The azido acid approach to β-peptides: parallel synthesis of a tri-β-peptide library by fluorous tagging

Article abstract of DOI:10.1016/j.tet.2007.03.034

A small tri-β-peptide library was prepared starting from three enantio- and diastereopure azido acids. Fluorous tagging followed by two cycles of azide reduction, fluorous solid phase extraction (f-SPE), peptide coupling with the original azido acids, and

Full text of DOI:10.1016/j.tet.2007.03.034

Tetrahedron 63 (2007) 6141–6145
The azido acid approach to b-peptides: parallel synthesis
of a tri-b-peptide library by fluorous tagging
*
Xiao Wang, Scott G. Nelson and Dennis P. Curran
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA
Received 19 January 2007; revised 28 February 2007; accepted 2 March 2007
Available online 12 March 2007
Abstract—A small tri-b-peptide library was prepared starting from three enantio- and diastereopure azido acids. Fluorous tagging followed
by two cycles of azide reduction, fluorous solid phase extraction (f-SPE), peptide coupling with the original azido acids, and f-SPE provided
27 protected azido peptides. Reduction and HPLC purification provided 25 of the 27 targeted tri-b-peptides in acceptable yields and excellent
purities.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
Nelson and co-workers recently introduced an approach to
b-peptides that starts from b-azido acids rather than b-amino
acids and involves an iterative sequence of reduction of the
azide to an amine followed by union of the amine with the
next b-azido acid by amide bond formation.3 a-Peptides have
also been made from a-azido acids.4 But the azide approach
is not used very often because a-amino acids are much more
readily available than a-azido acids and because a-azido acid
derivatives activated for peptide coupling reactions are prone
to racemization. This is unfortunate because atom economy
and small size make the azide group attractive compared to
protected amines.
Oligomers and polymers of b-amino acids, called b-pep-
tides, are of increasing interest because of their structures,
folding patterns, and potential biological activities.1 Most
syntheses of b-peptides are patterned after the traditional
approach to make a-peptides.2 The key building blocks are
N-protected b-amino acids, which are joined by an iterative
sequence of N-deprotection and amide coupling (Fig. 1).
Protected amino acid approach
1
1
2
For the b-peptide series, enantiopure b-azido acids are read-
ily available by several routes,5 and activated b-azido acids
for peptide coupling cannot epimerize at the azide-bearing
carbon. Thus, the azide approach merits serious consider-
ation as a general approach to b-peptides.
O
R
O
R
O
R
1) remove N-PG
2) couple with
R
R
N
H
NHPG
N
H
N
NHPG
H
1
1
2
R
R
R
2
O
R
PG = protecting group
HO
NHPG
2
R
Only a handful of di-b-peptides and a lone tri-b-peptide have
been made by the azide approach to date.3 We set out to ex-
tend the scope of the method by making a 27-member library
of tri-b-peptides in a 3ꢀ3ꢀ3 matrix starting from three
enantiopure b-azido acids. To expedite the library prepara-
tion, we used a light fluorous tag6,7 on the C-terminus of the
first b-azido acid so that intermediates could be quickly
purified by fluorous SPE (f-SPE).8 We describe herein the
results of this study.
Azido acid approach
1
1
2
O
R
O
R
O
R
1) reduce
2) couple with
R
R
N
H
N3
N
H
N
H
N3
1
1
2
R
R
R
2
O
R
N3
HO
2
R
2. Results and discussion
Figure 1. The ‘amino acid’ and ‘azido acid’ approaches to b-peptides.
The syntheses and fluorous tagging of the three b-azido acid
building blocks are summarized in Scheme 1. b-Lactones
1a–c are readily made in one step, on multi-gram scale, in
* Corresponding author. Tel.: +1 412 624 8240; fax: +1 412 624 9861;
e-mail: curran@pitt.edu
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.034

6142
a,b series
X. Wang et al. / Tetrahedron 63 (2007) 6141–6145
1) reduction
i. Ph3P, wave
ii. H2O, wave
iii. f-SPE
1
1
2
O
R
O
R
O
R
O
FPMBO
N3
FPMBO
O
R
FPMBOH, 3
EDCI, DMAP
CH2Cl2
O
N
N3
NaN3
2) coupling
1
H
R
2
1
i. divide in three
R
R
HO
N3
DMF
50 °C
H3C
R
ii. 2a-c, EDCI, DMAP
three precursors
4a-c
nine azido di- -peptides
CH3
iii. f-SPE
5aa–5cc
1a, R = CH2CH2Ph
1b, R = Ph
2a, 100%
2b, 100%
1
2
3
O
O
R
O
R
O
R
O
R
repeat
cycle
FPMBO
N
H
N
N3
FPM
BO
FPMB = p-C8F17 (CH2)3OC6H4CH2–
N3
H
1
2
3
R
R
R
R
CH3
27 azido tri- -peptides
4a, 80%
4b, 87%
6aaa–6ccc
1
2
3
c series, prepared similarly
R
O
R
O
R
H2, Pd(OH)2
tBuOH
–
+
O
N
N
NH3
H
H
1
2
3
i
i
R
R
O
Bu
O
Bu
O
O
HO
i
F
27 tri- -peptides
N3
O
PMB
N3
7aaa–7ccc
H3C
Bu
CH3
CH3
Scheme 2. Synthesis of the tri-b-peptide library.
1c, volatile
used crude
2c, 65%
two-step yield
4c, 53%
Scheme 1. Synthesis of azido acid precursors.
Ph
Ph
N3
Ph
O
O
O
>90% ee by the cinchona-alkaloid catalyzed cycloconden-
sation reactions between acyl halides and aldehydes (AAC
reaction).3 Reactions of purified b-lactones 1a,b with NaN3
in DMF at 50 ꢁC provided b-azido acids 2a,b in quantitative
yield. Due to its volatility, b-lactone 1c was not purified; in-
stead, the crude product of the AAC reaction was directly
subjected to azide opening, and then the azide was purified.
This provided 2c in 65% yield over the two steps. To com-
plete the precursor synthesis, the three b-azido acids (110–
140 mg) were esterified with 1.2 equiv of the fluorous PMB
alcohol 3 (FPMB–OH)9 in presence of 1-ethyl-3-(30-dime-
thylaminopropyl) carbodiimide (EDCI) and N,N-dimethyl-
aminopyridine (DMAP) to obtain the three azido-esters
4a–c. These key precursors were purified by standard flash
chromatography.
O
O
O
Ph
FPMBO
N
H
FPMBO
N
H
N3
5aa, 70%
5ab, 59%
Ph
N3
O
Ph
Ph
Ph
Ph
O
FPMBO
N
H
FPMBO
N
H
N3
N3
N3
5ba, 55%
5bb, 83%
Ph
N3
O
O
O
O
O
FPMBO
N
H
FPMBO
N
H
The synthesis of the tri-b-peptide library is summarized in
Scheme 2 and involves two cycles of azide reduction and
amide coupling (4/5 and 5/6), followed by a final hydro-
genation/hydrogenolysis (6/7) to reduce the terminal azide
and remove the fluorous PMB group.
5ca, 79%
5cb, 86%
Ph
O
O
O
O
Ph
The azides were reduced by a Staudinger procedure.10,11 The
three azido-esters 4a–c were treated with 1.2 equiv of tri-
phenylphosphine in THF under microwave irradiation at
120 ꢁC, 250 W. After 5 min, 31P NMR spectroscopic analy-
sis showed complete conversion to the aza-ylide (see
Supplementary data). Water (20 equiv) was added and the
mixtures were again irradiated in the microwave instrument
at 120 ꢁC, 250 W. After 10 min, 31P NMR analysis showed
disappearance of the aza-ylide with formation of triphenyl-
phosphine oxide. The samples were concentrated, taken up
in a small amount of acetonitrile, and loaded into a fluorous
SPE column.9 First pass elution with 70/30 acetonitrile/wa-
ter provided an organic fraction containing triphenylphosphine
FPMBO
N
H
N3
FPMBO
N
H
5ac, 60%
5bc, 75%
O
FPMBO
N
H
N3
5cc, 83%
Figure 2. Structures of the nine dipeptide azides 5.

X. Wang et al. / Tetrahedron 63 (2007) 6141–6145
6143
Table 1. Yields and MS data for protected azides 6 and final tri-b-peptides 7
Representative Structures
Ph
Ph
i
i
Ph
Ph
O
O
O
Bu
O
O
O
Bu
FPMBO
–
+
NH3
N
H
N
H
N3
N
H
N
H
O
CH3
CH3
6abc
CH3
CH3
CH3
CH3
7abc
Entry
6 (%)
MS of 6 (calcd/obs)a
7b (f-SPE) (%)
7c (HPLC) (%)
MS of 7 (calcd/obs)a
d
aaa
aab
aac
aba
abb
abc
aca
acb
acc
baa
bab
bac
bba
bbb
bbc
bca
bcb
bcc
caa
cab
cac
cba
cbb
cbc
cca
ccb
ccc
33
37
55
100
99
94
58
74
41
95
84
97
84
87
75
30
46
41
42
53
69
97
92
88
37
38
33
1177.4/1178.2
1149.4/1150.0
1129.4/1130.2
1149.4/1150.2
1121.3/1122.0
1101.4/1102.2
1129.4/1130.2
1101.4/1102.2
1081.4/1082.2
1149.4/1150.0
1121.3/1122.2
1101.4/1102.2
1121.3/1122.2
1093.3/1094.2
1073.3/1074.2
1101.4/1102.2
1073.3/1074.2
1053.4/1054.2
1129.4/1130.2
1101.4/1102.2
1081.4/1082.2
1101.4/1102.2
1073.3/1074.2
1053.4/1054.2
1081.4/1082.2
1053.4/1054.2
1033.4/1034.2
92
89
80
84
71
64
61
72
68
80
70
97
51
60
88
82
76
79
87
71
55
69
88
88
82
97
78
—
—
585.4/586.3
557.3/558.3
537.4/538.3
557.3/558.3
529.3/530.2
509.3/510.3
537.4/538.3
509.3/510.2
489.4/490.4
557.3/558.3
529.3/530.2
509.3/510.2
529.3/530.2
501.3/502.2
481.3/482.2
509.3/537.3e
481.3/482.3
461.3/462.3
537.4/538.3
509.3/510.4
489.4/490.3
509.3/510.2
481.3/482.2
461.3/462.3
489.4/490.4
461.3/469.2e
441.4/442.4
d
76
94
—
d
45
80
67
d
—
84
94
93
99
d
—
86
64
53
87
91
75
78
71
90
57
40
83
88
a
m/z for M+1 ion.
Yield of 7 after fluorous solid phase extraction.
Recovery of 7 after HPLC purification.
The product after f-SPE was pure by HPLC analysis and was not further purified.
The mass spectrum is not consistent with the target product (see text).
b
c
d
e
oxide and unreacted triphenylphosphine, which was dis-
carded. Second pass elution with THF provided the derived
amines.
The nine products 5 were then subjected to a second cycle
without further purification. First, reduction with triphenyl-
phosphine and f-SPE provided nine amino di-b-peptides
(80–100%). These were each divided into three equal por-
tions followed by coupling with the three azido acids 2a–c
as above. Evaporation of the THF fraction following f-SPE
provided the 27 azido tri-b-peptides 6aaa–6ccc in the yields
recorded in Table 1. Also shown in Table 1 is one represen-
tative structure (6abc); the full complement of structures is
in Supplementary data. LC–MS analysis of all 27 samples
showed the expected molecular weights for the products 6,
whose purities were typically 90% or better. Five of the
samples selected by molecular weight (including highest,
Without further characterization, each of the three interme-
diate amines was divided into three equal fractions, which
were coupled in parallel with each of the three azido acids
2a–c (1.2 equiv). Couplings were effected in dichlorome-
thane with EDCI (1.2 equiv) and DMAP (0.5 equiv). EDCI
was chosen because both EDCI and its derived urea are
relatively polar and eluted very quickly under the first pass
conditions of the fluorous solid phase extraction. The prog-
ress of the nine reactions was followed by TLC, and after
about 30 min, the solvent was removed and the crude prod-
ucts were subjected to f-SPE as above. Again the first pass
fraction was discarded and the second pass fraction (THF)
was concentrated to provide the nine coupled azido b-pep-
tides 5aa–5cc, whose complete structures are shown in Fig-
ure 2. Yields of these crude products ranged from 55 to 86%
over the two steps, and they all exhibited satisfactory 1H and
13C NMR spectra. Analyses by LC–MS also showed the
expected molecular weights (see Supplementary data).
1
median, and lowest) were also analyzed by H and 13C
NMR to provide additional support for structure and purity.
F
Finally, the terminal azides 6 were reduced and the PMB
groups were removed simultaneously by reduction with hy-
drogen in tert-butanol catalyzed by palladium hydroxide.
Three initial reactions were conducted in vials and the crude
products processed by f-SPE in cartridges as above to re-
move both the catalyst and the residual fluorous tag. This

6144
X. Wang et al. / Tetrahedron 63 (2007) 6141–6145
time, the first pass fraction was concentrated and the second
pass fraction was discarded. The remaining 24 samples were
then hydrogenated together in a 24-well parallel synthesizer,
followed by plate-to-plate solid phase extraction12 and
concentration.
(30 mL) was added. The resulting heterogeneous mixture
was diluted with water until all the precipitated salts dis-
solved. The resulting mixture was washed with ethyl acetate
(2ꢀ50 mL) and the aqueous layer was acidified with 1 M
aqueous HCl to pHz1. The acidic aqueous layer was
extracted with ethyl acetate (3ꢀ50 mL) and the combined
organic portions were washed with water (2ꢀ50 mL) and
brine (2ꢀ50 mL). The organic portion was dried (Na2SO4)
and evaporated in vacuo to afford the b-azido acid.
After a preliminary analysis by LC–MS (reverse phase
conditions), most of the crude tri-b-peptides 7 were purified
by serial reverse phase HPLC under a standard set of condi-
tions to provide purified products in the yields indicated in
Table 1 (see Supplementary data for all structures). These
zwitterionic products are generally white powders that
were sparingly soluble in most organic solvents tested.
They were then reanalyzed by LC–MS to confirm identity
and purity. Twenty-five of the products exhibited essentially
a single peak with the expected mass. Several of these prod-
ucts were again checked by 1H NMR analysis (D2O/
CD3CN) to confirm structure and purity (see Supplementary
data).
4.2. General procedure 2: FPMB tagging
To a solution of b-azido acid (0.2 mmol) in CH2Cl2
(10 mL) was added N,N-dimethylaminopyridine (DMAP)
(12 mg, 0.10 mmol). With stirring, FPMB–OH (140 mg,
0.240 mmol) was added to the solution followed by 1-ethyl-
3-(30-dimethylaminopropyl) carbodiimide (EDCI) (46 mg,
0.24 mmol). After 30 min, the mixture was partitioned
between Et2O (30 mL) and 1 M aqueous HCl (15 mL). The
organic layer was separated and washed with H2O (10 mL)
and brine (10 mL), then dried over Na2SO4 and evaporated
Two of the products do not appear to have the expected struc-
tures based on MS analysis. The product 7bca exhibited
peaks for (MꢂH2O+Na) and (MꢂH2O+2Na), suggesting
that it might be a dehydrated cyclic peptide. The MS for
7ccb suggests that this product results from reductive deam-
ination (hydrogenolysis) of the terminal benzylic amino
group. These side reactions seem to be sequence specific,
since they were not observed for any other members of the
library.
F
in vacuo to afford the crude PMB ester. This was purified
by flash chromatography (4:1 Hex/EtOAc).
4.3. General procedure 3: Staudinger reaction10
In a microwave tube, the azido ester or the azido b-peptide
(0.2 mmol) was dissolved in dry THF (0.5 mL). A solution of
triphenylphosphine (63 mg, 0.24 mmol) in dry THF (1 mL)
was added into the microwave tube by syringe. The mixture
was heated in the microwave reactor under stirring at
120 ꢁC, 250 W, for 5 min. H2O (72 mg, 4.0 mmol) was
added into the microwave tube via syringe. The resulting
mixture was microwaved for 10 min, at 120 ꢁC, 250 W.
The reaction progress can be monitored by 31P NMR if
desired. (31P NMR spectra were recorded at 121.5 MHz.
THF-d8 was used as solvent. For calibration, the chemical
shift of triphenylphosphine was set at ꢂ4.80 ppm. The
chemical shifts of triphenylphosphine oxide and phosphorus
ylide are at around 24 and 1 ppm, respectively.)13 The sol-
vent was removed in vacuo. A new f-SPE cartridge (5 g)
was washed with THF (20 mL) under vacuum on the SPE
manifold and preconditioned by passing through 70:30
MeCN/H2O (30 mL). The crude product was dissolved in
MeCN (1 mL) and loaded onto the cartridge using vacuum
to ensure that the sample was completely adsorbed onto the
silica. The cartridge was washed with 70:30 MeCN/H2O
(50 mL) to obtain the fraction containing the organic com-
pounds, and washed with THF (30 mL) to obtain the fraction
containing the fluorous compounds. The fluorous fraction
was dried over Na2SO4 and the solvent was evaporated in
vacuo to afford the amine.
3. Summary and conclusions
In summary, we have parlayed three readily available azido
acids 2a–c into a small library of tri-b-peptides 7 in amino
acid form by fluorous tagging, two cycles of azide reduction
and peptide coupling, and detagging with concomitant azide
reduction. To expedite the synthesis, intermediates were
purified only by fluorous solid phase extraction; however,
the final products were purified by preparative HPLC to
ensure good quality. This approach provided 25 of the 27
library members in acceptable yields and excellent purities.
The results suggest that the azido acid approach to make
b-peptide oligomers deserves serious consideration as an al-
ternative to the more traditional amino acid approach. The
usefulness of the new approach will grow as a function of
the availability of isomerically pure azido acids. The results
further show the generality of fluorous solid phase extrac-
tion, whether in cartridges or in plate-to-plate format, as a
method for rapid yet effective purification of molecules
bearing light fluorous tags.
4. Experimental
4.4. General procedure 4: amide coupling
4.1. General procedure 1: SN2 addition of NaN3
to b-lactones3,5a
DMAP (12 mg, 0.10 mmol) was added to a solution of amine
(0.2 mmol) in CH2Cl2 (2 mL). With stirring, b-azido acid
(0.24 mmol) was added to the solution, followed by the ad-
dition of EDCI (46 mg, 0.24 mmol) and CH2Cl2 (1 mL). The
mixture was stirred for 30 min, and then the solvent was re-
moved in vacuo. A new f-SPE cartridge (5 g) was washed
with THF (20 mL) under vacuum on the SPE manifold
and preconditioned by passing through 70:30 MeCN/H2O
The b-lactone (6.0 mmol) was added via syringe to a solution
of NaN3 (12.0 mmol) in anhydrous DMF (35 mL, 0.3 M in
lactone) at 50 ꢁC. The resulting homogeneous solution was
stirred for 4–5 h. The reaction mixture was cooled to ambi-
ent temperature (25 ꢁC), and saturated aqueous NaHCO3

X. Wang et al. / Tetrahedron 63 (2007) 6141–6145
6145
Med. Chem. 1999, 6, 905–925; (c) Cheng, R. P.; Gellman, S. H.;
DeGrado, W. F. Chem. Rev. 2001, 101, 3219–3232.
2. For recent leading references, see: (a) Murray, J. K.; Gellman,
S. H. Org. Lett. 2005, 7, 1517–1520; (b) Murray, J. K.; Farooqi,
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7506; (e) Watts, P.; Wiles, C.; Haswell, S. J.; Pombo-Villar,
E. Tetrahedron 2002, 58, 5427–5439.
(30 mL). The crude product was dissolved in MeCN (1 mL)
and loaded onto the cartridge using vacuum to ensure that
the sample was completely adsorbed onto the silica. The car-
tridge was washed with 70:30 MeCN/H2O (50 mL) to obtain
the fraction containing the organic compounds, and washed
with THF (30 mL) to obtain the fraction containing the
fluorous compounds. The fluorous fraction was dried over
Na2SO4 and the solvent was evaporated in vacuo to afford
the azido b-peptide.
4.5. General procedure 5: hydrogenation
3. Nelson, S. G.; Spencer, K. L.; Cheung, W. S.; Mamie, S. J.
Tetrahedron 2002, 58, 7081–7091.
4. (a) Garcia, J.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1984, 25,
4841–4844; (b) Meldal, M.; Juliano, M. A.; Jansson, A. M.
Tetrahedron Lett. 1997, 38, 2531–2534.
In a GreenHouse Classic Parallel Synthesizer, a solution of
each azido-tripeptide (8 mg) in tert-butanol (2 mL) was
loaded to each test tube. Pd(OH)2/C (2 mg, 25 wt %) was
added to each solution. The apparatus was evacuated and
then filled with hydrogen gas by a balloon. With stirring,
all reactions were done in 24 h according to TLC. The
solvent was removed in vacuo using a vacuum centrifuge.
The 24 reaction mixtures were directly loaded onto a precon-
ditioned SPE cartridge plate, with each cartridge packed
with FluoroFlashÔ silica gel (3 g).14 The cartridges were
first eluted with 70:30 MeCN/H2O (2ꢀ5 mL). The solvent
was removed in vacuo by vacuum centrifuge to afford the
b-tripeptides. The cartridges were washed with THF
(3ꢀ5 mL) to remove the FPMB residue and they were then
ready for reuse.
5. (a) For opening of enantioenriched b-lactones, see: Wang, Y.;
Tennyson, R. L.; Romo, D. Heterocycles 2004, 64, 605–658;
(b) For asymmetric azide conjugate addition, see: Horstmann,
T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed.
2000, 39, 3635–3638.
6. For reviews on light fluorous chemistry, see: (a) Curran, D. P.
Aldrichimica Acta 2006, 39, 3–9; (b) Curran, D. P. The
Handbook of Fluorous Chemistry; Gladysz, J. A., Curran,
D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim, 2004;
pp 128–155; (c) Zhang, W. Chem. Rev. 2004, 104, 2531–2556.
7. For overview of fluorous tagging in synthesis of peptides and
other biomolecules, see: Zhang, W. Curr. Opin. Drug Discov.
Dev. 2004, 7, 784–797.
4.6. Compound characterization
8. For reviews, see: (a) Zhang, W.; Curran, D. P. Tetrahedron
2006, 62, 11837–11865; (b) Curran, D. P. The Handbook of
Fluorous Chemistry; Gladysz, J. A., Curran, D. P., Horvath,
I. T., Eds.; Wiley-VCH: Weinheim, 2004; pp 101–127; (c)
Curran, D. P. Synlett 2001, 1488–1496.
Complete characterization data, including copies of NMR
spectra and HPLC traces, are provided in Supplementary
data.
9. (a) Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233–2235;
(b) For review on fluorous protecting groups, see: Zhang, W.
The Handbook of Fluorous Chemistry; Gladysz, J. A.,
Curran, D. P., Horvath, I. T., Eds.; Wiley-VCH: Weinheim,
2004; pp 222–235; (c) The fluorous PMB alcohol and fluorous
silica products were purchased from Fluorous Technologies,
Inc. DPC has an equity interest in this company.
Acknowledgements
We thank the National Institute of General Medical Sciences
of the National Institutes of Health for funding this work. We
thank Mr. Xiaoqiang Shen for helpful advice on making and
opening the lactones.
10. (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–
646; (b) Leffler, J. E.; Temple, R. D. J. Am. Chem. Soc. 1967,
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11. For the reverse approach with a fluorous phosphine and a non-
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R. C.; Leister, W. H.; Strauss, K. A. Tetrahedron Lett. 2002,
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Supplementary data
Contains full details of experiments and characterization
(147 pages). This material is available free of charge via
the Internet at http://www.sciencedirect.com. Supplemen-
tary data associated with this article can be found in the
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