Synthesis and antimalarial activity of chain substituted pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098

Article abstract of DOI:10.1016/j.bmc.2006.04.018

Fosmidomycin is a promising antimalarial drug candidate with a unique chemical structure and a novel mode of action. Chain substituted pivaloyloxymethyl ester derivatives of Fosmidomycin and its acetyl analogue FR900098 have been synthesized and their in vitro antimalarial activity versus the Chloroquine sensitive strain 3D7 of Plasmodium falciparum has been determined.

Full text of DOI:10.1016/j.bmc.2006.04.018

Bioorganic & Medicinal Chemistry 14 (2006) 5121–5135
Synthesis and antimalarial activity of chain substituted
pivaloyloxymethyl ester analogues of Fosmidomycin and FR900098
Thomas Kurz,a,* Katrin Schluter,a Uwe Kaula,a Ba¨rbel Bergmann,b
¨
Rolf D. Walterb and Detlef Geffkena
aInstitute of Pharmacy, University of Hamburg, Bundesstrasse 45, D-20146 Hamburg, Germany
bBernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, D-20359 Hamburg, Germany
Received 20 February 2006; revised 27 March 2006; accepted 4 April 2006
Available online 5 May 2006
Abstract—Fosmidomycin is a promising antimalarial drug candidate with a unique chemical structure and a novel mode of
action. Chain substituted pivaloyloxymethyl ester derivatives of Fosmidomycin and its acetyl analogue FR900098 have been
synthesized and their in vitro antimalarial activity versus the Chloroquine sensitive strain 3D7 of Plasmodium falciparum has
been determined.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
inhibitors of the DOXP/MEP pathway are expected to
be well tolerated (Fig. 1).
Malaria is a parasitic tropical infection disease which
affects approximately 40% of the world’s population.
According to estimations by the World Health Organi-
sation, 1.5–3 million people die of malaria every year,
most of them children. Almost all of the fatal cases
are caused by Plasmodium falciparum, the causative
agent of Malaria tropica. As the parasites’ resistance
to established antimalarial drugs steadily increases, the
need for the development of novel chemotherapeutic
principles is growing. New classes of compounds dis-
playing novel modes of action have to be developed.
Fosmidomycin (I) and its more active acetyl analogue
FR900098 (II) are potent, selective inhibitors of the 1-
desoxy-D-xylulose-5-phosphate (DOXP) reductoisomer-
ase, a key enzyme of the DOXP/MEP pathway of
isoprenoid biosynthesis.1,2 The DOXP/MEP pathway,
which leads to isopentenyl diphosphate (IPP), the com-
mon precursor of isoprenoids, is for instance present in
algae, higher plants, bacteria and the malaria parasite P.
falciparum, but not in humans and mammalians.3 As in
humans IPP is synthesized via the mevalonate pathway,
In previous studies, Fosmidomycin and FR900098
have been shown to inhibit the growth of multidrug-
resistant strains of P. falciparum in vitro. Further-
more, I and II have been proved to cure mice infected
with the rodent malaria parasite Plasmodium vinckei
O
P
OH
N
O
P
OH
N
RO
RO
RO
RO
H
O
O
Fosmidomycin (I):
R = H
FR900098 (II): R = H
Ia: R = CH2OOCC(CH3)3
IIa: R = CH2OOCC(CH3)3
O
O
OH
O
O
P
N
R1
O
R2 R3
O
O
O
R1: H, Me, R2: Me, CH2OH, Et, n-C3H7, i-C3H7, Ph,
substituted Ph, R3: H, Me
Keywords: Malaria; Targets; Fosmidomycin; Pivaloyloxymethyl ester
analogues of Fosmidomycin and FR900098.
*
Figure 1. Pivaloyloxymethyl ester analogues of Fosmidomycin and
FR900098.
Corresponding author. Tel.: +49 40 428383467; fax : +49 40
428386573; e-mail: kurz@chemie.uni-hamburg.de
0968-0896/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.04.018

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T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
by intraperitoneal or oral treatment.2 Clinical trials
conducted in Thailand and Gabon have shown that
Fosmidomycin is efficient in the treatment of acute,
uncomplicated Malaria tropica.4 However, due to their
low lipophilicity and the dissociation of the phosphon-
ic acid group at physiological pH values, I suffers
from low oral bioavailability with absorption rates
of approximately 30%.5 Furthermore, Fosmidomycin’s
short plasma half time of 2.5 h requires the repeated
administration of relatively high dosages.5 Recently,
Schlitzer described acyloxyalkyl and alkoxycarbonyl-
oxyethyl ester prodrugs of FR900098 with improved
in vivo antimalarial activity.6 As hydroxyurea and car-
boxylic acid analogues of I and II recently prepared in
our group are inactive, the phosphonic acid and
hydroxamic acid functionalities seem to be essential
for the antimalarial activity.7,8 So far only very little
research efforts have been dedicated to the structural
modifications of the carbon spacer between the
functional groups. Recently, we discovered that
a-phenylfosmidomycin displays high activity against
P. falciparum.9 In a publication, which is online avail-
able since January 2006, Van Calenbergh et al. con-
firmed the results of our patent.10 In order to get a
better understanding of the structure activity relation-
ships and to increase the lipophilicity, we investigated
the synthesis and antimalarial activity of chain substi-
tuted pivaloyloxymethyl ester analogues of Fosmido-
mycin and FR900098. Pivaloyloxymethyl esters of
phosphonic acids are known to be hydrolysed by
non-specific esterases to liberate the biologically active
phosphonic acid, formaldehyde and pivalic acid.11 In
contrast to the hygroscopic nature of phosphonohydr-
oxamic acids, the corresponding bis(pivaloyloxymeth-
yl) esters are stable and non-hygroscopic compounds.
O
P
O
P
H
i
O
EtO
EtO
N OBn
EtO
R2 R3
EtO
R2 R3
1: R2= H, Me, Et, n-C3H7, i-C3H7, Ph; R3= H, Me
2
ii
O
O
P
OBn
N
O
O
R1
O
P
OBn
iii
iv
EtO
N
R1
O
R2 R3
O
EtO
R2 R3
O
O
O
5: R1 = H; 6: R1 = Me
3: R1 = H; 4: R1 = Me
v
O
Reagents:
O
P
O
OH
N
i: BnONH2, NaCNBH3 / HCl
ii: HOOCH / Ac2O or Ac2O
iii: TMSBr, H2O
iv: ClCH2OOCC(CH3)3, Et3N
v: H2, Pd-C
O
O
R1
R2 R3
O
O
7: R1 = H; 8: R1 = Me
O
Scheme 1. Synthesis of chain substituted pivaloyloxymethyl ester
analogues of Fosmidomycin and FR900098.
O
P
O
P
EtO
EtO
Br
EtO
9
i
EtO
R2
R2
10
R2: substituted Ph
ii
O
O
P
EtO
OBn
N
H
iii
EtO
P
N OBn
EtO
Ot-Bu
EtO
R2
R2
11
O
12
O
2. Results and discussion
2.1. Synthesis
iv
O
P
O
OBn
N
O
O
R1
O
P
OBn
N
v
EtO
EtO
R1
R2
O
O
vi
R2
O
15: R1 = H;
16: R1 = CH3
The pivaloyloxymethyl ester prodrugs (Ia, IIa) of
Fosmidomycin (I) and FR900098 (II) were synthesized
according to the method of Schlitzer.6 Three different
synthetic routes have been developed for the synthesis
of the target compounds as shown in Schemes 1–3.
Starting materials 1 were prepared by reactions of
a,b-unsaturated aldehydes with triethyl phosphite
and ethanol followed by acidic hydrolysis of the dieth-
yl acetal intermediates according to a literature proce-
dure.12 Reactions of 1 with O-benzylhydroxylamine
and subsequent reduction of the resulting O-benzyloxi-
mes with sodium cyanoborohydride in presence of
hydrochloric acid afforded N,O-substituted hydroxyl-
amines 2 in excellent yields of 92–97%.7 Treatment
of 2 with acetic-formic anhydride or acetic anhydride
furnished hydroxamic acids 3 and 4 in 92–99% and
73–89% yield, respectively.8 Dealkylation of 3 and 4
by bromotrimethylsilane and subsequent alkylation
of the crude acids with chloromethyl pivalate led to
phosphonic acid esters 5 and 6.6,13 Cleavage of the
O-benzyl group was accomplished by catalytic hydro-
genation on Pd–C to provide compounds 7 and 8 in
O
13: R1 = H; 14: R1 = CH3
vii
O
Reagents:
O
P
OH
i: n-BuLi, BrCH2CH2Br
ii: NaH, BnONHBoc
iii: TFA / DCM
iv: HOOCH / Ac2O, or Ac2O
v: TMSBr, H2O
O
O
N
R1
R2
O
O
O
O
vi: ClCH2OOCC(CH3)3, Et3N
vii: H2, Pd-C, MeOH
17: R1 = H; 18: R1 = CH3
Scheme 2. Synthesis of aryl substituted pivaloyloxymethyl ester
analogues of Fosmidomycin and FR900098.
high yields (Scheme 1). Precursors 9 were prepared
by reactions of triethyl phosphite with substituted ben-
zyl chlorides and bromides. Alkylation of 9 with 1,2-
dibromoethane led to compounds 10, which were
reacted with N-Boc-O-Bn-hydroxylamine in presence
of sodium hydride. Cleavage of the Boc-protecting

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5123
pivalate led to pivaloyloxymethyl esters 15 and 16. Final-
ly, catalytic hydrogenation on Pd–C furnished com-
pounds 17 and 18 (Scheme 2). Alkylation of dioxolane
19 with benzylchloromethyl ether provided compound
20.14 Acidic hydrolysis of 20, oximation and subsequent
reduction with sodium cyanoborohydride in presence of
hydrochloric acid furnished N,O-substituted hydroxyl-
amine 21 in a high yield of 89%.7,12 Conversion of 21 into
the target compounds 26 and 27 was accomplished as de-
scribed for compounds 7, 8, 17 and 18 (Scheme 3). The
hydroxymethyl group could contribute to improve the
activity of compounds 26 and 27 by additional hydrogen
bonding.
O
P
EtO
O
P
EtO
O
EtO
O
EtO
i
O
O
OBn
20
19
ii
O
P
OBn
O
P
H
N
iii
EtO
EtO
N
R1
EtO
OBn
EtO
O
OBn
OBn
21
22: R1 = H; 23: R1 = CH3
2.2. Biological activity
iv, v
O
The in vitro antimalarial activity of analogues 7, 8, 17,
18, 26 and 27 was evaluated by 8-[3H]hypoxanthine
incorporation assay according to the method of Desja-
rdins using the Chloroquine-sensitive strain 3D7 of
P. falciparum.15 IC50 values as well as the inhibition of
parasite growth at 25 lM and 0.5 lM have been deter-
mined. The antimalarial activity was compared to the
pivaloyloxymethyl esters (Ia, IIa) of the leads Fosmido-
mycin (I) and FR900098 (II) (Tables 1–3).
O
OBn
N
O
O
P
O
R1
O
OBn
O
vi
O
24: R1 = H; 25: R1 = CH3
O
O
OH
N
O
O
P
R1
Reagents:
i: n-BuLi, BnOCH2Cl
O
O
OH
ii: HCl, BnONH2, NaCNBH3
iii: HOOCH / Ac2O or Ac2O
iv: TMSBr, THF, H2O;
v: ClCH2OOCC(CH3)3, Et3N
vi: H2, Pd-C, MeOH
O
Table 1. IC50 values of pivaloyloxymethyl ester analogues of Fosm-
idomycin and FR-900098 against P. falciparum
O
26: R1 = H; 27: R1 = CH3
Compound
Activity against P. falciparum
IC50 (lM)
n
SEMb
a
Scheme 3. Synthesis of hydroxymethyl substituted pivaloyloxymethyl
ester analogues of Fosmidomycin and FR900098.
7a
7b
8a
8b
26
27
17a
Ia
0.7
0.6
0.7
0.7
6.7
3.7
0.3
2.1
0.4
3
3
3
3
3
3
3
6
6
0.2
0.2
0.2
0.2
0.9
0.4
0.1
1.1
0.1
group in 11 with TFA in dichloromethane and subse-
quent formylation or acetylation afforded hydroxamic
acids 13 and14.8
IIa
As described above, cleavage of the phosphonic ester
functionality by bromotrimethylsilane followed by alkyl-
ation of the crude phosphonic acids with chloromethyl
a Mean values of 3 or 6 independent determinations.
b Standard errors of the means.
Table 2. Inhibition of P. falciparum growth (%) at 25 lM
Compound
R1
R2
R3
Inhibition of P. falciparum growth
Inhib.a (%)
n
SEMb
7a
7b
7c
7d
7e
7f
H
CH3
Ph
H
97
98
57
55
29
12
97
97
39
32
27
23
3
3
5
5
5
5
3
3
5
5
5
5
2
2
5
2
2
2
2
2
5
2
2
2
H
H
H
CH2CH3
CH(CH3)2
CH2CH2CH3
CH3
H
H
H
H
H
H
CH3
H
8a
8b
8c
8d
8e
8f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
H
CH2CH3
CH(CH3)2
CH2CH2CH3
CH3
H
H
H
CH3
a Mean values of 3 or 5 independent determinations.
b Standard errors of the means.

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T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
Table 3. Inhibition of P. falciparum growth (%) at 0.5 lM
a Heraeus CHN-O-Rapid instrument. IR spectra were
recorded on a Shimadzu FT-IR 8300. 1H NMR
(400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Bruker AMX 400 spectrometer using
tetramethylsilane as internal standard and DMSO-d6
or CDCl3 as solvents. Mass spectra were recorded
on a Micromass VG 70-250S mass spectrometer
(HRFAB), a Finnigan MAT 311 A mass spectrometer
(EI) or a Varian MS 1200 L mass spectrometer
(ESI).
Compound
R1
R2
Inhib.a (%)
n
SEMb
17a
18a
17b
17c
7b
H
3,4-F–Ph
3,4-F–Ph
2-F–Ph
2,6-CH3–Ph
Ph
43.7
37.9
31.7
2.0
4
4
4
4
4
2.2
3.6
3.9
2.7
0.9
CH3
H
H
H
39
a Mean values of 4 independent determinations.
b Standard errors of the means.
2.3. Structure–activity relationships
4.2. Bispivaloyloxymethyl esters of Fosmidomycin and
FR9000986a
In contrast to the higher activity of FR900098 com-
pared to Fosmidomycin, most of the tested formyl
derivatives were significantly more active than their
acetyl analogues.2,6,16 A considerable loss of antima-
larial activity was observed with the ethyl, propyl, iso-
propyl and dimethyl substituted pivaloyloxymethyl
ester anlogues (7c–f, 8c–f). In contrast, the methyl
and phenyl substituted derivatives (7a, b, 8a, b) were
approximately as active as the FR900098 prodrug
IIa, which exhibits an IC50 value of 0.4 lM. These
promising results encouraged us to investigate the
activity of the hydroxymethyl substituted derivatives
26 and 27 as well as the activity of substituted phenyl
analogues (17a–c, 18a). However, the replacement of
methyl by hydroxymethyl resulted in a significant
reduction of activity. In contrast, the substituted phen-
yl derivatives (17a, b, 18a) are approximately as active
as 7b, but slightly less plasmodicidal as IIa, whereas
electron-donating substituents lead to a significant
reduction of antiplasmodial activity (17c).
4.3. General procedure for the preparation of (3-benzyl-
oxyamino-propyl)-phosphonic acid diethyl esters 2a–f
A solution of the respective aldehyde 1 (30 mmol) in
MeOH (20 mL) was treated with O-benzylhydroxyl-
amine (30 mmol) and stirred for 1 h. After addition
of further 430 mL of MeOH, the mixture was treated
portionwise with NaBH3CN (90 mmol). Over a period
of 30 min, HCl (37%, 30 mL) was added dropwise un-
der ice cooling. The mixture was allowed to warm up
to room temperature, followed by treatment with
additional 20 mmol of NaBH3CN. After an overall
time of 2 h, the solution was concentrated and aque-
ous KOH (10%) was added under ice cooling until an
alkaline reaction was observed. The aqueous solution
was extracted 3 times with CH2Cl2 (50 mL). The
organic layers were combined, dried with MgSO4
and evaporated. The residue was purified by column
chromatography on silica gel using EtOAc/MeOH
(95:5) as an eluent to give (3-benzyloxyamino-pro-
pyl)-phosphonic acid diethyl esters 2 as colourless
oils.
3. Conclusion
The introduction of substituents into the a-position to the
phosphonic acid moiety of Fosmidomycin and FR900098
as well as masking the phosphonic acid functionality as
pivaloyloxymethyl esters led to a series of promising ana-
logues with comparable in vitro antimalarial activity.
This is noteworthy since former attempts to introduce
substituents in b- and c-position had resulted in almost
inactive compounds.14 To the best of our knowledge,
the 3,4-difluorophenyl substituted analogue of Fosmido-
mycin (17a) is one of the most active analogues reported
so far. Furthermore, it should be mentioned that all deriv-
atives were tested as racemates. Therefore, a resolution of
the racemic compounds should lead to an additional
improvement of the antimalarial activity. As the pivaloyl-
oxymethyl ester prodrugs are transformed into the corre-
sponding active phosphonic acids by non specific
esterases, no animal experiments were necessary so
far.11 Further investigations regarding the bioavailability
of the most active compounds are intended.
4.3.1. (3-Benzyloxyamino-1-methyl-propyl)-phosphonic
acid diethyl ester (2a). Yield: 93%. H NMR (DMSO-
1
d6),
d (ppm): 7.36–7.25 (m, 5H), 6.64 (t, 1H,
J = 5.9 Hz), 4.59 (s, 2H), 4.03–3.93 (m, 4H), 2.96–2.88
(m, 1H), 2.84–2.76 (m, 1H), 2.00–1.81 (m, 2H), 1.44–
1.32 (m, 1H), 1.22 (t, 6H, J = 7.1 Hz), 1.03 (dd, 3H,
3JH-P = 18.5 Hz, JH-H = 7.1 Hz). 13C NMR (DMSO-
d6), d (ppm): 138.9, 128.5, 128.4, 127.7, 75.5, 61.3 (d,
3
2JC-P = 6.6 Hz), 49.1 (d, JC-P = 13.2 Hz), 27.8 (d,
1
2JC-P = 3.6 Hz), 27.8 (d, JC-P = 140.4 Hz), 16.7 (d,
2
3JC-P = 5.1 Hz), 13.5 (d, JC-P = 5.1 Hz). IR: 3242 cmÀ1
(N–H), 1233 cmÀ1 (P@O). Anal. Calcd for
(C15H26NO4P): C, 57.13; H, 8.31; N, 4.44. Found: C,
56.87; H, 8.14; N, 4.45. HRFAB-MS C15H26NO4P
[M+H]+: calculated 316.1677; found 316.1680.
4.3.2. (3-Benzyloxyamino-1-phenyl-propyl)-phosphonic
acid diethyl ester (2b). Yield: 92%. H NMR (DMSO-
1
d6), d (ppm): 7.34–7.22 (m, 10H), 6.63 (t, 1H,
J = 5.3 Hz), 4.57 (dd, 2H, JAB = 11.8 Hz), 4.01–3.91
(m, 2H), 3.86–3.76 (m, 1H), 3.76–3.66 (m, 1H), 3.27
(dt, 1H, JH-P = 3.8 Hz, JH-H = 11.1 Hz), 2.70–2.62 (m,
1H), 2.60–2.52 (m, 1H), 2.25–2.14 (m, 1H), 2.02–1.91
(m, 1H), 1.19 (t, 3H, J = 7.1 Hz), 1.01 (t, 3H,
J = 7.1 Hz). 13C NMR (DMSO-d6), d (ppm): 138.7,
4. Materials and methods
4.1. Experimental
Melting points were determined on a Mettler FP 62
apparatus. Elemental analyses were carried out with
2
136.7 (d, JC-P = 6.6 Hz), 128.6, 128.6, 128.5, 128.3,

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5125
2
127.8, 127.2, 127.2, 75.6, 62.0 (d, JC-P = 7.1 Hz), 61.6
2
(ppm): 138.9, 128.4, 128.4, 127.7, 75.4, 61.6 (d, JC-P =
2
(d, JC-P = 6.6 Hz), 49.3 (d, JC-P = 15.8 Hz), 40.9 (d, JC-
3
1
3
7.1 Hz), 47.1 (d, JC-P = 8.1 Hz), 34.5, 33.2 (d,
2
3
2
P = 137.3 Hz), 27.6 (d, JC-P = 3.1 Hz), 16.6 (d, JC-P
=
1JC-P = 141.9 Hz), 22.4 (d, JC-P = 2.5 Hz), 16.8 (d,
5.6 Hz), 16.4 (d, JC-P = 5.6 Hz). IR: 3243 cmÀ1 (N–H),
1242 cmÀ1 (P@O). Anal. Calcd for C20H28NO4P: C,
63.65; H, 7.48; N, 3.71. Found: C, 63.15; H, 7.46; N,
3.56. HRFAB-MS C20H28NO4P [M+H]+: calculated
378.1834; found 378.1819.
3JC-P = 5.6 Hz). IR: 3246 cmÀ1 (N–H), 1232 cmÀ1
(P@O). HRFAB-MS C16H28NO4P [M+H]+: calculated
330.1834; found 330.1832.
3
4.4. General procedure for the preparation of [3-(N-
Benzyloxy-N-tert-butoxycarbonylamino)-propyl]-phos-
phonic acid diethyl esters 11a–c
4.3.3.
acid diethyl ester (2c). Yield: 97%. H NMR (DMSO-
d6), (ppm): 7.36–7.25 (m, 5H), 6.64 (t, 1H,
(3-Benzyloxyamino-1-ethyl-propyl)-phosphonic
1
d
A solution of 9 (40 mmol) in dry toluene (50 mL) was
cooled down to À78 ꢁC, treated with 40 mmol of n-
butyllithium (2.7 M solution in heptane) and stirred
for 1 h. 1,2-Dibromethane (160 mmol) was added in
one portion and the mixture was allowed to warm
up to room temperature. After stirring overnight,
water (100 mL) was added and the product extracted
with EtOAc (2· 50 mL). The organic layer was dried
over Na2SO4, evaporated and the resulting residue
(10) was purified by column chromatography on silica
gel with EtOAc as eluent. For the alkylation step,
NaH (20 mmol) was added to a solution of O-Bn-N-
Boc-hydroxylamine in anhydrous THF (20 mL) at
room temperature. After 30 min, a solution of the
appropriate alkylating agent 10 (10 mmol) in anhy-
drous THF (5 mL) was added. The reaction mixture
was refluxed for 8 h and cooled down to room temper-
ature. EtOAc (100 mL) was added and the organic
layer was washed twice with water (30 mL), dried over
Na2SO4 and evaporated. The resulting oil was purified
by column chromatography (EtOAc/n-hexane, 80:20)
on silica gel to give compounds 11 as colourless
oils.
J = 5.85 Hz), 4.60 (s, 2H), 4.02–3.93 (m, 4H), 2.93–
2.80 (m, 2H), 1.84–1.71 (m, 2H), 1.66–1.51 (m, 2H),
1.49–1.37 (m, 1H), 1.21 (t, 3H, J = 7.1 Hz), 0.93 (t,
3H, J = 7.4 Hz). 13C NMR (DMSO-d6), d (ppm):
2
138.8, 128.4, 128.3, 127.7, 75.5, 61.2 (d, JC-P
=
2
3
6.6 Hz), 61.1 (d, JC-P = 6.6 Hz), 49.5 (d, JC-2P = 9.7
1
Hz), 34.3 (d, JC-P = 138.4 Hz), 25.4 (d, JC-P
=
=
2
3
3.1 Hz), 21.3 (d, JC-P = 3.6 Hz), 16.7 (d, JC-P
5.6 Hz), 12.0 (d, JC-P = 8.7 Hz). IR: 3243 cmÀ1 (N–H),
1238 cmÀ1 (P@O). HRFAB-MS C16H28NO4P [M+H]+:
calculated 330.1834; found 330.1834.
3
4.3.4.
[1-(2-Benzyloxyamino-ethyl)-2-methyl-propyl]-
phosphonic acid diethyl ester (2d). Yield: 93%. 1H
NMR (DMSO-d6), d (ppm): 7.36–7.25 (m, 5H), 6.63
(t, 1H, J = 5.85 Hz), 4.59 (s, 2H), 4.00–3.92 (m, 4H),
2.96–2.88 (m, 1H), 2.86–2.78 (m, 1H), 2.11–1.97 (m,
1H), 1.81–1.53 (m, 3H), 1.21 (t, 6H, J = 7.1 Hz), 0.94
(t, 6H, J = 6.6 Hz). 13C NMR (DMSO-d6), d (ppm):
2
138.8, 128.4, 128.4, 127.7, 75.5, 61.1 (d, JC-P
=
2
3
6.6 Hz), 60.9 (d, JC-P = 6.6 Hz), 50.6 (d, JC-2P = 6.1
1
Hz), 39.1 (d, JC-P = 134.8 Hz), 27.3 (d, JC-P
=
2.5 Hz), 22.6 (d, JC-P = 3.1 Hz), 21.3 (d, JC-P = 13.2
2
3
3
Hz), 19.5 (d, JC-P = 2.5 Hz), 16.7 (d, JC-P = 5.6 Hz),
3
4.4.1. [3-(N-Benzyloxy-N-tert-butoxycarbonylamino)-1-
(3,4-difluorophenyl)-propyl]-phosphonic acid diethyl ester
(11a). Yield: 76%. 1H NMR (DMSO-d6), d (ppm):
7.46–7.27 (m, 7H), 7.17–7.09 (m, 1H), 4.74 (s, 2H),
4.03–3.92 (m, 2H), 3.89–3.74 (m, 2H), 3.35–3.22 (m,
2H), 3.18–3.09 (m, 1H), 2.28–2.16 (m, 1H), 2.03–1.19
(m, 1H), 1.38 (s, 9H), 1.18 (t, 3H, J = 7.1 Hz), 1.05 (t,
3H, J = 7.1 Hz). 13C NMR (CDCl3), d (ppm): 156.3,
16.7 (d, JC-P = 5.6 Hz). IR: 3242 cmÀ1 (N–H),
3
1234 cmÀ1 (P@O). Anal. Calcd for C16H26NO4P: C,
59.46; H, 8.81; N, 4.08. Found: C, 58.99; H, 8.84; N,
4.46. HRFAB-MS C17H30NO4P [M+H]+: calculated
344.1990; found 344.2017.
4.3.5.
acid diethyl ester (2e). Yield: 94%. H NMR (DMSO-
d6), (ppm): 7.36–7.25 (m, 5H), 6.63 (t, 2H,
[1-(2-Benzyloxyamino-ethyl)-butyl]-phosphonic
1
1
1
152.9 (dd, JC-F = 246.8 Hz), 150.0 (dd, JC-F
=
d
246.9 Hz), 135.7, 132.9, 129.8, 129.0, 128.9, 125.9,
118.6 (dd, JC-F = 18.0 Hz, JC-F = 6.0 Hz), 118.7 (dd,
2
3
J = 5.85 Hz), 4.59 (s, 2H), 4.02–3.92 (m, 4H), 2.93–
2.80 (m, 2H), 1.89–1.70 (m, 2H), 1.61–1.48 (m, 2H),
1.43–1.27 (m, 3H), 1.21 (t, 6H, J = 7.1 Hz), 0.85 (t,
3
2JC-F = 17.0 Hz, JC-F = 2.6 Hz), 82.0, 77.5, 63.1 (d,
2
3
2JC-P = 7.0 Hz), 62.5 (d, JC-P = 7.4 Hz), 47.9 (d, JC-P
=
=
3H, J = 7.1 Hz). 13C NMR (DMSO-d6), d (ppm):
17.0 Hz), 41.5 (d, 1JC-P = 140.3 Hz), 28.7, 27.6 (d, 2JC-P
2
138.8, 128.4, 128.4, 127.7, 75.5, 61.2 (d, JC-P
=
=
=
=
2.8 Hz), 16.8 (d, 3JC-P = 6.0 Hz), 16.7 (d, 3JC-P = 5.8 Hz).
IR: 1701 cmÀ1 (C@O), 1246 cmÀ1 (P@O). Anal. Calcd
for C25H34F2NO6P: C, 58.47; H, 6.67; N, 2.73. Found: C,
58.69; H, 6.83; N, 2.49.
3
1
6.6 Hz), 49.5 (d, JC-P = 9.2 Hz), 32.8 (d, JC-P
2
137.8 Hz), 30.6 (d, JC-P = 3.6 Hz), 26.0 (d, JC-P
2
3
3
3.1 Hz), 20.4 (d, JC-P = 8.6 Hz), 16.7 (d, JC-P
5.1 Hz), 14.4. IR: 3244 cmÀ1 (N–H), 1235 cmÀ1
(P@O). Anal. Calcd for C17H30NO4P: C, 59.46; H,
8.81; N, 4.08. Found: C, 59.38; H, 8.57; N, 4.24.
4.4.2. 3-(N-Benzyloxy-N-tert-butoxycarbonylamino)-1-
(2-fluorophenyl)-propyl]-phosphonic acid diethyl ester
(11b). Yield: 74%. 1H NMR (DMSO-d6), d (ppm):
7.45–7.39 (m, 1H), 7.38–7.30 (m, 6H), 7.25–7.16 (m,
2H), 4.75 (dd, 2H, JAB = 11.7 Hz), 4.02–3.92 (m, 2H),
3.90–3.72 (m, 2H), 3.48 (ddd, 1H, JH-P = 23.1 Hz,
JAB = 11.5 Hz), 3.33–3.27 (m, 1H), 3.24–3.17 (m, 1H),
2.35–2.25 (m, 1H), 2.12–2.01 (m, 1H), 1.36 (s, 9H),
1.18 (t, 3H, J = 7.1 Hz), 1.03 (t, 3H, J = 7.1 Hz). 13C
4.3.6.
(3-Benzyloxyamino-1,1-dimethyl-propyl)-phos-
phonic acid diethyl ester (2f). Yield: 94%. 1H NMR
(DMSO-d6), d (ppm): 7.35–7.25 (m, 5H), 6.57 (t, 1H,
J = 6.4 Hz), 4.59 (s, 2H), 4.03–3.96 (m, 4H), 2.89–2.84
(m, 2H), 1.65–1.57 (m, 2H), 1.22 (t, 6H, J = 7.1 Hz),
1.05 (d, 6H, JH-P = 16.5 Hz). 13C NMR (DMSO-d6), d
3

5126
T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
1
NMR (CDCl3), d (ppm): 159.1 (dd, JC-F = 246.3 Hz,
4.5.2.
[3-Benzyloxyamino-1-(2-fluorophenyl)-propyl]-
3JC-P = 8.3 Hz), 154.3, 133.5, 127.6, 126.7 (dd, JC-P
7.9 Hz, JC-F = 3.5 Hz), 122.3, 120.7 (dd, JC-P = 14.5
=
phosphonic acid diethyl ester (12b). Yield: 70%. 1H
NMR (DMSO-d6), d (ppm): 7.47–7.39 (m, 1H), 7.36–
7.13 (m, 8H), 6.65 (t, 1H, J = 4.8 Hz), 4.55 (dd, 2H,
JAB = 15.5 Hz), 4.03–3.93 (m, 2H), 3.89–3.72 (m, 2H),
3.62 (ddd, 1H, JH-P = 22.1 Hz, JAB = 10.9 Hz), 2.72–
2.63 (m, 1H), 2.60–2.52 (m, 1H), 2.26–2.16 (m, 1H),
2.06–1.94 (m, 1H), 1.20 (t, 3H, J = 7.1 Hz), 1.04 (t,
3H, J = 7.1 Hz). 13C NMR (CDCl3), d (ppm): 161.0
3
3
2
3
2
4
Hz, JC-F = 6.6 Hz), 113.3 (dd, JC-F = 22.9 Hz, JC-P
=
=
=
2
2.5 Hz), 79.4, 60.6 (d, JC-P = 7.2 Hz), 60.1 (d, JC-P
2
3
7.0 Hz), 45.9 (d, JC-P = 17.8 Hz), 30.9 (d, JC-P
1
3
2
141.9 Hz, JC-3F = 2.4 Hz), 27.7, 24.7 (d, JC-P = 2.2
3
Hz), 14.3 (d, JC-P = 6.0 Hz), 13.6 (d, JC-P = 5.9 Hz).
IR: 1712 cmÀ1 (C@O), 1242 cmÀ1 (P@O). Anal. Calcd
for C25H35FNO6P: C, 60.60; N, 2.83; H, 7.12. Found:
C, 60.88; N, 2.90; H, 7.32.
1
3
(dd, JC-F = 245.0 Hz, JC-P = 8.2 Hz), 137.8, 129.8,
128.6 (dd, JC-P = 8.5 Hz, JC-F = 3.2 Hz), 128.4, 127.8,
3
3
2
124.4, 123.2 (dd, JC-F = 14.8 Hz, JC-F = 6.7 Hz),
2
2
115.3 (d, JC-F = 22.8 Hz), 76.4, 62.5 (d, JC-P
2
4.4.3. [3-(N-Benzyloxy-N-tert-butoxycarbonylamino)-1-
(2,6-dimethylphenyl)-propyl]-phosphonic acid diethyl
ester (11c). Yield: 78%. 1H NMR (DMSO-d6), d (ppm):
7.39–7.29 (m, 5H), 7.16–7.11 (m, 1H), 7.09–7.04 (m,
1H), 7.00–6.94 (m, 1H), 4.74 (s, 2H), 3.99–3.89 (m,
2H), 3.84–3.74 (m, 1H), 3.71–3.61 (m, 1H), 3.33–3.23
(m, 2H), 3.19–3.12 (m, 1H), 2.34–2.23 (m, 4H), 2.20
(s, 3H), 2.13–2.00 (m, 1H), 1.37 (s, 9H), 1.18 (t, 3H,
J = 7.1 Hz), 1.00 (t, 3H, J = 7.1 Hz). 13C NMR
=
=
=
=
2
6.7 Hz), 62.0 (d, JC-P = 7.3 Hz), 49.7 (d, JC-P
3
1
15.5 Hz), 32.9 (d, JC-P = 141.0 Hz), 27.2 (d, JC-P
2
3
3
2.6 Hz), 16.4 (d, JC-P = 6.1 Hz), 16.2 (d, JC-P
5.6 Hz). IR: 3248 cmÀ1 (N–H), 1232 cmÀ1 (P@O). Anal.
Calcd for C20H27FNO4P: C, 60.75; H, 6.88; N, 3.54.
Found: C, 60.23; H, 6.59; N, 3.72.
4.5.3. [3-Benzyloxyamino-1-(2,6-dimethylphenyl)-propyl]-
phosphonic acid diethyl ester (12c). Yield: 75%. Mp:
53.3 ꢁC. H NMR (DMSO-d6), d (ppm): 7.35–7.24 (m,
5H), 7.17–7.13 (m, 1H), 7.06–7.02 (m, 1H), 7.97–7.91
(m, 1H), 6.63 (t, 1H, J = 4.8 Hz), 4.56 (dd, 2H,
JAB = 16.8 Hz), 4.01–3.91 (m, 2H), 3.84–3.74 (m, 1H),
3.70–3.60 (m, 1H), 3.49 (ddd, 1H, JHÀP = 22.9 Hz,
JAB = 10.9 Hz), 2.71–2.61 (m, 1H), 2.50–2.43 (m, 1H),
2.28–2.15 (m, 7H), 2.03–1.92 (m, 1H), 1.20 (t, 3H,
J = 7.1 Hz), 1.00 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3),
2
(CDCl3), d (ppm): 156.8, 135.9 (d, JC-P = 3.3 Hz),
3
135.8, 134.8 (d, JC-P = 8.1 Hz), 133.6 (d, JC-P
3
1
=
7.3 Hz), 130.7, 129.7, 128.9, 128.8, 128.2, 128.1, 81.8,
2
77.4, 63.1 (d, JC-P = 7.4 Hz), 62.2 (d, JC-P = 7.4 Hz),
2
3
1
48.2 (d, JC-P = 17.9 Hz), 36.9 (d, JC-P = 138.8 Hz),
3
28.6, 28.4, 27.7, 21.6, 20.1, 16.8 (d, JC-P = 6.0 Hz),
16.6 (d, JC-P = 6.0 Hz). IR: 1710 cmÀ1 (C@O),
3
1246 cmÀ1 (P@O). Anal. Calcd for C27H40NO6P: C,
64.14; H, 7.97; N, 2.77. Found: C, 64.22; H, 8.07; N,
2.51.
2
d (ppm): 138.2, 135.9 (d, JC-P = 3.2 Hz), 134.7 (d,
3JC-P = 8.2 Hz), 134.2 (d, 3JC-P = 6.5 Hz), 130.5,
128.9, 128.8, 128.7, 128.2, 128.1, 128.0, 76.8, 62.9
4.5. General procedure for the preparation of (3-benzyl-
oxyamino-propyl)-phosphonic acid diethyl esters 12a–c
2
(d, JC-P = 6.9 Hz), 62.1 (d, JC-P = 7.4 Hz), 50.0 (d,
2
3JC-P = 16.0 Hz), 50.5 (d, 3JC-P = 16.0 Hz), 36.9 (d, 1JC-P
138.8 Hz), 28.3, 21.5, 20.1, 16.8 (d, JC-P = 6.0 Hz),
=
3
A mixture of CH2Cl2 (20 mL) and trifluoro acetic acid
(20 mL) was added to 11 (10 mmol) and the mixture
was stirred at room temperature for 8 h. The solvent
was removed under reduced pressure, the resulting resi-
due was treated with a saturated NaHCO3-solution
(5 mL) and extracted with EtOAc (2· 50 mL). After dry-
ing over Na2SO4, the organic layer was evaporated and
the crude product was purified by column chromatogra-
phy on silica gel with EtOAc to give 12 as colourless oils
or solids, respectively.
16.6 (d, JC-P = 5.7 Hz). IR: 3263 cmÀ1 (N–H),
3
1230 cmÀ1 (P@O). Anal. Calcd for C22H32NO4P: C,
65.17; H, 7.95; N, 3.45. Found: C, 64.92; H, 7.41; N,
3.45.
4.5.4.
(3-Benzyloxyamino-1-benzyloxymethyl-propyl)-
phosphonic acid diethyl ester (21). Dioxolane 19
(50 mmol) was dissolved in dry toluene (50 mL),
cooled down to À78 ꢁC and treated with 50 mmol of
n-butyllithium (2.5 M solution in toluene). After stir-
ring for 1 h under nitrogen atmosphere, benzylchlor-
methylether (50 mmol) was added in one portion.
The reaction mixture was allowed to warm up to
room temperature and stirred overnight. A solution
of NH4Cl (10%, 50 mL) was added and the product
was extracted with diethyl ether. The organic layer
was dried over MgSO4, the solvent was removed un-
der reduced pressure and the remaining oil was puri-
fied by column chromatography on silica gel using
EtOAc and n-hexane (9:1) as eluents. The resulting
dioxolane 20 was reacted with 2 M HCl (100 mL)
and acetone (10 mL) at 50 ꢁC for 3 h. Acetone was re-
moved and the aqueous layer was extracted with
dichloromethane (3· 30 mL). Afterwards, the organic
layer was dried over MgSO4 and the solvent was
evaporated. Without further purification, the resulting
crude aldehyde was converted into the corresponding
4.5.1. [3-Benzyloxyamino-1-(3,4-difluorophenyl)-propyl]-
phosphonic acid diethyl ester (12a). Yield: 76%. 1H
NMR (CDCl3), d (ppm): 7.42–6.96 (m, 8H), 4.69 (dd,
2H, JAB = 2.63 Hz), 4.15–3.75 (m, 4H), 3.30–3.13 (m,
1H), 2.97–2.84 (m, 1H), 2.79–2.64 (m, 1H), 2.46–2.27
(m, 1H), 2.14–1.97 (m, 1H), 1.29 (t, 3H, J = 7.1 Hz),
1.16 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3),
d
(ppm): 150.0 (dd, JC-F = 245.9 Hz), 147.1 (dd,
1
1JC-F = 249.2 Hz), 137.9, 133.4, 128.9, 128.8, 125.8,
118.6 (dd, JC-F = 17.8 Hz, JC-F = 6.4 Hz), 118.4
2
3
2
(dd, JC-F = 17.4 Hz, JC-F = 2.7 Hz), 76.9, 63.1 (d,
3
2JC-P = 6.8 Hz), 62.5 (d, JC-P = 7.2 Hz), 49.6 (d, JC-P
=
2
3
15.3 Hz), 41.5 (d, 1JC-P = 140.5 Hz), 28.0 (d,
2JC-P = 2.7 Hz), 16.8 (d, JC-P = 5.5 Hz), 16.7 (d,
3
3JC-P = 5.5 Hz). IR: 3242 cmÀ1 (N–H), 1242 cmÀ1
(P@O). Anal. Calcd for C20H26F2NO4P: C, 58.11; H,
6.34; N, 3.39. Found: C, 58.12; H, 6.25; N, 3.46.

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5127
hydroxylamine 21 as described for compounds 2.
Yield: 45%. 1H NMR (CDCl3), d (ppm): 7.35–7.47
(m, 10H), 4.81 (s, 2H), 4.58 (s, 2H), 4.21–4.10 (m,
4H), 3.88–3.76 (m, 1H), 3.74–3.63 (m, 1H), 3.28–3.09
(m, 2H), 2.41–2.26 (m, 1H), 2.21–1.93 (m, 2H), 1.32
62.21; H, 6.96; N, 3.45. Found: C, 61.76; H, 7.08; N,
3.67. HRFAB-MS C20H28NO4P [M+H]+: calculated
406.1783; found 406.1769.
4.6.3. [3-(Benzyloxy-formyl-amino)-1-ethyl-propyl]-phos-
phonic acid diethyl ester (3c). Yield: 99%. 1H NMR
(DMSO-d6), d (ppm): 8.25 + 8.01 (2s, 1H), 7.45–7.36
(m, 5H), 4.91 (s, 2H), 4.03–3.94 (m, 4H), 3.75–3.52 (m,
2H), 1.93–1.82 (m, 1H), 1.74–1.56 (m, 3H), 1.52–1.39
(m, 1H), 1.21 (t, 6H, J = 7.1 Hz), 0.93 (t, 3H,
J = 7.4 Hz). 13C NMR (DMSO-d6), d (ppm): 163.0,
(t, 6H, J = 7.1 Hz). 13C NMR (CDCl3) d (ppm):
2
138.4, 128.8, 128.2, 128.1, 76.6, 73.6, 62.2 (d, JC-P
=
=
=
2
6.4 Hz), 62.1 (d, JC-P = 6.4 Hz), 50.5 (d, JC-P
3
1
2
10.1 Hz), 35.9 (d, JC-P = 138.2 Hz), 25.1 (d, JC-P
3
3.4 Hz), 16.8 (d, JC-P = 6.0 Hz), IR: 3249 cmÀ1
(N–H), 1232 cmÀ1 (P@O). Anal. Calcd for
C22H32NO5P: C, 62.69; H, 7.65; N, 3.32. Found: C,
62.29; H, 7.75; N, 3.20.
2
129.9, 129.1, 128.8, 77.1, 61.4 (d, JC-P = 6.6 Hz), 61.3
2
(d, JC-P = 6.6 Hz), 40.5, 34.0 (d, JC-P = 138.9 Hz),
1
2
24.9 (d, JC-P = 6.1 Hz), 24.8 (d, JC-P = 6.1 Hz), 20.9,
2
3
3
4.6. General procedure for the preparation of [3-(benzyl-
oxy-formyl-amino)-propyl]-phosphonic acid diethyl esters
3a–f, 13a–c and 22
16.7 (d, JC-P = 5.1 Hz), 11.9 (d, JC-P = 8.6 Hz). IR:
1679 cmÀ1 (C@O), 1239 cmÀ1 (P@O). HRFAB-MS
C17H28NO5P [M+H]+: calculated 358.1783; found
358.1791.
Formic acid (500 mmol) was treated with acetic acid
anhydride (50 mmol) and stirred under exclusion of
humidity. After 20 min, the solution was cooled to
0 ꢁC, and the respective hydroxylamine 2, 12, 21
(10 mmol), dissolved in dry THF (20 mL), was added
dropwise. After 10 min, the mixture was allowed to
warm up to room temperature and stirred for another
hour. The solution was treated with EtOAc (200 mL)
and successively washed with water (3· 50 mL), with
aqueous KOH (0.1 M, 3· 25 mL) and once again with
water. The organic layer was dried over MgSO4 and
the solvent was removed under reduced pressure.
The residue was purified by column chromatography
on silica gel with EtOAc to give [3-(benzyloxy-for-
myl-amino)-propyl]-phosphonic acid diethyl esters 3,
13, 22 as colourless oils.
4.6.4. {1-[2-(Benzyloxy-formyl-amino)-ethyl]-2-methyl-
propyl}-phosphonic acid diethyl ester (3d). Yield: 96%.
1H NMR (DMSO-d6), d (ppm): 8.25 + 8.00 (2s, 1H),
7.45–7.36 (m, 5H), 4.91 (s, 2H), 4.04–3.94 (m, 4H),
3.75–3.52 (m, 2H), 2.11–1.99 (m, 1H), 1.87–1.62 (m,
3H), 1.22 (t, 6H, J = 7.1 Hz), 0.95–0.93 (m, 6H). 13C
NMR (CDCl32), d (ppm): 162.9, 129.5, 129.1, 128.7,
2
77.6, 61.6 (d, JC1-P = 7.1 Hz), 61.3 (d, JC-P = 6.6 Hz),
2
43.5, 39.8 (d, JC-P = 137.8 Hz), 27.4 (d, JC-P
=
2.6 Hz), 22.4, 21.5 (d, JC-P = 13.7 Hz), 19.1, 16.5 (d,
3
3
3JC-P = 5.6 Hz), 16.5 (d, JC-P = 5.6 Hz). IR: 1680 cmÀ1
(C@O), 1237 cmÀ1 (P@O). HRFAB-MS C18H30NO5P
[M+H]+: calculated 372.1940; found 372.1976.
4.6.5.
{1-[2-(Benzyloxy-formyl-amino)-ethyl]-butyl}-
phosphonic acid diethyl ester (3e). Yield: 93%. 1H
NMR (DMSO-d6), d (ppm): 8.24 + 8.01 (2s, 1H), 7.45–
7.37 (m, 5H), 4.03–3.94 (m, 4H), 3.75–3.52 (m, 2H),
1.94–1.81 (m, 1H), 3.79–3.47 (m, 3H), 3.43–3.28 (m,
3H), 1.21 (t, 6H, J = 7.1 Hz), 0.85 (t, 3H, J = 7.1 Hz).
13C NMR (CDCl3), d (ppm): 163.0, 129.5, 129.1, 128.7,
4.6.1.
[3-(Benzyloxy-formyl-amino)-1-methyl-propyl]-
phosphonic acid diethyl ester (3a). Yield: 97%. 1H
NMR (DMSO-d6), d (ppm): 8.33–7.94 (m, 1H), 7.45–
7.36 (m, 5H), 4.91 (dd, 2H, JAB = 16.1 Hz), 4.03–3.93
(m, 4H), 3.80–3.50 (m, 2H), 2.40–1.93 (m, 1H), 1.88–
2
2
1.74 (m, 1H), 1.56–1.40 (m, 1H), 1.21 (t, 6H,
=
77.7, 61.7 (d, JC-P = 6.6 Hz), 61.6 (d, JC-P = 6.6 Hz),
3
J = 7.1 Hz), 1.07 (dd, 3H, JH-P = 18.4 Hz, JH-H
1
42.5, 33.5 (d, JC-P = 140.4 Hz), 30.5, 25.6, 20.6 (d,
7.1 Hz). 13C NMR (DMSO-d6): 163.1, 130.0, 129.1,
3JC-P = 9.7 Hz), 16.5 (d, JC-P = 6.1 Hz), 14.0. IR:
3
2
128.8, 77.1, 61.5 (d, JC-P = 6.6 Hz), 61.4 (d, JC-P
2
=
6.6 Hz), 41.2, 27.5 (d, JC-P = 139.4 Hz), 27.3, 16.7 (d,
1679 cmÀ1 (C@O), 1234 cmÀ1 (P@O). HRFAB-MS
C18H30NO5P [M+H]+: calculated 372.1940; found
372.1940.
1
3JC-P = 5.6 Hz),
13.2.
IR:
1680 cmÀ1
(C@O),
1241 cmÀ1 (P@O). HRFAB-MS C16H26NO5P [M+H]+:
calculated 344.1627; found 344.1638.
4.6.6. [3-(Benzyloxy-formyl-amino)-1,1-dimethyl-propyl]-
phosphonic acid diethyl ester (3f). Yield: 98%. H NMR
1
4.6.2.
[3-(Benzyloxy-formyl-amino)-1-phenyl-propyl]-
(DMSO-d6), d (ppm): 8.21 + 8.02 (2s, 1H), 7.45–7.36
(m, 5H), 4.90 (s, 2H), 4.06–3.98 (m, 4H), 3.70–3.49
(m, 2H), 1.75–1.67 (m, 2H), 1.23 (t, 6H, J = 7.1 Hz),
phosphonic acid diethyl ester (3b). Yield: 92%. 1H
NMR (DMSO-d6), d (ppm): 8.28–7.65 (m, 1H), 7.40–
7.26 (m, 10H), 4.83 (s, 2H), 4.02–3.88 (m, 2H), 3.86–
3.66 (m, 2H), 3.55–3.39 (m, 1H), 3.36–3.25 (m, 1H),
3.23–3.09 (m, 1H), 2.33–2.22 (m, 1H), 2.15–2.00 (m,
1H), 1.17 (t, 3H, J = 7.1 Hz), 1.01 (t, 3H, J = 7.1 Hz).
13C NMR (DMSO-d6), d (ppm): 162.6, 135.4 (d,
2JC-P = 7.1 Hz), 134.6, 129.4, 129.1, 129.0, 128.6, 128.4,
3
1.08 (d, 6H, JH-P = 16.5 Hz). 13C NMR (DMSO-d6),
d (ppm): 162.5, 134.8, 129.4, 128.6, 128.4, 76.7, 61.4
2
(d, JC-P = 7.1 Hz), 43.7, 33.5, 32.7 (d, JC-P
1
=
=
2
142.4 Hz), 21.7 (d, JC-P = 2.0 Hz), 16.3 (d, JC-P
3
5.1 Hz). IR: 1681 cmÀ1 (C@O), 1239 cmÀ1 (P@O).
HRFAB-MS C17H28NO5P
358.1783; found 358.1777.
[M+H]+:
calculated
3
2
128.3, 127.0 (d, JC-P = 2.5 Hz), 76.0, 61.8 (d, JC-P
7.1 Hz), 61.4 (d, JC-P = 7.1 Hz), 41.5, 40.4 (d, JC-P
=
=
2
1
2
3
132.8 Hz), 26.6 (d, JC-P = 3.6 Hz), 16.1 (d, JC-P = 5.6
4.6.7. [3-(Benzyloxy-formyl-amino)-1-(3,4-difluoro-phen-
yl)-propyl]-phosphonic acid diethyl ester (13a). Yield:
Hz), 15.9 (d, JC-P = 5.6 Hz). IR: 1680 cmÀ1 (C@O),
3
1245 cmÀ1 (P@O). Anal. Calcd for C21H28NO5P: C,
95%. H NMR (CDCl3), d (ppm): 8.37–7.80 (m, 1H),
1

5128
T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
7.45–6.93 (m, 8H), 5.11–4.65 (m, 2H), 4.18–3.73 (m,
4H), 3.58–3.33 (m, 1H), 3.08–2.93 (m, 1H), 2.53–2.35
(m, 1H), 2.23–1.85 (m, 2H), 1.28 (t, 3H, J = 7.2 Hz),
1.14 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3): 163.5,
10 mmol) in dry THF (10 mL) and stirred at room
temperature for 2 h. After addition of EtOAc
(100 mL), the organic layer was washed twice with
aqueous KOH (0.1 M, 50 mL), water (50 mL) and 3
times with aqueous 1 M HCl. The organic layer was
dried over MgSO4, evaporated, and the residue was
purified by column chromatography on silica gel with
EtOAc to give [3-(acetyl-benzyloxy-amino)-propyl]-
phosphonic acid diethyl esters 4, 14 and 23 as colour-
less oils.
1
1
151.1 (dd, JC-F = 244.6 Hz), 150.1 (dd, JC-F
246.5 Hz), 136.9, 132.6, 129.9, 129.6, 129.2, 125.9,
=
2
118.5 (dd, JC-F = 19.6 Hz, JC-F = 5.2 Hz), 117.8 (dd,
3
3
2
2JC-F = 18.3 Hz, JC-2F = 4.1 Hz), 78.4, 63.2 (d, JC-P
6.9 Hz), 62.6 (d, JC-P = 7.2 Hz), 42.7 (d, JC-P
=
=
=
=
3
1
14.7 Hz), 41.6 (d, JC-P = 141.0 Hz), 27.6 (d, JC-P
2
3
3.1 Hz), 16.8 (d, JC-P = 5.9 Hz), 16.7 (d, JC-P
3
5.9 Hz). IR: 1682 cmÀ1 (C@O), 1242 cmÀ1 (P@O). EI-
4.7.1.
[3-(Acetyl-benzyloxy-amino)-1-methyl-propyl]-
MS C21H26F2NO5P: calculated 441; found 441.
phosphonic acid diethyl ester (4a). Yield: 78%. 1H
NMR (DMSO-d6), d (ppm): 7.46–7.37 (m, 5H), 4.88
(dd, 2H, JAB = 15.8 Hz), 4.02–3.92 (m, 4H), 3.81–3.74
(m, 1H), 3.67–3.60 (m, 1H), 2.04–1.91 (m, 4H), 1.87–
4.6.8. [3-(Benzyloxy-formyl-amino)-1-(2-fluoro-phenyl)-
propyl]-phosphonic acid diethyl ester (13b). Yield: 98%.
1H NMR (CDCl3), d (ppm): 8.27–7.63 (m, 1H), 7.52–
7.00 (m, 9H), 5.06–4.65 (m, 2H), 4.16–3.75 (m, 4H),
3.68–3.11 (m, 3H), 2.57–2.10 (m, 2H), 1.28 (t, 3H,
J = 7.3 Hz), 1.11 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl3):
1.73 (m, 1H), 1.51–1.39 (m, 1H), 1.20 (t, 6H,
=
3
J = 7.1 Hz), 1.07 (dd, 3H, JH-P = 18.4 Hz, JH-H
7.1 Hz). 13C NMR (CDCl3), d (ppm): 172.3, 134.5,
129.2, 129.0, 128.7, 76.4, 61.7 (d, JC-P = 7.1 Hz), 61.6
2
1
3
2
(d, JC-P = 7.1 Hz), 43.3, 28.5 (d, JC-P = 142.4 Hz),
1
163.4, 161.4 (dd, JC-F = 244.5 Hz, JC-P = 7.6 Hz),
134.6, 129.9, 129.8, 129.5, 129.1, 124.9, 115.9 (dd,
3
2
27.6, 20.5, 16.5 (d, JC-P = 6.1 Hz), 13.4 (d, JC-P =
2
2JC-F = 22.2 Hz), 78.2, 63.1 (d, JC-P = 7.4 Hz), 62.7
(d, JC-P = 7.1 Hz), 42.8 (d, JC-P = 16.7 Hz), 33.4 (d,
5.1 Hz). IR: 1662 cmÀ1 (C@O), 1234 cmÀ1 (P@O). Anal.
Calcd for C17H28NO5P: C, 57.13; H, 7.90; N, 3.92.
Found: C, 57.00; H, 7.57; N, 4.07.
2
3
3
1JC-P = 143.4 Hz), 26.7, 16.7 (d, JC-P = 6.0 Hz), 16.6
3
(d, JC-P = 5.7 Hz). IR: 1682 cmÀ1 (C@O), 1231 cmÀ1
(P@O). EI-MS C21H26F2NO5P: calculated 423; found 423.
4.7.2.
[3-(Acetyl-benzyloxy-amino)-1-phenyl-propyl]-
phosphonic acid diethyl ester (4b). Yield: 73%. 1H
NMR (DMSO-d6), d (ppm): 7.41–7.25 (m, 10H), 4.78
(dd, 2H, JAB = 18.3 Hz), 4.00–3.89 (m, 2H), 3.86–3.76
(m, 1H), 3.75–3.66 (m, 1H), 3.59–3.49 (m, 1H),
3.38–3.33 (m, 1H), 3.23–3.12 (m, 1H), 2.32–2.21 (m,
1H), 2.11–2.01 (m, 1H), 1.96 (s, 3H), 1.17 (t, 3H,
4.6.9.
[3-(Benzyloxy-formyl-amino)-1-(2,6-dimethyl-
phenyl)-propyl]-phosphonic acid diethyl ester (13c).
Yield: 94%. 1H NMR (CDCl3), d (ppm): 8.28–7.46
(m, 1H), 7.42–6.92 (m, 8H), 5.05–4.62 (m, 2H),
4.13–3.75 (m, 4H), 3.71–3.28 (m, 3H), 2.52–2.33 (m,
2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.28 (t, 3H,
J = 7.2 Hz), 1.06 (t, 3H, J = 7.2 Hz). 13C NMR
J = 7.1 Hz), 1.01 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3),
2
(ppm): 172.2, 135.2 (d, JC-P = 7.1 Hz), 134.4,
d
129.4, 129.3, 129.2, 128.9, 128.7, 128.6, 128.6, 127.4 (d,
2
(CDCl3): 162.8, 136.1 (d, JC-P = 2.3 Hz), 134.8,
134.7, 133.1, 130.9, 129.8, 129.5, 129.1, 128.6, 128.4,
2
3JC-P = 3.1 Hz), 76.3, 62.7 (d, JC-P = 7.1 Hz), 61.9 (d,
2
78.2, 63.2 (d, JC-P = 6.8 Hz), 62.4 (d, JC-P = 7.9 Hz),
2
1
2JC-2P = 7.1 Hz), 43.8, 42.2 (d, JC-P = 138.4 Hz), 26.9
(d, JC-P = 2.0 Hz), 20.5, 16.4 (d, JC-P = 6.1 Hz), 16.2
1
42.9, 37.0 (d, JC-P = 138.9 Hz), 27.4, 21.5, 19.9, 16.8
3
3
3
3
(d, JC-P = 6.2 Hz), 16.5 (d, JC-P = 5.8 Hz). IR:
1682 cmÀ1 (C@O), 1244 cmÀ1 (P@O). Anal. Calcd
for C23H32NO5P: C, 63.73; H, 7.44; N, 3.23. Found:
C, 63.40; H, 7.67; N, 3.00.
(d, JC-P = 6.1 Hz). IR: 1665 cmÀ1 (C@O), 1245 cmÀ1
(P@O). Anal. Calcd for C22H30NO5P: C, 63.00; H,
7.21; N, 3.34. Found: C, 62.70; H, 7.32; N, 3.48.
4.7.3. [3-(Acetyl-benzyloxy-amino)-1-ethyl-propyl]-phos-
phonic acid diethyl ester (4c). Yield: 83%. 1H NMR
(DMSO-d6), d (ppm): 7.47–7.36 (m, 5H), 4.88 (s, 2H),
4.03–3.93 (m, 4H), 3.78–3.62 (m, 2H), 2.02 (s, 3H),
1.93–1.82 (m, 1H), 1.74–1.56 (m, 3H), 1.52–1.40 (m,
1H), 1.21 (t, 6H, J = 7.1 Hz), 0.93 (t, 3H, J = 7.4 Hz).
13C NMR (CDCl3), d (ppm): 172.2, 134.5, 129.3,
4.6.10. [3-(Benzyloxy-formyl-amino)-1-benzyloxymethyl-
propyl]-phosphonic acid diethyl ester (22). Yield: 85%. 1H
NMR (CDCl3), d (ppm): 8.26–7.84 (m, 1H), 7.51–7.16
(m, 10H), 5.10–4.70 (m, 2H), 4.51 (s, 2H), 4.14–4.02
(m, 4H), 3.88–3.42 (m, 4H), 2.24–1.93 (m, 3H), 1.35–
1.21 (m, 6H). 13C NMR (CDCl3), d (ppm): 163.5,
136.2, 134.7, 129.9, 129.5, 129.1, 128.8, 128.2, 77.2,
1
129.0, 128.7, 76.32 (d, JC-P = 140.4 Hz), 25.0, 21.4 (d,
2
2
3
73.7, 68.7, 62.4 (d, JC-P = 6.4 Hz), 62.33 (d, JC-P
=
2JC-P = 4.1 Hz), 20.5, 16.5 (d, JC-P = 6.1 Hz), 12.0 (d,
1
6.4 Hz), 43.1, 35.8 (d, JC-P = 133.6 Hz), 24.7, 16.8 (d,
3JC-P = 6.2 Hz). IR: 1674 cmÀ1 (C@O), 1236 cmÀ1
(P@O). Anal. Calcd for C23H32NO6P: C, 61.46; H,
7.18; N, 3.12. Found: C, 61.12; H, 7.44; N, 2.96.
2JC-P = 10.2 Hz). IR: 1665 cmÀ1 (C@O), 1239 cmÀ1
(P@O). HRFAB-MS C18H30NO5P [M+H]+: calculated
372.1940; found 372.1958.
4.7.4.
{1-[2-(Acetyl-benzyloxy-amino)-ethyl]-2-methyl-
4.7. General procedure for the preparation of [3-(acetyl-
benzyloxy-amino)-propyl]-phosphonic acid diethyl esters
4a–f, 14a and 23
propyl}-phosphonic acid diethyl ester (4d). Yield: 73%.
1H NMR (DMSO-d6), d (ppm): 7.45–7.37 (m, 5H),
4.87 (s, 2H), 4.03–3.94 (m, 4H), 3.79–3.72 (m, 1H),
3.68–3.61 (m, 1H), 2.02 (s, 3H), 1.86–1.62 (m, 3H),
1.21 (t, 6H, J = 7.1 Hz), 0.95–0.92 (m, 6H). 13C NMR
(CDCl3), d (ppm): 172.1, 129.3, 129.0, 128.7, 76.2, 61.6
Acetic acid anhydride (20 mmol) was added to a solu-
tion of the respective hydroxylamine (2, 12, 21;

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5129
2
(d, JC-P = 7.1 Hz), 61.2 (d, JC-P = 7.1 Hz), 44.8, 39.9
2
(P@O). HRFAB-MS C24H34NO6P [M+H]+: calculated
463.5155; found 463.5124.
1
(d, JC-P = 137.3 Hz), 27.5 (d, JC-P = 2.6 Hz), 22.3,
2
3
21.5 (d, JC-P = 14.3 Hz), 20.6, 19.1 (d, JC-P = 2.5 Hz),
2
3
3
16.6 (d, JC-P = 6.1 Hz), 16.5 (d, JC-P = 5.6 Hz). IR:
1665 cmÀ1 (C@O), 1239 cmÀ1 (P@O). HRFAB-MS
C19H32NO5P [M+H]+: calculated 386.2096; found
386.2117.
4.8. General procedure for the preparation of [3-(acyl-
benzyloxy-amino)-propyl]-(2,2-dimethyl-propionyloxy-
methoxy)- phosphinoyloxymethyl esters 5a–f, 6a–f,
15a–c, 16a, 24 and 25
4.7.5. {1-[2-(Acetyl-benzyloxy-amino)-ethyl]-butyl}-phos-
phonic acid diethyl ester (4e). Yield: 79%. 1H NMR
(DMSO-d6), d (ppm): 7.45–7.37 (m, 5H), 4.87 (s, 2H),
4.03–3.93 (m, 4H), 3.78–3.62 (m, 2H), 2.02 (s, 3H),
1.93–1.46 (m, 4H), 1.43–1.28 (m, 3H), 1.21 (t, 6H,
J = 7.1 Hz), 0.85 (t, 3H, J = 7.1 Hz). 13C NMR (CDCl3),
d (ppm): 172.2, 134.5, 129.3, 129.0, 128.7, 76.3, 61.6 (d,
Trimethylsilylbromide (15 mmol) was added to a stirred
solution of phosphonic acid diethyl esters 3, 4, 13, 14, 22
and 23 (3 mmol) in dry CH2Cl2 (10 mL) at 0 ꢁC. After
1 h, the solution was allowed to warm up to room tem-
perature and stirred for 24 h. The solvent was removed
under reduced pressure and the residue was dissolved
in dry THF (10 mL) and treated with water (0.1 mL).
After 5 min, the solvent was evaporated and the residue
was dried in vacuo overnight. For the alkylation step,
the resulting oil was dissolved in anhydrous DMF
(20 mL), treated with triethylamine (9 mmol) and stirred
for 5 min. Chloromethyl pivalate (30 mmol) was added
and the mixture was stirred at 70 ꢁC for 2 h. Another
3 mmol of triethylamine and 5 mmol of chloromethyl
pivalate were added and the solution was stirred for fur-
ther 2 h. The procedure of adding triethylamine and
chloromethyl pivalate was repeated once again. After
an overall time of 6 h, the mixture was allowed to cool
down and stirred overnight at room temperature.
Diethyl ether (100 mL) was added and the solution
was successively washed with water (50 mL), twice with
saturated aqueous NaHCO3-solution (50 mL) and again
with water (50 mL). The organic layer was dried over
MgSO4 and the solvent was removed under reduced
pressure. The resulting oil was purified by column chro-
matography on silica gel (Et2O) to give [3-(acyl-benzyl-
oxy-amino)-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl esters 5, 6, 15, 16, 24 and
25 as colourless products.
2
2JC-P = 6.1 Hz), 61.5 (d, JC-2P = 6.1 Hz), 43.8, 33.5 (d,
1JC-P = 139.4 Hz), 30.5, (d, JC-P = 3.1 Hz), 25.5, 20.6
(d, JC-P = 10.2 Hz), 20.5, 16.5 (d, JC-P = 5.1 Hz),
3
3
14.0. IR: 1664 cmÀ1 (C@O), 1238 cmÀ1 (P@O).
HRFAB-MS C19H32NO5P
386.2096; found 386.2108.
[M+H]+:
calculated
4.7.6. [3-(Acetyl-benzyloxy-amino)-1,1-dimethyl-propyl]-
phosphonic acid diethyl ester (4f). Yield: 89%. H NMR
1
(DMSO-d6), d (ppm): 7.45–7.36 (m, 5H), 4.87 (s, 2H),
4.05–3.98 (m, 4H), 3.70–3.66 (m, 2H), 2.00 (s, 3H),
1.73–1.65 (m, 2H), 1.22 (t, 6H, J = 7.1 Hz), 1.07 (d,
3
6H, JH-P = 16.5 Hz). 13C NMR (CDCl3), d (ppm):
2
172.2, 134.6, 129.2, 128.9, 128.7, 76.3, 61.9 (d, JC-P
=
7.1 Hz), 41.6, 34.0, 33.4 (d, JC-P = 141.4 Hz), 22.3 (d,
1
3
2JC-P = 3.1 Hz), 20.6, 16.6 (d, JC-P = 6.1 Hz). IR:
1665 cmÀ1 (C@O), 1230 cmÀ1 (P@O). HRFAB-MS
C18H30NO5P [M+H]+: calculated 372.1940; found
372.1977.
4.7.7. [3-(Acetyl-benzyloxy-amino)-1-(3,4-difluoro-phen-
yl)-propyl]-phosphonic acid diethyl ester (14a). Yield:
1
95%. H NMR (CDCl3), d (ppm): 7.41–6.93 (m, 8H),
4.72 (s, 2H), 4.13–3.73 (m, 4H), 3.66–3.32 (m, 2H),
3.10–2.89 (m, 1H), 2.51–2.34 (m, 1H), 2.22–2.08 (m,
1H), 2.04 (s, 3H), 1.27 (t, 3H, J = 7.1 Hz), 1.14 (t,
3H, J = 6.6 Hz).13C NMR (CDCl3): 164.9, 150.2
4.8.1. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-methyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (5a). Yield: 30%. 1H
NMR (CDCl3),
d
(ppm): 8.16 (s, 1H), 7.38
1
2
(dd, JC-F = 243.6 Hz, JC-F = 13.1 Hz), 149.7 (dd,
(m, 5H), 5.71–5.64 (m, 4H), 4.85 (s, 2H), 3.82–3.52
(m, 2H), 2.25–2.09 (m, 1H), 2.02–1.89 (m, 1H), 1.73–
1.57 (m, 1H), 1.24–1.15 (m, 21H). 13C NMR (CDCl3),
d (ppm): 176.9, 163.1, 134.3, 129.5, 129.2, 128.8, 81.5
2
1JC-F = 247.1 Hz, JC-F = 16.5 Hz), 134.2, 132.5, 130.9,
128.8, 129.1, 129.2, 125.4, 118.1 (dd, JC-F = 17.1
2
Hz, 3JC-F = 6.2 Hz), 117.3 (dd, 2JC-F = 17.1 Hz,
2
2
2
3JC-F = 2.8 Hz), 76.6, 62.8 (d, JC-P = 7.3 Hz), 62.2 (d,
(d, JC-P = 7.1 Hz), 81.4 (d, JC-P = 7.1 Hz), 77.8, 41.7
1
3
1
2JC-P = 6.5 Hz), 43.8, 41.6 (d, JC-P = 139.8 Hz), 27.0,
(d, JC-P = 14.2 Hz), 38.8, 28.9 (d, JC-P = 142.4 Hz),
27.0, 26.9, 12.8. IR: 1753 cmÀ1 (C@O), 1680 cmÀ1
(C@O), 1255 cmÀ1 (P@O). Anal. Calcd for
C24H38NO9P: C, 55.92; H, 7.43; N, 2.72. Found: C,
55.80; H, 7.51; N, 2.72.
3
3
20.4, 16.4 (d, JC-P = 6.0 Hz), 16.3 (d, JC-P = 5.4 Hz).
IR: 1663 cmÀ1 (C@O), 1242 cmÀ1 (P@O). Anal. Calcd
for C22H28F2NO5P: C, 58.02; H, 6.20; N, 3.08. Found:
C, 58.24; H, 6.19; N, 3.36.
4.7.8. [3-(Acetyl-benzyloxy-amino)-1-benzyloxymethyl-
propyl]-phosphonic acid diethyl ester (23). Yield: 79%.
1H NMR (CDCl3), d (ppm): 7.42–7.27 (m, 10H), 4.80
(s, 2H), 4.51 (s, 2H), 4.14–4.02 (m, 4H), 3.93–3.57 (m,
4H), 2.22–1.91 (m, 6H), 1.31–1.22 (m, 6H). 13C NMR
(CDCl3), d (ppm): 172.7, 138.4, 134.9, 129.6, 129.3,
129.1, 128.8, 128.1, 76.7, 73.6, 68.8, 62.3 (d,
4.8.2. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-phenyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (5b). Yield: 43%. 1H
NMR (CDCl3),
d
(ppm): 8.18–7.60 (m, 1H),
3
7.38–7.27 (m, 10H), 5.60 (ddd, 2H, JH-P = 12.0 Hz,
JAB = 17.0 Hz), 5.41 (ddd, 2 H, 3JH-P = 11.7 Hz,
JAB = 24.7 Hz), 4.98–4.64 (m, 2H), 3.54–3.07 (m, 3H),
2.50–2.39 (m, 1H), 2.32–2.16 (m, 1H), 1.21 (s, 9H),
1.17 (s, 9H). 13C NMR (CDCl3), d (ppm): 176.8, 176.8,
163.0, 134.2, 133.5, 129.5, 129.4, 129.3, 129.1, 128.9,
2
2JC-P = 6.3 Hz), 62.1 (d, JC2-P = 6.3 Hz), 44.2, 35.9 (d,
1JC-P = 139.7 Hz), 24.7 (d, JC-P = 3.0 Hz), 21.0, 16.8
3
(d, JC-P = 5.9 Hz). IR: 1660 cmÀ1 (C@O), 1234 cmÀ1

5130
T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
2
128.7, 127.9, 81.9 (d, JC-P = 7.1 Hz), 81.7 (d, JC-P
2
=
(C@O), 1680 cmÀ1 (C@O), 1256 cmÀ1 (P@O). Anal.
Calcd for C25H40NO9P: C, 56.70; H, 7.61; N, 2.64.
Found: C, 56.49; H, 7.38; N, 2.67.
1
7.1 Hz), 77.8, 42.2 (d, JC-P = 138.4 Hz), 42.1, 38.7,
38.7, 26.8, 26.8, 26.6. IR: 1753 cmÀ1 (C@O), 1680 cmÀ1
(C@O), 1260 cmÀ1 (P@O). Anal. Calcd for
C29H40NO9P: C, 60.30; H, 6.98; N, 2.42. Found: C,
59.93; H, 7.07; N, 2.42.
4.8.7. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1-methyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (6a). Yield: 35%. 1H
4.8.3. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-ethyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (5c). Yield: 27%. H
NMR (CDCl3),
d
(ppm): 7.39–7.37 (m, 5H),
5.71–5.63 (m, 4H), 4.82 (s, 2H), 3.85–3.76 (m, 1H),
3.73–3.66 (m, 1H), 2.23–2.10 (m, 1H), 2.07 (s, 3H),
2.02–1.88 (m, 1H), 1.71–1.58 (m, 1H), 1.22 + 1.21 (2s,
1
NMR (CDCl3), d (ppm): 8.16 (s, 1H), 7.44–7.32
(m, 5H), 5.72–5.64 (m, 4H), 5.02–4.78 (m, 2H), 3.83–
3.40 (m, 2H), 2.14–1.67 (m, 4H), 1.59–1.44 (m, 1H),
1.23 (s, 18H), 0.99 (t, 3H, J = 7.1 Hz). 13C NMR
(CDCl3), d (ppm): 176.9, 163.0, 134.4, 129.5, 129.1,
18H), 1.23–1.16 (m, 21H). 13C NMR (CDCl3), d (ppm):
2
176.9, 172.3, 134.4, 129.3, 129.0, 128.7, 81.5 (d, JC-P
=
7.1 Hz), 81.4 (d, JC-P = 7.1 Hz), 76.5, 43.1, 38.7, 29.1
2
1
2
(d, JC-P = 141.4 Hz), 27.1, 26.9, 20.5, 12.9 (d, JC-P
=
2
128.8, 81.4 (d, JC-P = 6.6 Hz), 77.6, 42.1, 38.8, 35.6
6.1 Hz). IR: 1753 cmÀ1 (C@O), 1666 cmÀ1 (C@O),
1258 cmÀ1 (P@O). HRFAB-MS C25H40NO9P [M+H]+:
calculated 530.2519; found 530.2542.
1
2
(d, JC-P = 142.4 Hz), 26.9, 24.7, 20.9 (d, JC-P
=
3.6 Hz), 11.8 (d, JC-P = 10.2 Hz). IR: 1753 cmÀ1
(C@O), 1680 cmÀ1 (C@O), 1257 cmÀ1 (P@O). Anal.
Calcd for C25H40NO9P: C, 56.70; H, 7.61; N, 2.64.
Found: C, 56.63; H, 7.71; N, 2.66.
3
4.8.8. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1-phenyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (6b). Yield: 64%. 1H
NMR (CDCl3), d (ppm): 7.37–7.27 (m, 10H), 5.59
4.8.4. 2,2-Dimethyl-propionic acid {1-[2-(benzyloxy-for-
myl-amino)-ethyl]-2-methyl-propyl}-(2,2-dimethyl-propio-
nyloxymethoxy)-phosphinoyloxymethyl ester (5d). Yield:
33%. 1H NMR (CDCl3), d (ppm): 8.15 (s, 1H), 7.38
(m, 5H), 5.73–5.64 (m, 4H), 5.03–4.79 (m, 2H), 3.80–
3.39 (m, 2H), 2.24–2.09 (m, 1H), 2.05–1.69 (m, 3H),
1.23 (s, 18H), 1.02–0.95 (m, 6H). 13C NMR (CDCl3),
d (ppm): 176.9, 162.9, 134.3, 129.6, 129.1, 128.8, 81.4
3
(ddd, 2H, JH-P = 12.2 Hz, JAB = 15.0 Hz), 5.40 (ddd,
3
2H, JH-P = 12.2 Hz, JAB = 22.8 Hz), 4.68 (dd, 2H,
JAB = 11.2 Hz), 3.60–3.42 (m, 2H), 3.17 (ddd, 1H,
2JH-P = 23.9 Hz, JAB = 11.5 Hz), 2.48–2.37 (m, 1H),
2.34–2.22 (m, 1H), 1.98 (s, 3H), 1.20 (s, 9H), 1.16 (s,
9H). 13C NMR (CDCl3), d (ppm): 176.8, 172.2,
2
134.3, 133.8 (d, JC-P = 7.1 Hz), 129.4, 129.3, 129.2,
=
2
2
2
129.0, 128.8, 128.8, 128.7, 127.8, 127.8, 81.9, (d, JC-P
(d, JC-P = 6.1 Hz), 81.2 (d, JC-P = 6.1 Hz), 77.5, 43.2,
1
40.4 (d, JC-P = 142.4 Hz), 38.8, 27.3 (d, JC-P
2
2
=
=
7.1 Hz), 81.7 (d, JC-P = 7.1 Hz), 76.4, 43.6, 42.4 (d,
1JC-P = 138.4 Hz), 38.7, 38.6, 26.8, 26.8, 26.3, 20.4.
IR: 1753 cmÀ1 (C@O), 1667 cmÀ1 (C@O), 1260 cmÀ1
(P@O). Anal. Calcd for C30H42NO9P: C, 60.90; H,
7.16; N, 2.37. Found: C, 60.89; H, 7.15; N, 2.48.
2
3
2.6 Hz), 26.9, 22.2 (d, JC-P = 2.0 Hz), 21.3 (d, JC-P
13.2 Hz), 19.0. IR: 1753 cmÀ1 (C@O), 1680 cmÀ1
(C@O), 1255 cmÀ1 (P@O). Anal. Calcd for
C26H42NO9P: C, 57.45; H, 7.79; N, 2.58. Found: C,
57.42; H, 7.89; N, 2.60.
4.8.9. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1-ethyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (6c). Yield: 29%. H
4.8.5. 2,2-Dimethyl-propionic acid {1-[2-(benzyloxy-for-
myl-amino)-ethyl]-butyl}-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (5e). Yield: 23%. 1H
1
NMR (CDCl3), d (ppm): 7.40–7.37 (m, 5H), 5.71–5.64
(m, 4H), 4.83 (s, 2H), 3.84–3.70 (m, 2H), 2.13–1.96 (m,
4H), 1.91–1.69 (m, 3H), 1.60–1.46 (m, 1H), 1.22 (s,
18H), 0.99 (t, 3H, J = 7.4 Hz). 13C NMR (CDCl3), d
(ppm): 176.9, 172.2, 134.4, 129.3, 129.0, 128.7, 81.4 (d,
NMR (CDCl3),
d
(ppm): 8.15 (s, 1H), 7.38
3
(m, 5H), 5.68 (d, 4H, JH-P = 12.5 Hz), 5.05–4.77 (m,
2H), 3.81–3.36 (m, 2H), 2.12–1.77 (m, 3H), 1.73–1.59
(m, 1H), 1.52–1.30 (m, 3H), 1.23 (s, 18H), 0.89 (t, 3H,
J = 7.1 Hz). 13C NMR (CDCl3), d (ppm): 176.9, 163.0,
2
2JC-P = 6.6 Hz), 81.4 (d, JC-P = 6.6 Hz), 76.4, 43.5,
2
1
38.7, 35.7 (d, JC-P = 138.4 Hz), 26.9, 24.6, 21.0
134.4, 129.6, 129.1, 128.8, 81.5 (d, JC-P = 6.1 Hz),
2
81.4 (d, JC-P = 6.1 Hz), 77.6, 42.2, 38.8, 34.1 (d, JC-P
1
2
3
=
(d, JC-P = 4.1 Hz), 20.5, 11.8 (d, JC-P = 10.2 Hz). IR:
1753 cmÀ1 (C@O), 1666 cmÀ1 (C@O), 1252 cmÀ1
(P@O). Anal. Calcd for C26H42NO9P: C, 57.45; H,
7.79; N, 2.58. Found: C, 57.37; H, 7.84; N, 2.59.
142.4 Hz), 30.0 (d, 2JC-3P = 2.0 Hz), 26.9, 25.3
2
(d, JC-P = 2.0 Hz), 20.4 (d, JC-P = 10.7 Hz), 13.9. IR:
1753 cmÀ1 (C@O), 1680 cmÀ1 (C@O), 1252 cmÀ1
(P@O). HRFAB-MS C26H42NO9P [M+H]+: calculated
544.2675; found 544.2643.
4.8.10. 2,2-Dimethyl-propionic acid {1-[2-(acetyl-benzyl-
oxy-amino)-ethyl]-2-methyl-propyl}-(2,2-dimethyl-propio-
nyloxymethoxy)-phosphinoyloxymethyl ester (6d). Yield:
4.8.6. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1,1-dimethyl-propyl]-(2,2-dimethyl-propionyloxy-
methoxy)-phosphinoyloxymethyl ester (5f). Yield: 22%.
1H NMR (CDCl3), d (ppm): 8.13 (s, 1H), 7.38 (m,
5H), 5.74–5.63 (m, 4H), 4.84 (s, 2H), 3.75–3.44 (m,
2H), 1.93–1.81 (m, 2H), 1.24–1.15 (m, 24H). 13C NMR
(CDCl3), d (ppm): 176.9, 162.9, 134.4, 129.5, 129.1,
1
43%. H NMR (CDCl3), d (ppm): 7.40–7.36 (m, 5H),
5.71–5.65 (m, 4H), 4.83 (s, 2H), 3.83–3.70 (m, 2H),
2.23–2.11 (m, 1H), 2.07 (s, 3H), 2.00–1.76 (m, 3H),
1.22 (s, 18H), 1.00 (d, 3H, J = 7.1 Hz), 0.98 (d, 3H,
J = 6.9 Hz). 13C NMR (CDCl3), d (ppm): 176.9, 172.1,
2
134.5, 129.4, 129.0, 128.7, 81.4 (d, JC-P = 7.1 Hz), 81.3
2
2
(d, JC-P = 7.1 Hz), 76.3, 44.6, 40.5 (d, JC-P =
1
128.8, 81.5 (d, JC-P = 7.1 Hz), 77.7, 40.1, 38.8, 33.6 (d,
2
135.3 Hz), 38.7, 27.3 (d, JC-P = 2.0 Hz), 26.9, 22.0 (d,
1JC-P = 139.9 Hz), 33.5, 26.9, 21.7. IR: 1753 cmÀ1

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5131
3
2
2JC-P = 3.1 Hz), 21.3 (d, JC-P = 14.2 Hz), 20.5. IR:
2JC-P = 7.7 Hz), 115.7 (d, JC-3F = 22.4 Hz), 81.8 (d,
1753 cmÀ1 (C@O), 1667 cmÀ1 (C@O), 1252 cmÀ1
(P@O). Anal. Calcd for C27H44NO9P: C, 58.16; H,
7.95; N, 2.51. Found: C, 58.03; H, 8.01; N, 2.54.
2JC-P = 7.0 Hz), 77.8, 42.1 (d, JC-P = 14.4 Hz), 38.7,
33.7 (d, JC-P = 143.7 Hz), 26.8, 25.9. IR: 1753 cmÀ1
1
(C@O), 1682 cmÀ1 (C@O), 1263 cmÀ1 (P@O). Anal.
Calcd for C29H39FNO9P: C, 58.48; H, 6.60; N, 2.35.
Found: C, 58.40; H, 6.70; N, 2.56.
4.8.11. 2,2-Dimethyl-propionic acid {1-[2-(acetyl-benzyl-
oxy-amino)-ethyl]-butyl}-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (6e). Yield: 46%. 1H
4.8.15. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-(2,6-dimethyl-phenyl)-propyl]-(2,2-dimethyl-
propionyloxymethoxy)-phosphinoyloxymethyl ester (15c).
Yield: 34%. 1H NMR (DMSO-d6), d (ppm): 8.17 (s,
0.5H), 7.62 (s, 0.5 H), 7.40–7.26 (m, 5H), 7.11–7.03
(m, 2H), 7.01–6.96 (m, 1H), 5.55 (ddd, 2H,
NMR (CDCl3),
d
(ppm): 7.40–7.36 (m, 5H),
5.71–5.64 (m, 4H), 4.83 (s, 2H), 3.83-3.70 (m, 2H), 2.09–
1.96 (m, 4H), 1.93–1.77 (m, 2H), 1.73–1.59 (m, 1H), 1.51–
1.31 (m, 3H), 1.22 (s, 18H), 0.88 (t, 3H, J = 7.1 Hz). 13C
NMR (CDCl3), d (ppm): 176.9, 172.2, 134.5, 129.3, 129.0,
2
2
128.7, 81.4 (d, JC-P = 6.1 Hz), 81.4 (d, JC-P = 7.1 Hz),
JH-P = 13.0 Hz, JAB = 18.2 Hz), 5.44 (d, 2H, JH-P =
12.2 Hz), 4.80 (dd, 2H, JAB = 12.5 Hz), 3.48–3.20 (m,
76.4, 43.5, 38.7, 34.1 (d, 1JC-P = 138.4 Hz), 33.0 (d, 2JC-P
=
4.1 Hz), 26.9, 25.2, 20.5, 20.4 (d, 3JC-P = 10.7 Hz), 14.0. IR:
1753 cmÀ1 (C@O), 1666 cmÀ1 (C@O), 1247 cmÀ1 (P@O).
HRFAB-MS C27H44NO9P [M+H]+: calculated 558.2832;
found 558.2811.
3H), 2.31–2.07 (m, 8H), 1.13 (s, 9H), 1.10 (s, 9H). 13C
NMR (CDCl3): 176.8, 162.9, 135.9 (d, JC-P = 2.7 Hz),
2
3
134.6 (d, JC-P = 8.5 Hz), 130.8, 129.5, 129.1, 128.7,
3
128.5, 128.0, 81.9 (d, JC-P = 6.1 Hz), 81.6 (d, JC-P
3
=
3
6.7 Hz), 77.8, 42.0 (d, JC-P = 14.2 Hz), 38.6, 36.7 (d,
3JC-P = 135.6 Hz), 29.7, 26.8, 21.1, 19.5. IR: 1757 cmÀ1
(C@O), 1682 cmÀ1 (C@O), 1262 cmÀ1 (P@O). Anal.
Calcd for C31H44NO9P: C, 61.48; H, 7.32; N, 2.31.
Found: C, 61.28; H, 7.35; N, 2.52.
4.8.12. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1,1-dimethyl-propyl]-(2,2-dimethyl-propionyloxy-
methoxy)-phosphinoyloxymethyl ester (6f). Yield: 38%.
1H NMR (CDCl3), d (ppm): 7.40–7.36 (m, 5H), 5.69
3
(ddd, 4H, JAB = 20.3 Hz, JHP = 12.1 Hz), 4.82 (s, 2H),
3.77–3.73 (m, 2H), 2.05 (s, 3H), 1.92–1.83 (m, 2H), 1.22
(s, 18H), 1.19(d, 6H, 3JHP = 17.8 Hz). 13CNMR(CDCl3),
4.8.16. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1-(3,4-difluoro-phenyl)-propyl]-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (16a).
d (ppm): 176.8, 172.2, 134.5, 129.3, 129.0, 128.7, 81.5 (d,
1
1
2JC-P = 7.1 Hz), 76.4, 41.3, 38.7, 33.6 (d, JC-P
=
Yield: 34%. H NMR (DMSO-d6), d (ppm): 7.40–7.31
2
139.4 Hz), 33.3, 26.9, 21.7, (d, JC-P = 2.0 Hz), 20.6. IR:
1752 cmÀ1 (C@O), 1667 cmÀ1 (C@O), 1251 cmÀ1
(P@O). Anal. Calcd for C26H42NO9P: C, 57.45; H, 7.79;
N, 2.58. Found: C, 57.36; H, 7.65; N, 2.64.
(m, 7H), 7.23–7.17 (m, 2H), 5.57 (ddd, 2H, JH-P=13.0
Hz, JAB = 17.3 Hz), 5.50 (d, 2H, JH-P = 12.5 Hz), 4.77
(dd, 2H, JAB = 15.33 Hz), 3.63–3.47 (m, 2H), 3.39–3.32
(m, 1H), 2.33–2.22 (m, 1H), 2.15–2.05 (m, 1H), 1.91 (s,
3H), 1.13 (s, 9H), 1.11 (s, 9H). 13C NMR (CDCl3):
1
4.8.13. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-(3,4-difluoro-phenyl)-propyl]-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (15a).
Yield: 32%. 1H NMR (CDCl3), d (ppm): 8.30–7.56
(m, 1H), 7.47–6.89 (m, 8H), 5.69 (m, 4H), 5.02–4.63
(m, 2H), 3.58-3.04 (m, 3H), 2.52–2.33 m, 1H),
2.21–2.05 (m, 1H), 1.21 (s, 9H), 1.18 (s, 9H).
13C NMR (CDCl3): 176.8, 163.1, 149.9 (dd,
1JC-F = 248.3 Hz, 2JC-F = 11.7 Hz), 134.0, 130.1,
176.8, 172.3, 150.3 (dd, JC-F = 246.2 Hz), 150.0 (dd,
1JC-F = 244.8 Hz), 134.1, 131.0, 129.2, 129.1, 128.8,
125.6, 118.2 (dd, JC-F = 18.2 Hz, JC-F = 6.8 Hz),
2
3
2
117.4 (dd, JC-F = 17.2 Hz, JC-F = 2.9 Hz), 81.8 (d,
3
1
2JC-P = 8.7 Hz), 76.3, 43.4, 41.6 (d, JC-P = 140.2 Hz),
38.7, 26.8, 26.4, 20.4. IR: 1753 cmÀ1 (C@O),
1666 cmÀ1 (C@O), 1257 cmÀ1 (P@O). Anal. Calcd for
C30H42F2NO9P: C, 59.11; H, 6.78; N, 2.30. Found: C,
59.11; H, 6.69; N, 2.16.
2
129.5, 129.3, 128.8, 125.7, 118.5 (dd, JC-F = 17.8
Hz, 3JC-F = 4.2 Hz), 117.8 (dd, 2JC-F = 17.8 Hz,
4.8.17. 2,2-Dimethyl-propionic acid [3-(benzyloxy-formyl-
amino)-1-benzyloxymethyl-propyl]-(2,2-dimethyl-propio-
nyloxymethoxy)-phosphinoyloxymethyl ester (24). Yield:
3
3JC-F = 3.0 Hz), 81.8, 78.0, 41.8 (d, JC-P = 18.8 Hz),
38.7, 29.7, 26.8. IR: 1753 cmÀ1 (C@O), 1682 cmÀ1
(C@O), 1259 cmÀ1 (P@O). Anal. Calcd for
C29H38F2NO9P: C, 56.77; H, 6.24; N, 2.28. Found: C,
57.02; H, 6.43; N, 2.47.
1
41%. H NMR (CDCl3), d (ppm): 8.35–7.85 (m, 1H),
7.49–7.21 (m, 10H), 5.72–5.52 (m, 4H), 4.88 (s, 2H),
4.48 (s, 2H), 3.86-3.49 (m, 4H), 2.39–2.23 (m, 1H),
1.99–1.78 (m, 2H), 1.17 (s, 18H). 13C NMR (CDCl3), d
(ppm): 176.4, 163.0, 138.2, 135.0, 129.9, 129.1, 128.8,
128.6, 127.9, 127.8, 81.7, 77.0, 72.6, 67.4, 41.8, 38.5,
4.8.14. 2,2-Dimethyl-propionic acid [3-(benzyloxy-for-
myl-amino)-1-(2-fluoro-phenyl)-propyl]-(2,2-dimethyl-
1
propionyloxymethoxy)-phosphinoyloxymethyl
ester
34.4 (d, JC-P = 134.5 Hz), 26.8, 23.7. IR: 1753 cmÀ1
(15b). Yield: 39%. 1H NMR (DMSO-d6), d (ppm):
8.17 (s, 0.5H), 7.62 (s, 0.5 H), 7.40–7.26 (m, 5H),
7.11–7.03 (m, 2H), 7.01–6.96 (m, 1H), 5.55 (ddd, 2H,
(C@O), 1676 cmÀ1 (C@O), 1257 cmÀ1 (P@O). Anal.
Calcd for C31H44NO10P: C, 60.26; H, 7.30; N, 2.25.
Found: C, 59.89; H, 7.13; N, 2.25.
JH-P = 13.0 Hz, JAB = 18.2 Hz), 5.44 (d, 2H, JH-P
=
12.2 Hz), 4.80 (dd, 2H, JAB = 12.5 Hz), 3.48-3.20 (m,
3H), 2.31–2.07 (m, 8H), 1.13 (s, 9H), 1.10 (s, 9H).
13C NMR (CDCl3): 176.8, 163.0, 161.0 (dd,
4.8.18. 2,2-Dimethyl-propionic acid [3-(acetyl-benzyloxy-
amino)-1-benzyloxymethyl-propyl]-(2,2-dimethyl-propio-
nyloxymethoxy)-phosphinoyloxymethyl ester (25). Yield:
44%. H NMR (CDCl3), d (ppm): 7.48–7.25 (m, 10H),
5.66–5.53 (m, 4H), 4.84 (s, 2H), 4.48 (s, 2H), 3.78-3.50
3
1
1JC-F = 247.6 Hz, JC-P = 10.9 Hz), 134.2, 129.5,
129.1, 128.7, 128.2, 124.6, 120.9 (dd, 2JC-F = 14.7 Hz,

5132
T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
(m, 4H), 2.37–2.21 (m, 1H), 1.99 (s, 3H), 1.96–1.76 (m,
0.5H), 8.23 (s, 0.5H), 7.91 (s, 0.5H), 5.66–5.56 (m, 4H),
3.59–3.44 (m, 2H), 1.93–1.78 (m, 2H), 1.73–1.40 (m,
3H), 1.17 (s, 18H), 0.92 (t, 3H, J = 7.4 Hz). 13C NMR
2H), 1.13 (s, 18H). 13C NMR (CDCl3), d (ppm): 176.5,
138.2, 135.0, 129.7, 129.0, 128.8, 128.6, 127.9, 127.8,
1
81.7, 75.7, 72.6, 67.4, 43.0, 38.5, 35.5 (d, JC-P
2
=
(CDCl3), d (ppm): 176.9, 163.4, 81.7 (d, JC-P = 6.1 Hz),
2
138.5 Hz), 26.8, 23.6 (d, JC-P = 2.7 Hz), 20.7. IR:
1758 cmÀ1 (C@O), 1668 cmÀ1 (C@O), 1257 cmÀ1
(P@O). Anal. Calcd for C32H46NO10P: C, 60.46; H,
7.29; N, 2.20. Found: C, 60.19; H, 7.49; N, 1.99.
81.4 (d, 2JC-P = 7.1 Hz), 44.9 (d, 3JC-P = 6.1 Hz), 38.8, 34.9
1
(d, JC-P = 138.4 Hz), 23.9 (d,2JC-P = 2.0 Hz), 21.6 (d,
2
2JC-P = 4.1 Hz), 11.8 (d, JC-P = 12.2 Hz). IR: 1754 cmÀ1
(C@O), 1673 cmÀ1 (C@O), 1231 cmÀ1 (P@O). Anal. Calcd
for C18H34 NO9P: C, 49.20; H, 7.80; N, 3.19. Found: C,
49.03; H, 7.84; N, 3.40.
4.9. General procedure for the preparation of 2,2-
dimethyl-propionic acid [3-(acyl-hydroxy-amino)-propyl]-
(2,2-dimethyl-propionyloxymethoxy)-phosphinoyloxy-
methyl esters 7a–f, 8a–f, 17a–c, 18a, 26 and 27
4.9.4. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-{1-[2-(formyl-hydroxy-amino)-ethyl]-2-
methyl-propyl}-phosphinoyloxymethyl ester (7d). Yield:
1
One millimole of the O-protected hydroxamic acids 5, 6,
15, 16, 24 and 25 was dissolved in freshly distilled meth-
anol (50 mL). After addition of the Pd–C catalyst,
hydrogen gas was added to generate a pressure of
3 bar and the mixture was hydrogenated for one hour.
The suspension was filtered through an SPE tube RP-
18 purchased from Supelco. The filtrate was evaporated
to give 2,2-dimethyl-propionic acid [3-(acyl-hydroxy-
amino)-propyl]-(2,2-dimethyl-propionyloxymethoxy)-
phosphinoyloxymethyl esters 7, 8, 17, 18, 26 and 27 as
pale yellow oils.
93%. H NMR (DMSO-d6), d (ppm): 10.01 (s, 0.5H),
9.59 (s, 0.5H), 8.23 (s, 0.5H), 7.89 (s, 0.5H), 5.67–5.57
(m, 4H), 3.60–3.45 (m, 2H), 2.13–2.00 (m, 1H), 1.89–
1.61 (m, 3H), 1.17 (s, 18H), 0.98–0.89 (m, 6H). 13C
NMR (CDCl3), d (ppm): 176.9, 176.8, 163.6, 81.8 (d,
2
2JC-P = 7.1 Hz), 81.4 (d, JC-P = 7.1 Hz), 45.8 (d,
1
3JC-2P = 4.1 Hz), 40.4 (d, JC-P = 134.3 Hz), 38.8, 27.9
(d, JC-P = 4.1 Hz), 26.9, 21.7 (d, JC-P = 14.2 Hz), 20.8
3
2
2
(d, JC-P = 3.1 Hz), 18.9 (d, JC-P = 5.1 Hz). IR:
1754 cmÀ1 (C@O), 1673 cmÀ1 (C@O), 1230 cmÀ1 (P@O).
Anal. Calcd for C19H36NO9P: C, 50.33; H, 8.00;
N, 3.09. Found: C, 50.09; H, 8.26; N, 3.24.
4.9.1. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-[3-(formyl-hydroxy-amino)-1-methyl-
propyl]-phosphinoyloxymethyl ester (7a). Yield: 85%.
1H NMR (DMSO-d6), d (ppm): 10.03 (s, 0.5H), 9.58
(s, 0.5H), 8.23 (s, 0.5H), 7.92 (s, 0.5H), 5.65–5.56
(m, 4H), 3.58-3.38 (m, 2H), 2.03–1.89 (m, 2H), 1.58–
4.9.5. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-{1-[2-(formyl-hydroxy-amino)-ethyl]-bu-
tyl}-phosphinoyloxymethyl ester (7e). Yield: 91%. 1H
NMR (DMSO-d6), d (ppm): 10.01 (s, 0.5H), 9.58 (s,
0.5H), 8.22 (s, 0.5H), 7.90 (s, 0.5H), 5.66–5.56 (m,
4H), 3.61-3.43 (m, 2H), 1.96–1.79 (m, 2H), 1.75–1.31
(m, 5H), 1.17 (s, 18H), 0.84 (t, 3H, J = 7.1 Hz). 13C
NMR (CDCl3), d (ppm): 176.9, 176.8, 163.4, 81.8 (d,
3
1.39 (m, 1H), 1.17 (s, 18H), 1.07 (dd, 3H, JH-P = 19.4
Hz, JH-H = 7.1 Hz). 13C NMR (CDCl3), d (ppm):
2
176.9, 163.2, 81.7 (d, JC-P = 7.1 Hz), 81.5 (d, JC-P
2
=
=
3
1
6.1 Hz), 44.1 (d, JC-P = 12.2 Hz), 38.7, 28.7 (d, JC-P
2
2JC-P = 6.1 Hz), 81.5 (d, JC-1P = 7.1 Hz), 44.9 (d,
2
139.4 Hz), 27.0, 26.8, 13.7 (d, JC-P = 5.1 Hz). IR:
1754 cmÀ1 (C@O), 1673 cmÀ1 (C@O), 1231 cmÀ1
(P@O). Anal. Calcd for C17H32NO9P: C, 48.00; H,
7.58; N, 3.29. Found: C, 48.12; H, 7.75; N, 3.48.
3JC-2P = 6.1 Hz), 38.8, 33.2 (d, JC-P = 138.4 Hz), 30.8
(d, JC-P = 5.1 Hz), 26.9, 24.3 (d, JC-P = 3.1 Hz), 20.4
2
3
(d, JC-P = 12.2 Hz), 13.9. IR: 1754 cmÀ1 (C@O),
1673 cmÀ1 (C@O), 1231 cmÀ1 (P@O). Anal. Calcd for
C19H36NO9P: C, 50.33; H, 8.00; N, 3.09. Found: C,
50.05; H, 8.23; N, 3.29.
4.9.2. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-[3-(formyl-hydroxy-amino)-1-phenyl-pro-
pyl]-phosphinoyloxymethyl ester (7b). Yield: 90%. 1H
NMR (DMSO-d6), d (ppm): 9.99 (s, 0.5H), 9.58 (s,
0.5H), 8.18 (s, 0.5 H), 7.60 (s, 0.5H), 7.38–7.24 (m, 5H),
4.9.6. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-[3-(formyl-hydroxy-amino)-1,1-dime-
thyl-propyl]-phosphinoyloxymethyl ester (7f). Yield:
3
1
5.57 (ddd, 2H, JH-P = 10.6 Hz, JAB = 17.3 Hz), 5.44
89%. H NMR (DMSO-d6), d (ppm): 10.03 (s, 0.5H),
9.57 (s, 0.5H), 8.19 (s, 0.5H), 7.93 (s, 0.5H), 5.66–
5.59 (m, 4H), 3.56-3.46 (m, 2H), 1.80–1.67 (m, 2H),
(ddd, 2 H, 3JH-P = 12.5 Hz, JAB = 7.6 Hz), 3.42–3.10 (m,
3H), 2.31–2.18 (m, 1H), 2.15–1.98 (m, 1H), 1.16 (s, 9H),
1.12 (s, 9H). 13C NMR (CDCl3), d (ppm): 176.9, 176.9,
3
1.17 (s, 18H), 1.11 (d, 6H, JH-P = 17.8 Hz). 13C NMR
2
2
163.4, 156.4, 133.3 (d, JC-P = 7.1 Hz), 129.3, 129.2,
(CDCl3), d (ppm): 176.9, 162.9, 81.7 (d, JC-P = 8.1 Hz),
2
129.1, 129.1, 128.8, 128.1, 128.1, 127.8, 81.9 (d, JC-P
2
81.5 (d, JC-P = 7.1 Hz), 43.9, 38.8, 35.1 (d, JC-P
2
=
=
=
=
2
7.1 Hz), 81.7 (d, JC-P = 7.1 Hz), 46.7 (d, JC-P
3
1
2
8.1 Hz), 33.8 (d, JC-P = 138.4 Hz), 26.9, 22.3 (d, JC-P
1
16.3 Hz), 41.0 (d, JC-P = 139.4 Hz), 38.8, 38.7, 27.1 (d,
2JC-P = 4.1 Hz), 26.9, 26.8. IR: 1754 cmÀ1 (C@O),
1673 cmÀ1 (C@O), 1259 cmÀ1 (P@O). Anal. Calcd for
C22H34NO9P: C, 54.21; H, 7.03; N, 2.87. Found: C,
54.09; H, 7.20; N, 2.72.
2.0 Hz). IR: 1754 cmÀ1 (C@O), 1673 cmÀ1 (C@O),
1231 cmÀ1 (P@O). Anal. Calcd for C18H34NO9P: C,
49.20; H, 7.80; N, 3.19. Found: C, 49.18; H, 8.00; N,
3.18.
4.9.7. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1-methyl-propyl]-(2,2-dimethyl-propionyloxy-
methoxy)-phosphinoyloxymethyl ester (8a). Yield:
90%. 1H NMR (CDCl3), d (ppm): 8.98 (s, 1H),
5.71–5.60 (m, 4H), 4.19–4.08 (m, 1H), 3.44–3.35
4.9.3. 2,2-Dimethyl-propionic acid (2,2-dimethyl-propio-
nyloxymethoxy)-[1-ethyl-3-(formyl-hydroxy-amino)-pro-
pyl]-phosphinoyloxymethyl ester (7c). Yield: 94%. 1H
NMR (DMSO-d6), d (ppm): 10.02 (s, 0.5H), 9.58 (s,

T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
5133
(m, 1H), 2.20–1.96 (m, 5H), 1.75–1.62 (m, 1H), 1.25–
5.60 (m, 4H), 4.17–4.08 (m, 1H), 3.41–3.32 (m, 1H),
2.21–2.04 (m, 4H), 1.92–1.60 (m, 3H), 1.52–1.28 (m,
3H), 1.24 + 1.23 (2s, 18H), 0.91 (t, 3H, J = 7.1 Hz).
13C NMR (CDCl3), d (ppm): 176.9, 176.8, 172.7, 81.7
1.18 (m, 21H). 13C NMR (CDCl3), d (ppm): 177.0,
176.9, 172.7, 81.7 (d, JC-P = 7.1 Hz), 81.4 (d,
2
3
2JC-1P = 7.1 Hz), 45.4 (d, JC-P = 10.2 Hz), 38.8, 28.8
(d, JC-P = 139.4 Hz), 27.1 (d, JC-P = 2.0 Hz), 26.9,
2
2
2
(d, JC-P = 7.1 Hz), 81.4 (d, JC-P = 8.1 Hz), 45.9 (d,
2
1
26.8, 20.5, 13.9 (d, JC-P = 5.1 Hz). IR: 1755 cmÀ1
3JC-P = 5.1 Hz), 38.9, 38.8, 34.0 (d, JC-P = 137.3 Hz),
30.9 (d, JC-P = 5.1 Hz), 26.8, 24.7 (d, JC-P = 3.1 Hz),
(C@O), 1622 cmÀ1 (C@O), 1234 cmÀ1 (P@O). Anal.
Calcd for C18H34NO9P: C, 49.20; H, 7.80; N, 3.19.
Found: C, 48.93; H, 7.91; N, 3.35.
2
2
3
20.6, 20.4 (d, JC-P = 13.2 Hz), 13.8. IR: 1755 cmÀ1
(C@O), 1623 cmÀ1 (C@O), 1235 cmÀ1 (P@O). Anal.
Calcd for C20H38NO9P: C, 51.38; H, 8.19; N, 3.00.
Found: C, 51.10; H, 8.42; N, 3.10.
4.9.8. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1-phenyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (8b). Yield: 92%. 1H
NMR (DMSO-d6), d (ppm): 9.71 (s, 1H), 7.36–7.24 (m,
4.9.12. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1,1-dimethyl-propyl]-(2,2-dimethyl-propionyloxy-
methoxy)-phosphinoyloxymethyl ester (8f). Yield: 92%.
1H NMR (CDCl3), d (ppm): 9.21 (s, 1H), 5.75–5.57
(m, 4H), 3.83–3.73 (m, 2H), 2.12 (s, 3H), 1.99–1.84
3
5H), 5.57 (ddd, 2H, JH-P = 12.8 Hz, JAB = 16.4 Hz),
3
5.44 (ddd, 2 H, JH-P = 12.4 Hz, JAB = 7.9 Hz), 3.43-
3.33 (m, 2H), 3.25–3.17 (m, 1H), 2.27–2.16 (m, 1H),
2.09–1.99 (m, 1H), 1.91 (s, 3H), 1.16 (s, 9H), 1.12 (s,
9H). 13C NMR (CDCl3), d (ppm): 176.9, 172.9, 134.7 (d,
2JC-P = 8.1 Hz), 133.5, 129.3, 129.2, 129.0, 128.7, 128.0,
3
(m, 2H), 1.24 (s, 18H), 1.00 (d, 6H, JHÀP = 17.3 Hz).
13C NMR (CDCl3), d (ppm): 176.8, 172.0, 81.7 (d,
3
2JC-P = 7.1 Hz), 45.1 (d, JC-P = 5.1 Hz), 38.8, 34.9,
2
2
1
127.7, 82.0 (d, JC-P = 7.1 Hz), 81.9 (d, JC-P = 7.1 Hz),
46.6, 41.8 (d, JC-P = 138.4 Hz), 38.7, 28.7, 26.8, 26.8,
33.9 (d, JC-P = 138.4 Hz), 26.9, 22.5, 20.6. IR:
1
1755 cmÀ1 (C@O), 1632 cmÀ1 (C@O), 1234 cmÀ1
(P@O). Anal. Calcd for C19H36NO9P: C, 50.33; H,
8.00; N, 3.09. Found: C, 49.93; H, 8.24; N, 3.23.
2
26.4 (d, JC-P = 4.1 Hz), 20.6. IR: 1754 cmÀ1 (C@O),
1621 cmÀ1 (C@O), 1243 cmÀ1 (P@O). Anal. Calcd for
C23H36NO9P: C, 55.08; H, 7.24; N, 2.79. Found: C,
54.65; H, 7.31; N, 2.66.
4.9.13. 2,2-Dimethyl-propionic acid [1-(3,4-difluoro-phen-
yl)-3-(formyl-hydroxy-amino)-propyl]-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (17a).
4.9.9. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1-ethyl-propyl]-(2,2-dimethyl-propionyloxymeth-
oxy)-phosphinoyloxymethyl ester (8c). Yield: 88%. 1H
NMR (CDCl3), d (ppm): 9.08 (s, 1H), 5.72–5.60 (m,
4H), 4.18–4.08 (m, 1H), 3.42-3.33 (m, 1H), 2.22–2.04
(m, 4H), 1.83–1.67 (m, 3H), 1.55–1.41 (m, 1H), 1.24 +
1
Yield: 87%. H NMR (DMSO-d6), d (ppm): 10.00 (s,
0.5H), 9.57 (s, 0.5H), 8.24–7.93 (m, 0.5H), 7.78–7.57
(m, 0.5H), 7.50–7.03 (m, 3H), 5.66–5.40 (m, 4H), 3.65-
3.40 (m, 3H), 2.34–1.91 (m, 2H), 1.15 (s, 9H), 1.11 (s,
9H). 13C NMR (CDCl3), d (ppm): 177.4, 177.3, 164.0,
1.23 (2s, 18H), 0.99 (t, 3H, J = 7.1 Hz). 13C NMR
163.7, 162.0, 150.4 (dd, JC-F = 248.1 Hz), 131.1, 126.1,
1
2
3
118.4, 117.9, 82.3, 47.1 (d, JC-P = 15.8 Hz), 44.6 (d,
(CDCl3), d (ppm): 176.9, 176.8, 172.8, 81.7 (d, JC-P
7.1 Hz), 81.4 (d, JC-P = 7.1 Hz), 45.9 (d, JC-P
=
=
2
3
1
3JC-P = 14.2 Hz), 41.1 (d, JC-P = 141.4 Hz), 40.6 (d,
1
2
6.1 Hz), 38.8, 35.8 (d, JC-P = 136.3 Hz), 26.9, 26.8,
24.3 (d, JC-P = 2.0 Hz), 22.1 (d, JC-P = 5.1 Hz), 20.6,
1JC-P = 142.7 Hz), 39.1, 30.1 (d, JC-P = 3.1 Hz), 27.2.
2
2
IR: 1753 cmÀ1 (C@O), 1674 cmÀ1 (C@O), 1256 cmÀ1
(P@O). EI-MS C21H26F2NO5P [M+H]+: calculated
524, found 524.
11.9 (d, JC-P = 13.2 Hz). IR: 1755 cmÀ1 (C@O),
3
1630 cmÀ1 (C@O), 1241 cmÀ1 (P@O). Anal. Calcd for
C19H36NO9P: C, 50.33; H, 8.00; N, 3.09. Found: C,
50.27; H, 8.30; N, 3.19.
4.9.14. 2,2-Dimethyl-propionic acid [1-(2-fluoro-phenyl)-
3-(formyl-hydroxy-amino)-propyl]-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (17b).
4.9.10. 2,2-Dimethyl-propionic acid {1-[2-(acetyl-hy-
droxy-amino)-ethyl]-2-methyl-propyl}-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (8d).
1
Yield: 84%. H NMR (DMSO-d6), d (ppm): 9.99 (m,
0.5H), 9.61 (m, 0.5H), 8.16 (m, 0.5H), 7.58 (m,
0.5H), 7.42–7.30 (m, 2H), 7.25–7.15 (m, 2H), 5.59
(ddd, 2H, JH-P = 13.5 Hz, JAB = 15.5 Hz), 5.50 (d,
2 H, JH-P = 12.2 Hz), 3.68-3.53 (m, 1H), 3.29-3.15
(m, 2H), 2.36–2.24 (m, 1H), 2.16–2.05 (m, 1H), 1.15
(s, 9H), 1.12 (s, 9H). 13C NMR (CDCl3), d (ppm):
1
Yield: 83%. H NMR (CDCl3), d (ppm): 9.06 (s, 1H),
5.73–5.64 (m, 4H), 4.18–4.08 (m, 1H), 3.39-3.31
(m, 1H), 2.19–1.99 (m, 5H), 1.83–1.66 (m, 2H), 1.24 (s,
18H), 1.00 (d, 3H, J = 6.9 Hz), 0.94 (d, 3H, J = 6.9
Hz). 13C NMR (CDCl3), d (ppm): 176.9, 176.8, 172.8,
2
2
1
81.7 (d, JC-P = 6.1 Hz), 81.3 (d, JC-P = 8.1 Hz), 46.7
176.8, 163.6, 160.9, 156.2 (dd, JC-F = 246.0 Hz,
3
(d, JC-P = 5.1 Hz), 40.3 (d, JC-P = 134.3 Hz), 3878,
1
2
3JC-P = 8.90 Hz), 129.6, 124.8, 115.9 (d, JC-F
22.7 Hz), 82.0, 46.7 (d, JC-P = 16.2 Hz), 44.7 (d, JC-P
=
=
2
38.8, 27.9 (d, JC-P = 4.1 Hz), 26.9, 21.7 (d, JC-P
3
3
3
=
3
1
14.2 Hz), 21.1, 20.6, 18.8 (d, JC-P = 6.1 Hz). IR:
1755 cmÀ1 (C@O), 1624 cmÀ1 (C@O), 1231 cmÀ1
(P@O). Anal. Calcd for C20H38NO9P: C, 51.38; H,
8.19; N 3.00. Found: C, 50.76; H, 8.00; N, 3.08.
11.4 Hz), 38.8, 33.1 (d, JC-P = 145.1 Hz), 26.8, 26.1.
IR: 1753 cmÀ1 (C@O), 1674 cmÀ1 (C@O), 1243 cmÀ1
(P@O). Anal. Calcd for C22H33FNO9P: C, 52.28; H,
6.58; N, 2.77. Found: C, 52.25; H, 6.66; N, 2.86.
4.9.11. 2,2-Dimethyl-propionic acid {1-[2-(acetyl-
hydroxy-amino)-ethyl]-butyl}-(2,2-dimethyl-propionyl-
oxymethoxy)-phosphinoyloxymethyl ester (8e). Yield:
4.9.15. 2,2-Dimethyl-propionic acid [1-(2,6-dimethyl-
phenyl)-3-(formyl-hydroxy-amino)-propyl]-(2,2-dimethyl-
propionyloxymethoxy)-phosphinoyloxymethyl ester (17c).
Yield: 87%. 1H NMR (DMSO-d6), d (ppm): 9.98
1
91%. H NMR (CDCl3), d (ppm): 9.09 (s, 1H), 5.72–

5134
T. Kurz et al. / Bioorg. Med. Chem. 14 (2006) 5121–5135
(m, 0.5H), 9.60 (m, 0.5H), 8.18 (m, 0.5H), 7.44 (m,
0.5H), 7.11–7.03 (m, 2H), 6.99–6.95 (m, 1H), 5.56
(ddd, 2H, JH-P = 13.0 Hz, JAB = 17.6 Hz), 5.44 (d, 2H,
JH-P = 12.0 Hz), 3.53–3.44 (m, 1H), 3.26-3.09 (m, 2H),
2.33–2.23 (m, 4H), 2.21–2.07 (m, 4H), 1.15 (s, 9H),
1.12 (s, 9H). 13C NMR (CDCl3), d (ppm): 176.9,
155.3, 136.2, 134.2, 131.0, 128.7, 81.6, 45.9, 38.8, 29.7,
26.8, 21.1, 19.5. IR: 1753 cmÀ1 (C@O), 1674 cmÀ1
(C@O), 1254 cmÀ1 (P@O). ESI-MS C24H38NO9P
[M+H]+: calculated 516, found 516.
The development of the cultures and the percentage of
infected RBC’s were determined by light microscopy
of Giemsa-stained thin smears.
4.10.2. Preparation of drug solutions. Twenty micromole
of the respective compounds was solved in 400 ll
DMSO and further diluted with water/ethanol (50/50)
to obtain the particular concentration.
4.10.3. Determination of parasite growth inhibition. The
tests were carried out in 96-well microtitre plates under
strict aseptic conditions, according to literature.15,17
Dilutions of each compound were added to 250 ll of a
suspension of P. falciparum infected erythrocytes (1.5%
hematocrit, 1.5–2% parasitemia). The plates were
flushed with a gas mixture consisting of 90% N2, 5%
O2 and 5% CO2, closed tightly and incubated at 37 ꢁC
for 24 h. Afterwards, 0.1 lCi 8-[3H]hypoxanthine was
added to each well. The plates were flushed with the
above-mentioned gas mixture, incubated for additional
24 h at 37 ꢁC and subsequently harvested with a cell har-
vester system (Inotech, Dottikon, Switzerland). Infected
erythrocytes were washed four times with distilled water
before they were analysed for incorporated radioactivity
in a multidetector liquid scintillation counter (Wallac,
Turku, Finland).
4.9.16. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1-(3,4-difluoro-phenyl)-propyl]-(2,2-dimethyl-pro-
pionyloxymethoxy)-phosphinoyloxymethyl ester (18a).
1
Yield: 89%. H NMR (CDCl3), d (ppm): 7.21–6.91 (m,
3H), 5.70–5.39 (m, 4H), 4.08-3.05 (m, 3H), 2.63–2.39
(m, 1H), 2.32–1.78 (m, 4H), 1.22 (s, 9H), 1.21 (s, 9H).
13C NMR (CDCl3), d (ppm): 176.9, 173.1, 148.8,
2
132.2, 125.7, 118.2, 118.1, 117.5, 81.9 (d, JC-P
=
1
6.6 Hz), 45.7, 41.0 (d, JC-P = 138.7 Hz), 38.8, 29.7,
27.8, 26.8. IR: 1753 cmÀ1 (C@O), 1622 cmÀ1 (C@O),
1246 cmÀ1 (P@O). EI-MS C23H34F2NO9P [M+H]+: cal-
culated 538, found 538.
4.9.17. 2,2-Dimethyl-propionic acid [1-benzyloxymethyl-
3-(formyl-hydroxy-amino)-propyl]-(2,2-dimethyl-propion-
yloxymethoxy)-phosphinoyloxymethyl ester (26). Yield:
87%. 1H NMR (DMSO-d6), d (ppm): 9.99 (s, 0.5H),
9.55 (s, 0.5H), 8.25–8.18 (m, 0.3H), 8.08–7.87 (m,
0.7H), 5.68–5.52 (m, 4H), 4.97 (br s, 1H), 3.75-3.43
(m, 3H), 3.24–3.13 (m, 1H), 2.09–1.63 (m, 3H), 1.17 (s,
18H). 13C NMR (DMSO-d6), d (ppm): 176.5, 162.1,
161.3, 157.5, 82.7, 59.2, 58.9, 47.9, 44.7, 38.6, 37.7 (d,
Acknowledgment
Financial support for this project was provided by
BioAgency AG, Hamburg.
2
1JC-P = 136.1 Hz), 26.8, 25.8 (d, JC-P = 3.0 Hz). IR:
3240 cmÀ1 (O–H), 1753 cmÀ1 (C@O), 1668 cmÀ1 (C@O),
1242 cmÀ1 (P@O). Anal. Calcd for C17H32NO10P: C,
46.26; H, 7.31; N, 3.17. Found: C, 46.09; H, 7.32; N, 3.25.
References and notes
1. Zeidler, J.; Schwender, J.; Muller, C.; Wiesner, J.; Weide-
¨
meyer, C.; Beck, E.; Jomaa, H.; Lichtentaler, H. K. Z.
Naturforsch. C 1998, 53, 980.
2. Jomaa, H.; Wiesner, J.; Sanderbrand, S.; Altincicek, B.;
4.9.18. 2,2-Dimethyl-propionic acid [3-(acetyl-hydroxy-
amino)-1-benzyloxymethyl-propyl]-(2,2-dimethyl-propion-
yloxymethoxy)-phosphinoyloxymethyl ester (27). Yield:
92%. 1H NMR (DMSO-d6), d (ppm): 9.73 (s, 1H),
5.68–5.57 (m, 4H), 4.96 (br s, 1H), 3.75-3.49 (m, 4H),
2.08–1.75 (m, 6H), 1.19 (s, 18H). 13C NMR (CDCl3),
Weidemeyer, C.; Hintz, M.; Turbachova, I.; Eberl, M.;
¨
Zeidler, J.; Lichtenthaler, H. K.; Soldati, D.; Beck, E.
Science 1999, 285, 1573.
3. (a) Kuzuyama, T.; Takahashi, S.; Takagi, M.; Seto, H.
J. Biolog. Chem 2000, 275, 19928; (b) Eisenreich, W.;
Rohdich, F.; Bacher, A. Trends Plant Sci. 2001, 6, 78; (c)
Rohmer, M. Nat. Prod. Rep. 1999, 16, 565.
4. (a) Missinou, M. A.; Borrmann, S.; Schindler, A.; Issifou,
S.; Adegnika, A. A.; Matsiegui, P. B.; Binder, R.; Lell, B.;
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2
d (ppm): 176.5, 170.6, 81.7, 58.9 (d, JC-P = 13.5 Hz),
3
45.9 (d, JC-P = 12.7 Hz), 38.6, 37.6 (d, JC-P
1
=
2
138.5 Hz), 26.9, 23.1 (d, JC-P = 2.1 Hz), 20.7. IR:
3219 cmÀ1 (O–H), 1753 cmÀ1 (C@O), 1627 cmÀ1
(C@O), 1236 cmÀ1 (P@O). Anal. Calcd for
C18H34NO10P: C, 47.47; H, 7.52; N, 3.08. Found: C,
47.13; H, 7.68; N, 3.05.
4.10. Determination of in vitro antimalarial activity
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blood group A positive), RPMI 1640 medium supple-
mented with 25 mM HEPES, 20 mM sodium bicarbon-
ate, and 0.5% AlbuMAX (Invitrogen, Karlsruhe,
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90% N2, 5% O2 and 5% CO2 and incubated at 37 ꢁC.

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