Stereoselective synthesis of syn,syn and syn,anti-1,3,5-triols via intramolecular hydrosilylation of substituted pent-3-en-1,5-diols

Article abstract of DOI:10.1021/ol9009877

A stereoselective method for synthesis of syn,syn- and syn,anti-1,3,5- trlols based on a double allylboration-Intramolecular hydrosllylation sequence has been developed. The 1,3-syn stereocontrol is achieved in the Intramolecular hydrosllylation of monopr

Full text of DOI:10.1021/ol9009877

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2932-2935
Stereoselective Synthesis of syn,syn-
and syn,anti-1,3,5-Triols via
Intramolecular Hydrosilylation of
Substituted Pent-3-en-1,5-diols
Fangzheng Li and William R. Roush*
Department of Chemistry, Scripps-Florida, Jupiter, Florida 33458
roush@scripps.edu
Received May 5, 2009
ABSTRACT
A stereoselective method for synthesis of syn,syn- and syn,anti-1,3,5-triols based on a double allylboration-intramolecular hydrosilylation
sequence has been developed. The 1,3-syn stereocontrol is achieved in the intramolecular hydrosilylation of monoprotected (Z)-1,5-syn-diols
and (E)-1,5-anti-diols with 87:13 to 95:5 and 86:14 to 88:12 diastereomeric ratios, respectively, by using 0.5 mol % of Karstedt’s catalyst in
toluene.
The 1,3,5-triol motif is a common subunit of many biologi-
cally active natural products.1,2 Consequently, the stereose-
Scheme 1
.
Intramolecular Hydrosilylation of Homoallylic
lective synthesis of these units has attracted much interest.1,3
During the course of our efforts toward the synthesis of
polyketide natural products, we became interested in explor-
ing the intramolecular hydrosilylation of substituted pent-
3(Z)-en-1,5-syn- and (E)-1,5-anti-diol monoethers, 1 and 5,
respectively, which are prepared using our double allylbo-
ration methodology,4 as a strategy for synthesis of syn,syn-
and syn,anti-1,3,5-triols 4 and 6, respectively (Scheme 1).
Alcohols 1 and 5
(1) For a review, see: Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021
.
(2) For several specific examples, see: (a) Hazen, E. L.; Brown, R.
Science 1950, 112, 423. (b) Kobinata, K.; Koshino, H.; Kudo, T.; Isono,
K.; Osada, H. J. Antibiot. 1993, 46, 1616. (c) Dong, L.; Victoria, A. G.;
Grange, R. L.; Johns, J.; Parsons, P. G.; Porzelle, A.; Reddell, P.; Schill,
Intramolecular hydrosilylation of acyclic homoallylic alcohols
followed by oxidative cleavage of the resultant carbon-silicon
bond presents a mild and efficient way to construct 1,3-diols.5-7
Several publications by the Tamao group described the regio-
and stereocontrolled synthesis of 1,3-diols from allylic and
H.; Williams, C. M. J. Am. Chem. Soc. 2008, 130, 15262
.
(3) For recent examples and additional reviews, see: (a) Zhang, Z.;
Aubry, S.; Kishi, Y. Org. Lett. 2008, 10, 3077. (b) Bode, S. E.; Wolberg,
M.; Muller, M. Synthesis 2006, 557. (c) Schneider, C. Angew. Chem., Int.
Ed. 1998, 37, 1375. (d) Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95,
2041
.
(5) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito, Y.
(4) Flamme, E. M.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 13644.
J. Am. Chem. Soc. 1986, 108, 6090
.
10.1021/ol9009877 CCC: $40.75
Published on Web 06/09/2009
 2009 American Chemical Society

homoallylic alcohols.5,6a However, 1,3-stereochemical con-
trol was not observed in hydrosilylation reactions of acyclic
(E)- and (Z)-disubstituted homoallylic alcohols by using
Speier’s catalyst (H2PtCl6·6H2O).5,8 Further investigations of
the 1,3-diastereoselective intramolecular hydrosilylation of
homoallylic alcohols have not been reported. We report
herein our studies of this reaction, using homoallylic alcohols
1 and 5 as the substrates, which demonstrate that syn,syn-
diols 4 and syn,anti-diols 6 are obtained with 87-95% and
84-88% diastereoselectivity, respectively, by using 0.5 mol
% of Karstedt’s catalyst9 in toluene.
Scheme 3. Synthesis of syn-1,3-Diol 15 and Proposal for Origin
of 1,3-syn Stereocontrol
Syntheses of 1,5-diol derivatives 1 and 5 were ac-
complished as summarized in Scheme 2. Sequential treatment
with excellent diastereo- and enantioselectivity.4 Treatment
of 1,5-diols 8 and 10 with 1.1 equiv of TES-Cl or TBS-Cl,
imidazole, and catalytic DMAP in CH2Cl2-DMF furnished
the targeted monosilyl ethers 1 and 5 with excellent
chemoselectivity and good yield (see Supporting Information
for details).10 We used homoallylic alcohol 11 to screen
catalysts and reaction conditions for the intramolecular
hydrosilylation reaction. We elected to use Speier’s catalyst8
(PtCl6·6H2O), Karstedt’s catalyst9 (14, platinum(0)-1,3-
divinyl-1,1,3,3-tetramethyl-disiloxane), and Pt(PPh3)4,11 be-
cause of their commercial availibility and known utility as
catalysts for hydrosilylation reactions. Hence, a mixture of
homoallylic alcohol 11 and (HMe2Si)2NH (2 equiv) was
stirred at room temperature overnight to ensure silylation of
the hydroxy group. The excess disilazane was removed under
Scheme 2. Synthesis of Monoprotected 1,5-Diols 1 and 5
of two aldehydes with γ-borylallylboranes 7 or 9 provided
(Z)-1,5-syn-diols 8 and (E)-1,5-anti-diols 10, respectively,
Table 1. Optimization of Conditions for Intramolecular
Hydrosilylation of (Z)-1,5-syn-Diol Monosilyl Ether 11
Table 2. Intramolecular Hydrosilylation of (Z)-1,5-syn-Diol
Monosilyl Ethers 19, 21, 23, and 25
a
1
Diastereomeric ratio and reaction conversion were determined by H
a Diastereomeric ratio determined by NMR spectroscopy.
NMR analysis of the reaction mixture.
Org. Lett., Vol. 11, No. 13, 2009
2933

Table 3. Optimization of Intramolecular Hydrosilylation of (E)-1,5-anti-Diol Monosilyl Ether 27
entry
hydrosilylation conditions
dr (syn:anti)a
conversion (%)a
1
2
3
0.5 mol %, H2PtCl6·6H2O toluene, 110 °C, 12 h
5 mol %,Pt(PPh3)4 toluene, 110 °C, 5 h
0.5 mol %, Karstedt’s catalyst (14) toluene, 0 °C, 2 h
then rt, 2 h
69:31
82:18
85:15
∼80
∼80
∼100
4
5
0.5 mol %, Karstedt’s catalyst (14) THF, 0 °C, 2 h then rt, 2 h
0.5 mol %, Karstedt’s catalyst (14) hexane, 0 °C, 2 h
then rt, 2 h
77:23
78:22
∼100
∼100
6
0.5 mol %, Karstedt’s catalyst (14) toluene, -40 °C, 10 h,
then 0 °C, 2 h and rt, 2 h
85:15
∼100
a
1
Diastereomeric ratio and reaction conversion were determined by H NMR analysis of the crude reaction mixture.
vacuum, and then the silane intermediate was subjected to a
range of hydrosilylation conditions as summarized in Table
1.
Speier’s catalyst (85:15 dr) and Pt(PPh3)4 (70:30 dr). The
stereochemistry of of siloxane 12 was assigned as discussed
subsequently. The overall reaction diastereoselectivity was
best in toluene and hexanes among the solvents that we
examined (entries 3-5).
Intermediate 12 was oxidized to 1,3-syn diol 15 by
treatment with 30% H2O2 (20 equiv) and KHCO3 (5 equiv)
in THF-MeOH (Scheme 3).12 The overall yield of 15 was
85% for this three-step sequence starting from 11.
The stereochemistry of 15 was assigned by conversion to
acetonide 16 (Scheme 3). 13C NMR analysis of 16 according
to Rychnovsky’s method13 established the 1,3-cis acetonide
stereochemistry. This also confirmed the 1,3-synstereochem-
istry of hydrosilylation product 12, since the oxidative
cleavage of the C-Si bond is known to proceed with
retention of configuration.12
The results indicated that hydrosilylation of 11 using 0.5
mol % of Karstedt’s catalyst (14) in toluene proceeded to
completion very smoothly at 0 °C in 3 h (entry 3). On the
other hand, elevated temperatures and longer reaction times
were needed for complete hydrosilylation using Speier’s
catalyst (0.5 mol %, 60 °C, 12 h, entry 1) and Pt(PPh3)4 (5
mol %, 110 °C, 5 h, entry 2). More importantly, use of
Karstedt’s catalyst (14) led to superior 1,3-syn diastereose-
lectivity (93:7), compared to the selectivity obtained by using
Table 4. Intramolecular Hydrosilylation of Monoprotected
(E)-1,5-anti-Diols
Tamao has suggested that the Pt-catalyzed intramolecular
hydrosilylation reaction preceeds through an oxidative
addition-hydrometalation-reductive elimination sequence.14
We speculate that the origin of 1,3-syn stereocontrol could
derive from a chairlike transition state 17 for the 6-exo
hydrometalation step with the olefin in a pseudoequatorial
position (Scheme 3). Intermediate 18 could then undergo
reductive elimination to provide the five-membered syn-
cyclic siloxane 3.
Having developed suitable conditions for intramolecular
hydrosilylation of 11, we explored the scope of this sequence
with additional substrates as summarized in Table 2. The
(Z)-1,5-syn-diol monosilyl ethers 19, 21, 23, and 25 were
converted into the corresponding syn,syn-1,3,5-triol mono-
(6) (a) Tamao, K.; Nakagawa, Y.; Arai, H.; Higuchi, N.; Ito, Y. J. Am.
Chem. Soc. 1988, 110, 3712. For other examples of intramolecular
hydrosilylation of acyclic allylic and homoallylic alcohols (the latter of
which are controlled by minimization of allylic interactions), see: (b) Young,
D. G. J.; Hale, M. R.; Hoveyda, A. H. Tetrahedron Lett. 1996, 37, 827. (c)
Hoveyda, A. H.; Hale, M. R. J. Org. Chem. 1992, 57, 1643. (d) Denmark,
S. E.; Forbes, D. C. Tetrahedron Lett. 1992, 33, 5037.
(7) For an example of polyol synthesis via intramolecular silylformation-
allylsilylation, see: Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000,
122, 8587.
a Diastereomeric ratio determined by NMR spectroscopy.
(8) Speier, J. L. AdV. Organomet. Chem. 1979, 17, 407.
2934
Org. Lett., Vol. 11, No. 13, 2009

Table 5. Effect of Silane Substituents on the Intramolecular Hydrosilylation Reaction
entry
R
hydrosilylation conditions
dr (syn:anti)
yield (%)
1
2
3
Me (36)
Ph (37)
i-Pr (38)
0.5 mol %, Karstedt’s catalyst toluene, 0 °C, 2 h then rt, 1 h
0.5 mol %, Karstedt’s catalyst toluene, rt, 12 h
0.5 mol %, Karstedt’s catalyst toluene, 110 °C, 12 h
84:16
84:16
81
80
0
ethers 20, 22, 24, and 26, respectively, in 72-78% yield
with 87: 13 to 95: 5 diastereoselectivity. This procedure
worked well for the sterically demanding substrate 23 (Table
2, entry 3). Moreover, from a practical standpoint, this
reaction can be performed essentially as a one-pot operation
without purification of the silyl ether and cyclic siloxane
intermediates.
internal olefin, leaving the distal trisubstitute olefin intact
without any olefin isomerization or intermolecular hydrosi-
lylation products being observed.
We also investigated the effect of greater steric bulk in
the silane unit in an attempt to improve the diastereoselec-
tivity of the intramolecular hydrosilylation process. Accord-
ingly, substrates 36, 37, and 38 were synthesized and
subjected to hydrosilyaltion conditions as summarized in
Table 5. The diphenylsilane 37 (Table 5, entry 2) underwent
hydrosilylation but required 12 h at room temperature for
complete conversion; subsequent oxidation of the intermedi-
ate siloxane gave triol 31 in good yield. However, the
reaction diasteroselectivity (84:16) was not improved as
compared to that of the analogous reaction of dimethylsilane
36 (Table 5, entry 1). On the other hand, diisopropylsilane
38 failed to undergo the intramolecular hyrosilylation,
presumely due to steric hindrance. When 38 was heated at
110 °C in toluene for 12 h in the presence of Karstedt’s
catalyst, an unidentified byproduct began to form.
We next turned our attention to the synthesis of the syn,anti
triol unit 6 from monoprotected (E)-1,5-anti-diols 5. Opti-
mization of the hydrosilylation conditions was conducted
using (E)-homoallylic alcohol 27. Therefore, as summarized
in Table 3, alcohol 27 was silylated with (HMe2Si)2NH and
then subjected to various hydrosilylation catalysts and
conditions to form the syn hydrosilylation product 28 as a
major diastereomer. Again, use of 0.5 mol % Karstedt’s
catalyst 14 (Table 3, entry 3) in toluene (0 °C, 2 h, then
room temperature, 2 h) provided the best reaction diaste-
reoselectivity (syn:anti ) 85:15). Attempts to improve the
diastereoselectivity by conducting the reaction in other
solvents (entries 4, 5), at lower temperatures (entry 6; only
trace amounts of 28 were observed after 12 h at -40 °C),
or with other catalysts (entries 1, 2) were unsuccessful.
Further investigation of the scope of the hydrosilylation
of (E)-1,5-anti-diol monoethers was performed as sum-
marized in Table 4. The intramolecular hydrosilylations of
30, 32, and 34 in Table 4 proceeded with 84:16 to 88:12
diastereoselectivity favoring the formation of the indicated
1,3-syn diols 31, 33, and 35 (which were obtained in
72-81% yield for the three-step sequence). It is also worth
noting that, as demonstrated by substrate 34 (Table 4, entry
4), the intramolecular hydrosilylation occurs on the proximal
In summary, we have developed a mild, stereoselective
procedure for synthesis of syn,syn- and syn,anti-1,3,5-triol
derivatives based on the intramolecular hydrosilylation of
1,5-diol monoethers 1 and 5. By using 0.5 mol % Karstedt’s
catalyst 14 in toluene, 87:13 to 95:5 syn diasteroselectivity
was achieved for the intramolecular hydrosilylation of (Z)-
1,5-syn-diol monoethers 1. Similarly, 84:16 to 88:12 syn
diasteroselectivity was achieved for the analogous intramo-
lecular hydrosilylation of (E)-1,5-anti-diol monoethers 5. In
all cases, the syn-1,3-diol derivatives were obtained in
72-85% yields for the simple three-step silyl ether
formation-hydrosilylation-oxidative cleavage sequence.
Applications of this method in natural products synthesis will
be reported in due course.
(9) (a) Hitchcock, P. B.; Lappert, M. F.; Warhurst, J. W. Angew. Chem.,
Int. Ed. Engl. 1991, 30, 438. (b) Faglioni, F.; Blanco, M.; Goddard, W. A.;
Sauners, D. J. Phys. Chem. B 2002, 106, 1714.
(10) For a detailed study of the selective silylation of 1,5-diols 8 and
10, see: (a) Hicks, J. D.; Huh, C. W.; Legg, A. D.; Roush, W. R. Org. Lett.
2007, 9, 5621. (b) Highly chemoselective silylation of the allylic alcohol
of all 1,5-diol substrates used in the present work proceeds with >95:5
selectivity by using the method reported in the paper cited in ref.10a This
selectivity is achieved even when the allylic and homoallylic alcohols have
similar steric environments.
Acknowledgment. We acknowledge the NIH (GM038436
and GM027682) for support of this research.
Supporting Information Available: Experimental pro-
1
cedures and copies of H NMR and 13C NMR spectra of
(11) Kusumoto, T.; Ando, K.; Hiyama, T. Bull. Chem. Soc. Jpn. 1992,
65, 1280.
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(13) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc. Chem.
Res. 1998, 31, 9.
(14) Tamao, K.; Nakagawa, Y.; Ito, Y. Organometallics 1993, 12, 2291.
OL9009877
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