T. C. McMahon et al. / Tetrahedron Letters 52 (2011) 2262–2264
2263
O
a
CO2H
I
1) CuI, K2CO3,
Nitrobenzene, 180°C
n-BuLi, THF
PivCl, Na2CO3
NMe
NH2
NHPiv
HN
CH2Cl2, H2O
(98% yield)
2) CH2N2, MeOH
then CO2
(84% yield)
OMe
OMe
OMe
(35% yield, two steps)
O
9
10
3
4
CO2H
NHPiv
CO2Me
NH2
O
1) HCl, H2O
2) CH2N2, Et2O
CO2Me
N
NMe
S
11 steps
O
(80% yield two steps)
S
OMe
OMe
N
OH
MeO
NMe
11
7
O
O
OH
5
2
O
b
Cl
Cl
Scheme 1. Conditions employed by Kishi for the coupling of aryl iodide 3 and DKP
4 en route to dehydrogliotoxin (2).
O
Me
N
Na2CO3
O
NHMe
HO
Cl
CH2Cl2, H2O
(89% yield)
HO
O
12
8
CO2Me
MeO2C
O
Scheme 3. Synthesis of precursors (a) aniline 7 and (b) acid 8.
H
N
Cl
O
N
N
Me
O
MeO
NMe
OMe
O
(COCl)2, DMF
MeO2C
O
O
5
6
H
CH2Cl2
Me
N
N
Cl
N
HO
Cl
CO2Me
NH2
O
Me
CO2Me
NH2
O
Me
then
O
OMe
N
HO
Cl
8
6
OMe
O
OMe
7
7
8
Et3N, CH2Cl2
(54% yield)
Scheme 2. Modified retrosynthetic analysis of DKP 5.
O
CO2Me
N
11 steps
Kishi
NMe
S
S
K2CO3, KI
O
N
OH
MeOH
for eventual analog generation. Efforts to affect this coupling using
more modern copper13 or palladium14 methodologies also failed to
produce the desired aryl amide in synthetically useful yields. At-
tempts to couple the benzylic alcohol15 or ester16 variants of 3 un-
der these types of conditions were also fruitless. These failures
ultimately led us to explore alternative methods for accessing
key intermediate 5. To this end, we explored an approach to the
DKP ring wherein the recalcitrant C–N bond was preassembled.
Specifically, we envisioned that 5 would arise from ring closure17,18
of alkyl chloride 6, the bis-amide derived from coupling of aniline 7
with acid 8 (Scheme 2). In addition to convergency, a potential
benefit of this approach was the absence of metal-mediated trans-
formations that would prohibit the preparation of analogs bearing
aryl halides.
MeO
NMe
(83% yield)
O
O
OH
5
2
Scheme 4. Synthesis of DKP 5.
In summary, we have accessed DKP 5, a key intermediate in the
synthesis of dehydrogliotoxin, using an approach that is conver-
gent, reproducible at scale and amenable to analog synthesis. Fi-
nally, we have advanced intermediate 5 to dehydrogliotoxin via
the synthetic route reported by Kishi and found that the derived
synthetic material exhibits an IC50 of 0.13 lM against MTB.
Although simple esterification of the commercially available
acid corresponding to aniline 7 would provide the first of the
two coupling partners required for our approach, the extravagant
cost of this acid prompted us to consider a more economical start-
ing material. We were pleased to find that large quantities of ani-
Acknowledgments
Dr. Chris Rithner, Don Heyse, and Don Dick are acknowledged
for their assistance with instrumentation. Research support from
Amgen is gratefully acknowledged.
line
7 could be accessed in high yield in four steps from
inexpensive o-anisidine (9).19 The second coupling partner, acid
8, was prepared in accordance with a procedure reported by Ciuf-
olini (Scheme 3).20
References and notes
1. Wright, A. Z. M. Anti-Tuberculosis Drug Resistance in the World; World Health
Organization: Geneva, 2008. Vol. Report No. 4.
2. Bell, M. R.; Johnson, J. R.; Wildi, B. S.; Woodward, R. B. J. Am. Chem. Soc. 1958, 80,
1001.
3. Weindling, R.; Emerson, O. H. Phytopathology 1936, 26, 1068–1070.
4. Lowe, G.; Taylor, A.; Vining, L. C. J. Chem. Soc. C 1966, 1799.
5. Tompsett, R.; McDermott, W.; Kidd, J. G. J. Immunol. 1950, 65, 59–63.
6. Müllbacher, A.; Waring, P.; Tiwari-Palni, U.; Eichner, R. D. Mol. Immunol. 1986,
23, 231.
7. Fukuyama, T.; Nakatsuka, S.-I.; Kishi, Y. Tetrahedron 1981, 37, 2045.
8. Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1976, 98, 6723.
9. Kishi, Y.; Fukuyama, T.; Nakatsuka, S. J. Am. Chem. Soc. 1973, 95, 6492.
10. Stanley, W. M.; McMahon, E.; Adams, R. J. Am. Chem. Soc. 1933, 55, 706.
With the two components in hand, coupling commenced via
initial conversion of 8 to the corresponding acid chloride followed
by exposure to aniline 7. Ring closure of the derived bis-amide 6
under basic conditions provided key intermediate 5 (Scheme 4).
Although completion of 5 by this alternative route constituted a
formal synthesis, our efforts continued through the remaining 11
steps reported by Kishi to deliver racemic 2. This material was as-
sayed for its ability to inhibit MTB and an IC50 of 0.13
lM was
observed.21