Effective Asymmetric Synthesis of 1,2,9,9a-Tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)

Article abstract of DOI:10.1021/jo035465x

A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI) analogue of the CC-1065 and duocarmycin alkylation subunits is detailed that employs an effective enzymatic desymmetrization reaction of prochiral diol 12 using a commercially available Pseudomonas sp. lipase. The optically active monoacetate (S)-13 is furnished in exceptional conversions (88%) and optical purity (99% ee) and serves as an intermediate for the preparation of either enantiomer of CBI. Similarly, the Pseudomonas sp. lipase resolved the racemic intermediate 19, affording advanced intermediates of CBI in good conversions and optical purity (99% ee), and provided an alternative approach to the preparation of optically active CBI derivatives.

Full text of DOI:10.1021/jo035465x

Effective Asym m etr ic Syn th esis of
1,2,9,9a -Tetr a h yd r ocyclop r op a [c]ben zo[e]in d ol-4-on e (CBI)
David B. Kastrinsky and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
boger@scripps.edu
Received October 6, 2003
A short, asymmetric synthesis of the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]indol-4-one (CBI)
analogue of the CC-1065 and duocarmycin alkylation subunits is detailed that employs an effective
enzymatic desymmetrization reaction of prochiral diol 12 using a commercially available Pseudo-
monas sp. lipase. The optically active monoacetate (S)-13 is furnished in exceptional conversions
(88%) and optical purity (99% ee) and serves as an intermediate for the preparation of either
enantiomer of CBI. Similarly, the Pseudomonas sp. lipase resolved the racemic intermediate 19,
affording advanced intermediates of CBI in good conversions and optical purity (99% ee), and
provided an alternative approach to the preparation of optically active CBI derivatives.
CC-1065 (1)1 and the duocarmycins (2-3)2,3 represent
the parent members of a class of potent antitumor
antibiotics4 that derive their biological properties through
a sequence selective alkylation of duplex DNA (Figure
1).5-10 In studies to define fundamental relationships
between structure, chemical reactivity, and biological
properties, the 1,2,9,9a-tetrahydrocyclopropa[c]benzo[e]-
indol-4-one (CBI) analogue of the natural product alky-
lation subunits has been found to possess especially
interesting properties. The natural enantiomers of the
CBI analogues have been shown to be 4 times more
stable, 4 times more potent, and synthetically more
accessible than the corresponding compounds incorporat-
(1) Chidester, C. G.; Krueger, W. C.; Mizsak, S. A.; Duchamp, D. J .;
Martin, D. G. J . Am. Chem. Soc. 1981, 103, 7629.
(2) Takahashi, I.; Takahashi, K.; Ichimura, M.; Morimoto, M.; Asano,
K.; Kawamoto, I.; Tomita, F.; Nakano, H. J . Antibiot. 1988, 41, 1915.
(3) Ichimura, M.; Ogawa, T.; Takahashi, K.; Kobayashi, E.; Kawa-
moto, I.; Yasuzawa, T.; Takahashi, I.; Nakano, H. J . Antibiot. 1990,
43, 1037.
(4) Yasuzawa, T.; Muroi, K.; Ichimura, M.; Takahashi, I.; Ogawa,
T.; Takahashi, K.; Sano, H.; Saito, Y. Chem. Pharm. Bull. 1995, 43,
378.
F IGURE 1. CC-1065 and the duocarmycins.
ing the natural CPI (7-methyl-1,2,8,8a-tetrahydrocyclo-
propa[c]pyrrolo[3,2-e]indol-4-one) alkylation subunit of
CC-1065.11-17 Additionally, they alkylate DNA with an
unaltered sequence selectivity at an enhanced rate and
with a greater efficiency than the corresponding CPI
analogues. Although not quite as effective as duocarmy-
cin SA (DSA) analogues, the ability to perform compre-
hensive structural and biological studies with CBI makes
these analogues especially attractive.18-23 These and
several additional features including its enhanced inher-
ent reaction regioselectivity (>20:1 vs 4-6:1 (3), 4:1 (1),
1.5:1 (2)) have made CBI the most widely examined
alkylation subunit not only in our studies but in those of
many others as well.24-29
(5) Reviews: Boger, D. L.; Garbaccio, R. M. Acc. Chem. Res. 1999,
32, 1043. Boger, D. L.; Garbaccio, R. M. Bioorg. Med. Chem. 1997, 5,
263. Boger, D. L.; J ohnson, D. S. Angew. Chem., Int. Ed. Engl. 1996,
35, 1438. Boger, D. L. Acc. Chem. Res. 1995, 28, 20. Boger, D. L.;
J ohnson, D. S. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 3642. Boger, D.
L. Chemtracts: Org. Chem. 1991, 4, 329.
(6) Review of synthetic studies: Boger, D. L.; Boyce, C. W.; Gar-
baccio, R. M.; Goldberg, J . A. Chem. Rev. 1997, 97, 787.
(7) CC-1065: Boger, D. L.; J ohnson, D. S.; Yun, W.; Tarby, C. M.
Bioorg. Med. Chem. 1994, 2, 115. Boger, D. L.; Coleman, R. S.; Invergo,
B. J .; Sakya, S. M.; Ishizaki, T.; Munk, S. A.; Zarrinmayeh, H.; Kitos,
P. A.; Thompson, S. C. J . Am. Chem. Soc. 1990, 112, 4623.
(8) Duocarmycin A: Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H.;
Munk, S. A.; Kitos, P. A.; Suntornwat, O. J . Am. Chem. Soc. 1990,
112, 8961. Boger, D. L.; Ishizaki, T.; Zarrinmayeh, H. J . Am. Chem.
Soc. 1991, 113, 6645. Sugiyama, H.; Hosoda, M.; Saito, I.; Asai, A.;
Saito, H. Tetrahedron Lett. 1990, 31, 7197.
(9) Duocarmycin SA: Boger, D. L.; J ohnson, D. S.; Yun, W. J . Am.
Chem. Soc. 1994, 116, 1635.
(10) Warpehoski, M. A.; Hurley, L. H. Chem. Res. Toxicol. 1988, 1,
315. Hurley, L. H.; Needham-VanDevanter, D. R. Acc. Chem. Res. 1986,
19, 230.
(11) Boger, D. L.; Ishizaki, T.; Kitos, P. A.; Suntornwat, O. J . Org.
Chem. 1990, 55, 5823.
10.1021/jo035465x CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/06/2004
2284
J . Org. Chem. 2004, 69, 2284-2289

Effective Asymmetric Synthesis of CBI
Despite this interest, most studies detailing the prepa-
ration of optically active CBI derivatives have relied on
an effective semipreparative Chiralcel OD chromato-
graphic resolution30 of a racemic precursor for access to
the materials. Given the efficiency of the resolution (R )
1.30) and the material requirements for such potent
agents (L1210 IC50 ) 5-50 pM), a semipreparative OD
column that separates up to 100 mg per injection satisfies
most laboratory needs. Although several approaches to
the asymmetric synthesis of optically active precursors
have been disclosed, none have supplanted this or related
chromatographic resolutions.11 In part, this may be
attributed to the stringent optical purity (g99-99.9% ee)
required to distinguish the activity of an unnatural
enantiomer from that of its contaminant natural enan-
tiomer with many of the derivatives. The asymmetric
approaches include our own introduction31 of two comple-
mentary strategies that rely on an asymmetric hydrobo-
(12) (a) Boger, D. L.; Ishizaki, T.; Wysocki, R. J ., J r.; Munk, S. A.;
Kitos, P. A.; Suntornwat, O. J . Am. Chem. Soc. 1989, 111, 6461. (b)
Boger, D. L.; Ishizaki, T. Tetrahedron Lett. 1990, 31, 793. (c) Boger,
D. L.; Ishizaki, T.; Zarrinmayeh, H.; Kitos, P. A.; Suntornwat, O.
Bioorg. Med. Chem. Lett. 1991, 1, 55. (d) Boger, D. L.; Ishizaki, T.;
Sakya, S. M.; Munk, S. A.; Kitos, P. A.; J in, Q.; Besterman, J . M.
Bioorg. Med. Chem. Lett. 1991, 1, 115. (e) Boger, D. L.; Munk, S. A.;
Ishizaki, T. J . Am. Chem. Soc. 1991, 113, 2779. (f) Boger, D. L.; Munk,
S. A. J . Am. Chem. Soc. 1992, 114, 5487. (g) Boger, D. L.; Yun, W. J .
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J ohnson, D. S. Bioorg. Med. Chem. 1995, 3, 611. (i) Boger, D. L.; Yun,
W.; Cai, H.; Han, N. Bioorg. Med. Chem. 1995, 3, 761. (j) Boger, D. L.;
Yun, W.; Han, N. Bioorg. Med. Chem. 1995, 3, 1429.
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57, 2873.
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1993, 36, 1956.
ration (80% ee)32 or a J acobsen epoxidation (92% ee),33
a
route based on a Sharpless AD reaction (30-60%, 70%
ee),16 Lown’s lipase-catalyzed resolution of 4 (1st cycle
48%, 74% ee; 2nd cycle 78%, 96-99% ee),34 and Moha-
madi’s asymmetric hydroboration (58%, 40% ee)35 (Figure
2).
Over the course of many years, we have periodically
examined an attractive approach that is based on the
enzymatic desymmetrization of diol 12. The lipases that
were examined all provided low conversions or low ee’s
and typically required near stoichiometric, rather than
catalytic, amounts of enzyme. In line with these findings,
Lown reported a resolution of 4 (Figure 2, vs desymme-
trization) that requires 3.1 g of enzyme/g of substrate and
two reaction cycles to achieve satisfactory results (37%,
96-99% ee).34 To date, the most successful implementa-
tion of such an approach was described by Cheˆnevert
with supported PPL (porcine pancreatic lipase) in an
asymmetric synthesis of a precursor to the CI (1,2,7,7a-
tetrahydrocyclopropa[c]indol-4-one) alkylation subunit
(Scheme 1).36 Still, modest conversions and nonoptimal
ee’s were observed especially for the approach leading
to the natural enantiomer, and the analogous CBI
precursors are not effective substrates for PPL.
Recently, Martin reported a total synthesis of FR900482,
illustrating what may be the first example of a lipase
capable of effectively acting on substrates resembling the
size and structure of typical CBI precursors.37 A diol
substrate similar to the one we examined was enanti-
oselectively acylated with a highly purified, commercially
available Pseudomonas sp. lipase (Sigma), affording
excellent yields and ee’s (68%, >95% ee) even when used
in a catalytic versus near stoichiometric quantity. In
Martin’s efforts, alternative and less effective lipases
were examined with results analogous to our own obser-
vations. Herein, we report an effective asymmetric
(17) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Searcey, M.
Tetrahedron Lett. 1998, 39, 2227.
(18) (a) Boger, D. L.; Brunette, S. R.; Garbaccio, R. M. J . Org. Chem.
2001, 66, 5163. (b) Boger, D. L.; Hughes, T. V.; Hedrick, M. P. J . Org.
Chem. 2001, 66, 2207. (c) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.;
Searcey, M.; J in, Q. Synthesis 1999, 1505. (d) Boger, D. L.; Santillan,
A., J r.; Searcey, M.; J in, Q. J . Org. Chem. 1999, 64, 5241. (e) Boger,
D. L.; Santillan, A., J r.; Searcey, M.; J in, Q. J . Am. Chem. Soc. 1998,
120, 11554. (f) Boger, D. L.; Han, N. Bioorg. Med. Chem. 1997, 5, 233.
(g) Boger, D. L.; Garbaccio, R. M.; J in, Q. J . Org. Chem. 1997, 62, 8875.
(19) MCBI: Boger, D. L.; McKie, J . A.; Cai, H.; Cacciari, B.; Baraldi,
P. G. J . Org. Chem. 1996, 61, 1710. CCBI: Boger, D. L.; Han, N.; Tarby,
C. M.; Boyce, C. W.; Cai, H.; J in, Q.; Kitos, P. A. J . Org. Chem. 1996,
61, 4894. Boger, D. L.; McKie, J . A.; Han, N.; Tarby, C. M.; Riggs, H.
W.; Kitos, P. A. Bioorg. Med. Chem. Lett. 1996, 6, 659. CNA: Boger,
D. L.; Turnbull, P. J . Org. Chem. 1997, 62, 5844. Iso-CI/Iso-CBI: Boger,
D. L.; Garbaccio, R. M.; J in, Q. J . Org. Chem. 1997, 62, 8875. CBIn:
Boger, D. L.; Turnbull, P. J . Org. Chem. 1998, 63, 8004. CPyI: Boger,
D. L.; Boyce, C. W. J . Org. Chem. 2000, 65, 4088.
(20) Boger, D. L.; Schmitt, H.; Fink, B. E.; Hedrick, M. P. J . Org.
Chem. 2001, 66, 6654.
(21) Boger, D. L.; Stauffer, F.; Hedrick, M. P. Bioorg. Med. Chem.
Lett. 2001, 11, 2021.
(22) Parrish, J . P.; Kastrinsky, D. B.; Boger, D. L. Org. Lett. 2003,
5, 2577.
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Hwang, I.; Boger, D. L. Bioorg. Med. Chem. 2003, 11, 3815.
(24) (a) Wang, Y.; Yuan, H.; Wright, S. C.; Wang, H.; Larrick, J . W.
Bioorg. Med. Chem. 2003, 11, 1569. (b) Wang, Y.; Li, L.; Ye, W.; Tian,
Z.; J iang, W.; Wang, H.; Wright, S. C.; Larrick, J . W. J . Med. Chem.
2003, 46, 634. (c) Wang, Y.; Yuan, H.; Ye, W.; Wright, S. C.; Wang, H.;
Larrick, J . W. J . Med. Chem. 2000, 43, 1541.
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Beerman, T. A. J . Biol. Chem. 2002, 277, 42431. (b) Chang, A. Y.;
Dervan, P. B. J . Am. Chem. Soc. 2000, 122, 4856.
(26) (a) Kumar, R.; Lown, J . W. Org. Biomol. Chem. 2003, 1, 2630.
(b) Kumar, R.; Rai, D.; Ching, S.; Ko, C.; Lown, J . W. Heterocycl.
Commun. 2002, 8, 521. (c) Kumar, R.; Lown, J . W. Org. Lett. 2002, 4,
1851. (d) J ia, G.; Lown, J . W. Bioorg. Med. Chem. 2000, 8, 1607. (e)
J ia, G.; Iida, H.; Lown, J . W. Synlett 2000, 5, 603. (f) J ia, G.; Iida, H.;
Lown, J . W. Heterocycl. Commun. 1999, 5, 497. (g) J ia, G.; Iida, H.;
Lown, J . W. Heterocycl. Commun. 1998, 4, 557.
(27) (a) Tercel, M.; Stribbling, S. M.; Sheppard, H.; Siim, B. G.; Wu,
K.; Pullen, S. M.; Botting, K. J .; Wilson, W. R.; Denny, W. A. J . Med.
Chem. 2003, 46, 2132. (b) Gieseg, M. A.; Matejovic, J .; Denny, W. A.
Anti-Cancer Drug Des. 1999, 14, 77. (c) Hay, M. P.; Sykes, B. M.;
Denny, W. A.; Wilson, W. R. Bioorg. Med. Chem. Lett. 1999, 9, 2237.
(d) Atwell, G. J .; Tercel, M.; Boyd, M.; Wilson, W. R.; Denny, W. A. J .
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A. Bioorg. Med. Chem. Lett. 1997, 7, 1493.
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(32) Brown, H. C. Chemtracts: Org. Chem. 1988, 1, 77. Brown, H.
C.; Singaram, B. Acc. Chem. Res. 1988, 21, 287. Brown, H. C.;
Singaram, B. Pure Appl. Chem. 1987, 59, 879.
(33) Zhang, W.; Loebach, J . L.; Wilson, S. R.; J acobsen, E. N. J . Am.
Chem. Soc. 1990, 112, 2801.
(34) Ling, L.; Xie, Y.; Lown, J . W. Heterocyl. Commun. 1997, 3, 405
(13 g of lipase for 4.12 g of 4, 18 h, 48%, 74% ee; 2nd cycle 78%, 96%
ee). For a similar extension to the CPI alkylation subunit of CC-1065,
see: Lei, L.; Lown, J . W. Chem. Commun. 1996, 1559 (PSL, 72 h, 1st
cycle 49%, 72% ee; 2nd cycle 75%, >99% ee).
(35) Mohamadi, F.; Spees, M. M.; Staten, G. S.; Marder, P.; Kipka,
J . K.; J ohnson, D. A.; Boger, D. L.; Zarrinmayeh, H. J . Med. Chem.
1994, 37, 232.
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E.; Hudson, S.; Lee, M. Med. Chem. Res. 2002, 11, 248.
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J . Org. Chem. 2002, 10, 1634. (b) Tietze, L. F.; Feuerstein, T.; Fecher,
A.; Haunert, F.; Panknin, O.; Borchers, U.; Schuberth, I.; Alves, F.
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Fecher, A.; Haunert, F.; Schuberth, I. ChemBioChem 2001, 2, 758.
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(36) Cheˆnevert, R.; Courchesne, G. Chem. Lett. 1997, 11. See also:
Shishido, K.; Haruna, S.; Yamamura, C.; Iitsuka, H.; Nemoto, H.;
Shinohara, Y.; Shibuya, M. Bioorg. Med. Chem. Lett. 1997, 7, 2617.
(37) Fellows, I. M.; Kaelin, D. E.; Martin, S. F. J . Am. Chem. Soc.
2000, 122, 10781.
J . Org. Chem, Vol. 69, No. 7, 2004 2285

Kastrinsky and Boger
SCHEME 2
TABLE 1. Desym m etr iza tion of 12 a t 35 °C
substrate enzymea time diol 12 % monoacetate diacetate
(mg)
(mg)
(h)
(%)
(S)-13 (% ee)
(%)
20
100
100
100
200
50
1
1
2
4
4
3
4
24
48
28
20
26
16
14
-
35
7
-
3
70 (96)
47 (96)
82 (97)
88 (99)
92 (96)
77 (99)
80 (98)
10
2
4
8
5
-
1
9
7
50
a
Pseudomonas sp. lipase (Sigma).
precipitations and purified by crystallization, avoiding
chromatographic purifications (Scheme 2). This follows
an approach that had been developed for CPI39 and CI,40
and its extension here for 12 proved straightforward. The
exception to this generalization was the diester reduction
of 11 to provide diol 12. Initial methods examined
including Dibal-H which has been reported in the CI
synthesis provided modest yields of the diol (typically 33-
42%) and many additional products. In contrast, the
reduction of 11 with BH3-SMe241 proceeded exceptionally
well, providing 12 cleanly in good conversions (73%).
Although not extensively optimized (Table 1), the
desymmetrization of 12 was run in vinyl acetate, which
serves as both solvent and acyl donor (35 °C, 20 h), with
the Pseudomonas sp. lipase (PSL, 4 mg/100 mg of 12),
providing a single enantiomer of 1342 in 88% yield and
99% ee. The corresponding enzyme-catalyzed deacylation
desymmetrization of the diacetate of 12 was not as
successful. Thus, treatment of the diacetate with PSL (1
mg, 20 mg substrate) in either i-Pr2O-EtOH36 (35 °C, 5
days, 6% at <5% ee and 83% recovered diacetate) or 0.02
M pH 7 phosphate buffer (35 °C, 5 days, 39% at 79% ee
and 52% recovered diacetate) provided (R)-13 in much
less satisfactory conversions. The stereochemistry of (S)-
F IGURE 2. Approaches to the asymmetric synthesis of CBI.
SCHEME 1
synthesis of CBI, enlisting this commercially available
Pseudomonas sp. lipase (Sigma) to desymmetrize prochiral
diol 12, providing (S)-13 in exceptional conversions (88%)
and optical purity (99% ee). In addition to the superb
chemical yields and optical purities, this procedure
employs catalytic quantities of the enzyme, requiring 40-
fold less enzyme than the Cheˆnevert PPL desymmetri-
zation of a CI precursor36 and 400-fold less enzyme than
the Lown CBI resolution.34
Asym m etr ic Syn th esis by Desym m etr iza tion of
P r och ir a l Diol 12. An effective six- to seven-step
synthesis of prochiral diol 12 was developed starting with
5,38 in which the intermediates could be isolated by
(38) Compound
5 is available in two steps from commercially
available 4-amino-1-naphthol hydrochloride: Ac2O, Et3N, CH2Cl2, 0
°C, 74-84%; 90% HNO3, 18 °C, 69-78%. See: Kamel, M.; Nasr, H. I.
Kolor. Ert. 1968, 10, 177. J acobson, P. Chem. Ber. 1891, 14, 1794. Han,
G.; Shin, K. J .; Kim, D. C.; Yoo, H. H.; Kim, D. J .; Park, S. W.
Heterocycles 1996, 43, 2495.
(39) Warpehoski, M. A.; Gebhard, I.; Kelly, R. C.; Krueger, W. C.;
Li, L. H.; McGovren, J . P.; Prairie, M. D.; Wicnienski, N.; Wierenga,
W. J . Med. Chem. 1988, 31, 590.
(40) Wang, Y.; Lown, J . W. Heterocycles 1993, 36, 1399.
(41) Choi, Y. M.; Emblidge, R. W. J . Org. Chem. 1989, 54, 1198.
(42) A sample of racemic 13 was prepared by treatment of 12 with
Ac2O (1 equiv, pyridine, 25 °C, 3 h, 41%).
2286 J . Org. Chem., Vol. 69, No. 7, 2004

Effective Asymmetric Synthesis of CBI
SCHEME 3
SCHEME 5
SCHEME 4
TABLE 2. Desym m etr iza tion of 25 a t 35 °C
substrate enzymea time diol 25 % monoacetate diacetate
(mg)
(mg)
(h)
(%)
(S)-26 (% ee)
(%)
50
50
50
1
2
4
48
48
43
17
24
-
73 (91)
66 (93)
85 (93)
9
9
12
a
Pseudomonas sp. lipase (Sigma).
13 was established upon conversion to optically active
N-Boc-CBI precursors (16-20), which correlated with the
natural 1S configuration of authentic materials (Scheme
3). Thus, activation of the primary alcohol of 13 by
conversion to mesylate 14 using conditions which do not
promote acetate migration and partial racemization
(established by chiral HPLC), followed by nitro reduction
and subsequent in situ cyclization and N-Boc protection,
provides 15. This intermediate, an oil in racemic form,
solidified when enantiomerically enriched. Recrystalli-
zation afforded 15 in g99.9% ee and provides a conven-
ient stage and procedure to further enrich and ensure
the optical purity of subsequent intermediates. Acetate
hydrolysis provided 16, a key intermediate in the CBI
synthesis, and its one-step conversion to chloride 17
provides the key seco-N-Boc-CBI derivative.11
catalyst cleanly provided both nitro reduction and benzyl
ether hydrogenolysis to afford 15 in high yields (Scheme
3).
The intermediates required for preparation of the CBI
unnatural enantiomer were generated by orthogonal
protection of the free alcohol of 13, acetate hydrolysis,
mesylate formation, and subjection of 23 to the reductive
cyclization conditions described above (Scheme 5). No-
tably, we also found that a single recrystallization of (R)-
17 (EtOAc-hexanes) serves to enrich its optical purity
(g99.9%), ensuring that analogues in the unnatural
enantiomer series are free of contaminant natural enan-
tiomer. Importantly, although not highlighted above, the
recrystallization of (S)-17 can also serve as an alternative,
convenient stage at which to enrich and ensure the
optical purity in the natural enantiomer series.
Asym m etr ic Syn th esis by Desym m etr iza tion of
P r och ir a l Diol 25. In a similar study, the Pseudomonas
sp. lipase was also found to be capable of asymmetric
desymmetrization of diol 2543 (4-8 mg of PSL/100 mg of
25, vinyl acetate solvent, 35 °C, 48 h), providing (S)-26
in good chemical yields (70-85%) and excellent ee’s (91-
93%, Table 2 and Scheme 6). Although this was not
investigated in the same detail as diol 12, the conversions
appeared to occur more slowly and the yields and ee’s
were slightly lower. Nonetheless, effective conversions
were observed using comparable amounts of catalytic
enzyme even with a substrate that now contains a large
N-Boc protecting group proximal to the prochiral diol
center. Interestingly, efforts to enrich the optical purity
of (S)-26 by recrystallization led to diminished ee’s in the
solvent examined (EtOAc-hexanes) resulting from pref-
The reductive cyclization of 14 (and 23) initially proved
to be a problematic step. Using Adam’s catalyst (PtO2),
H2 (1 atm), Et3N, and Boc2O in THF in one pot provided
18 in modest yields of 35-60% (Scheme 4). Other
procedures including the use of Al(Hg) and Lindlar’s
catalyst did not proceed as well. Variations of the reaction
sequence (hydrogenation, then filtration, and then ad-
dition of Et3N and Boc2O vs hydrogenation in the pres-
ence of Et3N, then filtration, and then addition of Boc2O)
did not provide better conversions than the one-pot
procedure. We consistently observed partial benzyl re-
moval, incomplete Boc protection, and decomposition of
the unstable secondary aniline formed. Nonetheless,
under carefully controlled conditions, satisfactory amounts
of 18 are produced and can be used to prepare precursors
(i.e., 18-20) that maintain the phenol benzyl ether
protection. Circumventing these problems and further
shortening the sequence, we found that the one-pot
reaction sequence using 10% Pd/C as the hydrogenation
(43) Prepared from 12 in four steps: Me2C(OMe)2, TsOH, DMF, 25
°C, 16 h, 62%; H2, Lindlar’s catalyst (5% Pd/CaCO3), quinoline, 25 °C,
16 h, 68%; (Boc)2O, THF, 70 °C, 24 h, 80%; TsOH, MeOH, 25 °C, 1 h,
88%.
J . Org. Chem, Vol. 69, No. 7, 2004 2287

Kastrinsky and Boger
SCHEME 6
SCHEME 7
evaluation of CC-1065 and duocarmycin analogues. The
first entails the desymmetrization of 12 enlisting a highly
purified Pseudomonas sp. lipase (PSL, Sigma) which
provided (1S)-13 in superb yield (88%) and excellent
optical purity (99% ee). All material is converted to a
single enantiomerically pure product, (1S)-13, from which
either enantiomer of CBI may be accessed. An alternative
and nearly as effective approach was developed that
entailed the PSL desymmetrization of diol 25, providing
(S)-26 in good chemical yield (70-85%) and satisfactory
optical purity (91-93% ee). A second approach enlisted
PSL for resolution of the racemic alcohol (()-19 and offers
an attractive alternative late stage access to both enan-
tiomers. Because the studies indicate that the PSL is
substantially more effective on CBI-like precursors than
any other enzyme previously disclosed, they also suggest
that it may be applicable to all related alkylation subunit
precursors (e.g., CPI, DSA, and CI).
erential crystallization of the racemate (with enhanced
ee’s of the recrystallization mother liquor). However, an
interesting distinction with 26 [(R ) 1.7) vs 13 (R ) 1.38)]
was that a direct chiral phase HPLC separation (Chiral-
cel OD) of the enantiomers is very effective. This level of
resolution (R ) 1.7) provides not only the opportunity to
enhance the optical purity of 26 by a preparatively useful
chromatography on a chiral phase but also the option of
a direct and preparatively useful chromatographic reso-
lution in itself. A single-step formation of the correspond-
ing mesylate and subsequent in situ -NHBoc displace-
ment with closure of the five-membered ring provided (S)-
18, confirming the assigned stereochemistry and providing
an alternative approach to the synthesis of natural
enantiomer (S)-17. Notably, the optical purity of (S)-17
could be enriched by recrystallization at this stage, as
detailed beforehand.
Similarly, the unnatural enantiomer series was ac-
cessed by alcohol protection to provide 27 and acetate
hydrolysis to provide alcohol 28, followed by single-step
mesylate formation and subsequent in situ -NHBoc
displacement to provide (R)-29 (Scheme 6). Silyl ether
deprotection provided (R)-19 and access to the unnatural
enantiomer series.
Asym m etr ic Syn th esis w ith Resolu tion of 19.
There is precedence34 with CPI for the asymmetric
synthesis of an alkylation subunit by the enzymatic
resolution of a racemic alcohol precursor. An alternative
approach to the asymmetric synthesis of CBI that
proceeds through racemic intermediate 19 was also
explored with the purified Pseudomonas sp. lipase.
Notably, the synthesis of (()-19 requires only seven steps
from readily available 1,3-dihydroxynaphthalene and is
straightforward to implement.17 The resolution of alcohol
19 (Scheme 7) provided the acetylated natural enantio-
mer in 39-54% yield (56-68% ee) and the unreacted
unnatural enantiomer in 34-47% yield and up to 99%
ee. The enriched acetylated natural enantiomer can be
obtained in optically pure form (g99.9% ee) by successive
recrystallizations (two times, EtOAc-hexanes).
Exp er im en ta l Section
(S)-1-Acetoxy-2-(4-ben zyloxy-2-n itr on a p h th a len -1-yl)-
p r op a n -3-ol ((S)-13). A sample of 12 (100 mg, 0.283 mmol),
4 Å molecular sieves (100 mg), and Pseudomonas sp. lipase (4
mg, Sigma) were dissolved in vinyl acetate (1.5 mL, distilled
from CaCl2). The reaction was stirred at 35 °C for 20 h and
filtered through a Celite plug. The Celite was washed with
CH2Cl2, and the combined organic solutions were concentrated
in vacuo. Flash chromatography (SiO2, 33% EtOAc-hexanes)
afforded monoacetate (S)-13 (98.2 mg, 88%) and diacetate (9.3
mg, 8%). The sample of (S)-13 was determined to be 99% ee
by HPLC (Chiralcel AS column; 0.46 cm × 25 cm; 4:1 hexanes-
i-PrOH; 1 mL/min; retention times, 21 min for (S)-13 and 29
min for (R)-13).42 For (S)-13: yellow oil; [R]D -73 (c 1.0,
23
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 8.46 (1H, d, J ) 9.2 Hz),
8.14 (1H, br s), 7.68 (1H, br t), 7.63 (1H, t, J ) 7.5 Hz), 7.52
(2H, d, J ) 7.0 Hz), 7.46 (2H, t, J ) 7.0 Hz), 7.43 (1H, t, J )
7.0 Hz), 7.06 (1H, s), 5.27 (2H, s), 4.86 (1H, br s), 4.55 (1H,
dd, J ) 6.2, 4.8 Hz), 4.28 (1H, br s), 4.18 (1H, br s), 3.86 (1H,
br s), 2.03 (3H, s), 1.96 (1H, br s); 13C NMR (CDCl3, 100 MHz)
δ 171.3, 154.8, 150.6, 135.8, 132.0, 129.0 (2C), 128.75, 128.66,
127.81 (2C), 127.76, 127.6, 126.4, 123.7, 121.4, 99.9, 70.9, 65.2,
63.8, 44.0, 21.1; IR (film) νmax 3395, 1734, 1593, 1527, 1237
cm-1; MALDIFT-HRMS (DHB) m/z 418.1265 (M + Na+,
Con clu sion s
C
22H21NO6 requires 418.1261).
For the diacetate [2-(4-benzyloxy-2-nitronaphthalen-1-yl)-
Effective asymmetric syntheses of key CBI precursors
were developed that provide the optically active inter-
mediates in good yields and sufficient optical purities
(g99-99.9% ee) to be useful in the preparation and
1,3-diacetoxypropane]: 1H NMR (CDCl3, 600 MHz) δ 8.45 (1H,
d, J ) 8.3 Hz), 8.09 (1H, br s), 7.68 (1H, br s), 7.64 (1H, br s),
7.52 (2H, d, J ) 7.4 Hz), 7.46 (2H, t, J ) 7.5 Hz), 7.41 (1H, t,
J ) 7.4 Hz), 7.07 (1H, br s), 5.27 (2H, s), 4.85 (1H, br s), 4.64
2288 J . Org. Chem., Vol. 69, No. 7, 2004

Effective Asymmetric Synthesis of CBI
(1H, br s), 4.55 (1H, d, J ) 6.1 Hz), 4.54 (1H, d, J ) 6.1 Hz),
3.99 (1H, br s), 2.02 (6H, s); 13C NMR (CDCl3, 100 MHz) δ
171.0 (2C), 155.0, 150.6, 135.8, 131.8, 129.0 (2C), 128.7, 127.8
(2C), 127.6, 126.2, 124.9, 123.9, 123.4, 120.4, 99.9, 71.0, 64.6
(2C), 40.3, 21.0 (2C); IR (film) νmax 1738, 1532, 1231 cm-1
;
MALDIFT-HRMS (DHB) m/z 460.1377 (M + Na+, C24H23NO7
requires 460.1367).
(R)-1-Acetoxy-2-(4-ben zyloxy-2-n itr on a p h th a len -1-yl)-
3-(m eth a n esu lfon yloxy)p r op a n e ((R)-14). A solution of (S)-
13 (106 mg, 0.268 mmol) in pyridine (1.0 mL) cooled to 0 °C
was treated dropwise with MsCl (41.0 µL, 0.536 mmol), and
the mixture was stirred at 0 °C for 1 h and then at 25 °C for
1 h. Ice water (5 mL) was added, and the mixture was
extracted with EtOAc (3 × 10 mL). The combined organic
layers were washed with 1 M aqueous HCl (3 × 5 mL), dried
(Na2SO4), and concentrated in vacuo to provide (R)-14 (116
mg, 92%) as a tan oil which was used in the next reaction
without further purification: [R]D -38 (c 1.2, CHCl3); 1H
23
NMR (CDCl3, 500 MHz, 25 °C) δ 8.48 (1H, d, J ) 8.4 Hz), 8.40
and 8.02 (1H, two br s), 7.72 (1H, br s), 7.66 (1H, br s), 7.53
(2H, d, J ) 7.3 Hz), 7.46 (2H, t, J ) 7.0 Hz), 7.42 (1H, t, J )
7.3 Hz), 7.12 (1H, br s), 5.27 (2H, s), 4.92 (2H, br s), 4.63 (2H,
br s), 4.56 (1H, dd, J ) 5.7, 5.2 Hz), 2.94 (3H, s), 2.05 (3H, s);
1H NMR (CDCl3, 500 MHz, 50 °C) δ 8.48 (1H, d, J ) 8.4 Hz),
8.17 (1H, br s), 7.73 (1H, t, J ) 7.0 Hz), 7.66 (1H, t, J ) 8.1
Hz), 7.53 (2H, d, J ) 7.0 Hz), 7.46 (2H, t, J ) 7.0 Hz), 7.42
(1H, t, J ) 7.3 Hz), 7.14 (1H, br s), 5.30 (2H, s), 4.88 (2H, br
s), 4.69 (2H, br s), 4.56 (1H, dd, J ) 5.9, 5.5 Hz), 2.93 (3H, s),
2.04 (3H, s); 13C NMR (CDCl3, 125 MHz) δ 170.9, 155.3, 150.7,
135.7, 131.7, 129.0 (2C), 128.7, 127.8 (2C), 127.6, 125.9, 124.7,
124.1, 123.5, 119.3, 100.0, 71.0, 69.1, 64.0, 40.6, 37.7, 21.0; IR
(film) νmax 1741, 1530, 1360, 1229 cm-1; MALDIFT-HRMS
(DHB) m/z 496.1041 (M + Na+, C23H23NO8S requires 496.1037).
(S)-1-Acet oxym et h yl-3-(ter t-b u t yloxyca r b on yl)-5-h y-
d r oxy-1,2-d ih yd r o-3H-ben z[e]in d ole ((S)-15). A solution of
(R)-14 (213 mg, 0.450 mmol) in THF (8.0 mL) was treated with
10% Pd/C (15 mg), Et3N (120 mL, 0.900 mmol), and Boc2O (196
mg, 0.900 mmol), and the mixture was stirred at 25 °C for 8
h under 1 atm of H2. The reaction mixture was filtered through
Celite and concentrated in vacuo. Flash chromatography (SiO2,
1-10% EtOAc-hexanes) provided (S)-15 (122 mg, 76%; typi-
cally 71-78%) as a beige solid: mp 147-148 °C (white needles,
F IGURE 3. HPLC trace of (S)-16 before (96% ee) and after
recrystallization (g99.9% ee) of (S)-15 from EtOAc-hexanes
(Chiralcel AS; 0.46 cm × 25 cm; 19:1 hexanes-i-PrOH; 1 mL/
min; retention times, 27.4 min for (S)-16 and 31.9 min for (R)-
16).
23
(99.9% ee) (Figure 3). For (S)-16: [R]D -1.4 (c 0.8, CHCl3);
1H NMR (CDCl3, 400 MHz) δ 8.19 (1H, d, J ) 8.2 Hz), 7.77
(1H, br s), 7.65 (1H, d, J ) 8.2 Hz), 7.43 (1H, td, J ) 6.8, 1.1
Hz), 7.30 (1H, t, J ) 8.2 Hz), 4.20 (1H, d, J ) 11.2 Hz), 4.10
(1H, d, J ) 8.8 Hz), 3.93 (1H, dd, J ) 10.3, 3.2 Hz), 3.82 (1H,
m), 3.75 (1H, t, J ) 7.3 Hz), 1.56 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 153.8, 153.2, 141.6, 130.9, 127.4, 123.7, 122.9,
122.5, 121.8, 114.3, 99.4, 81.5, 64.9, 52.7, 41.5, 28.7 (3C); IR
(film) νmax 3363, 2978, 1673, 1584, 1145 cm-1; MALDIFT-
HRMS (DHB) m/z 315.1466 (M+, C18H21NO4 requires 315.1465).
(S)-3-(ter t-Bu t yloxyca r b on yl)-1-(ch lor om et h yl)-5-h y-
d r oxy-1,2-d ih yd r o-3H-ben z[e]in d ole ((S)-17). A solution of
(S)-16 (89.8 mg, 0.285 mmol) in CH2Cl2 (2.0 mL) at 25 °C was
treated with Ph3P (262 mg, 0.854 mmol) and CCl4 (246 µL,
2.56 mmol) and stirred for 3 h. The reaction mixture was
concentrated in vacuo. Flash chromatography (SiO2, 10-20%
EtOAc-hexanes) provided (S)-17 (77.0 mg, 81%, typically 71-
81%) as a white solid (mp 161 °C)11 which was identical in all
respects to authentic compound. Compound (S)-17 exhibits a
23
1
EtOAc-hexanes); [R]D -1 (c 1.0, CHCl3); H NMR (CDCl3,
500 MHz) δ 8.17 (1H, d, J ) 7.0 Hz), 7.77 (1H, d, J ) 8.1 Hz),
7.75 (1H, br s), 7.51 (1H, t, J ) 8.0 Hz), 7.33 (1H, t, J ) 7.3
Hz), 4.57 (1H, d, J ) 8.4 Hz), 4.07 (2H, d, J ) 8.1 Hz), 3.95
(1H, m), 3.87 (1H, t, J ) 9.9 Hz), 2.11 (3H, s), 1.61 (9H, s); 13
C
NMR (CDCl3, 100 MHz) δ 171.5, 153.9, 153.2, 141.2, 130.9,
127.6, 123.5, 123.0, 122.7, 121.7, 114.0, 99.3, 81.7, 66.2, 52.9,
38.5, 28.7 (3C), 21.2; IR (film) νmax 3381, 1698, 1390, 1144 cm-1
;
MALDIFT-HRMS (DHB) m/z 357.1574 (M+, C20H23NO5 re-
quires 357.1574).
23
concentration dependent optical rotation: [R]D -65 (c 1.0,
23
CH2Cl2), -44 (c 0.31); lit. [R]D -70 (c 1.04, CH2Cl2), -48 (c
The recrystallization of (S)-15 (EtOAc-hexanes) may be
used to further enrich the optical purity of this and the
following synthetic intermediates (Figure 3).
0.30, CH2Cl2).
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41986) and the Skaggs Institute for Chemical Biol-
ogy. D.B.K. is a Skaggs Fellow.
(S)-3-(ter t-Bu t yloxyca r b on yl)-5-h yd r oxy-1-h yd r oxy-
m eth yl-1,2-d ih yd r o-3H-ben z[e]in d ole ((S)-16). A solution
of (S)-15 (41.7 mg, 0.117 mmol) in MeOH (1.0 mL) at 25 °C
was treated with K2CO3 (64.5 mg, 0.467 mmol) and stirred
for 1 h. A solution of 1 M aqueous HCl was added to adjust
the pH to 6, and the mixture was extracted with EtOAc (3 ×
5 mL). The combined organic layers were washed with aqueous
saturated NaCl (5 mL), dried (Na2SO4), and concentrated in
vacuo, providing (S)-16 (35.0 mg, 94%; typically 84-94%) as
a beige film which did not require further purification. The ee
of (S)-16 was determined by HPLC (Chiralcel AS column; 0.46
cm × 25 cm; 19:1 hexanes-i-PrOH; 1 mL/min; retention times,
27.4 min for (R)-16 and 31.9 min for (S)-16) before recrystal-
lization of (S)-15 (96% ee) and after recrystallization of (S)-15
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and compound characterization for the preparation of 12,
18, and 19, the conversion of (S)-13 to (R)-17 and of 12 to 25,
the desymmetrization of 25, and the conversion of (S)-26 to
(S)-18 or (R)-19, details of the resolution of (()-19, and copies
1
of the H NMR of all compounds are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O035465X
J . Org. Chem, Vol. 69, No. 7, 2004 2289