Asymmetric synthesis of a tetracyclic model for the aziridinomitosenes

Article abstract of DOI:10.1016/S0040-4039(01)01597-0

The conversion of (-)-2,3-O-isopropylidene-D-erythronolactone (9) into the N-phosphorylated aziridine 20, a model for the fundamental structure of aziridinomitosenes, has been accomplished in 11 steps by way of the vinylogous urethane 13. Key steps include the preparation of 13 by a Reformatsky reaction on a thiolactam precursor, Heck cyclisation of 13 to form the indole ring, and aziridine synthesis via a cyclic sulfite.

Full text of DOI:10.1016/S0040-4039(01)01597-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7513–7516
Asymmetric synthesis of a tetracyclic model for the
aziridinomitosenes
Joseph P. Michael,* Charles B. de Koning, Riaan L. Petersen and Trevor V. Stanbury
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, P.O. Wits 2050, South Africa
Received 13 August 2001; accepted 29 August 2001
Abstract—The conversion of (−)-2,3-O-isopropylidene-D-erythronolactone (9) into the N-phosphorylated aziridine 20, a model for
the fundamental structure of aziridinomitosenes, has been accomplished in 11 steps by way of the vinylogous urethane 13. Key
steps include the preparation of 13 by a Reformatsky reaction on a thiolactam precursor, Heck cyclisation of 13 to form the indole
ring, and aziridine synthesis via a cyclic sulfite. © 2001 Published by Elsevier Science Ltd.
The mitomycins, e.g. mitomycins A (1) and C (2), are a
group of Streptomyces metabolites having pronounced
antibacterial and antitumour activity.1 Considerable
effort has been devoted to the synthesis of these clini-
cally useful antibiotics and their bioactive degradation
products, the aziridinomitosenes (e.g. 3). Common to
stituents on the aromatic ring, including electron-donat-
ing groups such as methoxy; but in these cases it was
necessary to use a stoichiometric quantity of pallad-
ium(II) acetate and the hindered ligand tri(o-tolyl)phos-
phine in order to achieve reasonable yields. A similar
intramolecular Heck reaction featured in a mitosene
synthesis by Luly and Rapoport,7 who cyclised an
N-(2-bromobenzoquinone) analogue of 5 to give the
quinone version of the pyrrolo[1,2-a]indole system
directly.
these compounds is
a
tricyclic 2,3-dihydro-1H-
pyrrolo[1,2-a]indole core, the construction of which has
been approached in numerous ingenious ways.2,3 How-
ever, fusing the aziridine ring onto the tricyclic nucleus
is a more challenging synthetic problem, since many
simple routes to pyrrolo[1,2-a]indoles either do not
have the flexibility to handle the additional functional-
ity required in the target system, or make little provi-
sion for the requisite stereocontrol.4
The synthesis of aziridinomitosenes themselves requires
that the reaction sequence be modified by the introduc-
tion of functional groups at the positions destined to
become C-1 and C-2 of the condensed system 4. The
timing of the construction of the potentially labile
aziridine is obviously a critical feature in the synthetic
plan. We envisaged a late-stage construction of the
strained ring from a precursor of the form 6 (Scheme 2)
once the pivotal intramolecular Heck reaction had been
accomplished on a vinylogous urethane 7. The stereo-
chemistry of substituents X and Y thus assumes prime
importance, but the numerous published routes to
aziridines from 1,2-difunctionalised precursors offer
opportunities to explore methods involving both reten-
O
O
OCONH2
OMe
OCONH2
R
R1
A
B
N
NR2
N C
NH
Me
Me
O
O
3
1 R = OMe
2 R = NH2
We previously reported5 a synthesis of pyrrolo[1,2-
a]indoles 4, the key-step of which involved the con-
struction of ring B by intramolecular Heck reaction6 of
ethyl 2-[N-(2-bromoaryl)pyrrolidin-2-ylidene]acetates 5
(Scheme 1). This Heck reaction, unusual in involving
an enamine component, tolerated a variety of sub-
CO2Et
Br
CO2Et
i
R
R
1
2
N
N
3
4
5
Keywords: aziridinomitosene; thiolactams; Reformatsky reaction;
enaminones; Heck reaction.
* Corresponding author. Tel.: +27-11-717-6753; fax: +27-11-339-7967;
e-mail: jmichael@aurum.chem.wits.ac.za
Scheme 1. Reagents and conditions: (i) Pd(OAc)2 (0.2–1.0
equiv.), PPh3 or P(o-Tol)3, MeCN, reflux.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01597-0

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J. P. Michael et al. / Tetrahedron Letters 42 (2001) 7513–7516
3,4-difunctionalised pyrrolidin-2-ones,11 but not for the
O
O
OCONH2
NR2
CO2Et
preparation of analogous N-arylated lactams. We
found that 9 reacted poorly with 2-bromoaniline, our
model substrate, even with prolonged heating. How-
ever, the lactone ring could be opened by treatment
with the anion of 2-bromoaniline (Scheme 3). Although
several bases could be used for making the anion (e.g.
potassium hexamethyldisilazide, trimethylaluminum),
the most convenient for larger-scale operation (ca. 5 g
scale) was ethylmagnesium bromide. Yields of the
amido alcohol 10 were consistently around 90%. Mesyl-
ation of 10 followed by cyclisation of the intermediate
with sodium hydride in THF gave the N-(2-bromo-
phenyl) lactam 11 in a yield of 90% for the two-step
procedure. Thionation of this product with Lawesson’s
reagent completed the synthesis of the substituted
pyrrolidine-2-thione 12 in 90% yield.
R1
X
Y
R1
N
N
6
Br
Br
N
CO2Et
X
S
R1
R1
N
X
Y
Y
7
8
Scheme 2. Retrosynthetic plan for constructing the tetracyclic
core of aziridinomitosenes.
The transformation of thiolactam 12 into the vinyl-
ogous urethane 13 was problematic. When standard
Eschenmoser sulfide contraction12 and related conden-
sation methods failed, we turned to an atypical applica-
tion of the Reformatsky reaction that we13 and others14
have exploited in several rather specific cases involving
the thiocarbonyl group as the electrophilic partner.
Heating 12 at reflux in THF with an excess (3 equiv.) of
the organozinc reagent formed by sonicating activated
zinc powder with ethyl bromoacetate in THF in the
presence of iodine as catalyst afforded the desired
product 13 in reproducibly good yields of above 90%.
On the NMR spectroscopic timescale at ambient tem-
perature, this compound exists as an equal mixture of
two rotamers about the Nꢀaryl bond, but signals were
shown to coalesce at higher temperatures. The crucial
tion and inversion of configuration.8 In line with meth-
ods that we routinely use for preparing enaminones
related to 5,9 we chose to investigate routes that pro-
ceeded through non-racemic 3,4-disubstituted pyrro-
lidine-2-thione intermediates of general structure 8.
The precursor of choice proved to be the ‘chiral pool’
compound
(−)-2,3-O-isopropylidene-D-erythronolac-
tone (9), readily prepared in 77% yield by a published
method that entails oxidative cleavage of the relatively
cheap
D-isoascorbic acid with hydrogen peroxide, fol-
lowed by ketal exchange with 2,2-dimethoxypropane.10
Lactone 9 has been used by others as a chiral building
block for the synthesis of unsubstituted and N-alkyl
Br
Br
Br
O
O
S
O
O
N
H
i
ii, iii
iv
N
N
O
O
O
O
89%
90%
90%
O
O
O
O
90–
92%
HO
v
9
11
12
10
CO2Et
CO2Et
CO2Et
Br
N
CO2Et
O
O
O
OH
OH
O
O
viii
vii
vi
O
N
S
N
N
93%
99%
80%
O
16 (two diastereomers)
15
14
13 (rotamers)
CO2Et
CO2Et
CO2Et
ix
92%
N3
N3
OSO2Me
ii
x
N
NR
N
N
95%
60%
OH
19 R = H
20 R = PO(OMe)2
17
18
Scheme 3. Reagents and conditions: (i) 2-bromoaniline, EtMgBr, THF, −78°C; (ii) MeSO2Cl, NEt3, CH2Cl2, 0°C to rt; (iii) NaH,
THF, rt; (iv) Lawesson’s reagent, toluene, reflux; (v) Zn (5 equiv.), BrCH2CO2Et (3 equiv.), I2 (0.2 equiv.), THF, ultrasound, then
add 15, THF, reflux; (vi) Pd(OAc)2 (0.1 equiv.), PPh3 (0.4 equiv.), KOAc (7.5 equiv.), Bu4NBr (2.5 equiv.), DMF–MeCN–H2O
(1:1:0.2), 100°C, 5 h; (vii) TFA, THF–H2O (1:1), rt; (viii) SOCl2, NEt3, CH2Cl2, −15°C; (ix) NaN3, DMF, 55°C, then aq. H2SO4;
(x) P(OMe)3, THF, reflux, then NaH, rt.

J. P. Michael et al. / Tetrahedron Letters 42 (2001) 7513–7516
7515
intramolecular Heck cyclisation of 13 under conditions
that we had employed for the model systems (cf.
Scheme 1) gave disappointing yields of the ketal-pro-
tected pyrrolo[1,2-a]indole 14 (<30%). However, by a
judicious combination of solvent, base, ligand and
additive15 (Scheme 3), an almost quantitative yield of
14 could be obtained even when the reaction was
performed on a 2 g scale. The corresponding methyl
and menthyl esters, made by quite different routes,
have been reported by Sulikowski and co-workers.3e
tively short (11 steps based on the
D
-erythronolactone
derivative 9), the yields of individual steps are generally
good, and extension to the synthesis of aziridinomitose-
nes themselves can readily be envisaged. We are cur-
rently investigating the preparation of 2-bromoanilines
that contain the characteristic ring A substitution pat-
terns of mitomycins as well as functionality that will
favour oxidation of the ring to the quinone level found
in the target systems.
With several methods available for the transformation
of 1,2-diols into aziridines,8 our immediate task was to
remove the protecting group from 14. This simple
transformation proved troublesome, because under
standard conditions with aqueous mineral acid, or with
iodine in methanol,16 competing eliminations and reac-
tions in which one or both hydroxy groups were dis-
placed were found to occur. However, with
trifluoroacetic acid in a mixture of THF and water, diol
15 could be obtained in 80% yield. We chose to effect
the double SN2 displacement of the OH groups with a
nitrogen nucleophile via a cyclic sulfate, an approach
that has precedent for the synthesis of aziridines.17
Accordingly, diol 15 was treated with thionyl chloride
and triethylamine in dichloromethane18 to produce a
1:1 mixture of the two separable cyclic sulfite
diastereomers 16 in 93% yield. It was all the more
disappointing, therefore, that we were never able to
oxidise the sulfites to the desired sulfate under the
Sharpless conditions (catalytic ruthenium trichloride
with sodium periodate as oxidant18). However, we for-
tuitously discovered that the diastereomeric mixture of
sulfites underwent efficient nucleophilic ring opening
when treated with sodium azide in DMF—an unusual,
but not unprecedented,19 transformation. After acidic
work-up, the azidoalcohol 17 was isolated in 92% yield.
The regiochemistry and stereochemistry of the reaction
was confirmed by an X-ray crystal structure determina-
tion on compound 17.
Acknowledgements
We thank the National Research Foundation, the UK/
SA Science and Technology Fund, the Mellon Post-
graduate Mentoring Programme (sponsored by the
Andrew W. Mellon Foundation), and the University of
the Witwatersrand for funding this project, and for
bursaries to R.L.P. and T.V.S. We are grateful to Dr.
G. D. Hosken for preliminary experiments with racemic
precursors, Dr. P. R. Boshoff (Cape Technikon) for
mass spectra, and Mrs. S. Heiss and Mr. M. A.
Fernandes (University of the Witwatersrand) for NMR
spectra and X-ray crystallography, respectively.
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