Chirospecific synthesis of spirocyclic β-lactams and their characterization as potent type II β-turn inducing peptide mimetics

Article abstract of DOI:10.1021/jo0517287

Starting from natural proline, a practical chirospecific synthesis of spirocyclic β-lactmans of type 2 is described when a methylene moiety showing minimal steric demand is employed as a constraint element for adjusting the dihedral angle Ψ(i + 1). Employ

Full text of DOI:10.1021/jo0517287

Chirospecific Synthesis of Spirocyclic â-Lactams and Their
Characterization as Potent Type II â-Turn Inducing Peptide
Mimetics
Holger Bittermann and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander UniVersity,
Schuhstrasse 19, D-91052 Erlangen, Germany
gmeiner@pharmazie.uni-erlangen.de
ReceiVed August 15, 2005
Starting from natural proline, a practical chirospecific synthesis of spirocyclic â-lactams of type 2 is
described when a methylene moiety showing minimal steric demand is employed as a constraint element
for adjusting the dihedral angle Ψ(i + 1). Employing the concept of self-reproduction of chirality,
C-formylation of the oxazolidinone 5 afforded the key intermediate 7 taking advantage of an intermediate
protection of the bridging element as a vinyl moiety. NMR- and IR-based conformational studies clearly
indicated that spiro-â-lactams of type 2 can serve as efficient â-turn nucleators.
Introduction
Monocyclic Freidinger-type â-lactams rigidizing Ψ(i + 1) to
123° also displayed a significant capability of inducing type II
â-turns when the ethylene bridge is contracted to a one-atom
constraint element.11,12 Interestingly, contraction of the lactam
ring size enables for a more ideal calibration of the geometrical
properties required for the adoption of a canonical type II â-turn
leading to a coplanar spatial arrangement of N(i + 1), CR(i +
1), N(i + 2), and CR(i + 2) and, thus, to promising antiparallel
pleated â-sheet nucleators. The combination of both the spiro-
cyclic structure and further conformational constraints by a four-
membered lactam has been described when the synthetic
methodology, however, required both the separation of isomeric
mixtures and sterically demanding substituents at the constrain-
ing bridge which might lead to clashes when bound to a
biological target.13,14 In this article, we present an enantiospecific
synthesis and conformational studies of methylene-bridged
peptidomimetics of type 2.
Proline-derived spirocyclic γ-lactams of type 1 have been
shown to exhibit valuable conformational properties enabling
for their utilization as reverse turn nucleators with a spirocyclic
moiety occupying the i + 1 position.1-3 Upon introduction into
naturally occurring peptides as substitutes for Pro-X patterns,
bioactive peptide mimetics were obtained, benefiting from
decreased numbers of degrees of freedom caused by an ethylene
bridge as a constraining element.4-7 Displaying dihedral angles
Φ(Pro) and Ψ(Pro) of -51° and 129°, respectively, the
spirocyclic scaffold proved capable of inducing type II â-turns,
which are close to the ideal angles of -60° and 120°.8-10
* Corresponding author. Phone: +49-(0)9131-8529383. Fax: +49-(0)9131-
8522585.
(1) Mu¨ller, G.; Hessler, G.; Decornez, H. Y. Angew. Chem., Int. Ed.
2000, 39, 894-896; Angew. Chem. 2000, 112, 926-928.
(2) Hinds, M. G.; Richards, N. G. J.; Robinson, J. A. J. Chem. Soc.,
Chem. Commun. 1988, 1447-1449.
(3) Hinds, M. G.; Welsh, J. H.; Brennand, D. M.; Fisher, J.; Glennie,
M. J.; Richards, N. G. J.; Turner, D. L.; Robinson, J. A. J. Med. Chem.
1991, 34, 1777-1789.
(4) Ward, P.; Ewan, G. B.; Jordan, C. C.; Ireland, S. J.; Hagan, R. M.;
Brown, J. R. J. Med. Chem. 1990, 33, 1848-1851.
(5) Ward, P.; Ewan, G. B. U.S. Patent Application 5166136, 1992.
(6) Long, R. D.; Moeller, K. D. J. Am. Chem. Soc. 1997, 119, 12394-
12395.
(9) Hutchinson, E. G.; Thornton, J. M. Protein Sci. 1994, 3, 2207-2216.
(10) Robinson, J. A. Synlett 1999, 4, 429-441.
(11) Palomo, C.; Aizpurua, J. M.; Benito, A.; Miranda, J. I.; Fratila, R.
M.; Matute, C.; Domercq, M.; Gago, F.; Martin-Santamaria, S.; Linden,
A. J. Am. Chem. Soc. 2003, 115, 16243-16260.
(12) Sreenivasan, U.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1993,
36, 256-263.
(7) Bittermann, H.; Einsiedel, J.; Hu¨bner, H.; Gmeiner, P. J. Med. Chem.
2004, 47, 5587-5590.
(8) Genin, M. J.; Ojala, W. H.; Gleason, W. B.; Johnson, R. L. J. Org.
Chem. 1993, 58, 2334-2337.
(13) Alonso, E.; Lo´pez-Ortiz, F.; del Pozo, C.; Peralta, E.; Mac´ıas, A.;
Gonza´lez, J. J. Org. Chem. 2001, 66, 6333-6338.
(14) Khasanov, A. B.; Ramirez-Weinhouse, M. M.; Webb, T. R.;
Thiruvazhi, M. J. Org. Chem. 2004, 69, 5766-5769.
10.1021/jo0517287 CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/23/2005
J. Org. Chem. 2006, 71, 97-102
97

Bittermann and Gmeiner
CHART 1
SCHEME 1a
a (a) Cl3CCHO, CH3CN, rt, 2.5 h (87%). (b) 1. LDA, THF, -78 °C, 2.
HCOOCH3, -40 °C (65%). (c) 1. Methyltriphenylphosphonium bromide,
KOtBu, toluene, 80 °C, 2 h, 2. 6, rt, 1 h (74%). (d) AcCl, MeOH, 0 °C to
rt, 7 d. (e) DIPEA, Boc2O, CH2Cl2, rt, 2.5 d (73%). (f) NaOH, MeOH,
H2O, 50 °C, 1 h (78%).
Results and Discussion
With the aim to calculate the structural consequences of the
formal ring contraction, we employed density functional cal-
culations on a high level of theory (B3LYP/6-311G*) minimiz-
ing the energy of the model peptides 1 and 2 (Chart 1). In fact,
comparison of the Ψ(i + 1) angles showed a decrease from
132.4° to 124.2° upon reduction of the ring size, the latter more
ideally mimicking the geometrical properties of an ideal type
II â-turn. While the CdOi‚‚‚HNi+3 distance was not significantly
affected by ring size variation (2.1 Å for 1, 2.0 Å for 2), differing
â-pseudodihedral angles between C(i), CR(i + 1), CR(i + 2),
and N(i + 3) of 23.1° and 13.2° for for 1 and 2, respectively,
showed a higher potency for the adoption of a canonical â-turn
for the [3.4]-spiro-â-lactam 2 when compared to the homologous
spirolactam 1.
SCHEME 2a
Taking advantage of Seebach et al.’s self-reproduction of
chirality methodology15 that we have employed for the synthesis
of R-allylproline (3) derived â-turn mimetics,7 our plan of
synthesis was based on the protected R-vinylproline 4 as the
key intermediate when peptide coupling, reductive cleavage of
the C,C-double bond, and ring closure were envisaged to provide
target compounds of type 1. Since a C-allyl substituent proved
to be an excellent precursor for an ethylene bridge, we expected
a vinyl system to be suitable for masking a methylene unit as
a constraint element.
a (a) For 9a: HATU, DIPEA, NMP, GlyOMe‚HCl, rt, 30 min (64%);
for 9b: HATU, DIPEA, NMP, O-(2,6-dichlorobenzyl)tyrosine methyl ester
hydrochloride, rt, 25 min (92%). (b) 1. O3, CH2Cl2, -78 °C, 2. Na[B-
H(OAc)3], rt, 6-24 h (77-86%). (c) DEAD, PPh3, THF, rt, 2.5-5 h (63-
65%). (d) For 2: CH3NH2, EtOH, 0 °C, 40 min (97%); for 12: LiOH,
THF, H2O, 0 °C, 1 h (82%).
For the preparation of hitherto unknown enantiopure R-vi-
nylproline derivatives,16 (S)-proline was reacted with anhydrous
trichloroacetic aldehyde to afford the chiral building block 5
(Scheme 1).17 Our initial investigations to introduce a vinyl
substituent by deprotonation, subsequent hydroxyethylation with
acetic aldehyde, activation of the alcohol function, and â-elim-
ination failed since the final step could not be accomplished.
Thus, C-formylation and subsequent methenylation should be
elaborated as a straightforward alternative. In detail, treatment
of the proline derivative 5 with LDA, followed by addition of
methyl formate, furnished a 65% yield of the carbaldehyde 6
in diastereomerically pure form. When elaborating suitable
reaction conditions for a Wittig olefination of 6, we observed a
retro-Claisen reaction resulting in deformylation which we could
avoid by employing Li-free conditions. Thus, pretreatment of
methyl triphenylphosphonium bromide with KOtBu at elevated
temperature and subsequent olefination at room temperature
gave access to the bicyclic R-vinylproline derivative 7, which
was transformed into (R)-R-vinylproline methyl ester under
acidic conditions and, subsequently, N-protected by carbam-
oylation. Finally, basic hydrolysis of the methyl ester 8 led to
enantiomerically pure (R)-N-Boc-R-vinylproline (4).
For the synthesis of the spirocyclic model system 2, the
sterically demanding amino acid 4 was activated by HATU19
and coupled with glycine methyl ester hydrochloride, giving
rise to the protected peptide derivative 9a (Scheme 2). Ozo-
nolysis of the vinyl group and subsequent reduction with an
excess of Na[BH(OAc)3] yielded the hydroxymethyl-substituted
derivative 10a in 86% yield. Formation of the â-lactam was
accomplished by intramolecular Mitsunobu reaction with DEAD
and PPh3,20,21 furnishing the molecular scaffold 11a. Finally,
the molecular probe 2 was prepared by aminolysis of 11a. To
(18) Casimir, J. R.; Tourwe´, D.; Iterbeke, K.; Guichard, G.; Briand, J.-
P. J. Org. Chem. 2000, 65, 6487-6492.
(15) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem.
Soc. 1983, 105, 5390-5398.
(16) For the preparation of racemic, N-benzyl-protected 2-vinylproline
esters, see: Trancard, D.; Tout, J.-B.; Giard, T.; Chichaoui, I.; Cahard, D.;
Plaquevent, J.-C. Tetrahedron Lett. 2000, 41, 3843-3847.
(17) Wang, H.; Germanas, J. P. Synlett 1999, 1, 33-36.
(19) Carpino, L. A. J. Am. Chem. Soc. 1993, 15, 4397-4398.
(20) Bose, A. K.; Sahu, D. P.; Manhas, M. S. J. Org. Chem. 1981, 46,
1229-1230.
(21) Easton, C. J.; Love, S. G.; Wang, P. J. Chem. Soc., Perkin Trans.
1 1990, 277-282.
98 J. Org. Chem., Vol. 71, No. 1, 2006

â-Lactams as Type II â-Turn Inducing Peptide Mimetics
TABLE 1. Spectroscopic Data of Model Peptides 1 and 2 (2 mM,
CHCl3)
introduction of different protecting groups compatible with the
milder conditions of Fmoc SPPS protocols. According to our
computational studies, restriction of the Ψ(Pro) dihedral angle
to values more ideally mimicking the geometrical requirements
for an ideal type II â-turn found in the homologous [4.4]-
spirocycles favors reverse turn formation.
model peptide
1
2
IR absorption band
1H NMR: δ(NH)
3337 cm-1
7.81 ppm
-5.6 ppb/K
3338 cm-1
8.23 ppm
-4.6 ppb/K
1H NMR: ∆δ/∆T(NH)
demonstrate versatility of the synthesis toward the nature of
the amino acid in position i + 2, a lactam-bridged Pro-Tyr
scaffold was prepared when the central building block 2 was
activated and reacted with O-(2,6)-dichlorobenzyl-protected
tyrosine methyl ester hydrochloride18 to give the coupling
product 9b in 92% yield. Employing identical reaction condi-
tions, the protected methyl ester 11b was obtained via the
intermediate 10b. To investigate the configurational stability
of the Tyr CR moiety, LiOH-promoted hydrolysis was per-
formed,22 indicating partial epimerization (9% detected by
HPLC-MS) of the Pro-Tyr surrogate 12. As a reference com-
pound for conformational investigations, the [4.4]-spirocyclic
model peptide 1 was synthesized by aminolysis of the corre-
sponding methyl ester,8 which we prepared according to a
previous protocol.7,23
Experimental Section
Methods and Materials. Chemicals and solvents were purchased
in the highest purity available. All reactions were carried out under
nitrogen atmosphere except ozonolysis, aminolysis, and ester
hydrolysis. Column chromatography was performed using 60-µm
silica gel. For TLC silica gel, 60 F254 plates were used (UV, I2, or
ninhydrin detection). Melting temperatures were uncorrected. NMR
chemical shifts were noted in ppm relative to TMS. IR spectroscopy
was carried out on a FT/IR spectrometer. HPLC-MS and ESI-MS
analyses were carried out on an analytic HPLC system with a VWL
detector, coupled to a mass spectrometer with electron spray
ionization.
(2R,5S)-2-Trichloromethyl-1-aza-3-oxabicyclo[3.3.0]octane-4-
one (5). (S)-Proline (35.0 g, 0.304 mol) was suspended in
acetonitrile (150 mL). Anhydrous trichloroacetic aldehyde (74.0
mL, 0.758 mol) was added slowly while being stirred vigorously.
After 2.5 h, the clear solution was concentrated to dryness. The
residue was redissolved in CH2Cl2 (150 mL) and filtered, and the
solvent was removed. Repetition of this cycle, followed by thorough
drying in vacuo, yielded 65.0 g (87%) of 5. Analytical data were
in agreement with the literature.
(2R,5R)-4-Oxo-2-trichloromethyl-1-aza-3-oxabicyclo[3.3.0]-
octane-5-carbaldehyde (6). At -78 °C, LDA solution (0.8 M, 153
mL, 122 mmol), freshly prepared from diisopropylamine (18.1 mL,
128 mmol) and n-butyllithium solution (2.5 M in hexanes, 51.2
mL, 128 mmol) in THF (90.7 mL), was added to a solution of 5
(20.0 g, 81.8 mmol) in THF (100 mL). After 30 min methyl formate
(20.2 mL, 328 mmol) was added over 5 min. The mixture was
stirred at -78 °C for 10 min, and then it was allowed to warm to
-40 °C over 45 min. After 10 min at this temperature aqueous
citric acid (10%, 150 mL) was added, and the mixture was extracted
with ether (2 × 150 mL). The combined organic layers were washed
with brine (200 mL), dried with magnesium sulfate, and evaporated,
and the residue was purified by column chromatography (hexanes/
ethyl acetate 6:1 increasing to 3:1), furnishing 14.4 g (65%) of 6
as colorless crystals. mp 89 °C; Rf 0.40 (hexanes/ethyl acetate 1:1);
[R]25D 29.5° (c 2.0, CHCl3); IR (neat) 2978, 1811, 1732 cm-1; 1H
NMR (360 MHz, CDCl3) δ 1.80-1.91 (m, 1H), 1.92-2.03 (m,
1H), 2.29 (ddd, 1H, J ) 13.4, 6.7, 6.7 Hz), 2.40 (ddd, 1H, J )
13.4, 7.8, 6.7 Hz), 3.33 (ddd, 1H, J ) 11.5, 6.1, 5.6 Hz), 3.54
(ddd, 1H, J ) 11.5, 7.8, 6.4 Hz), 5.19 (s, 1H), 9.61 (s, 1H); 13C
NMR (90 MHz, CDCl3) δ 25.5, 33.8, 58.9, 78.2, 99.9, 102.4, 169.3,
193.5; EIMS 244, 242, 246 (M - CO; M+ not observed). Anal.
Calcd for C8H8Cl3NO3: C, 35.26; H, 2.96; N, 5.14. Found: C,
35.13; H, 2.72; N, 5.15.
To investigate the conformational properties of our â-turn
model system 2 in comparison to the [4.4]-spirocyclic template
1 being described as a highly potent type II â-turn mimetic,1
IR and NMR studies including variable temperature (VT)
experiments were performed in 2 mM solution thus excluding
intermolecular interactions.24,25 For a type II â-turn, a stable
hydrogen bond between the Boc CdO group and the NH will
be expected, which was clearly indicated by the extensive
absorption bands at 3337 (for 1) and 3338 cm-1 (for 2). On the
other hand, N-H stretching absorptions in the range of 3450
cm-1 being diagnostic for non-hydrogen-bonded states could
not be detected. In contrast to the IR data, NMR-derived δ-
(NH) values significantly differed when NH of the â-lactam 2
resonated even more downfield (8.23 ppm) than that of the
γ-lactam 1 (7.81 ppm). Temperature-dependent chemical shift
1
changes of H NMR signals as a measure for the stability of
secondary structures corroborated the assumption that the
spirocyclic â-lactam 2 might form a more stable intramolecular
H-bond when ∆δ/∆T values of -5.6 (for 1) and -4.6 ppb/K
(for 2) were observed (Table 1).
In conclusion, we could establish a versatile synthetic
approach toward enantiomerically pure [3.4]-spiro-â-lactam
containing type II â-turn mimetics. Applying the same synthetic
protocol, a [3.4]-spirocyclic Pro-Tyr mimicking template could
be synthesized, serving as an example for virtually any Pro-X
dipeptide. Choosing appropriate protecting groups may enable
for the introduction of these templates into SPPS, giving rise
to larger peptides bearing the [3.4]-spirocyclic constraint. Boc
strategy usually requires cleavage by HF or other strongly acidic
conditions potentially harmful to the integrity of the â-lactam
substructure. However, this issue might be circumvented by
(2R,5R)-2-Trichloromethyl-5-vinyl-1-aza-3-oxabicyclo[3.3.0]-
octane-4-one (7). Methyl triphenylphosphonium bromide (7.86 g,
22.0 mmol) and potassium tert-butoxide (2.47 g, 22.0 mmol) were
suspended in toluene (400 mL) and stirred vigorously for 2 h at 80
°C. After cooling to room temperature, a solution of 6 (5.00 g,
18.3 mmol) in toluene (50 mL) was added and stirring was
continued for 1 h. Ether (400 mL) was added, and the precipitate
formed was removed by fitration and washed with ether (2×100
mL). The filtrate was concentrated in vacuo, and the residue was
purified by column chromatography (hexanes/ethyl acetate 95:5
increasing to 9:1), yielding 3.67 g (74%) of 7 as a colorless oil. Rf
(22) Klein, L. L.; Li, L.; Chen, H.-J.; Curty, C. B.; DeGoey, D. A.;
Grampovnik, D. J.; Leone, C. L.; Thomas, S. A.; Yeung, C. M.; Funk, K.
W.; Kishore, V.; Lundell, E. O.; Wodka, D.; Meulbroek, J. A.; Alder, J.
D.; Nilius, A. M.; Lartey, P. A.; Plattner, J. J. Bioorg. Med. Chem. 2000,
8, 1677-1698.
(23) Gutie´rrez-Rodr´ıguez, M.; Garc´ıa-Lo´pez, M. T.; Herranz, R. Tetra-
hedron 2004, 60, 5177-5183.
0.27 (hexanes/ethyl acetate 4:1); [R]22 47.2° (c 0.25, CHCl3); IR
D
(24) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R. J. Am.
Chem. Soc. 1991, 113, 1164-1173.
(neat) 2952, 1805, 1641 cm-1; 1H NMR (360 MHz, CDCl3) δ 1.79-
1.89 (m, 1H), 1.89-1.99 (m, 1H), 2.03 (ddd, 1H, J ) 12.4, 6.2,
6.2 Hz), 2.19 (ddd, 1H, J ) 12.4, 7.3, 7.3 Hz,), 3.20 (ddd, 1H, J
(25) Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115, 4228-
4245.
J. Org. Chem, Vol. 71, No. 1, 2006 99

Bittermann and Gmeiner
) 11.0, 6.5, 6.5 Hz), 3.47 (ddd, 1H, J ) 11.0, 6.4, 6.4 Hz), 5.08
(s, 1H), 5.23 (dd, 1H, J ) 10.3, 1.1 Hz), 5.52 (dd, 1H, J ) 17.0,
1.1 Hz), 6.02 (dd, 1H, J ) 17.0, 10.3 Hz); 13C NMR (150 MHz,
CDCl3) δ 25.1, 38.5, 58.5, 73.7, 100.8, 102.8, 116.3, 136.0, 174.3;
EIMS 242 (M - CHdCH2), 152 (M - CCl3; M+ not observed).
Anal. Calcd for C9H10Cl3NO2: C, 39.96; H, 3.73; N, 5.18. Found:
C, 40.05; H, 3.82; N, 5.07.
were washed with saturated Na2CO3 solution (5 mL), brine (5 mL),
and water (5 mL), dried with magnesium sulfate, and evaporated.
The residue was purified by column chromatography (hexanes/ethyl
acetate 1:1), furnishing 166 mg (64%) of 9a as colorless crystals.
mp 65 °C; Rf 0.16 (hexanes/ethyl acetate 1:1); [R]20 -44.2° (c
D
1
0.5, CHCl3); IR (neat) 3362, 2978, 1756, 1695, 1681 cm-1; H
NMR (360 MHz, CDCl3, 330 K) δ 1.43 (s, 9H), 1.75-1.91 (m,
2H), 1.92-2.00 (m, 1H), 2.42-2.58 (m, 1H), 3.51-3.59 (m, 2H),
3.73 (s, 3H), 3.99 (dd, 1H, J ) 18.6, 5.3 Hz), 4.05 (dd, 1H, J )
18.6, 5.3 Hz), 5.16 (bd, 1H, J ) 17.6 Hz), 5.22 (dd, 1H, J ) 10.8,
0.6 Hz), 6.29 (dd, 1H, J ) 17.6, 10.8 Hz), 7.44 (bs, 1H); 13C NMR
(90 MHz, CDCl3; rotamers and broadened signals were observed)
δ 22.1 and 23.0, 28.5, 37.6 and 39.6, 41.7, 48.7, 52.3, 71.0 and
71.3, 80.7, 114.5 and 115.2, 138.2, 154.0 and 155.0, 170.3, 173.0;
EIMS 312 (M+). Anal. Calcd for C15H24N2O5: C, 57.68; H, 7.74;
N, 8.97. Found: C, 57.74; H, 7.62; N, 8.98.
(R)-N-tert-Butoxycarbonyl-2-vinylproline Methyl Ester (8).
Acetyl chloride (3.95 mL, 55.6 mmol) was added dropwise to
methanol (15 mL) while stirring in an ice bath. After 5 min, a
solution of 7 (1.51 g, 5.58 mmol) in methanol (5 mL) was added.
The ice bath was removed, and the mixture was stirred at room
temperature. After 7 days, the solvent was removed in vacuo, and
the residue was redissolved in methanol, concentrated, and dried
thoroughly. After addition of CH2Cl2 (15 mL) and DIPEA (1.91
mL, 11.2 mmol), a solution of Boc2O (3.65 g, 16.7 mmol) in CH2-
Cl2 (10 mL) was added, and the mixture was stirred at room
temperature for 2.5 days. The solvent was evaporated, and the
residue was purified twice by column chromatography (hexanes/
ethyl acetate 9:1 and hexanes/2-propanol 97:3), furnishing 1.04 g
(73%) of 8 as a colorless oil. Rf 0.15 (hexanes/ethyl acetate 4:1);
(2S,2′R)-N-(N-tert-Butoxycarbonyl-2-vinylprolin-1-yl)-O-(2,6-
dichlorobenzyl)tyrosine Methyl Ester (9b). 9b was prepared from
4 (200 mg, 0.892 mmol), HATU (378 mg, 0.995 mmol), DIPEA
(567 µL, 3.32 mmol) in NMP (4 mL), and O-(2,6-dichlorobenzyl)-
tyrosine methyl ester hydrochloride (597 mg, 2.07 mmol) in NMP
(3 mL) as described for 9a (preactivation time: 15 min, reaction
time: 25 min, washing with saturated NaHCO3, brine, and water).
Column chromatography (hexanes/ethyl acetate 2:1) yielded 440
mg (92%) of 9b as a colorless resin. Rf 0.37 (hexanes/ethyl acetate
[R]22D 62.4° (c 0.5, CHCl3); IR (neat) 2978, 1746, 1702, 1643 cm-1
;
1H NMR (360 MHz, CDCl3; rotamers were observed) δ 1.35 (s,
6H), 1.45 (s, 3H), 1.76-1.94 (m, 2H), 1.96-2.05 (m), 2.17 and
2.21 (2 × dd, 1H, J ) 11.6, 10.6, 7.2 and 12.2, 10.6, 6.9 Hz),
3.52-3.59 (m, 1H), 3.61-3.68 (m, 1H), 3.73 and 3.74 (2 × s, 3H),
5.04 and 5.05 (2 × dd, 1H, J ) 17.1, 1.0 and 17.1, 0.9 Hz), 5.15
and 5.17 (2 × dd, 1H, J ) 10.6, 1.0 and 10.5, 0.9 Hz), 6.32 and
6.33 (2 × dd, 1H, J ) 17.1, 10.6 and 17.1, 10.5 Hz); 13C NMR
(90 MHz, CDCl3; rotamers were observed) δ 21.9, 28.2 and 28.4,
38.0 and 39.2, 47.9 and 48.0, 52.2 and 52.4, 69.3 and 69.5, 79.8
and 80.0, 113.0 and 113.1, 136.5 and 137.2, 153.5, 173.7; EIMS
196 (M - COOCH3; M+ not observed). Anal. Calcd for C13H21-
NO4: C, 61.16; H, 8.29; N, 5.49. Found: C, 60.98; H, 8.25; N,
5.43.
1:1); [R]24 -27.5° (c 1.0, CHCl3); IR (neat) 3420, 2977, 1746,
D
1698 cm-1; 1H NMR (600 MHz, CDCl3, 320 K; broadened signals
were observed) δ 1.41 (bs, 9H), 1.63-2.63 (m, 4H), 2.97 (dd, 1H,
J ) 13.8, 7.2 Hz), 3.14 (dd, 1H, J ) 13.8, 5.6 Hz), 3.35-3.63 (m,
1H), 3.71 (s, 3H), 4.80 (ddd, 1H, J ) 7.4, 7.2, 5.6 Hz), 4.97-5.32
and 5.24 (m and s, 4H), 6.11-6.34 (m, 1H), 6.53 (bs, 0.5H), 6.91-
6.97 (m, 2H), 7.05-7.10 (m, 2H), 7.21-7.24 (m, 1H), 7.34-7.36
(m, 2H), 7.68 (bs, 0.5H); 13C NMR (90 MHz, CDCl3; rotamers
were observed) δ 22.0 and 23.1, 28.3 and 28.5, 37.4, 39.8, 48.5
and 48.7, 52.3, 53.5 and 53.8, 65.4, 71.0 and 71.4, 80.5 and 81.0,
113.9, 115.0 and 115.3, 128.6, 129.3, 130.4, 130.6, 132.3, 137.2,
138.3, 153.9 and 155.0, 172.0, 172.3 and 172.6; EIMS 576 (M+).
Anal. Calcd for C29H34Cl2N2O6: C, 60.31; H, 5.93; N, 4.85.
Found: C, 60.43; H, 5.87; N, 4.88.
(R)-N-tert-Butoxycarbonyl-2-vinylproline (4). To a solution of
8 (864 mg, 3.38 mmol) in methanol (15 mL) was added aqueous
NaOH (2 N, 15 mL), and the mixture was stirred at 50 °C for 1 h.
After cooling to room temperature, water (15 mL) was added, and
the methanol was removed under reduced pressure. The solution
was washed with ether (2 × 15 mL), then aqueous citric acid (20%,
45 mL) was added, and the mixture was extracted with ether (3 ×
15 mL). The combined organic layers were washed with water,
dried with magnesium sulfate, and concentrated, yielding 634 mg
(78%) of 4 as colorless crystals. mp 134 °C; Rf 0.49 (CH2Cl2/
methanol 9:1); [R]23D -60.3° (c 0.4, CHCl3); IR (neat) 2970, 1731,
(R)-N-(N-tert-Butoxycarbonyl-2-hydroxymethylprolin-1-yl)-
glycine Methyl Ester (10a). An ozone-enriched stream of oxygen
was bubbled through a -78 °C cold solution of 9a (128 mg, 0.409
mmol) in CH2Cl2 (5 mL) until it turned light blue. Excess ozone
was removed by flushing the solution with oxygen and nitrogen,
whereupon Na[BH(OAc)3] (434 mg, 2.05 mmol) was added. The
mixture was allowed to warm to room temperature while being
stirred vigorously. After 6 h, the reaction was stopped by addition
of aqueous NaOH (2 N, 0.5 mL), followed by drying with
magnesium sulfate and evaporation of the solvent. Column chro-
matography (hexanes/ethyl acetate 1:1) of the residue furnished 112
mg (86%) of 10a as a colorless resin. Rf 0.16 (100% ethyl acetate);
1701, 1638 cm-1 1H NMR (600 MHz, CDCl3; rotamers were
;
observed) δ 1.37 (s, 4.1H), 1.41 (s, 4.9H), 1.81-1.94 (m, 2.55H),
2.06 (ddd, 0.45H, J ) 12.1, 6.3, 3.3 Hz), 2.30 (dd, 0.45H, J )
12.1, 11.0. 6.8 Hz), 2.59-2.64 (m, 0.55H), 3.50-3.53 (m, 1.1H),
3.60 (ddd, 0.45H, J ) 10.1, 9.8, 6.8 Hz), 3.66 (ddd, 0.45H, J )
10.1, 7.7, 3.0 Hz), 5.07 (d, 0.45H, J ) 17.0 Hz), 5.16 and 5.17 (2
× d, 1H, J ) 17.6 and 10.6 Hz), 5.25 (d, 0.55H, J ) 10.6 Hz),
6.07 (dd, 0.55H, J ) 17.6, 10.6 Hz), 6.29 (dd, 0.45H, J ) 17.0,
10.6 Hz), 11.07 (bs, 1H); 13C NMR (150 MHz, CDCl3; rotamers
were observed) δ 21.9 and 22.8, 28.1 and 28.4, 37.8 and 39.4, 47.8
and 48.7, 69.3 and 71.3, 80.6 and 81.9, 113.3 and 115.1, 136.6,
153.5 and 156.2, 174.4 and 179.0; EIMS 241 (M+). Anal. Calcd
for C12H19NO4: C, 59.73; H, 7.94; N, 5.80. Found: C, 59.87; H,
7.87; N, 5.80.
(R)-N-(N-tert-Butoxycarbonyl-2-vinylprolin-1-yl)glycine Meth-
yl Ester (9a). To a solution of 4 (200 mg, 0.829 mmol) and HATU
(347 mg, 0.912 mmol) in NMP (2 mL) was added DIPEA (355
µL, 2.07 mmol). After stirring the mixture at room temperature
for 5 min, we added a suspension of glycine methyl ester
hydrochloride (208 mg, 1.66 mmol) and DIPEA (284 µL, 1.66
mmol) in NMP (2 mL) and continued stirring for 30 min. After
addition of aqueous citric acid (20%, 5 mL), the mixture was
extracted with ether (3 × 5 mL), and the combined organic layers
[R]20 -39.0° (c 0.5, CHCl3); IR (neat) 3342, 2976, 1755, 1696,
D
1669 cm-1; H NMR (360 MHz, CDCl3, 330 K) δ 1.44 and 1.46
1
(bs and s, 10H), 1.77-1.94 (m, 2H), 2.01-2.19 (m, 1H), 2.30 (ddd,
1H, J ) 12.4, 6.1, 6.1 Hz), 3.47 (ddd, 1H, J ) 10.7, 7.6, 7.6 Hz),
3.63 (ddd, 1H, J ) 10.7, 6.2, 6.2 Hz), 3.71-3.81 and 3.75 (m and
s, 4H), 4.00 (dd, 1H, J ) 18.2, 4.9 Hz), 4.09 and 4.09-4.14 (dd
and m, 2H, J ) 18.2, 5.4 Hz), 6.92 (bs, 1H); 13C NMR (150 MHz,
CDCl3; rotamers were observed) δ 22.1, 28.2 and 28.3, 35.4, 40.8
and 41.4, 48.1 and 49.3, 52.6 and 52.7, 64.3 and 66.5, 67.6 and
71.4, 81.1 and 81.4, 153.5 and 156.2, 170.0 and 170.5, 173.1 and
176.3; EIMS 316 (M+). Anal. Calcd for C14H24N2O6 × 0.3H2O:
C, 52.26; H, 7.71; N, 8.71. Found: C, 52.27; H, 7.71; N, 8.35.
(2S,2′R)-N-(N-tert-Butoxycarbonyl-2-hydroxymethylprolin-1-
yl)-O-(2,6-dichlorobenzyl)tyrosine Methyl Ester (10b). 10b was
prepared from 9b (384 mg, 0.665 mmol) in CH2Cl2 (10 mL) and
Na[BH(OAc)3] (705 mg, 3.32 mmol) as described for 10a (reaction
time: 24 h; after 5.5 h, a second portion of Na[BH(OAc)3] (282
mg, 1.33 mmol) was added; the reaction was stopped by addition
100 J. Org. Chem., Vol. 71, No. 1, 2006

â-Lactams as Type II â-Turn Inducing Peptide Mimetics
of aqueous NaOH (0.67 N, 3 mL); the crude product was obtained
by repeated extraction with CH2Cl2). Twofold column chromatog-
raphy (hexanes/ethyl acetate 1:1) furnished 297 mg (77%) of 10b
(R)-2-(5-tert-Butoxycarbonyl-1-oxo-2,5-diazaspiro[3.4]oct-2-
yl)-N-methylacetamide (2). 11a (16.0 mg, 0.0536 mmol) was
dissolved in methylamine solution (8 M in ethanol, 2 mL) while
cooling with an ice bath. The mixture was stirred at this temperature
for 40 min, whereupon the solvent was removed at low temperature
under reduced pressure. The residue was purified by column
chromatography (100% ethyl acetate), furnishing 15.4 mg (97%)
of 2 as a colorless oil. Rf 0.22 (CH2Cl2/methanol 95:5); [R]23D 72.8°
(c 0.25, CHCl3); IR (neat) 3483 (w), 3338 (s), 2976, 1767, 1680
cm-1; IR (CHCl3, 2 mM) 3338 cm-1; 1H NMR (600 MHz, CDCl3)
δ 1.48 (s, 9H), 1.81-1.89 (m, 1H), 1.96-2.01 (m, 1H), 2.16 (ddd,
1H, J ) 12.9, 6.7, 4.4 Hz), 2.36 (ddd, 1H, J ) 12.9, 10.2, 6.8 Hz),
2.82 (d, 3H, J ) 4.9 Hz), 3.25 (d, 1H, J ) 4.9 Hz), 3.44 und 3.41-
3.49 (d and m, 3H, J ) 17.8 Hz), 3.82 (d, 1H, J ) 4.9 Hz), 4.45
(d, 1H, J ) 17.8 Hz), 8.24 (bs, 1H); 13C NMR (150 MHz, CDCl3)
δ 23.3, 26.0, 28.4, 33.2, 45.2, 47.9, 54.4, 74.1, 81.3, 153.9, 168.0,
169.1; EIMS 298 (M + 1), 297 (M+). Anal. Calcd for C14H23N3O4
× 0.5H2O: C, 54.89; H, 7.90; N, 13.72; Found: C, 54.70; H, 7.45;
N, 13.56.
as colorless crystals. mp 143 °C; Rf 0.41 (100% ethyl acetate); [R]23
D
-15.8° (c 0.5, CHCl3); IR (KBr) 3342, 3259, 2981, 1744, 1697,
1654 cm-1; 1H NMR (600 MHz, CDCl3, 320 K; broadened signals
were observed) δ 1.21-1.50 and 1.43 (m and s, 10H), 1.61-1.71
(m, 1H), 1.73-1.80 (m, 1H), 1.85-2.38 (m, 2H), 3.03 (dd, 1H, J
) 13.9, 6.1 Hz), 3.15 (dd, 1H, J ) 13.9, 6.0 Hz), 3.37-3.44 (m,
1H), 3.49-3.53 (m, 1H), 3.61-3.91 and 3.72 (m and s, 4H), 3.97-
4.29 (m, 1H), 4.82 (ddd, 1H, J ) 6.2, 6.1, 6.0 Hz), 5.25 (s, 2H),
6.16-7.13 (m, 5H), 7.21-7.24 (m, 1H), 7.34-7.37 (m, 2H); 13C
NMR (90 MHz, CDCl3; broadened signals were observed) δ 22.3,
28.4, 35.5, 37.3, 49.1, 52.5, 53.5, 65.4, 66.4, 71.2, 81.3, 115.2,
128.6, 128.8, 130.5, 130.6, 132.3, 137.11, 156.0, 158.2, 171.9,
172.9; EIMS 580, 582 (M+). Anal. Calcd for C28H34Cl2N2O7: C,
57.84; H, 5.89; N, 4.82. Found: C, 57.82; H, 5.81; N, 4.86.
(R)-2-(5-tert-Butoxycarbonyl-1-oxo-2,5-diazaspiro[3.4]oct-2-
yl)acetic Acid Methyl Ester (11a). To a stirred solution of 10a
(77.1 mg, 0.244 mmol) and triphenylphosphine (95.9 mg, 0.366
mmol) in THF (5 mL) was added DEAD solution (40% in toluene,
106 µL, 0.366 mmol) at room temperature. After being stirred for
2 h, additional DEAD solution (21.1 µL, 48.7 µmol) was added,
and stirring was continued for 30 min, whereupon the solvent was
removed under reduced pressure. The residue was purified by 2-fold
column chromatography (hexanes/ethyl acetate 1:1), furnishing 47.0
mg (65%) of 11a as a colorless oil. Rf 0.35 (100% ethyl acetate);
(2S,4′R)-2-(5-tert-Butoxycarbonyl-1-oxo-2,5-diazaspiro[3.4]-
oct-2-yl)-3-[4-(2,6-dichlorbenzyloxy)phenyl]propionic Acid (12).
A solution of 11b (92.0 mg, 0.163 mmol) in THF (7 mL) was
cooled in an ice bath. Aqueous LiOH (0.5 N, 7 mL) was added
slowly, and the mixture was stirred at this temperature for 1 h.
After addition of aqueous citric acid (20%, 14 mL), THF was
removed under reduced pressure, and the remaining solution was
extracted with ether (3 × 15 mL). The combined organic layers
were washed with brine (2 × 15 mL) and water (15 mL), dried
with magnesium sulfate, concentrated, and purified by column
chromatography (CH2Cl2/methanol/formic acid 95:4:1), furnishing
73.2 mg (82%) of 12 as a colorless solid. HPLC-MS analysis
indicated the presence of 9% of the epimeric compound. mp 77-
83 °C; Rf 0.22 (CH2Cl2/methanol/formic acid 95:4:1); IR (neat)
[R]19 -4.2° (c 0.5, CHCl3); IR (neat) 2975, 1769, 1750, 1698
D
cm-1; 1H NMR (360 MHz, CDCl3; rotamers were observed) δ 1.44
and 1.45 (2 × s, 9H), 1.77-1.88 (m, 1H), 1.92-2.01 (m, 1H),
2.19-2.27 (m, 1H), 2.34-2.45 (m, 1H), 3.39-3.56, 3.45 and 3.48
(m, d and d, 3H, J ) 4.4 and 4.4 Hz), 3.66 and 3.66 (2 × d, 1.2 H,
J ) 17.9 and 4.4 Hz), 3.72, 3.74 and 3.75 (d, s and s, 3.4 H, J )
18.2 Hz), 3.86 (d, 0.4 H, J ) 4.4 Hz), 4.40 (d, 0.6H, J ) 17.9 Hz),
4.49 (d, 0.4H, J ) 18.2 Hz); 13C NMR (90 MHz, CDCl3; rotamers
were observed) δ 22.8 and 23.3, 28.3 and 28.5, 34.0 and 35.1, 42.6
and 43.0, 47.9 and 48.1, 52.2 and 52.3, 54.4 and 56.0, 73.6 and
73.8, 80.2 and 80.8, 153.4, 168.6 and 169.0, 170.4 and 170.5; EIMS
283 (M - CH3; M+ not observed). Anal. Calcd for C14H22N2O5 ×
0.2H2O: C, 55.69; H, 7.48; N, 9.28. Found: C, 55.88; H, 7.53; N,
9.19.
1
2974, 2929, 1764 (sh), 1746, 1698 cm-1; H NMR (600 MHz,
acetone-d6; rotamers were observed) δ 1.29 (s, 4.05H), 1.47 (s,
4.95H), 1.80-1.92 (m, 2H), 2.10-2.20 (m, 1.45H), 2.73-2.88 (m,
0.55H), 3.12 (dd, 0.45H, J ) 13.8, 7.9 Hz), 3.18 and 3.18-3.20
(dd and m, 1.55H, J ) 13.8, 6.6 Hz), 3.27 (d, 0.55H, J ) 4.6 Hz),
3.29-3.42 (m, 1.55H), 3.45 and 3.44-3.48 (d and m, 0.9H J )
4.6 Hz), 3.64 (d, 0.45H, J ) 4.6 Hz), 3.82 (d, 0.55H, J ) 4.6 Hz),
4.53 (dd, 0.55H, J ) 7.2, 7.2 Hz), 4.57 (dd, 0.45H, J ) 7.9, 6.6
Hz), 5.31 (s, 2H), 6.98-7.05 (m, 2H), 7.28-7.36 (m, 2H), 7.44-
7.47 (m, 1H), 7.51-7.53 (m, 2H); 13C NMR (90 MHz, CDCl3;
rotamers were observed) δ 23.5, 28.5, 32.6, 35.2, 48.0 and 55.5,
60.9, 65.6, 72.9, 82.0, 115.4, 128.7, 129.7, 130.3, 130.6, 130.7,
132.3 and 137.1, 154.1 and 158.1, 169.2 and 170.7; ESI-MS 549
(M + 1). Anal. Calcd for C27H30Cl2N2O6: C, 59.02; H, 5.50; N,
5.10. Found: C, 59.13; H, 5.39; N, 5.11.
(R)-2-(1-tert-Butoxycarbonyl-6-oxo-1,7-diazaspiro[4.4]non-7-
yl)acetic Acid N-Methyl Amide (1). 1 was prepared from (R)-2-
(1-tert-butoxycarbonyl-6-oxo-1,7-diazaspiro[4.4]non-7-yl)acetic acid
methyl ester (26.8 mg, 0.0858 mmol) and methylamine solution (8
M in ethanol, 2 mL) as described for 3 (2.75 h at 0 °C, then 15 h
at room temperature). Column chromatography (hexanes/ethyl
acetate 1:2 increasing to 0:1) yielded 21.0 mg (79%) of 1 as
yellowish crystals. mp 121 °C; Rf 0.46 (CH2Cl2/methanol 9:1);
[R]23D 69.6° (c 0.5, CHCl3) IR (neat) 3338, 2975, 2929, 1697, 1673
(2S,4′R)-3-(4-[2,6-Dichlorobenzyloxy]phenyl)-2-(5-tert-butoxy-
carbonyl-1-oxo-2,5-diazaspiro[3.4]oct-2-yl)propionic Acid Meth-
yl Ester (11b). 11b was prepared from 10b (69.4 mg, 0.119 mmol),
triphenylphosphine (47.0 mg, 0.179 mmol) in THF (2 mL), and
DEAD solution (40% in toluene, 73.0 + 16 µL, 0.167 + 0.0358
mmol) as described for 11a (after second DEAD addition stirring
was continued for 3 h). Column chromatography (CH2Cl2/methanol
97:3) yielded 42.5 mg (63%) of 11b as a colorless resin. Rf 0.18
(hexanes/ethyl acetate 1:1); [R]23D 19.2° (c 0.25, CHCl3); IR (neat)
2973, 1766, 1742, 1697 cm-1 1H NMR (600 MHz, CDCl3;
;
rotamers were observed) δ 1.36 (s, 4.5H), 1.46 (s, 4.5H), 1.74-
1.83 (m, 1H), 1.90-1.97 (m, 1H), 2.07-2.11 (m, 0.5H), 2.15-
2.19 (m, 0.5H), 2.27-2.34 (m, 1H), 3.06, 3.08 and 3.12 (dd, dd
and dd, 1.5H, J ) 14.0, 7.4 and 13.0, 7.3 and 13.0, 7.7 Hz), 3.23
(dd, 0.5H, J ) 14.0, 6.2 Hz), 3.33 (d, 0.5H, J ) 4.5 Hz), 3.37-
3.44 and 3.38 (m and d, 2H, J ) 4.3 Hz), 3.48-3.53 (m, 0,5H),
3.62 (d, 0.5H, J ) 4.3 Hz), 3.65 and 3.68 (2 × s, 3H), 3.83 (d,
0.5H, J ) 4.5 Hz), 4.67 (dd, 0.5H, J ) 7.7, 7.3 Hz), 4.75 (dd,
0.5H, J ) 7.4, 6.2 Hz), 5.25 (s, 2H), 6.93-6.97 (m, 2H), 7.12-
7.14 (m, 1H), 7.22-7.26 (m, 2H), 7.35-7.38 (m, 2H); 13C NMR
(90 MHz, CDCl3; rotamers were observed) δ 22.7 and 23.4, 28.3
and 28.6, 33.9 and 35.6, 35.5, 48.0, 52.2 and 52.4, 53.1 and 53.6,
55.0 and 55.5, 65.4, 72.1 and 72.6, 80.0 and 81.1, 115.2 and 115.4,
128.6, 128.8 and 129.3, 130.3 and 130.6, 130.5, 132.2 and 132.4,
137.1, 153.2 and 153.6, 158.0 and 158.3, 170.2 and 170.6, 171.0;
EIMS 461, 463 (M - Boc; M+ not observed). Anal. Calcd for
C28H32Cl2N2O6: C, 59.68; H, 5.72; N, 4.97. Found: C, 59.52; H,
5.66; N, 5.08.
(26) 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.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
J. Org. Chem, Vol. 71, No. 1, 2006 101

Bittermann and Gmeiner
cm-1; IR (2 mM, CHCl3) 3337 cm-1; 1H NMR (360 MHz, CDCl3)
δ 1.45 (s, 9H), 1.80-1.93 (m, 2H), 2.02-2.11 and 2.07 (m and
ddd, 2H, J ) 13.4, 9.2, 3.8 Hz), 2.20-2.31 (m, 1H), 2.47 (ddd,
1H, J ) 13.4, 9.8, 6.0 Hz), 2.80 (d, 3H, J ) 4.6 Hz), 3.29 (ddd,
1H, J ) 9.5, 9.2, 6.0 Hz), 3.38 (d, 1H, J ) 17.0 Hz), 3.48-3.52
(m, 2H), 3.57 (ddd, 1H, J ) 9.8, 9.5, 3.8 Hz), 4.57 (d, 1H, J )
17.0 Hz), 7.82 (bs, 1H); 13C NMR (90 MHz, CDCl3) δ 24.0, 26.2,
28.6, 31.5, 38.2, 44.7, 47.5, 47.8, 66.5, 80.7, 154.5, 168.3, 174.5;
EIMS 311 (M+). Anal. Calcd for C15H25N3O4: C, 57.86; H, 8.09;
N, 13.49. Found: C, 57.91; H, 8.11; N, 13.49.
DFT calculations using Gaussian98.26 A B3LYP density functional
with a 3-21G basis set was used to produce a reasonable geometry
in appropriate time. Then the basis set was increased in two
subsequent steps to the double-valence d-polarized level 6-31G(d)
and the triple-valence d,p-polarized level 6-311G(d,p) to enhance
the quality of the structure.
Acknowledgment. This work was supported by the Deutsche
Forschungsgemeinschaft (DFG) and the Fonds der Chemischen
Industrie. Dr. F. Boeckler and Dr. R. Waibel are acknowledged
for computational studies and NMR experiments, respectively.
Computational Studies. The structure of 2 was derived from
X-ray data of a suitable precursor, which was further used as a
template to build 1. Both structures were submitted to a series of
JO0517287
102 J. Org. Chem., Vol. 71, No. 1, 2006