Palladium-catalyzed asymmetric intermolecular cyclization

Article abstract of DOI:10.1002/anie.201303753

Domino cyclization: Alkylpalladium intermediates in an asymmetric Heck reaction were intercepted by a second alkene to give tricyclic products with high enantioselectivity (see scheme; Boc=tert-butoxycarbonyl). The method was applied to the asymmetric syn

Full text of DOI:10.1002/anie.201303753

Angewandte
Chemie
Communications
Heck Reaction
J. Hu, H. Hirao, Y. Li,
J. Zhou*
&&&& — &&&&
Palladium-Catalyzed Asymmetric
Intermolecular Cyclization
Domino cyclization: Alkylpalladium
intermediates in an asymmetric Heck
reaction were intercepted by a second
alkene to give tricyclic products with high
enantioselectivity (see scheme; Boc=
tert-butoxycarbonyl). The method was
applied to asymmetric synthesis of a pre-
cursor of (À)-martinellic acid, a folk eye
medicine in South America.
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DOI: 10.1002/anie.201303753
Heck Reaction
Palladium-Catalyzed Asymmetric Intermolecular Cyclization**
Jian Hu, Hajime Hirao, Yongxin Li, and Jianrong (Steve) Zhou*
Asymmetric Heck reactions have been used to directly couple
simple aryl electrophiles with carbocycles and heterocycles.[1]
In 1991, Hayashi and co-workers described the first example
of this kind using binap as a supporting ligand (Scheme 1a).[2]
Since then, many chiral ligands have been tested in the search
for more active and stereoselective catalysts. Most of those
fall into the categories of bisphosphanes, bisphosphites, and
mixed phosphane–oxazoline ligands.[3] For example, the
phosphanyldihydrooxazole (phox) catalysts developed by
Pfaltz and co-workers can minimize double-bond migration
in the Heck products, although the turnover was very slow
(Scheme 1b).[4] We envisioned that if a second alkene group
was present in the vicinity, alkylpalladium species from the
Heck reaction could undergo a second insertion. In this way,
chiral compounds with rather complex structures could be
accessed rapidly.
Numerous examples of palladium-catalyzed multiple
insertions of alkenes and alkynes have been reported, but
almost all were initiated by intramolecular insertion and
provided racemic or achiral products.[5] In a rare example
initiated by intermolecular insertion, de Meijere and co-
workers reported a cyclization between o-vinylphenyl bro-
mide and 2,3-dihydrofuran, albeit in moderate yield and with
limited scope (Scheme 1c).[6] In the presence of a phosphane
ligand, however, noncyclized products became the major
products.
Herein, we report an asymmetric domino cyclization that
formed fused carbo- and heterocycles with excellent stereo-
selectivity (Scheme 1d). The new method was used in a short
synthesis of a chiral diamine en route to a primary ingredient
in folk eye medicine in South America, (À)-martinellic acid.
Initially, we chose a model reaction between o-vinyl-
phenyl triflate and 2,3-dihydrofuran to search for a suitable
catalyst (Scheme 2). The ligand (R)-binap gave the desired
product in only low yield and a significant amount of
noncyclized isomers. In contrast, (R)-binap(O) gave the
Scheme 1. Examples of asymmetric Heck reactions and domino Heck
cyclization reactions. Boc=tert-butoxycarbonyl, dba=dibenzylidene-
acetone, NMP=N-methyl-2-pyrrolidinone, Tf=trifluoromethane-
sulfonyl, Xyl=xylyl.
[*] Dr. J. Hu, Prof. Dr. H. Hirao, Dr. Y. Li, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
E-mail: jrzhou@ntu.edu.sg
[**] We thank the Singapore National Research Foundation (NRF-
RF2008-10) and Nanyang Technological University for financial
support and Sijia Liu for some experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303753.
Scheme 2. Catalyst discovery.
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cyclized isomer in good yield with near-perfect enantioselec-
tivity (99% ee). The selectivity s, which is the ratio between
the amount of the cyclized isomer and the sum of the amounts
of other isomers, was determined to be 9:1 by GC. The size of
the P-aryl groups of the binap(O) ligand had little influence
on the reaction. (R)-Binap dioxide was not an active ligand.
Previously, Oestreich et al. reported that the (R)-
binap(O) ligand was much more active and stereoselective
than (R)-binap in simple Heck reactions. For example, when
the former was used as the supporting ligand, PhOTf and 2,3-
dihydrofuran reacted to give the (2R)-isomer with 92% ee.[7]
We assigned the absolute configuration of our tricyclic
products by analogy with the simple Heck products described
by Oestreich et al.
We also examined other bisphosphane oxides. When (R)-
Xyl-SDP(O) was used, a good yield and almost perfect
enantioselectivity were observed, although slightly more of
the noncyclized isomers were observed (s value: 5:1).[8]
Interestingly, the absolute configuration of the major product
was opposite to that of the product formed with the (R)-
binap(O) catalyst. In fact, (R)-binap(O) and (R)-SDP(O) are
considered to be “pseudoenantiomers” owing to the differ-
ence in nomenclature. (R)-Segphos oxide also provided good
results (74% yield, 99% ee, and s 11:1; segphos = 4,4’-bi-1,3-
benzodioxole-5,5’-diylbis(diphenylphosphane)). With phox
ligands, we observed very slow turnover, which mirrored the
earlier observations by Pfaltz and co-workers for simple
asymmetric Heck reaction.[4] Given a longer reaction time
(2 days), the tBu-phox catalyst gave almost exclusively the
desired isomer (90% yield, 99% ee).
Scheme 3. Cyclization of 2,3-dihydrofuran.
The less s-donating bisphosphane oxides formed more
active Heck catalysts than bisphosphanes. Alkene insertion
into cationic aryl palladium(II) complexes may be faster with
a more electron-deficient Pd center. Furthermore, base
deprotonation of palladium hydride complexes is probably
faster with more electron-poor palladium complexes. Fast
deprotonation is essential to regenerate the Heck catalyst[9]
and prevent double-bond migration in the Heck products.[10]
Next, we established that o-vinylaryl triflates bearing
electron-donating and electron-withdrawing groups can be
used in the cyclization with 2,3-dihydrofuran (Scheme 3a).
The tricyclic products were obtained with excellent enantio-
selectivity. A 1,3-dienyl triflate also underwent this cyclization
with 2,3-dihydrofuran (Scheme 3b).
Cyclic alkenes of five-, seven-, and eight-membered rings
were also coupled efficiently with o-vinylphenyl triflate
(Scheme 4). In the reactions of cycloheptene and cyclooctene
(Scheme 4b,c), double-bond migration to the endo position in
some products was observed if the (R)-binap(O) catalyst was
used. Use of the (R)-Xyl-SDP(O) catalyst minimized this side
reaction. N-Boc-2-pyrroline was also coupled very efficiently
(Scheme 4d). Cyclohexene did not react, because its half-
chair conformation interfered with its binding and insertion;
neither did six-membered cyclic enol ethers or enecarbamates
undergo the desired cyclization.
Scheme 4. Cyclization of simple alkenes. (The reactions were carried
out with 2.5 mol% of the Pd catalysts.)
b-hydrogen atoms for syn elimination, and hence the tricyclic
products were produced as single stereoisomers. According to
our conformational analysis, the preferred eclipsed insertion
could not proceed unless the vinyl group was oriented
towards the exo face of norbornane (Scheme 5a). Very little
by-product was formed by insertion into the second alkene
The cyclization was also applied successfully to norbor-
nene and related bicyclic alkenes (Scheme 5). The strained
olefin was known to readily insert into palladium–aryl
bonds.[11] The resulting norbornylpalladium species lacked
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Figure 1. Left: ORTEP diagram of [{(R)-binap(O)}(o-vinylphenyl)(Br)-
PdII] with 50% thermal-ellipsoid probability and hydrogen atoms
omitted for clarity. Right: front view with the ligand shown as a space-
filling model. Important bond angles [8]: P-Pd-Br 172, O-Pd-C 174,
Br-Pd-C 88, P-Pd-O 91.
We then conducted DFT calculations to investigate the
first alkene-insertion step with (R)-binap(O) as the support-
ing ligand and 2,3-dihydrofuran as the cyclic alkene. The cis
pathway was found to be preferred over the trans pathway. In
cationic trans-[(o-vinylphenyl)(alkene)(L)PdII] complexes,
the trans positioning of the strongly s-donating aryl and
triarylphosphane ligands at the Pd center destabilized these
trans complexes by approximately 10 kcalmolÀ1 as compared
to the cis complexes. Furthermore, the trans pathway, if
pperative, would produce the “wrong” enantiomers as the
major products.
In the cis insertion pathway with the (R)-binap(O)
ligand (Figure 2a), TSa’ was higher in energy than TSa by
> 3 kcalmolÀ1. In TSa’, close contacts were identified not only
between the 2,3-dihydrofuran and phosphane oxide fragment,
but also between the ortho-vinyl group and phosphane moiety
(marked with arrows). The vinyl group was preferentially
oriented anti to the cyclic olefin to avoid steric repulsion
during insertion. Thus, our TS analysis offered a clear
explanation as to why the presence of ortho substituents on
aryl triflates improved the enantioselectivity of this process
(99% ee in our cyclization versus 92% ee in the Heck reaction
of PhOTf described by Oestreich).[7] Similar close contacts
were also found in TSb for the complex of (R)-Xyl-SDP(O)
(Figure 2b).
The new method was applied to an asymmetric synthesis
toward (À)-martinellic acid. The natural product has been
used in folk medicine to treat eye infections in South
America, and it was found to be a potent bradykinin-receptor
antagonist.[13] Several asymmetric syntheses of martinellic
acid have appeared, but none of them used asymmetric
catalytic methods to set the absolute configurations.[14] Our
Heck reaction can quickly assemble a chiral diamine, by
modifying Miyataꢀs synthesis (Scheme 6).[15] The (R)-Xyl-
SDP(O) catalyst gave the core tricycle in 99% ee with the
right configuration. The olefin group was then oxidized to the
ketone followed by condensation to form O-methyloxime. In
comparison, 7 steps were used to arrive at a related N-
benzylketone in Miyataꢀs racemic synthesis. Selective reduc-
Scheme 5. Cyclization of bicyclic alkenes. (The reactions were carried
out with 2.5–5 mol% of the Pd catalysts.)
group of norbornadiene after the first insertion (Scheme 5b).
The key alkyl palladium intermediate could be reduced with
sodium formate (Scheme 5d). Furthermore, the ortho vinyl
group in the triflate substrate can be changed to an allyl group
(Scheme 5e).
To probe the origin of the stereoselectivity observed with
the (R)-binap(O) catalyst, we prepared a neutral oxidative-
addition complex of o-vinylphenyl bromide (Figure 1). In the
X-ray crystal structure of this complex, the o-vinylphenyl and
diphenylphosphanyl groups were found to be cis to each other
on the Pd center; thus, a so-called cis complex was formed.[12]
=
tion of the oxime C N bond proved to be difficult, without
À
cleaving the N O bond. After trying many procedures, we
In
the
crystal
structure
of
[(R)-Xyl-SDP(O)]-
found that only NaBH3CN in acetic acid can give satisfactory
(phenyl)(I)PdII[12] a cis-complex was also observed.
yield.[16] Subsequent treatment of the N-methoxyamine with
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Figure 2. Transition states and energies (kcalmolÀ1) of 2,3-dihydro-
furan insertion into cationic [(L)(alkene)(o-vinylphenyl)PdII] complexes.
L is (R)-binap(O) in (a) and (R)-Xyl-SDP(O) in (b). Close contacts are
indicated with arrows. To account for the dispersive effect in the
cationic transition states, calculations were performed with a large
basis set: M06-2X/[LANL2TZ(f)(Pd),6-31+G*(others)]//B3LYP/
[LANL2DZ(Pd),6-31G*(O,P),6-31G(H,C)]. The solvent effect of 1,4-
dioxane was taken into account by the polarizable continuum model
(PCM) method.
Scheme 6. Asymmetric synthesis towards (À)-martinellic acid.
aryl diazonium salts, see: e) E. W. Werner, T.-S. Mei, A. J.
Burckle, M. S. Sigman, Science 2012, 338, 1455.
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allyl-MgBr reagent induced ring expansion followed by in situ
trapping by Grignard addition to give exclusively the anti-
isomer. Interestingly, the N-Boc group must be removed.
Otherwise, the Beckmann-type ring expansion did not occur.
Thus, our route provided the key diamine intermediate in
44% yield and 99% ee after three isolations. The secondary
amine groups will not interfere with subsequent transforma-
tions towards (À)-martinellic acid.[14b,15]
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In conclusion, we realized asymmetric domino cycliza-
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synthesis of the chiral diamine en route to (À)-martinellic
acid.
Received: May 2, 2013
Revised: June 13, 2013
Published online: && &&, &&&&
Keywords: asymmetric synthesis · cyclization ·
.
domino reactions · Heck reaction · palladium catalysis
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