Dearomatizing anionic cyclization of phosphonamides. A route to phosphonic acid derivatives with antitumor properties

Article abstract of DOI:10.1021/ol801463g

(Chemical Equation Presented) Deprotonation of bis(N-benzyl-N-methyl)-P- arylphosphonic diamides with s-BuLi in THF at -90°C takes place selectively at the benzylic position. The anions undergo intramolecular attack to the P-aryl ring leading to dearomatized species that were trapped with a series of electrophiles (MeOH, ArOH, BnBr, aliphatic and aromatic aldehydes, and benzophenone) in very high yield, and with high regio- and stereocontrol. The dearomatized products were smoothly transformed into γ-aminophosphonic acids under acidic conditions. Preliminary screening for antitumor activity showed promising levels of activity.

Full text of DOI:10.1021/ol801463g

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3981-3984
Dearomatizing Anionic Cyclization of
Phosphonamides. A Route to
Phosphonic Acid Derivatives with
Antitumor Properties
Gloria Ruiz-Go´mez,† Andre´s Francesch,‡ Mar´ıa Jose´ Iglesias,†
Fernando Lo´pez-Ortiz,*,† Carmen Cuevas,‡ and Manuel Serrano-Ruiz§
´
Area de Qu´ımica Orga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento,
04120 Almer´ıa, Spain, PharmaMar S.A., AV. de los Reyes, 1, P.I. La Mina, 28770,
´
Colmenar Viejo, Madrid, Spain, and Area de Qu´ımica Inorga´nica, UniVersidad de
Almer´ıa, Carretera de Sacramento, 04120, Almer´ıa, Spain
flortiz@ual.es
Received June 27, 2008
ABSTRACT
Deprotonation of bis(N-benzyl-N-methyl)-P-arylphosphonic diamides with s-BuLi in THF at -90 °C takes place selectively at the benzylic
position. The anions undergo intramolecular attack to the P-aryl ring leading to dearomatized species that were trapped with a series of
electrophiles (MeOH, ArOH, BnBr, aliphatic and aromatic aldehydes, and benzophenone) in very high yield, and with high regio- and stereocontrol.
The dearomatized products were smoothly transformed into γ-aminophosphonic acids under acidic conditions. Preliminary screening for
antitumor activity showed promising levels of activity.
Heteroatom-directed metalation followed by electrophilic
trapping is a very useful strategy for introducing structural
Scheme 1
diversity into a molecule provided that both steps proceed
with high levels of regio- and stereoselectivity.1 The Ph2P(O)
(Pop) group of P-arylphosphinamides fulfills these criteria
2
nicely. Lithiation at either the NCR (Scheme 1, route a) or
ortho3 position (route b) can be achieved in THF with
†
´
Area de Qu´ımica Orga´nica, Universidad de Almer´ıa.
‡ PharmaMar S.A.
§
´
Area de Qu´ımica Inorga´nica, Universidad de Almer´ıa.
(1) (a) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Amsterdam, The Netherlands, 2002. (b) Whisler, M. C.; MacNeil, S.;
Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206. (c) Wu, G.;
Huang, M. Chem. ReV. 2006, 106, 2596.
excellent regiocontrol. The NCR anions are stable in diethyl
ether at low temperature,4 allowing their application in
carbon-carbon and carbon-heteroatom bond-forming reac-
10.1021/ol801463g CCC: $40.75
Published on Web 08/20/2008
2008 American Chemical Society

tions (route c).5 In contrast, in THF and in the presence of
HMPA or DMPU, NCR anions undergo dearomatization
through anionic cyclization quantitatively.2,6
Table 1. Dearomatization-Electrophilic Quench of 5
The dearomatization-alkylation process of phosphina-
mides furnishes a variety of products, including γ-amino-
phosphinic acids, showing antitumor activity.6a,7,8 Extending
this methodology to phosphonamides will lead to amino-
phosphonic acids, important compounds due to their biologi-
cal properties.9 Lithiations directed by a phosphonamide
moiety have been limited to the ortho deprotonation of
PhP(X)(NMe2)2 (X ) O,10 S11).12
Fortuitously, in the reaction of the ortho-lithiated 2 with
benzonitrile, a dearomatized bicycle 4 was obtained (Scheme
2, 3). Heterocycle 4 is the only dearomatized product
Scheme 2. Directed Lithiation of Phenylphosphonamide
described for phosphonamides.13 We report here the first
dearomatizing anionic cyclization (DAC) of N-benzyl-P-
arylphosphonamides and the application of the method to
the synthesis of functionalized γ-aminophosphonic acids.
Preliminary evaluation of antitumor properties is also re-
ported.
The treatment of bis(N-benzyl-N-methyl)-P-phenylphos-
phonic diamide 514 with s-BuLi at -90 °C in THF followed
by electrophilic quench affords dearomatized products 8-10
in high yields (Table 1). Wide structural diversity is obtained
through the combined effect of the electrophile used and the
site of binding to the dearomatized anion.
a Isolated yield. b E+ ) MeOH. c Epimer at the phosphorus atom: 8%.
e
d Epimer at the phosphorus atom: 7%. E+ ) DTBMP. f Epimer at the
phosphorusatom:17%.g Epimeratthephosphorusatom:11%.h Diastereomeric
ratio at the hydroxilated carbon, S*:R* with respect to the phosphorus atom.
i Epimer at the phosphorus atom: 18%.
position and the anion generated, 6, attacks the ortho position
of the P-phenyl ring to give the dearomatized species 7.
Similar to phosphinamides,2,6 quenching the reaction with
MeOH introduces a proton at the R carbon with respect to
the phosphorus leading to 8a (entry 1), whereas protonation
with 2,6-di(tert-butyl)-4-methylphenol (DTBMP) and alky-
lation with benzyl bromide takes place almost exclusively
at the γ position providing 10a and 10b, respectively (entries
3-5). Two aspects of these transformations are worth
mentioning. First, the effect of DMPU on the efficiency of
the reaction is electrophile dependent. Yields of products
obtained by protonation with DTBMP or alkylation with
BnBr and benzophenone are higher in the presence of DMPU
(entries 3, 4, 5, and 10). For aldehydes and methanol as
electrophiles, the DAC reaction proceeds reasonably well
in the absence of strong coordinating cosolvent provided that
the metalation time is increased to 7 h.15 Second, small
amounts of the corresponding epimer at the phosphorus atom
The formation of compounds 8-10 implies that s-BuLi
deprotonates phosphonamide 5 selectively at the benzylic
(2) (a) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Tejerina, B.; Garc´ıa-Granda, S.
Org. Lett. 2001, 3, 1339. (b) Ramallal, A.; Ferna´ndez, I.; Lo´pez-Ortiz, F.;
Gonza´lez, J. Chem. Eur. J. 2005, 11, 3022.
(3) Ferna´ndez, I.; On˜a-Burgos, P.; Ruiz-Go´mez, G.; Bled, C.; Garc´ıa-
Granda, S.; Lo´pez-Ortiz, F. Synlett 2007, 611.
(4) Ferna´ndez, I.; Lo´pez-Ortiz, F. Chem. Commun. 2004, 1142.
(5) On˜a-Burgos, P.; Ferna´ndez, I.; Iglesias, M. J.; Torre-Ferna´ndez, L.;
Garc´ıa-Granda, S.; Lo´pez-Ortiz, F. Org. Lett. 2008, 10, 537.
(6) (a) Ferna´ndez, I.; Lo´pez Ortiz, F.; Mene´ndez Vela´zquez, A.; Garc´ıa-
Granda, S. J. Org. Chem. 2002, 67, 3852. (b) Ruiz-Go´mez, G.; Lo´pez-
Ortiz, F. Synlett 2002, 781. (c) Ferna´ndez, I.; Force´n-Acebal, A.; Lo´pez-
Ortiz, F.; Garc´ıa-Granda, S. J. Org. Chem. 2003, 68, 4472. (d) Ferna´ndez,
´
I.; Ruiz-Go´mez, G.; Iglesias, M. J.; Lo´pez-Ortiz, F.; Alvarez-Manzaneda,
R. ArkiVoc 2005, 9, 375. (e) Ferna´ndez, I.; Ruiz-Go´mez, G.; Alfonso, I.;
Iglesias, M. J.; Lo´pez-Ortiz, F. Chem. Commun. 2005, 5408. (f) Ruiz-
Go´mez, G.; Iglesias, M. J.; Serrano-Ruiz, M.; Lo´pez-Ortiz, F. J. Org. Chem.
2007, 72, 9704.
(7) Ruiz-Go´mez, G.; Iglesias, M. J.; Serrano-Ruiz, M.; Garc´ıa-Granda,
S.; Francesch, A.; Lo´pez-Ortiz, F.; Cuevas, C. J. Org. Chem. 2007, 72,
3790.
(8) Lo´pez-Ortiz, F. ; Ferna´ndez, I. ; Ruiz-Go´mez, G. ; Yan˜ez-Rodr´ıguez,
V. PharmaMar S.A., PCT/WO, 2008/003809A1, 2008.
(9) (a) Kukhar, V. P., Hudson, H. R., Eds. Aminophosphonic and
Aminophosphinic Acids. Chemistry and Biological ActiVity; John Wiley:
New York, 2000. (b) Kafarski, P.; Lejczak, B. Curr. Med. Chem.-Anti-
Cancer Agents 2001, 1, 301. (c) Palacios, F.; Alonso, C.; De los Santos,
J. M. Chem. ReV. 2005, 105, 899.
(11) Craig, D. C.; Roberts, N. K.; Tanswell, J. L. Aust. J. Chem. 1990,
43, 1487.
(12) For NCa litiation-alkylation of P-alkylphosphonamidates, see: (a)
Afarinkia, K.; Jones, C. L.; Yu, H.-W. Synlett 2003, 509. (b) Pedrosa, R.;
Maestro, A.; Pe´rez-Encabo, A.; Raliegos, R. Synlett 2004, 1300. (c) Lo´pez,
B.; Maestro, A.; Pedrosa, R. Synthesis 2006, 817. (d) For ortho lithiation
of phosphonamidates, see: Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.;
Steiner, A.; Xiao, J. Org. Lett. 2006, 8, 215.
(10) Dashan, L.; Trippett, S. Tetrahedron Lett. 1983, 24, 2039.
3982
Org. Lett., Vol. 10, No. 18, 2008

Figure 1. ORTEP type plots (40% anisotropic displacement) of the molecular structure of 9aa, 9ab, and 14.
are also isolated. Seeing the dearomatized compounds as
precursors of aminophosphonic acids (see below), both
diastereoisomers will give rise to the same product. Thus,
the mixture can be used without separation, and therefore,
the overall yield increases.
synthesis of 514 by using the corresponding aryldichloro-
phosphine17 (Supporting Information).
Lithiation of p-methoxyphenylphosphonamide 11 with
s-BuLi in THF in the presence of DMPU at -90 °C and
subsequent reaction with methanol gives exclusively the
dearomatized derivative 12 in 60% yield. The slight decrease
in yield as compared with the synthesis of 8a may be a
consequence of the deactivation of the anionic cyclization
step induced by the electron-donating effect of the methoxy
group. The naphthyl ring of phosphinamide 13 is smoothly
dearomatized upon treatment with s-BuLi in THF. Similar
to naphthylphosphinamides,6b,f no coordinating cosolvents
are required. Protonation of the dearomatized anion with
methanol provides the trans fused tricyclic compound 14 in
good yield.18 The structure of 12 and 14 was assigned based
on their spectroscopic data. Additionally, the X-ray crystal
structure of 14 confirmed the assignments of relative con-
Trapping anionic species 7 with aromatic and aliphatic
aldehydes leads to products of R-attack 9a to 9d in high
yield, although with low face selectivity (entries 6-9). The
best results are obtained in the absence of DMPU. In sharp
contrast, the analogue reactions of phosphinamides require
the use of coordinating cosolvents and afford products of
γ-attack exclusively.6,13 The reaction with benzophenone
yields almost exclusively products of γ-attack (entry 10)16
and is carried out in the presence of DMPU (method A, Table
1). The less crowded γ position of 7 is now more accessible
to the bulky electrophile than the R position.
All compounds were isolated by flash chromatography.
The structural assignment was based on the analysis of their
APCI-MS and NMR spectra (Supporting Information). [1,3]-
and [1,4]-cyclohexadiene systems can be easily distinguished
based on their NMR data (e.g., the sp3/sp2-hybridized carbon
R to the phosphorus and 31P NMR data). The relative
configuration of the benzazaphosphole fragments were
deduced through the respective gNOESY spectra. For the
pair of epimers at the CHOH carbon 9aa and 9ab, the relative
configuration of the five stereogenic centers has been
confirmed by X-ray diffraction (Figure 1).
Scheme 3. Dearomatization-Electrophilic Quench of 11 and 13
Next, the dearomatizing methodology was extended to
other phosphonamides. Arylphosphonamides 11 and 13 are
easily prepared through the same route applied to the
(13) Lo´pez-Ortiz, F.; Iglesias, M. J.; Ferna´ndez, I.; Andu´jar-Sa´nchez,
C. M.; Ruiz-Go´mez, G. Chem. ReV. 2007, 107, 1580.
figuration made (Figure 1, see also the Supporting Informa-
tion).
(14) Prepared in multigram scale through addition of phenyldichloro-
phosphine to 2 equiv of N-methylbenzylamine in toluene in the presence
of Et3N at -80 °C, followed by oxidation with H2O2 in THF (Supporting
Information). This is a slight modification of the method described in the
literature: (a) Droadhurst, M. D.; Tsang, T. H.; Tomko, J. Patent No.
US5186733, 1993.
(17) p-Methoxyphenyldichlorophosphine: (a) Miles, J. A.; Beeny, M. T.;
Ratts, K. W. J. Org. Chem. 1975, 40, 343. (b) 1-Naphthyldichlorophosphine:
Reiter, S. A.; Nogai, S. D.; Karaghiosoff, K.; Schmidbauer, H. J. Am. Chem.
Soc. 2004, 126, 15833.
(15) Similar behavior has been observed for phosphinamides. However,
in this case, significant amounts of products of ortho lithiation were also
formed. (a) Ferna´ndez, I.; Gonza´lez, J.; Lo´pez-Ortiz, F. J. Am. Chem. Soc.
2004, 126, 12551.
(18) Formation of products of cis fusion 8a and 12 and trans fusion 14
upon protonation of the corresponding dearomatized species is in agreement
with the stereochemical outcome of the analogue reactions of phosphina-
mides. See ref 6b, f.
(16) 9d, a product of R-attack with 6% yield, is also formed.
Org. Lett., Vol. 10, No. 18, 2008
3983

The results obtained indicate that N-benzylarylphospho-
namides behave similarly to the analogue carboxamides in
DAC-electrophilic trapping processes. Clayden et al. showed
that the application of this methodology to tertiary carboxa-
mides is a valuable route to the synthesis of natural products
and non-natural derivatives.1a,19
Given that the rupture of the P-N linkage of 1,2-
azaphosphole rings can be easily achieved with diluted
acid,2a,6 we treated compounds 8a, 10a, and 10b with 2 N
HCl in acetone at room temperature. In this way, hydrolysis
of the P-N bond takes place quantitatively to give γ-(N-
methylamino)phosphonic acids 16, 17a, and 17b, respectively
(Scheme 4). As noted above, hydrolysis of epimers at the
(colon), LoVo-Dox (colon), and A549 (NSCLC) cells. The
best activities were obtained for 10a and 9ab benzazaphos-
pholes (growth inhibition next to 100%).
In addition, 9ab exhibited a cytostatic effect. To evaluate
the cytotoxic potential of these compounds, a panel of a total
11 tumor cells was subsequently used (Supporting Informa-
tion). The best results are sumarized in Table 2.
Table 2. GI50 (µM) Results of in Vitro Screening of 10a and
9ab
prostate
ovary
leukemia pancreas
colon
compd LN-caP IGROV
K-562
PANC1 LOVO-DOX
10a
9ab
7.99
5.74
12.8
16.3
10.2
12.5
16.1
15.7
7.74
4.23
Scheme 4. Synthesis of γ-(N-Methylamino)phosphonic Acids
In summary, we have demonstrated the feasibility of
anionic cyclization dearomatization-electrophilic trapping
reactions of arylphosphonamides. The starting materials are
readily available on a large scale, including functionalized
derivatives. The process can be applied to phenyl and
naphthyl rings affording dearomatized products in high yield
and stereoselectivity. Simple acid hydrolysis provides func-
tionalized γ-(N-methylamino)phosphonic acids, compounds
of pharmaceutical interest. The results from antitumor assays
support the application of the new methodology to the
synthesis of bioactive compounds.
phosphorus atom produce the same amino acid. Representa-
tive dearomatized compounds were submitted to in vitro
cytotoxicity assays to evaluate their properties as possible
antitumor agents.6a,7,8
Acknowledgment. Financial support through the Minis-
terio de Educacio´n, Cultura y Deporte (Project CTQ2005-
01792), is gratefully acknowledged. G.R.-G. thanks the
Ministerio de Ciencia y Tecnolog´ıa for a doctoral fellowship.
Preliminar screening was carried out for 8a, 10a and its
epimer at the phosphorus atom, 9aa and 9ab on HT29
Supporting Information Available: Synthetic procedures,
characterization and structural information, NMR spectra of
new products, and X-ray data of 9aa, 9ab, and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Reviews: (a) Clayden, J.; Kenworthy, M. N. Synthesis 2004, 1721.
(b) Clayden, J.; Read, B.; Hebditch, K. R. Tetrahedron 2005, 61, 5713.
For recent references, see: (c) Clayden, J.; Kenworthy, M. N.; Heliwell,
M. Org. Lett. 2003, 5, 831. (d) Clayden, J.; Knowles, F. E.; mMenet, C. J.
J. Am. Chem. Soc. 2003, 125, 9278. (e) Clayden, J.; Knowles, F. E.;
Baldwin, I. R. J. Am. Chem. Soc. 2005, 127, 2412
.
OL801463G
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Org. Lett., Vol. 10, No. 18, 2008