Convergent functional groups: Intramolecular acyl transfer through a 34- membered ring [5]

Full text of DOI:10.1021/ja9733806

5120
J. Am. Chem. Soc. 1998, 120, 5120-5121
Scheme 1
Convergent Functional Groups: Intramolecular
Acyl Transfer through a 34-Membered Ring
Christian M. Rojas‡ and Julius Rebek, Jr.*
The Skaggs Institute for Chemical Biology and
The Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road
La Jolla, California 92037
ReceiVed September 26, 1997
yields of 70-80% for the two-step BOC removal, acyl transfer
ReVised Manuscript ReceiVed March 27, 1998
sequence.8 Under these conditions, we detected no byproducts
1
or intermediates from intermolecular processes using H NMR
The synthesis of macrocyclic compounds is often aided by the
rigidity of the platform on which the reactive components are
attached and their initial “direction”. For example, the spectacu-
larly successful catenane syntheses of Sauvage1 and Stoddart2 owe
much to the intermolecular forces that gather the components and
position their electrophilic and nucleophilic sites in favorable
directions. These are also factors in the use of a cyclic porphyrin
trimer to catalyze an acyl transfer reaction as reported by Sanders.3
Nowhere is this directionality more pronounced than with
convergent functional groups (Scheme 1).4 When inwardly
directed groups are capable of reaction, high yields result, as
shown by the smooth macrocyclization that leads to 1 from the
appropriate diamine and diacid chloride.4c We describe here an
intramolecular transfer of an acyl group from oxygen to nitrogen
in this context. The reaction proceeds with high efficiency despite
the 34-membered ring formed as an intermediate.5,6
A perylene based cleft, derived from the C-shaped diacid 2,4c
provided the appropriate scaffold for this reaction. Specifically,
the isolated mixed anhydride 37 was used to acylate a BOC-
protected ethylenediamine unit as indicated in Scheme 2, and the
remaining acid function was used to acylate the aniline derivative
5. Deprotection of the phenol followed by acylation and removal
of the BOC group (HCl, dry dioxane) gave the amine, which was
stored as its hydrochloride salt 9.
(600 MHz) or, with 13C-acetyl labeled material, the 13C NMR
(151 MHz) to follow the reaction. Even so, monitoring the
1
kinetics of the acyl transfer in CDCl3 by H NMR (600 MHz),
we noted some change in the first-order rate constants with
concentration of substrate and base. Thus, using 2 equivs of
added Et3N we measured k ) 4.5 × 10-6 s-1 at 2.7 mM and k )
9.7 × 10-6 s-1 at 26 mM.
It is likely that triethylamine was acting as an external base in
the rate determining step of the acyl transfer process.9,10 When
we conducted the reaction in pyridine-d5 to maintain a constant
concentration of external base, the rate of acyl transfer was
unchanged over a concentration range from 3.8 to 38 mM.11
The first-order kinetics observed in both solvent systems and
the failure to detect the (independently synthesized) bis-acetate
11 in the reaction mixture argue against an intermolecular course
for the reaction. A bimolecular reaction with such ensconced
components is unlikely, but we prepared the two lumbering half-
cleft species, the nucleophile 15 and the electrophile 18, as a
realistic model for the bimolecular reaction.
These were prepared from amino acid 124c as outlined in
Scheme 4, but under the conditions of the intramolecular acyl
transfer (13 mM in each half cleft, CDCl3, 2 equiv of Et3N, 23 (
1 °C),12 we observed less than 5% formation of the (independently
prepared and characterized) acetamide 19 after 15 days, along
with slow decomposition of amine 15. Another control experi-
ment established that acetamide 19 was stable under these
conditions. Since the half-life of the intramolecular reaction under
these conditions is about 22 h, the value for the effective molarity13
may be estimated as 3 M.14 This is comparable with Kemp’s
results with thiol capture (EM ca. 5 M in a 12-membered-ring
acyl transfer),5a and Sanders’ results (E. M. ca. 2 in a 28-
membered-ring acyl transfer). Precedents for a 34-membered-
ring intermediate are unknown to us. At the suggestion of a
reviewer, streamlined reaction partners were prepared.14 The rate
of their bimolecular O to N acyl transfer (CDCl3, 2 equiv of Et3N,
When this material was neutralized in a degassed CDCl3
solution containing triethylamine (2 equiv) smooth O f N acyl
transfer occurred, providing acetamide 10 (Scheme 3) in isolated
* To whom correspondence should be addressed.
‡ Present address: Department of Chemistry, Barnard College, 3009
Broadway, New York, NY 10027.
(1) (a) Nierengarten, J.-F.; Dietrich-Buchecker, C. O.; Sauvage, J.-P. J.
Am. Chem. Soc. 1994, 116, 375. (b) Dietrich-Buchecker, C. O.; Sauvage, J.-
P.; Kintzinger, J.-P.; Maltese, P.; Pascard, C.; Guilhem, J. New J. Chem. 1992,
16, 931.
(2) For recent reviews, see: (a) Amabilino, D. B.; Stoddart, J. F. Chem.
ReV. 1995, 95, 2725. (b) Philp, D.; Stoddart, J. F. Angew. Chem., Int. Ed.
Engl. 1996, 35, 1154.
(3) Mackay, L. G.; Wylie, R. S.; Sanders, J. K. M. J. Am. Chem. Soc.
1994, 116, 3141.
(4) (a) Rebek, J., Jr.; Marshall, L.; Wolak, R.; Parris, K.; Killoran, M.;
Askew, B.; Nemeth, D.; Islam, N. J. Am. Chem. Soc. 1985, 107, 7476. (b)
Wolfe, J.; Nemeth, D.; Costero, A.; Rebek, J., Jr. J. Am. Chem. Soc. 1988,
110, 983. (c) Shimuzu, K. D.; Dewey, T. M.; Rebek, J., Jr. J. Am. Chem. Soc.
1994, 116, 5145.
(5) For examples of related acyl transfers in medium-sized rings, see: (a)
Kemp, D. S.; Kerkman, D. J.; Leung, S.-L.; Hanson, G. J. Org. Chem. 1981,
46, 490. (b) Kemp, D. S.; Galakatos, N. G.; Bowen, B.; Tan, K. J. Org. Chem.
1986, 51, 1829.
(8) It was important to use freshly distilled reagents and to maintain CO2-
free conditions to avoid the reversible formation of a carbamic acid
intermediate from the liberated amine (see Supporting Information for complete
experimental descriptions).
(9) For a related example, see: Neumann, H.; Shashoua, V. E.; Sheehan,
J. C.; Rich, A. Proc. Natl. Acad. Sci. U.S.A. 1968, 61, 1207.
(10) For mechanistic descriptions of ester aminolysis, see: (a) Blackburn,
G. M.; Jencks, W. P. J. Am. Chem. Soc. 1968, 90, 2638. (b) Menger, F. M.;
Smith, J. H. Tetrahedron Lett. 1970, 4163. (c) Menger, F. M.; Smith, J. H. J.
Am. Chem. Soc. 1972, 94, 3824.
(11) Six independent kinetic runs, two each at 3.8, 9.2, and 38 mM, agreed
to within 10% of the mean value, 3.8 × 10-6 s-1. For details of the kinetic
analyses, including representative 1H NMR traces and data plots, see the
Supporting Information.
(6) It appears that our present work encounters the largest ring-sized
intermediate yet reported for an intramolecular acyl transfer. For examples of
closures to 36-membered macrolides, see: (a) Kennedy, R. M.; Abiko, A.;
Takemasa, T.; Okumoto, H.; Masamune, S. Tetrahedron Lett. 1988, 29, 451.
(b) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y. J. Am.
Chem. Soc. 1988, 110, 4685. (c) Rychnovsky, S. D.; Khire, U. R.; Yang, G.
J. Am. Chem. Soc. 1997, 119, 2058. (d) Rychnovsky, S. D.; Yang, G.; Hu,
Y.; Khire, U. R. J. Org. Chem. 1997, 62, 3022. Review: Mandolini, L. AdV.
Phys. Org. Chem. 1986, 22, 1.
(12) At 12 mM 9 in CDCl3 with 2 equiv of Et3N added we measured the
first-order rate constant k ) 8.7 × 10-6 s-1 for the intramolecular acyl transfer.
(13) For a discussion of effective molarity, see: Kirby, A. J. AdV. Phys.
Org. Chem. 1980, 17, 183.
(7) Rojas, C. M.; Rebek, J., Jr. Bioorg. Med. Chem. Lett. 1996, 6, 3013.
(14) For details, see the Supporting Information.
S0002-7863(97)03380-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/07/1998

Communications to the Editor
J. Am. Chem. Soc., Vol. 120, No. 20, 1998 5121
Scheme 2a
a (a) PivCl, pyr, CH2Cl2, 62%. (b) H2N(CH2)2NHBOC, pyr, CH2Cl2, 88%. (c) i: SOCl2, pyr, CH2Cl2. ii: 5, pyr, CH2Cl2, 96%. (d) TBAF, THF, 96%.
(e) Ac2O or H3C13COCl, Pyr, DMAP (cat), 70-98%.
Scheme 3
Scheme 4a
a (a) 1,10-Naphthalic anhydride, Zn(OAc)2 (cat), quinoline, 220 °C, 76%. (b) H2N(CH2)2NHBOC, PyBOP, Et3N, CH2Cl2, 89%. (c) HCl/dioxane or
TFA/CH2Cl2, 85-90%, then Et3N. (d) Ac2O, Et3N, DMAP (cat), 95%. (e) 5, BOP-Cl, Et3N, CH2Cl2, 69% (f) TBAF, THF, 75%. (g) Ac2O, Pyr, DMAP
(cat), 98%.
trifluoroacetate (rather than the hydrochloride salt 9) or any excess
23 ( 1 °C) was 3.9 × 10-5 M-1 s-1, corresponding to an EM for
trifluoroacetate also increased the rate of acyl transfer.
the case at hand of 0.22 M.
In summary, the large and rigid molecular clefts here provide
One might well ask: Why are these values not larger? Many
a framework on which to present reaction partners in a manner
cyclizations of 30 to 40-membered-ring sizes show EM values
likely to resemble their bimolecular counterparts.18 It should be
in the 10-3 to 10-1 range6k and would, at first glance, be related
possible to use this scaffold to hold acidic and basic functions in
to the reactions here. But these processes, slow as they may be,
are generally exocyclic, and increase the number of molecules
place, prevent them from collapsing on one another, but still
provide sites for concerted catalysis on opposite sides of substrates
or ions. The transfer reaction is endocyclic and lacks this entropic
held in between.
advantage in the rate determining transition state. This may be
a more common determinant of EM magnitude than is generally
appreciated,13 and we are working to test the notion using the
cleft-shaped scaffolds.
Acknowledgment. We are grateful to the Skaggs Foundation and
the National Institutes of Health for support, and C.M.R. thanks the
National Institutes of Health for postdoctoral fellowship support.
We also examined some catalysts for the 34-membered acyl
transfer.15 The bifunctional 2-pyridone15,16 (1.3 equiv) under the
CDCl3/Et3N conditions (13 mM in cleft, 2 equiv of Et3N)
accelerated the acyl transfer by a factor of 10 (k ) 9.6 × 10-5
s-1), while δ-valerolactam15,17 (1.3 equiv) provided less than a
2-fold rate enhancement (k ) 1.3 × 10-5 s-1).12,15 Using the
Supporting Information Available: Experimental procedures, char-
acterization data, and copies of 1H NMR spectra for all new compounds,
as well as representative plots of kinetic data (60 pages, print/PDF). See
any current masthead page for ordering and Web access instructions.
JA9733806
(17) For amide-catalyzed aminolysis of carboxylic acid derivatives, see:
Titskii, G. D.; Litvinenko, L. M. Zh. Obsch. Khim. 1970, 40, 2680.
(18) For a rare but relevant example of a medum-ring endocyclic substitu-
tion see: Lok, R.; Coward, J. K. Bioorg. Chem., 1976, 5, 169.
(15) For discussion of various catalysis for ester aminolysis, see: Su, C.-
W.; Watson, J. W. J. Am. Chem. Soc. 1974, 96, 1854.
(16) Rony, P. R. J. Am. Chem. Soc. 1969, 91, 6090.