Enantiomeric phosphonate analogs of the paclitaxel C-13 side chain

Article abstract of DOI:10.1016/S0957-4166(99)00206-2

Both enantiomers of syn diethyl 2-(benzoylamino)-1-hydroxy-2- phenylethylphosphonate have been obtained by resolution via O- methylmandelate derivatives. Removal of the resolving ester moiety was easily achieved by ammonolysis with no trace of the retro-Abramov reaction. Absolute configurations of the enantiomeric phosphonate analogs were established from ¹H (the Trost model) and ³¹P NMR data of the O-methylmandelate derivatives.

Full text of DOI:10.1016/S0957-4166(99)00206-2

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2037–2043
Enantiomeric phosphonate analogs of the paclitaxel C-13 side
chain
Andrzej E. Wróblewski ∗ and Dorota G. Piotrowska
Institute of Chemistry, Faculty of Pharmacy, Medical University of Łódz´, 90-151 Łódz´, Muszyn´skiego 1, Poland
Received 11 May 1999; accepted 20 May 1999
Abstract
Both enantiomers of syn diethyl 2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonate have been obtained
by resolution via O-methylmandelate derivatives. Removal of the resolving ester moiety was easily achieved
by ammonolysis with no trace of the retro-Abramov reaction. Absolute configurations of the enantiomeric
1
phosphonate analogs were established from H (the Trost model) and 31P NMR data of the O-methylmandelate
derivatives. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Paclitaxel is considered as one of the most promising anticancer drugs.1 In the search for more
powerful and less toxic analogs and in order to study structure–activity relationships (SARs) a significant
number of derivatives have been reported.2–4 It appears that the structure of the C-13 side chain is
extremely important for the antitumor activity.
Recently, we have disclosed the synthesis of racemic syn and anti diethyl 2-[(tert-butoxy-
carbonyl)amino]-1-hydroxy-2-phenylethylphosphonates 1 and 2, respectively, and the transformation
of 1 into diethyl 2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonate 3, the phosphonate analogs
of docetaxel and paclitaxel C-13 side chains, respectively.5 Growing interest in the modification of
(2R,3S)-3-phenylisoserine has prompted our further studies in this area and herein we wish to describe
an improved synthesis of racemic 3 and its resolution via O-methylmandelate derivatives. In addition,
the absolute configurations of the enantiomers of 3 were established based on 1H and 31P NMR spectral
data.
∗
Corresponding author. Fax: 48-42-678-83-98; e-mail: aewplld@ich.am.lodz.pl
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00206-2

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2. Results and discussion
A synthetic pathway to racemic 5 followed by analogy with the Sharpless asymmetic epoxidation
process on 3-phenyl-2-propen-1-ol6 with minor modifications is shown in Scheme 1.
Scheme 1. Reagents and conditions: (a) MCPBA, 0.5 M NaHCO3; (b) PhC(O)Cl, NEt3, CH2Cl2; (c) NaN3, MeOH–H2O, 65°C;
(d) H2, Pd–C, MeOH; (e) NaIO4, CH2Cl2–H2O
Epoxide 7 prepared from 6 under standard conditions was benzoylated to give 8, which was subjected
to azidolysis to produce a 4:1 mixture of benzoates 9a and 9b. Hydrogenation of 9a/9b led to the diol 10
which was purified by crystallization. The periodate cleavage supplied N-benzoylphenylglycinal 5 which
was used immediately in the next step without purification.
Racemic 5 was reacted with diethyl phosphite in the presence of various basic catalysts to pro-
duce mixtures of diastereoisomeric diethyl (1S*,2S*)- and (1R*,2S*)-2-(benzoylamino)-1-hydroxy-
2-phenylethylphosphonates 3 and 4. The diastereoselectivity of the addition changed significantly
from those observed when N-Boc-phenylglycinal was used (in brackets):5 (EtO)2P(O)H/NEt3 65:35
(75:25); (EtO)2P(O)Li 54:46 (70:30); (EtO)2P(O)Na 78:22 (87:13);7 (EtO)2POTMS 81:19 (87:13);7
(EtO)2P(O)H/Ti(OiPr)4 46:54 (67:33).7
The mixture of diastereoisomeric N-Boc-phosphonates (1S*,2S*)-1 and (1R*,2S*)-2 was found to
be inseparable on silica gel.5 On the other hand, N-benzoyl analogs (1S*,2S*)-3 and (1R*,2S*)-4 were
separated by column chromatography, and the required syn diastereoisomer (1S*,2S*)-3 was obtained in
satisfactory yield from the mixture prepared using diethyl trimethylsilyl phosphite.
Resolution of 3 was achieved via O-methylmandelate derivatives. Thus, 3 was esterified with (S)-O-
methylmandelic acid8 in the presence of DCC9 to form the respective mandelates quantitatively. They
were cleanly separated on a silica gel column into a resinous less polar diastereomer 11 (43%) and a
crystalline more polar diastereomer 12 (36%), and their diastereoisomeric purity was ascertained from
1H, 13C and 31P NMR spectra.
Absolute configurations of the phosphonate fragments in 11 and 12 were assigned, based on the
1
analysis of H and 31P NMR spectral data of mandelates. Thus, according to the Trost model10 the
phenyl ring of the mandelic ester is expected to shield the P(O)(OEt)2 group in 11 as well as the CHPh-
NH-C(O)Ph residue in 12 (Fig. 1). Indeed, we noticed significant upfield shifts for one OCH2CH3 group

A. E. Wróblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 10 (1999) 2037–2043
2039
Figure 1. Preferred conformations of O-methylmandelates 11 and 12
in 11 (from 4.2–3.8 ppm in 3 and 12, to 3.64 and 3.41 ppm in 11) leading even to a first-order pattern for
the diastereotopic protons, and resonances of the Ph-C(O) in 12 were moved to 7.2–7.05 ppm (m- and
p-) and to 7.0–6.9 ppm (o-) regions. Although better probes for configurational assignments of secondary
1
alcohols than O-methylmandelates have been proposed very recently,11,12 the H NMR upfield shifts
observed for 11 and 12 were used with confidence. On the other hand, extensive configurational studies
of α-hydroxyphosphonates13 showed that for (R)-O-methylmandelates, esters of (S)-alcohols are less
polar and their 31P NMR chemical shifts appear in a higher field than (R)-O-methylmandelates of (R)-
alcohols. Our less polar (S)-O-methylmandelate 11 contains (1R)-alcohol and also absorbs at higher field
(17.01 ppm) than (S)-O-methylmandelate of (1S)-alcohol 12 (17.54 ppm). For this reason removal of the
resolving group from 11 would lead to (1R,2R)-3, while from 12, (1S,2S)-3 would be obtained.
The resolving moiety was simply removed with 25% aqueous ammonia at room temperature. Although
the ammonolysis was carried out in a basic solution no epimerization at C-1 (the retro-Abramov reaction)
was observed as judged from 31P NMR spectra, i.e. from 11 (δ31P=17.01 ppm) and from 12 (δ31P=17.54
ppm) only enantiomeric syn phosphonates (δ31P=22.6 ppm) were obtained. Thus, mandelate 11 gave
(1R,2R)-3, while from 12 the enantiomer (1S,2S)-3, having the same configuration as the C-13 side
chain of paclitaxel, was formed. On the other hand, attempts at cleaving O-methylmandelates 11/12 with
methanol in the presence of potassium carbonate10 led to complete decomposition of the phosphonate
via the retro-Abramov reaction. The present procedure for racemization-free deprotection of esters of
α-hydroxyphosphonates by ammonolysis seems superior to the method using NEt3–MeOH described by
Hammerschmidt14 (1–2 h vs. 1–11 days, respectively). The generality of this new deprotection method
is under extensive studies in this laboratory.
The enantiomeric purity of (1R,2R)-3 and (1S,2S)-3 was proved by esterification of small samples
(NMR tube experiments) with (−)-camphanyl chloride. After disappearance of the 31P NMR signals of
the hydroxyphosphonates 3 only single resonances for the corresponding camphanates at δ31P=17.74
ppm from (1R,2R)-3 and at δ31P=17.54 ppm from (1S,2S)-3 were observed at 202.5 MHz. Thus, within
NMR spectroscopy detection limits we judge the enantiomeric purity of both samples as better than 99%.
In conclusion, it was shown that preparation of pure 3 was efficiently accomplished from racemic
N-benzoylphenylglycinal and diethyl trimethylsilyl phosphite. Enantiomerically pure (1S,2S)-3 and
(1R,2R)-3 were obtained in good yield by resolution using O-methylmandelates. Ammonolysis (25%
aqueous NH3) of the mandelates of α-hydroxyphosphonates did not cause epimerization at C-1 of
enantiomeric phosphonates. Studies on asymmetric synthesis of (1S,2S)-3 and related phosphonates are
under way in this laboratory.
3. Experimental
1H NMR spectra were taken in CDCl3 on the following spectrometers: Tesla BM 567 (100 MHz) and
Bruker DPX (250 MHz) with TMS as an internal standard. 13C and 31P NMR spectra were recorded for

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A. E. Wróblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 10 (1999) 2037–2043
CDCl3 solutions on a Bruker DPX spectrometer at 62.9 and 101.25 MHz, respectively. For enantiomeric
excess determinations 31P NMR spectra were obtained with a Bruker DRX spectrometer at 202.5 MHz.
IR spectral data were measured on an Infinity 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
conducted 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 effected with iodine
vapors.
All solvents were purified by methods described in the literature.
3.1. N-(2,3-Dihydroxy-1-phenylpropyl)benzamide 10
To a suspension of cinnamyl alcohol (6, 6.71 g, 50.0 mmol) in aqueous NaHCO3 (0.5 M, 200 ml) was
added MCPBA (70%, 13.56 g, 55.00 mmol) at 0–3°C. The reaction mixture was stirred vigorously for
4 h at 25°C. After saturation with solid NaCl the aqueous phase was extracted with CH2Cl2 (4×50 ml)
and organic extracts were dried over MgSO4. Evaporation of the solvent left crude 7 (7.73 g, 103%) as a
colorless oil.15
To a solution of 7 in CH2Cl2 (40 ml) was added NEt3 (7.63 ml, 55.0 mmol), benzoyl chloride (6.70
ml, 57.75 mmol) and a few crystals of DMAP. After stirring for 3 h, the reaction mixture was washed
with water (3×30 ml). The organic layer was dried (MgSO4) and concentrated to give crude 8 (13.45 g,
106%) as yellowish oil. 1H NMR (250 MHz): δ=8.5–8.2 (m, 2H), 7.5–7.2 (m, 8H), 4.75 (dd, J=12.3 Hz,
J=3.3 Hz, 1H), 4.36 (dd, J=12.3 Hz, J=5.8 Hz, 1H), 3.90 (d, J=2.0 Hz, 1H), 3.41 (ddd, J=5.8 Hz, J=3.3
Hz, J=2.0 Hz, 1H).
The epoxide 8 was dissolved in methanol:water (8:1, v/v, 450 ml) containing NaN3 (16.25 g, 0.25
mol) and NH4Cl (5.84 g, 0.11 mol). The solution was gently refluxed for 10 h and then methanol was
evaporated. After addition of water (20 ml) the reaction mixture was extracted with CH2Cl2 (4×70 ml),
the organic layer was washed with brine (2×50 ml), dried (MgSO4), and concentrated to leave a 4:1
mixture of 9a and 9b (13.37 g, 90%) as a brownish oil. 1H (250 MHz): δ=8.1–7.9 (m, 2H), 7.6–7.3 (m,
8H), 5.36 (ddd, J=6.2 Hz, J=5.2 Hz, J=3.5 Hz, 9b), 5.05 (d, J=6.2 Hz, 9b), 4.72 (d, J=6.4 Hz, 9a), 4.47
(dAB, JAB=11.8 Hz, J=3.8 Hz, 9a), 4.41 (dAB, JAB=11.8 Hz, J=5.6 Hz, 9a), 4.2–4.1 (m, 9a), 3.9–3.7
(m, 9b).
The crude mixture of azides 9a and 9b (13.37 g, 45.00 mmol) was dissolved in methanol (100 ml)
and hydrogenated over 10% Pd–C (500 mg) overnight. After filtration through a pad of Celite, methanol
was removed and the product was recrystallized from ethyl acetate–hexanes leaving 10 (7.40 g, 55%) as
1
a white amorphous solid. Mp 160–161°C; H NMR (100 MHz, CD3OD): δ=7.8–7.7 (m, 2H), 7.5–7.1
(m, 9H), 5.14 (d, J=6.1 Hz, 1H), 4.0–3.8 (m, 1H), 3.60 (dAB, JAB=11.2 Hz, J=3.7 Hz, 1H), 3.40 (dAB,
J
AB=11.2 Hz, J=5.0 Hz, 1H).
3.2. N-(2-Oxo-1-phenylethyl)benzamide 5
A mixture of N-benzoylaminodiol 10 (2.71 g, 10.0 mmol), NaIO4 (2.57 g, 12.0 mmol), water (30
ml) and CH2Cl2 (50 ml) was stirred at room temperature for 2 h. The organic layer was separated and
the aqueous phase was extracted with CH2Cl2 (2×15 ml). The organic solution was dried (MgSO4) and
concentrated in vacuo to leave a crude 5 as a white solid (2.63 g, 110%), which was immediately used

A. E. Wróblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 10 (1999) 2037–2043
2041
in the next step without purification. 1H NMR (250 MHz): δ=9.65 (s, 1H), 7.9–7.8 (m, 2H), 7.5–7.2 (m,
9H), 5.77 (d, J=5.8 Hz, 1H).
3.3. Diethyl (1S*,2S*)- and (1R*,2S*)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates 3 and
4
(a) A mixture of the crude 5 (0.248 g, obtained from 0.271 g, 1.00 mmol of 10), diethyl phosphite
(0.116 ml, 0.90 mmol) and NEt3 (0.014 ml, 0.10 mmol) was stirred at room temperature for 24 h. After
removal of volatiles in vacuo the ratio of diastereoisomeric α-hydroxyphosphonates was estimated by
31P NMR spectroscopy. Column chromatography on silica gel with ethyl acetate:hexanes (2:1, v/v) gave
several fractions of poorly separated mixtures of 3 and 4 (total 0.252 g, 74%).
(b) To a solution of lithium diethyl phosphonate [from diethyl phosphite (0.93 ml, 7.2 mmol),
diisopropylamine (0.94 ml, 7.2 mmol), and 1.6 M BuLi (4.5 ml, 7.2 mmol) in THF (10 ml) cooled
to −60°C] was added crude 5 (2.48 g, obtained from 2.14 g, 8.00 mmol of 10) in THF (10 ml). The
reaction mixture was stirred at this temperature for 3 h and allowed to reach 25°C. A saturated aqueous
NH4Cl (5 ml) was added followed by CH2Cl2 (100 ml). The suspension was washed with water (2×70
ml), the organic layer was dried (MgSO4) and concentrated to leave a 54:46 mixture of 3 and 4 as a
viscous oil. Column chromatography on silica gel with ethyl acetate:hexanes (2:1, v/v) gave fractions
containing 4 (1.162 g, 43%), which were recrystallized from ethyl acetate–hexanes leaving 4 (0.667 g,
25%) as a white amorphous solid. Mp 117–118°C; IR (KBr): ν=3284, 1638, 1548, 1221, 1076, 1054,
1
1026 and 698 cm−1; H NMR (250 MHz): δ=8.33 (brd, J=8.2 Hz, 1H), 8.0–7.9 (m, 2H), 7.6–7.2 (m,
8H), 5.72 (ddd, J=25.5 Hz, J=8.2 Hz, J=4.6 Hz, 1H), 4.39 (ddd, J=8.5 Hz, J=6.2 Hz, J=4.6 Hz, 1H),
4.2–4.0 (m, 2H), 3.9–3.6 (m, 3H), 1.27 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H); 13C NMR: δ=167.52,
137.77 (d, J=2.1 Hz), 133.87, 131.65, 128.56, 128.27, 127.54, 127.30, 127.25, 70.76 (d, J=161.6 Hz),
63.61 (d, J=7.0 Hz), 62.05 (d, J=7.3 Hz), 56.37 (d, J=1.8 Hz), 16.39 (d, J=5.7 Hz), 15.83 (d, J=6.3 Hz);
31P NMR: δ=22.50. Anal. calcd for C19H24NO5P: C, 60.47; H, 6.41; N, 3.71. Found: C, 60.31; H, 6.61;
N, 3.98.
Further elution afforded mixed fractions of 4 and 3 (total 1.335 g, 49%).
(c) To a solution of sodium diethyl phosphite [from diethyl phosphite (0.26 ml, 2.0 mmol) and NaH
(55% suspension, 0.098 g, 2.2 mmol) in THF (5 ml)] a crude 5 (0.529 mg, obtained from 0.542 g, 2.0
mmol of 10) in THF (2 ml) was added at room temperature. The reaction mixture was stirred for 3 h and
CH3COOH (0.13 ml, 2.2 mmol) was injected. After dilution with CH2Cl2 (25 ml), anhydrous MgSO4 (3
g) was added and inorganic salts were filtered off. The organic phase was concentrated to leave a crude
mixture of 3 and 4 (78:22, by 31P NMR).
(d) To a cooled (0°C) solution of diethyl phosphite (0.129 ml, 1.00 mmol) in THF (1.0 ml) was injected
Ti(OiPr)4 (0.059 ml, 0.2 mmol). After 30 min at this temperature the crude aldehyde 5 (0.284 g, obtained
from 0.271 g, 1.00 mmol of 10) was added as a solution in THF (2 ml). The reaction mixture was stirred
at 0–5°C for 24 h and aqueous HCl (1.0 ml, 0.1 M) was added. The extraction with ether (3×10 ml)
followed by a brine wash (3×5 ml), drying (MgSO4) and concentration in vacuo led to crude 3 and 4 in a
46:54 ratio. After filtration through a pad of silica gel a mixture of 3 and 4 (0.300 g, 80%) was obtained.
(e) A solution of crude aldehyde 5 (4.35 g, obtained from 4.07 g, 15.0 mmol of 10) and (EtO)2POTMS
(3.10 ml, 13.5 mmol) in CH2Cl2 (5 ml) was kept at room temperature for 24 h. After removal of solvents
the residue was dissolved in THF (40 ml) containing aqueous H2SO4 (2%, 4 ml) and refluxed for 3 h.
Evaporation of THF led to a mixture which was diluted in CH2Cl2 (50 ml) and carefully treated with solid
NaHCO3 until evolution of CO2 ceased followed by anhydrous MgSO4. The inorganic salts were filtered
off, washed with CH2Cl2, and the solution was concentrated in vacuo to give a crude 81:19 mixture of

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3 and 4. Column chromatography on silica gel with ethyl acetate:hexanes (2:1, v/v) containing 0.1% of
methanol gave various mixtures of 3 and 4 (1.594 g, 31%) and 3 (3.427 g, 67%), which were crystallized
from ethyl acetate–hexanes leaving pure 3 (2.230 g, 44%). Mp 127–128°C.5
3.4. Esterification of (1S*,2S*)-3 with (S)-O-methylmandelic acid
To a solution of 3 (1.132 g, 3.00 mmol) and (S)-O-methylmandelic acid8 (0.648 g, 3.00 mmol) in
CH2Cl2 (10 ml) containing DMAP (0.037 mg, 0.30 mmol), DCC (0.805 g, 3.90 mmol) was added. After
stirring for 2 h at room temperature DCU was filtered off and the residue was concentrated. The crude
product was purified on silica gel with ethyl acetate:hexanes (2:1, v/v) containing 0.1% of methanol to
give 11 (0.684 g, 43%) as a colorless resin and 12 (0.727 g, 46%), which was recrystallized from ethyl
acetate–hexanes leaving 12 (0.567 g, 36%) as white needles.
20
1
11: [α] =+29.0 (c=1.4, ethyl acetate); IR (film): ν=3303, 1760, 1646, 1524, 1256, 1028 cm−1; H
D
NMR (250 MHz): δ=7.9–7.8 (m, 2H), 7.65 (brd, J=7.1 Hz, 1H), 7.6–7.2 (m, 13H), 5.7–5.6 (m, 2H), 4.71
(s, 1H), 4.1–3.9 (m, 2H), 3.64 (dqu, J=10.1 Hz, J=7.1 Hz, 1H), 3.41 (ddq, J=10.1 Hz, J=8.4 Hz, J=7.1
Hz, 1H), 3.21 (s, 3H), 1.19 (t, J=7.1 Hz, 3H), 0.91 (t, J=7.1 Hz, 3H); 13C NMR: δ=168.85 (d, J=4.7 Hz),
166.28, 137.35 (d, J=8.9 Hz), 135.43, 133.82, 131.61, 128.80, 128.54, 128.53, 128.39, 127.79, 127.09,
126.80, 82.12, 69.84 (d, J=166.0 Hz), 63.05 (d, J=6.7 Hz), 62.98 (d, J=7.1 Hz), 57.48, 53.40 (d, J=1.2
Hz), 16.14 (d, J=5.7 Hz), 15.95 (d, J=6.1 Hz); 31P NMR: δ=17.01. Anal. calcd for C28H32NO7P: C,
63.99; H, 6.14; N, 2.67. Found: C, 64.19; H, 6.41; N, 2.36.
12: mp 110–111°C. [α]20=−33.3 (c=1.3, ethyl acetate); IR (KBr): ν=3394, 1750, 1645, 1523, 1265,
D
1030 cm−1; 1H NMR (250 MHz): δ=7.85–7.80 (m, 2H), 7.6–7.4 (m, 3H), 7.4–7.3 (m, 6H), 7.2–7.05 (m,
3H), 7.0–6.9 (m, 2H), 5.68 (dAB, JAB=3.8 Hz, JAP=10.0 Hz, 1H), 5.59 (ddAB, JAB=3.8 Hz, JBP=12.0
Hz, JB,H-N=8.3 Hz, 1H), 4.81 (s, 1H), 4.3–4.1 (m, 2H), 4.0–3.8 (m, 2H), 3.36 (s, 3H), 1.26 (t, J=7.1
Hz, 3H), 1.13 (t, J=7.1 Hz, 3H); 13C NMR: δ=168.68 (d, J=4.8 Hz), 166.08, 137.30 (d, J=9.4 Hz),
135.51, 133.94, 131.63, 129.05, 128.78, 128.56, 128.33, 127.66, 127.36, 127.11, 126.57, 82.30, 70.11
(d, J=165.8 Hz), 63.30 (d, J=6.6 Hz), 63.09 (d, J=7.3 Hz), 57.42, 52.66, 16.32 (d, J=5.6 Hz), 16.19
(d, J=6.0 Hz); 31P NMR: δ=17.54. Anal. calcd for C28H32NO7P: C, 63.99; H, 6.14; N, 2.67. Found: C,
64.00; H, 6.20; N, 2.64.
3.5. Diethyl (1R,2R)- and (1S,2S)-2-(benzoylamino)-1-hydroxy-2-phenylethylphosphonates 3
A solution of 11 (0.550 g, 1.05 mmol) in ethanol (7 ml) containing aqueous NH3 (25%, 6 ml) was
left at room temperature for 2 h. The volatiles were removed in vacuo and the residue was evaporated
with anhydrous ethanol (3×10 ml), chloroform (3×20 ml) and chromatographed on silica gel with ethyl
acetate:hexanes (2:1, v/v) containing methanol (0.1%). Appropriate fractions were recrystallized from
ethyl acetate–hexanes to give (1R,2R)-3 (0.274 g, 73%). Mp 157.5–158.0°C; [α]20=+35.1 (c=1.0, ethyl
D
acetate). Anal. calcd for C19H24NO5P: C, 60.47; H, 6.41; N, 3.71. Found: C, 60.40; H, 6.41; N, 3.49.
Following the same procedure, from 12 (0.430 g, 0.82 mmol) (1S,2S)-3 (0.252 g, 82%) was obtained.
Mp 156.5–157.0°C; [α]20=−37.7 (c=1.4, ethyl acetate). Anal. calcd for C19H24NO5P: C, 60.47; H, 6.41;
D
N, 3.71. Found: C, 60.62; H, 6.41; N, 3.61.
3.6. Determination of the optical purity of (1R,2R)-3 and (1S,2S)-3
To a solution of (−)-camphanyl chloride (14.0 mg, 0.065 mmol) and enantiomeric alcohols 3 (10.0
mg, 0.026 mmol) in chloroform-d (0.6 ml) NEt3 (14.0 µl, 0.10 mmol) was injected followed by one

A. E. Wróblewski, D. G. Piotrowska / Tetrahedron: Asymmetry 10 (1999) 2037–2043
2043
crystal of DMAP. The progress of the esterification was monitored by 31P NMR spectroscopy. The
phosphonates (1R,2R)-3 and (1S,2S)-3 were transformed into corresponding camphanates: δ31P=17.74
ppm and δ31P=17.54 ppm, respectively.
Acknowledgements
We thank Miss Dorota Starostka for the preliminary experiments in the synthesis of racemic 3 and
Mrs. Małgorzata Pluskota for her skilled experimental contributions. Financial support from the Medical
University of Łódz´ is gratefully acknowledged.
References
1. Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15–44.
2. Cardillo, G.; Tolomelli, A.; Tomasini, C. Eur. J. Org. Chem. 1999, 155–161.
3. Barboni, L.; Lambertucci, C.; Ballini, R.; Appendino, G.; Bombardelli E. Tetrahedron Lett. 1998, 39, 7177–7180.
4. Georg, G. I.; Harriman, G. C. B.; Vander Velde, D. G.; Boge, T. C.; Cheruvallath, Z. S.; Datta, A.; Hepperle, M.; Park,
H.; Himes, R. H.; Jayasinghe, L. Medicinal Chemistry of Paclitaxel; Georg, G. I.; Chen, T. T.; Oijma, I.; Vyas, P. M., Eds.
Taxane Anticancer Agents; ACS Symposium Series, 83, 1995; pp. 217–246.
5. Wróblewski, A. E.; Piotrowska, D. G. Tetrahedron 1998, 54, 8123–8132.
6. Gao, Y.; Hansom, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem Soc. 1987, 109,
5765–5780.
7. Wróblewski, A. E.; Piotrowska, D. G. unpublished results.
8. Bonner, W. A. J. Am. Chem. Soc. 1951, 73, 3126–3132.
9. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 4475–4478.
10. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M. J. Org. Chem. 1986, 51, 2370–2374.
11. Chataigner, I.; Lebreton, J.; Durand, D.; Guingant, A.; Villiéras, J. Tetrahedron Lett. 1998, 39, 1759–1762.
12. Seco, J. M.; Quinˇoá, E.; Riguera, R. Tetrahedron 1999, 55, 569–584.
13. Kozlowski, J. K.; Rath, N. P.; Spilling, C. D. Tetrahedron 1995, 51, 6385–6396.
14. Drescher, M.; Hammerschmidt, F.; Kählig, H. Synthesis 1995, 1267–1272.
15. Fringuelli, F.; Germani, R.; Pizzo, F.; Santinelli, F.; Saveli, G. J. Org. Chem. 1992, 57, 1198–1202.