An Enantioselective 1,2-Aziridinomitosene Synthesis via a Chemoselective Carbon-Hydrogen Insertion Reaction of a Metal Carbene

Full text of DOI:10.1021/jo990469g

4224
J . Org. Chem. 1999, 64, 4224-4225
An En a n tioselective 1,2-Azir id in om itosen e
Syn th esis via a Ch em oselective
Ca r bon -Hyd r ogen In ser tion Rea ction of a
Meta l Ca r ben e
Sangku Lee, Wai-Man Lee, and Gary A. Sulikowski*
Department of Chemistry, Texas A&M University,
College Station, Texas 77843
Received March 16, 1999
Several concise routes to assembling the 1,2-aziridinomi-
tosene ring system common to the mitomycin antitumor
antibiotics (cf. mitomycin C (1)) have been published.1 Few
of these synthetic routes have led to the production of
nonracemic products.2 Earlier we reported an enantioselec-
tive approach to 1,2-disubstituted mitosenes which relied
on the desymmetrization of a meso diazoester by way of an
asymmetric intramolecular carbon-hydrogen insertion reac-
tion.3 Unfortunately, the levels of enantioselectivity in this
process were disappointingly low. Herein, we describe a
second generation strategy which ultimately provides a 1,2-
aziridinomitosene in high optical purity.
F igu r e 1.
The key elements of our synthetic strategy are outlined
in Figure 1 which shows metal carbene 5 may undergo an
intramolecular carbon-hydrogen insertion reaction by one
of two pathways (labeled a and b). Cyclization by way of path
a leads to azido ether 3 while the alternate cyclization (path
b) leads to 4. Subsequent closure of the azido alcohols derived
from 3 and 4 would lead to 1,2-aziridinomitosene 2 and ent-2
respectively. Thus, depending on the chemoselectivity of the
insertion reaction (path a versus path b), either enantiomer
of aziridinomitosene 2 may be derived from a common metal
carbene (5).4
Our investigations started with the synthesis of ester 10
from pyrrolidine 6 (Scheme 1). J acobsen has described the
efficient preparation of azido alcohol 6 by the asymmetric
ring opening of a meso epoxide with TMSN3 catalyzed by a
chiral (salen)Cr(III) complex.5 Following silylation of 6 and
removal of the Boc-protecting group, we determined the
enantiomeric excess of 8 to be 94.7% using capillary elec-
trophoresis as the analytical method.6 Palladium-catalyzed
cross-coupling of 8 with 2-bromoiodobenzene using Buch-
wald-Hartwig conditions7,8 gave aryl bromide 9 which was
subsequently coupled with the silylketene acetal derived
from tert-butyl acetate in the presence of tributyltin fluoride
to afford aryl acetate 10.9 At this point we examined a series
of diazotransfer reactions to produce a forerunner to metal
carbene 5. Unfortunately, all attempts to effect a diazotrans-
fer upon aryl acetate 10 and other derivatives failed; the
only detectable product in these cases was undesired azide
transfer.10 On the basis of experience with similiar sub-
strates, we determined the difficulty in effecting a diazo-
transfer to lie in the trans relationship of the azido and silyl
ether groups. This led us to convert azido ether 10 to
carbamate 18 starting with a reaction sequence develped
by J acobsen for the conversion of trans azido alcohols to cis
amino alcohols.11 To this end, hydrogenation of 10 gave
amine 11 which following acetylation and desilylation
yielded amide alcohol 13. Mesylation of 13 followed by DBU
treatment gave oxazoline 14, completing inversion of ster-
eochemistry at the oxygen-bearing carbon. Hydrolysis of 14
followed by tosylation and phosgene treatment gave car-
bamate 17. Finally, methanolysis provided methyl ester 18
which underwent diazotransfer without any observed azide
transfer to afford diazoester 19.
(1) (a) Danishefsky, S. J .; Schkeryantz, J . M. Synlett 1995, 475-490. (b)
Fukuyama, T.; Yang, L. H. Tetrahedron Lett. 1986, 27, 6299-6300. (c)
Fukuyama, T.; Yang, L. H. J . Am. Chem. Soc. 1987, 109, 7881-7882. (d)
Fukuyama, T.; Yang, L. H. J . Am. Chem. Soc. 1989, 111, 8303-8304. (e)
Benbow, J . W.; Schulte, G. K.; Danishefsky, S. J . Angew. Chem., Int. Ed.
Engl. 1992, 31, 915-917. (f) Wang, Z.; J imenez, L. S. Tetrahedron Lett.
1996, 37, 6049-6052.
Cyclization of diazoester 19 was examined under three
sets of reaction conditions. In each case the carbon-
hydrogen insertion products were not separated but instead
oxidized (chloranil, CH2Cl2, 23 °C) to the corresponding
mitosenes and the ratio of 20 and 21 determined by HPLC
analysis. Photolysis of 19 in benzene followed by oxidation
provided 20 and 21 in a 3:1 ratio (79% yield). Addition of a
solution of 19 in dichloromethane to a suspension of rhod-
ium(II) acetate in dichloromethane afforded a 4:1 ratio (96%
yield) of 20 and 21 following oxidation with chloranil.
Optimal selectivity was realized using the copper(I) complex
derived from 2,2′-(1-methylethylidene)bis(5,5-dimethyl-4,5-
(2) (a) Shaw, K. J .; Luly, J . R.; Rapoport, H. J . Org. Chem. 1985, 50,
4515-4523. (b) Ziegler, F. E.; Belema, M. J . Org. Chem. 1994, 59, 7962-
7967. (c) Ziegler, F. E.; Belema, M. J . Org. Chem. 1997, 62, 1083-1094. (c)
Ziegler, F. E.; Berlin, M. Y. Tetrahedron Lett. 1998, 39, 2455-2458. (d)
Utsunomiya, I.; Fuji, M.; Sato, T.; Natsume, M. Chem. Pharm. Bull. 1993,
41, 854-860. (e) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm.
Bull. 1995, 43, 37-48.
(3) (a) Lee, S.; Lim, H.-J .; Cha, K. L.; Sulikowski, G. A. Tetrahedron 1997,
53, 16521-16532. (b) Lim, H.-J .; Sulikowski, G. A. J . Org. Chem. 1995, 60,
2326-2327.
(4) For stereoelectronic effects of R heteroatoms on rhodium(II)-mediated
C-H insertion reactions, see: Wang, P.; Adams, J . J . Am. Chem. Soc. 1994,
116, 3296-3305.
(5) (a) Martinez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E. N.
J . Am. Chem. Soc. 1995, 117, 5897-5898. (b) Martinez, L. E.; Nugent, W.
A.; J acobsen, E. N. J . Org. Chem. 1996, 61, 7963-7966.
(8) (a) Hartwig, J . F. Synlett 1997, 329. (b) Hartwig, J . F. Acc. Chem.
Res. 1998, 31, 852-860.
(9) (a) Agnelli, F.; Sulikowski, G. A. Tetrahedron Lettt. 1998, 39, 8807-
8810. (b) Kuwajima, I.; Urabe, H. J . Am. Chem. Soc. 1982, 120, 837-838.
(10) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am. Chem.
Soc. 1990, 112, 4011-4030.
(6) Cai, H.; Vigh, G. J . Pharm. Biomed. Anal. 1998, 18, 615-621.
(7) (a) Wolfe, J . P.; Wagaw, S.; Buchwald, S. L. J . Am. Chem. Soc. 1996,
118, 7215-7216. (b) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62,
6066-6068. (c) Wolfe, J . P.; Wagaw, S.; Marcoux, J . F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805-818.
(11) Schaus, S. E.; Larrow, J . F.; J acobsen, E. N. J . Org. Chem. 1997,
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10.1021/jo990469g CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/25/1999

Communications
J . Org. Chem., Vol. 64, No. 12, 1999 4225
Sch em e 1
dihydrooxazole)12 and copper(I) triflate. Under these condi-
tions a 9:1 ratio (73% yield) of 20 and 21 was realized. The
major isomer 20 was hydrolyzed to amino alcohol 22, which
on treatment with MsCl/Et3N afforded chloride 23.13 The
structure of 23 was confirmed by single-crystal X-ray
analysis. Exposure of 23 to DBU in dichloromethane pro-
duced aziridine 24 (82% yield).
of the mitomycin antitumor antibiotics. Unfortunately, our
initial goal of generating either enantiomer from a common
diazoester (cf. 5, Figure 1) was derailed due to complications
in effecting a diazotransfer onto ester 10. Key transforma-
tions in the synthesis include the use of sequential pal-
ladium-mediated cross-coupling reactions to convert bro-
moiodobenzene to ester 10 and the application of a chemo-
selective carbon-hydrogen insertion reaction using a copper-
(I) catalyst to selectively produce mitosene 20 from diazo-
ester 19.
Ack n ow led gm en t. Support by the National Institutes
of Health and the Welch Foundation (A-1230) is gratefully
acknowledged. G.A.S. is an Alfred P. Sloan Fellow (1996-
1998) and Eli Lilly Grantee (1996-1998). The authors
thank Drs. Gyula Vigh and Hong Cai for the enantiomeric
excess determination of 8, Professor Eric J acobsen (Har-
vard University) for providing experimental detail for the
preparation of 6, and Dr. Charles Campana (Bruker Axs,
Inc., Analytical X-ray systems) for X-ray crystal structure
determination of 23. High-resolution mass spectra were
obtained at Texas A&M University Mass Spectrometry
Service Center by Drs. Lloyd Sumner and Barbara P. Wolf
on a VG Analytical 70S high resolution, double focusing,
sectored (EB) mass spectrometer. Funds to purchase the
VG magnetic instrument came from National Science
Foundation Grant CHE-8705697.
In conclusion, we have developed an enantioselective
synthesis of a 1,2-aziridinomitosene (24), a key substructure
(12) 2,2′-(1-Methylethylidene)bis(5,5-dimethyl-4,5-dihydrooxazole) (iii)
was prepared from dimethylmalonitrile (i) and amino alcohol ii.
Su p p or tin g In for m a tion Ava ila ble: Experimental procedure
and characterization data for all new compounds, and X-ray data
for compound 23. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Sanda, K.; Rigal, L.; Delmas, M.; Gaset, A. Synthesis 1992, 541-
542.
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