Total synthesis of the Fusarium toxin equisetin

Article abstract of DOI:10.1039/b411350k

A short stereoselective synthesis of the Fusarium toxin equisetin, a potent inhibitor of HIV-1 integrase enzyme is described, using as the key step a stereoselective intramolecular Diels-Alder reaction of a fully conjugated E,E,E-triene with a trisubstituted γ,δ-unsaturated β-ketothioester.

Full text of DOI:10.1039/b411350k

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A R T I C L E
Total synthesis of the Fusarium toxin equisetin
Lisa T. Burke, Darren J. Dixon,*† Steven V. Ley and F e´ lix Rodr ´ı guez‡
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK CB2 1EW
Received 23rd July 2004, Accepted 3rd November 2004
First published as an Advance Article on the web 7th December 2004
A short stereoselective synthesis of the Fusarium toxin equisetin, a potent inhibitor of HIV-1 integrase enzyme is
described, using as the key step a stereoselective intramolecular Diels–Alder reaction of a fully conjugated
E,E,E-triene with a trisubstituted c,d-unsaturated b-ketothioester.
Introduction
Results and discussion
Numerous biologically active natural products contain the
tetramic acid (pyrrolidine-2,4-dione) ring system as a central
element of their structure. The range of biological activities
possessed by individual members of this series includes potent
antibiotic, antiviral, and antiulcerative properties, cytotoxicity
and mycotoxicity, the inhibition of tumors as well as fungicidal
action. Moreover, certain members of this class are responsible
The approach to equisetin 1 was guided by the perception that
the formation of the octalin skeleton of the molecule with
all five stereogenic centers could be readily achieved by the
intramolecular Diels–Alder (IMDA) reaction of 2 (Scheme 1).
More specifically, previous work and modelling studies of this
pivotal IMDA reaction suggested that employment of a Lewis
acid would encourage an endo-mode of cyclisation, where the
methyl substituent is disposed in a pseudoequatorial position
1
for pigmentation of some sponges and molds.
8
The structural complexity, together with the extraordinary
biological activity, of many tetramic acids makes the total
synthesis of these compounds an attractive goal for organic
chemists, particularly in those cases where the natural supply
is scarce. In this context, our group has been engaged in
the development of new methods for the construction of the
of the reacting chair conformation. It was also clear that the
tetramic acid subunit could be easily obtained by manipulation
2
of a serine derivative in a Lacey–Dieckmann cyclisation. We
envisaged that preparation of 2 would require a Horner–
Wadsworth–Emmons (HWE) reaction of a novel phosphonate
thioester 4 and aldehyde 3. The triene aldehyde 3 was envisioned
as originating from the phosphonate ester 6 and commercially
2
acyl tetramic acid subunit. This effort has culminated in the
9
total syntheses of several natural products containing this
available (R)-citronellol 5 (Scheme 1).
3
heterocyclic unit.
The Fusarium toxin equisetin 1 (Fig. 1) is a fungal metabolite
4
first isolated in 1974 from the white mold Fusarium equiseti. It
belongs to the acyl tetramic acid family of natural products by
virtue of its N-methylserine-derived heterocycle. In addition, the
compound comprises a substituted octalin skeleton bearing five
stereogenic centers including one which is quaternary. It also
has an impressive biological activity profile including antibiotic
and HIV inhibitory activity, cytotoxicity and mammalian DNA
5
binding.
Fig. 1 Equisetin 1.
Our experience in the synthesis of tetramic acids coupled with
the complex structure of equisetin and its remarkable biological
properties encouraged us to embark upon a total synthesis of this
6
compound. Here, we wish to report in full the details of these
investigations and some improvements we have made leading to
a more efficient total synthesis of this intriguing molecule.
Scheme 1 Retrosynthetic analysis.
7
The synthesis began with the protection of the hydroxyl
group of (R)-citronellol 5 using acetic anhydride and pyridine in
dichloromethane at rt (Scheme 2). Compound 7 thus obtained,
was subjected to a standard reductive ozonolysis to give alcohol
†
Current address: Department of Chemistry, The University of Manch-
ester, Manchester, UK M13 9PL. Email: Darren.Dixon@man.ac.uk;
fax: +44 (0)161 2754939; tel: +44 (0)161 2751426.
‡
“
8
, which was protected using tert-butyldimethylsilylchloride and
imidazole in dimethylformamide at rt to get the differentially
Current address: Instituto Universitario de Qu ´ı mica Organomet a´ lica
Enrique Moles”, Universidad de Oviedo, Juli a´ n Claver ´ı a, 8, E-33006,
Oviedo, Spain.
protected diol 9 in high yield over the three steps. A simple
2
7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5

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◦
deprotection of the acetyl group under the Zemplin conditions
catalytic potassium carbonate in methanol) led to alcohol 10
sodium diethyl phosphite, at −10 C, to give isomerically pure
(
phosphonate 6 in 60% yield (Scheme 3).
which was oxidized to the corresponding aldehyde 11 following
the Swern protocol (Scheme 2). It should be remarked that all
these standard reactions were very high yielding allowing the
multigram synthesis of 11 from the commercially available (R)-
citronellol 5.
With the phosphonate 6 available in quantity we were able
to complete the synthesis of the triene 13. Hence, treatment of
◦
the phosphonate 6 with a base at low temperature (−78 C)
yielded the corresponding phosphonate anion, to which was
◦
added the aldehyde 11 at −10 C to give, after standard aqueous
work-up, the triene 13. The yield and selectivity (E : Z) of
this reaction were highly dependent on the base used for the
deprotonation of 6. Thus, when KHMDS was used, a 1 : 1
mixture of E : Z isomers of triene 13 was obtained. However,
success was achieved when lithium bases were employed. With
butyllithium, the (E,E,E)-triene 13 was afforded in 60% yield
with a very satisfactory E : Z ratio of 17 : 1 (attained from
1
H NMR 600 MHz analysis). The yield could be improved to
7
1%, maintaining the 17 : 1 E : Z selectivity, by the use of
sec-butyllithium as base. With 13 in hand, TBS removal with
◦
TBAF in THF at 0 C overnight gave the respective alcohol
1
4 in quantitative yield. Alcohol 14 crystallised on cooling in
◦
the freezer and was recrystallised from n-pentane at −20 C to
remove the small amount of minor geometrical isomer formed
in the previous step. Finally, oxidation of alcohol 14 to the
respective aldehyde 3 using the Swern protocol proceeded in
high yield without incident.
Scheme 2 Reagents and conditions: (a) Ac
2
O, pyridine, CH
2
Cl
, 0 C; (c) TBSCl, imidazole,
, Et N, CH Cl
2
;
For the synthesis of the key intermediate 2, we required the
preparation of the tert-butyl b-keto-c-diethylphosphonothiolate
◦
◦
(
b) O
3
, CH
2
Cl
2
, −78 C then MeOH, NaBH
4
THF, rt, (d) MeOH, K
2
CO
3
cat., rt; (e) DMSO, (COCl)
2
3
2
2
,
4
(Scheme 4). This was successfully accomplished starting
from Meldrum’s acid (15). Thus, treatment of this compound
◦
−
78 C to rt.
with 2-bromopropionyl bromide and pyridine in CH
2
Cl at
2
◦
With aldehyde 11 in hand, its conversion into the fully
conjugated E,E,E-triene derivative 3 was then investigated.
The apparently trivial step—formation of the fully conjugated
E,E,E)-triene 13 from prepared aldehyde 11— proved to be one
of the most challenging of the entire synthesis (Scheme 3). De-
spite the multitude of literature procedures available, recounting
the conditions necessary for transforming an aldehyde into an
alkene, our difficulty was in obtaining a high E : Z selectivity.
We believed the best chance of success was to use phosphonate
chemistry. However, preparation of the necessary phosphonate
0
C gave, after quenching with aqueous hydrobromic acid
followed by a standard aqueous work-up, a brown oil which
was subsequently transformed into intermediate 16 by treatment
with tert-butylthiol in refluxing benzene (63%). This compound
16 was reacted with sodium hydride in THF at temperatures
(
◦
◦
ranging between −30 C and −20 C, and then treated with
a THF solution of sodium diethyl phosphite to obtain, after
warming to rt, the desired phosphonate 4 (99%) as a red oil. The
Horner–Wadsworth–Emmons reaction of the dianion of tert-
butyl b-keto-c-diethylphosphonothiolate 4 and aldehyde 3 led
to the key intermediate 2. It should be noted that the selectivity
(E : Z) of this reaction was strongly dependent on the nature
of the base used for the deprotonation of 4. Thus, when BuLi
was used, compound 2 was obtained as a 5 : 1 mixture of the
E : Z diastereoisomers (56% isolated yield of the desired E
diastereoisomer). On the other hand, when KHMDS was used
6
was not trivial. After several attempts using different reaction
conditions, we found that treatment of commercially available
and isomerically pure alcohol 12 in THF with BuLi, followed
by treatment of the resulting alkoxide with TsCl gave the
corresponding tosylated derivative which was treated in situ with
◦
Scheme 3 Reagents and conditions: (a) BuLi, THF, −10 C; (b) TsCl,
3
Scheme 4 Reagents and conditions: (a) CH CHBrCOBr, pyridine,
◦
◦
s
◦
◦
t
◦
◦
−
10 C; (c) (EtO)
2
PONa, −78 C to rt; (d) BuLi, THF, −78 C, then
CH
2
Cl
2
0 C; (b) BuSH, PhH, reflux; (c) NaH, THF, − 30 C to − 20 C,
2
◦
◦
PONa, THF, −20 ◦C to rt; (d) KHMDS, THF, −78 ◦C,
1
1, −78 C to rt; (e) TBAF, THF, 0 C to rt; (f) DMSO, (COCl)
2
, Et
3
N,
then (EtO)
◦
CH
2
Cl
2
, −78 C to rt.
then 3.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0
2 7 5

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Table 1 Lewis acid-catalyzed intramolecular Diels–Alder reaction (IMDA) of 2
a
b
Entry
Lewis acid
Conditions
Yield/%
de/%
1
2
3
4
5
6
7
ZnCl
EtAlCl
MeAlCl
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
, rt
No reaction
Decomposition
Decomposition
35
41
70
71
—
—
—
>95
>95
85
◦
2
, −78 C
◦
2
, −78 C
◦
◦
Me
Me
2
AlCl
Al
, −78 C
3
, −78 C
LiClO
BF
·Et
4
◦
◦
3
2
O
2
2
, −78 C to 0 C
>95
a
b
1
Isolated yield based on precursor 2. Determined by 600 MHz H NMR analysis of the crude reaction mixture.
as base, the E : Z ratio was improved to 30 : 1. Chromatographic
separation of the isomers allowed isolation of the desired E
diastereoisomer 2 in a pleasing 88% yield (Scheme 4).
At this stage, with substantial quantities of isomerically pure
polyene 2 in hand, we turned our attention to the study of the
key reaction of our synthesis, the intramolecular Diels–Alder
reaction (IMDA). Several reaction conditions using different
Lewis acids were attempted (Scheme 5 and Table 1). The use of
Completion of the equisetin synthesis from intermediate 17,
entailed the installation of the N-methyl serine tetramic acid
component (Scheme 6). Firstly, direct aminolysis of the tert-
butyl thioester group of 17 with O-tert-butyldimethylsilyl N-
methyl serine methyl ester mediated by silver trifluoroacetate
2
following the protocol introduced by our group, afforded b-keto
amide 18 in excellent yield. Then, removal of tert-butyldimethyl
silyl protecting group with hydrofluoric acid in acetonitrile at
rt for 15 min, gave the intermediate hydroxy compound 19 in
85% yield. Finally, treatment of 19 with sodium methoxide in
methanol at rt for 10 min quantitatively afforded, after a simple
aqueous work-up, pure equisetin 1. The spectroscopic data as
ZnCl
2
, EtAlCl
2
or MeAlCl resulted in the recovery of starting
2
material 2 or in extensive decomposition to give mixtures of
unidentified products (entries 1–3). When the Lewis acid was
Me
could be isolated as a single diastereoisomer but in low yields
entries 4 and 5). More satisfactory results arose from the use of
LiClO (5 M in ether) as compound 17 could be isolated in 70%
yield with 12 : 1 selectivity in favor of the desired isomer (entry
). Finally, the best results were obtained from the treatment
of 2 with two equivalents of BF O in dichloromethane at
·Et
78 C and further warming to 0 C. These conditions led to the
2
AlCl or Me
3
Al the corresponding Diels–Alder adduct 17
2
D
8
well as the specific rotation {[a] −262 (c 0.038, CHCl
3
) [Lit.
2
D
3
(
(7b) [a] −253, (c 0.038, CHCl
3
)]} of our synthetic material was
4
in complete agreement with the literature values.
6
3
◦
2
◦
−
1
formation of 17 in >95% de (obtained from H NMR 600 MHz
analysis of the crude of the reaction) and in a pleasing 71% yield
(
entry 7). Although the structure of the minor diastereoisomer
in the Diels–Alder reaction was not determined, the relative
stereochemistry of 17 was proven by its subsequent conversion
to equisetin (vide infra).
Scheme 5 Lewis acid-catalyzed intramolecular Diels–Alder reaction
of 2.
The notable levels of diastereocontrol in the intramolecular
Diels–Alder reaction presumably arise from the methyl group,
attached to the stereogenic centre, adopting a pseudo equatorial
disposition in a chair-like transition state. Additionally, the
Lewis acid activated dieneophile must adopt an endo approach
to the “diene” of the conjugated (E,E,E)-triene (Fig. 2).
Scheme 6 Reagents and conditions: (a) (S)-N-methyl-O-tert-butyl-
◦
dimethylsilyl serine methyl ester, CF
CH CN, rt; (c) MeONa, MeOH, rt.
3
CO
2
Ag, THF, Et
3
N, 0 C; (b) HF,
3
Conclusions
The stereocontrolled synthesis of equisetin has been achieved
in 13 steps from commercially available (R)-citronellol in an
overall yield of 26.6%. This sequence has the potential to provide
multigram quantities of equisetin which could allow detailed
biological evaluation. The key step of this synthesis is a Lewis
acid-mediated intramolecular Diels–Alder reaction of a fully
conjugated E,E,E-triene with a trisubstituted c,d-unsaturated
b-ketothioester. Other highlights of the synthesis include the
development of a general route to allylic phosphonates and
Fig. 2 Proposed transition state for the IMDA.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0
2
7 6

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◦
−1
a stereocontrolled Horner–Wadsworth–Emmons reaction to
afford a trisubstituted alkene.
+16.9 (c 0.445, CHCl
3
); mmax(thin film)/cm = 3390s (OH),
1
2933, 2872, 1739s (OC=O), 1461, 1367, 1243s, 1056s; H NMR
(
400 MHz, CDCl
3
): d = 4.13–4.02 (m, 2H; CH
2
OCOCH
), 1.85 (br s, 1H;
and CHCH ),
3
), 3.59
(
t, J = 6.6 Hz, 2H; CH
2
OH), 2.01 (s, 3H; COCH
3
Experimental
OH), 1.70–1.32 and 1.22–1.13 (m, 7H; 3 × CH
2
3
1
3
General experimental details
0.89 (3H, d, J = 6.6 Hz, CHCH ). C NMR (100 MHz, CDCl ):
3
3
+
d = 171.4, 63.0, 62.9, 35.4, 32.8, 30.0, 29.6, 21.0, 19.4. m/z (EI ):
All reactions involving organometallic or other moisture-
sensitive reagents were performed under an atmosphere of
dry argon. All glass apparatus was oven dried and allowed
to cool under vacuum. In all cases, assessment of reaction
diastereoselectivity was carried out by peak integration in the
+
+
+
1
75 (100%, MH ), 115 (42%, MH –HOCOCH
3
). HRMS (EI ):
+
Found, 175.1326. C
9
H
18
O
3
(MH ) requires, 175.1334.
(
(9)
R)-(+)-1-tert-Butyldimethylsilyloxy-6-acetoxy-4-methylhexane
1
H NMR spectrum of the crude reaction products. Petroleum
ether refers to the fraction of petroleum ether boiling between 40
and 60 C and was redistilled before use. Ether refers to diethyl
ether. All other solvents were purified by standard procedures or
used from commercial sources as appropriate. All reagents were
used as supplied. Flash column chromatography was carried out
using Merck 9385 Kieselgel 60 silica gel 0.040–0.063 mm (230–
To a stirred solution of 8 (4.32 g, 24.79 mmol) and imidazole
◦
(2.565 g, 37.68 mmol) in DMF (40 ml) at rt was added
tert-butyldimethylsilylchloride in one portion and the reaction
mixture was left to stir overnight. The resulting solution was
diluted with diethyl ether (40 ml) and successively washed with
water (2 × 30 ml), brine, dried (magnesium sulfate), filtered
and concentrated in vacuo to afford a colourless oil. Purification
of this material by flash chromatography on silica gel [eluting
4
00 mesh). Thin layer chromatography (TLC) was performed
on precoated glass-backed plates (Merck Kieselgel 60 F254).
Visualisation was either by UV fluorescence (m = 254 nm) or by
heating plates after being dipped in potassium permanganate
solution. NMR spectra were recorded using either a Bruker
with petroleum ether–diethyl ether (gradient 50 : 1 to 5 : 1); R
f
(
product) 0.24 (10 : 1 petroleum ether–diethyl ether)] afforded
30
D
the title compound 9 as a colourless oil (7.118 g, 100%). [a]
+
2
9
1
13
AM400 ( H; 400 MHz and C; 100 MHz) or Bruker DRX600
(
◦
−1
7.74 (c 1.03, CHCl
3
); mmax(thin film)/cm = 2955s, 2859s,
1
13
H; 600 MHz and C; 150 MHz). All spectra were recorded
using deuteriochloroform (CDCl ) as solvent and internally
referenced to residual protiochloroform (d 7.27 ppm and
77.0 ppm). All chemical shifts (d and d ) are quoted
in ppm relative to tetramethylsilane (d 0.00) and coupling
872m, 1743s (OC=O), 1472, 1388, 1366, 1248s, 1098s, 1034,
1
3
38, 836s, 775m. H NMR (400 MHz, CDCl
3
): d = 4.04–4.03
2
H
(
(
(
(
m, 2H; CH
2
OCOCH
3
), 3.53 (t, J = 6.0 Hz, 2H; CH
and CHCH
), 0.84 (s, 9H; SiC(CH
), −0.01
): d = 171.0,
OSi), 1.98
d
C
H
C
s, 3H; COCH
3
), 1.62–1.12 (m, 7H; 3 × CH
2
3
), 0.86
H
d, J = 10.6 Hz, 3H; CHCH
3
)
3 3
constants (J) are given in Hertz. First order approximations
are employed throughout. Both high and low resolution mass
spectra were obtained on a Kratos MS890 spectrometer using EI
13
s, 6H, Si(CH
3
)
2
); C NMR (100 MHz, CDCl
3
6
3.3, 62.9, 35.5, 32.9, 30.1, 29.6, 25.9, 20.9, 19.4, 18.3, −5.4.
+ + +
3 3
m/z (EI ): 289 (68%, MH ), 231 (100%, MH –CH(CH
(
Found, 289.2200. C15
)
), 171
(
electron impact), chemical ionisation or positive FAB (fast atom
+
+
51%, MH –C
6
H
12(OH)
2
), 117 (94%, C
6
H
12
O
2
H). HRMS (EI ):
bombardment) techniques on a Bruker BIOAPEX 4.7 T FTICR
at the Department of Chemistry, University of Cambridge. All
infra-red spectra were obtained using a Perkin-Elmer 1600 series
FTIR spectrometer as thin film liquid samples between sodium
chloride plates. Only selected absorbances (mmax) are reported.
+
H
32SiO
3
(MH ) requires, 289.2199.
(
R)-(+)-1-tert-Butyldimethylsilyloxy-4-methylhexan-6-ol (10)
To a stirred solution of 9 (6.607 g, 22.94 mmol) in methanol
(150 ml) at rt was added anhydrous potassium carbonate
(250 mg) in one portion and the reaction mixture was left to
stir overnight. The methanol was removed in vacuo resulting
in a pale yellow viscous oil. This material was passed through
Optical rotations ([a]
D
) were recorded using an Optical Activity
AA-100 polarimeter which has a thermally jacketed 10 cm cell
−
1
2
−1
(
path length of 1 dm) and are given in units of 10 deg cm g
at 589 nm (sodium D-line).
a small plug of silica gel [eluting with neat diethyl ether; R
f
(
product) 0.43 (1 : 1 petroleum ether–diethyl ether)] affording
(
R)-(+)-6-Acetoxy-4-methylhexanol (8)
30
the title compound 10 as a colourless oil (5.526 g, 98%). [a]
+
2
9
(
(
CHCH
NMR (100 MHz, CDCl
2
D
To a stirred solution of (R)-(+)-Citronellol 5 (5.00 g, 0.032 mol)
and pyridine (3.36 ml, 0.042 mol) in dichloromethane (30 ml)
◦
−1
3.52 (c 1.42, CHCl
3
); mmax(thin film)/cm = 3342m (OH),
954, 2929, 2857, 1475, 1462, 1387, 1361, 1255s, 1097s, 1006,
◦
at −10 C was added acetic anhydride (3.62 ml, 0.038 mol).
1
38, 835s, 774s, 662. H NMR (400 MHz, CDCl
m, 2H, CH
m, 8H, 3 × CH
3
): d = 3.66
The reaction mixture was subsequently warmed to rt and
left to stir overnight. The resulting solution was diluted with
dichloromethane (50 ml) and washed with saturated copper
sulfate (3 × 20 ml), sodium hydrogencarbonate, brine, dried
2
OH), 3.59 (t, J = 6.6 Hz, 2H; CH
2
OSi), 1.64–1.11
2
, CHCH
3
and OH), 0.91 (d, J = 7.9 Hz, 3H;
13
3
), 0.89 (s, 9H; SiC(CH
3
)
3
), 0.04 (s, 6H; Si(CH
3
)
2
).
C
3
): d = 63.5, 61.1, 39.9, 33.0, 30.2, 29.3,
(
magnesium sulfate), filtered and concentrated in vacuo to yield
+
+
5.9, 19.6, 18.3, −5.3; m/z (EI ): 247 (100%, MH ), 189 (38%,
+ +
3 3 2
the crude acetate product as a colourless oil. This material was
used directly in the next step. A stirred solution of the crude
MH –CH(CH
)
). HRMS (EI ): Found, 247.2084. C13
H
30SiO
+
(MH ) requires, 247.2093.
◦
acetate (6.34 g, 0.032 mol) in dichloromethane (30 ml) at −78 C
was subjected to a steady flow of ozone until a blue coloration
was observed (30 min), and was then purged with oxygen
(
R)-(+)-1-tert-Butyldimethylsilyloxy-3-methyl-hexanal (11)
(
1 min). The resultant colourless solution was diluted with
To a stirred solution of oxalyl chloride (21.93 ml, 22.18 mmol) in
◦
◦
methanol (120 ml) and warmed to 0 C (10 min), before sodium
borohydride (13.0 g, 0.15 mol) was added portionwise with
caution, over 1 h. After stirring for a further 90 min, the reaction
material was partitioned between dichloromethane (30 ml) and
water (30 ml), and further extracted with dichloromethane (2 ×
dichloromethane (50 ml) at −78 C was added DMSO (3.15 ml,
44.36 mmol) dropwise via syringe. The resultant colourless
solution was left to stir for 20 min. A solution of 10 (2.717 g,
11.09 mmol) in dichloromethane (20 ml) was then added
◦
dropwise via cannula at −78 C (10 min), and left to stir for
2
0 ml). The combined organic portions were washed with brine,
45 min before addition of triethylamine (9.33 ml, 66.54 mmol).
Stirring was maintained at this temperature for a further 15 min
before the reaction mixture was allowed to slowly warm to rt.
The resulting solution was then poured into water (100 ml) and
extracted with dichloromethane (2 × 60 ml). The combined
organics were washed further with brine, dried (sodium sulfate),
dried (magnesium sulfate), filtered and concentrated in vacuo
to afford a colourless oil. Purification of this material by flash
chromatography on silica gel [eluting with petroleum ether–
diethyl ether (2 : 1, then 1 : 1); R
ether)] resulted in the title compound 8 (4.419 g, 79%). [a]D
f
(product) 0.44 (neat diethyl
30
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0
2 7 7

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filtered and concentrated in vacuo to afford a colourless oil.
Purification of this material by flash chromatography on silica
CH(CH)
2.09–1.93 (m, 2H; CHCH
CHCHCH ), 1.59–1.43 and 1.39–1.25 and 1.17–1.05 (m, 5H;
CH CH OSi, CH CH CH OSi and CH(CH )CH ), 0.89 (s,
9H; SiC(CH CH ), 0.05
(s, 6H; Si(CH
): d = 131.9,
4
CHCH
3
), 3.60–3.56 (t, J = 6.7 Hz, 2H; CH
2
OSi),
2
CH), 1.76 (d, J = 6.6 Hz, 3H;
gel [eluting with petroleum ether–diethyl ether (1 : 1); R
product) 0.63 (1 : 1 petroleum ether–diethyl ether)] afforded the
f
3
(
2
2
2
2
2
3
2
3
D
0
◦
title compound 11 as a colourless oil (2.60 g, 96%). [a] +12.6 (c
3
)
3
), 0.87 (d, J = 6.7 Hz, 3H; CHCH
3
2
−
1
13
1
1
8
.04, CHCl
3
); mmax(thin film)/cm = 2955s, 2930s, 2883s, 2857s,
3
)
2
). C NMR (100 MHz, CDCl
3
728s (C=O), 1475, 1462, 1387, 1361, 1255s, 1097s, 1006, 938,
131.7, 130.8, 130.6, 128.6, 125.9, 63.5, 40.3, 33.2, 32.7, 30.5,
1
+
+
36s, 813, 775s. H NMR (400 MHz, CDCl
3
): d = 9.74 (s, 1H;
26.0, 19.6, 18.3, 18.2, −5.3. m/z (EI ) = 308 (20%, M ),
+
+
CHO), 3.58 (t, J = 6.4 Hz, 2H; CH
CH
CO), 1.58–1.20 (m, 5H, 2 × CH
J = 6.7 Hz, 3H; CHCH ), 0.87 (s, 9H, SiC(CH
Si(CH ). C NMR (100 MHz, CDCl
2
OSi), 2.42–2.01 (m, 2H,
and CHCH ), 0.95 (d,
), 0.03 (s, 6H,
251 (100%, M −C(CH
3
) ). HRMS (EI ): Found, 308.2560.
3
+
2
2
3
C
19
H
36SiO (M ) requires, 308.2535.
3
3 3
)
1
3
3
)
2
3
): d = 202.9, 63.1, 51.0,
(
6E,8E,10E)-(R)-4-Methyl-1-hydroxydodeca-6,8,10-triene (14)
+
3
3.0, 30.2, 28.0, 25.9, 19.9, 18.3, −5.3. m/z (EI ): 243 (28%,
+
+
To a stirred solution of 13 (4.32 g, 14.0 mmol) in THF (100 ml)
[M–H] ), 203 (87%, C
7
H
13(OH)OSi(CH
). HRMS (EI ): Found, 244.1871. C13
3
)
3
), 185 (100%, M –
◦
+
+
at 0 C was added tetrabutylammonium fluoride (28.0 ml, 1 M
CH(CH
3
)
3
H
28SiO
2
(M )
in THF, 28.0 mmol) via syringe. The reaction mixture was
concentrated in vacuo to afford a colourless oil. Purification
by flash chromatography on silica gel [eluting with petroleum
requires, 244.1859.
9
(
2E,4E)-Hexadiene-1-diethylphosphonate (6)
ether–diethyl ether; (gradient elution, 1 : 1 to 0 : 1); R
.29 (1 : 1 petroleum ether–diethyl ether)] afforded the title
compound 14 as a colourless oil which crystallized on cooling
2.70 g, 100%). Isomerically pure material could be obtained
f
(product)
To a stirred solution of 2,4-hexadiene-1-ol 12 (2.23 ml,
0
◦
2
(
0.0 mmol) in THF (40 ml) at −78 C was added butyllithium
8.0 ml, 20.0 mmol) dropwise via syringe. The resultant yellow
(
◦
◦
30
◦
solution was stirred at −78 C for 10 min. A solution of p-
toluenesulfonylchloride (4.20 g, 22.0 mmol) in THF (20 ml)
was then added dropwise via cannula to the reaction mixture.
The resulting yellow solution was stirred for a further hour
by recrystallisation from pentane at −20 C. [a]D −1.05 (c
−
1
0
2
1
.573, CHCl
3
); mmax(Nujol mull)/cm = 3362m (OH), 2924s,
854s, 1680 (triene), 1652 (triene), 1459s, 1377m, 1275, 1089,
1
050, 994 (CH CH trans), 880. H NMR (400 MHz, CDCl
=
3
):
), 5.71–5.59 (m,
), 3.62 (dd, J = 12.0 and 6.4 Hz, 2H;
OH), 2.10 and 1.95 (m, 2H; CHCH
CH), 1.76 (d, J =
.7 Hz, 3H; CHCHCH ), 1.65–1.12 (m, 6H; CH CH OH,
CH CH CH OH, CH(CH )CH
and OH), 0.89 (d, J = 6.7 Hz,
H; CH CHCH ). C NMR (100 MHz, CDCl
): d = 132.6,
31.7, 131.6, 130.9, 130.5, 128.9, 63.3, 40.3, 33.2, 32.5, 30.4,
◦
at −78 C. Meanwhile, KHMDS (60.0 ml, 0.5 M in toluene,
d = 6.10–6.02 (m, 4H; CHCHCHCHCHCH
3
3
0.0 mmol) was added slowly via syringe to a stirred solution
2
CH
6
H; CH(CH)
2
4
CHCH
3
of diethyl phosphite (4.35 ml, 33.0 mmol) in 40 ml THF at
2
◦
◦
0
C. After 30 min, this solution was added to the −78
C
3
2
2
solution of the preformed tosylate via cannula. The reaction
2
2
2
3
2
◦
1
3
mixture was stirred at −78 C for 10 min then slowly warmed
3
1
1
(
1
2
3
3
to rt overnight. The residual solution was partitioned between
pH 7 buffer (30 ml) and diethyl ether (50 ml) and the organic
+
+
9.5, 18.2. m/z (EI ) = 194 (78%, M ), 107 (85%, C
8
H11), 94
+
portion was washed with NaHCO
3
(2 × 20 ml) and water (2 ×
54%, (CH)
6
CH
3
), 79 (100%, CH
2
(CH)
5
). HRMS (EI ): Found,
+
2
0 ml), dried (magnesium sulfate), filtered and concentrated in
94.1667. C13
H
22O (M ) requires, 194.1671.
vacuo to afford a colourless oil. Purification of this material by
flash chromatography on alumina [eluting with ether then neat
(
6E,8E,10E)-(R)-4-Methyl-1-dodecatriene-1-al (3)
ethyl acetate; R
the title compound 6 as a colourless oil (2.63 g, 60%). H
NMR (400 MHz, CDCl P),
): d = 6.13–6.08 (m, 1H; CHCHCH
.01 (dd, J = 14.8 and 10.7 Hz, 1H; CH CHCH), 5.66–5.60
m, 1H; CHCH
P), 5.50–5.44 (dq, J = 14.9 and 7.1 Hz, 1H;
CHCH), 4.12–4.03 (m, 6H; 2 × OCH CH ), 2.58 (dd, JPH
P), 1.72 (d, J = 7.0 Hz,
CHCH), 1.29 (t, J = 7.1 Hz, 6H; 2 × OCH CH ).
f
(product) 0.46 (neat ethyl acetate)] afforded
1
To a stirred solution of oxalyl chloride (0.52 ml, 6.0 mmol) in
◦
dichloromethane (30 ml) at −78 C was added DMSO (0.84 ml,
3
2
1
2.0 mmol) dropwise via syringe. The resultant colourless
6
3
solution was left to stir for 30 min. A solution of 14 (0.58 g,
3
(
2
.0 mmol) in dichloromethane (15 ml) was then added dropwise
CH
3
2
3
=
◦
via cannula at −78 C, and left to stir for 1 h before addition
of triethylamine (2.43 ml, 18.0 mmol). Stirring was maintained
at this temperature for a further 15 min before the reaction
mixture was allowed to slowly warm to rt over 30 min. The
resulting solution was then poured into water (100 ml) and
extracted with dichloromethane (2 × 60 ml). The combined
organics were washed further with brine, dried (sodium sulfate),
filtered and concentrated in vacuo to afford a colourless oil
2
2.3 Hz and JHH = 7.6 Hz, 2H; CHCH
2
3
H; CH
3
2
3
(
6
6E,8E,10E)-(R)-4-Methyl-1-tert-butyldimethylsilyloxydodeca–
,8,10-triene (13)
To a stirred solution of phosphonate 6 (1.683 g, 7.72 mmol) in
◦
THF (46 ml) at −78 C was added sec-butyllithium (5.94 ml,
1
.3 M, 7.72 mmol) dropwise via syringe. The resultant yellow
(
0.566 g, 98%) which was used directly in the next step without
◦
solution was stirred at −78 C for a further 20 min, before a
solution of 11 (1.450 g, 5.94 mmol) in THF (17 ml) was then
added dropwise via syringe. The resulting yellow solution was
−1
further purification. mmax(thin film)/cm = 3012m, 2957s, 2928s,
2
1
856, 2718, 1725s (C=O), 1684 (triene), 1652 (triene), 1558,
540, 1521, 1506, 1456, 1410, 1378, 1138, 996s (−CH=CH-
◦
stirred for 15 min at −78 C, warmed to rt and stirred for a
1
trans). H NMR (400 MHz, CDCl
3
): d = 9.76 (s, 1H; COH),
3
further 18 h. The residual red–orange solution was quenched
with phosphate buffer, then partitioned between water (50 ml)
and diethyl ether (2 × 50 ml). The combined organics were
washed further with brine (2 × 30 ml), dried (magnesium
sulfate), filtered and concentrated in vacuo to afford a colourless
oil. Purification of this material by flash chromatography on
alumina [eluting with petroleum ether–diethyl ether; (50 : 1
stepwise up to 30 : 1)] afforded the title compound 13 as a 17 : 1
mixture of geometrical isomers and as a colourless oil (1.30 g,
6
.08–6.03 (m, 4H; CHCHCHCHCHCH
CH(CH) CHCH ), 2.45–2.40 (m, 2H; CH
CH), 1.76 (d, J = 6.7 Hz, 3H; CHCHCH
CH CO and CH(CH )CH
) 0.89 (d, J =
CHCH ). C NMR (100 MHz, CDCl
): d =
), 5.70–5.57 (m, 2H;
CO), 2.10–1.97 (m,
), 1.72–
4
3
2
2
1
6
2
2
C
H, CHCH
2
3
.41 (m, 3H; CH
2
2
3
2
13
.6 Hz, 3H; CH
2
3
3
02.6, 132.6, 131.7, 131.7, 131.2, 130.3, 128.9, 41.7, 40.0, 32.9,
+
+
8.4, 19.3, 18.2. m/z (EI ) = 192 (100%, M ), 107 (97%,
+
+
8
H
11). HRMS (EI ): Found, 192.1505. C13
H
20O (M ) requires,
1
92.1514.
3
0
◦
−1
7
3
1
9
6
1%). [a]D −0.502 (c 0.996, CHCl
3
); mmax(thin film)/cm
=
013m (C=C), 2953s, 2928s, 2856s, 1684 (triene), 1652 (triene),
tert-Butyl-4-bromo-3-oxopentanethioate (16)
471, 1462, 1377, 1360, 1254s, 1097s, 994s (−CH=CH-trans),
1
38s, 835s, 813, 775s. H NMR (400 MHz, CDCl
3
): d =
To a stirred solution of Meldrum’s acid (15) (2.88 g, 20 mmol)
and pyridine (3.3 ml, 40 mmol) in dichloromethane (30 ml) at
.09–5.99 (m, 4H; CHCHCHCHCHCH
3
), 5.71–5.59 (m, 2H;
2
7 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0

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◦
0
C was added 2-bromopropionyl bromide (2.30 ml, 22.0 mmol)
(4E,10E,12E,14E)-(R)-4,8-Dimethyl-hexadeca-4,10,12,14-
dropwise via syringe. The reaction mixture was stirred for a
further 60 min before warming to rt and partitioning between
DCM (2 × 100 ml) and aqueous hydrobromic acid (200 ml, 2 M).
The organic layer was washed with brine, dried (magnesium
sulfate), filtered and concentrated in vacuo to afford a brown
oil. To a solution of this material in benzene (30 ml) was
added tert-butylthiol (6.76 ml, 60 mmol) via syringe and the
mixture heated for 1 h at reflux before cooling and evaporation
in vacuo to give a red–brown oil. Purification of this material
by flash chromatography on silica gel [eluting with 20 : 1
petroleum ether–diethyl ether→1 : 1 petroleum ether–diethyl
ether] afforded the title compound 16 as an orange oil (3.35 g,
butene-b-ketothioate (2)
To a stirred solution of phosphonate 4 (0.357 g, 1.1 mmol) in
◦
THF (10 ml) at −78 C was added KHMDS (4.20 ml, 0.5 M in
tol, 2.1 mmol) via syringe, slowly over 10 min. The resultant
◦
yellow solution was stirred at −78 C for a further 15 min
before a solution of aldehyde 3 (0.152 g, 0.79 mmol) in THF
(
3 ml) was added via cannula. The reaction mixture was stirred
◦
at −78 C for 30 min, warmed to rt, and stirred for another hour.
The residual solution was quenched with ammonium chloride,
then partitioned between water and diethyl ether. The combined
organics were washed further with water (3 × 20 ml), brine, dried
(
magnesium sulfate), filtered and concentrated in vacuo to afford
6
3%). In CDCl at rt the title compound exists as a (5 : 2)
3
1
a colourless oil. H NMR analysis of the crude material indi-
cated a 30 : 1 (E : Z) ratio of isomers had been formed. Purifica-
tion by flash chromatography on silica gel [eluting with petro-
leum ether–diethyl ether; (50 : 1)] afforded the title compound 2
−
1
keto : enol mixture. mmax(thin film)/cm = 2965, 2925, 1726,
1
1
672, 1618, 1476, 1455, 1444, 1402, 1365, 1310, 1194, 1160, 1086,
1
063, 1048, 973, 816, 781, 706. H NMR (400 MHz, CDCl
3
):
d(major keto-form) = 4.55 (q, J = 6.7 Hz, 3H; BrCH(CH
3
)), 3.96
as a red oil (0.252 g, 88% of pure E isomer). In CDCl
3
at rt the
ꢀ
(
d, J = 15.2 Hz, 1H; COCHH CO), 3.70 (d, J = 15.2 Hz, 1H;
title compound exists as a (10 : 3) keto : enol mixture. mmax(thin
ꢀ
COCHH CO), 1.70 (d, J = 6.7 Hz, 3H; BrCH(CH
3
)), 1.42 (s,
). d (minor enol-form) = 5.50 (s, 1H; C(OH)CHCO),
.32 (q, J = 6.7 Hz, 3H; BrCH(CH )), 1.77 (d, J = 6.7 Hz,
H; BrCH(CH )), 1.46 (s, 9H; C(CH ). C NMR (100 MHz,
): d (keto-form) = 195.8, 192.5, 54.0, 49.2, 47.4, 29.6,
9.5. d (enol-form) = 196.9, 171.1, 98.6, 48.8, 44.0, 30.0, 22.2.
−
1
film)/cm = 3013m, 2962s, 2926s, 1693s, 1661s, 1643s, 1584s,
9
4
3
H; C(CH
)
3 3
1
1455m, 1375m, 1364m, 1295, 1161, 1100s, 1063s, 996s. H NMR
3
(
400 MHz, CDCl
keto-form), 6.55 (t, J = 7.1 Hz, 1H; CHC(CH
.07–6.02 (m, 4H, CHCHCHCHCHCH ), 5.69–5.57 (m, 2H;
CH(CH CHCH ), 5.49 (s, 1H; C(OH)CHCO enol), 3.82 (s,
CO keto), 2.32–1.91 (m, 5H; CH CHC(CH )CO,
CHCH and OH), 1.77 (d, J = 7.3 Hz, 3H;
)CO keto), 1.72 (s, 3H;
)COH enol), 1.52 (s, 9H; C(CH keto), 1.46 (s,
enol), 1.30–1.18 (m, 3H, CH CH CHC(CH )CO
)CH CH );
), 0.89 (d, J = 6.7 Hz, 3H, CHCH
C NMR (100 MHz, CDCl
3
): d = 6.62 (t, J = 6.7 Hz, 1H; CHC(CH
3
)CO
1
3
3
)
3 3
3
)COH enol-form),
CDCl
3
6
3
1
2
)
4
3
+
+
m/z (+ESI) = 290.99 (100%, M + Na ), 288.99 (95%, M + Na ).
2
H; COCH
2
2
2
3
+
+
HRMS (+ESI ): Found, 288.9872. C
9
H
15
2
O SBrNa (M + Na )
CH CHCH
3
requires, 288.9874.
CHCHCH
CHC(CH
9H; C(CH
and CH(CH
3
), 1.75 (s, 3H; CHC(CH
3
3
3 3
)
tert-Butyl-4-diethylphosphono-3-oxopentanethioate (4)
3
)
3
2
2
3
3
2
3
2
Sodium metal (0.336 g, 14.61 mmol) was washed (petroleum
ether) and placed in a dry round bottom flask. THF (20 ml)
and diethyl phosphite (1.74 ml, 13.49 mmol) were then added
sequentially via syringe. The resulting mixture was refluxed
for 2 h in order to prepare the phosphite anion. Meanwhile,
sodium hydride (0.495 g, 12.36 mmol) in a dry round bottom
flask was washed (petroleum ether), slurried with THF (30 ml),
1
3
3
): d (keto-form) = 193.4, 193.2,
1
4
1
1
2
45.9, 137.0, 132.2, 131.9, 131.7, 131.1, 130.3, 129.0, 53.8, 48.8,
0.1, 35.0, 33.0, 29.6, 27.0, 19.4, 18.2, 11.3; d (enol-form) =
96.4, 169.9, 137.0, 97.3, 48.2, 40.1, 35.1, 33.0, 30.2, 26.3, 19.4,
+
+
+
2.0. m/z (EI ) = 362 (30%, M ), 305.2 (26%, M –C(CH
3
3
) ),
+
03 (100% M –COCH
2
COSC(CH
3
)
3
), 174 (94%, C13
H
28SiO
18), 107
+
+
◦
(70%, C
8
H
11). HRMS (EI ): Found, 362.2264. C13
H
2
(M )
and cooled with stirring to −30 C. A solution of 16 (3.00 g,
requires, 362.2279.
1
1.24 mmol) in THF (20 ml) was then added quickly via cannula
to this chilled mixture; effervescence was observed. The resulting
solution was stirred for a further 10 min, whilst warming to
3
,4,5,6,7,8,9,10-Octahydro-4-diketothioate-4,7-dimethyl-(3E)-
◦
(prop-1,2-ene)naphthalene (17)
−
20 C, before addition of the THF solution of sodium diethyl
phosphate via cannula. The reaction mixture was slowly warmed
to rt with continuous stirring overnight. The residual solution
was quenched with saturated ammonium chloride (30 ml), and
partitioned between diethyl ether and water. The aqueous layer
was back-extracted with diethyl ether (2 × 30 ml). The combined
organics were then washed further with water (2 × 50 ml), brine,
dried (magnesium sulfate), filtered and concentrated in vacuo
affording the title compound 4 (crude) as a red oil (3.605 g,
To a stirred solution of triene 3 (0.25 g; 0.69 mmol) in CH
2
Cl
2
◦
(30 ml) at −78 C was added BF
3
·Et
2
O (0.16 ml; 1.38 mmol)
◦
dropwise via syringe. The reaction mixture was stirred at −78 C
◦
for 1 h and then allowed to slowly warm to 0 C over 8 h.
Water (10 ml) was then added to the colourless solution, the
organic layer was separated and the aqueous layer extracted with
CH
solvents removed in vacuo to give a crude oil. H NMR analysis
of the crude material indicated only one diastereoisomer had
been formed in the reaction. Purification by chromatography on
silica gel [eluting with petroleum ether–diethyl ether; (50 : 1)]
afforded the title compound (0.177 g; 71% yield) as a colourless
2
Cl
2
(4 × 20 ml). The organics were dried over MgSO
4
and the
1
9
9%). This material was used without further purification. In
CDCl at rt the title compound exists as a (9 : 1) keto : enol
3
−
1
mixture. mmax(thin film)/cm = 2966m, 1723s, 1673s, 1615s,
1
478, 1456, 1393, 1365, 1314, 1250s, 1163, 1016s, 960, 836,
1
790, 732, 689. H NMR (400 MHz, CDCl
3
): d = 5.47 (s, 1H;
oil. In CDCl at rt the title compound exists as a (10 : 3)
3
30
D
◦
COCHCOH enol) 4.18–4.08 (dq, J = 15.3 and 7.1 Hz, 4H; 2 ×
keto : enol mixture. [a] −139 (c 0.258, CHCl
3
); mmax(thin
ꢀ
−1
(OCH
2
)), 4.05 (d, J = 15.1 Hz, 1H; COCHH CO), 3.73 (d, J =
film)/cm = 3015m, 2949s, 2913s, 2867, [1716s, 1682s, 1652,
ꢀ
1
7
J
1
5.1 Hz, 1H; COCHH CO), 3.47 (dq, JPH = 26.1 Hz and JHH
=
1599s (b-ketothioester, overlaps triene region)], 1558, 1540,
.0 Hz, 1H; POCH(CH
3
) keto), 2.60 (dq, JPH = 26.1 Hz and
1456s, 1394m, 1375m, 1384m, 1287, 1215, 1162, 1075s, 1044m,
975, 962, 923, 860, 832, 776, 753. H NMR (400 MHz, CDCl
1
HH = 7.0 Hz, 1H; POCH(CH
3
) enol), 1.46 (s, 9H; SC(CH
3
)),
3
):
.37 (d, J = 7.0 Hz, 3H; POCH(CH
3
)), 1.35–1.30 (m, 6H; 2 ×
d (major keto-form and some significant signals of enol-form) =
5.43–5.29 (m, 3H; CH=CH of octalin and CH=CHCH
), 5.15–
5.11 (ddq, J = 15.1, 9.4 and 1.4 Hz, 1H; CH=CHCH
), 3.62
(d, J = 15.5 Hz, 1H; COCHHCO), 3.46 (d, J = 15.6 Hz,
1H; COCHHCO), 2.54–2.52 (m, 1H; CHCH=CHCH
),
enol), 1.80–1.77 (m, 1H;
axCH), 1.75–1.65, (m, 3H; CH CHCH
axCH), 1.67–1.60
CH
1
3
(OCH
2
CH )). C NMR (100 MHz, CDCl
3
3
): d = 197.7, 192.5,
3
1
7
71.5 (d, J = 6.0 Hz, COCHCOH enol), 62.6 (dd, J = 19.0 and
.4 Hz, 2 × (OCH2)), 58.0, 48.8, 48.2, 46.9 (d, J = 126.6 Hz,
3
POCH(CH
3
)CO keto), 38.6 (d, J = 157.5 Hz, POCH(CH
3
)CO
3
enol), 29.9, 16.2 (d, J = 6.0 Hz, POCH(CH
3
)), 10.5 (d, J =
2.40–2.38 (m, 1H; CHCH=CHCH
3
+
6
2
.0 Hz, 2 × (OCH
2
CH
3
)). m/z (APCI) = 325.0 (100%, MH ),
CH
CH
3
CHCHeq
H
3
2
CHringjunc.,
+
36.0 (65%), 209.1 (70%). HRMS (+ESI ): Found, 347.1056.
3
CHCH
2
CHeq
H
axCH and CH
2
3
3
CHCHeqH
+
C
13
H
25
O
5
PSNa (M + Na ) requires, 347.1058.
(m, 2H, CH
3
CHCH CH and CH
CHCH
2
2
CHringjunc.), 1.62
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0
2 7 9

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◦
13
(
dd, J = 6.5 and 1.4 Hz, 3H; CH=CHCH
SC(CH enol), 1.46 (s, 9H; SC(CH keto), 1.22–0.99 (m, 1H;
CH CHCH axCH), 1.17 (s,3H; CH CCO keto), 1.05 (s,
H; CH CCO enol), 0.96–0.89 (m, 1H; CH ),
.90 (d, J = 6.6 Hz, 3H; CH CH), 0.86 (d, J = 12.1 Hz,
H; CH ): d
3
), 1.51 (s, 9H;
−192.0 (c 0.014, CHCl
3
); C NMR (100 MHz, CDCl
3
): d =
3
)
3
3
)
3
207.9, 169.8, 168.6, 130.8, 130.4, 126.8, 126.3, 60.9, 60.0, 53.4,
52.2, 49.7, 46.2, 41.8, 39.8, 38.3, 35.5, 35.4, 33.3, 27.1, 22.4, 17.8,
17.3. HRMS(EI): Found, 405.2528. C23
405.2517.
3
2
CHeq
H
3
+
3
0
1
3
3
CHCHeq
H
axCH
2
H
35
O
5
N (M ) requires,
3
1
CHCH
2
3
3
CHCHeq
H
axCH). C NMR (100 MHz, CDCl
3
(
1
3
(
keto & enol) = 205.0, 193.1, 181.0, 131.7, 130.6, 130.5, 130.0,
Equisetin (1)
27.5, 126.9, 126.4, 125.2, 99.6, 54.7, 53.5, 49.5, 48.6, 41.9, 39.7,
To a solution of ketoamide 19 (30 mg; 0.073 mmol) in methanol
12 ml) at rt was added 0.73 ml of a solution of sodium methoxide
+
8.3, 35.5, 33.3, 29.7, 27.2, 22.4, 17.8, 16.8. m/z (EI ) = 362
(
+
+
+
71%, M ). HRMS (EI ): Found, 305.1589. C22
H
34SO
2
(M −57)
in methanol (5 eq) via syringe. After 10 min the reaction was
quenched by the addition of 1 N HCl (3 ml). The mixture was
requires, 305.1572.
then partitioned between water (10 ml) and CH
and the aqueous phase was extracted with CH Cl
The combined organic portions were dried over MgSO
2
Cl
(5 × 20 ml).
and
2
(25 ml),
3
,4,5,6,7,8,9,10-Octahydro-4-diketo-N-methylserinemethyl-
2
2
ester-4-diketothioate-4,7-dimethyl-(3E)-(prop-1,2-ene)-
naphthalene (18)
7b
4
concentrated in vacuo to give pure equisetin 1 (27 mg, 100%).
A solution of (S)-O-tert-butyldimethylsilyl N-methylserine
methyl ester (0.445g, 1.79 mmol) in THF (10 ml) was added
via cannula to a stirred solution of 17 (0.260 g, 0.717 mmol)
in THF at rt. Triethylamine (0.55 ml, 2.87 mmol) was then
added dropwise via syringe. The reaction mixture was cooled
Analytical data were in complete accordance with literature
2
8
◦
values (see ref 7b). [a] = −262 (c 0.038, CHCl
3
); mmax(thin
D
−
1
1
film)/cm = 2923, 2854, 1602, 1453. H NMR (400 MHz,
CDCl
3
) d = 5.40 (br s, 2H), 5.30–5.10 (m, 2H), 4.03 (dd, J =
11.5, 3.7 Hz, 1H), 3.95–3.82 (m, 1H), 3.64 (t, J = 4.4 Hz, 1H),
3.32 (br s, 1H), 3.06 (s, 3H), 2.10–1.65 (m, 4H), 1.56 (d, J =
4.8 Hz, 3H), 1.60–1.40 (m, 7H), 1.30–0.90 (m, 3H), 0.92 (d, J =
◦
to 0 C before silver trifluoroacetate (0.33 g, 1.43 mmol)
was added in one portion. The resulting solution was stirred
for a further 2 h then concentrated in vacuo. Purification by
chromatography on silica gel [eluting with petroleum ether–
+
6.5 Hz, 3H); m/z (ES ) 374 (100%), 356 (15%); HRMS(ES):
+
Found, 396.2148. C22
H
31
O
4
NNa (M + Na) requires, 396.2151.
ethyl acetate (4 : 1); R
afforded the title compound 18 as a colourless oil (0.36 g,
7%). In CDCl at rt the title compound exists as a (5 : 2)
keto : enol mixture. H NMR is complicated by a mixture of
f
(product) 0.35 (1 : 2 EtOAc–hexane)]
9
3
References
1 B. J. L. Royles, Chem. Rev., 1995, 95, 1981.
1
1
amide rotamers. H NMR (400 MHz, CDCl
and 5.29–5.08 (m, 4H; CHCHCH and CHCHCHCHC(CH
and enolic COCHCOH), 4–42–4.37 (m, 1H; N(CH )CH), 4.15–
OSi), 3.75 (d, J = 15.8 Hz,
H; COCHHCO), 3.71 (s, 3H; OCH
) 3.38 (d, J = 15.8 Hz,
H; COCHHCO), 3.08–3.06 (m, 3H; NCH ), 2.60–2.52 (m,
H; CHCH=CHCH keto), 2.42–2.40 (m, 1H; CHCH=CHCH
3
): d = 5.41–5.36
2
(a) S. V. Ley, S. C. Smith and P. R. Woodward, Tetrahedron Lett., 1988,
3
3
)
2
2
9, 5829; (b) S. V. Ley and P. R. Woodward, Tetrahedron Lett., 1997,
8, 3019.
3
4
1
1
1
.11 and 4.01–3.97 (2 × m, 2H; CH
2
3
(a) D. A. Longbottom, A. J. Morrison, D. J. Dixon and S. V. Ley,
Angew. Chem., Int. Ed., 2002, 41, 2786; (b) D. J. Dixon, S. V. Ley and
D. A. Longbottom, J. Chem. Soc., Perkin Trans. 1, 1999, 2231; (c) D. J.
Dixon, S. V. Ley, T. Gratzca and P. Szolcsanyi, J. Chem. Soc., Perkin
Trans. 1, 1999, 839; (d) S. V. Ley, S. C. Smith and P. R. Woodward,
Tetrahedron, 1992, 48, 1145.
3
3
3
3
enol), 1.81–1.58, 1.47–1.43, 1.26–1.22 and 1.12–0.86 (4 × m,
1
0H; saturated protons of octalin ring), 1.60 (d, J = 6.2 Hz,
H; CHCHCH ), 1.22 (s, 3H; CHC(CH )CO), 0.90 (m, 3H;
CH CH(CH )), 0.87 (s, 9H; SiC(CH ), 0.06 (s, 6H;
Si(CH ). C NMR (100 MHz, CDCl
): d (major keto-form) =
4
5
(a) H. R. Burmeister, G. A. Bennet, R. F. Vesonder and C. W.
Hesseltine, J. Antimicrob. Chemother., 1974, 5, 634; (b) J. W. Sims,
J. P. Fillmore, D. D. Warner and E. W. Schmidt, Chem. Commun.,
2005, DOI: 10.1039/b413523g.
(a) S. B. Singh, D. L. Zink, M. A. Goetz, A. W. Dombrowski, J. D.
Polishook and D. J. Hazuda, Tetrahedron Lett., 1998, 39, 2243; (b) N. J.
Phillips, J. T. Goodwin, A. Fraiman, R. J. Cole and D. G. Lynn, J. Am.
Chem. Soc., 1989, 111, 8223; (c) R. F. Vesonder, L. W. Tjarks, W. K.
Rohwedder, H. R. Burmeister and J. A. Laugal, J. Antibiot., 1979, 32,
759.
3
3
3
CH
2
2
3
)
3 3
1
3
3
)
2
3
1
1
5
95.8, 192.5, 54.0, 49.2, 47.4, 29.6, 19.5. d (minor enol-form) =
+
96.9, 171.1, 98.6, 48.8, 44.0, 30.0, 22.2. HRMS (ES ): Found,
+
42.3289. C29
H
49SiO
5
(M + Na) requires, 542.3278.
7b
Preparation of 19
To a stirred solution of silyl ether 18 (0.36 g; 0.69 mmol) in
CH CN (25 ml) at rt was added 48% HF (0.3 ml). The reaction
mixture was stirred for 15 min and then quenched by the careful
addition of solid NaHCO (1.5 g) and water (15 ml). The CH CN
was removed in vacuo and the residue extracted with ethyl acetate
5 × 20 ml). The combined extracts were dried over MgSO
and evaporated. Purification by chromatography on silica gel
eluting with petroleum ether–ethyl acetate (4 : 1)] afforded 19
6
7
L. T. Burke, D. J. Dixon, S. V. Ley and F. Rodr ´ı guez, Org. Lett., 2000,
2
, 3611.
3
(a) To date, two other total synthesis of equisetin have been reported:
K. Yuki, M. Shindo and K. Shishido, Tetrahedron Lett., 2001, 42,
2517; (b) E. Turos, J. E. Audia and S. J. Danishefsky, J. Am. Chem.
Soc., 1989, 111, 8231.
3
3
8
(a) For excellent works on the outcome of IMDA reactions, see: W. R.
Roush, in Comprehensive Organic Synthesis, Vol. 5, ed. B. M. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, p. 513; (b) D. J. Witter
and J. C. Vederas, J. Org. Chem., 1996, 61, 2613.
(
4
[
(
1
0.24 g; 85% yield) as a colourless oil. H NMR data were in
9 H. J. Bestmann, K.-H. Koschatzky, A. S. J. Plenchette and O.
3
0
complete accordance with literature values (see ref 7b). [a]D
Vostrowsky, Liebigs Ann. Chem., 1982, 3, 536.
2
8 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 4 – 2 8 0