An efficient synthesis of the taxane-derived anticancer agent ABT-271

Article abstract of DOI:10.1021/jo0057203

ABT-271, 1, has been identified as a promising anticancer agent. ABT-271 is a novel taxane possessing a C9-(R)-hydroxyl group as opposed to a C9-ketone which is present in Taxol and Taxotere. To further evaluate ABT-271 as a potential anticancer agent, an efficient synthesis was developed which allows the large scale synthesis of ABT-271. Ketalization of the 7,9-diol of 9-DHAB-III, 2, allows selective removal of the C13-acetate with phenyllithium. The resulting C13-hydroxyl group is then acylated using LiHMDS and β-lactam 22 to give ABT-271 in protected form. The protecting groups were removed first by acidic hydrolysis followed by basic hydrolysis to provide ABT-271. Application of this synthetic sequence provided over 600 g of ABT-271, 1.

Full text of DOI:10.1021/jo0057203

3330
J . Org. Chem. 2001, 66, 3330-3337
An Efficien t Syn th esis of th e Ta xa n e-Der ived An tica n cer Agen t
ABT-271
J ohn A. DeMattei,* M. Robert Leanna, Wenke Li, Paul J . Nichols,
Michael W. Rasmussen, and Howard E. Morton
Process Research, Pharmaceutical Products Division, Abbott Laboratories,
North Chicago, Illinois 60064-4000
jdemattei@arraybiopharma.com
Received November 3, 2000
ABT-271, 1, has been identified as a promising anticancer agent. ABT-271 is a novel taxane
possessing a C9-(R)-hydroxyl group as opposed to a C9-ketone which is present in Taxol and
Taxotere. To further evaluate ABT-271 as a potential anticancer agent, an efficient synthesis was
developed which allows the large scale synthesis of ABT-271. Ketalization of the 7,9-diol of 9-DHAB-
III, 2, allows selective removal of the C13-acetate with phenyllithium. The resulting C13-hydroxyl
group is then acylated using LiHMDS and â-lactam 22 to give ABT-271 in protected form. The
protecting groups were removed first by acidic hydrolysis followed by basic hydrolysis to provide
ABT-271. Application of this synthetic sequence provided over 600 g of ABT-271, 1.
In tr od u ction
biological properties of 1 we required an efficient syn-
thesis which would allow the production of multigram
quantities.
Taxol (paclitaxel) and Taxotere (docetaxel) are two
promising antitumor agents undergoing clinical trials for
the treatment of a variety of cancers.1 Taxol has been
approved for the treatment of ovarian, breast, and lung
cancer and in 1998 it had sales of $1.2 billion.2 Although
Taxol is currently the agent of choice for the treatment
of these tumors, it suffers from low water solubility which
causes problems for the formulation and the administra-
tion of the drug.3 Taxol analogues with greater water
solubility, better tolerability, and less prone to resistance
would be of significant benefit for the treatment of solid
tumors.
The plan for the synthesis was to begin with the
commercially available 9-DHAB-III, 2.6 The overall re-
quired transformations were the removal of the C-10 and
C-13 acetates and selective acylation of the C-13 hydroxyl
with the desired side chain. These chemical transforma-
tions are not straightforward and require the develop-
ment of an efficient strategy. Initial efforts followed the
route published by Klein et al. attempting to selectively
remove the C-13 acetate of 2.7
In 1992 a new taxane, 13-acetyl-9(R)-dihydrobaccatin
III (9-DHAB-III, A-83793), 2, was isolated from the
Canadian bush Taxus canadensis.4 The significant dif-
ference between this taxane and the previously isolated
taxanes is at the C-9 position. The previously isolated
taxanes possess a carbonyl at C-9 whereas the newly
isolated taxane possesses an R-hydroxyl group at C-9.
This novel baccatin compound provides a new template
for the preparation of analogues with potentially greater
therapeutic benefits. One such compound under study
is ABT-271, 1.5 In our effort to further explore the
Resu lts a n d Discu ssion
Methyllithium was identified as the reagent which
gave the highest yield and selectivity, 64% yield for 3
after chromatography (eq 1).7 Invariably these optimized
conditions were accompanied by C-10 deacylated byprod-
ucts. Of particular concern was the observation that these
(1) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem. 1994, 106,
38-67; Angew. Chem., Int. Ed. Engl. 1994, 33, 15-44.
(2) (a) Future Oncol. 1999, 5, 1025-1039. (b) Future Oncol. 1997,
4, 614-620.
(3) (a) Weiss, R. B.; Donehower, R. C.; Wiernik, P. H.; Ohnuma, T.;
Gralla, R. J .; Trump, D. L.; Baker, J . R.; Van Echo, D. A.; Von Hoff, D.
D.; Leyland-J ones, B. J . Clin. Oncol. 1990, 8, 1263-1268. (b) Woodcock,
D. M.; J efferson, S.; Linsenmeyer, M. E.; Crowther, P. J .; Chojniowski,
G. M.; Williams, B.; Bertoncello, I. Cancer Res. 1990, 50, 4199-4203.
(c) 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.
(4) (a) Gunawardana, G. P.; Premachandran, U.; Burres, N. S.;
Whittern, D. N.; Henry, R.; Spanton, S.; McAlpine, J . B. J . Nat. Prod.
1992, 55, 1686-1689. (b) Zamir, L. O.; Nedea, M. E.; Belair, S.; Sauriol,
F.; Mamer, O.; J acqmain, E.; J ean, F. I.; Garneau, F. X. Tetrahedron
Lett. 1992, 33, 5173-5176. (c) Zhang, S.; Chen, W. M.; Chen, Y. H.
Acta Pharm. Sinica 1992, 27, 268-272.
(5) Gunawardana, G. P.; Klein, L. L.; McAlpine, J . B. US Patent
5,530,020, 1996; Gunawardana, G. P.; Klein, L. L.; McAlpine, J . B.
US Patent 5,352,806, 1994.
(6) Suppliers of 9-DHAB-III, 2, Atlantic Biochemical Research, Box
250, 1540 Plains Road, Building #397, Debert, N. S. Canada B0M 1G0;
L. D. Pharmaceutical, 277 Restigouche Road, Oromocto, N. B. Canada,
E2V 2H1.
(7) (a) Klein, L. L.; Li, L.; Maring, C. J .; Yeung, C. M.; Thomas, S.
A.; Grampovnik, D. J .; Plattner, J . J . J . Med. Chem. 1995, 38, 1482-
1492. (b) Klein, L. L.; Yeung, C. M.; Li, L.; Plattner, J . J . Tetrahedron
Lett. 1994, 35, 4707-4710. (c) Klein, L. L. Tetrahedron Lett. 1993, 34,
2047-2050.
10.1021/jo0057203 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/14/2001

Taxane-Derived Anticancer Agent ABT-271
J . Org. Chem., Vol. 66, No. 10, 2001 3331
Sch em e 1
Sch em e 2
On the basis of our results with the previously studied
substrates, our efforts focused on carbon nucleophiles for
C-13 deacylation of the 7,9-acetonide 8. From an exten-
sive study of organometallic reagents, the C-13 deacyla-
tion is optimally carried out by reacting acetonide 8 with
4.3 equiv of PhLi in THF at -60 °C, affording carbinol 9
in 92% yield. Presumably, the steric bulk of the phenyl-
lithium matched with the steric bulk of the 7,9-acetonide
results in enhanced selectivity for the C-13 acetate. It is
noteworthy that this combination yielded a reaction that
was tolerant of elongated addition times and extended
stir periods encountered upon scale-up. In addition to the
increased yield, the product of deacylation is readily
crystallized, allowing the removal of the phenyl contain-
ing byproducts of the reaction.9 Interestingly, phenyl-
lithium gave only a 50% yield for selective deacylation
at C-13 for compound 2. With the selective removal of
the C-13 acetate the baccatin core is poised for coupling
with an appropriately protected side chain precursor (eq
2).
byproducts increased with elongated addition times of the
methyllithium which would present a problem on scale-
up. The addition of Lewis acids, variation of the solvent,
and lowering the reaction temperature to -100 °C did
not provide any significant benefit. Efforts to increase
the efficiency of this conversion required the exploration
of alternative protecting group strategies for the baccatin
core.
The C-10 acetate of 2 could selectively be removed with
hydrazine in ethanol giving 4 in a 76% yield after
crystallization (Scheme 1). The C-7 and C-10 hydroxyl
groups of 4 were selectively protected as their TES ethers,
but unfortunately, the bis-TES ether 5 was not stable to
the basic conditions necessary for the removal of the
acetate at C-13. Alternatively, the C-13 acetate of 4 was
removed with MeLi (10 equiv) to give 6 in 75% yield.
However, due to difficulties in efficient purification of 6
and poor solubility characteristics of 7 our efforts turned
to a more robust approach (Scheme 2).
Protection of 2 as the 7,9-acetonide prevents the acidic
protons of the C-7 and C-9 hydroxyl groups from reacting
with the basic reagents being examined for the selective
deacylation of C-13 (Scheme 2). Several conditions proved
successful for the formation of the 7,9-acetonide 8, but
conditions employing Montmorillonite K10 and 2,2-
dimethoxypropane in CH3CN gave the highest yielding
and most direct procedure.8 The crude product is isolated
by filtration to remove the Montmorillonite K10 and
concentration of the filtrate. The acetonide 8 proved to
be crystalline, allowing its isolation and purification if
necessary, but it is typically used crude in the next step.
The 7,9-acetonide 8 was then examined for selectivity in
the deacylation at C-13.
An efficient synthesis of the requisite isobutyl isoserine
side chain was achieved by taking advantage of the
similar structure found in N-Boc-L-leucinol 10.10 N-Boc-
L-Leucinal 11 was prepared via a TEMPO-mediated
oxidation of N-Boc-L-leucinol 10 (Scheme 3). The TEMPO
oxidation avoids the unpleasant coproduction of dimethyl
sulfide in the Swern oxidation and the requirement of
(9) (a) Investigation of other organometallics, reducing agents, amide
bases, alkoxide bases, and hydroxide proved to be less selective and
lower yielding. (b) The reaction will tolerate up to 90 mol % water with
the only consequence that more phenyllithium is required to drive the
reaction to completion. (c) The reaction may be run as warm as -40
°C without consequence.
(8) The acidity of the Montmorillonite K10 varied from lot to lot.
For efficient acetonide formation, the pH of an aqueous suspension of
the Montmorillonite K10 should be between pH 3 and pH 3.5. When
the pH is above pH 3.5 the reaction is sluggish and does not go to
completion.
(10) Leanna, M. R.; DeMattei, J . A.; Li, W.; Nichols, P. J .; Rasmus-
sen, M.; Morton, H. E. Org. Lett. 2000, 2, 3627-3630.

3332 J . Org. Chem., Vol. 66, No. 10, 2001
DeMattei et al.
Sch em e 3
Sch em e 5
Sch em e 6
esters of the unreacted alcohols (∼1.8:1 anti/syn). The
reaction mixture was then washed with aqueous NaHCO3
to remove the undesired succinate esters 15. The desired
oxazolidine 14 is isolated as an oil in 91% yield (based
on the amount of 12 in the starting material mixture)
and 99% purity.13
Sch em e 4
The vinyl oxazolidine 14 was oxidized to the corre-
sponding carboxylic acid with catalytic RuO2 and NaIO4
as the oxidant in a 1:1 ratio of acetone:water using
modified Sharpless conditions (Scheme 5).14 The active
catalyst, RuO4, is generated by mixing RuO2‚xH2O (7 mol
%) and NaIO4 (33 mol %) prior to adding the acetone/
olefin mixture to minimize an exotherm that occurrs in
this oxidation. Control of this exotherm was necessary
for the reaction to be safely conducted on large scale. An
aqueous solution of the oxidant (6.2 equiv of NaIO4) was
then added to the olefin and catalyst over 3 h at 15 °C.
Following an alcohol quench, an extractive base/acid
purification gave the desired acid 16 in 85% yield with
98% purity.15
Following the approach of Commercon et al., the
oxazolidine acid 16 was coupled to the baccatin core 9
with DCC and DMAP in EtOAc at 45 °C in 2 h to provide
the coupled product 17 in 92% yield after chromatogra-
phy (Scheme 6).16 Interestingly this acylation is faster,
and it is conducted at a lower temperature than other
couplings with baccatin III that have been reported in
the literature.16,17 Unfortunately, attempts to remove the
2′,3′-N,O-acetal resulted in competitive decomposition of
the baccatin core as well as hydrolysis of the N-tert-butyl
carbamate. Because of the difficulty in removing the N,O-
ketal a more labile 2′ protecting group was necessary.
The Holton/Ojima â-lactam coupling method allows a
direct method of coupling and obviates the need for
additional protecting groups.18 The requisite â-lactam
cryogenic conditions. Furthermore, it affords the alde-
hyde in superior chemical yield and stereochemical
purity.11 After an aqueous workup, the CH2Cl2 solution
of the aldehyde 11 was added to 3.5 equiv of vinylmag-
nesium chloride in THF at 10 °C. The product was
isolated by crystallization giving the desired syn-amino
alcohol 12 in 56% yield (from 10) contaminated with 9%
of the epimeric anti-alcohol 13 (from 10).12
Removal of the undesired C-2 epimer 13 was ac-
complished via a kinetically controlled ketalization
(Scheme 4). The syn diasteromer 12 readily cyclizes in
CH2Cl2 at -20 °C with cat. pTSA to form the desired
trans-oxazolidine 14, whereas the anti-diastereomer 13
proceeds to the sterically congested cis-oxazolidine very
slowly. The reaction was quenched by addition of tri-
ethylamine and succinic anhydride to form the succinate
(13) Purity determined by HPLC analysis relative to a pure stan-
dard.
(14) (a) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K.
B. J . Org. Chem. 1981, 46, 3936. (b) Weber, A. E.; Halgren, T. A.; Doyle,
J . J .; Lynch, R. J .; Siegl, P. K. S.; Parsons, W. H.; Greenlee, W. J .;
Patchett, A. A. J . Med. Chem. 1991, 34, 2692-2701.
(15) The acid 16 could be further purified by preparation of the
dicyclohexylamine (DCHA) salt in acetonitrile.
(11) Leanna, M. R.; Sowin, T. J .; Morton, H. E. Tetrahedron Lett.
1992, 33, 5029-5032. The aldehyde 11 was reduced to the primary
alcohol with LAH and acylated with DNBCl. The DNB ester was
analyzed by chiral HPLC, >95% ee (see Supporting Information).
(12) By conducting the reaction in CH2Cl2, the crude ratio of 12:13
(prior to crystallization) is lowered to 3:1 as opposed to 4.5:1 for 1.2:1
CH2Cl2:THF. When the reaction temperature was lowered to -10 °C
for the 1.2:1 CH2Cl2:THF conditions, the crude ratio of 12:13 was
lowered to 2.8:1.
(16) Commercon, A.; Bezard, D.; Bernard, F.; Bourzat, J . D. Tetra-
hedron Lett. 1992, 33, 5185-5188.
(17) Denis, J .-N.; Greene, A. E.; Guenard, D.; Gueritte-Voegelein,
F.; Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
(18) (a) Holton, R. A. US Patent 5,539,103, 1996. (b) Ojima, I.; Sun,
C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kudud, S. Tetrahedron Lett.
1993, 34, 4149-4152. (c) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park,
Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.

Taxane-Derived Anticancer Agent ABT-271
J . Org. Chem., Vol. 66, No. 10, 2001 3333
Sch em e 7
ing that the purity of the â-lactam 22 is 72%22a and the
purity of 9 is only 86%.22b
Sch em e 8
The product of the side chain coupling provides ABT-
271 in protected form. A two-step deprotection of the
triethylsilyl group, the acetonide, and the C10 acetate is
required to yield ABT-271. First the triethylsilyl group
and the acetonide were removed under acidic conditions
to give the penultimate compound 24 which was hydro-
lyzed under basic conditions to give 1, ABT-271 (Scheme
9). Careful attention must be given to these final two
deprotections because of the lability of the oxetane ring,
the lability of the newly incorporated side chain, the
presence of an acetate and a benzoate, and the presence
of a tertiary alcohol at C-1 which is prone to ionization
leading to skeletal rearrangements. The acid-catalyzed
deprotection was achieved using 0.1 N HCl in methanol
at 40 °C for 13 h. The penultimate compound was isolated
by extractive workup to give a 90% yield for the acid
hydrolysis. The remaining 10% was comprised of several
impurities, but no impurity exceeded 2%. Other acids,
solvents, and concentrations were examined, but the
described conditions gave the best results. The penulti-
mate 24 could not be crystallized and was used crude in
the final step.
The penultimate compound 24 was hydrolyzed with 0.1
N KOH in methanol at -10 °C for 9 h to provide 1, ABT-
271. It was critical to use 0.5 equiv of 0.1 N KOH and
maintain the reaction temperature below -10 °C to
minimize the amount of side chain hydrolysis while
maintaining an acceptable rate of hydrolysis. The product
was isolated by crystallization from acetone/hexane in
86% yield (93% yield of crude product with a purity of
93%).23 The major impurity is the C13-OH compound 25
which is formed in 3-5% during the base hydrolysis. The
crystalline product is an acetone solvate and was deter-
mined not to be the most stable crystal form.24 When this
acetone solvate was slurried in 10% EtOH in H2O and
warmed to 45 °C it underwent a change in crystal form
was prepared by treating the trans-oxazolidine acid 16
with 1.2 equiv of methanesulfonic acid in refluxing IPA
followed by the addition of H2O to provide the isopropyl
ester 18 in 96% yield (Scheme 7). Although this solvolysis
works very well using a variety of alcohols, the isopropyl
ester was chosen because of its ease of extraction from
water mixtures and for its stability. Preparation of
straight-chain esters invariably afforded mixtures of
dimeric byproducts.
Preparation of the bis-silyl lactam 20 was accomplished
by in situ formation of the bis-triethylsilyl intermediate
19 followed by the addition of 4 equiv of tert-butylmag-
nesium chloride.19 Selective mono-hydrolysis of the N,O-
triethylsilyl lactam to the required O-triethylsilyl lactam
was achieved with 15:1 ethyl acetate:0.7% KF (0.06
equiv) solution in EtOH at -15 °C. The â-lactam nitrogen
was then protected as the tert-butyl carbamate in 91%
overall yield from 18. This protection of nitrogen also
activates the â-lactam for acylation of the baccatin core.
Acylation using the â-lactam strategy requires the
generation of a metal alkoxide at C-13 which opens the
â-lactam, providing the appropriately protected coupled
side chain. This was accomplished by adding lithium bis-
(trimethylsilyl)amide to a mixture of 9 and 22 in THF at
-40 °C which provided the coupled product 23 (Scheme
8). This approach is procedurally very simple, and the
desired product 23 is isolated by crystallization in 95%
yield with a purity of 97%.20,21 The high purity that is
obtained from this crystallization is remarkable consider-
(22) (a) The â-lactam 22 is contaminated with 23% ethoxytriethyl-
silane. (b) The crystalline alcohol 9 is contaminated with 1,1-diphe-
nylethanol and other phenyl impurities from the phenyllithium
addition reaction.
(23) Purity determined by HPLC analysis relative to a pure stan-
dard.
(24) X-ray diffraction studies were conducted by Geoff G. Z. Zhang
Ph.D., Research Scientist, Pharmaceutical Products Division and J ohn
Quick, Research Investigator, Pharmaceutical Analytical Research
Division, Abbott Laboratories.
(19) Lynch, J . K.; Holladay, M. W.; Ryther, K. B.; Bai, H.; Hsiao,
C.-N.; Morton, H. E.; Dickman, D. A.; Arnold, W.; King, S. A.
Tetrahedron: Asymmetry 1998, 9, 2791-2794.
(20) The reaction functions equally well at -25 °C, and the reaction
will tolerate water levels up to 60 mol %.
(21) Purity determined by HPLC analysis relative to a pure stan-
dard.

3334 J . Org. Chem., Vol. 66, No. 10, 2001
DeMattei et al.
Sch em e 9
as determined by X-ray diffraction.24 This crystal form
conversion removes the side chain hydrolysis impurity
25 giving a 97% recovery of 1, ABT-271, in a purity of
>99%.
61.37; H, 9.83; N, 6.51. Found: C, 61.16; H, 9.77; N, 6.43. The
ee of 11 was determined; see below in supplementary ad-
dendum.
To a solution of vinylmagnesium chloride in THF (17.5 wt
%, 13.8 kg, 27.9 mol) was added CH2Cl2 (18.8 kg). The resulting
solution was cooled to 10 °C and treated with N-Boc-L-leucinal
11/CH2Cl2 (3.80 kg) while maintaining an internal tempera-
ture <30 °C. The reaction was stirred for 25 min, poured into
a stirring solution of 15% NH4Cl (51.9 kg), and diluted with
MTBE (25.6 kg). Layers were separated, and the organic layer
was washed with brine (26.9 kg). The organic layer was
concentrated to approximately 6 L, whereupon heptane 20 kg
was added and concentrated to 3.65 kg, cooled to -20 °C
(overnight), filtered, and washed with cold heptane (1.2 kg)
to afford 1.48 kg of off-white solid as a mixture of 12 (1.28 kg
assay 58% overall) and the undesired isomer 13 (0.20 kg,
9.0%). (3S,4S)-4-[(ter t-Bu tyloxyca r bon yl)a m in o]-6-m eth -
yl-1-h ep ten -3-ol (12). TLC: 2:1 heptane:EtOAc; Rf ) 0.42;
Con clu sion
The potential anticancer agent ABT-271, 1, was ef-
ficiently prepared beginning with the commercially avail-
able 9-DHAB-III, 2. Protection of the 7,9-diol of 2 as the
acetonide allows the selective removal of the C-13 acetate.
The resulting C-13 hydroxyl group was acylated with the
â-lactam 22 to incorporate the desired side chain. The
â-lacam 22 was prepared from N-Boc-L-leucinol in eight
steps and 40% overall yield. Coupling of the baccatin core
with the side chain provides ABT-271, 1, in protected
form. Deprotection is accomplished by acidic hydrolysis
followed by basic hydrolysis to reveal ABT-271, 1. Final
purification is achieved by heating in 10% EtOH in H2O
which also converts ABT-271 to its most stable crystal
form. This optimzed synthesis provides ABT-271 in five
steps and 67% overall yield (54% with no chromato-
graphic purifications) from 9-DHAB-III, 2. The efficiency
of this synthesis allowed the preparation of over 600 g
of ABT-271, 1.
[R]25 -54.8° (C ) 0.81, CDCl3); IR (neat) 3383, 2955, 2868,
D
1688, 1506, 1367, 1169, 919 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 5.89 (ddd, J ) 17.3, 10.7, 5.9 Hz, 1H), 5.29 (ddd, J ) 17.3,
1.5, 1.5 Hz, 1 H), 5.18 (ddd, J ) 10.7, 1.5, 1.5 Hz, 1H), 4.68 (br
d, 1H), 4.06 (br s, 1H), 3.66 (br m, 1H), 2.60 (br s, 1H), 1.68
(hept, J ) 6.6 Hz, 1H), 1.43 (s, 9H), 1.71-1.35 (m, 2H), 0.92
(d, J ) 6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz) δ 156.3, 138.2,
116.1, 75.1, 52.9, 40.7, 28.3, 24.8, 23.3, 21.9; MS C13H25NO3
m/z 243, DCI/NH3+ [M + 1] 244, ESI+ [M + 1] 244, ESI- [M -
1] 242. Anal. Calcd for C13H25NO3: C, 64.16; H, 10.36; N, 5.76
Found: C, 64.00; H, 10.25; N, 5.65.
For the determination of the ee% of 12, see the Supporting
Information . Optical rotation of 12 is larger in magnitude to
previously published report by Franciotti et al. (Tetrahedron
Lett. 1991, 32, 6783-6786) where [R]25D -27° (c ) 0.8, CDCl3).
Exp er im en ta l Section
(3S,4S)-4-[(ter t-Bu tyloxyca r bon yl)a m in o]-6-m eth yl-1-
h ep ten -3-ol (12). To a solution of N-Boc-L-leucinol, 10 (2.00
kg, 9.126 mol), and 2,2,6,6-tetramethyl-1-piperidinyloxy free
radical (14.5 g, 92.7 mmol) in CH2Cl2 (36.6 kg) and H2O (5.54
kg) at 0 °C were added 7% NaHCO3 solution (28.9 kg) and
12.6% NaOCl solution (6.62 kg) over 2 h with vigorous stirring.
The biphasic mixture was stirred for 20 min, and then the
layers were separated. The organic layer was washed sequen-
tially with 10% NaHSO4 solution (25.7 kg) containing NaI (151
g), 10% Na2S2O3 (28.7 kg), 7% NaHCO3 (28.5 kg), and brine
(21.7 kg). The organic layer was dried over Na2SO4, filtered,
and concentrated to 3.80 kg of 11 in CH2Cl2 (a small portion
(3R,4S)-4-[(ter t-Bu tyloxyca r bon yl)a m in o]-6-m eth yl-1-
h ep ten -3-ol (13). TLC: 2:1 heptane:EtOAc; Rf ) 0.33; [R]25
D
-41.3 (c 1.01, CHCl3); IR (neat) 3358, 2949, 1682, 1527 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 5.82 (ddd, J ) 17.3, 10.6, 5.5
Hz, 1H), 5.31 (ddd, J ) 17.3, 1.5,1.5 Hz, 1 H), 5.21 (ddd, J )
10.6, 1.5, 1.5 Hz, 1H), 4.53-4.58 (br m, 1H), 4.17 (br s, 1H),
3.85-3.74 (br m, 1H), 3.14 (br s, 1H), 1.70-1.60 (m, 1H), 1.43
(s, 9H), 1.27-1.21 (m, 2H), 0.91 (d, J ) 5.5 Hz, 3H), 0.89 (d, J
) 5.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 156.8, 136.7, 116.5,
75.9, 53.5, 39.1, 28.3, 24.7, 23.4, 21.7; MS (APCI+) C13H25NO3
m/z 243 (relative intensity), 244 (M + 1, 85) 244, (100) 188,
(47) 170, 144 (90). Anal. Calcd for C13H25NO3: C, 64.16; H,
10.36; N, 5.76. Found: C, 63.91; H, 10.36; N, 5.85.
was concentrated to dryness for characterization [R]25 -32.4
D
(c 1.0, MeOH); IR (neat) 3346, 2955, 1731, 1713, 1694, 1515,
1363, 1249, 1166, 1054, 1017 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 9.43 (s, 1H), 7.22 (d, J ) 7.8 Hz, 1H), 3.86 (ddd, J ) 11.0, J
) 7.8, J ) 4.7 Hz, 1H), 1.65 (sept., J ) 6.8 Hz, 1H), 1.34-1.48
(m, 2H), 1.39 (s, 9H), 0.89 (d, J ) 6.8 Hz, 3H), 0.86 (d, J ) 6.8
Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 202.0, 155.7, 78.2, 57.8,
36.5, 28.1, 24.0, 22.9, 21.3. Anal. Calcd for C11H21NO3: C,
(4S,5S)-3-(ter t-Bu tyloxyca r bon yl)-2,2-d im eth yl-5-eth e-
n yl-4-(2-m eth ylp r op yl)oxa zolid in e (14). To a solution of
allylic alcohols 12 and 13 (20.5 g, 84.4 mmol, 12:13, 6:1; assay
for 12, 17.6 g, 72.3 mmol) in CH2Cl2 (200 mL) was added pTSA
(0.64 g, 3.4 mmol). The resulting mixture was cooled to -20

Taxane-Derived Anticancer Agent ABT-271
J . Org. Chem., Vol. 66, No. 10, 2001 3335
°C, and then 2,2-dimethoxypropane (35.4 g, 340 mmol) was
added. The reaction was stirred at -20 °C for 4 h. While
maintaining temperature at -20 °C, Et3N (30.4 g, 300 mmol),
succinic anhydride (25.1 g, 251 mmol), and DMAP (15.8 g, 129
mmol) were added to the reaction mixture. The reaction was
then allowed to warm to ambient temperature. The reaction
was quenched with MeOH (10.8 mL) and stirred for 30 min.
The volatiles were removed by concentration and then diluted
with heptane (210 mL), MTBE (55 mL), and a 5% NaH2PO4
solution (500 mL). The layers were separated, and the organic
layer was washed with a mixture of 5% NaHCO3 solution (450
mL) and methanol (75 mL). The layers were separated, and
the remaining organic layer was washed with brine (50 mL).
The organic layer was dried over Na2SO4, filtered, and
concentrated to give 14 (18.6 g, 91% yield based on starting
alcohol 12) as a viscous oil. TLC: 2:1 heptane:EtOAc; 14, Rf
J ) 6.6 Hz, 1H), 1.46 (t, J ) 7.0 Hz, 2H), 1.37 (s, 3H), 1.35 (s,
3H), 1.02 (d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 6.6 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) δ 175.3, 75.1, 70.8, 52.9, 44.9, 26.1,
24.5, 23.5, 23.2; MS (APCI+) C10H21NO5 m/z 245 (M + 42, 32)
204 (M + 1, 100). Anal. Calcd for C10H21 NO5: C, 59.08; H,
10.41; N, 6.89. Found: C, 58.70; H, 10.32; N, 6.80.
(3R,4S)-Bis-N,O-tr ieth ylsilyl-4-(2-m eth ylp r op yl)-3-h y-
d r oxy-a zetid in -2-on e (20). To a solution of isopropyl (2R,3S)-
3-amino-2-hydroxy-5-methylhexanoate (5) (10.0 g, 49.3 mmol)
in MTBE (200 mL) was added NEt3 (13.3 g, 131 mmol). The
mixture then was cooled to 0 °C and treated with TESCl (17.1
g, 113 mmol). The resulting white slurry was stirred at 23 °C
for 1.5 h. The mixture was cooled to 0 °C and treated dropwise
with tert-butylmagnesium chloride (197 mL, 1 M solution in
THF, 197 mmol). The reaction was stirred at 23 °C for 1 h
during which it became thick slurry. The reaction mixture was
poured into 15% NH4Cl solution (735 mL) and diluted with
MTBE (375 mL). The layers were separated, and the organic
layer was washed with brine (212 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated to afford the
crude bis-TES lactam 20 as a brown oil (23.4 g, 78% pure by
HPLC which indicates 18.3 g, 49.3 mmol). The crude 20 was
used directly in the next step. TLC: EtOAc/hexane (1:4), Rf )
0.82; [R]25D +83.14 (c 1.002, CHCl3); IR (neat) 2956, 1749, 1194,
) 0.56; [R]25 +17.8 (c 0.609, MeOH); IR (neat) 2950, 1702,
D
1460, 1385, 1178 cm-1; H NMR (DMSO-d6, 300 MHz) δ 5.97
1
(ddd, J ) 17.3, 10.3, 7.4 Hz, 1H), 5.32 (dt, J ) 17.3, 1.1 Hz,
1H), 5.19 (dt, J ) 10.3, 1.1 Hz, 1H), 4.29 (dd, J ) 7.4, 3.6 Hz,
1H), 3.66 (br d, J ) 8.5 Hz, 1H), 1.68-1.53 (m, 2H), 1.50 (s,
3H), 1.42 (s, 3H), 1.41 (s, 9H), 1.40-1.35 (m, 1H), 0.88 (dd, J
) 9.7, 6.1 Hz, 6H); 13C NMR (DMSO-d6, 75 MHz) δ 150.8,
138.8, 117.2, 93.7, 81.2, 79.3, 59.8, 28.3, 27.5, 24.8, 23.9, 21.4;
MS (APCI+) C16H29NO3 m/z (relative intensity) 284 (M + 1,
11), 184 (100). Anal. Calcd for C16H29NO3: C, 67.90; H, 10.33;
N, 4.95. Found: C, 67.66; H, 10.33; N, 4.83.
1
1017 cm-1; H NMR (CDCl3, 300 MHz) δ 4.82 (d, J ) 5.1 Hz,
1H), 3.62 (ddd, J ) 10.5, 5.3, 3.3 Hz, 1 H), 1.77 (ddd, J ) 13.2,
10.2, 4.5 Hz, 1H), 1.67-1.57 (m, 1H), 1.28 (ddd, J ) 13.2, 9.0,
3.0 Hz, 1H), 0.98-0.91 (m, 18 H), 0.90 (d, J ) 6.6 Hz, 3H),
0.88 (d, J ) 6.6 Hz, 3H), 0.76-0.61 (m, 12 H); 13C NMR (CDCl3,
75 MHz) δ 176.8, 79.0, 57.1, 41.8, 27.2, 25.6, 23.9, 8.64, 8.56,
6.7, 5.6; MS (ESI+) C19H41NO2Si2 m/z (relative intensity) 372
(MH+, 100), 342 (5). Anal. Calcd for C19H41NO2Si2: C, 61.39,
H, 11.12. Found: C, 61.27, H, 11.28.
(4S,5R)-3-(ter t-Bu t yloxyca r b on yl)-2,2-d im et h yl-4-(2-
m eth ylp r op yl)oxa zolid in e-5-ca r boxylic Acid (16). To a
suspension of RuO2‚xH2O (0.42 g, 3.1 mmol), acetone (17 mL),
and water (17 mL) at 0 °C was added NaIO4 (2.90 g, 13.6
mmol) in H2O (20 mL). After 5 min the vinyl oxazolidine 14
(12.0 g, 41.6 mmol) in acetone (375 mL) was added. Next,
NaIO4 (55.2 g, 256 mmol) in H2O (355 mL) was added dropwise
over 3 h, keeping the temperature below 15 °C. After 1 h of
additional stirring, the reaction was cautiously quenched with
2-propanol (21 mL) and stirred for 30 min while the reaction
warmed to ambient temperature. The reaction was then
filtered though Celite and the resulting filter cake washed with
a 1:1 acetone:water solution (300 mL). NaCl (20 g, 342 mmol)
was added to the combined filtrates and then extracted with
MTBE (500 mL). The organic extract was washed with a 1:1
mixture of 1 M NaHSO4 and 1 M NaHSO3 (190 mL total). The
organic layer was then extracted with 0.5 M K2CO3 aq solution
(380 mL). The alkaline aqueous layer was pH adjusted to pH
5 with portionwise addition of a concentrated citric acid
solution (47 g in 100 mL of H2O). The acidic aqueous layer
was extracted with MTBE (360 mL), and the organic layer was
washed with brine (90 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated to give 16 (10.6 g, 85%).
(3R,4S)-3-Tr ieth ylsilyloxy-4-(2-m eth ylp r op yl)a zetid in -
2-on e (21). To a solution of crude bis-TES lactam 20 (23.4 g
crude at 78% purity gives 18.3 g, 49.3 mmol) in EtOAc (250
mL) at -10 °C was added 0.7% KF in EtOH (16 mL), and then
the reaction mixture was stirred at -10 °C for 4 h. The reaction
mixture was diluted with 2% NaCl solution (100 mL), and the
layers were separated. The organic layer was diluted with
hexane (130 mL) and washed sequentially with 5% NaH2PO4
(50 mL), 7% NaHCO3 (50 mL), and brine (50 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated to
afford 21.0 g of the crude mono-TES lactam 21 (21.0 g, 60%
pure by HPLC which indicates 12.7 g, 49.3 mmol). The crude
21 was used directly in the next step. TLC EtOAc/hexane (1:
4), Rf ) 0.15; [R]25 +33.60 (c 1.093, CHCl3); IR (neat) 3228,
D
2957, 1760, 1182 cm-1; 1H NMR (CDCl3, 300 MHz) δ 6.77 (bs,
1H), 4.81 (dd, J ) 4.8, 2.7 Hz, 1H), 3.71 (ddd, J ) 7.6, 5.7, 5.0
Hz, 1H), 1.70-1.57 (m, 1H), 1.37-1.34 (m, 2H), 0.95 (t, J )
7.8 Hz, 9H), 0.92 (d, J ) 6.3 Hz, 3H), 0.89 (d, J ) 6.6 Hz, 3H),
0.68-0.59 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ 170.3, 77.2,
54.1, 38.7, 25.3, 23.0, 22.3, 6.5, 4.6; MS (ESI-) C13H27NO2Si
m/z (relative intensity) 256 (M+ - H, 100). Anal. Calcd for
TLC: 2:1 heptane:EtOAc; Rf ) 0. 12; mp 91-93.5 °C, [R]25
D
-7.4 (c 1.061, CHCl3); IR (neat) 3500 (br), 1704, 1381 cm-1
;
1H NMR (DMSO-d6, 300 MHz) δ 13.0 (br s, 1H), 4.35 (d, J )
1.5 Hz, 1H), 4.22-4.06 (br m, 1H), 1.80-1.55 (m, 2H), 1.51 (s,
3H), 1.47 (s, 3H), 1.41 (s, 9H), 1.40-1.32 (m, 1H), 0.96 (d, J )
6.7 Hz, 6H); 13C NMR (DMSO-d6, 75 MHz) δ 172.9, 150.3, 94.8,
79.2, 77.9, 58.2, 43.4, 28.1, 25.9, 25.0, 23.6, 21.1; MS (ESI-)
C
13H27NO2Si: C, 60.65, H, 10.57. Found: C, 60.45, H, 10.59.
(3R,4S)-1-(ter t-Bu tyloxyca r bon yl)-3-tr ieth ylsilyloxy-4-
(2-m eth ylp r op yl)a zetid in -2-on e (22). To a solution of mono-
TES lactam 21 (21.0 g, 60% pure by HPLC indicates 12.7 g,
49.3 mmol) in CH2Cl2 (80 mL) at 23 °C were added NEt3 (14.6
g, 144 mmol), a solution of di-tert-butyl dicarbonate (16.1 g,
73.9 mmol) in CH2Cl2 (15 mL), and DMAP (3.31 g, 27.1 mmol).
The reaction mixture was stirred at 23 °C for 1.5 h. The
reaction was diluted with hexane (90 mL) and washed
sequentially with 5% NaH2PO4 (3 × 255 mL), 7% NaHCO3 (120
mL), and brine (180 mL). The organic layer was dried over
Na2SO4 and concentrated to give the crude Boc lactam 22 (22.0
g crude oil, 74% pure by HPLC indicates 16.3 g, 91% yield
over three steps). The major impurity (∼20 wt %) is the
byproduct ethoxytriethylsilane carried over from the previous
C
15H27NO5 m/z 301 (relative intensity) 301 (M, 15), 300 (M -
1, 100). Anal. Calcd for C15H27NO5: C, 59.77; H, 9.03; N, 4.65.
Found: C, 59.46; H, 8.99; N, 4.66.
Isop r op yl (2R,3S)-3-Am in o-2-h yd r oxy-5-m et h ylh ex-
a n oa te (18). To a solution of the oxazolidine acid 16 (16.0 g,
53 mmol) in 2-propanol (95 mL) was added MeSO3H (6.5 g,
68 mmol), and the resulting solution was heated to 73 °C for
4 h. The reaction was then cooled to ambient temperature and
stirred for 1 h. Water (27 mL) was added to the reaction, which
was stirred for an additional 3 h. The reaction mixture was
concentrated to a low volume and then diluted with isopropyl
acetate (350 mL). The isopropyl acetate solution was washed
with 2 M K2CO3 solution (45 mL). The organic extract was
dried over Na2SO4, filtered, and concentrated to give 18 (10.3
desilylation step. TLC EtOAc/hexane (1:4), Rf ) 0.67; [R]25
D
+79.19 (c 1.007, CHCl3); IR (neat) 2957, 1805, 1731, 1330 cm-1
;
g, 96%). mp 54.6-55.8 °C; [R]25 -13.6 (c 0.527, CHCl3); IR
1H NMR (CDCl3, 300 MHz) δ 4.83 (d, J ) 5.7 Hz, 1H), 4.05 (q,
J ) 6.1 Hz, 1H), 1.78-1.64 (m, 3H), 1.49 (s, 9H), 0.96 (t, J )
7.8 Hz, 9H), 0.94 (d, J ) 6.3 Hz, 3H), 0.93 (d, J ) 5.9 Hz, 3H),
0.70-0.62 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ 166.4, 148.4,
D
(neat) 3085 (br), 1731, 1592, 1462, 1378, 1208; 1H NMR (CDCl3,
300 MHz) δ 5.20 (hept, J ) 6.3 Hz, 1H), 4.07 (d, J ) 2.6 Hz,
1H), 3.22 (td, J ) 7.0, 2.6 Hz, 1H), 2.33 (br s, 3H), 1.81 (hept,

3336 J . Org. Chem., Vol. 66, No. 10, 2001
DeMattei et al.
83.1, 75.7, 57.0, 36.5, 28.3, 28.0, 25.1, 23.0, 6.5, 4.6; MS (ESI+)
C
Anal. Calcd for C18H35NO4Si: C, 60.46, H, 9.87. Found: C,
60.57, H, 10.10.
give 23 (20.6 g, 95%). TLC: 20% ethyl acetate in 80% hexane;
18H35NO4Si m/z (relative intensity) 375 (M+ + NH4, 100).
C13-OH, 9, Rf ) 0.3 and acylated product, 23, Rf ) 0.7; [R]25
D
-3.75 (c 1.02, MeOH); IR (KBr) 3447, 2958, 1738, 1715, 1496,
1368, 1245, 1168, 1111, 1016 cm-1 1H NMR (CD3OD, 400
;
9(R)-Dih yd r o-7,9-isop r op ylid en e-13-a cet ylb a cca t in -
III (8). To a suspension of 9-DHAB-III, 2 (14.6 g, 23.1 mmol),
in CH3CN (150 mL) and 2,2-dimethoxypropane (54 mL, 439
mmol) at 20 °C was added Montmorillonite K10 (2.92 g, 20 wt
%). After 5 h the reaction mixture was filtered through Celite
and rinsed with CH3CN (2 × 20 mL). The filtrate was
concentrated to give the desired product (13.96 g, 90% yield).
TLC: 15% acetone in 85% CH2Cl2; 9-DHAB-III, 2, Rf ) 0.2
MHz) δ 8.15 (d, J ) 8.0 Hz, 2H), 7.64 (t, J ) 7.6 Hz, 1H), 7.51
(t, J ) 8.0 Hz, 2H), 6.49 (d, J ) 10.8 Hz, 1H), 6.02 (t, J ) 8.0
Hz, 1H), 5.85 (d, J ) 6.0 Hz, 1H), 4.92 (d, J ) 8.8 Hz, 1H),
4.56 (d, J ) 10.8 Hz, 1H), 4.28-4.19 (m, 4H), 4.08 (ddd, J )
10.8, 3.2, 3.2 Hz, 1H), 3.14 (d, J ) 6.0 Hz, 1H), 2.48 (ddd, J )
15.6, J ) 8.2, J ) 8.2 Hz, 1H), 2.45-2.35 (m, 2H), 2.37 (s,
3H), 2.10 (s, 3H), 1.98 (s, 3H), 1.77 (s, 3H), 1.77-1.63 (m, 3H),
1.58 (s, 3H), 1.50 (s, 3H), 1.41 (s, 3H), 1.38 (s, 9H), 1.23-1.16
(m, 1H), 1.17 (s, 3H), 1.04 (t, J ) 8.0 Hz, 9H), 0.98 (d, J ) 3.6
and acetonide product, 8, Rf ) 0.85; [R]25 +11.14 (c 1.01,
D
MeOH); IR (KBr) 3476, 2991, 2942, 2878, 1712, 1372, 1249,
Hz, 3H), 0.97 (d, J ) 4.0 Hz, 3H), 0.70 (q, J ) 8.0 Hz, 6H); 13
C
1
1080, 1018, 711 cm-1; H NMR (CD3OD, 400 MHz) δ 8.12 (d,
NMR (CD3OD, 100 MHz) δ 174.5, 172.1, 171.6, 168.0, 158.3,
140.6, 136.0, 134.7, 131.7, 131.5, 129.8, 98.6, 85.4, 83.1, 80.5,
80.3, 78.7, 77.9, 76.1, 75.9, 74.8, 73.3, 69.7, 53.2, 45.6, 44.0,
42.1, 41.9, 36.4, 35.6, 31.9, 28.7, 27.7, 25.9, 25.1, 23.9, 23.5,
23.1, 22.0, 21.0, 14.9, 14.8, 7.1, 5.5; MS C52H79NO15Si m/z 985
J ) 7.2 Hz, 2H), 7.64 (t, J ) 7.2 Hz, 1H), 7.52 (t, J ) 8.0 Hz,
2H), 6.48 (d, J ) 10.8 Hz, 1H), 6.12 (t, J ) 8.4 Hz, 1H), 5.84
(d, J ) 6.4 Hz, 1H), 4.92 (d, J ) 7.6 Hz, 1H), 4.55 (d, J ) 11.2
Hz, 1H), 4.25 (t, J ) 8.4 Hz, 1H), 4.21 (s, 2H), 3.14 (d, J ) 6.4
Hz, 1H), 2.47 (ddd, J ) 14.0, J ) 8.4, J ) 8.4 Hz, 1H), 2.36-
2.20 (m, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.99 (d, J
) 1.2 Hz, 3H), 1.77 (s, 3H), 1.71 (ddd, J ) 15.0, J ) 8.8, J )
1.5 Hz, 1H), 1.57 (s, 3H), 1.51 (s, 3H), 1.41 (s, 3H), 1.16 (s,
3H); 13C NMR (CD3OD, 100 MHz) δ 172.6, 172.0, 171.9, 168.0,
136.0, 134.7, 131.6, 131.4, 129.9, 129.8, 98.6, 85.4, 83.0, 80.5,
78.7, 77.8, 75.9, 74.9, 71.2, 69.8, 45.7, 43.8, 42.0, 36.8, 35.6,
31.9, 27.6, 25.0, 23.0, 22.8, 21.2, 20.9, 14.9, 14.6; MS C36H46O12
m/z 670 APCI+ [M + 18] 688, APCI- [M + 35] 705, ESI+ [M +
18] 688, ESI- [M - 1] 669. Anal. Calcd for C36H46O12: C 64.46,
H 6.91, O 28.62. Found: C 64.32, H 7.12, O 28.41.
ESI+ [M + 1] 986, ESI- [M - 1] 984. Anal. Calcd for C52H79
NO15Si: C 63.33, H 8.07, N 1.42. Found: C 63.25, H 8.07.
-
13-[(2′R,3′S)-3′-(N-ter t-b u t oxyca r b on yl)a m in o-2′-h y-
dr oxy-5′-m eth ylh exan oate]-9(R)-dih ydr o-baccatin -III (24).
To a solution of the coupled product 23 (15.3 g, 15.5 mmol) in
MeOH (475 mL) was added 0.1 N HCl (155 mL, 15.5 mmol)
over 40 min, and the reaction was warmed to 40 °C. After 13
h the reaction was cooled and quenched into pH 7 buffer (300
mL) and MTBE (600 mL). The layers were separated, and the
organic layer was washed with 23% aqueous NaCl solution
(200 mL). The combined aqueous layers were extracted with
MTBE (100 mL). The combined organic layers were washed
with 23% aqueous NaCl solution (200 mL). The organic layer
was dried over Na2SO4, filtered, and concentrated to give the
desired product 24 (11.6 g, 90%). TLC: 70% ethyl acetate in
30% hexane; 23 Rf ) 0.6 and hydrolyzed product, 24, Rf ) 0.5;
[R]25D -11.5 (c 1.01, MeOH); IR (KBr) 3403, 2959, 1714, 1498,
9(R)-Dih yd r o-7,9-isop r op ylid en e-ba cca tin -III (9). A so-
lution of the acetonide 8 (14.9 g, 22.3 mmol) in THF (500 mL)
was cooled to -60 °C, and then 1.8 M PhLi (54.0 mL, 97.2
mmol) was added over a period of 1 h. The opaque yellow
solution was stirred an additional 15 min, and then the
reaction was quenched by adding the reaction mixture to 20
wt % NH4Cl (1 L). The layers were separated, and the aqueous
layer was extracted with i-PrOAc (2 × 200 mL). The layers
were separated, and the combined organic layers were washed
with 5% NaCl solution (1 L). The organic layer was dried over
Na2SO4, filtered, and concentrated. Analysis of the crude
product by HPLC indicated a yield of 92%. The product, 9,
was purified by crystallization from di-n-butyl ether (10.5 g,
75% yield). TLC: 40% ethyl acetate in 60% hexane; ac-
1369, 1249, 1167, 1070, 1048 cm-1 1H NMR (CD3OD, 400
;
MHz) δ 8.15 (d, J ) 8.0 Hz, 2H), 7.64 (t, J ) 7.2 Hz, 1H), 7.52
(t, J ) 7.6 Hz, 2H), 6.22 (d, J ) 11.2 Hz, 1H), 6.08 (t, J ) 8.4
Hz, 1H), 5.78 (d, J ) 6.0 Hz, 1H), 4.96 (d, J ) 8.4 Hz, 1H),
4.50 (d, J ) 10.8 Hz, 1H), 4.39 (dd, J ) 9.6, J ) 8.0 Hz, 1H),
4.24-4.07 (m, 4H), 3.07 (d, J ) 5.6 Hz, 1H), 2.47 (ddd, J )
15.6, J ) 8.4, J ) 8.4 Hz, 1H), 2.37 (d, J ) 10.5 Hz, 1H), 2.35
(s, 3H), 2.11 (s, 3H), 1.94 (s, 3H), 1.78 (s, 3H), 1.67 (s, 3H),
1.87-1.63 (m, 4H), 1.38 (s, 9H), 1.29-1.22 (m, 1H), 1.23 (s,
3H), 0.97 (d, J ) 6.8 Hz, 3H), 0.95 (d, J ) 6.4 Hz, 3H); 13C
NMR (CD3OD, 100 MHz) δ 175.4, 172.4, 171.7, 167.9, 158.3,
140.4, 136.9, 134.7, 131.5, 135.5, 129.8, 85.7, 83.4, 80.4, 78.8,
78.2, 77.7, 75.0, 74.9, 74.7, 74.5, 73.1, 52.8, 48.0, 45.8, 44.9,
41.8, 38.6, 36.3, 28.6, 28.5, 25.9, 23.8, 23.7, 23.4, 22.1, 21.1,
14.9, 13.1; MS C43H61NO15 m/z 831 ESI+ [M + 18] 849, ESI-
[M - 1] 830. Anal. Calcd for C43H61NO15: C 62.08, H 7.39, N
1.68. Found: C 62.07, H 7.20, N 1.61.
etonide,8, Rf ) 0.3 and de-acylated product,9, Rf ) 0.15; [R]25
D
+28.3 (c 1.05, MeOH); IR (KBr) 3499, 2998, 2944, 2894, 1734,
1718, 1376, 1247, 1072, 1018, 712 cm-1; 1H NMR (CD3OD, 400
MHz) δ 8.14 (d, J ) 8.0 Hz, 2H), 7.63 (t, J ) 7.6 Hz, 1H), 7.52
(t, J ) 8.0 Hz, 2H), 6.50 (d, J ) 10.8 Hz, 1H), 5.80 (d, J ) 6.4
Hz, 1H), 4.91 (d, J ) 8.4 Hz, 1H), 4.71 (t, J ) 8.4 Hz, 1H),
4.51 (d, J ) 11.2 Hz, 1H), 4.27 (t, J ) 8.8 Hz, 1H), 4.23-4.17
(m, 2H), 3.20 (d, J ) 6.4 Hz, 1H), 2.50-2.18 (m, 3H), 2.22 (s,
3H), 2.11 (d, J ) 1.2 Hz, 3H), 2.08 (s, 3H), 1.75 (s, 3H), 1.69
(ddd, J ) 15.0, 8.5, 1.5, 1H), 1.52 (s, 3H), 1.51 (s, 3H), 1.40 (s,
3H), 1.05 (s, 3H); 13C NMR (CD3OD, 100 MHz) δ 172.4, 172.1,
168.2, 145.7, 134.7, 133.9, 131.8, 131.4, 129.8, 98.5, 85.4, 82.7,
80.4, 79.1, 77.8, 76.0, 75.5, 69.8, 68.3, 46.0, 43.2, 41.9, 40.2,
35.6, 31.9, 27.9, 25.0, 22.9, 22.3, 21.1, 15.0, 14.8; MS C34H44O11
m/z 628 APCI+ [M + 1] 629, APCI- [M + 35] 663. Anal. Calcd
for C34H44O11: C 64.95, H 7.05, O 27.99. Found: C 64.85, H
7.09, O 27.66.
ABT-271 (1). To a solution of the penultimate 24 (12.9 g,
15.5 mmol) in MeOH (380 mL) at -10 °C was added 0.1 N
KOH (80.0 mL, 8.0 mmol). The temperature was kept below
-7 °C, and after 9.5 h the reaction was quenched by adding it
to a stirred solution of pH 7 buffer (200 mL), 27% aqueous
NaCl solution (200 mL), H2O (200 mL), and MTBE (200 mL).
The layers were separated and the aqueous layer was ex-
tracted with MTBE (2 × 50 mL). The combined organic layers
were washed with 27% aqueous NaCl solution (200 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated
to give the desired product 1. Analysis of the crude product
by HPLC indicated a yield of 11.6 g, 95%. The product was
purified by crystallization from acetone in hexane to give 1
(10.5 g, 86%). TLC: 10% MeOH in 90% CH2Cl2; 24 Rf ) 0.5
13-[(2′R,3′S)-3′-(N-ter t-bu toxyca r bon yl)a m in o-2′-tr ieth -
ylsilyloxy-5′-m e t h ylh e xa n oa t e ]-9(R )-d ih yd r o-7,9-iso-
p r oylid en e-ba cca tin -III (23). To a solution of 9 (13.8 g, 21.9
mmol) and the â-lactam 22 (10.2 g, 28.5 mmol) in THF (500
mL) at -40 °C was added 1.0 M LiHMDS in THF (48.3 mL,
48.3 mmol) over 1 h. The yellow solution was stirred an
additional 30 min, and then the reaction was quenched by
adding the reaction mixture to pH 7 buffer (1 L) and MTBE
(500 mL). The layers were separated the yellow organic layer
was washed with 23 wt % aqueous NaCl solution (500 mL).
The layers were separated, and the organic layer was dried
over Na2SO4, filtered, and concentrated. Analysis of the crude
product by HPLC indicated a yield of 21.4 g, 99%. The product
was purified by crystallization from 12% MTBE in hexane to
and 1, ABT-271 Rf ) 0.4; [R]25 -8.60 (c 0.997, MeOH); IR
D
(KBr) 3481, 2960, 2937, 2897, 2872, 1748, 1722, 1712, 1688,
1
1495, 1370, 1244, 1177, 1052, 980, 717 cm-1; H NMR (CD3-
OD, 400 MHz) δ 8.14 (d, J ) 8.0 Hz, 2H), 7.62 (t, J ) 7.7 Hz,
1H), 7.51 (t, J ) 7.7 Hz, 2H), 6.13 (t, J ) 10.0 Hz, 1H), 5.78
(d, J ) 5.8 Hz, 1H), 4.95 (d, J ) 8.9 Hz, 1H), 4.91 (d, J ) 10.4
Hz, 1H), 4.38 (d, J ) 10.4,1H), 4.32 (dd, J ) 9.7, J ) 7.6 Hz,
1H), 4.38 (d, J ) 10.0 Hz, 1H), 4.19 (d, J ) 3.5 Hz, 1H), 4.17

Taxane-Derived Anticancer Agent ABT-271
J . Org. Chem., Vol. 66, No. 10, 2001 3337
(d, J ) 10.0 Hz, 1H), 4.10 (ddd, J ) 12.0, J ) 4.5, J ) 3.5 Hz,
1H), 3.08 (d, J ) 5.8 Hz, 1H), 2.44 (ddd, J ) 14.5, J ) 9.0, J
) 9.0 Hz, 1H), 2.35 (d, J ) 10.0 Hz, 1H), 2.35 (s, 3H), 1.87-
1.63 (m, 4H), 1.84 (s, 3H), 1.76 (s, 3H), 1.68 (s, 3H), 1.39 (s,
9H), 1.29 (s, 3H), 1.26 (ddd, J ) 14.0, J ) 9.5, J ) 4.5 Hz,
1H), 0.98 (d, J ) 6.4 Hz, 3H), 0.96 (d, J ) 6.4 Hz, 3H); 13C
NMR (CD3OD, 100 MHz) δ 175.4, 171.7, 167.9, 158.3, 139.9,
137.7, 134.7, 131.6, 131.5, 129.7, 85.8, 83.5, 80.3, 79.7, 79.1,
77.8, 75.5, 74.9 (C7), 74.5, 73.4, 71.9, 52.8, 47.9, 45.4, 44.6,
41.8, 38.5, 36.4, 28.8, 28.6, 25.9, 23.8, 23.7, 23.4, 22.1, 14.7,
13.0; MS C41H59NO14 m/z 789 ESI+ [M + 1] 790, ESI- [M - 1]
788, APCI- [M + 35] 824. Anal. Calcd for C41H59NO14: C 62.34,
H 7.53, N 1.77. Found: C 62.27, H 7.36, N 1.73.
ABT-271, 1 (4.85 g, 97% recovery). New crystal form melting
point: 166 °C.
Ack n ow led gm en t. The authors thank Dr. Steven
Hollis, Ian Marsden, and Momir Cirovic for assistance
in obtaining NMR data. We also thank Dr. Geoff G. Z.
Zhang and J ohn Quick for X-ray diffraction analysis.
Su p p or tin g In for m a tion Ava ila ble: General methods
and experimental details for the enantiomeric assay of com-
1
pound 11 and 12, a list of IR absorbances, MS, H NMR, 13C
NMR, and elemental analysis for 23b and 23c. 1H NMR
spectra of compounds 1, 8, 9, 11-14, 16, 18, 20-23, 23b, 23c,
24 and 1H and 13C spectra for compound 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
Cr ysta lliza tion fr om Aqu eou s Eth a n ol. ABT-271, 1 (5.0
g, acetone crystalline solvate containing 3-5% 25), was
slurried in 10% EtOH in H2O (210 mL), and the slurry was
warmed to 45 °C. After 5 h the slurry was cooled to 23 °C,
and then the product was isolated by filtration to give pure
J O0057203