A Rapid and Efficient Synthesis of a Bifunctional β-Silylketone, Precursor for a Solid Supported β-Silylethanol Anchoring Group

Article abstract of DOI:10.1081/SCC-120027279

A concise synthesis of 3-dimethyl(phenyl)silyl-5-oxo-hexanoic acid 1, the precursor for a solid supported β-silylethanol anchoring group has been achieved from ethyl 2-ethoxycarbonyl-3-dimethyl(phenyl)silyl-2-propenoate 2 featuring amino acid catalysed Mi

Full text of DOI:10.1081/SCC-120027279

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A Rapid and Efficient Synthesis of a Bifunctional
β‐Silylketone, Precursor for a Solid Supported
β‐Silylethanol Anchoring Group
Sonali M. Date a , Prema Iyer a & Sunil K. Ghosh a
a Bio‐Organic Division , Bhabha Atomic Research Centre , Mumbai, 400 085, India
Published online: 16 Aug 2006.
To cite this article: Sonali M. Date , Prema Iyer & Sunil K. Ghosh (2004) A Rapid and Efficient Synthesis of a Bifunctional
β‐Silylketone, Precursor for a Solid Supported β‐Silylethanol Anchoring Group, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:3, 405-411, DOI: 10.1081/SCC-120027279
To link to this article: http://dx.doi.org/10.1081/SCC-120027279
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 3, pp. 405–411, 2004
A Rapid and Efficient Synthesis of a
Bifunctional b-Silylketone, Precursor
for a Solid Supported b-Silylethanol
Anchoring Group
*
Sonali M. Date, Prema Iyer, and Sunil K. Ghosh
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai, India
ABSTRACT
A concise synthesis of 3-dimethyl(phenyl)silyl-5-oxo-hexanoic acid 1,
the precursor for a solid supported b-silylethanol anchoring group has
been achieved from ethyl 2-ethoxycarbonyl-3-dimethyl(phenyl)silyl-2-
propenoate 2 featuring amino acid catalysed Michael addition of acetone
as the key step.
Key Words: b-Silylketone; Michael addition; Amino acid; Catalysis.
*
Correspondence: Sunil K. Ghosh, Bio-Organic Division, Bhabha Atomic Research
Centre, Mumbai 400 085, India; Fax: þ91-22-25505151; E-mail: ghsunil@magnum.
barc.ernet.in.
405
DOI: 10.1081/SCC-120027279
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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406
Date, Iyer, and Ghosh
Development of novel linkers between the solid support and the substrates
cleavable under mild/specific conditions is an essential attribute of combina-
torial chemistry. In this perspective, organosilicon chemistry plays a vital role
with the development of many specific linkers.[1–3] The b-(trimethyl-
silyl)ethyl ester functionality is a popular protecting group largely due to its
chemical stability to the hydrolytic, oxidative, or reductive conditions that are
commonly used to cleave other ester protecting groups.[4] b-Silylethanol
linker could also be transformed into secondary linkers like b-silylethoxy-
methyl chloride[5] which then, could be used for the attachment of functiona-
lized molecules such as alcohols, thiols, amines, carboxylic acids and phenolic
compounds on to the resin. Silicon linkers based on the trimethylsilylethanol
group have, therefore, been designed to be cleaved by a b-elimination
mechanism. b-Silylethanol linkers are usually made by multi-step synthesis of
a bifunctionalized silane containing the b-silylethanol moiety and a second
functional group in solution phase. Subsequently, they are attached to the resin
via the latter functionality.[6–8] We[9] have recently applied the regio-directing
effect of a silicon group in the Baeyer-Villiger (B-V) oxidation[10] of a
resin bound b-silyl ketone to get exclusively the b-silylethyl acetate which was
subsequently hydrazinolyzed to provide the resin bound b-silylethanol
as depicted in Sch. 1. Herein, we report, a rapid synthesis of 3-di-
methyl(phenyl)silyl-5-oxo-hexanoic acid 1, the bifunctional precursor for the
solid supported b-silylethanol anchoring group.
We began our synthesis with the silyl substituted alkylidene malonate
2.[11] A low yielding (40%) synthesis of this compound was reported by
Knochel[12] using diethyl phenylsulfonylmethylene malonate and a bimetallic
silicon reagent. We have prepared it by a conjugate addition-elimination
reaction starting from the commercially available diethyl ethoxymethylene
malonate as shown in Sch. 2. Addition of dimethyl(phenyl)silyllithium[13] to it
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 intermediate triester which on Krapcho deethoxycarbonylation
Scheme 1.

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407
Scheme 2. Reagents and conditions: (i) (EtO)HC55C(CO2Et)2, THF, 278 to 08C;
(ii) EtO2CCH2COCH3, Et2NH, room temperature; and (iii) NaCl, DMSO, H2O,
125–1608C.
furnished the keto ester 3. However the last step was tricky and required great
care to get the desired keto ester 3 in appreciable yield and purity. Best yield
(61%) of 3 could be obtained by sequential heating the intermediate triester at
1258C/24 h, at 1408C/7 h and finally at 1608C for 7 h. An alternative and
more efficient protocol was therefore developed involving direct addition of
acetone on the alkylidene malonate 2 using amino acids as catalysts to give the
ketodiester 4. The conjugate addition of ketones to Michael acceptors has been
known[14] to be catalysed by proline and cyclic imines. In the present
endeavour, we studied a number of amino acids and different solvent systems
for the conjugate addition of acetone to compound 2 and the results are
presented in Table 1. Amongst the solvent and amino acid combinations
chosen, racemic tryptophan in dimethyl sulfoxide gave the best result (Table 1;
entry 7). The ketodiester 4 then easily underwent deethoxycarbonylation
(1708C, 4 h) to give the keto ester 3 in 82% yield. The desired keto-acid 1, in
turn, was obtained in high yield by its alkaline hydrolysis (Sch. 3).
In conclusion, we have developed a method for the preparation of the
bifunctional b-silylketone 1 in a rapid and efficient fashion from com-
mercially available cheap starting materials such as diethyl ethoxymethylene
malonate and racemic amino acids. This would facilitate the preparation of
b-silylethanol anchoring group[9] for use in solid phase organic synthesis and
combinatorial chemistry.
EXPERIMENTAL
All reactions were performed in oven-dried (1208C) or flame-dried glass
apparatus under dry N2 or argon atmosphere. THF was dried with sodium/

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Date, Iyer, and Ghosh
Table 1. Effect of solvent and amino acid on the conjugate addition of acetone to 2.
Entry
Amino acida
Solvent/time in days
Yield (%)
1
2
3
4
5
6
7
proline
proline
proline
DMSO/2
DMSO/2.5
NMP/2.5
DMSO/2
DMSO/3.5
DMSO/3.5
DMSO/2
89
85
84
phenylalanine
tyrosine
valine
70b
57b
62b
98
tryptophan
aAll reactions were conducted at room temperature using DL-amino acids.
bIncomplete reaction.
benzophenone and DMSO with CaH2. Ethyl acetoacetate acetate and
diethylamine were freshly distilled before use. Diethyl ethoxymethylene-
1
malonate was obtained from Spectrochem (India). H NMR and 13C NMR
spectra were recorded on a Bruker 200 MHz spectrometer. Mass spectra were
recorded on a Fissons VG Quatro II mass spectrometer or HP GCD G1800A
mass spectrometer. Infrared spectra (IR) were recorded on a Nicolet Impact
410 FT IR spectrophotometer.
Scheme 3. Reagents and conditions: (i) NaCl, DMSO, H2O, 1708C, 4 h; and (ii)
NaOH, MeOH, H2O.

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Bifunctional b-Silylketone
409
Ethyl 2-ethoxycarbonyl-3-dimethyl(phenyl)silyl-2-propenoate (2).
Dimethyl(phenyl)silyllithium[13] (0.85 M solution in THF) (105 mL,
89 mmol) was added dropwise to a stirred solution of diethyl ethoxymethy-
lenemalonate (18 mL, 89 mmol) in THF (200 mL) at 2788C over 0.5 h. After
the addition was over, the reaction mixture was stirred for 5 min and the cold
bath was removed. The reaction mixture was allowed to attain room tempera-
ture (ꢀ25 min), poured into saturated ammonium chloride solution and
extracted with Et2O. The organic extract was washed with water and brine,
dried (MgSO4) and evaporated. The residue was purified by chromatography
to give the diester 2 as an colorless oil.[12]
Yield: 21 g, 77%. Rf: 0.6 (hexane : EtOAc; 95 : 5). IR (film): 1731, 1600,
1237, 1115 cm21 1H NMR (200 MHz, CDCl3) 0.45 (s, 6H), 1.19 (t,
.
J ¼ 7.1 Hz, 3H), 1.29 (t, J ¼ 7.1 Hz, 3H), 4.00 (q, J ¼ 7.1 Hz, 2H), 4.24
(q, J ¼ 7.1 Hz, 2H), 7.32 (s, 1H), 7.34–7.38 (m, 3H), 7.50–7.55 (m, 2H). 13
C
NMR (50 MHz, CDCl3) 165.94, 163.57, 147.38, 141.52, 136.12, 133.75,
129.33, 127.74, 61.42, 61.08, 13.91, 13.69, 22.75. MS (ESI): m/z 329
(M þ Na, 15), 307 (M þ H, 5), 229 (M 2 Ph, 100), 201 (82), 173 (41), 155
(37).
Ethyl
(3RS)-3-dimethyl(phenyl)silyl-5-oxo-hexanoate
[(+)-3].
Diethylamine (0.25 mL, 2.42 mmol) was added to a mixture of ethyl aceto-
acetate (4.2 mL, 33.1 mmol) and ester 2 (5.08 g, 16.55 mmol) at 08C. After
stirring for 1.5 h at room temperature, the reaction mixture was diluted with
water and extracted with Et2O. The organic extract was washed with water and
brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was
subjected to Kugelrohr distillation to remove the excess ethyl acetoacetate
furnishes the intermediate keto-triester. A stirred solution of this triester,
sodium chloride (2.4 g) and water (0.9 mL) in DMSO (86 mL) was heated at
1258C under nitrogen for 24 h. The bath temperature was raised to 1408C and
heated further for 7 h and at 1608C for 7 h. The reaction mixture was diluted
with water and extracted with Et2O. The organic extract was washed with
water and brine, dried (Na2SO4) and evaporated under reduced pressure. The
residue was purified by chromatography to give (+)-3 as an colorless oil.
Yield: 3.02 g, 61%. Rf: 0.4 (hexane : EtOAc; 10 : 90) IR(film): 1731, 1251,
1112 cm21. 1H NMR (200 MHz, CDCl3) 0.30 (s, 6H), 1.21 (t, J ¼ 7.1 Hz, 3H),
1.83–2.08 (m, 1H), 2.05 (s, 3H), 2.17 (dd, J ¼ 8.9, 15.2 Hz, 1H), 2.39 (dd,
J ¼ 5, 15.2 Hz, 1H), 2.45 (d, J ¼ 6.42 H), 4.02 (q, J ¼ 7.1 Hz, 2H), 7.34–7.38
(m, 3H), 7.45–7.52 (m, 2H). 13C NMR (50 MHz, CDCl3) 208.10, 173.53,
136.92, 133.97, 129.29, 127.88, 60.35, 43.78, 34.70, 29.72, 17.46, 14.13,
24.31, 24.57. MS (ESI): m/z 292 (Mþ, 1.8), 277 (22), 247 (10.7), 215
(M 2 Ph, 100), 135 (24). Anal. Calcd for C16H24O3Si (292.456): C, 65.71; H,
8.27%. Found: C, 65.44; H, 8.50%.

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Date, Iyer, and Ghosh
(3RS)-3-Dimethyl(phenyl)silyl-5-oxo-hexanoic acid [(+)-1]. Sodium
hydroxide (2 M in water, 5 mL, 10 mmol) was added portionwise to a stirred
solution of the ketoester (+)-3 (1.7 g, 5.82 mmol) in MeOH (20 mL) in 4 h.
The solvent was evaporated and the residue was diluted with water, extracted
with ether. The aqueous phase was acidified with dil HCl and extracted with
EtOAc. The organic extract was washed with water and brine, dried
(Na2SO4) and evaporated under reduced pressure to give the acid (+)-1 as a
thick gum. Yield: 1.27 g, 92%. IR (film): 3500–2500 (br), 1720, 1251,
1
1112 cm21. H NMR (200 MHz, CDCl3) 0.32 (s, 6H), 1.86–2.01 (m, 1H),
2.05 (s, 3H), 2.22 (dd, J ¼ 8.8, 15.6 Hz, 1H), 2.39–2.50 (m, 3H), 6.62 (s-br,
1H), 7.34–7.38 (m, 3H), 7.46–7.52 (m, 2H). 13C NMR (50 MHz, CDCl3)
208.48, 179.14, 136.66, 133.92, 129.36, 127.92, 43.63, 34.37, 29.74, 17.20,
24.34, 24.62.
Amino acid catalysed Michael addition of acetone to 2; General
Procedure. A mixture of the diester 2 (1 mmol), amino acid (0.2 mmol) and
acetone (2 mL) in DMSO or DMF or NMP (8 mL) was stirred at r.t. for
appropriate time mentioned in Table 1. The contents were diluted with water
(30 mL) and extracted with Et2O (3 Â 30 mL). The organic extract was
washed with water and brine, dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by chromatography to give (+)-4 as a thick
oil.
Ethyl (3RS)-3-dimethyl(phenyl)silyl-2-ethoxycarbonyl-5-oxo-hexano-
ate [(+)-4]. Following the general procedure, diester 2 (11.3 g, 36.99 mmol),
(DL)-tryptophan (1.634 g, 7.4 mmol) and acetone (76 mL) in DMSO after 2
days gave (+)-4. Yield: 13.16 g (98%). Rf: 0.37 (hexane : EtOAc; 10 : 90). IR
(film): 1746, 1728, 1250, 1112 cm21 1H NMR (200 MHz, CDCl3) 0.33
.
(s, 3H), 0.34 (s, 3H), 1.21 (t, J ¼ 7.1 Hz, 6H), 1.97 (s, 3H), 2.30 (q, J ¼ 5.9 Hz,
1H), 2.60 (dd, J ¼ 5.8, 18.7 Hz, 1H), 2.78 (dd, J ¼ 6.5, 18.7 Hz, 1H), 3.48
(d, J ¼ 5.6 Hz, 1H), 4.06 (q, J ¼ 7.1 Hz, 4H), 7.30–7.40 (m, 3H), 7.45–7.55
(m, 2H). 13C NMR (50 MHz, CDCl3) 207.49, 169.78, 169.39, 137.11, 134.15,
129.11, 127.64, 61.25, 61.08, 51.66, 41.66, 29.56, 20.52, 13.87, 23.31,
23.54. MS (EI): m/z 349(M 2 Me, 3), 287 (12), 189 (15), 135 (Me2PhSi,
100), 127 (41), 111 (26), 105 (15), 75 (32). Anal. Calcd for C19H28O5Si
(364.516): C, 62.61; H, 7.74%. Found: C, 62.50; H, 7.96%.
Preparation of Ethyl (3RS)-3-dimethyl(phenyl)silyl-5-oxo-hexanoate
[(+)-3] from diester (+)-4. A stirred mixture of diester (+)-4 (13 g,
35.714 mmol), sodium chloride (4.48 g, 76.58 mmol) and water (1.5 mL) in
DMSO (150 mL) was heated at 1708C under nitrogen for 4 h. The reaction
mixture was cooled to room temperature, diluted with water and extracted
with ether. The organic extract was washed with water and brine, dried
(Na2SO4) and evaporated under reduced pressure. The residue was purified by
chromatography to give (+)-3 (8.5 g, 82%) as a colorless oil.

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411
ACKNOWLEDGMENT
We thank Shreenivas Shreenath and D. P. Mondal of IIT, Kharagpur, for
some help.
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Received in India July 31, 2003

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