Rhodium-catalyzed enantioselective addition to unsymmetrical α-diketones: Tandem one-pot synthesis of optically active 3-tetrasubstituted isochroman derivatives

Article abstract of DOI:10.1002/chem.201203701

The domino effect: An efficient and general catalytic one-pot synthesis of quaternary-substituted isochroman derivatives has been developed (see scheme). The cascade transformation relies on rhodium-catalyzed highly regio- and enantioselective 1,2-addition of arylboronic acids to unsymmetrical α-diketones and intramolecular etherification or esterification, and provides a variety of enantioenriched isochromanones under exceptionally mild conditions. Copyright

Full text of DOI:10.1002/chem.201203701

COMMUNICATION
DOI: 10.1002/chem.201203701
Rhodium-Catalyzed Enantioselective Addition to Unsymmetrical a-
DiACHTUNGTRENNUNG
Ting-Shun Zhu, Jian-Ping Chen, and Ming-Hua Xu*[a]
Isochromans (3,4-dihydro-1H-isochromene) constitute an
newly formed hydroxyl function to give the corresponding
3-tetrasubstituted isochromanones (Scheme 1).
important class of oxygenated heterocycles that are found in
a wide range of naturally occurring products and biological-
ly active compounds.[1] Although numerous synthetic strat-
egies have been developed for the construction of these
structural motifs, only a limited number of stereoselective
methods for preparing chiral 1- or 3-substituted isochromans
have been reported.[2] Particularly with respect to chiral qua-
ternary carbon-containing isochromans, which have already
shown unique pharmaceutical properties,[3] to the best of
our knowledge, there are no examples of their straightfor-
ward enantioselective synthesis.[4,5] Thus, the development of
new catalytic systems that are capable of the efficient syn-
thesis of highly optically active isochroman derivatives with
a quaternary carbon stereogenic center is highly desirable.
In this communication, we report a highly practical and effi-
cient asymmetric approach to chiral 3-tetrasubstituted iso-
chroman derivatives, 4-isochromanones, and 1,4-isochroman-
diones through a tandem 1,2-addition/cyclization one-pot
sequence that is catalyzed by a simple Rh/sulfur-olefin
catalyst.
We have recently designed a new family of chiral ligands,
sulfur-olefins, and successfully employed them in the rhodi-
um-catalyzed asymmetric 1,4-addition of aryl boronic acids
to a,b-unsaturated carbonyl compounds.[6,7] With the ex-
tremely simple structure of the chiral N-sulfinyl cinnamyla-
mine ligand, we developed a highly enantioselective 1,2-ad-
dition of arylboronic acids to a-ketoesters and a-diketones.
A variety of highly enantioenriched tertiary a-hydroxy car-
bonyl derivatives were easily accessed under mild conditions
at room temperature.[6d]
Scheme 1. Proposed intramolecular heterocyclization.
We began our studies by examining the reactions of un-
symmetrical a-diketones 1a and 1b with 4-methoxyphenyl-
boronic acid in the presence of [RhACTHNUTRGEN(UNG coe)2Cl]2 (1.5 mol%;
coe=cyclooctene) and chiral N-sulfinyl cinnamylamine
ligand (3.3 mol%) in aqueous KOH (0.1m)/THF at room
temperature. To our delight, the reactions proceeded
smoothly and gave the expected tertiary a-hydroxyketones 2
and 3 in nearly quantitative yield with 7:3 and 4:6 regiose-
lectivity, respectively. Notably, both regioisomers were ob-
tained with excellent enantiomeric excesses (97–98% ee).
These results suggested the possibility of a highly regio- and
enantioselective 1,2-addition to unsymmetrical a-diketones
that have large differences in the steric and electronic prop-
erties of each ketone moiety (Scheme 2).
In order to investigate the potential of this highly regio-
and enantioselective reaction, we prepared a variety of dif-
ferent substituted benzils. As expected, the use of a sub-
strate with large electronic differences between the two sub-
stituents on the benzene ring led to a great enhancement of
the regioselectivity. In the case of 1-(4-nitrophenyl)-2-para-
tolylethane-1,2-dione, the sole regioisomer 2c was observed
with 97% ee (Scheme 3). The regiochemistry is in accord-
ance with the observation by Inoue et al.[8b] that the addition
of arylstannane to benzil derivatives with a nitro group was
completely regioselective. On the other hand, the significant
influence of steric hindrance is seen in the addition. With
ortho-methyl-substituted unsymmetrical benzils, reactions
with different aryl boronic acids afforded the desired terti-
ary a-hydroxyketones in high yields with excellent regio-
In considering isochroman frameworks, we envisioned an
intramolecular heterocyclization protocol. If a highly regio-
and enantioselective 1,2-addition of unsymmetrical a-di-
ACHTUNGTRENNUNG
ketones can be achieved,[8] the resulting a-hydroxy ketone
product might be appropriately designed as a precursor ca-
pable of intramolecular etherification or esterification of the
[a] T.-S. Zhu, J.-P. Chen, Prof. Dr. M.-H. Xu
Shanghai Institute of Materia Medica
Chinese Academy of Sciences
555 Zuchongzhi Road, Shanghai 201203 (P.R. China)
Fax : (+86)21-50807388
E-mail: xumh@mail.shcnc.ac.cn
AHCTUNGTREGsNNUN electivity (>99:1) and enantioselectivities (96–99% ee; 2d,
2 f–k). When 3,3-dimethyl-1-phenylbutane-1,2-dione was
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203701.
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dition under the above conditions. However, the result was
disappointing. The reaction gave the expected isochroman
4a[9] in only 5% yield, but yielded mostly the uncyclized ad-
dition product 2l (Scheme 4). Typically, the catalytic cycle is
proposed to involve aryl rhodium intermediate formation
through transmetallation, followed by insertion and hydroly-
Scheme 2. Initial attempts at the Rh-catalyzed 1,2-addition to unsymmet-
rical a-diketones.
Scheme 4. Initial attempts at the 1,2-addition/etherification.
sis steps. However, the use of KOH (0.5m) or K2CO3 (1.5m)
led to the significant formation of the unexpected racemic
indanone byproduct, which is likely initiated by the oxida-
I
À
tive addition of the Rh species into the C Br bond of the
substrate, although the exact intermediate and its coordina-
tion status remains unclear at this time. These results clearly
indicate that the base has an important influence on the
tandem reaction. Fortunately, after careful screening of the
basic conditions, we were pleased to find that the addition–
etherification tandem reaction proceeded smoothly and
gave 4a in good yield (84%) and enantioselectivity (98%)
when performed with 1.2 equivalents of K3PO4 (1.5m;
Scheme 5). Moreover, it seemed that chloride substrates
were not prone to Rh-oxidative addition; they also under-
went the effective addition–etherification process to give the
corresponding 4-isochromanones in good yields and excel-
lent ee under proper conditions (4e–i, Scheme 5). In com-
parsion, the use of a chlorine leaving group allowed the re-
action to proceed more efficiently with diverse arylboronic
acids. The stereochemistry of the products was assigned ac-
cording to our previous report.
Scheme 3. Regio- and enantioselective 1,2-addition to unsymmetrical a-
diketones. Reactions were carried out with a-diketone (0.25 mmol) and
arylboronic acid (1.5 equiv) in the presence of Rh (3 mol%), ligand
(3.3 mol%), and KOH (0.1m, 0.08 equiv) in of THF (1.0 mL) for 3 h.
Yields of isolated product are shown, and ee was determined by chiral
HPLC analysis. For 2k, an accurate ee measurement was not achieved
due to the lack of full baseline resolution of its racemic compound, see
the Supporting Information for details.
employed, the same high level of regio- and enantioselectivi-
ty was obtained (2e). In all these cases, a strong regioselec-
tivity favoring addition to the less hindered and more elec-
tron deficient carbonyl group was found.
Encouraged by the above success, we then turned our at-
tention to the construction of isochroman frameworks. Ini-
tially, the benzil 1c, with an ortho-bromomethyl substituent
on one benzene ring, was prepared and subjected to 1,2-ad-
Following the success of the one-pot asymmetric synthesis
of 4-isochromanone, we decided to explore the possibility of
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Tandem One-Pot Synthesis of 3-Tetrasubstituted Isochroman Derivatives
COMMUNICATION
Scheme 6. One-pot synthesis of 1,4-isochromandiones by tandem 1,2-ad-
dition/esterification. Reactions were carried out with a-diketone
(0.25 mmol) and arylboronic acid (1.5 equiv) in the presence of Rh
(3 mol%), ligand (3.3 mol%), and KOH (0.1m, 0.08 equiv) in THF
(1.0 mL) for 3 h, then acidified with H2SO4 (0.1 mL conc.) in CH3OH
(1 mL) and stirred for a further 1 h. Yields of isolated product are shown,
and ee was determined by chiral HPLC analysis. For 5k, 5m, and 5o ac-
curate ee measurements were not achieved due to the lack of full base-
line resolution of their racemic compounds, see the Supporting Informa-
tion for details.
Scheme 5. One-pot synthesis of 4-isochromanones by tandem 1,2-addi-
tion/etherification. Reactions were carried out with a-diketone
(0.25 mmol), and arylboronic acid (2 equiv) in the presence of Rh
(3 mol%), ligand (3.3 mol%), and base in THF (1.0 mL) for 3 h. For
products 4a–d with bromide substrates (X=Br), K3PO4 (1.5m, 1.2 equiv)
was used; for products 4e–i with chloride substrates (X=Cl), KOH
(0.1m, 0.08 equiv) was used. Et3N (0.1 mL) and KI (50 mg, 1.2 equiv)
were added after the addition. Yields of isolated product are shown, and
ee was determined by chiral HPLC analysis.
tandem one-pot sequence under the same mild conditions.
In addition, useful functional groups, such as benzyloxy,
were introduced. Thus, this method allows the efficient and
stereoselective installation of versatile substituents at the 3-
position and provides access to highly enantioenriched 1,4-
isochromandiones.
a tandem 1,2-addition–esterification to generate chiral 1,4-
isochromandiones. Accordingly, a-diketone substrates with
an ester substituent (COOMe) at the ortho position of one
ketone phenyl ring were prepared and evaluated. The re-
sults are summarized in Scheme 6. As anticipated, the rhodi-
um-catalyzed enantioselective 1,2-addition can only take
place at the less sterically congested ketone, giving the de-
sired adducts with excellent ee under the same reaction con-
ditions shown in Scheme 3. Subsequently, by adding a small
amount of H2SO4 (conc.), the tandem intramolecular esteri-
fication was found to proceed smoothly and was complete
within 1 h, giving the cyclized product 5 in high yield and
maintaining enantioselectivity. It is noteworthy that a broad
range of arylboronic acids with distinct steric and electronic
properties can be successfully employed in the reaction (5a–
l). Furthermore, alkenylboronic acids can also participate in
the regio- and enantioselective 1,2-addition. Performing the
one-pot reaction with styrylboronic acid led to the desired,
functionalized product 5m with high enantioselectivity,
albeit in moderate yield (69%). To further expand the reac-
tion scope, we turned to an a-diketone substrate with a
linear alkyl group on one carbonyl. Remarkably, in the
cases of 5n and 5o, the 3-alkyl-3-aryl 1,4-isochromandiones
with high enantioselectivities were equally accessed with the
To further explore the synthetic utility of this chemistry, a
series of functional group transformations were studied
(Scheme 7). When the addition product 5n, with a 3-alkyl-3-
aryl quarternary stereogenic center, was subjected to AlCl3-
or CeCl3-mediated NaBH4 reduction, the corresponding 4-
hydroxyl-isochroman (6) and -isochromanone (7) were gen-
erated as single stereoisomers in 94% and 92% yield, re-
spectively. Interestingly, the 4-hydroxyl group of 6 under-
went a complete epimerization in trifluoroacetic acid, likely
through a cationic intermediate, giving epimer 8 in 96%
yield with 95% ee. Furthermore, by using Bartonꢁs radical
deoxygenation procedure, removal of the hydroxyl group in
7 was easily accomplished, providing 1-isochromanone 9 in
a relatively good yield with no racemization detected. It is
noteworthy that the DAST (diethylaminosulfur trifluoride)-
mediated dehydroxyfluorination of both 7 and 8 gave
mainly the same fluoride product, (4R)-10, without losing
optical purity (95% ee). This suggests that the reactions un-
dergo a typical SN1 process,[10] and the stereoselectivity is
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M.-H. Xu et al.
point of view, our current strategy represents a potentially
valuable enantioselective approach to the generation of a
wide range of isochroman-based urotensin-II agonists.
In summary, we have developed an efficient and general
catalytic one-pot protocol for the synthesis of an interesting
class of isochroman derivatives. A great variety of highly
enantioenriched tetrasubstituted isochromanones have been
efficiently generated by this method under exceptionally
mild conditions. The key transformation relies on the stereo-
selective creation of tertiary a-hydroxyketones from a rhodi-
um-catalyzed highly regio- and enantioselective 1,2-addition
of arylboronic acids to unsymmetrical a-diketones by using
an extremely simple chiral N-sulfinyl cinnamylamine ligand.
Moreover, the first asymmetric synthesis of the non-peptide
urotensin II receptor agonist AC-7954 has been successfully
achieved by taking advantage of this reaction. Further inves-
tigations of the application of this strategy in biologically in-
teresting, oxygen-containing heterocyclic compound synthe-
ses are ongoing in our laboratory.
Experimental Section
Scheme 7. Synthetic applicability towards various isochroman derivatives.
TFA=trifluoroacetic acid, AIBN=2-2’-azobisisobutyronitrile, Tf=tri-
fluoromethanesulfonyl.
General procedure for the synthesis of 4a–i: Under an Ar atmosphere, a
solution of the a-diketone compound (0.25 mmol), [RhClACTHNUGTRNEUNG(coe)2]2 (2.7 mg,
0.0075 mmol of Rh), N-sulfinyl cinnamylamine ligand (2.0 mg,
0.00825 mmol), and arylboronic acid (0.5 mmol) in THF (1.0 mL) was
stirred at room temperature for 30 min. Aqueous KOH (0.2 mL, 0.1m,
0.02 mmol) was then added to the mixture. After stirring at room temper-
ature for 3 h, KI (50 mg, 1.2 equiv) and Et3N (0.1 mL) were added, the
mixture was stirred for an additional 1 h, and then concentrated under re-
duced pressure. The residue was purified by silica gel column chromatog-
raphy to afford the corresponding addition products 4e–i.
again attributed to the steric differentiation at 3-position. In
addition, an attempt to use a carbon nucleophile was also
carried out. Treatment of 5n with an allylzinc reagent in the
[11]
presence of InACHTUNGTRENNUNG(OTf)3 gave two diastereoisomers, 11 and
12, in a 2:1 ratio, which were readily separated by column
chromatography. Thus, the isochroman architecture with
two contiguous quarternary stereocenters that is otherwise
difficult to access was established in a stereoselective fash-
ion.[12]
Finally, a particularly fascinating synthetic application of
the methodology was demonstrated. As illustrated in
Scheme 8, the adduct 5o was readily converted to 14 (AC-
General procedure for the synthesis of 5: Under an Ar atmosphere, a sol-
ution of the a-diketone compound (0.25 mmol), [RhClACTHNUGTRNEUNG(coe)2]2 (2.7 mg,
0.0075 mmol of Rh), N-sulfinyl cinnamylamine ligand (2.0 mg,
0.00825 mmol), and arylboronic acid (0.375 mmol) in THF (1.0 mL) was
stirred at room temperature for 30 min. Aqueous KOH (0.2 mL, 0.1m,
0.02 mmol) was then added to the mixture. After stirring at room temper-
ature for 3 h, MeOH (1 mL) and H2SO4 (conc., 0.1 mL),were added, the
mixture was stirred for another 1 h, and then concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
to afford the corresponding addition
product 5.
Acknowledgements
Financial support from the National
Natural Science Foundation of China
(20972172, 21021063), and the Chinese
Academy of Sciences is greatly ac-
knowledged.
Scheme 8. The first asymmetric synthesis of AC-7954. DMP=Dess–Martin periodinane.
7954),[3a–c] a drug lead that is a highly selective nonpeptidic
agonist of the urotensin-II receptor,[13] by two linear process
Keywords: AC-7954
·
asymmetric catalysis
·
domino
with a total of six steps in good yield. To our knowledge, the
asymmetric route to AC-7954 is unprecedented,[14] and the
known procedure to synthesize its racemic compound is
somewhat inefficient,[3a–c] which has largely limited the avail-
ability of this interesting class of compounds. From this
reactions · isochromans · rhodium
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Tandem One-Pot Synthesis of 3-Tetrasubstituted Isochroman Derivatives
COMMUNICATION
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Received: October 17, 2012
Revised: November 12, 2012
Published online: December 12, 2012
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