Asymmetric synthesis of α,α-difluoro-β-amino phosphonic acids using sulfinimines

Article abstract of DOI:10.1016/j.tetlet.2004.06.126

Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl α,α-difluoro- β-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically pure

Full text of DOI:10.1016/j.tetlet.2004.06.126

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6665–6667
Asymmetric synthesis of a,a-difluoro-b-amino phosphonic
acids using sulfinimines
b
c
b
Gerd-Volker Ro¨schenthaler,a, Valery Kukhar, Jan Barten, Natalia Gvozdovska,
*
Michael Belikb and Alexander Sorochinskyb,
*
aInstitute of Inorganic & Physical Chemistry, University of Bremen, Leobener Strasse, 28334 Bremen, Germany
bInstitute of Bioorganic Chemistry & Petrochemistry, NAS of Ukraine, Murmanska 1, Kiev-94, 02660, Ukraine
cHansa Fine Chemicals GmbH, Leobener Strasse, 28334 Bremen, Germany
Received 25 May 2004; revised 23 June 2004; accepted 29 June 2004
Available online 22 July 2004
Abstract—Addition of diethyl lithiodifluoromethylphosphonate to enantiopure sulfinimines afforded the corresponding N-sulfinyl
a,a-difluoro-b-amino phosphonates with good diastereoselectivity. A two-step deprotection involving treatment of diastereomerically
pure N-sulfinyl a,a-difluoro-b-amino phosphonates with trifluoroacetic acid in EtOH followed by refluxing with 10N HCl afforded
enantiopure a,a-difluoro-b-amino phosphonic acids.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Over the past two decades, amino phosphonic acids
have been recognized as important structural analogues
of amino acids because of their unique chemical and bio-
logical properties. Aminophosphonic acids have been
shown to exhibit antibacterial, antiviral as well as pesti-
cidal activities and act as transition-state analogue
inhibitors of proteolytic enzymes.1 Replacement of
hydrogen atoms by fluorine atoms in amino carboxylic
acids has been found to provide increased lipophilicity,
hydrogen bonding, and reactivity.2 For these reasons
the incorporation of fluorine atoms into amino phos-
phonic acids is of interest for the screening of new bio-
active compounds. In addition, the incorporation of
fluorinated amino phosphonic acids into key positions
in peptide chains plays an important role in rational de-
sign and synthesis of isosteric and isopolar phosphate
mimics.3 Current stereoselective approaches to biologi-
cally active fluorinated amino phosphonic acids include
the reactions of dialkyl lithiodifluoromethylphospho-
nates with primary triflates, aldehydes, and esters
derived from (R)-isopropylideneglycerol and D-serine,3
high yield coupling of [(diethoxyphosphinyl)difluoro-
methyl]zinc bromide in the presence of CuBr–2LiBr with
protected aspartic acid chloride4 and fluoride catalyzed
addition of trimethylsilyldifluoromethylphosphonate
to protected L-aspartate semialdehyde.5 Alternatively
nucleophilic fluorination of benzylic a-oxophosphonate
with (diethylamino)sulfur trifluoride followed by transi-
tion metal-mediated coupling of the corresponding ben-
zylic a,a-difluorophosphonates with an iodoalanine
derivative has also been used to prepare these amino
phosphonic acids.6 Recently synthetic methodology
relying on the addition of methyl- and halomethylphos-
phonates anions to enantiopure sulfinimines has proved
to be effective for the asymmetric syntheses of b-amino
phosphonic acids.7a,b However, this attractive method-
ology has not been used for the synthesis of fluorinated
b-amino phosphonic acids. In this communication we
report that the use of the readily available and inexpen-
sive chiral N-p-toluenesulfinylimines 1 in the addition
reaction with diethyl lithiodifluoromethylphosphonate
2 offers a synthetic alternative to previous approaches
affording a practical method for the preparation of
enantiomerically pure a,a-difluoro-b-amino phosphonic
acids 5.
Keywords: Asymmetric synthesis; Amino phosphonic acids and deriv-
atives; Fluorine and compounds; Sulfinimines; Diethyl difluoromethyl-
phosphonate.
We have found that enantiomerically pure sulfinimine
(S)-1a was easily reacted with 1.3equiv of diethyl lithio-
difluoromethylphosphonate 2 generated from diethyl
*
Corresponding authors. Tel.: +380-44-5732531; fax: +380-44-
5732552; e-mail addresses: gvr@chemie.uni-bremen.de; sorochinsky@
bpci.kiev.ua
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.126

6666
G.-V. Ro¨schenthaler et al. / Tetrahedron Letters 45 (2004) 6665–6667
O
LiCF2P(OC2H5)2
O
O
S
R
O
H
O
2
TFA/EtOH
R
P(OC2H5)2
S
P(OC2H5)2
p-Tolyl
N
H
p-Tolyl
N
R
H2N
-78oC, THF
F
F
F
F
(Ss,R)-3a-f
(R)-4a,d-f
(S)-1a-f
a: R=Ph
1) 10 N HCl
b: R=4-MeO-C6H4
c:R=4-CF3-C6H5
d: R=2-thienyl
e: R=n-C5H11
O
2)
O
P(OH)2
F
R
H2N
f: R=i-Pr
F
(R)-5a,d-f
Scheme 1.
Table 1. Addition of diethyl lithiodifluoromethylphosphonate 2 to
sulfinimines (S)-1
The (R) absolute configuration of the newly formed
stereogenic center in the major diastereomers 3 corre-
sponded to that observed for the addition of methyl-
and halomethylphosphonate anions to sulfinimines (S)-
1.7 The observed selectivity for addition of diethyl lithio-
difluoromethylphosphonate to sulfinimines is consistent
with a transition-state model in which the sulfinimine is
in the stereochemically favorable E-configuration and
the organometallic reagent preferably attacks the C@N
double bond from opposite to the p-tolylsulfinyl group
direction.
Entry
Sulfinimine 1
b-Amino phosphonate 3
(Ss,R):(Ss,S)a Yieldb (%)
Compound
R
1
2
3
4
5
6
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
Ph 95:5
p-MeO–C6H4 94:6
74
92c
70
67
72
75
p-CF3–C6H4
2-Thienyl
n-C5H11
i-Pr
94:6
92:8
92:8
91:9
a Determined by 19F NMR of the crude reaction mixtures.
b Isolated yield of major diastereoisomer.
c Yield of an inseparable mixture of diastereomers.
Deprotection of the diastereomerically pure adducts
(Ss,R)-3a,d–f was achieved in two steps. The N-sulfinyl
group was selectively removed by treatment with tri-
fluoroacetic acid in EtOH at 0ꢁC.7c Under these condi-
tions, the phosphonate group remained intact and the
a,a-difluoro-b-amino phosphonates (R)-4a,d–f were iso-
lated by flash chromatography in 78–97% yields.
Hydrolysis of (R)-4a,d–f was carried out by heating un-
der reflux in 10N HCl for 8h. After concentration of
reaction mixture in vacuo, the residue was treated with
ethanol and propylene oxide and the mixture was stirred
for 3h. The resulting precipitate was filtered, washed
with ether, and dried in vacuo affording the desired
a,a-difluoro-b-amino phosphonic acids (R)-5a,d–f in
75–86% yields. On the other hand hydrolysis of fully
protected (Ss,R)-3a,d–f in one-step to a,a-difluoro-b-
amino phosphonic acids (R)-5a,d–f using 10N HCl un-
der reflux was a low yielding procedure, with typical
yields of 30–35%. The enantiomeric purity of the a,a-di-
fluoro-b-amino phosphonic acids (R)-5a,d–f so obtained
was shown to be >98% ee (co-chromatography with
racemic OPA/NAC derivatives by RP-HPLC10). Thus
deprotection of N-sulfinyl a,a-difluoro-b-amino phos-
phonates (Ss,R)-3a,d–f occurred without epimerization
at the b-position under these conditions.
difluoromethylphosphonate and LDA in THF at ꢀ78ꢁC
(Scheme 1). After 1h the reaction mixture was quenched
at this temperature with saturated aqueous NH4Cl and
the crude N-sulfinyl a,a-difluoro-b-amino phosphonate
3a was isolated by simple extractive work-up in a dia-
stereomeric ratio of 95:5 (Table 1, entry 1). Due to its
crystalline nature, the major diastereomer of 3a could
be readily obtained in optically pure form by crystalliza-
tion of the crude reaction mixture from ether.8 The
stereochemistry of the major diastereomer 3a was deter-
mined to be (Ss,R) by X-ray analysis.9 The sulfinimines
(S)-1b,c having the 4-methoxyphenyl and 4-trifluoro-
methylphenyl groups afforded the expected addition
adducts 3b,c as mixtures of two diastereomers. The dia-
stereoselectivity of the additions was independent of
electronic factors and the adducts 3b,c were obtained
with the stereochemical outcome comparable with that
observed for unsubstituted N-benzylidene derivative
(S)-1a (Table 1, entries 2 and 3). The diastereoselectivity
slightly decreased when the phenyl substituent in sulfin-
imine (S)-1a was replaced by 2-thienyl (S)-1d, n-alkyl
(S)-1e, and i-propyl (S)-1f groups (Table 1, entries
4–6). The size of the alkyl group had no effect on the dia-
stereoselectivity of the addition as illustrated by sulfin-
imines (S)-1e,f where R=n-pentyl and isopropyl. The
isolation of the major products (Ss,R)-3c–f was achieved
effectively either by crystallization or flash chromatogra-
phy. On the other hand, all attempts to separate, by
flash chromatography, the diastereomeric mixture of
3b, which existed as an oil, were unsuccessful.
In summary, an asymmetric synthesis of N-sulfinyl a,a-
difluoro-b-amino phosphonates 3 from diethyl lithiodi-
fluoromethylphosphonate 2 and enantiomerically pure
N-p-toluenesulfinylimines 1 is described. The utility of
diastereomerically pure N-sulfinyl a,a-difluoro-b-amino
phosphonates 3 is illustrated by their transformation
into the corresponding enantiomerically pure a,a-di-

G.-V. Ro¨schenthaler et al. / Tetrahedron Letters 45 (2004) 6665–6667
6667
7. (a) Micolajczyk, M.; Lyzwa, P.; Drabowicz, J.; Wieczorek,
M.; Biaszczyk, J. J. Chem. Soc., Chem. Commun. 1996,
1503–1504; (b) Davis, F.; Wu, Y.; Yan, H.; McCoull, W.;
Prasad, K. J. Org. Chem. 2003, 68, 2410–2419; (c) Davis,
F.; Lee, S.; Yan, H.; Titus, D. Org. Lett. 2001, 3,
1757–1760.
fluoro-b-amino phosphonic acids 5. Extension of this
method to a,a-difluoro-b-amino phosphonic acids con-
taining a b-quaternary stereogenic carbon is currently
under study.
8. (Ss,R) Diethyl N-(p-toluenesulfinyl)-2-amino-1,1-difluoro-
2-phenylethylphosphonate (3a). To a solution of diethyl
difluoromethylphosphonate (245mg, 1.30mmol) in THF
(3mL) at ꢀ78ꢁC was added LDA (1.8M solution,
0.72mL, 1.30mmol). After 0.5h (S)-N-benzylidene-p-tolu-
enesulfinamide 1a (243mg, 1.00mmol) in THF (1mL)
was added dropwise. The reaction mixture was stirred for
1h at ꢀ78ꢁC and quenched at this temperature with satd
NH4Cl (10mL). The organic phase was extracted with
EtOAc (2·10mL), washed with H2O (10mL), and brine
(5mL), dried (MgSO4), and concentrated under reduced
pressure. Crystallization of the crude product from ether
afforded 320mg (74%) of (Ss,R)-3a as a white solid; mp
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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19
95–97ꢁC; ½aꢁD +53.7 (c 1.08, CHCl3); 1H NMR (300MHz,
CDCl3): d 1.15 (t, J 7.1Hz, 3H), 1.26 (t, J 7.1Hz, 3H), 2.32
(s, 3H), 3.94–4.23 (m, 4H), 4.87–5.02 (m, 1H), 5.43 (d, J
7.7Hz, 1H), 7.12 (d, J 8.0Hz, 2H), 7.24 (s, 5H), 7.51 (d, J
8.0Hz, 2H); 19F NMR (282MHz, CDCl3): d ꢀ114.01
(ddd, J 302.2, 101.2, and 13.2Hz, 1F), ꢀ115.58 (ddd, J
302.2, 103.6, and 15.0Hz, 1F); 31P NMR (121MHz,
CDCl3): d 5.90 (dd, J 103.6 and 101.2Hz). Anal. Calcd for
C19H24F2NO4PS: C, 52.90; H, 5.61; N, 3.25. Found: C,
53.14; H, 5.68; N, 3.30.
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(Ss,R)-3a have been deposited with the Cambridge
Crystallographic Data Center as supplementary publica-
tion number CCDC 239237. Copies of the data can be
obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
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