trilactams similar to structure 2. In each reaction the respective
substituted version of lactone 3 and the amides 20 and 21 were
also produced as by-products by unwanted imidate hydrolysis.
Before the cross-over experiment was performed, a mixture
of all of the possible differently alkyl-substituted trimers was
independently synthesised by treating a mixture of amides 7, 14
and 15 with TFA. Analysis of the crude reaction product from
this reaction by LCMS identified all ten of the possible trimers
from all combinations of hydrogen-, methyl- and butyl-substituted
monomers (including trimers with proposed structures 2, 16 and
17) by their distinct mass spectra. The key cross-over experiment
was then performed: a mixture of ‘symmetrical’ trimers 2, 16 and
17 was treated with TFA and the product mixture analysed by
LCMS. All ten of the possible trimers were observed, as in the
previous experiment, showing that monomer exchange is possible,
that the reaction is reversible, and that the synthesis of the trimers
is under thermodynamic control (Scheme 5). Simpler experiments
involving the mixture of only two starting amides or two trimers
were performed and also indicated that the trimerisation is
reversible.
Scheme 3
primary amide or nitrile, and may provide a common route to a
linear trimer that can then cyclise to give the proposed macrocycle
(Scheme 3). Lactone 3 is a simple hydrolysis product of the imidate
and is generally the major by-product in unoptimised reactions.
Further investigations sought to discover why the trimer, rather
than say the dimer, tetramer or polymer, is the major product. In
fact, no other cyclic oligomers could be identified in the reaction
product mixture.
It seemed possible that the oligomerisation and ring closure
were reversible, as for other nitrogen ring closures,3 and the trimer
product was significantly more stable than the alternative products
in the equilibrating system. To test the reversibility of the imidate
trimerisation, a three-way cross-over experiment was designed to
discover whether or not the individual units of the cyclic trimer
could exchange between different trimer molecules under the
reaction conditions. Two trimers with labelled monomer units,
differentiated by alkyl group substitution on the phenyl rings,
were synthesised. Differently substituted arylsulfanyl amides 14
and 15 were synthesised from 4-methyl- and 4-butyl-benzenethiols
10 and 11 via aldehydes4 12 and 13 (Scheme 4). Amides 14 and
15 were independently treated with TFA in toluene, as for amide
7, producing trimethyl- and tributyl-substituted trimers 16 and
17 respectively, which were originally thought to be macrocyclic
Scheme 5
The ease and selectivity of the synthesis of the ring-forming
trimerisation led to consideration of other related macrocyclisa-
tion experiments. The first aim for this part of the study was to
synthesise and cyclise linear peptides closely related to the possible
intermediates in the synthesis of originally proposed macrocyclic
trimer 2. 2-Nitropropane was converted into tert-butyl amino-
ester5 22, which was coupled onto the hydroxy acid 23, previously
used in the synthesis of amide 7 (Scheme 6). Conversion of the
tert-butyl ester 24 into the primary amide 27 had to be performed
without initiating episulfonium ion generation. Acid-catalysed
trans-esterification in methanol occurred cleanly, as higher tem-
peratures are usually needed to generate these episulfonium ions
in alcohol solvents.6 Base-mediated saponification of methyl ester
25, followed by primary amide formation, produced possible 10-
membered ring precursor 27. The coupling of acid 26 to amino-
ester 22 led to linear trimer 31. In addition structurally-related
8-membered ring precursor 32 was synthesised from 2-amino-
isobutyric acid (Scheme 6). The secondary amide product of the
initial coupling had to be purified from unreacted hydroxy acid
23, via conversion to their methyl esters.
Treatment of linear dimer 27 with TFA in toluene produced
10-membered ring dimer 34 in very low yield, and it could be
purified only after desulfurisation with Raney nickel to give bis-
lactam7 35 (Scheme 7). The other products of the ring closure
reaction were the product of benzenethiol elimination (36) from
the intermediate imidate 33 and lactone 3. The linear trimer 31
was also treated with acid but the expected 15-membered ring
was not formed. The only observed product was the initially
formed imidate 37. Neither the primary nor the secondary amides
made a lactam. The failure of the cyclisation of linear trimer 31
was surprising given its similarity to the proposed intermediate
in the synthesis of trimer 2 (Scheme 1). It seemed possible, but
Scheme
4 Reagents and conditions: i) SO2Cl2, Et3N then
=
Me3SiOCH CMe2, THF 12 92%, 13 79%; ii) EtOAc, LDA, THF;
iii) KOH, H2O, MeOH; iv) DCC, NHS, THF; then NH3, H2O, 14 49%, 15
41% (over 3 steps); v) TFA–toluene (1 : 10 v/v), 40 ◦C, 16 65%, 18 12%,
20 15% and 17 44%, 19 15%, 21 30%.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3120–3124 | 3121
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