Enantio- and Diastereoselective Synthesis of cis-2-Aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans via the Rh(II)-Catalyzed C-H Insertion Process

Article abstract of DOI:10.1021/ol0267127

(Matrix Presented) The enantioselective intramolecular C-H insertion reaction of aryldiazoacetates has been explored with use of dirhodium(II) carboxylate catalysts, which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as chiral bri

Full text of DOI:10.1021/ol0267127

ORGANIC
LETTERS
2
002
Vol. 4, No. 22
887-3890
Enantio- and Diastereoselective
Synthesis of
3
cis-2-Aryl-3-methoxycarbonyl-
2
,3-dihydrobenzofurans via the
Rh(II)-Catalyzed C−H Insertion Process
Hiroaki Saito, Hiroyuki Oishi, Shinji Kitagaki, Seiichi Nakamura,
Masahiro Anada, and Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
hsmt@pharm.hokudai.ac.jp
Received August 10, 2002
ABSTRACT
The enantioselective intramolecular C−H insertion reaction of aryldiazoacetates has been explored with use of dirhodium(II) carboxylate catalysts,
which incorporate N-phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as chiral bridging ligands. Dirhodium tetrakis[N-phthaloyl-(S)-
tert-leucinate], Rh (S-PTTL) , has proven to be the catalyst of choice for this process, providing exclusively cis-2-aryl-3-methoxycarbonyl-2,3-
2 4
dihydobenzofurans in up to 94% ee.
Chiral dirhodium(II) carboxamidate and carboxylate catalysts
offer a potentially powerful strategy for synthesizing optically
active carbocyclic and heterocyclic rings. The dirhodium
catalyst forms C-C bonds with a newly created stereogenic
center at an unactivated carbon atom by the enantioselective
intramolecular C-H insertion reactions of R-diazocarbonyl
compounds. Davies and co-workers recently developed a
major breakthrough in this field when they achieved inter-
1
molecular C-H insertion reactions with high enantioselec-
2
tivity. It is well-documented that the enantioselectivity of
C-H insertion reactions depends on many factors including
the type of R-diazocarbonyl compound, the substitution
(
1) For recent books and reviews, see: (a) Ye, T.; McKervey, M. A.
Chem. ReV. 1994, 94, 1091. (b) Doyle, M. P. Aldrichimica Acta 1996, 29,
. (c) Hashimoto, S.; Watanabe, N.; Anada, M.; Ikegami, S. J. Synth. Org.
Chem. Jpn. (Engl.) 1996, 54, 988. (d) Davies, H. M. L. Aldrichimica Acta
997, 30, 107. (e) Davies, H. M. L. Curr. Org. Chem. 1998, 2, 463. (f)
pattern at the C-H insertion site, the polarity of the solvent,
3
and the nature of chiral dirhodium(II) catalysts.1
1
Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York,
(2) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(b) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (c) Davies, H. M. L.;
Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (d) Davies,
H. M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 4153. (e) Davies, H. M.
L.; Ren, P.; Jin, Q. Org. Lett. 2001, 3, 3587. (f) Davies, H. M. L.;
Antoulinakis, E. G. J. Organomet. Chem. 2001, 617, 47. (g) Davies, H. M.
L.; Venkataramani, C. Angew. Chem., Int. Ed. 2002, 41, 2197. (h) Davies,
H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002, 67,
4165. (i) Davies, H. M. L.; Gregg, T. M. Tetrahedron Lett. 2002, 43, 4951.
(j) Davies, H. M. L.; Walji, A. M.; Townsend, R. J. Tetrahedron Lett. 2002,
43, 4981.
1
998. (g) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911. (h)
Sulikowski, G. A.; Cha, K. L.; Sulikowski, M. M. Tetrahedron: Asymmetry
1
998, 9, 3145. (i) Lydon, K. M.; McKervey, M. A. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, Chapter 16.2. (j) Doyle, M. P.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 5. (k) Timmons, D. J.; Doyle, M. P. J. Organomet. Chem.
2001, 617, 98. (l) Forbes, D. C.; McMills, M. C. Curr. Org. Chem. 2001,
5, 1091.
1
0.1021/ol0267127 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/28/2002

1
0
For example, the salient ability of Doyle’s chiral di-
rhodium(II) carboxamidate catalysts such as Rh (5S-MEPY)
Rh (4S-MEOX) , and Rh (4S-MPPIM) is characteristic of
intramolecular reactions with diazoacetates and diazoacet-
oxygen, we envisaged that an intramolecular C-H insertion
of aryldiazoacetates with an arylmethoxy group at the ortho
position should produce a dihydrobenzofuran neolignan
system with high levels of enantioselection. Using this
process, we now report that dirhodium tetrakis[N-phthaloyl-
2
4
,
2
4
2
4
1
,3
amides, but not with diazo ketones or diazo ketoesters.
Davies and co-workers have demonstrated that combining
Rh (S-DOSP) as a catalyst and aryl- or arylvinyldiazo-
(S)-tert-leucinate], Rh
methoxycarbonyl-2,3-dihydrobenzofurans as the sole product
in up to 94% ee.
2 4
(S-PTTL) , provides cis-2-aryl-3-
2
4
1
1
acetates as a carbene precursor in a hydrocarbon solvent is
crucial for highly enantioselective intermolecular C-H
insertion reactions. In recent years we have developed
In our initial studies, we explored the intramolecular C-H
insertion of methyl 2-(2-benzyloxyphenyl)-2-diazoacetate
2
dirhodium(II) carboxylate catalysts, which incorporate N-
phthaloyl- or N-benzene-fused-phthaloyl-(S)-amino acids as
2 4
(1a) in toluene using 1 mol % of Rh (S-PTPA) (Table 1,
entry 1). As expected, the reaction proceeded smoothly at
-60 °C to completion within 0.5 h, giving 2-phenyl-3-
methoxycarbonyl-2,3-dihydobenzofurans 2a and 3a in a
70:30 ratio of cis to trans isomers and 86% combined yield.
The enantioselectivities in this reaction were 70% ee and
80% ee, respectively, as determined from HPLC (Daicel
Chiralcel OD-H for the cis isomer and Daicel Chiralcel OJ-H
for the trans isomer). The preferred absolute stereochemistry
1
c,4
bridging ligands. These catalysts mediate intramolecular
C-H insertion reactions of diazo ketoesters, diazo ketones,
or R-methoxycarbonyldiazoacetamides site-selectively to give
5
6
7
optically active cyclopentanone, 2-indanone, 2-azetidinone,
8
and 2-pyrrolidinone derivatives with a maximum of 80%,
98%, 96%, and 90% ee, respectively.
2
1
of the trans isomer 3a [[R]
D
-58.2 (c 1.12, CHCl
3
) for
8
0% ee] was (2R,3R), which was established by comparing
12
the sign of the optical rotation with the literature value [lit.
21
[R]
D
3
+32.0 (c 0.3, CHCl ) for 50% ee of (2S, 3S)-3a]. The
2
1
major cis isomer 2a [[R]
D
3
+57.9 (c 1.00, CHCl ) for 70%
ee] was quantitatively epimerized with a catalytic amount
of sodium methoxides in THF to the thermodynamically
2
2
more stable trans isomer 3a [[R]
D
3
-54.4 (c 0.83, CHCl )
for 70% ee], which determined that (2R,3S) was the preferred
absolute configuration of 2a. While the stereochemical course
13
of the reaction cannot be rationalized at present, it is worth
noting that similar levels of asymmetric induction with the
same sense at the insertion site (C2) and the opposite sense
14
at C3 were observed with cis and trans isomers. To further
enhance the enantio- and diastereoselectivity, we evaluated
the abilities of two classes of dirhodium(II) carboxylate
catalysts, which incorporate N-phthaloyl- or N-benzene-
fused-phthaloyl-(S)-amino acids as bridging ligands. While
a uniform sense of asymmetric induction was observed in
all cases, the enantio- and diastereoselectivities were highly
dependent on the catalyst. Clearly, the best catalysts were
Recently, we found that insertion reactions of methyl
phenyldiazoacetate into the Si-H bond of silanes under the
influence of Rh (S-PTPA) proceeded smoothly even at -90
C to give enantioselectivities up to 74% ee. On the basis
2
4
9
°
of this result and the general finding that the insertion
2 4 2 4
Rh (S-PTTL) and Rh (S-BPTTL) , which are characterized
reaction into a C-H bond is activated by an adjacent ether
by a bulky tert-butyl group, as they provided the thermo-
(
3) (a) Doyle, M. P.; Tedrow, J. S.; Dyatkin, A. B.; Spaans, C. J.; Ene,
(9) Kitagaki, S.; Kinoshita, M.; Takeba, M.; Anada, M.; Hashimoto, S.
Tetrahedron: Asymmetry 2000, 11, 3855.
(10) (a) Adams, J.; Poupart, M.-A.; Grenier, L.; Schaller, C.; Ouimet,
N.; Frenette, R. Tetrahedron Lett. 1989, 30, 1749. (b) Wang, P.; Adams, J.
J. Am. Chem. Soc. 1994, 116, 3296.
(11) During the course of our studies, Davies and co-workers reported
Rh2(S-DOSP)4-catalyzed C-H insertion in a related system, where reactions
in hexanes at -50 °C took 72 h for completion. In their work, the
enantioselectivity up to 94% ee was obtained for insertion into methine
C-H bonds, whereas C-H insertion into a methylene group produced a
mixture of cis- and trans-dihydrobenzofurans with up to 63% ee of the cis
isomer. See: Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Org. Lett.
2001, 3, 1475.
D. G. J. Org. Chem. 1999, 64, 8907. (b) Doyle, M. P.; Hu, W. J. Org.
Chem 2000, 65, 8839. (c) Doyle, M. P.; Yan, M.; Phillips, I. M.; Timmons,
D. J. AdV. Synth. Catal. 2002, 344, 91. (d) Doyle, M. P.; Hu, W. Chirality
002, 14, 169. (e) Doyle, M. P.; Hu, W.; Valenzuela, M. V. J. Org. Chem.
002, 67, 2954.
2
2
(
4) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.;
Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417.
5) (a) Hashimoto, S.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S.
(
Tetrahedron Lett. 1993, 34, 5109. (b) Hashimoto, S.; Watanabe, N.; Ikegami,
S. Synlett 1994, 353.
(6) (a) Watanabe, N.; Ohtake, Y.; Hashimoto, S.; Shiro, M.; Ikegami, S.
Tetrahedron Lett. 1995, 36, 1491. (b) Watanabe, N.; Ogawa, T.; Ohtake,
Y.; Ikegami, S.; Hashimoto, S. Synlett 1996, 85. (c) Takahashi, T.; Tsutsui,
H.; Tamura, M.; Kitagaki, S.; Nakajima, M.; Hashimoto, S. Chem. Commun.
(12) Luh a´ sz, L.; Szil a´ gyi, L.; Antus, S.; Visy, J.; Zsila, F.; Simonyi, M.
Tetrahedron 2002, 58, 4261.
2
001, 1604.
7) (a) Watanabe, N.; Anada, M.; Hashimoto, S.; Ikegami, S. Synlett
994, 1031. (b) Anada, M.; Watanabe, N.; Hashimoto, S. Chem. Commun.
998, 1517.
(13) Very recently, Nakamura and co-workers have reported a mechanism
of dirhodium(II) tetracarboxylate-catalyzed C-H insertion reactions based
on a detailed computational analysis. See: Nakamura, E.; Yoshikai, N.;
Yamanaka, M. J. Am. Chem. Soc. 2002, 124, 7181.
(
1
1
(
8) (a) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79. (b)
Anada, M.; Mita, O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett
999, 1775.
(14) We confirmed that cis isomer 2a did not isomerize to trans isomer
3a under the C-H insertion reaction conditions [1 mol % of Rh2(S-PTPA)4,
toluene, -78 °C or room temperature].
1
3888
Org. Lett., Vol. 4, No. 22, 2002

Table 1. Enantioselective C-H Insertion Reaction of R-Phenyldiazoacetate 1a Catalyzed by Chiral Rh(II) Complexesa
%
2a f
ee
% ee
3a g
entry
Rh(II) catalyst
solvent
temp, °C
time, h
yield, %d
2a :3a e
1
2
3
4
5
6
7
8
9
0
1
2
3
4
Rh2(S-PTPA)4
Rh2(S-PTA)4
Rh2(S-PTV)4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
-60
-60
-60
-60
-60
-60
-60
-60
-60
-45h
0.5
0.5
0.5
0.5
0.5
1
86
84
86
83
87
57
69
73
84
63
78
78
86
70
70:30
81:19
89:11
99:1
70
61
61
71
90
65
63
61
86
90
88
70
94
91
80
79
69
Rh2(S-PTPG)4
Rh2(S-PTTL)4
Rh2(S-BPTPA)4
Rh2(S-BPTA)4
Rh2(S-BPTV)4
Rh2(S-BPTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-PTTL)4
Rh2(S-BPTTL)4
>99:1
68:32
82:18
89:11
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
77
80
57
1
0.5
0.5
0.5
0.5
0.2
1
1
1
1
1
1
h
-10
23
h
hexane
toluene
toluene
-78
-78
12
a
Typical procedure for the C-H insertion reaction (entry 1): Rh2(S-PTPA)4 (7.0 × 10-3 M in toluene, 0.5 mL, 0.0035 mmol) was added to a solution
of 1a (100 mg, 0.35 mmol) in toluene (3.0 mL) at -60 °C. After 0.5 h, the mixture was concentrated and the residue was purified by column chromatography
b
c
(
silica gel, hexane/EtOAc ) 20:1). Absolute stereochemistry of 2a was determined to be (2R,3S) by chemical correlation with 3a. See the text. Absolute
stereochemistry of 3a was determined to be (2R,3R) by specific rotation. See the text. Combined yield of 2a and 3a. e Determined by H NMR analysis.
d
1
f
Determined by HPLC (Daicel Chiralcel OD-H). Determined by HPLC (Daicel Chiralcel OJ-H). h The temperature limit allowing for smooth cyclization.
g
Below this temperature the reaction in this solvent markedly reduced a product yield as azine formation increased.
dynamically less stable cis isomer 2a as the sole product in
high yields with 90% ee and 86% ee, respectively (entries 5
and 9). The other catalysts afforded a mixture of cis and
trans isomers 2a and 3a with reasonable degrees of enan-
tioselectivity. It is worth noting that the substituents of the
amino acids more markedly influenced the enantio- and
diastereoselectivities than the choice of N-phthaloyl- or
N-benzene-fused-phthaloyl groups in the bridging ligands.
virtually exclusive cis selectivity, a high enantioselectivity
(up to 94% ee) was maintained with either electron-donating
or electron-withdrawing groups at the para position on the
benzene ring (Table 2, entries 1-4). The result obtained with
2 6 3
the 3,4-(TBSO) C H group is particularly noteworthy (entry
5), because product 2e contains a structural motif found in
a dihydrobenzofuran-type neolignan blechnic acid.15 The
present protocol also allowed for substituents other than aryl
groups at the insertion site, though a slight decrease or a
dramatic reversal in the diastereoselectivity was observed
2 4
The solvent survey with Rh (S-PTTL) revealed that toluene
was the optimal solvent for this transformation in terms of
both product yield and enantiocontrol, though little effect
of solvents on diastereoselectivity was observed (entries 5
vs 10-12). Although dichloromethane and ether exhibited
nearly the same enantioselectivities as toluene, -45 or -10
2 4
(entries 6-8). To our disappointment, Rh (S-PTTL) -
catalyzed insertion into a methine C-H bond or a methyl
group resulted in 22% ee and 44% ee, respectively (eq 1).11
°C was found to be the temperature limit for allowing smooth
cyclization. Below these temperatures product yields sub-
stantially reduced as azine formation increased. The use of
hexane, which is highly beneficial for Rh (S-DOSP) , was
2 4
also found to be less effective. Thus we were gratified to
find that the enantioselectivity was further enhanced up to
9
4% ee using toluene and Rh
temperature to -78 °C without affecting the reaction rate
much (entry 13). However, catalysis with Rh (S-BPTTL)
2 4
(S-PTTL) by lowering the
2
4
Finally, the Rh
methylene analogue 6 and an aliphatic substrate 8 were
2 4
(S-PTTL) -catalyzed cyclizations of a
under the same condition required significantly longer time
to reach completion and produced 91% ee (entry 14).
Having identified the effectiveness of the combinational
(15) (a) Wada, H.; Kido, T.; Tanaka, N.; Murakami, T.; Saiki, Y.; Chen,
C.-M. Chem. Pharm. Bull. 1992, 40, 2099. (b) Wang, C.-Z.; Davin, L. B.;
Lewis, N. G. Chem. Commun. 2001, 113.
2 4
use of Rh (S-PTTL) as the catalyst and toluene as the
solvent, we then investigated the scope of this process with
respect to the substituents at the insertion site. Aside from
(16) Baker, R.; Cooke, N. G.; Humphrey, G. R.; Wright, S. H. B.;
Hirshfield, J. J. Chem. Soc., Chem. Commun. 1987, 1102.
Org. Lett., Vol. 4, No. 22, 2002
3889

Table 2. Enantioselective Synthesis of Dihydrobenzofurans via
C-H Insertion Reaction Catalyzed by Rh (S-PTTL)
2 4
substrate
time, yield,
% ee % ee
entry no.
R
h
%a
2:3b
2
3
1
2
3
4
5
6g
1a C6H5
1b 4-ClC6H4
1c 4-MeC6H4
1d 4-MeOC6H4
1e 3,4-(TBSO)2C6H3
1f CH2dCH
1g cC6H11
1h Me
1
86
79
84
89
85
62
63
91
>99:1 94c
>99:1 94d,e
>99:1 91c,e
>99:1 94c,f
PTTL)
for the present methylene C-H insertion process to be
successful. It is also noteworthy that Rh (S-PTTL) and
Rh (S-DOSP) can complement each other in the enantio-
selective intramolecular C-H insertion reactions of this type
of aryldiazoacetates. Mechanistic and stereochemical stud-
ies are currently underway, as well as applications of this
method to the catalytic asymmetric synthesis of pharmaco-
logically active neolignans containing a dihydrobenzofuran
skeleton.
4
as the catalyst and toluene as the solvent is crucial
1.5
1.5
1
2
2
2
4
2
4
d,e
99:1 91
77:23 86e,h 92c,e
11
96e,h
7
8
7
0.5
96:4
14:86 78e,h 97c,e
a
Combined yield of 2 and 3. b Determined by 1H NMR analysis.
c
d
Determined by HPLC (Daicel Chiralcel OD-H). Determined by HPLC
Daicel Chiralcel AD-H). Absolute stereochemistry of the product was
not determined. Absolute stereochemistry of 2d was determined to be
2R,3S) by chemical correlation with the known compound. See the
Supporting Information. This reaction was carried out at -23 °C.
Determined by HPLC (Daicel Chiralcel OJ-H).
e
(
f
16
(
g
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research on Priority Areas
h
(A) “Exploitation of Multi-Element Cyclic Molecules” from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We thank Ms. S. Oka of the Center for
Instrumental Analysis at Hokkaido University for mass
measurements.
examined (eqs 2 and 3). While virtually exclusive cis
selectivities were observed in both cases, only modest
enantioselectivities were obtained. These results suggest that
the presence of both a phenyl ring and an oxygen atom
adjacent to the target C-H bond is responsible for the high
enantioselectivity.
Supporting Information Available: Experimental pro-
cedures and characterization data for selected compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed a highly efficient method
for the catalytic enantio- and diastereoselective synthesis of
cis-2-aryl-3-methoxycarbonyl-2,3-dihydrobenzofurans, which
are otherwise difficult to prepare. The combination of Rh
2
(S-
OL0267127
3890
Org. Lett., Vol. 4, No. 22, 2002