Enantioselective total syntheses of pygmaeocins B and C

Article abstract of DOI:10.1021/ol401543b

The first enantioselective total syntheses of pygmaeocins B and C have been accomplished using an efficient and highly diastereoselective intramolecular Heck cyclization for the construction of a quaternary stereogenic center and the functionalized A-ring of the natural products as the key step.

Full text of DOI:10.1021/ol401543b

ORGANIC
LETTERS
2013
Vol. 15, No. 14
3666–3669
Enantioselective Total Syntheses
of Pygmaeocins B and C
Akiko Obase, Akihito Kageyama, Yuki Manabe, Tsukasa Ozawa, Takaaki Araki,
Hiromasa Yokoe, Makoto Kanematsu, Masahiro Yoshida, and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima,
1-78-1 Sho-machi, Tokushima, 770-8505, Japan
shishido@ph.tokushima-u.ac.jp
Received June 1, 2013
ABSTRACT
The first enantioselective total syntheses of pygmaeocins B and C have been accomplished using an efficient and highly diastereoselective intramolecular
Heck cyclization for the construction of a quaternary stereogenic center and the functionalized A-ring of the natural products as the key step.
The pygmaeocins B (1) and C (2) comprise a novel class
of irregular abietane diterpenoids that were isolated by
Hesse and Meng from the roots of Pygmaeopremna
herbacea.1 Their structures were elucidated by extensive
spectroscopic studies and their absolute configurations,
while not determined directly, were deduced to be R on the
basis of the likely biogenetic pathway.1b These compounds
contain one quaternary stereogenic center at C5 and a
densely functionalized hydrophenanthrene skeleton with a
high oxidation state. The outstanding characteristic struc-
tural feature of these molecules is the C20-Me migration
Figure 1. Pygmaeocins B and C.
from C10 to C5 with an intact C4ꢀC5 bond. Although
we report the first enantioselective total syntheses of
their biological activities have never been reported, the
pygmaeocins B (1) and C (2), thereby establishing their
plant is used in the Yunnan province of China as a folk
absolute stereochemistries, via a diastereoselective intra-
medicine against inflammation and malaria.1b Conse-
molecular Heck (IMH) reaction4,5 for the construction of
quently, they are expected to be promising leads for drug
the functionalized A-ring of the natural products with a
discovery in these areas. To date, although the racemic
quaternary stereogenic center as the key step (Figure 1).
syntheses of pygmaeocins B2 and C3 have been reported,
Our retrosynthetic strategy is illustrated in Figure 2. The
no enantioselective synthesis has been completed. Herein,
preparation of pygmaeocins B (1) and C (2) was based on
chemistry we developed recently for the diastereoselective
(1) (a) Chen, W.; Meng, Q.; Piantint, U.; Hesse, M. J. Nat. Prod.
1989, 52, 581–587. (b) Meng, Q.; Hesse, M. Helv. Chim. Acta 1990, 73,
455–459.
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423–424.
(3) Chin, C. L.; Tran, D. D. P.; Shia, K. S.; Liu, H. J. Synlett 2005,
(4) For reviews, see: (a) Negishi, E.; Coperet, C.; Ma, S.; Liou, S. Y.;
Liu, F. Chem. Rev. 1996, 96, 365–393. (b) Link, J. T.; Overman, L. E. In
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Eds.; Wiley-VCH: Weinheim, 1998; Chapter 6. (c) Link, J. T.; Overman, L. E.
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417–420.
r
10.1021/ol401543b
Published on Web 06/28/2013
2013 American Chemical Society

construction of chiral building blocks for the synthesis
of indole alkaloids.5o We envisioned a sequential oxo-
carbenium ion-mediated FriedelꢀCrafts type cyclization,
desilylation, oxidation and demethylation of 3 to give
pygmaeocin C (2), which can be converted to pygmaeocin
B (1) by oxidation of the catechol functionality. The fully
functionalized cyclohexene 3 would be constructed by an
IMH reaction of 4, which has a tertiary stereogenic center
with the R configuration, via a 1,4-chirality transfer for
assembling a quaternary stereogenic center at C5 with the
R configuration. The vinyl iodide 4 would be derived from
the corresponding optically active acetylenic alcohol (R)-5,
which in turn would be prepared from the aldehyde 6 and
the aryl acetylene 7 (Figure 2).
Scheme 1. Preparation of 6 and 7
Scheme 2. Attempted Preparation of (R)-5
Figure 2. Retrosynthetic analysis.
The starting aldehyde 6 and the aryl acetylene 7 were
prepared as shown in Scheme 1. Treatment of the lactone
86 with MeLi followed by silylation provided the ketone 10,
which was subjected to HornerꢀWadsworthꢀEmmons
olefination to give the (E)-enoate 11. Sequential DIBAH
reduction, methylation, desilylation and Swern oxidation
provided the aldehyde 6 in 83% overall yield from 8. The aryl
acetylene, 3-ethynyl-4-isopropyl-1,2-dimethoxybenzene (7),
(5) (a) Abelman, M. M.; Overman, L. E. J. Am. Chem. Soc. 1988, 110,
2328–2329. (b) Abelman, M. M.; Overman, L. E.; Tran, V. D. J. Am.
Chem. Soc. 1990, 112, 6959–6964. (c) Overman, L. E.; Abelman, M. M.;
Kucera, D. J.; Tran, V. D.; Ricca, D. J. Pure Appl. Chem. 1992, 64, 1813–
1819. (d) Kucera, D. J.; O’Connor, S. J.; Overman, L. E. J. Org. Chem.
1993, 58, 5304–5306. (e) Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am.
Chem. Soc. 1993, 115, 2042–2044. (f) Overman, L. E. Pure Appl. Chem.
1994, 66, 1423–1430. (g) Negishi, E.; Ma, S.; Amanfu, J.; Coperet, C.;
Miller, J. A.; Tour, J. M. J. Am. Chem. Soc. 1996, 118, 5919–5931. (h)
Overman, L. E.; Ricca, D. J.; Tran, V. D. J. Am. Chem. Soc. 1997, 119,
12031–12040. (i) Coperet, C.; Negishi, E. Org. Lett. 1999, 1, 165–167. (j)
Fox, M. E.; Li, C.; Marino, J. P., Jr.; Overman, L. E. J. Am. Chem. Soc.
1999, 121, 5467–5480. (k) Trost, B. M.; Tang, W. Angew. Chem., Int. Ed.
2002, 41, 2795–2797. (l) Hughes, C. C.; Kennedy-Smith, J. J.; Trauner,
D. Org. Lett. 2003, 5, 4113–4115. (m) Miller, A. K.; Hughes, C. C.;
Kennedy-Smith, J. J.; Gradl, S. N.; Trauner, D. J. Am. Chem. Soc. 2006,
128, 17057–17062. (n) Kienzler, M. A.; Suseno, S.; Trauner, D. J. Am.
Chem. Soc. 2008, 130, 8604–8605. (o) Murakami, Y.; Yoshida, M.;
Shishido, K. Tetrahedron Lett. 2009, 50, 1279–1281.
was prepared from 157 via a three-step sequence. Thus,
ortho-lithiation followed by iodination furnished the io-
dobenzene 16, which was exposed to the conditions of
Sonogashira coupling with trimethylsilylacetylene, and the
resulting 17 was desilylated with K2CO3 in methanol to
give 7 in 64% yield from 15 (Scheme 1).
For the preparation of optically active acetylenic alcohol
(R)-5, we initially examined the asymmetric alkynylation of 6
with 7. After several attempts, we found that the procedure
(6) Yang, F.; Xi, P.; Yang, L.; Lan, J.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 5457–5460.
(7) Martinez-Solorio, D.; Jennings, M. P. Org. Lett. 2009, 11, 189–192.
Org. Lett., Vol. 15, No. 14, 2013
3667

reported by Pu et al.8 provided only the adduct 5.
Thus, treatment of 7 with Et2Zn in refluxing toluene
resulted in the zinc acetylide, which was reacted with 6 in
the presence of (S)-BINOL and titanium tetraisopropox-
ide in Et2O at room temperature to give 5 in 76% yield;
however, the enantiomeric excess was only 8% (HPLC
analysis). We then attempted asymmetric reduction of the
acetylenic ketone 18, which was prepared by Swern oxida-
tion of (()-5, generated from 6 and the lithium acetylide of
7. Treatment of 18 with (R)-methyl-CBS-oxazaborolidine
199 and BH3•THF provided 5 and the recovered 18 in 20
and 57% yield, respectively. However, the enantiomeric
excess of 5 still remained low (33% ee) (Scheme 2).
For the key IMH reaction, we treated the substrate 4,
obtained by silylation of 21 (Scheme 3), with 20 mol %
of bis(triphenylphosphine)palladium(II) dichloride and
Et3N (3 equiv) in a mixture of DMF and water to give a
chromatographically separable mixture of the requisite
cyclized product 3 (an inseparable 5.6:1 mixture of E and
Z olefinic isomers) and the bicycle[4.1.0]heptane 225g,13 in
46 and 21% yield, respectively (entry 1). The reaction that
Scheme 3. Preparation of Substrate 4
We next examined the asymmetric transfer hydrogena-
tion of the acetylenic ketone 18 using a chiral Ru (II)
catalyst.10 The results are shown in Table 1. Treatment of
18 with 3 mol % of (R,R)-20 in isopropanol at room
temperature for 19 h provided the alcohol 5 in 46% yield
with 92% ee (entry 1). Addition of acetonitrile as the solvent
resulted in a higher yield with comparable enantioselectivity
(88%, 93% ee) (entry 2). When the reaction was conducted
with 3 mol % of 20 in the presence of formic acid and Et3N in
THF at room temperature for 5 h,11 5 was obtained in 90%
yield with 94% ee (entry 3). The absolute configuration of 5
was deduced to be R from a mechanistic point of view and it
was firmly established by the following conversions (Table 1).
Table 2. Intramolecular Heck Reaction
Table 1. Asymmetric Transfer Hydrogenation
yield (%)
(R,R)-20 (3 mol %)
18
5
3
22
f
conditions
entry
1
conditions
product(s)
(E:Z)a
(ratio)a
(Ph3P)2PdCl2 (20 mol %)
Et3N, DMF, H2O
3 þ 22
46 (5.6:1)21 (3:1)
33 (1.8:1)22 (3:1)
80 °C, 30 h
2
3
Pd(OAc)2 (30 mol %)
3 þ 22
Ph3P (60 mol %)
Ag2CO3, THF, 65 °C, 19 h
Pd(OAc)2 (10 mol %) (o-tol)3P
(20 mol %), Et3N
3
quant (1:2.3)
MeCN, H2O, reflux, 30 h
a determined by 1H NMR
produced 3 took place with perfect diastereoselectivity
1
and was confirmed by the H and 13C NMR spectra, in
which only two sets of resonances corresponding to the
E/Z isomers were observed. The stereostructure of 3 was
confirmed by the NOESY spectroscopy14 and the config-
uration of a newly generated quaternary stereogenic center
at C5 provedtobe the requisite R asshowninFigure3. The
cyclopropane derivative 22, which would be generated
via a double Heck cyclization, was obtained as an insepar-
able 3:1 mixture of the rotational isomers, the NOESY
spectra of which showed the presence of two conformers
(Figure 3). That the minor isomer converged to the major
The optically active acetylenic alcohol 5 was then se-
quentially treated with Red-Al and iodine in one pot to
give the Z-vinyl iodide 21 in 83% yield. At this stage, the
absolute configuration was determined to be R by the
KusumiꢀMosher method12 of the MTPA ester of 21.
(8) Moore, D.; Pu, L. Org. Lett. 2002, 4, 1855–1857.
(9) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214–3217.
(10) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738–8739.
(11) Hamada, T.; Torii, T.; Izawa, K.; Ikariya, T. Tetrahedron 2004,
60, 7411–7417.
(12) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092–4096.
(13) Owczarczyk, Z.; Lamaty, F.; Vawter, E. J.; Negishi, E. J. Am.
Chem. Soc. 1992, 114, 10091–10092.
(14) Both E and Z isomers showed the same NOESY correlations as
indicated in Figure 3.
3668
Org. Lett., Vol. 15, No. 14, 2013

one upon heating was confirmed by the measurement of
1H NMR spectrum at 100 °C in DMSO-d6.15 The reaction
using 30 mol % of Pd(OAc)2, 60 mol % of Ph3P and
Ag2CO3 in THF at 65 °C5a provided a mixture of 3 and 22
in 33 and 22% yield, respectively (entry 2). When the reac-
tionwasconducted using10mol % ofPd(OAc)2, 20mol %
of (o-tol)3P and Et3N in refluxing aqueous acetonitrile, 3 was
produced as the sole product in a dramatic improvement in
the yield to quantitative (E:Z = 1:2.3) (entry 3) (Table 2).
Scheme 4. Plausible Mechanism for the Diastereoselection
Scheme 5. Syntheses of Pygmaeocins B (1) and C (2)
Figure 3. NOESY of 3 and 22.
One plausible mechanism for the diastereoselective for-
mation of 3 is outlined in Scheme 4. The cyclization would
proceed predominantly through the intermediate I1, de-
rived from the boat-like transition state T1, which has an
equatorially disposed TBS-oxy substituent and an eclipsed
orientation of the PdꢀC σ and alkene π bonds,5b to afford
3 exclusively via reductive elimination of the palladium
hydride species. The diastereoselection achieved in the Heck-
cyclization step can be attributed to an unfavorable allylic
strain in T2 (leading to 5-epi-3 via I2) as shown (Scheme 4).
In the final phase of the synthesis, treatment of 3 with
TBAF in THF, followed by oxidation of the resulting
allylic alcohol 23 with manganese dioxide provided the
enone 24, which was exposed to methanesulfonic acid in
dichloromethane at 0 °C to give the tricyclic enone 25
quantitatively. The methyl ethers in 25 were cleaved with
BBr3 in dichloromethane to give pygmaeocin C (2) in 74%
yield. Due to the less stable character of 2, its catechol moiety
was acetylated to give the diacetate 26 in 96% yield. On the
other hand, for the synthesis of pygmaeocin B (1), the crude 2
was immediately oxidized with silver carbonate in dichloro-
methane at room temperature to produce 1 in 80% yield
from 25. The spectral properties (1H and 13C NMR, IR and
HRMS) of the synthetic materials 1, 2 and 26 were identical
with those reported in the literature1b and the completion of
the total syntheses of pygmaeocins B and C was accom-
plished. Since the CD spectra of 1 and 2 were also identical
with those for the natural products,16 the absolute config-
uration at C5 was established to be R (Scheme 5).
In summary, we have completed the first enantioselective
total syntheses of pygmaeocins B and C using, as the key step,
a 1,4-chirality transfer that occurred with high diastereoselec-
tivity during the IMH reaction for the construction of the sole
quaternary stereogenic center at C5 and the functionalized
A-ring of the natural products in a longest linear sequence of
eighteen and seventeen steps, respectively, from the lactone 8
with overall yields of 30 and 28%. In addition, the absolute
configuration at the C5 quaternary stereogenic center was
firmly established by the total synthesis to be R, which had
been proposed by Hesse and Meng.1 The synthetic route
developed here is general and efficient and could also be
applied to the syntheses of other related natural products.
Acknowledgment. We are grateful to Dr. Meng,
AtheroGenics, Inc., for providing spectral data (1H and
13C NMR, IR, MS) of pygmaeocins B and C. This work
was supported by a Grant-in-Aid from the Program for the
Promotion of Basic and Applied Research for Innovation
in the Bio-oriented Industry (BRAIN).
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) On heating a solution of the corresponding ketone, which was
prepared from 22 by treatment with TBAF, in C6D6 in an NMR tube at
70 °C, the minor rotational isomer also converged cleanly to the major
one.
The authors declare no competing financial interest.
(16) See Supporting Information.
Org. Lett., Vol. 15, No. 14, 2013
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