Silicon-based aromatic transferring linkers for traceless solid-phase synthesis of aryl-, polyaryl-, and heteroaryl-containing compounds

Article abstract of DOI:10.1016/S0040-4020(01)00457-4

A number of arylsilane-based linkers are prepared for traceless solid-phase synthesis. General methodologies for introduction of the silyl group and various functional groups to aromatic, polyaromatic, and heteroaromatic rings are developed. Also, broad u

Full text of DOI:10.1016/S0040-4020(01)00457-4

TETRAHEDRON
Pergamon
Tetrahedron 57 *2001) 5339±5352
Silicon-based aromatic transferring linkers for traceless
solid-phase synthesis of aryl-, polyaryl-,
and heteroaryl-containing compounds
²
Younghee Lee and Richard B. Silvermanp
Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3113, USA
Received 13 March 2001; accepted 25 April 2001
AbstractÐA number of arylsilane-based linkers are prepared for traceless solid-phase synthesis. General methodologies for introduction of
the silyl group and various functional groups to aromatic, polyaromatic, and heteroaromatic rings are developed. Also, broad utilities of the
linkers are demonstrated by on-resin preparation of small organic molecules and subsequent cleavage of the products either by protiode-
silylation *TFA) or ipso-substitution *Br2). q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
is possible, which is desired for the maximum diversi®ca-
tion of a library. Given that nonpolar aromatic moieties play
important roles in numerous therapeutic agents, we
envisioned synthetic protocols which would be generally
applicable to the construction of a wide range of aromatic
building blocks utilizing silicon-based traceless linker
strategy. We report here these solid-phase strategies.
The practical applications of combinatorial chemistry and
high-throughput screening are apparent in medicinal
chemistry.1 To support the need for a variety of chemistries
on solid phase, much of the current effort is focused on the
development of new linkers. The most widely used
supports, such as Merri®eld, Wang, and Rink resins, require
speci®c polar functional groups *e.g. COOH, NHR, OH) for
attachment of the desired molecule to the resin. Upon
cleavage of the product obtained after a given sequence of
reactions, the polar group remains on the target molecules.
For the design of lead compounds for certain biological
activities, such polar functionalities may have unfavorable
pharmacological or pharmacokinetic properties, and more
lipophilic groups are required. A traceless linker strategy in
which a hydrophobic group is attached to a polymeric
support, then, after elaboration of the group, is cleaved
from the resin intact, would avoid the incorporation of an
unwanted polar group and leave no trace or `memory' of its
attachment to the solid support.1
2. Results and discussion
2.1. Phenylsilane linkers
Our synthetic approach to various phenylsilane linker
systems started from 1,4-dibromobenzene, which was
readily converted into 4-allyldimethylsilyl-1-bromobenzene
*1) by treatment with n-butyllithium followed by
allylchlorodimethylsilane.4 As shown in Scheme 1, treat-
ment of 1 with magnesium in THF generated the Grignard
reagent, which was treated with paraformaldehyde to afford
the benzyl alcohol derivative 2. Mitsunobu reaction of 2
with N-Boc protected ethyl oxamate and subsequent
hydrolysis provided an N-Boc protected benzylamine build-
ing block 3.6 The mild reaction conditions for the
conversion of the alcohol to the amino group was also
found to be ef®ciently adapted to solid-phase reactions.
Bromination of 2 was carried out with triphenylphosphine
and carbon tetrabromide. The resulting benzyl bromide
analogue 4 was previously used as a key intermediate for
the polymer-bound phenylalanine derivative 5.3 Quenching
of the Grignard reagent generated from 1 with carbon
dioxide followed by acidic workup, then esteri®cation
[MeOH, SOCl2 *cat)] gave the methyl benzoate analogue
6. Lithium±halogen exchange of 1 with t-butyllithium
at 2788C followed by addition of dry DMF afforded a
We previously reported silicon-based linking strategies2 to
attach the aromatic side chain of phenylalanine3 and
b-phenylalanine,4 which were ultimately used for the
ef®cient synthesis of small peptides and a cyclic peptide.5
By taking advantage of side chain tethered amino acids,
modi®cation of both the N- and C-termini of the peptides
Keywords: traceless solid-phase synthesis; aromatic; polyaromatic; hetero-
aromatic compounds.
Corresponding author. Tel.: 11-847-491-5653; fax: 11-847-491-7713;
e-mail: agman@chem.northwestern.edu
Current address: ChemRx, 9040 S. Rita Road, Tucson, AZ 85747, USA.
E-mail: ylee@chemrx.com.
p
²
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020*01)00457-4

5340
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
Scheme 1.
4-allyldimethylsilylbenzaldehyde *7). The two carbon
homologated product 8 was obtained when the lithiated
form of 1 was exposed to ethylene oxide. Compound 8
was also converted to the N-Boc protected phenylethyl-
amine derivative 9 under the same conditions employed
for the preparation of 3. Jones oxidation and PCC reactions
of 8 resulted in carboxylic acid 10 and aldehyde 11,
respectively. Compounds 2, 3, and 8 were loaded onto the
polymer *either bromopolystyrene *BPS) or iodobenzoyl-
aminomethylpolystyrene [IBAPS7]) in one-pot, two-step
reactions: hydroboration of the terminal ole®n with
9-BBN followed by in situ Suzuki coupling2e,8 *Scheme 2).
sulfonylation of the secondary amine; *3) hydrolysis of the
ester with LiOH *5 equiv.) in aqueous THF; *4) coupling of
the acid with O-ethyl hydroxylamine; *5) cleavage of the
product with Br2 in CH2Cl2 to provide a hydroxamic acid
analogue 14. Hydroxamic acids are known inhibitors of
matrix metalloproteinases. Deprotection of the N-Boc
protecting group of 15 with TFA afforded a resin-bound
benzylamine which was coupled to Fmoc-protected
b-alanine. After removal of the Fmoc group with 20%
piperidine in DMF, the resulting amino group was coupled
to butyric acid, then the product was cleaved from the resin
under two different conditions, 50% TFA in CH2Cl2 and Br2
in CH2Cl2, to give highly pure 16a *82% yield) and 16b
*92% yield), respectively. Solid-phase conversion of
alcohol 17 to N-Boc protected amine 18 was carried out
under the same conditions employed for the preparation
of 3. After deprotection of the Boc-protecting group, the
Resin-bound benzyl alcohol 12 was treated with PPh3 and
CBr4 to give benzyl bromide 13, which was subjected to the
following solid-phase reaction sequence: *1) reaction with
glycine ethyl ester to give a secondary amino group; *2)
Scheme 2. Reagents and conditions: *a) 9-BBN, THF, rt, 5 h, then BPS, DMF, Pd*PPh3)4, 2N Na2CO3, 758C, 2 days *b) PPh3, CBr4, CH2Cl2 *c) 1. H-Gly-OEt,
DMF 2. TsCl, TEA, DMAP *cat), CH2Cl2 3. LiOH, THF/H2O *8:1) 4. NH2OEt, EDC, HOBt, TEA, DMF 5. Br2, CH2Cl2 *d) 9-BBN, THF, rt, 5 h, then BPS,
DMF, Pd*PPh3)4, K3PO4, 758C, 2 days *e) 50% TFA in CH2Cl2 *f) 1. Fmoc-bAla-OH, EDC, HOBt, TEA, DMF 2. 20% piperidine in DMF 3. butyric acid,
EDC, HOBt, TEA, DMF *g) 50% TFA in CH2Cl2 *h) 9-BBN, THF, rt, 5 h, then IBAPS, DMF, Pd*PPh3)4, K3PO4, 758C, 2 days *i) N-Boc ethyl oxamate, PPh3,
DEAD, THF, then LiOH, THF/H2O *8:1) *j) 1. Fmoc-Leu-OH, EDC, HOBt, TEA, DMF 2. 20% piperidine in DMF 3. butyric acid, EDC, HOBt, TEA, DMF.

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5341
Scheme 3.
resulting amine was subjected to coupling reaction with
Fmoc-Leu-OH followed by Fmoc deprotection. Subsequent
coupling of the amine group with butyric acid and cleavage
of the product *50% TFA in CH2Cl2) afforded 19.
Nucleophilic substitution reaction of 24 with glycine ethyl
ester generated a secondary amino ester intermediate which
was allowed to react with TsCl in the presence of a catalytic
amount of DMAP. The sulfonamide 25 was obtained by
ipso-substitution of the arylsilyl linker with bromine.
2.2. Polyaromatic linkers
2.3. Heteroaromatic linkers
To expand the scope of aromatic systems tolerated by the
methodology, the functional group transformation strategy
developed for the silylated benzene ring was applied to
other aromatic systems. This would allow for construction
of a variety of polyaromatic compounds. As illustrated in
Scheme 3, lithium±halogen exchange of 1,4-dibromo-
naphthalene followed by treatment with allylchloro-
dimethylsilane at 2788C afforded silylated intermediate
20 in an 84% yield. Quenching of the lithiated 20 with
DMF provided aldehyde derivative 21. Alternatively,
formation of the Grignard reagent of 20 and subsequent
treatment with paraformaldehyde provided naphthalene
methanol 22. Loading of 22 onto bromopolystyrene under
the usual Suzuki conditions provided polymer-bound
naphthalene methanol 23. Solid-phase conversion of the
alcohol to bromide 24 was carried out by treatment with
PPh3 and CBr4 in THF. The loading level of this resin
*0.40 mmol/g) was determined by the mass balance of the
4-bromonaphthalene-1-methyl bromide, which was
obtained by cleavage of the resin-bound product with Br2.
As a representative model for a heteroaromatic system, thio-
phene transferring building block 30 was prepared as shown
in Scheme 4. Lithiation of thiophene with n-butyllithium
followed by treatment with allylchlorodimethylsilane
afforded 2-allyldimethylsilylthiophene *26) in 92% yield.
Lithiation of 26 with n-butyllithium followed by quenching
with anhydrous DMF resulted in 2-allyldimethylsilylthio-
phene-5-carboxaldehyde *27) in a 98% yield. Reduction
of the aldehyde group to alcohol 28 with sodium boro-
hydride in ethanol and subsequent coupling with bromo-
polystyrene under the usual Suzuki conditions provided
polymer-bound thiophenemethyl transferring building
block 29, which was further derivatized to the reactive
chloride analogue 30 *0.17 mmol/g). Final cleavage of the
resin-bound product with bromine afforded 31. This and the
previous Schemes 1±3 demonstrate that various aromatic
transferring building blocks could be utilized for solid-
phase synthesis of molecules containing the desired
aromatic moiety.
Scheme 4.

5342
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
Scheme 5.
2.4. Aryl-, polyaryl-, and heteroarylalanine derivatives
oligomerization side reaction. The unreacted iodine of
excess IBAPS is inert to most reaction conditions, so the
excess polymer does not interfere.
In our continuing interest in side-chain tethered amino acids
as building blocks with two diversity points as well as in the
synthesis of cyclic peptides, various amino acid derivatives
with aromatic side chains attached to the polymer through a
silyl linkage were prepared *Scheme 5). A tetramethyl-
guanidine-mediated Horner±Emmons ole®nation reaction
of naphthylaldehyde 21 with methyl 2-acetamido-2-
*dimethoxyphosphinyl)acetate in THF resulted in
exclusively the *Z)-isomer of the a-eneamide ester *32) in
a 91% yield.9 Asymmetric catalytic hydrogenation of 32
proceeded to completion to give the chiral a-amino acid
precursor 33 in a high yield *99%).10 The N-acetyl protect-
ing group of 33 was converted to a Boc protecting group by
treatment with di-tert-butyl dicarbonate in THF under
re¯uxing conditions in the presence of a catalytic amount
of DMAP followed by treatment with excess hydrazine in
THF/MeOH *1:1) to afford the desired N-Boc-protected
naphthylalanine methyl ester 34 in 92% yield for the two-
step, one-pot reaction.11 Hydroboration and Suzuki coupling
of 34 under the usual conditions produced the polymer-
bound building block 35 *0.10 mmol/g). The principal
reason for the low loading amount obtained was that the
polymer *IBAPS) was used in a 2.5-fold excess over 34.
This was done for two reasons: *1) 34 was economically
more valuable than the IBAPS resin and *2) the polymer-
bound building block was designed for use in cyclic peptide
synthesis; a low loading level of a linear peptide would be
desirable at the cyclization step to avoid a dimerization or
The same reaction sequence as described in Scheme 5 was
repeated to prepare other chiral amino acid analogues with
silylated aromatic side chain *36±38) from the correspond-
ing aldehyde precursors *Scheme 6). The silylated phenyl-
alanine derivative 36 was loaded *0.12 mmol/g) onto the
IBAPS resin under the usual Suzuki conditions and
subjected to ten solid-phase reactions leading to the
synthesis of the cytotoxic pentadepsipeptide sansalvamide
A in a 68% yield with 95% purity requiring no puri®cation.5
On the basis of this observation, other side chain modi®ed
amino acid building blocks could be used for solid-phase
synthesis of cyclic peptides in an automated fashion.
2.5. b-Arylamino acids
b-Amino acids are frequently found components in many
natural products and in therapeutic agents. As an ef®cient
tool for solid-phase synthesis of b-phenylalanine-containing
molecules, we recently reported a side-chain tethered
b-phenylalanine synthesis and its use in the preparation of
tripeptide analogues.4 Enantiomerically pure *R)-*1)-tert-
butylsul®namide12 was used as an essential chiral auxiliary/
protecting group for asymmetric induction of *R)-b-phenyl-
alanine. Prior to our knowledge of the availability of the
*S)-*2)-enantiomer we developed an alternative strategy
of silylated *l)-b-phenylalanine as a potential resin-bound
Scheme 6.

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5343
Scheme 7.
building block for the solid-phase synthesis of cyclic natural
products such as andrimid,13 dihydroperiphylline14 and the
family of astins.15 As shown in Scheme 7, commercially
available *1R,2S,5R)-*2)-menthyl-*S)-p-toluenesul®nate
was treated with LiHMDS *1.5 equiv.) at 2788C in THF,
then treated with 4-allyldimethylsilylbenzaldehyde in the
presence of cesium ¯uoride.16 The resulting *SR,R)-*1)-
methyl N-*p-tolylsul®nyl)-3-amino-3-*4-allyldimethylsilyl-
phenyl)propanoate *39) was allowed to react with the
sodium enolate of methyl acetate *2 equiv.) at 2788C for
7 h to provide the silylated *l)-b-phenylalanine precursor
40. Loading onto the IBAPS resin afforded the polymer
bound b-amino acid derivative 41. Hydrolysis of the
sul®namide group under acidic conditions and subsequent
coupling of the resulting amino group with *R)-*2)-a-
methoxy-a-*tri¯uoromethyl)-phenylacetic acid chloride
*MTPACl)17 provided the Mosher amide 42 after cleavage
from the resin using Br2 in CH2Cl2. The loading level of 41
*0.10 mmol/g) was determined by the mass balance of 42.
of functional groups for incorporation into parallel synthetic
schemes.
3. Experimental
3.1. General methods
Conventional organic solvents were purchased from Fisher.
All of the chemicals were purchased from Aldrich Chemical
Co and used without further puri®cation unless stated other-
wise. Aminomethylated polystyrene *1.02 mmol/g, 100±
200 mesh) and 4-bromopolystyrene *BPS, 1.94 mmol/g,
50±100 mesh) were obtained from NovaBiochem *San
Diego). [*COD)Rh*S,S)-Et-DuPHOS]OTf was purchased
from Strem Chemical, Inc. *Newburyport, MA). Tetra-
hydrofuran *THF) was distilled under N2 from sodium/
benzophenone ketyl and methylene chloride from calcium
hydride. Flash chromatography was performed with Merck
silica gel *230±400 mesh). TLC plates *silica gel 60-F254)
were purchased from VWR Scienti®c. All 1H NMR spectra
were recorded on Varian Gemini 300 MHz, Mercury 400, or
Inova 500 spectrometers *75, 100, or 125 MHz for 13C NMR
spectra). Chemical shifts *d) are reported down®eld from
tetramethylsilane *Me4Si) in parts per million *ppm).
Compounds were visualized with a ninhydrin spray reagent
or a UV/vis lamp. Mass spectra *EI and FAB) were recorded
on a VG Instrument VG70±250SE high-resolution mass
spectrometer. Mass spectra *APCI) were performed on a
Micromass Quattro II instrument.
1
Analysis of both the H NMR and 19F NMR spectra of the
Mosher amide showed less than 2% of the minor diastereo-
mer. As described in the previous report, 41 can be used as a
building block for combinatorial libraries of *l)-b-phenyl-
alanine containing molecules.4
2.6. Summary
In summary, we have developed general synthetic strategies
for disubstitution of aromatics with the allyldimethylsilyl
group and various functional groups. Under mild reaction
conditions *9-BBN and Suzuki coupling), the allyl group
was attached to a halide-substituted polymer, and the
other functional groups on the aromatics were elaborated
by solid-phase reactions. This process proves to be useful
for the rapid preparation of aromatic-, polyaromatic- and
heteroaromatic-containing molecules. If a certain nonpolar
aromatic moiety plays an important role in the biological
activity of a compound, an ef®cient way to synthesize a
multitude of analogues would be to attach the aromatic
moiety to the polymer and derivatize other parts of the
molecule by either parallel or combinatorial methods. The
silylated building block strategy we described here can
provide various polymer-bound aromatics with a variety
3.1.1. 1-Allyldimethylsilyl-4-bromobenzene -1). To a
solution of 1,4-dibromobenzene *28.3 g, 120 mmol) in
dried THF *300 mL) at 2788C was added n-butyllithium
*40.0 mL, 2.5 M solution in hexanes, 100 mmol) over a
period of 20 min. After being stirred at 2788C for 30 min,
allylchlorodimethylsilane *13.5 g, 100 mmol) in THF
*50 mL) was added dropwise over a period of 20 min, and
the reaction mixture was warmed to room temperature.
After stirring for 1 h at room temperature the reaction
mixture was concentrated, and the residue was extracted
with ether and brine. The organic layer was dried
*Na2SO4) and distilled under reduced pressure to provide a

5344
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
1
leave a colorless oil *287 mg, 94%); H NMR *300 MHz,
colorless liquid *21.9 g, 82%, bp 728C/0.1 mmHg); 1H
NMR *300 MHz, CDCl3) d 0.31 *s, 6H), 1.77 *d,
Jˆ8.07 Hz, 2H), 4.87 *m, 1H), 4.92 *m, 1H), 5.78 *ddt,
Jˆ17.55, 9.51, and 8.07 Hz, 1H), 7.41 *d, Jˆ8.28 Hz,
2H), 7.52 *d, Jˆ8.28 Hz, 2H); 13C NMR *75 MHz,
CDCl3) 23.5 *2 C), 23.6, 113.8, 123.9, 130.9 *2 C),
134.2, 135.3 *2 C), 137.5; HRMS calcd for C11H15BrSi
254.0127 and 254.0107, found 254.0128 and 256.0109.
CDCl3) d 0.30 *s, 6H), 1.47 *s, 9H), 1.76 *d, Jˆ7.83 Hz,
2H), 4.28 *d, Jˆ6.02 Hz, 2H), 4.86 *s, 1H), 4.90 *d,
Jˆ6.61 Hz), 5.31 *bs, NH, 1H), 5.78 *ddt, Jˆ16.53, 10.23,
8.14 Hz, 1H), 7.27 *d, Jˆ7.86 Hz, 2H), 7.49 *d, Jˆ7.86 Hz,
2H); 13C NMR *75 MHz, CDCl3) 23.2 *2C), 23.9, 28.7
*3C), 44.8, 79.4, 113.7, 127.1 *2C), 134.1 *2C), 134.7,
137.5, 140.3, 156.3; HRMS *EI) calcd for C17H27NO2Si
305.1811, found 305.1795.
3.1.2. Methyl 4-allyldimethylsilylbenzyl alcohol -2). To a
suspension of activated magnesium turning *294 mg,
12 mmol) in dry THF *20 mL) were added a piece of I2
and ethyl iodide *50 mL). The reaction mixture was heated
to re¯ux until the red color disappeared. Heating *658C) of
the suspension was continued while a solution of 1-allyl-
dimethylsilyl-4-bromobenzene *1, 2.6 g, 10 mmol) in THF
*20 mL) was added over a period of 15 min. Upon comple-
tion of the addition, the gray solution was heated further for
20 min. After the reaction was cooled to room temperature,
paraformaldehyde *0.9 g, 30 mmol) was added, and the
reaction mixture was stirred for 3 h at room temperature.
The clear solution was poured into a saturated NH4Cl
*10 mL) with vigorous stirring, and the suspension was
®ltered through a short pad of Celite. The solution was
diluted with ethyl acetate *20 mL), and the organic layer
was separated, dried over Na2SO4 and concentrated to
3.2.2. 4-Allyldimethylsilylbenzyl bromide -4). To a
mixture of 4-allyldimethylsilylbenzyl alcohol *2, 17.7 g,
86 mmol) and triphenylphosphine *22.5 g, 86 mmol) in
dichloromethane *200 mL) at 08C was added carbon tetra-
bromide *28.4 g, 86 mmol) portionwise. The reaction
mixture was stirred at room temperature for 2 h and concen-
trated. The residue was triturated with ethyl acetate
*200 mL) and the precipitated solid was removed by ®ltra-
tion. The ®ltrate was concentrated, and the residue was
triturated with ethyl acetate/hexanes *1:1), then the precipi-
tated solid was removed by ®ltration *this procedure was
repeated three times). After drying and concentration of the
residue, column chromatography *1:20 ethyl acetate/
1
hexanes) gave a colorless liquid *15.7 g, 68%); H NMR
*300 MHz, CDCl3) d 0.40 *s, 6H), 1.87 *d, Jˆ8.01 Hz,
2H), 4.57 *s, 2H), 4.96 *s, 1H), 5.00 *m, 1H), 5.88 *ddt,
Jˆ16.95, 10 47, 8.01 Hz, 1H), 7.48 *d, Jˆ8.01 Hz, 2H),
7.61 *d, Jˆ8.01 Hz, 2H); 13C NMR *75 MHz, CDCl3)
23.3 *2C), 23.7, 33.7, 113.8, 128.4 *2C), 134.3 *2C),
134.5, 138.5, 139.3; HRMS calcd for C12H17BrSi
268.0283 and 270.0263, found 268.0216 and 270.0232.
1
leave a colorless liquid *1.4 g, 70%); H NMR *300 MHz,
CDCl3) d 0.30 *s, 6H), 1.77 *dt, Jˆ8.10, 1.05 Hz, 2H), 2.28
*bs, OH, 1H), 4.66 *s, 2H), 4.85 *s, 1H), 4.92 *dt, Jˆ8.10,
1.05 Hz, 1H), 5.81 *ddt, Jˆ10 20, 8.70, 8.10 Hz, 1H), 7.36
*d, Jˆ8.10 Hz, 2H), 7.53 *d, Jˆ8.10 Hz, 2H); 13C NMR
*75 MHz, CDCl3) 23.3 *2C), 23.8, 65.2, 113.5, 126.4
*2C), 134.0 *2C), 134.6, 138.0, 141.8.
3.2.3. Methyl 4-allyldimethylsilylbenzoate -6). To a
suspension of activated magnesium turning *490 mg,
20 mmol) in dry THF *20 mL) were added a piece of I2
and ethyl iodide *50 mL). The reaction mixture was heated
to re¯ux until the red color disappeared. Heating *658C) of
the suspension was continued while a solution of 1-allyl-
dimethylsilyl-4-bromobenzene *1, 2.6 g, 10 mmol) in THF
*20 mL) was added over a period of 15 min. Upon comple-
tion of the addition, the gray solution was heated further for
20 min. After the reaction was cooled to room temperature,
anhydrous CO2 was gently bubbled through the reaction
mixture for 5 min and stirred further for 10 min. The clear
solution was poured into a saturated solution of NH4Cl
*10 mL) with vigorous stirring, and the suspension was
®ltered through a short pad of Celite. The solution was
diluted with ethyl acetate *20 mL), and the organic layer
was separated, dried over Na2SO4 and concentrated to
leave a white solid on standing. Without further puri®cation,
the solid was dissolved in MeOH *40 mL), and the solution
was treated with a catalytic amount of thionyl chloride
*50 mL), then stirred for 16 h at room temperature. The
reaction mixture was concentrated under reduced pressure,
and the resulting crude product was puri®ed by column
chromatography *1:20 ethyl acetate/hexanes) to afford a
3.2. Reaction of 4-allyldimethylsilylbenzyl alcohol with
N-Boc-ethyl oxamate
To a stirred mixture of 4-allyldimethylsilylbenzyl alcohol
*2, 413 mg, 2 mmol), N-Boc-ethyl oxamate *478 mg,
2.2 mmol), and triphenylphosphine *577 mg, 2.2 mmol) in
dry THF *15 mL) was added diethyl azodicarboxylate
*350 mL, 2.2 mmol). After being stirred for 1 h at room
temperature, the reaction mixture was concentrated, and
the residue was triturated with 1:6 ethyl acetate/hexanes.
The precipitated triphenylphosphine oxide was ®ltered.
The ®ltrate was concentrated, and the residue was puri®ed
on silica gel with 1:6 ethyl acetate/hexanes to afford a color-
less oil *722 mg, 89%); 1H NMR *300 MHz, CDCl3) d 0.27
*s, 2H), 1.36 *t, Jˆ7.50 Hz, 3H), 1.43 *s, 9H), 1.73 *d,
Jˆ8.40 Hz, 2H), 4.35 *q, Jˆ7.50 Hz, 2H), 4.80±4.87
*4H), 5.74 *m, 1H), 7.29 *d, Jˆ7.50 Hz, 2H), 7.47 *d,
Jˆ7.50 Hz, 2H); 13C NMR *75 MHz, CDCl3) 23.3, 14.0,
23.9, 27.9, 46.4, 62.4, 85.6, 113.6, 127.0, 127.7, 133.7,
134.5, 134.9, 137.4, 151.8, 162.0, 163.6; HRMS *EI)
calcd for C21H31NO5Si 405.1973, found 405.1972.
1
colorless oil *1.5 g, 64%); H NMR *300 MHz, CDCl3) d
3.2.1. N-Boc-4-allyldimethylsilylbenzylamine -3). The
oxamate derivative obtained above *406 mg, 1 mmol) was
vigorously stirred in a heterogeneous solution of LiOH
*210 mg, 5 mmol) in THF/H2O *4:1, 25 mL) for 2 h. The
reaction mixture was diluted with H2O *30 mL) and
extracted with methylene chloride *40 mL). The organic
layer was dried *Na2SO4) and concentrated in vacuo to
0.33 *s, 6H), 1.79 *d, Jˆ8.0 Hz, 2H), 3.93 *s, 1H), 4.87 *s,
1H), 4.90 *d, Jˆ5.0 Hz, 1H), 5.77 *m, 1H), 7.61 *d,
Jˆ8.0 Hz, 2H), 8.03 *d, Jˆ8.0 Hz, 2H); 13C NMR
*75 MHz, CDCl3) 23.4, 23.6, 52.3, 114.1, 128.7, 130.7,
133.9, 134.3, 145.2, 167.4. HRMS *EI) calcd for
C13H18O2Si 234.1076, found 234.1077.

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5345
3.2.4. 4-Allyldimethylsilylbenzaldehyde -7). To a solution
of 1-allyldimethylsilyl-4-bromobenzene *1, 1.3 g, 5 mmol)
in dry THF *70 mL) at 2788C was added t-butyllithium
*3.0 mL, 1.7 M solution in pentane, 5.1 mmol) over a period
of 10 min. After 30 min of stirring at 2788C, anhydrous
DMF *750 mL, 10 mmol) was added dropwise. The reaction
mixture was stirred further for 1 h and warmed to room
temperature. Concentrated NH4Cl *2 mL) was added to
the solution, and the reaction mixture was concentrated.
The residue was extracted with ethyl acetate *20 mL) and
brine *5 mL), and the organic layer was dried *Na2SO4) and
concentrated. The crude product was puri®ed by column
chromatography *1:15 ethyl acetate/hexanes) to afford a
solution of oxidizing agent [mixed solution of CrO3
*13 g), H2SO4 *11 mL), and water *40 mL)]. Upon addition
of each portion of Jones reagent to the vigorously stirred
reaction mixture, the orange color of the solution rapidly
changed to light green, and the end point was determined
when the orange color persisted. Acetone was carefully
decanted from the ¯ask and evaporated to leave an orange
colored oil which was extracted with brine/ethyl acetate
*1:4, 50 mL). The organic layer was dried *Na2SO4),
concentrated, and the residue was puri®ed by column chro-
matography *1:4 ethyl acetate/hexanes) to afford a colorless
oil *2.1 g, 71%); 1H NMR *300 MHz, CDCl3) d 0.36 *s, 6H),
1.84 *d, Jˆ8.10 Hz, 2H), 3.72 *s, 2H), 4.92 *m, 1H), 4.97
*m, 1H), 5.86 *ddt, Jˆ16.80, 10.35, 8.01 Hz, 1H), 7.36 *d,
Jˆ7.98 Hz, 2H), 7.58 *d, Jˆ7.98 Hz, 2H) 11.38 *bs, 1H);
13C NMR *75 MHz, CDCl3) 23.3 *2C), 23.7, 41.2, 113.6,
128.9 *2C), 134.0, 134.1 *2C), 134.6, 137.7, 178.3; HRMS
*M2CH3) calcd for C12H15O2Si 219.0841, found 219.0846.
1
colorless oil *860 mg, 82%); H NMR *300 MHz, CDCl3)
d 0.32 *s, 6H), 1.78 *d, Jˆ8.10 Hz, 2H), 4.84 *s, 1H), 4.89
*m, 1H), 5.76 *m, 1H), 7.67 *d, Jˆ8.10 Hz, 2H), 7.85 *d,
Jˆ8.10 Hz, 2H), 10.05 *s, 1H); 13C NMR *75 MHz, CDCl3)
23.4 *2C), 23.5, 114.2, 128.8 *2C) 133.7, 134.4, *2C),
136.9, 147.6, 192.8; HRMS calcd for C12H16OSi
204.0971, found 204.0972.
3.4.1. 4-Allyldimethylsilylphenyacetaldehyde -11). To a
suspension of pyridinium chlorochromate *8.6 g, 40
mmol) in dry CH2Cl2 *150 mL) was added 4-allyldimethyl-
silylphenethyl alcohol *8, 4.4 g, 20 mmol) in one portion,
and the mixture was stirred for 3 h at room temperature
under an N2 atmosphere. The reaction mixture was ®ltered
through Celite, and the combined solution of ®ltrate and
washings *CH2Cl2) were concentrated and puri®ed by
column chromatography *1:10 ethyl acetate/hexanes) to
3.3. 4-Allyldimethylsilylphenethyl alcohol -8)
To a solution 1-allyldimethylsilyl-4-bromobenzene *1,
5.1 g, 20 mmol) in dried THF *30 mL) at 2788C was
added t-butyllithium *12.9 mL, 1.7 M solution in pentane,
22 mmol) over a period of 5 min. The reaction mixture was
allowed to warm to room temperature and stirred further for
1 h. The solution was cooled to 2788C and transferred to a
cooled *2788C) solution of ethylene oxide *3.5 g, 78 mmol)
in dry THF *50 mL) via cannula. The reaction mixture was
warmed to room temperature over 30 min and quenched
with saturated NH4Cl *5 mL). After evaporation of THF,
the residue was extracted with ethyl acetate and water.
The organic layer was dried *Na2SO4) and concentrated to
give an oil which was distilled to afford the desired product
1
afford a colorless oil *2.0 g, 46%); H NMR *300 MHz,
CDCl3) d 0.34 *s, 6H), 1.81 *d, Jˆ8.40 Hz, 2H), 3.72 *s,
2H), 4.89 *s, 1H), 4.93 *d, Jˆ7.20 Hz, 1H), 5.81 *m, 1H),
7.26 *d, Jˆ7.80 Hz, 2H), 7.57 *d, Jˆ7.80 Hz, 2H), 9.79 *s,
1H); 13C NMR *75 MHz, CDCl3) 23.2 *2C), 23.9, 50.8,
113.8, 129.3 *2C), 132.9, 134.6 *2C), 134.7, 138.0, 199.6.
3.4.2. Preparation of resin 12. To a solution *4-allyl-
dimethylsilyl)benzyl alcohol *2, 2.1 g, 10 mmol) in dry
THF *50 mL) under an N2 atmosphere was added 9-BBN
*20 mL, 0.5 M solution in THF, 10 mmol) dropwise at 08C.
The mixture was gradually warmed to room temperature
and stirred for 5 h. Pd*PPh3)4 *70 mg), 4-bromopolystyrene
*5.0 g, 1.94 mmol/g), 2N aqueous Na2CO3 *10 mL,
20 mmol), and DMF *20 mL) were added. The reaction
¯ask and re¯ux condenser were wrapped with aluminum
foil, and the mixture was re¯uxed for 24 h. Pd*PPh3)4
*70 mg) was added to the reaction mixture which was
re¯uxed for an additional 24 h. The resin was ®ltered and
washed with THF *once), 1:1 THF/water *twice), water
*twice), methanol *twice), and CH2Cl2 *twice).
1
as a colorless oil *2.9 g, 67%, bp 1008C/0.1 mmHg); H
NMR *300 MHz, CDCl3) d 0.32 *s, 6H), 1.72 *bs, OH,
1H), 1.79 *d, Jˆ8.01 Hz, 2H), 2.90 *t, Jˆ6.60 Hz, 2H),
3.89 *t, Jˆ6.60 Hz, 2H), 4.88 *m, 1H), 4.92 *m, 1H), 5.83
*ddt, Jˆ16.83, 10.20, 8.04 Hz, 2H), 7.27 *d, Jˆ8.04 Hz,
2H), 7.52 *d, Jˆ8.04 Hz, 2H); 13C NMR *75 MHz,
CDCl3) 23.3 *2C), 23.8, 39.3, 63.6, 113.5, 128.6 *2C),
134.0 *2C), 134.7, 136.5, 139.5; HRMS *M2CH3) calcd
for C12H17OSi 205.1048, found 205.1045.
3.3.1. N-Boc-4-allyldimethylsilylphenethylamine -9).
This compound was synthesized according to the procedure
for 3 and puri®ed by column chromatography *1:8 ethyl
1
acetate/hexanes) to afford a colorless oil *83%); H NMR
*300 MHz, CDCl3) d 0.32 *s, 6H), 1.48 *s, 9H), 1.79 *d,
Jˆ7.5 Hz, 2H), 2.83 *app t, Jˆ6.9 Hz, 2H), 3.42 *m, 2H),
4.74 *bs, NH, 1H), 4.88 *s, 1H), 4.92 *d, Jˆ7.8 Hz, 1H),
5.81 *m, 1H), 7.24 *d, Jˆ7.8 Hz, 1H), 7.50 *d, Jˆ7.8 Hz,
2H); 13C NMR *75 MHz, CDCl3) 23.1, 24.0, 28.7, 36.5,
42.0, 79.4, 113.7, 128.6, 134.2, 134.9, 136.6, 140.2, 156.2;
HRMS *EI) calcd for C18H29NO2Si 319.1967, found
319.1984.
3.4.3. Polymer bound -4-alkyldimethylsilyl)benzyl bro-
mide -13). To the above described resin *12, 3 g) swelled
in CH2Cl2 *120 mL) at 08C was added PPh3 *2.6 g,
10 mmol) and CBr4 *3.3 g, 10 mmol), and the reaction
mixture was stirred for 4 h at 08C. The resin was ®ltered
and washed with CH2Cl2 *twice), methanol *twice), 1:1
methanol/water *twice), methanol *twice), CH2Cl2 *twice),
then dried under reduced pressure. An aliquot of the resin
*200 mg) was treated with a solution of CH2Cl2 *7 mL) and
Br2 *150 mL) for 5 min. The cleavage solution was
removed, and the resin was rinsed with CH2Cl2 *3 mL).
Concentration of the combined ®ltrates gave the known
4-bromobenzyl bromide *18.5 mg, 0.37 mequiv./g; purity
3.4. 4-Allyldimethylsilylphenylacetic acid -10)
To a solution of 4-allyldimethylsilylphenethyl alcohol *8,
2.8 g, 12.7 mmol) in acetone *60 mL) was added a stock

5346
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
1
was determined to be greater than 95% based on the H
NMR spectrum).
performed with butyric acid *91 mL, 1 mmol), EDC
*1 mmol), HOBT´H2O *1 mmol), and Et3N *1 mmol) in
DMF *8 mL) for 16 h at room temperature. After washing
with DMF, MeOH/H2O, MeOH, CH2Cl2, and drying, a
portion of the resin *250 mg) was treated with TFA/
CH2Cl2 *1:1, 14 mL) for 24 h at room temperature. The
cleavage solution was separated, and the resin was rinsed
with CH2Cl2 *3 mL). Concentration of the ®ltrates gave a
white solid *16a, 5.1 mg, 82%, purity was determined to be
higher than 95% based on the 1H NMR spectrum); 1H NMR
*500 MHz, CDCl3) d 0.91 *t, Jˆ6.3 Hz, 3H), 1.59 *m, 2H),
2.23 *m, 2H), 2.71 *m, 2H), 3.59 *m, 2H), 4.44 *s, 2H),
7.20±7.38 *5H); 13C NMR *125 MHz, CDCl3) 13.5, 19.3,
35.0, 36.8, 37.6, 44.8, 128.1, 128.4, 129.1, 136.3, 173.8,
178.2; HRMS *EI) calcd for C14H20N2O2 248.1524, found
248.1525.
3.4.4. N-Hydroxy-a-[[-4-methylphenyl)sulfonyl]-4-bromo-
benzyl)amino] acetamide -14) from polymer bound
-4-alkyldimethylsilyl)benzyl bromide. To an aliquot of
resin 13 *150 mg, 0.37 mequiv./g) swelled in DMF *7 mL)
were added glycine ethyl ester hydrochloride *10 equiv.)
and DIPEA *10 equiv.). The reaction mixture was agitated
for 16 h at room temperature, then washed with DMF
*twice), water *twice), methanol *twice), CH2Cl2 *twice).
To the resin swelled in CH2Cl2 *7 mL) were added
p-toluenesulfonyl chloride *10 equiv.), Et3N *10 equiv.),
and DMAP *cat). After agitation for 20 h at room tempera-
ture the resin was washed with CH2Cl2 *twice), methanol
*twice), CH2Cl2 *twice). The resin was agitated with LiOH
*5 equiv.) in THF/H2O *8:1, 9 mL) for 8 h, then washed with
THF *twice), CH2Cl2 *twice), methanol *twice) and
dried. Coupling of the resin bound amine was performed
with O-ethyl hydroxylamine *3 equiv.), EDC *3 equiv.),
HOBT´H2O *3 equiv.), Et3N *3 equiv.) in DMF *8 mL) for
20 h at room temperature. After washing with DMF, MeOH/
H2O, MeOH, CH2Cl2, and drying, the resin swelled in
CH2Cl2 *7 mL) was added Br2 *100 mL), and the mixture
was stirred for 10 min at room temperature. Filtration of the
cleavage solution from the resin followed by evaporation
3.4.7. N--4-Bromobenzyl)-3-butyrylamidopropanamide
-16b). The same procedure as described above was repeated
except that the cleavage of the ®nal product on the resin
*250 mg) was carried out with a solution of Br2 *100 mL) in
CH2Cl2 *8 mL) for 20 min. The cleavage solution was
®ltered, and the resin was rinsed with CH2Cl2 *3 mL).
Concentration of the combined ®ltrates gave an orange
powder *16b, 11.5 mg, 92%, purity was determined to be
higher than 95% based on the 1H NMR spectrum); 1H NMR
*500 MHz, CDCl3) d 1.03 *t, Jˆ7.25 Hz, 3H), 1.78 *app q,
Jˆ7.25 Hz, 2H), 2.57 *t, Jˆ7.25 Hz, 2H), 3.21 *bs, 2H),
3.71 *bs, 2H), 4.53 *d, Jˆ4 Hz, 2H), 7.29 *d, Jˆ8.00 Hz,
2H), 7.51 *d, Jˆ8.00 Hz, 2H); 13C NMR *125 MHz, CDCl3)
13.9, 19.3, 35.9, 37.0, 45.1, 122.6, 130.5, 132.3, 134.3,
176.0, 180.4; HRMS calcd for C14H19BrN2O2 326.0630
and 328.0609, found 326.0630 and 328.0625.
1
yielded 14 *21 mg, 87%); H NMR *300 MHz, CDCl3) d
1.15 *t, Jˆ7.05 Hz, 3H), 2.44 *s, 3H), 3.65 *bs, 2H), 3.72 *q,
Jˆ7.05 Hz, 2H), 4.31 *bs, 2H), 7.16 *d, Jˆ8.40 Hz, 2H),
7.34 *d, Jˆ7.80 Hz, 2H), 7.44 *d, Jˆ8.40 Hz, 2H), 7.72
*d, Jˆ7.80 Hz, H); 13C NMR *75 MHz, CDCl3) 13.5,
21.8, 49.8, 53.5, 72.5, 122.7, 127.7 *2C), 130.3 *2C),
130.9 *2C), 132.3 *2C), 133.9, 134.8, 144.7, 169.6.
3.4.5. Preparation of resin 15. To a solution of N-Boc-4-
allyldimethylsilylbenzylamine *3, 611 mg, 2 mmol) in dry
THF *4 mL) under a N2 atmosphere was added 9-BBN
*4 mL, 0.5 M solution in THF, 2 mmol) dropwise at 08C.
The mixture was gradually warmed to room temperature
and stirred for 2 h. THF was evaporated under reduced
pressure, and the reaction intermediate was dissolved in
toluene *8 mL). After adding ground K3PO4 *424 mg,
2 mmol), 4-bromopolystyrene *1.0 g, 1.94 mmol/g), and
Pd*PPh3)4 *70 mg), the reaction mixture was degassed by
bubbling with N2 and sealed. The reaction ¯ask was
wrapped with aluminum foil and heated at 758C for 2
days. The resin was ®ltered and washed with MeOH
*once), 1:1 MeOH/water *twice), water *twice), methanol
*twice), CH2Cl2 *twice), then dried under reduced pressure.
3.4.8. Preparation of -3-iodobenzoylamidomethyl)poly-
styrene -IBAPS). To pre-swelled aminomethylated poly-
styrene resin *7 g, 1.02 mmol/g) in DMF *100 mL) were
added 3-iodobenzoic acid *12.4 g, 50 mmol), HOBT´H2O
*6.8 g, 50 mmol), diisopropylethylamine *8.7 mL, 50
mmol), and 1,3-diisopropylycarbodiimide *7.8 mL,
50 mmol). The suspension was stirred for 2 days at 408C,
and the resin was washed with DMF, MeOH, dichloro-
methane, and MeOH and dried under reduced pressure to
provide the functionalized resin.
3.4.9. Hydroboration and Suzuki coupling of 4-allyldi-
methylsilylphenethylalcohol -8) to IBAPS. To a solution
of 4-allyldimethylsilylphenethyl alcohol *8, 440 mg,
2 mmol) in dry THF *4 mL) under a N2 atmosphere was
added 9-BBN *4 mL, 0.5 M solution in THF, 2 mmol) drop-
wise at 08C. The mixture was gradually warmed to room
temperature and stirred for 4 h. THF was evaporated under
reduced pressure, and the reaction intermediate was
dissolved in toluene *8 mL). After adding ground K3PO4
*424 mg, 2 mmol), the IBAPS resin prepared above
*1.1 g), and Pd*PPh3)4 *70 mg), the reaction mixture was
degassed by bubbling with N2 and sealed. The reaction
¯ask was wrapped with aluminum foil and heated at 808C
for 24 h. The resin *17) was ®ltered and washed with MeOH
*once), 1:1 MeOH/water *twice), water *twice), methanol
*twice), CH2Cl2 *twice), then dried under reduced pressure.
An aliquot of resin *100 mg) was treated with a solution of
Br2 *50 mL) in CH2Cl2 *8 mL) for 20 min. The cleavage
3.4.6. N-Benzyl-3-butyrylamidopropanamide -16a). An
aliquot of the resin 15 *500 mg) was treated with a solution
of thioanisole *100 mL) and 50% TFA/CH2Cl2 *7 mL) for
5 min followed by washing with CH2Cl2 *4£8 mL). The
resin was further washed with DMF *4£8 mL) and treated
with Fmoc-b-Ala-OH *312 mg, 1 mmol), EDC *192 mg,
1 mmol), HOBT´H2O *135 mg, 1 mmol), and Et3N
*140 mL, 1 mmol) in DMF *8 mL) for 15 h at room tempera-
ture and washed. The loading level of dried resin determined
by the Fmoc release UV/vis assay was 0.1 mmol/g. The
resin was stirred in 20% piperidine/DMF *8 mL) for
20 min, then washed with DMF, MeOH, CH2Cl2, and
DMF. Peptide coupling of the resin bound amine was

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5347
solution was ®ltered, and the resin was rinsed with CH2Cl2
*3 mL). Concentration of the combined ®ltrates gave
2-bromophenethyl alcohol *4 mg, loading level was deter-
CDCl3) 21.5 *2 C), 24.5, 114.3, 126.0, 126.9, 127.1,
128.6, 128.8, 129.7, 132.2, 134.2, 134.7.
1
mined to be 0.20 mmol/g); H NMR *500 MHz, CDCl3) d
3.4.11. 1-Allyldimethylsilyl-4-naphthaldehyde -21). To a
solution 1-allyldimethylsilyl-4-bromonaphthalene *20, 3.0 g,
10 mmol) in dry THF *150 mL) at 2788C was added
t-butyllithium *6.0 mL, 1.7 M solution in pentane,
10.2 mmol) over a period of 10 min. After 30 min of stirring
at 2788C, anhydrous DMF *1.5 mL, 20 mmol) was added
dropwise. The reaction mixture was stirred further for 1 h
and warmed to room temperature. Concentrated NH4Cl
*5 mL) was added to the solution, and the reaction mixture
was concentrated. The residue was extracted with ethyl
acetate *50 mL) and brine *10 mL), and the organic layer
was dried *Na2SO4) and concentrated. The crude product
was puri®ed by column chromatography *1:20 ethyl acetate/
2.11 *bs, OH, 1H), 2.86 *t, Jˆ6.5 Hz, 2H), 3.88 *t,
Jˆ6.5 Hz, 2H), 7.14 *d, Jˆ8.0 Hz, 2H), 7.46 *d,
Jˆ8.0 Hz, 2H); 13C NMR *125 MHz, CDCl3) 38.7, 63.7,
129.9, 131.0, 131.9, 132.3.
To an agitated mixture of resin prepared above *500 mg,
2.0 mmol/g), triphenylphosphine *4 equiv.) and N-Boc-
ethyl oxamate *4 equiv.) in THF *8 mL) was added diethyl-
azodicarboxylate *4 equiv.), and the mixture was further
agitated for 16 h at room temperature. After washing with
THF, the resin was transferred to a round bottomed ¯ask and
stirred with LiOH *5 equiv.) in THF/H2O *5:1, 12 mL) at
408C for 16 h. The resin was washed with THF, MeOH, and
CH2Cl2 and treated with a solution of thioanisole *50 mL)
and 50% TFA/CH2Cl2 *8 mL) for 5 min, then washed again
with CH2Cl2. The resin was further washed with DMF and
treated with Fmoc-Leu-OH *4 equiv.), EDC *4 equiv.),
HOBT´H2O *4 equiv.), and Et3N *4 equiv.) in DMF
*8 mL) for 16 h at room temperature and washed with
DMF, MeOH, and CH2Cl2. The loading level of dried
resin, determined by the Fmoc release UV/vis assay, was
0.18 mmol/g. The resin was stirred in 20% piperidine/DMF
*8 mL) for 20 min, then washed with DMF, MeOH, CH2Cl2,
and DMF. Peptide coupling of the resin bound amine was
performed with butyric acid *4 equiv.), EDC *4 equiv.),
HOBT´H2O *4 equiv.), and Et3N *4 equiv.) in DMF
*8 mL) for 16 h at room temperature. After being washed
with DMF, MeOH/H2O, MeOH, and CH2Cl2, and dried, a
portion of the resin *100 mg) was treated with TFA/CH2Cl2
*1:1, 8 mL) for 24 h at room temperature. The cleavage
solution was separated, and the resin was rinsed with
CH2Cl2 *3 mL). Concentration of the combined ®ltrates
gave a colorless oil *19, purity was determined to be higher
than 95% based on the 1H NMR spectrum); 1H NMR
*500 MHz, CDCl3) d 0. 0.86 *m, 6H), 0.94 *t, Jˆ7.50 Hz,
3H), 1.20±1.63 *3H), 1.65 *q, Jˆ7.5 Hz, 2H), 2.27 *t,
Jˆ7.5 Hz, 2H), 2.84 *m, 2H), 3.57 *m, 2H), 4.51 *m, 1H),
7.17 *d, Jˆ7.5 Hz, 2H), 7.31 *d, Jˆ7.5 Hz, 2H); 13C NMR
*125 MHz, CDCl3) 13.5, 19.3, 22.2, 22.6, 24.9, 35.1, 38.1,
40.7, 41.5, 127.0, 128.9, 129.0, 137.9, 173.6, 176.3.
1
hexanes) to afford a colorless oil *2.1 g, 88%); H NMR
*300 MHz, CDCl3) d 0.53 *s, 6H), 2.03 *d, Jˆ7.80 Hz,
2H), 4.88±4.97 *2H), 5.79 *m, 1H), 7.60±7.70 *2H), 7.84
*d, Jˆ7.50 Hz, 1H), 7.89 *d, Jˆ6.90 Hz, 1H), 8.20 *d,
Jˆ8.10 Hz, 1H), 9.35 *d, Jˆ8.10 Hz, 1H), 10.39 *s, 1H);
13C NMR *75 MHz, CDCl3) 21.7 *2C), 24.2, 114.5, 126.1,
126.9, 128.6, 128.7, 132.9, 134.3, 135.4, 137.6, 146.8, 194.1.
3.4.12. 1-Allyldimethylsilyl-4-naphthalenemethanol -22).
To a vigorously stirred suspension of activated magnesium
turnings *480 mg, 20 mmol) in dry THF *70 mL) were
added a piece of I2 and ethyl iodide *50 mL). The reaction
mixture was heated to re¯ux until the red color disappeared.
Heating *658C) of the suspension was continued while a
solution of 1-allyldimethylsilyl-4-bromonaphthalene *20,
3.0 g, 10 mmol) in THF *20 mL) was added over a period
of 15 min. Upon completion of the addition, the gray solu-
tion was heated further for 10 min and transferred via
cannula to a separate ¯ask containing paraformaldehyde
*700 mg) in THF *20 mL). After stirring the reaction
mixture at 508C for 30 min, concentrated NH4Cl *10 mL)
was added to the solution, and the reaction mixture was
concentrated. The residue was extracted with ethyl acetate
*70 mL) and brine *30 mL), and the organic layer was dried
*Na2SO4) and concentrated. The crude product was puri®ed
by column chromatography *1:5 ethyl acetate/hexanes) to
1
afford a colorless oil *1.8 g, 75%); H NMR *300 MHz,
CDCl3) d 0.58 *s, 6H), 2.08 *d, Jˆ7.50 Hz, 2H), 3.21 *s,
OH, 1H), 4.93±5.03 *2H), 5.04 *s, 2H), 5.89 *m, 1H), 7.47
*d, Jˆ7.20 Hz, 2H), 7.53±7.64 *2H), 7.69 *d, Jˆ6.90 Hz,
1H), 8.11 *d, Jˆ8.80 Hz, 1H), 8.23 *d, Jˆ8.80 Hz, 1H); 13C
NMR *75 MHz, CDCl3) 21.50 *2 C), 24.6, 63.5, 114.1,
124.5, 124.8, 125.9, 126.8, 129.1, 131.4, 133.7, 135.0,
137.3, 137.5, 138.3.
3.4.10. 1-Allyldimethylsilyl-4-bromonaphthalene -20).
To a solution 1,4-dibromonaphthalene *28.6 g, 0.1 mol) in
dry THF *800 mL) at 2788C was added t-butyllithium
*59.0 mL, 1.7 M solution in pentane, 0.1 mol) over a period
of 20 min. After 30 min stirring at 2788C, allylchloro-
dimethylsilane *13.5 g, 0.1 mol) in THF *25 mL) was
added dropwise over a period of 30 min. The reaction
mixture was stirred further for 1 h and warmed to room
temperature. Concentrated NH4Cl *5 mL) was added to
the solution, and the reaction mixture was concentrated.
The resulting yellow oil was concentrated, extracted with
ethyl acetate/water, and the organic layer was dried and
concentrated. The crude product was Kugelrohr distilled
3.4.13. Preparation of resin 23. To a solution 1-allyl-
dimethylsilyl-4-naphthalenemethanol *22, 750 mg, 3.1 mmol)
in dry THF *20 mL) under a N2 atmosphere was added
9-BBN *6.2 mL, 0.5 M solution in THF, 3.1 mmol) drop-
wise at 08C. The mixture was gradually warmed to
room temperature and stirred for 5 h. Pd*PPh3)4 *60 mg),
4-bromopolystyrene *1.5 g, 1.94 mmol/g), 2N aqueous
Na2CO3 *3.1 mL, 6.2 mmol), and DMF *10 mL) were
added. The reaction ¯ask and re¯ux condenser were
wrapped with aluminum foil, and the mixture was heated
to 658C for 24 h. Pd*PPh3)4 *60 mg) was added to the reac-
tion mixture which was heated to 658C for 24 h. The resin
1
to give a colorless oil *25.6 g, 84%); H NMR *300 MHz,
CDCl3) d 0.57 *s, 6H), 2.07 *d, Jˆ8.10 Hz, 2H), 4.94±5.04
*2H), 5.87 *ddt, Jˆ16.80, 10.20, 8.10 Hz, 1H), 7.56 *d,
Jˆ7.20 Hz, 1H), 7.61±7.70 *2H), 7.83 *d, Jˆ7.20 Hz,
1H), 8.19 *m, 1H), 8.43 *m, 1H); 13C NMR *75 MHz,

5348
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
was ®ltered and washed with THF *once), 1:1 THF/water
*twice), water *twice), methanol *twice), and CH2Cl2
*twice). The resin was used directly for the next reaction.
3.4.17. 2-Allyldimethylsilylthiophene-5-carboxaldehyde
-27). To a solution of 2-allyldimethylsilylthiophene *26,
10.6 g, 58.5 mmol) in dry THF *300 mL) at 2788C was
added n-butyllithium *23.4 mL, 2.5 M solution in hexanes,
58.5 mmol) over a period of 10 min. After 30 min of stirring
at 2788C, anhydrous DMF *6.8 mL, 87.8 mmol) was added
dropwise. The reaction mixture was stirred for 1 h and
warmed to room temperature. Concentrated NH4Cl *4 mL)
was added to the solution, and the reaction mixture was
concentrated. The residue was extracted with ethyl acetate
*150 mL) and brine *20 mL), and the organic layer was
dried *Na2SO4) and concentrated to afford a colorless oil
*12.1 g, 98%); 1H NMR *300 MHz, CDCl3) d 0.32 *s,
6H), 1.76 *dd, Jˆ8.10, 1.20 Hz, 2H), 4.85 *m, 1H), 4.89
*s, 1H), 5.72 *m, 1H), 7.30 *d, Jˆ3.60 1H), 7.77 *dd,
Jˆ3.60, 1.50 Hz, 1H), 9.90 *s, 1H); 13C NMR *75 MHz,
CDCl3) 22.4 *2C), 24.0, 114.9, 133.3, 135.4, 137,0,
148.7, 150.7, 182.7; HRMS *EI) calcd for C10H14OSSi
210.0533, found 210.0531.
3.4.14. Preparation of resin 24. To dried resin 23 *100 mg)
swelled in dry THF *8 mL) was added PPh3 *52 mg,
0.2 mmol) and CBr4 *66 mg, 0.2 mmol), and the reaction
mixture was agitated for 1 h at room temperature. The
resin was ®ltered and washed with CH2Cl2 *twice), metha-
nol *twice), and CH2Cl2 *twice), then dried under reduced
pressure. The resin was treated with a solution of CH2Cl2
*7 mL) and Br2 *150 mL) for 10 min. The cleavage solution
was removed, and the resin was rinsed with CH2Cl2 *3 mL).
Concentration of the combined ®ltrates gave the known
4-bromo-1-*bromomethyl)naphthalene *12 mg, 0.40 mequiv./
1
g); H NMR *300 MHz, CDCl3) d 4.92 *s, 2H), 7.39 *d,
Jˆ7.60 Hz, 1H), 7.60±7.70 *2H), 7.72 *d, Jˆ7.80 Hz,
1H), 8.14 *m, 1H), 8.32 *m, 1H).
3.4.15. Ethyl N--4-bromonaphthyl)methyl-N--4-methyl-
phenylsulfonyl)glycinate -25). To resin 23 *dried,
100 mg) swelled in dry THF *8 mL) was added PPh3
*52 mg, 0.2 mmol) and CBr4 *66 mg, 0.2 mmol), and the
reaction mixture was agitated for 1 h at room temperature.
The resin was ®ltered and washed with CH2Cl2 *twice),
methanol *twice), and CH2Cl2 *twice), then dried under
reduced pressure. To the resin swelled in DMF *7 mL)
were added glycine ethyl ester hydrochloride *10 equiv.)
and diisopropyl ethyl amine *10 equiv.). The reaction
mixture was agitated for 16 h at room temperature, then
washed with DMF *twice), water *twice), methanol
*twice), and CH2Cl2 *twice). To the resin swelled in
CH2Cl2 *7 mL) were added p-toluenesulfonyl chloride
*10 equiv.), Et3N *10 equiv.), and DMAP *30 mg). After
agitation for 20 h at room temperature the resin was washed
with CH2Cl2 *twice), methanol *twice), and CH2Cl2 *twice).
To the resin swelled in CH2Cl2 *7 mL) was added Br2
*100 mL), and the mixture was stirred for 10 min at room
temperature. Filtration of the cleavage solution from the
resin followed by evaporation yielded 25 *14 mg, 76%);
1H NMR *300 MHz, CDCl3) d 1.04 *t, Jˆ7.20 Hz, 3H),
2.46 *s, 3H), 3.79 *s, 2H), 3.88 *q, Jˆ7.20 Hz, 2H), 4.94
*s, 2H), 7.15 *d, Jˆ7.50 Hz, 2H), 7.30±7.70 *3H), 7.56±
7.82 *4H), 8.22±8.35 *2H).
3.4.18. 2-Allyldimethylsilyl-5-hydroxymethylthiophene
-28). To a solution of 2-allyldimethylsilylthiophene-5-
carboxaldehyde *27, 8.6 g, 40.8 mmol) in EtOH *150 mL)
was added sodium borohydride *3.0 g, 82 mmol) portion-
wise for 10 min at room temperature. After being stirred
for 30 min, excess sodium borohydride was quenched
by slow addition of acetone *5 mL) to the reaction
mixture. The solvent was evaporated, and the residue
was extracted with ethyl acetate/brine. The organic
layer was dried *Na2SO4) and concentrated to afford a
1
colorless oil *7.5 g, 87%); H NMR *300 MHz, CDCl3)
d 0.36 *s, 6H), 1.81 *d, Jˆ8.10, 2H), 2.85 *bs, OH, 1H),
4.81 *s, 2H), 4.91 *s, 1H), 4.96 *m, 1H), 5.84 *ddt, Jˆ16.50,
10.50, 8.10 Hz, 1H), 7.08 *d, Jˆ3.30 Hz, 1H), 7.17 *d,
Jˆ3.30 Hz, 1H); 13C NMR *75 MHz, CDCl3) 22.1 *2C),
24.6, 59.9, 114.2, 127.0, 134.3, 134.8, 138.8, 149.9;
HRMS *EI) calcd for C10H16OSSi 212.0692, found
212.0690.
3.4.19. 2-Bromo-5-chloromethylthiophene -31). To a
solution of 28 *850 mg, 4 mmol) in dry THF *8 mL) under
a N2 atmosphere was added 9-BBN *8 mL, 0.5 M solution in
THF, 2 mmol) under a N2 atmosphere. After stirring for
5 h at room temperature, Pd*PPh3)4 *140 mg), 4-bromo-
polystyrene *2.0 g, 1.94 mmol/g), 2N aqueous Na2CO3
*4 mL, 8 mmol), and DMF *20 mL) were added. The reac-
tion mixture was degassed by bubbling with N2 and sealed.
The mixture was heated to 758C for 24 h. The resin *29) was
®ltered and washed with THF *once), 1:1 THF/water
*twice), water *twice), methanol *twice), and CH2Cl2
*twice), then dried under reduced pressure. To an aliquot
of resin 29 *300 mg) in CH2Cl2 *8 mL) were added hexa-
chloroethane *236 mg, 1 mmol) and triphenylphosphine
*262 mg, 1 mmol), then the reaction vessel was gently
swirled for 16 h at room temperature. After washing with
CH2Cl2 *8 mL£4) resin 30 was treated with a solution of Br2
*150 mL) in CH2Cl2 *8 mL) for 20 min. The cleavage
solution was ®ltered, and the resin was rinsed with
CH2Cl2 *3 mL). Concentration of the combined ®ltrates
gave 2-bromo-5-chloromethylthiophene *10.7 mg, loading
level was determined to be 0.17 mequiv./g); 1H NMR
*300 MHz, CDCl3) d 4.74 *s, 2H), 6.86 *d, Jˆ3.9 Hz,
1H), 6.93 *d, Jˆ3.9 Hz, 1H).
3.4.16. 2-Allyldimethylsilylthiophene -26). To a solution
of thiophene *8.4 g, 0.1 mol) in dried THF *300 mL) at
2788C was added n-butyllithium *40 mL, 2.5 M solution
in hexanes, 0.1 mol) over a period of 5 min. After 30 min
of further stirring at 2788C, allylchlorodimethylsilane
*13.5 g, 0.1 mol) was added dropwise over a period of
20 min, and the reaction mixture was warmed to room
temperature. After 1 h of further stirring at room tempera-
ture, concentrated NH4Cl *3 mL) was added, and the reac-
tion mixture was concentrated. Kugelrohr distillation of the
crude oil under reduced pressure afforded a colorless oil
*16.7 g, 92%); 1H NMR *300 MHz, CDCl3) d 0.39 *s,
6H), 1.84 *dd, Jˆ8.10, 1.20 Hz, 2H), 4.92 *s, 1H), 4.97
*m, 1H), 5.85 *m, 1H), 7.24 *m, 1H), 7.33 *dd, Jˆ3.30,
1.50 Hz, 1H), 7.65 *dd, Jˆ5.70, 1.20 Hz, 1H); 13C NMR
*75M Hz, CDCl3) 22.0 *2C), 24.8, 114.2, 128.4, 131.0,
134.4, 134.8, 138.3; HRMS *EI) calcd for C9H15SSi
182.0585, found 182.0583.

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5349
3.4.20. -2Z)-Methyl-2-acetamido-3--2-allyldimethylsilyl-
4-naphthyl)prop-2-enoate -32). This compound was
synthesized according to the procedure described for 36
except that 21 was used instead of 4-allyldimethylsilyl-
benzaldehyde and the product was puri®ed by column
chromatography *1:1 ethyl acetate/hexanes) to afford a
mmol) in THF *50 mL) at 2788C was added tetramethyl-
guanidine *3.2 mL, 26 mmol), and the mixture was stirred
for 15 min. 4-Allyldimethylsilylbenzaldehyde *7, 4.1 g,
20.0 mmol) in THF *10 mL) was added, and the mixture
was stirred for 1 h at 2788C and 4 h at room temperature.
The mixture was diluted with EtOAc, washed with 1N HCl,
1N CuSO4, and saturated NaHCO3, dried over Na2SO4, and
concentrated in vacuo. The residue was puri®ed by column
chromatography *1:3 ethyl acetate/CH2Cl2) to afford a white
powder *5.5 g, 86%); 1H NMR *300 MHz, CDCl3) d 0.29 *s,
6H), 1.76*d, Jˆ8.40 Hz, 2H), 2.15 *s, 3H), 3.85 *s, 3H), 4.84
*s, 1H), 4.89 *m, 1H), 5.77 *m, 1H), 7.12 *bs, NH, 1H), 7.37 *s,
1H), 7.44 *d, Jˆ7.80 Hz, 2H), 7.52 *d, Jˆ7.80 Hz, 2H); 13C
NMR *75 MHz, CDCl3) 23.3, 23.3, 23.7, 52.8, 113.9, 125.1,
129.2, 132.8, 134.0, 134.3, 134.5, 141.1, 166.0, 169.8. HRMS
*EI) calcd for C17H23NO3Si 317.1448, found 317.1451.
1
colorless oil *91%); H NMR *300 MHz, CDCl3) d 0.50
*s, 6H), 1.83 *s, 3H), 2.00 *d, Jˆ7.80 Hz, 2H), 3.83 *s,
3H), 4.86±4.96 *2H), 5.81 *m, 1H), 7.45±7.58 *4H), 7.66
*d, Jˆ7.20 Hz, 1H), 7.79 *s, 1H), 7.99 *d, Jˆ7.80 Hz, 1H),
8.13 *d, Jˆ7.80 Hz, 1H); 13C NMR *75 MHz, CDCl3) 21.6,
22.9, 24.4, 52.9, 114.2, 125.5, 125.7, 126.3, 128.1, 128.9,
131.3, 132.6, 133.3, 134.7, 137.3, 139.0, 165.7, 170.0;
HRMS *EI) calcd for C21H25NO3Si 367.1603, found 367.1605.
3.4.21. -S)-Methyl-2-acetamido-3--[4-allyldimethylsilyl]-
naphthyl)propanoate -33). This compound was synthe-
sized according to the procedure as described for 36 and
puri®ed to afford a colorless oil *99%); 1H NMR
*300 MHz, CDCl3) d 0.49 *s, 6H), 1.97 *s, 3H), 2.00 *d,
Jˆ7.80 Hz, 2H), 3.61 *m, 2H), 3.67 *s, 3H), 4.80±4.94
*2H), 5.05 *m, 1H), 5.80 *bd, Jˆ7.20 Hz, NH, 1H), 7.22
*d, Jˆ6.60, 1H), 7.54±7.61 *3H), 8.10±8.18 *2H); 13C
NMR *75 MHz, CDCl3) 21.5, 23.1, 24.5, 35.5, 52.5, 53.5,
114.0, 124.7, 125.9, 126.1, 127.0, 129.2, 132.4, 133.5,
134.7, 136.6, 137.7, 172.8; HRMS *EI) calcd for
C21H27NO3Si 369.1757, found 369.1756.
3.5.2. -S)-Methyl-2-acetamido-3--[4-allyldimethylsilyl]-
phenyl)propanoate. To a round bottomed ¯ask containing
*2Z)-methyl-2-acetamido-3-*4-allyldimethylsilylphenyl)-
prop-2-enoate *3.2 g, 10 mmol) in deoxygenated CH2Cl2
*40 mL) was added [*COD)Rh*S,S)-Et-DuPHOS]OTf
*7 mg). After eight vacuum/H2 cycles, the reaction was
stirred for 23 h at room temperature under H2 *1 atm).
Once the reaction was ®nished, the solution was passed
through a short plug of silica to remove the catalyst and
1
afford a colorless oil *3.2 g. 100%); H NMR *300 MHz,
CDCl3) d 0.25 *s, 6H), 1.72 *dd, Jˆ8.10 Hz, 2H), 1.98 *s,
3H), 3.10 *m, 2H), 3.72 *s, 3H), 4.81 *d, Jˆ1.2 Hz, 1H),
4.83±4.92 *2H), 5.76 *m, 1H), 5.94 *bd, Jˆ7.80 Hz, NH,
1H), 7.06 *d, Jˆ7.20 Hz, 2H), 7.42 *d, Jˆ7.20 Hz, 2H); 13C
NMR *75 MHz, CDCl3) 23.2, 23.3, 23.9, 37.9, 52.6, 53.3,
113.7, 128.9, 134.1, 134.8, 136.9, 137.5, 170.1, 172.5; HRMS
*EI) calcd for C17H25NO3Si 319.1600, found 319.1602.
3.4.22. -S)-Methyl-3--[4-allyldimethylsilyl]naphthyl)-2-
-tert-butoxycarbamido)propanoate -34). This compound
was synthesized according to the procedure as described for
36 and puri®ed by column chromatography *1:5 ethyl
1
acetate/hexanes) to afford a colorless oil *92%); H NMR
*300 MHz, CDCl3) d 0.48 *s, 6H), 1.41 *s, 9H), 2.00 *d,
Jˆ8.40 Hz, 2H), 3.40±3.66 *2H), 3.67 *s, 3H), 4.75 *m,
1H), 4.85±4.95 *2H), 5.09 *bd, NH, 1H), 5.82 *m, 1H),
7.25±7.28 *2H), 7.50±7.63 *3H), 8.10±8.17 *2H); 13C
NMR *75 MHz, CDCl3) 21.5, 24.5, 28.6, 36.1, 52.4, 54.6,
80.1, 114.0, 124.8, 125.8, 126.1, 127.1, 129.2, 132.5, 133.5,
134.7, 135.0, 136.5, 137.7, 155.4, 172.9; HRMS *EI) calcd
for C24H32NO4Si 427.2180, found 427.2180.
3.5.3. -S)-Methyl-3--[4-allyldimethylsilyl]phenyl)-2--tert-
butoxycarbamido)propanoate -36). To a solution of *S)-
methyl-2-acetamido-3-*4-allyldimethylsilylphenyl)propano-
ate *1.5 g, 4.7 mmol) and DMAP *115 mg, 0.94 mmol) in
THF *16 mL) was added di-tert-butyl dicarbonate *2.0 g,
9.4 mmol), and the mixture was heated to re¯ux for 1 h.
After the solution was cooled to room temperature, MeOH
*15 mL) and hydrazine monohydrate *912 mL, 18.8 mmol)
were added, and the mixture was stirred for 2 h at room
temperature. The solvent was evaporated by rotary evapora-
tion, and the residue was subjected to high vacuum to
remove the remaining volatile materials. The oily residue
was puri®ed by column chromatography *1:7 ethyl acetate/
3.4.23. Preparation of resin 35. To a solution 34 *427 mg,
1 mmol) in dry THF *6 mL) under a N2 atmosphere was
added 9-BBN *2 mL, 0.5 M solution in THF, 1 mmol) drop-
wise at room temperature, and the mixture was stirred for
5 h. The IBAPS resin *3 g), DMF *6 mL), and 2N aqueous
Na2CO3 *1.0 mL, 2 mmol) were added to the reaction
mixture which was bubbled with a slow stream of argon
for 10 min. After the addition of Pd*PPh3)4 *70 mg), the
reaction ¯ask and re¯ux condenser were wrapped with
aluminum foil, then stirred at 758C for 24 h. Additional
Pd*PPh3)4 *40 mg) was added to the reaction mixture, and
stirring was continued further for 48 h. The resin was
washed sequentially with CH2Cl2, DMF, 1N HCl/THF
*1:7, 16 mL, 30 min), MeOH, and CH2Cl2, and dried.
1
hexanes) to afford a colorless oil *1.7 g, 93%); H NMR
*300 MHz, CDCl3) d 0.29 *s, 6H), 1.43 *s, 9H), 1.76 *d,
Jˆ7.80 Hz, 2H), 3.09 *m, 2H), 3.73 *s, 3H), 4.62 *m, 1H),
4.84 *s, 1H), 4.88 *d Jˆ6.60 Hz, 1H), 5.20 *bd, NH, 1H),
5.78 *m, 1H), 7.14 *d, Jˆ7.50 Hz, 2H), 7.46 *d, Jˆ7.50 Hz,
2H); 13C NMR *75 MHz, CDCl3) 23.2, 23.9, 28.5, 38.6,
52.5, 54.6, 80.1, 113.7, 129.0, 134.1, 134.8, 137.1, 137.3,
153.3, 172.6; HRMS *EI) calcd for C20H32NO4Si 378. 2100,
found 378.2101.
3.5. -S)-Methyl-3--[4-allyldimethylsilyl]phenyl)-2--tert-
butoxycarbamido)propanoate -36)
3.6. -S)-Methyl-4--[4-allyldimethylsilyl]phenyl)-2--tert-
butoxycarbamido)butanoate -37)
3.5.1. -2Z)-Methyl-2-acetamido-3--[4-allyldimethylsilyl]-
phenyl)prop-2-enoate. To
acetamido-2-*dimethoxyphosphinyl)-acetate *4.8 g, 20.0
a
solution of methyl-2-
3.6.1. -2Z)-Methyl-2-acetamido-4--[4-allyldimethylsilyl]-
phenyl)but-2-enoate. To a solution of methyl-2-acetamido-

5350
Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
2-*dimethoxyphosphinyl)-acetate *1.2 g, 5.0 mmol) in THF
*15 mL) at 2788C was added tetramethylguanidine
*815 mL, 6.5 mmol) and the mixture was stirred for
15 min. *4-Allyldimethylsilylphenyl)acetaldehyde *1.1 g,
5.0 mmol) in THF *4 mL) was added, and the mixture was
stirred for 1 h at 2788C and 4 h at room temperature. The
mixture was diluted with EtOAc, washed with 1N HCl, 1N
CuSO4, and saturated NaHCO3, dried over Na2SO4, and
concentrated in vacuo. The residue was puri®ed by column
chromatography *1:1 ethyl acetate/hexanes) to afford a
170.3; HRMS *EI) calcd for C15H21NO3SSi 323.1011,
found 323.1012.
3.7.2. -S)-Methyl-2-acetamido-3--2-allyldimethylsilyl-5-
thiophenyl)propanoate. This compound was synthesized
according to the procedure as described for 36 and
puri®ed to afford a colorless oil *98%); 1H NMR
*300 MHz, CDCl3) d 0.29 *s, 6H), 1.74 *d, Jˆ7.80 Hz,
2H), 2.03 *s, 3H), 3.39 *d, Jˆ4.80 Hz, 2H), 3.76 *s, 3H),
4.80±4.90 *3H), 5.75 *m, 1H), 6.24 *bd, Jˆ7.20 Hz, NH,
1H), 6.83 *d, Jˆ3.30 Hz, 1H), 7.07 *d, Jˆ3.30 Hz, 1H); 13C
NMR *75 MHz, CDCl3) 22.1, 23.4, 24.6, 32.1, 52.8, 53.3,
114.1, 128.3, 134.2, 134.9, 138.4, 143.3, 170.0, 171.8;
HRMS *EI) calcd for C15H23NO3SSi 325.1168, found
325.1165.
1
colorless oil *760 mg, 45%); H NMR *300 MHz, CDCl3)
d 0.29 *s, 6H), 1.76*d, Jˆ7.80 Hz, 2H), 2.17 *s, 3H), 3.52 *d,
Jˆ7.20 Hz, 2H), 3.78 *s, 3H), 4.85 *s, 1H), 4.91 *d,
Jˆ8.10 Hz, 1H), 5.77 *m, 1H), 6.84 *t, Jˆ7.20 Hz, 1H),
7.21 *d, Jˆ7.50 Hz, 2H), 7.47 *d, Jˆ7.50 Hz, 2H), 7.56
*s, 1H); 13C NMR *75 MHz, CDCl3) 23.2 *2C), 23.5,
23.9, 35.3, 52.7, 113.7, 125.8, 128.4 *2C), 134.3 *2C),
134.8, 136.8, 137.1, 165.4, 169.5; HRMS *EI) calcd for
C18H25NO3Si 331.1605, found 331.1606.
3.7.3. -S)-Methyl-3--2-[5-allyldimethylsilyl]thiophenyl)-
2--tert-butoxycarbamido)propanoate -38). This com-
pound was synthesized according to the procedure as
described for 36 and puri®ed by column chromatography
*1:5 ethyl acetate/hexanes) to afford a colorless oil
*90%); 1H NMR *300 MHz, CDCl3) d 0.30 *s, 6H),
1.45 *s, 9H), 1.75 *d, Jˆ8.10 Hz, 2H), 3.38 *m, 2H),
3.75 *s, 3H), 4.60 *m, 1H), 4.86 *s, 1H), 4.90 *m, 1H),
5.19 *d, Jˆ7.50 Hz, NH, 1H), 5.78 *m, 1H), 6.87 *d,
Jˆ3.00 Hz, 1H), 7.08 *d, Jˆ3.00 Hz, 1H); 13C NMR
*75 MHz, CDCl3) 22.1, 24.6, 28.6, 32.6, 52.6, 54.5,
80.2, 100.3, 114.1, 128.3, 134.3, 134.9, 138.1, 143.5,
155.3, 172.0; HRMS *EI) calcd for C18H29NO4SSi
383.1586, found 383.1585.
3.6.2. -S)-Methyl-2-acetamido-3--[4-allyldimethylsilyl]-
phenyl)butanoate. This compound was synthesized
according to the procedure as described for 36 and puri®ed
to afford a colorless oil *96%); 1H NMR *300 MHz, CDCl3)
d 0.28 *s, 6H), 1.75 *d, Jˆ7.50 Hz, 2H), 2.01 *s, 3H), 2.00±
2.30 *2H), 2.65 *m, 2H), 3.75 *s, 3H), 4.71 *m, 1H), 4.85 *s,
1H), 4.89 *d, Jˆ8.70 Hz, 1H), 5.79 *m, 1H), 5.97 *bd,
Jˆ8.10 Hz, NH, 1H), 7.19 *d, Jˆ7.80 Hz, 2H), 7.45 *d,
Jˆ7.80 Hz, 2H); 13C NMR *75 MHz, CDCl3) 23.2, 23.1,
23.9, 32.1, 33.8, 52.3, 52.4, 113.7, 128.2, 134.1, 134.8,
136.2, 141.9, 170.8, 173.3; HRMS *EI) calcd for
C18H27NO3Si 333.1757, found 333.1755.
3.7.4.
-S)--1)-N--4-Allyldimethylsilylbenzylidene)-p-
toluenesul®namide -39). To a solution of *1R,2S,5R)-*2)-
menthyl-*S)-p-toluenesul®nate *2.9 g, 10 mmol) in dry THF
*100 mL) at 2788C was added LiHMDS *1 M solution in
THF, 15 mL, 15 mmol) dropwise. After 15 min the
reaction mixture was warmed to room temperature and
stirred for 3 h. The reaction mixture was cooled to 08C,
and 7 *3.0 g, 15 mmol) was added dropwise, followed by
the addition of powdered CsF *3.0 g, 20 mmol). After
being stirred overnight at room temperature, the reaction
mixture was quenched with saturated NH4Cl *10 mL)
and diluted with ethyl acetate *150 mL). The organic
layer was separated, dried *Na2SO4), and concentrated to
give an orange oil which was puri®ed by silica gel
chromatography using EtOAc/hexanes *1:8) as eluent to
obtain a yellow oil *1.6 g, 47%); 1H NMR *400 MHz,
CDCl3) d 0.29 *s, 6H), 1.75 *d, Jˆ8.4 Hz, 2H), 2.38
*s, 3H), 4.82 *s, 1H), 4.86 *d, Jˆ4.0 Hz, 1H), 5.73 *m,
1H), 7.29 *d, Jˆ8.0 Hz, 2H), 7.61 *d, Jˆ8.0 Hz, 2H),
7.63 *d, Jˆ8.0 Hz, 2H), 7.81 *d, Jˆ8.0 Hz, 2H), 8.76 *s,
1H); 13C NMR *125 MHz, CDCl3) 23.1, 21.8, 23.7,
114.1, 125.0, 128.7, 130.0, 134.1, 134.3, 141.9, 145.0,
160.8; HRMS *EI) calcd for C19H23NOSSi 341.1269,
found 341.1268.
3.6.3. -S)-Methyl-4--[4-allyldimethylsilyl]phenyl)-2--tert-
butoxycarbamido)butanoate -37). This compound was
synthesized according to the procedure as described for 36
and puri®ed by column chromatography *1:5 ethyl acetate/
hexanes) to afford a colorless oil *88%); 1H NMR
*300 MHz, CDCl3) d 0.28 *s, 6H), 1.47 *s, 9H), 1.75 *d,
Jˆ7.80 Hz, 2H), 1.98 *m, 1H), 2.17 *m, 1H), 2.69 *m,
2H), 3.73 *s, 1H), 4.38 *m, 1H), 4.84 *s, 1H), 4.88 *d,
Jˆ8.10 Hz, 1H), 5.21 *bd, NH, 1H), 5.78 *m, 1H), 7.19
*d, Jˆ7.80 Hz, 2H), 7.45 *d, Jˆ7.80 Hz, 2H); 13C NMR
*75 MHz, CDCl3) 23.2, 24.0, 28.6, 31.9, 34.4, 52.5, 53.5,
80.1, 113.6, 128.2, 134.1, 134.9, 136.2, 142.0, 155.7, 173.4;
HRMS *EI) calcd for C21H33NO4Si 391.2178, found
391.2180.
3.7. -S)-Methyl-3--2-[5-allyldimethylsilyl]thiophenyl)-2-
-tert-butoxycarbamido)propanoate -38)
3.7.1. -2Z)-Methyl-2-acetamido-3--2-allyldimethylsilyl-
5-thiophenyl)prop-2-enoate. This compound was synthe-
sized according to the procedure as described for 36 except
that 2-allyldimethylsilylthiophene-5-carboxaldehyde was
used instead of 4-allyldimethylsilylbenzaldehyde and puri-
®ed by column chromatography *1:1 ethyl acetate/hexanes)
to afford a colorless oil *78%); 1H NMR *300 MHz, CDCl3)
d 0.32 *s, 6H), 1.77 *d, Jˆ8.10 Hz, 2H), 2.21 *s, 3H), 3.78
*s, 3H), 4.87 *s, 1H), 4.91 *m, 1H), 5.76 *m, 1H), 7.19 *d
Jˆ3.30 Hz, 1H), 7 32 *d, Jˆ3.30 Hz, 1H), 7.76 *s, 1H); 13C
NMR *75 MHz, CDCl3) 22.3, 23.7, 24.3, 52.7, 114.6,
122.0, 129.4, 133.8, 134.5, 134.7, 141.5, 145.3, 165.7,
3.7.5. -SR,R)--1)-Methyl 3--p-tolylsul®namido-3--[4-
allyldimethylsilyl]phenyl)propanoate -40). To a solution
of NaHMDS *1 M solution in THF, 22.4 mL, 22.4 mmol) in
dry ether *100 mL) at 2788C was added methyl acetate
*2.2 mL, 28.0 mmol), and the mixture was stirred for
30 min. A solution of 39 *4.8 g, 14 mmol) in ether
*15 mL) was added over a period of 15 min at 2788C.

Y. Lee, R. B. Silverman / Tetrahedron 57 -2001) 5339±5352
5351
S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385±
1401. *b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996,
96, 555.
After being stirred for 7 h at 2788C, the reaction was
quenched with saturated NH4Cl *20 mL) at 2788C and
warmed to room temperature. The organic layer was dried
*Na2SO4), and concentrated to give an oil which was puri-
®ed by silica gel chromatography using EtOAc/hexanes
*1:2) as eluent to obtain a white solid *4.2 g, 72%); mp
2. *a) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60,
6006±6007. *b) Plunkett, M. J.; Ellman, J. A. J. Org. Chem.
1997, 62, 2885±2893. *c) Chenera, B.; Finkelstein, J. A.;
Veber, D. F. J. Am. Chem. Soc. 1995, 117, 11999±12000.
*d) Boehm, T. L.; Showalter, H. D. H. J. Org. Chem. 1996,
61, 6498±6499. *e) Woolard, F. X.; Paetsch, J.; Ellman, J. A.
J. Org. Chem. 1997, 62, 6102±6103. *f) Hu, Y.; Porco, Jr.,
J. A.; Labadie, J. W.; Gooding, O. W.; Trost, B. M. J. Org.
Chem. 1998, 63, 4518±4521. *g) Newlander, K. A.; Chenera,
B.; Veber, D. F.; Yim, N. C. F.; Moore, M. L. J. Org. Chem.
1997, 62, 6726±6732. *h) Han, Y.; Walker, S. D.; Young, R. N.
Tetrahedron Lett. 1996, 37, 2703±2706. *i) Brase, S.; Enders,
D.; Kobberling, J.; Avemaria, F. Angew. Chem., Int. Ed. Engl.
1998, 37, 3413±3415. *j) Brase, S.; Schroen, M. Angew.
Chem., Int. Ed. Engl. 1999, 38, 1071±1073. *k) Stieber, F.;
Grether, U.; Waldmann, H. Angew. Chem., Int. Ed. Engl.
1999, 38, 1073±1077.
1
82±858C; H NMR *400 MHz, CDCl3) d 0.25 *s, 6H),
1.71 *d, Jˆ8.0 Hz, 2H), 2.33 *s, 3H), 2.81 *m, 3H), 3.51
*s, 3H), 4.80±4.85 *3H), 5.34 *bs, NH, 1H), 5.75 *m, 1H),
7.20 *d, Jˆ8.0 Hz, 2H), 7.39 *d, Jˆ8.0 Hz, 2H), 7.48 *d,
Jˆ8.0 Hz, 2H), 7.52 *d, Jˆ8.0 Hz, 2H); 13C NMR
*125 MHz, CDCl3) 23.0, 21.8, 24.0, 42.4, 52.1, 55.1,
113.7, 125.7, 126.7, 129.6, 134.2, 134.6, 138.4, 141.3,
141.6, 142.3, 171.2; HRMS *EI) calcd for C22H28NO3SSi
441.1559, found 414.1559.
3.7.6. Preparation of resin 41. To a solution of 40 *1.1 g,
2.6 mmol) in dry THF *20 mL) under a N2 atmosphere was
added 9-BBN *5.2 mL, 0.5 M solution in THF, 2.6 mmol)
dropwise at room temperature, and the mixture was
stirred for 3 h. The IBAPS resin *5 g, 0.96 mmol/g), DMF
*15 mL), and 2N aqueous Na2CO3 *2.0 mL, 4 mmol) were
added to the reaction mixture which was bubbled with a
slow stream of argon for 10 min. After the addition of
Pd*PPh3)4 *260 mg), the reaction ¯ask and re¯ux condenser
were wrapped with aluminum foil, then stirred at 758C
for 48 h. Additional Pd*PPh3)4 *140 mg) was added to
the reaction mixture, and stirring was continued further
for 24 h. The resin product *41) was washed sequentially
with THF, CH2Cl2, MeOH, and CH2Cl2, then dried in
vacuo.
3. Lee, Y.; Silverman, R. B. J. Am. Chem. Soc. 1999, 121, 8407±
8408.
4. Lee, Y.; Silverman, R. B. Org. Lett. 2000, 2, 303±306.
5. Lee, Y.; Silverman, R. B. Org. Lett. 2000, 2, 3743±3746.
6. Berree, F.; Michelot, G.; Le Corre, M. Tetrahedron Lett. 1998,
39, 8275±8276.
7. Prepared from amide coupling of 3-iodobenzoic acid *or
4-iodobenzoic acid) with aminomethylated polystyrene
*1.02 mmol/g, 100±200 mesh, purchased from Novabiochem
Corp.) employing diisopropylcarbodiimide and HOBT in
DMF for 2 days at room temperature.
8. Miyarura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
9. *a) Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984,
53±60. *b) Schmidt, U.; Griesser, H.; Leitenberger, V.;
Lieberknecht, A.; Mangold, R.; Meyer, R.; Riedl, B. Synthesis
1992, 487±490.
3.7.7. Determination of the loading level and enantio-
purity of the resin 41 by MPTA amide derivatization.
An aliquot of resin 41 *200 mg) was treated with a solution
*10 mL) of TFA/MeOH/CH2Cl2ˆ1:2:100 for 3 h, then
washed with CH2Cl2, THF, MeOH, and CH2Cl2. The resin
was suspended in dry CH2Cl2 *8 mL), then treated with
*R)-*2)-a-methoxy-a-*tri¯uoromethyl)-phenylacetic acid
chloride *76 mg, 0.3 mmol)) and DIPEA *87 mL,
0.5 mmol) for 5 h. After successive washing with CH2Cl2,
MeOH, and CH2Cl2, the resin was treated with a solution of
Br2 *15 mL) in CH2Cl2 *8 mL) for 20 min. The cleavage
solution was ®ltered, and the resin was rinsed with
CH2Cl2 *3 mL). Concentration of the combined ®ltrates
gave the MTPA amide as a colorless oil *42, 9.5 mg, the
loading level of resin 41 was determined to be 0.10 mmol/
g); 1H NMR *400 MHz, CDCl3) d 2.85 *dd, Jˆ16.4, 6.0 Hz,
1H), 2.90 *dd, Jˆ16.0, 6.8 Hz, 1H), 3.46 *d, Jˆ0.8 Hz, 3H),
3.63 *s, 3H), 5.39 *dd, Jˆ14.4, 6.4 Hz, 1H), 7.05 *d,
Jˆ8.8 Hz, 2H), 7.33±7.44 *7H), 7.80 *8.0 Hz, 1H); 13C
NMR *100 MHz, CDCl3) d 39.9, 49.5, 52.4, 55.5, 121.9,
127.6, 128.1, 128.7, 129.7, 132.0, 132.5, 139.1, 165.8,
10. *a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L.
J. Am. Chem. Soc. 1993, 115, 10125±10138. *b) Burk, M. J.;
Allen, J. G.; Kiesman, W. F. J. Am. Chem. Soc. 1998, 120,
657±663.
11. Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054±
7057.
12. *a) Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J. A.
J. Am. Chem. Soc. 1998, 120, 8011±8019. *b) Tang, T. P.;
Ellman, J. A. J. Org. Chem. 1999, 64, 12±13. *c) Both
enantiomers of 2-methyl-2-propanesul®namide *referred to
as tert-butylsul®namide) are available from Aldrich.
13. Fredenhagen, A.; Tamura, S. Y.; Kenny, P. T. M.; Komura,
H.; Naya, Y.; Nakanishi, K.; Nishiyama, K.; Sugiura, M.; Kita,
H. J. Am. Chem. Soc. 1987, 109, 4409±4411.
14. Kaseda, T.; Kikuchi, T.; Kibayashi, C. Tetrahedron Lett.
1989, 30, 4539±4542.
1
171.1; Analysis of the H NMR and 19F NMR spectral
15. *a) Kosemura, S.; Ogawa, T.; Totsuka, K. Tetrahedron Lett.
1993, 34, 1291±1294. *b) Morita, H.; Nagashima, S.; Takeya,
K.; Itokawa, H. Chem. Pharm. Bull. 1993, 41, 992±993.
*c) Morita, H.; Nagashima, S.; Shirota, O.; Takeya, K.;
Itokawa, H. Chem. Lett. 1993, 1877±1880. *d) Morita, H.;
Nagashima, S.; Takeya, K.; Itokawa, H. Heterocycles 1994,
38, 2247±2252. *e) Morita, H.; Nagashima, S.; Takeya, K.;
Itokawa, H. Chem. Lett. 1994, 11, 2009±2010. *f) Morita, H.;
Nagashima, S.; Takeya, K.; Itokawa, H. Tetrahedron 1994,
50, 11613±11622. *g) Schumacher, K. K.; Hauze, D. B.;
integration of the crude 42 showed less than 2% of
the minor diasteromer. HRMS *EI) calcd for
C20H19BrF3NO4 473.0450 and 475.0431, found 473.0450
and 475.0463.
References
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