Enantioselective copper-catalyzed intramolecular O-H insertion: An efficient approach to chiral 2-carboxy cyclic ethers

Article abstract of DOI:10.1021/ja1078464

A copper-catalyzed asymmetric intramolecular O-H insertion of ω-hydroxy-α-diazoesters has been accomplished by using chiral spiro bisoxazoline ligands. This highly enantioselective intramolecular O-H insertion reaction provides an efficient approach to a

Full text of DOI:10.1021/ja1078464

Published on Web 10/29/2010
Enantioselective Copper-Catalyzed Intramolecular O-H Insertion: An Efficient
Approach to Chiral 2-Carboxy Cyclic Ethers
Shou-Fei Zhu, Xiao-Guang Song, Yu Li, Yan Cai, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received September 10, 2010; E-mail: qlzhou@nankai.edu.cn
process for the preparation of the optically pure tetrahydrofuran-
Abstract: A copper-catalyzed asymmetric intramolecular O-H
insertion of ω-hydroxy-R-diazoesters has been accomplished by
using chiral spiro bisoxazoline ligands. This highly enantioselec-
tive intramolecular O-H insertion reaction provides an efficient
approach to a variety of synthetically important chiral 2-carboxy
cyclic ethers with different ring sizes as well as substitution
patterns.
2-carboxylic acid.9 This intermediate is generally obtained by means
of tedious and time-consuming chemical resolution via diastereo-
meric salts or by means of enzyme-catalyzed kinetic resolutions.10
We found that copper-catalyzed asymmetric intramolecular O-H
insertion of ω-hydroxy-R-diazoesters 2 provides a direct synthetic
route to chiral 2-carboxy cyclic ethers. Because ω-hydroxy-R-
diazoesters 2 can be prepared in good yields from a readily available
starting material (see the Supporting Information for details) and
are easily modified, the catalytic asymmetric intramolecular O-H
Because carbon-heteroatom (C-X) bonds are prevalent in
organic compounds, the development of reliable and efficient
methods for construction of such bonds is of high practical value.
Transition-metal-catalyzed insertion of carbenes into heteroatom-
hydrogen bonds (X-H, X ) O, N, S, etc.) provides one of the
most efficient approaches to the formation of C-X bonds.1 In
particular, the O-H insertion reaction has attracted increasing
attention over the past decades, and various O-H donors have been
used in this reaction.2 Recently, transition-metal-catalyzed asym-
metric intermolecular O-H insertions of alcohols, phenols, and
water have been accomplished with excellent enantioselectivities
by Fu’s group3 and our group.4 Although the catalytic intramo-
lecular O-H insertion is a very useful reaction for the construction
of cyclic ethers and esters, which are ubiquitous building blocks
for chiral drugs and natural products,5 the asymmetric version of
intramolecular O-H insertion has not been documented to date.6
Here we report a copper-catalyzed asymmetric intramolecular O-H
insertion reaction of ω-hydroxy-R-diazoesters (Scheme 1). By using
copper complexes of chiral spiro bisoxazoline ligands 1 as catalysts,
we obtained a variety of chiral 2-carboxy cyclic ethers 3 in high
yields (up to 98%) with excellent enantioselectivities (up to 97%
ee). To the best of our knowledge, this is the first highly
enantioselective intramolecular carbene insertion into X-H bonds.7
insertion reactions of 2 have high potential usefulness for the
synthesis of various chiral 2-carboxy cyclic ethers 3 with different
ring sizes and substitution patterns.
Figure 1. Representative biologically active compounds derived from
2-carboxy cyclic ethers.
In the initial study, we performed the intramolecular insertion
reaction of 2a using chiral copper catalysts prepared in situ from
copper chloride, ligand (Sa,S,S)-1a, and sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate (NaBArF) in dichloromethane at
25 °C. The reaction was complete within 1 h, and the desired
product, benzyl tetrahydro-2H-pyran-2-carboxylate (3a), was ob-
tained in 93% yield with 53% ee (Table 1, entry 1). Under identical
reaction conditions, ligand (Ra,S,S)-1a afforded only the racemic
product (entry 2), and this result clearly indicates that ligand
(Sa,S,S)-1a had matched chiralities in this reaction. Systematic
evaluation of the 4-substituents on the spiro bisoxazoline ligand
revealed that ligands with bulkier 4-substituents on the oxazoline
rings provided higher enantioselectivity; the ligand (Sa,S,S)-1d,
which has 4-tert-butyl groups, showed the highest enantioselectivity
(87% ee; entries 3-5). Varying the copper precursors also strongly
affected both the reactivity and the enantioselectivity. Cu(I) salts
were suitable precursors for the transformation, with CuOTf giving
the best result (93% ee; entry 6). Cu(II) salts such as Cu(OTf)2
and CuCl2 could also be used but showed lower yields (entries 8
and 9). However, CuSO4 was completely inert under the standard
reaction conditions (entry 10). The chlorinated solvents CH2Cl2,
CHCl3, and dichloroethane (DCE) were suitable for this transforma-
tion, whereas THF and toluene afforded poor yields (entries 11-14).
In contrast, the highly coordinating solvent MeCN completely
inhibited the insertion reaction (entry 15). As we observed in the
Scheme 1
Optically pure 2-carboxy cyclic ethers are important intermediates
in the preparation of biologically active compounds such as those
shown in Figure 1.8 Although great effort has been expended,
efficient methods for the preparation of optically pure 2-carboxy
cyclic ethers are still limited. For instance, (R)-tetrahydrofuran-2-
carboxylic acid is the key intermediate in the synthesis of the
clinically efficacious non-natural ꢀ-lactam antibiotic faropenem.8b
Although the structure looks simple, there is no enantioselective
9
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10.1021/ja1078464  2010 American Chemical Society

C O M M U N I C A T I O N S
copper-catalyzed asymmetric intermolecular insertions into O-H,4
N-H,11 and S-H12 bonds, the additive NaBArF was necessary to
achieve high yield and high enantioselectivity in the asymmetric
intramolecular insertion of 2a (compare entries 6 and 16). The
activity of the present catalyst was sufficiently high to catalyze the
intramolecular O-H insertion of 2a with a catalyst loading of 2
mol % (entry 17).
used as the substrate, the desired O-H insertion product with a
seven-membered ring (3m) was isolated in only 14% yield with
95% ee (entry 13). The competitive ꢀ-H elimination of the carbene
intermediate became the main reaction, giving benzyl 7-hydroxy-
hept-2-enoate (Z/E ) 2.2:1) in 81% yield. Interestingly, ꢀ-H
elimination of the carbene intermediate was markedly suppressed
when the ligand (Sa,S,S)-1c, which has less bulky isopropyl groups
on the oxazoline rings, was employed, and the desired O-H
insertion product (3m) was obtained in acceptable yield (70%) with
good enantioselectivity (83% ee).
Table 1. Copper-Catalyzed Asymmetric Intramolecular O-H
Insertion of 2a: Optimization of Reaction Conditionsa
Table 2. Copper-Catalyzed Asymmetric Intramolecular O-H
Insertion: Substrate Scopea
entry
[Cu]
ligand
solvent time (h) yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuCl
CuCl
(Sa,S,S)-1a CH2Cl2
1
93
91
86
88
74
80
92
52
55
-
68
72
36
27
-
53
rac
51
59
87
93
83
83
87
-
90
89
91
85
-
(Ra,S,S)-1a CH2Cl2 0.5
(Sa,S,S)-1b CH2Cl2 0.5
(Sa,S,S)-1c CH2Cl2 1.5
(Sa,S,S)-1d CH2Cl2 1.5
CuOTf ·1/2toluene (Sa,S,S)-1d CH2Cl2 0.1
CuPF6(MeCN)4
Cu(OTf)2
CuCl2
(Sa,S,S)-1d CH2Cl2 16
(Sa,S,S)-1d CH2Cl2 0.5
(Sa,S,S)-1d CH2Cl2
4
10 CuSO4
(Sa,S,S)-1d CH2Cl2 NRd
11 CuOTf ·1/2toluene (Sa,S,S)-1d CHCl3
12 CuOTf ·1/2toluene (Sa,S,S)-1d DCE
13 CuOTf ·1/2toluene (Sa,S,S)-1d THF
3
0.5
2
14 CuOTf ·1/2toluene (Sa,S,S)-1d toluene 36
15 CuOTf ·1/2toluene (Sa,S,S)-1d MeCN
16e CuOTf·1/2toluene (Sa,S,S)-1d CH2Cl2
NRd
6
48
78
87
91
17f CuOTf·1/2toluene (Sa,S,S)-1d CH2Cl2 1.5
a Reaction conditions: [Cu]/ligand/NaBArF/2a ) 0.02/0.024/0.024/0.4
(mmol) in
4
mL of CH2Cl2 at 25 °C. NaBArF
)
sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate. b Isolated yield. c Determined
by HPLC using a Chiralcel OD-H column. d No reaction. e Without the
NaBArF additive. f Using 2 mol % catalyst.
Under the optimal reaction conditions, various ω-hydroxy-R-
diazoesters 2 were subjected to the intramolecular O-H insertion
reaction (Table 2). For the substrates with 6-hydroxy chains (2a-i),
which afforded the corresponding six-membered cyclic ethers
(3a-i), the catalyst Cu-(Sa,S,S)-1d exhibited excellent activities and
enantioselectivities. The double bonds in the chains of 2b and 2c
were compatible with the standard reaction conditions, and no
competitive cyclopropanation reactions were observed (Table 2,
entries 2 and 3). A benzo group in the chain of the substrate was
helpful for increasing the yield of the reaction (entries 4-8).
Substrates with a less sterically hindered methyl (2d) or ethyl (2e)
ester gave 92% ee, which was close to that for benzyl ester 2a.
However, substrate 2f with a tert-butyl ester group afforded a lower
enantioselectivity (82% ee). Introducing an electron-withdrawing
substituent on the benzo ring increased the enantioselectivity, and
substrate 2g, with a 4-bromobenzo group, afforded the highest
enantioselectivity (97% ee; entry 7). The absolute configuration of
3g was determined to be R by X-ray diffraction analysis of a single
crystal (see the Supporting Information for detailed crystallographic
data). Diazo compound 2i with a naphthyl ring in the chain also
gave good enantioselectivity (93% ee; entry 9). The catalyst Cu-
(Sa,S,S)-1d was also suitable for the asymmetric intramolecular
O-H insertion reactions of 5-hydroxy-2-diazoesters 2j-l, which
yielded the corresponding cyclic ethers with five-membered rings
(3j-l). A carbon-carbon double bond (2k) or a benzo ring (2l) in
the chain of the substrate had a positive effect on the enantiose-
lectivity (entries 11 and 12). When 7-hydroxy-2-diazoester 2m was
a The reaction conditions were the same as those in Table 1, entry 6.
All of the reactions reached completion within 15 min. For analyses of
products, see the Supporting Information. b The results were obtained by
using ligand (Sa,S,S)-1c.
In summary, we have developed a highly enantioselective
catalytic intramolecular O-H insertion reaction. When copper
complexes of chiral spiro bisoxazoline ligands were used as the
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Acknowledgment. We thank the National Natural Science
Foundation of China, the National Basic Research Program of China
(2010CB833300), the Ministry of Health (2009ZX09501-017), and
the “111” Project (B06005) of the Ministry of Education of China
for financial support.
Supporting Information Available: Detailed experimental proce-
dures, characterizations and analytical data of ee values of products,
and crystallographic data for 3g (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
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