Benzoylureas as removable cis amide inducers: Synthesis of cyclic amides via ring closing metathesis (RCM)

Article abstract of DOI:10.1039/c0ob00723d

Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.

Full text of DOI:10.1039/c0ob00723d

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Organic &
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Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via
ring closing metathesis (RCM)†
Ryan M. Brady, Yelena Khakham, Guillaume Lessene* and Jonathan B. Baell*
Received 15th September 2010, Accepted 25th October 2010
DOI: 10.1039/c0ob00723d
Table 1 Conditions for attempted RCM of the substrate 9
Rapid and high yielding synthesis of medium ring lactams was
made possible through the use of a benzoylurea auxiliary that
serves to stabilize a cisoid amide conformation, facilitating
cyclization. The auxiliary is released after activation under the
mild conditions required to deprotect a primary amine, such
as acidolysis of a Boc group in the examples given here. This
methodology is a promising tool for the synthesis of medium
ring lactams, macrocyclic natural products and peptides.
Entry
GII (%)
Solvent
Temp/◦C
Time/h
% Yield
1
2
3
4
10
20
10
20
DCM
DCM
Toluene
Toluene
40
40
100
100
12
12
12
12
0
0
0
0
In the design of peptidomimetics, introducing covalent confor-
mational constraints through the formation of macrocycles such
as lactams and cyclopeptides is a proven strategy to reduce
unfavorable entropy loss upon binding and thus improve binding
affinity.1 However, the synthesis of cyclic structures is often difficult
due to a large energy cost in arranging the linear precursor into
a transition state prefigurating the cyclic final product.2 Ring
formations involving a secondary amide group are particularly
difficult if cyclization requires the thermodynamically disfavoured
cis-conformation to be adopted,3 which is typically the case for
rings that are 11-membered or smaller.4 Even for the preparation
of larger rings, such as hexapeptide 16-mers where all trans
peptide bonds may be tolerated, transient stabilization of a cisoid
peptide bond in the precursors may be required for efficient
cyclization to occur.5 The most popular approach to stabilizing
a cisoid conformation is the N-alkylation of secondary amides.6,7
This strategy includes the use of proline or pseudoprolines5,8
in cyclopeptides and has also been successfully applied to the
preparation of cyclic sulfonamides.9 Notably, pseudoprolines are
restricted to necessarily regenerate either serine8 or threonine7,10
and cyclisation involving N-benzyl tertiary amides can be fickle.7
During our investigations into the use of benzoylureas as a-
helical mimetics of the BH3-only proteins,11 we targeted cyclic
analogs such as 2 (Scheme 1) as a means to constrain t1 in these
scaffolds in order to induce the bioactive conformation. Efforts
to conformationally constrain the benzoylurea scaffold focused
on the synthesis of lactams of the type 3 as precursors of the
constrained targets 2 (Scheme 1).
Scheme 1 Retrosynthesis of constrained mimetics 2.
Grubbs Ring Closing Metathesis (RCM) is recognised as an
effective synthetic approach to forming cyclic moieties,12 partic-
ularly in the field of natural products13 and peptidomimetics.9,14
We envisaged that this chemistry would be particularly suitable
for the synthesis of our target macrolactams, employing dienes
such as 4 as substrates (Scheme 1). An exemplary synthesis for
metathesis substrates 8 and 9 is shown in Scheme 2, and occurs via
alkylation of ethyl salicylate 5 to give allyl ether 6 and 7, followed
by saponification of the ester group and amidation with allylamine.
Scheme 2 Diene synthesis and attempted RCM.
Walter and Eliza Hall Institute of Medical Research, 1G Royal Pa-
rade, Parkville, Victoria, 3052, Australia. E-mail: jbaell@wehi.edu.
au, glessene@wehi.edu.au
† Electronic supplementary information (ESI) available: Experimental
procedures; copies of 1H and 13C NMR spectra; references. See DOI:
10.1039/c0ob00723d
Unfortunately, RCM with substrates 8 and 9 failed to form the
target lactams (Scheme 2). Variation in conditions as shown in
Table 1 failed to affect the RCM. We suspected that the failure
to effect ring closure was a result of the nature of the substrate,
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particularly the secondary amide’s preference towards the trans
conformation.
We have shown11 that benzoylureas can adopt a ‘closed’
conformation maintained by a strong intramolecular hydrogen
bond as shown for 1 in Scheme 1, which effectively renders the
benzamide bond cisoid-like in character.
We postulated that this conformation could facilitate macro-
cyclization. A simple model system was employed to test this
hypothesis. As shown in Scheme 3, benzoylurea 12 was prepared
by reacting the silylated amide group of 8 with a carbonyl donor
(phosgene). The resulting carbamoyl chloride was then on-reacted
with propylamine. Gratifyingly, when the benzoylurea 12 was
subjected to RCM with 5 mol% Grubbs II in refluxing DCM, the
target lactam 13 was smoothly generated in 1 h and in 62% yield.
Scheme 6 Synthesis of macrocycle precursor 25, fitted with the benzoy-
lurea auxiliary.
the aryl iodide 22 and allyltributyltin, yielding 23 (Scheme 6).
The ester was then converted directly to the amide 24 us-
ing DABAL-Me3, an air stable, solid derivative of trimethyl
aluminium.16
With the necessary precursors in hand, the effect of the ‘closed’
conformation was evident by the rapid and high yielding RCM
(Scheme 7).
Scheme 3 Model RCM induced by a benzoylurea group.
Encouraged by this result, we envisaged that a suitably func-
tionalised macrocyclic acylurea such as 14 in Scheme 4 could
self-cleave via an intramolecular nucleophilic attack, to release
a lactam 16 and the auxiliary by-product 17. This strategy was
again evaluated on a model system, employing reaction of the
carbamoyl chloride of the commercially available lactam 18 with
Boc-protected 2-aminobenzylamine 19, to give 20 as shown in
Scheme 5. Following deprotection of the amine in 20 with TFA,
neutralisation with DIPEA and warming to 60 ◦C in DMF the
desired self-cleavage was indeed observed to give lactam 18 and
by-product 17.15
Scheme 7 Acylurea-induced RCM and release of auxiliary.
Removal of the auxiliary facilitated the release and subsequent
isolation of the desired lactams. In order to further extend the
general utility of this self-cleavage reaction, we next investigated
the possibility of using, in the acylurea synthesis, an appropriately
functionalised aniline that could give rise to a by-product more
readily removed than 17. In particular, we envisaged that a
second methylenamine unit on the auxiliary (compound 34,
Scheme 8) would allow efficient removal of the deprotection by-
product using an acidic work-up. Additionally, the use of similar
protecting groups on both primary amines would facilitate the
deprotection/removal step. Shown in Scheme 8 are the results of
our efforts. The functionalised auxiliary, tert-butyl-(4-amino-1,3-
phenylene)bis(methylene)dicarbamate 34 was prepared in 2 steps
from 2-amino-5-bromobenzonitrile 32. After aryl cyanation of 33,
a one-pot reduction/Boc-protection reaction afforded the desired
compound 34.
Scheme 4 Removal of auxiliary via intramolecular nucleophilic attack
with release of target lactams 16.
Scheme 5 Synthesis of model benzoylurea auxiliary 20 and self-cleavage
to release the expected lactams.
Scheme 8 Preparation of functionalized auxiliary.
With a cleavable auxiliary in hand, the ability to synthesise
and isolate lactams of various sizes was explored. In particular,
we focused on the 8–10 membered rings, as cyclisation was not
achievable using the precursor secondary amides.
In the case of the smaller 8-membered ring, we opted for a
carbon linked alkene formed using a Stille coupling between
The functionalised aniline 34 was then used to prepare the model
benzoylurea 35, which was then subjected to the deprotection
conditions (Scheme 9). Pleasingly, with this auxiliary, the amide
18 was regenerated cleanly following simple aqueous work up
without the need for column chromatography. With this improved
auxiliary in hand, we then demonstrated the effectiveness of our
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Acknowledgements
This work was supported by the NHMRC IRISS Grant 361646
and a Victorian State Government OIS grant
Scheme 9 Employing the functionalized auxiliary to isolate the amide
18.
Notes and References
1 D. G. Udugamasooriya and M. R. Spaller, Biopolymers, 2008, 89, 653–
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2 R. Nakagaki, H. Sakuragi and K. Mutai, J. Phys. Org. Chem., 1989, 2,
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3 R. M. Williams and J. W. Liu, J. Org. Chem., 1998, 63, 2130–
2132.
4 F. Carelier-Frontin, S. Achmad, J. Verducci, R. Jacquier and G. Pepe,
THEOCHEM, 1993, 286, 125.
approach for the synthesis of a lactam via RCM. As shown in
Scheme 10, the functionalised auxiliary 34 was able to effect the
cyclisation as well as auxiliary 19, and enable a much more facile
isolation of the desired macrocycle 11.
5 D. Skropeta, K. A. Jolliffe and P. Turner, J. Org. Chem., 2004, 69,
8804–8809.
6 C. J. Creighton, Y. M. Du and A. B. Reitz, Bioorg. Med. Chem., 2004,
12, 4375–4385.
7 M. El Haddadi, F. Cavelier, E. Vives, A. Azmani, J. Verducci and J.
Martinez, J. Pept. Sci., 2000, 6, 560–570.
8 N. Schmiedeberg and H. Kessler, Org. Lett., 2002, 4, 59–62. Mutter’s
pseudoprolines were reported to stabilize the cisoid conformation in the
very first report (; T. Haack and M. Mutter, Tetrahedron Lett., 1992,
33, 1589–1592) but, like subsequent studies with N-benzyl reversible
backbone protection (; T. Johnson and M. Quibell, Tetrahedron Lett.,
1994, 35, 463–466; L. P. Miranda, W. D. F. Meutermans, M. L. Smythe
and P. F. Alewood, J. Org. Chem., 2000, 65, 5460–5468), their use
was advocated for improving the synthesis of problematic sequences
through destruction of secondary structure interference. Schmiedeberg
and Kessler used pseudoprolines in this context, even though this was
for the specific purpose of enabling cyclization and where it was implicit
that cisoid amide bond stabilization underpinned their reasoning but
this was not stated as such. Two years later, Skropeta et al. (ref. 5)
made it explicit that their use of pseudoprolines was for the purpose of
stabilizing a cisoid amide bond in order to facilitate cyclizations.
9 A. J. Brouwer and R. M. J. Liskamp, J. Org. Chem., 2004, 69, 3662–
3668.
Scheme 10 Employing the functionalized aniline to facilitate isolation of
the lactam.
In summary, we have described a new auxiliary that facilitates
the formation of macrocyclic lactams via stabilization of a cisoid
amide bond, promoting rapid and high yielding ring closure via
RCM.
10 N. Sayyadi, I. Luck, J. Cleg,g and K. A. Jolliffe, Org. Lett., 2010, 12,
To the best of our knowledge, this is the first time that an
acylurea has been regarded as a masked cisoid secondary amide.
This conformation is maintained by the strong intramolecular
hydrogen bond characteristic of the closed form of the acylurea.11b
There are several attractive features of our approach. Firstly, the
masked amide is rigidly maintained in the cis conformation.17 This
is in contrast with N-alkylated tertiary amides where the cis form
is only relatively stabilized but not necessarily thermodynamically
preferred over the trans form. As such, it is not uncommon for
cyclization reaction times involving N-alkyl tertiary amides to be
measured in the order of days rather than hours.6 Secondly, the
use of amine deprotection to initiate self-cleavage allows for great
versatility in the choice of protecting groups beyond the use of Boc.
In principle Fmoc protecting groups could allow for initiation of
self-cleavage under basic conditions.
3136–3139.
11 (a) G. L. Lessene, J. Baell PCT Int. Appl. WO 2006002474; (b) G.
Lessene, B. J. Smith, R. W. Gable and J. B. Baell, J. Org. Chem., 2009, 74,
6511–6525; (c) Mimetic design has been disclosed in depth in a number
of fora, including posters (1st Conforth conference, Sydney 2002; 19th
RACI conference, Lorne 2003; 20th RACI conference, Cairns 2004)
and oral presentations (Connect 2005, 12th RACI Convention, Sydney
2005; 7th ESH conference on Mechanisms of Cell Death and Disease:
Advances in Therapeutic Intervention and Drug Development, 2004).
12 C. W. Lee and R. H. Grubbs, J. Org. Chem., 2001, 66, 7155–
7158.
13 H. Hagiwara, T. Katsumi, V. P. Kamat, T. Hoshi, T. Suzuki and M.
Ando, J. Org. Chem., 2000, 65, 7231–7234.
14 A. G. M. Barret, A. J. Hennessy, R. Le Vezouet, P. A. Procopiou, P. W.
Seale, S. Stefaniak, R. J. Upton, A. J. P. White and D. J. Williams, J.
Org. Chem., 2004, 69, 1028–1037.
15 No self-cleavage was observed in DCM when allowed to stand for 2–6 h
at room temperature.
16 D. Glynn, D. Bernier and S. Woodward, Tetrahedron Lett., 2008, 49,
We believe there is much scope for this auxiliary methodology
to become a valuable tool for the synthesis of macrocyclic lactams,
peptidomimetics, cyclic peptides and natural products via RCM.
5687–5688.
17 We have shown (ref. 11b) that when R1 in Scheme 1 is branched, a
second conformation can also exist.
658 | Org. Biomol. Chem., 2011, 9, 656–658
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The Royal Society of Chemistry 2011
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