Catalytic enantioselective O-H insertion reactions

Article abstract of DOI:10.1021/ja0607739

The first effective method for catalytic enantioselective insertions into O-H bonds has been developed. Specifically, a copper/bisazaferrocene catalyst couples alcohols such as 2-trimethylsilylethanol with α-aryl-α-diazo esters in high yield and good ee.

Full text of DOI:10.1021/ja0607739

Published on Web 03/21/2006
Catalytic Enantioselective O-H Insertion Reactions
Thomas C. Maier and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 1, 2006; E-mail: gcf@mit.edu
Table 1. Effect of a Range of Reaction Parameters on Catalytic
Enantioselective O-H Insertions
Remarkable advances have been reported in the discovery of
methods for catalytic asymmetric insertion into C-H bonds.1 In
contrast, there has been essentially no success in achieving
corresponding reactions of O-H bonds (maximum ee: 8%);2 in
fact, there has been only limited progress even with respect to
diastereoselective processes.3,4 In this communication, we describe
the first effective catalyst for enantioselective O-H insertions,
thereby generating R-alkoxy and R-hydroxy carbonyl compounds
in good ee (eq 1).5,6
entry
change from standard conditions
yield (%)a,b
ee (%)a
1
2
3
4
5
6
7
none
86
98
93
50
70
72
51
86
82
22
13
<2
40
9
30% H2O instead of 4.0% H2O
no H2O instead of 4.0% H2O
2.2% (+)-1 instead of 3.8% (+)-1
3.8% 2 instead of 3.8% (+)-1
3.8% 3 instead of 3.8% (+)-1 (4 h)
3.8% (R)-i-Pr-Pybox
instead of 3.8% (+)-1 (20 h)
3.8% (R)-Et-DUPHOS
instead of 3.8% (+)-1
3.8% (R)-BINAP instead of
3.8% (+)-1 (20 h)
no Cu(OTf)2 instead of
2.0% Cu(OTf)2 (24 h)
2.0% CuCl2 instead of
2.0% Cu(OTf)2 (20 h)
2.0% CuCl instead of
2.0% Cu(OTf)2 (20 h)
2.0% CuPF6(CH3CN)4 instead
8
45
73
0
<2
<2
-
9
10
11
12
13
37
39
95
<2
<2
76
Outlined in Table 1 are the effects of a number of reaction
parameters on the yield and the ee for the copper-catalyzed coupling
of ethanol with methyl R-diazo-R-phenylacetate.7 A key serendipi-
tous discovery was that the addition of a small amount of water
furnishes a much more enantioselective catalyst (entries 1 and 2
versus entry 3).8 A lower ligand:metal ratio leads to a lower yield
and ee (entry 4), as does the use of chiral bisoxazoline, semicorrin,
Pybox, DUPHOS, and BINAP ligands (entries 5-9). Under our
of 2.0% Cu(OTf)2
14
15
16
CH2Cl2 instead of ClCH2CH2Cl
Et2O instead of ClCH2CHCl (4 h)
toulene instead of ClCH2CH2Cl (4 h)
92
71
70
72
7
7
a Average of two experiments. b Determined by GC versus a calibrated
internal standard.
Table 2. Catalytic Enantioselective O-H Insertions: Dependence
of ee on the Choice of Alcohol
standard conditions, in the absence of Cu(OTf)2 or in the presence
of CuCl2 or CuCl, unsatisfactory yields and essentially no enantio-
selectivity are observed (entries 10-12). In contrast, CuPF6(CH3-
CN)4 provides an active, but somewhat less stereoselective, catalyst
(entry 13 versus entry 1). Insertions conducted in CH2Cl2 proceed
smoothly with fairly good enantioselectivity, whereas reactions in
Et2O or toluene afford low ee (entries 14-16).9
We have examined the impact of the structure of the alcohol on
the yield and the ee of copper/bisazaferrocene-catalyzed asymmetric
O-H insertion reactions (Table 2). The steric demand of the alkyl
group plays an important role, with ethanol furnishing the best
results among the four simple alcohols described in entries 1-4.
Among ethanol derivatives, dramatically different outcomes are
obtained, depending on the substituents on the remote carbon, e.g.,
yield
ee
yield
ee
entry
R
(%)a,b (%)a
entry
R
(%)a,b (%)a
1
2
3
4
5
Me
Et
i-Pr
t-Bu
86
85
76
<2
94
69
87
68
-
6
7
8
9
CH2CF3
<2
86
87
77
-
77
82
27
Bn
p-methoxybenzyl
allyl
CH2CH2TMS
90
10 Ph
56 11c
a Average of two experiments. b Isolated yield. c The opposite stereo-
isomer is produced.
2-trimethylsilylethanol reacts in excellent yield and ee (entry 5),
whereas 2,2,2-trifluoroethanol does not undergo insertion (entry 6).
2-Trimethylsilylethanol is a particularly attractive substrate, since
the insertion product can be deprotected to provide the R-hydroxy
ester in high yield without racemization (eq 2). Reactions of benzyl
9
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J. AM. CHEM. SOC. 2006, 128, 4594-4595
10.1021/ja0607739 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Catalytic Enantioselective O-H Insertions: Scope
Acknowledgment. This paper is dedicated to Prof. JoAnne
Stubbe on the occasion of her 60th birthday. Support has been
provided by the NIH (National Institute of General Medical
Sciences: R01-GM66960), Deutsche Forschungsgemeinschaft (post-
doctoral fellowship to T.C.M.), Merck Research Laboratories, and
Novartis. Funding for the MIT Department of Chemistry Instru-
mentation Facility has been furnished in part by NIH IS10RR13886
and NSF DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) For reviews and leading references, see: (a) Davies, H. M. L.; Long, M.
S. Angew. Chem., Int. Ed. 2005, 44, 3518-3520. (b) Davies, H. M. L. In
ComprehensiVe Asymmetric Catalysis (Supplement 1); Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 2004; pp 83-94.
(c) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: New York, 1999; pp 513-603. (d) Davies,
H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-2903. (e)
Mu¨ller, P.; Fuirt, C. Chem. ReV. 2003, 103, 2905-2919.
(2) Bulugahapitiya, P.; Landais, Y.; Parra-Rapado, L.; Planchenault, D.;
Weber, V. J. Org. Chem. 1997, 62, 1630-1641 (8% ee, 59% yield).
(3) For examples of diastereoselective O-H insertion reactions, see: (a) Aller,
E.; Cox, G. G.; Miller, D. J.; Moody, C. J. Tetrahedron Lett. 1994, 35,
5949-5952. (b) Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody,
C. J. J. Org. Chem. 1995, 60, 4449-4460. (c) Shi, G.-q.; Cao, Z.-y.; Cai,
W.-l. Tetrahedron 1995, 51, 5011-5018. (d) Bulugahapitiya, P.; Landais,
Y.; Parra-Rapado, L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997,
62, 1630-1641. (e) Miller, D. J.; Moody, C. J.; Morfitt, C. N. Aust. J.
Chem. 1999, 52, 97-107. (f) Pansare, S. V.; Jain, R. P.; Bhattacharyya,
A. Tetrahedron Lett. 1999, 40, 5255-5258. (g) Moody, C. J.; Morfitt, C.
N.; Slawin, A. M. Z. Tetrahedron: Asymmetry 2001, 12, 1657-1661.
(h) Jiang, N.; Wang, J.; Chan, A. S. C. Tetrahedron Lett. 2001, 42, 8511-
8513. (i) Doyle, M. P.; Yan, M. Tetrahedron Lett. 2002, 43, 5929-5931.
(j) Im, C. Y.; Okuyama, T.; Sugimura, T. Chem. Lett. 2005, 1328-1329.
(k) Bolm, C.; Saladin, S.; Classen, A.; Kasyan, A.; Veri, E.; Raabe, G.
Synlett 2005, 461-464.
(4) For reviews of catalyzed insertions of diazo compounds into O-H bonds,
see: (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley: New York, 1998;
Chapters 8.3 and 8.4. (b) Miller, D. J.; Moody, C. J. Tetrahedron 1995,
50, 10811-10843.
(5) For leading references to the synthesis and the utility of R-hydroxycarbonyl
compounds, see: (a) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292-
4300. (b) Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. Org. React.
2003, 62, 1-356.
a Average of two experiments. b Isolated yield. c Due to ease of synthesis,
the ethyl ester was used. d Value in parentheses: ee after one recrystalli-
zation.
alcohols proceed with fairly good enantioselectivity (entries 7 and
8), although insertions into allyl alcohol and phenol afford
unsatisfactory results (entries 9 and 10).10,11
(6) For previous applications of bisazaferrocene ligands in asymmetric
catalysis, see: (a) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120,
10270-10271. (b) Lo, M. M.-C.; Fu, G. C. Tetrahedron 2001, 57, 2621-
2634. (c) Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2002, 124, 4572-
4573.
(7) For transition metal-catalyzed insertions of diazo compounds into O-H
bonds, rhodium, not copper, complexes have generally been the catalysts
of choice (see ref 4). For a recent report of an effective copper-based
catalyst, see: Morilla, M. E.; Molina, M. J.; Diaz-Requejo, M. M.;
Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. Organo-
metallics 2003, 22, 2914-2918.
(8) We do not yet understand the role that water is playing in these reactions.
(9) Reactions of R-diazo esters derived from primary alcohols (rather than
secondary alcohols, tertiary alcohols, or phenols) proceed with the highest
yield and enantioselectivity. Insertions by R-diazo ketones and amides
furnish low ee.
(10) For the reaction of allyl alcohol, we observe no cyclopropanation of the
olefin (see also ref 7).
Copper/bisazaferrocene-catalyzed insertions into the O-H bond
of 2-trimethylsilylethanol proceed in high yield and generally good
enantioselectivity for a range of R-diazo esters (Table 3). Thus,
the aromatic ring can be substituted in the ortho (entries 2-5), meta
(entries 6 and 7), or para (entries 8-13) positions, and it can be
electronically diverse (for an exception, see entry 13). Furthermore,
bicyclic substituents are tolerated (entries 14 and 15), as is a
heterocycle (entry 16).12
Although we have not yet conducted detailed mechanistic studies,
we have made two observations worthy of mention. First, product
ee correlates linearly with catalyst ee.13 Second, there is a substantial
preference for O-H, rather than O-D, insertion (eq 3).14
(11) Under our standard conditions, when water is employed as a substrate,
O-H insertion occurs in moderate yield (∼55%) and low ee (∼15% ee).
Triphenylsilanol and triethylsilanol are unreactive.
(12) Notes: (a) Highly electron-rich R-aryl-R-diazo carbonyl compounds are
relatively unstable, and they are not suitable substrates under our standard
conditions. Insertions of R-pyridyl-R-diazo esters proceed in low ee. (b)
Reaction of an alkenyl-substituted (R-styryl) diazoacetate leads to the
formation of the desired product in 27% yield and 13% ee. We have not
yet attempted to optimize this process. (c) Under our standard conditions,
R-alkyl-R-diazoacetates undergo a 1,2-H shift to furnish R,â-unsaturated
esters. (d) For the insertion depicted in entry 1 of Table 3, decreasing the
catalyst loading to 0.5% Cu(OTf)2/0.95% 1 leads to a drop in ee (76%
ee, 96% yield).
(13) For a review of nonlinear effects in asymmetric catalysis, see: Kagan,
H. B.; Luukas, T. O. In ComprehensiVe Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Chapter
4.1.
(14) Insertions into the O-D bond of deuterated alcohols furnish a route to
enantioenriched R-deuterio-R-hydroxy esters (e.g., methyl R-diazo-R-
phenylacetate + TMSCH2CH2OD: 94% yield, 78% ee).
In summary, we have developed the first effective method for
catalytic enantioselective insertions into O-H bonds. Thus, a
copper/bisazaferrocene catalyst couples alcohols such as 2-tri-
methylsilylethanol with R-aryl-R-diazo esters in high yield and
generally good ee. Additional investigations of this and related
processes are underway.
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