Novel triazolopeptides: chirospecific synthesis and conformational studies of proline derived analogs

Article abstract of DOI:10.1016/j.tet.2009.05.045

Replacing the backbone amide function by a heterocyclic bioisostere, [3+2] azide-alkyne cycloaddition has been applied for the construction of biologically relevant peptidomimetics. Starting from aminoalkynoates, triazole formation was accomplished by add

Full text of DOI:10.1016/j.tet.2009.05.045

Tetrahedron 65 (2009) 6156–6168
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel triazolopeptides: chirospecific synthesis and conformational
studies of proline derived analogs
Andreas Paul a, Juergen Einsiedel a, Reiner Waibel a, Frank W. Heinemann b,
,
Karsten Meyer b, Peter Gmeiner a
*
a Department of Chemistry and Pharmacy, Emil Fischer Center, Chair of Medicinal Chemistry, Friedrich Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
b Department of Chemistry and Pharmacy, Chair of Inorganic Chemistry, Friedrich Alexander University, Egerlandstraße 1, D-91058 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Replacing the backbone amide function by a heterocyclic bioisostere, [3þ2] azide–alkyne cycloaddition
has been applied for the construction of biologically relevant peptidomimetics. Starting from amino-
alkynoates, triazole formation was accomplished by addition of hydrazoic acid. NMR studies displayed
that the newly developed 4,5-triazolopeptides, which incorporate a biomimetic triazole NH-function as
polar constraint element, showed a substantially higher tendency to form a cis-prolyl-geometry than
a comparable native peptide sequence.
Received 23 March 2009
Received in revised form 14 May 2009
Accepted 18 May 2009
Available online 23 May 2009
Keywords:
Triazolopeptide
Ó 2009 Elsevier Ltd. All rights reserved.
cis/trans Prolyl isomerization
Azide–alkyne cycloaddition
1. Introduction
b
-turn inducing peptidomimetics,3k we designed a novel class of
4,5-disubstituted triazolopeptides simulating the incorporation of
a backbone NH-function. The aim of this project was to develop
a novel class of biologically relevant backbone mimetic and to apply
the novel constraint element for the synthesis of proline derived
analogs with an increased cis prevalence.
Complementary to the use of terminal alkynes and alkyl azides,
our plan of synthesis depended on the construction of amino-
alkynoates that should be subjected to [3þ2] cycloaddition reaction
in presence of a hydrazoic acid equivalent.8,9
Poor bioavailability and in vivo enzymatic degradation sub-
stantially limit the potential of peptides as drugs and biomolecular
tools.1 Thus, the development of privileged molecular scaffolds
efficiently mimicking biologically relevant motifs of peptides is of
paramount importance in current drug discovery and chemical
biology.2 Structural constraints have been exploited to increase
both binding and selectivity and to elucidate bioactive
conformations.3
Replacing the amide function by a heterocyclic bioisostere,
[3þ2] azide–alkyne cycloaddition has been applied to the con-
struction of backbone modifications including nonpeptidic fol-
damers,4 macrocyclic peptide analogs,5 and click chemistry derived
molecular scaffolds that we termed triazolopeptides.6 Four types of
triazolopeptides were synthesized that we refer to as 1,4- and 1,5-
triazolopeptides as well as 4,1- and 5,1-linked derivatives (Chart 1).7
When mimicking a Pro-Gly dipeptide, structural studies indicated
the adjustability of both the cis/trans prolyl ratio and the confor-
mational stability toward intramolecular H-bonding effects. Dif-
ferent to the classical backbone amide function, the hitherto
reported triazolopeptides are devoid of an NH-function presented
in the natural lead compounds. As an extension of our previously
described incorporation of polar constraint elements into type-II
R
N
N
5
N
N
Y
Y
Y
NH
( )0,1
5
4
X
1 N
X
X
N1
N
( )0,1
N
N
N
4
O
O
N
O
O
O
O
1,4 - and
1,5 - triazolopeptides
4,1 - and
4,5-triazolopeptides
5,1 - triazolopeptides
R
_
OMe
N3
O
Y
Y
( )
Y
0,1
N3
OEt
X
X
X
N3
O
OEt
( )0,1
N
N
boc
N
boc
O
boc
* Corresponding author. Tel.: þ49 9131 8529383; fax: þ49 9131 8522585.
E-mail address: peter.gmeiner@medchem.uni-erlangen.de (P. Gmeiner).
Chart 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.045

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6157
2. Results and discussion
triazolopeptide 11 in 78% yield. Finally, the Boc groups of 8a and 11
were exchanged by acetyl to give the model peptidomimetics 9 and
12, respectively.
Whereas induction of an intramolecularly stabilized nine-
membered ring should be investigated for the triazolopeptide of
type 12, insertion of an additional carbon atom should facilitate
Taking advantage of N-Boc protected alkynes as versatile pre-
cursors,10 our initial investigations were directed to the synthesis of
a glycine based model system of type 5. Starting from suitable
aminoalkynoates, triazole formation9 was intended by addition of
hydrazoic acid. To obtain 2-alkynoate derivatives of type 3, we
aimed to deprotonate the respective terminal alkynes followed by
a reaction with chloroformate.10,11
formation of a b-turn nucleating 10-membered ring. We were in-
trigued by the question whether the introduction of an acetic acid
equivalent instead of a carboxylate synthon into the identical re-
action sequence might provide this extra carbon and, thus, lead to
a homologous backbone. In detail, we took advantage of a Cu(I)
catalyzed coupling17 of the terminal alkyne 1 with ethyl diazo-
acetate and benzyl diazoacetate18 to afford the aminopentyne de-
rivatives 13a and 13b in good yields (60–67%). It is worthy of note
that considerable amounts of the isomeric allenes 13a0 and 13b0
could be identified as side products (Scheme 3).
For the synthesis of the molecular scaffold 5, we started from
the Boc-protected propargylamines 112 and 2.13
Guided by a previously reported protocol,10a n-BuLi promoted
deprotonation of 1 and subsequent acylation resulted in formation
of the aminobutynoic acid 3a (Scheme 1). The yield of 3a was
limited by formation of the C,N-bis-acylated byproduct 4. As
a consequence, treatment of the N-methyl analog 2 under identical
conditions gave the alkynoate 3b in more acceptable yield. Cyclo-
addition in presence of NaN3/NH4Cl14,15 afforded the triazoles 5a,b
in 31% and 58% yields, respectively (Scheme 1).
i)
HN
HN
HN
+
OR
OR
O
O
O
O
O
O
O
O
N
N
O
i)
ii)
NH
RN
RN
RN
1
13a: R = Et (67%)
13b: R = Bn (60%)
13a`: R = Et (21%)
13b`: R = Bn (28%)
OBn
O
O
O
O
O
O
BnO
O
Scheme 3. (i) CuI, ethyl or benzyl diazoacetate, CH3CN, rt, 23–24 h.
1: (R = H)
3a: R = H (15%)
3b: R = Me (35%)
4: R = Cbz (9%)
5a: R = H (31%)
2: (R = Me)
5b: R = Me (58%)
To promote [3þ2] azide–alkyne cycloaddition, the hardly sep-
arable mixture of 13a and 13a0 was subjected to NaN3/NH4Cl. In-
terestingly, two cycloaddition products were formed in a 3:1 ratio.
However, none of these displayed a structure identical to the an-
ticipated scaffold 14 (Scheme 4). Careful NMR spectroscopic eluci-
dation including HMBC, HMQC, COSY, and NOESY experiments
indicated the formation of the triazole carboxylate 15a as the main
product. Thus, an isomerization step was obvious. Whereas re-
action of chromatographically purified 13a gave identical products,
NaN3/NH4Cl treatment of the allene 13a0 in pure form didn’t show
any cycloaddition indicating that the alkyne–allene isomerization
was not crucial to the formation of 15a.19 Isomerization of the triple
bond to give the conjugated alkyne as an intermediate could be
excluded since treatment of 13a with NH4Cl (excluding NaN3) did
not show any reaction.
Scheme 1. (i) (a) n-BuLi, THF, ꢀ78 ꢁC, 30 min; (b) benzyl chloroformate, ꢀ78 ꢁC to rt,
60–160 min; (ii) NaN3, NH4Cl, DMSO, rt, 9 h, 40 min.
As cis/trans prolyl isomerization plays a crucial role in various
biological processes16 peptide mimics capable of modifying the cis/
trans Xaa-Pro ratio are of particular interest. Thus, a 4,5-triazolo-
peptide simulating the sequences Ac-Pro-Gly-OEt and Ac-Pro-Gly-
NHMe should be synthesized and subjected to conformational
studies. Employing the pyrrolidinyl acetylene 6, which can be
obtained from N-Boc-proline10d as a chiral building block, lithiation
and subsequent treatment with ethyl and benzyl chloroformate
resulted in formation of the ethyl alkynoate 7a and the benzyl
alkynoate 7b, respectively (Scheme 2). Upon cycloaddition in
presence of hydrazoic acid, the triazoles 8a,b were formed in 76–
92% yield. Since aminolysis of 8a to give the corresponding
N-methylamide 11 failed we performed a hydrogenolytic deben-
zylation of 8b. The thus formed carboxylic acid 10 was subjected to
a promoted HATU coupling with methylamine to provide the
N
N
NH
i)
HN
HN
OR
O
O
O
O
EtO
14
O
O
N
N
i)
ii)
O
13a,b
NH
N
N
N
OR
R'
i) or ii)
O
O
O
O
O
RO
N
N
N
NH
N
N
8a: R = Et, R' = Boc (81%)
8b: R = Bn, R' = Boc (45%)
9: R = Et, R' = Ac (62%)
7a: R = Et (76%)
7b: R = Bn (92%)
6
N
HN
HN
iii)
+
O
O
O
O
RO
O
OEt
N
N
NH
N
N
O
vi)
iv)
or v)
NH
N
R
N
15a: R = Et (49%)
15b: R = Bn (32%)
15c: R = H
16 (16%)
O
iv)
O
O
O
HN
HO
Scheme 4. (i) NaN3, NH4Cl, DMF, 75 ꢁC, 3 h; (ii) NaN3, N(C4H9)4Br, H2O/CHCl3,
m-wave,
75 W, rt to 55 ꢁC, 2ꢂ5 min; (iii) NH2Me, EtOH, rt, 2 h; (iv) H2, Pd(OH)2/C, EtOAc, rt, 2 h.
11: R = Boc (78%)
12: R = Ac (77%)
10 (81%)
iii)
Scheme 2. (i) (a) n-BuLi, THF, ꢀ78 ꢁC, 30 min; (b) ethyl or benzyl chloroformate,
ꢀ78 ꢁC to rt, 45–100 min; (ii) NaN3, NH4Cl, DMSO, 100 ꢁC, 80–200 min; (iii) (a) TFA,
CH2Cl2, 0 ꢁC to rt, 50 min; (b) AcCl, DIPEA, CH2Cl2, 0 ꢁC to rt, 16 h; (iv) H2, Pd(OH)2/C,
EtOAc/MeOH 1:1, rt, 2 h; (v) LiOH, THF/H2O 1:1 refl., 70 min; (vi) (a) HATU, DMF, DI-
PEA, 0 ꢁC; (b) NH2Me, EtOH, 0 ꢁC to rt, 22 h.
Elemental analysis and mass spectroscopy of the side product 16
clearly indicated the incorporation of one more nitrogen. Sub-
sequent X-ray analysis unambiguously revealed formation of a tet-
razole system as a key feature of the molecular scaffold 16 (Fig. 1).

6158
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
Subsequently, the alkyne/allene mixtures were treated with NaN3,
NH4Cl to give the triazoles 18a and 18b. Tetrazole formation could
not be observed. Aminolysis of the ethyl ester 18a to afford the
model peptide surrogate 21 failed. Thus, we synthesized the car-
boxylic acid intermediate 20 by hydrogenolytic cleavage of 18b. The
carboxamide 21 was obtained by subsequent coupling with H2NMe
employing HATU. Finally, the Boc groups of 18a and 21 were ex-
changed by acetyl to furnish the model peptidomimetics 19 and 22
(Scheme 6).
Figure 1. Molecular structure of 16 (thermal ellipsoid plot, 50% probability).
Modification of reaction conditions allowed to influence the
triazole–tetrazole ratio significantly. Thus, microwave irradiation
and the addition of acetic acid instead of NH4Cl resulted in for-
mation of 13a and 14 in a 1:1 ratio. On the other hand, employment
of aqueous sodium azide, chloroform, and phase transfer catalysis
(N(C4H9)4Br) led to selective triazole formation. This was exem-
plified for the preparation of the benzyl triazole carboxylate 15b
from the linear precursor 13b/13b0. Hydrogenolytic debenzylation
afforded the carboxylic acid 15c. To the best of our knowledge,
comparable rearrangements have not been described in the liter-
ature, yet. To explain a possible reaction mechanism of both triazole
and tetrazole formation, we suggest the vinylazide derivative I,
resulting from the addition of azide to the triple bond as a common
intermediate (Scheme 5). Following the ‘red arrow pathway’,
isomerization of the double bond leads to the conjugated tautomer
III, which undergoes ring closure (V) and aromatization to give the
triazole of type VII. Alternatively, after N2-elimination (‘blue arrow
pathway’), the resulting nitrene II shows cyclization to give the
azirine IV,20 whichdafter acid promoted ring opening (VI)dfurn-
ishes the tetrazole derivative of type VIII (Scheme 5) via 1,3 dipolar
cycloaddition with an azide anion.
i)
N
N
+
6
O
O
O
O
O
O
RO
RO
17a: R = Et (57%)
17b: R = Bn (39%)
17a`: R = Et (14%)
17b`: R = Bn (10%)
N
N
N
N
NH
O
NH
ii)
iii)
N
N
O
RO
EtÔ
O
O
O
18a: R = Et (23%)
18b: R = Bn (49%)
19 (62%)
iv)
N
N
N
N
NH
O
NH
iii)
N
N
O
X
HN
O
O
O
N
20: X = OH (99%)
21: X = HNCH3 (93%)
22 (39%)
N+
v)
or
H
N
N
"HN3"
OR
-N2
H
Scheme 6. (i) CuI, ethyl or benzyl diazoacetate, CH3CN, rt, 4–21 h; (ii) NaN3, NH4Cl,
DMSO or DMF, 100 ꢁC, 1–3 h; (iii) (a) TFA, CH2Cl2, 0 ꢁC to rt, 25–45 min; (b) AcCl, DIPEA,
CH2Cl2, 0 ꢁC to rt, 5 h; (iv) Pd(OH)2/C, H2, EtOAc, rt, 80 min; (v) (a) HATU, DIPEA, DMF,
HNBoc
II
OR
HNBoc
HNBoc
OR
O
O
I
O
0
ꢁC; (b) NH2Me, EtOH, rt, 22 h.
Alkyne analogues 23a,b based on alanine and phenylalanine
H+
N
were synthesized10b and converted to the respective alkynoates
24,b accompanied by 33% and 41% of the allenes 25a0,b0. Triazole
formation with NaN3/NH4Cl gave the triazolopeptides 25a and 25b
in 23% and 49% yields (Scheme 7). Tetrazole formation was not
observed.
N+
N
N
HNBoc
OR
O
IV
III
HNBoc
OR
O
-
N3
N
N
H
H
N
NH
R
R
N+
N
N
H
OR
HN
HN
O
HNBoc
HNBoc
HNBoc
OR
V
VI
BnO
O
O
O
O
O
O
N
N
23a: R = Me
23b: R = Bn
25a: R = Me (36%)
25b: R = Bn (38%)
N
N
N
N
NH
OR
i)
ii)
HNBoc
OR
O
O
VIII
VII
R
R
Scheme 5. Suggested rearrangement mechanism explaining the triazole and tetrazole
HN
HN
pathway.
+
O
O
O
O
O
O
BnO
BnO
To demonstrate the general scope of the reaction sequence, the
synthesis of proline, alanine, and phenylalanine analogs was
intended. Initially, the proline derived alkyne 6 was reacted with
ethyl and benzyl diazoacetate to furnish the pyrrolidinyl
substituted alkynoates 17a and 17b, respectively, accompanied by
approximately 10% of the allene derivatives 17a0 and 17b0.
24a: R = Me (45%)
24b: R = Bn (41%)
24a`: R = Me (22%)
24b`: R = Bn (29%)
Scheme 7. (i) CuI, ethyl or benzyl diazoacetate, CH3CN, rt, 20 h; (ii) NaN3, NH4Cl, DMF,
105 ꢁC, 95 min.

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6159
To examine the optical integrity of the synthesis, the proline
5.60 ppm) were diagnostic for the population representing the cis-
isomer. Integration of baseline-separated signals allowed deducing
a 40% portion of the cis-rotamer. Due to solubility problems in CDCl3,
additionof5%DMSO-d6 was necessary for the NMR investigations
of the methylamide 12 when 45% of the cis-rotamer was de-
termined. It is worthy to note, that a highly diluted sample in
pure CDCl3 revealed a very similar cis/trans ratio. NMR studies
of the homologous triazole carboxylate 19 required the addition
of 2.5% DMSO-d6, a concentration that did not influence the cis/
trans ratio of the structural analog 9. The cis-population was
identified by a nuclear Overhauser enhancement of the acetyl
methyl signal at 2.11 ppm when irradiating at the H-2 reso-
nance (4.24 ppm). Under these conditions a 40:60 cis/trans ratio
was determined. For the methylamide 22, one single set of
signals was detected in pure CDCl3, when an NOE between the
acetyl methyl group and the pyrrolidine H-5 clearly proved
exclusive trans conformation. Very interestingly, the cis portion
significantly increased to 40%, when 2.5% DMSO-d6 was added
derived representatives 10 and 20 were coupled with (R)-
a-methyl-
benzylamine affording 26a and 27a and with (S)-
a
-methyl-
benzylamine yielding 26b and 27b, respectively (Scheme 8).
Careful HPLC analysis indicated diastereomeric excess >96%.
N
N
N
N
NH
NH
i)
10, 20
n
N
O
N
n
O
HN
HN
O
O
O
O
26a: n = 0 (46%)
27a: n = 1 (46%)
26b: n = 0 (24%)
27b: n = 0 (56%)
Scheme 8. (i) HATU (2.0 equiv), DMF, 0 ꢁC to rt, (R)-
a
-methylbenzylamine or (S)-a-
methylbenzylamine, 3 h 45 min to 10 h 30 min.
The importance of cis/trans isomerization for molecular recog-
nition has been shown many times. For example, introduction of
unnatural proline derivatives induced an increased cis prevalence
for a cyclic HIV-1 V3 loop analog. This loop has a common Gly-Pro-
to the sample indicating that a
b-turn like structure stabilized
by an intramolecular H-bond might be responsible for the
strong preference of the trans-geometry in pure CDCl3. Com-
pared to the native peptide sequence, the 4,5-triazolopeptides 9,
12, and 19 displayed a substantially higher tendency to form
the cis-prolyl-geometry. For the methylamide 22, this property
seems to be overcompensated by an intramolecular H-bond
Gly-Arg motif, representing a type-II
b-turn, which is supposed to
switch into a type-VI -turn, demanding a cis-proline peptide bond,
b
as the key step before getting the HIV-1 infective.16d These findings
underline the importance of molecular tools for a fine tuning of the
cis- versus trans-prolyl energy level ratio for the elucidation of bio-
logical systems. Such an adjustment has been commonly ac-
complished by modifying the pyrrolidine moiety employing ring
putatively stabilizing
a b-turn like conformation with trans-
prolyl-geometry. Thus, the model peptide mimetic of type 12
obviously represents the molecular scaffold with a robust cis-
proline peptide bond.
size variations,21 sterically demanding substituents22,23 as well
26
as introduction of fluorine,24,25 azide
or by introducing bridging
elements to furnish Freidinger-type lactams.27–29,3h
3. Conclusion
Aiming to better understand the conformational properties, our
newly developed 4,5-triazolopeptides, the Ac-Pro-Gly-NHMe sur-
rogates 12 and 22, were investigated by means of 1H NMR spec-
troscopy (Table 1). Involving the ethyl ester analogs 9 and 19 into
the study, we gave special attention to cis/trans prolyl ratios. N-
Acetylprolylglycine methyl ester and N-acetylprolylglycine N0-
methyl amide were used as reference peptides.30 Using CDCl3 as
a solvent, two sets of signals were identified for the triazole car-
boxylate 9. NOE measurements revealed a proximity of the acetyl
CH3 (2.14 ppm) and the pyrrolidine H-5 for one set of signals in-
dicating trans-geometry. On the other hand, NOEs between the
acetyl CH3 (1.87 ppm) and H-2 (represented by the signal at
In conclusion, [3þ2] azide–alkyne cycloaddition has been
applied for the construction of biologically relevant peptidomi-
metics. Starting from aminoalkynoates, triazole formation was ac-
complished by addition of hydrazoic acid. The newly developed
molecular scaffolds include a biomimetic NH moiety, thus, com-
plementing our previously described incorporation of polar lactam-
bridged constraint elements. Whereas the recently described
spirobarbiturates have been determined as type-II b-turn nucleat-
ing scaffolds incorporating a trans-proline peptide bond, NMR
studies displayed that the newly developed 4,5-triazolopeptides
showed a substantially higher tendency to form the cis-prolyl-ge-
ometry than a comparable native peptide sequence. Due to their
artificial backbone, substantial resistance toward in vivo enzymatic
is expected. Thus, 4,5-triazolopeptides represent a valuable alter-
native to previously reported cis-prolyl peptide analogs including
pseudo-prolines.16d Complementing those, differential positions of
the respective proximal side chains will provide a valuable oppor-
tunity for structure–activity relationship studies in medicinal
chemistry.
Table 1
NMR-derived prolyl cis-isomer ratios of the model peptide surrogates 9, 12, 19, and
22 compared to Ac-Pro-Gly-OMe, Ac-Pro-Gly-NHMe,30 respectively (5% steps)
Cpd
cis
Cpd
cis
H
H
N
N
10%
<1%
N
N
O
O
O
O
MeO
HN
N
O
O
4. Experimental
4.1. General
N
N
N
NH
NH
N
12a
45%
N
9
40%
40%
Reagents and solvents were obtained from commercial sources
unless stated otherwise, and were used as received. Unless other-
wise noted, reactions were conducted without inert atmosphere.
Evaporations of final product solutions were done in vacuo with
a rotary evaporator. Reaction temperatures were measured exter-
nally. Reactions were monitored by TLC on Merck silica gel plates
(0.25 mm), visualized by UV light, iodine and/or ninhydrin solution.
Flash chromatography was carried out with 230–400 mesh silica
gel and 0.8–1.0 bar nitrogen pressure. If not otherwise stated, mass
spectra were performed by EI ionization (70 eV) with solid inlet,
O
O
O
O
HN
N
EtO
N
N
N
NH
NH
19a
22
<5%
N
N
O
O
EtO
HN
O
O
a
Addition of DMSO-d6 was necessary to entirely dissolve the compounds 12
(5.0%) and 19 (2.5%). In order to obtain unambiguous resonance signals in the
selective NOE measurements, samples were diluted to 5–10 mM concentrations.

6160
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
HRMS were obtained employing peak matching M/
D
M¼5000. ESI
This biphasic mixture was cooled to 0 ꢁC and NaNO2 (1.570 g,
22.754 mmol), dissolved in water (5.0 mL), was added over a period
of 2 min whereas the solution turned bright yellow. After stirring
for 90 min at 0 ꢁC, the organic layer was poured into NaHCO3 satd
(50 mL) via a funnel (cave: bubbling). The aqueous and NaHCO3 satd
layers were re-extracted with CH2Cl2 (each 20 mL) and the com-
bined organic layers were washed with brine (30 mL), dried over
Na2SO4, and evaporated. Purification by flash column chromatog-
raphy (pentane/diethyl ether 8:2) furnished 2.83 g (85%) benzyl
diazoacetate as a clear yellow oil. Rf 0.51 (pentane/diethyl ether
and APCI-MS were performed using a Bruker Esquire 2000 coupled
with an Agilent 1100 analytic HPLC system. The NMR spectra were
recorded on a Bruker Avance 600 (1H at 600 MHz, 13C at 150 MHz)
or a Bruker Avance 360 (1H at 360 MHz, 13C at 90 MHz) spec-
trometer, if not otherwise stated, in CDCl3. Chemical shifts are
reported relative to the residual solvent peak (CHCl3: 7.26, CDCl3:
77.0) or to tetramethylsilane. NOEs were determined using the
DPFGSE-NOE pulse sequence with a selective Gaussian shaped
refocussing pulse of 50 ms length and a mixing time of 500 ms.31
Elemental analyses were performed by the Institute of Organic
Chemistry (Analytical Departments) of the Friedrich Alexander
University Erlangen-Nu¨rnberg and at Mikroanalytisches Labo-
ratorium Beetz. Melting points were determined with a Bu¨chi 510
apparatus and were uncorrected. HPLC analysis were run on Agi-
lent 1100 Series with a Diode Array Detector at 210, 230, and
250 nm. Optical rotations were measured on a Perkin Elmer 241
polarimeter. IR spectra were measured on a Jasco 410 apparatus.
7:3); IR (neat) 3113, 2924, 2112, 1744, 1695, 1631 cmꢀ1 1H NMR
;
(600 MHz, CDCl3; rotamers and broadened signals were observed)
d
4.80 (br s, 0.85H, HCꢀNþN), 5.20 (s, 2H, OCH2), 5.315þ5.317 (2ꢂs,
0.15H, HC]Nþ]Nꢀs-cisþs-trans), 7.30–7.41 (m, 5H, Ar–H) signals
were in accordance with Ref. 18, furthermore, we observed signals
of the second rotamer.
4.5. General procedure for synthesis of the 2-alkyne
carboxylic acid esters (3a,b, 7a,b)
4.2. N-Boc-propargylamine (1)12
Over a period of 5 min, n-butyllithium in hexanes was added to
a cooled (ꢀ78 ꢁC) solution of the respective alkyne derivative in
THF under nitrogen. After stirring for 10–20 min, the corresponding
chloroformate was added and the mixture was then treated in-
dividually (see below). After complete conversion of starting ma-
terials, the mixture was quenched and extracted. After washing the
organic layer with brine and drying over Na2SO4, the solvent was
removed in vacuo and the crude product was purified by flash
column chromatography.
Di-tert-butyl-dicarbonate (20.462 g, 93.8 mmol) was dissolved
in CH2Cl2 and cooled to 0 ꢁC. Propargylamine (5.164 g, 93.8 mmol)
was added over a period of 30 min, after warmed to room tem-
perature and stirred for 12 h. The organic layer was extracted suc-
cessively with HCl (2 N, 30 mL), NaOH (2 N, 30 mL) and NaHCO3 satd
(30 mL) and each time re-extracted with CH2Cl2 (20 mL). The
combined organic layers then were dried over MgSO4 and the
solvent concentrated until an oily residue was observed. n-Pentane
(100 mL) was added and after standing in the refrigerator for 12 h,
the precipitate was collected by filtration. The filtrate was con-
centrated in order to collect another crop of 1 to afford 12.20 g
(84%) as white needles. Mp 42 ꢁC [lit.12 mp 41–42 ꢁC]; Rf 0.71 (pe-
troleum ether/ethyl acetate 1:1); IR (neat) 3417, 3346, 3307, 2979,
4.5.1. N-tert-Butoxycarbonyl-4-aminobut-2-ynic acid benzyl ester
(3a) and N-benzyloxycarbonyl-N0-tert-butoxycarbonyl-4-
aminobut-2-ynic acid benzyl ester (4)
Compound 1 (310.4 mg, 2.0 mmol) in THF (15 mL) was reacted
with n-BuLi (1.68 mL, 2.5 M solution, 4.2 mmol) for 10 min and
2121, 1702 cmꢀ1
were observed)
;
1H NMR (360 MHz, CDCl3; broadened signals
d
1.45 (s, 9H, Boc CH3), 2.21 (t, 1H, J¼2.3 Hz, C^CH),
then with benzyl chloroformate (313 mL, 2.2 mmol) for 1 h at
3.92 (dd, J¼5.0, 2.3 Hz, 2H, NCH2), 4.69 (br s, 1H, NH); 13C NMR
ꢀ78 ꢁC following the general procedure. Quenching: H2O (20 ml),
extraction: diethyl ether. Chromatography (pentanes/diethyl ether
9:1) furnished 88.6 mg (15%) of 3a as a colorless solid and 72.1 mg
(9%) of 4 as a colorless oil.
(90 MHz, CDCl3)
d 28.3 (Boc CH3), 30.4 (NCH2), 71.2 (C-3), 80.06
(Boc Cq), 80.12 (C-2), 155.2 (Boc C]O).
4.3. N-Boc-N-methylpropargylamine (2)13
4.5.1.1. Compound 3a. Mp 74–76 ꢁC; Rf 0.30 (pentanes/diethyl
Potassium hydride (875.7 mg, 21.84 mmol) was suspended in
THF (10.0 mL) under nitrogen and 1 (3.104 g, 20.00 mmol) was
added as a solution in THF (10.0 mL) at 0 ꢁC. After 1 h, methyliodide
(1.50 mL, 3.420 g, 24.10 mmol) was added over a period of 5 min
and the solution was allowed to warm to room temperature. After
ether 6:4); IR (neat) 3402, 3355, 2926, 2239, 1714 cmꢀ1 1H NMR
;
(360 MHz, CDCl3; rotamers and broadened signals were observed)
1.45 (s, 9H, Boc CH3), 4.07 (d, J¼5.0 Hz, 2H, HN–CH2), 4.73 (br s,1H,
NH), 5.19 (s, 2H, OCH2), 7.27–7.43 (m, 5H, Ar–H); 13C NMR (90 MHz,
d
CDCl3; rotamers and broadened signals were observed) d 28.3 (Boc
140 min the mixture was poured in NaHCO3
(30 mL) and,
CH3), 30.4 (NCH2), 67.7 (OCH2), 74.8 (C-2), 80.5 (Boc Cq), 84.3 (C-3),
128.5 (br) and 128.65 (br) (5ꢂaryl CH), 134.7 (aryl C), 153.0 (ester
C]O), 155.0 (Boc C]O); EIMS 233 (Mþ-C4H8).
satd
subsequently, water (50 mL) and brine (20 mL) were added. After
extraction with diethyl ether (4ꢂ20 mL), the combined organic
layers were dried over Na2SO4, concentrated, and purified by flash
column chromatography (petroleum ether/ethyl acetate 93:7) fur-
nishing 3.01 g (89%) of 2 as a clear colorless oil. Rf 0.50 (petroleum
ether/ethyl acetate 9:1); IR (neat) 3351, 3295, 3264, 2978, 2127,
4.5.1.2. Compound 4. Rf 0.44 (pentanes/diethyl ether 6:4); IR (neat)
2979, 2876, 2241, 1796, 1759, 1715 cmꢀ1; 1H NMR (360 MHz, CDCl3)
d
1.48 (s, 9H, Boc CH3), 4.57 (s, 2H, NCH), 5.19 (s, 2H, OCH2 a), 5.25 (s,
1699 cmꢀ1
;
1H NMR (360 MHz, CDCl3; rotamers and broadened
2H, OCH2b), 7.30–7.43 (m,10H, Ar–H);13C NMR (90 MHz, CDCl3)
d
27.9
signals were observed)
d
1.46 and 1.47 (2ꢂs, 9H, Boc CH3), 2.20 and
(Boc CH3), 35.9 (NCH2), 67.7 and 69.0 (2ꢂOCH2Ph, Cbz and ester), 69.0
(OCH2), 74.6 (C^C–C]O), 83.6 and 84.3 (Boc Cq and C^C–C]O),
128.63 (10ꢂaryl CH), 134.7 and 135.0 (2ꢂaryl C), 150.6, 152.7 and
152.9 (2ꢂcarbamate C]O and ester C]O); EIMS367 (MþꢀC4H8), 276
[MꢀC4H8–/–C7H7]þ. Anal. Calcd for C24H25NO6ꢂ0.25H2O: C, 67.36; H,
6.01; N, 3.28. Found: C, 67.64; H, 6.27; N, 3.29.
2.21 (2ꢂt, each J¼2.2 Hz, 1H, C^CH), 2.91 (s, 3H, NCH3), 4.03 (br s,
2H, NCH2), signals were in accordance with Ref. 13, we also ob-
served signals of the second rotamer; 13C NMR (90 MHz, CDCl3)
d
28.4 (Boc CH3), 33.4 (NCH3), 37.7 (br, NCH2), 71.5 (C-3), 79.2 (Boc
Cq), 80.1 (C-2), 155.2 (Boc C]O); EIMS 113 (MþꢀIsobutene).
4.4. Benzyl diazoacetate18
4.5.2. N-tert-Butoxycarbonyl-N-methyl-4-aminobut-2-ynoic acid
benzyl ester (3b)
Glycine benzyl ester hydrochloride (3.820 g, 18.944 mmol) was
dissolved in water (30.0 mL) and then CH2Cl2 (30.0 mL) was added.
Compound 2 (338.6 mg, 2.0 mmol) in THF (15 mL) was reacted
with n-BuLi (0.84 mL, 2.5 M solution, 2.1 mmol) for 20 min and

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6161
then with benzyl chloroformate (313
m
L, 2.2 mmol) for 165 min at
according diazoacetate. In all cases, the mixture turned to a yellow-
green color. After TLC indicated complete conversion of starting
materials, the solvent was removed and the crude product was
purified by flash column chromatography.
ꢀ78 ꢁC, then at ꢀ55 ꢁC for 1 h and finally for 1 h at rt. Quenching:
H2O (20 mL) and brine (10 mL), extraction: diethyl ether. Flash
column chromatography (hexanes/ethyl acetate 9:1) furnished
214.2 mg (35%) of 3c as clear yellowish oil. Rf 0.45 (hexanes/diethyl
ether 6:4); IR (neat) 2977, 2237, 1709 cmꢀ1
;
1H NMR (360 MHz,
4.6.1. N-tert-Butoxycarbonyl-5-aminopent-2-yne acid ethyl ester
(13a) and N-tert-butoxycarbonyl-5-aminopenta-2,3-dienoic acid
ethyl ester (13a0)
Compound 1 (1.552 g, 10.0 mmol) in acetonitrile (20 mL) was
reacted with CuI (286 mg, 1.5 mmol) and ethyl diazoacetate
(1.104 mL, 10.5 mmol) for 24 h following the general procedure.
Flash column chromatography (CH2Cl2/ethyl acetate 95:5) fur-
nished 1.618 g (67%) of 13a as colorless wax and 511 mg (21%) of
13a0 as yellowish oil, respectively.
CDCl3)
d 1.46 (s, 9H, Boc CH3), 2.91 (s, 3H, NCH3), 4.18 (br s, 2H,
NCH2), 5.20 (s, 2H, OCH2), 7.31–7.41 (m, 5H, Ar–H); 13C NMR
(90 MHz, CDCl3; rotamers and broadened signals were observed)
d
28.3 (Boc CH3), 33.8 (NCH3), 37.7 and 38.6 (2ꢂbr, NCH2), 67.7
(OCH2), 75.3 (C-2), 80.7 (Boc Cq), 83.8 (C-3), 128.55, 128.63 and
128.64 (aryl CH), 134.7 (aryl C), 153.1, 154.7 (br) and 155.2 (br)
(3ꢂbr, ester and Boc C]O); EIMS 303 (Mþ). Anal. Calcd for
C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.36; H, 7.00; N,
4.60.
4.6.1.1. Compound 13a. Mp 60–62 ꢁC; Rf 0.46 (CH2Cl2/ethyl acetate
4.5.3. (S)-1-tert-Butoxycarbonylpyrrolidin-2-yl-propynoic acid
ethyl ester (7a)
Compound 6 (292.2 mg, 1.500 mmol) was reacted with n-BuLi
(0.99 mL, 1.6 M solution, 1.6 mmol) for 5 min and then with ethyl
9:1); IR (neat) 3392, 3361, 2979, 2289, 1743, 1714, 1697 cmꢀ1 1H
;
NMR (360 MHz, CDCl3)
d
1.28 (t, 3H, J¼7.1 Hz, OCH2CH3), 1.45 (s, 9H,
Boc CH3), 3.26 (t, J¼2.2 Hz, 2H, CH2C]O), 3.94 (br m, 2H, NCH2),
4.19 (q, J¼7.1 Hz, 2H, OCH2), 4.69 (br s, 1H, NH); 13C NMR (90 MHz,
chloroformate (290
mL, 3.0 mmol) at rt for 95 min following the
CDCl3) d 14.1 (ester CH3), 26.0 (CH2C]O), 28.3 (Boc CH3), 30.7
general procedure. Quenching with MeOH (3 mL) and subsequent
evaporation. Chromatography (hexanes/ethyl acetate 9:1) fur-
nished 302.5 mg (76%) of 7a as clear colorless oil. Rf 0.30 (hexanes/
(NCH2), 61.6 (OCH2), 74.9 and 79.5 (C^C), 79.9 (Boc Cq), 155.3 (Boc
C]O), 168.2 (ester C]O); EIMS 241 (Mþ). Anal. Calcd for
C12H19NO4: C, 59.73; H, 7.94; N, 5.80. Found: C, 59.73; H, 7.83; N,
5.85.
24
ethyl acetate 8:2); [
1710, 1695 cmꢀ1
were observed)
a
]
D
þ124.4 (c 1.0, CHCl3); IR (neat) 2979, 2235,
;
d
1H NMR (360 MHz, CDCl3; broadened signals
1.30 (t, J¼7.1 Hz, 3H, OCH2CH3), 1.48 (s, 9H, Boc
4.6.1.2. Compound 13a0. Rf 0.28 (CH2Cl2/ethyl acetate 9:1); IR (neat)
CH3), 1.87–2.20 (m, 4H, H-3/H-4 pyrrolidine), 3.25–3.54 (m, 2H, H-
5 pyrrolidine), 4.22 (br q, J¼7.1 Hz, 2H, OCH2CH3), 4.50 (m, 1H, H-2
pyrrolidine); 13C NMR (150 MHz, CDCl3; rotamers and broadened
3361, 2979, 1965, 1714, 1701 cmꢀ1 1H NMR (360 MHz, CDCl3;
;
rotamers and broadened signals were observed)
d 1.28 and 1.39
(2ꢂt, each J¼7.1 Hz, 3H, OCH2CH3), 1.44 (s, 9H, Boc CH3), 3.81–3.89
(br m, 2H, NCH2), 4.07 and 4.20 (2ꢂq, J¼7.1 Hz, 2H, OCH2), 4.72 (br
s, 1H, NH), 5.67–5.73 (m, 2H, HC]C]CH); 13C NMR (90 MHz,
signals were observed)
d 14.0 (ester CH3), 23.8 and 24.6 (C-4
pyrrolidine), 28.4 (Boc CH3), 32.4 and 33.0 (C-3 pyrrolidine), 45.7
and 46.0 (C-5 pyrrolidine), 47.8 and 48.0 (C-2 pyrrolidine), 61.9
(OCH2), 73.9 (C^C–C]O), 80.3 (br, Boc Cq), 87.6 (C^C–C]O),
153.6 and 153.7 (2ꢂbr, Boc C]O), 153.8 and 152.9 (2ꢂbr, C]O
ester); EIMS 267 (Mþ). Anal. Calcd for C14H21NO4ꢂ0.2H2O: C,
62.07; H, 7.96; N, 5.17. Found: C, 62.38; H, 7.95; N, 5.17.
CDCl3)
d 14.3 (br, ester CH3), 28.3 (Boc CH3), 38.2 (NCH2), 61.0
(OCH2), 79.8 (Boc Cq), 90.6 (HC–C]O), 94.1 (CH2HC), 155.5 (Boc
C]O), 165.5 (ester C]O), 211.7 (HC]C]CH); EIMS 185
[MꢀC4H8]þ.
4.6.2. N-tert-Butoxycarbonyl-5-aminopent-2-yne acid benzyl ester
(13b) and N-tert-butoxycarbonyl-5-aminopenta-2,3-dienoic acid
benzyl ester (13b0)
4.5.4. (S)-1-tert-Butoxycarbonylpyrrolidin-2-yl-propynoic acid
benzyl ester (7b)
Compound 6 (390.5 mg, 2.000 mmol) was reacted with n-BuLi
(1.31 mL, 1.6 M solution, 2.1 mmol) for 10 min and then with
Compound 1 (683.0 mg, 4.400 mmol) in acetonitrile (10 mL)
was reacted with CuI (76.2 mg, 0.440 mmol) and benzyl diazo-
acetate (705.0 mg, 10.5 mmol) for 23 h following the general
procedure. Flash column chromatography (hexanes/diethyl ether
9:1, separation was performed twice) furnished 454.4 mg (60%)
of 13b as ivory wax and 234 mg (28%) of 13b0 as yellowish oil,
respectively.
benzyl chloroformate (427
m
L, 3.0 mmol) for 50 min at ꢀ30 ꢁC and
then at rt for 5 min. Quenching: H2O (10 mL), extraction: diethyl
ether. Chromatography (pentanes/diethyl ether 8:2) furnished
608.8 mg (92%) of 7b as clear colorless oil. Rf 0.33 (pentanes/
24
diethyl ether 8:3); [
1713, 1700 cmꢀ1
were observed)
a]
ꢀ105.1 (c 1.0, MeOH); IR (neat) 2977, 2235,
D
;
d
1H NMR (360 MHz, CDCl3; broadened signals
1.47 (s, 9H, Boc CH3), 1.81–2.25 (m, 4H, H-3/H-4
4.6.2.1. Compound 13b. Mp 41 ꢁC; Rf 0.55 (hexanes/diethyl ether
pyrrolidine), 3.22–3.56 (m, 2H, H-5 pyrrolidine), 4.50 and 4.63
(2ꢂbr s, 1H, NCH), 5.19 (br s, 2H, OCH2), 7.30–7.39 (m, 5H, Ar–H);
13C NMR (90 MHz, CDCl3; rotamers and broadened signals were
9:1); IR (neat) 3376, 2978, 2287, 1743, 1716, 1691 cmꢀ1 1H NMR
;
(360 MHz, CDCl3)
d
1.45 (s, 9H, Boc CH3), 3.32 (t, J¼2.2 Hz, 2H,
CH2C]O), 3.94 (br m, 2H, NCH2), 4.66 (br s, 1H, NH), 5.17 (s, 2H,
observed)
d
23.8 and 24.6 (C-4), 28.4 (Boc CH3), 32.3 and 33.0 (C-
OCH2), 7.30–7.42 (m, 5H, Ar–H); 13C NMR (90 MHz, CDCl3; rotamers
3), 45.6 and 46.9 (NCH2), 47.8 and 48.0 (NCH), 67.5 (OCH2), 73.6
(C^C–C]O), 80.1 and 80.3 (Boc Cq), 88.3 and 88.4 (C^C–C]O),
128.4, 128.5 and 128.6 (aryl CH), 134.9 (aryl C), 153.4, 153.7 and
153.9 (ester, Boc C]O); EIMS 329 (Mþ). Anal. Calcd for
C19H23NO4ꢂ0.25H2O: C, 68.35; H, 7.09; N, 4.19. Found: C, 68.40; H,
7.14; N, 4.24.
and broadened signals were observed) d 26.2 (CH2C]O), 28.5 (Boc
CH3), 30.9 (NCH2), 67.5 and 67.8 (OCH2), 75.0 and 79.9 (C^C), 80.1
(Boc Cq), 128.5, 128.6, 128.7, 128.8, 128.9 (aryl CH), 135.4 (aryl C),
155.5 (Boc C]O), 168.3 (ester C]O); HRMS calcd for C17H21NO4
303.1471; found 303.1471.
4.6.2.2. Compound 13b0. Rf 0.47 (hexanes/diethyl ether 9:1); IR
4.6. General procedure for synthesis of the alk-3-yne acid
derivatives as a mixture with the allene isomers
(13a,a0, 13b,b0, 17a,a0, 17b,b0, 24a,a0, and 24b,b0)
(neat) 3417, 3356, 2925, 1963, 1714, 1693 cmꢀ1; 1H NMR (360 MHz,
CDCl3; rotamers and broadened signals were observed)
d 1.44 and
1.45 (2ꢂs, 9H, Boc CH3), 3.81–3.90 and 3.91–4.02 (2ꢂbr m, 2H,
NCH2), 4.12, 4.19 and 4.20 (3ꢂq, J¼7.1 Hz, 2H, OCH2), 4.69 (br s, 1H,
NH), 5.05 and 5.19 (2ꢂs, 2H, OCH2Ph), 5.29 and 5.96 (2ꢂs, each
0.5H, HC]C]CH–C]O), 5.67–5.79 (m, 1H, HC]C]CH–C]O),
At rt, dried CuI was added to a solution of the respective alkyne
in dry acetonitrile under nitrogen and, after stirring for 5 min, the

6162
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
7.28–7.42 (m, 5H, Ch2Ph); 13C NMR (90 MHz, CDCl3)
d
28.3 (Boc
(Boc CH3), 30.2 and 31.5 (C-3 pyrrolidine), 45.9 and 46.2 (C-5
pyrrolidine), 54.6 and 55.0 (C-2 pyrrolidine), 66.6 (OCH2), 79.7 (br,
Boc Cq), 90.1 (br, CHC]O), 97.4 and 97.8 (HC]C]C), 128.1 (br),
128.2 (br) and 128.5 (br) (10ꢂaryl CH), 135.9 (aryl C), 154.1 (br, Boc
C]O), 165.4 (br, ester C]O), 211.3 (br, C]C]C); EIMS 287
[MꢀC4H8]þ.
CH3), 30.9 (NCH2), 38.2 (NCH2), 66.7 (OCH2), 79.8 (Boc Cq), 90.3
(HC–C]O), 94.3 (CH2CH), 128.1, 128.3 and 128.6 (aryl CH), 135.8
(aryl C), 155.5 (Boc C]O), 165.4 (ester C]O), 212.1 (HC]C]CH);
EIMS 303 (Mþ). HRMS calcd for C17H21NO4 303.1471; found
303.1473.
4.6.3. (S)-2-(3-Ethoxycarbonylprop-1-ynyl)-pyrrolidine-1-
carboxylic acid tert-butyl ester (17a) and a mixture of diastereomers
of (S)-2-(3-ethoxycarbonylpropa-1,2-dienyl)-pyrrolidine-1-
carboxylic acid tert-butyl ester (17a0)
Compound 6 (390.5 mg, 2.0 mmol) in acetonitrile (3 mL) was
reacted with CuI (38.1 mg, 0.20 mmol) and ethyl diazoacetate
4.6.5. (S)-5-tert-Butoxycarbonylaminohex-3-ynoic acid benzyl
ester (24a) and a mixture of diastereomers of (S)-5-tert-
butoxycarbonylaminohexa-2,3-dienoic acid benzyl ester (24a0)
Compound 23a (507.7 mg, 3.000 mmol) in acetonitrile (10 mL)
was reacted with CuI (61.0 mg, 0.320 mmol) and benzyl diazo-
acetate (640.5 mg, 3.637 mmol) for 20 h following the general
procedure. Flash column chromatography (hexanes/ethyl acetate
95:5) furnished 641.5 mg (67%, still containing w33% of allene
fraction as determined by 1H NMR) of a non separable mixture of
24a/24a0 as yellowish viscous oil. Rf 0.26 (hexanes/ethyl acetate
(221 mL, 2.1 mmol) for 220 min following the general procedure.
Flash column chromatography (n-pentanes/diethyl ether 7:3)
furnished 402.6 mg (72%) of 17a/17a0 as yellowish oil. 1H NMR
integrals indicated about 10% of diastereomeric mixture of 17a0.
Separation of the three isomers/diastereomers failed. Rf 0.26
(pentanes/diethyl ether 7:3); IR (neat) 2977, 1962, 1779, 1746,
8:2); IR (neat) 3356, 2976, 1961, 1743, 1712, 1693 cmꢀ1 1H NMR
;
(600 MHz, CDCl3; mixture of diastereomers/isomers, all signals of
the mixture of alkyne, diastereomeric allene derivatives and
rotamers are given, peaks of common functional groups are not
separately disclosed, but regarded as if derived from a single
1698 cmꢀ1 1H NMR (360 MHz, CDCl3; mixture of isomers, all
;
signals of the mixture of alkyne, diastereomeric allene de-
rivatives and rotamers are given, peaks of common functional
groups are not separately disclosed, but regarded as if derived
compound)
d
1.25–1.29 (m, 1H, CHCH3,allenes), 1.37 (d, J¼6.9 Hz, 2H,
from a single compound)
d
1.26 and 1.27 (2ꢂt, J¼7.2 Hz, 3H,
CHCH3,alkyne), 1.43 and 1.44 (2ꢂs, 9H, Boc CH3), 3.30 and 3.31 (2ꢂs,
1.33H, CH2C]O), 4.18–4.83 (br m, 2H, NH–CH and NH–CH), 5.160,
5.163, 5.17, 5.20 and 5.21 (d, s, 3ꢂd, each J¼12.5 Hz, 2H, OCH2),
5.76–5.80 (m, 0.67H, HC]C]CH), 7.30–7.40 (m, 5H, Ar–H); 13C
OCH2CH3), 1.46 and 1.47 (2ꢂs, 9H, Boc), 1.78–2.15 (br m, 3H, H-3/
H-4 pyrrolidine), 3.16–3.51 (br m, 3.6H, H-2 pyrrolidine/
CH2C]O), 4.17 (q, J¼7.2 Hz, 2H, OCH2), 4.36–4.60 (m, 1H, NCH),
5.65–5.77 (m, 0.4H, HC]C]CH); EIMS 281 (Mþ). Anal. Calcd for
C15H23NO4ꢂ2/3H2O: C, 61.41; H, 8.36; N, 4.77. Found: C, 61.09; H,
8.18; N, 4.69.
NMR (90 MHz, CDCl3; mixture of diastereomers/isomers)
d 15.3,
20.7 and 22.7, 26.0 (3ꢂCHCH3 and CH2C]Oalkyne), 28.33 and 28.35
(Boc CH3), 38.5 (NCHalkyne), 44.3 (NCHallenes), 65.8 and 66.6, 67.2
(OCH2), 73.7 (C^C–CH2), 79.7 (Boc Cq), 84.2 (C^C–CH2), 90.7 and
91.1 (C]CH–C]O), 99.4 and 99.7 (HC]C]CH–C]O), 128.0, 128.1,
128.2, 128.4, 128.5, and 128.6 (aryl CH), 135.4 and 135.9 (aryl C),
154.6 (Boc C]Oalkyne), 154.86 and 154.90 (Boc C]Oallenes), 165.3
and 165.4 (ester C]Oallenes), 168.1 (ester C]Oalkyne), 211.3 and 211.5
(C]C]C); EIMS 317 (Mþ).
4.6.4. (S)-2-(3-Benzyloxycarbonylprop-1-ynyl)-pyrrolidine-1-
carboxylic acid tert-butyl ester (17b) and a mixture of diastereomers
of (S)-2-(3-benzyloxycarbonylpropa-1,2-dienyl)-pyrrolidine-1-
carboxylic acid tert-butyl ester (17b0)
Compound 6 (249.0 mg, 1.280 mmol) in acetonitrile (5 mL) was
reacted with CuI (25.5 mg, 0.134 mmol) and benzyl diazoacetate
(248.0 mg, 0.141 mmol) for 21 h following the general procedure.
Flash column chromatography (2ꢂseparation, hexanes/ethyl ace-
tate 9:1) furnished 169.6 mg (39%, still containing w10% of allene
fraction as determined by 1H NMR) of 17b as clear colorless oil and
42.4 mg (10%) of 17b0 as yellowish oil, respectively.
4.6.6. (S)-5-tert-Butoxycarbonylamino-6-phenylhex-3-ynoic acid
benzyl ester (24b) and a mixture of diastereomers of (S)-5-tert-
butoxycarbonylamino-6-phenylhexa-2,3-dienoic acid benzyl
ester (24b0)
Compound 23b (202.0 mg, 0.823 mmol) was reacted in aceto-
nitrile (5 mL) with CuI (21.5 mg, 0.113 mmol) and benzyl diazo-
acetate (183.8 mg, 1.043 mmol) for 20 h following the general
procedure. Flash column chromatography (hexanes/ethyl acetate
95:5) furnished 227.8 mg (70%, still containing w40% of the allene
fraction as a mixture of diastereomers as determined by 1H NMR) of
a non separable mixture of 24b/24b0 as yellowish, viscous oil. Rf
0.24 (hexanes/ethyl acetate 8:2); IR (neat) 3411, 3356, 2976, 1963,
4.6.4.1. Compound 17b (including the signals of 10% allene derivative
17b0). Rf 0.33 (hexanes/ethyl acetate 7:3); IR (neat) 2976, 2111, 1748,
1697 cmꢀ1
;
1H NMR (600 MHz, CDCl3; rotamers and broadened
signals were observed)
d
1.44 and 1.46 (2ꢂs, 9H, Boc CH3), 1.74–1.92
and 1.92–2.13 (2ꢂm, 4H, H-3/H-4 pyrrolidine), 3.18–3.51 and 3.31
(m and s, 3.8H, H-5 pyrrolidine and CH2C]O), 4.36–4.60 (2ꢂm, 1H,
H-2 pyrrolidine), 5.08–5.26 and 5.16 (m and s, 2H, OCH2/HC–C]O),
5.68–5.79 (m, 0.2H, HC]C]C), 7.28–7.40 (m, 5H, Ar–H); EIMS 343
(Mþ). Anal. Calcd for C20H25NO4ꢂ1/3H2O: C, 68.75; H, 7.40; N, 4.08.
Found: C, 68.82; H, 7.48; N, 4.00.
1743, 1712 cmꢀ1 1H NMR (600 MHz, CDCl3; all signals of the mix-
;
ture of alkyne, diastereomeric allene derivatives and rotamers are
given, peaks of common functional groups are not separately dis-
closed, but regarded as if derived from a single compound)
d 1.38,
1.39 and 1.42 (3ꢂs, 9H, Boc CH3), 2.79–3.01 (m, 2H, CHCH2), 3.29 (br
s, 1.2H, C^C–CH2), 4.50–4.71 (m, 2H, NH–CH), 5.16, 5.17 and 5.18
(3ꢂs, 2H, OCH2), 5.67–5.77 (m, 0.8H, HC]C]CH), 7.16–7.41 (m,
10H, Ar–H); 13C NMR (90 MHz, CDCl3; all signals of the mixture of
alkyne, diastereomeric allene derivatives and rotamers are given)
4.6.4.2. Compound 17b0. Rf 0.34 (hexanes/ethyl acetate 7:3); IR
(neat) 2976, 1961, 1720, 1695 cmꢀ1 1H NMR (600 MHz, CDCl3;
;
mixture of diastereomers, peaks of common functional groups are
not separately disclosed, but integrated as if derived from a single
compound)
d
1.45 (br s, 9H, Boc CH3), 1.74–2.08 (m, 4H, H-3/H-4
d 26.0 (C^C–CH2), 28.28 and 28.32 (Boc CH3), 41.2, 41.5, 41.8, 42.0,
pyrrolidine), 3.17–3.41 (m, 2H, H-5 pyrrolidine), 4.35–4.48 and
4.48–4.59 (2ꢂm, each 0.5H, NCH), 5.13 (d, J¼12.4 Hz, 1H, OCH2),
5.21 (d, J¼12.4 Hz, 1H, OCH2), 5.66–5.78 and 5.84–5.96 (2ꢂm, 1.5
and 0.5H, HC]C]CH), 7.28–7.43 (m, 5H, Ar–H); 13C NMR (90 MHz,
CDCl3; mixture of diastereomers, peaks of common functional
groups are not separately disclosed, but regarded as if derived
44.1 and 49.8 (CHCH2 and NCHallenes), 66.7 and 67.2 (OCH2), 75.7
(C^C–CH2), 79.8 (Boc Cq), 82.5 (C^C–CH2), 90.9 and 91.3 (CH–
C]O), 97.8 and 98.1 (HC]C]C), 126.7, 128.1, 128.2, 128.3, 128.4,
128.54,128.56,128.60,129.5,129.9 (30ꢂaryl CH),135.4,135.8,136.6,
136.8 and 136.9 (6ꢂaryl C), 154.6, 154.8 and 155.0 (3ꢂBoc C]O),
165.2 (ester C]Oallenes), 167.9 (ester C]Oalkyne), 211.0 and 211.3
(C]C]C); HRMS calcd for C17H21NO4 393.1940; found 393.1940.
from a single compound)
d 23.0 and 23.8 (C-4 pyrrolidine), 28.5

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6163
4.7. General procedure for synthesis of the 1,2,3-triazoles
(5a,b, 8a,b, 15a,b, 18a,b, 25a,b)
188.5 mg (81%) of 8a as a colorless solid. Mp 176 ꢁC; Rf 0.26 (CH2Cl2/
24
MeOH 95:5); [
a
]
ꢀ18.8 (c 0.25, MeOH); IR (neat) 3127, 2978, 2249,
D
1735, 1718, 1700, 1660 cmꢀ1
;
1H NMR (360 MHz, CDCl3; rotamers
1.21, 1.42 and 1.44 (3ꢂbr s,
The alkynoates were dissolved in DMSO or DMF and NaN3 and
NH4Cl were added under stirring at rt. The mixture was heated, if
required, to complete the reaction. Work up was done in different
ways: In case of 5a, b, 15b, and 18a, the reaction mixture was di-
luted with water (50 mL), brine (5 mL), and HCl (2 N, 5 mL) and
extracted with ethyl acetate (4ꢂ20 mL). The combined organic
layers were washed with brine (20 mL), dried over Na2SO4, and
concentrated. For 8a,b, 15a, 18b and 25a,b, water was added, the
reaction mixture was frozen in liquid nitrogen and lyophilized. In
all cases the dark residue was finally purified by flash column
chromatography. For the latter work up, the residue was dissolved
in CH2Cl2, silica gel was then added, and after evaporation the
residue was used for flash chromatography. Remark: yields were
not corrected with respect to the alkyne if alkyne/allene mixtures
were utilized. Due to the formation of rotamers and the absence of
protons, in some cases the 13C signals for the triazole C-4 and C-5
could not be detected.
and broadened signals were observed)
d
12H, Boc CH3 and OCH2CH3), 1.83–2.07 (br m, 3H, H-3/H-4 pyrro-
lidine), 2.29–2.49 (br m, 1H, H-3 or H-4 pyrrolidine), 3.39–3.76 (br
m, 2H, H-5 pyrrolidine), 4.45 (br m, 2H, OCH2), 5.46–5.54 (br m, 1H,
H-2 pyrrolidine), 13.63 and 14.07 (2ꢂbr s, 1H, triazole–NH); 13C
NMR (150 MHz, CDCl3; rotamers and broadened signals were ob-
served) d 14.2 (ester CH3), 23.4 and 23.7 (C-4 pyrrolidine), 28.1 and
28.5 (Boc CH3), 32.7 and 33.5 (C-3 pyrolidine), 46.7 and 47.1 (C-5
pyrrolidine), 52.9 and 53.4 (C-2 pyrolidine), 61.3 (OCH2), 80.0 (Boc
Cq), 134.7 (triazole C-5), 154.8 (Boc C]O), 161.4 (ester C]O), for the
determination of the triazole C-4 the amount of substance was not
sufficient; EIMS 310 (Mþ). Anal. Calcd for C14H22N4O4: C, 54.18; H,
7.15; N, 18.05. Found: C, 54.26; H, 7.19; N, 18.08.
4.7.4. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-yl)-3H-1,2,3-
triazole-4-carboxylic acid benzyl ester (8b)
Compound 7b (329.4 mg, 1.000 mmol) in DMSO (5.0 mL) was
reacted with NaN3 (325.0 mg, 5.00 mmol) and NH4Cl (53.5 mg,
1.000 mmol) in a sealed tube for 80 min at 100 ꢁC following the
general procedure. Flash column chromatography (CH2Cl2/acetone
4.7.1. 5-(N-tert-Butoxycarbonylaminomethyl)-3H-1,2,3-triazole-4-
carboxylic acid benzyl ester (5a)
Compound 3a (76.9 mg, 0.266 mmol) in DMSO (3.5 mL) was
reacted at rt with NaN3 (86.4 mg, 1.33 mmol) and NH4Cl (28.4 mg,
0.532 mmol) for 9 h following the general procedure. Flash column
chromatography (hexanes/ethyl acetate 6:4) furnished 27.3 mg
(31%) of 5a as a yellowish resin. Rf 0.31 (hexanes/ethyl acetate 1:1);
IR (neat) 3361, 3118, 2931,1739,1716,1687 cmꢀ1; 1H NMR (360 MHz,
9:1) furnished 167.1 mg (45%) of 8b as a yellowish resin. Rf 0.49
24
(CH2Cl2/acetone 7:3); [
a
]
ꢀ12.3 (c 1.0, CHCl3); IR (neat) 3112, 2977,
D
2266, 1730, 1717, 1700, 1697, 1687, 1654 cmꢀ1
;
1H NMR (360 MHz,
1.17 and
CDCl3; rotamers and broadened signals were observed)
d
1.43 (2ꢂs, 9H, Boc CH3), 1.73–2.03 (br m, 3H, H-3/H-4 pyrrolidine),
2.19–2.41 (br m,1H, H-3 or H-4 pyrrolidine), 3.37–3.57 (br m,1H, H-
5 pyrrolidine), 3.59–3.74 (br m, 1H, H-5 pyrrolidine), 5.24–5.53 (m,
3H, H-2 pyrrolidine/OCH2), 7.29–7.39 (m, 3H, Ar–H), 7.39–7.48 (m,
2H, Ar–H), 13.53 (br s, 1H, triazole–NH); 13C NMR (150 MHz, CDCl3;
CDCl3; rotamers and broadened signals were observed) d 1.43 (s, 9H,
Boc CH3), 4.63 (d, 2H, J¼5.9 Hz, NCH2), 5.41 (s, 2H, OCH2), 5.49 (br s,
1H, NH), 7.32–7.48 (m, 5H, Ar–H); 13C NMR (150 MHz, CDCl3;
broadened signals were observed)
d
28.3 (Boc CH3), 34.6 (NCH2),
rotamers and broadened signals were observed) d 23.3 and 23.7 (C-
67.1 (OCH2), 80.8 (Boc Cq),128.54 and 128.56 (5ꢂaryl CH),135.3 (aryl
C), 135.3 (br, triazole C-4), 144.1 (br, triazole C-5), both triazole
carbons also evaluated by HBMC-NMR,156.6 (Boc C]O),161.3 (ester
C]O); EIMS 332 (Mþ). Anal. Calcd for C16H20N4O4: C, 57.82; H, 6.07;
N, 16.86. Found: C, 57.98; H, 6.14; N, 16.81.
4 pyrrolidine), 28.1, 28.5 and 29.6 (Boc CH3), 32.8 and 33.5 (C-3
pyrrolidine), 46.7 and 47.0 (NCH2), 52.8 and 53.2 (C-2 pyrrolidine),
66.8 (OCH2), 80.0 and 80.3 (Boc Cq), 128.4, 128.5 and 128.6 (5CH),
134.2 (br, triazole C-4), 135.4 (aryl C), 150.1 (br, triazole C-5, signal is
very weak), 154.7 (Boc C]O), 161.0 and 161.2 (ester C]O); EIMS
372 (Mþ); HRMS calcd for C19H24N4O4 372.1798; found 372.1797.
4.7.2. 5-(N-tert-Butoxycarbonyl-N-methylaminomethyl)-3H-1,2,3-
triazole-4-carboxylic acid benzyl ester (5b)
4.7.5. 5-(N-tert-Butoxycarbonyl-2-aminoethyl)-3H-1,2,3-triazole-
4-carboxylic acid ethyl ester (15a) and 2-[1-(2-tert-Butoxycarbonyl-
aminoethyl)-1H-tetrazol-5-yl]-acetic acid ethyl ester (16)
Compound 13a (55.4 mg, 0.230 mmol) was reacted in DMF
(3.5 mL) at 75 ꢁC with NaN3 (74.5 mg, 1.148 mmol) and NH4Cl
(12.7 mg, 0.295 mmol) for 3 h following the general procedure.
Flash column chromatography (CH2Cl2/ethyl acetate 9:1) furnished
31.7 mg (49%) of 15a as a colorless solid and 11.1 mg (16%) of 16 as
colorless needles.
Compound 3b (100 mg, 0.330 mmol) was reacted at room
temperature in DMSO (2.0 mL) with NaN3 (214.5 mg, 3.30 mmol)
and NH4Cl (35.3 mg, 0.660 mmol) for 40 min following the general
procedure. Upon addition of the reactants, the mixture turned blue
and then quickly red. Flash column chromatography (hexanes/ethyl
acetate 6:4) furnished 66.2 mg (58%) of 5b as a yellowish resin. Rf
0.31 (hexanes/ethyl acetate 1:1); IR (neat) 3133, 2930, 1718, 1698,
1669 cmꢀ1
;
1H NMR (360 MHz, CDCl3; rotamers and broadened
signals were observed)
d
1.40 and 1.46 (2ꢂbr s, 9H, Boc CH3), 2.86
and 2.91 (2ꢂbr s, 3H, NCH3), 4.73 (s, 2H, NCH2), 5.41 (s, 2H, OCH2),
4.7.5.1. Compound 15a. Mp 93–95 ꢁC; Rf 0.25 (CH2Cl2/ethyl acetate
7.30–7.39 (m, 3H, Ar–H), 7.43–7.48 (m, 2H, Ar–H), 13.20 (br s, 1H,
7:3); IR (neat) 3356, 3176, 3122, 2979, 1717, 1691 cmꢀ1 1H NMR
;
triazole–NH); 13C NMR (90 MHz, CDCl3)
d
28.5 and 29.8 (Boc CH3),
(600 MHz, CDCl3)
d
1.37 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.38 (s, 9H, Boc
35.6 (NCH3), 41.8 and 44.1 (NCH2), 67.1 (OCH2), 81.2 (Boc Cq), 128.6,
128.7 and 128.8 (aryl CH), 135.5 (aryl C and br triazole C-4, evalu-
ated by HBMC-NMR), 141.4 and 145.8 (br, triazole C-5), 156.2 and
157.3 (Boc C]O), 161.3 (ester C]O); EIMS 346 (Mþ). Anal. Calcd for
C17H22N4O4: C, 58.95; H, 6.40; N, 16.17. Found: C, 59.11; H, 6.51; N,
16.21.
CH3), 3.17–3.26 (m, 2H, NCH2CH2), 3.48–3.56 (m, 2H, NCH2), 4.40 (q,
J¼7.1 Hz, 2H, OCH2), 5.25 and 5.49 (2ꢂbr s, 1H, NH); 13C NMR
(150 MHz, CDCl3)
d 14.2 (ester CH3), 25.5 (NCH2CH2), 28.3 (Boc
CH3), 39.2 and 40.4 (NCH2), 61.3 (OCH2), 80.0 and 80.7 (Boc Cq),
135.7 (triazole C-4), 144.0 (br, triazole C-5), both triazole carbons
also confirmed by HBMC-NMR,156.7 (Boc C]O),161.7 (ester C]O);
EIMS 284 (Mþ).
4.7.3. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-yl)-3H-1,2,3-
triazole-4-carboxylic acid ethyl ester (8a)
Compound 7a (200.0 mg, 0.748 mmol) in DMSO (10.0 mL) was
reacted with NaN3 (243.2 mg, 3.74 mmol) and NH4Cl (40.0 mg,
0.748 mmol) for 200 min at 100 ꢁC following the general procedure.
Flash column chromatography (CH2Cl2/MeOH 95:5) furnished
4.7.5.2. Compound 16. Mp 83–86 ꢁC; Rf 0.49 (CH2Cl2/ethyl acetate
7:3); IR (neat) 3365, 2979, 1739, 1711 cmꢀ1 1H NMR (360 MHz,
;
CDCl3)
d
1.29 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.42 (s, 9H, Boc CH3), 3.67
(dt, 2H, J¼5.9, 5.7 Hz, NCH2), 4.03 (s, 2H, CH2C]O), 4.22 (q, 2H,
J¼7.2 Hz, OCH2), 4.47 (t, 2H, J¼5.7 Hz, NCH2CH2), 4.95 (br s,1H, NH);

6164
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
13C NMR (90 MHz, CDCl3)
d
14.0 (ester CH3), 28.3 (Boc CH3), 29.5
7.44–7.49 (m, 2H, Ar–H), 14.80 (br s, 1H, triazole–NH); 13C NMR
(150 MHz, CDCl3; rotamers and broadened signals were ob-
served) d 22.6 and 23.3 (C-4 pyrrolidine), 28.4 (Boc CH3), 29.4 and
30.9 (C-3 pyrrolidine/CH2–triazole), 46.0 and 46.6 (C-5 pyrroli-
dine), 56.3 (C-2 pyrrolidine), 66.6 (OCH2), 79.8 and 80.8 (Boc Cq),
128.3 and 128.6 (aryl CH), 135.4 (br, triazole C-4), 135.7 (aryl C),
141.3 (very weak signal, triazole C-5), 154.9 and 155.9 (Boc C]O),
161.4 and 161.8 (ester C]O); EIMS 386 (Mþ). Anal. Calcd for
C20H26N4O4ꢂ2/3H2O: C, 60.29; H, 6.91; N, 14.06. Found: C, 59.94;
H, 6.66; N, 13.71.
(CH2C]O), 39.8 (NCH2), 47.2 (NCH2CH2), 62.4 (OCH2), 80.3 (Boc Cq),
149.7 (tetrazole C),155.9 (Boc C]O),166.6 (ester C]O); ESI-MS 322
[MþNa]þ, 300 [MþH]þ. Anal. Calcd for C12H21N5O4: C, 48.15; H,
7.07; N, 23.40. Found: C, 48.17; H, 7.12; N, 23.50.
4.7.6. 5-(2-tert-Butoxycarbonylaminoethyl)-3H-1,2,3-triazole-4-
carboxylic acid benzyl ester (15b)
For the preparation of 15b, we applied phase transfer conditions.
Compound 13b (105.2 mg, 0.347 mmol, contaminated with 13b0),
NaN3 (227.6 mg, 3.0501 mmol) and tetrabutylammonium bromide
(44.2 mg, 0.1371 mmol) were dissolved in CHCl3/water (1:1, 4.0 mL)
and three times subjected to microwave irradiation (constantly
75 W). Each time, the irradiation was stopped at a temperature of
55 ꢁC. Then the separated aqueous layer was extracted with CHCl3
(2ꢂ10 mL), the combined organic layers were washed with brine
(10 mL) and dried over Na2SO4. After removal of the solvent, flash
column chromatography (CH2Cl2/MeOH 95:5) furnished 38.5 mg
(32%) of 15b as a yellowish resin.
4.7.9. 5-((S)-2-tert-Butoxycarbonylamino-propyl)-3H-1,2,3-
triazole-4-carboxylic acid benzyl ester (25a)
The mixture of compounds 24a/a0 (246.7 mg, 0.777 mmol) in
DMF (6.0 mL) was reacted in a sealed tube with NaN3 (252.9 mg,
3.890 mmol) and NH4Cl (40.5 mg, 0.757 mmol) for 95 min at 105 ꢁC
following the general procedure. Flash column chromatography
(CH2Cl2/MeOH 98:2) furnished 102.0 mg (36%) of 25a as a yellowish
25
resin. Rf 0.46 (CH2Cl2/MeOH 9:1); [
a
]
ꢀ9.5 (c 1.833, CHCl3); IR
D
(neat) 3363, 3178, 3114, 2976, 2252, 2103, 1716 cmꢀ1
;
1H NMR
4.7.6.1. Compound 15b. Rf 0.32 (CH2Cl2/MeOH 95:5); IR (neat)
(600 MHz, CDCl3; broadened signals were observed) 1.20 (d, 3H,
d
3363, 3178, 3114, 2977, 2933, 2109, 1738, 1728, 1716, 1689,
J¼4.5 Hz, CHCH3), 1.37 (s, 9H, CH3 Boc), 3.00–3.25 (m, 2H, CH2–
triazole), 3.96–4.13 (m, 1H, CH), 4.85 (br s, 1H, NH), 5.40 (s, 2H,
OCH2), 7.29–7.38 (m, 3H, Ar–H), 7.42–7.50 (m, 2H, Ar–H),14.23 (br s,
1H, triazole–NH); 13C NMR (90 MHz, CDCl3; broadened signals were
1674 cmꢀ1
;
1H NMR (360 MHz, CDCl3)
d
1.41 (s, 9H, Boc CH3), 3.20
(br m, 2H, NCH2CH2), 3.51 (br m, 2H, NCH2), 5.02 (br s, 1H, NH), 5.39
(s, 2H, OCH2), 7.29–7.30 (m, 3H, Ar–H), 7.42–7.47 (m, 2H, Ar–H); 13
NMR (90 MHz, CDCl3) 26.0 (NCH2CH2), 28.3 (Boc CH), 38.7 (NCH2),
C
d
observed) d 21.5 (CHCH3), 28.3 (Boc CH3), 32.3 (CH2–triazole), 46.1
66.8 (OCH2), 80.6 (Boc Cq), 128.4, 128.5 and 128.6 (aryl CH), 135.5
(aryl C), 135.6 (br, triazole C-4), 143.5 (v br, triazole C-5), 156.9 (Boc
C]O), 161.4 (ester C]O); EIMS 346 (Mþ). Anal. Calcd for
C17H22N4O4: C, 58.95; H, 6.40; N, 16.17. Found: C, 58.47; H, 6.98; N,
15.88.
(NCH), 66.8 (OCH2), 80.5 (Boc Cq), 128.4, 128.5 and 128.6 (5ꢂaryl
CH), 135.5 (aryl C), 135.9 (triazole C-4), 142.4 (br, triazole C-5), 156.3
(Boc C]O), 161.6 (ester C]O); EIMS 360 (Mþ). Anal. Calcd for
C18H24N4O4ꢂ1/8H2O: C, 59.61; H, 6.74; N, 15.45. Found: C, 59.87; H,
6.77; N, 15.01.
4.7.7. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-ylmethyl)-3H-
1,2,3-triazole-4-carboxylic acid ethyl ester (18a)
Compound 17a (102.5 mg, 0.3643 mmol) in DMSO (10.0 mL)
was reacted in a sealed tube with NaN3 (118.4 mg, 1.821 mmol) and
NH4Cl (19.5 mg, 0.364 mmol) for 3 h at 100 ꢁC following the general
procedure. Flash column chromatography (CH2Cl2/MeOH 9:1) fur-
4.7.10. 5-((S)-2-tert-Butoxycarbonylamino-3-phenylpropyl)-3H-
[1,2,3]triazole-4-carboxylic acid benzyl ester (25b)
The mixture of compounds 24b,b0 (128.8 mg, 0.327 mmol) in
DMF (4.0 mL) was reacted in a sealed tube with NaN3 (120.0 mg,
0.327 mmol) and NH4Cl (18.5 mg, 0.346 mmol) for 95 min at 105 ꢁC
following the general procedure. Flash column chromatography
nished 26.4 mg (23%) of 18a as a yellowish resin. Rf 0.17 (CH2Cl2/
(CH2Cl2/MeOH 98:2) furnished 102.0 mg (38%) of 25b as a yellow-
22
25
MeOH 9:1); [
a
]
þ6.4 (c 1.0, CHCl3); IR (neat) 3179, 3118, 2977,
ish resin. Rf 0.50 (CH2Cl2/MeOH 9:1); [
a
]
ꢀ1.3 (c 1.505, CHCl3); IR
D
D
2106, 1718, 1694, 1666 cmꢀ1; 1H NMR (360 MHz, CDCl3; broadened
signals were observed)
(neat) 3368, 3172, 2929, 2251, 2104, 1714 cmꢀ1; 1H NMR (600 MHz,
CDCl3; broadened signals were observed) 1.31 (br s, 9H, CH3 Boc),
d
1.42 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.46 (s, 9H,
d
Boc CH3), 1.72–2.06 (br m, 3H, H-3/H-4 pyrrolidine), 3.18–3.52 (m,
4H, H-5 pyrrolidine and CHCH2–triazole), 4.16–4.31 (m, 1H, H-2
pyrrolidine), 4.42 (q, J¼7.2 Hz, 2H, OCH2), 14.70 (br s, 1H, triazole–
2.71–2.93 (m, 2H, CH2Ph or CH2–triazole), 3.04–3.28 (m, 2H,
CHCH2–Ph or CH2–triazole), 4.11–4.31 (m, 1H, NCH), 4.84 (br s, 1H,
NH), 5.36 (s, 2H, OCH2), 7.10–7.17 (m, 2H, Ar–H), 7.18–7.24 (m, 1H,
Ar–H), 7.24–7.30 (m, 2H, Ar–H), 7.30–7.39 (m, 3H, Ar–H), 7.41–7.46
(m, 2H, Ar–H), 13.95 (br s, 1H, triazole–NH); 13C NMR (150 MHz,
NH); 13C NMR (90 MHz, CDCl3)
d 14.3 (ester CH3), 23.3 (C-4 pyr-
rolidine), 28.4 (Boc CH3), 29.6 and 31.2 (C-3 pyrrolidine/CH2–tri-
azole), 46.6 (C-5 pyrrolidine), 56.4 (C-2 pyrrolidine), 61.0 (OCH2),
81.0 (Boc Cq), 135.6 (br, triazole C-4), 141.3 (v br, triazole C-5), 155.9
(Boc C]O), 162.0 (ester C]O); EIMS 324 (Mþ); HR-EIMS calcd for
C15H24N4O4 324.1798; found 324.1798.
CDCl3; broadened signals were observed)
d 28.2 (Boc CH3), 30.1
(CH2–triazole), 41.7 (CH2–Ph), 50.9 (NCH), 66.9 (OCH2), 80.5 (Boc
Cq), 126.8, 128.4, 128.57, 128.63 and 129.3 (10ꢂaryl CH), 135.4 (aryl
C), 135.8 (br, triazole C-4), 137.0 (aryl C), 143.4 (br, triazole C-5),
156.4 (Boc C]O), 161.5 (ester C]O); EIMS 345 [MꢀC7H7]þ. Anal.
Calcd for C24H28N4O4: C, 66.04; H, 6.47; N,12.84. Found: C, 65.93; H,
6.54; N, 12.21.
4.7.8. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-ylmethyl)-3H-
1,2,3-triazole-4-carboxylic acid benzyl ester (18b)
Compound 17b (429.3 mg, 1.250 mmol) in DMF (5.0 mL) was
reacted in a sealed tube with NaN3 (406.3 mg, 6.250 mmol) and
NH4Cl (67.0 mg, 1.250 mmol) for 1 h at 100 ꢁC following the
general procedure. Flash column chromatography (hexanes/ethyl
4.8. General procedure for hydrogenolytic debenzylation of
the benzyl esters (10, 15c, and 20)
acetate 9:1) furnished 239.1 mg (49%) of 18b as a yellowish resin.
The benzyl ester derivatives were dissolved in ethyl acetate or
ethyl acetate/methanol (1:1), then Pd(OH)2/C was added, then re-
petitive cycles of evaporation and exposition with H2 were per-
formed and stirring under H2 atmosphere at room temperature was
continued. After TLC indicated complete conversion of the starting
materials, the mixture was filtered over Celite, concentrated in
vacuo, and the crude product was purified by flash column
chromatography.
24
Rf 0.35 (hexanes/ethyl acetate 9:1); [
a
]
þ12.4 (c 0.5, CHCl3); IR
D
(neat) 3169, 3114, 2976, 2249, 2107, 1720, 1692, 1652 cmꢀ1
NMR (360 MHz, CDCl3; rotamers and broadened signals were
observed)
;
1H
d
1.32 and 1.46 (2ꢂs, 9H, Boc CH3), 1.60–2.04 (br m, 4H,
H-3/H-4 pyrrolidine), 3.05–3.47 (m, 4H, H-5 pyrrolidine and
CHCH2–triazole), 4.16–4.30 (m, 1H, H-2 pyrrolidine), 5.38 and
5.43 (2ꢂd, each J¼12.3 Hz, 2H, OCH2), 7.27–7.39 (m, 3H, Ar–H),

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6165
4.8.1. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-yl)-3H-1,2,3-
triazole-4-carboxylic acid (10)
corresponding primary amine derivative was added dropwise (in
case of 26a,b and 27a,b DIPEA was omitted). The mixture was
allowed to warm to room temperature, and, after TLC had indicated
complete conversion of the starting materials, the solvent was re-
moved. In case of 11, 21 27a,b, the residue was directly subjected to
flash column chromatography. In case of 26a,b the solid residue
was partitioned between CH2Cl2 (10 ml) and HCl (2 N, 10 mL), the
aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL), the combined
organic layers were washed with brine (10 mL), and dried over
Na2SO4. After removal of the solvent, the residue was subjected to
flash column chromatography.
Compound 8b (73.8 mg, 0.198 mmol) in ethyl acetate/methanol
1:1 (6 mL) was reacted for 50 min following the general procedure
with H2 and Pd(OH)2/C (40 mg; w20% Pd). Flash column chroma-
tography (CH2Cl2/MeOH/formic acid 95:5:0.025) furnished 45.1 mg
(81%) of 10 as a colorless solid. Mp 142–144 ꢁC; Rf 0.49 (CH2Cl2/
24
MeOH/formic acid 90:10:0.05); [
a]
ꢀ28.4 (c 0.25, MeOH); IR
D
(neat) 3549, 3464, 3103, 2981, 1693, 1660, 1598 cmꢀ1
;
1H NMR
1.14
(360 MHz, CDCl3/DMSO-d6¼1:3; rotamers were observed)
d
and 1.37 (2ꢂs, 9H, Boc CH3), 1.70–2.03 and 2.14–2.38 (2ꢂbr m, 4H,
H-3/H-4 pyrrolidine), 3.33–3.47 and 3.53–3.64 (2ꢂm, 2H, H-5
pyrrolidine), 5.40 (dd, J¼8.1, 3.5 Hz, 1H, H-2 pyrrolidine), 15.14 (br s,
1H, triazole NH); EIMS 282 (Mþ).
4.10.1. (S)-2-(5-Methylcarbamoyl-1H-1,2,3-triazol-4-yl)-
pyrrolidine-1-carboxylic acid tert-butyl ester (11)
Compound 10 (27.7 mg, 0.098 mmol) in DMF (2.0 mL) was
4.8.2. 5-(2-tert-Butoxycarbonylaminoethyl)-3H-1,2,3-triazole-4-
carboxylic acid (15c)
reacted with HATU (41.0 mg, 0.108 mmol)/DIPEA (18
0.108 mmol) and solution of methylamine in ethanol (8 M,
200 L) following the general procedure. Reaction time: 22 h.
Flash column chromatography (CH2Cl2/MeOH 95:5) furnished
22.7 mg (78%) of 11 as a colorless solid. Mp 118–120 ꢁC; Rf 0.51
mL,
Compound 15b (31.0 mg, 0.090 mmol) in ethyl acetate (2 mL)
was reacted for 2 h following the general procedure with H2 and
Pd(OH)2/C (62 mg; w20% Pd). Flash column chromatography
(CH2Cl2/MeOH/formic acid 90:10:0.05) furnished 7.5 mg (33%) of
15c as a colorless solid. Mp 155 ꢁC (decomposition); Rf 0.18 (CH2Cl2/
MeOH/formic acid 90:10:0.5); IR (neat) 3343, 3127, 2932, 1712,
1698 cmꢀ1; 1H NMR (360 MHz, DMSO-d6; rotamers were observed)
m
25
(CH2Cl2/MeOH 9:1); [
a
]
ꢀ26.4 (c 0.25, MeOH); IR (neat) 3427,
D
3328, 3131, 2977, 2247, 1691, 1653 cmꢀ1
CDCl3; rotamers were observed)
;
1H NMR (360 MHz,
1.28 and 1.46 (2ꢂbr s, 9H, Boc
d
CH3), 1.78–2.64 (m, 4H, H-3/H-4 pyrrolidine), 3.02 (d, 3H,
J¼5.0 Hz, NCH3), 3.48–3.61 (m, 1H, H-5 pyrrolidine), 3.62–3.68
(m, 2H, H-5 pyrrolidine), 5.36 and 5.51 (2ꢂbr s, 1H, H-2 pyrro-
d
1.29 and 1.35 (2ꢂbr s, 9H, Boc CH3), 2.99 (t, 2H, J¼6.8 Hz,
NCH2CH2), 3.22 (dt, J¼6.8, 6.4 Hz, 2H, NCH2), 6.50 and 6.89 (2ꢂbr s,
1H, J¼6.4 Hz, CONH); EIMS 256 (Mþ); HR-EIMS calcd for
C10H16N4O4 256.1172; found 256.1174.
lidine); 13C NMR (90 MHz, CDCl3)
d 23.6 (C-4), 25.8 (NCH), 28.3
(Boc CH3), 33.8 (C-3), 47.1 (C-5), 52.9 (C-2), 80.5 (Boc Cq), 136.5
(br, triazole C-5), 145.4 (br) (triazole C-4), 155.2 (Boc C]O), 161.4
(amide C]O); EIMS 295 (Mþ); HRMS calcd for C13H21N5O3
295.1644; found 295.1645.
4.8.3. 5-((S)-1-tert-Butoxycarbonylpyrrolidin-2-ylmethyl)-3H-
1,2,3-triazole-4-carboxylic acid (20)
Compound 18b (38.7 mg, 0.100 mmol) in ethyl acetate (2 mL) was
reacted for 80 min following the general procedure with H2 and
Pd(OH)2/C (22 mg; w20% Pd). Flash column chromatography
(CH2Cl2/MeOH/formic acid95:5:0.025) furnished 29.6 mg (99%)of 20
4.10.2. (S)-2-(5-Methylcarbamoyl-1H-1,2,3-triazol-4-ylmethyl)-
pyrrolidine-1-carboxylic acid tert-butyl ester (21)
Compound 20 (28.4 mg, 0.096 mmol) in DMF (2.0 mL) was
as a colorless solid. Mp 126–130 ꢁC; Rf 0.38 (CH2Cl2/MeOH/formic
reacted with HATU (40.7 mg, 0.107 mmol)/DIPEA (18
0.108 mmol) and a solution of methylamine in ethanol (8 M,
200 L) following the general procedure. Reaction time: 22 h.
mL,
24
acid 90:10:0.05); [
a
]
þ5.1 (c 1.0, MeOH); IR (neat) 3429, 3236, 3180,
D
3124, 2976, 1720, 1693, 1664, 1649 cmꢀ1; 1H NMR (360 MHz, CDCl3;
rotamers were observed) 1.48 (br s, 9H, Boc CH3), 1.70–2.21 (m, 4H,
m
d
Flash column chromatography (CH2Cl2/MeOH 98:2) furnished
H-3/H-4 pyrrolidine), 3.25–3.55 (m, 4H, H-5 pyrrolidine and CH2–
triazole), 4.25–4.37 (m, 1H, H-2 pyrrolidine), 9.54 (br s, 2H, OH and
27.4 mg (93%) of 21 as a colorless resin. Rf 0.59 (CH2Cl2/MeOH
25
9:1); [
a
]
þ1.3 (c 1.0, MeOH); IR (neat) 3427, 3330, 3143, 3114,
D
triazole NH); 13C NMR (90 MHz, CDCl3)
d
23.2 (C-4 pyrrolidine), 28.4
2976, 2242, 1666, 1601 cmꢀ1
;
1H NMR (360 MHz, CDCl3; broad-
d 1.46 (s, 9H, Boc CH3), 1.78–2.14 (m,
(Boc CH3), 29.0 (CH2–triazole), 30.8 (C-3 pyrrolidine), 46.7 (C-5 pyr-
rolidine), 56.5 (C-2 pyrrolidine), 81.1 (Boc Cq), (triazole C-4),135.2 (br,
triazole C-5), 141.6 (br, triazole C-4), 156.0 (Boc C]O), 163.3 (acid
C]O); HRMS calcd for C13H20N4O4 296.1485; found 296.1484.
ened signals were observed)
4H, H-3/H-4 pyrrolidine), 2.99 (d, J¼5.0, 3H, NCH3), 3.26 (dd, 1H,
J¼16.3, 7.2 Hz, CHCH2–triazole), 3.31–3.44 (m, 2H, H-5 pyrroli-
dine), 3.44 (dd, J¼16.3, 5.1 Hz, 1H, CHCH2–triazole), 4.14–4.25 (m,
1H, H-2 pyrrolidine), 7.40 (br s, 1H, CONH); 13C NMR (150 MHz,
4.9. 5-(2-tert-Butoxycarbonylaminoethyl)-3H-1,2,3-]triazole-
CDCl3) d 23.4 (C-4 pyrrolidine), 25.7 (NCH3), 28.5 (Boc CH3), 29.7
4-carboxylic acid (10)
and 31.5 (2ꢂbr, C-3 pyrrolidine/CH2–triazole), 46.7 (C-5 pyrroli-
dine), 56.5 (C-5 pyrrolidine), 81.0 (Boc Cq), 137.7 (br, triazole),
156.2 (Boc C]O), 162.2 (amide C]O), for the determination of
the other triazole carbon the amount of substance was in-
sufficient; EIMS 309 (Mþ); HRMS calcd for C13H21N5O3 295.1644;
found 295.1645.
A solution of 8a (15.4 mg, 0.054 mmol) in THF/H2O 1:1 (4.0 mL)
was stirred at 0 ꢁC and an aqueous solution of LiOH (2 N, 0.5 mL)
was added. The mixture was allowed to warm to room temperature
and was then refluxed for 70 min. After cooling to room tempera-
ture, HCl (2 N, 5.0 mL) and water (20 mL) were added and extrac-
tion with ethyl acetate (4ꢂ20 mL) was performed. The combined
organic layers were washed with brine, dried over Na2SO4, and the
solvent was evaporated. Flash column chromatography (CH2Cl2/
MeOH/formic acid 90:10:0.05) furnished 9.5 mg (69%) of 10 as
a colorless solid. Analytical data see 4.8.1.
4.10.3. (S)-2-(5-((R)-1-Phenylethylcarbamoyl)-1H-1,2,3-triazol-4-
yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (26a)
Compound 10 (2.7 mg, 0.0096 mmol) in DMF (1.5 mL) was
reacted with HATU (7.3 mg, 0.0192 mmol) and a 10% (m/V) solution
of (R)-phenylethylamine in DMF (25 mL, 0.0192 mmol) following
the general procedure stirring 4 h 30 min at 0 ꢁC and 6 h at room
temperature. Flash column chromatography (CH2Cl2/MeOH 97:3)
furnished 1.7 mg (46%) of 26a as a colorless resin. Rf 0.40 (CH2Cl2/
4.10. General procedure for amide formation via HATU
coupling (11, 21, 26a,b, and 27a,b)
MeOH 9:1); HPLC: tR 24.2 min (Luna silica gel 5
m
m, 4.6ꢂ250 mm,
The acids and HATU were dissolved in dry DMF and cooled to
0 ꢁC. Then base (1.1 equiv DIPEA) and subsequently the
hexanes/2-propanol 99:1, 0.25 mL/min, 219/230/254 nm detection;
23
98.3% de); [a]
D
ꢀ32.0 (c 0.100, CHCl3); IR (neat) 3407, 3138, 2925,

6166
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
1693, 1676, 1666, 1653 cmꢀ1
;
1H NMR (360 MHz, CDCl3; rotamers
4.11. General procedure for the synthesis of the N-acetyl
were observed)
d
1.26 (br s, 9H, Boc CH3), 1.59 (d, 3H, J¼6.9 Hz,
derivatives (9, 12, 19, 22)
CHCH3), 1.80–2.15 (m, 3H, H-3/H-4 pyrrolidine), 2.22–2.58 (m, 1H,
H-3 or H-4 pyrrolidine), 3.45–3.57 (m, 1H, H-5 pyrrolidine), 3.57–
3.67 (m, 1H, H-5 pyrrolidine), 5.27 (dq, J¼6.9, 6.9 Hz, 1H, CHCH3),
5.41–5.69 (br m, 1H, H-2 pyrrolidine), 7.20–7.56 (m, 6H, Ar–H/
CONH); EIMS 385 (Mþ); HRMS calcd for C20H27N5O3 385.2114;
found 385.2115.
The N-Boc protected compounds were dissolved in CH2Cl2 at
0 ꢁC, trifluoroacetic acid (TFA) was added and the mixture was
allowed to warm to rt. After 25–50 min, the solvent was removed
and residual TFA was removed by redissolving in CH2Cl2 and sub-
sequent evaporation. The residue was dissolved in CH2Cl2 and
DIPEA and subsequently acetyl chloride was added at 0 ꢁC. Stirring
was continued until TLC (detection: ninhydrin solution at 150 ꢁC for
15–25 min; in case of 19 HPLC–MS analysis) indicated complete
conversion. The solvent was removed and the crude products were
purified by flash column chromatography.
4.10.4. (S)-2-(5-((S)-1-Phenylethylcarbamoyl)-1H-1,2,3-triazol-4-
yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (26b)
Compound 10 (3.0 mg, 0.0106 mmol) in DMF (1.5 mL) was
reacted with HATU (8.1 mg, 0.0212 mmol) and a 10% (m/V) solution
of (S)-phenylethylamine in DMF (28 mL, 0.0212 mmol) following the
general procedure stirring 4 h 30 min at 0 ꢁC and 6 h at room
temperature. Flash column chromatography (CH2Cl2/MeOH 97:3)
furnished 1.0 mg (24%) of 26b as a colorless resin. Rf 0.40 (CH2Cl2/
4.11.1. 5-((S)-1-Acetylpyrrolidin-2-yl)-1H-1,2,3-triazole-4-
carboxylic acid ethyl ester (9)
A solution of compound 8a (40.0 mg, 0.130 mmol) in CH2Cl2
(2.0 mL) was reacted with TFA (1.0 mL) for 50 min. Acetylation:
DIPEA (48 mL, 0.299 mol) and acetyl chloride (17.0 mL, 0.236 mmol)
in CH2Cl2 (1.0 mL) for 16 h. Flash column chromatography (CH2Cl2/
MeOH 9:1); HPLC: tR 21.6 min (silica gel 5
anes/2-propanol 99:1, 0.25 mL/min, 219/230/254 nm detection;
m
m, 4.6ꢂ250 mm, hex-
23
96.4% de); [
2925, 1693, 2252, 1695, 1680, 1666, 1654 cmꢀ1; 1H NMR (360 MHz,
CDCl3; rotamers were observed)
a
]
þ33.0 (c 0.091, CHCl3); IR (neat) 3407, 3301, 3138,
D
MeOH 95:5) furnished 20.1 mg (62%) of 9 as a colorless solid. Mp
25
d
1.26, 1.43 (2ꢂbr s, 9H, Boc CH3),
228 ꢁC; Rf 0.29 (CH2Cl2/MeOH 9:1); [
a
]
D
ꢀ57.2 (c 0.5, MeOH); IR
1.59 (d, 3H, J¼7.0 Hz, CHCH3), 1.74–2.49 (br m, 4H, H-3/H-4 pyrro-
lidine), 3.27–3.71 (br m, 2H, H-5 pyrrolidine), 5.28 (dq, J¼7.0, 7.0 Hz,
1H, CHCH3), 5.20–5.63 (br m, 1H, H-2 pyrrolidine), 7.17–7.51 (m, 6H,
Ar–H/NH); EIMS 385 (Mþ); HRMS calcd for C20H27N5O3 385.2114;
found 385.2114.
(neat) 3437, 3153, 2960, 2885, 2785, 2717, 2615, 1734, 1606 cmꢀ1
;
1H NMR (600 MHz, CDCl3; rotamers were observed, for the de-
termination of the cis/trans ratio in CDCl3 see Supplementary data)
d
1.40 and 1.44 (2ꢂt, each J¼7.2 Hz, 3H, OCH2CH3), 1.87 (s, 1.2H,
acetyl CH3cis), 1.89–2.08 (m, 3H, H-3/H-4 pyrrolidine), 2.14 (s, 1.8H,
acetyl CH3trans), 2.30–2.38 and 2.43–2.51 (m, 1H, H-3 or H-4 pyr-
rolidine), 3.56–3.68 (m, 1H, H-5 pyrrolidine), 3.82–3.93 (m, 1H, H-
5 pyrrolidine), 4.35–4.48 (m, 2H, OCH2), 5.60 (dd, J¼8.0, 1.7 Hz,
0.4H, H-5 pyrrolidinecis), 5.63 (dd, J¼8.0, 1.7 Hz, 0.60H, H-5 pyr-
rolidinetrans); 13C NMR (90 MHz, CDCl3/DMSO-d6¼1:1; cis/trans
4.10.5. (S)-2-(5-((R)-1-Phenylethylcarbamoyl)-1H-1,2,3-triazol-4-
ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (27a)
Compound 20 (6.7 mg, 0.0226 mmol) in DMF (2.0 mL) was
reacted with HATU (17.2 mg, 0.0452 mmol) and (R)-phenylethyl-
amine (7
m
L, 0.0507 mmol) following the general procedure
rotamers were observed) d 13.3 (ester CH3), 21.1 (acetyl CH3cis or
stirring 4 h 50 min at room temperature. Flash column chroma-
tography (CH2Cl2/acetone 9:1) furnished 4.1 mg (46%) of 27a as
C-4 pyrrolidinecis), 21.2 (C-4 pyrolidinecis or acetyl CH3cis), 21.6
(acetyl CH3trans or C-4trans), 22.9 (C-4 pyrolidinetrans or acetyl
CH3trans), 31.4 and 33.1 (C-3 pyrrolidine), 45.4 and 46.9 (C-5 pyr-
rolidine), 51.5 and 53.1 (C-2 pyrrolidine), 59.7 and 60.1 (OCH2),
132.6 and 132.8 (triazole C-4), 146.6 and 146.7 (triazole C-5), 160.1
and 160.2 (ester C]O), 168.2 and 168.4 (amide C]O); EIMS 252
(Mþ); HRMS calcd for C11H16N4O3 252.1222; found 252.1222.
a
colorless resin. Rf 0.37 (CH2Cl2/acetone 85:15); HPLC: tR
15.8 min (silica gel
m, 4.6ꢂ250 mm, hexanes/2-propanol
92:8, 0.25 mL/min, 219/230/254 nm detection; 98.7% de); [
ꢀ42.6 (c 0.1833, CHCl3); IR (neat) 3409, 3126, 2925, 1689, 1668,
1657 cmꢀ1 1H NMR (600 MHz, CDCl3)
1.48 (br s, 9H, Boc
5
m
26
a
]
D
;
d
CH3), 1.59 (d, J¼7.0 Hz, 3H, CHCH3), 1.80–2.04 (m, 4H, H-3/H-4
pyrrolidine), 3.23 (dd, J¼17.0, 8.8 Hz, 1H, CH2–triazole), 3.33
(ddd, J¼11.0, 7.8, 3.1 Hz, 1H, H-5 pyrrolidine), 3.41–3.48 (m, 2H,
H-5 pyrrolidine/CH2–triazole), 4.18–4.24 (m, 1H, H-2 pyrroli-
dine), 5.25 (dq, J¼7.0, 7.0 Hz, 1H, CHCH3), 7.23–7.40 (m, 10H, Ar–
H), 7.54 (br s, 1H, CONH); EIMS 399 (Mþ); HRMS calcd for
C21H29N5O3 399.2270; found 399.2270.
4.11.2. 5-((S)-1-Acetylpyrrolidin-2-yl)-3H-1,2,3-triazole-4-
carboxylic acid methylamide (12)
A solution of compound 11 (15.0 mg, 0.051 mmol) in CH2Cl2
(3.0 mL) was reacted with TFA (1.0 mL) for 50 min. Acetylation:
DIPEA (20 mL, 0.122 mol) and acetyl chloride (17.0 mL, 0.236 mmol)
in CH2Cl2 (2.0 mL) for 16 h. Flash column chromatography
(CH2Cl2/MeOH 95:5 to 9:1) furnished 9.2 mg (77%) of 12 as a col-
25
4.10.6. (S)-2-(5-((S)-1-Phenylethylcarbamoyl)-1H-1,2,3-triazol-4-
ylmethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (27b)
Compound 20 (7.1 mg, 0.0478 mmol) in DMF (2.0 mL) was
reacted with HATU (18.2 mg, 0.0212 mmol) and (S)-phenylethyl-
orless solid. Mp 180–181 ꢁC; Rf 0.24 (CH2Cl2/MeOH 9:1); [
a]
D
ꢀ44.4 (c 0.25, MeOH); IR (neat) 3427, 3369, 3311, 3139, 3091, 2927,
1660, 1606 cmꢀ1
;
1H NMR (600 MHz, CDCl3/DMSO-d6¼95:5; cis/
trans rotamers were observed)
d 1.77 (s, 1.35H, acetyl CH3cis), 1.82–
amine (7
m
L, 0.0507 mmol) following the general procedure
1.89 and 1.90–1.98 (2ꢂm, 2H, H-4 or H-3 pyrrolidine), 2.00–2.06
and 2.07–2.18 (2ꢂm, 1H, H-3 or H-4 pyrrolidine), 2.02 (s, 1.65H,
acetyl CH3trans), 2.90 and 2.91 (2ꢂd, J¼5.7 and 5.3 Hz, 3H, NCH3),
3.44–3.55 (m, 1H, H-5 pyrrolidine), 3.70–3.79 (m, 1H, H-5 pyrro-
lidine), 5.47 (dd, J¼7.8, 1.6 Hz, 0.55H, H-2 pyrrolidinetrans), 5.68
(dd, J¼8.1, 2.1 Hz, 0.45H, H-2 pyrrolidinecis), 7.15 (br s, 0.45H,
CONHcis), 7.88 (br s, 0.55H, CONHtrans); 13C NMR (90 MHz, CDCl3/
stirring 3 h 45 min at room temperature. Flash column chroma-
tography (CH2Cl2/acetone 9:1) furnished 5.4 mg (56%) of 27b as
a colorless solid. Rf 0.18 (CH2Cl2/MeOH 95:5); HPLC: tR 14.4 min
(silica gel 5
min, 219/230/254 nm detection; 97.8% de); [
CHCl3); IR (neat) 3411, 3302, 3138, 2976, 1691, 1666, 1656 cmꢀ1
1H NMR (360 MHz, CDCl3)
1.47 (s, 9H, Boc CH3), 1.59 (d,
m
m, 4.6ꢂ250 mm, hexanes/2-propanol 92:8, 0.25 mL/
26
a]
þ13.6 (c 0.184,
D
;
d
DMSO-d6 3:1; cis/trans rotamers were observed) d 21.3, 21.7, 24.67
J¼6.9 Hz, 3H, CHCH3), 1.79–2.12 (m, 4H, H-3/H-4 pyrrolidine), 3.19
(dd, J¼16.6, 7.7 Hz, 1H, CH2–triazole), 3.27–3.37 (m, 1H, H-5 pyr-
rolidine), 3.37–3.52 (m, 2H, H-5 pyrrolidine/CH2–triazole), 4.14–
4.26 (m, 1H, H-2 pyrrolidine), 5.26 (dq, J¼6.9, 6.9 Hz, 1H, CHCH3),
7.21–7.42 (m, 5H, Ar–H), 7.51 (br s, 1H, CONH); EIMS 399 (Mþ);
HRMS calcd for C21H29N5O3 399.2270; found 399.2270.
and 24.73 (acetyl CH3/NCH3/C-4 pyrrolidine), 31.6 and 33.3 (C-3
pyrrolidine), 45.5 and 47.1 (NCH2–pyrrolidine), 51.3 and 52.9 (C-4
pyrrolidine), 135.3 and 135.8 (triazole C-4), 143.5 and 144.8 (v br,
triazole C-5), 160.6 and 160.7 (amide C]O), 168.4 and 168.6
(acetyl C]O); EIMS 237 (Mþ); HRMS calcd for C11H16N4O3
237.1226; found 237.1226.

A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
6167
4.11.3. 5-((S)-1-Acetylpyrrolidin-2-ylmethyl)-3H-1,2,3-triazole-4-
carboxylic acid ethyl ester (19)
A solution of compound 18a (13.7 mg, 0.042 mmol) in CH2Cl2
(1.5 mL) was reacted with TFA (0.5 mL) for 45 min. Acetylation:
and allowed to ride on their corresponding carbon atoms. The
isotropic displacement parameters of all hydrogen atoms were tied
to those of the adjacent carbon atoms by a factor of 1.5.
C12H21N5O4, triclinic, P-1 (no. 2), a¼6.1775(3), b¼10.8036(6),
DIPEA (9
CH2Cl2 (1.0 mL) for 5 h and after evaporation of the solvent again
with DIPEA (18 L, 0.170 mmol) and acetyl chloride (15 L,
mL, 0.084 mmol) and acetyl chloride (3
mL, 0.063 mmol) in
c¼12.8540(9) Å,
a
¼74.855(4)ꢁ,
b
¼88.887(4)ꢁ,
g
¼76.713(4)ꢁ,
V¼805.15(8) Å3, Z¼2, rcalcd¼1.235 Mg/m3,
m
(Mo K
a
)¼0.094 mmꢀ1
,
m
m
F(000)¼320, 17,856 reflections collected, 3541 independent re-
0.326 mmol) in CH2Cl2 (1.0 mL) for 3.5 h. Flash column chroma-
flections, 2701 observed reflection [I>2
s
(I)], R1[I>2
s
(I)]¼0.0463,
tography (CH2Cl2/MeOH 95:5) furnished 4.4 mg (62%) of 19 as
wR2 (all data)¼0.1140, GooF (all data)¼1.147, Drmax/min¼0.252/
25
a colorless solid. Mp 129–131 ꢁC; Rf 0.38 (CH2Cl2/MeOH 9:1); [
a
]
ꢀ0.268 e Åꢀ3
.
D
ꢀ4.0 (c 0.25, MeOH); IR (neat) 3103, 2980, 2276, 2102, 1732, 1717,
1652, 1634, 1608 cmꢀ1 1H NMR (600 MHz, CDCl3/DMSO-d6
97.5:2.5; cis/trans rotamers were observed)
1.39 (t, J¼7.2 Hz, 3H,
CCDC-724534 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
;
d
OCH2CH3), 1.71–2.01 (m, 4H, H-3/H-4 pyrrolidine), 2.06 (s, 1.8H,
acetyl CH3trans), 2.11 (s, 1.2H, acetyl CH3cis), 3.06–3.12, 3.16–3.26,
3.34–3.49, 3.46–3.54 and 3.61–3.66 (5ꢂm, 4H, CH2–triazole/H-5
pyrrolidine), 4.21–4.28 (m, 0.4H, H-2 pyrrolidinecis), 4.39 (q, 2H,
J¼7.2 Hz, OCH2), 4.44–4.50 (m, 1H, H-2 pyrrolidinetrans); 13C NMR
Acknowledgements
This work was supported by the Deutsche For-
schungsgemeinschaft (DFG). Iris Torres and Michaela Kettler are
acknowledged for skillful technical assistance.
(90 MHz, CDCl3; cis/trans rotamers were observed)
d 14.3 (ester
CH3), 21.8 (acetyl CH3cis), 22.8 (acetyl CH3trans), 23.6 (C-4 pyrroli-
dine), 27.7 (CH2–triazole), 29.9 and 30.3 (C-3 pyrrolidine), 45.6 and
48.0 (C-5 pyrrolidine), 56.8 and 57.8 (C-2 pyrrolidine), 61.0 (OCH2),
135.7 (br, triazole C-5), 140.7 (br, triazole C-4), 162.2 (ester C]O),
170.0 and 171.2 (amide C]O); EIMS 266 (Mþ); HRMS calcd for
C12H18N4O3 266.1379; found 266.1376.
Supplementary data
Copies of 1H and 13C NMR spectra of compounds 5a,b; 8a,b;
15a,b; 16; 18a,b; 25,a,b; 10; 15c, 20; 11; 21; 27a,b; 9; 12; 19; 22
including selective NOE spectra (DPFGSE pulse sequence) for 9; 12;
19; 22 as well as details of the X-ray crystal structure determination
of 16 in CIF format. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.05.045.
4.11.4. 5-((S)-1-Acetylpyrrolidin-2-ylmethyl)-3H-1,2,3-triazole-4-
carboxylic acid methylamide (22)
A solution of compound 21 (12.0 mg, 0.039 mmol) in CH2Cl2
(2.0 mL) was reacted with TFA (0.5 mL) for 25 min. Acetylation:
DIPEA (13 mL, 0.079 mol) and acetyl chloride (5.0 mL, 0.071 mmol) in
CH2Cl2 (1.0 mL) for 5 h, the same procedure was repeated for 4 h.
Flash column chromatography (CH2Cl2/MeOH 95:5) furnished
References and notes
3.8 mg (39%) of 22 as a colorless resin/solid. Mp 65–67 ꢁC; Rf 0.41
1. Hruby, V. J. Drug Discov. Today 1997, 2, 165–167 and references cited therein.
2. Giannis, A.; Kolter, T. Angew. Chem. 1993, 105, 1303–1326; Angew. Chem., Int. Ed.
Engl. 1993, 32, 1244–1267.
24
(CH2Cl2/MeOH 9:1); [
a
]
D
þ1.7 (c 0.33, MeOH); IR (neat) 3421, 3330,
3102, 2974, 2243, 1647, 1556, 1543 cmꢀ1; 1H NMR (360 MHz, CDCl3,
only the trans rotamer was observed) 1.84–2.09 (m, 3H, H-3/H-4
3. For recent reviews and articles see: (a) Cluzeau, J.; Lubell, W. D. Biopolymers
(Pept. Sci.) 2005, 80, 98–150; (b) Maison, W.; Prenzel, A. H. G. P. Biopolymers
2005, 7, 1031–1048; (c) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.;
Lubell, W. D. Tetrahedron 1997, 53, 12789–12854; (d) Freidinger, R. M. J. Med.
Chem. 2003, 46, 5553–5566; (e) Halab, L.; Gosselin, F.; Lubell, W. D. Biopolymers
(Pept. Sci.) 2000, 55, 101–122; (f) Hoffmann, T.; Waibel, R.; Gmeiner, P. J. Org.
Chem. 2003, 68, 62–69; (g) Weber, K.; Ohnmacht, U.; Gmeiner, P. J. Org. Chem.
2000, 65, 7406–7416; (h) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew.
Chem. 2001, 113, 3465–3468; Angew. Chem., Int. Ed. 2001, 40, 3361–3364; (i)
Bittermann, H.; Gmeiner, P. J. Org. Chem. 2006, 71, 97–102; (j) Bittermann, H.;
Boeckler, F.; Einsiedel, J.; Gmeiner, P. Chem.dEur. J. 2006, 24, 6315–6322; (k)
Lomlim, L.; Einsiedel, J.; Heinemann, F. W.; Meyer, K.; Gmeiner, P. J. Org. Chem.
2008, 73, 3608–3611; (l) Einsiedel, J.; Lanig, H.; Waibel, R.; Gmeiner, P. J. Org.
Chem. 2007, 72, 9102–9113.
4. Angelo, N. G.; Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134–17135.
5. (a) Van Maarseveen, J. H.; Seth Horne, W.; Reza Ghadiri, M. Org. Lett. 2005, 7,
4503–4506; (b) Bock, V. D.; Perciaccante, R.; Paul Jansen, T.; Hiemstra, H.; Van
Maarseveen, J. H. Org. Lett. 2006, 8, 919–922; (c) Hu, T.-S.; Tannert, R.; Arndt, H.-D.;
Waldmann, H. Chem. Commun. 2007, 3942–3944; (d) Turner, R. A.; Oliver, A. G.;
Lokey, R. S. Org. Lett. 2007, 9, 5011–5014.
d
pyrrolidine), 2.11–2.27 (m, 1H, H-3 or H-4 pyrrolidine), 2.17 (s, 3H,
acetyl CH3), 2.99 and 3.01 (2ꢂd, each J¼4.8 Hz, 3H, NCH3), 3.28 (dd,
J¼15.1, 5.4 Hz, 1H, CH2–triazole), 3.47 (ddd, J¼10.1, 9.9, 7.7 Hz, 1H,
H-5 pyrrolidine), 3.48–3.56 (m, 1H, CH2–triazole), 3.59 (ddd, 10.1,
8.7, 2.6 Hz, 1H, H-5 pyrrolidine), 4.27–4.55 (m, 1H, H-2 pyrrolidine),
7.13 and 7.24 (2ꢂbr s, 1H, CONH), 15.18 (br s, 1H, triazole NH); 13C
NMR (90 MHz, CDCl3)
d 22.8, 23.7, 25.6, 28.3 and 29.7 (acetyl CH3,
NCH3, CH2–triazole, C-4 pyrrolidine), 30.6 (C-3 pyrrolidine), 48.0
(C-5 pyrrolidine), 56.8 (C-2 pyrrolidine), 137.5 (br, triazole C-5),
162.2 (br, amide), for the determination of the triazole C-4 the
amount of substance was insufficient; HRMS calcd for C11H17N5O2
251.1382; found 251.1383.
4.12. X-ray crystal structure determination of 16
6. (a) Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674–1689; (b) Franke, R.;
Doll, C.; Eichler, J. Tetrahedron Lett. 2005, 46, 4479–4482; (c) Zhang, Z.; Fan, E.
Tetrahedron Lett. 2006, 47, 665–669; (d) Tornøe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057–3064; (e) Tam, A.; Arnold, U.; Soellner, M. B.;
Raines, R. T. J. Am. Chem. Soc. 2007, 129, 12670–12671.
A colorless needle of approximately 0.30ꢂ0.08ꢂ0.07 mm in size
was coated with protective perfluoropolyalkyl ether oil and
mounted in the cold nitrogen gas stream of a Bruker-Nonius Kap-
7. Paul, A.; Bittermann, H.; Gmeiner, P. Tetrahedron 2006, 62, 8919–8927 and
references cited therein.
paCCD diffractometer. Data were collected at 100 K using Mo K
a
8. McLaughlin, E. C.; Doyle, M. P. J. Org. Chem. 2008, 73, 4317–4319.
9. Sheehan, J. C.; Robinson, C. A. J. Am. Chem. Soc. 1951, 73, 1207–1210.
10. (a) Reginato, G.; Mordini, A.; Capperucci, A.; Degl’Innocenti, A.; Manganiello, S.
Tetrahedron 1998, 54, 10217–10226; (b) Reginato, G.; Mordini, A.; Degl’Innocenti,
A.; Caracciolo, M. Tetrahedron 1996, 52, 10985–10996; (c) Reginato, G.; Mordini,
A.; Messina, F.; Degl’Innocenti, A. Tetrahedron Lett. 1995, 36, 8275–8278; (d)
Cossy, J.; Cases, M.; Pardo, D. G. Bull. Soc. Chim. Fr. 1997, 134, 141–144.
11. Reetz, M. T.; Strack, T. J.; Kanand, J.; Goddard, R. Chem. Commun. 1996, 733–734.
12. Cheng, S.; Tarby, C. M.; Comer, D. D.; Williams, J. P.; Caporale, L. H.; Myers, P. L.;
Boger, D. Bioorg. Med. Chem. 1996, 4, 727–737.
radiation (graphite monochromator). Diffraction intensities were
corrected for Lorentz and polarization effects. A semi-empirical
absorption correction based on multiple measurements of re-
flections was applied (Tmin¼0.918, Tmax¼0.993).32 The structure
was solved by direct methods and refined by full-matrix least-
squares procedures on F2.33 All non-hydrogen atoms were refined
with anisotropic displacement parameters. The position of N5
bound hydrogen atom H5, which is involved in hydrogen bonding
was derived from a difference Fourier synthesis while all other
hydrogen atoms were placed in positions of optimized geometry
13. Bradbury, B. J.; Baumgold, J.; Jacobsen, K. A. J. Med. Chem. 1990, 33, 741–748.
14. Trybulski, E. J.; Benjamin, L.; Vitone, S.; Walser, A.; Fryer, R. I. J. Med. Chem. 1983,
26, 367–372.

6168
A. Paul et al. / Tetrahedron 65 (2009) 6156–6168
15. In acidic medium, toxic and explosive HN3 is formed, see: Bra¨se, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem. 2005, 117, 5320–5374; Angew.
Chem., Int. Ed. 2005, 44, 5188–5240.
23. An, S. S. A.; Lester, C. C.; Peng, J.-L.; Li, Y.-J.; Rothwarf, D. M.; Welker, E.;
Thannhauser, T. W.; Zhang, L. S.; Tam, J. P.; Scheraga, H. A. J. Am. Chem. Soc. 1999,
121, 11558–11566.
16. (a) Jabs, A.; Weiss, M. S.; Hilgenfeld, R. J. Mol. Biol. 1999, 286, 291–304; (b)
Dugave, C.; Demange, L. Chem. Rev. 2003, 103, 2475–2532 and references cited
therein; (c) Lummis, S. C. R.; Beene, D. L.; Lee, L. W.; Lester, H. A.; Broadhurst,
R. W.; Dougherty, D. A. Nature 2005, 438, 248–252; (d) Wittelsberger, A.;
Keller, M.; Scarpellino, L.; Partiny, H.; Acha-Orbea; Mutter, M. Angew. Chem.,
Int. Ed. 2000, 39, 1111–1115; Angew. Chem. 2000, 112, 1153–1156.
17. Sua`rez, A. U.; Fu, G. C. Angew. Chem. 2004, 116, 3664–3666; Angew. Chem., Int.
Ed. 2004, 44, 3580–3582.
24. Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.; Raines, R. T. J. Am.
Chem. Soc. 2001, 123, 777–778.
25. Renner, C.; Alefelder, S.; Bae, J. H.; Budisa, N.; Huber, R.; Moroder, L. Angew.
Chem., Int. Ed. 2001, 40, 923–925.
26. Sonntag, L.-S.; Schweizer, S.; Ochsenfeld, C.; Wennemers, H. J. Am. Chem. Soc.
2006, 128, 14697–14703.
27. Gramberg, D.; Weber, C.; Beeli, R.; Inglis, J.; Bruns, C.; Robinson, J. A. Helv. Chim.
Acta 1995, 78, 1588–1606.
18. Schroen, M.; Bra¨se, S. Tetrahedron 2005, 61, 12186–12192.
19. (a) Stimac, A.; Leban, I.; Kobe, J. Synlett 1999, 1069–1073; (b) Tamura, Y.;
Teruhisha, T,; Shin-Ichiro, M.; Yuko, N.; Yasuyuki, K. Chem. Pharm. Bull. 1985, 8,
3257–3262.
20. Banert, K. Tetrahedron Lett. 1985, 26, 5261–5264.
28. Curran, T. P.; McEnaney, P. M. Tetrahedron Lett. 1995, 36, 191–194.
29. Kim, K.; Dumas, J.-P.; Germanas, J. P. J. Org. Chem. 1996, 61, 3138–3144.
30. Ishimoto, B.; Tonan, K.; Ikawa, S.-i Spectrochim. Acta, Part A 1999, 56, 201–209.
31. Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T.-L.; Shaka, A. J. J. Am. Chem. Soc.
1995, 117, 4199–4200.
ˇ
21. Kern, D.; Schutkowski, M.; Drakenberg, T. J. Am. Chem. Soc. 1997, 119, 8403–8408.
22. Halab, L.; Lubell, W. D. J. Org. Chem. 1999, 64, 3312–3321.
32. SADABS, 2.10; Bruker AXS: Madison, WI, USA, 2002.
33. SHELXTL NT 6.12; Bruker AXS: Madison, WI, USA, 2002.