A stereoselective synthesis of platyphyllide

Article abstract of DOI:10.1039/a902410g

The norsesquiterpene lactone, platyphyllide has been synthesized in 8 steps in 23% overall yield via the Diels-Alder adduct of 2-(4-methylpent-3-enyl)furan with dimethyl acetylenedicarboxylate, the 3-substituted phthalic diester, and an o-formylbenzamide.

Full text of DOI:10.1039/a902410g

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A stereoselective synthesis of platyphyllide
Tse-Lok Ho* and Meng-Fen Ho
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan,
Republic of China
Received (in Cambridge) 25th March 1999, Accepted 12th May 1999
The norsesquiterpene lactone, platyphyllide has been synthesized in 8 steps in 23% overall yield via the Diels–Alder
adduct of 2-(4-methylpent-3-enyl)furan with dimethyl acetylenedicarboxylate, the 3-substituted phthalic diester, and
an o-formylbenzamide. An intramolecular ene reaction established the skeleton, and the final step involved inversion
of configuration at the benzylic site.
Platyphyllide (1) is a levorotatory norsesquiterpene lactone
isolated from Senecioneae species (family Compositae). Since
its structural elucidation1 in 1977, several reports of the syn-
thesis of platyphyllide have appeared.2 Unfortunately, all these
routes suffer from the generation of a mixture of stereoisomers.
Our interest in platyphyllide was related to occidol 23 which is
also a tetralin derivative.
enyl)furan (3). Whereas Scheme 2 summarizes our failed efforts,
the compound was successfully secured in three steps involving
the Feist–Benary furan synthesis by condensing methyl 3-oxo-
7-methyloct-6-enoate9 and chloroacetaldehyde in the presence
of pyridine as the key step.10 Saponification of the ester 4 and
decarboxylation of the resulting acid 5 furnished the required
furan 3.
Our initial approach is summarized in Scheme 1.4 The inten-
tion of pursuing an aromatic carboxylation as directed by the
hydroxy group5 of an α-tetralol intermediate was thwarted
by the preferential deprotonation of the isopropenyl group.
Accordingly, our tactics6 were changed while still retaining the
operation of an intramolecular ene reaction7 to establish the
tetralin system. In this key step two adjacent stereogenic centers
were created.
The Diels–Alder reaction of 3 with dimethyl acetylene-
dicarboxylate was best conducted in CH2Cl2 at reflux for 5 days.
Under these conditions a 95% yield of the adduct 6 was
obtained. At a higher temperature (e.g., 110 ЊC in a sealed tube)
the ene reaction adduct 7 was predominant. Heating the two
components at 100 ЊC without solvent resulted in polymeriz-
ation. In ether, the reaction either failed (25 ЊC, 20 h) or gave
only a 50% yield (reflux, 7 days).
The tactical change was also prompted by our recent fascin-
ation in exploiting the symmetry aspect in synthesis design.8
In other words, we wished to elaborate a 3-substituted phthalic
ester which, because of its local symmetry, can be obtained
from the 2-substituted furan and an acetylenedicarboxylic ester
by a Diels–Alder reaction followed by deoxygenative arom-
atization. The steric perturbation by the 3-substituent should
then permit a selective transformation initially at the unflanked
ester group, followed by the other ester group which was
destined to become a formyl residue.
Aromatization of 6 without affecting the ester groups was
accomplished on exposure to low-valent titanium species11
produced from TiCl4, LiAlH4 and Et3N. At this point we
examined several possibilities for manipulation of 8 towards
the target molecule. Thus, the straightforward reduction of the
diester with LiAlH4 to afford the diol 9 was followed by the
rather undesirable nonregioselective oxidation. Manganese
dioxide oxidation in refluxing CH2Cl2 furnished lactones 10a
and 10b in a ratio of 3:1; the Fetizon oxidation also showed the
same preference while PCC oxidation gave the lactones in a 2:3
ratio. When we subjected lactone 10a to Weinreb’s reagent12
Our work started with the preparation of 2-(4-methylpent-3-
Scheme 1 Reagents and conditions: (i) SOCl2; (ii) Et2NH; (iii) LDA, Me2C᎐CHCH2Cl; (iv) i-BuAlH/n-BuLi; (v) 200 ЊC; (vi) n-BuLi–TMEDA; CO2.
᎐
J. Chem. Soc., Perkin Trans. 1, 1999, 1823–1826
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mol) and chloroacetaldehyde (50% aq. solution, 12.8 g, 0.231
mol) in pyridine (27 mL) was stirred and warmed at 50 ЊC
under nitrogen for 24 h. The cooled product was diluted with
ether (200 mL), washed with 10% HCl, water and brine. After
drying over Na2SO4 the solution was evaporated in vacuo, to
give an essentially pure ester 4 (8.0 g). ν (film) 1745 cmϪ1; δH
(CDCl3, 300 MHz) 1.46 (3H, s), 1.56 (3H, s), 2.24 (2H, q,
J = 7.2 Hz), 2.9 (2H, t, J = 7.2 Hz), 3.7 (3H, s), 5.05 (1H, t,
J = 7.2 Hz), 6.51 (1H, d, J = 1.5 Hz), 7.12 (1H, d, J = 1.5 Hz); δC
(CDCl3, 75 MHz) 17.2 (q), 25.4 (q), 26.4 (t), 26.5 (t), 50.8 (q),
110.5 (d), 112.8 (s), 122.7 (d), 132.3 (s), 140.0 (d), 162.4(s), 164.0
(s); HRMS (m/z) 208.1099 (208.1095 calcd. for C12H16O3).
The above ester 4 (8.0 g) was refluxed with sodium hydroxide
(4.34 g, 0.109 mol) in water (36 mL) for 2 h, cooled, washed
with ether (2 × 50 mL) and slowly acidified with 10% HCl. The
carboxylic acid 5 (5.48 g, 52%) was obtained by extractive
workup with dichloromethane. Mp 68–69 ЊC; ν (film) 3306–
2350, 1680 cmϪ1; δH 1.45 (3H, s), 1.56 (3H, s), 2.25 (2H, m), 2.93
(2H, t, J = 7.2 Hz), 5.03 (1H, t, J = 7.2 Hz), 6.56 (1H, d, J = 1.5
Hz), 7.12 (1H, d, J = 1.5 Hz), 12.44 (1H, br s); δC 17.4 (q), 25.6
(q), 26.6 (t), 27.9 (t), 111.0 (d), 113.0 (s), 122.8 (d), 133.0 (s),
140.5 (d), 164.0 (s), 170.0 (s); HRMS (m/z) 194.0935 (194.0939
calcd. for C11H14O3).
Decarboxylation of the acid 5 (9.69 g, 0.05 mol) was accom-
plished by heating with copper powder (0.64 g, 0.01 mol) and
quinoline (12.9 g, 0.1 mol) for 2 h. The cooled mixture was
filtered, diluted with dichloromethane and washed with 10%
HCl. Drying, concentration, silica gel chromatography, and
evaporative distillation (75 ЊC/3 Torr) led to the isolation of
3 (6.75 g, 90%). ν (film) 1598 cmϪ1; δH 1.40 (3H, s), 1.50 (3H, s),
2.14 (2H, q, J = 7.5 Hz), 2.45 (2H, t, J = 7.5 Hz), 4.98 (1H, t,
J = 7.5 Hz), 5.75 (1H, s), 6.03 (1H, s), 7.04 (1H, s); δC 17.7 (q),
25.6 (q), 26.6 (t), 28.2 (t), 104.7 (d), 110.0 (d), 123.5 (d), 132.4
(s), 140.7 (d), 156.1 (s).
Scheme 2
to obtain the amide alcohol 11a, we entered a cul-de-sac un-
wittingly because the subsequent reoxidation of the benzylic
alcohol to the aldehyde with MnO2 was attained by a compet-
ing lactonization to return a portion of the material to 10a.
This complication led us to hydrolyze the diester 8 selectively,
and convert the half-ester 12 to the amide ester 13 and thence to
11b. It was estimated that this molecule having larger alkyl
groups on the nitrogen atom, would be less prone to lactoniz-
ation (by virtue of changing the relative orientation of the
OH and C᎐O groups). We were glad to be able to obtain the
᎐
amide aldehyde 14 by Swern oxidation of 11b in 70% yield.
The low reaction temperature definitely contributed to this final
success.
Having in our possession the key intermediate 14, we investi-
gated the intramolecular ene reaction. After several unfruitful
attempts at using Lewis acids to catalyze the cyclization, we
conducted the thermal process in sealed vessels using toluene as
solvent. From a reaction at 200 ЊC in a sealed glass tube we
detected the formation of platyphyllide 1 and its diastereomer
15 in a ratio of 28:72. However, in a Teflon vessel (within a
resealable stainless steel bomb) only 15 was produced. The
difference between the two reactions may be attributed to the
favored transition state A in which the aldehyde and the amide
groups were oriented such as to minimize dipole–dipole inter-
action. On the other hand, the silicon atoms of the glass surface
may have provided a binding site for the oxygen atoms of both
groups, and reaction of molecules in such a bound state B
would lead to the platyphyllide precursor. The products result
from the subsequent lactonization.
We were rather pleased to observe the stereoselective form-
ation of one lactone in the specified reaction conditions, even
though an additional step or steps would be required to convert
15 to the target 1. To that end we tried a Mitsunobu reaction to
invert the configuration of the benzylic carbon. Relactonization
did not take place under standard conditions probably due to
steric hindrance in the formation of the phosphonium inter-
mediate. This forced us to attempt other options such as
mesylation after cleavage of the lactone. On acidification of the
NaOMe treated lactone, in an attempt to isolate the hydroxy
ester intermediate, platyphyllide 1 was detected. This finding led
us to investigate the process more thoroughly, which resulted in
establishing a procedure for the conversion of 15 to 1 in 84%
yield. Because the benzylic cation was readily generated and the
relactonization was under thermodynamic control (with 1,2-
asymmetric induction by the isopropenyl group) the synthesis
was rendered stereoselective.
Dimethyl 1-(4-methylpent-3-enyl)-7-oxabicyclo[2.2.1]hepta-2,5-
diene-2,3-dicarboxylate (6)
Furan 3 (6.75 g, 0.045 mol) was mixed with dimethyl acetylene-
dicarboxylate (6.39 g, 0.045 mol) and dichloromethane (30
mL), and was refluxed for 5 days, cooled, and the solvent
removed. The residue was chromatographed over silica gel
using 1:9 EtOAc–hexane as eluent to give 6 (11.89 g, 90.5%).
ν (film) 1712, 1639 cmϪ1; δH 1.54 (3H, s), 1.65 (3H, s), 2.07–2.15
(4H, m), 3.75 (3H, s), 3.81 (3H, s), 5.09 (1H, t, J = 4 Hz), 5.60
(1H, d, J = 2.1 Hz), 6.95 (1H, d, J = 5.4 Hz), 7.12 (1H, dd,
J = 5.4, 2.1 Hz); δC 17.3 (q), 23.2 (t), 25.5 (q), 28.7 (t), 51.7 (q),
83.0 (d), 97.1 (s), 123.2 (d), 132.0 (s), 144.1 (d), 144.9 (d), 151.1
(s), 155.8 (s), 164.7 (s), 164.7 (s); HRMS (m/z) 292.1302
(292.1305 calcd. for C16H20O5).
Dimethyl 3-(4-methylpent-3-enyl)phthalate (8)
The low-valent titanium reagent was prepared by sequential,
dropwise addition of titanium() chloride (3 mL, 0.0274 mol)
and then triethylamine (0.86 mL, 0.00617 mol) in THF (5 mL)
to an ice-cooled, stirred suspension of lithium aluminium
hydride (0.52 g, 0.0137 mol) in dry tetrahydrofuran (30 mL),
which was then heated at 65 ЊC for 0.5 h, recooled to room
temperature and treated with a solution of 6 (2.0 g, 0.00685
mol) in tetrahydrofuran (10 mL). After 24 h at room temper-
ature the reaction mixture was poured into water (150 mL), and
extracted with dichloromethane (3 × 50 mL). The crude prod-
uct was chromatographed over silica gel (eluent: 1:9 EtOAc–
hexane) to afford the phthalate 8 (2.1 g, 99%). ν (film) 1731,
1594 cmϪ1; δH 1.43 (3H, s), 1.57 (3H, s), 2.16 (2H, m), 2.51 (2H,
t, J = 9 Hz), 3.76 (3H, s), 3.82 (3H, s), 5.03 (1H, t, J = 4.8 Hz),
7.25–7.28 (2H, m), 7.72 (1H, dd, J = 6.75, 2.1 Hz); δC 17.3 (q),
25.5 (q), 29.7 (t), 33.3 (t), 52.1 (q), 122.9 (d), 127.4 (d), 127.6 (s),
128.6 (d), 132.3 (s), 133.6 (d), 134.9 (s), 139.6 (s), 165.8 (s), 169.2
(s); HRMS (m/z) 276.1361 (276.1356 calcd. for C16H20O4).
Experimental
2-(4-Methylpent-3-enyl)furan (3)
A mixture of methyl 3-oxo-7-methyloct-6-enoate (10.0 g, 0.154
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2-(Methoxycarbonyl)-3-(4-methylpent-3-enyl)benzoic acid
(12)
142.0 (s), 168.1 (s), 170.2 (s); HRMS (m/z) 317.1985 (317.1984
calcd. for C19H27NO3).
Diester 8 (6.38 g, 0.023 mol) was heated with sodium hydroxide
(1.85 g, 0.046 mol) in 80% aqueous methanol (100 mL) under
reflux for 3 h. The cooled mixture was washed with ether
(2 × 50 mL), acidified with 10% HCl, and extracted with
dichloromethane (3 × 100 mL). The organic extracts were
combined, washed with brine, dried over Na2SO4 and concen-
trated to give the pure half-ester 12 (5.39 g, 89%). ν (film) 3687–
2225, 1729, 1600 cmϪ1; δH 1.52 (3H, s), 1.66 (3H, s), 2.27 (2H,
m), 2.62 (2H, t, J = 9.9 Hz), 3.90 (3H, s), 5.11 (1H, t, J = 6 Hz),
7.37–7.91 (3H, m); δC 17.5 (q), 25.7 (q), 29.8 (t), 33.4 (t), 52.5
(q), 123.0 (d), 127.5 (s), 128.4 (d), 128.9 (d), 132.7 (s), 134.6 (d),
135.4 (s), 139.9 (s), 169.5 (s), 170.8 (s); HRMS (m/z) 262.1202
(262.1200 calcd. for C15H18O4).
N,N-Diethyl-2-(hydroxymethyl)-3-(4-methylpent-3-enyl)benz-
amide (11b)
A solution of the ester amide 13 (1.57 g, 0.00495 mol) in dry
tetrahydrofuran (10 mL) was dropwise added to a stirred sus-
pension of lithium aluminium hydride (0.28 g, 0.007425 mol) in
tetrahydrofuran (40 mL) at 0 ЊC. After 1 h, the reaction mixture
was quenched with saturated Na2SO4 solution (5 mL), filtered,
and evaporated in vacuo. Silica gel chromatography (eluent: 4:6
EtOAc–hexane) provided the amide alcohol 11b (1.2 g, 84%).
ν (film) 3500–3280, 1612 cmϪ1; δH 1.07 (3H, t, J = 6.9 Hz), 1.28
(3H, t, J = 6.9 Hz), 1.51 (3H, s), 1.65 (3H, s), 2.26 (2H, m), 2.75
(2H, m), 3.20 (2H, d, J = 6.3 Hz), 3.53 (2H, dd, J = 6.3, 3.3 Hz),
4.40–4.69 (2H, m), 5.15 (1H, t, J = 6.3 Hz), 6.99–7.24 (3H, m);
δC 12.8 (q), 14.1 (q), 17.7 (q), 25.8 (q), 30.2 (t), 33.1 (t), 39.3 (t),
43.4 (t), 59.7 (t), 123.4 (d), 123.5 (d), 127.9 (d), 130.8 (d), 132.3
(s), 136.3 (s), 137.6 (s), 142.4 (s), 171.9 (s); HRMS (m/z)
289.2034 (289.2035 calcd. for C18H27NO2).
Methyl 2-[(diethylamino)carbonyl]-6-(4-methylpent-3-enyl)-
benzoate (13)
The half-ester 12 (200 mg, 0.76 mmol) was treated with thionyl
chloride (0.6 mL, 7.6 mmol) and N,N-dimethylformamide
(4 drops) at room temperature. After stirring for 0.5 h, the
excess thionyl chloride was removed in a rotary evaporator. The
residue was co-evaporated with some toluene, dissolved in dry
tetrahydrofuran (5 mL), and treated with diethylamine (0.32
mL, 3.04 mmol). The mixture was left at room temperature for
17 h, concentrated in vacuo, and purified by silica gel column
chromatography (eluent: 4:6 EtOAc–hexane) to furnish the
ester amide 13 (210 mg, 87%). ν (film) 1735, 1729, 1629 cmϪ1; δH
0.87 (3H, t, J = 7.2 Hz), 0.95 (3H, t, J = 7.2 Hz), 1.34 (3H, s),
1.48 (3H, s), 2.20 (2H, m), 2.72 (2H, t, J = 8.7 Hz), 3.20 (2H, q,
J = 7.2 Hz), 3.48 (2H, q, J = 7.2 Hz), 3.78 (3H, s), 5.08 (1H, t,
J = 7.2 Hz), 7.05–7.32 (3H, m); δC 12.5 (q), 13.7 (q), 17.6 (q),
25.7 (q), 30.2 (t), 34.0 (t), 38.7 (t), 43.0 (t), 52.0 (q), 123.4 (d),
123.8 (d), 129.7 (d), 130.2 (d), 130.5 (s), 132.4 (s), 137.5 (s),
2-[(Diethylamino)carbonyl]-6-(4-methylpent-3-enyl)benzalde-
hyde (14)
To the reagent prepared 15 min previously from oxalyl chloride
(0.6 mL, 6.8 mmol) and dimethyl sulfoxide (1.2 mL, 17.7 mmol)
in dichloromethane (5 mL) at Ϫ78 ЊC was added a solution
of the amide alcohol 11b (840 mg, 2.91 mmol) in dry dichloro-
methane (5 mL), and after 30 min, triethylamine (0.4 mL,
2.62 mmol). The cooling bath was removed 10 min later to
allow the reaction mixture to attain room temperature, when
it was quenched with water (5 mL). Extractive workup with
dichloromethane and silica gel chromatography (eluent: 4:6
EtOAc–hexane) provided the amide aldehyde 14 (600 mg, 72%).
ν (film) 2753, 1697, 1629 cmϪ1; δH 0.99 (3H, t, J = 7.2 Hz), 1.23
J. Chem. Soc., Perkin Trans. 1, 1999, 1823–1826
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(3H, t, J = 7.2 Hz), 1.46 (3H, s), 1.66 (3H, s), 2.22 (2H, m),
2.93–3.06 (4H, m), 3.52 (2H, q, J = 7.2 Hz), 5.08 (1H, t, J = 6
Hz), 7.05–7.43 (3H, m); δC 12.4 (q), 13.7 (q), 17.5 (q), 25.6 (q),
30.4 (t), 33.0 (t), 38.8 (t), 42.7 (t), 122.7 (d), 124.6 (d), 130.4 (d),
131.3 (d), 132.9 (d), 133.0 (s), 140.5 (s), 145.4 (s), 169.7 (s), 190.5
(s); HRMS (m/z) 287.1893 (287.1879 calcd. for C18H25NO2).
m), 3.11 (1H, dd, J = 12, 7.8 Hz), 4.95 (2H, s), 5.17 (1H, d,
J = 12 Hz), 7.33–7.64 (3H, m); δC 20.7 (q), 26.0 (t), 26.7 (t), 46.3
(d), 80.3 (d), 112.5 (t), 122.9 (d), 124.9 (s), 129.8 (d), 132.0 (d),
133.5 (s), 144.0 (s), 148.7 (s), 170.0 (s); HRMS (m/z) 214.0988
(214.0990 calcd. for C14H14O2).
Acknowledgements
We thank the National Science Council, ROC, for financial
support.
(8SR,8aRS)-8-Isopropenyl-6,7,8,8a-tetrahydro-2H-naphtho-
[1,8-bc]furan-2-one (15)
A solution of the amide aldehyde 14 (200 mg, 0.7 mmol) in dry
toluene (1 mL) was deoxygenated, placed in a Teflon vessel
inside a resealable stainless steel bomb, and heated at 200 ЊC for
15 h. After removal of the solvent from the cooled reaction
mixture in vacuo, the product was isolated by silica gel chrom-
atography (eluent: 25:75 EtOAc–hexane) and provided the
lactone 15 (130 mg, 65%). ν (film) 1762, 1643 cmϪ1; δH 1.49
(3H, s), 2.11–2.18 (2H, m), 2.73–2.82 (1H, m), 2.90–2.97 (1H,
m), 3.14–3.17 (1H, m), 4.00 (1H, s), 4.50 (1H, s), 5.41 (1H, d,
J = 6 Hz), 7.28–7.38 (2H, m), 7.56 (1H, d, J = 7.5 Hz); δC 23.0
(t), 24.0 (q), 24.8 (t), 40.8 (d), 79.3 (d), 113.1 (t), 122.7 (d), 124.9
(s), 129.6 (d), 131.9 (d), 134.0 (s), 141.6 (s), 147.0 (s), 170.2 (s);
HRMS (m/z) 214.0991 (214.0990 calcd. for C14H14O2).
References
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A solution of the lactone 15 (130 mg, 0.6 mmol) was refluxed
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platyphyllide 1 (110 mg, 84%). ν (film) 1762, 1643 cmϪ1; δH 1.84
(3H, s), 1.86–1.97 (1H, m), 2.10–2.24 (2H, m), 2.79–2.88 (1H,
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J. Chem. Soc., Perkin Trans. 1, 1999, 1823–1826