Cyclophellitol

An interesting approach to both enantiomers of biologically active cyclo-phellitol, based on the latent symmetry concept, from the same common starting material D-xylose was proposed by Kireev et. al. Functionalization of this monosaccharide at the C-l provided compound 64, while similar processes initiated from the end (C5) afforded the ent-64 (Fig. 23).36 Proper functionalization of these intermediates led to both enantiomers of cyclophellitol. 

Another approach to ( + )-cyclophellitol, proposed by Madsen, was based on the RCM cyclization of the sugar diolefin 68 (Fig. 24).37... 

Fig. 23 Approach towards both enantiomers of cyclophellitol from D-xylose.

S. Atsumi, K. Umezawa, H. Iinuma, H. Naganawa, H. Nakamura, Y. Iitaka, and T. Takeuchi, Production, isolation and structure determination of a novel P-glucosidase inhibitor, cyclophellitol, from Phellinus sp, J. Antihiot., 43 (1990) 49-53. 

S. Atsumi, H. Iinuma, C. Nosaka, and K. Umezawa, Biological activities of cyclophellitol,./. Antihiot.,... 

J. Marco-Contelles, Cyclohexane epoxides—Chemistry and biochemistry of (+)-cyclophellitol, Eur. J. Chem. (2001) 1607-1618. 

S. G. Withers and K. Umezawa, Cyclophellitol A naturally occurring mechanism-based inactivator of P-glucosidases, Biochem. Biophys. Res. Commun., 177 (1991) 532-537. 

K. Tatsuta, Y. Niwata, K. Umezawa, K. Toshima, and M. Nakata, Syntheses and enzyme inhibiting activities of cyclophellitol analogs, J. Antihiot., 44 (1991) 912—914. 

The kinetic resolution of C2-symmetric racemic substrate as shown in Scheme 8E.22 requires differentiation between the starting material and the monoalkylated product 113 in addition to the enantiodiscrimination in the ionization step. With a bulky carboxylic acid as nucleophile, the racemic tetraacetate of conduritol B was efficiently resolved under phase-transfer conditions [68]. Further elaboration of the hydrolytically desymmetrized alcohol resulted in the synthesis of the important glycosidase inhibitor, (+)-cyclophellitol. 

Scheme 8E.22. Kinetic resolution of conduritol B and synthesis of cyclophellitol.

In connection with a program on developing free radical methodology, Praser-Reid described several approaches to densely functionalized carbocycles. This led to the construction of the carbocyclic core of tetrodotoxin [326]. The synthesis of cyclophellitol 414 and its epi derivative, described here, illustrates the principles of this strategy [327]. 

A variant of the above method is the nitrone-olefin cycloaddition, exploited for the synthesis of shikimic acid [349] and for the synthesis of the carbocyclic nucleoside neplanocin [350]. RCM has been recently exploited in Ziegler s synthesis of cyclophellitol [351]. This synthesis encompasses a number of steps described throughout this chapter, including chain extensions at Cl, at C6 and branching by Michael addition followed by carbocyclization. 

Sato, K, Bokura, M, Moriyama, H, Igarashi, T, Total synthesis of a novel (i-glucosidase inhibitor, cyclophellitol starting from D-glucose, Chem. Lett., 37-40, 1994. 

McDevitt, R E, Fraser-Reid, B, A divergent route for a total synthesis of cyclophellitol and epicyclophellitol from a [2.2.2]oxabicyclic glycoside prepared from D-glucal, J. Org. Chem., 59, 3250-3252, 1994. 

Tatsuta, K, Niwata, Y, Umezawa, K, Toshima, K, Nakata, M, Enantiospecific total synthesis of a (3-D-glucosidase inhibitor, cyclophellitol. Tetrahedron Lett., 31, 1171-1172, 1990. 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

In the laboratory of B.M. Trost, the second generation asymmetric synthesis of the potent glycosidase inhibitor (-)-cyclophellitol was completed using a Tsuji-Trost allylation as the key step. The synthetic plan called for the conversion of the a-nitrosulfone allylation product to the corresponding carboxylic acid or ester. Numerous oxidative Nef reaction conditions were tested, but most of them caused extensive decomposition of the starting material or no reaction at all. Luckily, the nitrosulfone could be efficiently oxidized with dimethyidioxirane under basic conditions (TMG) to afford the desired carboxylic acid in high yield. 

Ishikawa, T., Shimizu, Y., Kudoh, T., Saito, S. Conversion of D-Glucose to Cyclitol with Hydroxymethyl Substituent via Intramolecular Siiyi Nitronate Cycloaddition Reaction Application to Total Synthesis of (+)-Cyclophellitol. Org. Lett. 2003, 5, 3879-3882. 

D-Xylose has been used as starting material in the synthesis of (+)-Conduritol C [88] and cyclophellitol [56] (Scheme 12). The combinatitMi of the zinc-mediated tandem reaction with RCM was also used in the synthesis of 7-deoxypancratistatin, a naturally occurring compound with activities against different cancer types. In the latter synthesis, the longest reaction sequence involves 13 steps from o-xylose with a 4% overall yield [58] (Scheme 12). 

Transformation of aldehydes 8 and ent-% into conduritols and inositols was achieved in a few steps via dienes 34 and 35. Conduritols B and F were easily obtained, after separation, by a RCM with the first-generation Grubbs ruthenium catalyst [46]. Syntheses of myo-inositol and c/ifro-inositol were achieved in a few further steps in good yields. Similarly, both enantiomers of cyclophellitol were synthesized from 2,3,4-tri-O-benzyl-D-xylopyranose according to the same strategy... 

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