Catalytic asymmetric [4 + 2] cycloadditions and Hosomi-Sakurai reactions of α-alkylidene β-keto imides

Article abstract of DOI:10.1021/ol303381c

Highly enantioselective catalytic asymmetric reactions of rationally designed α-alkylidene β-keto imides are described. The [4 + 2] cycloadditions and Hosomi-Sakurai reactions of α-alkylidene β-keto imides proceed with high enantioselectivity and yield. T

Full text of DOI:10.1021/ol303381c

ORGANIC
LETTERS
2013
Vol. 15, No. 4
768–771
Catalytic Asymmetric [4 þ 2]
Cycloadditions and HosomiꢀSakurai
Reactions of r‑Alkylidene β‑Keto Imides
Kohei Orimoto, Harufumi Oyama, Yuki Namera, Takashi Niwa, and Masahisa Nakada*
Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
mnakada@waseda.jp
Received December 12, 2012
ABSTRACT
Highly enantioselective catalytic asymmetric reactions of rationally designed R-alkylidene β-keto imides are described. The [4 þ 2] cycloadditions
and HosomiꢀSakurai reactions of R-alkylidene β-keto imides proceed with high enantioselectivity and yield. The [4 þ 2] cycloadditions of the
imides with various dienes afford products bearing an all-carbon quaternary stereogenic center at the ring junction. R-Alkylidene β-keto imides
should be useful for the enantioselective total synthesis of natural products and other catalytic asymmetric applications.
R-Alkylidene β-keto esters are reactive electrophiles
capable of forming bicyclic compounds containing an
all-carbon quaternary stereogenic center via cycloaddi-
tions and Michael reactions. Hence, R-alkylidene β-keto
esters have been utilized in the total synthesis of natural
products, e.g., oubain,1a drimane-type sesquiterpenoids,1e
and others.1 However, successful Lewis acid catalyzed
asymmetric reactions of R-alkylidene β-keto esters have
been limited thus far,2ꢀ4 probably because the complex
formed with a chiral Lewis acid has the disadvantage of
poor enantioselection. That is, in complex A (Figure 1),
which is a square-planar complex formed by the R-alkylidene
β-keto ester and a bisoxazoline-Cu(II) catalyst,5 the alkene
would be located far from the bisoxazoline substituent,
resulting in low enantioselectivity.6 On the other hand,
N-acryloyloxazolidin-2-one7 and its derivatives have been
used in many catalytic asymmetric reactions8 because, in
complex B (Figure.1), the bisoxazoline substituent effec-
tively shields one side of the s-cis alkene.5
(1) For recent examples, see: (a) Zhang, H.; Reddy, M. S.; Phoenix,
S.; Deslongchamps, P. Angew. Chem., Int. Ed. 2008, 47, 1272. (b) Hsieh,
M.-T.; Liu, H.-J.; Ly, T. W.; Shia, K.-S. Org. Biomol. Chem. 2009, 7,
3285. (c) Li, W.; Liu, X.; Zhou, X.; Lee, C.-S. Org. Lett. 2010, 12, 548. (d)
De Lorbe, J. E.; Lotz, M. D.; Martin, S. F. Org. Lett. 2010, 12, 1576. (e)
Shi, H.; Fang, L.-C.; Tan, C.-H.; Shi, L.-L.; Zhang, W.-B.; Li, C.-C.;
Luo, T.-P.; Yang, Z. J. Am. Chem. Soc. 2011, 133, 14944.
(2) (a) Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem.
Commun. 1997, 1411. (b) Yamauchi, M.; Aoki, T.; Li, M.-Z.; Honda, Y.
Tetrahedron: Asymmetry 2001, 12, 3113. (c) Schotes, C.; Mezzetti, A.
J. Am. Chem. Soc. 2010, 132, 3652.
(3) For the catalytic asymmetric MukaiyamaꢀMichael reactions of
alkylidene malonates, see: (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.
J. Am. Chem. Soc. 1999, 121, 1994. (b) Evans, D. A.; Rovis, T.;
Kozlowski, M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc.
2000, 122, 9134. For the catalytic asymmetric DielsꢀAlder reaction of
quinones with an ester group, see: (c) Evans, D. A.; Wu, J. J. Am. Chem.
Soc. 2003, 125, 10162.
(5) Strictly speaking, the bisoxazolineꢀCu(II) complex may have a
distorted square-planar geometry. See: (a) Evans, D. A.; Miller, S. J.;
Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460. (b) Evans, D. A.; Miller,
S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559.
(6) Ohfusa, T.; Nishida, A. Tetrahedron 2011, 67, 1893.
(7) (a) Narasaka, K.; Inoue, M.; Yamada, T. Chem. Lett. 1986, 1109.
(b) Narasaka, K.; Inoue, M.; Yamada, T. Chem. Lett. 1986, 1967. (c)
Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. Soc.
1989, 111, 5493. (d) Corey, E. J.; Imai, N.; Zhang, H. Y. J. Am. Chem.
Soc. 1991, 113, 728. (e) Jnoff, E.; Ghosez, L. J. Am. Chem. Soc. 1999,
121, 2617. (f) Owens, T. D.; Hollander, F. J.; Oliver, A. G.; Ellman, J. A.
J. Am. Chem. Soc. 2001, 123, 1539. (g) Sudo, Y.; Shirasaki, D.; Harada,
S.; Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588. (h) Shimizu, Y.; Shi,
S.-L.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int. Ed. 2010,
49, 1103.
(4) For the recent use of R-alkylidene β-keto esters in asymmetric
catalysis, see: Schotes, C.; Mezzetti, A. ACS Catal. 2012, 2, 528.
r
10.1021/ol303381c
Published on Web 01/31/2013
2013 American Chemical Society

two steps (Scheme 1). This method was successfully applied
for the preparation of 3bꢀd,15 allowing us to investigate the
reactions of R-alkylidene β-keto imides.
Scheme 1. Preparation of R-Alkylidene β-Keto Imide 3a
Figure 1. Proposed structures of complexes formed by a bisox-
azoline-Cu(II) catalyst with an R-alkylidene β-keto ester
(complex A), N-acryloyl oxazolidin-2-one (complex B), and an
R-alkylidene β-keto imide (complex C: X = CH2, NMe, O).
The catalytic asymmetric[4 þ 2] cycloaddition of3awith
4a was first examined (Table 1). The reaction with the
L116aꢀCu(OTf)2 catalyst (10 mol %) at 0 °C afforded 5aa
(71%, 77% ee, entry 1). The reactions with ligand L216b
(entry 2) and ligand L316a (entry 3) did not improve the
enantioselectivity (47% ee and 33% ee, respectively). The
reaction with L1ꢀCu(OTf)2 in mixed solvent A (CH2Cl2/
toluene = 1:5) required 7 h for completion, but the ee was
improved to 85% (entry 4). The reaction at ꢀ15 °C was
slow, but the ee further increased to 90% (entry 5). Use of
molecular sieves (MS 4A) asanadditiveimproved the yield
(entry 6), and finally, the reaction with ligand L416c
afforded ent-5aa in 98% yield and 97% ee (entry 7).
The [4 þ 2] cycloadditions of 3a with dienes 4b and 4c
were also examined (Table 2). The reaction of 3a with
reactive Danishefsky’s diene 4b in the presence of L1ꢀ
Cu(OTf)2 (10 mol %) proceeded at ꢀ78 °C to afford 5ab in
94% yield (endo/exo = 13:1) and 92% ee (entry 1). To the
best of our knowledge, this result is the first example of a
catalytic asymmetric [4 þ 2] cycloaddition with Danishefsky’s
diene affording a bicyclic product containing an all-carbon
quaternary stereogenic center in high ee. The reaction of 3a
and 4b with ligand L4 afforded 5ab with 58% yield and
60% ee (endo/exo = 15:1, entry 2), though the reason for
the low yield and ee is unknown.
R-Alkylidene β-keto imides are attractive compounds
because the acidic imide hydrogen can form an internal
hydrogen bond to restrict free rotation of the imide
(Figure 1). As a result, reactions via complex C are
expected to show high enantioselectivity because the alkene
would be located at the same position as that in complex B.
The chief concern in the reaction via complex C was
whether the weak hydrogen bonding would be retained
duringthe reaction. However, the hydrogen-bond-directed
stereoselective reactions9 are known and, moreover, asym-
metric organocatalysis utilizing hydrogen bonding has
recently been reported.10 In addition, since imides can be
transformed into a variety of functional groups,10,11 prod-
ucts of the reactions of R-alkylidene β-keto imides would
be useful synthetic intermediates. Therefore, we investigated
catalytic asymmetric reactions of R-alkylidene β-keto imides
and report herein their highly enantioselective catalytic
asymmetric [4 þ 2] cycloadditions and HosomiꢀSakurai
reactions.
R-Alkylidene β-keto imides were hardly accessible by
known methods owing to their sensitivity toward basic
conditions.12 However, we found that the palladium-
catalyzed coupling reaction13 of organostannane 1a with
methyl N-[methoxy(methylthio)methylene]carbamate 214
afforded the corresponding imino ether, which was con-
verted to R-alkylidene β-keto imide 3a in 93% yield over
The reaction of 3a and less reactive isoprene 4c did not
proceed with L1ꢀCu(OTf)2 (10 mol %) at room tempera-
ture (entry 3). In contrast, the reaction did proceed using
ligand L4atrttoafford 3ac (61%, 73% ee, entry 4), though
42 h were required for completion. Use of L4ꢀCu(NTf2)2
(20 mol %) reduced the reaction time to 16 h, and the yield
and ee were improved to 100% and 94%, respectively
(entry 5).
(8) Selected references for the utility of N-acryloyl oxazolidin-2-one
and its congeners. For 1,3-dipolar addition: (a) Kobayashi, S.;
Kawamura, M. J. Am. Chem. Soc. 1998, 120, 5840. (b) Suga, H.; Inoue,
K.; Inoue, S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124, 14836. (c) Sibi,
M. P.; Stanley, L. M.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 8276.
For Michael addition of organozinc reagent: (d) Hird, A. W.; Hoveyda,
A. H. Angew. Chem., Int. Ed. 2003, 42, 1276.
The [4 þ 2] cycloaddition of cyclohexenone derivative 3b
and 4a with L4ꢀCu(OTf)2 (10 mol %) at ꢀ20 °C suc-
cessfully afforded 5ba (82% yield, 95% ee, Scheme 2).
It was expected that the reaction of 3c would proceed
slowly owing to the steric hindrance derived from the all-
carbon quaternary center adjacent to the reacting alkene.
(9) For the stereoselective epoxidation of allylic alcohols, see: Henbest,
H. B.; Wilson, R. A. L. J. Chem. Soc. 1957, 1958. For the stereoselective
SimmonsꢀSmith reaction, see: Simmons, H. E.; Cairns, T. L.; Vladuchick,
S. A.; Hoiness, C. M. Org. React. 1973, 20, 1.
(10) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
8959. (b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
4442. (c) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
11204.
(11) Pihko, P. M., Ed. Hydrogen Bonding in Organic Synthesis; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2009.
(12) R-Alkylidene β-keto esters have the same problem. See: (a) Cox,
J. H.; Norman, L. R. J. Org. Chem. 1972, 37, 4489. (b) Liu, H. J.; Ngooi,
T. K.; Browne, E. N. C. Can. J. Chem. 1988, 66, 3143.
(13) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Yu, Y.; Liebeskind, L. S. J. Org. Chem. 2004, 69, 3554. (c)
Prokopcov, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276.
(14) For the preparation of alkenyl stannanes 1aꢀd and 2, see SI.
(15) Tomizawa, T.; Orimoto, K.; Niwa, T.; Nakada, M. Org. Lett.
2012, 14, 6294.
(16) (a) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M.
J. Am. Chem. Soc. 1991, 113, 726. (b) Denmark, S. E.; Nakajima, N.;
Nicaise, O. J.-C.; Faucher, A.-M.; Edwards, J. P. J. Org. Chem. 1995, 60,
4884. (c) Sakakura, A.; Kondo, R.; Matsumura, Y.; Akakura, M.;
Ishihara, K. J. Am. Chem. Soc. 2009, 131, 17762.
Org. Lett., Vol. 15, No. 4, 2013
769

Table 1. Catalytic Asymmetric [4 þ 2] Cycloaddition of 3a
with 4a
Scheme 2. Catalytic Asymmetric [4 þ 2] Cycloaddition of 3b and
3c with 4a
temp
time
(h)
yieldb
(%)
eec,d
(%)
entry
L*a
solvent
(°C)
1
L1
L2
L3
L1
L1
L1
L4
CH2Cl2
CH2Cl2
CH2Cl2
Ae
0
2.5
2.5
3.0
7.0
21
71
74
96
74
70
89
98
77
2
0
47
3
0
33
Scheme 3. Catalytic Asymmetric [4 þ 2] Cycloaddition of 3d and 4b
4
0
85
5
Ae
ꢀ15
ꢀ15
ꢀ15
90
6f
7f
Ae
Ae
19
91
ꢀ97g
17
a 10.1 mol % of ligand was used. b Isolated yields. c For HPLC
conditions, see Supporting Information (SI). d The absolute structure
was proposed based on the X-ray structure of 5db. e A: CH2Cl2/toluene =
1:5. f MS 4 A was added. g A minus sign “ꢀ” means reversal of the
enantioselectivity.
manzamine A,17 and the reaction with L4 gave better
results (81%, 95% ee) (Scheme 3).
The Lewis acid catalyzed asymmetric HosomiꢀSakurai
reactions18 of imides 3a and 3b with allyltrimethylsilane
6a and methallyltrimethylsilane 6b were also examined
(Table 3). To the best of our knowledge, only one study
on the Lewis acid catalyzed asymmetric HosomiꢀSakurai
reaction using 6a has been reported.18b The reaction of 3a
with 6a in the presence of L1ꢀCu(OTf)2 (10 mol %) was
very slow at rt. However, the reaction with L4ꢀCu(OTf)2
(10 mol %) at rt afforded 7aa in 87% yield with 82% ee
(entry 1, Table 3). The same reaction at 0 °C was sluggish,
but use of 20 mol % of the catalyst resulted in a 94% yield
and 92% ee (entry 2). The reaction of 3a with more reactive
6b19 went to completion even at ꢀ30 °C to afford 7ab in
95% yield with 92% ee (entry 3). Like the reaction of 3a,
the reaction of 3b with 6a using L1ꢀCu(OTf)2 (10 mol %)
proceededslowly atrt, giving 7ba in 68% yield with50% ee
(entry 4). The use of more acidic L4ꢀCu(OTf)2 (10 mol %)
improved the yield and ee (88%, 88% ee, entry 5), but the
same reaction at 0 °C was sluggish, though the ee was
improved to 90% (entry 6). Finally, the reaction using
20 mol % of L4ꢀCu(OTf)2 at 0 °C was found to afford 7ba
in 80% yield with 90% ee (entry 7). The reaction of 3b with
6b using L1ꢀCu(OTf)2 (10 mol %) proceeded at ꢀ30 °C to
afford 7bb in 93% yield, but the ee was only 77% (entry 8).
Table 2. Catalytic Asymmetric [4 þ 2] Cycloaddition of 3a with
4b or 4c
temp
time
(h)
yield
(%)b
eec,d
(%)
entry
4
L*a
X
(°C)
1
4b
4b
4c
4c
4c
L1
L4
L1
L4
L4
OTf
OTf
OTf
OTf
NTf2
ꢀ78
ꢀ78
rt
2
94 (13/1)e
92
2
3
58 (15/1)e
ꢀ60f
3
12
42
16
0
ꢀ
4
5g
rt
61
100
ꢀ73f
ꢀ94f
rt
a 10.1 mol % of ligand was used. b Isolated yields. c For HPLC
conditions, see SI. d The absolute structure was proposed based on the
X-ray structure of 5db. e The endo/exo (endo isomer is shown above) ratio
of 5ab is shown in parentheses. f A minus sign “ꢀ” means reversal of the
enantioselectivity. g Cu(NTf2)2 (20 mol %) and ligand (20.2 mol %) were
used.
Interestingly, the reaction of 3c and 4a with L3ꢀCu(BF4)2
(5 mol %) at 0 °C was completed after 5 h with 92% yield
and 99% ee, indicating the good reactivity of 3c or
L3ꢀCu(BF4)2.
(17) Sakai, R.; Higa, T.; Jefford, C. W.; Bernardinelli, G. J. Am.
Chem. Soc. 1986, 108, 6404.
(18) (a) Hosomi, A.; Sakurai, H. J. Am. Chem. Soc. 1977, 99, 1673. (b)
Shizuka, M.; Snapper, M. L. Angew. Chem., Int. Ed. 2008, 47, 5049. The
authors mention that the reactions with methallyltrimethylsilane af-
forded products with less than 50% ee.
The L1ꢀCu(OTf)2-catalyzed [4 þ 2] cycloaddition of
R,β-unsaturated lactam 3d with 4b proceeded at ꢀ30 °C to
afford 5db (80%, 92% ee), which is a core structure of
(19) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(20) See SI for the details.
770
Org. Lett., Vol. 15, No. 4, 2013

In summary, we demonstrated the utility of rationally
designed R-alkylidene β-keto imides for Lewis acid cata-
lyzed asymmetric reactions. The catalytic asymmetric
[4 þ 2] cycloadditions of R-alkylidene β-keto imides afford
products bearing an all-carbon quaternary stereogenic
center at the ring junction with high yield and ee. The
imide groups in the products could be convertible to
different functional groups. For example, compounds
7ba and 7bb were easily transformed to the corresponding
methyl esters in 83% and 81% yields, respectively.20
Hence, the products obtained by catalytic asymmetric
reactions of R-alkylidene β-keto imides would be useful
for the enantioselective total synthesis of natural products.
Moreover, HosomiꢀSakurai reactions of R-alkylidene
β-keto imides, which are different types of reactions when
compared with [4 þ 2] cycloaddition, give products with
high yield and ee as well, suggesting the versatile utility of
R-alkylidene β-keto imides in asymmetric catalysis. Con-
sequently, further studies on asymmetric catalysis utilizing
R-alkylidene β-keto imides are now underway and will be
reported in due course.
Table 3. Catalytic Asymmetric HosomiꢀSakurai Reaction of 3
and 6
temp
time
(h)
yield
(%)b
ee
(%)c,d
entry
3
6
L*a
(°C)
1
3a
3a
3a
3b
3b
3b
3b
3b
3b
6a
6a
6b
6a
6a
6a
6a
6b
6b
L4
L4
L4
L1
L4
L4
L4
L1
L4
rt
22
87e
94e
95e
68
ꢀ82
ꢀ92
ꢀ92
50
2f
3
0
36
ꢀ30
rt
7.5
20
4
5
rt
24
88
ꢀ88
ꢀ90
ꢀ90
77
6
0
71
39
7f
8
0
47
80
93
ꢀ30
36
9
ꢀ30
10.5
90
ꢀ97
a 10.1 mol % of ligand was used. b Isolated yields. c For HPLC
conditions, see SI. d The absolute structure was proposed based on the
X-ray structure of 5db. e Yield after treatment of the initial products with
TBAF. See SI for the details. f 20 mol % of L4ꢀCu(OTf)2 catalyst was used.
However, the same reaction with L4ꢀCu(OTf)2 (10 mol %)
gratifyingly gave better results (90%, 97% ee, entry 9).
As summarized above, L4ꢀCu(OTf)2 was found to be
suitable for the catalytic asymmetric HosomiꢀSakurai
reactions of 3.
Figure 2. X-ray crystal structures of (a) 3d and (b) 5db.
The crystal structure of 3d (Figure 2a) has a planar
π-conjugated system, and the imide NH bond is oriented
toward the carbonyl oxygen of the lactam. The 1H NMR
spectrum of 3d showed the downfield shift of the imide NH
signal, which appeared around 11 ppm, suggesting the
presence of the hydrogen bond. The absolute structure of
5db was also confirmed by X-ray crystallographic analysis
(Figure 2b), which suggests that the [4 þ 2] cycloaddition
of 3d proceeded at the less hindered side of the dienophile
in complex C (Figure 1). The 1H NMR spectra of imides
3aꢀ3d suggest the presence of the H-bonded imide NH.
Hence, we speculated that all the reactions of 3aꢀ3d would
proceed at the less-hindered side of the alkene in complex
C. These results indicate that the internal H-bond in 3 was
retained during the reactions, even those with the catalyst
formed by ligand L4 and the Cu(II) reagent, which was
proposed to have a H-bond between the counteranion and
the ligand.16c
Acknowledgment. This work was financially supported
in part by The Grant-in-Aid for Scientific Research on
Innovative Areas “Organic Synthesis based on Reaction
Integration. Development of New Methods and Creation
of New Substances” (No. 2105).
Note Added after ASAP Publication. Scheme 3 contained
errors in the version published ASAP on January 31,
2012; the correct version reposted February 15, 2013.
Supporting Information Available. Experimental pro-
cedures and compound characterization data. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
771