Lewis Base-Catalyzed, Asymmetric Aldol Additions of Methyl Ketone Enolates

Full text of DOI:10.1021/jo972168h

918
J . Org. Chem. 1998, 63, 918-919
Ta ble 1. Mer cu r y-Ca ta lyzed Meta th esis of TMS En ol
Eth er s to Tr ich lor osilyl En ola tesa
Lew is Ba se-Ca ta lyzed , Asym m etr ic Ald ol
Ad d ition s of Meth yl Keton e En ola tes†
Scott E. Denmark,* Robert A. Stavenger, and
Ken-Tsung Wong
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
entry
enol ether
R
enolate
yield,b %
Received December 2, 1997
1
2
3
4
5
6
2b
2c
2d
2e
2f
n-Bu
i-Bu
i-Pr
t-Bu
Ph
3b
3c
3d
3e
3f
83
74
83
81
69
65
The development of a general and highly effective catalytic
asymmetric aldol addition reaction has been the subject of
intense research in recent years.1 Most strategies rely on a
chiral Lewis acid to both activate the aldehyde and control
the stereochemical course of the reaction. As these reactions
most likely proceed through open transition structures
where nonbonding interactions dominate,2 acetate and
methyl ketone substrates often perform less well than their
substituted homologues.3 Recently, we reported a conceptu-
ally novel approach that employs Lewis base activation of
the trichlorosilyl enolate of methyl acetate.4a,b Although
selectivities were modest, our initial hypothesis of reaction
through an organized, closed transition structure was borne
out by the highly diastereo- and enantioselective additions
of geometrically defined trichlorosilyl enolates of ketones
catalyzed by the stilbene diamine-derived phosphoramide
(S,S)-1, Scheme 1.4c We felt that this strategy should prove
to be general for ketone enolates regardless of substitution
on the enol double bond and, hence, began investigating the
more challenging methyl ketone enolates. We wish to report
that trichlorosilyl enolates of methyl ketones undergo aldol
addition in the presence of catalytic (5-10 mol %) amounts
of (S,S)-1 to produce â-hydroxy ketones with very good
enantioselectivity.5
2g
TBDMSiOCH2
3g
1.0 equiv of 2, 2.0 equiv of SiCl4, 0.01 equiv of Hg(OAc)2. b Yield
of analytically pure material.
a
rosilane and tri-n-butylamine.6 Although this reaction
worked well in our hands, experimental limitations and the
lack of readily available R-chloro ketone substrates prompted
us to investigate other methods of preparation. Ideally, we
sought a reagent combination to prepare trichlorosilyl eno-
lates directly from readily available trialkylsilyl enol ethers.
Combination of 2d and SiCl4 (neat and in CDCl3 solution)
led to no reaction. However, upon addition of a catalytic
amount (1 mol %) of Hg(OAc)2, rapid and clean conversion
to the trichlorosilyl enolate, 3d , with concomitant formation
of TMSCl, was observed by 1H NMR spectroscopy.7 The
enolates 3b-g could be prepared in good yield starting from
the TMS enol ethers 2b-g, Table 1.8,9 Silicon tetrachloride
is a remarkably mild reagent as the mercury-catalyzed
metathesis reaction proceeds in reasonable yield even with
other silyl groups present in the enol ether (Table 1, entry
6).
Sch em e 1
Trichlorosilyl enolates 3a -g are efficacious aldol addition
reagents that react quickly with benzaldehyde at ambient
temperature (0.5 M, CH2Cl2), Table 2. In addition, enolate
3b reacted cleanly with a variety of different aldehydes
(Chart 1), Table 3.10 The uncatalyzed reaction of trimethy-
lacetaldehyde (10) was very slow (>2 days) and was ac-
companied by significant amounts of the elimination prod-
uct. However, in the presence of 10 mol % HMPA this
reaction proceeded rapidly at room temperature and pro-
duced only a small amount of unsaturated ketone (Table 3,
entry 6).
The trichlorosilyl enolate of acetone (3a ) has previously
been prepared from chloroacetone by treatment with trichlo-
† The Chemistry of Trichlorosilyl Enolates. 4.
Orienting studies on the catalytic asymmetric addition of
3a to benzaldehyde in CH2Cl2 at -78 °C with 10 mol % of
(S,S)-1 provided the adduct 4a in very good yield and in 92.5/
7.5 er.11 Lowering the temperature to -90 °C had es-
sentially no effect on the selectivity, and performing the
reaction in either less or more polar solvents led to poorer
(1) For reviews on catalytic, asymmetric aldol additions, see: (a) Bach,
T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417. (b) Franklin, A. S.; Paterson,
I. Contemp. Org. Synth. 1994, 1, 317. (c) Braun, M.; Sacha, H. J . Prakt.
Chem. 1993, 335, 653. (d) Sawamura, M.; Ito, Y. In Catalytic Asymmetric
Synthesis, Ojima, I., Ed.; VCH: New York, 1993; p 367. (e) Yamamoto, H.;
Maruoka, K.; Ishihara, K. J . Synth. Org. J pn. 1994, 52, 912. (f) Braun, M.
In Stereoselective Synthesis, Methods of Organic Chemistry (Houben-Weyl),
Edition E21; Helmchen, G., Hoffmann, R., Mulzer, J ., Schaumann, E., Eds.;
Thieme: Stuttgart, 1996; Vol. 3; p 1730.
(2) (a) Denmark, S. E.; Lee, W. J . Org. Chem. 1994, 59, 707. (b)
Kobayashi, S.; Horibe, M. Chem. Eur. J . 1997, 3, 1472.
(3) For a specific example, see: Kiyooka, S.-i.; Hena, M. A. Tetrahedron:
Asymmetry 1996, 7, 2181.
(4) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J . Am. Chem.
Soc. 1996, 118, 7404. (b) Denmark, S. E.; Winter, S. B. D. Synlett 1997,
1087. (c) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J . Am. Chem. Soc.
1997, 119, 2333.
(5) For examples of other catalytic asymmetric aldol additions of methyl
ketones, see: (a) Corey, E. J .; Cywin, C. L.; Roper, T. D. Tetrahedron Lett.
1992, 33, 6907. (b) Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta,
K.; Yamamoto, H. Bull. Chem. Soc. J pn. 1993, 66, 3483. (c) Mikami, K.;
Matsukawa, S. J . Am. Chem. Soc. 1993, 115, 7039. (d) Carreira, E. M.; Lee,
W.; Singer, R. A. J . Am. Chem. Soc. 1995, 117, 3649. (e) Sodeoka, M.;
Tokunoh, R.; Miyazaki, F.; Hagiwara, E.; Shibasaki, M. Synlett 1997, 463.
(f) Ando, A.; Miura, T.; Tatematsu, T.; Shioiri, T. Tetrahedron Lett. 1993,
34, 1507. (g) Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa,
K.; Yamamoto, H. J . Am. Chem. Soc. 1997, 119, 9319. (h) Yamada, Y. M.
A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl.
1997, 36, 1871.
(6) Benkeser, R. A.; Smith, W. E. J . Am. Chem. Soc. 1968, 90, 5307.
(7) We view this formal silicon-silicon metathesis as involving initial
formation of an R-mercurio ketone followed by O-complexation to SiCl4 and
loss of HgX2 as an electrofugal group. For examples of the synthesis of
R-mercurio ketones from silyl enol ethers see: (a) House, H. O.; Auerbach,
R. A.; Gall, M.; Peet, N. P. J . Org. Chem. 1973, 38, 514. (b) Yamamoto, Y.;
Maruyama, K. J . Am. Chem. Soc. 1982, 104, 2323. (c) Bluthe, N.; Malacria,
M.; Gore, J . Tetrahedron 1984, 40, 3277. (d) Drouin, J .; Boaventura, M.-A.;
Conia, J .-M. J . Am. Chem. Soc. 1985, 107, 1726.
(8) All new compounds were fully characterized by spectroscopic and
analytical methods. See the Supporting Information.
(9) Although the TMS enol ether derived from acetone is a good substrate
for this reaction, removing TMSCl from the volatile enolate 3a proved
difficult, and the modified Benkeser procedure was utilized for the synthesis
of this enolate.
(10) We assume that these reactions are proceeding though boatlike
closed transition structures as previously demonstrated for Lewis acidic
silyl (trichlorosilyl and silacyclobutyl) enolates. See: Denmark, S. E.;
Griedel, B. D.; Coe, D. M.; Schnute, M. E. J . Am. Chem. Soc. 1994, 116,
7026.
S0022-3263(97)02168-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/05/1998

Communications
J . Org. Chem., Vol. 63, No. 4, 1998 919
Ta ble 2. Un ca ta lyzed Ald ol Ad d ition s of 3a -g w ith
Ta ble 4. Ca ta lyzed Ald ol Ad d ition s of En ola tes 3 w ith
Ben za ld eh yd ea
Ben za ld eh yd ea
entry
enolate
product
erb
yield,c %
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
(-)-4a
(-)-4b
(-)-4c
(-)-4d
(-)-4e
(-)-4f
(-)-4g
93.6/6.4d
92.3/7.7
90.7/9.3
91.0/9.0
76.0/24.0
74.5/25.5
93.1/6.9
98
98
95
97
95
93
94
entry
enolate
time, h
product
yield,b %
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
4
4
4
5
10
4
4a
4b
4c
4d
4e
4f
92
95
94
93
97
91
93
3g
a
All reactions performed in CH2Cl2 at -78 °C with 5 mol %
(S,S)-1 at 0.5 M in aldehyde for 2h. bDetermined by CSP HPLC
analysis. cYield of analytically pure material. d Determined by CSP
HPLC analysis of the dinitrophenyl carbamate.
3g
6
4g
a
b
Ta ble 5. Ca ta lyzed Ald ol Ad d ition s of 3ba
All reactions performed at 0.5 M in aldehyde. Yield of
analytically pure material.
entry RCHO mol % 1 time, h product
erb
yield,c %
Ch a r t 1
1
2
3
4
5
6
5
6
7
8
9
5
5
5
5
10
10
2
2
2
2
6
6
(-)-11 92.0/8.0
(-)-12 95.6/4.4
(-)-13 92.9/7.1
(-)-14 92.7/7.3
(-)-15 94.6/5.4d
(-)-16 96.0/4.0d
94
95
92
95
79
81
10
a
All reactions performed in CH2Cl2 at -78 °C, 0.5 M in
aldehyde. Determined by CSP HPLC analysis. c Yield of analyti-
cally pure material. Determined by CSP HPLC analysis of the
b
d
dinitrophenyl carbamates.
Sch em e 2
Ta ble 3. Un ca ta lyzed Ald ol Ad d ition s of 3ba
yield,c %
good selectivity was observed with conjugated aldehydes,
and both enolizable (9) and hindered (10) aldehydes function
admirably with this catalyst system, although slightly higher
loading (10 mol %) and reaction time (6 h) were necessary
to provide acceptable yields of the aldol adducts 15 and
16.12,13
The invention of the mercury-catalyzed metathesis of
trimethyl to trichlorosilyl enolates allowed for the in-situ
generation of these reactive agents and set the stage for the
development of an operationally simple, one-pot reaction
protocol, Scheme 2. Thus, treatment of silyl enol ether 2b
(1.25 equiv relative to aldehyde) with 2 equiv of SiCl4 and 1
mol % Hg(OAc)2 in CH2Cl2 at room temperature for 1 h,
followed by removal of volatiles in vacuo, then dilution with
CH2Cl2 and addition of 5 mol % (S,S)-1, and 6 at -78 °C led
to an 89% yield of adduct 12, in 96/4 er.
In summary, we have demonstrated that the trichlorosilyl
enolates of methyl ketones are reactive toward aldehydes
and that these reactions are catalyzed by the phosphoramide
(S,S)-1 to give aldol adducts in excellent yield and high
enantioselectivity. In addition, we have developed a new,
mild method for the synthesis of trichlorosilyl enolates and
an operationally simple procedure for the in-situ generation
and reaction of these species. Our current efforts focus on
catalyst design, reaction mechanism, and extension to other
enolate types.
entry
RCHO
time, h
product
1
2
3
4
5
6
7
8
9
7
14
4
4
9
11
12
13
14
15
16
91
92
92
91
93
86
5
6b
10
1
a
b
All reactions performed at 0.5 M in aldehyde. 10 mol %
HMPA added. c Yield of analytically pure material.
results. Higher loadings of catalyst (20 mol %) did not
change the er significantly, so we briefly investigated
decreasing the catalyst amount and found, gratifyingly, that
5 mol % of (S,S)-1 could be used without diminution of either
yield or selectivity.
The catalytic additions of enolates 3a -g to benzaldehyde
were then investigated with the optimized procedure, utiliz-
ing 5 mol % of (S,S)-1 in CH2Cl2 at -78 °C. The results in
Table 4 reveal that the selectivities were all high, with the
exception of the pinacolone- (3e) and acetophenone-derived
(3f) enolates. Most satisfying was the observation that even
acid-labile functional groups are compatible as demonstrated
by the high-yielding and enantioselective reaction of the
(tert-butyldimethylsilyl)oxy-substituted enolate 3g (Table 4,
entry 7).
Finally, we investigated the dependence of aldehyde
structure on the catalytic reaction using 3b, Table 5. Very
Ack n ow led gm en t. We are grateful to the National
Science Foundation for generous financial support (CHE
9500397). R.A.S. thanks the Eastman Chemical Co. for a
graduate fellowship.
(11) Control experiments revealed that the reaction proceeds only
marginally under the conditions of the standard catalyzed reaction (0.5 M,
-78 °C, 2 h) in the absence of catalyst. With aldehyde 8 and enolate 3b,
only 4% of the aldol adduct 14 and 95% of unchanged 8 were isolated (cf.
Table 5, entry 4).
(12) Single-crystal X-ray analysis of the 4-bromobenzoate derived from
(-)-14 established the absolute configuration of the major enantiomer to
be S. All other configurational assignments were made by analogy.
(13) By analogy to the reactions of the substituted enolates,4 we believe
that these reactions also proceed through closed, chairlike transition states
organized around a hexacoordinate silicon atom.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation and full characterization of 2g, 3a -g, (()-4a -g, (()-
11-16 and enantiomerically enriched 4a -g and 11-16 and in situ
experimental procedures (40 pages).
J O972168H