Desymmetrization of 4,6-diprotected myo-inositol

Article abstract of DOI:10.1039/c3cc43663b

The asymmetric desymmetrization of 4,6-diprotected myo-inositol derivatives was achieved by using a bifunctional, readily available nucleophilic catalyst. The orthogonally protected products were obtained in 80-99% yield with 90-99% ee. Such structures serve as potential enantiopure building blocks for the synthesis of myo-inositol phosphates.

Full text of DOI:10.1039/c3cc43663b

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Desymmetrization of 4,6-diprotected myo-inositol†
Markus B. Lauber,a Constantin-Gabriel Daniliucb and Jan Paradies*a
Cite this: Chem. Commun., 2013,
49, 7409
Received 15th May 2013,
Accepted 26th June 2013
DOI: 10.1039/c3cc43663b
www.rsc.org/chemcomm
The asymmetric desymmetrization of 4,6-diprotected myo-inositol
derivatives was achieved by using a bifunctional, readily available
nucleophilic catalyst. The orthogonally protected products were
obtained in 80–99% yield with 90–99% ee. Such structures serve as
potential enantiopure building blocks for the synthesis of myo-
inositol phosphates.
Chart 1 Protected myo-inositol derivatives.
Phosphatidyl inositol phosphates are biologically ubiquitous
molecules, which serve as building blocks in membranes and However, other substitution patterns22 require alternative com-
take part in cell signalling and regulation events.1–4 Naturally mon intermediates. A suitable candidate for such a task is the
occurring inositol phosphates display various substitution patterns 3-benzoylated, orthogonally protected myo-inositol derivative 3.
(higher degree of phosphorylation of inositol at C1 to C6), which Here the carbinols C1, C2 and C5 can be selectively addressed.
are constantly modified in biological processes by enzymes, such This intermediate might be obtained by asymmetric desymme-
as kinases and phosphatases, during signalling.2–4 In depth trization of the readily accessible precursor meso-4 by enantio-
structure–activity relationship studies are dramatically limited selective acylation26,27 in the presence of a nucleophilic catalyst.
since inositol concentrations in biological systems are at the In this report we present the enantioselective desymmetrization of
detectable limit and do not allow for isolation. The full synthetic 4,6-protected myo-inositol derivatives in excellent yields, which are
access to this material is laborious since tedious protecting highly valuable phosphorylation precursors and building blocks
group transformation and separation of diastereomers are for the synthesis of enantiopure myo-inositol phosphates.
required.5–12 Only recently the first solid phase supported
The readily available phosphinit catalyst 5 (see Table 1) has
synthesis of myo-inositol phosphates13 has been described, but been successfully applied in the asymmetric desymmetrization
the access to suitable enantiopure, orthogonally protected inositol of meso 1,2-diols with benzoic acid chloride (6) providing the
precursors in synthetically useful amounts is limited. An efficient products in high yield with high enantioselectivity.28 We anti-
process for the organocatalytic asymmetric desymmetrization14 of cipated that the asymmetric acylation of 4a would occur selec-
myo-inositol (1) was developed by Miller.15–22 A key requirement tively on the C1 or C3-carbinol29,30 since cooperative substrate
for the highly enantioselective phosphorylation is the protection activation/recognition by the nucleophilic and the Brønsted-
of carbinol C2 in 2 (Chart 1) and the application of a tetrapeptide basic site was assumed earlier.28 We initiated our investigation
as a nucleophilic catalyst.20,23–25 This methodology is an elegant with the synthesis of the three derivatives 4a–c according to
entry to a variety of 3-phosphorylated myo-inositol derivatives. a three step synthesis from commercially available starting
materials. Myo-inositol (1) was converted into the ortho-ester
7
31 and selectively protected on carbinol C4 and C6 in only one
a Karlsruhe Institute of Technology, Institute for Organic Chemistry,
Fritz-Haber Weg 6, Germany. E-mail: jan.paradies@kit.edu;
step (7 - 8, Scheme 1).32,33 Subsequent cleavage of the ortho-
ester liberated the precursors 4a–c for the desymmetrization
step in excellent yields (90–99%).
Fax: +49 721-608 45637; Tel: +49 721 608 45344
b
¨
¨
University of Munster, Corrensstrasse 40, Munster, Germany.
E-mail: constantin.daniliuc@uni-muenster.de; Fax: +49 251 83-39772;
Tel: +49 251 83-33293
Next we turned our attention to the desymmetrization of 4a.
Indeed, when 5 (30 mol%) was subjected to the reaction of 4a
with benzoic acid chloride (6) in the presence of iPr2NEt as a
base at 0 1C in CH2Cl2 the benzoylation product 3a was obtained in
70% yield with an enantiomeric excess of 60% (Table 1, entry 1).
† Electronic supplementary information (ESI) available: Synthetic procedures and
analytical data; X-ray crystal structure data for 9 CCDC 938831, 4a 938829,
4c 938830. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc43663b
c
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Table 1 Desymmetrization of 4aa
Scheme 2 Derivatization of 3a for determination of the absolute configuration;
X-ray crystal structure of 9 (selected hydrogen atoms were omitted for clarity).
Temp. Cat. loading Time Yieldb Enantiomeric
Entry Solvent
[1C]
[mol%]
[h]
[%]
excessc [%]
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
Toluene
DMF
Acetonitrile
Propionitrile
Propionitrile À78
Propionitrile À78
Propionitrile À78
Propionitrile À78
Propionitrile À78
Propionitrile À78
0
30
30
30
30
30
30
30
20
10
2
5
5
5
5
5
70
75
40
0
88
72
94
99
74
26
72
65
60
80
87
—
81
87
99
99
97
96
99
97
0
0
0
0
0
5
24
24
24
24
48
48
9
10
11d
12d
Scheme 3 Benzoylation of 2-allylated myo-inositol derivative 11.
20
10
a
b
Reactions were performed on a 0.1 mmol scale of 4a. Yield after
The second benzoylation was found at carbinol C1. Con-
sequently the first catalyzed asymmetric esterification was achieved
at carbinol C3, which led to the enantioselective formation
of (1R, 2S, 3S, 4S, 5R, 6S)-3-o-benzoyl-4,6-di-o-benzyl-myo-
inositol (3a).
c
purification by column chromatography. Enantiomeric excess deter-
mined by HPLC with a chiral stationary phase (Chiralpak OD). The
d
reaction was performed on a 1.38 mmol scale.
From a mechanistic view, the lack of reactivity in the strongly
polar solvent DMF suggests that ion-pairing and hydrogen-bonding
is important for the product-formation and enantioselectivity
(Table 1, entry 4). This hypothesis is supported by the observa-
tion of the diminished enantioselectivity when carbinol C2 was
protected. The reaction of 2-allylated myo-inositol 11 with
benzoyl chloride (6) under identical reaction conditions pro-
vided only a somewhat enantioenriched product 12 (15% ee)
with slightly diminished yield (Scheme 3). This demonstrates
that the interaction of the quinuclidine-fragment in the
benzoylated catalyst at the phosphorous with the OH-group of
C2 is essential for high enantioselectivity.
Scheme 1 Synthesis of 4,6-diprotected myo-inositols 4a–c.
Finally we investigated the scope of the methodology.
Protecting groups other than benzyl offer a highly flexible
approach to enantiopure myo-inositol derivatives. Therefore we
subjected 4,6-bis-(4-methoxy-benzyl) and 4,6-allyl substituted
myo-inositol derivatives 4b and 4c to asymmetric benzoylation
(Scheme 4). The chiral products 3b and 3c were produced in high
yield with excellent enantioselectivity (90–99% ee) under identical
reaction conditions to those for 3a. This renders the presented
approach as a reliable tool for the synthesis of orthogonally
3,4,6-protected enantiopure myo-inositol derivatives which serve as
highly valuable starting materials for the synthesis of biologically
active compounds.
Chloroform, toluene and acetonitrile proved to be viable solvents
for the reaction (entries 2–5), but the best balance between the
yield and the enantiomeric excess was achieved with propio-
nitrile as a solvent (entry 6). The efficiency of the reaction was
significantly improved when performed at À78 1C for 24 h. The
product was obtained in high yield (94%) with an excellent
enantiomeric excess of 99% (entry 7). The catalyst loading was
reduced to 20 mol% without loss of reactivity or enantio-
selectivity (entry 8). A successive decrease in the catalyst loading
from 20 mol% to 2 mol% resulted in a significant decrease
in chemical yield without loss of enantioselectivity (entries 9
and 10). The synthetic practicability of this methodology was
demonstrated by the desymmetrization of 0.50 g (1.38 mmol)
4a with two different catalyst loadings (entries 11 and 12). In both
cases the enantiopure product 3a was obtained with excellent
enantiomeric excess (99% ee (20 mol%) and 97% ee (10 mol%))
with only marginally differing yields (72% and 65% yield).
For the determination of the absolute configuration enantio-
pure 3a was converted to 9 by reaction with 4-bromobenzoic acid
chloride (10). The absolute configuration of 9 was established
using X-ray crystal structure analysis (Scheme 2).‡
Scheme 4 Desymmetrization of 4-methoxy-benzyl- and allyl-protected myo-
inositol derivatives.
c
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metrization of 4,6-diprotected myo-inositol derivatives by acyl-
ation. The nucleophilic catalyst (one step) as well as the starting
materials (three steps) are readily accessible from commercially
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‡ X-ray crystal structure analysis 9: formula C34H31BrO8 Â 2H2O, M =
683.53, colourless crystal, 0.28 Â 0.23 Â 0.23 mm, a = 11.9744(2), b =
8.0367(2), c = 17.1372(3) Å, b = 108.858(1)1, V = 1560.67(2) Å3, rcalc
=
1.455 g cmÀ3, m = 1.376 mmÀ1, empirical absorption correction
(0.699 r T r 0.742), Z = 2, monoclinic, space group P21 (no. 4), l =
0.71073 Å, T = 223(2) K, o and j scans, 8893 reflections collected
(Æh, Æk, Æl), [(sin y)/l] = 0.67 ÅÀ1, 4744 independent (Rint = 0.021) and
4550 observed reflections [I > 2s(I)], 439 refined parameters, R = 0.031,
wR2 = 0.070, max. (min.) residual electron density 0.17(À0.21) e ÅÀ3
,
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water molecule (O71, O72 and O72A) were refined freely, but with O–H
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c
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Chem. Commun., 2013, 49, 7409--7411 7411