Szostak et al.
led to well-behaved MS spectra in which both 4 or 6 could be
observed regardless of how the samples were prepared for the
MS experiments. Interestingly, the ratio of 4 over 6 was higher
when the samples were prepared using water as a diluent versus
either THF or CH3CN. Additionally, the methyl ester of 6 was
observed when the MS experiments were prepared by dissolu-
tion with a ca. 95:4:1 MeOH/water/aqueous formic acid mixture
(entry 9). Overall, these experiments are consistent with the
assignments made from the NMR experiments.
(pH ca. 10) conditions. However, the phenyl-substituted analog
5b could be completely recovered following exposure to mixed
solvents.
A lactam containing an R-methylthio group and lacking the
tert-butyl substituent (5c) was fully water-soluble, which allowed
its study in pure aqueous solutions at pH ) 4, 7, and 10. Under
all of these conditions, lactam 5c was stable throughout the
course of study (Table 4, entries 6-8). The kinetic stability of
this compound was further demonstrated by comparing its 13C
NMR spectra taken in CDCl3 and D2O, which were similar
(Figure 5). These studies establish that the enhanced stability
of these “mid-range” twisted amides is not solely due to
scaffolding/reversibility effects but may also depend on their
degree of twist or steric effects arising from embedding the
amide carbonyl group into the middle of the ring system.
These data are consistent with both kinetic and thermody-
namic stability at neutral pH. When the amides are subjected
to strong acid or base, hydrolysis occurs, but the amide bond is
able to reform even in a medium containing 50% water. It is
possible that small amounts of unobserved amide persist in water
under extreme pH conditions, but the high yields of recovered
bridged amide jibe with the NMR results only if reclosure of
the amino acid form is possible. Numerous attempts were made
to retrieve validated samples of zwitterions 6 or derivated thereof
by concentrating the aqueous samples (acid or basic solutions)
and examining the residues by NMR. However, only starting
lactam 4 was observed under these conditions, strongly sug-
gesting that the removal of water from these samples by any
means is sufficient to shift the equilibrium of the compound
back to lactam 4.
Summary
This new class of medium bridged lactams will further the
study of the effect of dihedral angle and twist value on chemical
reactivity. These compounds are clearly twisted amides due to
their substantial twist values of ca. 60°, characteristic spectral
and chemical properties (i.e., N-protonation), and the fact that
they undergo unprecedented chemical reactivity such as adjacent
N-C cleavage (e.g., 4 f 7).20 However, they offer superior
kinetic and thermodynamic water stability relative to known
classes of twisted amides and are readily amenable to synthesis
and structural variation. It has been suggested that twisted
amides would provide an attractive platform for the study of
enzymatic folding and proteolysis properties.1 However, existing
systems were sufficiently unstable in water and/or insufficiently
diversifiable that nearly all aqueous studies of twisted amides
to date have been limited to their hydrolytic behavior. We
anticipate that medium bridged amides will enhance the range
of chemical and biological studies possible with compounds
containing unconventional amide linkages.
We hypothesize that the bridged amides are stabilized by a
scaffolding effect of the medium ring. In addition, once the
lactam bond is hydrolyzed, the resulting amino acid has the
carboxylic acid and amine moieties on the opposite sides of a
medium-size ring where they should be subject to strong
proximity effects. While transannular reactions across medium-
or large-size rings have been frequently observed, the formation
of a twisted amide in water is highly unusual. The most relevant
prior observations are the spontaneous formation of the quinu-
clidone system under mass spectrometry conditions17 and a
single example of amide bond formation in the highly con-
strained adamantane system in acid.24
Experimental Section
The role of conformation in constraining the open nine-
membered amino acid form was of interest as species 6 in Figure
2 exhibits in/out isomerism.37 Thus, the six-membered ring holds
the carboxylic acid in place following amide hydrolysis to the
medium-size ring. The importance of this was underlined when
exposure of lactam 5a, lacking this ring, to strongly acidic or
basic conditions did not permit reisolation of the unchanged
amide, as was the case for compound 4. Removal of all solvent
did afford a quantitative yield of amino acid 8. Here, X-ray
crystallography established that this compound was able to
undergo a conformational change that afforded an amino acid
in which the carboxylic acid has now flipped to the outside
perimeter of the nine-membered ring, where it is unable to reach
the amide group (Figure 4).38 These observations are consistent
with the proposed role of transannular interactions in contribut-
ing to the reversibility of the amide bond formation.
6-(Methylthio)-1-azabicyclo[4.3.1]decan-10-one (5c) and 9a-
(Methylthio)hexahydro-1H-pyrrolo[1,2-a]azepin-5(6H)-one. To
a solution of 2-(3′-azidopropyl)-2-(methylthio)cyclohexanone (0.0910
g, 0.40 mmol, 1.0 equiv, Supporting Information) in CH2Cl2 (8.0
mL, 0.05 M) was added TfOH (0.18 mL, 2.0 mmol, 5.0 equiv) in
one portion at 0 °C, and the resulting solution was stirred at 0 °C
for 2.5 min. The reaction was quenched with saturated NaHCO3
(10 mL) and extracted with CH2Cl2 (3 × 20 mL). The organic layer
was washed with brine (1 × 20 mL), dried (Na2SO4), and
concentrated. Flash chromatography (1/2 EtOAc/hexanes, followed
by EtOAc) afforded compound 5c as a pale yellow oil (Rf ) 0.57,
1/1 EtOAc/hexanes), yield 65% (0.0525 g, 0.26 mmol) and 9a-
(methylthio)hexahydro-1H-pyrrolo[1,2-a]azepin-5(6H)-one as a
colorless oil (Rf ) 0.31, 1/1 EtOAc/hexanes), yield 15% (0.0120
1
g, 0.06 mmol). Compound 5c: H NMR (400 MHz, CDCl3) δ
1.53-1.79 (complex, 4H), 1.80-1.99 (complex, 4H), 2.05-2.14
(complex, 4H), 2.22-2.29 (m, 1H), 2.80-2.86 (m, 1H), 3.18-3.24
(m, 1H), 3.43 (dt, J ) 2.8, 12.0 Hz, 1H), 3.86-3.94 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 12.8, 22.5, 24.3, 26.5, 36.4, 40.1, 47.9,
50.6, 57.0, 182.4; 1H NMR (500 MHz, D2O) δ 1.37-1.46 (m, 1H),
1.49-1.64 (complex, 2H), 1.65-1.71 (complex, 2H), 1.78-1.86
The determination of the limits of thermodynamic stability
in simple bicycles such as 5a allowed us to examine the kinetic
stability of this series of amides through extraction experiments
using organic solvents (either CH3CN or tetrahydrofuran (THF))
and buffer (Table 4). Although the unsubstituted amide 5a was
largely stable in neutral solutions (with a half-life of ca. 13 days,
as determined by NMR), it underwent irreversible conversion
to amino acid under even moderately acidic (pH ca. 4) or basic
(37) Alder, R. W.; East, S. P. Chem. ReV. 1996, 96, 2097–2111.
(38) The crystal of compound 8 contained 0.25 mol of cocrystallized NaCl
per mole of [C13H26NO2][Cl]. The Na ion was disordered over four general
position sites and was therefore included in the structural model with an
occupancy factor of 0.25. See cif file (Supporting Information) for details.
1874 J. Org. Chem. Vol. 74, No. 5, 2009