An efficient route to optically active inositol derivatives via the resolution of myo-inositol 1,3,5-orthoformate: A short synthesis of D-myo-inositol-4-phosphate

Article abstract of DOI:10.1016/j.tetasy.2004.02.020

An efficient method for the resolution of myo-inositol 1,3,5-orthoformate has been developed. The triol, 1 was converted to diastereomers via reaction with (S)-O-acetylmandeloyl chloride. Conditions were optimized for a diastereomeric ratio of 7:3. Both t

Full text of DOI:10.1016/j.tetasy.2004.02.020

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1193–1198
An efficient route to optically active inositol derivatives via
the resolution of myo-inositol 1,3,5-orthoformate: a short
synthesis of D-myo-inositol-4-phosphate
Kana M. Sureshan and Yutaka Watanabe*
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama 790-8577, Japan
Received 9 February 2004; accepted 20 February 2004
Abstract—An efficient method for the resolution of myo-inositol 1,3,5-orthoformate has been developed. The triol, 1 was converted
to diastereomers via reaction with (S)-O-acetylmandeloyl chloride. Conditions were optimized for a diastereomeric ratio of 7:3. Both
the diastereomers could be separated by column chromatography. The absolute configurations of the diastereomers were determined
by converting the less polar diastereomer to the known
illustrated by a short and efficient synthesis of -myo-inositol-4-phosphate in four steps from myo-inositol.
2004 Elsevier Ltd. All rights reserved.
L-2,4-di-O-benzyl-myo-inositol. The utility of the resolved derivatives is
D
ꢀ
1
. Introduction
of phosphoinositols has necessitated better synthetic
strategies for their preparation. Furthermore, the dis-
2
Recently, there have been significant advances in the
chemistry and biology of myo-inositol and its deriva-
closed therapeutic potential of inositol derivatives and
the recent use of inositol as a synthon for the synthesis
1
3
tives due to their important biological roles. The real-
ization that phosphatidylinositol phospholipase
of many natural products have given further impact to
the myo-inositol chemistry. This multi-faceted impor-
C
PIPLC) mediates hydrolysis of phosphatidylinositol
(
4
tance of inositol demands better methods for resolution
4
,5-bisphosphate [PI(4,5)P ] to the second messengers
2
-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P
and selective protection–deprotection for this meso
cyclohexane hexol.
D
3
] and
diacylglycerol (DAG), has augmented the pace of
research in this field. Many phosphoinositols are
involved in the myo-inositol cycle, through which
The most commonly used intermediates for the synthe-
ses of phosphoinositols are the orthoformate 1 and
diketal derivatives 2 and 3 (Fig. 1). Following Kishi’s
Ins(1,4,5)P
tionally, many other phosphatidylinositol phosphates
PIPns) have recently been found in living cells. How-
3 2
recycles back to the lipid PI(4,5)P . Addi-
5
first report, the efforts of different groups to improve
the yield of triol 1 has culminated in various excellent
(
6
ever a clear understanding of the biological significance
of these phosphoinositols has been lacking mainly due
to difficulties in isolating these derivatives from natural
resources. As the isolation of these phosphorylated
derivatives from natural sources is impracticable, bio-
logical studies rely on the efficient synthesis of these
phosphoinositol derivatives. On the other hand, the
judicious design and synthesis of structurally modified
natural substrates of different enzymes as prospective
effectors or inhibitors is also one of the major focuses of
inositol chemistry. The increased interest in the biology
methods for the isolation of triol 1 in very good yields.
Such a high yield (90%) of triol, 1 from myo-inositol
unlike diketals 2 and 3 (around 25% as a mixture of four
or more components) promote 1 as the preferred start-
ing material for various phosphoinositol syntheses. A
good distinction can also be made between the reactiv-
ities of the three hydroxyl groups [C-2-OH and C-4-OH
(C-6-OH)] of this triol. For instance, methods for the
selective protection of (a) only the C-4 (or C-6) hydroxyl
7
5;7b;8
group, (b) only the C-2 hydroxyl group,
9
(c) C-2 and
C-4 (or C-6) hydroxyl groups simultaneously, and (d)
7c;10
C-4 and C-6 hydroxyl groups
simultaneously, in 1
have been developed. Thus by choosing the appropriate
reagent, any required protection of the three hydroxyl
groups can be achieved. Acidic deprotection of the
*
Corresponding author. Tel.: +81-89-927-9921; fax: +81-89-927-9944;
e-mail: wyutaka@dpc.ehime-u.ac.jp
0
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.020

1194
K. M. Sureshan, Y. Watanabe / Tetrahedron: Asymmetry 15 (2004) 1193–1198
O
O
O
O
O
OH
OH
O
O
OH
O
O 6
3
1
5
HO
4
2
HO
HO
O
OH
O
1
2
3
Figure 1.
orthoester functionality of fully protected orthoesters
provides the 1,3,5-meso triol, which has been exploited
this triol has not kept pace with its diketal counterparts.
Efforts toward enzymatic resolution have been
15
as a starting material for the synthesis of
D
-myo-inosi-
tol-1-phosphate via enantioselective phosphorylation
reported to give no enantioselectivity, presumably
because of the faster acyl migration between C-6 and
C-4-OH due to their diaxial disposition and spatial
11
with synthetic polypeptide catalysts. Also, different
selectivities are reported for the partial deprotection of
the orthoester functionality (to form acetals or ketals) in
fully protected orthoester derivatives. Treatment of a
fully protected orthoester derivative with DIBALH gave
9b
proximity. Riley et al. resolved orthoformate, 1 via
chromatographic separation of its diastereomeric bis-
camphanates. During our ongoing studies to provide
easy access to many inositol phosphates and their lipid
analogues, we required enantiomerically pure orthoester
derivatives. We herein report the resolution of triol 1 as
its di-O-acetylmandelate derivatives. To illustrate the
utility and advantages of this method, an efficient syn-
12
access to the C-5 hydroxyl group while treatment with
10b;12b;13
3
AlMe gave access to the C-1(3)-hydroxyl group.
Treatment with 1 equiv of Grignard reagent gave access
to the C-1(3)-hydroxyl group while the use of excess
reagent provided the symmetrical diol (C-1 and C-3
thesis of
D
-myo-inositol-4-phosphate is also described.
14
OH). Thus access to any single or combination of
hydroxyl groups is possible with orthoesters unlike in
the case of diketals (Fig. 2). Due to this possible mod-
ulation of protecting groups, orthoesters of myo-inositol
are gaining more preference over the traditional dike-
tals. Another added advantage is the possible absolute
enantioselectivity (or diastereoselectivity) during reso-
lution, as the triol is a meso derivative.
2. Results and discussion
The acylation of triol 1 with 2.1 equiv of (S)-O-acetyl-
mandelic acid chloride in pyridine at 0 ꢁC (Scheme 1)
followed by work-up and chromatographic separation
(3% acetone in CH Cl ) yielded two unsymmetrical
diacylated derivatives, 12 and 13, with one of them being
enriched.
2 2
Despite this importance of triol 1 over diketal deriva-
tives 2 and 3, the exploration of resolution methods for
O
O
O
O
O
O
O
O
O
HO
RO
RO
5
RO
OH
RO
HO
2
,4(6)- OH
6
OH
4
OH
4
(6)-OH
4,6-OH
O
O
O
OR
O
O
O
OH
HO
HO
HO
OR
HO
RO
7
OR
OR 11
HO
1
OH
2-OH
1
,3,5-OH
HO
OR
OR
O
O
CHR12
O
HO
O
RO
OH
O
HO
1
RO
RO
RO
10
,3-OH
OR
8
RO
1(3)-OH
OR
-OH
9
5
Figure 2.

K. M. Sureshan, Y. Watanabe / Tetrahedron: Asymmetry 15 (2004) 1193–1198
1195
OO 4
O
1
O
O
OAc
O
O
C
3
5
6
H
5
i
AMO
AMO
1
1
+
6
3
4
2
2
AM =
AMO
Ph
HO
OH
OAM
12
13
Scheme 1. Reagents and conditions: (i) (S)-(þ)-O-acetylmandeloyl chloride (2.1 equiv), py, 0 ꢁC, 2 h.
The less polar diastereomer, 12 {mp 72 ꢁC, ½aŠ ¼ þ60 (c
(Scheme 2). Thus the free hydroxyl group in 12 was
protected as the THP ether to give 14 (92%). The chiral
auxiliaries were removed by aminolysis and the resulting
diol 15 converted to the dibenzyl ether 16 under stan-
dard conditions. Finally, the acid labile THP and
orthoformate functionalities were removed via treat-
D
1
, CHCl )}, was isolated in 59% as a white solid while
3
the more polar diastereomer, 13 {½aŠ ¼ þ65.7 (c 1,
D
3
CHCl )} was isolated in 26% as a gum. Since we ob-
tained a diastereomeric ratio of 7:3, we tried different
conditions (Table 1) to see whether we could optimize
the diastereomeric ratio (kinetic resolution). Lowering
of reaction temperature yielded a mixture of 12 and 13
in a 1:1 ratio. At room temperature (15 ꢁC), the ratio
could be slightly improved upon at the cost of chemical
yield due to charring. The exact reason for this variation
of diastereomeric ratio with temperature is not clear.
However acyl migration at higher temperatures may be
responsible for the difference in diastereomeric ratio.
DCC mediated coupling of (S)-O-acetylmandelic acid
ment with TFA and water to give L-2,4-di-O-benzyl-
myo-inositol 17 {½aŠ ¼ ꢀ28.9 (c 1, EtOH); lit.
6a
D
½aŠ ¼ ꢀ29.2 (c 1, EtOH)}. Thus the less polar diaste-
D
reomer 12 was assigned to be L-2,4-di-O-[(S)-O-acetyl-
mandeloyl]-myo-inositol 1,3,5-orthoformate. Similarly,
the more polar diastereomer 13 was assigned as -2,4-
di-O-[(S)-O-acetylmandeloyl]-myo-inositol 1,3,5-ortho-
D
formate.
(
diesters 12 and 13 along with other products. The use of
2 equiv) with triol 1 (1 equiv) gave a 1:1 mixture of
To check the feasibility of this method, we synthesized
D
-myo-inositol-4-phosphate from diester 12 (Scheme 3).
Thus the free hydroxyl group in 12 was phosphorylated
using dibenzyl N,N-diisopropylphosphoramidite fol-
16
(
chiral auxiliary also resulted in the formation of 1:1
S)-O-tert-butyldimethylsilylmandeloyl chloride as the
1
17
mixture (based on H NMR) of diastereomers insepa-
rable by chromatography. Hence entry 1 was taken as
the optimum condition.
lowing Fraser-Reid’s protocol to give diester phos-
phate 18 {½aŠ ¼ þ45 (c 1, CHCl )} in good yield (87%)
D
3
as a gum. The benzyl, orthoformate, and acyl func-
tionalities were removed successively, and the phosphate
isolated as its bis-cyclohexylammonium salt in 37% yield
The absolute configurations of diastereomers 12 and 13
were determined by converting the less polar diastereo-
18
from myo-inositol in four steps against a reported yield
of 0.99% in seven steps.
6a
mer 12 to the known
L
-2,4-di-O-benzyl-myo-inositol
Table 1
Entry no
Conditions
Chemical yield (%)
Ratio 12:13
1
2
3
4
5
(S)-O-Acetylmandeloyl chloride, py, CH
(S)-O-Acetylmandeloyl chloride, py, CH
(S)-O-Acetylmandeloyl chloride, py, CH
2
2
2
Cl
Cl
Cl
2
2
2
, 0 ꢁC
85
79
60
69
70
70:30
50:50
74:26
50:50
, ꢀ42 ꢁC
, 15 ꢁC
(S)-O-Acetylmandelic acid, DCC, DMAP, CH
(S)-O-TBDMS-mandeloyl chloride, py, CH Cl
2
Cl
2
, 0 ꢁC
a
2
2
, 0 ꢁC
50:50
a
This ratio is of corresponding derivatives with O-TBDMS-mandeloyl group.
O
O
O
O
O
O
O 4
3
O 4
1
3
O 4
1
5
5
3
5
i
ii
HO
AMO
AMO
1
6
6
2
6
2
2
HO
AMO
AMO
OTHP
OH
OTHP
15
12
14
OBn
OH
O
O
O 4
1
iii
3
5
iv
HO
HO
OH
BnO
6
2
BnO
BnO
OTHP
17
1
6
2 2
Scheme 2. Reagents and conditions: (i) 3,4-dihydro-2H-pyran, PPTS, CH Cl , rt, 6 h, 92%; (ii) isobutylamine, MeOH, rt, 6 h, 91%; (iii) BnBr, NaH,
DMF, rt, 10 min, 91%; (iv) TFA–H O (4:1 v/v), rt, 24 h, 97%.
2

1196
K. M. Sureshan, Y. Watanabe / Tetrahedron: Asymmetry 15 (2004) 1193–1198
OO 4
O
O
O
O
O
3
O 4
1
3
O 4
1
5
5
3
5
iii
i, ii
AMO
AMO
1
AMO
2
6
6
2
6
2
AMO
OPO(OBn)2
AMO
AMO
OH
OPO(OH)2
12
18
19
OH
OH
OAM
OH
+
-
OH
v-viii
iv
6 11
3 2(O) OPO
(C H NH )
2
(
HO) OPO
2
HO
OH
HO
HO
AMO
20
21
Scheme 3. Reagents and conditions: (i) (BnO)
H
2
PN(i-Pr)
þ
2
, tetrazole, CH
2
Cl
Cl
2
, ꢀ42 ꢁC; (ii) m-CPBA, ꢀ78 ꢁC, 90%; (iii) H
2
, 5% Pd/C, EtOAc; (iv) TFA–
, rt, 10 min.
þ
2
O, rt, 12 h; (v) 1 M LiOH, THF, rt, 12 h; (vi) H , extract with CH
2
2
6 2
; (vii) DIAION SK1BH (H form) resin; (viii) C H11NH
1
3
3
. Conclusion
C NMR spectra were recorded on a Bruker-DPX-400
instrument. Chemical shifts (d values relative to tetra-
methylsilane, d values relative to CDCl , and d values
relative to H PO ) and coupling constants (J values) are
H
In conclusion, we have achieved the optical resolution of
an important intermediate for the synthesis of many
myo-inositol phosphates and other derivatives. The
utility of this method has been illustrated by an efficient
C
3
P
3
4
given in ppm and Hz, respectively. Optical rotations
were recorded in a JASCO P-1010 Polarimeter. Ele-
mental analyses were carried out on a YANACO MT-5
elemental analyzer. Usual work-up refers to the evapo-
ration of the reaction solvent, followed by dissolving the
residue in ethyl acetate and washing successively with
synthesis of
D-myo-inositol-4-phosphate. The enriched
distribution of one of the diastereomers is advantageous
since any required diastereoselectivity can be achieved
by using the appropriate (R)- or (S)-mandelic acid
derivatives. Since meso triol can be obtained in very high
yield from inositol when compared to diketals, this
method offers access to optically active derivatives in an
economical way. The UV activity of the products
water, dil-HCl, satd NaHCO solution, and brine.
3
4.2. Resolution of myo-inositol 1,3,5-orthoformate
(
advantageous for chromatographic separation) and the
low cost of mandelic acid (both R and S) are added
advantages of using acetylmandelic acid over camphanic
acid. The high yield of triol from inositol, enriched
formation of one of the diastereomers by using a rela-
tively cheaper chiral auxiliary and the different known
selective reactions of orthoester derivatives offers effi-
cient access to many optically active inositol derivatives
in an economical way. We hope this resolution method
will be useful not only for inositol chemists but also to a
wider cross section of organic chemists as inositols are
increasingly being used as synthons for many natural
To a solution of triol 1 (190 mg, 1 mmol) in pyridine
(5 mL) at 0 ꢁC, was added a solution of (S)-O-acetyl-
mandeloyl chloride (446 mg, 2.1 mmol) in dichloro-
methane (5 mL) dropwise over a period of 10 min. After
1 h, the temperature was gradually raised to room tem-
perature and continued stirring for another 3 h. The
solvents were evaporated off and the residue dissolved in
ethyl acetate and taken into a separating funnel, washed
successively with water, cold dil-HCl, satd NaHCO3
solution, and brine, dried over anhydrous sodium sul-
fate, evaporated under reduced pressure to give a gum-
my residue, and chromatographed over silica gel with
3% acetone in dichloromethane as the eluent. The less
3
19
20
products, metal complexing agents, gelators, cata-
22
lysts, supramolecular assemblies, chiral auxiliary,
21
23
etc. Presently we are investigating to explore the syn-
thetic manipulation of these resolved derivatives to
achieve different phosphoinositols and other derivatives,
which will be reported elsewhere.
polar diastereomer, L-2,4-di-O-[(S)-O-acetylmandeloyl]-
myo-inositol 1,3,5-orthoformate 12 (320 mg, 59%) was
obtained as a colorless powder. Mp 72 ꢁC; ½aŠ ¼ þ60 (c
D
1
1, CHCl
3
); H NMR (400 MHz, CDCl ) d 2.19 (s, 3H),
.24 (s, 3H), 4.03 (m, 1H), 4.30 (m, 1H), 4.35 (m, 1H),
.40 (m, 1H), 5.22 (s, 1H), 5.49 (s, 1H), 5.56 (m, 1H),
.96 (s, 1H), 6.02 (s, 1H), 7.38–7.48 (m, 8H), 7.54–7.58
3
2
4
5
1
3
(
m, 2H); C NMR (100 MHz, CDCl
67.8, 68.7, 68.9, 70.8, 74.5, 102.5, 127.4, 128.7, 128.8,
29.3, 129.4, 132.7, 133.0, 167.1, 168.3, 170.4, 170.6;
Anal. Calcd for C27 12: C, 59.78; H, 4.83. Found: C,
9.61; H, 4.90. Further elution yielded the, -2,4-di-O-
[(S)-O-acetylmandeloyl]-myo-inositol 1,3,5-orthofor-
3
) d 20.4, 63.7, 66.6,
4. Experimental
1
4
.1. General
26
H O
5
D
All experiments were conducted under nitrogen atmo-
sphere. Melting points were determined with a Yanaco
Micro Melting Point Apparatus and are uncorrected.
Flash column chromatography was performed using
mate 13 (141 mg, 26%) as a colorless gum. ½aŠ ¼ þ65.7
D
1
(c 2, CHCl
3
); H NMR (400 MHz, CDCl
3
) d 2.21 (s,
3H), 2.22 (s, 3H), 2.92 (d, 4.4 Hz, OH), 4.04 (dt, 1.6 Hz,
1
31
silica gel (Fuji Silysia, Silica gel BW-300). H, P, and
3.6 Hz, 1H), 4.33 (dt, 4.0 Hz, 2.0 Hz, 1H), 4.46 (ddd,

K. M. Sureshan, Y. Watanabe / Tetrahedron: Asymmetry 15 (2004) 1193–1198
1197
5
5
.4 Hz, 3.2 Hz, 1.6 Hz, 1H), 4.61 (m, 1H), 5.23 (m, 1H),
.41 (ddd, 4.0 Hz, 1.6 Hz, 1H), 5.48 (d, 1.6 Hz, 1H,
128.8, 129.3, 132.9, 133.2, 135.1, 135.2, 167.8, 167.9,
170.1, 170.3. Phosphate 18 (108 mg, 0.13 mmol) was
dissolved in ethyl acetate (3 mL) and stirred with 5% Pd/
C (11 mg) under hydrogen atmosphere (balloon) at
room temperature for 12 h. The solid materials were
filtered off, washed several times with ethyl acetate and
methanol, and the combined washings and filtrate con-
centrated. The residue was dissolved in TFA (3 mL) and
a drop of water then added and stirred at ambient
temperature overnight. The solvents were evaporated
and the residue thus obtained dissolved in THF (1 mL)
and stirred with a 1 M solution of LiOH (1 mL) for 6 h.
THF was evaporated, the aqueous solution acidified
with dilute HCl and the organic acid (mandelic acid)
HCO ), 5.72 (s, 1H), 5.99 (s, 1H), 7.30–7.46 (m, 8H),
3
13
7
6
1
1
3
.50–7.54 (m, 2H); C NMR (100 MHz, CDCl ) d 20.5,
4.0, 66.8, 67.5, 68.4, 69.2, 70.7, 74.5, 74.8, 102.7,
27.37, 127.42, 128.7, 129.0, 129.3, 129.7, 131.9, 133.0,
67.3, 168.1, 170.4, 171.2; MS (FABþ) m=z (%): 543
þ
[
(MþH) , 100].
4
.3. Determination of the absolute configuration
Compound 12 (50 mg, 0.09 mmol) was dissolved in
dichloromethane (1 mL) and then pyridinium para-tol-
uene sulfonate (PPTS, 10 mg) and 3,4-dihydro-2H-pyran
residues extracted with CH
layer was concentrated and stirred with an ion exchange
2
Cl
2
(7 · 5 mL). The aqueous
(
37 lL, 0.4 mmol) added and stirred at room tempera-
þ
ture for 6 h. Usual work-up followed by column chro-
matography yielded the THP ether 14 as a mixture of
diastereomers (53 mg, 92%). The chiral auxiliaries were
removed by refluxing 14 with isobutylamine (0.5 mL) in
methanol (2 mL) for 6 h. Evaporation followed by col-
umn chromatography afforded diol 15 (21 mg, 91%),
which (20 mg, 0.07 mmol) was benzylated with benzyl
bromide (44 lL, 0.37 mmol) in the presence of NaH
resin (DIAION SK1BH H form) for 1 h. The filtrate
was treated with cyclohexylamine (excess) for 3 h and
evaporated to dryness. The residue thus obtained was
dissolved in the minimum amount of distilled water and
lyophilized with acetone to afford a white precipitate of
bis-cyclohexylammonium salt 21 of
D
-myo-inositol-4-
18
phosphate {50 mg, 81%, ½aŠ ¼ þ2 (c 2, H
2
O)}, lit.
D
½aŠ ¼ þ1.3 (c 5, H
2
O)]}. It was found that the ½aŠ
D
values varied with pH of the solution. At neutral pH an
D
(
10 mg, 0.42 mmol) in DMF (1 mL) at room temperature
for 10 min. Usual work-up followed by chromato-
graphic separation yielded dibenzyl ether 16 (30 mg,
½aŠ ¼ þ2 was observed and at a pH of around 10 (by
D
adding cyclohexylamine), the value increased to þ9.
9
H O (4:1 v/v, 1 mL) at ambient temperature for 24 h,
1%). Dibenzyl ether 16 (30 mg) was stirred with TFA–
Such a dependence of ½aŠ on pH of the solution has
D
been observed previously in this laboratory.
24
2
evaporated to dryness and washed with hexane to give
tetrol 17 (23 mg, 97%). ½aŠ ¼ ꢀ28.9 (c 1, EtOH); lit.
6a
D
1
½
aŠ ¼ ꢀ29.2 (c 1, EtOH); H NMR (400 MHz,
D
CD OD) d 3.33 (m, 1H), 3.46 (dd, 9.9 Hz, 2.5 Hz, 1H),
3
Acknowledgements
3
1
4
7
.61 (dd, 9.8 Hz, 2.5 Hz, 1H), 3.69 (dd, 10.0 Hz, 9.6 Hz,
H), 3.73 (t, 9.5 Hz, 1H), 3.93 (t, 2.5 Hz, 1H, H-2), 4.85–
.94 (m, 4H, benzylic), 7.25–7.36 (m, 6H, Ar–H), 7.45–
.48 (m, 4H, Ar–H).
We thank JSPS for a postdoctoral fellowship (K.M.S.)
and Grant-in-Aid (No. 02170). We also thank Venture
Business Laboratory and Advanced Instrumentation
Center for Chemical Analysis, Ehime University for
NMR and elemental analysis, respectively.
4
.4. D-myo-Inositol-4-phosphate
Compound 12 (240 mg, 0.44 mmol) and tetrazole
(
(
70.1 mg, 1 mmol) were dissolved in dichloromethane
5 mL) and cooled to ꢀ42 ꢁC. Dibenzyl N,N-diisopropyl
References and notes
phosphoramidite (227.7 mg, 0.66 mmol) was then added
and stirred for 3 h and then for another half an hour at
room temperature, while following the reaction by TLC.
It was then cooled to ꢀ78 ꢁC, m-CPBA (172.5 mg,
1
2
. (a) Berridge, M. J. Nature 1993, 361, 315; (b) Hinchliffe,
K.; Irvine, R. Nature 1997, 390, 123; (c) Phosphoinositides:
Chemistry, Biochemistry and Biomedical Applications;
Bruzik, K. S., Ed. ACS Symposium Series 718. 1999; (d)
Ferguson, M. A. J.; Williams, A. F. Annu. Rev. Biochem.
1
mmol) added and stirred for 1 h and then at room
temperature for another half an hour. Usual work-up
followed by chromatographic separation yielded phos-
1
988, 57, 285.
. (a) Qiao, L.; Nan, F.; Kunkel, M.; Gallegos, A.;
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phate 18 as a gum (350 mg, 87%). ½aŠ ¼ þ45 (c 1,
D
1
CHCl
2
(
2
4
1
3
); H NMR (400 MHz, CDCl ) d 2.13 (s, 3H),
.22 (s, 3H), 4.00 (ddd, 1.6 Hz, 2.0 Hz, 4.0 Hz, H-5), 4.03
3
ddd, 1.6 Hz, 3.6 Hz, 5.2 Hz, H-3), 4.37 (ddd, 1.6 Hz,
.0 Hz, 4.0 Hz, H-1), 4.84–4.89 (m, H-4), 4.92–5.11 (m,
H, benzylic), 5.20 (dd, 2.0 Hz, 3.6 Hz, H-2), 5.43 (d,
.0 Hz, 1H, HCO ), 5.48 (dt, 1.6 Hz, 4.0 Hz), 5.75 [s, 1H,
3
1
PhCH(OAC)], 6.02 [s, 1H, PhCH(OAC)], 7.22–7.55 (m,
13
3
31
2
0H, Ar–H); P NMR (400 MHz, CDCl3) d ꢀ0.99;
C
2
NMR (100 MHz, CDCl ) d 20.4, 20.6, 63.4, 67.1, 67.2,
6
7
3
8.0, 68.3, 69.1, 69.2, 69.79, 69.84, 69.9, 70.0, 70.1, 74.3,
4.4, 102.6, 127.5, 128.0, 128.1, 128.2, 128.6, 128.77,

1198
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