A facile synthesis of novel chiral phosphonoacetates bearing a stereogenic phosphorus atom

Article abstract of DOI:10.1248/cpb.53.131

Novel chiral phosphonoacetates bearing a stereogenic phosphorus atom were successfully synthesized by enzyme-catalyzed kinetic resolution of racemic phosphonoacetates.

Full text of DOI:10.1248/cpb.53.131

January 2005
Notes
Chem. Pharm. Bull. 53(1) 131—134 (2005)
131
A Facile Synthesis of Novel Chiral Phosphonoacetates Bearing a
Stereogenic Phosphorus Atom
a
Shigeki SANO,*,a Eiko KUJIME,a Yuka TAKEMOTO,a Motoo SHIRO,b and Yoshimitsu NAGAO
a Graduate School of Pharmaceutical Sciences, The University of Tokushima; Sho-machi, Tokushima 770–8505, Japan:
and b Rigaku Corporation; 3–9–12 Matsubara-cho, Akishima, Tokyo 196–8666, Japan.
Received September 6, 2004; accepted October 23, 2004
Novel chiral phosphonoacetates bearing a stereogenic phosphorus atom were successfully synthesized by en-
zyme-catalyzed kinetic resolution of racemic phosphonoacetates.
Key words chiral phosphonoacetate; stereogenic phosphorus atom; kinetic resolution; enzymatic hydrolysis; porcine liver es-
terase; Horner–Wadsworth–Emmons reagent
Asymmetric Horner–Wadsworth–Emmons (HWE) reac- matic hydrolysis utilizing PLE (Sigma, E-2884), as follows.
tion of prochiral cyclic ketones is of current interest.1—4) Sev- Phosphonoacetates rac-3a—d were dissolved in 1/15 M phos-
eral useful chiral HWE reagents such as phosphonates,5—9) phate buffer solution (pH 7.4) and acetone (9 : 1). After addi-
phosphonoamides,10) and phosphonoamidates11) have been tion of PLE (800 units/mmol), the mixture was stirred at
developed for the synthesis of olefins possessing an axis of room temperature for the appropriate time. The reaction
chirality. However, most of these reagents are restricted to mixture was treated with 10% HCl and then extracted
the compounds with non-stereogenic phosphorus atom. Al- with AcOEt. After evaporation of the extraction in vacuo,
though Motoyoshiya et al. reported geometrical selectivity of the residue was purified on a silica gel column with
HWE reactions of aldehydes with racemic phosphonoac- CHCl3–MeOH as eluent to give the corresponding carboxylic
etates,12) the asymmetric HWE reaction of P-stereogenic acid 8 and unreacted ester 3. The enantiomeric excess of res-
phosphonoacetates has never been established. Herein we de- olution product 8 was determined by means of HPLC analy-
scribe a facile synthesis of novel chiral phosphonoacetates sis with chiral-stationary-phase (CSP) after methylation with
bearing a stereogenic phosphorus atom utilizing the enzyme- (trimethylsilyl)diazomethane (TMSCHN2).20) Unreacted res-
catalyzed kinetic resolution of racemic phosphonoacetates olution compound 3 was also subjected to HPLC analysis
derived from two kinds of Z-selective HWE reagents, methyl with CSP. As the result of enzymatic kinetic resolution, novel
bis(2,2,2-trifluoroehtyl)phosphonoacetate (Still’s reagent, P-stereogenic phosphonoacetates (S)-3a [ꢀ99% ee, 43%
1)13) and ethyl diphenylphosphonoacetate (2).14)
yield, colorless oil, [a]D19 ꢁ6.2° (cꢂ1.00, MeOH)], and (R)-
8a (82% ee, 53% yield, white powder) were successfully ob-
tained (Table 1, entry 1). The biochemical stereoselectivity
factor of this reaction is excellent (Eꢀ52).21,22) Recrystalliza-
Fig. 1. Z-Selective HWE Reagents
Recently, we reported a new and efficient stereoselective
HWE reaction of aldehydes and ketones with bis(2,2,2-triflu-
oroehtyl)phosphonoacetic acid and found oxophilicity of a
phosphorus atom of phosphonoacetate 1.15,16) That is to say,
the phosphonate moiety of 1 was found to be more easily hy-
drolyzed than the ester moiety of 1 under aqueous alkaline
conditions. Thus, the phosphonoacetic acid was readily pre-
pared by enzymatic hydrolysis of 1 with porcine liver es-
terase (PLE). Although attempts to hydrolyze the ester moi-
ety of 1 under aqueous alkaline conditions were unsuccess-
ful, reactions of 1 with various alcohols in the presence of
triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
gave the corresponding phosphonoacetate rac-3a—d as the
major product (Chart 1). The similar transformation of 2
using various alcohols gave rac-4a—d as shown in Chart 2.
Attempts to hydrolyze 2 under aqueous alkaline conditions
were also unsuccessful, though phosphonoacetates 4a and
5—7 were obtained (Chart 2). It can be concluded that the
high oxophilicity of phosphorus atoms of these HWE
reagents 1 and 2 appears to be necessary for Z-selective
HWE reaction with aldehydes.17—19)
Chart 1
The phosphonoacetates rac-3a—d were subjected to enzy-
Chart 2
© 2005 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: ssano@ph.tokushima-u.ac.jp

132
Vol. 53, No. 1
Table 1. PLE-Catalyzed Kinetic Resolution of rac-Phosphonoacetates 3 and 4
8 or 9
3 or 4
Recovery (%)
Reaction
time
Entry
R1
R2
R3
Ee)
Yield (%)
Ee (%)a,b)
Ee (%)b)
1
2
3
4
5
6
7
8
CF3CH2
CF3CH2
CF3CH2
CF3CH2
Ph
Ph
Ph
Ph
Me
Et
i-Pr
Bn
Me
Et
Me
Me
Me
Me
Et
Et
Et
Et
30 min
15 min
15 min
2 h
30 h
7 d
53 (8a)
60 (8b)
29 (8c)
72 (8d)
52 (9a)
53 (9b)
14 (9c)
39 (9d)
82 (R)
46
43 (3a)
27 (3b)
68 (3c)
21 (3d)
42 (4a)
46 (4b)
84 (4c)
55 (4d)
ꢀ99 (S)
84
ꢀ52
7
29a,c)
12
13c)
37
2
2
ꢀ39
17
1
77
ꢀ99
86
73
i-Pr
Bn
7 d
7 d
6a,d)
31
2d)
17
2
a) HPLC analysis after methylation with TMSCHN2. b) HPLC analysis (CHIRALCEL OD, n-hexane/2-propanol). c) HPLC analysis (CHIRALPAK AS-H, n-hexane/2-
propanol). d) HPLC analysis (CHIRALPAK AD-H, n-hexane/2-propanol). e) Eꢂbiochemical stereoselectivity factor, see ref. 21 and 22.
spectively, by alcoholysis with various alcohols in the pres-
ence of triethylamine or DBU. PLE-catalyzed kinetic resolu-
tion of rac-3a and rac-4a proceeded in a highly effective
manner to give the novel P-stereogenic phosphonoacetates.
Further work that explores applications of these P-stere-
ogenic phosphonoacetates as chiral HWE reagents is cur-
rently underway.
Fig. 2. Computer-Generated Drawing of (R)-8a
Selected distances (Å): P(1)–O(1) 1.590(3), P(1)–O(2) 1.562(3), P(1)–O(3) 1.467(3),
P(1)–C(1) 1.785(3), P(1)–O(4) 2.966(3).
Experimental
All melting points were determined on a Yanaco micro melting point ap-
paratus and are uncorrected. IR spectra were obtained using a JASCO
FT/IR-420 IR Fourier transform spectrometer. 1H-NMR (400 MHz) and 13C-
NMR (75 MHz) spectra were recorded on JEOL JNM-AL400 and JEOL
JNM-AL300 spectrometers, respectively. Chemical shifts are given in d val-
ues (ppm) using tetramethylsilane (TMS) as an internal standard. Electron
impact (EI)-MS were recorded on a JEOL JMS SX-102A spectrometer. Ele-
mentary combustion analyses were performed using a Yanaco CHN
CORDER MT-5. All reactions were monitored by TLC employing 0.25-mm
silica gel plates (Merck 5715; 60 F254). Preparative TLC (PTLC) was per-
formed on 0.5-mm silica gel plates (Merck 5744; 60 F254). Column chro-
matography was carried out on silica gel [Kanto Chemical 60N; 63—
210 mm or Nacalai Tesque 75SL-II-PREP; 75 mm]. The usual workup refers
to washing an organic portion with brine, drying it over anhydrous MgSO4,
filtration, and concentration in vacuo. Anhydrous THF, CH2Cl2, MeOH, and
i-PrOH were commercially obtained from Kanto Chemical. Anhydrous
tion of (R)-8a (82% ee) from n-hexane–Et2O gave (R)-8a
in an enantiomerically pure form [colorless plates, mp
63.0—64.0 °C, [a]D21 ꢃ5.8° (cꢂ1.00, MeOH)]. The absolute
configuration of (R)-8a was explicitly determined by its X-
ray crystallographic analysis as shown in Fig. 2.23) The inter-
esting feature of the structure is the existence of intra-
molecular sub-van der Waals contacts in (R)-8a. The
P(1)···O(4) distance [2.966(3) Å, 87% of SrvdW] is shorter
than the sum of their van der Waals radii [3.42 Å;
rvdW(P)ꢂ1.90 Å, rvdW(O)ꢂ1.52 Å].24,25) The enantioselectiv-
ity in the PLE-catalyzed hydrolysis of 3a may be explained
in accordance with the Jones active-site model by regarding EtOH and BnOH were commercially obtained from Wako Pure Chemical
Industry and Aldrich, respectively. All reagents were used as purchased.
Typical Procedure for the Preparation of Phosphonoacetates rac-3
Triethylamine (1.05 ml, 7.56 mmol) was added to a solution of methyl
bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (1.60 ml, 7.56 mmol) in anhy-
drous MeOH (40 ml) at 0 °C under argon. After being stirred at room tem-
perature for 30 min, the reaction mixture was treated with 10% HCl, concen-
trated in vacuo, and then extracted with AcOEt (60 mlꢄ3). The extract was
washed with brine (15 ml) and dried over anhydrous MgSO4. The organic
layer was evaporated in vacuo to afford an oily residue, which was purified
by chromatography on silica gel (Kanto Chemical 60N) column
[CHCl3/MeOH (20 : 1)] to give rac-3a (1.67 g, 88%) and methyl di-
methylphosphonoacetate (7) (0.10 g, 7%) as a colorless oil.
the trifluoroethoxy group as accommodating a large hy-
drophobic zone (HL), the methoxy group a small hydropho-
bic zone (HS), and phosphoryl oxygen a back polar zone (PB)
of the PLE active-site in the same manner as that proposed
⁄
by Kielbasin´ski et al. concerning a PLE-catalyzed hydrolysis
of phosphinylacetates, phosphonylacetaets, and sulfinylac-
etates.26—29)
Subsequently, we investigated the PLE-catalyzed kinetic
resolution of rac-4 and found it to work well for rac-4a.
Novel P-stereogenic phosphonoacetates 4a [ꢀ99% ee, 42%
yield, colorless oil, [a]D21 ꢁ10.2° (cꢂ1.00, MeOH)], and 9a
(77% ee, 52% yield, colorless oil) were successfully obtained
(Eꢀ39) as shown in Table 1 (entry 5). Unfortunately, the ab-
solute configurations of oily chiral compounds 4a and 9a
were not determined. For the preparation of P-stereogenic
HWE reagents, the E values of rac-3b—d and rac-4b—d
were insufficient.
Methyl Methyl(2,2,2-trifluoroethyl)phosphonoacetate (rac-3a): Colorless
1
2
oil; H-NMR (400 MHz, CDCl3) d: 3.07 (2H, d, JH,Pꢂ21.5 Hz), 3.77 (3H,
s), 3.84 (3H, d, 3JH,Pꢂ11.7 Hz), 4.43 (1H, dquint, 2JH,Hꢂ12.2 Hz, 3JH,Fꢂ
3JH,Pꢂ8.3 Hz), 4.51 (1H, dquint, 2JH,Hꢂ12.2 Hz, 3JH,Fꢂ3JH,Pꢂ8.3 Hz); 13C-
NMR (75 MHz, CDCl3) d: 33.6 (d, 1JC,Pꢂ140.8 Hz), 52.9 (s), 53.1
(d, 2JC,Pꢂ6.9 Hz), 62.9 (qd, 2JC,Fꢂ37.7 Hz, 2JC,Pꢂ5.3 Hz), 122.8 (qd,
1JC,Fꢂ277.4 Hz, 3JC,Pꢂ8.1 Hz), 165.7 (d, 2JC,Pꢂ5.0 Hz); IR (neat) 2964,
1743, 1264, 1174, 1094, 1041 cmꢁ1; EI-MS Calcd for C6H10O5F3P MW
250.0218, Found m/z 250.0216 (Mꢃ); Anal. Calcd for C6H10O5F3P: C,
28.81; H, 4.03. Found: C, 28.85; H, 3.98%.
In summary, racemic phosphonoacetates 3 and 4 were
readily prepared from Z-selective HWE reagents 1 and 2, re-
Methyl Ethyl(2,2,2-trifluoroethyl)phosphonoacetate (rac-3b): Colorless

January 2005
133
1
3
oil; H-NMR (400 MHz, CDCl3) d: 1.37 (3H, t, JH,Hꢂ7.1 Hz), 3.06 (2H, d, (400 MHz, CDCl3) d: 1.24 (3H, t, 3JH,Hꢂ7.1 Hz), 3.12 (2H, d, 2JH,Pꢂ
2JH,Pꢂ21.3 Hz), 3.76 (3H, s), 4.14—4.30 (2H, m), 4.35—4.56 (2H, m); 13C- 21.5 Hz), 4.18 (2H, q, 3JH,Hꢂ7.1 Hz), 5.19 (1H, dd, 2JH,Hꢂ11.7 Hz,
3
1
2
3
NMR (75 MHz, CDCl3) d: 16.2 (d, JC,Pꢂ6.2 Hz), 34.0 (d, JC,Pꢂ140.8 Hz),
52.8 (s), 62.8 (qd, 2JC,Fꢂ37.6 Hz, 2JC,Pꢂ5.0 Hz), 68.2 (d, 2JC,Pꢂ6.9 Hz),
3JH,Pꢂ8.3 Hz), 5.24 (1H, dd, JH,Hꢂ11.7 Hz, JH,Pꢂ8.8 Hz), 7.15—7.23 (3H,
m), 7.28—7.39 (7H, m); 13C-NMR (75 MHz, CDCl3) d: 14.0 (s), 34.3 (d,
122.8 (qd, JC,Fꢂ277.8 Hz, JC,Pꢂ8.4 Hz), 165.8 (d, JC,Pꢂ5.0 Hz); IR (neat) 1JC,Pꢂ136.4 Hz), 61.8 (s), 68.8 (d, 2JC,Pꢂ6.9 Hz), 120.6 (d, 3JC,Pꢂ4.4 Hz),
1
3
2
2989, 1744, 1263, 1172, 1093, 1035 cmꢁ1; EI-MS Calcd for C7H12F3O5P 125.3 (d, 5JC,Pꢂ1.3 Hz), 128.0 (s), 128.6 (s), 129.8 (s), 135.5 (d,
MW 264.0374, Found m/z 264.0356 (Mꢃ); Anal. Calcd for C7H12F3O5P: C,
3JC,Pꢂ6.9 Hz), 150.0 (d, 2JC,Pꢂ8.1 Hz), 165.2 (d, 2JC,Pꢂ6.2 Hz); IR (neat)
31.83; H, 4.58. Found: C, 31.85; H, 4.49%.
2983, 1737, 1592, 1490, 1278, 1203, 1117, 1024, 767, 740, 692 cmꢁ1; EI-
Methyl Isopropyl(2,2,2-trifluoroethyl)phosphonoacetate (rac-3c): Color- MS Calcd for C17H19O5P MW 334.0970, Found m/z 334.0962 (Mꢃ); Anal.
less oil; 1H-NMR (400 MHz, CDCl3) d: 1.35 (3H, d, 3JH,Hꢂ6.4 Hz), 1.37
(3H, d, 3JH,Hꢂ6.6 Hz), 3.04 (2H, d, 2JH,Pꢂ21.5 Hz), 3.76 (3H, s), 4.34—4.54
Calcd for C17H19O5P: C, 61.08; H, 5.73. Found: C, 61.01; H, 5.80%.
Methanolysis of Ethyl Diphenylphosphonoacetate (2) To a solution of
(2H, m), 4.77—4.90 (1H, m); 13C-NMR (75 MHz, CDCl3) d: 23.76 (d, ethyl diphenylphosphonoacetate (2) (122 mg, 0.38 mmol) in MeOH (0.38
3JC,Pꢂ4.4 Hz) or 23.77 (d, 3JC,Pꢂ5.6 Hz), 23.84 (d, 3JC,Pꢂ5.0 Hz) or 23.83
ml) was added aqueous 1 N NaOH (0.38 ml) at 0 °C. After being stirred at
(d, 3JC,Pꢂ6.2 Hz), 34.4 (d, 1JC,Pꢂ140.8 Hz), 52.8 (s), 62.7 (qd, 2JC,Fꢂ37.4 room temperature for 40 min, the reaction mixture was treated with 5% HCl
Hz, 2JC,Pꢂ5.0 Hz), 72.8 (d, 2JC,Pꢂ7.5 Hz), 122.8 (qd, 1JC,Fꢂ277.8 Hz, and then extracted with AcOEt (15 mlꢄ5). The extract was submitted to the
3JC,Pꢂ8.6 Hz), 165.9 (d, 2JC,Pꢂ5.0 Hz); IR (neat) 2986, 1745, 1263, 1173, usual workup to give an oily residue, which was purified by column chro-
1090, 1009 cmꢁ1; EI-MS Calcd for C8H13F3O5P 277.0453, Found m/z
matography on silica gel (Kanto Chemical N60) [n-hexane/AcOEt (1 : 1 to
277.0439 (MꢃꢁH); Anal. Calcd for C8H14F3O5P: C, 34.54; H, 5.07. Found: 1 : 2) to CHCl3/MeOH (20 : 1)] to afford rac-4a (6.5 mg, 7%), rac-5
C, 34.48; H, 4.92%.
(30.0 mg, 32%), 6 (1.8 mg, 2%), and 7 (9.0 mg, 13%).
Methyl Benzyl(2,2,2-trifluoroethyl)phosphonoacetate (rac-3d): Colorless
Methyl Methylphenylphosphonoacetate (rac-5): Colorless oil; 1H-NMR
oil; 1H-NMR (400 MHz, CDCl3) d: 3.06 (2H, d, 2JH,Pꢂ21.2 Hz), 3.73 (400 MHz, CDCl3) d: 3.13 (2H, d, 2JH,Pꢂ21.7 Hz), 3.76 (3H, s), 3.89 (3H, d,
(3H, s), 4.25—4.45 (2H, m), 5.13 (1H, dd, 2JH,Hꢂ11.6 Hz, 3JH,Pꢂ8.5 Hz),
3JH,Pꢂ11.5 Hz), 7.16—7.28 (3H, m), 7.31—7.39 (2H, m); 13C-NMR
5.18 (1H, dd, 2JH,Hꢂ11.6 Hz, 3JH,Pꢂ10.0 Hz), 7.34—7.43 (5H, m); 13C- (75 MHz, CDCl3) d: 33.4 (d, 1JC,Pꢂ137.0 Hz), 52.8 (s), 53.8 (d,
NMR (75 MHz, CDCl3) d: 34.1 (d, 1JC,Pꢂ140.8 Hz), 52.8 (s), 62.7
(qd, 2JC,Fꢂ37.7 Hz, 2JC,Pꢂ5.3 Hz), 68.4 (d, 2JC,Pꢂ6.9 Hz), 122.7 (qd,
1JC,Fꢂ277.8 Hz, 3JC,Pꢂ8.1 Hz), 128.2 (s), 128.8 (s), 128.9 (s), 135.3 (d,
2JC,Pꢂ6.9 Hz), 120.5 (d, 3JC,Pꢂ4.4 Hz), 125.4 (d, 5JC,Pꢂ1.3 Hz), 129.8 (s),
150.0 (d, 2JC,Pꢂ8.1 Hz), 165.2 (d, 2JC,Pꢂ6.2 Hz) ; IR (neat) 2956, 1741,
1592, 1490, 1279, 1203, 1042, 768, 691 cmꢁ1; EI-MS Calcd for C11H15O5P
3JC,Pꢂ6.2 Hz), 165.6 (d, 2JC,Pꢂ5.0 Hz); IR (neat) 2959, 1743, 1498, 1265, MW 244.0501, Found m/z 244.0501 (Mꢃ); Anal. Calcd for C11H15O5P: C,
1173, 1093, 1013, 698 cmꢁ1; EI-MS Calcd for C12H14F3O5P MW 326.0531, 49.19; H, 5.37. Found: C, 49.04; H, 5.22%.
Found m/z 326.0533 (Mꢃ); Anal. Calcd for C12H14F3O5P: C, 44.18; H, 4.33.
Found: C, 44.18; H, 4.25%.
Ethyl Dimethylphosphonoacetate (6):30) Colorless oil; 1H-NMR (400
MHz, CDCl3) d: 1.29 (3H, t, 3JH,Hꢂ7.1 Hz), 2.98 (2H, d, 2JH,Pꢂ21.5
3
3
Typical Procedure for the Preparation of Phosphonoacetates rac-4
Hz), 3.82 (6H, d, JH,Pꢂ11.2 Hz), 4.21 (2H, q, JH,Hꢂ7.1 Hz); 13C-NMR (75
Anhydrous MeOH (0.79 ml, 19.51 mmol) and DBU (0.58 ml, 3.90 mmol) MHz, CDCl3) d: 14.1 (s), 33.4 (d, 1JC,Pꢂ135.1 Hz), 53.2 (d, 2JC,Pꢂ
were added to a solution of ethyl diphenylphosphonoacetate (2) (1.25 g,
6.2 Hz), 61.7 (s), 165.7 (d, 2JC,Pꢂ5.6 Hz).
3.90 mmol) and molecular sieves 3A (1.2 g) in anhydrous THF (30 ml) at
Methyl Dimethylphosphonoacetate (7):31) Colorless oil; 1H-NMR (400
room temperature under argon. After being stirred at room temperature for MHz, CDCl3) d: 3.00 (2H, d, 2JH,Pꢂ21.7 Hz), 3.76 (3H, s), 3.82 (6H, d,
3 h, the reaction mixture was treated with 5% HCl and then extracted with
3JH,Pꢂ11.2 Hz); 13C-NMR (75 MHz, CDCl3) d: 33.2 (d, 1JC,Pꢂ135.1 Hz),
AcOEt (70 mlꢄ3). The extract was washed with brine (20 ml) and dried over 52.7 (s), 53.2 (d, 2JC,Pꢂ6.2 Hz), 166.1 (d, 2JC,Pꢂ6.2 Hz).
anhydrous MgSO4. The organic layer was evaporated in vacuo to afford an
Typical Procedure for PLE-Catalyzed Kinetic Resolution of Phospho-
oily residue, which was purified by chromatography on silica gel (Kanto noacetates PLE (Sigma; E-2884, 224 units, 800 units/mmol) was added to
Chemical 60N) column [n-hexane/AcOEt (1 : 1 to 1 : 2)] to give rac-4a a stirred solution of methyl methyl(2,2,2-trifluoroethyl)phosphonoacetate
(768 mg, 76%) and trace amount of ethyl dimethylphosphonoacetate (6) as a
(rac-3a) (70 mg, 0.28 mmol) in 1/15 M phosphate buffer (pH 7.4, 9 ml) and
colorless oil.
acetone (1 ml) at room temperature. After being stirred at room temperature
Ethyl Methylphenylphosphonoacetate (rac-4a): Colorless oil; 1H-NMR for 30 min, the reaction mixture was treated with 10% HCl (10 ml) and then
(400 MHz, CDCl3) d: 1.28 (3H, t, 3JH,Hꢂ7.1 Hz), 3.12 (2H, d, 2JH,Pꢂ extracted with AcOEt (40 mlꢄ5). The extract was washed with brine (20 ml)
21.7 Hz), 3.89 (3H, d, 3JH,Pꢂ11.2 Hz), 4.22 (2H, q, 3JH,Hꢂ7.1 Hz), 7.16— and dried over anhydrous MgSO4. The organic layer was evaporated in
7.28 (3H, m), 7.32—7.38 (2H, m); 13C-NMR (75 MHz, CDCl3) d: 14.1 vacuo to afford an oily residue, which was purified by chromatography on
(s), 33.7 (d, 1JC,Pꢂ136.4 Hz), 53.8 (d, 2JC,Pꢂ6.2 Hz), 61.9 (s), 120.5 (d,
3JC,Pꢂ4.4 Hz), 125.3 (d, 5JC,Pꢂ1.3 Hz), 129.8 (s), 150.1 (d, 2JC,Pꢂ8.7 Hz),
silica gel (Nacalai Tesque 75SL-II-PREP) column [CHCl3/MeOH (20 : 1)] to
give (S)-3a (30.2 mg, 43%, ꢀ99% ee) as colorless oil and (R)-8a (35.0 mg,
165.2 (d, 2JC,Pꢂ5.6 Hz); IR (neat) 2984, 1736, 1592, 1490, 1279, 1203, 53%) as a white powder. To the solution of (R)-8a in MeOH (1 ml) and ben-
1118, 1042, 768, 691 cmꢁ1; EI-MS Calcd for C11H15O5P MW 258.0657, zene (3.5 ml) was added an excess amount of TMSCHN2 (2.0 mol/l solution
Found m/z 258.0654 (Mꢃ); Anal. Calcd for C11H15O5P: C, 51.17; H, 5.86. in n-hexane, ca. 0.3 ml, ca. 0.6 mmol). After being stirred at room tempera-
Found: C, 50.88; H, 5.92%.
Ethyl Ethylphenylphosphonoacetate (rac-4b): Colorless oil; 1H-NMR crude product, which was purified by chromatography on a silica gel (Kanto
(400 MHz, CDCl3) d: 1.28 (3H, t, 3JH,Hꢂ7.1 Hz), 1.34 (3H, t, 3JH,Hꢂ7.1 Hz),
Chemical 60N) column [CHCl3/MeOH (20 : 1)], giving (R)-3a (35.2 mg,
ture for 30 min, the reaction mixture was evaporated in vacuo to afford a
3.10 (2H, d, 2JH,Pꢂ21.7 Hz), 4.17—4.36 (4H, m), 7.15—7.28 (3H, m), 95%, 82% ee) as a colorless oil. Recrystallization of (R)-8a (82% ee) from
7.31—7.38 (2H, m); 13C-NMR (75 MHz, CDCl3) d: 14.1 (s), 16.3 (d,
3JC,Pꢂ6.2 Hz), 34.2 (d, 1JC,Pꢂ136.4 Hz), 61.8 (s), 63.7 (d, 2JC,Pꢂ6.2 Hz),
120.6 (d, 3JC,Pꢂ4.4 Hz), 125.3 (d, 5JC,Pꢂ1.2 Hz), 129.8 (s), 150.1 (d,
n-hexane–Et2O gave (R)-8a as an enantiomerically pure form.
(R)-Methyl(2,2,2-trifluoroethyl)phosphonoacetic Acid [(R)-8a] (ꢀ99%
ee): Colorless plates, mp 63.0—64.0 °C (Et2O–n-hexane); [a]D21 ꢃ5.8°
2JC,Pꢂ8.1 Hz), 165.3 (d, 2JC,Pꢂ6.2 Hz); IR (neat) 2984, 1738, 1593, 1490, (cꢂ1.00, MeOH); 1H-NMR (400 MHz, CDCl3) d: 3.10 (2H, d, 2JH,Pꢂ
1277, 1204, 1117, 1036, 768, 691 cmꢁ1; EI-MS Calcd for C12H17O5P MW 21.5 Hz), 3.85 (3H, d, 3JH,Pꢂ11.5 Hz), 4.44 (1H, dquint, 2JH,Hꢂ12.3 Hz,
272.0814, Found m/z 272.0815 (Mꢃ); Anal. Calcd for C12H17O5P: C, 52.94; 3JH,Fꢂ3JH,Pꢂ8.3 Hz), 4.60 (1H, dquint, 2JH,Hꢂ12.3 Hz, 3JH,Fꢂ3JH,Pꢂ
1
H, 6.29. Found: C, 52.66; H, 6.34%.
8.3 Hz), 8.43 (1H, bs); 13C-NMR (75 MHz, CDCl3) d: 33.4 (d, JC,Pꢂ142.0
1
Ethyl Isopropylphenylphosphonoacetate (rac-4c): Colorless oil; H-NMR Hz), 53.5 (d, 2JC,Pꢂ6.9 Hz), 63.3 (qd, 2JC,Fꢂ37.7 Hz, 2JC,Pꢂ5.3 Hz),
3
(400 MHz, CDCl3) d: 1.25—1.31 (6H, m), 1.38 (3H, d, JH,Hꢂ6.1 Hz), 3.08
122.8 (qd, 1JC,Fꢂ277.4 Hz, 3JC,Pꢂ8.1 Hz), 167.4 (d, 2JC,Pꢂ4.4 Hz);
IR (KBr) 2981, 2685, 2579, 1726, 1305, 1293, 1226, 1166, 1105, 1047
(2H, d, 2JH,Pꢂ21.5 Hz), 4.21 (2H, q, 3JH,Hꢂ7.2 Hz), 4.82—4.95 (1H, m),
7.15—7.28 (3H, m), 7.31—7.37 (2H, m); 13C-NMR (75 MHz, CDCl3) d: cmꢁ1; EI-MS Calcd for C5H8F3O5P MW 236.0061, Found m/z 236.0038
14.1 (s), 23.79 (d, 3JC,Pꢂ5.0 Hz), 23.85 (d, 3JC,Pꢂ3.1 Hz), 34.7 (d,
1JC,Pꢂ136.4 Hz), 61.7 (s), 72.9 (d, 2JC,Pꢂ6.9 Hz), 120.7 (d, 3JC,Pꢂ4.4 Hz),
125.2 (d, 5JC,Pꢂ1.2 Hz), 129.7 (s), 150.2 (d, 2JC,Pꢂ8.1 Hz), 165.4 (d,
(Mꢃ); Anal. Calcd for C5H8F3O5P: C, 25.44; H, 3.42. Found: C, 25.54;
H, 3.26%.
(R)-Methyl
Methyl(2,2,2-trifluoroethyl)phosphonoacetate
[(R)-3a]
2JC,Pꢂ6.2 Hz); IR (neat) 2982, 1739, 1593, 1491, 1277, 1205, 1118, 999, (ꢀ99% ee): Colorless oil; [a]D20 ꢃ6.3° (cꢂ1.00, MeOH); Anal. Calcd for
768, 691 cmꢁ1; EI-MS Calcd for C13H19O5P MW 286.0970, Found m/z C6H10F3O5P: C, 28.81; H, 4.03. Found: C, 28.89; H, 3.96%.
286.0961 (Mꢃ); Anal. Calcd for C13H19O5P: C, 54.54; H, 6.69. Found: C,
(R)-Methyl Methyl(2,2,2-trifluoroethyl)phosphonoacetate [(R)-3a] (82%
ee): Colorless oil; [a]D25 ꢃ6.0° (cꢂ0.50, MeOH); Anal. Calcd for
54.62; H, 6.59%.
Ethyl Benzylphenylphosphonoacetate (rac-4d): Colorless oil; 1H-NMR C6H10F3O5P: C, 28.81; H, 4.03. Found: C, 28.92; H, 4.01%.

134
Vol. 53, No. 1
[http://www.arkat-usa.org/ark/journal/2003/Fukumoto/KF-777H/KF-
777H.asp].
16) Sano S., Takemoto Y., Nagao Y., Tetrahedron Lett., 44, 8853—8855
(2003).
17) Brandt P., Norrby P.-O., Martin I., Rein T., J. Org. Chem., 63, 1280—
1289 (1998).
(S)-Methyl Methyl(2,2,2-trifluoroethyl)phosphonoacetate [(S)-3a] (ꢀ99%
ee): Colorless oil; [a]D19 ꢁ6.2° (cꢂ1.00, MeOH); Anal. Calcd for
C6H10O5F3P: C, 28.81; H, 4.03. Found: C, 28.86; H, 3.78%.
(ꢁ)-Ethyl Methylphenylphosphonoacetate [(ꢁ)-4a] (ꢀ99% ee): Colorless
oil; [a]D21 ꢁ10.2° (cꢂ1.00, MeOH); Anal. Calcd for C11H15O5P: C, 51.17; H,
5.86. Found: C, 51.35; H, 5.85%.
18) Norrby P.-O., Brandt P., Rein T., J. Org. Chem., 64, 5845—5852
(1999).
19) Ando K., J. Org. Chem., 64, 6815—6821 (1999).
20) Shioiri T., Aoyama T., J. Synth. Org. Chem., Jpn., 44, 149—159
(1986).
HPLC analyses were performed using a JASCO PU-980 apparatus
equipped with a JASCO UN/VIS detector, using the following columns.
CHIRALCEL OD (Daicel Chemical Industries, 0.46 cm i.d.ꢄ25 cm), eluent:
n-hexane/2-propanolꢂ5/1, flow rate: 1.0 ml/min, detection: 220 nm, tR of
(R)-(ꢃ)-3a: 8.57 min, (S)-(ꢁ)-3a: 10.18 min, (ꢃ)-3b: 5.71 min, (ꢁ)-3b:
7.04 min. CHIRALCEL OD (Daicel Chemical Industries, 0.46 cm i.d.
ꢄ25 cm), eluent: n-hexane/2-propanolꢂ9/1, flow rate: 1.0 ml/min, detection:
254 nm, tR of (ꢁ)-4a: 12.86 min, (ꢃ)-4a: 18.39 min.
21) Chen C.-S., Fujimoto Y., Girdaukas G., Sih C. J., J. Am. Chem. Soc.,
104, 7294—7299 (1982).
22) Sih C. J., Wu S.-H., Top. Stereochem., 19, 63—125 (1989).
23) Crystal data for (R)-8a: C5H8F3O5P, Mꢂ236.08, monoclinic, P21 (No.
4), aꢂ5.691(2) Å, bꢂ6.037(3) Å, cꢂ13.991(5) Å, bꢂ99.88(2) °, Vꢂ
Acknowledgement This work was partially supported by a Grant-in-
Aid for Scientific Research (C) from the Japan Society for the Promotion of
Science.
473.5(3) Å3, Tꢂ113 K, Zꢂ2, Dcalcꢂ1.656 gcmꢁ3, m(Cu-Ka)ꢂ31.09 cmꢁ1
.
Of the 5055 reflections that were collected, 1600 were unique
(Rintꢂ0.052); equivalent reflections were merged. WR2ꢂ0.118. The ab-
solute structure was correctly indicated by the Flack parameter being
zero within the range of experimental error [0.01(4)]. Crystallographic
data have been deposited with the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK, and copies of the
data can be obtained on request, free of charge, by quoting the publica-
tion citation and the deposition number 244418 [(R)-8a].
References and Notes
1) Rein T., Reiser O., Acta Chem. Scand., 1996, 369—379 (1996).
2) Sano S., Yakugaku Zasshi, 120, 432—444 (2000).
3) Sano S., Yokoyama K., Teranishi R., Shiro M., Nagao, Y., Tetrahedron
Lett., 43, 281—284 (2002).
4) Rein T., Pedersen T. M., Synthesis, 2002, 579—594 (2002).
5) Tömösközi I., Janzsó G., Chem. Ind., 1962, 2085—2086 (1962).
6) Narasaka K., Hidai E., Hayashi Y., Gras J.-L., J. Chem. Soc., Chem.
Commun., 1993, 102—104 (1993).
7) Abiko A., Masamune S., Tetrahedron Lett., 37, 1077—1080 (1996).
8) Tanaka K., Otsubo K., Fuji K., Tetrahedron Lett., 37, 3735—3738
(1996).
9) Sano S., Teranishi R., Nakano F., In K., Takeshige H., Ishii T., Shiro
M., Nagao Y., Heterocycles, 59, 793—804 (2003).
24) Nagao Y., Hirata T., Goto S., Sano S., Kakehi A., Iizuka K., Shiro M.,
J. Am. Chem. Soc., 120, 3104—3110 (1998).
25) Kilian P., Slawin A. M. Z., Woollins J. D., Dalton Trans., 2003,
3876—3885 (2003).
26) Toone E. J., Werth M. J., Jones J. B., J. Am. Chem. Soc., 112, 4946—
4952 (1990).
˙
⁄
⁄
27) Kielbasin´ski P., Zurawin´ski R., Pietrusiewicz K. M., Zablocka M.,
⁄
Mikolajczyk M., Polish J. Chem., 72, 564—572 (1998).
⁄
⁄
28) Kielbasin´ski P., Góralczyk P., Mikolajczyk M., Wieczorek M. W., Ma-
10) Hanessian S., Beaudoin S., Tetrahedron Lett., 33, 7655—7658 (1992).
11) Denmark S. E., Chen C.-T., J. Am. Chem. Soc., 114, 10674—10676
(1992).
jzner W. R., Tetrahedron: Asymmetry, 9, 2641—2650 (1998).
⁄
29) Kielbasin´ski P., Tetrahedron: Asymmetry, 11, 911—915 (2000).
30) Compound 6 is commercially available. Zhou W., Jiang B., Pan X.,
Tetrahedron, 46, 3173—3188 (1990).
12) Motoyoshiya J., Kusaura T., Kokin K., Yokoya S., Takaguchi Y., Narita
S., Aoyama H., Tetrahedron, 57, 1715—1721 (2001).
13) Still W. C., Gennari C., Tetrahedron Lett., 24, 4405—4408 (1983).
14) Ando K., Tetrahedron Lett., 36, 4105—4108 (1995).
15) Sano S., Takemoto Y., Nagao Y., Arkivoc, 2003, 93—101 (2003)
31) Compound
7 is commercially available. Fieser M., Fieser L.,
“Reagents for Organic Synthesis,” Vol. 2, John Wiley & Sons, New
York, 1969, p. 442.