Enzymes in organic chemistry VI [1]. Enantioselective hydrolysis of 1-chloroacetoxycycloalkylmethylphosphonates with lipase AP 6 from Aspergillus niger and chemoenzymatic synthesis of chiral, nonracemic 1-aminocyclohexyl-methylphosphonic acids

Article abstract of DOI:10.1007/PL00000099

Racemic α-chloroacetoxyphosphonates derived from cycloalkanecarbaldehydes and three branched aldehydes were prepared and tested for kinetic resolution by lipase AP 6 which hydrolyses preferentially the (S) esters. The enantiomeric excess and the reaction rate are significantly influenced by the size of the cycloalkyl group. The optical antipodes of α-hydroxycyclohexylmethylphosphonates (3d; ee 90% and ≥ 99%, respectively) were transformed into the corresponding α-aminophosphonic acids 6.

Full text of DOI:10.1007/PL00000099

Monatshefte fuÈr Chemie 129, 423±436 (1998)
Enzymes in Organic Chemistry VI [1].
Enantioselective Hydrolysis of
1-Chloroacetoxycycloalkylmethylphosphonates
with Lipase AP 6 from Aspergillus niger and
Chemoenzymatic Synthesis of Chiral,
Nonracemic 1-Aminocyclohexyl-
methylphosphonic Acids
Ã
Frank Wuggenig and Friedrich Hammerschmidt
È
Institut fuÈr Organische Chemie, Universitat Wien, A-1090 Wien, Austria
Summary. Racemic ꢀ-chloroacetoxyphosphonates derived from cycloalkanecarbaldehydes and
three branched aldehydes were prepared and tested for kinetic resolution by lipase AP 6 which
hydrolyses preferentially the (S) esters. The enantiomeric excess and the reaction rate are
signi®cantly in¯uenced by the size of the cycloalkyl group. The optical antipodes of ꢀ-
hydroxycyclohexylmethylphosphonates (3d; ee 90% and ꢀ99%, respectively) were transformed
into the corresponding ꢀ-aminophosphonic acids 6.
Keywords. ꢀ-Hydroxyphosphonates; ꢀ-Chloroacetoxyphosphonates; Enzymatic resolution; Lipase;
ꢀ-Aminophosphonic acids.
Enzyme in der organischen Chemie, 6. Mitt. [1]. Enantioselektive Hydrolyse
von 1-Chloracetoxycycloalkylmethylphosphonaten mit Lipase AP 6 aus
Aspergillus niger und chemoenzymatische Synthese chiraler nichtracemischer
È
1-Aminocyclohexylmethylphosphonsauren
Zusammenfassung. Racemische ꢀ-Chloroacetoxyphosphonate, die sich von Cycloalkancarbalde-
hyden und drei verzweigten Aldehyden ableiten, wurden hergestellt und fuÈr die kinetische
Racematspaltung mit der Lipase AP 6, die bevorzugt die (S)-Ester hydrolysiert, verwendet. Der
È
EnantiomerenuÈberschuû und die Reaktionsgeschwindigkeit werden signi®kant von der Ringgroûe
des Cycloalkylrestes beein¯uût. Die optischen Antipoden des ꢀ-Hydroxycyclohexylmethylphos-
È
phonates (3d; ee 90% bzw. ꢀ 99%) wurden in die entsprechenden ꢀ-Aminophosphonsauren 6
uÈbergefuÈhrt.
* Corresponding author

424
F. Wuggenig and F. Hammerschmidt
Introduction
Chiral, nonracemic ꢀ-hydroxyphosphonates are valuable starting materials for
other ꢀ-substituted phosphonates and phosphonic acids, especially ꢀ-aminophos-
phonic acids. They can be prepared by a number of methods, the more prominent
ones being resolution [2], enantioselective addition of dialkyl phosphites to
aldehydes [3], TiCl4 catalyzed enantioselective opening of homochiral 1,3-dioxane
acetals by triethyl phosphite [4], diastereoselective addition of homochiral
phosphorus acid derivatives to aldehydes [5], enantioselective reduction of ꢀ-
oxophosphonates [6], phosphate-phosphonate rearrangement [7], and lipase-
catalyzed [1] kinetic resolution of ꢀ-acyloxyphosphonates. In preceeding papers
we have developed protocols for the easy preparation [8] of racemic ꢀ-
hydroxyphosphonates, their acetylation [8] or chloroacetylation [9], and their
lipase catalyzed hydrolysis [8] in a stirred biphasic phosphate buffer at pH 7.0
using an autotitrator. Furthermore, the enantiomeric excesses and the absolute
con®gurations of the ꢀ-hydroxyphosphonates were determined using 31P NMR
spectroscopy of corresponding Mosher esters [10]. Two enzymes, lipases AP 6
(from Aspergillus niger) and FAP 15 (From Rhizopus oryzae) have shown good to
very good enantioselectivity with a variety of substrates derived from straight chain
aliphatic [8], aromatic, and heteroaromatic [9] aldehydes. Lipase AP 6 has the
broader substrate speci®city. In general, chloroacetates were hydrolyzed more
easily than acetates, and the ee was highest for diisopropyl phosphonates.
Results and Discussion
Lipase catalyzed kinetic resolution of ꢀ-acyloxyphosphonates
This paper focuses on the hydrolysis of ꢀ-chloroacetoxyphosphonates derived
from cycloalkanecarbaldehydes with a ring size ranging from cyclopropyl to
cyclooctyl. We intended to study the in¯uence of the alicyclic ring on the reaction
rate and the enantioselectivity as compared to planar ®ve and six membered
aromatic and heteroaromatic systems. Thus aldehydes 1a±f were transformed into
racemic ꢀ-hydroxyphosphonates (Æ)-3a±g by addition of diethyl- (2b) or
preferentially diisopropyl phosphite (2a) under catalysis of a substoichiometric
amount of the phosphazene base P1-t-Bu (tert-butylamino-tris-(dimethylamino)-
phosphorane) (Abramov reaction, Scheme 1) [8].
The aldehydes were of commericial origin or were prepared by Swern
oxidation and used without further puri®cation. The yields of ꢀ-hydroxyphos-
phonates were as high as 92%. The low yield (32%) for (Æ)-3g is attributed to the
low purity of the crude cyclooctanecarbaldehyde prepared from cyclooctanone
[11]. The ꢀ-hydroxyphosphonates (Æ)-3a±g were chloroacetylated [9] using
chloroacetic anhydride/pyridine to give chloroacetoxyphosphonates (Æ)-4
(Scheme 1). To see whether a dichloroacetate is more reactive or enantioselective
than a monochloroacetate, dichloroacetate (Æ)-4b was prepared as well. It was
obtained in 53% yield by esteri®cation of ꢀ-hydroxyphosphonate (Æ)-3a with the
imidazolide generated from N,N0-carbonyldiimidazole and dichloroacetic acid.
The enzymatic hydrolyses were carried out on a 1 mmol scale employing
an appropriate amount of lipase AP 6 or FAP 15 (entries 2, 3, and 5) in a well

Enantioselective Hydrolysis of Phosphonates
425
OH
j
Ref: ‰8Š
R1ꢁ CH ꢁ PꢂO†ꢂOR2†
ꢂƆ-3
R1CHO ‡ ꢂR2O†2PꢂO†H
ꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁ!
2
32ꢁ92%
1
2
Ref: ‰9Š 53--93%
#
1 R1
2
a
b
R2
OCOR3
a c-C3H5
b c-C4H7
i-Pr
j
R1ꢁ CH ꢁ PꢂO†ꢂOR2†
ꢂƆ-4
Et
2
c c-C5H9
d c-C6H11
e
f
c-C7H13
c-C8H15
g c-C6H11CH2CH2
h (CH3)2CH
i
(CH3)2CHCH2
(CH3)3C
j
3 R1
R2
4
R1
R2
R3
a c-C3H5
b c-C4H7
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
a
b
c
d
e
f
c-C3H5
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
CH2Cl
CHCl2
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
CH2Cl
c-C3H5
c c-C5H9
d c-C6H11
c-C4H7
c-C5H9
e
f
c-C7H13
c-C7H13
c-C6H11
c-C7H13
c-C7H13
c-C8H15
c-C6H11CH2CH2
(CH3)2CH
(CH3)2CHCH2
(CH3)3C
g c-C8H15
h c-C6H11CH2CH2
Et
g
h
i
Et
Et
i
(CH3)2CH
i-Pr
i-Pr
i-Pr
Et
j (CH3)2CHCH2
k (CH3)3C
j
i-Pr
i-Pr
i-Pr
k
l
Scheme 1
stirred biphasic system at room temperature as reported previously (Scheme 2,
Table 1) [8].
The biphasic system consisted of 17 ml of a 50 mM sterile phosphate buffer
( pH 7.0) and a mixture of tert-butyl methyl ether and hexanes (2 ml of each). The
pH was kept constant by an autotitrator, and the reaction was stopped at a
conversion of about 45% based on the consumption of 0.5 N NaOH by a addition of
2 N HCl ( pH 4.0). Extractive workup and separation by ¯ash chromatography
furnished ꢀ-hydroxyphosphonate (‡)-3 and ꢀ-acyloxyphosphonate (ꢁ)-4 which
was hydrolyzed chemically [8, 9] (Et3N/MeOH) to give (ꢁ)-3. The data of the
individual runs are compiled in Table 1. The chiral, nonracemic ꢀ-hydroxyphos-
1
phonates 3 were derivatized with (S)-(‡)-MTPA-Cl, and the H and 31P NMR

426
F. Wuggenig and F. Hammerschmidt
enzyme=phosphate
buffer pH 7=hexanes=
tert butyl methyl ether
-
ꢂƆ-4 ꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁꢁ! ꢂS†-ꢂ‡†-3 ‡ ꢂR†-ꢂꢁ†-4
Et3N=MeOH
r:t:
#
ꢂR†-ꢂꢁ†-3
Scheme 2
spectra were recorded to determine both enantiomeric excess and absolute
con®guration of the underlying ꢀ-hydroxyphosphonate 3 [10]. The phosphorus
resonances of the Mosher esters derived from (S)-3 resonate at lower ®eld than
those derived from (R)-3 throughout, and the chemical shift differences vary from
0.39 to 0.65 ppm except for ꢀ-hydroxyphosphonate 3k having a branched alkyl
group (see later) and displaying a shift difference of 0.11 ppm which is in
1
accordance with literature data (Table 2). The same relation is observed in the H
NMR spectra for the methoxy group of MTPA except for 3a, but the shift
differences are too small (‡0.10 to ꢁ0.01 ppm) to be used for a secure assignment
of the absolute con®guration. The reversal of the resonances for 3a is probably
caused by the deshielding effect of the cyclopropyl group.
Lipases AP 6 and FAP 15 hydrolyze in all cases tested preferentially the (S)
esters of (Æ)-4 (Table 1). The enzyme FAP 15 accepts only the cyclopropyl
derivative (Æ)-4a as substrate, but not the cyclobutyl derivative (Æ)-4c. The
reaction rate is fairly low compared to AP 6, and the ee is just 50% (entries 2 and
1). Surprisingly, the corresponding dichloroacetate (Æ)-4b is not hydrolyzed more
rapidly than chloroacetate (Æ)-4a (entry 3), and the ee is even lower (38%). Other
cyclic substrates were not investigated for kinetic resolution using lipase FAP 15.
Reaction rates of cyclic chloroacetates and the ee of (S) con®gurated ꢀ-
hydroxyphosphonates 4 formed are dramatically in¯uenced by the ring size. The
reaction rate decreases from the cyclopropyl derivative (Æ)-4a to the cyclobutyl
and cyclopentyl derivatives (Æ)-4c and (Æ)-4d, then increases by going to the
cyclohexyl derivative (Æ)-4e, and ®nally drops again for the cycloheptyl derivative
(Æ)-4f (entries 1, 4, 6, 7, 8). The ee is 71% for (Æ)-4a and 75% for (Æ)-4c. It
increases to 86% for (Æ)-4d and (Æ)-4e and then drops to 75% for (Æ)-4f. When
the isopropyl groups of (Æ)-4f are replaced by ethyl groups, the reaction rate
increases by a factor of ten, but the ee (54%) is reduced (entries 8 and 9). The
cyclooctylmethylphosphonate (Æ)-4h is still a substrate for lipase AP 6, but the
enantioselectivity of hydrolysis (17% ee) is too low to be of preparative value.
Addition of two extra methylene groups as spacers between the cyclohexyl and the
chloroacetoxy substituted carbon atoms of (Æ)-4e and replacement of the isopropyl
by ethyl groups has little in¯uence on reaction rate and ee (entries 7 and 11). The
acitve site of AP 6 accommodates best the ꢀ-chloroacetoxyphosphonates with a
cylcopentyl and cyclohexyl ring, the latter even when ®tted with a short spacer.
The transformation of these cyclic substrates which can be viewed as ꢀ-
acyloxyphosphonates with a branching at the ꢁ-carbon led us to reinvestigate the
enzyme catalyzed hydrolysis of acyloxyphosphonates with a branched alkyl group.

Enantioselective Hydrolysis of Phosphonates
427

428
F. Wuggenig and F. Hammerschmidt
Table 2. Assignment of con®guration at C-1 of diastereomeric Mosher esters prepared from ꢀ-
hydroxyphosphonates 3 on the basis of 1H (for methoxy group of MTPA) and 31P NMR chemical shifts
Mosher ester of
Chemical shifts ꢂ (ppm)
(S) (1H/31P)
Áꢂ (1H/31P)
(R) (1H/31P) at C-1 of 3
3a
3b
3c
3d
3e
3f
3.53/16.23
3.61/16.93
3.62/17.39
3.62/17.49
3.63/17.67
3.61/19.67
3.59/19.76
3.61/19.93
3.62/17.39
3.61/18.17
3.63/17.01
3.54/15.58
3.57/16.39
3.54/17.00
3.55/17.04
3.55/17.15
3.54/19.16
3.52/19.27
3.55/19.43
3.55/16.97
3.54/17.69
3.53/16.90
ꢁ0.01/0.65
0.04/0.54
0.08/0.39
0.07/0.45
0.08/0.52
0.07/0.51
0.07/0.49
0.06/0.50
0.07/0.42
0.07/0.48
0.10/0.11
3g
3h
3i
3j
3k
Diisopropyl 1-acetoxyphosphonates derived from isobutyraldehyde and 3-methyl-
butyraldehyde are not hydrolyzed by lipase AP 6 as reported recently [8].
Therefore, the ꢀ-chloroacetoxyphosphonates (Æ)-4j, 4k, and 41 derived from these
two aldehydes and pivalaldehyde, were prepared according to Scheme 1 and
tested as substrates for lipase AP 6 (Table 1, entries 12, 13 and 14). The ®rst two
were hydrolyzed and the enantiomeric excesses were 64% and 35%, respectively.
The reaction rate of (Æ)-4j is much slower than that of (Æ)-4a, although both are
structurally very similar. A cyclopropyl ring has been replaced by an isopropyl
group. The chloroacetate (Æ)-4l, derived from pivalaldehyde, is not a substrate of
lipase AP 6. The corresponding diethyl phosphonate is one, but the ee is merely
15% [8]. The results reported add further to the broad substrate speci®city of
lipase AP 6.
Chemoenzymatic synthesis of (R)- and
(S)-1-aminocyclohexylmethylphosphonic acid
To demonstrate its preparative utility, the antipodes of 1-aminocyclohexylmethyl-
phosphonic acid (6) were prepared from ꢀ-hydroxyphosphonates 3d (Scheme 3).
We are interested in this compound as a structural analogue of 2-phenyl-1-
aminoethylphosphonic acid, a phenyl alanine ammonia lyase inhibitor [12] with a
reduced ring being directly attached to the ꢀ-carbon of the phosphonic acid.
Protected (R)-1-aminophosphonic acid 6 has recently been synthesized for
incorporation into a hapten [13]. To get adequate amounts of the required ꢀ-
hydroxyphosphonates (R)- and (S)-3d, 10 mmol of chloroacetoxyphosphonate (Æ)-
4e were hydrolyzed in a biphasic system (50 ml of phosphate buffer pH 7.0, 10 ml
each of hexanes and tert-butyl methyl ether, 363 mg AP 6, 6.5 h). The reaction was
stopped at a conversion of 30% as determined by consumption of 0.5 N NaOH and
1H NMR spectroscopy to get a high ee for ꢀ-hydroxyphosphonate (S)-3d. Workup
and separation of ester and alcohol afforded ꢀ-hydroxyphosphonate (S)-3d (24%;

Enantioselective Hydrolysis of Phosphonates
429
Scheme 3
[ꢀ]2D0 ˆ ‡8.3 (c ˆ 1.0); ee 90%) and chloroacetate (R)-4e (63%; [ꢀ]2D0 ˆ ꢁ4.2
(c ˆ 1.3)) which was subjected to a second hydrolysis (50 ml buffer, 10 ml each of
hexanes and tert-butyl methyl ether, 281 mg AP 6, 94 h, conversion 48% by
1
consumption of 0.5 N NaOH, 51% by H NMR spectroscopy). The isolated ꢀ-
hydroxyphosphonate (S)-3d had a low enantiomeric excess (35%; [ꢀ]2D0 ˆ ‡1.6
(c ˆ 3.4)). The chloroacetate (R)-4e (42%; [ꢀ]2D0 ˆ ꢁ11.2 (c ˆ 1.5)) was hydro-
lyzed using MeOH/NEt3 to yield homochiral ꢀ-hydroxyphosphonate (R)-3d (97%;
[ꢀ]2D0 ˆ ꢁ9.9 (c ˆ 1.4); ee ꢀ99%). These two samples of antipodes were
transformed into the corresponding free aminophosphonic acids 6 (Scheme 3).
The hydroxyl group was replaced under Mitsunobu conditions [14, 15] to produce
azides 5 which were reduced catalytically on Pd/C. The products were then
deblocked by re¯uxing in 6 N hydrochloric acid and puri®ed by ion exchange
‡
chromatography on Dowex 50, H to give the desired ꢀ-aminophosphonic acids 6.
Assuming that inversion of con®guration upon azide formation is complete and all
intermediates on the way to the end products being con®gurationally stable, the
products should have ees of 90% and ꢀ 99%, respectively. We intend to have them
tested as phenyl alanine ammonia lyase inhibitors.
In summary, lipase AP 6 is a useful enzyme for the enantioselective hydrolysis
of ꢀ-chloroacetoxyphosphonates derived from cycloalkanecarbaldehydes with a
ring size ranging from cyclopropane to cycloheptane. The enantiomers of 1-
hydroxycyclohexylmethylphosphonate (3d) prepared on a preparative scale with
high optical purity are transformed by chemical means to the corresponding ꢀ-
aminophosphonic acids 6.
Experimental
All starting materials and enzymes were obtained from commercial suppliers and were generally
1
used without further puri®cation. H and 13C NMR (J modulated) spectra were recorded in CDCl3

430
F. Wuggenig and F. Hammerschmidt
unless otherwise given, using tetramethylsilane as internal standard, on a Bruker AM 400 WB NMR
spectrometer at 400.13 and 100.61 MHz, respectively. 31P NMR spectra were recorded on the same
spectrometer at 161.97 MHz using H3PO4 (85%) as external standard. In order to get undistorted 31
P
signal intensities for an accurate integration, adequate relaxation times were used without irradiation
during this period to avoid NOE enhancements. Chemical shifts (ꢂ) are given in ppm and coupling
constants (J) in Hz. IR spectra were run on a Perkin Elmer 1600 FT-IR spectrometer; liquid samples
were measured as ®lms between NaCl plates, solids as nujol mulls. Optical rotations were measured
at 20ꢃC on a Perkin Elmer 241 polarimeter in a 1 dm cell. TLC was carried out on 0.25 mm thick
Merck plates (silica gel 60 F254). Flash chromatography was performed with Merck silica gel 60
(230±400 mesh). Spots were visualized by dipping the plate into a solution of 24 g of
(NH4)6Mo7O24 Á 4H2O and 1 g of Ce(SO4)2 Á 4H2O in 500 ml of 10% H2SO4 in water, followed by
heating with a hot gun. A Metrohm 702 SM Titrino instrument was used as an autotitrator. (S)-(‡)-ꢀ-
Methoxy-ꢀ-(tri¯uoromethyl)phenylacetyl chloride (JPS Chimie; [ꢀ]2D0 ˆ ‡136.5 (c ˆ 5.2, CCl4), ee
> 99.5%) was used for derivatization of ꢀ-hydroxyphosphonates. Abbreviations
used: MC ˆ methylene chloride; EA ˆ ethyl acetate.
Aldehydes 1a, 1d, 1h, 1i, and 1j were used as supplied. Aldehydes 1b, 1c, 1e, and 1g were
obtained by Swern oxidation [16] of the corresponding alcohols; 1f was prepared in low yield and
purity from cyclooctanone [11].
Dialkyl 1-hydroxymethylphosphonates (Æ)-3 were prepared from phosphite (10 mmol) and
aldehyde (11 mmol of commercially available ones or crude aldehydes obtained by Swern oxidation
of 15 mmol of alcohol) as reported in a preceeding paper [8]. Yields refer to product puri®ed by ¯ash
chromatography. Solids were crystallized from hexanes and oils were bulb-to-bulb distilled for
analysis. The Rf values given at the individual compounds refer to MC:EA ˆ 5:3 (1:1 for compound
3a). ꢀ-Hydroxyphosphonate (Æ)-3g was prepared from 7 mmol of crude 1f. ꢀ-Hydroxyphosphonates
(Æ)-3i and 3j are known compounds [8].
Dialkyl 1-chloroacetoxyphosphonates (Æ)-4 were obtained by a known procedure [9]. All crude
products were puri®ed by ¯ash chromatography and were bulb-to-bulb distilled (except 4h). Rf
values given at the individual compounds refer to MC:EA ˆ 5:3. Esters (Æ)-4 were hydrolyzed
enzymatically using 1 mmol of substrate, 17 ml of phosphate buffer, 2 ml of hexanes, 2 ml of tert-
butyl methyl ether, and lipase AP 6 or FAP 15 (Table 1) [8].
Chloroacetates (ꢁ)-4 and dichloroacetoxyphosphonate (ꢁ)-4b recovered from enzymatic
resolution were hydrolyzed within about 16 h using Et3N/MeOH [8, 9].
Diisopropyl 1-hydroxy-cyclopropylmethylphosphonate ((Æ)-3a)
1
72% yield; oil; Rf ˆ 0.16; b.p.: 80±90ꢃC/0.05 torr; IR: ꢃ ˆ 3300, 1386, 1215, 988 cmꢁ1; H NMR:
ꢂ ˆ 0.42 (m, 2H, CH2), 0.60 (m, 2H, CH2), 1.14 (m, 1H, CH), 1.31 (d, J ˆ 7.4, 3H, Me), 1.32 (d,
J ˆ 6.4, 3H, Me), 1.33 (d, J ˆ 5.9, 6H, Me) 3.10 (1H, dt, J ˆ 5.7, 10.8, 1H, PCH), 3.44 (t, J ˆ 5.7, 1H,
OH), 4.62 (m, 2H, CHO); 13C NMR: ꢂ ˆ 3.12 (d, J ˆ 1.8), 3.35 (d, J ˆ 12.8), 12.23 (d, J ˆ 2.7),
23.97 (d, J ˆ 4.9), 24.15 and 24.19 (2d, J ˆ 3.8), 71.02 (d, J ˆ 7.5), 71.17 (d, J ˆ 7.2), 71.02 (d,
J ˆ 164.3); C10H21O4P (236.25); calc.: C 50.84, H 8.96; found: C 50.74, H 9.21.
Diisopropyl 1-hydroxy-cyclobutylmethylphosphonate ((Æ)-3b)
1
84% yield; oil; Rf ˆ 0.15; b.p.: 95±110ꢃC/0.1 torr; IR: ꢃ ˆ 3301, 1385, 1222, 987 cmꢁ1; H NMR:
ꢂ ˆ 1.29 (d, J ˆ 5.4, 3H, Me), 1.30 (d, J ˆ 5.9, 6H, Me), 1.31 (d, J ˆ 5.9, 3H, Me), 1.70ꢁ2.10 (m,
6H, CH2), 2.69 (sept, J ˆ 7.9 1H, CH), 3.30 (t, J ˆ 5.8, 1H, OH), 3.68 (dt, J ˆ 5.8, 6.9, 1H, PCH),
4.71 (dsept, J ˆ 6.4, 12.3, 2H, CHO); 13C NMR: ꢂ ˆ 18.37, 23.98 (d, J ˆ 5.5), 24.11 and 24.14 (2d,
J ˆ 2.8), 24.75 (d, J ˆ 5.5), 24.85, 36.49, 70.76 and 70.92 (2d, J ˆ 7.4), 72.26 (d, J ˆ 157.9);
C11H23O4P (250.28); calc.: C 52.79, H 9.26; found: C 52.93, H 9.51.

Enantioselective Hydrolysis of Phosphonates
431
Diisopropyl 1-hydroxy-cyclopentylmethylphosphonate ((Æ)-3c)
88% yield; oil; Rf ˆ 0.22; b.p.: 110±120ꢃC/0.5 torr; IR: ꢃ ˆ 3301, 1385, 1221, 987 cmꢁ1; 1H NMR:
ꢂ ˆ 1.30 and 1.31 (2d, J ˆ 6.4, 6H each, Me), 1.35±1.65 (m, 6H, CH2), 1.74 (m, 1H, CH2), 1.85 (m,
1H, CH2) 2.19 (sept, J ˆ 6.9, 1H, CH), 3.24 (t, J ˆ 5.4, 1H, OH), 3.62 (dt, J ˆ 5.4, 6.9, 1H, PCH),
4.72 (m, 2H, CHO); 13C NMR: ꢂ ˆ 23.99 (2 overlapping d, J ˆ 4.7), 24.14 and 24.15 (2d, J ˆ 3.6),
25.23, 25.43, 28.83 (d, J ˆ 10.0), 29.38 (d, J ˆ 6.3), 41.44, 70.88 (d, J ˆ 7.4), 70.92 (d, J ˆ 7.1),
71.67 (d, J ˆ 158.3); C12H25O4P (264.31); calc.: C 54.53, H 9.53; found: C 54.65, H: 9.70.
Diisopropyl 1-hydroxy-cyclohexylmethylphosphonate ((Æ)-3d)
83% yield; Rf ˆ 0.27; m.p.: 78±79ꢃC; IR: ꢃ ˆ 3222, 1261, 1202, 994 cmꢁ1; 1H NMR: ꢂ ˆ 1.05±1.33
(m, 5H, CH2) 1.33 (d, J ˆ 5.9, 6H, Me), 1.34 (d, J ˆ 6.4, 6H, Me), 1.65 (br d, J ˆ 11.8, 1H, CH2),
1.76 (m, 4H, CH2), (br d, 1H, J ˆ 12.3, CH), 2.35 (br s, 1H, OH) 3.56 (t, J ˆ 6.2, 1H, PCH), 4.75
(m, 2H, CHO); 13C NMR: ꢂ ˆ 23.97 (2 overlapping d, J ˆ 4.8), 24.12 (d, J ˆ 3.3), 24.15 (d,
J ˆ 3.0), 25.95, 26.17, 26.19, 27.95 (d, J ˆ 7.6), 29.91 (d, J ˆ 8.5), 39.76, 70.91 (d, J ˆ 7.3), 70.92
(d, J ˆ 7.5), 72.85 (d, J ˆ 156.6); C13H27O4P (278.33); calcd.: C 56.10, H 9.78; found: C 56.09,
H 9.72.
Diisopropyl 1-hydroxy-cycloheptylmethylphosphonate ((Æ)-3e)
1
86% yield; Rf ˆ 0.23; m.p.: 38±40ꢃC; IR: ꢃ ˆ 3226, 1196, 986 cmꢁ1; H NMR: ꢂ ˆ 1.31 and 1.32
(2d, J ˆ 6.4, 6H each, Me), 1.36±1.60 (m, 8H, CH2), 1.69 (m, 2H, CH2), 1.79 (m, 1H), 1.93 (m, 2H),
2.76 (t, J ˆ 6.9, 1H, OH), 3.63 (dt, J ˆ 5.4, 6.9, 1H, PCH), 4.73 (m, 2H, CHO); 13C NMR: ꢂ ˆ 23.94
(d, J ˆ 3.5), 23.98 (d, J ˆ 4.0), 24.11 (d, J ˆ 3.8), 24.15 (d, J ˆ 3.7), 26.60, 26.81, 28.10, 28.53, 28.57
(d, J ˆ 7.5), 31.81 (d, J ˆ 9.8), 41.31, 70.87 (2 overlapping d, J ˆ 7.6), 73.39 (d, J ˆ 155.8);
C14H29O4P (292.36) calcd.: C 57.52, H 10.00; found: C 57.81, H 10.11.
Diethyl 1-hydroxy-cycloheptylmethylphosphonate ((Æ)-3f)
38% yield; oil; Rf ˆ 0.15; b.p.: 130±140ꢃC/0.02 torr; IR: ꢃ ˆ 3301, 1392, 1216, 966 cmꢁ1; 1H NMR:
ꢂ ˆ 1.32 and 1.33 (2t, J ˆ 6.9, 3H each, Me), 1.35±1.65 (m, 8H, CH2), 1.69 (m, 2H, CH2), 1.79 (m,
1H), 1.93 (m, 2H), 2.76 (t, J ˆ 6.9, 1H, OH), 3.63 (dt, J ˆ 5.4, 6.9, 1H, PCH), 4.15 (m, 4H, CH2O);
13C NMR: ꢂ ˆ 16.47 (2 overlapping d, J ˆ 5.5), 26.55, 26.79, 28.08, 28.48, 28.56 (d, J ˆ 5.9), 31.73
(d, J ˆ 9.8), 41.33, 62.27 and 62.36 (2d, J ˆ 7.3), 73.09 (d, J ˆ 155.0); C12H25O4P (264.30), calc.:
C 54.53, H: 9.53; found: C 54.51, H 9.66.
Diethyl 1-hydroxy-cyclooctylmethylphosphonate ((Æ)-3g)
32% yield; oil (not distilled); Rf ˆ 0.22; IR: ꢃ ˆ 3301, 1392, 1220, 965 cmꢁ1; 1H NMR: ꢂ ˆ 1.32 and
1.33 (2t, J ˆ 6.9, 3H each, Me), 1.40±1.80 (m, 13H, CH2), 1.90 (m, 1H), 2.01 (m, 1H), 2.82 (t,
J ˆ 6.4, 1H, OH), 3.70 (q, J ˆ 6.4, 1H, PCH), 4.15 (m, 4H, CH2O); 13C NMR: ꢂ ˆ 16.48 (d, J ˆ 5.5),
25.25, 26.06, 26.43, 26.59, 26.88, 27.06 (d, J ˆ 6.2), 30.61, (d, J ˆ 9.8), 39.03 (d, J ˆ 2.2), 62.27 and
62.34 (2d, J ˆ 7.6), 73.37 (d, J ˆ 155.0); C13H27O4P (278.33); calc.: C 56.10, H 9.78; found:
C 56.26, H 10.04.
Diethyl 1-hydroxy-3-cyclohexylpropylphosphonate ((Æ)-3h)
92% yield; oil (not distilled); Rf ˆ 0.14; IR: ꢃ ˆ 3301, 1392, 1230, 966 cmꢁ1; 1H NMR: ꢂ ˆ 0.88 (m,
2H, CH2), 1.06±1.29 (m, 5H, CH2), 1.32 and 1.33 (2t, J ˆ 6.9, 3H each, Me), 1.52 (m, 1H), 1.58±1.73

432
F. Wuggenig and F. Hammerschmidt
(m, 6H, CH2), 1.77 (m, 1H), 3.34 (dd, J ˆ 4.4, 6.4, 1H, OH), 3.79 (m, 1H, PCH), 4.15 (m, 4H,
CH2O); 13C NMR: ꢂ ˆ 16.49 (d, J ˆ 5.1), 26.29, 26.32, 26.61, 28.76, 33.06, 33.35, 33.34 (d,
J ˆ 12.9), 37.44, 62.44 (d, J ˆ 7.1), 62.53, (d, J ˆ 7.3), 68.21 (d, J ˆ 159.7) C13H27O4P (278.33)
calc.: C 56.10, H 9.78; found: C 56.32, H 9.78.
Diisopropyl 1-hydroxy-2,2-dimethylpropylphosphonate ((Æ)-3k)
89% yield; Rf ˆ 0.35; m.p.: 73±74ꢃC; IR: ꢃ ˆ 3359, 1228, 1012 cmꢁ1; 1H NMR: ꢂ ˆ 1.07 (s, 9H, t-
Bu), 1.32 (d, J ˆ 6.4, 9H, Me), 1.33 (d, J ˆ 6.4, 3H, Me), 2.61 (t, J ˆ 6.9, 1H, OH), 3.46 (dd, J ˆ 6.9,
7.9, 1H, PCH), 4.75 (m, 2H, CHO); 13C NMR: ꢂ ˆ 23.94 (d, J ˆ 4.9), 23.99 (d, J ˆ 5.0), 24.14
(d, J ˆ 2.7), 24.23 (d, J ˆ 2.3), 26.70 (d, J ˆ 6.4), 34.58 (d, J ˆ 2.5), 70.89 (d, J ˆ 7.4), 70.95
(d, J ˆ 7.3), 76.64 (d, J ˆ 153.9); C11H25O4P (252.29) calc.: C 52.37, H 9.99; found: C 52.66,
H 9.76.
Diisopropyl 1-chloroacetoxy-cyclopropylmethylphosphonate ((Æ)-4a)
74% yield; oil; Rf ˆ 0.53; b.p.: 120±130ꢃC/0.1 torr; IR: ꢃ ˆ 1765, 1260, 995 cmꢁ1
;
1H NMR:
ꢂ ˆ 0.46 (m, 1H, CH2), 0.59 (m, 2H, CH2), 0.75 (m, 1H, CH2), 1.26 (m, 1H, CH), 1.31 and 1.32 (2d,
J ˆ 6.4, 3H each, Me), 1.34 (d, J ˆ 6.4, 6H, Me), 4.13 (AB system, J ˆ 14.8, CH2Cl), 4.56 (t,
J ˆ 10.1, 1H, PCH), 4.77 (m, 2H, CHO); 13C NMR: ꢂ ˆ 4.20, 4.41 (d, J ˆ 12.9), 10.79 (d, J ˆ 2.1),
23.86 and 23.98 (2d, J ˆ 5.2), 24.07 (d, J ˆ 3.6), 24.19 (d, J ˆ 3.2), 40.76, 71.59 (d, J ˆ 7.2), 71.69
(d, J ˆ 6.7), 75.12 (d, J ˆ 174.6), 166.56 (d, J ˆ 6.7); C12H22ClO5P (312.73); calc.: C 46.09, H 7.09;
found: C 46.08, H 7.12.
Diisopropyl 1-dichloroacetoxy-cyclopropylmethylphosphonate ((Æ)-4b)
Dichloroacetic acid (1.75 g, 1.12 ml, 13.6 mmol) was added dropwise to a suspension of N,N0-
carbonyldiimidazole (1.62 g, 13.6 mmol) in dry MC (30 ml). Stirring was continued for 20 min at
room temperature, and a solution of ꢀ-hydroxyphosphonate (Æ)-3a (1.60 g, 6.8 mmol) in dry MC
(15 ml) was added. After stirring for 3 h the mixture was diluted with H2O (20 ml), and the aqueous
phase was extracted with MC (3 Â 20 ml). The combined organic phases were dried (Na2SO4),
concentrated in vacuo, and puri®ed by ¯ash chromatography (MC:EA ˆ 5:3) and bulb to bulb
distillation under reduced pressure.
53% yield; oil; Rf ˆ 0.59; b.p.: 115±125ꢃC/0.1 torr; IR: v ˆ 1767, 1262, 995 cmꢁ1
;
1H NMR:
ꢂ ˆ 0.47 (m, 1H, CH2), 0.57 (m, 1H, CH2), 0.64 (m, 1H, CH2), 0.78 (m, 1H, CH2), 1.28 (m, 1H, CH),
1.32 and 1.35 (2d, J ˆ 6.4, 3H each, Me), 1.33 and 1.34 (2d, J ˆ 6.4, 3H each), 4.55 (t, J ˆ 9.8, 1H,
PCH), 4.78 (m, 2H, CHO), 6.00 (s, CHCI2); 13C NMR: ꢂ ˆ 4.12, 4.20, 10.59 (d, J ˆ 1.9), 23.84 (d,
J ˆ 3.9), 24.03 (d, J ˆ 4.7), 24.07 (d, J ˆ 3.3), 24.22 (d, J ˆ 3.2), 64.12, 71.85 (d, J ˆ 7.3), 71.96 (d,
J ˆ 6.6), 76.48 (d, J ˆ 173.9), 166.56 (d, J ˆ 6.7); C12H21Cl2O5P (347.18); calc.: C 41.51, H 6.10;
found: C 41.37, H 6.16.
Diisopropyl 1-chloroacetoxy-cyclobutylmethylphosphonate ((Æ)-4c)
93% yield; oil; Rf ˆ 0.57; b.p.: 115±130ꢃC/0.1 torr; IR: v ˆ 1768, 1250, 993 cmꢁ1
;
1H NMR:
ꢂ ˆ 1.29 (d, J ˆ 5.9, 3H, Me), 1.28, 1.30 and 1.31 (3d, J ˆ 6.4, 3H each, Me), 1.70±2.10 (m, 6H,
CH2), 2.85 (m, 1H, CH), 4.12 (AB system, J ˆ 15.0, CH2Cl), 4.70 (m, 2H, CHO), 5.21 (dd, J ˆ 7.9,
8.9, 1H, PCH); 13C NMR: ꢂ ˆ 18.28, 23.82 and 24.16 (2d, J ˆ 5.1), 23.98 (d, J ˆ 4.8), 24.03 (d,
J ˆ 3.7), 25.00, 25.10 (d, J ˆ 3.1), 34.92, 40.63, 71.36, (d, J ˆ 7.3), 71.52 (d, J ˆ 6.7), 73.04
(d, J ˆ 166.8), 166.65 (d, J ˆ 5.3); C13H24ClO5P (326.76); calc.: C 47.78, H 7.40; found: C 47.83,
H 7.47.

Enantioselective Hydrolysis of Phosphonates
433
Diisopropyl 1-chloroacetoxy-cyclopropylmethylphosphonate ((Æ)-4d)
81% yield; oil; Rf ˆ 0.62; b.p.: 125±140ꢃC/0.02 torr; IR: v ˆ 1767, 1253, 990 cmꢁ1; H NMR:
ꢂ ˆ 1.29 (d, J ˆ 6.4, 3H, Me), 1.31 (d, J ˆ 4.9, 3H, Me), 1.33 (d, J ˆ 5.9, 6H, Me), 1.34±1.90 (m, 8H,
CH2), 2.38 (sept, J ˆ 8.0, 1H, CH), 4.10 (AB system, J ˆ 15.0, CH2Cl), 4.73 (m, 2H, CHO), 5.17 (t,
J ˆ 8.0, 1H, PCH); 13C NMR: ꢂ ˆ 23.79, and 23.97 (2d, J ˆ 5.9), 24.03 (d, J ˆ 4.0), 24.16 (d,
J ˆ 3.2), 24.80, 25.23, 29.18 (d, J ˆ 9.8), 29.35 (d, J ˆ 5.8), 40.01, 40.65, 71.37 (d, J ˆ 7.4), 71.52 (d,
J ˆ 6.8), 73.60 (d, J ˆ 168.0), 166.65 (d, J ˆ 3.5); C14H26ClO5P (340.79); calc.: C 49.34, H: 7.69;
found: C 49.61, H 7.80.
1
Diisopropyl 1-chloroacetoxy-cyclohexylmethylphosphonate ((Æ)-4e)
83% yield; oil; Rf ˆ 0.68; b.p.: 160±165ꢃC/0.05 torr; IR: v ˆ 1768, 1248, 993 cmꢁ1
;
1H NMR:
ꢂ ˆ 1.00±1.25 (m, 5H, CH2), 1.29 (d, J ˆ 5.9, 3H, Me), 1.31 (d, J ˆ 5.9, 3H, Me), 1.33 (d, J ˆ 5.9,
6H, Me), 1.64 (br d, J ˆ 12.3, 1H, CH2), 1.74 (m, 2H, CH2), 1.89 (m, 3H), 4.12 (AB system,
J ˆ 15.0, CH2CI), 4.73 (m, 2H, CHO), 5.09 (dd, J ˆ 6.7, 9.6, 1H, PCH); 13C NMR: ꢂ ˆ 23.80
(d, J ˆ 5.2), 23.99 (d, J ˆ 4.7), 24.03 (d, J ˆ 3.9), 24.19 (d, J ˆ 3.5), 25.73, 25.86, 25.93, 28.26
(d, J ˆ 7.7), 29.84 (d, J ˆ 7.2), 38.52, 40.64, 71.41 (d, J ˆ 7.4), 71.53 (d, J ˆ 6.8), 74.40 (d,
J ˆ 167.3), 166.54 (d, J ˆ 5.2); C15H28ClO5P (354.81); calc.: C 50.78, H 7.95; found: C 50.48,
H: 8.08.
Diisopropyl 1-chloroacetoxy-cycloheptylmethylphosphonate ((Æ)-4f)
87% yield; oil; Rf ˆ 0.67; b.p.: 150±165ꢃC/0.05 torr; IR: v ˆ 1767, 1252, 989 cmꢁ1; 1H NMR: ꢂ ˆ
1.28 and 1.30 (2d, J ˆ 5.9, 3H each, Me), 1.32 (d, J ˆ 6.4, 6H, Me), 1.33±1.60 (m, 8H, CH2), 1.65
(m, 2H, CH2), 1.87 (m, 2H, CH2), 2.08 (m, 1H, CH), 4.10 (AB system, J ˆ 15.0, CH2Cl), 4.72 (m,
2H, CHO), 5.13 (dd, J ˆ 5.9, 9.8, 1H, PCH); 13C NMR: ꢂ ˆ 23.80 and 23.97 (2d, J ˆ 5.2), 24.03 and
24.18 (2d, J ˆ 3.6), 26.22, 26.43, 28.13, 28.22, 29.23 (d, J ˆ 6.1), 31.49 (d, J ˆ 8.5), 40.02 (d,
J ˆ 1.0), 40.69, 71.34 (d, J ˆ 7.5), 71.49 (d, J ˆ 6.8), 74.98 (d, J ˆ 166.7), 166.59 (d, J ˆ 5.1);
C16H30ClO5P (368.84); calc.: C 52.10, H 8.20; found: C 52.25, H 8.25.
Diethyl 1-chloroacetoxy-cycloheptylmethylphosphonate ((Æ)-4g)
84% yield; oil; Rf ˆ 0.58; b.p.: 120±130ꢃC/0.01 torr; IR: v ˆ 1766, 1252, 969 cmꢁ1
;
1H NMR:
ꢂ ˆ 1.29 and 1.30 (2d, J ˆ 6.9, 3H each, Me), 1.34±1.60 (m, 8H, CH2), 1.65 (m, 2H, CH2), 1.85 (m,
2H, CH2), 2.10 (m, 1H, CH), 4.10 (AB system, CH2Cl) overlapping with 4.11 (m, 4H, CH2O), 5.17
(dd, J ˆ 6.2, 9.1, 1H, PCH); 13C NMR: ꢂ ˆ 16.29 and 16.40 (2d, J ˆ 5.7), 26.13, 26.36, 28.08, 28.17,
29.21 (d, J ˆ 6.2), 31.33 (d, J ˆ 8.4), 39.87 (d, J ˆ 1.0), 40.57, 62.59 (d, J ˆ 6.3), 62.62 (d, J ˆ 7.2),
74.29 (d, J ˆ 164.0), 166.55 (d, J ˆ 3.6); C14H26ClO5P (340.79); calcd.: C 49.34, H 7.69; found:
C 49.59, H 7.87.
Diethyl 1-chloroacetoxy-cyclooctylmethylphosphonate ((Æ)-4h)
66% yield; Rf ˆ 0.56; oil (not distilled); IR: ꢃ ˆ 1766, 1252, 970 cmꢁ1; 1H NMR: ꢂ ˆ 1.30 and 1.32
(2t, J ˆ 6.9, 3H each, Me), 1.38±1.90 (m, 14H, CH2), 2.19 (m, 1H, CH), 4.11 (AB system, CH2Cl)
overlapping with 4.13 (m, 4H, CH2O), 5.16 (dd, J ˆ 6.4, 8.9, 1H, PCH); 13C NMR: ꢂ ˆ 16.34 (d,
J ˆ 6.0), 16.44 (d, J ˆ 5.7), 25.14, 25.44, 26.39, 26.45, 26.74, 27.54 (d, J ˆ 6.9), 29.87 (d, J ˆ 8.4),
37.83 (d, J ˆ 1.1), 40.62, 62.62 (d, J ˆ 7.3), 62.64 (d, J ˆ 6.1), 74.60 (d, J ˆ 164.4), 166.61 (d,
J ˆ 4.0); C15H28ClO5P (354.81); calc.: C 50.78, H 7.95; found: C 50.48, H 7.97.

434
F. Wuggenig and F. Hammerschmidt
Diethyl 1-chloroacetoxy-3-cyclohexylpropylphosphonate ((Æ)-4i)
88% yield; oil; Rf ˆ 0.59; b.p.: 140±150ꢃC/0.01 torr; IR: ꢃ ˆ 1767, 1256, 970 cmꢁ1
;
1H NMR:
ꢂ ˆ 0.86 (m, 2H, CH2), 1.05±1.28 (m, 6H, CH2), 1.31 and 1.32 (2t, J ˆ 7.2, 3H each, Me), 1.65 (m,
5H, CH2), 1.80 (m, 1H, CH2), 1.91 (m, 1H, CH2), 4.10 (AB system, CH2Cl) overlapping with 4.14
(m, 4H, CH2O), 5.24 (ddd, J ˆ 3.9, 8.1, 10.1, 1H, PCH); 13C NMR: ꢂ ˆ 16.35 (d, J ˆ 5.8), 16.35 (d,
J ˆ 5.5), 26.17, 26.20, 26.48, 26.69, 32.96, 33.16, 33.11 (d, J ˆ 9.8), 37.19, 40.57, 62.82 (d, J ˆ 7.5),
62.83 (d, J ˆ 5.8), 70.20 (d, J ˆ 167.1), 166.54 (d, J ˆ 4.8); C15H28ClO5P (354.81); calcd.: C 50.78,
H 7.95; found: C 51.00, H 7.68.
Diisopropyl 1-chloroacetoxy-2-methylpropylphosphonate ((Æ)-4j)
86% yield; oil; Rf ˆ 0.55; b.p.: 90±115ꢃC/0.1 torr; IR: ꢃ ˆ 1769, 1257, 1000 cmꢁ1
;
1H NMR:
ꢂ ˆ 1.02 and 1.04 (2d, J ˆ 6.9, 3H each, Me), 1.29, 1.31 and 1.33 (3d, J ˆ 6.4, 3H each, Me2CHO),
1.32 (d, J ˆ 5.4, 3H, Me2CHO), 2.24 (doct, J ˆ 6.9, 8.9, 1H, PCHCH), 4.11 (AB system, J ˆ 14.8,
CH2CI), 4.73 (m, 2H, CHO), 5.06 (dd, J ˆ 6.9, 9.4, 1H, PCH); 13C NMR: ꢂ ˆ 18.26 (d, J ˆ 7.7),
19.76 (d, J ˆ 8.2), 23.80 (d, J ˆ 5.0), 23.99 (d, J ˆ 4.8), 24.03 (d, J ˆ 3.6), 24.19 (d, J ˆ 3.3), 29.25,
40.62, 71.39 (d, J ˆ 7.3), 71.54 (d, J ˆ 6.8), 74.98 (d, J ˆ 167.8), 166.56 (d, J ˆ 5.3); C12H24ClO5P
(314.75); calc.: C 45.79, H 7.69; found: C 45.88, H 7.50.
Diisopropyl 1-chloroacetoxy-2-methylbutylphosphonate ((Æ)-4k)
97% yield; oil; Rf ˆ 0.52; b.p.: 100±120ꢃC/0.05 torr; IR: ꢃ ˆ 1766, 1261, 990 cmꢁ1
;
1H NMR:
ꢂ ˆ 0.90 and 0.93 (2d, J ˆ 6.4, 3H each, CH3), 1.30 (d, J ˆ 5.9, 3H, Me2CHO), 1.31 (d, J ˆ 5.4,
3H, Me2CHO), 1.33 (d, J ˆ 6.4, 6H, Me2CHO), 1.62 (m, 2H), 1.81 (m, 1H), 4.11 (AB system,
J ˆ 15.2, CH2Cl), 4.73 (m, 2H, CHO), 5.34 (ddd, J ˆ 2.3, 9.0, 11.2, 1H, PCH); 13C NMR: ꢂ ˆ 21.19,
23.15, 23.82 (d, J ˆ 5.1), 23.95 (d, J ˆ 5.3), 24.01 (d, J ˆ 3.9), 24.15 (d, J ˆ 3.3), 24.44 (d, J ˆ 12.8),
38.02, 40.64, 68.82 (d, J ˆ 169.9), 71.49 (d, J ˆ 7.1), 71.70 (d, J ˆ 6.8), 166.43 (d, J ˆ 4.6);
C13H26ClO5P (328.77); calc.: C 47.49, H 7.97; found: C 47.70, H 8.10.
Diisopropyl 1-chloroacetoxy-2,2-dimethylpropylphosphonate ((Æ)-4l)
88% yield; oil; Rf ˆ 0.59; b.p.: 100±120ꢃC/0.01 torr; IR: ꢃ ˆ 1770, 1251, 995 cmꢁ1
;
1H NMR:
ꢂ ˆ 1.06 (s, 9H, t-Bu), 1.26 and 1.28 (2d, J ˆ 5.9, 3H each, Me), 1.29 and 1.30 (2d, J ˆ 6.4, 3H each,
Me), 4.10 (AB system, J ˆ 14.8, CH2Cl), 4.70 (m, 2H, CHO), 5.03 (d, J ˆ 10.8, 1H, PCH); 13C NMR:
ꢂ ˆ 23.75 (d, J ˆ 5.3), 24.02 (d, J ˆ 4.7), 24.06 (d, J ˆ 3.5), 24.23 (d, J ˆ 3.4), 26.82 (d, J ˆ 6.1),
34.67 (d, J ˆ 2.3), 40.66, 71.36 (d, J ˆ 7.9), 71.44 (d, J ˆ 7.3), 77.51 (d, J ˆ 164.8), 166.42 (d,
J ˆ 4.6); C13H26ClO5P (328.77); calcd.: C 47.49, H 7.97; found: C 47.50, H 7.93.
(R)-(ꢁ)- and (S)-(‡)-Diisopropyl 1-azido-cyclohexylmethylphosphonate
((R)-(ꢁ)- and (S)-(‡)-5)
Diethyl azodicarboxylate (463 mg, 2.66 mmol) was added dropwise to a stirred solution of Ph3P
(698 mg, 2.66 mmol) in dry MC (6 ml) at ꢁ5ꢃC. The pale orange solution was then cooled to ꢁ10ꢃC,
and a solution of HN3 in toluene (3.6 ml, 0.77 M) was added dropwise. After stirring for 5 min at
0ꢃC, a solution of ꢀ-hydroxyphosphonate (S)-(‡)-3 (618 mg, 2.22 mmol, [ꢀ]2D0 ˆ ‡8.3 (c ˆ 1.0,
acetone), 90% ee) in dry MC (4 ml) was added. The mixture was stirred for 30 min at 0ꢃC and then
for 20 h at room temperature. The precipitate formed was removed, and the ®ltrate was evaporated
under reduced pressure. The residue was puri®ed by ¯ash chromatography (Rf ˆ 0.50, MC:EA

Enantioselective Hydrolysis of Phosphonates
435
ˆ 10:1) to afford azide (R)- (ꢁ)- (5) (384 mg (57%), [ꢀ]2D0 ˆ ꢁ46.6 (c ˆ 1.0, acetone)) as an oil. (R)-
(ꢁ)-3 (645 mg, 2.32 mmol, [ꢀ]2D0 ˆ ꢁ9.9 (c ˆ 1.4, acetone)) was transformed by a modi®ed
procedure [15] into (S)-(‡)-5 (425 mg (60%), [ꢀ]2D0 ˆ ‡50.2 (c ˆ 1.4, acetone)). The spectroscopic
data of (R)- (ꢁ)- and (S)-(‡)-5 are identical.
IR: ꢃ ˆ 2980, 2931, 2854, 2102, 1452, 1386, 1257, 1105, 987 cmꢁ1; 1H NMR: ꢂ ˆ 1.07±1.32 (m,
5H, CH2), 1.34 (d, J ˆ 5.9, 3H, Me), 1.35 (3 overlapping d, J ˆ 6.4, 9H, Me), 1.65 (m, 1H, CH2),
1.78 (m, 4H, CH2), 1.97 (br d, J ˆ 12.8, 1H, CH2), 3.23 (dd, J ˆ 5.7, 13.0, 1H, CHP), 4.78 (m, 2H,
OCH); 13C NMR: ꢂ ˆ 23.94 (d, J ˆ 4.7), 23.98 (d, J ˆ 4.9), 24.14 (d, J ˆ 3.7), 24.20 (d, J ˆ 3.5),
25.90 (2  CH2), 26.11, 28.84 (d, J ˆ 6.6), 31.14 (d, J ˆ 9.2), 38.63, 64.14 (d, J ˆ 155.5), 71.40 (d,
J ˆ 7.1), 71.56 (d, J ˆ 7.6); C13H26N3O3P (303.34); calc.: C 51.47, H 8.64, N 13.85; found: C 51.68,
H 8.36, N 14.11.
(R)-(ꢁ)- and (S)-(‡)-1-Amino-cyclohexylmethylphosphonic acid ((R)-(ꢁ)- and (S)-(‡)-6)
Azide (R)-(ꢁ)-5 (354 mg, 1.17 mmol) was hydrogenated in ethanol (60 ml, 1 ml of conc. HCl) on Pd/
C (10%, 120 mg) in a Parr apparatus (3.4 bar, 6.5 h, 20ꢃC). The catalyst was removed, and the
solvent was evaporated in vacuo. The residue was re¯uxed in 6 N HCl (50 ml) for 13 h and then
‡
concentrated. The crude product was puri®ed by ion exchange chromatography on Dowex 50, H
using water as eluent. Ninhydrine positive fractions were pooled, concentrated in vacuo, and ®nally
lyophilized to give 1-aminophosphonic acid (R)-(ꢁ)-6 (121 mg, 54%), m.p.: 280±282ꢃC,
[ꢀ]2D0 ˆ ꢁ6.3 (c ˆ 1.0, 0.5 N NaOH). Similarly, (S)-(‡)-5 (250 mg, 0.82 mmol) was transformed
into (S)-(‡)-6 (121 mg, 41%), m.p.: 277±279ꢃC, [ꢀ]D20 ˆ ‡6.5 (c ˆ 0.6, 0.5 N NaOH). The
spectoscopic data of (R)-(ꢁ)-and (S)-(‡)-6 are identical.
1
IR (Nujol): ꢃ ˆ 1626, 1524, 1142, 1052, 921 cmꢁ1; H NMR: (D2O/NaOD): ꢂ ˆ 0.83±1.28 (m,
5H, CH2), 1.58 (m, 5H, CH2), 1.81 (br d, J ˆ 12.3, 1H, CH2), 2.29 (dd, J ˆ 3.9, 12.3, 1H, PCH); 13
C
NMR: (D2O/NaOD): ꢂ ˆ 26.93, 27.01, 27.35, 26.97 (2 overlapping d, J ˆ 7.9), 39.81, 56.34 (d,
J ˆ 137.4); C7H16NO3P (193.18); calc.: C 43.52, H: 8.35, N: 7.25; found: C 43.12, H 8.21, N 6.75.
Acknowledgements
È
We thank the Fonds zur Forderung der wissenschaftlichen Forschung (projects no. P10566-CHE and
6537C) for support of this work and Amano Enzyme Limited (UK) for lipases AP 6 and FAP 15.
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È
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È
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Received November 10, 1997. Accepted November 16, 1997