Expeditious modular assembly of multisubstituted cyclohexanes via dioxanonedienes

Article abstract of DOI:10.1246/cl.2011.1192

An effective route to multisubstituted cyclohexanes has been developed by exploiting the DielsAlder reaction of easily available dienes within a dioxanone moiety with electrondeficient dienophiles.

Full text of DOI:10.1246/cl.2011.1192

doi:10.1246/cl.2011.1192
1192
Published on the web October 1, 2011
Expeditious Modular Assembly of Multisubstituted Cyclohexanes via Dioxanone-Dienes
Yoshifumi Aoki, Yuta Mochizuki, Tomohiro Yoshinari, Ken Ohmori, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, 2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551
(Received August 4, 2011; CL-110655; E-mail: ksuzuki@chem.titech.ac.jp)
An effective route to multisubstituted cyclohexanes has been
diene 3a (Scheme 3). To a mixture of iodide 1 and cyclo-
hexanecarbaldehyde in Et2O (¹90 °C) was added n-BuLi, where
a rapid halogen-lithium exchange followed by the carbonyl
addition gave alcohol 2a in 91% yield.8 Alcohol 2a, thus
obtained, was treated with triflic anhydride in the presence of
Hünig’s base, giving cleanly diene 3a as the single product in
80% yield. The (Z,Z) stereochemistry was proven by NOE study.
developed by exploiting the Diels-Alder reaction of easily
available dienes within a dioxanone moiety with electron-
deficient dienophiles.
Modular assembly of organic molecules with sizable
molecular weight and/or complexity is gaining increasing
importance for developing effective routes to architecturally
complex, biologically active natural/unnatural products.1 Asso-
ciated with the importance of cyclohexane motifs with func-
tional and stereochemical complexity,2 we report herein assem-
bly of a cyclohexane skeleton from three components, that is,
an olefin, an aldehyde, and a ¢-keto ester equivalent, that is,
iododioxinone I (Scheme 1).
HO
I
O
O
n-BuLi
+
O
O
O
O
OHC
Et2O, –90 °C
10 min
91%
NOE
2a
1
H
O
R3
R4
H
O
Tf2O
i-Pr2NEt
R3
R2
O
R2
R1
R4
O
H
O
I
CH2Cl2, –30 °C
O
10 min
O
R1
80%
O
O
O
3a
I
Scheme 3. Synthesis of diene 3a.
Scheme 1. Cyclohexane modular assembly.
Scheme 4 shows a rationale for the (Z,Z)-selectivity; Given
the 1,4-elimination occurred from the intermediary triflate with
the anti and/or syn relationship of the proton and the triflate,9 the
1,3-allylic strain10 suggests that the reaction would occur from
conformers A and/or B, either of which gives the (Z,Z) isomer.
As the key conjunctive agent of our plan for assembling
three components, we focused on diene II as the synthetic
platform, which could be derived from iododioxinone I and an
aldehyde (Scheme 2). Three promising features in II are, (1)
high Diels-Alder reactivity expected from two vicinal exocyclic
alkenes (s-cis diene), (2) characteristic reactivity by donor/
acceptor substitution pattern,3 and (3) capability of generating
acyl ketene species from the dioxinone moiety4 that is
regenerated by the Diels-Alder reaction, amenable for various
synthetic manipulations. In addition, the dioxanone scaffold may
also provide a platform for stereoselective reactions.5
OTf
Cy
OTf
Cy
O
O
O
O
H
H
H
H
Me
and/or
H
O
O
Me
H
A
B
Scheme 4. Possible conformations for 1,4-elimination.
We report herein facile synthesis of dienes II and their
excellent behaviors in the Diels-Alder reactions.
This protocol allowed facile access to several other dienes
3b-3e from the corresponding aldehydes (Scheme 5). Rigorous
(Z,Z)-selectivity applied in all of these cases. A limitation was
that the reaction of alcohol 2b, the propanal adduct, produced
also a positional isomer 4b in 38% yield.
R3
O
R4
R3
R4
R2
R1
R4
R2
I
H
O
O
O
R1
R1
O
O
O
O
O
O
Having these dienes in hand, we examined their reactivity in
the Diels-Alder reactions7 (Table 1). Upon reaction of 3a with
N-phenylmaleimide (toluene, room temp., 1 h), the endo cyclo-
adduct 5a was obtained as a single diastereomer in 95% yield
(Run 1). The stereochemistry of 5a was confirmed by X-ray
analysis11 (Figure 1). Other dienes were also subjected to the
reaction with N-phenylmaleimide, giving good to excellent yield
of the respective endo cycloadduct as a single isomer. Although
the diene 3c with sec-alkyl substituent provided the endo
cycloadduct 5c in excellent yield in a short time (Run 3), the
yields remained moderate for the reaction of prim-alkyl or
I
II
R3
R2
R1
R4
Further
Transformation
O
O
Scheme 2. Synthetic plan.
Readily available iododioxinone 16,7 served as a platform to
various dienes. The protocol is exemplified by the preparation of
Chem. Lett. 2011, 40, 1192-1194
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1193
O
O
R
O
CO2Me
MeO2C
HO
O
R
O
H
I
Yield/%
R
3
MeO2C
4
1
n-BuLi
MeO2C
toluene
room temp.
11 h
O
5
Et (2b)
i-Pr (2c)
t-Bu (2d)
64
90
69
81
2
O
O
Et2O
6
–90 °C
O
O
O
O
O
10 min
51%
Ph
(2e)
2b–e
3a
6a
1
H
4
CO2Me
H
R
O
O
H
O
6
1
5
Tf2
Yield/%
R
i-Pr2NEt
2
3
O
Me
Et (3b)
i-Pr (3c)
t-Bu(3d)
Ph (3e)
49
83
80
83
MeO2C
CH2Cl2
–30 °C
10 min
H
O
O
O
H
38%
NOE
3b–e
4b
Scheme 6. Reaction with dimethyl fumarate.
Scheme 5. Preparation of other dienes.
This one-pot protocol could be applied to the reactions of
alcohols 2 with various substituents, although the reaction
temperature and time were slightly different (Runs 2-5).
Table 1. Diels-Alder reaction of dienes 3a-3e
Ph
O
N
Ph
O
R
O
R
O
O
N
O
Table 2. One-pot reaction
O
O
Ph
Ph
toluene
room temp.
O
O
O
O
N
N
O
HO
O
R
O
R
O
O
Tf2O
i-Pr2NEt
3a–e
5a–e
endo adduct
O
O
CH2Cl2
–30 °C, 20 min
temp., time
Run
Substrate
R
Time/h Product
Yield/%
O
1
2
3
4
5
3a
3b
3c
3d
3e
Cya
Et
i-Pr
t-Bu
Ph
1
0.5
4
18
17
5a
5b
5c
5d
5e
95
46
90
80
52
2a–e
5a–e
Temp.
/°C
Cya ¹30 ¼ ¹15
Time
/h
Yield
/%
Run Substrate
R
Product
1
2
3
4
5
2a
2b
2c
2d
2e
4
0.5
1
8.5
4
5a
5b
5c
5d
5e
95
43
81
68
81
Et
i-Pr
¹30
¹30
aCy: cyclohexyl.
t-Bu ¹30 ¼ 25
Ph ¹30 ¼ 0
aCy: cyclohexyl.
The one-pot protocol was further applicable to a trinitrogen
heterocycle (Scheme 7). When 4-phenyl-1,2,4-triazole-3,5-di-
one was subjected to the one-pot reaction with alcohol 2a, the
cycloadduct 7a was obtained in 76% yield.
Ph
O
Ph
O
N
N
Figure 1. X-ray structure of 5a.
N
O
HO
O
N
O
N
Tf2O
N
i-Pr2NEt
O
O
CH2Cl2
–30 °C, 20 min
phenyl-substituted ones 3b and 3e (Runs 2 and 5). tert-Alkyl-
substituted diene 3d gave the endo cycloadduct 5d in high yield,
although longer reaction time was required (Run 4).
–30
–15 °C
4 h
O
O
O
76%
2a
7a
The reaction of diene 3a with dimethyl fumarate afforded
cycloadduct 6a in 51% yield as a single isomer among two
possible diastereomers (Scheme 6). The stereochemistry of
cycloadduct 6a was determined by NOE study.
These data convinced us of the successive one-pot reaction
of the diene formation and the Diels-Alder reaction, which
proved indeed the case7,12 (Table 2). Starting with the treatment
of alcohol 2a with Tf2O, and after confirming the formation of
diene 3a by TLC analysis, successive addition of N-phenyl-
maleimide cleanly affected the cycloaddition, giving the cyclo-
adduct 5a in excellent yield (Run 1).
Scheme 7. One-pot reaction with another dienophile.
The cycloadduct is amenable to various transformations by
exploiting the dioxinone moiety. An example is the following:7
upon heating of dioxinone 5a in toluene in the presence of
ethanol, ¢-keto ester 8a was obtained in 92% yield as the single
diastereomer, which has five contiguous stereogenic centers
(Scheme 8). The stereochemistry of 8a was determined by NOE
study. Interestingly, the ¢-keto ester 8a existed completely in the
keto form in CDCl3 as well as acetone-d6.
Chem. Lett. 2011, 40, 1192-1194
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1194
Ph
Ph
O
O
5
Selected examples are following: a) M. Demuth, A. Palomer,
H.-D. Sluma, A. K. Dey, C. Krüger, Y.-H. Tsay, Angew.
Chem., Int. Ed. Engl. 1986, 25, 1117. b) D. Seebach, J.
Zimmermann, Helv. Chim. Acta 1986, 69, 1147. c) M. Sato,
K. Takayama, T. Furuya, N. Inukai, C. Kaneko, Chem.
Pharm. Bull. 1987, 35, 3971. d) K. Ohmori, T. Suzuki, K.
Miyazawa, S. Nishiyama, S. Yamamura, Tetrahedron Lett.
1993, 34, 4981.
T. Iwaoka, T. Murohashi, N. Katagiri, M. Sato, C. Kaneko,
J. Chem. Soc., Perkin Trans. 1 1992, 1393.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
N
N
O
O
EtOH
toluene
reflux, 30 min
H
O
O
OEt
H
H
O
O
O
NOE
92%
5a
8a
Scheme 8. Transformation to ¢-keto ester 8a.
6
7
The ¢-keto ester 8a is regarded as an assemblage of three
components (Scheme 9), implying promising potential of this
approach in the modular synthesis of various natural/unnatural
compounds with a cyclohexane structure motif.
8
9
T. Yoshinari, K. Ohmori, K. Suzuki, Chem. Lett. 2010, 39,
1042.
For a review, see: F. M. Bickelhaupt, Mass Spectrom. Rev.
2001, 20, 347.
Ph
O
Ph
N
O
O
O
N
O
O
H
OEt
10 For a review, see: R. W. Hoffmann, Chem. Rev. 1989, 89,
1841.
OEt
O
O
O
11 Crystallographic data reported in this manuscript have been
deposited with Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC-838020. Copies
of the data can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge, CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
8a
Scheme 9. Three components assembly.
Further work is in progress on the exploration of the
synthetic potential of diene II, including its ambiphilic reactivity
coming from the substitution pattern with an electron-donating
and -withdrawing group.
12 A typical procedure for the one-pot reaction is described for
the reaction of alcohol 2a: To a solution of alcohol 2a
(20.2 mg, 75.3 ¯mol) in CH2Cl2 (0.75 mL) was added i-
Pr2NEt (52.5 ¯L, 301 ¯mol) at ¹30 °C followed by Tf2O
(19.0 ¯L, 113 ¯mol). After stirring for 20 min, N-phenyl-
maleimide (130 mg, 753 ¯mol) was added, and the stirring
was continued for 0.5 h. The resulting solution was allowed
to warm slowly to ¹15 °C. After stirring for 3 h at ¹15 °C,
phosphate buffer (pH 7) was added. Usual extractive workup
followed by purification by preparative TLC (hexane/
EtOAc = 4/1, three times) gave 5a (29.9 mg, 95%) as a
white powder.
References and Notes
1
2
3
4
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Chem. Lett. 2011, 40, 1192-1194
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/