Stereocontrolled construction of the tricyclic framework of tiglianes and daphnanes by an oxidative dearomatization approach

Article abstract of DOI:10.1021/ol5008263

An appropriately functionalized [5-7-6] tricyclic framework of tigliane and daphnane diterpenes containing seven contiguous stereocenters has been prepared in 10 steps from very simple building blocks in a modular and stereocontrolled fashion. The key fea

Full text of DOI:10.1021/ol5008263

Letter
pubs.acs.org/OrgLett
Stereocontrolled Construction of the Tricyclic Framework of
Tiglianes and Daphnanes by an Oxidative Dearomatization
Approach
Guanghu Tong, Zhi Liu, and Pengfei Li*
Frontier Institute of Science and Technology (FIST) and Frontier Institute of Chemistry, Xi’an Jiaotong University, Xi’an 710054, P.
R. China
S
* Supporting Information
ABSTRACT: An appropriately functionalized [5−7−6]
tricyclic framework of tigliane and daphnane diterpenes
containing seven contiguous stereocenters has been prepared
in 10 steps from very simple building blocks in a modular and
stereocontrolled fashion. The key features of this approach
involve an efficient visible light-induced singlet oxygen
oxidative dearomatization and an array of substrate-controlled
highly diastereoselective transformations. This work provides a
model strategy for rapid and diverted synthesis of natural and
unnatural molecules sharing the common skeleton.
iglianes and daphnanes (Figure 1) are two families of
diterpene natural products that share a characteristic [5−
promise as an analgesic agent through the desensitization of
nociceptive neurons.4 Stelleralide A5 (4) is an extremely potent
and selective anti-HIV agent. Importantly, more and more
natural products exhibiting antitumor,6 anti-HIV,7 and antivirus
activities8 have been recently added to these two families. The
structural complexity and the biological activities of these
molecules, therefore, continuously render them highly attractive
targets for organic synthesis.
T
Since the late 1980s, a number of elegant approaches have
been reported to construct the tricyclic core structure,9 and
total syntheses of phorbol (2) and resiniferatoxin (3) by
Wender and co-workers10 and a formal synthesis of phorbol (2)
by Cha11 have been accomplished. Recently, we have
commenced a research program aiming at development of
efficient and flexible synthetic approaches to natural and
unnatural tiglianes and daphnanes. Because the highly
substituted C ring poses significant challenges for all synthetic
efforts and the substitution pattern on the C ring often shows
dramatic impacts on the biological activities,2b,c,12 we were
particularly interested in addressing these issues by a late-stage
C-ring functionalization approach on an appropriate inter-
mediate. We proposed molecule 5 (Scheme 1) as a key model
to test our synthetic strategy because it includes not only the
tricyclic core but also a cross-conjugated cyclohexadienone
moiety for further multiple functionalizations. Moreover,
variations of the building blocks and/or later stage trans-
formations might produce a series of analogues. Retrosyntheti-
cally, 5 would be an oxidative dearomatization product of
phenol 6 which in turn might be assembled from three simple
Figure 1. Representative tigliane and daphnane deterpene natural
products and their common tricyclic core structure.
7−6] tricyclic carbon framework with a congested substitution
pattern and extensive oxygenation.1 Members of these families
exhibit a remarkable range of biological activities and have
attracted significant research interest in drug discovery.
Prostratin (1, Figure 1), for example, is under preclinical
development for its potential to eliminate latent HIV viruses.2
Phorbol (2) and its esters are potent tumor promoters that
activate protein kinase C (PKC).3 Resiniferatoxin (3) holds
Received: March 19, 2014
Published: April 9, 2014
© 2014 American Chemical Society
2288
dx.doi.org/10.1021/ol5008263 | Org. Lett. 2014, 16, 2288−2291

Organic Letters
Letter
Scheme 1. Synthetic Plan of the Tricyclic Framework
Scheme 2. Synthesis of the Cyclohexadienone 5
building blocks, aryl bromide 8, cyclopentene oxide 7, and
allylmagnesium bromide 9, by epoxide opening, allylation
reaction, and ring-closing metathesis (RCM). In this paper, we
describe our synthetic studies that lead to a rapid access to 5
and preliminary explorations of chemo- and stereoselective
functionalizations on the C ring.
In the forward direction of our synthesis (Scheme 2), the
Grignard reagent derived from aryl bromide 813 was mixed with
cyclopentene oxide 7 in the presence of copper(I) iodide to
effect the epoxide opening reaction, affording the desired
product in quantitative yield. The resulting alcohol was
subsequently treated with Dess−Martin periodinane14 to
form the racemic α-aryl ketone 10 in high yield (85%).
Addition of allyl magnesium bromide (9) to a solution of 10
produced the tertiary alcohol 11 in excellent yield (95%) and
good diastereoselectivity (dr = 10:1 based on crude 1H NMR).
After formation of the seven-membered B ring by a ring-closing
metathesis (RCM) using 0.1 mol % of the Grubbs second-
generation catalyst,15 the two diastereomers were separated by
column chromatography and the major isomer 12 was isolated
in 84% yield. Its relative configuration was then confirmed as
the desired 4,10-trans relationship by X-ray diffraction analysis.
Attempted removal of the methyl group by heating 12 or its
trimethylsilyl ether 13 together with sodium ethylthiolate led to
variable yields (30−60%) of the corresponding demethylation
products accompanied by side products derived from
competitive dehydration at the tertiary alcohol and thiol
addition to the alkene. Other methods using boron tribromide,
lithium iodide, etc. led to decomposition of the starting
materials. Finally, we found that the methyl group of 13 could
be efficiently cleaved by treatment with lithium diphenylphos-
phide,16 and the resulting phenol 6 was isolated in excellent
yield (96%).
At this stage, the crucial oxidative dearomatization reaction
was investigated. Hypervalent iodine reagents are arguably the
most widely used oxidants for dearomatization reactions of
phenols.17 In the case of phenol 6, however, we did not observe
the desired product 5 using various hypervalent iodine oxidants.
When it was treated with PhI(OAc)2 in a mixture of acetonitrile
and water, oxetane 14 was formed as the only isolable product.
To the best of our knowledge, this represents the first example
of oxetane ring formation by an oxidative dearomatization. The
result clearly demonstrated the unique reactivity of this rigid
substrate. Consequently, other oxidative dearomatization
methods were tested. A ruthenium-catalyzed peroxidation18 of
6 afforded the peroxide 15 in 49% yield. Unfortunately, neither
reductive cleavage of the O−O bond to form the desired tert-
alcohol19 nor direct use of this peroxide for next investigations
was successful.
Singlet oxygen has been reported to react with phenols to
produce peroxy quinols which, after reductive cleavage of the
O−O bond, produce tert-alcohols.20 Therefore, using 6 as the
substrate, we tested several protocols to effect such a
transformation. Finally, to our delight, when an oxygen-
saturated solution of 6 in chloroform containing tetraphenyl-
porphyrin (TPP) as a photosensitizer was irradiated by strong
visible light (400 W sodium lamp), the unstable peroxy quinol
1
was observed in high yield by crude H NMR. Therefore, after
full conversion, triphenylphosphine was added to reduce the
peroxy quinol, and the hydroxylated cyclohexadienone 5 could
be directly isolated in 74% yield as a single diastereoisomer. A
single crystal of 5 suitable for X-ray diffraction was obtained,
and thus, the relative configuration was unambiguously
established as the desired one. Probably because the
trimethylsilyl ether moiety occupies the concave space and
strongly shields one of the two faces of the phenol plane, singlet
2289
dx.doi.org/10.1021/ol5008263 | Org. Lett. 2014, 16, 2288−2291

Organic Letters
Letter
oxygen preferably reacts from the less hindered convex side to
exclusively form 5.
With the oxidative dearomatization product 5 in hand, we
explored the possibility of stereocontrolled transformations on
the C ring (Scheme 3). Most tigliane and daphnane natural
Me groups too. This deduction was consistent with the
observed H-13/H-14 coupling constant (3J = 4.8 Hz) of the
acetal 18 and further confirmed by the crystal structure of 17,
which unambiguously established the relative configurations of
the seven contiguous stereocenters.
In summary, we have described a rapid and modular
synthetic approach for construction of the highly functionalized
tricyclic framework of tigliane and daphnane diterpenoids
containing multiple stereocenters. The synthetic route features
several substrate-controlled highly stereoselective reactions
including the key visible light-induced singlet oxygen oxidative
dearomatization, directed 1,4-addition of methylmagnesium
bromide, and the 13-carbonyl reduction using the Luche
protocol. The applications of this approach in synthesis of
relevant natural products and their analogues are underway in
our laboratory and will be reported in due course.
Scheme 3. Chemo- and Stereoselective Functionalizations of
the Tricyclic Core
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, copies of all spectral data,
and X-ray crystallographic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: lipengfei@mail.xjtu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support by the NSFC (No.
21202129), the MOST (No. 2014CB548200), and Xi’an
Jiaotong University. We thank Mr. Guojun Zhou, Frontier
Institute of Science and Technology, Xi’an Jiaotong University,
for his help with X-ray diffraction analysis.
REFERENCES
■
products incorporate an 11-methyl group which is cis to the 9-
hydroxyl group, and sometimes, such as with stelleralide A (4),
the methyl group is further oxidized. Therefore, 1,4-addition of
alkyl metallic reagents onto 5 was investigated. After extensive
experimentation, we were able to stereoselectively introduce
the methyl group using a substrate-controlled 1,4-addition of
methylmagnesium bromide.21 Other methods based on
copper,22a,b zinc,22c,d and aluminum22e reagents did not give
any desired product. Thus, after deprotonation with lithium
hexamethyl disilazide, the resulting 9-alkoxide directs the
reaction’s regioselectivity as well as facial selectivity probably
via complexation with the magnesium reagent. The product 16
was isolated in 67% yield as a single isomer, and the relative
configuration was again confirmed by X-ray diffraction analysis.
The 13-carbonyl group was then reduced under the Luche
conditions,23 producing the secondary alcohol in excellent yield
and diastereoselectivity (dr = 24:1). Treatment of the
secondary alcohol with m-chloroperoxybenzoic acid (m-
CPBA) formed an unstable epoxide intermediate which, upon
silica gel chromatography, transformed into a triol 17 as the
sole isolable product. The cis relationship between the 13-OH
and 14-OH was proposed because the 13-OH might direct the
facial selection of the epoxidation reaction. Together with the
facile epoxide opening process presumably via SN2 type attack,
we reasoned that the 13-OH should be cis to the 9-OH and 11-
(1) (a) Liao, S.-G.; Chen, H.-D.; Yue, J. M. Chem. Rev. 2009, 109,
1092−1140. (b) He, W.; Cik, M.; Appendino, G.; Van Puyvelde, L.;
Leysen, J. E.; De Kimpe, N. Mini-Rev. Med. Chem. 2002, 2, 185−200.
(2) (a) Johnson, H. E.; Banack, S. A.; Cox, P. A. J. Nat. Prod. 2008,
71, 2041−2044. (b) Wender, P. A.; Kee, J.-M.; Warrington, J. M.
Science 2008, 320, 649−652. (c) Beansa, E. J.; Fournogerakis, D.;
Gauntlett, C.; Heumann, L. V.; Kramer, R.; Marsden, M. D.; Murray,
D.; Chun, T.-W.; Zack, J. A.; Wender, P. A. Proc. Natl. Acad. Sci. U.S.A.
2013, 110, 11698−11703. (d) AIDS Research Alliance website:
http://aidsresearch.org/cure-research/prostratin (accessed Feb 2014).
(3) Newton, A. C. Chem. Rev. 2001, 101, 2353−2364.
(4) (a) Szallasi, A.; Blumberg, P. M. Neuroscience 1989, 30, 515−520.
(b) Wong, G. Y.; Gavva, N. R. Brain Res. Rev. 2009, 60, 267−277.
(c) Kissin, I.; Szallasi, A. Curr. Top. Med. Chem. 2011, 11, 2159−2170.
(5) Asada, Y.; Sukemori, A.; Watanabe, T.; Malla, K. J.; Yoshikawa,
T.; Li, W.; Koike, K.; Chen, C.-H.; Akiyama, T.; Qian, K.; Nakagawa-
Goto, K.; Morris-Natschke, S. L.; Lee, K.-H. Org. Lett. 2011, 13,
2904−2907.
(6) (a) Miyamae, Y.; Villareal, M. O.; Abdrabbah, M. B.; Isoda, H.;
Shigemori, H. J. Nat. Prod. 2009, 72, 938−941. (b) Zhan, Z.-J.; Fan,
C.-Q.; Ding, J.; Yue, J.-M. Bioorg. Med. Chem. 2005, 13, 645−655.
(c) Hong, J.-Y.; Chung, H.-J.; Lee, H.-J.; Park, H. J.; Lee, S. K. J. Nat.
Prod. 2011, 74, 2102−2108.
(7) (a) Asada, Y.; Sukemori, A.; Watanabe, T.; Malla, K. J.;
Yoshikawa, T.; Li, W.; Kuang, X.; Koike, K.; Chen, C.-H.; Akiyama, T.;
Qian, K.; Nakagawa-Goto, K.; Morris-Natschke, S. L.; Lu, Y.; Lee, K.-
H. J. Nat. Prod. 2013, 76, 852−857. (b) Zhang, L.; Luo, R.-H.; Wang,
2290
dx.doi.org/10.1021/ol5008263 | Org. Lett. 2014, 16, 2288−2291

Organic Letters
Letter
F.; Jiang, M.-Y.; Dong, Z.-J.; Yang, L.-M.; Zheng, Y.-T.; Liu, J.-K. Org.
Lett. 2010, 12, 152−155.
T.; Fujii, A.; Inubushi, Y.; Komiya, N. Eur. J. Org. Chem. 2011, 5355−
5365. (c) Ratnikov, M. O.; Farkas, L. E.; Doyle, M. P. J. Org. Chem.
2012, 77, 10294−10303.
(8) Bourjot, M.; Delang, L.; Nguyen, V. H.; Neyts, J.; Gueritte, F.;
Leyssen, P.; Litaudon, M. J. Nat. Prod. 2012, 75, 2183−2187.
(9) (a) Catino, A. J.; Sherlock, A.; Shieh, P.; Wzorek, J. S.; Evans, D.
A. Org. Lett. 2013, 15, 3330−3333. (b) Murai, K.; Katoh, S.; Urabe, D.;
Inoue, M. Chem. Sci. 2013, 4, 2364−2368. (c) Stewart, C.; McDonald,
R.; West, F. G. Org. Lett. 2011, 13, 720−723. (d) Ritter, T.; Zarotti, P.;
Carreira, E. M. Org. Lett. 2004, 6, 4371−4374. (e) Jackson, S. R.;
Johnson, M. G.; Mikami, M.; Shiokawa, S.; Carreira, E. M. Angew.
Chem., Int. Ed. 2001, 40, 2694−2697. (f) Chairgulprasert, V.; Drew, M.
G. B.; Jahans, A.; Harwood, L. M. ARKIVOC 2002, (ix), 37−45.
(g) Drew, M. G. B.; Harwood, L. M.; Macias-Sanchez, A. J.; Scott, R.;
Thomas, R. M.; Uguen, D. Angew. Chem., Int. Ed. 2001, 40, 2311−
2313. (h) Ovaska, T. V.; Reisman, S. E.; Flynn, M. A. Org. Lett. 2001,
3, 115−117. (i) Carroll, G. L.; Little, R. D. Org. Lett. 2000, 2, 2873−
2876. (j) Shigeno, K.; Ohne, K.; Yamaguchi, T.; Sasai, H.; Shibasaki,
M. Heterocycles 1992, 33, 161−171. (k) Shigeno, K.; Sasai, H.;
Shibasaki, M. Tetrahedron Lett. 1992, 33, 4937−4940. (l) Sugita, K.;
Neville, C. F.; Sodeoka, M.; Sasai, H.; Shibasaki, M. Tetrahedron Lett.
1995, 36, 1067−1070. (m) Sato, H.; Kim, Y. S.; Shibasaki, M.
Tetrahedron Lett. 1999, 40, 2973−2976. (n) Sekine, A.; Kumagai, N.;
Uotsu, K.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2000, 41,
509−513. (o) Rigby, J. H.; Kierkus, P. C. J. Am. Chem. Soc. 1989, 111,
4125−4126. (p) Rigby, J. H.; Kierkus, P. C.; Head, D. Tetrahedron
Lett. 1989, 30, 5073−5076. (q) Harwood, L. M.; Ishikawa, T.; Phillips,
H.; Watkin, D. J. Chem. Soc., Chem. Commun. 1991, 527−530.
(r) Paquette, L. A.; Sauer, D. R.; Edmondson, S. D.; Friedrich, D.
Tetrahedron 1994, 50, 4071−4086. (s) McMills, M. C.; Zhuang, L.;
Wright, D. L.; Watt, W. Tetrahedron Lett. 1994, 35, 8311−8314.
(t) Magar, S. S.; Desai, R. C.; Fuchs, P. L. J. Org. Chem. 1992, 57,
5360−5369. (u) Dauben, W. G.; Dinges, J.; Smith, T. C. J. Org. Chem.
1993, 58, 7635−7637. (v) Page, P. C. B.; Jennens, D. C.; Porter, R. A.;
Baldock, A. N. Synlett 1991, 472−474. (w) Page, P. C. B.; Jennens, D.
C. J. Chem. Soc., Perkin Trans. 1 1992, 2587−2589. (x) Eckert, J. M.
Efforts toward the total syntheses of phorbol and CP-225917. Ph.D.
Thesis, Massachusetts Institute of Technology, Cambridge, MA, 1997.
(y) Wender, P. A.; Keenan, R. M.; Lee, H. Y. J. Am. Chem. Soc. 1987,
109, 4390−4392.
(20) (a) Matsuura, T.; Omura, K.; Nakashima, R. Bull. Chem. Soc. Jpn.
1965, 38, 1358−1362. (b) Wasserman, H. H.; Ives, J. L. Tetrahedron
1981, 37, 1825−1852. (c) Prein, M.; Maurer, M.; Peters, E. M.; Peters,
K.; Schnering, H. G.; Adam, W. Chem.Eur. J. 1995, 1, 89−94.
(d) Jones, K. M.; Hillringhaus, T.; Klussmann, M. Tetrahedron Lett.
2013, 54, 3294−3297.
(21) (a) Solomon, M.; Jamison, W. C. L.; McCormick, M.; Liotta, D.
J. Am. Chem. Soc. 1988, 110, 3702−3704. (b) Brocksom, T. J.; Coelho,
F.; Depres, J.-P.; Greene, A. E.; Lima, M. E. F.; Hamelin, O.;
Hartmann, B.; Kanazawa, A. M.; Wang, Y. J. Am. Chem. Soc. 2002, 124,
15313−15325.
(22) (a) Zimmerman, H. E.; Zhu, Z. J. Am. Chem. Soc. 1995, 117,
5245−5262. (b) Taber, D. F.; Christos, T. E.; Rahimizadeh, M.; Chen,
B. J. Org. Chem. 2001, 66, 5911−5914. (c) Imbos, R.; Minnaard, A. J.;
Feringa, B. L. Tetrahedron 2001, 57, 2485−2489. (d) Imbos, R.;
Brilman, M. H. G.; Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1, 623−
625. (e) Flemming, S.; Kabbara, J.; Nickisch, K.; Neh, H.;
Westermann, J. Synthesis 1995, 317−320.
(23) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226−2227.
(10) (a) Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.;
Tebbe, A. L.; Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976−12977.
(b) Wender, P. A.; Rice, K. D.; Schnute, M. E. J. Am. Chem. Soc. 1997,
119, 7897−7898. (c) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J.
D., Jr.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111,
8957−8958. (d) Wender, P. A.; Kogen, H.; Lee, H. Y.; Munger, J. D.;
Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954−
8957. (e) Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112,
4956−4958.
(11) Lee, K.; Cha, J. K. J. Am. Chem. Soc. 2001, 123, 5590−5591.
(12) Stanoeva, E.; He, W.; De Kimpe, N. Bioorg. Med. Chem. 2004,
13, 17−28. (b) Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.;
Kan, C.; Kee, J.-M.; Ohmura, H. Org. Lett. 2006, 8, 5373−5376.
(13) Grigg, R. D.; Hoveln, R. V.; Schomaker, J. M. J. Am. Chem. Soc.
2012, 134, 16131−16134.
(14) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277−
7287.
(15) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. 1995, 34, 2039−2041.
(16) (a) Ireland, R. E.; Walba, D. M. Org. Synth. 1977, 56, 44−48.
(b) Wipf, P.; Jung, J.-K. J. Org. Chem. 2000, 65, 6319−6337.
(17) (a) Roche, S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50,
4068−4093. (b) Marson, C. M.; Pink, J. H.; Hall, D.; Hursthouse, M.
B.; Malik, A.; Smith, C. J. Org. Chem. 2003, 68, 792−798.
(18) (a) Murahashi, S.-I; Naota, T.; Miyaguchi, N.; Noda, S. J. Am.
Chem. Soc. 1996, 118, 2509−2510. (b) Murahashi, S.-I; Miyaguchi, N.;
Noda, S.; Naota, T.; Fujii, A.; Inubushi, Y.; Komiya, N. Eur. J. Org.
Chem. 2011, 5355−5365.
(19) (a) Dai, P.; Dussault, P. H.; Trullinger, T. K. J. Org. Chem. 2004,
69, 2851−2852. (b) Murahashi, S.-I; Miyaguchi, N.; Noda, S.; Naota,
2291
dx.doi.org/10.1021/ol5008263 | Org. Lett. 2014, 16, 2288−2291