Stereoselective synthesis of polyhydroxycycloheptanes and their phosphate derivatives from 8-oxabicyclo[3.2.1]octenes

Article abstract of DOI:10.1002/ejoc.201201426

The first directed synthesis of seven-membered mono- and tris-phosphates is described. The key steps involve a DIBAL-H/DIBAL-Cl-mediated ring opening of 8-oxabicyclo[3.2.1]octenes in the presence of [Ni(acac)₂] and stereoselective syn-dihydroxylation with NMO and OsO₄. An enantioselective approach to ring opening has been examined with chiral phosphane. The phosphorylation of mono- and triols followed by deprotection gave the corresponding phosphates in high yields with structures similar to those of known inhibitors of myo-inositol monophosphatase (IMPase) and myo-inositol tris-phosphate receptor ligands. The inhibitory activities of the monophosphates thus formed were evaluated against IMPase.

Full text of DOI:10.1002/ejoc.201201426

Job/Unit: O21426
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FULL PAPER
DOI: 10.1002/ejoc.201201426
Stereoselective Synthesis of Polyhydroxycycloheptanes and Their Phosphate
Derivatives from 8-Oxabicyclo[3.2.1]octenes
Dmitry A. Khlevin,*[a,b] Sergey E. Sosonyuk,[a] Marina V. Proskurnina,[a,c] and
Nikolay S. Zefirov[a,c]
Keywords: Cyclitols / Carbasugars / Phosphorylation / Dihydroxylation / Inhibitors / Enantioselectivity
The first directed synthesis of seven-membered mono- and
tris-phosphates is described. The key steps involve a DIBAL-
H/DIBAL-Cl-mediated ring opening of 8-oxabicyclo-
[3.2.1]octenes in the presence of [Ni(acac)2] and stereoselec-
tive syn-dihydroxylation with NMO and OsO4. An enantio-
selective approach to ring opening has been examined with
chiral phosphane. The phosphorylation of mono- and triols
followed by deprotection gave the corresponding phosphates
in high yields with structures similar to those of known inhib-
itors of myo-inositol monophosphatase (IMPase) and myo-in-
ositol tris-phosphate receptor ligands. The inhibitory activi-
ties of the monophosphates thus formed were evaluated
against IMPase.
minimum energy path, thus facilitating its binding to en-
zymes[9] (e.g., glycosidases). The effect of the high flexibility
of polyhydroxycyloheptanes was clearly demonstrated by
Sinaÿ[4c] and Le Merrer[6c] and their co-workers: Some
seven-membered cyclitols inhibited α-d-glucosidase with
lower Ki values than the six-membered structural analogues.
Many examples of efficient glycosidase inhibition by seven-
membered iminocyclitols (polyhydroxyazepanes) have also
been reported.[10]
Introduction
In the last few decades, polyhydroxycarbocycles have
gained importance as pharmacological tools for investiga-
ting cellular processes related to the inositol cycle[1] and also
as potent glycosidase inhibitors.[2] Although a wide range
of cyclopentane and -hexane derivatives are readily avail-
able, the stereoselective synthesis of polyhydroxycyclohept-
anes (homoinositols, seven-membered cyclitols) is consid-
ered a difficult task.[3] A variety of synthetic carbohydrate-
based methods have been reported for the synthesis of
seven-membered carbocyclic frameworks, including ring-
closing metathesis,[4] 1,3-dipolar cycloaddition,[5] intramo-
lecular nucleophilic attack,[6] and radical-mediated cycliza-
tion[7] among others.[3] Synthetic approaches starting from
non-natural-product origin are less popular and the oxi-
dation of tropone is the most common route.[8]
There are two main targets to affect the inositol cycle in
the human body: myo-inositol monophosphatase (IMPase)
and the myo-inositol tris-phosphate (InsP3) receptor.[1b]
IMPase is known to play different physiological roles: It is
involved in the phosphatidylinositol (PI) signal transduc-
tion pathway and carbohydrate metabolism as well as exhi-
biting Zn2+-dependent tyrosine phosphatase activity.[11]
A
number of active six-membered monophosphates have been
synthesized (Figure 1) and studies of their inhibitory ac-
tivity have shown encouraging results.[12] InsP3 analogues
(different six-membered tris-phosphates) interact with the
InsP3 receptor, thus influencing the release of Ca2+ inside
Owing to the high flexibility of the seven-membered ring
(compared with five- and six-membered rings), cyclohept-
anes easily adopt the different conformations required to
mimic the transition state in different processes along the
[a] Department of Chemistry, Moscow State Lomonosov
University,
Lenin Hills, 1, 119991 Moscow, Russian Federation
Fax: +7-495-9390290
Homepage: www.chem.msu.ru/eng
[b] Institute of Physics and Chemistry, Mordovia State Ogarev
University,
Bolshevistskaya, 68, 430005 Saransk, Russian Federation
Fax: +7-8342-472913
Homepage: www.mrsu.ru/en
[c] Institute of Physiologically Active Compounds, RAS,
Severny proezd, 1, 142432 Chernogolovka, Russian Federation
Fax: +7-496-5249508
E-mail: khlevindmitry@yahoo.com
Homepage: www.ipac.ac.ru
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201426.
Figure 1. Examples of IMPase inhibitors.[12]
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D. A. Khlevin et al.
FULL PAPER
the cell. Other targets for them are InsP3 3-kinase and InsP3
5-phosphatase.[1b,13]
Thus, mono- and tris-phosphate derivatives of cyclitols
are a focus of interest. Although glucosidase active sites
revealed favorable binding towards seven-membered cycli-
tols, interactions of the corresponding phosphates with
IMPase and the InsP3 receptor have not been studied at all.
Moreover, to the best of our knowledge, no attempts have
been made to perform the directed synthesis of seven-mem-
bered mono- and tris-phosphates.
Results and Discussion
The assembly of the polyhydroxylated cycloheptane ring
with high diastereoselectivity in a few steps starting from
non-sugar materials is an intriguing challenge. In addition
to the tropone approach,[8] the 8-oxabicyclo[3.2.1]octene-
based protocol of Lautens et al.[14] seems to be convenient
and limited only by the availability of oxa-bridged cyclo-
heptenes. Thus, a number of 8-oxabicyclo[3.2.1]oct-6-ene-
2,4-diols are necessary for the synthesis of 2,4-dihydroxy-1-
Scheme 1. Available 8-oxabicyclo[3.2.1]octenes and the retrosynthe-
sis of seven-membered phosphates.
phosphates as analogues of IMPase inhibitors (Figure 1). acids to form ring-opened unsaturated compounds (e.g.,
As a part of our ongoing research directed towards the de- DIBAL-Cl). In the presence of phosphanes at elevated tem-
sign of new seven-membered cyclitols, we have recently re- peratures, the reaction proceeds by a different pathway.
ported[15] the stereoselective synthesis of the required 2,4-
Because initial attempts to apply the ring-opening pro-
diols 1–3 (Scheme 1) based on the Diels–Alder reaction of cedure to alkenes 1–3 showed low selectivity, the reaction
furan and tetrachlorocyclopropene.[16] In this work we ap- conditions were optimized for alkene 1a. The amount of
plied the ring-opening methodology to synthesize highly DIBAL-H was found to be of most importance for the total
substituted cycloheptanes and used them for the synthesis yield and selectivity. Hence, 1.5–8 equiv. of DIBAL-H were
of inositol mono- and tris-phosphate homoanalogues.
tested in the temperature range of 60–85 °C (Table 1).
The mechanism of reductive ring opening was proposed [Ni(cod)2] and [Ni(acac)2] were investigated as catalysts (15–
by Lautens et al.[14] The nickel-catalyzed reaction of 8-oxa- 30 mol-%) but no significant difference was found. Hence,
bicyclo[3.2.1]octenes with DIBAL-H involves two steps. In acetylacetonate was used in further reactions. The use of a
the first, organometallic species are generated. In the sec- large excess of DIBAL-H led to a dramatic decrease in both
ond, they undergo β-elimination in the presence of Lewis the yield and selectivity. Thus, for example, treatment with
Table 1. Optimization of ring-opening reaction of 1a.
Entry
DIBAL-H
[equiv.]
DIBAL-Cl
[equiv.]
T
[°C]
Heating
time [h]
Total yield
[%]
Ratio
4a/5a/6/7/8[a]
1
2
3
4
5
6
7
8
1.5
2.0
2.0
2.0
2.0
2.0
2.0
3.0
3.0
4.0
4.0
8.0
5
5
5
5
5
7
7
5
5
5
5
5
70
60
85
75
65
75
65
75
65
75
65
65
5
7
3
4
5
4
5
4
5
4
5
5
84
82
83
83
78
77
75
73
72
70
68
62
41:54:0:5:0[b]
24:63:4:7:2
21:64:5:8:2
20:70:3:5:2[c]
22:66:3:7:2
20:61:5:10:4
18:53:5:18:6
18:51:8:16:7
17:47:10:18:8
16:44:11:20:9
15:43:12:21:9
13:40:15:22:10[d]
9
10
11
12
1
[a] Ratio determined by H NMR spectroscopy. [b] 14% of alkene 1a was also recovered. [c] Isolated yields: 17% of 4a and 58% of 5a.
[d] Isolated yields: 8% of 4a, 23% of 5a, 9% of 6, 12% of 7, and 6% of 8.
2
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Synthesis of Polyhydroxycycloheptanes and Their Phosphates
8 equiv. of DIBAL-H and 5 equiv. of DIBAL-Cl gave a detected by NMR spectroscopy, but in amounts too small
complex mixture of products (at least seven substances ac- for isolation. Other nonchiral phosphanes gave results sim-
cording to TLC). Five of these products were isolated by ilar to those observed for alkene 1a.
column chromatography (entry 12). In addition to the satu-
Table 3. Ring-opening reaction of 8-oxabicyclo[3.2.1]octenes 1–3.
rated bicycle 4a (8%) and the desired cycloheptenol 5a
(23%), over-reduced cycloheptanol 6 (9%) and two prod-
ucts containing only one benzyl group were obtained: Com-
pound 7 (12%) lacks a benzyloxy group (BnOH was also
detected among the reaction products) and compound 8
(6%) lacks a benzyl group.
Finally, treatment with 2 equiv. of DIBAL-H and
5 equiv. of DIBAL-Cl in toluene/hexane gave the best re-
sults: 58% of the desired cycloheptenol 5a was isolated to-
gether with 17% of the saturated bicycle 4a (entry 4). The
process did not go to completion with a smaller amount of
DIBAL-H (1.5 equiv.). Thus, some unreacted alkene 1a was
recovered even after 5 h (entry 1).
The effect of the addition of phosphane ligands to the
nickel-catalyzed reductive ring-opening of alkene 1a was
next examined. In all cases, the optimized protocol with the
use of 30 mol-% phosphane was detrimental to the reaction
yield. Of the monodentate ligands tested [Ph3P, Cy3P (Cy
= cyclohexyl), (OiPr)3P], Ph3P was found to give the best
results (Table 2). The yield was increased by using a greater
amount of the nickel catalyst (30 mol-%) and by slowly
adding DIBAL-H and DIBAL-Cl (during 4 h). Finally, the
desired cycloheptene 5a was isolated in 64% yield (entry 5).
The bidentate 1,4-bis(diphenylphosphanyl)butane (dppb)
was not so efficient and gave 46% of the product under the
same conditions (entry 6).
Table 2. Effect of phosphane ligands on the ring-opening of 1a.
Entry Phosphane
(amount [mol-%])
[Ni(acac)2] Isolated yield: ee [%]
[mol-%]
of 5a [%]
We also examined the ring-opening protocol for asym-
metrical benzyl ethers 1b and 2b. According to the reaction
mechanism, a mixture of products can be obtained. In fact,
no selectivity was observed and mixtures of cycloheptenol
isomers 5b+5c and 9b+9c were produced in ratios of
around 1:1 along with reduced bicycles 4b and 11b
(Table 3). Their separation became possible only after re-
peated silica gel column chromatography. Pure dia-
stereomers were isolated in yields of 13–15% (see the Exptl.
Sect.). Note that the presence of other phosphanes did not
improve the yields and selectivity of the ring opening of
asymmetric products.
1
2
3
Cy3P (30)
(OiPr)3P (30)
Ph3P (30)
15
15
15
30
30
30
50
50
14
26
32
52
64
46
43
28
4
Ph3P (60)
Ph3P (50)
dppb (50)
(R)-BINAP (50)
(R)-BINAP (50)
5[a]
6[a]
7[a]
8[b]
82
95
[a] DIBAL-H (2 equiv.) and DIBAL-Cl (5 equiv.) were added over
4 h at 75 °C. [b] No DIBAL-Cl was added.
The enantioselective ring-opening approach was further
explored. Chiral (R)-BINAP (50 mol-%) was used as the
phosphane ligand in the protocol described above and the
amount of [Ni(acac)2] was increased to 50 mol-%. Under
these conditions, cycloheptene 5a was isolated in 43% yield
with 82% ee (Table 2, entry 7). The ee increased to 95% in
the absence of DIBAL-Cl, but the yield decreased to 28%
(entry 8). Other variations of the reaction parameters did
not improve the yield.
The stereochemistry of the benzyloxy groups was de-
duced from NMR data, including NOE measurements. As
expected for cycloheptane systems,[4c] a strong NOE effect
was detected between the cis protons (see Figure 2).
We then applied the optimized Ph3P-based protocol to
the ring-opening of symmetrical 3-substituted ethers 2a and
3. In this case, similar main products were isolated (Table 3)
with the desired cycloheptenols 9a and 10 isolated in yields
of 67 and 70%, respectively. Debenzylated products were Figure 2. NOEs observed for cycloheptenes 5c, 9b, and 9c.
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In some cases another unsymmetrical bicyclic product formed with these compounds showed encouraging results;
was detected in the reaction mixtures after the ring-opening they exhibited stronger inhibition than the six-membered
procedures. Although all the reactions were carried out un- analogues (Table 4, compare with Figure 1) and both sub-
der argon, the oxidation of organoalanes was suggested. To stances displayed a competitive mode of action.
confirm this proposal for compound 1a, the product of
hydroalumination was placed under oxygen. The exposure
of organoalane to air gave exo-alcohol 13 in 62% yield
(Scheme 2).
Table 4. Inhibition of IMPase by phosphates 15 and 17.
Phosphate
IC50 [μm]
Mode of action
15
17
0.8
13
Competitive
Competitive
On the other hand, the functionalization of the double
bond in alkenes 5, 9, and 10 led to the corresponding triols
that can be converted into tris-phosphates. The dihydrox-
ylation seemed to be a straightforward approach. Hence,
compounds 5a, 9a, and 10 were treated with NMO and
OsO4 in aqueous acetone/tert-butyl alcohol. As expected
from the structures of the substrates, high diastereoselecti-
vity was observed and the corresponding triols 18–20 were
obtained in high yields (Scheme 4). Other isomers (Ͻ7%)
were also detected in the reaction mixtures by NMR spec-
troscopy, but they were not isolated. The stereochemistry
was deduced from NOE experiments; a strong interaction
was observed between PhCH2 at the 7-position and 1-H.
Scheme 2. Oxidation of organoalane.
The cycloheptenol 5a thus obtained can be used for the
preparation of monophosphorylated derivatives structurally
similar to the known inhibitors of IMPase (Figure 1) be-
cause it requires 1,2,4-substitution. It was found that the
hydroxy groups at the 2- and 4-positions play a crucial role
in the recognition of InsP by the enzyme and other OH
groups can be removed. Moreover, it is usually necessary
to promote the inhibition properties.[1b] To demonstrate the
monophoshate synthesis, cycloheptene 5a was phosphory-
lated. Dibenzyl N,N-diisopropylphosphoramidite[17] was
the reagent of choice due to its relative stability and the
ease of benzyl group removal. A weak acid (1H-tetrazole)
was used as the catalyst and m-CPBA was employed as the
oxidant, resulting in the formation of the desired protected
phosphate 14 in high yield (Scheme 3).
Scheme 4. Synthesis of tris-phosphate 22.
Triol 18 was transformed into the corresponding tris-
phosphate 22 by phosphorylation followed by deprotection
(Scheme 4). This compound can be considered as the struc-
tural analogue of the known InsP3 receptor ligands.
Conclusions
A versatile synthesis of polyhydroxylated cycloheptanes
and their phosphate derivatives from 8-oxabicyclo[3.2.1]oc-
Scheme 3. Synthesis of monophosphates.
Cycloheptene 14 was hydroxylated with NMO and OsO4 tene precursors has been developed. The stereoselectivity of
to obtain a diastereoisomeric mixture of 16a and 16b in a the bicyclic approach is provided by reductive ring-opening
ratio of 5:1; the minor isomer 16b was not isolated and dihydroxylation procedures. The possibility of asym-
(Scheme 3). The stereochemistry of the major isomer 16a metric synthesis was demonstrated by using (R)-BINAP as
was determined by NOE experiments. A strong interaction the ligand. The mono- and tris-phosphates thus formed can
is observed between PhCH2 at the 4-position and 5-H. The be considered as racemic homoanalogues of the inositol
final phosphates 15 and 17 were obtained by catalytic hy- compounds involved in the signal transduction pathway.
drogenolysis of 14 and 16a, respectively, using Pd on carbon The inhibition of IMPase for two seven-membered mono-
without further purification. The biological assays per- phosphates was found to be in the low micromolar range.
4
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Synthesis of Polyhydroxycycloheptanes and Their Phosphates
1
yellow oil; Rf = 0.45 (Et2O/hexanes = 1:1). H NMR (CDCl3): δ =
7.30–7.43 (m, 10 H, 2 Ph), 5.97–6.01 (m, 1 H, 4-H), 5.74–5.80 (m,
1 H, 3-H), 4.68 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.58 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.51 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.47 (d, J =
11.8 Hz, 1 H, CH2Ph), 4.42 (br. d, J = 8.2 Hz, 1 H, 5-H), 3.72–
3.79 (m, 2 H, 1-H, 7-H), 2.64–2.68 (m, 1 H), 2.27–2.33 (m, 1 H),
1.98–2.04 (m, 1 H), 1.84–1.90 (m, 1 H) ppm. 13C NMR (CDCl3):
δ = 138.4, 137.8, 133.5, 128.6, 128.5, 128.1, 127.9, 127.8, 127.7,
124.7, 83.4, 74.7, 72.3, 71.3, 70.9, 35.6, 31.0 ppm. C21H24O3
(324.42): calcd. C 77.75, H 7.46; found C 77.72, H 7.34.
Experimental Section
General: All solvents were distilled prior to use. Dry solvents were
prepared according to standard procedures. Reactions requiring an
inert atmosphere were performed under argon. All reactions were
monitored by TLC using Merck 60 F254 precoated silica gel plates
(0.25 mm thickness). Flash and column chromatography were per-
formed on silica gel 60. 1H, 13C, and31P NMR spectra were re-
corded in CDCl3 or [D6]DMSO with a Bruker Avance 400 spec-
trometer (400 MHz for 1H NMR, 100 MHz for 13C NMR,
162 MHz for 31P NMR). The H NMR spectroscopic data are re-
1
(1S*,5R*,7R*)-5,7-Bis(benzyloxy)cyclohept-3-enol (5c): Compound
5c was afforded according to general method A from alkene 1b as
a 1:1 mixture with compound 5b in a yield of 46 mg (47%). Isolated
yield: 12 mg (13%) after repeated column chromatography; pale-
ported as chemical shift (δ [ppm]), multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet), coupling constant (J [Hz]),
and the number of protons. The 13C NMR spectroscopic data are
reported as chemical shifts (δ [ppm]). The chemical shifts were mea-
sured relative to the residual solvent as an internal standard. Ele-
mental analyses were performed with a Vario MICRO cube ana-
lyzer.
1
yellow oil; Rf = 0.43 (Et2O/hexanes = 1:1). H NMR (CDCl3): δ =
7.29–7.40 (m, 10 H, 2 Ph), 5.94–5.97 (dt, J = 2.4, 11.0 Hz, 1 H, 4-
H), 5.67–5.73 (m, 1 H, 3-H), 4.69 (d, J = 11.6 Hz, 1 H, CH2Ph),
4.59 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.6 Hz, 1 H,
CH2Ph), 4.47 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.27 (dd, J = 3.1,
9.0 Hz, 1 H, 5-H), 3.64–3.76 (m, 2 H, 1-H, 7-H), 2.40–2.45 (m, 2
H), 2.28–2.33 (m, 1 H), 1.84–1.90 (m, 1 H) ppm. 13C NMR
(CDCl3): δ = 138.2, 137.4, 136.6, 128.6, 128.5, 128.1, 128.0, 127.8,
127.6, 124.7, 79.4, 74.0, 72.7, 71.3, 70.9, 37.1, 31.0 ppm. C21H24O3
(324.42): calcd. C 77.75, H 7.46; found C 77.68, H 7.36.
General Method A. Nickel-Catalyzed Reductive Ring Opening
(Phosphane-Based Protocol): Ph3P (39.5 mg, 0.15 mmol) and 1.0 m
DIBAL-H in hexane (0.15 mL, 0.15 mmol) were added to [Ni-
(acac)2] (24.0 mg, 0.09 mmol) in a mixture of freshly distilled tolu-
ene (4 mL) and hexane (2 mL). The resulting yellow solution was
stirred for 3 h by which time the color was a deep red. The alkene
1a (0.30 mmol) was dissolved in toluene (1 mL) and transferred to
the catalyst solution. The reaction mixture was placed in an oil
bath preheated to 75 °C and 1.0 m DIBAL-H solution in hexane
(0.45 mL, 0.45 mmol) was slowly added together with DIBAL-Cl
(0.3 mL, 1.50 mmol) over 4 h through a syringe pump. The reaction
mixture was cooled to room temp. and quenched by the addition
of a saturated NH4Cl aqueous solution (5 mL) and then enough
10% H2SO4 was added to make the aqueous layer transparent. The
organic layer was separated and the aqueous layer was extracted
with Et2O and EtOAc. The combined organics were dried with
Na2SO4. The removal of the solvent in vacuo yielded product mix-
tures that were subjected to silica gel column chromatography (gra-
dient elution with 20–50% Et2O in hexane).
(1R*,5R*,6S*,7S*)-5,7-Bis(benzyloxy)-6-chlorocyclohept-3-enol
(9a): Compound 9a was afforded from alkene 2a according to gene-
ral method A. Yield: 72 mg (67%); pale-yellow oil; Rf = 0.55 (Et2O/
1
hexanes = 3:2). H NMR (CDCl3): δ = 7.30–7.45 (m, 10 H, 2 Ph),
5.90–5.95 (m, 1 H, 4-H), 5.82–5.86 (m, 1 H, 3-H), 5.06 (d, J =
11.1 Hz, 1 H, CH2Ph), 4.70 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.68 (s,
2 H, CH2Ph), 4.25 (t, J = 6.8 Hz, 1 H, 6-H), 4.17 (dd, J = 4.6,
7.6 Hz, 1 H, 5-H), 3.89 (t, J = 9.9 Hz, 1 H, 1-H), 3.60–3.64 (m, 1
H, 7-H), 2.49–2.56 (m, 1 H, 2-H), 2.24–2.32 (m, 1 H, 2-H) ppm.
13C NMR (CDCl3): δ = 137.8, 137.7, 130.8, 129.6, 128.7, 128.4,
128.2, 128.1, 127.9, 127.8, 89.9, 76.7, 75.3, 72.0, 70.7, 64.0,
32.1 ppm. C21H23ClO3 (358.86): calcd. C 70.29, H 6.46; found C
70.32, H 6.45.
(1S,5R,7S)-5,7-Bis(benzyloxy)cyclohept-3-enol (5a): The racemic
product was afforded according to general method A from alkene
1a in a yield of 64%. Enantioselective ring opening was also per-
formed by using (R)-BINAP instead of Ph3P and 50 mol-% of [Ni-
(acac)2]. The substrate purity and solvent quality were found to be
crucial for the success of the asymmetric reaction. In the presence
of DIBAL-Cl, the compound was isolated in a yield of 43%
(42 mg) and 82% ee; without DIBAL-Cl it was isolated in a yield
of 28% (27 mg) and 95% ee. The ee was determined by using
HPLC analysis on a chiral OD column [95:5 hexane/iPrOH, reten-
tion times of 15.7 and 16.4 min (major)]. Pale-yellow oil; Rf = 0.50
(Et2O/hexanes = 1:1); [α]2D5 = 35.2 (c = 1.0, CHCl3). 1H NMR
(CDCl3): δ = 7.30–7.41 (m, 10 H, 2 Ph), 6.03 (dt, J = 2.3, 11.1 Hz,
1 H, 4-H), 5.71–5.78 (m, 1 H, 3-H), 4.75 (d, J = 11.1 Hz, 1 H,
CH2Ph), 4.64 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.53 (d, J = 11.6 Hz,
1 H, CH2Ph), 4.51 (d, J = 11.1 Hz, 1 H, CH2Ph), 4.09 (dd, J =
2.3, 11.1 Hz, 1 H, 5-H), 3.33–3.45 (m, 2 H, 1-H, 7-H), 3.03 (s, 1
H, OH), 2.40–2.47 (m, 2 H, 2-H), 2.06–2.14 (m, 1 H, 6-H), 1.65–
1.74 (m, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 138.5, 138.2,
137.9, 128.7, 128.5, 128.0, 127.9, 127.8, 127.7, 124.6, 84.1, 74.1,
71.7, 71.2, 70.9, 36.3, 31.1 ppm. C21H24O3 (324.42): calcd. C 77.75,
H 7.46; found C 77.86, H 7.34.
(1R*,5S*,6S*,7S*)-5,7-Bis(benzyloxy)-6-chlorocyclohept-3-enol
(9b): Compound 9b was afforded according to general method A
from alkene 2b as a 1:1 mixture with compound 9c in a yield of
52 mg (49%). Isolated yield: 17 mg (15%) after repeated column
chromatography; pale-yellow oil; Rf = 0.55 (Et2O/hexanes = 1:1).
1H NMR (CDCl3): δ = 7.30–7.42 (m, 10 H, 2 Ph), 5.88 (dt, J =
5.1, 11.4 Hz, 1 H, 4-H), 5.79–5.83 (m, 1 H, 3-H), 4.82 (d, J =
11.1 Hz, 1 H, CH2Ph), 4.72 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.66 (d,
J = 11.1 Hz, 1 H, CH2Ph), 4.62 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.47
(d, J = 5.1 Hz, 1 H, 5-H), 4.27 (dd, J = 1.0, 6.0 Hz, 1 H, 6-H), 3.96
(t, J = 6.0 Hz, 1 H, 7-H), 3.78–3.84 (m, 1 H, 1-H), 3.18 (s, 1 H,
OH), 2.55–2.63 (m, 1 H, 2-H), 2.46 (dd, J = 5.3, 15.2 Hz, 1 H, 2-
H) ppm. 13C NMR (CDCl3): δ = 137.3, 137.2, 134.1, 129.7, 128.6,
128.5, 128.2, 128.1, 127.8, 127.7, 87.4, 81.3, 74.2, 70.9, 69.2, 61.4,
32.2 ppm. C21H23ClO3 (358.86): calcd. C 70.29, H 6.46; found C
70.15, H 6.58.
(1R*,5R*,6S*,7R*)-5,7-Bis(benzyloxy)-6-chlorocyclohept-3-enol
(9c): Compound 9c was afforded according to general method A
from alkene 2b as a 1:1 mixture with compound 9b in a yield of
52 mg (49%). Isolated yield: 16 mg (14%) after repeated column
chromatography; pale-yellow oil; Rf = 0.50 (Et2O/hexanes = 1:1).
1H NMR (CDCl3): δ = 7.30–7.41 (m, 10 H, 2 Ph), 5.82–5.87 (m, 1
H, 4-H), 5.74–5.81 (m, 1 H, 3-H), 5.09 (d, J = 11.5 Hz, 1 H,
CH2Ph), 4.82 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.68 (d, J = 11.6 Hz,
1 H, CH2Ph), 4.64 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.48 (br. d, J =
(1R*,5R*,7R*)-5,7-Bis(benzyloxy)cyclohept-3-enol (5b): Compound
5b was afforded according to general method A from alkene 1b as
a 1:1 mixture with compound 5c in a yield of 46 mg (47%). Isolated
yield: 13 mg (14%) after repeated column chromatography; pale-
Eur. J. Org. Chem. 0000, 0–0
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D. A. Khlevin et al.
FULL PAPER
9.6 Hz, 1 H, 5-H), 4.27 (s, 1 H, OH), 4.21 (dd, J = 1.3, 9.6 Hz, 1
H, 6-H), 3.64–3.79 (m, 2 H, 1-H, 7-H), 2.61–2.69 (m, 1 H, 2-H),
2.15 (dd, J = 7.3, 15.2 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3): δ
= 137.7, 137.6, 132.3, 131.2, 128.7, 128.4, 128.3, 128.2, 127.9, 127.8,
83.6, 77.4, 74.5, 70.7, 69.0, 62.4, 32.1 ppm. C21H23ClO3 (358.86):
calcd. C 70.29, H 6.46; found C 70.22, H 6.56.
31P NMR (CDCl3): δ = –1.4, –1.6, –1.7 ppm. C63H65O14P3
(1139.12): calcd. C 66.43, H 5.75; found C 66.38, H 5.79.
General Method C. syn-Dihydroxylation of Alkenes with NMO and
OsO4: An O-benzyl-protected alkene (0.30 mmol) was dissolved in
acetone (5 mL) and water (2 mL), OsO4 (0.01 mmol, 0.25 mL of a
2.5 wt.-% solution in tBuOH), and NMO (200 mg, 1.50 mmol)
were added. The mixture was stirred at room temperature for 48 h
and an aqueous solution of Na2SO3 (10 wt.-%, 10 mL) was added.
Acetone was removed from the resulting mixture by evaporation
under reduced pressure and the residue was extracted with EtOAc.
The organic phase was washed with brine (10 mL), dried (Na2SO4),
and concentrated. The syn-diols were purified by flash chromatog-
raphy on silica gel (gradient elution with 10–50% EtOAc in
CH2Cl2).
(1R*,5R*,6R*,7R*)-5,7-Bis(benzyloxy)-6-methylcyclohept-3-enol
(10): Compound 10 was afforded from alkene 3 according to gene-
ral method A. Yield: 71 mg (70%); pale-yellow oil; Rf = 0.50 (Et2O/
1
hexanes = 3:2). H NMR (CDCl3): δ = 7.30–7.41 (m, 10 H, 2 Ph),
5.78–5.82 (m, 2 H, 3-H, 4-H), 4.73 (d, J = 11.2 Hz, 1 H, CH2Ph),
4.63 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.52 (d, J = 12.0 Hz, 1 H,
CH2Ph), 4.44 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.19–4.22 (m, 1 H, 5-
H), 3.55 (ddd, J = 2.8, 9.2, 11.5 Hz, 1 H, 1-H), 3.33 (dd, J = 4.4,
9.2 Hz, 1 H, 7-H), 2.63–2.70 (m, 1 H, 2-H), 2.38–2.44 (m, 1 H, 2-
H), 2.02–2.10 (m, 1 H, 6-H), 1.00 (d, J = 7.1 Hz, 3 H, CH3) ppm.
13C NMR (CDCl3): δ = 138.4, 137.9, 136.0, 128.6, 128.4, 128.0,
127.6, 127.5, 127.0, 124.6, 87.1, 77.8, 71.0, 70.9, 66.3, 36.9, 31.4,
7.7 ppm. C22H26O3 (338.45): calcd. C 78.07, H 7.74; found C 78.15,
H 7.78.
Dibenzyl (1R*,2R*,4S*,5S*,6S*)-2,4-Bis(benzyloxy)-5,6-dihydroxy-
cycloheptyl Phosphate (16a): Compound 16a was afforded from
alkene 14 according to general method C. Yield: 96 mg (52%);
white viscous oil; Rf = 0.50 (Et2O/acetone = 4:1). 1H NMR
(CDCl3): δ = 7.21–7.38 (m, 20 H, 4 Ph), 4.98–5.05 (m, 4 H, 2
CH2Ph), 4.60–4.67 (m, 1 H, 1-H), 4.53–4.60 (m, 3 H, CH2Ph), 4.43
(d, J = 11.5 Hz, 1 H, CH2Ph), 4.06 (br. d, J = 7.7 Hz, 1 H, 4-H),
3.71–3.78 (m, 1 H, 2-H), 3.62 (dd, J = 2.9, 7.7 Hz, 1 H, 5-H), 3.53–
3.58 (m, 1 H, 6-H), 2.15 (br. d, J = 14.9 Hz, 1 H), 1.98 (dd, J =
4.2, 15.5 Hz, 1 H), 1.67 (ddd, J = 9.7, 14.9, 19.5 Hz, 1 H), 0.89–
0.96 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 138.2, 138.0, 135.7,
135.6, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7,
127.6, 127.5, 127.4, 80.4 (d, JCP = 6.6 Hz), 79.8 (d, JCP = 8.8 Hz),
78.3, 76.3, 72.3, 69.2 (d, JCP = 8.7 Hz), 69.1, 68.2, 34.0, 30.3 ppm.
31P NMR (CDCl3): δ = –1.8 ppm. C35H39O8P (618.66): calcd. C
67.95, H 6.35; found C 67.86, H 6.30.
General Method B Ϫ Phosphorylation of Alcohols: 1H-Tetrazole
(63 mg, 0.9 mmol, 2.0 mL of a 0.45 m solution in CH3CN) and di-
benzyl diisopropylphosphoramidite (200 μL, 0.6 mmol) were added
to a solution of the corresponding alcohol (0.30 mmol) in CH2Cl2
(3.0 mL) at room temperature and the mixture was stirred for 12 h.
The solution was cooled (0 °C) and NaH2PO4 (132 mg, 1.1 mmol)
and m-CPBA (155 mg, 0.9 mmol) were added. The reaction mix-
ture was then stirred at room temperature for 2 h and then diluted
with CH2Cl2, quenched with saturated aqueous Na2SO3, and
washed with saturated aqueous NaHCO3 followed by 1 n HCl. The
organic phase was neutralized with saturated aqueous NaHCO3
and dried with Na2SO4. The solvent was evaporated and the resi-
due was purified through a column of silica gel (gradient elution
with 10–30% of EtOAc in CH2Cl2) to give protected phosphates
as viscous oils.
(1S*,2S*,4R*,5R*,7S*)-5,7-Bis(benzyloxy)cycloheptane-1,2,4-triol
(18): Compound 18 was afforded from alkene 5a according to gene-
ral method C. Yield: 81 mg (75%); pale-yellow oil; Rf = 0.45 (Et2O/
1
acetone = 5:1). H NMR (CDCl3): δ = 7.30–7.42 (m, 10 H, 2 Ph),
4.65 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.63 (d, J = 11.6 Hz, 1 H,
CH2Ph), 4.60 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.48 (d, J = 11.5 Hz,
1 H, CH2Ph), 4.18 (d, J = 8.5 Hz, 1 H, 7-H), 3.84–3.91 (m, 1 H,
5-H), 3.54–3.62 (m, 3 H, 1-H, 2-H, 4-H), 3.33 (br. s, 1 H, OH),
3.17 (br. s, 1 H, OH), 3.09 (br. s, 1 H, OH), 2.24–2.29 (m, 1 H, 3-
H), 2.15 (ddd, J = 6.1, 8.6, 14.8 Hz, 1 H, 3-H), 1.91–1.96 (m, 1 H,
6-H), 1.56–1.65 (m, 1 H, 6-H) ppm. 13C NMR (CDCl3): δ = 138.3,
137.9, 128.7, 128.6, 128.1, 128.0, 127.9, 127.8, 82.1, 78.2, 77.1, 73.6,
71.8, 71.6, 69.3, 33.5, 31.7 ppm. C21H26O5 (358.43): calcd. C 70.37,
H 7.31; found C 70.44, H 7.38.
Dibenzyl (1R*,5S*,7R*)-5,7-Bis(benzyloxy)cyclohept-3-enyl Phos-
phate (14): Compound 14 was afforded from alcohol 5a according
to general method B. Yield: 140 mg (80%); pale-yellow oil; Rf =
0.40 (Et2O/hexanes = 2:1). 1H NMR (CDCl3): δ = 7.26–7.39 (m,
20 H, 4 Ph), 6.02 (br. d, J = 11.1 Hz, 1 H, 4-H), 5.57–5.64 (m, 1
H, 3-H), 5.01–5.06 (m, 4 H, 2 CH2Ph), 4.65 (s, 2 H, CH2Ph), 4.57
(d, J = 11.9 Hz, 1 H, CH2Ph), 4.50 (d, J = 11.9 Hz, 1 H, CH2Ph),
4.30–4.37 (m, 1 H, 1-H), 4.07 (br. d, J = 10.7 Hz, 1 H, 5-H), 3.56–
3.62 (m, 1 H, 7-H), 2.62–2.68 (m, 1 H), 2.27–2.38 (m, 2 H), 1.79–
1.88 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 138.5, 138.2, 138.1,
136.1, 136.0, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9, 127.8,
127.7, 127.6, 127.5, 127.4, 123.2, 81.0 (d, JCP = 7.3 Hz), 79.0 (d,
JCP = 5.9 Hz), 73.4, 72.1, 70.7, 69.2 (d, JCP = 11.7 Hz), 69.1, 37.5,
30.7 ppm. 31P NMR (CDCl3): δ = –1.9 ppm. C35H37O6P (584.65):
calcd. C 71.90, H 6.38; found C 72.05, H 6.36.
(1S*,2S*,4R*,5S*,6R*,7R*)-5,7-Bis(benzyloxy)-6-chlorocyclohept-
ane-1,2,4-triol (19): Compound 19 was afforded from alkene 9a ac-
cording to general method C. Yield: 85 mg (72%), pale-yellow oil;
1
Rf = 0.55 (Et2O/acetone = 5:1). H NMR (CDCl3): δ = 7.31–7.42
(m, 10 H, 2 Ph), 5.00 (d, J = 10.9 Hz, 1 H, CH2Ph), 4.92 (d, J =
11.0 Hz, 1 H, CH2Ph), 4.62–4.65 (m, 2 H, CH2Ph), 4.18–4.26 (m,
3 H, 5-H, 6-H, 7-H), 3.93–4.00 (m, 2 H, 1-H, 4-H), 3.78 (d, J =
6.5 Hz, 1 H, 2-H), 2.20 (ddd, J = 1.9, 4.9, 14.3 Hz, 1 H, 3-H), 2.01–
2.08 (m, 1 H, 3-H) ppm. 13C NMR (CDCl3): δ = 137.5, 137.3,
128.7, 128.6, 128.3, 128.2, 128.1, 128.0, 86.2, 80.3, 75.4, 74.7, 73.3,
69.2, 68.4, 65.7, 33.0 ppm. C21H25ClO5 (392.88): calcd. C 64.20, H
6.41; found C 64.32, H 6.53.
Dibenzyl (1R*,2S*,4R*,5R*,7S*)-5,7-Bis(benzyloxy)cycloheptane-
1,2,4-triyl Triphosphate (21): Compound 21 was afforded from triol
18 according to general method B. Yield: 246 mg (72%); pale-yel-
1
low oil; Rf = 0.43 (Et2O). H NMR (CDCl3): δ = 7.20–7.42 (m, 40
H, 8 Ph), 4.90–5.04 (m, 13 H, 6 CH2Ph, 1-H), 4.76 (t, J = 7.7 Hz,
1 H, 4-H), 4.62–4.69 (m, 1 H, 2-H), 4.41–4.55 (m, 4 H, 2 CH2Ph),
3.69–3.79 (m, 2 H, 5-H, 7-H), 2.40–2.48 (m, 1 H), 1.79–1.88 (m, 1 (1S*,2S*,4R*,5R*,6S*,7S*)-5,7-Bis(benzyloxy)-6-methylcyclohept-
H), 1.65–1.75 (m, 1 H), 1.27–1.37 (m, 1 H) ppm. 13C NMR
ane-1,2,4-triol (20): Compound 20 was afforded from alkene 10 ac-
(CDCl3): δ = 138.0, 137.9, 135.9, 135.8, 128.6, 128.5, 128.4, 128.3, cording to general method C. Yield: 95 mg (78%); pale-yellow oil;
1
128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 77.6 (dd, JCP = 5.1, 9.5 Hz),
75.0 (t, JCP = 8.0 Hz), 71.9 (d, JCP = 8.8 Hz), 69.1–69.5 (m), 32.9,
28.7 (some signals in the aromatic region are not resolved) ppm.
Rf = 0.50 (Et2O/acetone = 5:1). H NMR (CDCl3): δ = 7.29–7.41
(m, 10 H, 2 Ph), 4.59–4.63 (m, 2 H, CH2Ph), 4.56 (d, J = 11.5 Hz,
1 H, CH2Ph), 4.44 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.17 (dt, J = 2.5,
6
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Synthesis of Polyhydroxycycloheptanes and Their Phosphates
8.1 Hz, 1 H, 7-H), 3.86 (ddd, J = 5.1, 8.1, 10.1 Hz, 1 H, 5-H), 3.56– enzyme solution). The color was allowed to develop over a period
3.66 (m, 3 H, 1-H, 2-H, 4-H), 2.54–2.61 (m, 1 H, 6-H), 2.00–2.15 of 30 min and the absorbance at 660 nm was measured in a cuvette
(m, 2 H, 3-H), 1.00 (d, J = 7.3 Hz, 3 H, CH3) ppm. 13C NMR with a pathlength of 10 mm. Phosphate concentrations were deter-
(CDCl3): δ = 138.4, 138.0, 128.6, 128.6, 128.1, 127.9, 127.8, 127.7, mined by comparison of the absorbance value with a precon-
85.1, 81.1, 73.6, 72.2, 71.9, 70.7, 69.2, 34.9, 33.0, 7.7 ppm.
C22H28O5 (372.46): calcd. C 70.94, H 7.58; found C 70.84, H 7.65.
structed standard curve prepared with known phosphate concen-
trations. IC50 values of 0.8 μm for compound 15 and 13 μm for com-
pound 17 were obtained.
General Method D. Global Deprotection of the InsP1 and InsP3 Ana-
logues: 20% Pd/C (25 mg) was added to a solution of the protected
phosphate (0.15 mmol) in MeOH (3.0 mL) and H2 was bubbled
through the mixture for 14 h at room temperature. The solution
was then filtered through a pad of Celite and the filtrate concen-
trated to give the deprotected phosphates as syrups.
(1S*,2S*,4R*,5R*,6R*)-2,4-Bis(benzyloxy)-8-oxabicyclo[3.2.1]-
octan-6-ol (13): A 1.0 m DIBAL-H solution in hexane (0.26 mL,
0.26 mmol) was added to alkene 1a (0.30 mmol) and [Ni(acac)2]
(4.3 mg, 0.024 mmol) in toluene (3.0 mL) at room temperature. Af-
ter 15 min, when the starting material had been consumed, air was
bubbled through the dark-brown solution for 5 h. The reaction
mixture was worked up by adding an aqueous saturated NH4Cl
solution and then 10% H2SO4 was added to make the aqueous
layer transparent. The aqueous layer was extracted with Et2O
(3ϫ10 mL) and the combined organics were dried with Na2SO4.
The volatiles were removed under reduced pressure and the residue
purified by flash chromatography with 10–30% Et2O in hexanes to
afford alcohol 13 as a pale-yellow oil. Yield: 63 mg (62%); Rf =
0.45 (Et2O/hexanes = 2:1). 1H NMR (CDCl3): δ = 7.29–7.40 (m, 10
H, 2 Ph), 4.60 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.57 (d, J = 11.9 Hz, 1
H, CH2Ph), 4.54 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.51 (d, J =
11.6 Hz, 1 H, CH2Ph), 4.46–4.50 (m, 2 H, 1-H, 5-H), 4.10 (d, J =
4.4 Hz, 1 H, 6-H), 3.50–3.56 (m, 2 H, 2-H, 4-H), 2.51 (dd, J = 7.8,
14.1 Hz, 1 H, 7-H), 2.35 (dd, J = 5.7, 11.6 Hz, 1 H, 3-H), 2.08 (br.
s, 1 H, OH), 1.75–1.81 (m, 1 H, 7-H), 1.14–1.23 (m, 1 H, 3-H) ppm.
13C NMR (CDCl3): δ = 138.3, 138.2, 128.5, 128.4, 127.9, 127.8,
127.7, 127.6, 83.6, 76.2, 73.1, 72.3, 71.4, 71.0, 70.8, 36.2, 30.9 ppm.
C21H24O4 (340.42): calcd. C 74.09, H 7.11; found C 73.94, H 7.20.
(1R*,2R*,4R*)-2,4-Dihydroxycycloheptyl Dihydrogen Phosphate
(15): Compound 15 was afforded from phosphate 14 according to
1
general procedure D. Yield: 33 mg (98%). H NMR ([D6]DMSO/
D2O, 3:1): δ = 4.42–4.50 (m, 1 H, 1-H), 3.76–3.84 (m, 1 H, 2-H),
3.43–3.51 (m, 1 H, 4-H), 1.90–2.01 (m, 2 H), 1.65–1.73 (m, 1 H),
1.22–1.38 (m, 4 H), 0.95–1.02 (m, 1 H) ppm. 13C NMR ([D6]-
DMSO/D2O, 3:1): δ = 75.8 (d, JCP = 7.8 Hz), 67.3, 66.3 (d, JCP
=
6.1 Hz), 37.4, 34.0, 30.9 (d, JCP = 3.9 Hz), 21.8 ppm. 31P NMR
(CDCl3): δ = –2.3 ppm. C7H15O6P (226.17): calcd. C 37.17, H 6.69;
found C 37.35, H 6.56.
(1R*,2R*,4S*,5R*,6S*)-2,4,5,6-Tetrahydroxycycloheptyl Dihydro-
gen Phosphate (17): Compound 17 was afforded from phosphate
16 according to general procedure D. Yield: 38 mg (98%). 1H
NMR ([D6]DMSO/D2O, 2:1): δ = 4.87–4.94 (m, 1 H, 1-H), 3.99–
4.07 (m, 1 H, 5-H), 3.41–3.58 (m, 3 H, 2-H, 4-H, 6-H), 1.81–1.94
(m, 2 H), 1.39–1.51 (m, 1 H), 1.11–1.20 (m, 1 H) ppm. 13C NMR
([D6]DMSO/D2O, 2:1): δ = 79.8, 76.1 (d, JCP = 7.4 Hz), 69.7, 67.6
(d, JCP = 8.1 Hz), 66.1, 35.1, 31.3 ppm. 31P NMR (CDCl3): δ =
–3.2 ppm. C7H15O8P (258.16): calcd. C 32.57, H 5.86; found C
32.42, H 6.02.
Supporting Information (see footnote on the first page of this arti-
cle): 1H, 13C, and 31P NMR spectra of all new compounds and
experimental data for compounds 4a, 4b, 6–8, 11a, 11b, and 12.
(1R*,2S*,4R*,5R*,7S*)-5,7-Dihydroxycycloheptane-1,2,4-triyl Tris-
(dihydrogen phosphate) (22): Compound 22 was afforded from
phosphate 21 according to general procedure D. Yield: 61 mg
(98%). 1H NMR ([D6]DMSO/D2O, 1:1): δ = 4.50–4.59 (m, 1 H, 4-
H), 4.33–4.43 (m, 1 H, 1-H), 3.99–4.10 (m, 1 H, 3-H), 3.63–3.77
(m, 2 H, 5-H, 7-H), 1.75–1.88 (m, 1 H), 1.35–1.52 (m, 2 H), 1.11–
1.21 (m, 1 H) ppm. 13C NMR ([D6]DMSO/D2O, 1:1): δ = 77.4 (dd,
JCP = 5.2, 9.7 Hz), 75.1 (t, JCP = 8.0 Hz), 71.9 (d, JCP = 8.2 Hz),
70.1 (t, JCP = 7.1 Hz), 69.1 (d, JCP = 7.3 Hz), 32.8, 28.9 ppm. 31P
NMR (CDCl3): δ = 0.2, 0.4, 0.7 ppm. C7H17O14P3 (418.12): calcd.
C 20.11, H 4.10; found C 20.02, H 4.20.
Acknowledgments
We are grateful to the Russian Foundation for Basic Research (Pro-
ject No. 11-03-00641/12) and the Council on Grants of the Presi-
dent of the Russian Federation (Program for State Support of
Leading Scientific Schools of the Russian Federation, Grant
16.120.11.6464-NSH) for financial support.
[1] a) D. C. Billington, The Inositol Phosphates: Chemical Synthe-
sis and Biological Significance, VCH Verlagsgesellschaft,
Weinheim, Germany, 1993; b) B. V. L. Potter, D. Lampe, An-
gew. Chem. 1995, 107, 2085; Angew. Chem. Int. Ed. Engl. 1995,
34, 1933–1972; c) R. F. Irvine, M. J. Schell, Nature Rev. Mol.
Cell Biol. 2001, 2, 327–338; d) S. J. Conway, G. J. Miller, Nat.
Prod. Rep. 2007, 24, 687–707; e) M. J. Berridge, Biochim. Bio-
phys. Acta Mol. Cell Res. 2009, 1793, 933–940; f) J. Duchek,
D. R. Adams, T. Hudlicky, Chem. Rev. 2011, 111, 4223–4258.
[2] a) Y. Chapleur (Ed.), Carbohydrate Mimics: Concepts and
Methods, Wiley-VCH, Weinheim, Germany, 1998; b) N. Asano,
R. Nash, R. Molyneux, G. Fleet, Tetrahedron: Asymmetry
2000, 11, 1645–1680; c) E. J. Chenette, Nat. Rev. Mol. Cell Biol.
2009, 10, 238–239.
Biological Assay: The colorimetric assay according to Itaya et al.
was applied to test the phosphate compounds 15 and 17 as inhibi-
tors of IMPase.[18] Inositol monophosphatase from Bovine brain
was used. The rate determinations were performed at 37.8 °C in
triplicate in assay buffer A containing KCl (300 mmoldm–3),
MgCl2 (2 mmoldm–3), and Tris·HCl (50 mmoldm–3) at pH 7.8. The
colorimetric assay reagent malachite green (1.5 g) was dissolved in
hydrochloric acid (5 moldm–3; 25 cm3) and diluted with water
(750 cm3). Ammonium molybdate (10.5 g) in hydrochloric acid
(5 moldm–3; 225 cm3) was added to this solution, which was stirred
at room temperature for 10 min. The solution was filtered by grav-
ity and stored in the dark. Incubation samples were composed of
assay buffer A (210 mm3), substrate (InsP1) at various concentra-
tions in assay buffer (30 mm3), inhibitor at various concentrations
in assay buffer [30 mm3; in the absence of an inhibitor, this addition
was substituted by assay buffer (30 mm3)] and enzyme solution
(30 mm3). The assay solutions were incubated at 37.8 °C and the
reaction was quenched by the addition of colorimetric assay rea-
gent (2.0 cm3) at the required time (relative to the addition of the
[3] O. Arjona, A. M. Gomez, J. C. Lopez, J. Plumet, Chem. Rev.
2007, 107, 1919–2036.
[4] a) J. Marco-Contelles, E. Opazo, J. Org. Chem. 2000, 65, 5416–
5419; b) F. D. Boyer, I. Hanna, L. Ricard, Org. Lett. 2001, 3,
3095–3098; c) Y. Bleriot, A. Giroult, J. M. Mallet, E. Rodrig-
uez, P. Vogel, P. Sinay, Tetrahedron: Asymmetry 2002, 13, 2553–
2566; d) J. Marco-Contelles, E. Opazo, J. Org. Chem. 2002, 67,
3705–3717; e) P. R. Skaanderup, R. J. Madsen, J. Org. Chem.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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D. A. Khlevin et al.
FULL PAPER
2003, 68, 2115–2122; f) O. Andriuzzi, C. Gravier-Pelletier, P.
Vogel, Y. Le Merrer, Tetrahedron 2005, 61, 7094–7104; g) C.
Ramana, S. Chaudhuri, M. Gurjar, Synthesis 2007, 523–528.
[5] a) R. Patra, N. Bar, A. Roy, B. Achari, N. Ghoshal, S. Mandal,
Tetrahedron 1996, 52, 11265–11272; b) A. Roy, K. Chakrabarty,
P. Dutta, N. Bar, N. Basu, B. Achari, S. Mandal, J. Org. Chem.
1999, 64, 2304–2309; c) J. Marco-Contelles, E. Opazo, J. Car-
bohydr. Chem. 2002, 21, 201–218; d) T. Shing, W. Wong, T.
Ikeno, T. Yamada, Org. Lett. 2007, 9, 207–209; e) T. Shing, W.
Wong, T. Ikeno, T. Yamada, Chem. Eur. J. 2009, 15, 2693–2707.
[6] a) I. Dyong, R. Bonn, Chem. Ber. 1973, 106, 944–955; b) K.
Krohn, G. J. Boerner, Org. Chem. 1994, 59, 6063–6068; c) C.
Gravier-Pelletier, W. Maton, T. Dintinger, C. Tellier, Y.
Le Merrer, Tetrahedron 2003, 59, 8705–8720; d) Y. L. Chen, H.
Redlich, K. Bergander, R. Frohlich, Org. Biomol. Chem. 2007,
5, 3330–3339.
[10] a) X. H. Qian, F. Moris-Varas, M. C. Fitzgerald, C. H. Wong,
Bioorg. Med. Chem. 1996, 4, 2055–2069; b) Y. Le Merrer, L.
Poitout, J. Depazy, I. Dosbaa, S. Geoffroy, M. Foglietti, Bioorg.
Med. Chem. 1997, 5, 519–533; c) G. F. Painter, P. J. Eldridge,
A. Falshaw, Bioorg. Med. Chem. 2004, 12, 225–232; d) H. Li,
Y. Bleriot, C. Chantereau, J. M. Mallet, M. Sollogoub, Y.
Zhang, E. Rodriguez-Garcia, P. Vogel, J. Jimenez-Barbero, P.
Sinay, Org. Biomol. Chem. 2004, 2, 1492–1499; e) H. Li, C.
Schutz, S. Favre, Y. Zhang, P. Vogel, P. Sinay, Y. Bleriot, Org.
Biomol. Chem. 2006, 4, 1653–1662; f) H. Li, T. Liu, Y. Zhang,
S. Favre, C. Bello, P. Vogel, T. Butters, N. Oikonomakos, J.
Marrot, Y. Bleriot, ChemBioChem 2008, 9, 253–260; g) H. Li,
F. Marcelo, C. Bello, P. Vogel, T. Butters, A. Rauter, Y. Zhang,
M. Sollogoub, Y. Bleriot, Bioorg. Med. Chem. 2009, 17, 5598–
5604; h) N. B. Kalamkar, V. M. Kasture, S. T. Chavan, S. G.
Sabharwal, D. D. Dhavale, Tetrahedron 2010, 66, 8522–8526.
[11] a) C. Fauroux, M. Lee, P. M. Cullis, K. T. Douglas, M. G.
Gore, S. Freeman, J. Med. Chem. 2002, 45, 1363–1373; b) D. J.
Miller, R. K. Allemann, Mini-Rev. Med. Chem. 2007, 7, 107–
113.
[7] a) H. Redlich, W. Sudau, A. Szardenings, R. Vollerthun, Car-
bohydr. Res. 1992, 226, 57–78; b) L. Yet, Tetrahedron 1999, 55,
9349–9403; c) J. Marco-Contelles, E. Opazo, Tetrahedron Lett.
2000, 41, 5341–5346.
[8] a) C. Rucker, W. Seppelt, H. Fritz, H. Prinzbach, Chem. Ber.
1984, 117, 1801–1833; b) W. Seppelt, C. Rucker, C. Kaiser, H.
Prinzbach, Chem. Ber. 1984, 117, 1834–1855; c) C. Johnson, A.
Golebiowski, D. Steensma, J. Am. Chem. Soc. 1992, 114, 9414–
9418; d) A. Pearson, K. Srinivasan, J. Org. Chem. 1992, 57,
3965–3973; e) J. Soulie, T. Faitg, J. Betzer, J. Lallemand, Tetra-
hedron 1996, 52, 15137–15146; f) M. Falk-Heppner, U. Hugger,
M. Keller, C. Kaiser, R. Krieger, H. Fritz, H. Prinzbach, Lie-
bigs Ann./Recueil 1997, 1481–1498; g) A. Pearson, S. Katiyar,
Tetrahedron 2000, 56, 2297–2304.
[9] a) H. Johnson, N. Thomas, Bioorg. Med. Chem. Lett. 2002,
12, 237–241; b) S. Pino-Gonzalez, C. Assiego, N. Onas, Targ.
Heterocycl. Syst. 2004, 8, 364–397; c) K. Martınez-Mayorga,
J. L. Medina-Franco, S. Mari, F. J. Canada, E. Rodrıguez-
Garcıa, P. Vogel, H. Li, Y. Bleriot, P. Sinay, J. Jimenez-Barbero,
Eur. J. Org. Chem. 2004, 4119–4129; d) F. Marcelo, Y. He, S. A.
Yuzwa, L. Nieto, J. Jimenez-Barbero, M. Sollogoub, D. J. Vo-
cadlo, G. D. Davies, Y. Bleriot, J. Am. Chem. Soc. 2009, 131,
5390–5392; e) J. Perez-Castells, M. Fontanella, A. Arda, F. J.
Canada, M. Sollogoub, Y. Blériot, J. Jimenez-Barbero, New J.
Chem. 2012, 36, 1008–1013.
[12] a) R. Baker, J. J. Kulagowski, D. C. Billington, P. D. Leeson,
I. C. Lennon, N. J. Liverton, J. Chem. Soc. Perkin Trans. 1
1989, 1383–1385; b) R. Baker, P. D. Leeson, N. J. Liverton, J. J.
Kulagowski, J. Chem. Soc., Chem. Commun. 1990, 462–464; c)
R. Baker, C. Carrick, P. D. Leeson, I. C. Lennon, N. I. Liver-
ton, J. Chem. Soc., Chem. Commun. 1991, 298–300; d) C. M. J.
Faroux, S. Freeman, J. Enzyme Inhib. 1999, 14, 97.
[13] M. J. Berridge, M. D. Bootman, H. L. Roderick, Nat. Rev.
Mol. Cell Biol. 2003, 4, 517.
[14] a) M. Lautens, P. Chiu, J. Am. Chem. Soc. 1997, 119, 6478–
6487; b) M. Lautens, T. Rovis, J. Am. Chem. Soc. 1997, 119,
11090–11091; c) P. Chiu, M. Lautens, Top. Curr. Chem. 1997,
190, 1–85.
[15] D. A. Khlevin, S. E. Sosonyuk, M. V. Proskurnina, N. S. Zefi-
rov, Tetrahedron 2012, 68, 5785–5792.
[16] D. C. F. Law, S. W. Tobey, J. Am. Chem. Soc. 1968, 90, 2376–
2386.
[17] K. L. Yu, B. Fraser-Reid, Tetrahedron Lett. 1988, 29, 979–982.
[18] K. Itaya, M. Ui, Clin. Chim. Acta 1966, 14, 361–366.
Received: October 26, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21426
/KAP1
Date: 04-03-13 11:18:40
Pages: 9
Synthesis of Polyhydroxycycloheptanes and Their Phosphates
Oxabicyclic Carbasugars
New seven-membered cyclitols have been
synthesized from 8-oxabicyclo[3.2.1]oct-
enes by ring-opening followed by dihydrox-
ylation. High enantioselectivity was ob-
served with (R)-BINAP as ligand. The
polyhydroxycycloheptanes thus prepared
were phosphorylated to yield mono- and
tris-phosphates, which can be considered as
homoanalogues of inositol derivatives in-
volved in the signal transduction pathway.
D. A. Khlevin,* S. E. Sosonyuk,
M. V. Proskurnina, N. S. Zefirov ...... 1–9
Stereoselective Synthesis of Polyhydroxy-
cycloheptanes and Their Phosphate De-
rivatives from 8-Oxabicyclo[3.2.1]octenes
Keywords: Cyclitols / Carbasugars / Phos-
phorylation / Dihydroxylation / Inhibitors /
Enantioselectivity
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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