The chemistry of trichlorosilyl enolates. 2. Highly-selective asymmetric aldol additions of ketone enolates

Full text of DOI:10.1021/ja9636698

J. Am. Chem. Soc. 1997, 119, 2333-2334
The Chemistry of Trichlorosilyl Enolates. 2.
Scheme 1
2333
Highly-Selective Asymmetric Aldol Additions of
Ketone Enolates
Scott E. Denmark,* Ken-Tsung Wong, and
Robert A. Stavenger
Roger Adams Laboratory, Department of Chemistry
UniVersity of Illinois, Urbana, Illinois 61801
ReceiVed October 23, 1996
Chart 1
Asymmetric catalysis of the aldol addition reaction has been
1-4
an area of intense activity in recent years.
Despite consider-
able success to date, these efforts have identified the same
solution to the problem, namely, the invention/discovery of a
suitable chiral Lewis acid catalyst to effect the reaction between
an enoxysilane derivative and an aldehyde, Scheme 1 (X ) Me).
In a recent Communication we have described a conceptually
distinct approach which employs chiral Lewis bases (phos-
phoramides) in combination with trichlorosilyl enolates, Scheme
5
1
(X ) Cl). These reactions were designed to proceed via
highly-organized, hexacoordinate siliconate assemblies of eno-
late, aldehyde, and Lewis base and are thus distinguished from
the classic Mukaiyama aldol reactions which are believed to
proceed via open transition structures.6 Consequently, we
expected to observe a stereochemical dependence of enolate
geometry reflected in the product in contradistinction to the
geometry-independent, syn diastereoselectivity observed in
Lewis acid catalyzed reactions of silyl enolates.3
,6,7
We report
herein the highly diastereo- and enantioselectiVe aldol additions
of geometrically defined trichlorosilyl enolates of ketones.
Chart 1. An assortment of aromatic, olefinic, and aliphatic
aldehydes was surveyed to assay generality and structural effects
on rate and selectivity in all the subsequent reactions, Chart 1.
Both 1 and 2 were highly effective aldolization reagents albeit
much less reactive than the trichlorosilyl enolates of esters. Thus,
1 cleanly combined with eight different aldehydes at 0 °C in
5
The two trichlorosilyl enolates employed in this study, 1 and
, were prepared by SiCl4 metathesis of the stannyl ketones
8
2
9
which arise from treatment of enol acetates with n-Bu3SnOCH3,
(1) For reviews containing catalytic enantioselective aldol additions,
see: (a) Bach, T. Angew. Chem., Int. Ed. Engl. 1994, 33, 417. (b) Franklin,
A. S.; Paterson, I. Contemporary Org. Syn. 1994, 1, 317-416. (c) Braun,
M.; Sacha, H. J. Prakt. Chem. 1993, 335, 653-668. (d) Sawamura, M.;
Ito, Y. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York,
the absence of external promoters to afford the aldol adducts
8
3
in 78-92% yield, Table 1. The conjugated aldehydes gave
10
1
993; pp 367-388. (e) Yamamoto, H.; Maruoka, K.; Ishihara, K. J. Synth.
good to excellent diastereoselectivity favoring the syn isomer.
Org. Jpn. 1994, 52, 912.
The production of a syn stereoisomer from an E-enolate through
a closed transition structure necessarily implicates a boat-like
arrangement (i, Chart 2). We have previously demonstrated
that the E-enolate to syn adduct correlation is characteristic of
uncatalyzed aldol reactions of enoxysilacyclobutanes. The
putative pentacoordinate siliconate transition structures were
shown computationally to prefer boat-like arrangements in this
(2) For recent advances with silyl ketene acetals, see: (a) Kobayashi,
S.; Uchiro, H.; Shiina, I.; Mukaiyama, T. Tetrahedron 1993, 49, 1761. (b)
Carriera, E. M. Singer, R. A.; Lee, W. J. Am. Chem. Soc. 1994, 116, 8837.
(
c) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1994, 116, 4077. (d)
Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull. Jpn. 1994,
2, 839. (e) Kobayashi, S.; Horibe, M. J. Am. Chem. Soc. 1994, 116, 9805.
4
(
f) Keck, G. E.; Krishnamurthy, D. J. Am. Chem. Soc. 1995, 117, 2363. (g)
Carreira, E. M. Singer, R. A. J. Am. Chem. Soc. 1995, 117, 12360. (h)
Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995, 41, 1435.
1
1
array.
(i) Uotsu, K.; Sasai, H.; Shibasaki, M. Tetrahedron: Asymmetry 1995, 6,
7
1.
To examine the consequences of promoting the reaction with
chiral Lewis bases, we surveyed a variety of chiral phosphor-
amides, of which (S,S)-4 (Chart 1) proved to be the most
effective, Table 2. First, we noted a significant rate acceleration;
with only 10 mol % of (S,S)-4 the aldol additions proceeded in
(3) For recent advances with silyl enol ethers, see: (a) Furuta, K.;
Maruyama, T.; Yamamoto, H. J. Am. Chem. Soc. 1991, 113, 1041. (b)
Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907.
(
c) Ishihara, K.; Maruyama, T.; Mouri, M.; Furuta, K.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 1993, 66, 3483. (d) Ishihara, K.; Mouri, M.; Gao, Q.;
Maruyama, T.; Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115,
12
high yield within 2 h at -78 °C. Second, we were surprised
1
1490. (e) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115, 7039.
to discover the dramatic reversal in diastereoselectivity; in the
presence of (S,S)-4, the anti diastereomer now predominated in
all cases, often exclusively (compare entries 1-5, Tables 1 and
(
f) Barrett, A. G. M.; Kamimura, A. J. Chem. Soc., Chem. Commun. 1995,
755. For an example with a methyl enol ether, see: (g) Carreira, E. M.;
Lee, W.; Singer, R. A. J. Am. Chem. Soc. 1995, 117, 3649.
1
(4) For a recent summary of enzyme-catalyzed asymmetric aldol addition
2
). Finally, we were delighted to find that the major, anti
reactions see: Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic
Organic Chemistry; Pergamon: Oxford, 1994; Chapter 4.
diastereomer in all of these cases was produced with good to
(5) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem.
Soc. 1996, 118, 7404.
(10) The relative configuration of 3a has been established in the literature.
For all other compounds we made the assignment on the basis of the splitting
pattern of the hydroxyl bearing methine. In the anti isomer, this proton
typically appears as a doublet of doublets, Jd ) 7-8 Hz; Jd ) 2-4 Hz;
while in the syn isomer it typically appears as a broad singlet or a doublet,
J ) 3-4 Hz. In addition, this proton in the anti isomers resonates 0.3-0.5
ppm upfield of the syn isomers.
(11) Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute M. E. J. Am.
Chem. Soc. 1994, 116, 7026.
(12) Control experiments showed that no reaction took place under these
conditions of time, temperature, and concentration without the promoter.
(6) (a) Mukaiyama, T. Org. React. 1982, 28, 203. (b) Mukaiyama, T.;
Murakami, M. Synthesis 1987, 1043. (c) Denmark, S. E.; Lee, W. J. Org.
Chem. 1994, 59, 707.
(7) For a notable exception, see: Kobayashi, S.; Horibe, M.; Hachiya,
I. Tetrahedron Lett. 1995, 36, 3173.
8) All compounds described herein were fully characterized by spec-
troscopic and analytical methods. See Supporting Information.
(
(9) (a) Pereyre, M.; Bellegarde, B.; Mendelsohn, J.; Valade, J. J.
Organomet. Chem. 1968, 11, 97. (b) Yasuda, M.; Katoh, Y.; Shibata, I.;
Baba, A.; Matsuda, H.; Sonoda, N. J. Org. Chem. 1994, 59, 4386.
S0002-7863(96)03669-4 CCC: $14.00 © 1997 American Chemical Society

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334 J. Am. Chem. Soc., Vol. 119, No. 9, 1997
Communications to the Editor
Table 3. Unpromoted Aldol Reactions of 2a
Table 1. Unpromoted Aldol Reactions of 1a
entry
aldehyde
time, h
product
syn/antib
yield, %
c
entry
aldehyde
time, h
product
syn/antib
yield, %
92c
1
2
3
4
5
6
7
a
b
c
d
e
f
10
10
16
10
12
16
11
5a
5b
5c
5d
5e
5f
1:2.3
1:2.9
1:1.3
1:1.9
1:2.2
1:1.9
1:2.2
97
93
95
95
64
89
89
1
2
3
4
5
6
7
8
a
c
d
e
g
h
i
6
8
1
11
2
12
12
36
3a
3c
3d
3e
3g
3h
3i
49:1
16:1
49:1
5.7:1
36:1
7.3:1
5.3:1
1:1
d
90
83
86
91
78
82
c
d
c
c
g
5g
d
a
b
d
All reactions performed at 0 °C/0.5 M in aldehyde. Determined
c
j
3j
92
1
by H NMR (400 MHz) analysis. Chromatographically homogeneous
material.
a
b
All reactions performed at 0 °C/0.5 M in aldehyde. Determined
by H NMR (400 MHz) analysis. Analytically pure material. d Chro-
1
c
a
matographically homogeneous material.
Table 4. Aldol Reactions of 2 Catalyzed by (S,S)-4
aldehyde time, h product syn/antib ee (syn), % yield, %
c
d
a
Table 2. Aldol Reactions of 1 Catalyzed by (S,S)-4
syn/antib
c
d
a
b
c
d
f
6
6
8
6
8
6
5a
5b
5c
5d
5f
18:1
12:1
3:1
9.4:1
7:1
95
96
84
92
91
58
95
89
96
97
94
92
entry aldehyde product
ee (anti), % yield, %
1
2
3
4
5
a
c
d
e
3a
3c
3d
3e
3g
1:61
<1:99
<1:99
<1:99
1:5.3
93
97
88
92
82
95
94
94
98
90
g
5g
1:3.5
g
a
All reactions performed with 15 mol % of (S,S)-4 at -78 °C/0.1
a
b
1
All reactions performed with 10 mol % of (S,S)-4 at -78 °C/0.1
M in aldehyde. Determined by H NMR (400 MHz) analysis.
d
b
1
c
M in aldehyde for 2 h. Determined by H NMR (400 MHz) analysis.
Determined by chiral HPLC anaylsis. Analytically pure material.
c
d
Determined by chiral HPLC analysis. Analytically pure material.
be expected from a switch from boat- to chair-like transition
structures. However, the diastereoselectivity was highly alde-
hyde dependent. Gratifyingly, the enantiomeric excess of the
major (syn) diastereomer was very high except for 5g. The
absolute configuration of the major diastereomer was established
to be (2S,3S) by X-ray crystallographic analysis of syn-5b.13
The high diastereo- and enantioselectivity of the aldolization
process and the stereochemical response to the enolate geometry
strongly support our current hypothesis of a highly-ordered,
chair-like transition structure involving hexacoordinate siliconate
species. The fact that (S,S)-4 induced the same configuration
at the hydroxyl-bearing methine in both anti-3a and syn-5a
suggests that, even with single point binding, the phosphor-
amides are capable of creating a highly dissymmetric environ-
ment which maintains the same enantiofacial preference at the
coordinated aldehyde with either enolate geometry. However,
the lack of structural information about the coordination
geometry at silicon makes the formulation of a sensible transition
structure model tenuous at this stage. That notwithstanding,
the catalytic, enantioselective generation of anti aldol products
is noteworthy for practical applications.
Chart 2
excellent ee. The absolute configuration of the major diaste-
reomer was established to be (2R,1′S) by X-ray crystallographic
analysis of the 4-bromobenzoate of anti-3a. The generation of
an anti aldol product from an E-enolate suggests the change to
a chair-like transition structure involving the putative hexa-
coordinate siliconate species (ii, Chart 2)
The unpromoted reactions of (Z)-2 proceeded somewhat more
slowly than for 1 but still in excellent yields, Table 3. As
8
expected for a boat-like, closed transition structure, the anti
diastereomer was found to predominate, but the selectivity was
poor. The decreased rate and diastereoselectivity associated with
Z-configured trichlorosilyl enolates are presaged by the same
observations in the case of Z-enoxysilacyclobutanes. Here
again, the intervention of boat-like structures in pentacoordinate
siliconates (iii, Chart 2) leads to a nonbonded interaction
between the pseudoaxially placed substituent on the enolate with
a ligand on silicon.
In the presence of a catalytic amount (15 mol%) of (S,S)-4
the reactions of (Z)-2 were significantly faster but still slower
compared to the promoted reactions of 1 (Table 4). Excellent
yields of aldol adducts from conjugated aldehydes were obtained
after 6-8 h at -78 °C. Aliphatic aldehydes did not react,
presumably due to competitive enolization. The major diaste-
reomer produced in the promoted reactions was syn as would
Extension of this process to other enolate types and the
elucidation of structure/selectivity correlations for the promoters
will be reported in due course.
1
1
Acknowledgment. We are grateful to the National Science Founda-
tion for generous financial support (CHE 9500397).
Supporting Information Available: Procedures for the preparation
and full characterization of 1; 2; (()-syn-3a, c, d, e, g, h, i, j; (()-
anti-5a-g; enantiomerically enriched-anti-3a, c, d, e, g; and enantio-
merically enriched-syn-5a, b, c, d, f, g, (34 pages). See any current
masthead page for ordering and Internet access instructions.
JA9636698
(
13) Debromination of (2S,3S)-5b afforded the major enantiomer of syn-
a thus establishing its configuration as (2S,3S) as well. All others are
assigned by analogy.
5