Enzymes in Organic Chemistry, 11:[1] Hydrolase-Catalyzed Resolution of α- and β-Hydroxyphosphonates and Synthesis of Chiral, Non-Racemic β-Aminophosphonic Acids

Article abstract of DOI:10.1002/adsc.200303135

The enantioselective acylation of racemic diisopropyl α- and β-hydroxyphosphonates by hydrolases in t-butyl methyl ether with isopropenyl acetate as acyl donor is limited by the narrow substrate specificity of the enzymes. High enantiomeric excesses (up t

Full text of DOI:10.1002/adsc.200303135

FULL PAPERS
Enzymes in Organic Chemistry, 11:[1] Hydrolase-Catalyzed
Resolution of a- and b-Hydroxyphosphonates and Synthesis of
Chiral, Non-Racemic b-Aminophosphonic Acids
A. Woschek,a Wolfgang Lindner,b F. Hammerschmidta,*
a
Institut f¸r Organische Chemie der Universit‰t Wien, W‰hringerstra˚e 38, 1090 Wien, Austria
Fax: ( ‡ 43)-1-4277-9521, e-mail: friedrich.hammerschmidt@univie.ac.at
b
Institut f¸r Analytische Chemie der Universit‰t Wien, W‰hringerstra˚e 38, A-1090 Wien
Fax: ( ‡ 43)-1-4277-9523, e-mail: wolfgang.lindner@univie.ac.at
Received: August 8, 2003; Accepted: November, 2003
Abstract: The enantioselective acylation of racemic the lipase from Candida cylindracea and protease
diisopropyl a- and b-hydroxyphosphonates by hydro- subtilisin in a biphasic system gives (S)-b-hydroxy-
lases in t-butyl methyl ether with isopropenyl acetate phosphonates (ee 51 92%) enantioselectively. (S)-2-
as acyl donor is limited by the narrow substrate Phenyl-2-hydroxyethyl- and (S)-3-methyl-2-hydroxy-
specificity of the enzymes. High enantiomeric excess- butylphosphonates (ee 96% and 99%, respectively)
es (up to 99%) were obtained for the acetates of (S)- were transformed into (R)-2-aminophosphonic acids
diisopropyl 1-hydroxy-(2-thienyl)methyl-, 1-hydroxy- of the same ee.
ethyl- and 1-hydroxyhexylphosphonate and (R)-di-
isopropyl 2-hydroxypropylphosphonate. The hydroly- Keywords: aminophosphonic acids; enantioselectivity;
sis of a variety of b-chloroacetoxyphosphonates by hydrolases; hydroxyphosphonates; kinetic resolution
Introduction
organic solvent) is a well established method for the
preparation of chiral, non-racemic a-hydroxyphospho-
Hydrolytic enzymes are the most widely used biocata- nates of high enantiomeric excesses.[1] We reasoned that
lysts in organic chemistry.[2] In continuation of our work kinetic acetylation of a-hydroxyphosphonates in an
on a-acyloxyphosphonates[1] we decided to search for organic solvent using isopropenyl acetate as acyl donor
hydrolases kinetically resolving also b-acyloxyphos- would be an attractive alternative, as the preparation of
phonates and esterifying a- and b-hydroxyphospho- acetates for kinetic resolution by chemical means could
nates in an organic medium enantioselectively. Further- be omitted. The required a-hydroxyphosphonates ( Æ )-
more, we wanted to focus on the determination of the 3a f, except 1a[5b], were prepared by an improved
absolute configuration and the enantiomeric excess of procedure using a substoichiometric quantity of n-BuLi
chiral, non-racemic b-hydroxyphosphonates as well as at À 788C instead of phosphazene P1-t-Bu as base[5]
their transformation into b-aminophosphonic acids as (Scheme 1). Thus, the reaction time could be reduced
structural analogues of b-amino acids. Recent reports by from 16 18 h to one hour. We were primarily interested
others[3,4] on lipase-catalyzed acylation of a- and b- in diisopropyl phosphonates for synthetic reasons. The
hydroxyphosphonates underscore the relevance of such isopropyl group is more stable than the ethyl or methyl
organophosphorus compounds. In one case, part of the group when hydroxyphosphonates are transformed into
assigned configurations have had to be revised.[3]
other a-substituted phosphonates by substitution reac-
tions. 36 hydrolases (each 200 mg) were screened with
substrates ( Æ )-3a and ( Æ )-3b (each 100 mg) in a
mixture of t-butyl methyl ether (4 mL) and isopropenyl
acetate (1 mL) at room temperature for 24 h or in
combination with 48 h at 408C (Scheme 2).
Results and Discussion
Enantioselective Acetylation of a-
Hydroxyphosphonates
Only lipases SAM II[6] (Pseudomonas sp. lipase) and
SP 526 (fungal lipase) esterified ( Æ )-3a giving the
corresponding acetate in 34% yield with an ee of 28%
The lipase- and protease-catalyzed enantioselective hy- and 77%, respectively. Hydroxyphosphonate ( Æ )-3b
drolysis of a-acetoxy- and especially a-chloroacetoxy- was accepted as substrate by a number of lipases and
phosphonates in a biphasic system (phosphate buffer/ proteases. The most promising ones in terms of ee were
Adv. Synth. Catal. 2003, 345, 1287 1298
DOI: 10.1002/adsc.200303135
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A. Woschek et al.
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Aspergillus niger) and FAP 15 (from Rhizopus oryzae)
nor protease Chirazyme P-2 (alkaline endoprotease of
serine type), which kinetically resolve a large number of
a-hydroxyphosphonates in a biphasic system, catalyze
the reverse process in an organic medium.[5,7]
Enantioselective Acetylation of b-
Hydroxyphosphonates
Chiral, non-racemic b-hydroxyphosphonates were pre-
Scheme 1. Preparation of a-hydroxyphosphonates ( Æ )-3. a)
1 and 0.16 equiv. of n-BuLi, THF, À 788C, 30 min, then 2, 1 h; pared from b-ketophosphonates using homogenous
catalytic hydrogenation[8,9] on a chiral catalyst, CBS
reduction,[10] Saccharomyces cerevisiae[11] and Geotri-
chum candidum.[3] Furthermore, chiral non-racemic b-
hydroxyphosphonates were obtained by kinetic resolu-
tion of racemic b-hydroxyphosphonates through Sharp-
less epoxidation[12] or lipase-catalyzed acetylation[3,4,13]
and a rare example of the enantioselective hydrolysis[14]
of a b-acetoxyphosphonate.
b) H2SO4. ( Æ )-3a: 70%, ( Æ )-3b: 75%, ( Æ )-3c: 75%, ( Æ )-3d:
74%, ( Æ )-3e: 76%, ( Æ )-3f: 90%.
The biological importance of b-hydroxyphosphonates
is demonstrated with three examples. Certain g-amino-
b-hydroxyphosphonic acids are statin analogue renin
inhibitors.[15] The (R)-3-(N-formyl-N-hydroxyamino)-
Scheme 2. Hydrolase-catalyzed acetylation of a-hydroxy-
phosphonates. a) Lipase or protease, isopropenyl acetate, t-
BuOMe.
used to esterify ( Æ )-3b on a 1 mmol scale at 408C for and (R)-(N-acetyl-N-hydroxyamino)-2-hydroxypropyl-
24 h. When the conversion was about 50% (TLC), the phosphonic acids are cell wall active antibiotics pro-
mixture was filtered through Celite, concentrated under duced by Streptomyces rubellomurinus.[16] The former
vacuum, and ester 4 and alcohol 3 were separated by was found to be an efficient inhibitor of the 1-deoxy-d-
flash chromatography. The ester was hydrolyzed chemi- xylulose-5-phosphate reductoisomerase in the alterna-
cally.[5] The ee and configuration of the chiral, non- tive non-mevalonate pathway for terpenoid biosynthe-
racemic a-hydroxyphosphonates 3 were determined as sis.[17] Phosphonothrixin, a new herbicidal antibiotic, is a
reported. The data are collected in Table 1. a-Hydroxy- homochiral b-hydroxyphosphonic acid.[18]
phosphonate (S)-3b is acetylated preferentially (ee 99
We prepared b-hydroxyphosphonates ( Æ )-8a f with
100%) by lipases Novozym 435 (immobilized lipase B the diisopropyl esters predominating (Scheme 3). Met-
from Candida antarctica), SAM II, SP 524 (lipase from allation of methylphosphonates 5 with n- or s-BuLi gave
Aspergillus niger) and AK (lipase from Pseudomonas lithiomethylphosphonates 6a,b to which aldehydes 2
sp.). Yuan et al. who used only Novozym 435 in were added.[19] Work up and purification furnished
combination with vinyl acetate found that a-hydroxy- phosphonates ( Æ )-8a f.
phosphonates with a small group (R2 ˆ Me, Et, vinyl)
b-Hydroxyphosphonates ( Æ )-8a and ( Æ )-8d were
were resolved (ee>95%). Beside 3a,b only 3f was used as standard substrates for screening our collection
esterified and gave acetate (S)-4f with high enantiose- of hydrolases in the same way as for the a-hydroxy-
lectivity. Surprisingly, neither lipases AP 6 (from phosphonates for acetylation with isopropenyl acetate
Table 1. Enantioselective acetylation of ( Æ )-3 with lipases with isopropenyl acetate as acyl donor.
Compound
(1 mmol)
Enzyme
[mg]
Isolated alcohol
Isolated ester
Alcohol[a]
Yield
[%]
Conf.
ee[b]
[%]
[a]2D0 (c)[c]
Yield
[%]
[a]2D0 (c)[c]
Conf.
ee[b]
[%]
( Æ )-3b
( Æ )-3b
( Æ )-3b
( Æ )-3b
( Æ )-3e
Novozym
SAM II
AK
SP 524
SAM II
100
15
70
30
40
62
53
53
30
44
R
R
R
R
R
62/55
59/60
70/68
55/56
77/78
À 6.1 (1.2)
À 3.0 (1.4)
À 4.3 (1.5)
À 3.2 (1.4)
À 13.7 (1.6)
36
32
27
42
45
‡ 24.7 (1.5)
‡ 24.5 (1.6)
‡ 24.7 (1.3)
‡ 22.0 (1.0)
‡ 36.8 (1.8)
S
S
S
S
S
98/99
89/90
95/97
93/95
100/99
[a]
Alcohol obtained by chemical hydrolysis of ester.
[b]
[c]
1
Determined by H NMR/31P NMR spectroscopy of Mosher esters.
Measured in acetone, concentration rounded to the nearest tenth
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Synthesis of Chiral, Non-Racemic b-Aminophosphonic Acids
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Scheme 5. Chemical hydrolyses of chiral, non-racemic b-
acetoxyphosphonates 9. a) MeOH, H2O, Et3N.
Scheme 6. Synthesis of b-chloroacetoxyphosphonates ( Æ )-
10. a) Chloroacetic anhydride, CH2Cl2, pyridine, 08C; ( Æ )-
10a: 67%, ( Æ)-10b: 95%, ( Æ)-10c: 83%, ( Æ)-10d: 91%, ( Æ)-
10e: 86%, ( Æ )-10f: 98%.
Scheme 3. Preparation of b-hydroxyphosphonates ( Æ )-8. a)
BuLi/THF, À 788C; b) AcOH; ( Æ )-8a: 78%, ( Æ )-8b: 88%,
( Æ )-8c: 69%, ( Æ )-8d: 91%, ( Æ )-8e: 87%, ( Æ )-8f: 92%.
Table 2 shows that lipases gave b-hydroxyphospho-
nate (S)-8a and ester (R)-9a of high ee (94 97%), but
the protease acetylated preferentially (R)-8a. None of
the other diisopropyl b-hydroxyphosphonates was ace-
tylated significantly. Yuan et al. who used only Novozym
435 as hydrolase for the enantioselective esterification
of b-hydroxyphosphonates found that its substrate
specificity is high and that it acetylates only diethyl b-
hydroxyphosphonates with chains of up to 4 carbon
atoms.[4]
Scheme 4. Hydrolase-catalyzed acetylation of b-hydroxy-
phosphonates. a) Lipase or protease, isopropenyl acetate, t-
BuOMe.
As we did not find a hydrolase with a broad substrate
specificity for acetylation of b-hydroxyphosphonates,
we decided to prepare b-chloroacetoxyphosphonates
as acyl donor. While ( Æ )-8d was not esterified, ( Æ )-8a ( Æ )-10a f for studying enantioselective hydrolysis
was enantioselectively esterified by one protease (Chi- (Scheme 6).[20] Using ( Æ )-10e as substrate, our collec-
roCLECTM-BL, which is cross-linked crystalline subti- tion of enzymes was screened for hydrolases kinetically
lisin) and 5 lipases, SP 524, SAM II, Novozym 435, PS resolving it in a biphasic system (Scheme 7). The best
and AK (Scheme 4). Then 1 mmol quantities of ( Æ )-8a enzymes were selected for hydrolysis of 1 mmol of
were resolved with the protease and the three lipases racemic substrates 10a f in the same way as a-
giving the best ee. In general, the alcohols 8 and the acyloxyphosphonates.[5] When the conversion had
esters 9 have similar polarities, which might cause reached 45% using an autotitrator, the reaction was
trouble when the two have to be separated. The esters 9 stopped and worked up.
were hydrolyzed chemically[5] with triethylamine in a
mixture of methanol/water at room temperature phosphonates were separated and the esters were
(Scheme 5, Table 2). hydrolyzed under mild conditions (Scheme 5). The
The b-chloroacetoxyphosphonates and b-hydroxy-
Table 2. Enantioselective esterification of b-hydroxyphosphonate ( Æ )-8a.
Compound
(1 mmol)
Enzyme
mg
Isolated alcohol
Isolated ester
Alcohol[a]
Yield
[%]
Conf.
ee[b]
[%]
[a]2D0 (c)[c]
Yield
[%]
[a]2D0 (c)[a]
Conf.
ee[b]
[%]
( Æ )-8a
( Æ )-8a
( Æ )-8a
( Æ )-8a
Novozym[d]
SAM II
SP 524
20
50
50
20
35
49
39
42
S
S
S
R
63/67
59/58
47/43
56/57
‡ 7.2 (1.3)
‡ 6.3 (1.3)
‡ 8.0 (1.2)
À 8.4 (1.3)
26
34
23
26
‡ 11.1 (1.8)
‡ 12.8 (1.7)
‡ 10.1 (1.7)
À 12.5 (1.0)
R
R
R
S
97/94
94/95
97/94
94/91
ChiroCLEC-BL
[a]
Alcohol obtained by chemical hydrolysis of ester.
[b]
[c]
1
Determined by H NMR/31P NMR spectroscopy of Mosher esters.
Measured in acetone, concentration rounded to the nearest tenth.
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Table 3. Enantioselective hydrolysis of chloroacetates ( Æ )-10 in a biphasic system.
Sub-
strate
Enzyme
mg[a] Time Conv. Alcohol
[h] [%]
Ester
Alcohol obtained from
ester by chemical hydrolysis
Yield [a]2D0 (c)[b] ee[c] Conf. Yield [a]D20 (c)[b] Yield [a]D20 (c)[b] ee Conf.
[%]
[%]
[%]
[%]
[%]
( Æ )-10a Subtilisin
1.1 4.1 45
45
40 15.4 45
2.6 0.3 50
16.5 11.5 45
33
34
29
49
36
12
21
‡ 4.2 (1.0) 51
S
S
S
S
S
S
S
38
40
41
52
55
34
37
À 76.9 (1.4) 59
74
60
R
R
R
R
R
R
R
( Æ )-10b ChiroCLEC-BL 2.0 15
‡ 11.0 (1.0) 75
‡ 23.7 (0.3) 92
‡ 7.4 (1.1) 71
‡ 4.8 (0.8) 93
‡ 22.6 (1.8) 87
‡ 33.5 (1.0) 83
À 47.6 (1.6) 60
‡ 7.4 (1.0) 55
À 1.0 (1.2)
( Æ )-10c CCL
À 9 (1.5) 68
( Æ )-10d Subtilisin
( Æ )-10e CCL
À 16 (0.9)
66
‡ 12.4 (0.8) 83
À 62.6 (0.9) 96
À 37.9 (1.0) 90
À 4.4 (0.8) 65
À 20.1 (0.9) 71
À 27.6 (1.1) 64
( Æ )-10f Chirazyme P-2 34
2
5
45
45
( Æ )-10f CCL
34
[a]
Quantity of enzyme.
Measured in acetone, concentration rounded to the nearest tenth.
Determined by NMR spectroscopy of Mosher esters.
[b]
[c]
Table 4. Chemical shift differences of phosphorus and meth-
oxy resonances of Mosher esters 13 and 14.
Mosher Esters 13/14 Chemical shifts d (ppm)
(S) (1H/31P) (R) (1H/31P)
Dd[a]
Scheme 7. Enantioselective hydrolysis of chloroacetates ( Æ )-
10a f. a) Lipase or protease, biphasic system (phosphate
buffer pH 7.0/t-BuOMe/hexane).
a
b
c
d
e
f
3.52/24.12
3.49/24.99
3.51/24.41
3.41/24.70
3.39/22.43
3.41/23.18
3.53/24.20
3.56/25.30
3.55/24.50
3.51/24.82
3.51/22.63
3.54/23.43
0.01/0.08
0.07/0.31
0.04/0.09
0.10/0.12
0.12/0.20
0.13/0.25
[a]
Dd ˆ d(R) d(S).
Scheme 8. Correlation of configuration of (‡)-8a with that of
(S)-(‡)-12. a) Pd (10%)/C, H2.
by the same sequence as the dideuterated species except
using LiAlH4 instead of LiAlD4.[21] This assignment is in
agreement with Noyori×s assignment of (R) configura-
tion to levorotatory dimethyl 2-hydroxypropylphos-
phonate.[8] Therefore the reduction of diethyl 2-oxopro-
pylphosphonate by baker×s yeast gives (S)-, but not (R)-
12 previously assigned by analogy.[11] Noyori et al.
determined the absolute configurations of their dimeth-
yl 2-hydroxyphosphonates by a modified Mosher×s
method using (R)- and (S)-MTPA esters.
Scheme 9. Synthesis of (R)-Mosher esters from b-hydroxy-
phosphonates 8. a) (S)-MTPA-Cl, pyridine, CH2Cl2, 18 h;
H2O.
Diastereomeric (R)-Mosher esters 13 and 14 obtained
from (S)-MTPA-Cl and (R)- and (S)-8 are drawn in the
generally accepted conformation model with the tri-
results are collected in Table 3. The absolute config- fluoromethyl group and the carbinyl hydrogen being
urations and the ee were determined by 1H and eclipsed with the carbonyl oxygen.[22,23] The phosphorus
31P NMR spectroscopy of the Mosher esters. This point atom in the (R)-MTPA ester 14 is shielded by the phenyl
will be dealt with carefully, as wrong assignments have group when the b-hydroxyphosphonate has (S)-config-
been made. The absolute configuration of (‡)-8a was uration relative to the phosphorus in diastereomer 13.
assumed to be (S), as the corresponding diethyl ester Consequently, the phosphorus of Mosher ester 14 will
prepared from 2-benzyloxypropylphosphonate (R)-11 resonate at higher field than that of Mosher ester 13
by palladium-catalyzed deprotection gave levorotatory (Table 4). The methoxy group of the Mosher group of 13
(R)-12 (Scheme 8). The absolute configuration of (R)- is deshielded by the phosphonate group relative to the
11 is secure as it was prepared from (R)-isobutyl lactate methoxy group of 14. The signal of the methoxy group of
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Synthesis of Chiral, Non-Racemic b-Aminophosphonic Acids
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1
14 will therefore be upfield in the H NMR spectrum
relative to the signal of 13. The shift differences are
larger (0.08 0.25 ppm) for the phosphorus signal than
the methoxy signals (0.01 0.13 ppm). The shift differ-
ences are smallest for 2-hydroxypropylphosphonate 8a,
nevertheless the configuration is assigned correctly.
Noyori et al. found that dimethyl 2-hydroxy-2-phenyl-
ethylphosphonate prepared from (R)-styrene oxide is
levorotatory. We find that levorotatory diisopropyl
phosphonate 8f has also (R)-configuration. Wrong
absolute configurations have been assigned to (‡)-8f
in ref.[10], to (‡)-8a and very likely also to diethyl 2-(2-
pyridyl)-2-hydroxyethylphosphonate in ref.[3]
Scheme 10. Conversion of chiral, non-racemic b-hydroxy-
phosphonates
8 to b-aminophosphonic acids. a) Ph3P,
DIAD, HN3; b) Ph3P, H2O; 6 M HCl, reflux; Dowex 1, AcOÀ.
Synthesis of Chiral, Non-Racemic 2-Aminophosphonic
Acids
nobu reaction, previously used to transform an enantio-
b-Aminophosphonic acids are structural analogues of b- pure b-hydroxy-a-silyloxyethylphosphonate[31] into the
amino acids which have attracted much interest in corresponding b-azidophosphonates (Scheme 10, Ta-
recent years. 2-Amino-3-phosphonopropionic acid[24] ble 5).
and 2-amino-1-hydroxyethylphosphonic acid[25] are nat-
Chiral, non-racemic b-hydroxyphosphonates 8b and
urally occurring b-aminophosphonic acids. Substituted 8f with ee 50 98% prepared by hydrolase-catalyzed
b-aminodiphosphonic acids are pyrophosphate ana- resolution of the corresponding racemic chloroacetates
logues which inhibit osteoclastic bone resorption, one on a preparative scale (5 8 mmol), were treated with
is used as a therapeutic.[26] b-Amino-a-hydroxyphos- Ph3P/DIAD/HN3. In the case of the benzylic hydroxy
phonic acid derivatives are transition state analogue group, azides 15f were formed rapidly. In the case of the
inhibitors of human rennin.[27] Racemic b-aminophos- sterically more hindered alcohol 8b elimination was an
phonic acids are prepared by a variety of methods, alternative to substitution resulting in inseparable
especially reductive amination of b-ketophospho- mixtures of azide 15b and olefin 16b, which were used
nates.[28] Chiral, non-racemic b-aminophosphonic acids directly for the next step. Reduction of the azides to the
were prepared from chiral 2-aminoalcohols[29] or by amines was achieved in two steps: first Staudinger
diastereoselective addition[30] of lithiated methylphos- reaction and then hydrolysis of the iminophosphorane,
phonic acid esters to (S)-sulfinimines.
followed by removal of the isopropyl protecting groups
We show on two representative examples that chiral, with hot 6 M hydrochloric acid, and purification by ion
non-racemic b-hydroxyphosphonates can be trans- exchange chromatography furnished chiral, non-race-
formed into b-aminophosphonic acids using the Mitsu- mic b-aminophosphonic acids 17b and 17f.[7] Their
Table 5. Conversion of b-hydroxyphosphonates 8 to b-aminophosphonic acids 17.
Alcohol 8 ee [%][a]
Azide 15
Yield [%]
66[f]
b-Aminophosphonic acid 17
Conf.
[a]2D0 (c)[b]
À 0.5 (1.2)
Yield [%]
58
[a]2D0 (c)[c]
Conf.
ee [%][d]
99
(R)-8b
98
(S)-8b
65
(R)-8f
50
S
‡ 13.4 (0.6)
S
82[e]
90
R
S
‡ 2.6 (1.3)
‡ 34.9 (2.1)
À 68.8 (1.3)
77
93
79
À 8.2 (0.6)
À 9.4 (0.7)
‡ 13.2 (0.7)
R
S
68
44
96
(S)-8f
95
73
R
R
[a]
Determined by NMR spectroscopy of Mosher ester.
Measured in acetone, concentration rounded to the nearest tenth.
Measured in 1 M NaOH, concentration rounded to the nearest tenth.
Determined by HPLC on chiral stationary phase.
Mixture of azide 15b and olefin 16b (82: 18).
[b]
[c]
[d]
[e]
[f]
Mixture of azide 15b and olefin 16b (83: 17).
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A. Woschek et al.
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trator. (S)-(‡)-a-(Trifluoromethyl)phenylacetyl chloride {JPS
Chimie; [a]2D0: ‡ 126.5 (c 5.2, CCl4), ee>99.5%} was used for
derivatization of a- and b-hydroxyphosphonates. Enzymes
(lyophilized preparations of lipases and proteases) were stored
at ‡ 48C and were used as supplied.
racemic counterparts have been prepared by reductive
amination.28 The enantiomeric excesses of their N-2,4-
dinitrophenyl derivatives were determined by enantio-
selective HPLC on chiral, stationary phase based on O-
9-t-butylcarbamoylquinine as chiral selector CSP II[33]
and agreed (Table 5) with the ee of the starting b-
hydroxyphosphonates. The (R)-enantiomers of the de-
rivatives of the b-aminophosphonic acids were stronger
retained than the (S)-enantiomers.
Enzymes used: Acylase I (from porcine kidney), Pen-G
amidase, chymotrypsin A4 (from bovine pancreas), PPL (from
¾
bovine pancreas), Chirazyme L-9 (from Aspergillus niger,
¾
Boehringer Mannheim), Chirazyme P-2 (alkaline endopro-
tease, Boehringer Mannheim), CCL (lipase from Candida
cylindracea), protease papain (from Carica papaya), subtilisin
(from Bacillus subtilis), protease ChiroCLECTM-BL (cross-
linked microcrystalline subtilisin), pronase (from Streptomyces
griseus), lipases from Amano: SAM I (from Pseudomonas
fluorescens) and II (from Pseudomonas sp.), AP 6 (from
Aspergillus niger), F-AP 15 (from Rhizopus oryzae), D 20
(from Rhizopus delemar), GC 4 (from Geotrichum candidum);
PS (from Pseudomonas sp.), M 10 (from Mucor javanicus), G
50 (from Penicillium camembertii), N (from Rhizopus niveus),
R 10 (from Penicillium roqueforti), AK (from Pseudomonas
fluorescens), proteases from Amano: M (from Aspergillus), B
(from Penicillium), A (from Aspergillus), S (from Bacillus), N
(from Bacillus), acid protease II (from Rhizopus), proleather
(from Bacillus), prozyme 6 (from Aspergillus); lipases from
Novo Nordisk: 523 (from Humicola), SP 524 (from Mucor), SP
525 (lipase B from Candida antarctica ), SP 526 (lipase A from
Candida antarctica), Novozym 435 (immobilized CAL B, from
Candida antarctica).
Conclusion
We have demonstrated that the esterification of diiso-
propyl a- and b-hydroxyphosphonates by hydrolases
with isopropenyl acetate as acyl donor in organic
solvents is of limited value for the preparation of chiral,
non-racemic b-hydroxyphosphonates, although the ee
for compounds acting as substrates are high. The
alternative, the enantioselective hydrolysis of b-chloro-
acetoxyphosphonates in a biphasic system gives chiral,
non-racemic b-hydroxyphosphonates with ee up to 94%
at a conversion of 45%. Their ee and absolute config-
uration can be determined easily by NMR spectroscopy,
preferably 31P NMR, of the Mosher esters. Two chiral,
non-racemic b-hydroxyphosphonates were converted to
b-aminophosphonic acids via their azides with clean
inversion of configuration by the Mitsunobu reaction.
Preparation of a-Hydroxyphosphonates ( Æ )-3a f,
except 1a (General Procedure A)
Experimental Section
To a stirred solution of diethyl phosphite (1.38 g, 2.58 mL,
20 mmol) or diisopropyl phosphite (3.23 g, 3.26 mL, 20 mmol)
in dry diethyl ether (30 mL) n-BuLi(2 mL of a1.6M solution in
hexane) was added dropwise at À 788C. After 30 min a
solution of the aldehyde (22 mmol) in dry diethyl ether
(5 mL) was added and stirring was continued for 1 h. Con-
centrated H2SO4 (3.5 mmol) was added and stirring was
continued 10 min. The reaction mixture was concentrated.
The residue was taken up in water (10 mL) and extracted three
times with ethyl acetate. The combined organic layers were
dried (MgSO4) and concentrated under vacuum. The crude
product was purified by flash chromatography and if appro-
priate also by bulb-to-bulb distillation. The spectroscopic data
are identical with those reported.[5a] ( Æ )-1a was prepared by a
literature procedure.[5b]
General Remarks
All starting materials and enzymes were obtained form
commercial suppliers and were generally used without further
1
purification. H and 13C NMR (J modulated) spectra were
recorded in CDCl3 unless otherwise given, using residual
CHCl3 (d ˆ 7.24) for calibration of 1H NMR spectra and CDCl3
for calibration of 13C NMR spectra (d ˆ 77.00) on a Bruker
AM 400 WB spectrometer at 400.13 and 100.61 MHz, respec-
tively. 31P NMR spectra were recorded on the same spectrom-
eter at 161.97 MHz using H3PO4 (85%) as external standard. In
order to get undistorted 31P signal intensities for an accurate
integration, adequate relaxation times were used without
irradiation during this period to avoid NOE enhancements.
Chemical shifts (d) are given in ppm. IR spectra were run on a
Perkin-Elmer 1600 FT-IR spectrometer; liquid samples were
measured as films between NaCl plates or on a silicon disc.[34]
Optical rotations were measured at 208C on a Perkin-Elmer
351 polarimeter in a 1 dm cell. TLC was carried on 0.25 mm
thick Merck plates, silica gel 60 F254. Flash chromatography was
performed with Merck silica gel 60 (230 240 mesh). Spots
were visualized by UVand/or dipping the plate into a solution
of (NH4)6Mo7O24 ¥ 4 H2O (24.0 g) and of Ce(SO4)2 ¥ 4 H2O
(1.0 g) in 10% H2SO4 in water (500 mL), followed by heating
with a hot-air gun. Melting points were determined on a
Reichert Thermovar instrument and were uncorrected. A
Metrohm 702 SM Titrino instrument was used as an autoti-
Preparation of b-Hydroxyphosphonates ( Æ )-8a f
(General Procedure B)
To a stirred solution of diethyl methylphosphonate (1.52 g,
1.46 mL, 10 mmol) or diisopropyl methylphosphonate[35]
(1.80 g, 1.85 mL, 10 mmol) in dry THF (20 mL) s-BuLi
(10 mL of a 1.3 M solution in cyclohexane) or n-BuLi
(7.5 mL of a 1.6 M solution in hexane) was added dropwise at
À 788C under argon. After 30 min a solution of the aldehyde 2
(12 mmol) in dry THF (5 mL) was added and stirring was
continued for 1 h. Acetic acid (0.69 mL, 12 mmol) was added
and stirring was continued for 15 min. The reaction mixture
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Synthesis of Chiral, Non-Racemic b-Aminophosphonic Acids
FULL PAPERS
was concentrated under vacuum. The residue was taken up in
water (10 mL) and extracted three times with CHCl3. The
combined organic layers were dried (MgSO4) and concentrat-
ed under vacuum. The crude product was purified by flash
chromatography and if appropriate also by bulb-to-bulb
distillation.
Chemical Hydrolysis of Esters 4, 9 and 10 (General
Procedure E)
A solution of ester (0.5 mmol) in MeOH (5 mL), triethylamine
(1 mL) and water (1 mL) was stirred at room temperature until
all the ester was hydrolyzed (up to 18 h; TLC: CH2Cl2/ethyl
acetate, 1:1). The solvent was removed under vacuum. The
residue was purified by flash chromatography.
Preparation of b-Chloroacetoxyphosphonates ( Æ )-10
(General Procedure C)
Preparation of Mosher Esters 13 and 14 from b-
Hydroxyphosphonates 8 (General Procedure F)
Under argon at 08C, a solution of chloroacetic anhydride
(90%, 1.34 g, 7.84 mmol) in dry CH2Cl2 (5 mL) was added
dropwise to a solution of b-hydroxyphosphonate ( Æ )-8
(5 mmol) and dry pyridine (1.25 mL) in dry CH2Cl2 (20 mL).
After stirring for 1 h (TLC: hexane/ethyl acetate, 1:4), the
mixture was diluted with H2O (10 mL) and stirring was
continued for 10 min. After addition of concentrated hydro-
chloric acid (1 mL) the organic phase was separated and the
aqueous phase was extracted three times with CH2Cl2. The
combined organic layers were washed with H2O (5 mL), a
saturated aqueous solution of NaHCO3 (5 mL), dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was purified by flash chromatography.
A solution of b-hydroxyphosphonate 8 (0.05 mmol), (S)-(‡)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride [(S)-
(‡)-MTPA-Cl] (0.158 mmol, 0.2 mL of a 0.79 M solution of
(S)-(‡)-MTPA-Cl in dry CH2Cl2), dry pyridine (1 mL) and
CH2Cl2 (0.5 mL) was stirred under argon for 18 h at room
temperature (TLC: hexane/ethyl acetate, 1:2). After addition
of water (0.5 mL) the solvent was removed under reduced
pressure. The residue was diluted with hydrochloric acid (2 M,
5 mL) and extracted with CH2Cl2 (3 Â 10 mL). The combined
organic layers were washed with H2O (5 mL), a saturated
aqueous solution of NaHCO3 (5 mL), dried (Na2SO4) and
concentrated under reduced pressure. The crude product was
purified by flash chromatography (hexane/ethyl acetate, 1:2).
Enzymatic Hydrolysis of Chloroacetates ( Æ )-10
(General Procedure D)
Preparation of b-Aminophosphonic Acids 17 (General
Procedure G)
Chloroacetates ( Æ )-10a f (1 mmol) were hydrolyzed enzy-
matically in a biphasic system (17 mL of a 50 mM phosphate
buffer pH 7.0/4 mL of a mixture of hexane/t-butyl methyl
ether, 1:1) by lipases or proteases (Table 3) as described in the
literature except that the reaction mixture was extracted
directly after acidification.[36]
A solution of azide 15 (1 mmol) and triphenylphosphane
(1.16 mmol) in a mixture of dry THF (8 mL) and water
(0.8 mL) was stirred for 3 h at room temperature and 16 h at
508C (TLC: CH2Cl2/ethyl acetate, 1:2) and concentrated
under reduced pressure. Hydrochloric acid (10 mL, 6 M) was
added to the residue and the mixture was refluxed for 5 h. The
cooled reaction mixture was diluted with water (15 mL),
extracted with diethyl ether to remove triphenylphosphane
oxide, and concentrated under reduced pressure. The residue
was purified by ion exchange chromatography (Dowex 1X8,
100 200 mesh, acetate form, column: È 1.5 cm  74 cm).
Fractions containing product {TLC (2-propanol/water/concen-
trated ammonia, 6:3:1) or PC[37]} were pooled and concen-
trated under reduced pressure to give the respective b-amino-
phosphonic acid.
Hydrolysis of Chloroacetates ( Æ )-10b, f on a
Preparative Scale
Chloroacetate ( Æ )-10b (1.846 g, 5.61 mmol) was hydrolyzed
in a biphasic system [50 mL of a 50 mM phosphate buffer
pH 7.0/20 mL of mixture of hexane/t-butyl methyl ether, 1:1;
0.40 g of lipase from C. cylindracea (CCL); conversion: 49% by
consumption of base] to yield b-hydroxyphosphonate (S)-8b
{0.252 g (18%), [a]2D0: ‡ 9.9 (c 1.0, acetone), ee 65%}, a mixture
(0.264 g) of (S)-8b and ester (R)-10b, and (R)-10b {0.423 g
(23%), [a]2D0: À 2.5 (c 0.88, acetone)} which gave b-hydroxy-
phosphonate (R)-8b {0.306 g (94%), [a]2D0: À 14.8 (c 1.15,
acetone), ee 98%} on chemical hydrolysis by General Proce-
dure E.
Similarly, chloroacetate ( Æ )-10f (2.722 g, 7.5 mmol) was
hydrolyzed in a biphasic system [50 mL of a 50 mM phosphate
buffer pH 7.0/20 mL of mixture of hexane/t-butyl methyl ether,
1:1; 48 mg of protease P-2 (alkaline endoprotease); conver-
sion: 35% by consumption of base] to yield b-hydroxyphos-
phonate (S)-8f {0.56 g (26%), [a]2D0: ‡ 37.5 (c 0.55, acetone), ee
95%} and (R)-10b {1.349 g (50%), [a]2D0: À 31.0 (c 0.775,
acetone)} which gave b-hydroxyphosphonate (R)-8f {1.01 g
(95%), [a]2D0: À 22.9. (c 2.0, acetone), [a]2D0: À 15.2 (c 0.825,
CHCl3)[10] ee 50%} on chemical hydrolysis by General
Procedure E.
( Æ )-Diisopropyl 2-Hydroxypropylphosphonate
[( Æ )-3a]
This hydroxyphosphonate was prepared by General Procedure
B using acetaldehyde (10 mmol), diisopropyl methylphosph-
onate and n-BuLi. Flash chromatography (ethyl acetate, Rf ˆ
0.35) gave ( Æ )-3a[19c] as a colorless oil; yield: 1.75 g (78%).
1H NMR (400.1 MHz, CDCl3): d ˆ 1.19 (dd, J ˆ 2.5, 6.3 Hz,
3H, CH3), 1.25 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.26 [d, J ˆ
6.1 Hz, 6H, OCH(CH3)2], 1.27 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2],
1.79 (AB part of ABMX system, JAB ˆ 15.2 Hz, JAP ˆ 18.7 Hz,
JAH ˆ 3.0 Hz, JBP ˆ 17.2 Hz, JBH ˆ 8.8 Hz, 2H, CH2P), 3.61 (s,
1H, OH), 4.09 (m, 1H, CHOH), 4.65 [m, 2H, OCH(CH3)2];
13C NMR (100.6 MHz, CDCl3): d ˆ 23.97 [d, J ˆ 5.4 Hz,
OCH(CH3)2], 23.98 [d, J ˆ 3.1 Hz, OCH(CH3)2], 23.99 [d, J ˆ
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A. Woschek et al.
FULL PAPERS
4.6 Hz, 2C, OCH(CH3)2], 24.22 (d, J ˆ 18.4 Hz, CH3COH),
36.37 (d, J ˆ 138.4 Hz, CH2P), 62.90 (d, J ˆ 6.1 Hz, CHOH),
70.51 [d, J ˆ 6.9 Hz, OCH(CH3)2], 70.57 [d, J ˆ 6.9 Hz,
OCH(CH3)2].
OCH2CH3), 2.30 (m, 2H, CH2P), 4.09 (m, 5H, OCH2, OH),
5.33 (m, 1H, CHOH), 6.93 (dd, J ˆ 3.5, 4.9 Hz, 1H, Harom), 6.96
(dd, J ˆ 1.3, 3.5 Hz, 1H, Harom), 7.22 (dd, J ˆ 1.3, 4.9 Hz, 1H,
Harom); 13C NMR (100.6 MHz, CDCl3): d ˆ 16.32 (d, J ˆ 6.1 Hz,
OCH2CH3), 16.38 (d, J ˆ 5.4 Hz, OCH2CH3), 36.05 (d, J ˆ
136.9 Hz, PCH2), 61.97 (d, J ˆ 6.1 Hz, OCH2CH3), 62.16 (d,
J ˆ 6.1 Hz, OCH2CH3), 65.20 (d, J ˆ 3.8 Hz, CHOH), 123.40
(HCarom), 124.70 (HCarom), 126.60 (HCarom), 147.47 (d, J ˆ
19.1 Hz, Carom).
( Æ )-Diisopropyl 2-Hydroxy-3-methybutyl-
phosphonate [( Æ )-3b]
This hydroxyphosphonate was prepared by General Procedure
B using isobutyraldehyde (10 mmol), diisopropyl methyl-
phosphonate and n-BuLi. Flash chromatography (EtOAc,
Rf ˆ 0.35) gave ( Æ )-3b[19d] as a colorless oil; yield: 1.75 g (78%).
1H NMR (400.1 MHz, CDCl3): d ˆ 0.87 (d, J ˆ 6.3 Hz, 3H,
CH3), 0.90 (d, J ˆ 7.1 Hz, 3H, CH3), 1.296 [d, J ˆ 6.1 Hz, 3H,
OCH(CH3)2], 1.302 [d, J ˆ 6.3 Hz, 6H, OCH(CH3)2], 1.31 [d,
J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.69 [m, 1H, CH(CH3)2], 1.80 (m,
2H, CH2P), 3.59 (br. s, 1H, OH), 3.71 (ddt, J ˆ 2.0, 5.3, 11.1 Hz,
1H, CHOH), 4.70 [m, 2H, OCH(CH3)2]; 13C NMR
(100.6 MHz, CDCl3): d ˆ 17.56 (CH3), 17.94 (CH3), 23.98 [d,
J ˆ 3.8 Hz, OCH(CH3)2], 24.00 [d, J ˆ 3.8 Hz, OCH(CH3)2],
24.03 [d, J ˆ 3.8 Hz, 2C, OCH(CH3)2], 31.32 (d, J ˆ 140.0 Hz,
CH2P), 34.08 (d, J ˆ 16.8 Hz, CHCCP), 62.90 (d, J ˆ 6.1 Hz,
CHOH), 70.51 [d, J ˆ 6.9 Hz, 2C, OCH(CH3)2], 70.57 (d, J ˆ
6.9 Hz, CHOH).
( Æ )-Diisopropyl 2-Hydroxy-2-(2-
thienyl)ethylphosphonate [( Æ )-3e]
This hydroxyphosphonate was prepared by General Procedure
B using thiophene-2-carbaldehyde (10 mmol), diisopropyl
methylphosphonate and s-BuLi. Flash chromatography (hex-
ane/ethyl acetate, 1:2, Rf ˆ 0.44) gave ( Æ )-3e as a yellow solid;
yield: 2.54 g (87%), mp 668C (hexane). IR (Si): nÄ ˆ 3321, 2979,
1
1386, 1224, 993 cmÀ1; H NMR (400.1 MHz, CDCl3): d ˆ 1.28
[d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.31 [d, J ˆ 6.1 Hz, 3H,
OCH(CH3)2], 1.32 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.33 [d,
J ˆ 6.3 Hz, 3H, OCH(CH3)2], 2.25 (m, 2H, CH2P), 4.28 (d, J ˆ
2.5 Hz, 1H, OH), 4.71 [m, 2H, CH(CH3)2], 5.31 (m, 1H,
CHOH), 6.94 (m, 2H, Harom), 7.22 (dd, J ˆ 1.5, 5.0 Hz, 1H,
Harom); 13C NMR (100.6 MHz, CDCl3): d ˆ 23.89 [d, J ˆ 4.6 Hz,
OCH(CH3)2], 23.99 [d, J ˆ 4.6 Hz, OCH(CH3)2], 24.04 [d, J ˆ
5.4 Hz, OCH(CH3)2], 24.05 [d, J ˆ 3.1 Hz, OCH(CH3)2], 37.24
(d, J ˆ 137.7 Hz, CH2P), 65.36 (d, J ˆ 4.6 Hz, CHOH), 70.90 [d,
J ˆ 6.9 Hz, OCH(CH3)2], 71.06 [d, J ˆ 6.1 Hz, OCH(CH3)2],
123.24 (HCarom), 124.62 (HCarom), 126.55 (HCarom), 147.49 (d,
J ˆ 19.9 Hz, Carom); anal. calcd. (%) for C12H21O4PS: C 49.30, H
7.24; found: C 49.16, H 7.06.
( Æ )-Diisopropyl 2-Hydroxyheptylphosphonate
[( Æ )-3c]
This hydroxyphosphonate was prepared by General Procedure
B using hexanal (10 mmol), diisopropyl methylphosphonate
and n-BuLi. Flash chromatography (ethyl acetate/CH2Cl2, 2:1,
Rf ˆ 0.40) followed by bulb-to-bulb distillation (958C/16 Torr)
afforded ( Æ )-3c as a colorless oil; yield: 1.94 g (69%). IR (Si):
nÄ ˆ 3388, 2932, 1226, 987 cmÀ1; 1H NMR (400.1 MHz, CDCl3):
d ˆ 0.84 [t, J ˆ 6.8 Hz, 3H, CH3(CH2)4], 1.26 (m, 5H, CH2), 1.27
[d, J ˆ 5.8 Hz, 3H, OCH(CH3)2], 1.28 [m, J ˆ 6.1 Hz, 6H,
OCH(CH3)2], 1.29 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.40 (m,
2H, CH2), 1.52 (m, 1H, CH2), 1.82 (AB part of ABMX system,
JAB ˆ 15.2 Hz, JAP ˆ 19.2 Hz, JAH ˆ 2.3 Hz, JBP ˆ 15.2 Hz, JBH
ˆ
( Æ )-Diisopropyl 2-Hydroxy-2-
phenylethylphosphonate [( Æ )-3f]
9.6 Hz, 2H, CH2P), 3.33 (s, 1H, OH), 3.91 (m, 1H, CHOH), 4.68
[m, 2H, OCH(CH3)2]; 13C NMR (100.6 MHz, CDCl3): d ˆ
13.99 (CH3), 22.57 (CH2), 23.99 [d, J ˆ 4.6 Hz, OCH(CH3)2],
This hydroxyphosphonate was prepared by General Procedure
B using freshly distilled benzaldehyde (10 mmol), diisopropyl
methylphosphonate and n-BuLi. Flash chromatography (hex-
ane/ethyl acetate, 1:2, Rf ˆ 0.30) gave ( Æ )-3f as a solid; yield:
2.64 g (92%); mp 69 708C (hexane). IR (Si): nÄ ˆ 3350, 2979,
ˆ
24.01 [d, J
3.8 Hz, OCH(CH3)2], 24.04 [d, J ˆ 5.4 Hz,
OCH(CH3)2], 24.05 [d, J ˆ 3.8 Hz, OCH(CH3)2], 25.06 (d, J ˆ
1.5 Hz, CH2), 31.69 (CH2), 34.64 (d, J ˆ 138.4 Hz, CH2P), 38.15
(d, J ˆ 16.8 Hz, C-3), 66.57 (d, J ˆ 6.1 Hz, CHOH), 70.53 [d,
J ˆ 5.4 Hz, OCH(CH3)2], 70.54 [d, J ˆ 5.4, CH(CH3)2]; anal.
calcd. (%) for C13H29O4P: C 55.70, H 10.42; found: C 55.43, H
10.27.
1
1386, 1222, 993 cmÀ1; H NMR (400.1 MHz, CDCl3): d ˆ 1.26
[d, J ˆ 6.3 Hz, 3H, OCH(CH3)2], 1.30 [d, J ˆ 6.3 Hz, 3H,
OCH(CH3)2], 1.34 [d, J ˆ 6.3 Hz, 3H, OCH(CH3)2], 1.35 [d,
J ˆ 6.3 Hz, 3H, OCH(CH3)2], 2.13 (m, 2H, CH2P), 4.12 (d, J ˆ
2.0 Hz, 1H, OH), 4.68 [m, 1H, OCH(CH3)2], 4.76 [m, 1H,
OCH(CH3)2], 5.06 (m, 1H, CHOH), 7.25 (m, 1H, Harom), 7.34 (
m, 4H, Harom); 13C NMR (100.6 MHz, CDCl3): d ˆ 23.89 [d, J ˆ
4.6 Hz, OCH(CH3)2], 24.00 [d, J ˆ 3.8 Hz, OCH(CH3)2], 24.05
[d, J ˆ 3.8 Hz, OCH(CH3)2], 37.19 (d, J ˆ 136.9 Hz, CH2P),
68.81 (d, J ˆ 4.6 Hz, CHOH), 70.76 [d, J ˆ 6.8 Hz,
OCH(CH3)2], 70.87 [d, J ˆ 6.2 Hz, OCH(CH3)2], 125.48 (2C,
HCarom), 127.59 (HCarom), 128.46 (2C, HCarom), 143.53 (d, J ˆ
16.8 Hz, Carom); anal. calcd. (%) for C14H23O4P: C 58.73, H 8.09;
found: C 59.00, H 7.83.
( Æ )-Diethyl 2-Hydroxy-2-(2-
thienyl)ethylphosphonate [( Æ )-3d]
This hydroxyphosphonate was prepared by General Procedure
B using thiophene-2-carbaldehyde (20 mmol), diisopropyl
methylphosphonate and s-BuLi. Flash chromatography (hex-
ane/ethyl acetate, 1:2, Rf ˆ 0.35) gave ( Æ )-3d[19b] as a yellow
oil; yield: 4.81 g (91%). 1H NMR (400.1 MHz, CDCl3): d ˆ 1.28
(t, J ˆ 7.1 Hz, 3H, OCH2CH3), 1.31 (t, J ˆ 7.1 Hz, 3H,
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Synthesis of Chiral, Non-Racemic b-Aminophosphonic Acids
FULL PAPERS
OCH(CH3)2], 24.00 [d, J ˆ 6.9 Hz, OCH(CH3)2], 24.04 [d, J ˆ
6.0 Hz, OCH(CH3)2], 24.55 (CH2), 31.33 (CH2), 32.25 (d, J ˆ
142.3 Hz, CH2P), 34.95 (d, J ˆ 8.4 Hz, C-3), 41.08 (CH2Cl),
70.41 [d, J ˆ 6.9 Hz, OCH(CH3)2], 70.52 [d, J ˆ 6.9 Hz,
OCH(CH3)2], 71.51 (d, J ˆ 2.3 Hz, CHO), 166.58 (CO); anal.
calcd. (%) for C15H30ClO5P: C 50.49, H 8.47; found: C 50.42, H
8.22.
( Æ )-Diisopropyl 2-Chloroacetoxypropylphosphonate
[( Æ )-10a]
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3a (5 mmol) by General Procedure C. Flash chromatog-
raphy (hexane/ethyl acetate, 1:4, Rf ˆ 0.43) gave ( Æ )-10a as a
colorless liquid; yield: 1.01 g (67%). IR (Si): nÄ ˆ 2980, 2937,
1758, 1245, 1179, 1140, 1107, 982 cmÀ1; 1H NMR (400.1 MHz,
CDCl3): d ˆ 1.29 [d, J ˆ 6.3 Hz, 6H, OCH(CH3)2], 1.30 [d, J ˆ
6.3 Hz, 6H, OCH(CH3)2], 1.38 (d, J ˆ 6.3 Hz, 3H, CH3), 2.04
(AB part of ABMX system, JAB ˆ 15.2 Hz, JAH ˆ 6.1 Hz, JAP
ˆ
19.2 Hz, JBP ˆ 19.0 Hz, JBH ˆ 7.1 Hz, 2H, PCH2), 4.01 (AB
system, J ˆ 15.2 Hz, 2H, CH2Cl), 4.68 [m, 2H, OCH(CH3)2],
5.25 (dsext, J ˆ 6.6, 9.4 Hz, 1H, CHO); 13C NMR (100.6 MHz,
CDCl3): d ˆ 21.07 (d, J ˆ 7.7 Hz, CH3), 23.97 [d, J ˆ 5.4 Hz,
OCH(CH3)2], 23.98 [d, J ˆ 5.4 Hz, OCH(CH3)2], 24.01 [d, J ˆ
3.8 Hz, 2C, OCH(CH3)2], 33.99 (d, J ˆ 141.5 Hz, CH2P), 41.04
(CH2Cl), 68.66 (OCH), 70.47 [d, J ˆ 5.4 Hz, OCH(CH3)2],
70.54 [d, J ˆ 6.0 Hz, OCH(CH3)2], 166.39 (CO); anal. calcd.
(%) for C11H22ClO5P: C 43.94, H 7.37; found: C 43.72, H 7.11.
( Æ )-Diethyl 2-Chloroacetoxy-2-(2-
thienyl)ethylphosphonate [( Æ )-10d]
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3d (5 mmol) by General Procedure C. Flash chromatog-
raphy (hexane/ethyl acetate, 1:4, Rf ˆ 0.40) gave ( Æ )-10d as a
colorless oil; yield: 1.57 g (92%). IR (Si): nÄ ˆ 2984, 1762, 1440,
1
1393, 1260, 1163, 1100, 1024, 970 cmÀ1; H NMR(400.1 MHz,
CDCl3): d ˆ 1.21 (t, J ˆ 6.8 Hz, 3H, OCH2CH3), 1.23 (t, J ˆ
7.1 Hz, 3H, OCH2CH3), 2.54 (AB part of ABMX system, JAB
ˆ
ˆ
15.6 Hz, JAP ˆ 17.6 Hz, JAH ˆ 8.6 Hz, JBP ˆ 19.2 Hz, JBH
( Æ )-Diisopropyl 2-Chloroacetoxy-3-
methybutylphosphonate [( Æ )-10b]
ˆ
5.5 Hz, 2H, CH2P), 4.04 (AB system, JAB 14.9 Hz, 2H,
ˆ
CH2Cl), 4.05 (m, 4H, OCH2CH3), 6.44 (dt, J 5.5, 8.6 Hz,
1H, CHO), 6.94 (dd, J ˆ 3.5, 5.1 Hz, 1H, Harom), 7.12 (dd, J ˆ
1.2, 5.1 Hz, 1H, Harom), 7.29 (dd, J ˆ 1.2, 3.5 Hz, 1H, Harom);
13C NMR (100.6 MHz, CDCl3): d ˆ 16.25 (d, J ˆ 4.6 Hz,
OCH2CH3), 16.31 (d, J ˆ 6.1 Hz, OCH2CH3), 33.33 (d, J ˆ
142.3 Hz, CH2P), 40.85 (d, J ˆ 22.9 Hz, CH2Cl), 62.23 (d, J ˆ
6.9 Hz, OCH2CH3), 62.39 (d, J ˆ 6.9 Hz, OCH2CH3), 67.90 (d,
J ˆ 1.5 Hz, OCH), 123.39 (HCarom), 124.70 (HCarom), 126.57
(HCarom), 141.35 (d, J ˆ 19.1 Hz, Carom.), 165.98 (CO); anal.
calcd. (%) for C12H18ClO5PS: C 42.29, H 5.32; found: C 42.27, H
5.18.
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3b (6.05 mmol) by General Procedure C. Flash chroma-
tography (hexane/ethyl acetate, 1:2, Rf ˆ 0.50) gave ( Æ )-10b
as a colorless oil; yield: 1.89 g (95%). IR (Si): nÄ ˆ 2978, 1762,
1
1252, 1178, 987 cmÀ1; H NMR (400.1 MHz, CDCl3): d ˆ 0.89
[d, J ˆ 6.8 Hz, 6H, (CH3)2CH], 1.27 [d, J ˆ 6.3 Hz, 3H,
OCH(CH3)2], 1.277 [d, J ˆ 5.8 Hz, 3H, OCH(CH3)2], 1.28 [d,
J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.29 [d, J ˆ 5.8 Hz, 3H,
OCH(CH3)2], 1.97 (m, 2H, CH2P), 4.03 (AB system, J ˆ
14.6 Hz, 2H, CH2Cl), 4.66 [m, 2H, OCH(CH3)2], 5.13 (ddt,
J ˆ 4.6, 8.8, 10.9 Hz, 1H, CHO); 13C NMR (100.6 MHz,
CDCl3): d ˆ 16.88 [CH(CH3)2], 18.11 [CH(CH3)2], 23.93 [d,
J ˆ 5.4 Hz, OCH(CH3)2], 23.97 [d, J ˆ 6.2 Hz, OCH(CH3)2],
24.00 [d, J ˆ 5.4 Hz, 2C, OCH(CH3)2], 29.21 (d, J ˆ 143.8 Hz,
ˆ
CH2P), 32.29 [d, J 12.2 Hz, OCH(CH3)2], 41.08 (s, CH2Cl),
( Æ )-Diisopropyl 2-Chloroacetoxy-2-(2-
thienyl)ethylphosphonate [( Æ )-10e]
70.33 [d, J ˆ 6.1 Hz, OCH(CH3)2], 70.48 [d, J ˆ 6.1 Hz,
OCH(CH3)2], 74.79 (d, J ˆ 4.6 Hz, CHO), 166.5 (CO); anal.
calcd. (%) for C13H26ClO5P: C 47.49, H 7.97; found: C 47.61, H
7.75.
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3e (4.99 mmol) by General Procedure C. Flash chroma-
tography (hexane/ethyl acetate, 1:2, Rf ˆ 0.50) gave ( Æ )-10e
as a colorless oil; yield: 1.67 g (91%). IR (Si): nÄ ˆ 2980, 1763,
1
1244, 1164, 986 cmÀ1; H NMR(400.1 MHz, CDCl3): d ˆ 1.23
( Æ )-Diisopropyl 2-Chloroacetoxyheptylphosphonate
[( Æ )-10c]
[d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.24 [d, J ˆ 5.8 Hz, 3H,
OCH(CH3)2], 1.25 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.27 [d,
J ˆ 6.1 Hz, 3H, OCH(CH3)2], 2.45 (AB part of ABMX system,
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3c (5 mmol) by General Procedure C. Flash chromatog-
raphy (hexane/ethyl acetate, 1:2, Rf ˆ 0.60) gave ( Æ )-10c as a
colorless oil; yield: 1.47 g (83%). IR (Si): nÄ ˆ 2979, 2959, 1761,
JAB ˆ 15.4 Hz, JAP ˆ 17.2 Hz, JAH ˆ 8.6 Hz, JBP ˆ 19.2 Hz, JBH
ˆ
5.4 Hz, 2H, CH2P), 4.03 (AB system, JAB ˆ 15.2 Hz, 2H,
CH2Cl), 4.64 [m, 2H, OCH(CH3)2], 6.43 (dt, J ˆ 5.4, 8.6 Hz,
1H, OCH), 6.93 (dd, J ˆ 3.5, 5.1 Hz, 1H, Harom), 7.09 (dd, J ˆ
1.0, 3.5 Hz, 1H, Harom), 7.27 (dd, J ˆ 1.0, 5.1 Hz, 1H, Harom);
13C NMR (100.6 MHz, CDCl3): d ˆ 23.85 [d, J ˆ 4.6 Hz,
OCH(CH3)2], 23.89 [d, J ˆ 3.1 Hz, 2C, OCH(CH3)2], 23.99 [d,
J ˆ 3.8 Hz, OCH(CH3)2], 34.62 (d, J ˆ 143.0 Hz, CH2P), 40.09
(CH2Cl), 68.13 (d, J ˆ 2.3 Hz, OCH), 70.65 [d, J ˆ 6.9 Hz,
OCH(CH3)2], 70.76 [d, J ˆ 6.9 Hz, OCH(CH3)2], 126.15
(HCarom), 126.66 (HCarom), 126.77 (HCarom), 141.68 (d, J ˆ
13.1 Hz, Carom), 165.92 (CO); anal. calcd. (%) for C14H22ClO5PS
45.06, H 5.77.
1
1246, 1178, 986 cmÀ1; H NMR(400.1 MHz, CDCl3): d ˆ 0.85
(t, J ˆ 6.7 Hz, 3H, CH3), 1.27 (m, 6H, CH2), 1.28 [d, J ˆ 5.8 Hz,
3H, OCH(CH3)2], 1.289 [d, J ˆ 6.3 Hz, 3H, OCH(CH3)2], 1.29
[d, J ˆ 6.3 Hz, 3H, OCH(CH3)2], 1.30 [d, J ˆ 5.8 Hz, 3H,
OCH(CH3)2], 1.67 (m, 2H, CH2), 2.02 (AB part of ABMX
system, JAB ˆ 15.4 Hz, JAP ˆ 18.4 Hz, JAH ˆ 7.3 Hz, JBP
ˆ
19.2 Hz, JBH ˆ 6.1 Hz, 2H, CH2P), 4.02 (AB system, JAB
ˆ
14.9 Hz, 2H, CH2Cl), 4.67 [m, 2H, OCH(CH3)2] 5.21 (m, 1H,
CHO); 13C NMR (100.6 MHz, CDCl3): d ˆ 13.91 (CH3), 22.42
(CH2), 23.97 [d, J ˆ 5.4 Hz, OCH(CH3)2], 23.98 [d, J ˆ 2.3 Hz,
Adv. Synth. Catal. 2003, 345, 1287 1298
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1295

A. Woschek et al.
FULL PAPERS
The spectroscopic data of (S)- and (R)-15b are identical. IR
(Si): nÄ ˆ 211 cmÀ1; 1H NMR (400.1 MHz, CDCl3): d ˆ 0.90 [d,
J ˆ 6.8 Hz, 3H, (CH3)2CH2], 0.95 [d, J ˆ 6.8 Hz, 3H,
(CH3)2CH], 1.31 [d, J ˆ 6.3 Hz, 12H, OCH(CH3)2], 1.86 (m,
2H, CH2P), 3.53 (m, 1H, N3CH), 4.71 [m, 2H, OCH(CH3)2];
13C NMR (100.6 MHz, CDCl3): d ˆ 17.04 (CH3), 19.22 (CH3),
23.94 [d, J ˆ 4.0 Hz, OCH(CH3)2], 23.98 [d, J ˆ 3.5 Hz,
OCH(CH3)2], 24.03 [d, J ˆ 2.3 Hz, OCH(CH3)2], 24.07 [d, J ˆ
3.3 Hz, OCH(CH3)2], 30.10 (d, J ˆ 143.8 Hz, CH2P), 33.75 [d,
J ˆ 11.2 Hz, (CH3)2CH], 63.71 (d, J ˆ 5.4 Hz, CHN3), 70.48 [d,
J ˆ 6.9 Hz, OCH(CH3)2], 70.49 [d, J ˆ 6.9 Hz, OCH(CH3)2].
( Æ )-Diisopropyl 2-Chloroacetoxy-2-phenylethyl-
phosphonate [( Æ )-10f]
This chloroacetate was prepared from hydroxyphosphonate
( Æ )-3f (1.92 mmol) by General Procedure C. Flash chroma-
tography (hexane/ethylacetate, 1:2, Rf ˆ 0.23) gave ( Æ )-10fas
a colorless liquid; yield: 0.60 g (86%). IR (Si): nÄ ˆ 2980, 1764,
1
1252, 1170, 989 cmÀ1; H NMR (400.1 MHz, CDCl3): d ˆ 1.20
[d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.23 [d, J ˆ 5.8 Hz, 3H,
OCH(CH3)2], 1.25 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.28 [d,
J ˆ 6.3 Hz, 3H, OCH(CH3)2], 2.36 (AB part of ABMX system,
1
JAB ˆ 15.2 Hz, JAP ˆ 19.4 Hz, JAH ˆ 8.3 Hz, JBP ˆ 19.5 Hz, JBH
ˆ
16b: H NMR (400.1 MHz, CDCl3, from the mixture with
5.3 Hz, 2H, CH2P), 4.05 (AB system, JAB ˆ 14.9 Hz, 2H,
CH2Cl), 4.64 [m, 2H, OCH(CH3)2], 6.15 (dt, J ˆ 5.3, 8.3 Hz,
1H, CHO), 7.33 (m, 5H, Harom); 13C NMR (100.6 MHz, CDCl3):
d ˆ 23.89 [d, J ˆ 3.8 Hz, 2C, OCH(CH3)2], 23.92 [d, J ˆ 3.8 Hz,
OCH(CH3)2], 24.02 [d, J ˆ 3.1 Hz, OCH(CH3)2], 34.48 (d, J ˆ
142.3 Hz, CH2P), 40.90 (CH2Cl), 70.56 [d, J ˆ 6.1 Hz,
OCH(CH3)2], 70.69 [d, J ˆ 6.9 Hz, OCH(CH3)2], 72.92 (d, J ˆ
2.3 Hz, CHO), 126.68 (2C, HCarom), 128.65 (2C, HCarom), 128.71
(HCarom), 139.10 (d, J ˆ 10.7 Hz, Carom), 165.98 (CO); anal.
calcd. (%) for C16H24ClO5P: C 52.97, H 6.66; found: C 52.73, H
6.49.
azide): d ˆ 1.02 [d, J ˆ 6.8 Hz, 6H, (CH3)2CH], 1.26 [d,
J ˆ 6.3 Hz, 6H, OCH(CH3)2], 1.30 [d, J ˆ 6.6 Hz, 6H,
OCH(CH3)2], 2.4 [m, 1H, (CH3)2CH], 4.62 [m, 2H,
ˆ
OCH(CH3)2], 5.56 (ddd, J ˆ 1.5, 17.2, 20.5 Hz, 1H, CH CHP),
ˆ
9 (ddd, J ˆ 6.1, 17.2, 22.2 Hz, 1 H, CH CHP).
(S)-(‡)- and (R)-(À)-Diisopropyl 2-Azido-2-
phenylethylphosphonate [(S)- and (R)-15f]
To a stirred solution of b-hydroxyphosphonate (R)-8f {0.572 g,
2.00 mmol, [a]2D0: À 22.9 (c 2.0, acetone), ee 50%} and
triphenylphosphane (0.79 g, 3.0 mmol) in a mixture of dry
toluene (16 mL) and dry THF (4 mL) at 08C was added
diisopropyl azodicarboxylate (0.59 mL, 3.0 mmol) and HN3 in
toluene (1.98 mL, 1.5 M). The solution was stirred for 15 min at
08C and allowed to room temperature over 5 h. Evaporation of
the solvent under reduced pressure and column chromatog-
raphy (hexane/diethyl ether, 1:2, then diethyl ether for azide;
Rf ˆ 0.49 for hexane/diethyl ether, 1:3) afforded azide (S)-15f
as an oil; yield: 0.561 g (90%), [a]2D0: ‡ 34.87 (c 2.05, acetone).
(R)-(À)-Diethyl 2-Hydroxypropylphosphonate [(R)-
12]
A solution of (R)-(À)-diethyl 2-benzyloxyethylphosphonate
[(R)-11] (6.5 g, 22.7 mmol), prepared in analogy[21] to the
deuterated compound from (R)-isobutyl lactate except that
LiAlD4 was replaced by LiAlH4, in dry ethanol (75 mL) was
hydrogenated in a Parr apparatus for 3 h at 3.4 bar using
palladium on charcoal (0.2 g, 10%). The catalyst was removed
and the filtrate was concentrated under reduced pressure. The
residue was bulb-to-bulb distilled (90 928C/0. 3 Torr) to
afford b-hydroxyphosphonate (R)-12 as a colorless liquid;
yield: 4.35 g (98%), [a]2D0: À 7.0 (c 1.625, methanol), [a]57820: À
7.3 (c 1.625, methanol), [a]2D0: À 11.02 (c 1.625, acetone), lit.[11]
[a]57820: ‡ 7.3 (c 2.0, methanol); ee>98% [by 1H NMR of (R)-
Mosher ester]. The spectroscopic data are identical with those
of the racemate.[21]
Similarly,
a-hydroxyphosphonate
(S)-8b
{0.548 g,
1.92 mmol, [a]2D0: ‡ 37.45 (c 0.55, acetone), ee 95%} was
transformed into azide (R)-15f; yield: 0.439 g (73%); [a]2D0:
À 68.78 (c 1.275, acetone).
The spectroscopic data of (S)- and (R)-15f are identical. IR
(Si): nÄ ˆ 2980, 2103, 1249, 987 cmÀ1; 1H NMR (400.1 MHz,
CDCl3): d ˆ 1.18 [d, J ˆ 6.1 Hz, 3H, OCH(CH3)2], 1.24 [d, J ˆ
6.1 Hz, 3H, OCH(CH3)2], 1.26 [d, J ˆ 5.8 Hz, 3H, OCH(CH3)2],
1.27 [d, J ˆ 5.8 Hz, 3H, OCH(CH3)2], 2.22 (AB part of ABMX
system, JAB ˆ 15.4 Hz, JAP ˆ 17.7 Hz, JAH ˆ 8.3 Hz, JBP
ˆ
18.2 Hz, JBH ˆ 6.1 Hz, 2H, CH2P), 4.59 [m, 1H, OCH(CH3)2],
4.68 [m, 1H, OCH(CH3)2], 4.81 (dt, J ˆ 6.1, 8.3 Hz, 1H, CHN3),
7.35 (m, 5H, Harom); 13C NMR (100.6 MHz, CDCl3): d ˆ 23.81
[d, J ˆ 4.6 Hz, OCH(CH3)2], 23.85 [d, J ˆ 3.8 Hz, OCH(CH3)2],
23.99 [d, J ˆ 4.6 Hz, OCH(CH3)2], 24.03 [d, J ˆ 3.8 Hz,
OCH(CH3)2], 34.49 (d, J ˆ 142.3 Hz, CH2P), 61.22 (d, J ˆ
2.3 Hz, N3CH), 70.46 [d, J ˆ 6.9 Hz, OCH(CH3)2], 70.63 [d,
J ˆ 6.9 Hz, OCH(CH3)2], 126.85 (2C, HCarom), 128.59 (HCarom),
128.86 (2C, HCarom), 139.28 (d, J ˆ 10.7 Hz, Carom); 31P NMR
(161.98 MHz, CDCl3): d ˆ 24.99; anal. calcd. (%) for
C14H22N3O5P: C 54.01, H 7.12, N 13.50; found: C 53.96, H
6.95, N 13.24.
(S)-(À)- and (R)-(‡)-Diisopropyl 2-Azido-3-
metylbutylphosphonates [(S)- and (R)-15b]
Diisopropyl azodicarboxylate (0.222 g, 0.216 mL, 1.10 mmol)
was added to a stirred solution of b-hydroxyphosphonate (R)-
8b {0.185 g, 0.733 mmol, [a]D20: À 14.8 (c 1.15, acetone), ee 98%}
and triphenylphosphane (0.289 g, 1.1 mmol) in a mixture of dry
toluene (15 mL) and dry CH2Cl2 (3 mL) at 08C, followed
immediately by HN3 in toluene (0.73 mL, 1.5 M, 1.1 mmol).
The solution was stirred for 15 min at 08C and 4 h at 508C.
Evaporation of the solvent under reduced pressure and column
chromatography (hexane/diethyl ether, 1:2, then diethyl ether
for azide; Rf ˆ 0.32 for hexane/diethyl ether, 1:2) gave azide
1
(S)-15b as an oil (azide 15b/olefin 16b 87:13, by H NMR);
yield: 0.133 g (66%), [a]2D0: À 0.5 (c 1.19, acetone).
(S)-(À)- and (R)-(‡)-2-Amino-3-
Similarly,
b-hydroxyphosphonate
(S)-8b
{0.213 g,
methylbutylphosphonic Acids [(S)- and (R)-17b]
0.844 mmol, [a]2D0: ‡ 9.9 (c 1.0, acetone), ee 65%} was trans-
formed into azide (R)-15b as an oil (azide 15b/olefin 16b 82:18,
by 1H NMR); yield: 0.191 g (82%), [a]2D0: ‡ 2.6 (c 1.25, acetone).
Azide (R)-15b (0.191 g, 0.688 mmol, azide/olefin, 82:18) was
transformed by General Procedure H into b-aminophosphonic
1296
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
Adv. Synth. Catal. 2003, 345, 1287 1298

Synthesis of Chiral, Non-Racemic b-Aminophosphonic Acids
FULL PAPERS
acid (S)-17b as a crystalline solid using 0.1 M CH3CO2H as
eluent for column with Dowex 1X8, AcOÀ; yield: 86 mg (75%).
Similarly, azide (S)-15b (0.109 g, 0.392 mmol, azide/olefin
83:17) was transformed into b-aminophosphonic acid (R)-17b
as a crystalline solid; yield: 38 mg (58%).
[3] R. Zurawinski, K. Nakamura, J. Drabowicz, P. Kielba-
sinski, M. Miko¯ajczyk, Tetrahedron: Asymmetry 2001,
12, 3139 3145.
[4] Y. Zhang, C. Yuan, Z. Li, Tetrahedron 2002, 58, 2973
2978.
[5] a) M. Drescher, F. Hammerschmidt, H. K‰hlig, Synthesis
1995, 1267 1272; b) G. Eidenhammer, F. Hammersch-
midt, Synthesis 1996, 748 754.
[6] K. Laumen, M. P. Schneider, J. Chem. Soc. Chem.
Commun. 1988, 598 600.
The spectroscopic data (1H, 13C, 31P NMR) of (R)- and (S)-
17b are identical. 1H NMR (400.1 MHz, D2O): d ˆ 0.93 [d, J ˆ
6.8 Hz, 3H, (CH3)2CH], 0.94 [d, J ˆ 6.8 Hz, 3H, (CH3)2CH],
1.65 (dt, J ˆ 11.1, 15.4 Hz, 1H, CH2P), 1.97 [m, 2H, CH2P and
(CH3)2CH], 3.25 (ddt, J ˆ 3.0, 5.8, 11.0 Hz, 1H, CHCH2P);
13C NMR (100.6 MHz, D2O): d ˆ 17.37 [(CH3)2CH], 17.49
[(CH3)2CH], 28.02 (d, J ˆ 130.0 Hz, CH2P), 31.39 [d, J ˆ
13.0 Hz, (CH3)2CH], 54.41 (d, J ˆ 5.4 Hz, NCH); 31P NMR
(161.98 MHz, D2O): d ˆ 21.24.
[7] F. Hammerschmidt, F. Wuggenig, Tetrahedron: Asymme-
try 1999, 10, 1709 1721.
[8] M. Kitamura, M. Tokunaga, and R. Noyori, J. Am.
Chem. Soc. 1995, 117, 2931 2932.
[9] I. Gautier, V. Ratovelomanana-Vidal, P. Savignac, J.-P.
Genet, Tetrahedron Lett. 1996, 37, 7721 7724; G.
Michaud, M. Bulliard, L. Ricard, J.-P. Genet, A. Marine-
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[10] C. Meier, W. H. G. Laux, J. W. Bats, Liebigs Ann. Chem.
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[11] E. Zymanczczyk-Duda, B. Lejczak, P. Kafarski, Tetrahe-
dron 1995, 51, 11809 11814.
[12] C. Wawrzenczyk, J. Zon, E. Leja, Phosphorus, Sulfur,
and Silicon 1992, 71, 179 184.
[13] Z. Zhao, P. Liu, K. Murakami, T. Kuzuyama, H. Seto, H.
Liu, Angew. Chem. 2002, 114, 4711 4714; Angew. Chem.
Int. Ed. 2002, 41, 4529 4532.
[14] G. Guanti, M. T. Zannetti, L. Banfi, R. Riva, Adv. Synth.
Catal. 2001, 343, 682 691.
[15] J. F. Dellaria, Jr., R. G. Maki, Tetrahedron Lett. 1986, 27,
2337 2340; M. Ordonez, R. de la Cruz, M. Fernandez-
Zertuche, M.-A. Munoz-Hernandez, Tetrahedron: Asym-
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[16] T. Kamiya, K. Hemmi, H. Takeno, M. Hashimoto,
Tetrahedron Lett. 1980, 21, 95 98.
(S)-(‡)- and (R)-(-)-2-Amino-2-
phenylethylphosphonic Acids [(S)- and (R)-17f]
Azide (R)-15f (0.173 g, 0.556 mmol) was transformed by
General Procedure H into b-aminophosphonic acid (R)-17f
as a crystalline solid using 5% HCO2H as eluent for column
with Dowex 1X8, AcOÀ; yield: 88 mg (79%); TLC: Rf ˆ 0.46;
PC: Rf ˆ 0.85.
Similarly, azide (S)-15f (0.156 g, 0.50 mmol) was trans-
formed into b-aminophosphonic acid (S)-17f as a crystalline
solid; yield: 93 mg (93%)
The spectroscopic data (1H, 13C, 31P NMR) of (R)- and (S)-
17f are identical. 1H NMR (400.1 MHz, D2O): d ˆ 2.42 (dd, J ˆ
ˆ
7.3, 18.4 Hz, 2H, CH2P), 4.61 (dt, J 7.3, 9.1 Hz, 1H, NH2CH),
7.43 (m, 5H, Harom.); 13C NMR (100.6 MHz, D2O): d ˆ 32.72 (d,
J ˆ 130.8 Hz, CH2P), 52.49 (d, J ˆ 2.5 Hz, NH2CH), 127.44 (2C,
HCarom), 129.64 (2C, HCarom), 129.81 (HCarom),147.17 (d, J ˆ
14.5 Hz, Carom); 31P NMR (161.98 MHz, D2O): d ˆ 21.08; anal.
calcd. (%) for C8H12NO3P: C 47.77, H 6.01, N 6.96; found: C
46.24, H 5.65, N 6.12.
[17] T. Kuzuyama, T. Shimizu, S. Takahashi, H. Seto, Tetra-
hedron Lett. 1998, 39, 7913 7916.
[18] K. Nakamura, T. Kimura, E. Takahashi, Phosphorus,
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438.
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[21] F. Hammerschmidt, Monatshefte Chem. 1991, 122, 389
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[22] D. Parker, Chem. Rev. 1991, 91, 1441 1457.
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[24] J. S. Kittredge, R. R. Hughes, Biochemistry 1964, 3, 991
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Acknowledgements
The authors thank the Fonds zur Fˆrderung der wissenschaft-
lichen Forschung (project no. P15779/N03) for financial
support, Amano Enzyme Europe Ltd (England) and Novo
Nordisk (Denmark) and Boehringer Mannheim (Germany) for
generous gifts of enzymes.
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