Enantioselective Conjugate Alkynylation of Enones
COMMUNICATION
Alkynes bearing substituted aromatic rings reacted with sev-
eral enones 1 to give the expected products with enantiose-
lectivities similar to those observed with phenylacetylene
dure is complementary to the Pd-catalyzed allylic substitu-
tion of 1,3-diphenylallyl acetate with pentane-2,4-dione,
which favours the formation of the compound with an E-
[17]
(
entries 1–7). 3-Thienylacetylene, bearing a heteroaromatic
ring, also reacted under these conditions to give compound
ae with 80% ee (entry 8). However, 1-butyne required a
double bond (see the Supporting Information).
Further-
more, compound 3aa could be reduced with LiAlH with
4
3
good diastereoselectivity, which, followed by silver-catalyzed
cyclization, gave access to chiral tetrahydrofuran 7 having
four stereogenic centres. Finally, we achieved an asymmetric
tandem 1,4-addition–fluorination reaction by quenching the
alkynylation mixture with N-fluorobenzenesulfonimide
higher reaction temperature and gave the expected product
in 43% yield with 27% ee (entry 9), while trimethylsilylace-
tylene gave a complex mixture of products that was not
characterized. Finally, it is worth noting that most products
[18]
3
are crystalline solids, which can be obtained almost enan-
(NFSI) as the terminal electrophile to give 8.
tiomerically pure by a single crystallization from hexane/
CH Cl (Table 2, entries 2, 5 and 8; Table 3, entries 1 and 3).
The absolute configuration of the stereogenic centre of
In conclusion, we have reported the first zinc-mediated
asymmetric conjugate addition of terminal alkynes 2 to
arylidene-1,3-diketones 1 by using a catalytic amount of a
chiral inducer. The products 3 are obtained in good yields
and enantioselectivities (up to 99% ee after a single crystal-
lization). The reaction can be applied to differently substi-
tuted enones and terminal alkynes with aromatic or
heteroaromatic groups. The potential synthetic applicability
of the resulting products was shown by diverse transforma-
tions. Further studies to enlarge the scope of the reaction as
well as mechanistic studies are underway.
2
2
3
aa was determined to be R after complete hydrogenation
(
Pd/CaCO ) of the triple bond (Scheme 2) and comparison
3
Experimental Section
General: Reactions were carried out under nitrogen in round-bottomed
flasks that were oven-dried overnight at 1208C. Commercial reagents
were used as purchased. Arylidene-1,3-diketones 1 were prepared from
the corresponding aldehydes and 1,3-diketones as described in the litera-
2
ture. Toluene was distilled from CaH . Nitroethane was dried and stored
on 4 ꢅ molecular sieves. Reactions were monitored by TLC analysis
using Merck silica gel 60 F-254 thin layer plates. Flash column chroma-
tography was performed on Merck silica gel 60, 0.040–0.063 mm. Melting
points were determined in capillary tubes. NMR spectra were recorded
1
13
at 300 MHz for H and at 75 MHz for C NMR spectroscopy by using re-
sidual nondeuterated solvent (CHCl ) as internal standard (d=7.26 and
7.0 ppm), and at 282 MHz for F NMR spectroscopy by using CFCl as
3
1
9
7
3
internal standard. Chemical shifts are given in ppm. The carbon type was
determined by DEPT experiments. High resolution mass spectra (ESI)
were recorded on a Q-TOF spectrometer equipped with an electrospray
source with a capillary voltage of 3.3 kV. Mass spectra (EI) were record-
ed at 70 eV. Specific optical rotations were measured by using sodium
light (D line 589 nm). Chiral HPLC analyses were performed in a chro-
matograph equipped with a UV diode-array detector by using chiral sta-
tionary columns from Daicel.
Scheme 2. Modifications of compound 3aa and tandem 1,4-addition–fluo-
rination: i) H , Pd/CaCO , EtOH, 30 min, 99%; ii) H , Lindlar catalyst,
benzene, 1 h, 99%; iii) LiAlH (4 equiv), THF, 08C, 1 h, 86%;
iv) Ag(OTf) (cat.), THF, 08C, 77%; v) L9, Et Zn, toluene/EtNO , 4 h,
then NFSI (3 equiv), RT, 77 h, 48%.
2
3
2
4
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
General procedure for the enantioselective alkynylation reaction: A solu-
tion of Et Zn in toluene (1.5m, 0.17 mL, 0.25 mmol) was added dropwise
2
to a solution of (R)-VANOL (L9, 11.3 mg, 0.025 mmol) and phenylacety-
lene (2a, 103 mL, 0.94 mmol) in toluene (0.48 mL) at RT under nitrogen,
and the mixture was stirred for 1.5 h at 708C. Then, the reaction mixture
was cooled to RT. A solution of arylidene-1,3-diketone 1a (23.5 mg,
of the resulting product 4 with the hydrogenation product of
the known compound (+)-3-[(S,E)-1,3-diphenylallyl]pen-
0
.125 mmol) in nitroethane (1.0 mL) was added by using a syringe. The
solution was stirred until the reaction was complete (monitored by TLC).
The reaction mixture was quenched with aqueous NH Cl (20%, 1.0 mL),
extracted with CH Cl (2ꢆ15 mL), washed with brine (15 mL), dried
[17]
tane-2,4-dione, which was obtained by Pd-catalyzed enan-
tioselective allylic alkylation of (E)-1,3-diphenylallyl acetate
with pentane-2,4-dione (see the Supporting Information).
For the other products 3, the stereochemistry was assigned
by analogy.
On the other hand, reduction of the triple bond with Lin-
dlar catalyst quantitatively provided compound 5 with a Z-
double bond and an allylic stereogenic centre. This proce-
4
2
2
over MgSO , and concentrated under reduced pressure. Purification by
4
flash chromatography on silica gel eluting with hexane/EtOAc mixtures
2
0
afforded compound 3aa (26.2 mg, 72%). M.p. 75–778C; [a] = +46.7
D
1
(
(
3
c=0.73 in CHCl
3
, 87% ee); H NMR (300 MHz, CDCl
3
): d=7.42–7.27
m, 10H), 4.67 (d, J=11.1 Hz, 1H), 4.22 (d, J=11.1 Hz, 1H), 2.39 (s,
H), 1.93 ppm (s, 3H); C NMR (75.5 MHz, CDCl
13
3
) d=201.6 (C), 201.6
(C), 138.2 (C), 131.6 (2CH), 128.9 (2CH), 128.3 (CH), 128.2 (2CH), 128.1
Chem. Eur. J. 2012, 00, 0 – 0
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
3
&
ÞÞ
These are not the final page numbers!
Blay, Gonzalo
