Synthesis of phospholane 1-oxide having oxygen functional groups from a 4-bromobutylphoshinate derivative

Article abstract of DOI:10.3987/COM-05-S(K)15

Ethyl 4-bromo-2,3-dimethoxybutyl(phenyl)phosphinate (10a) was prepared from 2,3-di-O-methyl-L-threitol (12) in five steps. Reduction of 10a with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of hydrogen peroxide, afforded 3,4-dimetho

Full text of DOI:10.3987/COM-05-S(K)15

HETEROCYCLES, Vol. 66, 2005
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HETEROCYCLES, Vol. 66, 2005, pp. 251 – 261. © The Japan Institute of Heterocyclic Chemistry
Received, 12th August, 2005, Accepted, 12th October, 2005, Published online, 14th October, 2005. COM-05-S(K)15
SYNTHESIS OF PHOSPHOLANE 1-OXIDE HAVING OXYGEN
FUNCTIONAL GROUPS FROM A 4-BROMOBUTYLPHOSHINATE
DERIVATIVE
Tadashi Hanaya,* Shigeru Kawase, and Hiroshi Yamamoto
Department of Chemistry, Faculty of Science, Okayama University,
Tsushima-naka, Okayama 700-8530, Japan
Abstract – Ethyl 4-bromo-2,3-dimethoxybutyl(phenyl)phosphinate (10a) was
prepared from 2,3-di-O-methyl-L-threitol (12) in five steps. Reduction of 10a
with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by the action of
hydrogen peroxide, afforded 3,4-dimethoxy-1-phenylphospholane 1-oxide (3),
while the reaction of 10a with magnesium in boiling THF resulted in the
formation of ethyl 2-methoxy-3-butenyl(phenyl)phosphinate (26).
INTRODUCTION
Various sugar analogs containing a heteroatom instead of oxygen in the ring have been prepared because
of the wide interest in their chemical properties and potential biological activity.1 In view of such a
chemical modification by heteroatoms, we have prepared various sugar analogs having a phosphorus
atom in the ring (phospha sugars).2 Although some furanose-type phospha sugars having a phospholane
oxide structure, e.g., D-ribofuranose (1)3 and 2-deoxy-D-ribofuranose analogs (2)4 have been prepared,
synthesis of such sugar analogs remains to be rather difficult, because it usually requires long reaction
steps and only a few methods are available for stereoselective introduction of a phosphinoyl group into
sugar moiety. This led us to explore a simpler preparative method for phospha furanoses by
modification of the phospholane oxide in such a way as to attach oxygen functional groups to the ring
carbons (e.g. 3), followed by selective functionalization of the α-carbon of the ring phosphorus.5,6
O
O
P
O
P
HO
P
OMe
HO
Ph
R
R
OH
OH
OMe
HO
2 (R = OH, Me)
HO OH
1 (R = OH, Et, Ph)
3
Among the reported synthetic procedures for phospholane oxides, the following two methods attracted
our attention (Scheme 1). Namely, one method is the reductive cyclization of 4-bromobutylphosphinate
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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HETEROCYCLES, Vol. 66, 2005
(5) [prepared from 1,4-dibromobutane (4)] with sodium dihydrobis(2-methoxyethoxy)aluminate (SDMA),
to give 1-phenylphospholane 1-oxide (7a) via 6.7 The other method is the condensation of the di-
Grignard reagent (8) (generated from 4) with ethyl phosphorodichloridate, to give 1-ethoxyphospholane
1-oxide (7b).5,8 We now describe synthetic studies on the phospholane oxide (3) having two methoxy
groups as a model functional group by applying these two procedures to preparation of simple
phospholane oxides.
O
P
O
P
SDMA
Ph
Ph
H
(1.1 equiv.)
Br
PhP(OEt)
2
Br
OEt
Br
Br
THF, reflux
27%
6
4
5
O
P R
Cl P(O)OEt
2
Mg, Et O
2
MgBr
BrMg
30–50%
8
7a R = Ph
7b R = OEt
Scheme 1
RESULTS AND DISCUSSION
The 4-bromo-2,3-dimethoxybutylphosphinate derivative (10a) can be perceived as a key intermediate for
the present study. In a previous paper,9 we reported that Michaelis-Arubzov reaction of 1,4-dihalo-2,3-
dimethoxybutanes (9a,b) with diethyl phenylphosphonite10 afforded a cyclic phosphinate (11) and the
isolation of the anticipated acyclic 4-halobutylphosphinates (10a,b) was not achieved (Scheme 2).
Therefore we turned our attention to another approach for the preparation of 10, namely, by the sequence
of introduction of a phosphinoyl group and the subsequent halogenation of the terminal carbon.
X
X
O
MeO
O
OMe
OMe
O
PhP(OEt)
2
P
MeO
MeO
Ph
X
P Ph
OEt
OMe
11
9a X = Br
9b X = I
10a X = Br
10b X = I
Scheme 2
The starting material, 2,3-di-O-methyl-L-threitol (12)11,12 was prepared from diethyl L-tartrate according
to the reported method. For the mono-O-protection of 1,4-diol (12), we chose benzoyl group first
(Scheme 3). Acylation of 11 with 1.1 mol equiv. of benzoyl chloride afforded 1-O-benzoyl-L-threitol

HETEROCYCLES, Vol. 66, 2005
253
(13a) in 72% and 1,4-di-O-benzoyl derivative (13b) in 17%. Treatment of 13a with carbon tetrabromide
and triphenylphosphine at room temperature gave the corresponding bromide (14). Michaelis-Arbuzov
reaction of 14 with diethyl phenylphosphonite afforded the 4-deoxy-4-[(R and S)-ethoxy(phenyl)-
phosphinoyl]-L-threitol derivatives (15) as a 1:1 diastereomeric mixture concerning the phosphorus atom.
Cleavage of benzoyl group of 16 with sodium ethoxide in ethanol resulted in the formation of cyclic
phosphinates [11a (32%)] and [11b (42%)] instead of the desired acyclic phosphinate (16).
OH
OBz
OBz
CBr , PPh
4
PhP(OEt)
2
BzCl, Py
rt, 10 h
OMe
OMe
OMe
3
MeO
MeO
MeO
CHCl , rt, 20 min
3
150 °C, 2 h
92%
OH
OR
Br
86%
12
13a R = H (72%)
13b R = Bz (17%)
14
OBz
OMe
O
OH
O
Ph
O
P
MeO
MeO
OMe
O
NaOEt, EtOH
0 °C, 3 h
P
+
+
MeO
MeO
O
Ph
O
P Ph
P Ph
OMe
OMe
OEt
OEt
15
16 (0%)
11a (32%)
11b (42%)
OBn
OMe
OBn
OMe
O
OBn
CBr , PPh
4
PhP(OEt)
2
3
BnBr, NaH
OMe
12
MeO
MeO
MeO
DME
CHCl
150 °C, 3 h
93%
3
Br
P Ph
OEt
OR
rt, 8 h
0 °C, 6 h
55%
17a R = H (80%)
17b R = Bn (9%)
18
19
Br
Br
X
SDMA
(3 equiv.)
OMe
O
OMe
P Ph
OMe
H
CBr , PPh
4
2
3
16
MeO
MeO
20% Pd(OH) -C
2
CHCl
toluene
rt, 6 h
3
P Ph
P Ph
H
EtOH, rt, 6 h
92%
rt, 15 min
78%
OMe
OEt
10a
20
21 X = lone pair
H O
2
3 X = O
2
(48% from 10a)
Scheme 3
For an alternative protecting group for 12, we then employed benzyl group. Thus, benzylation of 12
with 1.1 mol equiv. of benzyl bromide in the presence of sodium hydride afforded 1-O-benzyl-L-threitol
(17a) in 80% and 1,4-di-O-benzyl derivative (17b) in 9%. It is known that benzyl ether having a leaving
group at δ-position causes debenzylation in the presence of nucleophile to afford a tetrahydrofuran
derivative.13 To avoid such cyclization, bromimation of 17a with carbon tetrabromide and

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HETEROCYCLES, Vol. 66, 2005
triphenylphosphine was performed at 0 °C to give the 4-bromo-4-deoxy-L-threitol derivative (18) in 55%
yield.14 Michaelis-Arbuzov reaction of 18 with diethyl phenylphosphonite afforded the 4-deoxy-4-
phosphinoyl derivative (19). Hydrogenolysis of 19 in the presence of 20% Pd(OH)2–C provided the
debenzylated product (16), which was coverted into the 1-bromo-1,4-dideoxy-4-phosphinoyl-L-threitol
derivative (10a) by use of the same conditions as those employed for bromination of 13a.
Compound (10a) was then reduced with 3 mol equiv. of SDMA at room temperature to the phosphine
intermediate (20), which rendered cyclization to phospholane (21). The crude syrup of 21 was treated
with hydrogen peroxide to afford the desired (3R,4R)-3,4-dimethoxy-1-phenylphospholane 1-oxide (3).15
The phosphine and phosphine oxide structures of 21 and 3 were confirmed on the basis of the
characteristic values of 31P NMR spectral data (δ –30.9 for 21 and δ 52.0 for 3).
Wetzel and Kenyon prepared phospholane oxide (7a) by reduction of phosphinate (5) with 1.1 mol equiv.
of SDMA in boiling THF to 4-bromobutylphosphine oxide (6) and the subsequent cyclization in 27%
yield7 (Scheme 1). However, phosphine intermediates (such as 20) are apparently more effective for
cyclization than the corresponding phosphine oxides, in view of their nucleophilicities. Thus,
phospholane oxide (7a) was prepared from 5 in an improved yield (51%), when our modified procedures
were employed; namely, the reductive cyclization of phosphinate to phospholane (phosphine) and the
following oxidation.
As the second approach to phospholane oxide (3), cyclization by use of Grignard reaction was
investigated (Scheme 4). We confirmed that the treatment of 1,4-butanediyldimagnesium dibromide (7),
generated from 4 with magnesium in THF, with phenylphosphonic dichloride afforded 1-phenyl-
phospholane oxide (6a) in 40% yield with minor modification of reported procedures.5,8 However, the
same reaction of dibromide (8a) having two methoxy groups resulted in the formation of a considerable
amount of dimethyl phenylphosphonate (22) instead of the anticipated phospholane oxide (3).
O
MgBr
R
Br
R
O
Cl P(O)Ph
2
Mg, THF
P Ph
Ph P OMe
OMe
R
+
R
R
reflux, 3 h
rt, 8 h
MgBr
Br
R
7a R = H (40% from 4)
3 R = OMe (0% from 9a)
4 R = H
8 R = H
22 R = OMe
23 (from 9a)
9a R = OMe
Br
R
MgBr
O
R
Mg, THF
P Ph
MeO
O
+
R
O
R
O
R
P Ph
reflux, 4 h
P Ph
P Ph
OEt
R
OEt
OEt
7a R = H (54% from 5)
5 R = H
10a R = OMe
24 R = H
3 R = OMe (2% from 10a)
26 (59% from 10a)
25 R = OMe
Scheme 4

HETEROCYCLES, Vol. 66, 2005
255
We therefore attempted more effective intramolecular cyclization by Grignard reagent instead of
intermolecular ring formation. As a comparative experiment, the reaction of the 4-bromobutyl-
phosphinate (5) with magnesium was found to give 7a (via 24) in 54% yield, despite the fact that
phosphinates are generally less reactive than the corresponding phosphinic chlorides for attack of
nucleophiles. However, the same treatment of 10a with magnesium resulted in the predominant
formation of the 3-butenylphosphinate derivative (26) in 59% yield; the desired cyclic phosphine oxide
(3) was obtained only in a small portion (2% yield).
Production of 26 can be perceived as the result of β-elimination of methoxy group from the intermediate
(25), which took place faster than intramolecular nucleophilic attack to phosphorus by the terminal anion.
The formation of 23 from 9a supports this mechanism. Namely, methoxide anion derived from the
intermediate (22) reacted with phenylphosphonic dichloride to afford 23, whereas the resultant 1,3-
butadiene must have been evaporated due to its volatility. Judging from these results, the use of
Grignard reaction seems to be unsuitable for preparation of phospholane oxides having alkoxy groups.
The present work demonstrates a convenient way for preparation of phospholane oxide having oxygen
functional groups. Extension of this work, including applications of these findings for preparation of
phosphorinane oxide, as well as derivation of phospholane oxides into phospha sugars, is under
investigation.
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) 1:2, (B) 1:1, (C) 2:1 AcOEt–hexane, (D) AcOEt, and (E) 1:9 EtOH–AcOEt]. Column
chromatography was performed with Daiso Silica Gel IR-60/210w. Components were detected by
exposing the plates to UV light and/or spraying them with 20% sulfuric acid–ethanol (with subsequent
1
heating). The NMR spectra were measured in CDCl3 with Varian VXR-500 (500 MHz for H) and
Mercury 300 (121 MHz for 31P) spectrometer at 23 °C. Chemical shifts are reported as δ values relative
1
to CHCl3 (7.26 ppm as an internal standard for H) and 85% phosphoric acid (0 ppm as an external
standard for 31P).
1-O-Benzoyl-2,3-di-O-methyl-L-threitol (13a) and 1,4-di-O-benzoyl-2,3-di-O-methyl-L-threitol
(13b).
To a solution of 12 (540 mg, 3.60 mmol) in dry DME (15 mL) was added benzoyl chloride (460 mg, 3.96
mmol) at 0 °C. The mixture was stirred at rt for 10 h and then water (1 mL) was added at 0 °C. The
mixture was stirred at rt for 20 min and evaporated in vacuo. The residue was dissolved in CHCl3,
washed with water, dried (Na2SO4), and evaporated in vacuo. The residue was separated by column
chromatography with 1:2 AcOEt-hexane to give 13a and 13b.
13a: Colorless oil (660 mg, 72%); Rf = 0.12 (A), 0.27 (B); 1H NMR δ = 2.28 (1H, br s, HO-4), 3.50 (1H,
dt, J3,4’ = 5.4, J2,3 = J3,4 = 4.6 Hz, H-3), 3.51, 3.53 (3H each, 2s, MeO-2,3), 3.73 (1H, dd, J4,4’ = 11.7 Hz,
H’-4), 3.75 (1H, dt, J1’,2 = 6.1, J1,2 = 4.2 Hz, H-2), 3.87 (1H, dd, H-4), 4.40 (1H, dd, J1.1’ = 11.7 Hz, H’-1),

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HETEROCYCLES, Vol. 66, 2005
4.59 (1H, dd, H-1), 7.44 [2H, t, Jo,m = Jm,p = 7.5 Hz, Ph(m)], 7.56 [1H, tt, Jo,p = 1.2 Hz, Ph(p)], 8.03 [2H,
dd, Ph(o)]. Anal. Calcd for C13H18O5: C, 61.41; H, 7.14. Found: C, 61.54; H, 7.11.
13b: Colorless needles (218 mg, 17%); mp 53–55 °C; Rf = 0.52 (A); 1H NMR δ = 3.57 (6H, s, MeO-2,3),
3.77 (2H, m, H-2,3), 4.51 (2H, dd, J1,1’ = 11.7, J1’,2 = 5.9 Hz, H’-1,4), 4.62 (2H, dd, J1,2 = 4.6 Hz, H-1,4),
7.44 [4H, t, Jo,m = Jm,p = 7.5 Hz, Ph(m)], 7.57 [2H, tt, Jo,p = 1.2 Hz, Ph(p)], 8.04 [4H, dd, Ph(o)]. Anal.
Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 67.15; H, 6.26.
1-O-Benzoyl-4-bromo-4-deoxy-2,3-di-O-methyl-L-threitol (14).
To a solution of 13a (250 mg, 0.983 mmol) in CHCl3 (5 mL) were added carbon tetrabromide (500 mg,
1.50 mmol) and triphenylphosphine (350 mg, 1.33 mmol) at 0 °C. The mixture was stirred at rt for 20
min, diluted with CHCl3 (10 mL), washed with water, dried (Na2SO4), and evaporated in vacuo. The
residue was purified by column chromatography with 1:3 AcOEt-hexane to give 14 (268 mg, 86%) as a
colorless oil: Rf = 0.61 (A); 1H NMR δ = 3.51, 3.57 (3H each, 2s, MeO-2,3), 3.51 (1H, m, H-3), 3.61 (1H,
dd, J4,4’ = 7.3, J3,4’ = 3.2 Hz, H’-4), 3.63 (1H, t, J3,4 = 6.6 Hz, H-4), 3.89 (1H, ddd, J1’,2 = 5.9, J1,2 = 5.4,
J2,3 = 2.9 Hz, H-2), 4.49 (1H, dd, J1,1’ = 11.5 Hz, H’-1), 4.52 (1H, dd, H-1), 7.45 [2H, t, Jo,m = Jm,p = 7.5
Hz, Ph(m)], 7.56 [1H, tt, Jo,p = 1.2 Hz, Ph(p)], 8.04 [2H, dd, Ph(o)]. Anal. Calcd for C13H17O4Br: C,
49.23; H, 5.40. Found: C, 49.29; H, 5.33.
1-O-Benzoyl-4-deoxy-4-[(R and S)-ethoxy(phenyl)phosphinoyl]-2,3-di-O-methyl-L-threitols (15).
A mixture of 14 (100 mg, 0.315 mmol) and diethyl phenylphosphonite10 (0.300 mL, 1.56 mmol) was
heated at 150 °C for 2 h under N2 and concentrated in vacuo. The residue was purified by column
chromatography with 2:1 AcOEt-hexane to give an inseparable diasteromeric mixture of 15 (118 mg,
1
92%) as a colorless syrup: Rf = 0.20 (C); H NMR δ = 1.28, 1.29* (3H, 2t, JEt = 7.1 Hz, C–CH3), 2.22,
2.29* (1H, 2ddd, J4,4’ = 15.4, 15.4*, J4’,P = 12.2, 16.3*, J3,4’ = 7.1, 6.4* Hz, H’-4), 2.38*, 2.46 (1H, 2ddd,
J4,P = 12.0*, 18.1, J3,4 = 6.3*, 5.9 Hz, H-4), 3.21, 3.32*, 3.40*, 3.55 (6H, 4s, MeO-2,3), 3.63, 3.75* (1H,
2ddd, J1’,2 = 5.9, 5.9*, J1,2 = 4.9. 5.4*, J2,3 = 3.2, 2.9* Hz, H-2), 3.79, 3.83* (1H, 2m, H–3), 3.85, 3.86*
2
(1H, 2m, POCH’), 4.07, 4.08* (1H, 2dquint, JH,H’ = 10.0, JH,P = 7.0 Hz, POCH), 4.405, 4.42* (1H, 2dd,
J1,1’ = 11.5, 11.7* Hz, H-1’), 4.44, 4.48* (1H, 2dd, H-1), 7.43, 7.43* [2H, t, Jo,m = Jm,p = 7.5 Hz, C–Ph(m)],
7.46, 7.46* [2H, m, P–Ph(m)], 7.53, 7.53* [1H, m, P–Ph(p)], 7.56, 7.56* [1H, tt, Jo,p = 1.2 Hz, C–Ph(p)],
7.79, 7.79* [2H, br dd, Jo,P = 11.7, Jo,m = 7.8 Hz, P–Ph(o)], 7.99, 8.01* [2H, 2br d, C–Ph(o)]; 31P NMR δ =
41.9*, 42.6 (52:48* mixture, the assignment of some of the δ values may have to be interchanged). Anal.
Calcd for C21H27O6P: C, 62.06; H, 6.70. Found: C, 62.12; H, 6.78.
Debenzoylation of 15 with sodium ethoxide.
To a solution of 15 (60.0 mg, 0.148 mmol) in abs EtOH (1.0 mL) was added a 21% ethanolic solution of
sodium ethoxide (0.02 mL, 0.05 mmol) at 0 °C. The mixture was stirred at 0 °C for 3 h and then

HETEROCYCLES, Vol. 66, 2005
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neutralized with Amberlite IR-120(H+). The resin was filtered off and the filtrate was evaporated in
vacuo. The residue was separated by column chromatography with AcOEt to give (2R,4R,5R)-4,5-
dimethoxy-2-oxo-2-phenyl-1,2-oxaphosphorinane (11a) and its (2S,4R,5R)-epimer (11b).
11a:9 Colorless syrup (12.1 mg, 32%); Rf = 0.35 (D); 1H NMR, see ref. 9.
11b:9 Colorless needles (16.0 mg, 42%); mp 127–129 °C (from AcOEt-hexane) (lit.,9 128–129 °C); Rf =
0.22 (D); 1H NMR, see ref. 9.
1-O-Benzyl-2,3-di-O-methyl-L-threitol (17a)12 and 1,4-di-O-benzyl-2,3-di-O-methyl-L-threitol (17b).
To a solution of 12 (840 mg, 5.60 mmol) in dry DME (15 mL) was added sodium hydride (62% in
mineral oil, 230 mg, 5.94 mmol) at 0 °C. After stirring at rt for 1 h, benzyl bromide (0.720 mL, 6.07
mol) was added. The mixture was stirred at rt for 8 h and saturated NH4Cl aqueous solution (4 mL) was
added. After distilling off most of DME in vacuo, the residue was dissolved in CHCl3, washed with
water, dried (Na2SO4), and evaporated in vacuo. The residue was separated by column chromatography
to give 17a and 17b.
1
17a: Colorless oil (1.07 g, 80%) (lit.,12 73% yield using DMF as solvent); Rf = 0.27 (B); H NMR δ =
2.12 (1H, br s, HO-4), 3.44 (1H, ddd, J3,4’ = 4.9, J2,3 = 4.8, J3,4 = 4.4 Hz, H-3), 3.465, 3.47 (3H each, 2s,
MeO-2,3), 3.54 (1H, ddd, J1’,2 = 4.9, J1,2 = 4.6 Hz, H-2), 3.59 (1H, dd, J1.1’ = 10.3 Hz, H’-1), 3.63 (1H, dd,
J4,4’ = 12.0 Hz, H’-4), 3.66 (1H, dd, H-1), 3.78 (1H, dd, H-4), 4.55 (2H, s, CH2O-1), 7.29 [1H, m, Ph(p)],
7.32–7.36 [4H, m, Ph(o,m)].
1
17b: Colorless oil (166 mg, 9%); Rf = 0.52 (A), 0.77 (B); H NMR δ = 3.46 (6H, s, MeO-2,3), 3.56 (4H,
m, H2-1,4), 3.65 (2H, m, H-2,3), 7.29 [2H, m, Ph(p)], 7.32–7.36 [8H, m, Ph(o,m)]. Anal. Calcd for
C20H26O4: C, 72.70; H, 7.93. Found: C, 72.61; H, 8.02.
1-O-Benzyl-4-bromo-4-deoxy-2,3-di-O-methyl-L-threitol (18).
To a solution of 17a (1.90 g, 7.91 mmol) in CHCl3 (50 mL) were added carbon tetrabromide (4.00 g, 12.1
mmol) and triphenylphosphine (3.16 g, 12.1 mmol) at 0 °C. The mixture was stirred at 0–5 °C for 6 h,
washed with saturated NaHCO3 and then water, dried (Na2SO4), and evaporated in vacuo. The residue
was purified by column chromatography with 1:3 AcOEt-hexane to give 18 (1.32 g, 55%) as a colorless
oil: Rf = 0.64 (A); 1H NMR δ = 3.45, 3.49 (3H each, 2s, MeO-2,3), 3.45 (1H, m, H-2), 3.58 (2H, m, H2-1),
3.64 (2H, m, H2-4), 3.68 (1H, m, H-3), 4.55 (2H, s, CH2O-1), 7.27–7.37 (5H, m. Ph). Anal. Calcd for
C13H19O3Br: C, 51.50; H, 6.32. Found: C, 51.23; H, 6.39.
1-O-Benzyl-4-deoxy-4-[(R and S)-ethoxy(phenyl)phosphinoyl]-2,3-di-O-methyl-L-threitols (19).
A mixture of 18 (550 mg, 1.81 mmol) and diethyl phenylphosphonite (3.00 mL, 15.6 mmol) was heated
at 150 °C for 3 h under N2 and concentrated in vacuo. The residue was purified by column
chromatography with 2:1 AcOEt-hexane to give an inseparable diasteromeric mixture of 19 (659 mg,

258
HETEROCYCLES, Vol. 66, 2005
1
93%) as a colorless syrup: Rf = 0.12 (B); H NMR δ = 1.275, 1.28* (3H, 2t, JEt = 7.2 Hz, C–CH3), 2.13,
2.19* (1H, 2ddd, J4,4’ = 15.3, 15.3*, J4’,P = 11.9, 16.5*, J3,4’ = 7.6, 7.0* Hz, H’-4), 2.31*, 2.36 (1H, 2ddd,
J4,P = 12.5*, 18.0, J3,4 = 5.8*, 5.2 Hz, H-4), 3.16, 3.26*, 3.33*, 3.48 (6H, 4s, MeO-2,3), 3.45* (0.5H, ddd,
J1’,2 = 5.8, J1,2 = 4.9, J2,3 = 3.4 Hz, H-2), 3.54* (0.5H, dd, J1,1’ = 10.1 Hz, H’-1), 3.55–3.60 (1.5H, m,
2
H2-1,H-2), 3.63* (0.5H, dd, H-1), 3.77, 3.79* (1H, 2m, H-3), 3.81, 3.84* (1H, 2dquint, JH,H’ = 10.0, JH’,P
= 7.0 Hz, POCH’), 4.06, 4.07* (1H, 2dquint, JH,P = 7.0 Hz, POCH), 4.48, 4.49*, 4.51, 4.52* (2H, 4d, 2J =
11.9, 12.2* Hz, CH2O-1), 7.26–7.32, 7.26–7.32* (5H, m, C–Ph), 7.46, 7.47* [2H, 2m, P–Ph(m)], 7.53,
31
7.54* [1H, 2m, P–Ph(p)], 7.77, 7.79* [2H, 2m, P–Ph(o)]; P NMR δ = 42.4*, 43.0 (52:48* mixture, the
assignment of some of the δ values may have to be interchanged). Anal. Calcd for C21H29O5P: C, 64.27;
H, 7.45. Found: C, 64.20; H, 7.51.
4-Deoxy-4-[(R and S)-ethoxy(phenyl)phosphinoyl]-2,3-di-O-methyl-L-threitols (16).
Compound (19) (550 mg, 1.40 mmol) was dissolved in ethanol (10 mL) and hydrogenated in the presence
of 20% Pd(OH)2–C (200 mg, 0.28 mmol) at rt. After 6 h, the catalyst was filtered off and the filtrate
was concentrated in vacuo. The residue was purified by short-path column chromatography with AcOEt
to give 16 (389 mg, 92%) as a colorless syrup: Rf = 0.12 (D); 1H NMR δ = 1.28*, 1.285 (3H, 2t, JEt = 7.2
Hz, C–CH3), 2.12, 2.23* (1H, 2ddd, J4,4’ = 15.6, 15.6*, J4’,P = 12.0, 16.8*, J3,4’ = 7.1, 6.6* Hz, H’-4), 2.32*,
2.38 (1H, 2ddd, J4,P = 11.5*, 18.1, J3,4 = 5.9*, 5.4 Hz, H-4), 2.55, 2.55* (1H, br s, HO-1), 3.16, 3.22*,
3.39*, 3.46 (6H, 4s, MeO-2,3), 3.30*, 3.42 (1H, 2ddd, J1’,2 = 4.4*, 4.9, J1,2 = 4.4*, 4.6, J2,3 = 4.1, 4.1* Hz,
H-2), 3.65*, 3.67 (1H, dd, J1,1’ = 11.7, 11.7* Hz, H’-1), 3.76*, 3.77 (1H, 2dd, H-1), 3.81, 3.82* (1H, 2m,
H-3), 3.83, 3.89* (1H, 2m, POCH’), 4.055, 4.06* (1H, 2m, POCH), 7.49, 7.49* [2H, m, Ph(m)], 7.55,
7.55* [1H, m, Ph(p)], 7.79, 7.79* [2H, m, Ph(o)]; 31P NMR δ = 42.5*, 43.0 (53:47* diastereomeric mixture,
the assignment of some of the δ values may have to be interchanged). Anal. Calcd for C14H23O5P: C,
55.62; H, 7.67. Found: C, 55.55; H, 7.71.
1-Bromo-1,4-dideoxy-4-[(R and S)-ethoxy(phenyl)phosphinoyl]-2,3-di-O-methyl-L-threitols (10a).
To a solution of 16 (300 mg, 0.992 mmol) in CHCl3 (8 mL) were added carbon tetrabromide (500 mg,
1.50 mmol) and triphenylphosphine (350 mg, 1.33 mmol) at 0 °C. The mixture was stirred at rt for 15
min, washed with water, dried (Na2SO4), and evaporated in vacuo. The residue was purified by column
chromatography with 4:1 AcOEt-CHCl3 as an eluant to give an inseparable diastereomeric mixture (1:1)
of 10a (282 mg, 78%) as a colorless syrup: Rf = 0.35 (D); 1H NMR δ = 1.29, 1.30* (3H, 2t, JEt = 7.2 Hz,
C–CH3), 2.15, 2.23* (1H, 2ddd, J4,4’ = 15.3, 15.3*, J4’,P = 12.8, 16.8*, J3,4’ = 6.4, 6.1* Hz, H’-4), 2.30*,
2.38 (1H, 2ddd, J4,P = 12.2*, 17.7, J3,4 = 7.0*, 6.7 Hz, H-4), 3.21, 3.29*, 3.37*, 3.50 (6H, 4s, MeO-2,3),
3.49, 3.58* (1H, 2m, H-2), 3.52, 3.55* (1H, 2dd, J1,1’ = 10.7, 9.2*, J1’,2 = 5.2, 5.2* Hz, H’-1), 3.63*, 3.67
(1H, 2dd, J1,2 = 5.8, 6.7* Hz, H-1), 3.82, 3.85* (1H, 2dtd, 2JH,H’ = 10.0, JH’,P = 7.0 Hz, POCH’), 3.83, 3.92*
(1H, 2m, H-3), 4.08, 4.09* (1H, 2dquint, JH,P = 7.0 Hz, POCH), 7.49, 7.50* [2H, 2m, Ph(m)], 7.56, 7.56*

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[1H, m, Ph(p)], 7.78, 7.80* [2H, 2m, Ph(o)]; 31P NMR δ = 41.6*, 42.2 (53:47* diastereomeric mixture, the
assignment of some of the δ values may have to be interchanged). Anal. Calcd for C14H22O4BrP: C,
46.04; H, 6.07. Found: C, 46.18; H, 6.01.
(3R,4R)-3,4-Dimethoxy-1-phenylphospholane 1-oxide (3).15
To a solution of 10a (40.8 mg, 0.112 mmol) in dry toluene (0.8 mL) was added, with stirring, a solution
of SDMA (3.4M toluene solution, 0.100 mL, 0.34 mmol) at 0 °C. The mixture was stirred at 0 °C for 30
min and then at rt for 6 h. The mixture was diluted with toluene (2 mL) and water (0.1 mL) was added
to decompose excess SDMA. Then the mixture was passed through celite and the filtrate was
evaporated in vacuo to give (3R,4R)-3,4-dimethoxy-1-phenylphospholane (21) as a colorless syrup: Rf =
0.56 (A); 31P NMR δ = –30.9.
This syrup was dissolved in CHCl3 (1 mL), treated with 30% H2O2 (0.2 mL, 2.0 mmol) at rt for 6 h. The
mixture was diluted with CHCl3 (10 mL), washed with water, dried (Na2SO4), and evaporated in vacuo.
The residue was purified by column chromatography with 1:19 EtOH-AcOEt to give 3 (13.0 mg, 48%) as
1
colorless prisms: mp 76–77 °C (from AcOEt-hexane); Rf = 0.07 (D), 0.24 (E); H NMR δ = 2.19 (1H,
ddd, J2,2’ = 15.9, J2’,P = 4.4, J2’,3 = 3.5 Hz, H’-2), 2.22–2.31 (2H, m, H,H’-5), 2.46 (1H, ddd, J2,P = 18.9,
J2,3 = 6.1 Hz, H-2), 3.41, 3.45 (3H each, 2s, MeO-3,4), 4.06 (1H, dq, J4,P = 23.1, J4,5 = J4,5’ = 3.7, J3,4
=
3.5 Hz, H-4), 4.17 (1H, ddt, J3,P = 23.7 Hz, H-3), 7.48–7.54 [3H, m, Ph(m.p)], 7.84 [2H, ddd, Jo,P = 12.2,
31
Jo,m = 8.2, Jo,p = 1.6 Hz, Ph(o)]; P NMR δ = 52.0. Anal. Calcd for C12H17O3P: C, 60.00; H, 7.13.
Found: C, 59.97; H, 7.21.
1-Phenylphospholane 1-oxide (7a).7,16
A. Reductive cyclization of 5. By employing the same procedures as those described above, compound
(5) was reduced with SDMA and then treated with H2O2 to give 7a (51% yield) as a colorless syrup: Rf =
0.06 (D), 0.17 (E).
B. Grignard reaction of 4. The mixture of magnesium (120 mg, 4.94 mmol) and 1,2-dibromoethane
(0.03 mL) in dry THF (3 mL) was stirred vigorously and a solution of 4 (0.300 mL, 2.54 mmol) in dry
THF (2 mL) was added dropwise. The mixture was refluxed for 3 h and then cooled. To the mixture
was added a solution of phenylphosphonic dichloride (0.360 mL, 2.54 mmol) in dry CH2Cl2 (4 mL) at
0 °C. The mixture was stirred at rt for 8 h and diluted with saturated NH4Cl aqueous solution (5 mL).
The mixture was extracted with CHCl3 three times. The combined organic layers were washed with
water, dried (Na2SO4), and evaporated in vacuo. The residue was purified by column chromatography
with 1:19 EtOH-AcOEt to give 7a (182 mg, 40%).
C. Grignard reaction of 5. A mixture of magnesium (16 mg, 0.66 mmol) and 1,2-dibromoethane (0.01
mL) in dry THF (2 mL) was stirred vigorously and a solution of 5 (100 mg, 0.328 mmol) in dry THF (2
mL) was added dropwise. The mixture was refluxed for 4 h and neutralized with saturated NH4Cl

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aqueous solution (5 mL). The mixture was extracted with CHCl3 three times. The combined organic
layers were washed with water, dried (Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography with 1:19 EtOH-AcOEt to give 7a (32.1 mg, 54%).
Grignard reaction of 9a.
Similar procedures to those for 7a from 4 were employed. Compound (9a) (97.0 mg, 0.35 mmol) was
treated with magnesium (25 mg, 1.03 mmol) in boiling THF and then phosphonic dichloride (0.050 mL,
0.35 mmol) at rt. Purification of the resulting mixture by column chromatography gave dimethyl
phenylphosphonate (23) (32.0 mg, 49%) as a colorless oil: Rf = 0.43 (D); 1H NMR δ = 3.75 (6H, d, JPOMe
= 10.8 Hz, Me), 7.47 [2H, td, Jo,m = Jm,p = 7.6, Jm,P = 4.3 Hz, Ph(m)], 7.56 [1H, tq, Jo,p = Jp,P = 1.4 Hz,
Ph(p)], 7.79 [2H, ddd, Jo,P = 13.2 Hz, Ph(o)]; 31P NMR δ = 20.5.
Grignard reaction of 10a.
The mixture of magnesium (30 mg, 1.23 mmol) and 1,2-dibromoethane (0.01 mL) in dry THF (2 mL)
was stirred vigorously and a solution of 10a (230 mg, 0.623 mmol) in dry THF (3 mL) was added
dropwise. The mixture was refluxed for 4 h and then diluted with saturated NH4Cl aqueous solution (5
mL). The mixture was extracted with CHCl3 three times. The combined organic layers were washed
with water, dried (Na2SO4), and evaporated in vacuo. The residue was separated by column
chromatography with AcOEt to give ethyl (R and S)-[(2R)-2-methoxy-3-butenyl](phenyl)phosphinate
(26) (93.8 mg, 59%) and 3 (3.0 mg, 2%).
1
26: Colorless syrup; Rf = 0.28 (D); H NMR δ = 1.27, 1.29* (3H, 2t, JEt = 7.2 Hz, C–CH3), 2.07*, 2.13
(1H, 2ddd, J1’,P = 12.8*, 18.3, J1,1’ = 15.3*, 15.3, J1’,2 = 5.5*, 4.9 Hz, H’-1), 2.26, 2.25* (1H, 2ddd, J1,P
=
11.3, 15.0*, J1,2 = 8.5, 7.9* Hz, H-1), 3.07, 3.19* (3H, 2s, MeO), 3.83, 3.88* (1H, 2dquint, JH,H’ = 10.4,
JH’,P = 7.0 Hz, POCH’), 3.93, 3.93* (1H, m, H-2), 4.04, 4.08* (1H, 2dquint, JH,P = 7.0 Hz, POCH), 5.09*,
5.165 [1H, 2ddd, J3,4E = 10.1, J4E, 4Z = 1.5, J2,4E = 1.0 Hz, H-4(E)], 5.17*, 5.19 [1H, 2dt, J3,4Z = 17.1, J2,4Z
= 1.0 Hz, H-4(Z)], 5.56*, 5.66 (1H, 2ddd, J2,3 = 7.6 Hz, H-3), 7.45, 7.46* [2H, 2m, P–Ph(m)], 7.52, 7.52*
[1H, m, P–Ph(p)], 7.76*, 7.77 [2H, 2m, P–Ph(o)]; 31P NMR δ = 41.1, 42.3* (56:44* diastereomeric mixture,
the assignment of some of the δ values may have to be interchanged). Anal. Calcd for C14H19O3P: C,
2
63.15; H, 7.19. Found: C, 63.28; H, 7.09.
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements.
REFERENCES AND NOTES
1. H. Paulsen, Angew. Chem., Int. Ed. Engl., 1966, 5, 495; M. J. Pitts, M. Chmielewski, M. S. Chen, M.
M. A. Abd El-Rahman, and R. L. Whistler, Arch. Biochem. Biophys., 1975, 169, 384; R. L. Whistler
and A. K. M. Anisuzzaman, ’Synthetic Methods for Carbohydrate’, ed. by H. S. El Khadem,

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261
American Chemical Society, Washington D.C., 1977, pp. 133–154; H. Yuasa, M. Izumi, and H.
Hashimoto, Yuki Gosei Kagaku Kyokai Shi, 2002, 60, 774.
2. T. Hanaya and H. Yamamoto, Trends in Heterocyclic Chemistry, 2003, 9, 1; T. Hanaya and H.
Yamamoto, Yuki Gosei Kagaku Kyokai Shi, 1993, 51, 377; H. Yamamoto and T. Hanaya, ’Studies in
Natural Products Chemistry’, ed. by T. I. Atta-ur-Rahman, Elsevier, Amsterdam, 1990, Vol. 6, pp.
351–384.
3. T. Hanaya and H. Yamamoto, Bull. Chem. Soc. Jpn., 1989, 62, 2320; H. Yamamoto, Y. Nakamura,
S. Inokawa, M. Yamashita, M.–A. Armour, and T. T. Nakashima, J. Org. Chem., 1984, 49, 1364.
4. T. Hanaya, A. Noguchi, M.–A. Armour, A. M. Hogg, and H. Yamamoto, J. Chem. Soc., Perkin
Trans. 1, 1992, 295; T. Hanaya, A. Noguchi, and H. Yamamoto, Carbohydr. Res., 1991, 209, c9.
5. R. P. Polniaszek and A. L. Foster, J. Org. Chem., 1991, 56, 3137.
6. A. Yabui, M. Yamashita, T. Oshikawa, T. Hanaya, and H. Yamamoto, Chem. Lett., 1993,93.
7. R. B. Wetzel and G. L. Kenyon, J. Org. Chem., 1974, 39, 1531.
8. S.-C. Wong, N. I. Carruthers, and T.-M. Chan, J. Chem. Res. (S), 1993, 268.
9. T. Hanaya, A. Akamatsu, S. Kawase, and H. Yamamoto, J. Chem. Res. (S), 1995, 194.
10. D. J. Collins, P. F. Drygala, and J. M. Swan, Aust. J. Chem., 1983, 36, 2095; L. Germanaud, S.
Brunel, Y. Chevalier, and P. Le Perchec, Bull. Soc. Chim. Fr., 1988, 699.
11. D. Seebach, H.-O. Kalinowski, B. Bastani, G. Crass, H. Daum, H. Dörr, N. P. DuPreez, V. Ehrig, W.
Langer, C. Nüssler, H.-A. Oei, and M. Schmidt, Helv. Chim. Acta, 1977, 60, 301; A. C. Cope and A.
S. Mehta, J. Am. Chem. Soc., 1964, 86, 5626.
12. K. Shishido, K. Takahashi, K. Fukumoto, T. Kametani, and T. Honda, J. Org. Chem., 1987, 52,
5704.
13. H. Dehmlow, J. Mulzer, C. Seilz, A. R. Strecker, and A. Kohlmann, Tetrahedron Lett., 1992, 33,
3607; P. A. Fowler, A. H. Haines, R. J. K. Taylor, E. J. T. Chrystal, and M. B. Gravestock, J. Chem.
Soc., Perkin Trans. 1, 1993, 1003.
14. Bromination of 17a with same reagents at room temperature resulted in a lower yield (30%) of 18.
15. The carbohydrate nomenclature for 3: 1,4-dideoxy-2,3-di-O-methyl-1,4-phenylphosphonoyl-L-
threitol.
16. K. Issleib, K. Krech, K. Gruber, Chem. Ber., 1963, 96, 2186; J. H. Davies, J. D. Downer, and P.
Kirby, J. Chem. Soc. (C), 1966, 245.