Angewandte
Chemie
Table 3: Asymmetric CuTC-catalyzed allylic alkylation on endocyclic allylic chlorides 7a,b with RMgX
(Scheme 3; L*=L2–L6).
disubstituted substrates, cinnamyl
derivatives and aliphatic endocyclic
allylic chlorides, afforded both
excellent regio- and enantioselec-
tivities. Ee values of up to 98 and
> 99%, respectively, were obtained
in both applications.
[a]
Entry
Substrate
n
R
L*
Conv. [%]
SN2’/SN2[b]
ee [%]
1
2
3
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7b
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
8a
8a
8c
8c
8d
8e
9a
9a
9a
9b
9c
9d
9d
9e
9e
L5
L6
L6
L6
L6
L6
ent-L2
ent-L3
L6
L6
L6
L5
L6
L5
L6
>99
>99
63:37
96:4
97:3
98:2
97:3
29 (S+)
98 (S+)
98 (S+)
98 (S+)
98 (R+)
98 (+)[d]
88 (+)
10 (+)
98 (+)
99.2 (+)
98 (+)
87 (R)
>99 (44)
>99 (91)
>99
96 (60)
>99
4[c]
5
6
7
8
9
10
11
12
13
14
15
98:2
70:30
44:56
81:19
97:3
Experimental Section
75
73
CuTC (3 mol%) and chiral ligand
(3.3 mol%) were charged in a dried
Schlenk tube under inert gas and sus-
pended in CH2Cl2 (2 mL). The mixture
was stirred at room temperature for
30 min, followed by addition of the
allylic chloride (1 mmol) at room tem-
perature before cooling the mixture to
À788C in an ethanol–dry ice bath. The
Grignard reagent (3m in diethyl ether,
1.2 equiv) diluted in CH2Cl2 (0.6 mL)
was added over 60 min with a syringe
pump. Upon completion of the addition,
the reaction mixture was left a further
4 h at À788C. The reaction was
>99 (83)
>99 (67)
>99
>99 (78)
94
97:3
72:28
85:15
73:27
91:9
99.4 (S)
74 (À)
>99
98.8 (+)
[a] Conversion determined by GC–MS (in parentheses, yield of isolated products after purification by
column chromatography on silica gel). [b] Ratio determined by 1H NMR spectroscopy and GC–MS.
[c] Reaction with 4 mmol of material; addition of RMgX over 4 h. [d] Determined by GC analysis of 8 f
(R=(CH2)4OCOCF3).
quenched by the addition of aqueous HCl (1n, 2 mL) and then
Et2O (10 mL). The aqueous phase was separated and further
extracted with Et2O (3 3 mL). The combined organic fractions
were washed with brine (5 mL), dried over anhydrous sodium sulfate,
filtered, and concentrated in a vacuum. The oily residue was purified
by flash column chromatography. Gas chromatography on a chiral
stationary phase showed the enantiomeric excess of the SN2’ product.
than these results, there are no accounts of copper-catalyzed
asymmetric SN2’ alkylation with chiral external ligands on
such allylic derivatives.
We were gratified to see that the addition of different
Grignard reagents with 3 mol% of the copper catalyst
proceeded highly selectively toward the g substitution and
delivered adducts 8 and 9 with excellent enantiomeric excess
up to > 99%. Here again, a small panel of phosphoramidite
ligands were tested for their asymmetric induction of the
allylic substitution, but it was clear from Table 3 that ligand
L6 (S,SS) once more was the most successful. As concerns the
five-membered-ring substrate 7a, constant ee values of 98%
were obtained, independent of the organomagnesium reagent
used (Table 3, entries 2–5). In the larger-scale synthesis of the
chiral adduct 8c (Table 3, entry 4) and allowing a slower
addition time of the Grignard reagent (to prevent the reaction
temperature from rising), we obtained excellent matching
selectivities toward the g product (98:2) and the enantiomeric
excess (98%). The six-membered-ring allylic chloride 7b
afforded equally good ee values and g selectivities according
to the RMgX. The highest noteworthy enantioselectivity for
such a reaction was recorded for the addition of 3-butenyl-
magnesium bromide on 7b with 3 mol% CuTC/L6 loading, to
afford 9b with 99.2% ee and a 97:3 branched-to-linear ratio
(Table 3, entry 10). All the products obtained in this series are
valuable starting materials for more elaborate chiral synthons.
For example, the n-hexyl adduct (Table 3, entry 4) is a
precursor for the formal asymmetric synthesis of lepadifor-
mine.[21,22] Other useful transformations can be envisioned on
the exocyclic double bond, such as oxidation to a ketone or
selective epoxidation.
Received: May 11, 2006
Published online: August 4, 2006
Keywords: alkylation · allylic compounds · asymmetric catalysis ·
.
copper · nucleophilic substitution
[1] a) B. M. Trost, C. Lee in Catalytic Asymmetric Synthesis (Ed.: I.
Ojima), 2nd ed., Wiley, NewYork, 2000, p. 593; b) A. Pfaltz, M.
Lautens in Comprehensive Asymmetric Catalysis I–III (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,
p. 833.
[2] For reviews of asymmetric allylic alkylation with various metals,
see: a) H. Miyabe, Y. Takemoto, Synlett 2005, 1641; b) B. M.
Trost, J. Org. Chem. 2004, 69, 5813; c) B. M. Trost, M. L.
Crawley, Chem. Rev. 2003, 103, 2921; d) R. Takeuchi, Synlett
2002, 1954.
[3] For recent reviews of asymmetric Cu-catalyzed allylic alkylation,
see: a) A. Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet,
C. Falciola, Chimia 2006, 60, 124; b) H. Yorimitsu, K. Oshima,
Angew. Chem. 2005, 117, 4509; Angew. Chem. Int. Ed. 2005, 44,
4435; c) A. Kar, N. P. Argade, Synthesis 2005, 2995.
[4] a) M. Van Klaveren, E. S. M. Persson, A. del Villar, D. M.
Grove, J. E. Bäckvall, G. van Koten, Tetrahedron Lett. 1995,
36, 3059; b) A. S. E. Karlstrom, F. F. Huerta, G. J. Meuzelaar,
J. E. Bäckvall, Synlett 2001, 923.
In conclusion, we have demonstrated that the asymmetric
methodology developed previously by our group can be
efficiently applied on more substituted allylic patterns with
phosphoramidite ligand L6 (S,SS) and a copper-catalyst
[5] a) F. Dübner, P. Knochel, Angew. Chem. 1999, 111, 391; Angew.
Chem. Int. Ed. 1999, 38, 379; b) F. Dübner, P. Knochel,
Tetrahedron Lett. 2000, 41, 9233.
[6] a) S. Tominaga, Y. Oi, T. Kato, D. K. An, S. Okamoto,
Tetrahedron Lett. 2004, 45, 5585; b) S. Okamoto, S. Tominaga,
loading as lowas 3 mol%. Two different classes of
b-
Angew. Chem. Int. Ed. 2006, 45, 5995 –5998
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