Asymmetric synthesis of 3β-angeloyloxy-4β-hydroxyeudesman-8-one, purported sesquiterpene from pluchea quitoc

Article abstract of DOI:10.1039/a909112b

Asymmetric synthesis of 3β-angeloyloxy-4βhyroxyeudesman-8-one, purported isolated from Pluchea quitoc was carried out. The synthesis exemplifies a flexible approach, which is applicable to the preparation of a number of eudesmane natural products. The res

Full text of DOI:10.1039/a909112b

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Asymmetric synthesis of 3ꢀ-angeloyloxy-4ꢀ-hydroxyeudesman-8-
one, purported sesquiterpene from Pluchea quitoc†
ab
a
b
a
Estela Muri, Alice Kanazawa, Eliezer Barreiro and Andrew E. Greene*
1
a
Université Joseph Fourier, LEDSS, BP 53X, 38041 Grenoble Cedex, France.
Tel: (33) 4-76-51-46-86; Fax: (33) 4-76-51-44-94; E-mail: Andrew.Greene@ujf-grenoble.fr
Universidade Federal do Rio de Janeiro, LASSBIO, RJ, 21.944 Brazil
b
Received (in Cambridge, UK) 17th November 1999, Accepted 21st December 1999
3
β-Angeloyloxy-4β-hydroxyeudesman-8-one, purportedly isolated from the aerial parts of Pluchea quitoc, has
been prepared by an unambiguous, stereocontrolled route and found to be different from the natural product.
Species of the genus Pluchea, which are often endowed with
beneficial medicinal properties, are an excellent source of
eudesmanes.
1–5
6–10
Quite recently, Guilhon and Müller reported
the isolation of a new eudesmane from the aerial parts of
Pluchea quitoc DC (Compositae, tribe Inuleae), a plant that has
been used in the northern and central-western areas of Brazil as
an expectorant and for its digestive and anti-rheumatic proper-
5
ties, to which they assigned on the basis of one and two dimen-
sional NMR data the structure and relative stereochemistry
11
depicted in 1. In this paper, an asymmetric synthesis is
presented of this putative natural product, 3β-angeloyloxy-4β-
hydroxyeudesman-8-one, which successfully addresses the
stereochemically difficult problem of the introduction of the
C-3,C-4 β-oxygen substituents.
12
The starting material for the synthesis was the known
octalone derivative 2 (Scheme 1), which was enantioselectively
prepared by using d’Angelo and co-workers’ effective deracemiz-
13
ing Michael addition procedure with (R)-(ϩ)-α-methylbenzyl-
amine. The initial enantiomeric excess of 84% could be improved
12
to 97% by simple recrystallization. That the proposed abso-
lute stereochemistry was, in fact, as depicted was demonstrated
14
by transformation of 2 into the dextrorotatory enone 9 of
15
known absolute stereochemistry (Scheme 2).
Reductive transposition of the enone function in 2 with the
introduction of the trans ring fusion was next readily accom-
plished through application of Ireland’s enol phosphate pro-
Scheme 1 Reagents and conditions: i, Li, NH
, THF–t-BuOH; CIPO-
3
(
OEt) ; Li, MeNH (61%); ii, AcOH–H O (95%); iii, NaH, HCO Et,
2
2
2
2
16
Et
2
O; iv, n-BuSH, p-TsOH, benzene (90%, 2 steps); v, LiMe
2
Cu, Et O
2
cedure. The desired product, 3, uncontaminated by the cis
(
99%); vi, m-ClC H CO H, Na CO , CH Cl (93%); vii, H SO , Me CO–
17
18
6 4 3 2 3 2 2 2 4 2
isomer, was obtained in 61% yield.
H O (40%); viii, C H NؒSO , Et N, DMSO (91%); ix, Zn(BH ) , DME
2
5
5
3
3
4 2
It appeared desirable, in order to avoid protection–
deprotection sequences, to introduce the C-7 isopropyl group at
this point in the synthesis, prior to oxidation of the double
bond. Thus, the dioxolane 3 was hydrolyzed and the resulting
ketone 4a converted via its hydroxymethylene derivative 4b into
thioether 4c (85% yield). On exposure to an excess of lithium
dimethylcopper, the thioether underwent smooth double addi-
(
70%); x, (Z)-MeC᎐C(Me)CO COC H Cl , DMAP, PhMe (74%).
2 6 2 3
exclusively β, in essentially quantitative yield. (Ketone 4d was
unchanged in the presence of DBU.)
20
From earlier work with related molecules, it seemed prob-
able that vicinal dihydroxylation of 4d, for steric reasons, would
be α-face-selective; in the event, a very predominant diol issued
from the reaction of 4d with osmium tetroxide in modest yield
19
tion to provide the desired isopropyl-substituted ketone 4d,
(
Scheme 3). The spectral data indicated that the expected α-face
21
†
The IUPAC name for angelic acid is (Z)-2-methylbut-2-enoic acid.
approach of the reagent had indeed occurred, which was later
DOI: 10.1039/a909112b
J. Chem. Soc., Perkin Trans. 1, 2000, 731–735
This journal is © The Royal Society of Chemistry 2000
731

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Scheme 2 Reagents and conditions: i, AcOH–H O, 80 ЊC, 20 min;
2
ii, NaBH , EtOH, 0 ЊC, 0.5 h; iii, NaH, CS , CH I, THF, 20 ЊC, 5 h;
4
2
3
iv, Bu SnH, AIBN, toluene, reflux, 3 h.
3
2
7
Fig. 1 Crystal structure of diol 8 (CHARON drawing, represen-
tation of an independent molecule).
Scheme 3
Experimental
confirmed indirectly by X-ray crystallography (see below).
Since it seemed unlikely that an effective method for the direct
introduction of the vicinal β-hydroxy functions would be
found, an alternative, indirect procedure was developed to
achieve this end.
Treatment of 4d with m-chloroperbenzoic acid led in high
yield to the formation of a unique epoxide, which was also
assigned the α-configuration on the basis of its spectral data
General details
The reaction mixture was generally poured into water and the
separated aqueous phase was then thoroughly extracted with
the specified solvent. After being washed with 10% aqueous
HCl and/or NaHCO (if required), water, and saturated aque-
ous NaCl, the combined organic phases were dried over
3
anhydrous Na SO or MgSO and then filtered and concen-
2
4
4
trated under reduced pressure on a Büchi Rotovapor to yield
the crude reaction product. Tetrahydrofuran and ether were dis-
tilled from sodium–benzophenone, and methanol and ethanol
from magnesium. Dichloromethane, DMSO, pyridine, toluene,
and triethylamine were distilled from calcium hydride, and
dimethoxyethane from lithium aluminium hydride.
(
a NOE was observed between the C-4 and C-10 methyls) and
22
close precedent. Both cyclic and acyclic trisubstituted
epoxides tend to suffer acid-catalyzed ring opening at the more
highly substituted terminus and with inversion of configur-
23
ation. Pleasingly, it was found that on exposure of epoxide
to dilute sulfuric acid in acetone, the major product formed
was the desired C-3α,C-4β diol 6 (40%), with lesser amounts
5
(
R)-5Ј,8Јa-Dimethyl-1Ј,3Ј,4Ј,7Ј,8Ј,8Јa-hexahydrospiro[[1,3]-
12,20,22
4(5)
also generated of the C-3α,C-4α isomer (4%) and the ∆ and
∆
dioxolane-2,2Ј-naphthalen]-6Ј-one 2
4(15)
dehydration derivatives (22%). These products could have
2
9
been, in principle, recycled in a few steps, but this was never
attempted. The stereochemistry of the major diol was readily
A stirred solution of 2-methyl-4-ethylenedioxycyclohexanone
3
(5.40 g, 31.7 mmol), R-(ϩ)-α-methylbenzylamine (15.80 cm ,
14.85 g, 122.6 mmol), and toluene-p-sulfonic acid monohydrate
24
established on Parikh–von Doering oxidation to give keto
alcohol 7, distinctly different from that secured by similar
treatment of the C-3α,C-4α isomer 10.
3
(0.089 g, 0.47 mmol) in toluene (100 cm ) was refluxed with
removal of water for 3 h, whereupon the solvent and excess
amine were removed by distillation under reduced pressure. The
residue was dissolved in anhydrous THF (90 cm ) and ethyl
vinyl ketone (57.0 cm , 48.2 g, 57.3 mmol) was added. After
25
In the presence of zinc borohydride, keto alcohol 7 under-
26
3
went a highly regioselective carbonyl reduction to afford an
easily separable 55:45 mixture of the sought β,β-diol 8 and
the original diol 6, respectively. Diol 8 was suitable for X-ray
diffraction analysis (Fig. 1) (see Experimental section), which
confirmed the relative stereochemistry assigned to not only 8,
but also, indirectly, the other intermediates.
3
being stirred for 4 days at 20 ЊC, the reaction mixture was
treated with 20% aqueous AcOH–THF (1:1, 20 cm ) and then
3
stirred for an additional 3 h. The solvents were eliminated
under reduced pressure and the crude reaction product was
isolated with ethyl acetate in the usual way and purified on silica
gel (pretreated with 2.5% triethylamine, v/v) with 30% ethyl
acetate in pentane to afford first starting ketone (1.86 g) and
then the desired Michael adduct (R)-7-methyl-7-(3-oxopentyl)-
1,4-dioxaspiro[4,5]decan-8-one (3.08 g, 38% or 58% based on
The final transformation required esterification of the
secondary hydroxy to form the angelate ester. Yamaguchi’s
28
procedure was successful for this purpose and furnished 3β-
angeloyloxy-4β-hydroxyeudesman-8-one (1). Unfortunately,
1
13
however, the optical rotation and the H and C NMR data for
this eudesmane were in obvious disagreement with those
reported for the native substance. With the forlorn hope that
the natural product might simply be a C-3,C-4 diastereomer of
what had been proposed, the 3 C-3,C-4 diastereomers of 1 were
also prepared: the α,β and α,α diol derivatives by esterification
of 6 and 10, respectively, and the β,α by sequential oxidation,
reduction, and esterification of 10. Disappointingly, though,
these too proved to be distinctly different from the natural
product.
2
5
25
D
consumed starting material): [α] Ϫ14.4 (c 1.0, CHCl ), [α]
Ϫ14.2 (c 0.6, CH Cl ) [lit., (enantiomer) [α]D ϩ13.8 (c 0.6,
D
3
12
25
2
2
Ϫ1
CH Cl )]; ν (neat)/cm 1716, 1461, 1367, 1310, 1276, 1180,
2
2
max
1111, 1089 and 1030; δ (300 MHz) 0.95 (3 H, t, J 7.3 Hz), 1.10
(3 H, s), 1.62–2.70 (12 H, m) and 3.80–4.00 (4 H, m); δC (75
MHz) 7.7, 23.5, 31.9, 34.3, 35.6, 35.7, 37.0, 45.2, 46.8, 64.1,
H
ϩ
64.3, 107.2, 210.7 and 213.9; m/z (CI): 272 (MH ϩ NH , 20%),
3
ϩ
255 (MH , 100%) and 237 (20%) [Found: C, 66.02; H, 8.67.
C H O requires C, 66.12; H, 8.72%].
14
22
4
In conclusion, through the unequivocal preparation of 3β-
angeloyloxy-4β-hydroxyeudesman-8-one (1) and its C-3,C-4
diastereomers, it has been shown that the natural product from
Pluchea quitoc is neither the previously proposed 1, nor a
C-3,C-4 diastereomer, and, consequently, its published structure
requires revision. The above synthesis, nevertheless, exemplifies
a flexible approach that should be applicable to the preparation
of a number of eudesmane natural products.
To a solution of the above adduct (3.27 g, 12.9 mmol) in
methanol (60 cm ) was added sodium methoxide (1.31 g, 24.3
3
mmol). After being stirred at 20 ЊC for 3 h, the reaction mixture
was concentrated under reduced pressure and the crude reac-
tion product was isolated with ethyl acetate in the usual manner
and purified on silica gel (pretreated with 2.5% triethylamine,
v/v) with 35% ethyl acetate in hexane to give octalone 2 (2.53 g,
83%; 84% ee by HPLC). Recrystallization from ether–hexane
7
32
J. Chem. Soc., Perkin Trans. 1, 2000, 731–735

View Article Online
provided material of 97% ee (HPLC, see thioether 4c below):
(20.5%), 107 (80%), 91 (85%), 77 (100%), 65 (21%), 55 (31%),
41 (34%).
25
Ϫ1
mp 56 ЊC; [α] ϩ165 (c 1.0, CHCl ); ν (neat)/cm 1651, 1613,
D
3
max
1
451, 1419, 1367, 1330, 1316, 1270, 1206, 1122, 1095 and 1031;
δH (200 MHz) 1.22 (3 H, s), 1.73 (3 H, s), 1.40–2.50 (9 H, m),
.65 (1 H, ddd, J 16.5, 5.0, 3.2 Hz) and 3.70–4.00 (4 H, m);
δ (75 MHz) 10.8, 23.4, 25.4, 33.2, 34.4, 36.7, 37.8, 48.3, 63.5,
4.4, 107.5, 128.5, 160.3 and 198.4; m/z (EI): 236 (M , 48%),
21 (12%), 99 (29%), 91 (61%), 86 (100%), 79 (40%), 55 (37%)
A solution of the above crude product (2.46 g) in benzene
3
(100 cm ) was refluxed for 30 min in the presence of TsOHؒH O
2
3
2
(0.410 g, 2.16 mmol) and butanethiol (1.96 cm , 1.65 g, 18.3
mmol) with removal of water. After being allowed to cool to
room temperature, the reaction mixture was processed with
ether in the usual way and the crude product was purified by
silica gel chromatography with 10% ethyl acetate in pentane to
afford thioether 4c [3.47 g, 90% from 4a, 97% ee by HPLC:
C
ϩ
6
2
and 43 (32%) [Found: C, 71.46; H, 8.52. C H O requires C,
7
14
20
3
1.16; H, 8.53%].
3
Ϫ1
Whelk-01, 5 µm, hexane–isopropanol = 9:1, 1.0 cm min , tr
25
(
4ЈaS,8ЈaR)-5Ј,8Јa-Dimethyl-3Ј,4Ј,4Јa,7Ј,8Ј,8Јa-hexahydro-1ЈH-
5.66 min (versus 6.75 min)]; [α] Ϫ80.3 (c 1.0, CHCl ); ν
D 3 max
Ϫ1
20,22
spiro[[1,3]dioxolane-2,2Ј-naphthalene] 3
(neat)/cm 3022, 1665, 1548, 1438, 1380, 1296, 1219 and 837;
δH (200 MHz) 0.81 (3 H, s), 0.91 (3 H, t, J 7.2 Hz), 1.30–1.75
(9 H, m), 1.80–2.40 (6 H, m), 2.65 (1 H, ddd, J 16.3, 5.3, 1.4 Hz),
3
Octalone 2 (1.20 g, 5.08 mmol) dissolved in THF (6 cm ) and
tert-butyl alcohol (0.38 cm ) was added slowly to liquid
ammonia (25 cm , freshly distilled from sodium metal) at
Ϫ78 ЊC, followed by lithium metal (until a blue color persisted,
ca. 0.1 g). After being stirred at Ϫ78 ЊC for 1 h, the reaction
mixture was treated with a few drops of isoprene, and the
ammonia was allowed to evaporate. Anhydrous THF (5 cm )
was then added and the reaction mixture was warmed briefly at
3
3
2.84 (2 H, t, J 7.3 Hz), 5.40 (1 H, br s) and 7.60 (1 H, m); δ (50
C
MHz) 13.3, 17.0, 20.6, 21.4, 22.1, 27.3, 32.4, 32.7, 34.1, 36.3,
4
(
2.5, 53.3, 122.0, 129.2, 133.1, 143.1 and 195.5; m/z (CI): 279
ϩ
MH , 100%), 221 (78%), 107 (7%) and 101 (12%) [Found: C,
3
73.54; H, 9.28. C H OS requires C, 73.33; H, 9.41%].
17
26
A solution of the above thioether 4c (0.780 g, 2.80 mmol) in
3
anhydrous ether (13 cm ) was added to a solution at Ϫ20 ЊC of
3
5 ЊC to ensure the complete removal of the ammonia. The
lithium dimethylcopper (prepared by dropwise addition of
resulting mixture at 0 ЊC was treated dropwise with diethyl
chlorophosphate (3.60 cm , 4.30 g, 24.9 mmol) and after 1 h
with methylamine (25 cm ) and lithium metal (until a blue color
3
3
methyllithium in ether (1.6 M, 10.2 cm , 16.3 mmol) to Cul
3
3
(1.58 g, 8.30 mmol) in ether (18 cm ) at Ϫ20 ЊC). The reaction
mixture was stirred at 0 ЊC for 2 h and then quenched by the
addition of aqueous ammonium chloride solution and filtered
over Celite. The crude reaction product was isolated in the
usual way and purified by silica gel chromatography with 5%
persisted for 1 h, ca. 0.4 g). The mixture was stirred overnight at
Ϫ10 to 0 ЊC and then the methylamine was allowed to evapor-
ate and the excess lithium metal was removed. The crude
product was isolated with ether in the usual way and chromato-
graphed on silica gel (pretreated with 2.5% triethylamine, v/v)
with 10% ethyl acetate in hexane to afford olefin 3 (0.690 g,
6
1
1
2
5
ethyl acetate in pentane to afford ketone 4d (0.610 g, 99%): [α]
D
Ϫ1
Ϫ45.9 (c 1.0, CHCl ); ν (neat)/cm 3030, 1710, 1458, 1381,
3
max
2
5
Ϫ1
1296, 1199, 1148 and 1064; δH (200 MHz) 0.70 (3 H, s), 0.85
3 H, d, J 6.8 Hz), 0.93 (3 H, d, J 6.8 Hz), 1.10–1.60 (3 H, m),
.65 (3 H, s), 1.90–2.40 (8 H, m) and 5.30 (1 H, br s); δC (50
MHz) 16.7, 18.2, 20.7, 21.2, 22.6, 25.5, 25.7, 36.8, 37.0, 45.6,
1%): [α] Ϫ2.3 (c 1.2, CHCl ); ν
(neat)/cm 3030, 1650,
D
3
max
(
1
451, 1432, 1378, 1367, 1257, 1242, 1219, 1140, 1130, 1115,
089, 1040 and 941; δ (300 MHz) 0.90 (3 H, s), 1.28–1.65 (9 H,
H
m), 1.66–2.18 (5 H, m), 3.79–4.01 (4 H, m) and 5.25 (1 H, br s);
ϩ
5
5.8, 56.0, 121.8, 133.5 and 211.6; m/z (CI): 238 (MH ϩ NH ,
3
ϩ
δ (75 MHz) 15.9, 21.3, 21.9, 22.8, 33.6, 36.5, 38.3, 46.6, 48.0,
C
ϩ
100%) and 221 (MH , 40%) [Found: C, 81.73; H, 10.86.
C H O requires C, 81.76; H, 10.98%].
6
3.4, 64.5, 109.3, 121.1 and 134.3; m/z (EI): 222 (M , 8%), 160
15
24
(
8
10%), 145 (18%), 126 (20%), 105 (24%), 99 (100%), 93 (20%),
6 (40%), 77 (59%) and 55 (24%) [Found: C, 75.44; H, 10.14.
C H O requires C, 75.63; H, 9.97%].
(
1aR,3aR,6R,7aR,7bS)-6-Isopropyl-3a,7b-dimethyloctahydro-1-
oxacyclopropa[a]napththalen-5(1aH)-one 5
1
4
22
2
(
2
4aS,8aR)-5,8a-Dimethyl-3,4,4a,7,8,8a-hexahydronaphthalen-
(1H)-one 4a
To a solution of ketone 4d (1.82 g, 8.29 mmol) in dichlorometh-
20
3
ane (73 cm ) was added aqueous sodium carbonate solution
3
(
0.5 M, 24 cm ) and m-chloroperbenzoic acid (70–75%, 2.0 g,
A solution of olefin 3 (2.30 g, 10.4 mmol) in 85% aqueous acetic
acid (10 cm ) was heated at 100 ЊC for 1.5 h. After evaporation
of the solvent, the residue was processed with ether in the usual
manner and the crude product was purified by silica gel
chromatography with 4% ethyl acetate in pentane to give keto
olefin 4a (1.75 g, 95%): [α] Ϫ103 (c 1.1, CHCl ); ν (neat)/
cm 3050, 1714, 1449, 1377, 1305, 1245 and 1203; δH (300
MHz) 0.70 (3 H, s), 1.25–1.55 (3 H, m), 1.60 (3 H, s), 1.85–2.45
3
ca. 8.40 mmol). The reaction mixture was stirred at 20 ЊC
for 1.5 h, whereupon the crude product was isolated with
dichloromethane in the usual way and purified by florisil
chromatography with 10% ethyl acetate in pentane to give
2
5
2
5
epoxide 5 (1.82 g, 93%): mp 48–49 ЊC; [α] Ϫ12.9 (c 1.0,
D
D
3
max
Ϫ1
Ϫ1
CHCl ); ν (neat)/cm 1710, 1451, 1380, 1245, 1206, 1173,
3
max
1
070 and 883; δH (200 MHz) 0.62 (3 H, s), 0.78 (3 H, d, J 6.9
Hz), 0.84 (3 H, d, J 6.9 Hz), 1.20 (3 H, s), 0.90–1.40 (3 H, m),
(
8 H, m) and 5.30 (1 H, br s); δ (75 MHz) 16.8, 21.0, 22.6, 24.5,
C
1
2
.75–2.40 (8 H, m) and 2.86 (1 H, br s); δ (50 MHz) 17.2, 18.2,
3
6.4, 37.2, 41.5, 45.4, 55.4, 121.8, 133.2 and 211.4.
C
0.7, 21.0, 21.1, 25.6, 25.9, 33.4, 35.9, 46.4, 55.1, 55.8, 57.6, 60.4
ϩ
(
3R,4aS,8aR)-3-Isopropyl-5,8a-dimethyl-3,4,4a,7,8,8a-hexa-
and 210.5; m/z (EI): 236 (M , 23%), 221 (40%), 137 (35%), 79
(36%), 69 (60%), 55 (55%) and 43 (100%) [Found: C, 76.08; H,
hydronaphthalen-2(1H)-one 4d
9
.99. C H O requires C, 76.23; H, 10.23%].
15 24 2
To a suspension of sodium hydride (60% dispersion, 1.85 g,
4
at 0 ЊC was added a solution of olefin 4a (2.49 g, 14.0 mmol) in
ethyl formate (1.55 cm , 1.42 g, 19.2 mmol). After being stirred
3
3
6.2 mmol) in anhydrous ether (56 cm ) and ethanol (0.185 cm )
(
3R,4aR,5R,6R,8aR)-5,6-Dihydroxy-3-isopropyl-5,8a-dimethyl-
octahydronaphthalen-2(1H)-one 6
3
for 4 h at 20 ЊC, the reaction mixture was treated carefully with
A solution of epoxide 5 (0.200 g, 0.846 mmol) in 1% aqueous
3
water and then processed with ether in the normal manner to
H SO –acetone (7:3 mixture, 3 cm ) was stirred at 0 ЊC for 1.5
2
4
Ϫ1
give crude hydroxy ketone 4b (2.47 g): νmax (neat)/cm 3060,
h, whereupon a small amount of solid sodium bicarbonate was
added. The solvent was evaporated under reduced pressure and
the residue was processed with ethyl acetate in the usual manner
to give the crude product, which was purified by silica gel
chromatography with 20% acetone in hexane to give diol 6
3
0
030, 1639, 1587, 1438, 1380, 1264 and 1173; δH (300 MHz)
.81 (3 H, s), 1.30–1.50 (2 H, m), 1.65 (3 H, br s), 1.85–2.30
(
6 H, m), 2.55 (1 H, d, J 10.4 Hz), 5.35 (1 H, br s), 8.75 (1 H, s)
and 13.50 (1 H, s); δC (75 MHz) 16.9, 20.8, 22.2, 23.3, 30.9,
6.1, 42.8, 46.1, 108.2, 122.1, 133.0, 183.3 and 188.9; m/z
25
3
(0.086 g, 40%): mp 110 ЊC; [α] Ϫ47.8 (c 1.0, CHCl ); ν (neat)/
D 3 max
Ϫ1
ϩ
(
EI): 206 (M , 35%), 191 (21%), 163 (14%), 135 (22.5%), 121
cm 3461, 1698, 1463, 1446, 1387, 1366 and 1068; δ (300 MHz)
H
J. Chem. Soc., Perkin Trans. 1, 2000, 731–735
733

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0
.82–0.95 (9 H, m), 1.11–1.40 (2 H, m), 1.30 (3 H, s), 1.45–2.30
1235, 1159, 1083 and 1045; δH (300 MHz) 0.89 (3 H, d, J 6.9
(
2
2
11 H, m) and 3.55 (1 H, br s); δC (75 MHz) 18.2, 19.1, 20.8,
Hz), 0.94 (3 H, d, J 6.9 Hz), 1.00 (3 H, s), 1.24 (3 H, m), 1.38–
2.18 (11 H, m), 1.90 (3 H, dq, J 1.4, 1.4 Hz), 1.98 (3 H, dq, J 7.2,
1.4 Hz), 2.28 (1 H, m), 4.74 (1 H, dd, J 11.5, 5.0 Hz) and 6.09
2.5, 25.2, 25.9, 27.3, 33.9, 38.1, 44.6, 55.7, 58.5, 73.7, 75.3 and
ϩ
11.3; m/z (EI): 254 (M , 51%), 236 (26%), 195 (80%), 161
(
6
22%), 139 (21%), 130 (24%), 111 (61%), 95 (40%), 83 (100%),
9 (85%), 55 (66%) and 43 (70%) [Found: (M ϩ H) , 255.1950.
(1 H, qq, J 7.2, 1.4 Hz); δ (75 MHz) 15.9, 18.2, 19.2, 20.7, 20.8,
C
ϩ
22.7, 23.3, 25.6, 26.0, 37.8, 38.4, 49.7, 55.1, 58.0, 73.2, 78.1,
ϩ
C H O requires M, 255.1960].
127.8, 138.4, 167.1 and 210.8; m/z (EI): 336 (M , 29%), 318
15
27
3
(
7%), 253 (6%), 236 (7%), 195 (28%), 153 (6%), 109 (14%),
(
1R,4aR,7R,8aR)-1-Hydroxy-7-isopropyl-1,4a-dimethylocta-
99 (16%), 83 (95%), 71 (37%), 55 (100%) and 43 (81%)
[Found: (M ϩ H) , 337.2393. C H O requires M, 337.2379].
ϩ
hydronaphthalene-2,6-dione 7
20
33
4
3
This ester displayed the expected 98.5:1.5 enantiomeric ratio
HPLC: Chiracel OD-H, 5 µm, hexane–isopropanol = 9:1, 0.5
A solution of PyؒSO (0.375 g, 2.36 mmol) in DMSO (2 cm )
3
(
was added to a stirred solution of diol 6 (0.200 g, 0.79 mmol) in
3
Ϫ1
3
3
cm min , t 15.56 min (versus 14.05 min)).
r
DMSO (2 cm ) and triethylamine (1.10 cm , 0.799 g, 7.89
mmol) at 20 ЊC. The reaction mixture was stirred for 50 min,
after which aqueous ammonium chloride solution was added.
The crude product was isolated with ethyl acetate in the usual
way and purified by silica gel chromatography with 40% ethyl
acetate in pentane to give diketone 7 (0.180 g, 91%): mp 80 ЊC;
(neat)/cm 3450, 1710, 1700,
457, 1424, 1380, 1367, 1250, 1151, 1120, 1090 and 1053;
δH (200 MHz) 0.80–1.05 (9 H, m), 1.35 (3 H, s), 1.62–1.85 (3 H,
m), 1.95–2.52 (7 H, m), 2.62 (1 H, br s) and 2.70–2.92 (1 H,
m); δC (50 MHz) 18.2, 18.7, 20.8, 23.4, 25.4, 25.8, 32.7, 37.8,
(
7
(
Z)-2-Methylbut-2-enoic acid (1R,2R,4aR,7R,8aR)-1-hydroxy-
-isopropyl-1,4a-dimethyl-6-oxodecahydronaphthalen-2-yl ester
angelate ester of C-3ꢁ,C-4ꢀ diol 6)
The angelate ester of diol 6 was prepared as described above
2
5
Ϫ1
25
[
α] ϩ18.3 (c 1.0, CHCl ); ν
(but without DMAP): [α]D Ϫ58.6 (c 1.0, CHCl ); ν
(neat)/
D
3
max
3
max
Ϫ1
1
cm 3514, 1706, 1645, 1463, 1390, 1235 and 1151; δH (300
MHz) 0.88 (3 H, d, J 6.9 Hz), 0.92 (3 H, d, J 6.9 Hz), 0.97 (3 H,
s), 1.25 (3 H, m), 1.48–2.38 (18 H, m), 4.84 (1 H, br s) and 6.08
(1 H, qq, J 7.2, 1.4 Hz); δ (75 MHz) 15.9, 18.3, 19.1, 20.8, 22.5,
C
3
8.7, 52.0, 54.6, 57.0, 76.0, 210.2 and 213.7; m/z (CI): 270
22.6, 26.0, 27.0 (2×), 35.0, 38.0, 46.5, 55.7, 58.7, 72.9, 76.4,
127.9, 138.4, 166.9 and 211.0; m/z (EI): 336 (M , 5%), 318 (1%),
ϩ
ϩ
ϩ
ϩ
(
MH ϩ NH , 100%) and 253 (MH , 25%) [Found: (M ϩ H) ,
3
2
53.1799. C H O requires M, 253.1804].
293 (1%), 253 (2%), 236 (4%), 218 (12%), 195 (26%), 176 (6%),
15
25
3
1
53 (6%), 109 (10%), 95 (9%), 83 (100%), 71 (15%), 55 (39%)
ϩ
(
3R,4aR,5R,6S,8aR)-5,6-Dihydroxy-3-isopropyl-5,8a-dimethyl-
and 43 (21%) [Found: M , 336.2313. C H O requires M,
20 32 4
octahydronaphthalen-2(1H)-one 8
336.2301].
To a stirred solution of diketone 7 (0.220 g, 0.87 mmol) in
3
(Z)-2-Methylbut-2-enoic acid (1S,2R,4aR,7R,8aR)-1-hydroxy-
7-isopropyl-1,4a-dimethyl-6-oxodecahydronaphthalen-2-yl ester
anhydrous DME (3 cm ) at 0 ЊC was added dropwise a solution
3
of Zn(BH ) in DME (0.18 M, 1.47 cm , 0.26 mmol). The result-
4
2
(
angelate ester of C-3ꢁ,C-4ꢁ diol 10)
ing mixture was stirred at 0 ЊC for 1 h, after which time satur-
ated aqueous ammonium chloride solution was added. The
crude product was isolated with ethyl acetate in the normal way
and purified by silica gel chromatography with 10% acetone in
hexane to provide diol 8 (0.108 g, 49%) and diol 6 (0.088 g,
To a stirred solution of keto olefin 4d (0.025 g, 0.11 mmol) in
3
dry pyridine (0.63 cm ) was added a 2.5 wt% solution of OsO
4
3
in t-BuOH (1.50 cm ). After being stirred at 20 ЊC for 40 h, the
reaction mixture was cooled to 0 ЊC and treated with pyridine
3
3
3
4
0%). The latter by oxidation–reduction gave additional diol 8
(0.60 cm ), 37% bisulfite solution (1.5 cm ), and water (3.0 cm )
and then stirred for 30 min. The crude product was isolated
with ethyl acetate in the normal way and purified by silica gel
chromatography with 30% ethyl acetate in hexane to give diol
25
(
0.047 g, 21%): mp 78 ЊC; [α] Ϫ28.4 (c 1.0, CHCl ); ν (neat)/
D 3 max
Ϫ1
cm 3453, 1706, 1455, 1379, 1265, 1112, 1083, 1063 and 1022;
δH (300 MHz) 0.86 (3 H, d, J 6.9 Hz), 0.93 (3 H, d, J 6.9 Hz),
25
Ϫ1
0
.95 (3 H, s), 1.20–2.16 (12 H, m), 1.33 (3 H, s), 2.25 (m, 1 H)
10 (7 mg, 24%): [α]D Ϫ73.5 (c 1.6, CHCl ); ν (neat)/cm 3438,
3 max
and 3.37 (1 H, dd, J 10.6, 5.8 Hz); δ (75 MHz) 18.2, 19.0, 20.8,
1698, 1463, 1387, 1366, 1083, 1060 and 1030; δH (300 MHz)
0.80 (3 H, s), 0.86 (3 H, d, J 6.8 Hz), 0.91 (3 H, d, J 6.8 Hz), 1.14
(3 H, s), 1.30–1.50 (1 H, m), 1.65–1.85 (5 H, m), 2.00–2.30 (5 H,
C
2
2
2.7, 25.4, 25.9, 26.8, 37.8, 38.4, 49.5, 55.2, 58.1, 73.5, 75.6 and
11.1; m/z (EI): 254 (M , 30%), 236 (14%), 203 (10%), 195
ϩ
(
1
28%), 177 (10%), 161 (14%), 153 (25%), 137 (14%), 130 (14%),
25 (15%), 111 (32%), 95 (36%), 83 (40%), 69 (36%), 55 (34%)
and 43 (100%) [Found: C, 70.89; H, 10.24. C H O requires C,
m), 2.40 (1 H, br s), 2.69 (1 H, br s) and 3.63 (1 H, br s); δ (75
C
MHz) 18.4, 18.4, 21.0, 21.7, 23.2, 25.7, 25.9, 33.1, 38.8, 46.7,
ϩ
56.3, 59.1, 73.1, 74.1 and 211.2; m/z (EI): 254 (M , 58%), 236
15
26
3
7
0.83; H, 10.30%].
(11%), 221 (6%), 203 (5%), 195 (39%), 177 (8%), 153 (24%), 137
(
11%), 130 (10%), 123 (9%), 111 (40%), 95 (29%), 83 (42%), 69
ϩ
(
7
(
Z)-2-Methylbut-2-enoic acid (1R,2S,4aR,7R,8aR)-1-hydroxy-
-isopropyl-1,4a-dimethyl-6-oxodecahydronaphthalen-2-yl ester
1) (angelate ester of C-3ꢀ,C-4ꢀ diol 8)
(30%), 55 (38%) and 43 (100%) [Found: M , 254.1882.
C H O requires M, 254.1882].
15
26
3
The angelate ester of diol 10 was prepared as described above
25
D
(
but without DMAP): [α] Ϫ84.6 (c 0.1, CHCl ); ν
(neat)/
3
max
To a solution of angelic acid (7.8 mg, 0.08 mmol) in toluene
Ϫ1
3
cm 3515, 1715, 1646, 1454, 1387, 1259, 1150 and 1084;
δH (300 MHz) 0.85 (3 H, s), 0.88 (3 H, d, J 6.8 Hz), 0.93 (3 H, d,
J 6.8 Hz), 1.08–1.33 (3 H, m), 1.22 (3 H, s), 1.33–1.68 (5 H, m),
(
0.10 cm ) was added 2,4,6-trichlorobenzoyl chloride (0.012
3
3
cm , 18.7 mg, 0.08 mmol) and triethylamine (0.011 cm , 8.0 mg,
.08 mmol). After being stirred for 3 h at 20 ЊC, the mixture was
treated with a solution of diol 8 (10.0 mg, 0.04 mmol) in toluene
0
1
.96 (3 H, dq, J 1.4, 1.4 Hz), 2.02 (3 H, dq, J 7.2, 1.4 Hz), 1.78–
3
2.32 (4 H), 4.93 (1 H, deformed t, J 2.8 Hz) and 6.13 (1 H, qq,
J 7.2, 1.4 Hz); δC (75 MHz) 16.0, 18.4, 18.5, 20.9, 21.0, 21.6,
2
1
3
(
7
0.10 cm ) and DMAP (1.0 mg, 0.01 mmol) and then heated at
0 ЊC for 4 h, after which ether was added and the resulting
3.0, 24.0, 25.9, 34.2, 38.6, 48.9, 56.2, 59.3, 72.3, 76.7, 127.7,
precipitate filtered. The solvents were evaporated under reduced
pressure and the crude product was purified by silica gel
chromatography with 10% ethyl acetate in hexane to provide
the angelate ester 1 (5.3 mg, 40%, or 74% based on non-
recovered 8), together with starting material (2.5 mg, 25%) and
tiglate ester (2.8 mg, 21%). The tiglate ester could be hydrolyzed
ϩ
39.0, 167.4 and 210.6; m/z (CI): 337 (MH , 18%), 319 (100%),
ϩ
12 (32%), 295 (6%) and 237 (12%) [Found: M , 336.2303.
C H O requires M, 336.2301].
20
32
4
(
Z)-2-Methylbut-2-enoic acid (1S,2S,4aR,7R,8aR)-1-hydroxy-
-isopropyl-1,4a-dimethyl-6-oxodecahydronaphthalen-2-yl ester
7
(
MeOH, K CO , 20 ЊC, 12 h, 100%) to allow recovery of addi-
2 3
25
(angelate ester of the C-3ꢀ,C-4ꢁ diol)
tional starting material. Angelate ester 1: [α] Ϫ10.9 (c 0.3,
D
Ϫ1
CHCl ); ν
(neat)/cm 3506, 1706, 1650, 1459, 1387, 1265,
Diol 10 was oxidized with the PyؒSO complex in DMSO as
3
max
3
7
34
J. Chem. Soc., Perkin Trans. 1, 2000, 731–735

View Article Online
described above to furnish the corresponding acyloin (76%),
5 J. G. S. Maia and M. H. L. Silva, Potencial Econômico de Plantas
Aromáticas do Pará, 1995, Museu Paraense Emilio Goeldi, Belém
(PA), Brazil.
F. Bohlmann, J. Ziesche, R. M. King and H. Robinson, Phyto-
chemistry, 1980, 19, 969.
which was reduced with NaBH in ethanol at 0 ЊC to give the
4
2
5
C-3β,C-4α diol (75%): mp 114–116 ЊC; [α] Ϫ55.6 (c 0.7,
D
6
Ϫ1
CHCl ); ν
(neat)/cm 3438, 1706, 1462, 1394, 1166 and
3
max
1
090; δH (300 MHz) 0.77 (3 H, s), 0.82 (3 H, d, J 6.8 Hz), 0.88
7 X. A. Dominguez, R. Franco, G. Cano, R. Villarreal, M. Bapuji and
F. Bohlmann, Phytochemistry, 1981, 20, 2297.
8 V. U. Ahmad, K. Fizza and A. Sultana, Phytochemistry, 1989, 28,
(3 H, d, J 6.8 Hz), 1.08 (3 H, s), 1.30–1.58 (3 H, m), 1.68–1.84
(1 H, m), 1.95–2.30 (7 H, m), 2.50–3.20 (2 H, br s) and 3.50
(1 H, dd, J 11.4, 4.3 Hz); δC (75 MHz) 16.6, 18.3, 18.9, 20.9,
3
081.
9
M. Ando, K. Arai, K. Kikuchi and K. Isogai, J. Nat. Prod., 1994,
7, 1189.
0 G. M. S. P. Guilhon and A. H. Müller, Phytochemistry, 1996, 43,
17.
2
2.9, 25.7, 27.5, 38.4, 39.1, 51.4, 55.4, 59.0, 75.7, 79.3 and 211.1;
5
ϩ
m/z (EI): 254 (M , 17%), 203 (5%), 195 (26%), 177 (6%), 153
1
(
(
16%), 137 (8%), 123 (6%), 111 (20%), 95 (16%), 83 (24%), 69
33%), 55 (32%), 49 (15%) and 43 (100%) [Found: M ,
4
ϩ
11 G. M. S. P. Guilhon and A. H. Müller, Phytochemistry, 1998, 47,
2
54.1884. C H O requires M, 254.1882].
227.
15
26
3
1
2 L. C. Sequeira, PhD Thesis, Universidade Federal do Rio de
Janeiro, 1996. The antipode for the present work was arbitrarily
chosen.
3 M. Pfau, G. Revial, A. Guingant and J. d’Angelo, J. Am. Chem.
Soc., 1985, 107, 273.
14 M. Pfau, I. Jabin and G. Revial, J. Chem. Soc., Perkin Trans. 1, 1993,
The angelate ester of this diol was prepared as described
2
5
above (but without DMAP): [α] Ϫ50.3 (c 0.6, CHCl ); ν
(
1
D
3
max
Ϫ1
neat)/cm 3483, 1713, 1653, 1455, 1387, 1356, 1235, 1174,
091 and 1045; δH (300 MHz) 0.84 (3 H, s), 0.87 (3 H, d, J 6.8
Hz), 0.92 (3 H, d, J 6.8 Hz), 1.17 (3 H, s), 1.36–1.72 (5 H, m),
1
1
2
.91 (3 H, dq, J 1.5, 1.5 Hz), 2.00 (3 H, dq, J 7.2, 1.5 Hz), 1.85–
.20 (7 H, m), 4.80 (1 H, dd, J 11.5, 4.7 Hz) and 6.09 (1 H, qq,
1935.
1
1
1
5 G. Revial, Tetrahedron Lett., 1989, 30, 4121.
6 R. E. Ireland and G. Pfister, Tetrahedron Lett., 1969, 2145.
7 An authentic sample of the cis isomer was prepared for comparison
by the procedure of Kabalka and coworkers: G. W. Kabalka,
D. T. C. Yang and J. D. Baker, Jr., J. Org. Chem., 1976, 41, 574;
G. W. Kabalka, J. D. Baker, Jr. and G. W. Neal, J. Org. Chem., 1977,
42, 512.
J 7.3, 1.4 Hz); δC (75 MHz) 15.9, 18.1, 18.4, 18.8, 20.6, 20.9,
2
1
3.0, 25.5, 25.9, 38.3, 38.8, 52.3, 55.5, 58.9, 74.3, 81.4, 127.8,
38.8, 168.4 and 210.7; m/z (EI): 336 (M , 13%), 321 (2%), 318
ϩ
(
(
(
4%), 293 (2%), 253 (5%), 236 (8%), 221 (8%), 218 (5%), 205
3%), 195 (50%), 177 (6%), 153 (10%), 109 (8%), 95 (7%), 83
100%), 71 (22%), 55 (63%) and 43 (35%) [Found: M ,
ϩ
18 This compound has been previously prepared in racemic form in a
similar manner. See references 20, 22.
9 R. M. Coates and R. L. Sowerby, J. Am. Chem. Soc., 1971, 93, 1027.
0 D. J. Goldsmith and I. Sakano, J. Org. Chem., 1976, 41, 2095.
1 Most diagnostically, the C-10 and C-4 methyls resonated at 0.80 and
3
36.2309. C H O requires M 336.2301].
20 32 4
1
2
2
Crystal data for diol 8 (racemic)
1
.14 ppm, respectively, and the C-3 (equatorial) hydrogen resonated
at 3.63 ppm (half-band width of 6.8 Hz). The corresponding values
see ref. 20) for the derivative lacking the isopropyl are 0.87, 1.14,
X-Ray data collection of C H O (M = 254.37) was carried
15
26
3
out on an Enraf-Nonius CAD-4 diffractometer (λ Kα =
(
3
0
0
1
.7107 Å) at 293 K. The crystal was monoclinic (P2 /a, no.
and 3.64 ppm (half-band width of 7 Hz), as opposed to 1.02, 1.32
and 3.38 ppm (half-band width of 25 Hz) for the β,β diol. In
addition, a NOE was observed between the C-4 and C-10 methyls.
1
4), with unit cell a = 10.453(4), b = 23.017(9), c = 12.223(3) Å,
β = 102.83(3)Њ, V = 2867(2) Å , Z = 8, D = 1.178 g cm
µ = 0.800 cm . Crystal structure determination and refine-
ments were performed with teXsan system. The structure was
3
Ϫ3
,
x
Ϫ1
22 R. B. Miller and E. S. Behare, J. Am. Chem. Soc., 1974, 96, 8102.
23 K. Nakanishi, D. A. Schooley, M. Koreeda and J. Dillon, J. Chem.
Soc., Chem. Commun., 1971, 1235; G. A. Olah, A. F. Fung and
D. Meidar, Synthesis, 1981, 280; R. M. Hanson, Tetrahedron Lett.,
1984, 25, 3783; W. S. Johnson and M. F. Chan, J. Org. Chem., 1985,
50, 2598; M. Chini, P. Crotti, C. Gardelli and F. Macchia, Synlett,
31
32
solved by direct methods, SIR92. Using 3055 reflections with
I > 2σ(I), final R and Rw values are 0.063 and 0.060 for 325
2
parameters. The weighting scheme is w = 1/[σ (F ) ϩ 0.00010
o
2
o
1
992, 673.
F ]. The present racemic atomic arrangement is characterized
2
4 J. R. Parikh and W. von Doering, J. Am. Chem. Soc., 1967, 89, 5505;
F. M. Hauser, P. Hewawasam and D. Mal, J. Am. Chem. Soc., 1988,
1
5 T. Nakata and T. Oishi, Tetrahedron Lett., 1980, 21, 1641; T.
Nakata, T. Tanaka and T. Oishi, Tetrahedron Lett., 1981, 22, 4723.
For a review, see: S. Narasimhan and R. Balakumar, Aldrichimica
Acta, 1998, 31, 19.
6 Although NaBH in EtOH was also highly regioselective, it provided
a much less favorable ratio (8 to 6, 1:3), as anticipated on the basis
of diminished chelation effects.
7 J. W. Lauher, 1989. CHARON, A Graphics Program for Postscript
Printers, The Research Foundation of the State University of
New York.
28 J. Inanaga, K. Hirata, H. Saeki, T. Katsuki and M. Yamaguchi, Bull.
Chem. Soc. Jpn., 1979, 52, 1989.
9 Prepared from commercially available cyclohexane-1,4-dione
monoethylene ketal: L. C. Sequeira, P. R. R. Costa, A. Neves and
P. Esteves, Tetrahedron: Asymmetry, 1994, 5, 1433. See also:
D. Crich, S. Natarajan and J. Z. Crich, Tetrahedron, 1997, 53, 7139.
0 Enraf-Nonius, 1989. CAD-4 Software. Version 5.0. Enraf-Nonius,
Delft, The Netherlands.
by the existence of two crystallographically independent mol-
ecules. Examination of these two independent units shows very
small geometrical differences between them except for the H
bond scheme. CCDC reference number 207/392. See http://
www.rsc.org/suppdata/p1/a9/a909112b/ for crystallographic
files in .cif format.
10, 2919.
2
2
4
2
5
Acknowledgements
2
We are thankful to Dr A. Durif and Dr M.-T. Averbuch for the
X-ray structure determination and to Ms G. M. S. P. Guilhon
for the spectra and a small sample of the natural product. A
fellowship from CAPES to E. M. and financial support from
the CNRS (UMR 5616) and the Université Joseph Fourier are
gratefully acknowledged.
2
3
References
1
V. S. Martino, S. L. Debenedetti and J. D. Coussio, Phytochemistry,
979, 18, 2052.
F. J. Arriaga-Giner, J. Borges-del-Castillo, M. T. Manresa-Ferrero,
P. Vásquez-Bueno, F. Rodriguez-Luis and S. Valdés-Iraheta,
Phytochemistry, 1983, 22, 1767.
31 teXsan, 1992–1997. Molecular Structure Corporation. Single
Crystal Structure Analysis Software. Version 1.7. MSC, 3200
Research Forest Drive, The Woodlands, TX 77381, USA.
32 A. Altamore, M. Cascarano, C. Giacovazzo and A. Guagliardi,
J. Appl. Crystallogr., 1993, 26, 343.
1
2
3
4
S. Mukhopadhyay, G. A. Cordell, N. Ruangrungsi, S. Rodkird,
P. Tantivatana and P. J. Hylands, J. Nat. Prod., 1983, 46, 671.
E. Scholz, M. Heinrich and D. Hunkler, Planta Med., 1994, 60, 360.
Paper a909112b
J. Chem. Soc., Perkin Trans. 1, 2000, 731–735
735