Controlling the facial selectivity of asymmetric [4 + 2] cyclo-additions: A concise synthesis of the cis-decalin core structure of superstolides A and B

Article abstract of DOI:10.1021/ol201095b

Regio-, stereo-, and facial selective [4 + 2] cycloadditions between highly activated vinyl sulfones and 1,3-dienes derived from (R)-4-tert- butyldimethylsilyloxy-2-cyclohexen-1-one provide a powerful approach for the asymmetric synthesis of compounds con

Full text of DOI:10.1021/ol201095b

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3580–3583
Controlling the Facial Selectivity of
Asymmetric [4 þ 2] Cyclo-additions:
A Concise Synthesis of the cis-Decalin
Core Structure of Superstolides A and B
Lei Chen, Zhengmao Hua, Gangqin Li, and Zhendong Jin*
Division of Medicinal and Natural Products Chemistry, Department of Pharmaceutical
Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa,
Iowa City, Iowa 52242, United States
zhendong-jin@uiowa.edu
Received April 26, 2011
ABSTRACT
Regio-, stereo-, and facial selective [4 þ 2] cycloadditions between highly activated vinyl sulfones and 1,3-dienes derived from (R)-4-tert-
butyldimethylsilyloxy-2-cyclohexen-1-one provide a powerful approach for the asymmetric synthesis of compounds containing the
bicyclo[2.2.2]octanone carbon skeleton. This new methodology has been successfully applied to the asymmetric synthesis of the cis-decalin
core structure of the potent anticancer marine natural products superstolides A and B.
Bicyclo[2.2.2]octanone derivatives have attracted con-
siderable interest from organic chemists because the
unique molecular architecture can be found in natural
products1 and can serve as scaffolds in the design of
therapeutic agents.2 In addition, the rigid bicyclo[2.2.2]-
octanone structure can undergo versatile transformations
to other molecular structures that are difficult to be
constructed.3 Although a number of methods have been
developed for the synthesis of racemic bicyclo[2.2.2]-
octanone derivatives,4 asymmetric synthesis of highly
functionalized bicyclo[2.2.2]octanone derivatives still poses
a formidable synthetic challenge.5
We have recently reported for the first time that 1,3-
dienes derived from (R)-4-tert-butyldimethyl-silyloxy-2-
cyclohexen-1-one can undergo stereo- and facial selective
asymmetric [4 þ 2] cycloadditions with various activated
(1) (a) Nicolaou, K. C.; Toh, Q.-Y.; Chen, D. Y.-K. J. Am. Chem.
Soc. 2008, 130, 11292. (b) Nicolaou, K. C.; Vassilikogiannakis, G.;
Simonsen, K. B.; Baran, P. S.; Zhong, Y.-L.; Vidali, V. P.; Pitsinos,
E. N.; Couladouros, E. A. J. Am. Chem. Soc. 2000, 122, 3071.
(c) Ishiuchi, K.; Kubota, T.; Hayashi, S.; Shibata, T.; Kobayashi, J.
Tetrahedron Lett. 2009, 50, 6534. (d) Huang, J.-M.; Yokoyama, R.;
Yang, C.-S.; Fukuyama, Y. J. Nat. Prod. 2001, 64, 428. (e) Srikrishna,
A.; Satyanarayana, G. Tetrahedron: Asymmetry 2005, 16, 3992. (f) Li,
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and references cited therein. (b) Finet, L.; Dakir, M.; Castellote, I.;
Arseniyadis, S. Eur. J. Org. Chem. 2007, 4116. (c) Hua, D. H.; Gung,
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r
10.1021/ol201095b
Published on Web 06/14/2011
2011 American Chemical Society

symmetric dienophiles (Scheme 1).6 These reactions are
exclusively endo selective and occur at the face syn to the
bulky TBSO group to afford predominantly (or sometimes
exclusively) syn/endo products. These controlled [4 þ 2]
cycloadditions 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 asymmetric synthesis
of compounds containing the bicyclo[2.2.2]octanone
carbon skeleton.
Table 1. [4 þ 2] Cycloadditions with Anti Facial Selectivitya
entry 1,3-diene 5
dienophile 6
7-anti/endo yieldb (%)
1
2
3
4
5
5
5
5
5
5
6a, R = Ph, Y = NPh
6b, R = Ph, Y = NBn
6c, R = Ph, Y = NEt
6d, R = Ph, Y = O
7a, 92
7b, 93
7c, 79
7d, 58
7e, 83
6e, R = t-Bu, Y = NPh
a All reactions were run in CH2Cl2 at 25 °C for 1 day under argon.
b These were isolated yields. All compounds were fully characterized.
Scheme 1. [4 þ 2] Cycloadditions with Syn Facial Selectivity
cycloaddition, and the results are summarized in Table 1.
All reactions provided exclusive 7-anti/endo products in
very good yields (entries 2ꢀ5, Table 1). These experiments
showed that the N-substituent on the maleimide moiety of
the dienophile had no effect on the stereo- and facial
selectivity of the [4 þ 2] cycloadditions (entries 1ꢀ3,
Table 1). In addition, R-(phenylsulfonyl)maleic anhydride
6d reacted with 1,3-diene 5 in the same fashion. The
relatively low yield of 7d was due to the decomposition
of the anhydride moiety of the product on the silica gel
during flash column chromatography.9 Furthermore, it
was found that the phenylsulfonyl group could be replaced
by the tert-butylsulfonyl group, and there was no change in
the facial selectivity of the reaction (entry 5, Table 1).
To expand the scope of these new asymmetric [4 þ 2]
cycloadditions, we decided to investigate the possibility of
employing unsymmetric dienophiles. We were particularly
interested in highly activated unsymmetric dienophiles such
as vinyl sulfone 6 (Scheme 2).7 Because of the steric hin-
drance between the alkyl (or aryl) sulfone moiety and TBSO
group, 7-anti/endo should be formed predominantly.
Scheme 3. [4 þ 2] Cycloadditions with Anti Facial Selectivity
Scheme 2. [4 þ 2] Cycloadditions with Anti Facial Selectivity
We then turned our attention to the scope of chiral 1,3-
dienes (Scheme 3). The results of asymmetric [4 þ 2]
cycloadditions between various chiral 1,3-dienes (8aꢀe)
and vinyl sulfone 6a are summarized in Table 2.10
In the event, 1,3-diene 5 reacted with dienophile 6a8 to
provide 7a in 92% yield (entry 1, Table 1). The reaction
was highly regioselective and completely stereo- and facial
selective. As expected, the [4 þ 2] cycloaddition occurred at
the face anti to the bulky TBSO group, and 7-syn/endo was
not detected. The facial selectivity observed in this reaction
is opposite to that of those reactions employing symmetric
dienophiles shown in Scheme 1.
Compound 9-anti/endo was the only product that was
isolated from the reaction, and the yields (9aꢀe) were
uniformly excellent. Experimental results show that intro-
ducing an alkyl group at the 1 and/or 4 position of the 1,3-
diene had no effect on the stereochemical outcome of the
reaction (entries 1 and 2, Table 2). It should be noted that
among four newly created stereogenic centers in 9b three of
them are quaternary carbons and two of them are bridge-
head quaternary carbons, which are difficult to construct.
In addition, the reactions were relatively faster when 1,3-
diene 8c with a vinyl carbonate moiety and 1,3-dienes 8d
and 8e with silyl enol ether moiety were employed (entries
Several highlyreactivevinyl sulfones(6bꢀe) werechosen
to study the scope and limitation of this asymmetric [4 þ 2]
(5) (a) Tzvetkov, N. T.; Schmoldt, P.; Neumann, B.; Stammler,
H.-G.; Mattay, J. Tetrahedron: Asymmetry 2006, 17, 993. (b) Friberg,
A.; Johanson, T.; Franzen, J.; Gorwa-Grauslund, M. F.; Frejd, T. Org.
Biomol. Chem. 2006, 4, 2304. (c) Luo, Y.; Carnell, A. J. J. Org. Chem.
2010, 75, 2057. (d) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am. Chem. Soc.
2008, 130, 2738. (e) Fisher, C.; Defieber, C.; Suzuki, T.; Carreira, E. M.
J. Am. Chem. Soc. 2004, 126, 1628. (f) Almqvist, F.; Ekman, N.; Frejd, T.
J. Org. Chem. 1996, 61, 3794. (g) Paquette, L. A.; Tsui, H.-C. J. Org.
Chem. 1996, 61, 142. (h) Hua, Z; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005,
7, 1939. (i) Kitahara, T.; Miyake, M.; Kido, M.; Mori, K. Tetrahedron:
Asymmetry 1990, 1, 775.
(8) Compounds 6aꢀe were prepared using the procedure for the
preparation of 6d from the following article: Ramezanian, M.; Abdelkader,
M.; Padias, A. B.; Hall, H. K., Jr.; Brois, S. J. J. Org. Chem. 1989, 54,
2852.
(9) The actual yield was much higher based on the analysis of the
(6) Hua, Z.; Chen, L.; Jin, Z. Tetrahedron Lett. 2009, 50, 6621.
(7) (a) El-Awa, A.; Noshi, M. N.; Mollat du Jourdin, X.; Fuchs, P. L.
Chem. Rev. 2009, 109, 2315. (b) Simpkins, N. S. Tetrahedron 1990, 46, 6951.
1H NMR spectrum of the crude product.
(10) Compounds 8aꢀe were prepared using the procedures published
in ref 6.
Org. Lett., Vol. 13, No. 14, 2011
3581

3ꢀ5, Table 2). Furthermore, entry 5 indicates that an iodo
group at the 3 position of the 1,3-diene had no effect on the
facial selectivity (entry 5, Table 2).
Scheme 4. Synthesis of the Core Structure of Superstolides A
and B
Table 2. [4 þ 2] Cycloadditions with Anti Facial Selectivitya
9-anti/endo
entry
1,3-diene
dienophile
yieldb (%)
1
8a: R1 = Ac, R2 = Me,
R3 = X = H
6a
9a, 83
2
3
4
5
8b: R1 = Ac, R2 = n-Bu,
R3 = Me, X = H
6a
6a
6a
6a
9b, 97
9c, 87
9d, 90
9e, 91
8c: R1 = CO2Me, R2 = H,
R3 = X = H
8d: R1 = TIPS, R2 = H,
R3 = Me, X = H
8e: R1 = TIPS, R2 = H,
R3 = Me, X = I
a All reactions were run in CH2Cl2 at 25 °C for 1 day under argon
unless other stated. b These were isolated yields. All compounds were
fully characterized.
The enantiopure products of these highly controlled [4 þ
2] cycloadditions contain the rigid bicyclo[2.2.2]octanone
carbon skeletons that are rich in both functionality and
stereochemicalcomplexity. Thesecompoundsareexcellent
scaffolds for further synthetic manipulations. To demon-
strate the synthetic utility we decided to design a concise
approach for the conversion of compound 7a to the cis-
decalin core structure present in the highly potent anti-
cancer marine natural products superstolides A (10) and B
(11) that were isolated from the deep-water marine
sponge Neosiphonia superstes collected off New Caledo-
nia (Figure 1).11,12
which was converted to a samarium enolate followed by
the addition of MeI to provide compound 14 with the
requisite stereochemistry of the quaternary carbon in 88%
yield. Compound 14was treated with1 N HCl in i-PrOH at
120 °C in a sealed tube to reach an equilibrium to give a
mixture of 15 and 16 in an approximately 1:3 ratio with a
combined yield of 95% (compound 15 could be recycled to
16 under the same reaction conditions). Compound 16 was
converted to olefin 17 in 84% yield under the standard
conditions. Vinyllithium 18, prepared from the corre-
sponding vinylstannane,13 underwent a stereospecific 1,2-
addition to ketone 17 to afford tert-alcohol 19, which
underwent an anionic oxy-Cope rearrangement to provide
cis-decalin20 withthe five requisite stereogenic centers and
the double bond at the desired positions. Stereoselective
reduction of ketone 20 by Me4NBH4 followed by the
methylation of the resulting alcohol gave compound 21
in 78% yield.
Figure 1. Anticancer marine natural products superstolides A
and B.
Compound 7a was chemo- and regioselectively reduced
to give compound 12 in 94% yield (Scheme 4). Hemiacetal
12 was protected by a TES group to afford compound 13,
The conversion of compound 21 to 23 failed under
various TamaoꢀFleming oxidation conditions because
of the quick cleavage of the isopropyl group of the hemi-
aminal ether moiety of compound 21 in the presence of
typical strong acidic conditions of the TamaoꢀFleming
oxidation and the labile olefin moiety toward various
electrophilic reagents such as Hg(OAc)2 and Br2.14
(11) For the isolation of superstolides A and B: (a) D’Auria, M. V.;
Debitus, C.; Paloma, L. G.; Minale, L.; Zampella, A. J. Am. Chem. Soc.
1994, 116, 6658. (b) D’Auria, M. V.; Paloma, L. G.; Minale, L.;
Zampella, A.; Debitus, C. J. Nat. Prod. 1994, 57, 1595.
(12) Synthetic efforts toward the synthesis of the cis-decalin core
structure of superstolide A: (a) Roush, W. R.; Champoux, J. A.;
Peterson, B. C. Tetrahedron Lett. 1996, 37, 8989. (b) Tortosa, M.;
Yakelis, N. A.; Roush, W. R. J. Am. Chem. Soc. 2008, 130, 2722.
(c) Tortosa, M.; Yakelis, N. A.; Roush, W. R. J. Org. Chem. 2008, 73,
9657. (d) Reference 5h.
(13) Cunico, R. F.; Clayton, F. J. J. Org. Chem. 1976, 41, 1480.
Org. Lett., Vol. 13, No. 14, 2011
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To solve these common problems in TamaoꢀFleming oxida-
tion it was imperative to develop a mild procedure that
avoids the strong acidic conditions as well as those electro-
philic reagents. We were delighted to observe that the
phenyl group of the dimethylphenylsilyl moiety could be
cleaved by TBAF in wet DMF at 65 °C to give compound
22, which was easily oxidized to alcohol 23 in 82% yield. It
was discovered that the reaction temperature of 65 °C was
critical. If the temperature was too low, the reaction was
very slow. If the temperature was too high, then compound
22 further reacted with TBAF resulting in protiode-
silylation.15,16 In 10 operations the [4 þ 2] cycloaddition
adduct 7a was converted to the cis-decalin core structure
present in superstolides A (10) and B (11), and two fused
rings, six stereogenic centers (including one quaternary
carbon), and a double bond were established.
In conclusion, we have demonstrated for the first time
that 1,3-dienes derived from (R)-4-tert-butyldimethyl-
silyloxy-2-cyclohexen-1-one react with highly activated
vinyl sulfones in a highly regio-, stereo-, and facial-
selective fashion. The facial selectivity of these cycload-
ditions is opposite to that of those [4 þ 2] cycloadditions
employing symmetric dienophiles. In addition, this new
methodology has been successfully applied to the asym-
metric synthesis of the cis-decalin core structure of the
potent anticancer marine natural products supersto-
lides A and B. Furthermore, a mild procedure was
developed to solve a long-standing problem in the
TamaoꢀFleming oxidation of the dimethylphenylsilyl
group. The scope and limitations of this protocol are
currently under investigation and will be reported in due
course.
(14) (a) Fleming, I.; Henning, R.; Plaut, H. J. Chem. Soc., Chem.
Commun. 1984, 29. (b) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52,
7599 and references cited therein.
Acknowledgment. This work was financially supported
by a grant (R01 CA109208) from the NIH.
(15) During the preparation of this manuscript, we learned that a
very similar protocol for the TamaoꢀFleming oxidation of methyldi-
phenylsilyl and triphenylsilyl groups to alcohols was reported (one
Supporting Information Available. Experimental pro-
cedures and compound characterization. This material
is available free of charge via the Internet at http://
pubs.acs.org.
€
example): Knolker, H.-J.; Wanzi, G. Synlett 1995, 378.
(16) Protiodesilylation by TBAF was reported by Roush. See:
Heitzman, C.; Lambert, W. T.; Mertz, E.; Shotwell, J. B.; Tinsley,
J. M.; Va, P.; Roush, W. R. Org. Lett. 2005, 7, 2405.
Org. Lett., Vol. 13, No. 14, 2011
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