Total synthesis of (-)-teucvidin

Article abstract of DOI:10.1021/ol301098s

A concise enantioselective synthesis of (-)-teucvidin has been achieved. Our synthetic strategy involved the diastereoselective Michael/Conia-ene cascade cyclization reaction for rapid establishment of the cis-decalin skeleton with three new stereogenic centers in one pot (72%, single diastereomer), the epoxidation/dealkoxycarbonylation protocol for construction of the fused furanone moiety, and the O-allylation/Claisen rearrangement protocol for construction of the all-carbon quaternary center at C9 of the clerodane skeleton.

Full text of DOI:10.1021/ol301098s

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2886–2889
Total Synthesis of (ꢀ)-Teucvidin
Xiaozu Liu and Chi-Sing Lee*
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen University Town, Xili,
Shenzhen 518055, China
lizc@pkusz.edu.cn
Received April 30, 2012
ABSTRACT
A concise enantioselective synthesis of (ꢀ)-teucvidin has been achieved. Our synthetic strategy involved the diastereoselective Michael/
Coniaꢀene cascade cyclization reaction for rapid establishment of the cis-decalin skeleton with three new stereogenic centers in one pot (72%,
single diastereomer), the epoxidation/dealkoxycarbonylation protocol for construction of the fused furanone moiety, and the O-allylation/Claisen
rearrangement protocol for construction of the all-carbon quaternary center at C9 of the clerodane skeleton.
During the pastyears, over 1000diterpenoids containing
the clerodane skeleton (Figure 1) and their 19-nor variants
have been reported, and they show a variety of interesting
biological activities, including antifeedant, antifungal,
antitumor, antimicrobial, and moluscicidal activities.1
Because of the structural diversity and the broad range
of biology activities, extensive efforts have been directed
toward the synthesis of clerodane diterpernoids.2 Interest-
ingly, synthetic efforts toward the 19-nor-clerodanes with a
spiro γ-lactone at C9 are still very limited presumably due
to their structural complexity. So far, only four racemic
total syntheses of this subclass have been reported by Liu’s
group using a DielsꢀAlder (DA) approach for construc-
tion of the cis-decalin ring system.3 Jung’sgroupreported a
DA approach for direct access of the spiro γ-lactone
clerodane ring system in one-pot using allenic spiro-γ-
lactones as the dienophiles.4 Recently, Ley’s group mod-
ified Jung’s DA approach by switching the dienophiles to
cis-furanospiro-γ-lactones.5 However, these approaches
are primarily racemic, and no enantioselective total synth-
esis on these spiro γ-lactone 19-nor-clerodanes has been
reported.
(1) (a) Hanson, J. R. Nat. Prod. Rep. 1989, 6, 347–358. (b) Simmonds,
M. S. J.; Blaney, W. M.; Ley, S. V.; Bruno, M.; Savona, G. Phytochem-
istry 1989, 28, 1069–1071. (c) Merritt, A. T.; Ley, S. V. Nat. Prod. Rep.
1992, 9, 243–287. (d) Tokoroyama, T. J. Synth. Org. Chem. Jpn. 1993,
51, 1164–1177. (e) Hanson, J. R. Nat. Prod. Rep. 2002, 19, 125–132. (f)
Rijo, P.; Gaspar-Marques, C.; Simoes, M. S.; Duarte, A.; Apreda-Rojas,
M. del-C.; Cano, F. H.; Rodriguez, B. J. Nat. Prod. 2002, 65, 1387–1390.
(g) Salah, M. A.; Bedir, E.; Toyang, N. J.; Khan, I. A.; Harries, M. D.;
Wedg, D. E. J. Agric. Food Chem. 2003, 51, 7607–7610. (h) Hanson, J. R.
Nat. Prod. Rep. 2005, 22, 594–602. (i) Coll, J.; Tandron, Y. Phytochem-
istry 2005, 66, 2298–2303. (j) Tamokou, J. D.; Kuiate, J. R.; Tene, M.;
Tane, P. Indian J. Pharmacol. 2009, 41, 60–63. (k) Stankovic, M. S.;
Curcic, M. G.; Zizic, J. B.; Topuzovic, M. D.; Solujic, S. R.; Markovic,
S. D. Int. J. Mol. Sci. 2011, 12, 4190–4205.
(2) For reviews, see: (a) Sarma, A. S. J. Sci. Ind. Res. 1987, 46, 492–
504. (b) Tokoroyama, T. Synthesis 2000, 5, 611–633. For selected
examples, see: (c) Grossman, R. B.; Rasne, R. M. Org. Lett. 2001, 3,
4027–4030. (d) Liu, H. J.; Ho, Y. L.; Wu, J. D. K.; Shia, S. Synlett 2001,
1805–1807. (e) Kato, M.; Kosugi, H.; Ichiyanagi, T.; Hagiwara, H.;
Kodaira, A.; Kusakari, T.; Suzuki, T.; Ando, M.; Lee, J.; Drechsel, P.;
Vogler, B. Tetrahedron 2001, 57, 8243–8256. (f) Ling, T. T.; Rivas, F.;
Theodorakls, E. A. Tetrahedron Lett. 2002, 43, 9019–9022. (g) Arns, S.;
Barriault, L. J. Org. Chem. 2006, 71, 1809–1816. (h) Wasnaire, P.;
In the course of developing an efficient and versatile
asymmetric approach to the synthesis of the clerodane
(3) (a) Liu, H.-J.; Zhu, J.-L.; Chen, I.-C.; Jankowska, R.; Han, Y.;
Shia, K.-S. Angew. Chem., Int. Ed. 2003, 42, 1851–1853. Chen, I.-C.; Wu,
Y.-K.; Liu, H.-J.; Zhu, J.-L. Chem. Commun. 2008, 4720–4722.
(4) (a) Jung, M. E.; Zimmerman, C. N. J. Am. Chem. Soc. 1991, 113,
7813–7814. (b) Jung, M. E.; Zimmerman, C. N.; Lowen, G. T.; Khan,
S. I. Tetrahedron Lett. 1993, 34, 4453–4456. (c) Jung, M. E.; Cordova, J.;
Murakami, M. Org. Lett. 2009, 11, 3882–3885.
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Wiaux, M.; Touillaux, R.; Marko, I. E. Tetrahedron Lett. 2006, 47,
985–989. (i) Veitch, G. E.; Beckmann, E.; Burke, B. J.; Boyer, A.;
Maslen, S. L.; Ley, S. V. Angew. Chem., Int. Ed. 2007, 46, 7629–7632.
(j) Kikuchi, T.; Mineta, M.; Ohtaka, J.; Matsumoto, N.; Katoh, T. Eur.
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Mitome, H.; Kawashima, E. Chem. Commun. 2012, 48, 901–903.
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r
10.1021/ol301098s
Published on Web 05/17/2012
2012 American Chemical Society

Scheme 1. Development of Diastereoselective Michael/Con-
iaꢀEne Cascade Cyclization
Figure 1. Synthetic strategy toward (ꢀ)-teucvidin and clerodane
diterpenoids.
intermediate (4a) (vide infra). After subsequent addition
of In(OTf)3 (0.5 equiv) and 4 A molecular sieves, the
Michael adduct (4a) generated in situ underwent Coniaꢀ
ene reaction and afforded the cis-decalin ring system of
(ꢀ)-3a in 72% yield as a single diastereomer. This one-pot
cascade cyclization effectively established the cis-decalin
skeleton containing three new stereogenic centers with
desired stereochemistry from an acyclic cyclization pre-
cursor ((ꢀ)-2) (Scheme 1). The structure of cyclized prod-
uct (ꢀ)-3a was fully characterized by NMR experiments.8
To study the effect of the alkene geometry on the
stereochemistry of the Michael reaction, the (E)- and
(Z)-isomers of 2 were separated. However, both (E)- and
(Z)-isomers were found to be unstable, and they gradually
equilibrated into E/Z mixtures in CDCl3 or 1,2-dichloro-
ethane. Based on the stereochemistry of (ꢀ)-3a and the
result of the E/Z isomerization, we proposed that (Z)-2
could be equilibrated to (E)-2 under the reaction condition
and the Michael reaction of (E)-2 could lead to 4a via the
twisted-chair-like transition state in Scheme 1.
After the alkene isomerization study, the equilibration
of the Michael reaction was investigated by using a variety
of bases with Zn(OTf)2. As shown in Scheme 2, all of the
equilibration conditions led to either no equilibration or
decomposition of 4a upon heating. Equilibration occurred
when the Michael adduct (4a) generated in situ was
allowed to heat with Zn(OTf)2 (0.5 equiv) and Et2NH
(10 equiv) at 40 °C for 1 day. However, the expected
thermodynamic Michael adduct (4c) with all the substitu-
ents being equatorial was not obtained and the equilibra-
tion condition gave another diastereomer (4b), which
could be resulted from the eqimerization of the aldehyde
moiety in 4a. The Michael adduct (4b) was converted to
the bicyclic products by addition of In(OTf)3 and 4 A
molecular sieves, which gave (ꢀ)-3b8 as the major product
diterpenoids and their 19-nor variants, we have recently
reported the amine-induced Michael/Coniaꢀene cascade
cyclization, which can rapidlyconstructthecis-decalinring
system from an acyclic substrate in one-pot with good
diastereoselectivity.6 We envisioned that by introducing
the stereogenic center at C8 of the clerodane skeleton, this
cascade cyclization would provide the cis-decalin core with
three new stereogenic centers stereoselectively in one-pot
via the substrate control (Figure 1). The cyclized product
(3) contains the required functionalities and stereogenic
centers for synthesis of a variety of cis-clerodanes and
the spiro γ-lactone 19-nor-clerodanes. Weherein reportthe
development ofthisdiastereoselectiveMichael/Coniaꢀene
cascade cyclization reaction and its application in the
first total synthesis of (ꢀ)-teucvidin (1) in enantiomeric
form. As isolated from Teucrium viscidum Blume var.
Miquelianum by Fujita’s group in 1975,7 compound 1 is
a 19-nor-clerdoane bearing an R,β-unsaturated γ-lactone
moiety fused into the decalin core and a spiro γ-lactone
moiety with a pendant furyl moiety at C9.
As shown in Scheme 1, the diastereoselectivity of the
Michael/Coniaꢀene cascade cyclization reaction via sub-
strate-control was studied using enantiomerically enriched
(ꢀ)-2 (a 1:1 E:Z isomers) as the cyclization precursor.
Upon treatment with ZnI2/Et2NH in 1,2-dichloroethane,6
hydrolysis of the 2-(trimethylsilyl)ethyl ester moiety of
(ꢀ)-2 resulted. Indeed, all Zn(II) or In(III) halides gave
similar results. After a survey of different combinations
of transition metal salts, amines and solvents, we found
that the optimal conditions is to treat (ꢀ)-2 with Zn(OTf)2
(0.2 equiv) and dietheylamine (0.3 equiv) in 1,2-dichloro-
ethane at room temperature. Michael addition of the
enamine derivative of 2 proceeded smoothly under this
condition and gave the kinetic Michael adduct as the
(6) Li, W.; Liu, X.; Zhou, X.; Lee, C.-S. Org. Lett. 2010, 3, 548–551.
(7) Uchida, I.; Fujita, T.; Fujita, E. Tetrahedron 1975, 31, 841–848.
(8) The characterization data and the NMR spectra of (ꢀ)-3a, 3b,
and 10 are available in the Supporting Information.
Org. Lett., Vol. 14, No. 11, 2012
2887

Scheme 2. Equilibration Study
Scheme 3. Total Synthesis of (ꢀ)-Teucvidin
(62%, a 1: 2.3 diastereomeric mixture of 3a and 3b). This
result indicated that the initial Michael reaction could be
irreversible and the equilibration condition can only lead
to the epimerization of the aldehyde moiety via enamine
formation.
With (ꢀ)-3a in hand, the β-keto β0-alkenyl ester moiety
could be converted to a furan moiety via the epoxidation/
dealkoxycarbonylation protocol9 that was recently devel-
oped by our group. As shown in Scheme 3, the aldehyde
moiety of (ꢀ)-3a was first reduced selectively with NaBH4
to avoid BaeyerꢀVillager oxidation under the epoxidation
condition. After epoxidation of the exocyclic alkene with
m-CPBA and oxidation of the alcohol, compound (ꢀ)-5
was converted to (ꢀ)-6 in one-pot using TBAF. Under the
reaction conditions, dealkoxycarbonylation of (ꢀ)-5 gen-
erated an enolate, which underwent epoxide ring opening,
acetal formation, and elimination of water to afford the
fused furan moiety of (ꢀ)-6 (81%, contains about 10% of
the aldehyde epimer). However, attempts of C-allylation
of the R-position of the aldehdye moiety in (ꢀ)-6 failed
probably due to the steric hindrance of the adjacent
substituents. The allyl moiety was then installed via the
O-allylation/Claisen rearrangement protocol,10 which
gave a 3:1 diastereomeric mixture (about 70% isolated
yield for (ꢀ)-8). Oxidative methoxylation of the major
diastereomer ((ꢀ)-8) using N-chlorobenzenesulfonamide
sodium salt followed by treatment with acid11 afforded the
R,β-unsaturated γ-lactone moiety of (ꢀ)-9 efficiently and
diastereoselectively. Pinnick oxidation of the aldehyde
moiety of (ꢀ)-9 followed by treatment with diazomethane
gave methyl ester (ꢀ)-10. The stereochemistry of (ꢀ)-10
was assigned by detail analysis of the NOESY data.8
Moreover, a sample of racemic 10 was prepared from
3-methylglutaric anhydride using a similar synthetic route,
and the crystals of (()-10 obtained by recrystallization
from n-hexane/diethyl ether were found to be suitable for
X-ray crystallography.12 The X-ray structure of (()-10
(Figure2) isfully consistentwith the stereochemicalassign-
ment of (ꢀ)-10 by NOESY. Finally, ozonolysis of the
terminal alkene followed by addition of furan-3-yllithium
installed the spiro γ-lactone moiety stereoselectively and
finish the total synthesis of (ꢀ)-teucvidin. The high stereo-
selectivity of the spiro γ-lactone formation is probably due
(9) Huang, S.; Du, G.; Lee, C.-S. J. Org. Chem. 2011, 76, 6534–6541.
(10) (a) Miysoks, H.; Yokokura, T.; Okamura, T.; Nagaoka, H.;
Yamada, Y. Synlett 2002, 227–230. (b) Nicolaou, K. C.; Zhang, H.;
Ortiz, A.; Dagneau, P. Angew. Chem. 2008, 120, 8733–8738.
(11) Shults, E. E.; Velder, J.; Schmalz, H.-G.; Chernov, S. V.;
Rubalova, T. V.; Gatilov, Y. V.; Henze, G.; Tolstikov, G. A.; Prokop, A.
Bioorg. Med. Chem. Lett. 2006, 16, 4228–4232.
(12) CCDC-868783 ((()-10) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
2888
Org. Lett., Vol. 14, No. 11, 2012

(ꢀ)-2a underwent diastereoselective Michael/Coniaꢀene
cascade cyclization and gave the cis-decalin skeleton con-
taining three new stereogenic centers in one-pot. The
cyclized product was concisely converted to (ꢀ)-teucvidin
in 12 steps with 22% overall isolated yield, which is the first
example of an enantioselective total synthesis of this sub-
class of clerodane diterpenoids. This cascade cyclization
approach could provide an efficient and versatile strategy
for asymmetric synthesis of a variety of cis-clerodane
diterpenoids and their 19-nor variants.
Figure 2. X-ray crystallography of (()-10.
Acknowledgment. This work is supported by the Na-
tional Natural Science Foundation of China (Grant Nos.
20672003 and 20972004) and the Peking University Shenz-
hen Graduate School.
tothelithium chelation ofthe 1,4-dicarbonylmoiety.13 The
1H and 13C NMR data of synthetic (ꢀ)-teucvidin are
consistent with that reported for the natural product.14
In summary, we have developed a concise total synthesis
of (ꢀ)-teucvidin in enantoimeric form. With the stereo-
genic center at C8 (clerodane skeleton), acyclic substrate
Supporting Information Available.
Experimental
procedures with characterization data for all new com-
pounds and X-ray data for (()-10 (CIF) (CCDC-
868783). This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Reissig, H. U.; Angert, H. J. Org. Chem. 1993, 58, 6280–6285.
(14) Rodrı
605–616.
´
guez1, B.; Jimeno, M. L. Magn. Reson. Chem. 2004, 42,
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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