Palladium-catalyzed sequential arylation and allylic alkylation of highly functionalized ketones: A concise synthesis of mesembrine

Article abstract of DOI:10.1021/ol802608r

(Chemical Equation Presented) An unprecedented palladium-catalyzed sequential procedure toward arylation and allylic alkylation of highly functionalized cyclohexenones was developed. This new protocol leads to useful building blocks containing a benzylic

Full text of DOI:10.1021/ol802608r

ORGANIC
LETTERS
2009
Vol. 11, No. 3
555-558
Palladium-Catalyzed Sequential Arylation
and Allylic Alkylation of Highly
Functionalized Ketones: A Concise
Synthesis of Mesembrine
Yuanhong Zhao, Yongyun Zhou, Leilei Liang, Xiaodong Yang, Fengxiang Du,
Liang Li, and Hongbin Zhang*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education,
School of Chemical Science and Technology, Yunnan UniVersity,
Kunming, Yunnan 650091, P. R. China
zhanghb@ynu.edu.cn; zhang_hongbin@hotmail.com
Received November 12, 2008
ABSTRACT
An unprecedented palladium-catalyzed sequential procedure toward arylation and allylic alkylation of highly functionalized cyclohexenones
was developed. This new protocol leads to useful building blocks containing a benzylic quaternary carbon in only one step. A concise total
synthesis of mesembrine based on this procedure was achieved in only five steps with 22% overall yield.
Benzylic quaternary carbon centers are widely presented in
bioactive natural products1 (Figure 1). Efficient methodolo-
gies leading to the construction of such a quaternary carbon
center represents one of the most synthetic challenge as well
as powerful entry into the structurally diverse family of
natural alkaloids.2 Although synthetic efforts toward those
units have generated a number of strategies or tactics over
the years, many unfortunately fail to meet adequate measures
of flexibility in terms of diversity-oriented synthesis.
Carefully analysis of the alkaloids shown in Figure 1, a
common motif is characteristic and might be derived from
synthetically valuable building blocks as shown in Scheme 1.
(1) For recent reviews, see: (a) Kornienko, A.; Evidente, A. Chem. ReV.
2008, 108, 1982–2014. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005,
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Hudlicky, T. Synlett 2005, 388–405. (e) Somei, M.; Yamada, F. Nat. Prod.
Rep. 2004, 21, 278–311.
Figure 1. Important bioactive alkaloids and common unit presented
in those structures.
(2) For recent reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006,
369–396. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473–
1482. (c) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 11934–11948. Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
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2003, 59, 10105–10146.
We envisaged that an arylation reaction followed by an allyl
alkylation of a highly functionalized ketone, namely 3-ethoxy-
10.1021/ol802608r CCC: $40.75
Published on Web 12/31/2008
2009 American Chemical Society

Scheme 1
.
Retrosynthetic Analysis of Representative Alkaloids
Table 2. Palladium-Mediated Arylation under Optimized
Conditionsa
2-cyclohexenone, would provide the versatile building blocks
for the synthesis of alkaloids as indicated in Figure 1.
Although palladium-mediated arylation of ketones has
been well documented in the literature, mainly simple
ketones being utilized as substrates.3 Few attempts4 have
been made toward ketones in high functionality that is of
importance for further synthetic manipulation. In this
paper, we wish to report the preliminary results concerning
construction of the benzylic quaternary carbon centers with
a single-pot catalysis of different transformation strategy5
and a concise route toward the total synthesis of (()-
mesembrine based on our new protocol.
With palladium acetate being a palladium source and
racemic BINAP as a ligand, we initiated our studies on the
arylation of 3-ethoxy-2-cyclohexenone, a commercially
available starting material with rich functionality for further
transformation. Our first arylation with 4-bromoveratrole in
the presence of cesium carbonate in toluene ended in failure.
After a few unsuccessful attempts, the desired arylation
occurred when sodium bis(trimethylsilyl)amide being em-
ployed as a base in 1,4-dioxane at 90 °C (see Table 1).
a For reaction conditions, see the experimental section of stage 1. b Yields
represent isolated yield based on 3-ethoxy-2-cyclohexenone. c 3-Isopropoxy-2-
cyclohexenone was used instead of 3-ethoxy-2-cyclohexenone.
Table 1. Arylation of Highly Functionalized Cyclohexanonea
Aiming to extend this process toward the synthesis of
structurally more complicated molecules, an intramolecular
version for arylation of derivative of 3-ethoxy-2-cyclohex-
enone was then developed (see Scheme 2). Treatment of
iodide 14 with 3-ethoxy-2-cyclohexenone in the presence of
lithium diisopropylamide6 afforded compound 15. The
intramolecular arylation was conducted in xylene in the
presence of cesium carbonate, spirocyclic compound 16
being obtained in 70% yield. After oxidation with tBuOOH
in the presence of cuprous iodide,7 an interesting building
entry
time (h)
base
solvent
toluene
toluene
toluene
1,4-dioxane
1,4-dioxane
1,4-dioxane
yieldb (%)
1
2
3
4
5
6
24
24
24
24
24
48
Cs2CO3
tBuOK
NaN(SiMe3)2
tBuOK
NaN(SiMe3)2
NaN(SiMe3)2
0
trace
<10
<10
67
70
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a Reaction conditions: anhydrous 1,4-dioxane was freshly distilled from
sodium benzophenone ketyl prior to use. Reactions in 1,4-dioxane were
carried out in a 90 °C oil bath for 24-48 h. Reactions in toluene were
carried out in a 100 °C oil bath. b Yields represent the isolated yield based
on 3-ethoxy-2-cyclohexenone (average of two runs).
In order to get further insight toward the generality of this
process, a number of aryl bromides were evaluated under
optimized condition, mild to good yields were obtained. The
results are summarized in Table 2. Although electron-neutral
and electron-deficient aryl bromides could be used in this
arylation, relatively low yields were obtained in both cases
(entries 1 and 3 in Table 2).
556
Org. Lett., Vol. 11, No. 3, 2009

block, compound 17, was obtained and should be of value
toward the synthesis of natural products (Scheme 2).
conducted by treatment of ketone 6 with sodium bis(trim-
ethylsilyl)amide and allyl acetate, another being carried out
by treatment of ketone 6 with sodium bis(trimethylsilyl)a-
mide and allyl bromide, both reaction being conducted in
the absence of palladium and BINAP in anhydrous 1,4-
dioxane at room temperature for 12 h. For reaction with allyl
acetate, only trace alkylation was observed by thin-layer
chromatography analysis. While in reaction with allyl
bromide, compound 18 was obtained in 32% yield. There-
fore, a Tsuji-Trost reaction rather than a simple allylation
led to the desired product. To the best of our knowledge,
this is the first example of palladium mediated sequential
arylation-allylation reaction.
Scheme 2
.
Intramolecular Palladium-Catalyzed Arylation of
Enolates
A number of sequential arylation-allylation reactions were
conducted and the results are listed in Table 3. No substantial
Table 3. Palladium-Mediated Sequential Arylation-Allylationa
Having established the arylation condition, our attention
was then focused on the sequential palladium-mediated
arylation-allylation, a “two birds with one metallic stone”
protocol4 which, we believed, would provide an efficient
access to the quaternary carbon center in a single-pot
catalysis. After the arylation, the reaction mixture was then
cooled to room temperature and 2 equiv of sodium bis(tri-
methylsilyl)amide was added followed by addition of allyl
acetate (2 equiv). To our delight, the desired product was
isolated in 47% yield (Scheme 3). At that stage, it was
Scheme 3
.
Sequential Palladium-Catalyzed Arylation and
Allylic Alkylation of Enolates
a For reaction conditions, see the Experimental Section. b Yields represent
isolated yield based on aryl halides. c The reaction was carried out with
R-BINAP. d 3-sec-Butoxy-2-cyclohexenone was used instead of 3-ethoxy-
2-cyclohexenone.
difference was observed by variation of palladium sources.
Pd(OAc)2, Pd2(dba)3, and allylpalladium chloride dimer
worked equally well in this sequential reaction. We also
conducted the sequential reaction with R-BINAP, unfortu-
nately, only 12% ee was obtained by chiral HPLC analysis
on a Chiralcel OD-RH column.
uncertain whether palladium participated in the allylation
reaction or not. Control experiments with pure isolated
R-arylketone 6 were then carried out. One reaction was
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Org. Lett., Vol. 11, No. 3, 2009
557

brine precursor.9 Alternatively, oxidative cleavage of the allyl
group of compound 1810 gave the aldehyde 25. Hydrolysis
of 25 afforded the crude aldehyde dione, which on reductive
amination11 was converted to the vinylogous amide 26 in
63% yield over two steps. Birch reduction converted 26 to
(()-mesembrine 112 in five steps and 22% overall yield from
commercial materials.
Scheme 4. Total Synthesis of (()-Mesembrine
In summary, we have developed an unprecedent sequential
procedure for palladium catalyzed arylation and allylic
alkylation of highly functional ketones. This new protocol
leads to useful building blocks in only one step. The highly
functional cyclohexenone derivatives represent one of the
most valuable synthons for the synthesis of natural products
that containing a benzylic quaternary carbon center. On the
basis of the new protocol, a concise total synthesis of
mesembrine was achieved in only five steps with 22% overall
yield.
Acknowledgment. This work was supported by a grant
(20662011) from the National Natural Science Foundation
of China and partially supported by a grant from the
foundation of the Chinese Ministry of Education for fostering
important scientific research programs (706052). We thank
the Yunnan Provincial Science & Technology Department
for financial support (2007B0006Z).
In order to demonstrate the importance of these allylated
ketones, vinylogous ketone 18 was converted to the serotonin
uptake inhibitor mesembrine 1.8 Diisobutylaluminum hydride
(DIBAL-H) reduction of 18 afforded 24, a known mesem-
Supporting Information Available: 1H NMR, 13C NMR,
MS, as well as HRMS spectra of all key intermediates. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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