The concept of P-H protection extended to phosphine oxides: Preparation of functional, unsymmetrical secondary and tertiary phosphine oxides

Article abstract of DOI:10.1080/10426500212269

Phosphine oxide analogues of Triazole fungicides and protected Threonine have been prepared. The enzymatic hydrolysis of phosphine oxide di-acetates has been investigated.

Full text of DOI:10.1080/10426500212269

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Phosphorus, Sulfur, and Silicon and the Related
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The Concept of P--H Protection Extended to Phosphine
Oxides: Preparation of Functional, Unsymmetrical
Secondary and Tertiary Phosphine Oxides
Roger G. Hall a & Peter Riebli a
a Syngenta Crop Protection AG, Basel, CH 4002, Switzerland
Published online: 27 Oct 2010.
To cite this article: Roger G. Hall & Peter Riebli (2002) The Concept of P--H Protection Extended to Phosphine Oxides:
Preparation of Functional, Unsymmetrical Secondary and Tertiary Phosphine Oxides, Phosphorus, Sulfur, and Silicon and the
Related Elements, 177:6-7, 1557-1562, DOI: 10.1080/10426500212269
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:1557–1562
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
DOI: 10.1080/10426500290093531
THE CONCEPT OF P H PROTECTION EXTENDED
TO PHOSPHINE OXIDES: PREPARATION
OF FUNCTIONAL, UNSYMMETRICAL SECONDARY
AND TERTIARY PHOSPHINE OXIDES
Roger G. Hall and Peter Riebli
Syngenta Crop Protection AG, CH 4002 Basel, Switzerland
(Received July 29, 2001; accepted December 25, 2001)
Phosphine oxide analogues of Triazole fungicides and protected Threo-
nine have been prepared. The enzymatic hydrolysis of phosphine oxide
di-acetates has been investigated.
Keywords: Analogues; phosphine oxide; threonine; triazole fungicides
Some 20 years ago, M. J. Gallagher1 reported the reaction of phosphinic
acid with ortho esters. Scientists at the Central Research Laboratories
of Ciba-Geigy seized upon this and developed a series of novel building
blocks for phosphinic acid synthesis. The synthesis and biological ac-
tivity of -aminopropyl phosphinic acids was subsequently reported.2
We have further shown3 that such building blocks (1) can be converted
into protected primary phosphine oxides (2). These stable, easily han-
dled intermediates can be elaborated into unsymmetrical secondary
and tertiary phosphine oxides (Scheme 1).
SCHEME 1
We then set out to prepare novel phosphine oxides which might dis-
play interesting biological activities either in the Crop Protection or
Address correspondence to R. G. Hall.
1557

1558
R. G. Hall and P. Riebli
pharmaceutical areas. On checking the literature, we found two ex-
amples where dimethyl phosphine oxides had been prepared. In one
case, an analogue of a 25-hydroxylation metabolite of Vitamin D3 was
prepared4 and tested for effects on calcium absorption. In a second
example, the experimental herbicide HOE 704 was found5 to inhibit
the enzyme Aceto-Lactate-Reducto-Isomerase (ALRI), involved in the
biosynthesis of Valine.
ANALOGUES OF TRIAZOLE FUNGICIDES
Our first targets were analogues of triazole fungicides. The synthe-
sis of the phenyl n-propyl phosphine oxide analogue is shown below
(Scheme 2). Alkylation of diethoxymethyl phenylphosphine oxide (3)3
with n-propyl bromide followed by acid deprotection gave the secondary
phosphine oxide (4). P H addition to formaldehyde and conversion of
the alcohol to the tosylate gave the tertiary phosphine oxide; displace-
ment of the tosyl group with triazole under basic conditions gave the
target molecule (5). The 2,4-dichloro analogue (6) was prepared in an
analogous way, using 2,4-dichlorophenyl magnesium halide and alky-
lation with n-butyl bromide.
SCHEME 2
Biological results were disappointing, however. Table I shows bio-
logical activity against four pathogens. The phenyl n-propyl phosphine

The Concept of P H Protection
1559
TABLE I Fungicidal Activity of Selected Triazole Derivatives
% Activity
Dose
(ppm)
Cercospora
arach.
Erysiphe
graminis
Puccinia
recondita
Venturia
inaequalis
Structure
200
0
0
0
0
200
200
n.t.
80
100
100
100
0
n.t.
90
60
20
50
0
100
50
0
0
90
0
200
60
100
100
100
100
100
100
100
100
100
100
100
100
20
oxide (5) is inactive at 200 ppm. Compound (6), a close analogue of the
market product Hexaconazol, shows good activity at 200 ppm, but at
lower rates the activity decreases.
ANALOGUES OF THREONINE
Threonine, an important amino acid, can provide, along with serine,
sites for phosphorylation by kinases. Inhibitors of certain kinases have
been studied as potential anti-cancer agents. The route chosen to syn-
thesize a phosphine oxide analogue (10) of Threonine is shown below
(Scheme 3).
Addition of the protected primary phosphine oxide (7) to the imine
derived from ethyl glyoxylate and benzylamine gave a tertiary phos-
phine oxide, which could be reductively deprotected to give the amino
phosphine oxide (8). Basic hydrolysis then gave the lithium salt (9)
as a mixture of diastereoisomers; it has been previously shown6 that

1560
R. G. Hall and P. Riebli
SCHEME 3
the diethoxy-ethyl group can be removed under very mild conditions
using timethylchlorosilane to regenerate the P H function; however,
deprotection of (9) led only to the formation of methyl phosphinic acid.
Deprotection at phosphorus was possible, however, when the nitrogen
was protected. Thus, protection of (8) as the benzyloxycarbonyl deriva-
tive gave (11) in good yield. Basic hydrolysis of the ester, followed by
mild deprotection at phosphorus, then gave the Z-Threonine analogue
(12) as a mixture of diastereoisomers (Scheme 4).
SCHEME 4
This finding has led us to speculate7 on a mechanism of P C bond
cleavage resulting from the zwitterionic nature of the fully deprotected
target molecule (10). Incorporation of (10) into peptides may serve to
stabilize this molecule.

The Concept of P H Protection
1561
ENZYMATIC HYDROLYSIS OF PHOSPHINE OXIDE
DI-ACETATES
The use of enzymes to prepare chiral molecules and intermediates is
well established. Ramos8 reported the use of lipases in organic solvents
to effect either hydrolysis of di-acetates or acetylation of diols to produce
chiral 1,3-propanediol monoacetates. We investigated whether this ap-
proach could be extended to phosphine oxides (13), and thus give an
entry into chiral phosphine oxides, and eventually phosphines. The syn-
thesis of the required starting materials is illustrated for the cyclohexyl
derivative (14) shown in Scheme 5.
SCHEME 5
Screening a number of enzymes, only in one case could we observe
any chiral differentiation, as determined by preparing Moscher deriva-
tives on the free alcohol function, as can be seen in Table II.
TABLE II Enzymatic Hydrolysis (Aqueous Media,
pH 7) of Phosphine Oxide Di-Acetates (13)
Lipase
R
Time
% ee
Candida cyl.-biocats
Lipase–sigma
Pseudomonas fluor.
Candida cyl.-biocats
Pseudomonas fluor.
C6H11
C6H11
C6H11
CH3
6 hr
24 hr
200 hr
24 hr
40
12
0
0
0
C6H5
200 hr

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R. G. Hall and P. Riebli
REFERENCES
[1] M. J. Gallagher and H. Honegger, Aust. J. Chem., 33, 287 (1980).
[2] J. G. Dingwall, J. Ehrenfreund, R. G. Hall, and J. Jack, Phosphorus and Sulfur, 30,
571 (1987).
[3] R. G. Hall and P. Riebli, Synlett, 1633 (1999).
[4] W. G. Dauben, R. R. Ollmann, A. S. Funhoff, and R. Neidlein, Tetrahedron Lett., 30,
677 (1989).
[5] A. Schulz, P. Spoenemann, H. Koecher, and F. Wengenmayer, FEBS Lett., 238, 375
(1988).
[6] E. K. Baylis, Tetrahedron Lett., 36, 9385 (1995).
[7] The zwitterionic form of (10), when drawn with phosphorus in the P-III form, can
readily promote a fragmentation, with loss of meta-phosphite:
[8] G. M. Ramos Tombo, H.-P. Schaer, X. Fernandez-Busquets, and O. Ghisalba, Tetra-
hedron Lett., 27, 5707 (1986).