Solid-phase synthesis of phosphine-oxazoline peptides

Article abstract of DOI:10.1016/S0040-4039(02)01596-4

An approach is presented that allows for the synthesis of phosphine-oxazoline ligands by solid-phase synthesis. The method involves the synthesis of amino oxazolines and their use in the cleavage of phosphine sulfide peptides from Kaiser oxime resin. It w

Full text of DOI:10.1016/S0040-4039(02)01596-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6961–6965
Solid-phase synthesis of phosphine–oxazoline peptides
Scott R. Gilbertson* and Ping Lan
Department of Chemistry, Washington University, St. Louis, MO 63130, USA
Received 13 July 2002; revised 29 July 2002; accepted 31 July 2002
Abstract—An approach is presented that allows for the synthesis of phosphine–oxazoline ligands by solid-phase synthesis. The
method involves the synthesis of amino oxazolines and their use in the cleavage of phosphine sulfide peptides from Kaiser oxime
resin. It was discovered that the addition of a catalytic amount of sodium cyanide allows the nucleophilic cleavage from the resin
to take place at room temperature and without the addition of acid. © 2002 Elsevier Science Ltd. All rights reserved.
We have been involved in the development of phos-
phine–oxazoline ligands as well as the use of peptide
chemistry in the synthesis of libraries of bis-phosphine
ligands.1–4 Consequently we have been interested in
routes to peptide based phosphine–oxazoline ligands.5
Ideally these ligands would be synthesized by standard
solid-phase methods. In addition to their considerable
use in asymmetric catalysis, oxazolines have been
shown to be selective inhibitors of a2-adrenoreceptors,6
as active derivatives of patellamide A7 and as a struc-
tural element in vibriobactin.8 Any general system that
allows for their facile incorporation into peptide struc-
ture would be of use in catalyst development as well as
the synthesis of biologically active molecules. This
paper reports the development of such a system
(Scheme 1).
After attempting a number of approaches for the incor-
poration of oxazolines and phosphines into peptides, a
method that involves the use oxime resin was devel-
oped.9,10 The Kaiser oxime linker allows for the cleav-
age of peptides synthesized on solid support by reaction
with a nucleophile. The approach reported here utilizes
a nucleophilic oxazoline building block as the agent
that both removes the peptide from the support and
adds to the peptide. For this approach to be viable, a
number of issues needed to be addressed. First, an
approach to a nucleophilic oxazoline building block
had to be developed. Second, conditions had to be
worked out that allowed for the efficient cleavage of the
phosphine–oxazoline peptides from the oxime resin.
Synthesis of oxazoline building blocks. Oxazolines with a
variety of alkyl groups as well as a carboxyl group were
synthesized (Scheme 2). The oxazoline with a carboxyl
Scheme 1.
Scheme 2. Reagent and conditions: (a) Burgess reagent in
THF at room temperature over night; (b) Burgess reagent in
THF, reflux at 70°C for 3 h. Also obtained 12% elimination
product.
* Corresponding author. Tel.: 1-314-935-6357; fax: 1-314-935-4481;
e-mail: srg@wuchem.wustl.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01596-4

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S. R. Gilbertson, P. Lan / Tetrahedron Letters 43 (2002) 6961–6965
group was used to allow for the addition of other
groups at that location of the molecule. As expected,
coupling of alanine with the selected amino alcohols
using EDC and HOBT proceeded in good yield. Oxazo-
line formation with Burgess reagent also proceeded in
good yield. For reasons that are not clear the carbonyl
containing oxazoline required elevated temperature
and, as a consequence, also produced a small amount
of the product from the elimination of the hydroxyl.
Removal of the Cbz group by reaction with H2 cata-
lyzed by palladium on carbon provided the free amines
in the series.
tuted nucleophiles produced the expected phosphine-
sulfide–oxazoline products but in low yield (Table 2,
Scheme 3). This may be due to the more hindered
nature of the a-branched oxazoline amine. It is quite
common that hindered nucleophiles can be problematic
in the nucleophilic cleavage from oxime resins.
Sodium cyanide has been used successfully in the
aminolysis of esters.11 Given this observation, it was
reasoned that the addition of sodium cyanide may act
as a catalyst for the desired cleavage. The belief was
that the small nucleophile, CN, would be able to
remove the peptide from the polymer support and once
in solution the acyl cyanide intermediate would then
react with the more hindered amine nucleophile. When
the cleavage of resin 26 is attempted with oxazoline 22
in methanol (Scheme 4), the peptide is removed from
Reaction with oxime resin. Next, conditions were
worked out for the removal of the phosphine moiety
from the oxime resin. While the reaction with glycine
proceeded in good yield, the addition of more substi-
Table 1. NaCN-catalyzed cleavage of oxime resin bound peptidec
a
Based on the isolated weight of peptide as compared to the loading. b Determined by NMR of crude product. c The
NMR data for the compounds in this table can be found in Ref. 13.

S. R. Gilbertson, P. Lan / Tetrahedron Letters 43 (2002) 6961–6965
6963
Scheme 3.
Table 2.
rates observed with substituted nucleophiles under neu-
tral to slightly basic conditions tend to require elevated
temperature.12 We observed this to be the case as well
with our oxazoline-containing nucleophiles. When
sodium cyanide is added to the reaction mixture the
reactions proceed at room temperature and give good
yields of the expected products. Within the confines of
our limited solvent study THF appears to be the best
solvent for the reaction giving the products in both
higher yields and purity.
Nucleophile
Yield (%)
Gly-OCH3
89
30
20
20
20
21
22
the support as the methyl ester rather than the desired
amide. Presumably methanol is sufficiently nucleophilic
to add to the acylcyanide intermediate before the
branched amine. When the reaction is run in
dichloromethane or THF, both non-nucleophilic sol-
vents that also swell the polymer support, the desired
amide bond is formed in good yield (Table 1).
Acknowledgements
This work was supported by NIH R01 GM56490. We
also gratefully acknowledge the Washington University
High-Resolution NMR Facility, partially supported by
NIH 1S10R02004, and the Washington University
Mass Spectrometry Resource Center, partially sup-
ported by NIHRR00954, for their assistance.
While the nucleophilic cleavage of peptides from oxime
resin is an extremely useful transformation the reaction
Scheme 4.

6964
S. R. Gilbertson, P. Lan / Tetrahedron Letters 43 (2002) 6961–6965
(32) 1H NMR (600 MHz, CDCl3) l 8.18–8.15 (m, 2H),
References
7.53–7.04 (m, 18H), 6.82 (d, J=7.2 Hz, 1H), 6.70 (d,
J=7.8 Hz, 1H), 4.55–4.47 (m, 2H), 4.42–4.39 (m, 1H),
4.00–3.99 (m, 1H), 3.77 (s), 3.62–3.60 (m, 1H), 3.38–3.33
(m, 1H), 3.15–2.98 (m, 3H), 2.56 (dd, J=9, 14.4 Hz, 1H),
2.20–1.55 (m, 4H), 1.29 (d, J=7.2 Hz, 3H); 13C NMR
1. Gilbertson, S. R.; Fu, Z.; Starkey, G. W. Tetrahedron
Lett. 1999, 40, 8509–8512.
2. Gilbertson, S. R.; Genov, D. G.; Rheingold, A. L. Org.
Lett. 2000, 2, 2885–2888.
3. Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161–164.
4. Gilbertson, S. R.; Fu, Z.; Xie, D. Tetrahedron Lett. 2001,
42, 365–368.
5. Gilbertson, S. R.; Lopez, O. D. Angew. Chem., Int. Ed.
1999, 38, 1116–1118.
6. Gentili, F.; Bousquet, P.; Brasili, L.; Caretto, M.; Carri-
eri, A.; Dontenwill, M.; Giannella, M.; Marucci, G.;
Perfumi, M.; Piergentili, A.; Wuaglia, W.; Rascente, C.;
Pigini, M. J. Med. Chem. 2002, 45, 32–40.
7. Berhardt, P. V.; Comba, P.; Fairlie, D. P.; Gahan, L. R.;
Hanson, G. R.; Lo¨tzbeyer, L. Chem. Eur. J. 2002, 8,
1527–1536.
(150 MHz, CDCl3) l 171.2, 171.1, 170.7, 170.3 (d, JCP
=
10.8 Hz), 169.9, 126–137, 70.3, 67.6, 60.1, 54.3, 52.6, 47.4,
43.6, 42.5 (d, JCP=51 Hz), 37.0, 35.4, 27.5, 24.5, 18.6; 31
NMR (121.5 MHz, CDCl3) l 52.0.
P
1
(33) H NMR (600 MHz, CDCl3) l 7.81–7.13 (m, 16H),
7.08 (d, J=7.8 Hz, 1H), 5.05–5.00 (m, 1H), 4.75 (d,
J=8.4 Hz, 1H), 4.71–4.68 (m, 1H), 4.65–4.62 (m, 1H),
4.57–4.55 (m, 1H), 4.39–4.36 (m, 1H), 4.28–4.23 (m, 1H),
4.16–4.10 (m, 1H), 3.67 (s, 3H), 3.66–3.61 (m, 2H), 3.12
(dd, J=6.0, 14.4 Hz, 1H), 3.05 (dd, J=8.4, 14.4 Hz, 1H),
2.81–2.79 (m, 1H), 2.60–2.52 (m, 1H), 1.99–1.76 (m, 4H),
1.34–1.18 (m, 12H); 13C NMR (150 MHz, CDCl3) l
171.4, 171.2, 171.1, 170.7. 170.2, 154.3, 126–137, 79.6,
70.3, 67.9, 67.4, 60.5, 53.9, 47.6, 47.4, 43.4, 37.0, 35.0 (d,
8. Keating, T. A.; Marshall, C. G.; Walsh, C. T. Biochem-
sitry 2000, 39, 15522–15530.
9. DeGrado, W. F.; Kaiser, E. T. J. Org. Chem. 1980, 45,
1295–1300.
10. DeGrado, W. F.; Kaiser, E. T. J. Org. Chem. 1982, 47,
3258–3261.
J
CP=56.4 Hz), 28.1, 27.8, 25.6, 18.3; 31P NMR (121.5
MHz, CDCl3) l 39.7, 38.0 (7:1).
11. Ho¨gberg, T.; Stro¨m, P.; Ebner, M.; Ra¨msby, S. J. Org.
Chem. 1987, 52, 2033–2036.
12. Voyer, N.; Lavoie, A.; Pinette, M.; Bernier, J. Tetra-
hedron Lett 1994, 35, 355–358.
13. Representative NMR spectra:
1
(34) H NMR (600 MHz, CDCl3) l 7.82–7.12 (m, 15H),
6.91 (d, J=7.2 Hz, 1H), 4.98–4.92 (m, 1H), 4.81 (d,
J=8.4 Hz, 1H), 4.64–4.59 (m, 1H), 4.55–4.52 (m, 1H),
4.28–4.26 (m, 1H), 4.17–4.14 (m, 1H), 3.91–3.89 (m, 1H),
3.79–3.75 (m, 1H), 3.62–3.56 (m, 2H), 3.11–3.00 (m, 2H),
2.84–2.65 (m, 2H), 1.94–1.80 (m, 4H), 1.68–1.61 (m, 1H),
1.27–1.18 (m, 12H), 0.83 (d, J=6.6 Hz, 3H), 0.76 (d,
J=7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) l 171.2 (d,
CP=15 Hz), 171.1, 169.7, 167.5, 154.2, 126–137, 79.6,
71.5, 70.6, 60.6, 54.1, 47.7, 47.4, 43.6, 37.5, 35.2 (d,
CP=56.5 Hz), 32.3, 28.1, 27.8, 24.8, 18.5; 31P (121.5
(29) 1H NMR (600 MHz, CDCl3) l 8.15–8.05 (m, 2H),
7.49–7.00 (m, 23H), 6.75–6.63 (m, 2H), 4.65–4.60 (m,
1H), 4.53–4.48 (m, 1H), 4.40–4.35 (m, 1H), 4.32–4.28 (m,
1H), 4.16–4.13 (1H), 3.96–3.93 (1H), 3.91–3.89 (m, 1H),
3.36–3.29 (m, 2H), 3.00–2.97 (m, 3H), 2.90 (dd, J=9.8,
16.6 Hz, 1H), 2.69 (dd, J=9.4, 16.6 Hz), 2.58 (dd, J=8.4,
14.4 Hz, 1H), 1.90–1.55 (m, 4H), 1.18 (d, J=7.2 Hz, 3H);
J
J
MHz, CDCl3) l 39.7, 37.5 (4:1).
13C NMR (150 MHz, CDCl3) l 170.1, 169.1 (d, JCP
=
10.8 Hz), 168.8, 167.2, 125.6–136.6, 71.6, 65.9, 59.4, 53.2,
46.6, 42.6, 41.7 (d, JCP=51 Hz), 40.6, 36.3, 34.5, 27.1,
23.6, 17.5; 31P NMR (121.5 MHz, CDCl3) l 52.4.
1
(35) H NMR (600 MHz, CDCl3) l 7.86–7.14 (m, 21H),
7.00 (d, J=7.2 Hz, 1H), 5.03–5.01 (m, 1H), 4.85 (d,
J=8.4 Hz, 1H), 4.68–4.58 (m, 2H), 4.32–4.28 (m, 2H),
4.19–4.16 (m, 1H), 3.97–3.94 (m, 1H), 3.68–3.61 (m, 2H),
3.21–3.18 (m, 1H), 3.06–3.03 (m, 1H), 3.00–2.96 (m, 1H),
2.89–2.68 (m, 2H), 2.63–2.58 (m, 1H), 1.94–1.81 (m, 4H),
1.32–1.23 (m, 12H); 13C NMR (150 MHz, CDCl3) l
171.1, 170.1, 168.1, 154.2, 125.6–137.6, 79.7, 72.6, 66.8,
60.6, 54.0, 47.7, 47.6, 43.4, 41.6, 37.5, 35.2 (d, JCP=56.6
Hz), 28.2, 28.1, 24.9; 31P (121.5 MHz, CDCl3) l 39.7,
37.6 (3:1).
(30) 1H NMR (600 MHz, CDCl3) l 8.11–8.08 (m, 2H),
7.61–7.03 (m, 18H), 6.78 (m, 2H), 4.65–4.61 (m, 1H),
4.51–4.47 (m, 1H), 4.40–4.36 (m, 1H), 4.14–4.02 (m, 2H),
3.88 (m, 1H,), 3.76–3.73 (m, 1H), 3.38–3.29 (m, 2H),
3.06–2.92 (m, 2H), 2.91–2.87 (m, 1H), 2.77–2.74 (m, 1H),
1.84–1.72 (m, 2H), 1.71–1.45 (m, 2H), 1.25 (d, J=8.6 Hz,
3H), 0.84 (s, 9H); 13C NMR (150 MHz, CDCl3) l 171.0,
170.1 (d, JCP=10.8 Hz), 169.8, 167.5, 126–137, 75.1, 69.4,
60.4, 54.2, 47.6, 43.6, 42.6 (d, JCP=51 Hz), 37.4, 35.6,
33.6, 25.6, 28.2, 24.5, 18.6; 31P NMR (121.5 MHz,
CDCl3) l 52.3.
1
(36) H NMR (600 MHz, CDCl3) l 7.82–7.11 (m, 16H),
6.87 (d, J=6.6 Hz, 1H), 4.96–4.91 (m, 1H a), 4.79 (d,
J=7.8 Hz, 1H), 4.61–4.58 (m, 1H), 4.55–4.53 (m, 1H),
4.27–4.26 (m, 1H), 4.11–3.94 (m, 2H), 3.72–3.67 (m, 1H),
3.60–3.54 (m, 2H), 3.14–3.10 (m, 1H), 2.85–2.61 (m, 2H),
1.92–1.79 (m, 4H), 1.25–1.17 (m, 12H), 0.78 (s, 9H); 13C
NMR (150 MHz, CDCl3) l 171.3 (d, JCP=14.5 Hz),
171.1, 170.0, 167.4, 154, 126–137, 79.7, 75.1, 69.4, 60.6,
54.2, 47.7, 47.6, 43.6, 37.6, 33.5, 28.2, 25.7, 25.2, 24.9,
18.6; 31P (121.5 MHz, CDCl3) l 39.7, 37.4 (3.6:1).
(31) 1H NMR (600 MHz, CDCl3) l 8.18–8.15 (m, 2H),
7.53–7.09 (m, 18H), 6.81 (d, J=7.8 Hz, 2H), 4.72–4.68
(m), 4.59–4.57 (m, 1H), 3.98–3.96 (m, 1H), 3.91–3.88 (m,
1H), 3.46–3.37 (m, 2H), 3.08–3.03 (m, 2H), 2.94 (dd,
J=6.0, 14.4 Hz, 1H), 2.80 (dd, J=7.2, 14.4 Hz, 1H),
1.95–1.66 (m, 5H), 1.26 (d, J=7.2 Hz, 3H), 0.91 (d,
J=6.6, 3H), 0.85 (d, J=6.6, 3H); 13C NMR (150 MHz,
CDCl3) l 171.0, 170.0 (d, JCP=10.8 Hz), 169.7, 167.5,
(37) 1H NMR (300 MHz, CDCl3) l 8.19–8.12 (m, 2H),
7.56–7.46 (m, 3H), 7.45–7.32 (m, 2H), 7.31–7.21 (m, 3H),
7.20–7.12 (m, 3H), 7.11–7.05 (m, 3H), 4.70 (dt, J=2.3,
126–137, 71.5, 70.6, 60.4, 54.1, 47.6, 43.6, 42.6 (d, JCP
=
51.0 Hz), 37.3, 35.6, 32.3, 28.1, 24.5, 18.6, 17.7; 31P NMR
(121.5 MHz, CDCl3) l 52.4.

S. R. Gilbertson, P. Lan / Tetrahedron Letters 43 (2002) 6961–6965
6965
10.8 Hz, 1H), 4.55 (t, J=6.9 Hz, 1H), 4.42–4.22 (m, 1H),
4.14 (dd, J=8.7, 10.2 Hz, 1H), 4.03 (dd, J=7.5, 8.7 Hz,
1H), 3.69 (dd, J=7.5, 10.2 Hz, 1H), 3.54–3.47 (m, 1H),
3.38–3.25 (m, 2H), 2.75 (ddd, J=2.7, 10.8, 16.2 Hz, 1H),
2.19–1.61 (m, 4H), 1.34 (d, J=6.9 Hz, 3H), 0.79 (s, 9H);
13C NMR (125 MHz, CDCl3) l 170.7 (minor) and 170.2
(major), 170.0 (d, JCP=17.0 Hz, major) and 169.9 (d,
131.5, 131.4, 131.3, 131.1, 130.9, 130.7, 129.8, 129.7,
129.6, 128.9, 128.8, 127.9, 127.8, 127.6, 127.4, 75.1
(major) and 75.1 (minor), 69.7 (minor) and 69.4 (major),
59.8, 47.5 (minor) and 47.4 (major), 43.7 (minor) and
43.6 (major), 42.3 (d, JCP=52.6 Hz, major) and 42.2 (d,
JCP=53.5 Hz, minor), 35.6, 33.6 (minor) and 33.5
(major), 27.8 (minor) and 27.7 (major), 19.2 (minor) and
19.0 (major); 31P NMR (120 MHz, CDCl3) l 51.3
(major), 52.1 (minor).
JCP=16.9 Hz, minor), 167.1 (major) and 167.0 (minor),
135.0, 134.9, 132.4, 132.3, 132.2, 131.9, 131.8, 131.7,