Synthetic studies towards furanocembrane diterpenes. A total synthesis of bis-deoxylophotoxin

Article abstract of DOI:10.1039/b504545b

Synthetic approaches to the furanocembrane family of natural products, e.g. lophotoxins, pukalides, bipinnatins, based on: i) an intramolecular cyclisation of an α,β-unsaturated acyl radical intermediate into a conjugated enone, viz. 18 → 17, and ii) an i

Full text of DOI:10.1039/b504545b

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A R T I C L E
Synthetic studies towards furanocembrane diterpenes. A total
synthesis of bis-deoxylophotoxin
Manuel Cases, Felix Gonzalez-Lopez de Turiso, Maria S. Hadjisoteriou and Gerald Pattenden*
School of Chemistry, The University of Nottingham, Nottingham, NG7 2RD, UK
Received 1st April 2005, Accepted 12th May 2005
First published as an Advance Article on the web 28th June 2005
Synthetic approaches to the furanocembrane family of natural products, e.g. lophotoxins, pukalides, bipinnatins,
based on: i) an intramolecular cyclisation of an a,b-unsaturated acyl radical intermediate into a conjugated enone,
viz. 18 → 17, and ii) an intramolecular Stille coupling reaction involving a 2-stannylfuran and a vinyl iodide, i.e.
67 → 68, are described. A total synthesis of bis-deoxylophotoxin 71a, the probable biological precursor to the
neurotoxin lophotoxin 1, isolated from species of the Pacific sea whip Lophogorgia, is then presented.
A (4), rubifolide 10 and Z-deoxypukalide 11, using an efficient
Introduction
intra-annular furan ring formation via either a conjugated
allenone or an a-keto acetylene intermediate10 in the latter two
cases. In some earlier studies, published in 1991, we described
an approach to the furanocembrane core in the lophotoxins,
pukalides, and bipinnatins based on an intramolecular 14-endo-
trig acyl radical cyclisation from the a,b-unsaturated phenyl
seleno ester 12 in the presence of Bu3SnH–AIBN leading
to the macrocyclic 1,4-dione 13 in 40% yield.11 Subsequent
treatment of 13 with p-TSA in hot chloroform then resulted
in furan ring formation, leading to the furanocembrane 14. In
later investigations we developed an alternative approach to
the furanobutenolide cembrane core 16 in the same families
of natural products using an intramolecular Stille reaction
from the iodo-stannane 15 as the key stratagem.12 In this
paper we describe the outcome of our attempts to extend
Lophotoxin 1, together with pukalide 2 and bipinnatin G (3),
and their various oxygenated and deoxygenated congeners are
representative of a novel family of furanocembrane natural
products isolated from marine soft corals and sea whips.1 Lopho-
toxin is a particularly potent neurotoxin that binds selectively
and irreversibly to acetylcholine recognition sites in nicotine
acetylcholine receptors, leading to paralysis and asphyxiation.2
Another family of interesting furanoterpenoid natural products
are the pseudopteranes, represented by kalloide A (4)3 and pseu-
dopterolide 5,4 which have 12-membered rings, instead of the 14-
membered rings found in cembrane diterpenes. The range and
variation in structure of furanoditerpenes found in soft corals
increases annually, including the recent isolation of the dimer
mayotolide A (6)5 and the first a-ylidenecyclobutanol member
providencin 7.6 With the plethora of interesting structural
variations found within the furan-based diterpenes, alongside
the novel biological properties found within their members, it
is not surprising that synthetic chemists have been lured into
studies of the total synthesis of these deceptively straightforward
structures.7 Paquette and co-workers8 were the first to complete
a synthesis of a furanocembrane, i.e. acerosolide 8, and also
a pseudopterane, i.e. gorgiacerone 9, using a macrocyclisation
strategy based on a Nozaki–Hiyama–Kishi protocol. More re-
cently, Marshall et al.9 have described total syntheses of kalloide
2 7 8 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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the radical macrocyclisation strategy, viz. 12 → 13, to more
oxygen-functionalised acyl radical precursors, and full details
of a synthesis of deoxylophotoxin using the aforementioned
intramolecular Stille reaction as the key reaction.
Results and discussion
The a,b-unsaturated acyl radical macrocyclisation approach
Over several years we have developed and tested the scope
of a number of alkyl radical macrocyclisation reactions in
the synthesis of natural products,13 including the cembrane
mukulol14 and the oestrogenic mycotoxin zearalenone.15 We
have also used radical macrocyclisation reactions in tandem
with radical transannulation reactions to synthesise a range
of polycyclic constructs, especially steroids.16 At the outset
of our investigations into the scope of a,b-unsaturated acyl
radical intermediates in the synthesis of furanocembranes, very
little was known about the reactivity profile of these unusual
species. Indeed, to our knowledge, the cyclisation 12 → 13 we
had developed in 1991, en route to the furanocembrane core
14 in lophotoxin, was unprecedented.11 The success of this
model reaction gave us the confidence to develop a strategy
to the more elaborate oxygen-substituted seleno ester 18, and
then to study its conversion into bis-deoxylophotoxin 17b, as
a precursor to lophotoxin 1 itself. Accordingly, we decided
to prepare the selenoester 18 via an intermolecular alkylation
reaction between the enantiopure phenylselenolactone 19 and
the chiral c-unsaturated aldehyde 20 (Scheme 1).
=
Scheme 3 Reagents and conditions: (i) [CH2 C[CH3]]2CuCNLi2, THF,
−78 to 40 ◦C, 1 h, 58%; (ii) Me3Al, (S)-(a)-PhCH(CH3)NH2, CH2Cl2,
0 ◦C, 15 min; r.t., 16 h; resolution, 39%; (iii) PPTS, PhMe, reflux, 16 h,
◦
=
60%; (iv) DIBAL, THF, −78 C, 30 min, 88%; (v) CH2 C(Li)CH2OLi,
Et2O, 0 ◦C, 2 h, 64%; (vi) PhCH(OCH3)2, PPTS, PhH, reflux, 2 h, 64%;
(vii) Swern oxidation, 95%.
lactone 28, using DIBAL, next gave the corresponding lactol 29
which underwent smooth alkylation with the dianion produced
from 2-bromopropen-1-ol20 leading to the triol 30 as a 2 :
1 mixture of diastereoisomers. After protection of 30 as the
corresponding benzylidene acetal 31, oxidation under Swern
conditions finally gave the cd-unsaturated aldehyde 20.
Treatment of the phenylselenolactone 19 with LDA at −78 ◦C
followed by alkylation of the resulting carbanion with the
aldehyde 20 led to the adduct 32 which was immediately sub-
jected to oxidative dehydroselenylation, using H2O2 in aq. THF,
resulting in the formation of a mixture of diastereoisomers of
the unsaturated lactone 33a (Scheme 4). The secondary hydroxyl
group in 33a was next protected as its acetate 33b and then the
silyl ether group was deprotected revealing the primary alcohol
34a. Oxidation of 34a, using Dess–Martin periodinane, followed
by oxidation of the resulting a,b-unsaturated aldehyde 34b,
next gave the corresponding carboxylic acid 34c.21 Treatment of
the acid 34c with N-phenylselenophthalimide and Bu3P22 then
produced the phenylselenoester 35 which, to our surprise, was
found to be a 1 : 1 mixture of Z- and E-isomers. In pursuit of
the key intermediate 18, the benzylideneacetal group in 35 was
removed using PPTS-MeOH, and the resulting doubly allylic
alcohol 36 was converted, into the PMB ether 3723 and then into
the conjugated enone 18 using standard reagents and conditions
(Scheme 4).
Scheme 1
Thus, a regioselective ring opening of the epoxide 22 derived
from (+)-glutamic acid17 with the high-order cuprate prepared
from the vinyl bromide 2118 first gave the a-hydroxy ester
23 in 70% yield (Scheme 2). Treatment of 23 with LDA in
THF at −78 ◦C next gave the corresponding c-lactone (24;
91%) which was then re-treated with LDA and quenched with
phenylselenium bromide leading to the phenylselenolactone 19
as a 2 : 1 mixture of diastereoisomers.
Much to our chagrin, when the phenylselenoester 18 was
treated under identical radical-initiating conditions to those
used to convert 12 into 13 (en route to 14) we were not
able to detect the macrocylclic 1,4-dione corresponding to 13
amongst the mixture of products. Although the availability of
material and spectroscopic data did not allow any unambiguous
assignment, the dearth of olefinic proton signals in the NMR
spectra in the products suggested that the unsaturated acyl
radical 38 produced from the phenylselenoester 18 had most
likely undergone a sequence of alternative radical cyclisation
reactions leading to a polycyclic structure similar to the spiro-
tetracycle 43. The production of this unusual structure could be
rationalised through isomerisation of the initially produced E-
a,b-unsaturated acyl radical 38 into the corresponding Z-isomer
40 via the novel a-ketene alkyl radical species 39 followed by: (i)
6-exo-trig acyl radical cyclisation into the adjacent butenolide
double bond, leading to 41, (ii) 6-endo-trig cyclisation of 41 to
42, and finally, (iii) 6-endo-trig cyclisation of the radical 42 into
the proximate enone electrophore producing the tetracycle 43
(Scheme 5). Although this analysis is speculative and the struc-
ture of 43 is complete conjecture, precedent for the isomerisation
of E- and Z-a,b-unsaturated acyl radicals via ketene alkyl radical
species, viz. 39, can be found in our contemporaneous studies
directed towards a synthesis of the PAF antagonist phomactin
Scheme 2 Reagents and conditions: (i) 21, tBuLi, THF, −78 ◦C, 20 min,
then CuCN, THF; BF3·OEt2, THF, −60 ◦C, then 22, 70%; (ii) LDA,
THF, −78 ◦C, 91%; (iii) LDA, THF, −78 ◦C, then PhSeBr, −78 ◦C,
30 min, 50%.
The cd-unsaturated aldehyde 20 was prepared in six straight-
forward steps starting from 5,6-dihydro-2H-pyran-2-one 25
(Scheme 3). Treatment of 25 with the high-order cuprate derived
from 2-bromopropene first led to the racemic d-lactone 26 which
could be resolved via its 2-methylphenylamide derivative 2719
to provide the required S-enantiomer 28. Reduction of the d-
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 8 7

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enone electrophores had limitations, and it was abandoned in
favour of a Stille coupling approach, which is described below.
The Stille coupling reaction approach
The Stille sp2–sp2 coupling reaction between alkene partners is
one of the most revered contemporary synthetic methods.27 The
method has been applied widely in the synthesis of a range of
target natural products including some from our own laboratory
e.g. recently pateamine A, rhizoxin D, amphidinolide A.28 Work-
ing alongside these contemporaneous investigations we designed
a new approach to a synthesis of the bis-deoxylophotoxin 17b
based on sequential carbanion alkylation and Stille coupling
between the enantiopure selenolactone-substituted vinyl iodide
44 and the enantiopure stannylfuran-substituted aldehyde 45.12
The selenolactone 44 was synthesised from the (R)-
epichlorohydrin29 via the known (R)-chlorotrimethylsilylpent-4-
yn-2-ol 46a30 in six straightforward steps as shown in Scheme 6.
Thus, the silane 46a was first deprotected to the monosubstituted
acetylene 46b. Carbometalation–iodination31 of 46b next gave
the E-vinyl iodide 47, which was smoothly converted into the
corresponding epoxide 48 in the presence of NaOH. Treatment
of 48 with the lithium salt of 1-ethoxyacetylene, followed by
reaction with p-TSA, work up and chromatography next gave
the enantiopure lactone 49 as an oil.32 When the lactone 49
was deprotonated with LiHMDS and the resulting anion was
Scheme 4 Reagents and conditions: (i) LDA, −78 ◦C, then 20, −78 ◦C,
55%; (ii) H2O2, THF (aq.), 90%; (iii) DMAP, Et3N, Ac2O, CH2Cl2, r.t.,
88%; (iv) PhH, MeOH, PPTS, r.t., 70%; (v) Dess–Martin periodinane,
◦
quenched with phenylselenium bromide at −78 C,33 a 2 : 1
t
CH2Cl2, 80%; (vi) NaClO2, KH2PO4, BuOH, 2-methyl-2-butene, r.t.,
100%; (vii) NPSP, PBu3, CH2Cl2, −30 ◦C to r.t., 80%; (viii) MeOH,
PPTS, r.t., 90%; (ix) PMB-trichloroacetimidate, p-TSA, CH2Cl2–hexane
(2 : 1), 0 ◦C; (x) Dess–Martin periodinane, CH2Cl2, r.t., 65%.
mixture of diastereoisomers of the a-phenylselenolactone 44
was obtained, but only in modest yield. A by-product from
Scheme 5
A.24 Indeed, the scope for ketene alkyl radical species in
synthesis has been subsequently developed by us and provided,
inter alia, new syntheses of triquinanes e.g. pentalenene25 and
modhephene.26 Notwithstanding these subsequent studies, it was
clear that the proposed route to furanoterpenes via intramolecu-
lar cyclisation of a,b-unsaturated acyl radical intermediates into
Scheme 6 Reagents and conditions: (i) TMSC≡CH, n-BuLi, BF3·OEt2,
−78 ◦C; (ii) TBAF, HCl, THF, r.t., 42% over two steps; (iii) Me3Al,
Cp2ZrCl2, CH2Cl2, r.t., 3 days, then I2/THF, −30 ◦C, 2 h, 60%; (iv)
NaOH, Et2O, r.t., 14 h, 84%; (v) 1-alkoxyacetylene, n-BuLi, BF3·OEt2,
2 h; (vi) p-TSA, EtOH, 2 h, then CHCl3, reflux, 14 h, 82% from 48; (vii)
LiHMDS, −78 ◦C; then PhSeBr; (viii) TMSCl, −78 ◦C; (ix) PhSeBr,
72% from 49.
2 7 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

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Scheme 7 Reagents and conditions: (i) n-BuLi, −78 ◦C, 20 min, then 3-methylbuten-2-oyl chloride, from −78 ◦C to r.t., 30 min, 75%; (ii) NaHMDS,
1 h, −78 ◦C, THF, then 1.2 equiv. of ethyl 2-bromomethyl-3-furoate, 65%; (iii) Super Hydride, toluene, −78 ◦C, 20 min, 80%; (iv) TsCl, Et3N, DMAP,
r.t., 75%; (v) DIBAL, CH2Cl2, −78 ◦C, 95%; (vi) n-Bu4NCN, 3 equiv, DMSO, 60 ◦C, 90%; (vii) TBSCl, Et3N, DMAP, r.t., 91%; (viii) DIBAL, 1.1
equiv., toluene, −78 ◦C to r.t., 85%; (ix) NaBH4, MeOH, 0 ◦C, 70%; (x) n-BuLi, 20 min, then TMEDA for 6 h and n-BuLi for 20 min, r.t.; then
Me3SnCl, 0 ◦C to r.t. 16 h, 80%; (xi) TPAP, NMO, 4 A molecular sieves, CH2Cl2, 1 h, 75%.
˚
the reaction was the corresponding bis-selenated lactone 50.
The formation of this bis-selenated lactone 50 could be avoided
completely, however, by trapping the intermediate lithium eno-
late 51 derived from 49 with trimethylsilyl chloride.34 Subsequent
treatment of the TMS ether 52 with phenylselenium bromide
then gave the a-phenylselenolactone 44 as the sole product in
72% yield (Scheme 6).
The stannylfuran-substituted aldehyde 45 was prepared
starting with the oxazolidinone 54 derived from 3-methylbutan-
2-oyl chloride and the chiral oxazolidinone 53.35 Deprotonation
of the imide 54 with NaHMDS in THF at −78 ◦C, followed
by addition of ethyl 2-bromomethyl-3-furoate36 first gave the
adduct 55a resulting from deconjugative alkylation (Scheme 7).
The relative stereochemistry of 55a was established from
Scheme 8 Reagents and conditions: (i) AsPh3, Pd2dba3, NMP, 40 ◦C,
16 h, 55%; (ii) MsCl, Et3N, 3 h, 87%.
X-ray measurements on◦the corresponding crystalline methyl
ester 55b, mp 59–61 C.37 Reduction of 55a, using two
at −78 ◦C, with the aldehyde 45 gave the unstable secondary
equivalents of Super Hydride produced the alcohol 56, which
alcohol adduct 63 as an oil in 71% yield. An intramolecular
was then converted into the corresponding nitrile 57a in three
Stille coupling reaction with 63, under high dilution, then gave
straightforward steps. After protection of the alcohol 57a
the furanocembrane 64 as a separable mixture of a- and b-
as its TBS ether 57b, the nitrile group was reduced to the
aldehyde 58, which, on further reduction with NaBH4, gave
of retention of the E-geometry of the trisubstituted double
OH epimers, in 41% yield (Scheme 9). The important feature
the alcohol 59. Initial attempts to deprotonate the furan ring
in 59 at the C-5 position were not successful.38 We eventually
achieved this objective, however, by treating 59 with an excess
of n-BuLi in the presence of TMEDA at room temperature.39
When the resulting furyllithium species was then quenched with
Me3SnCl, the desired stannylfuran 60 was isolated in 83% yield.
Oxidation of the alcohol group in 60 using TPAP40 finally gave
the stannylfuran-substituted aldehyde 45.
The proposed union of the stannylfuran 45 with the vinyl
iodide 44 was first examined using an intermolecular Stille
reaction between 60 and 44 in the presence of Pd2dba3–
Ph3As41 which, gratifyingly, led to the coupled product 61a
in 55% yield (Scheme 8). With the aim of carrying out an
intramolecular alkylation reaction, the alcohol 61a was con-
verted into the corresponding mesylate 61b, but all attempts
to induce macrocyclisation from this substrate under a variety
of different conditions (solvent, base, temperature) met with
failure. Similarly, we were also not able to effect macrocyclisation
from the analogous lactone iodide 62 (prepared from 49 and 60)
under a variety of reaction conditions.
We then decided to combine 44 with 45 by carrying out the
alkylation step first, followed by the Stille coupling reaction in
an intramolecular fashion, as the final step.42 This proposition
was first modelled using the stannylfuran 45 and the lactone
vinyl iodide 49 which was devoid of selenium substitution. Thus,
alkylation of the anion derived from 49 using LiHMDS in THF
Scheme 9 Reagents and conditions: (i) LiHMDS, −78 ◦C, 10 min; then
45, 50 min, 93%; (ii) AsPh3, Pd2dba3, 40 ◦C, 14 h, 10% from 64; (iii)
Ac2O, Et3N, DMAP, r.t., 4 h, 54%; (iv) CSA, MeOH, CH2Cl2, 3 h, 0 ◦C,
78%; (v) Dess–Martin periodinane, pyridine, CH2Cl2, 3 h, 0 ◦C, 61%.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 8 9

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bond in the vinyl iodide 63 during the Stille coupling was
confirmed by carrying out detailed NOE experiments with the
furanocembrane 64.43 Furthermore, acetylation of the major
epimeric alcohol resulting from the macrocyclisation, followed
by deprotection of the resulting TBS ether 65a led to a single
isomer of the furanylmethanol 65b. Oxidation of the alcohol
65b led to the corresponding aldehyde 65c, which was obtained
as a colourless crystalline solid. X-Ray crystallographic analysis
of this cembrane then established its relative stereochemistry,
which is shown in Fig. 1.37
furanocembrane 68, which was obtained as a mixture of epimeric
alcohols. Without purification, the labile furanocembrane 68
was acetylated in situ to give the corresponding acetate 69
as a 2.3 : 1 mixture of OAc epimers in 20% yield over two
steps. Deprotection of the TBS group in 69 then gave the 3-
furanylmethanol 70, from which the major (presumed a-OAc)
epimeric acetate could be separated by chromatography. Finally,
oxidation of the a-acetate 70, using Dess–Martin periodinane,
gave bis-deoxylophotoxin 71a. Corresponding oxidation of a
2 : 1 mixture of OAc epimers of 70 led to a mixture of OAc
epimers of 71. The structures of the a- and b-OAc epimers of
bis-deoxylophotoxin followed from comparison of their NMR
spectroscopic data with each other and with those of naturally
occurring furanocembranes.
The family of furanocembranes represented by lophotoxin
1, pukalide 2 and bipinnatin G (3) are deceptively demanding
targets for total synthesis. In this paper we have highlighted
the scope for two quite different synthetic approaches to these
targets which complement the contemporaneous synthetic work
of others and notably the studies of Paquette and Marshall
and their respective co-workers. Clearly there remains scope for
further innovation in this area, and particularly when it comes
to addressing the issue of introducing the epoxide functionalities
in furanocembranes such as 1–3 in both a chemo- and stereo-
selective manner.
Fig. 1 X-Ray crystal structure of the furanocembrane 65c.
With the aforementioned model studies, we next examined
the same sequence of carbanion alkylation and Stille coupling
reactions starting with the phenylselenyl-substituted lactone 44.
Deprotonation of the lactone 44, using LiHMDS in THF at
−78 ◦C, followed by addition of the aldehyde 45 gave the
corresponding alkylated product 66 as a mixture of diastereoiso-
mers in 93% yield (Scheme 10). After some optimisation of
reaction conditions, to avoid significant destannylation of the
sensitive stannylfuran unit in 66/67, oxidative elimination of
the phenylselenide residue in 66 using H2O2 in CH2Cl2–pyridine
gave the butenolide 67. An intramolecular Stille reaction with 67
under the conditions described by Farina et al.41 then led to the
Experimental
General details
1H NMR spectra were recorded on either a Varian 270 (270.
13 MHz), a Bruker DPX 360 (360.13 MHz), a Bruker AV
400 (400.13 MHz), or a Bruker DRX 500 (500.12 MHz)
spectrometer. Proton chemical shifts are quoted in parts per
million (ppm), and spectra were referenced to residual pro-
tonated solvent (dH = 7.27 for CDCl3). Abbreviations used
in the description of resonances are: s (singlet), d (doublet),
t (triplet), q (quartet), m (multiplet), bs (broad singlet) and
bd (broad). Coupling constants (J) are quoted to the nearest
0.1 Hz. 13C NMR spectra were recorded either on a Varian 270
(67.8 MHz), a Bruker DPX 360 (90.03 MHz) or a Bruker DRX
500 (125 MHz) spectrometer with complete proton decoupling.
Carbon chemical shifts are quoted in parts per million (ppm) and
spectra were referenced to residual protonated solvent (dC = 77.1
for CDCl3). Assignments were made on the basis of chemical
shift using the DEPT sequence with secondary pulses at 90◦ and
135◦, where appropriate. In the spectroscopic data, C refers to
quaternary carbon, CH to tertiary methine, CH2 to secondary
methylene and CH3 to primary methyl.
Infra-red spectra were recorded using a Perkin–Elmer FT
1600 spectrometer as dilute solutions in spectroscopic grade
chloroform or deuterated chloroform.
Mass spectra were recorded either on a VG Autospec,
MM-701CF, or a Micromass LCT spectrometer using electro
ionisation (EI), fast atom bombardment (FAB), or electrospray
(ES) techniques. High-resolution mass spectra are calculated
from the molecular formula corresponding to the observed
signal using the most abundant isotopes of each element, to
4 decimal places.
Optical rotations were recorded on a JASCO DIP 370 po-
larimeter and melting points were recorded on a Stuart Scientific
SMP3 melting point apparatus, and are uncorrected. Flash
chromatography was carried out on Merck silica gel 60 (230–
400 mesh ASTM) as the stationary phase or alumina Woelm
basic (cationotropic), where indicated. Petroleum ether refers to
the fraction b.p. 40–60 ◦C unless stated otherwise. All chemical
reactions were monitored by thin layer chromatrography (TLC)
using Merck silica gel 60 F254 precoated aluminium plates or
Merck aluminium oxide F254 plates, which were visualised under
Scheme 10 Reagents and conditions: (i) LiHMDS, −78 ◦C, 10 min; then
45, 50 min, 93%; (ii) H2O2, CH2Cl2/pyridine, 1 h; (iii) AsPh3, Pd2dba3,
40 ◦C, 14 h, 20% from 66; (iv) Ac2O, Et3N, DMAP, r.t., 4 h, 54%; (v)
CSA, MeOH, CH2Cl2, 3 h, 0 ◦C, 78%; (vi) Dess–Martin periodinane,
pyridine, CH2Cl2, 3 h, 0 ◦C, 61%.
2 7 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

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ultraviolet light and then developed with either basic potassium
permanganate solution or acidic alcoholic vanillin solution.
Unless stated otherwise, reactions requiring anhydrous condi-
tions were conducted under an inert atmosphere of nitrogen in
flame-dried or oven-dried apparatus. When necessary, solvents
were dried prior to use. Dichloromethane was either distilled
from calcium hydride or was obtained in high-grade form
from Fisher-Scientific. MeOH was distilled from magnesium
methoxide, and ether and tetrahydrofuran from sodium metal
and benzophenone ketyl. Anhydrous N,N-dimethylformamide
(DMF) and 1-methyl-2-pyrrolidinone (NMP) were purchased
from Aldrich.
aqueous layer was extracted with diethyl ether (2 × 40 mL),
and the combined organic extracts were then washed with
brine (40 mL), dried (MgSO4) and evaporated in vacuo to leave
a yellow oil. Flash chromatography with 1% diethyl ether in
CH2Cl2 as eluant gave the c -hydroxy ester (0.5 g, 70%) as a
colourless oil. (Found C, 60.7; H, 10.6, C16H32O4Si requires
C, 60.7; H, 10.2); [a]2D0 −10.5 (c 1.02 in CH2C12); mmax/cm−1
(film) 3442, 2956, 2856, 1740, 776; dH(270 MHz): 5.48 (m, 1H,
=
CH C), 4.20 (d, 2H, J 6.2, CH2OSi), 3.74 (s, 1H, CHOH),
3.68 (s, 3H, OCH3), 2.49 (td, 2H, J 7.3 and 1.9 CH2CO),
=
2.10 (m, 2H, CH2CH2CO), 1.66 (s, 3H, CCH3), 0.90 (s, 9H,
SiC(CH3)3), 0.00 (s, 6H, Si(CH3)2); dC(67.8 MHz): 174.4 (C),
133.4 (C), 128.4 (CH), 68.0 (CH), 60.0 (CH), 51.6 (CH3), 47.8
(CH2), 31.8 (CH2), 30.4 (CH2), 25.9 (CH3), 18.3 (CH3), 16.4
(C), −5.2 (CH3); m/z (EI) found 257 (M+ − 59) (5), 243 (14),
197 (15), 185 (12), 131 (5), 117 (39), 115 (26), 101 (19), 75 (100),
55 (25), 45 (29).
2-Bromo-4-(tert-butyldimethylsilyloxy)but-2-ene 21. Imida-
zole (9.94 g, 146 mmol) and tert-butyldimethylchlorosilane
(8.93 g, 59.5 mmol) were added sequentially to a stirred solution
of E-3-bromobut-2-en-1ol (7.94 g, 52.5 mmol)18 in dry DMF
(15 mL) at room temperature. The resulting mixture was stirred
at this temperature for 24 h and then poured into water (150 mL).
The aqueous phase was extracted diethyl ether (3 × 150 mL)
and the combined organic extracts were then washed with brine
(150 mL), dried (MgSO4) and evaporated in vacuo to leave an
oil. Flash column chromatography with 1% diethyl ether in
petroleum ether as eluant gave the silyl ether (13.1 g, 95%) as
a colourless oil. (Found C, 45.6; H, 8.0 C10H21BrOSi requires
C, 45.4; H, 8.15); dH(270 MHz): 6.00 (tq, 1H, J 7.0 and 1.0,
(4S)-6-Methyl-8-(tert-butyldimethylsilyloxy)oct-6-en-4-olide
24. n-Butyllithium (0.59 mL, 0.95 mmol, 1.6 M in hexane)
was added dropwise over 5 min to a stirred solution of
diisopropylamine (0.12 mL, 0.95 mmol) in dry THF (5 mL) at
0 ◦C. The mixture was stirred at 0 ◦C for 20 min, then cooled to
−78 ◦C and a solution of the hydroxy ester 23 (0.2 g, 0.63 mmol)
in dry THF (1 mL) was added over 5 min. The mixture was
stirred at −78 ◦C for 1 h and then quenched by the addition of
saturated ammonium chloride solution (5 mL). The mixture was
partitioned between water (10 mL) and diethyl ether (10 mL)
and the aqueous layer was further extracted with diethyl ether
(2 × 10 mL). The combined organic extracts were washed with
brine (20 mL), dried (MgSO4), and evaporated in vacuo to leave
a yellow oil. Flash chromatography with 20% diethyl ether in
petroleum ether as eluant gave the lactone (0.16 g, 91%) as a
colourless oil. (Found C, 63.1; H, 10.0, C15H28O3Si requires C,
63.3, H, 9.9); [a]D21 +33 (c 0.42 in CH2Cl2); mmax/cm−1 (film) 1777,
=
CHCH2OSi), 4.14 (dd, 2H, J 7.0 and 1.0, CH2OSi), 2.29
(m, 3H, CH3), 0.91 (s, 9H, SiC(CH3)3), 0.08 (s, 6H, Si(CH3)2);
dC(67.8 MHz) 131.6 (CH), 121.7 (C), 60.2 (CH2), 25.8 (3 × CH3),
23.6 (CH3), 18.2 (C), 5.3 (CH3), −5.3 (CH3); m/z (EI) found 208
(M+, 81Br − Bu) (46), 206 (M+, 79Br − Bu) (46), 185 (6), 139
t
t
(27), 137 (26), 75 (100).
(2S)-Methyl-4,5-epoxypentanoate 22. Potassium carbonate
(11.56 g, 83.8 mmol) was added to a stirred suspension of
(4S)-5-(p-toluenesufonyloxy)pent-4-olide (22.5 g, 83.8 mmol)17
in dry methanol (200 mL) at room temperature. The mixture
was stirred at this temperature for 20 h and then concentrated in
vacuo to leave a colourless solid which was partitioned between
water (150 mL) and diethyl ether (150 mL). The aqueous layer
was further extracted with diethyl ether (2 × 150 mL), and the
combined organic extracts were then washed in brine (100 mL),
dried (MgSO4) and evaporated in vacuo to leave a pale yellow
oil. Flash chromotography with 30% diethyl ether in petroleum
ether as eluent gave the epoxide (9.64 g, 89%) as a colourless
oil. (Found C, 55.11, H, 7.90, C6H10O3 requires C, 55.4; H,
7.8); [a]2D0 −16.6 (c 10.9 in CH2Cl2), lit.17 [a]D −16.3 (c 2.8 in
CH2Cl2); mmax/cm−1 (film) 1737, 1174; dH(270 MHz): 3.70 (s, 3H,
CO2CH3), 3.03–2.96 (m, 1H, OCHCH2CH2), 2.79–2.76 (m, 1H,
CHHCOCH), 2.58–2.50 (m, 1H, CHHCOCH), 2.48 (t, 2H, J
7.5 HZ, CH2CO2), 2.05–1.93 (m, 1H, CHHCH2CO2), 1.84–1.71
(m, 1H, CHHCH2CO2); dC(67.8 MHz): 173.2 (C), 51.6 (CH3),
51.1 (CH), 46.9 (CH2), 30.1 (CH2), 27.5 (CH2); m/z (EI) found
130.0618 (M+), C6H10O3 requires 130.0630.
=
836, 776; dH(270 MHz): 5.44–5.38 (m, 1H, CH C), 4.69–4.58
(m, 1H, CO(O)CH), 4.21 (dd, 2H, J 6.0 and 1.0, CH2OSi),
=
2.65–2.45 (m, 3H, CH(O)CHHC C and COCH2), 2.40–2.25
(m, 2H, CHHCH2CO and CH(O)CHHC C), 2.05–1.85 (m,
=
1H, CHHCH2CO), 1.69 (d, 3H, J 1.0, CH3), 0.91 (s, 9H,
SiC(CH3)3), 0.08 (s, 6H, Si(CH3)2); dC(67.8 MHz): 177.2 (C),
131.8 (C), 128.5 (CH), 79.4 (CH), 60.1 (CH2), 45.2 (CH2), 28.7
(CH2), 27.7 (CH2), 26.0 (CH3), 18.4 (C), 16.9 (CH3), −5.1
(CH3); m/z (EI) found 227 (M+ − 57) (43), 197 (54), 181 (4),
143 (8), 85 (37), 75 (100).
(4S)-2-(Phenylselenyl)-6-methyl-8-(tert-butyldimethylsilyloxy)-
oct-6-en-4-olide 19. For optimal yields, the reaction vessel
was first filled with diisopropylamine and allowed to stand at
room temperature for 16 h. The diisopropylamine was then
poured off and the flask was washed with acetone before being
oven and flame dried. n-Butyllithium (0.61 mL, 0.98 mmol,
1.6 M in hexane) was added dropwise over 5 min to a stirred
solution of diisopropylamine (0.14 mL, 1.02 mmol) in dry
THF (5 mL) at 0 ◦C. The solution was stirred at 0 ◦C for
20 min, then cooled to −78 ◦C and a solution of the lactone
24 (0.27 g, 0.93 mmol) in dry THF (5 mL) was added slowly,
over 5 min. The mixture was stirred at −78 ◦C for 40 min
and then a solution of phenylselenyl bromide was added via
cannula, and the mixture was stirred at −78 ◦C for a further
1 h. The mixture was quenched with saturated ammonium
chloride solution (10 mL) and then partitioned between water
(10 mL) and diethyl ether (10 mL). The separated aqueous
layer was further extracted with diethyl ether (2 × 10 mL)
and the combined organic extracts were then washed with
brine (20 mL), dried (MgSO4), and evaporated in vacuo to
leave a yellow oil. Chromatography with 30% diethyl ether in
petroleum ether as eluant gave the phenylselenide (0.20 g, 50%;
92% based on recovered starting material) as a pale yellow oil,
and as a 1 : 2 ratio of diastereoisomers. mmax/cm−1 (film) 1772,
1176, 1064; dH(500 MHz) (minor diastereoisomer): 7.72 (m,
(4S)-Methyl-4-hydoxy-6-methyl-8-(tert-butyldimethylsilyloxy)-
oct-6-enoate 23. t-Butyllithium (4.52 mL, 7.70 mmol, 1.7 M in
pentane) was added dropwise over 30 min to a stirred solution
of the bromide 21 (1.00 g, 3.84 mmol) in dry THF (10 mL) at
−78 ◦C. The yellow solution was stirred at −78 ◦C for 5 min
and then added via cannula over 20 min to a stirred suspension
of copper(I) cyanide (0.17 g, 1.93 mmol) in dry THF (10 mL)
at −78 ◦C. The mixture was warmed to −60 ◦C, and boron
trifluoride dietherate (0.71 mL, 11.5 mmol) was then added
dropwise followed by the addition of a solution of the epoxide
2217 (0.75 g, 5.77 mmol) in dry THF (2 mL). The yellow
solution was stirred at −60 ◦C for 1 h, then warmed slowly
to −20 ◦C, and quenched with 10% ammonium hydroxide in
saturated ammonium chloride solution (20 mL). The mixture
was warmed to room temperature and then partitioned between
water (40 mL) and diethyl ether (40 mL). The separated
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 9 1

View Article Online
=
2H, Ar–H); 7.39 (m, 3H, Ar–H), 5.35 (t, 1H, J 5.8, CH C),
4.57 (m, 1H, CH(O)), 4.20 (d, 2H, J 6.6, CH2OSi), 4.05 (t,
1H, J 9.5, CHSe), 2.75 (m, 1H, CHHCHSe), 2.37 (m, 1H,
J 7.5, CH2CH2OH), 2.19 (d, 2H, J 7.5, CH2CO), 1.65–1.45
(m, 1H, CH2CHCH2), 1.61 (s, 3H, CH3C C), 1.37 (d, 3H, J
=
7.0, CH3CH); dC(67.8 MHz): 171.3 (C), 146.7 (C), 143.1 (C),
128.5 (CH), 127.1 (CH), 126.1 (2 × CH), 112.1 (CH2), 60.1
(CH2), 48.6 (CH), 45.2 (CH2), 40.5 (CH2), 40.3 (CH), 35.7
(CH2), 21.6 (CH3), 19.0 (CH3); m/z (ES) 261 (M+) (26), 243
(72), 228 (100), 216 (14), 161 (23), 120 (30), 105 (83); and (ii)
the (S,S)-diastereoismer (3.50 g, 39%) (eluted second) as a pale
yellow oil. (Found C, 73.3; H, 9.2; N, 5.47); [a]2D1 −82.7 (c 0.36 in
CH2Cl2); mmax/cm−1 (film) 3300, 1645; dH(270 MHz): 7.28–7.14
(m, 5H, Ar–H), 6.09 (d, 1H, J 7.0, NH), 5.02 (d, 1H, J 7.0,
=
CHHCHSe), 2.1 (dd, 1H, J 14.1 and 6.5, CH(O)CHHC C),
=
=
2.02 (m, 1H, CH(O)CHHC C), 1.66 (s, 3H, CH3C C), 0.95
(s, 9H, SiC(CH3)3), 0.11 (s, 6H, Si(CH3)2); dH(500 MHz) (major
diastereoisomer): 7.72 (m, 2H, Ar–H), 7.39 (m, 3H, Ar–H),
=
5.39 (t, 1H, J 6.1, CH C), 4.44 (m, 1H, CH(O)), 4.22 (d,
2H, J 6.2 CH2OSi), 3.98 (dd, 1H, J 7.8 and 3.2, CHSe), 2.47
=
(dd, 1H, J 14.1 and 6.95 Hz, CH(O)CHHC C), 2.37 (m, 2H,
=
CHHCHSe), 2.26 (dd, 1H, J 14.1 and 6.3, CH(O)CHHC C),
=
=
1.66 (s, 3H, CH3C C), 0.95 (s, 9H, SiC(CH3)3), 0.11 (s, 6H,
CH3CH), 4.71 (s, 2H, H2C C), 3.51 (t, 2H, J 6.5, CH2OH),
Si(CH3)2); dC(125 MHz) (mixture of diastereoisomers): 175.6
(C), 136.0 (CH), 135.9 (CH), 131.3 (C), 129.5 (CH), 129.4 (CH),
129.3 (CH), 129.0 (CH), 128.8 (CH), 128.7 (CH), 126.9 (CH),
77.9 (CH2), 60.0 (CH2), 45.2 (CH2), 44.9 (CH2), 37.0 (CH), 36.6
(CH), 26.1 (CH3), 18.5 (C), 16.9 (CH3), −5.00 (CH3); m/z (EI)
2.67 (d, 2H, J 7.0, CH2CH2OH), 2.20 (d, 2H, J 7.5, CH2CO),
=
1.70–1.45 (m, 1H, CH2CHCH2), 1.59 (s, 3H, CH3C C), 1.38
(d, 3H, J 7.0, CH3CH); dC(67.8 MHz): 171.3 (C), 146.7 (C),
143.1 (C), 128.5 (CH), 127.1 (CH), 126.1 (2 × CH), 112.1 (CH2),
60.1 (CH2), 48.6 (CH), 45.2 (CH2), 40.6 (CH2), 40.3 (CH), 35.7
(CH2), 21.6 (CH3), 19.0 (CH3); m/z (EI) found 261.1723 (M+),
C16H23NO2 requires 261.1729.
found 383.0582 (M+ − Bu), C17H23O3SeSi requires 383.0555.
t
(3RS)-3-(Isopropenyl)pentanolide 26. t-Butyllithium (96.0 mL,
163 mmol) was added dropwise, over 10 min, to a stirred solution
of 2-bromopropene (7.25 mL, 82.0 mmol) in dry THF (100 mL)
at −78 C, and the mixture was stirred at this temperature for
(3S)-3-(Isopropenyl)pentan-5-olide 28. A solution of the
amide 27 (2.55 g, 9.77 mmol) and pyridinium p-toluenesulfonate
(2.00 g, 8.0 mmol) in dry toluene (75 mL) was heated under
reflux for 16 h. The mixture was cooled to room temperature
and the solvent was then removed in vacuo. The residue was
purified by flash chromatography with 60% diethyl ether in
petroleum ether as eluant to give the lactone (1.14 g, 85%) as a
colourless oil. (Found C, 68.3; H, 8.9, C8H12O2 requires: C, 68.5;
H, 8.6); [a]D21 −15.7 (c 1.5 in CH2Cl2); mmax/cm−1 (film) 2969,
◦
30 min. The solution was added via cannula over 20 min to
a stirred suspension of copper(I) cyanide (3.66 g, 40.8 mmol)
in dry THF (100 mL) at −78 ◦C. The mixture was warmed
to −40 ◦C for 30 min and then recooled to −78 ◦C. A solution
of commercially available 5,6-dihydro-2H-pyran-2-one (3.5 mL,
40.8 mmol) in dry THF (10 mL) was added dropwise via syringe,
the mixture allowed to slowly reach −40 ◦C, and stirred at
this temperature for a further 1 h. The mixture was warmed
to 0 ◦C, then quenched with 10% ammonium hydroxide in
saturated ammonium chloride solution (50 mL) and partitioned
between water (50 mL) and diethyl ether (50 mL). The separated
aqueous layer was extracted with diethyl ether (2 × 50 mL)
and the combined organic extracts were then washed with brine
(50 mL), dried (MgSO4) and evaporated in vacuo to leave a yellow
oil. Flash chromatography with 50% diethyl ether in petroleum
ether as eluant gave the lactone (3.30 g, 58%) as a colourless oil.
mmax/cm−1 (film) 1736, 1646; dH(270 MHz): 4.84 (d, 1H, J 1.0,
=
1738; dH(270 MHz): 4.87 (d, 1H, J 1.0, HHC C), 4.77 (d, 1H, J
1.0, HHC C), 4.44 (dt, 1H, J 4.5 and 11.0, OCHH), 4.29 (ddd,
=
1H, J 3.5, 10.0, and 11.5, OCHH), 2.73 (ddd, 1H, J 1.5, 5.5 and
16.5, CHHC O), 2.65–2.54 (m, 1H, CH), 2.43 (dd, 1H, J 9.5
and 16.5, CHHC O), 2.06–1.97 (m, 1H, CH2CHHCH), 1.76
(s, 3H, CH3), 1.85–1.71 (m, 1H, CH2CHHCH); dC(67.8 MHz):
171.0 (C), 145.6 (C), 110.9 (CH2), 68.4 (CH2), 38.2 (CH), 35.2
(CH2), 27.5 (CH2), 20.4 (CH3); m/z (EI) found 140.0846 (M+),
C8H12O2 requires 140.0837.
=
=
3-(Isopropenyl)tetrahydropyran-2-ol
29. Diisobutylalu-
minium hydride (5.70 mL, 1.5 M in toluene, 8.57 mmol) was
added dropwise over 5 min to a stirred solution of the lactone 28
(1.09 g, 7.77 mmol) in dry tetrahydrofuran (100 mL) at −78 ◦C,
and the mixture was stirred at this temperature for 30 min. The
mixture was warmed to room temperature and then quenched
by the addition of methanol (40 mL). The resulting mixture was
stirred at room temperature for 1 h, then magnesium sulfate
(6.00 g), was added and the stirring was continued for a further
2 h. The mixture was filtered and the residue was washed with
ethyl acetate (3 × 50 mL). The combined organic extracts were
evaporated in vacuo to leave an oil. Flash chromatography with
10% ethyl acetate in CH2Cl2 as eluant gave the lactol (0.97 g,
88%) as a colourless oil consisting of a mixture of inseparable
diastereoisomers. mmax/cm−1 (film) 3387, 1645; dH(270 MHz):
5.30 (bd, 0.5H, J 2.5, OCHO); 4.76–4.71 (m, 2.5H, 2 ×
=
=
HHC C), 4.75 (d, 1H, J 1, HHC C), 4.42 (dt, 1H, J 4.5 and
11.0, OCHH), 4.27 (ddd, 1H, J 3.5, 10.0, and 11.5, OCHH),
2.71 (ddd, 1H, J 1.5, 5.5 and 16.5, CHHC O), 2.63–2.53 (m,
=
=
1H, CH), 2.41 (dd, 1H, J 9.5 and 16.5, CHHC O), 2.04–1.94
(m, 1H, CH2CHHCH), 1.74 (s, 3H, CH3), 1.85–1.60 (m, 1H,
CH2CHHCH); dC(67.8 MHz): 171.0 (C), 145.6 (C), 110.9 (CH2),
68.4 (CH2), 38.2 (CH), 35.2 (CH2), 27.5 (CH2), 20.4 (CH3); m/z
(EI) found 140.0841 (M+), C8H12O2 requires 140.0837.
(1S,3R)-N-(1-Methylbenzyl)-3-isopropenyl-5-hydroxypentamide
and (1S,3S)-N-(1-methylbenzyl)-3-isopropenyl-5-hydroxypenta-
mide 27. Trimethylaluminium (33.0 mL, 6 mmol, 2 M in
hexane) was added dropwise over 5 min to a stirred solution
of (S)-a-methylbenzylamine (8.0 mL, 62 mmol) in dry CH2Cl2
(250 mL) at 0 ◦C, and the mixture was stirred at 0 ◦C for
15 min and then warmed to room temperature. A solution
of the lactone 26 (4.81 g, 34 mmol) in CH2Cl2 (20 mL) was
added dropwise over 5 min and the mixture was stirred at room
temperature for 16 h. The mixture was quenched by the careful
addition of 2 N hydrochloric acid (25 mL), then diluted with
water (200 mL) and extracted with CH2Cl2 (3 × 200 mL). The
combined organic extracts were washed with water (150 mL),
brine (150 mL), dried (MgSO4) and evaporated in vacuo to
leave a brown oil. Flash chromatography with 40% ethyl acetate
in diethyl ether as eluant gave (i) the (S,R)-diastereoisomer
(3.8 g, 42%) (eluted first) as colourless needle-like crystals,
mp 63–65 ◦C. (Found C, 73.1; H, 9.0; N, 5.5, C16H23NO2
requires C, 73.5; H, 8.9; N, 5.4); [a]2D1 −69.2 (c 0.45 in CH2Cl2);
mmax/cm−1 (film) 3300, 1644; dH(270 MHz): 7.28–7.14 (m, 5H,
Ar–H), 6.09 (d, 1H, J 6.5, NH), 5.02 (d, 1H, J 7, CH3CH),
=
CH2 C and 0.5H × OCHO), 4.13–4.01 (m, 1H, OCHH), 3.67
(ddd, 0.5H, J 11, 4.5 and 2, OCHH), 3.54 (app. dt, J 9.0 and
2.5, OCHH), 3.44 (bs, 0.5H, CHOH), 2.85 (bs, 0.5H, CHOH),
2.55 (app. tt, 0.5H, J 12.0 and 3.5, CH2CHCH2), 2.20 (app.
tt, 0.5H, J 12.0, and 3.5, CH2CHCH2), 1.99 (app. ddt, 0.5H,
J 13.0, 3.5 and 2.0, OCH2CHH), 1.85 (app. ddt, 0.5H, J 13,
3.5 and 2.0, OCH2CHH), 1.73 (s, 3H, CH3), 1.21–1.70 (m,
3H, CH2CHCHH); dC(67.8 MHz): 148.6 (C), 147.6 (2 × C),
109.3 (CH2), 108.8 (CH2), 96.2 (CH), 91.3 (CH), 65.4 (CH2),
59.5 (CH2), 41.4 (CH), 37.8 (CH2), 35.2 (CH), 35.1 (CH2), 30.7
(CH2), 30.1 (CH2), 20.5 (CH3), 20.4 (CH3); m/z (%) 142 (M+,
2), 124 (95), 98 (32), 81 (100), 69 (88), 55 (69); m/z (EI) found
142.1023 (M+), C8H14O2 requires 142.0994.
(5S)-2-Methylene-5-(isopropenyl)hepta-1,3,7-triol 30. t-Butyl-
lithium (23.5 mL, 40 mmol, 1.7 M in pentane) was added
=
4.72 (s, 2H, H2C C), 3.48 (t, 2H, J 6.5, CH2OH), 2.68 (d, 2H,
2 7 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

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dropwise, over 5 min, to a stirred solution of 2-bromoprop-
2-en-◦1-ol (1.81 g, 13.2 mmol)20 in diethyl◦ether (110 mL) at
−78 C and the mixture was warmed to 0 C and then stirred
at this temperature for a further 2 h. A solution of the lactol
29 (374 mg, 2.63 mmol) in diethyl ether (5 mL) was added
dropwise over 2 min, and the mixture was stirred at 0 ◦C for
2 h, then warmed to room temperature and stirred for 24 h. The
mixture was quenched with methanol (1 mL), followed by water
(20 mL), and then extracted continuously with ethyl acetate for
72 h. The organic extract was dried (MgSO4) and evaporated in
vacuo to leave a pale yellow oil. Flash chromatography with 30%
petroleum ether in ethyl acetate as eluant gave the triol (339 mg,
64%) as a colourless oil consisting of an inseparable mixture
of diastereoisomers. mmax/cm−1 (film) 3348, 1644; dH(270 MHz):
J 2.5, CHO), 9.65 (t, 0.5H, J 2.5, CHO), 7.51–7.48 (m, 2H,
Ar–H), 7.41–7.35 (m, 3H, Ar–H), 5.66 (s, 0.5H, CHPh), 5.65
=
(s, 0.5H, CHPh), 5.07–499 (m, 2H, H2C C), 4.93–4.84 (m, 2H,
=
H2C CCH3), 4.49 (s, 2H, CH2OCHPh), 4.35–4.27 (m, 1H,
CHOCHPh), 3.29–3.15 (m, 0.5H, CH2CHCH2), 2.97–3.09 (m,
0.5H, CH2CHCH2), 2.60–2.48 (m, 2H, CH2CHO), 2.01–1.71
(m, 5H, CH2 and CH3); dC(67.8 MHz): 202.2 (CH), 202.0 (CH),
146.6 (C), 144.9 (C), 142.0 (C), 141.7 (C), 138.1 (C), 138.0 (C),
128.8 (CH), 128.2 (2 × CH), 126.3 (2 × CH), 126.2 (CH), 126.1
(CH), 126.0 (CH), 113.6 (CH2), 112.0 (CH2), 109.4 (CH2),
108.8 (CH2), 101.2 (CH), 101.1 (CH), 75.5 (CH), 75.3 (CH),
71.9 (CH2), 71.8 (CH2), 47.7 (CH2), 46.9 (CH2), 37.0 (CH), 34.9
(CH2), 34.3 (CH2), 19.9 (CH3), 18.4 (CH3); m/z (%) 286 (M+,
1), 243 (5), 188 (17), 180 (29), 175 (69), 137 (29), 105 (100), 91
(46), 77 (52); m/z (EI) found 286.1535 (M+), C18H22O3 requires
286.1569.
=
=
5.17–5.08 (m, 2H, H2C C), 4.85–4.77 (m, 2H, H2C CCH3),
4.29–4.08 (m, 3H, CCH2OH and CHOH), 3.71–3.50 (m, 2H,
=
CH2OH), 3.40–2.70 (bs, 3H, 3 × OH), 2.66–2.53 (m, 0.4H,
CH2CHCH2), 2.37–2.29 (m, 0.6H, CH2CHCH2), 1.80–1.59 (m,
7H, 2 × CH2 and CH3); dC(67.8 MHz): 150.6 (C), 149.1 (C),
147.4 (C), 146.7 (C), 113.2 (CH2), 113.0 (CH2), 112.3 (CH2),
111.5 (CH2), 72.6 (CH), 71.6 (CH), 63.7 (CH2), 63.3 (CH2), 60.6
(CH2), 40.3 (CH), 40.2 (CH), 39.0 (CH2), 38.7 (CH2), 36.2 (CH2),
35.3 (CH2), 18.2 (CH3), 17.8 (CH3).
5-[(2E)-4-(tert-Butyldimethylsilyloxy)-2-methylbut-2-enyl]-3-
{(3S)-1-hydroxy-4-methyl-3-[(5-methylene-2-phenyl-1,3-dioxan-
4-yl)methyl]pent-4-enyl}-3-(phenylseleno)dihydrofuran-2(3H)-
one 32. n-Butyllithium (0.45 mL, 0.72 mmol, 1.6 M in
hexane) was added dropwise over 5 min to a stirred solution
of diisopropylamine (0.1 mL, 0.75 mmol) in dry THF (10 mL)
◦
at −10 C and the mixture was stirred at this temperature for
(3S)-Isopropenyl-5,7-0-benzylidene-6-methylene heptanol 31.
Benzaldehyde acetal (0.19 mL, 1.2 mmol) and pyridinium p-
toluene sulfonate (0.08 g, 0.32 mmol) were added to a stirred
solution of the triol 30 (0.26 g, 1.31 mmol) in dry benzene
(20 mL), and the mixture was heated under reflux for 2 h. The
solvent was removed in vacuo to leave a pale yellow oil. Flash
chromatography with 60% diethyl ether in petroleum ether as
eluant gave the acetal (0.34 g, 64%) as a colourless oil consisting
of a mixture of inseparable diastereoisomers. (Found C, 75.0;
H, 8.4, C18H24O3 requires C, 75.0; H, 8.4); mmax/cm−1 (film) 3418,
1644; dH(270 MHz): 7.53–7.49 (m, 2H, Ar–H), 7.43–7.34 (m,
3H, Ar–H), 5.71 (s, 0.4H, CHPh), 5.65 (s, 0.6H, CHPh), 5.05–
4.98 (m, 2H, H2C C), 4.92–4.82 (m, 2H, H2C CCH3), 4.50
(s, 2H, CH2OCHPh), 4.35 (t, 0.4 H, J 6.0, CHOCHPh), 4.26
(d, 0.6 H, J 10.0, CHOCHPh, one isomer), 3.68–3.52 (m, 2H,
CH2OH), 2.78–2.66 (m, 0.6 H, CH2CHCH2), 2.61–2.50 (m,
0.4 H, CH2CHCH2), 1.96–1.55 (m, 7H, 2 × CH2 and CH3);
dC(67.8 MHz): 147.5 (C), 146.3 (C), 142.4 (C), 142.1 (C), 138.1
(C), 128.7 (CH), 128.2 (CH), 128.1 (2 × CH), 126.2 (CH), 126.0
(2 × CH), 125.9 (CH), 113.1 (CH2), 112.0 (CH2), 109.3 (CH2),
108.7 (CH2), 101.1 (CH), 101.0 (CH), 76.2 (CH), 75.5 (CH), 72.0
(CH2), 71.8 (CH2), 61.2 (CH2), 61.1 (CH2), 40.1 (CH), 39.2 (CH),
36.5 (CH2), 35.2 (CH2), 35.1 (CH2), 34.2 (CH2), 18.5 (CH3), 17.7
(CH3); m/z (%) 288 (M+, 1), 257 (8), 188 (23), 182 (37), 175 (90),
105 (100); m/z (EI) found 288.1787 (M+), C18H24O3 requires
288.1726.
30 min, then cooled to −78 ◦C. A solution of the lactone 19
(0.3 g, 0.68 mmol) in dry THF (3 mL) was added dropwise over
5 min, and the mixture was stirred at −78 ◦C for 1 h before
a solution of the aldehyde 20 (0.22 g, 0.75 mmol) in dry THF
(3 mL) was added dropwise over 5 min. The solution was stirred
at −78 ◦C for 1 h, then quenched at −78 ◦C by the addition of
saturated ammonium chloride solution (2 mL). The mixture
was warmed to room temperature and then partitioned between
water (10 mL) and diethyl ether (10 mL). The aqueous layer
was further extracted with diethyl ether (2 × 10 mL) and the
combined organic extracts were dried (MgSO4), and evaporated
in vacuo to leave a pale yellow oil. Flash chromatography with
2.5% diethyl ether in CH2Cl2 as the eluant gave the aldol product
(0.29 g, 60%) as a colourless oil consisting of an inseparable
mixture of diastereoisomers. mmax/cm−1 (film) 3470, 1757, 1644;
dH(500 MHz): 7.67 (m, 2H, H–Ph), 7.49 (m, 2H, H–Ph), 7.38
(m, 1H, H–PhSe), 7.35 (m, 5H, 3 × H–Ph and 2 × H–PhSe),
5.70 (s, 0.35H, CHPh), 5.69 (s, 0.07H, CHPh), 5.64 (s, 0.64H,
=
=
=
CHPh), 5.64 (s, 0.07H, CHPh), 5.30 (m, 0.41H, CHCH20Si),
=
=
5.23 (m, 0.59H, CHCH20Si), 5.04–4.80 (m, 4H, CH2 C and
CH2 C(CH3)), 4.49 (m, 3H, CH2(O)CHPh and CH(O)CO),
=
4.39–4.33 (m, 0.37H, CH(O)CHPh), 4.25 (app. d, 0.63H, J 9.8,
CH(O)CHPh), 4.19 (2 × d, 2H, J 5.9, CH2OSi), 3.95 (m, 0.3H,
CHOH), 3.77 (app. t, 0.7H, J 11.6, CHOH), 2.90 (m, 0.6H,
CH2CHCH2), 2.81–2.53 (m, 2.4H, 2 × H, CH2CHSe and 0.4 ×
=
H CH2CHCH2), 2.37–2.02 (m, 2H, CH2C(CH3) C), 1.98–1.70
(m, 2H, HOCHCHH and CHHCH(O)CHPh), 1.63 (m, 2H,
HOCHCHH and CHHCH(O)CHPh), 1.58 (s, 3H, CH3C C),
1.57 (s, 3H, CH3C C), 0.92 (s, 9H, SiC(CH3)3), 0.08 (s, 6H,
(3S)-3-Isopropenyl-5,7-O-benzylidene-6-(methylene)heptanal
20. Dimethyl sulfoxide (0.21 mL, 2.84 mmol) was added
dropwise over 5 min to a stirred solution of oxalyl chloride
(0.13 mL, 1.42 mmol) in dry CH2Cl2 (6 mL) at 0 ◦C. The
mixture was stirred at this temperature for a further 5 min
before it was cooled to −78 ◦C and a solution of the alcohol
31 (0.21 g, 0.71 mmol) in dry CH2Cl2 (2 mL) was then added
dropwise over 1 min. The mixture was stirred at −78 ◦C
for 2 h and then quenched by the addition of triethylamine
(0.96 mL, 9.28 mmol) at −78 ◦C and subsequently warmed
to room temperature. The mixture was diluted with CH2Cl2
(30 mL) and washed with water (50 mL). The aqueous layer was
further extracted with CH2Cl2 (2 × 30 mL) and the combined
organic extracts were then washed with brine (30 mL), dried
(MgSO4), and evaporated in vacuo to leave a yellow-brown oil.
Flash chromatography with 50% diethyl ether in petroleum
ether as eluant gave the aldehyde (0.19 g, 95%) as a colourless
oil, consisting of an inseparable mixture of diastereoisomers.
(Found C, 75.4; H, 8.9, C18H22O3 requires C, 75.5; H, 7.7);
mmax/cm−1 (film) 2836, 1723, 1645; dH(270 MHz): 9.68 (t, 0.5H,
=
=
Si(CH3)2); dc(67.8 MHz): 176.7 (C), 176.5 (C), 146.4 (C), 144.9
(C), 142.2 (C), 141.9 (C), 138.2 (C), 138.1 (C), 137.8 (CH),
131.2 (CH), 129.8 (CH), 129.2 (CH), 128.6 (CH), 128.5 (CH),
128.1 (CH), 126.1 (CH), 126.0 (CH), 114.3 (CH2), 112.9 (CH2),
109.3 (CH2), 108.7 (CH2), 101.1 (CH), 101.0 (CH), 76.3 (CH),
76.2 (CH), 75.7 (CH), 72.0 (CH), 71.9 (CH2), 71.8 (CH2), 71.6
(CH2), 71.5 (CH), 59.9 (CH2), 55.6 (C), 55.5 (C), 53.4 (C),
45.3 (CH2), 39.9 (CH), 39.3 (CH), 36.1 (CH2), 35.6 (CH2), 35.4
(CH2), 35.1 (CH2), 34.7 (CH2), 34.6 (CH2), 25.8 (CH3), 18.3
(CH3), 18.2 (C), 17.2 (CH3), 16.6 (CH3), −0.5 (CH3); m/z FAB
found (%) 725 (M+ + 1, 0.3), 579 (1.5), 526 (16), 490 (2), 489
(9), 487 (5), 313 (6), 181 (17), 137 (22), 73 (100), 55 (85); m/z
(EI) found 725.2914 (M+), C35H55O6SeSi requires 725.2941.
5-[(2E)-4-(tert-Butyldimethylsilyloxy)-2-methylbut-2-enyl]-3-
{(3S)-1-hydroxy-4-methyl-3-[(5-methylene-2-phenyl-1,3-dioxan-
4-yl)methyl]pent-4-enyl}furan-2(5H)-one 33a. Hydrogen per-
oxide (1.08 mL, 100 vol.) was added dropwise over 5 min to a
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 9 3

View Article Online
stirred solution of the selenide 32 (0.6 g,◦0.28 mmol) in THF
(20 mL) containing water (1.4 mL), at 0 C. The mixture was
stirred at 0 ◦C for 30 min and then warmed to room temperature
and stirred for 2 h. Saturated sodium hydrogen carbonate
(10 mL) was added and the mixture was stirred vigorously
for 30 min before being partitioned between water (30 mL)
and diethyl ether (30 mL). The separated aqueous layer was
extracted with diethyl ether (2 × 30 mL) and the combined
organic extracts were dried (MgSO4), and evaporated in vacuo
to leave a pale yellow oil. Flash chromatography with 10%
petroleum ether in diethyl ether as eluant gave the butenolide
(0.45 g, 96%) as a colourless oil consisting of an inseparable
mixture of diastereoisomers. mmax/cm−1 (film) 3461, 1754, 1644;
dH(500 MHz): 7.49 (m, 2H, Ar–H), 7.36 (m, 3H, Ar–H), 7.19
71.8 (CH2), 67.6 (CH), 67.5 (CH), 59.9 (CH2), 42.0 (CH2),
39.6 (CH), 39.5 (CH), 38.9 (2 × CH), 38.8 (CH), 36.4 (CH2),
35.3 (CH3), 35.1 (CH2), 34.4 (CH3), 34.3 (CH2), 25.9 (CH3),
25.6 (CH3), 20.7 (CH3), 18.6 (C), 18.3 (CH3), 17.3 (CH3), 17.0
(CH3), −5.2 (CH3); m/z (%) FAB 611 (M+ + 1, 0.5), 553 (4),
505 (5), 373 (6), 313 (16), 295 (17), 227 (11), 175 (21), 154 (20),
145 (11), 136 (27), 105 (38), 73 (100); m/z (EI) found 611.3428
(M+), C35H49O6Si requires 611.3404.
(3R)-1-{5-[(2E)-4-Hydroxy-2-methylbut-2-enyl]-2-oxo-2,5-
dihydrofuran-3-yl}-4-methyl-3-[(5-methylene-2-phenyl-1,3-
dioxan-4-yl)methyl]pent-4-enyl acetate 34a. Dry methanol
(7.3 × 10−3 mL, 0.18 mmol) and pyridinium p-toluenesulfonate
(4.1 × 10−3 g, 0.016 mmol) were added to a stirred solution of
the silyl ether 33b (0.1 g, 0.16 mmol) in dry benzene (0.5 mL) at
room temperature and the mixture was stirred for three days
and then evaporated to dryness in vacuo. The residue was
purified by flash chromatography with 20% diethyl ether in
CH2Cl2 as eluant to give the alcohol (41 mg, 50%; 84% based
on recovered starting material) as a colourless oil consisting
of an inseparable mixture of diastereoisomers. mmax/cm−1 (film)
3478, 1747, 1731, 1643; dH(500 MHz): 7.50 (m, 2H, Ar–H),
=
(m, 1H, CH CCO(O)), 5.87 (s, 0.33H, CHPh), 5.70 (s, 0.11
H, CHPh), 5.69 (s, 0.44H, CHPh), 5.65 (s, 0.11H, CHPh), 5.42
=
(app. t, 0.8H, J 5.8, CHCH2OSi), 5.38 (app. t, 0.2H, J 5.6,
CHCH2OSi), 5.03–4.84 (m, 5H, CH2C C, CH2C(CH3) C
=
=
=
and CH(O)CO), 4.49 (m, 2H, CH2(O)CHPh), 4.42 (m, 0.6H,
CH(O)CHPh), 4.27 (app. d, 0.4H, J 10.6, CH(O)CHPh), 4.21
(app. d, 2H, J 6.1, CH2OSi), 3.95 (m, 1H, CHOH), 2.93 (m,
0.67H, CH2CHCH2), 2.80 (m, 0.33H, CH2CHCH2), 2.32 (m,
2H, CH2C(CH3) C), 1.93 (m, 2H, CH2CHOH), 1.77 (m,
2H, CH2CH(O)CHPh), 1.73 (s, 3H, CH3C C), 1.70 (s, 3H,
=
7.35 (m, 3H, Ar–H), 7.04 (app. d, 1H, J 10.8, CH CCO(O)),
=
5.70 (s, 0.22H, CHPh), 5.69 (s, 0.11H, CHPh), 5.65 (s, 0.56H,
=
=
CHPh), 5.62 (s, 0.11H, CHPh), 5.40 (m, 2H, CHCH2OH
=
CH3C C), 0.91 (s, 9H, SiC(CH3)), 0.08 (s, 6H, Si(CH3)2);
=
=
and CH(O)CO), 5.06–4.76 (m, 5H, CH2 CCH3, CH2
C
dC(67.8 MHz): 172.0 (C), 148.0 (CH), 147.1 (C), 145.2 (C),
142.2 (C), 141.9 (C), 138.2 (C), 138.1 (C), 137.1 (C), 137.0 (C),
130.9 (C), 130.8 (C), 128.9 (2 × CH), 128.6 (CH), 128.1 (CH),
128.0 (CH), 126.0 (CH), 125.9 (CH), 114.2 (CH2), 112.8 (CH2),
109.2 (CH2), 108.7 (CH2), 101.1 (CH), 100.9 (CH), 80.2 (CH),
75.9 (CH), 75.5 (CH), 71.8 (CH2), 71.7 (CH2), 65.2 (CH), 65.1
(CH), 59.9 (CH2), 43.2 (CH2), 42.9 (CH2), 39.2 (CH), 39.1
(CH2), 38.7 (CH), 37.3 (CH2), 35.2 (CH2), 35.1 (CH2), 34.4
(CH2), 25.9 (CH3), 25.6 (CH3), 18.4 (CH3), 18.2 (C), 17.6 (CH3),
17.4 (CH3), 16.9 (CH3), −5.2 (CH3).
and CHOAc), 4.49 (m, 2H, CH2(O)CHPh), 4.36 (m, 0.25H,
CH(O)CHPh), 4.25 (app. d, 0.75H, J 10.8, CH(O)CHPh), 4.12
(m, 2H, CH2OH), 2.81 (tt, 0.7H, J 11.3 and 4.1, CH2CHCH2),
=
2.64 (m, 0.3H, CH2CHCH2), 2.38 (m, 2H, CH2C(CH3) ),
2.07 (m, 1H, AcOCHCHH), 2.07 and 2.05 (2 × s (1 : 2),
3H, CH3CO), 1.91 (m, 1H, CHHCH(O)CHPh), 1.73 (m, 2H,
=
AcOCHCHH and CHHCH(O)CHPh), 1.73 (s, 3H, CH3C C),
1.69 (s, 3H, CH3C C); dC(67.8 MHz): 170.7 (C), 170.2 (C),
=
148.5 (CH), 148.3 (CH), 146.0 (C), 144.3 (C), 142.3 (C), 138.4
(C), 134.2 (C), 132.5 (C), 128.7 (2 × CH), 128.5 (CH), 128.3
(CH), 128.1 (CH), 126.0 (CH), 125.9 (CH), 114.8 (CH2), 113.1
(CH2), 109.2 (CH2), 108.8 (CH2), 101.0 (CH), 80.1 (CH), 75.6
(CH), 75.4 (CH), 71.9 (CH2), 71.8 (CH2), 67.8 (CH), 59.0 (CH),
42.4 (CH2), 39.0 (CH), 38.9 (CH), 36.4 (CH2), 35.2 (CH2), 34.2
(CH2), 20.7 (CH3), 18.5 (CH3), 17.3 (CH3), 17.2 (CH3); m/z
(%) FAB 497 (M+ + 1, 9), 391 (26), 331 (3), 307 (24), 227 (8),
154 (100); m/z (EI) found 497.2577 (M+), C29H37O7 requires
497.2539.
(3R)-1-{5-[(2E)-4-(tert-Butyldimethylsilyloxy)-2-methylbut-2-
enyl]-2-oxo-2,5-dihydrofuran-3-yl}-4-methyl-3-[(5-methylene-2-
phenyl-1,3-dioxan-4-yl)methyl]pent-4-enyl acetate 33b. Tri-
ethylamine (0.013 mL, 0.092 mmol), DMAP (1.0 mg, 8 ×
10−3 mmol) and acetic anhydride (0.013 mL, 0.1 mmol) were
added sequentially to a stirred solution of the alcohol 33a
◦
(43.7 mg, 0.077 mmol) in dry CH2Cl2 (2 mL) at 0 C, and the
mixture was stirred at this temperature for 3 h. The solvent
was removed in vacuo to leave a yellow-brown oil. Flash
chromatography with 50% diethyl ether in petroleum ether
as eluant gave the acetate (37.7 mg, 80%) as a colourless
oil consisting of an inseparable mixture of diastereoisomers.
mmax/cm−1 (film) 1757, 1644; dH(500 MHz): 7.50 (m, 2H,
Ar–H), 7.35 (m, 3H, Ar–H), 7.15 (app. dt, 0.22H, J 10.5
(3R)-4-Methyl-3-[(5-methylene-2-phenyl-1,3-dioxan-4-yl)-
methyl]-1-{5-[(2E)-2-methyl-4-oxobut-2-enyl]-2-oxo-2,5-dihydro-
furan-3-yl}pent-4-enyl acetate 34b. Dess–Martin periodinane
(0.162 g, 0.38 mmol) was added to a stirred solution of
the allyl alcohol 34a. (0.127 g, 0.26 mmol) in dry CH2Cl2
(2.5 mL) at 0 ◦C, and the mixture was stirred at 0 ◦C for
5 min, then warmed to room temperature and stirred for 1.5 h.
The solvent was removed in vacuo to leave a colourless solid.
Flash chromatography with 20% diethyl ether in CH2Cl2 as
eluant gave the aldehyde (0.121 g, 93%) as a colourless, viscous
oil consisting of an inseparable mixture of diastereoisomers.
mmax/cm−1 (film) 1755, 1673; dH(500 MHz): 9.99 (d, 0.4H, J
7.8, CHO), 9.98 (d, 0.6H, J 7.7, CHO), 7.49 (m, 2H, Ar–H),
=
and 1.3, CH CCO(O)), 7.09 (app. dt, 0.78H, J 11.3 and
1.4, CH CCO(O)), 5.70 (s, 0.25H, CHPh), 5.69 (s, 0.13H,
=
CHPh), 5.65 (s, 0.5H, CHPh), 5.61 (s, 0.13H, CHPh), 5.50
(m, 0.33H, CH(O)CO), 5.40 (m, 0.66H, CH(O)CO), 5.39 (m,
1H, CHCH20Si), 5.02–4.71 (m, 5H, CH2 CCH3, CH2
=
=
=
C
and CHOAc), 4.48 (m, 2H, CH2(O)CHPh), 4.35 (m, 0.33H,
CH(O)CHPh), 4.25 (app. d, 0.66H, J 10.6, CH(O)CHPh), 4.20
(app. d, 2H, J 5.1, CH2OSi), 2.79 (tt, 0.66H, J 11.2 and 7.3,
CH2CHCH2), 2.77 (m, 0.33H, CH2CHCH2), 2.39–2.24 (m, 2H,
=
7.34 (m, 3H, Ar–H), 7.15 (s, 0.11H, CH CCO(O)), 7.11 (s,
0.11H, CH CCO(O)), 7.07 (s, 0.22H, CH CCO(O)), 7.05 (s,
=
=
=
=
=
CH2C(CH3) ), 2.03 (m, 1H, AcOCHCHH), 2.03 and 2.00 (2 ×
0.55H, CH CCO(O)), 5.88 (d, 0.9H, J 7.7, CHCHO), 5.85
(d, 0.1H, J 7.4, CHCHO), 5.70 (s, 0.22H, CHPh), 5.68 (s,
0.11H, CHPh), 5.64 (s, 0.56H, CHPh), 5.61 (s, 0.11H, CHPh),
5.48 (app. d, 0.35H, J 7.6, CH(O)CO), 5.41 (app. d, 0.65H,
J 7.8, CH(O)CO), 5.07–4.76 (m, 5H, CH2 CCH3, CH2
and CHOAc), 4.46 (m, 2H, CH2(O)CHPh), 4.35 (m, 0.23H,
CH(O)CHPh), 4.22 (app. d, 0.77H, J 10.5, CH(O)CHPh),
2.78 (tt, 0.56H, J 11.3 and 3.9, CH2CHCH2), 2.56 (m, 1.44H,
=
s (1:2), 3H, CH3CO), 1.90 (m, 1H, CHHCH(O)CHPh), 1.75
(m, 2H, AcOCHCHH and CHHCH(O)CHPh), 1.73 (s, 3H,
=
=
CH3C C), 1.67 (s, 3H, CH3C C), 0.90 (s, 9H, SiC(CH3)3),
0.08 (s, 6H, Si(CH3)2); dC(67.8 MHz): 170.7 (C), 169.7 (C),
149.1 (CH), 148.8 (CH), 146.1 (CH), 144.3 (C), 142.3 (C), 142.2
(C), 142.1 (C), 138.4 (C), 138.3 (C), 133.9 (C), 133.7 (C), 130.7
(2 × C), 129.1 (CH), 128.8 (CH), 128.6 (CH), 128.2 (CH), 128.1
(CH), 126.2 (CH), 126.1 (2 × CH), 126.0 (CH), 125.9 (CH),
114.7 (CH2), 112.8 (CH2), 109.2 (CH2), 108.7 (CH2), 101.1
(CH), 100.9 (CH), 79.9 (CH), 77.5 (CH), 75.4 (CH), 71.9 (CH2),
=
=
C
=
1H × CHHC(CH3) and 0.44H CH2CHCH2), 2.42 (m, 1H,
=
=
CHHC(CH3) ), 2.19 (s, 3H, CH3C CHCO), 2.05 (m, 1H,
AcOCHCHH), 2.05 and 2.03 (2 × s (1:2), 3H, CH3CO), 1.87
2 7 9 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

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(m, 1H, CHHCH(O)CHPh), 1.74 (m, 2H, AcOCHCHH and
CHHCH(O)CHPh), 1.73 (s, 3H, CH3C C); dC(125 MHz):
(CH3),14.1 (CH3); m/z (%) Cl 670 (23), 668 (M+ + (NH4)+, 80Se,
100), 666 (51), 65 (20), 664 (15), 608 (4), 562 (9), 542 (13), 485
(6), 452 (8), 346 (11), 327 (8); m/z (EI) found 668.2155 (M+),
C35H42NO7Se requires 668.2115.
=
190.5 (C), 170.1 (C), 169.8 (C), 169.7 (C), 156.1 (C), 147.8
(CH), 147.7 (CH), 146.1 (C), 144.3 (C), 142.2 (C), 142.0 (C),
138.4 (C), 138.3 (C), 134.8 (C), 129.8 (CH), 128.9 (CH), 128.8
(CH), 128.7 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 126.0
(CH), 125.9 (CH), 114.8 (CH2), 112.9 (CH2), 109.2 (CH2), 108.8
(CH2), 101.2 (CH), 100.9 (CH), 78.6 (CH), 78.5 (CH), 75.6
(CH), 75.4 (CH), 71.9 (CH2), 71.8 (CH2), 67.5 (CH), 67.4 (CH),
43.6 (CH2), 43.5 (CH2), 39.4 (CH2), 39.3 (CH2), 38.8 (2 × CH2),
35.3 (CH2), 34.3 (CH2), 34.2 (CH2), 20.7 (CH3), 20.6 (CH3),
18.6 (CH3), 18.1 (CH3), 17.7 (CH3), 17.3 (CH3); m/z (FAB)
found 495.2357 (M+), C29H35O7 requires 495.2383.
(3R)-5-Hydroxy-6-(hydroxymethyl)-3-isopropenyl-1-{5-[(2E)-
2-methyl-4-oxo-4-(phenylseleno)but-2-enyl]-2-oxo-2,5-dihydro-
furan-3-yl}hept-6-enyl acetate 36. Pyridinium p-toluene-
sulfonate (3.7 mg, 0.015 mmol) was added to a stirred solution
of the acetonide 35 (32 mg, 0.049 mmol) in dry methanol
(1.5 mL) at room temperature and the mixture was stirred
for 60 h and then evaporated in vacuo to leave an oil. Flash
chromatography with ethyl acetate as eluant gave the diol
(32 mg, 94%) as a colourless oil consisting of an inseparable
mixture of diastereoisomers. mmax/cm−1 (CDCl3 solution) 3600,
1761, 1693, 1618; dH(500 MHz): 7.53 (m, 2H, Ar–H), 7.42 (m,
(3R)-5-Hydroxy-3-isopropenyl-6-{[(4-methoxybenzyl)oxy]-
methyl}-1-{5-[(2E)-2-methyl-4-oxo-4-(phenylseleno)but-2-
=
3H, Ar–H), 7.12 (app. s, 0.5H, CH CCO(O)), 7.11 (app. s,
0.5H, CH CCO(O)), 6.29 (s, 0.5H, CHCOSe), 6.17 (s, 0.5H,
enyl]-2-oxo-2,5-dihydrofuran-3-yl}hept-6-enyl acetate 35.
A
=
solution of sodium chlorite (0.09 g, 0.98 mmol) and potassium
dihydrogen ortho phosphate (0.1 g, 0.77 mmol)21 in water
(3.2 mL) was added to a stirred solution of the aldehyde 34b
(54 mg, 0.11 mmol) in tert-butanol (6 mL) and 2-methyl-2-
butene (3 cm3) at room temperature. The mixture was stirred
for 7 h and then evaporated in vacuo. The aqueous residue was
extracted with diethyl ether (3 × 10 mL) and the combined
organic extracts were dried (MgSO4), and evaporated in vacuo
to leave the carboxylic acid 34c (quantitative conversion) as a
colourless oil.
=
C
CHCOSe), 5.41 (m, 1H, CH(O)CO), 5.12 (m, 3H, CH2
=
and CHOAc), 4.86 (4 × d, 2H, J 14.2, CH2 CCH3), 4.27
(m, 0.3H, CH2OH and CHOH), 3.12 (dt, 0.45H, J 9 and 3.9,
=
CHHC(CH3) ), 2.64 (m, 0.73H, CH2CHCH2), 2.53 (m, 0.55H,
=
=
CHHC(CH3) ), 2.45 (m, 1.27H, 1H × CHHC(CH3) and
0.27H × CH2CHCH2), 2.13, 2.12 and 2.04 (3 × s (1 : 2.5 :
=
4), 3H, CH3C CHCO), 1.96 (m, 1H, AcOCHCHH), 2.04,
2.03 and 1.95 (3 × s (1 : 1.7 : 2.7), 3H, CH3CO), 1.82 (m, 1H,
CHHCHOH), 1.75, 1.73, 1.71, 1.67 (4 × s (1 : 1 : 1.5 : 1.5),
=
3H, CH3C C), 1.65 (m, 2H, AcOCHCHH and CHHCHOH);
Tri-n-butylphosphine (0.03 mL, 0.12 mmol) was added drop-
wise over 5 min to a stirred solution of the carboxylic acid
(11.2 mg, 0.02 mmol) in dry CH2Cl2 (1.5 mL) at −30 ◦C. N-
Phenylselenophthalimide (36 mg, 0.12 mmo◦l) was added in one
portion and the mixture was stirred at −30 C for 2 min.22 The
cold bath was removed and the reaction immediately warmed to
room temperature. The solution was stirred at room temperature
for 25 min and then diluted with CH2Cl2 (5 mL) and extracted
with 5% potassium carbonate solution (5 mL). The aqueous
layer was further extracted with CH2Cl2 (2 × 5 mL) and the
combined organic extracts were dried (MgSO4), and evaporated
in vacuo to leave a yellow oil. Flash chromatography with
petroleum ether and then 20% diethyl ether in CH2Cl2 as eluant
gave the selenide (11 mg, 80%) as a pale yellow oil consisting of
an inseparable mixture of diastereoisomers. mmax/cm−1 (CDCl3
solution) 1760, 1691, 1617; dH(500 MHz): 7.52 (m, 2H, Ar–
H), 7.34 (m, 3H, Ar–H), 7.10 (dt, 0.37H, J 15.8 and 1.5,
dC(125 MHz): 190.8 (C) 189.8 (C), 170.8 (C), 170.3 (C), 169.9
(C), 169.8 (C), 152.3 (C), 150.5 (C), 149.4 (CH), 148.8 (CH),
148.1 (C), 147.9 (C), 144.9 (C), 135.8 (CH), 134.9 (C), 134.1
(C), 129.5 (2 × CH), 129.2 (CH), 129.0 (CH), 127.6 (CH), 127.2
(CH), 126.9 (CH), 126.8 (CH), 114.9 (CH2), 114.8 (CH2), 114.1
(CH2), 113.2 (CH2), 112.0 (CH2), 111.9 (CH2), 81.1 (CH), 78.6
(CH), 73.4 (CH), 73.3 (CH), 71.7 (CH), 67.6 (CH), 67.4 (CH),
67.2 (CH), 64.4 (CH2), 64.1 (CH2), 53.5 (CH2), 44.2 (CH2), 41.0
(2 × CH), 40.3 (CH), 40.2 (CH), 39.4 (CH), 38.3 (CH2), 36.5
(CH2), 36.3 (CH2), 36.0 (CH2), 35.8 (CH2), 29.8 (CH2), 26.9
(CH3), 21.0 (CH3), 20.9 (CH3), 20.6 (CH3), 17.9 (CH3), 17.8
(CH3), 17.4 (CH3), 17.3 (CH3); m/z (EI) found 580.1794 (M+),
C25H35SNO7Se requires 580.1804.
(3S)-3-Isopropenyl-6-{[(4-methoxybenzyl)oxy]methyl}-1-{(5R)-
5-[(2E)-2-methyl-4-oxo-4-(phenylseleno)but-2-enyl]-2-oxo-
2,5-dihydrofuran-3-yl}-5-oxohept-6-enyl acetate 18. PMB-
trichloroacetimidate (8.9 mg, 0.032 mmol) and p-toluenesulfonic
acid (0.6 mg, 0.003 mmol) were added to a stirred solution
of the diol 36 (16.9 mg, 0.03 mmol) in dry CH2Cl2 (0.8 mL)
and hexane (0.4 mL) at 0 ◦C, and the mixture was stirred at
this temperature for 70 h.23 The mixture was warmed to room
temperature and the solvent was then removed under reduced
pressure to leave the PMB ether 37 as an oil. A solution of
the PMB ether in dry CH2Cl2 (0.9 mL) was cooled to 0 ◦C,
and then Dess–Martin periodinane (16.2 mg, 0.038 mmol) was
=
=
CH CCO(O)), 7.08 (dt, 0.63H, J 15 and 1.4, CH CCO(O)),
6.26 (app. s, 0.5H, CHCOSe), 6.15 (app. s, 0.5H, CHCOSe),
5.71 (s, 0.16H, CHPh), 5.70 (s, 0.16H, CHPh), 5.65 (s, 0.34H,
CHPh), 5.64 (s, 0.34H, CHPh), 5.52 (app. d, 0.18H, J 9.2,
CH(O)CO), 5.45 (app. d, 0.47H, J 10.3, CH(O)CO), 5.39 (app.
=
d, 0.35H, J 10.6, CH(O)CO), 5.07–4.75 (m, 5H, CH2 CCH3,
=
CH2 C and CHOAc), 4.49 (m, 2H, CH2(O)CHPh), 4.36 (m,
0.35H, CH(O)CHPh), 4.24 (app. t, 0.65H, J 9.8, CH(O)CHPh),
=
3.12 (m, 0.57H, CHHC(CH3) ), 2.78 (m, 0.62H, CH2CHCH2),
2.61 (m, 0.38H, CH2CHCH2), 2.48 (m, 0.43H, CHHC(CH3) ),
◦
=
added and the mixture was stirred at 0 C for 5 min and then
=
2.40–2.35 (m, 1H, CHHC(CH3) ), 2.12 and 2.09 (3 × s (1 :
warmed to room temperature where it was stirred for a further
40 min. The solvent was removed under reduced pressure to
leave a colourless oil. Flash chromatography, first with 20%
diethyl ether in petroleum ether, then with 20% ethyl acetate
in petroleum ether as eluant, gave the enone (9.2 mg, 50%) as
a colourless oil. mmax/cm−1 (CDCl3 solution) 2957 1759, 1687,
1613; dH(500 MHz): 7.53 (m, 2H, 2H × PhSe), 7.41 (m, 3H,
3H × PhSe), 7.27 (m, 2H, 2H × C6H4OCH3), 7.09 (d, 0.9H, J
=
2.5 : 4), 3H, CH3C CCHCO), 2.04 (m, 1H, AcOCHCHH),
2.01 and 1.99 (3 × s, (1 : 2.3 : 3), 3H, CH3CO), 1.91
(m, 1H, CHHCH(O)CHPh), 1.76 (m, 2H, AcOCHCHH and
CHHCH(O)CHPh), 1.74 and 1.71 (2 × s (1 : 1.4), 3H,
=
CH3C C); dC(125 MHz): 190.7 (C), 189.8 (C), 170.8 (C), 170.2
(C), 169.9 (C), 169.8 (2 × C), 152.4 (C), 148.7 (CH), 148.1 (CH),
142 4 (2 × C), 138.5 (C), 135.8 (CH), 134.7 (C), 129.5 (2 ×
CH), 129.1 (CH), 129.0 (CH), 128.8 (2 × CH), 128.2 (CH),
127.6 (CH), 127.2 (CH), 126.2 (CH), 126.1 (CH), 126.0 (2 ×
CH), 114.9 (CH2), 114.8 (CH2), 108.9 (CH2), 108.8 (CH2), 101.1
(CH), 81.1 (CH), 78.6 (CH), 75.7 (CH), 75.6 (CH), 75.5 (CH),
72.0 (CH2), 71.9 (CH2), 67.7 (CH), 67.6 (2 × CH), 67.5 (CH),
44.1 (CH2), 39.0 (2 × CH), 38.9 (CH), 38.3 (CH2), 36.6 (CH2),
36.4 (CH2), 34.4 (CH2), 34.3 (CH2), 27.0 (CH3), 20.9 (CH3),
20.8 (2 × CH3), 20.7 (CH3), 20.6 (2 × CH3), 17.5 (CH3), 17.4
=
=
12, CH CCO(O)), 7.06 (d, 0.1H, J 11.7, CH CCO(O)), 6.89
(m, 2H, 2H × C6H4–OCH3), 6.26 (app. s, 0.6H, CHCOSe),
=
6.16–6.01 (m, 2.4H, 2 × H, CH2 C(CH3), 0.4H CHCOSe),
5.43 (app. d, 0.4H, J 9.5, CH(O)CO), 5.38 (app. d, 0.6H, J
10.5, CH(O)CO), 5.07 (m, 1H, CHOAc), 4.79 (2 × d, 2H, J
=
15.2, CH2 C(CH3)), 4.50 (app. d, 2H, J 7.1, CH2C6H4–OCH3),
4.20 (app. d, 2H, J 6.2, CH2OPMB), 3.81 (s, 3H, OCH3), 3.12
(m, 0.6H, CHHC(CH3) ), 2.89 (m, 1H, CH2CHCH2), 2.81
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 9 5

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=
=
(m, 0.4H, CHHC(CH3) ), 2.70 (m, 1H, CHHCOC C), 2.52
to leave the epoxide (1.15 g, 84%) as a yellow oil which was
used without purification in the next step. A small sample
was purified by chromatography to leave the epoxide as a pale
yellow oil. [a]D22 +18.4 (c 0.3 in CH2Cl2); mmax/cm−1: 3057, 1618,
=
=
(m, 1H, CHHC(CH3) ), 2.43 (m, 1H, CHHCOC C), 2.07
(m, 1H, AcOCHCHH), 2.13 and 2.05 (2 × s (1.7 : 2.7), 3H,
=
CH3CO), 1.94 (s, 3H, CH3C ), 1.74, 1.73, 1.71 and 1.70 (4 × s
=
=
(1 : 1 : 1.5 : 1.5), 3H, CH3C C), 1.63 (m, 1H, AcOCHCHH);
1277; dH(360 MHz): 6.10–6.09 (m, 1H, CH), 3.05–3.00 (m,
dC(125 MHz): 199.6 (C), 193.9 (C), 190.7 (C), 189.8 (C), 170.7
(C), 169.9 (C), 169.8 (C), 152.3 (CH), 149.8 (CH), 148.7 (C),
147.8 (C), 145.3 (C), 144.8 (C), 135.8 (CH), 134.8 (C), 134.0
(C), 130.3 (CH), 130.2 (CH), 129.6 (CH), 129.5 (CH), 129.4
(CH), 129.1 (CH), 129.0 (CH), 127.2 (CH), 126.8 (CH), 126.7
(CH), 124.9 (CH2), 124.7 (CH2), 113.9 (CH), 113.8 (CH2), 113.1
(CH2), 81.1 (CH), 78.6 (CH), 72.7 (CH2), 67.7 (CH), 67.4 (CH),
67.2 (CH), 55.4 (CH3), 44.1 (CH2), 42.2 (CH2), 39.3 (CH), 39.1
(CH), 38.3 (CH2), 35.7 (CH2), 35.5 (CH2), 29.8 (CH2), 27.0
(CH3), 22.8 (CH3), 20.9 (CH3), 20.8 (CH3), 20.6 (CH3), 18.8
(CH3), 18.6 (CH3), 14.2 (CH3).
1H, CHO), 2.82–2.80 (m, 1H, CHHO), 2.52 (dd, 1H, J 5.0 and
=
2.6, CHHO), 2.50–2.36 (m, 2H, CH2), 1.94 (s, 3H, CCH3);
dC(90 MHz): 143.9 (C), 77.1 (CH), 50.3 (CH), 46.5 (CH2), 42.1
(CH2), 24.4 (CH3); m/z (EI) found 223.9694 (M+), C6H9OI
requires 223.9698.
(S)-5-((E)-3-Iodo-2-methylallyl)dihydrofuran-2-one 49.
A
solution of n-BuLi (2.5 M) in hexanes (2.2 mL) was added
dropwise over 5 min to a stirred solution of ethoxyacetylene (50%
solution w/w in hexanes, 1.3 mL, 6.7 mmol) in THF (7.4 mL) at
−78 ◦C under a nitrogen atmosphere. The mixture was stirred at
−78 ◦C for 20 min and then freshly distilled BF3·Et2O (0.7 mL,
5.6 mmol) was added via syringe over 1 min. The mixture was
stirred at −78 ◦C for 2 min and then a solution of the epoxide
48 (0.50 g, 2.2 mmol) in THF (3.7 mL) was added dropwise
over 5 min. The reaction was stirred at −78 ◦C for 2 h and
then quenched by the addition of a saturated aqueous solution
of NaHCO3 (50 mL). The resulting mixture was diluted with
Et2O (50 mL) and water (40 mL), and the separated aqueous
layer was then extracted with Et2O (2 × 80 mL). The combined
organic extracts were dried (MgSO4) and concentrated in vacuo.
p-Toluenesulfonic acid (30 mg) was added to the residue and
the mixture was dissolved in EtOH (10 mL) and stirred at room
temperature for 2 h. The solvent was removed in vacuo and the
residue was dissolved in CHCl3 (20 mL) and heated under reflux
for 16 h. The reaction was cooled to room temperature and
then quenched with a saturated aqueous solution of NaHCO3
(5 mL). The separated aqueous layer was extracted with CHCl3
(3 × 30 mL) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. Chromatography of the
residue (petroleum ether–Et2O 1 : 1) gave the lactone (0.49 g,
82%) as an oil. [a]D22 +41.8 (c 3.5 in CH2Cl2);32 mmax/cm−1: 1759;
(R)-1-Chloropent-4-yn-2-ol 46b. 2 M Hydrochloric acid
(12.7 mL, 25.3 mmol) was added to TBAF (1 M solution in THF,
13.2 g, 50.6 mmol), and the resulting yellow solution was added
in one portion to (R)-1-chloro-5-(trimethylsilyl)pent-4-yn-2-ol
46a30 (4.88 g, 25.3 mmol). The mixture was stirred at room
temperature for 40 h, and then diluted with Et2O (100 mL) and
water (50 mL). The separated aqueous layer was extracted with
Et2O (2 × 100 mL), and the combined organic extracts were then
dried (MgSO4) and concentrated in vacuo. Chromatography of
the residue (petroleum ether–Et2O 1 : 1) followed by bulb-to-
bulb distillation (water pump, 18 mmHg, 80 to 120 ◦C) gave the
acetylene (1.5 g, 50%) as a colourless oil. [a]2D2 −15.1 (c 2.9 in
CH2Cl2); mmax/cm−1: 3581, 3305, 2127; dH(360 MHz): 3.97–3.92
(m, 1H, CHOH), 3.65 (dd, 1H, J 11.1 and 4.5, CHHCl), 3.58
(dd, 1H, J 11.1 and 6.0, CHHCl), 2.77 (m, 1H, OH), 2.49–2.46
(m, 2H, CH2C≡), 2.04 (t, 1H, J 2.7, ≡CH); dC(90 MHz): 79.1
(C), 71.3 (CH), 69.5 (CH), 48.0 (CH2), 24.1 (CH2); m/z (EI)
found 118.0183 (M+), C5H7OCl requires 118.0185.
(R)-(E)-1-Chloro-5-iodo-4-methylpent-4-en-2-ol 47. A solu-
tion of trimethylaluminium (2 M) in hexanes (5.7 mL)
was added dropwise over 5 min to a stirred solution of
bis(cyclopentadienyl)zirconium dichloride (1.11 g, 3.8 mmol)31
in anhydrous CH2Cl2 (15 mL) under a nitrogen atmosphere. The
mixture was stirred at room temperature for 15 min, then cooled
to 0 ◦C. A solution of the acetylene 46b (0.45 g, 3.8 mmol)
in anhydrous CH2Cl2 (5 mL) was added dropwise via syringe
over 5 min and the orange solution was stirred in the dark
at room temperature for 72 h and then cooled to −30 ◦C. A
solution of I2 (2.41 g, 9.5 mmol) in THF (10 mL) was added
dropwise via syringe over 5 min and the dark solution was
stirred at −30 ◦C for 10 min and then allowed to warm to room
temperature over 2 h. The mixture was carefully quenched by the
addition of a saturated aqueous solution of K2CO3 (5 mL), then
treated with MgSO4 and stirred for 10 min. The mixture was
filtered and the filtrate was concentrated in vacuo. The resulting
heterogeneous residue was triturated with Et2O (250 mL) and
the combined organic extracts were then concentrated in vacuo.
Chromatography of the residue (petroleum ether–Et2O 2 : 1)
gave the vinyl iodide (0.61 g, 60%) as a pale yellow oil. [a]2D2 −2.3
(c 3.3 in CHCl3); mmax/cm−1: 3572, 1615; dH(360 MHz): 6.08–
=
dH(360 MHz): 6.11–6.10 (m, 1H, CH), 4.67–4.59 (m, 1H,
CHO), 2.67 (dd, 1H, J 14.2 and 7.4, CCHH), 2.57–2.48 (m,
=
=
3H, CCHH and CH2CO), 2.37–2.28 (m, 1H, CHHCH2CO),
1.94–1.83 (m, 4H, CCH3 and CHHCH2CO); dC(90 MHz):
176.5 (C), 142.6 (C), 78.5 (CH), 78.2 (CH), 44.8 (CH2), 28.4
(CH2), 27.5 (CH2), 24.3 (CH3); m/z (EI) found 265.9808 (M+),
C8H11O2I requires 265.9804.
=
(R)-5-((E)-3-Iodo-2-methylallyl)-3-phenylselanyldihydrofuran-
2-one 44. A solution of the lactone 49 (100 mg, 0.40 mmol)
in THF (2.0 mL) was added dropwise over 10 min via syringe
to a stirred solution of LiHMDS (1.0 M in THF, 0.38 mL,
0.38 mmol) in THF (2.0 mL) at −78 ◦C under a nitrogen
atmosphere. The mixture was stirred at −78 ◦C for 10 min,
and then a solution of PhSeBr (89 mg, 0.38 mmol) in THF
(2 mL) was added via syringe over 1 min. This mixture was
stirred at −78 ◦C for 50 min, then quenched by the addition of
a saturated aqueous solution of NH4Cl (15 mL) and allowed to
warm to room temperature over 5 min. The resulting solution
was diluted with water (20 mL) and Et2O (50 mL), and the
separated aqueous layer was then extracted with Et2O (3 ×
40 mL). The combined organic extracts were dried (MgSO4)
and concentrated in vacuo. Chromatography of the residue
(petroleum ether–Et2O 4 : 1) gave the phenylselenolactone
(80 mg, 51%, 75% based on recovered starting material)
separated as two diastereomers.
In an alternative procedure, a solution of the lactone 49
(400 mg, 1.50 mmol) in THF (3.0 mL) was added dropwise
over 10 min via syringe to a stirred solution of LiHMDS (1.0 M
in THF, 1.65 mL, 1.65 mmol) in THF (3.0 mL) at −78 ◦C
under a nitrogen atmosphere. The mixture was stirred at −78 ◦C
for 15 min, and then TMSCl (0.21 mL, 1.65 mmol) was added
dropwise over 1 minute. The mixture was stirred at −78 ◦C for
30 min and then a solution of PhSeBr (389 mg, 1.65 mmol) in
=
6.06 (m, 1H, CH), 4.05–3.95 (m, 1H, CHOH), 3.59 (dd, 1H, J
11.3 and 3.9, CHHCl), 3.49 (dd, 1H, J 11.3 and 6.1, CHHCl),
2.47–2.40 (m, 3H, CH2C and OH), 1.88 (s, 3H, CCH3);
dC(90 MHz): 143.5 (C), 78.3 (CH), 68.9 (CH), 49.3 (CH2), 43.9
(CH2), 24.1 (CH3); m/z (EI) found 259.9465 (M+), C6H10OClI
requires 259.9465.
=
=
(R)-2-((E)-3-Iodo-2-methylallyl)oxirane 48. Powdered
NaOH (0.73 g, 18.3 mmol) was added in one portion to a
stirred solution of the chlorohydrin 47 (1.59 g, 6.1 mmol) in
Et2O (32 mL) under a nitrogen atmosphere. The mixture was
stirred at room temperature for 16 h and then filtered through
Celite using Et2O as eluent. The solvent was removed in vacuo
2 7 9 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

View Article Online
THF (3 mL) was added via syringe over 1 minute. The resulting
mixture was stirred at −78 ◦C for 30 min, then allowed to warm
to room temperature over 30 min and quenched by the addition
of a saturated aqueous solution of NH4Cl (15 mL). The solution
was diluted with water (40 mL) and Et2O (80 mL), and the
separated aqueous layer was then extracted with Et2O (3 ×
80 mL). The combined organic extracts were dried (MgSO4)
and concentrated in vacuo. Chromatography of the residue
(petroleum ether–Et2O 4 : 1) separated the diastereoisomers
of the phenylselenolactone (447 mg, 71%): (i) [a]2D2 +38.3 (c 0.2
in CH2Cl2); mmax/cm−1: 1765; dH(360 MHz): 7.72–7.69 (m, 2H,
wR(all F2) was 0.0789. No meaningful Flack parameter could
be obtained for this experiment.†
2-{(S)-2-[1-((S)-4-Isopropyl-2-oxooxazolidin-3-yl)-methanoyl]-
3-methylbut-3-enyl}furan-3-carboxylic acid ethyl ester 55a.
A
solution of the chiral imide 5435 (5 g, 23.7 mmol) in THF (60 mL)
was added dropwise via cannula over 20 min to a stirred solution
of NaHMDS (2 M solution in THF, 14.7 mL, 29.5 mmol) in
THF (250 mL) at −78 ◦C under a nitrogen atmosphere. The
mixture was stirred at −78 ◦C for 1 h and then a solution
of 2-bromomethylfuran-3-carboxylic acid ethyl ester36 (8.9 g,
38.4 mmol) in THF (60 mL) was added via cannula over 20 min.
The solution was warmed from −78 ◦C to −20 ◦C over 4 h, then
quenched with a saturated aqueous solution of NH4Cl (100 mL)
and diluted with Et2O (100 mL) and water (100 mL). The sepa-
rated aqueous layer was extracted with Et2O (3 × 300 mL) and
the combined organic extracts were then dried (MgSO4) and con-
centrated in vacuo. Chromatography of the residue (petroleum
ether–Et2O5 : 1 to 3 : 1) gave the substituted furan(5.9g, 68%)as a
colourless oil. (Found: C, 63.0; H, 7.0; N, 3.7 C19H25NO6 requires
C, 62.8; H, 6.9; N, 3.85); [a]2D2 +125.7 (c 2.9 in CH2Cl2); mmax/cm−1
(CDCl3 solution): 1781, 1707, 1600; dH(360 MHz): 7.22 (d, 1H, J
=
ArH), 7.43–7.29 (m, 3H, ArH), 6.06 (m, 1H, CH), 4.43–4.35
(m, 1H, CHO), 3.96 (dd, 1H, J 5.1 and 5.1, CHSe), 2.61 (ddd,
=
1H, J 14.4, 7.3 and 0.6, CHHCHO), 2.45 (ddd, 1H, J 14.4, 5.5
=
and 0.6, CHHCHO), 2.37–2.33 (m, 2H, CH2CHSe), 1.85 (m,
=
3H, CCH3); dC(90 MHz): 175.2 (C), 142.3 (C), 135.8 (CH),
129.4 (CH), 129.2 (CH), 126.4 (C), 78.6 (CH), 76.8 (CH), 44.4
(CH2), 36.5 (CH), 36.2 (CH2), 24.1 (CH3); m/z (EI) 421.9289,
(M+, C14H15O2SeI requires 421.9282); (ii) [a]2D2 +48.0 (c 0.2 in
CH2Cl2); mmax/cm−1: 1767; dH(360 MHz): 7.70–7.68 (m, 2H,
=
ArH), 7.42–7.35 (m, 3H, ArH), 6.00 (m, 1H, CH), 4.59–
4.51 (m, 1H, CHO), 4.03 (dd, 1H, J 9.3 and 9.3, CHSe),
2.80–2.72 (m, 1H, CHHCHSe), 2.47 (ddd, 1H, J 14.4, 7.3
=
=
1.9, OCH CH), 6.66 (d, 1H, J 1.9, OCH CH), 4.96–4.90 (m,
3H, CH2 and CHCON), 4.45–4.41 (m, 1H, CHN), 4.32 (q,
=
=
and 0.7, CHHCHO), 2.32 (ddd, 1H, J 14.4, 5.7 and 0.7,
=
CHHCHO), 2.01–1.92 (m, 1H, CHHCHSe), 1.83 (m, 3H,
=
2H, J 7.1, CH3CH2O), 4.27–4.16 (m, 2H, OCH2), 3.56 (dd, 1H,
J 15.3 and 9.3, furan CHH), 3.40 (dd, 1H, J 15.3 and 5.4, furan
CHH), 2.38–2.29 (m, 1H, CH(CH3)2), 1.84 (s, 3H, CCH3), 1.37
(t, 3H, J 7.1, CH3CH2O), 0.89 (d, 3H, J 7.0, CHCH3), 0.82 (d,
3H, J 7.0, CHCH3); dC(90 MHz) 172.0 (C), 163.5 (C), 159.5 (C),
153.4 (C), 142.2 (C), 140.5 (CH), 114.1 (C), 113.8 (CH2), 110.8
(CH), 62.9 (CH2), 60.1 (CH2), 58.6 (CH), 48.3 (CH), 29.3 (CH2),
28.2 (CH), 21.0 (CH3), 17.7 (CH3), 14.3 (CH3), 14.2 (CH3); m/z
(ES) found 364.1738 (M+ + H), C19H26NO6 requires 364.1760.
CCH3); dC(90 MHz): 175.3 (C), 142.2 (C), 135.8 (CH), 129.4
=
(CH), 129.1 (CH), 126.7 (C), 78.8 (CH), 76.6 (CH), 44.8 (CH2),
36.9 (CH), 35.1 (CH2), 24.1 (CH3); m/z (EI) found 421.9279
(M+), C14H15O2SeI requires 421.9282.
2-{(S)-2-[1-((S)-4-Isopropyl-2-oxooxazolidin-3-yl)methanoyl]-
3-methylbut-3-enyl}furan-3-carboxylic acid methyl ester 55b.
A solution of the chiral imide 5435 (5 g, 23.7 mmol) in THF
(60 mL) was added dropwise via cannula over 20 min to a
stirred solution of NaHMDS (1 M solution in THF, 26.1 mL,
26.1 mmol) in THF (250 mL) at −78 ◦C under a nitrogen
atmosphere. The mixture was stirred at −78 ◦C for 1 h and then
a solution of 2-bromomethylfuran-3-carboxylic acid methyl
ester 44 (6.23 g, 28.4 mmol) in THF (60 mL) was added via
cannula over 20 min. The solution was warmed from −78 ◦C to
−20 ◦C over 4 h, then quenched by the addition of a saturated
aqueous solution of NH4Cl (100 mL) and finally diluted with
Et2O (100 mL) and water (100 mL). The separated aqueous
layer was extracted with Et2O (3 × 300 mL) and the combined
organic extracts were then dried (MgSO4) and concentrated in
vacuo. Chromatography of the residue (petroleum ether–Et2O 5 :
1 to 3 : 1) gave the substituted furan (5.6 g, 61%) as a colourless
solid, mp 59–61 ◦C. (Found: C, 61.9; H, 6.7; N, 4.0 C18H23NO6
requires C, 61.9; H, 6.6; N, 4.0); [a]2D2 +76.5 (c 0.7 in CH2Cl2);
mmax/cm−1 (CDCl3 solution): 1766, 1733, 1683; dH(360 MHz):
2-((S)-2-Hydroxymethyl-3-methylbut-3-enyl)furan-3-carboxylic
acid ethyl ester 56. A solution of Super Hydride (1 M) in
THF (29.7 mL) was added dropwise via syringe over 5 min to a
stirred solution of the imide 55a (4.9 g, 13.5 mmol) in anhydrous
toluene (210 mL) at −78 ◦C under a nitrogen atmosphere. The
mixture was stirred at −78 ◦C for 30 min and then quenched by
the careful addition of a saturated aqueous solution of NH4Cl
(80 mL). The resulting mixture was allowed to warm to room
temperature over 10 min and then diluted with Et2O (200 mL)
and water (80 mL). The separated aqueous layer was extracted
with Et2O (3 × 250 mL) and the combined organic extracts were
dried (MgSO4) and concentrated in vacuo. Chromatography of
the residue (petroleum ether–Et2O 1 : 1) gave the alcohol (2.4 g,
75%) as a colourless oil. (Found C, 65.5; H, 7.7; C13H18O4
requires C, 65.5; H, 7.6); [a]2D2 +1.9 (c 0.4 in EtOH); mmax/cm−1
(CDCl3 solution): 3418, 1713, 1646, 1599; dH(360 MHz): 7.26
=
=
7.21 (d, 1H, J 1.9, OCH CH), 6.63 (d, 1H, J 1.9, OCH CH),
4.94–4.88 (m, 3H, CH2 and CHCON), 4.44–4.40 (m, 1H,
=
=
(m, 1H, J 2.0, OCH CH), 6.66 (d, 1H, J 2.0, OCH CH),
=
=
=
4.91 (dd, 1H, J 1.3 and 1.3, CHH), 4.81 (s, 1H, CHH), 4.32
(q, 2H, J 7.1, CH3CH2O), 3.59 (d, 2H, J 5.9, CH2OH), 3.23
(dd, 1H, J 14.4 and 8.2, furan CHH), 3.12 (dd, 1H, J 14.4 and
CHN), 4.26–4.15 (m, 2H, OCH2), 3.84 (s, 3H, OCH3), 3.55
(dd, 1H, J 15.4 and 9.4, furan CHH), 3.38 (dd, 1H, J 15.4
and 5.3, furan CHH), 2.36–2.27 (m, 1H, CH(CH3)2), 1.84 (s,
=
6.6, furan CHH), 2.73–2.69 (m, 1H, CHC ), 2.24–2.27 (m,
=
3H, CCH3), 0.88 (d, 3H, J 7.0, CHCH3), 0.80 (d, 3H, J 7.0,
=
1H, OH), 1.80 (s, 3H, CCH3), 1.37 (t, 3H, J 7.1, CH3CH2O);
CHCH3); dC(90 MHz) 171.2 (C), 163.1 (C), 159.2 (C), 152.9
(C), 141.9 (C), 140.3 (CH), 113.3 (C), 113.0 (CH2), 110.2 (CH),
62.5 (CH2), 58.1 (CH), 50.6 (CH3), 47.7 (CH), 28.8 (CH2), 27.7
(CH), 20.4 (CH3), 17.0 (CH3), 13.8 (CH3); m/z (ES) found
372.1411 (M+ + Na), C18H23NO6Na requires 372.1423.
dC(90 MHz): 164.3 (C), 160.9 (C), 144.6 (C), 140.7 (CH), 114.2
(C), 112.9 (CH2), 110.4 (CH), 62.9 (CH2), 60.3 (CH2), 48.0
(CH), 27.8 (CH2), 20.2 (CH3), 14.2 (CH3); m/z (ES) found
237.1108 (M+ − H), C13H18O4Na requires 237.1126.
Reduction of 55b, under the same conditions, gave the methyl
ester analogous to 56. (Found: C, 63.9; H, 7.2, C12H16O4 requires
C, 64.3; H, 7.2); [a]2D2 −4.2 (c 0.2 in CH2Cl2); mmax/cm−1 (CDCl3
solution): 3623, 3488, 1766, 1733, 1683; dH(360 MHz): 7.28 (d,
X-Ray crystal structure of 55b. A crystal was encapsulated
in a film of RS3000 perfluoropolyether oil and mounted on a
dual-stage glass fibre before transfer to the diffractometer.
=
=
1H, J 2.0, OCH CH), 6.65 (d, 1H, J 2.0, OCH CH), 4.92–
=
=
Crystal data. C18H23NO6, M = 349.37, orthorhombic, a =
4.91 (m, 1H, CHH), 4.82–4.81 (m, 1H, CHH), 3.84 (s, 3H,
OCH3), 3.60 (d, 2H, J 5.9, CH2OH), 3.23 (dd, 1H, J 14.5 and
8.0, furan CHH), 3.13 (dd, 1H, J 14.4 and 6.7 furan CHH), 2.75–
3
˚
˚
10.816(2), b = 16.904(3), c = 19.350(4) A, U = 3538(2) A , T =
150(2) K, space group P212121 (No. 19), Z = 8, Dc = 1.312 g cm−3,
l(Mo-Ka) = 0.099 mm−1, 8076 unique reflections measured and
used in all calculations. Final R1 [5911 F ≥ 4U(F)] = 0.0400 and
=
=
2.67 (m, 1H, CHC C), 1.80 (s, 3H, CCH3); dC(90 MHz): 164.9
(C), 161.2 (C), 144.7 (C), 141.0 (CH), 114.0 (C), 113.1 (CH2),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 9 7

View Article Online
=
110.5 (CH), 63.0 (CH2), 51.6 (CH3), 48.1 (CH), 28.0 (CH2), 20.4
(CH3).
3493, 1621; dH(360 MHz): 7.29 (d, 1H, J 1.8, OCH CH), 6.37
(d, 1H, J 1.8, OCH CH), 4.94 (dd, 1H, J 1.4 and 1.4, CHH),
=
=
=
4.86 (s, 1H, CHH), 4.41 (s, 2H, CH2OH), 2.89–2.79 (m, 3H,
furan CH2 and CHC ), 2.49–2.38 (m, 3H, CH2CN and OH),
1.78–1.77 (m, 3H, CCH3); dC(90 MHz): 148.9 (C), 143.8 (C),
141.2 (CH), 120.9 (C), 118.4 (C), 113.1 (CH2), 110.7 (CH), 55.8
(CH2), 41.9 (CH), 29.3 (CH2), 20.8 (CH2), 19.9 (CH3); m/z (ES)
found 269.1261 (M+ + CH3CN + Na), C14H18O2N2Na requires
269.1265.
=
(S)-3-(3-Hydroxymethylfuran-2-ylmethyl)-4-methylpent-4-
enenitrile 57a. Triethylamine (2.2 mL, 16.1 mmol), DMAP
(0.20 g, 1.7 mmol) and tosyl chloride (1.84 g, 9.6 mmol) were
added sequentially to a stirred solution of the alcohol 56
(1.80 g, 8.6 mmol) in CH2Cl2 (45 mL) at room temperature
under a nitrogen atmosphere The reaction was stirred at room
temperature for 16 h, then diluted with CH2Cl2 (40 mL) and
washed successively with aqueous citric acid (10% w/w, 80 mL)
and a saturated aqueous solution of NaHCO3 (50 mL). The
separated organic layer was dried (MgSO4) and concentrated
in vacuo to leave the corresponding tosylate (2.2 g, 75%) as
a brown oil, which was used without purification in the next
step. A sample was purified by chromatography to leave the
corresponding tosylate as a pale yellow oil. (Found C, 61.15;
H, 6.1, C20H24O6S requires C, 61.2; H, 6.2); [a]2D2 −2.7 (c 3.8
in CH2Cl2); mmax/cm−1: 1698, 1595; dH(360 MHz): 7.77 (d,
2H, J 8.4, ArH), 7.34 (d, 2H, J 8.4, ArH), 7.23 (d, 1H, J
=
(S)-3-[3-(tert-Butyldimethylsilyloxymethyl)furan-2-ylmethyl]-
4-methylpent-4-enenitrile 57b. Triethylamine (3.0 mL,
21.4 mmol), DMAP (0.26 g, 2.1 mmol) and TBSCl (1.94 g,
11.7 mmol) were added sequentially to a stirred solution of the
furanyl alcohol 57a (2.20 g, 10.7 mmol) in anhydrous CH2Cl2
(80 mL) at room temperature under a nitrogen atmosphere.
The mixture was stirred at room temperature for 20 h and then
diluted with CH2Cl2 (100 mL) and water (80 mL). The separated
aqueous layer was extracted with CH2Cl2 (3 × 100 mL) and
the combined organic extracts were washed with NaHCO3
(100 mL), dried (MgSO4) and concentrated in vacuo to leave the
silyl ether (3.1 g, 91%) as an oil, which was used without further
purification. A sample was purified by chromatography to leave
the silyl ether as a colourless oil. (Found: C, 67.6; H, 9.2; N, 4.2
C18H29NO2Si requires C, 67.7; H, 9.1; N, 4.4); [a]2D2 −2.2 (c 2.7
in CH2Cl2); mmax/cm−1: 1649; dH(360 MHz): 7.30 (d, 1H, J 1.8,
OCH CH), 6.34 (d, 1H, J 1.8, OCH CH), 4.98 (dd, 1H, J 1.3
and 1.3, CHH), 4.91 (s, 1H, CHH), 4.54 (s, 2H, CH2OH),
2.92–2.81 (m, 3H, furan CH2 and CHC ), 2.53–2.38 (m, 2H,
CH2CN), 1.80 (s, 3H, CCH3); 0.94 (s, 9H, SiC(CH3)3), 0.12
(s, 6H, Si(CH3)2); dC(90 MHz): 148.3 (C), 143.8(C), 140.9 (CH),
121.1 (C), 118.3 (C), 113.2 (CH2), 110.9 (CH), 56.9 (CH2),
42.3 (CH), 29.7 (CH2), 25.8 (CH3), 20.9 (CH2), 19.9 (CH3),
18.2 (C), −5.2 (CH3); m/z (EI) found 262.1257 (M+ − C4H9),
C15H23O2SiN requires: 262.1263.
=
=
2.0, OCH CH), 6.63 (d, 1H, J 2.0, OCH CH), 4.81–4.80
(m, 1H, CHH), 4.71–4.70 (m, 1H, CHH), 4.29 (q, 2H,
J 7.1, CH3CH2O), 4.02–3.98 (m, 2H, CH2OTs), 3.13–3.11
=
=
=
(m, 2H, furan CH2), 2.94–2.88 (m, 1H, CHC ), 2.47 (s, 3H,
ArCH3), 1.64 (s, 3H, CCH3), 1.35 (t, 3H, J 7.1, CH3CH2O);
=
dC(90 MHz): 163.6 (C), 159.3 (C), 144.7 (C), 142.3 (C), 140.8
(CH), 132.8 (C), 129.7 (CH), 127.9 (CH), 114.5 (C), 113.9
(CH2), 110.6 (CH), 70.9 (CH2), 60.2 (CH2), 44.8 (CH), 28.2
(CH2), 21.6 (CH3), 19.6 (CH3), 14.2 (CH3); m/z (ES) found
415.1222 (M+ + Na), C20H24O6SNa requires 415.1191.
=
=
=
=
=
=
A solution of DIBAL (1.5 M) in toluene (28.6 mL) was added
dropwise over 5 min to a stirred solution of the furanyl ester
tosylate (5.4 g, 14.3 mmol) in anhydrous CH2Cl2 (175 mL) at
◦
−78 C under a nitrogen atmosphere. The mixture was stirred
at −78 ◦C for 1 h and then quenched by the careful addition of
a saturated aqueous solution of NH4Cl (50 mL). The mixture
was warmed to room temperature, and then filtered through a
pad of Celite. The residual cake was washed with CH2Cl2 (3 ×
150 mL) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo to leave toluene-4-sulfonic
acid (S)-2-[3-(hydroxymethyl)furan-2-ylmethyl]-3-methylbut-3-
enyl ester (3.9 g, 78%) as a yellow oil, which was used without
further purification. A sample was purified by chromatography
to leave the corresponding furanylmethanol as a colourless oil.
(Found C, 61.6; H, 6.4; C18H22O5S requires C, 61.7; H, 6.3); [a]D22
+1.9 (c 0.4 in EtOH); mmax/cm−1: 3672, 3609, 1598; dH(360 MHz):
7.78 (d, 2H, J 8.3, ArH), 7.36 (d, 2H, J 8.3, ArH), 7.24 (d,
(R)-3-[3-(tert-Butyldimethylsilyloxymethyl)furan-2-ylmethyl]-
4-methylpent-4-enal 58. A solution of DIBAL in toluene
(1.5 M, 3.8 mL) was added dropwise over 5 min via syringe to
a stirred solution of the◦nitrile 57b (1.50 g, 4.7 mmol) in dry
toluene (32 mL) at −78 C under a nitrogen atmosphere. The
mixture was allowed to warm to 0 ◦C over 4 h, then treated with
MeOH (2 mL) and stirred at 0 ◦C for 10 min. A suspension of
silica (37.5 g) in ethyl acetate (100 mL) was added to the mixture
and the resulting suspension was stirred at room temperature
for 1 h. The mixture was filtered and then water (20 mL) was
added to the filtrate. The separated aqueous layer was extracted
with Et2O (3 × 100 mL) and the combined organic extracts
were dried (MgSO4) and concentrated in vacuo to leave the
aldehyde (1.35 g, 89%) as a pale yellow oil which was used
without purification. A sample was purified by chromatography
to leave the aldehyde as a colourless oil. [a]2D2 +11.2 (c 1.1 in
CH2Cl2); mmax/cm−1: 1722, 1647; dH(360 MHz): 9.57 (dd, 1H,
J 2.2 and 2.2, CHO), 7.28 (d, 1H, J 1.8, OCH CH), 6.33 (d,
1H, J 1.8, OCH CH), 4.83 (dd, 1H, J 1.3 and 1.3, CHH),
4.80 (s, 1H, CHH), 4.51 (s, 2H, CH2OTBS), 3.13–3.05 (m,
1H, CHC ), 2.84 (dd, 1H, J 14.6 and 6.1, furan CHH), 2.72
(dd, 1H, J 14.6 and 8.7, furan CHH), 2.49 (dd, 2H, J 7.3 and
2.1, CH2CHO), 1.76 (s, 3H, CCH3), 0.94 (s, 9H, SiC(CH3)3),
0.12 (s, 6H, Si(CH3)2); dC(90 MHz): 201.7 (CH), 149.3 (C),
145.9 (C), 140.7 (CH), 120.8 (C), 112.1 (CH2), 111.0 (CH), 57.0
(CH2), 46.5 (CH2), 40.8 (CH), 30.8 (CH2), 25.9 (CH3), 19.9
(CH3), 18.4 (C), −5.2 (CH3); m/z (EI) found 322.1955 (M+),
C18H30O3Si requires 322.1964.
=
=
1H, J 1.8, OCH CH), 6.37 (d, 1H, J 1.8, OCH CH), 4.85
(dd, 1H, J 1.3 and 1.3, CHH), 4.69 (s, 1H, CHH), 4.48–
4.39 (m, 2H, CH2OH), 4.03–3.99 (m, 2H, CH2OTs), 2.88–2.70
(m, 3H, furan CH2 and CHC ), 2.47 (s, 3H, ArCH3), 1.64
(s, 3H, CCH3); dC(90 MHz): 149.3 (C), 144.8(C), 143.0 (C),
141.0 (CH), 132.6 (C), 129.7 (CH), 127.8 (CH), 120.7 (C), 113.3
(CH2), 110.8 (CH), 70.7 (CH2), 56.1 (CH2), 44.6 (CH), 26.7
(CH2), 21.5 (CH3), 20.5 (CH3); m/z (ES) found 373.1080 (M+ +
Na), C18H22O5SNa requires 373.1086.
=
=
=
=
=
=
=
=
=
Tetra-n-ethylammonium cyanide (3.33 g, 21.4 mmol) was
added portionwise over 5 min to a stirred solution of the above
tosylate (2.49 g, 7.1 mmol) in anhydrous DMSO (40 mL) at
room temperature under a nitrogen atmosphere. The mixture
was warmed to 60 ◦C, stirred for 1 h at this temperature, and then
recooled to room temperature and diluted with Et2O (300 mL)
and water (40 mL). The separated aqueous layer was extracted
with ethyl acetate (3 × 100 mL) and the combined organic
extracts were then washed successively with water (50 mL) and
brine (50 mL). The organic extracts were dried (MgSO4) and
concentrated in vacuo to leave the nitrile as a pale yellow oil
(1.0 g, 69%) which was used without further purification. A
sample was purified by chromatography to leave the nitrile as
a colourless oil. [a]2D2 −7.6 (c 2.1 in CH2Cl2); mmax/cm−1: 3611,
=
(S)-3-[3-(tert-Butyldimethylsilyloxymethyl)furan-2-ylmethyl]-
4-methylpent-4-en-1-ol 59. Sodium borohydride (65 mg,
1.7 mmol) was added portionwise over 1 min to a stirred
solution of the aldehyde 58 (1.10 g, 3.4 mmol) in MeOH
(30 mL) at 0 ◦C. The mixture was stirred at 0 ◦C for 1 h,
and then quenched by the addition of an aqueous solution
2 7 9 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

View Article Online
of citric acid (10% w/w, 6 mL). The resulting suspension
was concentrated in vacuo, and the residue was diluted with
Et2O (30 mL). The separated organic layer was dried (MgSO4)
and concentrated in vacuo. Chromatography of the residue
(petroleum ether–Et2O 4 : 1, 3 : 1) gave the alcohol (0.67 g, 61%)
as a colourless oil. [a]2D2 +11.2 (c 1.1 in CH2Cl2); mmax/cm−1: 3623,
(R)-5-(3-{4-tert-Butyldimethylsilyloxymethyl)-5-[(S)-2-(2-
hydroxyethyl)-3-methylbut-3-enyl]furan-2-yl}-2-methylallyl)-3-
phenylselanyldihydrofuran-2-one 61a. Triphenylarsine (22 mg,
0.08 mmol, 80%mol) and Pd2dba3 (18 mg, 0.02 mmol,
20% mol) were added sequentially to a stirred solution of
the furanostannane 44 (70 mg, 0.14 mmol) and the phen-
ylselenolactone 60 (40 mg, 0.10 mmol) in degassed NMP (3 mL)
under an argon atmosphere. The resulting dark solution was
=
3074, 1644; dH(360 MHz): 7.28 (d, 1H, J 1.8, OCH CH), 6.33
=
=
(d, 1H, J 1.8, OCH CH), 4.84 (dd, 1H, J 1.3 and 1.3, CHH),
4.80 (s, 1H, CHH), 4.51 (s, 2H, CH2OTBS), 3.58–3.50 (m,
◦
=
stirred at 45 C for 6 h and then cooled to room temperature
=
2H, CH2OH), 2.80–2.65 (m, 3H, furan CH2 and CHC ), 1.76
(s, 3H, CCH3), 1.75–1.65 (m, 2H, CH2CH2OH), 0.94 (s, 9H,
and diluted with water (20 mL) and Et2O (40 mL). The
separated aqueous layer was extracted with Et2O (2 × 40 mL),
and the combined organic extracts were washed successively
with a saturated aqueous solution of NaHCO3 (12 mL) and
brine (12 mL), then dried (MgSO4) and concentrated in vacuo.
Chromatography of the residue (petroleum ether–Et2O 5 : 1 to 2 :
1) gave the furanolactone (28 mg, 55%) as a separable mixture
of two diastereoisomers: (i) [a]2D2 +46.0 (c 0.2 in CH2Cl2);
mmax/cm−1: 3690, 1766, 1602; dH(500 MHz): 7.70–7.68 (m, 2H,
=
SiC(CH3)3), 0.12 (s, 6H, Si(CH3)2); dC(90 MHz): 150.4 (C),
147.1 (C), 140.4 (CH), 120.0 (C), 112.0 (CH2), 110.9 (CH),
61.3 (CH2), 57.1 (CH2), 43.5 (CH), 35.2 (CH2), 31.2 (CH2),
25.9 (CH3), 18.7 (CH3), 18.4 (C), −5.2 (CH3); m/z (EI) found
324.2119 (M+), C18H32O3Si requires: 324.2121.
(S)-4-Methyl-3-(3-trimethylsilyloxymethyl-5-trimethylstan-
nanylfuran-2-ylmethyl)pent-4-en-1-ol 60. A solution of n-BuLi
in hexanes (2.5 M, 0.54 mL) was added dropwise over 1 min to a
stirred solution of the furanyl alcohol 59 (220 mg, 0.7 mmol) in
dry Et2O (5 mL), and the resulting yellow solution was stirred
at room temperature for 20 min under a nitrogen atmosphere.
Freshly distilled TMEDA (0.19 mL, 1.4 mmol) was added over
1 min, and the resulting yellow solution was stirred at room
temperature for 6 h. The mixture was treated with a solution
of n-BuLi (2.5 M) in hexanes (4.3 mL) and was then stirred
at◦room temperature for 20 min. The solution was cooled to
0 C and then treated with a solution of trimethyltin chloride
(2.7 g, 13.6 mmol) in Et2O (3 mL). The solution was stirred
at room temperature for 12 h, and then diluted with water
(40 mL) and Et2O (40 mL). The separated aqueous layer was
extracted with Et2O (3 × 70 mL) and the combined organic
extracts were then washed successively with NaHCO3 (75 mL)
and brine (50 mL), dried (MgSO4) and concentrated in vacuo.
Chromatography of the residue over basic alumina (petroleum
ether–Et2O 3 : 1) gave the furanostannane (274 mg, 83%) as a
pale yellow oil. [a]2D2 +3.9 (c 2.1 in CH2Cl2); mmax/cm−1: 3620,
=
ArH), 7.39–7.33 (m, 3H, ArH), 6.14 (s, 1H, OC CH), 6.00
=
=
(s, 1H, CH CCH3), 4.77 (bs, 2H, CH2), 4.49–4.45 (m, 3H,
CH2OTBS and CHO), 3.95 (dd, 1H, J 8.0 and 2.9, CHSe),
3.62–3.55 (m, 2H, CH2OH), 2.71–2.62 (m, 3H, furan CH2 and
=
=
CHC CH2), 2.56 (dd, 1H, J 14.0 and 6.5, CCHHCHO),
2.41–2.32 (m, 3H, CH2CHSe and CCHHCHO), 1.94 (s, 3H,
=
=
=
CH CCH3), 1.71 (s, 3H, CH2 CCH3), 1.66 (q, 2H, J 6.8,
CHCH2CH2), 0.92 (s, 9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2),dC
(90 MHz): 175.7 (C), 150.7 (C), 149.3 (C), 147.1 (C), 136.0
(CH), 130.6 (C), 129.5 (CH), 129.3 (CH), 126.8 (C), 121.8
(C), 117.6 (CH), 112.2 (CH2), 110.3 (CH), 77.9 (CH), 61.4
(CH2), 57.2 (CH2), 46.0 (CH2), 43.6 (CH), 37.0 (CH), 36.4
(CH2), 35.3 (CH2), 31.4 (CH2), 26.0 (CH3), 18.9 (CH3), 18.8
(CH3), 18.5 (C), − 5.1 (CH3); m/z (ES) 641.2129, (M+
+
Na, C32H46O5SiSeNa requires 641.2177); (ii) [a]2D2 +37.5 (c
0.2 in CH2Cl2), mmax/cm−1: 1766; dH(500 MHz): 7.70–7.67 (m,
=
2H, ArH), 7.39–7.31 (m, 3H, ArH), 6.13 (s, 1H, OC CH),
=
=
5.95 (s, 1H, CH CCH3), 4.77 (bs, 2H, CH2), 4.62–4.55 (m,
1H, CHO), 4.48 (s, 2H, CH2OTBS), 4.02 (dd, 1H, J 9.4 and
9.4, CHSe), 3.61–3.55 (m, 2H, CH2OH), 2.77–2.62 (m, 4H,
CHC CH2, furan CH2 and CHHCHSe), 2.48 (dd, 1H, J
14.0 and 6.4, CCHHCHO), 2.22 (dd, 1H, J 14.0 and 6.4,
=
=
1645; dH(360 MHz): 6.50–6.46 (m, 1H, OCSn CH), 4.75 (d,
=
=
2H, J 1.1, CH2), 4.48 (s, 2H, CH2OTBS), 3.60–3.55 (m, 2H,
=
=
CH2OH), 2.77–2.64 (m, 3H, furan CH2 and CHC ), 1.70 (s,
CCHHCHO), 2.05–1.99 (m, 1H, CHHCHSe), 1.94 (s, 3H,
=
=
=
3H, CCH3), 1.69–1.60 (m, 2H, CH2CH2OH), 1.48 (bs, 1H,
CH CCH3), 1.72 (s, 3H, CH2 CCH3), 1.66 (q, 2H J 6.6,
CH2CH2OH), 0.92 (s, 9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2);
dC (90 MHz): 175.8 (C), 150.7 (C), 149.3 (C), 147.1 (C), 135.8
(CH), 130.5 (C), 129.5 (CH), 129.0 (CH), 126.7 (C), 121.8 (C),
117.7 (CH), 112.2 (CH2), 110.3 (CH), 77.7 (CH), 61.4 (CH2),
57.2 (CH2), 46.3 (CH2), 43.6 (CH), 37.4 (CH), 35.4 (CH2),
35.3 (CH2), 31.4 (CH2), 26.0 (CH3), 18.9 (CH3), 18.8 (CH3),
18.5 (C), −5.1 (CH3); m/z (ES) found 641.2129 (M+ + Na),
C32H46O5SiSeNa requires 641.2177.
OH), 0.92 (s, 9H, SiC(CH3)3), 0.37–0.22 (m, 9H, Sn(CH3)3),
0.11 (s, 6H, Si(CH3)2); dC(125 MHz): 158.0 (C), 155.4 (C), 147.6
(C), 122.5 (CH), 119.8 (C), 111.9 (CH2), 61.5 (CH2), 57.3 (CH2),
43.6 (CH), 35.5 (CH2), 31.6 (CH2), 26.0 (CH3), 18.8 (CH3),
18.6 (C), 1.1 (CH3), −5.1 (CH3), −9.2 (CH3); m/z (EI) found
356.0793 (M+ − H − OTBS), C15H24O2Sn requires 356.0806.
(R)-3-[(tert-Butyldimethylsilyloxymethyl)trimethylstannanyl-
furan-2-ylmethyl]-4-methylpent-4-enal 45. TPAP (10 mg) was
added in one portion to a suspension of the alcohol 60 (260 mg,
Methanesulfonic acid (S)-3-{3-(tert-butyldimethylsilyloxy-
methyl)-5-[(E)-2-methyl-3-((R)-5-oxo-4-phenylselanyl)tetrahy-
drofuran-2-yl)propenyl]furan-2-ylmethyl}-4-methylpent-4-enyl
ester 61b. Triethylamine (8 lL, 0.04 mmol) and mesyl chloride
(4 lL, 0.02 mmol) were added sequentially to a stirred solution
of the diastereoisomer of the 61a (eluting first) (18 mg,
0.02 mmol) in anhydrous CH2Cl2 (1.5 mL) at room temperature
under a nitrogen atmosphere. The resulting solution was stirred
at room temperature for 4 h and then diluted with CH2Cl2
(16 mL) and water (8 mL). The separated aqueous layer
was extracted with CH2Cl2 (2 × 16 mL) and the combined
organic extracts were washed successively with citric acid (10%
w/w, 4 mL) and a saturated aqueous solution of NaHCO3
(5 mL), then dried (MgSO4) and evaporated in vacuo to leave
the mesylate (17 mg, 87%) as a yellow oil. mmax/cm−1: 1770,
1606; dH(500 MHz): 7.70–7.68 (m, 2H, ArH), 7.40–7.32 (m,
˚
0.53 mmol), NMO (99.8 mg, 0.8 mmol) and powdered 4 A
molecular sieves (284 mg) in anhydrous CH2Cl2 under a nitrogen
atmosphere. The mixture was stirred at room temperature for
1 h and then filtered through a pad of alumina, eluting with
Et2O. The solvent was dried (Na2SO4) and concentrated in
vacuo to leave the aldehyde (220 mg, 85%) as a colourless oil.
[a]2D2 +2.7 (c 1.6 in CH2Cl2); mmax/cm−1: 1722; dH(360 MHz) 9.51
=
(dd, 1H, J 2.1, CHO), 6.50–6.44 (m, 1H, OCSn CH), 4.79 (dd,
=
=
1H, J 1.5 and 1.5, CHH), 4.76 (s, 1H, CHH), 4.48 (s, 2H,
=
CH2OTBS), 3.11–3.01 (m, 1H, CHC ), 2.84 (dd, 1H, J 14.7
and 6.1, furan CHH), 2.71 (dd, 1H, J 14.7 and 8.7, furan CHH),
2.45 (dd, 2H, J 7.3 and 2.1, CH2CHO), 1.73 (s, 3H, CCH3),
0.92 (s, 9H, SiC(CH3)3), 0.38–0.13 (m, 9H, Sn(CH3)3), 0.10 (s,
6H, (Si(CH3)2); dC(90 MHz): 201.9 (CH), 158.6 (C), 154.2 (C),
146.2 (C), 122.3 (CH), 120.7 (C), 112.0 (CH2), 57.2 (CH2), 46.6
(CH2), 41.0 (CH), 31.1 (CH2), 26.5 (CH3), 20.0 (CH3), 18.5 (C),
1.1 (CH3), −5.1 (CH3), −9.2 (CH3); m/z (ES) found 509.1507
(M+ + Na), C21H38O3SiSnNa requires 509.1510.
=
=
=
3H, ArH), 6.14 (s, 1H, OC CH), 6.00 (s, 1H, CH CCH3),
4.83 (bs, 1H, CHH), 4.76 (s, 1H, CHH), 4.48–4.46 (m,
3H, CHO and CH2OTBS), 4.20–4.16 (s, 1H, CHHOMs),
=
=
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 7 9 9

View Article Online
4.11–4.07 (s, 1H, CHHOMs), 3.96 (dd, 1H, J 8.0 and 2.9,
CHSe), 2.96 (s, 3H, SO2CH3), 2.76–2.62 (m, 4H, furan CH2,
CHC CH2 and CCHHCHO), 2.56 (dd, 1H, J 14.0 and 6.5,
diluted with CH2Cl2 (15 mL) and water (10 mL). The separated
aqueous layer was extracted with CH2Cl2 (2 × 15 mL) and
the combined organic extracts were washed successively with
aqueous citric acid (10% w/w, 10 mL) and a saturated aqueous
solution of NaHCO3 (20 mL), dried (MgSO4) and concentrated
in vacuo to leave the corresponding mesylate (69 mg, 93%) as a
yellow oil. [a]D22 +14.5 (c 1.1 in CH2Cl2); mmax/cm−1: 1773, 1604;
=
=
=
CCHHCHO), 2.39–2.32 (m, 2H, CH2CHSe), 1.95 (s, 3H,
=
CH CCH3),1.91–1.78 (m, 2H, CH2CH2OMs), 1.70 (s, 3H,
=
CH2 CCH3), 0.93 (s, 9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2);
dC(90 MHz): 175.6 (C), 150.9 (C), 148.5 (C), 145.2 (C), 135.9
(CH), 130.9 (C), 129.5 (CH), 129.2 (CH), 126.8 (C), 122.2 (C),
117.5 (CH), 113.2 (CH2), 110.2 (CH), 77.9 (CH), 68.4 (CH2),
57.1 (CH2), 46.0 (CH2), 42.8 (CH), 37.4 (CH3), 36.9 (CH), 36.4
(CH2), 31.4 (CH2), 31.2 (CH2), 26.0 (CH3), 18.9 (CH3), 18.7
(CH3), 18.4 (C), −5.1 (CH3); m/z (ES) found 719.1985 (M+ +
Na), C33H48O7SiSeSNa requires 719.1953.
=
=
dH(360 MHz): 6.15 (s, 1H, OC CH), 6.07 (s, 1H, CH CCH3),
=
=
4.83 (bs, 1H, CHH), 4.76 (s, 1H, CHH), 4.73–4.66 (m, 1H,
CHO), 4.47 (s, 2H, CH2OTBS), 4.20–4.15 (m, 1H, CHHOMs),
4.12–4.07 (m, 1H, CHHOMs), 2.95 (s, 3H, OSO2CH3), 2.75–
=
2.31, 1.98–1.75 (m, 11H, CHC and 5 × CH2), 2.02 (s, 3H,
=
=
CH CCH3), 1.69 (s, 3H, CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3),
0.09 (s, 6H, Si(CH3)2); dC(90 MHz): 177.1 (C), 151.0 (C), 148.4
(C), 145.2 (C), 131.3 (C), 122.2 (C), 117.4 (CH), 113.2 (CH2),
110.1 (CH), 79.4 (CH), 68.5 (CH2), 57.1 (CH2), 46.3 (CH2),
42.8 (CH), 37.3 (CH3), 31.4 (CH2), 31.2 (CH2), 28.7 (CH2), 27.7
(CH2), 26.0 (CH3), 19.1 (CH3), 18.7 (CH3), 18.5 (C), −5.1 (CH3);
m/z (ES) found 563.2499 (M+ + Na), C27H44O7SiSNa requires
563.2475.
Repetition of this experiment with the diastereoisomer of the
61a (eluting second), on the same scale and under the same
conditions, gave the corresponding mesylate (16 mg, 82%) as
a yellow oil. mmax/cm−1: 1766; dH(360 MHz) 7.69–7.66 (m, 2H,
=
ArH), 7.40–7.31 (m, 3H, ArH), 6.13 (s, 1H, OC CH), 5.96 (s,
=
=
=
1H, CH CCH3), 4.83 (s, 1H, CHH), 4.76 (s, 1H, CHH),
4.63–4.56 (m, 1H, CHO), 4.47 (s, 2H, CH2OTBS), 4.21–4.15
(s, 1H, CHHOMs), 4.12–4.08 (s, 1H, CHHOMs), 4.02 (dd,
1H, J 9.4 and 9.4, CHSe), 2.95 (s, 3H, SO2CH3), 2.80–2.61
A solution of the above mesylate (69 mg, 0.13 mmol) in THF
(1 mL) was added to a stirred suspension of sodium iodide
(20 mg, 0.13 mmol) in dry THF (1.5 mL) under a nitrogen
atmosphere. The resulting suspension was heated under reflux
for 2 h and then treated with more NaI (20 mg, 0.13 mmol) and
stirred further under reflux for 1 h. The reaction was cooled
to room temperature, then diluted with Et2O (30 mL) and
washed successively with a saturated aqueous solution of NH4Cl
(10 mL) and water (10 mL). The separated aqueous layer was
extracted with Et2O (2 × 20 mL) and the combined organic
extracts were dried (MgSO4) and concentrated in vacuo to leave
the iodide (73 mg, 100%) as a yellow oil. [a]2D2 +5.0 (c 0.2 in
CH2Cl2); mmax/cm−1: 1772, 1725, 1606; dH(360 MHz): 6.16 (s, 1H,
=
(m, 4H, CHC CH2, furan CH2 and CHHCHSe), 2.47 (dd,
1H, J 14.0 and 6.4, CCHHCHO), 2.23 (dd, 1H, J 14.0 and
6.4, CCHHCHO), 2.05–1.97 (m, 1H, CHHCHSe), 1.90–1.78
(m, 2H, CH2CH2OMs), 1.95 (s, 3H, CH CCH3), 1.70 (s, 3H,
=
=
=
=
CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2);
dC(90 MHz): 175.8 (C), 150.9 (C), 148.5 (C), 145.2 (C), 135.8
(CH), 130.9 (C), 129.5 (CH), 129.1 (CH), 127.1 (C), 122.2 (C),
117.6 (CH), 113.3 (CH2), 110.2 (CH), 77.7 (CH), 68.4 (CH2),
57.1 (CH2), 46.4 (CH2), 42.8 (CH), 37.4 (CH), 37.3 (CH3), 35.5
(CH2), 31.4 (CH2), 31.3 (CH2), 26.0 (CH3), 19.0 (CH3), 18.7
(CH3), 18.5 (C), −5.1 (CH3); m/z (ES) found 719.1985 (M+ +
Na), C33H48O7SiSeSNa requires 719.1953.
=
=
=
OC CH), 6.07 (s, 1H, CH CCH3), 4.82 (app. s, 1H, CHH),
4.78 (app. s, 1H, CHH), 4.73–4.66 (m, 1H, CHO), 4.47 (s,
=
(S)-5-((E)-3-{4-(tert-Butyldimethylsilyloxymethyl)-5-[2-(2-
iodoethyl)-3-methylbut-3-enyl]furan-2-yl}-2-methylallyl)dihy-
drofuran-2-one 62. Triphenylarsine (60 mg, 0.20 mmol,
80%mol) and Pd2dba3 (44 mg, 0.05 mmol, 20%mol) were added
sequentially to a stirred solution of the furanostannane 60
(150 mg, 0.31 mmol) and the lactone 49 (65 mg, 0.24 mmol)
in degassed NMP (3 mL) under an argon atmosphere. The
resulting dark solution was stirred at 45 ◦C for 16 h and
then cooled to room temperature and diluted with Et2O
(40 mL) and water (30 mL). The separated aqueous layer was
extracted with Et2O (2 × 40 mL) and the combined organic
extracts were washed successively with a saturated aqueous
solution of NaHCO3 (20 mL) and brine (20 mL), then dried
(MgSO4) and concentrated in vacuo. Chromatography of the
residue (petroleum ether–Et2O 4 : 1 to 2 : 1) gave (S)-5-(3-{4-
(tert-butyldimethylsilyloxymethyl)-5-[(S)-2-(2-hydroxyethyl)-3-
methylbut-3-enyl]furan-2-yl}-2-ethylallyl)dihydrofuran-2-one
(55 mg, 50%) as a yellow oil. [a]2D2 +34.8 (c 1.1 in CH2Cl2);
mmax/cm−1: 3616, 1770, 1645; dH(360 MHz): 6.15 (s, 1H,
2H, CH2OTBS), 3.19–3.13 (m, 1H, CHHI), 3.03–2.95 (m, 1H,
CHHI), 2.76–2.28, 2.00–1.87, 0.89–0.84 (m, 11H, CHC and
=
=
=
5 × CH2), 2.04 (s, 3H, CH CCH3), 1.68 (s, 3H, CH2 CCH3),
0.92 (s, 9H, SiC(CH3)3), 0.09 (s, 6H, Si(CH3)2); dC(90 MHz):
177.1 (C), 150.9 (C), 148.7 (C), 144.9 (C), 131.1 (C), 122.0 (C),
117.5 (CH), 113.3 (CH2), 110.2 (CH), 79.5 (CH), 57.2 (CH2),
47.2 (CH), 46.4 (CH2), 36.3 (CH2), 32.0 (CH2), 29.8 (CH2),
29.0 (CH2), 27.7 (CH2), 26.0 (CH3), 19.1 (CH3), 18.7 (CH3),
18.5 (C), −5.1 (CH3); m/z (ES) found 595.1689 (M+ + Na),
C26H41O4SiINa requires 595.1717.
{(S)-3-[(tert-Butyldimethylsilyloxymethyl)trimethylstannyl-
furan-2-ylmethyl]-1-hydroxy-4-methylpent-4-enyl}-5-((E)-3-
iodo-2-methylallyl)dihydrofuran-2-one 63. A solution of the
lactone 49 (119 mg, 0.45 mmol) in dry THF (2.0 mL) at
◦
−78 C was added dropwise over 10 min to a stirred solution
of LiHMDS (1.0 M in THF, 0.49 mL, 0.49 mmol) in THF
(1.7 mL) under a nitrogen atmosphere. The mixture was stirred
at −78 ◦C for 15 min and then a solution of the aldehyde 45
(209 mg, 0.43 mmol) in THF (2.5 mL) was added dropwise
over 10 min. The mixture was stirred at −78 ◦C for 50 min
and then quenched with saturated aqueous NH4Cl (30 mL).
The solution was allowed to warm to room temperature for
10 min and then diluted with water (30 mL) and Et2O (50 mL).
The separated aqueous layer was extracted with Et2O (3 ×
70 mL) and the combined organic extracts were dried (MgSO4)
and concentrated in vacuo to leave the furanolactone (265 mg,
71%) as a yellow oil, which was used without purification.
[a]2D2 +16.6 (c 1.0 in CH2Cl2), mmax/cm−1: 3529, 1756, 1645,
=
=
=
OC CH), 6.06 (s, 1H, CH CCH3), 4.76 (bs, 2H, CH2),
4.72–4.65 (m, 1H, CHO), 4.47 (s, 2H, CH2OTBS), 3.63–3.51
(m, 2H, CH2OH), 2.70–2.25, 2.05–1.90, 1.70–1.60, 0.90–0.80
=
=
(m, 11H, CHC and 5 × CH2), 2.02 (s, 3H, CH CCH3),
=
1.70 (s, 3H, CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.08 (s, 6H,
Si(CH3)2); dC(90 MHz): 177.1 (C), 150.8 (C), 149.3 (C), 147.1
(C), 131.0 (C), 121.8 (C), 117.6 (CH), 112.2 (CH2), 110.2 (CH),
79.5 (CH), 61.4 (CH2), 57.2 (CH2), 46.3 (CH2), 43.6 (CH),
35.3 (CH2), 31.4 (CH2), 28.7 (CH2), 27.7 (CH2), 26.0 (CH3),
19.1 (CH3), 18.8 (CH3), 18.5 (C), −5.1 (CH3); m/z (ES) found
485.2668 (M+ + Na), C26H42O5SiNa requires 485.2699.
=
1628; dH(360 MHz): 6.48 (1H, s, OC CH), 6.10–6.06 (1H, bs,
=
=
Triethylamine (38 lL, 0.29 mmol) and mesyl chloride (12 lL,
0.16 mmol) were added sequentially to a stirred solution of the
above alcohol (67 mg, 0.14 mmol) in anhydrous CH2Cl2 (2 mL)
at room temperature under a nitrogen atmosphere. The resulting
solution was stirred at room temperature for 3 h and then
CHI), 4.81–4.73 (2H, s, CH2), 4.72–4.59 (m, 1H, CHO),
4.48 (s, 2H, CH2OTBS), 4.00–3.41 (m, 1H, CHOH), 3.18–2.00
=
=
(m, 10H, CHC CH2, furan CH2, CHC CH2, CH2CHO,
CH2CHCH(OH), CHOHCH2, CH2CHCH(OH)), 1.85, 1.78
(s, 6H, CH CCH3 and CH2 CCH3), 0.90 (s, 9H, SiC(CH3)3),
=
=
2 8 0 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

View Article Online
0.38–0.21(m, 9H, Sn(CH3)3), 0.10 (s, 6H, (Si(CH3)2); dC
(90 MHz) (two main isomers): 178.1 (C), 178.0 (C), 158.2 (C),
157.9 (C), 154.9 (2 × C), 147.8 (C), 146.1 (C), 142.9(C), 142.7
(C), 122.6 (CH), 122.3 (CH), 120.0 (C), 119.8 (C), 112.7 (CH2),
112.3 (CH2), 78.8 (CH), 78.7 (CH), 77.2 (CH), 76.6 (CH), 70.0
(CH2), 69.1 (CH2), 46.3 (CH), 45.5 (CH), 45.3 (CH2), 44.9
(CH2), 44.4 (CH), 44.1 (CH), 43.0 (CH), 42.5 (CH), 37.9 (CH2),
37.6 (CH2), 31.7 (CH2), 31.3 (CH2), 30.3 (CH2), 29.7 (CH2),
26.0 (CH3), 25.9 (CH3), 24.4 (CH3), 18.9 (CH3), 18.8 (CH3),
18.5 (C), 1.00 (CH3), −5.1 (CH3), −11.2 (CH3); m/z (ES) found
775.1304, (M+ + Na), C29H49O5SnSiINa requires 775.1314.
Acetic acid (5S,11S)-14-(tert-butyldimethylsilyloxymethyl)-11-
isopropenyl-3-methyl-7-oxo-6,16-dioxatricyclo[11.2.1.15,8]hepta-
deca-1(15),2,13-trien-9-yl ester 65a (b-OAc). Triethylamine
(8 lL, 60.8 lmol), DMAP (1 mg, cat.) and acetic anhydride
(3.44 lL, 36.5 lmol) were added sequentially to a stirred
solution of the alcohol 64 (b-OH) (14 mg, 30.4 lmol) in
anhydrous CH2Cl2 (1 mL) at 0 ◦C under a nitrogen atmosphere.
The mixture was stirred at 0 ◦C for 2 h, then allowed to warm to
room temperature and treated with more triethylamine (8 lL,
60.8 lmol), DMAP (1 mg, cat.) and acetic anhydride (3.44 lL,
36.5 lmol). The mixture was stirred for a further 2 h and then
the solvent was partially removed in vacuo. Chromatography
of the residue (petroleum ether–Et2O 2 : 1) gave the acetylated
furanocembrane (8 mg, 52%) as a colourless oil. [a]2D2 +20.5 (c 0.4
in CH2Cl2); mmax/cm−1: 2953, 1767, 1727; dH(360 MHz): 6.19 (s,
(5S,11S)-14-(tert-Butyldimethylsilyloxymethyl)-9-hydroxy-
11-isopropenyl-3-methyl-6,16-dioxatricyclo[11.2.1.15,8]heptadeca-
1(15),2,13-trien-7-one 64. Triphenylarsine (53 mg, 80% mol)
and Pd2dba3 (21 mg, 10%mol) were added sequentially to a
degassed solution of NMP (40 mL) under an argon atmosphere.
The resulting yellow solution was stirred at room temperature
for 10 min and then a solution of the furanolactone 63
(150 mg, 0.20 mmol) in degassed NMP (40 mL) was added
via syringe over 2 min. The resulting yellow solution was
stirred at 40 ◦C under argon for 16 h, then cooled to room
temperature and diluted with water (50 mL) and Et2O (60 mL).
The separated aqueous layer was extracted with Et2O (3 ×
70 mL) and the combined organic extracts were washed with
water (60 mL), dried (MgSO4) and concentrated in vacuo.
Chromatography of the residue (petroleum ether–Et2O 3 : 1)
gave the furanocembrane (38 mg, 41%) which could be separated
into three diastereoisomers: (i) eluted first (traces), mmax/cm−1:
=
=
=
1H, OC CH), 6.08 (s, 1H, CH CCH3), 4.92 (s, 1H, CHH),
4.88–4.82 (m, 2H, CHH and CH2CHO), 4.71 (ddd, 1H, J
=
4.9, 4.9 and 1.8, CHOAc), 4.49 (s, 2H, CH2OTBS), 3.52–3.45
(m, 1H, CHCHOAc), 2.99–2.91 (m, 1H, CHC CH2), 2.77 (dd,
1H, J 13.6 and 2.2, CCHHCHO), 2.24 (dd, 1H, J 13.6 and
3.5, CCHHCHO), 2.75–2.40, 2.18–1.80 (m, 6H, furan CH2,
CHOCH2CH and CH(OAc)CH2), 2.00 (s, 6H, CH CCH3),
1.87 (s, 3H, CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.10 (s, 6H,
Si(CH3)2); dC (90 MHz): 175.3 (C), 171.8 (C), 149.7 (2 × C),
149.6 (C), 138.2 (C), 122.5 (C), 118.7 (CH), 110.8 (CH2), 110.7
(CH), 78.5 (CH), 73.0 (CH), 57.1 (CH2), 44.4 (CH2), 39.7 (CH),
38.4 (CH), 35.2 (CH2), 32.5 (CH2), 31.9 (CH2), 26.0 (CH3), 22.3
(CH3), 21.3 (CH3), 20.8 (CH3), 18.5 (C), −5.1 (CH3); m/z (ES)
found 525.2610 (M+ + Na), C28H42O6SiNa requires 525.2648.
=
=
=
=
=
=
3516, 1743; dH(360 MHz): 6.17 (s, 1H, OC CH), 6.10 (s, 1H,
Acetic acid (5S,11S)-14-hydroxymethyl-11-isopropenyl-3-methyl-
7-oxo-6,16-dioxatricyclo[11.2.1.15,8 ]heptadeca-1(15),2,13-trien-
9-yl ester 65b (b-OAc). A solution of 10-camphorsulfonic acid
(1.5 mg, 6.4 lmol) in CH2Cl2–MeOH (0.1 mL : 0.1 mL) was
added to a stirred solution of the furanocembrane 65a (b-OAc)
(8◦ mg, 15.9 lmol) in CH2Cl2–Me◦OH (0.5 mL : 0.5 mL) at
0 C. The mixture was stirred at 0 C for 1 h and then treated
with more 10-camphorsulfonic acid (1.5 mg, 6.4 lmol). The
mixture was further stirred at 0 ◦C for 2 h and then the solvent
was partially removed in vacuo. Chromatography of the residue
(petroleum ether–Et2O 1 : 1) gave the alcohol (4 mg, 65%) as
a colourless solid. [a]2D2 +21.0 (c 0.4 in CH2Cl2); mmax/cm−1:
=
=
CH CCH3), 5.05–5.01 (m, 1H, CHO), 4.75 (bs, 1H, CHH),
=
4.64 (s, 1H, CHH), 4.52–4.50 (m, 1H, CHOH), 4.48 (s, 2H,
CH2OTBS), 4.07 (bs, 1H, CHOH), 3.38–3.35, 3.00–1.95 (m,
=
10H, 4 × CH2, 2 × CH), 1.84 (s, 3H, CH CCH3), 1.80 (s, 3H,
=
CH2 CCH3), 0.95 (s, 9H, SiC(CH3)3), 0.11 (s, 6H, Si(CH3)2);
m/z (ES) 483.2512 (M+ + Na, C26H40O3SiNa requires 483.2543);
(ii) b-OH diastereomer, eluted second (14 mg), [a]2D2 +20.0 (c
0.1 in CH2Cl2); mmax/cm−1: 1746; dH(360 MHz): 6.19 (s, 1H,
=
=
=
OC CH), 6.10 (s, 1H, CH CCH3), 5.06 (s, 1H, CHH),
4.94–4.92 (m, 1H, CH2CHO), 4.86 (dd, 1H, J 1.5 and 1.5,
=
CHH), 4.48 (s, 2H, CH2OTBS), 4.22 (d, 1H, J 6.9, CHOH),
3.96–3.88 (m, 1H, CHOH), 3.47–3.38 (m, 1H, CHCHOH), 3.01
(app. q, 1H, J 8.0, CHC CH2), 2.82 (dd, 1H, J 13.8 and 2.4,
CCHHCHO), 2.66 (d, 2H, J 8.0, furan CH2), 2.31 (dd, 1H, J
=
3679, 1774, 1728, 1606; dH(360 MHz): 6.25 (s, 1H, OC CH),
=
=
=
6.08 (s, 1H, CH CCH3), 4.92 (s, 1H, CHH), 4.90–4.85 (m,
=
=
2H, CHH and CH2CHO), 4.70 (ddd, 1H, J 5.0, 5.0 and
1.9, CHCHOAc), 4.47 (s, 2H, CH2OH), 3.49–3.42 (m, 1H,
CHCHOAc), 2.99–2.95 (m, 1H, CHC CH2), 2.81–2.09 (m, 8H,
CCH2CHO, furan CH2, CHOCH2CH and CH(OAc)CH2),
2.01 (d, 3H, J 1.2, CH CCH3), 2.00 (s, 3H, COCH3), 1.87
(s, 3H, CH2 CCH3); dC(90 MHz): 175.2 (C), 171.8 (C), 150.9
(C), 150.1 (C), 149.5 (C), 138.7 (C), 122.1 (C), 118.5 (CH),
110.9 (CH2), 110.6 (CH), 78.3 (CH), 72.7 (CH), 56.3 (CH2),
44.4 (CH2), 39.7 (CH), 38.3 (CH), 35.2 (CH2), 32.2 (CH2), 31.8
(CH2), 22.3 (CH3), 21.6 (CH3), 20.8 (CH3); m/z (ES) found
411.1773 (M+ + Na), C22H28O6Na requires 411.1783.
=
14.0 and 4.0, CCHHCHO), 2.28–1.80 (m, 4H, CHOCH2CH
=
and CHOHCH2), 2.02 (d, 3H, J 1.2, CH CCH3), 1.84 (s, 3H,
=
=
CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.08 (s, 6H, Si(CH3)2);
=
dC(90 MHz): 179.6 (C), 150.4 (C), 150.1 (C), 149.4 (C), 138.1 (C),
122.4 (C), 119.1 (CH), 111.1 (CH2), 110.6 (CH), 79.5 (CH), 71.9
(CH), 57.1 (CH2), 44.2 (CH2), 39.8 (CH), 39.7 (CH), 37.1 (CH2),
32.4 (CH2), 31.9 (CH2), 26.0 (CH3), 22.4 (CH3), 20.2 (CH3), 18.5
(C), −5.1 (CH3); m/z (ES) 483.2544 (M+ + Na, C26H40O3SiNa
requires 483.2543); iii) a-OH diastereoisomer,eluted third
(13 mg), mmax/cm−1: 3610, 1763, 1602; dH(360 MHz): 6.18 (s,
=
=
=
=
=
1H, OC CH), 6.10 (s, 1H, CH CCH3), 4.96 (s, 1H, CHH),
4.96–4.91 (m, 1H, CH2CHO), 4.88 (dd, 1H, J 1.5 and 1.5,
Acetic acid (5S,11S)-(E)-14-formyl-11-isopropenyl-3-methyl-
7-oxo-6,16-dioxatricyclo[11.2.1.15,8 ]heptadeca-1(15),2,13-trien-
9-yl ester 65c (b-OAc). Dess–Martin periodinane (15% w/w
solution in CH2Cl2, 35 lL, 12.4 lmol) was added to a stirred
solution of the alcohol 65b (b-OAc) (4 mg, 10.4 lmol) and
pyridine (1 drop) in anhydrous CH2Cl2 (1 mL) at 0 ◦C under
a nitrogen atmosphere. The mixture was stirred at 0 ◦C for
2 h and then the solvent was partially removed in vacuo.
Chromatography of the residue (petroleum ether–Et2O 1 :
1) gave the aldehyde (3.5 mg, 87%) as a colourless solid.
[a]2D2 −9.8 (c 0.9 in CH2Cl2); mmax/cm−1: 1775, 1733, 1679;
=
CHH), 4.49 (s, 2H, CH2OTBS), 4.23–4.19 (m, 1H, CHOH),
3.27 (dd, 1H, J 13.3 and 8.5, CHCHOH), 2.80 (dd, 1H, J
13.8 and 2.4, CCHHCHO), 2.70 (d, 2H, J 8.0, furan CH2),
2.59–2.44 (m, 2H, CHOCHHCH and CHC CH2), 2.35 (dd,
=
=
=
1H, J 13.9 and 4.5, CCHHCHO), 2.10 (dd, 1H, J 12.3 and
=
8.5, CHOCHHCH), 1.95 (d, 3H, J 1.3, CH CCH3), 1.79 (s,
=
3H, CH2 CCH3), 1.52–1.43 (m, 2H, CHOHCH2), 0.92 (s, 9H,
SiC(CH3)3), 0.09 (s, 6H, Si(CH3)2); dC(90 MHz): 179.0 (C),
149.2 (C), 149.1 (C), 146.3 (C), 138.5 (C), 121.9 (C), 119.5 (CH),
113.1 (CH2), 110.4 (CH), 79.1 (CH), 67.2 (CH), 57.2 (CH2),
44.3 (CH2), 42.1 (CH), 41.9 (CH), 38.7 (CH2), 30.5 (CH2),
26.0 (CH3), 24.0 (CH2), 21.9 (CH3), 19.0 (CH3), 18.5 (C), −5.1
(CH3); m/z (ES) found 483.2504 (M+ + Na), C26H40O5SiNa
requires 483.2543.
=
dH(360 MHz): 9.90 (s, 1H, CHO), 6.55 (s, 1H, OC CH),
=
=
6.10 (s, 1H, CH CCH3), 4.95 (s, 1H, CHH), 4.90–4.85 (m,
=
2H, CHH and CH2CHO), 4.82–4.80 (m, 1H, CHCHOAc),
3.33 (m, 1H, CHCHOAc), 3.10–2.85 (m, 3H, furan CH2 and
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 8 0 1

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=
=
CHC CH2), 2.82 (dd, 1H, J 13.6 and 2.3, CCHHCHO),
2.52–2.44 (m, 1H, CHOCHHCH), 2.32 (dd, 1H, J 13.6 and
and pyridine (1 drop) in CH2Cl2 at 0 ◦C under a nitrogen
atmosphere. The mixture was stirred at 0 C for 2 h and then
the solvent was partially removed in vacuo. Chromatography
of the residue (petroleum ether–Et2O 1 : 1) gave the aldehyde
(3.5 mg, 74%) as a colourless solid. [a]2D2 +26.0 (c 0.9 in CH2Cl2);
mmax/cm−1: 1734, 1678, 1602; dH(360 MHz): 9.90 (s, 1H, CHO),
◦
=
4.0, CCHHCHO), 2.20–1.80 (m, 3H, CHOCHHCH and
=
CH(OAc)CH2), 2.02 (s, 3H, COCH3), 1.98 (s, 3H, CH CCH3),
=
1.89 (s, 3H, CH2 CCH3); dC(90 MHz): 184.4 (CH), 174.7 (C),
171.6 (C), 163.0 (C), 151.0 (C), 148.6 (C), 142.6 (C), 124.8 (C),
117.6 (CH), 111.6 (CH2), 106.9 (CH), 77.4 (CH), 72.3 (CH),
44.2 (CH2), 39.7 (CH), 38.4 (CH), 35.4 (CH2), 33.2 (CH2), 31.6
(CH2), 22.1 (CH3), 21.1 (CH3), 20.7 (CH3); m/z (ES) found
409.1601 (M+ + Na), C22H26O6Na requires 409.1627.
=
=
6.56 (s, 1H, OC CH), 6.12 (s, 1H, CH CCH3), 5.09–5.06
=
=
(m, 2H, CHCHOAc and CHH), 4.99 (s, 1H, CHH),
4.95–4.93 (bs, 1H, CH2CHO), 3.33 (dd, 1H, J 13.0 and 8.5,
CHCHOAc), 3.12–3.07 (m, 2H, furan CH2), 2.86 (dd, 1H, J
=
13.7 and 1.9, CCHHCHO), 2.65 (ddd, 1H, J 10.0, 10.0 and
3.6, CHC CH2), 2.37 (dd, 1H, J 13.7 and 4.0, CCHHCHO),
2.20–1.80 (m, 4H, CHOCH2CH, CH(OAc)CH2), 2.00 (s,
6H, CH CCH3 and COCH3), 1.84 (s, 3H, CH2 CCH3); dC
(90 MHz): 184.5 (CH), 177.0 (C), 169.8 (C), 162.4 (C), 150.9
(C), 144.4 (C), 141.8 (C), 124.9 (C), 117.9 (CH), 114.5 (CH2),
107.2 (CH), 78.3 (CH), 69.7 (CH), 44.4 (CH2), 40.9 (CH),
40.4 (CH), 35.6 (CH2), 31.6 (CH2), 25.4 (CH2), 22.2 (CH3),
20.9 (CH3), 18.7 (CH3); m/z (ES) found 409.1591 C22H26O6Na
(M+ + Na), C22H26O6Na requires 409.1627.
Acetic acid (5S,8S,9S,11S)-14-(tert-butyldimethylsilyloxymeth-
yl)-11-isopropenyl-3-methyl-7-oxo-6,16-dioxatricyclo[11.2.1.15,8]-
heptadeca-1(15),2,13-trien-9-yl ester 65a (a-OAc). Triethyl-
amine (7.4 lL, 56.5 lmol), DMAP (1 mg, cat.) and acetic
anhydride (3.4 mg, 33.9 lmol) were added sequentially to a
stirred solution of the alcohol 64 (a-OAc) (13 mg, 28.3 lmol)
in anhydrous CH2Cl2 at 0 ◦C under a nitrogen atmosphere.
The solution was stirred at 0 ◦C for 1 h and then the solvent
partially removed in vacuo. Chromatography of the residue
(petroleum ether–Et2O 2 : 1) gave the aceylated furanocembrane
=
=
=
=
(7 mg, 49%) as a colourless oil. [a]2D2 +50.9 (c 0.7 in CH2Cl2);
X-Ray crystal structure of 65c. A crystal was encapsulated in
a film of RS3000 perfluoropolyether oil and mounted on a dual-
stage glass fibre before transfer to a SMART1k diffractometer
on Station 9.8 of the Synchrotron Radiation Source at CCLRC
Daresbury Laboratory.
−1
=
mmax/cm : 1768, 1735; dH(360 MHz): 6.20 (s, 1H, OC CH),
=
=
6.09 (s, 1H, CH CCH3), 5.06–5.03 (m, 2H, CHH and
CHOAc), 4.94 (s, 1H, CHH), 4.91–4.88 (m, 1H, CH2CHO),
4.49 (s, 2H, CH2OTBS), 3.46 (dd, 1H, J 12.9 and 9.6,
CHCHOAc), 2.80 (dd, 1H, J 13.8 and 1.9, CCHHCHO),
2.72–2.65 (m, 3H, furan CH2, CHC CH2), 2.30 (dd, 1H, J
14.0 and 4.0, CCHHCHO), 2.22–1.80 (m, 4H, CHOCH2CH,
CH(OAc)CH2), 2.00 (s, 3H, CH CCH3), 1.98 (s, 3H, COCH3),
1.79 (s, 3H, CH2 CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.10 (s, 6H,
Si(CH3)2); dC (90 MHz): 177.6 (C), 169.8 (C), 149.4 (C), 149.1
(C), 145.3 (C), 137.6 (C), 122.5 (C), 119.1 (CH), 113.9 (CH2),
110.7 (CH), 78.6 (CH), 70.1 (CH), 57.1 (CH2), 44.6 (CH2),
40.9 (CH), 40.3(CH), 35.1 (CH2), 30.6 (CH2), 26.0 (CH3), 25.6
(CH2), 22.2 (CH3), 20.9 (CH3), 18.8 (CH3), 18.5 (C), −5.1
(CH3); m/z (ES) found 525.2609 (M+ + Na), C28H42O6SiNa
requires 525.2648.
=
=
Crystal data. C22H26O6, M = 386.43, orthorhombic, a =
3
=
˚
˚
6.565(4), b = 8.698(5), c = 34.72(2) A, U = 1983(3) A , T =
150(2) K, space group P212121 (No. 19), Z = 4, Dc = 1.295 g cm−3,
l(Mo-Ka) = 0.094 mm−1, 1680 unique reflections measured were
used in all calculations. Final R1 [1651 F ≥ 4U(F)] = 0.0878 and
wR(all F2) was 0.222. No meaningful Flack parameters could
be obtained for this experiment.†
=
=
=
(R)-3-{(S)-3-[(tert-Butyldimethylsilyloxymethyl)trimethyl-
stannanylfuran-2-ylmethyl]-1-hydroxy-4-methylpent-4-enyl}-
5-(3-iodo-2-methylallyl)-3-phenylselanyldihydrofuran-2-one 66.
A solution of the phenylselenolactone 44 (127 mg, 0.30 mmol)
in THF (2.0 mL) was added dropwise over 10 min to a
stirred solution of LiHMDS (0.33 mL, 0.33 mmol) in THF
(2.5 mL) at −78 ◦C under a nitrogen atmosphere. The mixture
was stirred at −78 ◦C for 15 min and then a solution of
the aldehyde 45 (146 mg, 0.30 mmol) in THF (2.0 mL) was
added dropwise over 10 min. The mixture was stirred at
−78 ◦C for 50 min and then quenched by the addition of a
saturated solution of aqueous NH4Cl (10 mL). The resulting
mixture was allowed warm to room temperature for 10 min
and then diluted with water (30 mL) and Et2O (50 mL). The
separated aqueous layer was extracted with Et2O (2 × 40 mL)
and the combined organic extracts were dried (MgSO4) and
concentrated in vacuo to leave the furanolactone (254 mg, 93%)
as a mixture of diastereoisomers. [a]2D2 +12.9 (c 0.7 in CH2Cl2);
mmax/cm−1: 3593, 1755, 1644, 1618; dH(360 MHz): 7.69–7.55
(m, 2H, ArH), 7.46–7.31 (m, 3H, ArH), 6.52, 6.48 (s, 1H,
Acetic acid (5S,8S,9S,11S)-14-hydroxymethyl-11-isopropenyl-
3-methyl-7-oxo-6,16-dioxatricyclo[11.2.1.15,8]heptadeca-1(15),2,13-
trien-9-yl ester 65b (a-OAc). A solution of 10-camphorsulfonic
acid (1.3 mg, 5.6 lmol) in CH2Cl2–MeOH (0.1 mL : 0.1 mL)
was added to a stirred solution of the furanocembrane 65a
(a-OAc) (7 mg, 13.9 lmol) in CH2Cl2–MeOH (0.5 mL : 0.5 mL)
at 0 ◦C. The solution was stirred at 0 ◦C for 1 h and then
treated with more 10-camphorsulfonic acid (1.3 mg, 5.6 lmol).
The reaction was stirred for 2 h and then the solvent was
partially removed in vacuo. Chromatography of the residue
(petroleum ether–Et2O 1 : 1) gave the alcohol (4 mg, 75%) as
a colourless solid. mmax/cm−1: 3854, 1773, 1734; dH(360 MHz):
=
=
6.27 (s, 1H, OC CH), 6.10 (s, 1H, CH CCH3), 5.07–5.04 (m,
=
=
2H, CHCHOAc and CHH), 4.95 (s, 1H, CHH), 4.92–4.88
(m, 1H, CH2CHO), 4.47 (s, 2H, CH2OTBS), 3.44 (dd, 1H,
J 13.0 and 9.1, CHCHOAc), 2.82 (dd, 1H, J 13.8 and 2.0,
CCHHCHO), 2.75–2.62 (m, 3H, furan CH2 and CH CCH3),
2.31 (dd, 1H, J 13.8 and 4.0, CCHHCHO), 2.28–1.85 (m, 4H,
CHOCH2CH, CH(OAc)CH2), 2.01 (d, 3H, J 1.2, CH CCH3),
1.98 (s, 3H, COCH3), 1.81 (s, 3H, CH2 CCH3); dC (90 MHz):
177.5 (C), 169.8 (C), 150.3 (C), 149.9 (C), 145.1 (C), 138.1 (C),
122.1 (C), 118.9 (CH), 114.0 (CH2), 110.7 (CH), 78.6 (CH),
70.1 (CH), 56.3 (CH2), 44.6 (CH2), 40.9 (CH), 40.3 (CH), 35.2
(CH2), 30.4 (CH2), 25.6 (CH2), 22.2 (CH3), 21.0 (CH3), 18.8
(CH3); m/z (ES) found 411.1750 (M+ + Na), C22H28O6Na
requires 411.1783.
=
=
OCSn CH), 5.98, 5.92, 5.86 (s, 1H, CHI), 4.80–4.68 (m,
2H, CH2), 4.52–4.48 (m, 3H, CHO and CH2OTBS), 3.76
=
=
=
=
=
(d, 1H, J 3.5, CHOH), 2.80–2.15 (m, 9H, CHC CH2, furan
CH2, CHOCH2CSe, CCH2CHO and CHOHCH2), 1.83,
=
=
=
=
=
1.81, 1.79, 1.76, 1.58 (s, 6H, CH CCH3 and CH2 CCH3),
0.92 (s, 9H, SiC(CH3)3), 0.37–0.21 (m, 9H, Sn(CH3)3), 0.09 (s,
6H, Si(CH3)2); dC(90 MHz) (main isomer): 176.4 (C), 158.1 (C),
155.0 (C), 145.8 (C), 142.5 (C), 138.0 (CH), 130.0 (CH), 129.4
(CH), 126.3 (C), 122.4 (CH), 119.9 (C), 113.2 (CH2), 78.7 (CH),
75.5 (CH), 71.8 (CH), 57.3 (C), 55.5 (CH2), 45.3 (CH2), 43.4
(CH), 35.6 (CH2), 35.1 (CH2), 33.4 (CH2), 26.1 (CH3), 18.5 (C),
18.1 (CH3), 1.1 (CH3), −5.1 (CH3), −9.1 (CH3).
Acetic acid (5S,8S,9S,11S)-(E)-14-formyl-11-isopropenyl-3-
methyl-7-oxo-6,16-dioxatricyclo[11.2.1.15,8]heptadeca-1(15),2,13-
trien-9-yl ester 65c (a-OAc). Dess–Martin periodinane (15%
w/w solution in CH2Cl2, 35 lL, 12.4 lmol) was added
to a stirred solution of the alcohol 65b (4 mg, 10.4 lmol)
† CCDC reference numbers 270128 and 270127. See http://dx.doi.
org/10.1039/b504545b for crystallographic data in CIF or other
electronic format.
2 8 0 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4

View Article Online
=
CH CCH3), 0.92 (s, 9H, SiC(CH3)3), 0.09 (s, 6H, Si(CH3)2);
(R)-3-{(S)-3-[3-(tert-Butyldimethylsilyloxymethyl)-5-trimethyl-
stannanylfuran-2-ylmethyl]-1-hydroxy-4-methylpent-4-enyl}-5-
((E)-3-iodo-2-methylallyl)-5H-furan-2-one 67. Hydrogen per-
oxide (30% w/w in water, 0.05 mL) was added dropwise over
1 min to a stirred solution of the phenylselenolactone 66
(150 mg, 0.16 mmol) in anhydrous CH2Cl2–pyridine (5 mL :
5 mL). The solution was stirred at room temperature for 1 h
and then treated with a saturated aqueous solution of NaHCO3
(15 mL). The separated aqueous layer was extracted with
CH2Cl2 (2 × 20 mL) and the combined organic layers were then
dried (Na2SO4) and concentrated in vacuo. Chloroform was
added to the residue and the solution was concentrated in vacuo
to leave a 2 : 1 mixture of diastereoisomers of the butenolide
(150 mg) which was used without purification. dH(360 MHz)
m/z (ES) 523.2484 (M+ + Na, C28H40O6SiNa requires 523.2492).
=
Minor isomer: dH(400 MHz, 318 K): 7.13 (bs, 1H, CHOCH ),
6.07 (s, 1H, OC CH), 5.97 (bs, 1H, CH CCH3), 5.43 (d,
1H, J 12, CHOAc), 5.24 (bs, 1H, CH2CHO), 5.12 (bs, 1H,
CHH), 4.97 (bs, 1H, CHH), 4.46 (s, 2H, CH2OTBS), 2.98
(dd, 1H, J 13.4 and 3.1, CHHCHO), 2.8–2.05 (m, 6H, furan
=
=
=
=
=
CH2, CHC CH2, CHHCHO and CH(OAc)CH2), 2.02 (s, 3H,
=
=
OCOCH3), 1.85 (s, 3H, CH2 CCH3), 1.81 (s, 3H, CH CCH3),
0.92 (s, 9H, SiC(CH3)3), 0.09 (s, 6H, Si(CH3)2); m/z (ES) found
523.2484 (M+ + Na), C28H40O6SiNa requires 523.2492.
Acetic acid (5R,11S)-14-hydroxymethyl-11-isopropenyl-3-methyl-
7-oxo-6,16-dioxatricyclo[11.2.1.15,8]heptadeca-1(15),2,8(17),13-
tetraen-9-yl ester 70. A solution of 10-camphorsulfonic acid
(6.0 lmol) in anhydrous CH2Cl2–MeOH (0.5 mL : 0.5 mL)
was added over 1 min to a stirred solution of the silyl ether
69 (2.3 : 1 mixture of OAc epimers) (7 mg, 15.0 lmol) in
anhydrous CH2Cl2–MeOH (0.5 mL : 0.5 mL) at 0 ◦C. The
mixture was stirred at 0 ◦C for 1 h, then treated with more
10-camphorsulfonic acid (6.0 lmol, 0.4 eq.) and stirred for
2 h. The solvent was partially removed in vacuo to leave a
residue which was purified by chromatography (petroleum
ether–Et2O 1 : 1) to leave the alcohol (4.5 mg, 78%) as a
2.3 : 1 mixture of diastereoisomers. Further chromatography
gave: (i) the major OAc-epimer, dH(400 MHz, 318 K): 7.34 (d,
=
(main isomer): 7.22–7.19 (bs, 1H, CHOCH C), 6.52–6.48
(bs, 1H, OC CH), 6.05–5.95 (bs, 1H, CHI), 5.00–4.90
=
=
=
=
(m, 1H, CHOCH C), 4.82–4.77 (m, 2H, CH2), 4.51 (s,
=
2H, CH2OTBS), 4.45–4.35 (m, 1H, CCHOH), 2.90–2.50,
=
=
1.75–1.60 (m, 7H, CHC CH2, furan CH2, CCH2CHO and
=
=
CHOHCH2), 1.93, 1.73 (s, 6H, CH CCH3 and CH2 CCH3),
0.92 (s, 9H, SiC(CH3)3), 0.37–0.21 (m, 9H, Sn(CH3)3), 0.09 (s,
6H, Si(CH3)2); dC(90 MHz) (main isomer): 171.8 (C), 154.8 (C),
146.2 (C), 145.3 (C), 141.9 (C), 140.6 (CH), 137.9 (C), 122.4
(CH), 120.2 (C), 113.2 (CH2), 111.1 (CH), 79.5 (CH), 65.3 (CH),
57.3 (CH2), 42.9 (CH2), 42.8 (CH), 37.9 (CH2), 29.5 (CH2),
26.0 (CH3), 24.5 (CH3), 18.5 (C), 1.1 (CH3), −5.1 (CH3), −9.1
(CH3); m/z (ES) found 773.1119 (M+ + Na), C29H47O5SiSnINa
requires 773.1157. Approximately 20% destannylated material
was also obtained, which could not be completely removed
from the product.
=
=
1H, J 1.4, CHOCH ), 6.12 (s, 1H, OC CH), 5.92 (bs, 1H,
=
CH CCH3), 5.73 (dd, 1H, J 5.8 and 2.6, CHOAc), 5.25 (bs,
=
=
1H, CH2CHO), 4.87 (s, 1H, CHH), 4.83 (s, 1H, CHH),
4.44 (d, 2H, J 5.2, CH2OH), 2.92 (dd, 1H, J 13.6 and 3.5,
=
=
CCHHCHO), 2.8–2.00 (m, 6H, furan CH2, CHC CH2,
CCHHCHO and CH(OAc)CH2), 1.95 (s, 3H, OCOCH3),
1.85 (s, 3H, CH2 CCH3), 1.74 (s, 3H, CH CCH3); m/z (ES)
found 409.1605 (M+ + Na) C22H26O6Na requires 409.1627;
(ii) a 2 : 1 mixture of diastereoisomers of the acetate, from
which the H NMR data for the minor epimeric acetate were
deduced. dH(400 MHz, 318 K): 7.13 (bs, 1H, CHOCH ), 6.14
(s, 1H, OC CH), 5.98 (bs, 1H, CH CCH3), 5.42 (bd, 1H, J
12, CHOAc), 5.25 (bs, 1H, CH2CHO), 5.16 (bs, 1H, CHH),
4.98 (bs, 1H, CHH), 4.44 (s, 2H, CH2OH), 2.98 (dd, 1H, J
13.7 and 3.6, CCHHCHO), 2.8–2.05 (m, 6H, furan CH2,
CHC CH2, CCHHCHO and CH(OAc)CH2), 2.02 (s, 3H,
COCH3), 1.85 (s, 3H, CH CH3), 1.81 (s, 3H, CH2 CH3).
=
Acetic acid (5R,11S)-14-(tert-butyldimethylsilyloxymethyl)-11-
isopropenyl-3-methyl-7-oxo-6,16-dioxatricyclo[11.2.1.15,8]hepta-
deca-1(15),2,8(17),13-tetraen-9-yl ester 69. Triphenylarsine
(49 mg, 80% mol) and Pd2dba3 (18 mg, 10% mol) were added
sequentially to a degassed solution of NMP (40 mL) under an
argon atmosphere. The resulting yellow solution was stirred
at room temperature for 10 min and then a solution of the
crude furanolactone 67 (150 mg, 0.20 mmol) in degassed NMP
(40 mL) was added dropwise via syringe over 2 min. The
resulting yellow mixture was stirred at 40 ◦C for 16 h under
an argon atmosphere and then diluted with water (40 mL)
and Et2O (50 mL). The separated aqueous layer was extracted
with Et2O (3 × 100 mL) and the combined organic extracts
were then washed with water (4 × 70 mL), dried (MgSO4) and
evaporated in vacuo. The residue was quickly forced through a
pad of silica (petroleum ether–Et2O 3 : 1) to leave the impure
furanocembrane 68 as a mixture of two diastereoisomers. The
reaction was repeated with the furanolactone 67 (150 mg,
0.20 mmol) and the combined products were used in the next
step (17 mg, 10% from 66).
Triethylamine (10 lL, 74.2 lmol), DMAP (1 mg, cat.) and
acetic anhydride (4 lL, 44.5 lmol) were added sequentially
to a stirred solution of the secondary alcohol 68 (17 mg, 37.1
lmol) in anhydrous CH2Cl2 (1.5 mL) at 0 ◦C under a nitrogen
atmosphere. The mixture was stirred at 0 ◦C for 2 h, then warmed
to room temperature and further treated with triethylamine
(5 lL, 37.1 lmol), DMAP (1 mg, cat.) and acetic anhydride
(2 lL, 22.2 lmol). The mixture was stirred at room temperature
for 3 h and the solvent was then partially removed in vacuo.
Chromatography of the residue (petroleum ether–Et2O 2 : 1) gave
the acetylated furanocembrane (10 mg, 54%) as a 2.3 : 1 mixture
of diastereoisomers, which could not be separated. Major
=
=
1
=
=
=
=
=
=
=
=
=
=
Acetic acid (5R,11S)-14-formyl-11-isopropenyl-3-methyl-7-
oxo-6,16-dioxatricyclo[11.2.1.15,8 ]heptadeca-1(15),2,8(17),13-
tetraen-9-yl ester 71. Dess–Martin periodinane (35% w/w in
CH2Cl2, 34 lL, 12.5 lmol) was added in one portion to a stirred
solution of the major, pure diastereoisomer of the alcohol 70a
(4 mg, 10.4 lmol) in anhydrous CH2Cl2 (1 mL) and pyridine (1
drop) at 0 ◦C under a nitrogen atmosphere. The mixture was
stirred at 0 ◦C for 2 h and then the solvent was partially removed
in vacuo. Chromatography of the residue (petroleum ether–Et2O
1 : 1) gave the a-OAc bis-deoxylophotoxin (2.5 mg, 61%) as
an oil. dH(400 MHz, 318 K): 9.86 (s, 1H, CHO), 7.31 (bs, 1H,
CHOCH ), 6.44 (s, 1H, OC CH), 5.95 (bs, 1H, CH CCH3),
5.77 (dd, 1H, J 4.3 and 4.3, CHOAc), 5.27 (bs, 1H, CH2CHO),
4.91 (s, 1H, CHH), 4.88 (s, 1H, CHH), 2.92 (dd, 1H, J
13.6 and 3.6, CCHHCHO), 2.8–2.5 (m, 6H, furan CH2,
CHC CH2, CCHHCHO and CH(OAc)CH2), 1.95 (s, 3H,
=
=
=
=
=
=
=
=
=
=
OCOCH3), 1.85 (s, 3H, CH CCH3), 1.74 (s, 3H, CH2 CCH3);
m/z (ES) 407.1444, (M+ + Na, C22H24O6Na requires 407.1470).
Oxidation of a 2 : 1 mixture of diastereoisomers of 70, under
the same conditions, gave a 2 : 1 mixture of diastereoisomers
of 71, from which the 1H NMR data for the minor b-OAc
epimer were deduced. dH(400 MHz, 318 K): 9.84 (s, 1H, CHO),
=
isomer: dH(400 MHz, 318 K): 7.34 (d, 1H, J 1.2, CHOCH ),
6.04 (s, 1H, OC CH), 5.90 (bs, 1H, CH CCH3), 5.74 (dd, 1H,
J 6.3 and 2.5, CHOAc), 5.24 (bs, 1H, CH2CHO), 4.86 (bs, 1H,
=
=
=
=
7.16 (s, 1H, CHOCH ), 6.44 (s, 1H, OC CH), 5.95 (bs, 1H,
=
=
=
CHH), 4.82 (bs, 1H, CHH), 4.47 (s, 2H, CH2OTBS), 2.91
(dd, 1H, J 13.6 and 3.6, CCHHCHO), 2.80–2.00 (m, 6H,
furan CH2, CHC CH2, CCHHCHO and CH(OAc)CH2),
1.94 (s, 3H, OCOCH3), 1.85 (s, 3H, CH2 CCH3), 1.73 (s, 3H,
CH CCH3), 5.46 (bd, 1H, J 11.0, CHOAc), 5.27 (bs, 1H,
=
=
=
CH2CHO), 5.21 (s, 1H, CHH), 5.02 (s, 1H, CHH), 2.98
=
=
=
(dd, 1H, J 13.6 and 3.6, CCHHCHO), 2.80–2.00 (m, 6H, 2 ×
=
=
=
CH2, CHC CH2 and CCHHCHO), 2.03 (s, 3H, OCOCH3),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4
2 8 0 3

View Article Online
=
=
1.87 (s, 3H, CH2 CCH3), 1.84 (s, 3H, CH CCH3); m/z (ES)
16 G. Pattenden, L. K. Reddy and W. Affo, Tetrahedron Lett., 2004,
45, 4027–4030; G. Pattenden, M. A. Gonzalez, S. McCulloch, W.
Affo and S. J. Woodhead, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
12024–12029.
found 407.1441 (M+ + Na), C22H24O6Na requires 407.1470.
17 For a synthesis of 22 see: P.-T. Ho and N. Davies, Synthesis, 1983, 462;
J. P. Vigneron, R. Meric, M. Larcheveque, A. Debal, J. Y. Lallemand,
G. Kunesch, P. Zagatti and M. Gallois, Tetrahedron, 1984, 40, 3521–
3529.
18 For a synthesis of 21 see: E. J. Corey, M. G. Bock, A. P. Kozikowski,
A. V. R. Rao, D. Floyd and B. Lipshutz, Tetrahedron Lett., 1978, 19,
1051–1054.
Acknowledgements
We thank the EPSRC for support of this work by a fellowship (to
MC), and AstraZeneca for financial provision. We also thank
Martin P. Astley for some preliminary studies with the acyl
radical approach to lophotoxin.
19 T. Rosen, M. Watanabe and C. H. Heathcock, J. Org. Chem., 1984,
49, 3657–3659.
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29 (R)-(−)-Epichlorohydrin was resolved from racemic epichlorohydrin
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32 For a synthesis of the enantiomer of 49, see ref. 7a.
33 S. Hanessian and P. J. Murray, Tetrahedron, 1987, 43, 5055–5072.
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35 For a synthesis of 53, see: D. A. Evans, D. J. Mathre and W. L. Scott,
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Galatsis, S. D. Millan and G. Ferguson, J. Org. Chem., 1997, 62,
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36 For a synthesis of ethyl 2-bromomethyl-3-furoate, see: A. Salimbeni,
R. Canevotti, F. Paleari, D. Poma, S. Caliari, F. Fici, R. Cirillo,
A. R. Renzetti, A. Subissi, L. Belvisi, G. Bravi, C. Scolastico and A.
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37 We thank Drs A. J. Blake and C. Wilson of this Department for these
X-ray data. We also thank Mr R. J. Hill (University of Nottingham)
and Dr S. J. Teat (Daresbury Laboratory) for experimental assistance
and advice. We are grateful to CCLRC for the award of beam time
on the SRS.
38 Compare with: S. J. Shimshock, R. E. Waltermire and P. DeShong,
J. Am. Chem. Soc., 1991, 113, 8791–8796.
39 Deprotonation of 59 with excess of n-BuLi followed by quenching
the anion with MeOH-d4 gave >95% incorporation of deuterium at
C-5.
9 (a) J. A. Marshall and C. A. Sehon, J. Org. Chem., 1997, 62, 4313–
4320; (b) J. A. Marshall and E. A. Van Devender, J. Org. Chem.,
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10 For other studies, see: P. Wipf, L. T. Rahman and S. R. Rector, J. Org.
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11 (a) M. P. Astley and G. Pattenden, Synlett, 1991, 335–336; (b) M. P.
Astley and G. Pattenden, Synthesis, 1992, 101–105. Much later,
we investigated this intramolecular radical cyclisation in more
detail to ascertain whether or not the E-geometry of the alkene
bond in the a,b-unsaturated selenoester 12 underwent any E-to-Z
equilibration during acyl radical formation. Interestingly, in addition
to isolating the E-macrocyclic dione 13a (38%) we also separated
smaller amounts (∼17%) of the corresponding Z-isomer 13b. The Z-
stereochemistry of 13b followed from NOE experiments. M. Cases,
unpublished observations.
12 M. Cases, F. Gonzalez-Lopez de Turiso and G. Pattenden, Synlett,
2001, 12, 1869–1872.
40 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis,
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references therein.
1994, 639–666.
41 V. Farina and B. Krishnan, J. Am. Chem. Soc., 1991, 113, 9585–9595.
42 For a similar study carried out contemporaneously, see: (a) I.
Paterson, R. E. Brown and C. J. Urch, Tetrahedron Lett., 1999, 40,
5807–5810; (b) I. Paterson, M. Gardner and B. J. Banks, Tetrahedron,
1989, 45, 5283–5292.
43 Compare with the corresponding spectroscopic and NOE data in ref
1b.
14 N. J. G. Cox, G Pattenden and S. D. Mills, Tetrahedron Lett., 1989,
30, 621–624; N. J. G. Cox, S. D. Mills and G. Pattenden, J. Chem
Soc., Perkin Trans. 1, 1992, 11, 1313–1321.
15 S. A. Hitchcock and G. Pattenden, Tetrahedron Lett., 1990, 31, 3641–
3644; S. A. Hitchcock and G. Pattenden, J. Chem. Soc., Perkin Trans.
1, 1992, 11, 1323–1328.
2 8 0 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 7 8 6 – 2 8 0 4