Catalytic asymmetric carbong-carbon bond formation via allylic alkylations with organolithium compounds

Article abstract of DOI:10.1038/nchem.1009

Carbon-carbon bond formation is the basis for the biogenesis of nature's essential molecules. Consequently, it lies at the heart of the chemical sciences. Chiral catalysts have been developed for asymmetric C-C bond formation to yield single enantiomers from several organometallic reagents. Remarkably, for extremely reactive organolithium compounds, which are among the most broadly used reagents in chemical synthesis, a general catalytic methodology for enantioselective C-C formation has proven elusive, until now. Here, we report a copper-based chiral catalytic system that allows carbon-carbon bond formation via allylic alkylation with alkyllithium reagents, with extremely high enantioselectivities and able to tolerate several functional groups. We have found that both the solvent used and the structure of the active chiral catalyst are the most critical factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active form of the chiral catalyst has been identified through spectroscopic studies as a diphosphine copper monoalkyl species.

Full text of DOI:10.1038/nchem.1009

ARTICLES
PUBLISHED ONLINE: 13 MARCH 2011 | DOI: 10.1038/NCHEM.1009
Catalytic asymmetric carbon–carbon bond
formation via allylic alkylations with organolithium
compounds
´
´
˜
´
Manuel Perez, Martın Fananas-Mastral, Pieter H. Bos, Alena Rudolph, Syuzanna R. Harutyunyan
*
and Ben L. Feringa
*
Carbon–carbon bond formation is the basis for the biogenesis of nature’s essential molecules. Consequently, it lies at the
heart of the chemical sciences. Chiral catalysts have been developed for asymmetric C–C bond formation to yield single
enantiomers from several organometallic reagents. Remarkably, for extremely reactive organolithium compounds, which
are among the most broadly used reagents in chemical synthesis, a general catalytic methodology for enantioselective C–C
formation has proven elusive, until now. Here, we report a copper-based chiral catalytic system that allows carbon–carbon
bond formation via allylic alkylation with alkyllithium reagents, with extremely high enantioselectivities and able to
tolerate several functional groups. We have found that both the solvent used and the structure of the active chiral catalyst
are the most critical factors in achieving successful asymmetric catalysis with alkyllithium reagents. The active form of the
chiral catalyst has been identified through spectroscopic studies as a diphosphine copper monoalkyl species.
ince their discovery by Wilhelm Schlenk in 1917 (ref. 1), and
In our mechanistically guided investigations on the subtle inter-
his vivid description of their chemical properties, alkyllithium play between catalyst structure and reaction parameters, we discov-
S
reagents have beguiled the chemical community. ered that copper complexes generated in situ from CuBr and chiral
Methyllithium was reported to be extremely reactive, burning in phosphorus-based ligands in dichloromethane allowed us to
air with ‘a brilliant red flame with a shower of golden sparks’2, harness the reactivity of alkyllithium compounds and provide an
and, initially, alkyllithium compounds were not considered efficient and highly selective catalyst for the alkylation of allylic
useful because of their instability. It is remarkable how dramatically halides31 (Fig. 1).
this situation has changed over the intervening decades.
Organolithium reagents have arguably become some of the most Results and discussions
versatile and widely used reagents3,4 in the daily repertoire of chemi- Starting with ferrocenyl-type chiral diphosphines32, which have
cal synthesis, and are indispensable in the preparation of a myriad of been shown previously to be effective with organomagnesium
industrial products from pharmaceuticals to polymers5,6.
reagents17, we found that the enantioselectivity in the reaction
In recent decades, asymmetric catalysis has undergone substantial between cinnamyl bromide 1a and the most common organo-
developments, and a broad range of C–C and C–X bond formations lithium reagent n-BuLi could be increased dramatically by changing
with high enantioselectivities are currently known7–9. In particular, the chiral ligand from (R,Sp)-JosiPhos L1 to reversed (S,Rp)-L2
less reactive organozinc10–12, aluminium13–15 and Grignard16,17 (entries 1–2, Table 1). However, in both cases, the achiral linear
reagents have been shown to be highly effective in asymmetric C–C compound 4 resulting from an SN2 substitution reaction was predo-
bond formation18. In stark contrast, the only glimmer of hope for minantly found. It should be emphasized that at least four compet-
enantioselective reactions with organolithium reagents was in the stoi- ing reaction pathways are possible, including transmetallation of the
chiometric use of chiral ligands5,19,20. Tantalisingly, catalytic asym- halide, formation of the homo-coupled product, SN2 substitution
metric reactions of organolithiums using high catalyst loading with a leading to the achiral linear product 4, and SN2′ substitution, with
specific substrate21, catalytic asymmetric deprotonations22,23 and only the last reaction affording the desired branched chiral
additions to imines have been reported24–28. Despite these great product 3. These problems of chemo- and regioselectivity represent
efforts, a general method for the direct use of alkyllithium reagents additional complicating factors typically associated with the use of
for catalytic and highly enantioselective C–C bond formation, to the
best of our knowledge, has not been developed5,29. Several factors com-
CuBr•SMe2 (5mol%)
plicate the control of stereochemistry in this organometallic-based
transformation and cause unpredictable behaviour; this includes the
high reactivity of organolithium reagents leading to uncatalysed reac-
tions and the presence of the aggregates30 common to organolithium
reagents. Challenged by this long-standing problem of merging highly
enantioselective C–C bond formation and the synthetic power and
R'
Ligand (6mol%)
+
R'Li
R
X
CH2Cl2, –80°C
R
X=Br, Cl
Regio up to 100%
e.e. up to 99%
high reactivity of alkyllithium reagents, we have developed a practical Figure 1 | Catalytic asymmetric allylic alkylation with organolithium
chiral catalytic system for this purpose.
reagents (X 5 bromide or chloride).
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
e-mail: b.l.feringa@rug.nl; s.harutyunyan@rug.nl
*
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377

NATURE CHEMISTRY DOI: 10.1038/NCHEM.1009
ARTICLES
enantioselectivities (Table 2). Using longer alkyl moieties in the
lithium reagent (in these cases 1.2 equiv. diluted with n-hexane)
gave over 98% e.e. without exception (entries 1–4, Table 2).
Importantly, allyl chloride 1b is equally efficient in this transform-
ation when chiral phosphoramidite ligand (S,S,S)-L5 is used (entry
5, Table 2). With this protocol, it is not only primary organolithium
reagents that can be used; secondary ones are well tolerated when
phosphoramidite ligand (S,R,R)-L4 is used in combination with
Table 1 | Screening of chiral ligands for asymmetric allylic
alkylation.
n–Bu
R
R
X
CuBr•SMe2 (5mol%)
Ligand (6mol%)
3
SN2' product
1a, X=Br
1b, X=Cl
+
CH2Cl2, –80°C
.
CuBr SMe2. In stark contrast with other organometallic reagents,
+
R
n–Bu
we could achieve regioselectivities of more than 90% and enantio-
selectivities up to 91% in the allylic alkylation of cinnamyl chloride
1b with i-PrLi and s-BuLi (entries 6 and 7, Table 2). Our example
demonstrates the highest value reported to date for the transfer of
an i-Pr moiety (entry 6, Table 2) from organometallic reagents to
this allylic substrate33–35. In addition, no examples have been
reported for the synthesis of the compound with the addition of
s-BuLi (entry 7, Table 2). This reaction system also tolerates
more sterically demanding substrates; in particular, high e.e.
values (96–99%) are achieved with allyl bromide 1c bearing a
1-naphthyl substituent, using a copper catalyst based on ligand
L6 (entries 8 and 9, Table 2). Remarkably, the catalytic system
can even tolerate the presence of halides in the aromatic moieties
of the allylic substrates (entries 10–16, Table 2). There was no
evidence of the common lithium–halogen exchange in the case of
p-bromo-cinnamyl bromide 1e (entry 16, Table 2), demonstrating
the extremely high activity of the chiral catalyst, which can dominate
over the reactivity of the organolithium compound towards
competing reactions.
Addition of aryllithium compounds, in particular PhLi, provided
more than 99% enantioselectivity when phosphoramidite ligand
(S,R,R)-L4 was used for the allylic alkylation of p-chloro-cinnamyl
bromide 1d. However, the regioselectivity in this case needs to be
improved (entry 15, Table 2).
With aliphatic substrate 1f, the TaniaPhos L6 based catalyst was
found to be the best, providing 95% e.e. (entry 17, Table 2). A
major challenge and potential limitation of using alkyllithium com-
n–BuLi
2c
4
SN2 product
Ph2P
PCy2
PPh2
PAr2
PAr2
Fe
Cy2P
Fe
(R,Sp)-Josiphos
(S,Rp)-L2
Ar=3,5–Xylyl
L1
(R)-L3
PPh2
N
Ph2P
Fe
Ar
O
O
P N
Ar
(R,Rp)-Taniaphos
Ar=C6H5 (S,R,R)-L4
Ar=o–MeO–Ph (S,S,S)-L5
L6
Entry
X
Ligand
SN2′:SN2 (%)
e.e. (%)
1
Br
Br
Br
Br
Br
Cl
Br
L1
23:77
17:83
87:13
73:27
87:13
91:9
25
82
94
62
91
2
3
4
5
6
7
L2
L3
L4
L5
L5
L6
95
98
83:17
Conditions: 1.5 equiv. n-BuLi diluted with hexane, 0.1 M in CH2Cl2, 2 h addition time.
highly reactive organolithium reagents in catalysis. A major increase pounds in synthesis is related to functional group tolerance, because
in regioselectivity towards the branched product 3 was achieved of the high basicity and nucleophilicity of organolithium species.
using the ligands (R)-L3 and phosphoramidites9 (S,R,R)-L4 and Allylic substrates with various functional groups known to be
(S,S,S)-L5 (entries 3–5, Table 1). Enantioselectivities (e.e.) up to sensitive to organolithium reagents were therefore examined.
94% were obtained (entries 3 and 5, Table 1). Interestingly, high Importantly, the catalyst system tolerates the benzyloxy and
values of regio- and enantioselectivities were obtained not only N-Boc-protected amine groups, with only a slight decrease in enan-
when using cinnamyl bromide 1a, but also with cinnamyl chloride tioselectivity, and provides chiral building blocks for natural product
1b (entry 6, Table 1). The highest enantioselectivities for allyl synthesis (entries 18–22, Table 2). It is well known that esters and
bromide 1a were reached in the SN2′ allylic alkylation with the alcohols are highly reactive to alkyllithium reagents, and the ultimate
copper catalyst based on TaniaPhos (R,Rp)-L6 (entry 7, Table 1).
test of our catalytic system was therefore the allylic alkylations with
An intriguing observation is that both monodentate (phosphor- n-BuLi and MeLi of a highly sensitive ester-substituted allylic sub-
amidites L4 and L5) and bidentate (L2, L3 and L6) chiral ligands strate 1i (ref. 36) bearing a heteroatom directly at the g-position of
are effective in controlling the stereoselectivity in C–C bond the allyl bromide and substrate with unprotected alcohol 1j
formation with n-BuLi. Judicious selection of solvents, rate and (entries 23–25, Table 2). To our delight, the ester-protected allylic
order of addition of the reagents and reaction temperature, in alcohol from the asymmetric SN2′ reaction with n-BuLi was obtained
.
combination with the chiral CuBr SMe2/TaniaPhos L6 catalyst, as the exclusive product in 82% isolated yield and 98% e.e., with only
resulted in an optimized catalytic system, allowing for almost full a small decrease in selectivity when MeLi was used (entries 23 and 24,
control with respect to side reactions and non-catalysed ‘back- Table 2). In addition, high regioselectivity and an e.e. of 90% were
ground’ transformations. The choice of dichloromethane as obtained with hydroxymethyl-substituted allyl bromide 1j bearing
the solvent is key to obtain high regio- and enantioselectivity. an unprotected hydroxyl group without formation of any side pro-
The use of ethereal solvents caused a drastic drop in both regio- ducts (entry 25, Table 2).
and enantioselectivity.
So, which chiral copper complex is responsible for this unique
Using our optimized reaction protocol, involving the slow activity and selectivity, and what is the role of the solvent in the
addition of 1.5 equiv. of MeLi (diluted with toluene) over 2.5 h to allylic alkylation with organolithium reagents?
a solution of substrate 1a and 5 mol% catalyst in dichloromethane
As with the formation of organocuprates, we surmised that a
at –80 8C, provided the corresponding chiral product 3aa in 90% transmetallation between the organolithium and copper bromide
isolated yield, 90:10 ratio of regioisomers and 99% e.e. (entry 1, would occur before catalytic asymmetric C–C bond formation37.
.
Table 2). The optimized CuBr SMe2/TaniaPhos L6 catalyst system The formation of the chiral transmetallated copper catalyst in
1
6
proved to be remarkably effective for a range of allylic substrates dichloromethane-d2 was examined by H, 31P and Li/7Li nuclear
and alkyllithium reagents, with, in nearly all cases, excellent magnetic resonance (NMR) spectroscopy using different combinations
378
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1009
ARTICLES
a
complex 5 at –75°C
S1
10
S2 5+10 equiv. MeLiether at –75°C
B
A
B
C
A
C
S3 5+10 equiv. MeLiether at –100°C
B
B
S4 5+10 equiv. MeLiether at –50°C
S5 5+10 equiv. MeLidry at –80°C
C
A
C
A
–7
–8
–9
–10 –11 –12 –13 –14 –15 –16 –17 –18 –19 –20 –21 –22 –23 –24 –25 –26 –27
f1 (ppm)
b
c
Co-solvent
in n-BuLi
P
P
P
P
Me2CuLi
SN2':SN2
e.e
+
Me2CuLi
D
Br
P
P
Hexane
Et2O
88:12
27:73
75:25
81:19
99
28
90
97
Cu
MgBr
Me
C
CuBr
MeMgBr
t-BuOMe
Toluene
Dioxane
(–80°C) to (–110°C)
10 equiv. MeLiether
(–30°C) to (–70°C)
P
P
Cu Br
5
10 equiv. MeLidry
d
SN2':SN2
e.e
CuX
–
P
+
Li
Me
Me
P
P
Me
Cu
Cu
CuBr•SMe2
CuCl
88:12
83:17
85:15
81:19
99
98
99
97
Ether
P
A
B
Cul
PPh2
Fe
Cu(TC)
P
P
=
PPh2
Me2N
Figure 2 | Mechanistic study of chiral catalyst formation and the effect of copper salt and co-solvents present in the alkyllithium reagent. a, 31P NMR
spectroscopic studies of TaniaPhos–CuBr complex 5 in dichloromethane-d2 with MeLi. S1 is the copper complex of TaniaPhos 5, dissolved in dichloromethane-
d2 at –75 8C. S2 is 5 dissolved in dichloromethane-d2 at –75 8C followed by addition of 10 equiv. of MeLi in Et2O. In this case, the immediate formation of
four different species (A, B, C and D) was observed. A temperature-dependent dynamic equilibrium was observed between species B and C. Species B is the
major species between –80 and –110 8C (S3), but at temperatures higher than –80 8C, species C is dominant (S4). An equilibrated mixture of species B and
C can also be obtained by mixing Me2CuLi and TaniaPhos L6 in dichloromethane-d2. S5 is species A, which can be obtained exclusively by using nearly dry
MeLi as well as Me2Mg. Similarly, if diethyl ether is added to this mixture it causes dissolution of excess dry MeLi and formation of an equilibrated mixture
of species B and C. Species D is only observed by 1H NMR (see Supplementary Information) and corresponds to Me2CuLi. b, Chemical structures and
transformations proposed for species A, B, C and D. c,d, Dependence of regio- and enantioselectivity of n-BuLi addition to cinnamyl bromide 1a on cosolvent
(c) used to dilute n-BuLi and copper source (d).
of copper salt, solvents and quantities of MeLi over a range of proposed structure (for details, see Supplementary Information). To
temperatures (Fig. 2a).
establish the relevance of species A in the catalytic allylic substitution,
A full account of our mechanistic studies will be reported in due it was used in the stoichiometric alkylation of cinnamyl bromide 1a,
course. However, the most striking observation is that in dichloro- resulting in greater than 98% enantioselectivity. Additional control
methane, in the presence of diethyl ether using 10 equiv. of MeLi experiments confirmed the detrimental effect of ether on enantioselec-
and the copper bromide–TaniaPhos complex 5 (Fig. 2a), four distinct tivity, due to the formation of multiple copper species. We also
species are observed (Fig. 2a; Supplementary Fig. S2). In the absence of observed an absence of any influence of the copper source used in
an ether, TaniaPhos–CuMe (complex A, Fig. 2a; Supplementary the allylic alkylation (Fig. 2d) on the catalytic process, in accordance
Fig. S5b) is found exclusively at –80 8C. This chiral monomethyl with the presence of the unique catalytic complex A.
copper species was independently prepared using copper complex 5
Solvents and co-solvents (used for dilution of organolithium
with MeLi in the absence of ether or with Me2Mg, confirming the reagents) had a prominent effect on the stereo- and chemoselectivity
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1009
ARTICLES
Table 2 | Scope of asymmetric allylic alkylation.
CuBr•SMe2 (5mol%)
Ligand (6mol%)
R'
+
R'Li
+
R
X
R
R'
CH2Cl2, –80°C
R
1
2
3
4
SN2' product
SN2 product
Entry*
1, R
X
2, R′
Ligand
3:4 (%)†
Yield‡ (%)
3, e.e. (%)§
1
2
3
4
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1b, Ph
1b, Ph
1b, Ph
1c, 1-Naphthyl
1c, 1-Naphthyl
1d, p-Cl-C6H4
1d, p-Cl-C6H4
1d, p-Cl-C6H4
1d, p-Cl-C6H4
1d, p-Cl-C6H4
1d, p-Cl-C6H4
1e, p-Br-C6H4
1f, n-Pent
1g, BnOCH2
1g, BnOCH2
1g, BnOCH2
1g, BnOCH2
1h, TosN(Boc)CH2
1i, PhCO2
Br
Br
Br
Br
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
2a, Me
2b, Et
L6
L6
L6
L6
L5
L4
L4
L6
L6
L6
L6
L6
L6
L6
L4
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
90:10
84:16
90:10
90:10
91:9
90
80
88
92
90
77
80
96
97
90
91
91
3aa, 99 (S)
3ab, 98 (S)
3ac, 99 (S)
3ad, .99 (S)
3bc, 95 (S)
3be, 91 (S)
3bf, 82 (þ)
3ca, 99 (–)
3cc, 96 (–)
3da, .99 (þ)
3db, 96 (þ)
3dc, 97 (S)
3dc, 97 (S)
3dd, .99 (þ)
3dg, 99 (S)
3ec, 98 (S)
3fb, 95 (ND)
3ga, 90 (S)
3gb, 91 (þ)
3gc, 90 (S)
3gd, 86 (þ)
3hb, 86 (–)
3ic, 98 (þ)
3ia, 96 (S)
3jc, 90 (ND)
2c, n-Bu
2d, n-Hex
2c, n-Bu
2e, i-Pr
2f, s-Bu
2a, Me
2c, n-Bu
2a, Me
2b, Et
2c, n-Bu
2c, n-Bu
2d, n-Hex
2g, Ph
2c, n-Bu
2b, Et
2a, Me
2b, Et
2c, n-Bu
2d, n-Hex
2b, Et
2c, n-Bu
2a, Me
2c, n-Bu
5
6
90:10
97:3
7ꢀ
8
80:20
81:19
85:15
82:18
86:14
85:15
83:17
40:60
88:12
94:6
9
10
11
12
13}
14
15
16
17
18
19
20
21
22
23††
24
25‡‡
90
93
39#
93
100**
98
90
.99
96
72
82
62
99**
85:15
93:7
86:14
85:15
84:16
100:0
90:10
96:4
1i, PhCO2
1j, HOCH2
*Conditions: 1.2 equiv. RLi diluted in hexane (1.5 equiv. diluted in toluene in the case of MeLi) was added over 2–5 h (see Supplementary Information) to the 0.1 M solution of substrate in CH2Cl2. †Ratio of
SN2′:SN2 products was determined by gas chromatography analysis. ‡Refers to the isolated yield of SN2′:SN2 products. §Determined by gas or high-performance liquid chromatography analysis (see
Supplementary Information). (S)-indicates absolute configuration; (þ) and (–) are signs of optical rotation. ꢀRatio of diastereomers was determined as 1:1 with e.e. values of 82% and 81%, respectively.
Pre-formed CuBrL6 complex was used. #The SN2′ product could be isolated pure in this case. **This value refers to conversion; very volatile product. ††4% of double 1,2-addition product was isolated in
}
.
this case. ‡‡2.2 equiv. of n-BuLi were used. ND, not determined.
mixture over 2 h (over 5 h when using phosphoramidite ligands) using a syringe
pump. The flow of inert gas was turned off during the addition. Once the addition
was complete, the mixture was stirred for another 2 h at –80 8C. The reaction was
quenched with a saturated aqueous NH4Cl solution (2 ml) and the mixture was
of the organolithium reaction (Fig. 2c). The reactivity of alkyl-
lithium reagents is highly dependent on their structure and aggrega-
tion state, which in turn is strongly dependent on solvent30. Thus, by
excluding or minimizing ethereal solvents we were able to prevent
the formation of highly reactive organolithium species, and by
selecting dichloromethane as a solvent we were able to enhance
the catalytic reaction exclusively.
warmed to room temperature, diluted with dichloromethane, and the layers
separated. The aqueous layer was extracted with dichloromethane (3 × 5 ml) and
the combined organic layers were dried with anhydrous Na2SO4, filtered, and the
solvent evaporated in vacuo. Gas chromatography analysis was carried out to
determine the SN2′:SN2 ratio on a sample obtained after aqueous extraction with
dichloromethane, which had been passed through a short plug of silica gel to remove
transition-metal residues. Purification was performed by flash chromatography on
silica gel using different mixtures of n-pentane:Et2O as the eluent, and the
enantiomeric excess was determined by gas or high-performance liquid
chromatography analysis by comparison using authentic racemic material.
Summary
In conclusion, for the first time since the discovery of organolithium
compounds, it has been demonstrated that near absolute levels of
enantioselectivity can be achieved in catalytic asymmetric C–C
bond formation through allylic alkylation with these organometallic
reagents. This is possible as a result of our ability to tune a dynamic
system towards a unique and highly reactive catalyst featuring a
chiral monoalkyl copper phosphine complex. Now that the elusive
alkyllithium reagents have finally been tamed for catalytic asym-
metric C–C bond formation, the stage is set for the discovery of a
myriad of new catalytic applications for organolithium reagents,
for the practical synthesis of highly valuable chiral products.
Received 24 November 2010; accepted 10 February 2011;
published online 13 March 2011; corrected online 15 March 2011
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Acknowledgements
The authors acknowledge the Netherlands Organization for Scientific Research (NWO-
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Author contributions
M.P. and M.F.-M. studied solvent effects and optimized the reaction conditions. P.H.B.
performed ligand screening. A.R. performed copper salt screening. S.R.H. carried out NMR
studies. M.P., M.F.-M, P.H.B. and A.R. evaluated the scope of the organolithium addition
reaction. All authors contributed to designing the experiments, analysing the data and
editing the manuscript. S.R.H. and B.L.F. guided the research and wrote the manuscript.
Additional information
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://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be addressed
to S.R.H. and B.L.F.
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