Remarkable phosphine-effect on the intramolecular aldol reactions of unsaturated 1,5-diketones: Highly regioselective synthesis of cross-conjugated dienones

Article abstract of DOI:10.1021/ja054085l

We report a phosphine-mediated intramolecular aldol cyclization of unsaturated diketones that proceeds with extremely high levels of regioselectivity for the cross-conjugated bicyclic dienone products. The sense of regioselectivity observed in this reacti

Full text of DOI:10.1021/ja054085l

Published on Web 11/10/2005
Remarkable Phosphine-Effect on the Intramolecular Aldol Reactions of
Unsaturated 1,5-Diketones: Highly Regioselective Synthesis of
Cross-Conjugated Dienones
Reema K. Thalji† and William R. Roush*,‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055, and
Department of Chemistry, Scripps Florida, Jupiter, Florida 33485
Received June 20, 2005; E-mail: roush@scripps.edu
Table 1. Survey of Solvents for the Tandem Cyclizationa
As part of a target-oriented synthetic study, we were interested
in developing selective syntheses of linear- and cross-conjugated
dienones via aldol cyclizations of diketones (eq 1). Methods for
the regioselective aldol reaction of such diketones are scarce,
especially in cases where the steric environments of the two
carbonyl groups are very similar.1 1,5-Diketones such as 1 were of
interest because they are readily prepared via the phosphine-
catalyzed intramolecular vinylogous Morita-Baylis-Hillman (MBH)
cyclization of bis-R,â-unsaturated carbonyl compounds,2 a reaction
that was developed simultaneously in the Krische group3 and in
our laboratory.4,5 During the course of our studies of the vinylogous
MBH reaction, competitive intramolecular aldol cyclizations were
observed for vinylogous MBH products 1 bearing enolizable
carbonyl units when these reactions were performed in protic
solvents such as t-amyl alcohol.4a This observation is consistent
with the notion that the aldol reactions are catalyzed by alkoxide
generated via deprotonation of alcoholic solvent by the zwitterionic
phosphonium enolate intermediates.6 During efforts to optimize this
tandem MBH/aldolization process, we discovered and report herein
remarkable and unprecedented regioselectivity in the aldol step,
resulting in extremely high selectivity for the less stable cross-
conjugated dienones. We also provide evidence for the involvement
of the phosphonium unit of the phosphine-enone Michael adduct
(e.g., 6) in controlling the regiochemistry of these reactions.
entry
solvent
T (
°
C)
time (h)
% 4
+
5
ratio (4:5)
1b
2
3
MeOH
MeOH
t-AmylOH
i-PrOH
CF3CH2OH
CF3CH2OH
25
60
60
60
60
60
24
10
48
3
24
22
83c
82c
10d
80
80
76
94:6
93:7
90:10
71:29
>99:1
>99:1
4
5b
6e
a Conditions: 0.25 equiv of PBu3, 0.05 M 2. b PBu3 (1 equiv) was used.
c Contaminated with 20% MeOH adducts of 4 and 5. d Aldol product (19%)
and 3 (42%) were also isolated. e PMe3 (1 equiv) was used.
The very high regioselectivity for 4 in these reactions was
unexpected. A priori, we had anticipated that poor kinetic selectivity
would occur in the aldol step due to the similarity in pKa and steric
environment of the two ketone units in intermediate 3; moreover,
the linearly conjugated isomer 5 was expected to predominate if
the reaction was subject to thermodynamic control.1 Therefore, it
is noteworthy that we observe such high regioselectivity and that
the reaction is highly selective for the less stable cross-conjugated
isomer.8 We postulate that the high degree of selectivity derives
from an interaction between the phosphonium unit and the adjacent
carbonyl in intermediate 6. This would increase the acidity of the
â-phosphonium-substituted methyl ketone such that it is deproto-
nated regioselectively by the alkoxide (6 f 7, eq 2).9
Symmetrical bisenone 2 was selected for initial reaction develop-
ment studies (Table 1). The cyclization of 2 at room temperature
in the presence of 1 equiv of PBu3 in MeOH as the solvent produced
regioisomeric aldol condensation products 4 and 5 with excellent
selectivity (4:5 ) 94:6) for the cross-conjugated isomer 4 (entry
1). The Bu3P loading can be decreased to 0.25 equiv if the reaction
is performed at 60 °C, and the selectivity is only slightly lower
(4:5 ) 93:7, entry 2). Unfortunately, these products were contami-
nated with inseparable adducts of MeOH-Michael addition to 4
and 5.7 Use of t-AmylOH as the reaction solvent resulted in
inefficient aldol condensation (entry 3), while use of i-PrOH gave
a very clean, high yield (80%) of products, but with poor selectivity
(4:5 ) 71:29, entry 4). Remarkably, however, use of CF3CH2OH
as solvent for the tandem reaction gave clean aldol condensation
product with exclusive selectivity for 4; isomer 5 was undetected
by 1H NMR analysis (entry 5). PMe3 can also be used to promote
this reaction with identical selectivity to that obtained using PBu3
(entry 6).
Experimental evidence for this phosphine effect was obtained
by subjecting MBH product 3 to a catalytic amount of CF3CH2ONa
in CF3CH2OH (eq 3). No reaction was observed, indicating that
CF3CH2ONa is not basic enough to deprotonate 3 in the absence
of phosphine. While 3 undergoes efficient aldol cyclization when
treated with i-PrONa (eq 4), the selectivity (4:5 ) 18:82) is opposite
to that observed using PBu3/i-PrOH (4:5 ) 71:29). Furthermore,
treatment of 3 with PBu3 in CF3CH2OH affords 4 exclusively (eq
† University of Michigan.
‡ Scripps-Florida.
9
16778
J. AM. CHEM. SOC. 2005, 127, 16778-16779
10.1021/ja054085l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scope of the Tandem Cyclization
Scheme 1. Synthesis of Cross-Conjugated or Linear Dienones
In summary, we have discovered a phosphine-mediated intra-
molecular aldol cyclization of unsaturated diketones 1 that proceeds
with extremely high levels of regioselectivity for the cross-
conjugated bicyclic dienone products. The sense of regioselectivity
observed in this reaction is unattainable using traditional aldol
conditions and is governed by the chemistry of the phosphine
Michael adduct 6. Applications of this method to the synthesis of
natural products will be reported in due course.
Acknowledgment. We thank the National Institutes of Health
for financial support (GM26782) and a postdoctoral fellowship to
R.K.T. (GM073325).
Supporting Information Available: Complete experimental details
and spectroscopic data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
a The only product isomers detected by H NMR analysis of the crude
material are those indicated. b Method A: 1 equiv of PMe3, 0.05 M substrate
in CF3CH2OH, 60 °C. c Method B: 5 equiv of PMe3, 0.05 M substrate in
t-AmylOH, 80 °C. d The MBH intermediate (cf., 1) was isolated in 7-8%
yield.
References
(1) For leading references on the regioselectivity of base-catalyzed aldol
cyclizations of 1,4- and 1,5-diketones, see: (a) Singh, R. K.; McCurry,
P. M. J. Org. Chem. 1974, 39, 2316. (b) Danishefsky, S.; Zimmer, A. J.
Org. Chem. 1976, 41, 4059. (c) For a review, see: Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: New York, 1991; Vol. 2, p 181.
(2) For selected reviews on the Morita-Baylis-Hillman reaction, see: (a)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811.
(b) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627. (c) Langer, P.
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5), demonstrating that 3 is a viable intermediate in the conversion
of 2 to 4. These results support our proposal that 6 plays a key
role in controlling the regioselectivity of the aldol step.
Other bisenone substrates cyclize to afford exclusively the cross-
conjugated isomers (Table 2). Bisenone 8, bearing a shorter tether,
cyclizes to dienone 9 in 76% yield (Table 2, entry 2). Substrate 10
can theoretically afford two vinylogous MBH adducts (cf., 1), each
of which in principle can cyclize to give two aldol regioisomers.
Remarkably, 10 cyclized to afford only one out of four possible
products (11) in 71% yield (entry 3). Evidently, the vinylogous
MBH cyclization of 10 occurs with selectivity that is consistent
with initial phosphine addition to the least hindered enone, while
the selectivity of the aldol step is governed by the phosphine effect
outlined above.
(3) (a) Wang, L.-C.; Luis, A.-L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J. J.
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Sterically differentiated bisenones 12, 14, 16, and 18 (Table 2,
entries 7-10), which contain a hindered â,â-disubstituted enone,
undergo efficient and selective MBH cyclization and subsequent
aldol condensation to give the cross-conjugated products. Again,
only one out of four possible products is formed. For these
substrates, the optimal conditions involved use of 5 equiv of PMe3
in t-AmylOH at 80 °C; the MBH cyclization in these cases was
unsuccessful using CF3CH2OH as solvent. In all cases, products
bearing quaternary centers were generated in good yield (58-64%).
MBH product 20, which can be isolated from the cyclization of
bisenone 18, undergoes phosphine-mediated aldol cyclization with
the most hindered enolate serving as the nucleophile to generate
isomer 19 (Scheme 1). Interestingly, a base-promoted aldol cy-
clization of 20 in the absence of phosphine results in a complete
reversal of selectivity, and the linearly conjugated isomer 21 is
obtained in >95:5 selectivity. This example highlights the striking
complementarity of the phosphine-mediated aldol condensation to
a traditional aldol process.
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(7) Solvent mixtures of THF, MeCN, or CH2Cl2 and MeOH significantly
reduced the amount of MeOH Michael adducts (from 20 to 3%), but
conversions and/or selectivities were lower in these solvent systems.
(8) Isomers 4 and 5 do not equilibrate under the reaction conditions.
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