C O M M U N I C A T I O N S
Table 2. Asymmetric Catalytic Carbenoid Insertion into O-H
Scheme 2
Bonds of Phenolsa
example, the hydrolysis of R-aryloxypropionates 4a and 4l with
aqueous KOH at 0 °C afforded the acids (R)-5a and (R)-5l in
quantitative yields (Scheme 2). Thus, the copper/(Sa,S,S)-1a-
catalyzed asymmetric insertion of the O-H bond of phenols by
R-diazoesters provided a new efficient access to the synthesis of
optically pure R-aryloxypropionic acids from simple substrates in
two steps.
In summary, the first highly enantioselective insertion of
carbenoids into O-H bonds of phenols has been realized. By using
copper complexes of chiral spiro bisoxazolines as catalysts, the
optically active R-aryloxypropionates and the related acids were
synthesized conveniently. The successful use of spiro bisoxazolines
in the asymmetric insertion of O-H bonds of phenols indicates
the potential of these novel nitrogen ligands in asymmetric insertion
reactions of heteroatom-hydrogen bond (X-H) of a wide range
of substrates.
entry
R1
R2
R3
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
tBu
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
87
71
68
83
79
71
78
82
88
78
70
83
85
62
80
84
77
83
63
85
71
70
80
99 (R)
98
95
99.2
99.3
99
99
99
99
99
o-MePh
o-MeOPh
o-PhPh
m-MePh
m-MeOPh
m-BrPh
m-PhPh
p-MePh
p-MeOPh
p-tBuPh
p-ClPh
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
98
99.1 (R)
99.6
99
99
99
99.1 (R)
98 (R)
59
61 (R)
10 (R)
98 (R)
99
p-BrPh
p-MeO2CPh
2,4-diMePh
3,5-diPhPh
1-naphthyl
2-naphthyl
Ph(CH2)3
PhCHdCHCH2
Ph
Acknowledgment. We thank the National Natural Science
Foundation of China, the Major Basic Research Development
Program (Grant No. 2006CB806106), the “111” project (B06005)
of the Ministry of Education of China, and Merck Research
Laboratories for financial support.
4t
4u
4v
4w
Ph
Ph
Me
Me
a Reaction conditions were the same as those in Table 1, entry 8. All
reactions were completed within 3 h. For the characterization and analysis
of ee values of insertion products, see Supporting Information.
Supporting Information Available: Experimental procedures, the
characterizations of products, and the analysis of ee values of products.
This material is available free of charge via the Internet at http://
pubs.acs.org.
i
(Sa,S,S)-1c, having an Pr unit, gave the insertion product in 99%
ee (entry 19), identical to that obtained with ligand (Sa,S,S)-1a. The
ligands (Sa,S,S)-1b and (Sa,S,S)-1d, containing benzyl and tert-butyl
groups, respectively, showed lower enantioselectivities (entries 18
and 20).
References
(1) For reviews, see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds; Wiley:
New York, 1998; Chapters 3 and 8. (b) Ye, T.; Mckervey, M. A. Chem.
ReV. 1994, 94, 1091.
Under the optimized reaction conditions, a variety of substituted
phenols were examined in the copper/Spirobox-catalyzed asym-
metric O-H insertion of ethyl R-diazopropionates (Table 2). All
substituted phenols including naphthols completed the insertion
reaction in 3 h to produce the corresponding R-aryloxypropionates
in good yields and extremely high enantioselectivities (g95% ee)
regardless of the nature and the position of the substituents (entries
1-18). In addition to phenols, aliphatic alcohols such as 3-phe-
nylpropanol and cinnamic alcohol also underwent O-H insertion
reaction under the same reaction conditions, although the enanti-
oselectivities were not as high as those in the reactions with phenols
(entries 19 and 20). The methyl of the R1 group in the R-diazoester
is vital for the reaction. When the methyl was changed to phenyl,
the O-H insertion product was obtained in a negligible ee value
(entry 21). In the reaction of benzyl R-diazobutyrate (R2 ) Et),
only the â-elimination product of carbenoid, benzyl 2-butenoic ester
(81%) was isolated. The reactions with methyl and tert-butyl
R-diazopropionates gave O-H insertion products in good yields
and with excellent enantiomeric excess (entries 22 and 23), showing
that the size of R3 group in the R-diazoester has almost no influence
on the enantioselectivity and reactivity in the O-H insertion
reaction.
(2) For recent review, see: Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV.
2003, 103, 2861.
(3) For enantioselective Si-H insertion, see: (a) Buck, R. T.; Doyle, M. P.;
Drysdale, M. J.; Ferris, L.; Forbes, D. C.; Haigh, D.; Moody, C. J.; Pearson,
N. D.; Zhou, Q.-L. Tetrahedron Lett. 1996, 37, 7631. (b) Davies, H. M.
L.; Hansen, T.; Rutberg, J.; Bruzinski, P. R. Tetrahedron Lett. 1997, 38,
1741. (c) Dakin, L. A.; Schaus, S. E.; Jacobsen, E. N.; Panek, J. S.
Tetrahedron Lett. 1998, 39, 8947.
(4) For recent examples, see: (a) Liao, M.; Dong, S.; Deng, G.; Wang, J.
Tetrahedron Lett. 2006, 47, 4537. (b) Ronan, B.; Bacque´, E.; Barrie`re,
J.-C. Tetrahedron 2004, 60, 3819. (c) Nagai, K.; Sunazuka, T.; Omura,
S. Tetrahedron Lett. 2004, 45, 2507. (d) Xu, C.; Zhang, Y.; Yuan, C.
Eur. J. Org. Chem. 2004, 2253. (e) Morilla, M. E.; Molina, M. J.; D´ıaz-
Requejo, M. M.; Belderra´ın, T. R.; Nicasio, M. C.; Trofimenko, S.; Pe´rez,
P. Organometallics 2003, 22, 2914. (f) Doyle, M. P.; Yan, M. Tetrahedron
Lett. 2002, 43, 5929. (g) Moody, C. J.; Morfitt, C. N.; Slawin, A. M. Z.
Tetrahedron: Asymmetry 2001, 12, 1657. (h) Jones, K.; Toutounji, T.
Tetrahedron 2001, 57, 2427. (i) Jiang, N.; Wang, J.; Chan, A. S. C.
Tetrahedron Lett. 2001, 42, 8511. (j) Kettle, J. G.; Faull, A. W.; Fillery,
S. M.; Flynn, A. P.; Hoyle, M. A.; Hudson, J. A. Tetrahedron Lett. 2000,
41, 6905. (k) Nelson, T. D.; Song, Z. J.; Thompson, A. S.; Zhao, M.;
DeMarco, A.; Reamer, R. A.; Huntington, M. F.; Grabowski, E. J. J.;
Reider, P. J. Tetrahedron Lett. 2000, 41, 1877.
(5) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594 and refs therein.
(6) Liu, B.; Zhu, S.-F.; Zhang, W.; Chen, C.; Zhou, Q.-L. J. Am. Chem. Soc.
2007, 129, 5834.
(7) BARF- ) tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
(8) (a) Perron, Y. G.; Minor, W. F.; Holdrege, C. T.; Gottstein, W. J.; Godfrey,
J. C.; Crast, L. B.; Babel, R. B.; Cheney, L. C. J. Am. Chem. Soc. 1960,
82, 3934. (b) Kawashima, Y.; Hanioka, N.; Kozuka, H. J. Pharmacobio-
Dyn. 1984, 7, 286. (c) Bettoni, G.; Loiodice, F.; Tortorella, V.; Conte-
Camerino, D.; Mambrini, M.; Ferrannini, E.; Bryant, S.-H. J. Med. Chem.
1987, 30, 1267. (d) Chimichi, S.; Boccalini, M. Tetrahedron Lett. 2006,
47, 2405.
The R-aryloxypropionic acids are biologically important com-
pounds and have been widely utilized as crop protection reagents
and as key intermediates in the preparation of chiral drugs.8 They
can be easily prepared from our O-H insertion products. For
JA074729K
9
J. AM. CHEM. SOC. VOL. 129, NO. 42, 2007 12617