Synthesis of pipecolic acid-based spiro bicyclic lactam scaffolds as β-turn mimics

Article abstract of DOI:10.1021/jo050529k

A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence of reactions that was initiated with the α-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative cleavage of the olefin to give an aldehyde followed

Full text of DOI:10.1021/jo050529k

Synthesis of Pipecolic Acid-Based Spiro Bicyclic Lactam Scaffolds
as â-Turn Mimics
Ravindranadh V. Somu and Rodney L. Johnson*
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St. SE,
Minneapolis, Minnesota 55455
johns022@umn.edu
Received March 15, 2005
A series of 6.5.5 spiro bicyclic lactam scaffolds were synthesized from pipecolic acid in a sequence
of reactions that was initiated with the R-allylation of tert-butoxycarbonyl pipecolic acid. Oxidative
cleavage of the olefin to give an aldehyde followed by condensation with D-cysteine methyl ester
gave a mixture of pipecolyl thiazolidines. Cyclization of the pipecolyl thiazolidines with Mukaiyama’s
reagent yielded the spiro bicyclic lactams 4a-d. Epimerization of the 7′a bridgehead carbon under
acidic conditions was observed for those spiro bicyclic lactam scaffolds with an S stereochemistry
at this position. The 6.5.5 spiro bicyclic lactam scaffold with the 3′S,6′R,7′aR stereochemistry
mimicked a type II â-turn, while the scaffold with the 3′S,6′S,7′aR stereochemistry mimicked a
right-handed poly-D-proline II helix.
Introduction
Proteins and peptides play important roles in numer-
ous fundamental physiological processes. Reverse turns
constitute ubiquitous structural motifs of many peptides
and proteins1 and they are considered to play a major
role in protein-protein and peptide-protein recognition
events.2 Type I and type II â-turns are among the most
important reverse turns observed in peptides.3 â-Turns
are defined by the φ and ψ torsion angles of the i+1 and
i+2 residues occupying the turn region (Figure 1).
Hydrogen bonding between the carbonyl of residue i and
the amide hydrogen of residue i+3 is often indicative of
a â-turn, though it is not an essential feature.
Knowledge of the bioactive conformation of a peptide
or protein for its receptor becomes important in under-
standing the recognition process and in developing
compounds that potentially can affect such systems and
be used as drugs. Several non-peptide based scaffolds
FIGURE 1. Schematic representation of a â-turn.
have been developed in the process of elucidating biologi-
cally active conformations of peptides and they have been
successfully used for the development of potent enzyme
inhibitors and receptor modulators.4 A common method
to mimic the bioactive conformation of peptides is to
synthesize conformationally constrained analogues via
backbone-backbone or backbone-side chain cyclization.5
Lactam or bicyclic lactam formation is a widely used
(3) (a) Gillespie, P.; Cicariello, J.; Olson, G. L. Biopolymers 1997,
43, 191-217. (b) Cai, Y.-D.; Yu, H.; Chou, K.-C. J. Protein Chem. 1998,
17, 363-376.
(1) (a) Venkatachalam, C. M. Biopolymers 1968, 6, 1425-1436. (b)
Lewis, P. N.; Momany, F. A.; Scheraga, H. A. Biochim. Biophys. Acta
1973, 303, 211-229. (c) Chou, P. Y.; Fasman, G. D. J. Mol. Biol. 1977,
115, 135-175. (d) Kabsch, W.; Sander, C. Biopolymers 1983, 22, 2577-
2637. (e) Rose, G. D.; Gierasch, L. M.; Smith, J. A. Adv. Protein Chem.
1985, 37, 1-109. (f) Wilmot, C. M.; Thornton, J. M. J. Mol. Biol. 1988,
203, 221-232. (g) Serrano, L. Adv. Protein Chem. 2000, 53, 48-85.
(2) (a) Mu¨ller, G. Angew. Chem., Int. Ed. Engl. 1996, 35, 2767-
2769. (b) Cochran, A. G. Chem. Biol. 2000, 7, R85-R94. (c) Burgess,
K. Acc. Chem. Res. 2001, 34, 826-835. (d) Hruby, V. J. Nat. Rev. Drug
Discovery 2002, 1, 847-858. (e) Mathur, P. S.; Ramakumar, V. S.;
Chauhan Biopolymers 2004, 76, 150-161.
(4) (a) Freidinger, R. M.; Veber, D. F.; Perlow, D. S.; Brooks, J. R.;
Saperstein, R. Science 1980, 210, 656-658. (b) Freidinger, R. M.;
Perlow, D. S.; Randall, W. C.; Saperstein, R.; Arison, B. H.; Veber, D.
F. Int. J. Peptide Protein Res. 1984, 23, 142-150. (c) Souers, A. J.;
Virgilio, A. A.; Schrer, S. S.; Ellman, J. A.; Kogan, T. P.; West, H. E.;
Ankener, W.; Vanderslice, P. Bioorg. Med. Chem. Lett. 1998, 8, 2297-
2302. (d) Cho, N.; Harada, M.; Imaeda, T.; Imada, T.; Matsumoto, H.;
Hayase, Y.; Sasaki, S.; Furuya, S.; Suzuki, N.; Okubo, S.; Ogi, K.; Endo,
S.; Onda, H.; Fujino, M. J. Med. Chem. 1998, 41, 4190-4195. (e)
Souers, A. J.; Virgilio, A. A.; Rosenquist, A° .; Fenuik, W.; Ellman, J. A.
J. Am. Chem. Soc. 1999, 121, 1817-1825. (f) Long, R. D.; Moeller, K.
D. J. Am. Chem. Soc. 1997, 119, 12394-12395.
10.1021/jo050529k CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
5954
J. Org. Chem. 2005, 70, 5954-5963

Pipecolic Acid-Based Spiro Bicyclic Lactams
SCHEME 1. Retrosynthesis of Pipecolyl Spiro
Bicyclic Lactam Scaffold 4
method for constraining the torsion angles for the
synthesis of peptidomimetics.6,7 Most lactam constraints
that have been developed and incorporated into peptides,
however, only restrict one or two torsion angles out of
the four that define a â-turn conformation.
We developed a class of spiro bicyclic lactams that
restrict three out of four torsion angles that define a
â-turn.8 Spiro bicyclic lactams such as 1-3 were synthe-
sized to explore the bioactive conformation of L-prolyl-L-
leucyl-glycinamide (PLG), an endogenous peptide known
to exert important modulatory effects on dopaminergic
neurotransmission in the central nervous system.9,10 In
our early studies, the ring size of the bicyclic portion of
the scaffold was altered. Such changes were found to have
an effect on the ψ2 and φ3 torsion angles, that in turn
had an effect on the pharmacological activity of the PLG
peptidomimetics.10 In a continuation of these studies, we
wanted to explore the effect of increasing the conforma-
tional freedom of the φ2 torsion angle. We envisioned this
could be achieved by changing the spiro pyrrolidine
residue found in 1-3 to the six-membered piperidine
moiety as illustrated in spiro bicyclic lactam scaffold 4.
The present report describes the synthesis and chemistry
of the diastereomeric 6.5.5 spiro bicyclic lactam scaffolds
4a-d.
this scaffold could be obtained through the condensation
of D-cysteine with pipecolyl aldehyde 5 in a manner
analogous to that used in the synthesis of the prolyl-
based spiro bicyclic lactam scaffolds.8-10 Aldehyde 5 could
be obtained from the R-allyl pipecolic acid derivative 6.
This route provided a potential means to control the
stereochemistry of the spiro center provided 6 could be
obtained in chiral form. Unfortunately, Seebach’s method
of self-reproduction of chirality, an excellent method for
asymmetric alkylation of proline and the method used
to control the spiro center stereochemistry in the prolyl-
based spiro bicyclic lactam scaffolds, could not be ex-
tended to pipecolic acid, as this compound does not
condense with pivalaldehyde under a variety of condi-
tions.11
Although the pool of methods available for the asym-
metric synthesis of 2-alkyl pipecolic acid derivatives is
rather limited, we initially investigated several chiral
auxiliary mediated alkylations in an effort to obtain 6 in
chiral form. The method of Wanner and colleagues12
provided R-allylpipecolic acid, but only in modest yield
after 10 steps. The use of this method on a large-scale
preparation of 6 was viewed as prohibitive, however,
because of the costly (-)-camphanic acid required for the
chiral auxiliary synthesis. When either William’s oxazi-
none13 or Husson’s 2-cyano-6-phenyloxazolopiperidine14
was used as the chiral auxiliary excellent stereoselectiv-
ity in the alkylation with allyl bromide was observed.
However, cleavage of the chiral auxiliary without affect-
ing the allyl group could not be achieved. Due to these
limitations, we felt it would be more efficient and cost-
effective to carry out the synthesis of the pipecolyl-based
spiro bicyclic lactams starting with the cheap and widely
available racemic pipecolic acid. Although this approach
would yield a mixture of diastereoisomers, successful
separation of the diastereoisomers would provide a family
of pipecolyl-based spiro bicyclic lactams. Described below
is the successful synthesis and isolation of the diaster-
eomeric spiro bicyclic lactam scaffolds 4a-d.
Results and Discussion
The retrosynthetic analysis for spiro bicyclic lactam
scaffold 4 is depicted in Scheme 1. We envisioned that
(5) (a) Hruby, V. J. Life Sci. 1982, 31, 189-199. (b) Ball, J. B.;
Alewood, P. F. J. Mol. Recognit. 1990, 3, 55-64. (c) Baca, M.; Alewood,
P. F.; Kent, S. B. H. Protein Sci. 1993, 2, 1085-1091. (d) Viles, J. H.;
Patel, S. U.; Mitchell, J. B.; Moody, C. M.; Justice, D. E.; Uppenbrink,
J.; Doyle, P. M.; Harris, C. J.; Sadler, P. J.; Thornton, J. M. J. Mol.
Biol. 1998, 279, 973-986. (e) Jean, F.; Buisine, E.; Melnyk, O.; Drobecq,
H.; Odaert, B.; Hugues, M.; Lippens, G.; Tartar, A. J. Am. Chem. Soc.
1998, 120, 6076-6083. (f) Kaul, R.; Angeles, A. R.; Jager, M.; Powers,
E. T.; Kelly, J. W. J. Am. Chem. Soc. 2001, 123, 5206-5212.
(6) (a) Abell, A. D.; Gardiner, J. J. Org. Chem. 1999, 64, 9668-9672.
(b) Cristau, M.; Devin, C.; Oiry, C.; Chaloin, O.; Amblard, M.; Bernad,
N.; Heitz, A.; Fehrentz, J.-A.; Martinez, J. J. Med. Chem. 2000, 43,
2356-2361. (c) Freidinger, R. M. J. Med. Chem. 2003, 46, 5554-5566.
(d) Dolbeare, K.; Pontoriero, G. F.; Gupta, S. K.; Mishra, R. K.; Johnson,
R. L. J. Med. Chem. 2003, 46, 727-733. (e) Hoffmann, T.; Waibel, R.;
Gmeiner, P. J. Org. Chem. 2003, 68, 62-69. (f) Scott, W. L.; Alsina,
J.; Kennedy, J. H.; O’Donnell, M. J. Org. Lett. 2004, 6, 1629-1632.
(7) (a) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789-12854. (b) Beal, L. M.;
Moeller, K. D. Tetrahedron Lett. 1998, 39, 4639-4642. (c) Feng, Z.;
Lubell, W. D. J. Org. Chem. 2001, 66, 1181-1185. (d) Krelaus, R.;
Westermann, B. Tetrahedron Lett. 2004, 45, 5987-5990. (e) Colombo,
L.; Di Giacomo, M.; Vinci, V.; Colombo, M.; Manzoni, L.; Scolastico, C.
Tetrahedron 2003, 59, 4501-4513. (f) Artale, E.; Banfi, G.; Belvisi, L.;
Colombo, L.; Colombo, M.; Manzoni, L.; Scolastico, C. Tetrahedron.
2003, 59, 6241-6250. (g) Hanessian, S.; Sailes, H.; Munro, A.;
Therrien, E. J. Org. Chem. 2003, 68, 7219-7233. (h) Kim, K.; Dumas,
J.-P.; Germanas, J. P. J. Org. Chem. 1996, 61, 3138-3144.
(8) Genin, M. J.; Johnson, R. L. J. Am. Chem. Soc. 1992, 114, 8778-
8783.
Our initial approach to the 6.5.5 spiro bicyclic lactam
scaffold was to synthesize pipecolyl thiazolidine deriva-
tives that could be cyclized under thermal conditions to
give the 6.5.5 scaffold, since this was an approach that
(11) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem.
Soc. 1983, 105, 5390-5398.
(12) (a) Wanner, K. Th.; Kartner, A. Synthesis 1988, 968-969. (b)
Wanner, K. Th.; Stamenitis, T. Leibigs Ann. Chem. 1993, 477-484.
(13) Williams. R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276-
9286.
(9) Genin, M. J.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1993,
36, 3481-3483.
(10) Khalil, E. M.; Ojala, W. H.; Pradhan, A.; Nair, V. D.; Gleason,
W. B.; Mishra, R. K.; Johnson, R. L. J. Med. Chem. 1999, 42, 628-
637.
(14) Berrien, J.-F.; Royer, J.; Husson, H.-P. J. Org. Chem. 1994, 59,
3769-3774.
J. Org. Chem, Vol. 70, No. 15, 2005 5955

Somu and Johnson
SCHEME 2
SCHEME 3
previously proved successful in the synthesis of the 5.5.5
and 5.5.6 spiro bicyclic lactam scaffolds.8-10 This approach
is depicted in Scheme 2. Racemic pipecolic acid was
protected with the tert-butoxycarbonyl group in 95%
yield, using the conditions of Khalil et al.15 to give 7. An
LDA mediated allylation16 of 7 afforded racemic 2-allyl
pipecolic acid 8 in excellent yield (90%). This material
was treated with diazomethane to give methyl ester 9 in
98% yield. Initially, oxidative cleavage of olefin 9 was
carried out with OsO4 and NaIO4,10 but this method only
provided aldehyde 11 in a very modest 33% yield after
column chromatography. A modified procedure involving
first the dihydroxylation of 9 to give 10, followed by the
ucts was detected. In another attempt, the diester pipe-
colyl thiazolidine 13 was synthesized in an 81% yield by
condensing D-Cys-OMe with 11 in the presence of NaH-
CO3. However, subjecting 13 to thermal cyclization
conditions also failed to yield any of the desired cycliza-
tion products. These cyclization problems were similar
to those observed previously when attempts were made
to obtain the 5.6.5 spiro bicyclic lactam scaffold under
thermal conditions.10
To overcome the cyclization problems encountered
above, an alternate route to the spiro bicyclic lactams 4
was employed as outlined in Scheme 3. Compound 8 was
treated with BnBr in the presence of DBU to afford the
benzyl ester 14 in quantitative yield.18 Oxidative cleavage
of 14 with the OsO4/NMO and NaIO4/SiO2 sequence gave
aldehyde 15 in a 75% yield. Hydrogenolysis of 15 resulted
in deprotection of the benzyl ester. However, the product
that was isolated in 80% yield when benzene was used
as the solvent was not carboxylic acid 16, but rather
hydroxy lactone 17. When EtOH was used as the solvent
in the hydrogenolysis reaction the formation of unwanted
hemiacetal/acetal products resulted. If the hydrogenolysis
of 15 was carried out in EtOH under pressure (60 psi),
17 was obtained in a 26% yield along with about 5% of
the corresponding ethoxy lactone derivative and 53% of
the ethyl hemiacetal of 15. Hydroxy lactone 17 also could
be obtained directly through the oxidative cleavage of 8
17
treatment of 10 with silica adsorbed with NaIO4 gave
a superior yield (>90% over two steps) of 11 without the
need for column chromatography.
Aldehyde 11 was condensed with D-Cys-OH to give a
mixture of thiazolidines (12), which was subsequently
heated in toluene in the presence of Et3N. The reaction
mixture showed the formation of several nonpolar prod-
ucts along with unreacted starting material after pro-
longed heating. One of the nonpolar products was char-
acterized to be the decarboxylation product of the spiro
bicyclc lactam, but none of the desired cyclization prod-
(15) Khalil, E. M.; Subhasinghe, N. L.; Johnson, R. L. Tetrahedron
Lett. 1996, 3441-3444.
(16) Kim, D. H.; Chung, H. Tetrahedron: Asymmetry 1999, 10, 3769-
3776.
(17) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622-
(18) Ono, N.; Yamada, T.; Saito, T.; Tanaka, K.; Kaji, A. Bull. Chem.
Soc. Jpn. 1978, 51, 2401-2404.
2624.
5956 J. Org. Chem., Vol. 70, No. 15, 2005

Pipecolic Acid-Based Spiro Bicyclic Lactams
with OsO4/NaIO4. In this case a 55% yield of 17 was
obtained after column chromatography.
The condensation of 17 with D-Cys-OMe gave the
pipecolyl thiazolidine 18 as a mixture of diastereoisomers
as indicated by 1H NMR and mass spectral analyses.
Interestingly, the presence of molecular ion peaks cor-
responding to the cyclization product in the mass spec-
trum of the condensation reaction mixture suggested that
18, in contrast to the pipecolyl thiazolidines 12 and 13,
had a propensity to cyclize to the spiro bicyclic lactam
system under mild reaction conditions. Thus, a CHCl3
solution of 18 and Et3N was heated at reflux. TLC
analysis of the reaction mixture showed the formation
of two products, which were isolated by column chroma-
tography (∼15% isolated yield for each) and subsequently
shown to be the spiro bicyclic lactams 4a and 4b. The
formation in this case of the two spiro-bicyclic lactam
scaffolds having the 3′ and 7a′ hydrogens in an anti
configuration was consistent with the results obtained
previously by us in the thermal cyclization of the 5.5.5
and 5.5.6 spiro bicyclic lactam systems.8,10
FIGURE 2. ORTEP representation of the X-ray structure of
4a at the 50% probability level for non-hydrogen atoms with
the crystallographic numbering system.
When the cyclization of the diastereoisomeric mixture
18 was carried out with Mukaiyama’s reagent (2-chloro-
1-methylpyridinium iodide) under the conditions previ-
ously reported by Khalil et al.10 for the synthesis of the
5.6.5 spiro bicyclic lactam scaffold, four cyclization prod-
ucts, 4a-d, were obtained. On TLC (EtOAc/hexanes, 1:1)
4a-d possessed Rf values of 0.75, 0.58, 0.51, and 0.48,
respectively. The chromatographic isolation of 4a from
the mixture of isomers was straightforward and provided
4a in an 18% yield. The separation of the other isomers
from one another, on the other hand, proved more
difficult because of their relatively close Rf values.
However, 4b could be isolated in pure form and in a 21%
yield through the use of Ready Sep prepacked silica gel
columns. Although 4c and 4d could be separated from
one another in this system, these compounds were
contaminated by the presence of the byproduct of Mu-
kaiyama’s reagent, 1-methyl-1H-pyridin-2-one. They were
obtained in yields of 12% and 10%, respectively.
FIGURE 3. ORTEP representation of the X-ray structure of
20b at the 50% probability level for non-hydrogen atoms with
the crystallographic numbering system.
The assignment of the stereochemistry of the spiro
carbon 6′ and the bridgehead carbon 7′a of 4a and 4b
was delineated through X-ray crystallographic analysis.
An X-ray crystal structure of compound 4a unambigu-
ously established the stereochemistry of both the bridge-
head and spiral carbon atoms (Figure 2) to have the R
configuration. Likewise, an X-ray crystal structure of a
derivative of 4b, compound 20b (Figure 3), established
the stereochemistry of the bridgehead and spiral carbon
atoms for this isomer to be R and S, respectively. In the
case of 4d, 1D and 2D NOE studies (Figure 4) showed a
significant NOE between the 3′ hydrogen and the bridge-
head hydrogen. Also, a weak NOE was observed between
the bridgehead hydrogen and the hydrogens of the
piperidine ring. These results suggested that the spiral
and bridgehead carbon atoms possessed the R and S
configurations, respectively. By the process of elimina-
tion, 4c was postulated to possess the S stereochemistry
at both the bridgehead and spiro carbon atoms. Support
for this assumption was an observed weak NOE between
the 3′ and 7′a hydrogens of 4c.
FIGURE 4. Observed NOEs for 4d and 4c (m ) medium,
w ) weak).
cinamide. The tert-butoxycarbonyl group was removed
from each diastereoisomer with HCl in dioxane and the
deprotected species then was coupled to Boc-Pro-OH. In
the case of 4a, a number of coupling conditions were
investigated. Coupling of the Boc-deprotected 4a to Boc-
Pro-OH (2.5 equiv) with EDCI and HOBt (2.5 equiv of
each in dry DMF for 3 days) yielded only 10% of 19a.
Increasing the amount of EDCI and Boc-Pro-OH 3-fold
resulted in a 30% yield of 19a. When DCC, HOBt, and
Boc-Pro-OH (7.5 equiv of each) were reacted for 3 days
the yield of 19a was increased to 50%. However, the best
results were obtained when the coupling was performed
in DMF with Mukaiyama’s reagent (2.5 equiv) in the
presence of Hunig’s base (Scheme 4). An overnight
reaction gave the desired coupled product in a 70% yield
after purification. The 1H NMR spectrum of 19a showed
the presence of rotamers in the ratio of 7:3 at room
temperature. Similar coupling of the Boc-deprotected
The spiro bicyclic lactam scaffolds 4a-d were carried
on in reactions that would give analogues of the dopa-
mine receptor modulating peptide, L-prolyl-L-leucyl-gly-
J. Org. Chem, Vol. 70, No. 15, 2005 5957

Somu and Johnson
SCHEME 4
SCHEME 6
the fact that the 1H NMR spectra of the HCl salts result-
ing from the deprotection of 4a and 4d were identical.
These results suggest that the spiro bicyclic ring system
of 4a wherein the bridgehead hydrogen is in a R-orienta-
tion is more thermodynamically stable than the spiro
bicyclic system of 4d, wherein the bridgehead hydrogen
is in a â-orientation. Ab initio calculations on 22 and the
corresponding isomer with the bridgehead hydrogen in
a â-orientation using the Gaussian 0319 suite of programs
at the Hartree-Fock level of theory showed that the
isomer with the bridgehead hydrogen in a â-orientation
is 3.81 kcal/mol higher in energy compared to 22 in which
the bridgehead hydrogen is in a R-orientation.
SCHEME 5
The treatment of 4c first with HCl/dioxane followed
by Hunig’s base gave compound 23, which was identical
with the compound obtained when 4b was treated with
HCl/dioxane followed by Hunig’s base (Scheme 6). Like
4d, 4c underwent epimerization at the bridgehead posi-
tion during the deprotection reaction. However, when 4c
was treated with HCl/dioxane followed by treatment with
NH3 overnight two compounds were formed. One com-
pound corresponded to the epimerized bridgehead spe-
cies, 23. The second compound showed a molecular ion
peak in the mass spectrum that was the same as that
for 23, but the NMR was different than that for either
22 or 23. This suggested that the 3′ position also might
have epimerized during the treatment with ammonia. A
significant NOE between the bridgehead hydrogen and
the 3′-hydrogen indicated a syn relationship. On the basis
of these observations the structure of this product was
tentatively assigned to be 24 (Scheme 7).
derivative of 4b to Boc-Pro-OH gave 19b in a 75% yield.
The 1H NMR spectrum of 19b also showed the presence
of rotamers about the carbamate bond in the ratio of 9:1.
Transformation of 19a and 19b to the corresponding
carboxamides 20a and 20b was smoothly achieved in 81%
and 78% yields, respectively, with a saturated solution
of NH3 in MeOH. Deprotection of 20a and 20b gave the
PLG peptidomimetics 21a and 21b, respectively.
When either 4c or 4d was Boc-deprotected with HCl/
dioxane and the corresponding HCl salts then coupled
to Boc-Pro-OH with Mukaiyama’s reagent in the presence
of Hunig’s base, the expected peptidomimetics were not
obtained. Rather, 4c was found to yield 19b, while 4d
gave 19a. These results indicated that epimerization of
the bridgehead carbon occurred during the deprotection
and coupling sequence of the reactions.
To explore further the epimerization of the spiro bicy-
clic lactam scaffolds possessing an S stereochemistry at
the bridgehead carbon, 4d was treated with HCl/dioxane
and the hydrochloride salt that was obtained was neu-
tralized with different bases (Hunig’s base, Et3N, or
NaHCO3). This gave the free amine spiro bicyclic lactam
scaffold 22 (Scheme 5). This same compound was ob-
tained when 4a was subjected to the same treatment as
4d, suggesting that 4d underwent epimerization during
the acidic deprotection reaction. This was supported by
Conformational Analysis. A comparison of the tor-
sion angles of the piperidine-based spiro bicyclic lactam
scaffolds 4a, 20a, and 20b described in this paper with
(19) Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J.
R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.;
Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian 03, revision A.1; Gaussian, Inc.: Pittsburgh, PA, 2003.
5958 J. Org. Chem., Vol. 70, No. 15, 2005

Pipecolic Acid-Based Spiro Bicyclic Lactams
SCHEME 7
TABLE 1. Torsion Angle Comparisons of the Spiro
Bicyclic Lactam Scaffolds
FIGURE 5. ORTEP representation of the X-ray structure of
20a at the 50% probability level for non-hydrogen atoms with
the crystallographic numbering system.
system
φ2
ψ2
φ3
ψ3
ideal type II â-turn -60 ( 30 120 ( 30 80 ( 30 0 ( 30
5.5.5 (1)a
-40.3
-48.9
-56.0
-47.4
-41.8
50.1
108.1
134.1
133.7
131.2
117.0
-146.9
77.7
-16.7
-29.8
-19.9
-121.2
-11.2
-167.5
5.5.6 (2)b
116.0
97.3
5.6.5 (3)b
6.5.5 (4a)c
6.5.5 (20a)c
6.5.5 (20b)c
115.6
102.5
121.3
a Data for the 5.5.5 spiro bicyclic lactam scaffold are from ref 8.
b Data for the 5.5.6 and 5.6.5 spiro bicyclic lactam scaffolds are
from ref 10. c Data for this 6.5.5 spiro bicyclic lactam scaffold are
derived from the X-ray structure.
the corresponding pyrrolidine-based spiro bicyclic lactam
scaffolds described by us previously8,10 is summarized in
Table 1. The torsion angles for the 6.5.5 spiro bicyclic
lactams 4a, 20a, and 20b were obtained from their X-ray
structures, which are shown in Figures 3, 5, and 4,
respectively. In the case of 4a and 20a, which possess
the 6.5.5 spiro bicyclic lactam scaffold with the 3′S,6′R,7′aR
stereochemistry, the φ2, ψ2, and φ3 torsion angles were
found to be constrained close to the values found in an
ideal type II â-turn. An overlay of the X-ray structure of
20a with Pro-Leu-Gly-NH2 (PLG) in its type II â-turn
conformation (Figure 6) gave an RMS deviation of 0.37
Å, thereby illustrating the ability of the 6.5.5 spiro
bicyclic lactam scaffold with the 3′S,6′R,7′aR stereochem-
istry to mimic a type II â-turn. Although both 4a and
20a contain the same spiro bicyclic lactam scaffold,
differences of up to 14° were observed between the two
compounds in the values of the constrained torsion angles
indicating that there is some degree of flexibility in the
6.5.5 scaffold.
In the case of 20a wherein the 3′-carboxyl moiety was
in the form of a carboxamide, the N‚‚‚O distance of 3.125
Å seen in the X-ray structure (Figure 5) indicated the
presence of a hydrogen bond between the trans carbox-
amide hydrogen and the carbonyl of the N-terminal prolyl
residue.3a The presence of such a hydrogen bond also was
supported in H1 NMR studies. The 1H NMR spectrum of
20a in the non-hydrogen bonding solvent CDCl3 showed
a high downfield shift for one of the carboxamide hydro-
gens (δ 7.7 ppm) suggesting its participation in an
intramolecular hydrogen bond. The chemical shift for the
suspected non-H-bonded hydrogen was 5.5 ppm. Also, the
low value of the temperature coefficient for downfield
hydrogen (∆δ/∆T ) 0.28 ppb/K) suggested that this
hydrogen was involved in a hydrogen-bonded conforma-
tion.20 Furthermore, 1H NMR titration studies with
DMSO-d6, which were carried out by the sequential
FIGURE 6. Overlay of the X-ray structure of peptidomimetic
20a (maroon) and Pro-Leu-Gly-NH2 (PLG) in an ideal type II
â-turn (green). The superimposition was carried out with
Insight II by calculating the best fit for the 10 backbone atoms
(RMS ) 0.37 Å). For clarity, the hydrogens of 20a and PLG
and the Boc group of 20a have not been included.
addition of 50 µL of DMSO-d6 each time to 10 mg of 20a
in 500 µL of CDCl3 up to a total of 300 µL of DMSO-d6,
resulted in a gradual disruption of the intramolecular
hydrogen bond, ultimately rendering the two carboxam-
ide protons equivalent (δ 6.5 ppm).
Compound 20b showed no hydrogen bonding between
the 3′-carboxamide hydrogens and the prolyl carbonyl in
the X-ray structure. The torsion angles observed for 20b
(Table 1) clearly show that it does not exist in a â-turn.
Instead, the φ2 and ψ2 torsion angels for 20b were found
to be similar to the values that are observed for a right-
handed poly-D-proline II helix (75° and -145° respec-
tively for φ and ψ).21 An overlay of seven backbone atoms
from the X-ray crystal structure of 20b with the corre-
sponding atoms of an energy minimized structure of
D-Pro-D-Pro-D-Pro-NH2 in a poly-D-prolyl II helix (Figure
7) gave an RMS deviation of 0.24 Å.
Conclusion
In summary, this report describes the first synthesis
and characterization of a series of pipecolic acid-based
(20) (a) Belvisi, L.; Gennari, A.; Mielgo, D.; Potenza, C.; Scolastico.
C. Eur. J. Org. Chem. 1999, 389-400. (b) Belvisi, L.; Bernardi, A.;
Manzoni, L.; Potenza, D.; Scolastico, C. Eur. J. Org. Chem. 2000, 2563-
2569.
(21) Adzhubei, A. A.; Sternberg, M. J. E. J. Mol. Biol. 1993, 229,
472-493.
J. Org. Chem, Vol. 70, No. 15, 2005 5959

Somu and Johnson
7 (7.1 g, 31.0 mmol) in dry THF (30 mL) was added dropwise
over a period of 20 min. The resulting yellowish solution was
stirred for 40 min and then allyl bromide (5.36 mL, 62.0 mmol)
was added dropwise. The reaction mixture was stirred for 24
h to give a colorless solution. The pH of the solution was
adjusted to 2.5 with 3 N HCl. The organic layer was separated
and extracted with saturated NaHCO3 solution. The aqueous
layer was acidified with 3 N HCl to pH 2, saturated with
sodium chloride, and then extracted with EtOAc (3 × 50 mL).
The combined extracts were dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure to give 8 as
a light yellow oil in a 90% yield. This material was used
directly for the next reaction without further purification. 1H
NMR (300 MHz, CDCl3) δ 11.0 (br s, 1H), 5.80-6.0 (m, 1H),
5.02-5.20 (m, 2H), 3.88 (dt, 1H, J ) 12.9 Hz), 2.94-3.10 (m,
1H), 2.86 (dd, 1H, J ) 7.2 and 13.8 Hz), 1.43 (s, 9H), 2.62 (dd,
1H, J ) 7.2 and 13.8 Hz), 1.50-2.0 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 180.7, 155.5, 134.1, 118.6, 81.2, 62.7, 41.2, 38.8, 32.1,
28.6, 23.1, 17.8; HRMS (ESI) m/z 292.1524, C14H23NO4 + Na+
[M + Na]+ requires 292.1520.
N-tert-Butoxycarbonyl-2-allylpipecolic Acid Methyl
Ester (9). To a solution of 8 (2.0 g, 7.4 mmol) in dry Et2O (40
mL) at 0 °C was added an Et2O solution of diazomethane until
the evolution of gas ceased. The reaction mixture then was
stirred for an additional 1 h. The reaction was stripped of
solvent and excess reagent under reduced pressure to give 9
as pale yellow oil in a 98% yield. An analytically pure sample
for spectral analysis was obtained by purification through flash
chromatography with EtOAc and hexanes (1:10). 1H NMR (300
MHz, CDCl3) δ 5.82-6.02 (m, 1H), 5.0-5.14 (m, 2H), 3.87 (br
d, 1H, J ) 12.9 Hz), 3.71(s, 3H), 2.99 (m, 1H), 2.82 (dd, 1H, J
) 7.5 and 13.8 Hz), 2.61 (dd, 1H, J ) 7.5 and 13.8 Hz), 1.46-
1.92 (m, 6H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 174.9,
155.5, 134.4, 118.3, 80.6, 62.8, 52.2, 41.3, 38.9, 32.1, 28.6, 23.3,
18.1; HRMS (ESI) m/z 306.1682, C15H25NO4 + Na+ [M + Na]+
requires 306.1681.
N-tert-Butoxycarbonyl-2-(2-oxoethyl)pipecolic Acid
Methyl Ester (11): Method A. Methyl ester 9 (1.9 g, 6.7
mmol) was placed in a mixture of THF and water (4:1, 115
mL). To this solution was added a tert-butyl alcohol solution
of OsO4 (2.5 wt %, 3.46 mL, 0.34 mmol) dropwise. After the
reaction was stirred for 5 min, NaIO4 was added in several
portions. The reaction mixture was stirred overnight. The
solids that formed were removed by gravity filtration and the
clear filtrate was concentrated to one-fourth of its volume after
which time it was extracted with EtOAc (3 × 75 mL). The
combined organic layers were dried over Na2SO4 and then were
concentrated under vacuum to give a brown oil, which upon
purification by silica gel chromatography gave 0.64 g of
aldehyde 11 (33%) along with 0.60 g of intermediate diol 10
(31%).
Method B. In a modified procedure, 9 (0.5 g, 1.77 mmol)
was placed in a mixture of THF and water (4:1, 20 mL) to
which was added a tert-butyl alcohol solution of OsO4 (2.5 wt
%, 0.87 mL, 0.09 mmol) followed by the addition of N-
methylmorpholine oxide (NMO, 50% aqueous solution, 0.72
g, 2.6 mmol). The reaction was stirred overnight, and then it
was quenched with a saturated solution of Na2SO3 (15 mL).
The reaction was concentrated to remove THF and the aqueous
fraction was extracted with EtOAc (3 × 50 mL). The combined
EtOAc fractions were washed with 10% citric acid and then
dried over Na2SO4. Removal of the EtOAc gave a mixture of
diastereomeric diols (10) as a pale brown thick syrup (0.52 g,
93%). MS (ESI) m/z 340.2 [M + Na]+.
FIGURE 7. Overlay of the X-ray structure of peptidomimetic
20b (maroon) and D-Pro-D-Pro-D-Pro-NH2 in a right-handed
poly-D-proline II type helix (green). The superimposition was
carried out with Insight II by calculating the best fit for the
seven backbone atoms (RMS ) 0.24 Å). For clarity, the
hydrogens of 20b and D-Pro-D-Pro-D-Pro-NH2 and the Boc
group of 20b have not been included.
spiro bicyclic lactam scaffolds as potential â-turn mimics.
X-ray studies showed that the system possessing the
3′S,6′R,7′aR stereochemistry (20a) was capable of mim-
icking a type II â-turn, while the system possessing the
3′S,6′S,7′aR stereochemistry (20b) mimicked a right-
handed poly-D-proline II helix. This work extends our
efforts to determine the effect that alterations in ring size
have on the torsion angles that are constrained by these
novel and highly conformationally constrained scaffolds.
Experimental Section
Ab Initio Calculations. Ab initio calculations were carried
out with the Gaussian 0319 suite of programs at the Hartree-
Fock level of theory. Initial optimizations were conducted at
the level of HF/STO-3G and further optimized sequentially at
the HF/3-21G** and HF/6-31G* levels. Characterization of
stationary points as minima was done by harmonic vibrational
frequency analysis of analytic second derivative at each level.
Single-point energies were calculated at the 6-31G* level22 by
enforcing Tight convergence of the wave function for the more
accurate energies.
N-(tert-Butoxycarbonyl)-DL-pipecolic Acid (7). DL-Pipe-
colic acid (5 g, 38.7 mmol) and tetramethylammonium hydrox-
ide pentahydrate (TMAH, 7.02 g, 38.7 mmol) were suspended
in CH3CN. The mixture was stirred at room temperature until
a solution was obtained. (Boc)2O (12.7 g, 58.0 mmol) was then
added and the reaction was stirred for a day. On the second
day, additional (Boc)2O (4.2 g, 19.4 mmol) was added and the
mixture was stirred for another day. The CH3CN was removed
under reduced pressure and the white solid obtained was
partitioned between H2O (100 mL) and Et2O (50 mL). The
aqueous layer was reduced to one-third of its volume under
reduced pressure and then was acidified with solid NaHSO4
until the pH of the solution was between 3 and 4. The aqueous
layer was extracted with EtOAc (2 × 100 mL). The combined
organic extracts were dried (Na2SO4) and then concentrated
to give 7 as a white solid in a 95% yield. Mp 128-130 °C (lit.23
mp 130-131 °C). 1H and 13C NMR spectra matched the
previously reported data.23
N-tert-Butoxycarbonyl-2-allyl-DL-pipecolic Acid (8). To
an ice-chilled solution of diisopropylamine (10.9 mL, 77.5
mmol) in dry THF (55 mL) was added slowly under N2
n-butyllithium (38.5 mL of a 2.0 M solution in n-hexane, 77.5
mmol). After the mixture was stirred for 30 min, a solution of
To a solution of 10 (0.52 g, 1.64 mmol) in dichloromethane
(25 mL) was added NaIO4 adsorbed onto silica gel (3.28 g, 2.0
g of reagent/mmol of diol). The reaction was stirred for 20 min
and then it was filtered through a sintered glass funnel. The
silica gel was washed with CHCl3 (3 × 20 mL) and the
combined organic layers were concentrated to give a quantita-
tive yield of 11. 1H NMR (300 MHz, CDCl3) δ 9.88 (t, 1H, J )
2.7 Hz), 3.85 (dt, 1H, J ) 3.6 and 13.8 Hz), 3.75 (s, 3H), 3.04
(22) A detailed description of methods, basis sets, and standard
computational methods can be found in: Forceman, J. B.; Frisch, A.
E. Exploring Chemistry with Electronic Structure Methods, 2nd ed.;
Gaussian Inc.: Pittsburgh, PA, 1996.
(23) Heller, B.; Sundermann, B.; Buschmann, H.-J.; Drexler, H.;
You, J.; Holzgrabe, U.; Heller, E.; Oehme, G. J. Org. Chem. 2002, 67,
4414-4422.
5960 J. Org. Chem., Vol. 70, No. 15, 2005

Pipecolic Acid-Based Spiro Bicyclic Lactams
(ddd, 1H, J ) 3.6, 10.2, and 13.8 Hz), 2.80-2.94 (m, 2H), 1.46-
1.98 (m, 6H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 200.5,
174.2 and 171.7, 155.6, 81.4 and 81.6, 62.7 and 62.0, 52.7 and
53.2, 46.4, 41.5, 33.7 and 31.9, 28.5 and 28.2, 23.8, 18.5; MS
(ESI) m/z 308.1 [M + Na]+; HRMS (ESI) m/z 286.1644, C14H23-
NO5 + H+ [M + H]+ requires 286.1649.
(2RS,4S)-2-[[2′-(RS)-N-(tert-Butoxycarbonyl)-2′-carb-
methoxypiperidinyl]methyl]thiazolidine-4-carboxylic
Acid (12). D-Cysteine‚HCl (0.35 g, 2.0 mmol) was dissolved
in H2O (3 mL). NaOH (80 mg, 2.0 mmol) in H2O (3 mL) was
added to the solution followed by a solution of 11 (0.6 g, 2.11
mmol) in 95% EtOH (8.5 mL). The reaction mixture was stirred
overnight at room temperature and then it was concentrated
under reduced pressure. The white solid that was obtained
was partitioned between H2O and EtOAc. The aqueous layer
was extracted with EtOAc (2 × 50 mL). The combined organic
layers were dried over anhydrous Na2SO4 and the solvent was
removed in vacuo to give 12 in the form of a white solid and
as a mixture of diastereomers (0.7 g, 88%). Mp 77-79 °C; MS
(ESI) m/z 411.2 [M + Na]+; HRMS (ESI) m/z 389.1745,
C17H28N2O6S + H+ [M + H]+ requires 389.1741.
(2RS,4S)-2-[[2′-(RS)-N-(tert-Butoxycarbonyl)-2′-carb-
methoxypiperidinyl]methyl]thiazolidine-4-carboxylic
Acid Methyl Ester (13). To the suspension 11 (0.45 g, 1.58
mmol) in H2O (5.0 mL) at 0 °C was added solid NaHCO3 (0.13
g, 1.58 mmol) and EtOH (5.0 mL) followed by the addition of
D-cysteine methyl ester‚HCl (0.27 g, 1.58 mmol) in one portion.
The pH of the reaction mixture was adjusted to ca. 7 with 10%
NaHCO3 and the reaction was warmed to room temperature.
The reaction was stirred for 16 h and the solvents then were
removed under vacuum. The residue obtained was dissolved
in H2O (15.0 mL), which was extracted with EtOAc (2 × 35
mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated to a light yellow oil, which was
passed through a small silica gel column with 40% EtOAc in
hexanes to give 0.5 g (81.5%) of 13 as a mixture of diastere-
oisomers. HRMS (ESI) m/z 403.1892, C18H30N2O6S + H+ [M
+ H]+ requires 403.1903.
Na2SO4 and it was concentrated to give a mixture of diaster-
eomeric diols as a pale brown thick syrup (5.09 g, 99%). HRMS
(ESI) m/z 416.2043, C21H31NO6 + Na+ [M + Na]+ requires
416.2044.
To a solution of the above diol (5.0 g, 12.9 mmol) in
dichloromethane (150 mL) was added NaIO4 adsorbed onto
silica gel (25.9 g, 2 g of reagent/mmol of diol). The reaction
was stirred for 20 min and then it was filtered through a
sintered glass funnel. The silica gel was washed with CHCl3
(3 × 30 mL). The combined organic layers were concentrated
to give 4.8 g of the crude aldehyde, which was purified by
column chromatography (EtOAc/hexanes, 1:2) to give 15 in a
1
75% yield. H NMR (300 MHz, CDCl3) δ 9.91 (t, 1H, J ) 3.0
Hz), 7.28-7.45 (m, 5H), 5.18 (dd, 2H, J ) 12.3 and 16.2 Hz),
3.84 (dt, 1H, J ) 4.2 and 13.8 Hz), 3.0-3.15 (m, 1H), 2.93 (d,
2H, J ) 3.0 Hz), 1.22-1.98 (m, 6H), 1.38 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 200.5, 173.5, 159.1, 128.8, 128.5, 128.4, 100.4,
67.5, 62.8, 46.6, 41.7, 33.8, 28.5, 23.8, 18.5; HRMS (ESI) m/z
384.1775, C20H27NO5 + Na+ [M + Na]+ requires 384.1782.
3-Hydroxy-1-oxo-2-oxa-6-(N-tert-butoxycarbonyl)-
azaspiro[4.5]decane (17). To a flask containing 15 (2.0 g,
5.54 mmol) dissolved in benzene (40 mL) was added 10% Pd/C
(0.40 g, 20 mol % by wt). The mixture was stirred vigorously
under a hydrogen atmosphere overnight. The reaction mixture
was filtered through a plug of Celite, which was then washed
copiously with EtOAc. The combined filtrates were concen-
trated to give the corresponding debenzylated product 16,
which spontaneously cyclized to the corresponding hydroxy
lactone 17. Mp 147-150 °C; IR (film) 1694, 1775, 3380 (br)
cm-1 13C NMR (75 MHz, CDCl3) δ 96.1 (OCHOH); HRMS
;
(ESI) m/z 294.1306, C13H21NO5 + Na+ [M + Na]+ requires
294.1312.
(2RS,4S)-2-[[2′-(RS)-N-(tert-Butoxycarbonyl)-2′-car-
boxypiperidinyl]methyl]thiazolidine-4-carboxylic Acid
Methyl Ester (18). To the suspension of 17 (5.7 g, 21.0 mmol)
in H2O (57.0 mL) at 0 °C was added solid NaHCO3 (1.76 g,
31.0 mmol) and ethanol (57 mL) followed by the addition of
D-cysteine methyl ester‚HCl (3.61 g, 21.0 mmol) in one portion.
The pH of the reaction mixture was adjusted to ca. 7 with 10%
NaHCO3 and the reaction was warmed to room temperature.
The reaction was stirred for 16 h and the solvents were
removed under vacuum. The resulting residue was dissolved
in H2O (50 mL) and this solution was extracted with EtOAc
(2 × 100 mL). The pH of the aqueous layer was adjusted to 6
with 1 N HCl and then it was extracted with more EtOAc. To
facilitate the partitioning of the thiazolidine product into the
organic solvent, the aqueous layer was saturated with solid
NaCl and then it was extracted with CHCl3. This process was
repeated three times with readjustment of the pH to 6 between
extractions. The combined organic layers were dried over
anhydrous Na2SO4 and then they were concentrated to give
the diastereomeric mixture of crude thiazolidines as an off
white foam (6.0 g, 75%). MS (ESI) m/z 411.2 (M + Na)+; HRMS
(ESI) m/z 389.1730, C17H28N2O6S + H+ [M + H]+ requires
389.1741.
Methyl (3′S,6′R,7′aR)-, (3′S,6′S,7′aR)-, (3′S,6′S,7′aS)-,
or (3′S,6′R,7′aS)-1-(tert-Butoxycarbonyl)tetrahydro-5′-
oxospiro[piperidine-2,6′-pyrrolo[2,1-b]thiazolidine]-3′-
carboxylate (4a-d). To a solution of the thiazolidine mixture
18 (3.0 g, 7.73 mmol) in freshly distilled CH2Cl2 (550 mL) was
added 2-chloro-1-methylpyridinium iodide (2.17 g, 8.5 mmol)
followed by Et3N (2.37 mL, 17.0 mmol). The resulting pale
yellow solution was heated at reflux for 8 h under an Ar
atmosphere. The reaction mixture was cooled to room tem-
perature and then it was extracted with 10% citric acid, 1 N
NaHCO3, and brine. The CH2Cl2 layer was dried over anhy-
drous Na2SO4 and subsequent removal of solvent gave a
mixture of four diastereomers, 4a-d, as a thick yellow oil (TLC
(EtOAc/hexanes, 1:1) Rf 0.75, 0.58, 0.51 and 0.48), along with
the byproduct of the Mukaiyama’s catalyst 1-methyl-1H-
pyridin-2-one. Separation of the isomers was carried out on a
Ready Sep prepacked silica gel column by eluting with EtOAc/
N-tert-Butoxycarbonyl-2-allylpipecolic Acid Benzyl
Ester (14). To a solution of 8 (3.5 g, 13.0 mmol) in benzene
(50 mL) at 0 °C was added 1,8-diazabicyclo[5.4.0]undec-7-ene
(1.94 mL, 13.0 mmol), followed by the dropwise addition of
benzyl bromide (1.55 mL, 14.3 mmol). A white precipitate
appeared after ca. 10 min. The mixture was refluxed for 3 h
after which time the reaction mixture was cooled to room
temperature where it was filtered to remove the precipitate.
The residue was washed with benzene and EtOAc and the
combined filtrates were washed with H2O, 10% citric acid, 5%
NaHCO3, and finally again with H2O. The organic layer was
dried over Na2SO4 and it was concentrated to give 14 in a
quantitative yield as a pale brown oil. An analytically pure
sample for spectral analyses was prepared by purification
through flash chromatography with EtOAc/hexanes (1:19) as
1
the eluting solvent. H NMR (300 MHz, CDCl3) δ 7.22-7.37
(m, 5H), 5.87-6.01 (m, 1H), 4.99-5.30 (m, 4H), 3.85 (m, 1H),
2.98-3.08 (m, 1H), 2.92 (dd, 1H, J ) 6.8 and 13.2 Hz), 2.64
(dd, 1H, J ) 7.2 and 13.2 Hz), 1.47-1.91 (m, 6H), 1.40 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 174.3, 155.5, 134.4, 128.6, 128.3,
128.2, 127.8, 118.4, 80.6, 66.9, 62.9, 41.4, 39.3, 32.1, 28.7, 23.2,
18.0; HRMS (ESI) m/z 382.1993, C21H29NO4 + Na+ [M + Na]+
requires 382.1989.
N-tert-Butoxycarbonyl-2-(2-oxoethyl)pipecolic Acid
Benzyl Ester (15). Benzyl ester 14 (4.7 g, 13.1 mmol) was
placed in a mixture of THF and H2O (4:1, 100 mL). To this
solution was added a tert-butyl alcohol solution of OsO4 (2.5
wt %, 6 mL, 0.3 mmol) followed by the addition of N-
methylmorpholine oxide (50% aqueous solution, 5.3 g, 19.6
mmol). The reaction was stirred overnight and then it was
quenched with a saturated solution of Na2SO3 (15 mL). The
reaction mixture was concentrated to remove THF. The residue
was extracted with EtOAc, which then was washed with 10%
citric acid, followed by H2O. The organic layer was dried over
J. Org. Chem, Vol. 70, No. 15, 2005 5961

Somu and Johnson
hexanes (1:3). Isomer 4a was obtained as a white solid (18%),
which on recrystallization from hot hexane gave long white
needles. Further elution gave isomer 4b as a thick syrup (21%)
followed by isomers 4c (12%) and 4d (10%) with each of the
latter two contaminated with the byproduct of Mukaiyama’s
catalyst.
base (204 µL, 1.17 mmol). The reaction mixture was stirred
overnight under an inert atmosphere after which time it was
concentrated to remove excess DMF. EtOAc was added to the
residue and the mixture was filtered to remove the undissolved
solids. The filtrate was dried over anhydrous Na2SO4 and then
it was concentrated. The residue was purified by silica gel
Isomer 4a: mp 116-119 °C; [R]20D +108.5 (c 0.69, CHCl3);
1H NMR (300 MHz, CDCl3) δ 5.28 (d, 1H, J ) 7.5 Hz), 5.13
(dd, 1H, J ) 3.3 and 7.5 Hz), 3.90 (dt, 1H, J ) 4.2 and 12.9
Hz), 3.29 (dd, 1H, J ) 3.6 and 11.1 Hz), 3.71 (s, 3H), 3.22 (dd,
1H, J ) 7.5 and 11.1 Hz), 2.83 (ddd, 1H, J ) 4.2, 10.2, and
13.2 Hz), 2.44 (d, 1H, J ) 13.8 Hz), 2.32 (dd, 1H, J ) 7.8 and
13.8 Hz), 1.38 (s, 9H), 1.55-1.82 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 177.9, 170.3, 155.1, 81.6, 63.2, 62.8, 59.4, 52.9, 42.8,
36.4, 34.5, 32.9, 28.5, 24.0, 18.9; HRMS (ESI) m/z 393.1458,
C17H26N2O5S + Na+ [M + Na]+ requires 393.1455. Anal. Calcd
for C17H26N2O5S: C, 55.12; H, 7.07; N, 7.56; S, 8.66. Found:
C, 55.26; H, 7.14; N, 7.68; S, 8.46.
chromatography with 2% MeOH in EtOAc to give 64 mg (70%)
1
of 19a as a glassy syrup. [R]20 + 65.1 (c 2.2, CHCl3). H and
D
13C NMR showed the presence of rotamers about the carbam-
ate bond in a ratio of 7:3. H NMR (300 MHz, CDCl3) δ 5.11
1
(m, 1H) and 5.31 (m, 1H), 4.51 and 4.57 (dd, 1H, J ) 3.3 and
8.0 Hz), 3.75 and 3.82 (m, 1H), 3.71 and 3.72 (s, 3H), 3.16-
3.56 (m, 5H), 2.52 (m, 1H), 2.35 (m, 1H), 1.48-2.2 (m, 10H),
1.37 and 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 177.3 and
176.6, 174.3 and 173.4, 170.5 and 170.4, 154.8 and 153.8, 79.7
and 79.6, 63.3 and 63.2, 63.0, 59.3 and 59.1, 57.2 and 56.7,
53.2 and 53.1, 47.2 and 46.9, 43.2 and 44.2, 36.3, 33.8 and 33.5,
33.4 and 33.0, 31.1 and 30.4, 28.9 and 28.8, 24.8 and 23.9, 24.1
and 23.7, 18.6 and 18.0; HRMS (ESI) m/z 490.1991, C22H33-
N3O6S + Na+ [M + Na]+ requires 490.1983.
Isomer 4b: [R]20D +262.2 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 5.18 (br s, 1H), 5.02 (t, 1H, J ) 6.9 Hz), 3.84 (dt, 1H,
J ) 4.2 and 12.6 Hz), 3.69 (s, 3H), 3.48 (dd, 1H, J ) 7.2 and
10.5 Hz), 3.25 (dd, 1H, J ) 1.8 and 10.8 Hz), 2.79 (m, 1H),
2.67 (dd, 1H, J ) 7.2 and 12.3 Hz), 2.19 (dd, 1 H, J ) 6.6 and
12.3 Hz), 1.50-1.90 (m, 6H), 1.36 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 174.6, 170.3, 155.6, 81.0, 65.5, 61.1, 58.9, 53.0, 43.2,
39.0, 35.3, 32.8, 28.6, 23.8, 19.4; HRMS (ESI) m/z 393.1439,
C17H26N2O5S + Na+ [M + Na]+ requires 393.1455. Anal. Calcd
for C17H26N2O5S: C, 55.12; H, 7.07; N, 7.56; S, 8.66. Found:
C, 55.27; H, 7.20; N, 7.40; S, 8.41.
Methyl [3′S,6′S,7′aR]-1-[[1-(tert-Butoxycarbonyl)-2-(S)-
pyrrolidinyl]carbonyl]tetrahydro-5′-oxospiro[piperidine-
2,6′-pyrrolo[2,1-b]thiazolidine]-3′-carboxylate (19b). Com-
pound 4b (40 mg, 0.11 mmol) was treated with 4 N HCl in
dioxane (2 mL) under Ar for 3 h. Solvent and excess HCl were
removed under vacuum. The white solid obtained was thor-
oughly dried and used for the coupling reaction. The amine
HCl salt (30 mg, 0.098 mmol) was dissolved in dry DMF (3.0
mL). Mukaiyama’s catalyst (63.0 mg, 0.24 mmol) was added
followed by the addition of Boc-L-Pro-OH (53 mg, 0.24 mmol)
and Hunig’s base (102 µL, 0.58 mmol). The reaction mixture
was stirred overnight under an Ar atmosphere. The reaction
was worked up as described for 19a. Column chromatographic
purification afforded 34.5 mg (75.5%) of pure 19b. [R]20D +5.7
(c 2.52, CHCl3). 1H and 13C NMR showed the presence of
rotamers about the carbamate bond in a ratio of 9:1. 1H NMR
(300 MHz, CDCl3) δ 5.19 (d, 1H, J ) 6.0 Hz), 5.05 (t, 1H, J )
7.2 Hz), 4.47 (dd, 0.9H, J ) 3.9 and 8.7 Hz) and 4.64 (br d,
0.1H), 3.62 (s, 3H), 3.7 (m, 1H), 3.51 (dd, 1H, J ) 6.9 and 10.5
Hz), 3.32-3.48 (m, 3H), 3.19 (dd, 1H, J ) 1.2 and 10.5 Hz),
3.04 (dt, 1H, J ) 6.9 and 12.9 Hz), 2.61 (dd, 1H, J ) 7.5 and
12.9 Hz), 2.15 (dd, 1H, J ) 6.3 and 12.9 Hz), 1.62-2.12 (m,
9H), 1.37 and 1.41 (s, 9H). 13C NMR (75 MHz, CDCl3, major
rotamer) δ 173.8, 172.4, 170.4, 154.3, 80.5, 64.8, 60.8, 59.9,
57.9, 52.9, 46.7, 42.6, 40.3, 34.8, 31.9, 30.0, 28.3, 23.9, 23.8,
18.2; HRMS (ESI) m/z 490.1979, C22H33N3O6S + Na+ [M +
Na]+ requires 490.1983. Anal. Calcd for C22H33N3O6S: C, 56.51;
H, 7.11; N, 8.99; S, 6.86. Found: C, 56.60; H, 6.94; N, 8.68; S,
6.47.
Isomer 4c: 1H NMR (300 MHz, CDCl3) δ 5.17 (t, 1H, J )
6.0 Hz), 4.32 (d, 1H, J ) 6.9 Hz), 3.90 (dt, 1 H, J ) 4.2 and
13.5 Hz), 3.76 (s, 3H), 3.57 (dd, 1 H, J ) 7.5 and 12.6 Hz),
3.33 (dd, 1H, J ) 2.4 and 12.6 Hz), 2.8-2.9 (m, 1H), 2.20-
2.45 (m, 2H), 1.60-2.10 (m, 6H), 1.43 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 173.5, 169.3, 155.5, 81.2, 65.7, 64.8, 57.2, 52.9,
42.9, 39.0, 35.8, 34.8, 28.6, 24.1, 18.8; MS (ESI) m/z 393.2 [M
+ Na]+; HRMS (ESI) m/z 371.1648, C17H26O5N2S + H+ [M +
H]+ requires 371.1656.
Isomer 4d: 1H NMR (300 MHz, CDCl3) δ 4.91 (t, 1H, J )
6.9 Hz), 3.99 (t, 1H, J ) 6.9 Hz), 3.7-3.7 (m, 1H), 3.79 (s, 3H),
3.53 (dd, 1H, J ) 7.2 and 11.1 Hz), 3.27 (dd, 1 H, J ) 6.6 and
11.1 Hz), 2.90-3.10 (m, 1H), 2.53 (d, 1H, J ) 7.2 Hz), 1.55-
1.95 (m, 6H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 175.0,
168.2, 155.2, 80.9, 66.1, 62.1, 59.2, 52.9, 42.5, 37.5, 36.1, 32.1,
28.7, 23.6, 18.6; MS (ESI) m/z 393.2 [M + Na]+; HRMS (ESI)
m/z 393.1452, C17H26O5N2S + Na+ [M + Na]+ requires 393.1455.
Methyl [3′S,6′R,7′aR]-1-[[1-(tert-Butoxycarbonyl)-2(S)-
pyrrolidinyl]carbonyl]tetrahydro-5′-oxospiro[piperidine-
2,6′-pyrrolo[2,1-b]thiazolidine]-3′-carboxylate (19a). Com-
pound 4a (0.1 g, 0.27 mmol) was treated with 4 N HCl in
dioxane under Ar for 3 h. Solvent and excess HCl were
removed under vacuum. The white solid obtained was thor-
oughly dried and used for the following coupling reaction.
Method A. The amine HCl salt (83 mg, 0.27 mmol) was
dissolved in dry DMF (3 mL) and to this solution was added
Boc-L-Pro-OH (0.40 mg, 1.9 mmol), DCC (390 mg, 1.9 mmol),
and HOBt‚H2O (255 mg, 1.9 mmol) followed by triethylamine
(56 µL, 0.27 mmol). The reaction mixture was stirred under
an Ar atmosphere for 4 days. The excess DMF was removed
under reduced pressure and the residue remaining was
dissolved in EtOAc. The solution was filtered to remove the
undissolved solids and the filtrate was washed successively
with 1 N NaHCO3, H2O, 10% citric acid, 1 N NaHCO3, H2O,
and finally brine. The organic layer was dried over Na2SO4
and then it was evaporated under reduced pressure to give
the crude product. This material was chromatographed on a
silica gel column with 2% MeOH in EtOAc to give 55 mg (50%)
of 19a as a thick glassy syrup.
[3′S,6′R,7′aR]-1-[[(1-tert-Butoxycarbonyl)-2(S)-pyrro-
lidinyl]carbonyl]tetrahydro-5′-oxospiro[piperidine-2,6′-
pyrrolo[2,1-b]thiazolidine]-3′-carboxamide (20a). Spiro
bicyclic ester 19a (55 mg, 0.12 mmol) was treated with a
saturated solution of NH3 (prepared by bubbling a stream of
NH3 into MeOH at -78 °C for about 15 min). The reaction
mixture was closed with a balloon and the flask was warmed
to room temperature where it was stirred until the reaction
was complete. After about 8 h, Ar was bubbled through the
reaction mixture to remove the excess NH3. The solution was
concentrated to give crude 20a, which upon purification by
silica gel chromatography with 2-5% MeOH in EtOAc as the
eluting solvent gave 43 mg (81%) of 20a. Mp 226-228 °C; [R]20
D
1
+56.1 (c 2.31, CHCl3). H and 13C NMR showed the presence
of rotamers about the carbamate bond in a ratio of 7:3. 1H
NMR (300 MHz, CDCl3) δ 7.71 and 7.28 (br s, 1H), 5.5 (br s,
1H), 5.05 (m, 1H), 4.8 (dd, 1H, J ) 5.1 and 8.4 Hz), 4.5-4.65
(m, 1H), 3.8 (m, 1H), 3.10-3.66 (m, 5H), 2.43 (dd, 0.3H, J )
7.8 and 13.8 Hz) and 2.59 (dd, 0.7H, J ) 7.8 and 13.8 Hz),
2.20 (dd, 0.7H, J ) 3.9 and 14.1 Hz) and 2.31 (dd, 0.3H, J )
3.9 and 14.1 Hz), 1.46-2.16 (m, 10H), 1.35 and 1.38 (s, 9H).
13C NMR (75 MHz, CDCl3) δ 174.6 and 174.1, 173.7 and 173.3,
172.3 and172.0, 153.8 and 154.6, 79.8 and 79.7, 65.3 and 64.9,
Method B. The amine HCl salt (60 mg, 0.195 mmol) was
dissolved in dry DMF (5.0 mL). To this solution was added
Mukaiyama’s catalyst (124 mg, 0.49 mmol) followed by the
addition of Boc-L-Pro-OH (105 mg, 0.49 mmol) and Hunig’s
5962 J. Org. Chem., Vol. 70, No. 15, 2005

Pipecolic Acid-Based Spiro Bicyclic Lactams
62.7 and 62.5, 57.8 and 57.7, 57.1 and 57.6, 44.2 and 46.8, 35.0
and 34.4, 36.2 and 36.4, 30.2 and 31.1, 28.8 and 28.9, 24.8 and
23.9, 24.3 and 23.6, 18.7 and 18.1; HRMS (ESI) m/z 475.2000,
C21H32N4O5S + Na+ [M + Na]+ requires 475.1986. Anal. Calcd
for C21H32N4O5S: C, 55.73; H, 7.13; N, 12.38; S, 7.09. Found:
C, 55.43; H, 6.90; N, 12.38; S, 6.71.
were removed under vacuum to give 22‚HCl. [R]20 + 180 (c
D
0.31, MeOH); 1H NMR (300 MHz, MeOH-d4) δ 5.29 (dd, 1H, J
) 2.4 and 7.5 Hz), 5.07(dd, 1H, J ) 5.1 and 8.4 Hz), 3.79 (s,
3H), 3.62 (dd, 1H, J ) 8.7 and 11.7 Hz), 3.46 (dd, 1 H, J ) 5.1
and 11.7 Hz), 3.39 (dt, 1H, J ) 2.4 and 12.9 Hz), 3.1-3.24 (m,
1H), 2.81 (dd, 1 H, J ) 7.8 and 15.3 Hz), 2.63 (dd, 1H, J ) 2.4
and 15.3 Hz), 1.60-2.10 (m, 6H); 13C NMR (75 MHz, MeOH-
d4) δ 172.8, 170.8, 64.4, 63.8, 59.6, 53.5, 42.7, 37.1, 33.2, 32.5,
22.5, 18.9. The white hygroscopic solid obtained was suspended
in EtOAc and Hunig’s base was added until the pH of the
reaction mixture was basic. The reaction mixture was concen-
trated and the residue was dried thoroughly. It was purified
by column chromatography with 2% MeOH in EtOAc to give
43 mg (93%) of 22. 1H NMR (300 MHz, CDCl3) δ 5.19 (dd, 1H,
J ) 3.9 and 7.5 Hz), 5.05 (dd, 1H, J ) 4.8 and 7.2 Hz), 3.74 (s,
3H), 3.30-3.45 (m, 2H), 3.05 (dt, 1H, J ) 3.6 and 12.9 Hz),
2.66-2.78 (m, 1H), 2.57 (dd, 1H, J ) 7.2 and 13.8 Hz), 2.2
(dd, 1H, J ) 3.9 and 13.8 Hz), 1.4-2.0 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 177.1, 170.2, 63.4, 63.1, 57.8, 53.2, 42.8, 38.4,
36.5, 34.5, 26.4, 20.8; HRMS (ESI) m/z 271.1123, C12H18N2O3S
+ H+ [M + H]+ requires 271.1111.
[3′S,6′S,7′aR]-1-[[(1-tert-Butoxycarbonyl)-2(S)-pyrro-
lidinyl]carbonyl]tetrahydro-5′-oxospiro[piperidine-2,6′-
pyrrolo[2,1-b]thiazolidine]-3′-carboxamide (20b). Spiro
bicyclic ester 19b (60 mg, 0.13 mmol) was treated with 30 mL
of a saturated methanolic solution of NH3 for 8 h. Concentra-
tion followed by column purification afforded 45 mg of pure
product (77.5%) as a white solid. An analytically pure sample
was prepared by crystallization from EtOAc and Et2O. Mp
140-142 °C; [R]20 +42.6 (c 1.69, CHCl3). 1H and 13C NMR
D
showed the presence of rotamers about the carbamate bond
1
in a ratio of 7:3. H NMR (300 MHz, CDCl3) δ 6.82 and 7.06
(br s, 1H), 5.91 and 5.93 (br s, 1H), 4.98 (t, 1H, J ) 6.9 Hz),
4.82-4.88 (m, 1H), 4.48 (dd, 0.7H, J ) 3.9 and 8.4 Hz) and
4.60 (m, 0.3H), 3.28-3.62 (m, 4H), 3.03 (m, 1H), 2.62 (dd, 1H,
J ) 8.0 and 12.4 Hz), 1.59-2.4 (m, 12H), 1.39 and 1.42 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 175.2 and 175.4, 172.4 and
172.2, 172.0 and 171.7, 154.1 and 154.6, 80.4 and 80.2, 65.1
and 65.5, 61.3 and 61.7, 61.1 and 60.3, 57.8 and 57.9, 46.7 and
47.1, 42.8 and 43.1, 39.3 and 38.4, 34.3 and 34.8, 32.1 and 31.8,
29.9 and 28.9, 28.3 and 28.8, 23.9 and 24.3, 23.8 and 23.7, 18.4
and 18.6; HRMS (ESI) m/z 475.2001, C21H32N4O5S + Na+ [M
+ Na]+ requires 475.1986. Anal. Calcd for C21H32N4O5S: C,
55.73; H, 7.13; N, 12.38; S, 7.09. Found: C, 56.14; H, 6.97; N,
12.12; S, 6.92.
Methyl [3′S,6′S,7′aR]-Tetrahydro-5′-oxospiro[piperi-
dine-2,6′-pyrrolo[2,1-b]thiazolidine]-3′-carboxylate (23).
A similar procedure to that used for the deprotection of 4a
was used. Compound 4b (50 mg, 0.14 mmol) was treated with
0.5 mL of 4 N HCl/dioxane. Treatment with Hunig’s base
followed by column chromatographic purification with 2%
MeOH in EtOAc gave 34 mg (89%) of 23 as pale brown thick
syrup. [R]20 +173.6 (c 1.59, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 5.02-5.13 (m, 2H), 3.75 (s, 3H), 3.27-3.38 (m, 2H),
3.15 (dt, 1H, J ) 4.2 and 13.2 Hz), 2.75 (dd, 1H, J ) 6.9 and
13.2 Hz), 2.6 (m, 1H), 2.07 (dd, 1H, J ) 6.0 and 12.9 Hz), 1.90
(br s, 1H), 1.40-1.88 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
176.8, 170.1, 63.7, 62.5, 57.6, 53.2, 42.4, 41.4, 35.9, 33.2, 26.2,
21.2; HRMS (ESI) m/z 271.1120, C12H18N2O3S + H+ [M + H]+
requires 271.1111.
(3′S,6′R,7′aR)-1-[(2S)-2-Pyrrolidinylcarbonyl]tetrahy-
dro-5′-oxospiro[piperidine-2,6′-pyrrolo[2,1-b]thiazoline]-
3′-carboxamide Hydrochloride (21a). Spiro bicyclic amide
20a (45 mg, 0.1 mmol) was treated with 4 N HCl in dioxane
(3 mL) for 8 h under an Ar atmosphere. The solvent and excess
HCl were removed in vacuo. The resulting residue was twice
suspended in CH2Cl2 and the mixture was stripped of solvent.
A white solid was obtained, which was dissolved in water and
the solution then lyophilized to give a white hygroscopic solid
Methyl [3′R,6′S,7′aR]-Tetrahydro-5′-oxospiro[piperi-
dine-2,6′-pyrrolo[2,1-b]thiazolidine]-3′-carboxylate (24).
Fifty milligrams of 4c (contaminated with 1-methyl-1H-
pyridin-2-one) was treated with 4 N HCl/dioxane. The HCl salt
obtained was dissolved in MeOH and an aqueous ammonia
solution (0.1 mL) was added. The reaction was stirred over-
night. The reaction mixture was concentrated and the residue
was dried. Column chromatography of the residue with 2%
MeOH in EtOAc gave 12 mg of 23 and 11 mg of 24. [R]20D +16.7
(c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.19 (dd, 1H, J )
3.9 and 7.5 Hz), 5.05 (dd, 1H, J ) 4.8 and 7.2 Hz), 3.74 (s,
3H), 3.30-3.45 (m, 2H), 3.05 (dt, 1H, J ) 3.6 and 12.9 Hz),
2.66-2.78 (m, 1H), 2.57 (dd, 1H, J ) 7.2 and 13.8 Hz), 2.2
(dd, 1H, J ) 3.9 and 13.8 Hz), 1.4-2.0 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 177.1, 170.2, 63.4, 63.1, 57.8, 53.2, 42.8, 38.4,
36.5, 34.5, 26.4, 20.8; HRMS (ESI) m/z 271.1099, C12H18N2O3S
+ H+ [M + H]+ requires 271.1111.
in quantitative yield. [R]20 +93.6 (c 1.06, MeOH); 1H NMR
D
(300 MHz, CD3OD) δ 5.24 (dd, 1H, J ) 2.7 and 7.8 Hz), 4.60-
4.78 (m, 2H), 3.75 (dt, 1H, J ) 4.5 and 13.5 Hz), 3.55 (dd, 1H,
J ) 8.4 and 11.4 Hz), 3.43 (dd, 1H, J ) 5.4 and 11.4 Hz), 3.22-
3.28 (m, 3H), 2.66 (d, 1H, J ) 8.1 and 14.4 Hz), 2.52 (m, 1H),
2.47 (dd, 1H, J ) 3.0 and 14.4 Hz), 1.52-2.05 (m, 9H); 13C
NMR (75 MHz, CD3OD) δ 176.5, 174.3, 170.6, 66.2, 64.4, 60.7,
39.9, 47.4, 44.7, 37.1, 35.1, 34.6, 30.1, 25.0, 24.4, 18.8; HRMS
(ESI) m/z 353.1643, C16H24N4O3S + H+ [M + H]+ requires
353.1641.
(3′S,6′S,7′aR)-1-[(2S)-2-Pyrrolidinylcarbonyl]tetrahy-
dro-5′-oxospiro[piperidine-2,6′-pyrrolo[2,1-b]thiazoline]-
3′-carboxamide Hydrochloride (21b). Spiro bicyclic amide
20b (40 mg, 0.088 mmol) was treated with 4 N HCl-dioxane
(3 mL) for 8 h under an N2 atmosphere. The solvent and excess
HCl were removed under reduced pressure. The residue was
twice suspended in CH2Cl2 and the mixture stripped of solvent
to give a white solid, which was dried under vacuum to give a
Acknowledgment. This work was supported by
grant NS20036 from the National Institutes of Health.
We thank Dr. Victor Young, Jr. of the Department of
Chemistry’s X-ray Crystallographic Laboratory for the
X-ray crystal structure analyses and the Medicinal
Chemistry/Supercomputing Institute Visualization-
Workstation Laboratory and John Goodell for assistance
on the ab initio calculations.
white hygroscopic solid (35 mg, 100%). [R]20 +68.2 (c 0.61,
D
MeOH); 1H NMR (300 MHz, CD3OD) δ 5.15 (t, 1H, J ) 7.2
Hz), 5.09 (dd, 1H, J ) 2.4 and 6.6 Hz), 4.64 (t, 1H, J ) 7.8
Hz), 3.76 (dt, 1H, J ) 4.2 and 12.9 Hz), 3.48 (dd, 1H, J ) 6.6
and 10.5 Hz), 3.28-3.42 (m, 3H), 3.23 (dd, 1H, J ) 3.9 and
13.2 Hz), 2.89 (dd, 1H, J ) 7.5 and 12.9 Hz), 2.48 (m, 1 H),
2.24 (dd, 1H, J ) 6.6 and 12.6 Hz), 1.60-2.18 (m, 9H); 13C
NMR (75 MHz, CD3OD) δ 174.9, 172.1, 169.5, 67.3, 61.9, 60.4,
60.3, 47.5, 43.9, 40.4, 35.2, 32.1, 29.3, 25.2, 24.1, 18.6; HRMS
(ESI) m/z 353.1640, C16H24N4O3S + H+ [M + H]+ requires
353.1641.
Supporting Information Available: General experimen-
tal procedures; proton and carbon NMR spectra of 4a-d, 8,
9, 11, 14, 15, 17, 19a,b, 20a,b, 21a,b, 22, 22‚HCl, 23, and 24;
2D-NOESY spectra of 4c and 4d; 1D NOE spectra for 24; X-ray
structure data for compounds 4a, 20a, and 20b in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Methyl [3′S,6′R,7′aR]-Tetrahydro-5′-oxospiro[piperi-
dine-2,6′-pyrrolo[2,1-b]thiazolidine]-3′-carboxylate (22).
Compound 4a (60 mg, 0.27 mmol) was treated with 4 N HCl
in dioxane (0.5 mL) under Ar for 3 h. Solvent and excess HCl
JO050529K
J. Org. Chem, Vol. 70, No. 15, 2005 5963