Diastereoselective addition of diethyl difluoromethylphosphonate to enantiopure sulfinimines: synthesis of α,α-difluoro-β-aminophosphonates, phosphonic acids, and phosphonamidic acids

Article abstract of DOI:10.1016/j.tet.2006.08.017

Addition of diethyl lithiodifluoromethylphosphonate to enantiomerically pure aromatic, heteroaromatic, and aliphatic aldehyde-derived sulfinimines afforded N-sulfinyl α,α-difluoro-β-aminophosphonates with generally good enantioselectivity and in high yiel

Full text of DOI:10.1016/j.tet.2006.08.017

Tetrahedron 62 (2006) 9902–9910
Diastereoselective addition of diethyl difluoromethylphosphonate
to enantiopure sulfinimines: synthesis of a,a-difluoro-
b-aminophosphonates, phosphonic acids,
and phosphonamidic acids
a
Gerd-Volker Roschenthaler, Valery P. Kukhar, Michael Yu. Belik,
b
b
€
Kateryna I. Mazurenkob and Alexander E. Sorochinskyb,
*
aInstitute of Inorganic and Physical Chemistry, University of Bremen, Leobener Strasse, 28334 Bremen, Germany
bInstitute of Bioorganic Chemistry and Petrochemistry, NAS of Ukraine, Murmanska 1, Kiev-94 02660, Ukraine
Received 6 June 2006; revised 18 July 2006; accepted 3 August 2006
Available online 23 August 2006
Abstract—Addition of diethyl lithiodifluoromethylphosphonate to enantiomerically pure aromatic, heteroaromatic, and aliphatic aldehyde-
derived sulfinimines afforded N-sulfinyl a,a-difluoro-b-aminophosphonates with generally good enantioselectivity and in high yield. The
reaction with acetophenone-derived sulfinimine resulted in the formation of the addition product with high diastereoselectivity and in only
moderate yield. A two-step deprotection involving treatment of diastereomerically pure N-sulfinyl a,a-difluoro-b-aminophosphonates
with trifluoroacetic acid in EtOH followed by refluxing with 10 N HCl provided enantiopure a,a-difluoro-b-aminophosphonates and
a,a-difluoro-b-aminophosphonic acids. The N-Cbz derivative of (R)-2-amino-1,1-difluoro-2-phenylethylphosphonate was a convenient
starting point for the preparation of corresponding difluorophosphonate monoester, difluorophosphonic acid, and difluorophosphonamidic
acid. At 21 ꢀC difluorophosphonamidic acid was stable in aqueous solution at pH above 5.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Current approaches to nonracemic difluoromethylene con-
taining aminophosphonic acids have been largely based on
the coupling of phosphonodifluoromethyl organometallic
reagents with electrophilic substrates for the preparation of
chain-extended adducts. The difluoromethylene analog of
phosphoserine 1 was obtained in a multistep pathway using
the reaction of dialkyl lithiodifluoromethylphosphonate with
a primary triflate derived from (R)-isopropylideneglycerol as
source of chirality.5a Owing to the inertness of dialkyl lithio-
difluoromethylphosphonate toward secondary triflates, the
condensation of dialkyl lithiodifluoromethylphosphonates
with an ester, methyl Grignard addition, and radical deoxy-
genation of an intermediate tertiary alcohol sequence has
been applied for the synthesis of difluoromethylene analogs
of phosphothreonine 2 and allo-phosphothreonine 3 from
L-glycerate and D-serine, respectively.5b Stereoselective
synthesis of phosphothreonine 2 and allo-phosphothreonine
3 mimetics as well as their enantiomers was also achieved by
applying a Cu(I)-mediated coupling reaction of [(diethoxy-
phosphinyl)difluoromethyl]zinc bromide and b-iodo-a,b-
unsaturated ester followed by diastereoselective hydrogenation
and amination using bornane-10,2-sultam as a chiral
auxiliary.5c Nucleophilic opening of furanosylamines with
diethyl lithiodifluoromethylphosphonate led to the forma-
tion of diastereomeric mixture of acyclic aminophos-
phonates with moderate diastereoselectivity. Separation of
The importance of the aminophosphonic acids as structural
analogs of amino carboxylic acids is well recognized.1
Replacement of hydrogen atoms by fluorine atoms in amino
carboxylic acids has been found to provide increased lipo-
philicity, resistance to oxidative and proteolytic degradation,
changes in basicity or acidity of neighboring groups, confor-
mational restrictions on the peptide chain, and modification
of enzyme/substrate interaction,2 therefore fluorinated
aminophosphonic acids are of interest as biologically active
compounds as well as building blocks for the preparation
of peptidic materials with unique structural properties. Par-
ticular attention is devoted to aminophosphonic acids that
contain a difluoromethylene group connected to a phospho-
rus atom in their role as hydrolytically stable phosphoamino
acid mimetics in terms of both steric factors and pKa value
(Fig. 1).3 Such mimetics have found application in the
design of protein phosphatases, glycosyltransferases, and
L-aspartate-b-semialdehyde dehydrogenase inhibitors.4
Keywords: Asymmetric synthesis; Aminophosphonic acids and derivatives;
a,a-Difluoroalkylphosphonates; Sulfinimines; Diethyl difluoromethyl-
phosphonate.
* Corresponding author. Tel.: +380 44 5732531; fax: +380 44 5732552;
e-mail: sorochinsky@bpci.kiev.ua
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.017

G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
9903
NH2
NH2
NH2
HO
CF P(O)(OH)2
2
HO
CF P(O)(OH)2
CF P(O)(OH)2
HO
2
2
O
O
O
O
1
2
3
O
Bn
N
R1
Bn
N
CF P(O)(OH)2
R4
CF2P(O)(OEt)2
R4
R3
2
HO
R1
NH2
CF P(O)(OEt)2
R3
2
6
NH2
HO
O
R2
2
BnO
BnO
R
CF P(O)(OH)2
4a-c
5a-c
2
a) R1=Bn, R2=R4=H, R3=CH2OBn
7
b) R1=R4=H, R2=OBn, R3=CH2OBn
c) R1=OBn, R2=R3=H, R4=CH2OBn
Figure 1.
aminophosphonates followed by cyclization afforded
azasugars 4 and 5 bearing difluoromethylenephosphonate
group in good yields.6
both cases was the opposite to that obtained in reaction of
sulfinimines with organometallic reagents including eno-
lates, Grignard reagents, metallo phosphite, and ethylalumi-
num cyanoisopropoxide.10 Recently, in our preliminary
communication, we reported that sulfinimines are also effec-
tive substrates for the addition of a difluoromethylphospho-
nate carbanion.12 In this paper, we wish to report in full our
studies concerning the addition reactions of difluoromethyl-
phosphonate carbanion to sulfinimines with diverse steric
and electronic properties. The effect of different methods
for the preparation of the difluoromethylphosphonate carb-
anion on stereoselectivity is also discussed.
Preparation of the difluoromethylene analog of b-aspartyl
phosphate 6 was reported through addition of trimethylsilyl-
difluoromethylphosphonate in the presence of a catalytic
amount of TBAF to protected L-aspartate semialdehyde,7a,b
or directly by Cu(I)-mediated coupling reaction of [(diethoxy-
phosphinyl)difluoromethyl]zinc bromide and protected
aspartic acid chloride.7c Another methodology involving
the use of benzylic a,a-difluorophosphonates in transition
metal-catalyzed cross-coupling and alkylation reactions
with L-alanine8a and glycine8b derivatives has been applied
for the preparation of the difluoromethylene analog of phos-
photyrosine 7.
2. Results and discussion
Initially, we have found that addition of the phosphono-
difluoromethyl carbanion, prepared by deprotonation of
diethyl difluoromethylphosphonate 8 with LDA in THF at
ꢁ78 ꢀC, to enantiomerically pure sulfinimine (S)-9a pro-
ceeded smoothly within 1 h to afford, after mild acidic
work-up, the corresponding N-sulfinyl a,a-difluoro-b-
aminophosphonate 10a with 90% de (Scheme 1, Table 1,
entry 1). In spite of the relatively weak nucleophilicity and
thermal instability of diethyl lithiodifluoromethylphospho-
nate,13 N-sulfinyl a,a-difluoro-b-aminophosphonate 10a
was obtained in high combined yield. Direct crystallization
of the crude reaction mixture from ether afforded the pure
major diastereoisomer. Variation of the base (Table 1, entry
2) and the solvent (Table 1, entries 3 and 4) did not improve
the selectivity of addition and resulted in incomplete con-
version of the starting sulfinimine (S)-9a, as indicated by
1H NMR and TLC analysis of crude products.
The nucleophilic addition of methyl- and chloromethyl-
phosphonate carbanions to the C]N bond of enantiopure
sulfinimines was found to be effective in the asymmetric
syntheses of b-aminophosphonates and b-aminophosphonic
acids due to exceptional characteristics of the chiral sulfinyl
group.9 The N-p-toluenesulfinyl substituent in imines pro-
vides high diastereofacial selectivity and activates the
C]N bond for addition of different classes of nucleo-
philes.10 Moreover a wide range of N-p-toluenesulfinyl-
imines can be easily prepared by condensation of
p-toluenesulfinamide, which is readily available in either
configuration, with appropriate aldehydes and ketones
according to the procedures reported by Davis et al.11 Addi-
tion of a methylphosphonate carbanion to aldehyde-derived
(S)-sulfinimines afforded N-sulfinyl b-aminophosphonates
with the (R)-absolute configuration at the newly generated
stereocenter of the major diastereomers. Stereoselectivity
ranged between 66 and 82% de depending on the nature
of the imine and the reaction conditions.9a,b The highest
de was observed in the addition of dimethyl lithiomethyl-
phosphonate to a benzaldehyde-derived sulfinimine in
THF. In the analogous reactions of aldehyde-derived (S)-
sulfinimines with chloromethylphosphonate carbanions,
the corresponding a-chloro-b-amino adducts were isolated
with the exclusive (R)-absolute configuration at the b-carbon
atom.9c The induced configuration at the b-carbon atom in
R1
R2
O
S
O
O
1. base
2.
P(OC2H5)2
HCF2P(OC2H5)2
p-Tolyl
N
R2
H
O
S
F
F
8
R1
p-Tolyl
N
(Ss,R)-10
(S)-9
Scheme 1.

9904
G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
Table 1. Reaction of the diethyl lithiodifluoromethylphosphonate with sulfinimines (S)-9a–ha
Entry
Sulfinimine (S)-9
R1
Conditions
Product (Ss,R)-10
de (%)b
R2
Yield (%)c
74
69
1
2
3
4
5
6
7
8
9a
9a
9a
9a
9b
9c
9d
9e
9f
9g
9h
9h
9h
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
LDA, THF, ꢁ78 ꢀC, 1 h
t-BuLi, THF, ꢁ78 ꢀC, 1 h
LDA, Et2O, ꢁ78 ꢀC, 1 h
LDA, DME, ꢁ60 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 1 h
LDA, THF, ꢁ78 ꢀC, 5 h
LDA, CeCl3, THF, ꢁ78 ꢀC, 1 h
10a
10a
10a
10a
10b
10c
10d
10e
10f
10g
10h
10h
10h
90
90
70
82
88
88
84
84
82
88
92
92
92
d
d
p-MeO–C6H4
p-CF3–C6H4
2-Thienyl
n-C5H11
i-Pr
E-PhCH]CH
Ph
Ph
92e
70
67
72
75
76
9
10
11
12
13
40 (51)f
42 (49)f
36 (45)f
Ph
a
Reactions were performed using 1 equiv of sulfinimine (S)-9 and 1.3 equiv of diethyl difluoromethylphosphonate 8.
Determined by 1H and 19F NMR analyses of the crude reaction mixtures.
Isolated yield of major diastereoisomer.
Not determined.
Combined yield of diastereoisomers.
Yield of the recovered starting sulfinimine (S)-9h.
b
c
d
e
f
The base and solvent optimizations outlined above permitted
mixture of 10b, which exists as an oil, by flash chromato-
graphy were unsuccessful. The stereochemistry of the major
diastereomer of 10a was determined to be (Ss,R) by X-ray
analysis.15 The stereochemistry of the remaining products
(Ss,R)-10b–h have been assigned by analogy.
the use of LDA in THF for addition of diethyl difluoro-
methylphosphonate 8 to other sulfinimines. In the cases of
4-substituted benzaldehyde-derived sulfinimines (S)-9b,c
with either electron-withdrawing or electron-donating
groups, the corresponding adducts 10b,c were obtained
with the stereochemical outcome compared to that observed
for N-benzylidene derivative (S)-9a (Table 1, entries 5 and
6). However, the use of heteroaromatic and alkyl-substituted
sulfinimines (S)-9d–f as substrates provided lower stereo-
selectivity (Table 1, entries 7–9). The size of the alkyl group
has no effect on the diastereoselectivity of addition as illus-
trated by sulfinimines (S)-9e,f where R¼n-pentyl and iso-
propyl. When trans-cinnamaldehyde-derived sulfinimine
(S)-9g was subjected to our reaction conditions, the 1,2-
addition product 10g was obtained exclusively in good yield
and with high stereocontrol (Table 1, entry 10).
The (R)-absolute configuration of the newly formed stereo-
center in the major diastereomers 10 corresponds to that
observed for the addition of methylphosphonate carbanions
to sulfinimines (S)-9. Thus, the stereochemical outcome is
consistent with the transition state TS proposed in the
nonfluorinated series by Mikolajczyk et al.:9a,b the lithium
cation coordinates to both the phosphonate oxygen of 8
and the sulfinyl oxygen of the substrate (S)-9 in an s-cis
conformation, and addition to the C]N bond occurs on
the side that is opposite to the p-tolyl group (Fig. 2).
With a high-yielding synthesis of N-sulfinyl a,a-difluoro-
b-aminophosphonates (Ss,R)-10 in hand, we proceeded to
investigate its reactivity. A significant advantage of sulfinyl
methodology is that N-sulfinyl b-aminophosphonates have
the potential to undergo further synthetic manipulations.9
The diastereomerically pure (Ss,R)-10a,d–f,h were N-desul-
finylated by treatment with trifluoroacetic acid in EtOH at
room temperature (Scheme 2). Under these conditions, the
phosphonate group remained intact, and the a,a-difluoro-
b-aminophosphonates (R)-11a,d–f,h were isolated by flash
chromatography in good yields. Hydrolysis of (R)-11a,d–
f,h in refluxing 10 N HCl provided, after treatment with pro-
pylene oxide, crystalline a,a-difluoro-b-aminophosphonic
acids (R)-12a,d–f,h in good to excellent isolated yields.
Attempts to expand the scope of the reaction by employing
imines derived from ketones have met with limited success.
Deprotonation of 8 with LDA in THF at ꢁ78 ꢀC, followed
by addition of acetophenone-derived sulfinimine (S)-9h led
to the formation of adduct 10h with a 92% de and in only
moderate yield after 1 h (Table 1, entry 11). Purification
by chromatography allowed the isolation of major diastereo-
mer 10h in 40% yield as well as unreacted starting sulfini-
mine (S)-9h in 51% yield. The diastereoselectivity and
yield remained essentially unchanged with a longer reaction
time (Table 1, entry 12). Competitive deprotonation of the
sulfinimine (S)-9h was likely responsible for the moderate
yield observed in the addition reaction. It was anticipated
that the effect of a cerium salt on the reactivity of dialkyl
lithiodifluoromethylphosphonate14 might favor addition to
acetophenone-derived sulfinimine (S)-9h over deprotona-
tion. However, running the reaction in the presence of 1 M
equiv of cerium(III) chloride did not significantly change
both the yield and selectivity in this case (Table 1, entry 13).
OR
RO
P
F2C
O
RL
RS
Li
N
:
The N-sulfinyl a,a-difluoro-b-aminophosphonate dia-
stereomers 10c–h were separated by chromatography or
crystallization to give the pure major diastereomers. At the
same time all attempts to separate the diastereomeric
S
O
TS
Tolyl
Figure 2.

G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
9905
R1
R2
O
O
S
Ph
F
O
P(OH)2
P(OC2H5)2
CbzHN
p-Tolyl
N
H
F
)-14
69%
F
F
(
R
(Ss,R)-10a,d-f,h
TFA
C2H5OH
1) (CH3)3SiBr
2) H2O
R2
R1
H2N
R2
R1
H2N
O
Ph
O
O
CbzCl, K2CO3
THF
1) 10 N HCl
P(OH)2
P(OC2H5)2
P(OC2H5)2
CbzHN
O
2)
F
F
F
F
F
F
(
R
)-13
91%
1) NaI, acetone
(
R
)-12a,d-f,h
70-90%
(
R
)-11a,d-f,h
77-97%
+
2) H
1) C2H5ONa, C2H5OH
2) (COCl)2, DMF
Ph
O
P
Ph
O
Ph
F
O
P
OC2H5
NHBn
OC2H5
OH
ONa
NaI
methyl ethyl
ketone
P
CbzHN
CbzHN
3) Et3N
NHBn
CbzHN
F
F
F
F
F
)-17
4) PhCH2NH2
( )-15
R
(
Rp,R)-16 + (Sp,R)-16
(
R
75%
73%
61%
Scheme 2.
1
The enantiomeric purity of a,a-difluoro-b-aminophos-
phonic acids (R)-12a,d–f,h so obtained was >98% ee.
Consequently deprotection of N-sulfinyl a,a-difluoro-b-
aminophosphonates (Ss,R)-10a,d–f,h occurred under
the conditions described above without epimerization at
the b-position. For the determination of enantiomeric purity
of a,a-difluoro-b-aminophosphonic acids, we adopted
previously developed method16 of chiral precolumn deriva-
tization followed by chromatographic separation of dia-
stereomeric OPA/NAC derivatives. Racemic samples of
a,a-difluoro-b-aminophosphonic acids 12a,d–f,h were pre-
pared according to the described method using racemic
9a,d–f,h as starting compounds. The a,a-difluoro-b-
aminophosphonate (R)-11a was further elaborated to the
N-carbobenzyloxy derivative (R)-13 by treatment with
benzyloxycarbonyl chloride/potassium carbonate in 91%
yield. Transformation of (R)-13 into N-Cbz-protected a,a-
difluoro-b-aminophosphonic acid (R)-14 was achieved
with bromotrimethylsilane and subsequent addition of water.
The difluorophosphonic acid (R)-14 was obtained after
crystallization from acetone as solvate with 1 M equiv of
acetone, which could not be completely removed from
solvate by heating at 60 ꢀC for 4 h under reduced pressure.
Selective hydrolysis of difluorophosphonate diester (R)-13
using sodium iodide in acetone afforded difluorophos-
phonate monoester (R)-15. The structural assignment for
difluorophosphonate monoester (R)-15 was based on 1H
NMR, which confirmed the loss of one ethyl group. The
N-Cbz-protected difluorophosphonate monoester (R)-15
was converted by treatment of the corresponding sodium
salt with oxalyl chloride followed by triethylamine to give
an intermediate phosphonyltriethylammonium salt.17 The
obtained reaction mixture was then treated with benzyl-
amine to produce difluorophosphonamide 16. Difluorophos-
phonamide 16 was purified chromatographically after
standard work-up. The overall yield of the procedure was
61%. As the reaction generated a new stereogenic center at
phosphorus, the product was obtained as mixture of
diastereomers in ratio 1:1 according to H, 19F, and 31P
NMR analyses. Purification of difluorophosphonamide 16
by chromatography on silica gel did not alter the diastereo-
meric ratio. After repeated deprotection of difluorophos-
phonamide 16 with sodium iodide under more vigorous
conditions in methyl ethyl ketone, the sodium salt of
difluorophosphonamidic acid (R)-17 was isolated in 73%
yield as a nonhygroscopic yellow powder. The 1H, 19F, and
31P NMR spectra are consistent with the assigned structure
and have confirmed the absence of impurities in the product.
Further characterization of sodium salt (R)-17 involved the
examination of the hydrolytic stability of the phosphon-
amide linkage. Previously it has been found that phosphon-
amides serve as analogs of the transition state of the
enzyme-catalyzed amide bond hydrolysis owing to the tetra-
hedral configuration around the phosphorus, and therefore,
act as inhibitors of zinc metalloproteases.18 However,
several publications have reported instability of phosphon-
amides at acidic pH.18e,19 For example, the half-life of
N-[[(benzyloxycarbonyl)amino]hydroxyphosphinyl]-L-phenyl-
alanine at pH 7.5 is more than eight days, but at pH 6.2 it is
4 h; it is hydrolyzed in minutes at pH 2.3.19a The stability of
phosphonamides can be increased by reducing the basicity
of the nitrogen, as has been shown in the case of b-fluoro-
a-amino phosphonamidic acids.20 In our study sodium salt of
difluorophosphonamidic acid (R)-17 was stable at pH above
5.0 for two weeks at 21 ꢀC. Only slow hydrolysis was
observed at pH 2.18 (half-life was 36 h). Thus, introduction
of fluorine atoms in the a-position relative to phosphorus
increased the hydrolytic stability of phosphonamides.
3. Conclusion
In summary, we have described an efficient route to
diastereomerically pure N-sulfinyl a,a-difluoro-b-amino-
phosphonates via addition of diethyl difluoromethyl-
phosphonate to enantiopure sulfinimines. The usefulness

9906
G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
of N-sulfinyl a,a-difluoro-b-aminophosphonates has been
demonstrated in its application to a concise synthesis of
enantiomerically pure a,a-difluoro-b-aminophosphonates
and a,a-difluoro-b-aminophosphonic acids. N-Cbz-pro-
tected (R)-2-amino-1,1-difluoro-2-phenylethylphosphonate
was employed for the synthesis of the corresponding
difluorophosphonate monoester, difluorophosphonic acid,
and difluorophosphonoamidic acid. At 21 ꢀC difluorophos-
phonoamidic acid was stable at pH above 5. Only slow
hydrolysis was observed at pH 2.18 (half-life was 36 h).
Hydrolytically stable at physiological pH, difluorophosphon-
amides may find applications as inhibitors in biochemical
processes.
101.2 Hz); IR (CH2Cl2): n 3482, 2982, 1259, 1022 cmꢁ1
.
Anal. Calcd for C19H24F2NO4PS: C, 52.90; H, 5.61; N,
3.25. Found: C, 53.14; H, 5.68; N, 3.30.
4.1.2. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-2-(p-methoxyphenyl)ethylphosphonate (10b).
Chromatography on silica gel (hexane/ethyl acetate 1:1);
1
yield 92% (oil); 88% de; [a]2D0 +39.8 (c 1.17, CHCl3); H
NMR (200 MHz, CDCl3): d 1.19 (t, J 7.0 Hz, 3H), 1.28 (t,
J 7.0 Hz, 3H), 2.34 (s, 3H), 3.76 (s, 3H), 3.99–4.24 (m,
4H), 4.81–5.03 (m, 1H), 5.29 (d, J 7.6 Hz, 1H), 6.76 (d, J
8.2 Hz, 2H), 7.12–7.20 (m, 4H), 7.53 (d, J 8.2 Hz, 2H);
19F NMR (188 MHz, CDCl3): d ꢁ114.73 (ddd, J 301.2,
101.5, and 14.0 Hz, 1F), ꢁ116.60 (ddd, J 301.2, 103.4,
and 15.1 Hz, 1F); 31P NMR (81 MHz, CDCl3): d 6.79 (dd,
J 103.4 and 101.5 Hz); IR (CH2Cl2): n 3159, 1512, 1253,
1052 cmꢁ1. Anal. Calcd for C20H26F2NO5PS: C, 52.06; H,
5.68; N, 3.04. Found: C, 52.21; H, 5.78; N, 3.09.
4. Experimental
4.1. General
All reagents were obtained from commercial suppliers and
were used without further purification. THF and ether
were distilled from sodium/benzophenone immediately
before use. Reactions requiring anhydrous conditions were
4.1.3. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-2-(p-trifluoromethylphenyl)ethylphosphonate
(10c). Chromatography on neutral aluminum oxide
(CH2Cl2/ethyl acetate 2:1); yield 70% (oil); [a]2D0 +25.38
1
1
run under an atmosphere of dry argon. H, 19F, and 31P
(c 1.32, CHCl3); H NMR (200 MHz, CDCl3): d 1.09 (t, J
NMR spectra were determined in the indicated solvent and
referenced to TMS and CFCl3 as internal standard and
85% H3PO4 as external standard, respectively. IR spectra
were recorded on Specord M-80 spectrometer. Optical rota-
tions were measured on a Perkin–Elmer 243 polarimeter.
Column chromatography was carried out with Merck silica
gel 60 (230–400 mesh) and Woelm Pharma neutral alumi-
num oxide activity grade Super I (type W 200). Thin-layer
chromatography was performed on Merck TLC plates pre-
coated with silica gel 60 F254 and aluminum oxide 60 F254
neutral of 0.25 mm thickness. TLC plates were visualized
with ultraviolet light (254 nm) and/or in an iodine chamber.
The sulfinimines were prepared by condensation of commer-
cially available (S)-(+)-toluenesulfinamide with appropriate
aldehyde or ketone as previously described.11a
7.0 Hz, 3H), 1.24 (t, J 7.0 Hz, 3H), 2.19 (s, 3H), 3.93–4.24
(m, 4H), 4.84–5.05 (m, 1H), 5.70 (d, J 6.0 Hz, 1H), 6.94
(d, J 8.0 Hz, 2H), 7.22 (d, J 8.0 Hz, 2H), 7.30–7.36 (m,
4H); 19F NMR (188 MHz, CDCl3): d ꢁ63.30 (s, 3F),
ꢁ113.12 (ddd, J 304.0, 99.2, and 12.1 Hz, 1F), ꢁ117.19
(ddd, J 304.0, 104.0, and 16.8 Hz, 1F); 31P NMR
(81 MHz, CDCl3): d 6.17 (dd, J 104.0 and 99.2 Hz); IR
(CH2Cl2): n 3149, 1249, 1019 cmꢁ1. Anal. Calcd for
C20H23F5NO4PS: C, 48.10; H, 4.64; N, 2.80. Found: C,
48.30; H, 4.74; N, 3.08.
4.1.4. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-2-(2-thienyl)ethylphosphonate (10d). Crystalli-
zation from hexane/ether; yield 67%; mp 70–71 ꢀC; [a]D20
+58.7 (c 1.07, CHCl3); 1H NMR (200 MHz, CDCl3):
d 1.15 (t, J 7.2 Hz, 3H), 1.24 (t, J 7.2 Hz, 3H), 2.29 (s,
3H), 3.86–4.26 (m, 4H), 5.07–5.29 (m, 2H), 6.82 (dd,
J 5.0 and 3.6 Hz, 1H), 6.95 (d, J 3.6 Hz, 1H), 7.13 (d,
J 8.0 Hz, 2H), 7.17–7.20 (m, 1H), 7.52 (d, J 8.0 Hz, 2H);
19F NMR (188 MHz, CDCl3): d ꢁ114.21 (ddd, J 300.4,
100.8, and 11.2 Hz, 1F), ꢁ116.63 (ddd, J 300.4, 102.2,
and 12.4 Hz, 1F); 31P NMR (81 MHz, CDCl3): d 6.50 (dd,
J 102.2 and 100.8 Hz); IR (CH2Cl2): n 3457, 3137, 1260,
1018 cmꢁ1. Anal. Calcd for C17H22F2NO4PS2: C, 46.68;
H, 5.07; N, 3.20. Found: C, 47.01; H, 5.17; N, 3.21.
4.1.1. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-2-phenylethylphosphonate (10a). Typical proce-
dure: to a solution of diethyl difluoromethylphosphonate 8
(245 mg, 1.30 mmol) in THF (3 mL) at ꢁ78 ꢀC was added
LDA (1.8 M solution, 0.72 mL, 1.30 mmol). After 0.5 h
sulfinimine (S)-9a (243 mg, 1.00 mmol) in THF (1 mL)
was added dropwise and the solution was stirred at
ꢁ78 ꢀC for 1 h. At this time the reaction was quenched by
addition of saturated aqueous NH4Cl (5 mL) and the solution
was warmed to room temperature. After dilution with H2O
(2 mL) the solution was extracted with EtOAc (2ꢂ5 mL).
The combined organic layers were washed with brine
(5 mL) and dried (MgSO4). Concentration under reduced
pressure gave the crude phosphonate 10a with 90% de. Crys-
tallization from ether afforded 320 mg (74%) of (Ss,R)-10a
as a white solid; mp 95–97 ꢀC; [a]D20 +53.7 (c 1.08,
4.1.5. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoroheptylphosphonate (10e). Chromatography on
silica gel (hexane/ethyl acetate 3:2); yield 72% (oil); [a]D25
+68.38 (c 2.34, CHCl3); 1H NMR (300 MHz, CDCl3):
d 0.89 (t, J 7.0 Hz, 3H), 1.25–1.71 (m, 7H), 1.37 (t,
J 7.0 Hz, 3H), 1.39 (t, J 7.0 Hz, 3H), 1.88–1.99 (m, 1H),
2.40 (s, 3H), 3.78–3.94 (m, 1H), 4.12 (d, J 8.8 Hz, 1H),
4.23–4.34 (m, 4H), 7.29 (d, J 8.0 Hz, 2H), 7.71 (d,
J 8.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): d ꢁ115.22
(m, 1F), ꢁ115.61 (m, 1F); 31P NMR (121 MHz, CDCl3):
d 4.5 (t, J 100.2 Hz); IR (CH2Cl2): n 3481, 3157, 1239,
1091 cmꢁ1. Anal. Calcd for C18H30F2NO4PS: C, 50.81; H,
7.11; N, 3.29. Found: C, 50.54; H, 7.32; N, 3.51.
1
CHCl3); H NMR (300 MHz, CDCl3): d 1.15 (t, J 7.1 Hz,
3H), 1.26 (t, J 7.1 Hz, 3H), 2.32 (s, 3H), 3.97–4.21 (m,
4H), 4.87–5.02 (m, 1H), 5.43 (d, J 7.6 Hz, 1H), 7.12 (d, J
8.1 Hz, 2H), 7.24 (s, 5H), 7.51 (d, J 8.1 Hz, 2H); 19F NMR
(282 MHz, CDCl3): d ꢁ114.01 (ddd, J 302.2, 101.2, and
13.4 Hz, 1F), ꢁ115.58 (ddd, J 302.2, 103.6, and 15.0 Hz,
1F); 31P NMR (121 MHz, CDCl3): d 5.9 (dd, J 103.6 and

G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
9907
4.1.6. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-3-methylbutylphosphonate (10f). Chromato-
graphy on silica gel (CH2Cl2/MeOH 10:0.2); yield 71%;
mp 87–88 ꢀC; [a]D20 +51.34 (c 2.24, CHCl3); 1H NMR
(300 MHz, CDCl3): d 0.95 (d, J 6.8 Hz, 3H), 1.16 (d,
J 6.8 Hz, 3H), 1.38 (t, J 6.9 Hz, 3H), 1.40 (t, J 6.9 Hz,
3H), 2.41 (s, 4H), 3.76–3.90 (m, 1H), 4.22 (d, J 10.6 Hz,
1H), 4.26–4.35 (m, 4H), 7.31 (d, J 7.8 Hz, 2H), 7.76 (d,
J 7.8 Hz, 2H); 19F NMR (282 MHz, CDCl3): d ꢁ112.72
(ddd, J 305.2, 104.8, and 14.6 Hz, 1F), ꢁ115.35 (ddd,
J 305.2, 104.8, and 12.8 Hz, 1F); 31P NMR (121 MHz,
CDCl3): d 7.00 (t, J 104.8 Hz); IR (CH2Cl2): n 3484, 2978,
1240, 1068 cmꢁ1. Anal. Calcd for C16H26F2NO4PS: C,
48.36; H, 6.59; N, 3.52. Found: C, 48.11; H, 6.57; N, 3.92.
ꢁ121.26 (ddd, J 299.0, 106.0, and 17.5 Hz, 1F); 31P NMR
(81 MHz, CDCl3): d 7.95 (dd, J 106.0 and 103.5 Hz); IR
(CH2Cl2): n 3294, 2979, 1236, 1026 cmꢁ1. Anal. Calcd for
C12H18F2NO3P: C, 49.15; H, 6.19; N, 4.78. Found: C,
49.37; H, 6.13; N, 4.87.
4.1.10. (R)-Diethyl 2-amino-1,1-difluoro-2-(2-thienyl)-
ethylphosphonate (11d). Chromatography on silica gel
(CH2Cl2/EtOH 10:0.4); yield 97%; mp 69–70 ꢀC; [a]D20
ꢁ2.6 (c 0.96, CHCl3); 1H NMR (200 MHz, CDCl3): d 1.24
(t, J 7.1 Hz, 6H), 1.92 (br s, 2H), 3.96–4.27 (m, 4H), 4.59–
4.75 (m, 1H), 6.94 (dd, J 5.0 and 3.4 Hz, 1H), 7.07 (d, J
3.4 Hz, 1H), 7.23 (dd, J 5.0 and 1.0 Hz, 1H); 19F NMR
(188 MHz, CDCl3): d ꢁ115.17 (ddd, J 298.5, 103.0, and
10.0 Hz, 1F), ꢁ122.03 (ddd, J 298.5, 104.4, and 17.4 Hz,
1F); 31P NMR (81 MHz, CDCl3): d 7.76 (dd, J 104.4 and
4.1.7. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-4-phenyl-3E-butenylphosphonate (10g). Chro-
matography on silica gel (hexane/ethyl acetate 2:1); yield
76% (oil); [a]2D0 +38.5 (c 1.25, CHCl3); 1H NMR (300 MHz,
CDCl3): d 1.28 (t, J 7.1 Hz, 3H), 1.35 (t, J 7.1 Hz, 3H),
2.32 (s, 3H), 4.15–4.34 (m, 4H), 4.52–4.70 (m, 1H), 5.05
(d, J 8.2 Hz, 1H), 6.08 (dd, J 16.0 and 7.2 Hz, 1H), 6.58
(dd, J 16.0 and 1.0 Hz, 1H), 7.23 (d, J 8.2 Hz, 2H), 7.28–
7.29 (m, 5H), 7.66 (d, J 8.2 Hz, 2H); 19F NMR (282 MHz,
CDCl3): d ꢁ114.52 (ddd, J 300.0, 103.4, and 12.2 Hz, 1F),
ꢁ116.60 (ddd, J 300.0, 103.4, and 12.2 Hz, 1F); 31P NMR
(121 MHz, CDCl3): d 6.30 (t, J 103.4 Hz); IR (CH2Cl2):
103.0 Hz); IR (CH2Cl2): n 3360, 2986, 1232, 1015 cmꢁ1
.
Anal. Calcd for C10H16F2NO3PS: C, 40.13; H, 5.39; N,
4.68. Found: C, 40.22; H, 5.01; N, 4.31.
4.1.11. (R)-Diethyl 2-amino-1,1-difluoroheptylphospho-
nate (11e). Chromatography on silica gel (CH2Cl2/EtOH
1
10:0.2); yield 77% (oil); [a]2D0 +14.08 (c 1.42, CHCl3); H
NMR (300 MHz, CDCl3): d 0.90 (t, J 6.7 Hz, 3H), 1.30–
1.49 (m, 14H), 1.55–1.67 (m 1H), 1.74–1.83 (m, 1H),
3.07–3.23 (m, 1H), 4.24–4.34 (m, 4H); 19F NMR
(282 MHz, CDCl3): d ꢁ117.74 (ddd, J 299.2, 108.2, and
11.0 Hz, 1F), ꢁ121.33 (ddd, J 299.2, 109.4, and 17.9 Hz,
1F); 31P NMR (121 MHz, CDCl3): d 4.5 (dd, J 109.4 and
n
3159, 1581, 1240, 1059 cmꢁ1
. Anal. Calcd for
C21H26F2NO4PS: C, 55.14; H, 5.73; N, 3.06. Found: C,
55.29; H, 5.61; N, 3.31.
108.2 Hz); IR (CH2Cl2): n 3482, 2982, 1236, 1090 cmꢁ1
.
Anal. Calcd for C11H24F2NO3P: C, 45.99; H, 8.42; N,
4.88. Found: C, 46.30; H, 8.36; N, 4.57.
4.1.8. (Ss,R)-Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-
difluoro-2-phenylpropylphosphonate (10h). Chromato-
graphy on silica gel (hexane/ethyl acetate 1:1); yield 40%
4.1.12. (R)-Diethyl 2-amino-1,1-difluoro-3-methylbutyl-
phosphonate (11f). Chromatography on silica gel
(CH2Cl2/EtOH 10:0.2); yield 87% (oil); [a]2D5 +12.04
1
(oil); [a]2D0 +19.6 (c 0.98, CHCl3); H NMR (300 MHz,
CDCl3): d 1.08 (t, J 7.2 Hz, 3H), 1.26 (t, J 7.2 Hz, 3H),
2.16 (s, 3H), 2.42 (s, 3H), 3.69–3.82 (m, 1H), 3.85–3.98
(m, 1H), 4.07–4.20 (m, 2H), 5.91 (s, 1H), 7.31–7.41 (m,
5H), 7.63–7.69 (m, 4H); 19F NMR (282 MHz, CDCl3):
d ꢁ115.21 (dd, J 299.6 and 103.8 Hz, 1F), ꢁ116.75 (dd,
J 299.6 and 103.8 Hz, 1F); 31P NMR (121 MHz, CDCl3):
d 7.08 (t, J 103.8 Hz); IR (CH2Cl2): n 3457, 3137, 1238,
1067 cmꢁ1. Anal. Calcd for C20H26F2NO4PS: C, 53.93; H,
5.88; N, 3.14. Found: C, 53.72; H, 6.22; N 3.23.
1
(c 1.57, CHCl3); H NMR (300 MHz, CDCl3): d 0.95 (d,
J 6.8 Hz, 3H), 1.06 (d, J 6.8 Hz, 3H), 1.39 (t, J 7.0 Hz,
6H), 1.46 (br s, 2H), 2.20–2.30 (m, 1H), 3.11 (ddt, J 21.2,
11.0, and 3.0 Hz, 1H), 4.27 (q, J 7.0 Hz, 2H), 4.32 (q,
J 7.0 Hz, 2H); 19F NMR (282 MHz, CDCl3): d ꢁ116.28
(ddd, J 298.4, 110.4, and 11.0 Hz, 1F), ꢁ120.09 (ddd,
J 298.4, 110.4, and 21.2 Hz, 1F); 31P NMR (121 MHz,
CDCl3): d 8.30 (t, J 110.4 Hz); IR (CH2Cl2): n 3394, 2950,
1257, 1013 cmꢁ1. Anal. Calcd for C9H20F2NO3P: C,
41.70; H, 7.78; N, 5.40. Found: C, 41.78; H, 7.74; N, 5.15.
4.1.9. (R)-Diethyl 2-amino-1,1-difluoro-2-phenylethyl-
phosphonate (11a). Typical procedure: trifluoroacetic acid
(0.38 mL, 4.93 mmol) was added to the solution of (Ss,R)-
10a (425 mg, 0.99 mmol) in dry EtOH (30 mL) at 0 ꢀC
and the reaction mixture was stirred at room temperature
for 4 h. The solution was concentrated, residue was dis-
solved in CH2Cl2 (30 mL), and neutralized to pH 7.5 with
saturated NaHCO3. The organic layer was separated and
the aqueous layer was extracted with CH2Cl2 (2ꢂ5 mL).
The combined organic layers were washed with water
(10 mL), dried (Na2SO4), and concentrated. Purification by
chromatography on silica gel (CH2Cl2/EtOH 10:0.4)
afforded 0.266 g (92%) of (R)-11a as a white solid;
mp 63–64 ꢀC; [a]D20 ꢁ13.1 (c 0.98, CHCl3); 1H NMR
(200 MHz, CDCl3): d 1.18 (t, J 6.9 Hz, 3H), 1.21 (t,
J 6.9 Hz, 3H), 1.85 (s, 2H), 3.91–4.21 (m, 4H), 4.29–4.46
(m, 1H), 7.27–7.32 (m, 5H); 19F NMR (188 MHz, CDCl3):
d ꢁ116.13 (ddd, J 299.0, 103.5, and 11.4 Hz, 1F),
4.1.13. (R)-Diethyl 2-amino-1,1-difluoro-2-phenylpropyl-
phosphonate (11h). Chromatography on silica gel (CH2Cl2/
EtOH 10:0.4); yield 84% (oil); [a]2D0 +1.22 (c 1.47, CHCl3);
1H NMR (200 MHz, CDCl3): d 0.94 (t, J 7.0 Hz, 3H), 1.23 (t,
J 7.0 Hz, 3H), 1.56 (m, 3H), 2.26 (br s, 2H), 3.33–3.53 (m,
1H), 3.62–3.81 (m, 1H), 4.00–4.19 (m, 2H), 7.21–7.33 (m,
3H), 7.51–7.55 (m, 2H); 19F NMR (188 MHz, CDCl3):
d ꢁ114.65 (dd, J 297.4 and 101.8 Hz, 1F), ꢁ116.94 (dd,
J 297.4 and 109.2 Hz, 1F); 31P NMR (81 MHz, CDCl3):
d 7.63 (dd, J 109.2 and 101.8 Hz); IR (CH2Cl2): n 3432,
3060, 1236, 1026 cmꢁ1. Anal. Calcd for C13H20F2NO3P:
C, 50.82; H, 6.56; N, 4.56. Found: C, 51.02; H, 6.70; N, 4.69.
4.1.14. (R)-2-Amino-1,1-difluoro-2-phenylethylphos-
phonic acid (12a). Typical procedure: a solution of (R)-
11a (850 mg, 2.90 mmol) in 10 N HCl (20 mL) was refluxed

9908
G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
for 8 h. The solution was concentrated under reduce pressure
to dryness. The resulting solid was treated with EtOH
(15 mL) and propylene oxide (0.61 mL, 8.7 mmol) and the
reaction mixture was stirred for 3 h. Precipitate was filtered
off and washed with ether to provide 580 mg (84%) of (R)-
12a as a white solid; mp 286–288 ꢀC (decomp.); [a]D20 ꢁ11.9
(c 1.01, H2O); 1H NMR (200 MHz, D2O): d 4.75 (dd, J 19.4
and 9.4 Hz, 1H), 7.32 (s, 5H); 19F NMR (188 MHz, D2O):
d ꢁ114.45 (ddd, J 295.9, 85.0, and 9.4 Hz, 1F), ꢁ123.13
(ddd, J 295.9, 85.0, and 19.4 Hz, 1F); 31P NMR (81 MHz,
D2O): d 1.84 (t, J 85.0 Hz); IR (KBr): n 3040, 1200, 1088,
1048 cmꢁ1. Anal. Calcd for C8H10F2NO3P: C, 40.52; H,
4.25; N, 5.91. Found: C, 40.62; H, 4.40; N, 5.92.
(0.5 mL) was added K2CO3 (95 mg, 0.69 mmol), followed
by benzyl chloroformate (0.097 mL, 0.69 mmol) at 0 ꢀC.
The reaction mixture was stirred for 1 h at room temperature
and then diluted with ethyl acetate (5 mL) and water (5 mL).
The organic phase was separated and the aqueous layer was
extracted with ethyl acetate (5 mL). The combined organic
layers were washed with 1 N HCl (4 mL), saturated aqueous
NaHCO3 (4 mL), water (4 mL), dried (Na2SO4), and con-
centrated. Purification by chromatography on silica gel
(hexane/ethyl acetate 2:1) afforded 186 mg (91%) of (R)-
13 as a white solid; mp 104–105 ꢀC; [a]D20 +10.3 (c 1.07,
CHCl3); 1H NMR (300 MHz, (CD3)2CO): d 1.21 (t,
J 7.0 Hz, 3H), 1.22 (t, J 7.0 Hz, 3H), 3.96–4.21 (m, 4H),
5.04 (d, J 12.5 Hz, 1H), 5.14 (d, J 12.5 Hz, 1H), 5.36–5.51
(m, 1H), 7.30–7.43 (m, 8H), 7.54–7.56 (m, 2H); 19F NMR
(282 MHz, (CD3)2CO): d ꢁ112.90 (ddd, J 303.2, 99.2, and
11.8 Hz, 1F), ꢁ117.44 (ddd, J 303.2, 103.0, and 19.1 Hz,
1F); 31P NMR (121 MHz, (CD3)2CO): d 7.00 (dd, J 103.0
and 99.2 Hz); IR (CH2Cl2): n 3432, 3060, 1730, 1248,
1222, 1027 cmꢁ1. Anal. Calcd for C20H24F2NO5P: C,
56.21; H, 5.66; N, 3.28. Found: C, 56.18; H, 5.67; N, 3.22.
4.1.15. (R)-2-Amino-1,1-difluoro-2-(2-thienyl)ethylphos-
phonic acid (12d). Yield 86%; mp 265–266 ꢀC (decomp.);
[a]2D0 ꢁ1.9 (c 0.96, H2O); 1H NMR (200 MHz, D2O):
d 5.18 (dd, J 20.3 and 8.2 Hz, 1H), 6.98 (dd J 5.0 and
3.4 Hz, 1H), 7.23 (d, J 3.4 Hz, 1H), 7.45 (d, J 5.0 Hz, 1H);
19F NMR (188 MHz, D2O): d ꢁ115.26 (ddd, J 294.4, 84.9,
and 8.2 Hz, 1F), ꢁ124.18 (ddd, J 294.4, 83.7, and 20.3 Hz,
1F); 31P NMR (81 MHz, D2O): d 1.59 (dd, J 84.9 and
83.7 Hz); IR (KBr): n 3144, 2857, 1208, 1100 cmꢁ1. Anal.
Calcd for C6H8F2NO3PS: C, 29.64; H, 3.32; N, 5.76. Found:
C, 29.70; H, 3.35; N, 5.80.
4.1.20. (R)-N-Benzyloxycarbonyl-2-amino-1,1-difluoro-
2-phenylethylphosphonic acid (14). Bromotrimethylsilane
(0.55 mL, 4.2 mmol) was added dropwise to a solution of
(R)-13 (300 mg, 0.70 mmol) in CH2Cl2 (3 mL). The reaction
mixture was stirred for six days at room temperature and
then evaporated under reduced pressure. The residue was
treated with water (3 mL) and the mixture was stirred for
2 h. After the water was removed under reduced pressure
the residue was crystallized from acetone. The precipitate
was filtered, washed with acetone to give 209 mg (69%) of
(R)-14$(CH3)2CO as white crystals; mp 144–146 ꢀC; [a]D20
4.1.16. (R)-2-Amino-1,1-difluoroheptylphosphonic acid
(12e). Yield 70%; mp 280–282 ꢀC (decomp.); [a]D20 +9.9 (c
1.01, 0.5 N NaOH); 1H NMR (300 MHz, DMSO-d6):
d 0.87 (t, J 6.3 Hz, 3H), 1.17–1.51 (m, 6H), 1.53–1.67 (m,
1H), 1.72–1.87 (m, 1H), 3.41 (d, J 21.6 Hz, 1H); 19F NMR
(282 MHz, DMSO-d6): d ꢁ118.95 (dd, J 292.4 and
79.6 Hz, 1F), ꢁ125.28 (ddd, J 292.4, 79.6, and 21.6 Hz,
1F); 31P NMR (121 MHz, DMSO-d6): d 4.60 (t, J
1
ꢁ24.96 (c 1.21, DMSO); H NMR (500 MHz, DMSO-d6):
79.6 Hz); IR (KBr): n 3248, 2956, 1229, 1084, 1029 cmꢁ1
.
d 5.04 (s, 2H), 5.21–5.29 (m, 1H), 7.30–7.36 (m, 8H),
7.43–7.45 (m, 2H), 8.23 (d, J 9.8 Hz, 1H); 19F NMR
(470 MHz, DMSO-d6): d ꢁ115.09 (ddd, J 295.6, 95.9, and
11.3 Hz, 1F), ꢁ120.20 (ddd, J 295.6, 95.9, and 19.2 Hz,
1F); 31P NMR (202 MHz, DMSO-d6): d 7.70 (t, J 95.9);
IR (KBr): n 3293, 2982, 1710, 1259, 1022 cmꢁ1. Anal. Calcd
for C16H16F2NO5P$C3H6O: C, 53.15; H, 5.16; N, 3.26.
Found: C, 53.11; H, 5.12; N, 2.86.
Anal. Calcd for C7H16F2NO3P: C, 36.37; H, 6.96; N, 6.06.
Found: C, 36.48; H, 7.20; N, 6.19.
4.1.17. (R)-2-Amino-1,1-difluoro-3-methylbutylphos-
phonic acid (12f). Yield 75%; mp 264–266 ꢀC (decomp.);
[a]2D0 ꢁ5.9 (c 0.81, H2O); 1H NMR (300 MHz, D2O):
d 1.04 (d, J 7.0 Hz, 3H), 1.13 (d, J 7.0 Hz, 3H), 2.56–
2.66 (m, 1H), 3.74 (dd, J 20.6 and 9.8 Hz, 1H); 19F NMR
(282 MHz, D2O): d ꢁ110.27 (dd, J 299.2 and 86.4 Hz,
1F), (ddd, J 299.2, 86.4, and 20.6 Hz, 1F); 31P NMR
(121 MHz, D2O): d 1.90 (t, J 86.4 Hz); IR (KBr): n
3144, 2976, 1208, 1100, 1028 cmꢁ1. Anal. Calcd for
C5H12F2NO3P: C, 29.57; H, 5.95; N, 6.90. Found: C,
29.60; H, 5.85; N, 6.71.
4.1.21. (R)-Monoethyl N-benzyloxycarbonyl-2-amino-
1,1-difluoro-2-phenylethylphosphonate (15). A solution
of diester (R)-13 (850 mg, 1.99 mmol) and sodium iodide
(328 mg, 2.19 mmol) in acetone (4 mL) was heated at reflux
for 6 h. After cooling the reaction mixture was evaporated
to dryness and residue was dissolved in water (3 mL). The
aqueous solution was acidified with 1 N HCl until pH
reaches 1 and extracted with EtOAc (2ꢂ30 mL). The
combined organic layers were washed with water, dried
(Na2SO4), and concentrated. Crystallization from acetone
gave 596 mg (75%) of (R)-15 as white solid; mp 186–
187 ꢀC; [a]2D0 ꢁ9.8 (c 0.81, (CH3)2CO). 1H NMR
(300 MHz, (CD3)2CO): d 1.20 (t, J 7.2 Hz, 3H), 4.02–4.12
(m, 2H), 5.09 (d, J 12.6 Hz, 1H), 5.15 (d, J 12.6 Hz, 1H),
5.41–5.53 (m, 1H), 5.64 (br s, 1H), 7.34–7.44 (m, 8H),
7.57–7.60 (m, 2H); 19F NMR (282 MHz, (CD3)2CO):
d ꢁ113.46 (dd, J 302.2 and 100.8 Hz, 1F), ꢁ118.88
(ddd, J 302.2, 100.8, and 19.0 Hz, 1F); 31P NMR
(121 MHz, (CD3)2CO): d 5.80 (t, J 100.8 Hz); IR (KBr): n
3310, 2528, 1692, 1235, 1051 cmꢁ1. Anal. Calcd for
4.1.18. (R)-2-Amino-1,1-difluoro-2-phenylpropylphos-
phonic acid (12h). Yield 90%; mp 284–286 ꢀC (decomp.);
[a]2D0 ꢁ4.0 (c 0.75, H2O); 1H NMR (300 MHz, D2O):
d 1.97 (s, 3H), 7.48–7.54 (m, 5H); 19F NMR (282 MHz,
D2O): d ꢁ117.03 (dd, J 300.6 and 88.2 Hz, 1F), ꢁ118.13
(dd, J 300.6 and 88.2 Hz, 1F); 31P NMR (121 MHz, D2O):
d 2.50 (t, J 88.2 Hz); IR (KBr): n 3100, 2930, 1150,
1075 cmꢁ1. Anal. Calcd for C9H12F2NO3P: C, 43.04; H,
4.82; N, 5.58. Found: C, 42.95; H, 4.73; N, 5.67.
4.1.19. (R)-Diethyl N-benzyloxycarbonyl-2-amino-1,1-
difluoro-2-phenylethylphosphonate (13). To solution of
(R)-11a (140 mg, 0.48 mmol) in THF (6 mL) and H2O

G.-V. Ro€schenthaler et al. / Tetrahedron 62 (2006) 9902–9910
9909
C18H20F2NO5P: C, 54.14; H, 5.05; N, 3.51. Found: C, 54.36;
H, 5.09; N, 3.53.
buffering systems were employed: 20 mM phosphoric acid,
pH 2.18; 20 mM phosphoric acid adjusted to pH 5.20 and
6.82 with concentrated sodium hydroxide. The stock solu-
tion of (R)-17 (6 mM) was prepared by dissolving (R)-17
in buffer at pH 6.82. Reactions were initiated by addition
of aliquots of stock solution to 5 mL of buffers. The concen-
tration of substrate ranged from 0.09 to 0.4 mM. At appro-
priate intervals three consecutive within 10-min samples
were collected and injected onto C18 chromatographic
column equipped with UV-detector monitoring at 220 nm.
The absolute calibration method gave us acceptable level
of quantitation accuracy. The sodium salt (R)-17 was stable
at pH above 5.00 for two weeks at 21 ꢀC; the half-life of
(R)-17 at pH 2.18 was 36ꢃ1 h.
4.1.22. (Rp,R) and (Sp,R)-Ethyl N-benzyl-2-(N0-benzyl-
oxycarbonylamino)-1,1-difluoro-2-phenylethylphospho-
noamidate (16). Sodium ethoxide (48 mg, 0.71 mmol) was
added to suspension of (R)-15 (282 mg, 0.71 mmol) in dry
ethanol (6 mL). The resulting solution was stirred at room
temperature for 2 h and concentrated. The residue was dis-
solved in CH2Cl2 (5 mL) and DMF (two drops) was added.
The solution was cooled to 0 ꢀC and treated with oxalyl
chloride (180 mg, 1.42 mmol). After stirring at 0 ꢀC for
0.5 h the reaction mixture was concentrated to dryness, the
residue was dissolved in CH2Cl2 (5 mL), and Et3N (79 mg,
0.78 mmol) and then benzylamine (380 mg, 3.55 mmol)
were added at 0 ꢀC. The reaction mixture was stirred for
1 h at room temperature and then treated with cold water
(5 mL). The organic phase was separated and the aqueous
layer was extracted with CH2Cl2 (5 mL). The combined
organic layers were washed with 1 N HCl (10 mL), saturated
aqueous NaHCO3 (10 mL), water (10 mL), and dried
(Na2SO4). Concentration afforded crude 16 as mixture of
(Rp,R) and (Sp,R) diastereomers in ratio 1:1. Chromato-
graphy purification (CH2Cl2/Et2O 10:1) gave 209 mg
(61%) of 16 as white solid and did not alter the ratio of dia-
stereomers. 1H NMR (500 MHz, CDCl3): d 1.08 (t, J 6.8 Hz,
1.5H), 1.26 (t, J 6.8 Hz, 1.5H), 2.59–2.64 (m, 0.5H), 3.06–
3.11 (m, 0.5H), 3.88–3.96 (m, 2H), 4.04–4.19 (m, 2H),
5.12 (s, 2H), 5.36–5.48 (m, 1H), 6.34–6.42 (m, 1H), 7.12–
7.14 (m, 1H), 7.25–7.38 (m, 12H), 7.42–7.45 (m, 2H); 19F
NMR (470 MHz, CDCl3): d ꢁ112.17 (ddd, J 301.2, 94.2,
and 8.6 Hz, 1F), ꢁ117.66 (ddd, J 301.2, 101.2, and
18.3 Hz, 1F) (first diastereomer); ꢁ113.17 (ddd, J 300.0,
106.0, and 10.2 Hz, 1F), ꢁ115.62 (ddd, J 300.0, 90.6, and
16.0 Hz, 1F) (second diastereomer); 31P NMR (202 MHz,
CDCl3): d 16.61 (dd, J 101.2 and 94.2 Hz) (first diastereo-
mer); 17.14 (dd, J 106.0 and 90.6 Hz) (second diastereo-
Acknowledgements
The financial support of this work by DFG (Grant 436 UKR
17/24/03) is acknowledged with thanks.
References and notes
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