The syntheses of rac-inthomycin A, (+)-inthomycin B and (+)-inthomycin C using a unified synthetic approach

Article abstract of DOI:10.1016/j.tet.2008.01.116

The Stille coupling between a common oxazole vinyl iodide and stereodefined stannyl-diene units is described as the cornerstone of a unified synthetic route to the inthomycin family of bioactive Streptomyces metabolites. This procedure has been utilised to prepare (+)-inthomycin B and (+)-inthomycin C for the first time; in these examples the stereogenic centre was introduced using the Kiyooka ketene acetal/amino acid-derived oxazaborolidinone variant of the Mukaiyama aldol reaction. In addition, a convenient preparation of rac-inthomycin A is described based on the same strategy.

Full text of DOI:10.1016/j.tet.2008.01.116

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4778e4791
www.elsevier.com/locate/tet
The syntheses of rac-inthomycin A, (þ)-inthomycin B and
(þ)-inthomycin C using a unified synthetic approach
Michael R. Webb a, Matthew S. Addie a, Catherine M. Crawforth a, James W. Dale a,
Xavier Franci a, Mathieu Pizzonero a, Craig Donald b, Richard J.K. Taylor a,
*
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK
Received 5 September 2007; accepted 17 October 2007
Available online 2 February 2008
Abstract
The Stille coupling between a common oxazole vinyl iodide and stereodefined stannyl-diene units is described as the cornerstone of a unified
synthetic route to the inthomycin family of bioactive Streptomyces metabolites. This procedure has been utilised to prepare (þ)-inthomycin B
and (þ)-inthomycin C for the first time; in these examples the stereogenic centre was introduced using the Kiyooka ketene acetal/amino acid-
derived oxazaborolidinone variant of the Mukaiyama aldol reaction. In addition, a convenient preparation of rac-inthomycin A is described
based on the same strategy.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and reported the isolation of inthomycin A 4 (shown to possess
the same structure as phthoxazolin A) together with the geo-
metrical isomers inthomycin B 6 and C 5.10 Subsequently,
this family was expanded when a series of novel naturally-oc-
curring hydroxylated inthomycins were described.11 It should
be noted that although the inthomycins AeC contain the meth-
ylene-interrupted oxazolyl-triene motif present in oxazolomy-
cin family (Fig. 1), biosynthetic studies have established that
inthomycin A 4 is not an intermediate in the biosynthesis of
oxazolomycin A 1.12
Over the past twenty years a large number of complex bio-
active natural products containing a methylene-interrupted
oxazolyl-triene motif have been isolated from strains of Strep-
tomyces sp. Oxazolomycin A 1,1 isolated in 1985, is the parent
member of this class of antibiotics, which also includes ox-
azolomycins B 2 and C 3,2 neooxazolomycin,3 curromycins A
and B,4 16-methyloxazolomycin,5 KSM-2690 A and B,6
and lajollamycin.7,8
However, in the early 1990s, the groups of Omura and
Zeeck discovered related compounds containing primary am-
ides in place of the complex spirocyclic pyrrolidinone-
amine-derived systems present in the oxazolomycin family.9,10
Thus, in 1990, Omura et al. described the isolation of the
Streptomyces-derived methylene-interrupted oxazolyl-triene
4, which they named phthoxazolin A.9 Then, the following
The inthomycins have been shown to be highly specific in-
hibitors of cellulose biosynthesis, displaying selective in vitro
antimicrobial activity against Phytophtora parasitica and P.
cactorum.9 Herbicidal activity has also been noted with radish
seedlings13 and velvet leaf14 when treated with inthomycin A
4 after emergence; novel derivatives of inthomycin A 4 have
been prepared and evaluated as herbicidal agents (leading to
the discovery that the allylic alcohol is required for activity).15
In 2004, inthomycin A 4 was also shown to inhibit the growth
of prostate cancer cells.16
year, Henkel and Zeeck studied Streptomyces (strain Go 2)
¨
* Corresponding author. Tel.: þ44 (0) 1904 432606; fax: þ44 (0) 1904
434523.
E-mail address: rjkt1@york.ac.uk (R.J.K. Taylor).
To date, there has been only one published synthesis of any
member of the inthomycin family: in 1999, Henaff and
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.116

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4779
N
O
N
O
O
OH
O
MeO
HO
O
OH
O
O
N
N
H
NH2
Inthomycin A / Phthoxazolin A (4)
OH
Oxazolomycin A (1)
O
O
O
OH
O
MeO
HO
N
OH
O
N
N
N
H
O
NH2
O
OH
Oxazolomycin B (2)
Inthomycin C (5)
N
N
O
O
O
O
MeO
HO
O
O
O
N
HO
N
H
HO
NH2
OH
Oxazolomycin C (3)
Inthomycin B (6)
Figure 1.
Whiting reported the preparation of racemic inthomycin A 4
based on a route, which utilised the Stille coupling between
oxazole vinylstannane 7 and dienyl iodide 8 as the final step
(Scheme 1).17 It should be noted that this coupling mirrored
the process used earlier by Kende et al. when preparing R-
11 from the same oxazole vinylstannane 7 and dienyl iodide
9 (Scheme 1) during their ground-breaking enantioselective
total synthesis of neooxazolomycin.18 However, the synthetic
routes were very different in terms of the construction of the
vinyl iodide coupling partners: Henaff and Whiting utilised
novel vinylboronate-Heck chemistry whereas Kende et al.
used Sonogashira coupling with a late-stage diastereoselective
Reformatsky-type condensation involving an Evans auxiliary
to produce the required R-configured product. Nevertheless,
both routes were long (10e17 steps) and low-yielding
(ꢀ3%). More recently, Moloney et al. have prepared novel an-
alogues of the inthomycins (e.g., the racemic phenyl analogue
12), again using Stille coupling as the cornerstone of the
sequence.19
inthomycin analogues20 proved problematic and so the conver-
gent route shown in retrosynthetic form in Scheme 2 was de-
signed. Thus, the aim was to employ the oxazole vinyl iodide
13 as a common precursor to prepare all three inthomycins.
We assumed that iodide 13 would be easily obtained from
the known18 oxazole methanol 15. The stereodefined dienyl-
stannanes 14 would then be required for the key Stille coup-
ling reactions and we envisaged that they would be readily
prepared from the dienals 16 via the Mukaiyama aldol reaction
with ketene acetal 17; indeed, we envisaged coupling partners
14 would be accessible in enantioenriched form by carrying
out the reaction in the presence of a chiral Lewis acid as
pioneered by Kiyooka.21,22 We felt that the strength of this ret-
rosynthetic analysis lay in the ready availability of E- and Z-3-
(tributylstannyl)propenal (see later) and assumed that standard
HornereWadswortheEmmons or StilleGennari methodology
could be employed to convert aldehydes 18 into dienals 16 in
a stereocontrolled manner. We have recently described, in
communication format,23 the successful implementation of
this strategy for the preparation of (þ)-inthomycin B 6. We
now report full details of the (þ)-inthomycin B 6 study and
the extension of this methodology to prepare (þ)-inthomycin
C 5 (for the first time) and rac-inthomycin A 4.
As part of a programme to prepare members and synthetic
analogues of the oxazolomycin family,8b we required efficient
and stereocontrolled procedures to prepare all of the inthomy-
cins AeC and their precursor acids. Our initial approaches to
I
OH
O
N
NH2
Ph
8
OH
O
OH
O
O
O
N
OH
NH2
( )-4
22%
12
PdCl2(MeCN), rt
DMF, 91-120 h
SnBu3
O
7
N
N
i. HF, 92%
I
TBSO
O
TBSO
OH
O
O
ii. LiOH, 94%
O
OMe
OMe
OH
10
79%
11
9
Scheme 1.

4780
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
OH
O
N
OH
O
N
I
+
NH2
Bu3Sn
O
OMe
O
13
14
4, 5, 6
OTMS
OMe
17
CHO
N
CHO
Bu3Sn
Bu3Sn
OH
HWE or
Still-Gennari
O
16
18
15
Scheme 2.
2. Synthesis of (D)-inthomycin B 6
CuI or KI}. Unfortunately, given the thermal instability of bro-
mide 20, conditions for coupling at rt could not be found. The
most reliable and reproducible procedure utilised Pd2dba3
(5 mol %) with freshly prepared bromide 20 in THF at reflux
giving the known17,18 vinylstannane 7 (>50%). By the use of
bromide 20 in excess (1.3 equiv) the isolated yield could be im-
proved to 66% based on the stannane (but excess 20 could not be
recovered; no double coupling was seen in any of these
reactions).
With vinylstannane 7 in hand, its conversion to the required
vinyl iodide 13 proceeded smoothly using iodine in dichloro-
methane (86%); alternatively the coupling and iodination steps
could be telescoped into a one pot process, giving iodide 13 in
46% overall yield based on bromide 20.
The stannyl-diene Z,E-14 required for the preparation of in-
thomycin B 6 was next prepared from propargyl alcohol as
shown in Scheme 4. The conversion of propargyl alcohol
into E-3-(tributylstannyl)propenal E-18 was easily accom-
plished using a modification of Wender’s procedure.26 Thus,
silylation, hydrostannylation and desilylation were accom-
plished as described giving alcohol 21, but barium manganate
was replaced by activated manganese dioxide producing alde-
hyde E-18 in 92% yield (other oxidation conditions required
purification by silica gel chromatography resulting in lower
yields due to the acid-sensitivity of aldehyde E-18).
The initial objective was to develop an efficient preparation
of the oxazole vinyl iodide 13, central to the synthesis of all of
the inthomycins, and van Leusen’s TosMIC methodology24
proved to be applicable on a multi-gram scale (Scheme 3).
Thus, treatment of ethyl glyoxylate and TosMIC with
K2CO3 under strictly anhydrous conditions gave oxazole 19
in 86% yield. Reduction of the ethyl ester with NaBH4 cleanly
afforded the primary alcohol 15 in 85% yield, which was con-
verted into the corresponding bromide 20 using the pub-
lished18 procedure (NBS/PPh3). The reported yield for this
conversion was a moderate 44% and our initial efforts were
subjected to great variability (14e45%) and efforts to prepare
either the iodide or triflate corresponding to bromide 20 led to
products that were too unstable to isolate. We eventually
established that bromide 20 is thermally unstable and decom-
poses on lengthy exposure to chromatography; by purification
of the crude reaction mixture using rapid filtration through
a ‘plug’ of silica, and then ensuring that the temperature
remained below 25 ꢁC during evaporation of the solvent, bro-
mide 20 could be isolated in a reproducible 94% yield on
scales up to 6 mmol.
An sp3esp2 Stille coupling reaction between bromide 20 and
E-1,2-bis-(tri-n-butylstannyl)ethane25 was envisaged to effect
the two-carbon homologation. A range of catalysts and reaction
conditions were screened to optimise the yield of 7
{Pd(PPh3)2Cl2, Pd(PPh3)4, Succ-Pd(PPh3)2Br, Pd(CH3CN)2Cl2,
BnPd(PPh3)2Cl, Pd2(dba)3 with AsPh3 or P(2-furyl)3, adding
Reaction of E-18 with ethyl 2-[bis-(2,2,2-trifluoroethoxy)-
phosphoryl]propanoate 22, under StilleGennari conditions,27
afforded the Z,E-diene 23 exclusively in 94% yield (Ando’s
reagent, ethyl 2-[bis-(phenoxy)phosphoryl]propanoate28 gave
N
O
N
i
ii
Ts
N
OEt
+
C
OH
EtO
O
O
O
O
19
15
N
N
N
iii
SnBu3
v
iv
I
Br
O
O
O
7
13
20
vi
Scheme 3. Reagents and conditions: (i) K2CO3, EtOH, 80 ꢁC, 86%; (ii) NaBH4, EtOH, rt, 60 h, 85%; (iii) NBS, PPh3, CH2Cl2, 0 ꢁC, 1 h, 94%; (iv) Pd2dba3
(5 mol %), E-Bu3SnCH]SnBu3, THF, 80 ꢁC, 4 h, 51%; (v) I2, CH2Cl2, 0 ꢁC, 20 min, 86%; (vi) Pd2dba3 (5 mol %), E-Bu3SnCH]SnBu3, THF, 80 ꢁC, 4 h,
then I2 at 0 ꢁC, overnight, 46%.

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4781
O
P
O
CF3CH2O
CF3CH2O
nOe 8.9%
OEt
H
ref. 27
i
22
CHO
OH
Bu3Sn
Bu3Sn
Bu3Sn
OH
ii
O
23
OEt
E-18
21
O
25 a, R = iPr
b, R = Ph
R
N
O
Ts
B
H
iii
iv
Bu3Sn
Bu3Sn
O
Bu3Sn
+
Bu3Sn
OTMS
CHO
OTMS
HO
OMe
OH
17
24
OMe
Z,E-16
26
Z,E-14
see Table 1
Scheme 4. Reagents and conditions: (i) MnO2, CH2Cl2, rt, 3 d then 40 ꢁC, 21 h, 92%; (ii) 22, 18-crown-6, KHMDS, ꢂ78 ꢁC, 30 min, then 18, THF, ꢂ78 ꢁC, 4.5 h,
ꢁ
˚
94%; (iii) DIBAL-H, DCM, ꢂ10 C, 1.5 h, 84%; (iv) TPAP, NMO, 4 A molecular sieves, DCM, rt, 1.5 h, quant.
Table 1
Asymmetric Mukaiyama aldol reactions giving Z,E-14
(a) N-Ts-L-valine (1 equiv), BH3$THF (1.1 equiv) (25a), 0 ꢁC, 30 min then rt,
Z,E-14, 50%; 26, 38% (ee, n/d)
30 min, then Z,E-16, 17, ꢂ78 ꢁC, 45 min
(b) N-Ts-L-valine (2 equiv), BH3$THF (1.2 equiv) (25a), 0 ꢁC to rt, overnight, then Z,E-16, 17, ꢂ78 ꢁC, 1.5 h
(b) N-Ts-L-Phenylalanine (2 equiv), BH3$THF (1.2 equiv) (25b), 0 ꢁC to rt, overnight, then Z,E-16, 17, ꢂ78 ꢁC, 2.5 h
Z,E-14, 74% (64% ee)
Z,E-14, 63% (60% ee)
a 9:1 Z/E ratio and a modest 55% yield). The configuration of
the newly formed alkene was confirmed by NOE studies as
shown. A two-step reductioneoxidation sequence then af-
forded the highly acid sensitive aldehyde Z,E-16 in 84% yield.
The asymmetric MukaiyamaeKiyooka aldol reaction for
the conversion of Z,E-16 into Z,E-14 was investigated next
(Scheme 4, Table 1). In the initial attempt (entry a), standard
Kiyooka conditions22 were employed utilising ketene acetal
17 and the N-Ts-L-valine-derived oxazaborolidinone 25a
(R¼iPr) at ꢂ78 ꢁC. This procedure gave the hoped-for aldol
product Z,E-14 in 50% yield accompanied by the silylated re-
duction product 26 in 38% yield (Scheme 4). Extensive exper-
imentation using trans-a-methyl-cinnamaldehyde29 indicated
that the direct reduction could be minimised by the use of
an excess of N-Ts-L-valine (a two-fold excess compared to
the borane reagent) and extending the time for oxazaborolidi-
none formation from 1 h to overnight. It was also found that
recrystallisation of the N-tosyl-L-valine to constant [a]D was
necessary for optimum enantioselectivity. In addition, the
use of an aqueous sodium bicarbonate work-up procedure
gave only alcohol 14 (and no silyl ether 26). In this way (entry
b), aldol product Z,E-14 was obtained in 74% yield and 64%
ee {[a]D þ5.4 (c 1.07, CHCl3)} (the ee was disappointing in
view of the 84% ee obtained in the model studies29). Other
oxazaborolidinones were explored without improvement
although the N-tosyl-L-phenylalanine-derived system gave
the product Z,E-14 in 60% ee (entry c). The diene stereochem-
istry was retained in all cases as demonstrated by the isolation
of a single product and inspection of the diene J values. Liter-
ature precedent22 suggested that the use of N-tosyl-L-amino
acids should produce a predominance of the required R-Z,E-
14 (as shown) and this was confirmed by Mosher’s studies at
a subsequent stage (see later).
The next step involved the key palladium-catalysed Stille
coupling of iodide 13 with stannyl-diene Z,E-14 (Table 2). A
number of palladium catalysts were screened to mediate the
coupling to produce triene 27 but Pd(CH3CN)2Cl2 appeared
to offer the greatest initial promise (Table 2, entries aee).
Thus (entry a), using 7 mol % of the catalyst in DMF at rt pro-
duced triene 27 in 55% yield. However, analysis of this prod-
uct by 1H NMR spectroscopy indicated that extensive
isomerisation of the triene unit had occurred giving a mixture
of inseparable stereoisomers. Attempts to minimise isomerisa-
tion by carefully degassing the solvent and excluding light
failed to offer any improvement but lowering the catalyst load-
ing (1 mol %) gave 27 with very little isomerisation although
the reaction was very slow (entry b, 24 h, 37% with recovered
starting materials). Retaining the low catalyst loading but rais-
ing the temperature (entry c) or using microwave acceleration
(entry d) resulted in faster reactions but again isomerisation
proved to be a problem. However, by keeping the reaction
at 50 ꢁC (entry e), coupling could be accomplished in quan-
titative yield with negligible isomerisation, the downside
being the prolonged reaction time (5 d).30 It was eventually
established that the Pd(0)/CuI/CsF conditions developed by
Baldwin’s group31 gave triene 27 in quantitative yield after
3 h with only trace levels of isomerisation (entry f). Stannyl
by-products were effectively removed by purifying the product
on flash silica doped with 10% KF32 to afford spectroscopi-
cally pure 27.
To confirm the stereochemistry of the aldol product, alco-
hol 27 was derivatised with both R- and S-Mosher acids.33
1
Comparison of the H NMR chemical shifts of 28 and 29 by
spectroscopy (see Scheme 5) confirmed the required (and anti-
cipated22) 3R-stereochemistry of the hydroxyl centre (and
confirmed the expected mixture of diastereoisomers, ca. 80:20).

4782
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
Table 2
Screening conditions for Stille coupling between 13 and Z,E-14 to give 27
N
N
I
Bu3Sn
O
+
O
O
O
HO
OMe
HO
OMe
Z,E-14
27
13
Entry
Catalyst
mol %a
Time
Temp (ꢁC)
Yield (%)
Isomerisation (%)
a
b
c
d
e
f
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
7
1
1
1
1
1
4.5 h
24 h
14 h
7 hc
5 dd
3 h
rt
55
30
rt
37b
72
Trace
20
15
80
50
50
45
22b
Quant.
Quant.
Trace
Trace
Pd(PPh3)4, CuI, CsF (2 equiv)
a
Reaction concentration 0.12 M in degassed DMF.
Mainly recovered coupling partners.
b
c
d
Reaction performed in a CEM microwave.
If stopped after 24 h, 27 was isolated in 43% yield.
N
N
N
O
i
δ 1.75
δ 1.62
O
O
O
O
O
Ph
OMe
MeO
F3C
Ph
HO
OMe
O
OMe
δ 1.16 δ 1.24
O
OMe
28
27
29
F3C
δ 1.18 δ 1.27
O
O
Derived from R-MTPA
Derived from S-MTPA
ii
N
N
N
16
4
13
iv
iii
O
O
O
O
O
O
HO
OH
AcO
OH
HO
1 NH2
3
30
31
6
Scheme 5. Reagents and conditions: (i) MTPA-Cl, DMAP, Et3N, DCM, 14 h, quant.; (ii) LiOH, THFeMeOHeH2O (3:1:1), 4.5 h, 73%; (iii) (a) Ac2O, py, rt, 14 h,
(b) NaHCO3 (aq), CH2Cl2, 8 h, rt, 62%; (iv) (a) (COCl)2, DMF, CH2Cl2, 0 ꢁC, 3.5 h, (b) NH4OH, rt, overnight, 50%.
In order to complete the synthesis of inthomycin B 6,
a functional group transformation of methyl ester to primary
amide was required but this was complicated by the steric hin-
drance of the a-gem-dimethyl groups and the presence of
a free hydroxyl group in ester 27. Model studies34 indicated
that direct amidation was not straightforward and so methyl
ester 27 was hydrolysed to the corresponding acid 30. Disap-
pointingly, subsequent HATU-mediated coupling with ammo-
nia led to decomposition and no inthomycin B 6 could be
isolated. After extensive experimentation, it was found that
the required transformation could be accomplished by conver-
sion to acetate 31 followed by acid activation with oxalyl chlo-
ride and then in situ treatment with ammonium hydroxide to
give concomitant amide formation and acetate removal. This
sequence produced inthomycin B 6 in reasonable isolated
yield {[a]D þ19.3 (c 1.0, CHCl3); no [a]D reported in the lit-
erature}. The spectral data were consistent with those previ-
ously reported [e.g., dC 19.6 (C-16), 75.9 (C-3), 139.9 (C-4),
151.7 (C-13); Lit.10 dC 19.6 (C-16), 75.8 (C-3), 139.9 (C-4),
151.6 (C-13)] and compound 6 was fully characterised.
Inthomycin B 6 has thus been prepared in a total of nine
steps (eight flasks) from ethyl glyoxylate and dienylstannane
Z,E-14 (itself prepared in four steps from known aldehyde
E-18) in 7% overall yield and ca. 64% ee.
3. Synthesis of inthomycin A 4
Having succeeded with the synthesis of inthomycin B, we
went on to explore the preparation of inthomycin A starting
from the common vinyl iodide 13 (Scheme 6). The first task
was to prepare Z-3-(tributylstannyl)propenal Z-18, which
was easily accomplished by LiAlH4 reduction of propargyl
alcohol then transmetallation with Bu3SnCl35 followed by oxi-
dation of the resulting alcohol 32 using the LeyeGriffith
TPAP procedure.36,37 Surprisingly, reaction of aldehyde Z-18
with the StilleGennari trifluoroethoxyphosphonate 22 using
the standard conditions gave mainly the E,Z-product 35
(E,Z/Z,Z¼9:1).37 Fortunately, on changing to the Ando phe-
noxy phosphonate 3328 the desired Z,Z-diene 34 was formed
as the major product (E,Z/Z,Z¼13:87). Reduction of this mix-
ture allowed the Z,Z-isomeric alcohol to be isolated and oxida-
tion afforded aldehyde Z,Z-16 in 68% yield (Z,Z-16 undergoes
isomerisation readily and so has to be elaborated immediately
after preparation). Application of the optimised Mukaiyamae

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4783
O
P
PhO
PhO
CO2Et
nOe 9.1%
i35
33
iii
ii
H
Bu3Sn
Bu3Sn
Bu3Sn
+
Bu3Sn
OH
CO2Et
CHO
CH2OH
H
CO2Et
32
Z-18
34
35
nOe 7.3%
N
I
O
13
iv, v
vi
Bu3Sn
Bu3Sn
Bu3Sn
OH O
vii
viii
CHO
CO2Et
OMe
Z,Z-16
34
( )-Z,Z-14
N
O
N
O
N
O
xi
ix, x
OH
O
OH
O
OAc O
OH
NH2
NH2
( )-4
37
36
35
Scheme 6. Reagents and conditions: (i) (a) LiAlH4, THF, 0 ꢁC to rt, 26 h, (b) Bu3SnCl, rt, 24 h, 63%; (ii) TPAP, NMO, 4 A molecular sieves, DCM, rt, 3 h, 81%;
˚
(iii) 33, NaH, THF, ꢂ78 ꢁC then 0 ꢁC, 20 min, then added Z-18, ꢂ78 ꢁC to rt, overnight, 80% (34:35¼87:13); (iv) DIBAL-H, DCM, ꢂ35 ꢁC to 0 ꢁC, 2 h, 68%; (v)
ꢁ
ꢁ
˚
TPAP, NMO, 4 A molecular sieves, DCM, 0 C, 2 h, quant.; (vi) Me2CHCO2Me, LDA, THF, ꢂ78 C, 25 min then Z,Z-16, 2 h, 83%; (vii) 13, 5 mol %
Pd(CH3CN)2Cl2, DMF, rt, 5 h, 77%; (viii) LiOH$H2O, THF, MeOH, H2O, rt, 3.5 h, 92%; (ix) Ac2O, py, rt, 20 h, then NaHCO3 (aq), DCM, rt, 2 h, quant.; (x)
SOCl2, DMF, DCM, 0 ꢁC to rt, 2.5 h, then NH4OH, rt 1 h, 70%; (xi) LiOH$H2O, THF, MeOH, H2O, rt, 1 h, 92%.
Kiyooka conditions using the N-Ts-L-valine-derived oxazaboro-
lidinone 25a, discussed earlier, led to a complex mixture of
products from which it was concluded that alkene isomerisa-
tion, aldehyde reduction and destannylation were rife.
After extensive optimisation, the highest yield of adduct Z,Z-
14 to be obtained was a disappointing 7%. The inherent instabil-
ity of Z,Z-16, coupled with its lability under the Lewis acidic
conditions, forced us to continue with a racemic synthesis utilis-
ingthelithium enolate ofmethyliso-butyrate toformthe required
ester Z,Z-14 in racemic form. Under these basic conditions the
condensation was effective giving Z,Z-14 in 83% yield.
The Stille coupling betweenvinyl iodide 13 and Z,Z-14 using
Pd(CH3CN)2Cl2 (5 mol %) proceeded in 77% yield (some triene
isomerisation was observed during coupling but it was <20%)
and saponification gave acid 36. Then, following the previous
sequence, acetylation, acid chloride formation and quenching
with ammonium hydroxide formed acetate 37 (Scheme 6).
The isolation of acetate 37 provided yet another illustration of
the marked differences between the different triene stereoiso-
mers; Z,E,E-triene 31 underwent in situ amide formation and
acetate removal whereas the acetate remained intact under these
conditions with Z,Z,E-triene 37. However, saponification of ace-
tate 37 using lithium hydroxide produced racemic inthomycin A
4. The spectral data were consistent with those previously re-
ported9,10 [e.g., dC 19.8 (C-16), 75.5 (C-3), 140.7 (C-4), 151.6
(C-13); Lit.10 dC 19.8 (C-16), 75.4 (C-3), 140.6 (C-4), 151.6
(C-13)] and compound 4 was fully characterised.
4. Synthesis of (D)-inthomycin C 5
The final target was inthomycin C 5. Using the approach
outlined in Scheme 2, we proceeded to prepare the required
dienylstannane E,E-14 as shown in Scheme 7. Thus, using
the aforementioned E-18, a standard E-selective HWE reaction
with triethyl 2-phosphonopropionate 38 was employed to
prepare diene 39 (E/Z¼19:1, separable). DIBAL-H reduction
followed by MnO2 oxidation afforded aldehyde E,E-16 with
retention of stereochemistry (NMR spectroscopy). Utilisation
of the optimised MukaiyamaeKiyooka conditions with the
N-Ts-L-valine-derived oxazaborolidinone 25a, discussed ear-
lier, gave a negligible amount of the required dienylstannane
E,E-14 but only the corresponding destannylated product 40
was obtained.
A range of reaction conditions were explored but the de-
stannylation process could not be prevented. However, in the
inthomycin C 5 case,38 a slight variation to the original
approach was devised, which ensured that the asymmetric Mu-
kaiyama aldol reaction could still be utilised (Scheme 8).
Thus, in this revised approach, Stille coupling was carried
out prior to aldol homologation.
Therefore, Stille coupling of aldehyde E,E-16 with vinyl
iodide 13 using Pd(CH3CN)2Cl2 as catalyst gave trienal 41
in 74% yield (Baldwin’s conditions31 gave no coupling in
this instance). We were delighted to observe that aldehyde
41 underwent the MukaiyamaeKiyooka aldol reaction; thus,
treatment with silyl ketene acetal 14a gave the required
a-hydroxy ester 43 in 50% yield and 76% ee (as determined
by Mosher ester analysisdwhich again confirms the R-stereo-
chemistry of the major enantiomer). An excess of
Thus, (ꢃ)-inthomycin A 4 was obtained in a total of 10
steps from ethyl glyoxylate and dienylstannane Z,Z-14 (itself
prepared in 6 steps from propargyl alcohol) in 14% overall
yield, a clear improvement on other17,18 routes.

4784
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
O
P
EtO
EtO
CO2Et
38
ii, iii
CHO
CO2Et
CHO
Bu3Sn
E-18
Bu3Sn
Bu3Sn
i
E,E-16
39
OTMS
OMe
OH
O
OH
O
17
+
Bu3Sn
OMe
OMe
25a
iv
40 (major product)
E,E-14 (trace)
Scheme 7. Reagents and conditions: (i) KHMDS, 18-crown-6, THF, ꢂ78 ꢁC, 30 min then 38, ꢂ78 ꢁC to rt, overnight, 98%; (ii) DIBAL-H, DCM, ꢂ10 ꢁC to rt, 3 h,
quant.; (iii) MnO2, DCM, rt, 2 d, quant.; (iv) N-Ts-L-valine, BH3$THF, DCM, 0 ꢁC, 5 min then rt, 25 min then ꢂ78 ꢁC, E,E-16 and 25a, 3 h.
OTMS
OMe
N
17
N
i
CHO
+
I
CHO
Bu3Sn
25a
O
O
ii
41
13
E,E-16
N
OH
O
N
iii
+
OH
OMe
O
O
42
43
OH
O
N
OH
O
N
iv
NH2
O
OH
O
(+)-5
44
Scheme 8. Reagents and conditions: (i) 5 mol % Pd(CH3CN)2Cl2, DMF, rt, 2 h, 74%; (ii) N-Ts-L-valine, BH3$THF, DCM, 0 ꢁC, 20 min then rt, 30 min then
ꢂ78 ꢁC, 2 h, 41 and 17, 50% 43 (76% ee) and 43% 42; (iii) LiOH$H2O, THF, MeOH, H2O, rt, 22 h, 89%; (iv) HATU, EtNiPr2, NH4Cl, THF, rt, 15 h, 33%.
oxazaborolidinone 25a was required to effect the aldol reac-
tion, presumably due to complexation with the oxazole, and
as a result competitive reduction was observed with alcohol
42 being isolated in 43% yield.
ketene acetal/amino acid-derived oxazaborolidinone proce-
dure as its cornerstones. The same route was employed to
complete a short synthesis of (ꢃ)-inthomycin A 4 and (þ)-
inthomycin C 5 was prepared using a slight modification in
which Stille coupling was carried out prior to the Mukaiyamae
Kiyooka reaction. A noteworthy feature of this study is the
dramatically different reactivities observed for the different
polyene stereoisomers in HWE,23,37 Stille coupling,
MukaiyamaeKiyooka and other reactions. Although optimi-
sation is still required, particularly in terms of the enantio-
control of the MukaiyamaeKiyooka processes, these
synthetic routes should provide ready access to the precursor
acids (36, 44 and 30) required to complete the syntheses of
oxazolomycins AeC 1e3.
The synthesis was completed by hydrolysis of ester 43 to
give acid 44 and then HATU-mediated coupling with ammonia
to produce (þ)-inthomycin C 5 for the first time. The spectral
data were consistent with those previously reported [e.g., dC
13.3 (C-16), 83.9 (C-3), 140.1 (C-4), 151.8 (C-11); Lit.10 dC
13.4 (C-16), 83.7 (C-3), 140.0 (C-4), 151.6 (C-11)] and com-
pound 5 was fully characterised. The success of this direct
coupling is noteworthy but the yield was modest (33%) and
it was impossible to remove all traces of the tetramethyl
urea by-product; it seems likely that the acetylationeacid
chloride-amidation sequence used for inthomycins A and B
would have given higher yields but insufficient material was
available to confirm this proposal.
5. Experimental
In summary, we have completed the first synthesis of (þ)-
inthomycin B 6 using a concise, convergent and stereocon-
trolled route with the Stille coupling of a stannyl-diene with
an oxazole vinyl iodide unit, and a MukaiyamaeKiyooka
5.1. General directions
Reagents and anhydrous DMF were purchased from com-
mercial sources and were used directly without further

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4785
purification, unless specified otherwise. THF was dried with
sodium and benzophenone and was distilled prior to use.
Et2O and CH2Cl2 were dried on an MBraun SPS Solvent Pu-
rification System. Petroleum ether refers to the fraction boiling
in the range 40e60 ꢁC. All procedures requiring inert atmo-
spheres were performed in dry glassware under an atmosphere
of nitrogen. Flash column chromatography was carried out
using silica gel 35e70 mesh and the eluent specified under
bellows pressure. Thin layer chromatography (TLC) was car-
ried out using Merck silica gel 60 F254 pre-coated aluminium
foil plates with a thickness of 250 mm, and visualised with UV
light (254 nm), followed by heating after treatment with
KMnO4 or vanillin solutions. Infra-red spectra were recorded
on a Thermo Nicolet IR100 spectrometer, as thin films be-
tween NaCl plates. Optical rotation values were recorded
with a JASCO model DIP-370 digital polarimeter using
sodium D line; 589 nm radiation and are expressed in units
46%) as a pale yellow oil, Rf¼0.23 (DCM); nmax (film) 3125,
3049, 1607, 1509, 1421, 1283, 1199, 1102, 947 cmꢂ1; dH
(400 MHz, CDCl3) 3.43 (2H, d, J 6.5), 6.26 (1H, dt, J 14.5,
1.5), 6.59 (1H, dt, J 14.5, 6.5), 6.83 (1H, s), 7.80 (1H, s); dC
(100 MHz, CDCl3) 32.5, 79.3, 123.7, 140.0, 149.4, 151.3;
m/z (CI) 236 (MHþ, 100) [Found (CI): MHþ, 235.9576;
C6H7NOI requires MH, 235.9572, 1.5 ppm error].
5.1.3. Ethyl 2Z,4E-2-methyl-5-(tributylstannyl)-2,4-
pentadienoate 23
To a stirred mixture of 18-crown-6 (0.384 g, 1.45 mmol)
and ethyl 2-[bis-(2,2,2-trifluoroethoxy)phosphoryl]propanoate
2227 (0.153 g, 0.44 mmol) in THF (6 mL) was added KHMDS
([0.5 M in toluene]; 0.83 mL, 0.42 mmol) at ꢂ78 ꢁC. The so-
lution was stirred for 30 min at ꢂ78 ꢁC, before the addition of
E-3-(tributylstannyl)propen-1-al E-1826 (0.120 g, 0.35 mmol)
in THF (4 mL). The reaction mixture was stirred for 4.5 h at
ꢂ78 ꢁC, then allowed to warm to rt, quenched with a saturated
solution of NH4Cl (2 mL) and diluted with Et2O (25 mL). The
layers were separated, the organic layer washed with brine
(5 mL), dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by flash silica column chromatogra-
phy (DCM) to afford compound 23 (0.140 g, 94%) as a pale
yellow oil, Rf¼0.78 (petroleum ethereEtOAc, 20:1); nmax
(neat) 2927, 1710, 1617, 1462, 1375, 1241, 1191, 1124,
999 cmꢂ1; dH (400 MHz, CDCl3) 0.82e0.98 (18H, m),
1.20e1.38 (6H, m), 1.40e1.56 (6H, m), 1.97 (3H, s), 4.23
(2H, q, J 7.0), 6.39 (1H, d, J 10.5), 6.53 (1H, d, J 18.5),
7.52 (1H, dd, J 18.5, 10.5); dC (100 MHz, CDCl3); 9.7, 13.8,
14.4, 20.8, 27.4, 29.3, 60.4, 124.9, 142.3, 142.9, 143.6,
167.8; m/z (CI) 431 (MHþ, 9), 390 (38), 373 (37), 308
(100),139 (36) [Found (CI): MHþ, 427.1974; C20H39O2Sn
requires MH, 427.1967, 1.6 ppm error].
1
of 10ꢂ2 deg cmꢂ2 gꢂ1. The H and 13C NMR spectra along
with 2D experiments were recorded with a Jeol EX-400 spec-
trometer. The solutions were prepared in suitable deuterated
solvents and referenced using residual protonated solvent or
TMS. HPLC analyses were performed on Daicel columns
with a chiral stationary phase as specified, using a Gilson
321 pump and 170 diode array system. Low and high field
resolution chemical-ionisation (CI), electron-ionisation (EI)
and electrospray-ionisation (ESI) mass spectrometry were per-
formed with a Micromass Autospec spectrometer. High reso-
lution molecular ions described are within ꢃ5 ppm of the
required molecular mass.
5.1.1. 5-(Bromomethyl)oxazole 20
To a stirred solution of (oxazol-5-yl)methanol 1518
(0.600 g, 6.06 mmol) in DCM (30 mL) at 0 ꢁC were added
PPh3 (1.78 g, 6.79 mmol) and N-bromosuccinimide (recrystal-
lised from water, 1.21 g, 6.80 mmol). The reaction mixture
was stirred at 0 ꢁC for 1 h, then concentrated in vacuo (main-
taining water bath temperature below 25 ꢁC) and the residue
directly purified by flash silica column chromatography
(DCM) to provide bromide 2018 (0.92 g, 94%) as a colourless
oil, Rf¼0.56 (petroleum ethereEtOAc, 2:1); dH (400 MHz,
CDCl3) 4.50 (2H, s), 7.10 (1H, s), 7.89 (1H, s); m/z (CI)
162 (MHþ, 100).
5.1.4. 2Z,4E-2-Methyl-5-(tributylstannyl)-2,4-penta-
dien-1-ol 24
To a stirred solution of ester 23 (0.432 g, 1.01 mmol) in
DCM (10 mL) at ꢂ10 ꢁC was added DIBAL-H ([1.0 M in tol-
uene]; 3.0 mL, 3.0 mmol). The reaction was stirred at ꢂ10 ꢁC
for 1.5 h, then quenched with methanol (5 mL), the cool bath
removed and the mixture stirred for 5 min before adding
potassium-sodium tartrate (20% in water, 5 mL). The resulting
emulsion was vigorously stirred for 2 h, then the layers sepa-
rated and the aqueous extracted with DCM (3ꢄ25 mL). The
organic extracts were combined, dried over Na2SO4, filtered
and concentrated in vacuo. The residue was purified by flash
silica column chromatography (petroleum ethereEtOAc,
9:1) to afford compound 24 (0.326 g, 84%) as a colourless
oil, Rf¼0.33 (petroleum ethereEtOAc, 9:1); nmax (neat)
3326, 2925, 2851, 1462, 1376, 1006 cmꢂ1; dH (400 MHz,
CDCl3) 0.82e0.98 (15H, m), 1.22e1.38 (6H, m), 1.40e1.56
(6H, m), 1.88 (3H, s), 4.30 (2H, d, J 5.5), 5.95 (1H, d,
J 10.5), 6.19 (1H, d, J 18.5), 6.80 (1H, dd, J 18.5, 10.5); dC
(100 MHz, CDCl3) 9.7, 13.9, 21.5, 27.4, 29.3, 62.0, 131.6,
134.3, 135.6, 141.6; m/z (EI) 331 (MþꢂBu, 100), 177 (41),
137 (55), 81 (66) [Found (EI): MꢂBu, 327.1069;
C14H27OSn requires MꢂBu, 327.1079, 3.1 ppm].
5.1.2. 5-[E-3-Iodo-2-propenyl]oxazole 13
To a stirred solution of 5-(bromomethyl)oxazole 20 (1.14 g,
7.04 mmol) in degassed THF (40 mL) at rt were added E-1,2-
bis-(tributylstannyl)ethene (4.70 g, 7.75 mmol) and Pd2dba3
(0.322 g, 0.35 mmol) whilst protecting the flask from light.
The reaction mixture was heated at 80 ꢁC for 4 h whereupon
it was slowly cooled to 0 ꢁC and iodine (9.62 g, 37.9 mmol)
added. The resulting solution was stirred overnight, gradually
warming to rt, then aqueous sodium sulfite (1 M, 30 mL) and
Et2O (60 mL) added. The layers were separated and the aque-
ous extracted with Et2O (2ꢄ60 mL), the combined organic ex-
tracts dried over MgSO4, filtered and concentrated in vacuo.
The crude product was purified by flash silica column chroma-
tography (hexaneeEtOAc 3:1) to afford compound 13 (0.76 g,

4786
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
5.1.5. 2Z,4E-2-Methyl-5-(tributylstannyl)-2,4-pentadien-1-
al Z,E-16
To a stirred solution of alcohol 24 (0.043 g, 0.11 mmol) in
0.9 mmol) in degassed DMF (0.1 mL) and CuI (0.0017 g,
0.009 mmol). The reaction mixture was heated at 45 ꢁC for
3 h in the dark, cooled to rt and purified directly by flash silica
column chromatography doped with 10% KF (petroleum
ethereEt2O, 1:1). DMF was still present, thus DCM (10 mL)
and H2O (10 mL) were added, the layers separated and the
aqueous extracted once with DCM (10 mL). The combined
organic extracts were dried over MgSO4, filtered and concen-
trated in vacuo to afford compound 27 (0.027 g, quant.) as an
amorphous yellow foam, [a]2D1 þ57.9 (c 0.80, CHCl3),
Rf¼0.34 (petroleum ethereEtOAc 1:1); nmax (film) 3419,
3136, 2981, 2951, 1726, 1511, 1471, 1435, 1260, 1192,
1140, 1055, 912 cmꢂ1; dH (400 MHz, CDCl3) 1.15 (3H, s),
1.27 (3H, s), 1.75 (3H, s), 3.48 (2H, d, J 7.0), 3.72 (3H, s),
4.71 (1H, s), 5.73 (1H, dt, J 14.5, 6.5), 6.03 (1H, d, J 11.5),
6.10e6.23 (2H, m), 6.43 (1H, dd, J 13.5, 11.5), 6.79 (1H,
s), 7.79 (1H, s); dC (100 MHz, CDCl3) 19.6, 21.1, 24.5,
29.0, 46.9, 52.4, 75.2, 122.6, 127.3, 128.0, 130.3, 131.8,
133.5, 137.0, 150.6, 150.9, 178.5; m/z (EI) 305 (Mþ, 1), 269
(8), 204 (100), 102 (29), 82 (39), 57 (22), 41 (32) [Found
(EI): Mþ 305.1637; C17H23NO4 requires M, 305.1627,
3.4 ppm error].
˚
DCM (1.5 mL) at rt was added 4 A molecular sieves (0.050 g),
4-methylmorpholine-N-oxide (0.020 g, 0.17 mmol) and tetra-
propylammonium perruthenate (0.004 g, 0.01 mmol). The re-
action mixture was stirred at rt for 1.5 h, then passed
through a plug of alumina (deactivated with 6% H2O; eluting
DCM), to afford compound Z,E-16 (0.043 g, quant.) as a col-
ourless oil, Rf¼0.30 (petroleum ethereEt2O, 30:1); nmax (neat)
2959, 2926, 1683, 1261, 1111, 1018, 802 cmꢂ1; dH (400 MHz,
CDCl3) 0.82e0.98 (15H, m), 1.22e1.38 (6H, m), 1.40e1.56
(6H, m), 1.84 (3H, s), 6.72 (1H, d, J 18.5), 6.88 (1H, d,
J 11.0), 7.50 (1H, dd, J 18.5, 11.0), 10.35 (1H, s); dC
(100 MHz, CDCl3) 9.8, 13.8, 16.3, 27.4, 29.2, 133.4, 138.7,
146.9, 148.0, 190.9; m/z (CI) 387 (MHþ, 84), 346 (28), 329
(48), 308 (96), 291 (59), 95 (100) [Found (CI): MHþ,
383.1705; C18H35OSn requires MH, 383.1705, 0.1 ppm error].
5.1.6. Methyl 3R,4Z,6E-3-hydroxy-2,2,4-trimethyl-7-
(tributylstannyl)-4,6-heptadienoate Z,E-14
To stirred solution of N-tosyl-L-valine39 (0.565 g,
2.08 mmol) in DCM (8.5 mL) at 0 ꢁC was added a solution
of BH3$THF (1.0 M in THF, 1.40 mL, 1.40 mmol). The mix-
ture was slowly warmed to rt and stirred for 18 h then cooled
to ꢂ78 ꢁC and aldehyde Z,E-16 (0.400 g, 1.04 mmol) in DCM
(2 mL) added. After 5 min 1-methoxy-2-methyl(trimethyl-
siloxy)propene 17 (0.42 mL, 2.07 mmol) was added and the re-
sulting solution stirred at ꢂ78 ꢁC for 2 h. The reaction mixture
was quenched with saturated aqueous NaHCO3 (10 mL) and
allowed to warm to rt. DCM (50 mL) was added, the layers
were separated and the aqueous extracted with DCM
(3ꢄ50 mL). The combined organic extracts were washed
with brine (10 mL), dried over Na2SO4, filtered and concen-
trated in vacuo. The crude product was purified by flash silica
column chromatography (petroleum ethereEtOAc, 9:1) to
afford compound Z,E-14 (0.428 g, 84%, 64% ee, see text) as
a colourless oil, [a]2D1 þ5.4 (c 1.07, CHCl3), Rf¼0.24 (petro-
leum ethereEtOAc, 9:1); nmax (film) 3502, 2957, 2927,
2872, 2853, 1727, 1464, 1377, 1259, 1192, 1136, 1053,
987 cmꢂ1; dH (400 MHz, CDCl3) 0.73e1.02 (15H, m), 1.15
(3H, s), 1.27 (3H, s), 1.19e1.38 (6H, m), 1.40e1.52 (6H,
m), 1.72 (3H, s), 3.30 (1H, d J 6.5), 3.71 (3H, s), 4.80 (1H,
d, J 6.5), 6.01 (1H, d, J 10.5), 6.15 (1H, d, J 18.5), 6.77
(1H, dd, J 18.5, 10.5); dC (100 MHz, CDCl3) 9.7, 13.8, 19.2,
21.1, 24.7, 27.4, 29.3, 47.0, 52.3, 75.3, 133.9, 134.2, 134.5,
142.0, 178.5; m/z (CI) 489 (MHþ, 48), 431 (76), 308 (79),
291 (80), 181 (51), 95 (100) [Found (CI): MHþ, 485.2385;
C23H45O3Sn requires MH, 485.2386, 0.2 ppm error].
5.1.8. 3R,4Z,6E,8E-3-Hydroxy-2,2,4-trimethyl-10(oxazol-5-
yl)-4,6,8-decatrienoic acid 30
To a stirred solution of ester 27 (0.023 g, 0.08 mmol) in
THF (0.6 mL), methanol (0.2 mL), water (0.2 mL) at rt was
added lithium hydroxide monohydrate (0.013 g, 0.31 mmol).
The reaction mixture was stirred for 14 h, then concentrated
in vacuo and Et2O (5 mL) and water (5 mL) added. The layers
were separated and the aqueous washed once with Et2O
(5 mL). The aqueous layer was acidified to pH 1e2 with aq
HCl (0.3 M) and extracted with Et2O (2ꢄ20 mL). The organic
extracts were combined, dried over MgSO4, filtered and con-
centrated in vacuo to afford compound 30 (0.020 g, 91%) as
an amorphous yellow foam, [a]2D2 þ26.0 (c 0.60, CHCl3),
Rf¼0.39 (EtOAcemethanol, 9:1); nmax (film) 3398, 3135,
2925, 1707, 1512, 1467, 1263, 1124, 1052, 991 cmꢂ1; dH
(400 MHz, CDCl3) 1.12 (3H, s), 1.30 (3H, s), 1.79 (3H, s),
3.47 (2H, d, J 7.0), 4.74 (1H, s), 5.72 (1H, dt, J 14.5, 7.0),
6.02 (1H, d, J 11.0), 6.10e6.21 (2H, m), 6.42 (1H, dd, J
13.5, 11.5), 6.81 (1H, s), 7.87 (1H, s); dC (100 MHz, CDCl3)
19.5, 20.9, 25.1, 28.9, 46.1, 74.9, 122.0, 127.2, 127.8, 130.5,
132.0, 133.6, 136.8, 150.9, 151.3, 181.7; m/z (ESI) 290
(MꢂHþ, 100) [Found (ESI): MꢂHþ, 290.1397; C16H21NO4
requires MꢂH, 290.1398, 0.4 ppm].
5.1.9. 3R,4Z,6E,8E-3-Acetoxy-2,2,4-trimethyl-10(oxazol-5-
yl)-4,6,8-decatrienoic acid 31
To a stirred solution of acid 30 (0.037 g, 0.13 mmol) in pyr-
idine (1 mL) was added acetic anhydride (0.12 mL,
1.27 mmol) at rt. The solution was stirred for 22 h, concen-
trated in vacuo, DCM (2 mL) and saturated aqueous NaHCO3
(2 mL) added, then the biphasic reaction mixture stirred vigor-
ously at rt for 8 h. The layers were separated, the aqueous
acidified to pH 1e2 with aq HCl (2.9 M) and extracted with
DCM (3ꢄ10 mL). The combined organic extracts were dried
5.1.7. Methyl 3R,4Z,6E,8E-3-hydroxy-2,2,4-trimethyl-10-
(oxazol-5-yl)-4,6,8-decatrienoate 27
To a stirred solution of stannane Z,E-14 (0.043 g,
0.09 mmol) in degassed DMF (1 mL) at rt was added iodide
13 (0.023 g, 0.10 mmol) and then nitrogen bubbled through
the solution (to further degas) for 30 min. To the solution
were added CsF (0.027 g, 0.18 mmol), Pd(PPh3)4 (0.001 g,

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4787
over MgSO4, filtered and concentrated in vacuo to afford com-
pound 31 (0.026 g, 62%) as a yellow oil, [a]2D1 þ50.8 (c 1.30,
CHCl3), Rf¼0.57 (EtOAc); nmax (film) 3354, 2925, 1739,
1708, 1655, 1510, 1373, 1237, 1042 cmꢂ1; dH (400 MHz,
CDCl3) 1.23 (3H, s), 1.28 (3H, s), 1.79 (3H, s), 2.06 (3H, s),
3.49 (2H, d, J 7.0), 5.73 (1H, dt, J 14.5, 7.0), 5.98 (1H, s),
6.09 (1H, d, J 11.5), 6.14 (1H, dd, J 14.5, 10.5), 6.24 (1H,
dd, J 14.5, 10.5), 6.56 (1H, dd, J 14.5, 11.5), 6.82 (1H, s),
7.82 (1H, s); m/z (EI) 333 (Mþ, 7), 204 (100), 82 (28), 43
(61) [Found (EI): Mþ, 333.1575; C18H23NO5 requires M,
333.1576, 3.6 ppm error].
silica column chromatography (petroleum ethereEtOAc,
20:1) to afford compound Z-18 (0.076 g, 81%) as a colourless
oil, Rf¼0.69 (petroleum ethereEtOAc, 9:1), nmax (film) 2957,
2923, 2871, 2852, 1691, 1550, 1463, 1377, 1188, 1073, 1023,
928 cmꢂ1; dH (400 MHz, CDCl3) 0.88 (9H, t, J 7.0), 1.05 (6H,
m), 1.31 (6H, m), 1.50 (6H, m), 6.98 (1H, dd, J 12.5, 7.0), 7.69
(1H, d, J 12.5), 9.50 (1H, d, J 7.0); dC (100 MHz, CDCl3) 12.0,
14.3, 27.8, 29.6, 146.2, 163.6, 195.3; m/z (CI) 364 (MNHþ4 ,
66), 347 (MHþ, 77), 308 (48), 289 (98) [Found (CI):
MNHþ4 , 360.1662; C15H34NOSn requires MNH4, 360.1658,
1.2 ppm error].
5.1.10. Inthomycin B 6
5.1.12. Ethyl 2Z,4Z-2-methyl-5-(tributylstannyl)-2,4-
pentadienoate 34
To a stirred solution of acid 31 (0.014 g, 0.04 mmol) in
DCM (0.5 mL) at 0 ꢁC was added oxalyl chloride (6 mL,
0.07 mmol) and a drop of DMF. The reaction mixture was
stirred for 3.5 h slowly warming to rt, then NH4OH (35% am-
monia, 1 mL) was added. The resulting solution was stirred at
rt overnight, diluted with DCM (5 mL) and water (5 mL)
added. The layers were separated, the aqueous extracted
with DCM (3ꢄ10 mL), the combined organic extracts washed
with brine (5 mL), dried over MgSO4, filtered and concen-
trated in vacuo. The crude product was purified by flash silica
column chromatography (chloroformemethanol, 12:1) to af-
ford the (þ)-inthomycin B 6 (0.006 g, 50%) as an amorphous
foam, [a]2D2 þ19.3 (c 1.00, CHCl3), Rf¼0.47 (chloroforme
methanol, 9:1); nmax (film) 3342, 2923, 2852, 1732, 1659,
1652, 1601, 1511, 1375, 1242, 1106, 1046, 990 cmꢂ1; UV
(methanol) lmax (3)¼200 nm (14,000), 266 nm (27,000),
275 nm (33,600), 286 nm (27,400) molꢂ1 dm3 cmꢂ1; dH
(400 MHz, CDCl3) 1.10 (3H, s), 1.36 (3H, s), 1.81 (3H, s),
3.48 (2H, d, J 6.5), 4.04 (1H, d, J 5.5), 4.61 (1H, d, J 5.5),
5.52 (1H, br s), 5.74 (1H, dt, J 14.0, 6.5), 6.02 (1H, d, J
11.5), 6.11e6.25 (2H, m), 6.27 (1H, br s), 6.42 (1H, dd, J
14.0, 11.5), 6.80 (1H, s), 7.79 (1H, s); dH (400 MHz, ace-
tone-d6) 1.06 (3H, s), 1.28 (3H, s), 1.78 (3H, s), 3.51 (2H, d,
J 6.5), 4.64 (1H, s), 5.78 (1H, dt, J 15.0, 6.5), 5.99 (1H, d, J
11.5), 6.15 (1H, dd, J 14.5, 10.5), 6.28 (1H, dd, J 15.0,
10.5), 6.42 (1H, br s), 6.62 (1H, dd, J 14.5, 11.5), 6.83 (1H,
s), 7.04 (1H, br s), 8.01 (1H, s); dC (100 MHz, CDCl3) 19.3,
21.8, 26.3, 29.0, 44.6, 76.0, 122.7, 127.6, 127.6, 130.2,
132.1, 133.4, 137.7, 150.6, 150.9, 181.2; dC (100 MHz, ace-
tone-d6) 19.6, 22.2, 26.4, 27.5, 45.3, 75.9, 123.2, 128.3,
129.0, 129.9, 132.3, 134.2, 139.9, 151.7, 151.8, 181.1; m/z
(CI) 291 (MHþ, 15), 273 (70), 204 (94), 186 (32), 133 (28),
105 (100), 88 (77), 52 (46) [Found (CI): MHþ, 291.1706;
C16H23N2O3 requires MH, 291.1709, 1.1 ppm error]. This
data was consistent with the (sparse) data available in the
literature.10
To a stirred suspension of sodium hydride (60% in mineral
oil, 0.165 g, 4.13 mmol) in THF (40 mL) at ꢂ78 ꢁC was added
ethyl 2-[bis-(phenoxy)phosphoryl]propanoate28 33 (1.59 g,
4.76 mmol). The reaction mixture was warmed to 0 ꢁC and
stirred for 20 min, then recooled to ꢂ78 ꢁC and a solution of
aldehyde Z-18 (1.10 g, 3.18 mmol) in THF (10 mL) was added
via cannula. The stirred solution was slowly warmed to rt
overnight, water (15 mL) and Et2O (250 mL) added, the layers
separated and the aqueous extracted with Et2O (3ꢄ40 mL).
The combined organic extracts were dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was pu-
rified by flash silica column chromatography (petroleum
ethereether, 20:1) to afford compounds 34 and 35 (1.09 g,
80%) as an inseparable mixture (87:13) as a colourless oil,
Rf¼0.30 (petroleum ethereEtOAc, 20:1); nmax (film) 2957,
2926, 1713, 1463, 1374, 1320, 1239, 1200, 1123, 1072,
1025 cmꢂ1; m/z (CI) 431 (MHþ, 6), 308 (100), 291 (31)
[Found (CI): MHþ, 427.1968; C20H39O2Sn requires MH,
427.1967, 0.1 ppm error].
NMR data for 34: dH (400 MHz, CDCl3) 0.85e1.00 (18H,
m), 1.22e1.38 (6H, m), 1.45e1.55 (6H, m), 1.98 (3H, s), 4.23
(2H, q, J 7.0), 6.28 (1H, d, J 11.5), 6.46 (1H, d, J 13.0), 7.89
(1H, dd, J 13.0, 11.5); dC (100 MHz, CDCl3) 10.6, 13.7, 14.3,
21.1, 27.2, 29.1, 60.4, 127.2, 141.9, 142.7, 143.2, 167.6.
NMR data for 35: dH (400 MHz, CDCl3) 0.81e1.09 (15H,
m), 1.22e1.37 (9H, m), 1.41e1.62 (6H, m), 1.97 (3H, s), 4.21
(2H, q, J 7.0), 6.63 (1H, d, J 11.0), 7.11 (1H, d, J 11.0), 7.34
(1H, dd, J 11.0, 11.0); dC (100 MHz, CDCl3) 10.8, 13.8, 14.4,
21.8, 27.3, 29.3, 60.6, 128.0, 140.4, 141.6, 145.8, 168.6.
5.1.13. 2Z,4Z-2-Methyl-5-(tributylstannyl)-2,4-pentadien-1-
al Z,Z-16
(a) To a stirred solution of inseparable esters 34 and 35
(1.09 g, 2.54 mmol) in DCM (40 mL) at ꢂ35 ꢁC was added
DIBAL-H (1.0 M in DCM, 7.6 mL, 7.6 mmol). The solution
was stirred for 2 h, warming from ꢂ35 ꢁC to 0 ꢁC, quenched
with methanol (10 mL), warmed to rt and stirred for a further
50 min. After this time an aqueous solution of potassium-
sodium tartrate (20%, 30 mL) was added and the mixture
stirred overnight. The phases were partitioned and the aqueous
extracted with DCM (4ꢄ60 mL), the combined organic layers
were washed with brine (10 mL), dried over Na2SO4, filtered
and concentrated in vacuo. The crude product was purified
5.1.11. 3-(Tributylstannyl)-2Z-propen-1-al Z-18
To a stirred solution of 3-(tributylstannyl)-(2Z)-propen-1-ol
3235 (0.095 g, 0.27 mmol) in DCM (4 mL) were added 4 A
˚
molecular sieves (0.10 g), 4-methylmorpholine-N-oxide
(0.048 g, 0.41 mmol) and tetrapropylammonium perruthenate
(0.005 g, 0.01 mmol). The reaction was stirred at rt for 3 h
then concentrated in vacuo. The residue was purified by flash

4788
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
by flash silica column chromatography (petroleum ethere
EtOAc, 9:1) to afford (2Z,4Z)-2-methyl-5-(tributylstannyl)-
178.6; m/z 489 (MHþ, 17), 387 (50), 331 (37), 308 (100),
291 (48), 181 (39), 95 (32), 71 (43) [Found (CI): MHþ,
485.2388; C23H45O3Sn requires MH, 485.2386, 0.4 ppm
error].
2,4-pentadien-1-ol (0.670 g, 68%) as
a colourless oil,
Rf¼0.36 (petroleum ethereEt2O, 5:1); nmax (film) 3360,
2958, 2927, 1463, 1001, 908 cmꢂ1; dH (400 MHz, CDCl3)
0.89 (9H, t, J 7.5), 0.92e0.96 (6H, m), 1.24e1.36 (6H, m),
1.46e1.57 (6H, m), 1.90 (3H, s), 4.29 (2H, d, J 6.0), 5.84
(1H, d, J 11.0), 6.07 (1H, d, J 12.5), 7.33 (1H, dd, J 12.5,
11.0); dC (100 MHz, CDCl3) 10.4, 13.7, 21.7, 27.3, 29.1,
61.7, 130.8, 134.2, 137.7, 140.8; m/z (EI) 331 ([MꢂBu]þ,
1), 251 (61), 177 (37), 137 (63), 121 (35), 81 (36), 57 (40),
41 (100) [Found (EI): MþꢂBu, 327.1071; C14H27OSn requires
MꢂBu, 327.1079, 2.6 ppm error].
5.1.15. 4Z,6Z,8E-3-Hydroxy-2,2,4-trimethyl-10-(oxazol-5-
yl)-4,6,8-decatrienoic acid 36
(a) A flask containing a stirred solution of iodide 13
(0.027 g, 0.11 mmol) and stannane (ꢃ)-Z,Z-14 (0.050 g,
0.10 mmol) in degassed DMF (0.5 mL) at rt was evacuated,
then flushed with nitrogen three times. Pd(CH3CN)Cl2
(0.0012 g, 0.005 mmol) was added, the flask stirred at rt in
the dark for 5 h, then saturated NH4Cl (5 mL) and EtOAc
(10 mL) were added and the layers separated. The aqueous
was extracted with EtOAc (3ꢄ10 mL) and the combined or-
ganic extracts washed with brine (5 mL), dried over Na2SO4,
filtered and concentrated in vacuo. The crude product was
purified by flash silica column chromatography (petroleum
ethereEtOAc, 2:1) to afford methyl (4Z,6Z,8E)-3-hydroxy-
2,2,4-trimethyl-10-(oxazol-5-yl)-4,6,8-decatrienoate (0.024 g,
77%) as a pale yellow oil, Rf¼0.23 (petroleum ethereEtOAc,
2:1); (400 MHz, CDCl3) 1.15 (3H, s), 1.26 (3H, s), 1.79 (3H,
s), 3.51 (2H, d, J 7.0), 3.71 (3H, s), 4.76 (1H, s), 5.77 (1H, dt, J
15.0, 7.0), 5.94 (1H, dd, J 11.5, 11.0), 6.20 (1H, dd, J 12.0,
11.0), 6.44 (1H, d, J 12.0), 6.64 (1H, dd, J 15.0, 11.5), 6.80
(1H, s), 7.79 (1H, s); m/z (CI) 306 (MHþ, 5), 216 (37), 209
(29), 192 (42), 183 (45), 148 (26), 112 (100), 100 (38). The
data for this compound were consistent with those published.18
(b) To a stirred solution of the ester from part (a) (0.076 g,
0.25 mmol) in THF (1.5 mL), methanol (0.5 mL) and water
(0.5 mL) at rt was added lithium hydroxide monohydrate
(0.031 g, 0.75 mmol). The reaction mixture was stirred for
3.5 h, concentrated in vacuo and the residue dissolved in water
(5 mL). The aqueous layer was extracted with Et2O (5 mL),
acidified to pH 4 with aq HCl (1.5 M) and extracted with
EtOAc (4ꢄ10 mL). The organic extracts were combined, dried
over MgSO4, filtered and concentrated in vacuo to afford com-
pound 36 (0.067 g, 92%) as a pale yellow oil, Rf¼0.38
(EtOAc); dH (400 MHz, CDCl3) 1.14 (3H, s), 1.33 (3H, s),
1.85 (3H, s), 3.53 (2H, d, J 7.0), 4.80 (1H, s), 5.78 (1H, dt,
J 14.5, 7.0), 5.97 (1H, dd, J 11.5, 11.0), 6.20 (1H, dd, J
12.0, 11.0), 6.46 (1H, d, J 12.0), 6.65 (1H, dd, J 14.5, 11.5),
6.84 (1H, s), 7.87 (1H, s); m/z (ESI) 290 (MH, 100). The
data for this compound were consistent with those published.18
(b) To a stirred solution of (2Z,4Z)-2-methyl-5-(tributyl-
stannyl)-2,4-pentadien-1-ol (0.161 g, 0.42 mmol) in DCM
ꢁ
˚
(4 mL) at 0 C were added 4 A molecular sieves (0.10 g),
4-methylmorpholine-N-oxide (0.073 g, 0.62 mmol) and tetra-
propylammonium perruthenate (0.014 g, 0.04 mmol). The
mixture was stirred for 2 h, then passed through a plug of alu-
mina (deactivated with 6% water; eluting DCM), to afford
compound Z,Z-16 (0.160 g, quant.) as a pale yellow oil,
Rf¼0.76 (petroleum ethereEtOAc, 20:1); nmax (film) 2958,
2927, 2872, 2854, 1680, 1658, 1464, 1378, 1072, 909 cmꢂ1
;
dH (400 MHz, CDCl3) 0.89 (9H, t, J 7.0), 0.98e1.02 (6H,
m), 1.27e1.36 (6H, m), 1.48e1.62 (6H, m), 1.87 (3H, s),
6.69 (1H, d, J 12.5), 6.79 (1H, d, J 12.0), 8.01 (1H, dd, J
12.5, 12.0), 10.36 (1H, s); dC (100 MHz, CDCl3) 10.7, 13.7,
16.6, 27.2, 29.1, 135.1, 138.2, 146.8, 147.6, 190.9; m/z (CI)
387 (MHþ, 23), 308 (100) [Found (CI): MHþ, 383.1698;
C18H35OSn requires MH, 383.1705, 1.9 ppm error].
5.1.14. Methyl 4Z,6Z-3-hydroxy-2,2,4-trimethyl-7-
(tributylstannyl)-4,6-heptadienoate (ꢃ)-Z,Z-14
To
a stirred solution of diisopropylamine (290 mL,
2.07 mmol) in THF (10 mL) at ꢂ78 ꢁC was added n-butyl-
lithium (2.30 M in hexanes; 0.77 mL, 1.78 mmol). The solu-
tion was stirred for 30 min then methyl iso-butyrate (203 mL,
1.78 mmol) was added. This was allowed to stir at ꢂ78 ꢁC
for a further 25 min, then a solution of aldehyde Z,Z-16
(0.570 g, 1.48 mmol) in THF (10 mL) was added to the reac-
tion mixture over 3 min. The reaction mixture was stirred at
ꢂ78 ꢁC for 2 h, then saturated aqueous NH4Cl (10 mL) was
added and the solution allowed to warm to rt. The layers
were separated and the aqueous extracted with Et2O
(3ꢄ40 mL), the combined organic extracts were dried over
Na2SO4, filtered and concentrated in vacuo to afford a yellow
oil. The crude product was purified by flash silica column
chromatography (petroleum ethereEtOAc, 20:1 to 10:1) to af-
ford the title compound (ꢃ)-Z,Z-14 (0.597 g, 83%) as a colour-
less oil, Rf¼0.44 (petroleum ethereEtOAc, 20:1); nmax (film)
3488, 2956, 2925, 2854, 1725, 1461, 1377, 1260, 1193,
1135, 1051 cmꢂ1; dH (400 MHz, CDCl3) 0.85e0.96 (15H,
m), 1.16 (3H, s), 1.22e1.37 (9H, m), 1.44e1.56 (6H, m),
1.75 (3H, s), 3.30 (1H, d, J 6.5), 3.72 (3H, s), 4.81 (1H, d, J
6.5), 5.92 (1H, d, J 11.0), 6.05 (1H, d, J 12.5), 7.29 (1H, dd,
J 12.5, 11.0); dC (100 MHz, CDCl3) 10.6, 13.8, 19.5, 21.1,
24.7, 27.4, 29.3, 47.0, 52.4, 75.1, 133.4, 134.4, 136.7, 141.4,
5.1.16. 4Z,6Z,8E-3-Acetoxy-2,2,4-trimethyl-10-(oxazol-5-
yl)-4,6,8-decatriene amide 37
(a) To a stirred solution of acid 36 (0.052 g, 0.18 mmol) in
pyridine (1 mL) was added acetic anhydride (0.15 mL,
1.58 mmol) at rt. The solution was stirred for 20 h, concen-
trated in vacuo and the residue passed through a plug of flash
silica eluting with EtOAc. The filtrate was concentrated in va-
cuo and the resulting yellow oil dissolved in DCM (5 mL).
Saturated NaHCO3 (4 mL) was added and the reaction mixture
vigorously stirred at rt for 2 h, then acidified to pH 1 with aq
HCl (2.9 M). The aqueous was extracted with DCM
(4ꢄ10 mL), the organic extracts combined, washed with brine

M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
4789
(5 mL), dried over MgSO4, filtered and concentrated in vacuo
to afford (4Z,6Z,8E)-3-acetoxy-2,2,4-trimethyl-10-(oxazol-5-
yl)-4,6,8-decatrienoic acid (0.060 g, quant.) as an amorphous
yellow powder, Rf¼0.48 (EtOAc); dH (400 MHz, CDCl3)
1.21 (3H, s), 1.27 (3H, s), 1.82 (3H, s), 2.05 (3H, s), 3.51
(2H, d, J 7.0), 5.77 (1H, dt, J 14.5, 7.0), 5.96e6.02 (2H, m),
6.36 (1H, dd, J 12.0, 11.0), 6.51 (1H, d, J 12.0), 6.63 (1H,
dd, J 14.5, 11.5), 6.82 (1H, s), 7.84 (1H, s); m/z (EI) 333
(Mþ, 7), 204 (100), 82 (28), 43 (61).
11.5), 6.84 (1H, s), 8.01 (1H, s); dC (100 MHz, CDCl3) 19.6,
21.8, 26.3, 29.2, 44.7, 75.5, 122.7, 123.8, 125.0, 128.3,
128.3, 128.8, 138.5, 150.6, 150.9, 181.2; dC (100 MHz, ace-
tone-d6) 19.8, 22.2, 26.4, 29 (masked by solvent peak), 45.4,
75.5, 123.2, 124.7, 125.0, 128.4, 129.0, 129.8, 140.7, 151.6,
151.7, 181.1; m/z 290 (Mþ, 3), 204 (28), 87 (100) [Found
(EI): Mþ, 290.1633; C16H22N2O3 requires M, 290.1630,
0.8 ppm error]. These data were consistent with those previ-
ously published.9,10
(b) To a stirred solution of the acid from part (a) (0.010 g,
0.03 mmol) in DCM (0.5 mL) at 0 ꢁC were added thionyl
chloride (3.5 mL, 0.05 mmol) and a drop of DMF. The reaction
mixture was stirred for 2.5 h slowly warming to rt, then
NH4OH (35% ammonia, 1 mL) was added. The resulting solu-
tion was stirred at rt for 1 h, diluted with DCM (5 mL) and
water (5 mL) added. The layers were separated, the aqueous
extracted with DCM (3ꢄ10 mL), the combined organic ex-
tracts washed with brine (5 mL), dried over MgSO4, filtered
and concentrated in vacuo. The crude product was purified
by flash silica column chromatography (EtOAc) to afford com-
pound 37 (0.007 g, 70%) as a yellow oil, Rf¼0.44 (DCMe
methanol, 9:1); nmax (film) 2977, 2928, 1735, 1674, 1603,
1509, 1372, 1241, 1029 cmꢂ1; dH (400 MHz, CDCl3) 1.19
(3H, s), 1.23 (3H, s), 1.82 (3H, s), 2.10 (3H, s), 3.52 (2H, d,
J 7.0), 5.54 (1H, br s), 5.79 (1H, dt, J 14.5, 7.0), 5.85 (1H,
s), 5.99e6.04 (2H, m), 6.36 (1H, dd, J 12.0, 11.0), 6.50
(1H, d, J 12.0), 6.62 (1H, dd, J 14.5, 11.5), 6.82 (1H, s),
7.81 (1H, s); dC (100 MHz, CDCl3) 20.6, 21.1, 21.8, 25.0,
29.2, 46.3, 76.9, 122.4, 124.1, 126.9, 128.3, 129.1, 129.1,
133.1, 150.8, 151.0, 169.5, 178.1; m/z (EI) 332 (Mþ, 8), 204
(81), 87 (86), 43 (100) [Found (EI): Mþ 332.1735,
C18H24N2O4; requires M, 332.1736, 0.3 ppm error].
5.1.18. 2E,4E-2-Methyl-5-(tributylstannyl)-2,4-pentadien-1-
al E,E-16
(a) To a stirred solution of ethyl (2E,4E)-2-methyl-5-(tribu-
tylstannyl)-2,4-pentadienoate 3940 (0.433 g, 1.01 mmol) in
DCM (10 mL) at ꢂ10 ꢁC was added DIBAL-H ([1.0 M in tol-
uene]; 3.0 mL, 3.0 mmol). The solution was stirred for 3 h
slowly warming to rt, then methanol (5 mL) was added and
the reaction mixture stirred for 15 min. An aqueous solution
of potassium-sodium tartrate (20%, 5 mL) was added, the re-
sulting suspension stirred overnight then filtered through Cel-
iteÒ washing with DCM (50 mL). Water (30 mL) was added,
the layers separated and the aqueous extracted with DCM
(2ꢄ50 mL). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, filtered and concentrated
in vacuo to afford (2E,4E)-2-methyl-5-(tributylstannyl)-2,4-
pentadien-1-ol (0.408 g, quant.) as a colourless oil, Rf¼0.21
(petroleum ethereEtOAc, 10:1); dH (400 MHz, CDCl3)
0.85e0.94 (15H, m), 1.26e1.37 (6H, m), 1.46e1.58 (6H,
m), 1.84 (3H, s), 4.08 (2H, d, J 6.0), 6.06 (1H, d, J 10.5),
6.26 (1H, d, J 18.5), 6.77 (1H, dd, J 18.5, 10.5); m/z (EI)
331 (MꢂBuþ, 98), 291 (36), 275 (71), 235 (42), 219 (56),
177 (82), 137 (100), 121 (71), 81 (51).
(b) To a stirred solution of (2E,4E)-2-methyl-5-(tributyl-
stannyl)-2,4-pentadien-1-ol (0.064 g, 0.16 mmol) in DCM
(2 mL) at rt was added manganese dioxide (0.140 g,
1.63 mmol). The solution was vigorously stirred at rt for 2 d,
diluted with DCM (20 mL) and filtered through CeliteÒ wash-
ing with DCM (50 mL). The filtrate was concentrated in vacuo
to afford compound E,E-16 (0.064 g, quant.) as a pale yellow
oil, Rf¼0.71 (hexaneeEt2O, 30:1); nmax (film) 2956, 2926,
2871, 2852, 1677, 1619, 1464, 1395, 1377, 1354, 1237,
1159, 998 cmꢂ1; dH (400 MHz, CDCl3) 0.90 (9H, t, J 7.5),
0.98 (6H, t, J 8.0), 1.29e1.36 (6H, m), 1.50e1.57 (6H, m),
1.88 (3H, s), 6.75 (1H, d, J 9.0), 6.97 (1H, d, J 18.5), 7.04
(1H, dd, J 18.5, 9.0), 9.44 (1H, s); dC (100 MHz, CDCl3)
9.5, 9.8, 13.7, 27.2, 29.2, 135.9, 141.4, 149.6, 150.2, 195.7;
m/z (EI) 329 (MꢂBuþ, 72), 273 (60), 217 (77), 95 (100)
[Found (EI): MꢂBuþ, 329.0929; C14H25O120Sn requires
MꢂBu, 329.0927, 0.5 ppm error].
5.1.17. Inthomycin A 10
To a stirred solution of amide 37 (0.007 g, 0.02 mmol) in
THF (0.3 mL), methanol (0.1 mL) and water (0.1 mL) at rt
was added lithium hydroxide monohydrate (0.002 g,
0.04 mmol). The reaction mixture was stirred for 1 h, concen-
trated in vacuo and the residue dissolved in water (5 mL). The
aqueous was acidified to pH 1 with aq HCl (1 M) and ex-
tracted with DCM (5ꢄ5 mL). The combined organic extracts
were washed with brine (5 mL), dried over MgSO4, filtered
and concentrated in vacuo to afford the title compound 10
(0.006 g, 92%) as an amorphous yellow powder, Rf¼0.31
(DCMemethanol, 9:1); nmax (film) 3334, 2921, 2851, 1660,
1600, 1511, 1464, 1378, 1262, 1107, 1043, 910 cmꢂ1; UV
(methanol) lmax (3)¼202 nm (25,300), 266 nm (24,900),
275 nm (29,200), 286 nm (22,700) molꢂ1 dm3 cmꢂ1; dH
(400 MHz, CDCl3) 1.09 (3H, s), 1.36 (3H, s), 1.84 (3H, s),
3.52 (2H, d, J 7.0), 4.64 (1H, s), 5.58 (1H, br s), 5.78 (1H,
dt, J 15.0, 7.0), 5.95 (1H, dd, J 11.5, 11.0), 6.20 (1H, dd, J
12.0, 11.0), 6.29 (1H, br s), 6.42 (1H, d, J 12.0), 6.65 (1H,
dd, J 15.0, 11.5), 6.80 (1H, s), 7.80 (1H, s); dH (400 MHz,
acetone-d6) 1.06 (3H, s), 1.28 (3H, s), 1.83 (3H, s), 3.56 (2H,
d, J 6.5), 4.67 (1H, s), 5.24 (1H, br s), 5.82 (1H, dt, J 15.0,
6.5), 5.96 (1H, dd, J 11.5, 11.0), 6.32 (1H, dd, J 12.0, 11.0),
6.38 (1H, br s), 6.48 (1H, d, J 12.0), 6.79 (1H, dd, J 15.0,
5.1.19. 2E,4E,6E-2-Methyl-8-(oxazol-5-yl) 2,4,6-octatrienal
41
Nitrogen was bubbled through a solution of iodide 13
(0.048 g, 0.20 mmol) and stannane E,E-16 (0.072 g,
0.19 mmol) in degassed DMF (3 mL) for 30 min.
Pd(CH3CN)2Cl2 (0.002 g, 0.008 mmol) was added and the re-
action mixture stirred at rt in the dark for 2 h. Saturated NH4Cl

4790
M.R. Webb et al. / Tetrahedron 64 (2008) 4778e4791
(5 mL) and EtOAc (10 mL) were then added, the layers sepa-
rated and the aqueous extracted with EtOAc (3ꢄ10 mL). The or-
ganic extracts were combined, dried over Na2SO4, filtered and
concentrated in vacuo, then the resulting orange oil purified by
flash silica column chromatography (petroleum ethereEtOAc,
1:1 to EtOAc) to afford compound 41 (0.028 g, 74%) as a yellow
oil, Rf¼0.43 (petroleum ethereEtOAc, 1:1); nmax (film) 3131,
2956, 2928, 1680, 1613, 1510, 1464, 1366, 1257, 1226, 1101,
991, 964 cmꢂ1; dH (400 MHz, CDCl3) 1.86 (3H, s), 3.56 (2H,
d, J 6.5), 6.03 (1H, dt, J 15.5, 6.5), 6.33 (1H, dd, J 15.5, 9.0),
6.62e6.65 (2H, m), 6.82e6.86 (2H, m), 7.82 (1H, s), 9.45
(1H, s); dC (125 MHz, CDCl3) 9.9, 29.3, 123.2, 127.5, 133.0,
133.3, 138.2, 140.5, 148.1, 150.9, 194.9; m/z (CI), 204 (MHþ,
100%) [Found (CI): MHþ, 204.1022; C12H14O2N requires
MH, 204.1025, 1.1 ppm error].
concentrated in vacuo to afford compound 44 (0.028 g, 89%)
as an orange oil, [a]D20 þ17.1 (c 0.82, CHCl3), Rf¼0.45
(EtOAc); nmax (film) 3406, 3136, 2980, 2926, 1714, 1263,
1130, 990 cmꢂ1; dH (400 MHz, CDCl3) 1.13 (3H, s), 1.24
(3H, s), 1.77 (3H, s), 3.48 (2H, d, J 7.0), 4.17 (1H, s), 5.73
(1H, dt, J 13.5, 7.0), 6.03 (1H, d, J 11.0), 6.18e6.23 (2H,
m), 6.38 (1H, dd, J 13.5, 11.5), 6.80 (1H, s), 7.85 (1H, s);
dC (100 MHz, CDCl3) 13.9, 20.7, 24.4, 28.9, 46.5, 82.4,
122.1, 127.3, 128.2, 129.0, 132.5, 133.7, 137.2, 150.8,
151.2, 181.6; m/z (ESI) 290 ({MꢂH}þ, 100) [Found (ESI):
MꢂHþ, 290.1395; C16H20NO4 requires MH, 290.1398,
0.8 ppm error].
5.1.22. Inthomycin C 5
To a stirred solution of acid 44 (0.015 g, 0.05 mmol) in THF
(1 mL) were added EtNiPr2 (27 mL, 0.15 mmol), HATU
(0.029 g, 0.08 mmol) and NH4Cl (0.005 g, 0.09 mmol). The re-
action mixturewas stirred for 15 h at rt, then partitioned between
Et2O (10 mL) and aq HCl (0.3 M, 10 mL). The layers were sep-
arated, the aqueous extracted with Et2O (3ꢄ10 mL) and the
combined organic extracts dried over Na2SO4, filtered and con-
centrated invacuo. The crude product was purified twice by flash
silica column chromatography (EtOAc) to afford compound
(þ)-5 (0.004 g, 27%) containing inseparable tetramethyl urea
(ca. 20%) as a yellow oil, [a]2D1 þ25.9 (c 0.27, CHCl3),
Rf¼0.41 (EtOAc); nmax (film) 3345, 2925, 2855, 1658, 1511,
1465, 1381, 1109, 991 cmꢂ1; UV (methanol) lmax (3)¼203 nm
(53,900), 271 nm (18,400), 276 nm (19,600), 290 nm
(15,500), molꢂ1 dm3 cmꢂ1; dH (400 MHz, CDCl3) 1.10 (3H,
s), 1.31 (3H, s), 1.79 (3H, s), 3.49 (2H, d, J 6.5), 4.01 (1H, s),
5.51 (1H, br s), 5.75 (1H, dt, J 14.0, 6.5), 6.02 (1H, d, J 11.0),
6.18e6.27 (3H, m), 6.39 (1H, dd, J 13.5, 11.0), 6.80 (1H, s),
7.80 (1H, s); dH (400 MHz, acetone-d6) 1.07 (3H, s), 1.21 (3H,
s), 1.76 (3H, s), 3.52 (2H, d, J 7.0), 4.01 (1H, s), 5.79 (1H, dt,
J 14.5, 7.0), 6.03 (1H, d, J 11.5), 6.20e6.33 (3H, m), 6.48
(1H, dd, J 14.0, 11.5), 6.83 (1H, s), 6.95 (1H, br s), 8.00 (1H,
s); dC (100 MHz, CDCl3) 13.5, 21.8, 25.8, 29.0, 45.1, 83.9,
122.7, 127.6, 128.2, 129.0, 132.5, 133.6, 138.0, 150.6, 150.6,
180.8; dC (100 MHz, acetone-d6) 13.3, 22.5, 25.6, 29 (masked
by solvent peak), 45.6, 83.9, 122.7, 128.4, 128.7, 129.1, 132.7,
134.2, 140.1, 151.2, 151.8, 180.6; m/z (EI) 290 (Mþ, 2), 204
(29), 87 (100) [Found (EI): Mþ, 290.1631; C16H22N2O3 requires
M, 290.1630, 0.2 ppm error]. This data was consistent with the
(sparse) data available in the literature.10
5.1.20. Methyl 3R,4E,6E,8E-3-hydroxy-2,2,4-trimethyl-
10(oxazol-5-yl)-4,6,8-decatrienoate 43
To a stirred solution of N-L-tosyl-valine (0.352 g, 1.30 mmol)
in DCM (5 mL) at 0 ꢁC was added a solution of BH3$THF
(1.0 M in THF, 1.18 mL, 1.18 mmol), the mixture was stirred
at 0 ꢁC for 20 min, and then rt for 30 min. The solution was
cooled to ꢂ78 ꢁC and aldehyde 41 (0.120 g, 0.59 mmol) in
DCM (1 mL) was added followed by 1-methoxy-2-methyl(tri-
methylsiloxy)propene (0.14 mL, 0.71 mmol). The reaction
mixture was stirred at ꢂ78 ꢁC for 2 h, a buffer solution (pH
6.865, 8 mL) added and the suspension slowly warmed to rt.
The organic layers were separated, the aqueous layer extracted
with DCM (3ꢄ20 mL), the organic extracts combined, washed
with brine (5 mL), dried over Na2SO4, filtered and concentrated
in vacuo. The crude product was purified by flash silica column
chromatography (petroleum ethereEtOAc 2:1) to afford com-
pound 43 (0.090 g, 50%, 76% ee established by Mosher ester de-
rivatisation) as a yellow oil, [a]2D2 þ5.2 (c 1.55, CHCl3), Rf¼0.35
(hexaneeEtOAc, 1:1); nmax (film) 3402, 2981, 2951, 1728,
1512, 1468, 1435, 1257, 1132, 989 cmꢂ1; dH (400 MHz,
CDCl3) 1.15 (3H, s), 1.21 (3H, s), 1.74 (3H, s), 3.19 (1H, br
s), 3.49 (2H, d, J 7.0), 3.71 (3H, s), 4.17 (1H, s), 5.76 (1H, dt,
J 13.5, 7.0), 6.02 (1H, d, J 11.0), 6.15e6.25 (2H, m), 6.37
(1H, dd, J 13.5, 11.0), 6.78 (1H, s), 7.77 (1H, s); dC
(67.9 MHz, CDCl3) 14.3, 21.1, 24.1 (CH3), 29.2, 47.3, 52.5,
82.6, 122.9, 127.7, 128.4, 128.9 (2ꢄCH), 132.5, 133.8, 137.6,
150.8, 178.5; m/z (CI), 306 (MHþ, 22%), 288 (100), 204 (27),
192 (17), 183 (10), 112 (24) [Found (CI): MHþ, 306.1706;
C17H23O4N requires 306.1705, 0.4 ppm error].
Acknowledgements
5.1.21. 3R,4E,6E,8E-3-Hydroxy-2,2,4-trimethyl-10-(oxazol-
5-yl)-4,6,8-decatrienoic acid 44
We are grateful to the EPSRC (X.F. and J.W.D.) and the
University of York (M.S.A. and M.P.) for postdoctoral support,
and the EPSRC for studentship support (C.M.C. and M.R.W.).
We also thank Dr. M. McGrath (University of York) for assis-
tance with HPLC.
To a stirred solution of ester 43 (0.033 g, 0.11 mmol) in
THF (1.5 mL), methanol (0.5 mL) and water (0.5 mL) was
added lithium hydroxide hydrate (0.014 g, 0.32 mmol) at rt
and the solution stirred for 22 h. The reaction mixture was
concentrated in vacuo and the residue partitioned between
EtOAc (15 mL) and NaOH (1 M, 5 mL). The layers were sep-
arated, the aqueous layer acidified to pH 3e4 with aq HCl
(2 M) and extracted with EtOAc (3ꢄ10 mL). The combined
organic extracts were dried over Na2SO4, filtered and
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¨
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