Efficient preparation of β-branched γ,δ-unsaturated esters through copper-catalyzed allylic alkylation of ketene silyl acetal

Article abstract of DOI:10.1055/s-0031-1289712

Copper-catalyzed allylic alkylation of ketene silyl acetals proceeded with excellent γ-E-selectivity. Efficient α-to-γ chirality transfer with anti-selectivity occurred in the reaction of enantioenriched secondary allylic phosphates, affording enantioenri

Full text of DOI:10.1055/s-0031-1289712

1304
PRACTICAL SYNTHETIC PROCEDURES
Efficient Preparation of b-Branched g,d-Unsaturated Esters through
Copper-Catalyzed Allylic Alkylation of Ketene Silyl Acetal
Dong Li, Hirohisa Ohmiya,* Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81(11)7063749; E-mail: ohmiya@sci.hokudai.ac.jp; E-mail: sawamura@sci.hokudai.ac.jp
PSP
Received 17 December 2011
No220
Abstract: Copper-catalyzed allylic alkylation of ketene silyl acetals proceeded with excellent g-E-selectivity. Efficient a-to-g chirality
transfer with anti-selectivity occurred in the reaction of enantioenriched secondary allylic phosphates, affording enantioenriched b-
branched g,d-unsaturated esters. The reaction was readily scalable and highly reliable in terms of product yield and stereoselectivities.
Key words: g,d-unsaturated esters, copper, allylic alkylation, ketene silyl acetal, regioselectivity
O
O
F3C
CuBr (5 mol%)
ligand (10 mol%)
Cs2CO3 (3.2 mmol)
OPO(OEt)2
OSiMe3
OEt
O
CF3
Ph
α
γ
+
L1
Ph
OEt
THF, r.t., 12 h
1a
α
γ
2
O
O
1.0 g (3.2 mmol)
(6.4 mmol)
3a
E/Z >99:1
CF3
L1: 86%, γ/α 96:4
L2: 88%, γ/α 96:4
L2
Scheme 1 Copper-catalyzed g-E-selective allylic alkylation of allylic phosphates with an acetate-derived ketene silyl acetal
Transition-metal catalyzed allylic alkylations of enolates offers an alternative to Claisen rearrangement routes to
are useful methods for carbon–carbon bond formation in g,d-unsaturated esters from allylic alcohols.13 Mild reac-
organic synthesis due to the versatility of the carbonyl and tion conditions and the resulting broad functional group
alkene functionalities for stereoselective derivatization.1–3 compatibility would be primary benefits of using the
However, control of regioselectivity in the reaction with present copper-catalyzed method.14,15 Herein, we report
unsymmetrically substituted secondary allylic substrates that the copper-catalyzed enolate allylic alkylation is
is still difficult.4–9 Most studies focused on cases in which readily scalable. Thus, the protocol allows practical syn-
an allylic system is located at a terminal of a molecule or thetic access to functionalized, enantioenriched, b-
is highly asymmetrized by electronic and/or steric substit- branched g,d-unsaturated esters.
uent effects. Among those, the rhodium-catalyzed allylic
The allylic phosphate substrates are readily accessible in
alkylation of a copper enolate developed by Evans and co-
large scale from the corresponding allylic alcohols with-
workers would be most relevant to the present issue.4
out elaborate purification.16 (E)-Allylic phosphate 1a (3.2
mmol) and ketene silyl acetal 2 (6.4 mmol) were subjected
to the standard conditions: CuBr (5 mol%), electron-defi-
Nevertheless, regioselective enolate alkylation with inter-
nal allylic systems has yet to be explored.5
Previously, we reported a copper-catalyzed allylic alkyla- cient benzoylacetone L117 (10 mol%) as a ligand and
tion of allylic phosphates with acetate-derived ketene silyl Cs2CO3 (3.2 mmol) in tetrahydrofuran (THF) for 12 hours
acetals that proceeds with excellent g- and E-selectivi- at room temperature. The gram-scale reaction proceeded
ties.10–12 The reactions of enantioenriched allylic phos- smoothly to afford the corresponding g,d-unsaturated es-
phates having an a-stereogenic center occurred with ter with excellent regio- (g/a 96:4) and E/Z- (>99:1) selec-
excellent a-to-g chirality transfer with anti-stereochemis- tivities (Scheme 1). Moreover, 1-(2-naphthoyl)-3,3,3-
try, and gave the corresponding enantioenriched b- trifluoroacetone (L2) can be used instead of L1 without
branched g,d-unsaturated esters with an allylic stereogen- being detrimental to the product yield, or to the regio- or
ic center at the b-position of the ester carbonyl group. In stereoselectivities. It is noteworthy that L2 is commercial-
view of the applicability to organic synthesis, the protocol ly available and is reasonably priced, and thus should be
more appealing as a practical synthetic procedure.
Various substrates (Table 1) were subjected to the 2
mmol-scale reaction (>500 mg), and the reactions pro-
SYNTHESIS 2012, 44, 1304–1307
Advanced online publication: 15.02.2012
x
x
.
x
x
.2
0
1
2
DOI: 10.1055/s-0031-1289712; Art ID: Z116111SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
g-Selective Allylic Alkylation of Ketene Silyl Acetal
1305
ceeded in good to excellent yields, with high levels of as silyl ether, ester, arylbromide, and acetal were compat-
g/a- (96:4 to 99:1) and E/Z-selectivities (>99:1). ible in the allylic substrates (Table 1, entries 2–5).
The reaction was not significantly influenced by the alk- Steric demand was tolerated in the allylic substrate; the 2-
ene geometry of the allylic substrate. The reaction of the phenylethyl group at the a-position of 1a could be re-
allylic phosphate (Z)-1a, with Z-configuration, proceeded placed by a butyl group (1f) without significant change in
with somewhat higher regioselectivity with the excellent the product yield or regioselectivity (Table 1, entry 6).
E stereoselectivity retained (90% yield; g/a ratio 98:2; When a much bulkier isopropyl group was attached to the
E/Z ratio >99:1; Table 1, entry 1). Functional groups such a-position (1g), the product yield slightly decreased while
Table 1 Copper-Catalyzed Allylic Alkylation of Allylic Phosphates 1 with Ketene Silyl Acetal 2
CuBr (5 mol%)
L2 (10 mol%)
OSiMe3
OEt
OPO(OEt)2
R2
R2
O
Cs2CO3 (2 mmol)
R1
+
R1
OEt
THF, r.t., 12 h
1
2
3
(2 mmol)
(4 mmol)
E/Z >99:1
Entry
1
Allylic phosphate (1)
Product (3)
Yield (%)a,b
90
g/a ratioc
(EtO)2(O)PO
O
98:2
Ph
Ph
OEt
O
(Z)-1a
3a
OPO(OEt)2
2
3
91
90
99:1
98:2
TIPSO
3b
OEt
TIPSO
1b
O
O
O
OPO(OEt)2
EtO
OEt
EtO
1c
3c
OPO(OEt)2
O
OEt
4
5
86
78
96:4
99:1
Br
Br
1d
3d
O
OPO(OEt)2
O
O
O
OEt
O
1e
1f
3e
O
OPO(OEt)2
6
7
85
80
96:4
99:1
OEt
3f
OPO(OEt)2
OPO(OEt)2
O
OEt
1g
1h
3g
O
8
78
98:2
OEt
3h
a Isolated yield.
b Isomeric ratio E/Z >99:1.
c Determined by 1H NMR and/or GC analysis.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1304–1307

1306
D. Li et al.
PRACTICAL SYNTHETIC PROCEDURES
CuBr (5 mol%)
L2 (10 mol%)
Cs2CO3 (1 mmol)
2 (2 mmol)
OPO(OEt)2
O
OEt
THF, r.t., 12 h
86%
(S)-(E)-1f, 96% ee
(R)-(E)-3f, 95% ee
γ/α 96:4; E/Z >99:1
(1 mmol)
OPO(OEt)2
O
same as above
92%
TIPSO
TIPSO
OEt
(S)-(E)-3b, 96% ee
γ/α 99:1; E/Z >99:1
(R)-(E)-1b, 97% ee
(1 mmol)
Scheme 2 Synthesis of enantioenriched b-branched g,d-unsaturated esters
Copper-Catalyzed Allylic Alkylation of Ketene Silyl Acetal
(Scheme 1); (E)-Ethyl 3-Methyl-7-phenyl-4-heptenoate (3a);
Typical Procedure
the regioselectivity was much higher (Table 1, entry 7).
The g-methyl substituent of 1g could be replaced by a bu-
tyl group with virtually no deviation in the product yield
or selectivity (Table 1, entry 8). No reaction occurred un-
der identical conditions with a substrate bearing a cyclo-
hexyl group at the g-position, a cinnamyl-type substrate,
or cyclic substrates such as 2-cyclopentenyl, 2-cyclohex-
enyl, or 2-cycloheptenyl phosphates (data not shown).
CuBr (23.0 mg, 0.16 mmol), L2 (85.2 mg, 0.32 mmol) and Cs2CO3
(1.04 g, 3.20 mmol) were placed in a round-bottom flask, which was
sealed with a rubber plug. The flask was evacuated and refilled three
times with argon. THF (16 mL) was introduced and the mixture was
stirred at r.t. for 5 min. (1-Ethoxyvinyloxy)trimethylsilane (2; 1.03
g, 6.40 mmol) was added, the mixture was stirred for 5 min, then al-
lylic phosphate 1a (1.00 g, 3.2 mmol) was added. After stirring for
12 h at r.t., the mixture was filtered through a short plug of alumi-
num oxide, washed with Et2O and the solvent was removed under
reduced pressure. Flash silica gel chromatography (EtOAc–hexane,
5%) of the crude product provided 3a.
The reaction of enantioenriched allylic phosphates was
also scalable and proceeded with excellent a-to-g chirality
transfer with 1,3-anti stereochemistry to afford enantioen-
riched, b-branched, g,d-unsaturated esters (Scheme 2).
The reaction of (S)-(E)-1f (96% ee), which has a-butyl
Yield: 694 mg (2.81 mmol, 88%); colorless liquid; Rf = 0.40
and g-methyl substituents, with 2, gave (R)-(E)-3f (95% (EtOAc–hexane, 5%).
1H NMR (300 MHz, CDCl3): d = 1.01 (d, J = 6.9 Hz, 3 H), 1.24 (t,
J = 7.2 Hz, 3 H), 2.17–2.32 (m, 4 H), 2.58–2.68 (m, 3 H), 4.12 (q,
J = 7.2 Hz, 1 H), 5.36 (dd, J = 15.3, 6.9 Hz, 1 H), 5.48 (dt, J = 15.3,
6.3 Hz, 1 H), 7.15–7.20 (m, 3 H), 7.25–7.30 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 14.14, 20.19, 33.52, 34.22,
35.89, 41.82, 60.07, 125.78, 128.29, 128.51, 128.54, 134.88,
142.04, 172.79.
ee) with virtually no reduction of enantiomeric purity. The
allylic phosphate [(R)-(E)-1b], with a siloxy group in the
a-substituent, also reacted with 2 to afford (S)-(E)-3b in
92% yield with excellent 1,3-chirality transfer.
In summary, we have demonstrated that a copper-cata-
lyzed g-selective and stereospecific allylic alkylation of a
ketene silyl acetal was readily scalable and highly reliable
in terms of product yield and stereoselectivity.
HRMS (EI): m/z [M]+ calcd for C16H22O2: 246.16198; found:
246.16198.
Copper-Catalyzed Allylic Alkylation of Enantioenriched Allylic
Phosphate (Scheme 2); (S)-(E)-Ethyl 3-Methyl-7-triisopropylsi-
lyloxy-4-heptenoate (3b); Typical Procedure
All reactions were carried out under either nitrogen or argon atmo-
sphere. Unless otherwise noted, materials obtained from commer-
cial suppliers were used without further purification. CuBr was
purchased from Wako Pure Chemicals. Cs2CO3 was purchased
from Junsei Chemical Co. Ligand L2 was purchased from Tokyo
Kasei Kogyo Co., Ltd. THF was purchased from Kanto Chemical
Co., and stored under argon. NMR spectra were recorded with a
CuBr (7.20 mg, 0.05 mmol), L2 (26.6 mg, 0.10 mmol) and Cs2CO3
(325.8 mg, 1.0 mmol) were placed in a round-bottom flask, which
was sealed with a rubber plug. The flask was evacuated and then re-
filled three times with argon. THF (5 mL) was introduced and the
mixture was stirred at r.t. for 5 min. (1-Ethoxyvinyloxy)trimethylsi-
lane (2; 320 mg, 2.0 mmol) was added to the mixture and the result-
ing mixture was stirred for 5 min. Allylic phosphate (R)-(E)-1b
(408.6 mg, 1.0 mmol) was added and, after 12 h stirring at r.t., the
mixture was filtered through a short plug of alumina and washed
with Et2O. The solvent was removed under reduced pressure and
flash silica gel chromatography (EtOAc–hexane, 5%) of the crude
product provided (S)-(E)-3b. The enantiomeric excess was deter-
mined by chiral HPLC analysis of the p-nitrobenzoate derivative
obtained by desilylation followed by benzoylation from 3b. HPLC
analysis was performed with a Chiralcel OD-3 column {4.6  250
mm; hexane–2-propanol, 99:1; Daicel Chemical Industries; 0.5 mL/
min; 40 °C; 254 nm UV detector; retention time = 41.1 (S-isomer),
42.5 min (R-isomer)}.
1
Varian Gemini 2000 spectrometer, operating at 300 MHz for H
NMR and 75.4 MHz for 13C NMR. HRMS were recorded with a
Thermo Scientific Exactive or JEOL JMS-T100LP mass spectrom-
eter at the Instrumental Analysis Division, Equipment Management
Center, Creative Research Institution, Hokkaido University. Ele-
mental analysis was performed at the Instrumental Analysis Divi-
sion, Equipment Management Center, Creative Research
Institution, Hokkaido University. HPLC analyses were conducted
on a Hitachi Elite LaChrom system with a Hitachi L-2455 diode ar-
ray detector. TLC analyses were performed on commercial glass
plates bearing 0.25-mm layer of Merck silica gel 60F254. Silica gel
(Kanto Chemical Co., Silica gel 60 N, spherical, neutral) and alumi-
num oxide (Nacalai Tesuque, Alumina Activated 200) were used
for column chromatography.
Yield: 316 mg (0.92 mmol, 92%); Rf = 0.45 (EtOAc–hexane, 5%);
96% ee; [a]D21 +13.65 (c 1.03, CHCl3).
Synthesis 2012, 44, 1304–1307
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
g-Selective Allylic Alkylation of Ketene Silyl Acetal
1307
1H NMR (300 MHz, CDCl3): d = 1.01–1.10 (m, 24 H), 1.24 (t, J =
7.2 Hz, 3 H), 2.18–2.34 (m, 4 H), 2.59–2.68 (m, 1 H), 3.67 (t, J =
6.9 Hz, 3 H), 4.12 (q, J = 7.2 Hz, 1 H), 5.37–5.52 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 11.85, 14.15, 17.89, 36.27,
41.81, 60.07, 63.37, 125.85, 136.11, 172.83.
tions, see: Muraoka, T.; Matsuda, I.; Itoh, K. Tetrahedron
Lett. 2000, 41, 8807.
(6) For Rh-catalyzed a-selective allylic alkylations of malonates
with secondary allylic substrates, see: (a) Evans, P. A.;
Nelson, J. D. Tetrahedron Lett. 1998, 39, 1725. (b) Evans,
P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581.
(c) Ashfeld, B. L.; Miller, K. A.; Martin, S. F. Org. Lett.
2004, 6, 1321.
Anal. Calcd for C19H38O3Si: C, 66.61; H, 11.18. Found: C, 66.31;
H, 11.19.
(7) For iridium-catalyzed a-selective allylic alkylations of
malonates with secondary allylic substrates, see:
(a) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc. 1998, 120,
8647. (b) Bartels, B.; Helmchen, G. Chem. Commun. 1999,
741.
(8) For iron-catalyzed a-selective allylic alkylations of soft
carbon nucleophiles with secondary allylic substrates, see:
(a) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Synlett
1991, 513. (b) Plietker, B. Angew. Chem. Int. Ed. 2006, 45,
1469. (c) Holzwarth, M.; Dieskau, A.; Tabassam, M.;
Plietker, B. Angew. Chem. Int. Ed. 2009, 48, 7251.
(9) For ruthenium-catalyzed a-selective allylic alkylations of
malonates with secondary allylic substrates, see: (a) Trost,
B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed. 2002,
41, 1059. (b) Kawatsura, M.; Ata, F.; Hayase, S.; Itoh, T.
Chem. Commun. 2007, 4283.
Acknowledgment
This work was supported by Grants-in-Aid for Scientific Research
(B) and for Young Scientists (B), JSPS. We thank MEXT for finan-
cial support in the form of a Global COE grant (Project No. B01:
Catalysis as the Basis for Innovation in Materials Science).
References
(1) For reviews on transition-metal-catalyzed allylic
substitutions, see: (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144.
(b) Trost, B. M. Tetrahedron 1977, 33, 2615. (c) Trost, B.
M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(d) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921. (e) Lu, Z.; Ma, S. Angew. Chem. Int. Ed. 2008, 47,
258.
(10) Li, D.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc. 2011,
133, 5672.
(2) For selected examples on transition-metal-catalyzed
enantioselective allylic alkylations with ketone enolates,
see: (a) Trost, B. M.; Shroeder, G. M. J. Am. Chem. Soc.
1999, 121, 6759. (b) Braun, M.; Laicher, F.; Meier, T.
Angew. Chem. Int. Ed. 2000, 39, 3494. (c) Burger, E. C.;
Tunge, J. A. Org. Lett. 2004, 6, 4113. (d) Behenna, D. C.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 126, 15044. (e) Yan,
X.-X.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao, B.-X.; Dai,
L.-X.; Hou, X.-L. Angew. Chem. Int. Ed. 2005, 44, 6544.
(f) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 17180.
(g) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L.
J. Am. Chem. Soc. 2007, 129, 7718. (h) Chen, J.-P.; Ding,
C.-H.; Liu, W.; Hou, X.-L.; Dai, L.-X. J. Am. Chem. Soc.
2010, 132, 15493. (i) Braun, M.; Meier, T. Angew. Chem.
Int. Ed. 2006, 45, 6952; and references therein.
(j) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 127,
17192.
(3) The regioselectivity in palladium-catalyzed allylic
substitutions that involve a (p-allyl)palladium intermediates
is highly dependent on the substitution pattern of allylic
substrates. See refs 1 and 2a–i.
(4) For rhodium-catalyzed a-selective allylic alkylations of
copper enolates derived from aryl ketones with chiral
secondary allylic alcohol derivatives bearing a terminal
alkene moiety, see: (a) Evans, P. A.; Leahy, D. K. J. Am.
Chem. Soc. 2003, 125, 8974. (b) Evans, P. A.; Lawler, M. J.
J. Am. Chem. Soc. 2004, 126, 8642.
(5) Rhodium-catalyzed allylic substitution of allylic carbonates
having an allylic system in the internal position with
enoxysilanes occurred competitively at the a- and g-posi-
(11) For copper-catalyzed g-selective and stereospecific allyl–
alkyl and allyl–aryl couplings with organoboron
compounds, see: (a) Ohmiya, H.; Yokobori, U.; Makida, Y.;
Sawamura, M. J. Am. Chem. Soc. 2010, 132, 2895.
(b) Ohmiya, H.; Yokokawa, N.; Sawamura, M. Org. Lett.
2010, 12, 2438. (c) Whittaker, A. M.; Rucker, R. P.; Lalic,
G. Org. Lett. 2010, 12, 3216. (d) Shintani, R.; Takatsu, K.;
Takeda, M.; Hayashi, T. Angew. Chem. Int. Ed. 2011, 50,
8656.
(12) For palladium-catalyzed g-selective and stereospecific allyl–
aryl coupling between allylic esters and arylboronic acids,
see: (a) Ohmiya, H.; Makida, Y.; Tanaka, T.; Sawamura, M.
J. Am. Chem. Soc. 2008, 130, 17276. (b) Ohmiya, H.;
Makida, Y.; Li, D.; Tanabe, M.; Sawamura, M. J. Am. Chem.
Soc. 2010, 132, 879. (c) Li, D.; Tanaka, T.; Ohmiya, H.;
Sawamura, M. Org. Lett. 2010, 12, 3344. (d) Makida, Y.;
Ohmiya, H.; Sawamura, M. Chem. Asian J. 2011, 6, 410.
(13) For reviews on the Claisen rearrangement, see: (a) Ziegler,
F. E. Chem. Rev. 1988, 88, 1423. (b) Castro, A. M. M.
Chem. Rev. 2004, 104, 2939.
(14) For the rhodium-catalyzed reductive Claisen rearrangement
and discussions on the functional group compatibility of the
Ireland–Claisen rearrangement, see: Miller, S. P.; Morken, J.
P. Org. Lett. 2002, 4, 2743.
(15) For discussions on the functional group compatibility of the
Johnson–Claisen rearrangement, see: (a) Cosgrove, K. L.;
McGeary, R. P. Synlett 2009, 1749. (b) Cosgrove, K. L.;
McGeary, R. P. Tetrahedron 2010, 66, 3050.
(16) See the Supporting Information of ref. 6 for procedures
(17) Menéndez Pérez, B.; Hartung, J. Tetrahedron Lett. 2009, 50,
960.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1304–1307