mmol). The
reaction mixture was stirred at 0 °C for 1 h, and the reaction
was quenched with an NH4Cl-saturated solution (1 mL). The
reaction mixture was extracted with EtOAc (2 × 25 mL), and
the combined organic layers were washed with brine and then
dried and concd in vacuo. The residue was chromatographed
(20-30% EtOAc/hexane) to afford 34 mg (53%) of 21. A part
of this material (26.6 mg, 0.027 mmol) was dissolved in CH3-
CN (0.7 mL) and treated at 0 °C with pyridine (0.08 mL),
followed by 48% HF (0.24 mL). The reaction mixture was kept
at 5 °C for 12 h. The reaction mixture was then diluted with
EtOAc (25 mL) and washed with 1N HCl (3 mL), an NaHCO3-
saturated solution (3 × 5 mL), and brine. The resulting
organic layer was dried and concd in vacuo. The residue was
chromatographed (60-80% EtOAc/hexane) to provide 15.6 mg
(71%) of the desired product 4.
1H NMR (300 MHz, CDCl3): δ 8.15-8.12 (m, 2H), 7.55-
7.40 (m, 3H), 6.40 (s, 1H), 5.63 (d, J ) 5.8 Hz, 1H), 4.75 (dd,
J ) 3.7 Hz, J ′ ) 9.7 Hz, 1H), 4.57 (m, 1H), 4.22 (ABq, J ) 7.7
Hz, 2H), 4.05 (m, 2H), 3.65 (d, J ) 5.8 Hz, 1H), 2.60-0.50 (m,
34H, includes singlets at 2.19, 6H, 1.57, 1.13, 0.98, 3H each),
0.03 (d, J ) 2.7 Hz, 3H), -0.30 (d, J ) 2.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 201.8, 169.6, 165.2, 139.0, 136.2, 133.0,
130.2, 130.1, 128.3, 88.8, 81.1, 79.8, 76.0, 74.6, 73.5, 72.7, 59.2,
51.2, 49.7, 43.0, 37.4, 36.1, 29.4, 20.9, 18.8, 16.7, 9.5, 6.6, 5.1.
HRMS: calcd for C37H58NO9Si2 (MH+) 716.3650, found 716.3635.
P r ep a r a tion of Com p ou n d 16. To a triethylamine solu-
tion (2 mL) of 15 (84.0 mg, 0.105 mmol) was added PhSeH
(0.033 mL, 0.315 mmol) at room temperature. The reaction
mixture was heated at 60 °C for 3 h. The reaction mixture
was then directly chromatographed (30-60% EtOAc/hexane)
to provide 65 mg (80%) of the desired product 16.
1H NMR of 21 (300 MHz, CDCl3): δ 8.33-7.99 (m, 5H),
7.61-7.22 (m, 11H), 6.26 (s, 1H), 5.59 (m, 2H), 4.95 (m, 1H),
4.61 (m, 2H), 4.53 (m, 1H), 4.24 (ABq, J ) 8.4 Hz, 2H), 3.77
(dd, J ) 5.5 Hz, J ′ ) 11.6 Hz, 1H), 3.31 (d, J ) 5.9 Hz, 1H),
2.60-0.50 (m, 34H, includes singlets at 2.15, 1.53, 1.46, 1.12,
1.00, 3H each), 0.02 (d, J ) 2.6 Hz, 3H), -0.33 (d, J ) 2.6 Hz,
3H).
1H NMR of 4 (300 MHz, CDCl3): δ 8.15-7.26 (m, 15H), 6.16
(s, 1H), 5.79 (d, J ) 9.1 Hz, 1H), 5.58 (d, J ) 5.3 Hz, 1H), 5.29
(m, 1H), 5.15 (m, 1H), 4.63 (bs, 2H), 4.23 (ABq, J ) 8.4 Hz,
2H), 3.83 (m, 1H), 3.76 (d, J ) 5.3 Hz, 1H), 2.64-0.86 (m, 19H,
includes singlets at 2.20, 1.53, 1.51, 1.09, 1.05, 3H each). 13C
NMR of 4 (75 MHz, CDCl3): δ 204.1, 171.4, 171.2, 167.6, 166.8,
142.5, 137.8, 134.9, 133.5, 133.3, 132.3, 130.0, 128.9, 128.8,
128.5, 128.0, 127.1, 126.9, 88.0, 80.5, 77.5, 75.3, 74.0, 73.5, 72.2,
58.7, 55.1, 50.0, 47.6, 42.2, 35.4, 34.3, 27.3, 20.8, 18.9, 17.2,
9.3. HRMS: calcd for C45H51N2O12(MH+) 811.3442, found
811.3422.
1H NMR (300 MHz, CDCl3): δ 8.12-8.09 (m, 2H), 7.58-
7.42 (m, 3H), 6.44 (s, 1H), 5.71 (d, J ) 6.9 Hz, 1H), 4.95 (d, J
) 8.2 Hz, 1H), 4.52 (m, 1H), 4.38 (dd, J ) 6.6 Hz, J ′ ) 10.6
Hz, 1H), 4.22 (ABq, J ) 8.2 Hz, 2H), 4.15 (m, 1H), 3.87 (s,
3H), 3.82 (d, J ) 6.9 Hz, 1H), 2.50-0.50 (m, 34H, includes
singlets at 2.19, 2.17, 1.67, 1.19, 1.06, 3H each), 0.04 (d, J )
2.7 Hz, 3H), -0.30 (d, J ) 2.7 Hz, 3H). HRMS: calcd for
C39H60NO11Si2 (MH+) 774.3705, found 774.3729.
P r ep a r a tion of Com p ou n d s 17 a n d 18. C-4 carbinol 12
(281 mg, 0.379 mmol) was dissolved in toluene (3.8 mL). To
this solution were added Ac2O (0.72 mL, 7.584 mmol) and
DMAP (92.7 mg, 0.758 mmol). The reaction mixture was
heated at 80 °C for 13 h and then cooled to room temperature
and diluted with dichloromethane (75 mL). The resulting
mixture was washed with an NaHCO3-saturated solution (2
× 15 mL) and brine (15 mL). The organic layer was dried and
filtered. The filtrates were concd in vacuo, and the resulting
residue was perified by silica gel chromatography (20-25%
EtOAc/hexanes) to provide 54 mg (20%) of the A-ring contrac-
tion product 17 along with 61 mg (22%) of the desired product
18.
P r ep a r a tion of Com p ou n d 23a . To a toluene solution
(0.5 mL) of amine 16 (25 mg, 0.032 mmol) and acid 22a (13.9
mg, 0.052 mmol) were added DCC (10.7 mg, 0.052 mmol) and
DMAP (6.3 mg, 0.052 mmol). The reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was then
subjected to direct silica gel chromatography (30% EtOAc/
hexane) to afford 31 mg (92%) of the desired product 23a .
1H NMR of 23a (300 MHz, CDCl3): δ 8.22-8.03 (m, 4H),
7.59-7.25 (m, 11H), 7.12 (d, J ) 8.8 Hz, 1H), 6.34 (s, 1H),
5.72 (d, J ) 5.3 Hz, 1H), 5.36 (m, 1H), 4.98 (d, J ) 9.4 Hz,
1H), 4.92 (d, J ) 5.1 Hz, 1H), 4.57 (m, 1H), 4.30 (ABq, J ) 8.6
Hz, 2H), 4.20 (m, 1H), 4.06 (s, 3H), 3.76 (d, J ) 4.6 Hz, 1H),
2.70-0.47 (m, 34H, includes singlets at 2.15, 1.91, 1.68, 1.23,
1.16, 3H each), 0.11 (d, J ) 2.7 Hz, 3H), -0.28 (d, J ) 2.7 Hz,
3H). 13C NMR of 23a (75 MHz, CDCl3): δ 201.3, 170.2, 169.2,
165.0, 162.4, 153.7, 141.2, 139.1, 135.1, 133.4, 132.1, 130.0,
129.7, 128.7, 128.6, 128.4, 128.3, 127.8, 126.5, 84.1, 84.0, 83.4,
81.4, 76.1, 65.4, 74.5, 74.0, 72.3, 58.4, 55.4, 47.5, 46.9, 44.0,
37.1, 35.4, 26.8, 20.8, 20.7, 15.5, 9.8, 6.6, 5.1, 2.4, 1.4. HRMS:
calcd for C55H71N2O13Si2 (MH+) 1023.4495, found 1023.4494.
P r ep a r a tion of Com p ou n d 5a via 23a . Compound 23a
(29 mg, 0.028 mmol) was dissolved in THF (0.3 mL) and MeOH
(0.3 mL) and treated at 0 °C with 1 N HCl (0.142 mL). The
reaction mixture was stirred at 0 °C for 30 min and then kept
at 5 °C for 12 h. The reaction mixture was then treated at
room temperature with a saturated solution of NaHCO3 (0.71
mL) for 4 h. The reaction mixture was poured into water (2
mL) and extracted with EtOAc (5 × 10 mL). The combined
organic layers were dried and concd in vacuo. The residue
was chromatographed (50-60-70% EtOAc/hexane) to provide
15 mg (61%) of the desired product 5a .
1H NMR of 17 (300 MHz, CDCl3): δ 8.02-8.00 (m, 2H),
7.61-7.45 (m, 3H), 6.35 (s, 1H), 5.62 (d, J ) 7.9 Hz, 1H), 5.00
(d, J ) 8.5 Hz, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 4.50 (dd, J ) 7.3
Hz, J ′ ) 9.4 Hz, 1H), 4.36 (t, 1H), 4.23 (s, 2H), 3.46 (d, J ) 7.8
Hz, 1H), 2.59-1.66 (m, 19H, includes singlets at 2.25, 2.17,
1.81, 1.72, 1.68, 3H each), 0.93 (m, 9H), 0.63 (m, 6H). 1H NMR
of 18 (300 MHz, CDCl3): δ 8.10-8.07 (m, 2H), 7.62-7.46 (m,
3H), 6.43 (s, 1H), 5.62 (d, J ) 7.1 Hz, 1H), 4.93 (d, J ) 8.8 Hz,
1H), 4.74 (t, J ) 8.4 Hz, 1H), 4.46 (dd, J ) 6.7 Hz, J ′ ) 10.5
Hz, 1H), 4.20 (ABq, J ) 8.3 Hz, 2H), 3.71 (d, J ) 7.0 Hz, 1H),
2.53-0.52 (m, 31H, includes singlets at 2.33, 2.18, 2.18, 1.66,
1.20, 1.10, 3H each).
P r ep a r a tion of C-13 Am in e 19. C-13 azidobaccatin 18
(102 mg, 0.141 mmol) was dissolved in triethylamine (2 mL),
and the resulting solution was degassed with dry N2. To this
solution was added PhSeH (59 uL, 0.563 mmol), and the
resulting suspension was heated at 60 °C for 3 h. At this point,
the reaction mixture was allowed to cool to room temperature.
After usual silica gel chromatography, 57 mg (58%) of the
correponding C-13 free amine 19 was obtained.
1H NMR (300 MHz, CDCl3): δ 8.99-8.96 (m, 1H), 8.06-
7.26 (m, 14H), 6.66 (d, J ) 8.6 Hz, 1H), 6.13 (s, 1H), 5.93 (dd,
J ) 5.0 Hz, J ′ ) 9.6 Hz, 1H), 5.66 (d, J ) 7.0 Hz, 1H), 5.34 (m,
1H), 4.95 (d, J ) 9.1 Hz, 1H), 4.70 (m, 1H), 4.26 (m, 1H), 4.21
(ABq, J ) 8.5 Hz, 2H), 3.70 (s, 3H), 3.59 (d, J ) 6.9 Hz, 1H),
2.50-1.00 (m, 19H, includes singlets at 2.23, 1.62, 1.34, 1.29,
1.12, 3H each). HRMS: calcd for C47H53N2O14 (MH+) 869.3497,
found 869.3487.
1H NMR (300 MHz, CDCl3): δ 8.10-8.07 (m, 2H), 7.59-
7.43 (m, 3H), 6.46 (s, 1H), 5.63 (d, J ) 7.1 Hz, 1H), 4.91 (d, J
) 8.0 Hz, 1H), 4.45 (dd, J ) 6.8 Hz, J ′ ) 10.5 Hz, 1H), 4.21
(ABq, J ) 8.3 Hz, 2H), 4.13 (m, 1H), 3.86 (d, J ) 7.0 Hz, 1H),
2.60-0.53 (m, 37 H, includes singlets at 2.33, 2.17, 2.15, 1.68,
1.20, 1.12, 3H each). HRMS: calcd for C37H54NO10Si (MH+)
700.3517, found 700.3520.
P r ep a r a tion of Com p ou n d 4 via 21. A THF solution (1.2
mL) of 13 (47 mg, 0.0657 mmol) was treated at -40 °C with
P r ep a r a tion of Com p ou n d 5b fr om 23b. These two
compounds were prepared in the exact same way as their

2070 J . Org. Chem., Vol. 61, No. 6, 1996
Chen et al.
conterparts 23a and derivative 5a . The physical data of 23b
and 5b are listed below.
mixture was treated with an NaHCO3-saturated solution (4
mL) at room temperature for 4 h. The reaction mixture was
then diluted with water (1 mL) and extracted with EtOAc (5
× 10 mL). The extracts were combined, dried, and concd in
vacuo. The resulting residue was chromatographed (60-80%
EtOAc/hexanes) to afford 15.3 mg (50%) of the desired C-13
amidopaclitaxel 6.
1H NMR of 23b (300 MHz, CDCl3): δ 8.15-8.03 (m, 4H),
7.58-7.25 (m, 7H), 7.10 (d, J ) 8.9 Hz, 1H), 6.41-6.35 (m,
2H), 6.33 (s, 1H), 5.73 (m, 2H), 5.33 (m, 1H), 5.17 (d, J ) 4.9
Hz, 1H), 4.99 (d, J ) 7.8 Hz, 1H), 4.55 (m, 1H), 4.31 (ABq, J
) 8.5 Hz, 2H), 4.19 (dd, J ) 6.7 Hz, J ′ ) 10.7 Hz, 1H), 4.12 (s,
3H), 3.76 (d, J ) 6.3 Hz, 1H), 2.70-0.46 (m, 34H, includes
singlets at 2.14, 1.90, 1.67, 1.22, 1.14, 3H each), 0.10 (d, J )
2.8 Hz, 3H), -0.28 (d, J ) 2.7 Hz, 3H). HRMS: calcd for
C53H69N2O14Si2 (MH+) 1013.4287, found 1013.4265.
1H NMR (300 MHz, CDCl3): δ 8.82 (d, J ) 8.9 Hz, 1H), 8.02
(d, J ) 7.8 Hz, 2H), 7.91 (d, J ) 7.6 Hz, 2H), 7.61-7.30 (m,
11H), 7.07 (d, J ) 9.4 Hz, 1H), 6.40 (d, J ) 4.2 Hz, 1H), 6.15
(s, 1H), 5.90 (dd, J ) 3.9 Hz, J ′ ) 8.8 Hz, 1H), 5.60 (d, J ) 6.8
Hz, 1H), 5.28 (dd, J ) 9.2 Hz, J ′ ) 22.8 Hz, 1H), 4.84 (d, J )
8.6 Hz, 1H), 4.69 (m, 1H), 4.28 (m, 1H), 4.21 (ABq, J ) 8.4
Hz, 2H), 3.82 (d, J ) 6.8 Hz, 1H), 2.55-1.11 (m, 22H, includes
singlets at 2.35, 2.22, 1.65, 1.27, 1.23, 1.11, 3H each). 13C NMR
(75 MHz, CDCl3): δ 203.7, 172.0, 171.4, 167.3, 166.9, 143.0,
136.5, 133.6, 133.2, 132.8, 132.2, 129.9, 129.1, 128.7, 128.5,
128.3, 128.0, 127.5, 127.1, 84.6, 81.8, 79.2, 76.7, 76.0, 74.7, 73.2,
72.2, 58.7, 56.1, 46.7, 45.0, 42.9, 37.2, 35.7, 26.1, 22.2, 21.3,
20.8, 15.0, 9.3. HRMS: calcd for C47H53N2O13 (MH+) 853.3548,
found 853.3560.
1H NMR of 5b (300 MHz, CDCl3): δ 8.45-8.42 (d, 1H),
8.07-7.85 (m, 4H), 7.58-7.37 (m, 6H), 6.88 (d, J ) 8.5 Hz,
1H), 6.41-6.36 (m, 2H), 6.21 (s, 1H), 6.14 (d, J ) 5.0 Hz, 1H),
5.79 (dd, J ) 4.1 Hz, J ′ ) 8.7 Hz, 1H), 5.68 (d, J ) 6.9 Hz,
1H), 5.40 (m, 1H), 5.99 (d, J ) 9.1 Hz, 1H), 4.64 (m, 1H), 4.32
(m, 2H), 4.14 (d, J ) 8.7 Hz, 1H), 3.85 (s, 1H), 3.69 (d, J ) 6.8
Hz, 1H), 2.57-1.12 (m, 19H, includes singlets at 2.21, 1.69,
1.64, 1.34, 1.13, 3H each). HRMS: calcd for C45H51N2O15
(MH+) 859.3290, found 859.3312.
P r ep a r a tion of Com p ou n d 24. To a toluene solution (1
mL) of the C-13 amine 19 (26 mg, 0.037 mmol) was added the
carboxylic acid 22a (19.8 mg, 0.074 mmol) followed by DCC
(15.1 mg, 0.074 mmol) and DMAP (4.5 mg, 0.037 mmol). The
reaction mixture was stirred vigorously at room temperature
for 16 h. The reaction mixture was then purified by silica gel
chromatography (10-20-30% EtOAc/hexanes) to provide 36
mg (100%) of the desired coupling product 24.
Ack n ow led gm en t. We thank Ms. J . M. Wei for the
preparation of the reference compound 3. We are
indebted to Dr. S. E. Klohr for the measurements of
high-resolution mass spectra. Acknowledgment should
also be made to Drs. S. Huang and D. Langley for
helpful discussion. Finally, we also thank Dr. J . F.
Kadow for helping with the manuscript.
1H NMR (300 MHz, CDCl3): δ 8.32-8.29 (m, 2H), 8.05-
8.02 (m, 2H), 7.62-7.22 (m, 12H), 6.36 (s, 1H), 5.67 (m, 2H),
5.31 (q, 1H), 4.91 (m, 2H), 4.38 (dd, J ) 6.8 Hz, J ′ ) 10.3 Hz,
1H), 4.27 (ABq, J ) 8.4 Hz, 2H), 4.07 (d, J ) 7.9 Hz, 1H), 3.94
(d, J ) 6.7 Hz, 1H), 3.47 (m, 1H), 2.60-0.47 (m, 37H, includes
singlets at 2.42, 2.15, 1.94, 1.70, 1.24, 1.20, 3H each). HRMS:
calcd for C53H64N2O12SiNa (MNa+) 971.4126, found 971.4128.
P r ep a r a tion of C-13 Am id op a clita xel 6 via 24. Com-
pound 24 (34 mg, 0.036 mmol) was dissolved in THF (0.4 mL)
and MeOH (0.4 mL). This solution was treated at 0 °C with
1 N HCl (0.18 mL, 0.180 mmol) for 30 min. The reaction
mixture was kept at 5 °C for 18 h. At this point, the reaction
Su p p or tin g In for m a tion Ava ila ble: 1H NMR (300 MHz)
spectra for compounds 4, 5a , 5b, 6, 8, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 21, 23b, and 24 and 13C (75 MHz) spectra for
compounds 8, 12, 13, and 15 (22 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 ACS; see any current masthead page for ordering
information.
J O952067O