Enantioselective biomimetic total syntheses of katsumadain and katsumadain C

Article abstract of DOI:10.1021/ol2029433

Enantioselective total syntheses of katsumadain and katsumadain C were achieved concisely through a biomimetic approach. Assembly of styryl-2-pyranone (3) and monoterpene 6 via acid-promoted regio- and stereoselective C-C bond formation afforded katsumada

Full text of DOI:10.1021/ol2029433

ORGANIC
LETTERS
2012
Vol. 14, No. 1
162–165
Enantioselective Biomimetic Total
Syntheses of Katsumadain and
Katsumadain C
Pengtao Zhang,† Yongguang Wang,† Ruiyang Bao,† Tuoping Luo,§ Zhen Yang,*,‡
and Yefeng Tang*,†
The Comprehensive AIDS Research Center, Department of Pharmacology &
Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084,
China, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education and Beijing National Laboratory for Molecular Science
(BNLMS), College of Chemistry, Peking University, Beijing 100871, China
yefengtang@tsinghua.edu.cn; zyang@pku.edu.cn
Received November 1, 2011
ABSTRACT
Enantioselective total syntheses of katsumadain and katsumadain C were achieved concisely through a biomimetic approach. Assembly of styryl-
2-pyranone (3) and monoterpene 6 via acid-promoted regio- and stereoselective CꢀC bond formation afforded katsumadain (2), which underwent
the photoinduced [2 þ 2] dimerization in a head-to-tail mode to furnish katsumadain C (1).
Naturally occurring 2-pyranone derivatives constitute a
large family of natural products that displaydiverse molec-
ular architectures and a wide range of biological profiles,
such as antitumor, antimicrobial, and anti-HIV activities.1
Recently, katsumadain C (1, Figure 1) was isolated from
the plants of Alpinia katsumadai byKongand co-workers.2
Preliminary biological evaluations showed that katsuma-
dain C displayed significant growth inhibitory effects against
SMMC-772 cells with IC50 at 4.8 μM and exhibited
moderate antitumor activity against several other human
tumor cell lines.
From the structural point of view, katsumadain C re-
presents the first monoterpene substituted kavalactone
dimer conjugated in the head-to-tail mode. The proposed
biosynthetic pathway2 suggests katsumadain C is derived
from katsumadain (2) through a [2 þ 2] cycloaddition
(Figure 1). Indeed, 2 was also isolated from the same
natural resource by Wang and co-workers in 2010.3 The
structure and relative configurations of 1 were determined
by spectroscopic evidence, while its absolute configuration
remains uncertain.
As part of our continuous interests in the total synthesis
of natural products with a unique molecular architecture,
important biological activity, and intriguing biosynthetic
pathway,4 we initiated a program to develop a synthetic
strategy that will allow accessing structural analogues in
addition to a large quantity of natural products for further
biological studies. Herein we report our progress that leads
to the first enantioselective biomimetic total syntheses of
katsumadain and katsumadain C in a highly efficient,
regio- and diastereocontrolled manner.
The synthetic strategy coupled with a plausible bio-
synthetic pathway for katsumadain C (1) is depicted in
Figure 1. According to Kong’s hypothesis,2 katsumadain
† Tsinghua University.
‡ Peking University.
§ Current address: H3 Biomedicine Inc., 300 Technology Square, Cambridge,
MA 02139.
(1) (a) McGlacken, G. P.; Fairlamb, I. J. S. Nat. Prod. Rep. 2005, 22,
369–385. (b) Atul, G.; Vishnu, J. R. Tetrahedron 2009, 65, 7865–7913.
(2) Yang, C. S.; Wang, X. B.; Wang, J. S; Luo, J. G.; Luo, L.; Kong,
L. Y. Org. Lett. 2011, 13, 3380–3383.
(3) Li, Y. Y.; Chou, G.; X.; Wang, Z. T. Helv. Chim. Acta 2010, 93,
382–388.
(4) Zhang, Z. Y.; Chen, J. H.; Yang, Z.; Tang, Y. F. Org. Lett. 2010,
12, 5554–5557.
r
10.1021/ol2029433
Published on Web 12/13/2011
2011 American Chemical Society

Scheme 1. Acid-Promoted Assembly of Fragment 8 and 5
the C-3 functionalization of 8 with an allylic alcohol
acetate via Pd-catalyzed allylic substitution has been well
documented,7 the more direct acid-promoted SN1 substi-
tution with the allylic alcohol has rarely been investigated,8
presumably due to the expected complicated regio- and
diastereoselectivity issues. Thus, we performed a systema-
tic condition screening on this transformation (for details,
see Table-S1 of the Supporting Information). It was ob-
served that when a strong Brønsted acid (2 N HCl or 2 N
H2SO4) or Lewis acid (TiCl4, BF3•Et2O, or TMSOTf) was
employed with CH3CN as solvent, only a trace amount of
the desired product 9(5ꢀ10% yield) was obtained (Scheme 1).
Instead, compound 10, possibly generated from 9 via an
intramolecular etherification reaction, was isolated as the
major product in 25ꢀ30% yield. We envisioned that the
formation of 10 might be attributed to the relatively harsh
acidic conditions, and therefore, some weak acids such as
AcOH, HCOOH, PhCOOH, and CH3CH3COOH were
examined in this transformation. Gratifyingly, it was
found that in these cases 9 was isolated as the major
product (30ꢀ55% yield) without formation of 10. How-
ever, other byproducts 11, 12, and 13, which are either the
regio- or diastereoisomers of 9, were isolated in substantial
amounts (18ꢀ40% in combined yield). To further mini-
mize the formation of byproducts, the solvent effect was
thenevaluated. Eventually, a satisfyingresultwas obtained
Figure 1. Proposed biosynthetic pathway for katsumadain C
and bioinspired synthetic strategy.
C is derived from katsumadain via a [2 þ 2] dimerization.
In turn, katsumadain could be generated from styryl-
2-pyranone (3) and R-terpinene (4) via a CꢀC bond forma-
tion between C-3 and C-30. In view of the fact that both
3 and 4 are achiral substrates, while katsumadain and
kasumadain C were isolated as enatiopure compounds, the
CꢀC bond formation should be an enzyme-catalyzed
enantioselective process, which, though feasible in natural
medium, would be rather challenging for synthetic chemists.
Alternatively, we envision that some other easily accessible
chiral monoterpenes, suchaspiperitol (5),5 2-menthen-1-ol
(6),6 or R-phellandrene (7), could also serve as the pre-
cursors for the biosynthesis of katsumadain. Within this
context, the CꢀC bond formation between 3 and 5, 6, or 7
could proceed through SN1 substitution via carbocation
intermediate A under acidic conditions, with the stereo-
chemical outcome controlled by the stereogenic centers
at C-40.
~
(7) (a) Moreno-Manas, M.; Prat, M.; Ribas, J.; Virgili, A. Tetrahe-
~
dron Lett. 1988, 29, 581–584. (b) Moreno-Manas, M.; Ribas, J.; Virgili,
~
A. J. Org. Chem. 1988, 53, 5323–5335. (c) Moreno-Manas, M; Ribas, J.
To validate our biosynthetic hypothesis and explore a
feasible method for assembling the 2-pyranone and mono-
terpene fragments, a simple model study was conducted
with commercially available triacetic acid lactone 8 and
racemic allylic alcohol 55b as substrates. Notably, although
Tetrahedron Lett. 1989, 30, 3109–3112. (d) Prat, M.; Ribas, J.; Moreno-
Manas, M. Tetrahedron 1992, 48, 1695–1706.
~
(8) To the best of our knowledge, there is no study on C-3 functio-
nalization of 8 with the allylic alcohol reported. The transformations
using benzylic alcohol, propargylic alcohol, aldehyde, or styrene as
resources for electrophiles are well documented; for selected examples,
see: (a) Reddy, C. R; Srikanth, B.; Narsimha, R. N.; Shin, D. S.
Tetrahedron 2008, 64, 11666–11672. (b) Huang, W.; Wang, J. L.; Shen,
Q. S.; Zhou, X. G. Tetrahedron 2007, 63, 11636–11643. (c) Rueping, M.;
Bootwicha, T.; Sugiono, E. Adv. Synth. Catal. 2010, 352, 2961–2965. (d)
Hagiwara, H.; Kobayashi, K.; Hoshi, T.; Suzuki, T.; Ando, M. Tetra-
(5) For a leading review on synthesis of chiral monoterpenes, see: (a)
Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Chem. Rev. 2011, 111,
4036–4072. (b) Serra, S.; Brenna, E.; Fuganti, C.; Maggioni, F. Tetra-
hedron: Asymmetry 2003, 14, 3313–3319.
~
hedron 2001, 57, 5039–5043. (e) Moreno-Manas, M.; Papell, E.; Pleixats,
(6) Kenji, M. Tetrahedron: Asymmetry 2006, 17, 2133–2142.
R.; Ribas, J.; Virgili, A. J. Heterocycl. Chem. 1986, 23, 413–416.
Org. Lett., Vol. 14, No. 1, 2012
163

by using AcOH as the promoter and a mixture of CH3CN/
H2O (3:1) as the solvent, which provided 9 in 72% iso-
lated yield, with only a trace amount of other byproducts
observed.
in 18% yield, whose structure was assigned as 18. Apparently,
(()-katsumadain C (17) was generated from the homo-
dimerization of one single enantiomer of 16 via transition
state TS-1, while 18 was derived from the heterodimeriza-
tion of two different enantiomers via transition state TS-2.
In both cases the [2 þ 2] dimerization proceeded domi-
nantly in the head-to-tail mode, which could be attributed
to the favorable electronic effect (πꢀπ stacking interaction
between the phenyl ring of one molecule and the 2-pyra-
none ring of the other, as shown in Scheme 3) and steric
effect (severe steric interactions could be imagined between
the two monoterpene moieties in the head-to-head mode,
which are not shown herein). The observation that the
homodimerization was more favorable than the hetero-
dimerization in the transformation might be ascribed to
the trivial difference between the steric interactions asso-
ciated with TS-1 and TS-2 (Scheme 3).
With the method for assembly of 2-pyranone and mono-
terpene fragments established, we next turned our atten-
tion to the synthesis of katsumadain. Thus, 9 was first
treated with n-BuLi (2.5 equiv) at ꢀ78 °C to form the
corresponding dianion intermediate which underwent nu-
cleophilic addition to benzaldehyde to furnish 14 in 90%
yield.9 Upon treatment of 14 with Ac2O/TEA followed by
the addition of an excess amount of DBU,10 15 was
generated in 60% yield, accompanied by the formation
of a substantial amount of (()-katsumadain (16) (30%).
Removal of the acetyl group of 15 using DBU/CH3OH led
to (()-katsumadain in 88% yield (Scheme 2). Notably, the
transformations from 14 to 16 could be also operated in a
one-pot manner, which resulted in a comparable overall
yield (77%).
Scheme 3. Total Synthesis of (()-Katsumadain C
Scheme 2. Synthesis of (()-Katsumadain
With (()-katsumadain(16) in hand, various photochem-
ical conditions involving different photoresources, sol-
vents, and temperature were investigatedtoeffectits [2þ 2]
dimerization into (()-katsumadain C. After extensive
attempts, it was found that when 16 was irradiated with
a mercury lamp (365 nm) in its solid state11 in thin-film
form under N2 protection, the desired [2 þ 2] dimerization
proceeded smoothly to provide (()-katsumadain C (17) in
30% yield. Interestingly, in addition to the recovery of
40% of starting material 16, another product was isolated
(9) Zhang, X. J.; McLaughlin, M.; Lizeth, R.; Munoz, P.; Hsung,
R. P.; Wang, J.; Swidorski, J. Synthesis 2007, 5, 749–753.
(10) Oikawa, H.; Kobayashi, T.; Katayama, K.; Oikawa, H.; Suzuki,
Notably, when 15 was submitted to the same [2 þ 2] re-
action conditions, only the homodimerization product 19
was isolated in 45% yield, without formation of the
heterodimerization product 20 being observed (with 45%
of starting material 15 recovered). The structure of 19 was
confirmed by its conversion to (()-katsumadain C (17)
after removal of the acetyl groups. This result indicated
Y.; Ichihara, A. J. Org. Chem. 1998, 63, 8748–8756.
(11) For examples of photoinduced [2 þ 2] dimerization in the solid
state, see: (a) Ortmann, I.; Werner, S.; Kriiger, C.; Mohr, S.; Schaffner,
K. J. Am. Chem. Soc. 1992, 114, 5048–5054. (b) Ichikawa, M.; Takaha-
shi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2004, 126, 16553–
16558. (c) Liu, J.; Wendt, N. L.; Boarman, K. J. Org. Lett. 2005, 7, 1007–
1010. (d) Liu, D.; Ren, Z. G.; Li, H. X.; Lang, J. P.; Li, N. Y.; Abrahams,
B. F. Angew. Chem., Int. Ed. 2010, 49, 4767–4770. (e) Tan, H. B.; Zheng,
C.; Liu, Z.; Wang, Z. G. Org. Lett. 2011, 13, 2192–2195.
164
Org. Lett., Vol. 14, No. 1, 2012

that 15 displayed interesting self-recognition behavior (i.e.,
(þ)-15 þ (þ)-15 or (ꢀ)-15 þ (ꢀ)-15 via TS-3) in the [2 þ 2]
cycloaddition. So far itstill remains unclearaboutthe exact
factorsresponsiblefor suchphenomena;12 however, simple
analysis of the molecular model of 15 suggested that
introduction of the acetyl group on the 3-OH will increase
the steric hindrance around the 2-pyranone-monoterpene
moiety (Scheme 3), which might render the transition state
TS-4 much more sterically unfavorable than TS-3. It is
worth noting that the [2 þ 2] dimerization of 16 or 15 could
also proceed upon direct exposure to sunlight, and com-
parable results were obtained. However, an attempt to im-
prove the conversion of the transformation by elongating
the reaction time proved fruitless, only leading to substan-
tial decomposition of the starting material and product.
of 5 in the following transformation due to the anticipated
equilibrium between the carbocation A and B. Indeed, the
assembly of styryl-2-pyranone (3)14 with 6 worked well as
expected under the optimized conditions (HOAc, CH3CN/
H2O = 3:1, 85 °C, 6ꢀ10 h) to afford katsumadain (2) in
65% yield (Scheme 4).
Finally, the photoinduced [2 þ 2] dimerization of katsu-
madain (2) (neat, Hg lamp, 365 nm, 1 h) proceeded
smoothly to provide katsumadain C (1) in 45% yield,
along with the recovery of 45% of starting material. The
recovered 2 could be reused in the [2 þ 2] cycloaddition
with the same efficiency, and thus the overall yield of the
reaction could be increased to 65% after two runs. Nota-
bly, the spectroscopic data of synthetic katsumadain and
katsumadain C (1H and 13C NMR, IR, HRMS) were fully
identical with those reported for natural products. More-
over, their measured optical rotations were also in agree-
ment with those of natural substances (for katsumadain:
[R]D22 = þ172.4, c 0.20, CH3OH, lit.[R]D22 = þ170.0, c
0.40, CH3OH; for katsumadainC: [R]D22 =þ140.4, c 0.10,
CH3OH/CHCl3 (1:1), lit.[R]D22 = þ173.2, c 0.05, CH3OH/
CHCl3 (1:1)), indicating that the absolute stereochemis-
tries of C-30 and C-40 stereogenic centers of katsumadain
and katsumadain C are R and R configurations respec-
tively (Scheme 4).
Scheme 4. Enantioselective Total Synthesis of Katsumadain C
In summary, the first enantioselective total syntheses of
katsumadain and katsumadain C were achieved through
an efficient and biomimetic strategy, which features an
acid-mediated regio- and stereoselective CꢀC bond for-
mation between styryl-2-pyranone (3) and monoterpene
6 to afford katsumadain (2), and a photoinduced topo-
chemically controlled [2 þ 2] dimerization of 2 to give
katsumadain C (1). Our study provides strong evidence for
the proposed biosynthtetic pathways of these two natural
products. Moreover, it also paves the way to access large
quantities of natural products as well as their analogs for
further biological studies, which is underway in our la-
boratory and will be communicated in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support from the National Science of Foundation
of China (20832003), China’s 985 project (411307141), and
the Support Fund for Key Personnel from Tsinghua
University (563107002) to Y.T. We also thank Prof.
J. M. Quan (Peking University, Shenzhen Graduate School)
for his helpful discussion.
With the racemic synthesis of (()-katsumadain C (17)
accomplished, the stage was then set for its asymmetric
version. To this end, the chiral monoterpene (R)-cryptone
(21) was prepared according to a known method in
enantioenriched form (89% ee).13 Treatment of 21 with
MeLi/LiBratꢀ78°C affordeda mixtureof(1S,4R)-6aand
its stereoisomer (1R,4R)-6b in a 3:1 ratio,6 which could be
used directly in the next step without separation. We en-
visioned that monoterpene 6 could be used as the surrogate
Supporting Information Available. Experimental pro-
cedure and characterization data for all of new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) Efforts to obtain the crystal structure of 15 to understand its
unusual behavior in the [2 þ 2] dimerization failed after extensive tries.
(13) Same procedure was employed as Baran’s method, except for
ꢀ
that (R)-catalyst was used; see: Chen, K.; Ishihara, Y.; Galan, M. M.;
Baran, P. S. Tetrahedron 2010, 66, 4738–4744.
(14) Styryl-2-pyranone (3) was prepared according to the following
references: (a) Katritzky, A. R.; Wang, Z. Q.; Wang, M. Y.; Hall, C. D.;
Suzuki, K. J. Org. Chem. 2005, 70, 4854–4856. (b) Bach, T.; Kirsch, S.
Synlett 2001, 1974–1976.
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