Inositol synthesis: Concise preparation of L-chiro-inositol and muco- inositol from a common intermediate

Article abstract of DOI:10.1016/S0957-4166(98)00182-7

Fully stereoselective large-scale syntheses have been attained for L- chiro-inositol (2) and muco-inositol (3) by means of controlled peripheral oxygenation of cyclohexadiene diol 1.

Full text of DOI:10.1016/S0957-4166(98)00182-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2011–2014
Inositol synthesis: concise preparation of L-chiro-inositol and
muco-inositol from a common intermediate
Larry E. Brammer Jr. and Tomas Hudlicky∗
Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Received 3 March 1998; accepted 22 April 1998
Abstract
Fully stereoselective large-scale syntheses have been attained for L-chiro-inositol (2) and muco-inositol (3) by
means of controlled peripheral oxygenation of cyclohexadiene diol 1. © 1998 Elsevier Science Ltd. All rights
reserved.
Developing a general protocol for the preparation of all nine isomeric inositols in a practical fashion
has comprised a significant part of our program for the last few years. Motivated by the medicinal value
of certain inositol phosphates,1 for which the parent compounds or, more importantly, their homochiral
precursors would serve as intermediates, we formulated a general strategy of synthesis based on the
peripheral oxygenation of the diene diol 12 derived from the biooxidation of bromobenzene.3
Previous efforts in this area from our laboratory included a medium-scale three-step synthesis of
D-chiro-4 and allo-inositol,5 as well as the preparation of neo-inositol6 and both enantiomers of pinitol.3
In addition to several conduritols7 and conduramines8,9 many other syntheses of natural products have
been attained; these are summarized in several recent reviews.10 In this communication we report a fully
stereoselective total synthesis of L-chiro-inositol11 and an efficient total synthesis of muco-inositol.12 For
the preparation of the latter compound we have taken advantage of ‘chemically redundant’ opening of
diastereomeric epoxides leading to the same isomer of a trans-diol.
Diol 1 was obtained in a yield of 10 g/L by exposing bromobenzene in a 15 L fermentor to E. coli
JM109 (pDTG601) cells grown on a glucose medium with i-propylthiogalactopyranoside as an inducer.13
∗
Corresponding author. E-mail: hudlicky@chem.ufl.edu
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00182-7

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L. E. Brammer Jr., T. Hudlicky / Tetrahedron: Asymmetry 9 (1998) 2011–2014
Protection and epoxidation of 1 afforded epoxide 414 in 96% yield from diol 1, with this sequence
performed on a 40 g scale (Scheme 1). Regio- and stereoselective opening was accomplished with dilute
aqueous hydroxide in 87% yield (for 5) and with excess benzyl alcohol in 85% yield (for 6), respectively.
In both cases the crude reaction mixtures were subjected to dehalogenation (n-Bu3SnH/AIBN) to
provide trans-diol 5 and benzyl ether 6 in 90% and 78% yield, respectively. Benzyl ether 6 was
subjected to osmylation (75%) followed by acid-catalyzed deprotection to furnish pentol 8 in 79% yield.
Hydrogenation of this material on 10% Pd(C) furnished L-chiro-inositol in 81% yield (30% overall from
4 for the five-step sequence). The entire sequence was carried out on a scale of 40 g of diol 1, with
only two purifications necessary, chromatography following osmylation and recrystallization of the final
product.
Scheme 1.
The trans-diol 5 was subjected to epoxidation with m-CPBA to provide a mixture of α- and β-epoxides
7a and 7b in a 1:1.8 ratio and in 71% yield. In contrast, oxidation of benzyl ether 6 under the same
conditions produced a 53% yield of α- and β-epoxides 9a and 9b in a 3.6:1 ratio. The contrasting product
ratios resulting from the epoxidations of 5 and 6 can be explained based on the nature of the substituent
present on the allylic oxygen.
The mixture of epoxides produced from the oxidation of 5 resulted from the apparent competition
between the syn-directing effect of the free allylic hydroxyl and the hindering effect of the acetonide
moiety, with the former predominantly controlling the ratio of epoxides. The syn-directing effect
is eliminated in 6 through replacement of the allylic hydroxyl group with a benzyl ether. Steric
hindrance thus becomes the determining factor in the ratio of α- and β-epoxides produced and results in
predominance of the α-epoxide.

L. E. Brammer Jr., T. Hudlicky / Tetrahedron: Asymmetry 9 (1998) 2011–2014
2013
Table 1
Inositol syntheses from aromatic precursors
Literature precedent,15 as well as our previous experience in the regiospecific opening of conduritol
epoxides of type 7 which are similar to the intermediates employed in the pancratistatin synthesis,16
indicated that hydrolysis of these diastereomers should proceed in a chemically redundant17 manner
to afford a single isomer of the trans-diol by the expected trans-diaxial attack of the nucleophile.18
This finding is of enormous value to the planning and execution of inositol syntheses as it allows for
non-stereoselective epoxidations whose final conversions to the desired trans-diol proceed to a single
isomer. The conditions employed in the hydrolysis of epoxides also led to the concomitant deprotection
of the acetonide providing pure muco-inositol in 89% yield from 7a (45% overall yield from 4) and
78% yield from 7b (40% overall yield from 4). The epoxides were not separated during the large-
scale (>20 g) synthesis of muco-inositol but rather treated as a mixture under conditions identical to
those used in the conversion of 7b. In this fashion a 75% yield of a 16:1 mixture of muco- and myo-
inositol was achieved. These diastereomers were readily separable by recrystallization from mixtures of
2-propanol/water (70/30).
The synthesis of muco-inositol described here apparently proceeded without the previously reported
Payne rearrangement of hydroxy epoxides of this type.5 It is superior in yield to the synthesis previously
reported in 1993 (45% versus 10%). The current status of our quest for all nine inositols is summarized
in Table 1. Further endeavors that include preparation of selected inositol phosphates and various inositol
conjugates and oligomers will be reported in due course.
Acknowledgements
The authors are grateful to the National Science Foundation (CHE-9615112), the US Environmental
Protection Agency (R826113), and TDC Research, Inc., for financial support of this work.
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