Concerning the selective protection of (Z)-1,5-syn-ene-diols and (E)-1,5-anfi-ene-diols as allylic triethylsilyl ethers

Article abstract of DOI:10.1021/ol702588h

Treatment of unsaturated 1,5-diols 2 with TES-CI (1.1 equiv), imidazole, and catalytic DMAP in 1:1 CH₂Cl₂-DMF at -78 °C effects selective silylation of the allylic alcohol with >95:5 chemoselectivity when the allylic and homoallylic

Full text of DOI:10.1021/ol702588h

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5621-5624
Concerning the Selective Protection of
(Z)-1,5-syn-Ene-diols and
(E)-1,5-anti-Ene-diols as Allylic
Triethylsilyl Ethers
Jacqueline D. Hicks, Chan Woo Huh, Ashley D. Legg, and William R. Roush*
Department of Chemistry, Scripps Florida, Jupiter, Florida 33458
roush@scripps.edu
Received October 25, 2007
ABSTRACT
Treatment of unsaturated 1,5-diols 2 with TES-Cl (1.1 equiv), imidazole, and catalytic DMAP in 1:1 CH2Cl2−DMF at −78 °C effects selective
silylation of the allylic alcohol with >95:5 chemoselectivity when the allylic and homoallylic alcohols are in similar steric environments.
Our laboratory has reported a one-pot double allylboration
reaction involving the sequential reaction of two aldehydes
with the γ-boryl-substituted allylboranes 1 and 3 which
provides (Z)-1,5-syn-diols 2 and (E)-1,5-anti-diols 4, respec-
tively, with excellent diastereo- and enantioselectivity (Figure
1).1 In order to apply this method to the synthesis of
structurally complex targets, including natural products, it
is sometimes necessary to differentiate the two alcohols that
result from the one-pot double allylboration reaction.2 We
have previously reported that the allylic alcohol unit of 2
can be selectively protected with modest chemoselectivity
as TBS ethers.3 We have examined this reaction in greater
Figure 1. Synthesis of (Z)-1,5-syn-diols and (E)-1,5-anti-diols.
depth and report herein that optimal selectivity (g95:5) is
achieved by treating sterically unbiased diols 2 and 4 with
differences in the steric environment surrounding the two
hydroxyl groups.
triethylsilyl chloride (TES-Cl), imidazole, and catalytic
DMAP in 1:1 CH2Cl2-DMF at -78 °C. This selective
silylation of the allylic alcohol is attributed to subtle
While examples are known of the selective silylation of a
secondary allylic alcohol in the presence of a saturated
secondary alcohol, the majority of cases involve sterically
hindered or geometrically biased substrates in which the
allylic alcohol undergoes preferential silylation.4,5 Relatively
few examples of chemoselective silylation of allylic alcohols
in the presence of saturated alcohols on substrates that lack
(1) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
(2) (a) Hicks, J. D.; Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7,
5509. (b) Flamme, E. M.; Roush, W. R. Org. Lett. 2005, 7, 1411. (c) Lira,
R.; Roush, W. R. Org. Lett. 2007, 9, 533. (d) Owen, R. M.; Roush, W. R.
Org. Lett. 2005, 7, 3941.
(3) Flamme, E. M.; Roush, W. R. Beilstein J. Org. Chem. 2005, 1, 7.
10.1021/ol702588h CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/21/2007

a steric bias have been reported.3,6 With this background in
mind, we examined the selective protection of diol 52a (Table
1). Examination of reaction conditions previously applied
of TES-Cl, imidazole (1.15 equiv), and DMAP (0.05 equiv)
in 1:1 CH2Cl2-DMF at -78 °C (entry 3).8
The optimal silylation conditions defined for 5 provided
high levels of selectivity for allylic alcohol silylation with
other unsaturated (Z)-1,5-syn-diols (Table 2).9 Pseudo-
Table 1. Optimization of Selective Silylation Conditions
Table 2. Selective Protection of (Z)-1,5-syn-Diols
allylic/
bis-TES recovered
1,5-diol
entry
1
conditionsa
yield homoallylic ether
TBS-Cl (1.05 equiv), 39% 86:14
imidazole, DMAP,
CH2Cl2-DMF
NA
58%
rt, 2 days
2
3
TES-Cl (1.05 equiv), 65
imidazole, DMAP,
CH2Cl2-DMF
>95:5
7%
8%
0 °C, 2 h
TES-Cl (1.1 equiv),
imidazole, DMAP,
CH2Cl2-DMF
81
>97:3
14%
NA
-78 °C, 2 h
a With 1.15 equiv of imidazole, 0.05 equiv of DMAP.
to sterically unbiased substrates (TBS-Cl, imidazole, DMAP,
rt)3 provided a 39% yield of the mono-TBS ether consisting
of an 86:14 mixture of allylic silyl ether 6 and the
corresponding homoallylic silyl ether (entry 1). After explor-
ing other conditions,7 we found the yield and chemoselec-
tivity of silylation could be improved through the use of the
more reactive silylating reagent, TES-Cl, which allowed these
reactions to proceed at lower reaction temperatures. Optimal
reaction conditions involved treatment of 5 with 1.1 equiv
a Reactions were performed by treating a solution of the 1,5-diol (1
equiv), imidazole (1.15 equiv), and DMAP (0.05 equiv) in CH2Cl2-DMF
(1:1, 0.1 M) at -78 °C with TES-Cl (1.1 equiv). b Combined yield of mono-
TES ethers (allylic and homoallylic). c Bis-TES ethers were obtained as
follows: entry 1, 17%; entry 2, 6%; entry 3, not isolated; entry 4, 12%;
entry 5, 9% yield.
(4) (a) Chen, S.-H.; Wei, J.-M.; Vyas, D. M.; Doyle, T. W.; Farina, V.
Tetrahedron Lett. 1993, 34, 6845. (b) Wyatt, P. G.; Coomber, B. A.; Evans,
D. N.; Jack, T. I.; Fulton, H. E.; Wonacott, A. J.; Colman, P.; Varghese, J.
Bioorg. Med. Chem. Lett. 2001, 11, 669. (c) Kaneko, M.; Nakashima, T.;
Uosaki, Y.; Hara, M.; Ikeda, S.; Kanda, Y. Bioorg. Med. Chem. Lett. 2001,
11, 887. (d) Horiguchi, T.; Oritani, T.; Kiyota, H. Tetrahedron 2003, 59,
1529. (e) Nicolaou, K. C.; Koftis, T. V.; Vyskocil, S.; Petrovic, G.; Ling,
T.; Yamada, Y. M. A.; Tang, W.; Frederick, M. O. Angew. Chem., Int. Ed.
2004, 43, 4318. (f) Jaunzems, J.; Kashin, D.; Schonberger, A.; Kirschning,
A. Eur. J. Org. Chem. 2004, 3435. (g) Cho, J. H.; Dernard, D. L.; Sidwell,
R. W.; Kern, E. R.; Chu, C. K. J. Med. Chem. 2006, 49, 1140.
(5) (a) Ramsay, M. V. J.; Roberts, S. M.; Russell, J. C.; Shingler, A. H.;
Slawin, A. M. Z.; Sutherland, D. R.; Tiley, E. P.; Williams, D. J.
Tetrahedron Lett. 1987, 28, 5353. (b) Bliard, C.; Escribano, F. C.; Lukacs,
G.; Olesker, A.; Sarda, P. J. Chem. Soc., Chem. Commun. 1987, 368. (c)
Banks, B. J.; Bishop, B. F.; Evans, N. A.; Gibson, S. P.; Goudie, A. C.;
Gration, K. A. F.; Pacey, M. S.; Perry, D. A.; Witty, M. J. Bioorg. Med.
Chem. 2000, 8, 2017. (d) Konoki, K.; Sugiyama, N.; Murata, M.; Tachibana,
K.; Hatanaka, Y. Tetrahedron 2000, 56, 9003. (e) Crimmins, M. T.; Katz,
J. D.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc.
2002, 124, 5661. (f) Nagai, K.; Sunazuka, T.; Omura, S. Tetrahedron Lett.
2004, 45, 2507.
symmetrical 1,5-diols 81 and 106 which contain the same R1
and R2 substituents were silylated with excellent levels of
chemoselectivity, providing nearly exclusive formation of
the allylic silyl ether (entries 1 and 2). With substrates 10
and 12 (entries 2 and 3) that have increased steric bulk around
the 1,5-diol core, improved yields of the allylic monosilyl
ethers 11 and 13 were obtained since formation of the bis-
silyl ether product was suppressed (e6% yield). The selective
protection of dienylic alcohol 14, an intermediate in the
(6) (a) Karanewsky, D. S. Tetrahedron Lett. 1991, 32, 3911. (b) Marco-
Contelles, J.; de Opazo, E. J. Org. Chem. 2000, 65, 5416. (c) Smith, A. B.,
III; Adams, C. M.; Barbosa, S. A.; Degnan, A. P. J. Am. Chem. Soc. 2003,
125, 350. (d) Terauchi, T.; Tanaka, T.; Terauchi, T.; Morita, M.; Kimijima,
K.; Sato, I.; Shoji, W.; Nakamura, Y.; Tsukada, T.; Tsunoda, T.; Hayashi,
G.; Kanoh, N.; Nakata, M. Tetrahedron Lett. 2003, 44, 7747.
(8) The use of imidazole improved the selectivity for allylic alcohol
silylation compared to other bases, while DMF and DMAP have little effect
on chemoselectivity. See Supporting Information for details.
(9) The identity of the major products as the allylic TES ethers was
confirmed by acylation (Ac2O, DMAP) of the homoallylic hydroxyl groups
to give the homoallylic acetate that was characterized by 1H NMR
spectroscopy.
(7) A table of other conditions examined during efforts to optimize the
selectivity of silylation of diol 8 is provided in the Supporting Information.
5622
Org. Lett., Vol. 9, No. 26, 2007

synthesis of amphidinol 3,2b proceeds in good yield and
chemoselectivity (76%, >97:3, entry 4).
The scope of this selective protection reaction is not limited
to (Z)-1,5-syn-diols, as (E)-1,5-anti-diols can also be monosi-
lylated with good chemoselectivity (Table 3). Therefore, the
between allylic and homoallylic alcohols. Generally, the pKa
values of alcohols that are adjacent to an alkene or alkyne
are lower than those of the corresponding saturated alcohols
due to the increased electronegativity of the unsaturated
substituents.12 The increased acidity of the allylic alcohol
could potentially facilitate hydrogen bonding to the base,
thereby increasing the nucleophilicity of the allylic alcohol
relative to the homoallylic alcohol. The second hypothesis
focused on the subtle differences in the steric environment
surrounding the allylic and homoallylic alcoholssnamely,
the additional hydrogen atom flanking the homoallylic
position. This hypothesis was initially less appealing because
it did not appear to account for the allylic selective silylation
of (E)-1,5-anti-diol 24 (Table 3), which contained a more
sterically demanding cyclohexyl ring adjacent to the allylic
alcohol.
Table 3. Selective Protection of (E)-1,5-anti-Diols
Table 4. Protection of Electronically Biased Substrates at
Room Temperature
a Reactions were performed by treating a solution of the 1,5-diol (1
equiv), imidazole (1.15 equiv), and DMAP (0.05 equiv) in CH2Cl2-DMF
(1:1, 0.1 M) at -78 °C with TES-Cl (1.1 equiv). b Combined yield of mono-
TES esters (allylic and homoallylic). c Bis-TES ethers were obtained as
follows: entry 1, 20%; entry 2, 2%, entry 3, 2%, entry 4, 16%, entry 5,
16%.
selectivity for allylic alcohol silylation is not due to confor-
mational effects specific to (Z)-1,5-syn-diols, e.g., deriving
from A1,3 interactions,10 or to an intramolecular hydrogen
bonding network.11 Substrates 18 and 20 containing similar
steric environments surrounding the allylic and homoallylic
positions provided allylic silyl ethers 19 and 21 with g95:5
chemoselectivity. Increasing the size of the homoallylic
substituent relative to the allylic substituent (22, entry 3) led
to an improved yield of the allylic TES ether as less bis-
silylation product was generated (2%). Increasing the size
of the group neighboring the allylic alcohol, relative to the
substituent adjacent to the homoallylic alcohol, as in 24, led
to decreased selectivity for allylic alcohol protection, al-
though interestingly, silylation of this position was still
favored (84:16, entry 4). Modification of the sterics and
electronics of the system by introduction of an ester at the
homoallylic position (26) led to a decreased selectivity for
silylation of the allylic alcohol (77:22, entry 5).
a Reactions were performed by treating a solution of the 1,5-diol (1
equiv), imidazole (1.15 equiv), and DMAP (0.05 equiv) in CH2Cl2-DMF
(1:1, 0.1 M) at rt with TES-Cl (1.1 equiv). b Combined yield of mono-TES
ethers (allylic and homoallylic).
We decided to investigate the first hypothesis by adjusting
the acidities of the allylic and homoallylic alcohols. To probe
the effect of changing the pKa of the two hydroxyl groups,
a series of substrates were synthesized that contained similar
steric environments but differing electronic environments
(Table 4). Silylation of 1,5-diol 28 containing phenyl groups
We considered two hypotheses to account for the selective
allylic alcohol silylation presented in Tables 2 and 3. The
first hypothesis focused on the differences in acidities
(12) The pKa of allyl alcohol is 15.5, while that of 1-propanol is 16.1.
Serjeant, E. P.; Dempsey, B. IUPAC Chemical Data Series, No. 23:
Ionization Constants of Organic Acids in Aqueous Solution; Pergamon: New
York, 1979.
(10) Hoffman, R. W. Chem. ReV. 1989, 89, 1841.
(11) Haines, A. H. Tetrahedron Lett. 1969, 15, 1201.
Org. Lett., Vol. 9, No. 26, 2007
5623

in both the R1 and R2 positions provided an 88:12 mixture
of regioisomers at room temperature. The placement of an
electron-withdrawing group on the aryl ring neighboring the
homoallylic alcohol as in 30 and 32 (entries 2 and 3, Table
4) was predicted to decrease the amount of allylic alcohol
silylation due to the increased acidity of the homoallylic
alcohol.13 However, TES protection of 30 and 32 resulted
in increased allylic alcohol protection, providing 31 and 33
with 95:5 and 94:6 selectivity, respectively (at room tem-
perature). The installment of an electron-withdrawing group
on the aryl ring neighboring the allylic alcohol as in entry 4
(Table 4) resulted in a decrease in allylic selectivity, lowering
the allylic/homoallylic silyl ether ratio to nearly 50:50. These
results contradict the hypothesis that the greater acidity of
the allylic alcohol results in preferential silylation. Rather,
these results suggest instead that electron-withdrawing groups
neighboring an alcohol affect selectivity by decreasing the
nucleophilicity of that position (Table 4).14,15
We also investigated the relationship between the stoi-
chiometry of triethylsilyl chloride and the yield and chemose-
lectivity of the selective silylation reaction (Table 6). We
Table 6. Effect of Increasing Equivalents of TES-Cl on Ratio
of Allylic/Homoallylic Ethers
equiv of
TES-Cl
bis-TES
mono-TES
allylic/
homoallylica
recovered
SM 8
36
9
0.10
0.25
0.50
0.75
0.90
1.1
-
-
2%
6%
4%
17%
6%
16%
35%
54%
57%
61%
94:6
94:6
95:5
95:5
96:4
98:2
ND
ND
ND
30%
25%
10%
Data summarized in Table 5 for silylation of 8 with a series
a Allylic/homoallylic TES ether ratio determined by NMR spectroscopy
(integration of homoallylic protons; S/N > 200:1, relaxation delay (d1) of
g6 s).
Table 5. Variation of Silyl Chloride
observed that increasing the equivalents of TES-Cl in the
reaction led to an increase in the ratio of allylic/homoallylic
silyl ether products, from 94:6 when 0.1 equiv of TES-Cl is
used (entry 1) to 98:2 when 1.1 equiv of TES-Cl is used
(entry 6). These data imply that some of the initially formed
homoallylic mono-TES ether undergoes a second silylation
to give the 1,5-bis-protected ether 36 somewhat faster than
the second silylation of homoallylic ether 9. It is quite clear
from the data in Table 6 that homoallylic TES ether 9 is
formed with excellent selectivity even at short conversion.
In conclusion, the selective protection of the allylic alcohol
unit of unsaturated 1,5-diols 2 and 4 proceeds with high
selectivity for substrates in which the allylic and homoallylic
alcohols are in otherwise similar steric environments. These
reactions are optimally executed at low temperatures using
TES-Cl as the silylating agent and provide the allylic TES
ethers in good yields (typically 61-81%). The decreased
steric environment surrounding the allylic alcohol relative
to that surrounding the homoallylic alcohol is invoked to
rationalize the selective allylic alcohol silylation described
herein.
silyl
mono-silyl
9a-e
allylic/
homoallylic
recovered
SM
chloridea
bis-silyl
TMS
27%
16%
8%
12%
5%
26%
59%
55%
53%
54%
78:22
89:11
89:11
92:8
19%
14%
33%
33%
27%
TES-Cl
TBS-Cl
TBDPS-Cl
TIPS
94:6
a Reactions were performed by treating a solution of the 1,5-diol (1
equiv), imidazole (1.15 equiv), and DMAP (0.05 equiv) in CH2Cl2-DMF
(1:1, 0.1 M) at room temperature with silyl chloride (1.1 equiv).
of trialkylsilyl chlorides are consistent with the second
hypothesis that selective silylation of the allylic alcohol
derives from the fact that the olefin adjacent to the allylic
alcohol is less sterically demanding than the methylene group
neighboring the homoallylic alcohol. The results summarized
in Table 5 show the ratio of allylic to homoallylic silyl ether
improves as the size and steric demands of the silyl chloride
is increased.
Acknowledgment. This work was supported by the
National Institutes of Health (GM038436).
(13) (a) Marin, M. A. B.; Nome, F.; Zanette, D.; Zucco, C.; Romsted,
L. S. J. Phys. Chem. 1995, 99, 10879. (b) Strong, L. E.; Brummel, C. L.;
Lindower, P. J. Solution Chem. 1987, 16, 105.
(14) (a) Phan, T. B.; Mayr, H. Can. J. Chem. 2005, 83, 1554. (b)
Minegishi, S.; Mayr, H. J. Am. Chem. Soc. 2003, 125, 286.
(15) Example in 1,2-diol system: Sunazuka, T.; Hirose, T.; Harigaya,
Y.; Takamatsu, S.; Hayashi, M.; Komiyama, K.; Omura, S.; Sprengeler, P.
A.; Smith, A. B., III. J. Am. Chem. Soc. 1997, 119, 10247.
Supporting Information Available: Experimental pro-
cedures and tabulated spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702588H
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Org. Lett., Vol. 9, No. 26, 2007