A cobalt-phosphine complex directed Reformatsky approach to a stereospecific synthesis of the dolastatin 10 unit dolaproine (Dap)

Full text of DOI:10.1021/jo010530t

8640
J . Org. Chem. 2001, 66, 8640-8642
Notes
(1a ) by total syntheses6a of dolastatin 10 (2) and by an
A Coba lt-P h osp h in e Com p lex Dir ected
X-ray crystal structure determination of (6R)-isodolas-
tatin 10.6b Our initial synthesis of Dap involved using
the magnesium enolate of a chiral propionate in an aldol
reaction. That led to all four diastereoisomers in varying
yields.8 Subsequently, we greatly improved the aldol
approach by condensing S-prolinal with a chiral oxazo-
lidinone using dibutylboron triflate to direct the stereo-
chemical course.9 Other boron-catalyzed aldol approaches
to Dap have also been described.10 Because of the
increasing need for Dap to meet clinical supply require-
ments for dolastatin 10 (1) and our SAR studies11 of this
quite remarkable sea hare constituent, we undertook a
cobalt-phosphine complex mediated asymmetric Refor-
matsky approach to Boc-Dap (1b).
Refor m a tsk y Ap p r oa ch to a Ster eosp ecific
Syn th esis of th e Dola sta tin 10 Un it
Dola p r oin e (Da p )1
George R. Pettit* and Matthew P. Grealish
Cancer Research Institute and Department of Chemistry
and Biochemistry, Arizona State University,
Tempe, Arizona 85287-2404
bpettit@asu.edu
Received May 24, 2001
The well-known Reformatsky reaction for forming
carbon-carbon bonds has been undergoing extensive
improvements by replacing the classic zinc-based proce-
dure2 with, e.g., germanium3 or samarium4 metal-
promoted reactions. The activated germanium3-catalyzed
asymmetric Reformatsky reaction between enantiomeri-
cally pure oxazolidinones and aldehydes has been found
to afford good diastereoselectivity with (1S,2R)-2-amino-
1,2-diphenylethanol-derived precursors. Prior to avail-
ability of the germanium/chiral oxazolidinone/aldehyde
procedure,3 we began to evaluate an analogous reaction
with a tetrakis(triphenylphosphine)cobalt(0)5-directed
asymmetric Reformatsky reaction as a new stereospecific
route to the dolaproine (1a , Dap) unit of dolastatin 10
(2)6 now in Phase II human cancer clinical trials.7
The Orsini5 cobalt-phosphine Reformatsky-type reac-
tions of R-halocarbonyl derivatives with aldehydes or
ketones to give secondary and tertiary alcohols offers
several advantages over the classic zinc-mediated Refor-
matsky reaction, the most notable being milder condi-
tions and higher yields of addition products.
Cobalt-triphenylphosphine-promoted Reformatsky re-
action between N-Boc-S-prolinal9 (3) and 3-(2-bromopro-
pionyl)-4R-methyl-5S-phenyloxazolidin-2-one (4)9,12 ste-
reoselectively furnished the â-hydroxy amide 5 in 70%
yield. Subsequent O-methylation of alcohol 5 with tri-
methyloxonium tetrafluoroborate13 led to methyl ether
6 in 86% yield. Hydrolysis of the chiral auxiliary with
Previously we established the absolute configuration
of the three-chiral-centered amino acid unit dolaproine
* To whom correspondence should be addressed.
(1) Contribution 475 in the series Antineoplastic Agents: for part
474 refer to Bai, R.; Verdier-Pinard, P.; Sausville, E. A.; Pettit, G. R.;
Bates, R. B.; Hamel E. Mol. Pharm. 2000, in press.
(2) (a) Pini, D.; Uccello-Barretta, G.; Mastantuono, A.; Salvadori,
P. Tetrahedron 1997, 53, 6065. (b) Rathke, M. W. In Organic Reactions;
Dauben, W. G. et al., Eds.; J ohn Wiley & Sons: New York, 1975; Vol.
22, pp 423-449.
(3) Kagoshima, H.; Hashimoto, Y.; Oguro, D.; Saigo, K. J . Org.
Chem. 1998, 63, 691.
(4) (a) Fukuzawa, S.; Matsuzawa, H.; Yoshimitsu, S. J . Org. Chem.
2000, 65, 1702-1706. (b) Ichikawa, S.; Shuto, S.; Minakawa, N.;
Matsuda, A. J . Org. Chem. 1997, 62, 1368. (c) Shen, Z.; Zhang, J .; Zou,
H.; Yang, M. Tetrahedron Lett. 1997, 38, 2733.
(5) (a) Orsini, F.; Pelizzoni, T.; Pulici, M.; Vallarino, L. M. J . Org.
Chem. 1994, 59, 1-3. (b) Orsini, F.; Pulici, M. Highlights on Recent
Advancement on Reformatsky-Type Reactions: the Cobalt Approach.
In Trends in Organometallic Chemistry; Research Trends Ed., Trivan-
drum: India, 1994; Vol. 1, pp 625-667. (c) Orsini, F. Tetrahedron Lett.
1998, 39, 1425. (d) Orsini, F. J . Org. Chem. 1997, 62, 1159.
hydrogen peroxide and lithium hydroxide provided Boc-
(2S,2′R,3′R)-Dap (1b) in 94% yield. Attempts to cleave
(6) (a) Pettit, G. R.; Srirangam, J . K.; Singh, S. B.; Williams, M. D.;
Herald, D. L.; Barko´czy, J .; Kantoci, D.; Hogan, F. J . Chem. Soc., Perkin
Trans. 1 1996, 859. (b) Pettit, G. R.; Srirangam, J . K.; Herald, D. L.;
Hamel, E. J . Org. Chem. 1994, 59, 6127. (c) Pettit, G. R. The
Dolastatins. In Progress in the Chemistry of Organic Natural Products;
Springer-Verlag: New York, 1991; No. 57, pp 153-195.
(7) Madden, T.; Tran, H. T.; Beck, D.; Huie, R.; Newman, R. A.;
Pusztai, L.; Wright, J . J .; Abbruzzese, J . L. Clin. Cancer Res. 2000, 6,
1293.
(8) Pettit, G. R.; Singh, S. B.; Herald, D. L.; Lloyd-Williams, P.;
Kantoci, D.; Burkett, D. D.; Barko´czy, J .; Hogan, F.; Wardlaw, T. R.
J . Org. Chem. 1994, 59, 6287.
10.1021/jo010530t CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/09/2001

Notes
J . Org. Chem., Vol. 66, No. 25, 2001 8641
Melting points were recorded employing an Electrothermal
9100 digital melting point apparatus and are uncorrected. The
IR spectra were obtained using a Mattson FTIR model 2020
instrument. Low-resolution mass spectral data were collected
using a Varian MAT 312 instrument (EIMS). The high-resolu-
tion FAB spectra were obtained employing a Kratos MS-50 mass
spectrometer at the Midwest Center for Mass Spectrometry,
University of Nebraska, Lincoln, NE. All 1H and 13C NMR
spectra were determined using a Varian Gemini 300 MHz
instrument with CDCl3 (TMS internal reference) as solvent
unless otherwise noted. Elemental analyses were determined
by Galbraith Laboratories Inc., Knoxville, TN.
the oxazolidinone (5) prior to O-methylation leads to
byproducts and makes purification more difficult.9 The
stereochemistry of the Reformatsky product was further
confirmed by conversion9 to the known9 pyrrolizidinone
derivative 7. While the Reformatsky reaction (70% yield)
was certainly competitive with the boron-directed aldol
approach9 (60% yield), the cobalt-phosphine complex
method was also more convenient experimentally to
perform and the results more reproducible.
P r ep a r a tion of th e Coba lt-Tr ip h en ylp h osp h in e Com -
p lex.5 Activated magnesium turnings (0.5 g), anhydrous cobalt-
(II) chloride (0.13 g, 1 mmol), and triphenylphosphine (1.05 g, 4
mmol) were added to THF (5 mL). The mixture was stirred until
the blue color turned to dark-brown. Immediately before use,
the supernatant was transferred by syringe to the reaction flask.
(4R,5S,2′R,3′R,2′′S)-3-[3′-(N-ter t-Bu toxyca r bon yl-2′′-p yr -
r olidin yl)-3′-h ydr oxy-2′-m eth ylpr opan oyl)-4-m eth yl-5-ph en -
yl-2-oxa zolid in on e (5). To a solution cooled to 0 °C containing
3-(2-bromopropionyl)-4R-methyl-5S-phenyloxazolidin-2-one (4,
0.31 g, 1 mmol) in anhydrous THF (5 mL) was added (dropwise
over 30 min) the cobalt-triphenylphosphine complex (1 mmol).
Next N-Boc-L-prolinal (3, 0.20 g, 1 mmol)8 was added to the dark
brown solution and stirring was continued for 2 h. The reaction
mixture was poured into cold 0.1 N HCl and extracted with ethyl
acetate and the solvent evaporated under reduced pressure. The
crude product was separated by flash column chromatography
(4:1 hexane-ethyl acetate) to afford the title compound as a
No attempt was made to determine the enolate geom-
etry or the oxidation state of the cobalt species in the
present Reformatsky reactions. However, on the basis of
the absolute configuration of the product, diastereofacial
selection was considered to occur in the same manner as
in the aldol reaction of boron enolates9,10c derived from
enantiomerically pure 2-oxazolidinones.14 Thus, the ob-
served syn/anti selectivity of the present Reformatsky
reaction can be interpreted in terms of the Zimmerman-
Traxler model,15 in which the geometry of the enolate
correlates with the relative configuration of the products.
In summary, the cobalt-triphenyl phosphine complex
mediated Reformatsky synthesis of the Dap (1a ) unit of
dolastatin 10 (2) was found to proceed smoothly under
mild and neutral conditions. In general, the new synthe-
sis was very easy to implement and, for example, did not
require anhydrous solvents, a temperamental aldol boron
enolate, or very low reaction temperature.9 The method
therefore represents a valid improvement to the existing
procedures for synthesizing dolaproine.
colorless foam (0.30 g, 70%): [R]25 -9.77° (c 1.73, CHCl3); lit10c
D
[R]23 -10.2° (c 1.0, CHCl3); EIMS m/z 432 (M+), 414, 359, 262,
D
170, 114, 70; IR (KBr, cm-1) νmax 3445, 2978, 1782, 1694, 1393,
1
1196, 1121; H NMR δ 7.44-7.29 (5H, m), 5.67 (1H, d, J ) 7.2
Hz), 4.76 (1H, p, J ) 3.9 Hz), 3.97-3.92 (2H, m), 3.91-3.85 (1H,
m), 3.54-3.46 (1H, m), 3.26-3.19 (1H, m), 2.15 (1H, bs), 1.93-
1.79 (3H, m), 1.51 (1H, s), 1.50-1.47 (9H, s), 1.33 (3H, d, J )
6.6 Hz), 0.88 (3H, d, J ) 6.6 Hz).
(4R,5S,2′R,3′R,2′′S)-3-[3′-(N-ter t-Bu toxyca r bon yl-2′′-p yr -
r olidin yl)-3′-m eth oxy-2′-m eth ylpr opan oyl)-4-m eth yl-5-ph en -
yl-2-oxa zolid in on e (6). To a flask containing alcohol 5 (0.36
g, 0.84 mmol) and molecular sieves (4 Å, 0.37 g) was added
anhydrous dichloromethane (10 mL), and the mixture was cooled
to 0 °C. Proton sponge (0.47 g, 2.2 mmol, 2.6 equiv) and
trimethyloxonium tetrafluoroborate (0.31 g, 2.1 mmol, 2.5 equiv)
were added to the clear colorless liquid at 0 °C. The solution
slowly turned a turbid tan-yellow and was stirred for 48 h at
r.t. The yellow cloudy solution was filtered and the solvent
evaporated under reduced pressure to a yellow solid. The solid
was separated by flash chromatography (3:1 hexane-ethyl
Exp er im en ta l Section
All solvents were redistilled. Anhydrous cobalt(II) chloride
was heated at 120-150 °C for 2 h prior to use. Magnesium
(turnings) was activated by grinding the metal in a mortar and
treatment with a solution of 1,2-dichloroethane in tetrahydro-
furan (THF), followed by washing with THF. Both the course
and products from reactions were monitored by thin-layer
chromatography using Analtech silica gel GHLF uniplates. All
reactions were carried out under an inert atmosphere. Solvent
extracts of aqueous solutions were dried over anhydrous sodium
sulfate unless otherwise noted. Flash column chromatography
was performed using silica gel (230-400 mesh ASTM).
acetate) to afford a colorless oil (0.32 g, 86%): [R]25 -44.9° (c
D
0.53 CH3OH); EIMS m/z 446 (M+), 414, 373, 331, 276, 213; IR
1
(KBr, cm-1) νmax 2978, 1782, 1694, 1393, 1196, 1121; H NMR
(400 MHz) δ 7.42-7.29 (5H, m), 5.63 (1H, d, J ) 7.2 Hz), 4.71
(1H, m), 3.93 (2H, m), 3.84 (2H, m), 3.47 (3H, s, OCH3), 3.20
(1H, m), 1.96 (2H, m), 1.78 (2H, m), 1.50 (9H, s), 1.30 (3H, d, J
) 6.8 Hz), 0.88 (3H, d, J ) 6.8 Hz).
(2R,3R,2′S)-3-(N-ter t-Bu toxyca r bon yl-2′-p yr r olid in yl)-3-
m eth oxy-2-m eth ylp r op a n oic Acid (1b, Boc-d ola p r oin e). To
a solution of oxazolidinone amide protected Dap (0.14 g, 0.32
mmol) in THF (10 mL) at 0 °C was added hydrogen peroxide
(0.14 g of 30% 1.2 mmol, 3.8 equiv) over 10 min. Lithium
hydroxide monohydrate (0.022 g, 0.53 mmol, 1.7 equiv) was
added and the resulting turbid white mixture stirred for 3 h.
To the solution was added sodium sulfite (0.16 g, 1.3 mmol, 4.0
equiv) and stirring continued for 18 h at 0 °C to r.t. The reaction
mixture was concentrated and extracted with dichloromethane
to remove the oxazolidinone auxiliary. The aqueous layer was
acidified to pH 2 and extracted with ethyl acetate, and the
combined extract was washed with water and evaporated in
vacuo to give carboxylic acid 1b as a colorless oil (0.86 g, 94%):
(9) Pettit, G. R.; Burkett, D. D.; Barko´czy, J .; Breneman, G. L.;
Pettit, W. E. Synthesis 1996, 719.
(10) (a) Tomioka, K.; Kamai, M.; Koga, K. Tetrahedron Lett. 1991,
32, 2395. (b) Roux, F.; Maugras, I.; Poncet, J .; Niel, G.; J ouin, P.
Tetrahedron 1994, 50, 5345. (c) Shioiri, T.; Hayashi, K.; Hamada, Y.
Tetrahedron 1993, 49, 1913.
(11) (a) Pettit, G. R.; Srirangam, J . K.; Barkoczy, J .; Williams, M.
D.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Hogan, F.; Bai, R.; Chapuis,
J .-C.; McAllister, S. C.; Schmidt, J . M. Anti-Cancer Drug Design 1998,
13, 243. (b) Pettit, G. R.; Srirangam, J . K.; Barkoczy, J .; Williams, M.
D.; Durkin, K. P. M.; Boyd, M. R.; Bai, R.; Hamel, E.; Schmidt, J . M.;
Chapuis, J .-C. Anti-Cancer Drug Design 1995, 10, 529.
(12) Song, C. E.; Lee, S. G.; Lee, K. C.; Kim, I. O.; J eong, J . H. J .
Chromatogr. A 1993, 654, 303.
(13) Diem, M. J .; Burow, D. F.; Fry, J . L. J . Org. Chem. 1990, 42,
180.
(14) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127. (b) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68,
83. (c) Yan, T. H.; Tan, C. W.; Lee, H. C.; Lo, H. C.; Huang, T. Y. J .
Am. Chem. Soc. 1993, 115, 2613.
[R]25 -57° (c 2.08, CH3OH); lit.8 [R]D -61.4° (c 0.5, CH3OH);
D
EIMS m/z 287 (M+), 255, 214, 170, 114, 70; IR (KBr, cm-1) νmax
3084, 2978, 2938, 2884, 1736, 1696, 1402, 1167, 1099; 1H NMR
(500 MHz, CD3CN, 50 °C) δ 3.80 (2H, m), 3.44 (1H, m), 3.39
(3H, s, OCH3), 3.16 (1H, m), 2.47 (1H, m), 1.96-1.82 (4H, m),
1.72 (1H, m), 1.44 (9H, s), 1.18 (3H, d, J ) 7 Hz).
(15) Zimmerman, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.

8642 J . Org. Chem., Vol. 66, No. 25, 2001
Notes
(1R,2R,8S)-Hexah ydr o-1-h ydr oxy-2-m eth yl-3H-pyr r olizin -
3-on e (7). To a flask containing Reformatsky product 5 (1.03 g,
2.4 mmol) was added trifluoracetic acid (10 mL). The mixture
was stirred at room temperature for 20 min and concentrated
in vacuo. The remaining solvent was codistilled with toluene.
The resulting pink oil was dissolved in ethanol-water (1:2, 30
mL) and cooled to 0 °C. Potassium carbonate (0.45 g, 3.3 mmol)
was added, and the mixture was stirred for 1.5 h, concentrated
in vacuo, and extracted with dichloromethane. The combined
organic extract was concentrated, and the resulting yellow oil
was separated by flash column chromatography (1:5:10 ethanol-
ethyl acetate-dichloromethane) to afford the chiral oxazolidi-
none first and then lactam 7 (0.32 g, 86%) as a tan solid that
was recrystallized from ethyl acetate-hexane to give colorless
3.56 (1H, dt, J ) 11.1, 7.5 Hz), 3.06 (1H, m), 2.73 (1H, m), 2.34
(1H, bs, disappeared with D2O), 2.17 (1H, m), 2.01 (2H, m), 1.50
(1H, m), 1.21 (3H, d, J ) 7.2 Hz).
Ack n ow led gm en t. We are pleased to thank the
following for very necessary financial support: Out-
standing Investigator Grant CA44344-05-12 awarded by
the Division of Cancer Treatment and Diagnosis, Na-
tional Cancer Institute DHHS; the Arizona Disease
Control Research Commission; the Fannie E. Rippel
Foundation; the Robert B. Dalton Endowment Fund;
Gary L. and Diane Tooker; Polly J . Trautman; Billie
J ean Baguley; Lottie Flugal; Dr. J ohn C. Budzinski, and
the Eagles Art Ehrmann Cancer Fund. For other helpful
assistance, we thank Dr. Fiona Hogan.
crystals: mp 100-101 °C, lit.8 mp 100-101 °C; [R]23 +4.8° (c
D
1.03, CHCl3), lit.8 [R]25D +2.0° (c 3.7, CHCl3); EIMS m/z 155 (M+),
140, 126, 70, 59, 28; IR (KBr, cm-1) νmax 3418, 2972, 2888, 1659,
1458, 1366, 1082; 1H NMR (300 MHz, CHCl3) δ 3.67 (2H, m),
J O010530T