Novel silyl linkers for solid-phase synthesis

Article abstract of DOI:10.1016/S0040-4039(02)01213-3

The syntheses of two silyl chloride resins, 2 and 10 are described starting from Merrifield resin, 3-methyl-1,3-butanediol and diphenyldichlorosilane or dimethyldichlorosilane, respectively. The silyl chloride resin 2 was used for the attachment of 1° alcohols, 2° alcohols and phenols to the solid phase. A preliminary study of the stability of the diphenylsiloxane linker towards certain reaction conditions was also carried out. A more reactive silyl chloride resin 10 was found to be suitable for the attachment of 3° alcohols to the solid phase.

Full text of DOI:10.1016/S0040-4039(02)01213-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6023–6026
Novel silyl linkers for solid-phase synthesis
Marco M. Meloni,a R. C. D. Brown,a,* Peter D. Whiteb and Duncan Armourc
aCentre for Combinatorial Chemistry, Department of Chemistry, University of Southampton, Highfield,
Southampton SO17 1BJ, UK
bNovabiochem, CN Biosciences (UK) Ltd, Padge Road, Beeston NG9 2JR, UK
cPfizer Global Research & Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
Received 10 May 2002; revised 20 June 2002; accepted 24 June 2002
Abstract—The syntheses of two silyl chloride resins, 2 and 10 are described starting from Merrifield resin, 3-methyl-1,3-butanediol
and diphenyldichlorosilane or dimethyldichlorosilane, respectively. The silyl chloride resin 2 was used for the attachment of 1°
alcohols, 2° alcohols and phenols to the solid phase. A preliminary study of the stability of the diphenylsiloxane linker towards
certain reaction conditions was also carried out. A more reactive silyl chloride resin 10 was found to be suitable for the attachment
of 3° alcohols to the solid-phase. © 2002 Elsevier Science Ltd. All rights reserved.
The use of the silicon linkers in solid-phase organic
synthesis is well known,1 both for the immobilisation of
alcohols and for the ‘traceless’ release of unsaturated
compounds.2 We recently began to investigate the
development of new silicon linkers, with the objective
that their synthesis should be simple and use only
cheap, readily available materials (Scheme 1). It was
felt that the linker 2 based upon the tert-butoxy-
diphenylsilyl protecting group should satisfy the criteria
outlined above, and that the corresponding siloxanes
would display a good level of acid and base stability.3
In addition, tert-butoxydiphenylsilyl chloride 6 is
known to react readily with a variety of alcohols,
including hindered tertiary alcohols, and that the result-
ing siloxanes are readily cleaved using a source of
fluoride anion.4
returning the desired alcohols in excellent yields (98 and
94% for trans-cinnamyl alcohol and menthol, respec-
tively). After the encouraging results obtained in the
solution-phase model, attention was turned to the solid-
phase chemistry. Attachment of 3-methyl-1,3-butane
Before attempting to prepare the chlorosilane resin 2,
model studies were carried out in solution to validate
the chemistry (Scheme 2).
Scheme 1. Approach to the synthesis of chlorosiloxanes 1 and
2.
According to Scheme 2, 3-methyl-1,3-butanediol 7 was
selectively benzylated prior to reaction with
diphenyldichlorosilane 5. The resulting chlorosiloxane 1
was quite stable, surviving TLC analysis and an
aqueous workup, although 1 was routinely prepared in
situ prior to use. Reaction with a number of 1° and 2°
alcohols was investigated, leading to the formation of
siloxanes 8a–c in good yield (Table 1). Exposure of
siloxanes 8a and 8c to TBAF resulted in rapid cleavage,
Scheme 2. Reagents and conditions: (a) NaH, DMF, 0°C,
then BnCl; (b) Ph2SiCl2, Et3N, DMAP, CH2Cl2, rt; (c) R2OH,
Et3N, DMAP, CH2Cl2, rt; (d) TBAF, THF, rt.
* Corresponding author. E-mail: rcb1@soton.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01213-3

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M. M. Meloni et al. / Tetrahedron Letters 43 (2002) 6023–6026
Table 1. Siloxanes derived from reaction between 1 and
various alcohols
Table 2. Alcohols cleaved from resins 9 and 11
Resin
9a
Product cleaved
Conditions
TBAF
Yield (%)a
100b
Siloxane
Reaction time (min)
Yield (%)a
trans-Cinnamyl
alcohol
trans-Cinnamyl
alcohol
8a
8b
8c
15
10
20
Quantitative
90
88
9a
KF, 18-crown-6 100
9b
9c
9d
n-Decanol
TBAF
TBAF
TBAF
70
0c
96
a Yields refer to siloxanes 8a–c isolated after purification by flash
column chromatography.
E-E-Nerolidol
(1R,2S,5R)-
(−)-Menthol
endo-Borneol
trans-Cinnamyl
alcohol
E-E-Nerolidol
(1R,2S,5R,)-
(−)-Menthol
9e
11a
TBAF
TBAF
95
diol
7
to Merrifield resin (100–200 mesh, 2%
100b
crosslinked, loading 1.6 mmol/g, Novabiochem) with
potassium tert-butoxide5,6 under microwave irradiation,
using a Personal Chemistry Smith Synthesiser, gave
resin 4. Subsequent reaction with diphenyldichlorosi-
lane 5 afforded resin 2,7 which was coupled with a
variety of alcohols to afford siloxanes 9a–e (Scheme 3).8
As anticipated, subsequent cleavage of siloxanes, with
TBAF or KF in THF with 18-crown-6, returned the
corresponding alcohols in good to excellent yields,
apart from the hindered 3° alcohol nerolidol (Table 2).
11c
11d
TBAF
TBAF
98
95
a Yields are based on the loading of resin 2, that was estimated
indirectly by coupling of trans-cinnamyl alcohol followed by cleav-
age with TBAF and quantification using GC.
b Based on the assumption that trans-cinnamyl alcohol reacted com-
pletely with 2 and 10.
c Coupling reaction carried out for 24 h at room temperature.
To allow attachment of 3° alcohols, a less hindered silyl
chloride resin 10 was prepared (Scheme 4). The loading
of 10 (0.35 mmol/g) was somewhat lower than that of 2
(0.73 mmol/g), possibly due to crosslinking, although
no evidence for this was seen in either 13C or 29Si NMR
spectra of resin 11d. 2° and 3° Alcohols, menthol and
nerolidol, were efficiently attached and released from
the dimethylchlorosiloxane resin 10 (Table 2).
After the successful reactions with various alcohols,
some preliminary stability studies were carried out on
the diphenylsiloxane linker. S-Methyl lactate was cou-
pled to 2, and the resulting immobilised ester 12 was
treated with phenylmagnesium bromide followed by
cleavage with TBAF to afford diol 14 in good yield
(60%, based upon the loading of the silyl chloride resin,
0.73 mmol/g),9 demonstrating the stability of siloxane
linker to Grignard reagents (Scheme 5).
Scheme 4. Reagents and conditions: (a) Me2SiCl2, Et3N,
DMAP, CH2Cl2; (b) R2OH, Et3N, DMAP, CH2Cl2 rt; (c)
TBAF, THF, or KF 18-crown-6, THF, rt.
Scheme 3. Reagents and conditions: (a) 3-methyl-1,3-butane-
diol, KOtBu, 18-crown-6, 0°C, then Merrifield resin pre-swol-
len, THF, microwave irradiation, 120°C, 10 min; (b) Ph2SiCl2,
Et3N, DMAP, CH2Cl2; (c) R2OH, Et3N, DMAP, CH2Cl2 rt;
(d) TBAF, THF, or KF 18-crown-6, THF, rt.
Scheme 5. Reagents and conditions: (a) S-methyl lactate,
Et3N, DMAP, CH2Cl2, rt; (b) PhMgBr, THF, 0°C, then rt;
(c) TBAF, THF, rt.

M. M. Meloni et al. / Tetrahedron Letters 43 (2002) 6023–6026
6025
Yamada, H.; Takahashi, T.; Porco, J., Jr. Tetrahedron
Lett. 1999, 40, 2141–2144; (e) Hu, Y.; Porco, J., Jr.
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Liu, H. Q.; Darling, G. D. J. Org. Chem. 1997, 62,
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hedron Lett. 2001, 42, 1463–1466. For general reviews on
linkers, see: (k) Brown, R. C. D. Recent developments in
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Trans. 1 1998, 3293–3320; (l) Guillier, F.; Orain, D.;
Bradley, M. Chem. Rev. 2000, 100, 2091–2157.
2. For application of silyl linkers in traceless cleavage, see:
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60, 6006–6007; (b) Plunkett, M. J.; Ellmann, J. A. J. Org.
Chem. 1997, 62, 2885–2893; (c) Woolard, F. X.; Paetsch,
J.; Ellmann, J. A. J. Org. Chem. 1997, 62, 6102–6103; (d)
Lee, Y.; Silverman, R. B. Org. Lett. 2000, 3, 303–306; (e)
Lee, Y.; Silverman, R. B. Tetrahedron 2001, 57, 5339–
5352; (f) Schuster, M.; Lucas, N.; Blechert, S. Chem.
Commun. 1997, 823–824.
3. For general reviews on protecting groups for hydroxyl
function, see: (a) Kocienski, P. J. Protecting groups;
Thieme Ed: New York, 1994; pp. 28–42; (b) Greene, T.
W.; Nuts, P. G., Protective Groups in Organic Chemistry,
2nd ed.; John Wiley: New York, 1991; pp. 68–87.
4. For stability studies and use of tert-butoxydiphenylsilyl
chloride in organic synthesis, see: (a) Gillard, J. W.;
Fortin, R.; Morton, H. E.; Yoakim, C.; Quesnelle, A.;
Daignault, S.; Guindon, Y. J. Org. Chem. 1998, 53,
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Yoakim, C.; Quesnelle, A.; Daignault, S.; Guindon, Y.
Tetrahedron Lett. 1984, 25, 4717–4720.
Scheme 6. Reagents and conditions: (a) 4-hydroxybenzalde-
hyde, Et3N, DMAP, CH2Cl2 rt; (b) BnNH2, HC(OCH3)3, rt;
(c) Me4NHB(OAc)3, 1% AcOH in CH2Cl2, rt; (d) TBAF,
THF, rt.
We also investigated reductive amination of an immo-
bilised aldehyde 15, which was prepared under the
usual conditions.8 Condensation of 15 with benzyl-
amine, followed by reduction of the intermediate imine
and TBAF exposure afforded 17 in good yield (70%,
based on the loading of the silyl chloride resin 2, 0.73
mmol/g, Scheme 6).10,11
In conclusion, we have synthesised two new silyl chlo-
ride resins. The synthesis is straightforward and starts
from inexpensive and readily available reagents. The
linkers obtained are reactive towards a range of
hydroxyl containing molecules, including hindered
ones, and could represent a valuable alternative to
other commercially available silyl resins. Further appli-
cations of the silyl linkers described are currently under
investigation.
5. Hernandez, A. S.; Hodges, J. C. J. Org. Chem. 1997, 62,
3153–3157.
6. The presence of the tertiary alcohol on resin was con-
firmed by the methyl red test, see: Burkett, B. A.; Brown,
R. C. D.; Meloni, M. M. Tetrahedron Lett. 2001, 42,
5773–5775.
Acknowledgements
7. A typical procedure for the synthesis of resin 2 is as
follows: resin 4 (100 mg) was washed with dry THF (5×5
mL, 5 min) and dry CH2Cl2 (5×5 mL, 5 min) dried under
high vacuum for 48 h. The resin was suspended in dry
CH2Cl2 (1 mL) under a N2 flow in a peptide vessel and
freshly dry Et3N (133 mL, 0.96 mmol) was added, fol-
lowed by Ph2SiCl2 (134 mL, 0.64 mmol) and DMAP (40
mg, 0.32 mmol). After 10 min agitation with N2 the
system was sealed and the suspension shaken for 1 h.
Then the resin was drained under a N2 flow and washed
with dry CH2Cl2 (3×3 mL, 1 min) and used immediately
for the successive reactions.
The authors acknowledge the supporting partners of
the Centre for Combinatorial Chemistry for financial
support. The funding partners are: Nycomed, Amer-
sham, AstraZeneca, GlaxoSmithKline, Lilly, CN Bio-
sciences, Inc., Organon, Pfizer and Roche. R.C.D.B.
also acknowledges the Royal Society for a University
fellowship. The authors thank Joan Street and Neil
Wells for solid-phase 13C NMR, the University of
Durham for solid-phase 29Si NMR and Personal Chem-
istry for the donation of a Smith Synthesiser™.
8. General procedure for immobilisation of alcohols: Syn-
thesis of 12: resin 2 (100 mg, loading 0.65 mmol/g) was
suspended in dry CH2Cl2 (1 mL) under N2 flow in a
peptide vessel and freshly dried Et3N (133 mL, 0.96
mmol) was added, followed by S-methyl lactate (61 mL,
0.64 mmol) and DMAP (40 mg, 0.32 mmol). After 10
min agitation with N2 the system was sealed and the
suspension shaken 1 h. The resin was washed with dry
CH2Cl2 (5×5 mL, 5 min) and dried under high vacuum at
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6026
M. M. Meloni et al. / Tetrahedron Letters 43 (2002) 6023–6026
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