A general route to the Streptomyces-derived inthomycin family: The first synthesis of (+)-inthomycin B

Article abstract of DOI:10.1016/j.tetlet.2005.11.042

A concise, convergent and stereocontrolled synthesis of (+)-inthomycin B, based on the Stille coupling of a stannyl-diene with an oxazole vinyl iodide unit, is described. The asymmetric centre was introduced using the Kiyooka ketene acetal/amino acid-derived oxazaborolidinone procedure.

Full text of DOI:10.1016/j.tetlet.2005.11.042

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 549–552
A general route to the Streptomyces-derived inthomycin family:
the first synthesis of (+)-inthomycin B
Michael R. Webb,a Craig Donaldb and Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bAstraZeneca, Alderley Park, Macclesfield SK10 5DD, UK
Received 30 August 2005; revised 2 November 2005; accepted 8 November 2005
Available online 28 November 2005
Abstract—A concise, convergent and stereocontrolled synthesis of (+)-inthomycin B, based on the Stille coupling of a stannyl-diene
with an oxazole vinyl iodide unit, is described. The asymmetric centre was introduced using the Kiyooka ketene acetal/amino acid-
derived oxazaborolidinone procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
The methylene-interrupted oxazolyl-triene motif is
found in a number of bioactive natural products
including the oxazolomycins and neooxazolomycin,1
triedimicin B,2 the curromycins,3 and the phthoxazolin/
inthomycins.4–6 Phthoxazolin (1) was first isolated by
Omuraꢀs group from Streptomyces in 1990 and shown
to possess useful levels of antimicrobial and herbicidal
activity, via specific inhibition of cellulose biosynthesis.4
Subsequent studies5 confirmed the potent herbicidal
activity (e.g., against radish seedlings and velvet leaf in
pre- and post-emergence treatments) and demonstrated
low cytotoxicity to animal cells. In 1991, Henkel and
Zeeck isolated three isomeric compounds, which they
named inthomycins A–C (1–3), inthomycin A being
identical to phthoxazolin.6
one reported synthesis of inthomycin A (1), in racemic
8
´
form, by Henaff and Whiting, although the acid corre-
sponding to inthomycin A has been prepared by Kende
et al. as part of their ground-breaking enantioselective
total synthesis of neooxazolomycin.9
As part of our programme to prepare members of the
oxazolomycin family, together with synthetic ana-
logues,10 we required an efficient and stereocontrolled
procedure to prepare all of the inthomycins. After con-
siderable experimentation,11 the convergent route shown
in retrosynthetic form in Figure 1 was investigated.
Thus, the aim was to employ Stille coupling of the vinyl
iodide 4 and the dienylstannane 5 to construct the requi-
site triene unit, on the assumption that iodide 4 would
be easily obtained from the known9 oxazole 6. We felt
that the coupling partner 5 would be accessible in enan-
tioenriched form via reaction of a dienal 7, formed in a
stereocontrolled manner, with ketene acetal 8 in the
presence of a chiral Lewis acid (see later).12 Herein, we
The inthomycins have attracted considerable synthetic
attention, with a number of analogues being made7
(including some with the oxazole moiety replaced by a
phenyl ring7b). However, to date there has only been
OH
O
N
N
N
NH
O
OH
O
O
O
O
2
HO
NH
2
NH
2
Inthomycin B (2)
Inthomycin A (1)
(Phthoxazolin)
Inthomycin C (3)
*
Corresponding author. Fax: +44 (0)1904 434523; e-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.042

550
M. R. Webb et al. / Tetrahedron Letters 47 (2006) 549–552
OH
O
OH
O
N
N
OMe
I
Bu Sn
3
NH
O
O
2
5
1, 2, 3
4
N
CHO
OTMS
OMe
Bu Sn
OH
3
O
7
8
6
Figure 1.
N
O
N
ii
i
OEt
OEt
OH
O
O
O
O
9
6
iii
N
N
N
v
iv
I
SnBu
3
Br
O
O
O
4
11
10
vi
Scheme 1. Reagents and conditions: (i) TOSMIC, 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@CHSnBu3, THF, 80 °C, 4 h, 51%; (v) I2, CH2Cl2, 0 °C, 20 min, 86%; (vi) Pd2dba3 (5 mol %), THF, 80 °C,
4 h, then I2 at 0 °C, o/n, 46%.
describe the successful implementation of this route as
exemplified by the first asymmetric synthesis of any
member of the inthomycin family in the form of (+)-
inthomycin B (2).
Coupling partner Z,E-5 was prepared from the known15
E-3-(tributylstannyl)propenal 12 as shown in Scheme 2.
As we have previously reported,16 reaction of aldehyde
12 with the Still-Gennari bis-trifluoroethoxy phospho-
nate reagent 13 proceeds in excellent yield (94%) and
with complete stereoselectivity to give ester 14. Sub-
sequent reduction of ester 14 using Dibal-H and TPAP
oxidation afforded aldehyde Z,E-7 as a single isomer
(d 10.35, s, 1H, CHO), which underwent isomerisation
on silica gel and hence was purified on deactivated
alumina, in 83% yield over two steps.
The route to vinyl iodide 4 is shown in Scheme 1.13
Oxazole 914 was prepared in good yield (86%) by
treating ethyl glyoxylate with tosyl methyl isocyanate
(TOSMIC) provided rigorously anhydrous conditions
were employed. Reduction of the ethyl ester with NaBH4
then afforded the primary alcohol 69 in 85% yield. Using
a published procedure (NBS/PPh3),9 alcohol 6 was
converted into the highly unstable bromide 10,9 which
was immediately coupled to E-1,2-bis-(tri-n-butylstann-
yl)ethene. A range of catalysts and reaction conditions
were screened to optimise the yield of the ꢁmono-Stilleꢀ
coupled product 11:8,9 eventually the use of catalytic
Pd2dba3 in refluxing THF was chosen in view of the
reproducible yield (>50%), although the high tempera-
ture required did result in degradation of the starting
bromide. Tin–iodine exchange then proceeded unevent-
fully to give the novel vinyl iodide 4. The final two steps
could be telescoped in a one-pot process, which gave
iodide 4 in 46% overall yield from bromide 10 and which
could be carried out on a multi-gram scale (producing 4
in >3.5 g in a single operation).
With aldehyde Z,E-7 in hand, we explored asymmetric
directed aldol reactions using ketene acetal 8. Kiyookaꢀs
group, and others, have carried out extensive studies
using 8 with a range of amino acid-derived oxazaboro-
lidinones.12 In our studies, we concentrated on the use
of the oxazaborolidinone derived from N-tosyl-L-valine
and BH3ÆTHF. In initial studies, oxazaborolidinone for-
mation was carried out for the recommended12a 1 h per-
iod, and extensive reduction of the aldehyde was
observed. However, this could be minimised by allowing
the oxazaborolidinone to form over 16 h and by using a
defined ratio of amino acid/BH3ÆTHF/aldehyde
(2:1.2:1). Optimisation of the reaction conditions in
terms of solvent, concentration and temperature

M. R. Webb et al. / Tetrahedron Letters 47 (2006) 549–552
551
CF CH O
3
2
P
CO Et
13
2
CF CH O
3
2
O
Bu Sn
3
Bu Sn
3
O
i
ii, iii
O
OEt
12
14 (Z:E = 100:0)
OTMS
OMe
8
Bu Sn
3
Bu Sn
3
O
iii
O
HO
OMe
Z,E-7
Z,E-5
Scheme 2. Reagents and conditions: (i) KHMDS, 18-crown-6, THF, ꢀ78 °C to rt, 16 h, 94%; (ii) Dibal-H, CH2Cl2, ꢀ10 to 5 °C, 90 min, 85%; (iii)
˚
TPAP (5 mol %), NMO, 4 A molecular sieves, rt, 4 h, 97%; (iv) N-tosyl-L-valine, BH3ÆTHF, CH2Cl2, 0 °C to rt slowly, 16 h then at ꢀ78 °C add 7 and
after 5 min 8, 2 h, 74%, 64% ee.
resulted in a gratifying 74% yield of Z,E-5 (Scheme 2).
The diene stereochemistry was retained as demonstrated
by the isolation of a single product. The product was
optically enriched {[a]D +5.4 (c 1.07, CHCl3)} and an
enantiomeric excess of 64% was established after the
next reaction. Literature precedent suggested that the
use of N-tosyl-L-valine should produce a predominance
of the required R-Z,E-5 (as shown); this was also con-
firmed at the next stage.
isomerisation) to 1% palladium bis-acetonitrile bis-chlo-
ride in DMF completely precluded isomerisation13 giv-
ing the required triene 15 in quantitative yield.17
Alcohol 15 was converted into diastereomeric R- and
S-Mosher ester derivatives and analysis of the resulting
1
high field H NMR spectra18 confirmed the predomi-
nance of the expected R-stereochemistry in 64% ee (also
confirmed by HPLC studies19).
The final transformation required the conversion of
methyl ester 15 into the corresponding primary amide
2. Many unsuccessful attempts at the direct conversion
were followed by similar disappointments with the
derived carboxylic acid 16. Success was eventually
achieved by the initial formation of acetate 17 followed
by formation of the corresponding acid chloride; subse-
quent in situ treatment with ammonium hydroxide gave
amide formation and deprotection leading to inthomy-
cin B 2 in reasonable isolated yield (Scheme 3). The
spectral data were consistent with those previously
We were now in a position to investigate the crucial
Stille coupling reaction between iodide 4 and enantiome-
rically enriched R-Z,E-5. The coupling was found to
proceed in high yield with a range of catalysts/condi-
tions but initial problems were encountered concerning
isomerisation of the Z,E,E-triene unit during the course
of the reaction. Experimentation revealed that isomeri-
sation was mostly dependent on the catalyst loading
rather than the type of palladium catalyst or the nature
of reaction solvent/additives. Moving from 5 (ca. 20%
N
N
i
Bu Sn
3
O
+
I
O
O
O
HO
Z,E-5
OMe
HO
OMe
4
15
ii
N
N
16
O
4
13
iv
O
O
O
3
RO
iii
OH
HO
NH
2
2
16, R = H
17, R = Ac
Scheme 3. Reagents and conditions: (i) 1 mol % Pd(CH3CN)2Cl2, DMF, 50 °C, 5 d, quant.; (ii) LiOH, THF/MeOH/H2O (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, o/n, 50%.

552
M. R. Webb et al. / Tetrahedron Letters 47 (2006) 549–552
11. Addie, M. S.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans.
1 2000, 527–531; Crawforth, C. M.; Burling, S.; Fairlamb,
I. J. S.; Taylor, R. J. K.; Whitwood, A. C. Chem. Commun.
2003, 2194–2195; Addie, M. S.; Crawforth, C. M.; Dale, J.
W.; Franci, X.; Pizzonero, M.; Webb, M. R., unpublished
results (to be reported in a full paper).
12. (a) Kiyooka, S.-I.; Keneko, Y.; Komura, M.; Matsuo, H.;
Nakano, M. J. Org. Chem. 1991, 56, 2276–2278; (b)
Kiyooka, S.-I. Rev. Heteroatom. Chem. 1997, 17, 245–270;
Fujiyama, R.; Goh, K.; Kiyooka, S.-I. Tetrahedron Lett.
2005, 46, 1211–1215, and references cited therein.
13. All novel compounds were fully characterised (including
high field NMR spectroscopy and HRMS).
14. For an alternative route to this compound see: Vedejs, E.;
Luchetta, L. M. J. Org. Chem. 1999, 64, 1011–1014.
15. Wender, P. A.; Sieburth, S. McN.; Petraitis, J. J.; Singh, S.
K. Tetrahedron 1981, 37, 3967–3975.
reported [e.g., dC 19.6 (C-16), 75.9 (C-3), 139.9 (C-4),
151.7 (C-13); lit.6 dC 19.6 (C-16), 75.8 (C-3), 139.9
(C-4), 151.6 (C-13)] and compound 2 was completely
characterised {HRMS [found (CI): MH+: 291.1706.
C16H23N2O3 requires MH+: 291.1709, 1.1 ppm error];
kmax (MeOH) 286 nm (27,400), 275 nm (33,600),
266 nm (27,000); [a]D +19.3 (c 1.0, CHCl3); no [a]D
reported in the literature}.
In summary, we have completed the first synthesis of
(+)-inthomycin B using a concise, convergent and ste-
reocontrolled route with the Stille coupling of a stan-
nyl-diene with an oxazole vinyl iodide unit, and a
Kiyooka ketene acetal/amino acid-derived oxazaboro-
lidinone procedure as its cornerstones. We are currently
optimising this route, particularly the Kiyooka step, and
we will then use it to prepare inthomycins A and C.
16. Franci, X.; Martina, S. L. X.; McGrady, J. E.; Webb, M.
R.; Donald, C.; Taylor, R. J. K. Tetrahedron Lett. 2003,
44, 7735–7740.
17. Experimental procedure: To a stirred solution of iodide 4
(63 mg, 0.27 mmol) in anhydrous degassed DMF (1 mL)
at rt, was added stannane Z,E-5 (119 mg, 0.24 mmol),
followed by a solution of dichloro bis(acetonitrile) palla-
dium (0.63 mg, 2.4 lmol) in anhydrous degassed DMF
(1 mL). The reaction mixture was heated at 55 °C for 5 d
in the dark, and then concentrated in vacuo. The residue
was partitioned between ethyl acetate (10 mL) and ammo-
nium hydroxide (0.880 sg (35% ammonia), 10 mL), and
the aqueous layer was extracted once more with ethyl
acetate (20 mL). The combined organic fractions were
washed with brine (5 mL), dried over magnesium sulfate,
filtered and concentrated in vacuo. Purification by flash
silica chromatography (petroleum ether/diethyl ether, 1:1)
Acknowledgements
We are grateful to the EPSRC and AstraZeneca for stu-
dentship support (M.R.W.; Industrial CASE). We
would also like to acknowledge the preliminary research
carried out by Dr. M. Addie, Dr. C. Crawforth and Dr.
X. Franci, and the helpful contributions of Dr. J. Dale
and Dr. M. Pizzonero. We are particularly grateful for
the assistance of Dr. M. McGrath (HPLC).
References and notes
21
gave adduct 15 (75 mg, quant.) as a yellow oil, ½aꢁD +57.9
(c 0.80, CHCl3); Rf 0.34 (petroleum ether/ethyl acetate,
1:1); mmax (film) 3419, 3136, 2981, 2951, 1726, 1511, 1471,
1435, 1260, 1192, 1140, 1055, 912 cmꢀ1; dH (400 MHz,
CDCl3) 1.15 (3H, s, H-14/15), 1.27 (3H, s, H-14/15), 1.75
(3H, s, H-16), 3.48 (2H, d, J 7.0, H-10), 3.72 (3H, s, H-17),
4.71 (1H, s, H-3), 5.73 (1H, dt, J 14.5, 7.0, H-9), 6.03 (1H,
d, J 11.5, H-5), 6.10–6.23 (2H, m, H-7 and H-8), 6.43 (1H,
dd, J 11.5, 13.5, H-6), 6.79 (1H, s, H-12), 7.79 (1H, s, H-
13); dC (100 MHz, CDCl3) 19.6 (C-16), 21.1 (C-14/15),
24.5 (C-14/15), 29.0 (C-10), 46.9 (C-2), 52.4 (C-17), 75.2
(C-3), 122.6 (C-12), 127.3 (C-9), 128.0 (C-6), 130.3 (C-5),
131.8 (C-7/8), 133.5 (C-7/8), 137.0 (C-4), 150.6 (C-13),
150.9 (C-11), 178.5 (C-1); m/z (EI) 305 (M+, 1), 269 (8),
204 (100), 102 (29), 82 (39), 57 (22), 41 (32); [found (EI):
M+ 305.1637; C17H23NO4 requires M 305.1627, 3.4 ppm
error].
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12
N
16
13
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14 15
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´
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