Asymmetric [4+2] cycloadditions employing 1,3-dienes derived from (R)-4-t-butyldimethyl-silyloxy-2-cyclohexen-1-one

Article abstract of DOI:10.1016/j.tetlet.2009.09.055

1,3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with activated dienophiles to form predominately (or sometimes exclusively) syn/endo products. These controlled [4+2] cycloadditions increase the asymmetric complexity from one

Full text of DOI:10.1016/j.tetlet.2009.09.055

Tetrahedron Letters 50 (2009) 6621–6623
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Tetrahedron Letters
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Asymmetric [4+2] cycloadditions employing 1,3-dienes derived
from (R)-4-t-butyldimethyl-silyloxy-2-cyclohexen-1-one
*
Zhengmao Hua, Lei Chen, Yan Mei, Zhendong Jin
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, IA 52242, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2009
Revised 8 September 2009
Accepted 9 September 2009
Available online 15 September 2009
1,3-Dienes derived from (R)-4-t-butyldimethylsilyloxy-2-cyclohexen-1-one react with activated dieno-
philes to form predominately (or sometimes exclusively) syn/endo products. These controlled [4+2] cyc-
loadditions increase the asymmetric complexity from one asymmetric center in the starting material to
five asymmetric centers in the products in a single step, and provide a powerful approach for the asym-
metric synthesis of compounds containing the bicyclo[2.2.2]octanone carbon skeleton.
Ó 2009 Elsevier Ltd. All rights reserved.
(R)-4-t-Butyldimethylsilyloxy-2-cyclohexen-1-one 1 and its (S)-
isomer are very useful chiral building blocks and have been widely
used in organic synthesis.1 The advantage of using this compound
as a starting material is due to its excellent diastereoselectivity in
conjugate additions since all stereochemistry is introduced by com-
munication from the stereogenic center at the C-4 position of 1.
Recently, we reported for the first time that the cross-conju-
gated dienolate 2 derived from 1 can be employed in the double
Michael reaction for the asymmetric synthesis of a highly function-
alized bicyclo[2.2.2]octanone 4 (Scheme 1).2 The reaction was
exclusively endo selective and occurred at the face anti to the bulky
TBSO group to afford only one of the eight possible diastereomers.
We have also shown that the combination of the double Michael
reaction and an anionic Oxy-cope rearrangement is a powerful ap-
proach for the synthesis of the cis-decalin portion of the antitumor
natural product superstolide A.2
2D NMR analysis (Scheme 3). The reaction was exclusively endo
selective, but the facial selectivity was poor. Surprisingly, the ma-
jor product 8-syn was formed when N-benzyl maleimide 7 ap-
proached 1,3-diene 5 from the same face of TBSO substituent on
the diene plane, which was opposite to what was observed in the
double Michael reaction.2
The stereochemical outcome of this reaction is similar to vari-
ous [4+2] cycloadditions involving 1,3-dienes bearing an OR group
at the allylic stereogenic center,3 and is proposed to be controlled
by the Cieplak effect.4 The preferential syn facial selectivity seen in
our system was also observed by others when compound 1 was
employed as a dienophile.1q,1s However, the syn versus anti pi-fa-
cial selectivity seen during cycloaddition for such systems appears
to depend on many factors including the specific diene and the
reactivity of the dienophile.5
To improve the facial selectivity the effect of various enol ether
substituents was investigated (Scheme 4). It was discovered that
the [4+2] cycloaddition between 9 and 7 provided exclusively endo
products with the facial selectivity being improved to 4.3:1 (syn:an-
ti), and the combined yield for 10-syn and 10-anti was 95%. To the
best of our knowledge, this is the first successful application of a
1,3-diene derived from 1 in a [4+2] cycloaddition.
Eight different solvents were screened to determine the solvent
effect on the facial selectivity of the asymmetric [4+2] cycloaddi-
tion between 1,3-diene 9 and N-benzyl maleimide 7. The results
are summarized in Table 1. It was found that the facial selectivity
(syn:anti) was higher in solvents such as benzene, methylene chlo-
ride, and chloroform. Reactions in polar solvents such as acetone,
methanol, and acetonitrile gave lower facial selectivity. The pre-
ferred choice of solvent is benzene or methylene chloride since
chloroform may contain a trace amount of acid that might promote
the formation of side products.
The successful double Michael reaction prompted investigation
of [4+2] cycloadditions. Although the (S)-isomer of 1 was used as a
dienophile in Diels–Alder reactions,1q,s [4+2] cycloadditions using
1,3-dienes derived from 1 or its (S)-isomer have never been
reported.
Compound 1 was converted to 1,3-diene 5 in 87% yield
(Scheme 2). To our surprise, [4+2] cycloaddition between 5 and
various
a,b-unsaturated compounds proved to be very difficult
because 5 was quite unreactive. In addition, 5 was prone to
decomposition and aromatization in the presence of a Lewis acid.
Therefore, the desired [4+2] adducts were never detected. To
accelerate the reaction, more reactive dienophiles were needed.
We were delighted to observe that the [4+2] cycloaddition be-
tween 1,3-diene 5 and N-benzyl maleimide 7 gave compounds
8-syn (51%) and 8-anti (43%), which were confirmed by 1D and
Seven reactive dienophiles were chosen to study the scope and
limitation of this asymmetric [4+2] cycloaddition, and the results
* Corresponding author. Tel.: +1 319 353 5359; fax: +1 319 335 8766.
E-mail address: zhendong-jin@uiowa.edu (Z. Jin).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.055

6622
Z. Hua et al. / Tetrahedron Letters 50 (2009) 6621–6623
Table 2
Me
O
Asymmetric [4+2] cycloadditions between 1,3-diene
dienophiles
9
and various reactive
O
4
O-Li+
O
TBSO
O
Me
O
3
LDA
Entry
Diene
Dienophile
Productsa,b
THF. 0 ºC, 42%
(60% BRSM)
O
MeO2C
O
TBSO
O
OTBS
OTBS
TBSO
AcO
OAc
anti/endo
1
2
4
O
NH
1
2
9
Scheme 1. Asymmetric double Michael reaction.
NH
O
O
11
HN
O
12-anti 14%
12-syn 81%
R
O
OTIPS
TBSO
TBSO
AcO
O
OAc
i. LDA
ii. TIPSOTf
6
E
O
[4+2] cycloaddition
products
NPh
O
9
9
87%
conditions
O
NPh
O
13
PhN
14-syn 77%
O
E=COR, CO2R, SO2Ph
OTBS
5
14-anti 17%
OTBS
1
O
O
TBSO
TBSO
AcO
Scheme 2. Failed [4+2] cycloaddition.
OAc
O
O
3
O
O
O
15
O
O
16-anti 13%c
16-syn 87%c
OTIPS
O
TBSO
O
TBSO
TIPSO
OTIPS
C6D6
+
NBn
TBSO
+
O
O
25 ºC
2 d
OAc
N
N
O
O
NBn
O
NPh
N
BnN
OTBS
5
O
N
4
5
6
9
9
9
7
8-syn
8-anti
O
17
PhN
18-syn 98%
O
51%
43%
Scheme 3. [4+2] Cycloaddition.
O
No reaction
O
OAc
TBSO
O
19
i. LDA
TBSO
OAc
ii. Ac2O
7, C6D6
AcO
+
O
O
25 ºC
4 d
90%
O
TBSO
TBSO
AcO
O
NBn
OTBS
1
OTBS
9
OAc
BnN
O
O
10-syn
10-anti
O
77%
18%
O
O
O
Scheme 4. A facial and stereoselective [4+2] cycloaddition.
20
21-anti 16%
21-syn 73%
TBSO
TBSO
AcO
Table 1
O
OAc
Solvent effect on the facial selectivity (10-syn:10-anti)
O
O
Entry
Solvent
10-syn:10-antia
7
9
O
O
1
2
3
4
5
6
7
8
CDCl3
C6D6
CD2Cl2
Et2O
Acetone-d6
THF
CD3OD
CD3CN
4.5:1
4.2:1
4.0:1
3.3:1
2.5:1
2.0:1
2.0:1
1.7:1
O
22
23-anti 18%
23-syn 66%
a
All reactions were run in either CH2Cl2 or C6H6 at 25 °C for 3–4 days under
argon unless otherwise stated.
b
All yields were isolated yields unless otherwise stated. All compounds were
fully characterized.
The yields were calculated based on the integration of 1H NMR spectrum of the
c
The syn:anti ratio was calculated based on the integration of 1H NMR spectra of
a
crude mixture of two [4+2] adducts.
the mixture of the [4+2] adducts. The reaction was run at 25 °C under argon.
decomposed on silica gel during flash column chromatography,
resulting in lower yields. Since the reaction was very clean, and
only these two products were detected in its unpurified 1H NMR
spectrum, and therefore spectral integration of the respective
products was used to reflect the real ratio of 16-syn and 16-anti.
Compound 17 was a much more reactive dienophile, and the
reaction was complete in 15 min at À20 °C to afford exclusively
18-syn with nearly quantitative yield (Table 2, entry 4). On the
other hand, no desired [4+2] cycloaddition product was isolated
are summarized in Table 2. All reactions provided exclusive endo
products with the facial selectivity favoring the syn product, and
the yields for the syn/endo products were very good. The reaction
between 9 and 15 had to be carried out in the presence of 0.1 equiv
of 2,6-lutidine (Table 2, entry 3), otherwise traces of maleic acid
promoted formation of the aromatized side product, phenyl ace-
tate. The yields for 16-syn and 16-anti were not isolated yields. This
was because both products contain the anhydride moiety, which

Z. Hua et al. / Tetrahedron Letters 50 (2009) 6621–6623
6623
Table 3
sively) syn/endo products. These highly controlled [4+2] cycloaddi-
tions can increase the asymmetric complexity from one
asymmetric center in the starting material to five asymmetric cen-
ters in the products in a single step, and provide a powerful ap-
proach for the asymmetric synthesis of compounds containing
the bicyclo[2.2.2]octanone carbon skeleton. Application of this
new method to total synthesis of natural products is underway,
and will be reported in due course.
Asymmetric [4+2] cycloadditions between N-benzyl maleimide 7 and various 1,3-
dienes derived from compound 1
Entry Diene
AcO
Dienophile
Productsa,b
TBSO
O
TBSO
AcO
I
I
OAc
I
O
1
2
3
4
7
O
NBn
BnN
O
OTBS
25-anti 17%
25-syn 79%
24
Acknowledgments
AcO
TBSO
Me
Me
TBSO
AcO
This work was financially supported by a Grant (R01 CA109208)
from the National Institutes Health. We thank Dr. Ying Kang and Mr.
Changgang Lou for the preparation of compounds 28 and 24.
Me
OAc
O
O
7
7
7
NBn
O
BnN
O
OTBS
26
27-anti 14%
27-syn 81%
References and notes
AcO
1. (a) Nicolaou, K. C.; Li, A. Angew. Chem., Int. Ed. 2008, 47, 6579; (b) Edwards, M. G.;
Kenworthy, M. N.; Kitson, R. R. A.; Scott, M. S.; Taylor, R. J. K. Angew. Chem., Int. Ed.
2008, 47, 1935; (c) Nicolaou, K. C.; Li, H.; Nold, A. L.; Pappo, D.; Lenzen, A. J. Am.
Chem. Soc. 2007, 129, 10356; (d) Barfoot, C. W.; Burns, A. R.; Edwards, M. G.;
Kenworthy, M. N.; Ahmed, M.; Shanahan, S. E.; Taylor, R. J. K. Org. Lett. 2008, 10,
353; (e) Xia, J.; Brown, L. E.; Konopelski, J. P. J. Org. Chem. 2007, 72, 6885; (f)
Wilson, E. M.; Trauner, D. Org. Lett. 2007, 9, 1327; (g) Dirat, O.; Elliott, J. M.; Jelley,
R. A.; Jones, A. B.; Reader, M. Tetrahedron Lett. 2006, 47, 1295; (h) Matsuzawa, M.;
Kakeya, H.; Yamaguchi, J.; Shoji, M.; Onose, R.; Osada, H.; Hayashi, Y. Chem. Asian
J. 2006, 1, 845; (i) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006, 128,
6931; (j) Williams, D. R.; Kammler, D. C.; Donnell, A. F.; Goundry, W. R. F. Angew.
Chem., Int. Ed. 2005, 44, 6715; (k) Rodeschini, V.; Van de Weghe, P.; Salomon, E.;
Tarnus, C.; Eustache, J. J. Org. Chem. 2005, 70, 2409; (l) Tachihara, T.; Kitahara, T.
Tetrahedron 2003, 59, 1773; (m) Evarts, J. B.; Fuchs, P. L. Tetrahedron Lett. 2001, 42,
3673; (n) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Chem. Soc., Perkin Trans. 1
2001, 166; (o) Lopez-Pelegrin, J. A.; Janda, K. D. Chem. Eur. J. 2000, 6, 1917; (p)
Rucker, M.; Bruckner, R. Tetrahedron Lett. 1997, 38, 7353; (q) Sas, B.; De Clercq, P.;
Vandewalle, M. Synlett 1997, 1167; (r) Witschel, M. C.; Bestmann, H. J.
Tetrahedron Lett. 1995, 36, 3325; (s) Jeroncic, L. O.; Cabal, M.-P.; Danishefsky, S.
J. J. Org. Chem. 1991, 56, 387; (t) Danishefsky, S. J.; Simoneau, B. J. Am. Chem. Soc.
1989, 111, 2599; (u) Jones, A. B.; Yamaguchi, M.; Patten, A.; Danishefsky, S. J.;
Ragan, J. A.; Smith, D. B.; Schreiber, S. L. J. Org. Chem. 1989, 54, 17; (v) Kitahara, T.
Tetrahedron 2003, 59, 1773.
TBSO
TBSO
AcO
OAc
Me
O
O
Me
Me
O
NBn
BnN
O
OTBS
28
29-anti 13%
29-syn 83%
AcO
TBSO
Me
O
OAc
Me
n-Bu
O
31-syn 87%
n-Bu
BnN
OTBS
30
a
All reactions were run in either CH2Cl2 or C6H6 at 25 °C for 3–4 days under
argon.
b
All yields were isolated yields. All compounds were fully characterized.
after 9 and the relatively less reactive 196 were heated in a sealed
tube at 120 °C (Table 2, entry 5). The reaction between 9 and 20
was carried out at 60 °C in a sealed tube whereas the reaction be-
tween 9 and 22 had to be heated to 100 °C in a sealed tube. These
experiments have shown that various active dienophiles are suit-
able substrates for this asymmetric [4+2] cycloaddition.
We then turned our attention to the scope of chiral 1,3-dienes.
Four chiral 1,3-dienes 24,7 26,8 28,9 and 3010 were prepared from
compound 1 and investigated in the asymmetric [4+2] cycloaddi-
tion with N-benzyl maleimide 7 (Table 3).
Entry 1 indicates that an iodo group at the 3 position of the 1,3-
diene had no effect on the facial selectivity (Table 3, entry 1). How-
ever, introducing a methyl group at either the 1 or 4 position of the
1,3-diene slightly improved the facial selectivity, and the yields of
the major syn adducts were also improved to over 80% (Table 3,
entries 2 and 3). These results were consistent with the reaction be-
tween 1,3-diene 30 and 7 (Table 3, entry 4). The [4+2] adduct 31-syn
was isolated in 87%, and the anti product was not detected. It should
be noted that among four newly created stereogenic centers in
31-syn two of them are bridgehead quaternary carbons, which are
difficult to construct.
2. Hua, Z.; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005, 7, 1939.
3. (a) Auksi, H.; Yates, P. Can. J. Chem. 1981, 59, 2510; (b) Holmberg, K.; Kirudd, H.;
Westin, G. Acta Chem. Scand., Ser. B. 1974, 28, 913; (c) Gillard, J. R.; Burnell, D. J.
J. Chem. Soc., Chem. Commun. 1989, 1439; (d) Macaulay, J. B.; Fallis, A. G. J. Am.
Chem. Soc. 1988, 110, 4074; (e) Kahn, S. D.; Hehre, W. J. J. Am. Chem. Soc. 1987,
109, 663.
4. Cieplak, A. S. Chem. Rev. 1999, 99, 1265. and references cited therein.
5. Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
4625.
6. (a) DePuy, C. B.; Zaweski, E. F. J. Am. Chem. Soc. 1959, 81, 4920; (b) Ramesh, N.
G.; Bakkeren, F. J. A. D.; Groot, D.; Passamonti, U.; Klunder, A. J. H.; Zwanenburg,
B. Tetrahedron 2001, 57, 9877.
7. Synthesis of compound 24: compound 1 reacted with I2 in the presence of
pyridine to provide (R)-4-(t-butyldimethylsilyloxy)-2-iodo-2-cyclohexen-1-
one in 63% yield, which was transformed to 24 in 71% yield via the same
procedure used in the preparation of 9.
8. Synthesis of compound 26: compound 1 reacted with LDA followed by the
addition of MeI to give (4R)-4-(t-butyldimethylsilyloxy)-6-methyl-2-
cyclohexen-1-one in 66% yield, which was transformed to 26 in 92% yield via
the same procedure used in the preparation of 9.
9. Synthesis of compound 28: conjugate addition of lithium cyano methyl cuprate to
compound 1 in the presence of TMSCl provided silyl enol ether that underwent
Saegusa oxidation to give (4R)-3-methyl-4-(t-butyldi- methylsilyloxy)-2-
cyclohexen-1-one in 68% yield, which was transformed to 28 in 84% yield via
the same procedure used in the preparation of 9.
10. Synthesis of compound 30: conjugate addition of lithium cyano n-butyl
cuprate to compound
1 in the presence of TMSCl provided silyl enol
In summary, a facial- and stereoselective [4+2] cycloaddition
employing 1,3-dienes derived from (R)-4-t-butyldimethyl-silyl-
oxy-2-cyclohexen-1-one 1 has been developed. We have demon-
strated for the first time that these 1,3-dienes can react with
activated dienophiles to form predominately (or sometimes exclu-
ether that underwent Saegusa oxidation to give (4R)-3-n-butyl-4-(t-
butyldimethyl-silyloxy)-2-cyclohexen-1-one in 70% yield. Treatment with
LDA followed by the addition of MeI afforded (4R)-3-n-butyl-4-(t-
butyldimethylsilyloxy)-6-methyl-2-cyclohexen-1-one in 82% yield, which
was transformed to 30 in 70% yield via the same procedure used in the
preparation of 9.