Cyclophellitol synthesis

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). 

In a recent asymmetric synthesis of cyclophellitol, Trost employed a Nef reaction for the conversion of nitrosulfone 46 to carboxylic acid 47.26 As shown below, 46 was treated with tetramethylguanidine to generate a nitronate salt, which was then oxidized with DMDO to afford the acid in 78% yield. The adjacent double bond was not epoxidized under these conditions. 

Reviews have appeared on the synthesis of inositols, carba sugars, conduritols and amino conduritols utilizing the non-carbohydrate sources of benzene cis-diols, quinic acid and Vogel s naked sugar methodology. Other reviews on the preparation of cyclophellitol and ep/-cyclophellitol from glycals and the use of D-glyceraldehyde as a chiral precursor in Diels-Alder and 1,3-dipolar cycloaddition approaches to carbocyclic derivatives have also been reported. 

Cyclitols and Derivatives. - A review on the application of the Pd(II)-catalysed Ferrier (II) carbocyclization in the synthesis of p-glucosidase inhibitors, cyclophellitol, all the diastereoisomers of inositol, and D-myo-inositol phosphates has been published. ... 

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

Figure 13.5 Synthesis of broad-spectrum retaining fi-exoglucoside probe cyclophellitol aziridine 13 and IS. (a) (i) CCIjCN, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), CHjClj, 0°C, 2h, (ii) followed by the addition of HjO, NaHCOj, Ij, 18h, (b) (i) 37% HCI, MeOH, 3.5 h, (ii) 37% HCI, dioxane, 60 °C, 1 h, (ill) NaHCOj MeOH, 4 days (over five steps 60%), (c) (i)...

The first example involves the kinetic resolution of allylic acetates. In the asymmetric synthesis of (+)-cyclophellitol, the two enantiomers of the tetraacetate in Figure 14.26 were resolved by substitution of a pivalate group for one acetate. The palladium catalyst bearing the (R,R)-L ligand shown reacted faster with the (R)-allylic acetate. ... 

Bis-C-aryl glycosides as model kidamycins are mentioned in Chapter 3, and amino acid analogues of 3-deoxyprumycin are referred to in Chapter 9. Cyclophellitol and its diastereomers are covered in Chapter 18, and the synthesis of intermediates for antibiotics is mentioned in Chapter 24. 

A total synthesis of the natural product cyclophellitol, 38, a P-glucosidase inhibitor, has been described starting from >-glucose, in which the key transformations are Fenier rearrangement of 35 and a stereoselective epoxidation of 37 (Scheme 10). The natural product (-)-ovalicine 39, another epoxy cyclohexane, has been prepared from the cyclitol L-quebrachitol (Scheme 11). ... 

Recently, Trost and Hembre reported a concise asymmetric synthesis of (+)-cyclophellitol based on the Pd-catalyzed kinetic resolution of racemic conduritol B tetraacetate using the chiral ligand (R,R)A. Most syntheses have started with enantiomerically pure natural products, notably carbohydrates. Such a strategy normally entails rather a long route. A pivalate was chosen as the carboxylate nucleophile for the resolution because the resultant allyl pivalate was anticipated to ionize much more slowly than the starting material. The tetraacetate ( )-conduritol was synthesized from benzo-quinone the kinetic resolution was carried out using 0.65 equiv of sodium pivalate with 1 mol % of (i7 -C3H5PdCl)2 and 3 mol % of (R,R)-AA in a two-phase system with tetra-hexylammonium bromide as the phase transfer catalyst. 

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