Catalysis of the Hajos-Parrish-Eder-Sauer-Wiechert reaction by cis- and trans-4,5-methanoprolines: Sensitivity of proline catalysis to pyrrolidine ring conformation

Article abstract of DOI:10.1002/adsc.200404127

Methanoprolines are found to be catalysts for the Hajos-Parrish-Eder-Sauer- Wiechert reaction.^[1] cis-4,5-Methanoproline exhibits catalytic ability similar to proline (86% yield, 93% ee), whereas the trans-4,5- methanoproline is less selective (67% yield, 83% ee) and shows less acceleration. The reaction was also studied with hybrid density functional theory (B3LYP). The nearly planar cis-4,5-methanoproline amine better reflects the planar iminium of the transition states than the pyramidalized trans4,5-methanoproline. This difference in conformation is responsible for the observed higher enantioselectivity and enhanced catalytic behavior of the cis-4,5-methanoproline.

Full text of DOI:10.1002/adsc.200404127

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Catalysis of the Hajos Parrish Eder Sauer Wiechert Reaction
by cis- and trans-4,5-Methanoprolines: Sensitivity of Proline
Catalysis to Pyrrolidine Ring Conformation
Paul Ha-Yeon Cheong,a K. N. Houk,a,* Jayakumar S. Warrier,b
Stephen Hanessianb,*
a
Department ofChemistry and Biochemistry, University ofCalifornia, Los Angeles, CA 90095-1569, USA
Fax: (þ1)-310-206-1843, e-mail: houk@chem.ucla.edu
b
´
´
´
´
Department ofChemistry, Universite de Montreal, C. P. 6128, Succursale Centre-Ville, Montreal, Quebec H3C 3J7,
Canada
Fax: (þ1)-514-343-5728, e-mail: stephen.hanessian@umontreal.ca
Received: May 3, 2004; Accepted: July 26, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Methanoprolines are found to be catalysts
for the Hajos–Parrish–Eder–Sauer–Wiechert reac-
tion.[1] cis-4,5-Methanoproline exhibits catalytic abil-
ity similar to proline (86% yield, 93% ee), whereas
the trans-4,5-methanoproline is less selective (67%
yield, 83% ee) and shows less acceleration. The reac-
tion was also studied with hybrid density functional
theory (B3LYP). The nearly planar cis-4,5-methano-
proline amine better reflects the planar iminium of
the transition states than the pyramidalized trans-
4,5-methanoproline. This difference in conformation
is responsible for the observed higher enantioselec-
tivity and enhanced catalytic behavior ofthe cis-
4,5-methanoproline.
Eder–Sauer–Wiechert reaction (Scheme 1) experimen-
tally and computationally.[11]
cis-4,5-Methanoproline (entry 2, Table 1) exhibits
catalytic and enantioselective behavior much akin to
proline (93% and 95% ee, respectively), whereas the
trans-4,5-methanoproline (entry 3, Table 1) was found
to be slower and less enantioselective (83% ee) than ei-
ther proline or the cis derivative.
Transition structures for the Hajos–Parrish–Eder–
Sauer–Wiechert reaction catalyzed by proline, cis- and
trans-4,5-methanoproline are shown in Figure 1. Transi-
tion states in which the enamine is anti to the carboxylic
acid are more favorable than the corresponding syn en-
amine transition states. The activation energies ofcycli-
zations for proline and cis-4,5-methanoproline are
10.5 kcal/mol and 10.7 kcal/mol, respectively. The
trans-4,5-methanoproline-catalyzed reaction has a high-
er activation energy of12.4 kcal/mol, approximately a
25-fold decrease in rate. The anti-syn transition state en-
ergy differences for proline and the cis-4,5-methano de-
rivative are nearly identical at 2.2 kcal/mol and 2.1 kcal/
mol, respectively, while trans-4,5-methanoproline has a
Keywords: aldol; asymmetric catalysis; cyclization;
hybrid density functional theory; organic catalysis;
proline
Proline has received attention asan efficient and general substantially lower difference of 1.3 kcal/mol.
organic catalyst for several powerful asymmetric trans-
Our calculated results are compared with experiment
formations such as the aldol,[2] Mannich,[3] Michael,[4] re- in Table 2. There is an excellent agreement between the
actions and, most recently, the asymmetric a-carbonyl experimental free energy difference and the calculated
oxidations.[5] However, despite the success ofproline,
few useful catalytic proline derivatives have been re-
gas phase enthalpy differences (MAD¼0.1 kcal/mol).
Bicyclo[3.1.0]hexanes are known to favor the boat
conformation over the chair due to the torsional interac-
[6]
ported in literature. Theoretical studies ofthe aldol
and the Mannich[7] reactions at UCLA led to the identi- tions involving the cyclopropane ring.[12] We have calcu-
fication of iminium planarity[8] as a key component in lated the lowest energy conformations of the cis- and
proline catalysis. Interestingly, at Montreal the syn- trans-methanoproline enamines, and our results show
thesis[9] of3,4-methanoprolines and their use as confor-
the trans-methanoproline enamine to be the expected
[13]
mationally rigid planar proline replacements in enzyme boat (ws ¼ ꢀ138) with a significantly pyramidalized
inhibitors has been accomplished.[10] We have now amine (cN ¼468). The cis-methanoproline is also the
[14]
joined forces to explore the use of cis- and trans-4,5- expected boat; however, the steric repulsion ofthe car-
methanoproline as catalysts for the Hajos–Parrish– boxylic acid group cis to the cyclopropane ring results
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Paul Ha-Yeon Cheong et al.
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Scheme 1. Mechanism ofproline derivative-catalyzed Hajos–Parrish Eder–Sauer Wiechert reaction.
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Table 1. Proline derivative-catalyzed Hajos–Parrish Eder–Sauer Wiechert reaction.
Entry
1
Catalyst
% mol cat.
3%
Time [h]
48
Yield [%] (% ee)
98% (95%)
2
3%
3%
140
125
86%[a] (93%)
67%[b] (83%)
3
[a]
14% starting material recovered.
28% starting material recovered. Reaction never goes to completion.
[b]
in a rather planar cis-methanoprolineenamine (ws ¼88),
with a relatively planar amine (cN ¼ ꢀ108).
Table 2. Comparison ofexperimentally observed and calcu-
lated enantioselectivity ofmethanoproline derivative cata-
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lyzed Hajos–Parrish Eder–Sauer Wiechert reaction.
The anti-syn selectivity is dictated by this conforma-
tional bias ofthe respective methanoproline derivatives.
The origin ofenantioselectivity ofproline-catalyzed re-
actions arises from the different degrees to which each
diastereomeric transition state satisfies iminium planar-
ity and stabilizes the forming alkoxide.[15] The anti tran-
sition structures have a planar iminium (cis-methano-
proline TS 6a: cN ¼ ꢀ38 and trans-methanoproline TS
7a: cN ¼08), while the syn transition structures have a
pyramidalized iminium (cis-methanoproline TS 6b
cN ¼138 and trans-methanoproline TS 7b: cN ¼128). In
the cis-methanoproline case, the planar enamine (cN ¼
ꢀ108) allows for a facile transition to the anti, planar
iminium transition structure, whereas the realization
Entry
1
Catalyst
Experiment
Calculated
(DG‡)
(DH‡)
2.1
1.9
1.4
2.2
2.1
1.3
2
3
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Catalysis ofthe Hajos–Parrish–Eder–Sauer–Wiechert Reaction
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Figure 1. anti and syn transition structures for proline, cis- and trans-4,5-methanoproline catalyzed cyclization ofenamine 2
(Hajos–Parrish–Eder–Sauer–Wiechert reaction). Shown on the tables are dihedral angles relevant to the measure ofiminium
planarity.
ofthe pyramidalized syn transition structure would re- the trans-methanoproline, where the naturally pyrami-
quire heavy geometric distortion. This is in contrast to dalized enamine (cN ¼ ꢀ468) requires less geometric
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Paul Ha-Yeon Cheong et al.
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distortion to reach the syn, pyramidalized iminium tran- Acknowledgements
sition states, than the planar anti. Despite this conforma-
We are grateful to the National Institute of General Medical Sci-
ences, National Institutes of Health for financial support of this
research. We thank the National Computational Science Alli-
ance, the National Science Foundation, and UCLA Academic
Technology Services for computer resources. The Montreal
group acknowledges financial support from the Natural Science
and Engineering Council of Canada, and X-ray crystallograph-
tional bias, trans-methanoproline is still anti-selective
not only due to the stability gained by the more planar
iminium ofthe anti transition structure, but because of
the accentuated NCHdþ –Od– interactions ofthe cyclo-
propyl protons.
The observed catalytic ability ofthe two derivatives
can also be explained by the conformational biases. Giv-
en the enamine-mediated mechanism ofthe Hajos–Par-
rish–Eder–Sauer–Wiechert reaction,[16] it stands to rea-
son that the activation barrier to distort the enamines
from their lowest energy conformations to reflect the
partial iminium (ideal cN ¼08) ofthe transition states
is higher for the non-planar trans-methanoproline
(cN ¼468) and lower for the planar cis-methanoproline
(cN ¼ ꢀ108). The energy required for the trans stereo-
isomer toachieve the necessary planar iminium arrange-
ment in the aldol transition state is responsible for its
poorer catalytic ability. It is ofinterest to note that de-
spite this planar conformational preference of cis-meth-
anoproline, it is still slightly slower than the parent pro-
line catalyst by a factor of ꢁ3. We attribute the most
probable cause to the retardation ofthe hydrolysis of
the product iminium by the above unusual conforma-
tional biases.
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ic analyses by Michel Simard and Francine Belanger-Gariepy.
References and Notes
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We have demonstrated the use ofunique conforma-
tional preferences imparted by the fused cyclopropanes
to identify a new catalytic proline derivative for the Ha-
jos–Parrish–Eder–Sauer–Wiechert reaction. Analo-
gous studies ofmethanoproline-catalyzed intermolecu-
lar aldol reactions are in progress.
Experimental Section
Typical Procedure
4 mg each of (S)-proline, cis-4,5-methanoproline, and trans-
4,5-methanoproline, were mixed respectively with 0.5 mL of
DMF and stirred at 15–168C for 15 min. A solution of trike-
tone (0.182 gm) in 1 mL ofDMF was added and stirred of r
140 h at 15–168C in a reaction tube, immersed in a water
bath and protected from light. DMF was removed under re-
duced pressure and the residual dark oil was chromatographed
using 1:1 EtOAc:hexanes. The product was dehydrated using
1 N H2SO4 inDMFat958C for 5–6 h. The solvent was removed
under reduced pressure, dissolved in EtOAc, washed with satu-
rated sodium bicarbonate and dried over sodium sulfate. The
solution was passed through a silica gel bed, and the solvent
was removed under reduced pressure. The enantiomeric excess
was determined using chiral phase HPLC [Chiralpak AS-RH.
72% H2O (0.1% TFA)/28% CH3CN; tr (S)¼9 min and tr (R)¼
14 min].
[6] S. Bahmanyar, K. N. Houk J. Am. Chem. Soc. 2001, 123,
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[8] C. E. Cannizzaro, K. N. Houk, J. Am. Chem. Soc. 2002,
124, 7163.
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Catalysis ofthe Hajos–Parrish–Eder–Sauer–Wiechert Reaction
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[11] a) The stationary points (reactants and transition struc-
tures) were optimized and characterized by frequency
analysis using hybrid density functional theory
(B3LYP) and the 6–31G(d) basis set as implemented
in Gaussian 98. Enthalpies, DH298, and free energies,
DG298, were computed at the same level oftheory ofr
the gas phase. The electronic energies were taken from
a single point at the B3LYP/6–311þG(2df, p) level of
theory. Stereoselectivities were predicted using transition
state theory; b) M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, V. G.
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Ayala, Q. Cui, K. Morokuma, D. K. Malick, A. D. Ra-
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Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y.
Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
[13] The dihedral ws reflects the boat or chair conformation
ofthe methanoprolines. Positive angles relfect an axial
orientation ofthe carboxylic acid group whereas nega-
tive angles reflect equatorial carboxylic acid groups. It
then follows that cis-methanoprolines prefer positive
ws, and trans-methanoprolines prefer negative ws.
[14] The choice and definition of these dihedral angles have
been adapted from K. L. Brown, L. Damm, J. D. Dunitz,
A. Eschenmoser, R. Hobi, C. Kratky, Helv. Chim. Acta
1978, 61, 104; cN and cC reflect the deviation from planar-
ity ofthe iminium nitrogen and the carbon atoms.
[15] a) Electrostatic stabilizations are provided by the dona-
tion ofthe acidic proton as well as the dþNCH–Od– elec-
trostatic interactions, as described in reference for the
Hajos–Parrish–Eder–Sauer–Wiechert reaction; b) the
relative magnitudes and chemical significances of
dþNCH–Od– electrostatic interactions are discussed in:
S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001,
123, 11273.
[16] a) Ref.[6]; b) “New mechanistic studies on the proline-
catalyzed aldol reaction”, B. List, L. Hoang, H. J. Martin.
PNAS 2004, 101, 5839.
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