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Cation-Cyclization Selectivity Variable Structures of Protonated Cyclopropanes and Selectivity Control by Catalytic Antibodies.

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[9] Crystal structure analyses: 2- C,04H,,2N,022Si,,Ti,, M , = 2407.32, monoclinic. space group P2,/n, a = 1513.4(3), h = 1652.5(3), c = 2605.3(5) pm,
,B = 90.22(3) . V = 6.516(2) nm’, 2 = 2, prnhd= 1.227 Mgm-’. F(OO0) =
2580. 7 = 193 K. p(MoKo)= 0.41 mm-’, crystal dimensions 0.5 x 0.3 x
0.3 mm’. 6 < 2 0 < 4 4 . 10074 reflections, 7921 unique, 726 parameters refined
with the help of 109 restraints. R1 (I>2a) = 0.070, wR2 (all data) = 0.199.
minimum/maximum residual electron density -496/493 enm-’. 3:
C,,H,,,CI,N,O, ,Si,Ti;(C,H,),O,
M , = 2061.78, monoclinic, space group
P2,:c. u = 1463.9(16). h = 2436.4(14), c = 3114.9(18) pm, fl =103.38(8)”,
V = 10.808(15)nm’, 2 = 4, psalCd
= 1.267 Mgm-. F(OO0) = 4352, i. =
71.073 pm, T = 153 K, ~(Mo,,) = 0.602 mm-’, crystal dimensions 0 6 x 0.6 x
0.4mm’. 5 5 2 0 1 4 2 ’ ; 12284 measured relections, 11294 unique, 1120
parameters refined with the help of 1826 restraints. R1 = 0.078 (I>2a(I)) and
wR2 = 0.195 (all data); minimum/maximum residual electron density: - 5101
568 enm-’ 4: Cb5H,,N06Si2Ti3,M , = 921.91. monoclinic, space group
P2,,’m. 0=1170.3(2). h=1917.0(3), c=1243.9(2)pm, 8=117.92(2)‘, V =
2.4658(7)nm’. 2 = 2, pcaicd
= 1.242 Mgm-3, F(OO0)= 980, 7. =71.073 pm,
T = 153 K. ~(Mo,,) = 0.566 mm- I , crystal dimensions 0.6 x 0.3 x 0.3 mm’,
5 5 20 S48’ ; 4468 measured reflections, 3506 unique, 326 parameters refined
wiht the help of 93 restraints. Rl = 0.056 (f>Za(I)) and wR2 = 0.137 (all
data); minimumimaximum residual electron density: -302/444 enm-’. The
data were collected on a Stoe-Siemens-AED four-circle diffractometer. All
measurements were made with a cooled crystal in an oil drop [14] by using the
Learnt Profile Method [15]. The structures were solved by direct methods
(SHELXS-90,/96)[16]and refined on all data by full-matrix least-squares on F2
[I 71 All non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were added in idealized positions and included in the refinement except for the
hydroxyl hydrogen atoms in 2. which were located in the difference map and
refined with restrained 1 - 2 distances and a common isotropic U value. The
disordered positions of the solvent n-hexane molecule in 2 and the coordinated
THF molecule in 3 were refined with the help of distance and ADP-restraints.
Crystallographic data (excluding structure factors) for the structures reported
in this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publications nos. CCDC-100 133 (2) and CCDC100 145 (3 and 4). Copies of the data can be obtained free of charge on application to The Director, CCDC, 12 Union Road, Cambridge CB2 lEZ, U K
(fax: lnt. code +(1223) 336-033; e-mail: deposit(
[lo] C . J. Howard, ,4irr1 Crytulkogr. Sect. B 1991, 47, 462
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358, 147
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[17] SHELXL-93!96. Program for Crystal Structure Refinement: G. M. Sheldrick,
Universitiit Gottingen, 1993.
Angew. Churn. Int. Ed. Enpl. 1997, 36, No. 9
Cation-Cyclization Selectivity: Variable
Structures of Protonated Cyclopropanes and
Selectivity Control by Catalytic Antibodies**
Jeehiun K. Lee and Kendall N. Houk*
Cation cyclizations provide nature with selective routes to
complex steroids and terpenes.”] Biomimetic analogs are useful
synthetic pathways to steroids.Lz1Many different products such
as alkenes and alcohol stereoisomers as well as partially cyclized
materials may be formed in solution, whereas enzyme-catalyzed
processes are in general highly selective. Several antibodies have
been found that catalyze cyclizations leading selectively to cyclopropanes, alcohols, or alkenes, depending on the sub~tituents.1~
- 5l
Ah initio calculations reported here on the protonated cyclopropane intermediates formed in these reactions show how the
substituents perturb the geometry of the protonated cyclopropane. The calculated variations in nonclassical ion structure,
combined with recent studies of the 1-methylcyclohexyl ion,[61
provide a map of geometrical variations induced by substitution
in cyclohexyl cations. The stereochemistry of deprotonation of
a protonated cyclopropane to form the cyclopropane product
has also been determined for the first time. Force-field modeling
of the binding of these intermediates in an antibody complementarity site adapted from the cation-binding region of the antibody McPC603 suggests a novel way in which the binding orientation can influence the reaction selectivity. Our finding is
relevant to a recent report on synthetic analogs of this same
antibody.[’] We have discovered that amplification of a slight,
inherent propensity for reaction can occur in the binding sites of
antibodies. This amplification of selectivity may explain why
antibody catalysts give high yields of a single product even when
the background reaction produces low selectivity. The catalysis
of reactions that are disfavored or minor in the absence of catalyst is one of the major promises of antibody catalysis.[8.91
Antibody IgGTM1-87D7, elicited against hapten 1, catalyzes
a series of selective reactions with 2a-c, including cyclopropaAll reactions are believed to proceed
nation (4-6, Scheme
through 3, a protonated cyclopropane belonging to a class of
species that is experimentally and theoretically well-established“ O - 15] and includes the famous nonclassical norbornyl
cation.r16*71 Increasingly accurate quantum mechanical methods have led to the capability to predict reliably the structures
and energies of these important intermediate^.['^.
Calculations were conducted at the MP2/6-311G* level to
pinpoint the most stable structures for 3 a - ~ ; [ ’ ~the
] CPhMe,
group was replaced by H. At lower levels (RHF 3-21G and
6-31G*) the nonclassical structure cannot be found for any of
the cations, and the cyclohexyl cation is the most stable structure. However, when electron correlation is included (MP2),
protonated cyclopropane geometries with varying degrees of
bridging are found for these three species. Structure 3c‘
(Scheme 2) has the least amount of bridging, but considerable
hyperconjugative stabilization results from interaction of the
[‘I Prof. K. N. Houk, Dr. J. K. Lee
Department of Chemistry and Biochemistry
University of California
Los Angeles, CA 90095-1569 (USA)
Fax: Int. code +(310)206-1843
e-mail: houk@,
[**I We are grateful to the National Science Foundation and the National Institutes
of Health (postdoctoral fellowship for J. K. L., 1F32GM17460-01) for financial support of this work. We also thank the San Diego Supercomputer Center
and the National Center for Supercomputing Applications for computational
Q VCH Verlugsgesellschajt mbH, 0-69451 Weinheim. 1997
3 003
It is useful to visualize this species as a
trans-alkene that is bridged symmetrically
by an alkyl cation. Reaction with nucleophiles at either “alkene” carbon or deprotonation of the bridging alkyl group are
likely fates of such a species. In cis-substituted 3a the C1-C6 bond is longer than the
C2-C6 bond (1.88 and 1.84& respectively), which indicates a perturbation towards
a more classical structure (3a’). The cisTM1-87D7
methyl group makes 3a’ 1.6 kcal molR
less stable than 3b’. Extensive, unsuccessful
attempts to locate other structures for 3a-c
show that 3a’-c‘ are the only stable species
in the gas phase. Solvation studies on the
a, R=cis-Me
norbornyl cation indicate that the nonclas3
b, R = trans-Me
sical structure is not perturbed by solvent,[’71and it is thus quite likely that these
structures are also maintained in solution.
Therefore, variation in substitution
causes differences in the structures of 3a’c’, which may lead to altered reactivity.
However, no cyclized products are experif H
mentally observed in solution from the reMe2 Ph
actions of 2a-c, and so the degree of selectivity in the absence of antibody is
Formation of the fused-ring cyclopropane from 3a or 3b might occur by
base-induced removal of either the equato4
rial or axial proton on C6. Calculations at
Scheme 1. Structure of hapten 1 and reactions catalyzed by antibody TM1-87D7.Ar = p-acetaminothe MP2/6-31 lG* level on deprotonation
of either proton by water indicate that
eauatorial deprotonation is preferred at all
distances. This not oily establishes the stereochemistry of deprotonation, but also provides an additional reason why deprotonation is more facile for 3b than for 3a, which has a cis-methyl
group partially blocking the access of a base to the equatorial
hydrogen atom. Another interesting aspect of cyclopropane formation is that the fusedring product has a boat
and not a chair conformation (7,Scheme 3).[l9]
Despite the intrinsic
differences in geometry
among 3a-c, the high seP
lectivities observed in the
antibody-catalyzed reacI
tions are still astoundScheme 3. Calculated structure (MP2/6ing. The antibody clearly
31,G,) of bicycle 7.
plays a role in amplifying
the intrinsic selectivities.
To model the manner by which an antibody might do this, we
examined the active site of McPC603, an antibody that is
specific for phosphorylcholine (PC) .[”The active site
residues elicted by the ammonium group of PC are charged
Scheme 2. Calculated structures (MP2/6-311G*) of three protonated cyclo(aspartate and glutamate) as well as aromatic (tyrosine and
tryptophan) .[”, 231 The Asp97L, Tyr 33H, and Trp 107H
residues in the X-ray crystal structure of McPC603 form a possible binding site for 1 and 3a-c. It has recently been shown that
C2-C3 and C5-C6 bonds with the unoccupied equatorial p
orbital. The isomeric axial cation with C-H hyperconjugation
a synthetic analog with these features could also bind PC
analogs.[’] Hapten 1 was docked with the cation near the asparis 4.9 kcal mol- higher in energy.
tate, and the remaining steric repulsions were minimized. ForceBoth 3a’ and 3b‘ are closer to fully bridged, protonated cyclopropane. Trans 3b’ has the corner-protonated cyclopropane
field minimizations yielded the overall geometry shown in
structure and is a nonclassical cation, like the norbornyl cation.
Figure 1 (1”) .[241 The ammonium cation is nestled in the binding
Verlagsgesellschaft mbH. 0-694Sl Weinheim, 1997
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Angew. Chem. Int. Ed. Engl. 1997,36, No. 9
Keywords: catalytic antibodies
cations * cyclopropanes * molecular
modeling nonclassical structures
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Figure 1 . Computer model of the binding of 1" and three cyclohexyl cations in the binding site of a model
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[18] GAUSSIAN 94, revision B.3: M. J Frisch, G. W. Trucks, H. B. Schlegel,
near the carboxylate group ( ~ 2 which is placed to stabilize
P. M. W. Gill, B. G. Johnson, M. A. Robb. J. R. Cheesman. T. Keith, G. A.
Petersson. J. A. Montgomery, K. Raghavachari, M. A. Al-Laham. V. G. Zdthe forming cation as the sulfonate group leaves. The carboxykrzewski, J. V. Ortiz, J. B. Foreman, C. Y. Peng, P. Y Ayala. W. Chen, M. W.
late may act as a base to deprotonate the cation or as a general
Wong, J. L. Andres, E S. Replogle, R. Gomperts, R. L. Martin, D. J. Fox, J. S .
base to deprotonate water as it attacks. The results for 3a-c are
Binkley, D. J. Defrees, J. Baker, J. P. Stewart, M. Head-Gordon, C . Gonzalez,
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J. A. Pople, Gaussian, Inc., Pittsburgh, PA, 1995
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near the carboxylate of Asp 97, whereas Trp 107H and Tyr 33H
I201 D. M. Segal, E. A. Padlan, G. H. Cohen, S . Rudikoff, M. Potter, D. R. Davies.
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charge near the carboxylate group. However, each substrate is
F. S. Lee, Z:T. Chu, M. B. Bolger. A. Warshel, Protein Engineering
bound in a slightly different manner depending on its structure.
1992, 5. 5215
The antibody may enhance and amplify predisposed selectivity
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by differential binding of the substrates. For example, 3b" binds
1241 MM2' implemented in MacroModel, version 4.5.- F. Mohamddi, N. G. J.
in such a manner that water capture at C1 o r C2 is not favored;
Richards, W. C. Guida, R. Liskamp, C. Caufield, G. Chang. T. Hendrickson.
the best pathway available is deprotonation to yield the fused
W. C. Still, J Comput. Chem. 1990, 11, 440. The residues in the antibody, and
ring product. In contrast, 3a" cannot be readily deprotonated to
the angles and distances in the substrate were constrained so that only translational movement of the substrate was allowed. The residues and hapten were
a fused-ring structure, since C1, and not C6, is near the carboxytruncated at the amide bond and terminated with a methyl group.
late group. The aspartate carboxylate presumably plays a role in
deprotonation. either to actually deprotonate or as a general
base. The structure of 3c" is predisposed to form cyclohexanol;
its mode of binding also discourages any alternate pathway.
In conclusion, substituents cause significant perturbations in
the structures of protonated cyclopropanes causing a tendency
to follow different reaction pathways. Antibodies that bind and
stabilize these perturbed cations are likely to amplify the inherent biases of structure, resulting in high selectivity.
Received: October 9. 1996 [Z96381E]
German version: Angen. Cheni. 1997, 109, 1039-1042
Angiw C h i m lnr. Ed Enx/. 1997, 36, No. 9
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structure, antibodies, selectivity, variables, cyclization, catalytic, cyclopropane, cation, protonated, control
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