Butitaxel analogues: Synthesis and structure-activity relationships

Article abstract of DOI:10.1021/jm960505t

N-Acyl analogues 8, 9, and 12-26 of butitaxel (3) were prepared in one or two steps from amines 5 and 6 through Schotten-Baumann acylation. Seventeen novel analogues, consisting of aliphatic carbamates, alicyclic amides, and heteroaromatic amides, were sy

Full text of DOI:10.1021/jm960505t

236
J . Med. Chem. 1997, 40, 236-241
Bu tita xel An a logu es: Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s
Syed M. Ali,*,† Michael Z. Hoemann,‡ J effrey Aube´, Gunda I. Georg, and Lester A. Mitscher
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045
Lalith R. J ayasinghe*,§
Oread Laboratories Inc., 1501 Wakarusa Drive, Lawrence, Kansas 66047
Received J uly 15, 1996X
N-Acyl analogues 8, 9, and 12-26 of butitaxel (3) were prepared in one or two steps from
amines 5 and 6 through Schotten-Baumann acylation. Seventeen novel analogues, consisting
of aliphatic carbamates, alicyclic amides, and heteroaromatic amides, were synthesized. They
were evaluated for their in vitro ability to stimulate the formation of microtubules, their
cytotoxicity toward B16 melanoma cells, and their solubility in water. The most potent analogue
found in this study was N-debenzoyl-N-(2-thenoyl)butitaxel (20), possessing ca. 2-fold better
tubulin assembly properties and cytotoxic activity against B16 melanoma cells than paclitaxel.
Compound 20 was ca. 25 times more water soluble than paclitaxel.
The structurally and biologically unique diterpenoid
paclitaxel (1)1 has been approved by the Food and Drug
Administration for the treatment of metastatic ovarian
cancer and breast cancer.2 In addition, paclitaxel has
shown promise for the therapy of lung cancer, head and
neck cancer, and esophageal carcinomas.2 Docetaxel (2),
a semisynthetic analogue of paclitaxel,3 is currently in
clinical trials and awaiting FDA approval.2 Docetaxel
has shown slightly better activity when compared to
paclitaxel in an in vitro microtubule assembly assay and
several in vivo tumor models.4 The demonstrated
clinical activity along with a unique mechanism of
action5 has made paclitaxel a target of extensive re-
search directed toward the preparation of second-
generation analogues with outstanding biological prop-
erties and improved drug delivery profiles.6 Extensive
structure-activity studies have included modifications
on both the C13 side chain and the diterpene skeleton
of paclitaxel.3,7-13
bility compared to the parent compound paclitaxel.15
Inspired by the interesting activity profile and solubility
data of these initial analogues, we decided to explore
the structure-activity relationship profile of these
derivatives in more detail. We are now reporting on
the synthesis, biological activity, and aqueous solubility
of novel N-acyl analogues of butitaxel. This report
supplements our earlier disclosure by focusing on side
chains containing carbo- and heterocyclic moieties.
Compounds 8-26 (Table 1) were synthesized accord-
ing to the sequences shown in Scheme 1. The key
intermediates for their synthesis, the amines 5 and 6,
were prepared from L-tert-leucine and 10-deacetyl-
baccatin III as described by us previously.15 When
amine 5 was used in the reaction, treatment with
chloroformates or acid chlorides under Schotten-
Baumann conditions18 was followed by removal of the
Troc protection of the C7 and C10 alcohols with zinc
and acetic acid to give the corresponding N-substituted
taxanes. Employing amine 6 as the starting material
in the Schotten-Baumann acylation allows for the one-
step synthesis of the desired analogues.18 All of the
novel derivatives prepared for this study were charac-
terized by 1H NMR, 13C NMR, and MS and showed
satisfactory purity by HPLC analysis (>90%). The new
taxanes were evaluated for biological activity in a
microtubule assembly assay and for their cytotoxicity
against B16 melanoma cells (Table 1). In addition, they
were subjected to aqueous solubility studies (Table 2)
to allow comparison with paclitaxel and docetaxel.
Our earlier investigation had revealed that various
aliphatic 3′-carbamate derivatives of butitaxel possessed
slightly better or similar efficacy compared to paclitaxel
when tested for their ability to cause the polymerization
of tubulin and their cytotoxicity toward B16 melanoma
cells.15 We therefore decided to synthesize and evaluate
(Table 1) additional aliphatic carbamates as well as
amides containing open chain, alicyclic, and hetero-
aromatic groups at the 3′-nitrogen.
We14,15 and others16,17 have recently reported that the
3′-phenyl group of paclitaxel can be replaced by aliphatic
moieties to provide taxanes with significant in vitro
cytotoxicity. Among the analogues prepared, butitaxel
(3) and N-(tert-butoxycarbonyl)-N-debenzoylbutitaxel (4)
possess excellent cytotoxicity and improved water solu-
† Current address: Gliatech Inc., 23420 Commerce Park Rd, Cleve-
land, OH 44122.
First, we investigated the influence of aliphatic chain
length of the carbamate moiety on tubulin assembly
properties and cytotoxicity against B16 melanoma cells.
Since we had found that the butoxycarbonyl analogue
10 of butitaxel was more active in both assays than its
‡ Current address: Sepracor Inc., 111 Loche Dr, Marlborough, MA
01752-7231.
§ Current address: Hauser Chemical Research Inc., 5555 Airport
Blvd, Boulder, CO 80301.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1997.
S0022-2623(96)00505-5 CCC: $14.00 © 1997 American Chemical Society

Butitaxel Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 237
Sch em e 1a
a
(a) Zn dust, AcOH-MeOH, 60 °C, 2 h, 65%; (b) R1COCl, EtOAc, aq NaHCO3, room temperature, 20 min. For R1, see Table 1.
Ta ble 1. In Vitro Biological Evaluation of N-Modified
Butitaxel Analogues
better properties than the corresponding n-propoxy
derivative 9. Similar microtubule assembly data and
ED50/ED50(paclitaxel)
B16 melanoma cell cytotoxicity were reported for the
related N-(isopropoxycarbonyl)-9-dihydropaclitaxel ana-
logue of 12.19
microtubule
B16
assembly
melanoma
compound
R1
assaya
cytotoxicityb
Next, we investigated alicyclic amides 13-15 and 17.
All compounds displayed tubulin assembly properties
similar to paclitaxel. However, they showed reduced
cytotoxicity toward B16 melanoma cells. The almost
4-fold reduced cytotoxicity of cyclohexanecarboxamide
17 is somewhat surprising since a related 3′-cyclohexyl-
paclitaxel analogue was only 1.6-fold less active than
paclitaxel against B16 melanoma cell growth.14 The
most cytotoxic alicyclic amide in this series was cyclo-
pentylcarbonyl derivative 15 (ED50/ED50(paclitaxel) ) 1.4).
To further probe the potential of this analogue, we
prepared its open chain derivative, 2-ethylbutyric amide
16. We found that 16 had similar activity in the tubulin
assay but showed greatly decreased cytotoxicity against
B16 melanoma cells, demonstrating that the cyclic
structure of 15 is of significant importance for its B16
melanoma cell cytotoxicity.
1, paclitaxel
1.0
0.45
1.8
0.38
1.4
1.7
0.86
2.3
0.84
0.95
0.67
1.5
1.7
1.5
1.5
1.6
0.42
0.85
2.4
1.4
2.7
1.0
0.41
7.5
0.40
3.4
1.5
2.1
12
1.2
2.1
3.0
1.4
26
3.8
2.1
2.3
0.53
1.2
32
1.3
2.7
3.3
1.2
2, docetaxel14
3, butitaxel15 Ph
415
8
tert-butoxy
ethoxy
9
propoxy
butoxy
1015
1115
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
hexyloxy
isopropoxy
cyclopropyl
cyclobutyl
cyclopentyl
1-ethylpropyl
cyclohexyl
2-furyl
3-furyl
2-thienyl
3-thienyl
5-methyl-2-thienyl
3-methyl-2-thienyl
2-thienyl-2-ethenyl
2-thienylmethyl
1-methyl-2-pyrrolyl
The excellent cytotoxicity reported for N-furoylpacli-
taxel analogues prompted us to investigate hetero-
aromatic N-acyl derivatives in the butitaxel series.20
2-Furamide 18 and 3-furamide 19 both showed activity
similar to paclitaxel in the tubulin assay but only one-
half of the cytotoxicity of paclitaxel. This is different
from the trends observed in the paclitaxel series, in
which the 3-furamide was 2 times as cytotoxic relative
to paclitaxel and the 2-furamide derivative.21 Bio-
isosteric replacement of the oxygen in the furyl moiety
with sulfur provided 2-thenoyl analogue 20 which was
the most active compound prepared in this study.
2-Thenoyl derivative 20 was more active than paclitaxel
1.9
0.96
a
ED50 is the concentration which causes polymerization of 50%
b
of the tubulin present in 15 min at 37 °C. ED50 refers to the
concentration which produces 50% inhibition of proliferation after
40 h incubation.
hexyloxy derivative 11,15 we prepared and tested the
two lower homologues, the ethoxycarbonyl and propoxy-
carbonyl derivatives 8 and 9. Both carbamates were
less potent in the tubulin assembly assay than the
corresponding butoxy analogue 10 and paclitaxel. How-
ever, the propoxy derivative 9 was found to be slightly
more cytotoxic (ED50/ED50(paclitaxel) ) 1.5) than the butoxy
analogue 10 (ED50/ED50(paclitaxel) ) 2.1). Thus, the most
cytotoxic carbamates in this series of compounds are the
propoxy and butoxy analogues 9 and 10. The cytotoxic
potencies of the higher and lower homologues 11 and 8
were clearly decreased. The results obtained for ethoxy
derivative 8, good microtubule assembly properties and
reduced cytotoxicity against B16 melanoma cells, are
similar to the findings for the 9-dihydropaclitaxel
analogue of 8.19 Branching of the aliphatic side chain
provided the isopropoxy analogue 12, which is similar
to paclitaxel in both assays, thus possessing slightly
in both the microtubule assembly assay (ED50
/
ED50(paclitaxel) ) 0.42) and the B16 melanoma cell cyto-
toxicity assay (ED50/ED50(paclitaxel) ) 0.53). Encouraged
by the activity of this compound, we decided to extend
our study to substituted thienyl derivatives. Most of
the thienyl analogues 21-25 showed activity slightly
less than or similar to paclitaxel, with the exception of
5-methyl-2-thenoyl analogue 22, which was found to be
about 2 times less active in the microtubule assembly
assay and 32 times less cytotoxic than the parent. None
of the analogues, however, was as active as the original
2-thenoyl compound 20. It is of interest to note that

238 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Ali et al.
Ta ble 2. Water Solubility of Butitaxel Analogues
Gen er a l P r oced u r e for th e Rem ova l of th e [(2,2,2-
Tr ich lor oeth yl)oxy]ca r bon yl (Tr oc) P r otectin g Gr ou p s.
Meth od B: A mixture of either amine 5 or 7 (0.3 mmol), zinc
dust (0.3 g), methanol (8 mL), and acetic acid (8 mL) was
heated at 60 °C for 2 h. The reaction mixture was cooled to
room temperature and filtered. The solvents were removed
under reduced pressure, and the residue was dissolved in ethyl
acetate (15 mL). The heterogeneous mixture was washed with
aqueous NaHCO3 solution (10 mL) and brine (10 mL) and dried
(Na2SO4). Removal of the solvent followed by flash column
chromatography over silica gel (CH2Cl2/MeOH, 20:1) gave the
7,10-deprotected product.
analogue
water
solubility/
paclitaxel
solubility
solubility
(µg/mL)
compound
R1
1, paclitaxel
0.30
5.0-6.0
2.8
28-33
9.7
1
2, docetaxel
17-20
9.3
93-110
32
90-97
1.7
120-150
80
150
73
23-28
16
13
3
23
1.8
3, butitaxel15
Ph
415
8
tert-butoxy
ethoxy
1015
12
13
14
17
18
20
21
22
24
25
26
butoxy
isopropoxy
cyclopropyl
cyclobutyl
cyclohexyl
2-furyl
2-thienyl
3-thienyl
5-methyl-2-thienyl
2-thienyl-2-ethenyl
2-thienylmethyl
1-methyl-2-pyrrolyl
27-29
0.50
33-45
24
45
22
6.8-8.4
4.7
4.0
1.0
N-Deben zoyl-N-(eth oxyca r bon yl)bu tita xel (8). Amine
5 (0.045 g, 0.043 mmol) was reacted with ethyl chloroformate
(0.011 mL, 0.11 mmol, 2.6 equiv) according to the procedure
described in method A to give a carbamate that was depro-
tected as discussed in method B to give (0.015 g, 45% overall)
as a solid: mp 168-171 °C dec; Rf 0.40 (CHCl3); 1H NMR (300
MHz, CDCl3) δ 1.05 (s, 9H), 1.11 (t, J ) 6.9 Hz, 3H), 1.24 (s,
3H), 1.25 (s, 3H), 1.74 (s, 3H), 1.85 (s, 1H), 1.90 (s, 3H), 2.20
(m, 1H), 2.27 (m, 2H), 2.44 (s, 3H), 2.58 (m, 1H), 3.39 (s, 1H),
3.86 (d, J ) 10.3 Hz, 1H), 3.90 (d, J ) 6.9 Hz, 1H), 3.95 (q, J
) 6.9 Hz, 2H), 4.20 (d, J ) 8.3 Hz, 1H), 4.26 (m, 1H), 4.30 (d,
J ) 8.3 Hz, 1H), 4.58 (s, 1H), 4.94 (d, J ) 8.0 Hz, 1H), 5.13 (d,
J ) 10.3 Hz, 1H), 5.21 (s, 1H), 5.67 (d, J ) 6.9 Hz, 1H), 6.23
(t, J ) 7.8 Hz, 1H), 7.50 (t, J ) 7.6 Hz, 2H), 7.61 (t, J ) 7.4
Hz, 1H), 8.13 (d, J ) 7.3 Hz, 2H); 13C NMR (300 MHz, CDCl3)
δ 211.5, 174.4, 170.5, 167.0, 156.5, 138.6, 135.7, 133.6, 130.3,
129.2, 128.7, 84.2, 81.0, 79.0, 74.9, 74.5, 72.7, 72.0, 70.6, 61.1,
60.0, 57.6, 46.4, 43.1, 36.9, 35.9, 35.3, 29.7, 27.4, 26.5, 22.8,
21.0, 14.5, 14.3, 10.0; HRMS (FAB) m/ z calcd for C39H54NO14
760.3544, found 760.3558; MS (FAB) m/ z 760 (M + H)+, 742,
6.7
0.5
the introduction of a 5-methyl group at the 2-thenoyl
moiety (compound 22) reduced cytotoxicity greatly,
whereas a methyl group at position 3 provided a very
cytotoxic analogue (23). The final heteroaroyl derivative
prepared was the 1-methyl-2-pyrrolyl analogue 26
which showed activity similar to paclitaxel in both
assays.
The aqueous solubility of all the active compounds
was measured (Table 2) and compared with that of
paclitaxel using the method described earlier.15 It was
found that most of the active compounds in the butitaxel
series were more water soluble than the parent com-
pound paclitaxel. Although this improved solubility is
not sufficient for these analogues to be formulated
without a surfactant, it should allow their formulation
with a wider variety of surfactants in order to avoid
vehicle-related side effects.6
527, 509, 345, 327, 234; [R]20 -36.4° (c ) 1.24, CHCl3).
D
N-Deben zoyl-N-(pr opoxycar bon yl)bu titaxel (9). Amine
5 (0.10 g, 0.096 mmol) was reacted with propyl chloroformate
(0.015 g, 0.13 mmol, 1.3 equiv) according to the procedure
described in method A to give a carbamate (0.08 g), which was
deprotected as discussed in method B to give 9 (0.04 g, 49%
overall yield) as a white solid: mp 155-157 °C; Rf 0.49
(EtOAc); 1H NMR (300 MHz, CDCl3) δ 0.77 (t, J ) 7.4 Hz,
3H), 1.04 (s, 9H), 1.11 (s, 3H), 1.22 (s, 3H), 1.74 (s, 3H), 1.87
(m, 1H), 1.89 (s, 3H), 2.22 (m, 2H), 2.43 (s, 3H), 2.57 (m, 1H),
3.35 (bs, 1H), 3.85 (m, 4H), 4.20 (d, J ) 8.3 Hz, 1H), 4.28 (d,
J ) 9.2 Hz, 2H), 4.58 (d, J ) 4.9 Hz, 1H), 4.94 (d, J ) 8.4 Hz,
1H), 5.14 (d, J ) 10.3 Hz, 1H), 5.21 (s, 1H), 5.65 (d, J ) 6.8
Hz, 1H), 6.21 (t, J ) 8.9 Hz, 1H), 7.49 (t, J ) 7.7 Hz, 2H), 7.60
(t, J ) 7.6 Hz, 1H), 8.12 (d, J ) 7.4 Hz, 2H); 13C NMR (300
MHz, CDCl3) δ 211.4, 174.4, 170.4, 167.0, 156.6, 138.6, 135.7,
133.6, 130.3, 129.2, 128.7, 84.2, 81.0, 79.0, 74.9, 74.5, 72.7, 72.0,
70.6, 66.7, 59.7, 57.6, 46.4, 43.1, 36.9, 35.8, 35.3, 27.4, 26.5,
22.8, 22.3, 21.0, 14.3, 10.0, 9.9; HRMS (FAB) m/ z calcd for
C40H56NO14 774.3701, found 774.3703; MS (FAB) m/ z 774 (M
Su m m a r y
It can be concluded from this study that modifications
at the N-acyl group of butitaxel are tolerated well in
many cases, as had been observed for paclitaxel previ-
ously.6 In addition to several analogues that showed
paclitaxel-like activity, we identified 2-thenoyl analogue
20 as a derivative possessing about 2-fold increased
potency compared to paclitaxel in both assays. Most of
the analogues demonstrated slightly better water solu-
bility than paclitaxel. Further evaluation of these
derivatives is in progress in our laboratory.
+ H)+, 756, 527, 509, 387, 345, 327, 248; [R]20 -34.0° (c )
D
1.41, CDCl3).
N-Deb en zoyl-N-(isop r op oxyca r b on yl)b u t it a xel (12).
Amine 6 (0.019 g, 0.028 mmol) was treated with isopropyl
chloroformate (1 M solution in toluene, 0.036 mL, 0.036 mmol,
1.3 equiv) according to the procedure described in method A
to give 12 (0.019 mg, 80%) as an amorphous solid: 1H NMR
(300 MHz, CDCl3) δ 1.04 (s, 9H), 1.11 and 1.15 (2s, 6H), 1.13
(s, 3H), 1.23 (s, 3H), 1.71(s, 3H), 1.90 (s, 3H), 2.28 (m, 2H),
2.43 (s, 3H), 2.58 (m, 1H), 3.30 (bs, 1H), 3.86 (d, J ) 10 Hz,
1H), 3.89 (d, J ) 6.9 Hz, 1H), 4.20 and 4.31 (2d, J ) 8.3 Hz,
2H), 4.27 (m, 1H), 4.58 (bs, 1H), 4.71 (m, 1H), 4.95 (d, J ) 8.1
Hz, 1H), 5.06 (d, J ) 10.5 Hz, 1H), 5.21 (s, 1H), 5.67 (d, J )
7.2 Hz, 1H), 6.19 (t, J ) 8.4 Hz, 1H), 7.49, 7.60, and 8.13 (m,
5H); 13C NMR (300 MHz, CDCl3) δ 211.4, 174.5, 170.4, 166.9,
156.1, 138.6, 135.7, 133.6, 130.2, 129.1, 128.6, 84.1, 81.0, 78.8,
74.9, 74.4, 72.8, 71.9, 70.5, 68.4, 59.8, 57.5, 46.3, 43.1, 36.9,
35.8, 35.2, 29.7, 27.3, 26.4, 22.7, 21.9, 21.0, 14.3, 9.9; HRMS
(FAB) m/ z calcd for C40H55NO14Li 780.3783, found 780.3751;
MS (FAB) m/ z 796 (M + Na)+, 780 (M + Li)+, 774 (M + H)+,
Exp er im en ta l Section
Gen er a l. For general synthetic procedures, see ref 22. For
a description of the biological assays, see refs 15 and 23. For
the preparation of butitaxel (3), N-(tert-butoxycarbonyl)-N-
debenzoylbutitaxel (4), amines 5 and 6, and carbamates 10
and 12 and the conditions of the solubility studies, see ref 15.
Gen er a l P r oced u r e for th e N-Acyla tion of 5 a n d 6.
Meth od A: The chloroformate or acid chloride (1.2 equiv) was
added dropwise to a solution of amine 5 or 6 (0.2 mmol) in
ethyl acetate (7 mL), saturated aqueous NaHCO3 solution (10
mL), and water (10 mL). The mixture was stirred at 24 °C
for 30 min and extracted with ethyl acetate (2 × 30 mL). The
organic extracts were washed with water and brine and dried
(Na2SO4). The solvent was removed under reduced pressure,
and the crude product was purified by flash column chroma-
tography over silica gel using ethyl acetate/hexane (1:3) as the
eluent to provide the N-acylated product.
756, 738, 549, 533, 509, 480, 449, 411, 387, 345; [R]20 -37.4°
D
(c ) 0.735, CHCl3).
N-(Cyclop r op ylca r b on yl)-N-d eb en zoylb u t it a xel (13).
Amine 6 (0.025 g, 0.036 mmol) was treated with cyclopropane-

Butitaxel Analogues
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 239
carbonyl chloride (0.004 mL, 0.046 mmol, 1.3 equiv) according
to the procedure described in method A to give 13 (0.017 g,
62%) as an amorphous solid: 1H NMR (300 MHz, CDCl3) δ
0.68 (m, 2H), 1.05 (s, 9H), 1.11 (s, 3H), 1.23 (s, 3H), 1.34 (m,
2H), 1.73 (s, 3H), 1.88 (s, 3H), 2.22 (m, 2H), 2.42 (s, 3H), 2.56
(m, 1H), 3.86 (d, J ) 6.8 Hz, 1H), 4.17-4.31 (m, 4H), 4.59 (bs,
1H), 4.94 (d, J ) 8.4 Hz, 1H), 5.20 (s, 1H), 5.67 (d, J ) 7.2 Hz,
N-(Cycloh exylca r bon yl)-N-(d eben zoyl)bu tita xel (17).
Amine 6 (0.04 g, 0.058 mmol) was treated with cyclohexane-
carbonyl chloride (0.01 mL, 0.075 mmol, 1.3 equiv) according
to the procedure described in method A to give 17 (0.037 g,
1
80%) as amorphous solid; H NMR (300 MHz, CDCl3) δ 1.04
(s, 9H), 1.12 (s, 3H), 1.23 (s, 3H), 1.34 (m, 2H), 1.6-1.8 (m,
6H), 1.74 (s, 3H), 1.88 (s, 3H), 2.30 (m, 2H), 2.42 (s, 3H), 2.58
(m, 1H), 3.87 (d, J ) 6.8 Hz, 1H), 4.14 (d, J ) 10.2 Hz, 1H),
4.23-4.32 (m, 3H), 4.58 (bs, 1H), 4.95 (d, J ) 7.7 Hz, 1H),
5.19 (s, 1H), 5.70 (d, J ) 6.8 Hz, 1H), 5.84 (d, J ) 10 Hz, 1H),
6.09 (t, J ) 9.2 Hz, 1H), 7.50, 7.61 and 8.13 (m, 5H); 13C NMR
(300 MHz, CDCl3) δ 211.4, 176.1, 174.8, 170.2, 166.7, 138.4,
135.8, 133.5, 130.2, 129.3, 128.7, 84.2, 81.1, 78.5, 74.9, 74.4,
73.2, 71.8, 70.3, 57.5, 56.9, 46.2, 45.6, 43.2, 36.8, 35.8, 35.0,
29.9, 29.5, 27.4, 26.4, 25.6, 25.5, 22.7, 21.1, 14.1, 9.9; HRMS
(FAB) m/ z calcd for C43H59NO13Li 804.4146, found 804.4108;
MS (FAB) m/ z 821 (M+Na)+, 804 (M + Li)+, 798, 784, 758,
707, 604, 551, 533, 523, 466, 443, 425, 397, 369, 329, 313, 289,
1H), 6.11 (t, J ) 9.3 Hz, 1H), 7.49, 7.60, and 8.11 (m, 5H); 13
C
NMR (300 MHz, CDCl3) δ 211.4, 174.6, 173.6, 170.4, 166.8,
138.5, 135.8, 133.6, 130.3, 129.2, 128.6, 84.2, 81.0, 78.6, 74.9,
74.4, 72.9, 71.9, 70.5, 57.7, 57.5, 46.2, 43.1, 36.8, 35.8, 35.2,
27.4, 26.4, 22.7, 21.1, 14.6, 14.2, 9.9, 7.4, 1.4; HRMS (FAB)
m/ z calcd for C40H53NO13Li 762.3677, found 762.3652; MS
(FAB) m/ z 762 (M + Li)+, 756 (M + H)+, 677, 664, 604, 577,
551, 533, 523, 466, 460, 405, 397, 369, 341, 329, 320, 313, 289,
230, 154 (base peak), 136, 120, 107; [R]20 -39° (c ) 0.80,
D
CHCl3).
N-(Cyclob u t ylca r b on yl)-N-d eb en zoylb u t it a xel (14).
Amine 6 (0.019 g, 0.0276 mmol) was treated with cyclobutane-
carbonyl chloride (0.004 g, 0.035 mmol, 1.3 equiv) according
to the procedure described in method A to give 14 (0.017 g,
80%) as an amorphous solid: 1H NMR (300 MHz, CDCl3) δ
1.04 (s, 9H), 1.11 (s, 3H), 1.23 (s, 3H), 1.25 (m, 2H), 1.74 (s,
3H), 1.88 (s, 3H), 2.10 (m, 4H), 2.30 (m, 2H), 2.44 (s, 3H), 2.58
(m, 1H), 2.97 (m, 1H), 3.36 (bs, 1H), 3.88 (d, J ) 7.2 Hz, 1H),
4.16 (d, J ) 10.2 Hz, 1H), 4.19 and 4.32 (2d, J ) 8.3 Hz, 2H),
4.26 (m, 1H), 4.59 (bs, 1H), 4.95 (d, J ) 8 Hz, 1H), 5.20 (s,
1H), 5.69 (d, J ) 7.1 Hz, 1H), 5.75 (d, J ) 10.2 Hz, 1H), 6.13
(t, J ) 8.3 Hz, 1H), 7.51, 7.61, and 8.14 (m, 5H); 13C NMR
(300 MHz, CDCl3) δ 211.4, 174.9, 174.7, 170.3, 166.8, 138.4,
135.8, 133.6, 130.3, 129.2, 128.7, 84.1, 81.0, 78.6, 74.8, 74.4,
73.0, 71.9, 70.3, 57.5, 57.2, 46.2, 43.2, 39.8, 36.9, 35.9, 35.0,
29.7, 27.4, 26.4, 25.5, 25.4, 22.8, 21.0, 18.2, 14.2, 9.9; HRMS
(FAB) m/ z calcd for C41H55NO13Li 776.3833, found 776.3867;
MS (FAB) m/ z 776 (M + Li)+, 770 (M + H)+, 752, 683, 663,
619, 551, 533, 466, 460, 443, 397, 379, 313, 289, 244, 226, 154,
278, 272, 254, 226; [R]20 -37° (c ) 0.66, CHCl3).
D
N-Deben zoyl-N-(2-fu r oyl)bu tita xel (18). Amine 5 (0.080
g, 0.077 mmol) was treated with 2-furoyl chloride (0.01 mL,
0.10 mmol, 1.3 equiv) according to the procedure described in
method A to give an amide which was deprotected as discussed
in method B to give 18 (0.030 g, 50% overall yield) as an
amorphous solid: 1H NMR (300 MHz, CDCl3) δ 1.08 (s, 3H),
1.10 (s, 9H), 1.17 (s, 3H), 1.73 (s, 3H), 1.82 (s, 3H), 2.26 (m,
2H), 2.46 (s, 3H), 2.58 (m, 1H), 3.61 (bs, 1H), 3.86 (d, J ) 6.8
Hz, 1H), 4.26 (m, 3H), 4.35 (d, J ) 10.6 Hz, 1H), 4.67 (bs, 1H),
4.94 (d, J ) 8.8 Hz, 1H), 5.19 (s, 1H), 5.66 (d, J ) 6.8 Hz, 1H),
6.15 (t, J ) 8.8 Hz, 1H), 6.43 (s, 1H), 6.79 (d, J ) 10.3 Hz,
1H), 6.96 (d, J ) 3.3 Hz, 1H), 7.43 (s, 1H), 7.52, 7.67, and 8.15
(m, 5H); 13C NMR (300 MHz, CDCl3) δ 211.3, 174.0, 170.4,
166.8, 158.0, 147.2, 144.1, 138.3, 135.8, 133.6, 130.2, 129.3,
128.6, 114.9, 112.3, 84.2, 81.1, 78.7, 74.8, 74.4, 72.7, 71.9, 70.5,
57.5, 57.3, 46.3, 43.0, 36.8, 35.9, 35.4, 29.7, 27.4, 26.5, 22.8,
20.9, 14.2, 9.9; HRMS (FAB) m/ z calcd for C41H51NO14Li
788.3470, found 788.3468; MS (FAB) m/ z 804 (M + Na)+, 782
(M + H)+, 764, 746, 682, 549, 527, 509, 491, 387, 345, 327;
136; [R]20 -40° (c ) 0.75, CHCl3).
D
N-(Cyclop en tylca r bon yl)-N-d eben zoylbu tita xel (15).
Amine 5 (0.10 g, 0.096 mmol) on treatment with cyclopentane-
carbonyl chloride (0.017 g, 0.13 mmol, 1.3 equiv) according to
the procedure described in method A gave an amide (0.04 g)
that was deprotected as described in method B to yield 15 (0.01
g, 13% overall yield) as an amorphous solid: 1H NMR (300
MHz, CDCl3) δ 1.05 (s, 9H), 1.24 (s, 3H), 1.13 (s, 3H), 1.48-
1.74 (m, 9H), 1.75 (s, 3H), 1.90 (s, 3H), 2.20-2.40 (m, 2H), 2.44
(s, 3H), 2.48-2.62 (m, 2H), 3.23 (d, J ) 4.4 Hz, 1H), 3.88 (d, J
) 6.8 Hz, 1H), 4.20 (m, 3H), 4.31 (d, J ) 8.4 Hz, 1H), 4.58 (d,
J ) 3.4 Hz, 1H), 4.95 (d, J ) 7.8 Hz, 1H), 5.19 (s, 1H), 5.69 (d,
J ) 7.3 Hz, 1H), 5.78 (d, J ) 10.3 Hz, 1H), 6.14 (t, J ) 9.0 Hz,
1H), 7.50 (t, J ) 7.1 Hz, 2H), 7.61 (t, J ) 7.4 Hz, 1H), 8.13 (d,
J ) 7.0 Hz, 2H); 13C NMR (300 MHz, CDCl3) δ 211.6, 176.0,
174.8, 170.3, 166.9, 138.5, 135.8, 133.6, 130.3, 129.2, 128.7,
84.1, 81.0, 78.7, 77.2, 74.9, 74.5, 73.1, 72.0, 70.4, 57.6, 57.2,
46.3, 45.9, 43.2, 37.0, 36.0, 35.1, 30.6, 30.5, 27.4, 26.4, 25.8,
[R]20 +16.4° (c ) 0.795, CHCl3).
D
N-Deben zoyl-N-(3-fu r oyl)bu tita xel (19). Amine 5 (0.045
g, 0.043 mmol) was treated with 3-furoyl chloride (0.011 g, 0.86
mmol, 2 equiv) according to the procedure described in method
A followed by deprotection as discussed in method B to give
19 (0.015 g, 45% overall) as an amorphous solid: 1H NMR (300
MHz, CDCl3) δ 1.09 (bs, 12H), 1.19 (s, 3H), 1.75 (s, 3H), 1.84
(s, 3H), 2.28 (m, 2H), 2.48 (s, 3H), 2.59 (m, 1H), 3.88 (d, J )
7.2 Hz, 1H), 4.22 (bd, J ) 8.28 Hz, 2H), 4.24 (d, J ) 8.4 Hz,
1H), 4.39 (d, J ) 10.3 Hz, 1H), 4.66 (s, 1H), 4.94 (d, J ) 8.3
Hz, 1H), 5.17 (s, 1H), 5.67 (d, J ) 7.2 Hz, 1H), 6.19 (m, 2H),
6.52 (s, 1H), 7.38 (s, 1H), 7.51 (t, J ) 7.5 Hz, 2H), 7.61 (t, J )
7.23 Hz, 1H), 7.81 (s, 1H), 8.16 (d, J ) 7.1 Hz, 2H); 13C NMR
(300 MHz, CDCl3) δ 211.4, 174.1, 170.5, 166.9, 162.1, 144.8,
143.9, 138.3, 135.9, 133.7, 130.3, 129.2, 128.7, 122.1, 108.1,
84.1, 81.1, 78.8, 77.3, 77.2, 76.8, 76.4, 74.8, 74.4, 72.7, 72.0,
70.5, 57.6, 57.3, 46.3, 43.1, 37.0, 35.9, 35.4, 27.4, 26.5, 22.8,
20.9, 14.3, 9.9; MS (FAB) m/ z 804 (M + Na)+, 782 (M + H)+,
25.7, 22.8, 21.1, 14.2, 10.0; HRMS (FAB) m/ z calcd for C42H58
-
NO13 784.3908, found 784.3870; MS (FAB) m/ z 784 (M + H)+,
307, 258, 185; [R]20 -41° (c ) 0.70, CHCl3).
D
N-Deben zoyl-N-(2-eth ylbu tyr yl)bu tita xel (16). Amine
6 (0.02 g, 0.09 mmol) was treated with 2-ethylbutyryl chloride
(0.006 g, 0.108 mmol, 1.2 equiv) according to the procedure
described in method A to give 16 (0.017 g, 75%) as an
amorphous solid: 1H NMR (300 MHz, CDCl3) δ 0.80 (t, J )
7.3 Hz, 3H), 0.88 (t, J ) 7.3 Hz, 3H), 1.06 (s, 9H), 1.11 (s, 3H),
1.21 (s, 3H), 1.48 (m, 4H), 1.73 (s, 3H), 1.83 (m, 1H), 1.88 (s,
3H), 2.02 (m, 1H), 2.30 (m, 2H), 2.42 (s, 3H), 2.57 (m, 1H),
3.36 (d, J ) 3.9 Hz, 1H), 3.86 (d, J ) 6.9 Hz, 1H), 4.20-4.30
(m, 4H), 4.59 (d, J ) 3.9 Hz, 1H), 4.94 (d, J ) 8.7 Hz, 1H),
5.20 (s, 1H), 5.68 (d, J ) 6.9 Hz, 1H), 5.84 (d, J ) 10.2 Hz,
764, 748, 551, 523; [R]20 -0.73° (c ) 0.33, CHCl3).
D
N-Deben zoyl-N-(2-th en oyl)bu tita xel (20). Amine 5 (0.40
g, 0.39 mmol) was treated with 2-thiophenecarbonyl chloride
(0.048 mL, 0.46 mmol, 1.2 equiv) according to method A to
give an amide (0.42 g, 95%) that was deprotected as described
in method B to provide 20 (0.19 g, 67% overall yield) as white
1
crystals: mp 214 °C dec; H NMR (300 MHz, CD3OD) δ 1.11
(s, 3H), 1.12 (s, 9H), 1.14 (s, 3H), 1.69 (s, 3H), 1.85 (s, 3H),
2.20 (m, 2H), 2.40 (m, 1H), 2.48 (s, 3H), 3.87 (d, J ) 7.3 Hz,
1H), 4.21 (m, 3H), 4.37 (bs, 1H), 4.73 (bs, 1H), 5.01 (d, J ) 8.8
Hz, 1H), 5.24 (s, 1H), 5.66 (d, J ) 7 Hz, 1H), 6.13 (t, J ) 9 Hz,
1H), 7.11, 7.55, 7.63, 7.71, and 8.15 (m, 8H); 13C NMR (300
MHz, CDCl3 + CD3OD) δ 211.0, 174.2, 170.3, 166.5, 162.3,
138.2, 138.0, 136.0, 133.3, 130.4, 130.1, 129.6, 128.5, 128.3,
127.7, 84.4, 81.2, 77.9, 74.9, 74.2, 72.8, 71.4, 70.5, 58.3, 58.2,
57.5, 46.1, 43.2, 36.4, 35.7, 35.5, 27.3, 26.6, 26.3, 22.7, 21.0,
13.8, 9.8; HRMS (FAB) m/ z calcd for C41H51NO13SLi 804.3241,
found 804.3279; MS (FAB) m/ z 820 (M + Na)+, 798 (M + H)+,
1H), 6.11 (t, J ) 8.8 Hz, 1H), 7.50, 7.61, and 8.12 (m, 5H); 13
C
NMR (300 MHz, CDCl3) δ 211.4, 175.6, 174.9, 170.1, 166.8,
138.5, 135.8, 133.6, 130.2, 129.2, 128.7, 84.1, 81.0, 78.6, 74.9,
74.4, 73.2, 71.9, 70.3, 57.5, 57.2, 51.5, 46.2, 43.2, 36.9, 35.8,
35.1, 27.5, 26.3, 25.6, 25.4, 22.8, 21.1, 14.1, 12.2, 11.9, 9.9;
HRMS (FAB) m/ z calcd for C42H60NO13 786.4065, found
786.4089; MS (FAB) m/ z 808 (M+Na)+, 786 (M + H)+, 770,
527, 509, 327, 311, 260; [R]20 -44° (c ) 0.67, CHCl3).
D

240 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2
Ali et al.
780, 762, 700, 617, 549, 527, 509, 491, 480, 449, 429, 405, 399,
387, 378, 369, 327, 307, 272, 254, 226; [R]20D +11.2° (c ) 0.365,
MeOH).
1H), (8.20 (d, J ) 7.1 Hz, 2H); 13C NMR (300 MHz, CDCl3) δ
211.9, 174.3, 170.6, 166.9, 165.4, 140.0, 139.7, 138.5, 135.7,
134.6, 133.7, 130.5, 130.4, 129.3, 128.8, 127.9, 127.5, 118.8,
84.2, 81.0, 78.9, 74.9, 74.4, 72.7, 71.9, 70.5, 57.7, 57.6, 46.3,
43.1, 36.9, 36.0, 35.4, 27.5, 26.5, 22.8, 32.2, 14.3, 10.0; HRMS
(FAB) calcd for C43H54NO13S 824.3316, found 824.3341; MS
(FAB) m/ z 824 (M + H)+, 595, 509, 406, 360, 298, 280, 252,
N-Deben zoyl-N-(3-th en oyl)bu titaxel (21). Amine 6 (0.020
g, 0.029 mmol) was reacted with 3-thiophenecarbonyl chloride
(0.008 mL, 0.058 mmol, 2.0 equiv) as described in method A
to give 21 (0.017 g, 74%) as an amorphous solid: 1H NMR (300
MHz, CDCl3) δ 1.08 (bs, 12H), 1.15 (s, 3H), 1.61 (s, 3H), 1.80
(s, 3H), 2.22 (m, 2H), 2.46 (s, 3H), 2.54 (m, 1H), 3.57 (bs, 1H),
3.85 (d, J ) 6.8 Hz, 1H), 4.18-4.30 (m, 3H), 4.38 (d, J ) 10.2
Hz, 1H), 4.64 (bs, 1H), 4.92 (d, J ) 8.0 Hz, 1H), 5.16 (s, 1H),
5.64 (d, J ) 7.0 Hz, 1H), 6.15 (t, J ) 9.0 Hz, 1H), 6.39 (d, J )
10 Hz, 1H), 7.25 (bs , 2H), 7.49-8.14 (m, 5H); 13C NMR (300
MHz, CDCl3) δ 211.4, 174.1, 170.5, 166.9, 162.6, 138.4, 136.9,
135.8, 133.7, 130.3, 129.2, 128.7, 128.4, 126.7, 125.9, 84.1, 81.0,
78.8, 74.8, 74.4, 72.6, 71.9, 70.5, 57.6, 46.3, 43.0, 36.9, 35.9,
35.5, 27.5, 26.5, 22.8, 20.9, 14.3, 9.9; HRMS (FAB) m/ z calcd
for C41H51NO13SLi 804.3241, found 804.3267; MS (FAB) m/ z
820 (M + Na)+, 804 (M + Li)+, 780, 533, 509, 447, 377, 313,
137; [R]20 +78.3° (c ) 1.36, MeOH).
D
N-Deben zoyl-N-(2-th ien yla cetyl)bu tita xel (25). Amine
5 (0.10 g, 0.096 mmol) was reacted with 2-thiopheneacetyl
chloride (0.020 g, 0.13 mmol) according to procedure A to give
an amide (0.07 g, 63%) that was deprotected following method
B to give 25 (0.02 g, 26% overall yield) as a white solid: mp
160-162 °C; Rf 0.48 (EtOAc); 1H NMR (300 MHz, CDCl3) δ
0.97 (s, 9H), 1.11 (s, 3H), 1.22 (s, 3H), 1.75 (s, 3H), 1.80 (m,
1H), 1.86 (s, 3H), 2.02 (m, 1H), 2.28 (m, 1H), 2.42 (s, 3H), 2.58
(m, 1H), 3.17 (d, J ) 4.4 Hz, 1H), 3.70 (d, J ) 2.1 Hz, 2H),
3.84 (d, J ) 6.9 Hz, 1H), 4.24 (m, 3H), 4.31 (d, J ) 8.3 Hz,
1H), 4.53 (d, J ) 3.3 Hz, 1H), 4.92 (d, J ) 7.7 Hz, 1H), 5.67 (d,
J ) 7.1 Hz, 1H), 5.98 (d, J ) 10.2 Hz, 1H), 6.14 (t, J ) 8.7 Hz,
1H), 6.93 (dd, J ) 5.3, 3.4 Hz, 1H), 6.96 (d, J ) 3.4 Hz, 1H),
7.17 (d, J ) 5.3 Hz, 1H), 7.51 (t, J ) 7.8 Hz, 2H), 7.61 (t, J )
7.4 Hz, 1H), 8.13 (d, J ) 7.1 Hz, 2H); 13C NMR (300 MHz,
CDCl3) δ 211.5, 174.4, 170.3, 169.4, 166.9, 138.3, 136.1, 135.9,
133.6, 130.4, 129.3, 128.7, 127.4, 125.6, 84.1, 81.0, 78.7, 74.9,
74.4, 72.9, 71.9, 70.3, 60.4, 57.5, 46.2, 43.1, 37.5, 36.9, 36.1,
35.1, 27.3, 26.5, 22.9, 21.1, 14.2, 10.0; HRMS (FAB) calcd for
C42H54NO13S 812.3316, found 812.3304; MS (FAB) m/ z 812
272, 226, 176, 154; [R]20 +4.5° (c ) 0.58, CHCl3).
D
N-Deb en zoyl-N-(5-m et h yl-2-t h en oyl)b u t it a xel (22).
Amine 5 (0.10 g, 0.096 mmol) was treated with 5-methyl-2-
thiophenecarbonyl chloride (0.02 g, 0.13 mmol, 1.3 equiv) as
described in method A to give an amide that was deprotected
as described in method B to provide 22 (0.04 g, 52% overall
yield) as a white solid: mp 192-194 °C dec; Rf 0.52 (EtOAc);
1H NMR (300 MHz, CD3OD) δ 1.11 (s, 3H), 1.12 (s, 9H), 1.16
(s, 3H), 1.70 (s, 3H), 1.87 (s, 3H), 2.21 (m, 1H), 2.41 (m, 3H),
2.47 (s, 3H), 2.48 (s, 3H), 3.88 (d, J ) 7.1 Hz, 1H), 4.19 (m,
1H), 4.22 (s, 2H), 4.35 (d, J ) 1.7 Hz, 1H), 4.73 (d, J ) 1.6 Hz,
1H), 5.02 (d, J ) 8.1 Hz, 1H), 5.25 (s, 1H), 5.67 (d, J ) 7.3 Hz,
1H), 6.13 (t, J ) 9.2 Hz, 1H), 6.80 (d, J ) 2.7 Hz, 1H), 7.51 (d,
J ) 3.8 Hz, 1H), 7.56 (t, J ) 9.6 Hz, 2H), 7.66 (t, J ) 7.4 Hz,
1H), 8.16 (d, J ) 7.1 Hz, 2H); 13C NMR (300 MHz, CD3OD) δ
212.7, 177.1, 173.3, 169.3, 165.9, 148.9, 141.0, 139.3, 138.5,
136.0, 133.0, 132.8, 131.8, 131.3, 129.0, 87.5, 83.9, 80.7, 79.2,
78.0, 77.2, 74.7, 74.2, 73.7, 61.3, 60.4, 46.2, 39.1, 38.5, 38.4,
29.6, 28.7, 25.0, 23.5, 17.0, 15.9, 12.1; HRMS (FAB) calcd for
C42H54NO13S 812.3316, found 812.3322; MS (FAB) m/ z 812
(M + H)+, 286, 268, 240, 210, 184, 162, 149, 116, 105; [R]20
-31.5° (c ) 1.01, CHCl3).
D
N-Deben zoyl)-N-((1-m eth yl-2-p yr r olyl)ca r bon yl)bu ti-
t a xel (26). Amine 5 (0.1 g, 0.096 mmol) was reacted with
1-methyl-2-pyrrolecarbonyl chloride (0.018 g, 0.13 mmol) ac-
cording to procedure A to give an amide (0.055 g) that was
deprotected following method B to give 26 (0.010 g, 13% overall
yield) as a white solid: mp 194-195 °C dec; Rf 0.50 (EtOAc);
1H NMR (300 MHz, CD3OD) δ 0.94 (s, 9H), 1.14 (s, 3H), 1.24
(s, 3H), 1.72 (s, 3H), 1.85 (m, 2H), 1.97 (s, 3H), 2.42 (s, 3H),
2.49 (m, 2H), 3.69 (s, 1H), 3.91 (d, J ) 6.8 Hz, 1H), 4.23 (m,
3H), 4.61 (s, 1H), 5.02 (d, J ) 8.4 Hz, 1H), 5.30 (s, 1H), 5.67
(d, J ) 7.3 Hz, 1H), 6.19 (t, J ) 9.3 Hz, 1H), 7.09 (t, J ) 4.2
Hz, 1H), 7.52 (t, J ) 7.4 Hz, 2H), 7.60 (m, 2H), 7.72 (d, J )
4.9 Hz, 1H), 8.14 (d, J ) 7.4 Hz, 1H); 13C NMR (300 MHz,
CD3OD) δ 211.0, 176.7, 173.3, 141.3, 139.2, 136.0, 134.4, 134.3,
133.2, 132.8, 131.3, 129.8, 87.5, 84.0, 81.2, 79.23, 78.4, 77.2,
75.1, 74.2, 73.7, 66.6, 60.4, 49.4, 46.1, 39.1, 38.9, 38.2, 29.6,
28.8, 24.9, 23.6, 16.1, 12.2; HRMS (FAB) calcd for C42H55N2O13
834.2829, found 834.2828; MS (FAB) m/ z 834 (M + H)+, 688,
(M + H)+, 549, 308, 286, 240, 133, 125; [R]20 -42° (c ) 0.65,
D
MeOH).
N-Deb en zoyl-N-(3-m et h yl-2-t h en oyl)b u t it a xel (23).
Amine 5 (0.10 g, 0.096 mmol) on reaction with 3-methyl-2-
thiophenecarbonyl chloride (0.019 g, 0.12 mmol) according to
procedure A gave an amide (0.093 g) that was deprotected
following method B to provide 23 (0.041 g, 32% overall yield)
1
as a white amorphous solid: Rf 0.61 (EtOAc); H NMR (300
MHz, CD3OD) δ 1.15 (s, 9H), 1.21 (s, 3H), 1.71 (s, 3H), 1.80
(m, 1H), 1.89 (s, 3H), 2.02 (s, 3H), 2.31 (m, 1H), 2.35 (m, 1H),
2.41 (m, 1H), 2.46 (s, 3H), 2.49 (s, 3H), 3.90 (d, J ) 7.0 Hz,
1H), 4.23 (s, 2H), 4.24 (m, 1H), 4.36 (s, 1H), 4.74 (s, 1H), 5.28
(s, 1H), 5.02 (d, J ) 9.3 Hz, 1H), 5.69 (d, J ) 7.0 Hz, 1H), 6.17
(t, J ) 9.3 Hz, 1H), 6.93 (d, J ) 5.0 Hz, 1H), 7.45 (d, J ) 5.0
Hz, 1H), 7.55 (t, J ) 7.3 Hz, 2H), 7.66 (t, J ) 6.7 Hz, 1H), 8.17
(d, J ) 8.3 Hz, 2H); 13C NMR (300 MHz, CD3OD) δ 212.8,
177.2, 173.2, 169.3, 167.3, 143.1, 141.1, 139.3, 136.1, 134.3,
133.0, 132.8, 131.3, 130.1, 87.5, 84.0, 80.9, 80.7, 79.2, 78.1, 77.2,
75.0, 74.2, 73.3, 61.5, 60.4, 52.0, 46.2, 39.1, 38.5, 38.1, 30.0,
29.6, 29.5, 28.7, 25.0, 23.5, 17.4, 16.0, 12.1; HRMS (FAB) calcd
for C42H54NO13S 812.3316, found 812.3338; MS (FAB) m/ z 812
(M + H)+, 549, 527, 509, 387, 345, 327, 308, 286, 268, 240;
549, 527, 509, 330, 262, 232, 206, 185, 162, 147, 115, 105; [R]20
-51.3° (c ) 0.238, MeOH).
D
Ack n ow led gm en t. These studies were supported by
a grant from Oread Laboratories (Grant No. 5339). We
gratefully acknowledge Professor R. H. Himes, Depart-
ment of Biochemistry at the University of Kansas, for
carrying out the assays in Table 1 and Larry Lee and
Carrie Skawinski of Oread Laboratories for performing
the solubility assays in Table 2.
Refer en ces
[R]20 +1.5° (c ) 1.3, MeOH).
D
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. Plant Antitumor Agents. VI. The Isolation and Structure of
Taxol, a Novel Antileukemic and Antitumor Agent from Taxus
Brevifolia. J . Am. Chem. Soc. 1971, 93, 2325-2327.
N-Deben zoyl-N-(2-th ien ylacr yloyl)bu titaxel (24). Amine
5 (0.10 g, 0.096 mmol) on reaction with 2-thienylacrylic acid
chloride (0.022 g, 0.13 mmol, 1.3 equiv) according to procedure
A gave an amide (0.09 g) that was deprotected as described in
method B to give 24 (0.03 g, 40% overall yield) as a white
solid: mp 203-205 °C dec; Rf 0.54 (EtOAc); 1H NMR (300
MHz, CDCl3) δ 1.06 (s, 9H), 1.09 (s, 3H), 1.20 (s, 3H), 1.74 (s,
3H), 1.86 (s, 3H), 1.88 (m, 1H), 2.19 (m, 1H), 2.34 (m, 1H),
2.49 (s, 3H), 2.58 (m, 1H), 3.57 (s, 1H), 3.88 (d, J ) 7.2 Hz,
1H), 4.24 (m, 2H), 4.32 (d, J ) 10.2 Hz, 2H), 4.62 (d, J ) 4.5
Hz, 1H), 4.95 (d, J ) 8.8 Hz, 1H), 5.20 (s, 1H), 5.68 (d, J ) 7.2
Hz, 1H), 6.05 (d, J ) 9.8 Hz, 1H), 6.15 (d, J ) 15.2 Hz, 1H),
6.19 (t, J ) 9 Hz, 1H), 7.26 (s, 1H), 6.93 (m, 2H), 7.54 (t, J )
7.3 Hz, 2H), 7.55 (d, J ) 15.2 Hz, 1H), 7.63 (t, J ) 7.4 Hz,
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