Rapid cleavage of cyclic tertiary amides of Kemp's triacid: Effects of ring structure

Article abstract of DOI:10.1016/j.bmcl.2004.06.024

The piperidyl and prolyl amides of Kemp's triacid (7 and 8, respectively) have been prepared and their rates of intramolecular acylolysis measured as a function of pD. The piperidyl derivative 7 reacts approximately four-times faster (e.g., t_1/2=3min at 20°C and pD7.7) than the previously reported pyrrolidyl and methylphenethyl amide derivatives, while the prolyl derivative 8 reacts two-times more slowly (e.g., t_1/2=30min at 20°C and pD7.8). Molecular-mechanics calculations indicate that the nonbonded interactions in the piperidyl derivative 7 are distinct from those in the prolyl, pyrrolidyl, and methylphenethyl amide derivatives, a result that supports the suggestion that ground-state pseudoallylic strain contributes to the enormous reactivity of Kemp's triacid tertiary amides. In sum, the results reported indicate that the Kemp's triacid scaffolding provides a general means of activating tertiary amide derivatives.

Full text of DOI:10.1016/j.bmcl.2004.06.024

Bioorganic & Medicinal Chemistry Letters 14 (2004) 4153–4156
Rapid cleavage of cyclic tertiary amides of Kemp’s triacid:
effects of ring structure
Michael L. Dougan, Jonathan L. Chin,à Ken Solt§ and David E. Hansen*
Department of Chemistry, Amherst College, Amherst, MA 01002, USA
Received 21 May 2004; revised 9 June 2004; accepted 9 June 2004
Available online
Abstract—The piperidyl and prolyl amides of Kemp’s triacid (7 and 8, respectively) have been prepared and their rates of intra-
molecular acylolysis measured as a function of pD. The piperidyl derivative 7 reacts approximately four-times faster (e.g.,
t1=2 ¼ 3 min at 20 °C and pD 7.7) than the previously reported pyrrolidyl and methylphenethyl amide derivatives, while the prolyl
derivative 8 reacts two-times more slowly (e.g., t1=2 ¼ 30 min at 20 °C and pD 7.8). Molecular-mechanics calculations indicate that
the nonbonded interactions in the piperidyl derivative 7 are distinct from those in the prolyl, pyrrolidyl, and methylphenethyl amide
derivatives, a result that supports the suggestion that ground-state pseudoallylic strain contributes to the enormous reactivity of
Kemp’s triacid tertiary amides. In sum, the results reported indicate that the Kemp’s triacid scaffolding provides a general means
of activating tertiary amide derivatives.
Ó 2004 Elsevier Ltd. All rights reserved.
In 1988, Menger and Ladika1 reported that the pyrrol-
idyl amide of Kemp’s triacid2 (1a, Fig. 1) undergoes
intramolecular acylolysis (k1) with a half-life of 8 min at
pD 7.05 and 21.5 °C. The anhydride formed (2a) then
opens (k2) to generate Kemp’s triacid itself (3a), and the
overall transformation is thus the hydrolysis of an
unactivated amide. pH-rate studies revealed that just
one of the carboxylic acid functionalities, in its conju-
gate acid form, participates in the reaction.
Menger and Ladika also determined that the pyrrolidyl
amide, methyl ester derivative 1b reacts with a half-life
comparable to that observed for 1a, confirming that
only one of the carboxylic acid functionalities in 1a is
necessary for rapid reaction. Remarkably, the amide
functionality in 1b cleaves rather than the ester, due
presumably to initial protonation of the more-basic
amide by the adjacent carboxylic acid.
Figure 1. Reaction of pyrrolidyl amide derivatives of Kemp’s triacid.
Under comparably mild conditions, an unactivated
peptide bond hydrolyzes with a half-life of approxi-
mately 500 years, in a reaction independent of buffer
catalysis and apparently involving direct attack of
water.3;4 In comparison to this rate, the cleavage of the
amide bond in 1a or 1b occurs 3 million times faster,
due, concluded Menger and Ladika, to the ‘sustained
proximity’ of the amide and carboxylic acid function-
alities. They noted as well that ‘relief of internal com-
pression’ of these functionalities upon anhydride
formation also contributes to the rate acceleration, but
that this effect must be relatively small. In 1990, Menger
and Ladika5 showed that the pyrrolidyl amide monoacid
Keywords: Amide cleavage; Kemp’s triacid.
* Corresponding author. Tel.: +1-413-542-2731; fax: +1-413-542-2735;
e-mail: dehansen@amherst.edu
Present address: Department of Medical Oncology, Dana-Farber
Cancer Institute, Boston, MA 02115, USA.
Present address: Department of Urology, David Geffen School of
à
Medicine, University of California, Los Angeles, CA 90095, USA.
Present address: Department of Anesthesia and Critical Care,
Massachusetts General Hospital, Boston, MA 02114, USA.
§
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.06.024

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M. L. Dougan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4153–4156
Figure 2. Pyrrolidyl amide monoacid derivative.
derivative 4 (Fig. 2) reacts at essentially the same rate as
1a and 1b, an observation that conclusively established
that any reduction in activation barrier due to com-
pression must be less than the 3.7 kcal/mol cost of
placing two methyl groups in the 1,3-diaxial conforma-
tion (since, otherwise, the cyclohexane ring would sim-
ply undergo a chair flip).
Figure 5. The piperidyl (7) and prolyl (8) amides of Kemp’s triacid.
In 1994, Curran et al.6 demonstrated that while the
methylphenethyl amide of Kemp’s triacid (5, Fig. 3)
undergoes intramolecular acylolysis at a rate almost
identical to that of the derivative 1a, the secondary
phenethyl amides 6a and 6b react 102–104 times more
slowly, depending on the pH. These workers proposed,
therefore, that an important factor in the enormous
reactivity of the tertiary amides is relief of ‘pseudoallylic
strain’7 (Fig. 4) upon nucleophilic attack of the amide
bond.
Figure 6. Synthesis of Kemp’s anhydride amide derivatives 10 and 11.
Regardless of the underlying reasons, tertiary amide
derivatives of Kemp’s triacid cleave extremely rapidly,
and we have been interested in exploiting this fact in the
development of catalysts for the hydrolysis of simple
amides. In particular, we hope to create ‘artificial’
The derivatives 7 and 8 were then generated from 10 and
11 by in situ hydrolysis of the anhydride functionality
(and for 11, also the benzyl ester protecting group) in
KOD, followed by acidification with DCl to the desired
pD.10;11 The cleavage reaction was then immediately
enzymes for the hydrolysis of piperidyl and
L-prolyl
peptide derivatives. We thus wished to establish whether
the corresponding Kemp’s triacid derivatives 7 and 8
(Fig. 5) react with a rate similar to that of 1a and 5.
1
monitored at 20(ꢀ1) °C via H NMR.12 As a point of
reference, we also repeated the original work of Menger
and Ladika with pyrrolidyl amide 1a. The kinetic results
we obtained for the intramolecular acylolysis of deriv-
atives 1a, 7, and 8 are summarized in the pD-rate profile
shown in Figure 7.
To measure these rates, we employed the approach
Menger and Ladika had described in their 1988 paper.
First, the corresponding Kemp’s anhydride amides 10
and 11 were synthesized from the anhydride acid chlo-
ride 92 (Fig. 6).8;9
piperidyl amide 7
pyrrolidyl amide 1a
prolyl amide 8
-1
-2
-3
-4
-5
-6
Figure 3. Tertiary (5) and secondary (6a,b) amide derivatives.
6
7
8
9
10
11
pD
Figure 7. Plot of log k (sꢁ1) versus pD at 20(ꢀ1) °C for the acylolysis of
the Kemp’s triacid amide derivatives 1a, 7, and 8. To convert pD to
pH, subtract 0.5.11 The measurement of accurate rates at lower pDs
proved impossible since the reactions were essentially over before the
first NMR spectrum could be recorded.
Figure 4. Pseudoallylic strain in tertiary amide derivatives relative to
secondary. For the tertiary amide, a steric clash (one is shown
explicitly) is unavoidable.

M. L. Dougan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4153–4156
4155
Theoretical fits for the data in Figure 7 are not given,
since, as noted in the earlier reports,1;6 the rate depen-
dence on pD for cleavage of Kemp’s diacid amide
derivatives is not readily modeled.
In summary, we have demonstrated that the Kemp’s
triacid piperidyl amide derivative 7 and prolyl amide
derivative 8 undergo intramolecular acylolysis at rates
comparable to that of the previously reported pyrrolidyl
and methylphenethyl amide derivatives 1a and 5.
Molecular mechanics calculations suggest that relief of
pseudoallylic strain in these tertiary amide derivatives
does contribute to the rapid rate of reaction.
In our hands, pyrrolidyl amide 1a shows the same
reactivity as previously reported.1 Across the pD range
studied, piperidyl amide 7 cleaves approximately four-
times more quickly than 1a, whereas prolyl amide 8
cleaves approximately two-times more slowly (to yield
the acid anhydride 2a and proline––thus the prolyl
carboxylic acid functionality does not directly partici-
pate in the reaction). At pD 7.7, for example, piperidyl
amide 7 has a half-life of 3 min; at pD 7.8, prolyl amide 8
has half-life of 30 min, and the half-life for pyrrolidyl
amide 1a is 13 min. These results indicate that the
Kemp’s triacid scaffolding provides a general means of
activating tertiary amide derivatives.
Acknowledgements
We thank Richard Schowen for extremely helpful advice
on the use of pH paper for determining pD. We are
grateful to the National Institutes of Health (R15
GM63776) for financial support, as well as to the Am-
herst College Faculty Research Award Program, as
funded by the H. Axel Schupf ’57 Fund for Intellectual
Life. We also are grateful to the Pfizer Summer
Undergraduate Research Fellowship Program in Syn-
thetic Organic Chemistry for support of J.L.C. and
M.L.D. and to the Howard Hughes Medical Institute
for support of K.S. (through Amherst College’s
Undergraduate Biological Sciences Education Program
award).
We used molecular mechanics to explore whether, fol-
lowing the suggestion of Curran et al.,6 greater
pseudoallylic strain in piperidyl derivative 7 might be the
reason for its enhanced reactivity relative to the previ-
ously reported tertiary amide derivatives 1a and 5. The
minimized structures13 of the three species are shown in
Figure 8. The nonbonded interactions in the pyrrolidyl
and methylphenethyl amide derivatives 1a and 5 are
remarkably similar, each having three almost identical
hydrogen–hydrogen close contacts. However, due to the
pseudo-chair conformation of the piperidyl ring, deriv-
ative 7 uniquely has two nonbonded interactions with a
References and notes
ꢀ
hydrogen–hydrogen distance of only 2 A.
1. Menger, F. M.; Ladika, M. J. Am. Chem. Soc. 1988, 110,
6794–6796.
2. Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140–
5143.
3. Radzicka, A.; Wolfenden, R. J. Am. Chem. Soc. 1996, 118,
6105–6109.
4. Smith, R. M.; Hansen, D. E. J. Am. Chem. Soc. 1998, 120,
8910–8913.
While it is not possible to quantify accurately the relief
of strain upon formation of the rate-determining tran-
sition state(s), the above modeling results do support the
notion that ground-state pseudoallylic strain contributes
to the enhanced reactivity of tertiary amide derivatives.
Since the nonbonded interactions in the minimized
structure of prolyl derivative 8 (not shown) are identical
to those in 1a, its slower rate of cleavage likely arises
from a perturbation of the carboxylic acid group di-
rectly participating in the reaction by the nearby prolyl
carboxylic acid functionality.
5. Menger, F. M.; Ladika, M. J. Org. Chem. 1990, 55, 3006–
3007.
6. Curran, T. P.; Borysenko, C. W.; Abelleira, S. M.;
Messier, R. J. J. Org. Chem. 1994, 59, 3522–3529.
7. Johnson, F. Chem. Rev. 1968, 68, 375–413.
8. To a stirred suspension of anhydride, acid chloride 92
(889 mg, 3.44 mmol) in 120 mL of dry acetonitrile under
argon was added dry pyridine (8.7 mL). The mixture was
cooled to ꢁ40 °C (CO2/acetonitrile), and piperidine
(305 lL) was then added. A yellow color quickly devel-
oped. The mixture was allowed to warm to room
temperature and was stirred for 12 h. The solvent was
removed by evaporation under reduced pressure to yield a
bright yellow solid, which was purified by column chro-
matography (1:1 hexanes–ethyl acetate, Rf ¼ 0:36) to give
anhydride amide 10 as a white solid (116 mg, 11%). 1H
NMR (CDCl3, 400 MHz) d 3.49 (m, 4H), 2.80 (d,
J ¼ 12:8 Hz, 2H), 2.01 (dt, J ¼ 13:5, 1.8 Hz, 1H), 1.55–
1.65 (m, 6H), 1.35 (d, J ¼ 13:5 Hz, 1H), 1.35 (s, 6H), 1.31
(s, 3H), 1.23 (d, J ¼ 13:9 Hz, 2H). 13C NMR (CDCl3,
100 MHz) d 171.55, 171.51, 46.8, 43.1, 42.4, 40.5, 40.1,
28.64, 28.62, 25.76, 25.74, 25.1, 24.5. IR (CHCl3, cmꢁ1
)
Figure 8. Pseudoallylic strain in energy-minimized conformations of
derivatives 1a, 5, and 7. The distances of all hydrogen–hydrogen close
contacts are shown. The structures are truncated to emphasize the
nonbonded interactions.
1801, 1764, 1621, 1015. HRMS (TOF ESþ) calculated for
C17H26NO4 (MþH)þ 308.1862. Found 308.1859.
9. To a stirred suspension of anhydride, acid chloride 9
(404 mg, 1.56 mmol) in 50 mL dry acetonitrile under argon

4156
M. L. Dougan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4153–4156
was added dry pyridine (4.0 mL). The mixture was cooled
derivative 11, 20 lL of 40% KOD was added. The
resultant solution was vigorously shaken. A 1H NMR
spectrum was recorded to ensure that the anhydride (and
in the case of prolyl derivative 11, the benzyl ester) had
completely hydrolyzed. An aliquot of DCl solution was
then added (from between 7 and 20 lL depending on the
final pD for the pyrrolidyl and piperidyl amide derivatives,
or from between 33 and 40 lL for prolyl amide derivative).
The NMR tube was rapidly inverted many times to mix
the solution.
to ꢁ40 °C (CO2/acetonitrile), and a solution of proline
benzyl ester (400 mg, 1.95 mmol) in 10 mL of dry aceto-
nitrile was added. (Proline benzyl ester was prepared by
dissolving the hydrochloride in 5% sodium bicarbonate
and extracting three times with ethyl acetate; the combined
organic layers dried, and the solvent removed.) A yellow
color quickly developed. The mixture was allowed to
warm to room temperature and was stirred for 12 h. The
solvent was removed by evaporation under reduced
pressure to yield a bright yellow solid, which was purified
by column chromatography (2:1 dichloromethane–ethyl
acetate, Rf ¼ 0:80) to yield anhydride amide 11 as a white
11. Narrow-range Baker-pHIXâ or EM Science colorpHastâ
pH strips were used to measure the pD of each solu-
tion. The pD was taken as the ‘pH’ indicated plus
0.5, the correction factor for borate buffer (Schowen, K.
B.; Schowen, R. L. Methods Enzymol. 1982, 87, 551–
606).
12. H NMR spectra were recorded at 20(ꢀ1) °C, the temper-
ature of the (unthermostatted) internal probe, for, typi-
cally, at least two half-lives. For each data point, either 8
or 16 transients were collected; the time for each point was
taken to be when the collection was half completed.
Spectra were integrated, and the relative intensities of
reactant amide and product amine –N–CH2–, and/or –N–
CH– for the prolyl derivative, signals were used to
determine the extent of reaction. Rate constants were
then calculated using the integrated first-order rate equa-
tion.
1
solid (476 mg, 71%). H NMR (CDCl3, 400 MHz) d 7.31
(m, 5H), 5.17 (d, J ¼ 12:5 Hz, 1H), 4.99 (d, J ¼ 12:5 Hz,
1H), 4.53 (app. d, J ¼ 6:6 Hz, 1H), 3.71 (m, 1H), 3.47 (m,
1H), 2.93 (d, J ¼ 13:6 Hz, 1H), 2.77 (d, J ¼ 14:6 Hz, 1H),
2.04–1.82 (m, 5H), 1.40 (d, J ¼ 13:6 Hz, 2H), 1.32 (s, 6H),
1.21 (s, 3H), 1.06 (d, J ¼ 13:6 Hz, 1H). 13C NMR (CDCl3,
100 MHz) d 172.0, 171.5, 171.4, 170.4, 135.5, 128.0, 127.7,
127.6, 65.9, 61.0, 48.3, 46.1, 42.4, 42.3, 42.2, 39.92, 39.89,
27.0, 26.8, 25.3, 24.9, 24.7. IR (CHCl3, cmꢁ1) 1801, 1762,
1740, 1622, 1012. HRMS (TOF ESþ) calculated for
C24H30NO16 (MþH)þ 428.2073. Found 428.2067.
10. In a typical kinetic run, 1 mg of anhydride amide and
10 lL CD3CN were added to a 5 mm NMR tube, followed
by 0.5 mL of 50 mM sodium tetraborate decahydrate
(Borax) solution in D2O. The pD was raised to >12 by
addition of 7 lL of 40% KOD for the piperidyl anhydride
amide derivative 10 and for the corresponding pyrrolidyl
derivative; for the prolyl benzyl ester anhydride amide
13. Molecular mechanics calculations were performed using
HyperCheme RELEASE 5.11 Pro for Windows (Hyper-
cube, Inc.). The MMþ force field with the block-diagonal
Newton–Raphson algorithm was employed.