Synthetic study of marine lobane diterpenes. Enantioselective syntheses of lobatrienolide and lobatrientriol from (+)-nopinone

Article abstract of DOI:10.1039/a809983i

Michiharu Kato,. The first enantioselective syntheses of highly oxygenated lobane diterpenes, (+)-lobatrienolide 4 and (+)-lobatrientriol 5, have been achieved, starting with (4R,5R)-1-acetoxy-4-isopropenyl-5-methyl-5-vinyl-cyclohex-1-ene 10b which itself has been prepared from (+)-nopinone 7 as a versatile building block toward the asymmetric synthesis of natural products.

Full text of DOI:10.1039/a809983i

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Synthetic study of marine lobane diterpenes. Enantioselective
syntheses of lobatrienolide and lobatrientriol from (؉)-nopinone
Michiharu Kato,* Hiroshi Kosugi, Tsuyoshi Ichiyanagi and Osamu Yamabe
Institute for Chemical Reaction Science, Tohoku University, Katahira, Aoba-ku,
Sendai 980-8577, Japan
Received (in Cambridge) 23rd December 1998, Accepted 22nd February 1999
The first enantioselective syntheses of highly oxygenated lobane diterpenes, (ϩ)-lobatrienolide 4 and
(ϩ)-lobatrientriol 5, have been achieved, starting with (4R,5R)-1-acetoxy-4-isopropenyl-5-methyl-5-vinyl-
cyclohex-1-ene 10b which itself has been prepared from (ϩ)-nopinone 7 as a versatile building block
toward the asymmetric synthesis of natural products.
metric synthesis, and reported the effective transformation of
Introduction
7 into (1R,4S,5S)-(ϩ)-4,7,7-trimethyl-4-vinylnopinone 8 via
(1R,5R)-(ϩ)-verbenone 9a, followed by BF3-promoted cyclo-
butane opening9 to give (4S,5S)-(Ϫ)-1-acetoxy-4-isopropenyl-
5-methyl-5-vinylcyclohex-1-ene 10a.10,11 Furthermore, we have
developed a general transformation of 7 into (1S,5S)-(Ϫ)-
verbenone 9b.11 This made it possible to prepare (4R,5R)-(ϩ)-
10b from 7 as the common starting material. Both enol acetates
10a,b are obtainable in more than 40% overall yield from 7 and
its enantiomer, respectively.
The enol acetates 10a,b could serve as promising chiral tem-
plates for the asymmetric synthesis of elemane sesqui- and
lobane diterpenoids, since these natural products possess, as
their major framework, the same carbon skeleton as that of
10a,b. In fact, the usefulness of 10a has been demonstrated by
the synthesis of (ϩ)-eleman-8β,12-olide,10 and that of 10b was
recently demonstrated by the efficient synthesis of (ϩ)-fuscol 1
(vide ante).6 As part of a synthetic study on lobane diterpenes,
the present paper describes the effective application of 10b in
the synthesis of lobatrienolide 4 and lobatrientriol 5.
Marine lobane natural products are the first diterpenes possess-
ing a unique prenylated elemane carbon skeleton.1,2 Fuscol 1,
7
8
1
15
10
4
2
13
14
18
H
OR
H
R
O
OH
1 R = H
2 R = arabinose
3 R = H, H
4 R = O
OH
O
H
OH
H
OH
OAc
6
5
isolated from the Gorgonian Eunicea fusca by Schmitz et al.,3 is
representative, and its arabinose glycoside, fuscoside B 2, iso-
lated from E. fusca by Fenical et al., is known as a promising
lead compound for new antiinflammatory agents, and as a
selective inhibitor of leukotriene synthesis.4 Enantioselective
total synthesis of 1 has been accomplished by Yamada et al.5
and recently by our group.6 More highly oxygenated congeners,
lobatriene 3,2,7 lobatrienolide 4,8 lobatrientriol 58 and acetoxy-
lobaoxide 68 were recently isolated from the Okinawan soft
coral Sinularia flexibilis by Kusumi and Kakisawa et al., and
their structural elucidations were carried out mainly by use of
1H NMR studies.8 The absolute configuration of 3 and 4 were
elucidated by use of the modified Mosher method for the
former, and chemical correlations with 3 for the latter.8 Syn-
thetic studies of these natural products have not been reported
yet.
Results and discussion
We chose lobatrienolide 4 as the first synthetic target among the
two mentioned above, since lobatrientriol 5 could be derived by
reduction of 4. Lobatrienolide 4 is regarded as 2-substituted
pent-2-en-5-olide possessing a (1,1-dimethylmethanol) function
at the C(5) position, so this view led us to consider an enantio-
selective synthesis of 4 by the combination of two fragments,
ester 11 which could be obtained from 10b and the known
(5R)-5-(2Ј-iodoethyl)-2,2,4,4-tetramethyl-1,3-dioxolane 12,12 as
shown in the retrosynthetic disconnections in Scheme 1.
CO2Me
We have been studying the utility of (1S,5S)-(ϩ)-nopinone 7,
readily available from (Ϫ)-β-pinene, as a chiral source in asym-
H
H
O
O
OH
11
4
5
O
O
OAc
I
R2
[H]
O
O
H
R1
10b
12
7 R1 = R2 = H
8 R1 = Me, R2 = CH=CH2
9a
10a
9b (other enantiomer) 10b (other enantiomer)
Scheme 1
J. Chem. Soc., Perkin Trans. 1, 1999, 783–788
783

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width 21.8 Hz) at δ 2.89 for the former and that (half band
width, 14.4 Hz) at δ 3.02 for the latter. Compound 14b was
smoothly isomerised into thermodynamically stable 14a upon
treatment with K2CO3 in methanol. On the other hand, the
sodium salt of the keto ester 15, which had been prepared from
10b in the synthesis of fuscol 1,6 was treated with methyl
bromoacetate to give diester 16 as the sole product. The stereo-
chemistry of 16 was tentatively assigned as depicted in Scheme
2, from an analysis of the stereoelectronic effects governing the
approach of the nucleophile, away from the axially oriented
angular methyl group. Hydrolysis of 16 with concomitant de-
carboxylation followed by esterification of the resulting carbox-
ylic acid with diazomethane afforded 14a in 61% overall yield.
In order to remove the ketone carbonyl group in 14a, two
kinds of derivatives, thio acetal 23 and tosyl hydrazone 24, were
O
O
i
ii
4
10b
1
CO2Me
H
H
13
14a 4S
14b 4R
Ref. 6
iii
v
O
O
iv
vi
CO2Me
CO2Et
H
H
CO2Et
15
16
R
OH
viii
OS2Me
OH
CO2Me
CO2Me
H
H
OTBDMS
OR
H
H
23 R = SCH2CH2S
24 R = NNH-p-Ts
25
19
17 R = H
18 R = TBDMS
vii
ix
O
O
xi
H
11
OR
H
26
20 R = TBDMS
21 R = H
x
prepared from 14a. However, attempted desulfurisation of 23
with Raney nickel (W-4) proved to be fruitless, because the
reaction provided a mixture of products arising from concomi-
tant reduction of the double bonds, from which the desired
ester 11 could not be isolated. In addition, reduction of 24 with
sodium cyanoborohydride in the presence of toluene-p-sulfonic
acid under the standard reaction conditions13 resulted in
recovery of the starting material. Stereoselective reduction of
14a with lithium tri-tert-butoxyaluminium hydride in THF at
low temperature provided hydroxy ester 25 in quantitative yield.
It is worth mentioning that 25 was unstable and easily lacton-
ised, mostly in the work-up process, to lead to cis-fused
γ-lactone 26.
Scheme 2 Reagents and conditions: i, K2CO3, MeOH (98%); ii, LDA,
BrCH2CO2Me, THF, HMPA, Ϫ78 to Ϫ40 ЊC; iii, K2CO3, MeOH, room
temp. (60% from 13); iv, NaH, BrCH2CO2Me, THF, HMPA, 0 ЊC to
room temp. (95%); v, (1) NaOH, DMSO, H2O then aqueous HCl, (2)
CH2N2, ether (81% from 15); vi, LiAlH4, THF (81%); vii, TBDMSCl,
imidazole, DMF (87%); viii, BuLi, CS2, MeI, THF (quant.); ix,
Bu3SnH, AIBN, toluene, 90 ЊC (quant.); x, Bu4NF, THF (90%); xi, (1)
Jones reagent, acetone, (2) CH2Cl2, ether (73%).
To prepare compound 11, our synthesis started with the
chemical transformation of 10b into keto ester 14a (Scheme 2).
In the synthesis of (ϩ)-β-elemenone,10 we have prepared the
enantiomer of 14a by treatment of 10a with MeLi (2 equiv.) in
THF followed by addition of methyl bromoacetate. However,
the reproducibility of this reaction was poor, and the dialkyl-
ation product 22 was invariably produced as a by-product,
A conventional method frequently employed for removal of
a ketone function, i.e. chemical transformation into a double
bond and subsequent catalytic hydrogenation, is not applicable
in our synthesis, so instead 14a was reduced with excess LiAlH4
to give diol 17;14 regioselective protection of the primary
hydroxy group provided silyl ether 18. Chemical transformation
of 18 into the alcohol 21 was carried out by a sequence of
reactions; (1) preparation of xanthate 19, (2) reductive removal
of the xanthate ester group with formation of 20, and (3)
deprotection to give 21. Finally, Jones oxidation of 21 followed
by esterification of the resulting carboxylic acid with diazo-
methane provided, in ca. 35% overall yield from 10b, the requis-
O
CO2Me
H
CO2Me
22
1
ite ester 11 whose H NMR, and HPLC analyses proved to be
probably because of the action of the concomitantly produced
lithium tert-butoxide. In the present synthesis, compound 10b
was first converted into ketone 13 by hydrolysis. Treatment of
13 with LDA in THF and HMPA followed by addition of
methyl bromoacetate provided a mixture (ca. 1:9 ratio) of keto
esters 14a and b in 60% yield with no formation of 22. From
1H NMR studies, the stereochemistry of the acetate moiety at
the C(1) position† in 14a and b were assigned to be axial and
equatorial, respectively, on the basis of a multiplet (half band
homogeneous.
The alkylating agent, (5R)-5-(2Ј-iodoethyl)-2,2,4,4-tetra-
methyl-1,3-dioxolane 12, necessary for construction of the
oxygenated side-chain at the C(1) position, was prepared from
(ϩ)-malic acid (100% ee) according to the procedures reported
by Serra et al.12 First, we attempted to use α-phenylthio ester
27, which is available from 11 by phenylsulfenylation, because
not only would 27 be more reactive in the alkylation reaction
than 11 itself, but also the phenylthio group would serve as a
means for introduction of an enone function into the product.
Compound 27 was readily prepared by treatment of the lithium
salt of 11 with S-phenyl benzenethiosulfonate (LDA, THF,
70%).15 However, attempted alkylation of 27 with 12 (NaH,
† The numbering system used here and in the Experimental Section
follows IUPAC rules, and is different from the natural product number-
ing used for fuscol 1.
784
J. Chem. Soc., Perkin Trans. 1, 1999, 783–788

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H
H
H
CO2Me
SPh
O
H
R
H
OH
OH
O
H
HO
27 R = H
28 R = Et
OH
i
32
THF or DMF,16 rt) proved to be fruitless, because the reaction
was sluggish and a large proportion of 27 was recovered
unchanged, although the reaction of 27 with ethyl iodide as a
model produced smoothly the ethylated compound 28 (NaH,
DMF, rt, 66%).
ring provided the selenide as a mixture of diastereomers in 63%
yield (73% yield from the consumed 31). Oxidation of the selen-
ide with 30% H2O2 followed by elimination of the selenoxide
gave the target lobatrienolide 4 in 70% yield. It is interesting to
note that, in the selenoxide elimination, no regioisomer with
respect to the newly formed double bond could be detected in
spite of a careful inspection of the reaction mixture. The 1H and
13C NMR, IR and mass spectral data of the synthetic 4, [α]D26
ϩ81.0 (c 0.30, CHCl3) {lit., [α]D25 ϩ89.3 (c 0.63, CHCl3)7},
including the sign of optical rotation, were identical with those
of the authentic sample.7 Since the absolute configuration of
lobatrienolide 4 has been assigned in chemical correlation with
lobatriene 6 whose absolute configuration was elucidated by use
of the modified Mosher method,8 the present study also sup-
ports the absolute stereostructure of 4 by a synthetic means.
Lobatrientriol 5 could be derived from 4 by reduction of the
δ-lactone ring. However, reduction of 4 with lithium aluminium
hydride produced the desired 5 only in 11% yield, and the major
product obtained in 29% yield was surmised to be an over-
reduction product 32 by the 1H NMR analysis. Then, a stepwise
method; reduction of 4 with DIBALH, followed by reduction
of the resulting hemiacetal with NaBH4, was employed, thus
giving, in more than 80% overall yield, lobatrientriol 5, [α]D26
ϩ14.9 (c 0.22, CHCl3) {lit., [α]D25 ϩ15.0 (c 0.20, CHCl3)5}.
Spectral data of synthetic 5 were identical with those of
natural 5,5 indicating the absolute configuration of 5 to be
(1S,2R,4S,17R).
O
i
11
O
H
CO2Me
29
ii
OH
iii
OH
H
H
CO2Me
O
O
OH
31
30
iv
v
4
5
In summary, as part of the enantioselective synthesis of
lobane diterpenes from (ϩ)-nopinone 7, the first syntheses
of (ϩ)-lobatrienolide 4 and (ϩ)-lobatrientriol 5 from the enol
acetate 10b were accomplished in 14 and 17 steps and ca. 7 and
6% overall yield, respectively, thus synthetically supporting
their absolute configurations which were elucidated by 1H
NMR studies and chemical correlations. Since all of the lobane
natural products possess commonly an oxygenated eight-
carbon side chain at the C(4) position, the present study
demonstrates that compound 10b could serve as a versatile
building block for the enantioselective synthesis of lobane
natural products.
Scheme 3 Reagents and conditions: i, 12, LDA, THF–HMPA (3:1),
Ϫ78 to 0 ЊC (98%); ii, PPTS, MeOH (quant.); iii, p-TsOH, CH2Cl2
(80%); iv, (1) LDA, PhSeCl, THF, HMPA, (2) 30% H2O2, THF (44%
from 31); v, (1) DIBALH, toluene, Ϫ78 ЊC, (2) NaBH4, MeOH, 0 ЊC
(80%).
The alkylation reaction of 11 with 12 was examined next in
some detail (Scheme 3). We conducted reactions of 11 with
LDA in THF (Ϫ78→0 ЊC) followed by addition of 12 in the
presence and absence of additives [HMPA and 12-crown-4]. No
reactions occurred in THF in the presence or absence of 12-
crown-4 (2 equiv.). Many of the reactions in the presence of
HMPA (2–10 equiv.) proceeded very slowly and were
incomplete after 20 h (0 ЊC to rt; trace–16% yield of 29). After
considerable experimentation, the reaction conditions using a
large excess of HMPA (THF–HMPA, 3:1) resulted in complete
alkylation, giving 29 in a shorter reaction time (2 h) and 98%
isolated yield.
Deprotection of the acetal function in 29 was effected by
heating gently with PPTS in aqueous methanol to give diol 30
in 82% isolated yield, along with a trace amount of a lactone
product 31. Upon treatment of 30 with a catalytic amount of
toluene-p-sulfonic acid in CH2Cl2, dihydrolobatrienolide 31, the
key synthetic intermediate, was successfully produced in 80%
isolated yield (65% overall yield from 29) as a separable mixture
of two diastereomers (a 2:1 ratio) with respect to the substitu-
ent at the α position of the δ-lactone ring. This was evidenced
by the 1H NMR (400 MHz, C6D6) analysis; the stereochemistry
of both of the hydrogen atoms on the carbon flanking the 1,1-
dimethylmethanol group in diastereomers 31 was established to
be axial, on the basis of the chemical shifts and coupling con-
stants at δ 3.58 (dd, J 11.0, 3.4) for the major product and at
δ 3.65 (dd, J 11.5, 3.2) for the minor one. These findings suggest
the stereostructure of diastereomers 31 as depicted in i.
Experimental
1H NMR spectra were recorded at 400 MHz. J Values are given
in Hz. [α]D Values are given in units of 10Ϫ1 deg cm2 gϪ1. All
reactions were carried out under dry N2 or Ar atmosphere.
Extracts obtained on aqueous work-up of the reaction mixtures
were washed successively with water and brine, and dried over
Na2SO4. Column chromatography was performed on 70–230
mesh silica gel (Merck). Medium pressure chromatography
(MPLC) utilised a 22 i.d. × 300 mm silica gel (10 µm) column.
Solvents for elution are shown in parentheses. Ether refers to
diethyl ether.
(3R,4R)-3-Methyl-4-isopropenyl-3-vinylcyclohexanone 13
The compound 13, [α]D ϩ30.0 (c 0.54, in CHCl3), was prepared
from 10b6 according to the procedure described for preparation
of its enantiomer reported earlier.10
Methyl 2-[(1S,4R,5R)-5-isopropenyl-4-methyl-4-vinyl-2-oxo-
cyclohexyl]acetate 14a
Phenylselenenylation of 31 at the 2-position of the lactone
Method 1. To a stirred solution of diisopropylamine (0.35 ml,
J. Chem. Soc., Perkin Trans. 1, 1999, 783–788
785

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2.49 mmol) in THF (3 ml) was added dropwise at Ϫ78 ЊC a 1.61
M solution of BuLi in hexane (1.55 ml, 2.48 mmol). After being
stirred for 20 min, a solution of 13 (362 mg, 2.04 mmol) in THF
(2 ml) was added dropwise and stirring was continued for an
additional 30 min. To the reaction mixture was added a solu-
tion of methyl bromoacetate (1.09 g, 7.14 mmol) and HMPA
(408 mg, 2.48 mmol) in THF (2 ml). The reaction mixture
was stirred for 4 h, during which the reaction temperature rose
slowly to Ϫ40 ЊC, quenched by addition of aqueous NH4Cl,
and extracted with EtOAc. Removal of the solvent followed
by filtration of the residue through a short silica gel column
(hexane–EtOAc, 9:1) gave a mixture of 14a and b as an oil. A
mixture of the oil and K2CO3 (280 mg, 2.0 mmol) in methanol
(5 ml) was stirred at room temperature for 20 h, and concen-
trated. Water was added to the residue, and the product was
extracted into EtOAc. Evaporation of the solvent followed by
purification of the residue with MPLC (hexane–EtOAc, 9:1)
gave the title compound 14a (306 mg, 60%) as an oil, [α]D ϩ3.35
4.90 (1H, d, J 11.0), 5.76 (1H, dd, J 17.3, 11.0); m/z (EI) 206
(Mϩ Ϫ H2O, 25), 191 (12), 175 (18), 161 (30), 93 (100).
To a solution of 17 (2.41 g, 10.7 mmol) and imidazole (2.19 g,
32.2 mmol) in DMF (20 ml) was added a solution of TBDM-
SCl (1.68 g, 11.2 mmol) in DMF (10 ml) with stirring. The
reaction mixture was stirred for 1 h, quenched by addition of
aqueous NaHCO3, and extracted with ether–hexane (1:1).
Concentration of the extract followed by purification of the
residue with chromatography on silica gel (hexane–AcOEt,
12:1) gave the title compound 18 (3.15 g, 87%) as an oil
(Found: C, 70.89; H, 11.48. C20H38O2Si requires C, 70.94; H,
11.31%); [α]D ϩ18.3 (c 0.35, in CHCl3); νmax(neat)/cmϪ1 3510,
1250, 1093, 836; δH(CDCl3) 0.07 (6H, s), 0.90 (9H, s), 1.17 (3H,
s), 1.22–1.27 (2H, m), 1.57–1.87 (5H, m), 1.71 (3H, s), 1.99 (1H,
m), 2.67 (1H, br s, OH), 3.59 and 3.69 (1H, m each), 4.02 (1H,
br s, 1/2H = 8.5‡), 4.62 and 4.81 (1H, s each), 4.87 (1H, d,
J 17.5), 4.90 (1H, d, J 10.5), 5.77 (1H, dd, J 17.5, 10.5).
1
(c 0.34, in CHCl3). The IR and H NMR spectra of 14a were
2-[(1S,3R,4R)-(3-Isopropenyl-4-methyl-4-vinylcyclohexyl)]-
ethanol 21
identical with those of its enantiomer prepared earlier.10
To a stirred solution of 18 (4.55 g, 13.4 mmol) in THF (50 ml)
at Ϫ78 ЊC was added dropwise a 1.54 M solution of BuLi in
hexane (13.0 ml, 20.0 mmol). After being stirred for 30 min, CS2
(1.6 ml, 26.7 mmol) was added, and after being stirred for an
additional 30 min, MeI (1.7 ml, 27.3 mmol) was added drop-
wise. Stirring was continued for an additional 50 min, the reac-
tion mixture was quenched by addition of aqueous NH4Cl, and
the product was extracted with ether. Removal of the solvent
left an oil which was chromatographed on silica gel (hexane–
AcOEt, 50:1) to give 19 (5.70 g, quant.), [α]D Ϫ11.5 (c 0.60, in
CHCl3); νmax(neat)/cmϪ1 1231, 1216, 1050, 835; δH(CDCl3) 0.04
(6H, s), 0.89 (9H, s), 1.06 (3H, s), 1.51–1.63 (5H, m), 1.75 (3H,
s), 1.79–1.95 (2H, m), 2.03–2.11 (2H, m), 2.59 (3H, s), 3.64 (2H,
td, J 6.1, 1.2), 4.67 (1H, s), 4.87 (1H, d, J 17.3), 4.91 (1H, d,
J 10.7), 4.93 (1H, s), 5.78 (1H, dd, J 17.3, 10.7).
To a stirred solution of 19 (6.15 g, 14.3 mmol) in toluene (40
ml) at 90 ЊC was added dropwise a solution of AIBN (449 mg,
2.73 mmol) and tributyltin hydride (11.2 ml, 40.2 mmol) in
toluene (20 ml), and stirring was continued for an additional 30
min. After being cooled at room temperature, the reaction mix-
ture was added to a silica gel column. Toluene and organic tin
compounds were removed by use of hexane as an eluent, then
the product was eluted with hexane–AcOEt (50:1), giving 20
(4.50 g, quant.) as an oil, [α]D ϩ9.30 (c 0.60, in CHCl3);
νmax(neat)/cmϪ1 1254, 1100, 835, 775; δH(CDCl3) 0.05 (6H, s),
0.90 (9H, s), 0.95 (3H, s), 1.02–1.17 (2H, m), 1.70 (3H, s), 1.26–
1.61 (7H, m), 1.96 (1H, dd, J 12.4, 3.0), 3.68 (2H, t, J 7.1), 4.57
(1H, s), 4.85 (1H, s), 4.87 (1H, d, J 10.4), 4.90 (1H, d, J 17.8),
5.81 (1H, dd, J 17.8, 10.4).
To a stirred solution of 20 (4.50 g) in THF (30 ml) was added
dropwise a 1.0 M solution of Bu4NF in THF (16.1 ml, 16.1
mmol), and stirring was continued for an additional 6 h. The
reaction mixture was quenched by addition of aqueous
NaHCO3, and extracted with ether. Removal of the solvent
followed by chromatography of the residue on silica gel gave the
title compound 21 (2.52 g, 90% from 19) as an oil (Found:
C, 80.39; H, 11.70. C14H24O requires C, 80.71; H, 11.61%);
νmax(neat)/cmϪ1 3332, 1375, 1045, 890; δH(CDCl3) 0.98 (3H, s),
1.12–1.65 (10H, m), 1.70 (3H, s), 1.97 (1H, dd, J 12.4, 2.4), 3.71
(2H, br s), 4.57 and 4.81 (1H, s each), 4.88 (1H, d, J 10.5), 4.89
(1H, d, J 17.8), 5.81 (1H, dd, J 17.8, 10.5); m/z (EI) 208 (Mϩ,
12%), 193 (34), 163 (59), 121 (60), 107 (100).
Method 2. To a stirred mixture of NaH (715 mg, 0.85 mmol)
in THF (20 ml) was added dropwise at 0 ЊC a solution of 15
(3.38 g, 13.5 mmol) in THF (20 ml). After being stirred for 30
min, HMPA (2.5 ml, 13.8 mmol) followed by methyl bromo-
acetate (2.2 ml, 16.7 mmol) was added dropwise, and the
reaction mixture was stirred for 4 h, during which the reaction
temperature rose slowly to room temperature. The reaction
mixture was quenched with aqueous NH4Cl, and extracted
with ether. Concentration of the extract gave an oil which was
filtered through a short silica gel column (hexane–ether, 3:1) to
give diester 16 (4.13 g, 95%) as an oil (Found: C, 66.69; H, 8.17.
C18H26O5 requires C, 67.06; H, 8.13%); νmax(neat)/cmϪ1 3085,
1747, 1739, 1714, 911, 862; δH(CDCl3) 1.05 (3H, s), 1.27 (3H, t,
J 7.0), 1.77 (3H, s), 2.04 (1H, br s), 2.06 (1H, dd, J 13.4, 3.2),
2.22 (1H, d, J 13.4), 2.43 (1H, dd, J 13.4, 3.2), 2.67 (1H, d,
J 13.4), 2.80 (1H, d, J 16.4), 3.09 (1H, d, J 16.4), 3.63 (3H, s),
4.23 (2H, q with fine splitting, J 7.0), 4.76 and 4.96 (1H, s each),
4.94 (1H, d, J 17.8), 5.00 (1H, d, J 10.8), 5.84 (1H, dd, J 17.8,
10.8).
A mixture of 16 (4.10 g, 12.7 mmol), DMSO (20 ml) and
aqueous NaOH (20%, 20 ml) was stirred at 50 ЊC for 12 h. After
cooling at 0 ЊC, the reaction mixture was acidified by addition
of aqueous HCl and saturated with brine. The product was
extracted with EtOAc, and the residue obtained by concen-
tration of the extracts was filtered through a short silica gel
column (EtOAc). Concentration of the eluate left an oil, which
was dissolved in ether (100 ml). The ethereal solution was
treated at 0 ЊC with a diazomethane–ether solution and con-
centrated. An oily residue was chromatographed on silica gel
(hexane–EtOAc, 12:1) to give the title compound 14a (2.73 g,
81% from 15).
(1S,2S,4R,5R)-2-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-iso-
propenyl-5-methyl-5-vinylcyclohexanol 18
To a stirred mixture of lithium aluminium hydride (507 mg,
13.4 mmol) in THF (25 ml) was added dropwise at Ϫ50 ЊC a
solution of 14a (3.37 g, 13.4 mmol) in THF (20 ml). The reac-
tion mixture was stirred for 2 h, quenched carefully by addition
of aqueous NH4Cl, and filtered. The solid was washed with
ether, and the combined filtrates were dried. Evaporation of the
solvent left an oil which was chromatographed on silica gel
(hexane–AcOEt, 1:1) to give diol 17 (2.46 g, 81%) as an oil, [α]D
ϩ41.6 (c 0.03, in CHCl3); νmax(neat)/cmϪ1 3355, 1446, 1006, 891;
δH(CDCl3) 1.17 (3H, s), 1.24–1.32 (2H, m), 1.60–2.04 (8H,
m), 1.72 (3H, s), 3.69 and 3.76 (1H, m each), 4.03 (1H, br s,
1/2H = 8.3‡), 4.62 and 4.82 (1H, s each), 4.90 (1H, d, J 17.3),
Methyl 2-[(1S,3R,4R)-3-isopropenyl-4-methyl-4-vinylcyclo-
hexyl]acetate 11
To a stirred solution of 21 (650 mg, 3.12 mmol) in acetone (10
ml) at 0 ЊC was added Jones reagent dropwise, prepared from
CrO3 (13.4 g), concentrated H2SO4 (12 ml) and water (25 ml),
until the orange colour of the reagent persisted for a few minutes.
‡ 1/2H Refers to the half band width, with values given in Hz.
786
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The excess reagent was destroyed by addition of a small
quantity of isopropyl alcohol. Saturated brine was added to the
reaction mixture, and the product was extracted with ether.
Removal of the solvent left an oil, which was dissolved in ether
(10 ml). To this ethereal solution, an ethereal diazomethane
solution was added at 0 ЊC dropwise, until the yellow colour of
diazomethane persisted. Concentration followed by chromatog-
raphy of the residue on silica gel gave the title compound 11
(539 mg, 73%) as an oil (Found: C, 75.98; H, 10.15. C15H24O2
requires C, 76.23; H, 10.23%); [α]D ϩ66.7 (c 0.54, CHCl3);
νmax(neat)/cmϪ1 1740, 1151, 1045, 891; δH(CDCl3) 0.98 (3H, s),
1.16–1.62 (6H, m), 1.69 (3H, s), 1.77–1.90 (1H, m), 2.00 (1H,
dd, J 12.8, 3.3), 2.26 (2H, d, J 7.0), 3.67 (3H, s), 4.56 and 4.81
(1H, s each), 4.87 (1H, d, J 10.5), 4.89 (1H, d, J 17.8), 5.80 (1H,
dd, J 17.8, 10.5); m/z (EI) 236 (Mϩ, 3%), 221 (10), 162 (97), 147
(52), 106 (100).
cation of the residue with MPLC (hexane–AcOEt, 1:1) gave
the title compound 31 (106 mg, 80%) as an oil (Found: C, 74.77;
H, 10.09. C20H32O3 requires C, 74.96; H, 10.06%); νmax(neat)/
cmϪ1 3446, 1734, 1372, 1181, 1083, 890; δH(CDCl3) 0.99 (3H, s),
1.21 and 1.22 (3H in total, a 1:2 ratio, s each), 1.27 and 1.28
(3H in total, a 1:2 ratio, s each), 1.30–1.81 (8H, m), 1.70 (3H,
s), 1.86–2.08 (4H, m), 2.21 and 2.27 (1H in total, a 2:1 ratio, s
each, OH), 2.35–2.46 (1H, m), 4.57 and 4.58 (1H in total, a 2:1
ratio, s each), 4.82 (1H, s), 4.89 (1H, d, J 17.8), 4.90 (1H, d,
J 10.5), 5.79 and 5.81 (1H in total, a 1:2 ratio, dd, J 17.8, 10.5
each); δH(C6D6) 1.01 and 1.04 (3H in total, a 1:2 ratio, s each),
1.03 and 1.05 (3H in total, a 1:2 ratio, s each), 1.06–1.68 (11H,
m), 1.11 and 1.14 (3H in total, a 2:1 ratio, s each), 1.74 and 1.75
(3H, in total, a 2:1 ratio, s each), 1.79–2.22 (2H, m), 2.32 and
2.35 (1H in total, s each, OH), 3.58 and 3.65 (1H in total, a 1:2
ratio, dd each, J 11.0, 3.4 and 11.5, 3.2, respectively), 4.69 and
4.73 (1H in total, a 1:2 ratio, s each), 4.92–4.99 (3H, m), 5.77
and 5.82 (1H in total, a 1:2 ratio, dd, J 17.8, 10.5 each); m/z
(EI) 320 (Mϩ, 4%), 162 (100), 158 (37), 147 (41), 107 (43).
Methyl 2-[(1S,3R,4R)-3-isopropenyl-4-methyl-4-vinylcyclo-
hexyl]-4-[(5R)-2,2,4,4-tetramethyl-1,3-dioxalan-5-yl]butanoate
29
Lobatrienolide 4
To a stirred solution of diisopropylamine (0.35 ml, 2.50 mmol)
in THF (1 ml) at 0 ЊC was added dropwise a 1.59 M solution of
BuLi in hexane (1.26 ml, 2.00 mmol). The reaction mixture was
stirred for 30 min, and then cooled at Ϫ78 ЊC. A solution of 11
(237 mg, 1.00 mmol) in THF (2 ml) followed by HMPA (1.6 ml)
was added dropwise, and stirring was continued at Ϫ78 to 0 ЊC
for 2 h. The reaction mixture was recooled at Ϫ78 ЊC, and a
solution of iodide 1212 (860 mg, 3.03 mmol) in THF (2 ml) was
added dropwise. After being stirred for 2 h, the reaction mixture
was quenched by addition of aqueous NH4Cl, and extracted
with ether. Removal of the solvent left the residue which was
chromatographed on silica gel (hexane–AcOEt, 12:1) to give
the title compound 29 (387 mg, 98%) as an oil (Found: C, 73.27;
H, 10.47. C24H40O4 requires C, 73.43; H, 10.27%); νmax(neat)/
cmϪ1 1733, 1371, 1217, 909; δH(CDCl3) 0.97 (3H, s), 1.07 (3H,
s), 1.14–1.70 (10H, m), 1.24 (3H, s), 1.33 (3H, s), 1.41 (3H, s),
1.69 (3H, s), 1.78–1.87 (1H, m), 1.95 (1H, dd, J 12.4, 3.3), 2.25
(1H, m), 3.69 (3H, s), 3.70 (1H, m), 4.56 and 4.81 (1H, s each),
4.87 (1H, d, J 17.8), 4.89 (1H, d, J 10.5), 5.79 (1H, dd, J 17.8,
10.5).
To a stirred solution of diisopropylamine (122 mg, 1.21 mmol)
in THF (2 ml) was added dropwise at Ϫ78 ЊC a 1.54 M solution
of BuLi in hexane (0.71 ml, 1.11 mmol). After being stirred for
20 min, a solution of 31 (155 mg, 0.48 mmol) in THF (2 ml) was
added dropwise and stirring was continued for an additional
1 h. To the reaction mixture was added over a period of 30 min
a solution of benzeneselenenyl chloride (230 mg, 1.20 mmol)
and HMPA (2 ml) in THF (2 ml). The reaction mixture was
stirred for 3 h, during which the reaction temperature rose to
Ϫ30 ЊC, quenched with aqueous NH4Cl, and extracted with
EtOAc. Removal of solvent left the residue which was purified
by MPLC (hexane–EtOAc, 2:1) to give the selenide (145 mg,
63%) as a mixture of diastereomers; δH(CDCl3) 0.97 and 0.98
(3H in total, ca. 9:1 ratio, s each), 1.21 and 1.24 (3H, s each),
1.32–1.49 (6H, m), 1.74–1.89 (3H, m), 1.75 (3H, s), 1.95–2.15
(2H, m), 2.17 (1H, m), 2.35 (1H, m), 4.06 and 4.20 (1H in total,
ca. 9:1 ratio, dd, J 12.0, 3.2 and 11.0, 2.2, respectively), 4.61
and 4.64 (1H in total, ca. 9:1 ratio, s each), 4.84–4.93 (3H,
m), 5.73 (1H, dd with fine splittings, J 16.8, 10.5 each), 7.3–7.7
(5H, m).
A solution of the selenide (144 mg, 0.3 mmol) in THF (6 ml)
was stirred and cooled at 0 ЊC as 30% H2O2 (3 drops) was added,
and the resulting solution was stirred for 12 h. The reaction
mixture was filtered through a short silica gel column, and the
filtrate was concentrated. Purification of the residue by MPLC
(hexane–EtOAc, 1:1) gave the title compound 4 (68 mg, 70%)
as an oil, [α]D26 ϩ81.0 (c 0.30, CHCl3) {lit., [α]D25 ϩ89.3 (CHCl3)7},
whose 1H NMR, IR and MS data were identical with those of
the authentic sample.7
Methyl (5R)-2-[(1S,3R,4R)-3-isopropenyl-4-methyl-4-vinyl-
cyclohexyl]-5,6-dihydroxy-6-methylheptanoate 30
A mixture of 29 (207 mg, 0.53 mmol), PPTS (20 mg) and
methanol (3 ml) was gently refluxed for 5 h. To the reaction
mixture, water (1 ml) and PPTS (10 mg) were added, and stir-
ring was continued for an additional 4 h. After being cooled to
room temperature, water was added, and the product was
extracted with AcOEt. Removal of the solvent left an oily resi-
due which was chromatographed on silica gel (hexane–AcOEt,
2:1) to give the title compound 30 (186 mg, quant.) as an oil
(Found: C, 71.28; H, 10.45. C21H36O4 requires C, 71.55;
H, 10.29%); νmax(neat)/cmϪ1 3411, 1734, 1374, 1157, 891;
δH(CDCl3) 0.96 (3H, s), 1.14 (3H, s), 1.16–1.52 (6H, m), 1.20
(3H, s), 1.57–1.70 (3H, m), 1.68 (3H, s), 1.80–1.88 (2H, m), 1.95
(1H, dd, J 12.4, 3.4), 2.05 (1H, s, OH), 2.17 and 2.35 (1H in
total, a 1:2 ratio, d, J 5.1, OH), 2.21–2.31 (1H, m), 3.31 and
3.38 (1H in total, a 1:2 ratio, ddd, J 10.5, 4.6, 2.2), 3.68 (3H, s),
4.56 and 4.81 (1H, s each), 4.86 (1H, d, J 17.8), 4.89 (1H, d,
J 10.5), 5.79 (1H, dd, J 17.8, 10.5).
Lobatrientriol 5
With DIBALH followed by NaBH4. To a stirred solution of 4
(67 mg, 0.21 mmol) in toluene (2 ml) was added at Ϫ78 ЊC a
0.95 M solution of DIBALH in toluene (0.66 ml, 0.63 mmol),
and stirring was continued for 3 h. The reaction mixture was
quenched by addition of phosphoric acid buffer solution (pH
7.0), and filtered through a short silica gel column with toluene.
Concentration of the filtrate left an oil, which was dissolved in
methanol (1 ml). The methanol solution was cooled at 0 ЊC, and
NaBH4 (18 mg, 0.46 mmol) was added portion by portion with
stirring. After being stirred for 2 h, most of the methanol was
removed, and aqueous HCl was added to the oily residue. The
product was extracted with EtOAc and the combined extracts
were concentrated. Purification of the residue with MPLC
(hexane–EtOAc, 1:2) gave 5 (55 mg, 80%) as an oil, [α]D26 ϩ14.9
(c 0.22, CHCl3) {lit., [α]D25 ϩ15.0 (c 0.20, CHCl3)5}, whose
spectral data (1H NMR and IR) were identical with those of
natural 5.5
(2R,5R)-2-[(1S,3R,4R)-3-Isopropenyl-4-methyl-4-vinylcyclo-
hexyl]-5-(1-hydroxy-1-methylethyl)-5-pentanolide (dihydro-
lobatrienolide) 31
A mixture of 30 (145 mg, 0.42 mmol), toluene-p-sulfonic acid
(ca. 10 mg) and CH2Cl2 (3 ml) was gently refluxed for 8 h. After
being cooled to room temperature, the reaction mixture was
washed with water. Removal of the solvent followed by purifi-
J. Chem. Soc., Perkin Trans. 1, 1999, 783–788
787

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4 J. Shin and W. Fenical, J. Org. Chem., 1991, 56, 3153.
5 M. Iwashima, H. Nagaoka, K. Kobayashi and Y. Yamada, Tetra-
hedron Lett., 1992, 33, 81.
6 H. Kosugi, O. Yamabe and M. Kato, J. Chem. Soc., Perkin Trans. 1,
1998, 217.
7 T. Kusumi, T. Hamada, M. O. Ishitsuka, I. Ohtani and H.
Kakisawa, J. Org. Chem., 1992, 57, 1033.
8 T. Hamada, T. Kusumi, M. O. Ishitsuka and H. Kakisawa, Chem.
Lett., 1992, 33.
9 M. Kato, V. P. Kamat, Y. Tooyama and A. Yoshikoshi, J. Org.
Chem., 1989, 54, 1536.
10 M. Kato, M. Watanabe, B. Vogler, B. Z. Awen, Y. Masuda,
Y. Tooyama and A. Yoshikoshi, J. Org. Chem., 1991, 56, 7071.
11 M. Watanabe, B. Z. Awen and M. Kato, J. Org. Chem., 1993, 58,
3923.
12 (a) G. Vidari, G. Lanfranchi, P. Sartori and S. Serra, Tetrahedron:
Asymmetry, 1995, 6, 2977; (b) R. J. Sterling and D. Barasch,
Tetrahedron Lett., 1987, 28, 1685.
13 (a) R. O. Hutchins, B. E. Maryanoff and C. J. Milewski, J. Am.
Chem. Soc., 1971, 93, 1793; (b) C. F. Lane, Synthesis, 1975, 135.
14 For the analogous reduction of the ketone group, see refs. 6 and 10.
15 B. M. Trost and G. S. Massiot, J. Am. Chem. Soc., 1997, 99, 4405.
16 For the use of sodium enolates in DMF, see (a) H. Kotake,
K. Inomata, S. Aoyama and H. Kinoshita, Chem. Lett., 1977, 73;
(b) P. Brownbridge, I. Fleming, A. Pearce and S. Warren, J. Chem.
Soc., Chem. Commun., 1976, 751.
With LiAlH4. A mixture of 4 (50 mg, 0.16 mmol) and lithium
aluminium hydride (28.8 mg, 0.76 mmol) in THF (1 ml) was
stirred at 0 ЊC for 4 h, and quenched by addition of aqueous
NH4Cl. Extraction with EtOAc followed by concentration of
the combined extracts left the residue which was purified by
MPLC (hexane–EtAOc, 1:2) gave 5 (6 mg, 11%) and 32a,b
(15 mg, 29%) as a separable mixture of diastereomers (ca. 2:1
ratio).
32a (Major): δH(CDCl3) 0.98, 1.17, 1.22 and 1.70 (3H, s
each), 1.13–2.45 (16H, m), 3.38 (1H, d, J 10.0), 3.58 (1H, dd,
J 10.7, 5.7), 3.72 (1H, dd, J 10.7, 4.9), 4.57 (1H, m), 4.82 (1H,
m), 4.87 (1H, m), 4.92 (1H, m), 5.80 (1H, dd, J 17.8, 10.5).
32b (Minor): δH(CDCl3): 0.98, 1.13, 1.21 and 1.67 (3H, s
each), 1.10–2.40 (15 H, m), 3.37 (1H, dd, J 10.2, 1.8), 3.64 (1H,
dd, J 10.8, 6.1), 3.70 (1H, dd, J 10.8, 4.2), 4.57 (1H, m), 4.81
(1H, m), 4.82 (1H, m), 4.90 (1H, m), 5.80 (1H, dd, J 17.8, 10.5).
References
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2 R. W. Dunlop and R. Wells, Aust. J. Chem., 1979, 32, 1345.
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Paper 8/09983I
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J. Chem. Soc., Perkin Trans. 1, 1999, 783–788