Synthesis of functionalized phospholane oxides and phosphorinane oxides from 1,4- and 1,5-di-o-mesyloxy compounds

Article abstract of DOI:10.3987/COM-06-S(O)28

Treatment of 1,4-di-O-mesyl-2,3-di-O-methyl-L-threitol (8b) with phenylphosphine in the presence of sodium hydride in DMSO, followed by the action of hydrogen peroxide, afforded 3,4-dimethoxy-l-phenylphospholane 1-oxide (7), while the same treatment of 1,

Full text of DOI:10.3987/COM-06-S(O)28

HETEROCYCLES, Vol. 69, 2006
283
HETEROCYCLES, Vol. 69, 2006, pp. 283 - 294. © The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2006, Accepted, 27th July, 2006, Published online, 28th July, 2006. COM-06-S(O)28
SYNTHESIS OF FUNCTIONALIZED PHOSPHOLANE OXIDES AND
PHOSPHORINANE OXIDES FROM 1,4- AND 1,5-DI-O-MESYLOXY
COMPOUNDS
Tadashi Hanaya,* Karsten Schürrle, and Hiroshi Yamamoto
Department of Chemistry, Faculty of Science, Okayama University,
Tsushima-naka, Okayama 700-8530, Japan
Abstract – Treatment of 1,4-di-O-mesyl-2,3-di-O-methyl-L-threitol (8b) with
phenylphosphine in the presence of sodium hydride in DMSO, followed by the
action of hydrogen peroxide, afforded 3,4-dimethoxy-1-phenylphospholane 1-
oxide (7), while the same treatment of 1,5-di-O-mesyl-2,3,4-tri-O-methyl-meso-
xylitol (11b) provided 2,3,4-trimethoxy-1-phenylphosphorinane 1-oxide (14).
INTRODUCTION
In view of the wide interest in their chemical and potential biological properties,1 various sugar analogs
having a heteroatom (instead of oxygen) in the ring have been prepared. Among such a chemical
modification by heteroatoms, we have prepared various sugar analogs (phospha sugars) containing a
phosphorus atom in the ring2: e.g. D-ribose (1)3 and 2-deoxy-D-ribose analogs (2)4 of furanose-type
(phospholane oxide), D-xylose (3)5 and D-glucose analogs (4)6 of pyranose-type (phosphorinane oxide).
Although some procedures available for introduction of a phosphinoyl group into sugar moiety were
developed,7 synthesis of such sugar analogs often requires rather long reaction steps. Attempts are thus
needed to explore a simpler preparative method for the phospholane oxide and the phosphorinane oxide
having oxygen functional groups on the ring carbons, since these compounds are potentially useful
precursors for various types of phospha furanoses and pyranoses by introducing substituents on the α-
carbon of the ring phosphorus.8
2
O
R O
1
HO
1
P
R
P R
OH
OH
OH
HO
1
HO R
OH
1
R = OH, Et, Ph
2
2
1 R = OH
3 R = H
2
2
2 R = H
4 R = CH OH
2

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HETEROCYCLES, Vol. 69, 2006
In a previous paper,9 we reported synthesis of phospholane 1-oxide having oxygen functional groups
from a 4-bromobutylphosphinate derivative (Scheme 1): 3,4-dimethoxy-1-phenylphospholane 1-oxide (7)
was obtained in 48% yield by the reductive cyclization of ethyl 4-bromo-2,3-
dimethoxybutyl(phenyl)phosphinate (6) [prepared from 2,3-di-O-methyl-L-threitol (5) in five steps (29%
total yield)] with sodium dihydrobis(2-methoxyethoxy)aluminate (SDMA), followed by the action of
hydrogen peroxide. In this procedure, the formation of phospholane ring is based on a two-step
approach for C-P bond introduction and an improvement is desirable to prepare the 4-substituted
butylphosphinate precursor.
Meanwhile, the ring formation of α,ω-dihaloalkanes with metallic phosphide has also been reported as a
procedure for synthesis of phospholanes and phosphorinanes: 1-phenylphospholane was obtained in 30%
yield from 1,4-dichlorobutane and dilithium phenylphosphide.10 As such an approach appeared more
suitable for our purposes, we have examined a modification of the leaving groups of substrate (8) as well
as the reaction conditions to provide 7 in a satisfactory yield (Scheme 1). We describe herein our
synthetic studies on the phospholane oxides and phosphorinane oxides having oxygen functional groups
on the ring-carbons via the ring formation of α,ω-disubstituted compounds with phenylphosphide.
OH
Br
O
MeO
MeO
MeO
MeO
P Ph
1) SDMA
2) H O
O
OMe
OH
P Ph
2
2
OMe
OEt
5
6
7
X
1) PhPH , base
2
MeO
MeO
X
2) H O
2
2
8 (X = leaving group)
Scheme 1
RESULTS AND DISCUSSION
For the precursors of phospholane-ring formation we chose the 1,4-dibromide and 1,4-di-O-mesylate of 5
(Scheme 2). Bromination of 5 with NBS in the presence of triphenylphosphine in DMF afforded the
1,4-dibromo-1,4-dideoxy-L-threitol derivative (8a)11 in 64% yield, while mesylation of 5 with mesyl
chloride in the presence of pyridine in dichloromethane provided the 1,4-di-O-mesyl derivative (8b)12 in
93%. The dibromide (8a) was also obtained from 8b by the reaction with tetraethylammonium bromide
in DMF in 86%.
Conversion of 8a,b to 3,4-dimethoxy-1-phenylphospholane (9) was then examined and the results are
summarized in Table 1. Treatment of 1,4-dibromo compound (8a) with dilithium phenylphosphide,10
prepared from phenylphosphine13 and n-butyllithium in THF, afforded 9 in 52% yield (Entry 1), while
application of the Kabachnik’s procedures14 for alkylation of phenylphosphine (use of aqueous KOH in

HETEROCYCLES, Vol. 69, 2006
285
DMSO at 60 °C) improved the yield of 9 (Entry 2). In order to enhance the concentration of
phenylphosphide anion, the Kabachnik’s conditions were modified by use of stronger base in anhydrous
solvent. Thus, treatment of 8a with phenylphosphine in the presence of sodium hydride in dry DMSO at
60 °C afforded 9 in a satisfactory yield (86%) (Entry 3). By employing the same conditions, the 1,4-di-
O-mesyl derivative (8b) also gave 9 in a similar yield (Entry 4). Therefore the di-O-mesylate (8b) is
apparently a more suitable precursor for our purposes in comparison with the dibromide (8a). The
phenylphospholane (9) was converted into the desired phenylphospholane oxide (7) in a quantitative yield
by oxidation with hydrogen peroxide.
Preparation of the functionalized phosphorinane oxide was then examined by applying the optimized
procedures described above for the ring formation with phenylphosphide (Scheme 3). As the starting
material for 3,4,5-trimethoxyphosphorinane 1-oxide (14), 2,3,4-tri-O-methyl-meso-xylitol (10) was made
from D-xylose in four steps according to the reported method.15
Bromination of 10 with
triphenylphosphine and NBS resulted in a predominant formation of 1,4-anhydro-5-bromo-5-deoxy-2,3-
di-O-methyl-DL-xylitol (12) in 38% yield; the desired 1,5-dibromo compound (11a)16 was obtained in a
minor portion (22% yield). Production of 12 can be perceived as the result of the intramolecular
substitution of 11a caused by a methoxy oxygen locating in δ-position of a leaving group.17 However,
when 10 was subjected to mesylation at 0 °C with mesyl chloride in dichloromethane in the presence of
pyridine, the 1,5-di-O-mesyl-meso-xylitol derivative (11b)15,16 was obtained in 89% yield. We therefore
employed 11b as a preferable precursor for the following steps.
O
X
a) NBS, PPh
o
3
P Ph
OMe
P Ph
MeO
MeO
DMF, 40 C, 2 h
PhPH
H O
2 2
2
OMe
5
X
see, Table 1
CH Cl
2
rt, 1 h
b) MsCl, Py
CH Cl , rt, 1h
2
OMe
OMe
2
2
98%
8a X = Br (64%)
9
7
Et NBr, DMF
4
o
8b X = OMs (92%)
100 C, 3 h
86%
Scheme 2
Table 1. Preparation of 3,4-dimethoxy-1-phenylphospholane (9) a
——————————————————————————————————————————————
b
Entry
Substrate
Base
Solvent
Temperature, Time
Yield of 9
——————————————————————————————————————————————
1
2
3
4
8a
8a
8a
8b
n-BuLi
KOH
NaH
THF
20 °C, 2 h
60 °C, 2 h
60 °C, 1 h
60 °C, 1 h
52%
72%
86%
88%
DMSO-H2O
DMSO
DMSO
NaH
——————————————————————————————————————————————
a
b
All reactions were carried out by use of 1.3 mol equiv of phenylphosphine and 3 mol equiv of base.
Isolated
yield by column chromatography. In all cases, a minor amount (ca. 5%) of phospholane oxide (7) was also isolated.

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HETEROCYCLES, Vol. 69, 2006
OH
Br
Br
MeO
MeO
MeO
MeO
O
OMe
NBS, PPh
3
+
DMF
OH
Br
o
OMe
40 C, 2 h
OMe
OMe
10
11a (22%)
12 (38%)
OMs
Ph
P
Ph
MsCl,Py
CH Cl
rt, 1 h
89%
MeO
MeO
P O
OMe
PhPH , NaH
H O
2 2
2
2
2
OMe
OMs
DMSO
CH Cl
2
2
MeO
MeO
o
OMe
60 C, 1 h
rt, 1 h
OMe
OMe
14
83% (from 11b)
11b
13
Scheme 3
Treatment of compound (11b) with phenylphosphine in the presence of sodium hydride in DMSO at
60 °C afforded a crude mixture of the phenylphosphorinane (13) and a minor portion of its oxidized
product. The mixture was oxidized with hydrogen peroxide and then purified on a silica gel column.
The product thus obtained was a sole isomer, whose structure was assigned to be the (1S)-
1-phenylphosphorinane 1-oxide derivative (14) on the basis of 1H NMR spectra (see below).
An application of these procedures to the ring formation of an asymmetric 1,4-dimesyloxy compound was
exemplified by the synthesis of (3S)-3-hydroxy-1-phenylphospholane 1-oxide (21) (Scheme 4). Taking
into consideration de-O-protection of the oxygen functional group on the ring, we employed acid-labile
methoxymethyl (MOM) group. Thus, dimethyl L-malate (15) was treated with chloromethyl methyl
ether in the presence of N-ethyldiisopropylamine to give the 2-O-MOM-L-malate (16). Compound (16)
was reduced with lithium aluminum hydride to afford the diol (17),18 which was then mesylated with
mesyl chloride to provide the 1,4-di-O-mesyl-2-O-MOM derivative (18).19
OH
COOMe
COOMe
HO
MOMO
MOMO
MsCl, Py
MOMCl
LiAlH
4
i
COOMe
COOMe
OH
Pr NEt
2
ether
CH Cl , rt, 1 h
2
2
CH Cl , rt, 2 h
rt, 1 h
2
2
90%
15
16
17
96%
91%
O
O
P
OMs
P
Ph
P
Ph
Ph
PhPH
NaH
H O
2 2
HCl
THF
2
MOMO
CH Cl
2
2
OMs
o
40 C, 12 h
DMSO
rt, 1 h
79% (from 18)
MOMO
MOMO
HO
o
92%
60 C, 1 h
18
19
20
21
Scheme 4

HETEROCYCLES, Vol. 69, 2006
287
According to the synthetic procedures for 7 and 14, the treatment of 18 with phenylphosphine and sodium
hydride (to give 19) and the subsequent oxidation with hydrogen peroxide afforded (1RS,3S)-3-O-MOM-
1-phenylphospholane 1-oxides (20) as an inseparable diastereomeric mixture (9:1) with regard to
phosphorus atom. Cleavage of MOM group of 20 was achieved by acid hydrolysis, affording 21 in 92%.
1
The major isomer of 21 was isolated by crystallization and assigned to be the (1R)-epimer (21a) by H
NMR spectra (see below).
The structural and conformational assignments of 7, 14, 21a were made on basis of their 1H NMR data by
referring to characteristic tendency of coupling constants and chemical shifts of phospha sugars (1–4)
having similar ring structures.2–6 The favored conformations of 7, 14, 21a in CDCl3 are shown in Figure
1.
(1) Compound (7) has large values of J3,P and J4,P (ca. 23 Hz) and thus is considered to exist
4
4
4
predominantly in the T3 conformation (or readily variable E ⇄ T3 ⇄ E3).3,4,20 Although the
2
phosphorus atom is not asymmetric, orientation of P=O can be derived from the magnitude of two J2,P
values. Namely, the small J2R,P and J5S,P values (4.4 and 8.3 Hz) indicate a trans (or anti) relationship of
the HR-2 (HS-5) and P=O, whereas the large J2S,P and J5R,P values (18.6 and 13.4 Hz) points out a cis (or
gauche) relationship of the HS-2 (HR-5) and P=O.21 All ring protons being in the cis connection with
P=O (HS-2, H-3, HR-5) appear at lower field compared with the corresponding trans protons (HR-2, H-4,
HS-5). This can be explained in terms of a deshielding effect of P=O bond oriented to the same side of
the ring and thus supports the structural assignments described above for 7.
(2) The large coupling constant (10.5 Hz) between HR-2 and H-3 of 14 indicates the axial orientation of
5
these two protons and thus a predominant existence in the C2 conformation having three equatorial
methoxy groups. As for the orientation of P=O bond, the large J2R,P value (17.6 Hz) suggests the gauche
connection of HR-2–C-2–P=O, namely an equatorial P=O bond having the (S)-configuration.
(3) The assignments for HR-2 (δ 2.20) and HR-4 (δ 1.99) of 21a were confirmed by observation of NOE
between these signals and H-3 signal (δ 4.68). The large value of J3,P (23.2 Hz) and the small value of
3
J4R,P (8.6 Hz)22 indicate 21a exists preponderantly in the 3T4 conformation (or readily variable 3E ⇄ T4
⇄ E4).3,4,20 The (R)-configuration of the phosphorus is derived from relatively small J2R,P and J5S,P
values (6.2 and 8.6 Hz)22 which suggest the anti relationship of HR-2 (HS-5) and P=O. This configuration
is supported by the existence of weak NOE between HR-2, HS-5 signals and ortho protons of the phenyl
group.
O
P
O
P
Ph
P
H
5
OH
MeO
6
Ph
Ph
HR
HS
2 HS
H
5
MeO
MeO
O
HR
HS
HR
3
2
HS
4
4
3
5
2
3
4
H
H
MeO
HS
HR
HR
HS
HR
MeO
7
14
21a
Figure 1. Structures and favored conformations for phospholane oxides (7, 21a) and phosphorinane
oxide (14)

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HETEROCYCLES, Vol. 69, 2006
The present work demonstrates a convenient way for preparation of phospholane oxides and
phosphorinane oxides having oxygen functional groups, which are potencially useful precursors for
phospha sugars; e.g., phospholane oxide (20) for 2-deoxy-D-ribofuranose analog (2). Application of
these findings in further synthesizing other functionalized phospholane oxides and phosphorinane oxides,
as well as their derivation into various phospha sugar derivatives, is in progress.
EXPERIMENTAL
All reactions were monitored by TLC (Merck silica gel 60F, 0.25 mm) with an appropriate solvent system
[(A) 1:2, (B) 2:1 AcOEt–hexane, and (C) 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 heating). Optical rotations were
measured with a JASCO P-1020 polarimeter. The NMR spectra were measured in CDCl3 with Varian
1
Unity Inova AS600 (600 MHz for H, 151 MHz for 13C) and Mercury 300 (121 MHz for 31P)
spectrometer at 23 °C. Chemical shifts are reported as δ values relative to CHCl3 (7.26 ppm as an
internal standard for 1H), CDCl3 (77.0 ppm as internal standard for 13C), and 85% phosphoric acid (0 ppm
as an external standard for 31P). The assignments of 13C signals were made with the aid of 2D C-H
COSY measurements.
1,4-Dibromo-1,4-dideoxy-2,3-di-O-methyl-L-threitol (8a).11
A. From 5. To a solution of 5 (160 mg, 1.07 mmol) and triphenylphosphine13 (840 mg, 3.20 mmol) in
dry DMF (4 mL) was added NBS (570 mg, 3.20 mmol) at 0 °C. The mixture was stirred at 40 °C for 2 h
and then methanol (1 mL) was added at 0 °C. The mixture was concentrated in vacuo. The residue
was dissolved in CHCl3, washed with water, dried (Na2SO4), and evaporated in vacuo. The residue was
purified by column chromatography with 1:4 AcOEt-hexane to give 8a (189 mg, 64%) as a colorless oil:
Rf = 0.73 (A).
B. From 8b. A solution of 8b (185 mg, 0.604 mmol) and tetrabutylammonium bromide (400 mg, 1.90
mmol) in DMF (5 mL) was stirred at 100 °C for 3 h and then concentrated in vacuo. After addition of
water, the solution was extracted with CHCl3 three times. The combined extracts were washed with
water, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed to give 8a (143 mg,
86%) (lit.,11 82% yield from the 1,4-di-O-tosyl derivative).
1,4-Di-O-mesyl-2,3-di-O-methyl-L-threitol (8b).12
To a solution of 5 (2.00 g, 13.3 mmol) and pyridine (2.40 ml, 29.7 mmol) in dry CH2Cl2 (20 mL) was
added mesyl chloride (2.25 mL, 29.1 mmol) at 0 °C. The mixture was stirred at rt for 1 h and then
diluted with CHCl3 (30 mL). The mixture was washed with water, dried (Na2SO4), and evaporated in
vacuo. The residue was purified by column chromatography with 1:4 AcOEt-hexane to give 8b (3.75 g,
92%) as colorless needles: mp 53–54 °C (from AcOEt-hexane) (lit.,12 92% yield using pyridine as a

HETEROCYCLES, Vol. 69, 2006
289
solvent, mp 53.8–54.5 °C).
(3R,4R)-3,4-Dimethoxy-1-phenylphospholane (9).9
To a suspension of sodium hydride (60% in mineral oil, 460 mg, 11.5 mmol) in dry DMSO (4 mL) was
added, with stirring, phenylphosphine (0.550 mL, 5.00 mol) at 0 °C under argon. After stirring at rt for
15 min, a solution of 8b (1.17 g, 3.82 mol) in dry DMSO (3 mL) was added. Then the mixture was
stirred at 60 °C for 1 h, diluted with water (40 mL), and extracted with CHCl3 three times. The
combined extracts were dried (Na2SO4), and evaporated in vacuo. The residue was purified by column
1
chromatography with 1:3 AcOEt-hexane to give 9 (753 mg, 88%) as a colorless syrup: Rf = 0.56 (A); H
NMR δ = 1.96 (1H, ddd, J2R,2S = 14.4, J2R,P = 5.7, J2R,3 = 4.8 Hz, HR-2), 2.04 (1H, ddd, J5R,P = 22.4, J5R,5S
= 14.2, J4,5R = 6.8 Hz, HR-5), 2.22 (1H, ddd, J5S,P = 5.4, J4,5S = 3.5 Hz, HS-5), 2.46 (1H, ddd, J2S,P = 23.9,
J2S,3 = 6.5 Hz, HS-2), 3.36, 3.37 (3H each, 2s, MeO-3,4), 3.87 (1H, dddd, J4,P = 17.0, J3,4 = 5.7 Hz, H-4),
3.88 (1H, dddd, J3,P = 17.0 Hz, H-3), 7.28 [1H, tq, Jm,p = 7.2, Jo,p = Jp,P = 1.4 Hz, Ph(p)], 7.33 [2H, ddd,
Jo,P = 7.6, Jo,m = 7.2 Hz, Ph(o)], 7.51 [2H, td, Jm,P = 1.8 Hz, Ph(m)]; 31P NMR δ = –29.3.
(3R,4R)-3,4-Dimethoxy-1-phenylphospholane 1-oxide (7).9,23
Compound (9) (200 mg, 0.892 mmol) was dissolved in CHCl3 (4 mL) and treated with 30% H2O2 (1.0
mL, 10 mmol) at rt for 1 h. The mixture was diluted with CHCl3 (20 mL), washed with water, dried
(Na2SO4), and evaporated in vacuo. The residue was purified by column chromatography with 1:19
EtOH-AcOEt to give 7 (210 mg, 98%) as colorless prisms: mp 76–77 °C (from AcOEt-hexane) (lit.,9 mp
76–77 °C); Rf = 0.24 (C); [α]D27 +63.6° (c = 1.23, CHCl3); 1H NMR δ = 2.19 (1H, ddd, J2R,2S = 15.9, J2R,P
= 4.4, J2R,3 = 3.4 Hz, HR-2), 2.23 (1H, ddd, J5R,5S = 15.6, J5S,P = 8.3, J4,5S = 5.1 Hz, HS-5), 2.27 (1H, dddt,
J5R,P = 13.4, J4,5R = 3.7, J3,5R = J2S,5R = 1.0 Hz, HR-5), 2.46 (1H, dddd, J2S,P = 18.6, J2S,3 = 5.9 Hz, HS-2),
3.41, 3.45 (3H each, 2s, MeO-3,4), 4.06 (1H, dddd, J4,P = 23.0, J3,4 = 3.7 Hz, H-4), 4.17 (1H, ddtd, J3,P
23.2 Hz, H-3), 7.48 [2H, tdd, Jo,m = Jm,p = 7.3, Jm,P = 2.9, Jo’,m = 1.5 Hz, Ph(m)], 7.52 [1H, tq, Jo,p = Jp,P
=
=
1.6 Hz, Ph(p)], 7.83 [2H, ddt, Jo,P = 12.2 Hz, Ph(o)]; 13C NMR δ = 32.54 (d, 1J5,P = 65.1 Hz, C-5), 33.02
1
2
2
(d, J2,P = 64.5 Hz, C-2), 56.99 (MeO), 57.08 (MeO), 82.17 (d, J3,P = 8.6 Hz, C-3), 82.42 (d, J4,P = 6.9
Hz, C-4), 128.55 [d, 3Jm,P = 12.7 Hz, Ph(m)], 130.54 [d, 2Jo,P = 10.9 Hz, Ph(o)], 131.67 [d, 4Jp,P = 2.9 Hz,
Ph(p)], 133.55 [d, 1Jipso,P = 94.4 Hz, Ph(ipso)]; 31P NMR δ = 53.6.
1,5-Dibromo-1,5-dideoxy-2,3,4-tri-O-methyl-meso-xylitol (11a) and 1,4-anhydro-5-bromo-5-deoxy-
2,3-di-O-methyl-DL-xylitol (12).
Similar procedures to those for 8a from 5 were employed. Compound (10) (80.0 mg, 0.412 mmol) was
treated with triphenylphosphine (324 mg, 1.24 mmol) and NBS (220 mg, 1.24 mmol) in dry DMF (2 mL)
at 40 °C for 1 h. Purification of the resulting mixture by column chromatography with 1:3 AcOEt-
hexane gave 11a (29.1 mg, 22%) and 12 (35.4 mg, 38%).
11a: Colorless oil: Rf = 0.63 (A); 1H NMR δ = 3.44 (2H, dd, J1,1’ = 10.5, J1’,2 = 5.1 Hz, H’-1,5), 3.47 (6H,
s, MeO-2,4), 3.59 (3H, s, MeO-3), 3.62 (2H, dd, J1,2 = 6.1 Hz, H-1,5), 3.67 (2H, ddd, J2,3 = 4.3 Hz, H-2,4),
3.76 (1H, t, H-3). Anal. Calcd for C8H16Br2O3: C, 30.03; H, 5.04. Found: C, 29.93; H, 4.92.

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HETEROCYCLES, Vol. 69, 2006
12: Colorless oil: Rf = 0.55 (A); 1H NMR δ = 3.38, 3.45 (3H each, 2s, MeO-2,3), 3.43 (1H, dd, J5,5’ = 9.8,
J4,5’ = 6.1 Hz, H’-5), 3.52 (1H, dd, J4,5 = 8.3 Hz, H-5), 3.78 (1H, dd, J3,4 = 3.7, J2,3 = 0.8 Hz, H-3), 3.83
(1H, dd, J1,1’ = 10.0 Hz, J1’,2 = 1.7 Hz, H’-1), 3.88 (1H, ddd, J1,2 = 4.6 Hz, H-2), 4.09 (1H, dd, H-1), 4.21
(1H, ddd, H-4). Anal. Calcd for C7H13BrO3: C, 37.35; H, 5.82. Found: C, 37.19; H, 5.71.
1,5-Di-O-mesyl-2,3,4-tri-O-methyl-meso-xylitol (11b).15
By use of same procedures described for 8b from 5, compound (10) (2.80 g, 14.4 mmol) was treated with
mesyl chloride (2.45 mL, 31.7 mmol) and pyridine (2.60 mL, 32.2 mmol) in dry CH2Cl2 (20 mL) to give
1
11b (4.51 g, 89%) (lit.,15 78% yield using triethylamine as a base) as a colorless syrup: Rf = 0.30 (B); H
NMR24 δ = 3.05 (6H, s, MsO-1,5), 3.49 (6H, s, MeO-2,4), 3.51 (1H, t, J2,3 = 4.4 Hz, H-3), 3.52 (3H, s,
MeO-3), 3.76 (2H, dt, J1’,2 = 6.1, J1,2 = 4.3 Hz, H-2,4), 4.29 (2H, dd, J1,1’ = 11.0 Hz, H’-1,5), 4.46 (2H, dd,
H-1,5).
(1S,3R,4S,5S)-3,4,5-Trimethoxy-1-phenylphosphorinane 1-oxide (14).23
By use of same procedures described for 9 from 8b, compound (11b) (2.00g, 5.71 mmol) was treated
with phenylphosphine (0.820 mL, 7.45 mmol) and sodium hydride (60% in mineral oil, 685 mg, 17.1
mmol) in dry DMSO (15 mL). The resulting crude syrup which mainly consisted of (1R,3R,4S,5S)-
3,4,5-trimethoxy-1-phenylphosphorinane (13) was used for the next step without further purification.
A pure sample of 13 was obtained by column chromatography: colorless syrup; Rf = 0.45 (A); 1H NMR δ
= 1.70 (2H, ddd, J2R,2S = 15.2, J2R,3 = 11.3, J2R,P = 9.5 Hz, HR-2,6), 2.51 (1H, ddd, J2S,3 = 3.8, J2S,P = 3.5
Hz, HS-2), 2.95 (1H, t, J3,4 = 9.0 Hz, H-4), 3.23 (2H, ddd, J3,P = 0 Hz, H-3,5), 3.42 (6H, s, MeO-3,5), 3.54
(3H, s, MeO-4), 7.22 [1H, tq, Jm,p = 7.2, Jo,p = Jp,P = 1.5 Hz, Ph(p)], 7.32–7.36 [4H, m, Ph(o,m)]; 31P
NMR δ = –41.2.
The above crude syrup was dissolved in CHCl3 (10 mL), treated with 30% H2O2 (2.0 mL, 20 mmol) at rt
for 1 h. The mixture was diluted with CHCl3 (20 mL), washed with water, dried (Na2SO4), and
evaporated in vacuo. The residue was purified by column chromatography with 1:19 EtOH-AcOEt to
give 14 (1.32 g, 81%) as colorless needles: mp 76–77 °C (from AcOEt-hexane); Rf = 0.27 (C); 1H NMR δ
= 2.25 (2H, ddd, J2R,P = 17.6, J2R,2S = 15.1, J2R,3 = 10.5 Hz, HR-2,6), 2.71 (1H, ddd, J2S,P = 14.2, J2S,3 = 2.9
Hz, HS-2,6), 3.27-3.32 (3H, m, H-3,4,5), 3.43 (6H, s, MeO-3,5), 3.56 (3H, s, MeO-4), 7.54 [2H, tdd, Jo,m
= Jm,p = 7.4, Jm,P = 3.2, Jo’,m = 1.4 Hz, Ph(m)], 7.57 [1H, tq, Jo,p = Jp,P = 1.5 Hz, Ph(p)], 7.75 [2H, ddt, Jo,P
1
= 11.5 Hz, Ph(o)]; 13C NMR δ = 30.20 (d, J2,P = 61.6 Hz, C-2,6), 57.64 (MeO-3,5), 60.29 (MeO-4),
77.73 (d, 2J3,P = 4.0 Hz, C-3,5), 86.72 (C-4), 129.21 [d, 3Jm,P = 11.5 Hz, Ph(m)], 129.49 [d, 2Jo,P = 9.8 Hz,
1
4
Ph(o)], 132.27 [d, Jipso,P = 96.7 Hz, Ph(ipso)], 132.36 [d, Jp,P = 2.3 Hz, Ph(p)]; 31P NMR δ = 29.7.
Anal. Calcd for C14H21O4P: C, 59.15; H, 7.45. Found: C, 59.29; H, 7.61.
Dimethyl 2-O-(methoxymethyl)-L-malate (16).
To a solution of 15 (1.32 g, 8.14 mmol) and N-ethyldiisopropylamine (2.10 mL, 12.1 mmol) in dry
CH2Cl2 (10 mL) was added chloromethyl methyl ether (0.92 mL, 12.1 mmol) at 0 °C. The mixture was
stirred at rt for 2 h and then diluted with CHCl3 (20 mL). The mixture was washed with water, dried

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(Na2SO4), and evaporated in vacuo. The residue was purified by column chromatography with 1:2
27
AcOEt-hexane to give 16 (1.61 g, 96%) as a colorless oil: Rf = 0.40 (A); [α]D = –67.1° (c = 2.34,
1
CHCl3); H NMR δ = 2.81 (1H, dd, J3,3' = 10.5, J2,3' = 6.8 Hz, H'-3), 2.815 (1H, dd, J2,3 = 5.6 Hz, H-3),
2
3.38 (3H, s, MeO-C-O-2), 3.71, 3.76 (3H each, 2s, COOMe), 4.70, 4.74 (1H each, 2d, JCH2 = 7.1 Hz,
13
CH2O-2); C NMR δ = 37.66 (C-3), 51.98 and 52.30 (COOMe), 56.12 (MeOCH2), 71.75 (C-2), 96.44
(CH2O), 170.39 (C-4), 171.65 (C-1). Anal. Calcd for C8H14O6: C, 46.60; H, 6.84. Found: C, 46.72; H,
6.63.
(S)-2-O-(Methoxymethyl)-1,2,4-butanetriol (17).18
To a solution of 16 (1.65 g, 8.00 mmol) in dry diethyl ether (20 mL) was added a suspension of lithium
aluminum hydride (610 mg, 16.0 mmol) in dry diethyl ether (20 mL) at 0 °C under argon. The mixture
was stirred at rt for 1 h and then water (2 mL) was added. The mixture was diluted with ethyl acetate
(30 mL) and filtered through Celite. The filtrate was evaporated in vacuo and the residue was purified
by short-path column chromatography with AcOEt to give 17 (1.09 g, 91%) [lit.,18 69% yield by
reduction of bis(methoxymethyl) 2-O-(methoxymethyl)-L-malate with borane-dimethyl sulfide]: colorless
oil; Rf = 0.09 (B).
(S)-1,4-Di-O-mesyl-2-O-(methoxymethyl)-1,2,4-butanetriol (18).19
By use of same procedures described for 8b from 5, compound (17) (1.74 g, 11.6 mmol) was treated with
mesyl chloride (2.00 mL, 25.8 mmol) and pyridine (2.10 mL, 26.0 mmol) in dry CH2Cl2 (20 mL) to give
18 (3.21 g, 90%) [lit.,19 100% yield by methoxymethylation of 1,4-di-O-mesyl-1,2,4-butanetriol with
dimethoxymethane]: colorless syrup; Rf = 0.26 (B).
(1RS,3S)-3-Methoxymethoxy-1-phenylphospholane 1-oxide (20).
By use of same procedures described for 9 from 8b, compound (11b) (2.98 g, 9.72 mmol) was treated
with phenylphosphine (1.35 mL, 12.3 mmol) and sodium hydride (60% in mineral oil, 1.16 g, 29.0 mmol)
in dry DMSO (20 mL). The resulting crude syrup which mainly consisted of (3S)-3-methoxymethyl-1-
phenylphospholane (19) was used for the following step without further purification.
A pure sample of 19 was obtained by column chromatography: pale yellow syrup; Rf = 0.67 (A); 31P
NMR δ = –19.7, –20.1* (89:11* diastereomeric mixture with regard to the phosphorus atom); 1H NMR for
the major isomer δ = 1.88–2.08 (3H, m, H’-2,4,5), 2.11–2.25 (3H, m, H-2,4,5), 3.37 (3H, s, MeO), 4.36
2
(1H, sext, J2,3 = J2’,3 = J3,4 = J3,4’ = J3,P = 5.3–5.5 Hz, H-3), 4.625, 4.66 (1H each, 2d, JCH2 = 6.9 Hz,
CH2O-3), 7.25 [1H, tq, Jm,p = 7.2, Jo,p = Jp,P = 1.4 Hz, Ph(p)], 7.32 [2H, ddd, Jo,P = 7.6, Jo,m = 7.3 Hz,
Ph(o)], 7.38 [2H, td, Jm,P = 1.5 Hz, Ph(m)].
The above crude syrup was dissolved in CHCl3 (15 mL), treated with 30% H2O2 (2.0 mL, 20 mmol) at rt
for 1 h. The mixture was diluted with CHCl3 (30 mL), washed with water, dried (Na2SO4), and
evaporated in vacuo. The residue was purified by column chromatography with 1:19 EtOH-AcOEt to
give an inseparable diastereomeric mixture of 20 (18.4 g, 79% from 11b) as a colorless syrup; Rf = 0.40
31
1
(C); P NMR δ = 55.6, 58.5* (90:10*); H NMR for the major isomer δ = 2.03–2.15 (2H, m, H’-4,5),

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2.25–2.39 (3H, m, H,H’-2,H-4,5), 3.41 (3H, s, MeO), 4.37 (1H, dquint, J3,P = 15.9, J2,3 = J2’,3 = J3,4 = J3,4’
= 5.4–5.6 Hz, H-3), 4.73 (2H, s, CH2O-3), 7.49 [2H, tdd, Jo,m = Jm,p = 7.4, Jm,P = 2.9, Jo’,m = 1.4 Hz,
Ph(m)], 7.53 [1H, tq, Jo,p = Jp,P = 1.5 Hz, Ph(p)], 7.70 [2H, ddt, Jo,P = 11.7 Hz, Ph(o)]. Anal. Calcd for
C12H17O3P: C, 60.00; H, 7.13. Found: C, 59.91; H, 7.28.
(1RS,3S)-3-Hydroxy-1-phenylphospholane 1-oxide (21).23
Compound (20) (500 mg, 2.08 mmol) was dissolved in THF (5.0 mL) and 2M HCl (1.0 mL) was added.
o
The mixture was stirred at 40 C for 12 h, neutralized with aqueous ammonia and evaporated in vacuo.
The residue was dissolved in CHCl3, washed with water, dried (Na2SO4), and evaporated in vacuo. The
residue was purified by short-path column chromatography with 1:9 EtOH-AcOEt to give a
diastereomeric mixture of 21 (375 mg, 92%): Rf = 0.15 (C).
The major (1R)-epimer (21a) was crystallized from 1:9 EtOH-AcOEt as colorless needles: mp
107–108 °C: [α]D27 = +6.41° (c = 1.54, CHCl3); 1H NMR δ = 1.99 (1H, dqd, J4R,4S = 13.8, J4R,5S = J4R,5R
=
J4,P = 8.6, J3,4R = 3.9 Hz, HR-4), 2.11 (1H, ddd, J5R,5S = 14.2, J5S,P = 5.3, J4S,5S = 3.5 Hz, HS-5), 2.20 (1H,
ddd, J2R,2S = 15.6, J2R,P = 6.2, J2R,3 = 5.0 Hz, HR-2), 2.46 (2H, m, HS-2, HS-4), 2.48 (1H, m, HR-5), 4.39
(1H, br s, HO-3), 4.68 (1H, ddq, J3,P = 23.2, J2S,3 = J3,4S = 3.9 Hz, H-3), 7.49 [2H, tdd, Jo,m = Jm,p = 7.3,
Jm,P = 2.9, Jo’,m = 1.4 Hz, Ph(m)], 7.54 [1H, tq, Jo,p = Jp,P = 1.5 Hz, Ph(p)], 7.69 [2H, ddt, Jo,P = 12.0 Hz,
Ph(o)]; 13C NMR δ = 27.00 (d, 1J5,P = 65.1 Hz, C-5), 33.75 (d, 2J4,P = 6.9 Hz, C-4), 38.65 (d, 1J2,P = 66.8
2
3
2
Hz, C-2), 70.75 (d, J3,P = 8.6 Hz, C-3), 128.83 [d, Jm,P = 11.5 Hz, Ph(m)], 129.71 [d, Jo,P = 10.4 Hz,
Ph(o)], 131.97 [Ph(p)], 133.37 [d, Jipso,P = 88.1 Hz, Ph(ipso)]; 31P NMR δ = 61.4. Anal. Calcd for
1
C10H13O2P: C, 61.22; H, 6.68. Found: C, 61.08; H, 6.79.
ACKNOWLEDGEMENTS
We are grateful to the SC-NMR Laboratory of Okayama University for the NMR measurements. One
of us (K.S.) thanks the EC Commission’s program for a fellowship.
REFERENCES AND NOTES
1. H. Paulsen, Angew. Chem., Int. Ed. Engl. 1966, 5, 495; B. Hellman, A. Lernmark, J. Sehlin, I.-B.
Taljedal, and R. L.Whistler, Biochem. Pharmacol., 1973, 22, 29; M. Chen and R. L. Whistler, Arch.
Biochem. Biophys., 1975, 169, 392; 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.

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4. T. Hanaya, A. Noguchi, M.-A. Armour, A. M. Hogg, and H. Yamamoto, J. Chem. Soc., Perkin
Trans. 1, 1992, 295; H. Yamamoto, A. Noguchi, K. Torii, K. Ohno, T. Hanaya, H. Kawamoto, and S.
Inokawa, Chem. Lett., 1988, 1575.
5. H. Yamamoto, T. Hanaya, S. Inokawa, K. Seo, M.-A. Armour, and T. T. Nakashima, Carbohydr.
Res., 1983, 114, 83; H. Yamamoto, T. Hanaya, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T.
Nakashima, Carbohydr. Res., 1984, 128, C5; T. Hanaya, N. Shigetoh, and H. Yamamoto, Bull.
Chem. Soc. Jpn., 1988, 61, 2499; T. Hanaya, N. Shigetoh, H. Yamamoto, M.-A. Armour, and A. M.
Hogg, Bull. Chem. Soc. Jpn., 1990, 63, 421.
6. H. Yamamoto, T. Hanaya, H. Kawamoto, S. Inokawa, M. Yamashita, M.-A. Armour, and T. T.
Nakashima, J. Org. Chem., 1985, 50, 3516; T. Richter, P. Luger, T. Hanaya, and H. Yamamoto,
Carbohydr. Res., 1989, 193, 9; T. Hanaya, A. Akamatsu, H. Kawamoto, M.-A. Armour, A. M. Hogg,
and H. Yamamoto, Bull. Chem. Soc. Jpn., 1991, 64, 2398.
7. T. Hanaya, H. Yamamoto, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1992, 65, 1154; T. Hanaya, K.
Yasuda, H. Yamamoto, and H. Yamamoto, Bull. Chem. Soc. Jpn., 1993, 66, 2315; T. Hanaya, K.
Sugiyama, H. Kawamoto, and H. Yamamoto, Carbohydr. Res., 2003, 338, 1641.
8. R. P. Polniaszek and A. L. Foster, J. Org. Chem., 1991, 56, 3137; A. Yabui, M. Yamashita, T.
Oshikawa, T. Hanaya, and H. Yamamoto, Chem. Lett., 1993, 93.
9. T. Hanaya, S. Kawase, and H. Yamamoto, Heterocycles, 2005, 66, 251.
10. K. Issleib and S. Häusler, Chem. Ber., 1961, 94, 113.
11. T. Hanaya, A. Akamatsu, S. Kawase, and H. Yamamoto, J. Chem. Res. (S), 1995, 194.
12. I. Takahashi, Y. Hirano, H. Arakawa, H. Kitajima, M. Hatanaka, K. Isa, K. Odashima, and K. Koga,
Heterocycles, 1997, 46, 589.
13. Phenylphosphine was prepared from phenylphosphonic dichloride and lithium aluminum hydride
according to lit.: L.D. Freeman and G. O. Doak, J. Am. Chem. Soc., 1952, 74, 3414.
14. E. N. Tsvetkov, N. A. Bondarrenko, I. G. Malakhova, and M. I. Kabachnik, Synthesis, 1986, 198.
15. M. G. García-Martin, R. R. Pérez, E. B. Hernández, and J. A. Galbis, Carbohydr. Res., 2001, 333,
95.
16. Compounds (11a,b) are unstable and gradually change into the corresponding 1,4-anhydro-DL-
xylitol derivatives when set aside at room temperature.
17. G. R. Gray, F. C. Hartman, and R. Barker, J. Org. Chem., 1965, 30, 2020; H. Dehmlow, J. Mulzer, C.
Seilz, A. R. Strecker, and A. Kohlmann, Tetrahedron Lett., 1992, 33, 3607.
18. S. Bailey, M. R. Harndern, R. L. Jarvest, A. Parkin, and M. R. Boyd, J. Med. Chem., 1991, 34, 57.
19. P. Marino, T. Tejero, J. Revuelta, P. Romero, S. Cicchi, V. Mannucci, A. Brandi, and A. Goti,
Tetrahedron: Asymmetry, 2003, 14, 367.
20. L. D. Hall, P. R. Steiner, and C. Pedersen, Can. J. Chem., 1970, 48, 1155.
21. The assignments of HR-5 and HS-2 signals were confirmed by the presence of a long-range W-
coupling (J3,5R = J2S,5R = 1.0 Hz).
22. The potentially informative J2S,P, J4S,P, and J5R,P values are uncertain because HS-2, HS-4, and HR-5
signals overlap with each other.

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23. The carbohydrate nomenclature for 7: 1,4-dideoxy-2,3-di-O-methyl-1,4-phenylphosphonoyl-L-
threitol. For 14: 1,5-dideoxy-2,3,4-tri-O-methyl-1,5-[(S)-phenylphosphonoyl]-meso-xylitol. For
21a: 1,2,4-trideoxy-1,4-[(R)-phenylphosphonoyl]-D-glycero-tetritol.
24. The complete parameters for 11b obtained in the present study are shown here, because NMR data
for this compound including insufficient assignments were reported in Ref.15.