Total synthesis of lodopyridone

Article abstract of DOI:10.1021/ol302121w

A convergent total synthesis of the structurally unprecedented alkaloid lodopyridone was achieved using a cross-coupling of an iodopyridone fragment with a quinolinethiazolylstannane. Key features of the syntheses of the pentasubstituted 4-pyridone were a

Full text of DOI:10.1021/ol302121w

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4674–4677
Total Synthesis of Lodopyridone
Tobias Burckhardt, Klaus Harms, and Ulrich Koert*
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse,
D-35032 Marburg, Germany
koert@chemie.uni-marburg.de
Received July 31, 2012
ABSTRACT
A convergent total synthesis of the structurally unprecedented alkaloid lodopyridone was achieved using a cross-coupling of an iodopyridone
fragment with a quinolinethiazolylstannane. Key features of the syntheses of the pentasubstituted 4-pyridone were a regioselective bromination
of a 4-pyridone derived from kojic acid, a subsequent Cu-mediated introduction of the thioether, and a directed lithiation/iodination step. A
chemoselective Negishi cross-coupling of a dibromothiazole and a quinolinylzinc reagent was used to assemble the chloroquinolinethiazol moiety.
4-Pyridones are important heterocyclic substructures
occurring in a variety of organic compounds.1 They are
found inter alia in natural products (mimosine/leucenol,2
piericidin A13), antibiotics (cefazedone4 and cefpiramid5),
and contrast media (propyliodone).
C9 to a chloroquinoline moiety. A short ethanolamine side
chain is attached to C1.
Lodopyridone (1) was isolated by Fenical’s group from
the marine bacterial strain CNQ490 which was collected
near the mouth of the La Jolla Canyon.6 The name was
derived from the Spanish Lodo (mud) because of the
muddy marine sediments the bacterial sample was isolated
from. Lodopyridone exhibits cytotoxic activity against
HCT-116 human colon cancer cells with IC50 = 3.6 μM.6
The structure of lodopyridone (1) (Figure 1) was eluci-
dated by X-ray crystallography.6 The unprecedented ske-
leton of the new alkaloid natural product contains a
pentasubstituted 4-pyridone with a rare methyl thioether
at C3. C6 is linked to a thiazole which itself is connected at
Figure 1. Structure of lodopyridone (1).
The unprecedented structure of lodopyridone, in parti-
cular the pentasubstituted 4-pyridone substructure, makes
it an attractive synthetic target. Here, we present a total
synthesis of lodopyridone (1). Our synthetic strategy was
basedona latecross-coupling of aniodopyridone2withan
chloroquinolineÀthiazolyl metal compound 3 (Scheme 1).
The synthesis of the pyridone fragment 9 started with
kojic acid (4) (Scheme 2). The methyl ether at C2 was
introduced by treatment of compound 4 with dimethyl
sulfate to give pyrone 5.7
(1) Keller, P. A. Science of Synthesis; Thieme: Stuttgart, 2005; Vol.
15.2, pp 285À387.
(2) (a) Adams, R.; Johnson, J. L. J. Am. Chem. Soc. 1949, 71,
705–708. (b) Nokihara, K.; Hirata, A.; Sogon, T.; Ohyama, T. Amino
Acids 2012, 43, 475–482.
(3) (a) Takahashi, N.; Suzuki, A.; Tamura, S. J. Am. Chem. Soc.
1965, 87, 2066–2068. (b) Schnermann, M. J.; Boger, D. L. J. Am. Chem.
Soc. 2005, 127, 15704–15705.
(4) Dingeldein, E.; Wahlig, H.; Bergmann, R. Curr. Chemother.,
Proc. Int. Congr. Chemother. 10th 1978, 2, 832–834.
(5) Matsui, H.; Yano, K.; Okuda, T. Antimicrob. Agents Chemother.
1982, 22, 213–217.
Jones oxidation of the primary alcohol 5 yielded the
carboxylic acid 6.8 The acid could be converted via EDC
(7) Campbell, K. N.; Ackerman, J. F.; Campbell, B. K. J. Org. Chem.
1950, 15, 221–226.
(8) Becker, H.-D. Acta Chem. Scand. 1962, 16, 78–82.
(6) Maloney, K. N.; MacMillan, J. B.; Kauffman, C. A.; Jensen,
P. R.; DiPasquale, A. G.; Rheingold, A. L.; Fenical, W. Org. Lett. 2009,
11, 5422–5424.
r
10.1021/ol302121w
Published on Web 08/21/2012
2012 American Chemical Society

4-pyridone 9 with 3 equiv of n-BuLi gave the double-
lithiated intermediate 15, which could be cleanly methy-
lated to 16 or iodinated to 17.
Scheme 1. Retrosynthesis of Lodopyridone (1)
Scheme 3. Ortho-Lithiation of the Pyridone 9
Scheme 2. Synthesis of the Pyridone Fragment 9
Next, the regioselective functionalization of the C3
position was investigated (Scheme 4). NBS-bromination
of pyridone 9 provided the C3-bromination product 18
exclusively. The carboxamide at C2 has no deactivating
effect on the C2ÀC3 double bond. As indicated by X-ray
of the pyridone 20 (vide infra), the carboxamide adopts an
orthogonal conformation with respect to the pyridone
ring, due to steric interference. Thus, bromination at C3
is strongly favored over bromination at C6. Having in-
stalled a bromine at C3 in 18, different conditions for its
conversion into a methyl thioether 19 were tested. NaSMe
addition alone gave a very low yield (<25%) even at
elevated temperature. Considerable side reactions includ-
ing cleavage of the methyl ether and TBDPS deprotection
were observed. Optimal was the combination of NaSMe
and CuI in dioxane, which led to the desired thioether 19 in
very good yield. The lithiation/iodination protocol devel-
oped for 9 (Scheme 3) could be applied successfully to the
introduction of the iodo substituent at C6 (19 f 20), even
in the presence of the thioether. An X-ray structure of the
iodopyridone 20 proved the correct position of all five
substituents at the 4-pyridone.
coupling with the amine 79 into the amide 8. The subse-
quent pyroneÀpyridone transformation10 proceeded
smoothly. Treatment of the 4-pyrone 8 with methylamine
gave the 4-pyridone 9 in excellent yield.
Introduction of the C3 and C6 substituents at the
4-pyridone ring were addressed next. First, the possibility
of a regioselective lithiation of compound 9 was examined
(Scheme 3). The ortho-lithiation of 3-methoxy pyridines
is a reliable tool for the introduction of a substituent in
the C2-pyridine position (10 f 11).11 For the present case,
it was found that the ortho-lithiation of a 3-methoxy-
4-pyridone 12 results in the formation of the lithiated
pyridone 13. The zwitterionic structure 14 indicates the
stabilization of this reactive intermediate.12 Treatment of
(9) Papahatjis, D. P.; Nahmias, V. R.; Nikas, S. P.; Schimpgen, M.;
Makriyannis, A. Chem.;Eur. J. 2010, 16, 4091–4099.
(10) Iwamatsu, K.; Atsumi, K.; Sakagami, K.; Ogino, H.; Yoshida,
T.; Tsuruoka, T.; Shibahara, S.; Inouye, S.; Kondo, S. J. Antibiot. 1990,
43, 1450–1463.
(11) (a) Trecourt, F.; Mallet, M.; Mongin, O.; Gervais, B.; Queguiner,
G. Tetrahedron1993, 49, 8373–8380. (b)Schlosser, M.; Mongin, F. Chem.
Soc. Rev. 2007, 36, 1161–1172.
The synthesis of the chloroquinolinethiazolyl fragment
started with amide 21 (Scheme 5). Conversion into 6-chloro-
quinol-2-one following Turner’s route13 and subsequent
(12) Meghani, P.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1988, 1–8.
(13) Turner, J. A. J. Org. Chem. 2000, 55, 4744–4750.
Org. Lett., Vol. 14, No. 17, 2012
4675

Scheme 4. Regioselective Synthesis of the Pentasubstitued
Iodopyridone 20 and X-ray Structure of 20
Scheme 5. Synthesis of the Chloroquinolinethiazolylstannane 26
treatment with POBr3 yielded 2-bromo-6-chloroquinoline
(22).14 Different cross-coupling scenarios were investi-
gated for the linkage between the quinoline and the
thiazole. Initially, a longer Stille route that required the
transformation of bromide 22 into the corresponding
2-stannylquinoline was used. Later, a shorter, more effi-
cient Negishi coupling was applied. Bromide 22 was con-
verted via bromineÀlithium exchange and subsequent
transmetalation into the quinolinyl zinc reagent 23. Reac-
tion of the quinolinylzinc 23 with 2,3-dibromothiazole 24
using Pd(PPh3)4 gave the coupling product 25 in good
yield. The chemoselectivity observed for this step matches
Bach’s observation15 for related cases. After Pd-mediated
conversion of bromide 25 into a trimethylstannyl16 group,
the desired chloroquinolineÀthiazolylstannane 26 was
obtained.
Scheme 6. Final Part of the Lodopyridone Synthesis
The chloroquinolineÀthiazolyl substructure could also
be obtained starting from 6-chloroquinoline (27) via the
nitrile 28.17 Reaction with mercaptoacetic acid and sub-
sequent conversion of the hydroxythiazole into the corre-
sponding triflate using N-(5-chloro-2-pyridyl)triflimide
(Comins’ reagent) gave compound 30, however, in low
yield.18
With both fragments 20 and 26 in hand, we turned our
attention to the final coupling (Scheme 6). A priori, a
Pd-catalyzed Stille reaction16 or a Cu-mediated Liebeskind
(14) Amstutz, E. D.; Young, T. E. J. Am. Chem. Soc. 1951, 73,
4773–4775.
(15) (a) Gross, S.; Heuser, S.; Ammer, C.; Heckmann, G.; Bach., T.
Synthesis 2011, 199–206. (b) Heuser, S.; Bach., T. Synlett 2002,
2089–2091.
(16) Stille, J. K. Angew. Chem., Int. Ed. 1986, 25, 508–524.
(17) Yoshikawa, K. Bioorg. Med. Chem. 2009, 17, 8221–8233.
(18) Sadek, K. U.; Mourad, A.-F. E.; Abd-Elhafeez, A. E.; Elnagdi,
M. H. Synthesis 1983, 739–741.
coupling19 are suitable to link an alkenyl iodide with an
alkenylstannane.
Stille coupling of the R-N-alkylated, ortho-substituted
iodopyridone 20 with Pd(PPh3)4 or Pd(dppf)Cl2 was suc-
cessful, but only gave yields lower than 30%. Purification
(19) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118,
2748–2749.
4676
Org. Lett., Vol. 14, No. 17, 2012

of the desired product 32 required HPLC to remove traces
of ligand and iodopyridone 20. Similar results were
achieved under Liebeskind conditions using copper(I)
thiophene carboxylate. Even though product 32 could be
obtained, yields did not exceed 24%. Considering these
results, we decided to focus on Stille coupling. Second-
generation Buchwald Pd precatalyst 3120 provided access
to coupling product 32 in very good yield.
convergent synthesis include a regioselective construction
of the pentasubstitued 4-pyridone and a cross-coupling of
this highly hindered system utilizing a second-generation
Buchwald Pd precatalyst. A Cu-mediated protocol was
established to introduce the thioether moiety. Our obser-
vations concerning the regioselectivity will allow the effi-
cient sythesis of analogous, highly substituted 4-pyridones.
Acknowledgment. The Deutsche Forschungs-gemeins-
chaft and the Fonds der Chemischen Industrie are grate-
fully acknowledged for financial support.
After removal of the TBDPS group, lodopyridone (1)
was obtained. The spectra and analytical data of the
synthetic sample were identical to those reported for the
natural material.6
In conclusion, we have reported the first total synthesis
of lodopyridone in nine linear steps and 23% overall
yield (longest linear sequence). Salient features of our
Supporting Information Available. Experimental pro-
1
cedures and H and 13C NMR data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4677