Complex-induced proximity effects. Temperature-dependent regiochemical diversity in lithiation-electrophilic substitution reactions of N-BOC-2-azabicyclo[2.1.1]hexane. 2,4- and 3,5-methanoprolines.

Article abstract of DOI:10.1021/ol026509b

[reaction: see text] Azabicycle 4 and sec-butyllithium/TMEDA afford the C(1) bridgehead alpha-lithio anion at 0 degrees C. Anion quenching with carbon dioxide, methyl chloroformate, or DMF provide the bridgehead acid 8a (N-BOC-2,4-methanoproline), ester 8b, or aldehyde 8c, respectively. By contrast, at -78 degrees C these same reagents give a mixture of regioisomeric methylene and bridgehead anions whose quenching leads to mixtures of regioisomeric methylene and bridgehead acids 6a/8a, esters 6b/8b, or aldehydes 6c/8c, respectively. The previously unknown 3,5-methanoproline was prepared as its N-BOC methyl ester 6b.

Full text of DOI:10.1021/ol026509b

ORGANIC
LETTERS
2002
Vol. 4, No. 18
3151-3154
Complex-Induced Proximity Effects.
Temperature-Dependent Regiochemical
Diversity in Lithiation−Electrophilic
Substitution Reactions of
N-BOC-2-Azabicyclo[2.1.1]hexane.
2,4- and 3,5-Methanoprolines
Grant R. Krow,* Seth B. Herzon, Guoliang Lin, Feng Qiu, and Philip E. Sonnet
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
grantkrow@aol.com
Received July 12, 2002
ABSTRACT
Azabicycle 4 and sec-butyllithium/TMEDA afford the C bridgehead r-lithio anion at 0 °C. Anion quenching with carbon dioxide, methyl
1
chloroformate, or DMF provide the bridgehead acid 8a (N-BOC-2,4-methanoproline), ester 8b, or aldehyde 8c, respectively. By contrast, at −78
°C these same reagents give a mixture of regioisomeric methylene and bridgehead anions whose quenching leads to mixtures of regioisomeric
methylene and bridgehead acids 6a/8a, esters 6b/8b, or aldehydes 6c/8c, respectively. The previously unknown 3,5-methanoproline was prepared
as its N-BOC methyl ester 6b.
The naturally occurring amino acid proline (1), which has
the R-amino substituent incorporated into a five-membered
ring, is an important component of numerous biologically
significant proteins such as collagen,1 gramicidin,2 R-mel-
anotropin,3 and phosmidosine,4 as well as pharmaceutically
produced N-acyl derivatives used to treat hypertension and
congestive heart failure such as Captopril,5 Enalapril,6 and
Lisinopril.6 Conformationally constrained molecules that
mimic naturally occurring amino acids have importance in
helping us to understand the substrate-receptor interactions
of bioactive peptides.1,7 They also have importance as
synthons for generation of new bioactive molecules.8 We
desired derivatives of the more conformationally constrained
3-carboxy-2-azabicyclo[2.1.1]hexane 2 as part of a study of
conformational effects on collagen stability1 and as a synthon
(1) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.;
Raines, R. T. J. Am. Chem. Soc. 2001, 123, 777.
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Acta 1999, 1462, 201-221. (b) Tamaki, M.; Okitsu, T.; Araki, M.;
Sakamoto, H.; Takimoto, M.; Muramatsu, I. Bull. Chem. Soc. Jpn. 1985,
58, 531.
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A. M.; Hadley, M. E. J. Med. Chem. 1984, 27, 1186. (b) Hruby, V. J.;
Wilkes, B. C.; Cody, W. L.; Sawyer, T. K.; Hadley, M. E. Pept. Protein
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T.; Taub, D.; Peterson, E. R.; Ikeler, T. J.; Ten Broeke, J.; Payne, L. G.
Ondeyka, D. L.; Thorsett, E. D.; Greenlee, W. J.; Lohr, N. S.; Hoffsommer,
R. D.; Joshua, H.; Ruyle, W. V.; Rothrock, J. W.; Aster, S. D.; Maycock,
A. L.; Robinson, F. M.; Hirschmann, R.; Sweet, C. S.; Ulm, E. H.; Gross,
D. M.; Vassil, T. C.; Stone, C. A. Nature 1980, 288, 280.
(7) (a) Tamaki, M.; Han, G.; Hruby, V. J. J. Org. Chem. 2001, 66, 3593.
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10.1021/ol026509b CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/14/2002

for the preparation of new nicotinic receptor agonists9 and
antibiotics.10 Amino acid 2, a 3,5-methanoproline, is isomeric
with the naturally occurring 2,4-methanoproline 3.11
finding a new route to 3-substituted methanobridged proline
derivatives 6.15
We have recently described a simple four-step route from
pyridine to the 2-azabicyclo[2.1.1]hexane ring system.12 It
was envisioned that application of the protocol of Beak13a
to the N-BOC-2-azabicyclo[2.1.1]hexane 4 could be used to
generate a lithio anion 5 and that subsequent addition of
electrophiles (CO2, ClCOOMe, DMF) could be used to
generate structures 6a-d, desirable derivatives of 3,5-
methanoproline 2. However, would azabicycle 4 lose a
methylene proton to give anion 5, or would a bridgehead
proton be lost to afford the lithio anion 7, whose quenching
would provide isomeric structures 8?14
The established conformational principle for reactions that
provide R-lithioamine derivatives of amides is that “an
orthogonal relationship between the lithio carbanion and the
pi system of the amide. . . (is) faVorable.”15 In the case of
N-BOC-2-methyl-pyrrolidine 9, this means that lithiation
followed by methylation occurs only at the methylene
position to afford a stereochemical mixture of 2,5-dimethyl-
pyrrolidines 10.13a However, the system 9 has flexibility not
found in azabicycle 4. The objective of the present study
was to determine the regiochemical outcome of R-substitution
reactions of the rigid ring azabicycle 4 with the goal of
N-BOC-2-azabicyclo[2.1.1]hexane 4 was prepared accord-
ing to our previously described procedure from its N-(benzyl-
oxycarbonyl) analogue12 by hydrogenolysis of the benzyloxy
group in the presence of (BOC)2O.17 To generate the lithio
anions 5 and 7, the azabicycle 4 in ether, which had been
dried by passing through a Glass Contour alumina column,
was reacted with 1.1-1.6 equiv of sec-butyllithium (s-BuLi)/
TMEDA for 2 h at either -78 or 0 °C.13a The anions were
then quenched. The electrophilic reagent carbon dioxide was
bubbled in excess into the anion mixture over 5-15 min by
warming of dry ice and passing the gas sequentially through
dry calcium chloride and then concentrated sulfuric acid.18
Methyl chloroformate (5 equiv) was injected by syringe into
the preformed anion(s) 5/7. Formylations were carried out
by adding a mixture of the lithio anions 5/7 to dry precooled
DMF (5 equiv) in ether. Following addition of the electro-
phile, the reaction mixture was maintained at the target
temperature for 0.5 h and then allowed to warm to room
temperature. The carbon dioxide addition product was
acidified to give acid 8a, which could be converted to ester
8b using Me3SiCHN2.19a Aldehyde products either were
isolated as aldehydes 6c/8c, reduced with sodium borohy-
dride to form alcohols 6d/8d, or oxidized with sodium
(9) Elliot, R. L.; Kopecka, H.; Lin, N.-H.; He, Y.; Garvey, D. S. Synthesis
1995, 772.
(10) Park, T. H.; Ha, Y. H.; Jeong, D. Y. Patent Application WO 98-
KR246 19989898; Chem. Abstr. 1999, 130, 182388.
(11) (a) Bell, E. A.; Qureshi, M. Y.; Pryce, R. J.; Janzen, D. H.; Lemke,
P.; Clardy, J. J. Am. Chem. Soc. 1980, 109, 1409. (b) Talluri, S.; Montelione,
B. T.; van Duyne, G.; Piela, L.; Clardy, J.; Scheraga, H. A. J. Am. Chem.
Soc. 1987, 109, 4473. (c) Piela, L.; Nemethy, G.; Scheraga, H. A. J. Am.
Chem. Soc. 1987, 109, 4477. (d) Montelione, G. T.; Hughes, P.; Clardy, J.;
Scheraga, H. A. J. Am. Chem. Soc. 1986, 108, 6765.
(12) Krow, G. R.; Lee, Y. B.; Lester, W. S.; Christian, H.; Shaw, D. A.;
Yuan, J. J. Org. Chem. 1998, 63, 8558.
(13) (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109. For reviews,
see: (b) Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356. (c) Beak,
P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem.
Res. 1996, 29, 552. (d) Gawley, R. E.; Rein, K. ComprehensiVe Organic
Synthesis, Pergamon Press: New York, 1991; Vol. 1, pp 459-485.
(14) (a) Monn, J. A.; Rice, K. D. Tetrahedron Lett. 1989, 30, 911.
Regioselective R-lithiation of a tert-butylformamide at a dibenzylic
bridgehead position in preference to a monobenzylic position has been
reported. For other examples of related regioselective lithiation-substitution
reactions, see: (b) Kopach, M. E.; Meyers, A. I. J. Org. Chem. 1996, 61,
6764. (c) Meyers, A. I.; Milot, G. J. Org. Chem. 1993, 58, 6538. (d)
Coldham, I.; Copley, R. C. B.; Haxell, T. F. N.; Howard, S. Org. Lett.
2001, 3, 3799. (e) Coldham, I.; Judkins, R. A.; Witty, D. R. Tetrahedron
1998, 54, 14255. (f) Park, Y. S.; Beak, P. Tetrahedron 1996, 52, 12333.
(15) (a) Gross, K. M. B.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
and refs 3-9 therein. For calculated energies and favored geometries of
R-lithioamides, see: (b) Wiberg, K. B.; Bailey, W. F. J. Org. Chem. 2002,
67, 5365. (c) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.; Wiberg, K. B.
J. Am. Chem. Soc. 2002, 124, 1889. (d) Wiberg, K. B.; Bailey, W. F. J.
Am. Chem. Soc. 2001, 123, 8231. (e) Wiberg, K. B.; Bailey, W. F.
Tetrahedron Lett. 2000, 41, 9365. (f) Bartolotti, L. J.; Gawley, R. E. J.
Org. Chem. 1989, 54, 2980. (g) Bach, R. D.; Braden, M. L.; Wolber, G. J.
J. Org. Chem. 1983, 48, 1509. (h) Rondan, N. G.; Houk, K. N.; Beak, P.;
Zajdel, W. J.; Chandrasekhar, J.; Schleyer, P. v. R. J. Org. Chem. 1981,
46, 4108.
(16) For an alternative route to 3-substituted 2-azabicyclo[2.1.1]hexanes,
see: (a) Krow, G. R.; Yuan, J.; Lin, G.; Sonnet, P. E. Org. Lett. 2002, 4,
1259. (b) Krow, G. R.; Lester, W. S.; Liu, N.; Yuan, J.; Hiller, A.; Duo, J.;
Herzon, S. B.; Nguyen, Y.; Cannon, K. J. Org. Chem. 2001, 66, 1811. (c)
Krow, G. R.; Lee, Y. B.; Lester, W. S.; Liu, N.; Yuan, J.; Duo, J.; Herzon,
S. B.; Nguyen, Y.; Zacharias, D. J. Org. Chem. 2001, 66, 1805.
(17) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. Tetrahedron Lett.
1989, 30, 837.
(18) Mander, L. N. Carbon Dioxide. In Encyclopedia of Reagents for
Organic Synthesis: Paquette, L. A., Ed.; Wiley & Sons: New York, 1995;
pp 985-988.
(19) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
5, 1475. (b) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559.
3152
Org. Lett., Vol. 4, No. 18, 2002

When carefully dried DMF22 was used to quench the
reaction of 4 with sec-butyllithium (1.2 equiv) at 0 °C, only
the 1-formyl structure 8c (entry 5) was observed. When the
reaction was carried out at -78 °C, NMR of the crude
reaction mixture indicated nearly equal amounts of the
3-formyl and 1-formyl isomers 6c/8c were formed. It was
observed that separation of the aldehyde mixture by silica
gel column chromatography resulted in loss of a portion of
the 1-CHO isomer 8c (trial 6). The same regiochemical
mixture was obtained with 1.6 equiv of s-BuLi (trial 7). To
facilitate isolation without material loss, the mixture of
3-CHO/1-CHO 6c/8c isomers was reduced to the separable
alcohols 6d/8d (trial 8). Alternatively, the mixture of
aldehydes 6c/8c was oxidized using sodium hypochlorite and
converted to the corresponding esters 6b/8b (entry 9);
however, the esters were not conveniently separated.
Table 1. Lithiation of Azabicycle 4 and Electrophile Additions
to Provide Methylene 6 and Bridgehead 8 E-Substituted
Productsa
s-BuLi
entry reagent (equiv)
T
(°C)
ratiob yieldc
product of 6:8 (%)
E
1
2
3
4
5
6
7
8
9
CO2
CO2
1.1
1.2
0
-78
COOH
8a
98
43:57 76
70
50:50 81 (95)
38 (57)
COOMed 6b/8b
COOMe 8b
ClCO2Me 1.2f
ClCO2Me 1.2
0
-78
0
-78
-78
-78
-78
0
COOMe 6b/8b
DMF
DMF
DMF
DMF
DMF
1.2
1.2
1.6
1.2
1.2
1.2
1.2
1.2
CHO
CHO
CHO
8c
6c/8c
6c/8c
50:50 32 (40)e
49:51 71 (83)
50:50 51
47:53 31h
63
CH2OHf 6d /8d
CO2Meg 6b/8b
To estimate the ratio of anions 5 and 7, an anionic mixture
at 0 °C was quenched with CD3OD quench (entry 10). NMR
integration of deuterated 4 indicated loss of solely the H1
proton. Repetition of the experiment at -78 °C resulted in
loss of 43% of an H3 proton and 47% loss of the H1 proton
(entry 11). Generation of the anionic mixture of 5 and 7 at
-78 °C and then allowing the mixture to stir for 40 min at
0 °C prior to addition of DOCD3 (entry 12) resulted in 43%
loss of an H3 proton and 54% loss of an H1 proton.
10 CD3OD
11 CD3OD
12 CD3OD
D
D
D
8e
6e/8e
6e/8e
-78
45:55i 87
44:56 98
-78 to 0j
a Lithium anions were generated and quenched from 4 containing
TMEDA at either 0 or -78 °C in ether solvent dried using a Glass Contour
alumina column. Electrophiles CO2 and ClCOOMe were added to the cold
solution of anion before warming to room temperature, neutralization, and
isolation of the products. Anions were added to DMF in ether via cannula.
CO2 was dried by passing over CaCl2 and anhydrous sulfuric acid. DMF
was dried by passing through a commercially available Glass Contour
alumina column for DMF (LaGuna Beach, CA). b Ratios refer to crude
mixtures prior to chromatographic purification and are based upon integra-
tion of appropriate H1 and H3 1H NMR resonances. c Isolated yields.
Numbers in parentheses are corrected yields based upon recovered 4.
d Workup with trimethylsilyl diazomethane afforded the ester. e Chromatog-
raphy afforded 20% 6c and 12% 8c. f Workup includes sodium borohydride.
g Workup includes NaOCl oxidation and Me3SiCHN2 esterification. h Iso-
mers were not separated. i Average of two runs ((2). j See ref 23.
Dynamic regioisomeric discrimination in the reactions of
4 are the result of complex-induced proximity effects
operating through preequilibrium complexes. The transfor-
mations shown in Scheme 1, as previously outlined by Beak
in his studies of dynamic diastereomeric equilibrations,15a
depict the key species leading from structure 4 to the products
6/8. A mixture of s-cis- and s-trans-carbamates 4 is
present.14d,24 Each of these conformations is expected to be
in rapid equilibrium with an s-BuLi/TMEDA complex prior
to the irreversible deprotonation steps to afford the TMEDA
complexed anions 5 and 7. Quenching of the anions affords
the products 6/8.
hypochlorite19b and esterified to give esters 6b/8b. The
identities of azabicycles 6 and 8 and their ratios in the crude
reaction mixtures were determined by NMR. Methylene-
substituted structures 6 retain the resonance for H1 at δ 4.1-
4.4. Bridgehead-functionalized structures 8 lack H1 and have
1
planar symmetry, which simplifies their H and 13C NMR
spectra.
(22) Our initial experiments, which used DMF distilled from CaH2, gave
erratic results. In one trial at -78 °C with sec-BuLi (1.6 equiv), azabicycle
4 afforded only aldehyde 8c (31%). In another trial, a 15:85 mixture of
aldehydes 6c/8c (57%) was observed. Under the same conditions except
with less base (1.05-1.10 equiv), there were numerous failures to observe
any reaction; one trial gave unreacted 4/6c/8c ) 67:0:33 (23%). These results
may reflect selective quenching of the less stable 3-anion 5 with a proton
source (water, dimethylamine?). In a trial in which reaction was allowed
to continue overnight rather than 2 h, the 3-isomer was found to
predominate: 6c/8c ) 97:3 (41%). This result is consistent with the
preferential loss of bridgehead aldehyde 8c noted during purification.
(23) It is important to use ether dried with a Glass Contour alumina
column to obtain the results shown in Table 1. Azabicycle 4 was reacted
with s-BuLi (1.2 equiv) in ether distilled from sodium/ benzophenone at
-78 °C for 2 h, and half of the solution was then allowed to warm to 0 °C
for 40 min. Quench of the -78 °C solution with DOCD3 over 30 min
resulted in 60% loss of an H1 proton (56% recovery), and quench of the 0
°C solution resulted in 79% loss of an H1 proton (90% recovery). No H3
exchange was observed in either case.
(24) (a) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc.
1994, 116, 3231. Restricted rotation about the C-N bond of N-BOC
pyrrolidine was presumed at -78 °C. (b) Price, B. J.; Smallman, R. V.;
Sutherland, I. O. Chem. Commun. 1966, 319. An N-COOMe rotational
barrier of 16 kcal/mol was determined at -3 °C. (c) Gawley, R. E.; Zhang,
Q. Tetrahedron 1994, 50, 6077. See ref 27 therein in comparing carbamates
to amides: “few amides have rotational barriers of less than 15 kcal/mol
and coordination of the carbonyl raises the barrier.”
As shown in Table 1, anion generation from carbamate 4
at 0 °C followed by addition of carbon dioxide and
acidification afforded only the bridgehead acid 8a (entry 1).
By contrast, at -78 °C, addition of carbon dioxide, acidifica-
tion, and esterification afforded a 4:6 mixture of esters 6b/
8b (entry 2).20 The same esters could be formed directly by
quenching of the anions with methyl chloroformate. At 0
°C, only the 1-ester 8b was obtained (entry 3), while at -78
°C, a 1:1 mixture of esters 6b/8b was observed (entry 4).
The above preparations of the methyl ester of N-BOC-2,4-
methanoproline 8b21a serve as formal syntheses of 2,4-
methanoproline 3, found in the seeds of Ateleia herberet
smithii Pittier (Leguminosae)11 and previously synthesized
by photochemical routes using acyclic precursors.21
(20) Our first anion quenching experiment with s-BuLi (1.6 equiv) at
-78 °C using CO2 passed only through dry CaCl2 afforded only bridgehead
acid 8a (49%). Traces of water may have selectively quenched the 3-anion 5.
(21) (a) Hughes, P.; Clardy, J. J. Org. Chem. 1988, 53, 4793. (b) Pirrung,
M. C. Tetrahedron Lett. 1980, 21, 4577. (c) Hughes, P.; Martin, M.; Clardy,
J. Tetrahedron Lett. 1980, 21, 4579.
Org. Lett., Vol. 4, No. 18, 2002
3153

bond nearly in the desired orthogonal relationship to the
carbamate π-system.15a The minimized secondary methylene
anion 5 has a Li-C-N-(C)dO dihedral angle of 11.8°,
while the tertiary bridgehead lithium anion 7 has a Li-C-
N-(C)dO dihedral of 0.34°.26
Scheme 1. Key Species in Dynamic Regioisomeric
Discrimination
The results in Table 1 might then be explained in the
following way using Scheme 1. At 0 °C, k1, k2, k3, k4, k7,
and k8 are fast relative to the deprotonation steps k5 and k9
and the conformational equilibria between s-cis-4/s-trans-4
and their TMEDA/s-BuLi complexes is maintained through-
out the reaction. Under these sets of conditions, the Curtin-
Hammett principle applies to the reaction.27 The product ratio
of 6/8 will reflect the difference in free energies of the
transition states for formation of anions 5/7 and the propor-
tions of the s-cis-4/s-trans-4/TMEDA/s-BuLi complexes in
solution. Clearly, the formation of the more stable anion 7
from a complex of the favored s-cis-4 conformation controls
the product formation at the higher temperature. At -78 °C,
interconversion of s-cis-4/s-trans-4/TMEDA/s-BuLi com-
plexes is slow relative to the subsequent deprotonation steps
to afford anions 5/7. In this circumstance, the relative
formation of products 6/8 partially reflects the 58:42 equi-
librium population of s-cis-4/s-trans-4.
To gain information about the s-cis/s-trans conformational
preference of the N-BOC carbonyl group in azabicycle 4,
we carried out low-temperature H NMR experiments (See
1
Supporting Information). No observed change in the reso-
nance of the tert-butyl substituent was observed at the range
of temperatures used (296-178 K). However, the bridgehead
proton H1, found at δ 4.26 (dt, J ) 6.8, 1.6 Hz) at 0 °C,
coalesced into a broad peak at δ 4.28 at -31 °C. At -76
°C, it separated into two separate resonances at δ 4.31 (d,
J1,4 ) 6.8 Hz) and δ 4.26 (d, J ) 6.8 Hz) with a relative
intensity of 58:42. Calculations using the B3LYP/6-31G(d)
method25 indicate a 0.02 kcal energy difference favoring the
s-cis over the s-trans conformation of azabicycle 4 (activation
energy to interconversion uncorrected for zero point energies
) 16.2 kcal/mol). Clearly, significant populations of car-
bamate conformations having the carbonyl oxygen directed
toward either H1 or H3 are present at -78 °C, and these are
averaged at 0 °C.
The lithiation of N-BOC carbamate 4 has been shown to
occur with temperature-dependent dynamic regioisomeric
discrimination. The synthetic utility of dynamic diastereo-
meric thermodynamic equilibration of R-lithio amine anions
has been clearly identified previously.13c,28
Acknowledgment is made to the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, the National Science Foundation (CHE 0111208),
and the Temple University Research Incentive Fund for
support of this research, to Hans Reich, Scott Sieburth, and
Kauirayani Prasad for helpful insights, to Yuhong Fang,
Deepa Rapolu, Jen Thomas, Ana Cobani, Hajnalka Hartl,
Linda Mascavage, Charles W. Roth III and George Kemmer-
er for NMR/HRMS assistance.
To gain insight into anion stabilities and geometries, we
performed calculations of ground-state energies for the
N-BOC-R-anions 5 (C3-anion) and 7 (C1-anion) at the
B3LYP-631G(d) level25 as their TMEDA-lithium com-
plexes. At this level, the 1-lithio species 7 is calculated to
be 5.9 kcal/mol lower in energy than the 3-lithio species 5.
Notably, both regioisomeric anions have the carbon-lithium
Supporting Information Available: All experimental
procedures, spectroscopic data, as well as copies of 1H NMR
and 13C NMR for compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9; Gaussian,
Inc.: Pittsburgh, PA, 1998.
OL026509B
(26) Geometrical access to both anionic structures is not surprising. Both
N-acetyl-2,4-methanoproline-N-methyl amide 11b,c and N-(methoxycarbonyl)-
5,6-anti-dibromo-3-methyl[2.1.1]hexane16c are somewhat pyramidal.
(27) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley & Sons: New York, 1994; pp 648-655.
(28) Beak, P.; Anderson, D. R.; Curtis, M. D.; Laumer, J. M.; Pippel,
D. J.; Weisenburger, G. A. Acc. Chem. Res. 2000, 33, 715.
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