An enantiospecific approach to triazolylalanine derivatives

Article abstract of DOI:10.1055/s-0028-1083270

An efficient and practical route to an enantiomerically pure aziridinylmethyl azide is described that can be transformed to the corresponding triazole by a copper-catalysed [3+2] alkyne cycloaddition reaction. The transformation of these intermediates int

Full text of DOI:10.1055/s-0028-1083270

PAPER
133
An Enantiospecific Approach to Triazolylalanine Derivatives
A
n
E
nantiospecif
l
ic
A
pp
a
roachto
T
ri
r
a
zolylal
e
anine
D
erivativesE. Jamookeeah,a Christopher D. Beadle,b Joseph P. A. Harrity*a
a
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK
Fax +44(114)2229346; E-mail: j.harrity@sheffield.ac.uk
Eli Lilly and Company Ltd, Lilly Research Centre, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
b
Received 8 October 2008
Nu1
Nu1
Nu1
1. TFA
TsO
Abstract: An efficient and practical route to an enantiomerically
pure aziridinylmethyl azide is described that can be transformed to
the corresponding triazole by a copper-catalysed [3+2] alkyne cy-
cloaddition reaction. The transformation of these intermediates into
triazolylalanine-type derivatives by aziridine ring-opening reac-
tions is also described.
2. E-X
N
N
N
Tr
Tr
E
deactivated
activated
Nu1
Nu2
Nu2
N(H)E
Key words: copper catalyst, 1,2,3-triazole, aziridine, cycloaddi-
tion, ring-opening reaction, alanine
R
N
N
Nu2
R
R
Nu1: N3
N
N
N
N(H)E
N
N
Tr
'click'
The ability of aziridines to function as reactive electro-
philes has made this a popular class of synthetic interme-
diates in organic synthesis.1 Recent studies in our
laboratories have uncovered an efficient and enantiospe-
cific route to aziridines via the homologation of an azirid-
inylmethyl tosylate by a variety of Grignard reagents in
the presence of a copper catalyst.2 Notably, the aziridine
is protected with a non-activating trityl group that allows
chemoselective substitution of the primary alkyl tosylate,
whilst subsequently providing the opportunity to activate
the ring towards nucleophilic addition via a one-pot
Scheme 1 Enantiospecific approach to triazolylalanine derivatives
OH
MeO2C
(i)–(iii)
N
Tr
2
MeO2C
NH2⋅HCl
1
4
(iv), (v)
(vi)
N3
TsO
N
N
Tr
Tr
3
deprotection–sulfonylation/acylation protocol (Scheme 1). Scheme 2 Synthesis of key azide intermediate 4. Reagents and con-
ditions: (i) TrCl, Et3N, CH2Cl2, r.t., 16 h, 83%; (ii) TsCl, pyridine, 0
°C, 8 h, 74%; (iii) Et3N, THF, reflux, 16 h, 73%; (iv) LiAlH4, Et2O,
r.t., 4 h, 91%; (v) TsCl, Et3N, cat. DMAP, CH2Cl2, r.t., 16 h, 82%; (vi)
NaN3 (5 equiv), DMF, 60 °C, 16 h, 96%.
Among the potential substitution processes envisaged in
step 1 of Scheme 1, the use of azide was particularly ap-
pealing because the intermediate aziridine could be con-
verted into a range of enantiomerically pure triazole
derivatives by sequential [3+2]-cycloaddition–ring acti-
mally promoted reaction with terminal alkynes generally
vation/opening processes. This strategy would represent a
provides a mixture of 1,4- and 1,5-substituted triazole
convenient method for the synthesis of arrays of 1,2,3-tri-
products. The emergence of the ‘click’ chemistry7 concept
azoles, an increasingly popular class of pharmacophores
in drug discovery research,3 and would provide a useful
alternative to existing approaches to amino acid based de-
rivatives of these heterocycles.4 We report herein our
studies towards this end.
has however resulted in significant advances in this field
and mild, efficient metal-catalyzed variants for both ter-
minal and internal alkyne substrates are now available.8
We decided to employ copper-catalysed cycloaddition
methodology to carry out the reaction of 4 with a series of
commercially available alkynes. As highlighted in
Table 1, we were pleased to find that the cycloaddition of
4 proceeded smoothly with alkynes bearing a selection of
alkyl and aryl substituents. A single regioisomer was pro-
vided in good to high yield in each case.
As outlined in Scheme 2, we developed a simple and prac-
tical method for the synthesis of the key tosylate interme-
diate 3,5 this route provided the compound on ~50-gram
scale from (S)-serine methyl ester hydrochloride (1), and
could be carried out without recourse to chromatographic
purification. Finally, azide substitution of 3 took place in
high yield to provide compound 4.2
Our next goal was to perform the protecting group switch
on the aziridine to activate the three-membered ring to nu-
cleophilic addition. Our preliminary studies on this pro-
cess had used a large excess of trifluoroacetic acid to
remove the trityl group.2 We wanted to reduce the loading
of Brønsted acid and were attracted to the conditions re-
ported by Vedejs and co-workers, who employed a small
excess of trifluoroacetic acid in the presence of triethylsi-
With enantiopure azide 4 in hand, we turned out attention
to the cycloaddition reactions. 1,3-Dipolar cycloadditions
of azides was studied in detail by Huisgen,6 but the ther-
SYNTHESIS 2009, No. 1, pp 0133–0137
0
2
.
0
1
.2
0
0
9
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1083270; Art ID: C05708SS
© Georg Thieme Verlag Stuttgart · New York

134
C. E. Jamookeeah et al.
PAPER
Table 1 [3+2] Cycloadditions of Azide 4 and Terminal Alkynes
(i)
N
N
N
N
N
CuSO4 (4 mol%)
R
N
Bn
Bn
Bn
Bn
Bn
Bn
N
N
N
N
N
N
Ts
Tr
N3
N
ascorbic acid (20 mol%)
45 °C, 16 h
R
13
14
15
11
11
11
+
N
N
N
N
Tr
Tr
4
(i)
5–8
9–12
N
N
N
N
N
N
Cbz
Tr
Entry Substrate R
Product
Yield
(%)
(ii), (iii)
N
N
N
N
1
2
3
5
6
7
Bn
9
Bn
71
61
75
N
N
N
N
N
N
Dpp
Tr
Tr
N
N
o-Tol
10
o-Tol
Scheme 3 Deprotection–protection of aziridine 11. Reagents and
conditions: (i) (a) TFA (4 equiv), Et3SiH (4 equiv), CH2Cl2, 0 °C, 0.5
h, (b) Et3N (7 equiv), RCl, (1.1 equiv), r.t., 4 h; R = Ts, 73%; R = Cbz,
85%; (ii) (a) TFA (4 equiv), Et3SiH (4 equiv), CH2Cl2, 0 °C, 0.5 h, (b)
Et3N (5 equiv); (iii) Et3N (1 equiv), Ph2P(O)Cl, (1.1 equiv), CH2Cl2,
r.t., 16 h, 46%.
N
N
Tr
N
N
(CH2)2Ph 11
N
Bn
N
Tr
N
4
8
i-Bu
12
86
N
N
N
Tr
could be generated by simply isolating the crude free azir-
idine and converting it into 15 under standard conditions
(Scheme 3).
lane to trap the trityl cation.9 In the event, we were able to
successfully apply this technique to convert triazole 11 Our final goal was to demonstrate that this approach could
into tosyl-protected aziridine 13 after addition of triethyl- be employed to generate new enantiomerically pure scaf-
amine and tosyl chloride. Moreover, we were able to ex- folds after nucleophilic aziridine ring cleavage. Accord-
tend these conditions for the one-pot protecting group ingly, we opted to carry out ring-opening reactions of
switch to prepare the benzyloxycarbonyl-protected aziri- aziridine 13 with a selection of nucleophiles. As outlined
dine 14, however, attempts to generate a diphenylphos- in Table 2, a series of efficient ring-opening reactions
phoryl (Dpp)-protected aziridine 15 using the one-pot were achieved that allowed the incorporation of N-, S-, or
method proved to be unsatisfactory. Nonetheless, 15 O-centred nucleophiles in good to excellent yield.10
Table 2 Ring-Opening Reactions of Aziridine 13
N
N
Nu
conditions
N
N
Bn
N
N
Bn
N
Ts
Nu
TsHN
13
16–19
Entry
1
Reagents and conditions
Product
Yield (%)
70
N
N
N
TMSN3, DMSO, 40 °C, 4 h
16
Bn
Bn
Bn
N3
N
TsHN
TsHN
TsHN
N
N
2
3
PhNH2, DMSO, 60 °C, 4 h
17
18
95
95
N(H)Ph
N
N
N
4-ClC6H4SH, DMSO, 60 °C, 4 h
S
Cl
N
N
N
4
PhOH, Cs2CO3, DMSO, 70 °C, 16 h
19
73
Bn
OPh
TsHN
Synthesis 2009, No. 1, 133–137 © Thieme Stuttgart · New York

PAPER
An Enantiospecific Approach to Triazolylalanine Derivatives
135
fication provided 10 (1.22 g, 61%) as a colourless solid; mp 81–84
°C.
catalysed [3+2] cycloaddition of alkynes with an enantio- [a]D22 –8.3 (c 1.2, CHCl3).
In conclusion, we have developed a flexible enantiospe-
cific strategy to triazolylalanine derivatives by a copper-
FT-IR (film): 3027 (w), 2928 (w), 2360 (w), 1487 (m), 1448 cm–1
(m).
1H NMR (400 MHz, CDCl3): d = 1.27 (d, J = 6.0 Hz, 1 H), 1.83–
1.88 (m, 2 H), 2.43 (s, 3 H), 4.54 (dd, J = 14.0, 5.5 Hz, 1 H), 4.88
(dd, J = 14.0, 5.0 Hz, 1 H), 7.21–7.73 (m, 20 H).
merically pure aziridinylmethyl azide. Activation of the
aziridine by a protecting group switch allows a series of
nucleophiles to be introduced via aziridine ring-opening
reactions.
13C NMR (100.6 MHz, CDCl3): d = 21.3, 25.8, 31.9, 52.7, 74.1,
121.9, 126.0, 126.9, 127.6, 128.1, 128.9, 129.2, 129.9, 130.8, 135.4,
143.9, 147.1.
HRMS (TOF ESI): m/z [M + H+] calcd for C31H29N4: 457.2392;
found: 457.2396.
Flash chromatography was performed on silica gel (BDH Silica Gel
60 43–60, or Fluorochem Davisil silica gel 43–60). The solvent sys-
tem used was a gradient of petroleum ether–EtOAc (90:10) increas-
ing in polarity to EtOAc. TLC was performed on aluminium-backed
plates pre-coated with silica gel (0.2 mm, Merck DC-alufolien Kie-
selgel 60 F254), which were developed using standard visualizing
agents: UV light or KMnO4. 1H/13C NMR spectra were recorded on
Bruker AC-250 or Av1-250 instruments or AMX-400 or AV1-400
instruments. 1H: solvent resonance as the internal standard
(CHCl3:d = 7.27). 13C: complete proton decoupling, solvent reso-
nance as the internal standard (CDCl3: d = 77.0). FT-IR spectra
were recorded on a Perkin-Elmer Paragon 100 FT-IR spectropho-
tometer; samples were recorded as thin films using NaCl plates, as
a CH2Cl2 soln or as a KBr disc. LR-MS were recorded on Micro-
mass Autospec, operating in EI, CI, or FAB mode; or a Perkin-
Elmer Turbomass Bench top GC-MS operating in either EI or CI
mode. HRMS recorded for accurate mass analysis, were performed
on either a MicroMass LCT (TOF ESI+ mode) or a MicroMass
Prospec (FAB+, EI+, or CI+ mode). Optical rotation values were re-
corded on a Perkin-Elmer 241 automatic polarimeter at 589 nm (Na
D-line) with a path length of either 1 dm or 0.1 dm, and are given in
10–1 deg·cm2·g–1 with concentrations (c) quoted in g/100 mL. Melt-
ing points were performed on recrystallized solids and recorded on
a Gallenkamp melting point apparatus and are uncorrected. Com-
pounds 1, 2,5 and 3, 42 were prepared according to literature proce-
dures.
4-Phenethyl-1-{[(S)-1-tritylaziridin-2-yl]methyl}-1H-1,2,3-tri-
azole (11)
Following the typical procedure, 4 (1.85 g, 5.44 mmol), 4-phenyl-
but-1-yne (0.76 mL, 5.44 mmol), 1 M ascorbic acid in H2O (1.08
mL, 1.09 mmol, 20 mol%), and 0.3 M CuSO4 in H2O (0.73 mL, 0.22
mmol,) in t-BuOH–H2O (1:1, 20 mL) was heated overnight. Purifi-
cation provided 11 (1.95 g, 76%) as a colourless solid; mp 78–81
°C.
[a]D22 –23.8 (c 2.5, CHCl3).
FT-IR (film): 3059 (m), 2930 (m), 1596 (m), 1490 cm–1 (s).
1H NMR (400 MHz, CDCl3): d = 1.20 (d, J = 6.0 Hz, 1 H), 1.71–
1.77 (m, 2 H), 2.94–3.05 (m, 4 H), 4.34 (dd, J = 14.0, 5.5 Hz, 1 H),
4.78 (dd, J = 14.0, 4.0 Hz, 1 H), 7.16–7.48 (m, 21 H).
13C NMR (62.9 MHz, CDCl3): d = 25.9, 27.4, 31.8, 35.5, 52.7, 74.0,
121.0, 126.0, 126.9, 127.6, 128.3, 128.4, 129.2, 141.2, 143.9, 144.0.
HRMS (TOF ESI): m/z [M + H+] calcd for C32H31N4: 471.2571;
found: 471.2549.
4-Isobutyl-1-{[(S)-1-tritylaziridin-2-yl]methyl}-1H-1,2,3-tri-
azole (12)
4-Benzyl-1-{[(S)-1-tritylaziridin-2-yl]methyl}-1H-1,2,3-triazole
(9); Typical Procedure
Following the typical procedure, 4 (1.5 g, 4.41 mmol), 4-methyl-
pent-1-yne (0.52 mL, 4.41 mmol), 1 M ascorbic acid in H2O (0.88
mL, 0.88 mmol, 20 mol%), and 0.3 M CuSO4 in H2O (0.59 mL, 0.18
mmol) in t-BuOH–H2O (1:1, 17 mL) was heated overnight. Purifi-
cation provided 12 (1.59 g, 86%) as a colourless solid; mp 72–75
°C.
[a]D22 –17.0 (c 1.1, CHCl3).
FT-IR (film): 3029 (w), 2955 (m), 1594 (w), 1486 (m) 1447 cm–1
(m).
To a soln of 4 (0.2 g, 0.59 mmol) and 1-(prop-2-ynyl)benzene (73
mL, 0.59 mmol) in t-BuOH–H2O (1:1, 2.26 mL) was added 1 M
ascorbic acid in H2O (120 mL, 0.118 mmol, 20 mol%), followed by
0.3 M CuSO4 in H2O (80 mL, 0.024 mmol). The mixture was heated
to 45 °C overnight. Upon cooling, the mixture was extracted with
CH2Cl2, the combined organic layers were washed with brine, dried
(MgSO4), and concentrated in vacuo to provide crude 9. Purifica-
tion by flash chromatography provided 9 (192 mg, 71%) as a clear
oil.
[a]D22 –15.3 (c 1.3, CHCl3).
FT-IR (film): 3057 (w), 2932 (w), 1450 (m), 1448 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 1.20 (d, J = 6.0 Hz, 1 H), 1.66–
1.73 (m, 1 H), 1.75 (d, J = 3.0 Hz, 1 H), 4.05 (s, 2 H), 4.35 (dd,
J = 14.0, 5.5 Hz, 1 H), 4.76 (dd, J = 14.0, 5.5 Hz, 1 H), 7.16–7.44
(m, 21 H).
13C NMR (100.6 MHz, CDCl3): d = 25.8, 32.0, 32.3, 52.8, 74.0,
121.5, 126.4, 126.8, 127.6, 128.6, 128.7, 129.2, 139.1, 143.9, 147.8.
HRMS (TOF ESI): m/z [M + H+] calcd for C31H29N4: 457.2392;
1H NMR (400 MHz, CDCl3): d = 0.93 (d, J = 4.0 Hz, 3 H), 0.94 (d,
J = 4.0 Hz, 3 H), 1.21 (d, J = 4.0 Hz, 1 H), 1.73 (d, J = 6.0 Hz, 1 H),
1.74–1.79 (m, 1 H), 1.89–1.99 (m, 1 H), 2.56 (dd, J = 14.5, 2.0 Hz,
1 H), 2.58 (dd, J = 14.5, 2.0 Hz, 1 H), 4.41 (dd, J = 14.0, 5.5 Hz, 1
H), 4.83 (dd, J = 14.0, 5.0 Hz, 1 H), 7.21–7.48 (m, 16 H).
13C NMR (100.6 MHz, CDCl3): d = 22.2, 22.3, 25.7, 28.6, 31.9,
34.7, 52.4, 74.0, 121.4, 126.9, 127.6, 129.2, 144.0, 147.2.
HRMS (TOF ESI): m/z [M + H+] calcd for C28H31N4: 423.2549;
found: 423.2531.
found: 457.2378.
4-Phenethyl-1-{[(R)-1-tosylaziridin-2-yl]methyl}-1H-1,2,3-tri-
azole (13); Typical Procedure
4-(2-Tolyl)-1-{[(S)-1-tritylaziridin-2-yl]methyl}-1H-1,2,3-tri-
azole (10)
Following the typical procedure, 4 (1.5 g, 4.41 mmol), 2-tolylacet-
ylene (0.52 mL, 4.41 mmol), 1 M ascorbic acid in H2O (0.88 mL,
0.88 mmol, 20 mol%), and 0.3 M CuSO4 in H2O (0.59 mL, 0.18
mmol,) in t-BuOH–H2O (1:1, 17 mL) were heated overnight. Puri-
To a soln of 11 (0.2 g, 0.42 mmol) in CH2Cl2 (8.8 mL) at 0 °C was
added Et3SiH (0.272 mL, 1.7 mmol, 4 equiv) and TFA (0.126 mL,
1.7 mmol, 4 equiv). After 30 min, Et3N (0.415 mL, 2.98 mmol, 7
equiv) was added and the mixture was stirred for a further 10 min
upon which TsCl (85 mg, 0.45 mmol, 1.05 equiv) was added. The
mixture was stirred at 0 °C for 4 h and NaHCO3 soln was added. The
soln was extracted with CH2Cl2 and the combined organic extracts
Synthesis 2009, No. 1, 133–137 © Thieme Stuttgart · New York

136
C. E. Jamookeeah et al.
PAPER
were dried (MgSO4) and concentrated in vacuo to provide crude 13.
Purification by flash chromatography provided 13 (0.12 g, 73%) as
a colourless solid; mp 82–85 °C.
13C NMR (100.6 MHz, CDCl3): d = 27.8, 28.2, 34.2, 35.7, 52.3,
121.1, 126.5, 128.7–129.1 (m, 2 C), 131.7–131.9 (m, 2 C), 132.5 (d,
J = 145 Hz), 131.5, 132.5, 141.5, 147.8.
[a]D22 –20.7 (c 1.4, CHCl3).
HRMS (TOF ESI): m/z [M + H+] calcd for C25H26N4OP: 429.1844;
found: 429.1857.
FT-IR (film): 3027 (w), 2859 (w), 1597 (m), 1495 (m), 1454 (m),
1326 (s), 1226 (m), 1162 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 2.16 (d, J = 4.0 Hz, 1 H), 2.44 (s,
3 H), 2.75 (d, J = 7.0 Hz, 1 H), 2.87–2.98 (m, 4 H), 3.12–3.21 (m, 1
H), 4.09 (dd, J = 15.0, 7.0 Hz, 1 H), 4.67 (dd, J = 15.0, 4.0 Hz, 1 H),
7.16–7.74 (m, 10 H).
13C NMR (100.6 MHz, CDCl3): d = 21.7, 27.3, 31.2, 35.5, 38.0,
50.4, 121.3, 126.1, 128.0, 128.3, 128.4, 129.8, 134.0, 141.0, 145.0,
147.5.
1-[(R)-3-Azido-2-(tosylamino)propyl]-4-phenethyl-1H-1,2,3-
triazole (16); Typical Procedure
To a soln of 13 (0.1 g, 0.26 mmol) in DMSO (2.1 mL) was added
TMSN3 (35 mL, 0.26 mmol); the mixture was heated to 40 °C for 4
h. Upon cooling, H2O was added, the soln was extracted with
EtOAc, and the combined organic extracts were dried (MgSO4) and
concentrated in vacuo to provide crude 16. Purification by flash
chromatography provided 16 (0.078 g, 70%) as a clear oil.
[a]D22 –24.9 (c 1.2, CHCl3).
HRMS (TOF ESI): m/z [M + H+] calcd for C20H23N4O2S: 383.1542;
found: 383.1526.
FT-IR (film): 3027 (w), 2916 (w), 2106 (s), 1599 (w), 1453 (w),
1329 (m), 1219 cm–1 (m).
1H NMR (250 MHz, CDCl3): d = 2.43 (s, 3 H), 2.91–3.03 (m, 4 H),
3.23–3.38 (m, 2 H), 3.64–3.76 (m, 1 H), 4.29–4.44 (m, 2 H), 5.97
(br, 1 H), 7.14–7.75 (m, 10 H).
13C NMR (100.6 MHz, CDCl3): d = 21.5, 27.1, 35.4, 50.5, 51.5,
52.5, 122.9, 126.2, 126.9, 128.4, 128.5, 129.9, 136.9, 140.8, 144.0,
147.2.
Benzyl (S)-2-[(4-Phenethyl-1H-1,2,3-triazol-1-yl)methyl]aziri-
dine-1-carboxylate (14)
Following the typical procedure, Et3SiH (0.068 mL, 0.42 mmol, 4
equiv) and TFA (0.032 mL, 0.42 mmol, 4 equiv) were added to a
soln of 11 (0.05 g, 0.11 mmol) in CH2Cl2 (2.2 mL). After 30 min,
Et3N (0.10 mL, 0.74 mmol, 7 equiv) and CbzCl (18 mL, 0.13 mmol,
1.2 equiv) were added. Purification provided 14 (34 mg, 85%) as a
yellow oil.
HRMS (TOF ESI): m/z [M + H+] calcd for C20H24N7O2S: 426.1712;
found: 426.1695.
[a]D22 –16.6 (c 1.2, CHCl3).
FT-IR (film): 3029 (w), 2961 (m), 2851 (w), 1720 (s), 1597 (m),
1497 cm–1 (w).
1H NMR (400 MHz, CDCl3): d = 2.10 (d, J = 3.5 Hz, 1 H), 2.51 (d,
J = 6.5 Hz, 1 H), 2.87–2.92 (m, 1 H), 2.94–3.05 (m, 4 H), 4.23 (dd,
J = 14.5, 7.0 Hz, 1 H), 4.67 (dd, J = 14.5, 4.0 Hz, 1 H) 5.11 (d,
J = 12.0 Hz, 1 H), 5.15 (d, J = 12.0 Hz, 1 H), 7.18–7.43 (m, 11 H).
4-Phenethyl-1-[(S)-3-(phenylamino)-2-(tosylamino)propyl]-
1H-1,2,3-triazole (17)
Following the typical procedure, 13 (0.1 g, 0.26 mmol) and aniline
(24 mL, 0.26 mmol) in DMSO (2.1 mL) were heated to 60 °C for 4
h. Purification provided 17 (0.12 g, 95%) as a yellow solid; mp 84–
88 °C.
13C NMR (100.6 MHz, CDCl3): d = 27.4, 29.8, 35.4, 36.0, 51.4,
68.6, 121.5, 126.0, 128.2, 128.3, 128.4, 128.6, 128.7, 135.2, 141.1,
147.6, 162.3.
HRMS (TOF ESI): m/z [M + H+] calcd for C21H23N4O2: 363.1821;
found: 363.1831.
[a]D22 –13.0 (c 1.5, CHCl3).
FT-IR (film): 3027 (w), 2917 (w), 1919 (w), 1603 (s), 1497 (m),
1453 (m), 1327 cm–1 (s).
1H NMR (250 MHz, CDCl3): d = 2.43 (s, 3 H), 2.99–3.01, (m, 6 H),
3.67–3.78 (m, 1 H), 4.00 (br, 1 H), 4.41 (dd, J = 14.5, 4.5 Hz, 1 H),
4.54 (dd, J = 14.5, 4.0 Hz, 1 H), 5.46 (br, 1 H), 6.29–7.73 (m, 15 H).
13C NMR (100.6 MHz, CDCl3): d = 21.5, 27.2, 35.4, 44.4, 51.1,
51.6, 112.7, 118.1, 123.2, 126.1, 127.1, 128.4, 128.5, 129.3, 129.8,
136.5, 141.0, 143.9, 146.6, 147.2.
1-{[(R)-1-(Diphenylphosphoryl)aziridin-2-yl]methyl}-4-phen-
ethyl-1H-1,2,3-triazole (15)
To a soln of 11 (0.2 g, 0.42 mmol) in CH2Cl2 (8.8 mL) at 0 °C was
added Et3SiH (0.272 mL, 1.7 mmol, 4 equiv) and TFA (0.126 mL,
1.7 mmol, 4 equiv). After 30 min, Et3N (0.370 mL, 2.13 mmol, 5
equiv) was added and the mixture stirred for a further 10 min upon
which NaHCO3 soln was added. The soln was extracted with Et2O
and the combined organic extracts were dried (MgSO4) and concen-
trated in vacuo to provide crude free aziridine. The crude residue
was dissolved in CH2Cl2 (2.1 mL) and cooled to 0 °C. Et3N (0.058
mL, 0.42 mmol, 1 equiv) and Ph2P(O)Cl (0.080 mL, 0.42 mmol, 1
equiv) were added to the mixture. The mixture was left to warm to
r.t. overnight upon which NaHCO3 soln was added. The soln was
extracted with CH2Cl2 and the combined organic extracts were
dried (MgSO4) and concentrated in vacuo to provide crude 15. Pu-
rification by flash chromatography provided 15 (0.08 g, 46%) as a
yellow oil.
HRMS (TOF ESI): m/z [M + H+] calcd for C26H30N5O2S: 476.2120;
found: 476.2137.
1-[(R)-3-(4-Chlorophenylsulfanyl)-2-(tosylamino)propyl]-4-
phenethyl-1H-1,2,3-triazole (18)
Following the typical procedure, 13 (0.05 g, 0.13 mmol) and 4-chlo-
rothiophenol (18 mg, 0.13 mmol) in DMSO (2.1 mL) were heated
at 60 °C for 4 h. Purification provided 18 (65 mg, 95%) as a clear
oil.
[d]D22 –18.0 (c 1.3, CHCl3).
FT-IR (film): 3026 (w), 2091 (w), 1497 (m), 1477 (m), 1329 cm–1
(m).
[a]D22 +10.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 2.44 (s, 3 H), 2.91–3.05 (m, 6 H),
3.51–3.59 (m, 1 H), 4.47 (dd, J = 14.0, 4.5 Hz, 1 H), 4.61 (dd,
J = 14.0, 3.5 Hz, 1 H), 6.17 (br, 1 H), 7.03 (d, J = 8.5 Hz, 2 H),
7.17–7.31 (m, 10 H), 7.64 (d, J = 8.5 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 21.5, 27.2, 35.4, 35.6, 51.3,
51.9, 123.2, 126.1, 127.1, 128.4, 128.5, 129.3, 129.7, 130.9, 132.3,
132.9, 136.6, 140.9, 143.8, 147.0.
FT-IR (film): 3060 (m), 3027 (m), 2859 (m), 2228 (s), 1603 (m),
1591 (m), 1552 (m), 1496 (m), 1438 (s), 1334 cm–1 (m).
1H NMR (400 MHz, CDCl3): d = 2.06 (dd, J = 12.5, 3.0 Hz, 1 H),
2.64 (dd, J = 17.0, 6.0 Hz, 1 H), 2.84–2.87 (m, 4 H), 3.11–3.19 (m,
1 H), 4.27 (dd, J = 14.0, 7.0 Hz, 1 H), 4.55 (dd, J = 14.0, 3.0 Hz, 1
H), 7.13–7.92 (m, 16 H).
Synthesis 2009, No. 1, 133–137 © Thieme Stuttgart · New York

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An Enantiospecific Approach to Triazolylalanine Derivatives
137
HRMS (TOF ESI): m/z [M + Na+] calcd for C26H2835ClN4O2S2:
(2) Jamookeeah, C. E.; Beadle, C. D.; Jackson, R. F. W.;
527.1342; found: 527.1323.
Harrity, J. P. A. J. Org. Chem. 2008, 73, 1128.
(3) Fan, W.-Q.; Katritzky, A. R. In Comprehensive Heterocyclic
Chemistry II, Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, 1996, 1–126.
(4) (a) For a recent report and lead references see: Kuijpers, B.
H. M.; Groothuys, S.; Hawner, C.; ten Dam, J.; Quaedflieg,
P. J. L. M.; Schoemaker, H. E.; van Delft, F. L.; Rutjes, F. P.
J. T. Org. Process Res. Dev. 2008, 12, 503. (b) For an
excellent overview, see: Dondoni, A. Chem. Asian J. 2007,
2, 700.
4-Phenethyl-1-[(R)-3-phenoxy-2-(tosylamino)propyl]-1H-1,2,3-
triazole (19)
To a soln of 13 (48 mg, 0.13 mmol) in DMSO (1.0 mL) was added
phenol (12 mg, 0.13 mmol) and Cs2CO3 (40 mg, 0.13 mmol); the
mixture was heated to 70 °C overnight. Upon cooling H2O was add-
ed, the soln was extracted with EtOAc, and the combined organic
extracts were dried (MgSO4) and concentrated in vacuo to provide
crude 19. Purification by flash chromatography provided 19 (44 mg,
73%) as a clear oil.
(5) The aziridine synthesis is based on studies by Baldwin and
co-workers: Baldwin, J. E.; Spivey, A. C.; Schofield, C. J.;
Sweeney, J. B. Tetrahedron 1993, 49, 6309.
[a]D22 –19.0 (c 1.4, CHCl3).
FT-IR (film): 3141 (w), 3063 (w), 2924 (s), 2854 (m), 1496 (s),
1454 cm–1 (s).
(6) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(b) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 633.
(7) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Bock, V. D.; Hiemstra, H.;
van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
(8) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. (b) Tornoe, C.
W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67,
3057. (c) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.;
Williams, I. D.; Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am.
Chem. Soc. 2005, 127, 15998. (d) Majireck, M. M.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 8680. (e) Boren, B.
B.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao, H.; Lin,
Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008, 130, 8923.
(f) For a recent comprehensive review, see: Meldal, M.;
Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
1H NMR (400 MHz, CDCl3): d = 2.43 (s, 3 H), 2.91–3.01 (m, 4 H),
3.68 (dd, J = 10.0, 6.0 Hz, 1 H), 3.83 (dd, J = 10.0, 5.0 Hz, 1 H),
3.93–4.00 (m, 1 H), 4.47 (dd, J = 14.0, 5.0 Hz, 1 H), 4.55 (dd,
J = 14.0, 5.0 Hz, 1 H), 5.46 (br, 1 H), 6.74 (d, J = 8.0 Hz, 2 H),
6.98–7.31 (m, 11 H), 7.75 (d, J = 8.5 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 21.5, 27.2, 35.3, 50.2, 52.4,
66.2, 114.3, 121.8, 122.6, 126.1, 127.0, 128.4 (2 C), 129.6, 129.8,
136.8, 140.9, 143.9, 147.3, 157.4.
HRMS (TOF ESI): m/z [M + Na+] calcd for C26H29N4O3S:
477.1960; found: 477.1971.
Acknowledgment
(9) Vedejs, E.; Klapars, A.; Warner, D. L.; Weiss, A. H. J. Org.
Chem. 2001, 66, 7542.
(10) Whilst the product ee values were not determined, we have
previously shown that nucleophilic additions to 3 and
subsequent manipulations preserve stereochemical integrity
and hence assume that these processes are enantiospecific.
We are grateful to the EPSRC and Eli Lilly and Company Ltd for
financial support.
References and Notes
(1) For reviews on aziridine chemistry, see: (a) McCoull, W.;
Davis, F. A. Synthesis 2000, 1347. (b) Sweeney, J. B.
Chem. Soc. Rev. 2002, 31, 247. (c) Hu, X. E. Tetrahedron
2004, 60, 2701.
Synthesis 2009, No. 1, 133–137 © Thieme Stuttgart · New York