Synthesis of the antimalarial drug FR900098 utilizing the nitroso-ene reaction

Article abstract of DOI:10.1021/ol702082k

The antimalarial drug FR900098 was prepared from diethyl allylphosphonate involving the nitroso-ene reaction with nitrosocarbonyl methane as the key step followed by hydrogenation and dealkylation. The utilization of dibenzyl allylphosphonate as the start

Full text of DOI:10.1021/ol702082k

ORGANIC
LETTERS
2007
Vol. 9, No. 21
4379-4382
Synthesis of the Antimalarial Drug
FR900098 Utilizing the Nitroso-Ene
Reaction
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Andrey A. Fokin,*, Alexander G. Yurchenko, Vladimir N. Rodionov,
Pavel A. Gunchenko, Raisa I. Yurchenko, Armin Reichenberg,‡
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Jochen Wiesner,‡ Martin Hintz,‡ Hassan Jomaa,‡ and Peter R. Schreiner*,§
Department of Organic Chemistry, KieV Polytechnic Institute, pr. Pobedy 37,
03056 KieV, Ukraine, UniVersita¨tsklinikum Giessen und Marburg, Institut fu¨r Klinische
Chemie und Pathobiochemie, Gaffkystrasse 11, 35392 Giessen, Germany, and
Institut fu¨r Organische Chemie, Justus-Liebig UniVersity, Heinrich-Buff-Ring 58,
D-35392 Giessen, Germany
aaf@xtf.ntu-kpi.kieV.ua; prs@org.chemie.uni-giessen.de
Received August 27, 2007
ABSTRACT
The antimalarial drug FR900098 was prepared from diethyl allylphosphonate involving the nitroso−ene reaction with nitrosocarbonyl methane
as the key step followed by hydrogenation and dealkylation. The utilization of dibenzyl allylphosphonate as the starting compound allows
one-step hydrogenation with dealkylation, which simplifies the preparative scheme further.
The most deadly malaria parasite plasmodium falciparum
has already developed resistance to the major classes of
antimalarial drugs. A possible solution to the problem lays
in the development of drugs with new mechanisms of
action.1,2 FR900098 (1) was first found in nature as a
phosphonic acid antibiotic3 but its antimalarial activity was
discovered only in 1999;4 the clinical studies of 1 are
currently underway. This drug inhibits the mevalonate-
independent pathway of isoprenoid biosynthesis in plasmo-
dium falciparum that includes 1-deoxy-D-xylulose-5-phos-
phate5 as the key metabolite.
A critical step in the known synthesis of compound 1
involves incorporation of the acetyl hydroxamate function
that is introduced by acetylation of the respective hydroxy-
lamines (2, Scheme 1) with Ac2O.6 The starting compounds
2, however, are difficult to prepare through the reaction of
organic bromides with hydroxyl amine, especially if ad-
ditional functional groups X are present. The reaction of (3-
bromopropyl)diethyl phosphonate {3, X ) CH2P(O)(OEt)2}
with hydroxylamine7 for the synthesis of 1 gives only
moderate yields of the substituted hydroxylamine derivative
(Scheme 1, pathway A); protection of the oxime (e.g., with
the benzylic group) increases the yields substantially.
Selected alternative routes for the preparation of function-
alized hydroxylamines 2 in the presence of strong bases
(usually NaH) are shown in Scheme 1. These involve the
| Kiev Polytechnic Institute.
‡ Institut fu¨r Klinische Chemie und Pathobiochemie.
§ Justus-Liebig University.
(1) Thayer, A. M. Chem. Eng. News 2005, 83, 69-82.
(2) Ridley, R. G. Nature 2002, 415, 686-693.
(3) Kamiya, T.; Hemmi, K.; Takeno, H.; Hashimoto, M. Tetrahedron
Lett. 1980, 21, 95-98.
(4) Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.; Weidemeyer,
C.; Hintz, M.; Tu¨rbachova, I.; Eberl, M.; Zeidler, J.; Lichtenthaler, H. K.;
Soldati, D.; Beck, E. Science 1999, 285, 1573-1576.
(5) Proteau, P. J. Bioorg. Chem. 2004, 32, 483-493.
(6) Fadeev, E. A.; Luo, M.; Groves, J. T. J. Am. Chem. Soc. 2004, 126,
12065-12075.
(7) Suita, T. K.; Takaruzuka, M. H.; Kyoto, K. H.; Nara, H. T.
Hydroxyaminohydrocarbonphosphonic acids. US Patent 4206156, 1980.
10.1021/ol702082k CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/22/2007

tively, the oxidation of functionalized amines 6 {X ) (CH2)2-
CH(NHCBn)CO2Me} with dimethyldioxirane22-24 or imines
7 with peracids {X ) (CH2)3COOH},25 followed by reaction
with TFA, led to unprotected N-substituted hydroxyl amines
(Scheme 1).
Scheme 1. Existing Synthetic Approaches to Functionalized
Hydroxylamines Potentially Applicable for the Preparation of
FR900098
The nitroso-ene reaction26 represents a convenient method
for the preparation of hydroxylamine derivatives through the
addition of nitroso-reagents to olefins. Herein we present a
new approach to 1 involving the nitroso-ene reaction of
commercially available diethyl allylphosphonate 9 with in
situ prepared nitrosocarbonyl methane (10) as the key step.
This leads to the unsaturated derivative 11, whose hydro-
genation gives diethyl phosphonic ester 12. Upon hydrolysis
to acid 13 and partial neutralization, 1 was isolated in 64%
overall preparative yield over four steps (Scheme 2).
Scheme 2. Preparation of FR900098 (1) from Diethyl
Allylphosphonate via the Nitroso-Ene Reaction
reaction of protected hydroxyl amines BnONHBoc and
HN(Ts)OBn with esters {3, X ) CH2C(O)OBn8 and X )
CH2COOEt},9 BnONH2 with amino acid derivatives {3, X
) (CH2)nCH2CH(NHAc)COOt-Bu}10 and amines {3, X )
(CH2)3NHBoc},11 or BocONHBoc with phosphites {3, X )
CH2P(O)(OAr)2},12 as well as some others.13-15 The hy-
droxylamines 2 were also prepared from substituted alde-
hydes 4 {X ) CH(R)P(O)(OEt)2} via imination with
NH2OBn and further reduction of the intermediate imines 5
with NaBH3CN.16 This approach was developed for the
preparation of the imino derivatives 5 {X ) (CH2)2NHBoc}17
and phosphonic esters 2 {X ) CH2P(O)(OEt)2}16,18-20 and
5 {X ) CH(Ar)P(O)(OEt)2}.21
Difficulties arise from the fact that the transformations of
protected hydroxylamines require the reagents, e.g., strong
bases, which are difficult for large-scale synthesis. Alterna-
Nitrosocarbonyl methane27 is among the most powerful
enophiles28 and it is highly reactive toward many nucleophilic
functional groups. This is the main reason why the nitroso-
ene additions of 10 were previously studied only for
unfunctionalized alkanes.29-33 Owing to its instability, 10 is
usually generated in situ via thermolysis of its 9,10-
dimethylanthracene adduct34 and we have chosen this method
for the preparation of 11 (Scheme 2). Alternative less
(8) Kurz, T.; Geffken, D.; Wackendorff, C. Z. Naturforsch. 2003, 58b,
457-461.
(9) Woo, Y.-H.; Fernandes, R. P. M.; Proteau, P. J. Bioorg. Med. Chem.
2006, 14, 2375-2385.
(10) Nishino, N.; Yoshikawa, D.; Watanabe, L. A.; Kato, T.; Jose, B.;
Komatsu, Y.; Sumida, Y.; Yoshidab, M. Bioorg. Med. Chem. Lett. 2004,
14, 2427-2431.
(11) Wu, T. Y. H.; Hassig, C.; Wu, Y.; Ding, S.; Schultz, P. G. Bioorg.
Med. Chem. Lett. 2004, 14, 449-453.
(12) Reichenberg, A.; Wiesner, J.; Weidemeyer, C.; Dreiseidler, E.;
Sanderbrand, S.; Altincicek, B.; Beck, E.; Schlitzer, M.; Jomaa, H. Bioorg.
Med. Chem. Lett. 2001, 11, 833-835.
(13) Ramurthy, S.; Miller, M. J. J. Org. Chem. 1996, 61, 4120-4124.
(14) Devreux, V.; Wiesner, J.; Goeman, J. L.; Van der Eycken, J.; Jomaa,
H.; Van Calenbergh, S. J. Med. Chem. 2006, 49, 2656-2660.
(15) Hamer, R. R. L.; Tegeler, J. J.; Kurtz, E. S.; Allen, R. C.; Bailey,
S. C.; Elliott, M. E.; Hellyer, L.; Helsley, G. C.; Przekop, P.; Freed, B. S.;
White, J.; Martin, L. L. J. Med. Chem. 1996, 39, 246-252.
(16) Kurz, T.; Schlu¨ter, K.; Kaula, U.; Bergmann, B.; Walter, R. D.;
Geffken, D. Bioorg. Med. Chem. 2006, 14, 5121-5135.
(17) Chaubet, F.; Nguen Van Duong, M.; Gref, A.; Courtieu, J.;
Crumbliss, A. L.; Gaudemer, A. Tetrahedron Lett. 1990, 31, 5729-5732.
(18) Ortmann, R.; Wiesner, J.; Reichenberg, A.; Henschker, D.; Beck,
E.; Jomaa, H.; Schlitzer, M. Arch. Pharm. 2005, 338, 305-314.
(19) Kurz, T.; Geffken, D.; Wackendorff, C. Z. Naturforsch. 2003, 58b,
106-110.
(22) Hu, J.; Miller, M. J. J. Org. Chem. 1994, 59, 4858-4861.
(23) Hu, J.; Miller, M. J. Tetrahedron Lett. 1995, 36, 6379-6382.
(24) Hu, J.; Miller, M. J. J. Am. Chem. Soc. 1997, 119, 3462-3468.
(25) Lin, Y.-M.; Miller, M. J. J. Org. Chem. 1999, 64, 7451-7458.
(26) Adam, W.; Krebs, O. Chem. ReV. 2003, 103, 4131-4146.
(27) Sklarz, B.; al-Sayyab, A. F. J. Chem. Soc. 1964, 1318.
(28) Kirby, G. W. Chem. Soc. ReV. 1977, 6, 1-24.
(29) Keck, G. E.; Yates, J. B. Tetrahedron Lett. 1979, 48, 4627-4630.
(30) Quadrelli, P.; Mella, M.; Caramella, P. Tetrahedron Lett. 1998, 39,
3233-3236.
(31) Keck, G. E.; Webb, R. R.; Yates, J. B. Tetrahedron 1981, 37, 4007-
4016.
(32) Adam, W.; Bottke, N.; Krebs, O.; Saha-Mo¨ller, C. R. Eur. J. Org.
Chem. 1999, 1963-1965.
(20) Ortmann, R.; Wiesner, J.; Reichenberg, A.; Henschker, D.; Beck,
E.; Jomaa, H.; Schlitzer, M. Bioorg. Med. Chem. Lett. 2003, 13, 2163-
2166.
(33) Keck, G. E.; Webb, R. R. J. Am. Chem. Soc. 1981, 103, 3173-
3177.
(21) Haemers, T.; Wiesner, J.; Busson, R.; Jomaa, H.; Van Calenbergh,
S. Eur. J. Org. Chem. 2006, 3856-3863.
(34) Kirby, G. W.; Sweeny, J. C. J. Chem. Soc., Chem. Commun. 1973,
19, 704-705.
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Org. Lett., Vol. 9, No. 21, 2007

convenient methods for the generation of 10 are based on
the oxidation of hydroxamic acids with iodosobenzene32,34,35
or through the reactions of nitrile oxides with N-methylmor-
pholine N-oxide.30,36
As the reactivities of unactivated olefins are generally low,
we used a ca. 1.2 molar excess of the complex of 10 to
achieve satisfactory conversions of 9. Remarkably, the
phosphoryl group remains untouched in 11. This is the first
example of the nitroso-ene reaction of nitrosocarbonyl
methane with a functionalized olefin.
Previous experimental and computational mechanistic
studies37-40 revealed that the nitroso-ene reaction proceeds
stepwise through biradical intermediates.40 Although we were
not able to identify biradical minima at the MP2 level of
theory,41 the hydrogen shift transition structures are strongly
spin-contaminated (up to S2 ) 0.96 for a broken spin
symmetry MP2 wave function). We found that the barriers
for hydrogen shift via conformationally related transition
structures TS1 and TS2 (Figure 1 and Scheme 2) for the
formation of E- and Z-isomers, respectively, are comparable
in energies at both the MP2/6-31G* and DFT (B3PW91/
6-31+G**) levels of theory, as well as with correlation
consistent basis sets (cc-pVDZ).
This agrees well with our experimental result for the
stereochemistry of the reaction of 9 with 10 that gives a
mixture of E- and Z-11 in ca. 1:1 ratio. This is also in line
with the known stereochemistry of the reaction of 1-octene
with 10.29,31 We separated the diastereomers of 11 by column
chromatography and characterized them individually. The
Figure 1. The B3PW91/6-31+G** optimized geometries of the
conformeric transition structures for the nitroso-ene reaction of
diethyl allylphosphonate with nitrosocarbonyl methane (critical bond
distances in Å).
structural assignments were based on the analysis of the 13
C
NMR spectra of the allylic fragments for which the larger
3J-values (24 vs 9 Hz) of the 13C-31P coupling are
characteristic for the E-isomer of 11.
Further transformation of adduct 11 involved the hydro-
genation on PtO2 or Pd/C at atmospheric pressure that gives
diester 12 in 95% yield. Since the acetylhydroxamate
function is sensitive toward hydrolysis in acidic media,
traditional treatment with HCl/H2O is not viable for the
dealkylation of 12 to acid 13. We employed McKenna’s42
mild protocol, based on a treatment with trimethylbromo-
silane and in situ hydrolysis of the thus formed trimethylsilyl
triester. This procedure gave acid 13 in 90% yield with
complete conservation of the acetylhydroxamic function.
Compound 1 derived after partial neutralization of 13 with
NaOH was identical with an authentic sample of FR900098
obtained independently.
Thus, we developed a simple methodology for the
preparation of 1 from commercially available 9 in 64% total
yield. The main drawback of the scheme arises from the
hydrolytic step, which utilizes trimethylbromosilane. To
avoid the use of this reagent and to simplify the procedure
further, we also developed another pathway (Scheme 3) to
1 utilizing the nitroso-ene reaction of allylbenzyl phospho-
nate (14). Hovewer, the literature procedure for the synthesis
of 14 was not satisfactory for us because it is, again, based
(35) Keck, G. E. Tetrahedron Lett. 1978, 48, 4767-4770.
(36) Quadrelli, P.; Mella, M.; Invernizzi, A. G.; Caramella, P. Tetrahe-
dron 1999, 55, 10497-10510.
(37) Adam, W.; Bottke, N.; Engels, B.; Krebs, O. J. Am. Chem. Soc.
2001, 123, 5542-5548.
(38) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243-1255.
(39) Lu, X. Org. Lett. 2004, 6, 2813-2815.
(40) Leach, A. G.; Houk, K. N. J. Am. Chem. Soc. 2002, 124, 14820-
14821.
(41) All computations were performed with the GAUSSIAN03 program
suite (Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, Revision D.02; Gaussian, Inc.: Wallingford CT, 2004) utilizing
analytical first and second energy derivatives. Harmonic vibrational
frequencies were computed to ascertain the nature of the stationary points.
We used 6-31+G** basis sets for DFT and correlation-consistent cc-pVDZ
for MP2 computations. The B3PW91 functional was chosen because it is
more trustworthy for large molecules than other popular DFT methods (see,
for instance: Schreiner, P. R.; Fokin, A. A.; Pascal, R. A.; de Meijere, A.
Org. Lett. 2006, 8, 3635-3638).
(42) McKenna, C. E.; Higa, M. T.; Cheung, N. H.; McKenna, M.-C.
Tetrahedron Lett. 1977, 155-158.
Org. Lett., Vol. 9, No. 21, 2007
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hydrogenation of the diastereomeric mixture of phosphonates
(15) in methanol at 1 atm followed by partial neutralization,
1 was obtained in 50% overall preparative yield with NMR
spectra identical with those for the authenic sample of
FR900098.
Scheme 3. An Alternative Route to FR900098 (1) Utilizing
the Nitroso-Ene Reaction and Dibenzyl Allylphosphonate
We conclude that the nitroso-ene reaction of allyl
phosphonates is highly effective for the preparation of
antimalarial drug FR900098. The addition of nitrosocarbonyl
methane to the olefin moiety of allylphosphonic esters gives
mixtures of unsaturated diastereomeric acetylhydroxamic
derivatives. Since the acetylhydroxamic function is quite
sensitive toward hydrolysis, milder hydrolytic reaction condi-
tions were employed for deprotection. Whereas the removal
of the ethyl groups in the product of the nitroso-ene reaction
requires dealkylation in the presence of Me3SiBr, this can
be circumvented in the case of benzylic esters for which
deprotection occurs simultaneously with hydrogenation.
Incorporation of the acetylhydroxamate function for the
synthesis of FR900098 seems quite promising in view of
the previously developed approaches to acetylhydroxamates
outlined in Scheme 1.
on the Me3SiBr-promoted hydrolysis of diethyl allylphos-
phonate (9).43
Hence, we developed an alternative method for the
preparation of 14 utilizing the Michaelis-Becker reaction44
of lithium dibenzyl phosphite with allyl bromide in dry ether
(see experimental details in the Supporting Information). The
use of the benzyl protecting group avoids the Me3SiBr-
assisted hydrolytic step since the benzyl function may be
simply removed by catalytic hydrogenation with the extrusion
of toluene. As expected, the diastereoselectivity of the
nitroso-ene reaction of dibenzyl allylphosphonate (14) does
not change relative to the respective diethyl derivative (9).
A mixture of E/Z-diastereomers, which forms in 52%
preparative yield (not optimized), was separated by column
chromatography and the diastereomeric phosohonates 15
were isolated and characterized individually. After the
Acknowledgment. This work was supported by the
European Commission AntiMal FP6 Malaria Drug Initiative
Framework Program (project LSHP-CT-2005-018834). We
thank Prof. Dr. Martin Schlitzer (University of Marburg) for
fruitful discussions and for the procedure for the experimental
details for the preparation of dibenzyl phosphite.
Supporting Information Available: The experimental
procedures, spectral data for compounds 11e, 11z, 12, and
15, as well as XYZ-coordinates of computed species. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(43) Yamagishi, T.; Fujii, K.; Shibuya, S.; Yokomatsu, T. Tetrahedron
2006, 62, 54-65.
(44) Engel, R. Synthesis of Carbon-Phosphorous Bonds; CRC Press:
Boca Raton, FL, 1988; p 7.
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