Towards the total synthesis of spirovibsanin A: Total synthesis of (±)-5,14-bis-epi-spirovibsanin A

Article abstract of DOI:10.1002/ejoc.200800574

Studies towards the total synthesis of the complex diterpene spirovibsanin A are herein presented, which culminate in an 18-step total synthesis. Considering the perceived stereo-chemical uncertainty surrounding the assignment of spirovibsanin A these studies have allowed a direct spectroscopic comparison of the (±)-5,14-bis-epi derivative to that of natural spirovibsanin A demonstrating that the carbon framework and stereochemistry assigned to natural spirovibsanin A is most likely correct. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800574

FULL PAPER
DOI: 10.1002/ejoc.200800574
Towards the Total Synthesis of Spirovibsanin A: Total Synthesis of
؎)-5,14-Bis-epi-spirovibsanin A
(
[a]
[a]
Michael J. Gallen and Craig M. Williams*
Keywords: Spirovibsanin A / (Ϯ)-5,14-Bis-epi-spirovibsanin A / Spirolactone / Diterpene / Natural product
Studies towards the total synthesis of the complex diterpene
spirovibsanin A are herein presented, which culminate in an
ral spirovibsanin A demonstrating that the carbon framework
and stereochemistry assigned to natural spirovibsanin A is
18-step total synthesis. Considering the perceived stereo- most likely correct.
chemical uncertainty surrounding the assignment of spiro-
vibsanin A these studies have allowed a direct spectroscopic
comparison of the (Ϯ)-5,14-bis-epi derivative to that of natu-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
ration at position 14 (Figure 1). Considering that neovib-
[
3]
[3]
sanin F (7) and 14-epi-neovibsanin F (8), as well as, neo-
[
3]
[3]
Spirovibsanin A (1), isolated from Viburnum awabuki by vibsanin G (9) and 14-epi-neovibsanin G (10) are also
[
1]
Fukuyama, is the only vibsanin-type diterpene not be- epimeric at position 14 led us to question the relative stereo-
longing to the three traditional sub-classes, represented by chemical assignment of the isopropyl methyl ether function
vibsanin B (2), vibsanin C (3), and neovibsanin A (4) (Fig- at position 14 of spirovibsanin A (1) (Figure 1). Efforts to
[
2]
ure 1). There are, however, structural aspects of spirovib- investigate the stereochemical incertitude of spirovibsanin
[
3]
sanin A (1) present in 15-O-methylneovibsanin F (5), and A (1) were therefore warranted, especially considering no
4-epi-15-O-methylneovibsanin F (6),[ for example, bicy- synthetic studies had been reported and our group had
3]
[4]
1
clo[3.3.1]nonane and isopropyl methyl ether moieties. The prior experience with a variety of vibsanin family mem-
[
5]
intriguing facet of 5 and 6 is that they only differ in configu- bers.
Figure 1. Spirovibsanin A (1) and various sub-classes of vibsane-type diterpenes.
[
a] School of Molecular and Microbial Sciences, University of
Results and Discussion
Queensland,
Brisbane, 4072, Queensland, Australia
E-mail: c.williams3@uq.edu.au
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Retrosynthetic analysis of the target was based on pre-
[
6]
vious work, which described the formation of the bicy-
clo[3.3.1]nonane 11 from the treatment of the ketone 12
Eur. J. Org. Chem. 2008, 4697–4705
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4697

M. J. Gallen, C. M. Williams
FULL PAPER
Scheme 1.
with o-iodoxybenzoic acid (IBX) (Scheme 1). Eventhough
the functionality at position 6 of 11 was epimeric to that of
spirovibsanin A (1) at position 14 this was deemed accept-
able due to the stereochemical uncertainty posed above. The
side chain would be installed last, using the method of
[
7]
Davies, which requires masked aldehyde functionality (i.e.
13). The spirolactone moiety was perceived best constructed
from a palladium-catalysed carboxylic acid alkene oxidative
insertion reaction ultimately accessed from allyl and ester
functional groups (i.e. 14). Access to 14 would most likely
be achieved with a 1,4-conjugate addition alkylation proto-
col involving enone 15, which is derived by functional group
manipulation of the bicycle 11 (Scheme 1).
Central to this study was accessing bicycle 11, which at
[
5a–5c]
best was obtained in 20% yield from the ketone 12
via
intermediate 16 (Scheme 2).[ All attempts to improve this Scheme 2.
result by screening a barrage of reagents and conditions,
failed. When investigations focused on enone 16, which is
better accessed using IBX N-methylmorpholine complex
6]
(IBX·NMO) in 78% yield, it was discovered that by simply
dissolving 16 in methanol and adding trace amounts of
concentrated hydrochloric acid, 17 was obtained in 76%
yield (Scheme 2). This very fortuitous outcome, confirmed
by X-ray crystal structure analysis, gave cyclisation with
concomitant methyl ether formation as the sole dia-
stereomer on mass (i.e 60% over 2 steps on a 20-gram
scale). All efforts to obtain the β-isomer (i.e. 18) with such
conceivable methods as oxymercuration/radical cyclis-
[
8]
ation, failed.
Functional-group manipulation arriving at the advanced
intermediate 21 proceeded via a novel keto transposition/
carbonylation sequence (Scheme 3). Regioselective conver-
sion of 17 into hydroxy ketone 19, via DMDO oxidation of
the corresponding silyl enol ether (4:1 ratio of silyl enol
ethers in favour of the desired), proceeded in 79% isolated
yield over 2 steps. Moffatt–Swern oxidation gave the keto-
transposed diosphenol 20 (62%) as confirmed by X-ray
crystal structure analysis. Palladium-catalysed carbon-
[
9]
ylation of the corresponding triflate, formed using either
[
10]
[11]
Comins’ or McMurry’s reagents, then gave rise to the
enone 21 in 58% over 2 steps (Scheme 3).
Scheme 3.
4698
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4697–4705

Total Synthesis of (Ϯ)-5,14-Bis-epi-spirovibsanin A
The advanced intermediate 21 was now well set for the at the ester/allyl group juncture to that described for the
addition of a 2C-protected aldehyde unit via a 1,4-cuprate natural product, which is probably due to the dimeth-
addition. (1,3-Dioxolan-2-ylmethyl)magnesium bromide ylmethoxy moiety congesting the endo face. Wacker oxi-
(
22) was chosen as it satisfied this criteria. Following the dation of 26 afforded 27, but conversion of the 1,4-dicar-
[
12]
[17]
literature however, which unfortunately lacks detail,
using 2-bromomethyl-1,3-dioxolane to generate the Grig- voked. One-step iodolactonisation
bonyl to the spirolactone (i.e. Al O
) could not be in-
2
[
3
18]
accessed 28, but the
nard 22 only gave a maximum yield of ca. 10%. Fortu- hydrogen iodide formed in situ destroyed the dimethylmeth-
nately, 22 was available commercially and underwent oxy moiety, and addition of base prevented the reaction
smooth conjugate addition to enone 21, which occurred from proceeding. Global reduction (DIBALH) of 26 fol-
stereoselectively affording enol 23 in 70% yield (Scheme 3). lowed by global oxidation gave only the aldehyde 29, which
Of note was the observation that alkylation of the resulting was very resistant to further oxidation.
conjugate addition enolate, with electrophiles such as allyl
iodide, completely failed.
Considering the spirolactone moiety seen in spirovib- tion with sodium chlorite or N-methylmorpholine N-ox-
sanin A (1) is rare it is worthy, for educational purposes, ide (NMO)
Fortunately, dihydroxylation of 26 proceeded with cata-
lytic (≈ 5 mol-%) potassium osmate dihydrate, in conjunc-
[
19]
[
20]
as co-oxidant, however, the use of NMO as
to briefly detail the failed attempts made to construct this co-oxidant gave superior yields of diol 30. Intramolecular
fragment (Scheme 4). Pinhey coupling,[ proceeded poorly transesterification of diol 30, using sodium hydride afforded
affording acetylene 24 in only 13%, and subsequent hy- the undesired six-membered ring 31, but it was later discov-
droysis could not be forced. Transesterification with allyl ered treating the diol 30 with potassium carbonate afforded
13]
[
14]
alcohol
gave 25 in 65%, but palladium-mediated re- the desired five-membered lactone 32 (as confirmed by X-
[
15]
[4]
arrangement to the C- or O-allylated product failed, only ray crystal structure analysis ) in 80% yield over two steps
serving to decarboxylate. Direct C-allylation failed, but O- (Scheme 5). Elimination of the pendent alcohol function in
allylation proceeded with potassium hydride and allyl 32 was achieved (i.e. 33), by conversion to the mesylate fol-
iodide in 75%, which subsequently underwent Claisen re- lowed by a one-pot Finkelstein elimination under micro-
arrangement in 93% yield (i.e. 26) when subjected to micro- wave irradiation, in excellent overall yield. Surprisingly, di-
wave irradiation (195 °C). The only detracting feature of the rect elimination of the mesylate or direct conversion of the
rearrangement (most likely occurring via a boat transition alcohol 32 to an iodide failed. Isomerisation of the double
[
16]
state ) was that it procured the incorrect stereochemistry bond to the endo position (i.e. 34), via palladium cata-
Scheme 4. a) Pb(OAc)
4
, tri-n-butyltin methylacetylene, 13%; b) Na, Allyl alcohol, 65%; c) KH, allyl iodide, 75%; d) microwave, 195 °C,
, 65%; f) DIBALH; g) Jones reagent, Celite, 55%.
9
3%; e) PdCl , CuCl, O
2
2
Eur. J. Org. Chem. 2008, 4697–4705
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4699

M. J. Gallen, C. M. Williams
FULL PAPER
lysts,[21] Wilkinson’s catalyst
fonic acid,
[22]
or anhydrous p-toluenesul-
[
23,24]
were known in the literature. Slight modifi-
cation (i.e. microwave irradiation) of Jäger’s method, which
uses anhydrous p-toluenesulfonic acid,[
23,24]
gave the desired
spirolactone moiety in 75% yield (Scheme 5).
Scheme 5.
Of much disappointment was the slow realisation that
deprotection of the dioxolane moiety could not be achieved
in the presence of the spirolactone function. Therefore the
synthetic strategy was redesigned so that the final stages of
the spirolactone construction (i.e. elimination/isomeris-
ation) could be performed toward the end of the sequence.
In this view mesylate 35 was deprotected with (trimethyl-
silyl)methanesulfonate (TMSOTf)[ to give the aldehyde
Scheme 6.
lactone double bond carbon (C-6) chemical shifts differ by
ca. 3 ppm (Figure 2). Position 9 is also worth noting with a
chemical shift difference of 0.55 ppm in the H NMR spec-
25]
3
6 (64%), which was, using a modified procedure to that of
1
[
7]
Davies, converted to a mixture of E- (38) and Z-isomers
1
13
tra. Overlapping H and C NMR spectra of both 1 and
2 are presented in the Supporting Information
(37) of the desired side chain in a ratio of 7:3 (55%)
4
(Scheme 6). The one-pot, microwave-mediated, Finkelstein/
elimination reaction developed above gave the exo-cyclic en-
lactones 39 and 40. The final step required the Jäger exo-
to endo-cyclic double-bond isomerisation, which to our sat-
isfaction, unveiled the desired material as a mixture of iso-
mers [i.e. 41 (Z)/42 (E)], using PPTS rather than TsOH
(Scheme 6).
Separation of the isomers 41 and 42 by HPLC allowed
1
13
direct comparison of H NMR and C NMR spectro-
scopic data of both 1 and 42. The most notable differences
being; position 14 of spirovibsanin A (1) has a proton
1
3
chemical shift of 2.32 ppm ( C 50.4 ppm) as opposed to
1
3
2
(
.73 ppm ( C 52.5 ppm) for 42. The spirolactone carbon
Figure 2. Comparison of relevant H and 13C NMR signals, which
differentiate spirovibsanin A (1) from the synthesized bisepimer
1
C-5) is close to identical at δ = 68.1 ppm and 68.2 ppm,
whereas both the spirolactone carbonyl carbon (C-4) and (42).
4700
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4697–4705

Total Synthesis of (Ϯ)-5,14-Bis-epi-spirovibsanin A
1
24.0, 50.1, 41.4, 38.1, 36.5, 25.6, 24.7, 22.3, 17.5 ppm. Mass spec-
Conclusions
+
·
trum: GCMS (EI): m/z (%) = 192 (12.0) [M ], 149 (10), 124 (25),
+
·
In conclusion, considering the stereochemical incertitude 109 (100), 95 (5), 81 (13), 69 (18), 55 (10). C H O: calcd. M
1
3
20
over spirovibsanin A 1, a total synthesis campaign arriving 192.1514; found M+ 192.1507
·
at (Ϯ)-5,14-bis-epi-spirovibsanin A 42 was warranted. This
work gives strong support to Fukuyama’s proposed connec-
tivity and relative stereochemistry, but also identifies an ef-
ficient route to vibsane type family members containing α 3-methyl-(4-methylpent-3-enyl)cyclohexanone
6
-Isopropenyl-1-methylbicyclo[3.3.1]nonan-3-one (11): A mixture of
2-iodoxybenzoic acid (IBX) (1.46 g, 5.1 mmol) in dimethyl sulfox-
ide (17 mL) was heated to 70 °C. After complete solvation of IBX,
(12) (582 mg,
stereochemistry at position 14, for example, 15-O-methyl- 3 mmol) was added in one portion to the stirring solution. The
neovibsanin F (5), neovibsanin F (7) and neovibsanin G reaction was monitored by GC and ceased after 70 h. The mixture
was added to water, extracted with diethyl ether (3ϫ30 mL), dried
(9).
(
4
MgSO ), and concentrated in vacuo. Column chromatography of
the residue (petroleum ether/ethyl acetate, 17:1) provided the title
1
compound (125 mg, 22%). H NMR (CDCl
s, 1 H), 4.58 (s, 1 H), 2.41 (m, 1 H), 2.35–2.32 (m, 1 H), 2.23–2.20
(m, 1 H), 2.08 (m, 1 H), 2.04 (m, 2 H), 1.82–1.79 (m, 1 H), 1.67 (s,
3
, 500 MHz): δ = 4.82
Experimental Section
(
General: 1H and 13C NMR spectra were recorded with a Bruker
AV300 (300.13 MHz; 75.47 MHz), AV400 (400.13 MHz;
3
H), 1.62–1.53 (m, 3 H), 1.35–1.31 (m, 2 H), 0.97 (s, 3 H) ppm.
1
3
C NMR (CDCl
3
, 126 MHz): δ = 212.7, 146.5, 110.6, 53.8, 46.9,
100.62 MHz), DRX500 (500.13 MHz; 125.77 MHz), AV750
41.2, 40.8, 39.2, 33.9, 32.6, 31.0, 23.4, 22.5 ppm. Mass spectrum:
(749.41 MHz;
188.46 MHz)
and
AV900
(900.13 MHz;
+
·
GCMS (EI): m/z (%) = 192 (14.0) [M ], 134 (10), 121 (26), 111
2
26.36 MHz) in deuteriochloroform (CDCl
3
) or hexadeuterioben-
(
(
49), 110 (11), 109 (100), 108 (13), 107 (17), 95 (13), 93 (29), 91
6 6
zene (C D ) unless otherwise stated. Coupling constants are given
13), 81 (17), 79 (16), 77 (13). C13H
20O: calcd. M+ 192.1514; found:
·
in Hz and chemical shifts are expressed as δ values in ppm. Micro-
wave irradiation was conducted with a CEM Discover microwave
in 10 mL or 80 mL pressurized vials. Low-resolution electrospray
ionisation mass spectrometry measurements (LRESIMS) were re-
corded in positive ionization mode with a Bruker Esquire HCT
+
·
M
192.1509.
6-(2-Methoxypropan-2-yl)-1-methylbicyclo[3.3.1]nonan-3-one (17):
5-Methyl-5-(4-methylpent-3-enyl)-2-cyclohexenone (16) (15.0 g,
78.0 mmol) was added dropwise to a flask containing methanol
(High Capacity 3D ion trap) instrument with a Bruker ESI source.
(
400 mL) and concentrated (32%) hydrochloric acid (0.5 mL). The
High-resolution electrospray ionisation (HRESIMS) accurate mass
measurements were recorded in positive mode on a Bruker MicrO-
TOF-Q (quadrupole – Time of Flight) instrument with a Bruker
ESI source. Accurate mass measurements were carried out with
external calibration using sodium formate as reference calibrant.
Microanalyses were performed by the University of Queensland
Microanalytical Service. Column chromatography was undertaken
on silica gel (Flash Silica gel 230–400 mesh), with distilled solvents.
Analytical high performance liquid chromatography was per-
formed on an Agilent 1100 with Phenomenex Luna 18C 5 µm col-
umn. Tetrahydrofuran was freshly distilled from a sodium/benzo-
phenone still. Melting points were determined with a Fischer Johns
Melting Point apparatus and are uncorrected.
solution was stirred at room temperature and after 30 min, satu-
rated sodium hydrogen carbonate solution (20 mL) was added. The
methanol was removed in vacuo and the solution diluted with
water (300 mL) and extracted with diethyl ether (4ϫ250 mL). The
organic phase was washed with brine, dried (MgSO ) and concen-
4
trated in vacuo. Column chromatography (petroleum ether/ethyl
acetate, 9:1) provided the title compound (13.3 g, 76%) as a white
solid. Colourless crystals (m.p. 53 °C) were obtained by recrystalli-
1
sation from petroleum ether. H NMR (CDCl
3
, 300 MHz): δ = 3.12
(
s, 3 H), 2.82 (ddd, J = 16.2, 4.3, 2.1 Hz, 1 H), 2.57–2.50 (m, 1 H),
2
1
.20–2.01 (m, 3 H), 1.75–1.70 (bdt, J = 13.0, 3.0 Hz, 1 H), 1.57–
.45 (m, 4 H), 1.32–1.26 (m, 2 H), 1.11 (s, 3 H), 1.09 (s, 3 H), 0.93
13
3
(s, 3 H) ppm. C NMR (CDCl , 75 MHz): δ = 212.9, 76.1, 53.8,
CCDC-689990 (for 17) and -689991 (for 20) contain the supple-
mentary 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.
50.3, 48.8, 42.9, 42.6, 40.0, 34.1, 32.1, 31.0, 23.6, 23.1, 20.6 ppm.
Mass spectrum: GCMS (EI): m/z (%) = 224 (0.4) [M ], 135 (5),
+
·
109 (11), 93 (5), 81 (5), 79 (5), 74 (17), 73 (100). C14
calcd. C 74.95, H 10.78; found C 74.96, H 11.05.
24 2
H O (224.18):
5
-Methyl-5-(4-methylpent-3-enyl)-2-cyclohexenone (16):[5a–5c]
A
4-Hydroxy-6-(2-methoxypropan-2-yl)-1-methylbicyclo[3.3.1]nonan-
[
26]
mixture of 2-iodoxybenzoic acid (IBX) (7.42 g, 26.5 mmol) and N-
methylmorpholine N-oxide (NMO) (3.23 g, 27.6 mmol) was dis-
solved in dimethyl sulfoxide (25 mL) and heated to 45 °C. 3-
3-one (19): Following a procedure similar to Myers and Liu, 6-
(2-methoxypropan-2-yl)-1-methylbicyclo[3.3.1]nonan-3-one (17)
(300 mg, 1.34 mmol) was dissolved in anhydrous tetrahydrofuran
(5 mL) under argon. The solution was cooled to –78 °C (dry ice/
Methyl-3-(4-methylpent-3-enyl)cyclohexanone
(12)
(2.14 g,
11.04 mmol) was added in one portion at 45 °C and the mixture
2
acetone bath) and freshly distilled (CaH ) chlorotrimethylsilane
heated at that temperature for 17 h. On cooling the mixture was
extracted directly with petroleum ether (4ϫ150 mL) and the com-
bined extracts washed with saturated sodium hydrogen carbonate
(187 µL, 1.47 mmol) added. Separately, at 0 °C, anhydrous 2,2,6,6-
tetramethylpiperidine (285 µL, 1.68 mmol) was added to a flask
containing anhydrous tetrahydrofuran (2 mL) under argon. To this
n-butyllithium (1.4 , 1.05 mL, 1.47 mmol) was added dropwise via
syringe, and the solution stirred for 15 min. The lithium 2,2,6,6-
tetramethylpiperidide solution was then added dropwise via can-
nula to the above solution at –78 °C and the mixture stirred at
4
solution and brine. The organic layer was dried (MgSO ), and con-
centrated in vacuo. The residue was subjected to column
chromatography (petroleum ether/ethyl acetate, 20:1) yielding the
1
title compound (1.65 g, 78%) as a pale yellow oil. H NMR
(CDCl
3
, 400 MHz): δ = 6.85–6.81 (m, 1 H), 5.99 (dt, J = 10.1, this temperature for 1 h. The solution was then warmed to room
2
1
1
.0 Hz, 1 H), 5.06–5.01 (m, 1 H), 2.33–2.27 (m, 2 H), 2.25–2.21 (m, temperature over 2 h before addition to ice/water and extraction
H), 2.17–2.13 (m, 1 H), 1.98–1.85 (m, 2 H), 1.64 (br. d, J =
.1 Hz, 3 H), 1.56 (br. s, 3 H), 1.38–1.30 (m, 2 H), 1.00 (s, 3 H)
with diethyl ether (4ϫ30 mL). The organic phase was washed with
saturated ammonium chloride (50 mL), saturated sodium hydrogen
13
ppm. C NMR (CDCl
3
, 100 MHz): δ = 199.8, 148.2, 131.7, 129.0,
carbonate (30 mL), brine (20 mL), dried (MgSO
4
) and concen-
Eur. J. Org. Chem. 2008, 4697–4705
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 4701

M. J. Gallen, C. M. Williams
trated in vacuo. Column chromatography (petroleum ether/ethyl oled to –78 °C. Sodium hydride (60 wt.-% in paraffin oil, 141 mg,
FULL PAPER
acetate, 50:1) of the residue provided [8-(2-methoxypropan-2-yl)-5-
methylbicyclo[3.3.1]non-2-en-3-yloxy]trimethylsilane (377 mg,
3.52 mmol), washed with petroleum ether (2ϫ3 mL), was added to
the flask in portions and the solution stirred for 30 min after which
9
5%) as a colourless oil in a ratio of 8:2 in favour of the desired
time effervescence ceased. N-Phenyl-bis(trifluoromethanesulfonim-
1
1
regioisomer ( H NMR). H NMR (CDCl
3
, 300 MHz): δ = 4.84 (d, ide) (943 mg, 2.64 mmol) was then added and the solution stirred
J = 6.8 Hz, 1 H), 3.14 (s, 3 H), 2.54 (bm, 1 H), 1.90,1.72 (AB
quartet, J = 17.8 Hz, 2 H), 1.53–1.42 (m, 5 H), 1.25 (bd, 1 H), 1.22
for 40 min after which time TLC (petroleum ether/ethyl acetate,
10:1) indicated consumption of starting material. Water (10 mL)
was added at –78 °C and the solution warmed to room temperature
over 1 h. The mixture was extracted with diethyl ether (3ϫ20 mL),
and the combined organic phase washed with brine (10 mL), dried
(
m, 1 H) 1.08 (s, 3 H), 1.06 (s, 3 H), 0.89 (s, 3 H), 0.17 (s, 9 H)
13
ppm. C NMR (CDCl
3
, 75 MHz): δ = 151.6, 105.7, 76.7, 49.3,
4
8.7, 43.8, 42.1, 41.9, 31.8, 31.2, 31.0, 23.9, 23.3, 20.8, –0.5 (SiMe )
3
+
·
ppm. Mass spectrum: GCMS (EI): m/z (%) = 296 (3.8) [M ], 223
(MgSO
6), 182 (12), 181 (69), 180 (6), 179 (6), 165 (26), 105 (5), 93 (6), 91 subsequent reactions without further purification; however, purifi-
10), 81 (5), 79 (6), 77 (5), 75 (13), 74 (7), 73 (100), 59 (7), 55 (10). cation by column chromatography (petroleum ether/ethyl acetate,
4
) and concentrated in vacuo. The triflate was often used in
(
(
[27]
Following a procedure analogous to Adam and Prechtl,
6-(2-
15:1) in this case afforded 6-(2-methoxypropan-2-yl)-1-methyl-4-
methoxypropan-2-yl)-1-methylbicyclo[3.3.1]non-3-en-3-trimethyl-
silyl ether (1.27 g, 4.3 mmol) was dissolved in distilled acetone
(
oxobicyclo[3.3.1]non-2-en-3-yl trifluoromethanesulfonate (518 mg,
1
80%) as a colourless oil. H NMR (CDCl
3
, 300 MHz): δ = 6.40
50 mL) and cooled to –78 °C. Dimethyldioxirane[28] (≈ 0.08 ,
(m, 1 H), 3.04 (s, 3 H), 2.96 (m, 1 H), 2.14 (ddd, J = 13.0, 2.9,
2.9 Hz, 1 H), 1.83–1.78 (m, 1 H), 1.72–1.49 (m, 5 H), 1.17 (s, 3 H),
4.5 mmol, 57 mL) was added dropwise over 10 min. The reaction
1
3
was monitored by TLC (petroleum ether/ethyl acetate, 10:1), which
showed complete consumption of starting material after 20 min.
After pouring the solution (–78 °C) into water (100 mL) at room
temperature and removal of acetone in vacuo the aqueous phase
was extracted with diethyl ether (4ϫ60 mL). The organic phase
3
1.12 (s, 3 H), 1.10 (s, 3 H) ppm. C NMR (CDCl , 75 MHz): δ =
192.7, 145.3, 143.6, 122.8 (q, CFJ = 320 Hz), 75.5, 49.5, 48.6, 44.0,
43.0, 35.0, 35.0, 28.4, 22.7, 22.4, 19.8 ppm. Mass spectrum: GCMS
+
·
(EI): m/z (%) = 370 (0.2) [M ] 355 (10), 93 (5), 91 (5), 82 (8), 81
(5), 79 (5), 77 (5), 74 (15), 73 (100), 72 (5), 69 (17), 67 (6), 55 (10).
4
) and concentrated
15 21 5 3
C H O SF
Na calcd. [M + Na]+ 393.0954; found: [M + Na]
+
+
was washed with brine (50 mL), dried (MgSO
in vacuo which provided 19 (850 mg, 83%) as a colourless oil that
was used without further purification. 1H NMR (CDCl
00 MHz): δ = 4.39–4.37 (m, 1 H), 3.13 (s, 3 H), 2.87–2.80 (m, 1
[
9]
393.0942. Following a procedure analogous to Yamamoto tetra-
kis(triphenylphosphane)palladium(0) (373 mg, 0.32 mmol) was
added in one portion to a flask containing 8-(2-methoxypropan-2-
3
,
3
H), 2.46–2.42 (m, 1 H), 2.43, 2.12 (AB quartet, J = 17.2 Hz, 2 H), yl)-5-methylbicyclo[3.3.1]non-3-en-2-one-3-yl trifluoromethanesul-
2
1
.00–1.92 (bdt, 1 H), 1.69–1.62 (m, 1 H), 1.59–1.54 (m, 1 H), 1.43–
fonate (2.33 g, 6.30 mmol) dissolved in anhydrous tetrahydrofuran
(100 mL) under argon at room temperature. Carbon monoxide was
slowly bubbled through the solution (solution became dark red) for
30 min before the addition of anhydrous triethylamine (4.70 mL,
33.8 mmol) and anhydrous methanol (10.3 mL, 0.25 mol). The
mixture was heated at reflux for 90 min with a continuous stream
of carbon monoxide being passed through the solution. At this
point a further addition of palladium catalyst, triethylamine and
methanol (two-thirds of the original quantities) was carried out.
The reaction was complete (TLC) within 30 min. The reaction mix-
ture was cooled to room temperature, then poured onto water
.32 (m, 3 H), 1.20 (s, 3 H), 1.18 (m, 1 H) 1.14 (s, 3 H), 0.97 (s, 3
13
H) ppm. C NMR (CDCl
3
, 75 MHz): δ = 213.2, 76.0, 72.5, 49.9,
49.1, 49.0, 39.9, 39.7, 37.5, 34.6, 31.3, 23.6, 23.5, 20.9 ppm. Mass
+
·
spectrum: GCMS (EI): m/z (%) = 240 (0.4) [M ], 196 (5), 136 (5),
+
1
[
35 (8), 95 (5), 93 (6), 81 (5), 79 (5), 73 (100). C14
H
24
O
3
Na : calcd.
M + Na]+ 263.1618; found: [M + Na] 263.1611.
+
3
-Hydroxy-8-(2-methoxypropan-2-yl)-5-methylbicyclo[3.3.1]non-3-
[29]
en-2-one (20): Following a procedure similar to Kawada et al.,
to a solution of anhydrous dimethyl sulfoxide (0.34 mL, 4.8 mmol)
in anhydrous dichloromethane (15 mL) under argon was added tri-
fluoroacetic anhydride (0.5 mL, 3.57 mmol) at –78 °C. After 10 min
of stirring, hydroxyketone 19 (500 mg, 2.08 mmol) in anhydrous
dichloromethane (5 mL) was added. The solution was stirred for
(
100 mL) and extracted with diethyl ether (3ϫ100 mL). The or-
ganic layer was dried (MgSO ) and concentrated in vacuo. Column
4
chromatography (petroleum ether/ethyl acetate, 15:1) of the residue
1
provided the title compound (1.27 g, 72%) as a colourless oil. H
3
0 min at –78 °C before addition of anhydrous triethylamine
NMR (CDCl
3
, 300 MHz): δ = 7.12 (d, J = 2.5 Hz, 1 H), 3.74 (s, 3
(1.72 mL, 12.4 mmol). The reaction was warmed to room tempera-
H), 3.01 (s, 3 H), 2.80–2.75 (m, 1 H), 2.09 (ddd, J = 12.9, 3.1,
ture over 40 min and then poured into water (20 mL). The mixture
was extracted with dichloromethane (4ϫ15 mL) and the organic
phase washed with brine (20 mL), dried (MgSO ) and concentrated
4
in vacuo. The crude was subjected to column chromatography (pe-
troleum ether/ethyl acetate, 15:1) affording the title compound
1
3
3
(
4
.1 Hz, 1 H), 1.76–1.37 (m, 6 H), 1.10 (m, 9 H) ppm. C NMR
CDCl , 75 MHz): δ = 198.1, 165.0, 160.4, 133.9, 75.5, 51.9, 48.7,
8.6, 45.4, 42.2, 34.9, 34.2, 27.9, 22.8, 22.5, 19.9 ppm. Mass spec-
3
+
·
trum: GCMS (EI): m/z (%) = 280 (0.1) [M ], 247 (8), 209 (8), 208
(
(
14), 119 (5), 115 (5), 107 (5), 105 (8), 93 (7), 91 (16), 81 (6), 79
(308 mg, 62%) as a white solid. A sample was then crystallised from
+
+
24 4
16), 77 (15), 74 (19), 73 (100). C16H O Na : calcd. [M + Na]
(50:50) petroleum ether/diethyl ether giving colourless crystals (m.p.
+
1
303.1567; found: [M + Na] 303.1563.
8
1
2
1
1
2
7
2 °C). H NMR (CDCl
3
, 300 MHz): δ = 5.98 (s, 1 H), 5.67 (d, J =
.8 Hz, 1 H), 3.10 (s, 3 H), 2.91 (m, 1 H), 2.11 (ddd, J = 12.6, 2.9,
.9 Hz, 1 H), 1.76–1.52 (m, 5 H), 1.47–1.41 (m, 1 H), 1.17 (s, 3 H),
Methyl 4-[(1,3-Dioxolan-2-yl)methyl]-2-hydroxy-8-(2-methoxypro-
pan-2-yl)-5-methylbicyclo[3.3.1]non-2-ene-3-carboxylate (23): Cop-
per(I) iodide (658 mg, 3.46 mmol) was added to a flask containing
anhydrous tetrahydrofuran (130 mL) under argon. The flask was
cooled to –78 °C and commercial (1,3-dioxolan-2-ylmethyl)magne-
sium bromide (22) (0.5 , 13.8 mL, 6.92 mmol) was added dropwise
via syringe over 10 min. The solution was stirred for 30 min before
addition of 21 (1.29 g, 4.60 mmol) in anhydrous tetrahydrofuran
(5 mL) dropwise over 5 min. The mixture was warmed to room
temperature (≈ 4 h) and then stirred overnight. The mixture was
then gently heated at 45 °C until consumption of 21 was complete
.11 (s, 6 H) ppm. 13C NMR (CDCl
, 75 MHz): δ = 198.6, 148.3,
23.3, 75.7, 49.0, 48.6, 44.4, 42.5, 35.6, 33.0, 29.5, 22.7, 22.4,
3
+
·
0.0 ppm. Mass spectrum: GCMS (EI): m/z (%) = 238 (1.4) [M ],
9 (4), 77 (4), 74 (5), 73 (100), 67 (5), 55 (9). C14 (238.33):
22 3
H O
calcd. C 70.56, H 9.30; found C 70.40, H 9.47.
Methyl 6-(2-Methoxypropan-2-yl)-1-methyl-4-oxobicyclo[3.3.1]non-
-ene-3-carboxylate (21): Following a procedure similar to Kuroso
2
[
30]
et al., compound 20 (420 mg, 1.76 mmol) was dissolved in anhy-
drous tetrahydrofuran (20 mL) under argon and the solution co-
4702
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4697–4705

Total Synthesis of (Ϯ)-5,14-Bis-epi-spirovibsanin A
(
TLC). The mixture was poured onto a saturated ammonium chlo-
ride solution (100 mL) and then extracted with diethyl ether
3ϫ80 mL). The combined organic fractions were washed with
brine (50 mL), dried (MgSO ) and concentrated in vacuo. Column
chromatography (petroleum ether/ethyl acetate, 8:1) provided the
75 MHz): δ = 212.9, 173.7, 134.9, 116.3, 103.6, 76.6, 65.6, 64.8,
64.6, 52.1, 51.4, 48.5, 44.9, 42.9, 39.7, 37.6, 36.1, 32.8, 31.0, 27.9,
22.5, 21.2, 20.8 ppm. Mass spectrum: GCMS (EI): m/z (%) = 408
(
+
·
4
(0.1) [M ] 213 (4), 196 (8), 181 (6), 164 (5), 136 (4), 121 (3), 109
(3), 107 (3), 93 (5), 91 (5), 81 (4), 79 (6), 73 (100), 67 (5), 55 (6).
1
23 36 6
C H O
Na : [M + Na] 431.2404; found: [M + Na]+ 431.2523.
+
+
title compound (1.19 g, 70%) as a colourless oil. H NMR (CDCl
3
,
3
3
2
6
3
7
4
00 MHz): δ = 12.35 (s, 1 H), 4.86 (dd, J = 6.0, 3.9 Hz, 1 H), 3.94–
Dihydroxylation/Lactonisation of 26 Affording 32: Following a pro-
.84 (m, 2 H), 3.81–3.71 (m, 2 H), 3.73 (s, 3 H), 3.11 (s, 3 H), 2.68–
.63 (m, 1 H), 2.39 (dd, J = 6.6, 3.3 Hz, 1 H), 1.97 (ddd, J = 15.1,
.7, 3.9 Hz, 1 H), 1.93–1.86 (m, 1 H), 1.72–1.12 (m, 7 H), 1.18 (s,
[19]
cedure similar to Köckritz et al.,
compound 26 (442 mg,
1.08 mmol) was dissolved in tert-butyl alcohol/water (1:1, 20 mL).
To this was added potassium carbonate (168 mg, 1.22 mmol), N-
methylmorpholine N-oxide (140 mg, 1.20 mmol) and potassium os-
mate(VI) dihydrate (26 mg, 0.08 mmol). The mixture was stirred at
room temperature for 16 h. Saturated sodium sulfite solution
1
3
3
H), 1.02 (m, 3 H), 0.92 (m, 3 H) ppm. C NMR (CDCl ,
5 MHz): δ = 172.4, 172.3, 104.5, 104.3, 76.6, 64.7, 64.4, 51.2, 50.3,
8.7, 43.4, 39.2, 38.8, 37.5, 36.7, 32.7, 29.2, 22.5, 22.1, 21.1 ppm.
+
·
Mass spectrum: GCMS (EI): m/z (%) = 368 (4.0) [M ], 295 (4),
(
2 mL) was added and the solution stirred for 30 min. The solvent
208 (4), 206 (4), 196 (5), 175 (5), 150 (4), 148 (5), 141 (7), 137 (6),
was removed in vacuo and the residue dissolved in dichlorometh-
131 (4), 126 (4), 113 (7), 107 (7), 74 (5), 73 (100), 59 (7), 55 (11).
®
ane and passed through a plug of Celite . The residue was redis-
20 32 6
H O
Na : calcd. [M + Na] 391.2091; found: [M + Na]+
+
+
C
solved in tert-butyl alcohol/water (1:1, 10 mL), potassium carbon-
ate (750 mg, 5.40 mmol) added and the mixture stirred at room
temperature overnight. The solvent was removed in vacuo, the resi-
due dissolved in dichloromethane and passed through a plug of
391.2101.
Methyl 2-[(1,3-Dioxolan-2-yl)methyl]-3-allyl-6-(2-methoxypropan-2-
yl)-1-methyl-4-oxobicyclo[3.3.1]nonane-3-carboxylate (26): Com-
pound 23 (1.19 g, 3.23 mmol) was dissolved in freshly distilled, an-
hydrous N,NЈ-dimethylpropylene urea (35 mL). Potassium hydride
®
Celite . After concentration in vacuo, the residue was dissolved in
ethyl acetate to facilitate crystallisation of the lactone (32). Any
unreacted diol (30) remaining in solution was re-subjected to the
lactonisation protocol. This procedure provided the desired lactone
(30 wt.-% dispersion in mineral oil) (431 mg, 6.46 mmol) was added
and the solution stirred for 35 min until effervescence had ceased.
Allyl iodide (705 mg, 4.20 mmol) was added and the reaction moni-
tored (TLC) until consumption of 23 (30 min). The reaction mix-
ture was carefully poured onto water (50 mL) and then extracted
with diethyl ether (3 ϫ60 mL). The combined organic fractions
(
32) as a mixture of diastereomers (60:40), partially separable on
recrystallisation, as colourless crystals (386 mg, 87 % over two
1
steps). Minor diastereomer only: H NMR (CDCl
3
, 300 MHz): δ
=
4.90 (dd, J = 6.4, 3.5 Hz, 1 H), 4.57–4.49 (m, 1 H), 3.98–3.75
(
(
m, 5 H), 3.62 (dd, J = 12.4, 5.4 Hz, 1 H), 3.10 (s, 3 H), 2.89–2.86
m, 1 H), 2.79 (bdd, J = 8.9, 3.5 Hz, 1 H), 2.35 (dd, J = 13.7,
were washed with brine (40 mL), dried (MgSO
in vacuo. Column chromatography (petroleum ether/ethyl acetate,
4
) and concentrated
9
.3 Hz, 1 H), 2.19–1.94 (m, 3 H), 1.92–1.63 (m, 5 H), 1.45–1.21 (m,
1
2
0:1) of the residue provided methyl 4-[(1,3-dioxolan-2-yl)methyl]-
1
3
3
H), 1.20 (s, 3 H), 1.09 (s, 3 H), 1.08 (s, 3 H) ppm. C NMR
, 75 MHz): δ = 215.0, 176.7, 103.6, 77.9, 76.2, 64.8, 64.7,
4.2, 61.9, 51.4, 48.6, 44.0, 41.4, 40.9, 36.8, 33.7, 31.7, 30.5, 28.0,
2.4, 22.0, 20.8 ppm. Mass spectrum: GCMS (EI): m/z (%) = 410
-allyloxy-8-(2-methoxypropan-2-yl)-5-methylbicyclo[3.3.1]non-2-
1
(CDCl
3
6
2
ene-3-carboxylate as a colourless oil (0.99 g, 75 %). H NMR
(CDCl
3
, 300 MHz): δ = 5.97 (dddd, J = 17.2, 10.6, 5.6, 5.4 Hz, 1
H), 5.29–5.22 (m, 1 H), 5.15–5.10 (m, 1 H), 4.90 (dd, J = 6.1,
+
·
(
(
0.03) [M ], 379 (0.4), 364 (0.3), 363 (0.5), 348 (0.1), 337 (2), 322
0.2), 316 (0.2), 309 (0.3), 292 (0.3), 280 (0.2), 273 (0.2), 269 (0.1),
3.9 Hz, 1 H), 4.39–4.24 (m, 2 H), 3.94–3.83 (m, 2 H), 3.81–3.70 (m,
2 H), 3.70 (s, 3 H), 3.15 (s, 3 H), 2.77–2.73 (m, 1 H), 2.45–2.42 (m,
1 H), 1.87–1.20 (m, 9 H), 1.08 (s, 3 H), 1.06 (s, 3 H), 0.94 (s, 3 H)
2
56 (0.1), 249 (0.4), 233 (0.4), 219 (0.2), 215 (4), 207 (1), 196 (4),
191 (0.4), 181 (1), 175 (1), 173 (1), 164 (4), 153 (2), 149 (1), 147 (1),
37 (2), 136 (3), 135 (2), 122 (2), 121 (3), 109 (3), 95 (3), 93 (4), 91
13
ppm. C NMR (CDCl
3
, 75 MHz): δ = 168.5, 157.8, 134.4, 122.7,
16.8, 103.7, 76.8, 71.2, 64.7, 64.5, 51.3, 50.7, 48.6, 43.9, 41.1, 38.6,
7.2, 32.4, 32.2, 28.7, 23.5, 21.4, 21.0 ppm. Mass spectrum: GCMS
1
1
3
+
(
34 7
5), 81 (5), 79 (5), 77 (3), 73 (100), 67 (5), 55 (7). C22H O Na :
calcd. [M + Na] 433.2197; found: [M + Na]+ 433.2186.
+
+
·
(EI): m/z (%) = 408 (0.2) [M ], 393 (0.4), 377 (1), 345 (1), 316 (1),
2
1
9
88 (1), 281 (3), 267 (2), 254 (1), 228 (1), 213 (4), 207 (5), 196 (6), {2-[(1,3-Dioxolan-2-yl)methyl]-6-(2-methoxypropan-2-yl)-1-methyl-
81 (9), 164 (12), 149 (4), 137 (4), 135 (6), 109 (6), 107 (6), 95 (5), 2Ј,4-dioxodihydro-2ЈH-spiro[bicyclo[3.3.1]nonane-3,3Ј-furan]-5Ј-
3 (14), 91 (8), 81 (6), 79 (8), 73 (95), 67 (5), 59 (5), 45 (25), 44 yl}methyl Methanesulfonate (35): Compound 32 (250 mg,
+
+
(
100). C23
H
36
O
6
Na : calcd. [M + Na] 431.2404; found: [M +
Na] 431.2412. Methyl 4-[(1,3-dioxolan-2-yl)methyl]-2-(allyloxy)-8-
2-methoxypropan-2-yl)-5-methylbicyclo[3.3.1]non-2-ene-3-carbox-
ylate (300 mg, 0.82 mmol) was dissolved in anhydrous toluene
2.5 mL) under argon and the mixture heated under microwave ir-
0.61 mmol) was dissolved in anhydrous dichloromethane (6 mL)
under argon. To this was added anhydrous triethylamine (170 µL,
1.22 mmol) followed by mesyl chloride (71 µL, 0.92 mmol). The
solution was stirred at room temperature for 30 min and then
added to water (5 mL). The aqueous phase was extracted with
dichloromethane (3ϫ5 mL) and the organic phase then washed
+
(
(
radiation for 60 min (maximum temperature 195 °C, 250 W). This
provided an approximately 12:1 ratio of C-allylated material (26)
to O-allylated material. The solvent was removed in vacuo, and
column chromatography (petroleum ether/ethyl acetate, 10:1) of the
4
with brine, dried (MgSO ) and concentrated in vacuo to provide
the title compound (Ͼ95%) as a mixture of diastereomers (50:50)
1
3
which was used without further purification. H NMR (CDCl ,
residue provided the title compound 26 [279 mg, 93%] as a colour-
300 MHz): δ = 4.87–4.80 (m, 1 H), 4.72–4.62 (m, 1 H), 4.41–4.23
(m, 2 H), 3.96–3.85 (m, 2 H), 3.83–3.72 (m, 2 H), 3.08–3.05 (m, 6
H), 2.92–2.73 (m, 2 H), 2.52–2.19 (m, 1 H), 2.18–1.90 (m, 2 H),
1
less oil. H NMR (CDCl
3
, 400 MHz): δ = 5.74–5.62 (m, 1 H), 4.91
(m, 1 H), 4.89–4.86 (m, 1 H), 4.83 (dd, J = 6.3, 3.5 Hz, 1 H), 3.91–
3
2
2
.82 (m, 2 H), 3.79–3.73 (m, 2 H), 3.64 (s, 3 H), 3.10 (s, 3 H), 2.99– 1.94–1.62 (m, 5 H), 1.39–1.23 (m, 3 H), 1.18–1.15 (m, 3 H), 1.09–
1
3
.94 (m, 1 H), 2.73 (dd, J = 9.2, 4.5 Hz, 1 H), 2.55–2.52 (m, 1 H),
.15–2.10 (m, 1 H), 2.07 (dd, J = 14.3, 9.8 Hz, 1 H), 1.99 (ddd, J
1.08 (m, 3 H), 1.04–1.03 (m, 3 H) ppm. C NMR (CDCl
75 MHz): δ = 214.5, 176.1, 103.4, 76.1, 74.0, 69.6, 64.9, 64.7, 60.9,
3
,
=
14.6, 9.2, 3.5 Hz, 1 H), 1.75–1.61 (m, 4 H), 1.42 (ddd, J = 14.7, 51.4, 48.6, 44.1, 41.4, 40.7, 37.8, 36.8, 33.6, 32.0, 30.5, 27.9, 22.4,
6
1
.3, 3.4 Hz, 1 H), 1.27 (dd, J = 14.1, 2.0 Hz, 1 H), 1.24 (s, 3 H),
22.1, 20.7 ppm. Mass spectrum: GCMS (EI): m/z (%) = 488 (0)
[M ], 392 (5), 323 (4), 175 (5), 145 (6), 135 (6), 131 (6), 121 (6),
.20 (m, 1 H), 1.07 (s, 3 H), 1.01 (s, 3 H) ppm. 1 C NMR (CDCl
3
,
+·
3
Eur. J. Org. Chem. 2008, 4697–4705
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4703

M. J. Gallen, C. M. Williams
FULL PAPER
119 (7), 117 (6), 107 (8), 105 (10), 93 (7), 91 (5), 87 (5), 81 (5), 79 diation for 30 min (maximum temperature 155 °C, 270 W). The
(
C
5
12), 77 (13), 74 (7), 73 (100), 69 (7), 67 (9), 59 (7), 55 (6). mixture was diluted with diethyl ether (2 mL) on cooling and then
H
36
O
9
SNa : calcd. [M + Na] 511.1972; found: [M + Na]+
+
+
washed with sodium metabisulfite solution (1 mL) and water
(2 mL). The organic phase was dried (MgSO ) and solvent removed
23
11.1963.
4
in vacuo providing the title compound as a mixture of unresolved
E/Z (7:3) diastereomers (colourless oil). E-Isomer (40): H NMR
{
6-(2-Methoxypropan-2-yl)-1-methyl-2Ј,4-dioxo-2-(2-oxoethyl)dihy-
1
dro-2ЈH-spiro[bicyclo[3.3.1]nonane-3,3Ј-furan]-5Ј-yl}methyl Meth-
anesulfonate (36): Following a procedure similar to Fujioka et
(
1
3
CDCl
3
, 300 MHz): δ = 7.62 (d, J = 12.2 Hz, 1 H), 5.53–5.50 (m,
H), 5.33 (dd, J = 12.1, 11.2 Hz, 1 H), 4.62–4.58 (m, 1 H), 3.92–
.87 (m, 1 H), 3.21 (d, J = 11.2 Hz, 1 H), 3.01 (s, 3 H), 2.67–2.62
[
25]
al.; mesylate 35 (528 mg, 1.08 mmol) was dissolved in anhydrous
dichloromethane (30 mL) under argon. To this was added anhy-
drous 2,6-lutidine (1.14 mL, 9.80 mmol), followed by trimethylsilyl
trifluoromethanesulfonate (1.17 mL, 6.5 mmol). The reaction was
followed (TLC) to note disappearance of the starting material and
appearance of a polar spot on the baseline of the TLC plate
(
m, 1 H), 2.53–2.44 (dm, 1 H), 2.26–2.20 (dm, 1 H), 2.11–2.03 (m,
1
1
H), 1.97 (d, J = 1.3 Hz, 3 H), 1.85–1.28 (m, 4 H), 1.34 (d, J =
.3 Hz, 3 H), 1.19–1.14 (m, 6 H), 1.08–0.78 (m, 2 H), 0.68 (s, 3 H)
13
3
ppm. C NMR (CDCl , 75 MHz): δ = 211.1, 173.7, 162.6, 160.0,
1
4
53.0, 139.1, 114.9, 108.2, 88.5, 75.8, 62.0, 52.1, 48.6, 44.3, 41.9,
1.2, 39.6, 34.8, 31.1, 28.2, 27.0, 22.5, 21.9, 20.9, 20.3 ppm. Mass
(30 min). At this point water (20 mL) was added and the mixture
monitored (TLC) for the formation of a newly running spot. The
mixture was then extracted with dichloromethane (3ϫ 30 mL),
washed with brine (20 mL), dried (MgSO ) and concentrated in
4
vacuo. Column chromatography (petroleum ether/ethyl acetate, 1:2)
of the residue provided the title compound (305 mg, 64%), as a
colourless oil (dr = 45:55). H NMR (CDCl
=
+·
spectrum: GCMS (EI): m/z (%) = 430 (0.1) [M ], 399 (0.1), 398
0.2), 370 (0.2), 355 (0.1), 330 (0.1), 317 (0.2), 316 (0.8), 288 (0.2),
(
270 (0.4), 235 (0.3), 227 (0.3), 196 (1), 164 (1), 137 (1), 136 (1),
1
C
35 (1), 107 (1), 105 (1), 93 (2), 91 (2), 83 (100), 73 (26), 55 (19).
+·
+·
25
H
34
1
O
6
Na: calcd. M 453.2248; found: M 453.2242. Z-Isomer
, 300 MHz): δ = 7.39 (d, J = 6.6 Hz, 1 H),
1
3
, 400 MHz) Minor: δ
(
39): H NMR (CDCl
3
9.40 (m, 1 H), 4.43–4.37 (m, 1 H), 4.15 (d, J = 4.1 Hz, 1 H), 4.01
5
1
2
2
.75–5.72 (m, 1 H), 4.62–4.58 (m, 1 H), 4.36 (dd, J = 10.7, 6.6 Hz,
(dd, J = 11.8, 4.6 Hz, 1 H), 3.39 (dd, J = 10.1, 3.1 Hz, 1 H), 2.99
(s, 3 H), 2.73 (m, 1 H), 2.55 (s, 3 H), 2.52–2.45 (m, 1 H), 1.93–1.77
(m, 3 H), 1.71–1.62 (m, 2 H), 1.57–1.33 (m, 3 H), 1.14 (m, 6 H),
H), 4.16 (d, J = 10.7 Hz, 1 H), 3.92–3.87 (m, 1 H), 2.99 (s, 3 H),
.71–2.66 (m, 1 H), 2.53–2.44 (dm, 1 H), 2.20–2.15 (dm, 1 H), 2.11–
.03 (m, 1 H), 2.00 (d, J = 1.3 Hz, 3 H), 1.85–1.28 (m, 4 H), 1.26
0
4
6
.97–0.88 (m, 2 H), 0.64 (s, 3 H) ppm. Major: δ = 9.36 (m, 1 H),
.38–4.31 (m, 1 H), 4.19 (dd, J = 11.8, 2.7 Hz, 1 H), 4.14 (d, J =
.5 Hz, 1 H), 3.26 (dd, J = 10.4, 2.9 Hz, 1 H), 3.00 (s, 3 H), 2.69
(
(
1
4
d, J = 1.4 Hz, 3 H), 1.19–1.14 (m, 6 H), 1.08–0.78 (m, 2 H), 0.71
13
s, 3 H) ppm. C NMR (CDCl
3
, 75 MHz): δ = 211.4, 173.7, 162.8,
60.3, 153.3, 137.0, 115.1, 107.0, 88.2, 75.9, 60.9, 52.2, 48.6, 44.3,
2.1, 39.8, 37.9, 35.1, 31.2, 28.4, 26.9, 22.6, 21.9, 21.1, 20.4 ppm.
(s, 1 H), 2.54 (s, 3 H), 2.38–2.30 (m, 1 H), 1.93–1.77 (m, 3 H), 1.71–
1
.62 (m, 2 H), 1.57–1.33 (m, 3 H), 1.13 (m, 6 H), 0.97–0.88 (m, 2
+·
Mass spectrum: GCMS (EI): m/z (%) = 430 (0.2) [M ], 399 (0.2),
98 (0.3), 370 (0.2), 355 (0.1), 330 (0.1), 317 (0.5), 316 (0.8), 288
13
H), 0.66 (s, 3 H) ppm. C NMR (CDCl
3
, 75 MHz): δ = 213.9,
3
2
6
4
2
12.1, 199.8, 199.4, 176.1, 175.4, 75.8, 75.8, 74.4, 73.9, 70.0, 68.7,
(
(
(
0.5), 270 (0.3), 235 (0.2), 227 (0.3), 196 (1), 164 (1), 137 (1), 136
1), 135 (1), 107 (1), 105 (1), 93 (3), 91 (3), 83 (100), 73 (32), 55
22).
1.8, 60.6, 51.9, 51.8, 48.6, 48.6, 44.3, 44.1, 44.1, 43.7, 41.3, 41.1,
0.6, 40.2, 37.1, 37.0, 35.8, 34.6, 32.3, 31.8, 30.3, 30.2, 27.4, 27.3,
2.6, 22.5, 22.2, 22.2, 21.1, 20.9 ppm. Mass spectrum: GCMS (EI):
+
·
m/z (%) = 348 (0.4) [M ], 298 (1), 281 (2), 249 (1), 207 (3), 196 (3),
(
(
(
E/Z)-5,14-Bis-epi-spirovibsanin A (42/41): Compounds 39 and 40
8 mg, 0.02 mmol) were dissolved in anhydrous 1,2-dichloroethane
0.5 mL). A catalytic amount (≈ 1 mol-%) of anhydrous pyridinium
1
1
6
91 (2), 173 (2), 164 (19), 153 (7), 149 (5), 135 (9), 121 (5), 119 (4),
09 (10), 107 (8), 96 (11), 93 (12), 91 (10), 81 (9), 79 (13), 73 (100),
+
+
32 8
7 (7), 55 (10). C21H O SNa : calcd. [M + Na] 467.1710; found:
p-toluenesulfonate was added and the mixture heated under micro-
wave irradiation for 30 min (maximum temperature 110 °C, 50 W).
The mixture was diluted with dichloromethane (2 mL), and the or-
ganic layer was washed with saturated sodium hydrogen carbonate
[
M + Na]+ 467.1724.
(
E/Z)-2-(6-(2-Methoxypropan-2-yl)-1-methyl-5Ј-methylene-2Ј,4-di-
oxodihydro-2ЈH-spiro[bicyclo[3.3.1]nonane-3,3Ј-furan]-2-yl}vinyl 3-
Methylbut-2-enoate (40/39): To aldehyde 36 (179 mg, 0.40 mmol)
dissolved in anhydrous toluene (3 mL) was added 4-(dimeth-
ylamino)pyridine (82 mg, 0.67 mmol) and 3-methylbut-2-enoic an-
hydride (102 mg, 0.56 mmol). The mixture was heated under mi-
crowave irradiation for 20 min (maximum temperature 85 °C,
(
4
0.5 mL), water (1 mL), brine (0.5 mL), dried (MgSO ) and concen-
trated in vacuo. Column chromatography (petroleum ether/ethyl
acetate, 5:1, with 1 % triethylamine) of the residue provided a
colourless oil (crude yield 53%) consisting of a 65:35 mixture of
[
31]
(
E/Z)-5,14-bis-epi-spirovibsanin A (42/41). HPLC (0.2 mL/min,
methanol/water gradient elution) purification provided the E (42)
2
50 W). On cooling, diethyl ether (10 mL) was added and the or-
ganic layer washed with water (2ϫ10 mL), saturated sodium hy-
drogen carbonate solution (10 mL), brine (5 mL), dried (MgSO
1
(
0.5 mg, 6%) and Z (41) (1.5 mg, 19%) isomers. E-Isomer (42): H
NMR (C , 900 MHz): δ = 7.58 (d, J = 11.7 Hz, 1 H), 5.51 (br.
s, 1 H), 5.35 (dd, J = 11.7, 11.7 Hz, 1 H), 4.58 (br. s, 1 H), 3.13
dd, J = 11.7 Hz, 1 H), 3.04 (s, 3 H), 2.73–2.71 (m, 1 H), 1.98 (s, 3
H), 1.74–1.70 (m, 1 H), 1.68–1.64 (m, 1 H), 1.58 (ddd, J = 13.5,
.6, 3.6 Hz, 1 H), 1.50 (ddd, J = 12.6, 3.6, 3.6 Hz, 1 H), 1.43–1.40
m, 1 H), 1.42 (s, 3 H), 1.32 (s, 3 H), 1.22 (s, 3 H), 1.21 (s, 3 H),
6
D
6
4
)
and concentrated in vacuo. Column chromatography (petroleum
ether/ethyl acetate, 2:3, with 1% triethylamine) provided the title
compounds (115 mg, 55%) as an inseparable mixture of (E)-2-{6-
(
3
(
0
(
2
2-methoxypropan-2-yl)-1-methyl-5Ј-[(methylsulfonyloxy)methyl]-
Ј,4-dioxodihydro-2ЈH-spiro[bicyclo[3.3.1]nonane-3,3Ј-furan]-2-
1
3
.99–0.94 (m, 1 H), 0.93–0.89 (m, 1 H), 0.77 (s, 3 H) ppm.
, 226 MHz): δ = 209.6, 176.0, 162.7, 159.7, 155.2,
37.6, 115.0, 110.3, 104.1, 76.0, 68.1, 52.5, 48.6, 45.0, 43.6, 41.9,
9.5, 31.5, 28.1, 26.9, 22.5, 21.8, 21.2, 20.2, 13.7 ppm. Mass spec-
C
yl}vinyl 3-methylbut-2-enoate (38) and (Z)-2-{6-(2-methoxypro-
pan-2-yl)-1-methyl-5Ј-[(methylsulfonyloxy)methyl]-2Ј,4-dioxodihy-
dro-2ЈH-spiro[bicyclo[3.3.1]nonane-3,3Ј-furan]-2-yl}vinyl 3-meth-
ylbut-2-enoate (37) (7:3) isomers (colourless oil).
6 6
NMR (C D
1
3
+
·
trum: GCMS (EI): m/z (%) = 430 (0.1) [M ], 316 (1), 295 (0.1),
273 (0.1), 270 (0.1), 236 (0.1), 227 (0.1), 218 (0.1), 196 (1), 173 (0.1),
164 (2), 153 (1), 149 (0.4), 137 (1), 136 (2), 135 (1), 127 (1), 121 (1),
109 (1), 107 (1), 105 (1), 95 (1), 93 (3), 83 (100), 73 (15).
To mesylates 37 and 38 (27 mg, 0.05 mmol) dissolved in anhydrous
dioxane (1.5 mL) under argon was added tetra-n-butylammonium
iodide (21 mg, 0.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene
+
+·
+·
(12 µL, 0.08 mmol). The mixture was heated under microwave irra-
25 34 6
C H O Na : calcd. M 453.2248; found: M 453.2249. Z-Iso-
4704
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4697–4705

Total Synthesis of (Ϯ)-5,14-Bis-epi-spirovibsanin A
1
mer (41): H NMR (C
6
D
6
, 750 MHz): δ = 7.42 (d, J = 6.5 Hz, 1
Tilly, R. Heim, S. Wiedemann, C. M. Williams, P. V. Bernhardt,
Eur. J. Org. Chem. 2006, 3181; d) B. D. Schwartz, C. M. Wil-
liams, E. Anders, P. V. Bernhardt, Tetrahedron 2008, 64, 6482;
e) A. P.-J. Chen, C. M. Williams, Org. Lett. DOI: 10.1021/
ol801117e; f) B. D. Schwartz, J. R. Denton, H. M. L. Davies,
C. M. Williams, J. Am. Chem. Soc. 2008, submitted.
H), 5.73–5.72 (m, 1 H), 4.56 (br. s, 1 H), 4.49 (dd, J = 10.7, 6.6 Hz,
1
2
1
1
4
H), 4.09 (d, J = 10.4 Hz, 1 H), 3.01 (s, 3 H), 2.75–2.74 (m, 1 H),
.10–2.05 (m, 1 H), 2.01 (d, J = 1.1 Hz, 3 H), 1.86–1.84 (m, 2 H),
.61–1.59 (m, 1 H), 1.57–1.54 (m, 1 H), 1.45 (d, J = 1.1 Hz, 3 H),
.28 (s, 3 H), 1.22 (s, 3 H), 1.19 (s, 3 H), 1.10–1.07 (td, J = 12.9,
.4 Hz, 1 H), 1.01 (dd, J = 13.7, 1.9 Hz, 1 H), 0.79 (s, 3 H) ppm.
C NMR (C D , 125 MHz): δ = 209.8, 176.0, 163.0, 106.0, 155.3, [7] a) H. M. L. Davies, Ø. Loe, D. G. Stafford, Org. Lett. 2005, 7,
6 6
35.8, 115.2, 108.8, 140.4, 76.1, 67.3, 52.6, 48.6, 45.0, 42.8, 39.7,
9.5, 31.5, 28.3, 26.9, 22.6, 21.7, 21.4, 20.4, 13.7 ppm. Mass spec-
trum: GCMS (EI): m/z (%) = 430 (0.1) [M ], 398 (0.1), 370 (0.1),
33 (0.1), 330 (0.3), 316 (1), 301 (0.1), 298 (0.2), 288 (0.1), 273 (0.1),
70 (0.2), 255 (0.1), 246 (0.1), 235 (0.2), 229 (0.1), 227 (0.1), 218
0.1), 207 (0.1), 200 (0.2), 196 (1), 180 (0.1), 173 (0.1), 164 (2), 159
0.2), 153 (1), 149 (1), 147 (0.3), 137 (1), 136 (2), 135 (1), 131 (0.4),
[
6] M. J. Gallen, R. Goumont, T. Clark, F. Terrier, C. M. Williams,
Angew. Chem. Int. Ed. 2006, 45, 2929.
13
1
3
5561; b) J. Nikolai, Ø. Loe, P. M. Dominiak, O. O. Gerlitz, J.
Autschbach, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129,
10763.
+
·
[
8] S. J. Danishefsky, S. Chackalamannil, B.-J. Uang, J. Org. Chem.
3
2
(
(
1982, 47, 2231.
[
[
[
9] K. Yamamoto, C. H. Heathcock, Org. Lett. 2000, 2, 1709.
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1
C
27 (1), 121 (1), 109 (1), 107 (1), 105 (1), 93 (3), 83 (100), 73 (17).
25 34 6
H O
Na : calcd. [M + Na] 453.2248; found: [M + Na]+
+
+
4607.
453.2238.
[12] M. Schmeichel, H. Redlich, Synthesis 1996, 1002.
[13] M. G. Moloney, J. T. Pinhey, E. G. Roche, J. Chem. Soc. Perkin
Trans. 1 1989, 333.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of H and C NMR spectra for all compounds. Com-
parisons of spirovibsanin A and bis-epi-spirovibsanin A.
1
13
[
[
[
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We thank the University of Queensland and the Australian Re-
search Council (DP0666855) for financial support. NMR spectro-
scopic data of spirovibsanin A (1) provided by Prof. Y. Fukuyama
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of Stuttgart) are gratefully acknowledged. HPLC and X-ray crystal
structure analysis provided by J. Johns (Queensland Institute of
Medical Research) and Prof. P.V. Bernhardt (School of Molecular
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also gratefully acknowledged.
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Received: June 13, 2008
Published Online: July 31, 2008
Eur. J. Org. Chem. 2008, 4697–4705
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4705