An expeditious synthesis of a β-silylethanol anchoring group by a silicon directed Baeyer-Villiger oxidation on solid-phase

Article abstract of DOI:10.1016/S0040-4039(02)02319-5

A concise synthesis of a β-silylethanol anchoring group on an aminomethylated Merrifield resin has been achieved from 3-dimethyl(phenyl)silyl-5-oxohexanoic acid featuring a solid-phase silicon directed Baeyer-Villiger oxidation of a β-silylketone as the key step.

Full text of DOI:10.1016/S0040-4039(02)02319-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9437–9440
An expeditious synthesis of a b-silylethanol anchoring group by
a silicon directed Baeyer–Villiger oxidation on solid-phase
Prema Iyer and Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 2 May 2002; revised 1 October 2002; accepted 11 October 2002
Abstract—A concise synthesis of a b-silylethanol anchoring group on an aminomethylated Merrifield resin has been achieved from
3-dimethyl(phenyl)silyl-5-oxohexanoic acid featuring a solid-phase silicon directed Baeyer–Villiger oxidation of a b-silylketone as
the key step. © 2002 Elsevier Science Ltd. All rights reserved.
Organic transformations that can be successfully
demonstrated on solid supports, development of novel
linkers between the solid support and the substrates
cleavable under mild/specific conditions, and the design
of new solid phases which can provide favourable reac-
tion surroundings are essential attributes of combinato-
rial chemistry.1 In this arena, organosilicon chemistry
plays a vital role and has already started showing its
fruits with the development of many specific linkers.2 It
is well known that a silicon group exerts a strong
b-effect3 thus controlling the selectivity and the rate of
many organic reactions.4,5 The propensity of b-elimina-
tion of organosilicon compounds was first demon-
strated by Peterson6 for olefin synthesis and has
subsequently been exploited for the development of
b-silylethyl based protecting groups7 for many function-
alities. The b-(trimethylsilyl)ethyl ester functionality is a
popular protecting group largely due to its chemical
stability to the hydrolytic, oxidative, or reductive condi-
tions that are commonly used to cleave other ester
protecting groups.8 Silicon linkers based on the
trimethylsilylethyl ester group have, therefore, been
designed to be cleaved by a b-elimination mechanism.
Polymer bound b-silylethanols are made either by
hydroboration-oxidation of polymer bound vinyl
silanes9,10 or by multi-step synthesis of bifunctionalized
silanes containing the b-silylethanol and a second func-
tional group in solution phase and subsequent attach-
ment to a resin via the latter functionality.11–13 We
envisaged that the regio-directing effect of a silicon
group could possibly be used in solid-phase organic
reactions. It is known that the Baeyer–Villiger (B–V)
oxidation of a b-silyl ketone is controlled14 by the
silicon substituent and gives exclusively the b-silylethyl
ester. Herein, we report a comprehensive method for
the direct generation of the b-silylethanol linker on a
Merrifield solid support with a good loading capacity.
The b-silyl-5-oxohexanoic acid 1 was prepared as
shown in Scheme 1. Addition of dimethyl(phenyl)-
silyllithium to diethyl ethoxymethylenemalonate gave
the silyl substituted unsaturated diester 2 in 77% yield.
Michael addition of ethyl acetoacetate in the presence
of a catalytic amount of diethylamine gave the triester
3 which on Krapcho decarboxylation provided the
ethyl 3-silyl-5-oxohexanoate 4 in 61% overall yield from
2. Its hydrolysis gave the desired keto-acid 1 in quanti-
tative yield.
Scheme 1. Reagents and conditions: i. diethyl ethoxymethylene-
malonate, THF, −78 to 0°C; ii. EtO2CCH2COCH3, Et2NH,
room temperature; iii. NaCl, DMSO, H2O, 125–160°C; iv.
NaOH, MeOH, H2O.
Keywords: b-silylethanol; Baeyer–Villiger oxidation; silicon directed;
solid-phase synthesis; anchoring group.
* Corresponding author. Tel.: 091 22 5590265; fax: 091 22 5505151;
e-mail: ghsunil@magnum.barc.ernet.in
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02319-5

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P. Iyer, S. K. Ghosh / Tetrahedron Letters 43 (2002) 9437–9440
The Merrifield resin was first aminomethylated15 (amine
capacity 0.6 mmol/g) and reacted with the keto acid 1 to
provide the resin bound methyl ketone 5 (Scheme 2).
This, on B–V oxidation, gave the resin bound acetate 6.
The acetyl group was successfully removed by hydrazi-
nolysis in N-methylpyrrolidone to give the resin bound
alcohol 7. For the determination of the OH capacity of
this resin, it was coupled with N-Fmoc-Gly via the
1-hydroxybenzotriazolyl active ester to give 8. The load-
ing capacity was estimated† (0.52 mmol/g of resin; ca.
overall 87% over five steps based on the initial loadings)
after its deprotection and measurement of the UV for the
Fmoc-derived chromophore liberated upon treatment
with 20% piperidine–DMF.16 The high loading value
attests that all the reactions performed on the solid-phase
must have taken place with high selectivity and conver-
sions.
silicon-directed B–V oxidation on solid-phase had taken
place with complete regiocontrol and in a quantitative
manner.
To establish a suitable cleavage protocol for this b-
silylethyl linker 7, we first established the cleavage
conditions using the acetate amide 10 in solution which
was made from keto acid 1 via keto amide 11 as shown
in Scheme 4. The best conditions for cleavage were
BF3·OEt2 (0.05 M) in dichloromethane or chloroform
and the cleavage was complete within 15 min at room
temperature.
The acetate resin 6 was subjected to cleavage under the
above conditions which was completed within 1 h as
monitored by IR of the cleaved resin. The cleavage of the
Fmoc-Gly coupled resin 8 was slower than that of 6, but
proceeded smoothly with 0.1 M BF3.OEt2 in dichloro-
methane. After 6 h at room temperature, the amount of
Fmoc-Gly recovered corresponded to 70–75% cleavage.
The selectivity and the efficacy of the silicon directed B–V
oxidation on solid-phase is the key feature of the above
strategy. For a critical assessment of these aspects, the
acid 9 was first prepared in solution phase (in very good
yield) from the keto acid 1 by a Si-directed B–V oxidation
as shown in Scheme 3. The acid 9 on subsequent coupling
with aminomethylated resin (amine capacity 0.6 mmol/g)
provided the resin bound acetate 6. Hydrazinolysis gave
the resin bound b-silyl alcohol 7 which was coupled with
N-Fmoc-Gly to give 8. The loading capacity16 of 7
prepared by this route was found† to be 0.54 mmol/g
(overall 90% over four steps). This confirmed that the
In order to evaluate further the scope of attaching
different substrates onto the solid supported b-silylethyl
linker 7, different cleaving reagents/conditions and
the possibility of the use of Merrifield aminomethylated
resin with higher loading capacity (amine capacity
0.92 mmol/gm) were studied. For this, we coupled
Fmoc-Gly and Fmoc-Phe to the linker 7 (OH capacity
0.81 mmol/g) and studied their cleavage using 0.1
M BF3·OEt2 in dichloromethane. The time dependent
cleavage of Fmoc-Gly‡ is presented in Fig. 1 which
showed that the initial rate of cleavage was faster and
became sluggish after 4.5 h. At this time, the amount of
cleaved Fmoc-Gly corresponds to 74% cleavage based on
initial loadings. The amount of Fmoc-Gly obtained
Scheme 4. Reagents and conditions: i. BnNH2, DCCI, DMAP,
CH2Cl2; ii. MCPBA, Na2HPO4, CH2Cl2, 0°C to room temper-
ature.
Scheme 2. Reagents and conditions: i. aminomethylated Mer-
rifield resin, DCCI, pentafluorophenol, DMAP, CH2Cl2, 0°C
to room temperature; ii. MCPBA, Na2HPO4, CH2Cl2, 0°C to
room temperature; iii. 15% N2H4 in NMP, room temperature;
iv. Fmoc-Gly, DIC, 1-HOBt, DMAP, 0°C to room tempera-
ture. 2.5–3 equivalents of reagents with respect to resin amine
capacity were used. Reactions on solid-phase were monitored
by recording FT-IR of resin samples as KBr disks.
Scheme 3. Reagents and conditions: i. MCPBA, Na2HPO4,
CH2Cl2, room temperature; ii. aminomethylated Merrifield
resin, DIC, pentafluorophenol, DMAP, pyridine.
Figure 1. Course of cleavage of Fmoc-Gly from 8.
‡ Cleavage was monitored by measurement of UV absorption at
u=300 nm (m=4636).
† Capacity based on capacity of the aminomethylated resin.

P. Iyer, S. K. Ghosh / Tetrahedron Letters 43 (2002) 9437–9440
9439
after 12 h was quantified§ which corresponds to 71%
cleavage. Under the same conditions Fmoc-Phe was
also quantified§ and the amount also corresponded to
71%. The cleavage of Fmoc-Gly from the resin using
TBAF in dichloromethane13 was also carried out, but
the Fmoc group was only partially cleaved.¶ For the
attachment of 1-naphthylamine onto the resin, the
linker 7 (OH capacity 0.81 mmol/gm) was reacted with
1-naphthylisocyanate which provided the resin bound
carbamate of 1-naphthylamine 12 as shown in Scheme
5. The cleavage of 1-naphthylamine from 12 was
achieved using 0.1M TBAF in dichloromethane and
was quantifiedꢀꢀ (79% based on OH capacity) and char-
acterized as its acetate 13.
b-silyl-keto acids.19 This is expected to assist in carrying
out asymmetric transformations on solid-phase. There-
fore, the silicon based linkers which work on the princi-
ple of b-elimination9–13 or otherwise20 will enrich
solid-phase library synthesis because of their specific
advantages.
Acknowledgements
We thank Shri D. P. Mondal, IIT, Kharagpur, for the
preparation of some starting materials.
In conclusion, we have achieved the synthesis of a
b-silylethanol anchoring group on an aminomethyl-
ated Merrifield resin from 3-silyl-5-oxohexanoic acid
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