Enantioselective synthesis of a mitosane core assisted by diversity-based catalyst discovery.

Article abstract of DOI:10.1021/ol016372+

[reaction: see text]. Synthesis of mitosane 1 in optically pure form is reported. A retrosynthetic plan that proceeds through racemic allylic alcohol 3 was carried out. This intermediate served as a test substrate for a rapid screen of a small library (15

Full text of DOI:10.1021/ol016372+

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2879-2882
Enantioselective Synthesis of a
Mitosane Core Assisted by
Diversity-Based Catalyst Discovery
Nikolaos Papaioannou, Catherine A. Evans, Jarred T. Blank, and Scott J. Miller*
Department of Chemistry, Merkert Chemistry Center, Boston College,
Chestnut Hill, Massachusetts 02467-3860
scott.miller.1@bc.edu
Received June 29, 2001
ABSTRACT
Synthesis of mitosane 1 in optically pure form is reported. A retrosynthetic plan that proceeds through racemic allylic alcohol 3 was carried
out. This intermediate served as a test substrate for a rapid screen of a small library (152 members) of peptide-based kinetic resolution
catalysts. Peptide 9 was found to effect kinetic resolution with krel ) 27. Alcohol (−)-3 was then converted to optically pure (−)-1 in eight steps.
The mitomycin antitumor agents maintain an important status
in both experimental and clinical cancer chemotherapy.1 In
addition to being used as drugs for the treatment of tumors,
they have been prototypes for mechanistic studies in the field.
Mitomycin C has been shown to act by covalent cross-linking
of duplex DNA.2 Asymmetric synthesis continues to be an
essential component of this research, with the recent finding
that the two enantiomers of mitomycin C possess different
specificities for alkylation of DNA.3 Synthetic studies on the
mitomycins are producing a wealth of important information
on these significant targets. The field has been highlighted
by the total syntheses of members of the class including
several mitomycins and the related FR900482 by the Kishi,4
Fukuyama,5 Danishefsky,6 Martin,7 and Terashima8 labora-
tories. In addition, a number of other important advances
have been reported in the literature.9 We report herein an
enantioselective synthesis of a mitosane core (Scheme 1, 1).
In particular, we wished to investigate the possibility of
screening a library of peptide-based acylation catalysts as a
means of discovering a kinetic resolution catalyst for a key
secondary alcohol intermediate.10-12 Such a strategy could
(5) Mitomycin C: (a) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1989,
111, 8303-8304. (b) Fukuyama, T.; Yang, L. J. Am. Chem. Soc. 1987,
109, 7881-7882. FR900482: (c) Fukuyama, T.; Xu, L.; Goto, S. J. Am.
Chem. Soc. 1992, 114, 383-385.
(6) Danishefsky, S. J.; Schkeryantz, J. M. Synlett 1995, 475-490. This
paper also provides an excellent bibliography to the mitomycin literature.
(7) Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc.
2000, 122, 10781-10787.
(8) (a) Katoh, T.; Itoh, E.; Yoshino, T.; Terashima, S. Tetrahedron 1997,
53, 10229-10238. (b) Yoshino, T.; Nagata, Y.; Itoh, E.; Hashimoto, M.;
Katoh, T.; Terashima, S. Tetrahedron 1997, 53, 10239-10252. (c) Katoh,
T.; Nagata, Y.; Yoshino, T.; Nakatani, S.; Terashima, S. Tetrahedron 1997,
53, 10253-10270.
(1) (a) Carter, S. K.; Crooke, S. T. Mitomycin C, Current Status and
New DeVelopments; Academic Press: New York, 1979. (b) Remers, W.
A.; Iyengar, B. S. In Cancer Chemotherapeutic Agents; Foye, W. O., Ed.;
American Chemical Society: Washington, DC, 1995; pp 584-592.
(2) Tomasz, M.; Lipman, R.; Chowdary, D.; Pawlak, J.; Verdine, G.;
Nakanishi, K. Science 1987, 235, 1204-1208.
(9) For example, see: (a) Vedejs, E.; Klapars, A.; Naidu, B. N.;
Piotrowski, D. W.; Tucci, F. C. J. Am. Chem. Soc. 2000, 122, 5401-5402.
(b) Lee, S.; Lee, W. M.; Sulikowski, G. A. J. Org. Chem. 1999, 64, 4224-
4225. (c) Dong, W.; Jimenez, L. S. J. Org. Chem. 1999, 64, 2520-2523.
(d) Edstrom, E. D.; Yu, T. Tetrahedron 1997, 53, 4549-4560. (e) Wang,
Z.; Jimenez, L. S. J. Org. Chem. 1996, 61, 816-818. (f) Katoh, T.; Yoshino,
T.; Nagata, Y.; Nakatani, S.; Terashima, S. Tetrahedron Lett. 1996, 37,
3479-3482. (g) Shaw, K. J.; Luly, J. R.; Rapoport, H. J. Org. Chem. 1985,
50, 4515-4523. (h) Ban, Y.; Nakajima, S.; Yoshida, K.; Mori, M.;
Shibasaki, M. Heterocycles 1994, 39, 657-607.
(3) Gargiulo, D.; Musser, S. S.; Yang, L.; Fukuyama, T.; Tomasz, M. J.
Am. Chem. Soc. 1995, 117, 9388-9398.
(4) For a review of the Kishi laboratory’s synthetic studies, see: Kishi,
Y. J. Nat. Prod. 1979, 42, 549-568.
10.1021/ol016372+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/03/2001

flux)18,19 then yielded cyclooctene 7 in 83% yield. Reduction
of ketone 7 (LiAlH4, 0 °C) proceeded in quantitative yield
to give allylic alcohol 3 in racemic form.
Scheme 1
Scheme 2a
prove generally useful in the context of target-oriented
synthesis because chiral secondary alcohols so often figure
in target retrosyntheses.
Our retrosynthetic analysis is predicated on the expectation
that aminal-ether 1 could be accessed through an ap-
propriately functionalized eight-membered ring (Scheme 1).
We envisioned that allylic alcohol (-)-3 could be obtained
in optically pure form from the racemate, provided we could
rapidly identify an enantioselective catalyst for kinetic
resolution. For this goal, we planned to screen catalysts from
a peptide-based library of candidates.13
a (a) Ethylene glycol, TsOH, PhCh3, reflux; (b) BOC2O, DMAP,
Et3N, CH2Cl2, 25 °C; (c) NaOH, THF/H2O, reflux; (d) allyl bromide,
NaH, DMF, 0 °C to rt; (e) NaOH, THF/H2O, reflux; (f)
MeNH(OMe), EDC, CH2Cl2, 25 °C; (g) vinyl magnesium bromide,
THF, 0 °C; (h) LiAlH4, Et2O, 0 °C.
The synthesis of 3 was realized as follows. Isatin was
converted to the ethylene-bridged ketal upon treatment with
ethylene glycol and TsOH (PhCH3, reflux; 99%).14 The
indolinic nitrogen was then converted to the BOC-protected
aniline under standard conditions (86%).15 Saponification
(99%) was followed by simultaneous allylation of the aniline
and carboxylic acid functional group by treatment with allyl
bromide and sodium hydride (87%) to provide ester 4 in
73% overall yield (four steps). Vinyl ketone 5 was then
obtained by a three-step sequence wherein ester 4 was
subjected to hydrolysis (NaOH, THF/H2O; 99%) and conver-
sion to the intermediate Weinreb amide (64%).16 Addition
of vinylmagnesium bromide under carefully controlled
conditions (THF, 0 °C) to avoid conjugate addition of the
expelled MeNH(OMe)17 was achieved to afford 5 in 99%
yield (63% from 4, three steps). Ring-closing metathesis
employing the Ru-alkylidene 6 (10 mol %, CH2Cl2, re-
We then turned our attention to the identification of a
catalyst for the kinetic resolution of 3 (eq 1). Since compound
3 does not bear close resemblance to substrates we had
studied previously,13 we sought to screen a diverse set of
catalyst candidates; we prepared 152 peptides of the general
structure 8 (Figure 1a).20 Screening of the unpurified catalysts
at room temperature for kinetic resolution of compound 3
21
resulted in selectivity factors (kfast/kslow
)
that ranged from
1 to 10 (Figure 1b). Catalyst 9 in particular proved to be
promising and was therefore purified to homogeneity for
further study. We then found that when the resolution was
conducted at 0 °C and in the presence of Et3N (6 equiv), the
observed krel value improved to 27. From a practical point
of view, recovered alcohol 3 can be obtained in high optically
purity (90% ee, 53% conv), with isolated yields of >40%
(theoretical ) 47%).22 A single recrytallization affords 3 in
>99% ee.
The stereochemical identitity of the slow reacting enan-
tiomer was established by conversion of the recovered
(10) Jandeleit, B.; Schaefer, D. J.; Powers, T. S.; Turner, H. W.;
Weinberg, W. H. Angew. Chem., Int. Ed. 1999, 38, 2494-2532.
(11) For several recent reviews of combinatorial catalysis, see: (a) Kuntz,
K. W.; Snapper, M. L.; Hoveyda, A. H. Curr. Opin. Chem. Biol. 1999, 3,
313-319. (b) Francis, M. B.; Jamison, T. F.; Jacobsen, E. N. Curr. Opin.
Chem. Biol. 1998, 2, 422-428.
(18) (a) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 2247-2250. (b) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18-29.
(12) For reviews of catalytic kinetic resolution, see: (a) Keith, J. M.;
Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5-26. (b)
Hoveyda, A. H.; Didiuk, M. T. Curr. Org. Chem. 1998, 2, 537-574.
(13) (a) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
6496-6502. (b) Jarvo, E. R.; Copeland, G. T.; Papaioannou, N.; Bonitatebus,
P. J.; Miller, S. J. J. Am. Chem. Soc. 1999, 121, 11638-11643.
(14) Rajopadhye, M.; Popp, F. D. J. Med. Chem. 1988, 31, 1001-1005.
(15) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983, 48,
2424-2426.
(19) For recent reviews of RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413-4450. (b) Fuerstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. For related RCM reactions in mitomycin model
systems, see: (c) Martin, S. F.; Wagman, A. S. Tetrahedron Lett. 1995,
36, 1169-1170. (d) Miller, S. J.; Kim, S. H.; Chen, Z.-R.; Grubbs, R. H.
J. Am. Chem. Soc. 1995, 117, 2108-2109.
(20) The identity of each catalyst and the general procedure for their
syntheses may be found in the Supporting Information.
(21) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.
(22) The screening experiments, exclusive of peptide synthesis, were
accomplished in 4 days.
(16) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-3818.
(17) Gomtsyan, A. Org. Lett. 2000, 2, 11-13.
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Org. Lett., Vol. 3, No. 18, 2001

Scheme 3a
Figure 1. (a) Library of 152 catalysts for kinetic resolutions of 3
and the optimum member of the library, 9. (b) Distribution of
s-factors for library (8) observed for screening of substrate 3
(reactions conducted at 25 °C).
a (a) Oxone, NaHCO3, acetone/H2O (3:1); (b) (ClCO)2, DMSO,
Et3N, CH2Cl2; (c) trace HNO3, MeOH, 135 °C; (d) Sm(O-i-Pr)3,
TMSN3, CH2Cl2; (e) HCl/MeOH; (f) MsCl, Et3N, CH2Cl2; (g) resin-
bound PPh3, Hunig’s base, THF/H2O; (h) Bz2O, DMAP, CH2Cl2.
alcohol (-)-3 to the derived Mosher ester 10 employing the
acid chloride derived from (R)-Mosher’s acid;23 inspection
of the X-ray crystal structure allowed an assignment of
absolute configuration (eq 2).
the presence of (-)-3 led to production of epoxide 11 with
high diastereoselectivity (>98:2, quantitative yield). The
assignment of the anti-stereochemistry was secured by X-ray
crystallographic analysis of the benzoate (11-Bz) derived
from epoxyalcohol 11. Swern oxidation afforded epoxy-
ketone 12 in 94% yield. Removal of the protecting groups,
with concomitant cyclization to epoxide 13, was achieved
in a single step under thermolysis conditions (135 °C, 81%).
We found that trace amounts of nitric acid (5 mol %)
facilitated the rate of the reaction. X-ray analysis of epoxide
13 revealed the anti-orientation of the epoxide and methoxy
group. Conversion of 13 to aziridine 1 was initiated with a
Lewis acid promoted (Sm(O-i-Pr)3) ring opening in the
presence of TMSN3 to produce hydroxy azide 14, which was
then converted to a mixture of epimers under acidic condi-
tions (HCl/MeOH, combined yield, 86%).25 Activation of
14 toward aziridine formation was accomplished by conver-
sion to mesylate 15. Reductive cyclization was effected by
With access to (-)-3 in optically enriched form, we set
out to convert this compound to the tetracyclic mitosane core
1 (Scheme 3). In situ generation of dimethyldioxirane24 in
(23) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549. (b) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32,
7165-7166.
(24) Wang, Z.-X.; Miller, S. H.; Anderson, O. P.; Shi, Y. J. Org. Chem.
1999, 64, 6443-6458.
(25) See: Martinez, L. E.; Leighton, J. L.; Cartsen, D. H.; Jacobsen, E.
N. J. Am. Chem. Soc. 1995, 117, 5897-5898 and references therein.
Org. Lett., Vol. 3, No. 18, 2001
2881

resin-bound PPh3 to afford aziridine 1 in 42% yield (two
steps) with the trans-configuration, corresponding to natural
mitomycin stereochemistry.
Acknowledgment. The authors wish to thank Mr. James
P. Jewell for assistance in the preparation of intermediates.
This research is supported by National Science Foundation
(CHE-9874963). We also thank the National Institutes of
Health (GM-57595) for additional research support. In
addition, we are grateful to DuPont, Eli Lilly, Glaxo-
Wellcome, and the Merck Chemistry Council for research
support. S.J.M. is a Fellow of the Alfred P. Sloan Foundation,
a Cottrell Scholar of Research Corporation, and a Camille
Dreyfus Teacher-Scholar.
In conclusion, we report a concise synthesis of the
tetracyclic mitosane skeleton with high optical purity.
Enantioselectivity was achieved in rapid fashion by screening
a moderately sized peptide library of acylation catalysts for
kinetic resolution of a key intermediate. We now intend to
explore this strategy of catalyst identification in the context
of enantioselective total synthesis of these and other biologi-
cally active agents. Since so many targets of diverse structure
can be addressed with retrosyntheses that involve chiral and
racemic alcohol intermediates, the ability to rapidly identify
catalysts for kinetic resolution may facilitate enantioselective
syntheses by providing a straightforward and potentially
unified approach.
Supporting Information Available: Experimental pro-
cedures and compound characterization for all aspects of the
study. X-ray crystallographic data for compounds 1, 10, 11-
Bz, and 13. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Org. Lett., Vol. 3, No. 18, 2001