The first synthesis of the epoxide-containing macrolactone nucleus of oximidine I

Article abstract of DOI:10.1016/S0040-4039(03)01775-1

A synthesis of the epoxydiene-containing macrolide nucleus of oximidine I is reported, starting from commercially available 3-butyn-1-ol. The key macrocyclisation step is achieved using Horner-Wadsworth-Emmons methodology in the presence of an epoxide.

Full text of DOI:10.1016/S0040-4039(03)01775-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7209–7212
The first synthesis of the epoxide-containing macrolactone
nucleus of oximidine I
Joanne E. Harvey, Steven A. Raw and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 23 June 2003; accepted 18 July 2003
Abstract—A synthesis of the epoxydiene-containing macrolide nucleus of oximidine I is reported, starting from commercially
available 3-butyn-1-ol. The key macrocyclisation step is achieved using Horner–Wadsworth–Emmons methodology in the
presence of an epoxide.
© 2003 Elsevier Ltd. All rights reserved.
Oximidines I and II (1 and 2) were recently isolated1
from Pseudomonas sp. Q52002 and are part of an
expanding family of cytotoxic natural products based
on a salicylate-macrolactone core having a pendant
unsaturated enamide side-chain. Other members of this
family include salicylihalamide A,2 apicularen A3 and
lobatamide C4 which have all succumbed to total syn-
thesis. This class of compound exhibits significant and
selective cytotoxicity towards ras and src oncogene-
transformed cells, with mammalian vacuolar-type (H+)-
ATPases being the cellular targets.5
of natural product, we were attracted to the possibility
of macrocyclisation in the presence of an epoxide, as
there are potential pitfalls associated with subsequent
introduction of this moiety. Furthermore, methods are
known for the conversion of epoxides into alkenes,10
and so the triene system of oximidine II might also be
accessible by this route. While epoxides are generally
thought of as extremely reactive functional groups,
there is some evidence that they can survive a variety of
reaction conditions.11 We decided to tackle the synthe-
sis of the target model macrocycle 3 (Scheme 1) from
two
angles:
namely,
intermolecular
Horner–
Wadsworth–Emmons (HWE) reaction followed by
macrolactonisation (route a); and esterification with
subsequent intramolecular HWE reaction (route b).
The known cis-epoxy aldehyde 4,12 which was common
to both our proposed routes, was prepared from 3-
butyn-1-ol (5) via a modification of the original
sequence (Scheme 2). Stabilised Wittig reaction of this
intermediate with (ethoxycarbonylmethylene)triphenyl-
phosphorane was carried out in methanol to enhance
the Z-selectivity13 and this afforded the conjugated
ethyl ester 6 (alkene coupling J=11.8 Hz) as a 5:1
mixture with its E-isomer (alkene coupling J=15.8
Hz).14 The isomers were separable and DIBAL-H
reduction of Z-6 to the aldehyde 7 occurred in 74%
yield.
There has been considerable work towards the synthesis
of the complex conjugated enamide O-methyl oxime
side-chain present in the oximidines and lobatamides.6
In addition, there have been two published syntheses of
model systems related to the macrocycles of oximidine
I and II.7,8 Very recently, Porco and Wang have
reported an elegant total synthesis of oximidine II
which makes use of alkene metathesis in the key ring-
closing step.9 Nevertheless, the epoxydiene functionality
of oximidine I has remained elusive. In connection with
our on-going research into synthetic routes to this class
The aryl methyl phosphonate 10 (Scheme 3) was pre-
pared from commercially available methyl 2-methylben-
zoate (8) via the intermediate bromide 9. The
(trimethylsilyl)ethyl ester 12 (vide infra) was accessible
from 10 by saponification to acid 11 and subsequent
carbodiimide-promoted esterification.
Keywords: oximidine; Horner–Wadsworth–Emmons; epoxide.
* Corresponding author. E-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01775-1

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J. E. Har6ey et al. / Tetrahedron Letters 44 (2003) 7209–7212
Scheme 1.
A number of bases were tested for the key intramolecu-
lar HWE: only KOtBu and KHMDS afforded the
desired product 3. After much optimisation of condi-
tions, it was found that KOtBu in the presence of
18-crown-6 at 70°C in toluene furnished the macrocycle
3 with the highest reproducibility. Formation of the
highly conjugated product 3 was obvious by TLC due
to its strong fluorescence under short-wave UV irradia-
tion. Unfortunately, the yields remained poor (14–25%)
We were now in a position to evaluate the HWE-
macrolactonisation approach (Scheme 4). Thus, base-
treatment of compounds 7 and 10 afforded epoxydiene
13 in 36% yield. Desilylation proceeded smoothly but
subsequent saponification did not give the expected
hydroxy acid 14. Instead, phthalide 15 was the only
identifiable component of the reaction mixture. Com-
pound 15 presumably forms by 5-exo-trig cyclisation of
the acid carboxylate in the desired product 14 on to the
epoxydiene system with concomitant opening of the
epoxide. In an effort to avoid the problematic saponifi-
cation step, the (trimethylsilyl)ethyl ester 12 was sub-
jected to HWE reaction with aldehyde 7 to provide the
diene 16 in excellent yield (77%) (Scheme 4). Unfortu-
nately, when this was treated with tetra-n-butylammo-
nium fluoride for double-desilylation, the phthalide 15
again formed.
1
over a broad range of reaction times. The H NMR
spectrum of product 3 was entirely consistent and in
general agreement with that reported for oximidine I; a
COSY experiment fully confirmed the peak assign-
These problems encouraged investigation of the alter-
native route: esterification followed by final intramolec-
ular HWE reaction (Scheme 5). Thus, Z-selective
Wittig reaction of the aforementioned aldehyde 4 to
afford Z-methyl ester 17 (alkene coupling J=11.8 Hz),
followed by reduction gave the allylic alcohol 18. The
efficacy of this reduction was highly dependant on the
quality of the DIBAL-H reagent. More reproducible
results could be obtained by performing the reduction
in two stages with aqueous workup after each stage.
Protection as the acetate 19 and desilylation provided
alcohol 20 in high yield. After Yamaguchi-type activa-
tion of aryl acid 11, the alcohol 20 was added and ester
21 was obtained in 70% yield. Deacetylation proved
challenging, giving the dihydrofuran 22 under standard
conditions.15 Eventually it was found that treatment of
the acetate 21 with Cs2CO3 and triethylamine in
methanol at 0°C for 30 min gave solely the desired
allylic alcohol 23 (88% yield). Pyridinium dichromate
oxidation of alcohol 23 was accompanied by isomerisa-
tion of the Z-double bond, while attempted in situ
manganese dioxide oxidation/HWE reaction16 gave
dihydrofuran 24, resulting from cyclisation by the alco-
hol onto the epoxide functionality and ester cleavage.
Nevertheless, Swern oxidation cleanly gave aldehyde 25
in an excellent 86% yield.
t
Scheme 2. Reagents and conditions: (i) BuPh2SiCl, imidazole,
n
DMF, 92%; (ii) (a) BuLi, Et2O, −78°C, (b) (CH2O)n, −78 to
20°C, 74%; (iii) H2, Lindlar’s catalyst, quinoline, MeOH; (iv)
BuOOH, VO(acac)2, 4 A molecular sieves, toluene, 74% over
two steps; (v) pyridinium dichromate, 4 A molecular sieves,
CH2Cl2, 76%; (vi) Ph3PꢀCHCO2Et, NEt3, MeOH, −10 to
0°C, 85% (5:1 Z:E mixture); (vii) DIBAL-H, CH2Cl2, −75°C,
74%.
t
,
,
Scheme 3. Reagents and conditions: (i) N-Bromosuccinimide,
AIBN, CCl4, 77°C; (ii) P(OEt)3, 120°C, 89% over two steps;
(iii) NaOH, EtOH, 91%; (iv) Me3Si(CH2)2OH, 1-(N,N-
dimethylaminopropyl)-3-ethylcarbodiimide, 4-(N,N-dimethyl-
amino)pyridine, CH2Cl2, 87%.

J. E. Har6ey et al. / Tetrahedron Letters 44 (2003) 7209–7212
7211
Scheme 4. Reagents and conditions: (i) KOtBu, THF, −10°C, 36% (13), 77% (16); (ii) nBu4NF, THF, −10 to 20°C, 75%; (iii) LiOH,
n
THF, MeOH, H2O; (iv) Bu4NF, dimethylsulfoxide, 39%.
Scheme 5. Reagents and conditions: (i) Ph3PꢀCHCO2Me, NEt3, MeOH, −15°C, 93% (5:1 Z:E mixture); (ii) DIBAL-H (2×1.3
n
equiv.), CH2Cl2, −78°C, 74%; (iii) Ac2O, pyridine, CH2Cl2, 84%; (iv) Bu4NF, THF, −15 to 10°C, 92%; (v) 11, 2,4,6-trichloroben-
zoyl chloride, NEt3, THF then 20, 4-(N,N-dimethylamino)pyridine, toluene, 70%; (vi) Cs2CO3, NEt3, MeOH, 0°C, 88%; (vii)
Me2SO, (ClCO)2, CH2Cl2, −78°C then NEt3, 86%; (viii) KOtBu, 18-crown-6, toluene, 70°C, 14–25%.
ments.17 Significantly, the alkene proton corresponding
to H-11 appeared as a doublet (l 5.61, 3J10,11=10.1
Hz), while the epoxide peak H-12 was a broad singlet
maintenance of the epoxide moiety, which may aid
efforts towards the natural product itself. Our applica-
tion of this approach towards the synthesis of
oximidine I is continuing.
3
(l 3.71, J12,13 not resolved) suggesting a near-perpen-
dicular relationship between these protons, as seen in
the natural product.1 Full 13C and 2D NMR data were
obtained which further confirmed the assigned struc-
ture. The mass spectra were also in agreement with the
structure of the macrocycle. Finally, the UV spectrum
of the product showed a maximum at 276 nm (m 24,205)
which compares with the natural product value of 272
nm (m 30,500).1
Acknowledgements
J.E.H. thanks the Anglo-Australian Fellowships Trust
and the Ramsay Memorial Fellowships Trust for finan-
cial support. S.A.R. is grateful to the BBSRC for a
Quota studentship.
In conclusion, the epoxy-diene macrolide 3 has been
prepared from the known aldehyde 4 in eight steps
(4–8% overall yield) using Horner–Wadsworth–
Emmons methodology for the key cyclisation. This
synthesis of a simplified version of the anti-tumour
natural product oximidine I has allowed the develop-
ment of methodology, particularly with respect to
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