Regioselective hydrosilylation of propargylic alcohols: An aldol surrogate

Article abstract of DOI:10.1002/anie.200351587

Aldol products from a non-aldol reaction: A one-pot protocol effects hydrosilylation of propargyl alcohols and subsequent oxidative cleavage to yield β-hydroxy ketones in a chemo-, regio-, and enantioselective fashion. Further structural elaboration of th

Full text of DOI:10.1002/anie.200351587

Angewandte
Chemie
Regioselective Hydrosilylation
Regioselective Hydrosilylation of Propargylic
Alcohols: An Aldol Surrogate**
Barry M. Trost,* Zachary T. Ball, and Thomas Jöge
and geometrical selectivity in ruthenium-catalyzed trans
ꢀ
The aldol reaction has emerged as one of the most powerful
ways to assemble complex targets with high stereochemical
control in both a relative and an absolute
hydrosilylation using [Cp*Ru(NCCH3)3]+PF6 (1, Cp* =
C5Me5).
Table 1: Hydrosilylation of propargylic alcohols catalyzed by 1.[a]
sense. Despite the tremendous successes,
deficiencies exist. As aldol adducts are
prone to further reactions such as elimina-
tion, further substitution at the a-carbon
becomes difficult.[1] Asymmetric additions of
methyl alkyl ketones have been very lim-
ited.[2] Propargylic alcohols can become sur-
rogates for aldols provided that a chemo- and
regioselective introduction of a carbonyl
group at the alkyne carbon b to the alcohol
can be performed. The asymmetric access[3,4]
to propargylic alcohols makes this approach
an attractive alternative to the asymmetric
aldol reaction. Although the direct hydration
of a propargylic alcohol is a potentially
attractive solution, the difficulty of obtaining
regioselectivity as well as of avoiding elimi-
nation of the hydroxy ketone product under
generally acidic hydration conditions led us
to another approach.[5] As outlined in Equa-
tion 1, we chose to pursue selective incorpo-
Entry
1[e]
Alkyne
Silane[b]
1 [mol%]
Major product
Yield,[c] sel.[d]
30%,[f] n.d.
A
2.5
2[e]
B
A
1.0
3.0
99%, 13:1
73%,[f] 5:1
3[e]
4[e]
5
B
C
2.0
2.0
91%, 20:1
91%,[f] 14:1
6[e]
C
C
3.0
4.0
96%, 9:1
7
8%, 6:1
ꢀ
ration of a vinyl C Si bond, which can serve
as a versatile ketone precursor.
During the course of our studies of the
8
9
C
B
2.0
5.0
65%,[f] 5:1
ruthenium-catalyzed
hydrosilylation
of
alkynes,[6] our attention was drawn to the
regioselective hydrosilylation of internal
alkynes.[7,8] For some systems the regioselec-
tivity could be simply resolved by tethering
the silyl group, wherein a most interesting
endo-selective intramolecular hydrosilyla-
tion occurred.[8a] Unfortunately, such a strat-
egy failed with propargyl alcohols. We, there-
fore, hoped to harness the electronic bias—or
perhaps catalyst ligation—of unprotected
propargylic alcohols to effect regiochemical
63%[f] (84),[g]
>20:1
10
C
2.0
83%,[f] 8:1
[a] All reactions were performed with 1.2 equiv silane in acetone from 08C to room temperature and
were complete within 30 min unless otherwise indicated. [b] A=Me2(EtO)SiH, B=Et3SiH (TES-H), C=
BzMe2Si-H (BDMS-H). [c] Yield of both isomers isolated except where indicated. [d] Regiochemistry of
silane addition from NMR spectrum of the crude product. [e] Performed with 2.5 equiv silane in CH2Cl2.
[f] Yield of pure major isomer isolated. [g] Numbers in parenthesis refer to yields based on recovered
starting material.
[*] Prof. Dr. B. M. Trost, Z. T. Ball, T. Jöge
Department of Chemistry
Stanford University
Stanford, CA 94305-5080 (USA)
Fax: (+1)650-725-0002
Initial experiments with (EtO)3SiH and 2-nonyn-1-ol
catalyzed by complex 1 produced only extensive decomposi-
tion. On the other hand, the reaction of monoalkoxysilane
Me2(EtO)SiH (Table 1, entry 1) gave the b-silyl compound,
E-mail: bmtrost@stanford.edu
[**] We thank the National Science Foundation and the National
Institutes of Health, General Medical Science (GM-13598), for their
generous support of our programs. Z.T.B. is a Stanford Graduate
Fellow. Mass spectra were provided by the Mass Spectrometry
Regional Center of the University of California–San Francisco
supported by the NIH Division of Research Resources.
but mediocre selectivity and poor product stability led to
yields of only about 30%. A bulkier secondary alcohol greatly
improved product stability, and the desired vinylsilane was
isolated in respectable yield (entry 3). A switch to triethylsi-
lane (TES-H) improved the situation dramatically, and the
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DOI: 10.1002/anie.200351587
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Communications
desired vinylsilanes could be produced in excellent
yield with synthetically useful regioselectivity with-
out any product stability issues (entries 2 and 4). In
this and in all cases, only the Z products of trans
addition are observed for the two regioisomers.
Although for some subsequent applications
triethylvinylsilanes are suitable, we sought
a
silane that would maintain this clean reactivity
and still permit a wide variety of subsequent
operations. In our hands, the optimal choice was
benzyldimethylsilane (BDMS-H), which we found
to react in a manner very similar to triethylsilane,
requiring only slightly higher catalyst loadings
(generally 2–4%). The propargylic alcohol sub-
strate itself also displays some unique reactivity.
Conjugated alkene units and nearby double bonds
lead to generally inferior results in the hydro-
silylation reaction with 1, but the substrates in
entries 8 and
9 show meaningful reactivity.
Entry 10 demonstrates that propargylic alcohols
do not overcome the preference for silylation b to
conjugated carbonyl groups, and the vinylsilane of
opposite regiochemistry is obtained.
Having achieved selective formation of the
necessary vinylsilanes, we sought to, first, unmask
the ketone through oxidation and, second, utilize
the vinylsilane as a handle for functionalization at
the a-carbon atom. A key question becomes the
fate of the presumed initial oxidation product.
Scheme 1. Hydrosilylation–oxidation protocol for propargylic alcohols.
a) 1. BDMS-H, 5% 1, CH2Cl2, 08C to RT, 2. TBAF, then H2O2, MeOH, KHCO3;
b) octyne, nBuLi, (iPrO)3TiCl, ꢀ788C, then 5; c) 1. BDMS-H, cat. 1 (2% for 9,
13, 17; 3% for 6), acetone, 08C to RT, 2. TBAF, then H2O2, MeOH, KHCO3;
d) 5-phenyl-1-pentyne, nBuLi, ZnBr2, ꢀ788C, then 8; e) 0.20 equiv Zn(OTf)2,
0.22 equiv (+)-N-methylephedrine, Et3N, PhMe, 608C. RT=room temperature.
Since oxidation of the BDMS group of b-silyl allylic
alcohols produces the enol of a b-hydroxy ketone,
dehydration may accompany the unmasking.[9]
Gratifyingly, elimination did not compete when methanolic
basic hydrogen peroxide was used after initial debenzylation
with tetrabutylammonium fluoride (TBAF, Scheme 1).[10] In
this case, BDMS oxidation was compatible with our hydro-
silylation conditions and could be performed directly as a one-
pot operation to afford regioselective hydrolysis of the
alkyne, whereby 4 was obtained directly from 2 in 88% yield.
The net diasteroselective aldol requires a diastereoselec-
tive addition of an acetylide ion to a chiral aldehyde. Thus, a
Felkin–Anh addition of a titanium acetylide complex[11]
converts aldehyde 5 into the anti adduct 6 with a diastereomer
ratio of 9:1. On the other hand, a chelation-controlled
addition to the a-alkoxy aldehyde 8 using zinc bromide[12]
provides the syn adduct 9 (10:1 d.r.). In both cases one-pot
hydrosilylation followed by oxidation unmasks the aldol
adducts 7 and 10. Chiral propargylic alcohols can be
synthesized readily by the asymmetric hydrogenation of
ketones or addition to aldehydes.[3,4] Addition to aldehydes
11 and 15 produced their respective alcohols 13 and 17 in 94%
and 85% ee, respectively.[4] One-pot hydrosilylation/oxidative
desilylation gave the corresponding aldols 14 and 18 in high
enantioselectivity in a two-pot sequence.
provides the respective syn-epoxy alcohols 21 and 24 with high
efficiency and with a facial selectivity of >20:1. Owing to the
BDMS group, oxidation provides a,b-dihydroxyketones 20 and
23 of defined relative and absolute stereochemistry.[14] The
added alkyne unit functions as a hydroxymethyl ketone
equivalent, and the hydroxy and ketone groups are unmasked
simultaneously. Attempts to carry out this process in one or
two pots without purification of the intermediates resulted in
significantly lower yields. Since the amount of TBAF in the
oxidation step is crucial to good yields, the epoxide was best
fully purified prior to oxidation. Finally, differentiated diols
could be produced by protection of the alcohol prior to
epoxidation, though in this case the oxidation (25!26) was less
efficient and accompanied by significant protodesilylation,
which accounts for the lower yield of 26.
The regioselective hydrosilylation presented here allows
for the selective functionalization of propargylic alcohols.
Focusing on oxidative pathways, we show that the alkyne
added can serve as a methyl ketone enolate or hydroxy-
methyl–ketone–enolate equivalent.
Additional complexity can be introduced through epox-
idation of the vinylsilane. The bulky (Z)-silyl group serves as an
excellent diastereocontrol element to provide syn-epoxides for
what is otherwise a challenging class for diastereoselective
epoxidation (Scheme 2).[13] Protodesilylation of 19 and 22
Experimental Section
Typical procedure for the hydrosilylation of propargylic alcohols:
Preparation of vinylsilane 3: 1-Phenyl-2-propyn-1-ol (500 mg,
3.42 mmol) and benzyldimethylsilane (0.591 mL, 4.10 mmol) were
taken up in acetone (7.0 mL) under Ar at 08C. Solid 1 (35 mg,
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(0.60 mL) and KHCO3 (60 mg, 0.60 mmol) were added,
followed by 30% aqueous H2O2 (0.20 mL). The mixture
was then allowed to warm to room temperature. After
14 h, saturated aqueous sodium bicarbonate (3 mL) was
added and the mixture extracted with ether (3 ” 10 mL).
The combined organic layers were dried over MgSO4 and
concentrated in vacuo. Purification on a silica gel column
(eluent: petroleum ether/ethyl acetate 4:1 then 1:1)
afforded the desired diol as a viscous gum (25.1 mg, 74%
yield).
Received: April 7, 2003 [Z51587]
Keywords: aldol products · asymmetric synthesis ·
.
hydrosilylation · organosilanes · ruthenium catalysis
[1] G. Frater, W. Guenther, U. Mueller, Helv. Chim.
Acta 1989, 72, 1846.
[2] For approaches to asymmetric aldol reactions of
methyl alkyl ketones see: a) R. T. Ruck, E. N.
Jacobsen, J. Am. Chem. Soc. 2002, 124, 2882;
b) S. E. Denmark, R. A. Stavenger, J. Am. Chem.
Soc. 2000, 122, 8837; c) N. Yoshikawa, Y. M. A.
Yamada, J. Das, H. Sasai, M. Shibasaki, J. Am.
Chem. Soc. 1999, 121, 468; d) A. Yanagisawa, Y.
Matsumoto, H. Nakashima, K. Asakawa, H. Yama-
moto, J. Am. Chem. Soc. 1997, 119, 9319; e) E. M.
Carreira, W. Lee, R. A. Singer, J. Am. Chem. Soc.
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Chem. Soc. 1993, 115, 7039; g) E. J. Corey, C. L.
Cywin, T. D. Roper, Tetrahedron Lett. 1992, 33, 6907; for reviews
see h) E. M. Carreira, in Catalytic Asymmetric Synthesis, 2nd Ed.
(Ed: I. Ojima), Wiley-VCH, New York, 2000, Ch. 8-2; i) B. List,
Tetrahedron 2002, 58, 5573; j) S. G. Nelson, Tetrahedron: Asym-
metry 1998, 9, 357.
Scheme 2. Elaboration of silanes by diastereoselective epoxidation. a) BDMS-H,
2% 1, acetone, 08C to RT; b) mCPBA, CH2Cl2, 08C; c) 1 equiv TBAF, THF,
ꢀ108C, then H2O2, MeOH, KHCO3, RT; d) TBAF, DMF, RT; e) MOM-Cl, pyr.,
DCM, 08C to RT. DCM=dichloromethane, mCPBA=m-chloroperbenzoic acid,
MOM=methoxymethyl, pyr.=pyridine.
0.069 mmol) was added, and the solution was allowed to warm to
room temperature and stirred for 30 min. The crude reaction mixture
was concentrated directly under reduced pressure and applied to a
silica gel column (eluent: petroleum ether/diethyl ether 6:1). The
minor olefin regioisomers could be separated to afford the desired
vinylsilane (920 mg, 91% yield).
[3] T. Ohkuma, M. Kitamura, R. Noyori, in Catalytic Asymmetric
Synthesis 2nd Ed. (Ed: I. Ojima), Wiley-VCH, New York, 2000,
Ch. 1.
[4] a) D. E. Frantz, R. Fassler, E. M. Carreira, J. Am. Chem. Soc.
2000, 122, 1806–1807; b) N. K. Anand, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 9687–9688; c) D. Boyall, D. E. Frantz,
E. M. Carreira, Org. Lett. 2002, 4, 2605–2606.
[5] For a recent example of catalyzed alkyne hydration see a) E.
Mizushima, K. Sato, T. Hayashi, M. Tanaka, Angew. Chem. Int.
Ed. 2002, 41, 4563; b) E. Mizushima, K. Sato, T. Hayashi, Angew.
Chem. 2002, 114, 4745.
[6] a) B. M. Trost, Z. T. Ball, T. Joege, J. Am. Chem. Soc. 2002, 124,
7922–7923; b) B. M. Trost, Z. T. Ball, J. Am. Chem. Soc. 2001,
123, 12726–12727.
[7] Intermolecular hydrosilylation of internal alkynes: a) G. A.
Molander, W. H. Retsch, Organometallics 1995, 14, 4570–4575;
for instances of selective hydrosilylation of propargylic alcohols:
b) D. Humiliere, S. Thorimbert, M. Malacria, Synlett 1998, 1255;
c) M. Isobe, R. Nishizawa, T. Nishikawa, K. Yoza, Tetrahedron
Lett. 1999, 40, 6927–6932; d) K. Kahle, P. J. Murphy, J. Scott, R.
Tamagni, J. Chem. Soc. Perkin Trans. 1 1997, 997–999; e) P. J.
Murphy, J. L. Spencer, G. Procter, Tetrahedron Lett. 1990, 31,
1051–1054.
[8] Intramolecular hydrosilylation: a) B. M. Trost, Z. T. Ball, J. Am.
Chem. Soc. 2003, 125, 30–31; b) S. E. Denmark, S. Pan, Org. Lett.
2002, 4, 4163–4166; c) J. A. Marshall, M. M Yanik, Org. Lett.
2000, 2, 2173–2175; d) K. Tamao, K. Maeda, T. Tanaka, Y. Ito,
Tetrahedron Lett. 1988, 29, 6955–6956.
Typical procedure for the one-pot hydrosilylation/oxidation to
afford b-hydroxy ketones: Preparation of ketone 18: To a solution of
propargylic alcohol 17 (118 mg, 0.40 mmol) and benzyldimethylsilane
(83 mL, 0.48 mmol) in acetone (0.8 mL) was added solid 1 (4.0 mg,
0.008 mmol) at 08C. The solution was allowed to warm to room
temperature and stirred for 30 min. The solution was cooled again to
08C and treated with THF (1.0 mL) followed by TBAF (0.48 mL,
0.58 mmol, 1m in THF). The reaction mixture was stirred for 15 min,
then 30% aqueous H2O2 (1.9 mL, 10.7 mmol), MeOH (0.7 mL), and
KHCO3 (176 mg, 1.76 mmol) were added sequentially. The reaction
mixture was allowed to warm to room temperature and stirred for
18 h. Water (20 mL) was added and the mixture extracted with ethyl
acetate (3 ” 15 mL). The combined organic layers were washed with
saturated aqueous Na2S2O3 (10 mL) and dried over Na2SO4. The
crude product was applied to a silica gel column (eluent: petroleum
ether/ethyl acetate/methanol 80:20:1 then 70:30:1 ) to afford the
desired hydroxyketone as a clear, colorless oil (97 mg, 78% yield).
Typical procedure for the production of dihydroxyketones:
preparation of ketone 20: Vinylsilane 3 (650 mg, 2.19 mmol) was
taken up in CH2Cl2 (20 mL) and treated with mCPBA (662 mg,
3.07 mmol assuming 80% purity) at 08C. After the reaction mixture
had been stirred 14 h, saturated aqueous sodium bicarbonate (10 mL)
and solid Na2S2O3 (ca. 2 g) were added. The mixture was extracted
with ether (3 ” 30 mL), and the combined organic layers were dried
over Na2SO4 and concentrated under reduced pressure. Silica gel
chromatography (eluent: petroleum ether/ethyl acetate/methanol
100:10:1) afforded the desired epoxyalcohol as a single isomer
(615 mg, 90% yield). Epoxysilane 19 (59 mg, 0.19 mmol) was taken
up in THF (0.6 mL) under Ar at 08C. TBAF (0.19 mL, 0.19 mmol,
1.0m in THF) was added dropwise, and after 5 min, methanol
[9] The intramolecular hydrosilylation of homopropargylic alcohols
has also been used to create b-hydroxy ketones. In that case
elimination from the initial enol is not possible, and the
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vinylsilane intermediate does not allow functionalization at the
a-carbon. See refs. [8c,d].
[10] K. Miura, T. Hondo, T. Takahashi, A. Hosomi, Tetrahedron Lett.
2000, 41, 2129–2132; K. Miura, T. Hondo, T. Nakagawa, T.
Takahashi, A. Hosomi, Org. Lett. 2000, 2, 385–388.
[11] M. Shimizu, M. Kawamoto, Y. Niwa, Chem. Commun. 1999,
1151–1152.
[12] K. T. Mead, Tetrahedron Lett. 1987, 28, 1019–1022.
[13] H. Tomioka, T. Suzuki, K. Oshima, H. Nozaki, Tetrahedron Lett.
1982, 23, 3387–3390; I. Hasan, Y. Kishi, Tetrahedron Lett. 1980,
21, 4229–4232.
[14] For a report on the oxidation of a,b-epoxysilanes: K. Tamao, K.
Maeda, Tetrahedron Lett. 1986, 27, 65–68.
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