Total synthesis of (+)-Z-deoxypukalide, a furanobutenolide-based cembranoid isolated from the pacific octocoral Leptogorgia spp.

Article abstract of DOI:10.1016/j.tet.2010.01.059

A total synthesis of (+)-Z-deoxypukalide 3 using a combination of Stille and Nozaki-Hiyama-Kishi(NHK) coupling reactions as key steps, is described. During this study a new practical synthesis of the substituted butenolide intermediate 10, based on a comb

Full text of DOI:10.1016/j.tet.2010.01.059

Tetrahedron 66 (2010) 2492–2500
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Total synthesis of (þ)-Z-deoxypukalide, a furanobutenolide-based cembranoid
isolated from the pacific octocoral Leptogorgia spp.
*
Bencan Tang, Christopher D. Bray, Gerald Pattenden , Joseph Rogers
School of Chemistry, The University of Nottingham, University Park, Nottingham, NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of (þ)-Z-deoxypukalide 3 using a combination of Stille and Nozaki–Hiyama–Kishi(NHK)
coupling reactions as key steps, is described. During this study a new practical synthesis of the
substituted butenolide intermediate 10, based on a combination of RCM and CM reactions from the
cyclobutene ester 21 in the presence of 2-methylpropenol was also developed. Attempts to apply the
intramolecular NHK reaction to the substrates 8a and 8b containing an ester group adjacent to the re-
acting aldehyde functionality gave disappointing low yields (<6%) of the corresponding coupled products
9. The synthetic (þ)-Z-deoxypukalide 3 was correlated with naturally derived material, and also with
pukalide 1, the first member of the furanobutenolide-based cembranoids to be isolated from corals.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 13 October 2009
Received in revised form 10 December 2009
Accepted 18 January 2010
Available online 22 January 2010
CO2Me
1. Introduction
CO2Me
O
O
O
The furanobutenolide-based cembranoid pukalide 1 occupies
a special place in natural product chemistry, since it was the first
member of this burgeoning family of secondary metabolites to be
described, in 1975, from corals, i.e. Sinularia abrupta.1 Since then
pukalide has been isolated from many other coral species,2 and has
also been found in the dendronoid nudibranch Tochuina tetraque-
O
O
O
O
O
2
O
3
O
1
tra, together with rubifolide 2.3 (þ)-Z-Deoxypukalide
3
was
CO2Me
CO2Me
reported only recently alongside the corresponding E-isomer 4
from the Pacific coral Leptogorgia spp.4 The enantiomer 5 of natural
Z-deoxypukalide 3 was synthesised by Marshall and van Devender5
in 2001, and was correlated with the (þ)-enantiomer produced by
reducing natural pukalide 1 with zinc in ethanol. A synthesis of the
same non-natural, (ꢀ)-Z-deoxypukalide 5 was also achieved re-
cently by Donohoe et al.6 We now report our own studies directed
towards the pukalides 1–3, which have culminated in a concise
synthesis of natural (þ)-Z-deoxypukalide 3 for the first time.
O
O
O
O
O
5
O
4
Nozaki–Hiyama–Kishi (NHK) reaction,8 intrannular furan and
butenolide ring synthesis,9 the intramolecular Stille reaction,10
radical macrocyclisations,11 ring closure metathesis (RCM),12
Wittig rearrangements and intramolecular Wadsworth–Emmons
olefination.7 Indeed, many of these approaches have subsequently
been applied in the synthesis of naturally occurring
furanobutenolides.5,6,10a,13
Our own research group has developed synthetic routes to
both deoxylophotoxin 610 and to bipinnatin J (7)14 using methods
which have featured intramolecular Stille and NHK reactions, re-
spectively, as key steps. Our experience suggested that the most
practical route to the Z- and E-deoxypukalides 3 and 4 would
be via intramolecular NHK reactions from appropriate Z- and
2. Results and discussion
2.1. Synthetic plan
A variety of synthetic methods have been developed for elabo-
rating the macrocyclic cores in furanobutenolide cembranoids.7
Many of these methods have been based on the intramolecular
* Corresponding author. Tel.: þ44 115 9513530; fax: þ44 115 9513564.
E-mail address: gp@nottingham.ac.uk (G. Pattenden).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.059

B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
2493
E-D
7,8-alkene isomers of the bromoaldehyde precursor 8, leading
Me2Al
AlMe
O
Me3Al
Δ
to 9, as the key step. This synthetic approach had the added
benefit that we had already developed a concise synthesis of the
enantiomerically pure Z-vinyl iodide 10 during our total synthesis
of (ꢀ)-bipinnatin J (7).14 This same synthetic approach to 10 could
easily be adapted to a synthesis of the corresponding E-vinyl
iodide 11.
OAlMe2
OH
OH
Cp2ZrCl2
(CH2Cl)2
25 °C
reflux
72h
OH
OH
12
13
14
I2/THF
−30 °C
I2/THF
−30 °C
I
I
OH
CHO
OH
OH
OH
OH
O
O
15
16
I
I
OAc
O
iii
i, ii
O
PhSe
OTBS
15/16
O
O
6
7
HO
O
CO2Me
I
18
CO2Me
CO2Me
CHO
5
4
3
v, vi
iv
6
PhSe
10/11
2
OH
15
OTBS
7
3
O
O
8
17
1
O
19
9
11
14
13
Br
4
16
O
10
O
12
Scheme 1. Reagents and conditions: (i) TsCl, Py, 4 ꢁC, 28 h; (ii) K2CO3, MeOH, rt, 1.5 h,
73%; (iii) NaHMDS, MeO2CCH(SePh)CH2CH2CH]C(Me)CH2OTBS, THF, ꢀ78 ꢁC, 0.5 h,
then epoxide, BF3$Et2O, ꢀ78 ꢁC to rt overnight, 72%; (iv) PTSA (0.1 equiv), DCM, rt, 3 h;
(v) H2O2, THF, 0 ꢁC to rt, 2 h; (vi) PPTS (0.2 equiv), DCM/MeOH(1:1), rt, 24 h, 62% for
three steps.
O
20
O
O
8
9
a, Z-Δ7,8; b, E-Δ7,8
I
I
More recently we developed a new and practical five-step synthetic
route to the substituted butenolide 10 starting from 3-butynol,
which featured a combination of RCM and cross-metathesis (CM)
reactions involving the cyclobutene ester intermediate 21 and
2-methylpropenol. Thus, a Negishi anti-carbometalation iodination
sequence from the butynol 17 first gave the known Z-alkenyl iodide
18,19 which, in two steps was next converted into the racemic allylic
alcohol 19 (Scheme 2). Treatment of 19 with the mixed anhydride
20 derived from cyclobutene carboxylic acid and pivalic acid then
gave the cyclobutene derivative 21. Finally, when a refluxing solu-
tion of the cyclobutene ester 21 in dichloromethane was reacted
with Grubbs’ catalyst in the presence of 2-methylpropenol, it un-
derwent RCM leading to 22 presumably followed by CM with the
propenol leading to the substituted racemic butenolide 10 in 57%
overall yield; NMR data established that <5% of the Z-allylic alcohol
corresponding to 10 was produced concurrently.20
OH
OH
O
O
O
O
11
10
2.2. Synthesis of the Z- and E-alkenyl iodides 10 and 11
In our synthesis of 10, the Z-alkenyl iodide moiety was gen-
erated from the corresponding homopropargylic alcohol 12, using
an anti-carbometalation protocol described by Negishi and Ma.15
In this sequence, the first-formed syn-carbometalation product 13
derived from the alcohol 12 is heated under reflux for 72 h
resulting in a chelation-controlled thermodynamic E- to Z- iso-
merisation producing 14, which is then quenched by iodine
leading to 16. When the same carbometalation of 12 was instead
carried out at room temperature, iodination of the intermediate
13 gave the anticipated E-alkenyl iodide isomer 15. Each of the
isomeric alkenyl iodides 15 and 16 were then converted into the
corresponding enantiomerically pure substituted 10 and 11, re-
spectively, using the published synthetic sequence summarised in
Scheme 1.14
I
I
O
O
i
ii, iii
O
OH
OH
OH
17
18
19
20
The isomeric substituted butenolides 10 and 11 gave closely
similar 1H and 13C NMR spectra. They were distinguished however
by the appearance of the diastereotopic methylene protons adja-
I
I
OH
cent to the butenolide as double doublets at
d 2.66 (J 13.6 and
iv
v
6.1 Hz) and
d
2.54 (J 13.6 and 7.4 Hz) in the 1H NMR spectrum of the
10
Ru
Z-isomer 10, which appeared as an unresolved multiplet at
d 2.54–
O
O
2.57 ppm in the 1H NMR spectrum of the corresponding E-isomer
11. In addition, the same CH2 in the Z-isomer, together with the
adjacent CH were shielded relative to the same carbon centres in
O
O
22
21
the 13C NMR spectra of the isomers, i.e.
and 42.8 and 79.0 ppm for 11.
d 42.4 and 78.5 ppm for 10,
Scheme 2. Reagents and conditions: (i) AlMe3, Cp2ZrCl2, DCM, reflux 72 h, then I2,
THF, ꢀ30 ꢁC–0 ꢁC, 1 h, 81%; (ii) DMP, DCM, NaHCO3, 25 ꢁC, 15 min; (iii) vinyl-
magnesium bromide, THF, ꢀ78 ꢁC, 1 h, 40% over two steps; (iv) LiHMDS, THF, ꢀ78 ꢁC,
20 min, reflux, then 20, THF, 1.5 h, 65%; (v) Grubbs’ second generation catalyst, DCM
reflux 2 h, 2-methylpropenol, 57%.
d
In contemporaneous studies three other research groups de-
scribed alternative synthetic routes to the Z-alkenyl iodide 10.16–18

2494
B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
2.3. Elaboration of 10 and 11 to the isomeric 2-alkenylfurans
28 and 29, respectively, using Stille coupling reactions
the anti-diastereoisomer 31 could be separated in only approxi-
mately 6% yield. Although we had expected that the macro-
cyclisation of the E-isomer 8b would be more problematic than the
Z-isomer, taking into account the distance between the reacting
centres, we were particularly surprised by the poor yield and lack of
specificity in the intramolecular NHK cyclisation with 8a. It seems
probable that in this instance the methoxycarbonyl and the alde-
hyde functionalities in 8a conspire to deactivate the substrate in the
presence of CrCl2, and thus inhibit a facile NHK cyclisation.
With the enantiomerically pure iodoalkenes 10 and 11 to hand,
we next planned to couple them, separately, to the substituted
stannylfuran 27 in the presence of Pd(0) leading to the fur-
anobutenolides 8a/8b en route to the targets 3 and 4. The
substituted stannylfuran 27 was prepared in five steps starting from
methyl 2-methyl-3-furanoate 23 (Scheme 3). Thus, bromination of
23 using NBS in DMF first gave the bromofuran 24a, which on
further treatment with NBS in the presence of AlBN was converted
into the corresponding furanmethyl bromide 24b. Hydrolysis of
24b, using aqueous K2CO3 in DMF and THF at 50 ꢁC next gave the
furanmethanol 25, which was then oxidised to the corresponding
furan aldehyde 26 using MnO2 in CH2Cl2. When a solution of the
bromofuran 26 in NMP was reacted with hexabutyldistannane in
the presence of Pd2(dba)3–Ph3 As, work up and chromatography
gave the stannyfuran 27 as a colourless oil.
CO2Me
CHO
CO2Me
CHO
O
O
10
27
11
27
OH
OH
O
O
O
O
29
28
CO2Me
OH
CO2Me
OH
CO2Me
CO2Me
CO2Me
i
iii
O
O
Br
Br
O
O
O
R
OH
O
23
O
24
25
O
O
a, R = H
b, R = Br
30
31
ii
CO2Me
O
CO2Me
O
v
iv
Bu3Sn
Br
2.5. Efficient intramolecular NHK coupling reaction of the
bromoaldehyde 36 leading to the macrocyclic homoallylic
alcohol 37
O
O
26
27
Scheme 3. Reagents and conditions: (i) NBS, DMF, 25–50 ꢁC, 0.5 h, 91%; (ii) NBS, AIBN,
CCl4, 24 h, 98%; (iii) aqueous K2CO3, DMF, THF, 50 ꢁC, 24 h, 38%; (iv) MnO2, DCM, 25 ꢁC,
2 h, 96%; (v) Pd2(dba)3, Ph3As, NMP, Bu6Sn2, 21%.
The poor yield and disappointing diastereoselectivity of 30
resulting from the NHK cyclisation of 8a did not provide us with
sufficient material to investigate its conversion into (þ)-Z-deoxy-
pukalide 3. We therefore decided to synthesise the fur-
anmethanol derivative 36 corresponding to the furanoate 8a and
examine its conversion into 37 under NHK conditions, antici-
pating that this cyclisation would be relatively facile. A series of
functional group interconversions with 37 should then provide
access to (þ)-Z-deoxypukalide 3. Thus, protection of the known
furan aldehyde 3221 as its dioxolan 33a, followed by reduction of
the ester group in 33a and protection of the resulting alcohol 33b
first gave the furanmethanol TBDPS ether 33c. Deprotonation of
33c, using n-BuLi at ꢀ40 ꢁC followed by treatment of the
resulting furyllithium species with Me3SnCl next gave the stan-
nylfuran 34 (Scheme 4). A Stille reaction between 34 and the
vinyl iodide 10, using Pd(PPh3)4 and CuI in DMF in the presence
of Et3N then led to the adduct 35 in a pleasing 90% yield.
Treatment of the adduct 35 with PPh3-NBS at ꢀ78 ꢁC resulted in
simultaneous bromination of the allyl alcohol group and depro-
tection of the dioxolane giving the bromide–aldehyde 36. When
a solution of 36 in THF was stirred in the presence of CrCl2 and
4 Å molecular sieves at room temperature for 16 h, work up and
chromatography gave a 63% yield of the anti-diastereoisomer 37
of the anticipated macrocyclic homoallylic alcohol, together with
smaller amounts of the syn-diastereoisomer 38 (9%) and the
isomeric anti-diastereoisomer 39 (6%).
Separate Stille coupling reactions between the stannylfuran 27
and the Z- and E-alkenyl iodides 10 and 11, using Pd(PPh3)4eCuI
and CsF in DMF, next led to the isomeric 2-alkenylfurans 28 and 29,
respectively, in 60–65% yields. The allyl alcohol groups in 28 and 29
were then brominated, using NBSePPh3, leading to the corre-
sponding allyl bromides 8a and 8b, which we now planned to
cyclise to the macrocyclic homoallylic alcohols 9a and 9b, under
NHK conditions. The isomeric alkenylfurans 28/29 and 8a/8b were
distinguished in their NMR spectroscopic data where the Z-isomers
showed characteristic signals at
d 3.26 ppm (dd, J 13.9 and 3.1 Hz)
for H-9 in the proton spectrum for 28; the corresponding proton
a
resonance in the E-isomer 29 appeared as a multiplet,
d 2.50–
2.65 ppm. In addition, the 13C resonances for C19 Me in the E-iso-
mer 8b and for C9 CH2 in the Z-isomer 8a were significantly
shielded, i.e.
d 19.1 and 38.3 ppm, in comparison with the corre-
sponding resonances in the isomeric pairs, i.e. 26.8 and 44.7 ppm,
respectively.
2.4. Inefficient intramolecular NHK coupling reactions
leading to the macrocycles 30 and 31
The intramolecular NHK reaction with a substrate identical to 8
but accommodating a methyl group instead of a methoxycarbonyl
residue on the furan ring, had previously been used successfully by
us, and others, in a total synthesis of bipinnatin J (7).14,16,17 It was
much to our chagrin therefore to find that when 8a was subjected
to the same NHK cyclisation conditions, i.e. CrCl2 in the presence of
4 Å molecular sieves, the macrocycle 30 was produced in very low
yields (<5%), and as a complex mixture of diastereoisomers. Like-
wise, the E-isomer 8b, corresponding to 8a, underwent a similar
disappointing macrocyclisation under NHK conditions from which
The relative stereochemistries of the macrocyclic homoallylic
alcohols 37–39 were determined by the magnitude of the vicinal
coupling constants between their H-atoms at C1 and C2 (cembrane
ring numbering; Structure 9), i.e. J(H1-H2)>10 Hz(anti) and
<2 Hz(syn) and by comparison of these data with corresponding
data recorded for bipinnatin J (7)14,22 (for diastereoisomer 37) and
other bipinnatins.23

B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
2495
Table 1
R
OTBDPS
CO2Me
O
i
iv
NMR Spectroscopic data for synthetic and natural (þ)-Z-Deoxypukalide 3
Me3Sn
O
O
O
O
Position Synthetic deoxypukalide
Natural deoxypukalide
13C NMR 1H NMR
42.6, d 2.41, dd (3.5, 14.4)
O
O
O
1H NMR
13C NMR
32
33
34
a, R = CO2Me
1
2
2
3
4
5
6
7
8
9
9
2.49–2.39, m
3.51, dd (13.0, 16.7)
2.68, dd (3.6, 16.7)
42.6, d
32.3, t
ii
a
b
32.3, t
3.48, dd (12.9, 16.7)
2.67, dd (3.6, 16.7)
b, R = CH2OH
iii
c, R = CH2OTBDPS
160.7, s
115.9, s
110.7, d 6.42, s
150.6, s
116.8, d 6.10, s
130.1, s
160.7, s
115.9, s
110.7, d
150.6, s
116.8, d
130.1, s
39.9, t
OTBDPS
O
OTBDPS
O
6.44, s
O
O
vi
v
O
6.11, br s
OH
Br
a
b
3.15, app t (11.8)
2.76, dd (4.2, 11.8)
39.9, t
3.13, dd (11.8, 11.8)
2.75, dd (4.2, 11.9)
O
O
O
35
O
36
10
11
12
13
13
14
14
15
16
16
17
18
19
20
5.02 ddt (11.8, 4.0, 1.6) 78.5, d 5.0, dd (4.2, 11.8)
78.5, d
151.5, d
133.3, s
19.9, t
6.96, app. t (w1.6)
151.5, d 6.94, s
133.3, s
OTBDPS
OH
OTBDPS
OH
OTBDPS
OH
a
b
a
b
2.16–2.09, m
2.49–2.39, m
1.81–1.71, m
1.15, ddt (3.6, 1.0, 14.0)
20.0, t
32.0, t
144.7, s
2.10, m
2.45, m
1.76, m
1.12, ddd (3.6, 13.9, 16.9)
vii
O
O
32.0, t
O
144.8, s
113.5, t
a
b
4.90, br s
4.95–4.92, m
1.76, br s
113.5, t 4.89, s
4.92, dd (1.5, 1.5)
19.1, q 1.75, s
164.1, s
O
O
O
O
38
O
39
O
37
19.1, q
164.1, s
25.8, q
174.2, s
51.4, q
Scheme 4. Reagents and conditions: (i) L-tartaric acid, MgSO4, ethylene glycol, ben-
zene, reflux, 48 h, 97%; (ii) LiAlH4, Et2O, rt, 1 h, 89%; (iii) TBDPSCl, imi, DMF, 0 ꢁC,
10 min, rt, 20 min, 74%; (iv) n-BuLi, THF, ꢀ40 ꢁC, 50 min, Me3SnCl, ꢀ40–0 ꢁC, 1.25 h,
86%; (v) 10, Pd(PPh3)4, CuI, Et3N, DMF, rt, 2 h, 90%; (vi) Ph3P, NBS, ꢀ78 ꢁC, 45 min, 67%;
(vii) CrCl2, 4 Å MS, THF, rt, 16 h, 63%.
2.03, d (1.0)
3.83, s
25.8, q 2.01, s
174.2, s
51.5, q 3.78, s
OMe
synthesis features a combination of RCM and CM to prepare the
substituted butenolide 10, and of intermolecular Stille, and intra-
molecular NHK, coupling reactions to elaborate the advanced in-
termediate 37. The synthetic study also highlights a limitation to
the use of the intramolecular NHK reaction in instances where an
ester function is proximal to the reacting aldehyde group, i.e. sub-
strates 8a and 8b.
2.6. Completion of the synthesis of (D)-Z-deoxypukalide 3
To complete a synthesis of (þ)-Z-deoxypukalide 3 from the
macrocycle 37, all that was needed was to reduce the secondary
alcohol group in 37 and then oxidise the remaining protected fur-
anmethanol group to the corresponding methoxycarbonyl func-
tionality. Thus, the secondary alcohol group was first reduced using
TFA–Et3SiH in DCM at 0 ꢁC, leading to the deoxy compound 40 in
82% yield (Scheme 5). Deprotection of the TBDPS protecting group
in 40 next led to the furanmethanol 41a, which was then oxidised,
using MnO2 in DCM, to the corresponding aldehyde 41b. Finally, the
aldehyde group in 41b was converted into the corresponding
methoxycarbonyl group, and hence Z-(þ)-deoxypukalide 3, using
4. Experimental
4.1. General
For general experimental details see Ref. 14.
Corey’s protocol.24 The synthetic deoxypukalide was obtained as
4.2. Z-6-Iodo-5-methylhexa-1,5-dien-3-ol (19)
27
a colourless powder, mp 133–136 ꢁC, [
a
]
D
þ15.5 (c 0.38, CHCl3) Lit.4
20
[
a]
þ11.0 (c 0.4, CHCl3) whose 1H and 13C NMR spectroscopic data
D
Dess–Martin periodinane (7.50 g, 17.7 mmol) was added in one
portion to a stirred solution of (Z)-4-iodo-3-methyl-but-3-en-1-ol
1815 (2.50 g, 11.8 mmol) and NaHCO3 (4.95 g, 59.0 mmol) in DCM
(60 ml) at room temperature, and the mixture was then stirred for
45 min. Saturated aqueous Na2S2O3 (15 ml), water (15 ml) and
saturated aqueous NaHCO3 (15 ml) were added, and the resulting
biphasic mixture was then stirred vigorously for 45 min. The sep-
arated aqueous phase was extracted with DCM (3ꢂ60 ml) and the
combined organic extracts were then dried (MgSO4) and concen-
trated in vacuo to leave the corresponding aldehyde as colourless
oil, which was used without further purification. Vinylmagnesium
bromide (35.4 ml, 35.4 mmol, 1.0 M in THF) was added dropwise
over 15 min to a stirred solution of the aldehyde in THF (150 ml) at
ꢀ78 ꢁC under a nitrogen atmosphere, and the mixture was then
stirred for 1 h. Water (60 ml) and diethyl ether (60 ml) were added,
and the mixture was then warmed to room temperature. The
separated aqueous phase was extracted with diethyl ether
(3ꢂ60 ml) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. The residue was purified by
chromatography on silica gel, eluting with a gradient of 20–30%
diethyl ether in petroleum ether (product eluted at 30%), to give the
were identical to those reported for the natural product (Table 1).
3. Summary
A concise total synthesis of (þ)-Z-deoxypukalide 3 isolated re-
cently from the Pacific coral Leptogorgia spp. has been achieved. The
R
OTBDPS
O
O
i
ii
iv
3
37
(+)-Z-Deoxypukalide
O
O
O
O
41
40
a, R = CH2OH
b, R = CHO
iii
Scheme 5. Reagents and conditions: (i) TFA, Et3SiH, DCM, 0 ꢁC, 2.5 h, 82%; (ii) TBAF,
THF, 0 ꢁC, 1.5 h, 51%; (iii) MnO2, DCM, rt, 2 h, 97%; (iv) HOAc, NaCN, MeOH, rt, 1 h, then
MnO2, 21 h, 65%.

2496
B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
allylic alcohol (1.27 g, 45%) as a colourless oil. nmax (CHCl3 cmꢀ1):
3605, 2945, 2915,1645,1614; dH (360 MHz; CDCl3): 6.00 (q,1H, J 1.4,
ICH]C(Me)CH2), 5.92 (ddd, 1H, J 17.1, 10.4 and 6.1, CH]CH2), 5.27
(ddd, 1H, J 17.1, 1.3 and 1.3, CH]CHH), 5.12 (dd, 1H, J 10.4 and 1.3,
CH]CHH), 4.39–4.31 (m, 1H, CH(OH)CH), 2.52 (dd, 1H, J 13.5 and
8.2, C]C(Me)CHH), 2.42 (dd, 1H, J 13.5 and 5.6, C]C(Me)CHH), 1.95
(d, 3H, J 1.4, ICH]C(Me)CH2), 1.93 (br s, 1H, CH(OH)CH); dC
(90 MHz; CDCl3): 144.3 (s), 140.2 (d), 114.9 (t), 76.9 (d), 71.2 (d), 45.8
(t), 24.5 (q); HRMS (ESI) 209.9520 (MþꢀC2H4, C5H7OI requires
209.9542).
ICH]C(Me)CHH),
2.41–2.25
(4H,
m,
CH2CH]C
and
CH2CH2CH]C), 1.98 (3H, d, J 1.4, ICH]C(Me)CH2), 1.77 (1H, br s,
CH2OH), 1.66 (3H, br s, CH]C(Me)CH2); dC (100 MHz): 173.4 (s),
147.8 (d), 142.3 (s), 136.2 (s), 133.9 (s), 123.8 (d), 79.4 (d), 78.5 (d),
68.4 (t), 42.4 (t), 25.3 (t), 25.0 (t), 24.8 (q), 13.7 (q). HRMS (ESI)
385.0274 (MþNaþ, C14H19IO3Na requires 385.0276).
4.5. (S)-3-((E)-5-Hydroxy-4-methyl-pent-3-enyl)-5-((E)-
3-iodo-2-methylallyl)-5H-furan-2-one (11)
The furanone was prepared starting from S-pent-4-yne-1, 2-diol
12, and proceeded via the E-iodoalkene 15, using the same se-
4.3. Cyclobut-1-enecarboxylic acid (Z)-4-iodo-3-methyl-
1-vinyl-but-3-enyl ester (21)
quence of reactions that have been published for the synthesis of
25
the corresponding Z-iodoalkene-substituted furanone 1014; [
a]
D
Triethylamine (2.12 ml, 15.2 mmol) was added dropwise over
2 min to a stirred solution of 1-cyclobutene-1-carboxylic acid25
(1.49 g, 15.2 mmol) and pivaloyl chloride (1.87 ml, 15.2 mmol) in
THF (30 ml) at room temperature under a nitrogen atmosphere,
and the mixture was then stirred for 30 min. Meanwhile, a solution
of LiHMDS (7.61 ml, 7.61 mol, 1.0 M in THF) was added dropwise
over 2 min to a stirred solution of the allylic alcohol 19 (1.51 g,
6.34 mmol) in THF (75 ml) at ꢀ78 ꢁC under a nitrogen atmosphere,
and the mixture was then stirred at ꢀ78 ꢁC for 20 min. The solution
of the mixed anhydride was filtered quickly and then added
dropwise over 15 min to the stirred solution of the allylic alcohol
anion at ꢀ78 ꢁC under a nitrogen atmosphere. The mixture was
stirred at ꢀ78 ꢁC for 90 min, and then water (50 ml), saturated
aqueous NaHCO3 (50 ml) and diethyl ether (50 ml) were added
sequentially, and the mixture was then warmed to room temper-
ature. The separated aqueous phase was extracted with diethyl
ether (3ꢂ75 ml) and the combined organic extracts were then
dried (MgSO4) and concentrated in vacuo. The residue was purified
by chromatography on silica gel, eluting with a gradient of 100%
petroleum ether, 5–10% diethyl ether in petroleum ether (product
eluted at 10%) to give the cyclobutene ester (1.32 g, 65%) as a light
yellow oil. nmax/cmꢀ1 (CHCl3 solution): 2928, 2852, 2254, 1712,
1647, 1610; dH (400 MHz; CDCl3): 6.82 (1H, t, J 1.2, C]CHCH2), 6.02
(1H, q, J 1.4, ICH]C(Me)CH2), 5.88 (1H, ddd, J 17.2, 10.5 and 6.3,
CH]CH2), 5.57–5.50 (1H, m, CH(O)CH), 5.32 (1H, ddd, J 17.2, 1.2
and 1.2, CH]CHH), 5.20 (1H, ddd, J 10.5, 1.2 and 1.2, CH]CHH),
2.77–2.66 (3H, m, CH2CH2CH]C and ICH]C(Me)CHH), 2.54–2.45
(3H, m, CH2CH2CH]C and ICH]C(Me)CHH), 1.94 (3H, d, J 1.4,
ICH]C(Me)CH2); dC (100 MHz; CDCl3): 161.2 (s), 147.0 (d), 143.2 (s),
138.5 (s), 135.7 (d), 117.0 (t), 77.5 (d), 72.1 (d), 43.2 (t), 29.1 (t), 27.1
(t), 24.2 (q); m/z (ESI) found 341.0017 (MþNaþ, C12H15O2INa
requires 341.0009).
þ26.5 (c 0.8, CHCl3); nmax (film)/cmꢀ1 1753; dH (360 MHz; CDCl3)
7.02 (1H, q, J 1.5, CHCH]), 6.11 (1H, q, J 1.5, ICH]), 5.36–5.39 (1H,
m, ]CHCH2), 5.0–5.03 (1H, m, CHCH]), 4.0 (2H, CH2O), 2.54–2.57
(2H, m), 2.3–2.55 (4H, m), 2.0 (1H, OH), 1.91 (3H, ICH]CMe), 1.65
(3H, ]CMe); dC (90 MHz; CDCl3) 173.3 (s), 147.6 (d), 142.0 (s), 136.3
(s), 134.2 (s), 123.5 (d), 79.2 (d), 79.0 (d), 68.2 (t), 42.8 (t), 25.4 (t),
25.0 (t), 24.5 (q), 13.7 (q). HRMS (ESl) 385.0284 (MþNaþ,
C14H19IO3Na requires 385.0276).
4.6. Methyl 5-bromo-2-hydroxymethyl-3-furanoate (25)
N-Bromosuccinimide (4.9 g, 27.5 mmol) was added to a solu-
tion of methyl 2-methyl-3-furancarboxylate 23 (3.5 g, 25 mmol)
in DMF (7 ml) at 0 ꢁC, and the mixture was then stirred at 0 ꢁC for
10 min under a nitrogen atmosphere. The mixture was warmed
to 25 ꢁC over 20 min, and then heated at 50 ꢁC for 30 min. The
cooled mixture was quenched with diethyl ether and water, and
the separated aqueous layer was then extracted with diethyl
ether. The combined ether extracts were evaporated in vacuo and
the residue was purified by chromatography on silica, eluting
with petroleum ether–ethyl acetate (20:1), to give methyl 5-
bromo-2-methyl-3-furancarboxylate 24a (5 g, 91%) as a pale
yellow oil, dH (400 MHz; CDCl3) 6.56 (1H, s, ]CH), 3.80 (3H, s,
OMe), 2.58 (3H, s, Me), which was used immediately. A stirred
solution of the 5-bromofuran (5 g) in carbon tetrachloride
(80 ml) containing N-bromosuccinimide (4.5 g) and AIBN
(190 mg) was heated at 50 ꢁC overnight and then cooled to room
temperature. The mixture was filtered and the filtrate was
washed with water (3ꢂ10 ml), dried (Na2SO4) and evaporated in
vacuo to leave the furanmethyl bromide 24b (98%), dH (400 MHz;
CDCl3) 6.66 (1H, s, ]CH), 4.80 (2H, s, CH2Br), 3.91 (3H, s, OMe), as
a pale yellow oil. A mixture of 24b (6 g, 20.1 mmol) and saturated
aqueous K2CO3 (33 ml) in THF (17 ml) and DMF (33 ml) was
heated at 50 ꢁC overnight, then cooled to room temperature and
extracted with ethyl acetate (3ꢂ70 ml). The combined organic
extracts were dried (MgSO4) and then evaporated in vacuo. The
residue was purified by chromatography on silica, eluting with
petroleum ether–ethyl acetate (5:1), to give the furanmethanol
(2.0 g, 42%) as a colourless oil, dH (360 MHz; CDCl3) 6.60 (1H, s,
]CH), 4.76 (2H, d, J 7.1, CH2OH), 3.86 (3H, s, OMe), 3.54 (1H, br t, J
w7, CH2OH); dC (100 MHz; CDCl3) 163.7 (s), 162.4 (s), 121.8 (s),
117.2 (s), 112.1 (d), 56.9 (t), 52.2 (q); HRMS (ESI) 256.9416
(MþNaþ, C7H7BrO4Na requires 256.9425).
4.4. ( )-3-((Z)-5-Hydroxy-4-methyl-(E)-pent-3-enyl)-5-((Z)-
3-iodo-2-methyl-allyl)-5H-furan-2-one (10)
A solution of Grubbs’ second generation catalyst (467 mg,
0.55 mmol) in DCM (10 ml), and a solution of the (ꢃ)-cyclobutene
ester 21 (1.75 g, 5.50 mmol) and 2-methyl-2-propen-1-ol
(0.93 ml, 11.0 mmol) in DCM (10 ml) were added simultaneously
over 8 h to a refluxing solution of DCM (1.75 l) under a nitrogen
atmosphere. 2-Methyl-2-propen-1-ol (3.70 ml, 44.0 mmol) was
added dropwise over 1 h, and the mixture was then stirred under
reflux for 12 h. The mixture was cooled to room temperature and
then concentrated in vacuo. The residue was purified by chro-
matography on silica gel, eluting with 50% ethyl acetate in pe-
troleum ether, to give a 7:1 mixture of E/Z-isomers of the known
allylic alcohol14,16 (1.13 g, 57%) as a yellow oil. dH (400 MHz;
CDCl3): (E-isomer) 7.11 (1H, q, J 1.4, CH]CCH2), 6.11 (1H, q, J 1.4,
ICH]C(Me)CH2), 5.44–5.34 (1H, m, CH]C(Me)CH2), 5.05 (1H,
ddd, J 7.4, 6.1 and 1.4, CH(O)CH), 3.99 (2H, br s, CH2OH), 2.66 (1H,
dd, J 13.6 and 6.1, ICH]C(Me)CHH), 2.54 (1H, dd, J 13.6 and 7.4,
4.7. Methyl 5-(tri-n-butylstannyl)-2-formyl-3-furanoate (27)
Manganese dioxide (2.5 g, 28.8 mmol) was added to a solution
of the furanmethanol 25 (0.5 g, 2.1 mmol) in dry dichloromethane
(30 ml) and the mixture was stirred at room temperature for 2 h,
and then filtered through Celite. The filtrate was evaporated in
vacuo to leave the corresponding furan aldehyde 26 (0.48 g, 96%) as
a viscous oil, dH (360 MHz; CDCl3) 10.10 (1H, s, CHO), 6.85 (1H, s,

B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
2497
]CH), 3.96 (3H, s, OMe); dC (100 MHz; CDCl3) 178.0 (d), 161.5 (s),
4.10. 5-{(Z)-3-[(S)-4-((E)-5-Bromo-4-methyl-pent-3-enyl)-
153.0 (s), 132.2 (s), 127.5 (s), 125.0 (d), 53.0 (q); HRMS (ESI)
254.9257 (MþNaþ, C7H5BrO4Na requires 254.9269), which was
used immediately. Pd2(dba)3 (94 mg, 5% equiv) and Ph3As (110 mg)
were added to a solution of 26 (0.48 g, 2.1 mmol) in NMP (10 ml),
which had been degassed with argon three times. The mixture was
again degassed with argon three times, and then hex-
abutyldistannane (1.43 g, 2.1 mmol) was added via syringe under
an argon atmosphere. The mixture was heated at 80 ꢁC for 1 h, then
cooled and filtered through Celite using petroleum ether–diethyl
ether (5:1) as eluent. The filtrate was washed with water, then dried
(K2CO3) and evaporated. The residue was purified by chromato-
graphy on Florisil, eluting with petroleum ether–diethyl ether
(10:1) to give the stannylfuran (0.2 g, 21%) as a colourless oil, nmax
(film)/cmꢀ11727, 1681, 1577; dH (500 MHz; CDCl3) 10.2 (1H, s, CHO),
7.0 (1H, s, ]CH), 3.9 (3H, s, OMe), 1.7–1.5 (6H, m), 1.4–1.3 (6H, m),
1.2–1.15 (6H, m), 0.9 (9H, t, J 7, Me); dC (100 MHz; CDCl3) 178.6 (d),
170.9 (s), 162.8 (s), 157.1 (s), 126.2 (s), 123.8 (d), 52.4 (q), 28.8 (t),
27.3 (t), 13.6 (t), 10.5 (q).
5-oxo-2,5-dihydro-furan-2-yl]-2-methyl-propenyl}-2-formyl-
furan-3-carboxylic acid methyl ester (8a)
Triphenylphosphine (50 mg, 0.19 mmol) and N-bromosuccini-
mide (34 mg, 0.19 mmol) were added to a stirred solution of the
allylic alcohol 28 (67 mg, 0.17 mmol) in DCM (3.7 ml) at 0 ꢁC, and
the mixture was stirred at 0 ꢁC for 20 min, and then poured into
water (1.5 ml). The separated aqueous layer was extracted with
DCM (2ꢂ5 ml), and the combined organic extracts were then dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica, eluting with petroleum ether–ethyl
acetate (4:1), to give the corresponding allyl bromide (52 mg, 67%)
as a pale yellow oil. nmax (film)/cmꢀ1 1756, 1727, 1670; dH (360 MHz;
CDCl3) 10.15 (1H, s, CHO), 7.32 (1H, q, J 1.4, H-11), 6.62 (1H, s, H-5),
6.24 (1H, br s, H-7), 5.58 (1H, t, J 6.5, H-1), 5.16–5.11 (1H, m, H-10),
3.96 (2H, s, H-16), 3.95 (3H, s, OMe), 3.23 (1H, dd, J 3.5 and 14.0, H-
9a), 2.49 (1H, dd, J 8.7 and 14.0, H-9b), 2.42–2.27 (4H, m, H-13 and
H-14), 2.09 (3H, d, J 1.3, Me-19), 1.76 (3H, s, Me-17); dC (90 MHZ;
CDCl3) 178.0 (d), 173.5(s), 161.9 (s), 156.3 (s), 150.6 (s), 148.9 (d),
143.0 (s), 133.6 (s), 133.3 (s), 129.3 (d), 127.4 (s), 114.8 (d), 110.7 (d),
81.2 (d), 52.5 (q), 41.1 (t), 38.3 (t), 26.8 (q), 26.0 (t), 24.6 (t), 14.7 (q);
HRMS (ESI) 473.0571 (MþNaþ, C21H23BrO6Na requires 473.0575).
4.8. 2-Formyl-5-{(Z)-3-[(S)-4-((E)-5-hydroxy-4-methyl-pent-
3-enyl)-5-oxo-2,5-dihydro-furan-2-yl]-2-methyl-propenyl}-
furan-3-carboxylic acid methyl ester (28)
A solution of the enantiomerically pure vinyl iodide 1014
(100 mg, 0.28 mmol) and the furanylstannane 27 (184 mg,
0.41 mmol) in DMF (2 ml) was degassed with argon for 30 min
and then added via cannula to a stirred mixture of Pd(PPh3)4
(13 mg, 0.011 mmol), CuI (4.2 mg, 0.022 mmol) and CsF (84 mg,
0.56 mmol) at room temperature. The resulting yellow mixture
was stirred at room temperature for 20 min, whereupon the
colour of the mixture changed to brown, first, then dark green.
The mixture was poured into a mixture of a saturated solution of
aqueous NH4Cl (6 ml) and Et2O (6 ml), and the separated aqueous
layer was then extracted with Et2O (3ꢂ6 ml). The combined or-
ganic extracts were washed with brine (2 ml), then dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
flash chromatography on silica, eluting with petroleum ether–
ethyl acetate (1:1), to give the alkenylfuran (67 mg, 63%) as
a viscous orange oil, dH (360 MHz; CDCl3) 10.13 (1H, s, CHO), 7.36
(1H, q, J 1.3, H-11), 6.62 (1H, s, H-5), 6.23 (1H, br s, H-7), 5.45–
5.41 (1H, m, H-1), 5.16–5.11 (1H, m, H-10), 4.02 (2H, d, J 6.3, H-
4.11. Methyl 5-((E)-3-((S)-4-((E)-5-bromo-4-methylpent-
3-enyl)-5-oxo-2,5-dihydrofuran-2-yl)-2-methylprop-1-enyl)-
2-formylfuran-3-carboxylate (8b)
The E-
agents and reaction conditions as those used to convert 28 into the
corresponding Z-
7,8–isomer (8a); nmax (film)/cmꢀ1 1755, 1730,
D
7,8-isomer was prepared from 29 using the same re-
D
1672; dH (360 MHz; CDCl3) 10.13 (1H, s, CHO), 7.02–7.05 (1H, s, H-
11), 6.65–6.67 (1H, s, H-5), 6.23 (1H, br s, H-7), 5.50–5.60 (1H, m, H-
1), 5.05–5.09 (1H, m, H-10), 3.90 (2H, s, H-16), 3.93 (3H, s, OMe),
2.50–2.62 (2H, m, H-9), 2.20–2.50 (4H, m, H-13, H-14), 2.16 (3H, s,
Me-19), 1.74 (3H, s, Me-17); dC (90 MHz; CDCl3) 178.2 (d), 172.9 (s),
161.9 (s), 156.3 (s), 150.2 (s), 147.7 (d), 140.8 (s), 133.8 (s), 133.7 (s),
129.1 (d), 127.5 (s), 116.2 (d), 111.0 (d), 79.2 (d), 52.5 (q), 44.7 (t), 41.0
(t), 25.8 (t), 24.6 (t), 19.1 (q), 14.7 (q).
4.12. (E)-(5S,11S,12S)-12-Hydroxy-11-isopropenyl-3-methyl-
7-oxo-6,16-dioxa-tricyclo[11.2.1.15,8]heptadeca-1(15),2,8(17),
13-tetraene-14-carboxylic acid methyl ester (31)
16), 3.95 (3H, s, OMe), 3.26 (1H, dd, J 3.1 and 13.9, H-9
a), 2.44–
2.30 (5H, m, H-9 , H-13 and H-14), 2.08 (3H, d, J 1.4, Me-19), 1.78
b
(1H, t, J 6.3, OH), 1.68 (3H, s, Me-17); dC (90 MHz, CDCl3) 178.2 (d),
173.7 (s), 161.8 (s), 156.5 (s), 150.5 (s), 148.8 (d), 143.4 (s), 136.4
(s), 133.6 (s), 127.6 (s), 123.8 (d), 114.7 (d), 110.8 (d), 81.3 (d), 68.5
(t), 52.5 (q), 38.3 (t), 26.8 (q), 25.3 (t), 24.8 (t), 13.7 (q); HRMS
(ESI) 411.1415 (MþNaþ, C21H24O7Na requires 411.1419).
A solution of the bromoaldehyde (8b) (136 mg) in THF was
treated with CrCl2-4 Å MS, under the same conditions as those used
to convert 36 into 37. Work up and chromatography on Florisil,
eluting with petroleum ether–ethyl acetate (3:2), gave the E-D7,8
-
alkene 31 (7 mg, 6%) as a pale yellow oil vmax (film/cmꢀ1) 1756; dH
(500 MHz; CDCl3) 7.05 (1H, t, J 1.5, H-11), 6.42 (1H, s, H-5), 6.02 (1H,
4.9. Methyl 2-formyl-5-((E)-3-((S)-4-((E)-5-hydroxy-
4-methylpent-3-enyl)-5-oxo-2,5-dihydrofuran-2-yl)-
2-methylprop-1-enyl)furan-3-carboxylate (29)
br s, H-7), 5.2 (1H, br, H-10), 5.05 (1H, m, H-16
16 ), 4.9 (1H, dd, J 10 and 3, H-2), 3.88 (3H, s, OMe), 3.05 (1H, dd, J
12 and 4, H-9 ), 2.83 (1H, t, J 12, H-9 ), 2.4–2.0 (2H, m, H-13 and
H-1), 2.15–2.10 (1H, m, H-13 ), 1.91 (3H, s, Me-19), 1.87 (3H, s, Me-
17), 1.75–1.70 (1H, m, H-14 ), 0.98–0.85 (1H, m, H-14 ); dC
(125 MHz, CDCl3) 173.4 (s), 164.5 (s), 159.7 (s), 149.7 (d), 145.4 (s),
144.0 (s), 137.4 (s), 135.3 (s), 117.8 (d), 117.3 (s), 115.6 (t), 108.3 (d),
78.6 (d), 66.1 (d), 51.8 (q), 50.5 (d), 40.7 (t), 25.7 (t), 23.9 (q), 23.6 (t),
17.3 (q); HRMS (ESI) 395.1468 (MþNaþ, C21H24O6Na requires
395.1465).
a), 5.0 (1H, br s, H-
b
a
b
a
b
The alkenylfuran was prepared using a Stille coupling reaction
between the E-D7,8 vinyl iodide 11 and the furanylstannane 27,
using the same reaction conditions that had been used to synthe-
a
b
sise the corresponding Z-D
7,8–alkenylfuran 28; nmax (film)/cmꢀ1
1753, 1728, 1670; dH (500 MHz; CDCl3) 10.13 (1H, s, CHO), 7.06 (1H,
s, H-11), 6.69 (1H, s, H-5), 6.22 (1H, br s, H-7), 5.35–5.37 (1H, m, H-
1), 5.06–5.08 (1H, m, H-10), 3.94 (2H, d, J 6, H-16), 3.92 (3H, s, OMe)
2.50–2.65 (2H, m, H-9), 2.28–2.34 (4H, m), 2.30 (3H, s, Me-19), 1.62
(3H, s, Me-17); dC (100 MHz; CDCl3) 178.2 (d), 173.2 (s), 162.0 (s),
156.3 (s), 150.1 (s), 147.5 (d), 140.8 (s), 136.3 (s), 134.4 (s), 127.6 (s),
123.4 (d), 116.3 (d), 111.0 (d), 79.2 (d), 68.2 (t), 52.5 (q), 44.7 (t), 25.3
(t), 25.0 (t), 17.8 (q), 13.7 (q).
4.13. 2-[1,3]Dioxolan-2-yl-furan-3-carboxylic acid methyl
ester (33a)
Following the procedure developed by Lu et al.,26 ethylene
glycol (3.47 g, 55.9 mmol) was added dropwise, over 10 min, to

2498
B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
a vigorously stirred solution of the furfural 3221 (2.15 g, 14.0 mmol),
-tartaric acid (52 mg, 0.35 mmol) and anhydrous MgSO4 (3.35 g,
33c (1.79 g, 4.40 mmol) in anhydrous THF (52 ml) at ꢀ40 ꢁC un-
der a nitrogen atmosphere. The resulting suspension was stirred
at ꢀ40 ꢁC for 50 min and then a solution of trimethyltin chloride
(1.05 g, 5.28 mmol) in anhydrous THF (20 ml) was added drop-
wise over 10 min. The mixture was warmed to 0 ꢁC over 1.25 h
and then a saturated solution of aqueous NH4Cl (30 ml) was
added. The separated aqueous extract was extracted with diethyl
ether (70 ml) and the combined organic extracts were then dried
(Na2SO4) and concentrated in vacuo. The oily residue of the
stannylfuran (2.17 g, 86%) was left under high vacuum for 48 h to
remove residual Me3SnCl, and then used without further purifi-
cation. nmax (film)/cmꢀ1 3071, 2930, 1472, 1428, 703; (360 MHz;
CDCl3) 7.74–7.69 (4H, m, TBDPS), 7.44–7.37 (6H, m, TBDPS), 6.53
(1H, s, OC]CH), 5.94 (1H, s, O–CH–O), 4.68 (2H, s, CH2OTBDPS),
4.07–4.01 (2H, m, CH2), 3.97–3.90 (2H, m, CH2), 1.07 (9H, s,
TBDPS), 0.33 (9H, s, SnMe3); dC (90 MHZ; CDCl3) 161.1 (s), 149.9
(s), 135.6 (4ꢂd), 134.8 (s), 133.5 (s), 129.6 (2ꢂd), 127.7 (4ꢂd),
124.0 (s), 122.4 (d), 97.3 (d), 65.1 (2ꢂt), 57.5 (t), 26.8 (3ꢂq), 19.2
(s), ꢀ9.02 (3ꢂq); HRMS (ESI) 595.1289 (MþNaþ, C27H36O4SiSnNa
requires 595.1302).
L
27.9 mmol) in benzene (49 ml) in a 100 ml flash, equipped with
a Dean and Stark adaptor and a condenser. The mixture was heated
under reflux for 44 h and the progress of the reaction was moni-
tored by 1H NMR spectroscopy. Further amounts of
L-tartaric acid
(26 mg, 0.18 mmol), anhydrous MgSO4 (1.68 g, 14.0 mmol) and
ethylene glycol (1.74 g, 28.0 mmol) were added, and the mixture
was heated under reflux for a further 4 h. The mixture was cooled
to room temperature. Solid NaHCO3 (44 mg) was added, and the
resulting mixture was stirred for 30 min before it was filtered
through a thin layer of NaHCO3, and washed with DCM (150 ml).
The filtrate was evaporated in vacuo to leave the dioxolane (2.69 g,
97%) as an oil. nmax (film)/cmꢀ1 1723; dH (400 MHz; CDCl3) 7.38 (1H,
d, J 1.9, CH]CHCCO2Me), 6.70 (1H, d, J 1.9, CH]CHCCO2Me), 6.55
(1H, s, OCHO), 4.26–4.18 (2H, m, CH2), 4.10–4.03 (2H, m, CH2), 3.85
(3H, s, OMe); dC (100 MHZ; CDCl3) 163.1 (s), 155.5 (s), 142.4 (d), 117.2
(s), 110.9 (d), 95.6 (d), 65.6 (2ꢂt), 51.8 (q); HRMS (ESI) 221.0421
(MþNaþ, C9H10O5Na requires 221.0426).
4.14. (2-[1,3]Dioxolan-2-yl-furan-3-yl)-methanol (33b)
4.17. (S)-5-{(Z)-3-[4-(tert-Butyl-diphenyl-silanyloxymethyl)-
5-[1,3]dioxolan-2-yl-furan-2-yl]-2-methyl-allyl}-3-((E)-
5-hydroxy-4-methyl-pent-3-enyl)-5H-furan-2-one (35)
A solution of the ester 33a (2.69 g, 13.6 mmol) in anhydrous
diethyl ether (27 ml) was added dropwise, over 10 min, to
maintain a steady reflux, to a stirred suspension of lithium al-
uminium hydride (671 mg, 17.7 mmol) in anhydrous diethyl
ether (44 ml) under a nitrogen atmosphere. The mixture was
stirred at room temperature for 1 h, and then quenched carefully
with water (0.67 ml), followed by aqueous NaOH (20% w/w,
0.67 ml) and water (3ꢂ0.67 ml). The mixture was stirred at room
temperature for a further 1 h and then filtered. The filtrate was
dried (Na2SO4) and concentrated in vacuo to leave the alcohol
(2.05 g, 89%) as a yellow oil. nmax (film)/cmꢀ1 3385; dH (400 MHz;
CDCl3) 7.36 (1H, br s, CH]CHCCH2OH), 6.40 (1H, br s,
CH]CHCCH2OH), 5.96 (1H, s, OCHO), 4.56 (2H, br s, CH2OH),
4.19–4.11 (2H, m, CH2), 4.06–3.97 (2H, m, CH2), 2.46 (1H, br s,
OH); dC (90 MHZ; CDCl3) 146.2 (s), 142.5 (d), 124.2 (s), 111.5 (d),
97.3 (d), 65.2 (2ꢂt), 55.8 (t); HRMS (ESI) 193.0482 (MþNaþ,
C8H10O4Na requires 193.0477).
A solution of the (þ)-vinyl iodide 10 (865 mg, 2.39 mmol) and
the furanylstannane 34 (2.73 g, 4.78 mmol) in anhydrous DMF
(12 ml) was degassed with nitrogen for 30 min and then added via
cannula to a stirred mixture of Pd(PPh3)4 (276 mg, 0.24 mmol), CuI
(91 mg, 0.48 mmol), Et3N (241 mg, 0.33 ml, 2.39 mmol) was added
dropwise via a syringe over 2 min and the resulting mixture was
stirred at room temperature for 2 h. The mixture was poured into
a saturated solution of aqueous NH4Cl (50 ml) and diethyl ether
(50 ml). The separated aqueous layer was then extracted with
diethyl ether (50 ml) and the combined organic extracts were
dried (Na2SO4), and concentrated in vacuo. The residue was pu-
rified by flash chromatography on silica, neutralised with 3% Et3N
in petroleum ether (300 ml), eluting with petroleum ether–ethyl
acetate (2:1), to give the allylic alcohol–aldehyde (1.38 g, 90%) as
25
a viscous oil. [
a
]
þ52.1 (c 1.41, CHCl3); nmax (film)/cmꢀ1 3483,
D
4.15. tert-Butyl-(2-[1,3]dioxolan-2-yl-furan-3-ylmethoxy)-
diphenyl-silane (33c)
1756; dH (400 MHz; CDCl3) 7.70–7.68 (4H, m, Ph), 7.47–7.37 (6H,
m, Ph), 7.05 (1H, br s, H-11), 6.18 (1H, s, H-5), 6.15 (1H, br s, H-7),
5.87 (1H, s, CH(OCH2CH2O)), 5.38–5.35 (1H, m, H-1), 5.17–5.13
(1H, m, H-10), 4.65 (2H, s, H-18), 4.07–3.99 (2H, m, OCH2CH2O),
3.95 (2H, br s, H-16), 3.97–3.91 (2H, m, OCH2CH2O), 2.88 (1H, dd, J,
tert-Butyldiphenylsilyl chloride (10.0 g, 36.4 mmol) and imid-
azole (2.70 g, 39.7 mmol) were added to a stirred solution of the
alcohol 33b (5.62 g, 33.1 mmol) in DMF (11 ml) at 0 ꢁC. The mixture
was stirred at 0 ꢁC for 10 min and then at room temperature for
20 min before it was diluted with diethyl ether (10 ml). The mixture
was then evaporated with silica (ca. 10.0 g) before it was purified by
chromatography on silica, eluting with petroleum ether–diethyl
ether (9:1), to give the silyl ether (10.0 g, 74%) as a colourless solid,
mp 64–68 ꢁC. (Found: C, 70.6; H, 7.2. C24H28O4Si requires C, 70.5; H,
6.9%); nmax (film)/cmꢀ1 3071, 2998, 1428, 703; dH (360 MHz; CDCl3)
7.73–7.71 (4H, m, TBDPS), 7.48–7.38 (7H, m, TBDPS, OCH]CH), 6.43
(1H, d, J 1.8, OCH]CH), 5.91 (1H, s, O–CH–O), 4.71 (2H, s,
CH2OTBDPS), 4.09–4.02 (2H, m, CH2), 3.95–3.91 (2H, m, CH2), 1.09
(9H, s, TBDPS); dC (90 MHZ; CDCl3) 145.1 (s), 142.4 (d), 135.5 (4ꢂd),
133.3 (2ꢂs), 129.7 (2ꢂd), 127.7 (4ꢂd), 124.4 (s), 111.0 (d), 96.9 (d),
65.1 (2ꢂt), 57.4 (t), 26.7 (3ꢂq), 19.2 (s); HRMS (ESI) 431.1634
(MþNaþ, C24H28O4SiNa requires 431.1655).
13.5 and 7.0, H-9a), 2.82 (1H, dd, J 13.5 and 6.9, H-9b), 2.37–2.33
(2H, m, H-13), 2.29–2.24 (2H, m, H-14), 1.97 (3H, d, J 1.2, Me-19),
1.78–1.66 (1H, m, OH), 1.63 (3H, s, Me-17), 1.07 (9H, s, TBDPS); dC
(100 MHZ; CDCl3) 173.7 (s), 152.1 (s), 148.5 (d), 144.1 (s), 136.2 (s),
135.5 (4ꢂd), 133.7 (s), 133.3 (2ꢂs), 133.0 (s), 129.8 (2ꢂd), 127.8
(4ꢂd), 125.9 (s), 124.0 (s), 117.0 (d), 110.0 (d), 96.9 (d), 80.7 (d), 68.5
(t), 65.3 (2ꢂt), 57.4 (t), 37.8 (t), 26.8 (3ꢂq), 26.3 (q), 25.4 (t), 25.2
(t), 19.2 (s), 13.7 (q); HRMS (ESI) 665.2889 (MþNaþ, C38H46O7SiNa
requires 665.2910).
4.18. 5-{(Z)-3-[(S)-4-((E)-5-Bromo-4-methyl-pent-3-enyl)-5-
oxo-2,5-dihydro-furan-2-yl]-2-methyl-propenyl}-3-(tert-
butyl-diphenyl-silanyloxymethyl)-furan-2-carbaldehyde (36)
Triphenylphosphine (1.07 g, 4.07 mmol) and N-bromosuccini-
mide (725 mg, 4.07 mmol) were added to a stirred solution of the
(þ)-alcohol 35 (1.19 g, 1.85 mmol) in DCM (110 ml) at ꢀ78 ꢁC. The
mixture was stirred at ꢀ78 ꢁC for 45 min, then poured into water
(30 ml), and allowed to warm to 0 ꢁC. The separated aqueous layer
was extracted with DCM (2ꢂ100 ml), and the combined organic
extracts were then dried (Na2SO4) and concentrated in vacuo. The
4.16. tert-Butyl-(2-[1,3]dioxolan-2-yl-5-trimethylstannanyl-
furan-3-ylmethoxy)-diphenyl-silane (34)
A solution of n-BuLi (2.5 M) in hexane (2.64 ml, 6.60 mmol)
was added dropwise over 3 min to a stirred solution of the furan

B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
2499
residue was purified by flash chromatography on silica, eluting
with petroleum ether–ethyl acetate (5:1), to give the allyl bromide
4.20. (Z)-(5S,11R)-14-(tert-Butyl-diphenyl-silanyloxymethyl)-
11-isopropenyl-3-methyl-6,16-dioxa-tricyclo[11.2.1.15,8]-
heptadeca-1(15),2,8(17),13-tetraen-7-one (40)
29
(818 mg, 67%) as a yellow viscous oil. [
a
]
D
þ31.5 (c 1.1 CHCl3); nmax
(film)/cmꢀ1 1757; dH (400 MHz; CDCl3) 9.65 (1H, s, CHO), 7.68–7.66
(4H, m, Ph), 7.48–7.38 (6H, m, Ph), 7.27 (1H, s, H-11), 6.37 (1H, s, H-
5), 6.22 (1H, br s, H-7), 5.57 (1H, t, J 6.7, H-1), 5.16–5.13 (1H, m, H-
10), 4.90 (2H, s, H-18), 3.95 (2H, s, H-16), 3.21 (1H, dd, J 4.1 and 13.9,
Trifluoroacetic acid (13.4 mg, 8.8
a stirred solution of the secondary alcohol 37 (62 mg, 0.11 mmol)
and triethylsilane (27 mg, 37 l, 0.23 mmol) in anhydrous DCM
ml, 0.12 mmol) was added to
m
H-9a), 2.53 (1H, dd, J 8.4 and 13.9, H-9
b
), 2.40–2.28 (4H, m, H-13
(8 ml) at 0 ꢁC under an atmosphere of nitrogen. The mixture was
stirred at 0 ꢁC for 2.5 h, and then it was quenched with a saturated
solution of aqueous NaHCO3 (2.6 ml). The separated aqueous layer
was extracted with DCM (10 ml). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo. The residue was
purified by flash chromatography on silica, eluting with petroleum
and H-14), 2.07 (3H, d, J 1.2, Me-19), 1.75 (3H, s, Me-17), 1.09 (9H, s,
TBDPS); dC (100 MHZ; CDCl3) 176.9 (d), 173.5 (s), 156.7 (s), 149.0 (d),
146.3 (s), 141.3 (s), 139.4 (s), 135.4 (4ꢂd), 133.6 (s), 133.2 (s), 132.6
(2ꢂs), 130.0 (2ꢂd), 129.3 (d), 127.9 (4ꢂd), 115.7 (d), 111.2 (d), 81.3
(d), 58.2 (t), 41.1 (t), 38.2 (t), 26.7 (q), 26.7 (3ꢂq), 26.0 (t), 24.7 (t),
19.2 (s), 14.8 (q); HRMS (ESI) 683.1795 (MþNaþ, C36H41BrO5SiNa
requires 683.1804).
ether–ethyl acetate (10:1), to give the furanobutenolide (51 mg,
26
82%) as a colourless foam. [
a]
þ31.1 (c 0.44, CHCl3); nmax (film)/
D
cmꢀ1 1757, 822, 702; dH (400 MHz; CDCl3) 7.71–7.68 (4H, m, Ph),
7.47–7.38 (6H, m, Ph), 6.93 (1H, t, J 1.5, H-11), 6.17 (1H, s, H-5), 6.12
4.19. (Z)-(5S,11S,12S)-14-(tert-Butyl-diphenyl-
silanyloxymethyl)-12-hydroxy-11-isopropenyl-3-methyl-6,16-
dioxa-tricyclo[11.2.1.15,8]heptadeca-1(15),2,8(17),13-tetraen-
7-one (37)
(1H, br s, H-7), 5.01–4.96 (1H, m, H-10), 4.89 (1H, d, J 1.7, H-16
4.84 (1H, br s, H-16 ), 4.52 (1H, d, J 12.4, H-18 ), 4.48 (1H, d, J 12.4,
H-18 ), 3.22 (1H, app. t, J 11.8, H-9 ), 2.72 (1H, dd, J 4.2 and 11.8,
H-9 ), 2.53–2.28 (4H, m, H-13 , H-1 and H-2), 2.09–2.04 (1H, m,
H-13 ), 2.01 (3H, br s, Me-19), 1.66 (3H, br s, Me-17), 1.55 (1H, tdd,
J 3.3, 10.8 and 13.9, H-14 ), 1.15–1.09 (1H, m, H-14 ), 1.07 (9H, s,
a),
b
a
b
b
a
b
A solution of the (þ)-bromoaldehyde 36 (409 mg, 0.62 mmol)
in anhydrous THF (453 ml) was degassed with nitrogen for 1 h at
room temperature, and then added via a cannula to a mixture of
4 Å MS (activated powder, 2.93 g) and anhydrous CrCl2 (1.53 g,
12.4 mmol) at room temperature under an argon atmosphere.
The resulting green coloured mixture was stirred at 25 ꢁC for 16 h
and then filtered through Celite. The filtrate was concentrated in
vacuo and the residue was diluted with diethyl ether (260 ml),
and then washed with water (2ꢂ35 ml) and brine (17 ml). The
separated organic extract was dried (Na2SO4) and concentrated
in vacuo to leave a residue, which was purified by chromato-
graphy on silica, eluting with petroleum ether–ethyl acetate
a
b
a
TBDPS); dC (90 MHz; CDCl3) 174.5 (s), 152.1 (d), 150.3 (s), 150.1 (s),
145.3 (s), 135.6 (4ꢂd), 133.5 (s), 133.4 (s), 132.9 (s), 129.7 (2ꢂd),
127.7 (4ꢂd), 127.5 (s), 122.2 (s), 117.5 (d), 113.1 (t), 112.1 (d), 78.7
(d), 57.6 (t), 43.1 (d), 39.6 (t), 31.3 (t), 30.9 (t), 26.8 (3ꢂq), 25.8 (q),
20.0 (t), 19.2 (s), 19.2 (q); HRMS (ESI) 589.2769 (MþNaþ,
C36H42O4SiNa requires 589.2744).
4.21. (Z)-(5S,11R)-14-Hydroxymethyl-11-isopropenyl-
3-methyl-6,16-dioxa-tricyclo[11.2.1.15,8]heptadeca-
1(15),2,8(17),13-tetraen-7-one (41a)
(10:1), to give (i) the C-2b-hydroxy epimer 37 (227 mg, 63%) as
27
a foaming oil. [
a
]
ꢀ54.0 (c 0.8, CHCl3); nmax (film)/cmꢀ1 3457,
Tetrabutylammonium fluoride (24 mg, 0.09 mmol) was added
in portions to a stirred solution of the TBDPS ether 40 (51 mg,
0.09 mmol) in THF (8 ml) at 0 ꢁC. The mixture was stirred at 0 ꢁC
for 1 h, and then another portion of tetrabutylammonium fluoride
(24 mg, 0.09 mmol) was added. The mixture was stirred for a fur-
ther 30 min, and then concentrated in vacuo in the presence of
silica (ca. 10 mg). The residue was purified by flash chromatogra-
phy on silica, eluting with petroleum ether–ethyl acetate (2:1), to
D
1756; dH (400 MHz; CDCl3) 7.72–7.68 (4H, m, Ph), 7.49–7.38 (6H,
m, Ph), 6.88 (1H, t, J 1.5, H-11), 6.18 (1H, s, H-5), 6.16 (1H, br s, H-
7), 5.13–5.12 (1H, m, H-16
(1H, m, H-10), 4.62 (2H, s, H-18), 4.50 (1H, d, J 11.0, H-2), 3.20
(1H, t, J 11.8, H-9 ), 2.75 (1H, dd, J 4.3 and 11.8, H-9 ), 2.44–2.35
(2H, m, H-13 and H-1), 2.10–2.05 (1H, m, H-13 ), 2.03 (3H, d, J
1.0, Me-19), 1.83 (1H, br s, OH), 1.72 (3H, s, Me-17), 1.57 (1H, tdd, J
3.3, 11.1 and 14.1, H-14 ), 1.07 (9H, s, TBDPS), 0.91 (1H, m, H-14 );
b), 5.02 (1H, br s, H-16a), 5.03–4.99
b
a
b
a
b
a
give the alcohol (15 mg, 51%) as a colourless powder, mp 174–
23
dC (100 MHz; CDCl3) 174.2 (s), 152.2 (d), 151.2 (s), 149.9 (s), 142.1
(s), 135.6 (4ꢂd), 133.2 (s), 133.1 (s), 132.6 (s), 129.9 (d), 129.8 (d),
129.4 (s), 127.8 (2ꢂd), 127.7 (2ꢂd), 125.4 (s), 118.3 (t), 117.4 (d),
111.9 (d), 78.6 (d), 65.3 (d), 57.6 (t), 50.5 (d), 39.8 (t), 30.1 (t), 26.8
(3ꢂq), 25.8 (q), 19.6 (t), 19.1 (s), 17.6 (q); HRMS (ESI) 605.2712
176 ꢁC. [
a
]
D
þ36.9 (c 1.0, CHCl3); nmax (film)/cmꢀ1 3514, 1751; dH
(500 MHz; CDCl3) 6.92 (1H, t, J 1.6, H-11), 6.20 (1H, s, H-5), 6.11
(1H, br s, H-7), 5.00–4.96 (1H, m, H-10), 4.93–4.92 (1H, m, H-16
4.90–4.89 (1H, m, H-16 ), 4.49 (1H, dd, J 12.4 and 5.4, H-18 ), 4.45
(1H, dd, J 12.4 and 5.4, H-18 ), 3.22 (1H, app. t, J 11.8, H-9 ), 2.73
(1H, dd, J 4.2 and 11.8, H-9 ), 2.69 (1H, dd, J 15.5 and 12.7, H-2 ),
2.59 (1H, dd, J 15.5 and 4.0, H-2 ), 2.47–2.37 (2H, m, H-13 and H-
1), 2.14–2.08 (1H, m, H-13 ), 2.01 (3H, d, J 1.0, Me-19), 1.74 (3H, dd,
J 1.3 and 0.7, Me-17), 1.68 (1H, tdd, J 3.4, 3.4, 13.9 and 10.9, H-14 ),
1.40 (1H, app. t, J 5.4, OH), 1.18 (1H, ddt, J 1.1, 3.6, 13.9 and 13.9, H-
14 ); dC (125 MHz; CHCl3) 174.4 (s), 152.0 (d), 151.0 (s), 150.8 (s),
b),
a
a
b
b
(MþNaþ, C36H42O5SiNa requires 605.2699); (ii) the C-2
a
-hydroxy
a
a
epimer 38 (33 mg, 9%): dH (400 MHz; CDCl3) 7.69–7.66 (4H, m,
Ph), 7.47–7.36 (6H, m, Ph), 6.98 (1H, t, J 1.6, H-11), 6.10 (1H, br s,
b
b
a
H-7), 6.04 (1H, s, H-5), 5.09–5.06 (1H, m, H-16
m, H-10), 4.91 (1H, br s, H-16 ), 4.93 (1H, br s, H-2), 4.75 (1H, d, J
12.8, H-18 ), 4.71 (1H, d, J 12.8, H-18 ), 3.37 (1H, d, J 4.7, OH),
3.06 (1H, t, J 11.8, H-9 ), 2.74 (1H, dd, J 4.4 and 11.8, H-9 ), 2.44–
2.33 (2H, m, H-13 , H-1), 2.23–2.16 (1H, m, H-13 ), 2.00 (3H, br s,
Me-19), 1.86 (3H, s, Me-17), 2.02–1.97 (1H, m, H-14 ), 1.23–1.13
(1H, m, H-14 ), 1.06 (9H, s, TBDPS); (iii) the diastereoisomer 39
b
), 5.05–4.99 (1H,
b
a
a
b
a
b
a
145.1 (s), 133.0 (s), 128.3 (s), 122.1 (s), 117.3 (d), 113.3 (t), 111.6 (d),
78.7 (d), 56.2 (t), 43.1 (d), 39.7 (t), 31.4 (t), 30.8 (t), 25.8 (q), 20.0
(t), 19.2 (q); HRMS (ESI) 351.1582 (MþNaþ, C20H24O4Na requires
351.1566).
b
a
a
b
(20 mg, 6%): dH (400 MHz; CDCl3) 7.71–7.66 (4H, m, Ph), 7.47–7.37
(6H, m, Ph), 7.18 (1H, br s, H-11), 6.07 (1H, br s, H-7), 5.99 (1H, s,
4.22. (Z)-(5S,11R)-11-Isopropenyl-3-methyl-7-oxo-6,16-dioxa-
tricyclo[11.2.1.15,8]heptadeca-1(15),2,8(17),13-tetraene-14-
carbaldehyde (41b)
H-5), 5.12 (1H, t, J 8.7, H-10), 5.06 (1H, br s, H-16
H-16 ), 4.63–4.52 (3H, m, H-2 and H-18), 3.64 (1H, br s, OH), 2.76
(1H, t, J 10.2, H-1), 2.43–2.37 (2H, m, H-9 and H-13 ), 2.15–2.02
(2H, m, H-9 and H-13 ), 1.99 (3H, br s, Me-19), 1.77 (3H, s, Me-
), 1.08–1.21 (1H, m, H-14 ), 1.06 (9H,
b), 4.97 (1H, br s,
a
b
b
a
a
Manganese dioxide (100 mg,1.15 mmol) was added to a solution
17), 1.58–1.50 (1H, m, H-14
s, TBDPS).
a
b
of the alcohol 41a (15 mg, 46
mmol) in anhydrous DCM (7 ml) and
the mixture was stirred at room temperature for 2 h and then

2500
B. Tang et al. / Tetrahedron 66 (2010) 2492–2500
filtered through a short pad of Celite. The filtrate was washed with
DCM (15 ml), and the combined organic extracts were concentrated
1H and 13C NMR spectroscopic data were identical to those reported
for the natural product.4
in vacuo to leave the aldehyde (14.6 mg, 97%) as a colourless foam.
26
[
a]
þ44.7 (c 0.73, CHCl3); nmax (film)/cmꢀ1 1755, 1679; dH
Acknowledgements
D
(360 MHz; CDCl3) 9.93 (1H, s, CHO), 6.95 (1H, t, J 1.5, H-11), 6.47
(1H, s, H-5), 6.16 (1H, br s, H-7), 5.06–5.00 (1H, m, H-10), 4.96–4.98
We thank the University of Nottingham for a Dorothy Hodgkin
Postgraduate-Hutchinson Whampoa Award (to B.T.) and for a Fel-
lowship (to C.D.B.). We also thank the EPSRC for a postgraduate
studentship (to J.R.) and Merck Sharp and Dohme for financial
support.
(1H, m, H-16
H-2 ), 2.85–2.76 (2H, m, H-9
and H-1), 2.15 (1H, m, H-13 ), 2.04 (3H, d, J 1.0, Me-19),1.78 (3H, dd,
J 1.3 and 0.8, Me-17), 1.85–1.75 (1H, m, H-14 ), 1.18 (1H, ddt, J 1.1,
3.7, 13.8 and 13.8, H-14 ); dC (90 MHz; CHCl3) 184.4 (d), 174.1 (s),
b
), 4.93 (1H, br s, H-16
a
), 3.24–3.12 (2H, m, H-9
a and
a
b
and H-2b), 2.52–2.41 (2H, m, H-13b
a
b
a
163.1 (s), 152.1 (s), 151.5 (d), 144.1 (s), 133.3 (s), 131.4 (s), 125.0 (s),
116.6 (d), 114.0 (t), 107.8 (d), 78.5 (d), 42.6 (d), 40.0 (t), 31.9 (t), 31.6
(t), 25.9 (q), 20.0 (t), 19.2 (q); HRMS (ESI) 349.1418 (MþNaþ,
C20H22O4Na requires 349.1410).
References and notes
1. Missakian, M. G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron 1975, 31, 2513–2515.
2. Bowden, B. F.; Coll, J. C.; Wright, A. D. Aust. J. Chem. 1989, 42, 757–763.
3. Williams, D.; Andersen, R. J.; Van Duyne, G. D.; Clardy, J. J. Org. Chem. 1987, 52,
332–335.
´
4. Dorta, E.; Dıaz-Marrero, A. R.; Brito, I.; Cueto, M.; D’Croz, L.; Darias, J. Tetrahe-
dron 2007, 63, 9057–9062.
4.23. (D)-Z-Deoxypukalide (3)
5. Marshall, J. A.; Van Devender, E. A. J. Org. Chem. 2001, 66, 8037–8041.
6. Donohoe, T. J.; Ironmonger, A.; Kershaw, N. M. Angew. Chem., Int. Ed. 2008, 47,
7314–7316.
7. For a recent review covering aspects of these synthetic studies see: Roethle, P.
A.; Trauner, D. Nat. Prod. Rep. 2008, 25, 298–317 and references cited therein.
8. Fu¨rstner, A. Chem. Rev. 1999, 99, 991–1046.
9. (a) Marshall, J. A.; Liao, J. J. Org. Chem. 1998, 63, 5962–5970; (b) Tsubuki, M.;
Takahashi, K.; Honda, T. J. Org. Chem. 2003, 68, 10183–10186.
10. (a) Cases, M.; Gonzalez-Lopez de Turiso, F.; Pattenden, G. Synlett 2001, 1869–
1872; Cases, M.; Gonzalez-Lopez de Turiso, F.; Hadjisoteriou, M. S.; Pattenden,
G. Org. Biomol. Chem. 2005, 3, 2786–2804; (b) see also: Paterson, I.; Brown, R. E.;
Urch, C. J. Tetrahedron Lett. 1999, 40, 5807–5810.
Acetic acid (6.7 mg, 6.5 ml, 0.11 mmol) and NaCN (11 mg,
0.22 mmol) were added to a stirred solution of the aldehyde 41b
(14.6 mg, 0.045 mmol) in anhydrous methanol (0.5 ml) at room
temperature. The mixture was stirred at room temperature for 1 h,
and then MnO2 (78 mg, 0.90 mmol) was added in one portion. The
mixture was left to stir at room temperature for 21 h, then filtered
through a short pad of Celite, and the filtrates was washed with
ethyl acetate (5 ml). The combined filtrates were evaporated in
vacuo to remove methanol, and the residue was then dissolved in
ethyl acetate (10 ml), washed with water (2 ml), dried (Na2SO4) and
concentrated in vacuo. The residue was purified by flash chroma-
tography on silica, eluting with petroleum ether–ethyl acetate
11. Astley, M. P.; Pattenden, G. Synthesis 1992, 101–105.
12. Gaich, T.; Weinstabl, H.; Mulzer, J. Synlett 2009, 1357–1366.
13. Rayner, C. M.; Astles, P. C.; Paquette, L. A. J. Am. Chem. Soc. 1992, 114, 3926–3936;
Paquette, L. A.; Astles, P. C. J. Org. Chem. 1993, 58, 165–169; Marshall, J. A.; Se-
hon, C. A. J. Org. Chem. 1997, 62, 4313–4320; Marshall, J. A.; Liao, J. J. Org. Chem.
1998, 63, 5962–5970.
(5:1), to give (þ)-deoxypukalide (10.4 mg, 65%) as a colourless
14. Tang, B.; Bray, C. D.; Pattenden, G. Tetrahedron Lett. 2006, 7, 6401–6404; Tang,
B.; Bray, C. D.; Pattenden, G. Org. Biol. Chem. 2009, 7, 4448–4457.
15. Ma, S.; Negishi, E.-I. J. Org. Chem. 1997, 62, 784–785.
16. Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345–347.
17. Huang, Q.; Rawal, V. H. Org. Lett. 2006, 8, 543–545.
27
powder, mp 133–136 ꢁC. [
a
]
þ15.5 (c 0.38, CHCl3); nmax (film)/
D
cmꢀ11753, 1723; dH (360 MHz; CDCl3) 6.96 (1H, app t, J w1.6, H-11),
6.44 (1H, s, H-5), 6.11 (1H, br s, H-7), 5.05–4.90 (1H, ddt, J 11.8, 4.0,
18. Tsubuki, M.; Takahashi, K.; Sakata, K.; Honda, T. Heterocycles 2005, 65, 531–540.
19. Rand, C. L.; Van Horn, D. E.; Moore, H. W.; Negishi, E.-I. J. Org. Chem. 1981, 46,
4093–4096.
20. cf.: Yasui, H.; Yamamoto, S.; Takao, K.; Tadano, K. Heterocycles 2006, 70,
135–141.
21. Pevzner, L. M. Russ. J. Gen. Chem. (Translation of Zhurnal Obshchei Khimii) 2001,
71, 1045–1049.
22. Rodrı´guez, A. D.; Shi, J.-G. J. Org. Chem. 1998, 63, 420–421.
23. Wright, A. E.; Burres, N. S.; Schulte, G. K. Tetrahedron Lett. 1989, 30, 3491–3494;
1.6, H-10), 4.95–4.92 (1H, m, H-16
(3H, s, OMe), 3.51 (1H, dd, J 16.7 and 13.0, H-2
11.8, H-9 ), 2.76 (1H, dd, J 11.8 and 4.2, H-9 ), 2.68 (1H, dd, J 16.7
and 3.6, H-2 ), 2.49–2.39 (2H, m, H-13 and H-1), 2.16–2.09 (1H, m,
H-13 ), 2.03 (3H, d, J 1.0, Me-19), 1.76 (3H, br s, Me-17), 1.81–1.71
(1H, m, H-14 ), 1.15 (1H, ddt, J 3.6, 1.0, 14.0, H-14 ); dC (90 MHz;
CHCl3) 174.2 (s), 164.1 (s), 160.7 (s), 151.5 (d), 150.6 (s), 144.7 (s),
133.3 (s), 130.1 (s), 116.8 (d), 115.9 (s), 113.5 (t), 110.7 (d), 78.5 (d),
51.5 (q), 42.6 (d), 39.9 (t), 32.3 (t), 32.0 (t), 25.8 (q), 20.0 (t), 19.1 (q);
HRMS (ESI) 379.1531 (MþNaþ, C21H24O5Na requires 379.1521). The
b
), 4.90 (1H, br s, H-16
a), 3.83
a
), 3.15 (1H, app t, J
a
b
b
b
a
a
b
´
Rodrıguez, A. D.; Shi, J.-G.; Huang, S. D. J. Nat. Prod. 1999, 62, 1228–1237.
24. Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968, 90, 5616–5617.
25. Campbell, A.; Rydon, H. N. J. Chem. Soc. 1953, 3002–3008.
26. Lu, T.-J.; Yang, J.-F.; Sheu, L.-J. J. Org. Chem. 1995, 60, 2931–2934.