Synthesis of the C-13 side chain precursors of the 9-dihydrotaxane analogue ABT-271.

Article abstract of DOI:10.1021/ol006508o

N-Boc-L-Leucinol was converted to two C-13 side chain precursors of the 9-dihydrotaxane analogue ABT-271. The trans-oxazolidine acid 4 and the cis-Boc-lactam 2b were prepared in 44% and 40% overall yield, respectively, and with excellent (>98%) stereochemical purity.

Full text of DOI:10.1021/ol006508o

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3627-3630
Synthesis of the C-13 Side Chain
Precursors of the 9-Dihydrotaxane
Analogue ABT-271
M. Robert Leanna,* John A. DeMattei, Wenke Li, Paul J. Nichols,
Michael Rasmussen, and Howard E. Morton
Process Chemistry, D-45L/R8, Pharmaceutical Products DiVision, Abbott Laboratories,
1401 Sheridan Road, North Chicago, Illinois 60064-6285
rob.r.leanna@abbott.com
Received August 28, 2000
ABSTRACT
N-Boc-L-Leucinol was converted to two C-13 side chain precursors of the 9-dihydrotaxane analogue ABT-271. The trans-oxazolidine acid 4 and
the cis-Boc-lactam 2b were prepared in 44% and 40% overall yield, respectively, and with excellent (>98%) stereochemical purity.
The naturally occurring diterpene paclitaxel (Taxol) has
shown remarkable antitumor activity and is currently ap-
proved for the treatment of metastatic ovarian, breast, and
lung cancer.1 However, paclitaxel exhibits poor water
solubility and requires the use of a relatively toxic vehicle,
containing Cremophor EL, for administration.2 Identification
of new analogues with increased water solubility that
maintain potent antimicrotubular properties could potentially
obviate this excipient, leading to a better safety profile.
The isolation and characterization of 13-acetyl-9(R)-
dihydrobaccatin III (9-DHAB III) from a bush (Taxus
canadensis) common to the northeastern United States and
southern Quebec was reported in 1992 by several laborato-
ries.3 Extensive investigation of this 9-dihydrobaccatin core
has led to the identification of new paclitaxel analogues with
improved water solubility that maintain impressive antitumor
activity.4 From this study, ABT-271 was identified for further
evaluation.
Central to the preparation of ABT-271 (1) was the design
of a scalable stereoselective synthesis of the isoserine side
chain coupling precursors 2b and 4 and their efficient
(1) Taxol is the registered trademark of Bristol-Myers Squibb Company
for paclitaxel. (a) For a review, see: Nicolaou, K. C.; Dai, W.-M.; Guy, R.
K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15-44; (b) Future Oncol. 1997,
4, 614-620.
(4) Li, L.; Thomas, S. A.; Klein, L. L.; Yeung, C. M.; Maring, C. J.;
Grampovnik, D. J.; Lartey, P. A.; Plattner, J. J. J. Med. Chem. 1994, 37,
2655.
(5) (a) Holton, R. A. U.S. Patent 5,015,744, 1991. (b) Ojima, I.; Habus,
I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron
1992, 48, 6985-7012.
(6) (a) Commerc¸on, A.; Be´zard, D.; Benard, F.; Bourrzat, J. D.
Tetrahedron Lett. 1992, 33, 5185-5188. (b) Denis, J.-N.; Green, A. E.;
Guenard, D.; Gueritte-Voegelein, F.; Mangatal, L.; Potier, P. J. Am. Chem.
Soc. 1988, 110, 5917-5919.
(7) Boge, T. C.; Georg, G. I. EnantioselectiVe Synthesis of â-Amino Acids;
Juaristi, E., Ed.; Wiley-VCH: New York, 1997; pp 1-43.
(2) (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-Jones, B. J. Clin. Oncol. 1990, 8, 1263-1268. (b) Woodcock,
D. M.; Jefferson, S.; Linsenmeyer, M. E.; Crowther, P. J.; Chojniowski, G.
M.; Williams, B.; Bertoncello, I. Cancer Res. 1990, 50, 4199-4203.
(3) (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.; Jacqmain, E.; Jean, F. I.; Garneau, F. X. Tetrahedron Lett. 1992, 33,
5173-5176. (c) Zhang, S.; Chen, W. M.; Chen, Y. H. Yaoxue Xuebao 1992,
27, 268-272.
10.1021/ol006508o CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

conversion to ABT-271 utilizing two standard coupling
methods5,6 (Scheme 1). Herein, we report a scalable stereo-
carbon framework. N-Boc-L-leucinol 5 was oxidized to
N-Boc-L-leucinal 6 via a TEMPO-mediated oxidation (Scheme
2).10 This method afforded the aldehyde in superior chemical
Scheme 1. C13 Baccatin Coupling Methods
Scheme 2
selective synthesis of the isoserine side chain precursors of
ABT-271 on a kilogram scale.
purity in comparison to the Swern oxidation and without any
detectable racemization.11 After an aqueous workup, the
dichloromethane solution of the aldehyde was added to 2.5
equiv of vinylmagnesium chloride (1.9 M THF solution) at
room temperature to afford a 57% overall recystallized yield
of the desired syn-amino alcohol (chelation controlled)
contaminated with 9% of the epimeric anti-alcohol.12 It was
found that the crude epimeric mixture could be increased
from 3:1 to 4.5:1 by carrying out the reaction in CH2Cl2/
THF mixtures. Attempts to further increase selectivity by
carrying out the reaction at -10 instead of 30 °C actually
decreased the epimeric mixture from 4.5:1 to 2.8:1. Crystal-
lization of the crude reaction mixture from cold heptane (-20
°C) afforded a 57% overall recrystallized yield of the desired
syn diastereomer 7.13
Strategic protection of the alcohol as its N,O-acetonide
serves a dual purpose of protection of the alcohol during
oxidative cleavage of the olefin and removal of the unwanted
epimer via a kinetically controlled ketalization.14 The syn
diastereomer readily cyclizes in CH2Cl2 at -20 °C (with 5
mol % PPTS) to form the desired trans-oxazolidine, whereas
the anti-diastereomer proceeds to the sterically congested cis-
oxazolidine very slowly as a result of torsional strain. The
reaction was quenched after approximately 95% of the
desired epimer had reacted by addition of Et3N.
As a result of the importance of paclitaxel, the most
extensively studied isoserine is (2R,3S)-N-benzoyl-3-phen-
ylisoserine; several stereoselective syntheses exist for this
â-amino acid.7 A number of these syntheses take advantage
of the stereoelectronic effects of the aromatic ring to induce
good regiocontrol of nucleophilic opening of the styrene
oxide8 or Sharpless amino-hydroxylation methodology.9
However, these methods suffer from poor regiocontrol when
applied to the requisite alkyl acrylate.9b
Utilization of the chiral pool was an attractive starting
point, since leucine possesses a significant portion of the
(8) Denis, J.-N.; Greene, A. E., Serra, A. A.; Luche, M.-J. J. Org. Chem.
1992, 57, 4320.
(9) Li, G.; Angert, H. H.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl.
1996, 108, 2995-2999. (b) Extensive investigation into Sharpless amino-
hydroxylation methodology on the requisite ethyl acrylate optimally
afforded, after chromatagraphy, the desired N-acetyl-protected isoserine ester
in 35% yield, regioselectivity 1.5:1, 90% ee. Conditions: (DHQ)2PHAL/
t-BuOH/H2O, 4 °C.
(10) Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron Lett. 1992,
33, 5029-5032.
(11) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman,
B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359-1362. The enantiomeric
excess was determined by conversion back to N-Boc-leucinol (LAH/THF)
and subsequently converted to its 3,5-dinitrobenzoate. Analysis by chiral
HPLC (D-naphthylalanine, 9/1 hexane/IPA, 1.5 mL/min, 35 °C): retention
times 12.5 (R-isomer) and 15.2 min (S-isomer).
(12) The relative stereochemistry was confirmed by conversion of both
epimers independently to lactam 2b and epi-2b, where their coupling
constants were 5.7 Hz for 2b and 1.9 Hz for epi-2b, which is consistent
with cis (syn) and trans (anti) relative stereochemistry for â-lactams, see:
Alcaide, B.; Esteban, G.; Martin-Cantalejo, Y.; Plumet, J.; Rodriguez-Lopez,
J. J. Org. Chem. 1994, 59, 7994-8002.
Efficient separation of the oxazolidine 9 away from the
unreacted alcohols 7 and 8 was initially accomplished with
chromatography. This was adequate for small scale but would
hamper large scale synthesis. Instead we directed our efforts
toward an in situ chemical modification of the unreacted
alcohols (Scheme 3). Removal of the unreacted alcohols 7
and 8 (∼1:3 syn/anti) from the desired oxazolidine 9 was
conveniently accomplished extractively by reacting the
quenched reaction mixture with succinic anhydride (with 1.5
equiv DMAP).15 After an aqueous workup, the desired
(13) Crystallization from 4 vol of heptane at -20 °C increased the
epimeric ratio to ∼ 6:1 syn/anti alcohols.
(14) 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 use of succinic anhydride as an acyl donor in biocatalytic kinetic
resolutions of alcohols has been established as a practical method for the
extractive separation of product (succinate) away from the neutral unreacted
starting material (alcohol): Terao, Y.; Tsuji, K.; Murata, M.; Achiwa, K.;
Nishio, T.; Watanabe, N.; Seto, K. Chem. Pharm. Bull. 1989, 37, 1653.
3628
Org. Lett., Vol. 2, No. 23, 2000

consumption of starting olefin 9 was rapidly and exothermi-
cally converted to the desired acid. This gave excellent yields
but was considered unsafe. After several permutations, it was
determined that pregeneration of the active catalyst RuO4
(5 mol %) eliminated the observed exotherm. This was
accomplished by mixing RuO2 (5 mol %) with NaIO4 (30
mol %) in water and aging 20 min before addition of the
olefin/acetone mixture. More NaIO4 was then added as an
aqueous solution over 3 h at 15 °C. The reaction clearly
proceeds in a different mode when run under this pregen-
eration protocol, as evidenced by the concomitant formation
of diol, aldehyde, and acid. Additionally, no induction period
was observed. This modification allowed for safe reaction
conditions on a multi-kilogram scale. Following a 2-propanol
quench and extractive base/acid purification, the desired acid
4 was isolated in 85% yield with 98% HPLC purity.17
Scheme 3
Oxazolidine acid 4 was then successfully coupled to the
baccatin core (9-DHAB III) using the DCC protocol (Scheme
1), in 94% yield, but ultimately suffered poor conversion to
ABT-271 as a result of the relatively harsh reaction condi-
tions required for N,O-acetonide cleavage.
Attracted by the flexibility of the 2′-hydroxyl protecting
groups utilized with the Ojima/Holton â-lactam coupling
method,5 the synthesis of the lactam 2b was investigated.
We and others have prepared â-lactams by intramolecular
cyclocondensation of â-amino esters.18 Preparation of the
requisite norstatine ester 13 was accomplished by a one-pot
solvolysis/esterification (Scheme 5). This was optimally
accomplished by treatment of the trans-oxazolidine acid 4
with 1.2 equiv of MeSO3H in refluxing IPA. After the
esterification was complete as judged by LC/MS, the reaction
mixture was cooled to 25 °C, and water was added to
facilitate removal of the acetonide. This gave norstatine
isopropyl ester 13 in a one-pot yield of 96%. The isopropyl
ester was chosen for its ease of extraction from water
mixtures and its stability.19
oxazolidine 9 was isolated as a neat oil in 91% yield with
>99.5% de and 99% HPLC purity versus a standard.
The vinyl oxazolidine 9 was then oxidized to the corre-
sponding carboxylic acid with catalytic RuO2 (5 mol %) and
NaIO4 (6.5 equiv) as the net oxidant in a 1:1 ratio of acetone/
water (0.05 M) using modified Sharpless conditions (Scheme
4).16 Initial reaction attempts were based on a literature
Scheme 4
Preparation of the bis-silyl lactam 15a,b was accomplished
by in situ formation of the bis-silylated intermediate 14a,b
followed by addition of t-BuMgCl (4 equiv) (Scheme 6).
Selective monohydrolysis of the N,O-bis-TMS lactam 15a
to the desired O-TMS lactam 16a was modestly selective
(10:1); however, the corresponding TES derivative was better
controlled. Extensive investigation led to the identification
of conditions that selectively N-desilylate the N,O-bis-TES
procedure in which RuO2 was mixed with the substrate prior
to slow addition of the NaIO4.14 Under these conditions, we
observed exclusive formation of the aldehyde, which upon
Scheme 5
Org. Lett., Vol. 2, No. 23, 2000
3629

Scheme 6
In summary, both side chain precursors 4 and 2b can be
lactam 15b (>100:1 [OTES/OH]) using 15:1 EtOAc/0.7%
KF (0.06 equiv) solution in EtOH (with 20 mol % H2O) at
- 15 °C. After an aqueous workup and solvent switch, the
lactam 16b was reacted with 1.5 equiv Boc2O (0.5 equiv
DMAP) in 5 vol of CH2Cl2, to afford the Boc-lactam silyl
ether 2b in 91% overall yield from 13.20
synthesized in excellent stereochemical purity (>98%)21 from
commercially available N-Boc-Leu-ol without chromotog-
raphy in 44% and 40% (4 and 2b, respectively) overall yield.
This process should be amenable to other alkyl isoserines
derived from the chiral pool, where other general methods
are not satisfactory. This process has been carried out on
multi-kilogram scale and has been utilized in the synthesis
of ABT-271. Synthesis of ABT-271 and full experimental
details will be reported elsewhere.
(16) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J
Org. Chem. 1981, 46, 3936-3938. (b) Piatak, D. M.; Bhat, H. B.; Caspi,
E. J. Org. Chem. 1969, 34, 112-118.
(17) Preparing its DCHA salt in acetonitrile could further purify the acid.
For a nonstereoselective route to this oxazolidine acid, see: Veeresha, G.;
Datta, A. Tetrahededron Lett. 1997, 38, 5223-5224.
(18) (a) 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
Asymm. 1998, 9, 2791-2794. (b) Alcaide, B.; Biurrun, C.; Plumet, J.;
Borredon, E.; Tetrahedron Lett. 1992, 33, 7413-7416.
(19) Preparation of straight-chain alkyl esters invariably afforded mixtures
of dimeric byproducts, especially upon scale-up. Although the isopropyl
ester greatly enhances stability, this lactamization method has only been
previously demonstrated on unbranched isoserine esters.
Supporting Information Available: Experimental pro-
cedures and characterization data for 2b, 4, 6-9, 13, 15b,
and 16b. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL006508O
1
(21) The C3-epi-2b was not detected by H NMR; furthermore 2b was
(20) The lactam was isolated in approximately 70-75% potency,
contaminated with 20 wt % of ethoxytriethylsilane, which could be removed
by concentrating under very good vacuum (94% potency).
reacted with both (R)- and (S)-R-methylbenzylamine to provide diastere-
oisomers set. By HPLC, <1% of a diastereomeric impurity was observed
from this diastereomeric set.
3630
Org. Lett., Vol. 2, No. 23, 2000