The total synthesis of pygmaeocin C

Article abstract of DOI:10.1055/s-2004-837222

Making use of a recently developed intramolecular Friedel-Crafts alkylation process as the key operation, the first total synthesis, in racemic form, of pygmaeocin C has been achieved. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2004-837222

LETTER
417
The Total Synthesis of Pygmaeocin C
S
ynthesis of Pygm
h
aeocin
C
in-Long Chin,a Duong Duc-Phi Tran,b Kak-Shan Shia,a,b Hsing-Jang Liu*a,b
a
Department of Chemistry, National Tsing Hua University Hsinchu, Taiwan 30013, P. R. China
Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada
Fax +886-3-5720711; E-mail: hjliu@mx.nthu.edu.tw
b
Received 1 November 2004
The synthetic work began with the preparation of compo-
nent molecules 2 and 3 required for the convergent
approach (Scheme 2) towards the projected key inter-
mediate 4 en route to the target compound 1 involving an
intramolecular Friedel–Crafts reaction. Keto aldehyde 2
was prepared from dimedone (5) according to the reaction
sequence shown in Scheme 3. Treatment of 5 with p-tolu-
enesulfonic acid and ethanol in refluxing benzene gave
the corresponding vinylogous ester 6 in 94% yield. This
compound was subjected to Stork–Danheiser alkylation3
using lithium diisopropylamide and methyl iodide, and
the resulting product 7 was further alkylated with ethyl
bromoacetate to yield the dialkylated compound 8 in 83%
yield over two steps. Compound 8 was reduced with lith-
ium aluminum hydride, and the unstable diol thus ob-
tained was immediately treated with hydrochloric acid to
give a 94% yield of keto ether 9, most likely as a result of
the spontaneous cyclization of the expected product.4
Keto ether 9 was subjected to catalytic hydrogenation in
methanol in the presence of sodium methoxide using 10%
Pd/C as a catalyst. These conditions are expected to in-
duce ether ring cleavage via b-elimination and hydrogena-
tion of the resulting double bond successively, giving rise
to keto alcohol 10. Indeed, the expected product was
formed in 74% yield, from which keto aldehyde 2,5 one of
the component molecules required for the projected syn-
thesis of pygmaeocin (1), was obtained in 95% yield after
oxidation with pyridinium dichromate.6
Abstract: Making use of a recently developed intramolecular
Friedel–Crafts alkylation process as the key operation, the first total
synthesis, in racemic form, of pygmaeocin C has been achieved.
Key words: pygmaeocin C, total synthesis, intramolecular Friedel–
Crafts alkylation
The roots of Pygmaeopremna herbacea Moldenke, a
small shrub indigenous to the Yunan and Hainan provinc-
es of China and the northern part of India, have long been
used by local people as a folk medicine for the treatment
of inflammation and malaria. In 1990, Meng and Hesse
reported the isolation of pygmaeocin C (1),1 a rearranged
abietane diterpenoid, from the roots thereof. In spite of its
potential medicinal interest, the biological activity of this
naturally occurring hydrophenanthrene has not been ex-
plored due to insufficient supply of the material from nat-
ural sources. Several years ago, we observed that, as
illustrated in Scheme 1 with a specific example, the cross
conjugated b-keto ester system is an excellent promoter to
facilitate the construction of highly functionalized hydro-
phenanthrene derivatives via intramolecular Friedel–
Crafts alkylation.2 This finding forms the basis of our
synthetic design for pygmaeocin C (1), the implementa-
tion of which has culminated in its first total synthesis as
described herein.
O
For the construction of the other component molecule 3,
veratrole (11) was subjected to deprotonation with n-bu-
tyllithium,7 and the ensuing anion trapped with methyl
chloroformate to give benzoate 12 (Scheme 4). This
compound was treated with methylmagnesium bromide to
OH
OH
natural 1
O
O
O
O
CO2CH3
H
CO2CH3
CO2CH3
SnCl4, CH2Cl2
OH
OH
OCO2CH3
–78 °C, 30 min
100%
OCH3
OCH3
OCH3
_
(+ )-1
4
OCH3
O
Scheme 1
O
OCH3
OCH3
+
OH
OCH3
OCH3
Br
OHC
3
2
SYNLETT 2005, No. 3, pp 0417–0420
1
6.
0
2.
2
0
0
5
Advanced online publication: 22.12.2004
DOI: 10.1055/s-2004-837222; Art ID: U30404ST
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

418
C.-L. Chin et al.
LETTER
O
O
LDA, THF, –78 °C, 1 h
then MeI, r.t., 15 h, 97%
p-TsOH, EtOH, benzene
reflux, 24 h, 94%
OEt
O
6
5
O
EtO2C
O
LiAlH4, THF, r.t., 15 h
LDA, THF, –78 °C, 1 h
then 1 N HCl, r.t., 10 h
94%
then BrCH2COOEt, r.t.
15 h, 86%
OEt
OEt
7
8
O
O
O
PDC, CH2Cl2
r.t., 4 h, 95%
NaOMe, MeOH,10% Pd/C
H2, r.t., 6 h, 74%
O
OHC
9
OH
10
2
Scheme 3
furnish alcohol 13 in 93% yield over two steps. For the stereomeric keto alcohols 16 (1:1) in modest yield (50%).
subsequent introduction of a bromine atom, a number of Subsequent treatment of 16 with sodium hydride in re-
conditions were explored, using molecular bromine or N- fluxing dimethyl carbonate10 afforded an 81% yield of
bromosuccinimide in various solvents including methyl- keto ester 17, existing partially (ca. 15%) in the corre-
ene chloride, N,N-dimethylformamide, and glacial acetic sponding enol form. This compound was converted to the
acid. All of the conditions applied gave either a mixture of desired enone ester 4 using the phenylselenenylation–ox-
products or the undesired regioisomers with the exception idative elimination protocol.11
of bromine in acetic acid. With this combination, the reac-
tion occurred cleanly to give the desired bromide 14 ex-
As delineated early, compound 4 was expected to undergo
facile intramolecular Friedel–Crafts alkylation to provide
clusively in excellent yield (95%). The observed high
the tricyclic system present in the target molecule. Unfor-
regioselectivity could be attributed to hydrogen bonding
tunately, under none of the conditions applied, the ring-
between the hydroxyl of the starting substrate and acetic
closure could be effected. As shown in Scheme 6, the
acid, making the isopropanol substituent sufficiently elec-
problem was the highly competitive ether ring formation
tron-withdrawing to serve as an effective meta-director.
and elimination reactions leading to cyclic ether 18 (ex-
Bromide 14 was subjected to dehydration with p-toluene-
clusively with BF3·OEt2) and olefin 1912 (exclusively with
sulfonic acid, and the resulting olefin 15 was hydrogenat-
SnCl4), respectively. After considerable experimentation,
ed using Wilkinson’s catalyst8 to give the corresponding
however, it was realized that, to our delight, the required
saturated bromide 39 in 83% yield.
cyclization could be induced with olefin 19 with a high
To prepare the projected key intermediate 4, the Grignard degree of efficiency. Upon exposure to trifluoroacetic ac-
reagent generated from bromide 3 was added to aldehyde id, this compound was found to undergo Friedel–Crafts
2 (Scheme 5) to give an inseparable mixture of two dia- reaction intramolecularly to give an 88% yield of the
OCH3
OCH3
OCH3
OCH3
MeMgBr, THF, 60 °C
18 h, 95%
n-BuLi, THF, –78 °C, 1 h
then ClCO2Me, r.t., 15 h
98%
CO2CH3
11
12
OCH3
OCH3
OCH3
OCH3
OH
p-TsOH, benzene
Br2, HOAc, NaOAc, r.t.
18 h, 95%
reflux, 14 h, 92%
Br
OH
13
14
OCH3
OCH3
OCH3
OCH3
Wilkinson's catalyst, H2
MeOH, r.t., 8 h, 90%
Br
Br
3
15
Scheme 4
Synlett 2005, No. 3, 417–420 © Thieme Stuttgart · New York

LETTER
Synthesis of Pygmaeocin C
419
O
O
O
OCH3
CO2CH3
CO2CH3
OCH3
Mg, THF, 65 °C, 2 h
BF3·OEt2, CH2Cl2
OH
OCO2CH3
O
then 2, 0 °C, 4 h, 50%
Br
OCH3
OCH3
r.t., 4 h, 65%
OCH3
OCH3
3
OCH3
OCH3
4
18
16
O
CO2CH3
O
NaH, CH3OCO2CH3
reflux, 3 h, 81%
CO2CH3
OCO2CH3
OCH3
OCH3
CF3CO2H, CH2Cl2
r.t., 15 h, 88%
SnCl4, CH2Cl2
–78 °C, 3 h, 60%
17
OCH3
OCH3
O
19
CO2CH3
PhSeCl, pyridine, CH2Cl2, 0 °C
O
OCO2CH3
CO2CH3
1 h, then H2O2, 0 °C, 30 min
78%
OCH3
OCH3
OCH3
H
OCH3
4
20
Scheme 5
Scheme 6
desired cyclization product 20 as a result of double bond
isomerization followed by ring-closure. The tricyclic keto
ester 20 was shown to exist completely in the enol form.
The stereochemistry of its ring junction follows from the
subsequent transformation (vide infra). The finding that
the required cyclization could be effectively carried out
via compound 19 led us to adjusting the synthetic route for
its more effective formation. This was achieved as follows
(Scheme 7). Keto alcohol 16 was first treated with p-tolu-
enesulfonic acid, and the dehydration product 21 thus ob-
tained was subjected to carbomethoxylation with sodium
hydride in refluxing dimethyl carbonate to give keto ester
22, which was shown to be completely enolized. A double
bond was then introduced using the phenylselenenyl-
ation–oxidative elimination process. In this way, com-
pound 19 was obtained in 65% yield over three steps from
16.
those reported for the natural material.1 Accordingly, the
first total synthesis, in racemic form, of pygmaeocin C (1)
has been accomplished from dimedone (5) in fourteen
steps with an overall yield of 4.6%.
O
O
p-TsOH, acetone
OH
reflux, 30 min, 82%
OCH3
OCH3
OCH3
OCH3
16
21
O
CO2CH3
PhSeCl, pyridine,
CH2Cl2, 0 °C
Towards the end of the synthesis, the tricyclic compound
20 was subjected to sequential treatment with aqueous so-
dium hydroxide and sulfuric acid for the removal of the
carbomethoxy group. Ketone 23 (Scheme 8) was obtained
as a crystalline compound, mp 127–128 °C, and its struc-
ture was fully established by a X-ray crystallographic
analysis. For the incorporation of the required double
bond, ketone 23 was first converted to the corresponding
silyl enol ether using lithium diisopropylamide and tri-
methylsilyl chloride. Oxidation of the silyl enol ether thus
prepared in situ with 2,3-dichloro-5,6-dicyanoquinone13
gave the desired enone 24 in 52% yield. This was fol-
lowed by treatment with sodium ethylmercaptide14 to ef-
fect the final removal of the ether protecting groups. The
spectroscopic properties of ( )-pygmaeocin C (1)15 thus
obtained in 67% yield was found to be in agreement with
NaH, MeOCO2Me
reflux, 5 h, 96%
OCH3
OCH3
1 h, then H2O2, 0 °C,
30 min, 82%
22
O
CO2CH3
OCH3
OCH3
19
Scheme 7
Synlett 2005, No. 3, 417–420 © Thieme Stuttgart · New York

420
C.-L. Chin et al.
LETTER
O
O
CO2CH3
OCH3
OCH3
H
H
10% NaOH (aq), MeOH, THF
OCH3
OCH3
reflux, 6 h, then 10% H2SO4 (aq)
reflux, 30 min, 90%
23
20
O
O
OCH3
OCH3
OH
OH
LDA, TMSCl, THF, –78 °C
NaSEt, DMF
1 h, then DDQ, THF, r.t.
5 h, 52%
reflux, 48 h
67%
14
( )-1
Scheme 8
(10) Liu, H. J.; Sun, D. Tetrahedron Lett. 1997, 38, 6159.
(11) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.;
Kezar, H. S. J. Org. Chem. 1981, 46, 2920.
Acknowledgment
We are grateful to the National Science Council (NSC 90-2113-M-
007-037) of the Republic of China for financial support.
(12) Compound 19: IR (neat): 2963, 2874, 1744, 1716, 1690,
1580, 1487, 1463, 1318, 1280, 1234, 1148, 1067, 1010 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.27 (s, 1 H), 6.77 (d,
J = 1.6 Hz, 1 H), 6.73 (d, J = 1.6 Hz, 1 H), 6.26 (d, J = 16.4
Hz, 1 H), 6.06 (d, J = 16.4 Hz, 1 H), 3.84 (s, 3 H), 3.80 (s, 3
H), 3.77 (s, 3 H), 3.29 (sep, J = 6.8 Hz, 1 H), 2.58 (d,
J = 16.0 Hz, 1 H), 2.22 (d, J = 16.0 Hz, 1 H), 1.33 (s, 3 H),
References
(1) (a) Meng, Q.; Hesse, M. Helv. Chim. Acta 1990, 73, 455.
(b) The optical rotation of pygmaeocin C has not been
reported. Its diacetate shows [a]D22 –425.5 (c 0.235, MeOH).
(2) Liu, H. J.; Tran, D. D. P. Tetrahedron Lett. 1999, 40, 3827.
(3) Stork, G.; Danheiser, R. J. Org. Chem. 1973, 38, 1775.
(4) Liu, H. J.; Shia, K. S.; Han, Y.; Wang, Y. Synlett 1995, 545.
(5) Compound 2: IR (neat): 2973, 2847, 2746, 1729, 1705,
1465, 1384, 1300, 1253, 1205, 1185, 1144 cm–1. 1H NMR
(400 MHz, CDCl3): d = 9.92 (t, J = 3.2 Hz, 1 H), 2.56–2.24
(m, 2 H), 2.36 (t, J = 3.2 Hz, 2 H), 2.31 (d, J = 14.4 Hz, 1 H),
2.16 (d, J = 14.4 Hz, 1 H), 1.94–1.89 (m, 2 H), 1.28 (s, 3 H),
0.93 (s, 6 H). 13C NMR (100 MHz, CDCl3): d = 210.1 (C=O),
202.8 (CHO), 51.8 (CH2), 48.8 (CH2), 41.1 (C), 38.1 (C),
37.5 (CH2), 33.7 (CH2), 24.0 (2 × CH3), 20.1 (CH3). HRMS
(EI): m/z (%) = 182.1305 (5) [M+] (calcd for C11H18O2:
182.1307), 138.1036 (100, calcd for C9H14O: 138.1045),
123.0801 (69, calcd for C8H11O: 123.0810).
(6) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 399.
(7) Barnes, R. A.; Bush, W. M. J. Am. Chem. Soc. 1959, 81,
4705.
(8) Jourdant, A.; Gonzalez-Zamora, E.; Zhu, J. J. Org. Chem.
2002, 67, 3163.
(9) Compound 3: IR (neat): 2963, 2936, 1588, 1574, 1481,
1464, 1429, 1411, 1334, 1294, 1219, 1172, 1058, 1008 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.93 (d, J = 2.2 Hz, 1 H),
6.85 (d, J = 2.2 Hz, 1 H), 3.81 (s, 3 H), 3.76 (s, 3 H), 3.29
(sep, J = 6.8 Hz, 1 H), 1.17 (d, J = 6.8 Hz, 6 H). 13C NMR
(100 MHz, CDCl3): d = 153.2 (C), 145.4 (C), 144.0 (C),
121.3 (CH), 116.4 (C), 113.1 (C), 60.7 (CH3), 55.7 (CH3),
26.7 (CH), 23.2 (2 × CH3). HRMS (EI): m/z (%) = 258.0245
(1) [M+] (calcd for C11H15BrO2: 258.0255), 180.9873 (100,
calcd for C5H10BrO2: 180.9864).
1.18 (d, J = 6.8 Hz, 6 H), 1.01 (s, 3 H), 0.99 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 194.7 (C), 164.7 (C), 161.1
(CH), 152.6 (C), 146.3 (C), 142.4 (C), 132.2 (C), 131.2
(CH), 130.3 (C), 129.4 (CH), 117.0 (CH), 107.1 (CH), 60.8
(CH3), 55.6 (CH3), 52.1 (CH3), 50.0 (CH2), 45.8 (C), 39.1
(C), 26.7 (CH), 24.7 (CH3), 24.1 (CH3), 23.3 (2 × CH3), 20.3
(CH3). HRMS (EI): m/z (%) = 400.2243 (60) [M+] (calcd for
C24H32O5: 400.2250), 369.2062 (20, calcd for C23H29O4:
369.2066), 316.1677 (100, calcd for C19H24O4: 316.1675),
301.1456 (34, calcd for C18H21O4: 301.1440).
(13) Zoretic, P. A.; Chamber, R. J. J. Org. Chem. 1985, 50, 2981.
(14) Bartlett, P. A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459.
(15) ( )-Pygmaeocin C: IR (neat): 3369, 2966, 2934, 2873, 1627,
1574, 1440, 1337, 1307, 1292, 1264, 1131, 1037 cm–1. 1H
NMR (600 MHz, CDCl3): d = 7.95 (br s, 1 H), 7.05 (s, 1 H),
6.53 (s, 1 H), 6.35 (d, J = 9.7 Hz, 1 H), 5.90 (d, J = 9.7 Hz,
1 H), 3.26 (sep, J = 6.8 Hz, 1 H), 2.66 (d, J = 17.0 Hz, 1 H),
2.14 (d, J = 17.0 Hz, 1 H), 1.24 (d, J = 6.8 Hz, 3 H), 1.22 (s,
3 H), 1.21 (d, J = 6.8 Hz, 3 H), 1.16 (s, 3 H), 0.93 (s, 3 H).
13C NMR (150 MHz, CDCl3): d = 201.0 (C), 163.0 (C),
144.5 (C), 142.1 (C), 138.5 (C), 130.5 (CH), 127.2 (C),
125.6 (CH), 124.1 (CH), 116.6 (CH), 114.8 (C), 48.3 (CH2),
45.3 (C), 38.8 (C), 27.3 (CH), 26.1 (CH3), 24.3 (CH3), 22.5
(CH3), 22.2 (CH3), 21.3 (CH3). HRMS (EI): m/z (%) =
312.1724 (14) [M+] (calcd for C20H24O3: 312.1725),
294.1626 (16, calcd for C20H22O2: 294.1620), 256.1094 (55,
calcd for C16H16O3: 256.1099), 228.1148 (100, calcd for
C15H16O2: 228.1150), 213.0916 (28, calcd for C14H13O2:
213.0916).
Synlett 2005, No. 3, 417–420 © Thieme Stuttgart · New York