LETTER
1871
A Multicomponent Coupling Strategy for the Synthesis of the Triene
Component of the Oxazolomycin Antibiotics
S
ynthesis of th
a
e
T
riene
C
u
omponent of
l
the
O
xazolom
G
ycin
A
ntibiotics . Bulger, Mark G. Moloney,* Paul C. Trippier
The Department of Chemistry, Dyson Perrins Laboratory, The University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
E-mail: mark.moloney@chem.ox.ac.uk
Received 29 August 2002
N
13'
O
7'
R1
Abstract: Concise and versatile routes suitable for the synthesis of
three geometric isomers of an analogue of the left hand triene sub-
unit of oxazolomycin are reported, using a Stille coupling strategy.
H
O
R2
HO
O
1'
MeMeO
O
10'
5
5'
N
H
NMe
1
HO
11
Me Me
Me
OH
Key Words: Stille reaction, natural products, diastereoselectivity,
organometallic reagents
Me
O
1a Oxazolomycin A: R1 = H, R2 = H; 4'Z,6'Z,8'E
1b Oxazolomycin B: R1 = H, R2 = H; 4'E,6'E,8'E
1c Oxazolomycin C: R1 = H, R2 = H; 4'Z,6'E,8'E
1d 16-Methyloxazolomycin: R1 = Me, R2 = H; 4'Z,6'Z,8'E
1e Curromycin A: R1 = CH3OCH2, R2 = Me; 4'Z,6'Z,8'E
1f Curromycin B: R1 = Me, R2 = Me; 4'Z,6'Z,8'E
Oxazolomycin A 1a is the parent member of a class of an-
tibiotics,1 other members being oxazolomycins B and C
1b,c,2 16-methyloxazolomycin 1d, neooxazolomycin,3
and the curromycins 1e,f.4–6 They possess an unusual
spiro fused -lactone/ -lactam linked via a triene and
(E,E)-diene spacer to an oxazole terminal residue. The
phthoxazolins, which are essentially the left hand domain
of oxazolomycin, are also known,7,8 although these have
markedly different biological activity.9–11 The oxazolo-
mycins and curromycins 1a–f (Figure 1) are isolated from
Streptomyces and exhibit wide ranging and potent antibi-
otic activity, including inhibition of Gram positive bac-
teria, antiviral activity against vaccinia, herpes simplex
type I, and influenza A, as well as in vivo antitumour ac-
tivity; notably, this biological activity is coupled with low
toxicity. Oxazolomycin 1a is an effective protonophore
at pH < 7.0, but conveys both protons and monovalent
cations (e.g. K+) at 7.0 < pH < 7.5,12 and it is this activity
which is thought to be responsible for its antibacterial,
antiviral, and cytotoxic properties.
Figure 1
drostannylation of propargyl alcohol in a modification of
the literature procedure21 (involving purification by col-
umn chromatography rather than distillation followed by
preparative HPLC), which gave the product in 67% isolat-
ed yield. Swern oxidation then afforded aldehyde 2b in
excellent yield (90%), whereas oxidation with PCC gave
only a 40% yield.22 After several unsuccessful attempts
under various conditions, Wadsworth–Emmons olefina-
tion with phosphonate 3c, prepared from -dicarbonyl 3a
via bromide 3b, was found to occur using NaH as the base,
which gave (E,E)-diene 4 as the sole product, albeit in
moderate yield (50%). The third double-bond was intro-
duced by reaction of vinyl iodide 5, prepared by Takai
homologation23 of phenylacetaldehyde with CrCl2/CHI3,
with stannane 4 to give (E,E,E)-triene 6a in 84% isolated
yield. Reduction with NaBH4 then gave alcohol 6b in 92%
yield, in which the polyene system had not been shifted
into conjugation with the phenyl group.
Notwithstanding the potent and wide-ranging but ill-un-
derstood biological activity of this class of compounds,
the oxazolomycins have received little synthetic attention.
There is only one total synthesis of any of these com-
pounds,13 although we14 and others15 have examined
routes for the synthesis of the lactam unit, and a synthesis
of phthoxazolin16 has been reported. The synthesis of the
required oxazole unit has also received recent attention.17
We report here a concise and versatile route for the
synthesis of the three known geometric isomers of the
C1 -C13 triene subunit of oxazolomycin in racemic
form,18 with the oxazole ring replaced by a phenyl group,
conducted as part of a long-term plan to identify the bio-
logical action of these compounds.
Encouraged by the successful use of a Stille reaction to
construct the (E,E,E)-triene system of oxazolomycin B in
a mild and stereoselective manner, attention was then fo-
cused on the development of an analogous strategy to-
wards the (Z,Z,E)- and (Z,E,E)-triene systems present in
oxazolomycin A and oxazolomycin C respectively. It was
decided to adopt a strategy involving coupling between a
divinyl halide and a vinylstannane in the key step
(Scheme 2).
Iodide 7a was prepared as a single isomer from propargyl
alcohol following the literature procedure,24 and the free
hydroxyl group then protected as its TBDMS-ether 7b in
excellent yield (99%). Conversion of this iodide to stan-
nane 7c was then effected via metal-halogen exchange
followed by Bu3SnCl quench, but the course of this reac-
tion was found to be very solvent dependent: in THF, the
major product was in fact vinyl silane 8 whereas in Et2O
Our routes made use of regioselective Stille couplings19,20
in a three-component coupling strategy (Scheme 1). Al-
lylic alcohol 2a was synthesised by AIBN-catalysed hy-
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1871,1873,ftx,en;D18202ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214