Highly diastereoselective aldol additions of a chiral ethyl ketone enolate under Lewis base catalysis

Article abstract of DOI:10.1021/ol0160497

(Matrix presented) The aldol addition of a chiral ethyl ketone enolate bearing an oxygen substituent (OTBS) at the α-position proceeds with high internal and relative diastereoselectivities with various achiral aldehydes in good yields. The profound influ

Full text of DOI:10.1021/ol0160497

ORGANIC
LETTERS
2
001
Vol. 3, No. 14
201-2204
Highly Diastereoselective Aldol
Additions of a Chiral Ethyl Ketone
Enolate under Lewis Base Catalysis
2
Scott E. Denmark* and Son M. Pham
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received May 1, 2001
ABSTRACT
The aldol addition of a chiral ethyl ketone enolate bearing an oxygen substituent (OTBS) at the r-position proceeds with high internal and
relative diastereoselectivities with various achiral aldehydes in good yields. The profound influence of the resident stereogenic center allows
for the use of an achiral catalyst, such as HMPA, with minor attenuation in internal stereoselectivity.
4
Modern variants of the aldol reaction are among the most
important methods for achieving acyclic stereoselection in
synthesis. Our most recent contribution to this edifice of
with achiral aldehydes. The sensitive trichlorosilyl enolate
could be prepared in situ from the corresponding TMS enol
ether via a mercury-catalyzed trans-silylation. The resultant
trichlorosilyl enolate can then be combined with aldehydes
in the presence of catalytic amounts of chiral phosphoramides
to afford aldol products in good yields over two steps. When
using R-oxygenated ketone enolates, high 1,4-syn diastereo-
selectivity is achieved with (R,R)-2a. However, it was not
possible to reverse the sense of diastereoselection with the
use of (S,S)-2a. Interestingly, reactions using a chiral methyl
ketone enolate bearing a â-oxygen substituent give good 1,4-
1
chemical technology is the development of trichlorosilyl
enolates as asymmetric aldolization partners with various
2
aldehydes in the presence of chiral Lewis bases. This
reaction is believed to proceed through a closed, chairlike
transition structure centered around a cationic, hexacoordinate
silicon center. Kinetic analysis and nonlinear asymmetric
induction studies have shown that the reactions are second
3
order with respect to catalyst when 2a is employed.
syn diastereoselectivity when (R,R)-2a is employed but afford
5
1
,4-anti adducts with (S,S)-2a. In continuation of our studies,
we have extended the scope of chiral enolate structures to
6
include an R-oxygenated chiral ethyl ketone enolate. We
describe herein the in situ generation and aldol addition of
(
2) (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000, 33, 432.
b) Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem.
Soc. 1999, 121, 4982.
3) (a) Denmark, S.; Su, X.; Nishigaichi, Y. J. Am. Chem. Soc. 1998,
(
To extend the utility of these agents, we recently reported
the use of chiral methyl ketone enolates in aldol reactions
(
1
20, 12990. (b) Denmark, S. E.; Pham, S. M. HelV. Chim. Acta 2000, 83,
1
846.
(
1) Reviews: (a) Paterson, I.; Cowden, C. J.; Wallace, D. J. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter
. (b) Cowden, C. J.; Paterson, I. Org. React. 1997, 51, 1.
(4) Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122,
8837.
(5) Denmark, S. E.; Fujimori, S. Synlett 2001, 1024.
9
1
0.1021/ol0160497 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/12/2001

enolate 5 to achiral aldehydes using chiral and achiral
phosphoramides to accelerate the reaction and enhance the
stereoselectivity.
Scheme 1
Ethyl ketone 3 was readily prepared in three steps from
(S)-methyl lactate, Scheme 1. Treatment of the ester with
N,O-dimethylhydroxylamine hydrochloride in the presence
7
of trimethylaluminum afforded the Weinreb amide 6 in 83%
8
yield. Addition of ethylmagnesium chloride to the free
9
hydroxy amide provided hydroxy ketone 7 in 91% yield.
Finally, silylation with tert-butyldimethylsilyl chloride using
a catalytic amount of 4-(dimethylamino)pyridine provided
the protected ketone 3 in 92% yield. Initial attempts at
enolization of 3 using lithium diisopropylamide (LDA) and
trimethylsilyl chloride at -78 °C afforded the desired TMS
enol ether 4 and the corresponding regioisomer as a 2/1
mixture. The regioisomers could be separated by silica gel
chromatography albeit sacrificially with significant losses
from hydrolysis. Using a more sterically demanding base,
structure would be highly dependent upon the ratio of E and
Z enolate isomers. Orienting studies revealed that the
trichlorosilyl enolate geometry is independent of the starting
TMS enol ether geometry. Moreover, the size of the spectator
group plays a significant role in determining the ratio of Z/E
isomers; bulkier substituents such as tert-butyl and phenyl
afford the Z-trichlorosilyl enolate almost exclusively.13
Cognizant of these features, we treated TMS enol ether 4
10
such as lithium tetramethylpiperidide, afforded little to no
improvement. Although this procedure was adequate for
providing small quantities of enol ether for our initial studies,
a more selective method for the generation of 4 is required
if this process is to be synthetically useful. Ultimately we
found that the use of a more electrophilic silylating agent
improved selectivity for the desired regioisomer. Thus,
4 2
with SiCl and 1 mol % of Hg(OAc) to effect trans-
silylation, Scheme 2. The metathetical process was easily
1
monitored by H NMR and was found to be complete in 18
h. Gratifyingly, 5 could be isolated in 65% yield following
distillation to afford a 15/1 mixture of Z/E trichlorosilyl
enolates. Through the course of optimizing the trans-
silylation of 4, we were able to improve the selectivity of
the reaction such that 5 could be reproducibly generated as
a 19/1, Z/E mixture of enolates.
11
treatment of 3 with trimethylsilyl trifluoromethanesulfonate
and Et N in benzene at room temperature afforded TMS enol
ether 4 as a single regioisomer with a Z/E ratio greater than
3
1
2
0/1 (by H NMR analysis). Yields as high as 96% were
obtained following fractional distillation.
With a reliable method for the selective preparation of 4
in hand, we then focused on the preparation of trichlorosilyl
enolate 5. Achieving high geometric selectivity for the trans-
silylation was of great concern, since the relative diastereo-
induction12 in the aldol process through a closed transition
Scheme 2
(6) (a) For a discussion of aldol additions of boron, titanium, and lithium
enolates of chiral ethyl ketones, see: Braun, M. In StereoselectiVe Synthesis,
Methods of Organic Chemistry (Houben-Weyl), Edition E21; Helmchen,
G., Hoffman, R., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996;
Vol. 3, pp 1612-1622. For related benzyl and benzoate derivatives, see:
We could now evaluate the effect of the resident stereo-
genic center on the stereochemical course of the aldol
reactions to benzaldehyde in the presence of various phos-
phoramides. Following our established procedure, benzal-
dehyde was added to a 0.1 M solution of 5 and 15 mol % of
(
b) Paterson, I.; Wallace, D. J.; Vel a´ zquez, S. M. Tetrahedron Lett. 1994,
5, 9083. (c) Paterson, I.; Wallace, D. J. Tetrahedron Lett. 1994, 35, 9087.
d) For a more recent discussion, see: Galobardes, M.; Gasc o´ n, M.; Mena,
M.; Romea, P.; Urp ´ı , F.; Vilarrasa, J. Org. Lett. 2000, 2, 2599.
7) Following a modified procedure: Luke, G. P.; Morris, J. J. Org.
Chem. 1995, 60, 3013.
8) All compounds have been fully characterized; see the Supporting
Information for details.
3
(
(
2 2
(R,R)-2a in CH Cl at -78 °C. Disappointingly, the reaction
(
was very sluggish compared to that of the corresponding
methyl ketone enolates. This is presumably due to the added
steric encumbrance encountered by the substituted enolate
upon approach to an aldehyde through a closed transition
structure which is not present when using simple enolates.
Increasing the concentration of the reaction to either 0.5 or
(
(
9) Paterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639.
10) Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991,
1
13, 9571.
11) (a) Trost, B. M.; Urabe, H. J. Org. Chem. 1990, 55, 3982. (b)
Vorbr u¨ ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber. 1981, 114, 1234.
c) Corey, E. J.; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett. 1981,
2, 3455.
12) For a discussion regarding internal and relative diastereoselectivity,
(
(
2
1
.0 M allowed the aldol reaction to proceed to completion
(
see: Denmark, S. E.; Almstead, N. G. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 10.
(13) Denmark, S. E.; Pham, S. M. Unpublished results.
2202
Org. Lett., Vol. 3, No. 14, 2001

within 2 h using (R,R)-2a, Table 1, entry 1. The addition
product 8a was obtained in 87% yield. The relatiVe diaste-
reoselectivity for the two new stereogenic centers mirrored
the starting trichlorosilyl enolate geometry to give a 16/1
ratio of syn/anti diastereomers. We were delighted to find
that the internal diastereoselectivity for the major syn adduct
catalysts for the aldol reaction. As a further synthetic
simplification, we performed the aldol reactions by in situ
generation of trichlorosilyl enolate 5. This obviates the need
for handling of a sensitive compound and improves the
overall yield of aldol product with respect to the TMS enol
ether. Finally, to demonstrate the efficiency of our chiral
phosphoramides, the aldol reactions were performed using
only 5 mol % of (R,R)-2a, while still using 15 mol % of
HMPA, Table 2.
14
was greater than 50/1 in favor of the (syn,syn) stereoisomer.
Table 1. Survey of Phosphoramides in the Stereoselective
Addition of 5 to Benzaldehyde
relative dr internal dr
entry catalyst time, h yield, %a
syn/antib
syn/antib
Table 2. Survey of Various Aldehydes in the Stereoselective
1
2
3
4
5
6
7
(R,R)-2a
(S,S)-2a
(R,R)-2b
1a
1b
1c
2
2
8
7
7
5
7
87
80
65
76
82
67
79
16/1
15/1
15/1
15/1
15/1
15/1
15/1
>50/1
30/1
3/1
34/1
37/1
3/1
Aldol Addition
HMPA
30/1
loading,
mol %
drb
a
Yield of chromatographically homogeneous material. b Determined by
yield, %a
RCHO
catalyst
(syn,syn)/minors
CSP-SFC.
a
a
b
b
c
c
d
d
e
e
f
(R,R)-2a
HMPA
(R,R)-2a
HMPA
(R,R)-2a
HMPA
(R,R)-2a
HMPA
(R,R)-2a
HMPA
(R,R)-2a
HMPA
(R,R)-2a
HMPA
5
15
5
15
5
15
5
15
5
15
5
15
5
88
87
81
79
85
83
79
82
82
76
72
62
71
59
95/5
94/2/2/2
93/5/2
91/6/3
93/4/3
84/15/1
95/3/2
89/5/4/3
94/6
93/5/1
98/1/1
83/12/3/1
94/3/3
89/6/4/1
A survey of chiral and achiral phosphoramides showed
variation in the influence of the resident stereogenic center
on the internal stereoselectivity of the reaction, Table 1. As
before, the relative diastereoselectivity of 8a corresponds well
with the initial composition of 5, suggesting that the aldol
reaction proceeds nearly exclusively through a closed,
chairlike transition structure. Surprisingly, the configuration
of the catalyst employed in the aldol reaction has only a
marginal effect on the stereochemical outcome. For example
the use of (S,S)-2a led to only a slight decrease in internal
diastereoselectivity from 50/1 to 30/1 for (R,R)-2a and (S,S)-
f
g
g
15
a
Yield of analytically pure material. b Ratio determined by CSP-SFC.
2
a, respectively. Although from an energetic perspective this
change may be significant, from a practical aspect, for
synthetic purposes, these numbers are virtually identical.
Perhaps the most profound illustration of the influence of
the resident stereogenic center was shown when we employed
the achiral N,N′-dimethyl-[1,3,2]-diazaphospholidine catalysts
The entries in Table 2 illustrate that excellent diastereo-
selectivities can be achieved even when using catalyst
loadings as low as 5 mol %. Moreover, the results reveal a
marked improvement for the in situ procedure over one in
which the trichlorosilyl enolate is prepared independently.
Although the diastereoselectivity and yields using HMPA
are slightly poorer, the results remain synthetically viable.
1a and 1b. In both cases, the internal diastereoselectivity
was greater than 30/1. Even the use of HMPA afforded 8a
with an internal diastereoselectivity of 30/1, albeit at a
reduced rate. Interestingly, only the N,N′-diphenyl-derived
phosphoramides (R,R)-2b and 1c gave significantly attenu-
ated internal diastereoselectivities (vide infra).
1
5
Even though (R,R)-2a is easy to prepare, the benefits of
using HMPA are clear.
To determine the absolute configuration of the various
aldol products, material from reactions using (R,R)-2a were
To establish the generality of reactions with 5, we surveyed
various aldehydes using both (R,R)-2a and HMPA as
1
6
desilylated with 1% HCl in EtOH. The keto diols were
(
15) Denmark, S. E.; Su, X.; Nishigaichi, Y.; Coe, D. M.; Wong, K.-T.;
(
14) In this nomenclature, the first descriptor is relative, the second is
Winter, S. B. D.; Choi, J. Y. J. Org. Chem. 1999, 64, 1958.
(16) (a) Wetter, H.; Oertle, K. Tetrahedron Lett. 1985, 26, 5515. (b)
Cunico, R. F.; Bedell, L. J. Org. Chem. 1980, 45, 4797.
internal. The configuration assignment follows degradation to propanoates
and chemical correlation as described below.
Org. Lett., Vol. 3, No. 14, 2001
2203

then subjected to oxidative cleavage using NaIO 17
by treatment with CH to afford the known methyl
followed
4
2
N
2
propanoate aldol adducts (see the Supporting Information).
1
Chemical correlation via H NMR and optical rotation
confirmed the major diastereomer to be (syn,syn)-8.
To rationalize the stereochemical outcome, we make
recourse to the familiar, nonchelation model which places
the TBS ether in an antiperiplanar orientation relative to the
C-O bond of the enoxytrichlorosilane to reduce dipole-
dipole interactions, Figure 1.1 In this manner, approach of
benzaldehyde would be toward the face of the enolate (Si)
which contains the hydrogen to minimize steric interactions.
Additionally, the proposed chairlike arrangement would
,4
situate the phenyl group of benzaldehyde equatorially, to
prevent 1,3-diaxial interactions.18 As depicted in Figure 1,
Figure 1. Proposed transition structures for stereoselective aldol
reactions with 5.
reaction through i containing two phosphoramide molecules
would afford (syn,syn)-8a. Bulky catalysts bearing N-phenyl
substituents ((R,R)-2b and 1c) reduce the coordinating ability
of the phosphoramides, such that a “one phosphoramide
pathway would position the TBS ether synperiplanar to the
enoxy C-O bond. This forces the aldehyde to approach the
opposite enolate face (Re) as observed in i, but again
maintaining the same relative orientation of the phenyl group.
Thus, reaction through ii containing one phosphoramide
molecule would provide (syn,anti)-8a.
Extension of these studies to other chiral ethyl ketones
with more strongly coordinating substituents as well as to
chiral ketones with remote stereogenic centers is in progress.
1
9
pathway” for aldolization now becomes competitive. It is
conceivable that in such an event the remaining coordination
site on the octahedral silicon is occupied by the oxygen in
the R-position of the trichlorosilyl enolate. Although the
2
0
binding propensity of a TBS ether is modest at best, the
proximity of this group to a cationic siliconate surely
21
enhances the probability of chelation. Thus, a coordinative
(
17) Following a procedure described by Urp ´ı , ref 6d.
Acknowledgment. We are grateful to the National
Science Foundation for generous financial support (NSF
CHE-9803124). S.M.P. thanks the University of Illinois and
the Eastman Kodak Company for Graduate Fellowships.
(18) Masamune, S.; Choy, W.; Kerkesky, F. A. J.; Imperiali, B. J. Am.
Chem. Soc. 1981, 103, 1566.
19) For a detailed discussion regarding the mechanistic aspects of a
(
one phosphoramide pathway vs a two phosphoramide pathway in Lewis
base-catalyzed aldol reactions of trichlorosilyl enolates, see ref 3.
(
20) For a discussion of the coordinating abilities of various ether
Supporting Information Available: Full experimental
procedures and characterization data for aldol adducts
described. This material is available free of charge via the
Internet at http://pubs.acs.org.
substituents, see: (a) Reetz, M. T. Acc. Chem. Res. 1993, 26, 462. (b) Chen,
X.; Hortellano, E. R.; Eliel, E. L.; Frye, S. V. J. Am. Chem. Soc. 1990,
1
12, 6130. (c) Mori, S.; Nakamura, M.; Nakamura, E.; Koga, N.; Morokuma,
K. J. Am. Chem. Soc. 1995, 117, 5055.
21) For a discussion of chelation as a stereocontrol element in lactate-
derived stannous enolates, see: Paterson, I.. Tillyer, R. Tetrahedron Lett.
992, 33, 4233.
(
1
OL0160497
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Org. Lett., Vol. 3, No. 14, 2001