A diastereocontrolled synthesis of perseitol using a dioxabicyclo[3.2.1]octane chiral building block

A diastereocontrolled route to the naturally occurring heptiol, perseitol (D-glycero-D-galacto-heptiol) isolated as a complex with K + ion from leaves of Scurrula fusca (Loranthaceae), has been developed starting from a chiral building block containing a 7,8-dioxabicyclo[3.2.1]octane framework.


Introduction
The leaves of a parasitic plant Scurrula fusca (BL.)G. Don.(Loranthaceae), whose host-plant is Ficus riedelli MIQ.(Moraceae), are used as the traditional folk medicine for the treatment of cancer in Sumatra and the Sulawesi Islands, Indonesia. 1 From the methanol extract of the dried leaves, perseitol (D-glycero-D-galacto-heptiol) (1) has been isolated as a complex with K + ions, and this complex has recently been shown to exhibit a potent inhibitory effect on [ 3 H]-leucine incorporation for protein synthesis on Ehrlich ascites tumor cells in mice. 2 Intriguingly, it was found that complexation of 1 with K + ion in a molar ratio of 20:1 is essential for expression of the anti-tumor activity.2c Although perseitol is known as a naturally occurring heptitol, first isolated from avocado, 3 and several preparative methods for perseitol have been developed, 4 no stereocontrolled synthesis capable of producing 1 in complete enantio-and diastereo-controlled manner has yet been reported.Since we have developed an efficient preparation from furfural of the highly functionalized bicyclic enone 2 having the 7,8-dioxabicyclo[3.2.1]octane framework, in both enantiomeric forms, by employing either chemical 5 or enzymatic procedures, 6 and since we have demonstrated its potential 7 as a versatile chiral building block, 8 especially for carbohydrates, 9 we decided to attempt the diastereo-controlled construction of perseitol in its naturally occurring form, utilizing 2 to extend its versatility (Scheme 1).

Results and Discussion
The synthesis commenced with the reaction of the (+)-enone (+)-2 9 with alkaline hydrogen peroxide.The reaction proceeded diastereoselectively from the convex face to give the exoepoxide 3 in 75% yield.The epoxide 3 was next exposed to hydrazine hydrate in the presence of acetic acid 10 to give the allylic alcohol 4 in 60% yield, which furnished the enone 5 in 72% yield after PCC oxidation. 5The enone 5 was treated with sodium hypochlorite in pyridine to give the exo-epoxide 6, again in a completely diastereoselective fashion, which was sequentially reduced to the endo-alcohol by employing Luche's protocol, 11 and benzoylated to give the endo-benzoate 7 in 52% yield from 5. Upon exposure of 7 to boron trifluoride etherate, the benzoate-assisted regio-and diastereo-selective epoxide cleavage 12 occurred, presumably through the transient oxonium intermediate 8, to afford the single triol 9 in 65% yield after alkaline methanolysis of the mono-benzoate mixture (Scheme 2).
Having constructed the required five contiguous stereocenters for perseitol on the sevencarbon backbone of the building block, the only remaining tasks were the removal of the protecting group and reductive cleavage of the cyclic acetal moiety to unfold the bicyclo[3.2.1]octane structure.The benzyl group of 9 was smoothly cleaved hydrogenolytically on a Pd-C catalyst to give the tetraol, 10.Although hydrolysis of the acetal moiety buried in the 7,8-dioxabicyclo[3.2.1]octane framework of 10 was quite sluggish under conventional conditions, i.e., 90% CF 3 CO 2 H, or reflux in 1M HCl, heating of an aqueous solution of 10 in the presence of the cationic ion-exchange resin Dowex-50W (H + form) in a sealed tube at 150 °C allowed smooth reaction to afford the hemiacetal 11 in 63% yield at best, together with 31% of recovered, unchanged 10.Finally, reduction of 11 with NaBH 4 furnished perseitol (1), which was fully characterized as the hepta-acetate 12.

Conclusions
We have established a diastereocontrolled synthesis of perseitol (D-glycero-D-galacto-heptiol) (1) starting from the (+)-enone, 2, on the basis of its inherent diastereoselectivity and high functionality.Although only the synthesis of perseitol is shown in this report, the antipodal perseitol (L-glycero-L-galactoheptiol) has been synthesized in the formal sense.

Experimental Section
General Procedures.Unless otherwise mentioned, all reactions were performed in oven-dried glassware under an atmosphere of argon