Synthesis of a novel silicon bearing linker for solid phase synthesis

Article abstract of DOI:10.1016/j.tetlet.2004.01.093

A novel linker for solid phase synthesis is described, which exhibits rapid cleavage under selective, orthogonal conditions, including stability under acidic conditions. The linker incorporates a pyridyl propionate system, with a pendant β-silyl group. Rapid cleavage of the product is effected by elimination of the silyl group on treatment with fluoride. Two systems of this type have been synthesised, and the stability of the linkers has been tested under acidic and basic conditions in solution.

Full text of DOI:10.1016/j.tetlet.2004.01.093

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2403–2404
Synthesis of a novel silicon bearing linker for solid phase synthesis
Robert Ramage,a,* Martin J. I. Andrews,a Jenny Raphyb and Pu Wanga
aDepartment of Chemistry, University of Edinburgh, Joseph Black Building, West Mains Road, Edinburgh EH8 3JJ, UK
bParke-Davis Pharmaceuticals, Forvie Site, Robinson Way, Cambridge, UK
Received 4 December 2003; revised 7 January 2004; accepted 16 January 2004
Abstract—A novel linker for solid phase synthesis is described, which exhibits rapid cleavage under selective, orthogonal conditions,
including stability under acidic conditions. The linker incorporates a pyridyl propionate system, with a pendant b-silyl group. Rapid
cleavage of the product is effected by elimination of the silyl group on treatment with fluoride. Two systems of this type have been
synthesised, and the stability of the linkers has been tested under acidic and basic conditions in solution.
Ó 2004 Elsevier Ltd. All rights reserved.
The continued development of solid phase peptide syn-
thesis depends on the development of improved meth-
odology, thus allowing the synthesis of more complex
structures. Previously a linker system 1 was designed
that would allow cleavage of a tethered ester using
fluoride ions, thus ensuring retention of ancillary pro-
tecting groups.1 This system was found to undergo rapid
cleavage using TBAF in DMF. However, it was also
found to be labile under acidic conditions, and attempts
to improve acid stability by aryl substitution with elec-
tron withdrawing groups were unsuccessful (Fig. 1).
logues. In particular, the route shown (Scheme 1),
although effective, was found to be lengthy and conju-
gate silyl addition was found to be low yielding.2;3 It is
possible that the cyanocuprate salts used were chelated
strongly by the pyridine ring, thus hindering the desired
reaction. However, in each case the major product was
the required linker 3.
An alternative strategy (Scheme 2) has now been
devised, based upon the nucleophilic free radical sub-
stitution of pyridines.4 This process uses the suscepti-
bility of protonated pyridine rings to free radical
The pyridine analogue 2 of this linker should avoid this
unwanted instability, due to pyridine protonation and
destabilisation of the cationic intermediate invoked in
the proposed alkyl-oxygen mechanism of acidolytic
cleavage, without affecting the fluoride ion cleavage
process. In other respects the linker design was based on
the systems previously examined. The established route
used for the synthesis of this type of molecule was found
to be troublesome when applied to the pyridine ana-
OTf
OH
a,b,c
AcO
N
N
O
d
e
O
O
O
OEt
B
OEt
AcO
O
N
A
SiRnR'm
SiRnR'm
O
O
O
N-Resin
O
N-Resin
PEPT
PEPT
N
2
Si R
O
Si R
O
f
1
R= Me, R'= Ph
n= 1-3, m= 0-2
HO
HO
OH
OEt
N
N
Figure 1. Structure of linkers.
3
7
Scheme 1. Reagents and conditions: (a) Ac2O, (b) H2O2, pH 9.5, (c)
Tf2O, (d) A, Pd(PPh3)4, TEA, (e) Li(SiMenPhm), CuCN, )78 °C and (f)
0.5 M HCl.
* Corresponding author. Tel.: +44-(0)-1875-408150; fax: +44-(0)-1875-
408151; e-mail: r.ramage@albachem.co.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.093

2404
R. Ramage et al. / Tetrahedron Letters 45 (2004) 2403–2404
O
Si R2
Si R2
a
O
OMe
a
HO
RCO
4
2
N
N
O
R1
N
O
R1
N
8 R= napthylacetic
R1= OH, OEt
R2= Me, Ph
9 R= Fmoc Phe-OH
b
Scheme 3. Reagents and conditions: (a) RCO2H, DIC, DMAP.
Si Ph
5
O
OMe
N
gested that TBAF cleavage would be more difficult
(Scheme 3).
c
In conclusion, a fluoride ion-cleavable linker has been
designed and synthesised, which has orthogonality with
respect to the conditions required for the removal of
acid and base labile protecting groups. The potential
exists for use of this linker in the synthesis of full side
chain protected peptide fragments by solid phase syn-
thesis after specific fluoride cleavage from resin. This
linker could now be applied to peptide and small mole-
cule synthesis.
Si Ph
Si Ph
d
HO
HO
O
OMe
N
6
O
N
7
OH
Scheme 2. Reagents and conditions: (a) NaH, (EtO)2P(O)CH2CO2Me,
(b) Li(SiMe2Ph), ZnMe2, (c) (PhCO2)2, MeOH, TFA and (d) 0.5 M
HCl.
substitution, most usually by radicals generated from
alcohols or aldehydes. The route requires the synthesis
of a simpler pyridyl propionate system prior to incor-
poration of the desired silyl side chains. The initial step
in this synthesis was condensation of 3-formylpyridine
under Horner–Wadsworth–Emmons conditions to give
the pyridyl cinnamate system 4.5 The silyl groups were
now introduced to afford 5 by use of either higher order
cyanocuprates, or the silyl alkyl zinc reagents.3;6 The
trimethyl- and phenyldimethyl silyllithium species used
in the study were generated by literature procedures.7
The latter method using dimethylzinc has been found to
be superior, requiring only 1 equiv of the silyllithium
species. Higher yields were obtained in shorter reaction
times, and with a simplified workup.
Acknowledgements
The authors would like to thank Brian Whigham and
Kevin Shaw for technical assistance, and Parke-Davis
Pharmaceuticals for funding.
References and notes
1. Ramage, R.; Barron, C. A.; Bielecki, S.; Holden, R.;
Thomas, D. W. Tetrahedron 1992, 48, 499–514.
2. Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201–2208; Kamabuchi, A.; Moriya, T.; Miyaura, N.;
Suzuki, A. Synth. Commun. 1993, 23, 2851–2859.
3. Fleming, I.; Newton, T. W. J. Chem. Soc., Perkin Trans. 1
1984, 1805–1808.
4. Citterio, A.; Gentile, A.; Minisci, F.; Serraavalle, M.;
Ventura, S. Tetrahedron 1985, 41, 617–620.
5. Agarwal, K. C.; Knaus, E. E. J. Heterocycl. Chem. 1985,
22, 65–69.
Hydroxymethylation was now performed using the
Minisci reaction. Heating 5 at reflux in methanol/TFA
in the presence of a stoichiometric quantity of benzoyl
peroxide gave the desired product 6 in acceptable
yield.4;8 Only the desired 6-substituted product was
obtained, presumably due to steric hindrance preventing
reaction at the 2- and 4-positions. No cleavage of the
silyl group was observed over the reaction times used.
The linker 7 was obtained by cleavage of the ester group
of 6 using either sodium hydroxide in aqueous THF or,
preferably, 0.5 M aqueous HCl/THF mixture.1
6. Crump, R. A. N. C.; Fleming, I.; Urch, C. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 701–706.
7. Schlosser, M. Organometallics in Synthesis, 2nd ed.; Wiley:
NY, pp 726–727.
8. A solution of 5 (2.40 g, 8.03 mmol), trifluoroacetic acid
(0.67 mL, 8.80 mmol) and benzoyl peroxide (5.83 g,
24.1 mmol) in methanol (100 mL) was degassed thoroughly
(Ar stream, 15 min), and then heated to reflux for 4 h. After
this time, the solvents were removed in vacuo, and the
residue was taken up in EtOAc (60 mL). The organic
solution was then washed with satd NaHCO3 solution, and
then brine. After drying (Na2SO4), the residue on evapo-
ration was purified by silica chromatography (70% EtOAc/
hexane), to give 6 yield 0.811 g, 2.46 mmol, 31%. (250 MHz,
CDCl3) dH ¼ 8:20 (1H, d, J 1.99), 7.35 (5H, s), 7.16 (2H,
m), 5.14 (1H, s), 3.21 (3H, s), 2.69 (3H, complex m), 2.13
(2H, s), 0.25 (6H, s); (67.8 MHz, CDCl3) dC ¼ 172:3, 170.6,
151.9, 148.5, 136.9, 135.2, 129.6, 127.8, 121.3, 66.5, 60.4,
34.3, 29.5, 20.8, 13.8, )4.5, )5.6; m=z (FAB) 331 (M+1,
82%), 300 (29), 135 (100).
The stability of the linker design has been exemplified
under normal peptide synthetic conditions in solution,
allowing monitoring by HPLC. 2-Naphthylacetic acid
and Fmoc-phenylalanine were coupled by standard
methods to the free alcohol 3, and the stability of the
products 8 and 9 on exposure to 20% piperidine in DMF
was followed over 1 h. Only cleavage of the Fmoc group
was observed. A series of cleavage conditions were then
tested employing 9, using both TFA and TBAF,1 which
showed that the linker system exhibits stability under
acidic conditions, whilst showing very rapid cleavage on
treatment with fluoride ions. Previous results1 with the
more hindered phenyldimethylsilyl group in 1 had sug-