Yb(OTf)3-Catalyzed Desymmetrization of myo-Inositol 1,3,5-Orthoformate and Its Application in the Synthesis of Chiral Inositol Phosphates

Article abstract of DOI:10.1021/acs.joc.7b01919

A variety of inositol phosphates including myo-inositol 1,4,5-trisphosphate, which is a secondary messenger in transmembrane signaling, were selectively synthesized via Yb(OTf)₃-catalyzed desymmetrization of myo-inositol 1,3,5-orthoformate using a proline-based chiral anhydride as an acylation precursor. The investigated catalytic system could regioselectively differentiate the enantiotopic hydroxy groups of myo-inositol 1,3,5-orthoformate in the presence of a chiral auxiliary. This key step to generate a suitably protected chiral myo-inositol derivatives is described here as a unified approach to access inositol phosphates.

Full text of DOI:10.1021/acs.joc.7b01919

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Article
Yb(OTf)3-Catalyzed Desymmetrization of myo-Inositol-1,3,5-Orthoformate
and Its Application in the Synthesis of Chiral Inositol Phosphates
Laxmansingh T. Padiyar, Medel Manuel L. Zulueta, Narayana Murthy Sabbavarapu, and Shang-Cheng Hung
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01919 • Publication Date (Web): 11 Oct 2017
Downloaded from http://pubs.acs.org on October 13, 2017
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Yb(OTf)3-Catalyzed Desymmetrization of myo-Inositol-1,3,5-
Orthoformate and Its Application in the Synthesis of Chiral Inositol
Phosphates
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Laxmansingh T. Padiyar, Medel Manuel L. Zulueta, Narayana Murthy Sabbavarapu, and Shangꢀ
Cheng Hung*
Genomics Research Center, Academia Sinica, 128 Section 2 Academia Road, Taipei 115,
Taiwan. Fax: (+886)2ꢀ2789ꢀ8771; Eꢀmail: schung@gate.sinica.edu.tw
O
N
N
Ts
Ts
O
O
O
O
O
O
O
RO
OR
steps
1 mol% Yb(OTf)3
62%
O6
HO
OR
OR
HO
O
RO
4
2
OH
HO
OR
9 inositol
OH
N
O
Ts
phosphates
(R = PO32– or H)
ABSTRACT
A variety of inositol phosphates including myoꢀinositolꢀ1,4,5ꢀtrisphosphate, which is a
secondary messenger in transmembrane signaling, were selectively synthesized via Yb(OTf)3ꢀ
catalyzed desymmetrization of myoꢀinositolꢀ1,3,5ꢀorthoformate using a prolineꢀbased chiral
anhydride as an acylation precursor. The investigated catalytic system could regioselectively
differentiate the enantiotopic hydroxy groups of myoꢀinositolꢀ1,3,5ꢀorthoformate in the presence
of a chiral auxiliary. This key step to generate a suitably protected chiral myoꢀinositol
derivatives is described here as a unified approach to access inositol phosphates.
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INTRODUCTION
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The phosphate esters of myoꢀinositol and its derivatives have multitude of biological
functions through the regulation of diverse signal transduction pathways (Figure 1).1
D
ꢀmyoꢀ
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Inositolꢀ1,4,5ꢀtrisphosphate [Ins(1,4,5)P3 (1)], for instance, is a secondary messenger that affects
many cellular processes by eliciting internal calcium channel signals.2 The secondary
messengers Ins(1,4,5)P3 and diacylglycerol are obtained from agonistic stimulative hydrolysis of
phosphatidylinositol phospholipaseꢀC precursor in the plasma membrane. Ins(1,4,5)P3 regulates
the release of Ca+2 from internal stores by specific interaction with its receptor located in the
endoplasmic reticulum.3 Currently, Ins(1,4,5)P3 and its immediate phosphorylated metabolites
are much needed compounds especially in eukaryotic cell biology due to their applications in
ionꢀchannel physiology, membrane dynamics, and nuclear signaling.1
Owing to their broad range of implicated applications, the chemical synthesis and
biological properties of inositol phosphates and their analogues have been comprehensively
reviewed.1,2,4 However, while the biomedical importance of inositol phosphates are wellꢀ
documented, their mechanisms of action in various physiological events have not yet been fully
elucidated. As an example in this context, ꢀmyoꢀinositolꢀ1,3,4,5,6ꢀpentakisphosphate
D
[Ins(1,3,4,5,6)P5 (6)] specifically inhibit phosphoinositide 3ꢀkinase protein activity by selectively
binding to the pleckstrin homology domain, which inherently induces apoptosis and suppresses
tumorigenicity in the human cancer cell lines.5 It was further shown that Ins(1,3,4,5,6)P5
restrains serine phosphorylation on protein kinase B in vivo similar to the effect of cisplatin and
etoposide, proving its importance in cancer therapy. However, the general concern in the use of
inositol polyphosphates is associated with their cellular uptake due to the presence of multiple
negatively charged phosphate groups. In order to illustrate the dogma of inositol polyphosphate
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internalization to get access to cytosol, Potter and coꢀworkers7 synthesized a fluorescent
Ins(1,3,4,5,6)P5 conjugate and demonstrated the visualization of its uptake by various malignant
cell types and further postulated the underlying mechanism of nonꢀreceptor mediated
endocytosis.
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Figure 1. Some important representative examples of naturally occurring and synthetic inositol
polyphosphates. The compounds enclosed in squares are synthesized in the current study along
with other inositol phosphates.
Due to their ubiquitous presence in a wide variety of flora and fauna,7 researchers both
from academia and industry try to unravel the biological roles of inositol phosphates.
Nevertheless, lack of enantiomerically pure forms of inositol phosphates hampers further in vivo
biochemical investigations due to their difficult isolation from natural sources. Because of this,
the demand for the development of rapid and efficient scalable synthetic strategies for the
preparation of optically active pure myoꢀinositol phosphate derivatives is high. Hence, much
interest has centered upon new synthetic avenues of access, posing challenging tasks to chemists.
D
-myoꢀInositolꢀ1,3,5ꢀorthoformate (10) was first studied by Kishi et al.8 in the
preparation of scylloꢀinositol. From its inception, ꢀmyoꢀinositolꢀ1,3,5ꢀorthoesters have been
D
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extensively explored for its utility as rudimentary synthons for the synthesis of phosphoinositols
and their analogues. These orthoesters have rigid, conformationally locked adamantaneꢀlike
structures, enabling the possible regioselective differentiation of the equivalent 1,3ꢀdiaxial
hydroxy groups from the equatorial 2ꢀhydroxyl.9 There are constant efforts to expand and
exploit the desymmetrization or resolution of myoꢀinositol orthoesters to uncover the latent
precursor for inositol phosphates and its congeners of biological relevance.9a,10 In pursuit of siteꢀ
selective functionalization of meso compounds, desymmetrization processes are underscored for
the synthesis of stereochemically complex molecules.11 For example, phosphorylated histidyl
peptides were synthesized as a mimic of phosphohistidine intermediate in proteins12 and utilized
in the desymmetrization of enantiotopic 1,3ꢀpositions of myoꢀinositol derivatives via catalytic
asymmetric phosphorylation.13 Using a peptide catalyst containing nonproteinogenic amino acid,
this methodology was further exploited in the stereoꢀdifferentiation of the more challenging and
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chemically equivalent enantiotopic 4ꢀ and 6ꢀpositions for the enantioselective synthesis of Dꢀ
myoꢀinositolꢀ6ꢀphosphate through kinetic resolution of racemic monophosphate.14 Moreover,
serendipitous regioselective conversion of myoꢀinositolꢀ1,3,5ꢀorthobenzoate to the corresponding
2ꢀOꢀbenzoyl cyclitol under acidꢀcatalyzed hydrolysis of orthobenzoate was reported as a novel
route to the anticancer agent Ins(1,3,4,5,6)P5 (6).15 Very recently, a C2ꢀsymmetrical chiral
phosphoramidite reagent was developed for chiral resolution via phosphitylation to synthesize
chiral inositol bisphosphates.16 However, the aforementioned synthetic routes have limitations
such as multiple orthogonal protection and deprotection manipulations, phosphate functionality
migration within the inositol frame work, tedious isolation of densely charged inositol
phosphates and require multiple intermediates.
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Our previous endeavors to extend the synthetic toolbox toward inositol derivatives
included the desymmetrization of orthoformate 10 with mannosyl donor for the preparation of
biologically relevant phosphatidylinositol mannosides.17 Furthermore, we reported the metal
triflate [M(OTf)3]ꢀcatalyzed desymmetrization of 10 using (+)ꢀcamphanic anhydride (Figure 2).18
We now report the extension of this desymmetrization methodology using various chiral
acylating agents and its application in the synthesis of various inositol phosphates.
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RESULTS AND DISCUSSION
Initially, we sought to use the conformational rigidity of orthoformate 10 as a structural
platform to regioselectively introduce an acyl group at either of the chemically equivalent and
axially oriented Cꢀ4 or Cꢀ6 hydroxy group while leaving the equatorial 2ꢀOH untouched. This
manner of regioselective acylation should offer a short, direct, and unified synthetic route toward
several chiral ꢀmyoꢀinositol phosphates of interest. With M(OTf)3 as catalyst, the asymmetric
D
acylation of 10 could possibly occur according to the cycle depicted in Figure 2. Here, M(OTf)3
coordinates preferably with the axial hydroxy groups of 10 and simultaneously activates the acid
anhydride to assemble the intermediate complex. Such coordination enables the acid anhydride
to be properly positioned for nucleophilic attack at either 4ꢀO (path I) or 6ꢀO (path II) of 10 to
furnish the 2,6ꢀdiol 11 and the 2,4ꢀdiol 12, respectively. The capability of using chiral acid
anhydrides in the presence of M(OTf)3 to provide a level of selectivity between the 4ꢀ and 6ꢀ
hydroxyls was realized in our preliminary data.18 Rareꢀearth metal triflates are considered as
new class of Lewis acids, which occupied much space in the field of enantioselective catalysis
with respect to their exquisite features such as water compatibility, environmentally benign
nature, and recyclability.19 Of these late transition metal triflates, Yb(OTf)3 is wellꢀstudied in
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organic synthesis and carbohydrate chemistry due to its higher catalytic activity attributed to its
small ionic radius.19,20
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O6
R*
O
R*
HO
O
O
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2
HO
OH
10
O
O
O
O
O
HO
n
HO
HO
M3+
M(OTf)3
+
O
O
3
II
OTf
O
O
I
R*
O
R*
intermediate
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O
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O
O
+
+
HO
HO
HO
R*
HO
R*
O
O
R*
OH
O
O
11 (path I)
12 (path II)
Figure 2. Proposed catalytic cycle for the M(OTf)3ꢀcatalyzed asymmetric acylation of myoꢀ
inositolꢀ1,3,5ꢀorthoformate.
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Table 1. Late Transition Metal TrifluoromethanesulfonateꢀCatalyzed Asymmetric Acylation of
myoꢀInositolꢀ1,3,5ꢀOrthoformate
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9
O
O
O
O
[R*C(O)]2O,
O
O
O
O
1 mol% M(OTf)3
O6
+
HO
HO
HO
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HO
R*
O
4
1,4-dioxane, 40 °C
[R*C(O)]2O
HO
O
R*
OH
OH
O
10
O
11
14
12
OAc
O
13:
15
Ph
O
2
16:
19:
R' = Cbz
R' = Ts
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20
18
21
O
N
O
R'
2
OBz
O
BzO
O
22
23
24
O
entry
1
M(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
La(OTf)3
Pr(OTf)3
Nd(OTf)3
anhydride
t (h) product (yield)a
14 (49%) + 15 (35%)
24
72
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48
13
16
19
22
19
19
19
19
19
19
19
2
17 (30%) + 18 (50%)
20 (24%) + 21 (62%)
23 (0%) + 24 (0%)
3
4
b
5
20 (17%) + 21 (35%)
20 (22%) + 21 (59%)
20 (23%) + 21 (60%)
20 (21%) + 21 (51%)
20 (24%) + 21 (54%)
20 (23%) + 21 (54%)
20 (27%) + 21 (54%)
6
7
8
9
Sm(OTf)3
Eu(OTf)3
Gd(OTf)3
10
11
a Isolated yields. b 5 mol% was used.
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We prepared various chiral anhydrides from their corresponding acid precursors21 and
utilized those in the resolution of 10 in the presence of catalytic Yb(OTf)3 (Table 1). The acid
precursors used herein are relatively cheaper and more readily accessible than (1S)ꢀ(–)ꢀ
camphanic acid that we used previously.18 The insight as well as inputs from our previous work
prompted us to choose 1,4ꢀdioxane as solvent at moderate temperatures. Treatment of 10 with
acid anhydride 13 in the presence of 1.0 mol% Yb(OTf)3 generated the chiral esters 14 and 15 in
49% and 35% yields, respectively (entry 1). Isomer 14 was isolated as a crystalline solid and its
structure was confirmed by Xꢀray analysis as a 4ꢀOꢀsubstituted ester (CCDC 934229, see
Supporting Information). To further expand the scope of this desymmetrization methodology,
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two Nꢀsubstituted
were studied in this chelationꢀassisted regioselective acylation of orthoformate 10. When Nꢀ
Cbzꢀ ꢀproline anhydride (16) was used as desymmetrization agent, the formation of 17 (30%)
and 18 (50%) was observed, showing a reversal of regioselectivity in comparison to that of the
acid anhydride 13 (entry 2). Similarly, when Nꢀtosylꢀ ꢀproline anhydride (19, entry 3) was
Lꢀproline anhydrides were prepared as chiral auxiliaries, and their efficacy
L
L
employed, the desymmetrization process yielded the 6ꢀOꢀacylated derivative 21 as major product.
The best regioselectivity in terms of product ratio and reaction yield was observed in this case.
The acylated derivatives 17 and 18 existed as rotamers and showed complex NMR spectra. To
determine their structures, we relied on chemical correlation methods (Scheme 1). Compound
17 was treated with benzyl Nꢀphenylꢀ2,2,2ꢀtrifluoroacetimidate in the presence of
trifluoromethanesulfonic acid (TfOH) followed by basic hydrolysis to form the dibenzyl
derivative 27, whose spectral and analytical data are in good agreement with the literature.22 The
alternative Williamson etherification to properly install the dibenzyl groups did not proceed as
planned due to concomitant hydrolysis of the ester linkage. The structures of 18, 20, and 21
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were established in the same manner. The rigid backbone of the cyclic anhydride 22 derived
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6
from ꢀtartaric acid probably prevented proper chelation during the M(OTf)3 catalytic cycle, and
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thus, 22 failed to provide any products with 1.0 mol% Yb(OTf)3 (entry 4). Increasing the
catalyst loading to 5.0 mol% provided the desired 4ꢀO and 6ꢀO esters albeit in low yields
because of orthoformate hydrolysis (entry 5). Subsequently, other late transition metal triflates,
such as La(OTf)3, Pr(OTf)3, Nd(OTf)3, Sm(OTf)3, Eu(OTf)3, and Gd(OTf)3 were screened in the
presence of anhydride 19 (entries 6–11). In all these cases, the regioselective acylation results
are comparable to Yb(OTf)3, with ester 21 being the major product.
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Scheme 1. Structure Confirmation by Chemical Correlation
O
O
O
O
O6
O6
HO
HO
4
4
O
HO
OH
O
NR
NR
O
O
17: R = Cbz
18: R = Cbz
21: R = Ts
20: R = Ts
Ph
Ph
N
N
BnO
CF3, TfOH
BnO
CF3, TfOH
O
O
O
O
O
O
BnO
BnO
BnO
O
O
OBn
NR
NR
O
O
25: R = Cbz, 64%
26: R = Ts, 59%
28: R = Cbz, 41%
29: R = Ts, 68%
LiOH, THF, H2O
LiOH, THF, H2O
O
O
O
O
O
O
BnO
BnO
BnO
OH
HO
OBn
27
92% (from 26)
30
90% (from 29)
With the asymmetric inositol derivative 21 in hand, we continued further to install the
phosphate functionality selectively to afford various inositol phosphates. The inositol phosphate
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structures prepared herein were specifically chosen to demonstrate the utility of our
desymmetrization approach and the opportunity it presents in providing ready access to such
compounds. To start with, orthoformate 21 was transformed to compound 30 as outlined in
Scheme 1. Phosphitylation using dibenzylꢀN,Nꢀdiisopropyl phosphoramidite/1Hꢀtetrazole and
subsequent mꢀCPBA23 oxidation of the resulting phosphite delivered the fully protected
dibenzylphosphate 31 (Scheme 2). Further hydrogenolysis removed all the benzyl groups and
acidic hydrolysis cleaved the orthoformate protection to give a compound that was passed
through a Na+ ion exchange resin to afford Ins(6)P (32). The presence of phosphate in 32, as
with all other inositol phosphates prepared in this paper, was verified by 31P NMR (see
Supporting Information).
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The synthesis of Ins(2,4)P2 (34) was carried out by reacting the same key diol 21 with the
phosphorylation reagent followed by oxidation, leading to the formation compound 33 in
excellent yield (Scheme 3). Hydrogenolysis, acid hydrolysis of the orthoformate, and NaOHꢀ
mediated Nꢀtosylꢀ ꢀproline ester cleavage in water provided the target bisphosphate 34.
L
Scheme 2. Synthesis of Ins(6)P (32)
O
O
(BnO)2PN(i-Pr)2,
O
O
O
O
1H-tetrazole, then, m-CPBA
BnO
BnO
O
O
98%
OBn
OBn
HO
OBn
30
P
BnO
31
O– Na+
O– Na+
O
O
1. H2, Pd/C
HO
OH
P
2. HCl, H2O, MeOH
3. DOWEX 50WX8 (Na+ form)
96% overall
HO
OH
OH
32
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Scheme 3. Synthesis of Ins(2,4)P2 (34)
5
6
7
8
BnO
O
O
O
O
(BnO)2PN(i-Pr)2,
O
O
O
P
1H-tetrazole, then, m-CPBA BnO
O
HO
OBn
O
O
98%
O
OH
P
9
OBn
NTs
33
NTs
21
O
O
O
10
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Na+ –
Na+ –
O
O
O
P
O
OH
1. H2, Pd/C
OH
OH
HO
Na+ –
Na+ –
34
2. HCl, H2O, MeOH
3. NaOH, H2O
94% overall
O
O
P
O
O
Scheme 4. Synthesis of Ins(1,4,5)P3 (1) and Ins(3,4,5)P3 (43)
MeO OMe
O
O
Ts
N
Ts
N
Ts
N
Ts
N
O
O
O
O
O
HO
OH
O
O
O
HO
(5 equiv)
HCl
OH
O
O
O
OH
O
O
O
O
OH
O
O
+
+
HO
OH
O
O
HO
H2O, MeOH
95%
Condition 1:
0.2 equiv p-TSA,
DMF, 25 °C, 12 h
Condition 2:
OH
O
O
O
NTs
21
O
35
36
37
38
1 equiv p-TSA,
DMF, 25 °C, 6 h
OBn
O
Ts
O– Na+
O
BnO
O
Ts
N
O
P
Na+ –
HO
O
O
O
OH
2
N
P
O
O
O
O
O
O
OH
OH
O
O
3
O
HO
OH
O– Na+
O
BnO
P
O
O
39
(BnO)2PN(i-Pr)2,
1H-tetrazole,
P
BnO
Na+ –
Na+ –
O
OBn
P
O– Na+
O
(Condition 1: 18%
Condition 2: 72%)
O
P
BnO
41 (98%)
then, m-CPBA
O
1. H2, Pd/C
2. NaOH, H2O
toluene
1 (98%)
+
Ts
HO
OH
O
Ts
O
O
Na+ –
O
N
OH
O
O
O
N
O
1
O
Na+ –
O
O– Na+
O– Na+
2
P
O
O
BnO
O
O
HO
OH
P
O
O
P
O
O
OH
BnO
O
P
O
BnO
O
P
O– Na+
O
Na+ –
O
40
BnO
OBn
P
(Condition 1: 43%
Condition 2: 7%)
43 (98%)
BnO
42 (98%)
We next turned our attention toward the synthesis of the trisphosphates. Acid hydrolysis
of the orthoformate in 21 supplied the pentaol 35 with the chiral auxiliary at 6ꢀO position
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(Scheme 4). Compound 35 needed to be regioselectively protected at 2ꢀO and 3ꢀO positions to
acquire the triol that could be further transformed into the trisphosphate 1. Treatment of myoꢀ
inositol with excess 1,1ꢀdimethoxycyclohexane is known to produce a mixture of ketal
derivatives, and selective cleavage of the more strained transꢀketal in the presence of its cis
counterpart is wellꢀdocumented.24 From the inherent asymmetric nature of 35, we speculated
that ketal formation using 1,1ꢀdimethoxycyclohexane in the presence of pꢀtoluenesulfonic acid
(pꢀTSA) followed by selective cleavage of the transꢀketal could provide the 2,3ꢀ and 1,2ꢀ
cyclohexylidene derivatives 39 and 40, respectively, with some degree of regioselectivity. Our
ketalization of pentaol 35 provided a mixture of monoꢀ and diꢀcyclohexylidene derivatives (36-
40) upon NMR inspection. Further exposure to pꢀTSA with added toluene in an open flask also
promoted the cleavage of the transꢀketals and produced the monoꢀcyclohexylidene derivatives
39 and 40. The yields and ratio of 39 and 40 varied depending on the amount of pꢀTSA, with 1
equiv. of pꢀTSA providing 39 as major product (72%) and 0.2 equiv. of pꢀTSA providing 40 as
major product (43%). The structures of 39 and 40 were confirmed by extensive NMR
experiments (see Supporting Information), where the free hydroxyls clearly showed correlation
with the respective carbonꢀbound protons. As anticipated, phosphorylation of 39 with dibenzylꢀ
N,Nꢀdiisopropyl phosphoramidite in CH2Cl2 followed by oxidation with m-CPBA gave
compound 41 in excellent yield. The trisphosphate 41 was then subjected to successive
hydrogenolysis in the presence of Pd/C and saponification with NaOH. It is worth mentioning
that the cyclohexylidene ketal in 41 was also removed during hydrogenolysis, most likely due to
the formation of phosphoric acid, which could promote the cleavage. Being more soluble in
10
11
12
13
14
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17
18
19
20
21
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23
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29
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
methanol, the hydrolyzed Nꢀtosylated ꢀproline was easily separated by methanol elution through
L
a cellulose column. Subsequent elution with deionized water gave Ins(1,4,5)P3 (1). Following
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similar synthetic transformations as 39, the regioisomer 40 was converted to another
trisphosphate, Ins(3,4,5)P3 (43).
7
8
9
Next, we focused on the selective functionalization of 2ꢀOH in the chiral derivative 21 to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
synthesize other optically active Dꢀmyoꢀinositol polyphosphates. In this direction, the diol 21
was subjected to benzylation using benzylꢀNꢀphenylꢀ2,2,2ꢀtrifluoroacetimidate, which afforded
the corresponding 2ꢀOꢀbenzylated derivative in very low yield (50%). When Ac2O in the
presence of Sc(OTf)3 was used to study the regioselective esterification, a mixture of 2ꢀOꢀ
acylated (65%) and 2,4ꢀdiꢀOꢀacylated (13%) derivatives were produced. The traditional
benzoylation with BzCl in pyridine mainly provided the desired 2ꢀOꢀbenzoyl derivative 44 in
58% yield. Alternatively, when 1ꢀNꢀ(benzoyloxy)ꢀbenzotriazole (BzOBt)25 was employed as
benzoylation reagent in the presence of Et3N, the ester 44 was obtained exclusively in an
excellent yield (Scheme 5). With 44 in hand, the orthoformate protection was removed under
acid hydrolysis to give tetraol 45 in 96% yield. The hydroxy groups in 45 were then
phosphorylated to provide the protected tetrakisphosphate 46, which was readily converted as
described to Ins(1,3,4,5)P4 (2).
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Scheme 5. Synthesis of Ins(1,3,4,5)P4 (2)
5
6
7
8
N
N
N
O
O
O
O
OBz
O
O
Et3N
HCl, H2O, MeOH
96%
HO
BzO
9
O
O
98%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
OH
NTs
21
NTs
44
O
O
OBn
BnO
P
Ts
N
(BnO)2PN(i-Pr)2,
1H-tetrazole,
O
O
Ts
N
BzO
O
O
BzO
OH
BnO
then, m-CPBA
O
O
O
P
O
O
OH
BnO
O
96%
HO
O
P
BnO
BnO
OH
45
OBn
P
O
BnO
46
O– Na+
O
Na+ –
HO
O
P
O
Na+ –
O
1. H2, Pd/C
OH
O
O
Na+ –
O– Na+
O– Na+
P
O
2. NaOH, H2O
98% overall
O
P
O
O
O
P
O– Na+
Na+ –
O
2
Scheme 6. Synthesis of Ins(1,4,5,6)P4 (51) and Ins(3,4,5,6)P4 (52)
OBn
O
O– Na+
BnO
O
P
Na+ –
HO
O
OH
OBn
O
O– Na+
O
OR
OH
OH
P
O
O
P
O
O
P
O
OBn
O
O
O– Na+
O
O
O
O
HO
O
O– Na+
O
NTs
P
39: R =
O
O
P
(BnO)2PN(i-Pr)2,
1H-tetrazole,
BnO
BnO
O
Na+ –
Na+ –
O
OBn
P
H2NNH2•H2O
O– Na+
O
P
BnO
47: R = H, 98%
then, m-CPBA
O
1. H2, Pd/C
49 (98%)
51 (quant.)
2. DOWEX 50WX8
(Na+ form)
O– Na+
O
HO
OH
O
O
P
Na+ –
O
O– Na+
OBn
O
O
O
OR
OH
P
O
O
O
O
O
Na+ –
O– Na+
HO
P
O
BnO
OBn
O
O
P
OH
O
O
P
O
O– Na+
O
BnO
O
P
O
P
O– Na+
O
Na+ –
O
NTs
BnO
40: R =
BnO
O
OBn
P
H2NNH2•H2O
52 (quant.)
BnO
50 (98%)
48: R = H, 98%
To make the tetrakisphosphates Ins(1,4,5,6)P4 (51) and Ins(3,4,5,6)P4 (52), we started
from the monocyclohexylidene derivatives 39 and 40, respectively (Scheme 6). Treatment of 39
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and 40 with hydrazine hydrate in methanol provided the respective tetraols 47 and 48 in
excellent yields. Phosphitylation followed by oxidation of the respective phosphite with mꢀ
CPBA furnished the tetrakisphosphates 49 and 50, which were subjected to hydrogenolysis to
remove all benzyl groups, and subsequently, the ketal protection. Final Na+ ion exchange
delivered the target tetrakisphosphates 51 and 52.
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11
12
13
14
15
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18
19
20
21
22
23
24
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33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Synthesis of Ins(1,3,5,6)P4 (55)
(BnO)2PN(i-Pr)2,
1H-tetrazole,
O
O
BnO
OH
O
then, m-CPBA
HCl
OH
OH
OBn
BnO
HO
H2O, MeOH
96%
98%
HO
OBn
30
53
OBn
O– Na+
BnO
BnO
Na+ –
O
O– Na+
P
P
OBn
O
O
O
O
HO
O– Na+
P
P
O
O
1. H2, Pd/C
OBn
O– Na+
O
BnO
O
O
O
O
P
O
O
O
O
P
2. DOWEX
50WX8
(Na+ form)
O
OBn
BnO
OH
P
P
OBn
O– Na+
Na+ –
O
OBn
O– Na+
54
55
quant.
Scheme 8. Synthesis of Ins(1,2,3,4,5)P5 (57)
OBn
OBn
BnO
P
(BnO)2PN(i-Pr)2,
1H-tetrazole,
O
O
Ts
N
BnO
Ts
N
P
O
O
HO
OH
O
then, m-CPBA
O
BnO
O
O
OH
O
O
P
HO
BnO
OBn
OBn
92%
O
P
O
OH
O
O
OBn
P
35
BnO
56
O– Na+
O– Na+
Na+ –
Na+ –
O
O
O
O
P
P
O
Na+ –
O
O
1. H2, Pd/C
OH
O
O
Na+ –
O– Na+
O– Na+
P
O
2. NaOH, H2O
98% overall
O
P
O
O
O
P
O– Na+
Na+ –
O
57
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To afford another tetrakisphosphate, we converted the dibenzylated 30 into compound 53
by acid hydrolysis (Scheme 7). Phosphitylation of 53 and concomitant oxidation of the
polyphosphite delivered the fully protected 54. Palladiumꢀcatalyzed hydrogenolysis followed by
ion exchange chromatography gave Ins(1,3,5,6)P4 (55).
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40
41
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44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Finally, our effort was extended to the synthesis of Ins(1,2,3,4,5)P5 (57) from the 6ꢀOꢀ
acylated 35, which was phosphorylated to form the corresponding fully protected
pentakisphosphate 56 (Scheme 8). The target compound 57 was obtained after hydrogenolysis
and alkaline hydrolysis of the ester.
CONCLUSIONS
We described an efficient Yb(OTf)3ꢀcatalyzed desymmetrization strategy for the siteꢀ
selective functionalization of
desymmetrization strategy further enabled a short and direct synthetic access to a wide range of
chiral ꢀmyoꢀinositol phosphates. These compounds and their derivatives may find widespread
Dꢀmyoꢀinositolꢀ1,3,5ꢀothoformate using a chiral auxiliary. The
D
applications in field of organic synthesis and chemical biology.
EXPERIMENTAL SECTION
General Information. Unless otherwise stated, materials and all other reagents obtained
from commercial sources were used without further purification. All reactions were conducted
in glassware that was dried in an oven and cooled under argon atmosphere. CH2Cl2 was dried
from a safe purification system filled with anhydrous Al2O3. Water was either distilled or Milliꢀ
Qꢀpurified. Flash column chromatography was carried out on Silica Gel 60 (230–400 mesh, E.
Merck). Cotton linters and cellulose powder for column chromatography were purchased from
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SigmaꢀAldrich. TLC was performed on glass plates preꢀcoated with Silica Gel 60 F254 (0.25 mm,
E. Merck); detection was executed by spraying with a solution of Ce(NH4)2(NO3)6,
(NH4)6Mo7O24, and H2SO4 in water followed subsequent heating on a hot plate. Specific
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
rotations were taken at ambient conditions. H, 13C, and 31P NMR spectra were recorded on 400
and 600 MHz spectrometers. Proton peaks were assigned with the aid of 2D NMR techniques
(1Hꢀ1H COSY, HMQC, and NOESY). The hydrogen multiplicities of carbon peaks were
determined using DEPTꢀ90 and DEPTꢀ135 experiments, the spectra of which were provided in
the Supporting Information together with the powerꢀgatedꢀdecoupled 13C NMR spectrum. The
high resolution mass spectra (HRMS) were obtained using either a FAB–double focusing,
MALDI–TOF, or ESI–quadrupole ion trap mass analyzer.
General procedure for M(OTf)3-catalyzed regioselective acylation of myo-inositol-
1,3,5-orthoformate. A mixture of compound 10 (190 mg, 1.00 mmol), M(OTf)3 (1 mol%), and
chiral anhydride (13, 16, 19, and 22) (1.2 mmol) was dried under vacuum for 1 h. Anhydrous
1,4ꢀdioxane (8 mL) was added to the mixture under N2 atmosphere, and the solution was stirred
at 40 °C. After the triol 10 was consumed, 1,4ꢀdioxane was removed in vacuo, the crude residue
was dissolved in CH2Cl2 (15 mL), and the mixture was sequentially washed with saturated
NaHCO3(aq) and water. The organic layer was dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash column chromatography
(2% MeOH in CHCl3) to afford the diols. With 13 (444 mg, 1.20 mmol) as chiral anhydride,
diols 14 (166 mg, 49%) and 15 (119 mg, 35%) were obtained. With 16 (576 mg, 1.20 mmol) as
chiral anhydride, diols 17 (126 mg, 30%) and 18 (210 mg, 50%) were obtained. With 19 (624
mg, 1.20 mmol) as chiral anhydride, diols 20 (106 mg, 24%) and 21 (273 mg, 62%) were
obtained.
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4-O-[(S)-O-Acetylmandeloyl]-
D-myo-inositol-1,3,5-orthoformate (14). [
α]
D +78.5 (c
5
6
7
1.0, CHCl3); mp 163–165 °C; IR (KBr, thin film):
ν
3466, 2957, 1745, 1375, 1161, 990, 748 cm–
8
9
1; 1H NMR (600 MHz, CDCl3):
δ 7.44–7.39 (m, 5H, ArꢀH), 5.70 (s, 1H), 5.46–5.45 (m, 2H, Hꢀ6,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H; orthoformateꢀH), 4.60 (br s, 1H, Hꢀ6), 4.46–4.44 (m, H, Hꢀ5), 4.19–4.18 (m, 1H, Hꢀ1), 4.10–
4.08 (m, 1H, Hꢀ3), 3.95 (br s, 1H, Hꢀ2), 3.17 (br s, 1H, 2ꢀOH), 2.98 (br s, 1H, 6ꢀOH), 2.19 (s, 1H,
CH3); 13C NMR (150 MHz, CDCl3):
δ 171.4 (C), 167.4 (C), 132.0 (C), 129.9 (CH), 129.1 (CH),
127.5 (CH), 102.9 (CH), 74.9 (CH), 73.6 (CH), 71.4 (CH), 69.5 (CH), 67.3 (CH), 66.9 (CH),
60.7 (CH), 20.6 (CH3); HRMS (ESI): m/z calcd for C17H18O9Na ([M + Na]+) 389.0849, found
389.0848. An Xꢀray analysis of the crystal confirmed the structure of 14 (CCDC 934229).
25
6-O-[(S)-O-Acetylmandeloyl]-
1.0, CHCl3); IR (KBr, thin film):
(600 MHz, CDCl3): 7.43–7.39 (m, 5H, ArꢀH), 5.88 (s, 1H), 5.55 (td, J = 3.9, 1.9 Hz, 1H, Hꢀ6),
D-myo-inositol-1,3,5-orthoformate (15). [
α]
D +44.0 (c
ν
3479, 2965, 1746, 1374, 1161, 1005, 992, 752 cm–1; 1H NMR
δ
5.44 (d, J = 1.3 Hz, 1H, orthoformateꢀH), 4.42 (td, J = 3.9, 1.9 Hz, 1H, Hꢀ5), 4.24–4.21 (m, 2H,
Hꢀ1, Hꢀ3), 4.13–4.11 (m, 1H, Hꢀ4) 3.97 (br s, 1H, Hꢀ2), 2.18 (s, 1H, CH3); 13C NMR (150 MHz,
CDCl3): δ 170.0 (C), 167.0 (C), 132.6 (C), 129.7 (CH), 129.1 (2 × CH), 127.4 (2 × CH), 102.8
(CH), 74.3 (CH), 73.8 (CH), 71.4 (CH), 69.3 (CH), 67.6 (CH), 66.9 (CH), 60.6 (CH), 20.6
(CH3); HRMS (FAB): m/z calcd for C17H19O9 ([M + H]+) 367.1029, found 367.1000.
4-O-(N-Benzyloxycarbonyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (17).
D
25
[
α]
D –8.4 (c 1.0, CHCl3); IR (KBr, thin film):
ν 3430, 2960, 1750, 1688, 1424, 1357, 1161, 994,
755 cm–1; 1H NMR (600 MHz, CDCl3): (two rotamers present)
δ
7.38–7.29 (m, 5H, ArꢀH), 5.53,
5.32 (2 × br s, 1H, Hꢀ4), 5.48, 5.41 (2 × s, 1H, orthoformateꢀH), 5.21 (d, J = 12.4 Hz, 0.2 H),
5.13, 5.07 (ABq, J = 12.4 Hz, 1.7 H), 4.95 (d, J = 12.4 Hz, 0.2 H), 4.61 (br s, 0.8H), 4.45 (br s,
0.8H), 4.25–4.19 (m, 3.7H), 4.05–3.89 (m, 0.6 H), 3.59–3.55. (m, 1H), 3.50–3.46 (m, 1H), 2.24–
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2.18 (m, 1H), 2.07–1.98 (m, 2H), 1.92–1.87 (m, 1H); 13C NMR (150 MHz, CDCl3): (two
3
4
5
6
7
rotamers present) δ 171.5, 171.0 (C), 155.1, 154.1 (C), 136.1 (C) 128.7 (CH),128.6 (CH), 128.5
8
9
(CH), 128.2 (CH), 127.9 (CH), 103.1, 102.9 (CH), 73.9, 73.7 (CH), 72.0, 71.6 (CH), 69.1, 68.7
(CH), 67.6.61, 67.60 (CH2), 67.4, 67.0, 66.8 (CH), 61.0, 60.6 (CH), 59.3, 58.7 (CH), 47.0, 46.8
(CH2), 30.7, 29.6 (CH2), 24.7, 23.4 (CH2); HRMS (ESI): m/z calcd for C20H23NO9Na ([M +
Na]+) 444.1271, found 444.1278.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-O-(N-Benzyloxycarbonyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (18).
D
25
[
α]
D –28.0 (c 1.0, CHCl3); IR (KBr, thin film):
ν 3419, 2925, 1751, 1682, 1424, 1355, 1161,
993, 755 cm–1; 1H NMR (600 MHz, CDCl3): (two rotamers present)
δ
7.35–7.30 (m, 5H, ArꢀH),
5.54, 5.33 (2 × br, 1H, Hꢀ6), 5.46, 5.42 (2 × s, 1H, orthoformateꢀH), 5.18 (d, J = 12.3 Hz, 0.3 H),
5.12, 5.10 (ABq, J = 12.3 Hz, 2 H), 4.98 (d, J = 12.3 Hz, 0.3 H), 4.48 (br s, 0.6H), 4.40–4.38 (m,
1H), 4.35 (br s, 0.6 H), 4.31 (dd, J = 8.3, 3.2 Hz, 0.3 H), 4.18 (dd, J = 15.5, 1.3 Hz, 1.3 H), 4.09
(br, 0.3 H), 3.98 ( br s, 1H), 3.92 (d, J = 12 Hz, 0.6 H), 3.56–3.47 (m, 2H), 2.22–2.12 (m, 2H),
1.93–1.84 (m, 2H); 13C NMR (150 MHz, CDCl3): (two rotamers present)
δ 171.0, 170.5 (C),
155.6, 154.3(C), 136.2 (C) 128.5 (CH),128.4 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 103.0
(CH), 74.2, 74.1 (CH), 71.6 (CH), 69.0, 68.7 (CH), 67.9 (CH), 67.5, 67.3 (CH2), 66.9 (CH), 60.7
(CH), 59.4, 58.9 (CH), 46.9, 46.6 (CH2), 30.6, 29.3 (CH2), 24.4, 23.5 (CH2); HRMS (ESI): m/z
calcd for C20H23NO9Na ([M + Na]+) 444.1271, found 444.1263.
4-O-(N-Tosyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (20). White foam;
D
22
[
α]
D –75.4 (c 1.0, CHCl3); IR (KBr, thin film):
ν 3494, 2962, 1747, 1339, 1161, 1095, 952, 755
cm–1; 1H NMR (400 MHz, CDCl3):
δ
7.68 (d, J = 8.2 Hz, 2H, ArꢀH), 7.31 (d, J = 8.2 Hz, 2H, Arꢀ
H), 5.55 (td, J = 3.6, 2 Hz, 1H, Hꢀ4), 5.49 (s, 1H, orthoformateꢀH), 4.59 (br, 1H, Hꢀ6), 4.46–4.45
(m, 1H, Hꢀ5), 4.24–4.22 (m, 3H, Hꢀ1, Hꢀ2, Hꢀ3), 4.12–4.08 (m, 1H, prolineꢀH) 3.52, 3.47 (m,
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1H), 3.38–3.33 (m, 2H, 2ꢀOH, 6ꢀOH), 3.17–3.11 (m, 1H), 2.42 (s, 3H), 2.04–1.90 (m, 3H), 1.71–
5
6
7
1.65 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ 170.7 (C), 144.3 (C), 133.9 (C), 129.9 (CH),
8
9
127.4 (CH), 103.0 (orthoformateꢀCH), 73.9 (CH), 71.7 (CH), 69.3 (CH), 67.8 (CH), 67.1 (CH),
60.7 (CH), 60.4 (CH), 48.6 (CH2), 30.6 (CH2), 24.8 (CH2), 21.5 (CH3); HRMS (ESI): m/z calcd
for C19H23NO9SNa ([M + Na]+) 464.0991; found 464.0997.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
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48
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54
55
56
57
58
59
60
6-O-(N-Tosyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (21). White foam;
D
22
[
α]
D –71.1 (c 1.0, CHCl3); IR (KBr, thin film):
ν
3480, 2961, 1755, 1339, 1161, 955, 755 cm–1;
1H NMR (400 MHz, CDCl3):
δ
7.66 (d, J = 8.2 Hz, 2H, ArꢀH), 7.30 (d, J = 8.2 Hz, 2H, ArꢀH),
5.58 (td, J = 3.6, 1.6 Hz, 1H; Hꢀ6), 5.48 (s, 1H; orthoformateꢀH), 4.58 (br s, 1H; Hꢀ4), 4.41–4.39
(m, 1H; Hꢀ5), 4.24–4.21 (m, 2H; Hꢀ1, Hꢀ3), 4.15–4.12 (m, 2H; Hꢀ2, prolineꢀH), 3.51–3.46 (m,
1H), 3.14–3.08 (m, 1H), 2.40 (s, 3H), 2.09–2.00 (m, 1H), 1.94–1.83 (m, 2H), 1.71–1.64 (m, 1H);
13C NMR (100 MHz, CDCl3):
δ 170.3 (C), 144.2 (C), 133.8 (C), 129.9 (CH), 127.4 (CH), 102.9
(orthoformateꢀCH), 74.0 (CH), 71.6 (CH), 69.1 (CH), 68.0 (CH), 67.1 (CH), 60.7 (CH), 48.6
(CH2), 30.3 (CH2), 24.6 (CH2), 21.5 (CH3); HRMS (ESI): m/z calcd for C19H23NO9SNa ([M +
Na]+) 464.0991, found 464.0986.
General procedure for dibenzylation. A solution of the myoꢀinositol orthoformateꢀ
derived ester (1 equiv.) and Nꢀphenylꢀ2,2,2ꢀtrifluoroacetimidate (4 equiv.) in 1,4ꢀdioxane (20 mL
per total gram of the benzyl donor and acceptor) in the presence of flame dried 3 Å molecular
sieves was stirred for 30 min at room temperature. TfOH (0.4 equiv.) was then added and the
resulting solution was stirred at room temperature for further 1 h. The reaction was quenched
with Et3N and filtered through Celite. The filtrate was concentrated in vacuo, and the crude mass
was purified by flash column chromatography (hexane/EtOAc = 3/1) to afford the dibenzylated
compounds.
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2,6-Di-O-benzyl-4-O-(N-benzyloxycarbonyl- -prolinoyl)-D-myo-inositol-1,3,5-
L
5
6
orthoformate (25). Compound 17 (86 mg, 0.20 mmol) was transformed into compound 25 (78
7
8
9
25
mg, 64%) as a gum, following the general procedure for dibenzylation. [
CHCl3); IR (KBr, thin film):
α]
D –10.2 (c 1.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ν
2925, 1751, 1750, 1416, 1355, 1164, 949, 744 cm–1; 1H NMR
(600 MHz, CDCl3): (two rotamers present) δ 7.39–7.25 (m, 13H, ArꢀH), 7.18–7.16 (m, 1H),
7.02ꢀ7.01 (m, 1H), 5.53 (d, J = 1 Hz, 0.5H, orthoformateꢀH), 5.50 (d, J = 1.1 Hz, 0.5H,
orthoformateꢀH), 5.45(td, J = 3.8, 1.2 Hz, 0.5H, Hꢀ4), 5.23 (d, J = 12.2 Hz, 0.5H), 5.17(td, J =
3.8, 1.5 Hz, 0.5H), 5.10, 5.06 (ABq, J = 12.4 Hz, 1H), 4.88 (d, J = 12.2 Hz, 0.5H), 4.67 (d, J =
12.5 Hz, 1H), 4.60 (d, J = 12.6 Hz, 0.5H), 4.57 (d, J = 11.8 Hz, 0.5H), 4.53–4.51 (m, 1H), 4.41
(d, J = 11.8 Hz, 0.5H), 4.30ꢀ4.25 (m, 2.5H), 4.23ꢀ4.17 (m, 1.5H), 4.16 (dd, J = 8.8, 4.5 Hz, 0.5H),
4.05 (dd, J = 8.5, 4.7 Hz, 0.5 H), 3.82–3.81 (m, 0.5H), 3.75–3.74 (m, 0.5H), 3.68–3.67 (m, 0.5H),
3.40–2.21 (m, 1.5H), 3.22–3.21 (m, 0.5H), 1.89–1.85 (m, 1H), 1.65–1.38 (m, 3H); 13C NMR
(150 MHz, CDCl3): (two rotamers present) δ 171.2, 171.1 (C), 154.7, 153.9 (C), 137.6, 137.5 (C)
137.2, 136.9 (C), 136.5, 136.4 (C), 128.6 (CH), 128.53 (CH), 128.5 (CH), 128.4 (CH), 128.3
(CH), 128.2 (CH), 128.14 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH), 127.8 (CH), 127.7 (CH),
127.6 (CH), 103.1, 103.0 (CH), 73.5, 73.2 (CH), 71.8, 71.6 (CH2), 71.0 (CH2) 70.0, 69.9 (CH),
69.2, 68.9 (CH), 68.7, 68.5 (CH), 67.2, 67.1(CH), 67.01, 67.0 (CH2), 66.4, 65.8 (CH), 59.1, 58.8
(CH), 46.8, 46.3 (CH2), 30.2, 29.4 (CH2), 24.2, 23.3 (CH2); HRMS (ESI): m/z calcd for
C34H35NO9Na ([M + Na]+) 624.2210, found 624.2202.
2,6-Di-O-benzyl-4-O-(N-tosyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (26).
D
Compound 20 (100 mg, 0.23 mmol) was transformed into compound 26 (84 mg, 59%) as a gum,
27
following the general procedure for dibenzylation. [
film):
α]
D –39.3 (c 1.0, CHCl3); IR (KBr, thin
7.64 (d, J
ν
1745, 1454, 1346, 1164, 1096, 949, 751 cm–1; 1H NMR (400 MHz, CDCl3):
δ
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= 8.2 Hz, 2H, ArꢀH), 7.46–7.44 (m, 2H, ArꢀH), 7.38–7.26 (m, 9H, ArꢀH), 7.17–7.15 (m, 2H, Arꢀ
H), 5.54 (d, J = 1.2 Hz,1H, orthoformateꢀH), 5.40 (td, J = 3.8, 1.5 Hz, 1H, Hꢀ4),4.76, 4.70 (ABq,
J = 12.5 Hz, 2H), 4.49, 4.40 (ABq, J = 11.6 Hz, 2H), 4.48–4.46 (m, 1H, Hꢀ5), 4.28 (td, J = 3.8,
1.5 Hz, 1H, Hꢀ6), 4.26–4.21 (m, 2H, Hꢀ1, Hꢀ3), 3.99 (dd, J = 8.7, 4.5 Hz, 1H, prolineꢀH), 3.94ꢀ
3.92 (m, 1H, Hꢀ2), 3.13–3.03 (m, 2H), 2.40 (s, 3H), 1.74–1.65 (m, 1H), 1.60–1.42 (m, 2H), 1.37–
10
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15
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17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.29 (m, 1H); 13C NMR (100 MHz, CDCl3):
δ 170.7 (C), 143.7 (C), 137.8 (C), 137.1 (C), 134.9
(C), 129.6 (CH), 128.4 (CH),128.2 (CH), 128.0 (CH), 127.8 (CH), 127.2 (CH), 103.1
(orthoformateꢀCH), 73.7 (CH), 72.0 (CH2), 71.2 (CH2), 70.2 (CH), 69.1 (CH), 68.8 (CH), 67.4
(CH), 66.3 (CH), 60.5 (CH), 48.2 (CH2), 30.2 (CH2), 24.3 (CH2), 21.4 (CH3); HRMS (ESI): m/z
calcd for C33H35NO9SNa ([M + Na]+) 644.1930, found 644.1932.
2,6-Di-O-benzyl- -myo-inositol-1,3,5-orthoformate (27). Compound 26 (100 mg, 0.16
D
mmol) was dissolved in THF/H2O (1/1) (2 mL). LiOH·H2O (13 mg, 0.32 mmol) was then added
and the resulting solution stirred for 2 h at room temperature. The reaction mixture was diluted
with Et2O and washed with water and brine. The organic layer was dried over MgSO4,
concentrated in vacuo and purified by flash column chromatography to afford 27 (54 mg, 92%)
26
25
as a colorless gum. [
α] α]
D –4.8 (c 1.0, EtOH) [lit.22 [ D –8.0 (c 1,EtOH)]; 1H NMR (400 MHz,
CDCl3): 7.41–7.30 (m, 8 H, ArꢀH), 7.16 (dd, J = 3.6, 6.5, 2H, ArꢀH), 5.49 (d, J = 1 Hz, 1H,
δ
orthoformateꢀH), 4.74, 4.64 (ABq, J = 12.4 Hz, 2H, BnꢀH), 4.52, 4.47 (ABq, J = 11.6 Hz, 2H,
BnꢀH), 4.46–4.41 (m, 1H), 4.37–4.32 (m, 2H), 4.26–4.23 (m, 2H), 3.87–3.86 (m, 1H), 3.59 (d,
1H, J = 10.3 Hz, OH); 13C NMR (100 MHz, CDCl3):
δ 137.5 (C), 135.9 (C), 128.8 (CH), 128.7
(CH), 128.5 (CH), 128.0 (CH), 102.6 (CH), 74.5 (CH), 72.9 (CH2), 72.1 (CH), 71.3 (CH2), 69.9
(CH), 68.0 (CH), 67.6 (CH), 66.1 (CH); HRMS (ESI): m/z calcd for C21H22O6Na ([M + Na]+)
393.1314, found 393.1320.
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2,4-Di-O-benzyl-6-O-(N-benzyloxycarbonyl-
L
-prolinoyl)- -myo-inositol-1,3,5-
D
5
6
orthoformate (28). Compound 18 (120 mg, 0.28 mmol) was converted to compound 28 (70 mg,
7
8
9
25
41%) as a gum, following the general procedure for dibenzylation. [
IR (KBr, thin film):
CDCl3): (two rotamers present)
α]
D –28.2 (c 1.0, CHCl3);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ν
2958, 1754, 1705, 1416, 1354, 1163, 949, 749 cm–1; 1H NMR (600 MHz,
7.42–7.11 (m, 15H, ArꢀH), 5.53, 5.50 (2 x s, 1H, orthoformateꢀ
δ
H) 5.45, 5.21, (2 x br, 1H, Hꢀ6), 5.17 (d, J = 12.2 Hz, 0.5 H), 5.14, 5.08, (ABq, J = 12.4 Hz, 1
H),4.97 (d, J = 12.2 Hz, 0.5 H), 4.76, 4.67 (ABq, J = 12.4 Hz, 1 H), 4.63, 4.54 (ABq, J = 12.4 Hz,
1 H), 4.45ꢀ4.30 (m, 3.5H), 4.26 (br, 1 H), 4.23 (br, 1H), 4.19 (dd, J = 7.6, 3.3 Hz, 0.5 H), 4.09 .
(dd, J = 4.2, 3.3 Hz, 0.5 H), 4.01 (br, 0.5 H), 3.95 (br, 0.5H), 3.75 (br, 0.5H), 3.42ꢀ3.31 (m, 2H),
1.71ꢀ1.62(m, 5H); 13C NMR (150 MHz, CDCl3): (two rotamers present)
δ 171.43, 171.4 (C),
154.8, 154.0(C), 137.7, 137.5 (C) 137.15, 137.1 (C), 136.6, 136.4 (C), 128.5 (CH), 128.4 (CH),
128.3 (CH), 128.2 (CH), 128.1 (CH), 128.04 (CH), 128.0 (CH), 127.90 (CH), 127.85 (CH),
127.7 (CH), 103.2, 103.1 (CH), 73.8, 73.6 (CH), 72.1, 71.9 (CH2), 71.3, 71.0 (CH2) 70.2, 69.8
(CH), 69.1 (CH), 68.9, 68.7 (CH), 67.4, 67.2 (CH), 67.15, 67.1 (CH2), 66.5, 66.2 (CH), 59.0–
58.6 (CH), 46.8, 46.3 (CH2), 30.0, 29.0 (CH2), 24.4, 23.4 (CH2); HRMS (ESI): m/z calcd for
C34H35NO9Na ([M+Na]+) 624.2210, found 624.2219.
2,4-Di-O-benzyl-6-O-(N-tosyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate (29).
D
Compound 21 (200 mg, 0.45 mmol) was transformed to compound 29 (191 mg, 68%) as a gum,
23
following the general procedure for dibenzylation. [
film):
α]
D –39.9 (c 1.0, CHCl3); IR (KBr, thin
7.65 (d, J
ν
1756, 1454, 1347, 1164, 1096, 949, 751 cm–1; 1H NMR (400 MHz, CDCl3):
δ
= 8.2 Hz, 2H, ArꢀH), 7.42–7.40 (m, 2H, ArꢀH), 7.35–7.23 (m, 9H, ArꢀH), 7.17–7.15 (m, 2H, Arꢀ
H), 5.54 (d, J = 1 Hz,1H, orthoformateꢀH), 5.41 (app. t, J = 4.2, 3.3 Hz, 1H, Hꢀ6), 4.76, 4.61
(ABq, J = 12.4 Hz, 2H), 4.49, 4.43 (ABq, J = 11.8 Hz, 2H), 4.45–4.40 (m, 2H, Hꢀ5, Hꢀ1), 4.28
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(br, 2H, Hꢀ3, Hꢀ4), 4.03 (dd, J = 8.2, 4.2 Hz, 1H, prolineꢀH), 3.95 (br, 1H, Hꢀ2), 3.25–3.20 (m,
5
6
1H), 3.12–3.06 (m, 1H), 2.40 (s, 3H), 1.70–1.53 (m, 3H), 1.51–1.42 (m, 1H); 13C NMR (100
7
8
9
MHz, CDCl3): δ 170.8 (C), 143.7 (C), 137.7 (C), 137.2 (C), 135.0 (C), 129.6 (CH), 128.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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44
45
46
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48
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60
(CH),128.1 (CH), 128.0 (CH), 127.8 (CH), 127.6 (CH), 127.4 (CH), 103.1 (orthoformateꢀCH),
73.7 (CH), 71.8 (CH2), 71.3 (CH2), 70.2 (CH), 69.1 (CH), 69.0 (CH), 67.2 (CH), 66.4 (CH), 60.1
(CH), 48.2 (CH2), 30.0 (CH2), 24.5 (CH2), 21.5 (CH3); HRMS (ESI): m/z calcd for
C33H35NO9SNa ([M + Na]+) 644.1930, found 644.1932.
2,4-Di-O-benzyl- -myo-inositol-1,3,5-orthoformate (30). Compound 29 (100 mg, 0.16
D
mmol) was dissolved in THF/H2O (1/1) (2 mL). LiOH·H2O (13 mg, 0.32 mmol) was then added
and the resulting solution stirred for 2 h at room temperature. The reaction mixture was diluted
with Et2O and washed with water and brine. The organic layer was dried over MgSO4,
concentrated in vacuo and purified by flash column chromatography to afford 30 (53 mg, 90%)
23
25
as a colorless gum. [
α] α]
D +7.5 (c 1.0, EtOH) [lit.22 [ D +8.8 (c 1.1, EtOH)]; 1H NMR (400
MHz, CDCl3): 7.41–7.30 (m, 8 H, ArꢀH), 7.16 (dd, J = 3.6, 6.3, 2H, ArꢀH), 5.49 (d, J = 1.1 Hz,
δ
1H, orthoformateꢀH), 4.74, 4.63 (ABq, J = 12.3 Hz, 2H, BnꢀH), 4.52, 4.48 (ABq, J = 11.5 Hz,
2H, BnꢀH), 4.46–4.42 (m, 1H), 4.37–4.32 (m, 2H), 4.26–4.23 (m, 2H), 3.87–3.86 (m, 1H), 3.59
(d, 1H, J = 10.3 Hz, OH); 13C NMR (100 MHz, CDCl3):
δ 137.5 (C), 135.9 (C), 128.8 (CH),
128.6 (CH), 128.0 (CH), 102.6 (CH), 74.5 (CH), 72.9 (CH2), 72.1 (CH), 71.4 (CH2), 69.9 (CH),
68.0 (CH), 67.7 (CH), 66.1 (CH); HRMS (ESI): m/z calcd for C21H22O6Na ([M + Na]+)
393.1314, found 393.1322.
General procedure for phosphorylation. A mixture of the alcohol compound (1
equiv.) and 1Hꢀtetrazole (3 equiv. per phosphorylation site) was dissolved in CH2Cl2 (10 mL,
unless otherwise stated) and allowed to stir for 10 min. Dibenzyl N,Nꢀ
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diisopropylphosphoramidite (1.5 equiv. per phosphorylation site) was then added and the
reaction mixture was stirred at room temperature for 1 h. The reaction flask was then cooled to –
40 °C and mꢀCPBA (77% purity, 2.25 equiv. per phosphorylation site) was added in one portion.
The reaction mixture was gradually warmed to room temperature over a period of 2 h. CH2Cl2
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10 mL) was then added to the mixture, the organic layer was washed with saturated NaHCO3(aq)
water, and brine, dried over MgSO4, and concentrated under reduced pressure. The soꢀobtained
crude compound was purified by flash column chromatography (2% MeOH in CHCl3) to afford
the phosphorylated inositol derivative.
,
2,4-Di-O-benzyl- -myo-inositol-1,3,5-orthoformate-6-dibenzylphosphate (31).
D
Compound 30 (150 mg, 0.40 mmol) was transformed into the monophosphate 31 (250 mg, 98%)
28
as a gum, following the general procedure for phosphorylation. [
(KBr, thin film):
NMR (600 MHz, CDCl3):
α]
D +12.5 (c 1.0, CHCl3); IR
ν
3032, 1455, 1280, 1166, 1097, 1000, 950, 891, 737, 698, 603, 510 cm–1; 1H
7.33–7.19 (m, 21H, ArꢀH), 7.16–7.15 (m, 2H, ArꢀH), 5.48 (d, J =
δ
1.3 Hz, 1H, orthoformateꢀH), 5.02–4.99 (m, 1H, Hꢀ6), 4.90–4.85 (m, 4H, CH2), 4.61, 4.55 (ABq,
J = 12.2 Hz, 2H, CH2ꢀAr), 4.53, 4.36 (ABq, J = 11.6 Hz, 2H, CH2ꢀAr), 4.40–4.38 (m, 1H, Hꢀ5),
4.26–4.25 (m, 2H, Hꢀ3, Hꢀ1), 4.24–4.22 (m, 1H, Hꢀ4), 3.90 (br, 1H, Hꢀ2); 13C NMR (150 MHz,
CDCl3): δ 137.5 (C), 137.2 (C), 135.41 (C), 135.36 (C), 128.8 (CH), 128.7 (CH), 128.64 (CH),
128.60 (CH), 128.4 (CH), 128.0 (CH), 127.97 (CH), 127.93 (CH), 127.89 (CH), 127.5 (CH),
102.9 (orthoformateꢀCH), 73.4 (CH), 71.6 (CH2), 71.3 (CH2), 71.0 (CH), 70.9 (CH), 70.3 (CH),
70.0 (CH), 69.9 (CH), 69.7 (CH2), 69.6 (CH2), 67.8 (CH), 67.7 (CH), 66.2 (CH); 31P NMR (121
MHz, CDCl3):
653.1919.
δ
–1.34; HRMS (ESI): m/z calcd for C35H35O9PNa ([M + Na]+) 653.1916, found
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D
-myo-Inositol-6-monophosphate disodium salt (32). To a solution of compound 31
5
6
7
8
(100 mg, 0.16 mmol) in MeOH (5 mL) was added 10% Pd/C (50 mg). The mixture was placed
under vacuum and the atmosphere was replaced first with nitrogen gas and then with hydrogen
gas. The suspension was then allowed to stir under hydrogen atmosphere for 16 h. The
heterogenous mixture was filtered through a pad of Celite, the residue was washed with MeOH,
and the combined filtrate was concentrated under reduced pressure. The resulting crude product
was washed with CHCl3, dissolved in a solution of 1 N HCl(aq)/MeOH, (1/1, 1 mL) and stirred at
ambient temperature overnight. The solvents were evaporated, and the residue was eluted
through Dowex 50WX8 ion exchange resin (Na+ form) using deionized water as the eluent. The
fractions containing the product were combined and lyophilized to afford (32) (46 mg, 96%) a
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white fluffy solid. [
α]
D +0.93 (c 2.1, H2O, pH 9.2) [lit.26 [
α]
D +1.1 (c 5, H2O, pH 9)]; 1H
NMR (600 MHz, D2O):
δ
4.15 (q, J = 9.2 Hz, 1H, Hꢀ6), 4.06 (t, J = 2.8 Hz, 1H, Hꢀ2), 3.69 (t, J =
9.7 Hz, 1H, Hꢀ4), 3.67 (dd, J = 9.7, 2.8 Hz, 1H, Hꢀ1), 3.55 (dd, J = 10.0, 2.6 Hz, 1H, Hꢀ3), 3.44
(t, J = 9.3 Hz, 1H, Hꢀ5); 13C NMR (150 MHz, D2O):
(CH), 72.1 (CH), 71.8 (CH), 70.9 (CH), 70.8 (CH), 70.7 (CH); 31P NMR (121 MHz, D2O):
2.48; HRMS (ESI): m/z calcd for C6H12O9PNa2 ([M – H + 2Na]+) 305.0014, found 305.0015.
δ
77.7 (CH), 77.6 (CH), 73.64 (CH), 73.62
δ
6-O-(N-Tosyl-
L
-prolinoyl)- -myo-inositol-1,3,5-orthoformate-2,4-bis(dibenzyl
D
phosphate) (33). Diol 21 (150 mg, 0.34 mmol) was transformed into the bisphosphate 33 (319
25
mg, 98%) as a gum, following the general procedure for phosphorylation. [
CHCl3); IR (KBr, thin film):
(600 MHz, CDCl3): 7.72–7.70 (m, 2H, ArꢀH), 7.33–7.27 (m, 22H, ArꢀH), 5.50 (d, J = 1.2 Hz,
α
]
D –36.8 (c 1.0,
ν
2960, 1761, 1456, 1348, 1283, 1163, 998, 740 cm–1; 1H NMR
δ
1H, orthoformate H), 5.47–5.46 (app m, 1H, Hꢀ6), 5.08–4.94 (m, 9H, 4 × CH2, Hꢀ2), 4.86–4.84
(m, 1H, Hꢀ4), 4.36–4.34 (m, 2H, Hꢀ3, Hꢀ5), 4.30–4.28 (m, 1H, Hꢀ1), 4.06 (dd, J = 8.5, 4.7 Hz,
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1H, prolineꢀH), 3.44–3.41 (m, 1H), 3.15–3.11 (m, 1H), 1.93–1.88 (m, 1H), 1.82–1.69 (m, 2H),
5
6
7
1.51–1.45 (m, 1H); 13C NMR (150 MHz, CDCl3):
δ 170.8 (C), 143.7 (C), 135.5 (C), 135.4 (C),
8
9
135.2 (C), 135.1 (C), 134.7 (C), 129.8 (C), 128.9 (C), 128.8 (C), 128.7 (C), 128.6 (C), 128.24 (C),
128.20 (C), 128.0 (C), 127.5 (C), 102.8 (orthoformateꢀCH), 70.6 (CH), 70.5 (CH), 70.3 (CH),
70.04 (CH2), 70.0 (CH2), 69.9 (CH2), 69.73 (CH2), 69.70 (CH2), 69.6 (CH2), 69.49 (CH), 69.45
(CH), 68.1 (CH), 66.80 (CH), 66.77 (CH), 66.19 (CH), 66.16 (CH), 48.5 (CH2), 30.3 (CH2), 24.7
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(CH2), 21.5 (CH3); 31P NMR (121 MHz, CDCl3):
C47H49NO15P2SNa ([M + Na]+) 984.2196, found 984.2196.
δ –1.08, –1.13; HRMS (ESI): m/z calcd for
D-myo-Inositol-2,4-bisphosphate tetrasodium salt (34). To a solution of compound 33
(100 mg, 0.10 mmol) in MeOH (5 mL) was added 10% Pd/C (50 mg). The mixture was placed
under vacuum and the atmosphere was replaced first with nitrogen gas and then with hydrogen
gas. The suspension was then allowed to stir under hydrogen atmosphere for 16 h. The
heterogenous mixture was filtered through a pad of Celite, the residue washed with MeOH, and
the combined filtrate was concentrated under reduced pressure. The resulting crude product was
washed with CHCl3, dissolved in a solution of 1 N HCl(aq)/MeOH (1/1, 1 mL) and stirred at
ambient temperature overnight. The solvents were evaporated, and the residue was dissolved in
a cold solution of 1 N NaOH (0.62 mmol) and stirred at ambient temperature for 2 h. The
reaction mixture was concentrated under reduced pressure and purified by cellulose column
chromatography, first eluting with MeOH, then MeOH/water, 1/1, and finally with water. The
fractions containing product were concentrated and lyophilized to afford the bisphosphate 34 (42
27
mg, 94%) as a white fluffy solid. [
α]
D +9.03 (c 0.77, H2O, pH 11.5) [lit.27 for the enantiomer
4.37 (dt, J = 7.2, 2.2 Hz, 1H, Hꢀ
27
[
α]
D –4.3 (c 0.7, H2O, pH 10)]; 1H NMR (600 MHz, D2O):
δ
2), 4.03 (q, J = 9.2 Hz, 1H, Hꢀ4), 3.66 (t, J = 9.7 Hz, 1H, Hꢀ6), 3.46 (dt, J = 9.7, 2.0 Hz, 1H, Hꢀ
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3), 3.34–3.29 (m, 2H, Hꢀ1, Hꢀ5); 13C NMR (150 MHz, D2O):
73.0 (CH), 71.6 (CH), 70.94 (CH); 31P NMR (121 MHz, D2O):
calcd for C6H10O12P2Na3 ([M – 4H + 3Na]–) 404.9341, found 404.9332.
δ 76.7 (CH), 75.2 (CH), 74.7 (CH),
δ
5.49, 5.45; HRMS (ESI): m/z
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6-O-(N-Tosyl-
L
-prolinoyl)- -myo-inositol (35). Compound 21 (450 mg, 1 mmol) was
D
dissolved in 1 N HCl(aq)/MeOH (1/10 v/v, 10 mL) and allowed to reflux for 30 min. After
completion of the reaction monitored by TLC, the mixture was allowed to cool to room
temperature. The solvents were removed in vacuo to obtain a white solid. The crude solid was
filtered, washed with water, then, with acetone, and dried to give 35 (417 mg, 95%) as a fluffy
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white solid. [
α]
D –95.5 (c 1.0, DMF); mp 233–235 °C; IR (KBr, thin film):
ν 3338, 1719, 1344,
1156, 1091, 724 cm–1; 1H NMR (600 MHz, DMSOꢀd6):
δ
7.74 (d, J = 8.1 Hz, 2H, ArꢀH), 7.42 (d,
J = 8.1 Hz, 2H, ArꢀH), 4.94 (t, J = 9.8 Hz, 1H, Hꢀ6), 4.81 (d, J = 3.4 Hz, 1H, OH) 4.76(d, J = 5.5
Hz, 1H, OH), 4.71 (d, J = 4.7 Hz, 1H, OH), 4.54 (d, J = 6.7 Hz, 1H, OH), 4.51 (d, J = 5.7 Hz, 1H,
OH), 4.33 (dd, J = 8.3, 2.7 Hz, 1H, prolineꢀH), 3.75–3.74 (m, 1H, Hꢀ2), 3.44–3.39 (m, 2H, Hꢀ1,
Hꢀ4), 3.34–3.29 (m, 1H), 3.19–3.13 (m, 3H, Hꢀ3, Hꢀ5), 2.40 (s, 3H), 2.05–2.03 (m, 1H), 1.77–
1.72 (m, 2H), 1.62–1.59 (m, 1H); 13C NMR (150 MHz, DMSOꢀd6):
δ 171.0 (C), 143.4 (C), 134.9
(C), 129.8 (CH), 127.2 (CH), 76.4 (CH), 72.9 (CH), 72.7 (CH), 71.5 (CH), 69.3 (CH), 60.7 (CH),
48.2 (CH2), 30.3 (CH2), 23.9 (CH2), 21.0 (CH3); HRMS (ESI): m/z calcd for C18H25NO9SNa([M
+ Na]+) 454.1148, found 454.1146.
Ketalization of pentaol 35. A mixture of the pentaol 35 (100 mg, 0.23 mmol) and pꢀ
TSA (8 mg, 0.05 mmol) was dissolved in anhydrous DMF (1 mL). After a clear solution was
obtained, 1,1ꢀdimethoxycyclohexane (0.176 mL, 1.16 mmol) was added dropwise, and the
reaction mixture was allowed to stir at 25 °C. After completion of the reaction monitored by
TLC, the solvents were removed under reduced pressure at 35 °C. Regular solvent grade toluene
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(5 mL) was then added, and the reaction mixture was allowed to stir at room temperature for 2 h
in an open flask. The reaction was then quenched with Et3N (1 mL) and the solvents were
removed in vacuo. The soꢀobtained crude residue was purified by flash column chromatography
(5% MeOH in CHCl3) to afford the compounds 39 (0.084 mg, 72%) and 40 (0.008 mg, 7%).
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2,3-O-Cyclohexylidene-6-O-(N-tosyl-
L
-prolinoyl)-
D
-myo-inositol (39). Colorless solid;
3428, 3335, 2352, 1696, 1344,
7.75 (d, J = 8.3 Hz, 2H, ArꢀH),
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[
α
]
D –78.0 (c 1.0, DMF); mp 202–204 °C; IR (KBr, thin film):
ν
1155, 1095, 1002, 926 cm–1; 1H NMR (600 MHz, DMSOꢀd6):
δ
7.43 (d, J = 8.3 Hz, 2H, ArꢀH), 5.15 (d, J = 6.0 Hz, 1H, 1ꢀOH), 5.11 (d, J = 5.0 Hz, 1H, 4ꢀOH),
4.88 (m, 2H, Hꢀ6, 5ꢀOH), 4.35 (dd, J = 8.4, 2.3 Hz, 1H, prolineꢀH), 4.20 (t, J = 4.6 Hz, 1H, Hꢀ2),
3.85 (dd, J = 7.1, 5.3 Hz, 1H, Hꢀ3), 3.79–3.76 (m, 1H, Hꢀ1), 3.42–3.39 (m, 1H, Hꢀ4), 3.33–3.12
(m, 1H), 3.15–3.12 (m, 2H, Hꢀ5), 2.40 (s, 3H), 1.79–1.72 (m, 2H), 1.69–1.59 (m, 5H), 1.54–1.47
(m, 4H), 1.37–1.31 (m, 2H); 13C NMR (150 MHz, DMSOꢀd6):
δ 171.0 (C), 143.4 (C), 134.9 (C),
129.8 (CH), 127.2 (CH), 108.9 (Spiro C), 78.5 (CH) 76.1 (CH), 75.4 (CH), 75.00 (CH), 71.9
(CH), 60.6 (CH), 48.2 (CH2), 37.6 (CH2), 34.9 (CH2), 30.3 (CH2), 24.6 (CH2), 23.9 (CH2), 23.6
(CH2), 23.3 (CH2), 21.0 (CH3); HRMS (ESI): m/z calcd for C24H33NO9SNa ([M + Na]+)
534.1774, found 534.1767.
1,2-O-Cyclohexylidene-6-O-(N-tosyl-
L
-prolinoyl)-
D
-myo-inositol (40). Colorless solid;
3377, 2936, 1748, 1338,
7.73 (d, J = 8.3 Hz, 2H; Arꢀ
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[
α]
D –120.2 (c 1.0, DMF); mp 159–161 °C; IR (KBr, thin film):
ν
1159, 1097, 1002, 927, 752 cm–1; 1H NMR (600 MHz, DMSOꢀd6):
δ
H), 7.40 (d, J = 8.3 Hz, 2H; ArꢀH), 5.01 (d, J = 5.5 Hz, 1H; 3ꢀOH) 4.98 (d, J = 4.6 Hz, 1H; 4ꢀ
OH), 4.97 (d, J = 5.5 Hz, 1H; 5ꢀOH), 4.22 (t, J = 4.4 Hz, 1H; Hꢀ2), 4.06 (dd, J = 8.0, 5.0 Hz, 1H;
Hꢀ1), 3.55ꢀ3.52 (m, 1H; Hꢀ3), 3.40 (td, J = 9.0, 4.2 Hz, 1H; Hꢀ4), 3.31–3.29 (m, 1H;), 3.15–3.09
(m, 1H; Hꢀ5), 2.40 (s, 3H), 2.03–1.99 (m, 1H), 1.82–1.61 (m, 5H),1.57–1.45 (m, 6H), 1.38–1.31
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