A novel strategy for the synthesis of medium-sized lactams

Article abstract of DOI:10.1021/ol0261579

(Matrix presented) A novel method for the synthesis of medium-sized lactams based on an auxiliary-mediated combined tethered/templated strategy is presented. Cyclization by a tethered ring-closing metathesis reaction was followed by a templated transannular aminolysis reaction to give seven-to ten-membered lactams in good yields.

Full text of DOI:10.1021/ol0261579

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2673-2674
A Novel Strategy for the Synthesis of
Medium-Sized Lactams
Hans Biera1ugel,† T. Paul Jansen,† Hans E. Schoemaker,†,‡ Henk Hiemstra,† and
,†
Jan H. van Maarseveen*
Institute of Molecular Chemistry, UniVersity of Amsterdam, Nieuwe Achtergracht 129,
1018 WS Amsterdam, The Netherlands, and DSM Research, Life Science Products,
PO Box 18, 6160 MD Geleen, The Netherlands
jVm@science.uVa.nl
Received May 8, 2002
ABSTRACT
A novel method for the synthesis of medium-sized lactams based on an auxiliary-mediated combined tethered/templated strategy is presented.
Cyclization by a tethered ring-closing metathesis reaction was followed by a templated transannular aminolysis reaction to give seven- to
ten-membered lactams in good yields.
Medium-sized lactams (seven- to ten-membered) find wide
application in important fields such as natural product
chemistry and pharmaceutical research. Despite their rel-
evance, the closure of seven- to ten-membered lactams
especially remains a synthetic challenge.1 Direct closure by
lactamization proceeds in high yields only if appropriate
substituents on the chain induce a conformation to the linear
precursor molecule that brings the terminal groups in close
proximity.2 In the case of ω-amino acids lacking a structural
bias to facilitate ring-closure, the main product is often the
dimeric lactam. Besides conducting the reaction at high
dilution, difficult lactams were closed by the use of tem-
plating metals,2a-c within micelles2e and within polymers.2f
However, all of the methods described have drawbacks and
often only moderate cyclization yields were obtained.
In this letter our first results are presented on the
development of novel and generally applicable methods for
the closure of medium-sized lactams. Our approach is based
on the use of an auxiliary that facilitates two subsequent key
reactions by playing a dual tethering and templating role
(Scheme 1). The final templated transannular ring-contracting
Scheme 1. Retrosynthetic Outline of the Combined Tethered/
Templated Approach toward Lactams
† University of Amsterdam.
‡ DSM Research.
(1) For review articles, see: (a) Nubbemeyer, U. Top. Curr. Chem. 2001,
216, 125. (b) Evans, P. A.; Holmes, A. B. Tetrahedron 1991, 47, 9131.
(2) For some earlier work on difficult lactamizations, see: (a) Steliou,
K.; Poupart, M.-A. J. Am. Chem. Soc. 1983, 105, 7130. (b) Mader, M.;
Helquist, P. Tetrahedron Lett. 1988, 29, 3049. (c) Yamamoto, Y.; Furuta,
T. Chem. Lett. 1989, 797. (d) Bosch, I.; Romea, P.; Urp´ı, F.; Vilarrasa, J.
Tetrahedron Lett. 1993, 34, 4671. (e) Rico, I.; Halvorsen, K.; Dubrule, C.;
Lattes, A. J. Org. Chem. 1994, 59, 415. (f) Huang, W.; Kalivretenos, A. G.
Tetrahedron Lett. 1995, 36, 9113. See also references cited in these articles.
lactamization step is preceded by a macrocyclization reaction
in which the auxiliary serves as a tether to bring together
the mutually reactive X and Y groups.
10.1021/ol0261579 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/18/2002

For this first proof of principle, salicylaldehyde was chosen
as the auxiliary. Pioneering work of Meutermans and co-
workers showed the power of similar auxiliaries in an
approach toward difficult small cyclopeptides.3
The high reactivity of an aryl ester to aminolysis is
combined with a correct spatial positioning of the secondary
amine and carbonyl functional groups for the transannular
ring-contraction reaction. As a model reaction, the versatile
ring-closing metathesis (RCM) process was chosen for the
tethered macrocyclization step.4
After removal of the Boc protective group by TFA
treatment, the stage was set for the final transannular O f
N acyl transfer reaction. Prior to liberation of the amine by
the addition of base, the solution was diluted to a concentra-
tion of 0.01 M with EtOAc. In contrast to tertiary amine
bases the use of NaHCO3 gave a clean conversion to the
medium-sized lactams 4a-e in isolated yields ranging from
54% to 70%.6
Removal of the remaining 1-(2-hydroxy-benzyl) group was
easily accomplished by mild reduction with sodium in liquid
ammonia after methylation of the phenolic-OH group, as was
demonstrated for 4a to give caprolactam 5 in an overall yield
of 65% (Scheme 3).7
The synthesis of the starting materials commenced with a
reductive amination reaction of salicylaldehyde (1) with
allylamine using Na(OAc)3BH as the reducing agent (Scheme
2). After Boc-protection of the resulting secondary amine,
Scheme 3. Removal of Remaining 1-(2-Hydroxy-benzyl)
Group
Scheme 2. Synthesis of Cyclization Precursors and Tethered
RCM and Templated Lactamization Reactions
In conclusion, a powerful method was developed for
difficult lactamizations. Studies are ongoing to expand this
strategy toward the synthesis of small homo- and heterodetic
cyclopeptides, which are synthetically inaccessible by current
methods.8
Acknowledgment. We thank Adri van den Hoogenband
and Karel Stegman (Solvay Pharmaceuticals, Weesp, The
Netherlands) for measuring the ESI-MS spectra. This re-
search has been financially supported by the Council for
Chemical Sciences of the Netherlands Organization for
Scientific Research (CW-NWO).
Supporting Information Available: Representative ex-
perimental procedures and spectroscopic data of the com-
pounds 2a-e, 3a-e, 4a-e, and 5 are available free of charge
via the Internet at http://pubs.acs.org.
OL0261579
(5) (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J. Am.
Chem. Soc. 1999, 121, 2674. (b) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. (c) Scholl, M.; Ding, S.;
Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. (d) Zhu, S. S.; Cefalo,
D. R.; La, D. S.; Jamieson, J. Y.; Davis, W. M.; Hoveyda, A. H.; Schrock,
R. R. J. Am. Chem. Soc. 1999, 121, 8251. (e) Wheaterhead, G. S.; Ford, J.
G.; Alexanian, E. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc.
2000, 122, 1828. (f) Fu¨rstner, A.; Ackermann, L.; Gabor, B.; Goddard, R.;
Lehmann, C. W.; Mynott, R.; Stelzer, F.; Thiel, O. R. Chemistry 2001, 7,
3236.
(6) Especially in the case of the six-membered lactam, conducting the
final lactamization reaction at a higher concentration also gave the dimeric
12-membered bislactam. At 0.01 M the content of dimer was <5%.
(7) Treatment with trifluoromethane sulfonic acid (see: Johnson, T.;
Quibell, M. Tetrahedron Lett. 1994, 35, 463) gave unsatisfactory results.
Treatment with other strong acids (i.e., concentrated H2SO4, concentrated
HBr) or oxidative methods (cerium ammonium nitrate or DDQ) gave
complex mixtures. Finally, catalytic reduction (H2, Pd(C) or H2, Pd(OH)2)
resulted in full recovery of the starting material.
the phenolic alcohol was esterified with several ω-alkenyl
acids employing DCC/DMAP activation, giving the precur-
sors 2a-e for the tethered RCM reactions in high overall
yields.
All tethered RCM reactions were conducted with the
second-generation Ru-imidazolidine type catalysts and gave,
after hydrogenation of the double bonds, the macrocyclic
lactones 3a-e in good overall yields from 2a-e.5
(3) Meutermans, W. D. F.; Golding, S. W.; Bourne, G. T.; Miranda, L.
P.; Dooley, M. J.; Alewood, P. F.; Smythe, M. L. J. Am. Chem. Soc. 1999,
121, 9790. In their approach, the auxiliary solely facilitated the final
transannular lactamization step.
(4) For review articles, see: (a) Fu¨rstner, A. Angew. Chem., Int. Ed.
2000, 39, 3012. (b) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (c) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(8) For an excellent review on modern approaches towards cyclic
peptides, see: Lambert, J. N.; Mitchell, J. P.; Roberts, K. D. J. Chem. Soc.
Perkin Trans. 1 2001, 471.
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Org. Lett., Vol. 4, No. 16, 2002