Practical synthesis of a differentially protected myo-inositol

Article abstract of DOI:10.1016/S0957-4166(98)00302-4

An enantiospecific synthesis of 3,4,5-tri-O-benzyl-6-O- triisopropylsilyl-D-myo-inositol from D-xylose is reported. The synthesis features a diastereofacially selective SmI₂-promoted pinacol cyclization.

Full text of DOI:10.1016/S0957-4166(98)00302-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2783–2786
Practical synthesis of a differentially protected myo-inositol
Alexander Kornienko, David I. Turner, Christine H. Jaworek and Marc d’Alarcao ∗
Michael Chemistry Laboratory, Department of Chemistry, Tufts University, Medford, MA 02155, USA
Received 8 July 1998; accepted 20 July 1998
Abstract
An enantiospecific synthesis of 3,4,5-tri-O-benzyl-6-O-triisopropylsilyl-D-myo-inositol from D-xylose is
reported. The synthesis features a diastereofacially selective SmI2-promoted pinacol cyclization. © 1998 Elsevier
Science Ltd. All rights reserved.
The rich biochemistry of inositol phosphates identified as second messengers in a variety of cellular
signal transduction systems has stimulated intense interest in these compounds and their analogs.1
Consequently, extensive efforts have been made toward the preparation of differentially protected,
enantiomerically pure myo-inositol derivatives. Of these, D-myo-inositol derivatives orthogonally pro-
tected at positions (1,2), (6), and (3,4,5) as in compound 1 are of special interest for the synthesis of
inositol phosphate glycans (IPGs) implicated in insulin signal transduction.2
Four general synthetic strategies have been employed in the synthesis of differentially protected
myo-inositols. The most frequently used are the procedures starting from parent achiral myo-inositol.3
Although this strategy provides a wide array of differential protection schemes, the major drawbacks
include tedious manipulations of the many hydroxyl groups and the necessity of enantiomeric resolution.
Other strategies which circumvent some of these difficulties are the syntheses based on microbial oxida-
tion of aromatic compounds4 and derivatization of naturally occurring enantiomerically pure cyclitols.5
In addition, approaches utilizing other readily available, enantiomerically pure starting materials such
as glucose,6 mannitol,7 diethyltartrate,8 quinic acid9 and dehydroshikimic acid10 have been reported. In
view of the practicality of the latter, we sought to utilize this strategy for the preparation of an inositol
precursor suitable for use in the synthesis of IPGs. We report herein a new enantiospecific synthesis of
compound 1 from D-xylose.
We recently reported a synthesis of a differentially protected L-chiro-inositol11 wherein 2(S),3(R),4(S)-
tribenzyloxyhex-5-enal, prepared in five steps from D-xylose, was treated with vinylmagnesium bromide
in the presence of 3 equiv. of MgBr2·OEt2 in CH2Cl2 to give a 1:8 mixture of syn and anti alcohols
2a and 2b (Scheme 1). Further experimentation allowed us to reverse the selectivity to 3:1 favoring
2a by performing the reaction in the absence of MgBr2·OEt2 in CH2Cl2:THF (5:1) solvent pair. The
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00302-4

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A. Kornienko et al. / Tetrahedron: Asymmetry 9 (1998) 2783–2786
crude mixture of the diastereomeric alcohols was treated with triisopropylsilyl chloride in DMF–py in
the presence of AgNO3 and the resulting TIPS-protected derivatives 3a and 3b were separated by silica
gel chromatography eluting with hexane:ether, 24:1 (61% for 3a over two steps).
Scheme 1.
Ozonolysis of 3a gave 4, which was subjected to SmI2-mediated reductive ring closure to produce
myo-inositol derivatives 1 and 5 in >20:1 ratio.12 The diols could be conveniently separated by column
chromatography eluting with CH2Cl2:benzene:ethyl acetate (50:50:3)13 providing 1 in 67% isolated yield
(from 3a).
The exclusive formation of cis-diols in this reaction is not surprising and has been amply precedented
in cyclitol syntheses utilizing this technology in a six-membered ring construction step.7,8,14 However,
the face selectivity is noteworthy. The previously reported methodologies have employed either C2-
symmetric dialdehydes similar to 67,8,14a–c (Fig. 1), where the face discrimination is inconsequential, or
asymmetric dialdehydes similar to 8,11,14c,d where the face selection is controlled by the two adjacent
alkoxy substituents both oriented trans to the incipient hydroxyl groups. Type 8 dialdehydes do not
produce myo-inositols, whereas the dialdehydes of type 6 result in less versatile protection schemes.
The SmI2 reaction of 4 is, to the best of our knowledge, the first example of a face-selective pinacol
coupling resulting in a myo-inositol.
1
The structure of 1 was established by H NMR and confirmed by an independent synthesis of
10 starting from unprotected myo-inositol. The enantiomeric identity of 10 from each source was
demonstrated by conversion to the Mosher ester 12 (Scheme 2). Compound 12 prepared via 1 was
identical to that prepared via 1115 by mixed TLC, 1H and 19F NMR.
To confirm unequivocally the structure of 5, the mixture of 5 and 1 obtained in a reaction quenched at
room temperature12 was desilylated (TBAF, THF, 2 h, 90%) and exhaustively benzylated (BnBr, DMF,
NaH, rt, 2 days, 85%) to give a single compound, hexabenzyl-myo-inositol (established by TLC and
Fig. 1.

A. Kornienko et al. / Tetrahedron: Asymmetry 9 (1998) 2783–2786
2785
Scheme 2.
1H NMR analyses). The preparation of a single mono-Mosher ester of 5 demonstrated its enantiomeric
integrity.
The synthesis of the differentially protected and enantiomerically pure myo-inositol derivative 1 is
relatively short and requires only three facile chromatographic purifications starting from inexpensive D-
xylose. It could be further extended for the preparation of the enantiomer of 1 provided that commercially
available L-xylose is used as a starting material. We believe that this method will be applicable for the
preparation of a variety of myo-inositol containing compounds.
Acknowledgements
We are grateful to Professor James Panek and his group for assistance with the ozonolysis reaction and
to the National Institutes of Health for financial support.
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