Preparation of novel 2-(trialkylsilyl)ethyl linkers and first synthesis of Tryprostatin B on solid phase

Article abstract of DOI:10.1016/S0040-4039(00)02312-1

Two synthetic methods for novel polymer-supported 2-(trialkylsilyl)ethanol linkers 3 are described. The new silyl linker has been examined as a C-terminal linkage to provide several diketopiperazines. Using this synthetic method, the first solid phase synthesis of Tryprostatin B was accomplished. Several functionalized 2-(trialkylsilyl)ethyl linkers 12-17 are synthesized from 2-(trialkylsilyl)ethanol linkers. During the course of preparations, the new silyl linkers proved resistant to various reaction conditions such as basic and moderately acidic media, oxidation, and elevated thermal conditions.

Full text of DOI:10.1016/S0040-4039(00)02312-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1463–1466
Preparation of novel 2-(trialkylsilyl)ethyl linkers and first
synthesis of Tryprostatin B on solid phase
Bingbing Wang, Li Chen and Kyungjin Kim*
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA
Received 23 October 2000; accepted 8 December 2000
Abstract—Two synthetic methods for novel polymer-supported 2-(trialkylsilyl)ethanol linkers 3 are described. The new silyl linker
has been examined as a C-terminal linkage to provide several diketopiperazines. Using this synthetic method, the first solid phase
synthesis of Tryprostatin B was accomplished. Several functionalized 2-(trialkylsilyl)ethyl linkers 12–17 are synthesized from
2-(trialkylsilyl)ethanol linkers. During the course of preparations, the new silyl linkers proved resistant to various reaction
conditions such as basic and moderately acidic media, oxidation, and elevated thermal conditions. © 2001 Elsevier Science Ltd.
All rights reserved.
Solid phase synthetic methodologies have played an
important role in the successful application of high-
throughput chemistry to accelerate the pharmaceutical
lead generation and lead optimization process.1 In
order to expand the scope of functional groups and
chemistries that can be adapted to solid phase, there is
a continuing need for the development of new linkers.2
A representative linker is Si-based, where the corre-
sponding substituted silicon commonly serves as a pro-
tecting group in solution phase. While several
applications using Si on solid phase have been reported
as a traceless linker or silyl-based spacer, our interest in
developing new silicon-based linkers has led us to
explore more diverse polymeric silyl linkers and their
facile applications to library synthesis.3 Herein, we
report a series of convenient methods to prepare poly-
mer-supported 2-(trialkylsilyl)ethyl linkers and describe
their application for solid phase synthesis.4
Several preparative methods of 2-(trialkylsilyl)ethanols
and their applications for the protection of carboxylic
acids and alcohols have been reported.5 Based on the
preliminary results in solution phase, we designed the
polymer-bound 2-(trialkylsilyl)ethanol resins with care-
ful consideration of the possibility of ‘protodesilation’
or ‘Peterson olefination’.6 The silyl linker synthesis
outlined in Scheme 1 starts with direct lithiation7 of
commercially available 4-bromopolystyrene resin 1.
Chlorodimethylvinylsilane or methyl-phenyl-vinyl-
chlorosilane was added to 4-lithiated polystyrene
resin in a THF solution to provide the corresponding
polymer-bound vinylsilane 2a or 2b in high yield
Scheme 1.
Keywords: combinatorial chemistry; protecting group; solid-supported reagent.
* Corresponding author. Tel.: 937-235-3844; fax: 973-235-6084; e-mail: kyungjin.kim@roche.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02312-1

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B. Wang et al. / Tetrahedron Letters 42 (2001) 1463–1466
(>90%) (method A). Following hydroboration of the
vinylsilanes 2 with 9-BBN and subsequent oxidation,
the desired polymer-bound 2-(trialkylsilyl)ethanol
linker 3a or 3b was successfully prepared in 67–85%
yield.8 However, due to a lack of commercially avail-
able chlorodialkylvinylsilanes, a different synthetic
route was explored. To this end, dialkyldichlorosilanes
were employed to introduce various polymer-supported
vinylsilanes. Diisopropyldichlorosilane addition to the
4-lithiated polystyrene resin in a THF solution followed
by the addition of vinyllithium provided diisopropyl-
vinylsilane 2c in 71% yield (method B).9 It is important
that vinyllithium should be prepared immediately
before use to get a good yield. The sequential hydrobo-
ration and oxidation of polymer-bound diisopropy-
lvinylsilane 2c provided the corresponding silyl ethanol
resin 3c in 58–70% yield. The polymeric 2-(trialkyl-
silyl)ethanol linkers 3 can be successfully prepared in
15–25 g scale. The final resin loadings were determined
to be 0.9–1.3 mmol/g.10
from Aspergillus fumingatus prevents the interaction
between microtubule-associated proteins with the car-
boxy-terminal domain of tubulin.13 The coupling of
prenyltryptophan derivative 7a prepared from the cor-
responding methyl ester 7b14 and silyl resin 3b was
successfully conducted to provide 8. Hydrazinolysis of 8
followed by Fmoc-Pro coupling and deprotection of
Fmoc afforded 10 in 78% yield from 3b. The loading
capacity of 10 was determined to be 0.43 mmol/g based
on quantitation of the Fmoc chromophore. Subsequent
acid-induced cyclization provided the desired Trypro-
statin B (11) and the corresponding diastereoisomer in
76% yield with 100% purity. The physical and spectral
data of 11 are consistent with those of Tryprostatin B
synthesized by Danishefsky and colleagues.14,15
We next turned our attention to the modifications of
2-(trialkylsilyl)ethanol linker 3 to explore various func-
tionalized 2-(trialkylsilyl)ethyl linkers. Our initial
efforts were directed toward the preparation of poly-
mer-supported 2-(trialkylsilyl)ethyl bromide 12, tosylate
13, 4-nitrophenyl carbonate 14, and imidazolide carba-
mate 15 (Scheme 4). Similar applications have fre-
quently been utilized in solution phase as protection
groups for 2-(trimethylsilyl)ethyl carbamate (Teoc-
NR2), carbonate (TMSEC), and glycoside (TMSEt-gly-
coside).16 Mild bromination conditions were chosen to
prepare silyl bromide linker 12 using the preformed
adducts of triphenylphosphine with carbon tetra-
bromide. For the tosylation, a solution of 2-(trialkylsi-
lyl)ethanol resin 3, p-toluenesulfonyl chloride, and
pyridine in CH2Cl2 was shaken overnight to afford
tosylate 13. In order to verify the progress of both
bromination and tosylation, the disappearance of the
OꢀH stretch at 3428 cm−1 was monitored by FT-IR
spectroscopy. Carbonate 14 and imidazolide carbamate
15 resins were successfully prepared from the standard
coupling conditions. After acylation of 3 with either
4-nitrophenyl chloroformate or 1,1%-dicarbonylimida-
After synthesizing diverse silyl linkers, we investigated
their application in solid phase synthesis. The acylation
of polymeric 2-(diphenylmethylsilyl)ethanol linker 3b
with Fmoc-Ala using standard coupling conditions fol-
lowed by subsequent amino acid coupling and Fmoc
deprotection yielded dipeptide 5 (Scheme 2). Cleavage
of the silyl linker in acidic media induced cyclization to
provide diketopiperizines 6 in high yield (76–88%) and
purity (>99%).11 This silyl linker application directed
toward the synthesis of diketopiperazines proved
efficient and convenient at the final cleavage step when
compared with the approach derived from Wang
resin.12 The isolated yield and purity of some diketo-
piperizines are given in Scheme 2.
Further application of our new silyl linkers was exam-
ined for a more complicated diketopiperazine, Trypro-
statin B (11) (Scheme 3). This natural product isolated
Scheme 2.

B. Wang et al. / Tetrahedron Letters 42 (2001) 1463–1466
1465
Scheme 3.
Scheme 4. Reagents and conditions: (a) PPh3 (5.0 equiv.), CBr4 (5.0 equiv.), THF, overnight, rt. (b) p-toluenesulfonyl chloride (5.0
equiv.), pyridine (10 equiv.), CH2Cl2, rt. (c) 4-nitrophenyl chloroformate (2.5 equiv.), NMM (5.0 equiv.), CH2Cl2, 0°C“rt. (d)
1,1%-dicarbonylimidazole (5.0 equiv.), THF, rt.
Scheme 5.
zole, the OꢀH stretch at 3428 cm−1 disappeared and a
new CꢁO stretch was observed at 1761 and at 1762
cm−1, respectively. These silyl-based linkers are resistant
to the described reaction conditions and are envisioned
to serve as precursors that can be easily attached to
various scaffolds possessing an amine or alcohol func-
tional group. The final loading capacity of each linker
was determined by bromine (12), sulfur (13), and nitro-
gen (14 and 15) elementary analysis.17
Further modifications were explored to provide more
diverse Si-based linkers (Scheme 5). A Mitsunobu reac-
tion of 3b with phthalimide followed by hydrazinolysis
was carried out to obtain amino-substituted silyl linker
16 in two steps with a 71% yield overall. The loading
capacity of 16 was determined to be 1.05 mmol/g by
quantitation of the Fmoc chromophore after acylation
with Fmoc-Ala and was confirmed by nitrogen analysis.
Several oxidation conditions were examined for the

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B. Wang et al. / Tetrahedron Letters 42 (2001) 1463–1466
preparation of silyl aldehyde 17. We determined that
Dess–Martin periodinane proved to be most efficient
oxidant to provide the desired silyl aldehyde 17. The
progress of oxidation was monitored by FT-IR spec-
troscopy. The OꢀH stretch of 3b disappeared and
simultaneously the CꢁO stretch of aldehyde at 1703
cm−1 and the corresponding HꢀC stretch at 2721 cm−1
were observed.
9. The yield and loading of 2 determined by silicon elemen-
tary analysis: 2a (R1=CH3, R2=CH3; 95%, 1.85 mmol/g),
2b (R1=CH3, R2=Ph; 90%, 1.77 mmol/g), 2c (R1=iso-
propyl, R2=iso-propyl; 71%, 1.38 mmol/g).
10. The respective yield and loading was determined by silicon
elementary analysis and confirmed by quantitation of the
Fmoc chromophore after acylation with Fmoc-alanine.
General procedures for the preparation of 2-(trialkylsi-
lyl)ethanol linkers 3 are described as follows: to a stirred
solution of vinylsilane 2 (1.0 equiv.) in dry THF (0.2 M)
solution at 0°C was added slowly 9-BBN in THF (0.5 M,
3.0 equiv.) and the mixture was allowed to warm to room
temperature. After shaking overnight, the mixture was
cooled to 0°C and water was cautiously added followed by
the dropwise addition of equal volumes of 3 M NaOH and
30% hydrogen peroxide, respectively (volume equal to
volume of 9-BBN solution). After stirring overnight at
40°C, the resin was filtered, washed and dried in vacuo at
40°C overnight to provide 3.
11. The purity was determined by a C18 reverse phase HPLC
column, WR-C18 3u 120A (30×3.2 mm) of ES Industries
in 10–90% CH3CN/H2O containing 0.02% TFA and mon-
itored at 215 nm using a UV detector and by SEDEX 55
Evaporative Light Scattering Detector (ELSD). The purity
scores reported herein are based on ELSD.
12. We examined the diketopiperazines synthesis using Wang
resin. Numerous cleavage conditions were attempted such
as acid- or base-induced cyclization and elevated reaction
temperature. However, only moderate results were
achieved in refluxing toluene to yield 6a–c in high purity
(87–97%), but poor isolated yield (8–23%).
In conclusion, several polymer-supported 2-(trialkylsi-
lyl)ethanol linkers 3 were prepared using two different
synthetic pathways. Because the novel silyl-based resins
are found to be resistant to various reaction conditions
used in peptide synthesis, our initial efforts were
directed toward application of the silyl linker as a
C-terminal linkage. Using the silyl linker, diketopiper-
azine synthesis on solid phase was successfully carried
out with high yield and purity. In addition, the first solid
phase synthesis of Tryprostatin B was accomplished.
Polymer-supported 2-(trialkylsilyl)ethyl bromide 12,
tosylate 13, 4-nitrophenyl carbonate 14, imidazolide
carbamate 15, amine 16, and aldehyde 17 were also
prepared from 2-(trialkylsilyl)ethanol linkers 3. The new
synthetic silyl linkers can be applied as protecting
groups, traceless linkers, and polymer-supported
reagents. Additional details and applications of silyl
linkers will be reported in a full account of this work.
References
1. Review: (a) Thompson, L. A.; Ellman, J. A. Chem. Rev.
1996, 96, 555–600. (b) Fruchtel, J. S.; Jung, G. Angew.
Chem., Int. Ed. Engl. 1996, 35, 17–42. (c) Booth, S.;
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1998, 54, 15385–15443.
13. (a) Cui, C. B.; Kakeya, H.; Okada, G.; Onose, R.;
Ubukata, M.; Takahashi, I.; Isono, K.; Osada, H. J.
Antibiot. 1995, 48, 1382–1384; (b) Osada, H.; Cui, C. B.;
Onose, R.; Hanaoka, F. Bioorg. Med. Chem. 1997, 5,
193–203.
2. Review: (a) Backes, B. J.; Ellman, J. A. Curr. Opin. Chem.
Biol. 1997, 1, 86–93. (b) James, I. W. Tetrahedron 1999, 55,
4855–4946. (c) Hudson, D. J. Comb. Chem. 1999, 1,
333–360. (d) Hudson, D. ibid 1999, 1, 403–457.
3. (a) Chan, T. H.; Huang, W. Q. J. Chem. Soc., Chem.
Commun. 1985, 909–911; (b) Randolph, J. T.; McClure, K.
F.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117,
5712–5719; (c) Plunkett, M. J.; Ellman, J. A. J. Org. Chem.
1995, 60, 6006–6007; (d) Woolard, F. X.; Paetsch, J.;
Ellman, J. A. J. Org. Chem. 1997, 62, 6102–6103; (e) Hu,
Y.; Proco, Jr., J. A. Tetrahedron Lett. 1998, 39, 2711–2714;
(f) Koot, W. J. J. Comb. Chem. 1999, 1, 467–473.
4. Wang, B.; Kim, K. Book of Abstract, 220th ACS. National
Meeting, Washington DC, 20–24 August, 2000, ORGN-
231.
5. (a) Soderquist, J. A.; Rivera, I.; Negron, A. J. Org. Chem.
1989, 54, 4051–4055; (b) Marlowe, C. K. Bioorg. Med.
Chem. Lett. 1993, 3, 437–440; (c) Fotouhi, N.; Kemp, D.
S. Int. J. Peptide Protein Res. 1993, 41, 153–161.
6. Weber, W. P. Silicon Reagents for Organic Synthesis;
Springer-Verlag, 1983; (a) protodesilation; pp. 114–115 (b)
Peterson olefination: pp. 58–78.
14. Tryprostatin B was synthesized in solution phase and the
methyl ester 7b was prepared according to the precedent:
Schkeryantz, J. M.; Woo, J. C. G.; Siliphaivanh, P.;
Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11964–11975.
15. Tryprostatin B (11) synthesized on solid phase: [h]2D5=−74
(c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3) l 8.02 (s, 1H),
7.47 (d, J=7.7 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.15 (t,
J=8.1 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H), 6.10 (s, 1H),
5.4–5.21 (br s, 1H), 5.31 (t, J=7.3 Hz, 1H), 4.42 (br d,
J=8.1 Hz, 1H), 4.08 (t, J=7.3 Hz, 1H), 3.71–3.40 (m, 4H),
3.0 (dd, J=15 Hz, 11 Hz, 1H), 2.39–2.27 (m, 1H), 2.05–1.85
(m, 3H), 1.79 (s, 3H), 1.75 (s, 3H); 13C NMR (100 MHz,
CDCl3) l 169.9, 165.9, 136.7, 135.5, 135.4, 127.9, 121.9,
119.9, 119.6, 117.7, 110.8, 104.1, 59.2, 54.7, 45.5, 28.3, 25.7,
25.1, 22.5, 17.9; HRMS (FAB) calculated for C21H25N3O2
(M)+ 351.1947, found 351.1954.
16. (a) Teoc-NR2: Carpino, L. A.; Tsao, J. H. J. Chem. Soc.,
Chem. Commun. 1978, 358–359; (b) TMSEC: Roush, W.
R.; Blizzard, T. A. J. Org. Chem. 1984, 49, 4332–4339; (c)
TMSEt-glycoside: Lipshutz, B. H.; Pegram, J. J.; Morey,
M. C. Tetrahedron Lett. 1981, 22, 4603–4606.
7. Farral, M. J.; Frechet, J. M. J. Org. Chem. 1976, 41,
3877–3882.
8. b-Dimethylphenylsilylethyl linker 3a was independently
prepared by M. Kurth and his colleagues: Tetrahedron
Lett. 2000, 41, 5617–5622.
17. The yield and loading determined by elementary analysis
follow: 12 (42% yield, loading: 0.5 mmol/g), 13 (94% yield,
loading: 1.13 mmol/g), 14 (72%, loading: 0.86 mmol/g), 15
(quantitative yield, loading: 1.28 mmol/g).