Switchable stereoselectivity: The effects of substituents on the D 2-symmetric biphenyl backbone of phosphoramidites in copper-catalyzed asymmetric conjugate addition reactions with triethylaluminium

Article abstract of DOI:10.1002/adsc.201101007

A highly enantioselective copper-catalyzed conjugate addition with triethylaluminium was developed using phosphoramidite ligands bearing a D ₂-symmetric biphenyl backbone. For these ligands we demonstrated that the 3,3',5,5'-substituents on the biphenyl backbone can completely reverse the absolute configuration of the products. Copyright

Full text of DOI:10.1002/adsc.201101007

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DOI: 10.1002/adsc.201101007
Switchable Stereoselectivity: The Effects of Substituents on the
D2-Symmetric Biphenyl Backbone of Phosphoramidites in
Copper-Catalyzed Asymmetric Conjugate Addition Reactions
with Triethylaluminium
Han Yu,a Fang Xie,a Zhenni Ma,a Yangang Liu,a and Wanbin Zhanga,*
a
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240,
Peopleꢀs Republic of China
Fax : (+86)-21-5474-3265; phone: (+86)-21-5474-3265; e-mail: wanbin@sjtu.edu.cn
Received: December 23, 2011; Revised: March 30, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201101007.
Abstract: A highly enantioselective copper-cata-
lyzed conjugate addition with triethylaluminium
was developed using phosphoramidite ligands bear-
ing a D2-symmetric biphenyl backbone. For these li-
gands we demonstrated that the 3,3’,5,5’-substitu-
ents on the biphenyl backbone can completely re-
verse the absolute configuration of the products.
Keywords: chirality; conjugate addition; copper;
Figure 1. Phosphoramidite ligands with D2-symmetric bi-
phosphoramidite ligands; stereoselectivity reversal
phenyl backbone.
Trialkylaluminium reagents have also been shown
Carbon-carbon bond formation via the asymmetric to be good candidates as replacements for dialkylzinc
conjugate addition of organometallic reagents to a,b- in related asymmetric copper-catalyzed conjugate ad-
unsaturated carbonyl substrates catalyzed by a chiral ditions.[8,9] A number of organoaluminium reagents is
catalyst, is one of the most useful synthetic methodol- either commercially available or prepared by simple
ogies in organic synthesis.[1,2] Copper-catalyzed enan- hydro- and carboalumination reactions, providing
tioselective addition reactions of diethylzinc to a,b- readily available nucleophilic regents. For example,
unsaturated carbonyl enones have attracted much at- triethylaluminium is produced in industry in large
tention in the past decade and a number of efficient quantities for the Ziegler–Natta polymerization. How-
copper catalysts with chiral ligands has been report- ever, in contrast to the many examples of trialkylalu-
ed.[2–6] Among the successful chiral ligands, BINOL-,[3] minium addition to cyclic enones,[9] there are current-
TADDOL-,[4] and BIPOL-derived phosphoramidites[5] ly few reports about the conjugate addition of
have shown remarkable enantioselectivities in the re- trialkyl
aluminium
to
acyclic
a,b-unsaturated
actions of diethylzinc with enones. New types of bi- enones.[10] In particular, additions to acyclic aromatic
phenyl phosphoramidite ligands L1–L4 containing a,b-unsaturated enones[11] such as chalcone, are not
a D2-symmetric backbone were developed by our widely exploited. It was envisaged that such a synthet-
group (Figure 1). They provided excellent asymmetric ic route would provide valuable compounds for use as
catalytic results for the 1,4-conjugate addition of di- intermediates or building blocks in organic chemistry
ethylzinc to a,b-unsaturated ketones and nitroalkenes. because of their easy derivatization.[12] In order to ex-
Their excellent chiral environment and their ability to plore the behavior of phosphoramidite ligands with
be easily modified at the 3,3’,5,5’-positions of the bi- a D2-symmetric biphenyl backbone, we utilized them
phenyl backbone, make phosphoramidites excellent li- in asymmetric conjugate additions of triethylalumini-
gands.[7]
um to a,b-unsaturated acyclic aromatic enones. Excel-
lent catalytic results were obtained.
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Table 1. Screening of reaction conditions.[a]
Entry
Cu salt
Cu(I)(MeCN)4PF6
Solvent
Temp. [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
G
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Et2O
THF
DCM
DMF
DIPE
MTBE
Et2O
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À30
À20
À40
À50
À78
À50
73
55
88
78
63
83
82
82
69
81
58
78
80
84
80
79
56
78
48 (R)
36 (R)
85 (R)
28 (R)
60 (R)
87 (R)
83 (R)
92 (R)
38 (R)
83 (R)
10 (R)
90 (R)
92 (R)
92 (R)
92 (R)
93 (R)
86 (R)
80 (R)
Cu(II)
ACHTUNGTRENNUNG
Cu(II)ACHTNUGTRENNUNG
Cu(I)TC
Cu(I)(C6H6)OTf
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
(OAc)2·H2O
5
ACHTUNGTRENNUNG
6
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
T
E
AHCTUNGTRENNUNG
R
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
E
G
N
7[d]
8
9
10
11
12
13
14[e]
15
16
17[f]
18[g]
Et2O
Et2O
Et2O
Et2O
A
[a]
1 mol% Cu salt, 2 mol% ligand, 1.2 equiv. AlEt3.
Yield of the isolated product.
[b]
[c]
Determined by HPLC, Chiralcel OJ-H column. The absolute configuration was determined by comparison with literature
data.[12]
[d]
[e]
[f]
1 mol% Cu salt, 1 mol% ligand, 1.2 equiv. AlEt3.
The reaction mixture was stirred for 6 h.
The reaction mixture was stirred for 16 h.
1 mol% Cu salt, 2 mol% ligand, 1.2 equiv. AlMe3.
[g]
trans-L2 provided excellent enantioselectivities for yields were obtained from À208C to À508C with the
the asymmetric conjugate addition of diethylzinc to best enantioselectivity being observed at À508C. Re-
a,b-unsaturated carbonyl substrates and nitroal- ducing the temperature of the reaction to À788C re-
kenes.[7] The conjugate addition of triethylaluminium
to chalcone 1a was performed in the presence of
2 mol% of trans-L2 and 1 mol% of copper salt in tol-
Table 2. Screening of ligands.[a]
uene, at
a
temperature of À308C (Table 1).
Cu(OAc)2·H2O was found to be the most suitable cat-
ACHTUNGTRENNUNG
alyst precursor because of its high reactivity and
enantioselectivity (entries 1–6). The reaction was orig-
inally performed using a 1:1 ratio of copper:ligand.
The enantioselectivity of the reaction was found to be
lower compared to that when the amount of ligand
was increased (Cu:ligand=1:2) (entries 6 and 7). This
phenomenon was also observed in our previous re-
ports using similar ligands.[7a,b] With trans-L2 as the
Entry
L
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
cis-L1
trans-L1
cis-L2
trans-L2
trans-L3
trans-L4
78
76
80
82
81
75
81 (S)
68 (S)
82 (R)
93 (R)
62 (R)
56 (R)
ligand and CuACHTUNGTRENNUNG(OAc)2·H2O as the copper source, we
investigated the effect that the solvent had on the re-
action. Ether solvents such as Et2O, DIPE and MTBE
all provided excellent results (entries 6, 8–13).
Using the aforementioned conditions and Et2O as
a solvent, the reaction was performed at varying tem-
peratures (Table 1, entries 8, 14–16). Similarly good
[a]
1 mol% Cu salt, 2 mol% ligand, 1.2 equiv. AlEt3.
Yield of the isolated product.
Determined by HPLC, Chiralcel OJ-H column. The ab-
solute configuration was determined by comparison with
literature data.[12]
[b]
[c]
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Switchable Stereoselectivity: The Effects of Substituents on the D2-Symmetric Biphenyl Backbone
sulted in an obvious drop in yield and a slight de- (Table 2). The substituents at the 3,3’,5,5’-positions of
crease in enantioselectivity. This was probably due to the biphenyl backbone of the ligands showed a signifi-
the poor solubility of the substrate in Et2O at this cant influence on the catalysis. To our surprise, both
temperature (entry 17). We replaced triethylalumini- enantiomers could be obtained with high enantiose-
um with trimethylaluminium using the optimal condi- lectivities (S-2a: up to 81% ee; R-2a: up to 93% ee)
tions and discovered that the enantioselectivity, while (entries 1 and 4) by using ligands with different sub-
still good (80% ee), was lower than that obtained stituents at the 3,3’,5,5’-positions of the D2-symmetric
when using triethylaluminium (entries 16 and 18).
biphenyl backbone. Both cis- and trans-L1 lacking
With the optimal conditions in hand, several phos- substituents at the 3,3’,5,5’-positions, gave S configura-
phoramidites containing a D2-symmetric biphenyl tion products. cis-L1 gave a higher enantioselectivity
backbone were investigated to identify the most effi- than trans-L1 (entries 1 and 2). Ligands cis-L2 and
cient ligand. Ligand screening revealed that all the trans-L2–L4, containing substituents on the biphenyl
phosphoramidite ligands in Figure 1 were effective for backbone, all provided R configuration products. Up
this transformation (75–82% yield, 56–93% ee)
Table 3. Scope of substrates.[a]
Entry
1
Substrate
R1
Ph
R2
Ph
L
Yield [%][b]
ee [%][c]
1a
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
trans-L2
cis-L1
78
82
79
76
85
82
79
84
81
81
86
87
80
83
78
77
83
80
82
85
87
82
87
87
82
83
79
84
89
90
80
82
81 (S)
93 (R)
78 (S)
80 (R)
90 (S)
94 (R)
90 (S)
94 (R)
95 (S)
96 (R)
73 (S)
92 (R)
88 (S)
91 (R)
76 (S)
79 (R)
90 (S)
94 (R)
92 (S)
96 (R)
91 (S)
97 (R)
71 (S)
87 (R)
73 (S)
80 (R)
86 (S)
91 (R)
>99.9 (S)
>99.9 (R)
85 (S)
92 (R)
2
1b
1c
1d
1e
1f
1g
1h
1i
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-BrC6H4
2-naphthyl
Ph
Ph
3
Ph
4
Ph
5
Ph
6
Ph
7
Ph
8
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-CF3C6H4
2-naphthyl
p-MeOC6H4
Me
9
Ph
10
11
12
13
14
15
16
1j
Ph
1k
1l
Ph
Ph
1m
1n
1o
1p
Ph
Ph
trans-L2
cis-L1
trans-L2
cis-L1
p-MeOC6H4
Ph
trans-L2
[a]
1 mol% Cu salt, 2 mol% ligand, 1.2 equiv. AlEt3.
Yield of the isolated product.
[b]
[c]
Determined by HPLC, Chiralcel OJ-H column. The absolute configuration was determined by comparison with literature
data.[12]
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to 93% ee was obtained with methyl-substituted trans-
L2 (entries 3–6).
With cis-L1 (R=H) and trans-L2 (R=Me) used as
a reversal ligand pair, we expected to induce the for-
mation of both absolute configurations in the prod-
ucts. A wide range of aromatic enones was examined
to investigate the scope of the substrates and the re-
versal in stereoselectivity (Table 3). To our delight,
a complete switch in stereoselectivity was observed
for all of the substrates. The introduction of a methyl
group at the ortho-position on the phenyl ring (R1 or
R2) of substrate 1, led to a drop in enantioselectivity
for both of the ligands. This may be attributed to the
effect of steric hindrance (entries 1, 2 and 8). Howev-
er, the introduction of a methyl group at the meta-
and para-positions of the phenyl ring R1 or R2 led to
an increase in enantioselectivity (entries 1, 3, 4, 9 and
10). When a methoxy group was introduced at the
para-position of the phenyl ring R1 or R2, a much
higher increase in enantioselectivity was observed
(entries 1, 5 and 11). Conversely, electron-withdraw-
ing substituents such as a para-bromo group on the
Figure 2. X-ray crystal structure of cis-L1.
Table 4. Dihedral angles of ligands.
Entry
Ligand
Dihedral angle
1
2
3
4
cis-L1
42.468
42.168
46.678
43.868
trans-L1
trans-L2
trans-L3
phenyl ring R1 or para-chloro or trifluoromethyl angle decreased to a value similar to those of cis-L1
groups on the phenyl ring R2, were detrimental to the and trans-L1. However, trans-L3 gave the opposite
enantioselectivity (entries 1, 6, 12 and 13). Further- absolute configuration of the conjugate addition prod-
more, replacing the phenyl ring, R1 or R2, with 2- ucts when compared to cis-L1 and trans-L1. These re-
naphthyl-substituted substrates, increased the enantio- sults indicate that it is the substituents at the 3,3’,5,5’-
selectivity of the reaction when using cis-L1 as the positions of the biphenyl backbone that affect the ab-
ligand. The related trans-L2 ligand gave slightly lower solute configuration of the conjugate addition prod-
enantioselectivity (entries 7 and 14). The above re- ucts, rather than the dihedral angle of the ligands.
sults suggested that the electron-donating properties
In order to explain the reversal phenomenon, a ste-
of the para-position substituent on the phenyl ring R1 reochemical pathway has been proposed according to
or R2 gave a proportional greater improvement in our experimental results (Figure 3). As a copper ion
terms of enantioselectivity. Therefore we chose 1o coordinates to one phosphorus on the ligand,[14] the
containing para-methoxy groups on both phenyl rings other phosphorus remains relatively far away from
of R1 and R2 as the substrate to carry out the reaction the reaction center. Both the cis and trans configura-
(entry 15). As expected, both enantiomers were ob- tions of the ligands therefore have little effect on the
tained in >99.9% ee (entry 15), in which the switch in absolute configuration of the products. The steric re-
stereoselectivity was achieved by only changing the pulsion between the substituents at the 3,3’- or 5,5’-
substituent and not the chirality of the ligand. We positions of the biphenyl backbone and the aryl
also performed the reaction using a typical acyclic groups of the substrate, may determine the result of
enone, benzalacetone (1p). Using cis-L1 and trans-L2 the reversed stereochemical phenomenon in the 1,4-
as a ligand pair, products were obtained with high addition. For the transition states involving L1 (the
enantioselectivities and reversed absolute configura- ligand bearing no substituents at the 3,3’,5,5’-positions
tions (entry 16).
of the biphenyl backbone) and coordination with the
We tried to use the single crystal X-ray structure of copper ion, steric repulsion between the phenyl group
cis-L1 (Figure 2) for an explanation for the above of ligand L1 and the aryl group of the substrate in L1-
phenomenon by comparison with the previously re- TS2 was larger than that in L1-TS1. This leads to the
ported X-ray crystal structures of trans-L1–L3.[13] The 1,4-adduct with an S isomer configuration. However,
dihedral angles of these ligands are summarized in when substituents at the 3,3’,5,5’-positions of the bi-
Table 4. The dihedral angles of cis-L1 and trans-L1 phenyl backbone were introduced, the steric repulsion
lacking substituents at the 3,3’,5,5’-positions were un- between the phenyl group of ligand L2 and the aryl
affected. When methyl groups were introduced to the group of the substrate in transition state L2-TS2, was
3,3’,5,5’-positions of the biphenyl backbone, the dihe- smaller than that between the substituent at the
dral angles of the ligand increased compared to those 3,3’,5,5’-positions of the biphenyl backbone and aryl
of cis-L1 and trans-L1. When the substituent was group of the substrate in L2-TS1. This leads to the
changed to an ethyl group (trans-L3), the dihedral 1,4-adduct with the R isomer configuration.
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Switchable Stereoselectivity: The Effects of Substituents on the D2-Symmetric Biphenyl Backbone
Figure 3. Proposed stereochemical pathway showing the facial coordination of the copper atom with the enone substrate.
Scheme 1. Asymmetric synthesis of the alkene 4.
Finally, we utilized the ligand pair cis-L1 and trans- >99.9% ee), with phosphoramidite ligands bearing
L2 to synthesize enantiopure alkene 4 via an asym- a D2-symmetric biphenyl backbone. These types of li-
metric conjugate addition reaction (Scheme 1). gands demonstrated that the 3,3’,5,5’-substituents on
Alkene 4 exhibits a diverse range of biological prop- the biphenyl backbone can completely reverse the ab-
erties such as antimalarial and antiplasmodial activi- solute configuration of the products, thus simplifying
ties (Scheme 1).[15] Thus utilizing ligands cis-L1 and the process of accessing either enantiomer. The syn-
trans-L2, the S and R enantiomers of 2o were ob- thesis of chiral alkene 4 was also completed, with
tained via the asymmetric 1,4-addition of triethylalu- both enantiomers being obtained in high overall
minium to 1,3-bis(4-methoxyphenyl)pentan-1-one yields and excellent enantioselectivities.
(1o). NaBH4 reduction of the ketones (S- and R-2o)
followed by alcohol elimination (S- and R-3) gave the
desired compounds with high overall yields and com-
plete enantioselectivity (both >99.9% ee). To the best
Experimental Section
of our knowledge, this is the first example of the
asymmetric synthesis of 4.
Typical Procedure for the Conjugate Addition to
Chalcone 1a
In conclusion, we have developed a highly enantio-
selective copper-catalyzed conjugate addition of tri-
flame-dried Schlenk tube was charged with
ethylaluminium to acyclic aromatic enones (up to CuACTHUGNTERNNU(G OAc)2·H2O (1.0 mg, 0.005 mmol) and ligand (7.8 mg,
A
G
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0.01 mmol) under an N2 atmosphere, and the mixture was
dissolved in dry Et2O (1.5 mL). The solution was stirred at
258C for 30 min and then cooled to À508C. Triethylalumini-
um (1.2 mmol, 1.2 mL of 1M hexane solution) was added
dropwise to the above solution. The colour of the solution
gradually turned to light yellow after 5 min at À508C. The
substrate 1a (104.3 mg, 0.5 mmol dissolved in 1.0 mL dry tol-
uene) was then added dropwise. The mixture was stirred at
À508C for 8 h before quenching with aqueous saturated
NH4Cl. The layers were separated and the aqueous layer
was extracted with ethyl acetate (5 mLꢂ2). The combined
organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column
chromatography on silica gel to give the addition product.
The enantiomeric excess of the product was determined by
chiral HPLC.
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Acknowledgements
This work was partially supported by the National Natural
Science Foundation of China (Nos. 20972095 and 21172143),
Science and Technology Commission of Shanghai Municipal-
ity (No. 10dz1910105), Nippon Chemical Industrial Co.,
Ltd., and Shanghai Jiao Tong University.
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[13] CCDC 857960 (cis-L1) contains the supplementary
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obtained free of charge from The Cambridge Crystallo-
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Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
8 Switchable Stereoselectivity: The Effects of Substituents on
the D2-Symmetric Biphenyl Backbone of Phosphoramidites
in Copper-Catalyzed Asymmetric Conjugate Addition
Reactions with Triethylaluminium
Adv. Synth. Catal. 2012, 354, 1 – 8
Han Yu, Fang Xie, Zhenni Ma, Yangang Liu,
Wanbin Zhang*
8
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