Enantioselective intramolecular C-H insertion reactions of donor-donor metal carbenoids

Article abstract of DOI:10.1021/ja508586t

The first asymmetric insertion reactions of donor-donor carbenoids, i.e., those with no pendant electron-withdrawing groups, are reported. This process enables the synthesis of densely substituted benzodihydrofurans with high levels of enantio- and diaste

Full text of DOI:10.1021/ja508586t

Communication
pubs.acs.org/JACS
Enantioselective Intramolecular C−H Insertion Reactions of Donor−
Donor Metal Carbenoids
Cristian Soldi, Kellan N. Lamb, Richard A. Squitieri, Marcos Gonzalez-Lopez, Michael J. Di Maso,
́
́
and Jared T. Shaw*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
S
* Supporting Information
We have explored C−H insertion reactions of donor−donor
ABSTRACT: The first asymmetric insertion reactions of
donor−donor carbenoids, i.e., those with no pendant
electron-withdrawing groups, are reported. This process
enables the synthesis of densely substituted benzodihy-
drofurans with high levels of enantio- and diastereose-
lectivity. Preliminary results show similar efficiency in the
preparation of indanes. This new method is used in the
first enantioselective synthesis of an oligoresveratrol
natural product (E-δ-viniferin).
carbenoids for the rapid synthesis of complex natural products
and other molecules with interesting biological properties. The
highly substituted benzodihydrofurans and indanes embedded in
1−3 could each be accessed from strategic C−H insertion
reactions of diarylcarbenoids (Figure 2). The requisite starting
materials, i.e., diaryldiazomethane analogues, are easily prepared
from hydrazones or toluenesulfonyl hydrazones. Herein we
report our initial findings in the enantioselective intramolecular
C−H insertion reactions of donor−donor rhodium carbenoids,
culminating in the first enantioselective synthesis of E-δ-viniferin
(3).
etal carbenoids, usually derived from diazo compounds,
1
Mare important intermediates in organic synthesis. The
dual electrophilic and nucleophilic character has enabled these
intermediates to participate in a wide array of useful trans-
formations. In particular, asymmetric reactions involving chiral
metal complexes have resulted in highly enantioseletive cyclo-
propanations as well as C−H,2 N−H,3 and O−H4 insertion
reactions. Early work in this area focused on the reactivity of
diazo-dicarbonyl compounds and unsubstituted α-diazo esters,
which form acceptor−acceptor and acceptor-substituted carbe-
noids (Figure 1). Subsequent pioneering studies by Davies
explored the reactivity of donor−acceptor carbenes,5 which
engaged in selective intermolecular reactions. Although donor−
donor-substituted diazo compounds have been known for many
years,6,7 metal-catalyzed insertion reactions with these substrates
are rare,8,9 and no enantioselective reactions have been reported
to date.
Figure 2. Target molecules featuring benzodihydrofuran and indane
core structures.
Our initial studies explored the reactions of diaryl-diazo-
methanes. Commercially available 2-hydroxybenzophenone,
alkylated with a PMB group, was converted to a diazo compound
in two steps and then added by syringe pump to a solution of
various catalysts (1 mol %; Table 1). Dirhodium tetraacetate was
a highly effective catalyst, producing predominantly the syn
diastereomer of dihydrobenzofuran 5 in high yield. Variation of
solvent, temperature, and catalyst (to Rh2(TFA)4) maintained
the high yield of product and had little impact on the
diastereoselectivity. Initial exploration of chiral catalysts was
Received: August 20, 2014
Published: October 12, 2014
Figure 1. Structures of metal carbenoids.
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
Table 1. Catalyst Optimization
entry
catalyst (1 mol%)
solvent (temp.)
dr
er
yield
1
Rh2(OAc)4
CH2Cl2 (0−23 °C)
CH2Cl2 (−42−23 °C)
CH2Cl2 (0−23 °C)
benzene (10−23 °C)
toluene (0−23 °C)
pentane (0−23 °C)
CH2Cl2 (0−23 °C)
CH2Cl2 (0−23 °C)
CH2Cl2 (0−23 °C)
76:24
80:20
50:50
80:20
80:20
80:20
94:6
−
−
−
−
−
78%
89%
89%
94%
85%
85%
95%
0%
2
Rh2(OAc)4
3
Rh2(TFA)4
4
Rh2(OAc)4
5
Rh2(OAc)4
6
Rh2(OAc)4
−
36:64
8
Rh2(R-DOSP)4
Rh2(4S-MPPIM)4
Rh2(R-PTAD)4
9
−
99:1
−
99:1
10
90%
immediately fruitful. Davies’s catalyst (Rh2(R-DOSP)4) resulted
in high diastereoselectivity, albeit with little control of
enantioselectivity.10 Doyle’s imidazolone catalyst ((Rh2(4S-
MPPIM)4) gave no conversion.11 Finally, the phthalimide-
Table 2. Catalyst Loading and Scale-up
12
based catalyst Rh2(R-PTAD)4 produced 5 in high yield (90%)
and with exquisite diastereo- and enantioselectivities, both of 99:1.
We explored several avenues for enhancing the efficiency of
this new method. A brief solvent screen (not shown) revealed
that acetonitrile often improves both yield and diastereoselec-
tivity while maintaining high enantioselectivity. Unlike acceptor-
substituted diazo compounds, which are typically made from
diazo-transfer reagents, diphenyldiazo methane is typically made
by oxidation of the corresponding hydrazine. After examining
several methods, including the recently reported Swern
entry
1
mol %
time (h)
dr
er
yield
1.0
16
4
>99:1
>99:1
>99:1
>95:5
>95:5
>99:1
>99:1
99:1
97:3
96:4
93:7
94:6
94:6
96:4
90%
93%
63%
82%
83%
51%
95%
a
2
0.1
a
3
a
0.01
0.01
0.001
0.0001
0.1
4
4
24
24
144
4
5
6
b
14
conditions,13 we found that MnO2 oxidized 6 to 4 in
7
a
b
Catalyst was dissolved in CH2Cl2 Reaction performed at −20 °C on
gram scale.
quantitative yield after simple filtration. Moreover, generation
of 4 and the subsequent C−H insertion reaction could be carried
out in one pot by simply mixing MnO2 and the rhodium catalyst
with the hydrazone, without the need for slow addition. Finally,
the limits of the catalyst loading were also explored (Table 2). We
were pleased to see that despite the longer required reaction
times, high yield and selectivity were maintained down to 0.001
mol % of the rhodium catalyst. The reaction was also amenable to
scale-up, and a gram-scale insertion was accomplished with only
0.1 mol % in 95% yield (Table 2, entry 7). The low catalyst
loading and avoidance of diazo transfer reagents and diazoalkane
intermediates all contribute to the high efficiency of this
transformation.
The Rh-catalyzed C−H insertion reaction of donor−donor
carbenoids is useful in the synthesis of a broad range of
benzodihydrofurans. Benzyl ethers of 2-hydroxybenzophenones
are consistently converted to dihydrobenzofurans in high yield,
with high enantioselectivity and high disatereoselectivity for the
formation of the syn isomer (Table 3). Although the reaction is
most efficient when the substrate is appended with electron-
donating groups, good reactivity is maintained when a cyano
group is added to either the benzyl ether or the phenyl ring of the
benzophenone (Table 3, entries 2 and 7). The absolute and
relative configuration of 5 was determined by X-ray crystallog-
raphy, and the remaining substrates are tentatively assigned
based on chemical shift correlation. The coupling constants of
the syn and anti isomers are too similar to provide any confidence
in the assignment of the two diastereomers.
Allylic ethers also reacted smoothly in the C−H insertion
process (Scheme 1). In all cases, only insertion was observed with
no detectable products of cyclopropanation. Substituted allylic
substrates with either E- or Z-configured alkenes provided
dihydrobenzofuran products with no change in the alkene
geometry (10c and 10d).
The success of the insertion reaction with benzylic and allylic
ethers prompted us to explore a wide variety of related substrates.
Diastereoselectivities for alkyl ethers were generally lower than
for the benzylic and allylic substrates. Alkyl methylene groups
reacted with high yield and enantioselectivity (19−21) (Scheme
2), while the methine group of an isopropyl ether exhibited
slightly eroded enantioselectivity or yield depending on the
solvent used. Propargyl ether 24 reacted efficiently, albeit with
low enantioselectivity. The reaction of substrate 23, which is
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dx.doi.org/10.1021/ja508586t | J. Am. Chem. Soc. 2014, 136, 15142−15145

Journal of the American Chemical Society
Communication
Table 3. Insertion into Benzylic C−H Bonds
Scheme 2. Insertion Reactions of Various Substrates
yield, er
entry product
R1
Br
R2
R3
R4
(conditions)
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8f
H
H
H
H
H
H
H
H
H
H
H
H
90%, 95:5 (A)
77%, 97:3 (A)
92%, 95:5 (A)
68%, 92:8 (A)
70%, 98:2 (B)
83%, 97:3 (B)
97%, 98:2 (B)
CN
H
CH3O
CH3O
CH3O
CH3O
CH3O
H
OPMB
CH3O
CN
H
H
H
8g
H
a
One mol % catalyst, 8 equiv of MnO2. Catalyst added to reaction
mixture at 0 °C before warming the reaction mixture to room
temperature for 4−16 h.
Scheme 1. Reactions of Allylic Substrates
Scheme 3. Synthesis of E-δ-Viniferin
derived from an alkyl−aryl ketone, also provided insertion
product efficiently, suggesting that the carbenoid’s insertion is
significantly faster than elimination. Finally, preliminary results
into the synthesis of other five-membered rings are encouraging
with the successful syntheses of indane 25 and indoline 26 from
alkane and sulfonamide substrates, respectively.
The enantioselective insertion of donor−donor carbenoids is a
useful method for the assembly of complex natural products. E-δ-
Viniferin is a resveratrol dimer isolated from grapes in response
to fungal infection.15 This secondary metabolite is a member of a
large family of oligoresveratrol natural products, which has
received intense synthetic effort in recent years.16 Although these
molecules sometimes occur as racemates, presumably from
nonenzymatic processes, many are isolated as single enantiomers
and few methods for the enantioselective installation of the
requisite dihydrobenzofuran rings have been reported. Benzo-
phenone 27, available in five steps from commercially available
starting materials, was easily converted to the corresponding
hydrazone (Scheme 3). The hydrazone underwent smooth C−H
insertion with high selectivity and in high yield. Simultaneous
demethylation and epimerization17 was accomplished with BCl3
and TBAI. Control experiments confirmed that epimerization
occurred with no loss of enantiomeric purity.18 The benzodihy-
drofuran core was acetylated and employed in Heck coupling
with styrene 30. Global deacetylation19 provided E-δ-viniferin,
1
which exhibited H- and 13CNMR spectra identical to those
reported for the natural material. In addition, the optical rotation
of the synthetic sample compared favorably to the reported
value.20 This route represents the first enantioselective synthesis
of any member of the oligoresveratrol family of natural products.
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Journal of the American Chemical Society
Communication
2001, 331, 239−245. (d) Petursson, S.; Jonsdottir, S. Tetrahedron:
Asymmetry 2012, 23, 157−163.
The enantioselective intramolecular insertion of donor−
donor carbenoids is a useful method for the assembly of complex
molecules. Insertion into a variety of ethers proceeds with high
efficiency and stereoselectivity, and preliminary results indicate
that this strategy might be generalized to the construction of
carbon- and nitrogen-based compounds.
(9) Tosylhydrazones are also known to serve as precursors to metal
carbenoids: (a) Cheung, W.-H.; Zheng, S.-L.; Yu, W.-Y.; Zhou, G.-C.;
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6204. (g) Yao, T.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed.
2012, 51, 775−779.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures with characterization data and NMR
spectra for all compounds, HPLC traces for all enantiomerically
enriched insertion products, and X-ray crystallographic data
(.cif) for compound 5. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) (a) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.; Kong, N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897−6907. (b) Davies, H. M. L.;
Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075−9076.
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(12) The phthalimide-based catalysts were developed by Hashimoto
and the adamantyl-substituted variant was reported by Davies. See:
(a) Watanabe, N.; Ogawa, T.; Ohtake, Y.; Ikegami, S.; Hashimoto, S.-i.
Synlett 1996, 85−86. (b) Saito, H.; Oishi, H.; Kitagaki, S.; Nakamura, S.;
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(15) (a) Shikishima, Y.; Takaishi, Y.; Honda, G.; Ito, M.; Takeda, Y.;
Kodzhimatov, O. K.; Ashurmetov, O. Phytochemistry 2001, 56, 377−
381. (b) Pezet, R.; Perret, C.; Jean-Denis, J. B.; Tabacchi, R.; Gindro, K.;
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AUTHOR INFORMATION
Corresponding Author
*jtshaw@ucdavis.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.S. thanks CAPES (Coordenaca
̧
o de Aperfeico
̧
amento de
̃
́
Pessoal de Nivel Superior) and the Brazilian Ministry of
Education for a postdoctoral fellowship. K.N.L. and M.J.D.
acknowledge support in the form of predoctoral fellowships from
GAANN/DOEd. M.G.L. was supported by a postdoctoral
(16) (a) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y. Q.;
Zografos, A. L. J. Am. Chem. Soc. 2009, 131, 1753−1765. (b) Snyder, S.
A.; Brill, Z. G. Org. Lett. 2011, 13, 5524−5527. (c) Snyder, S. A.; Gollner,
A.; Chiriac, M. I. Nature 2011, 474, 461. (d) Snyder, S. A.; Thomas, S. B.;
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Angew. Chem., Int. Ed. 2011, 50, 8629−8633. (f) Snyder, S. A.; Zografos,
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́
fellowship from Fundacion Ramon Areces. J.T.S. thanks the
NSF for a CAREER award. Acknowledgment is made to the
Donors of the American Chemical Society Petroleum Research
Fund for partial support of this research. The authors thank Prof.
Michael P. Doyle (University of Maryland) for providing a
sample of Rh2(4S-MPPIM)4. Funding by NIH (NIAID/
R01AI08093) is also acknowledged.
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