Synthesis of novel deoxy λ5 phospha sugar nucleosides: 1,3-dipolar cycloaddition of an azidophospholane with alkynes

Article abstract of DOI:10.1016/S0008-6215(01)00264-6

Several novel phospha sugar nucleosides, analogs of normal sugar nucleosides, were synthesized from a phospholene 1-oxide derivative. Bromination of a phospholene precursor in aqueous organic medium gave regio diastereomers, the threo and erythro bromohydrins 3 (1-bromo-1,3,4-trideoxy-1,4-C-[(R,S)-phenylphosphinylidene]-glycero- tetrofuranose). Further substitution of the threo isomer 3a with sodium azide led to its corresponding azidophospholane 4 (1-azido-1,3,4-trideoxy-2-methyl-1,4-C-[(R)-phenylphosphinylidene]-β-D- glycero-tetrofuranose). 1,3-Dipolar cycloaddition of 4 with various electron-deficient and electron-rich alkynes afforded triazole derivatives that are nucleoside analogues. The strong electron-withdrawing phosphoryl group in the hemiacetal ring exerted no effect over reaction regioselectivity of the 1,3-dipolar cycloaddition, but steric effects of the alkynes played a vital role on the selectivity, since the regioisomer ratios and the rates and yields of cycloadducts changed as the bulkiness of the substituents on the acetylene changes. Structures of all compounds were unequivocally confirmed by ¹H, ¹³C, and ³¹P NMR and mass spectral studies. Single crystal X-ray crystallographic analysis of some derivatives allowed determination of configuration of the phospha sugar nucleosides.

Full text of DOI:10.1016/S0008-6215(01)00264-6

Carbohydrate Research 336 (2001) 257–270
www.elsevier.com/locate/carres
Synthesis of novel deoxy l5 phospha sugar nucleosides:
1,3-dipolar cycloaddition of an azidophospholane with
alkynes
Mitsuji Yamashita,* Putta Mallikarjuna Reddy,† Yukihiro Kato,
Valluru Krishna Reddy, Kazumitsu Suzuki, Tatsuo Oshikawa
Department of Materials Chemistry, Faculty of Engineering, Shizuoka Uni6ersity, Hamamatsu 432-8561, Japan
Received 27 July 1999; received in revised form 20 September 2001; accepted 24 September 2001
Abstract
Several novel phospha sugar nucleosides, analogs of normal sugar nucleosides, were synthesized from a phospho-
lene 1-oxide derivative. Bromination of a phospholene precursor in aqueous organic medium gave regio
diastereomers, the threo and erythro bromohydrins 3 (1-bromo-1,3,4-trideoxy-1,4-C-[(R,S)-phenylphosphinylidene]-
glycero-tetrofuranose). Further substitution of the threo isomer 3a with sodium azide led to its corresponding
azidophospholane 4 (1-azido-1,3,4-trideoxy-2-methyl-1,4-C-[(R)-phenylphosphinylidene]-b-D-glycero-tetrofuranose).
1,3-Dipolar cycloaddition of 4 with various electron-deficient and electron-rich alkynes afforded triazole derivatives
that are nucleoside analogues. The strong electron-withdrawing phosphoryl group in the hemiacetal ring exerted no
effect over reaction regioselectivity of the 1,3-dipolar cycloaddition, but steric effects of the alkynes played a vital role
on the selectivity, since the regioisomer ratios and the rates and yields of cycloadducts changed as the bulkiness of
1
the substituents on the acetylene changes. Structures of all compounds were unequivocally confirmed by H, 13C, and
31P NMR and mass spectral studies. Single crystal X-ray crystallographic analysis of some derivatives allowed
determination of configuration of the phospha sugar nucleosides. © 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Phospha sugars; Hetero sugars; Nucleoside analogues, Bromohydrins; 2-Azidophospholane; 1,3-Dipolar cycloaddition,
X-ray crystallography, Absolute configuration
synthetic nucleoside analogues has prompted
the synthesis of analogues and explore their
possible use as anti-HIV, and anti-cancer
agents.1–3 In searches for therapeutically im-
proved inhibitors of HIV, a wide variety of
sugar-modified nucleosides have been devel-
oped and found to possess potential bioactiv-
ity. Among them, Ribavirin,4 AZT,5
4%-thio-ddC,6 Aristeromycin,7 and others
(Scheme 1) are the most interesting, because
of their potent anti-HIV activities. Recent de-
velopments have indicated that functional
changes of the sugar moiety may lead to po-
tent bioactivity.8 Replacement of hemiacetal
1. Introduction
Sugars having other atoms replacing the
ring oxygen are inherent and interesting sub-
stances because of their wide range of poten-
tial biological activities in living systems. The
potential bioactivity of natural, as well as
* Corresponding author. Fax: +81-53-4781144.
E-mail address: tcmyama@ipc.shizuoka.ac.jp (M. Ya-
mashita).
† Current address: Department of Chemistry and Biochem-
istry, University of California at Santa Barbara, Santa Bar-
bara, CA 93106, USA.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00264-6

258
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
particularly on phospha sugar nucleosides and
glycosides, as they have not been found in
natural sources. Considerable recent attention
has been focused on the synthesis and bioac-
tivity of simple phospha sugar analogues,13
but not on phospha sugar nucleosides. Riley14
and co-workers reported some ribavirin ana-
logues of nucleosides containing phosphorus
in the nucleoside base subunit, but not in the
sugar subunit. Synthesis of phospha sugars is
rather difficult due to long reaction sequences
and low yields,15 and preparations generally
use normal sugars as starting materials.16,17
We wished to develop a more general route to
such phospha sugars as 2 and have reported
the synthesis of tetrofuranose analogs18 using
phospholenes (Scheme 2) as potential starting
materials.19 Our interest to develop potential
inhibitors of HIV led us to synthesize phospha
sugar nucleosides containing a triazole ring,
report here the synthesis of a key intermediate
2-azidophospholane and its 1,3-dipolar cy-
cloaddition reactions with various electron-
rich and electron-deficient alkynes.20
Scheme 1.
ring oxygen with methylene, nitrogen, or sul-
fur is one approach for making functional
changes in the nucleoside subunits.8,9 Several
bioactive sugar-modified glycosides and nu-
cleosides in which the hemiacetal ring oxygen
is replaced by methylene, sulfur, or nitrogen
have also been isolated from natural sources.2
Several novel classes of heterosugars such as
carba,10 aza,11 and thia sugar12 nucleosides
been studied extensively. Our interest was that
of synthesis of phosphafuranose nucleoside
analogues, in which the oxygen of the hemiac-
etal ring is replaced by phosphorus.‡
2. Results and discussion
Our primary aim was to develop a general
route for the synthesis of phospha sugar nu-
cleosides from non sugar starting materials.
To prepare the desired triazole derivatives 6–
15, of phospha sugar nucleosides, we started
from 3-methyl-1-phenyl-2-phospholene 1-ox-
ide (1a) because introduction of the azido
group at 2-position was expected to be rela-
tively easy through its 2-bromophospholane
derivative 3.21 Bromination of 2-phospholene
1a in an aqueous organic medium afforded
Despite extensive studies on the synthesis,
spectral, and bioactivity of such ‘pseudo sug-
ars’ as carba, aza, and thia sugars, little re-
search has been done on phospha sugars,
‡ The term ‘phospha’ strictly denotes replacement of a
carbon atom in the parent structure by phosphorus (see
2-Carb-34.1).
2-bromo-3-hydroxyphospholane
diastereo-
Scheme 2.

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
259
mamide (DMF) at 70 °C for 24 h gave 1-
azido - 1,3,4 - trideoxy - 2 - methyl - 1,4 - C - [(R)-
phenylphosphinylidene] - b -
D
- glycero - tetro-
furanose (4) in 87% yield. In the conversion of
compound 3a to 4, the retention of configura-
tion was observed at C-2 where bromine was
substituted by the azido group. The retention
of configuration at C-2 via a double inversion
presumably involves formation of an epoxide
intermediate.22 This is supported by the l
values and as 2JP,H coupling constants for H-2.
Scheme 3.
mers 3a (threo) and 3b (erythro), in addition
to the minor regiodiastereomers, threo-3-
bromo-2-hydroxyphospholane 1-oxide (3c)
and the erythro isomer 3d (Scheme 3). Prelim-
inary TLC analysis of the reaction mixture
shows only two spots, suggesting formation of
1
The H NMR spectra of compounds 3a and 4
exhibited doublets at l 4.20 and 4.00 with
2
coupling constants, JP,H, of 4.0 and 2.0 Hz,
respectively, indicating a similar arrangement
of H-2 in both compounds. Several unex-
plained failures were observed when at-
tempted to convert the mixture of 3b, 3c, and
3d into their corresponding azides under simi-
lar conditions. The azide 4 permitted the syn-
thesis of a large number of nucleoside
analogues of phospha sugars via 1,3-dipolar
cycloaddition with various alkynes 5 in a sin-
gle step reaction (Scheme 4).
two major isomers, 3a and 3b, and 3a (1
-
bromo-1,3,4-trideoxy-1,4-C-[(R,S)-phenyl-
phosphinylidene]-glycero-tetrofuranose) was
separated by fractional crystallization from
chloroform and n-hexane. Detailed spectral
analysis of the 3b fraction revealed that the
presence of the minor regiodiastereomers 3c
(threo) and 3d (erythro), but attempts to sepa-
rate 3c and 3d from 3b were unsuccessful, and
hence the isomer ratios were determined by
31P NMR spectroscopy. The isomer ratios of
3a, 3b, 3c, and 3d are 4:2:1:1, respectively. In
contrast, bromination of a 3-unsubstituted-2-
phospholene, 1-phenyl-2-phospholene, 1-oxide
(1b) under similar conditions gave only threo
and erythro 2-bromo-3-hydroxy-1-phenyl-
phospholane 1-oxides (homologs of 3a and
3b) in 2:1 ratio with no indication of regio-
diastereomers homologous with 3c and 3d.21
This difference is explicable by the involve-
ment of a cyclic bromonium ion intermediate.
Such a cyclic bromonium ion intermediate
formed between bromine and the phospholene
may be destabilized by the presence of the
electron-donating methyl group and the
strongly electron-withdrawing PꢀO group on
each side of the alkene. Therefore, the equi-
librium of a p complex with bromine may be
altered and the nucleophilic, OH− group
could attack at C-2 to give isomers 3c and 3d.
The azidophospholane intermediate 4 was
readily prepared from threo-2-bromo-3-
methyl-1-phenylphospholane 1-oxide (3a) in
reasonably good yield (87%). Treatment of 3a
with sodium azide in N,N%-dimethylfor-
1,3-Dipolar cycloaddition of 4 with mono-
and disubstituted alkynes 5a–5j containing
electron-donating and electron-withdrawing
groups, proceeded in good yields (Table 1) in
1,2-dimethoxyethane (DME) at reflux temper-
ature. As expected, the reaction of monosub-
stituted alkynes 5f–5j gave two regioisomers,
4%- and 5%-substituted triazole derivatives a and
b, whose chromatographical and spectroscopi-
cal properties were markedly different, permit-
ting easy separation and unequivocal
structural assignment of both regioisomers.
The regioisomers a and b were separated by
silica gel column chromatography using 10:1
CHCl3–MeOH as the eluent. Interestingly,
analysis of the reaction product of
(trimethylsilyl)acetylene (5e) with azide 4 re-
vealed only one isomer, 10a, in contrast to the
adducts of other monosubstituted alkynes.
The results (Table 1) show that the rate of
reaction of more electron-deficient dipolar-
ophiles with azide 4 is faster than those of less
electron-deficient or electron-rich dipolar-
ophiles. Even though the phosphoryl group in
the hemiacetal ring of the phospha sugar is a
strongly electron-withdrawing group, little ef-
fect was exerted over the dipolar cycloaddition

260
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
Scheme 4. (a) NaN3, DMF, 70 °C, 24 h; (b) substituted acetylenes (5), DME, reflux.
Table 1
1,3-Dipolar cycloaddition of azide 4 with various substituted alkynes 5a–j
Alkyne
R%
R2
Reaction time (h)
Product
Yields (%)
Mp (°C)
5a
5b
5c
5d
5e
5f
CO2Me
CO2Et
CH2OH
CO2H
H
CO2Me
CO2Et
CH2OH
CO2H
SiMe3
CH2OH
12
16
75
24
24
48
6a
7a
8a
79
84
68
79
57
36
38
42
25
49
37
33
17
55
21
205–706
175–176
205–206
175–176
221–222
184–185
227–228
204–205
215–216
206–207
219–220
230–232
228–229
224–227
247–250
9a
10a
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
H
48
5g
5h
5i
H
H
H
H
CMe2OH
CO2Me
Ph
120
120
12
12
96
96
5j
CMe3
36
36
phospholane ring in compounds 6–15 was
conditions and also on the ratio of regioiso-
mers, since the obtained results were very
similar to those of other reported cycloaddi-
tion reactions.23,24 The steric effects of sub-
stituents on the acetylene played a major role
on the regioisomer ratios, since the reaction of
propargyl alcohol (5f) with azide 4 afforded
regioisomers 11a and 11b in 1:1 ratio, whereas
(trimethylsilyl)acetylene (5e) gave only one
isomer, the 4%-trimethylsilyl derivative 10a.
This type of dominating effect on regioselec-
tivity by the trimethylsilyl group has been
observed in the cycloaddition reactions of
diazoalkenes25,26 and also N-(azidomethyl)-
benzisothiazoles.24 The steric effect of the
trimethylsilyl group is more dominant in re-
gioselectivity than the electronic effect of sub-
stituents, because of the high ability of silicon
to stabilize the transition state.24
established from the chemical shifts of H-2
2
and the JP,H coupling constants (Table 2).
2
The downfield shift of H-2 and its larger JP,H
coupling constant suggests the cis (or gauche)
relationship of H-2ꢁC-2ꢁPꢀO.27 Interestingly
the H-2 proton resonated as a doublet of
doublets indicating long-range coupling be-
tween H-2 and H-4e, which was also confi-
rmed by homospin decoupling studies. The
smaller coupling constants (1.6–2.1 Hz) were
attributed to long-range couplings
4JHꢁH and
larger coupling constants 9.2–11.6 Hz were
2
attributed to JPꢁH couplings (Table 2). The
long-range coupling between H-2 and H-4e
suggests the presence of a ‘W conformation’
of the four s-bonds between H-2 and H-4e
4
(Fig. 1). From the JHꢁH long-range coupling
2
and the larger JPꢁH coupling constants for
3
The structure of products 6a–15a and 11b–
15b were confirmed by their analytical and
spectral (1H, 13C and 31P NMR and mass)
data. The orientation of the PꢀO group of the
H-2 suggest the presence of the T2 conforma-
tion in the central phospholane ring. Further-
more, the configurations of compounds 8a
and 15b were determined unambiguously by

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
261
Table 2
1
Chemical shifts (l values for H-2, H-4%, and H-5%) and long range JHꢁH and JPꢁH coupling constants a in H , and 31P NMR l
values b of compounds 6a–15a and 11b–15b
Compound
1H NMR
H-2
31P NMR
JHꢁH, JPꢁH
H-4%
H-5
6a
7a
8a
l 5.59
l 5.53
l 5.00
l 5.41
l 5.00
l 4.91
l 5.04
l 4.77
l 5.67
l 6.12
l 5.31
l 4.92
l 4.84
l 5.09
l 5.36
1.9, 10.3
1.5, 10.0
1.9, 11.0
1.9, 11.1
1.9, 11.1
1.9, 10.5
1.9, 10.8
1.9, 10.0
2.2, 11.3
2.1, 11.6
2.2, 10.3
1.6, 9.2
+68.3
+68.7
+70.9
+70.3
+68.8
+70.3
+71.3
+70.0
+71.2
+69.2
+69.0
+68.9
+69.8
+69.6
+69.9
9a
10a
11a
11b
12a
12b
13a
13b
14a
14b
15a
15b
7.34
7.73
7.28
7.10
7.98
7.44
7.10
7.37
7.82
7.36
6.97
1.6, 9.7
2.2, 9.2
1.6, 10.0
a Coupling constants (J) values are shown in Hz.
b 31P NMR l values are in ppm.
1
Fig. 1. Favored conformations for the central phospholane ring of nucleosides 6–15, based on H NMR analysis.
downfield chemical shifts of H-4% and upfield
shift of H-5% protons.24 In our studies, re-
gioisomers 11a and 12a, having the hydroxy
group substituted, exhibited characteristic
downfield chemical shifts for H-5% of the tria-
zole, where as 11b and 12b exhibited upfield
single-crystal X-ray crystallography (Figs. 2
and 3). The chemical shifts of H-5% and H-4%
of the triazole ring in compounds 11a–15a
and 11b–15b varied (Table 2) because of the
variety of substituents on the triazole ring, but
earlier reports showed the characteristic

262
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
Fig. 2. ORTEP drawing of compound 8a.
shifts for the triazole H-4%. On the other hand,
regioisomers 13a–15a exhibited characteristic
upfield shifts for the triazole H-5% and isomers
13b–15b exhibited downfield shifts for the
triazole H-4% (Table 2). This may be due to the
relative magnitude of electron-withdrawing
and electron-donating capacities of sub-
stituents on the triazole ring. Electron density
(MOPAC, PM3) calculations28 also supported
the change in the chemical shifts of the tria-
zole protons in the regioisomers.
Recrystallization of products 6a–15a and
11b–15b from CHCl3 and n-hexane produced
crystals, but only 8a and 15b gave crystals
suitable for X-ray studies. Attempts to grow a
suitable crystal of regioisomer 15a was unsuc-
cessful. A single-crystal X-ray study of com-
pounds 8a and 15b afforded the structures
depicted in Figs. 2 and 3, respectively (see
Section 4). The determination of stereochem-
istry at P-1, C-1, and C-2 [the number accord-
ing to heterocycle (phospholene) terminology
are 1, 2, and 3, respectively] paved the way for
establishing the absolute configuration for the
phospholane ring as (1RP,2R,3R) and
(1SP,2S,3S) for its enantiomer.
The X-ray crystallographic studies of com-
pounds 8a and 15b revealed that the phenyl
ring on phosphorus and the triazole ring at
C-1 lie almost parallel (see torsion angles,
Table 5). Interestingly, in the crystal packing
of compound 8a, pairs of symmetrically re-
lated molecules are linked by PꢀO···HꢁO in-
termolecular hydrogen bonding (Fig. 4) to
form dimers. The oxygen atom of the phos-
phoryl group and hydrogen of the hydroxy-
methyl group at C-7 of the triazole ring are
involved in intermolecular H-bonding linking
the symmetrical molecules into dimers (see
Fig. 4). The substitution of O by P in the
hemiacetal ring caused several changes in the
geometry and conformation of the five-mem-

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
263
Fig. 3. ORTEP drawing of compound 15b.
bered ring (Tables 3–6 and Figs. 2 and 3).
Considerable changes in the C-1ꢁP-1ꢁC-4
bond angle of the phospha sugars was ob-
served as (96.6°), as compared to the 110° of
C-1ꢁOꢁC-4 in ribofuranose and 93.5° of C-
1ꢁSꢁC-4 in thio sugars.29 Comparison of the
P-1ꢁC-1 and P-1ꢁC-4 bond lengths indicated
that the P-1ꢁC-1 bond is longer than that of
formation of the central phospholane ring is a
twisted en6elope in the solid state.
Preliminary studies on some of the com-
pounds revealed considerable activity and will
be reported elsewhere.
,
P-1ꢁC-4 by ꢀ0.05 A. The positive C-1ꢁP-
1ꢁC-4ꢁC-3 torsion angle and the negative P-
1ꢁC-4ꢁC-3ꢁC-2 torsion angle in the
phospholane ring (Table 5) show that the
conformation is C-3-exo and C-2-endo. The
C-3 atom of the cyclophospholane is displaced
,
by +0.588 A (21.05°) from the best possible
four-atom mean-square plane of C-4ꢁP-1ꢁC-
,
1ꢁC-2, and C-2 is displaced by −0.596 A
(21.17°) from the next best possible four-atom
mean-square plane C-1ꢁP-1ꢁC-4ꢁC-3, sup-
3
porting the existence of the T2 (C-3-exo and
C-2-endo) conformation.§ Therefore, the con-
§ These values are for compound 8a. For compound 15b,
,
C-3 is displaced by +0.468 (16.81°) A from the C-4ꢁP-1ꢁC-
Fig. 4. Intermolecular H-bonding P-1%ꢀO-1%···H-35ꢁO-3 be-
tween symmetrically related molecules of 8a, forming dimers
in the crystal packing.
,
1ꢁC-2 plane, and C-2 is displaced by −0.607 A (21.97°) from
the C-1ꢁP-1ꢁC-4ꢁC-3 plane.

264
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
Table 3
melting point apparatus and are uncorrected.
Thin-layer chromatography was performed by
using 0.2 mm coated silica gel plates. Column
chromatography was performed on silica gel
Waco gel C-200 using 10:1 mixture of CHCl3
,
Selected bond lengths (A) of compounds 8a and 15b
Bond lengths a (A)
,
8a
15b
1
and MeOH as the eluent. H and 13C NMR
P-1ꢁO-1
P-1ꢁC-1
P-1ꢁC-4
P-1ꢁC-8
N-1ꢁN-2
N-1ꢁC-1
N-1ꢁC-7
N-2ꢁN-3
N-3ꢁN-6
C-1ꢁC-2
C-2ꢁC-3
C-3ꢁC-4
C-2ꢁC-5
C-6ꢁC-7
C-7ꢁC-14
C-6ꢁC-15
1.456(7)
1.867(7)
1.824(7)
1.821(7)
1.370(9)
1.449(8)
1.357(8)
1.298(8)
1.367(8)
1.552(9)
1.528(10)
1.520(1)
1.512(10)
1.359(9)
1.478(10)
1.502(9)
1.494(3)
1.861(4)
1.812(5)
1.800(5)
1.359(5)
1.463(5)
1.365(6)
1.316(5)
1.348(6)
1.549(6)
1.525(7)
1.516(7)
1.518(7)
1.374(6)
1.499(6)
spectra were recorded on a Jeol GX-270 MHz
instrument using Me4Si as the internal stan-
dard and 31P NMR was recorded on a Jeol
JNM-EX90 (at 36.18 MHz) instrument using
H3PO4 as the external standard. Coupling
constant (J) values are given in Hz. Mass
spectra were recorded on Hitachi RMU7M
GC-MS or Shimadzu GCMS-AP5050 gas
chromatograph-mass spectrometer instru-
ments using electron impact at 70 eV, and
X-ray crystallographic studies were made on a
Rigaku AFC7R diffractometer with graphite
monochromated Cu Ka radiation and a rotat-
ing anode generator. Phase determination was
made by a direct method (SIR92).30
a Estimated standard deviations in the least significant
figure are given in parentheses.
Table 5
Table 4
Selected torsion angles of compounds 8a and 15b
Selected bond angles (°) of compounds 8a and 15b
Torsion Angle a (°)
Bond angles a (°)
8a
15b
71.2(4)
8a
15b
P-1ꢁC-1ꢁN-1ꢁN-2
P-1ꢁC-lꢁN-1ꢁC-7
P-1ꢁC-1ꢁC-2ꢁO-2
P-1ꢁC-1ꢁC-2ꢁC-3
P-1ꢁC-1ꢁC-2ꢁC-5
P-1ꢁC-4ꢁC-3ꢁC-2
O-1ꢁP-1ꢁC-1ꢁN-1
O-1ꢁP-1ꢁC-1ꢁC-2
O-1ꢁP-1ꢁC-4ꢁC-3
O-2ꢁC-2ꢁC-1ꢁN-1
O-2ꢁC-2ꢁC-3ꢁC-4
N-1ꢁC-1ꢁP-1ꢁC-4
N-1ꢁC-1ꢁP-1ꢁC-8
N-1ꢁC-1ꢁC-2ꢁC-3
N-1ꢁC-1ꢁC-2ꢁC-5
N-2ꢁN-lꢁC-1ꢁC-2
N-3ꢁN-2ꢁN-1ꢁC-1
C-1ꢁP-1ꢁC-4ꢁC-3
C-1ꢁP-1ꢁC-8ꢁC-9
C-1ꢁC-2ꢁC-3ꢁC-4
C-2ꢁC-1ꢁP-1ꢁC-4
C-2ꢁC-1ꢁP-1ꢁC-8
C-3ꢁC-4ꢁP-1ꢁC-8
C-4ꢁC-3ꢁC-2ꢁC-5
58.9(7)
O-lꢁP-1ꢁC-1
O-1ꢁP-1ꢁC-4
O-1ꢁP-1ꢁC-8
C-1ꢁP-1ꢁC-4
C-1ꢁP-1ꢁC-8
C-4ꢁP-1ꢁC-8
N-1ꢁN-2ꢁN-3
P-1ꢁC-1ꢁN-1
P-1ꢁC-1ꢁC-2
N-1ꢁC-1ꢁC-2
O-2ꢁC-2ꢁC-1
O-2ꢁC-2ꢁC-3
C-1ꢁC-2ꢁC-3
C-1ꢁC-2ꢁC-5
C-3ꢁC-2ꢁC-5
C-2ꢁC-3ꢁC-4
P-1ꢁC-4ꢁC-3
N-3ꢁC-6ꢁC-7
114.8(4)
115.9(3)
112.7(3)
95.6(3)
111.7(2)
115.2(2)
109.9(2)
95.6(2)
−110.3(7)
77.1(5)
−110.8(5)
70.7(4)
−37.3(6)
−163.1(6)
−34.7(7)
127.5(5)
−106.3(5)
131.4(5)
−156.95(5)
−60.4(7)
−110.6(5)
2.0(6)
−40.9(4)
−167.6(4)
−26.7(6)
136.5(3)
−97.5(3)
118.9(4)
−161.9(3)
−66.8(5)
−103.4(4)
12.7(4)
106.5(3)
109.8(3)
106.6(6)
114.6(5)
104.0(4)
114.8(6)
101.2(5)
109.5(6)
106.3(5)
113.1(6)
114.0(6)
109.0(6)
105.6(5)
109.1(6)
112.1(2)
111.7(2)
107.2(4)
116.7(3)
102.6(3)
114.4(3)
105.7(4)
104.9(4)
107.2(4)
113.9(4)
113.7(4)
109.1(4)
107.1(4)
111.4(4)
88.8(7)
86.5(5)
−37.1(8)
−61.4(9)
−174.5(6)
10.3(6)
−107.6(8)
48.1(7)
−40.2(6)
−48.6(5)
178.3(4)
1.7(4)
−61.9(5)
45.2(6)
a Estimated standard deviations in the least significant
figure are given in parentheses.
15.6(5)
22.5(5)
128.2(5)
−99.5(5)
173.4(6)
138.6(3)
−114.8(4)
172.1(5)
3. Experimental
a The sign is positive if, when looking from atom 2 to atom
3, a clockwise motion of atom 1 would superpose it on atom
4.
General methods.—Melting points were
recorded on a Yanagimoto MP-S2 micro-

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
265
Table 6
2-Bromo-3-hydroxy-3-methyl-1-phenylphos-
pholane 1-oxide (3).—2-Phospholene 1 (3.41
g, 17.7 mmol) was dissolved in 25 mL of a 4:1
water–CHCl3 mixture and 3.5 mL of Br2 was
added at rt and the solution was stirred for 3
days. To the stirred solution, 40 mL of satd aq
Na2SO3 was added and the solution stirred for
few minutes. After disappearance of the
bromine color, the CHCl3 layer was separated
and the water layer extracted with CHCl3
(3×30 mL). The combined CHCl3 extracts
were washed with water, dried (Na2SO4) and
evaporated under diminished pressure. The
residue was recrystallized from 1:1 CHCl3–
hexane.
Summary of crystal data, data collection, and structure solu-
tion of compounds 8 and 15b
Compound
8
15
Empirical formula
Formula weight
Temperature (K)
Crystal dimensions 0.20×0.20×0.30 0.30×0.20×0.20
(mm)
C15H20N3PO4
337.31
296
C17H24N3PO2
333.37
223
Crystal system
Lattice parameters
orthorhombic
triclinic
,
a (A)
14.833(2)
8.720(2)
25.951(2)
9.611(1)
11.556(1)
,
b (A)
,
c (A)
h (°)
i (°)
93.01(1)
108.14(1)
111.193(10)
873.6(2)
P1 (no. 2)
2
1.267
356.00
15.01
2748
k (°)
Compound 3a (threo), yield: 2.33 g (46%);
3
mp 146–148 °C; IR: w(cm−1) (neat) 3150
,
V (A )
3356(1)
Pca21 (no. 29)
8
1.335
1424.00
16.65
(
Space group
Z value
1
(OH); H NMR (CDCl3): l 7.48–7.91 (m, 5
Dcalc (g/cm3)
F000
H, Ph), 5.62 (br s, 1 H, OH), 4.22 (d, 1 H, J2,P
4.0 Hz, H-2), 2.08–2.61 (m, 4 H, H-4,5), 1.66
(s, 3 H, 3-CH3); 13C NMR (CDCl3): l 132.5
(d, J 2 Hz, C-3,5 of P-Ph), 131.9 (d, J 10 Hz,
C-2,6 of P-Ph), 129.6 (C-4 of P-Ph), 128.1 (d,
J 12 Hz, C-1 of P-Ph), 79.5 (d, J 13 Hz, C-3),
50.1 (d, J 66 Hz, C-2), 35.7 (d, J 2 Hz, C-4),
26.0 (d, J 7 Hz, CH3), 25.4 (d, J 65 Hz, C-5);
31P NMR (H3PO4): l +68.3. Anal. Calcd for
C11H14BrO2P: C, 45.70; H, 4.88. Found: C,
45.42; H, 5.02.
v(Cu Ka) (cm−1
Total reflections
measured
)
2880
Unique reflections
measured
(Rint=0.029)
2597
Structure solution
direct methods
direct methods
(
SIR92)
(SIR92)
Function minimized ꢀ ꢀ(ꢁFoꢁ−ꢁFcꢁ)2
ꢀ ꢀ(ꢁFoꢁ−ꢁFcꢁ)2
p-factor
0.0040
2289
0.0320
Observations
[I\3.00|(I)]
Residuals: R, Rw
1636
2-Azido-3-hydroxy-3-methyl-1-phenylphos-
pholane 1-oxide (4).—To a solution of 2-bro-
mophospholane 3a (3.09 g, 10.7 mmol) in
DMF (30 mL) was added NaN3 (1.27 g, 17.5
mmol) and the mixture stirred at 70 °C for 24
h. DMF was distilled off under diminished
pressure and the residue was dissolved in
CHCl3 (50 mL) and washed with water (3×
20 mL). The CHCl3 layer was dried (Na2SO4)
and evaporated under diminished pressure.
The resultant crude yellow compound was
recrystallized from CHCl3 and n-hexane to
afford white colorless crystals of 4, yield: 2.33
g (87%); mp 174–175 °C; IR: w(cm−1) (neat)
0.038, 0.035
0.056, 0.065
Phospholene 1-oxide was prepared by the
reported procedure31 via the cycloaddition of
2-methyl-1,3-butadiene and phenylphospho-
nus dichloride.
3-Methyl-1-phenyl-2-phospholene
1-
oxide31.—Isoprene (70 mL, 500 mmol) and
phenylphosphonus dichloride (68 mL, 500
mmol) were mixed at rt in a thick-walled flask,
sealed and left for 3 weeks. The resultant
brown solid was dissolved in CHCl3, poured
into ice water and neutralized with NaHCO3.
The CHCl3 layer was separated, washed with
water (3×200 mL) and dried over anhyd
Na2SO4. Chloroform was evaporated under
diminished pressure and the residue was dis-
tilled at 149–150 °C/0.3 mmHg to afford
phospholene 1, 76 g (79%), mp 62 °C; bp31
149 °C/0.3 mmHg, mp31 60–65 °C.
1
3150 (OH), 2120 (N3); H NMR (CDCl3): l
7.44–7.78 (m, 5 H, Ph), 5.61 (br s, 1 H, OH),
4.00 (d, 1 H, J2,P 2.1 Hz, H-2), 1.80–2.53 (m,
4 H, H-4,5), 1.46 (s, 3 H, 3-CH3); 13C NMR
(CDCl3): l 132.6 (d, J 3 Hz, C-3,5 of P-Ph),
131.5 (d, J 10 Hz, C-2,6 of P-Ph), 129.8 (C-4
of P-Ph), 128.6 (d, J 12 Hz, C-1 of P-Ph), 78.7
(d, J 13 Hz, C-3), 67.9 (d, J 73 Hz, C-2), 36.3

266
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
(1S,2R,3R)-3-Hydroxy-2-(4,5-diethoxycar-
bonyl - 1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1-
(d, J 5 Hz, C-4), 26.4 (d, J 64 Hz, C-5), and
24.2 (d, J 7 Hz, CH3); 31P NMR (H3PO4): l
+66.1. Anal. Calcd for C11H14N3O2P: C,
52.59; H, 5.62; N, 16.73. Found: C, 52.68; H,
5.38; N, 16.64.
phenylphospholane
1-oxide
(7a).—2-Azi-
dophospholane 4 (0.50 g, 2.0 mmol) and di-
ethylacetylene dicarboxylate (5b, 0.51 g, 3.0
mmol) in 10 mL of DME were refluxed for 16
h with stirring. The solvent was evaporated
under diminished pressure and the residue re-
crystallized from CHCl3 and n-hexane to give
General procedure for the synthesis of
(1S,2R,3R)-3-hydroxy-2-(4- and 5-substi-
tuted - 1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1-
phenylphospholane 1-oxides (6–15).—2-Azi-
dophospholane 4 (0.50 g, 2.0 mmol) and the
substituted acetylene 5 (2.0 mmol) were dis-
solved in 10 mL of dimethoxyethane (DME)
and the solution refluxed with stirring. After
completion of the reaction (indicated by
TLC), solvent was removed under diminished
pressure and the product recrystallized from
CHCl3 and n-hexane. Regioisomers were sep-
arated by column chromatography on silica
gel using 10:1 CHCl3 –MeOH mixture as elu-
ent.
(1S,2R,3R)-3-Hydroxy-2-(4,5-dimethoxy-
carbonyl-1H-1,2,3-triazol-1-yl)-3-methyl-1-
phenylphospholane 1-oxides (6a).—2-Azi-
dophospholane 4 (0.50 g, 2.0 mmol) and
dimethylacetylene dicarboxylate (5a, 0.43 g,
3.0 mmol) were dissolved in 10 mL of DME
and the solution refluxed for 12 h with stir-
ring. The solvent was removed under dimin-
ished pressure and the residue was
recrystallized from CHCl3 and n-hexane to
give 6a, yield: 0.62 g (79%); mp 205–206 °C.
1H NMR (CDCl3): l 7.28–7.70 (m, 5 H, Ph),
6.00 (br s, 1 H, OH), 5.59 (dd, 1 H, J2,4 1.9,
J2,P 10.3 Hz, H-2), 3.98 (s, 3 H, 5%-COOCH3);
3.87 (s, 3 H, 4%-COOCH3), 2.47–3.00 (m, 4 H,
H-4,5), 1.32 (s, 3 H, 3-CH3); 13C NMR
(CDCl3): l 159.9 (4%-COOCH3), 158.4 (5%-
COOCH3), 138.5 (C-4%), 132.9 (C-4 of P-Ph),
131.8 (C-5%), 131.3 (d, J 11 Hz, C-2,6 of P-Ph),
128.3 (d, J 11 Hz, C-3,5 of P-Ph), 127.0 (d, J
12 Hz, C-1 of P-Ph), 80.3 (d, J 17 Hz, C-3),
68.3 (d, J 66 Hz, C-2), 58.8 (4%-COOCH3),
52.6 (5%-COOCH3), 37.9 (C-4), 25.1 (d, J 66
Hz, C-5), 23.6 (d, J 7 Hz, CH3); 31P NMR
(H3PO4): l +68.3; EIMS: m/z 394 [M+H]+,
275 (5), 195 (64), 157 (12), 141 (23), 125 (22),
109 (9), 91 (15), 77 (36), 59 (44), 43 (100).
Anal. Calcd for C17H20N3O6P: C, 51.91; H,
5.12; N, 10.68. Found: C, 51.68; H, 5.06; N,
10.57.
1
7a, yield: 0.71 g (84%); mp 175–176 °C; H
NMR (CDCl3): l 7.29–7.68 (m, 5 H, Ph), 5.53
(dd, 1 H, J2,4 1.6, J2,P 10.0 Hz, H-2), 4.42 (q,
2 H, JH,H 7.2 Hz, 4%-COOCH2CH3), 4.31(q, 2
H, JH,H 7.2 Hz, 5%-COOCH2CH3), 3.75 (br s, 1
H, OH), 2.47–3.00 (m, 4 H, H-4,5), 1.37 (t, 3
H, JH,H 7.2 Hz, 4%-COOCH2CH3); 1.33 (t, 3 H,
JH,H 7.2 Hz, 5%-COOCH2CH3), 1.32 (s, 3 H,
3-CH3); 13C NMR (CDCl3): l 159.5 (4%-
COOEt), 158.1 (5%-COOEt), 138.8 (C-4%),
132.9 (C-4 of P-Ph), 131.7 (C-5%), 131.3 (d J 10
Hz, C-2,6 of P-Ph), 128.3 (d, J 12 Hz, C-3,5 of
P-Ph), 127.4 (d, J 92 Hz, C-1 of P-Ph), 80.4
(d, J 17 Hz, C-3), 68.2 (d, J 67 Hz, C-2), 63.3
(4%-COOCH2CH3), 61.8 (5%-COOCH2CH3),
37.9 (C-4), 25.0 (d, J 66 Hz, C-5), 23.6 (d, J 6
Hz, CH3), 14.1 (4%-COOCH2CH3), 13.8 (5%-
COOCH2CH3); 31P NMR (H3PO4): l +68.7;
EIMS: m/z 422 [M+H]+, 275 (16), 207 (3),
195 (94), 179 (6), 157 (8), 141 (28), 125 (31),
109 (9), 91 (17), 77 (33) and 43 (100). Anal.
Calcd for C19H24N3O6P: C, 54.16; H, 5.74; N,
9.97. Found: C, 54.00; H, 5.70; N, 9.83.
(1S,2R,3R)-3-Hydroxy-2-(4,5-dihydroxy-
methyl - 1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1-
phenylphospholane
1-oxide
(8a).—2-Azi-
dophospholane 4 (0.50 g, 2.0 mmol) and 2-bu-
tyn-1,4-diol (5c, 0.30 g, 3.4 mmol) in 10 mL of
DME were refluxed for 75 h with stirring. The
solvent was evaporated under diminished
pressure and recrystallized from CHCl3 and
n-hexane to give 8a, yield: 0.46 g (68%); mp
1
205–206 °C; H NMR (CDCl3): l 7.26–7.61
(m, 5 H, Ph), 5.65 (br s, 1 H, OH), 5.00 (dd,
1 H, J2,4 1.9, J2,P 11.0 Hz, H-2), 4.60 (s, 2 H,
4%-CH2OH), 4.43 (s, 2 H, 5%-CH2OH), 3.52 (br
s, 2 H, 4%,5%-CH2OH), 2.42–2.97 (m, 4 H,
H-4,5), 1.25 (s, 3 H, 3-CH3); 13C NMR
(CDCl3): l 143.7 (C-4%), 135.1 (C-5%), 132.5 (d,
J 2 Hz, C-4 of P-Ph), 130.9 (d, J 10 Hz, C-2,6
of P-Ph), 127.9 (d, J 12 Hz, C-3,5 of P-Ph),
127.5 (d, J 94 Hz, C-1 of P-Ph), 79.6 (d, J 17

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
267
C16H24N3O2PSi: C, 54.99; H, 6.92; N, 12.02.
Found: C, 54.59; H, 7.02; N, 11.89.
(1S,2R,3R) - 3 - Hydroxy - 2 - (4 - hydroxy-
methyl - 1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1-
Hz, C-3), 67.1 (d, J 70 Hz, C-2), 54.4 (4%-
CH2OH), 50.6 (5%-CH2OH), 37.8 (C-4), 24.7
(d, J 66 Hz, C-5), 23.1 (d, J 7 Hz, CH3); 31P
NMR (H3PO4): l +70.9. Anal. Calcd for
C15H20N3O4P: C, 53.41; H, 5.98; N, 12.46.
Found: C, 53.10; H, 5.97; N, 12.19.
phenylphospholane
1-oxide
(11a)
and
(1S,2R,3R)-3-hydroxy-2-(5-hydroxymethyl-
1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1 - phenyl-
phospholane 1-oxide (11b).—2-Azidophospho-
lane 4 (0.75 g, 3.0 mmol) and propargyl alco-
hol (5f, 0.56 g, 10 mmol) were dissolved in 10
mL of DME and refluxed for 48 h with stir-
ring. The solvent was removed and the residue
separated by column chromatography on sil-
ica gel using 10:1 CHCl3–MeOH as eluent,
giving two compounds. Compound 11a, yield:
0.33 g (36%); mp 184–185 °C. 1H NMR
(CD3OD): l 7.73 (s, 1 H, H-5%), 7.32–7.66 (m,
5 H, Ph), 4.91 (dd, 1 H, J2,4 1.9, J2,P 10.5 Hz,
H-2), 4.37 (s, 2 H, 4%-CH2OH), 2.39–2.99 (m,
4 H, H-4,5), 1.19 (s, 3 H, 3-CH3), OH peaks
were not observed by H/D exchange; 13C
NMR (CD3OD): l 147.3 (C-4%), 132.7 (C-5%),
131.0 (d, J 10 Hz, C-2,6 of P-Ph), 128.1 (d, J
12 Hz, C-3,5 of P-Ph), 127.1 (C-1 of Ph not
clear), 124.0 (d, J 9 Hz, C-4 of P-Ph) 79.2 (d,
J 18 Hz, C-3), 69.9 (d, J 70 Hz, C-2), 55.3
(4-CH2OH), 37.8 (C-4), 24.6 (d, J 74 Hz, C-5),
23.3 (CH3); 31P NMR (H3PO4): l +70.3;
EIMS: m/z 308 [M+H]+, 261 (2), 242 (8),
207 (3), 215 (6), 196 (23), 195 (18), 179 (2), 164
(16), 157 (12), 141 (16), 125 (19), 117 (12), 109
(9), 91 (35), 77 (49), 55 (64), 47 (100), 43 (73).
Anal. Calcd for C14H18N3O3P·0.5 H2O: C,
51.69; H, 6.19; N, 12.91. Found: C, 51.59; H,
6.18; N, 12.79.
(1S,2R,3R)-3-Hydroxy-2-(4,5-dicarboxyl-
1H-1,2,3-triazol-1-yl)-3-methyl-1-phenylphos-
pholane 1-oxide (9a).—2-Azidophospholane 4
(0.38 g, 1.5 mmol) and acetylenedicarboxylic
acid (5d, 0.18 g, 1.6 mmol) in 10 mL of DME
were refluxed for 24 h with stirring. The sol-
vent was evaporated under diminished pres-
sure and the residue recrystallized from
CHCl3–MeOH and n-hexane to give 9a, yield:
0.43 g (79%); mp 175–176 °C. 1H NMR
(CD3OD): l 7.32–7.63 (m, 5 H, Ph), 5.41 (dd,
1 H, J2,4 1.9, J2,p11.1 Hz, H-2), 2.20–3.05 (m,
4 H, H-4,5), 1.28 (s, 3 H, 3-CH3); 13C NMR
(CD3OD): l 163.3 (4%-COOH), 157.7 (5%-
COOH), 137.9 (C-4%), 132.3 (C-4 of P-Ph),
131.5 (C-5%), 130.3 (d, J 10 Hz, C-2,6 of P-Ph),
127.8 (d, J 11 Hz, C-3,5 of P-Ph), 127.7 (C-1
of P-Ph was not clear), 79.3 (d, J 16 Hz, C-3),
68.6 (d, J 68 Hz, C-2), 37.6 (C-4), 24.5 (d, J 66
Hz, C-5), 22.8 (d, J 7 Hz, CH3); 31P NMR
(H3PO4): l +70.3. Anal. Calcd for C15H16N3-
O6P: C, 49.32; H, 4.41; N, 11.50. Found: C,
48.98; H, 4.51; N, 11.05.
(1S,2R,3R)-3-Hydroxy-2-(4-trimethylsilyl-
1H-1,2,3-triazol-1-yl)-3-methyl-1-phenylphos-
pholane 1-oxide (10a).—2-Azidophospholane
4 (0.20 g, 0.80 mmol) and (trimethylsi-
lyl)acetylene (5e, 0.20 g, 2.0 mmol) in 10 mL
of DME were refluxed for 24 h with stirring.
The solvent was evaporated under diminished
pressure and the residue recrystallized from
CHCl3 and n-hexane to give 10a, yield: 0.16 g
Compound 11b, yield: 0.35 g (38%); mp
1
227–228 °C. H NMR (CDCl3): l 7.30–7.66
(m, 5 H, Ph), 7.28 (s, 1 H, H-4%), 5.04 (dd, 1
H, J2,4 1.9, J2,P 10.8 Hz, H-2), 4.61 (s, 2 H,
5%-CH2OH), 2.35–3.02 (m, 4 H, H-4,5), 1.20
(s, 3 H, 3-CH3); 13C NMR (CDCl3): l 140.6
(C-4%), 134.5 (d, J 4 Hz, C-5%), 133.3 (d J 15
Hz, C-2,6 of P-Ph), 133.0 (C-4 of P-Ph), 130.4
(d, J 94 Hz, C-1 of P-Ph), 130.1 (d, J 12 Hz,
C-3,5 of P-Ph), 81.6 (d, J 17 Hz, C-3), 69.5 (d,
J 70 Hz, C-2), 55.7 (5%-CH2OH), 40.0 (d, J 5
Hz, C-4), 26.1 (d, J 66 Hz, C-5), 24.7 (d, J 7
Hz, CH3); 31P NMR (H3PO4): l +71.3; m/z
308 [M+H]+, 261 (4), 208 (2), 196 (32), 195
(24), 179 (2), 157 (20), 141 (21), 125 (18), 109
(9), 91 (21), 77 (43), 55 (46), 43 (100). Anal.
1
(57%); mp 221–222 °C. H NMR (CDCl3): l
7.20–7.70 (m, 5 H, Ph), 7.34 (s, 1 H, H-5%),
6.36 (br s, 1 H, OH), 5.00 (dd, 1 H, J2,4 1.9,
J2,P 11.1 Hz, H-2), 2.35–3.25 (m, 4 H, H-4,5),
1.46 (s, 3 H, 3-CH3), 0.12 (s, 9 H, 5%-Si(CH3)3);
13C NMR (CDCl3): l 145.9 (C-4%), 132.4 (d, J
3 Hz, C-4 of P-Ph), 130.9 (d, J 10 Hz, C-2,6 of
P-Ph), 130.8 (C-5%), 128.0 (d, J 11 Hz, C-3,5 of
P-Ph), 127.9 (d, J 93 Hz, C-1 of P-Ph), 79.8
(d, J 16 Hz, C-3), 68.5 (d, J 69 Hz, C-2), 38.0
(d, J 4 Hz, C-4), 25.2 (d, J 63 Hz, C-5), 24.0
(d, J 7 Hz, CH3), 0.00 (s, 3 C, Si(CH3)3; 31P
NMR (H3PO4): l +68.8. Anal. Calcd for

268
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
(1S,2R,3R)-3-Hydroxy-2-(4-methoxycar-
bonyl - 1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1-
Calcd for C14H18N3O3P: C, 54.72; H, 5.90; N,
13.67. Found: C, 54.89; H, 6.00; N, 13.64.
(1S,2R,3R)-3-Hydroxy-2-[4-(1-hydroxy-1-
methylethyl)-1H-1,2,3-triazol-1-yl]-3-methyl-
1-phenylphospholane 1-oxide (12a) and
(1S,2R,3R) - 3 - hydroxy - 2 - [5 - (1 - hydroxy - 1-
methylethyl)-1H-1,2,3-triazol-1-yl]-3-methyl-
1-phenylphospholane 1-oxide (12b).—2-Azi-
dophospholane 4 (0.50 g, 2.0 mmol) and 2-
methyl-3-butyn-2-ol (5g, 0.25 g, 3.0 mmol)
were dissolved in 10 mL of DME and refluxed
for 5 days with stirring. The solvent was re-
moved and the residue separated by column
chromatography on silica gel using 10:1
CHCl3–MeOH as eluent.
phenylphospholane
1-oxide
(13a)
and
(1S,2R,3R)-3-hydroxy-2-(5-methoxycarbonyl-
1H - 1,2,3 - triazol - 1 - yl) - 3 - methyl - 1 - phenyl-
phospholane 1-oxide (13b).—2-Azidophospho-
lane 4 (0.50 g, 2.0 mmol) and propargylic acid
methyl ester (5h, 0.25 g, 3.0 mmol) were dis-
solved in 10 mL of DME and refluxed for 12
h with stirring. The solvent was removed and
the residue separated by column chromatogra-
phy on silica gel using 10:1 CHCl3–MeOH as
eluent.
Compound 13a, yield: 0.33 g (49%); mp
1
206–207 °C. H NMR (CDCl3): l 7.82 (s, 1
H, H-5%), 7.23–7.66 (m, 5 H, Ph), 6.12 (dd, 1
H, J2,4 2.1, J2,P 11.6 Hz, H-2), 5.82 (br s, 1 H,
OH), 3.83 (s, 3 H, 4%-COOCH3), 2.48–3.01 (m,
4 H, H-4,5), 1.38 (s, 3 H, CH3); 13C NMR
(CDCl3): l 160.8 (4%-COOMe), 139.0 (C-4%),
133.1 (d, J 2 Hz, C-5%), 131.2 (d, J 10 Hz,
C-2,6 of P-Ph), 129.4 (C-4 of P-Ph), 128.4 (d,
J 12 Hz, C-3,5 of P-Ph), 127.2 (d, J 93 Hz,
C-1 of P-Ph), 79.9 (d, J 17 Hz, C-3), 69.7 (d,
J 67 Hz, C-2), 52.2 (5%-COOCH3), 37.8 (d, J 4
Hz, C-4), 25.2 (d, J 66 Hz, C-5), 23.7 (d, J 6
Compound 12a, yield: 0.28 g (42%); mp
1
204–205 °C. H NMR (CDCl3): l 7.26–7.57
(m, 5 H, Ph), 7.37 (s, 1 H, H-5%), 4.77 (dd, 1
H, J2,4 1.9, J2,P 10.0 Hz, H-2), 2.40–3.01 (m, 4
H, H-4,5), 1.38 (s, 3 H, 4%-C(CH3)2), 1.34 (s, 3
H, 4%-C(CH3)2), 1.26 (s, 3 H, 3-CH3), OH
peaks were not clear; 13C NMR (CDCl3): l
155.3 (C-4%), 132.5 (C-5%), 130.7 (d, J 10 Hz,
C-2,6 of P-Ph), 127.9 (d, J 12 Hz, C-3,5 of
P-Ph), 127.5 (d, J 94 Hz, C-1 of P-Ph), 121.5
(C-4 of P-Ph), 79.0 (d, J 17 Hz, C-3), 69.7 (d,
J 70 Hz, C-2), 67.6 (4%-C(CH3)2OH), 37.8
(C-4), 29.9 and 29.5 (4%-C(CH3)2OH), 24.4 (d,
J 65 Hz, C-5), 23.2 (d, J 6 Hz, CH3); 31P
NMR (H3PO4): l +70.0. Anal. Calcd for
C16H22N3O3P: C, 57.31; H, 6.61; N, 12.53.
Found: C, 57.14; H, 6.64; N, 12.37.
31
Hz, CH3); P NMR (H3PO4): l +69.2. Anal.
Calcd for C15H18N3O4P·0.5 H2O: C, 52.32; H,
5.56; N, 12.20. Found C, 52.28; H, 5.38; N,
11.99.
Compound 13b, yield: 0.25 g (37%); mp
1
219–220 °C. H NMR (CDCl3): l 7.98 (s, 1
H, H-4%), 7.21–7.67 (m, 5 H, Ph), 5.94 (br s, 1
H, OH), 5.31 (dd, 1 H, J2,4 2.2, J2,P 10.3 Hz,
H-2), 3.86 (s, 3 H, 5%-COOCH3), 2.51–3.03
(m, 4 H, H-4,5), 1.32 (s, 3 H, 3-CH3); 13C
NMR (CDCl3): l 160.6 (5%-COOMe), 139.0
(C-4%), 133.1 (d, J 2 Hz, C-5%), 131.3 (d, J 10
Hz, C-2,6 of P-Ph), 129.4 (d, J 2 Hz, C-4 of
P-Ph), 128.5 (d, J 12 Hz, C-3,5 of P-Ph), 127.2
(d, J 93 Hz, C-1 of P-Ph), 80.0 (d, J 16 Hz,
C-3), 69.7 (d, J 68 Hz, C-2), 52.2 (5%-
COOCH3), 37.3 (d, J 4 Hz, C-4), 25.2 (d, J 66
Hz, C-5), 23.7 (d, J 6 Hz, CH3); 31P NMR
Compound 12b, yield: 0.17 g (25%); mp
1
215–216 °C. H NMR (CDCl3): l 7.25–7.68
(m, 5 H, Ph), 7.10 (s, 1 H, 4%-H), 5.67 (dd, 1
H, J2,4 2.2, J2,P 11.3 Hz, H-2), 2.37–3.11 (m, 4
H, H-4,5), 1.58 (s, 3 H, 5%-C(CH3)2OH), 1.48
(s, 3 H, 5%-C(CH3)2OH), 1.27 (s, 3 H, 3-CH3),
13
OH peaks not observed; C NMR (CDCl3): l
144.4 (C-4%), 132.3 (d, J 4 Hz, C-5%), 131.4 (d,
J 10 Hz, C-2,6 of P-Ph), 129.3 (C-4 of P-Ph),
127.6 (d, J 94 Hz, C-1 of P-Ph), 127.5 (d, J 12
Hz, C-3,5 of P-Ph), 79.8 (d, J 18 Hz, C-3),
68.1 (d, J 71 Hz, C-2), 66.3 (5%-C(CH3)2OH),
37.9 (d, J 5 Hz, C-4), 30.4 and 30.3 (5%-
C(CH3)2OH), 24.9 (d, J 66 Hz, C-5), 23.1 (d,
J 7 Hz, CH3); 31P NMR (H3PO4): l +71.2.
Anal. Calcd for C16H22N3O3P·0.5 H2O: C,
55.80; H, 6.73; N, 12.20. Found: C, 55.68; H,
6.78; N, 12.13.
(H3PO4):
l
+69.0. Anal. Calcd for
C15H18N3O4P: C, 53.73; H, 5.41; N, 12.53.
Found: C, 53.43; H, 5.44; N, 12.53.
(1S,2R,3R) - 3 - Hydroxy - 2 - (4 - phenyl - 1H-
1,2,3 - triazol - 1 - yl) - 3 - methyl - 1 - phenylphos-
pholane 1-oxide (14a) and (1S,2R,3R)-3-hy-
droxy-2-(5-phenyl-1H-1,2,3-triazol-1-yl)-3-

M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
269
for 36 h with stirring. The solvent was re-
moved and the residue separated by column
chromatography on silica gel using 10:1
CHCl3–MeOH as eluent.
methyl-1-phenylphospholane 1-oxide (14b).—
2-Azidophospholane 4 (0.50 g, 2.0 mmol) and
phenylacetylene (5i, 0.31 g, 3.0 mmol) were
dissolved in 10 mL of DME and refluxed for
4 days with stirring. The solvent was removed
and the residue separated by column chro-
matography on silica gel using 10:1 CHCl3–
MeOH as eluent.
Compound 15a, yield: 0.37 g (55%); mp
1
224–227 °C. H NMR (CDCl3): l 7.26–7.59
(m, 5 H, Ph), 6.97 (s, 1 H, H-5%), 5.88 (br s, 1
H, OH), 5.09 (dd, 1 H, J2,4 2.2, J2,P 9.2 Hz,
H-2), 2.47–3.15 (m, 4 H, H-4,5), 1.49 (s, 3 H,
3-CH3), 1.08 (s, 9 H, 4%-C(CH3)3); 13C NMR
(CDCl3): l 157.0 (C-4%), 132.5 (C-5%), 131.0 (d,
J 10 Hz C-2,6 of P-Ph), 128.1 (d, J 12 Hz,
C-3,5 of P-Ph), 127.8 (d, J 93 Hz, C-1 of
P-Ph), 120.6 (C-4 of P-Ph), 79.9 (d, J 17 Hz,
C-3), 69.1 (d, J 70 Hz, C-2), 38.1 (d, J 1 Hz,
C-4), 30.3 (5%-C(CH3)3), 30.1 (5%-C(CH3)3),
25.3 (d, J 65 Hz, C-5), 24.0 (d, J 7 Hz, CH3);
31P NMR (H3PO4): l +69.6. Anal. Calcd for
C17H24N3O2P: C, 61.25; H, 7.25; N, 12.60.
Found: C, 60.87; H, 7.35; N, 12.47.
Compound 14a, yield: 0.23 g (33%); mp
1
230–232 °C. H NMR (CDCl3): l 7.05–7.67
(m, 10 H, Ph), 7.36 (s, 1 H, H-5%), 5.15 (br s,
1 H, OH), 4.92 (dd, 1 H, J2,4 1.6, J2,P 9.2 Hz,
H-2), 2.35–3.19 (m, 4 H, H-4,5), 1.27 (s, 3 H,
3-CH3); 13C NMR (CDCl3): l 139.4 (C-4%),
132.8 (d, J 4 Hz, C-5%), 132.5 (C-2,6 of 4%-Ph),
131.4 (d, J 10 Hz, C-2,6 of P-Ph), 129.7 (C-4
of 4%-Ph), 129.3 (d, J 6 Hz, C-4 of P-Ph), 128.2
(d, J 12 Hz, C-3,5 of P-Ph), 127.8 (d, J 93 Hz,
C-1 of P-Ph), 125.8 (C-3,5 of 4%-Ph), 123.3
(C-1 of 4%-Ph), 80.7 (d, J 18 Hz, C-3), 66.6 (d,
J 70 Hz, C-2), 38.2 (d, J 4 Hz, C-4), 25.1 (d,
J 66 Hz, C-5), 23.8 (d, J 6, CH3); 31P NMR
Compound 15b, yield: 0.14 g (21%), mp
1
247–250 °C. H NMR (CDCl3): l 7.28–7.72
(H3PO4):
l
+68.9. Anal. Calcd for
(m, 5 H, Ph), 7.10 (s, 1 H, H-4%), 6.13 (br s, 1
H, OH), 5.36 (dd, 1 H, J2,4 1.6, J2,P 10.0 Hz,
H-2), 2.44–3.21 (m, 4 H, H-4,5), 1.35 (s, 9 H,
5%-C(CH3)3), 1.25 (s, 3 H, 3-CH3); 13C NMR
(CDCl3): l 146.7 (C-4%), 132.6 (d, J 4 Hz,
C-5%), 131.9 (d, J 10 Hz C-2,6 of P-Ph), 130.2
(C-4 of P-Ph), 127.9 (d, J 93 Hz, C-1 of P-Ph),
127.8 (d, J 12 Hz, C-3,5 of P-Ph), 81.0 (d, J 18
Hz, C-3), 67.8 (d, J 68 Hz, C-2), 38.4 (C-4),
30.2 (5%-C(CH3)3), 30.0 (5%-C(CH3)3), 25.6 (d, J
C19H20N3O2P: C, 64.58; H, 5.70; N, 11.89.
Found: C, 64.22; H, 5.71; N, 11.82.
Compound 14b, yield: 0.12 g (17%); mp
1
228–229 °C. H NMR (CDCl3): l 7.44 (s, 1
H, H-4%), 7.29–7.65 (m, 10 H, Ph), 4.84 (dd, 1
H, J2,4 1.6, J2,P 9.7 Hz, H-2), 2.43–3.02 (m, 4
H, H-4,5), 1.33 (s, 3 H, 3-CH3), OH peak was
not observed clearly; 13C NMR (CDCl3): l
146.8 (C-4%), 132.6 (d, J 4 Hz, C-5%), 130.7 (d,
J 10 Hz C-2,6 of P-Ph), 129.2 (C-4 of 5%-Ph),
128.5 (C-4 of P-Ph), 128.1 (C-3,5 of 5%-Ph),
127.9 (d, J 12 Hz, C-3,5 of P-Ph), 125.3 (C-2,6
of 5%-Ph), 121.9 (C-1 of 5%-Ph), 78.8 (d, J 17
Hz, C-3), 69.8 (d, J 70 Hz, C-2), 37.7 (C-4),
24.2 (d, J 65 Hz, C-5), 23.0 (d, J 6 Hz, CH3),
C-1 of P-Ph not clear; 31P NMR (H3PO4): l
+69.8. Anal. Calcd for C19H20N3O2P: C,
64.58; H, 5.70; N, 11.89. Found: C, 64.21; H,
5.78; N, 11.75.
(1S,2R,3R)-3-Hydroxy-2-(4-t-butyl-1H-
1,2,3 - triazol - 1 - yl) - 3 - methyl - 1 - phenylphos-
pholane 1-oxide (15a) and (1S,2R,3R)-3-hy-
droxy-2-(5-t-butyl-1H-1,2,3-triazol-1-yl)-3-
methyl-1-phenylphospholane 1-oxide (15b).—
2-Azidophospholane 4 (0.50 g, 2.0 mmol) and
3,3-dimethyl-1-butyne (5j, 0.33 g, 4.0 mmol)
were dissolved in 10 mL of DME and refluxed
31
66 Hz, C-5), 23.7 (d, J 7 Hz, CH3); P NMR
(H3PO4):
l
+69.9. Anal. Calcd for
C17H24N3O2P: C, 61.25; H, 7.25; N, 12.60.
Found: C, 61.05; H, 7.37; N, 12.46.
4. Supplementary material
Full crystallographic details excluding struc-
ture features have been deposited with the
Cambridge Crystallographic Data Centre
(CCDC). These data may be obtained, on
request, from The Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (Tel. +44-
1223-336408; fax. +44-1223-336033; e-mail.
deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk).

270
M. Yamashita et al. / Carbohydrate Research 336 (2001) 257–270
(b) Takayama, S.; Martin, R.; Wu, J.; Laslo, K.; Siuzdak,
Acknowledgements
G.; Wong, C. H. J. Am. Chem. Soc. 1997, 119, 8146–
8151;
We thank Ms Miyuki Takei, Nagoya Insti-
tute of Technology for the elemental analyses.
One of the authors (P.M.R.) is thankful to the
Satellite Venture Business Laboratory,
Shizuoka University, Japan for financial sup-
port and also financial support by Shizuoka
Science and Technology Foundation, Nippon
Soda Co. Ltd. and Suzuroku Dyeing Co. Ltd.
are greatly acknowledged.
(c) Momotake, A.; Togo, H.; Yokoyama, M. J. Chem.
Soc., Perkin Trans. 1 1999, 1193–1200.
12. (a) Branalt, J.; Kvarnstrom, I.; Niklasson, G.; Svensson,
S. C. T. J. Org. Chem. 1994, 59, 1783–1788;
(b) Secrist, III, J. A.; Riggs, R.; Tiwari, K. N.; Mont-
gomery, J. A. J. Med. Chem. 1992, 35, 533–538;
(c) Dyson, M. R.; Coe, P. L.; Walker, R. T. J. Med.
Chem. 1991, 34, 2782–2786.
13. Darrow, J. W.; Drueckhammer, D. G. J. Org. Chem.
1994, 59, 2976–2985.
14. Riley, T. A.; Larson, S. B.; Avery, T. L.; Finch, R. A.;
Robins, R. K. J. Med. Chem. 1990, 33, 572–576.
15. Yamamoto, H.; Inokawa, S. Ad6. Carbohydr. Chem.
Biochem. 1984, 42, 135.
16. Yamashita, M.; Yamada, M.; Sugiura, M.; Nomoto, H.;
Oshikawa, T. Nippon Kagaku Kaishi 1987, 1207–1213.
17. Yamamoto, H.; Hanaya, T. In Studies in Natural Prod-
ucts Chemistry; Atta-ur-Rahaman, Ed. Sugar Analogs
Containing Carbon–Phosphorus Bonds; Elsevier: Am-
sterdam, 1990; Vol. 6, pp. 351–384.
18. Yamashita, M.; Yabui, A.; Suzuki, K.; Kato, Y.;
Uchimura, M.; Iida, A.; Mizuno, H.; Ikai, K.; Oshikawa,
T.; Parkanayi, L.; Clardy, J. J. Carbohydr. Chem. 1997,
16, 499–519.
19. Yamashita, M.; Uchimura, M.; Iida, A.; Parkanayi, L.;
Clardy, J. J. Chem. Soc., Chem. Commun. 1988, 569–570.
20. Yamashita, M.; Kato, Y.; Suzuki, K.; Oshikawa, T.
Heterocycl. Commun. 1998, 4, 411–414.
21. Yamashita, M.; Iida, A.; Mizuno, H.; Miyamoto, Y.;
Morishita, T.; Sata, N.; Kiguchi, K.; Yabui, A.; Os-
hikawa, T. Heteroatom Chem. 1993, 4, 553–557.
22. Yamashita, M.; Iida, A.; Ikai, K.; Oshikawa, T.; Hanaya,
T.; Yamamoto, H. Chem. Lett. 1992, 407–410.
23. Sasaki, T.; Eguchi, S.; Yamaguchi, M.; Esaki, T. J. Org.
Chem. 1981, 46, 1800–1804.
References
1. Bobek, M.; Whistler, R. L.; Bloch, A. J. Med. Chem.
1972, 15, 168–171.
2. Nicotra, F. Carbohydr. Chem. 1998, 384–429.
3. Garcia, J. I.; Flores, F. G. C.; Mateo, F. H.; Gonzalez, F.
S. Eur. J. Chem. 1999, 5, 1512–1525 and references cited
in.
4. McCormack, J. B.; Getchell, J. P.; Mitchel, S. W.; Hicks,
D. R. Lancet ii 1984, 1367-, 1369.
5. Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St.Clair,
M. H.; Lehrmann, S. N.; Gallo, R. S.; Bolognes, D.;
Barry, D. W.; Broder, S. Proc. Nat. Acad. Sci. USA 1985,
82, 7096–7100.
6. Secrist, III, J. A.; Riggs, R. M.; Tiwari, K. N.; Mont-
gomery, J. A. J. Med. Chem. 1992, 35, 533–538.
7. Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1966, 88,
3885–3887.
8. (a) Montgomery, J. A. Med. Res. Re6. 1982, 2, 271–308;
(b) Secrist, III, J. A.; Tiwari, K. N.; Riordan, J. M.;
Montgomery, J. A. J. Med. Chem. 1991, 34, 2361–2366.
9. Kim, H. O.; Ahn, S. K.; Alves, A. J.; Beach, J. W.;
Jeong, L. S.; Choi, B. G.; Roey, P. V.; Schinazi, R. F.;
Chu, C. K. J. Med. Chem. 1992, 35, 1987–1995.
10. (a) Madhavan, G. V. B.; Martin, J. C. J. Org. Chem.
1986, 51, 1287–1293;
24. Hlasta, D. J.; Ackwrman, J. H. J. Org. Chem. 1994, 59,
6184–6189.
25. Guillerm, G.; Honore, A. L.; Veniard, I.; Pourcelot, G.;
Benaim, J. Bull. Soc. Chim. Fr. 1973, 2739–2746.
26. Padwa, A.; Wannamaker, M. W. Tetrahedron 1990, 46,
1145–1162.
(b) Maag, H.; Rydzwski, R. M. J. Org. Chem. 1992, 57,
5823–5831;
(c) Patil, S. D.; Koga, M.; Schneller, S. W.; Snoeck, R.;
De Clercq, E. J. Med. Chem. 1992, 35, 2191–2195;
(d) Wang, P.; Agrofoglio, L. A.; Newton, M. G.; Chu, C.
K. J. Org. Chem. 1999, 64, 4173–4178;
27. Hanaya, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1989,
62, 2320–2327.
28. Stewart, J. J. P. J. Comput. Chem. 1989, 209–220.
29. Bobek, M.; Bloch, A.; Parthasarathy, R.; Whistler, R. L.
J. Med. Chem. 1975, 18, 784–787.
30. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, M.;
Giacovazzo, C.; Guagliardi, A.; Polidori, G. J. Appl.
Cryst. 1994, 27, 435–439.
(e) Cowart, M.; Bennett, M. J.; Kerwin, Jr., J. F. J. Org.
Chem. 1999, 64, 2240–2249.
11. (a) Legler, G.; Julich, E. Carbohydr. Res. 1984, 128,
61–72;
31. Quin, L. D.; Gratz, J. P.; Barket, T. P. J. Org. Chem.
1968, 33, 1034–1041.