Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor.

Article abstract of DOI:10.1021/ol010089t

[structure: see text] Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1-C8 and C9-C18 segments were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia olefination, and converted to nafuredin.

Full text of DOI:10.1021/ol010089t

ORGANIC
LETTERS
2001
Vol. 3, No. 15
2289-2291
Total Synthesis of Nafuredin, a Selective
NADH-fumarate Reductase Inhibitor
Daisuke Takano,† Tohru Nagamitsu,‡,§ Hideaki Ui,† Kazuro Shiomi,‡
,‡
Yuuichi Yamaguchi,‡ Rokuro Masuma,‡ Isao Kuwajima,‡,§ and Satoshi Ohmura*
School of Pharmaceutical Science, Kitasato UniVersity, Kitasato Institute for Life
Sciences, Kitasato UniVersity, and CREST, The Japan Science and Technology
Corporation (JST), 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
omura-s@kitasato.or.jp
Received May 1, 2001
ABSTRACT
Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1−C8
and C9−C18 segments were derived efficiently from D-glucose and (S)-(−)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia
olefination, and converted to nafuredin.
In the course of our screening for NADH-fumarate reductase
(NFRD) inhibitors, nafuredin (1), which is potentially a
selective antiparasitic agent,1,2 was isolated from the fer-
mentation broth of a fungal strain, Aspergillus niger FT-
0554. Nafuredin (1) inhibited NFRD of Ascaris suum with
an IC50 value of 12 nM. The target of 1 was revealed as
complex I, and 1 showed selective inhibition of complex I
in helminth mitochondria. In addition, 1 exerted anthelmintic
activity against Haemonchus contortus in in vivo trials with
sheep.1 These useful biological activities of 1 attracted our
attention and prompted us to undertake the total synthetic
study. We previously reported the elucidation of the absolute
configuration of 1 by degradation and synthetic studies.3 In
this Letter, we wish to report the first total synthesis of
nafuredin (1).
We envisioned a convergent approach toward nafuredin
(1) via a stereoselective one-pot Julia olefination4 between
sulfone 3 and aldehyde 4 followed by appropriate functional
group elaboration of the resulting 2 (Scheme 1). Requisite
stereocontrol on the lactol moiety of 3 could be performed
by using D-glucose derivative 7 previously prepared in our
laboratory,3 and use of commercially available (S)-(-)-2-
methyl-1-butanol 6 would allow enantioselective construction
of the side chain segment 4 via Wittig olefination and Evans
alkylation.
On the basis of the synthetic plan, we initially prepared
aldehyde 4 as follows (Scheme 2). The starting material 6
was converted to the known (14E)-alcohol 8 in 50% overall
yield by a slight modification of Kitahara’s procedure,5 e.g.,
oxidation with 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),6
Wittig olefination, and DIBAL reduction. Allylic oxidation
of 8 with MnO2 followed by Wittig olefination with
(1-carboethoxyethylidene)triphenylphosphorane afforded the
desired (12E,14E)-dienyl ester 9 in 62% yield (two steps).
† School of Pharmaceutical Science, Kitasato University.
‡ Kitasato Institute for Life Sciences, Kitasato University.
§ CREST.
(1) Ohmura, S.; Miyadera, H.; Ui, H.; Shiomi, K.; Yamaguchi, Y.;
Masuma, R.; Nagamitsu, T.; Takano, D.; Sunazuka, T.; Harder, A.; Ko¨lbl,
H.; Namikoshi, M.; Miyoshi, H.; Sakamoto, K.; Kita, K. Proc. Natl. Acad.
Sci. U.S.A. 2001, 98, 60-62.
(2) Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.; Nagamitsu, T.;
Takano, D.; Sunazuka, T.; Namikoshi, M.; Ohmura, S. J. Antibiot. 2001,
54, 234-238.
(3) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.;
Masuma, R.; Kuwajima, I.; Ohmura, S. Tetrahedron Lett. 2001, 42, 3017-
3020.
(4) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
1991, 32, 1175-1178. (b) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.;
Morley, A. Synlett 1998, 1, 26-28.
(5) Akao, H.; Kiyota, H.; Nakajima, T.; Kitahara, T. Tetrahedron 1999,
55, 7757-7770.
(6) Portonovo, P.; Liang, B.; Joullie´, M. M. Tetrahedron: Asymmetry
1999, 10, 1451-1455.
10.1021/ol010089t CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/30/2001

Scheme 1
Scheme 2a
a (a) TEMPO, NaClO, KBr, CH2Cl2; (b) Ph3PdCHCO2Me,
benzene, 50 °C; (c) DIBAL, CH2Cl2, -78 °C; (d) MnO2, CH2Cl2;
(e) Ph3PdCMeCO2Et, benzene, 50 °C; (f) DIBAL, CH2Cl2, -78
°C; (g) Ac2O, Et3N, catalytic DMAP, CH2Cl2; (h) diethyl malonate,
NaH, catalytic Pd(PPh3)4, THF, 50 °C; (i) KOH, MeOH-H2O; (j)
Cu2O, CH3CN, reflux; (k) PivCl, Et3N, THF, 0 °C, then (R)-4-
benzyl-2-oxazolidinone, n-BuLi, THF, -78 to 0 °C; (l) NaHMDS,
MeI, THF, -78 °C; (m) LiBH4, EtOH (1.1 equiv), Et2O, 0 °C; (n)
Dess-Martin periodinane, CH2Cl2.
DIBAL reduction of the ester 9 and acetylation of the
resulting allyl alcohol furnished acetate 10, quantitatively.
Treatment of 10 with diethyl malonate and sodium hydride
in the presence of a catalytic amount of Pd(PPh3)4 led to
diester 11 quantitatively, which was subjected to alkali
hydrolysis to afford dicarboxylic acid 12. Decarboxylation
of 12 with copper(I) oxide7 gave monocarboxylic acid 13 in
71% overall yield from 11. Acid 13 was converted to a mixed
anhydride by treatment with pivaloyl chrolide and then
acylated with (R)-4-benzyl-2-oxazolidinone8 to produce 5,
quantitatively. Methylation of 5 with sodium hexamethyl-
disilazide (NaHMDS) and methyl iodide gave 14 in 85%
yield with its epimer (5% yield). The absolute configuration
of the newly introduced C10 methyl group was tentatively
assigned as the desired R according to the empirical rule
generally accepted9 and could be confirmed by completion
of the total synthesis. Reductive removal10 of the chiral
auxiliary with LiBH4 and oxidation of the resulting alcohol
15 with Dess-Martin periodinane11 afforded the desired
aldehyde 4 in 85% overall yield.
The sulfone 3 corresponding to the C1-C8 segment was
prepared as illustrated in Scheme 3. Debenzylation of
D-glucose derivative 7 by hydrogenolysis with palladium
hydroxide led to triol 16 quantitatively. Protection of the
primary alcohol as the TBS ether followed by treatment with
TIPSOTf furnished â-TIPS glycoside 17 in 74% yield (two
steps). Selective deprotection of the TBS ether was performed
by treatment with the TBAF-BF3‚Et2O complex,12 giving
diol 18 in 95% yield.13 Oxidation of 18 with Dess-Martin
periodinane followed by Horner-Wadsworth-Emmons
reaction of the corresponding aldehyde with allyl diethyl-
phosphonoacetate, LiCl, and diisopropylethylamine14 af-
forded (6E)-R,â-unsaturated allyl ester 19 in 75% yield (two
(7) Toussaint, L.; Capdevielle, P.; Maumy, M. Synthesis 1986, 1029-
1031.
(12) Kawahara, S.; Wada, T.; Sekine, M. Tetrahedron Lett. 1996, 37,
509-512.
(13) All attempts to convert the sterically hindered primary alcohol in
18 to Wittig reagent and aryl sulfone, which would allow the olefination at
C6, were unsuccessful. These results led us to construct the sterically less
hindered sulfone 3.
(14) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183-
2186.
(8) Evans, D. A.; Gaze, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992,
114, 9434-9453.
(9) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc. 1982,
104, 1737-1739.
(10) Penning, T. D.; Djuric′, S. W.; Haack, R. A.; Kalish, V. J.;
Miyashiro, J. M.; Rowell, B. W.; Yu, S. S. Synth. Commun. 1990, 20, 307-
312.
(11) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
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Org. Lett., Vol. 3, No. 15, 2001

Scheme 3a
Scheme 4a
a (a) H2, Pd(OH)2, EtOH; (b) TBSCl, i-Pr2NEt, DMF; (c)
TIPSOTf, 2,6-lutidine, CH2Cl2; (d) TBAF, BF3‚Et2O, CH3CN; (e)
Dess-Martin periodinane, CH2Cl2; (f) (EtO)2P(O)CH2CO2allyl,
i-Pr2NEt, LiCl, CH3CN; (g) catalytic Pd(PPh3)4, NaBH4, EtOH; (h)
MeO2CCl, Et3N, THF, then LiAlH(t-BuO)3; (i) DEAD, PBu3,
1-phenyl-1H-tetrazole-5-thiol, THF; (j) H2O2, catalytic Mo7O24(NH4)6‚
4H2O, EtOH.
a (a) KHMDS (2 equiv), THF, then 4; (b) NaH, THF; (c) DIBAL,
CH2Cl2; (d) AllocCl, DMAP, pyridine; (e) HF‚pyridine, THF; (f)
Dess-Martin periodinane, CH2Cl2; (g) HCO2H, Et3N, catalytic
Pd(PPh3)4, THF.
23 in 88% yield (two steps). The TIPS protecting group in
23 was then removed by exposure to HF‚pyridine, and the
resulting lactol was oxidized with Dess-Martin periodinane
to afford lactone 24 in 77% yield (two steps). Finally,
removal of the allyloxycarbonyl group by treatment with
HCO2H and Et3N in the presence of a catalytic amount of
Pd(PPh3)4 gave nafuredin (1) in 92% yield. Synthetic
nafuredin (1) was identical with natural (1) in all respects
([R]D, 1H and 13C NMR, IR, FAB-MS, and inhibitory activity
against NFRD).
steps). Deprotection of the allyl ester by treatment with a
catalytic amount of Pd(PPh3)4 and sodium borohydride
afforded carboxylic acid 20 quantitatively. Acid 20 was
subjected to reduction with lithium tri-tert-butoxyalumino-
hydride through the formation of a mixed anhydride with
methyl chloroformate to produce allyl alcohol 21 in 71%
yield. Mitsunobu reaction15 of 21 with 1-phenyl-1H-tetrazole-
5-thiol followed by oxidation with H2O2 in the presence of
a molybdenum(VI) catalyst16 furnished the desired sulfone
3 in 96% yield (two steps).
In conclusion, we have achieved the first total synthesis
of nafuredin. Investigations of the structure-activity rela-
tionship and biological studies of 1 are currently in progress.
Under the influence of potassium hexamethyldisilazide
(KHMDS, 2 equiv in this case),4b the one-pot Julia olefination
between 3 and 4 could be effected to provide the desired
(6E,8E,12E,14E)-alcohol 2 in 79% yield as a single isomer17
(Scheme 4). Treatment of 2 with sodium hydride gave
epoxide 22 in 99% yield. Epoxide 22 was subjected to
DIBAL reduction in order to remove the benzoyl group,18
and subsequent protection with allyl chloroformate furnished
Acknowledgment. H.U. acknowledges a Grant-in-Aid for
Encouragement of Young Scientists from Japan Society for
the Promotion of Science (12771373).
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds of the
synthesis. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL010089T
(15) Mitsunobu, O. Synthesis 1981, 1-28.
(16) Schultz, H. S.; Freyermuth, H. B.; Buc, S. R. J. Org. Chem. 1963,
28, 1140-1142.
(17) On warming up at this stage, epoxide formation could not be
effected.
(18) Attempts to remove the benzoyl group under various basic conditions
at the final step in the total synthesis did not afford nafuredin (1) without
decomposition.
Org. Lett., Vol. 3, No. 15, 2001
2291