Palladium-catalyzed synthesis of substituted cycloheptane-1,4-diones by an asymmetric ring-expanding allylation (AREA)

Article abstract of DOI:10.1002/anie.200604553

(Chemical Equation Presented) The right AREA: Functionalized, seven-and eight-membered carbocycles are available from an asymmetric Pd-catalyzed decarboxylative fragmentation of strained bicyclo[3.2.0]heptane-2-ones (see scheme, dba = trans,trans-dibenzylidene-acetone). The products were formed in a sequence of [2+2] cycloaddition, retro-aldol reaction, and asymmetric allylation of ketone enolates.

Full text of DOI:10.1002/anie.200604553

Communications
DOI: 10.1002/anie.200604553
Asymmetric Catalysis
Palladium-Catalyzed Synthesis of Substituted Cycloheptane-1,4-diones
by an Asymmetric Ring-Expanding Allylation (AREA)**
Sabrina R. Schulz and Siegfried Blechert*
Oxygenated seven-membered carbocycles are a common
motif in many natural products, prominent examples being
found in the classes of the perhydroazulenes (such as
olefin to give a bicyclic cyclobutane which subsequently
undergoes a retro-aldol reaction that leads to seven- and
eight-membered 1,4- and 1,5-diketones. The potential of this
transformation has been demonstrated with the huge number
of natural product syntheses that use the de Mayo reac-
[
1,2]
procurcumadiol and (+)-aphanamol I),
pene diterpenes, or the scabronines, a family of cyathane-
type diterpenoids (Scheme 1). These molecules have interest-
the guanacaste-
[
3]
[4]
[
9–11]
tion.
[
5]
ing biological and pharmaceutical properties, and thus much
The asymmetric transition-metal-catalyzed decarboxyla-
tive allylation of ketone or b-ketoester enolates is an
extremely valuable tool for the construction of stereocenters
[
6,7]
effort has been made towards their asymmetric synthesis.
[
12,13]
adjacent to carbonyl groups.
The reaction is broadly
applicable as they generally proceed with high yields and
under very mild reaction conditions. During the course of the
de Mayo reaction, a ketone enolate is formed which is
normally protonated, and analogously to our previous work
we wanted to intercept this protonation reaction by trapping
the enolate with a chiral p-allyl palladium complex to give
[
14]
enantioenriched 5-allyl-1,4-cycloheptanediones. In partic-
ular we wished to target allylated cycloheptanediones with
quaternary stereocenters, the construction of which still
[
15]
remains an elusive goal in organic synthesis. Herein we
report on a catalytic asymmetric ring-expanding allylation
(AREA) reaction for the synthesis of chiral oxygenated
seven- and eight-membered carbocycles.
Early experiments used bicyclo[3.2.0]heptane-2-one
derivative (ꢀ )-1 with a methyl group at the bridgehead
position (Table 1). Different palladium sources such as [Pd -
2
Scheme 1. Natural products with oxygenated seven-membered ring
systems. Bn=benzyl.
(
(
dba) ](dba = trans,trans-dibenzylideneacetone) and [{Pd-
3
C H )Cl} ]were investigated along with a number of chiral
3
5
2
ligands 3–8 which are commonly used in palladium chemistry
[
16]
(
Scheme 2). Furthermore, the influence of the solvent was
explored.
We were pleased to see that the AREA reaction of (ꢀ )-1
During the course of our research directed towards the
asymmetric total synthesis of perhydroazulene-type diter-
penes we became interested in the enantioselective synthesis
of functionalized seven-membered diketones. The de Mayo
reaction constitutes an attractive route to medium-sized
carbocycles from 1,3-cyclopentanediones and 1,3-cyclohexa-
under various conditions gave the cycloheptane-1,4-dione 2 in
good yields and enantioselectivities (Table 1). The reaction
times ranged from one hour to three days, depending on both
the nature of the chiral ligand and the solvent employed, and
were longer compared to a test reaction in which the achiral
tetrakis(triphenylphosphine)palladium(0) was used (Table 1,
entry 1). All the reactions could be performed with low
catalyst loadings at room temperature. The best results were
[
8]
nediones.
The reaction consists of a sequence of a
[
2+2]cycloaddition of an enolized 1,3-diketone with an
[
*] Dipl.-Chem. S. R. Schulz, Prof. Dr. S. Blechert
Institut für Chemie
Technische Universität Berlin
Strasse des 17. Juni 135, 10623 Berlin (Germany)
Fax: (+49)30-3142-3619
achieved when substrate 1 was treated with 2.5 mol% [Pd -
2
[
17]
(
dba) ]and 6.5 mol% ( S)-tBu-phox ((S)-7)
in a 1,4-
3
dioxane/THF (3:1) mixture at 108C. The product (ꢁ)-2 was
isolated in 92% yield and 90% ee (Table 1, entry 9a). Only
slightly worse results were achieved when [Pd (dba) ]and ( S)-
2
3
E-mail: blechert@chem.tu-berlin.de
iPr-phox ((S)-6) were used (Table 1, entry 6). However,
throughout our investigations the ligand (S)-7 proved to be
superior. In general, the AREA reaction gave enantioselec-
tivities that were somewhat lower than those reported for the
[
**] We gratefully acknowledge the donation of a sample of the ligand
(S)-tBu-phox from Prof. G. Helmchen, Heidelberg.
Supportinginformation (experimental procedures and spectro-
scopic data) for this article is available on the WWW under http://
www.angewandte.org or from the author.
[
13f]
allylation of enolates in six-membered ring systems.
We
3
966
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Angewandte
Chemie
[
a]
Table 1: Test reactions for the asymmetric ring-expanding allylation (AREA).
which contained diversity at the a-
carbonyl bridge, the allyl carbonate,
and the cyclobutane ring, were
prepared. Thus, following the
method reported by Kuwajima and
[
18]
co-workers,
bis(trimethylsilyloxy)cyclobutene
(
1,2-
[
19]
[
b]
[c]
20) was treated with the corre-
sponding dimethyl acetal in the
presence of Lewis acid
Scheme 4). subsequent rear-
Entry Pd source
Ligand
Solvent
Product
t
Yield [%] ee [%]
1
2
3
4
5
6
7
8
a
[Pd(PPh ) ]
–
1,4-dioxane
THF
THF
rac-2
–
2
10 min 92
–
–
<5
63
<10
87
85
84
90
89
<10
–
3
4
a
[Pd (dba) ]
(R)-3
(R)-4
(S,S)-5
(S,S)-5
(S)-6
(S)-6
(S)-7
(S)-7
(S)-7
48 h
24 h
24 h
24 h
1 h
–
2
3
(
A
[Pd (dba) ]
57
60
85
91
90
2
3
[Pd (dba) ]
THF
(R)-2
(R)-2
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
2
rangement mediated by trifluoro-
acetic acid (TFA) gave the 2-sub-
stituted cyclopentane-1,3-diones 21.
This was followed by a selective O-
alkylation with the desired allyl
chloroformate to give the allylic
carbonates 22 in excellent yield. A
[2+2]cycloaddition reaction with
either an excess of ethylene or
allene using a mercury vapor lamp
2
3
[Pd (dba) ]
1,4-dioxane
1,4-dioxane
toluene
1,4-dioxane
1,4-dioxane/THF
1,4-dioxane/THF
2
3
[Pd (dba) ]
2
3
[Pd (dba) ]
78 h
2
3
[Pd (dba) ]
70 min 90
2
3
[
d]
9
9
1
1
[Pd (dba) ]
16h
16 h
78 h
48 h
92
94
40
–
2
3
[
e]
[d]
b
0
1
[Pd (dba) ]
2
3
[Pd (dba) ]
(S,S,S)-8 THF
2
3
[{Pd(C H )Cl} ] (S)-6 THF
–
3
5
2
[
a] The reactions were performed on a 0.29-mmol scale with 5.0 mol% of Pd source and 6.5 mol%
ligand at a substrate concentration of 0.033m at RT (22–258C). [b] Yields of isolated product. [c] The
ee values were determined by GC analysis on a chiral stationary phase (Lipodex E column). The absolute gave the substrates 23 for the
configuration was established by transformation of 2 to the correspondingmono-deoxy eg nated
cycloheptanone and comparison of its optical rotation with the value given in Ref. [13f] (see the
SupportingInformation). [d] The reaction was performed at 10 8C. [e] The reaction was performed on a
AREA reaction in reasonable 50–
7
0% yield (Scheme 4).
The subsequent AREA reac-
2
-mmol scale.
tions were conducted with a catalyst
loading of 2.5 mol% [Pd (dba) ]
2
3
and 6.5 mol% (S)-tBu-phox ((S)-7)
in 1,4-dioxane/THF (3:1) at 108C or for slower reacting
substrates either at room temperature or at 408C. The yields
of the isolated products exceeded 80% in each case, which
makes this reaction a useful methodology for organic syn-
thesis (Table 2).
Bicyclic substrate 9a, with an exo methylene group was
converted into the corresponding seven-membered carbo-
cycle 9b in 89% yield and 90% ee (Table 2, entry 1).
Although the intermediately formed enolate could undergo
allylation at the a or g position, it selectively reacted at the
a position, thus conserving the exo methylene group. Com-
Scheme 2. Chiral ligands for the asymmetric Pd-catalysis.
attribute this lower selectivity to the higher conformational
flexibility of the seven-membered ring.
We propose the following mechanism for the AREA
0
reaction: The neutral Pd species A inserts into the CꢁO bond
of the substrate to give the allyl palladium carbonate B
(
Scheme 3). This undergoes decarboxylative fragmentation
and opening of the strained bicycle to give the palladium
enolate C. Alkylation of this enolate by the chiral p-allyl
moiety then gives the product 2 with release of the neutral
palladium catalyst A. Consequently, this means that the
enantioenriched product (ꢁ)-2 is formed in an enantiocon-
vergent fashion from the racemic starting material (ꢀ )-1.
Our preliminary results prompted an investigation into
the scope of the AREA reaction. Thus, the substrates 9a–19a,
Scheme 3. Postulated mechanism of the decarboxylative ring-expand-
ingallylation.
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Communications
[
a]
Table 2: Exploration of the substrate scope in the AREA reaction.
[
b]
[c]
Entry Substrate
Product
t [h] Yield [%] ee [%]
1
20
20
20
89
93
87
90
92
91
[
d]
2
3
1
Scheme 4. Reagents and conditions: a) R CH(OMe) , BF ·OEt ,
2
3
2
CH Cl , ꢁ788C!RT, 4 h; b) TFA, reflux, 24 h; c) ClCO CH CR=CH ,
2
2
2
2
2
[d]
K CO , acetone, 08C!RT, 3 h; d) ethylene or allene (large excess),
2
3
CH Cl , hn, 8–20 h. R1, R2: see Table 2 and 3. TMS=trimethylsilyl.
2
2
pound 9b could be further transformed into a synthetically
interesting enone when treated with 1,8-diazabicyclo[5.4.0]-7-
undecene (see the Supporting Information). This result
underlines the versatility of this methodology as both
products, 9b and the corresponding enone, represent valuable
intermediates for further synthetic transformations. Use of
substrates 10a and 11a, which contained an ethyl or a n-hexyl
group in place of the methyl group in the a position to the
carbonyl group, gave a slightly increased selectivity to give the
products 10b and 11b with enantiomeric excesses of 92% and
4
5
20
25
91
82
86
[d]
83
9
1%, respectively (Table 2, entries 2 and 3). A further
increase in the steric bulk of the alkyl group, however, did
not significantly reduce the ee (Table 2, entries 4 and 5): The
phenethyl- and cyclohexyl-substituted products 12b and 13b
were isolated in 86% and 83% ee, respectively. The incorpo-
ration of a coordinating oxygen atom in substrate 14a led to
the formation of compound 14b with a moderate ee value
[e]
[e]
6
7
3
85
83
68
(
68%), presumably because the reaction had to be performed
at room temperature to obtain a reasonable reaction rate
Table 2, entry 6). Substrate 15a with a methallyl group
(
afforded the product 15b in 83% yield. However, presumably
because of the reluctance of the starting methallyl carbonate
to react with the sterically encumbered tBu-phox palladium
complex, the smaller iPr-phox ligand had to be used and the
reaction heated to 408C, which resulted in a lower selectivity
of 53% ee (Table 2, entry 7).
[f]
[d]
3
53
[
a] All reactions were performed on a 0.29-mmol scale with 2.5 mol%
Some of the products had to be converted into the
corresponding methyl ketones to be able to resolve the
enantiomers by GC on a chiral stationary phase. This was
[Pd (dba) ] and 6.5 mol% (S)-tBu-phox in 1,4-dioxane/THF (3:1) at 108C
2
3
unless otherwise stated. [b] Yields of isolated product. [c] The ee values
were determined by GC analysis on a chiral stationary phase (Lipodex E
column). [d] The ee values were determined after conversion of the
olefin to the correspondingmethyl ketone. [e] The reaction was
performed at RT. [f] The reaction was performed with (S)-iPr-phox in
[
20]
achieved by means of a Wacker oxidation or—in the case of
the methallyl substituted compound 15b—by ozonolysis. The
reactions proceeded cleanly and delivered the methyl ketones
that could be used for further elaboration to enone or azulene
1,4-dioxane at 408C.
[
21]
systems.
Finally, we investigated the formation of cycloheptane-
,4-diones with tertiary stereocenters (Table 3). Decarboxy-
quaternary stereocenters as they cannot epimerize under the
reaction conditions. The AREA reactions that led to products
with tertiary stereocenters worked best when carried out in
1,2-dimethoxyethane or diethyl ether. Bicycle 16a, which was
1
lative allylations that lead to tertiary stereocenters have been
[
13b]
rarely reported.
Most examples used substrates that led to
3
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Angewandte
Chemie
Table 3: AREA reactions that led to products with tertiary stereocen-
ters.
In conclusion, we have introduced an asymmetric decar-
[
a]
boxylative ring-expanding allylation reaction. This method
allows for the first time the preparation of enantioenriched
substituted cycloheptane-1,4-dione and cyclooctane-1,5-
dione derivatives. These compounds are valuable intermedi-
ates for the synthesis of functionalized medium-sized carbo-
cycles that can be further elaborated to important natural
products. The AREA reaction proceeded under mild con-
ditions in high yield and with reasonable to very good
enantioselectivities. The reaction has a broad substrate
spectrum to give diketone compounds with both tertiary
and quaternary stereocenters.
[
b]
[c]
Entry Substrate
Product
t [h] Yield [%] ee [%]
[
d]
1
2
3
4
12
82
73
60
41
48
[
e]
0.7 45, (90)
Experimental Section
General procedure for the AREA reaction: A Schlenk flask (100 mL)
was equipped with a magnetic stirrer and flame dried under vacuum.
After cooling and flushing the flask with argon, [Pd (dba) ](45 mg,
2
3
[f]
4
76
34
2
.5 mol%) and (S)-tBu-phox (50 mg, 6.5 mol%) were added to the
flask in a glovebox. The flask was evacuated for 10 min and then
refilled with argon. A dry degassed mixture of 1,4-dioxane/THF (3:1,
0 mL) was then added. The resulting deep red solution was stirred at
58C for 30 min until the color of the solution changed orange. The
solution then was cooled to 108C using a cryostat and the allyl
carbonate (2 mmol) was added by syringe in one portion. When the
reaction was complete (usually after stirring overnight; monitored by
TLC), the reaction mixture was allowed to warm to RT, evaporated
under vacuum, and the residue purified by column chromatography
6
2
10
(
SiO , cyclohexane/tert-butyl methyl ester 7:1).
2
[
[
[
a] All reactions were performed on a 0.29-mmol scale with 2.5 mol%
Pd (dba) ] and 6.5 mol% (S)-iPr-phox at RT unless otherwise stated.
b] Yields of isolated product. [c] The ee values were determined by
2
3
Received: November 7, 2006
Revised: January 30, 2007
Published online: April 19, 2007
GC analysis on a chiral stationary phase (Lipodex E column). [d] The
reaction was performed usingthe ( S)-tBu-phox ligand in 1,2-dimethoxy-
ethane. [e] The yield is based on recovered startingmaterial. [f] The
reaction was performed at 408C.
Keywords: allylation · asymmetric catalysis · carbocycles ·
.
palladium · ringexpansion
accessible in two steps from the commercially available 1,3-
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