Highly stereoselective Michael reduction/intramolecular Michael reaction cascade to synthesize trans-stereodiad comprising an all-carbon quaternary stereogenic center

Article abstract of DOI:10.1016/j.tetlet.2013.12.110

A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cascade is initiated by the regioselective Michael reduction of an α-methylidene ester with L-Selectride. This is followed by the highly stereoselective i

Full text of DOI:10.1016/j.tetlet.2013.12.110

Tetrahedron Letters 55 (2014) 1100–1103
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Tetrahedron Letters
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Highly stereoselective Michael reduction/intramolecular Michael
reaction cascade to synthesize trans-stereodiad comprising an
all-carbon quaternary stereogenic center
⇑
Tomohiro Fujii, Kohei Orimoto, 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
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly stereoselective Michael reduction/intramolecular Michael reaction cascade is described. The cas-
Received 13 November 2013
Revised 14 December 2013
Accepted 26 December 2013
Available online 4 January 2014
cade is initiated by the regioselective Michael reduction of an a-methylidene ester with L-Selectride. This
is followed by the highly stereoselective intramolecular Michael reaction which efficiently constructs a
six-membered carbocyclic ring with formation of the trans-stereodiad, composed of an all-carbon quater-
nary center and a tertiary stereogenic center. The stereoselectivity is perfectly controlled by the choice of
alkene geometry in the Michael acceptor.
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Stereoselective
Intramolecular
Michael
Cascade
Quaternary stereogenic center
Many bioactive terpenoids contain a six-membered carbocyclic
ring including a trans-stereodiad composed of an all-carbon qua-
ternary center and a tertiary stereogenic center. For example, such
a six-membered carbocyclic ring can be found as a partial structure
1 in bruceantin (Fig. 1),1 an antitumor terpenoid.
One of the effective construction methods of a six-membered
carbocyclic ring which includes a stereodiad, is [4+2] cycloaddition
(Scheme 1). However, to enhance the reaction, the use of reactive
dienes and trisubstituted dienophiles under heating or Lewis acidic
conditions is necessary; this is because [4+2] cycloaddition, which
generates an all-carbon quaternary stereogenic center is usually
slow.2
An alternative method for the construction of such a six-mem-
bered carbocyclic ring is the intramolecular Michael reaction
(Scheme 1).3 An intramolecular Michael reaction is generally fast,
proceeds below room temperature, and effectively generates an
all-carbon quaternary stereogenic center. Hence, the development
of the intramolecular Michael reaction is important for the con-
struction of such a six-membered carbocyclic ring.
OH
COOMe
HO
H
O
R1
R2
O
O
H
H
O
O
HO
O
H
H
1
bruceantin
Figure 1. Structures of 1 and bruceantin.
R1
R2
R1
H
[4+2]
+
R2
R1
H
R1
Intramolecular
Michael reaction
Z
Z
We were interested in the Michael reduction/Michael reaction
cascade, which initiates with the intermolecular Michael reduction
H
Scheme 1.
of an
a-methylidene ester 2 (Scheme 2), because the aforemen-
tioned reaction cascade of compound 2 would effectively generate
a
six-membered carbocyclic ring with the formation of the
stereodiad, composed of an all-carbon quaternary and tertiary
stereogenic centers. However, the use of -methylidene ester has
not been reported previously, though Michael reduction/Michael
reaction cascades of
,b-unsaturated esters have been reported.3,4
a
⇑
Corresponding author. Tel./fax: +81 3 5286 3240.
E-mail address: mnakada@waseda.jp (M. Nakada).
a
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.110

T. Fujii et al. / Tetrahedron Letters 55 (2014) 1100–1103
1101
Table 1
O
COR1
CO2R2
R
R –
CO2Ph
CO2Et
L-Selectride
(1.2 equiv)
R1
CO2R2
Michael
TIPSO
conditions, 2h
2
R
R
9E
CO2Ph
CO2Et
COR1
COR1
Michael
H
O
CO2Ph
CO2Et
CO2R2
OR2
+
H
H
TIPSO
TIPSO
3
10
11
Scheme 2.
Entry
Solvent
Temp (°C)
Yielda (%)
Ratio
10
11
10:11
The Michael reduction of compound 2 was expected to prefer-
entially take place at the less-hindered, reactive methylene termi-
1
2
3
4
5
6
7
8
Toluene
Toluene
CH2Cl2
Et2O
À78
0
31
40
30
22
29
20
26
0
31
27
25
10
12
50
31
82
1:1
1.5:1
1.2:1
2.2:1
2.4:1
1:2.5
1:1.2
0:1
nal of the
a,b-unsaturated ester in order to generate an enolate,
À78
À78
À78
À78
À78
À78
which would undergo an intramolecular Michael reaction to afford
compound 3 after workup (Scheme 2).
Et2Ob
THF
We selected compound 9E (Scheme 3) as a substrate to examine
the Michael reduction/intramolecular Michael reaction cascade be-
cause expected products prepared by the reaction of compound 9E
could be used for the enantioselective total synthesis of bruceantin.
Moreover, the reaction of compound 9E was thought to be useful
for understanding the stereoselective cascade reaction because
the intramolecular Michael reaction of the enolate generated by
the Michael reduction of 9E would proceed via a six-membered
transition state in which the two substituents, the methyl and
the TIPS-oxy groups would be equatorial.
THFc
THF/DMF = 1/2
a
b
c
Isolated yield.
LiClO4 (2.0 equiv) was added.
HMPA (2.0 equiv) was added.
H
Compound 9E was prepared from the known compound 4.5 The
Johnson–Claisen rearrangement of 2 with triethylortho acetate and
subsequent DIBAL-H reduction afforded aldehyde 5. The Evans al-
dol reaction6–8 of 5 successfully afforded compound 6, which was
converted to methyl ester 7 by reaction with sodium methoxide
and subsequent TIPS ether formation. DIBAL-H reduction of 7,
HO
OH
OH
H
H
12
Figure 2.
1) (EtO)3CCH3,
propionic acid
NOE
HO
H
H
O
I
I
reflux, 72%
OH
Me
CHO
I
H
2) DIBAL-H, toluene
5
4
–78 °C, 76%
H
O
O
CO2Et
N
NOE
O
13
HO
N
O
Figure 3.
O
I
Bu2BOTf, Et3N
CH2Cl2, –78 °C, 88%
O
6
subsequent Horner–Wadsworth–Emmons (HWE) reaction, and a
Pd-catalyzed carbonylation afforded compound 9E.
NaOMe, CH2Cl2, 0 °C
The Michael reduction/intramolecular Michael reaction cascade
of 9E was examined (Table 1). The reaction of 9E with K-Selectride
resulted in low conversion, but the reaction with L-Selectride in
toluene at À78 °C afforded compounds 10 and 11 in 62% yield with
a 1:1 ratio (entry 1). The structure of 10 was determined by X-ray
crystallographic analysis of its derivative 12 (Fig. 2),9 and the struc-
ture of 11 was determined by the NOESY analysis of the derivative
13 (Fig. 3). The reaction of 9E in toluene at 0 °C increased the ratio
of 10 with respect to 11 (entry 2, 10:11 = 1.5:1).
CO2Me
TIPSO
then; TIPSOTf, 2,6-lutidine
CH2Cl2, rt, 98% (2 steps)
7
I
1) DIBAL-H, CH2Cl2
–78 °C, 70%
CO2Et
TIPSO
2) (EtO)2P(O)CH2CO2Et
THF, rt, 93%
8E
The reaction in CH2Cl2 (entry 3) gave almost the same results as
those in toluene and the reaction in Et2O slightly increased the ra-
tio of 10 (entry 4). The use of LiClO4 as an additive increased the
combined yield of products and the ratio of 10 (entry 5). The reac-
tion in THF, a more polar solvent, afforded products in 70% com-
bined yield with an increased ratio of 11 (entry 6, 10:11 = 1:2.5).
The use of 10.0 equiv of HMPA as an additive in the reaction in
CO2Ph
CO2Et
Pd(PPh3)4 , Et3N
CO, PhOH
TIPSO
THF, 50 °C, 72%
9
E
Scheme 3.

1102
T. Fujii et al. / Tetrahedron Letters 55 (2014) 1100–1103
steric repulsion between two large groups (enolate and ethyloxy-
LiO
OPh
carbonylmethyl) is minimum in TS2E. Other two possible transi-
tion state models, TS3E and TS4E are energetically unfavorable
because the unstable chelate is formed in TS3E and the steric
repulsion between two large groups (enolate and ethyloxycarbon-
ylmethyl) is relatively large in both models The models in Figure 4
also explain the trans-stereoselectivity of the reaction.
OPh
OEt
RO
RO
RO
O
O
Li
CO2Et
TS1E
TS2E
As the reaction conditions for the stereoselective formation of
compound 11 were optimized, the stereoselective formation of
compound 10 was then examined. We envisioned that when the
substrate with a Z-enoate is used for the reaction, TS2E in Figure 4
would be energetically unfavorable owing to the A(1,3)-strain.
Consequently, compound 9Z (Scheme 4) was prepared to exam-
ine the Michael reduction/intramolecular Michael reaction cas-
cade. The HWE reaction of Ando’s phosphonate 1511 with
aldehyde 14, which was obtained by the DIBAL-H reduction of
compound 7 (Scheme 3), stereoselectively afforded 8Z, which suc-
cessfully underwent the Pd-catalyzed carbonylation to afford 9Z.
Having prepared 9Z, we examined the Michael reduction/intra-
molecular Michael reaction cascade of 9Z (Table 2). No desired
products were formed in toluene, CH2Cl2, Et2O at À78 °C, and the
product derived from the first Michael reduction was obtained (en-
tries 1–4). The reaction in THF afforded compound 10 as the sole
product but the yield was low (entry 5). The reaction in a mixed
solvent (THF/DMF = 1:2) reduced the yield (22%, entry 6), but the
same reaction at 0 °C afforded compound 10 in 61% yield without
forming other isomers (entry 7). The reaction in DMF did not im-
prove the yield (24%, entry 8). Finally, the reaction in THF using
10.0 equiv of HMPA as an additive afforded compound 10 in 78%
yield as the sole isomer (entry 9). The reaction of 9Z with K-Select-
ride was also attempted (entries 10–12), but the yield was low
even though compound 10 was formed as the sole product.
The reaction of compound 9Z should proceed via the six-mem-
bered transition state, which has the equatorial methyl and TIPS-
oxy groups. Among four possible transition state models of
LiO
OPh
OPh
OLi
CO2Et
RO
CO2Et
TS3E
TS4E
Figure 4.
THF resulted in a low stereoselectivity (entry 7), but, interestingly,
the reaction in a mixed solvent (THF/DMF = 1:2) afforded 11 as the
sole product (entry 8). In all the reactions in Table 1, only trans-iso-
mers were formed. The results in Table 1 indicate that reactions of
9E in the relatively low-polar solvent (entries 1–5) afford com-
pound 10 as the major product, and reactions in the polar solvent
(entries 6–8) afford compound 11 as the major product.
Chamberlin reported that enolates which were generated by the
Michael reduction of
trapped as their Z-silyl enol ethers;10 hence, the enolate formed by
the Michael reduction of -methylene esters with L-Selectride
a-methylene ketones with L-Selectride were
a
could have an E-configuration. Considering the stereoselective
enolate formation by the Michael reduction, the stereoselectivity
of the intramolecular Michael reaction could be explained by the
proposed transition state models in Figure 4. Thus, in the less-polar
solvent, the enolate generated by the initial Michael reduction
could form a chelate with another
a,b-unsaturated ester to stabi-
lize TS1E. This would be an energetically favored, fused system
composed of a chair six-membered ring and a boat-chair eight-
membered ring to afford compound 10. On the other hand, the
reaction in the polar solvent could proceed via a non-chelated
TS2E owing to the solvation to afford compound 11 because the
Table 2
CO2Ph
CO2Et
L-Selectride
(1.2 equiv)
TIPSO
9Z
conditions, 2h
15
Triton B,
I
CO2Ph
CO2Et
CO2Ph
CO2Et
THF, 0 °C, 20 min
+
TIPSO
O
93% (8E/8Z = 1/10)
TIPSO
TIPSO
14
10
11
I
I
Entry
Solvent
Temp (°C)
Yielda (%)
Ratio
+
CO2Et
10
11
10:11
TIPSO
TIPSO
1b
2b
3b
4b
5
6
7
8
9
Toluene
CH2Cl2
Et2O
À78
À78
À78
À78
À78
À78
0
0
0
0
0
45
22
61
24
78
38
48
20
0
0
0
0
0
0
0
0
0
0
0
0
—
—
—
—
1:0
1:0
1:0
1:0
1:0
1:0
1:0
1:0
CO2Et
8E
8Z
Et2Oc
THF
Pd(PPh3)4, CO
TEA, PhOH
CO2Ph
THF/DMF = 1:2
THF/DMF = 1:2
DMF
8Z
THF, 50 oC
8 h, 68%
TIPSO
OEt
0
CO2Et
THFd
THF
À78
À78
À78
À78
10e
11e
12e
9Z
THF/DMF = 1:2
THF
O
P
O
a
b
c
o-MeC6H4O
o-MeC6H4O
Isolated yield.
LiClO4 (2.0 equiv) was added.
HMPA (2.0 equiv) was added.
HMPA (10.0 equiv) was added.
K-Selectride was used.
15
Scheme 4.
d
e

T. Fujii et al. / Tetrahedron Letters 55 (2014) 1100–1103
1103
Acknowledgments
LiO
OPh
CO2Et
CO2Et
This work was financially supported in part by Waseda Univer-
sity Grant for Special Research Projects, The Grant-in-Aid for Scien-
tific Research on Innovative Areas ‘Organic Synthesis based on
Reaction Integration, Development of New Methods and Creation
of New Substances’ (No. 2105), and Grants for Excellent Graduate
Schools (Practical Chemical Wisdom), MEXT, Japan.
OPh
TIPSO
TIPSO
TIPSO
OLi
H
H
TS1Z
TS2Z
favored
LiO
OPh
Supplementary data
OPh
OLi
TIPSO
Supplementary data (full characterization of new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2013.12.110.
EtO2C
TS3Z
EtO2C
TS4Z
References and notes
Figure 5.
1. Kupchan, S. M.; Britton, R. W.; Lacadie, J. A.; Ziegler, M. F.; Sigel, C. W. J. Org.
Chem. 1975, 40, 648–654.
2. See our approach to solve this problem: Orimoto, K.; Oyama, H.; Namera, Y.;
Niwa, T.; Nakada, M. Org. Lett. 2013, 15, 768–771.
3. Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin, J. I. Org. React.
1995, 47, 315–552.
4. Yoshii, E.; Hori, K.; Nomura, K.; Yamaguchi, K. Synlett 1995, 568–570.
5. Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049–3051.
6. The vinylogous aldol reaction7 of 5 unfortunately did not afford the desired
product probably because 5 is sensitive toward Lewis acid.
7. Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.; Nakazaki, A.;
Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 13604–13605.
8. Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103, 1440–1441.
9. Crystallographic data (excluding structure factors) for the structure in this
paper have been deposited with the Cambridge Crystallographic Data centre as
supplementary publication numbers CCDC 970837. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 IEZ, UK [fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
10. Chamberlin, A. R.; Reich, S. H. J. Am. Chem. Soc. 1985, 107, 1440–1441.
11. Ando, K. J. Org. Chem. 1997, 62, 1934–1939.
TS1Z–4Z in Figure 5, TS1Z, 3Z, and 4Z are energetically unfavorable
owing to the A(1,3)-strain and 1,3-diaxial interaction. Consequently,
the reaction would proceed via the least strained TS2, but the rel-
atively strained nature of TS2 could lead to slow cyclization, result-
ing in the formation of the acyclic by-product (entries 1–4).
In summary, we found that the highly stereoselective Michael
reduction/intramolecular Michael reaction cascade which is initi-
ated by the Michael reduction of an
a-methylidene ester with L-
Selectride. The cascade efficiently synthesizes the trans-stereodiad
composed of an all-carbon quaternary center and a tertiary stere-
ogenic center. The stereoselectivity is perfectly controlled by the
choice of alkene geometry in the Michael acceptor. A natural prod-
uct synthesis utilizing the herein reported highly stereoselective
construction method is now underway and will be reported in
due course.