Enantiomeric phosphonate analogs of the docetaxel C-13 side chain

Article abstract of DOI:10.1016/S0957-4166(00)00203-2

Addition of dimethyl phosphite to racemic N-Boc-phenylglycinal led to a 75:25 mixture of syn and anti dimethyl 2-[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethylphosphonates. The syn-diastereoisomer was obtained in 50% yield after a single crystallization. Resolution of the syn-isomer was achieved via the (S)-O-methylmandelate esters. Racemization-free ammonolysis gave both enantiomers in high enantiomeric excess. Benzoates of both N-Boc syn-enantiomers were transformed into dimethyl (1R,2R)- and (1S,2S)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates in good yields. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00203-2

Tetrahedron: Asymmetry 11 (2000) 2615±2624
Enantiomeric phosphonate analogs of the docetaxel
C-13 side chainy
Andrzej E. Wroblewski* and Dorota G. Piotrowska
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Institute of Chemistry, Faculty of Pharmacy, Medical University of —odz, 90-151 —odz, Muszynskiego 1, Poland
Received 9 May 2000; accepted 23 May 2000
Abstract
Addition of dimethyl phosphite to racemic N-Boc-phenylglycinal led to a 75:25 mixture of syn and anti
dimethyl 2-[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethylphosphonates. The syn-diastereoisomer
was obtained in 50% yield after a single crystallization. Resolution of the syn-isomer was achieved via the
(S)-O-methylmandelate esters. Racemization-free ammonolysis gave both enantiomers in high enantio-
meric excess. Benzoates of both N-Boc syn-enantiomers were transformed into dimethyl (1R,2R)- and
(1S,2S)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates in good yields. # 2000 Elsevier Science
Ltd. All rights reserved.
1. Introduction
The natural anticancer agent paclitaxel and its semisynthetic analog docetaxel are used clini-
cally against various tumors, especially breast and ovarian cancers.1 The importance of the C-13
side chains, N-benzoyl- and N-Boc-(2R,2S)-3-phenylisoserine 1 and 2, for achieving the anti-
tumor activity has prompted the search for structural analogs, by replacing the phenyl group with
other substituents,2 9 and also by introducing alkyl groups at Ca.10,11 We proposed another
modi®cation of this important amino acid based on the idea that phosphonates can serve as
bioisosters12 of carboxylic acids.13,14 So far, we have described the synthesis of phosphonate
analogs of 1 and 2, i.e. diethyl (1S*,2S*)-2-(benzoylamino)- and 2-[(tert-butoxycarbonyl)amino]-
1-hydroxy-2-phenylethylphosphonates (þ)-3a15,16 and (þ)-5a,15 respectively, and the resolution of
racemic 3a.16 However, when a future coupling of these esters to Baccatin III (the diterpene part
of paclitaxel and docetaxel) was considered, the major problems to overcome would have been
the selective monodeprotection of diethyl phosphonates under neutral conditions and, most
importantly,ꢀextreme steric congestion of HO^C-13 in the Baccatin III skeleton.17 20 Although
thermal (100 C) monodealkylation of diethyl phosphonates has recently been described,21 clean
and quantitative removal of one methyl group from dimethyl a-hydroxyphosphonates can be
* Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@ich.pharm.am.lodz.pl
y
Dedicated to Professor John G. Verkade on the occasion of his 65th birthday.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00203-2

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A. E. Wroblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 11 (2000) 2615±2624
2616
achieved with NaI in boiling acetone.22 On steric grounds, one can expect faster coupling of the
monomethyl phosphonates in comparision with the monoethyl analogs.
For these reasons, and prompted by the recent publication from the Sharpless group on the
asymmetric synthesis of structurally related phosphonates,23 we decided to study the synthetic
availability and stability of dimethyl (1S*,2S*)-2-(benzoylamino)- and 2-[(tert-butoxycarbonyl]-1-
hydroxy-2-phenylethylphosphonates 4a and 6a as prospective starting materials in the synthesis
of phosphonate analogs of paclitaxel and docetaxel, respectively. In this paper, signi®cant
improvements in the preparation of the racemic analog of docetaxel side chain 6a, the resolution
of 6a and the transformation of both enantiomeric phosphonates 6a into (1R,2R)- and (1S,2S)-4a
via the respective benzoates will be described.
2. Results and discussion
Phosphonate (1S*,2S*)-5a and its C-1 epimer (1R*,2S*)-5b were ®rst obtained as a 75:25
mixture by the addition of diethyl phosphite to racemic N-Boc-phenylglycinal 7.15 The syn-dia-
stereoisomer 5a having the same relative con®gurations as the natural (2R,3S)-phenylisoserine
could not be separated from the crude product either by column chromatography or fractional
crystallization from various solvent mixtures. The stereochemistry of the addition did not change
when dimethyl phosphite was used instead of the diethyl derivative. In the presence of NEt3
the aldehyde 7 was transformed into a 75:25 mixture of the phosphonates (1S*,2S*)-6a and
(1R*,2S*)-6b, respectively (Scheme 1). However, after a single crystallization of the crude pro-
duct, pure syn-diastereoisomer 6a was obtained in 50% yield. Attempts at separating diastereo-
isomeric methyl esters 6a and 6b on silica gel proved ine€ective, as had been observed for the
diethyl phosphonates 5a and 5b.
Scheme 1. Reagents and conditions: (a) (MeO)2P(O)H, NEt3 (10 mol%)
The anti-diastereoisomer (1R*,2S*)-6b was isolated in the following way: The mother liquors
after crystallization of 6a containing 6a and 6b in a 1:1 ratio were subjected to isopropylidenation
(Scheme 2) to produce a mixture of 8a (51%), 8b (27%) and unreacted 6b (13%) together with an
unidenti®ed organophosphorus compound (ꢀ 31P=18.14 ppm) (9%). After column chromato-
graphy pure 8a and 8b were obtained followed by more polar 6b.

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2617
Scheme 2. Reagents and conditions: (a) H2CˆC(OCH3)CH3, PPTS, (b) PhCOCl, NEt3, DMAP
Alternatively, benzoylation of a 4:6 mixture of 6a and 6b was carried out, and the respective
benzoates 9a and 9b (Scheme 2) were separated on silica gel to give 9b in 47% yield. The analo-
gous approach to separating mixtures of the benzoates of 5a and 5b (ethyl derivatives) met with
partial success and led to pure products in signi®cantly lower yields.15 The benzoates 9a and 9b
were subjected to ammonolysis16,24 to a€ord pure 6a24 and 6b in 65 and 77% yield, respectively.
After removal of the tert-butoxycarbonyl group the benzoates 9a and 9b were transformed into
the racemic phosphonate analog of the paclitaxel C-13 side chain 4a and its C-1 epimer 4b in
excellent yields (Scheme 3). High concentration of anhydrous hydrogen chloride in ethyl acetate
did not appear to be deleterious for the (MeO)2P(O) group. Furthermore, an excess of NEt3
caused neither epimerization at C-1 (via the retro-Abramov reaction) nor demethylation of the
ester function.
Scheme 3. Reagents and conditions: (a) 3 M HCl±AcOEt, (b) NEt3
The relative con®gurations in diastereoisomeric pairs 4a and 4b, and 6a and 6b were assigned
1
based on similarities of H and 13C NMR spectra of the respective ethyl and methyl esters, e.g.
3a15 and 4a or 5a15 and 6a. Furthermore, the stereochemistry of the addition to the carbonyl
group of 7 would be expected to be unaltered between diethyl and dimethyl phosphites.
In an alternative approach to the phosphonates 4a and 4b NEt3-catalyzed addition of dimethyl
phosphite to the racemic N-benzoylphenylglycinal 1016 was explored (Scheme 4). However, a 63:38
mixture of diastereoisomers 4a and 4b was contaminated with several impurities, and separation
Scheme 4. Reagents and conditions: (a) (MeO)2P(O)H, NEt3

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2618
of 4a and 4b on silica gel proved extremely tedious. This observation is in contrast with our
®ndings for 3a and 3b (ethyl esters) which were separated on silica gel to a€ord 3a in 67% yield.16
The resolution of (1S*,2S*)-6a was achieved via esters with (S)-O-methylmandelic acid 11.25
To this end racemic 6a was quantitatively esteri®ed with 11 in the presence of DCC/DMAP,26
and pure esters 12 (less polar) and 13 (more polar) were obtained after column chromatography
in 45 and 43% yield, respectively (Scheme 5).
Scheme 5. Reagents and conditions: (a) (S)-Ph(MeO)CHCOOH, DCC, DMAP, (b) aqueous NH3, THF
Treatment of 12 with aqueous ammonia followed by separation of O-methylmandelamide by
column chromatography gave (1R,2R)-6a in 94% yield. In a similar manner, (1S,2S)-6a was
obtained from 13 in 92% yield. Absolute con®gurations of (1R,2R)- and (1S,2S)-6a were assigned
1
from the similarities of H NMR spectral patterns for 12 or 13 and their ethyl analogs.16 The
Trost model27 was applied once again.16 The 31P NMR chemical shifts of 12 (19.48 ppm) and 13
(20.14 ppm) were also useful for the assignments.16,28 Since we were able to obtain minute
quantities of pure racemic 5a,15 the enantiomeric phosphonate analogs of docetaxel side chain
became available as methyl esters 6a only.
Enantiomeric excesses of enantiomeric phosphonates 6a were estimated based on 31P NMR
spectral data for the respective (^)-camphanyl esters. After completion of the esteri®cation (NMR
tube experiments) the camphanate derivative obtained from (1S,2S)-6a showed a single resonance
at 20.08 ppm, while from (1R,2R)-6a two esters were formed as judged from the appearance of
the two 31P NMR signals at 20.34 and 20.08 ppm in a 99:1 ratio. Thus, the prepared samples of
(1R,2R)- and (1S,2S)-6a had 98 and 100% enantiomeric excess, respectively. The enantiomeric
excess of our resolving acid 11 was 97.6%,{ and (S)-O-methylmandelic esters 12 and 13 were
®nally puri®ed by crystallization.
With the enantiomeric phosphonates 6a in hand, we decided to synthesize phosphonates 4a
taking advantage of a clean transformation of racemic N-Boc phosphonates 5a into N-benzoyl
derivatives 3a.15 Benzoylation of (1R,2R)-6a and (1S,2S)-6a provided crystalline benzoates
(1R,2R)-9a and (1S,2S)-9a in 58 and 57% yield, respectively. They were treated with hydrogen
chloride in ethyl acetate followed by an excess of triethylamine (Scheme 3) to give crystalline
{
Estimated by 1H NMR spectroscopy after esteri®cation with natural menthol. Integrals of Me8±C±Me9 doublets29 at
ꢀ 0.40 ppm for the ester of (R)-11 and 13C satellites at ꢀ 0.46 ppm for the ester of (S)-11 were compared. This region of
the 1H NMR spectrum is free from other 13C satellites or spinning side-bands. Enantiomeric excess of natural menthol
(100%) was proved in a similar way after derivatization with (^)-camphanyl chloride.

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A. E. Wroblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 11 (2000) 2615±2624
2619
phosphonates (1R,2R)-4a and (1S,2S)-4a. Their enantiomeric excesses were again estimated by 31
P
NMR spectroscopy as camphanyl esters and it appeared that ee's of both enantiomers were 100%.
In conclusion, it was demonstrated that the racemic phosphonate analog of the docetaxel C-13
side chain was easily obtained in gram quantities as the methyl ester 6a. Enantiomers of this
analog were obtained by resolution of the (S)-O-methylmandelate esters followed by racemiza-
tion-free ammonolysis. Benzoates of these enantiomeric phosphonates were quantitatively trans-
formed into enantiomeric phosphonate analogs of the paclitaxel C-13 side chain 4a.
3. Experimental
1H NMR spectra were taken in CDCl3 on the following spectrometers: Bruker DPX (250
MHz) and Varian Mercury-300 with TMS as an internal standard. 13C and 31P NMR spectra
were recorded for CDCl3 solutions on a Bruker DPX spectrometer at 62.9 and 101.25 MHz, or a
Varian Mercury-300 machine at 75.5 and 121.5 MHz, respectively. IR spectral data were measured
on an In®nity MI-60 FT-IR spectrometer. Melting points were determined on a Boetius apparatus
and are uncorrected. Elemental analyses were performed by the Microanalytical Laboratory of
this Institute on a Perkin±Elmer PE 2400 CHNS analyzer. Polarimetric measurements were con-
ducted on a Perkin±Elmer 241 MC apparatus.
The following absorbents were used: column chromatography, Merck silica gel 60 (70±230
mesh); analytical TLC, Merck TLC plastic sheets silica gel 60 F254. TLC plates were developed in
various ethyl acetate±hexanes or CHCl3±CH3OH solvent systems. Visualization of spots was
e€ected with iodine vapours. All solvents were puri®ed by methods described in the literature.
3.1. Addition of dimethyl phosphite to the aldehyde 7
A mixture of the crude aldehyde 7 prepared15 from 1,1-dimethylethyl-(2,3-dihydroxy-1-phenyl-
propyl)carbamate (3.385 g, 12.66 mmol), dimethyl phosphite (1.16 ml, 12.66 mmol) and NEt3
(0.176 ml, 1.27 mmol) was stirred at room temperature for 24 h. The crude product was recrys-
tallized from ethyl acetate±hexanes to give dimethyl (1S*,2S*)-2-[(tert-butoxycarbonyl)amino]-1-
hydroxy-2-phenylethylphosphonate 6a (2.045 g, 47%) as colorless plates. Mp 119.5±120.5ꢀC; IR
(KBr): ꢁ=3357, 3314, 1704, 1525, 1238, 1163 and 1040 cm^1; 1H NMR (250 MHz): ꢀ=7.41±7.22
(m, 5H), 6.09 (d, J=10.0 Hz, 1H), 5.09 (brs, 1H), 4.48 (brs, 1H), 4.21 (brs, 1H), 3.79 (d, J=10.5
Hz, 3H), 3.74 (d, J=10.5 Hz, 3H), 1.40 (s, 9H); 13C NMR (62.9 MHz): ꢀ=155.41, 140.20 (brd,
J=13.7 Hz), 128.19, 127.24, 126.80, 79.41 (brs), 71.02 (d, J=161.3 Hz), 54.52 (vbrs), 53.67 (d,
J=7.1 Hz), 53.12 (d, J=7.3 Hz), 28.18; 31P NMR (101.25 MHz): ꢀ=24.73. Anal. calcd for
C15H24NO6P: C, 52.17; H, 7.00; N, 4.06. Found: C, 52.17; H, 7.18; N, 4.02.
Mother liquors were concentrated to leave a 1:1 mixture of 6a and 6b as a yellowish oil (0.520 g).
When this reaction was repeated using 7 [from the carbamate (0.802 g, 3.00 mmol)], dimethyl
phosphite (0.250 ml, 2.70 mmol) and NEt3 (0.042 ml, 0.30 mmol), the phosphonate 6a (0.480 g,
51%) was obtained after crystallization from acetate±hexanes.
3.2. Isopropylidenation of a mixture of 6a and 6b
A 1:1 mixture of 6a and 6b (1.45 g, 4.19 mmol) was dissolved in toluene (40 ml) and 2-methoxy-
propene (4.01 ml, 41.9 mmol) followed by PPTS (53 mg, 0.21 mmol) were added. The solution

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2620
was kept at 80±90ꢀC (bath) for 2 h. The toluene solution was washed with water (2Â20 ml), dried
over MgSO4 and concentrated in vacuo. The crude product was chromatographed on silica gel
using ethyl acetate:hexanes (2:1, v/v) containing methanol (0.1%) to give 8a (0.639 g, 40%), var-
ious mixtures of 8a and 8b (0.134 g, 8%), 8b (0.105 g, 7%) and 6b (0.140 g, 10%).
1,1-Dimethyl (4S*,5S*)-5-(dimethoxyphosphinyl)-2,2-dimethyl-4-phenyl-3-oxazolidinecarboxy-
late 8a: colorless needles after crystallization from ethyl acetate±hexanes (0.308 g, 19%). Mp 101±
102ꢀC; IR (KBr): ꢁ=1707, 1387, 1261, 1094, 1048 and 1026 cm^1; 1H NMR (250 MHz): ꢀ=7.38±
7.24 (m, 5H), 5.04 (vbrdd, JH P=ꢁ14 Hz, JH H=ꢁ8 Hz, 1H), 4.20 (d, J=8.3 Hz, 1H), 3.75 (d,
J=10.5 Hz, 6H), 1.75 (s, 6H), 1.09 (brs, ꢁ1/2=21 Hz, 9H); 13C NMR (62.9 MHz): ꢀ=151.61,
140.45 (brs), 128.45, 127.70, 126.61, 96.82 (d, J=9.3 Hz), 80.27 (brs), 77.77 (d, J=172.3 Hz),
63.01 (d, J=3.4 Hz), 53.74 (d, J=6.6 Hz), 53.39 (d, J=6.8 Hz), 28.02, 26.3 (vbrs, ꢁ1/2=21 Hz),
26.0 (vbrs, ꢁ1/2=13 Hz); 31P NMR (101.25 MHz): ꢀ=22.22. Anal. calcd for C18H28NO6P: C,
56.10; H, 7.32; N, 3.63. Found: C, 56.13; H, 6.97; N, 3.54.
1,1-Dimethyl (4S*,5R*)-5-(dimethoxyphosphinyl)-2,2-dimethyl-4-phenyl-3-oxazolidinecarboxy-
1
late 8b: a colorless oil. IR (®lm): ꢁ=3483, 2978, 1699, 1456, 1377, 1247, 1099 and 1047 cm^1; H
NMR (300 MHz): ꢀ=7.44±7.22 (m, 5H), 5.18 (vbrd, J=ꢁ6 Hz, 0.25ÂH, E), 5.05 (dd, J=6.6 Hz,
J=2.1 Hz, 0.75ÂH, Z), 4.66 (dd, J=8.1 Hz, J=6.6 Hz, 1H), 3.63 (d, J=10.8 Hz, 0.75Â3H, Z),
3.60 (brd, J=11 Hz, 0.25Â3H, E), 3.19 (brd, J=11 Hz, 0.25Â3H, E), 3.14 (d, J=11.1 Hz,
0.75Â3H, Z), 1.95 (brs, 0.75Â3H, Z), 1.84 (brs, 0.25Â3H, E), 1.61 (s, 3H), 1.44 (brs, ꢁ1/2=4.8 Hz,
0.25Â9H, E), 1.14 (brs, ꢁ1/2=2.4 Hz, 0.75Â9H, Z); 13C NMR (75.5 MHz): ꢀ=151.5 (brs, E),
151.45 (s, Z), 139.40 (d, J=4.3 Hz, 75%, Z), 138.6 (brs, 25%, E), 128.34 (75%, Z), 128.19 (25%,
E), 128.03 (25%, E), 127.86 (25%, E), 127.74 (75%, Z), 95.74 (d, J=13.7 Hz, 75%, Z), 95.27 (d,
J=14.6 Hz, 25%, E), 81.00 (25%, E), 80.26 (75%, Z), 73.81 (d, J=179.5 Hz, Z), 73.74 (d,
J=179.0 Hz, E), 62.88 (brs, 25%, E), 62.73 (d, J=3.8 Hz, 75%, Z), 53.20 (d, J=6.6 Hz, E+Z),
53.02 (d, J=6.6 Hz, E+Z), 28.58 (25%, E), 28.25 (75%, Z), 27.16 (25%, E), 26.31 (75%, Z), 24.17
(25%, E), 23.03 (75%, Z); 31P NMR (121.5 MHz): ꢀ=19.00. Anal. calcd for C18H28NO6P: C,
56.10; H, 7.32; N, 3.63. Found: C, 55.80; H, 7.51; N, 3.86.
Dimethyl (1R*,2S*)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-2-phenylethylphosphonate 6b:
a white amorphous solid after crystallization from ether±hexanes (0.072 g, 5%). Mp 96.2±96.8ꢀC;
IR (KBr): ꢁ=3256, 1694, 1389, 1248, 1165, 1086 and 1047 cm^1; 1H NMR (300 MHz): ꢀ=7.4±7.2
(m, 5H), 6.02 (brd, J=8.1 Hz, 1H), 5.17 (vbrd, J=ꢁ20 Hz, 1H), 4.32 (ddd, J=8.1 Hz, J=8.1 Hz,
J=4.5 Hz, 1H), 3.71 (brd, J=10.5 Hz, 3H), 3.38 (brd, J=10.0 Hz, 3H), 3.29 (brs, 1H), 1.43 (brs,
9H); 13C NMR (75.5 MHz): ꢀ=155.63, 138.00, 128.28, 127.70, 127.56, 80.02, 70.99 (d, J=159.7
Hz), 56.55 (brd, J=3.0 Hz), 53.72 (d, J=6.6 Hz), 53.12 (d, J=7.2 Hz), 28.55; 31P NMR (121.5
MHz): ꢀ=23.94. Anal. calcd for C15H24NO6P: C, 52.17; H, 7.00; N, 4.06. Found: C, 52.53; H,
7.34; N, 4.17.
When pure 6a (0.652 g, 1.89 mmol) was subjected to isopropylidenation as described above, 8a
(0.658 g, 90%) was obtained after column chromatography. Crystallization of this material from
ethyl acetate±hexanes gave 8a (0.439 g, 60%). Mp 102.1±102.3ꢀC.
3.3. Benzoylation of 6a and 6b
A 4:6 mixture of 6a and 6b (0.540 g, 1.56 mmol) was subjected to benzoylation (PhCOCl 1.05
equiv., NEt3 1.1 equiv., DMAP 0.1 equiv.) to give crude benzoates 9a and 9b (0.745 g). This
material was chromatographed three times on silica gel using ethyl acetate:hexanes (2:1, v/v) containing
methanol (0.1%) to give 9b (0.333 g, 47%) after crystallization from ethyl acetate±hexanes.

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2621
Dimethyl (1R*,2S*)-1-(benzoyloxy)-2-[(tert-butoxycarbonyl)amino]-2-phenylethylphosphonate
9b. Colorless plates. Mp 140.0±140.5ꢀC; IR (KBr): ꢁ=3391, 1728, 1711, 1521, 1303, 1262, 1244
and 1016 cm^1; 1H NMR (300 MHz): ꢀ=8.09±8.05 (m, 2H), 7.63±7.57 (m, 1H), 7.5±7.4 (m, 4H),
7.4±7.3 (m, 2H), 7.3±7.24 (m, 1H), 6.38 (brd, J=ꢁ7 Hz, 1H), 5.82 (dd, J=10.5 Hz, J=5.1 Hz,
1H), 5.42 (vbrd, JH Pꢁ26 Hz, 1H), 3.67 (d, J=10.8 Hz, 3H), 3.30 (brd, J=10.8 Hz, 3H), 1.42 (s,
ꢁ
1/2=7 Hz) and ꢁ1.30 (vbrs) total 9H; 13C NMR (75.5 MHz): ꢀ=164.69 (d, J=6.3 Hz), 155.25
(brs), 137.10 (brs), 133.48, 129.82, 128.76, 128.37, 128.30, 127.69, 126.92, 79.63 (brs), 70.12 (d,
J=166.1 Hz), 54.88 (brs), 53.78 (d, J=6.6 Hz), 52.61 (d, J=6.6 Hz), 28.36; 31P NMR (121.5
MHz): ꢀ=21.32. Anal. calcd for C22H28NO7P: C, 58.79; H, 6.28; N, 3.12. Found: C, 58.87; H,
6.59; N, 3.27.
In a similar manner pure 6a (0.690 g, 2.00 mmol) was transformed into 9a (0.817 g, 91%) after
column chromatography. Crystallization from ethyl acetate±hexanes gave pure 9a (0.661 g, 74%)
as colorless needles.24
3.4. Dimethyl (1S*,2S*)- and (1R*,2S*)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates
4a and 4b
To a solution of the phosphonate 9a (0.759 g, 1.69 mmol) in CH2Cl2 (4 ml) 3.8 M HCl±AcOEt
(2 ml) was added at room temperature and the reaction mixture was stirred for 3 h. Methylene
chloride (5 ml) was added followed by NEt3 (1.4 ml, 10 mmol). The suspension was stirred at
room temperature for 2 h. After dilution with CH2Cl2 (10 ml) the organic phase was washed with
water (3Â10 ml), dried (MgSO4) and concentrated. The crude product was chromatographed on
silica gel using ethyl acetate:hexanes (3:1, v/v) containing methanol (0.5%) to a€ord 4a (0.534 g,
91%). Crystallization from eꢀthyl acetate±hexanes gave pure 4a (0.485 g, 82%) as a white amor-
phous solid. Mp 139.6±140.0 C; IR (KBr): ꢁ=3372, 3233, 1645, 1523, 1487, 1202 and 1042 cm^1;
1H NMR (300 MHz): ꢀ=7.51±7.24 (m, 11H), 5.59 (ddd, J=9.5 Hz, J=8.4 Hz, J=3.0 Hz, 1H),
4.60 (brs, 1H), 4.33 (ddd, J=8.9 Hz, J=7.3 Hz, J=3.0 Hz, 1H), 3.76 and 3.68 (2Âd, J=10.5 Hz,
2Â3H); 13C NMR (75.5 MHz): ꢀ=166.94, 139.12 (d, J=12.9 Hz), 134.06, 131.42, 128.32, 128.26,
127.42, 127.14, 126.89, 70.75 (d, J=161.8 Hz), 54.02 (d, J=1.6 Hz), 53.76 and 53.46 (2Âd, J=7.5
Hz): 31P NMR (121.5 MHz): ꢀ=24.66. Anal. calcd for C17H20NO5P: C, 58.45; H, 5.77; N, 4.01.
Found: C, 58.35; H, 5.86; N, 3.87.
In a similar way, from 9b (0.334 g, 0.74 mmol) phosphonate 4b (0.213 g, 83%) was obtained
after column chromatography on silica gel with chloroform:methanol (50:1, v/v). Crystallization
from chloroform±hexanes gave pure 4b (0.189 g, 73%) as a white amorphous solid. Mp 163.8±
164.0ꢀC; IR (KBr): ꢁ=3250, 1632, 1545, 1232, 1081 and 1058 cm^1; 1H NMR (300 MHz): ꢀ=8.27
(brd, J=8.1 Hz, 1H), 7.96±7.90 (m, 2H), 7.55±7.40 (m, 4H), 7.40±7.25 (m, 2H), 5.73 (ddd, J=26.2
Hz, J=8.1 Hz, J=4.8 Hz, 1H), 4.44 (ddd, J=8.4 Hz, J=6.6 Hz, J=4.8 Hz, 1H), 3.85±3.65 (brs,
1H), 3.77 (d, J=10.5 Hz, 3H), 3.33 (brd, J=10.8 Hz, 3H); 31P NMR (121.5 MHz): ꢀ=24.65.
Anal. calcd for C17H20NO5P: C, 58.45; H, 5.77; N, 4.01. Found: C, 58.84; H, 6.08; N, 4.23.
3.5. Ammonolysis of the benzoate 9b
To a solution of 9b (0.045 g, 0.10 mmol) in methanol (1 ml) 25% aqueous ammonia (1 ml) was
added at room temperaure. When the ester 9b disappeared (4 h), all volatiles were removed in
vacuo. The residue was evaporated with anhydrous ethanol (3Â5 ml) and chromatographed on
silica gel with ethyl acetate±hexanes to give 6b (0.028 g, 80%). After crystallization from ether±
hexanes pure 6b (0.027 g, 77%) was obtained. Mp 96.4±97.0ꢀC.

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A. E. Wroblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 11 (2000) 2615±2624
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3.6. Optical resolution of racemic 6a
To a solution of 6a (2.00 g, 5.80 mmol) and (S)-O-methylmandelic acid (1.16 g, 6.96 mmol) in
CH2Cl2 (20 ml) DCC (1.44 g, 6.96 mmol) was added followed by DMAP (0.071 mg, 0.58 mmol).
The reaction mixture was stirred at room temperature for 24 h. After removal of DCU by ®ltration
the residue was chromatographed on silica gel with ethyl acetate:hexanes (2:1, v/v) containing
methanol (0.1%) to give 12 (1.275 g, 45%) and 13 (1.222 g, 43%). Crystallizations from ethyl
acetate±hexanes a€orded 12 (1.113 g, 39%) and 13 (0.939 g, 33%).
Compound 12: mp 114.4±114.9ꢀC; [ꢂ]D=+6.6 (c=1.4, ethyl acetate); IR (KBr): ꢁ=3411, 1757,
1696, 1512, 1267 and 1043 cm^1; 1H NMR (300 MHz): ꢀ=7.4±7.3 (m, 5H), 7.3±7.2 (m, 5H), 5.66±
5.50 (brm, 2H), 5.32-5.18 (brs, 1H), 4.73 (s, 1H), 3.52 (d, J=10.8 Hz, 3H), 3.27 (s, 3H), 3.25 (brd,
J=11 Hz, 3H), 1.44 (brs) and ꢁ1.32 (vbrs)-total 9H; 13C NMR (75.5 MHz): ꢀ=168.74 (d, J=4.2
Hz), 154.60, 137.90 (brd, J=ꢁ10 Hz), 135.23, 128.78, 128.49, 128.39, 127.73, 127.09, 126.58 (brs),
82.12, 79.93 (brs), 70.31 (d, J=166.6 Hz), 57.55, 53.97 (brs), 53.11 (brd, J=ꢁ6 Hz), 53.05 (d,
J=6.3 Hz), 28.36; 31P NMR (121.5 MHz): ꢀ=19.48. Anal. calcd for C24H32NO8P: C, 58.41; H,
6.54; N, 2.84. Found: C, 58.58; H, 6.51; N, 3.12.
Compound 13: mp 122.4±122.8ꢀC; [ꢂ]D=+22.6 (c=1.3, ethyl acetate); IR (KBr): ꢁ=3300,
1
1765, 1720, 1523, 1251, 1164 and 1065 cm^1; H NMR (300 MHz): ꢀ=7.41±7.30 (m, 5H), 7.14±
7.04 (m, 3H), 6.89-6.82 (m, 2H), 5.6-5.4 (brm, 2H), 5.16 (brt, J=ꢁ9 Hz, 1H), 4.79 (s, 1H), 3.73
(d, J=10.5 Hz, 3H), 3.60 (brd, J=ꢁ10 Hz, 3H), 3.34 (s, 3H), 1.42 (brs) and ꢁ1.34 (vbrs) total
9H; 13C NMR (75.5 MHz): ꢀ=168.43 (d, J=4.3 Hz), 154.43, 137.93 (brd, J=ꢁ12 Hz), 135.27,
128.91, 128.66, 128.17, 127.35, 127.22, 126.02, 82.08, 79.83 (brs), 70.27 (brd, J=166.0 Hz), 57.33,
53.37 (d, J=6.3 Hz), 53.29 (d, J=6.3 Hz), 53.3 (vbrs), 28.29; 31P NMR (121.5 MHz): ꢀ=20.14.
Anal. calcd for C24H32NO8P: C, 58.41; H, 6.54; N, 2.84. Found: C, 58.74; H, 6.83; N, 2.92.
To a solution of 12 (0.602 g, 1.22 mmol) in THF (6 ml) aqueous ammonia (25%, 4 ml) was
added and the reaction mixture was stirred at room temperature for 2 h. After removal of all
volatiles the crude product was chromatographed on silica gel with ethyl acetate:hexanes (3:1, v/v)
containing methanol (0.1%) to give (1R,2R)-6a (0.394 g, 94%) as a colorless oil; [ꢂ]D=^21.7
(c=1.3, ethyl acetate). Anal. calcd for C15H24NO6P: C, 52.17; H, 7.00; N, 4.06. Found: C, 51.71;
H, 6.86; N, 4.39.
In a similar way, from 13 (0.610 g, 1.24 mmol) (1S,2S)-6a (0.393 g, 92%) was obtained as a
colorless oil; [ꢂ]D=+20.4 (c=1.4, ethyl acetate). Anal. calcd for C15H24NO6P: C, 52.17; H, 7.00;
N, 4.06. Found: C, 52.31; H, 6.80; N, 4.10.
3.7. Benzoylation of (1R,2R)- and (1S,2S)-6a
Enantiomeric phosphonates 6a were subjected to benzoylation as described above. From
(1R,2R)-6a (0.307 g, 0.89 mmol) the benzoate (1R,2R)-9a (0.387 g, 97%) was obtained after
chromatography on silica gel using chloroform:methanol (50:1, v/v). This material was recrys-
tallized from ether±hexanes to give pure ester (0.230 g, 58%) as colorless plates. Mp 92.5±93.5ꢀC;
[ꢂ]D=^60.5 (c=1.1, ethyl acetate). Anal. calcd for C22H28NO7P: C, 58.79; H, 6.28; N, 3.12.
Found: C, 58.65; H, 6.14; N, 3.08.
From (1S,2S)-6a (0.364 g, 1.06 mmol) the benzoate (1S,2S)-9a (0.463 g, 98%) was obtained
after chromatography. Crystallization from ether±hexanes gave pure ester (0.272 g, 57%) as color-
less plates. Mp 93.6±94.2ꢀC; [ꢂ]D=+63.9 (c=1.1, ethyl acetate). Anal. calcd for C22H28NO7P: C,
58.79; H, 6.28; N, 3.12. Found: C, 58.66; H, 6.30; N, 3.07.

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A. E. Wroblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 11 (2000) 2615±2624
2623
3.8. Enantiomeric phosphonates (1R,2R)- and (1S,2S)-4a
A solution of the benzoate (1R,2R)-9a (0.200 g, 0.445 mmol) in methylene chloride (5 ml)
containing 3.7 M HCl±AcOEt (1 ml) was left at room temperature for 3 h. The reaction mixture
was diluted with CH2Cl2 (10 ml), neutralized with NEt3 (0.56 ml, 4.0 mmol) and left for 2 h. After
washing with water (3Â10 ml) the organic layer was dried (MgSO4) and concentrated. The crude
product was chromatographed on silica gel with chloroform:methanol (50:1, v/v) to give (1R,2R)-
4a (0.155 g, 100%). After crystallization from chloroform±ether pure phosphonate (0.106 g, 68%)
was obtained as a white amorphous solid. Mp 117.4±118.4ꢀC; [ꢂ]D=+42.4 (c=1.3, ethyl acetate).
Anal. calcd for C17H20NO5P: C, 58.45; H, 5.77; N, 4.01. Found: C, 58.55; H, 5.66; N, 3.97.
In a similar manner from the benzoate (1S,2S)-9a (0.230 g, 0.512 mmol), (1S,2S)-4a (0.179 g,
100%) was obtained. Crystallization of this material from chloroform±ether gave pure product
(0.130 g, 73%) as a white amorphous solid. Mp 117.4±118.1ꢀC; [ꢂ]D=^44.6 (c=1.2, ethyl acetate).
Anal. calcd for C17H20NO5P: C, 58.48; H, 5.77; N, 4.01. Found: C, 58.54; H, 5.71; N, 3.98.
3.9. Determination of the enantiomeric excess of (1R,2R)- and (1S,2S)-4a and (1R,2R)- and
(1S,2S)-6a
A general procedure described earlier16 was followed. 31P NMR spectra of (^)-camphanyl
esters of (1R,2R)-4a and (1S,2S)-4a were taken for the chloroform-d solutions; 31P NMR (121.5
MHz): 20.14 and 19.42 ppm, respectively. 31P NMR spectra of (^)-camphanyl derivatives of
(1R,2R)-6a and (1S,2S)-6a were obtained for the benzene-d6 solutions; 31P NMR (121.5 MHz):
20.34 and 20.08 ppm, respectively.
3.10. Determination of the enantiomeric excess of (S)-O-methylmandelic acid 11
To a solution of the acid 11 (17.0 mg, 0.1 mmol) in CH2Cl2 (2 ml), natural menthol (31.0 mg,
0.2 mmol) was added followed by DCC (43.0 mg, 0.21 mmol) and DMAP (two crystals). After 24 h
at room temperature DCU was ®ltered o€ and washed with CH2Cl2 (4 ml). The organic solution
1
was concentrated, dissolved in chloroform-d (0.7 ml) and H NMR spectrum was taken at 300
MHz; NS=256.
Acknowledgements
We thank Mrs. Jolanta Plocka for her skilled experimental contributions. Financial support
from the Medical University of —odz (503-302-4) is gratefully acknowledged.
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