Synthesis of β-lactams bearing functionalized side chains from a readily available precursor

Article abstract of DOI:10.1021/ol802274x

(Chemical Equation Presented) The reaction of chlorosulfonyl isocyanate (CSI) with alkenes provides β-lactams in quantity, and the products have frequently been used for ring-opening polymerization to generate nylon-3 materials. Prior uses of this approach have focused almost entirely on β-lactams with purely hydrocarbon substitutents. We show how a variety of β-lactams bearing protected polar substituents can be generated from CSI-derived building blocks.

Full text of DOI:10.1021/ol802274x

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5317-5319
Synthesis of ꢀ-Lactams Bearing
Functionalized Side Chains from a
Readily Available Precursor
Myung-ryul Lee, Shannon S. Stahl,* and Samuel H. Gellman*
Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706
gellman@chem.wisc.edu; stahl@chem.wisc.edu
Received September 30, 2008
ABSTRACT
The reaction of chlorosulfonyl isocyanate (CSI) with alkenes provides ꢀ-lactams in quantity, and the products have frequently been used for
ring-opening polymerization to generate nylon-3 materials. Prior uses of this approach have focused almost entirely on ꢀ-lactams with purely
hydrocarbon substitutents. We show how a variety of ꢀ-lactams bearing protected polar substituents can be generated from CSI-derived
building blocks.
ꢀ-Lactams can serve as precursors for the synthesis of
polymers in the nylon-3 family via ring-opening polymeri-
zation (ROP).1 We recently identified cationic nylon-3
copolymers that display antibacterial activity.2 These random
copolymers mimic the behavior of host-defense peptides,3
which are natural oligomers that selectively disrupt bacterial
membranes in preference to eukaryotic cell membranes.
Described below is the synthesis of new ꢀ-lactams that will
be useful for future efforts to refine the biological activity
of nylon-3 polymers.
available. In contrast, stepwise chemical synthesis of peptides
or other discrete oligomers with a defined subunit sequence
is laborious. Reaction of chlorosulfonyl isocyanate (CSI) with
alkenes is a well-established method for generating large
quantities of ꢀ-lactams,4 and this route has been popular for
preparing ROP substrates. However, the intrinsic reactivity
of CSI limits the types of alkenes that can be used for
ꢀ-lactam formation; prior to our recent report2a CSI had been
used largely to generate ꢀ-lactams with pure hydrocarbon
appendages, as illustrated by the example in Scheme 1.5 Our
The development of random copolymers as antibacterial
agents could be significant from a practical perspective
because preparation of large quantities of these polymers
should be straightforward, if the precurors are readily
Scheme 1
(1) (a) Hashimoto, K.; Hotta, K.; Okata, M.; Nagata, S. J. Polym. Sci.
Part A: Polym. Chem. 1995, 33, 1995. (b) Hashimoto, K. Prog. Polym.
Sci. 2000, 25, 1411. (c) García-Martíin, M. D. G.; Ba´n˜ez, M. V. D. P.;
Galbis, J. A. J. Carbohydr. Chem. 2000, 19, 805.
(2) (a) Mowery, B. P.; Lee, S. E.; Kissounko, D. A.; Epand, R. F.; Epand,
R. M.; Weisblum, B.; Stahl, S. S.; Gellman, S. H. J. Am. Chem. Soc. 2007,
129, 15474. (b) Epand, R. M.; Mowery, B. P.; Lee, S. E.; Stahl, S. S.;
Lehrer, R. I.; Gellman, S. H.; Epand, R. M. J. Mol. Biol. 2008, 379, 38.
(3) (a) Tossi, A.; Sandri, L.; Giangaspero, A. Biopolymers 2000, 55, 4.
(b) Zasloff, M. Nature 2002, 415, 389.
development of antibacterial nylon-3 derivatives hinged on
extension of the CSI method to an alkene bearing a protected
amino group. Because the resulting ꢀ-lactam proved to be
10.1021/ol802274x CCC: $40.75
Published on Web 10/29/2008
2008 American Chemical Society

so valuable, we were motivated to explore other strategies
for generating ꢀ-lactams bearing protected polar groups from
CSI-derived products. Here we describe routes to several new
ꢀ-lactams, derived from 1, with appendages that contain
protected amino or hydroxyl groups.
Scheme 3
Scheme 2 illustrates the conversion of 1 to ꢀ-lactams that
bear two side chains, one on each saturated ring carbon, with
Scheme 2
verted to dimesylate 11. Treatment of 11 with HCl provided
monosubstituted product 12 in moderate yield. The identity
of 12 was retrospectively established after two additional
reactions, radical-mediated replacement of chlorine with
hydrogen followed by displacement of mesylate with azide.
This process yielded 13, the structure of which was deduced
from COSY data (Figure S1, Supporting Information).
Reduction of the azide and in situ Boc protection provided
14, which could be oxidatively deprotected11 to generate 3,
a ꢀ-lactam that can participate in ROP reactions.
cis stereochemistry. This route provides ꢀ-lactams in which
both side chains bear the same functional group. After the
lactam nitrogen has been protected with a silyl group5 (5),
the alkene can be oxidatively cleaved with ozone,6 and a
reductive workup provides dihydroxy ꢀ-lactam 6. The
hydroxyl groups can be protected by cyclic acetal formation.
Removal of the silyl group then provides ꢀ-lactam 2, which
is suitable for ROP under standard anionic conditions.
Alternatively, dihydroxy ꢀ-lactam 6 can be efficiently
converted to diiodide7 8, which could serve as a precursor
for ꢀ-lactams bearing a variety of other polar group pairs in
the side chains.
Scheme 4 shows a strategy for generating ꢀ-lactams that
retain the cis-cyclohexyl constraint and bear polar substitution
Scheme 4
A variation on the route in Scheme 2, which is shown in
Scheme 3, provides cis-disubstituted ꢀ-lactams in which the
side chains are different. A silyl protecting group on the
ꢀ-lactam nitrogen proved to be inadequate for this approach,
but the p-methoxyphenyl (pMP) protecting group8 was
effective. In this route, oxidative alkene cleavage was
achieved via OsO4-mediated9 dihydroxylation followed by
reaction with NaIO4 in the presence of NaBH4,10 to generate
dihydroxy ꢀ-lactam 10. This compound was readily con-
(4) Graf, R.; Lohaus, G.; Borner, K.; Schmidt, E.; Bestian, H. Angew.
Chem., Int. Ed. 1962, 1, 481.
(5) Singh, R.; Cooper, R. D. G. Tetrahedron 1994, 50, 12049.
(6) (a) Criegee, R. Angew. Chem., Int. Ed. 1975, 14, 745. (b) Georg,
G.; Durst, T. J. Org. Chem. 1983, 48, 2092.
(7) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Perkin Trans. 1 1980,
2866.
(8) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(9) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973. (b) Trost, B. M.; Crawley, M. L.; Lee, C. Chem. Eur. J. 2006,
12, 2171.
on the cyclohexyl ring. Treatment of racemic silyl-protected
ꢀ-lactam 5 with N-bromosuccinimide in aqueous DMSO
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Org. Lett., Vol. 10, No. 22, 2008

generated the four possible bromohydrin products,12 15a-d.
The structures of these bromohydrins were ultimately
established by repeating this reaction with stereochemically
pure (1S,6R)-5 (the synthesis of which is described below)
and isolating the products via chromatography. High-quality
crystals could be grown for three of the stereochemically
pure bromohydrins, 15a, 15c and 15d (Figure S2, Supporting
Information), and the crystal structures were obtained.
Racemic 15d was carried on via radical-mediated replace-
ment of bromine with hydrogen followed by mesylation, to
generate 16d, which could be easily converted to azide 17d.
Reduction with in situ Boc protection of the amino group
and subsequent silyl group removal yielded 4d. Nylon-3
polymers containing constrained residues that bear a polar
group may prove to have particularly interesting properties.
The synthetic routes outlined in Schemes 2-4 provide
racemic ꢀ-lactams, which will be useful in some applications;
the antibacterial nylon-3 polymers we have reported were
generated from chiral but racemic ꢀ-lactams.2 However, it
would be valuable to have access to enantiopure ꢀ-lactam
building blocks because some biomedical applications may
require homochiral polymers. In addition, the ability to
compare homochiral and heterochiral versions of a given
polymer may prove useful for analyzing the mode of
biological action. Enantiopure samples of ꢀ-lactams such as
2, 3, and 4d can in principle be prepared from enantiopure
1, and this key intermediate is available via enzymatic
resolution.
comparison with the diastereomeric mixture of Mosher
amides that is generated from racemic 1 indicates that
enzymatic resolution provides a single enantiomer of 1 in
98% ee.14 We assign the configuration of this isomer as
(1S,6R)-1 on the basis of 1H NMR comparison of the
enantioenriched Mosher amide and the diastereomeric mix-
ture of Mosher amides generated from racemic 1 (Figure
S3, Supporting Information). This assignment is consistent
with the absolute configurations determined from crystal-
lographic data for stereochemically pure 15a, 15c, and 15d.
We have developed serviceable routes to ꢀ-lactams that
bear side chain polar groups protected in ways that should
be amenable to the synthesis of nylon-3 materials via anionic
ring-opening polymerization. Recent work from our group
has shown that such building blocks can lead to materials
with very interesting biological activities,2 but only one
example of a polar-functionalized ꢀ-lactam was used in that
study. The synthetic approaches developed here provide new
ꢀ-lactams that are of interest as ROP substrates, and key
intermediates in the routes we report should enable synthesis
of additional ꢀ-lactams bearing a diverse range of side chain
functionality. The ꢀ-lactams made available through the
chemistry reported here include examples with two identical
side chains, with two different side chains, and with a
functionalized cyclic constraint. Because key intermediate
1 can be generated in highly enantioenriched form, all of
these routes can potentially provide enantiopure ꢀ-lactams
and thus homochiral nylon-3 polymers.
Treatment of racemic 1 with a commercially available
polymer-bound lipase13 generates (1S,6R)-1 (Scheme 5). The
Acknowledgment. This work was supported in part by
the Nanoscale Science and Engineering Center at UW-
Madison (DMR-0425880) and the NSF Collaborative Re-
search in Chemistry program (CHE-0404704). M.-r.L. was
supported in part by Korea Research Foundation Grant
funded by the Korean Government (MOEHRD) (KRF-2006-
214-C00053). We thank Dr. Ilia Guzei at UW-Madison for
solution of crystal structures. We thank Dr. Fe´lix Freire at
UW-Madison for helpful discussions.
Scheme 5
Supporting Information Available: Experimental details
and spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802274X
(10) (a) Suzuki, T.; Suzuki, S. T.; Yamada, I.; Koashi, Y.; Yamada, K.;
Chida, N. J. Org. Chem. 2002, 67, 2874. (b) Kiss, L.; Kazi, B.; Forro´, E.;
Fu¨lo¨p, F. Tetrahedron Lett. 2008, 49, 339.
(11) (a) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem.
1982, 47, 2765. (b) Mukai, C.; Kataoka, O.; Hanaoka, M. J. Chem. Soc.,
Perkin Trans. 1 1993, 563.
(12) (a) Dalton, D. R.; Hendrickson, J. B.; Jones, D. Chem. Commun.
1966, 591. (b) Crombie, L.; Mistry, K. M. J. Chem. Soc., Perkin Trans. 1
1991, 1981.
enantiopurity of this material was determined by hydrolysis
to the ꢀ-amino acid, Fmoc protection, and conversion to the
Mosher amide. As shown in Scheme 5 19F NMR-based
(13) Forro´, E.; Fu¨lo¨p, F. Tetrahedron: Asymmetry 2004, 15, 2875.
(14) Seco, J. M.; Quin˜oa´, E.; Riguera, R. Chem. ReV. 2004, 104, 17.
Org. Lett., Vol. 10, No. 22, 2008
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