Triazolopeptides: chirospecific synthesis and cis/trans prolyl ratios of structural isomers

Article abstract of DOI:10.1016/j.tet.2006.07.007

As cis/trans prolyl isomerization plays a crucial role in various biological processes, peptide mimics capable of modifying the cis/trans Xaa-Pro ratio are of particular interest. A practical approach toward proline derived triazolopeptides employing [3+2] azide-alkyne cycloadditions as the key reaction step and the analysis of their cis/trans prolyl ratios are reported. Structural investigations indicated the adjustability of both the cis-percentage and the conformational stability toward intramolecular H-bonding effects.

Full text of DOI:10.1016/j.tet.2006.07.007

Tetrahedron 62 (2006) 8919–8927
Triazolopeptides: chirospecific synthesis and cis/trans prolyl ratios
of structural isomers
*
Andreas Paul, Holger Bittermann and Peter Gmeiner
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19,
D-91052 Erlangen, Germany
Received 18 May 2006; revised 28 June 2006; accepted 1 July 2006
Available online 28 July 2006
Abstract—As cis/trans prolyl isomerization plays a crucial role in various biological processes, peptide mimics capable of modifying the cis/
trans Xaa-Pro ratio are of particular interest. A practical approach toward proline derived triazolopeptides employing [3+2] azide–alkyne
cycloadditions as the key reaction step and the analysis of their cis/trans prolyl ratios are reported. Structural investigations indicated the
adjustability of both the cis-percentage and the conformational stability toward intramolecular H-bonding effects.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
click chemistry, we herein report on the fine tuning of cis/
trans prolyl ratios by bioisosteric replacement of the back-
bone amide group with a 1,2,3-triazole based moiety.14,15
Representing the only naturally occurring cyclic amino acid,
proline displays properties distinct from those of open chain
amino acids, when amide cis/trans isomerization deserves
particular attention.1,2 While engineering a number of mu-
tant proteins to contain artificial proline analogs, Lummis
et al. revealed very recently that cis/trans isomerization of
a Pro in a hinge position of the 5-HT3 receptor elicits open-
ing of an ion channel.3 In fact, mutants bearing Pro mimetics
with a high prevalence for the cis conformer proved consti-
tutively active, while amino acids with very low cis/trans
ratios rendered the receptor inactive. The importance of
cis/trans isomerization for molecular recognition has also
been shown by introduction of unnatural proline derivatives
with an increased cis prevalence into a cyclic HIV-1 V3 loop
analog. This loop has a common Gly-Pro-Gly-Arg motif,
representing a type II b-turn, which is supposed to switch
into a type VI b-turn, demanding a cis-proline peptide
bond, as the key-step before getting the HIV-1 infective.4
These findings underline the importance of molecular tools
for a fine tuning of the cis/trans prolyl energy level ratio
for the elucidation of biological systems.
In contrast to the established methods, this strategy leaves
the geometric properties of the pyrrolidine moiety unmodi-
fied, which can be of particular interest if alterations on
the sterical demand of the heterocyclic residue are consid-
ered unfavorable for the desired application.
[3+2] Azide–alkyne cycloadditions have been applied to var-
ious research areas, including drug discovery processes, bio-
conjugate chemistry, and solid phase organic synthesis.16–19
Very recently, copper-promoted [3+2] cycloaddition reac-
tions between amino acid derived building blocks gave rise
to different ‘1,4’ linked peptide mimetics that we call triazo-
lopeptides. In principal, four types of triazolopeptides can be
differentiated that we refer to as 1,4- and 1,5-triazolopep-
tides as well as 4,1- and 5,1-linked derivatives (Chart 1).
N
5
N
N
Y
4
1
X
N
O
O
O
Y
Such an adjustment has been commonly accomplished by
modifying the pyrrolidine moiety employing ring size vari-
ations,5 sterically demanding substituents6,7 as well as intro-
duction of fluorine8,9 or by introducing bridging elements to
furnish Freidinger-type lactams.10–13 Just few employing
H
N
1,4 - and
X
1,5 - triazolopeptides
R
N
O
R
Y
5
O
X
N
1
N
O
4
X = H, CH2
Y = aa side chain, CH2
N
N
O
Keywords: Triazolopeptide; cis/trans Prolyl isomerization; Click chemistry;
Azide–alkyne cycloaddition.
* Corresponding author. Tel.: +49 9131 8529383; fax: +49 9131 8522585;
e-mail: gmeiner@pharmazie.uni-erlangen.de
4,1 - and
5,1 - triazolopeptides
Chart 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.007

8920
A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
The sequence of the numbering that we use here corresponds
to the substitution pattern of the triazole moiety, following
the direction of the backbone (N to C terminal).20–23
enantiomers of phenylglycine as an amino acid, which is
highly prone to racemization were reacted with trifluoro-
methylsulfonic azide and CuSO4 to yield the respective
azido acids 7a–e (Scheme 2).30 Employing analogous con-
ditions, diazo transfer was also done starting from the
corresponding methyl ester hydrochlorides to give rise to
azido acid esters 8a–e.
2. Results and discussion
In this paper, we describe a divergent synthetic approach to
all four subtypes and their impact on cis/trans isomerization
when natural proline was employed as the common chiral
building block. Taking advantage of previously described
protocols,24–27 commercially available N-Boc protected pro-
linol (1) was O-activated and subsequently reacted with so-
dium azide to give the azidomethylpyrrolidine 2 (Scheme 1).
On the other hand, Swern oxidation of 1 with SO3/pyridine
and DMSO yielded the carbaldehyde 3 that could be trans-
formed into the dibromo-substituted alkene 4 by Corey–
Fuchs olefination. Subsequent treatment with 2 equiv of
n-BuLi gave the pyrrolidinylacetylene 5.
R
R
OR'
OR'
i)
H2N
N3
O
O
R' = H, Me (hydrochloride)
7a-e (R' = H)
8a-e (R' = OMe)
ii)
7-10a: R = (S)-Me
7-10b: R = (S)-Bn
7-10c: R = (R)-Bn
7-10d: R = (S)-Ph
7-10e: R = (R)-Ph
R
N
N
OR'
N
N
O
O
O
With the aim to understand the influence of the mode of tri-
azole linkage on cis/trans prolyl ratios, we envisioned to
transform the cyclization precursors 2 and 5 into the tria-
zole-linked Pro-Gly mimetics 6a,b and 6c,d, respectively.
In detail, azide 2 was reacted with ethyl propiolate when
[3+2] azide–alkyne cycloadditions were carried out using
both classical and CuI catalyzed conditions.14,28 While Huis-
gen’s 1,3-dipolar cycloaddition gave rise to an easily separa-
ble mixture of the 1,4- and 1,5-triazoles 6a and 6b in a 3:7
ratio, the copper assisted variant reported by Meldal and
Sharpless exclusively yielded the protected 1,4-triazolopep-
tide 6a. To approach to the 4,1- and 5,1-subtypes, the proline
derived alkyne 5 was reacted with azidoacetic acid ethyl
ester,29 which was freshly prepared from ethyl bromoacetate
and sodium azide. As expected, complete regiocontrol was
observed under CuI catalysis resulting in the formation of
the 4,1-substituted congener 6c while heating in ethyl ace-
tate afforded a 3:1 ratio of the regioisomers 6c and 6d.
9a-e: R' = H
10a-e: R' = Me
Scheme 2. (i) (1) 7a–e: CuSO4$5H2O, H2O/MeOH, K2CO3, TfN3, 12 h
(62–86%); (2) 8a–e:CuSO4$5H2O, MeOH, DIPEA, TfN3, 2.5–15 h, (71–
91%); (ii) 5, CuSO4$5H2O, Na-ascorbate, t-BuOH/H2O, rt or 40 ꢀC,
1–3 d (36–92%).
While the synthesis of building blocks 7a–e and 8a–c pro-
ceeded straightforward, the Phg derivatives 8d,e displayed
partial racemization, as detected by HPLC on a chiral
column. However, pure enantiomers 8d and 8e could be
prepared by esterification of 7d and 7e, respectively, using
thionyl chloride in methanol.
Copper-promoted [3+2] azide–alkyne cycloaddition reac-
tions of the azido acids 7a–e and the azido esters 8a–e
with the central alkyne 5 proceeded smoothly resulting
in the formation of the triazoles 9a–e and 10a–e, respec-
tively. When starting from the phenylglycine derivatives
8d,e, which are expectedly prone to epimerization,31
room temperature proved to be necessary to diminish
epimerization.
To evaluate a general access to triazole-linked Pro-Xaa
mimetics, we intended an introduction of representative
chiral a-amino acids into triazolopeptides of type 4,1.
Therefore, (S)-alanine, (S)- and (R)-phenylalanine, and both
N
N
O
N
N
OEt
N
N
OEt
i)
CH2N3
CH2OH
N
N
N
N
O
A or B
OEt
O
O
O
O
O
O
O
O
O
2
1
6a
6b
+
:
:
A
B
100
72
0
(85%)
28 (90%)
O
ii)
EtO
O
OEt
O
N3
iv)
OEt
N
X
N
N
N
N
N
N
A or B
N
N
N
O
O
O
O
O
O
O
O
5
6c
100
75
6d
+
3: X = O
4: X = CBr2
A: CuSO4, Na-ascorbate, t-BuOH/H2O, rt to 40 °C
B: PhMe (6a,b) or EtOAc (6c,d), reflux
A
B
:
:
0
25
(80%)
(76%)
iii)
Scheme 1. (i) (1) MsCl, DIPEA, CH2Cl2, 0 ꢀC to rt, 2.5 h (86%); (2) NaN3, DMF, 70 ꢀC, 24 h (83%); (ii) SO3/pyridine, DIPEA, DMSO/CH2Cl2, ꢁ5 ꢀC, 5 h
(92% crude); (iii) PPh3, CBr4, CH2Cl2, ꢁ5 to 0 ꢀC, 2 h (90%); (iv) n-BuLi, THF, ꢁ78 ꢀC, 1 h 15 min (83%).

A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
8921
Exchange of the Boc protecting groups of the four isomeric
triazolopeptides 6a–d with acetyl groups gave rise to model
Pro-Gly surrogates more ideally mimicking a cis/trans
prolyl isomerization when treated with TFA and subsequent
acetylation with acetyl chloride and DIPEAyielded N-acetyl
analogs 11a–d (Scheme 3).
The additional amide NH function of N-acetylprolylglycine
N0-methyl amide facilitates formation of an intramolecular
hydrogen bond toward the acetyl carbonyl group. A b-turn
can be adopted if the peptide bond between the amino acid
in position i and proline in position i+1 displays trans geo-
metry. As a consequence, almost exclusive formation of the
trans prolyl isomer was observed.32 Interestingly, substantial
decrease of the cis-population was observed for the 1,5 and
5,1-triazolopeptides 12b,d incorporating an NH that can
form an intramolecular 10-membered ring. On the other
hand the 1,4- and 4,1-linked isomers 12a,c could only
form an 11-membered ring, which is obviously less favored.
As a consequence, introduction of an amide functionality did
not significantly change the cis/trans ratio. FTIR spectros-
copy of a 2 mM CDCl3 solution clearly corroborated our
observation revealing strong absorption bands at 3330–
3350 cmꢁ1 (besides absorptions at 3430–3455 cmꢁ1) for
12b,d and the reference carboxamide clearly indicating an
equilibrium between an intramolecular hydrogen bond and
a non-associated conformation. Molecular origins for the
distinct conformational behavior of our triazolopeptides
might be attractive or repulsive dipolar interactions between
the carbonyl group of the N-acetyl substituent and the
triazole moiety.33
i)
COOEt
COR
X
X
N
N
O
O
O
6a-d
11a-d: R = OEt
ii)
X
12a-d: R = NHMe
N
N
b:
d:
=
=
N
X
X
a:
=
=
N
N
N
X
N
N
c:
N
N
N
N
Scheme 3. (i) (1) TFA, CH2Cl2, 0 ꢀC, 35 min; (2) AcCl, DIPEA, CH2Cl2, rt,
19 h (23–88%; two steps); (ii) MeNH2, EtOH, 0 ꢀC, 2 h (18–86%).
To investigate the influence of intramolecular hydrogen
bonding on the conformational behavior of our test set, the
ethyl esters 11a–d were converted to the N-methyl amides
12a–d by treatment with methylamine.
3. Conclusion
In conclusion, we applied [3+2] azide–alkyne cycloaddition
reactions for the synthesis of four different types of triazolo-
peptides mimicking a Pro-Gly dipeptide. While 1,4- and 4,1-
triazolopeptides were regioselectively accessible employing
a CuI catalyzed protocol, the 1,5- and 5,1-linked subtypes re-
sulted from separation of a mixture of regioisomers. A regio-
controlled approach toward 1,5- and 5,1-triazolopeptides
employing ruthenium-catalyzed methodology appears very
promising.34 Structural studies indicated the adjustability
of both the cis-percentage and the conformational stability
toward intramolecular H-bonding effects. Investigations to-
ward the application of triazolopeptides on the development
of neurotensin analogs and TetR-based artificial transactiva-
tors are currently ongoing in our laboratory.
The conformational properties of the model triazolopeptides
11a–d and 12a–d were examined by means of NMR spec-
troscopy in 2 mM CDCl3 solution. The cis/trans ratios
were determined on the basis of the triazole protons, which
exhibited clearly separated signals for the two conformers in
each case. NOESY experiments were done with the peptide
mimetics 11a–d and 12a in order to unambiguously assign
signal sets to particular isomers by comparing dipolar cou-
plings of the acetyl methyl group with the C2H or C5H2
protons of the pyrrolidine moiety. N-Acetylprolylglycine
methyl ester and N-acetylprolylglycine N0-methyl amide
were employed as reference peptides (Table 1).32
Table 1. NMR-derived cis/trans prolyl ratios of the model peptide surro-
gates 11a–d and 12a–d (2 mM, CDCl3) compared to AcProGlyOMe and
AcProGlyNHMe,32 respectively (5% steps)
4. Experimental
4.1. General
Cpd (type)
% cis
Cpd (type)
% cis
11a (1,4)
11b (1,5)
11c (4,1)
11d (5,1)
AcProGlyOMe
5
30
30
10
10
12a (1,4)
12b (1,5)
12c (4,1)
12d (5,1)
AcProGlyNHMe
<1
15
30
5
Although we did not observe problems associated with a
putatively explosive character of the used azides, the low
weight azidoacetic acid ethyl ester was not distilled but
used as a solution. Reagents and solvents were obtained
from commercial sources unless stated otherwise, and
were used as received. Unless otherwise noted, reactions
were conducted without inert atmosphere. Evaporations of
final product solutions were done under vacuo with a rotatory
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. EIMS was carried out using EI ionization
(70 eV) with solid inlet on a Finnigan MAT TSQ 70 or
<1
NMR data indicated a 1:9 cis/trans prolyl ratio for the 5,1-
triazolopeptide 11d, which is very similar to N-acetylprolyl-
glycine methyl ester.32 Investigation of the 4,1-regioisomer
11c showed a substantially higher cis-fraction of 30%.
Thus, the homologization of the backbone led to an increase
of the cis-isomer. Interestingly, the NMR spectra indicated
an inverse behavior for the triazolopeptides 11a,b when
the 1,4-regioisomer with an elongated backbone displayed
a low tendency to form a cis prolyl structure (11a: 5% cis)
whereas the 1,5-isomer 11b existed as 3:7 mixture of cis/
trans isomers.

8922
A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
a Jeol GCmate II spectrometer. HRMS was carried out with
a resolution of M/DM ¼ 5000 relative to PFK on a Jeol
GCmate II spectrometer. Standard NMR spectra were re-
corded at 300 K 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). Chemical shifts are reported relative to
the residual solvent peak (CHCl3: 7.26, CDCl3: 77.0). Ele-
mental analyses were performed at the Institute of Organic
Chemistry (Analytical Departments) of the Friedrich
methyl ester hydrochloride was converted to 8b (91%) as
a colorless oil. Rf 0.63 (CH2Cl2); [a]2D8 ꢁ47.8 (c 1.0,
CHCl3); IR (Neat) 3030, 2954, 2109, 1746 cmꢁ1; 1H NMR
(360 MHz, CDCl3) d 3.01 (dd, 1H, J¼14.0, 8.7 Hz, CH2),
3.18 (dd, 1H, J¼14.0, 5.4 Hz, CH2), 3.77 (s, 3H, OCH3),
4.07 (dd, 1H, J¼8.7, 5.4 Hz, CH), 7.19–7.36 (m, 5H,
Ar–H); 13C NMR (90 MHz, CDCl3) d 37.6 (CH2), 52.6
(OCH3), 63.3 (CH), 127.3+128.7+129.2 (aryl CH), 135.9
(aryl C–C), 170.4 (C]O); EIMS 162 (MꢁHN3), 118
(MꢁN2ꢁCOOMe), 91 (Bn+); M+ not detected.
€
Alexander University, Erlangen-Nurnberg. Melting points
were determined with a Buchi 510 apparatus and are
€
uncorrected. HPLC analysis were run on a Agilent 1100
Series with a Diode Array Detector at 190, 230 and 250 nm.
Optical rotations were measured on a Perkin–Elmer 241
polarimeter. IR spectra were measured on a Jasco 410 FTIR
spectrometer.
4.3.3. (R)-2-Azido-3-phenylpropionic acid methyl ester
(8c). Following the general procedure, (R)-phenylalanine
methyl ester hydrochloride was converted to 8c (85%).
[a]2D8 48.5 (c 1.0, CHCl3).
4.4. Esterification of phenylglycine derivates
4.2. Azidoacetic acid ethyl ester
4.4.1. (S)-2-Azido-2-phenylacetic acid methyl ester (8d).
Methanol (10.0 mL) was cooled to ꢁ10 ꢀC, whereupon thio-
nyl chloride (1.09 mL, 15.0 mmol) was added dropwise over
5 min while stirring vigorously. Subsequently, a solution of
7d (895 mg, 5.05 mmol) in methanol (10 mL) was added
over 2 min and the mixture was allowed to warm to room
temperature. After 6 h 50 min, ice (30 g) and water
(80 mL) were added and the pH was adjusted to 8 with
a NaH2PO4 buffer. The mixture was extracted with ether
(4ꢂ20 mL), the combined organic layers were dried with
MgSO4, concentrated, and the crude product (862 mg,
89%) was used without further purification, as a HPLC
analysis indicated sufficient purity. Colorless oil; Rf 0.46
(hexanes/ethyl acetate 4:1); TLC detection was done with
a PPh3/hexanes solution (1% m/v) followed by ninhydrin;
HPLC: tR 19.5 min, >99% ee (ChiralcelÒ OD, 4.6ꢂ
250 mm, hexanes/isopropanol 99:1, 0.5 mL/min, 254 nm
detection); [a]2D2 157.5 (c 1.0, CHCl3); IR (Neat) 2955,
Bromoacetic acid ethyl ester (3.34 g, 2.22 mL, 20.0 mmol)
and NaN3 (2.60 g, 40.0 mmol) were dissolved in DMF
(15 mL), heated to 60 ꢀC, and stirred for 2 h. After cooling
to room temperature, the solution was diluted with water
(100 mL), extracted with ethyl acetate (4ꢂ10 mL) and the
organic layer was washed with saturated aqueous NaHCO3
(50 mL). This layer was re-extracted with ethyl acetate
(2ꢂ10 mL). The combined organic layers were washed
with brine (50 mL), and the aqueous layer was re-extracted
with ethyl acetate (2ꢂ10 mL). The combined organic layers
were dried with Na2SO4, and the resulting solution was
diluted to 100 mL, stored over molecular sieves under
nitrogen, and was used for cycloaddition reactions without
further purification.
4.3. General procedure for the diazo transfer on amino
acid methyl ester hydrochlorides
2844, 2105, 1746 cmꢁ1 1H NMR (360 MHz, CDCl3)
;
The hydrochlorides of the amino acid methyl esters (approx.
16.0 mmol) were dissolved in methanol (12 mL). An aque-
ous solution of CuSO4$5H2O (10 g/L, approx. 0.01 equiv)
and diisopropylethylamine (1.5 equiv) were added at room
temperature, whereupon the color of the solution changed
from turquoise to deep blue. Subsequently, a freshly pre-
pared trifluoromethane sulfonic azide solution (1 M in
CH2Cl2, 1.8 equiv) was added. After stirring for 15 h, the
solvent was removed, and the crude product was purified
either by Kugelrohr distillation under reduced pressure (8a)
or by flash column chromatography (8b,c). TLC detection
was done with a PPh3/hexanes solution (1% m/v) followed
by ninhydrin.
d 3.78 (s, 3H, OCH3), 4.98 (s, 1H, CH), 7.33–7.49 (m, 5H,
ArH); 13C NMR (90 MHz, CDCl3) d 52.9 (OCH3), 65.3
(CH), 127.6+129.1+129.3 (aryl CH), 133.8 (aryl C–C),
196.6 (C]O); EIMS 191 (M+).
4.4.2. (R)-2-Azido-2-phenylacetic acid methyl ester (8e).
Compound 7e was reacted under the conditions described
above, furnishing 8e (88%) as a colorless oil. HPLC: tR
17.9 min, >99% ee (ChiralcelÒ OD, 4.6ꢂ250 mm, hex-
anes/isopropanol 99:1, 0.5 mL/min, 254 nm detection);
[a]2D2 ꢁ159.2 (c 1.0, CHCl3).
4.5. (S)-1-(1-tert-Butoxycarbonylpyrrolidin-2-yl-methyl)-
(1,2,3)-triazole-4-carboxylic acid ethyl ester (6a) and
(S)-1-(1-tert-Butoxycarbonylpyrrolidin-2-ylmethyl)-
(1,2,3)-triazole-5-carboxylic acid ethyl ester (6b)
4.3.1. (S)-2-Azidopropionic acid methyl ester (8a). Fol-
lowing the general procedure, alanine methyl ester hydro-
chloride was converted to 8a (90%) as a colorless oil. Rf
0.46 (hexanes/ethyl acetate 4:1); [a]2D5 12.2 (c 1.0, CHCl3);
To a solution of 2 (3.92 g, 17.3 mmol) in toluene (60 mL)
was added ethyl propiolate (5.26 mL, 51.9 mmol). The mix-
ture was heated to reflux for 19 h, whereupon another portion
of ethyl propiolate (1.75 mL, 17.3 mmol) was added and re-
fluxing was continued for 5 h. After cooling to room temper-
ature, the solvent was removed and the residue was purified
by flash column chromatography (hexanes/ethyl acetate 9:1
increasing to 1:1), furnishing 3.68 g (66%) of 6a and 1.40 g
(25%) of 6b as a waxy solid and viscous oil, respectively.
IR (Neat) 2958, 2138, 2108, 1748 cmꢁ1
;
1H NMR
(360 MHz, CDCl3) d 1.49 (d, 3H, J¼7.7 Hz, CHCH3),
3.80 (s, 3H, OCH3), 3.96 (q, 1H, J¼7.7 Hz, CHCH3); 13C
NMR (90 MHz, CDCl3) d 16.8 (CH3), 52.6 (OCH3), 57.3
(CH), 171.4 (C]O).
4.3.2. (S)-2-Azido-3-phenylpropionic acid methyl ester
(8b). Following the general procedure, (S)-phenylalanine

A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
8923
4.5.1. Compound 6a. Mp 86–88 ꢀC, Rf 0.20 (hexanes/ethyl
acetate 1:1); [a]2D2 ꢁ68.6 (c 1.0, CHCl3); IR (Neat) 3132,
10d and 10e, maintaining room temperature and interrupting
the reaction after 20 h were crucial for suppression of the
epimerization rate. The mixtures were diluted with water
(50 mL). In case of 9a–e, the pH was adjusted to 2–3 by
addition of aqueous HCl. The compounds were isolated by
extraction with CH2Cl2 or ethyl acetate (4ꢂ20 mL), washed
with brine (20 mL), re-extraction of the washing liquid
(20 mL), drying of the combined organic layers with
NaSO4 or MgSO4, evaporation, and flash column chromato-
graphy.
2978, 1739, 1723, 1693 cmꢁ1
;
1H NMR (360 MHz,
CDCl3; rotamers were observed) d 1.410+1.415 (2ꢂt, 3H,
J¼7.1 Hz, CH2CH3), 1.50 (s, 9H, Boc CH3), 1.59–2.10 (br
m, 4H, CH2), 3.00–3.53+3.29 (br m+dd, 2H, J¼14.2,
6.0 Hz, NCH2), 4.12 (br s, 1H, CH), 4.36–4.85+4.42+4.52
+4.75 (br m+q+q+dd, 4H, J¼7.1 Hz+7.1 Hz+12.8, 5.4 Hz,
OCH2+CHCH2-triazole), 8.00+8.04 (br s+s, 1H, triazole
H); EIMS 324 (M+).
4.5.2. Compound 6b. Rf 0.36 (hexanes/ethyl acetate 1:1);
[a]2D2 ꢁ8.8 (c 1.0, CHCl3); IR (Neat) 3132, 2977, 1731,
4.8.1. (S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-yl)-
(1,2,3)-triazol-1-yl]acetic acid ethyl ester (6c). Compound
5 and azidoacetic acid ethyl ester in ethyl acetate were
reacted at 40 ꢀC following the general procedure (reaction
time: 38 h). Flash column chromatography (hexanes/ethyl
acetate 3:2) furnished 6c (79%) as a colorless solid. Mp
75–76 ꢀC; Rf 0.21 (hexanes/ethyl acetate 3:2); [a]2D9 ꢁ59.3
(c 1.0, methanol); IR (Neat) 3141, 2977, 2270, 1756,
1691 cmꢁ1; 1H NMR (360 MHz, CDCl3; rotamers were ob-
served) d 1.29 (t, 3H, J¼7.1 Hz, CH2CH3), 1.36+1.43 (2ꢂbr
s, 9H, Boc CH3), 1.83–2.56 (br m, 4H, CH2), 3.30–3.63 (br
m, 2H, NCH2), 4.25 (q, 2H, J¼7.1 Hz, CH2CH3), 4.95–5.19
(br m, 3H, CH2CO+NCH), 7.45+7.61 (br s+br s, 1H, triazole
H); EIMS 324 (M+).
1696 cmꢁ1 1H NMR (360 MHz, CDCl3; rotamers were
;
observed) d 1.3–1.43+1.38 (br s+t, 12H, J¼6.9 Hz, Boc
CH3+CH2CH3), 1.61–1.98 (br m, 4H, CH2), 3.22–3.49 (br
m, 2H, NCH2), 4.28–4.57+4.38 (m+br q, 3H, J¼6.9 Hz,
CH+CH2CH3), 4.67–4.90+4.74 (m+dd, 2H, J¼13.5,
5.6 Hz, CHCH2-triazole), 8.09 (s, 1H, triazole H); EIMS
324 (M+).
4.6. (S)-1-(1-tert-Butoxycarbonylpyrrolidin-2-yl-methyl)-
(1,2,3)-triazole-4-carboxylic acid ethyl ester (6a)
Compound 2 (226 mg, 1.00 mmol) and ethyl propiolate
(122 mL, 1.20 mmol) were dissolved in tert-butanol. Aque-
ous solutions of CuSO4$5H2O (1 M, 20 mL) and sodium
ascorbate (1 M, 100 mL) were added. After stirring at room
temperature for 1 d, water (50 mL) was added and the mix-
ture was extracted with ethyl acetate (3ꢂ20 mL). The com-
bined organic layers were washed with brine (20 mL), dried
with MgSO4, concentrated, and the residue was purified by
flash column chromatography (hexanes/ethyl acetate 4:1),
furnishing 276 mg (85%) of 6a.
4.8.2. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]propionic acid (9a). Compounds 5
and 7a were reacted at 40 ꢀC following the general proce-
dure (reaction time: 48 h). Flash column chromatography
(CH2Cl2/methanol/HCOOH 97:3:0.5) furnished 9a (76%)
as a colorless solid. Mp 58–62 ꢀC; Rf 0.13 (CH2Cl2/metha-
nol/HCOOH 95:5:0.5); [a]2D6 ꢁ47.5 (c 1.0, methanol); IR
(Neat) 3481, 3142, 2977, 2881, 2484, 2249, 1743,
1687 cmꢁ1 1H NMR (360 MHz, CDCl3; rotamers and
;
4.7. (S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-yl)-
(1,2,3)-triazol-1-yl]acetic acid ethyl ester (6c) and (S)-2-
[5-(1-tert-butoxycarbonylpyrrolidin-2-yl)-(1,2,3)-tri-
azol-1-yl]acetic acid ethyl ester (6d)
broadened signals were observed) d 1.16–1.56 (2ꢂbr s,
9H, Boc CH3), 1.72–2.48+1.82 (br m+d, 7H, J¼6.6 Hz,
CH2+CHCH3), 3.35–3.63 (br m, 2H, NCH2), 5.05 (dd, 1H,
J¼7.4, 2.4 Hz, NCH), 5.42 (br s, 1H, CH3CH), 6.00 (br s,
1H, OH), 7.67 (br s, 1H, triazole H); 13C NMR (90 MHz,
CDCl3; rotamers and broadened signals were observed)
d 18.3+18.6 (CH3), 23.4+24.4 (CH2), 28.5 (Boc CH3),
31.4+33.3 (CH2), 46.5+47.0, 53.0+54.0, 58.4 (2ꢂCH+CH2),
80.5 (Boc Cq), 120.8+121.9, 149.1+150.9, 155.1 (2ꢂtriazole
C+Boc C]O), 171.2 (COOH); EIMS 310 (M+); Anal. Calcd
for C14H22N4O4$0.25H2O: C, 53.41; H, 7.20; N, 17.79.
Found: C, 53.41; H, 7.06; N, 17.89 (the percentage of H2O
was corroborated by 1H NMR spectroscopy).
Compound 5 (195 mg, 1.00 mmol) was dissolved in a solu-
tion of azidoacetic acid ethyl ester (approx. 0.2 M in ethyl
acetate, 7.5 mL, approx. 1.50 mmol) and heated to reflux
for 48 h. After cooling to room temperature, the solvent
was removed and the mixture of regioisomers was obtained
by flash column chromatography (hexanes/ethyl acetate
4:1), furnishing 248 mg (76%) of a colorless oil that was
used in the next step without further separation. Rf 0.15
(hexanes/ethyl acetate 1:1).
4.8.3. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-3-phenylpropionic acid (9b).
Compounds 5 and 7b were reacted at 40 ꢀC following the
general procedure (reaction time: 48 h). Flash column chro-
matography (CH2Cl2/methanol/HCOOH 97:3:0.5) fur-
nished 9b (73%) as a colorless solid. Mp 75–78 ꢀC; Rf
0.18 (CH2Cl2/methanol/HCOOH 95:5:0.5); [a]2D6 ꢁ139.0
(c 1.0, methanol); IR (Neat) 3469, 3148, 2977, 2880,
4.8. General procedure for cycloaddition reactions with
5 under catalytic conditions (6c, 9a–e, 10a–e)
Compound 5 (50–200 mg) and the corresponding azide
(1.0–1.2 equiv; slight excesses with respect to 5 resulted in
higher yields) were dissolved in tert-butanol (1–2 mL).
After addition of aqueous solutions of CuSO4$5H2O (1 M,
0.02 equiv) and sodium ascorbate (1 M, 0.1 equiv), water
(0.5–1 mL) was added. In cases where addition of water
caused solubility issues, the latter was replaced by methanol.
The mixture was stirred either at room temperature or at
40 ꢀC until TLC indicated either stagnation or completion
of the reaction, which was the case after 1–4 d. In case of
1
2511, 2250, 1740, 1689, 1640 cmꢁ1; H NMR (360 MHz,
CDCl3; rotamers were observed) d 1.13–1.56 (2ꢂbr s, 9H,
Boc CH3), 1.72–2.40 (br m, 4H, CH2), 3.30–3.59+3.53 (br
m+dd, 2H, J¼13.5, 5.6 Hz, NCH2+PhCH2), 5.01 (br d,
1H, J¼5.5 Hz, NCH), 5.41–6.00 (br m, 2H, NCHCO+OH),
7.02 (br s, 2H, ArH), 7.15–7.23 (m, 3H, ArH), 7.58+7.69

8924
A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
(br s+br s, 1H, triazole H); 13C NMR (150 MHz, CDCl3;
rotamers and broadened signals were observed) d 23.1+24.5
(CH2), 28.4+28.6 (Boc CH3), 31.0+33.4, 39.0+39.1 (CH2),
46.3+46.9, 52.8+54.1, 64.0+64.2 (NCH2+2ꢂNCH),
80.4+80.8 (Boc Cq), 121.6+122.9, 127.4+127.6, 128.8,
129.1, 135.2+135.3 (5ꢂaryl C), 148.6+150.6, 154.9+155.3
(aryl C+Boc C]O), 169.7 (COOH); EIMS 386 (M+);
Anal. Calcd for C20H26N4O4: C, 62.16; H, 6.78; N, 14.50.
Found: C, 61.93; H, 6.60; N, 14.40.
4.8.6. (2R,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-2-phenylacetic acid (9e). Com-
pounds 5 and 7e were reacted at 40 ꢀC following the general
procedure (reaction time: 48 h). Flash column chromato-
graphy (CH2Cl2/methanol/HCOOH 97:3:0.5) furnished 9e
(81%) as a colorless solid. Mp 74–76 ꢀC; Rf 0.10 (CH2Cl2/
methanol/HCOOH 95:5:0.5); [a]2D6 ꢁ117 (c 1.0, methanol);
IR (Neat) 3155, 2977, 2880, 2555, 2487, 2249, 1738, 1690,
1642 cmꢁ1; 1H NMR (360 MHz, CDCl3; rotamers were ob-
served) d 0.93–1.50 (2ꢂbr s, 9H, Boc CH3), 1.72–1.96 (br m,
1.8H, CH2), 2.00–2.38 (br m, 2.2H, CH2), 3.25–3.71+3.40
(br m+ddd, 2H, J¼10.5, 8.0, 7.8 Hz, NCH2), 5.03 (ddd,
1H, J¼7.4, 2.8, 0.6 Hz, NCH), 5.96 (br s, 1H, OH),
5.55+6.62 (br s+br s, 1H, NCHCO), 7.23–7.49 (br m, 5H,
ArH), 8.06 (s, 0.1H, triazole H), 8.25 (br s, 0.9H, triazole
H); 13C NMR (90 MHz, CDCl3; rotamers and broadened
signals were observed) d 23.1 (CH2), 28.2+28.5 (Boc
CH3), 33.6, 46.7, 54.7, 64.2+66.0 (2ꢂCH2+2ꢂNCH), 81.0
(Boc Cq), 121.8, 127.5, 129.3, 129.4, 135.0, 151.0, 156.0
(6ꢂaryl C+Boc C]O), 169.0 (COOH); EIMS 372 (M+);
Anal. Calcd for C19H24N4O4$0.25H2O: C, 60.54; H, 6.55;
N, 14.86. Found: C, 60.74; H, 6.45; N, 14.95 (the percentage
of H2O was corroborated by 1H NMR spectroscopy).
4.8.4. (2R,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-3-phenylpropionic acid (9c).
Compounds 5 and 7c were reacted at 40 ꢀC following the
general procedure (reaction time: 48 h). Flash column
chromatography (CH2Cl2/methanol/HCOOH 97:3:0.5)
furnished 9c (87%) as a colorless solid. Mp 72–75 ꢀC; Rf
0.15 (CH2Cl2/methanol/HCOOH 95:5:0.5); [a]2D6 14.7 (c
1.0, methanol); IR (Neat) 3474, 3138, 2978, 2880, 2512,
2249, 1740, 1689, 1640 cmꢁ1
;
1H NMR (360 MHz,
CDCl3; rotamers were observed) d 1.23–1.48 (2ꢂbr s,
9H, Boc CH3), 1.61–2.27 (br m, 4H, CH2), 3.23–3.61+
3.47+3.54 (br m+dd+dd, 4H, J¼14.2, 8.3 Hz+14.2, 5.9 Hz,
NCH2+PhCH2), 5.06 (dd, 1H, J¼5.7, 3.9 Hz, NCH), 5.44–
5.99 (br m, 2H, NCHCO+OH), 6.92–7.02 (br m, 2H,
ArH), 7.12–7.26 (m, 3H, ArH), 7.48 (br s, 0.4H, triazole
H), 7.93 (br s, 0.6H, triazole H); H/D exchange: 5.55 (br
m, 1H, NCHCO); 13C NMR (150 MHz, CDCl3; rotamers
and broadened signals were observed) d 22.7+24.0 (CH2),
28.6 (Boc CH3), 32.2+33.3, 39.3+39.5 (CH2), 46.3+47.0,
53.0+54.4, 64.1+64.3 (NCH2+2ꢂNCH), 80.7+80.9 (Boc
Cq), 121.3+122.7, 127.5 (s), 128.7 (w), 128.9 (s), 129.2
(w), 135.3+135.3 (5ꢂaryl C), 148.9+150.7, 155.0+155.8
(aryl C+Boc C]O), 169.9+170.0 (COOH); EIMS 386
(M+); Anal. Calcd for C20H26N4O4$0.25H2O: C, 61.44; H,
6.83; N, 14.33. Found: C, 61.57; H, 6.62; N, 14.48 (the per-
4.8.7. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]propionic acid methyl ester (10a).
Compounds 5 and 8a were reacted at room temperature fol-
lowing the general procedure (reaction time: 4 d). Flash col-
umn chromatography (hexanes/ethyl acetate 8:2) furnished
10a (36%) as a colorless resin. Rf 0.11 (hexanes/ethyl acetate
1:1); [a]2D7 ꢁ50.6 (c 1.0, methanol); IR (Neat) 3136, 2975,
2877, 1753, 1692 cmꢁ1 1H NMR (360 MHz, CDCl3;
;
rotamers were observed) d 1.27–1.50 (2ꢂbr s, 9H, Boc CH3),
1.72–2.60+1.81 (br m+d, 7H, J¼7.3 Hz, CH2+CHCH3),
3.32–3.63 (br m, 2H, NCH2), 3.75 (s, 3H, OCH3), 5.03 (br
s, 1H, NCH), 5.45 (br s, 1H, CH3CH), 7.49+7.67 (br s+br
s, 1H, triazole H); EIMS 324 (M+); HRMS calculated for
C15H24N4O4: 324.1798, found: 324.1798.
1
centage of H2O was corroborated by H NMR spectros-
copy).
4.8.5. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-2-phenylacetic acid (9d). Com-
pounds 5 and 7d were reacted at 40 ꢀC following the general
procedure (reaction time: 48 h). Flash column chromato-
graphy (CH2Cl2/methanol/HCOOH 97:3:0.5) furnished 9d
(92%) as a colorless solid. Mp 77–78 ꢀC; Rf 0.21 (CH2Cl2/
methanol/HCOOH 95:5:0.5); [a]2D6 35.6 (c 1.0, methanol);
IR (Neat) 3469, 3155, 2977, 2880, 2555, 2501, 2250,
4.8.8. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-3-phenylpropionic acid methyl
ester (10b). Compounds 5 and 8b were reacted at room tem-
perature following the general procedure (reaction time:
4 d). Flash column chromatography (hexanes/ethyl acetate
8:2) furnished 10b (49%) as a colorless solid. Mp 69–
72 ꢀC; Rf 0.26 (hexanes/ethyl acetate 1:1); HPLC: tR
32.8 min (silica gel 5 mm, 4.6ꢂ250 mm, diisopropyl ether/
acetonitrile 94:6, 0.5 mL/min, 254 nm detection); [a]D24
ꢁ112 (c 1.0, methanol); IR (Neat) 3136, 2976, 2876,
1
1742, 1687, 1638 cmꢁ1; H NMR (600 MHz, CDCl3; ro-
tamers were observed) d 1.14–1.49 (2ꢂbr s, 9H, Boc
CH3), 1.68–1.95 (br m, 1.7H, CH2), 2.01–2.29 (br m, 2H,
CH2), 2.34–2.49 (br m, 0.3H, CH2), 3.36+3.38 (dd+dd,
2H, J¼16.6, 5.5 Hz+16.6, 10.0 Hz, NCH2), 4.99 (br d, 1H,
J¼5.7 Hz, NCH), 5.50–6.46 (br s, 1H, OH), 6.47–6.60 (br
m, 1H, NCHCO), 7.32–7.48 (m, 5H, ArH), 7.79+7.86 (br
s+br s, 1H, triazole H); 13C NMR (150 MHz, CDCl3; ro-
tamers and broadened signals were observed) d 23.4+24.5
(CH2), 28.3+28.4 (Boc CH3), 30.8+33.2, 46.4+46.8,
52.9+53.9, 66.3+66.4 (2ꢂCH2+2ꢂNCH), 80.5+80.9 (Boc
Cq), 121.5+122.4, 123.2, 128.1–128.4, 129.3–129.7,
133.8+134.0, 150.5, 154.9+155.4 (6ꢂaryl C+Boc C]O),
169.0 (COOH); EIMS 372 (M+); Anal. Calcd for
C19H24N4O4$0.25H2O: C, 60.54; H, 6.55; N, 14.86; Found:
C, 60.44; H, 6.40; N, 14.73 (the percentage of H2O was
corroborated by 1H NMR spectroscopy).
2246,1750, 1693 cmꢁ1
;
1H NMR (360 MHz, CDCl3;
rotamers were observed) d 1.26–1.56 (2ꢂbr s, 9H, Boc
CH3),1.79–2.50 (br m, 4H, CH2), 3.31–3.56+3.49 (br
m+dd, 4H, J¼14.1, 6.6 Hz, NCH2+PhCH2), 3.73 (s, 3H,
OCH3), 4.99 (br s, 1H, NCH), 5.54 (br s, 1H, NCHCO),
6.98–7.07 (m, 2H, ArH), 7.17–7.29 (m, 3H, ArH), 7.36 (br
s, 0.6H, triazole H), 7.64 (br s, 0.4H, triazole H); EIMS
400 (M+); Anal. Calcd for C21H28N4O4: C, 62.98; H, 7.05;
N, 13.99. Found: C, 62.75; H, 7.06; N, 13.96.
4.8.9. (2R,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-3-phenylpropionic acid methyl
ester (10c). Compounds 5 and 8c were reacted at room tem-
perature following the general procedure (reaction time:

A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
8925
4 d). Flash column chromatography (hexanes/ethyl acetate
8:2) furnished 10c (81%) as a colorless solid. Mp 97–
99 ꢀC; Rf 0.28 (hexanes/ethyl acetate 1:1); HPLC: tR
34.4 min (silica gel 5 mm, 4.6ꢂ250 mm, diisopropyl ether/
acetonitrile 94:6, 0.5 mL/min, 254 nm detection); [a]D24
10.8 (c 1.0, methanol); IR (Neat) 3138, 2975, 2877, 2251,
the mixture was stirred at room temperature for 17 h. Addi-
tional amounts of DIPEA (15.0 mL, 0.090 mmol) and acetyl
chloride (15.0 mL, 0.185 mmol) were added. After 1 h
45 min, TLC indicated complete conversion. Aqueous HCl
(2 N, 5 mL) was added and the mixture was extracted with
CH2Cl2 (4ꢂ5 mL). The combined organic layers were
washed with brine (20 mL), dried with Na2SO4, evaporated,
and the residue was purified by flash column chromato-
graphy (CH2Cl2/methanol 95:5), furnishing 18.9 mg (88%)
of 11c as a colorless solid. TLC detection: ninhydrin,
150 ꢀC, 15 min. Mp 80–81 ꢀC; Rf 0.27 (CH2Cl2/methanol
95:5); [a]2D6 ꢁ73.1 (c 2.0, CHCl3); IR (Neat) 3137, 2270,
1
1751, 1692 cmꢁ1; H NMR (360 MHz, CDCl3; rotamers
were observed) d 1.18–1.58 (2ꢂbr s, 9H, Boc CH3), 1.81–
2.51 (br m, 4H, CH2), 3.31–3.56+3.42+3.50 (br m+dd+dd,
4H, J¼14.1, 8.9 Hz+14.1, 6.6 Hz, NCH2+PhH2), 3.72 (s,
3H, OCH3), 4.99 (br s, 1H, NCH), 5.45 (br s, 1H, NCHCO),
6.99–7.07 (m, 2H, ArH), 7.17–7.28 (m, 3H, ArH), 7.40+7.54
(br s+br s, 1H, triazole H); EIMS 400 (M+); Anal. Calcd for
C21H28N4O4: C, 62.98; H, 7.05; N, 13.99. Found: C, 62.99;
H, 7.07; N, 13.91.
1
1751, 1636 cmꢁ1; H NMR (600 MHz, CDCl3; cis/trans
rotamers were observed) d 1.29+1.30 (t+t, 3H, J¼7.2 Hz,
CH2CH3), 1.83–1.93 (m, 0.33H, CH2,cis), 1.93–2.00+1.97
(m+s, 1.33H, CH2,cis+acetyl CH3,cis), 2.03–2.10+2.04
(m+s, 2.67H, CH2,trans+acetyl CH3,trans), 2.12–2.22 (m, 1H,
CH2), 2.39–2.42 (m, 1H, CH2), 2.56–2.62 (m, 0.67H,
CH2,trans), 3.50 (ddd, 0.67H, J¼9.5, 9.5, 7.1 Hz, NCH2,trans),
3.57 (ddd, 0.33H, J¼11.8, 10.0, 7.4 Hz, NCH2,cis), 3.63
(ddd, 0.67H, J¼9.5, 8.5, 2.9 Hz, NCH2,trans), 3.68 (ddd,
0.33H, J¼11.8, 8.6, 2.7 Hz, NCH2,cis), 4.25+4.26 (q+q,
2H, J¼7.2 Hz, CH2CH3), 5.04 (d, 0.67H, J¼17.5 Hz,
NCH2COtrans), 5.11 (d, 0.67H, J¼17.5 Hz, NCH2COtrans),
5.13 (s, 0.67H, NCH2COcis), 5.15 (dd, 0.33H, J¼7.9,
1.3 Hz, NCHcis), 5.28 (dd, 0.33H, J¼7.9, 1.6 Hz, NCHcis),
7.42 (s, 0.33H, triazole Hcis), 7.69 (s, 0.67H, triazole Htrans);
13C NMR (90 MHz, CHCl3; cis/trans rotamers were
observed) d 14.2 (CH2CH3), 22.3+25.1 (acetyl CH3), 22.6+
22.9, 30.2+34.2, 46.2+48.1 (3ꢂCH2), 50.9+51.1, 52.4+
55.4, 62.4+62.7 (2ꢂCH2+CH), 122.2+124.6, 148.8+150.8
(2ꢂtriazole C), 166.2+166.5, 169.4+169.9 (2ꢂC]O);
EIMS 266 (M+); HRMS: calculated for C12H18N4O3:
266.1379, found: 266.1378.
4.8.10. (2S,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-2-phenylacetic acid methyl ester
(10d). Compounds 5 and 8d were reacted at room tempera-
ture following the general procedure (reaction interrupted
after 20 h). Flash column chromatography (hexanes/ethyl
acetate 7:3) furnished 10d (26%) as a colorless resin. Rf
0.26 (hexanes/ethyl acetate 1:1); HPLC: tR 67.6 min, 56%
de (silica gel 5 mm, 4.6ꢂ250 mm, diisopropyl ether/acetoni-
trile 99:1, 1.0 mL/min, 254 nm detection); [a]2D2 19.5 (c 1.0,
methanol); IR (Neat) 3144, 2976, 2875, 1754, 1692 cmꢁ1
;
1H NMR (360 MHz, CDCl3; rotamers were observed)
d 1.02–1.51 (m, 9H, Boc CH3), 1.80–2.53 (br m, 4H,
CH2), 3.27–3.60 (br m, 2H, NCH2), 3.83 (s, 3H, OCH3),
4.85–5.08 (br m, 1H, NCH), 6.53+6.56 (br s+br s, 1H,
NCHCO), 7.29–7.76+7.58+7.67 (m+br s+br s, 6H, Ar–H+
2ꢂtriazole H).
4.8.11. (2R,20S)-2-[4-(1-tert-Butoxycarbonylpyrrolidin-2-
yl)-(1,2,3)-triazol-1-yl]-2-phenylacetic acid methyl ester
(10e). Compounds 5 and 8e were reacted at room tempera-
ture following the general procedure (reaction interrupted
after 20 h). Flash column chromatography (hexanes/ethyl
acetate 7:3) furnished 10e (26%) as a colorless resin. Rf
0.26 (hexanes/ethyl acetate 1:1); HPLC: tR 75.3 min,
>98% de (silica gel 5 mm, 4.6ꢂ250 mm, diisopropyl
ether/acetonitrile 99:1, 1.0 mL/min, 254 nm detection);
[a]2D2 ꢁ108 (c 1.0, methanol); IR (Neat) 3144, 2976, 2877,
Starting from 6a,b,d, 11a,b,d, respectively, were prepared
analogously (direct column chromatography, no extraction
steps):
4.9.2. (S)-1-(1-Acetylpyrrolidin-2-ylmethyl)-(1,2,3)-tri-
azole-4-carboxylic acid ethyl ester (11a). Reaction time:
3.5 h. Flash column chromatography (CH2Cl2/methanol
98:2) furnished 11a (56%) as a colorless solid. TLC detec-
tion: ninhydrin, 150 ꢀC, 15 min. Mp 71–72 ꢀC; Rf 0.29
(CH2Cl2/methanol 95:5); [a]2D7 ꢁ64.4 (c 1.0, CHCl3); IR
1
1754, 1692 cmꢁ1; H NMR (360 MHz, CDCl3; rotamers
were observed) d 1.02–1.51 (m, 9H, Boc CH3), 1.80–2.53
(br m, 4H, CH2), 3.27–3.60 (br m, 2H, NCH2), 3.82+3.83
(2ꢂs, 3H, OCH3), 4.85–5.08 (br m, 1H, NCH), 6.53+6.56
(br s+br s, 1H, NCHCO), 7.29–7.76+7.58+7.67 (m+br
s+br s, 6H, Ar–H+2ꢂtriazole H).
(Neat) 2975, 1735, 1641 cmꢁ1
;
1H NMR (360 MHz,
CDCl3; approx. 3% of a cis rotamer were visible; the trans
rotamer is described) d 1.40 (t, 3H, J¼7.2 Hz, CH2CH3),
1.46–1.62 (m, 1H, CH2), 1.76–1.90 (m, 1H, CH2), 1.91–
2.04 (m, 2H, CH2), 2.09 (s, 3H, acetyl CH3), 3.25 (ddd,
1H, J¼9.9, 7.8, 4.4 Hz, NCH2), 3.38 (ddd, 1H, J¼9.9, 7.6,
7.6 Hz, NCH2), 4.30–4.47+4.42 (m+s, 3H, J¼7.2 Hz,
NCH+CH2CH3), 4.63 (dd, 1H, J¼13.7, 2.8 Hz, NCHCH2-
triazole), 4.75 (dd, 1H, J¼13.7, 6.6 Hz, NCHCH2-triazole),
8.07 (s, 1H, triazole H); 13C NMR (90 MHz, CDCl3) d 14.5
(CH2CH3), 23.1+23.9 (acetyl CH3+CH2), 28.1 (CH2), 48.4,
51.4, 57.1, 61.5 (3ꢂNCH2+OCH2), 128.4, 140.6 (2ꢂtriazole
C), 160.8 (ester C]O), 170.5 (amide C]O); EIMS 266
(M+); HRMS calculated for C12H18N4O3: 266.1379, found:
266.1379.
4.9. Exchange of the N-Boc group by an N-acetyl group
4.9.1. (S)-2-[4-(1-Acetylpyrrolidin-2-yl)-(1,2,3)-triazol-1-
yl]acetic acid ethyl ester (11c). Compound 6c (26.2 mg,
0.081 mmol) was dissolved in CH2Cl2 (1.0 mL) and treated
with TFA in CH2Cl2 (1:1, 1.0 mL) while stirring on an ice
bath. After 35 min the mixture was evaporated to dryness.
After addition of CH2Cl2 (2 mL), the evaporation was re-
peated and the residue was dried thoroughly. Then CH2Cl2
(1.0 mL) and DIPEA (30.0 mL, 0.181 mmol) were added
and the mixture was cooled to 0 ꢀC. After addition of acetyl
chloride (10.0 mL, 0.123 mmol), the temperature was main-
tained for 12 min, whereupon the ice bath was removed and
4.9.3. (S)-1-(1-Acetylpyrrolidin-2-ylmethyl)-(1,2,3)-tri-
azole-5-carboxylic acid ethyl ester (11b). Reaction time:

8926
A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
1.5 h. Flash column chromatography (CH2Cl2/methanol
95:5) furnished 11b (76%) as a colorless resin. TLC detec-
tion: ninhydrin, 150 ꢀC, 15 min. Rf 0.56 (CH2Cl2/methanol
9:1); [a]2D7 ꢁ13.6 (c 1.0, CHCl3); IR (Neat) 3122, 2976,
d 1.87–2.52+1.99+2.07 (m+s+s, 7H, CH2+acetyl CH3,cis+
acetyl CH3,trans), 2.79 (d, 2.25H, J¼4.8 Hz, NCH3,trans),
2.82 (d, 0.75H, J¼4.8 Hz, NCH3,cis), 3.52 (ddd, 1H, J¼
9.7, 9.4, 6.9 Hz, NCH2), 3.66 (ddd, 1H, J¼9.7, 8.0, 3.2 Hz,
NCH2), 4.90 (d, 0.75H, J¼16.3 Hz, NCH2C]Otrans), 4.96
(d, 0.75H, J¼16.3 Hz, NCH2C]Otrans), 4.90 (d, 0.50H,
J¼0.90 Hz, NCH2C]Ocis), 5.14 (dd, 0.25H, J¼7.7,
1.8 Hz, NCHcis), 5.26 (dd, 0.75H, J¼7.7, 2.4 Hz, NCHtrans),
6.34+6.46 (br s+br s, 1H, NH), 7.58 (s, 0.25H, triazole Hcis),
7.65 (s, 0.75H, triazole Htrans); 13C NMR (150 MHz, CDCl3;
cis/trans rotamers were observed) d 22.4 (w), 22.8 (w), 22.9
(s), 24.9 (s), 26.5+26.6, 30.8+34.1 (2ꢂCH3+2ꢂCH2),
46.2+48.1, 52.6 (s), 53.0 (s), 53.1 (w), 55.1 (w)
(2ꢂNCH2+NCH), 122.6+124.5, 149.3+150.5 (2ꢂtriazole
C), 165.5+165.9, 169.7+170.0 (2ꢂC]O); EIMS 251
(M+); HRMS calculated for C11H17N5O2: 251.1382, found:
251.1382.
1
1728, 1648, 1639 cmꢁ1; H NMR (360 MHz, CDCl3; cis/
trans rotamers were observed) d 1.40 (t, 3H, J¼7.2 Hz,
CH2CH3), 1.58–2.07+1.97+1.99 (m+s+s, 7H, CH2+acetyl
CH3,cis+acetyl
CH3,trans),
3.33–3.63+3.38+3.44
(m+ddd+ddd, 2H, J¼9.8, 9.1, 7.0 Hz+9.8, 8.5, 3.1 Hz),
NCH2CH2), 4.39+4.40 (q+q, 2H, J¼7.2 Hz, CH2CH3),
4.68–4.76 (m, 1H, NCH), 4.86+4.90 (dd+dd, 2H, J¼13.7,
5.7 Hz+13.7, 6.4 Hz, NCHCH2-triazole), 8.09 (s, 0.74H, tri-
azole Htrans), 8.12 (s, 0.26H, triazole Hcis); 13C NMR
(150 MHz, CDCl3; cis/trans rotamers were observed)
d 14.3 (CH2CH3), 21.7 (w), 21.75 (w), 22.8 (s), 23.9 (s) (ace-
tyl CH3+CH2), 27.6+28.7 (CH2), 45.8+47.8, 51.2+51.3,
55.8+58.1, 62.0+62.3 (3ꢂNCH2+OCH2), 128.5+129.0,
137.9+138.0 (2ꢂtriazole C), 158.7+158.8 (ester C]O),
169.9+170.1 (amide C]O); EIMS 266 (M+); HRMS calcu-
lated for C12H18N4O3: 266.1379, found: 266.1379.
Starting from 11a,b,d, 12a,b,d, respectively, were prepared
analogously:
4.9.4. (S)-2-[5-(1-Acetylpyrrolidin-2-yl)-(1,2,3)-triazol-1-
yl]acetic acid ethyl ester (11d). The title compound was ob-
tained from a mixture of 6c and 6d as obtained from thermal
cycloaddition and was separated from 11c by flash column
chromatography (CH2Cl2/acetone 7:3) furnishing 11d
(31%) as a colorless resin. TLC detection: ninhydrin,
150 ꢀC, 20 min. Rf 0.27 (CH2Cl2/acetone 1:1); [a]2D4 37.2
4.10.2. (S)-1-(1-Acetylpyrrolidin-2-ylmethyl)-(1,2,3)-tri-
azole-4-carboxylic acid N-methyl amide (12a). Reaction
interrupted after 2 h 25 min. Flash column chromatography
(CH2Cl2/methanol 95:5) furnished 12a (19%; 54% of the
starting material were recovered) as a colorless solid. TLC
detection: ninhydrin, 150 ꢀC, 25 min. Mp 150–151 ꢀC; Rf
0.08 (CH2Cl2/methanol 95:5); [a]2D6 ꢁ88.4 (c 0.25,
CHCl3); IR (Neat) 3330, 2241, 1649, 1578 cmꢁ1; 1H NMR
(360 MHz, CDCl3) d 1.32–1.45 (m, 1H, CH2), 1.74–2.07
(m, 4H, CH2), 2.10 (s, 3H, acetyl CH3), 3.01 (d, 3H,
J¼5.0 Hz, NCH3), 3.24 (ddd, 1H, J¼10.0, 7.9, 4.3 Hz,
NCH2), 3.37 (ddd, 1H, J¼10.0, 7.8, 7.6 Hz, NCH2), 4.31–
4.44 (m, 1H, NCH), 4.61 (dd, 1H, J¼13.9, 3.0 Hz,
CHCH2-triazole), 4.77 (dd, 1H, J¼13.9, 6.1 Hz, CHCH2-tri-
azole), 7.11 (q, 1H, J¼5.0 Hz, NH), 8.01 (s, 1H, triazole H);
13C NMR (90 MHz, CDCl3) d 23.1, 23.9, 25.9, 27.9
(2ꢂCH3+2ꢂCH2), 48.4, 51.5, 56.9 (2ꢂNCH2+NCH),
126.1, 143.7 (2ꢂtriazole C), 160.7, 170.5 (2ꢂamide
C]O); EIMS 251 (M+); HRMS calculated for
C11H17N5O2: 251.1382, found: 251.1382.
(c 1.0, CHCl3); IR (Neat) 3125, 1748, 1644 cmꢁ1 1H
;
NMR (360 MHz, CDCl3; cis/trans rotamers were observed)
d 1.291+1.297 (t+t, 3H, J¼7.2 Hz, CH2CH3), 1.84–
2.44+1.94+2.01 (m+s+s, 7H, CH2+acetyl CH3,cis+acetyl
CH3,trans), 3.56 (ddd, 1H, J¼10.0, 7.4, 7.4 Hz, NCH2),
3.65 (ddd, 1H, J¼10.0, 7.3, 4.3 Hz, NCH2), 4.21+4.26
(dq+dq, 2H, J¼11.0, 7.2 Hz, CH2CH3), 4.96 (d, 0.12H,
J¼17.6 Hz, NCH2COcis), 5.03 (dd, 1H, J¼7.4, 3.1 Hz,
NCH), 5.29 (d, 0.12H, J¼17.6 Hz, NCH2COcis), 5.42 (d,
0.88H, J¼17.7 Hz, NCH2COtrans), 5.69 (d, 0.88H,
J¼17.7 Hz, NCH2COtrans), 7.48 (s, 0.12H, triazole Hcis),
7.54 (s, 0.88H, triazole Htrans); 13C NMR (90 MHz,
CDCl3; cis/trans rotamers were observed)
d 14.2
(CH2CH3), 22.2 (w), 22.4 (w), 22.6 (s), 25.2 (s) (acetyl
CH3+CH2), 32.3+33.3, 46.2+47.6, 49.4+49.8, 50.2+53.2,
62.3+62.9 (4ꢂCH2+CH), 131.0+132.6, 140.3 (2ꢂtriazole
C), 167.5, 169.8 (2ꢂC]O); EIMS 266 (M+); HRMS: calcu-
lated for C12H18N4O3: 266.1379, found: 266.1379.
4.10.3. (S)-1-(1-Acetylpyrrolidin-2-ylmethyl)-(1,2,3)-tri-
azole-5-carboxylic acid N-methyl amide (12b). Reaction
time: 2.5 h. Flash column chromatography (CH2Cl2/metha-
nol 95:5) furnished 12b (64%) as a colorless solid. TLC de-
tection: ninhydrin, 150 ꢀC, 30 min. Mp 176–177 ꢀC; Rf 0.04
(CH2Cl2/methanol 95:5); [a]2D6 11.9 (c 1.0, CHCl3); IR
(Neat) 3282, 3120, 2970, 2242, 1670, 1652, 1626,
1627 cmꢁ1; 1H NMR (360 MHz, CDCl3; cis/trans rotamers
were observed) d 1.79 (s, 0.66H, acetyl CH3,cis), 1.92–
2.06+1.98 (m+s, 6.34H, CH2+acetyl CH3,trans), 2.95+2.96
(d+d, 3H, J¼4.6 Hz, NCH3), 3.35–3.66 (m, 2H, NCH2),
4.37–4.47 (m, 0.22H, NCHcis), 4.59–4.81+4.73 (m+dd,
1.78H, J¼13.3, 7.0 Hz, NCHtrans+CHCH2-triazole),
4.87+4.91 (dd+dd, 1H, J¼13.3, 5.7 Hz+13.3, 6.8 Hz,
NCHtrans+NCHcis), 7.06 (q, 0.22H, J¼4.6 Hz, NHcis), 7.54
(q, 0.78H, J¼4.6 Hz, NHtrans), 7.99 (s, 0.22H, triazole
Hcis), 8.03 (s, 0.78H, triazole Htrans); 13C NMR (150 MHz,
CDCl3; cis/trans rotamers were observed) d 21.4 (w), 21.8
(w), 22.6 (s), 23.8 (s), 26.5+26.6, 28.0+28.8
(2ꢂCH3+2ꢂCH2), 45.8+47.7, 51.1+51.4, 56.3+58.4
(2ꢂNCH2+NCH), 131.7+132.2, 133.8+134.6 (2ꢂtriazole
4.10. Methylaminolysis of ethyl esters 11a–d
4.10.1. (S)-2-[4-(1-Acetylpyrrolidin-2-yl)-(1,2,3)-triazol-
1-yl]acetic acid N-methyl amide (12c). Compound 11c
(31.7 mg, 0.119 mmol) was dissolved in ethanol (1.0 mL)
and cooled to 0 ꢀC. After addition of methylamine solution
(8 M in ethanol, 0.5 mL), the mixture was stirred for 2 h,
whereupon TLC indicated complete conversion. The solvent
was removed under reduced pressure, CH2Cl2 (2 mL) was
added, evaporated to dryness and the residue was purified
by flash column chromatography (CH2Cl2/methanol 95:5),
furnishing 23.0 mg (77%) of 12c as a colorless solid. TLC
detection: ninhydrin, 150 ꢀC, 25 min. Mp 109–112 ꢀC; Rf
0.30 (CH2Cl2/methanol 95:5); [a]2D6 ꢁ68.5 (c 1.0, CHCl3);
1
IR (Neat) 3293, 3247, 3127, 3085, 1679, 1627 cmꢁ1; H
NMR (360 MHz, CDCl3; cis/trans rotamers were observed)

A. Paul et al. / Tetrahedron 62 (2006) 8919–8927
8927
C), 158.5+158.7, 170.1+170.5 (2ꢂC]O); EIMS 251 (M+);
HRMS calculated for C11H17N5O2: 251.1382, found:
251.1383.
7. An, S. S. A.; Lester, C. C.; Peng, J.-L.; Li, Y.-J.; Rothwarf,
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4.10.4. (S)-2-[5-(1-Acetylpyrrolidin-2-yl)-(1,2,3)-triazol-
1-yl]acetic acid N-methyl amide (12d). Reaction time:
3.5 h. Flash column chromatography (CH2Cl2/methanol
9:1) furnished 12d (86%) as a colorless solid. TLC detec-
tion: ninhydrin, 150 ꢀC, 30 min. Mp 142–144 ꢀC; Rf 0.33
(CH2Cl2/methanol 9:1); [a]2D2 ꢁ50.0 (c 0.5, CHCl3); IR
1H NMR (360 MHz, CDCl3; cis/trans rotamers were ob-
served) d 1.90–2.42+1.92+2.06 (m+s+s, 7H, CH2+acetyl
CH3,cis+acetyl CH3,trans), 2.81+2.82 (d+d, 3H, J¼4.8 Hz,
NCH3), 3.60 (ddd, 1H, J¼10.0, 7.4, 7.4 Hz, NCH2), 3.73
(ddd, 1H, J¼10.0, 7.3, 4.8 Hz, NCH2), 4.91 (d, 0.09H,
J¼16.5 Hz, NCH2C]Ocis), 5.04 (d, 0.91H, J¼16.5 Hz,
NCH2C]Otrans), 5.09 (dd, 1H, J¼8.2, 3.6 Hz, NCH), 5.18
(d, 0.09H, J¼16.5 Hz, NCH2C]Ocis), 5.37 (d, 0.91H,
J¼16.5 Hz, NCH2C]Otrans), 6.58 (br s, 0.09H, NHcis),
6.75 (br s, 0.91H, NHtrans), 7.47+7.58 (s+s, 1H, triazole
H); 13C NMR (150 MHz, CDCl3) d 22.7, 24.8, 26.6, 32.4
(2ꢂCH3+2ꢂCH2), 47.9, 51.0, 51.5 (2ꢂNCH2+NCH),
131.2, 140.5 (2ꢂtriazole C), 165.9, 169.9 (2ꢂC]O);
EIMS 251 (M+); HRMS calculated for C11H17N5O2:
251.1382, found: 251.1382.
(Neat) 3294, 3119, 3086, 2951, 2881, 1684, 1627 cmꢁ1
;
120.
18. Bettinetti, L.; Lober, S.; Hubner, H.; Gmeiner, P. J. Comb.
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Chem. 2005, 7, 309–316.
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Acknowledgements
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19. Rodriguez Loaiza, P.; Lober, S.; Hubner, H.; Gmeiner, P.
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J. Comb. Chem. 2006, 8, 252–261.
This work was supported by the Deutsche Forschungsge-
meinschaft (DFG). Dr. Reiner Waibel is acknowledged for
helpful discussions.
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Supplementary data
Copies of 1H and 13C NMR spectra of the target compounds
11a–d and 12a–d; copies of NOESY spectra of 11a–d and
12a. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/
j.tet.2006.07.007.
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