Versatile Enantioselective Synthesis of Functionalized Lactones via Copper-Catalyzed Radical Oxyfunctionalization of Alkenes

Article abstract of DOI:10.1021/jacs.5b04821

A versatile method for the rapid synthesis of diverse enantiomerically enriched lactones has been developed based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes. The scope of this strategy encompasses a series of enantioselective difunctionalization reactions: oxyazidation, oxysulfonylation, oxyarylation, diacyloxylation, and oxyalkylation. These reactions provide straightforward access to a wide range of useful chiral lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access traditionally. (Chemical Equation Presented).

Full text of DOI:10.1021/jacs.5b04821

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Article
Versatile Enantioselective Synthesis of Functionalized Lactones
via Copper-Catalyzed Radical Oxyfunctionalization of Alkenes
Rong Zhu, and Stephen L. Buchwald
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b04821 • Publication Date (Web): 12 Jun 2015
Downloaded from http://pubs.acs.org on June 15, 2015
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Versatile Enantioselective Synthesis of Functionalized Lactones via
Copper-Catalyzed Radical Oxyfunctionalization of Alkenes
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Rong Zhu and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Supporting Information Placeholder
Scheme 1. Catalytic enantioselective synthesis of function-
alized lactones from alkenes.
ABSTRACT: A versatile method for the rapid synthesis of
diverse enantiomerically enriched lactones has been developed
based on Cu-catalyzed enantioselective radical oxyfunctional-
ization of alkenes. The scope of this strategy encompasses a
series of enantioselective difunctionalization reactions: ox-
yazidation, oxysulfonylation, oxyarylation, diacyloxylation
and oxyalkylation. These reactions provide straightforward
access to a wide range of useful chiral lactone building blocks
containing tetrasubstituted stereogenic centers, which are hard
to access traditionally.
[X+]
O
n
X
O
R
cat*
additional steps
or
inaccessible
Established strategy: halolactonization
O
R
HO
n
R1
O
n
O
R1
R
cat. [CuL*]
structurally diverse
chiral lactones
New strategy: radical oxyfunctionalization
scope of R1
INTRODUCTION
♦ One step
O
O
Ar
N3
♦ Good scope
S
Ar
Chiral γ- and δ-lactones are valuable compounds which are not
only found in a large number of biologically active natural and
unnatural molecules, but also serve as versatile synthetic in-
termediates en route to many related architectures such as
chiral tetrahydrofuran, tetrahydropyran and hydroxycarboxylic
acid derivatives.1 Among the numerous efforts towards effi-
cient catalytic asymmetric syntheses of γ- and δ-lactones from
achiral precursors, the direct cyclization of unsaturated car-
boxylic acids in the presence of an electrophile is an attractive
approach due to the readily availability of the starting materi-
als and the simultaneous incorporation of a second useful
functional group.2,3 In particular, elegant solutions have been
recently devised for enantioselective halolactonization reac-
tions, delivering halogenated γ- and δ-lactones in high yields
with good enantioselectivity.4,5 However, successful examples
of enantioselective lactonization are thus far largely limited to
the use of electrophilic halogen electrophiles. While chiral
halolactones themselves are certainly useful, subsequent steps
are required to convert the alkyl halides in these compounds
into a more diverse array of functional groups. Moreover,
many useful functional groups, such as an aryl group, are dif-
ficult to access from the alkyl halides generated using this
approach. In order to access a broader scope of structurally
diverse chiral lactones in a step-economical and versatile fash-
ion, a new strategy allowing the use of other electrophiles is
required (Scheme 1).
♦ Mild conditions
Alkyl
RCO2
We envisioned a new synthesis of chiral lactones incorporat-
ing the features discussed above based on a strategy that we
recently established during the investigation of the copper-
catalyzed enantioselective oxytrifluoromethylation reaction.6
We found that the tandem CF3 radical addi-
tion/enantioselective C−O bond forming lactonization of un-
saturated carboxylic acid substrates could be achieved effi-
ciently in one step. Given the intrinsic versatility associated
with the stepwise nature of this radical addition/interception
mechanism, we were interested in applying this strategy to the
use of a broad range of other radical species for enantioselec-
tive lactonization reactions, which would afford products that
require multiple synthetic steps or are hard to access tradition-
ally.
A simplified generic catalytic cycle proposed is depicted in
Scheme 2. Initial reaction between the Cu(I) catalyst and the
radical source R1−X (1) would generate a Cu(II) species and a
radical ŸR1. This radical would then add to the alkene sub-
strate 2, affording a tertiary alkyl radical intermediate I. Final-
ly, the enantioselective C−O bond forming process of I medi-
ated by the Cu(II) complex would furnish the lactone product
3 and regenerate the Cu(I) species. Herein, we report a series
of copper-catalyzed enantioselective lactonization reactions
enabled by the radical oxyfunctionalization of alkenes, includ-
ing: oxyazidation (R1 = N3−), oxysulfonylation (R1 = ArSO2−),
oxyarylation (R1 = Ar−), diacyloxylation (R1 = RCO2−), and
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Page 2 of 10
oxyalkylation (R1 = alkyl). Some mechanistic features of this
type of reactions are also discussed in the last part.
Table 1. Cu-Catalyzed enantioselective alkene oxyazida-
tion.a
1
2
3
4
5
6
7
8
9
5% Cu(MeCN)4PF6, 5% L
2.5 equiv PhI(OAc)2
2.4 equiv TMSN3
Me Me
Scheme 2. Proposed generic catalytic cycle.
O
O
O
R
O
O
N
N
R
HO
n
Et2O, -10 °C
tBu
tBu
O
O
N3
R
n
L
[CuIL*]
R1
4
2
R1
X
n
3
1
Yield
b
ee
Enantioselective
Entry
Substrate
Product
c
C-O bond formation
[%]
[%]
X
[CuIIL*]
HO
O
R1
10
11
12
13
14
15
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17
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R
R
O
O
n
O
O
HO
R
HO
n
N3
R
R1
I
2
1
2
3
4
R = H
R = Br
R = Cl
2a
2b
2c
4a
4b
4c
4d
63
55
56
50
89
89
89
90
RESULTS AND DISCUSSION
R = CN
R = CF3
R = OMe
2d
2e
2f
e
4e
4f
46
68
91
75
5
Reaction scope. We first applied this general strategy to the
catalytic enantioselective alkene oxyazidation reaction (R1 =
N3) that would give rise to chiral azidolactones.7,8 This trans-
formation would yield a straightforward yet rarely explored
approach to enantiomerically enriched 1,2-aminoalcohol de-
rivatives, which are useful synthetic building blocks and are
found in many biologically relevant compounds.9 To evaluate
the proposed transformation, a combination of two simple
commercially available reagents, (diacetoxyiodo)benzene as
the oxidant and trimethylsilyl azide as the azidyl radical pre-
cursor (eq. 1) is used to react with 4-phenyl-4-pentenoic acid
(2a).10 It was found that, in the presence of a catalytic amount
of Cu(MeCN)4PF6 and (S,S)-tBuBox (L), the desired oxyazida-
tion product 4a could be obtained in 63% yield and 89% ee
(Table 1, entry 1). The use of preformed azido-iodine(III) rea-
gents did not yield detectable amount of desired product.11
6
S
O
S
d
O
O
69
82
7
HO
N3
2g
2h
4g
O
Ac
e
O
53
62
68
50
44
90
89
92
72
8
O
HO
Ac
N3
4h
Ph
O
Ph
O
O
9
N3
OH
2i
4i
Cu(II)
Cu(I)
Ph
O
O
O
Ph
Me Me
AcO−
+
(1)
+
N3
+
PhI +
TMSOAc
PhI(OAc)2
TMSN3
10
N3
HO
Me Me
2j
2k
2l
4j
We next explored the scope of this transformation and repre-
sentative examples are summarized in Table 1. A series of
unsaturated carboxylic acids bearing different aryl substituents
on the alkene were found to undergo the desired oxyazidation
reaction to afford the corresponding azidolactones in good
enantioselectivity (4a-j). Electron-neutral and -deficient aryl
substituents were well tolerated (4a-e), while slightly lower
enantioselectivity was observed with substrates containing a
very electron-rich p-methoxyphenyl substituent (4f). The mild
reaction conditions were compatible with a range of functional
groups including aryl halides (4b, 4c), nitriles (4d), ketones
(4h), and 3-thiophenyl groups (4g). In addition, both γ- and δ-
lactones (4i, 4j) proved accessible under the standard reaction
conditions. The incorporation of a geminal dimethyl group in
the substrate showed little effect on the enantioselectivity ob-
tained.
Ph
O
Ph
e
O
11
O
HO
N3
4k
TMS
O
TMS
e,f
O
82
12
O
HO
N3
4l
aReaction conditions: Cu(MeCN)4PF6 (5 mol%), L (5 mol%), 2
(0.50 mmol, 1.0 equiv), PhI(OAc)2 (2.5 equiv), TMSN3 (2.4
equiv), in 30 mL Et2O at -10 °C for 16 h. bYields of isolated
c
products are an average of two runs. Determined by HPLC anal-
ysis using a chiral stationary phase. dAdditional 2,6-di-tert-
e
butylpyridine (1.1 equiv) was added. Cu(MeCN)4PF6 (8 mol%)
f
and L (8 mol%) was used. The enantiomeric excess was deter-
mined by HPLC analysis of the derivatized product, see the sup-
porting information.
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It was found that, regardless of the alkene geometry of the
1
2
3
4
5
6
7
8
substrate (E or Z), the same product diastereomeric ratio
(4m:4n = 10:1) and same enantiomeric excess for each dia-
stereomer were obtained (4m: 11 and 12% ee, 4n: 93 and 93%
ee). This observation was consistent with the radical addition
type mechanism proposed in Scheme 2.6a,13
We next sought to apply this protocol to substrates without a
styrenyl unit (2k and 2l). Substrates containing a 1,3-enyne
structure are especially interesting because further transfor-
mation of the alkyne group in the product would give access to
a more diverse class of structures. It was found that the ox-
yazidation of these substrates proceeded smoothly to furnish
the enantiomerically enriched lactone product in moderate
yields and moderate to good enantiomeric excesses (4k, 4l).
Notably, a silyl protecting group on the alkyne was tolerated
which allows for further elaboration of the product (4l).12
With these results in hand, the copper-catalyzed enantioselec-
tive oxysulfonylation involving the addition of a sulfonyl radi-
cal was next examined.14 This transformation would furnish
enantiomerically enriched β-hydroxyl sulfone derivatives,
which are found in many biologically relevant molecules.15
Compounds containing this structure are also frequently used
as intermediates in the synthesis of a variety of natural prod-
9
10
11
12
13
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The azide group in the lactone product can be easily converted
to a number of useful nitrogen-containing functional groups in
good yields (Scheme 3). For example, palladium-catalyzed
hydrogenation of lactone 4a in methanol afforded chiral ter-
tiary alcohol-containing δ-lactam 5 via an azide reduc-
tion/translactamization cascade. Conversely, hydrogenation of
4a in the presence of di-tert-butyl dicarbonate furnished the
Boc-protected aminolactone 6. The azide group could also
undergo [3+2] cycloaddition with phenylacetylene to give a
triazole derivative 7. No erosion of enantiomeric excess was
observed in any of these cases.
ucts.16 Traditional means of preparation of chiral β-
hydroxysulfones typically involves the asymmetric reduction
17
of β-ketosulfones,
which does not provide access to β-
sulfonyl tertiary alcohol derivatives. We hypothesized that
these could be accessed via our enantioselective oxyfunction-
alization strategy in combination with the generation of a sul-
fonyl radical from arylsulfonyl chlorides (eq. 2).18
Cu(II)
Cu(I)
O
O
Cl−
(2)
+
ArSO2Cl
S
Scheme 3. Derivatization of the oxyazidation product 4a.a
Ar
Ph
O
O
To test this hypothesis, we studied the reaction of 2a with to-
syl chloride (10a) in the presence of Cu(I) catalyst and L (Ta-
ble 2). Our initial attempt, carried out in ethyl acetate provided
the oxysulfonylation product 8a in 12% yield and 28% ee (en-
try 1). It was found that the yield of 8a could be improved by
the addition of a base to neutralize the HCl generated during
the reaction (entry 2). We reasoned that the enantioselectivity
might be adversely affected by the chloride ion generated from
the reduction of tosyl chloride. Based on this hypothesis, the
reaction was carried out in the presence of silver acetate as
both an acid and a chloride scavenger, and a significant in-
crease in yield and enantioselectivity was observed (entry 3).
After evaluation of a series of silver salts, the use of silver
carbonate was determined to provide the optimal results, lead-
ing to an excellent yield of the desired product with over 70%
ee (entry 4). The use of methyl tert-butyl ether or ethyl ether
as the solvent was found to provide inferior results compared
to when ethyl acetate was utilized with regard to both the yield
and enantioselectivity (entry 5 and 6).
b
c
NHBoc
6
Ph
N3
89% ee
O
a
Ph
O
O
HO
N
N
NH
Ph
Ph
O
5
4a
89% ee
N
O
89% ee
7
89% ee
aReaction conditions: (a) Pd/C, H2 (balloon), MeOH, RT; then
DMAP (10 mol%), RT, 78%; (b) Pd/C, H2 (balloon), Boc2O, THF,
RT, 88%; (c) Sodium ascorbate (0.8 equiv), CuSO4Ÿ5H2O (0.4
equiv), phenylacetylene (1.1 equiv), tBuOH/H2O, RT, 96%.
Scheme 4. Cu-Catalyzed oxyazidation of trisubstituted
alkenes.a
O
O
Me
Me
Ph
O
O
O
O
+
N3
Me
N3
Me
Ph
OH
80%
OH
60%
Ph
Ph
4n
Table 2. Selected optimizations for the Cu-catalyzed enan-
tioselective alkene oxysulfonylation.a
(E)-2m
E:Z > 20:1
(Z)-2m
Z:E = 14:1
4m
4m
4n
ratio of stereoisomers
substrate
d.r.b
Me
ee [%]b ee [%]b
4m : ent-4m : 4n : ent-4n
10% Cu(MeCN)4PF6
10% L
O
Ph
Me
O
10 : 1
10 : 1
12
11
93
93
51.1 : 40.0 : 8.6 : 0.3
50.6 : 40.3 : 8.8 : 0.3
(E)-2m
(Z)-2m
+
O
HO
S
additive, solvent
RT, 16 h
Ph
O
O
SO2Cl
2a
10a
8a
aReaction conditions: Cu(MeCN)4PF6 (10 mol%),
L
(10
Yield
[%][b]
ee
mol%), 2m (0.10 mmol, 1.0 equiv), PhI(OAc)2 (2.5 equiv),
TMSN3 (2.4 equiv), in 6 mL Et2O at -10 °C for 16 h. bDetermined
by HPLC analysis using a chiral stationary phase.
Entry
Base
Solvent
[%][c]
28
-
1
2
3
4
5
6
EtOAc
EtOAc
EtOAc
EtOAc
MTBE
Et2O
12
37
62
95
31
48
NaOAc (1.1 equiv)
AgOAc (1.1 equiv)
Ag2CO3 (0.55 equiv)
Ag2CO3 (0.55 equiv)
Ag2CO3 (0.55 equiv)
18
74
To provide further evidence for our mechanistic hypothesis,
oxyazidation reactions with trisubstituted alkene substrates
were examined. As shown in Scheme 4, both geometric iso-
mers of 5-phenyl-5-heptenoic acid ((E)-and (Z)-2m) were
synthesized and subjected to the standard reaction conditions.
74
66
38
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1
2
3
4
5
6
Scheme 6. Examples of the Cu-catalyzed enantioselective
oxyarylation.a
aReaction conditions: Cu(MeCN)4PF6 (10 mol%),
L (10
mol%), 2a (0.10 mmol, 1.0 equiv), tosyl chloride (1.1 equiv), base
(x equiv), in 2 mL solvent at RT for 16 h. bThe yields were deter-
12% Cu(MeCN)4PF6, 10% L
2.0 equiv DTBP
1
O
mined by H NMR spectroscopic analysis using a internal stand-
R
O
O
ard. cThe enantiomeric excesses were determined by HPLC analy-
sis using a chiral stationary phase.
+
Ar
N N BF4
HO
n
EtOAc, RT
Ar
n
R
2
11
9
7
CN
8
Cl
CF3
9
Ph
Representative examples of the enantioselective oxysulfonyla-
tion process are shown in Scheme 5. In general, this method
delivers enantiomerically enriched sulfonyl-substituted lac-
tones in good to high yields and good enantioselectivity. The
readily availability of arylsulfonyl chlorides allows quick ac-
cess to chiral building blocks containing a diverse array of
arylsulfonyl groups using this method.
O
O
CF3
O
O
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
CO2Et
CN
CN
9d
9a
9b
77% yield, 71% ee
9c
74% yield, 73% ee
53% yield, 76% ee
84% yield, 56% ee
aReaction conditions: Cu(MeCN)4PF6 (12 mol%),
L
(10
Scheme 5. Examples of the Cu-catalyzed enantioselective
oxysulfonylation.a
mol%), 2 (0.50 mmol, 1.0 equiv), aryl diazonium tetrafluorobo-
rate (2.0 equiv), 2,6-di-tBupyridine (2.0 equiv), in 8 mL ethyl
acetate at RT for 16 h. Yields are of isolated products (average of
two runs). The enantiomeric excesses were determined by HPLC
analysis using a chiral stationary phase.
Cl
Me
O
Ph
Me
Br
CF3
O
O
O
O
O
O
S
S
S
In addition to nitrogen-, sulfur- and carbon-centered radicals,
we also wanted to explore the use of oxygen-centered radicals
in a Cu-catalyzed enantioselective oxyfunctionalization reac-
tion. Peroxides are readily available precursors for the genera-
tion of oxygen-centered radicals. However the reduction of
peroxides by Cu(I) tends to be so rapid that a relatively high
concentration of radical species is quickly built up. This leads
to significant amount of unproductive radical-radical termina-
tion processes as a termination event, leaving the copper cata-
lyst in the Cu(II) oxidation state and resulting in a low conver-
sion of the alkene. We therefore sought to use a mild reducing
agent to expedite the reduction of the Cu(II) species back to
Cu(I). As shown in Scheme 7, good conversion was achieved
when 2c was treated with dibenzoyl peroxide (12) in the pres-
ence of the chiral catalyst and manganese(0). Two lactone
products were formed in this process: the diacyloxylation
product 13 (29% yield, 65% ee) from benzoyloxyl radical
addition and the oxyarylation product 14 (40% yield, 66% ee)
from the addition of a phenyl radical presumably derived from
the decarboxylation of the original benzoyloxyl radical. The
rate constants of the addition of aroyloxyl radicals to styrenes
typically lie in the range between 107 to 108 M-1s-1, while the
ones for the decarboxylation processes have been determined
to be ca. 106 s-1.22 Therefore comparable rates for the two
competing pathways are expected at the concentration of sub-
strate (~ 0.05 M), consistent with the product distribution ob-
served.
O
O
O
O
O
O
8a
92% yield, 74% ee
8b
95% yield, 77% ee
8c
68% yield, 80% ee
aReaction conditions: Cu(MeCN)4PF6 (10 mol%),
L
(10
mol%), 2 (0.50 mmol, 1.0 equiv), arylsulfonyl chloride (1.1
equiv), silver carbonate (0.60 equiv), in 8 mL ethyl acetate at RT
for 16 h. Yields are of isolated products (average of two runs).
The enantiomeric excesses were determined by HPLC analysis
using a chiral stationary phase.
Next, we sought to expand the scope of this method further to
include not only C−heteroatom but also C−C bond formation,
such as C−aromatic carbon bond formation. Transition metal-
catalyzed processes to effect this transformation have been the
subject of intense study, due to their potential applications in
synthetic chemistry.19 To date, however, limited success has
been achieved on the development of an enantioselective ver-
sion of this type of transformation.20 We felt that the merger of
our copper-catalyzed strategy and the classic Meerwein aryla-
tion conditions using aryl diazonium salts (eq. 3) would be a
viable means to develop an enantioselective process.21,19d,19e
Cu(II)
Cu(I)
-
−
+
ArN2+BF4
Ar
+
N2
BF4
(3)
It was found that in the presence of the copper chiral catalyst
and 2,6-di-tBupyridine (DTBP) as an acid scavenger, a series
of unsaturated carboxylic acids bearing electron-neutral and -
deficient aryl groups reacted with aryl diazonium salts to fur-
nish the desired oxyarylation products in good yields with
moderate to good enantioselectivity (Scheme 6, 9a-9d). A
number of common functional groups were found to be com-
patible with the reaction conditions, such as an aryl chloride
(9a), an ethyl benzoate (9b) and a nitrile group (9c). In addi-
tion, a δ-unsaturated carboxylic acid afforded the correspond-
ing aryl-substituted δ-lactone in good yield, albeit with a lower
ee (9d).
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Scheme 9. Hammett plot of oxytrifluoromethylation reac-
Scheme 7. Cu-Catalyzed radical diacyloxylation and de-
1
carboxylative oxyalkylation.
tion.
2
3
4
5
6
7
O
previous reported oxytrifluoromethylation (ref. 6a):
Cl
Cl
O
Ph
Ph
O
O
7.5% Cu(MeCN)4PF6
Ar
O
O
7.5% L
Cl
12
(1.5 equiv)
O
n
O
O
+
O
O
HO
CF3
O
O
n
+
I
MTBE, RT
O
O
HO
O
Ph
Ar
Ph
CF3
10% Cu(MeCN)4PF6, 10% L
Mn (2.0 equiv)
2
16
17
2c
13
14
40% yield, 66% ee
EtOAc, RT
44−88% yield
74−83% ee
n = 1, 2
1.0 equiv
29% yield, 65% ee
8
9
(a) Independent reactions
CO2
Cu(I)
Cu(II)
R
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
10% Cu(MeCN)4PF6
R
O
O
10% L
(BzO)2
Ph
OMe
H
Cl
+
O
O
O
Ph
O
~ 106 s-1
HO
I
DCM, RT
CF3
BzO
CF3
CN
~ 107−108 M-1s-1
~ 107−108 M-1s-1
2
16
1.0 equiv
17
1.0 equiv
addition to 2c
addition to 2c
(b) Competition reactions
R/H
16 (0.1 equiv)
R
10% Cu(MeCN)4PF6
R
O
O
The decarboxylation of an alkyl carbonyloxyl radical to gener-
ate the corresponding alkyl radical is much more rapid than
that of its aryl analogues (k ~ 109 s-1), which provides a viable
method to generate alkyl radicals under conditions that are
compatible with our method.23 As such, we found that a me-
thyl radical could be generated from PhI(OAc)2 and utilized in
the copper-catalyzed enantioselective oxyfunctionalization
reaction. As shown in Scheme 8, the reaction of 2c and
PhI(OAc)2 produced oxymethylation product 15 in 20% yield
and 60% ee. No acetoxyl radical addition product was ob-
served as expected. The low yield obtained might be attributa-
ble to the sluggish addition of the methyl radical (k ~ 105 M-1s-
1) to 2c.24
10% L
O
OMe
Cl
CN
O
+
HO
HO
DCM, RT, 1 min
CF3
2
2a
17/17a
0.5 equiv
0.5 equiv
0.3"
0.2"
0.1"
0"
(a)
OMe
H
y"="$0.48x"$"0.03"
R²"="0.99"
Cl
$0.1"
$0.2"
$0.3"
$0.4"
CN
Scheme 8. Cu-Catalyzed radical oxyalkylation.
$0.5"
$0.4"
$0.2"
0"
0.2"
σ"
0.4"
0.6"
0.8"
Cl
0.3"
0.2"
0.1"
0"
Cl
PhI(OAc)2 (2.0 equiv)
O
OMe
(b)
O
O
HO
Me
20% Cu(MeCN)4PF6, 20% L
KF (0.5 equiv)
MTBE, RT
15
2c
20% yield, 60% ee
H
y"="$0.53x"+"0.05"
R²"="0.97"
Cl
$0.1"
$0.2"
$0.3"
$0.4"
CO2
Cu(I)
Cu(II)
CN
O
PhI(OAc)2
Me
~ 109 s-1
Me
O
+
PhI
AcO
~ 105 M-1s-1
$0.5"
$0.4"
$0.2"
0"
0.2"
0.4"
0.6"
0.8"
addition to 2c
addition to 2c
σ"
Mechanistic considerations. To gain further mechanistic
insight into these copper-catalyzed enantioselective radical
oxyfunctionalization reactions, the oxytrifluoromethylation
reaction of 2 was selected as a model system for study. A
Hammett study was performed to probe the electronic effects
of the substrate alkene on the reaction rate (Scheme 9). Rela-
tive reaction rate measurements by independent reactions
(Scheme 9a) and one-pot competition experiments (Scheme
9b) yielded similar small negative ρ values (-0.48 and -0.53
respectively). This indicated a small partial positive charge
develops in the transition state of the turnover-limiting step, a
feature that is consistent with the polar effect expected for the
addition of an electrophilic CF3 radical onto the alkene.25
The relationship of the relative stoichiometry of ligand and
metal on reaction rate was also investigated. Conversion to
product at 1.5 and 3 min was determined using a fixed quanti-
ty of Cu(MeCN)4PF6 (10 mol%) while the amount of L was
varied. As shown in Figure 1, when [L]/[Cu] < 1, higher [L]
increased the initial reaction rate, in contrast higher [L] result-
ed in reaction inhibition when [L]/[Cu] ≥ 1. On the basis of
these results, we deduced that active catalyst incorporates only
one L, while the 2:1 complex [CuL2]x+ is an off-cycle spe-
cies.26 In addition, we noted that although greater initial rates
were obtained with [L]/[Cu] < 1, these reactions stopped at
low conversion of the substrate. In contrast, more persistent
turnovers were observed in the cases where [L]/[Cu] ≥ 1. This
suggests that the [CuL]x+ species is somewhat unstable; the
use of excess ligand helps ameliorate this.27 Thus, there is a
balance between stability and reactivity.
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Page 6 of 10
ate 20 would react with 16 to afford a Cu(II) carboxylate com-
Figure 1. Effect of ligand stoichiometry on reaction rate.a
1
2
3
4
5
6
7
8
plex 21 as well as a CF3 radical. The turnover-limiting step
likely involves the irreversible addition of the CF3 radical onto
the alkene, which generates the tertiary radical 22. Since it was
found that the enantioselectivity is insensitive to the structural
change in the backbone of the reagent 16, and no C−O bond
formation product derived from 2-iodobenzoate was detected
in any of the cases investigated, we postulate that tricoordinate
complex 23 is ultimately formed from the reaction between 21
and 22. Complex 23 undergoes the enantioselective C−O bond
forming step to furnish the oxytrifluoromethylation product 17
and regenerate the Cu(I) catalyst. Although ŸR1 and X− differ
in these cases (see Scheme 2), we anticipate that the related
oxyazidation, oxysulfonylation, oxyarylation, diacyloxylation
and oxyalkylation reactions proceed via similar mechanisms.
Cl
O
5% Cu(MeCN)4PF6
x% L
Cl
O
+
O
O
O
HO
I
DCM, RT
CF3
CF3
2c
16
1.0 equiv
17c
1.0 equiv
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The nature of the enantiodetermining C−O bond forming step
is intriguing but hard to probe experimentally because it likely
proceeds through unobservable transient intermediates. How-
ever, the classic asymmetric Kharasch oxidation reaction via
allylic radical intermediates derived from cyclic alkenes cata-
lyzed by Cu-chiral bisoxazoline complexes has been well doc-
umented in the literature, where a pericyclic rearrangement
from a distorted square planar allyl-Cu(III) carboxylate inter-
mediate has been proposed to account for the C−O bond for-
mation.28 Although such pericyclic rearrangement pathway is
not viable for the tertiary alkyl radicals involved in this study,
it is nevertheless reasonable to consider an addition/reductive
elimination pathway via a Cu(III) intermediate based on these
precedents.28b,29,30
aReaction conditions: Cu(MeCN)4PF6 (10 mol%), L (x mol%),
2c (0.10 mmol, 1.0 equiv), 16 (1.0 equiv), in 1.2 mL CH2Cl2 at
RT. Yields are determined by 19F NMR spectroscopy.
A possible catalytic cycle that is consistent with all the mech-
anistic data we have accorded is depicted in Scheme 10. An
equilibrium likely exists between the mono-ligated complex
[CuL]+ (20) and bis-ligated complex [CuL2]+ (19). Intermedi-
Scheme 10. Proposed catalytic cycle for the enantioselective oxytrifluoromethylation reaction.
L2CuI
O
19
R
O
O
I
O
L
- L
CF3
CF3
16
O
R
17
LCuI
HO
2
20
CF3
O
I
CF3
LCuII
O
O
O
R
LCuII
23
21
CF3
O
O
R
HO
HO
22
I
18
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Journal of the American Chemical Society
torted square planar geometry is likely adopted by the copper
Scheme 11. Possible pathways for the enantioselective C−O
1
2
3
4
5
6
7
8
bond forming process.
complex. The SOMO interacting with the copper atom is like-
ly close to perpendicular to the benzene plane due to the stabi-
lization offered by delocalization. In general, these two transi-
tion states are energetically differentiated by the orientations
of the aryl and alkyl groups. The transition state in which the
aryl group occupies the pseudo-equatorial position (leading to
II) should be favored on steric grounds and is consistent with
the observed sense on enantioinduction.31
R1
O
O
LCuII
24
(a)
enantiodetermining addition to Cu(II)
This model can be used to qualitatively explain the significant-
ly lower reactivity and enantioselectivity obtained by the use
of copper halides as precatalysts instead of the cationic salt
Cu(MeCN)4PF6. The halide group is likely to occupy a coor-
dination site at the copper atom throughout the entire catalytic
cycle. The relatively small size of a halide group as opposed to
a carboxylate ligand would still allow the combination be-
tween the tetracoordinated Cu(II) center and the tertiary alkyl
radical to occur without prior ligand dissociation. However,
this additional ligand would slow down the process due to the
added steric hindrance, and more importantly, change the ge-
ometry of the transition state dramatically as the radical might
be forced to approach the copper atom from the direction of z-
axis. This is also in line with the increased yield and enanti-
oselectivity observed in the oxysulfonylation reaction with
Ag(I) salts as additives, where copper(II)-chloride complex is
formed in situ by the reaction with arylsulfonyl chlorides (Ta-
ble 2).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
LCuIII
LCuIII
R1
III
R1
II
fast reductive
elimination
with retention
of configuration
(b)
(b)
R1
O
O
O
O
R1
major enantiomer
minor enantiomer
Conclusion. We have developed a general and versatile
method for the catalytic enantioselective oxyfunctionalization
of alkenes based on a Cu-mediated enantioselective C−O bond
forming process of prochiral alkyl radical intermediates. A
wide range of radicals were found to participate this type of
reaction, including azidyl, arylsulfonyl, aryl, acyloxyl and
alkyl radicals. This method provides rapid access to a broad
spectrum of interesting enantiomerically enriched lactones
through tandem C−N/C−O, C−S/C−O, C−Caryl/alkyl/C−O or
C−O/C−O bond formation, in good yields and useful enantio-
meric excesses in most instances with good functional group
compatibility. Kinetic data are consistent with the radical addi-
tion of alkene being the turnover-limiting step. A model for
the transition state of the enantiodetermining step is proposed
based on a hypothesis involving an alkyl radical-Cu(II) com-
bination and subsequent reductive elimination.
H
R1
H
Me
Me
Me
Me
Me
O
O
H
N
N
Cu
O
Me
Me
Me
H
O
favored TS, leads to II
H
Me
Me
Me
Me
H
O
O
Me
ASSOCIATED CONTENT
H
N
N
Cu
R1
O
Supporting Information. Experimental procedures, characteriza-
tion and spectra data. This material is available free of charge via
the Internet at http://pubs.acs.org.
Me
Me
Me
H
O
AUTHOR INFORMATION
disfavored TS, leads to III
Corresponding Author
As shown in Scheme 11, we propose that the enantiodetermin-
ing C−O bond formation from tricoordinate Cu(II) carboxylate
complex 24 might occur through 1) Cu−C bond formation
between Cu(II) center and the prochiral alkyl radical, and 2)
C−O bond forming reductive elimination of the resulting
Cu(III) complex. Since the reductive elimination from Cu(III)
center is generally considered to be a rapid process, it is likely
that the radical addition to Cu(II) is the enantiodetermining
step, through which two diastereomeric Cu(III) complexes II
and III are produced and undergo reductive elimination with
retention of the configurations.28b Possible transition states for
the Cu−C bond form leading to II and III are depicted. A dis-
* sbuchwal@mit.edu
ACKNOWLEDGMENT
We thank the National Institutes of Health for financial support of
this work (Grant GM58160). R. Z. thanks the Wellington and
Irene Loh fund for a fellowship. The content is solely the respon-
sibility of the authors and does not necessarily represent the offi-
cial views of the National Institutes of Health. We thank Dr. Aa-
ron. C. Sather, Dr. Yiming Wang and Yang Yang for help with
the preparation of the manuscript.
7
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Page 8 of 10
Wang, R. Org. Lett. 2014, 16, 1562; (d) Yin, H.; Wang, T.; Jiao, N.
Org. Lett. 2014, 16, 2302; (e) Trahanovsky, W. S.; Robbins, M. D. J.
Am. Chem. Soc. 1971, 93, 5256; aminoazidation: (f) Sequeira, F. C.
Turnpenny, B. W.; Chemler, S. R. Angew. Chem. Int. Ed. 2010, 49,
6365; (g) Zhang, B.; Studer, A. Org. Lett. 2014, 16, 1790;
carboazidation: (h) Panchaud, P.; Renaud, P. J. Org. Chem. 2004, 69,
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2014, 53, 5078; (j) hydroazidation: Waser, J.; Nambu, H.; Carreira, E.
M. J. Am. Chem. Soc. 2005, 127, 8294.
1
2
3
4
5
6
7
8
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Journal of the American Chemical Society
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(30) For iron- and copper-catalyzed enantioselective diamina-
tion/oxyamination reactions that possibly involve similar radical in-
termediates: (a) Williamson, K. S.; Yoon, T. P. J. Am. Chem. Soc.
2012, 134, 12370; (b) Lu, D.-F.; Zhu, C.-L.; Jia, Z.-X.; Xu, H. J. Am.
Chem. Soc. 2014, 136, 13186; (c) Zhao, B.; Du, H.; Shi, Y. J. Org.
Chem. 2009, 74, 8392; For selected examples of transition metal-
catalyzed enantioselective functionalization via alkyl radicals derived
from processes other than the radical addition of alkenes: (d)
Zultanski, S.; Fu, G. C. J. Am. Chem. Soc. 2011, 133, 15362; (e)
Hamachi, K.; Irie, R, Katsuki, T. Tetrahedron Lett. 1996, 37, 4979;
(f) Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O. J. Am. Chem.
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Güler, M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
948
(31) (a) Radical capture at oxygen atom has been proposed as an
alternative mechanism for the C−O bond formation: Gephart, R. T.;
McMullin, C. L.; Sapiezynski, N. G.; Jang, E. S.; Aguila, M. J. B.;
Cundari, T. R.; Warren, T. H. J. Am. Chem. Soc. 2012, 134, 17350;
(b) The involvement of a tertiary carbocation intermediate cannot be
excluded, although a fully developed benzylic carbocation is unlikely
based on the Hammett plot results.
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(27) The rate dependence on the total copper catalyst concentration
is unclear as the result of the incomplete dissolvation of the
Cu(MeCN)4PF6 precatalyst.
(28) Representative contributions: (a) Gokhale, A. S.; Minidis, A.
B. E.; Pfaltz, A. Tetrahedron Lett. 1995, 36, 1831; (b) Andrus, M. B.;
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scope of R1
R
O
1
HO
O
O
R1
O
n
Ar
N3
S
O
2
3
4
R1
n
[CuL*]
Ar
R
Alkyl
RCO2
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