Sharpless asymmetric dihydroxylation of trans-propenylphosphonate by using a modified AD-mix-α and the synthesis of fosfomycin

Full text of DOI:10.1021/jo010701u

J . Org. Chem. 2001, 66, 7903-7906
7903
Sch em e 1
Sh a r p less Asym m etr ic Dih yd r oxyla tion of
tr a n s-P r op en ylp h osp h on a te by Usin g a
Mod ified AD-m ix-r a n d th e Syn th esis of
F osfom ycin
Yuichi Kobayashi,* Anthony D. William, and
Yuko Tokoro
Department of Biomolecular Engineering,
Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8501, J apan
ykobayas@bio.titech.ac.jp
Received J uly 11, 2001
Fosfomycin (1) is not only a naturally occurring orga-
nophosphonic acid isolated from fermentation broths
of Streptomyces fradiae1 but also a component of fos-
fadecin (2) isolated recently from the culture filtrates
of Pseudomonas viridiflava PK-5.2 Both of these pro-
ducts are antibiotics against Gram-negative and Gram-
positive bacteria. Due to its excellent properties as a
drug, fosfomycin is manufactured by a method that
involves epoxidation of the corresponding (E)-1-prope-
nylphosphonate and optical resolution of the resulting
racemic epoxide.3 However, a method that does not rely
upon such resolution is desirable. Several syntheses of
optically active fosfomycin along this idea have been
published recently.4 The key reactions used in these
syntheses are asymmetric hydrogenation of â-oxo-R-
bromopropylphosphonate,5a bromohydroxylation of a chiral
1-propenylphosphonate,5b addition of (TMSO)P(OR)2 or
HP(dO)(OR)2 to R-alkoxy propanal,5c-e reduction of an
R-oxo-â-acyloxypropylphosphonate,5f and microbial epoxid-
ation.5g In addition to fosfomycin, analogues probably
synthesized by these methods would be useful to start a
biochemical study of fosfadecin. These methods, however,
suffer from low enantio-(or diastereo-)selectivity, produc-
tion of byproduct(s), and/or insufficient efficiency.
reaction of 3 and subsequent monosulfonylation of the
resulting diol 4 at either the R- or â-side of the hydroxyl
groups. High regioselection in the latter step is pivotal
to transfer the enantiomeric purity of 4 into the epoxide
moiety of 1. The stereochemistry of 4 tentatively drawn
in Scheme 1 assumes the sulfonylation at the R side.
Investigation of the literature revealed that diethyl
phosphonate 3a (R ) Et), investigated for the other
purposes, is a poor substrate for the AD reaction even
though the loading of the osmium catalyst and/or the
chiral ligand ((DHQ)2PHAL) in the AD reagent is in-
creased from the original.8-11 On the other hand, regi-
oselective sulfonylation of 4 is less predictable by the fact
that silyation of R,â-dihydroxyalkylphosphonates prefers
the â side,12 while sulfonylation of R,â-dihydroxyal-
kanoates prefers the R side,13 respectively. However, the
proposed short-step method (Scheme 1) was attractive
enough for us to reinvestigate the AD reaction of 3 and
(5) (a) Kitamura, M.; Tokunaga, M.; Noyori, R. J . Am. Chem. Soc.
1995, 117, 2931-2932. (b) Giordano, C.; Castaldi, G. J . Org. Chem.
1989, 54, 1470-1473. (c) Hammerschmidt, F. Liebigs Ann. Chem. 1991,
469-475. (d) Bandini, E.; Martelli, G.; Spunta, G.; Panunzio, M.
Tetrahedron: Asymmetry 1995, 6, 2127-2130. (e) Oshikawa, T.;
Yamashita, K. J pn. Kokai Tokkyo Koho J P 07,324,092; Chem. Abstr.
1996, 124, 232132b. (f) Castaldi, G.; Giordano, C. Eur. Pat. Appl, EP
299,484; Chem. Abstr. 1989, 111, 57412a. (g) Itoh, N.; Kusaka, M.;
Hirota, T.; Nomura, A. Appl. Microbiol. Biotechnol. 1995, 43, 394-
401.
(6) (a) Kobayashi, Y.; Nakayama, Y.; Yoshida, S. Tetrahedron Lett.
2000, 41, 1465-1468. (b) Kobayashi, Y.; Nakano, M.; Kumar, G. B.;
Kishihara, K. J . Org. Chem. 1998, 63, 7505-7515.
(7) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G.
A.; Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-
M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992, 57, 2768-2771. (b) Kolb,
H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94,
2483-2547.
Our recent research work6 using the Sharpless asym-
metric dihydroxylation (AD) reaction7 inspired a method
illustrated in Scheme 1. The key reactions are the AD
(8) Original stoichiometries for K2OsO2(OH)2 and the chiral ligand
are 0.2 and 1 mol %, respectively. Shibuya9 added K2OsO2(OH)2 (0.8
mol %) in AD-mix-R (from Aldrich) to obtain diol 4a (R ) Et) with
33% ee in 48% yield from 3a (R ) Et) after 2 days at 25 °C, while
Lohray10 increased concentration of OsO4 and (DHQ)2PHAL to 1 and
2 mol % to obtain the same diol with 32% ee in 45% yield.
(9) (a) Yokomatsu, T.; Yoshida, Y.; Suemune, K.; Yamagishi, T.;
Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 365-368. (b) Yokomatsu,
T.; Yamagishi, T.; Suemune, K.; Yoshida, Y.; Shibuya, S. Tetrahedron
1998, 54, 767-780.
(1) (a) Hendlin, D.; Stapley, E. O.; J ackson, M.; Wallick, H.; Miller,
A. K.; Wolf, F. J .; Miller, T. W.; Chaiet, L.; Kahan, F. M.; Foltz, E. L.;
Woodruff, H. B.; Mata, J . M.; Hernandez, S.; Mochales, S. Science 1969,
166, 122-123. (b) Christensen, B. G.; Leanza, W. J .; Beattie, T. R.;
Patchett, A. A.; Arison, B. H.; Ormond, R. E.; Kuehl, F. A., J r.; Albers-
Schonberg, G.; J ardetzky, O. Science 1969, 166, 123-125.
(2) Katayama, N.; Tsubotani, S.; Nozaki, Y.; Harada, S.; Ono, H. J .
Antibiot. 1990, 43, 238-246.
(3) (a) Glamkowski, E. J .; Gal, G.; Purick, R.; Davidson, A. J .;
Sletzinger, M. J . Org. Chem. 1970, 35, 3510-3512. (b) Slates, H. L.;
Wendler, N. L. Chem. Ind. 1978, 430-431.
(4) Reviews: (a) Iorga, B.; Eymery, F.; Savignac, P. Synthesis 1999,
207-224. (b) Fields, S. C. Tetrahedron 1999, 55, 12237-12273.
(10) Lohray, B. B.; Maji, D. K.; Nandanan, E. Indian J . Chem. 1995,
34B, 1023-1025.
(11) AD reaction of vinylphosphonate derivatives of uridine and
cytidine: J ung, K.-Y.; Hohl, R. J .; Wiemer, A. J .; Wiemer, D. F. Bioorg.
Med. Chem. 2000, 8, 2501-2509.
(12) Yokomatsu, T.; Suemune, K.; Yamagishi, T.; Shibuya, S. Synlett
1995, 847-849.
10.1021/jo010701u CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/23/2001

7904 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Ta ble 1. AD Rea ction of 3b a n d 3a a
Ta ble 2. Su lfon yla tion of Diol 4b
sub-
entry strate
T
time
yield
%
Ar of ArSO2Cl
(equiv)
amine
(equiv)
T
time
reagent
(°C) (days) productb (%) eec
entry
(°C) (h)
yield of 5a
1
2
3
4
3b
3b
3b
3a
AD-mix-Rd
rt
8
5
6
4b
4b
4b
4a
<30 62
51 72
95 78
1
2
3
4
5
4-Me-C6H4 (1.3)
4-Me-C6H4 (1.3)
4-Me-C6H4 (1.3)
4-Me-C6H4 (1.7)
Et3N (1.8)
pyridine (1.8) rt
i-Pr2NEt (1.8) rt
Et3N (2.0)
rt
41 5a (28%)b
73 no reaction
73 no reaction
53 5a (49%)b
30 5b (> 67%)c
AD-mix-R-(x 3)e rt
AD-mix-R-(x 3)e
AD-mix-R-(x 3)e
0
0
10
62
-
5
5
4-NO2-C6H4 (1.3) Et3N (1.8)
a
b
3b: R ) Bn. 3a : R ) Et. 4b: R ) Bn. 4a : R ) Et.
a
c Calculated by 1H NMR spectroscopy of the corresponding bis-
5a : R ) Bn, Ar ) 4-Me-C6H4 for entries 1-4. 5b: R ) Bn, Ar
d
b
MTPA ester. Prepared according to ref 7a. e Three times stan-
) 4-NO2C6H4 for entry 5. In addition to 5a , ditosylate 8 and diol
dard quantity of K2OsO2(OH)4 and (DHQ)2PHAL (0.6 and 3.0 mol
%, respectively) were used.
4b were isolated. c Yield of 6 from 4b via 5b was 67%.
3 mol %, respectively, were loaded on a mixture of K3-
Fe(CN)6 (3 equiv) and K2CO3 (3 equiv) to give AD-mix-
R-(×3). The modified reagent thus prepared not only
accelerated the reaction (Table 1, entry 2) but also
allowed the reaction to proceed at a lower temperature
(0 °C), providing better ee (Table 1, entry 3). Enantio-
meric purity of 4b thus obtained was increased to >99%
ee by recrystallization from hexane/EtOAc in 65% yield.
Next, AD reaction of diethyl phosphonate 3a with the
modified reagent was examined. However, the reaction
was not remarkably accelerated and the yield of 4a was
moderate even after 10 days (Table 1, entry 4).
to explore the other steps. In this paper, we present
successful results with a modified AD reagent and the
synthesis of fosfomycin.
We envisioned that the inefficiency of the above AD
reaction of diethyl phosphonate 3a (R ) Et) arises mainly
from a lack of the lipophilic part in molecule 3a , which
is a necessary part to be trapped into the cavity of the
chiral ligand. Thus, dibenzyl derivative 3b (R ) Bn) was
chosen as an alternative substrate for AD reaction.
Phosphonate 3b was once synthesized by a rather
tedious method because a simpler method through a
base-catalyzed isomerization of dibenzyl 2-propenylphos-
phonate, the reaction originally reported for diethyl
phosphonate,14 was unsuccessful.15 Among the other
methods published,3,16 the palladium-catalyzed reaction16a
of alkenyl halides and dialkyl phosphite (HP(dO)(OR)2)
was investigated. Phosphonate 3b was obtained from (E)-
1-propenyl bromide (7) and HP(dO)(OBn)2 in moderate
yield (52%) under the reported conditions (Pd(PPh3)4 (5
mol %), Et3N (1 equiv), toluene, 90 °C, 6 h). Although
use of i-Pr2NEt as a base did not improve the yield,
reaction in THF at 60 °C furnished 3b in 94% yield (eq
1). Under similar conditions, 3a was prepared from 7 and
HP(dO)(OEt)2 in good yield.
Regioselective sulfonylation of diol 4b (R ) Bn) and
subsequent transformation to 1 was then investigated.
In this particular case, steric hindrance around the diol
moiety (Me vs phoshonate group) seems to prefer sulfo-
nylation at the â-hydroxyl group, and the electron-
withdrawing nature of the phosphonate group vice versa
on the basis of the related reactions.11-13 With these
tendencies in mind, sulfonylation with MsCl, TsCl, or
4-NO2C6H4SO2Cl was examined. Mesylation was margin-
ally regioselective (data not shown). On the other hand,
tosylation at room temperature took place regioselectively
at the R-hydroxyl group to furnish 5 of R ) Bn, Ar )
4-MeC6H4 (Table 2, entry 1). However, more than a small
quantity of ditosylation product 8 was detected by TLC
analysis before 4b was consumed completely. Reaction
proceeded little with other bases, and 4b was recovered
quantitatively (Table 2, entries 2 and 3), while use of a
larger quantity of TsCl and a lower temperature of 5 °C
(in a refrigerator) improved the yield to 49% (Table 2,
entry 4), though substantial formation of 8 was still
accompanied with monotosylate 5 and diol 4b. Efficiency
of this transformation was enhanced with 4-NO2C6H4-
SO2Cl. After 30 h at the same temperature (5 °C), TLC
analysis showed no diol 4b, major production of mono-
sulfonate 5 (R ) Bn, Ar ) 4-NO2C6H4), and a trace
amount of disulfonate 9.11,17 Subsequently, the mixture
was treated with K2CO3 in acetone to afford the dibenzyl
epoxide 6 ([R]30 +4.7 (c 0.32, CDCl3) (lit.5d [R]20 +4.4 (c
AD reaction of dibenzyl phosphonate 3b was investi-
gated, and the results are summarized in Table 1. For
comparison, that obtained with diethyl derivative 3a is
also presented in Table 1. AD reaction of 3b, carried out
with standard AD-mix-R, was sluggish even at room
temperature to produce diol 4b (R ) Bn) in <30% yield
(Table 1, entry 1). However, enantiomeric purity was 62%
ee, which was much higher than that of 4a (R ) Et)
synthesized previously by other groups,8-10 thus confirm-
ing our proposed effect of the benzyl ester on AD reaction
(vide supra). To speed up the reaction, we prepared a
reagent enriched with the catalyst: three times standard
quantity of K2OsO2(OH)4 and (DHQ)2PHAL, i.e., 0.6 and
D
D
2.15, CDCl3))) in 67% yield from diol 4b. Hydrogenolysis
of this epoxide to produce 1 is reported,5d and hence, the
method proposed in Scheme 1 was established.
(13) (a) Watson, K. G.; Fung, Y. M.; Gredley, M.; Bird, G. J .; J ackson,
W. R.; Gountzos, H.; Matthews, B. R. J . Chem. Soc., Chem. Commun.
1990, 1018-1019. (b) Denis, J .-N.; Correa, A.; Greene, A. E. J . Org.
Chem. 1990, 55, 1957-1959. (c) Fleming, P. R.; Sharpless, K. B. J .
Org. Chem. 1991, 56, 2869-2875.
(14) Horner, L.; Ertel, I.; Ruprecht, H.-D.; Be´lovsk’y, O. Chem. Ber.
1970, 103, 1582-1588.
(15) Ruiz, M.; Ojea, V.; Shapiro, G.; Weber, H.-P.; Pombo-Villar, E.
Tetrahedron Lett. 1994, 35, 4551-4554.
(16) (a) Hirao, T.; Masunaga, T.; Yamada, N.; Ohshiro, Y.; Agawa,
T. Bull. Chem. Soc. J pn. 1982, 55, 909-913. (b) Waszku’c, W.; J anecki,
T.; Bodalski, R. Synthesis 1984, 1025-1027.
(17) The inherent low regioselectivity of diol 4b for sulfonylation
with TsCl is likely to be improved by the high reactivity of 4-NO2C6H4-
SO2Cl.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7905
in THF (15 mL) was added Pd(PPh3)4 (452 mg, 0.391 mmol)
under argon atmosphere. The resulting mixture was stirred at
60 °C for 8 h. After being cooled to 0 °C, the mixture was
quenched with EtOAc and saturated NaHCO3 (1:1, 30 mL). The
organic layer was separated, and the aqueous layer was ex-
tracted with EtOAc twice. The combined organic layers were
dried and concentrated to afford an oil, which was purified by
chromatography (EtOAc/hexane) to furnish 3b (2.16 g, 94%): bp
190 °C (1 Torr); IR (neat) 3033, 1637, 1254, 996 cm-1; 1H NMR
δ 1.84 (dm, J ) 7 Hz, 3 H), 5.01 (d, J ) 8 Hz, 4 H), 5.68 (ddq, J
) 22, 17, 2 Hz, 1 H), 6.78 (ddq, J ) 22, 17, 7 Hz, 1 H), 7.32 (br
s, 10 H); 13C NMR δ 20.0 (d, J ) 24 Hz), 67.0 (d, J ) 5 Hz),
118.0 (d, J ) 188 Hz), 127.6, 128.0, 128.3, 136.1 (d, J ) 7 Hz),
149.2 (d, J ) 5 Hz). Anal. Calcd for C17H19O3P: C, 67.54; H,
6.33. Found: C, 67.16; H, 6.40.
Sch em e 2
Diben zyl (1S,2S)-1,2-Dih yd r oxyp r op ylp h osp h on a te (4b)
(R ) Bn ). To an ice-cold suspension of the modified AD-mix-R-
(×3) (2.31 g) and MeSO2NH2 (157 mg, 1.65 mmol) in t-BuOH (8
mL) and H2O (8 mL) was added 3b (500 mg, 1.65 mmol). The
resulting mixture was stirred at 0 °C for 6 days. Brine (10 mL)
was added, and the mixture was extracted with EtOAc twice.
The combined organic layers were dried and concentrated. The
residue obtained was purified by chromatography (EtOAc/
hexane) to afford 4b (526 mg, 95%), which was 78% ee by 1H
NMR spectroscopy of the corresponding bis-MTPA ester. This
product was recrystallized from hexane and EtOAc to obtain 4b
Since the Me group in substrate 3b (R ) Bn) is the
smallest alkyl group, homologues of 3b would surely be
better substrates than 3b for the AD reaction due to the
increased lipophilic property provided by the alkyl chain.
In fact, dibenzyl phosphonate 11, prepared from iodide
10 and HP(O)(OBn)2 under the palladium catalysis in
78% yield, was converted into diol 12 with 96% ee in 85%
yield by using the modified reagent (AD-mix-R-(×3)). This
result is better than that of entry 3 in Table 1 for 3b.
Subsequently, diol 12 was transformed into epoxide 14
in 75% yield through monosulfonate 13, which was
produced with high regioselectivity. In summary, syn-
thesis of fosfomycin was achieved through the AD reac-
tion of dibenzyl (E)-1-propenylphosphonate (3) with
modified AD-mix-R-(×3) and the highly regioselective
sulfonylation of 4b at the R-hydroxyl group. High ef-
ficiency in the AD reaction was realized not only by the
lipophilic nature of the benzyl group in the substrate but
also by the modification of the AD reagent. In addition,
conditions for regioselective R-sulfonylation were estab-
lished. R-Sulfonyloxyalkyl phosphonates available by the
present method would be useful for synthesis of R-amino-
â-hydroxy- or â-amino-R-hydroxyalkylphosphonic acids,
which are important analogues of the corresponding
carboxylic acids.12,18
(mp 90-91 °C) in 65% yield with >99% ee: [R]28 -1.2 (c 1.0,
D
CHCl3); IR (Nujol) 3392, 1189, 991 cm-1; 1H NMR δ 1.28 (dd, J
) 7, 1.5 Hz, 3 H), 3.46 (d, J ) 5 Hz, 1 H), 3.70-3.84 (m, 2 H),
4.10-4.24 (m, 1 H), 4.98-5.19 (m, 4 H), 7.34 and 7.35 (2s, 10
H); 13C NMR δ 19.3 (d, J ) 11 Hz), 66.6 (d, J ) 3 Hz), 68.1 (d,
J ) 7 Hz), 68.8 (d, J ) 7 Hz), 72.1 (d, J ) 157 Hz), 128.03, 128.09,
128.52, 128.61, 128.64, 135.8 (d, J ) 6 Hz), 136.0 (d, J ) 6 Hz).
Anal. Calcd for C17H21O5P: C, 60.71; H, 6.29. Found: C, 60.85;
H, 6.42.
Diben zyl (1R,2S)-1,2-Ep oxyp r op ylp h osp h on a te (6). To an
ice-cold solution of diol 4b (30 mg, 0.089 mmol, > 99% ee) and
Et3N (0.022 mL, 0.16 mmol) in CH2Cl2 (0.5 mL) was added
4-nitrobenzenesulfonyl chloride (26 mg, 0.117 mmol). The flask
was kept in a refrigerator (5 °C) for 30 h. The solution was
diluted with EtOAc and saturated NH4Cl. The phases were
separated, and the aqueous phase was extracted with EtOAc.
The combined extracts were dried and concentrated to afford a
an oil, which was a mixture of monosulfonate 5b (R ) Bn, Ar )
4-NO2C6H4) and a trace of 9 by TLC analysis. This mixture was
subjected to the next reaction without further purification.
Analytically pure monosulfonate 5b was obtained from a crude
product of another run by chromatography (hexane/EtOAc): 1H
NMR δ 1.35 (dd, J ) 6, 1 Hz, 3 H), 2.70 (br d, J ) 6 Hz, 1 H),
4.21-4.34 (m, 1 H), 4.83-5.15 (m, 5 H), 7.18-7.38 (m, 10 H),
7.96 (dt, J ) 9, 2 Hz, 2 H), 8.11 (dt, J ) 3, 2 Hz, 2 H).
A mixture of crude 5b and K2CO3 (37 mg, 0.27 mmol) in
acetone (0.8 mL) was stirred at room temperature for 30 h and
filtered through a pad of Celite with EtOAc. The filtrate was
concentrated, and the residue was purified by chromatography
to afford 6 (19 mg, 67% from diol 4b): [R]30D +4.7 (c 0.32, CDCl3)
Exp er im en ta l Section
Gen er a l Meth od s. Infrared (IR) spectra are reported in
wavenumbers (cm-1). 1H NMR (300 MHz) and 13C NMR (75
MHz) spectra were measured in CDCl3 using SiMe4 (δ ) 0 ppm)
and the center line of CDCl3 triplet (δ ) 77.1 ppm) as internal
standards, respectively. Coupling constants between carbon and
phosphorus atom in 13C NMR spectra are given in hertz (Hz)
with indication of d (doublet). THF and Et2O were distilled from
Na/benzophenone before use. After the reactions, products were
extracted with given solvents, and the extracts were dried over
MgSO4 and concentrated by using a rotary evaporator unless
otherwise specified. The crude products were purified by chro-
matography on silica gel using a mixture of solvents as eluents.
Mod ified AD-m ix-r (AD-m ix-r-(×3)). K2OsO2‚2H2O (11 mg,
0.030 mmol) and (DHQ)2PHAL (117 mg, 0.150 mmol) were added
to a mixture of powdered K3Fe(CN)6 (4.90 g, 15 mmol) and K2-
CO3 (2.06 g, 15 mmol). The resulting mixture was grounded to
afford AD-mix-R-(×3).
(lit.5d [R]20 +4.4 (c 2.15, CDCl3)). The 1H NMR (300 MHz) and
D
13C NMR (75 MHz) spectra of 6 were identical with the data
reported.5d
Dieth yl (E)-1-P r op en ylp h osp h on a te (3a ) (R ) Et). Ac-
cording to the procedure for preparation of 3b, bromide 7 (0.75
mL, 8.73 mmol, 99% trans) was converted into 3a 14 (1.23 g, 96%)
by using HP(O)(OEt)2 (0.93 mL, 7.22 mmol), Et3N (1.0 mL, 7.17
mmol), and Pd(PPh3)4 (430 mg, 0.372 mmol) in THF (15 mL) at
60 °C for 8 h: bp 55 °C (1 Torr); IR (neat) 1239, 1027, 964 cm-1
;
1H NMR δ 1.33 (t, J ) 7 Hz, 6 H), 1.92 (dt, J ) 7, 2 Hz, 3 H),
4.07 (quintet, J ) 7 Hz, 4 H), 5.68 (ddq, J ) 21, 17, 2 Hz, 1 H),
6.80 (ddq, J ) 22, 17, 7 Hz, 1 H); 13C NMR δ 16.3 (d, J ) 7 Hz),
20.0 (d, J ) 24 Hz), 61.4 (d, J ) 6 Hz), 118.3 (d, J ) 187), 148.6
(d, J ) 5 Hz).
Diben zyl (E)-1-P r op en ylp h osp h on a te (3b) (R ) Bn ). To
a solution of bromide 7 (0.78 mL, 9.15 mmol, 99% trans), HP-
(O)(OBn)2 (1.68 mL, 7.61 mmol), and Et3N (1.06 mL, 7.56 mmol)
Dieth yl (1S,2S)-1,2-Dih yd r oxyp r op ylp h osp h on a te (4a )
(R ) Et). Asymmetric dihydroxylation of 3a (100 mg, 0.561
mmol) was carried out according to the procedure for preparation
of 4b by using the modified AD-mix-R-(×3) (785 mg) and MeSO2-
NH2 (53 mg, 0.56 mmol) in t-BuOH (3 mL) and H2O (3 mL) at
0 °C for 10 days to afford a 1:1.6 mixture of 3a and 4a
(determined by 1H NMR spectroscopy), which was separated by
(18) (a) Sawamura, M.; Ito, Y.; Hayashi, T. Tetrahedron Lett. 1989,
30, 2247-2250. (b) Bongini, A.; Camerini, R.; Hofman, S.; Panunzio,
M. Tetrahedron Lett. 1994, 35, 8045-8048. (c) Yokomatsu, T.; Yoshida,
Y.; Shibuya, S. J . Org. Chem. 1994, 59, 7930-7933. (d) Thomas, A.
A.; Sharpless, K. B. J . Org. Chem. 1999, 64, 8379-8385. (e) Barco, A.;
Benetti, S.; Bergamini, P.; Risi, C. D.; Marchetti, P.; Pollini, G. P.;
Zanirato, V. Tetrahedron Lett. 1999, 40, 7705-7708.

7906 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
chromatography. The 1H NMR (300 MHz) spectrum of 4a thus
Diben zyl (1R,2S)-1,2-Ep oxyh ep tylp h osp h on a te (14). By
using the same procedure described for the preparation of 5b,
diol 12 (50 mg, 0.127 mmol) was converted into R-sulfonate 13
(62 mg, 85%) by using 4-NO2C6H4SO2Cl (36 mg, 0.16 mmol) and
Et3N (0.032 mL, 0.23 mmol) in CH2Cl2 (1 mL) at 0 °C for 20 h:
1H NMR δ 0.88 (t, J ) 7 Hz, 3 H), 1.20-1.90 (m, 8 H), 2.82 (d,
J ) 6 Hz, 1 H), 3.98-4.15 (m, 1 H), 4.80-5.13 (m, 5 H), 7.17-
7.42 (m, 10 H), 7.95 (dt, J ) 9, 2 Hz, 2 H), 8.07 (dt, J ) 9, 2 Hz,
2 H).
synthesized was identical with that reported.9b,10
Diben zyl (E)-1-Hep ten ylp h osp h on a te (11). According to
the procedure for preparation of 3b, iodide 10 (1.53 g, 6.85 mmol)
was converted into 11 (1.59 g, 78%) by using HP(O)(OBn)2 (1.26
mL, 5.71 mmol), Et3N (0.79 mL, 5.67 mmol), and Pd(PPh3)4 (339
mg, 0.293 mmol) in THF (12 mL) at 60 °C for 8 h: IR (neat)
1
3033, 1630, 1253, 996 cm-1; H NMR δ 0.88 (t, J ) 7 Hz, 3 H),
1.18-1.46 (m, 6 H), 2.11-2.22 (m, 2 H), 5.03 (d, J ) 8 Hz, 4 H),
5.65 (ddt, J ) 22, 17, 1.5 Hz, 1 H), 6.78 (ddt, J ) 22, 18, 7 Hz,
1 H), 7.34 (br s, 10 H); 13C NMR δ 14.0, 22.4, 27.3 (d, J ) 1 Hz),
31.2, 34.1 (d, J ) 22 Hz), 67.1 (d, J ) 5 Hz), 116.2 (d, J ) 187
Hz), 127.7, 128.1, 128.3, 136.2 (d, J ) 7 Hz), 154.3 (d, J ) 5
Hz). Anal. Calcd for C21H27O3P: C, 70.37; H, 7.59. Found: C,
70.21; H, 7.73.
A mixture of the above sulfonate 13 (62 mg, 0.107 mmol) and
K2CO3 (45 mg, 0.33 mmol) in acetone (1 mL) was stirred at room
temperature to furnish 14 (35 mg, 88%): [R]23 -2.4 (c 0.67,
D
1
CHCl3); IR (neat) 3033, 1457, 1262, 996 cm-1; H NMR δ 0.87
(t, J ) 7 Hz, 3 H), 1.20-1.54 (m, 6 H), 1.80-1.92 (m, 2 H), 2.98
(dd, J ) 28, 5 Hz, 1 H), 3.13 (ddd, J ) 12, 7, 5 Hz, 1 H), 4.97-
5.17 (m, 4 H), 7.34 (br s, 10 H); 13C NMR δ 14.2, 22.7, 26.5, 28.5,
31.6, 50.2 (d, J ) 204 Hz), 58.2 (d, J ) 1 Hz), 67.8 (d, J ) 6 Hz),
68.3 (d, J ) 6 Hz), 128.0, 128.1, 128.52, 128.56, 128.59, 135.79,
135.8 (d, J ) 6 Hz), 135.9 (d, J ) 6 Hz). Anal. Calcd for
C21H27O4P: C, 67.37; H, 7.27. Found: C, 67.65; H, 7.47.
Diben zyl (1S,2S)-1,2-Dih yd r oxyh ep tylp h osp h on a te (12).
Asymmetric dihydroxylation of olefin 11 (200 mg, 0.56 mmol)
was carried out according to the procedure for preparation of
4b by using the modified AD-mix-R-(×3) (780 mg) and MeSO2-
NH2 (53 mg, 0.56 mmol) in t-BuOH (3 mL) and H2O (3 mL) at
0 °C for 2 days to afford diol 12 as a solid (185 mg, 85%), which
was 96% ee by 1H NMR spectroscopy of the corresponding bis-
MTPA ester. This diol was recrystallized from hexane and EtOAc
Ack n ow led gm en t. This work was supported by a
Grand-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, Government
of J apan.
(mp 76-77 °C): [R]23 -2.4 (c 0.21, CHCl3); IR (Nujol) 3400,
D
1
1189, 1012, 992 cm-1; H NMR δ 0.87 (t, J ) 7 Hz, 3 H), 1.2-
1
1.8 (m, 8 H), 3.37 (d, J ) 5 Hz, 1 H), 3.62 (dd, J ) 10, 2 Hz, 1
H), 3.83 (ddd, J ) 10, 8, 2 Hz, 1 H), 3.90-4.01 (m, 1 H), 4.98-
5.19 (m, 4 H), 7.34 and 7.35 (2s, 10 H); 13C NMR δ 14.2, 22.7,
25.5, 31.8, 33.1 (d, J ) 11 Hz), 68.2 (d, J ) 7 Hz), 68.8 (d, J )
7 Hz), 70.4, 70.9 (d, J ) 157 Hz), 128.0, 128.07, 128.45, 128.56,-
128.60, 135.9 (d, J ) 6 Hz), 136.1 (d, J ) 6 Hz). Anal. Calcd for
C21H29O5P: C, 64.27; H, 7.45. Found: C, 63.93; H, 7.27.
Su p p or tin g In for m a tion Ava ila ble: The H NMR spec-
tra of the bis-MTPA esters derived from racemic 4b, enantio-
merically enriched 4b of 78% ee, and recrystallized 4b of >99%
ee. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O010701U