Stereochemistry of the addition of dialkyl phosphites to (S)-N,N-dibenzylphenylglycinal

Article abstract of DOI:10.1016/S0957-4166(01)00526-2

The addition of various dialkyl phosphite derivatives to (S)-N,N-dibenzylphenylglycinal 6 led to the preponderance of anti over syn diastereoisomers: from 75:25 when NEt₃ or Ti(Oi Pr)₄ were used to 51:49 for Li or Mg salts. In the NEt₃-catalysed reaction, partially racemised phosphonates were formed, while enantiomeric products were obtained after addition of lithium O,O-dimethylphosphonate to (S)-6 at -70°C. Because the syn-isomers were found to be resistant to O-benzoylation, mixtures of diastereoisomers were easily separated after esterification of the anti products. Hydrogenation of the syn-phosphonates in the presence of Boc₂O gave enantiomeric dialkyl N -Boc-2-amino-1-hydroxy-2-phenylethylphosphonates - phosphonate analogues of the docetaxel C-13 side chain.

Full text of DOI:10.1016/S0957-4166(01)00526-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2977–2984
Stereochemistry of the addition of dialkyl phosphites to
(S)-N,N-dibenzylphenylglycinal
Andrzej E. Wro´blewski* and Dorota G. Piotrowska
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz, 90-151 Ło´dz, Muszyn´skiego 1, Poland
Received 16 October 2001; accepted 19 November 2001
Abstract—The addition of various dialkyl phosphite derivatives to (S)-N,N-dibenzylphenylglycinal 6 led to the preponderance of
anti over syn diastereoisomers: from 75:25 when NEt3 or Ti(OiPr)4 were used to 51:49 for Li or Mg salts. In the NEt3-catalysed
reaction, partially racemised phosphonates were formed, while enantiomeric products were obtained after addition of lithium
O,O-dimethylphosphonate to (S)-6 at −70°C. Because the syn-isomers were found to be resistant to O-benzoylation, mixtures of
diastereoisomers were easily separated after esterification of the anti products. Hydrogenation of the syn-phosphonates in the
presence of Boc2O gave enantiomeric dialkyl N-Boc-2-amino-1-hydroxy-2-phenylethylphosphonates—phosphonate analogues of
the docetaxel C-13 side chain. © 2002 Elsevier Science Ltd. All rights reserved.
with various substituents2–16 or H-Ca with alkyl
1. Introduction
groups.17,18 For some time we have been involved in the
synthesis of dialkyl (1S,2S)-2-(benzoylamino)- and 2-
[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethyl-
phosphonates 319 and 420 as possible bioisosteric
analogues21 of the paclitaxel and docetaxel C-13 side
chains. Having accomplished the synthesis of enan-
tiomers of 3 and 4 we turned to the asymmetric synthe-
sis of these compounds. Our experience with the
chemistry of the phosphonates 3 and 4 led us to con-
clude that the most straightforward approach would
involve the addition of dimethyl phosphite to N-Boc-
(S)-phenylglycinal 5, separation of the syn- and anti-a-
hydroxyphosphonates via the O-benzoyl derivatives,
followed by two one-step transformations of the syn-
diastereoisomer into 3 and 4 (Alk=Me) (Scheme 1).
Unfortunately in our hands attempts at preparation of
Paclitaxel and its semi-synthetic analogue docetaxel are
among the most important anti-cancer agents clinically
used for the treatment of various tumours.1
The search for structural analogues of 1 and 2 has
focused on the modification of the C-13 side chains, i.e.
N-benzoyl- and N-Boc-(2R,2S)-3-phenylisoserine 1 and
2 and has included replacement of the phenyl group
Scheme 1.
* Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@ich.pharm.am.lodz.pl
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00526-2

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A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
enantiomerically pure (S)-5 by the DIBAL-H reduction
of methyl N-Boc-(S)-phenylglycinate22 failed.†
ing these mixtures by chromatography on silica gel with
various solvent systems met with partial success.
For this reason a search for other phenylglycinal
The e.e. of the a-hydroxyphosphonates 7 and 8 (methyl
esters), and 9 and 10 (ethyl esters) obtained in the
NEt3-catalysed reactions were studied by the 31P NMR
spectroscopy after esterification of the crude reaction
mixtures with (S)-O-methylmandelic acid.32 It appeared
that after the 24 h usually required to complete the
esterification, the anti-diastereoisomers 7 and 9 were
quantitatively transformed into esters, while the syn-
isomers remained unreacted. Based on these data, the
e.e.s of (1R,2S)-7 and (1R,2S)-9 were established as 84
and 55%, respectively. It is reasonable to assume that
the e.e. of the syn-diastereoisomers (1S,2S)-8 and
(1S,2S)-10 are the same as those measured for the
respective anti-isomers.
derivatives was conducted and
brought to our attention N,N-dibenzylphenylglycinal24–27
as stereochemically stable alternative to (S)-5.
a
recent review23
a
However, several literature reports23,24,28–30 noticed the
predominance of the anti products in nucleophilic addi-
tions to N,N-disubstituted a-amino aldehydes opposite
to N-monosubstituted analogues, which afforded syn-
isomers as the major products (Scheme 2). Herein, the
stereochemistry of the addition of dialkyl phosphites to
(S)-N,N-dibenzylphenylglycinal 6 will be described fol-
lowed by transformation of the syn adducts into
diastereoisomeric N-Boc-2-amino-1-hydroxy-2-phenyl-
ethylphosphonates.
We suspect that the application of NEt3 as a catalyst in
the Abramov reaction was responsible for the partial
racemisation of the aldehyde (S)-6, and in consequence,
phosphonates 7 and 8 (O-methyl) and 9 and 10 (O-
ethyl) were obtained with lower e.e. Significantly dimin-
ished e.e. of the ethyl ester 9 could be associated with
the lower rate of the addition of diethyl phosphite in
comparison with its methyl analogue, in agreement
with our previous observations for the additions to
Garner aldehyde.33 We reasoned that in the presence of
NEt3 dialkyl phosphites are not sufficiently nucleophilic
to add to the carbonyl group of (S)-6 faster than the
rate of racemisation of the aldehyde.
2. Results and discussion
Oxidation of (S)-N,N-dibenzylphenylglycinol to the
respective aldehyde (S)-6 was accomplished with the
DMSO–oxalyl
chloride–NEt3
mixture
(Swern
oxidation31). The crude product was sufficiently pure by
1H NMR to be used in the next step. We found that a
chloroform solution of 6 was stable at room tempera-
ture for at least 24 h. Addition of dialkyl phosphites
was, however, carried out immediately after the purifi-
cation of the aldehyde. In NEt3-catalysed reactions,
mixtures of diastereoisomeric dimethyl or diethyl
2-(N,N-dibenzylamino)-1-hydroxy-2-phenylethylphos-
phonates were obtained (Scheme 3). Ratios of 78:22
and 80:20 for 7:8 and 9:10, respectively, were estab-
lished from the 31P NMR spectra. Attempts at separat-
To further support these conclusions, a preliminary
study of the racemisation of (S)-6 in the presence of
NEt3 was undertaken. A mixture of (S)-6 and NEt3 (30
Scheme 2.
Scheme 3. Reagents and conditions: (a) (MeO)2P(O)H or (EtO)2P(O)H 1 equiv., NEt3 10 mol%.
† Removal of aluminium salts was an extremely time consuming step which led to significant racemisation.

A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
2979
mol%)‡ was kept at room temperature for 24 h. Sam-
ples were withdrawn after 1, 2 and 3 h after the
addition of the amine and were immediately reduced
with sodium borohydride at 0°C.22 The e.e. of the
catalysed addition of dimethyl phosphite to (S)-6. At
first, the O-benzoate 11 was subjected to hydrogenoly-
sis (Scheme 4). The reaction was extremely sluggish,
leading to traces of dimethyl 2-(benzoylamino)-2-
phenyl-1-hydroxyethylphosphonate 12 (l 31P NMR=
24.45 ppm).
1
(S)-N,N-dibenzylphenylglycinols were estimated by H
NMR spectroscopy after derivatisation with (S)-O-
methylmandelic acid.32 Including the e.e. of (S)-N,N-
dibenzylphenylglycinol obtained from (S)-6 just before
addition of NEt3 (time 0 h), the following rate of the
racemisation was observed: t=0 h, e.e. 90%; t=1 h, e.e.
44%; t=2 h, e.e. 28% and t=3 h, e.e.=20%. Further-
more, in the presence of NEt3 (S)-6 was simultaneously
undergoing decomposition to unidentified products and
no aldehyde resonance was found in the 1H NMR
spectrum after 24 h.
Although both diastereoisomers of this compound are
known,19 we noticed that their 31P NMR chemical
shifts are solvent and concentration dependent and for
this reason we were unable to assign the configuration
unequivocally. However, the (1R*,2S*) configuration
was extremely likely to be in agreement with our previ-
ous observations of slow intramolecular OꢀN trans-
benzoylation in structurally similar systems.34 On the
other hand, hydrogenolysis of racemic 7 in the presence
of Boc2O gave dimethyl (1R*,2S*)-2-[(tert-butoxy-
carbonyl)amino]-1-hydroxy-2-phenylethylphosphonate
1319 in almost quantitative yield (Scheme 5).
In order to circumvent the problem of the low nucle-
ophilicity of the dialkyl phosphite and, at the same
time, minimise racemisation of (S)-6 by triethylamine,
lithium O,O-dimethylphosphonate was added at −70°C
to the in situ generated aldehyde (S)-6. Under these
conditions a 75:25 mixture of (1R,2S)-7 and (1S,2S)-8
was formed, while using Li+−P(O)(OEt)2 the respective
diastereoisomeric phosphonates were produced in a
72:28 ratio. After purification on a silica gel column,
the e.e. of (1R,2S)-7 was estimated by 31P NMR spec-
troscopy as 100% after derivatisation with v-camphanyl
chloride.
This assignment clearly showed that the addition of
dialkyl phosphites to the aldehyde (S)-6 in the presence
of NEt3 led to anti-diastereoisomers as the major prod-
ucts. In connection with our synthetic efforts directed
Table 1. Diastereoselectivity of the addition to (S)-6
Reagent
7
8
9
10
(MeO)2P(O)H/NEt3
(EtO)2P(O)H/NEt3
(MeO)2P(O)Li
(EtO)2P(O)MgBr
(EtO)2POTMS
78
–
57
–
–
–
22
–
43
–
–
–
–
80
–
51
61
72
–
20
–
49
39
28
In establishing the relative configurations of the
diastereoisomeric phosphonates 7/8 and 9/10 we relied
on the transformation of 7 into the known compounds
12 and 13. Pure 7 was isolated as a racemate§ after
crystallisation of a 78:22 mixture of diastereoisomeric
dimethyl phosphonates 7 and 8 obtained in NEt3-
(EtO)2P(O)H/Ti(OiPr)4
Scheme 4. Reagents and conditions: (a) PhCOOH, DCC, DMAP; (b) H2–Pd(OH)2/C, methanol, 14 days.
Scheme 5. Reagents and conditions: (a) H2–Pd(OH)2/C, Boc2O, methanol, 24 h.
‡ Although 10 mol% of NEt3 was usually applied in the Abramov reaction, a three-fold excess of the amine was used to speed the racemisation
up.
§ Esterification of this material with (S)-O-methylmandelic acid gave a 1:1 mixture (by 31P NMR) of the respective esters.

2980
A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
towards asymmetric synthesis of the phosphonate ana-
logues of the paclitaxel and docetaxel C-13 side chains,
we were interested in the preponderance of the syn
diastereoisomers. For this reason, the diastereoselectiv-
ity of additions to (S)-6 using other phosphonylating
reagents was examined. The results collected in Table 1
left no doubt that the protection of the nitrogen atom
in phenylglycinal with two benzyl groups led to a
reversal of the stereochemistry of the reaction in com-
parison to those of the monosubstituted aldehydes, e.g.
5.20,35
gave increased amounts of syn-diastereoisomers due to
involvement of the chelated conformation C.
As mentioned above, esterification of mixtures of syn-
and anti-diastereoisomers with (S)-O-methylmandelic
acid revealed unexpected selectivity leading to forma-
tion of the anti esters while leaving the syn alcohols
remained unreacted. We thought that this observation
could be employed for the separation of the syn- and
anti-diastereoisomers. Benzoylation of the 6:4 mixture
of (1R,2S)-7 and (1S,2S)-8 (left after crystallisation of
( )-7) with 1 equiv. of benzoic acid gave O-benzoates
(1R,2S)-11 and (1S,2S)-14 containing unreacted
(1S,2S)-8 in a 62:6:32 ratio (Scheme 6). Column chro-
matography of this mixture allowed us to separate pure
(1R,2S)-11, (1S,2S)-14 and (1S,2S)-8 in 58, 1 and 14%
yield, respectively.
These results can be rationalised by referring to appro-
priate models of transition states in the additions to
(S)-5 or (S)-6.23–25,28–30,36 Dimethyl phosphite
approaches the re face of the carbonyl group in (S)-6
preferentially, because in the presence of NEt3 chelation
is not possible (model A). On the other hand, in (S)-5
(N-Boc) the intramolecular hydrogen bond stabilises
conformation B, and the dialkyl phosphite attacks the
si face of the carbonyl group, thus leading to the
formation of the syn-adduct. This bonding is appar-
ently stronger in (S)-5 than in N-benzoylphenylglyci-
nal, since in the presence of NEt3 better
diastereoselectivity was observed for the former.20
Additions of metalated phosphites (Li+, Mg2+) to (S)-6
Encouraged by the successful separation of (1R,2S)-7
(as the O-benzoate) from (1S,2S)-8 prepared from the
partially racemised aldehyde (S)-6, we applied this pro-
cedure to the phosphonates obtained from the enan-
tiomerically pure (S)-6 and Li+−P(O)(OMe)2. A sample
of enantiomerically pure (1R,2S)-7 was separated from
the crude product by column chromatography leaving a
1:1 mixture of (1R,2S)-7 and (1S,2S)-8. In the next step
this mixture was benzoylated with 0.5 equiv. of benzoic
acid in the presence of DCC and DMAP,32 and the less
polar (1R,2S)-11 was cleanly separated from the unre-
acted (1S,2S)-8, which was obtained in 13% yield. In a
similar way the phosphonate (1S,2S)-10 was also
obtained in 13% yield.
Hydrogenolysis of the syn-diastereoisomers (1S,2S)-8
and (1S,2S)-10 (Scheme 7) in the presence of Boc2O led
to the methyl and ethyl N-Boc-phosphonates (1S,2S)-4,
respectively, in 91 and 89% yield. After derivatisation
with v-camphanyl chloride, both phosphonates were
found to be enantiomerically pure.
Scheme 6. Reagents and conditions: (a) PhCOOH, DCC, DMAP.
Scheme 7. Reagents and conditions: (a) H2–Pd(OH)2/C, Boc2O, methanol or ethanol, 24 h.

A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
2981
3. Conclusions
NMR: l=7.48–7.18 (m, 15H), 4.67 (ddd, J=8.4 Hz,
J=6.9 Hz, J=4.5 Hz, 1H, H-1), 4.21 (dd, J=8.4 Hz,
J=6.9 Hz, 1H, H-2), 3.96 (d, J=13.8 Hz, 2H), 3.62 (d,
J=10.5 Hz, 3H), 3.54 (d, J=10.5 Hz, 3H), 3.23 (d,
J=13.8 Hz, 2H), 2.16 (dd, J=13.3 Hz, J=4.5 Hz, 1H,
OH); 13C NMR (75.5 MHz): l=139.53, 134.64 (d,
J=8.6 Hz), 130.42, 128.96, 128.24, 128.00, 127.74,
126.97, 69.25 (d, J=161.5 Hz, C-1), 64.10 (brs, C-2),
55.16, 53.26 (d, J=7.4 Hz), 53.15 (d, J=7.5 Hz); 31P
NMR: l=25.52. Anal calcd for C24H28O4NP: C, 67.75;
H, 6.63; N, 3.29. Found: C, 67.93; H, 6.65; N, 3.23%.
It was found that the stereochemistry of the addition of
dialkyl phosphites to N,N-dibenzylphenylglycinal is
opposite to that observed earlier for the additions to
N-Boc- and N-benzoylphenylglycinal. Mixtures of anti-
and
syn-2-(N,N-dibenzylamino)-1-hydroxy-2-phenyl-
ethylphosphonates were easily separated after selective
benzoylation of the anti-isomers. Enantioselec-
tive synthesis of the phosphonate analogue of docetaxel
C-13 side chain was accomplished, when the in situ
generated (S)-N,N-dibenzylphenylglycinal (Swern oxi-
dation) was treated with lithium dialkyl phosphonates
at −70°C followed by separation of the syn- and anti-
diastereoisomers and hydrogenolysis in the presence of
Boc2O.
The residue from crystallisation was subjected to
column chromatography on silica gel using ethyl acet-
ate–hexanes (2:1, v/v). The appropriate fractions were
collected to give a 6:4 mixture of 7 and 8 (0.782 g,
62%).
4. Experimental
In a similar way from diethyl phosphite (0.383 mL, 2.97
mmol) and (S)-6 (1.24 g, 3.30 mmol) a 80:20 mixture of
phosphonates 9 and 10 was obtained. Column chro-
matography on silica gel with ethyl acetates–hexanes
(2:1, v/v) gave fractions containing 9 (0.478 g, 35%),
which were recrystallised from ethyl acetate–hexanes
leaving racemic 9 as a white amorphous solid (0.144 g,
11%).
General procedures and instrumentation were as
1
described earlier.19,20 However, H, 13C and 31P NMR
spectra were obtained on a Varian-Mercury spectrome-
ter at 300, 75.5 and 121.5 MHz, respectively. In addi-
tion, some 13C NMR spectra were taken at 62.9 MHz
on a Bruker DPX (250 MHz). Bromomagnesium O,O-
diethylphosphonate was obtained from diethyl phos-
phite and ethylmagnesium bromide in THF at room
temperature by analogy to the literature.37
4.2.2. (1R*,2S*)-9. Mp: 148.9–149.4°C; IR (KBr): w=
3293, 2982, 2928, 1494, 1454, 1229, 1055, 1020 cm−1; 1H
NMR: l=7.46–7.21 (m, 15H), 4.64 (ddd, J=8.8 Hz,
J=5.4 Hz, J=5.3 Hz, 1H, H-1), 4.16 (dd, J=8.1 Hz,
J=5.4 Hz, 1H, H-2), 4.03–3.78 (m, 4H), 3.99 (d, J=
13.9 Hz, 2H), 3.27 (d, J=13.9 Hz, 2H), 2.38 (dd,
J=11.0 Hz, J=5.3 Hz, 1H, OH), 1.11 (t, J=7.2 Hz,
3H), 1.10 (t, J=6.9 Hz, 3H); 13C NMR (75.5 MHz):
l=139.73, 135.02 (d, J=6.3 Hz), 130.58, 128.79,
128.10, 127.73, 127.44, 126.78, 70.23 (d, J=160.5 Hz,
C-1), 63.38 (d, J=6.2 Hz, C-2), 62.52 (d, J=7.0 Hz),
62.31 (d, J=7.3 Hz), 55.05, 16.17 (d, J=5.8 Hz), 16.08
(d, J=5.6 Hz); 31P NMR: l=23.78. Anal. calcd for
C26H32NO4P: C, 68.86; H, 7.11; N, 3.09. Found: C,
68.63; H, 7.29; N, 3.30%.
4.1. (S)-N,N-Dibenzylphenylglycinal 6
To a stirred solution of oxalyl chloride (0.700 mL, 8.18
mmol) in CH2Cl2 (15 mL) under argon atmosphere,
DMSO (1.2 mL, 17 mmol) dissolved in CH2Cl2 (5 mL)
was added dropwise at −60°C. After 30 min a solution
of (S)-2-(N,N-dibenzylamino)-2-phenyl-1-ethanol (2.1
g, 6.6 mmol) in CH2Cl2 (10 mL) was added over 15
min. The reaction mixture was stirred for 30 min at
−70°C followed by addition of triethylamine (2.80 mL,
19.8 mmol). The cooling bath was removed, and satu-
rated aqueous NaHCO3 (10 mL) was added at 0°C.
Aqueous layer was re-extracted with CH2Cl2 (10 mL).
The organic phases were combined, dried (MgSO4) and
then concentrated to yield the crude aldehyde 6 as a
yellowish oil (2.47 g, 119%). 1H NMR: l=9.72 (d,
J=2.1 Hz, 1H), 7.90–7.22 (m, 15H), 4.33 (d, J=2.1 Hz,
1H), 3.85 (d, J=13.9 Hz, 2H), 3.44 (d, J=13.9 Hz,
2H).
Further elution afforded fractions containing 9 and 10
(total 0.421 g, 31%).
4.3. Benzoylation of 7 and 8
To a 6:4 mixture of 7 and 8 (0.719 g, 1.69 mmol) and
benzoic acid (0.206 g, 1.69 mmol) in CH2Cl2 (5 mL)
was added DCC (0.348 g, 1.69 mmol) followed by
DMAP (0.020 g, 0.169 mmol). The reaction mixture
was stirred at room temperature for 24 h. After
removal of DCU by filtration, the residue was chro-
matographed on silica gel with ethyl acetate–hexanes
(2:1, v/v) containing methanol (0.1%) to give 11 (0.520
g, 58%), 14 (0.010 g, 1%) and 8 (0.103 g, 14%).
4.2. Addition of dialkyl phosphites to (S)-6
A mixture of the crude aldehyde 6 (1.24 g, 3.30 mmol),
dimethyl phosphite (0.275 mL, 2.97 mmol) and NEt3
(0.046 mL, 0.33 mmol) was stirred at room temperature
for 24 h. The crude product was dissolved in CH2Cl2
(50 mL), washed with water (4×20 mL) and dried
(MgSO4). After evaporation of the solvent, the residue
was crystallised from ethyl acetate–hexanes to give pure
racemic 7 as white needles (0.360 g, 28%).
4.3.1. (1R,2S)-11. IR (film): w=3061, 3027, 2952, 2847,
1725, 1495, 1453, 1249, 1053, 1028 cm−1; 1H NMR:
l=7.71–7.68 (m, 2H), 7.56–7.52 (m, 4H), 7.49–7.42 (m,
1H), 7.37–7.20 (m, 13H), 6.35 (dd, J=9.6 Hz, J=8.4
4.2.1. (1R*,2S*)-7. Mp: 133.7−134.7°C; IR (KBr): w=
3307, 2952, 1495, 1233, 1075, 1057, 1032 cm−1; 1H

2982
A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
Hz, 1H, H-1), 4.58 (t, J=9.6 Hz, 1H, H-2), 3.97 (d,
J=13.5 Hz, 2H), 3.72 (d, J=10.8 Hz, 3H), 3.57 (d,
J=10.8 Hz, 3H), 3.18 (d, J=13.5 Hz, 2H); 13C NMR
(62.9 MHz): l=165.10 (d, J=2.9 Hz, CꢁO), 138.96,
133.57 (d, J=11.3 Hz), 133.15, 129.55, 129.31, 129.09,
128.25, 128.13, 127.98, 127.73, 126.97, 67.07 (d, J=
166.2 Hz, C-1), 62.72 (d, J=3.0 Hz, C-2), 54.43, 53.21
(d, J=6.2 Hz), 52.84 (d, J=7.3 Hz); 31P NMR: l=
21.83. Anal. calcd for C31H32NO5P: C, 70.31; H, 6.09;
N, 2.64. Found: C, 70.09; H, 5.91; N, 2.84%.
4.5. Addition of lithium dialkyl phosphonates to (S)-6
The crude aldehyde 6 was obtained from the corre-
sponding alcohol (3.74 g, 11.8 mmol) as described in
4.1. After addition of NEt3 (4.90 mL, 35.4 mmol) at
−60°C, the reaction mixture was cooled to −78°C and a
solution of lithium dimethyl phosphonate [from reac-
tion of diisopropylamine (1.98 mL, 14.5 mmol) 1.6 M
n-BuLi (8.85 mL, 14.5 mmol) and dimethyl phosphite
(1.30 mL, 14.5 mmol), in THF (25 mL) at −70°C] was
added dropwise via cannula. After 3 h the reaction
mixture was quenched with saturated aqueous NH4Cl
(25 mL) and the temperature was allowed to reach
25°C. The organic layer was separated, washed with
brine (20 mL), dried (MgSO4) and concentrated to
leave a 75:25 mixture of phosphonates (1R,2S)-7 and
(1S,2S)-8 as a yellowish oil (5.60 g, 111%).
4.3.2. (1S,2S)-14. IR (film): w=3061, 3028, 2953, 2850,
1724, 1494, 1454, 1259, 1051, 1028 cm−1; 1H NMR:
l=8.26–8.21 (m, 2H), 7.75–7.68 (m, 1H), 7.63–7.54 (m,
2H), 7.50–7.40 (m, 3H), 7.38–7.31 (m, 2H), 7.22–7.12
(m, 10H), 6.36 (dd, J=11.4 Hz, J=10.5 Hz, 1H, H-1),
4.40 (dd, J=11.4 Hz, J=8.4 Hz, 1H, H-2), 3.93 (d,
J=13.8 Hz, 2H), 3.50 (d, J=10.8 Hz, 3H), 3.11 (d,
J=10.8 Hz, 3H), 3.03 (d, J=13.8 Hz, 2H); 13C NMR
(75.5 MHz): l=165.34 (d, J=5.2 Hz, CꢁO), 139.15,
133.68, 131.59, 130.72, 130.42, 129.58, 128.81, 128.67,
128.36, 128.23, 128.00, 126.97, 66.93, (d, J=168.1 Hz,
C-1), 62.58 (d, J=9.2 Hz, C-2), 53.61, 52.70 (d, J=6.6
Hz), 52.69 (d, J=6.6 Hz); 31P NMR: l=22.84. Anal.
calcd for C31H32NO5P: C, 70.31; H, 6.09; N, 2.64.
Found: C, 70.21; H, 6.34; N, 2.52%.
In a similar way a crude 72:28 mixture of phosphonates
(1R,2S)-9 and (1S,2S)-10 (2.91 g, 104%) was obtained
after treatment of the aldehyde 6 [from (1.967 g, 6.196
mmol) of the corresponding alcohol] with lithium
diethyl phosphonate (7.44 mmol).
4.6. Separation of (1R,2S)-7 and (1S,2S)-8
The crude mixture of the phosphonates 7 and 8 (5.6 g)
was chromatographed on silica gel with chloroform–
methanol (50:1, v/v) to give a 1:1 mixture of (1R,2S)-7
and (1S,2S)-8 (1.190 g, 24%), the phosphonate (1R,2S)-
7 (2.019 g, 40%) and (1R,2S)-7 (0.82 g, 16%) with a
small amount of unidentified organophosphorus com-
pound. To the fraction containing a 1:1 mixture of 7
and 8 (1.190 g, 2.79 mmol) dissolved in CH2Cl2 (5 mL),
benzoic acid (0.161 g, 0.132 mmol) and DCC (0.271 g,
1.32 mmol) were added followed by DMAP (0.016 g,
0.13 mmol). After stirring the mixture for 24 h DCU
was filtered off and the solution was concentrated in
vacuo. The residue was chromatographed on silica gel
using ethyl acetate–hexanes (2:1, v/v) to afford (1R,2S)-
11 (0.566 g), (1S,2S)-8 (0.330 g, 7%) and (1S,2S)-8
(0.297 g, 6%) containing small amounts of unidentified
impurities.
4.3.3. (1S,2S)-8. IR (film): w=3347, 3061, 3028, 2954,
2850, 1602, 1494, 1452, 1249, 1048, 1030 cm−1; 1H
NMR: l=7.48–7.38 (m, 3H), 7.38–7.24 (m, 12H), 4.98
(brs, 1H, OH), 4.49 (dd, J=11.5 Hz, J=3.6 Hz, 1H,
H-2), 4.12 (dd, J=12.5 Hz, J=11.5 Hz, 1H, H-1), 3.91
(d, J=12.9 Hz, 2H), 3.50 (d, J=10.5 Hz, 3H), 3.22 (d,
J=10.5 Hz, 3H), 3.11 (d, J=12.9 Hz, 2H); 13C NMR
(75.5 MHz): l=137.68 (brs), 132.27 (brs), 130.34,
129.30, 128.84, 128.73 (brs), 128.40, 127.77, 65.47 (d,
J=173.2 Hz, C-1), 63.18 (brs, C-2), 53.51, 52.87 (d,
J=6.6 Hz); 31P NMR: l=25.34. Anal. calcd for
C24H28NO4P: C, 67.75; H, 6.63; N, 3.29. Found: C,
67.81; H, 6.40; N, 3.39%.
4.4. General procedures for the e.e. determinations of
the a-hydroxyphosphonates 7/8 and 9/10
4.6.1. (1R,2S)-7. Colourless oil; [h]D=+73.8 (c=2.0,
ethyl acetate). Anal. calcd for C24H28NO4P: C, 67.75;
H, 6.63; N, 3.29. Found: C, 67.86; H, 6.58; N, 3.17%.
4.4.1. Via mandelate. To a solution of the correspond-
ing phosphonates (0.1 mmol) in CH2Cl2 (2 mL), (S)-O-
methylmandelic acid (20.5 mg, 0.12 mmol) was added
followed by DCC (25 mg, 0.12 mmol) and DMAP (two
crystals). The mixture was stirred for 24 h at room
temperature. DCU was filtered off and washed with
CH2Cl2 (4 mL). The organic solution was concentrated,
the residue was dissolved in benzene-d6 (0.7 mL), and
the solution was subjected to 31P NMR analysis.
4.6.2. (1R,2S)-11. Colourless oil; [h]D=+79.2 (c=1.25,
ethyl acetate). Anal. calcd for C31H32NO5P: C, 70.31;
H, 6.09; N, 2.64. Found: C, 70.57; H, 5.89; N, 2.84%.
4.6.3. (1S,2S)-8. Colourless oil; [h]D=+73.5 (c=0.95,
ethyl acetate). Anal. calcd for C24H28NO4P: C, 67.75;
H, 6.63; N, 3.29. Found: C, 68.01; H, 6.85; N, 3.36%.
4.7. Separation of (1R,2S)-9 and (1S,2S)-10
4.4.2. Via camphanate. To a solution of (−)-camphanyl
chloride (16.0 mg, 0.075 mmol) and corresponding
phosphonates (0.03 mmol) in benzene-d6 (0.7 mL),
NEt3 (14.0 mL, 0.10 mmol) was injected followed by
two crystals of DMAP. The progress of the esterifica-
tion was monitored by 31P NMR spectroscopy.
The crude mixture of phosphonates 9 and 10 (2.91 g)
was chromatographed on silica gel with chloroform–
methanol to give several fractions containing various
ratios of phosphonates 9 and 10 (total 2.080 g, 4.586
mmol, 74%). This mixture was treated with benzoic

A. E. Wro´blewski, D. G. Piotrowska / Tetrahedron: Asymmetry 12 (2001) 2977–2984
2983
acid (0.377 g, 2.92 mmol), DCC (0.637 g, 2.92 mmol)
4.9. Racemisation of (S)-6
and DMAP (0.037 g, 0.29 mmol). After stirring the
mixture for 24 h at room temperature, DCU was
filtered off. After concentration the residue was twice
purified on silica gel with ethyl acetate–hexanes (2:1,
v/v) to give less polar benzoate (1R,2S)-15 (1.03 g),
unreacted phosphonate (1S,2S)-10 (0.202 g, 7%) and
the phosphonate 10 contaminated with minute quanti-
ties of unidentified organophosphorus compound
(0.163 g, 6%).
The aldehyde (S)-6 was prepared from (S)-N,N-dibenz-
ylphenylglycinol (0.317 g, 1.00 mmol) as described in
4.1. A sample (ca. 50 mg) was withdrawn and immedi-
ately added to a mixture of NaBH4 (12 mg, 0.32 mmol)
and methanol (1 mL) cooled to 0°C. Then the aldehyde
was treated with NEt3 (34 mL, 0.24 mmol) and the
mixture was stirred at room temperature for 24 h.
Samples (ca. 50 mg) of this mixture were withdrawn
after 1, 2 and 3 h and reduced with NaBH4 at 0°C.
After derivatisation of the N,N-dibenzylphenylglycinols
with (S)-O-methylmandelic acid as described in Section
4.7.1. (1R,2S)-15. Colourless oil; [h]D=+42.1 (c=1.07,
ethyl acetate). IR (film): w=3061, 3028, 2960, 2910,
1
1
1726, 1494, 1452, 1246, 1025 cm−1; H NMR: l=7.78–
4.4.1. H NMR spectra in CDCl3 were taken. Integrals
7.71 (m, 2H), 7.54–7.20 (m, 18H), 6.34 (t, J=9.1 Hz,
1H, H-1), 4.58 (t, J=9.1 Hz, 1H, H-2), 4.17–3.83 (m,
4H), 3.95 (d, J=13.7 Hz, 2H), 3.23 (d, J=13.7 Hz,
2H), 1.15 (t, J=6.9 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H);
13C NMR (75.5 MHz): l=165.13 (d, J=3.1 Hz, CꢁO),
139.14, 134.07 (d, J=10.9 Hz), 133.19, 129.77, 129.59,
129.38, 129.31, 128.36, 128.20, 127.98, 127.71,127.02,
67.92 (d, J=165.5 Hz, C-1), 62.89 (d, J=6.3 Hz), 62.84
(d, J=7.2 Hz), 62.79 (d, J=3.8 Hz, C-2), 54.64, 16.58
(d, J=6.0 Hz), 16.50 (d, J=6.0 Hz); 31P NMR: l=
19.80. Anal. calcd for C33H36NO5P: C, 71.08; H, 6.51;
N, 2.51. Found: C, 71.11; H, 6.26; N, 2.72%.
of signals at 4.714 and 4.695 ppm (H–C–OCH3) and at
3.366 and 3.334 ppm (CH3O–C–H) were selected for
calculation of e.e.
Acknowledgements
We thank Mrs. Jolanta Płocka for her skilled experi-
mental contributions. Financial support from the Medi-
cal University of Lo´dz (503-302-4) is gratefully
acknowledged.
4.7.2. (1S,2S)-10. Colourless oil; [h]D=+81.4 (c=1.88,
ethyl acetate). IR (film): w=3309, 3061, 3028, 2980,
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