Towards the total synthesis of vibsanin E, 15-O-methylcyclovibsanin B, 3-hydroxyvibsanin E, furanovibsanin A, and 3-O-methylfuranovibsanin A

Article abstract of DOI:10.1002/ejoc.200600246

Studies detailing synthetic approaches to a variety of biosynthetically related vibsanin-type diterpenes (i.e. vibsanin E, 15-O-methylcyclovibsanin B, 3-hydroxy-vibsanin E, furanovibsanin A, and 3-O-methylfuranovibsanin A) are discussed. Biogenetically modelled approaches are coupled with an investigation of classical and modern six- to seven-membered ring-expansion protocols, which gain access to the central core of these natural products. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200600246

FULL PAPER
DOI: 10.1002/ejoc.200600246
Towards the Total Synthesis of Vibsanin E, 15-O-Methylcyclovibsanin B,
3-Hydroxyvibsanin E, Furanovibsanin A, and 3-O-Methylfuranovibsanin A
Brett D. Schwartz,[a] David P. Tilly,[a] Ralf Heim,[a] Stefan Wiedemann,[a]
Craig M. Williams,*[a] and Paul V. Bernhardt[a]
Keywords: Natural products / Terpenoids / Diterpenes / Vibsanin / Ring expansion
Studies detailing synthetic approaches to a variety of biosyn-
thetically related vibsanin-type diterpenes (i.e. vibsanin E,
15-O-methylcyclovibsanin B, 3-hydroxy-vibsanin E, furano-
vibsanin A, and 3-O-methylfuranovibsanin A) are discussed.
Biogenetically modelled approaches are coupled with an in-
vestigation of classical and modern six- to seven-membered
ring-expansion protocols, which gain access to the central
core of these natural products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
3-hydroxyvibsanin E 11, furanovibsanin A 12, and 3-O-
methylfuranovibsanin A 13 (Figure 2), results of which are
reported herein.
In the process of elucidating vibsane biochemical path-
ways Y. Fukuyama investigated the conversion of vibsanin
C (2) to vibsanin E (3)[12] and found that conversion pro-
ceeded smoothly using borontrifluoride–diethyl ether, albeit
in moderate yield (50%) (Scheme 1).
In addition to Fukuyama’s biosynthetic insight above
(Scheme 1), which is further summarized as path A
(Scheme 2), he also postulated a relationship to the cyclo-
vibsanins (e.g. 5, 14–16) originating from the same interme-
diate according to path B (Scheme 2).[5]
Vibsane-type diterpenes can be regarded as quite rare
natural products as they occur exclusively in Viburnum spe-
cies such as V. awabuki,[1] V. odoratissimum[2] and V. suspen-
sum.[3] This family maintain a wide variety of structure
types which consist of nine structure subtypes, vibsanin B
1,[1] vibsanin C 2,[1] vibsanin E 3,[1] vibsanin O 4,[4] cyclovib-
sanin A 5,[5] furanovibsanin D 6,[6] spirovibsanin A 7,[7] al-
dolvibsanin B 8,[8] and neovibsanin A 9[9] (Figure 1).
Our group has an attraction to caged bicyclic moieties
within a natural product carbon skeleton[10] and as such we
were attracted to the vibsanin family of molecules, espe-
cially those of type 3, 5, 6 and 7[11] (Figure 1). More specifi-
cally, however, we targeted direct routes to advanced inter-
Fukuyama’s very plausible biosynthetic relationships
mediates of vibsanin E 3, 15-O-methylcyclovibsanin B 10, formed the basis of our retrosynthetic frame[13] (Scheme 3),
Figure 1. A collection of the structural diversity seen in the vibsanin type diterpene family.
in that the aim was to utilise functionality seen in vibsanin
[a] School of Molecular and Microbial Science
C (2) in the form of a six-membered ring 17 rather than a
seven-membered ring. Different modes of cyclisation would
then gain access to intermediates 18 and 20, which would
University of Queensland
Brisbane, 4072, Queensland, Australia
E-mail: c.williams3@uq.edu.au
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C. M. Williams et al.
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Figure 2. Vibsanin type diterpene synthetic targets.
Scheme 1.
Scheme 2.
be subjected to ring expansion affording 19 and 21. If this the allylic alcohol 22 in 32% yield (43% based on recovered
protocol found success, the approach could essentially be starting material). A number of other reported procedures
applied to total syntheses of multiple vibsanin targets (e.g. either failed to react[16] or were lower yielding.[17] In the
vibsanin E 3, 3-hydroxyvibsanin E 11 and furanovibsanin view that yields in the order of 32% are unsatisfactory for
A 12).
early stages of total syntheses we set about improving this
Pivotal to the success of this endeavour was to gain ac- result. Considering the substrate 25 is very lipophilic and
cess to cyclohexenones of type 17. A number of direct ap- the transition state for the Baylis–Hillman reaction is very
proaches based on the carboxylic acid function were investi- polar surfactants [i.e. sodium dodecyl sulfate (SDS)] were
gated, which consisted of attempts reliant on electrocyclic employed so that the substrate could be dissolved in polar
cyclisations or intramolecular Knoevenagel condensations media (water). This change in conditions afforded 22 in
but these failed. Utilising the El Gaïed[14] Baylis–Hillman over double the yield (63%), although on larger scale a
protocol, however, furnished a cyclohexenone 22 containing lower yield of 53% was obtained which was still a major
the more desirable methylene hydroxy function. 3-Methyl- improvement (Scheme 4).[18]
cyclohexenone (23) was treated with the homoprenylcuprate
Cyclisation studies involving cyclohexenone 22 utilising
giving the 1,4-addition product 24 in 85% yield and subse- borontrifluoride–diethyl ether, as demonstrated by Fukuy-
quent dehydrogenation with IBX·NMO[15] afforded the α,β- ama in the conversion of vibsanin C (2) to vibsanin E (3),
unsaturated ketone 25 (64%). For the Baylis–Hillman reac- gave cyclized material 26, albeit only on small scale. Scaling
tion it was found that reaction of 25 using DMAP afforded up the reaction always gave unidentified material until it
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Scheme 3.
cyclisation to 26 and afford the desired material, however,
this failed. After much thought, in that protonated OH (i.e.
ROH2+) also acts as a leaving group, 22 was heated in diox-
ane in the presence of 2  hydrochloric acid, however, only
the oxygenated tricycle 26 was obtained (68%). Increasing
the temperature resulted in substantial decomposition. Al-
though, when dioxane was removed and 22 (0.6 mmol) was
heated in 3  hydrochloric acid at 120 °C carbotricycle 27
was obtained in 67% along with 26 (10%). If the scale of
the reaction was increased to 2.5 mmol 27 was obtained in
50%, and 26 in 15%, but this time the hydroxylated car-
botricycle 28 was also formed in 14% (mixture of diastereo-
isomers, ca. 1:1; Scheme 5).
Scheme 4.
With precursor tricycles 26–28 in hand further elabora-
tion of these ring systems 26–28 was required before ring
expansion studies could be performed. For example, to gain
access to the cores of 3-hydroxyvibsanin E 11, furanovib-
sanin A 12, and 3-O-methylfuranovibsanin A 13, 26 must
undergo regioselective alpha hydroxylation (or meth-
oxylation). Tricycle 27 must also undergo regioselective hy-
droxylation (or methoxylation) for access to cyclovibsanins
5, 14–16. Even though 28 contains oxygen functionality at
the required position it was not utilized further due to the
low yield and lack of stereoselection.
was realised that BF3·Et2O was most likely not the active
agent, but rather hydrofluoric acid. Treating 22 with anhy-
drous ethereal hydrochloric acid conversely gave 26 in 58%
yield, whereas simply stirring 22 in dichloromethane with
Amberlyst® ion exchange resin afforded 26 in 68%
(Scheme 5). In fact subsequent investigations showed that
all synthetic operations starting from 23 could be per-
formed without purification up to 26 making the whole se-
quence much more practical (22% overall yield).
In the case of 26 a number of alpha hydroxylation proto-
cols were investigated. Koser’s reagent[20] [PhI(OH)(OTs)]
was found to be superior to that of Davis’ reagent
(PhCHONSO2Ph)[21] (no reaction) and dimethyldioxir-
ane[22] (mixture of regioisomers) in that only the desired
regioisomer (i.e. 29) was obtained, albeit in moderate yield
(47%) (Scheme 6). It is worthy of note that to the best of
our knowledge this is the first instance that Koser’s reagent
has given α-hydroxylation directly instead of the normal α-
tosylation (which is applicable to 3-hydroxyvibsanin E 11,
furanovibsanin A 12). Although access to the methoxy de-
rivative (i.e. 33) is conceivable via alcohol 29 a different
Scheme 5.
Initial attempts at utilising 22 to probe Fukuyama’s vib- route via iodides 31 and 32 was investigated to avoid the
sanin C (2) to cyclovibsanin biosynthetic postulate[19] were moderate yield of 29 (Scheme 6). Treating tricycle 26 with
unsuccessful. It was first envisaged that treating 22 with a lithium diisopropylamide (LDA) at –78 °C followed by ad-
suitable protecting group (i.e. trifluoroacetyl) that would dition of iodine gave a mixture of iodides 31 and 32 in 80%
also act as leaving group might induce elimination, prevent and 14% yield respectively. The method of Pan et al.[23] was
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C. M. Williams et al.
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Scheme 6.
also found to give iodide 32, however, in much lower yield
(46%). Initially we had assumed iodide 32, when reacted
with potassium carbonate in methanol, a slight modifica-
tion to that of Fraser-Reid,[24] was responsible for the for-
mation of 33 (X-ray crystal structure Figure 3) in 93%
yield. This result was somewhat confusing as 33 maintained
retention of stereochemistry. As both iodides are readily
separable both were treated with potassium carbonate in
methanol, which gave rise to the same product 33. This re-
sult is easily explained in that a Favorskii type cyclopro-
panone 34 must have formed which was attacked by meth-
anol (or KOMe) giving 33. Surprisingly, the reaction did
not work in the absence of potassium carbonate and treat-
ment with sodium methoxide in methanol gives lower yields
of 33 accompanied by an unidentified product, which is as-
sumed to be associated with Favorskii ring contraction
(Scheme 6).
Scheme 7.
Ring expansion studies were performed on 26 in the first
instance and required considerable effort in determining the
appropriate protocol. Attempts with stabilized carbenoids
(e.g. EtO2CCHN2), known to insert regioselectively at
the least-substituted carbon alpha to ketones, using
BF3·Et2O[26] or Meerwein’s salt[27] failed, as did non-stabi-
lized carbenoids,[28] ethyl diazolithioacetate[29] and silyloxy-
cyclopropane homologation.[30] Considering Beckwith–
Dowd[31] and variant[32] ring expansion protocols are widely
reported, 26 was converted, using Mander’s reagent[33] and
subsequent retro Dieckmann/Dieckmann reaction, to 36
(X-ray crystal structure of α-CO2Et, see Figure 4) in 69%
overall yield. All attempts to convert 36 to the methylene
iodide 37 or bromide 38 failed when 36 was reacted directly
with diiodo- or dibromomethane. Reaction of 36 with for-
malin[34] gave the methylene hydroxy derivative 39 (84%),
which using triphenylphosphane iodine and imidazole gave
iodide 37 (75%). Unfortunately, treating iodide 37 with sa-
Figure 3. ORTEP3 drawing of compound 33 (30% probability el-
lipsoids).
Methoxy functionality was easily introduced into 27
both regioselectively and stereoselectively by treating 27
with mercuric acetate in methanol, followed by sodium hy-
droxide (3 ) and sodium borohydride,[25] which afforded
35 in 61% yield (Scheme 7).
Figure 4. ORTEP3 drawing of compound 36 (30% probability el-
lipsoids).
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marium diiodide[35] only afforded cyclopropanol 40 (72%)
Ring expansion of 33 was also investigated. When given
and unidentified products, whereas zinc metal[36] only re- the choice tricycle 26 will undergo regioselective deproton-
turned starting material (Scheme 8). Attempts (e.g. DBU, ation at the tertiary position alpha to the carbonyl, which
NaOEt) to ring-open 40, the only donor-acceptor-substi- was a limiting factor (regioselection) in choosing 6- to
tuted cyclopropane known to-date,[37] surprisingly failed. seven-membered ring expansion methods above. However,
Applying the Zercher reaction (ZnEt2/CH2I2)[38] however, now that the tertiary position had been blocked by the
afforded the desired ring-expanded material 41 in 50% yield methoxy function it was possible to investigate the Saegusa
(dr Ͼ95:5). The yield was not increased using Xue’s modi- ring expansion[42] protocol. The Saegusa protocol has the
fied Zercher conditions.[39] Molecular mechanics calcula- added advantage in that it achieves two goals in the one
tions suggest the lowest energy arrangement is where C2 transformation, that is, ring expansion and formation of en-
has the ester function in the β position.[40]
one functionality, which at the time was seen as important
for developing the required side chains seen in the natural
products. Davies’ recently demonstrated that a photochemi-
cal [4+2] cycloaddition will achieve this goal, albeit with the
incorrect stereochemistry.[43] Tricycle 33 was deprotonated
with LDA in the presence of trimethylsilyl chloride afford-
ing the silyl enol ether, which was cyclopropanated (ZnEt2/
CH2I2) without purification affording 45. Reaction of 45
with anhydrous iron(III) chloride in N,N-dimethylform-
amide followed by treatment with sodium acetate led to a
separable mixture of desired endocyclic ring-expanded en-
one 46 (13%) as the minor product and undesired exocyclic
enone 47 (41%) as the major product (Scheme 10). The
overall yield (i.e. 33–46) was a very disappointing 4%.
Scheme 8.
Applying this ring expansion protocol to the cyclovib-
sanin case (i.e. 35) performed less admirably, for example,
tricycle 35 was converted into 42 in only 54% overall yield.
In this instance ethoxide only converted the 1:1 (42:43) mix-
ture, obtained from the reaction with Mander’s reagent,
into a mixture of 8:2 (42/43). Subjecting 42 to the Zercher
ring expansion protocol afforded the core 44 in only 15%
yield with the choice of conditions being critical. After
much experimentation it was found that when the number
Scheme 10.
For comparative purposes the Zercher reaction was em-
of equivalents of both diethylzinc and diiodomethane was ployed, but firstly tricycle 33 was converted via Mander rea-
increased to 16 in toluene[41] the reaction proceeded (dr Ϸ gent (EtO2CCN) into ester 48 in 63% yield. Subsequent
1:1; see Scheme 9).
reaction with Zercher’s reagent under a variety of condi-
Scheme 9.
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C. M. Williams et al.
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Scheme 11.
ratus and are uncorrected. Fine chemicals were purchased from the
Aldrich Chem. Co. Gas Chromatography was performed on a Var-
ian 3300 fitted with an Altech Econo-Cap EC-5 column
(30 m×0.25 mm×0.25 µ) (flame ionization detection). CCDC-
299909 to -299911 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
tions led to epimeristion of the stereocentre attached to the
ester function (i.e. 49, see Figure 5) without formation of
the ring-expanded product 50 (Scheme 11).
3-Methyl-3-(4-methylpent-3-enyl)cyclohexanone (24): 5-Bromo-2-
methyl-2-pentene: Following the method of Biernacki and
Gdula.[44] To a solution of methylmagnesium bromide (80.0 mL,
240.0 mmol) (3.0  in diethyl ether) in anhydrous THF (80 mL)
under an argon atmosphere was added dropwise (30 min) a solu-
tion of cyclopropyl methyl ketone (16.82 g, 200.0 mmol) in THF
(30 mL). The mixture was then heated to reflux for 20 min. On
cooling to room temp. the reaction mixture was slowly added to a
cooled solution of conc. sulfuric acid in water (1:2, 150 mL) at a
rate that the temperature does not raise above 10 °C. After addition
stirring was continued for 30 min. The organic layer was then sepa-
rated, the aqueous solution was extracted with diethyl ether and the
combined organic phases were washed with sat. sodium carbonate
solution and brine. After drying over sodium sulfate the solvent
was removed in vacuo and the residue was distilled (60–65 °C/water
aspirator) to afford 5-bromo-2-methyl-2-pentene (25.0 g, 77%) as
a colourless oil. 1H NMR (200 MHz, CDCl3): δ = 1.61 (s, 3 H),
1.70 (s, 3 H), 2.48–2.62 (m, 2 H), 3.32 (t, J = 7.3 Hz, 2 H), 5.04–
5.19 (m, 1 H). Magnesium turnings (5.59 g, 230.0 mmol) were
stirred under high vacuum and an argon atmosphere introduced.
Figure 5. ORTEP3 drawing of compound 49 (30% probability el-
lipsoids).
In conclusion we have demonstrated that the cores (i.e.
41, 44 and 46) of vibsanin E (3), cyclovibsanins (5, 14–16)
and 3-O-methylfuranovibsanin A 13 can be constructed in
overall yields ranging from 0.8–9% and serendipitously
without the use of a single protecting group. We are in-
debted to the El Gaïed Baylis–Hillman variant and the re-
markable Zercher reaction which will pave the way for a
successful total synthesis and structural confirmation of
vibsanin E (3). Finally, this work lends strong support to Iodine crystals (20 mg) were added followed by freshly distilled
THF (250 mL). 5-Bromo-2-methyl-2-pentene (24.9 g, 152.7 mmol),
a portion (2 mL) of which was added directly to the THF suspen-
sion to start the reaction (heat was required to initiate), was dis-
solved in anhydrous THF (20 mL) and the solution added dropwise
to the above suspension over 20 min with heating. The mixture was
then refluxed for 1.5 h. Copper bromide–dimethyl sulfide com-
plex[45] (1.54 g, 7.5 mmol) was dissolved in anhydrous THF
Fukuyama’s proposed biosynthesis of these natural prod-
ucts.
Experimental Section
1H and 13C NMR spectra were recorded on Bruker AV400
(400.13 MHz; 100.62 MHz), AV300 (300.13 MHz; 75.47 MHz) and (100 mL) under an argon atmosphere. The solution was then co-
DRX500 (500.13 MHz; 125.76 MHz) instruments in deuteriochlor-
oform (CDCl3). Coupling constants are given in Hz and chemical
shifts are expressed as δ values in ppm. High and low resolution
EI mass spectroscopic data were obtained on a KRATOS MS 25
RFA. Microanalyses were performed by the University of Queens-
land Microanalytical Service. Column chromatography was under-
taken on silica gel (Flash Silica gel 230–400 mesh), with distilled
solvents. Anhydrous solvents were prepared according to Perin and
Armarego, “Purification of laboratory solvents”, 3rd edition. Melt-
ing points were determined on a Fischer Johns Melting Point appa-
oled to –20 °C and the Grignard solution added via syringe over
5 min. After 30 min at –20 °C 3-methyl-2-cyclohexenone (23)[46]
(16.0 g, 145.2 mmol) was added (30 min) and the reaction stirred
for 15 min at –20 °C before warming to room temperature out of
the bath. The reaction mixture was then treated with sat. NH4Cl
solution and the organic layer separated. The aqueous solution was
extracted with diethyl ether and the combined organic layers were
washed with brine and dried (Na2SO4). After removal of the sol-
vent in vacuo the residue was subjected to vacuum distillation (66
°C/0.8 Torr) yielding the title compound as a colourless oil (23.91 g,
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85%). [Note: similar results were obtained when copper(I) iodide
(5 mol-%), washed with anhydrous ethanol (×2) then with anhy-
drous diethyl ether (×4)] was used.] Rf (petroleum ether/ethyl ace-
chromatography (ethyl acetate/petroleum ether, 1:2) to give com-
pound 22 (608 mg, 53%) as colourless liquid. [Note: on smaller
scale (ca. 100 mg) a yield of 63% was obtained.] Rf (petroleum
1
1
tate, 20:1) = 0.43. H NMR (400 MHz, CDCl3): δ = 0.91 (s, 3 H),
ether/ethyl acetate, 5:2) = 0.27. H NMR (CDCl3, 500 MHz): δ =
1.22–1.27 (m, 2 H), 1.48–1.67 (m, 2 H), 1.56 (br. s, 3 H), 1.62 (br.
d, J = 1.2 Hz Hz, 3 H), 1.78–1.94 (m, 4 H), 2.06–2.11 (m, 2 H),
2.15–2.19 (m, 2 H), 2.24 (t, J = 6.6 Hz, 2 H), 5.02–5.07 (m, 1 H).
0.91 (s, 3 H), 1.22–1.29 (m, 2 H), 1.48 (s, 3 H), 1.56 (s, 3 H), 1.79–
1.90 (m, 2 H), 2.10–2.30 (m, 4 H), 2.94 (br. s, OH), 4.14–4.15(m, 2
H), 4.94–4.98 (m, 1 H), 6.70–6.73 (m, 1 H). 13C NMR (CDCl3,
13C NMR (100 MHz, CDCl3): δ = 17.4, 21.93, 21.96, 24.7, 25.5, 125 MHz): δ = 17.6, 22.4, 24.7, 25.6, 36.7, 38.0, 41.3, 50.3, 60.6,
35.7, 38.4, 40.8, 41.5, 53.5, 124.2, 131.3, 212.0. Mass spectrum:
124.1, 131.7, 137.5, 144.2, 200.4. Mass spectrum: m/z (EI) 222
m/z (EI) 194 (M+·, 7%), 151 (8), 111 (100), 97 (5), 83 (6), 69 (23), (M+·, 9%), 204 (14), 189 (10), 164 (8), 161 (15), 139 (22), 121 (86),
55 (18). C13H22O (194.31): calcd. C 80.35, H 11.41; found C 80.25,
H 11.64.
109 (53), 97 (22), 83 (18), 69 (49), 55 (39), 41 (100). C14H22O2
(222.32): calcd. C 75.63, H 9.97; found C 75.65, H 10.27.
1,7,7-Trimethyl-6-oxatricyclo[6.2.2.0[4,9]]dodecan-3-one
(26).
5-Methyl-5-(4-methylpent-3-enyl)-2-cyclohexenone (25): A mixture
of o-iodoxybenzoic acid (IBX)[47] (7.42 g, 26.5 mmol) and N-meth-
ylmorpholine N-oxide (NMO) (3.23 g, 27.6 mmol) was dissolved in
25 mL of DMSO and heated to 70 °C. 3-Methyl-3-(4-methylpent-
3-enyl)cyclohexanone (2.145 g, 11.04 mmol) was added at 70 °C
and the mixture heated at that temperature for 4.5 h. (The comple-
tion of the reaction was determined by GC). On cooling the mix-
ture was diluted with sodium hydrogen carbonate solution
(500 mL) (1:1 saturated sodium hydrogen carbonate/water), ex-
tracted with diethyl ether (4×150 mL) and the combined extracts
washed with saturated sodium hydrogen carbonate solution and
brine. The diethyl ether layer was dried (Na2SO4) and the solvent
was removed in vacuo. The residue was subjected to column
chromatography (petroleum ether/ethyl acetate, 20:1) yielding the
title compound (1.35 g, 64%) as a pale yellow oil. Rf (petroleum
ether/ethyl acetate, 20:1) = 0.26. 1H NMR (CDCl3, 500 MHz): δ =
1.00 (s, 3 H), 1.30–1.38 (m, 2 H), 1.56 (br. s, 3 H), 1.64 (br. d, J =
1.1 Hz Hz, 3 H), 1.85–1.98 (m, 2 H), 2.13–2.17 (m, 1 H), 2.21–2.25
(m, 1 H), 2.27–2.33 (m, 2 H), 5.01–5.06 (m, 1 H), 5.99 (dt, J = 2.0,
10.1 Hz Hz, 1 H), 6.81–6.85 (m, 1 H). 13C NMR (CDCl3,
125 MHz): δ = 17.5, 22.3, 24.7, 25.6, 36.5, 38.1, 41.4, 50.1, 124.0,
129.0, 131.7, 148.2, 199.8. Mass spectrum: m/z (EI) 192 (M+·,
12%), 149 (10), 124 (25), 109 (100), 95 (5), 81 (13), 69 (18), 55 (10).
Method A: A solution of 2-hydroxymethyl-5-methyl-5-(4-meth-
ylpent-3-enyl)-2-cyclohexenone (22) (260 mg, 1.17 mmol) in anhy-
drous CH2Cl2 (40 mL) was cooled to –78 °C under an argon atmo-
sphere. Anhydrous ethereal hydrochloric acid (1.25 mL, 2.5 mmol,
2 ) was added and the solution stirred at –78 °C for 1 h and then
warmed to 0 °C over 3 h. The reaction was quenched at 0 °C by
addition of saturated sodium hydrogen carbonate solution (4 mL).
On warming to room temperature a further portion of saturated
sodium hydrogen carbonate solution (5 mL) was added and the
layers separated. The aqueous layer was extracted with dichloro-
methane (5×10 mL) and the combined organic phases washed with
brine, dried (MgSO4) and the solvent removed in vacuo. The resi-
due was subjected to column chromatography (petroleum ether/
ethyl acetate, 10:1) yielding 22 (150 mg, 58%) as a colourless oil,
which crystallised on refrigeration to produce colourless needles,
m.p. 61–62 °C. [Note: Column chromatography fractions were ana-
lysed by GC as TLC detection of 26 is difficult.]
Method B: To a vigorously stirring solution of 22 (614 mg,
2.77 mmol) in dichloromethane (20 mL) at 0 °C was added Am-
berlyst-15 (600 mg) in one portion followed by warming to room
temperature over 2 h. After additional stirring at room temperature
for 2 h the mixture was filtered and concentrated in vacuo. The
residue was then purified by flash chromatography (ethyl acetate/
petroleum ether, 1:5) on silica affording 26 (420 mg, 68%) as a
white solid. Rf (petroleum ether/ethyl acetate, 10:1) = 0.2. 1H NMR
(CDCl3, 500 MHz): δ = 0.94 (s, 3 H), 1.04 (s, 3 H), 1.20–1.32 (m,
3 H), 1.24 (s, 3 H), 1.49–1.59 (m, 3 H), 1.76–1.80 (m, 1 H), 1.93–
1.95 (m, 1 H), 2.07 (d, J = 16.5 Hz Hz, 1 H), 2.29 (dd, J = 16.5 Hz,
3 Hz, 1 H), 2.66–2.70 (m, 1 H), 3.52 (dd, J = 3.6, 11.9 Hz Hz, 1
H), 4.46 (d, J = 11.9 Hz Hz, 1 H). 13C NMR (CDCl3, 125 MHz):
δ = 20.8, 22.8, 27.8, 28.7, 31.0, 31.9, 33.9, 38.9, 41.46, 42.3, 46.4,
53.3, 58.6, 73.7, 210.3. Mass spectrum: m/z (EI) 222 (M+·, 14%),
207 (18), 164 (10), 146 (3), 136 (4), 129 (6), 121 (6), 109 (8), 106
(10), 94 (100), 79 (14). C14H22O2: calcd. M+· 222.1614; found M+·
222.1619.
1,7-Dimethyltricyclo[6.2.2.04,9]dodec-6-en-3-one (27): Small-scale
synthesis: 2-Hydroxymethyl-5-methyl-5-(4-methylpent-3-enyl)-2-cy-
clohexenone (22) (130 mg, 0.58 mmol) was placed in a sealed tube
with aqueous 3  hydrochloric acid (8 mL). The mixture was
heated at 120 °C for 2 h. On cooling, diethyl ether (30 mL) was
added, and the aqueous layer extracted with diethyl ether
(2×30 mL). The combined organic layers were dried (MgSO4) and
the solvent removed in vacuo. The residue was subjected to column
chromatography (petroleum ether/ethyl acetate, 95:5) on silica,
which afforded two fractions. Fraction one was the product 27
(79 mg, 67%) as a colourless oil and fraction 2 was 1,7,7-trimethyl-
6-oxatricyclo[6.2.2.04,9]dodecan-3-one (26) (13 mg, 10%) as colour-
less needles.
2-Hydroxymethyl-5-methyl-5-(4-methylpent-3-enyl)-2-cyclohexenone
(22). Method A: 5-Methyl-5-(4-methylpent-3-enyl)-2-cyclohexenone
25 (2.89 g, 15.0 mmol) was dissolved in THF (15 mL) and 4-(di-
methylamino)pyridine (DMAP) (1.83 g, 15.0 mmol) added. The
mixture was heated at 50 °C for 30 min before the addition of for-
malin (15 mL, 37 wt.-%). After 4 h at 50 °C a further portion of
formalin (15 mL) and THF (15 mL) was added and the mixture
stirred for an additional 5 h. On cooling the reaction was quenched
with 1  hydrochloric acid (250 mL) and extracted with diethyl
ether (5×50 mL). The combined organic phases were washed with
saturated sodium hydrogen carbonate solution, brine, and then
dried with MgSO4. The solvent was removed in vacuo and the resi-
due subjected to column chromatography (petroleum ether/ethyl
acetate, 5:2) yielding starting material (780 mg, 27%) and 22
[1.05 g, 32% (43% based on recovered starting material)] as a pale
yellow oil. A minor (Ͻ5%) impurity could not be removed from
the title compound. [Note: using 25 in crude form (no silica column
or plug) for this reaction does not give 22.]
Method B: To a mixture of water (5 mL) and ketone 25 (1 g,
5.15 mmol) were added SDS (148 mg, 0.52 mmol) and DMAP
(630 mg, 5.15 mmol). After stirring for 15 min, formalin (5 mL)
was added and the stirring was continued at room temperature.
After 3 h additional formalin (5 mL) and DMAP (100 mg) were
added and the reaction was stirred for 12 h. The mixture was then
quenched with brine (10 mL) and extracted with diethyl ether
(3×40 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo. The residue was then purified by column
Large-scale synthesis: Compound 22 (550 mg, 2.47 mmol) placed
in a sealed tube with aqueous 3  hydrochloric acid (35 mL). The
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3187

C. M. Williams et al.
FULL PAPER
reaction mixture was stirred at 120 °C for 2.5 h. On cooling the
mixture was extracted with diethyl ether (3×30 mL), and the or-
ganic phase, dried (Na2SO4) and concentrated. The oily residue
was purified by chromatography on silica gel (petroleum ether/ethyl
acetate, 95:5) affording compound 27 (248 mg, 50%), the alcohol
28 (76 mg, 14%) and tricycle 26 (83 mg, 15%).
(4 mL) was added. After stirring for 10 min, sodium borohydride
(35 mg, 0.8 mmol) in sodium hydroxide 3  (3 mL) was added and
after 30 min the mixture was filtered. The filtrate was extracted
with diethyl ether (2×20 mL), the combined organic layers dried
(MgSO4), and the solvent removed in vacuo. The residue was sub-
jected to column chromatography (petroleum ether/ethyl acetate,
95:5) on silica yielding the 35 as a colourless oil (115 mg, 61%),
which crystallised (hexane) on standing at +5 °C for about 12 h.
1,7-Dimethyltricyclo[6.2.2.04,9]dodec-6-en-3-one (27):1H NMR
(CDCl3, 300 MHz): δ = 0.95 (s, 3 H), 1.25–1.38 (m, 1 H), 1.44–
1.54 (m, 1 H), 1.58 (dd, J = 3.7, 1.8 Hz, 3 H), 1.63 (dt, J = 13.3,
2.6 Hz, 2 H), 1.72–1.86 (m, 3 H), 1.88–2.02 (m, 1 H), 2.09 (br. dt,
J = 15.8, 1.2 Hz, 1 H), 2.25 (dd, J = 16.0, 2.8 Hz, 1 H), 2.31–2.38
(m, 2 H), 2.86 (ddd, J = 17.8, 4.3, 1.7 Hz, 1 H), 5.14–5.19 (m, 1
H). 13C NMR (CDCl3, 75 MHz): δ = 22.1, 23.3, 26.5, 31.0, 35.3,
35.7, 39.2, 39.5, 41.5, 45.9, 53.3, 117.9, 137.9, 212.3. Mass spec-
trum: m/z (EI) 204 (M+·, 100%), 189 (20), 181 (15), 175 (20), 167
(20), 159 (31), 149 (30), 135 (92), 130 (15), 119 (34), 111 (15), 105
(20), 95 (15), 91 (35). HRMS (EI): [M]+ calcd. for C14H20O M+
204.1514, found M+· 204.1519.
1
M.p. 28 °C. H NMR (C6D6, 300 MHz): δ = 0.69 (s, 3 H), 0.79 (s,
3 H), 0.91–1.22 (m, 4 H), 1.23–1.57 (m, 6 H), 1.72–1.85 (m, 2 H),
2.17 (dd, J = 15.9, 3.0 Hz, 1 H), 2.39–2.48 (m, 1 H), 2.51–2.62 (m,
1 H), 2.94 (s, 3 H). 13C NMR (C6D6, 75 MHz): δ = 20.1, 22.0, 22.5,
26.4, 30.9, 33.3, 34.3, 39.4, 41.6, 43.7, 46.5, 47.8, 53.5, 76.2, 210.4.
Mass spectrum: m/z (EI) 236 (M+·, 35%), 221 (6), 204 (16), 189 (7),
175 (6), 162 (7),n 143 (10), 142 (14), 121 (5), 109 (6), 94 (24), 85
(100), 79 (7), 72 (56). HRMS (EI): [M]+ C15H24O2 calcd. M+
236.1776, found M+· 236.1779.
Ethyl 1,7,7-Trimethyl-3-oxo-6-oxatricyclo[6.2.2.04,9]dodecane-2-car-
boxylate (36): To a solution of ketone 26 (552 mg, 2.49 mmol) at
–78 °C in anhydrous THF (15 mL) under n argon atmosphere was
added dropwise a solution of lithium diisopropylamide [prepared
from diisopropylamine (418 µL, 2.99 mmol) in THF (24 mL) and
n-butyllithium 1.3  (2.1 mL, 2.74 mmol, solution in hexanes) at
0 °C]. After 30 min ethyl cyanoformate was added followed by
hexamethylphosphorous triamide (600 µL) and then the reaction
was warmed to room temperature over 12 h. The reaction was
quenched by pouring onto ice-cold satd. aqueous ammonium chlo-
ride (15 mL) then extracted with diethyl ether (3×25 mL) and the
combined organic layers were then washed with brine (15 mL),
dried (MgSO4) and concentrated in vacuo. The crude product was
dissolved in anhydrous THF (3 mL) and added dropwise to an ice
cold solution of sodium ethoxide [prepared from ethanol (620 µL,
9.96 mmol) in anhydrous THF (10 mL) and sodium hydride
(200 mg, 4.98 mmol, 60% dispersion on mineral oil) at 0 °C] then
warmed to room temperature over 2 h. The reaction was worked
up as above then purified by flash chromatography (ethyl acetate/
petroleum ether, 1:10) to afford the title compound 36 [337 mg,
46% (based on recovered starting material 69%)] as a white solid
(m.p. 122–123 °C) and recovered starting material (185 mg, 33%).
1H NMR (CDCl3, 300 MHz): δ = 0.99 (s, 3 H), 1.07 (s, 3 H), 1.07–
1.24 (m, 2 H), 1.25 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.29–1.47
(m, 1 H), 1.54–1.68 (m, 2 H), 1.85 (dt, J = 13.3, 3.2 Hz, 1 H), 2.03–
2.07 (m, 1 H), 2.35–2.45 (m, 1 H), 2.67–2.75 (m, 1 H), 3.06 (s, 1
H), 3.58 (dd, J = 12.0, 3.6 Hz, 1 H), 4.12–4.29 (m, 2 H), 4.44 (d, J
= 12.0 Hz, 1 H). 13C NMR (CDCl3, 75 MHz): δ = 14.2, 20.6, 22.5,
27.5, 29.1, 31.8, 34.6, 37.5, 42.3, 43.2, 46.2, 58.1, 60.6, 66.2, 73.5,
168.8, 204.5. Mass spectrum: m/z (EI) 294 (M+·, 14%), 279 (18),
276 (3), 266 (4), 249 (9), 236 (9), 233 (7), 221 (2), 205 (2), 190 (11),
181 (3), 175 (3), 162 (8), 143 (26), 134 (11), 115 (9), 109 (12), 94
(100), 79 (19). C17H26O4: calcd. M+· 294.1831, found: M+·
294.1831.
1,7-Dimethyl-7-hydroxytricyclo[6.2.2.04,9]dodecan-3-one (28): 1H
NMR (CDCl3, 300 MHz) [mixture of diastereoisomers, ca. 2:1] δ
= 0.94 (s, 3 H), 0.96 (s, 3 H), 1.08 (s, 3 H), 1.20–1.34 (m), 1.26 (s,
3 H), 1.45–1.61 (m), 1.78 (br. dt), 2.05–2.41 (m), 2.66–2.71 (m). 13
C
NMR (CDCl3, 75 MHz): δ = 19.7, 20.3, 21.8, 22.5, 26.9, 29.1, 29.7,
30.6, 30.7, 33.4, 34.3, 34.5, 36.2, 38.7, 38.9, 41.3, 41.4, 46.3, 46.4,
46.5, 46.7, 53.2, 53.3, 72.5, 72.8, 195.5, 193.8. Mass spectrum:
m/z (EI) 222 (M+·, 25%), 204 (10), 189 (2), 179 (10), 165 (9), 152
(20), 129 (10), 121 (14), 109 (13), 94 (100). HRMS (EI): [M]+ calcd.
for C14H22O2 M+ 222.1614, found M+· 222.1616.
4-Methoxy-1,7,7-trimethyl-6-oxatricyclo[6.2.2.04,9]dodecan-3-one
(33): To a solution of lithium diisopropylamide [prepared from di-
isopropylamine (103 µL, 0.74 mmol) in THF (5 mL) and n-butyl-
lithium 1.32  (511 µL, 0.67 mmol, solution in hexanes) at 0 °C]
at –78 °C was added a solution of 26 (136 mg, 0.61 mmol) in THF
(3.0 mL) via cannula dropwise. After stirring for 30 min a solution
of iodine (171 mg, 0.67 mmol) in THF (3.0 mL) was added drop-
wise via syringe. After stirring for 10 min at –78 °C the reaction
was quenched by pouring onto ice cold aqueous Na2S2O4 (5%) and
extracted into diethyl ether (3×30 mL). The organic phases were
combined and washed with brine then dried (Na2SO4), concen-
trated in vacuo and the resulting oil (31/32) was used in the follow-
ing reaction without purification. To a vigorously stirring solution
of potassium carbonate (170 mg, 1.23 mmol) in methanol (10 mL)
at 50 °C was added a solution of iodides 31 and 32 in methanol
(2.0 mL). After 2 h the mixture was cooled to room temparature,
diluted with diethyl ether (50 mL) and filtered through a short plug
of silica and concentrated in vacuo. The resulting residue was puri-
fied by flash chromatography (ethyl acetate/petroleum ether, 1:5)
on silica affording 33 (114 mg, 74%, 2 steps) as a white solid (m.p.
1
41–42 °C). H NMR (CDCl3, 300 MHz): δ = 0.96 (s, 3 H), 1.07 (s,
3 H), 1.15 (dt, J = 13.1, 2.8 Hz 1 H), 1.20–1.44 (m, 3 H), 1.30 (s,
3 H), 1.54–1.65 (m, 2 H), 2.16–2.36 (m, 3 H), 2.49–2.54 (m, 1 H),
3.05 (s, 3 H), 3.29 (d, J = 11.0 Hz 1 H), 4.42 (d, J = 11.0 Hz, 1 H).
13C NMR (CDCl3, 75 MHz): δ = 21.6, 22.7, 26.9, 30.7, 34.4, 35.8,
38.2, 38.4, 42.6, 50.9, 51.0, 60.8, 73.7, 74.3, 207.5. HRMS (ESI):
[M]+ calcd. for C15H24NaO3 M+ 275.1623, found M+· 275.1616.
Tetracyclic Compound 40: Ester 36 (70 mg, 0.238 mmol) was dis-
solved in ethanol (3.0 mL). Formalin (1.5 mL) was added followed
by potassium hydrogen carbonate (50 mg) and triethylamine
(0.5 mL). The mixture was then heated at 65 °C for 1 h. On cooling
the reaction mixture was filtered and evaporated in vacuo and the
residue subjected to silica gel column chromatography (ethyl ace-
tate/petroleum ether, 1:1), which afforded to product 39 (77 mg,
84%) as a colourless oil. Alcohol 39 (50 mg, 0.154 mmol), tri-
phenylphosphane (0.162 mg, 0.616 mmol) and imidazole (42 mg,
0.616 mmol) were dissolved in anhydrous diethyl ether (2.0 mL)
and anhydrous acetonitrile (1.0 mL) under an argon atmosphere.
The reaction flask was placed in an ice-bath and iodine (117 mg,
7-Methoxy-1,7-dimethyltricyclo[6.2.2.04,9]dodecan-3-one
(35):
Ketone 27 (165 mg, 0.8 mmol) and mercury acetate (205 mg,
0.8 mmol) were dissolved in anhydrous methanol (20 mL) under an
argon atmosphere. The mixture was stirred at room temperature
for 5 h before a further portion of mercury acetate (410 mg,
1.6 mmol) was added. At the completion of the reaction [TLC (pe-
troleum ether/ethyl acetate, 90:10)], sodium hydroxide solution 3 
3188
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Towards the Total Synthesis of Vibsanin Derivatives
FULL PAPER
0.462 mmol) added in one portion. After 5 min the flask was re-
moved from the ice-bath and the mixture stirred at room tempera-
ture for 3.5 h. Cooling with an ice-bath the reaction was firstly
diluted with diethyl ether (5 mL) and quenched with aqueous so-
dium thiosulfate (20%, 5 mL). The ether layers were combined,
dried (Na2SO4) and evaporated in vacuo. The residue was subjected
to silica gel column chromatography (ethyl acetate/petroleum ether,
8:92), which afforded iodide 37 (50 mg, 75%) as a colourless oil.
Iodide 37 (25 mg, 0.0058 mmol) was dissolved in anhydrous tetra-
hydrofuran (3.0 mL) under an argon atmosphere. To this solution
was added hexamethylphosphorous triamide (0.6 mL, 0.345 mmol)
followed by cooling to –78 °C. On cooling samarium iodide
amide (260 µL, 1.5 mmol) was stirred at –50 °C under an argon atmo-
sphere for 10 min. Lithium diisopropylamide (1.5 mmol) [prepared
from diisopropylamine (1 mL, 7.1 mmol) in tetrahydrofuran
(10 mL) and n-butyllithium 1.6  (4.5 mL, 7.1 mmol, solution in
hexanes) between –20 and 0 °C] cooled to –50 °C was added drop-
wise, and the mixture was warmed to 0 °C over 1 h. The mixture
was then stirred for 30 min at –80 °C, and ethyl cyanoformate
(250 µL, 2.5 mmol) added neat. The mixture was warmed to room
temperature overnight. The mixture was quenched with saturated
aqueous ammonium chloride (8 mL), and the aqueous phase ex-
tracted with diethyl ether (4×15 mL). The combined organic layers
were dried (MgSO4) and the solvent removed in vacuo. Column
(3.45 mL, 0.1 , 0.345 mmol) was added dropwise over 60 s and chromatography (petroleum ether/ ethyl acetate, 9:1) of the residue
after 10 min the reaction was quenched [satd. ammonium chloride
solution (4 mL)] and warmed to room temperature over 20 min.
The reaction mixture was then diluted with water (5 mL) and ex-
tracted with a mixture of diethyl ether and petroleum ether (2:1,
20 mL). The combined extracts were evaporated, dried (Na2SO4)
and the residue subjected to silica gel column chromatography
(ethyl acetate/petroleum ether, 3:7), which afforded 40 (13 mg,
gave a colourless oil (281 mg) as a mixture of isomers (1:1). Sodium
hydride (65 mg, 1.61 mmol, 60% dispersion in oil) was suspended
in anhydrous tetrahydrofuran (3 mL) at 0 °C under an argon atmo-
sphere. Anhydrous ethanol (190 µL, 3.2 mmol) was then slowly
added. After effervescence ceased, the above residue (249 mg) in
anhydrous tetrahydrofuran (3 mL) was cooled to 0 °C before slow
addition. The reaction mixture was stirred at room temp. overnight.
72%) as a colourless oil. 1H NMR (CDCl3, 500 MHz): δ = 0.36 (d, Ethyl acetate (6 mL) followed by saturated aqueous ammonium
J = 5.9 Hz, 1 H), 0.57 (d, J = 5.9 Hz, 1 H), 0.92 (s, 3 H), 0.99–1.09 chloride were added, and the aqueous layer extracted with ethyl
(m, 3 H) 1.12 (s, 3 H), 1.26–1.33 (m, 1 H), 1.28 (t, J = 7.2 Hz, 3 acetate (3×30 mL). The combined organic layers were dried
H), 1.31 (s, 3 H), 1.40 (dt, J = 13.8, 3.4 Hz, 1 H), 1.52–1.58 (m, 1 (MgSO4), the solvent removed in vacuo, and the residue subjected
H), 1.62–1.68 (m, 1 H), 2.03–2.13 (m, 1 H), 2.39 (br. q, 1 H), 2.98 to column chromatography (petroleum ether/ethyl acetate, 95:5) on
(s, 1 H), 3.66 (d, J = 12.1 Hz, 1 H), 3.85 (d, J = 12.1 Hz, 1 H),
4.13–4.26 (m, 2 H). 13C NMR (CDCl3, 125 MHz): δ = 14.4, 18.4,
19.9, 22.5, 27.4, 27.6, 29.4, 31.3, 31.4, 37.0, 37.7, 43.0, 57.3, 57.6,
60.6, 62.2, 74.0, 173.1. Mass spectrum: m/z (EI) 308 (M+·, 55%),
290 (9), 262 (18), 247 (10), 233 (7), 219 (12), 204 (16), 194 (11), 177
(12), 161 (21), 148 (28), 136 (43), 121 (32), 111 (40), 94 (70), 73
(80), 55 (100). C18H28O4: calcd. M+· 308.1988, found: M+·
308.1992.
silica. Compound 42 was isolated as a colourless oil (169 mg, 44%)
along with recovered starting material (33 mg, 13%) and a (1:1)
mixture isomers 42 and 43 (69 mg, 20%). Spectral data reported
1
for 42 only. H NMR (C6D6, 300 MHz): δ = 0.74 (s, 3 H), 0.88 (s,
3 H), 0.90–0.96 (m, 1 H), 1.04 (t, J = 7.0 Hz, 3 H), 1.17 (dd, J =
13.5, 3.6 Hz, 1 H), 1.20–1.28 (m, 2 H), 1.30–1.52 (m, 5 H), 1.77
(br. t, J = 2.8 Hz, 1 H), 2.24–2.36 (m, 1 H), 2.45–2.52 (m, 1 H),
2.68 (dd, J = 6.4, 3.4 Hz, 0.5 H), 2.64 (dd, J = 6.4, 3.4 Hz, 0.5 H),
2.91 (s, 3 H), 2.96 (s, 1 H), 4.02–4.18 (m, 2 H). 13C NMR (C6D6,
100 MHz): δ = 14.3, 20.0, 22.0, 22.6, 26.2, 29.3, 33.5, 35.1, 38.3,
43.3, 43.7, 46.4, 47.8, 60.3, 66.0, 76.1, 169.0, 206.2. Mass spectrum:
m/z (EI) 308 (M+·, 11%) 276 (19), 263 (6), 247 (6), 243 (3), 202 (6),
94 (13), 85 (100), 72 (48). HRMS (EI): C18H28O4 calcd. M+
308.1988, found M+· 308.1988.
Ethyl
1,8,8-Trimethyl-4-oxo-7-oxatricyclo[6.3.2.05,10]dodecane-2-
carboxylate (41): To a solution of diethylzinc (3.77 mL, 3.77 mmol,
1  in hexanes) in anhydrous dichloromethane (10 mL) at 0 °C was
added diiodomethane (1 g, 3.77 mmol) dropwise under an argon
atmosphere. The reaction was stirred for 30 min then a solution of
keto ester 36 (270 mg, 0.88 mmol) in anhydrous dichloromethane
(5.0 mL) was added dropwise and then stirred at room temperature.
After 12 h the mixture was poured onto ice cold aqueous ammo-
nium chloride (15 mL, sat.) and extracted with diethyl ether
(3×25 mL) and combined. The organic layers were washed with
brine (15 mL), dried (MgSO4) and concentrated in vacuo to give a
residue that was purified by flash chromatography (ethyl acetate/
petroleum ether, 1:5) on silica affording recovered 36 (203 mg) and
41 [34 mg, 12% (yield based on recovered starting material 50%)]
as a colourless oil. 1H NMR (CDCl3, 300 MHz): δ = 1.04 (s, 3 H),
1.09 (s, 3 H), 1.10–1.21 (m, 1 H), 1.22–1.28 (m, 1 H), 1.25 (t, J =
7.1 Hz, 3 H), 1.27 (s, 3 H), 1.31–1.47 (m, 1 H), 1.52–1.62 (m, 1 H),
1.73 (dd, J = 14.5, 5.4 Hz, 1 H), 1.95 (dt, J = 14.5, 2.5 Hz, 1 H),
2.16–2.25 (m, 2 H), 2.54–2.62 (m, 1 H), 2.63 (s, 1 H), 2.64 (AB, 1
H), 3.05–3.18 (m, 1 H), 3.62 (dd, J = 11.8, 3.6 Hz, 1 H), 4.13 (q, J
= 7.1 Hz, 2 H), 4.31 (dd, J = 10.7, 1.1 Hz, 1 H). 13C NMR (CDCl3,
75 MHz): δ = 14.2, 21.9, 23.8, 27.4, 31.2, 33.0, 33.7, 34.2, 42.8,
44.3, 46.4, 51.3, 51.6, 60.4, 61.7, 73.6, 174.0, 210.1. Mass spectrum:
m/z (EI) 308 (M+·, 4%), 293 (14), 290 (4), 275 (1), 269 (1), 263 (5),
250 (68), 245 (1), 214 (1), 204 (19), 196 (6), 177 (10), 156 (90), 135
(10), 128 (18), 110 (23), 101 (94), 94 (100). C18H28O4: calcd. M+·
308.1988, found: M+· 308.1989.
Ethyl 8-Methoxy-1,8-dimethyl-4-oxotricyclo[6.3.2.05,10]dodecane-2-
carboxylate (44): To a solution of diethylzinc 1  (2 mL, 2.0 mmol,
16 equiv.) in anhydrous toluene (4 mL) at 0 °C under an argon at-
mosphere was added neat freshly distilled diiodomethane (170 µL,
2.0 mmol). The mixture was stirred at 0 °C for 15 min, then tricycle
42 (50 mg, 0.13 mmol) in anhydrous toluene (3 mL) was added.
The reaction was stirred for 24 h at room temperature. On comple-
tion the reaction was quenched with saturated aqueous ammonium
chloride (2 mL) followed by addition of diethyl ether (8 mL). The
layers were separated and the aqueous layer was extracted with
diethyl ether (3×15 mL). The combined organic layers were dried
(MgSO4), the solvent was removed in vacuo, and the residue was
subjected to column chromatography (petroleum ether/ethyl ace-
tate, 95:5) on silica affording 44 as a colourless oil (6 mg, 15%). 1H
NMR (C6D6, 300 MHz; mixture of diastereomers, ca. 1:1): δ =
0.787 (s, 3 H), 0.792 (s, 3 H), 0.84 (s, 3 H), 0.85–1.15 (m, 4 H), 0.96
(t, J = 7.1 Hz, 3 H), 0.99 (s, 3 H), 1.00 (t, J = 7.1 Hz, 3 H), 1.20–
1.42 (m, 6 H), 1.46–1.52 (m, 5 H), 1.55 (dt, J 15, 2.5, 1 H), 1.67
(dt, J 15, 2.5, 1 H), 1.86–1.95 (m, 3 H), 2.18 (dt, J 10, 2.7, 1 H),
2.22–2.28 (m, 1 H), 2.30–2.40 (m, 2 H), 2.41–2.50 (m, 3 H), 2.55
(d, J 15, 1 H), 2.84–3.02 (m, 2 H), 2.94 (s, 3 H), 2.95 (s, 3 H), 3.54
(dd, J 15, 0.7, 1 H), 3.74 (d, J = 9.5 Hz, 1 H), 3.87–4.10 (m, 4 H).
13C NMR (C6D6, 75 MHz; mixture of diastereomers, ca. 1:1): δ =
14.0, 14.2, 16.8, 21.9, 22.0, 22.6, 22.7, 22.8, 23.1, 26.9, 27.4, 31.1,
Ethyl 7-Methoxy-1,7-dimethyl-3-oxotricyclo[6.2.2.04,9]dodecane-2-
carboxylate (42): A solution of 35 (296 mg, 1.25 mmol) in anhy-
drous tetrahydrofuran (6 mL) and hexamethylphosphorous tri-
Eur. J. Org. Chem. 2006, 3181–3192
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C. M. Williams et al.
FULL PAPER
31.7, 33.1, 33.7, 34.3, 35.1, 37.7, 39.6, 40.3, 44.1, 45.9, 46.2, 46.4,
1.32 (s, 3 H), 1.62–1.70 (m, 1 H), 2.31 (dt, J = 13.1, 3.2 Hz, 1 H),
47.9, 50.7, 51.1, 51.1, 52.7, 53.5, 60.0, 60.9, 75.9, 76.0, 172.3, 174.0, 2.48 (br. q, 1 H), 3.00 (s, 1 H), 3.31 (d, J = 11.1 Hz, 1 H), 4.46 (d,
209.3, 210.0. Mass spectrum: m/z (EI) 322 (M+·, 9%), 304 (11), 290 J = 11.1 Hz, 1 H), 5.25 (m, 1 H), 5.92 (m, 1 H). 13C NMR (CDCl3,
(30), 277 (10), 250 (9), 232 (13), 225 (14), 217 (10), 205 (9), 193
100 MHz): δ = 21.9, 22.7, 26.9, 27.3, 36.2, 36.9, 37.6, 40.4, 42.4,
(31), 121 (10), 111 (10), 105 (17), 91 (21), 85 (95), 72 (100). HRMS 50.8, 61.5, 73.6, 74.9, 119.6, 153.6, 196.6. Mass spectrum (GCMS):
(EI): C19H30O4 calcd. M+ 322.2144, found M+· 322.2145.
m/z (EI) 264 (M+·, 9%), 249 (8), 232 (100), 219 (28), 206 (53), 191
(46), 177 (22), 163 (52), 150 (81), 137 (37), 124 (39), 105 (33).
HRMS: C16H24O3 calcd. 264.1725, found 264.1721.
Saegusa Ring Expansion. Preparation of 46 and 47: To an ice cold
solution of lithium diisopropylamide, under an argon atmosphere,
[prepared from diisopropylamine (248 µL, 1.78 mmol) in THF
(12 mL) and n-butyllithium 1.35  (1.21 mL, 1.63 mmol, solution
in hexanes) at 0 °C] was added a solution of ketone 33 (359 mg,
1.42 mmol) and trimethylsilyl chloride (177 mg, 208 µL,
1.63 mmol) in THF (5.0 mL) dropwise via cannula. The reaction
was stirred for 35 min then poured onto ice cold aqueous NaHCO3
(20 mL) and extracted with diethyl ether (3×20 mL). The organic
layers were combined, washed with brine (15 mL), dried (Na2SO4)
and concentrated in vacuo which afforded an oil that was used
in the following procedure without purification. To a solution of
diethylzinc (8.52 mL, 8.52 mmol, 1  solution in hexanes) in anhy-
drous diethyl ether (15 mL), under an argon atmosphere, was
added diiodomethane (2.28 g, 8.52 mmol). The reaction was gently
heated to reflux for 15 min then after the reaction cooled to room
temperature a solution of the silylenol ether in anhydrous diethyl
ether (10 mL) was added via syringe then stirred for 30 min at room
temperature. After additional diethylzinc (1.50 mL) and diiodome-
thane (400 mg, 1.50 mmol) were added the reaction was refluxed
for 2.5 h then cooled to room temperature and poured onto aque-
Ethyl (2β)-4-Methoxy-1,7,7-trimethyl-3-oxo-6-oxatricyclo[6.2.2.04,9]-
dodecane-2-carboxylate (48): To a solution of ketone 33 (200 mg,
0.79 mmol) at –78 °C in THF (5.0 mL) under an argon atmosphere
was added a solution of lithium diisopropylamide dropwise [pre-
pared from diisopropylamine (121 µL, 0.87 mmol) in THF (6 mL)
and n-butyllithium 1.3  (640 µL, 0.83 mmol, solution in hexanes)
at 0 °C]. After 30 min ethyl cyanoformate (82 mg, 0.83 mmol) was
added followed by hexamethylphosphorous triamide (100 µL) and
stirring continued for 40 min. The reaction was quenched by pour-
ing onto ice cold aqueous ammonium chloride (sat. 15 mL) fol-
lowed by extraction with diethyl ether (3×25 mL). The combined
organic layers were washed with brine (15 mL), dried (MgSO4) and
concentrated in vacuo. The crude product was then purified by
flash chromatography (ethyl acetate/petroleum ether, 1:10) afford-
ing 48 (101 mg, 39%) as a colourless oil and recovered starting
material (75 mg, 38%). 1H NMR (CDCl3, 400 MHz; one dia-
stereoisomer only): δ = 1.00 (s, 3 H), 1.01 (s, 3 H) 1.18–1.45 (m, 4
H), 1.22 (t, J = 7.0 Hz, 3 H), 1.28 (s, 3 H), 1.55–1.66 (m, 2 H), 2.50
(br. q, 1 H), 2.85 (dt, J = 13.6, 3.2 Hz, 1 H), 2.94 (s, 3 H), 3.22 (d,
ous NaHCO3 (20 mL) and extracted with diethyl ether (3×20 mL). J = 2.0 Hz, 1 H), 3.29 (d, J = 11.2 Hz, 1 H), 4.02–4.20 (m, 2 H),
The organic layers were combined, washed with brine (15 mL),
dried (Na2SO4) and concentrated in vacuo which gave a residue
that was purified by flash chromatography (5% TEA in petroleum
ether) to give 45 (147 mg, 31%) as a colourless oil that was some-
4.39 (d, J = 11.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 14.1,
21.0, 22.5, 26.8, 27.0, 31.6, 35.0, 37.2, 41.2, 42.2, 50.6, 60.9, 61.4,
65.1, 73.5, 74.3, 167.2, 200.3. Mass spectrum (GCMS): m/z (EI)
324 (M+·, 6%), 309 (1), 294 (40), 279 (24), 264 (59), 247 (11), 228
what acid-sensitive. To a solution of iron trichloride (155 mg, (6), 218 (28), 212 (36), 203 (10), 190 (22), 183 (45), 175 (12), 165
0.96 mmol) in anhydrous N,N-dimethylformamide (5.0 mL) at 0 °C
was added 45 in solution of anhydrous N,N-dimethylformamide
(3.5 mL) and anhydrous dichloromethane (3.0 mL) dropwise over
1 h followed by stirring overnight at room temperature. The reac-
tion was poured into ice cold hydrochloric acid (1 , 20 mL) and
extracted with dichloromethane (3×15 mL). The organic phases
were combined then washed with aqueous sodium hydrogen car-
bonate (15 mL), brine, dried (Na2SO4) and concentrated in vacuo.
The crude material was then dissolved in methanol (5 mL, sat. with
NH4OAc) and refluxed overnight. The resulting residue, after con-
centration in vacuo, was suspended in brine (10 mL) and extracted
with diethyl ether (3×10 mL), dried (Na2SO4) and concentrated in
vacuo to give a residue that was purified by flash chromatography
(ethyl acetate/petroleum ether, 1:10) affording 46 (15 mg, 4%) and
47 (47 mg, 13%) as colourless oils.
(24), 151 (19), 135 (31), 121 (18), 107 (28), 94 (100). HRMS calcd.
for C18H28NaO5: 347.1834; found 347.1826.
Ethyl (2α)-4-Methoxy-1,7,7-trimethyl-3-oxo-6-oxatricyclo[6.2.2.04,9]-
dodecane-2-carboxylate (49): To a solution of diethylzinc (440 µL,
0.44 mmol, 1  in hexanes) in anhydrous dichloromethane (3.0 mL)
at 0 °C under an argon atmosphere was added trifluoroacetic acid
(32 µL, 0.44 mmol). After 30 min. diiodomethane (36 µL,
0.44 mmol) was added and the mixture stirred for a further 30 min.
followed by dropwise addition keto ester 48 (48 mg, 0.15 mmol) in
anhydrous dichloromethane (1.0 mL). After 12 h at room tempera-
ture the mixture was poured onto ice-cold satd. aqueous ammo-
nium chloride (15 mL) and extracted with diethyl ether (3×15 mL).
The combined organic layers were washed with brine (15 mL),
dried (MgSO4) and concentrated in vacuo to give a residue that
was purified by flash chromatography (dichloromethane) on silica
affording 49 (29 mg, 58%) as a white solid. 1H NMR (CDCl3,
1,8,8-Trimethyl-7-oxatricyclo[6.3.2.05,10]dodecan-2-en-4-one
(46):
1H NMR (CDCl3, 400 MHz): δ = 1.11 (s, 3 H), 1.14 (s, 3 H) 1.10– 400 MHz): δ = 0.99 (s, 3 H), 1.07–1.17 (m, 1 H), 1.08 (s, 3 H) 1.22
1.39 (m, 4 H), 1.31 (s, 3 H), 1.49–1.60 (m, 2 H), 1.57 (s, 3 H), 2.45– (dd, J = 13.2, 3.0 Hz, 1 H), 1.27 (t, J = 7.2 Hz, 3 H), 1.29 (s, 3 H),
2.50 (m, 1 H), 2.62 (dt, J = 14.0, 2.4 Hz, 1 H), 3.03 (s, 1 H), 3.24 1.33–1.48 (m, 2 H), 1.59–1.68 (m, 1 H), 2.32 (dt, J = 9.9, 3.3 Hz,
(d, J = 10.8 Hz, 1 H), 4.51 (d, J = 10.8 Hz, 1 H), 6.02 (AB, 1 H). 1 H), 2.40 (br. dq, 1 H), 2.53 (br. q, 1 H), 3.07 (s, 3 H), 3.30 (d, J
13C NMR (CDCl3, 100 MHz): δ = 20.4, 23.9, 27.2, 32.0, 36.4, 36.5,
37.3, 38.2, 44.1, 51.1, 62.7, 73.5, 130.3, 151.7, 198.5. Mass spectrum
(GCMS): m/z (EI) 264 (M+·, 4%), 249 (58), 232 (85), 217 (24), 204
(10), 189 (26), 175 (20), 161 (23), 147 (40), 137 (50), 119 (51), 105
= 11.2 Hz, 1 H), 3.38 (AB, 1 H), 4.18–4.25 (m, 2 H), 4.40 (d, J =
11.2 Hz, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 14.2, 21.5, 22.5,
26.8, 28.9, 34.1, 37.5, 38.1, 38.3, 42.5, 51.0, 60.5, 63.2, 73.6, 74.8,
168.8, 202.4. Mass spectrum (GCMS): m/z (EI) 324 (M+·, 1%), 309
(53), 93 (60), 81 (59), 67 (50), 41 (100). HRMS: C16H24NaO3 calcd. (2), 294 (22), 279 (7), 264 (28), 247 (7), 228 (3), 218 (10), 203 (4),
287.1623, found 287.1615.
183 (10), 173 (19), 160 (7), 139 (12), 122 (11), 107 (14), 94 (100).
HRMS: C18H28O5 calcd. 324.1937, found 324.1934.
1,7,7-Trimethyl-2-methylene-6-oxatricyclo[6.2.2.04,9]dodecan-3-one
1
(47): H NMR (CDCl3, 400 MHz): δ = 1.10 (s, 3 H), 1.15 (s, 3 H) X-ray Crystallography: X-ray data were collected on an Enraf–
1.20 (dd, J = 13.0, 3.0 Hz, 1 H), 1.15 (s, 3 H), 1.24–1.59 (m, 4 H),
Nonius CAD4 diffractometer with graphite-monochromatized
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3181–3192

Towards the Total Synthesis of Vibsanin Derivatives
FULL PAPER
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33: C15H24O3, M = 252.34, monoclinic, space group P21/n, a =
6.472(2) Å, b 19.291(2) Å, c = 11.852(2) Å, β = 104.62(3)°, V =
1431.8(5) Å3, Z = 4, Dc = 1.171 g cm–3, T = 293 K, µ = 0.080 mm–1,
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49: C18H28O5, M = 324.40, monoclinic, space group P21/a, a =
10.019(2) Å, b 10.006(1) Å, c = 17.750(3) Å, β = 101.46(2)°, V =
1744.0(5) Å3, Z = 4, Dc = 1.236 g cm–3, T = 293 K, µ = 0.089 mm–1,
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Published Online: May 12, 2006
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Eur. J. Org. Chem. 2006, 3181–3192