An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis

Article abstract of DOI:10.1021/ol050370y

(Chemical Equation Presented) A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.

Full text of DOI:10.1021/ol050370y

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1777-1780
An Acid-Stable tert-Butyldiarylsilyl
(TBDAS) Linker for Solid-Phase Organic
Synthesis
Christine M. DiBlasi,† Daniel E. Macks,† and Derek S. Tan*,†,‡
Molecular Pharmacology & Chemistry Program and Tri-Institutional Research
Program, Memorial Sloan-Kettering Cancer Center, 1275 York AVenue, Box 422,
New York, New York 10021
tand@mskcc.org
Received February 21, 2005
ABSTRACT
A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic
and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection,
olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.
An important ongoing challenge in solid-phase organic
synthesis is the development of new linkers for attaching
substrates to solid supports.1 Ideally, a linker should with-
stand a wide variety of reaction conditions used to process
the attached substrates, yet also be cleaved under specific,
mild, chemoselective conditions that do not degrade the
products. A variety of silyl ether linkers have been developed
for this purpose on the basis of the pioneering work of
Frechet2 and the extensive use of silyl protecting groups in
Figure 1. Silyl ether linkers with all-carbon attachments to the
solid support.
solution-phase synthesis. Linkers having an “all-carbon”
attachment to the solid support have been particularly useful.
Examples include the aryldiisopropylsilyl linker 13 and
n-alkyldiisopropylsilyl linkers such as 24,5 (Figure 1). In
general, these linkers are stable to a variety of reaction
conditions and can be cleaved orthogonally with fluoride
reagents.
† Molecular Pharmacology & Chemistry Program.
In the course of our research program in the diversity-
oriented synthesis (DOS) of natural product-based libraries,6
‡ Tri-Institutional Research Program.
(1) (a) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091-
2157. (b) Wills, A. J.; Balasubramanian, S. Curr. Opin. Chem. Biol. 2003,
7, 346-352.
we required a linker that was stable to strong protic and
Lewis acidic conditions to carry out reactions such as acetal
deprotections, Lewis acid-catalyzed cycloadditions, and
aldehyde addition reactions. Encouraged by preliminary
experiments with triisopropylsilyl-protected alcohols as solu-
tion-phase analogues, we explored the utility of 2 in such
(2) Farrall, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41, 3877-3882.
(3) Randolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem.
Soc. 1995, 117, 5712-5719.
(4) Tallarico, J. A.; Depew, K. M.; Pelish, H. E.; Westwood, N. J.;
Lindsley, C. W.; Shair, M. D.; Schreiber, S. L.; Foley, M. A. J. Comb.
Chem. 2001, 3, 312-318.
(5) (a) Stranix, B. R.; Liu, H. Q.; Darling, G. D. J. Org. Chem. 1997,
62, 6183-6186. (b) Hu, Y. H.; Porco, J. A.; Labadie, J. W.; Gooding, O.
W.; Trost, B. M. J. Org. Chem. 1998, 63, 4518-4521.
(6) Tan, D. S. Comb. Chem. High Through. Screen. 2004, 7, 631-643.
10.1021/ol050370y CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/30/2005

reactions on polystyrene beads.7 Unfortunately, the linker
was degraded significantly under acidic conditions (e.g.,
TsOH), resulting in premature cleavage of the substrates from
the solid support. We report herein our solution to this
problem, entailing the synthesis and evaluation of a new,
robust tert-butyldiarylsilyl (TBDAS) linker 3.8
We then evaluated various methods of activating the silyl
hydride resin 6b for alcohol loading (Table 1) including
Table 1. Activation of the Silyl Hydride Resin 6b and Alcohol
Loading
By analogy to the tert-butyldiphenylsilyl (TBDPS) pro-
tecting group for alcohols,9 we envisioned that the TBDAS
linker 3 would be significantly more stable to acids than 1
or 2. Moreover, since the solution-phase analogues of 1 and
2 are uncommon, we recognized that the direct cor-
respondence between 3 and the well-established TBDPS
protecting group would offer a further advantage with respect
to predicting the stability of the linker and the reactivity of
TBDAS-linked substrates.
activating reagent
NBSa
NBSa
NBSa
NBSb
TfOHc
trichloroisocyanuric acida imidazole
1,3-dichloro-5,5-dimethyl- imidazole
hydantoind
basee
Et3N, DMAP CH2Cl2 69
Et3N, DMAP DMF 21
solvent yield (%)f
Our initial approach to 3 involved lithiation of bromopoly-
styrene resin 42,7 (Scheme 1), followed by treatment with
imidazole
imidazole
2,6-lutidine
CH2Cl2 78
CH2Cl2 73
CH2Cl2
0
CH2Cl2 23g
Scheme 1. Synthesis of the TBDAS Linker.
CH2Cl2 93-100
a Performed with 2 equiv. b Performed with 10 equiv. c Performed with
6 equiv. d Performed with 12 equiv. e Base (8-12 equiv) was added to the
washed resin in the solvent indicated, followed by 3 equiv of N-Fmoc-â-
alaninol. f Yields determined by Fmoc quantitation, relative to Si loading
level determined by elemental analysis. g Not optimized.
N-bromosuccinimide,16 triflic acid,17 and trichloroisocyanuric
acid.4 The best results were achieved via chlorination using
1,3-dichloro-5,5-dimethylhydantoin,5b which afforded highly
efficient loading of N-Fmoc-â-alaninol (Fmoc quantitation)
relative to the silyl hydride loading level.18
We also investigated loading of the TBDAS linker onto
brominated polystyrene SynPhase L-Series Lanterns,19 which
were lithiated, silylated, chlorinated, and loaded with N-Fmoc-
â-alaninol as described above. Elemental analysis indicated
16-19 µequiv of Si per Lantern (45-55% yield based on
the initial Br loading level). Residual bromine was detected
at 5.7-6.7 µequiv of Br per Lantern (16-19%).20 Fmoc
quantitation indicated 13-18 µequiv of alcohol loaded per
Lantern (37-52% overall yield). Although these yields are
lower than those achieved using the polystyrene beads above,
tert-butyldichlorophenylsilane 5a, which is commercially
available, albeit at relatively high cost.10 A large molar excess
of 5a was used, both to drive the silylation reaction to
completion and to reduce the amount of anticipated intrabead
cross-linking. The support-bound silyl chloride 6a was then
treated with N-Fmoc-â-alaninol and imidazole in CH2Cl2.
We were encouraged to find that standard Fmoc quantita-
tion11 indicated 38% alcohol loading. However, in view of
the expensive dichlorosilane 5a required, we elected to
pursue a second-generation approach to provide more practi-
cal access to the TBDAS linker.
Thus, we synthesized the known monochlorosilane 5b12
by addition of t-BuLi to dichlorophenylsilane. The freshly
prepared and distilled monochlorosilane was then used to
silylate lithiated bromopolystyrene to afford the shelf-stable
silyl hydride resin 6b. After significant optimization, linker
loading levels of 1.03-1.39 mequiv/g were achieved (Si
elemental analysis), corresponding to a 60-81% yield
relative to the initial bromine loading level (see Supporting
Information). Residual bromine was also detected at 0-10%
of the initial loading level (Br elemental analysis).13 Additives
such as HMPA, CuCN,14 or TMSCN15 did not increase the
loading level.
(13) An alternative metalation with i-Pr(n-Bu)2MgLi has been reported
recently: Thomas, G. L.; Ladlow, M.; Spring, D. R. Org. Biomol. Chem.
2004, 2, 1679-1681. This procedure also provided efficient metalation
(0.6% residual Br, elemental analysis) but did not improve net linker loading
(49% yield, Si elemental analysis).
(14) Shirahata, A. Tetrahedron Lett. 1989, 30, 6393-6394.
(15) Lennon, P. J.; Mack, D. P.; Thompson, Q. E. Organometallics 1989,
8, 1121-1122.
(16) Petit, M.; Chouraqui, G.; Aubert, C.; Malacria, M. Org. Lett. 2003,
5, 2037-2040.
(17) (a) Hu, Y.; Porco, J. A. Tetrahedron Lett. 1999, 40, 3289-3292.
(b) Smith, E. M. Tetrahedron Lett. 1999, 40, 3285-3288.
(18) Overall loading level with 3 is comparable to the levels we achieved
using 1 (62-65%, Fmoc quantitation, relative to initial Br loading level)
and 2 (40-59%).
(7) Polymer Laboratories: PL-PBS Resin, 150-300 µm, 25%
p-bromostyrene, 1% divinylbenzene, 2.0 mequiv Br/g.
(8) For a report of an amide-linked anilino-tert-butylphenylsilyl linker,
see: Mullen, D. G.; Barany, G. J. Org. Chem. 1988, 53, 5240-5248.
(9) Hanessian, S.; Lavallee, P. Can. J. Chem. 1975, 53, 2975-2977.
(10) Lancaster Synthesis, $94.80/5 g.
(19) Mimotopes: SynPhase PS L-Series brominated Lanterns, 35 µequiv
Br/Lantern.
(11) Meienhofer, J.; Waki, M.; Heimer, E. P.; Lambros, T. J.; Makofske,
R. C.; Chang, C. D. Int. J. Pept. Protein Res. 1979, 13, 35-42.
(12) Maier, G.; Kratt, A.; Schick, A.; Reisenauer, H. P.; Barbosa, F.;
Gescheidt, G. Eur. J. Org. Chem. 2000, 1107-1112.
(20) Use of the alternative i-Pr(n-Bu)2MgLi metalation procedure (ref
13) yielded Lanterns with 16.1 µequiv of residual Br (46% of initial loading,
Br elemental analysis) and 12.7 µequiv of linker loading (36% yield, Si
elemental analysis).
1778
Org. Lett., Vol. 7, No. 9, 2005

we note that the loading leVel is on par with that for
commercially available Lanterns that are preloaded with other
linkers (15 µequiv) and is sufficient to produce up to 7-9
mg of cleaved product (500 MW) per Lantern.
Our attention next turned to developing suitable cleavage
conditions for TBDAS-linked alcohols (Table 2). Biphenyl-
Figure 2. Secondary alcohol and phenol were successfully loaded
onto and cleaved from the TBDAS linker.
Table 2. Cleavage of a TBDAS-Linked Alcohol
stability to various reaction conditions (Table 3). The
diisopropylsilyl linkers 1 and 2 were used for comparison.
Thus, biphenylmethanol 10 was loaded onto polystyrene
beads via each of the three linkers. The beads were exposed
to “stressing” conditions and washed thoroughly. The bi-
phenylmethanol remaining on the resin was cleaved with
TBAF and quantitated by HPLC analysis relative to internal
standard 9 as above.
cleavage conditions
temp (°C)
time (h)
cleavage (%)a
HF‚pyr, pyr, THF
HF‚pyr, pyr, THF
HF‚pyr, pyr, THF
Et3N‚3HF, Et3N, THF
NH4F, DMF
25
35
55
35
35
25
25
17
31
16
70
70
<1
<1
20
60
97
74
74
Table 3. Comparative Stability of Silyl Linkers to Various
Reaction Conditions
TBAF, THF
TAS-F, THF
100
100
3
1
2
entry
stressing conditionsa
recovered 10 (%)c
a Percent cleavage was determined by comparison of HPLC peak
integrations for 9 and 10, adjusted for extinction coefficients, relative to Si
or Fmoc quantitation of maximum loading level.
1
2
3
4
5b
6
7
8
TsOH, acetone, THF, 24 h, rt
TFA, CH2Cl2, 20 h, rt
BF3‚OEt2, CH2Cl2, 1.5 h, -78 °C
AlMe3, CH2Cl2, 20 h, rt
K2CO3, MeOH, 1 h, rt
KOt-Bu, THF, 1 h, rt
MeLi, THF, 1 h, rt
HF (aq), CH3CN, 24 h, rt
100
85
100
79
92
100
90
17
68
69
60
100
96
3
8
50
89
98
88
39
nd
methanol 10 was loaded onto polystyrene resin via the
TBDAS linker as described above. The beads were then
exposed to cleavage conditions in the presence of an internal
standard 9, and the amount of cleaved biphenylmethanol was
determined by HPLC analysis.21
69
nd
100
a Each reagent was used as a 0.2 M solution. b Used as a 0.1 M solution.
c Average of two experiments, relative to the amount of biphenylmethanol
recovered from unstressed resin. Maximum standard deviation ) 5.7%.
nd ) not determined.
Interestingly, in contrast to 2, hydrogen fluoride‚pyridine
(HF‚pyr) cleavage of the TBDAS linker proceeded slowly
at room temperature. However, the alcohol could be released
at elevated temperature and recovered by quenching of the
excess HF with TMSOMe and simple evaporation.22 Tet-
rabutylammonium fluoride (TBAF) also induced rapid cleav-
age at room temperature, and the alcohol could be recovered
in g90% purity by filtration through a short plug of normal-
phase and reverse-phase silica gel, or by treatment with
Amberlyst A15 acidic resin, to remove the residual tetrabu-
tylammonium salts. The extremely mild tris(dimethylamino)-
sulfur (trimethylsilyl)difluoride (TAS-F)23 reagent also ef-
fected rapid, efficient cleavage, providing an alternative to
TBAF for base-sensitive substrates.
The secondary alcohol 11 and the phenol 12 (Figure 2)
were also successfully loaded onto and cleaved from the
TBDAS linker under our standard conditions (two-step
yields, NMR quantitation vs internal standard 13).
With optimized procedures in hand for synthesis, loading,
and cleavage of the TBDAS linker, we next investigated its
We were gratified to find that our TBDAS linker 3 is
substantially more stable to protic acids than the previously
reported diisopropylsilyl linkers 1 and 2 (entries 1, 2).
Moreover, the TBDAS linker exhibits good stability to Lewis
acids (entries 3, 4) and also performs well under basic
conditions (entries 5-7). All three linkers were stable to
ZnCl2 and t-BuLi (not shown). Finally, we noted that the
TBDAS linker 3 is stable to extended exposure to aqueous
HF in CH3CN (entry 8), raising the intriguing possibility of
using orthogonal HF-labile protecting groups in solid-phase
synthetic schemes.
To investigate the feasibility of this idea, 4-(tert-butyl-
dimethylsilyloxymethyl)benzyl alcohol24 was loaded onto
polystyrene resin via the TBDAS linker and then treated with
HF‚pyr buffered with pyridine at room temperature (Scheme
2). The resin was washed and subjected to exhaustive
acetylation. Cleavage with TAS-F in the presence of internal
standard 13 provided the acetate 15a in g85% purity (55%
(21) Sternson, S. M.; Schreiber, S. L. Tetrahedron Lett. 1998, 39, 7451-
7454.
(22) Hu, Y.; Porco, J. A. Tetrahedron Lett. 1998, 39, 2711-2714.
(23) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437.
(24) Cumming, J. N.; Wang, D. S.; Park, S. B.; Shapiro, T. A.; Posner,
G. H. J. Med. Chem. 1998, 41, 952-964.
Org. Lett., Vol. 7, No. 9, 2005
1779

and then treated with Leighton’s allylsilane reagent26 22
(Scheme 4). The resulting homoallylic alcohol 23a was
Scheme 2. Silyl Protecting Group Manipulation.
Scheme 4. Ozonolysis and Asymmetric Allylation of
TBDAS-Linked Substrates.
over four steps, NMR quantitation). Diol 15b, whose
presence would indicate incomplete removal of the TBS
group by HF‚pyr, was not detected. Thus, this experiment
provides a preliminary indication that such silyl protecting
group manipulations are, indeed, possible with the TBDAS
linker.
We next carried out other representative solid-phase
reactions using substrates attached to polystyrene resin via
the TBDAS linker. As hoped, the acetal deprotection reaction
that had originally caused premature cleavage of alkyldiiso-
propylsilyl linker 2 proceeded efficiently with the TBDAS-
linked substrate 16a, with no evidence of substrate cleavage
(Scheme 3). The resulting resin-bound aldehyde 17a was then
cleaved from the resin and then selectively protected at the
primary hydroxyl group with TBDPSCl to provide 23b.
Separately, 23b was also synthesized in solution from the
TBDPS-protected analogue 21b. We were pleased to find
that Mosher ester analysis27 of both the solid- and solution-
phase synthesis-derived alcohols 23b indicated identical
levels of enantiomeric excess. Thus, the stereogenic Si center
of the TBDAS linker did not adversely affect the stereose-
lectivity of this asymmetric allylation reaction.
In conclusion, we have developed a versatile new TBDAS
linker for solid-phase organic synthesis. This linker has
marked advantages over previously reported silyl linkers in
that it is stable to protic and Lewis acidic reaction conditions.
Furthermore, TBDPS-protected alcohols can be used as
convenient solution-phase analogues for reaction develop-
ment. We have demonstrated that the TBDAS linker can be
cleaved under mild, chemoselective conditions to afford
cleavage products in high purity and yield. The TBDAS
linker is compatible with acetal deprotection, Wittig and Julia
coupling, asymmetric allylation, and even silyl protecting
group manipulation reactions. This new linker should be a
valuable addition to the chemist’s toolkit for solid-phase
organic synthesis.
Scheme 3. Acetal Deprotection and Aldehyde Olefinations of
TBDAS-Linked Substrates.
Acknowledgment. We thank Mr. James Roge´r and Prof.
Kwesi Amoa for carrying out preliminary experiments and
Dr. George Sukenick, Anna Dudkina, Hui Fang, and Sylvia
Rusli (MSKCC Analytical Core Facility) for mass spectral
analyses. Financial support from the NIH (CA104685), the
William Randolph Hearst Fund in Experimental Therapeu-
tics, Mr. William H. Goodwin and Mrs. Alice Goodwin and
the Commonwealth Foundation for Cancer Research, and
the Experimental Therapeutics Center of MSKCC is grate-
fully acknowledged.
converted to (E)- and (Z)-olefins 18a and 19a via Julia and
Wittig couplings, respectively.25 TBAF cleavage provided
the (E)-olefin 18c (69% over four steps, >8.5:1 E/Z, NMR
quantitation vs internal standard 10) and the (Z)-olefin 19c
(74% over four steps, >20:1 Z/E). Notably, optimization of
this reaction sequence was facilitated by use of the TBDPS-
protected solution-phase analogues 16b-19b.
We recognized that direct coupling of the TBDAS linker
to the polystyrene support resulted in a stereogenic Si center
that might adversely affect asymmetric reactions of support-
bound substrates. Such reactions are of increasing interest
for introducing stereochemical diversity, and hence increased
structural diversity, in DOS. To investigate this possibility,
3-buten-1-ol was loaded onto polystyrene resin via the
TBDAS linker, converted to aldehyde 21a by ozonolysis,
Supporting Information Available: Experimental pro-
cedures and analytical data for 5b, 6b, 7, 9, 10, 15a, 17a,
18c, 19c, 21a, and 23a,b. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL050370Y
(26) Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X. L.; Leighton,
J. L. J. Am. Chem. Soc. 2002, 124, 7920-7921.
(27) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549.
(25) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-
2585. (b) Maryanoff, B. E.; Reitz, A. B. Chem. ReV. 1989, 89, 863-927.
1780
Org. Lett., Vol. 7, No. 9, 2005