Synthesis of β-hydroxy ketones and vinylsilanes from homopropargylic alcohols by intramolecular hydrosilation

Article abstract of DOI:10.1021/ol0061182

matrix presented Catalytic intramolecular hydrosilation of nonracemic homopropargylic alcohols affords the corresponding five-membered cyclic siloxanes regiospecifically. Oxidation or alkylmetal addition converts these intermediates into β-hydroxy ketones

Full text of DOI:10.1021/ol0061182

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2173-2175
Synthesis of â-Hydroxy Ketones and
Vinylsilanes from Homopropargylic
Alcohols by Intramolecular Hydrosilation
James A. Marshall* and Mathew M. Yanik
Department of Chemistry, McCormick Road, P.O. Box 400319, UniVersity of Virginia,
CharlottesVille, Virginia, 22904
jam5x@Virginia.edu
Received May 27, 2000
ABSTRACT
Catalytic intramolecular hydrosilation of nonracemic homopropargylic alcohols affords the corresponding five-membered cyclic siloxanes
regiospecifically. Oxidation or alkylmetal addition converts these intermediates into â-hydroxy ketones or vinylsilanes under mild conditions.
Recently we disclosed a conversion of homopropargylic
alcohols to â-hydroxy ketones through iodolactonization.1
After the completion of our work, we discovered a prelimi-
nary report by Tamao which effected a like conversion of
homopropargylic alcohols to ketones through intramolecular
hydrosilation and oxidation of the resulting cyclic siloxane.2
While the concept had been demonstrated with three simple
examples, no further studies or applications of this conversion
have appeared. With the aim of improving upon our merger
of allenylmetal with aldol methodology for polyketide
synthesis, we decided that further investigation was war-
ranted.
The addition of nonracemic allenylmetal reagents I to
Figure 1. Merged allenylmetal/aldol approach to polyketide
aldehydes affords syn or anti homopropargylic adducts II
with high levels of diastereoselectivity, particularly with
R-branched aldehydes (Figure 1).3 This methodology pro-
synthesis.
vides ready access to any of the eight possible stereotriads
of general structure II. Subsequent regioisomeric hydration
would afford the derived â-hydroxy ketones III whose utility
in highly stereoselective aldol condensations has been
convincingly demonstrated by Paterson and co-workers.4
The hydrosilation approach was felt to offer certain
advantages over the aformentioned iodolactonization1 se-
(1) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(2) Tamao, K.; Maeda, K.; Tanaka, T.; Ito, Y. Tetrahedron Lett. 1988,
29, 6955.
(3) (a) Marshall, J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995,
60, 5556. (b) Marshall J. A.; Palovich, M. R. J. Org. Chem. 1997, 62, 6001.
(c) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201. (d)
Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 696. (e) Marshall, J.
A.; Maxson, K. J. Org. Chem. 2000, 65, 630.
10.1021/ol0061182 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/17/2000

quence by virtue of milder reaction conditions and the
potential for utilizing the intermediate siloxanes as masked
ketones or as precursors to vinylsilanes. The present inves-
tigation was designed to test the overall feasibility of the
approach and to determine the effect of triad stereochemistry
on the efficiency of the process.
Initial studies were conducted with racemic anti homopro-
pargylic alcohols 2a and 2b, prepared by addition of the
transient allenylzinc reagents, generated in situ from racemic
propargylic mesylates 1a and 1b, to cyclohexanecarbox-
aldehyde (Scheme 1). Conversion of alcohols 2a and 2b to
or alumina resulted in decomposition. Compounds not
amenable to distillation were carried on without purification.
Surprisingly the siloxanes proved stable to both strong acid
(6.0 M HCl/THF, 3 h) and aqueous base (1 N KOH/MeOH,
reflux, 2 h).
Oxidation of siloxanes 4a and 4b was best achieved by a
modification of Tamao’s conditions.6 Several aspects deserve
comment. Use of a large quantity of hydrogen peroxide (20-
40 equiv) was required to minimize side reactions. In the
absence of KF only a trace of product was formed after 24
h. Substitution of LiOH for KHCO3 accelerated the rate but
caused epimerization of the R′ stereocenter prior to complete
oxidation (24 h). With KHCO3 as the base, in the presence
of 3 equiv of KF and excess H2O2, smooth conversion to
ketone product took place. Additional studies with racemic
homopropargylic adducts are summarized in Table 1.
Scheme 1a
Table 1. Hydrosilation-oxidation of Racemic
Homopropargylic Alcohols
a (a) 5 mol % of Pd(OAc)2‚PPh3, Et2Zn, C6H11CHO, THF, 76%;
(b) (Me2SiH)2NH, 60 °C, 100%; (c) 0.5 mol % of H2PtCl6, THF,
50 °C, 92%; (d) MeOH, THF, H2O2, KF, KHCO3, 85%.
We next turned our attention to the stereotriads 6, 8, 10,
and 12 prepared as outlined in Scheme 2.3
hydrodimethylsilyl ethers 3a and 3b occurred quantitatively
in neat tetramethyldisilazane. Excess silazane was found to
poison the catalyst in the ensuing hydrosilation step so its
complete removal under high vacuum was essential to
success.
Silylation of hindered homopropargylic alcohols 6, 8, 10,
and 12 required more vigorous conditions (90 °C, 14 h) but
was quantitative in all cases. Subsequent hydrosilation of 7,
9, 11, and 13 in THF also proceeded smoothly (Scheme 3).7
The reaction mixtures were filtered to remove the catalyst
Intramolecular hydrosilation with 0.5 mol % of chloro-
platinic acid afforded cyclic siloxane intermediates 4a and
4b. Initially this reaction was performed in toluene at
concentrations ranging from 2 to 6 M. An induction period
ranging from several minutes to only a few seconds was
noted prior to initiation of a highly exothermic reaction under
these conditions. This observation is consistent with the
formation of a Pt(0) colloidal suspension from the catalyst
precursor.5 The subsequent uncontrolled exotherms resulted
in the formation of variable amounts of intractable polymers.
Changing the solvent to THF and lowering the concentration
to 0.5 M moderated the rate of the reaction and suppressed
polymerization. The progress of the hydrosilation could
conveniently be monitored by infrared spectral analysis
(Si-H 2121 cm-1). The siloxane intermediates were isolated
by distillation as all attempts to purify these compounds by
chromatography on silica gel, Et3N deactivated silica gel,
(6) (a) Tamao, K.; Kumada, M.; Maeda, K. Tetrahedron Lett. 1984, 25,
321. (b) Review: Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599.
(7) Typical procedure for the conversion of homopropargylic alcohol
(10b) to ketone (16b): A dry flask was charged with alcohol 10b (520
mg, 1.89 mmol) and tetramethyldisilazane (0.66 mL, 3.79 mmol), and the
mixture was heated to 90 °C for 15 h. After cooling to 40 °C, excess silazane
was removed in vacuo (0.05 mmHg, 2 h), affording silyl ether 11b as a
light yellow oil. The oil was diluted with THF (4 mL), and H2PtCl6 (0.056
M in THF, 60 µL, 0.0044 mmol) was added at rt. The mixture was heated
to 55 °C for 4 h, diluted with ether (25 mL), filtered through Celite, and
concentrated, affording the cyclic siloxane as a yellow oil which was used
without further purification. A solution of this oil in THF/MeOH (1:1, 8
mL) was treated with KHCO3 (600 mg, 6.00 mmol), KF (111 mg, 1.90
mmol), and 30% H2O2 (8 mL, ca. 70 mmol). After 3 h, excess peroxide
was quenched with solid Na2S2O3 (Caution: exothermic, induction period).
The mixture was extracted with ether, dried over MgSO4, concentrated,
and purified by chromatography on silica gel (5-20% EtOAc/hexanes),
affording 372 mg (68%) of ketone 16b as a colorless oil. Rf ) 0.50 (20%
EtOAc/hexanes); [R]D +11.8 (c 1.0, CHCl3); IR 3501, 2960, 2864, 1710
cm-1; 1H NMR δ 0.05 (s, 6H), 0.87 (s, 9H), 0.95 (t, J ) 7.2 Hz, 6H), 1.04
(d, J ) 7.2 Hz, 3H), 1.70 (m, 1H), 2.51 (q, J ) 7.2 Hz, 2H), 2.66 (dq, J )
7.2, 9.3 Hz, 1H), 3.21 (br, 1H), 3.65 (dd, J ) 4.8, 9.9 Hz, 1H), 3.75 (dd,
J ) 3.9, 9.9 Hz, 1H), 3.97 (dd, J ) 1.8, 9.3 Hz, 1H); 13C NMR δ -5.6,
7.4, 9.2, 13.6, 18.2, 25.8, 35.6, 36.2, 48.8, 68.6, 76.2, 215.8. Anal. Calcd
for C15H32O3Si: C, 62.45; H, 11.18. Found: C, 62.73; H, 11.28.
(4) Paterson, I.; Scott, J. P. Tetrahedron Lett. 1997, 38, 7441. (b)
Review: Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(5) Lewis, L. N.; Lewis, N. J. Am. Chem. Soc. 1986, 108, 7228
2174
Org. Lett., Vol. 2, No. 14, 2000

Representative siloxanes 4b and 4d were converted to the
corresponding γ-hydroxy vinylsilanes 18a-e upon treat-
ment with organolithium or Grignard reagents as summarized
in Table 2. These vinylsilanes are easily purified by
Scheme 2
Table 2. Conversion of Cyclic Siloxanes to Hydroxy Silanes
chromatography. The three-step protocol affords the Mark-
ovnikov hydrosilation product with terminal alkynes, op-
posite in regiochemistry to that of an intermolecular hy-
drosilation.8 This aspect could prove useful for the synthesis
of substituted olefins since such vinylsilanes can be converted
to vinyl halides with either retention or inversion of con-
figuration.9 Additionally, vinylsilanes can be employed in
Pd-catalyzed cross-coupling reactions.10
Conversion to phenyl- and benzyl-substituted vinylsilanes
leads to intermediates with increased stability relative to their
siloxane precursors. These silanes can also serve as umpolung
equivalents to ketones.11 For example, the oxidation12 of
benzylsilane 18e afforded the corresponding ketone 5d in
84% yield.
The present methodology provides a convenient and
efficient route to enantioenriched â-hydroxy ketones from
readily available homopropargylic alcohols of any desired
stereochemical configuration. The methodology also provides
access to stable vinylsilanes for use as masked ketones in
multistep transformations.
and then subjected to oxidation directly, affording ketones
14, 15, 16, and 17. If the catalyst was not removed prior to
the oxidation step, the peroxide was rapidly decomposed and
incomplete oxidation resulted.
Use of the standard oxidation conditions led to cleavage
of the primary TBS ethers. However, cleavage was negligible
when only 1 equiv of KF was employed. The decreased
amount of KF did not appreciably affect the rate of oxidation.
Scheme 3
Acknowledgment. This research was supported by
Research Grant CHE9901319 from the National Science
Foundation. M.M.Y. thanks Nick Adams for preparing
compounds 8 and 10a.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0061182
(8) Murphy, P. J.; Spencer, J. L.; Procter, G. Tetrahedron Lett. 1990,
31, 1051.
(9) Miller, R. B.; McGarvey, G. J. Org. Chem. 1978, 43, 4424.
(10) a) Hatanaka, Y.; Hiyama. T. J. Org. Chem. 1988, 53, 918. (b)
Tamao, K.; Kobayashi, K.; Ito, Y. Tetrahedron Lett. 1989, 30, 6051. (c)
Denmark, S. E.; Wehrli, D. Org. Lett. 2000, 2, 565.
(11) Fleming, I. Chemtracts: Org. Chem. 1996, 9, 1.
(12) For recent examples demonstrating oxidation of the benzylsilyl
group, see: (a) Miura, K.; Hondo, T.; Nakagawa, T.; Takahashi, T.; Hosomi,
A. Org. Lett. 2000, 2, 385. (b) Miura, K.; Hondo, T.; Nakagawa, T.;
Takahashi, T.; Hosomi, A. Tetrahedron Lett. 2000, 41, 2129. (c) Zhi-Hui,
P.; Woerpel, K. A. Org. Lett. 2000, 2, 1379.
Org. Lett., Vol. 2, No. 14, 2000
2175