A practical total synthesis of plaunotol via highly Z-selective Wittig olefination of α-acetal ketones

Article abstract of DOI:10.1039/b001977l

Plaunotol (1), a known antiulcer drug, is the most important component of the Thai folk medicinal plant, Plau-noi, which has remarkable antipeptic ulcer activity. Recently, it was found that plaunotol (1) has antibacterial activity against Helicobacter priori, a causative agent in gastric ulcers and gastric adenocarcinoma, for example. In our investigation of the practical synthesis of 1, we have developed an efficient method for stereoselective synthesis of trisubstituted olefins via a Z-selective Wittig reaction. The olefination of readily available aliphatic α-acetal ketones with triphenylphosphonium salts in the presence of a potassium base and 18-crown-6 ether proceeded with excellent Z-selectivity. The Z-selective olefination provides a useful method for the construction of a range of trisubstituted olefin moieties; the practical and stereoselective total synthesis of plaunotol (1) was achieved via this Wittig reaction.

Full text of DOI:10.1039/b001977l

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A practical total synthesis of plaunotol via highly Z-selective
Wittig olefination of ꢀ-acetal ketones†1
Keiko Tago, Masami Arai and Hiroshi Kogen*
1
Exploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome,
Shinagawa-ku, Tokyo 140-8710, Japan
Received (in Cambridge, UK) 13th March 2000, Accepted 19th April 2000
Published on the Web 9th June 2000
Plaunotol (1), a known antiulcer drug, is the most important component of the Thai folk medicinal plant, Plau-noi,
which has remarkable antipeptic ulcer activity. Recently, it was found that plaunotol (1) has antibacterial activity
against Helicobacter pylori, a causative agent in gastric ulcers and gastric adenocarcinoma, for example. In our
investigation of the practical synthesis of 1, we have developed an efficient method for stereoselective synthesis of
trisubstituted olefins via a Z-selective Wittig reaction. The olefination of readily available aliphatic α-acetal ketones
with triphenylphosphonium salts in the presence of a potassium base and 18-crown-6 ether proceeded with excellent
Z-selectivity. The Z-selective olefination provides a useful method for the construction of a range of trisubstituted
olefin moieties; the practical and stereoselective total synthesis of plaunotol (1) was achieved via this Wittig reaction.
Introduction
Since it was first discovered in human stomach tissue in 1982,2
Helicobacter pylori (H. pylori) has been demonstrated to be a
major causative agent in gastritis,3 gastric ulcers,4 and duodenal
ulcers.5 The World Health Organization (WHO) recently
labeled H. pylori as a class 1 carcinogen6 since chronic infection
is known to be associated with the development of gastric
adenocarcinoma, one of the most common types of cancer
in humans. Thus, an effective antibiotic therapy to eliminate
H. pylori would reduce the risk of ulcer recurrence and gastric
cancers. Recently, Koga and co-workers8 reported that
plaunotol (1), a known antiulcer drug,7 has antibacterial
activity against H. pylori. Plaunotol (1), an acyclic diterpene
alcohol, is the most important component of Plau-noi, a Thai
folk medicine with remarkable activity against peptic ulcers.7 In
our recent studies to develop an antibacterial drug against
H. pylori, we have been investigating an efficient method for
the synthesis of 1 and its derivatives. Several groups7,9 have
succeeded in the total synthesis of 1, however, these methods
lack synthetic efficiency and/or stereoselectivity.
Retrosynthetic analysis is dictated by considerations of prac-
ticality with highly stereoselective trisubstituted olefination as
a key step (Scheme 1). Chemical advantages of this synthetic
route include the use of a common and inexpensive reagent,
commercially available geraniol (8), as the starting material
for both intermediates (3 and 4), and the highly stereoselective
Wittig reaction which provides trisubstituted Z-allylic alco-
hols. In addition, regioselective modification of each hydroxy
group of 1 for synthesis of various derivatives would be readily
Scheme 1
accessible using this route.1
In order to achieve highly stereoselective olefination, we
selectivity.10 To obtain even higher stereoselectivity, α-acetal
investigated Z-selective Wittig olefination of α-acetal ketones 3
ketone 3 was selected as a precursor to the trisubstituted
as a key step of the synthesis of 1 (Scheme 1). In 1980, Still et al.
Z-allylic alcohol because 3 was expected to have bulkier
achieved the Z-selective Wittig reaction of unstabilized ylides
α-substitutents than an α-alkoxyketone. It was also anticipated
and acyclic α-alkoxyketones to provide protected trisubstituted
that 3 would be more readily prepared than the corresponding
α-alkoxyketone, since various α-diethoxyketones can be pre-
allylic alcohols, and they reported that substitutions at the
α-carbon of the α-alkoxyketone tended to improve stereo-
pared from commercially available ethyl diethoxyacetate in two
steps.11–14
This article reports an effective synthetic route to plaunotol
(1) from geraniol (8) via a highly stereoselective trisubstituted
olefination.
† Spectroscopic and analytical data for compound 21 are available as
supplementary data. For direct electronic access see http://www.rsc.org/
suppdata/p1/b0/b001977l/
DOI: 10.1039/b001977l
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078
This journal is © The Royal Society of Chemistry 2000
2073

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Table 1 Wittig reaction between α-acetal ketone 3 and phosphonium salt 12 under various conditions
Run a
3 (R)
Base
Additive
Temp.
Time/h
Yield (%)b
Z:Ec
1
2
3
4
5
6
7
8
3a (Et)
3a (Et)
3a (Et)
3a (Et)
3a (Et)
3a (Et)
3b (Cy)
3c (Pri)
KHMDS
KHMDS
KHMDS
KHMDS
KH
HMPA
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
Ϫ78 ЊC to rt
16
1.5
2
16
16
16
16
16
52
82
84
95
4:1
13:1
16:1
38:1
61:1
41:1
>99:1
>99:1
Ϫ78 ЊC to 0 ЊC
Ϫ78 ЊC to Ϫ20 ЊC
Ϫ78 ЊC to Ϫ60 ЊC
Ϫ78 ЊC to Ϫ60 ЊC
Ϫ78 ЊC to Ϫ45 ЊC
Ϫ78 ЊC to rt
83
ButOK
89
ButOK
62d
63d
ButOK
Ϫ78 ЊC to rt
a One equiv. of 3, 1.5 equiv. of 15, 1.5 equiv. of base and 1.8 equiv. of additive were used in all runs except for run 1. For run 1, see ref. 10. b Isolated
yield. c Determined by 1H NMR analysis of the aldehyde proton after deprotection of acetal. d Aldehyde yield after deprotection of acetal (2 steps).
Results and discussion
The synthesis of two precursors for the Wittig reaction is shown
in Schemes 2 and 3. O-TBDMS protected phosphonium iodide
Scheme 311,12 Reagents and conditions: i, Na, EtOAc, reflux; ii, NaH-
MDS, EtOAc, THF, Ϫ78 ЊC to rt; iii, 5, RONa, ROH, 0 ЊC to rt; iii,
KOH, H2O, EtOH, reflux.
Scheme 2 Reagents and conditions: i, Ac2O, Py, THF, 0 ЊC to rt,
In order to further evaluate the Z-selectivity of this Wittig
reaction, we explored a range of α-acetal ketones and phos-
phonium salts as summarized in Scheme 4. All of the α-acetal
quant.; ii, MCPBA, CH2Cl2, 81%; iii, HIO4, H2O, THF, 0 ЊC, 89%;
iv, NaBH4, EtOH, 0 ЊC to rt, 67%; v, p-TsCl, Py, 0 ЊC to rt; vi, NaI,
acetone, rt, 89% (2 steps); vii, K2CO3, MeOH, rt, 92%; viii, TBDMSCl,
imidazole, 0 ЊC, 93%; ix, PPh3, benzene, reflux, 96%.
15 was prepared from geraniol (8) according to the literature
procedure employed for the synthesis of the O-benzyl derivative
(Scheme 2).9d The second precursor, α-acetal ketone 3a, was
easily prepared from geranyl bromide (5) and ethyl diethoxy-
acetoacetate (17a), which was prepared from commercially
available ethyl diethoxyacetate (16a) (Scheme 3).11,12 The
bulkier α-acetal ketones 3b and 3c were also synthesized simi-
larly from 16b and 16c respectively.
The results of the Z-selective Wittig reaction between phos-
phonium salt 15 and α-acetal ketones 3 are summarized in
Table 1. The combined use of KHMDS and HMPA, a method
which was reported by Still et al.,10 gave poor results in
terms of both yield and stereoselectivity (run 1). However,
high Z-selectivity and excellent yield were observed (run
2) using 18-crown-6 ether (18-c-6) as an additive instead
of HMPA. The additive for trapping the potassium cation
was necessary because ylide formation scarcely occurred
without 18-c-6. A lower reaction temperature increased the
Z-selectivity (runs 2–4), and the use of other potassium
bases gave similar results (runs 5 and 6). As we anticipated,
the bulkier α-acetal ketones (3b and 3c) exclusively yielded
Z-olefins, even when the reaction was performed at room
temperature (runs 7 and 8).
Scheme 4
ketones except for 20a were readily prepared by addition of the
corresponding Grignard reagent to N-(diethylacetyl)piper-
idine.13,14 As shown in Table 2, olefination of α-acetal ketones
with triphenylphosphine ylides proceeded with excellent
Z-selectivity, except for runs 13 and 14. The Wittig reaction
between aromatic α-acetal ketone (20d) and triphenylphos-
phonium salts produced (E)-olefins predominately (runs 13 and
14).16 To summarize, this Z-selective olefination of readily
available aliphatic α-acetal ketones provides a useful method
for the synthesis of natural products consisting of a range of
trisubstituted olefin moieties.
2074
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078

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Table 2 The results of the Wittig reaction shown in Scheme 4
Method of
Run a
20 (R1)
19 (R2)
Product
deprotectionb
Yield (%)c
Z:Ed
1
20a (geranyl)
19a ((CH2)4CH3)
19b (Bui)
21aa
21ab
21ac
21ad
A
A
A
A
56
44
62
45
95:5
93:7
83:17
95:5
2
3e
4
19c ((CH2)2OBn)
᎐
19d ((CH2)2C᎐CH)
᎐
5
6
7
8
20b ((CH2)4CH3)
20c (Bui)
19a ((CH2)4CH3)
19b (Bui)
21ba
21bb
21bc
21bd
A
A
A
A
51
50
60
70
91:9
93:7
95:5
92:8
19c ((CH2)2OBn)
᎐
19d ((CH2)2C᎐CH)
᎐
9
10
11
12
19a ((CH2)4CH3)
19b (Bui)
21ca
21cb
21cc
21cd
B
B
B
B
48
46
51
49
94:6
93:7
97:3
98:2
19c ((CH2)2OBn)
᎐
19d ((CH2)2C᎐CH)
᎐
13f
14f
20d (Ph)
19a ((CH2)4CH3)
19b (Bui)
21da
21db
A
A
Quant.
93
18:82
28:72
a See the corresponding footnotes in Table 1. b Method A; Amberlyst 15, aqueous acetone, Method B; 50% aqueous AcOH, THF. c Isolated yields of
21 (2 steps). d Determined by 1H NMR analysis of 21. e For 3 days. f At Ϫ78 ЊC.
1
Finally, the total synthesis of plaunotol (1) was achieved
by using the (Z)-olefin 18a as shown in Scheme 5. Cleavage
were used as received. H NMR and 13C NMR spectra were
recorded on a JEOL JNM-EX-270 or Varian 400 spectrometer.
The following abbreviations were used to explain the multiplici-
ties: s = singlet, d = doublet, t = triplet, q = quartet, m = multi-
plet. In NMR spectral lists, chemical shifts that are assigned to
the enol form are marked with an asterisk. Infrared spectra
were recorded on a JASCO FT-IR-8900 spectrometer. Mass
spectra were obtained on a JEOL HX-100, an SX-102A or a
JMS-AX-505H mass spectrometer. Analytical TLC was per-
formed on 0.25 mm pre-coated Merck silica gel 60 F254 plates.
Flash column chromatography was performed on Merck silica
gel 60 (230–400 mesh).
(E,E)-3,7-Dimethyl-6,7-epoxyoct-2-enyl acetate 9
A solution of m-chloroperbenzoic acid (11.2 g, 51.9 mmol) in
CH2Cl2 (100 mL) was added to a solution of geranyl acetate
(9.3 g, 47.4 mmol) in CH2Cl2 (200 mL) at 0 ЊC and the reaction
mixture was stirred for 4 h at room temperature. Calcium
hydroxide (15.0 g, 202 mmol) was added to the solution, then
the mixture was stirred at room temperature for 40 min. After
filtration, the residue was washed with ether and the filtrate was
concentrated in vacuo. The crude product was distilled under
reduced pressure (3 mmHg, bp 89 ЊC) to give 8.1 g of
epoxide 9 as a colorless liquid (81% yield): IR (film) νmax 2963,
2928, 1740, 1450, 1379, 1368, 1234, 1122, 1024 cmϪ1; 1H NMR
(270 MHz, CDCl3) δ 1.26 (3 H, s), 1.31 (3 H, s), 1.63–1.71 (2 H,
m), 1.73 (3 H, s), 2.05 (3 H, s), 2.10–2.30 (2 H, m), 2.70 (1 H, t,
J 6.2 Hz), 4.60 (2 H, d, J 7.2 Hz), 5.39 (1 H, t, J 7.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 16.5, 18.8, 21.0, 24.8, 27.1, 36.2,
58.4, 61.2, 63.9, 118.9, 141.2, 171.0; HRMS (EI) calc. for
C10H17O (M Ϫ OAc)ϩ: 153.1279; found 153.1276.
Scheme 5 Reagents and conditions: i, AcOH–H2O (1:1), THF, rt; ii,
NaBH4, EtOH, 0 ЊC, 90% (2 steps); iii, cat. p-TsOH, MeOH, rt, 93%.
of the acetal group in 18a under acidic conditions gave an
α,β-unsaturated aldehyde. We were concerned that the resulting
(Z)-α,β-unsaturated aldehyde would isomerize to the (E)-α,β-
unsaturated aldehyde; thus the (Z)-aldehyde was reduced
immediately with sodium borohydride to give the allylic alcohol
22 as the sole product in 90% yield (2 steps). Finally, removal of
the O-TBDMS group in 22 with a catalytic amount of p-TsOH
in methanol provided plaunotol (1) in 98% yield. The spectro-
scopic data of synthetic product 1 (1H NMR and 13C NMR)
were identical with those of an authentic sample.
In conclusion, we have developed a highly Z-selective tri-
substituted olefination of aliphatic α-acetal ketones in the pres-
ence of a potassium base and 18-c-6, and using this Wittig
reaction as the key step, a stereoselective and practical total
synthesis of plaunotol (1) was achieved. Furthermore, over 10
grams of pure 1 were readily obtained and the two hydroxy
groups of 1 were modified independently via this route.
(E)-6-Acetoxy-4-methylhex-4-en-1-al 10
A solution of periodic acid dihydrate (44.9 g, 0.20 mol) in water
(180 mL) was added to a solution of epoxide 9 (38.0 g, 0.18
mol) in THF (300 mL) at 0 ЊC. After stirring for 30 min, brine
was added, and the organic material was extracted with ether.
The combined organic extracts were washed with saturated
aqueous NaHCO3 and brine, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. The residue was distilled
under reduced pressure (3 mmHg, bp 84–86 ЊC) to give 27.8
g of aldehyde 10 as a colorless liquid (71% yield): IR (film) νmax
2943, 2922, 2833, 2727, 1733, 1673, 1445, 1386, 1368, 1236,
Experimental
Unless otherwise noted, all reactions were carried out in oven-
dried glassware under a nitrogen atmosphere. Tetrahydrofuran
(THF) was distilled from sodium metal–benzophenone ketyl.
Dichloromethane (CH2Cl2) was distilled from calcium hydride.
All other dry solvents were purchased from Aldrich in Sure-
SealTM containers. All other commercially obtained reagents
1
1025, 956 cmϪ1; H NMR (270 MHz, CDCl3) δ 1.73 (3 H, d,
J 1.2 Hz), 2.05 (3 H, s), 2.38 (2 H, t, J 7.3 Hz), 2.58 (2 H, td,
J 7.3, 1.3 Hz), 4.51 (2 H, d, J 7.0 Hz), 5.36 (1 H, td, J 7.0, 1.2
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078
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Hz), 9.78 (1 H, t, J 1.3 Hz); 13C NMR (100 MHz,
CDCl3) δ 16.6, 21.0, 31.5, 41.7, 61.1, 119.3, 140.0, 171.0, 201.6;
HRMS (EI) calc. for C7H11O (M Ϫ OAc)ϩ: 152.0837; found
152.0824.
(E)-1-tert-Butyldimethylsilyloxy-6-iodo-3-methylhex-2-ene 14
TBDMSCl (4.4 g, 27.5 mmol) was added to a solution of
alcohol 13 (6.6 g, 27.5 mmol) and imidazole (2.1 g, 30.2 mmol)
in DMF (30 mL) at 0 ЊC. After stirring for 1 h, a saturated
aqueous NaHCO3 solution was added, the organic material was
extracted with ethyl acetate, and the combined organic extracts
were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. Silica gel flash chromato-
graphy (n-hexane–ethyl acetate 9:1) provided 9.09 g (93%) of
silyl ether 14 as a colorless oil: IR (film) νmax 2955, 2929, 2896,
2886, 2857, 1671, 1472, 1463, 1445, 1383, 1361, 1255, 1218,
1167, 1101, 1066, 1006, 836 cmϪ1; 1H NMR (270 MHz, CDCl3)
δ 0.07 (6 H, s), 0.91 (9 H, s), 1.62 (3 H, d, J 1.1 Hz), 1.91–2.00
(2 H, m), 2.10 (2 H, t, J 7.1 Hz), 3.16 (2 H, t, J 6.9 Hz), 4.19
(2 H, d, J 6.1 Hz), 5.36 (1 H, td, J 6.1, 1.1 Hz); 13C NMR
(100 MHz, CDCl3) δ Ϫ5.1, 6.3, 16.3, 18.4, 26.0, 31.4, 40.0, 60.2,
125.8, 134.8; HRMS (EI) calc. for C9H18SiI (M Ϫ C4H9)ϩ:
297.0172; found 297.0160.
(E)-6-Acetoxy-4-methylhex-4-en-1-ol 11
Sodium borohydride (6.0 g, 0.16 mol) was added portionwise to
a solution of aldehyde 10 (27.0 g, 0.16 mol) in ethanol (300 mL)
at 0 ЊC, the reaction mixture was stirred for 2 h. Acetone and
water were added, the organic material was extracted with
ether, and the combined organic extracts were washed with 1 M
HCl solution and brine, dried over anhydrous MgSO4, and con-
centrated in vacuo after filtration. Purification by silica gel flash
chromatography (n-hexane–ethyl acetate 3:1) furnished 18.3 g
(67%) of alcohol 11 as a colorless oil: IR (film) νmax 3411, 2943,
2876, 1739, 1671, 1445, 1382, 1368, 1237, 1060, 1024, 954 cmϪ1
;
1H NMR (270 MHz, CDCl3) δ 1.40 (1 H, br, D2O exchange-
able), 1.72 (3 H, d, J 1.3 Hz), 1.66–1.76 (2H, m), 2.06 (3 H, s),
2.13 (2 H, t, J 7.6 Hz), 3.65 (2 H, t, J 6.3, 1.3 Hz), 4.59 (2 H, d,
J 7.2 Hz), 5.38 (1 H, td, J 7.2, 1.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 16.4, 21.0, 30.5, 35.8, 61.3, 62.5, 118.7, 141.9, 171.2;
HRMS (EI) calc. for C9H17O3 (M ϩ H)ϩ: 173.1178; found
173.1183.
(E)-(6-tert-Butyldimethylsilyloxy-4-methylhex-4-enyl)triphenyl-
phosphonium iodide 15
A solution of silyl ether 14 (9.1 g, 25.6 mmol) and triphenyl-
phosphine (20.1 g, 76.8 mmol) in benzene (50 mL) was refluxed
for 8 h. The solvent was removed in vacuo and the resulting
residue was recrystallized with ether to afford 15.1 g (96%) of
phosphonium salt 15 as colorless prisms: mp 135–136 ЊC; IR
(KBr) νmax 2953, 2927, 2855, 1668, 1587, 1484, 1472, 1462,
(E)-1-Acetoxy-6-iodo-3-methylhex-2-ene 12
A solution of toluene-p-sulfonyl chloride (30.5 g, 0.16 mol) in
CH2Cl2 (200 mL) was added dropwise to a solution of alcohol
11 (18.3 g, 0.11 mol) in pyridine (100 mL) at 0 ЊC, then the
reaction mixture was stirred for 7 h at room temperature. The
reaction mixture was cooled to 0 ЊC, then water was added, and
the organic material was extracted with AcOEt. The combined
organic layers were washed with a 1 M aqueous HCl solution, a
saturated aqueous solution of NaHCO3, and brine, dried over
anhydrous MgSO4, and concentrated in vacuo after filtration to
provide the crude tosylate. Sodium iodide (79.8 g, 0.53 mol) was
added to a solution of the tosylate in acetone (300 mL), then
the reaction mixture was stirred for 24 h at room temperature.
The acetone was removed under reduced pressure, a 5% solu-
tion of Na2S2O3 was added to the residue. The organic material
was extracted with n-hexane, and the combined organic extracts
were washed with brine, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. Purification by silica gel
flash chromatography (n-hexane–ethyl acetate 5:1) furnished
26.6 g (89%) of iodide 12 as a colorless oil: IR (film) νmax 2938,
1438, 1253, 1112, 1060, 1033 cmϪ1 1H NMR (270 MHz,
;
CDCl3) δ 0.03 (6 H, s, SiCH3 × 2), 0.85 (9 H, s, C(CH3)3), 1.52
(3 H, d, J 1.2 Hz, CH᎐CCH ), 1.72–1.88 (2 H, m, CH CH -
᎐
3
2
2
CH ), 2.36 (2 H, t, J 7.3 Hz, CH CH C᎐C), 3.64–3.75 (2 H, m,
᎐
2
2
2
CH2PPh3), 4.13 (2 H, d, J 6.4 Hz, CH2OTBDMS), 5.26 (1 H, td,
J 6.3, 1.2 Hz, CH᎐C), 7.68–7.75 (6 H, m, Ph), 7.79–7.93 (9 H,
᎐
m, Ph); 13C NMR (100 MHz, CDCl3) δ Ϫ5.1, 16.4, 18.4, 20.4,
22.4 (d, J 49 Hz), 26.0, 39.2 (d, J 15 Hz), 60.0, 118.2 (d, J 85
Hz), 126.4, 130.6 (d, J 12 Hz), 133.7 (d, J 9 Hz), 134.9, 135.2;
anal. calc. for C31H42OSiPI: C, 60.38; H, 6.87. Found: C, 60.19;
H, 6.72%.
Bis(cyclohexyloxy)acetic acid ethyl ester 16b
Using a known procedure,11 16b was obtained in 49% yield as a
colorless oil (bp 138–142 ЊC; 3 mmHg): IR (film) νmax 2979,
2935, 2858, 1758, 1742, 1466, 1451, 1381, 1371, 1358, 1342,
1284, 1262, 1247, 1205, 1193, 1159, 1114, 1095, 1065, 1049,
1024, 973, 926, 890, 862, 846 cmϪ1 1H NMR (270 MHz,
;
2852, 1739, 1671, 1444, 1381, 1367, 1233, 1169, 1023, 955 cmϪ1
;
1H NMR (270 MHz, CDCl3) δ 1.71 (3 H, d, J 1.2 Hz), 1.90–2.00
(2 H, m), 2.06 (3 H, s), 2.15 (2 H, t, J 7.3 Hz), 3.16 (2 H, t, J 6.9
Hz), 4.59 (2 H, d, J 7.1 Hz), 5.40 (1 H, td, J 7.1, 1.2 Hz); 13C
NMR (100 MHz, CDCl3) δ 6.1, 16.5, 21.0, 31.2, 39.9, 61.2,
119.7, 140.1, 171.0; HRMS (EI) calc. for C9H15O2I (M)ϩ:
282.0117; found 282.0101.
CDCl3) δ 1.17–1.57 (15 H, m), 1.73–1.82 (4 H, m), 1.82–1.90
(4 H, m), 3.56–3.66 (2 H, m), 4.24 (2 H, q, J 7.2 Hz), 5.00 (1 H,
s); 13C NMR (100 MHz, CDCl3) δ 14.1, 24.1, 24.2, 25.6, 32.4,
32.9, 61.2, 75.5, 95.5, 168.8; HRMS (FAB) calc. for C16H29O4
(M ϩ H)ϩ: 285.2066; found 285.2047.
Bis(isopropyloxy)acetic acid ethyl ester 16c
Using a known procedure,11 16c was obtained in 46% yield as
a colorless oil (bp 103–105 ЊC; 22 mmHg): IR (film) νmax
2977, 2936, 2907, 2877, 1758, 1743, 1467, 1383, 1371, 1323,
(E)-6-Iodo-3-methylhex-2-en-1-ol 13
Potassium bicarbonate (2.6 g, 7.2 mmol) was added to a solu-
tion of iodide 12 (24.6 g, 94.4 mmol) in methanol (200 mL),
then stirred for 2 h. Water was added and the organic material
was extracted with ether. The combined organic layers were
washed with a 1 M aqueous HCl solution, a saturated aqueous
solution of NaHCO3 solution, and brine, dried over anhydrous
MgSO4 and concentrated in vacuo after filtration. Silica gel
flash chromatography (n-hexane–ethyl acetate 4:1) provided
20.8 g (92%) of alcohol 13 as a colorless oil: IR (film) νmax 3333,
2934, 1667, 1441, 1428, 1382, 1218, 1167, 1001 cmϪ1; 1H NMR
(270 MHz, CDCl3) δ 1.68 (3 H, d, J 1.1 Hz), 1.90–2.05 (2 H, m),
2.14 (2 H, t, J 7.3 Hz), 3.17 (2 H, t, J 6.8 Hz), 4.16 (2 H, d, J 6.7
Hz), 5.47 (1 H, td, J 6.7, 1.1 Hz); 13C NMR (100 MHz, CDCl3)
δ 6.1, 16.2, 31.3, 39.9, 59.3, 124.7, 137.6; HRMS (EI) calc. for
C7H13OI (M)ϩ: 240.0011; found 240.0008.
1285, 1208, 1183, 1108, 1046, 964, 912, 851, 790, 460 cmϪ1
;
1H NMR (270 MHz, CDCl3) δ 1.20 (6 H, d, J 6.1 Hz), 1.24
(6 H, d, J 6.1 Hz), 1.31 (3 H, t, J 7.1 Hz), 3.88–4.02 (2 H,
m), 4.25 (2 H, q, J 7.1 Hz), 4.92 (1 H, s); 13C NMR (100
MHz, CDCl3) δ 14.1, 22.3, 22.9, 61.3, 69.7, 95.9, 168.7;
HRMS (EI) calc. for C10H21O4 (M ϩ H)ϩ: 205.1440; found
205.1455.
4,4-Bis(cyclohexyloxy)-3-oxobutyric acid ethyl ester 17b
1.0 M NaHMDS solution in THF (37 mL, 37 mmol) was added
dropwise to a solution of ethyl acetate (3.6 mL, 37 mmol) in
THF (70 mL) at Ϫ78 ЊC. After stirring for 30 min at the same
temperature, a solution of 16b in THF (30 mL) was added to
2076
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078

View Article Online
the reaction mixture, then the stirring was continued at rt for
3 h. A saturated aqueous NH4Cl solution was mixed in, the
organic material was extracted with ether, and the combined
organic extracts were washed with water and brine, dried over
anhydrous MgSO4, and concentrated in vacuo after filtration.
The crude product was purified by flash column chromato-
graphy (hexane–ethyl acetate 20:1) to afford 5.53 g (67%) of
17b as a colorless oil: IR (film) νmax 2980, 2935, 2859, 1754,
1730, 1659, 1641, 1466, 1451, 1405, 1390, 1367, 1319, 1303,
1260, 1223, 1195, 1157, 1112, 1097, 1039, 970, 927, 889, 846,
812 cmϪ1; 1H NMR (270 MHz, CDCl3) δ 1.15–1.55 (15 H, m),
1.65–1.95 (8 H, m), 3.40–3.60 (2 H, m), 3.65 (1.8 H, s), 4.19
(2 H, q, J 7.2 Hz), 4.77 (1 H, s), 5.04* (0.1 H, s), 5.48* (0.1 H, s);
13C NMR (100 MHz, CDCl3) δ 14.15, 14.24*, 23.8, 24.0, 25.5,
32.2, 32.5*, 32.9, 33.1*, 43.2, 60.3*, 61.2, 74.8*, 76.0, 89.7*,
95.6*, 99.5, 167.5, 173.4*, 199.2; HRMS (FAB) calc. for
C18H30KO5 (M ϩ K)ϩ: 365.1730; found 365.1759.
in 10 mL of THF at room temperature. After mixing for 1 h at
this temperature, and then cooling to Ϫ78 ЊC, a solution of
diethoxyketone 3a (285 mg, 1.0 mmol) in THF was added, and
stirring was continued for another 15 min. The reaction mixture
warmed up to Ϫ45 ЊC, the stirring was continued for 24 h.
Next, a saturated aqueous NH4Cl solution was mixed in, the
organic material was extracted with n-hexane, and the com-
bined organic extracts were washed with a 1 M solution of
Na2S2O3 and water, dried over anhydrous MgSO4, and concen-
trated in vacuo after filtration. Silica gel flash chromatography
(n-hexane–ethyl acetate 40:1) provided 443 mg (89%) of 18a as
a colorless oil: IR (film) νmax 2958, 2929, 2858, 1671, 1445, 1382,
1255, 1109, 1064, 1005 cmϪ1
δ 0.07 (6 H, s, SiCH3 × 2), 0.91 (9 H, s, C(CH3)3), 1.22 (6 H, t,
J 7.0 Hz, CH CH O), 1.60 (6 H, s, CH C᎐C × 2), 1.63 (3 H,
;
1H NMR (270 MHz, CDCl3)
᎐
3
3
2
s, CH C᎐C), 1.68 (3 H, s, CH C᎐C), 1.91–2.00 (10 H, m,
᎐
᎐
3
3
CH C᎐C × 5), 2.20–2.34 (2 H, m, CH ᎐C), 3.38–3.50 (2 H,
᎐
᎐
2
2
m, OCH2CH3), 3.55–3.68 (2 H, m, OCH2CH3), 4.19 (2 H, d,
4,4-Bis(isopropyloxy)-3-oxobutyric acid ethyl ester 17c
J 6.3 Hz, CH OTBDMS), 5.04–5.19 (3 H, m, CH᎐C × 2
᎐
2
and CH(OEt) ), 5.28–5.42 (2 H, m, CH᎐C × 2); 13C NMR
᎐
2
Using a similar procedure to that described above, compound
17c was obtained in 79% yield from 16c as a colorless oil (bp
98–100 ЊC; 4 mmHg): IR (film) νmax 2977, 2936, 2907, 2879,
1754, 1731, 1660, 1468, 1406, 1383, 1371, 1322, 1306, 1262,
1226, 1183, 1141, 1121, 1101, 1037, 964, 944, 850, 821, 639, 574
(100 MHz, CDCl3) δ –5.0, 15.2, 15.3, 16.1, 16.4, 17.7, 18.5,
25.7, 25.8, 26.0, 26.8, 27.5, 31.0, 39.8, 60.3, 62.1, 100.4,
124.5, 124.6, 124.8, 129.1, 131.2, 134.8, 136.4, 137.0; anal.
calc. for C30H56O3Si: C, 73.11; H, 11.45. Found: C, 72.87; H,
11.42%.
1
cmϪ1; H NMR (270 MHz, CDCl3) δ 1.17 (6 H, d, J 6.2 Hz),
1.23 (6 H, d, J 6.2 Hz), 1.27 (3 H, t, J 7.2 Hz), 3.63 (1.8 H, s),
3.81–3.95 (2 H, m), 4.19 (2 H, q, J 7.2 Hz), 4.69 (1 H, s),
4.96 (0.1 H, s), 5.46* (0.1 H, s); 13C NMR (100 MHz, CDCl3)
δ 14.1, 14.2*, 22.2, 22.4*, 22.9, 23.0*, 43.2, 43.4*, 60.4*, 61.2,
69.1*, 70.3, 89.8, 96.0*, 99.8*, 167.5, 172.7*, 173.0*, 199.1;
HRMS (EI) calc. for C10H17O4 (M Ϫ OEt)ϩ: 201.1127; found
201.1135.
(E,Z,E)-1-tert-Butyldimethylsilyloxy-7-hydroxymethyl-3,11,15-
trimethylhexadecatetra-2,6,10,14-ene 22
Aqueous acetic acid (50%, 2 mL) was added to a solution of
acetal 18a (93 mg, 0.19 mmol) in THF (3 mL) at room tem-
perature and the reaction mixture was stirred for 5 min at
this temperature. Water was added, the organic material was
extracted with n-hexane, and the combined organic extracts
were washed with a saturated aqueous NaHCO3 solution and
brine, dried over anhydrous MgSO4 and concentrated in
vacuo after filtration. The resulting residue was dissolved in
ethanol (2 mL) and then cooled to 0 ЊC. Sodium borohydride
(14 mg, 0.37 mmol) was added to this solution and the
reaction mixture was stirred for 30 min at this temperature.
Acetone and water were added, the organic material was
extracted with n-hexane, and the combined organic extracts
were washed with water, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. Purification by silica gel
flash chromatography (n-hexane–ethyl acetate 7:1) furnished
55 mg (90%) of alcohol 22 as a colorless oil: IR (film) νmax
3359, 2957, 2928, 2857, 1670, 1472, 1463, 1446, 1382, 1255,
1,1-Bis(cyclohexyloxy)-6,10-dimethylundeca-5,9-dien-2-one 3b
Using a known procedure,12 compound 3b was obtained in
67% yield from 17b as a colorless oil: IR (film) νmax 2934, 2858,
1728, 1450, 1407, 1376, 1357, 1341, 1310, 1270, 1262, 1247,
1193, 1159, 1112, 1094, 1093, 1061, 1049, 1037, 1025, 965, 926,
889, 846 cmϪ1; 1H NMR (270 MHz, CDCl3) δ 1.10–2.10 (33 H,
m, CH × 3, CH × 10, and CH C᎐C × 2), 2.26 (2 H, q, J 7.4
᎐
2
3
2
Hz, CH2CH2CO), 2.65 (2 H, t, J 7.4 Hz, CH2CH2CO), 3.47–
3.56 (2 H, m, (CH2)2CHO × 2), 4.66 (1 H, s, CH(OCy)2),
5.08–5.13 (2 H, m, CH᎐C × 2); 13C NMR (100 MHz, CDCl3)
᎐
δ 16.0, 17.7, 21.8, 23.9, 24.1, 25.6, 25.7, 26.7, 32.4, 33.0, 36.1,
39.7, 75.8, 100.5, 123.0, 123.1, 124.3, 131.4, 136.0, 207.0;
HRMS (FAB) calc. for C25H42O3 (M)ϩ: 390.3134; found
390.3161.
1
1109, 1064, 1006 cmϪ1; H NMR (270 MHz, CDCl3) δ 0.07
(6 H, s, SiCH3 × 2), 0.91 (9 H, s, C(CH3)3), 1.60 (6 H, s,
1,1-Bis(isopropyloxy)-6,10-dimethylundeca-5,9-dien-2-one 3c
CH C᎐C × 2), 1.64 (3 H, s, CH C᎐C), 1.68 (3 H, s, CH C᎐C),
᎐
᎐
᎐
3
3
3
Using a known procedure,12 compound 3c was obtained in
45% yield from 17c as a colorless oil (bp 136–140 ЊC; 4 mmHg):
IR (film) νmax 2975, 2929, 2732, 1728, 1681, 1466, 1455, 1408,
1.92–2.25 (12 H, m, CH C᎐C × 6), 4.10 (2 H, d, J 4.9 Hz,
᎐
2
CH2OH), 4.18 (2 H, d, J 6.5 Hz, CH2OTBDMS), 5.04–5.17
(2 H, m, CH᎐C × 2), 5.23–5.33 (2 H, m, CH᎐C × 2); 13C NMR
᎐
᎐
1
1381, 1321, 1311, 1235, 1183, 1142, 672, 449 cmϪ1; H NMR
(100 MHz, CDCl3) δ Ϫ5.2, 16.1, 16.5, 17.7, 18.5, 25.7, 25.9,
26.1, 26.8, 27.0, 35.1, 39.5, 39.7, 60.2, 60.3, 124.1, 124.4, 125.0,
127.9, 131.3, 135.4, 136.6, 138.9; HRMS (FAB) calc. for
C26H48O2SiK (M ϩ K)ϩ 459.3061, found 459.3053. Anal. calc.
for C26H48O2Si: C, 74.22; H, 11.50. Found: C, 74.47; H, 11.64%.
(270 MHz, CDCl3) δ 1.15 (6 H, d, J 5.9 Hz, (CH3)2CH), 1.23
(6 H, d, J 6.6 Hz, (CH ) CH), 1.59 (3 H, s, CH C᎐C), 1.61 (3 H,
᎐
3
3
2
s, CH C᎐C), 1.68 (3 H, s, CH C᎐C), 1.91–2.00 (2 H, m,
᎐
᎐
3
3
CH C᎐C), 2.00–2.11 (2 H, m, CH C᎐C), 2.25 (2 H, q, J 7.3 Hz,
᎐
᎐
2
2
CH2CH2CO), 2.63 (2 H, t, J 7.3 Hz, CH2CH2CO), 3.78–3.92
(2 H, m, OCH(CH3)2 × 2), 4.58 (1 H, s, CH(OPri)2), 5.04–5.15
Plaunotol 1
(2 H, m, CH᎐C × 2); 13C NMR (100 MHz, CDCl3) δ 16.0, 17.7,
᎐
Toluene-p-sulfonic acid monohydrate (2 mg, 0.01 mmol) was
added to a solution of alcohol 22 (53 mg, 0.13 mmol) in meth-
anol (5 mL) and the reaction mixture was stirred for 15 min at
room temperature. Water was added, the organic material was
extracted with n-hexane, and the combined organic extracts
were washed with water, dried over anhydrous MgSO4, and
concentrated in vacuo after filtration. Flash chromatography
(n-hexane–ethyl acetate 3:2) provided 38 mg (93%) of
plaunotol 1 as a colorless oil: IR (film) νmax 3322, 2966, 2923,
21.8, 22.3, 22.9, 25.7, 26.7, 36.0, 39.7, 100.8, 123.0, 124.3, 131.3,
136.0, 206.8; HRMS (FAB) calc. for C19H35O3 (M ϩ H)ϩ:
311.2586; found 311.2565.
(E,Z,E)-1-tert-Butyldimethylsilyloxy-7-diethoxymethyl-3,11,15-
trimethylhexadecatetra-2,6,10,14-ene 18a
1.0 M Potassium tert-butoxide in THF solution (1.5 mL, 1.5
mmol) was added to a solution of phosphonium salt 15 (925
mg, 1.5 mmol) and 18-crown-6–CH3CN (550 mg, 1.8 mmol)
2857, 1669, 1445, 1381, 1006 cmϪ1
;
1H NMR (270 MHz,
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078
2077

View Article Online
CDCl ) δ 1.60 (6 H, s, CH C᎐ C × 2), 1.69 (6H, s, CH C᎐C × 2),
᎐
᎐
3
Acknowledgements
We thank the late Mr M. Kurabayashi (Sankyo Co., Ltd.) for
providing a sample of plaunotol.
3
3
1.93–2.28 (12 H, m, CH C᎐C × 6), 4.10 (2 H, s, CH OH), 4.14
᎐
2
2
(2 H, d, J 7.0 Hz, CH OH), 5.05–5.19 (2 H, m, CHC᎐C × 2),
᎐
2
5.28 (1 H, t, J 7.4 Hz, CHC᎐C), 5.40 (1 H, t, J 7.4 Hz, CHC᎐C);
᎐
᎐
13C NMR (100 MHz, CDCl3) δ 16.1, 16.4, 17.7, 25.7, 25.9, 26.8,
26.9, 35.0, 39.4, 39.7, 59.2, 60.1, 124.0, 124.1, 124.3, 127.7,
131.4, 135.4, 138.9, 139.1; HRMS (EI) calc. for C20H34O2 (M)ϩ
306.2559, found 306.2554.
References
1 Part of this work has been reported in preliminary form in H.
Kogen, K. Tago, M. Arai, E. Minami, K. Masuda and T. Akiyama,
Bioorg. Med. Chem. Lett., 1999, 9, 1347.
2 J. R. Warren, Lancet, 1983, i, 1273; B. J. Marshall, Lancet, 1983, i,
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3 B. J. Marshall, J. A. Armstrong, D. B. McGechie and R. J. Glancy,
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Am. J. Gastroenterol., 1987, 82, 192.
General procedure: Wittig reaction
A solution of phosphonium salt 19 (1.5 mmol) and 18-crown-
6–CH3CN (1.8 mmol) in toluene (2 mL) was dried in vacuo,
then it was dissolved in THF (9 mL). 1.0 M Potassium tert-
butoxide solution in THF (1.5 mL, 1.5 mmol) was added to the
solution at room temperature and the reaction mixture was
stirred for 1 h at room temperature, and was then cooled to
Ϫ78 ЊC. After a solution of diethoxyketone 20 (1.0 mmol) in
THF was added, the mixture was warmed up to Ϫ40 ЊC and
stirring was continued overnight. Next, a saturated aqueous
NH4Cl solution was added, and the organic material was
extracted with ether. Combined organic extracts were washed
with a 10% solution of Na2S2O3 and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo after filtration.
Triphenylphosphine oxide was removed by short silica gel
flash chromatography, then the resulting crude product was
deprotected.
4 M. J. Blaser, Gastroenterology, 1987, 93, 371.
5 G. E. Buck, Clin. Microbiol. Rev., 1990, 3, 1.
6 R. P. H. Logan, Lancet, 1994, 344, 1078; International Agency for
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7 A. Ogiso, E. Kitazawa, M. Kurabayashi, A. Sato, S. Takahashi,
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8 T. Koga, H. Kawada, Y. Utsui, H. Domon, C. Ishii and H. Yasuda,
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H. Kawada, K. Takahashi, Y. Utsui, H. Domon, C. Ishii, T. Narita
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1994, 35, 1581; ( f ) T. Fujiwara, Y. Tsuruta and T. Takeda,
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M. Asami and S. Inoue, Synlett, 1998, 685.
Deprotection: Method A17
Amberlyst 15 (20 mg) was added to a solution of acetal (crude
product of Wittig reaction) in aqueous acetone (5 mL), and
the reaction mixture was stirred at room temperature. After the
reaction was completed, the reaction mixture was filtered
and evaporated. The residue was purified by flash column
chromatography.
10 C. Sreekumar, K. P. Daest and W. C. Still, J. Org. Chem., 1980, 45,
4260.
11 T. B. Johnson and L. H. Cretcher, Jr., J. Am. Chem. Soc., 1915, 37,
2144; T. B. Johnson and L. A. Mikeska, J. Am. Chem. Soc., 1919, 41,
810.
Deprotection: Method B17
12 S. Takahashi, Synth. Commun., 1976, 6, 331.
Aqueous acetic acid (50%, 2 mL) was added to a solution of
acetal in THF (3 mL) at room temperature and the reaction
mixture was stirred for 5 min at this temperature. Water was
added, the organic material was extracted with ether, and com-
bined organic extracts were washed with a saturated aqueous
NaHCO3 solution and brine, dried over anhydrous Na2SO4 and
concentrated in vacuo after filtration. The residue was purified
by flash column chromatography.
13 A. Wohl and N. Lange, Chem. Ber., 1908, 41, 3614.
14 (a) H. R. Henze and D. W. Carrol, J. Am. Chem. Soc., 1954, 76,
4580; (b) H. D. Dakin and H. W. Dudley, J. Biol. Chem., 1914, 18,
37; (c) J. B. Wright, J. Am. Chem. Soc., 1955, 77, 4883.
15 K. Sato, S. Inoue and S. Ota, J. Org. Chem., 1970, 35, 565.
16 The reason for this phenomenon is unknown and we are currently
working on the mechanistic aspects.
17 For the spectroscopic and analytical data of compound 21, see
electronic supplementary information.
2078
J. Chem. Soc., Perkin Trans. 1, 2000, 2073–2078