Aziridinomitosenes by anionic cyclization: Deuterium as a removable blocking group

Article abstract of DOI:10.1021/ja0120835

Treatment of 11a with methyllithium affords the destannylated product 12 together with a small amount of tetracyclic product derived from intramolecular Michael addition. The same procedure from the deuterated analogue 11b gives the tetracyclic 18 as the

Full text of DOI:10.1021/ja0120835

Published on Web 01/12/2002
Aziridinomitosenes by Anionic Cyclization: Deuterium as a Removable
Blocking Group
Edwin Vedejs* and Jeremy Little
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received August 31, 2001
Metabolic activation of FR66979 (1) and FR900482 (2) is
believed to generate transient intermediates 3 that have the ability
to cross-link DNA.1-3 The structurally related leucoaziridinomito-
senes 4 play a similar role as the species responsible for the
antitumor activity of the mitomycin antiobiotics.4 Danishefsky and
Egbertson were able to observe 4b in solution using NMR methods,
but the molecule was too labile for isolation and decomposed within
minutes in the presence of water.5 So far, there have been no reports
of the direct observation of 3, although derivatives resulting from
aziridine ring cleavage have been characterized.3
Synthetic access to the tetracyclic skeleton common to 3 and 4
has been achieved,6 and aziridinomitosene A, the quinone corre-
sponding to hydroquinone 4a, has been prepared by total synthesis.6a
The quinone is considerably more stable than is 4a because the
carbonyls participate in vinylogous amide delocalization, a factor
that is important for survival of the aziridine. Similar delocalization
helps to stabilize carbonyl derivatives such as 5, and several
examples of related aldehydes, esters, or quinones are known.6b
Lactam analogues of the leucoaziridinomitosenes are also well
structural assignments had to be made based on NMR spectra of
characterized.6c However, analogues of 3 or 4 that lack carbonyl
the mixtures, it proved helpful to evaluate the product ratios after
stabilization for the indole nitrogen are virtually unknown. As far
workup with deuterated ethanol, as shown in experiment (1).
as we are aware, the bis-triethylsilyl ether of naturally derived 4b
Deuterium quench simplified the spectra, and allowed the tentative
is the only reported leucoaziridinomitosene that has been isolated.5
conclusion that 11a had been converted into its monodeuterio
No other examples containing the nonstabilized core structure 6
derivative 11b, the corresponding de-stannylated dideuterio structure
(basic indole nitrogen; alcohol oxidation state in the side chain)
could be found in the literature. In contrast, leucoaziridinomitosane
13, and a small amount of the desired tetracyclic 14. The identity
of 11b was easily confirmed by comparison of NMR signals with
analogues containing the subunit 7 are well-known (indoline subunit
11a, and by the observation that 11b is formed cleanly if 11a is
in place of indole).6e,7 These observations reflect the activating role
treated with phenyllithium with subsequent quenching of the
C-lithio indole intermediate with deuterated ethanol.
Numerous attempts to improve the conversion to 14 gave no
more than 10-15% of the tetracyclic product, and prolonged
reaction times or higher temperatures increased the relative amount
of destannylation to 13. A key observation was made in the course
of the indole double bond on heterolysis of adjacent C-N and C-O
leaving groups, a factor that destabilizes 3-6 and leads to DNA
cross-linking by 1-4.3,4
We have been interested in the possibility that 5 might be
available from a stannyl aziridine precursor 88,9 by coupling with
10 followed by metal exchange and intramolecular Michael
of the deuterioethanol quenching experiments starting from 11a.
addition. While our studies were in progress, Ziegler and Belema
Destannylated 13 was always obtained with the indole proton
reported a closely related intramolecular radical cyclization that
completely replaced by deuterium, within the limits of NMR assay,
affords substituted derivatives of 7.7 We anticipated that the anionic
while 14 was formed with the original indole proton intact (δ 4.80
(internal Michael) variation would prove better suited for access
to sensitive leucoaziridinomitosene derivatives 5, assuming that the
intermediate enolate could be intercepted by electrophiles that can
undergo facile elimination to the indole.
To test the above proposition, 11a was prepared from the serine-
derived aziridine alcohol 88,9 via the mesylate 9 and coupling with
the indole carboxylate 10. Preliminary attempts to effect metal
exchange and internal Michael addition from 11a revealed a
complex situation. Typical experiments using excess methyllithium
at -65 °C followed by aqueous quench produced a mixture of
starting material 11a, the destannylated 12, as well as two
stereoisomeric products that could not be separated. Since the initial
ppm). This suggested that formation of 15 prevents Michael
addition, and that the 10:1 ratio of (11b + 13):14 reflects the relative
rates of indole C-H lithiation vs tin-lithium exchange. If this is
correct, then monodeuterated 11b (easily available from the PhLi;
EtOD experiment, above) should be a better substrate for cyclization
because it is protected from the undesired indole lithiation by a
kinetic isotope effect, and might be used in place of 11a.
Accordingly, 11b was treated with 4 equiv of methyllithium at -65
°C (15 min), followed by quenching with EtOH. This gave a
dramatically altered ratio of products, including recovered 11a (5%,
from quenching of the undesired 15), 12 (17%, from 15 followed
by tin-lithium exchange), and 18 (78%, from the desired cycliza-
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10.1021/ja0120835 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
examples where considerably larger kH/kD values have been
observed.11c,d,g,h,12 Clive et al. have also described a case where a
deuterium isotope effect helps protect against an undesired C-H
abstraction by a radical intermediate,12 and Clayden et al. have
commented on the protecting group implications of deuterium in
lithiations.11g However, the conversion from 11b to 19 is unique
in that deuterium serves as a blocking group in the tin-lithium
exchange step and is removed in the subsequent cyclization,
selenenylation, elimination sequence. The strategic benefits are
reflected in a concise synthesis of sensitive aziridinomitosene
derivatives.
Acknowledgment. The authors thank Dr. L. M. Seaney for the
preparation of 9, and for early experiments to probe the possibility
of anionic cyclizations in related substrates. This work was
supported by the National Institutes of Health (CA17918).
Supporting Information Available: Characterization of isolable
intermediates and key experimental procedures (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
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There are a number of prior reports where substantial deuterium
isotope effects have been encountered in lithiations, and were used
to address issues of selectivity.11 A value of kH/kD of ca. 35 for
indole ring lithiation implies tunneling, as discussed in related
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