Synthesis of diastereomeric, deoxy and ring-expanded sulfone analogues of aigialomycin D

Article abstract of DOI:10.1016/j.tet.2013.10.042

Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These include the stereoisomer 5′R,6′S-AmD, 2,4-di-deoxyAmD, 1′,2′,7′,8′-tetrahydroAmD and a 15-membered macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC₅₀ values to the natural product, whereas the 5′R,6′S-stereoisomer was inactive. Energy minimisation of AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone. The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereodivergent route to both enantiomers of the diol fragment from d-ribose was also achieved.

Full text of DOI:10.1016/j.tet.2013.10.042

Tetrahedron 69 (2013) 10581e10592
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of diastereomeric, deoxy and ring-expanded sulfone
analogues of aigialomycin D
Samuel Z.Y. Ting, Lynton J. Baird, Elyse Dunn, Reem Hanna, Dora Leahy, Ariane Chan,
*
John H. Miller, Paul H. Teesdale-Spittle, Joanne E. Harvey
Centre for Biodiscovery, Schools of Chemical and Physical Sciences, and Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington
6140, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2013
Received in revised form 24 September 2013
Accepted 14 October 2013
Available online 21 October 2013
Several analogues of the fungal natural product aigialomycin D (AmD) have been synthesised. These
include the stereoisomer 50R,60S-AmD, 2,4-di-deoxyAmD, 10,20,70,80-tetrahydroAmD and a 15-membered
macrocyclic sulfone. Growth inhibitory activities of these compounds against the HL-60 leukaemic cell
line were measured. The ring-expanded sulfone and tetrahydro-analogue were found to have similar IC50
values to the natural product, whereas the 50R,60S-stereoisomer was inactive. Energy minimisation of
AmD and the synthesised analogues resulted in a range of lowest energy conformers, from planar, open
arrangements of the macrocycle in AmD and tetrahydroAmD to bent, L-shaped structures for the sulfone.
The synthesis of methyl orsellinate was investigated and optimised as part of this work. A stereo-
Keywords:
Aigialomycin D
Resorcylic acid lactone
Analogue
divergent route to both enantiomers of the diol fragment from
D-ribose was also achieved.
Ó 2013 Elsevier Ltd. All rights reserved.
Methyl orsellinate
€
RambergeBacklund
Ring closing metathesis
1. Introduction
the ring system. Further structural variation is available through the
preparation of analogues, which has been achieved in a de novo
synthetic fashion,13e15 biosynthetically through heterologous gene
expression16 and by semisynthesis.17 Notable examples of synthetic
analogues include cycloproparadicicol and related species,13a
pochonin-based macrolactams,13b,c oxime derivatives of radi-
cicol,9,13d deoxygenated L-783,277 variants,13e and alkene-13f,g and
O-modified analogues of the RALs.2,14
Through these and other studies, an understanding of the
structureeactivity relationships for these compounds is beginning
to be realised. For instance, the potent kinase inhibitors among this
class all have a Z-enone moiety at C70eC80.3 In contrast, the C70eC80
‘trans’-configured species radicicol (with its trans-epoxide) and
pochonin D (with an E-alkene) behave as HSP90 inhibitors, binding
competitively at the ATP-binding site.2,18 Among the RALs, aigia-
lomycin D (AmD) seems to be an outlier, in that it has the C70eC80 E-
alkene, is a moderate kinase inhibitor, but does not inhibit
HSP90.13a,14a Aigialomycin D was originally isolated from a marine
mangrove fungus (Aigialus parvus)5 and has subsequently been
found in two further fungus species.6,19 It displays moderate
growth inhibitory activity against the human epidermoid carci-
noma (KB) and breast cancer (BC-1) cell lines and interacts with
kinase targets (CDK1, CDK5, GSK3). Its unusual properties and
synthetically tractable structure make it a useful starting point for
The resorcylic acid lactones (RALs, Fig. 1), a class of macrocyclic
natural products with a variety of biological actions, have gained
widespread attention as leads for drug discovery.1e3 These myco-
toxins4 have a wide range of activities, from antimalarial (aigialo-
mycin D, paecilomycin E)5,6 to antifouling (cochliomycin A)
properties.7 With respect to biochemical targets, estrogen agonism
(zearalenone)8 and inhibition of the heat-shock protein HSP90
(radicicol, pochonin D)9e11 are known within the class, yet the
majority of the naturally occurring RALs act as protein kinase in-
hibitors (hypothemycin, L-783,277, LL-Z1640-2, radicicol A and
aigialomycin D).2,3,12
The privileged benzo-fused 14-membered macrolactone ring of
the RALs represents a rich scaffold for structural variation. This is
evidenced biosynthetically by the diversity of natural compounds
in this class (see Fig. 1), which differ particularly in the degree and
positioning of oxidation and unsaturation about the macrolactone
ring. The array of bioactivity noted for these compounds indicates
the subtle interplay of the functionality and stereochemistry about
* Corresponding author. Tel.: þ64 4 4635956; fax: þ64 4 4635237; e-mail ad-
dress: Joanne.Harvey@vuw.ac.nz (J.E. Harvey).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.042

10582
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
synthesis of AmD20 invoked a combination of ring-closing me-
23,24
€
tathesis and RambergeBacklund reactions.
This strategy pre-
vents the undesired cyclohexene formation that has been observed
if metathesis at C70eC80 is performed in the presence of the internal
C10eC20 alkene.14a,22a,25 A 15-membered sulfone-containing mac-
rolactone is the penultimate intermediate in the synthetic strategy,
and its deprotection would afford a novel analogue that is uniquely
accessible through this methodology. The sulfone-containing ana-
logue 6, therefore, was also pursued in this work.
During the course of the present study, Chen and co-workers
reported syntheses of two of these AmD-based analogues (3, 4),
amongst others.15 Their analogues were screened against CDK2 (a
cyclin-dependent kinase) and MNK2 (a mitogen-activated protein
kinase-interacting kinase that phosphorylates the oncogene eIF4E),
which are both susceptible to AmD. 100R-AmD (3) and 4-O-methyl-
AmD were found to inhibit CDK2/cyclin A with similar potency to
AmD, while 50,60-dideoxy-AmD, 50,60-acetonido-AmD and 70,80-
dihydro-AmD were similarly active against MNK2.26 Tetrahy-
droAmD (4) did not show strong inhibition of either kinase.15
2. Results and discussion
The target analogues were prepared using a synthetic strategy
related to that already reported by us for the total synthesis of AmD
(Scheme 1).20 The full carbon skeleton, 7, would be accessed by
substitution of the benzyl bromide 8 or 9 with thiol 10, and ester-
ification with the homoallylic alcohol 11. Macrocycle formation
would be achieved through ring-closing metathesis (RCM) of the
€
benzylic sulfone 7. A subsequent RambergeBacklund reaction
(RBR) would provide the styrene moiety of analogues 1e5, while
the RBR step would be omitted for the sulfone analogue 6.
Fig. 1. Representative naturally occurring RALs.
novel analogue synthesis. Preparation of new analogues will shed
more light on structural features of the RALs required for thera-
peutic applications.
To this end, we chose to pursue analogues of aigialomycin D
differing from the natural material in the stereochemistry at the
diol (C50 and C60) (analogue 2) and methyl (C100) (analogue 3)
substituents, in the degree of unsaturation on the macrocyclic ring
(analogue 4) and in the oxygenation of the aromatic ring (analogue
5) (Fig. 2). The RAL ring system embodied by AmD is synthetically
accessible by numerous diverse routes.13,14a,20e22 Our total
Scheme 1. Retrosynthesis of proposed analogues 1e6.
Benzylic bromide 8 was to be prepared from methyl orsellinate
(12), as before.20 The latter compound has been prepared numerous
times by Claisen self-condensation of methyl acetoacetate and
subsequent cyclisation of the resulting triketoester (Scheme 2).27,28
Good yields are typically obtained by isolating the triketoester and
allowing the subsequent cyclisation to occur under (usually) basic
conditions.27,29 A one-pot method, developed to expedite the syn-
thesis, was reported to afford methyl orsellinate in a 60% yield.28
However, in our hands, the one-pot variant gave consistently
poor results (ꢀ40% yield).20 As part of our analogue studies, we had
Fig. 2. Proposed analogues for this study.

S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
10583
as the base in this Wittig reaction, none of the desired product 18
was formed, and only starting material was recovered. The dis-
covery that KHMDS afforded traces of trimethylsilylated product 19
led to an optimisation campaign, which culminated in de-
velopment of a procedure that used a combination of KHMDS and
TMSCl for this transformation. The optimised procedure provided
a mixture of the desired alkene 18 and mono- and bis-O-silylated
derivatives 19e21, which was homogenised by treatment with an
aqueous acid to afford diol 18. This desilylation procedure also re-
quired care to avoid competing deprotection of the labile acetonide
protecting group over time. Ultimately, treatment of the ice-water
cooled reaction mixture with aqueous hydrochloric acid for
15e30 min was found to provide 18 in a high (87%) yield. Diol
cleavage of 18 with sodium periodate, followed immediately by
a Wittig reaction with the stabilised ylide methyl (triphenylphos-
Scheme 2. Formation of methyl orsellinate (12) from methyl acetoacetate.
phoranylidene)acetate produced the
in 83% yield.
a,b-unsaturated ester ent-16
occasion to revisit the methyl orsellinate synthesis and noticed that
degradation of the material was occurring in the cyclisation step. In
the one-pot approach, this step is typically achieved with acid in
order that the anionic species from the Claisen condensation are
quenched. It became apparent that the reported28 conditions in-
volving addition of dilute HCl were prone to over-acidification, with
apparent reversion to methyl acetoacetate as well as production of
highly polar materials (thought to be orsellinic acid or an acyclic
precursor). Use of a milder acid (aqueous acetic acid) led to im-
proved results (up to 60% isolated yield of methyl orsellinate), al-
though there were indications that hydrolysis of the methyl ester
was still occurring. Avoiding the presence of water by quenching
with methanol and glacial acetic acid gave improved and consistent
results, with methyl orsellinate yields of 60e66% obtained. It is
important to note that rapid and complete removal of the acetic
acid in the work-up (under reduced pressure) is crucial in order to
circumvent hydrolysis of the product 12 and erosion of the isolated
yield.
The enantiomeric dienes 16 and ent-16 were individually sub-
jected to our optimised conjugate reduction conditions20 to afford
the partially saturated esters 22 and ent-22, respectively
(Scheme 5). High yielding ester reduction (81e97%), mesylation
(91e97%) and substitution (82e95%) provided the thioacetates
2320 [overall 43% yield from
yield from -ribose (seven steps)].
D
-ribose (seven steps)] and ent-23 [32%
D
Coupling of the three main fragments was achieved by in situ
deacetylation of thioacetates 23 and ent-23 and substitution of the
benzylic bromide functionalities within orsellinate 8 or benzoate 9
(Scheme 6). The phenolic groups of the resulting thioethers 24 and
ent-24 were reprotected with MOMCl to give 25 and ent-25, re-
spectively.20 The methyl esters 25, ent-25 and 26 were saponified to
liberate the corresponding carboxylic acids, which were esterified
with the homoallylic alcohols R-11 and S-11 using Mitsunobu
chemistry. The resulting products 27e30 contained the full carbon
skeleton of aigialomycin D and the proposed analogues.
Oxidation of the thioether within compounds 27e30 and RCM
of the resulting sulfones afforded 15-membered macrocycles
31e34 (Scheme 7). Compound 31, with the natural stereochemistry,
was deprotected under acidic conditions to give sulfone analogue 6.
The remaining protected sulfones were subjected to a ring-
Acetylation and bromination of methyl orsellinate (12) afforded
8 as before,20 albeit in an improved yield (79% over two steps,
Scheme 3). Methyl 2-bromomethylbenzoate (9) was prepared from
methyl 2-methylbenzoate (13), in accordance with our reported
method,30 as a precursor to 2,4-dideoxy-AmD (5).
€
contractive RambergeBacklund reaction to provide dienes 35e38.
The AmD precursor 35 was hydrogenated and subjected to acid
hydrolysis to afford tetrahydroAmD (4). Aigialomycin D (1) and
analogues 2 and 5 were obtained in high yields by global depro-
tection of 35, 36 and 38, respectively, under acidic conditions. In the
formation of 2, a small quantity of a stereoisomer was present in
the reaction mixture; this was separable by careful chromatogra-
phy. It is tentatively proposed to be the 60-epimer of 2, i.e., 50R-AmD,
which could result from acid-catalysed isomerisation of the allylic
alcohol. Surprisingly, deprotection of the 100R-compound 37 under
similar conditions but with a prolonged reaction time (5 days) led
to an inseparable mixture of two compounds in a low yield. Neither
of these displayed the same 1H NMR signals as analogue 2, as would
be expected for the desired product, 3, due to the enantiomeric
relationship between compounds 2 and 3. It is tentatively proposed
that epimerisation of the allylic alcohol and/or isomerisation of the
C70eC80 alkene occurred in the acidic conditions over the lengthy
reaction time.34
The bioactivities of aigialomycin D and the prepared ana-
logues against the human promyelocytic leukaemia HL-60 cell
line were determined using an MTT cell proliferation assay35
(n¼1e2 experiments) (Table 1). The measured activity of aigia-
lomycin D towards this cancer cell line was comparable to that
reported for KB and BC-1 cells (entry 1).5 Interestingly, the 15-
membered macrocyclic sulfone 6 was similarly potent (entry 2),
which perhaps indicates that this compound intercepts a differ-
ent cellular target to the 14-membered RALs, since kinases
1) 12, Ac2O, NEt3
2) NBS, [PhC(O)O]2
R
O
R
O
OCH3
OCH3
Br
or
13, NBS, hυ
R
R
12 R = OH
13 R = H
8 R = OAc (79%)
9 R = H (90%)
Scheme 3. Synthesis of benzyl bromides 8 and 9.
The pseudo-symmetry of -ribose (14) allowed for the stereo-
D
divergent preparation of both enantiomers of the diol fragment, 10
(viz. Scheme 1). Optimisation of our earlier route to (50S,60R)-1020
has afforded improved step economy and yield. Thus,
(14) can be converted to methyl 2,3-O-isopropylidene-b-D-ribo-
D-ribose
furanoside in a higher yield (80%) by employing acetyl chloride as
an anhydrous source of HCl (Scheme 4). Direct conversion of the
resulting primary alcohol to iodide 1531 in a single step and high
yield (83%) is followed by the VasellaeWittig reaction sequence, as
reported before,20 to efficiently produce the diene 16.
For the enantiomeric series (i.e., synthesis of ent-16), 2,3-O-
isopropylidene-
D
-ribose (17) was prepared in high yield from D-ri-
bose (14).32 Hemiacetal 17 was then treated with the ylide derived
from methyl triphenylphosphonium bromide. Unfortunately, when
potassium tert-butoxide,33 n-butyllithium or LDA were employed

10584
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
Scheme 4. Enantiodivergent synthesis of 16 and ent-16 from D-ribose.
Scheme 5. Conversion of 16 and ent-16 into thioacetates 23 and ent-23.y
Scheme 6. Fragment coupling.y
typically have fairly specific substrate requirements.2,3,15 Satura-
tion of the aigialomycin D macrocycle, providing 4, led to only
a marginal loss of potency (entry 3). Chen and colleagues showed
that this compound (4) does not inhibit MNK2, a kinase that
regulates oncogene eIF4E and is very sensitive to aigialomycin
D,15 and it only demonstrated weak inhibition of CDK2/cyclin A.
Thus, its interaction with an alternative target may be re-
sponsible for the HL-60 activity. In comparison, the diastereomer
of aigialomycin D differing at both diol centres (2) had no de-
deprotection of the acetonide occurs in the conditions of the
assay.
These results demonstrate the complex and finely tuned nature
of the relationship between RAL structure and cytotoxicity. In order
to gain a preliminary understanding of the possible reasons for this
relationship, the lowest energy conformations of AmD (1), its tet-
rahydro analogue 4, diol stereoisomer 2 and sulfones 6 and 34 were
calculated using a mixed torsional/low-mode sampling conforma-
tional search as implemented in MacroModel.36 For comparison,
radicicol was modelled under various conditions and with a number
of forcefields. As the OPLS-2005 forcefield with vacuum simulation
tectable activity up to 100
mM (entry 4). Unfortunately, 2,4-
dideoxy-AmD (5) decomposed before it was tested. In-
terestingly, its precursor, the acetonide-protected sulfone 34, had
growth inhibitory activity (entry 5) similar to the natural product
(entry 1) and the resorcylic sulfone 6 (entry 2). Given the simi-
larities in structure and activity of 34 and 6, it is possible that
y
Aigialomycin D numbering is used for precursors.

S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
10585
Scheme 7. End-game sequence and synthesised analogues.y
most accurately reproduced the conformation of radicicol bound to
HSP90 (within the pdb file 2WER), this method was chosen for the
calculations of the compounds described in our work. For com-
pleteness, the simulations were also performed on AmD in a water
continuum solvent model, providing comparable results.
The lowest energy conformations calculated for aigialomycin D
(1) and analogues 2, 4, 6 and 34 are shown in Fig. 3. A range of gross
conformations is seen, from open, largely planar arrangements in 1,
2 and 4, to highly bent in 6 and 34. For comparison, Karplus and
Winssinger have previously defined three favoured conformations
for various natural and synthetic RALs based on radicicol11,9 and
pochonins D/E14c as:
Table 1
Growth inhibitory activity against HL-60 cells
Entry
Compound
IC50 (mM)
1
2
3
4
5
AmD (1)
6
4
2
12.50
14.30
19.73
>100
14.0
34
Fig. 3. Lowest energy conformations of compounds 1, 2, 4, 6, 34.

10586
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
1) being essentially planar (P-shape);
was measured on a PerkineElmer 241 Polarimeter or a Rudolph
Research Analytical Autopol II Polarimeter (sodium lamp) and
specific rotation was calculated according to the formula
2) having the macrocyclic ring perpendicular to the aromatic ring
with the macrocycle to the right of the aromatic ring and bent
in the anti-clockwise direction (L-shape);
3) having the alternative perpendicular arrangement where the
macrocycle bends away from the aromatic ring in the clockwise
direction (L0-shape).
[
a
]D¼(
a
$100)/c$l; where concentration (c) is given in g/100 mL,
pathlength of light (l) is in dm and optical rotation (
a
) is in degrees.
Infrared spectra were obtained on either a Biorad FTS-7 spec-
trometer or a Bruker Tensor 27 FTIR spectrometer. High-resolution
mass spectrometry (HRMS) was recorded on a Mariner 5158 time-
of-flight spectrometer or a Waters Q-TOF PremierÔ Tandem Mass
Spectrometer.
Lowest energy conformers of aigialomycin D and the analogues
studied were obtained by molecular mechanics. Each structure was
subjected to exhaustive conformational searching using the mixed
torsional/low-mode sampling routine as implemented in Macro-
Model version 9.7 and visualised in Maestro 9.0. Structures ob-
tained were minimised using the OPLS-2005 forcefield in both
vacuum and the GB/SA water continuum solvent model37 using the
Of these, molecules that favour the L-shape conformation were
found to be active towards HSP90, which corresponds to the con-
former modelled9 and observed in the crystal structure18 of radi-
cicol in the ATP-binding site of HSP90. Our modelling studies
demonstrate that AmD (1) favours a fairly planar conformation
(akin to the P-shape), as does the hydrogenated analogue 4. In
contrast, the sulfones 6 and 34 favour an L-shape. The 50S,60R di-
astereomer of AmD, 2, favours a conformation somewhat different
to the natural product that lies between the P- and L-shapes. These
data might help to explain the growth inhibition, in that the
measured IC50 values could result from inhibition of different tar-
gets by the various compounds according to their favoured con-
formations. Thus, AmD (micromolar active) is known to interact
with several kinases, while HSP90 inhibition might be the primary
interaction for the sulfones 6 and 34 that prefer the L-conforma-
tion. The poorly active compound 2 would, by this argument, not be
involved in interactions with the kinases or HSP90 due to its con-
formational profile, with no P- or L-shape conformations available
within 5 kJ molꢁ1 of the lowest energy conformer. The situation
with tetrahydroAmD is not clear, since the calculated conformers
are similar in shape to AmD, yet it was not a potent inhibitor of
CDK2 or MNK2 in Chen’s study.15 Assays that allow investigation of
the protein targets involved in the cellular interactions are needed
in order to clarify the mode(s) of action of these compounds.
ꢀ
PolakeRibiere conjugate gradient (PRCG) method and terminated
on a gradient threshold of 0.05 kJ molꢁ1
A . The simulation was
ꢁꢁ1
repeated until the lowest energy structure reported had been
replicated at least 100 times and no conformer within 5 kJ molꢁ1 of
the lowest energy conformer was obtained fewer than 50 times.
4.2. Improved synthesis of methyl 2,4-dihydroxy-6-
methylbenzoate (methyl orsellinate, 12)
Methyl acetoacetate (2.00 mL, 18.53 mmol) was added to a stir-
red solution of NaH (1.12 g, 27.79 mmol, 60% in mineral oil) in THF
(40 mL) at 0 ꢂC and allowed to warm to room temperature over
20 min. The solution was then cooled to ꢁ78 ꢂC, nBuLi (8.80 mL,
17.61 mmol, 2.0 M in cyclohexane) added and the solution allowed
to warm to room temperature. After 17 h the solution was refluxed
for 12 h, cooled to 0 ꢂC, slowly quenched with MeOH (20 mL), then
acidified to pH 3 with glacial AcOH (ca. 5 mL) and warmed to room
temperature. After 18 h, the reaction mixture was concentrated
rapidly under reduced pressure to remove all the acetic acid. The
residue was extracted with EtOAc (4ꢃ40 mL) and the combined
organic layers were dried over MgSO4, filtered and the solvent
evaporated under reduced pressure to yield a red solid, which was
purified by flash column chromatography (silica, 2:1 hexanes/
EtOAc) to afford the desired compound as a colourless solid (1.01 g,
60%). Rf¼0.45 (2:1 hexanes/EtOAc). 1H NMR (500 MHz, CDCl3)
3. Conclusion
In conclusion, we have synthesised a series of analogues of
aigialomycin
D
using our previously established Ram-
€
bergeBacklund/RCM strategy. The synthetic approach allowed ac-
cess to novel sulfone analogues with enlarged 15-membered rings,
an analogue with a saturated macrocycle, and diastereoisomeric
variants. Determination of the growth inhibitory activity of the
analogues against HL-60 cells demonstrated a series of finely tuned
structureeactivity relationships, with the larger-ring sulfones 6 and
34 and tetrahydroaigialomycin D 4 showing similar activity to the
natural product. Molecular modelling provided calculated lowest
energy conformers for these compounds that ranged from planar,
open macrocycles (for AmD [1] and tetrahydroAmD 4) to bent, L-
shaped structures (for sulfones 6 and 34).
d
11.75 (s, 1H), 6.25 (d, J¼2.5 Hz, 1H), 6.21 (d, J¼2.5 Hz, 1H), 5.50 (s,
1H), 3.89 (s, 3H), 2.46 (s, 3H). The spectral data matched those re-
ported previously.28
4.3. Improved synthesis of (2R,3R,4S)-3,4-O-(1-
methylethylidene)hex-5-en-1,2-diol (18)
4. Experimental section
4.1. General information
KHMDS (13.60 mL, 6.78 mmol, 0.5 M in toluene) was added to
a solution of CH3PPh3Br (1.85 g, 5.20 mmol) in THF (20 mL) at
ꢁ78 ꢂC. After 1 h at ꢁ78 ꢂC, the reaction was warmed to 0 ꢂC and
a
solution of the acetonide-protected ribose 17 (430 mg,
All reactions were performed under argon in oven-dried or
flame-dried glassware using dry solvents and standard syringe
techniques. All reagents were of commercial quality unless other-
wise specified. MW-assisted reactions were carried out in a Mile-
stone Microsynth reactor, monitored by a fibre optic temperature
and pressure probe. 1H and 13C NMR spectra were recorded on ei-
ther a Varian Unity Inova 300 (300 MHz for 1H and 75 MHz for 13C),
or a Varian Unity Inova 500 (500 MHz for 1H and 125 MHz for 13C)
2.26 mmol) and TMSCl (0.35 mL, 2.71 mmol) in THF (15 mL) was
added. The resulting solution was allowed to warm to room tem-
perature and stirred overnight. It was then cooled to 0 ꢂC and
acidified to pH 0e1 with 10% HCl(aq). After 15 min, the aqueous
layer was separated and extracted with EtOAc (3ꢃ30 mL). The
combined organic layers were dried over MgSO4, filtered, concen-
trated under reduced pressure and the resultant cream-coloured
solid purified with flash column chromatography (silica, gradient
elution 1:1 to 1:2 hexanes/EtOAc) to afford the desired compound
as a clear oil (370 mg, 87%). Rf¼0.08 (2:1 hexanes/EtOAc). 1H NMR
spectrometer. All chemical shifts (d) were referenced to solvent
peaks (for 1H NMR, the corresponding residual protic solvent peaks
were used) as follows: for spectra in CDCl3, 1H 7.26 ppm, 13C
77.0 ppm; for spectra in acetone-d6, 1H 2.05 ppm, 13C 29.8 ppm; for
spectra in MeOH-d4, 1H 3.31 ppm, 13C 49.0 ppm. Optical rotation
(500 MHz, CDCl3)
d
5.96 (ddd, J¼17.1, 11.0, 6.0 Hz, 1H), 5.41 (d,
J¼17.0 Hz, 1H), 5.26 (d, J¼11.0 Hz, 1H), 4.65 (t, J¼6.0 Hz, 1H), 4.09
(dd, J¼6.4, 8.4 Hz, 1H), 3.75 (m, 1H), 3.62 (m, 2H), 3.20 (br s, 2H),

S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
10587
1.42 (s, 3H), 1.31 (s, 3H). The spectral data matched those reported
previously.32b
1.80e1.70 (m, 2H), 1.47 (s, 3H), 1.36 (s, 3H). The spectral data
matched those of the enantiomer (22) reported previously.20
4.6. (4R,5S)-4,5-O-(1-Methylethylidene)hept-6-en-1-
thioacetate (ent-23)
4.4. Methyl (2Z,4R,5S)-4,5-O-(1-methylethylidene)hepta-2,6-
dienoate [(Z)-ent-16] and methyl (2E,4R,5S)-4,5-O-(1-
methylethylidene)hepta-2,6-dienoate [(E)-ent-16]
A solution of ester ent-22 (296 mg, 1.38 mmol) in Et2O (10 mL)
was added to a suspension of LiAlH4 (315 mg, 8.29 mmol) in Et2O
(15 mL) and stirred at ꢁ10 ꢂC. After 30 min, TLC analysis suggested
there was remaining starting material, so additional LiAlH4 (44 mg,
1.17 mmol) was added. After an additional 10 min, the reaction was
quenched with wet Na2SO4, dried over anhydrous Na2SO4 and
concentrated under reduced pressure to afford the desired com-
pound (4R,5S)-4,5-O-(1-methylethylidene)hept-6-en-1-ol as a col-
NaIO4 (841 mg, 3.93 mmol) was added to a solution of diol 18
(370 mg, 1.97 mmol) in MeOH (20 mL). After 3 h, TLC suggested the
consumption of starting material. Silica gel was then added and the
solution stirred for 30 min, then filtered through a CeliteÒ plug and
eluted with MeOH (20 mL). The filtrate was then cooled to 0 ꢂC
under argon, Ph3P]CHCO2CH3 (789 mg, 2.36 mmol) was added
and the solution allowed to warm to room temperature. After
stirring overnight, the solvent was evaporated under reduced
pressure to yield a yellow solid, which was partitioned between
EtOAc (20 mL) and satd NH4Cl (20 mL). The aqueous layer was
separated and extracted with EtOAc (2ꢃ10 mL). The combined or-
ganic layers were dried over MgSO4, filtered, concentrated under
reduced pressure and the resultant yellow solid purified with flash
column chromatography (silica, gradient elution, 10:1 to 5:1 hex-
anes/EtOAc) to afford a mixture of the alkene stereoisomers as
colourless crystals in oil [346 mg, 83% (E/Z¼1:5.1)]. A sample was
further purified with flash column chromatography (silica, gradient
elution 10:1 to 5:1 hexanes/EtOAc) for characterisation purposes to
afford separated (E)-ent-16 as colourless crystals and (Z)-ent-16 as
ourless oil (209 mg, 81%). Rf¼0.10 (2:1 hexanes/EtOAc). ½a D18
þ2.5 (c
ꢄ
1.00, CHCl3) [cf. lit.20 for the enantiomer ½a 2D2
ꢁ6.1 (c 1.00, CHCl3)].
ꢄ
1H NMR (500 MHz, CDCl3)
d
5.81 (ddd, J¼17.1, 10.3, 7.8 Hz, 1H), 5.29
(ddd, J¼17.1, 1.6, 1.1 Hz, 1H), 5.23 (ddd, J¼10.3, 1.6, 0.9 Hz, 1H), 4.51
(dd, J¼7.4, 6.7 Hz, 1H), 4.17 (ddd, J¼8.5, 6.2, 5.0 Hz, 1H), 3.67 (t,
J¼5.8 Hz, 2H), 1.91 (s, 1H), 1.80e1.60 (m, 2H), 1.55 (m, 2H), 1.49 (s,
3H),1.37 (s, 3H). The spectral data matched those of the enantiomer
reported previously.20
MsCl (0.11 mL, 1.48 mmol) was added to solution of the alcohol
above (209 mg, 1.12 mmol), NEt3 (0.24 mL, 0.27 mmol) and DMAP
(14 mg, 0.11 mmol) in CH2Cl2 (10 mL) and stirred at 0 ꢂC. TLC analysis
suggested the consumption of starting material after 17 h. The sol-
vent was then evaporated under reduced pressure to yield a yellow
solid, which was partitioned between EtOAc (20 mL) and water
(20 mL). The organic layer was then separated, washed with satd
NaHCO3 (10 mL), dried over MgSO4, filtered, concentrated under
reduced pressure and the resultant yellow oil purified by flash col-
umn chromatography (silica, 3:1 hexanes/EtOAc) to afford the de-
sired compound (4R,5S)-4,5-O-(1-methylethylidene)hept-6-en-1-
methanesulfonate as a colourless oil (270 mg, 91%). Rf¼0.25 (2:1
hexanes/EtOAc). þ6.1 (c 1.00, CHCl3) [cf. lit.20 for the enantiomer
a colourless oil. [(Z)-ent-16]: Rf¼0.59 (2:1 hexanes/EtOAc). ½a D21
ꢄ
ꢁ167.4 (c 3.00, CHCl3) [cf. lit.20 for the enantiomer (Z)-16 ½a 2D2
ꢄ
þ216.84 (c 1.00, CHCl3)]. 1H NMR (500 MHz, CDCl3)
d 6.20 (dd,
J¼11.5, 7.4 Hz, 1H), 5.90 (dd, J¼11.8, 1.7 Hz, 1H), 5.68 (ddd, J¼7.4, 7.2,
1.6 Hz, 1H), 5.66 (ddd, J¼17.1, 10.4, 7.3 Hz, 1H), 5.26 (ddd, J¼17.1, 3.0,
1.7 Hz, 1H), 5.15 (ddd, J¼10.3, 1.6, 1.0 Hz, 1H), 4.86 (ddd, J¼8.3, 2.2,
1.0 Hz, 1H), 3.72 (s, 3H), 1.54 (s, 3H), 1.41 (s, 3H). [(E)-ent-16]:
Rf¼0.50 (2:1 hexanes/EtOAc). ½a D21
ꢄ
þ30.2 (c 1.00, CHCl3). 1H NMR
(500 MHz, CDCl3)
d
6.79 (dd, J¼15.7, 5.6 Hz, 1H), 6.07 (dd, J¼15.7,
½
a 2D2
ꢄ
ꢁ14.3 (c 1.09, CHCl3)]. 1H NMR (500 MHz, CDCl3)
d 5.84 (ddd,
1.5 Hz, 1H), 5.69 (ddd, J¼17.1, 10.3, 7.6 Hz, 1H), 5.36 (dd, J¼17.1,
1.5 Hz, 1H), 5.26 (ddd, J¼10.3, 1.5, 0.9 Hz, 1H), 4.78 (ddd, J¼7.0, 5.6,
1.6 Hz, 1H), 4.71 (tt, J¼7.0, 0.9 Hz, 1H), 3.75 (s, 3H), 1.55 (s, 3H), 1.41
(s, 3H). The spectral data matched those of the enantiomers re-
ported previously.20
J¼17.1, 10.3, 7.7 Hz, 1H), 5.33 (ddd, J¼17.1, 1.6, 1.1 Hz, 1H), 5.30 (ddd,
J¼10.3, 1.6, 0.9 Hz, 1H), 4.57 (dd, J¼7.5, 6.4 Hz, 1H), 4.30 (dt, J¼9.9,
6.3 Hz, 1H), 4.25 (ddd, J¼9.8, 7.0, 6.0 Hz, 1H), 4.19 (ddd, J¼9.0, 6.2,
4.7 Hz, 1H), 3.01 (s, 3H), 1.99 (tdd, J¼12.3, 9.2, 6.2 Hz, 1H), 1.88e1.78
(m,1H),1.60e1.52 (m, 2H),1.52 (s, 3H),1.40 (s, 3H). The spectral data
matched those of the enantiomer reported previously.20
4.5. Methyl (4R,5S)-4,5-O-(1-methylethylidene)hept-6-enoate
(ent-22)
KSAc (58 mg, 0.51 mmol) was added to a solution of the
mesylate above (112 mg, 0.42 mmol) in DMF (4 mL) stirred at 0 ꢂC,
then allowed to warm to room temperature. TLC suggested the
consumption of starting material after 20 h. The reaction mixture
was then partitioned between Et2O (10 mL) and water (10 mL). The
organic layer was then separated, washed with satd NaHCO3
(2ꢃ5 mL), brine (5 mL), dried over MgSO4, concentrated under
reduced pressure and the resultant faint yellow liquid purified with
flash column chromatography (silica, 10:1 hexanes/EtOAc) to afford
the desired compound (4R,5S)-4,5-O-(1-methylethylidene)hept-6-
en-1-thioacetate as a colourless liquid (85 mg, 82%). Rf¼0.60 (2:1
hexanes/EtOAc). þ11.5 (c 1.00, CHCl3) [cf. lit.20 for the enantiomer
NaBH4 (162 mg, 4.27 mmol) was added to a solution containing
a 1:5.1 mixture of a,b-unsaturated ester isomers (E)- and (Z)-ent-16
(189 mg, 0.89 mmol), CuCl (88 mg, 0.89 mmol) and cyclohexene
(0.36 mL, 3.56 mmol) in Et2O (5 mL) stirred at ꢁ78 ꢂC. After 30 min,
TLC suggested the presence of starting material, so additional CuCl
(9 mg, 0.09 mmol) and NaBH4 (7 mg, 0.18 mmol) were added. After
an additional 15 min, TLC suggested the consumption of starting
material. The solvent was then evaporated under reduced pressure
to yield a grey solid. The crude mixture was partitioned between
EtOAc (10 mL) and satd NH4Cl (10 mL), and the aqueous layer
separated and extracted with EtOAc (2ꢃ5 mL). The combined or-
ganic layers were then dried over MgSO4, filtered, concentrated
under reduced pressure and the resultant yellow oil purified with
flash column chromatography (silica, gradient elution, 15:1 to 9:1
hexanes/EtOAc) to afford the desired compound as a colourless oil
(167 mg, 88%). Rf¼0.52 (2:1 hexanes/EtOAc). þ27.2 (c 2.00, CHCl3)
23 ½
aꢄ2D2 ꢁ9.5 (c 1.05, CHCl3)]. 1H NMR (500 MHz, CDCl3)
d 5.79 (ddd,
J¼17.1, 9.7, 7.8 Hz, 1H), 5.30 (d, J¼17.1 Hz, 1H), 5.24 (d, J¼10.3 Hz,
1H), 4.49 (t, J¼6.9 Hz, 1H), 4.13 (m, 1H), 2.95e2.83 (m, 2H), 2.32 (s,
3H), 1.80e1.68 (m, 1H), 1.66e1.50 (m, 2H), 1.49e1.41 (m, 1H), 1.47 (s,
3H),1.35 (s, 3H). The spectral data matched those of the enantiomer
(23) reported previously.20
[cf. lit.20 for the enantiomer 22 ½a 2D2
ꢄ
ꢁ31.0 (c 1.00, CHCl3)]. 1H NMR
4.7. Methyl (60R,70S)-6-(60,70-O-(100-methylethylidene)-20-thia-
non-80-enyl)-2,4-di(hydroxy)benzoate (ent-24)
(500 MHz, CDCl3)
d
5.82 (ddd, J¼17.2, 10.5, 7.7 Hz, 1H), 5.34 (ddd,
J¼17.1, 2.7, 1.2 Hz, 1H), 5.26 (ddd, J¼10.2, 1.4, 1.0 Hz, 1H), 4.54 (dd,
J¼7.5, 6.4 Hz, 1H), 4.15 (ddd, J¼8.8, 6.2, 5.4 Hz, 1H), 3.68 (s, 3H), 2.50
(ddd, J¼16.3, 8.3, 6.4 Hz, 1H), 2.39 (ddd, J¼16.4, 8.5, 7.4 Hz, 1H),
A solution of thioacetate ent-23 (195 mg, 0.79 mmol) and
resorcylic bromoester 8 (339 mg, 0.79 mmol) in MeOH (20 mL) was

10588
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
degassed by sonicating while flushing with argon for 10 min. K2CO3
(276 mg, 2.00 mmol) was then added to the reaction mixture. After
24 h, the solvent was evaporated under reduced pressure and the
crude product dissolved in EtOAc (20 mL) and satd NH4Cl (20 mL).
The aqueous layer was then separated and extracted with EtOAc
(2ꢃ15 mL). The combined organic layers were then washed with
brine (10 mL), dried over MgSO4, filtered, concentrated under re-
duced pressure and the resultant brown oil purified with flash
column chromatography (silica, gradient elution 5:1 to 3:1 hex-
anes/EtOAc) to afford the desired compound as a colourless oil
(321 mg, 97%). Rf¼0.28 (2:1 hexanes/EtOAc). þ25.7 (c 1.00, CHCl3)
(R)-4-Penten-2-ol (43 mL, 0.42 mmol) was added to a stirred
solution of PPh3 (230 mg, 0.88 mmol) and DIAD (0.18 mL,
0.88 mmol) in THF (6 mL) at 0 ꢂC. After 20 min, a solution of the
benzoic acid above (160 mg, 0.35 mmol) in THF (5 mL) was added
and the solution allowed to warm to room temperature. After 24 h,
a small portion of silica was added to the solution and the solvent
evaporated under reduced pressure. The dry silica was then loaded
on a silica column and eluted with 20:1 to 7:1 hexanes/EtOAc to
afford the desired compound 28 as a colourless oil (96 mg, 52% over
two steps). Rf¼0.37 (2:1 hexanes/EtOAc). ꢁ3.6 (c 1.00, CHCl3). 1H
NMR (500 MHz, CDCl3)
d
6.71 (d, J¼2.2 Hz, 1H), 6.68 (d, J¼2.2 Hz,
[cf. lit.20 for the enantiomer 24 ½a 1D8
ꢄ
ꢁ21.5 (c 1.06, CHCl3)]. 1H NMR
1H), 5.85 (ddt, J¼17.2, 10.2, 7.0 Hz, 1H), 5.78 (ddd, J¼17.9, 10.3,
7.8 Hz, 1H), 5.28 (d, J¼17.1 Hz, 1H), 5.25e5.20 (m, 2H), 5.15 (s, 2H),
5.14 (m, 2H), 5.13e5.07 (complex m, 2H), 4.46 (dd, J¼7.3, 6.6 Hz,
1H), 4.09 (ddd, J¼8.5, 6.0, 4.8 Hz, 1H), 3.73 (d, J¼13.7 Hz, 1H), 3.69
(d, J¼13.7 Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 2.51e2.42 (complex m,
3H), 2.40e2.33 (m, 1H), 1.72 (m, 1H), 1.60e1.40 (complex m, 3H),
1.46 (s, 3H), 1.34 (s, 3H), 1.34 (d, J¼6.2 Hz, 3H). 13C NMR (125 MHz,
(500 MHz, CDCl3)
d
11.68 (s, 1H), 6.33 (d, J¼2.5 Hz, 1H), 6.27 (d,
J¼2.5 Hz, 1H), 5.78 (ddd, J¼17.2, 10.3, 7.8 Hz, 1H), 5.30 (ddd, J¼17.1,
1.7, 1.1 Hz, 1H), 5.24 (ddd, J¼10.3, 1.5, 0.9 Hz, 1H), 4.49 (dd, J¼7.7,
6.4 Hz, 1H), 4.09 (ddd, J¼9.1, 6.1, 4.3 Hz, 1H), 3.91 (d, J¼13.6 Hz, 1H),
3.92 (s, 3H), 3.86 (d, J¼13.6 Hz, 1H), 2.42 (t, J¼7.4 Hz, 2H), 1.75e1.65
(m, 1H), 1.64e1.49 (m, 2H), 1.48 (s, 3H), 1.49e1.39 (m, 1H), 1.37 (s,
3H). The spectral data matched those of the enantiomer reported
previously.20
CDCl3)
d 166.9, 158.6, 155.8, 139.0, 134.3, 133.8, 118.4, 118.3, 117.7,
110.4, 108.2, 102.3, 94.7, 94.3, 79.7, 77.8, 71.2, 56.2, 56.1, 40.2, 33.8,
31.6, 29.5, 28.2, 25.9, 25.6, 19.4. IR (KBr): 3094, 2980, 2902, 2840,
1711, 1607, 1584, 1434, 1380, 1213, 1160, 1029, 924 cmꢁ1. HRMS (ESI)
calculated for C27H40O8SNaþ [MþNa]þ 547.2342, found 547.2339.
4.8. Methyl (60R,70S)-6-(60,70-O-(100-methylethylidene)-20-thia-
non-80-enyl)-2,4-di-(methoxymethoxy)benzoate (ent-25)
NaH (14 mg, 0.35 mmol, 60% dispersion in mineral oil) was
4.10. (5S,7E,9S,10R)-1,2-(30,50-Di-O-methoxymethyl)benzo-4-
oxa-14-thia-3-oxo-5-methyl-9,10-O-(1-methylethylidene)pen-
tadec-7-ene 14,14-dioxide (32)
added to a stirred solution of diol ent-24 (54 mg, 0.14 mmol) in DMF
(1 mL) at 0 ꢂC. After 20 min, MOMCl (35
mL, 0.42 mmol) was added
and the solution allowed to warm to room temperature. After 21 h,
the reaction was diluted with satd NH4Cl (10 mL) and extracted
with Et2O (10 mL, then 2ꢃ5 mL). The combined organic layers were
then washed with brine (3ꢃ5 mL), dried over MgSO4, filtered,
concentrated under reduced pressure and the resultant yellow oil
purified with flash column chromatography (silica, gradient elution
10:1 to 5:1 hexanes/EtOAc) to afford the desired compound as
a colourless oil (54 mg, 81%). Rf¼0.30 (2:1 hexanes/EtOAc). þ34.5 (c
m-CPBA (75 mg, 77% w/w, 0.33 mmol) was added to a 0 ꢂC
stirred solution of thioether 28 (77 mg, 0.15 mmol) in CH2Cl2
(4 mL). After 2 h, TLC suggested there was remaining starting ma-
terial, so additional m-CPBA (38 mg, 77% w/w, 0.17 mmol) was
added. After 1 h, the reaction was quenched with 20% Na2SO3
(10 mL), the aqueous layer separated and extracted with CH2Cl2
(3ꢃ10 mL). The combined organic layers were then washed with
NaHCO3 (10 mL), dried over MgSO4, filtered, concentrated under
reduced pressure and the resultant yellow oil purified with flash
column chromatography (silica, 3:1 hexanes/EtOAc) to afford the
desired compound (4S)-pent-1-en-4-yl (60R,70S)-6-(60,70-O-(100-
methylethylidene)-20-thianon-80-enyl)-2,4-di(methoxymethoxy)
benzoate 20,20-dioxide as a colourless oil (50 mg, 61%). Rf¼0.17 (2:1
hexanes/EtOAc). ꢁ2.7 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
1.00, CHCl3) [cf. lit.20 for the enantiomer 25 ½a 1D8
ꢁ30.3 (c 0.08,
ꢄ
CHCl3)]. 1H NMR (500 MHz, CDCl3)
d
6.73 (d, J¼2.2 Hz, 1H), 6.67 (d,
J¼2.2 Hz, 1H), 5.78 (ddd, J¼17.1, 10.3, 7.8 Hz, 1H), 5.28 (ddd, J¼17.1,
1.6, 1.1 Hz,1H), 5.21 (ddd, J¼10.3, 1.6, 0.9 Hz,1H), 5.16 (s, 2H), 5.15 (s,
2H), 4.46 (dd, J¼7.6, 6.4 Hz, 1H), 4.08 (ddd, J¼8.6, 6.1, 4.7 Hz, 1H),
3.88 (s, 3H), 3.70 (s, 2H), 3.47 (s, 3H), 3.46 (s, 3H), 2.48e2.40 (m,
2H), 1.77e1.67 (m, 1H), 1.60e1.43 (m, 3H), 1.46 (s, 3H), 1.34 (s, H).
The spectral data matched those of the enantiomer (25) reported
previously.20
d
6.87 (d, J¼2.2 Hz, 1H), 6.85 (d, J¼2.2 Hz, 1H), 5.84 (ddt, J¼17.1, 10.1,
7.0 Hz, 1H), 5.74 (ddd, J¼17.1, 10.3, 7.7 Hz, 1H), 5.29 (dt, J¼17.0,
1.2 Hz, 1H), 5.25e5.00 (complex m, 8H), 4.46 (app. t, J¼7.0 Hz, 1H),
4.38 (d, J¼14.1 Hz,1H), 4.28 (d, J¼14.1 Hz,1H), 4.09 (dt, J¼7.4, 6.2 Hz,
1H), 3.46 (s, 3H), 3.45 (s, 3H), 3.02 (ddd, J¼13.9, 10.3, 5.9 Hz, 1H),
2.94 (ddd, J¼13.9, 10.1, 5.7 Hz, 1H), 2.46 (m, 1H), 2.37 (m, 1H), 1.95
(m, 1H), 1.84 (m, 1H), 1.53e1.48 (complex m, 2H), 1.45 (s, 3H), 1.34
4.9. (4S)-Pent-1-en-4-yl (60R,70S)-6-(60,70-O-(100-methyl-
ethylidene)-20-thianon-80-enyl)-2,4-di(methoxymethoxy)ben-
zoate (28)
KOH (98 mg, 1.73 mmol) was added to a solution of ester ent-25
(163 mg, 0.35 mmol) in 2:1 MeOH/H2O (4 mL) and the stirred so-
lution heated to 80 ꢂC. After 2 days, the solution was washed with
Et2O, the aqueous layer acidified to pH¼6 with 10% KHSO3 and
extracted with Et2O. The latter organic layer was then washed with
water (5 mL), dried over MgSO4, filtered and concentrated under
reduced pressure to afford (60R,70S)-6-(60,70-O-(100-methyl-
ethylidene)-20-thianon-80-enyl)-2,4-di-(methoxymethoxy)benzoic
acid as a yellow oil (160 mg), which was used in the next step
(d, J¼6.3 Hz, 3H), 1.33 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 166.6,
159.0, 156.4, 134.0, 133.6, 128.5, 119.2, 118.5, 117.9, 112.1, 108.4, 104.1,
94.7, 94.3, 79.5, 77.6, 71.7, 56.7, 56.32, 56.28, 51.4, 40.2, 29.3, 28.1,
25.5, 19.4, 18.7. IR (KBr): 3046, 2981, 2908, 2837, 1715, 1605, 1580,
1438, 1389, 1211, 1161, 1025, 924, 766, 746, 667 cmꢁ1. HRMS (ESI)
calculated for C27H40O10SNaþ [MþNa]þ 579.2240, found 579.2232.
Grubbs’ second generation catalyst (8 mg, 0.009 mmol) was
added to a solution of the diene above (50 mg, 0.090 mmol) in
CH2Cl2 (20 mL) in a 100 mL TeflonÔ reaction vessel. The vessel was
then flushed with argon, sealed and heated in a microwave reactor
to 75 ꢂC over 2 min, and held at this temperature for a further
28 min. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure and the resultant dark
green oil purified with flash column chromatography (silica, gra-
dient elution, 5:1 to 1:1 hexanes/EtOAc) to yield a green oil. This
green oil was then dissolved in CH2Cl2 (6 mL), activated carbon
added (10 mg) and the solution stirred for 30 min to remove
without further purification. 1H NMR (500 MHz, CDCl3)
d 6.79 (d,
J¼2.2 Hz, 1H), 6.75 (d, J¼2.2 Hz, 1H), 5.81 (ddd, J¼17.2, 10.2, 7.8 Hz,
1H), 5.30 (ddd, J¼17.1, 1.6, 1.0 Hz, 1H), 5.25 (s, 2H), 5.22 (dt, J¼10.3,
0.8 Hz, 1H), 5.18 (s, 2H), 4.49 (dd, J¼7.6, 6.4 Hz, 1H), 4.14 (ddd, J¼8.4,
6.1, 4.6 Hz, 1H), 3.98 (d, J¼13.4 Hz, 1H), 3.94 (d, J¼13.4 Hz, 1H), 3.52
(s, 3H), 3.49 (s, 3H), 2.50 (t, J¼7.0 Hz, 2H),1.76 (m,1H),1.66e1.50 (m,
3H), 1.49 (s, 3H), 1.36 (s, 3H). The spectral data matched those of the
enantiomer reported previously.20

S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
10589
remaining Grubbs’ catalyst by-product. The solution was then fil-
tered through a CeliteÒ plug and evaporated to afford the desired
compound 32 as a faint-green oil (32 mg, 67%) Rf¼0.11 (2:1 hex-
J¼15.9, 9.8, 3.4 Hz, 1H), 2.56 (dtd, J¼15.9, 3.2, 2.6 Hz, 1H), 2.25 (m,
1H), 2.07e1.94 (complex m, 2H), 1.53 (partially obscured m, 1H),
1.50 (d, J¼6.6 Hz, 3H). 13C NMR (150 MHz, acetone-d6)
d 172.3,166.3,
anes/EtOAc). þ50.5 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
d
6.98
163.4, 144.7, 132.9, 131.9, 131.5, 128.5, 108.2, 103.8, 102.5, 80.7, 77.7,
72.0, 38.1, 30.4, 28.9, 18.5. IR (KBr): 3300, 3021, 2975, 2921, 1651,
1601, 1410, 1251, 1212, 1142, 1010, 930 cmꢁ1. HRMS (ESI) calculated
for C18H22O6Naþ [MþNa]þ 357.1314, found 357.1319.
(d, J¼2.2 Hz, 1H), 6.86 (d, J¼2.2 Hz, 1H), 5.86 (ddd, J¼15.7, 7.0,
6.2 Hz, 1H), 5.68 (dd, J¼15.6, 8.6 Hz, 1H), 5.39 (dqd, J¼7.3, 6.4,
3.2 Hz, 1H), 5.21e5.16 (complex m, 4H), 4.52 (dd, J¼8.6, 6.4 Hz, 1H),
4.41 (d, J¼14.4 Hz, 1H), 4.17 (m, 1H), 4.14 (d, J¼14.4 Hz, 1H), 3.47 (s,
3H), 3.46 (s, 3H), 3.08 (ddd, J¼14.7, 9.8, 4.9 Hz, 1H), 2.86 (m, 1H),
2.50e2.39 (complex m, 2H),1.86e1.61 (complex m, 4H),1.47 (s, 3H),
1.42 (d, J¼6.3 Hz, 3H), 1.34 (s, 3H). 13C NMR (125 MHz, CDCl3)
4.13. (4R)-Pent-1-en-4-yl (60S,70R)-6-(60,70-O-(100-methyl-
ethylidene)-20-thianon-80-enyl)-2,4-di(methoxymethoxy)ben-
zoate (29)
d
166.7, 159.1, 156.2, 130.4, 129.4, 128.0, 119.0, 111.7, 108.2, 104.0,
94.7, 94.4, 79.2, 77.0, 72.5, 56.4, 56.3, 56.1, 51.9, 37.7, 28.1, 27.7, 25.4,
20.1, 18.5. IR (KBr): 3035, 2981, 2902, 2821, 1706, 1612, 1582, 1281,
1215, 1142, 1120, 1015, 927, 668 cmꢁ1. HRMS (ESI) calculated for
(S)-4-Penten-2-ol (30
PPh3 (158 mg, 0.60 mmol) and DIAD (120
m
L, 0.28 mmol) was added to a solution of
mL, 0.60 mmol) in THF
(5 mL). After 20 min, a solution of the carboxylic acid derived from
25 by saponification20 (110 mg, 0.24 mmol) in THF (5 mL) was
added and the solution allowed to warm to room temperature.
After 16 h, silica gel was added to the reaction mixture and the
solvent evaporated under reduced pressure. The residue was dry
loaded onto a silica column and eluted (gradient elution, 20:1 to
10:1 hexanes/EtOAc) to afford the desired compound as a colour-
C
25H36O10SNaþ [MþNa]þ 551.1927, found 551.1925.
4.11. (50R,60S,100S)-2,4-Di-O-(methoxymethyl)-50,60-O-(1-
methylethylidene)aigialomycin D (36)
KOH (68 mg, 1.21 mmol) was added to a solution of sulfone 32
(32 mg, 0.06 mmol) in tBuOH (0.25 mL) and CH2Cl2 (0.10 mL). After
2 min, CCl4 (0.24 mL) was added dropwise and the solution heated
to 30 ꢂC. After 30 min, TLC suggested the consumption of starting
material. The solvent was then evaporated under reduced pressure,
the crude mixture partitioned between EtOAc (5 mL) and satd
NH4Cl (5 mL), the layers separated and the aqueous layer further
extracted with EtOAc (2ꢃ5 mL). The combined organic layers were
then dried over MgSO4, filtered, concentrated under reduced
pressure and the resultant brown oil purified with flash column
chromatography (silica, 5:1 hexanes/EtOAc) to afford the desired
compound as a colourless oil (18 mg, 64%) Rf¼0.25 (2:1 hexanes/
less oil (105 mg, 86%). Rf¼0.60 (2:1 hexanes/EtOAc). ½a D22
þ30.4 (c
ꢄ
1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
d
6.72 (d, J¼2.2 Hz, 1H), 6.69
(d, J¼1.9 Hz, 1H), 5.85 (ddt, J¼17.2, 10.2, 7.0 Hz, 1H), 5.78 (ddd,
J¼17.7, 10.4, 7.9 Hz, 1H), 5.28 (d, J¼16.6 Hz, 1H), 5.26e5.07 (complex
m, 6H), 5.15 (s, 2H), 4.46 (t, J¼7.0 Hz, 1H), 4.08 (m, 1H), 3.75e3.67
(complex m, 2H), 3.46 (s, 3H), 3.45 (s, 3H), 2.51e2.41 (m, 3H), 2.37
(m,1H),1.71 (m,1H),1.60e1.40 (complex m, 3H),1.46 (s, 3H),1.34 (s,
3H), 1.33 (d, J¼6.2 Hz, 3H). 13C NMR (125 MHz, CDCl3)
d 167.1, 158.7,
156.0, 139.2, 134.4, 134.0, 118.6, 118.5, 117.8, 110.5, 108.3, 102.4, 94.9,
94.4, 79.9, 77.9, 71.3, 56.4, 56.3, 40.4, 33.9, 31.7, 29.7, 28.4, 26.0, 25.8,
19.6. IR (KBr): 3464, 3059, 3024, 1956, 1809, 1597, 1489, 1445, 1329,
EtOAc). þ4.8 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
d 6.70 (d,
1157, 1010, 758, 695, 638 cmꢁ1
. HRMS (ESI) calculated for
J¼2.1 Hz, 1H), 6.68 (d, J¼2.1 Hz,1H), 6.43 (d, J¼15.6 Hz, 1H), 6.09 (dt,
J¼15.8, 6.4 Hz, 1H), 5.86 (ddd, J¼15.6, 7.8, 5.5 Hz, 1H), 5.67 (dd,
J¼15.6, 8.0 Hz, 1H), 5.20e5.10 (complex m, 5H), 4.57 (dd, J¼7.8,
6.1 Hz, 1H), 4.16 (dt, J¼7.2, 5.6 Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 2.63
(ddd, J¼15.8, 7.8, 2.9 Hz, 1H), 2.45e2.30 (complex m, 2H), 2.05 (m,
C
27H40O8SNaþ [MþNa]þ 547.2342, found 547.2338.
4.14. (5R,7E,9R,10S)-1,2-(30,50-Di-O-methoxymethyl)benzo-4-
oxa-14-thia-3-oxo-5-methyl-9,10-O-(1-methylethylidene)pen-
tadec-7-ene 14,14-dioxide (33)
1H), 1.83 (m, 2H), 1.49 (s, 3H), 1.41 (d, J¼6.3 Hz, 3H), 1.35 (s, 3H). 13
C
NMR (125 MHz, CDCl3)
d 167.2, 158.8, 155.4, 137.6, 132.8, 130.3,
128.8, 128.2, 117.4, 107.8, 106.4, 102.5, 94.7, 94.3, 79.6, 78.0, 72.2,
56.2, 56.1, 37.5, 28.3, 28.2, 28.1, 25.6, 20.2. IR (KBr): 3320, 3059,
3024, 2981, 2913, 2877, 1722, 1612, 1580, 1251, 1212, 1142, 1010,
930 cmꢁ1. HRMS (ESI) calculated for C25H34O8Naþ [MþNa]þ
485.2151, found 485.2152.
m-CPBA (62 mg, 0.28 mmol, 77% w/w) was added to a solution
of thioether 29 (64 mg, 0.13 mmol) in CH2Cl2 (4 mL) stirred at 0 ꢂC
then allowed to warm to room temperature. After 3 h, the solution
was quenched with 20% Na2SO3 (5 mL), the aqueous layer sepa-
rated and extracted with CH2Cl2 (3ꢃ5 mL). The combined organic
layers were dried with MgSO4, filtered, concentrated under re-
duced pressure and the resultant colourless oil purified by flash
column chromatography (silica, gradient elution, 3:1 to 1:1 hex-
anes/EtOAc) to afford the desired compound (4R)-pent-1-en-4-yl
(60S,70R)-6-(60,70-O-(100-methylethylidene)-20-thianon-80-enyl)-
2,4-di(methoxymethoxy)benzoate 20,20-dioxide as a colourless oil
4.12. (50R,60S)-Aigialomycin D (2)
Protected 50R,60S-AmD 36 (17 mg, 0.037 mmol) was stirred in
a mixture of MeOH/1 M aqueous HCl (1:1 v/v, 5 mL). After 2 days,
TLC suggested full conversion to a single product. The reaction
mixture was then extracted with EtOAc (3ꢃ10 mL), the combined
organic layers were washed with brine (3 mL), dried over MgSO4,
filtered, evaporated under reduced pressure and the resultant yel-
low solid purified by flash column chromatography (silica, gradient
elution 1e5% MeOH/CH2Cl2) to yield a mixture of two compounds
(ratio 95:5) as a colourless solid (11 mg, 90%). Rf¼0.45 (9:1 CH2Cl2/
MeOH). A portion was purified by HPLC for characterisation and
bioassay [C18 column, 3:1 MeOH/(1% v/v formic acid in H2O) elu-
ent]. For the major compound, proposed to be 2: Rt¼13.0 min [C18,
3:1 MeOH/(1% v/v formic acid in H2O) eluent]. þ15.6 (c 0.20,
(53 mg, 78%). Rf¼0.13 (2:1 hexanes/EtOAc). ½a D22
þ54.3 (c 1.00,
ꢄ
CHCl3). 1H NMR (500 MHz, CDCl3)
d
6.87 (d, J¼2.2 Hz, 1H), 6.85 (d,
J¼2.2 Hz, 1H), 5.85 (ddt, J¼17.1, 10.1, 7.0 Hz, 1H), 5.78 (ddd, J¼17.7,
10.4, 7.8 Hz, 1H), 5.29 (dt, J¼17.1, 1.3 Hz, 1H), 5.26e5.08 (complex m,
7H), 4.46 (t, J¼7.0 Hz, 1H), 4.38 (d, J¼14.1 Hz, 1H), 4.28 (d, J¼14.1 Hz,
1H), 4.10 (dt, J¼7.3, 6.3 Hz, 1H), 3.46 (s, 3H), 3.45 (s, 3H). 3.02 (ddd,
J¼13.9, 10.2, 5.7 Hz, 1H), 2.94 (ddd, J¼13.9, 10.1, 5.7 Hz, 1H), 2.47 (m,
1H), 2.38 (m, 1H), 1.96 (m, 1H), 1.85 (m, 1H), 1.54e1.49 (complex m,
2H), 1.45 (s, 3H), 1.34 (d, J¼6.3 Hz, 3H), 1.33 (s, 3H). 13C NMR
(125 MHz, CDCl3)
d 166.6, 159.0, 156.4, 134.0, 133.7, 128.5, 119.3,
MeOH). 1H NMR (500 MHz, acetone-d6)
d
11.89 (s, 1H), 9.25 (broad
118.6, 117.9, 112.2, 108.4, 104.2, 94.8, 94.3, 79.6, 77.6, 71.7, 56.7, 56.4,
56.3, 51.5, 40.2, 29.3, 28.1, 25.5, 19.5, 18.7. IR (KBr): 3042, 2950,
2840, 1716, 1604, 1580, 1438, 1393, 1218, 1162, 1022, 924, 766,
667 cmꢁ1. HRMS (ESI) calculated for C27H40O10SNaþ [MþNa]þ
579.2240, found 579.2239.
s, 1H), 7.02 (d, J¼15.3 Hz, 1H), 6.43 (d, J¼2.2 Hz, 1H), 6.28 (d,
J¼2.5 Hz, 1H), 6.08 (ddd, J¼15.1, 10.0, 3.4 Hz, 1H), 5.88 (ddd, J¼15.2,
9.5, 4.5 Hz, 1H), 5.67 (ddd, J¼15.1, 9.5, 1.7 Hz, 1H), 5.46 (m, 1H), 4.66
(dd, J¼9.5, 5.9 Hz, 1H), 4.24 (ddd, J¼11.5, 5.9, 2.5 Hz, 1H), 2.67 (ddd,

10590
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
A 100 mL MW TeflonÔ reaction vessel was charged with a so-
8.5, 4.7 Hz, 1H), 5.72 (dd, J¼15.9, 6.7 Hz, 1H), 5.46 (m, 1H), 4.88 (d,
J¼13.3 Hz, 1H), 4.76 (d, J¼13.4 Hz, 1H), 4.20 (m, 1H), 3.94 (broad s,
1H), 3.74 (broad s, 1H), 3.66 (broad m, 1H), 3.16 (dt, J¼14.5, 6.9 Hz,
1H), 2.87 (partially obscured m, 1H), 2.67 (broad d, J¼15.0 Hz, 1H),
2.41 (apparent dt, J¼15.0, 7.4 Hz, 1H), 2.12e2.02 (obscured m, 1H),
1.92e1.79 (m, 2H), 1.57 (m, 1H), 1.43 (d, J¼6.4 Hz, 3H). 13C NMR
lution of Grubbs’ second generation catalyst (8 mg, 0.01 mmol) and
the diene above (50 mg, 0.09 mmol) in CH2Cl2 (20 mL), flushed with
argon and sealed. The reaction was then heated in a microwave
reactor to 75 ꢂC over 2 min and held at this temperature for a fur-
ther 28 min. After cooling to room temperature, the reaction mix-
ture was concentrated under reduced pressure and the resultant
dark green oil purified by flash column chromatography twice
(silica, 1:1 hexanes/EtOAc) to afford the title compound 33 as
(125 MHz, acetone-d6) d 171.0, 165.4, 162.7, 135.3, 132.8, 127.4, 114.9,
106.7,104.3, 76.0, 74.6, 73.9, 57.7, 53.7, 38.2, 31.7,19.7,19.0. IR (neat):
3396, 2927, 1711, 1650, 1620, 1597, 1453, 1357, 1304, 1299, 1264,
1173, 1115 cmꢁ1. HRMS (ESI) calculated for C18H24O8SNaþ [MþNa]þ
423.1090, found 423.1082.
a colourless oil (36 mg, 76%). Rf¼0.07 (2:1 hexanes/EtOAc). ½a D18
ꢄ
ꢁ41.0 (c 1.00, CHCl3). 1H NMR (500 MHz, CDCl3)
6.98 (d, J¼2.2 Hz,
d
1H), 6.86 (d, J¼2.2 Hz, 1H), 5.86 (ddd, J¼15.7, 13.2, 6.4 Hz, 1H), 5.68
(dd, J¼15.6, 8.6 Hz, 1H), 5.39 (m, 1H), 5.21e5.16 (m, 4H), 4.52 (dd,
J¼8.6, 6.4 Hz,1H), 4.41 (d, J¼14.4 Hz,1H), 4.17 (partially obscured m,
1H), 4.14 (d, J¼14.4 Hz, 1H), 3.47 (s, 3H), 3.46 (s, 3H), 3.08 (ddd,
J¼14.7, 9.8, 4.9 Hz, 1H), 2.86 (m, 1H), 2.50e2.39 (complex m, 2H),
1.85e1.60 (complex m, 4H), 1.47 (s, 3H), 1.42 (d, J¼6.3 Hz, 3H), 1.33
4.17. 10,20,70,80-Tetrahydroaigialomycin D (4)
To a solution of unsaturated macrocycle 3520 (16 mg, 34.6
mmol)
in EtOH (1 mL) was added 10% Pd/C (1.5 mg). The flask was briefly
evacuated and flushed with H2(g) by means of a H2(g)-filled balloon.
The reaction was stirred under the H2(g) atmosphere for 2 h before
being filtered through CeliteÒ and concentrated under reduced
pressure to yield a colourless oil (14 mg, 87%). This product was
carried forward without further purification. 1H NMR (500 MHz,
(s, 3H). 13C NMR (125 MHz, CDCl3)
d 166.7, 159.2, 156.2, 130.2, 129.4,
128.0, 119.0, 111.7, 108.2, 104.0, 94.7, 94.4, 79.2, 72.5, 56.39, 56.36,
56.1, 51.9, 37.7, 28.1, 27.7, 25.4, 20.1, 18.5 (the peak at 77.0 was not
resolvable from the solvent peak). IR (KBr): 3021, 2980, 2900, 2822,
d
1711, 1613, 1582, 1499, 1288, 1218, 1130, 1128, 1014, 926, 665 cmꢁ1
.
CDCl3)
d
6.66 (d, J¼2.2 Hz, 1H), 6.55 (d, J¼2.1 Hz, 1H), 5.25 (m, 1H),
HRMS (ESI) calculated for C25H36O10SNaþ [MþNa]þ 551.1927, found
5.18e5.10 (complex m, 4H), 4.11e4.06 (complex m, 2H), 3.45 (s, 6H),
2.63 (ddd, J¼13.6, 11.0, 5.8 Hz, 1H), 2.49 (ddd, J¼13.7, 10.6, 5.2 Hz,
1H), 1.88e1.66 (complex m, 4H), 1.66e1.50 (complex m, 4H), 1.40 (s,
3H), 1.50e1.30 (complex m, 2H), 1.34 (d, J¼6.3 Hz, 3H), 1.31 (s, 3H),
551.1926.
4.15. (50S,60R,100R)-2,4-Di-O-(methoxymethyl)-50,60-O-(1-
methylethylidene)-aigialomycin D (37)
1.30e1.19 (complex m, 2H). 13C NMR (125 MHz, CDCl3)
d 168.3,
158.6,155.1,141.5,119.1,109.2,107.1,101.0, 94.6, 94.3, 77.7, 77.0, 72.4,
56.2, 56.1, 36.5, 33.2, 31.3, 31.3, 28.4, 27.6, 25.9, 24.7, 23.0, 21.0.
To a solution of the protected hydrogenated material (14 mg,
KOH (64 mg, 1.14 mmol) was added to a solution of sulfone 33
(30 mg, 0.06 mmol) in BuOH (0.25 mL) and CH2Cl2 (0.10 mL) and
t
stirred under argon. After 2 min, CCl4 (22
mL) was added dropwise
30.0 mmol) in MeOH (1.5 mL) was added 10% HCl (1.5 mL) and the
and the solution heated to 35 ꢂC. After 45 min, TLC suggested the
consumption of starting material. The solvent was then evaporated
under reduced pressure, the crude mixture partitioned between
EtOAc (5 mL) and satd NH4Cl (5 mL), the layers separated and the
aqueous layer extracted with EtOAc (2ꢃ5 mL). The combined or-
ganic layers were then dried over MgSO4, filtered, concentrated
under reduced pressure and the resultant yellow oil purified by
flash column chromatography (silica, gradient elution, 9:1 to 4:1
hexanes/EtOAc) to afford the desired compound as a colourless oil
mixture was stirred at room temperature for 3 days. The reaction
mixture was extracted with EtOAc (3ꢃ10 mL). The combined organic
fractions were washed repeatedly with H2O (4ꢃ10 mL) until the
aqueous layer was neutral (pH 7). It was then dried over MgSO4,
filtered and concentrated under reduced pressure. The crude oil was
purified by flash column chromatography (silica, gradient elution
1:1 hexanes/EtOAc to EtOAc) to yield the title compound as a col-
ourless oil (6.5 mg, 64% over two steps). ½a D19
ꢄ
ꢁ8.2 (c 0.11, MeOH).1H
NMR (500 MHz, acetone-d6)
d 11.77 (s, 1H), 9.09 (s, 1H), 6.34 (d,
(15 mg, 57%) Rf¼0.30 (2:1 hexanes/EtOAc). ½a D24
ꢄ
ꢁ3.9 (c 1.00,
J¼2.5 Hz,1H), 6.24 (d, J¼2.5 Hz,1H), 5.10 (m,1H), 3.83e3.76 (m, 2H),
3.53 (td, J¼12.3, 4.0 Hz, 1H), 2.36 (td, J¼12.1, 4.6 Hz, 1H), 1.92e1.79
(m, 3H), 1.77e1.67 (m, 2H), 1.61 (m, 1H), 1.55e1.35 (m, 6H), 1.33 (d,
CHCl3). 1H NMR (500 MHz, CDCl3)
d
6.71 (d, J¼2.1 Hz, 1H), 6.69 (d,
J¼2.1 Hz, 1H), 6.43 (dt, J¼15.6, 1.3 Hz, 1H), 6.09 (dt, J¼15.8, 6.4 Hz,
1H), 5.86 (ddd, J¼15.6, 7.6, 5.9 Hz, 1H), 5.67 (ddt, J¼15.6, 8.0, 1.3 Hz,
1H), 5.22e5.11 (complex m, 5H), 4.57 (dd, J¼7.8, 6.0 Hz, 1H), 4.16
(m, 1H), 3.47 (s, 3H), 3.46 (s, 3H), 2.64 (ddd, J¼15.7, 7.7, 2.8 Hz, 1H),
2.43 (m, 1H), 2.35 (m, 1H), 2.05 (m, 1H), 1.83 (m, 2H), 1.49 (s, 3H),
1.41 (d, J¼6.3 Hz, 3H), 1.35 (s, 3H). 113C NMR (125 MHz, CDCl3)
J¼6.1 Hz, 3H). 13C NMR (125 MHz, acetone-d6)
d 172.7, 166.2, 163.1,
149.4, 111.8, 105.2, 101.8, 74.6, 73.9, 69.3, 37.2, 36.5, 34.6, 32.9, 28.3,
26.6, 21.6, 21.0. IR (neat): 3410, 3063, 2943, 2869, 1643, 1607, 1489,
1443, 1312, 1258, 1161, 1009, 759, 698, 638 cmꢁ1. HRMS (ESI) cal-
culated for C18H26O6Naþ [MþNa]þ 361.1627, found 361.1627. The
data were consistent with those reported previously.15
d
167.2, 158.8, 155.4, 137.7, 132.8, 130.3, 128.8, 128.2, 117.4, 107.8,
106.4, 102.5, 94.8, 94.3, 79.6, 78.1, 72.2, 56.2, 56.1, 37.5, 28.4, 28.2,
28.1, 25.6, 20.2. IR (KBr): 3230, 3022, 2975, 2910, 2872, 1721, 1611,
1584, 1495, 1252, 1217, 1144, 1015, 950, 669 cmꢁ1. HRMS (ESI) cal-
culated for C25H34NaO8Naþ [MþNa]þ 485.2151, found 485.2151.
4.18. Methyl (60S,70R)-6-(60,70-O-(100-methylethylidene)-20-
thianon-80-enyl)benzoate (26)
A stirred solution of bromide 9 (531 mg, 2.32 mmol) and thio-
acetate 23 (566 mg, 2.32 mmol) in MeOH (10 mL) was degassed
with argon for 10 min. To this solution was added K2CO3 (641 mg,
4.64 mmol) and the reaction stirred for 18 h at room temperature.
The solvent was removed and the crude residue partitioned be-
tween EtOAc (20 mL) and H2O (20 mL). The aqueous layer was
further extracted with EtOAc (3ꢃ10 mL). The combined organic
fractions were washed with satd NH4Cl(aq) (10 mL), dried over
MgSO4, filtered and reduced to give a colourless oil. The product
was purified using flash column chromatography (silica, gradient
elution 20:1 to 5:1 hexanes/EtOAc) to afford the desired compound
4.16. (5S,7E,9R,10S)-1,2-(30,50-Dihydroxy)benzo-4-oxa-14-thia-
3-oxo-5-methyl-9,10-dihydroxypentadec-7-ene 14,14-dioxide
(6)
To a solution of the protected macrocyclic sulfone 3120 (9.5 mg,
0.018 mmol) in MeOH (1 mL) was added 1 M HCl (1 mL). The re-
action was stirred at room temperature for 3 days. The reaction
mixture was extracted with EtOAc (3ꢃ10 mL), washed with brine
(5 mL), dried over MgSO4, filtered and concentrated under reduced
pressure to yield a colourless oil (6.4 mg, 89%). ½a D19
ꢁ7.2 (c 0.69,
ꢄ
MeOH). 1H NMR (500 MHz, acetone-d6)
d
11.28 (s,1H), 9.51 (broad s,
as a colourless oil (683 mg, 84%). ½a D22
ꢄ
ꢁ14.6 (c 0.55, CHCl3). 1H NMR
1H), 6.63 (d, J¼2.5 Hz, 1H), 6.41 (d, J¼2.5 Hz, 1H), 5.79 (ddd, J¼15.9,
(500 MHz, CDCl3)
d
7.90 (dd, J¼7.7, 1.1 Hz, 1H), 7.43 (td, J¼7.6, 1.4 Hz,

S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
10591
1H), 7.33e7.28 (complex m, 2H), 5.78 (ddd, J¼17.3, 10.3, 7.8 Hz, 1H),
5.29 (d, J¼17.1 Hz, 1H), 5.22 (d, J¼10.3 Hz, 1H), 4.46 (dd, J¼7.9,
6.9 Hz, 1H), 4.12e4.05 (complex m, 3H), 3.90 (s, 3H), 2.45 (td, J¼7.1,
2.5 Hz, 2H), 1.79e1.67 (complex m, 2H), 1.58e1.45 (complex, par-
tially obscured m, 2H), 1.46 (s, 3H), 1.34 (s, 3H). 13C NMR (125 MHz,
reaction was quenched by the addition of 20% Na2SO3 (10 mL). The
resulting mixture was stirred for 20 min before the organic layer
was separated. The aqueous layer was further extracted with
CH2Cl2 (3ꢃ10 mL). The combined organic fractions were washed
with satd NaHCO3(aq) (10 mL), dried over MgSO4 and filtered. The
crude product was purified using flash column chromatography
(silica, 5:1 hexanes/EtOAc), affording the desired compound (4S)-
pent-1-en-4-yl (60S,70R)-6-(60,70-O-(100-methylethylidene)-20-thia-
non-80-enyl)benzoate 20,20-dioxide as a colourless oil (124 mg,
CDCl3)
d 167.8, 140.6, 134.3, 131.7, 131.1, 130.9, 129.5, 127.0, 118.3,
108.2, 79.7, 77.8, 52.1, 34.5, 31.6, 29.5, 28.2, 25.9, 25.6. IR (KBr):
2986, 2938, 1723, 1434, 1379, 1262, 1216, 1123, 1077, 1046, 1011, 928,
872, 769, 716 cmꢁ1. HRMS (ESI) calculated for C19H26O4SNaþ
[MþNa]þ 373.1449, found 373.1444; C19H26O4SKþ [MþK]þ
389.1189, found 389.1189.
92%). Rf¼0.39 (2:1 hexanes/EtOAc). 1H NMR (500 MHz, CDCl3)
d 7.98
(d, J¼7.4 Hz,1H), 7.57e7.51 (complex m, 2H), 7.45 (m, 1H), 5.84 (ddt,
J¼17.2, 10.2, 7.0 Hz, 1H), 5.75 (ddd, J¼17.2, 9.8, 7.7 Hz, 1H), 5.29 (d,
J¼17.1 Hz, 1H), 5.23e5.16 (partially obscured m, 1H), 5.22 (d,
J¼10.0 Hz, 1H), 5.15 (dd, J¼17.1 Hz, 1H), 5.11 (d, J¼10.3 Hz, 1H), 4.94
(d, J¼13.5 Hz,1H), 4.84 (d, J¼13.5 Hz,1H), 4.49 (apparent t, J¼6.5 Hz,
1H), 4.09 (apparent q, J¼6.6 Hz, 1H), 3.06e2.89 (complex m, 2H),
2.50 (m, 1H), 2.43 (m, 1H), 2.07e1.79 (complex m, 2H), 1.55e1.47
(complex m, 2H), 1.44 (s, 3H), 1.37 (d, J¼6.3 Hz, 3H), 1.33 (s, 3H). IR
4.19. (4S)-Pent-1-en-4-yl (60S,70R)-6-(60,70-O-(100-methyl-
ethylidene)-20-thianon-80-enyl)benzoate (30)
To a stirred solution of ester 26 (252 mg, 0.72 mmol) in MeOH
(5 mL) was added a solution of KOH (202 mg, 3.61 mmol) in H2O
(5 mL), and the reaction was heated at 80 ꢂC for 4 h. The reaction
mixture was then cooled to room temperature and washed with
Et2O (2ꢃ15 mL). The aqueous layer was acidified to pH 1 with 10%
HCl and extracted with Et2O (3ꢃ10 mL). These latter combined
organic layers were dried over MgSO4, filtered and concentrated
under reduced pressure to give the acid as a colourless oil (212 mg,
88%). The product (60S,70R)-6-(60,70-O-(100-methylethylidene)-20-
thianon-80-enyl)benzoic acid was used in the next reaction without
(neat): 2980, 2928, 1711, 1299, 1268, 1116, 1076, 911, 733 cmꢁ1
.
HRMS (ESI) calculated for C23H32O6SNaþ [MþNa]þ 459.1817, found
459.1817. This material was used in the next reaction without fur-
ther characterisation.
To a solution of the diene above (120 mg, 28
(55 mL) in a 50 mL TeflonÔ reactor vessel was added a catalytic
amount of Grubbs’ second generation catalyst (23 mg, 28 mol).
mmol) in CH2Cl2
m
further purification. ½a D20
ꢄ
ꢁ26.5 (c 0.12, CHCl3). 1H NMR (500 MHz,
The vessel was flushed with argon before sealing and heating at
75 ꢂC for 30 min with microwave irradiation. Once the reaction
vessel had cooled to room temperature the cap was removed and
the solution transferred to a round bottom flask. The solvent was
removed under reduced pressure to yield a brown oil. This material
was dry loaded onto a silica column and eluted (10:1 hexanes/
EtOAc) to afford the macrocycle 34 as a colourless solid (97 mg,
CDCl3)
d
8.05 (dd, J¼7.8, 1.4 Hz, 1H), 7.49 (td, J¼7.5, 1.4 Hz, 1H),
7.38e7.32 (complex m, 2H), 5.79 (ddd, J¼17.2, 10.3, 7.8 Hz, 1H), 5.28
(ddd, J¼17.1, 1.7, 1.3 Hz, 1H), 5.22 (ddd, J¼10.3, 1.5, 0.8 Hz, 1H), 4.47
(dd, J¼7.6, 6.4 Hz, 1H), 4.18 (d, J¼13.3 Hz, 1H), 4.14 (partially over-
lapping d, J¼ca. 13 Hz, 1H), 4.10 (ddd, J¼8.9, 6.2, 4.3 Hz, 1H), 2.48 (t,
J¼7.1 Hz, 2H), 1.75 (m, 1H), 1.66e1.49 (complex m, 2H), 1.47 (s, 3H),
1.45 (m, 1H), 1.35 (s, 3H). IR (neat): 1692, 1372, 1298, 1267, 1242,
86%). Rf¼0.32 (2:1 hexanes/EtOAc). Mp 180e181 ꢂC. ½a D22
ꢁ11.3 (c
ꢄ
1218, 1046, 913, 873, 733 cmꢁ1
.
HRMS (ESI) calculated for
0.54, CHCl3). 1H NMR (500 MHz, CDCl3)
d
8.03 (dd, J¼7.9, 1.4 Hz,1H),
C
18H24O4SNaþ [MþNa]þ 359.1293, found 359.1288.
7.84 (d, J¼7.8 Hz, 1H), 7.58 (td, J¼7.6, 1.5 Hz, 1H), 7.45 (td, J¼7.7,
1.3 Hz, 1H), 5.94 (d, J¼14.8 Hz, 1H), 5.83 (ddd, J¼15.1, 10.2, 3.6 Hz,
1H), 5.49 (ddd, J¼15.3, 9.6, 1.8 Hz, 1H), 5.40 (m, 1H), 4.42 (dd, J¼9.6,
5.7 Hz, 1H), 4.13 (dd, J¼14.8, 1.2 Hz,1H), 4.07 (ddd, J¼9.8, 5.6, 3.6 Hz,
1H), 2.57e2.49 (complex m, 3H), 2.42 (dt, J¼15.6, 10.4 Hz, 1H), 1.68
(m, 1H), 1.61e1.52 (complex m, 2H), 1.43 (partially obscured m, 1H),
1.42 (d, J¼6.4 Hz, 3H), 1.41 (s, 3H), 1.32 (s, 3H). 13C NMR (125 MHz,
To a stirred solution of alcohol R-11 (46
mL, 0.446 mmol) and PPh3
(195 mg, 0.744 mmol) in THF (5 mL) at 0 ꢂC was added DIAD (145
m
L,
0.744 mmol). The solution was stirred at 0 ꢂC for 20 min, during
which time a white precipitate formed. After this time, a solution of
the benzoic acid above (100 mg, 0.298 mmol) in THF (2 mL) was
added dropwise and the reaction mixture left to stir at room tem-
perature for 16 h. The crude reaction mixture was adsorbed onto
silica gel by evaporation of the solvent. The residue was dry loaded
onto a silica column and eluted (20:1 hexanes/EtOAc) to yield ester
30 as a colourless oil (103 mg, 85%). Rf¼0.66 (2:1 hexanes/EtOAc).
CDCl3)
d 166.3, 133.2, 132.9, 132.8, 131.6, 130.6, 129.4, 128.9, 127.7,
107.8, 79.6, 77.3, 71.2, 54.4, 50.9, 40.6, 28.4, 27.9, 25.6, 21.4, 19.0. IR
(neat): 2932, 2879, 1706, 1448, 1295, 1244, 1223, 1109, 1072, 1033,
973, 915, 731 cmꢁ1. HRMS (ESI) calculated for C21H28O6SNaþ
[MþNa]þ 431.1504, found 431.1502.
½
a 2D2
ꢄ
ꢁ21.9 (c 0.75, CHCl3). 1H NMR (500 MHz, CDCl3)
d 7.86 (dd,
J¼7.7, 1.5 Hz, 1H), 7.41 (td, J¼7.6, 1.3 Hz, 1H), 7.32e7.27 (complex m,
2H), 5.85 (ddt, J¼17.2, 10.2, 7.1 Hz, 1H), 5.78 (ddd, J¼17.1, 9.8, 7.8 Hz,
1H), 5.29 (ddd, J¼17.1, 1.7, 1.0 Hz, 1H), 5.25e5.19 (complex m, 2H),
5.15 (ddt, J¼17.1,1.9,1.5 Hz,1H), 5.11 (ddt, J¼10.2,1.7,1.0 Hz,1H), 4.46
(dd, J¼7.8, 6.8 Hz, 1H), 4.12 (d, J¼13.3 Hz, 1H), 4.08 (partially ob-
scured m, 1H), 4.07 (d, J¼13.2 Hz, 1H), 2.55e2.38 (complex m, 4H),
1.72 (m, 1H), 1.61e1.41 (complex, partially obscured m, 3H), 1.47 (s
3H), 1.37 (d, J¼6.3 Hz, 3H), 1.35 (s, 3H). 13C NMR (125 MHz, CDCl3)
4.21. (50S,60R,100S)-2,4-Dideoxy-50,60-O-(1-methylethylidene)-
aigialomycin D (38)
To a solution of sulfone 34 (70 mg, 0.172 mmol) in tBuOH/CH2Cl2
(0.75 mL/0.30 mL) at room temperature was added powdered KOH
(214 mg, 3.82 mmol). To the resulting suspension was added CCl4
(0.75 mL) dropwise over 2 min. The reaction was then heated at
35 ꢂC for 30 min. After cooling to room temperature the solvent was
evaporated under reduced pressure and the residue partitioned
between satd NH4Cl(aq) (10 mL) and EtOAc (10 mL). The aqueous
layer was further extracted with EtOAc (2ꢃ10 mL). The combined
organic phases were dried over MgSO4, filtered and concentrated.
The product was purified using column chromatography (silica,
10:1 hexanes/EtOAc) yielding 38 as a colourless solid (47 mg, 80%).
d
167.0, 140.4, 134.3, 133.7, 131.5, 130.9, 130.8, 126.9, 118.4, 117.9,
108.2, 79.7, 77.8, 70.9, 40.3, 34.4, 31.6, 29.5, 28.2, 25.9, 25.6, 19.5 (1 C
overlapping or missing). IR (neat): 2983, 2934, 1713, 1379, 1260,
1216, 1118, 1072, 1047, 994, 922 cmꢁ1. HRMS (ESI) calculated for
C
23H32O4SNaþ [MþNa]þ 427.1919, found 427.1914.
4.20. (5S,7E,9R,10S)-1,2-Benzo-4-oxa-14-thia-3-oxo-5-methyl-
9,10-O-(1-methylethylidene)-pentadec-7-ene 14,14-dioxide (34)
Rf¼0.61 (2:1 hexanes/EtOAc). ½a D22
ꢄ
ꢁ34.8 (c 0.59, CHCl3). 1H NMR
(500 MHz, CDCl3)
d
7.62 (dd, J¼7.7, 1.1 Hz, 1H), 7.47 (d, J¼7.9 Hz, 1H),
To a solution of thioether 30 (125 mg, 0.309 mmol) in CH2Cl2
(7 mL) at 0 ꢂC was added w75% m-CPBA (157 mg, 0.681 mmol). The
solution was warmed to room temperature and stirred for 2 h. The
7.39 (td, J¼7.4, 1.0 Hz, 1H), 7.25 (td, J¼7.5, 1.2 Hz, 1H), 6.67 (d,
J¼15.5 Hz, 1H), 6.12 (ddd, J¼15.3, 9.3, 5.2 Hz, 1H), 5.80 (ddd, J¼15.4,
6.9, 6.1 Hz, 1H), 5.66 (ddt, J¼15.4, 8.9, 1.4 Hz, 1H), 5.24 (apparent

10592
S.Z.Y. Ting et al. / Tetrahedron 69 (2013) 10581e10592
13. For selected examples of analogues synthesised, see: (a) Yang, Z.-Q.; Geng,
X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky, S. J. J. Am. Chem. Soc.
2004, 126, 7881e7889; (b) Day, J. E. H.; Sharp, S. Y.; Rowlands, M. G.;
Aherne, W.; Hayes, A.; Raynaud, F. I.; Lewis, W.; Roe, S. M.; Prodromou, C.;
Pearl, L. H.; Workman, P.; Moody, C. J. ACS Chem. Biol. 2011, 6, 1339e1347;
(c) Day, J. E. H.; Sharp, S. Y.; Rowlands, M. G.; Aherne, W.; Lewis, W.; Roe,
S. M.; Prodromou, C.; Pearl, L. H.; Workman, P.; Moody, C. J. Chem.dEur. J.
2010, 16, 10366e10372; (d) Ikuina, Y.; Amishiro, N.; Miyata, M.; Narumi,
H.; Ogawa, H.; Akiyama, T.; Shiotsu, Y.; Akinaga, S.; Murakata, C. J. Med.
Chem. 2003, 46, 2534e2541 and references cited therein; (e) Liniger, M.;
Neuhaus, C.; Hofmann, T.; Fransiolo-Ignazio, L.; Jordi, M.; Drueckes, P.;
Trappe, J.; Fabbro, D.; Altmann, K.-H. ACS Med. Chem. Lett. 2011, 2, 22e27;
(f) Napolitano, C.; Palwai, V. R.; Eriksson, L. A.; Murphy, P. V. Tetrahedron
2012, 68, 5533e5540; (g) Napolitano, C.; McArdle, P.; Murphy, P. V. J. Org.
Chem. 2010, 75, 7404e7407.
sextet, J¼6.1 Hz, 1H), 4.60 (dd, J¼8.9, 5.5 Hz, 1H), 4.19 (ddd, J¼11.5,
5.5, 2.9 Hz, 1H), 2.58e2.54 (complex m, 2H), 2.31 (m, 1H), 2.04 (m,
1H), 1.91 (m, 1H), 1.64 (m, 1H), 1.48 (s, 3H), 1.40 (d, J¼6.1 Hz, 3H),
1.36 (s, 3H). 13C NMR (125 MHz, CDCl3)
d 169.6, 136.2, 131.3, 131.1,
130.9, 130.4, 130.1, 129.6, 129.1, 126.9, 125.8, 108.2, 79.7, 77.3, 72.4,
39.5, 29.3, 29.1, 28.5, 25.8, 20.3. IR (neat): 2984, 2936, 1703, 1450,
1379, 1291, 1257, 1216, 1121, 1043, 971 cmꢁ1. HRMS (ESI) calculated
for C21H26O4Naþ [MþNa]þ 365.1729, found 365.1722.
4.22. 2,4-Dideoxyaigialomycin D (5)
To a solution of macrolide 38 (34 mg, 99 mmol) in MeOH (1.5 mL)
14. (a) Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.; Winssinger, N. Angew.
Chem., Int. Ed. 2006, 45, 3951e3954; (b) Jogireddy, R.; Dakas, P.-Y.; Valot, G.;
Barluenga, S.; Winssinger, N. Chem.dEur. J. 2009, 15, 11498e11506; (c) Karth-
keyan, G.; Zambaldo, C.; Barluenga, S.; Zoete, V.; Karplus, M.; Winssinger, N.
Chem.dEur. J. 2012, 18, 8978e8986; (d) Jogireddy, R.; Barluenga, S.; Winssinger,
N. ChemMedChem 2010, 5, 670e673.
was added 1 M HCl (1.5 mL). The reaction was stirred for 2 days at
room temperature. The reaction mixture was extracted with EtOAc
(3ꢃ10 mL). The combined organic phases were dried over MgSO4,
filtered and evaporated under reduced pressure to dryness. The
crude product was purified by flash column chromatography (DIOL
silica, gradient elution CH2Cl2 to 5% MeOH/CH2Cl2) yielding a col-
15. Xu, J.; Chen, A.; Go, M. L.; Nacro, K.; Liu, B.; Chai, C. L. L. ACS Med. Chem. Lett.
2011, 2, 662e666.
16. Zhou, H.; Qiao, K.; Gao, Z.; Vederas, J. C.; Tang, Y. J. Biol. Chem. 2010, 285,
41412e41421.
17. Hearn, B. R.; Sundermann, K.; Cannoy, J.; Santi, D. V. ChemMedChem 2007, 2,
1598e1600.
18. Roe, S. M.; Prodromou, C.; O’Brien, R.; Ladbury, J. E.; Piper, P. W.; Pearl, L. H. J.
Med. Chem. 1999, 42, 260e266.
19. Yang, S.-X.; Gao, J.-M.; Zhang, Q.; Laatsch, H. Bioorg. Med. Chem. Lett. 2011, 21,
1887e1889.
ourless solid (26 mg, 80%). ½a D23
ꢄ
ꢁ117.0 (c 0.02, CHCl3). 1H NMR
(500 MHz, CDCl3)
d
7.75 (d, J¼7.8 Hz, 1H), 7.51 (d, J¼7.9 Hz, 1H), 7.41
(t, J¼7.6 Hz, 1H), 7.27 (m, 1H), 6.97 (d, J¼16.2 Hz, 1H), 6.23 (dt,
J¼16.1, 5.4 Hz, 1H), 5.88 (m, 1H), 5.67 (dd, J¼15.7, 6.0 Hz, 1H), 5.35
(m, 1H), 4.41 (d, J¼5.5 Hz, 1H), 3.75 (br s, 1H), 2.60 (m, 1H), 2.44 (dd,
J¼15.3, 7.6 Hz, 1H), 2.38 (dd, J¼11.8, 6.1 Hz, 2H), 2.18 (br s, 1H), 2.09
(m, 1H), 2.04 (s, 1H), 1.65 (m, 1H), 1.39 (d, J¼6.4 Hz, 3H). 13C NMR
20. Baird, L. J.; Timmer, M. S. M.; Teesdale-Spittle, P. H.; Harvey, J. E. J. Org. Chem.
2009, 74, 2271e2277.
(125 MHz, CDCl3)
d 169.0, 137.3, 132.5, 132.0, 131.5, 130.5, 130.2,
21. (a) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413e416; (b) Lu, J.; Ma, J.; Xie,
X.; Chen, B.; She, X.; Pan, X. Tetrahedron: Asymmetry 2006, 17, 1066e1073; (c)
Vu, N. Q.; Chai, C. L. L.; Lim, K. P.; Chia, S. C.; Chen, A. Tetrahedron 2007, 63,
7053e7058; (d) Chrovian, C. C.; Knapp-Reed, B.; Montgomery, J. Org. Lett. 2008,
10, 811e814; (e) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett. 2009, 11,
4910e4913.
127.9, 127.8, 126.7, 126.2, 76.0, 73.0, 71.8, 38.0, 27.4, 26.9, 19.7. IR
(neat): 3435, 2976, 2932, 1710, 1448, 1357, 1263, 1123, 1076, 977,
756 cmꢁ1. HRMS (ESI) calculated for C18H22O4Naþ [MþNa]þ
325.1416, found 325.1412.
22. For further examples of synthetic routes to the RALs, see: (a) Bajwa, N.; Jen-
nings, M. P. Tetrahedron Lett. 2008, 49, 390e393; (b) Martinez-Solorio, D.;
Belmore, K. A.; Jennings, M. P. J. Org. Chem. 2011, 76, 3898e3908; (c) Lin, A.;
Willis, A. C.; Banwell, M. G. Heterocycles 2010, 82, 313e318; (d) Lin, A.; Willis, A.
C.; Banwell, M. G. Tetrahedron Lett. 2010, 51, 1044e1047; (e) Choi, H. G.; Son, J.
B.; Park, D.-S.; Ham, Y. J.; Hah, J.-M.; Sim, T. Tetrahedron Lett. 2010, 51,
4942e4946; (f) Jana, N.; Nanda, S. Tetrahedron: Asymmetry 2012, 23, 802e808;
(g) Dakas, P.-Y.; Jogireddy, R.; Valot, G.; Barluenga, S.; Winssinger, N. Chem.
dEur. J. 2009, 15, 11490e11497; (h) Sugiyama, S.; Fuse, S.; Takahashi, T. Tetra-
hedron 2011, 67, 6654e6658.
Acknowledgements
We are grateful to Drs. John Ryan and A. Jonathan Singh for help
with NMR spectroscopy, and to Associate Professor Peter Northcote
for valuable discussions. The Tertiary Education Commission of
New Zealand is acknowledged for provision of a Bright Futures PhD
Scholarship (to LJB). The Cancer Society of New Zealand and the
Wellington Medical Research Foundation are thanked for their
support.
23. (a) Taylor, R. J. K.; Casy, G. Org. React. 2003, 62, 357e475; (b) Harvey, J. E.;
Bartlett, M. J. Chem. N.Z. 2010, 74, 63e69.
24. There was one prior report combining ring-closing metathesis and the Ram-
€
bergeBacklund reaction in this way: Yao, Q. Org. Lett. 2002, 4, 427e430.
25. Barrett et al. resolved this problem by installing a methyl-substituted alkene at
C70 in place of the terminal alkene. This promoted initial carbene formation at
C80 and avoided the competing small-ring cyclisation.
Supplementary data
26. Hydrolysis of the acetonide-protected material in the MNK2 assay would ex-
plain its similar inhibitory magnitude compared to AmD.
Full details of experimental procedures and spectra for new
compounds can be found. Supplementary data related to this article
can be found at http://dx.doi.org/10.1016/j.tet.2013.10.042.
27. (a) Barrett, A. G. M.; Morris, T. M.; Barton, D. H. R. J. Chem. Soc., Perkin Trans. 1
1980, 2272e2277; (b) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343e1351;
(c) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159e2185 and references
cited therein.
References and notes
ꢂ
28. Chiarello, J.; Joullie, M. M. Tetrahedron 1988, 44, 41e48.
29. Basset, J.-F.; Leslie, C.; Hamprecht, D.; White, A. J. P.; Barrett, A. G. M. Tetrahe-
dron Lett. 2010, 51, 783e785.
30. Baird, L. J.; Colomban, C.; Turner, C.; Teesdale-Spittle, P. H.; Harvey, J. E. Org.
1. (a) Winssinger, N.; Barluenga, S. Chem. Commun. 2007, 22e36; (b) Serba, C.;
Winssinger, N. Eur. J. Org. Chem. 2013, 4195e4214.
2. Barluenga, S.; Dakas, P.-Y.; Boulifa, M.; Moulin, E.; Winssinger, N. C. R. Chim.
2008, 11, 1306e1317.
Biomol. Chem. 2011, 9, 4432e4435.
31. (a) Wender, P. A.; Bi, F. C.; Buschmann, N.; Gosselin, F.; Kan, C.; Kee, J.-M.;
Ohmura, H. Org. Lett. 2006, 8, 5373e5376; (b) Paquette, L. A.; Bailey, S. J. Org.
Chem. 1995, 60, 7849e7856.
3. Hofmann, T.; Altmann, K.-H. C. R. Chim. 2008, 11, 1318e1335 and references
therein.
€
32. (a) Srihari, P.; Kumaraswamy, B.; Yadav, J. S. Tetrahedron 2009, 65, 6304e6309;
(b) Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron: Asymmetry 2002,
13, 1189e1193 and references cited therein; (c) Sun, F.; Metz, P. Synlett 2013,
457e460.
4. Brase, S.; Encinas, A.; Keck, J.; Nising, C. F. Chem. Rev. 2009, 109, 3903e3990.
5. Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kongsaeree, P.; Thebt-
aranonth, Y. J. Org. Chem. 2002, 67, 1561e1566.
6. Xu, L.; He, Z.; Xue, J.; Chen, X.; Wei, X. J. Nat. Prod. 2010, 73, 885e889.
7. Shao, C.-L.; Wu, H.-X.; Wang, C.-Y.; Liu, Q.-A.; Xu, Y.; Wei, M.-Y.; Qian, P.-Y.; Gu,
Y.-C.; Zheng, C.-J.; She, Z.-G.; Lin, Y.-C. J. Nat. Prod. 2011, 74, 629e633.
33. Potassium tert-butoxide has been previously used for this reaction32 but, in our
hands, no Wittig reaction occurred. This was possibly due to the quality of the
potassium tert-butoxide used, which has been noted to be an important factor
in the success of this reaction.32b
ꢂ
~
8. Zinedine, A.; Soriano, J. M.; Molto, J. C.; Manes, J. Food Chem. Toxicol. 2007, 45,
1e18.
34. Work to identify the unexpected products from acid deprotection of 37 is
underway.
35. Wilmes, A.; Bargh, K.; Kelly, C.; Northcote, P. T.; Miller, J. H. Mol. Pharmaceut.
2007, 4, 269e280 and references cited therein.
36. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem. 1990, 11, 440e467.
37. Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J. Am. Chem. Soc. 1990,
112, 6127e6129.
9. Spichty, M.; Taly, A.; Hagn, F.; Kessler, H.; Barluenga, S.; Winssinger, N.; Karplus,
M. Biophys. Chem. 2009, 143, 111e123.
10. Hellwig, V.; Mayer-Bartschmid, A.; Muller, H.; Greif, G.; Kleymann, G.; Zitz-
mann, W.; Tichy, H.-V.; Stadler, M. J. Nat. Prod. 2003, 66, 829e837.
11. Moulin, E.; Zoete, V.; Barluenga, S.; Karplus, M.; Winssinger, N. J. Am. Chem. Soc.
2005, 127, 6999e7004.
€
12. Ikemori-Kawada, M.; Kawai, T.; Goto, M.; Wang, Y. J.; Kawakami, Y. J. Chem. Inf.
Model. 2009, 49, 2650e2659.