Catalytic asymmetric carbon-carbon bond formation using alkenes as alkylmetal equivalents

Article abstract of DOI:10.1038/nchem.1394

Catalytic asymmetric conjugate addition reactions with organometallic reagents are powerful reactions in synthetic chemistry. Procedures that use non-stabilized carbanions have been developed extensively, but these suffer from a number of limitations that prevent their use in many situations. Here, we report that alkylmetal species generated in situ from alkenes can be used in highly enantioselective 1,4-addition initiated by a copper catalyst. Using alkenes as starting materials is desirable because they are readily available and have favourable properties when compared to pre-made organometallics. High levels of enantioselectivity are observed at room temperature in a range of solvents, and the reaction tolerates functional groups that are not compatible with comparable methods-a necessary prerequisite for efficient and protecting-group-free strategies for synthesis.

Full text of DOI:10.1038/nchem.1394

ARTICLES
PUBLISHED ONLINE: 15 JULY 2012 | DOI: 10.1038/NCHEM.1394
Catalytic asymmetric carbon–carbon bond
formation using alkenes as alkylmetal equivalents
Rebecca M. Maksymowicz, Philippe M. C. Roth and Stephen P. Fletcher
*
Catalytic asymmetric conjugate addition reactions with organometallic reagents are powerful reactions in synthetic
chemistry. Procedures that use non-stabilized carbanions have been developed extensively, but these suffer from a number
of limitations that prevent their use in many situations. Here, we report that alkylmetal species generated in situ from
alkenes can be used in highly enantioselective 1,4-addition initiated by a copper catalyst. Using alkenes as starting
materials is desirable because they are readily available and have favourable properties when compared to pre-made
organometallics. High levels of enantioselectivity are observed at room temperature in a range of solvents, and the
reaction tolerates functional groups that are not compatible with comparable methods—a necessary prerequisite for
efficient and protecting-group-free strategies for synthesis.
he conjugate addition of carbon nucleophiles to a,b-unsatu- would be strategically important because they would accomplish
rated carbonyl compounds is one of the most powerful tools transformations that are not currently possible. As well as offering
T
for C–C bond formation and is frequently used as a key step new synthetic strategies, it was anticipated that, by replacing pre-
in syntheses1–3. Copper-catalysed asymmetric 1,4-addition of orga- made organometallic reagents, the procedures might overcome
nometallic reagents has been viewed as an important solution to the some of the limitations of current methods (Fig. 1).
problem of asymmetric C–C bond formation for over twenty years4–7
.
Grignard reagents, dialkylzincs and alkylaluminiums are gener-
Tremendous advances in the catalytic enantioselective addition of ally formed (Fig. 1b) from the corresponding halide, which is
unstabilized organometallic nucleophiles such as Grignard either reacted directly with a metal in an oxidative process or is
reagents8–11
, ,
dialkylzincs12–14 alkyl aluminiums15–17 and alkyl involved in a transmetallation reaction with a stoichiometric
lithiums18 have recently been achieved.
amount of a different pre-formed organometallic reagent23–25. The
In these reactions, the use of Grignard reagents is considered par- oxidative processes are limited in their functional group compatibil-
ticularly attractive because they are readily available, easy to handle ity, and transmetallation procedures contribute to excessive waste
and are able to transfer all of the alkyl groups of the organometallic generation. As noted by Krische, many of these processes actually
compound6,7. Furthermore, very useful complementary reactivity
with alkyl aluminium and dialkyzinc reagents4,7 is observed.
Procedures involving the addition of a pre-made organometallic
are inherently limited by the availability and reactivity profiles of
the reagent itself. As previously noted, sensitivity to solvent, temp-
erature, concentration, method of addition and the presence of addi-
tives is the rule, rather than the exception, in copper-catalysed
Grignard reagent addition6, and this can limit the options available
in reaction design. In the synthesis of complex molecules, functional
groups are often present that are incompatible with organometallic
reagents, and the sensitivity of many asymmetric procedures to reac-
tion conditions can make even the use of protecting group strategies
ineffective19. The reactivity of organometallic reagents presents chal-
lenges in the use of functionalized reagents6,20, and is associated with
safety issues that can restrict implementation in industrial pro-
cesses21. Perhaps most importantly, the asymmetric addition of
these reagents often requires the use of cryogenic temperatures to
obtain high levels of selectivity. This is difficult in industry and is
a limitation of these methods21. A principle of green chemistry is
that synthetic methods should be conducted at ambient tempera-
ture22, and the need to develop new methods for copper-catalysed
conjugate addition reactions that are effective at room temperature
is well recognized7.
a
R
R
MgX
R
Zn
R
R
Al
R
Alkene
Dialkyl zinc
Grignard
R
Trialkyl
aluminium
b
Oxidative addition
Metal
R
X
R
M
M
X = Cl, Br, I
or
Transmetallation
R1–M
R
X
R
X = Cl, Br, I, B or metal
c
Hydro-
metallation
R1
Catalyst
H
R'
E
E
R
R
ACA
M
R1
H–M
Figure 1 | Comparing alkenes and the organometallics typically used in
catalytic asymmetric addition reactions. a, Structure of alkenes, dialkyl
zincs, Grignard reagents and trialkyl aluminiums. Alkenes are more readily
available and less reactive than organometallic reagents. b, Typical
preparation of alkylmetal reagents for use in asymmetric conjugate addition
reactions. c, Generating an organometallic reagent from an alkene by
reductive hydrometallation. Here we show that this approach allows alkenes
Results and discussion
We decided to evaluate the use of alkenes as alkylmetal equivalents to be used as alkylmetal equivalents in asymmetric catalysis (E ¼ electron-
in catalytic asymmetric conjugate addition (ACA). These reactions withdrawing group).
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
e-mail: stephen.fletcher@chem.ox.ac.uk
*
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649

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1394
ARTICLES
research pioneered by Schwartz and extensively developed by
Table 1 | Copper and ligand screen for the HM-ACA reaction.
Wipf and others28,38–45
.
Cp2ZrHCl, CH2Cl2;
O
The key to developing a successful asymmetric procedure is
finding a suitable catalyst system, and our initial experiments
involved examining combinations of copper sources and chiral
non-racemic ligands. Using 4-phenyl-1-butene and cyclohexenone
as HM–ACA coupling partners, we conducted a series of exper-
iments as described in Table 1. We evaluated a variety of copper
salts in combination with the easily accessible and commercially
available ligand A (ref. 46), in CH2Cl2 at room temperature
(Table 1, entries 1–7). Here, the nature of the counterion was
found to have a stunning effect on enantioselectivity and only
strongly electron-deficient copper salts were found to provide asym-
metric induction. The enantioselectivity was improved dramatically,
from racemic in most cases to 80% enantiomeric excess (e.e.), by
using freshly prepared copper(I) triflate benzene complex. When
the HM–ACA was examined with other phosphoramidite ligands
cyclohexenone
1
10 mol% copper
10 mol% ligand
CH2Cl2, r.t.
Ph
O
O
O
O
O
P
N
P
N
P N
O
A
B
C
OMe
O
O
O
O
P
N
P
N
P N
.
and (CuOTf)2 PhH (Table 1, entries 8–12) a striking dependence
O
O
of ligand structure on enantioselectivity was observed: ligands
B–F gave vastly inferior levels of selectivity, despite the appearance
of only subtle structural differences compared to A.
OMe
D
E
F
We were delighted that the above experiments led to reaction
conditions where high levels of enantioselectivity could be observed
at room temperature, and next examined the effect of solvent on the
enantioselectivity of the reaction. For these experiments we chose 1-
hexene and cyclohexenone as asymmetric reductive coupling part-
ners (Table 2). Remarkably, and in contrast to other catalytic asym-
metric addition procedures6,7,11,18, we found the selectivity to be
highly tolerant of the solvent used. The reactions in Table 2 gave
full conversion of the starting material overnight, but the resulting
enolate underwent further reaction with unreacted cyclohexenone
at a rate comparable to 1,4-addition47, which tended to lower the
yields of 2 and made the reactions difficult to reproduce. In four
cases (using CH2Cl2, diglyme, tetrahydrofuran (THF) and 2-Me-
THF as solvent) we attempted to optimize the reaction temperature
to obtain higher levels of selectivity. With CH2Cl2 and diglyme,
room temperature was optimal, but cooling reactions with THF
and 2-Me-THF (to 5 and 10 8C, respectively) increased the
Entry
Copper source
Ligand
e.e.*,†
1
2
3
4
5
CuCl
A
A
A
A
A
A
A
B
Racemic
Racemic
Racemic
Racemic
12%
55%
80%
17%
20%
.
CuBrMe2S
Cu(TC)
CuI
Cu(OTf)2
6
7
[Cu(MeCN)4]PF6
.
(CuOTf)2 PhH
.
8
9
10
11
12
(CuOTf)2 PhH
.
(CuOTf)2 PhH
C
D
E
.
(CuOTf)2 PhH
7%
30%
8%
.
(CuOTf)2 PhH
.
(CuOTf)2 PhH
F
Conditions: alkene (2.5 equiv.), Cp2ZrHCl (2 equiv.), cyclohexenone (1 equiv.), copper (10 mol%),
ligand (10 mol%); room temperature. *Absolute configuration determined by circular dichroism
spectroscopy. †Enantiomeric excess determined by HPLC.
use multiple pre-formed organometallic reagents, giving rise to
super-stoichiometric amounts of by-products and requiring the
use of multiple air- and moisture-sensitive materials26.
Table 2 | Effect of solvent on enantioselectivity.
O
O
The direct use of organometallics generated by the reductive
hydrometallation (Fig. 1c) of alkenes as nucleophiles in enantiose-
lective catalysis would offer many powerful opportunities.
However, to the best of our knowledge, the hydrometallation or
hydroboration of olefins followed by direct asymmetric 1,4-addition
Cp2ZrHCl, CH2Cl2;
.
2
+
5 mol% (CuOTf)2 PhH
10 mol% A, solvent
Entry
Solvent
e.e.*,†
is unknown2,27
, even though hydrometallation of alkynes
1
CH2Cl2
1,2-Dichloroethane
CHCl3
Et2O
t-BuOMe
i-Pr2O
2,2-Dimethoxypropane
THF
89%
75%
80%
85%
84%
84%
86%
80%
92%‡
88%
94%§
89%
75%
75%
83%
75%
50%
followed by transmetallation7,26,28 and direct stoichiometric29,30
and catalytic31 alkyne reduction followed by asymmetric C–C
bond formation has been reported. The ability to use simple and
readily available starting materials in C–C bond formation is
extremely important. In this respect, the work of Krische, who
has developed asymmetric C–C bond-forming reductive
hydrogenation26 and redox-neutral transfer hydrogenation32
reactions with alkynes and other p-bond-containing starting
materials, is especially noteworthy. Alkenes are particularly
desirable as starting materials as they are abundant and commonly
used feedstocks in industrial processes. Methods that convert
alkenes into functionalized compounds are among the most
useful processes known33,34, and the asymmetric oxidation and
hydrogenation of olefins has revolutionized synthesis35.
2
3
4
5
6
7
8
9
2-Me-THF
10
11
12
13
14
15
Diglyme
1,4-Dioxane
Hexane
Toluene
m-Xylene
Bromobenzene
To test the feasibility of a hydrometallation–ACA (HM–ACA)
process with alkenes (Fig. 1c), we chose to examine the readily pre-
pared36 and commercially available Schwartz reagent37.
Hydrometallation with this reagent produces zirconium species
that can undergo C–C bond-forming processes, a fruitful area of
.
Conditions: 1-hexene (2.5 equiv.), Cp2ZrHCl (2.0 equiv.), cyclohexenone (1.0 equiv.), (CuOTf)2 PhH
(5 mol%), ligand A (10 mol%); room temperature unless specified, full conversion overnight.
*Absolute configuration determined by circular dichroism spectroscopy. †Enantiomeric excess
determined by derivatization and 13C NMR spectroscopy, see Supplementary Information.
‡Reaction peformed at 5 8C. §Reaction performed at 10 8C.
650
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1394
ARTICLES
Table 3 | Scope of alkenes.
TfO–
+Cu
O
O
Ph
N
Cp2ZrHCl, CH2Cl2;
Benzene
+ Tf2O Reflux
O
O
A
Cu2O
.
P
(CuOTf)2 PhH
+
R
CH2Cl2
10 mol% G,
Et2O, TMSCl
r.t.
Ph
R'
Yield* e.e.†
G
(air stable complex)
Entry
Substrate
Product
Entry
Substrate
Product
Yield* e.e.†
O
O
3 (n =1)
4 (n =3)
13 (n =1)
14 (n =2)
1 (n ¼ 1)
2 (n ¼ 3)
74% 89%‡,§ 11
65% 89%‡ 12
66%
58%
76%‡,§
76%‡,§
Br
n
Br
n
n
n
O
O
O
O
O
O
5 (n =1)
6 (n =9)
O
O
15
13
54%
49%
80%‡
3 (n ¼ 1)
4 (n ¼ 9)
67% 89%§
n
70% 89%§
n
Si
5ꢁ
65% 84%§ 14
O
94%§
Si
O
7
16
8 (X=CH2)
9 (X=CH)
6 (X ¼ CH2)
7 (X ¼ CH)
74% 93%§
X
17
Cl
15
19%
71%§
60%} 87%§
Cl
X
X
X
O
O
O
O
8#
71%
78%§ 16**
53%
62%
96%§
10
11
18
Si
Si
17ꢁ
72%‡
56% 82%‡
19
9
O
O
62%} 85%§,††
93%} 70%††,‡‡
10
52% 71%‡
Si
Si
12
18
19
O
O
20
Cl
Cl
Conditions: alkene (2.5 equiv.), Cp2ZrHCl (2 equiv.), enone (1 equiv.), G (0.1 equiv.). *Isolated yield. †Absolute configurations known, determined or assigned by analogy (see Supplementary Information). ‡e.e.
determined by HPLC. §e.e. determined by derivatization and 13C NMR spectroscopy. ꢁReaction heated at hydrometallation stage. }Isolated as a 1:1 mixture of diastereomers. #10 equiv. of the alkene was used.
**Reaction performed at 0 8C. ††e.e. determined by removal of the silyl group and HPLC. ‡‡Conditions: alkene (2.0 equiv.), Cp2ZrHCl (1.7 equiv.), G (0.05 equiv.), 1.90 g of product isolated.
enantioselectivity to 92 and 94% e.e., respectively (Table 2, entries 8 as Michael acceptor, with 4-phenyl-1-butene as starting alkene
and 9). The ability to use a wide variety of solvents allows for vari- (Table 3, entry 1). As copper triflate benzene complex is air-sensitive,
ations in conditions and is advantageous for many reasons. we found it convenient to use pre-formed catalyst complex G
Different starting materials, for example, may demonstrate different (Table 3) in these experiments. Complex G can be weighed and
solubility behaviour. The reaction was even found to tolerate handled in air and is stable for at least a month when stored at
bromobenzene as a solvent (Table 2, entry 15).
ambient temperature under an inert gas. No step in the process
We then explored the possibility of evaluating the scope of requires a glovebox and no special procedures (such as a slow
the alkene reagent in the HM–ACA process. It was decided to addition of the reagents49 over time) are necessary. We found that
perform all reactions at room temperature, and we chose and opti- using diethyl ether as a co-solvent and trimethylsilyl chloride
mized conditions for a sterically hindered and challenging48 a,b- (TMSCl)49 as an additive increased the e.e. of 3 by ꢀ5–10%.
unsaturated carbonyl compound—4,4-dimethyl-cyclohexenone— Under these conditions, the reaction shown in Table 3, entry 1,
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1394
ARTICLES
We next examined the HM–ACA procedure with two highly
challenging activated alkenes, allyl chloride and allylsilane, both of
which gave products with high levels of enantiopurity (Table 3,
entries 15 and 16). Although the yield is poor, any tolerance for
allyl chloride in this procedure is surprising as the organometallic
nucleophile is necessarily generated in the presence of unreacted
allyl chloride, an electrophile. Curiously, the major by-product of
the reaction is a material where the chloride in 17 has been replaced
with a hydrogen atom to give the product of simple n-propyl
addition, and no cyclized product is observed. In the case of
electron-rich allylsilane, excellent enantioselectivity was obtained.
The reaction was performed at 0 8C to minimize competitive 1,2-
reduction of the carbonyl, which we speculate arises from retro-
hydrometallation to regenerate Schwartz reagent, which can then
reduce the carbonyl.
Table 4 | Scope of enones.
Entry
Enone
Product
21
Yield* e.e.†
1a
23% 75%‡
O
O
1b§
29% 85%‡
2 R¼Ph
59% 90%‡ꢁ
59% 93%ꢁ
O
O
O
1 (R=Ph)
2 (R=CH2CH3)
3 R¼CH2CH3
R
4
75% 90%‡
O
We were also delighted to observe that a substrate featuring an
internal alkyne (Table 3, entry 17) and an alkene bearing multiple
functional groups (entry 18) could undergo HM–ACA. These
experiments clearly demonstrate that the HM–ACA procedure is
compatible with common functional groups, suggesting that (i)
very high levels of chemoselectivity may be possible when these pro-
cesses are fully developed and (ii) useful tandem reaction sequences
for the rapid synthesis of complex materials may be initiated with
this methodology.
22
O
O
5
6
73% 91%‡
23
To examine the potential for scaling up these reactions21, we per-
formed a single experiment on a preparative scale (Table 3, entry 19)
in which we decided to lower the catalyst loading to 5% and reduce
the amount of alkene and Schwartz reagent used in our normal
screening reactions. On a gram scale, at room temperature, using
5% catalyst complex G, we were able to obtain 1.90 g of product
20 (93%) with only a moderate loss of enantioselectivity (70%
e.e.). Although more work is needed to fully optimize these pro-
cedures, this result suggests that these room-temperature HM–
ACA reactions will be much more amenable to scale than the
ACA reactions that have been reported using pre-made organome-
tallic nucleophiles21.
50% 60%‡,}
O
O
24
Conditions: alkene (2.5 equiv.), Cp2ZrHCl (2 equiv.), enone (1 equiv.), G (0.1 equiv.). *Isolated yield.
†Absolute configurations known, determined or assigned by analogy (see Supplementary
Information). ‡e.e. determined by HPLC. §Reaction performed at 0 8C. ꢁe.e. determined by
derivatization and 13C NMR spectroscopy. }Absolute configuration not determined.
The scope of the reaction with respect to the enone coupling
partner was also briefly examined, using the conditions optimized
above, as shown in Table 4. Cyclopentenone, a notoriously difficult
substrate for catalytic asymmetric 1,4-addition7,13,49, was found to
give only modest yields. Slightly better enantioselectivity was
observed when the reaction was performed at 0 8C (Table 4, entry
1b). Cyclohexenone (entries 2 and 3), 4,4-diphenyl-cyclohexenone
(entry 4) and cycloheptenone (entry 5) are all suitable substrates
without reoptimization of the reaction conditions. In one case
(Table 4, entry 6) we examined a macrocyclic ring bearing a
trans-enone moiety. The results obtained (50% yield, 60% e.e.)
using our standard conditions demonstrate that additional optimi-
zation will be required to achieve high levels of selectivity for this
class of substrates.
proceeds to full conversion in ꢀ2.5 h. With the exception of Table 3,
entries 8 (which required an excess of the alkene to statistically
favour mono-hydrometallation) and 16 (carried out at 0 8C to mini-
mize by-product formation) all further reactions were performed
using these conditions without further optimization.
Examination of a variety of alkenes illustrated that these con-
ditions are remarkably general. High levels of e.e. were observed
with linear alkenes (Table 3, entries 1–4) and sterically hindered
tert-butyl and cyclohexyl substituted olefins (entries 5 and 6). We
were able to access products 9 and 10 containing internal and
terminal alkenes in the HM–ACA sequence (entries 7 and 8). The
method was also successful with styrenyl substrates (entries 9 and
10). The ability to add a naphthyl-containing unit and access pro-
ducts such as 12 may be useful, as this functional group frequently Conclusions
appears in material science and ligand design because of its steric We have demonstrated that alkylmetal species generated in situ
bulk and ability to induce p-stacking interactions.
from alkenes can be used as nucleophiles in highly enantioselective
The presence of an alkyl bromide substituent, a functional group 1,4-addition initiated by a copper-based catalyst. The process is for-
incompatible with the Grignard formation step25, was tolerated in mally an asymmetric reductive coupling of an alkene to an enone.
our method (entries 11 and 12). These products (13 and 14) are The approach of hydrometallating an alkene for use in asymmetric
directly suitable for further synthetic elaboration. The ease of this catalysis has tremendous potential as a strategy in synthesis and can
reaction, using conditions optimized for a different substrate, is in overcome some of the limitations of methods using pre-made orga-
direct contrast to the extensive efforts that have been made to nometallics. It is anticipated that the tolerance of the reaction to
develop useful methods for generating functionalized organometal- solvents, temperature and additives will allow optimization of the
lics. There are still major challenges involved in such procedures, yield and selectivity for many other substrates, and there are
and alkyl-magnesium reagents are particularly problematic6,7,20
.
many additional possibilities in alternative catalysts, ligands and
The presence of benzyl ether and silyl ether groups is also tolerated hydrometallating agents that could also be examined. The robust-
(entries 13 and 14), demonstrating that protected alcohols such as ness, tolerance of functional groups and the ability to use mild
15 and 16 can be obtained in very high enantiopurity.
conditions may allow the future development of more scalable
652
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1394
ARTICLES
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Methods
Preparation of complex G. To a flame-dried Schlenk flask containing
(CuOTf).2(C6H6) (239 mg, 0.48 mmol, 0.5 equiv.), at room temperature under an
argon atmosphere, was added the phosphoramidite ligand (513 mg, 0.95 mmol,
1.0 equiv.) then CH2Cl2 (10 ml). This mixture was stirred for 1 h before
canula-filtering the resulting clear colourless solution into another Schlenk flask.
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nitrogen trapping). The resulting off-white solid was dried for at least one
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(206 mg, 0.80 mmol, 2.0 equiv.) was added to a stirred, room-temperature solution
of alkene (1.0 mmol, 2.5 equiv.) in CH2Cl2 (0.40 ml) under an argon atmosphere.
After stirring for ꢀ40 min, the resulting clear yellow solution was transferred via
syringe over ꢀ1 min to a clear colourless stirred solution of G (30.0 mg, 0.040 mmol,
0.10 equiv.) in Et2O (2.0 ml) under an argon atmosphere. The resulting dark
mixture was allowed to stir for an additional 10 min before cyclic enone (0.40 mmol,
1.0 equiv.) and then TMSCl (0.25 ml, 2.0 mmol, 5.0 equiv.) were added dropwise via
syringe. The reaction was stirred until complete (TLC control; EtOAc/petrol 1:9).
The reaction was quenched by the addition of Et2O (ꢀ3 ml) then NH4Cl (1 M, aq.,
ꢀ1.5 ml). The mixture was partitioned between water and Et2O and the aqueous
phase extracted with Et2O (3 × 10 ml). The combined organic phase was washed
with NaHCO3 (aq. sat., ꢀ10 ml), dried (Na2SO4), filtered and concentrated in vacuo
to give an oil. Flash column chromatography of the residue (EtOAc/petrol; SiO2)
gave the desired cyclic ketone.
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Received 23 March 2012; accepted 28 May 2012;
published online 15 July 2012
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1394
Acknowledgements
The authors acknowledge financial support from the EPSRC (EP/H003711/1, a Career
Acceleration Fellowship to S.P.F.) and the Oxford University Press John Fell Fund.
D. Daniels and B. Odell are thanked for their generous technical assistance with HPLC
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Author contributions
R.M.M. and P.M.C.R. performed the experiments. All authors contributed to designing the
experiments, analysing the data and editing the manuscript. S.P.F. guided the research
and wrote the manuscript.
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phosphine–phosphite ligands in the enantioselective 1,4-addition of Grignard
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The authors declare no competing financial interests. Supplementary information
and chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints. Correspondence and requests for materials should be addressed to S.P.F.
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