Lewis base activation of Lewis acids. Vinylogous aldol addition reactions of conjugated N,O-silyl ketene acetals to aldehydes

Article abstract of DOI:10.1021/ja056747c

N,O-Silyl dienyl ketene acetals derived from unsaturated morpholine amides have been developed as highly useful reagents for vinylogous aldol addition reactions. In the presence of SiCl₄ and the catalytic action of chiral phosphoramide (R,R)-3,

Full text of DOI:10.1021/ja056747c

Published on Web 01/06/2006
Lewis Base Activation of Lewis Acids. Vinylogous Aldol Addition Reactions
of Conjugated N,O-Silyl Ketene Acetals to Aldehydes
Scott E. Denmark* and John R. Heemstra, Jr.
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois, Urbana, Illinois 61801
Received October 2, 2005; E-mail: denmark@scs.uiuc.edu
The potent biological activity and structural diversity of the
polyketide class of natural products has provided attractive targets
for total synthesis as well as potential leads for the development
of promising pharmaceutical agents.1 The structural characteristic
common to these natural products is the complex polyol subunits
residing within their core, and one of the most widely applied
methods for polyol synthesis is the aldol addition reaction. The
selectivity, generality, and predictability obtainable with current
aldol technology have elevated this reaction to strategy-level status
in natural product synthesis.2
Whereas the normal aldol addition provides access to 1,3-
difunctional relationships, the vinylogous extension3 of this reaction
allows 1,5-difunctional subunits to be constructed. This vinylogous
modification of the aldol reaction is possible when γ-enolizable
R,â-unsaturated carbonyl substrates are employed as “extended
dienolates”. This process leads to the formation of δ-hydroxy-â-
keto esters or δ-hydroxy-R,â-unsaturated carbonyl compounds in
which up to two stereocenters and one double bond can be created
simultaneously.4
Although similar to simple aldol additions, the vinylogous aldol
reaction overlays the challenge of site selectivity onto the already-
present issues of diastereo- and enantioselectivity. Addition of a
dienolate to an aldehyde has the possibility of generating a mixture
of both the R- and γ-addition products (Scheme 1). A strategy that
allows for γ-site selectivity is the use of silyl dienolates as
nucleophiles in Lewis acid promoted vinylogous Mukaiyama aldol
additions.2 For example, silyl dienol ether 1 is a synthetic equivalent
of a diketone or keto ester dianion that reacts with exclusive γ-site
selectivity owing to the high nucleophilicity at C(4). However, silyl
dienol ethers derived from R,â-unsaturated carbonyl compounds
(2) are not as electronically biased, and steric effects from both
the dienolate and catalyst structure are needed to achieve high site
selectivity. Indeed, both R- and γ-addition products have been
observed in vinylogous aldol reactions employing ester-derived
dienol ethers.4,8
is overwhelmingly favored under conditions of kinetically controlled
enolization, the extended dienolates of R,â-unsaturated ketones are
difficult to obtain when R′-protons are present and mixtures of the
cross and extended conjugated dienolates are typically isolated.8
To address the issue of nucleophile reactivity, we have explored
the potential of dienol ethers derived from R,â-unsaturated amides
in the vinylogous aldol addition to aldehydes. Amide-derived silyl
enol ethers are known to be highly reactive species.9 Moreover,
the ability to transform the amide function into either ketones or
aldehydes provides indirect access to aldol products derived from
these R,â-unsaturated carbonyl compounds.10 We report herein a
general, catalytic, and enantioselective vinylogous addition of silyl
dienol ethers derived from R,â-unsaturated amides to aldehydes.11
Previous studies in these laboratories with ester-derived dieno-
lates demonstrated that the site selectivity of the addition is largely
influenced by the size of the alkoxy substituent.6 Therefore, amides
derived from various amine structures were chosen to probe their
effect on site (as well as stereo-) selectivity. Surprisingly, at the
outset of these studies, a general procedure for the synthesis of
conjugated N,O-silyl ketene acetals was absent in the literature.
However, these dienolates are easily accessed by deprotonation of
the corresponding R,â-unsaturated amide with 1.1 equiv of potas-
sium hexamethyldisilazide (KHMDS) at -78 °C followed by
trapping of the resulting potassium dienolate with TBSCl. This
protocol allowed for the synthesis of tert-butyldimethylsilyl dienol
ethers 5-8 in good to high yields (Table 1). These dienolates are
distillable oils with a wide range of stabilities. Whereas dienolate
6 shows significant decomposition at -15 °C within a week of
synthesis, morpholine-derived dienolate 8 could be stored indefi-
nitely at this temperature without any noticeable sign of decomposi-
tion. In all cases, the products were obtained as single geometrical
isomers determined to be of the 1Z configuration by analysis of
their 1H nOe NMR spectra. The reactivity of these conjugated N,O-
silyl ketene acetals was assayed in the addition to hydrocinnama-
ldehyde (4), an aldehyde that resisted addition by ketone-derived
dienolates (Table 1).12 Gratifyingly, the corresponding aldol
products were isolated in uniformly high yield; however, the
enantioselectivity of the addition was highly dependent on the
structure of the nitrogen substituents. Whereas the acyclic amine-
derived dienolates reacted with modest enantioselectivity (Table
1, entries 1 and 2), the cyclic amines afforded higher selectivity.
Indeed, the morpholine-derived silyl dienol ether 8 reacted with
exclusive γ-selectivity and excellent enantioselectivity (Table 1,
entry 4). In all cases, the resulting aldol product was exclusively
of the E configuration.
Scheme 1
Recent disclosures from these laboratories have demonstrated
that the catalytic action of chiral bis-phosphoramide (R,R)-35 and
silicon tetrachloride promotes the addition of simple R,â-unsaturated
ester-6 and ketone-derived7 dienol ethers to aldehydes with almost
exclusive γ-site selectivity for a variety of substitution patterns on
the dienol ether while maintaining high enantio- and diastereose-
lectivity. However, two limitations persisted for the addition of
ketone-derived dienolates.7 First, the dienolates were found to be
unreactive with aliphatic aldehydes under Lewis base catalysis.
Furthermore, although the formation of cross-conjugated dienolates
The addition of the morpholine-derived silyl dienolate 8 was next
surveyed with a variety of aldehyde structural types (Table 2).
Reactions with linear, R-, and â-branched aliphatic aldehydes
afforded the γ-addition products exclusively in good to high yields
and excellent enantioselectivities (entries 1-4). Both aromatic and
heteroaromatic aldehydes reacted rapidly (entries 5-8), providing
vinylogous aldol adducts in high yields and selectivities. With a
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J. AM. CHEM. SOC. 2006, 128, 1038-1039
10.1021/ja056747c CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
tallic nucleophiles to form ketones.16,17 After protection of 12 as a
tert-butyldimethylsilyl ether, MeMgBr cleanly converted the mor-
pholine amide 26 to the methyl ketone 27 in high yield without
any evidence for the formation of the tertiary alcohol arising from
overaddition (Scheme 3).
Table 1. Vinylogous Aldol Reactions of Amide-Derived Dienolates
with Hydrocinnamaldehydea
Scheme 3
dienolate
(yield, %)b
yield
c
entry
X
product
%
γ:
Rd
ere
1
2
3
4
5 (77)
6 (89)
7 (80)
8 (78)
NMe2
NEt2
N(CH2)5
9
10
11
12f
69
78
70
80
92:8 91.0:9.0
95:5 84.8:15.2
93:7 96.0:4.0
>99:1 99.0:1.0
These findings represent the first catalytic and enantioselective
vinylogous aldol reactions that employ silyl ketene acetals derived
from R,â-unsaturated amides. Further studies are underway to
extend this method to other morpholine-derived amides and for the
synthesis of complex polyol-containing natural products.
N(CH2CH2)2O
a Reactions employed 1.1 equiv of SiCl4, 1.2 equiv of dienolate, 0.05
equiv of (R,R)-3, 0.1 equiv of i-Pr2NEt, 0.05 equiv of TBAOTf at 0.1 M in
CH2Cl2 at -72 °C for 16 h. b Yields of dienolate synthesis. c Yields after
chromatography. d Determined by 1H NMR analysis. e Determined by CSP-
SFC. f S absolute configuration.13
Acknowledgment. We are grateful to the National Science
Foundation (CHE 0414440) for generous financial support. J.R.H.
acknowledges the University of Illinois for a Seemon H. Pines
Graduate Fellowship.
Table 2. Vinylogous Aldol Reactions of Morpholine-Derived
Dienolates 8 with Aldehydesa
Supporting Information Available: Full characterization of all
dienol ethers and aldol products along with representative procedures
for the addition reactions. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
entry
R
product
yield, %b
γ
:
Rc
erd
(1) O’Hagan, D. The Polyketide Metabolites, 1st ed.; Ellis Horwood:
Chichester, 1991.
1e
2e
3e
4e
5
PhCH2CH2
CH3(CH2)4
(CH3)2CHCH2
cyclohexyl
C6H5
4-CH3OC6H4
4-CF3C6H4
2-furyl
12
13
14
15
16
17
18
19
20
21
80f
79f
84f
63
95
95
93
94
94
91
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
99.0:1.0
94.3:5.7
99.7:0.3
99.4:0.6
97.2:2.8
99.0:1.0
95.4:4.6
93.8:6.2
98.2:1.8
75.5:24.5
(2) (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
2004. (b) Carreira, E. M. In Modern Carbonyl Chemistry; Otera, J., Ed.;
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6
7
8
9g
10
(E)-PhCHdCH
(E)-PhCHdC(CH3)
(3) (a) Fuson, R. C. Chem. ReV. 1935, 16, 1-27. (b) Krishnamurthy, S. J.
Chem. Educ. 1982, 59, 543-547. (c) Bruneau, P.; Taylor, P. J.; Wilkinson,
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a All reactions employed 1.1 equiv of SiCl4, 1.2 equiv of 8, 0.05 equiv
of (R,R)-3, 0.1 equiv of i-Pr2NEt at 0.1 M in CH2Cl2 at -72 °C. b Yield of
analytically pure material. c Determined by 1H NMR analysis. d Determined
by CSP-SFC. e 0.05 equiv of TBAOTf was added. f Yield after chroma-
tography. g Reaction employed 0.02 equiv of (R,R)-3.
(5) Catalyst (R,R)-3 is commercially available from Obiter Research, LLC.
Contact waboulanger@obiterresearch.com.
(6) (a) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am.
Chem. Soc. 2005, 127, 3774-3789. (b) Denmark, S. E.; Beutner, G. L. J.
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method in total synthesis, see: (c) Aubele, D. L.; Wan, S.; Floreancig, P.
E. Angew. Chem., Int. Ed. 2005, 44, 3485-3488.
catalyst loading of only 2 mol %, the addition of dienolate 8 to
cinnamaldehyde afforded γ-addition product in excellent yield, site-,
and enantioselectivity (entry 9). Unfortunately, R-methyl branched
olefinic aldehydes continue to afford low enantioselectivity (entry
10). Although aliphatic aldehydes require longer reaction times com-
pared to that of conjugated aldehydes, the fact that aliphatic aldehy-
des afford the highest selectivity is particularly noteworthy as these
are typically the least selective substrates in this catalytic system.6
In a preliminary survey of structural generality, we have prepared
ketene acetals 22 and 23 bearing methyl groups on the R and â
atoms of the dienyl unit, respectively.14a These nucleophiles also
reacted with exclusive γ-selectivity to afford the addition products
in high yield and high geometrical14b and excellent enantioselectivity
with hydrocinnamaldehyde (Scheme 2).15
(7) Denmark, S. E.; Heemstra, J. R., Jr. Synlett 2004, 2411-2416.
(8) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000,
100, 1929-1972.
(9) Myers, A. G.; Widdowson, K. L. J. Am. Chem. Soc. 1990, 112, 9672-
1974.
(10) O’Neill, B. T. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford; 1991; Vol. 1, pp 397-458.
(11) For an example of diastereoselective additions of vinylketene silyl N,O-
acetals to aldehydes, see: Shirokawa, S.; Kamiyama, M.; Nakamura, T.;
Okada, M.; Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem.
Soc. 2004, 126, 13604-13605.
(12) The addition of tetrabutylammonium trifluoromethanesulfonate and di-
isopropylethylamine to the solution was found to increase the yield of
the aldol adducts. For a discussion of the role of these additives, see ref
6a.
(13) Absolute configuration of 12 was determined by chemical correlation to
(3S)-5-phenylpentane-1,3-diol (O3 then LiAlH4). Nunez, M. T.; Martin,
V. S. J. Org. Chem. 1990, 55, 1928-1932.
(14) (a) N,O-Silyl ketene acetal 22 is formed as a 2.6:1, E/Z mixture, whereas
23 is a 19:1 Z/E mixture. (b) Product 24 formed as a single E isomer
whereas 25 is formed as an 88:12, E/Z mixture.
Scheme 2
(15) Ketene acetals 22 and 23 also reacted with excellent yield and enanti-
oselectivity with benzaldehyde (90-97% yield, 98.4:1.6-98.6:1.4 er) and
cinnamaldehyde (95-97% yield, 98.9:1.1-99.3:0.7 er).
(16) (a) Martin, R.; Romea, P.; Tey, C.; Urpi, F.; Vilarrasa, J. Synlett 1997,
1414-1416. (b) Tosaki, S.; Horiuchi, Y.; Nemoto, T.; Ohshima, T.;
Shibasaki, M. Chem.-Eur. J. 2004, 10, 1527-1544.
(17) Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450.
Coincidentally, of all the amides employed, the morpholine
derivative is also the most effective at the acylation of organome-
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