Acarbose synthesis

Likewise, complete synthesis of acarbose was conveniently accomplished by use of the anhydro derivative 392b prepared from maltotriose. Condensation of 392b with optically active 359 afforded two products, one of which was, after deprotection, shown to be identical to an authentic sample of acarbose. 

The main synthetic challenge in a synthesis of -acarbose is the attachment of the polyhydroxylated cyclohexene unit, by a nitrogen atom, to the 6"-deoxy trisaccharide. If one accepts that molecular ammonia is not likely to be the ideal reagent to link the cyclohexene and trisaccharide units together, then one also realizes that only two approaches are left either a trisaccharide amine may be attached to a cyclohexene unit or, conversely, a cyclohexenyl amine may be joined to a trisaccharide. 

It would, in principle, be possible to convert the polyol 115 into the 6"-deoxy sugar 118, a direct precursor of /3-acarbose. However, we decided that it would be better to reassess the whole synthesis and reasoned that a 1,6-epithio sugar such as 119 would be an ideal pivot for a synthesis of acarbose the amine 81 could easily be introduced at C-4, the sulfur at C-1 allows for activation to produce a glycosyl donor ready for attachment to the disaccharide alcohol 113 and, finally, desulfurization at C-6 leads to the necessary methyl group. 

The bicyclic sugars 121 and 128-130 should all be capable of some sort of chemical activation to produce glycosyl donors. To date, we have investigated just the related sulfide 133. Treatment of 133 with a range of alcohols, 134-138, in the presence of N-iodosuccinimide and triflic acid, has given rise to intermediate disulfides, e. g. 139 in good yield and capable of reduction (Ra/Ni) to the 6,6 -dideoxy /3-disaccharide 140 [66]. This is truly an excellent result in terms of a direct synthesis of -acarbose. 

Exogenous insulin or insulinotropic oral agents such as sulphonylureas are not suitable for improving insulin resistance. Non-insulinotropic hypoglycaemic medication such as biguanides and/or acarbose, however, is recommended if diet alone fails to achieve sufficient metabolic control. It is still controversial, however, whether the reduction of endogenous insulin also reduces the synthesis of islet amyloid polypeptide (IAPP) sufficiently to slow down the progression of NIDDM (Clark et al., 1987). 

Acarviosin 441, an a-glycosidase inhibitor, is a maltose-type pseudodisaccharide that can be prepared from methanolysis of acarbose 442 [255]. It has been shown to have five times more inhibitory activity than its precursor acarbose, for which the first total synthesis has been described by Ogawa s group in 1989 [256]. 

Ogawa, S., Shibata, Y. (1988). Total synthesis of acarbose and adiposin-2, J. Chem. Soc., Chem. Commun., p. 605. 

A total synthesis reported for the pseudo-tetrasaccharide oc-gluc-osldase inhibitor acarbose and its hydroxylated analogue adiposin involved converting 1,6-anhydromaltotriose into 3",4"-anhydro analogues which were then condensed with 4,7 5,6-di-0-isopropylidene-valienamine.A synthesis of dihydroacarbose is referred to in Chapter 4. 

A new and exciting application to the synthesis of branched cyclodextrins has recently been reported, whereby acarbose (68), the known potent inhibitor of glu-coamylase, has been tethered to a cyclodextrin via flexible spacers of different length [46]. The functionalized spacers (69 and 70) were S-deacetylated and the corresponding thiolates coupled easily to 6-deoxy-6-iodocyclodextrin (53), affording the branched fully acetylated cyclodextrins 71 (76%) and 72 (64%), respectively. 

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