Aziridinomitosanes via lactam cyclization

Article abstract of DOI:10.1021/ol101595u

Aziridinomitosane ketones 4 and 24 are accessed by internal acyl anion equivalent-lactam cyclization of 29 in a convergent route. The key aziridinolactam 6 is prepared by tin-lithium exchange via the lithiated aziridine 11.

Full text of DOI:10.1021/ol101595u

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4030-4033
Aziridinomitosanes via Lactam
Cyclization
Susan D. Wiedner and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue,
Ann Arbor, Michigan, 48109
edVed@umich.edu
Received July 11, 2010
ABSTRACT
Aziridinomitosane ketones 4 and 24 are accessed by internal acyl anion equivalent-lactam cyclization of 29 in a convergent route. The key
aziridinolactam 6 is prepared by tin-lithium exchange via the lithiated aziridine 11.
Mitomycin C (1) and FR900482 (2) are known for their
anticancer activity1 and for their remarkable reductive
activation pathway via bis-electrophilic aziridino-mitosenes
that cross-link DNA.2 It has been hypothesized that these
structurally distinct heterocycles not only share key func-
tionality and mode of activation but also have partially
overlapping biosynthetic pathways.3 Early common biosyn-
thetic intermediates have been identified using isotopic
labeling studies,4 but the point where the biosynthetic
pathways diverge is still unknown. In principle, the point
of divergence can be investigated using pyrrolo[1,2a]indole-
derived aziridines such as 3; however, synthetic access
to derivatives of 3 is challenging due to the expected facile
aromatization to the indole.5 With the ultimate goal of
synthesizing analogues of 3, we have developed an
enantiocontrolled route to the more stable6 9-oxo-
pyrrolo[1,2a]indole 4 as described below. The new route
also allows access to the ring system of FR900482 (2) by
oxidative ring expansion.7
A convergent synthetic strategy designed to access the
tetracyclic ketol 4 is outlined in Scheme 1, based on the
Scheme 1
.
Strategies Leading to Mitosane Ketol 4 via C9-C9a
Bond Formation
(1) Rajski, S. R.; Williams, R. M. Chem. ReV. 1998, 98, 2723.
(2) Wolkenberg, S. E.; Boger, D. L. Chem. ReV. 2002, 102, 2477.
(3) Chamberland, S.; Gru¨schow, S.; Sherman, D. H.; Williams, R. M.
Org. Lett. 2009, 11, 791.
(4) (a) Hornemann, U.; Kehrer, J. P.; Nunez, C. S.; Ranieri, R. L. J. Am.
Chem. Soc. 1974, 96, 320. (b) Hornemann, U.; Eggert, J. H. J. Antibiot.
1974, 28, 841. (c) Anderson, M. G.; Kibby, J. J.; Rickards, R. W. Chem.
Commun. 1980, 1277. (d) Fujita, T.; Takase, S.; Otsuka, T.; Terano, H.;
Kohsaka, M. J. Antibiot. 1988, 41, 392.
(5) For examples of nonstabilized aziridinomitosenes, see: (a) Feigelson,
G. B.; Egbertson, M.; Danishefsky, S. J. J. Org. Chem. 1988, 53, 3390. (b)
Feigelson, G. B.; Danishefsky, S. J. J. Org. Chem. 1988, 53, 3393.
(6) (a) Wang, Z.; Jimenez, L. S. J. Am. Chem. Soc. 1994, 116, 4977.
(b) Papioannou, N.; Blank, J. T.; Miller, S. J. Org. Lett. 2001, 3, 2879.
10.1021/ol101595u  2010 American Chemical Society
Published on Web 08/25/2010

coupling of an aromatic subunit 7 with the bicyclic aziridi-
nolactam 6 followed by C(9)-C(9a) bond formation (mi-
tomycin numbering) using intramolecular nucleophilic ad-
dition to the lactam carbonyl group of 5. The aziridine
stereochemistry of 5 might be expected to control hemiaminal
configuration in 4 based on kinetic or thermodynamic factors.
Depending on the outcome of the cyclization step, the C(9a)
hemiaminal stereochemistry might then be exploited as one
of the factors that set configuration at C(9) corresponding
to either the mitomycin or the FR900482 series.
in toluene (100-110 °C). Although the yields were generally
modest (57-73%; Table 1), the reactions were very clean,
Table 1. Copper-Catalyzed Coupling of Aryl Iodides and 6a
First, the chiral bicyclic aziridinolactam 6 was targeted
(Scheme 2). Although a number of related bicyclic aziridines
entry
substrate
CuI
time
product
yield
1
2
3
4
C6H5I
14
16
0.1
0.30
1.0
4 h
20 h
20 h
48 h
13
15
17
19
63%
61%b
57%
73%
Scheme 2. Construction of the Bicylic Aziridine 6
18
0.30
a 1.2 equiv of 6 and 1.0 equiv of aryl iodide were dissolved in toluene
with K3PO4 and trans-N,N′-dimethyl-1,2-cyclohexanediamine and heated
to 100 °C. b Reaction conducted at 110 °C.
and unreacted 6 could be recovered along with the products
13, 15, 17, or 19. The reaction was faster with the unhindered
iodobenzene (entry 1), and 10 mol % of CuI catalyst was
sufficient for conversion over several hours. In the other
examples, increased catalyst loading and longer reaction
times were necessary (see entries 2-4).12
Lactams 15 and 17 offer several options for C(9)-C(9a)
bond formation, one of which (cyclization via acyl anion
equivalent generation) was investigated in detail. Initial
attempts to deprotonate dithiane 15 with n-BuLi resulted in
alkyllithium addition to the lactam carbonyl group, while
LDA treatment caused unproductive bimolecular side reac-
tions. Furthermore, reaction of 15 or 17 with KHMDS
afforded no products of cyclization, and quenching the
reaction mixtures with a deuterium source did not result in
are known,8 no bicyclic NH lactam analogue of 6 has been
reported. We sought to establish convenient access to 6
and to obtain the aziridine stereocenters from the chiral
pool, starting with the known chiral aziridinol 8.9 Conver-
sion into mesylate 9 (MsCl, Et3N, 99%) and azide 10
(91%) was followed by reduction and subsequent treatment
of the unstable amine with ethyl chloroformate to provide
11 (81%, 2 steps). Carbamate 11 was converted to dianion
12, which was then trapped with diethyl carbonate to
afford aziridinolactam 6 (65% isolated; gram scale).
Complete deprotonation of the carbamate nitrogen prior
to tin-lithium exchange was essential to avoid significant
protodestannylation in this sequence10 (see Supporting
Information for details).
With bicyclic aziridinolactam 6 in hand, conditions were
screened for coupling with aryl iodides containing function-
ality that might eventually be used to form the tetracycle
C(9)-C(9a) bond. The best yields of coupling products were
obtained using CuI with K3PO4 and the highly active trans-
N,N′-dimethyl-1,2-cyclohexanediamine ligand11 upon heating
1
deuterium incorporation (assay by H NMR spectroscopy).
Attempts to close the C(9)-C(9a) bond therefore focused
on lithium amide bases with the silylated cyanohydrin lactam
17 as substrate.
Choice of temperature, base, and solvent proved critical
for successful cyclization of 17. The first hints of cyclization
were observed using LDA/THF at low temperatures, but the
product mixture was complex, and the presumed cyclization
product did not survive chromatography. Better control was
achieved by switching from LDA to LiHMDS for deproto-
nation at -78 °C and by allowing the reaction temperature
to reach 0 °C prior to quenching. Improved conversion was
observed when the THF was replaced by ether, and the best
experiments could be monitored visually as the cloudy
(12) Conversion of i to ii was also demonstrated using the conditions
of Table 1. However, attempted cyclization following Cha’s alkene
analogy13 (modified Kulinkovich conditions) gave predominant alkyne
reduction. Tetracyclic products derived from ii were not detected.
(7) Dmitrienko, G. I.; Denhar, D.; Mithani, S.; Prasad, G. K. B.; Taylor,
N. J. Tetrahedron Lett. 1992, 33, 5705.
(8) (a) Kametani, T.; Kigawa, Y.; Ihara, M. Tetrahedron 1979, 35, 313.
(b) Trost, B. M.; O’Boyle, B. M. Org. Lett. 2008, 10, 1369.
(9) Vedejs, E.; Moss, W. O. J. Am. Chem. Soc. 1993, 115, 7.
(10) Goswami, R.; Corcoran, D. E. Tetrahedron Lett. 1982, 23, 1463.
(11) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
Org. Lett., Vol. 12, No. 18, 2010
4031

reaction mixture of the presumed intermediate 22 became
clear over time. These optimized conditions produced a 3:1
mixture of two diastereomeric products corresponding to
structure 23 according to NMR assay of the crude product.
The minor isomer was identical by NMR comparisons with
the unstable product from low temperature LDA experiments,
but attempted purification at the stage of 23 resulted in
significant decomposition.14 On the other hand, treatment
of the crude cyclization mixture with TBAF provided the
stable and easily purified ketol 24 in 74% yield over the two
steps (Scheme 3). Only one dominant diastereomer was
Scheme 4. Coupling and Cyclization
Scheme 3. Model of Ketol 24
26 with triflic anhydride/K3PO4 afforded triflate 27,17 but
attempts to convert 27 to the analogous iodide required
for copper -catalyzed amidation were unsuccessful. There-
fore, alternative catalytic procedures were evaluated that
might allow coupling of the aziridinolactam 6 directly with
the triflate 27, and conditions developed by Buchwald et
al. using Pd2(dba)3/xantphos worked well after optimiza-
tion.18 The commonly used Cs2CO319 gave poor yields of
the desired product 28, and a carbonylamide byproduct
was obtained by amide addition to the aldehyde group.
However, a similar experiment using K3PO4 as base
provided the lactam 28 in acceptable (64%) yield.11,20
Subsequent treatment of 28 with TBSCN and catalytic KCN
in the presence of 18-crown-6 then gave a 1:1 diastereomeric
mixture of 29 (83%), setting the stage for the key cyclization
(Scheme 5).21
Deprotonation of the cyanohydrin 29 was performed with
LiHMDS in ether, the same conditions that were used in
the model study from 17. Unlike the model system, the
cyclization gave only one diastereomer of aminal 30 (58%)
along with unreacted starting material (25-30%). Extended
reaction time at 0 °C (>40 min) was needed for good
conversion to 30, but unreacted starting material was always
recovered after aqueous quench even after 1.5 h. The
differences between cyclization of 17 and 29 are attributed
to the para electron-withdrawing ester substituent of 29. The
ester would help stabilize the intermediate carbanion, result-
ing in the higher reaction temperature and lower conversion
to the alkoxide precursor of 30. Subsequent removal of the
cyanohydrin with TBAF afforded the desired ketol 4 (77%).
Analysis of 4 by NOE spectroscopy showed a 16% correla-
tion between Ha and Hc, consistent with the same stereo-
chemistry at C(9a) as in the model 24.
detected after OTBS deprotection. Presumably, the unstable
diastereomer differs at the hemiaminal carbon, but its fate
under the conditions of silyl ether cleavage is not clear. The
C(9a) stereochemistry of 24 was initially assigned based on
NOE data and was eventually confirmed by X-ray crystal-
lography. The preferred formation of the corresponding
diastereomer 23 in the cyclization step from 17 is tentatively
attributed to decreased lone pair repulsion compared to the
unstable hemiaminal isomer having the C(9a)-O bond and
aziridine nitrogen on the same face of the tetracycle.
According to this interpretation, the major diastereomer of
23 is formed under thermodynamic control (hemiaminal
anion equilibration at 0 °C).
Having successfully demonstrated construction of the
C(9-C(9a) bond in the model tetracycle 24, we turned to
the synthesis of an appropriately functionalized aryl halide
7 that might be used in a route similar to 4. The known
aldehyde 25, obtained in 4 steps from commercially
available 4-bromo-3,5-dihydroxybenzoic acid,15 was se-
lectively monodebenzylated under hydrogenolysis condi-
tions to provide phenol 26 (Scheme 4).16 Treatment of
(13) Lee, J.; Du Ha, J.; Cha, J. K. J. Am. Chem. Soc. 1997, 119, 8127.
(14) The major diastereomer of 23 survived chromatography, but
purification at the stage of the stable 24 was more efficient. The relative
proportion of the minor (unstable) diastereomer of 23 increased if the
reaction mixture was quenched at -12 °C but did not affect the yield of
24.
(15) Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H.
J. Org. Chem. 1996, 61, 4572.
(16) (a) Curtis, W. D.; Stoddart, F. J. Chem. Soc., Perkin Trans. I 1977,
220. (b) Hendrickson, J. B.; Ramsay, M. V. J.; Kelly, T. R. J. Am. Chem.
Soc. 1972, 94, 6834.
(17) Frantz, D. E.; Weaver, D. G.; Carey, J. P.; Kress, M. H.; Dolling,
U. H. Org. Lett. 2006, 8, 2627.
4032
Org. Lett., Vol. 12, No. 18, 2010

the ring-expansion-derived acetal 35 (55%). An NOE cor-
relation between the C(1) aziridine proton and one of the
C(10) methylene protons supported the assignment as shown.
Next, the trityl and t-butyl ester protecting groups of 35 were
removed with excess TFA/triethylsilane;23 addition of Hu¨nig’s
base/Boc2O provided the Boc-protected carboxylic acid 36;
and treatment with trimethylsilyl diazomethane gave a
mixture of products including methyl ester 37.
Scheme 5. Correlation of Stereochemistry
We had expected to obtain a diastereomer of 38, an
intermediate reported by O’Boyle and Trost in their synthesis
of epi-FR900482,8b and were surprised to find that NMR
signals of our material appeared to match those of 38.
Initially, this was concerning because the stereochemistry
might conceivably have been altered during the correlation
sequence from 34 to 37. However, we soon learned that the
structure of 38 had been reassigned in the PhD dissertation
of O’Boyle to match 37.24 Comparison of NMR spectra
established the identity of 37 obtained according to Scheme
5 with the major product reported by O’Boyle and Trost.
Because 37 is a precursor of 7-epi-FR900482 rather than
the natural diastereomer, we opted not to pursue further
synthetic steps from 35 in the expectation that differences
in the protecting groups would not alter the outcome of
reductive deoxygenation at C(7). However, the concise,
convergent route leading to 4 has interesting potential for
accessing elusive mitosane-like structures such as 3. Efforts
toward this goal are underway that will exploit the superior
stability profile of 4 as the key intermediate. The unusual
intramolecular cyclization leading to acetals 23 and 30 holds
considerable promise in this regard. We could find no prior
report describing the cyclization of an acyl anion equivalent
with the carbonyl group of a lactam, although analogous
cyclizations involving lithiated substrates and the carbonyl
group of lactams, amides, and imides are known,25 including
a related case of enolate-lactam cyclization.25a The chem-
istry described herein also demonstrates a convenient syn-
thesis of the bicyclic lactam 6 via a lithiated aziridine
intermediate.
The diastereoselective synthesis of the key mitosane ketol
4 was accomplished in 9 linear steps (11 total) in 12% overall
yield from known aldehyde 25 and chiral aziridinol 8.
However, further confirmation of hemiaminal stereochem-
istry was desired, as well as added insight regarding the
potential of 4 in the context of possible synthetic applications.
We therefore initiated a correlation of stereochemistry with
intermediates reported in prior synthetic studies. Following
precedent from the work of Danishefsky and McClure,22
4
was treated with Me3SiCH2MgCl to afford diol 31 as one
diastereomer (79%; Scheme 5), followed by Peterson elimi-
nation to 32. Attempted purification of 32 by chromatography
resulted in allylic alcohol rearrangement to the isomeric
indole, so crude 32 was treated with stoichiometric OsO4 in
pyridine3 to provide triol 33 (33% from 31) followed by
triphosgene/pyridine to afford the cyclic carbonate 34
(74%).8b The C(9) and C(9a) stereochemistry of 34 was
eventually established by X-ray crystallography. Among
several choices, we had opted to compare intermediates
having the more stable FR900482 skeleton that should be
accessible from 34 via Dmitrienko oxidation.7 In the event,
carbonate 34 was treated with buffered m-CPBA to provide
Acknowledgment. This work was supported by the
National Institutes of Health (CA17918). The authors also
thank Prof. B. M. Trost and B. M. O’Boyle of the
Department of Chemistry, Stanford University, for providing
comparison spectra of 37.
Supporting Information Available: Experimental pro-
cedures and characterization data for new substances. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(19) (a) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1264.
(b) Ahman, J.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6363.
(20) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L. J.
Org. Chem. 2000, 65, 1158.
(21) Conversion of aldehyde 27 into the silylated cyanohydrin followed
by treatment with 6 under the optimized coupling conditions with Pd2dba3
gave no coupled product.
OL101595U
(22) McClure, K. F.; Benbow, J. W.; Danishefsky, S. J. J. Am. Chem.
Soc. 1991, 113, 8185.
(24) O’Boyle, B. M. Ph. D. Dissertation, Stanford University, 2009.
(25) (a) Flitsch, W.; Russkamp, P. Liebigs Ann. 1985, 1398. (b) Lorion,
M.; Couture, A.; Deniau, E.; Grandclaudon, P. Synthesis 2009, 1897, and
references therein.
(23) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org. Chem.
2001, 66, 7542.
Org. Lett., Vol. 12, No. 18, 2010
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