Enantioselective total synthesis of (+)-duocarmycin A, epi-(+)-duocarmycin A, and their unnatural enantiomers

Full text of DOI:10.1021/ja953777e

J. Am. Chem. Soc. 1996, 118, 2301-2302
2301
Scheme 1
Enantioselective Total Synthesis of
(+)-Duocarmycin A, epi-(+)-Duocarmycin A, and
Their Unnatural Enantiomers
Dale L. Boger,* Jeffrey A. McKie, Takahide Nishi, and
Tsuyoshi Ogiku
Department of Chemistry
The Scripps Research Institute
10666 North Torrey Pines Road
La Jolla, California 92037
ReceiVed NoVember 9, 1995
Duocarmycin A (1)1 represents one of the newest additions
and the structurally most challenging member of a class of
naturally occurring potent antitumor antibiotics2-4 that derive
their properties through sequence-selective alkylation of duplex
DNA.5,6 In addition to 1 being the most reactive member of
the natural products and thus the most difficult to handle,
synthetic approaches to the control of the relative and absolute
stereochemistry of its two remote stereocenters have not been
forthcoming. Herein, we report a divergent and diastereose-
lective total synthesis of natural (+)-duocarmycin A and its C6
diastereomer, (+)-epi-duocarmycin A, in which solutions to the
remote stereocenter introductions are provided.7,8
Regiospecific Lewis acid-catalyzed addition9 of allyltributyltin
(0.5 equiv of BF3-OEt2, CH2Cl2, -20 °C, 3 h, 83-89%) to
the activated p-quinodiimide 210 cleanly provided 3 (Scheme
1). Catalytic dihydroxylation (catalytic OsO4, 2 equiv of
NMMO, acetone-H2O 4:1, 25 °C, 12 h, 95%), followed by
selective protection of the primary alcohol of 4 (1.1 equiv of
Bu2SnO, toluene-THF 10:1, reflux, -H2O, 6 h; 1.2 equiv of
TsCl, catalytic Et3N, 25 °C, 12 h, 89%), provided 5. Protection
of the remaining secondary alcohol (1.5 equiv of TBDMSOTf,
2 equiv of 2,6-lutidine, CH2Cl2, 0 °C, 3 h, 73%), followed by
base-promoted intramolecular alkylation (2.0 equiv of NaH,
THF, 0 °C, 2 h, 92-97%), provided the first key intermediate,
7. Optically active 7 was obtained by catalytic asymmetric
dihydroxylation11 of 3 in the presence of (DHQD)2-PHAL12
(0.1 equiv, 0.01 equiv of OsO4, 3 equiv of K3Fe(CN)6, 3 equiv
of K2CO3, 3 equiv of CH3SO2NH2, THF-H2O 4:1, 16 h, 89-
92%, 78% ee). Notably, the (S) absolute configuration of the
newly introduced secondary hydroxyl group was determined
to be opposite that predicted from the established models, and
the complementary ligand, (DHQ)2-PHAL, provided the cor-
responding (R) enantiomer (89%, 77% ee).12 Further enrichment
in the optical purity of the intermediates could be accomplished
by direct chromatographic resolution of 7, [R]25D -116° (c 0.5,
CH3OH), on a semipreparative ChiralCel OD column (2 cm ×
25 cm, 25% i-PrOH-hexane), which provided a preparatively
useful (150-250 mg/injection) and unusually effective separa-
(1) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J. Antibiot. 1988, 41, 1915.
Yasuzawa, T.; Iida, T.; Muroi, K.; Ichimura, M.; Takahashi, K.; Sano, H.
Chem. Pharm. Bull. 1988, 36, 3728. Yasuzawa, T.; Muroi, K.; Ichimura,
M.; Takahashi, I.; Ogawa, T.; Takahashi, K.; Sano, H.; Saitoh, Y. Chem.
Pharm. Bull. 1995, 43, 378.
(2) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawamoto,
I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J. Antibiot. 1990, 43, 1037.
(3) Ohba, K.; Watabe, H.; Sasaki, T.; Takeuchi, Y.; Kodama, Y.;
Nakazawa, T.; Yamamoto, H.; Shomura, T.; Sezaki, M.; Kondo, S. J.
Antibiot. 1988, 41, 1515.
(4) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp, D. J.;
Martin, D. G. J. Am. Chem. Soc. 1981, 103, 7629.
(5) Boger, D. L.; Johnson, D. S. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
3642. Boger, D. L. Acc. Chem. Res. 1995, 28, 20. Boger, D. L. Chemtracts:
Org. Chem. 1991, 4, 329.
(6) Boger, D. L.; Johnson, D. S.; Yun, W. J. Am. Chem. Soc. 1994, 116,
1635. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Munk, S. A.; Kitos, P.
A.; Suntornwat, O. J. Am. Chem. Soc. 1990, 112, 8961.
(7) For the nondiastereoselective synthesis of duocarmycin A and its
isomers, see: Fukuda, Y.; Itoh, Y.; Nakatani, K.; Terashima, S. Tetrahedron
1994, 50, 2793. Fukuda, Y.; Nakatani, K.; Terashima, S. Tetrahedron 1994,
50, 2809.
(8) (+)- and ent-(-)-duocarmycin SA: Boger, D. L.; Machiya, K. J.
Am. Chem. Soc. 1992, 114, 10056. Boger, D. L.; Machiya, K.; Hertzog, D.
L.; Kitos, P. A.; Holmes, D. J. Am. Chem. Soc. 1993, 115, 9025. (()-
Duocarmycin SA: Muratake, H.; Abe, I.; Natsume, M. Tetrahedron Lett.
1994, 35, 2573. (+)-Duocarmycin SA: Muratake, H.; Matsumura, N.;
Natsume, M. Chem. Pharm. Bull. 1995, 43, 1064.
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV.
1994, 94, 2483.
(9) Boger, D. L.; Zarrinmayeh, H. J. Org. Chem. 1990, 55, 1379.
(10) p-Quinodiimide 2 was prepared in six steps from commercially
available 2-hydroxy-4-nitroaniline: (1) 1.05 equiv of BnCl, 2.2 equiv of
K2CO3, catalytic KI, DMF, 25 °C, 24 h, 90-94%; (2) 1.05 equiv of NBS,
CH3CN, 25 °C, 2 h, 100%; (3) 1.1 equiv of CuCN, DMF, 160 °C, 16 h,
95%; (4) 10 equiv of Fe, HOAc-H2O, 120 °C, 15 min, 52% or Al(Hg),
Et2O-EtOH-H2O, 0 to 25 °C, 2 h, 95-100%; (5) 2.5 equiv of BzCl, 4
equiv of K2CO3, 0.3 equiv of DMAP, THF, 25 °C, 16 h, 92-96%; (6) 1.0
equiv of Pb(OAc)4, CHCl3, 0 to 25 °C, 4 h, 84%.
(12) Amberg, W.; Bennani, Y. L.; Chadha, R. K.; Crispino, G. A.; Davis,
W. D.; Hartung, J.; Jeong, K.-S.; Ogino, Y.; Shibata, T.; Sharpless, K. B.
J. Org. Chem. 1992, 57, 2768. The unusual switch in the absolute
configuration of the ADH was unambiguously established in a single-crystal
X-ray structure determination of the (S)-Mosher ester of the primary alcohol
4 (S) derived from the (DHQD)2-PHAL AD reaction and confirmed upon
conversion to natural (+)-1, for which the absolute configuration has also
been established by X-ray.3
0002-7863/96/1518-2301$12.00/0 © 1996 American Chemical Society

2302 J. Am. Chem. Soc., Vol. 118, No. 9, 1996
Communications to the Editor
Scheme 2
Scheme 3
and the TBDMS protecting groups, followed by coupling with
5,6,7-trimethoxyindole-2-carboxylic acid (16,16 3 equiv of EDCI,
DMF, 25 °C, 4 h, 68%), provided 17. Removal of the benzyl
ether (H2, 10% Pd-C, CH3OH, 25 °C, 30 min, 95-98%),
followed by direct transannular spirocyclization of the alcohol
18 upon Mitsunobu activation (1.5 equiv of ADDP, 1.5 equiv
of Bu3P, C6H6, 50 °C 1 h, 99%), provided (+)-duocarmycin A
(1), identical in all respects with authentic material, [R]25D +291°
(c 0.01, CH3OH).17 Alternatively, treatment of 17 with MsCl
(3 equiv, pyridine, 0 °C, 1 h, 87-91%), followed by hydro-
genolysis of the benzyl ether (H2, 10% Pd-C, CH3OH, 25 °C,
30 min, 82-88%) and spirocyclization effected by treatment
with DBU (2 equiv, CH3CN, 25 °C, 2 h, 70-83%), also
provided (+)-duocarmycin A in conversions that proved more
dependable on a small scale.
tion of the enantiomers (tR ) 48.2 (3R) and 93.4 (3S) min, 5
mL/min flow rate, R ) 1.94, >99.9% ee).13 Removal of the
two benzoyl protecting groups (NH2NH2-EtOH 10:1, 140 °C,
20 h, sealed tube, 58-65%), followed by immediate reprotection
of the free amine 8 with BOC2O (6 equiv, catalytic DMAP,
THF, reflux, 4 h, 95%; 5 equiv of TFA, CH2Cl2, -30 to 0 °C,
3 h, 93%), provided 10 and set the stage for introduction of the
C ring and its remaining C6 quaternary center.
Alkylation of 10 with the oxazolidinone 1114 (1.5 equiv of
NaH, DMF, 0 °C, 1 h, 88%), followed by condensation of 12a
under thermodynamically controlled reaction conditions achieved
by inverse addition of base to the substrate (6 equiv of LDA,
THF, -78 to -50 °C, 0.5 h, 78%), cleanly provided the (3S,6R)
diastereomer 13a (g8-10:1) as the nearly exclusive closure
product and a small amount of recovered 12a (7%), (Scheme
2). Alternatively, condensation of 12b containing the enanti-
omer of the acyl oxazolidinone under kinetically controlled
reaction conditions,14 achieved by slow addition (30 min) of
substrate to base maintained at -78 °C (4-6 equiv of LDA,
THF, -78 °C, 10 min, 56%), cleanly provided 21a, also
possessing the desired (3S,6R) stereochemistry.15 Notably, the
diastereomeric pairs 21a/21b (SiO2, R ) 2.3, 30% EtOAc-
hexane) or 13a/13b (SiO2, R ) 1.4, 20% EtOAc-hexane)
bearing Evans’s optically active acyl oxazolidinones were
readily separable by chromatography, thereby providing the pure
diastereomers (>99.9% de). That the latter constitutes the
kinetic product and the former the thermodynamic product of a
reversible closure was established by resubjecting the kinetic
product 21a to the reaction conditions (1.5 equiv of LDA, -78
°C, 6 h) with equilibration to the thermodynamic product 21b
(8:1). The stereochemical outcome is consistent with the
derivation of the kinetic product from the reaction of a chelated
(Z)-enolate, while the latter equilibration process provides the
most stable of the two possible diastereomers (∆E ) 0.76 and
0.4 kcal/mol, MM2 and AM1, respectively). Both results are
dependent on the size of the adjacent N-protecting group (BOC
> CHO) and its interaction with the chiral auxiliary substituent
in either the diastereomeric transition states (kinetic product,
chelated (Z)-enolate) or the final products (nonchelated anti
carbonyl conformation). Methanolysis of 13a or 21a (30 equiv
of LiOCH3, THF-CH3OH, 0 °C, 0.5 h, 78-84%), which served
to remove the oxazolidinone to provide 14, followed by imine
hydrolysis (2 equiv of TsOH-H2O, THF-H2O 8:1, 0 °C, 3 h,
76-80%), afforded 15. Acid-catalyzed deprotection of 15 (4
M HCl-CH3OH, 0 °C, 1 h), which served to remove both BOC
Similarly, closure of 12b under conditions of thermodynamic
control or condensation of 12a under kinetic control, where
product equilibration is minimized, provided 21b (81%) or 13b
(56%), respectively, possessing the (3S,6S) stereochemistry
(Scheme 2). Methanolysis of 21b or 13b and conversion of 22
to epi-(+)-duocarmycin A (28), [R]25 +155° (c 0.02, CH3-
D
OH),17 was accomplished as detailed for (+)-1 (Scheme 3).
Thus, the diastereoselective preparation of 1 or its epimer 28
was achieved on the basis of a divergent Dieckmann-like
condensation in which either C6 absolute configuration could
be introduced through choice of kinetic or thermodynamic
reaction conditions on the same intermediate (e.g., 12a) or
through choice of complementary auxiliaries (e.g., 12a/12b).
By means of the same approach but employing (3R)-8, the
unnatural enantiomers of 1, [R]25 -284° (c 0.025, CH3OH),
D
and 28, [R]25 -156° (c 0.025, CH3OH), were also prepared.
D
Extensions of these studies to the preparation of key partial
structures of 1 and their comparative examination are in progress
and will be reported in due course.
Acknowledgment. We gratefully acknowledge the financial support
of the National Institutes of Health (CA41986) and the award of a NIH
postdoctoral fellowship (J.A.M., CA62589).
Supporting Information Available: Physical and spectroscopic
characterization of all synthetic intermediates is provided (13 pages).
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JA953777E
(13) This latter procedure, which benefits from an unusually large
separation, was employed to further enrich the mixture obtained from ADH
or to resolve racemic material and dependably assured the optical purity of
the samples (>99.9% ee).
(14) Boger, D. L.; Nishi, T. Bioorg. Med. Chem. 1995, 3, 67.
(15) The minor diastereomer (10-14%) was readily removed upon
chromatography.
(16) Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.; Suntornwat,
O. J. Org. Chem. 1990, 55, 4499.
(17) (+)-Duocarmycin A: lit.1 [R]25D +282° (c 0.1, CH3OH), lit.7 [R]25
D
+332° (c 0.14, CHCl3). epi-(+)-Duocarmycin A: lit.7 [R]25D +161° (c 0.07,
CHCl3).