Copper-catalyzed desymmetrization of oxabenzonorbornadienes with aluminum reagents

Article abstract of DOI:10.1016/j.tetlet.2009.02.219

The desymmetrization of oxabenzonorbornadienes with aluminum reagents and SimplePhos as chiral ligand is described. The corresponding homoallylic alcohols are obtained in high yield, diastereoselectivity, and enantiomeric excess. Furthermore the first ant

Full text of DOI:10.1016/j.tetlet.2009.02.219

Tetrahedron Letters 50 (2009) 3474–3477
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Copper-catalyzed desymmetrization of oxabenzonorbornadienes with
aluminum reagents
*
Renaud Millet, Tania Bernardez, Laëtitia Palais, Alexandre Alexakis
Université de Genève, Département de chimie organique, Quai E. Ansermet 30, 1211 Genève 4, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The desymmetrization of oxabenzonorbornadienes with aluminum reagents and SimplePhos as chiral
ligand is described. The corresponding homoallylic alcohols are obtained in high yield, diastereoselectiv-
ity, and enantiomeric excess. Furthermore the first anti enantioselective desymmetrization with aromatic
nucleophiles is reported.
Received 8 December 2008
Accepted 27 February 2009
Available online 5 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The copper-catalyzed enantioselective addition of organometal-
lic nucleophiles to activated double bonds is a very important
methodology to form C–C bond.1 Selective creation of multiple ste-
reocenters in one step is a highly valuable process. One way to con-
struct multiple stereocenters is the enantioselective ring-opening
reaction of oxabenzonorbornadienes with organometallic nucleo-
philes.2 Two different pathways lead to diastereomeric products.
The syn product is obtained via a carbometallation of the double
bond from the less hindered exo face.3 The anti product is obtained
in the copper-catalyzed reaction via a pure SN20 mechanism.4,5
Formation of the syn adduct is extensively documented with a
large variety of transition metal complexes as catalyst (Pd, Rh, Ti,
Zr).6 These catalysts have been mainly used in combination with
dialkylzinc reagents and more recently with aryl boronic acids.
Among all these examples the use of aluminum reagents is rare.
The sole report was published by Waymouth and co-workers, in
which organoaluminum compounds were used in combination
with early transition metals. The desymmetrization of oxabicyclic
alkenes could be achieved in good yield with very high enantio-
selectivity.6p
Formation of the anti adduct with hard nucleophiles has been
less studied. Dialkylzinc reagents were used with phosphoramidite
ligands by Pineschi, Feringa, and co-workers.4 High diastereoselec-
tivity and enantioselectivity were obtained. However a stoichiom-
etric amount of a Lewis acid was necessary and transfer of the
useful methyl group gave low yields. The more reactive Grignard
reagents have also been applied. The first report was presented
by Carretero and co-workers on the non-enantioselective desym-
metrization of oxabicyclic alkenes with PPh3 as ligand.7 Following
their work, Zhou and co-workers described the enantioselective
version of the same reaction using chiral spiro phosphoramidite
as ligand, and more recently they improved their results with spiro
phosphine ligands.8 However the use of commercially available
and inexpensive trialkylaluminum reagents was not reported so
far.
There are only a few reports of allylic alkylation with organo-
aluminum reagents. They have been employed in the copper-
catalyzed desymmetrization of bicyclic hydrazines9 and allylic
substitution of allylic phosphates.10
Herein we wish to report the use of organoaluminum reagents
in the copper-catalyzed desymmetrization of oxabenzonorborna-
dienes in presence of SimplePhos9d as chiral ligand (Scheme 1).
The aim of the use of trialkylaluminum reagents was mainly to
transfer the methyl group in high yield, diastereoselectivity, and
enantioselectivity.
The initial tests were conducted on the oxabenzonorbornadiene
1. Different copper salt and solvent were screened as the choice of
the reaction conditions is known to have a large impact on the out-
come of the reaction.11
It appears that the counter-ion of the copper salt plays a very
important role on the reaction. When OTf was used as the coun-
ter-ion, the desired alcohol was not detected. Only aromatization
product was obtained (Table 1, entries 1 and 2).12 The halogen ser-
ies of counter ion was studied and going from the chloride to the
bromide and finally the iodide led to a decrease in conversion, dia-
stereoselectivity, and enantioselectivity. While CuCl gave an inter-
esting 80% de with 81% ee (Table 1, entry 3), CuBr or CuBrꢀMe2S gave
only 60% de, 50% ee (Table 1, entries 4 and 5) and CuI did not cata-
lyze the reaction (Table 1, entry 6). With Cu(OAc)2ꢀH2O a high
OH
Ph
N
O
AlMe3
L1 =
P
CuTC
L1
Ph
1
2a
* Corresponding author. Tel.: +41 22 379 6522; fax: +41 22 379 652.
E-mail address: alexandre.alexakis@unige.ch (A. Alexakis).
Scheme 1. Desymmetrization of 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.219

R. Millet et al. / Tetrahedron Letters 50 (2009) 3474–3477
3475
Table 1
We also took advantage of the coordinating solvent to test phos-
phoramidite ligands.9c
Screening of copper salt and solventa
Conversionb (%)
anti:sync
eec (%)
First, the bulk around the phosphorous part was increased with
L2. Alcohol 2a was obtained with full conversion in a very good
anti/syn ratio with 90% ee (Table 2, entry 2). This value was slightly
lower than that obtained with L1 (Table 2, entry 1). The bulk
around the amine part was then increased by using L3 and once
more total conversion to 2a was obtained with nearly perfect dia-
stereoselectivity and ee in the same range than previously ob-
served (Table 2, entry 3). It appears that the outcome of the
reaction is not sensible to the bulk of the ligand. We next turned
our attention on another class of successful ligands in asymmetric
allylic alkylation, the phosphoramidite ligands (L4–L6). They were
compatible with the reaction conditions as the reaction was car-
ried out in coordinating solvent.9c A match/mismatch effect was
pointed out by testing the diastereomeric pair L4 and L5. (S,S,S)-
L4 is the match ligand with 66% ee (Table 2, entry 4), while the
other diastereomer (R,S,S)-L5 is the mismatch one with only 45%
ee (Table 2, entry 5). We also noticed that the side of the attack
was dictated by the binaphthol part. The tropos L6 gave a result
in between with 57% ee. However the phosphoramidite ligands
were less efficient than the SimplePhos ligands for this transforma-
tion. The SimplePhos L1 was Selected as ligand for the next part of
the study.
Entry
Copper
Solvent
d
1
2
3
4
5
6
7
8
9
10
11
12
13
14f
Cu(OTf)2
CuOTfꢀC6H6
CuCl
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
—
—
—
—
—
—
d
40d
35
36
90:10
80:20
80:20
—
95:5
95:5
99:1
91:9
—
81
50
50
—
89
88
89
90
—
CuBr
CuBrꢀMe2S
CuI
0
Cu(OAc)2ꢀH2O
Cu(CH3CN)4ꢀBF4
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
30
66e
54
90
THF
0
PhMe
MTBE
MTBE
15
100 (93)
100
—
99:1
99:1
—
91
92
a
Reaction conditions: 1 (0.5 mmol), L1 (3 mol %), Cu (3 mol %), solvent (3 ml),
Me3Al (1.2 equiv), rt, 20 h.
Determined by 1H NMR, isolated yield in parentheses.
b
c
Determined by chiral GC.
d
No traces of desired alcohol were detected.
1-Naphthol and 1-methylnaphthalene were detected as by-products.
e
f
Reaction preformed at 0 °C.
enantioselectivity was observed but the conversion remained low
(Table 1, entry 7). The weakly coordinated Cu(CH3CN)4ꢀBF4 led to
the formation of substantial amount of by-products despite good
conversion and enantioselectivity (Table 1, entry 8). Finally, copper
thiophene-2-carboxylate (CuTC) appeared as the most efficient
copper salt as after 20 h 54% conversion was reached with complete
diastereoselectivity and 89% ee (Table 1, entry 9). In order to im-
prove the reactivity, we investigated other solvents. Diethyl ether
increased the reactivity as well as the enantioselectivity (Table 1,
entry 10). Changing the solvent to THF led to no conversion (Table
1, entry 11), while employment of toluene resulted in only 15% con-
version after 20 h (Table 1, entry 12). Finally, with the safe and envi-
ronmentally friendly methyl tert-butyl ether (MTBE), the reaction
proceeded to completion in 20 h, with complete diastereoselectivi-
ty and 91% ee (Table 1, entry 13). Performing the reaction at 0 °C did
not improve the result (Table 1, entry 14).
The scope of the reaction was then studied by modifying the
substrate (Scheme 2). The electron density around the aromatic
part was modified. It was decreased by adding two fluorine atoms
3 and increased by adding two methoxy groups in different posi-
tions 4 and 5.
Table 2
Modification of the liganda
Entry
Ligand
Conversionb (%)
anti:sync
eec (%)
1
2
3
4
5
6
L1
L2
L3
(S,S,S)-L4
(R,S,S)-L5
L6
100
100
100
100
100
100
99:1
99:1
99:1
99:1
99:1
99:1
91 (ꢁ)
90 (ꢁ)
92 (ꢁ)
66 (+)
45 (ꢁ)
57 (ꢁ)
The next step was to study the influence of the ligand on the
reaction under optimized conditions (Fig. 1). The high tunability
of the SimplePhos family around both the phosphorous atom and
the amine moiety was used to increase the bulk around each part.
a
Reaction conditions:
1 (0.5 mmol), CuTC (3 mol %), ligand (3 mol %), MTBE
(3 ml), Me3Al (1.2 mmol), rt, 20 h.
b
c
Determined by 1H NMR.
Determined by chiral GC.
Ph
Ph
Ph
P
N
P
N
P
N
Ph
Ph
Ph
L1
L2
L3
Ph
N
Ph
Ph
N
O
P
O
P
O
P
N
O
O
O
Ph
Ph
Ph
(S,S,S)-L4
(R,S,S)-L5
L6
Figure 1. Ligands used in this study.

3476
R. Millet et al. / Tetrahedron Letters 50 (2009) 3474–3477
same level of enantioselectivity was maintained (Table 4, entries
R2
R2
R2 OH
Me3Al (1.2 equiv.)
CuTC (3 mol%)
L1 (3 mol%)
1–3). Bulky i-Bu3Al gave the highest enantioselectivity with 94%
ee, a good isolated yield, and a high diastereoselectivity (Table 4,
entry 4). Electron-rich alcohols 7b and 8b were obtained in high
diastereoselectivity with the same level of enantioselectivity as
for the reaction with Me3Al (Table 4, entries 5 and 6). Only the
more hindered i-Bu3Al is not a good nucleophile as the reaction re-
sulted in the aromatization of the substrate (Table 4, entry 7).
Very recently, the group of Hoveyda15a and our group15b de-
scribed tandem lithium/aluminum exchange from aryl lithium re-
agents followed by an asymmetric conjugate addition. The ratio of
the transferred aryl group is very high and the product is obtained
in high enantioselectivity. We envisaged that this approach could
be used to perform the desymmetrization of oxabenzonorbornadi-
enes with aryl nucleophiles (Scheme 3).
Two reactants were used to transmetallate from lithium to alu-
minum. When Et2AlCl was used the ratio of phenyl group versus
ethyl group transfer was 40:60 with 84% ee and 94% ee, respec-
tively. To increase the amount of phenyl group transfer we decided
to use the more hindered i-Bu2AlCl as transmetallating agent.
Unfortunately the effect on the aryl/alkyl transfer was not the ex-
pected one as more alkyl group was transferred.
R1
R1
R1
R1
O
MTBE, rt, 20h
R2
3; R1=F, R2=H
4; R1=OMe, R2=H
5; R1=H, R2=OMe
6a; R1=F, R2=H
7a; R1=OMe, R2=H
8a; R1=H, R2=OMe
Scheme 2. Substrate scope.
The different substrates are compatible with the reaction condi-
tions. The electron-deficient alcohol 6a was isolated in good yield
with a slightly lower diastereoselectivity but a high enantiomeric
excess (Table 3, entry 2). Electron-rich substrates were also good
candidates for this reaction as the corresponding alcohols were iso-
lated in good yield with good diastereoselectivity and 87–88% ee
(Table 3, entries 3 and 4).13 The developed conditions appeared
to accept substrates with different electron density around the aro-
matic part.14
A large range of trialkylaluminum reagents are commercially
available and we wanted to check if our methodology could be ap-
plied to other aluminum reagents.
The substrates 1, 4, and 5 were then tested with different trial-
kylaluminum reagents. When the chain length was increased, the
We have shown that organoaluminum reagents are efficient
and cheap reagents for the desymmetrization of oxabenzonorbor-
nadienes. The methyl group can be transferred in high yield and
with high enantioselectivity.16 The reaction can be extended to
other alkyl group. We also have shown that the tandem lithium
aluminum exchange desymmetrization reaction can be applied in
this case. This work is currently under development, especially
the transfer of aryl group and new tandem reactions.
Table 3
Scope substrate with Me3Al
Entry
Substrate
Product
Yielda (%)
anti:synb
eec (%)
1
2
3
4
1
3
4
5
2a
6a
7a
8a
93
85
69
88
99:1
94:6
99:1
93:7
91
91
88
87
Acknowledgments
The authors thank the Swiss National Research Foundation
(Grant No. 200020-113332) and COST action D40 (SER contract
No. C07.0097) for financial support, as well as BASF for the gener-
ous gift of chiral amines.
a
Isolated yield of the anti alcohols.
Determined by 1H NMR.
Determined by chiral GC or chiral SFC.
b
c
References and notes
Table 4
Reactions with various trialkylaluminum reagents
1. (a) Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev.
2008, 108, 2796–2823; (b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.;
Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824–2852.
Entry
Substrate
R
Product
Yielda (%)
anti:synb
eec (%)
2. (a) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48–58; (b)
Pineschi, M. New J. Chem. 2004, 28, 657–665.
3. Lautens, M.; Renaud, J.-L.; Hiebert, S. J. Am. Chem. Soc. 2000, 122, 1804–1805.
4. Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L.
Org. Lett. 2002, 4, 2703–2705.
1
2
3
4
5
6
7
1
1
1
1
4
5
5
Et
2b
2c
2d
2e
7b
8b
8e
79
50
95
71
95
(100)
—
99:1
95:5
99:1
99:1
99:1
99:1
—
92
87
87
94
89
88
—
n-Pr
n-Bu
i-Bu
Et
Et
i-Bu
5. Persson, E. S. M.; van Klaveren, M.; Grove, D. M.; Bäckvall, J. E.; van Koten, G.
Chem. Eur. J. 1995, 1, 351–359.
6. For palladium catalysis see: (a) Lautens, M.; Hiebert, S.; Renaud, J.-L. Org. Lett.
2000, 2, 1971–1973; (b) Lautens, M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc.
2001, 123, 6834–6839; (c) Priego, J.; García Mancheño, O.; Cabrera, S.; Gómez
Arrayás, R.; Llamas, R.; Carretero, J. C. Chem. Commun. 2002, 2512–2513; (d)
Lautens, M.; Hiebert, S. J. Am. Chem. Soc. 2004, 126, 1437–1447; (e) Cabrera, S.;
Gómez Arrayás, R.; Carretero, J. C. Angew. Chem., Int. Ed. 2004, 43, 3944–3947;
a
Isolated yield of the anti alcohols, conversion in parentheses
Determined by 1H NMR.
Determined by chiral GC or chiral SFC.
b
c
R2AlCl (3 equiv.)
-30°C, 30-60 min
PhLi (3 equiv.)
PhAlR2 (3 equiv.)
OH
OH
Ph
R
CuTC/L1 (3 mol%)
MTBE, rt, 20h
+
O
1
2f
2b, R=Et
2e, R=i-Bu
R=Et, 2f:2b 40:60, 2f 84% ee, 2b 94% ee
R=i-Bu, 2f:2e 35:65, 2f 84% ee, 2e 94% ee
Scheme 3. Tandem Li–Al exchange desymmetrization reaction.

R. Millet et al. / Tetrahedron Letters 50 (2009) 3474–3477
3477
(f) Dotta, P.; Kuwar, P. G. A.; Pregosin, P. S.; Albinati, A.; Rizzato, S.
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T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934–11935; (i) Cabrera,
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17947; (j) Imamoto, T.; Kumada, A.; Yoshida, K. Chem. Lett. 2007, 36, 500–501; (k)
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Sammis, G.; Waymouth, R. M. J. Org. Chem. 2000, 65, 3902–3909.
11. Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124,
5262–5263.
12. 1-Naphthol and 2-methylnaphthalene were obtained. For Cu(OTf)2 catalyzed
aromatization of oxabenzonorbornadienes see: Peng, F. Z.; Fan, B. M.; Shao,
Z. H.; Pu, X. W.; Li, P. H.; Zhang, H. B. Synthesis 2008, 3043–3046.
13. The lower yield in 7a is mainly due to aromatization during the purification
steps.
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7358–7362; (b) Hawner, C.; Li, K. Y.; Cirriez, V.; Alexakis, A. Angew. Chem., Int.
Ed. 2008, 47, 8211–8214.
16. Typical procedure: In a dried Schlenck tube under nitrogen atmosphere were
placed CuTC (2.9 mg, 0.015 mmol, 3 mol %) and L1 (6.8 mg, 0.015 mmol,
3 mol %). MTBE was added (3 ml) and mixture was stirred at room
temperature for 20 min. The oxabicyclic alkene (0.5 mmol) was added.
R3Al in hexanes (0.6 mmol) was added dropwise over a period of 3 min. The
reaction was stirred for 20 h and then quenched with water and HCl (1 N).
The organic layer was separated and the aqueous phase was extracted with
CH2Cl2. The combined organic phases were dried (MgSO4), filtered, and
concentrated. The crude was purified by flash chromatography (c-Hex then
EtOAc:c-Hex 15:85). The alcohol 2a was obtained with 90% yield (80 mg).
7. (a) Gomez Arrayas, R.; Cabrera, S.; Carretero, J. C. Org. Lett. 2003, 5, 1333–1336;
(b) Gomez Arrayas, R.; Cabrera, S.; Carretero, J. C. Synthesis 2006, 1205–1219.
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½
a 2D0
ꢂ
ꢁ242.6 (c = 0.69, CHCl3, ee 91%). 1H NMR (400 MHz, CDCl3): 7.38 (d,
J = 6.2 Hz, 1H), 7.29–7.19 (m, 2H), 7.09 (d, J = 6.2 Hz, 1H), 6.43 (d, J = 9.5 Hz,
1H), 5.91 (dd, J = 9.5, 4.4 Hz, 1H), 4.44 (d, J = 5.8 Hz, 1H), 2.68–2.56 (m, 1H),
1.74 (d, J = 5.8 Hz, 1H), 1.05 (d, J = 6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3):
135.7, 132.3, 128.3, 127.6, 127.2, 126.4, 125.8, 125.7, 74.1, 37.4, 16.9.