Method for the production of D-chiroinositol

The invention relates to the synthesis of D-chiro-inositol from glucodialdose comprising the steps of condensing glucodialdose by a acylon condensation reaction, protecting the carbon atoms of the 1,2,5 and 6 position, epimerizing the protected carbon atom at position 5, reducing the ketone of the condensed compound and removing the protect groups.

FIELD OF THE INVENTION 
A lack of D-chiroinositol, DCI, one of nine stereoisomers of the inositol 
series, has been implicated in the etiology of insulin resistant diabetes 
or non-insulin dependant diabetes mellitus (NIDDM). When DCI has been 
administered to animal models of diabetes it has been shown to lower blood 
glucose and insulin levels. Use of DCI as a therapeutic agent in the 
treatment of NIDDM and the insulin resistant condition is expected to 
service a significant segment of the population. This invention relates to 
a de novo synthesis of DCI of a quantity and quality suitable for 
pharmaceutical use. There have been several syntheses reported for DCI. 
Unfortunately, the most efficient methodologies are not appropriate for 
this purpose. 
In addition to DCI, the stereospecific synthesis of myoinositol and its 
phosphate(s), an important class of compounds involved in secondary 
cellular signalling, have proven to be laborious. This invention is also 
useful in the applied stereospecific syntheses of myoinositol derivatives 
and other inositol isomers. These inositol derivatives should be 
applicable to syntheses of higher order carbohydrates as well. 
BACKGROUND OF THE INVENTION 
DCI has shown promise as a therapeutic agent to treat insulin resistance 
and those conditions associated with the disease such as NIDDM. Studies on 
primate models indicate that 1 gram per day is a reasonable dose upon 
which to base initial forecasts. There are 14 million diagnosed NIDDM 
patients in the United States. It is estimated that 20% of the general 
population is genetically predisposed to insulin resistance and therefore 
it is expected that daily manufacturing capacities for DCI will need to 
approach megagram quantities. 
DCI can be isolated in kilogram quantities from natural sources. One of 
these sources is the California sugar pine. It has been shown that a 15 
weight percent of pinitol (the 3-0 methyl ether of DCI) can be extracted 
from the sawdust of this tree's stump. Pinitol can easily be converted to 
DCI in quantitative yield. With a yield of 1 kg/stump, an estimated 35 
million stumps per year will be needed to supply the United States market 
demand with DCI (this calculation does not incorporate the fact that the 
stump ideally should be aged 5 years or more). Therefore, it is unlikely 
that the projected demand of DCI will be satisfied through this source. 
DCI is also 40% of the antibiotic kasugamycin and is easily cleaved and 
purified from the antibiotic. Sources for kasugamycin have yet to prove to 
be economical. Attempts to produce a viable strain of S. kasugaensis 
either by natural selection techniques or fermentation process 
modifications have yet to yield a desirable result. 
There have been several reported syntheses of chiroinositol (or its easily 
converted methyl ether) and they either entail a series of exhaustive 
protection/deprotection steps or fail to give the pure D-chiro isomer in a 
reasonable fashion. Martin-Lomas, et. al., reported a synthesis of 
1-0-methyl-D-chiroinositol from methyl glucopyranose (compound 1) 
utilizing the well-known Ferrier rearrangement. This approach required 
that the glucose molecule be subjected to a 4-step protection sequence 
leading to compound 2 which when rearranged yielded the key intermediate 
compound 3. Converting compound 3 to 1-0-methyl-D-chiroinositol involved 
four synthetic steps. Demethylation, as described above, would require an 
additional step for a total synthesis of DCI in 10 steps. 
Ozaki and coworkers devised an approach to DCI starting from 
glucuronolactone (a.k.a. glucurone, compound 4). This synthesis involves a 
total of 17 steps, involving seemingly unnecessary manipulations and 
utilizes exotic reagents such as titanium tetrachloride which is the key 
reagent in the sequence shown in entry 2 of FIG. 1. In 1990, Shen and 
coworkers synthesized DCI from myoinositol by selectively epimerizing the 
3-D position of myoinositol as shown in entry 3 of FIG. 1. This was done 
in 5 steps, however, one of the steps yielded a relatively small amount of 
product and another step involved a labor intensive separation of 
diastereomers. 
The last two syntheses of DCI (entry 4 of FIG. 1) reported are similar in 
that the key step is a Pseudomonas putida oxidation of benzene) which 
generates a meso compound) or chlorobenzene (which generates an optically 
active compound) to the cyclohexadienediol derivatives 10 and 11. Hudlicky 
imparted a novel approach to convert 11 to DCI in 4 steps for a total of 5 
steps; the final product, however, was contaminated with alloinositol, 
another of the nine isomers of inositol.

DETAILED DESCRIPTION OF THE INVENTION 
A novel methodology to synthesize inososes has been developed wherein a 
previously unknown intramolecular thiazolium acyloin condensation is 
utilized. The advantage is that the use of the thiazolium salt allows the 
acyloin condensation to occur without the need for anhydrous conditions or 
the use of hazardous and expensive reagents such as sodium metal. A 
thiazolium salt catalyzed intramolecular acyloin condensation (analogous 
intermolecular reactions have been reported), and a new method for 
preparing inosose are disclosed. 
Conversion of glucurone (compound 4) into glucodialdose in quantitative 
yield has been reported. Dahalloff, W. V. et al., Synthesis, 1982 pp. 
650-52. Application of the thiazolium catalyzed acyloin condensation as 
shown in FIG. 2 results in inososes 27 and 28. Formation of 29 and 30 
adopt the relatively unstable diaxial configuration. When inososes 
compounds 27 and 28 are protected as the diacetonide the major products 
are compounds 31 and 32, respectively. 
Refluxing an aqueous mixture of myoinositol and Raney nickel (Sasaki, K. et 
al., carbohydrate Research, 1987 vol. 166, pp. 171-80) or treating 
scylloinosose with mild aqueous base yields a mixture of myoinositol, 
chiroinositol and scylloinositol (plus the other 5 inositols in very low 
combined yield). The stereoselectivities observed in these reactions are 
presumably due to the fact that the isomers have adopted the preferred 
cis-trans configurations about the ring under thermodynamic conditions--a 
phenomenon most easily understood by recognizing that scylloinositol is 
the only isomer of the inositol series which is all-trans. In base 
catalysis, equilibrium is achieved through repetitive deprotonation and 
protonation from the carbon alpha to the carbonyl carbon until the system 
is thermodynamically stable, whereas in Raney nickel catalysis, similar 
effects are realized through a ketone reduction--alcohol oxidation 
equilibration sequence. Combining both equilibrium conditions in one 
experiment and imparting these conditions to compound 12 results in a 
mixture of myoinositol, D-chiroinositol and scylloinositol with little or 
no alloinositol present. 
Subjecting compounds 31 and 32 to mild base followed by refluxing the 
compounds in Raney nickel in mild base transforms the molecules such that 
the major product is compound 21 which can be hydrolyzed to remove the 
protective groups, thereby generating DCI. Positions 1 and 6 are 
unaffected under these conditions, are thereby chemically anchored and 
thus dictate the stereochemistry of positions 2 and 5, respectively. (For 
purposes of this application, the numbering system for DCI is applied to 
its inosose precursors, which may be considered pro-DCI.) Since cis 6-5 
fused ring dioxanes are more stable than the trans conformers, these 
positions should become cis to positions 1 and 6 and position 5 is duly 
epimerized. Positions 2 and 5, in turn, dictate the stereochemistry of 
positions 3 and 4 which should adopt a trans conformation, respectively. 
In conclusion, Raney nickel and base preferably yields chiroinositol since 
chemically anchoring strategic positions will preclude the formation of 
the myo- and scyllo- isomers. It should be noted that by starting with 
D-glucurone, L-chiroinositol formation is also precluded. 
This total synthesis of DCI is shown in FIG. 3 and is done in 4 steps. It 
may be reduced to a one pot synthesis if one uses the boron protecting 
groups in step 1 to carry into the subsequent steps as shown in FIG. 4.