Synthesis of Cyclophellitol Utilizing a Palladium Chloride Mediated-Ferrier-II Rearrangement

Cyclophellitol and its C3-epimer have been synthesized from 5-enoglucopyranoside and 5-enomannopyranoside, respectively. The carbocyclic skeleton was constructed through a Ferrier-II reaction meditated by PdCl2.


Introduction
Since Ferrier developed a cyclization of saccharides using mercurate [Ferrier-II reaction] in 1979 [1], the ring conversion of 6-membered rings using saccharides has been intensively studied [2,3]. Because naturally occurring and biologically active compounds often contain a ring structure with multi-functional groups, stereochemical control of chiral centers on these rings becomes crucial in the total synthesis of these compounds. The Ferrier-II reaction is remarkably useful for the total synthesis of compounds with a complicated conformation such as cyclitols. Cyclophellitol is a β-D-glucosidase inhibitor first isolated by Umezawa in 1990 [4]. It is known to have high activity, and its application has been expected to range from an anti-virus and anti-HIV agent to an inhibitor of cancer metastasis. The structure of cyclophellitol, an epoxy ring in the β-position on a multi-substituted cyclitol in the glucose-conformation, resembles that of β-D-glucoside. We investigated synthetic methods of not only cyclophellitol but also its epimers, ultimately aiming at the study of structure activity relationship [5]. Figure 1 shows the strategy for the synthesis of cyclophellitol. Commercially available D-glucoside is converted into a cyclohexane ring through Ferrier-II reaction, and then an epoxy ring is formed stereoselectively. For the introduction of a hydroxymethyl group as a C1 unit, regio-and stereoselective nucleophilic addition to the epoxy ring is examined. Finally, an elimination reaction forms a β-epoxy ring to complete the total synthesis of cyclophellitol.   In the beginning, 5-enoglucopyranoside 1 [6] was used in Ferrier-II reaction mediated by a catalytic amount of palladium chloride. We have recently reported on the Ferrier-II reaction using palladium chloride instead of mercury salt [7]. This reaction is more advantageous than the conventional methods because it proceeds under very mild conditions, which especially suit the reaction of multi-substituted carbohydrates [8]. In this case, the ring conversion was completed by using 0.05 equivalent of palladium chloride and the obtained cyclohexanone was converted to an enone 2 [6] via an elimination reaction. The enone 2 was reduced under Luche's conditions [9] to provide a β-alcohol 3 [10]. Then β-form epoxide was formed stereoselectively on the cyclohexane ring, and the hydroxyl group was protected by an MPM group to provide an intermediate, the epoxide 4 ( Figure 2). The key reaction in this total synthetic pathway is the regioselective and nucleophilic attack of hydroxymethyl group to the epoxide 4. Generally, a nucleophile predominantly attacks at the axial position of epoxide in the ring opening reaction of cyclohexane. Therefore, we expected that the nucleophilic substitution to this epoxide would occur at the axial position C5, and would not show the desired regioselectivity ( Figure 3) We then thought that if the conformation of the epoxide could be changed, we would be able to introduce a hydroxymehyl group from the desired C6 position. As shown in Figure 3, chelation between metals and oxygen atoms of the epoxide and an ether oxygen may drastically change the conformation of the cyclohexane ring, resulting in the axial nucleophilic attack at the C6 position. For induce such chelation, we used a boron reagent Mes 2 BCH 2 Li [11] and studied the regio-selectivity of ring opening of the epoxide using substrates that are protected at the C1, a coordinative position of chelation, with variation of the protecting groups (Table 1). Unfortunately, because acyl protective groups react with the boron reagent, we did not obtain the hydroxymethylated products (entry 5). Hydroxymethyl addition, however, occurred smoothly in the substrate with an ether protective group. Interestingly, the substrate protected with MPM, benzyl, and BOM groups produced the hydroxymethyl products 9a~11a in which the nucleophile attacked at the opposite C6 position due to the chelation, but protection by a TBDMS groups resulted in only 12b in which nucloephile attacked at the originally axial C5 position. Thus, a significant difference in the selectivity was observed depending on the nature of the protecting group. Presumably, this change in selectivity originated from differences in the coordinative power by the oxygen of the protected OH group. As shown in Figure 3, chelation of the metal to the oxygens of both the oxirane and C1 alkoxy group might change the conformation of the substrates to cause unusual regioselectivity. On the other hand, the oxygen of the siloxy group might not coordinate to the metal because of bulkiness of the silyl group. In this case, the usual selectivity was observed. Based on these results, we selected the MPM group as the most appropriate protective group, and carried out the synthesis illustrated in Figure 4.

Figure 4
BnO Two hydroxy groups of the diol 9a obtained through the hydroxymethylation process were protected by benzyl groups and the MPM group was converted to a mesyl group. Then, all the benzyl groups were simultaneously deprotected by catalytic hydrogenation to obtain the pentaol 16. The pentaol readily underwent epoxide cyclization under alkaline conditions, and cyclophellitol was thus synthesized from 1 in 14% total yield.
In this synthetic method, the initial D-glycosides readily give rise to various epimers depending on the conformation of glycosides and types of protective groups. The same method could be successfully applied to the synthesis of the epimer of cyclophellitol with a different configuration at C3 ( Figure 5).
The Ferrier-II reaction of the 5-enomannoside 19 promoted by a catalytic amount of PdCl 2 provided the corresponding cyclohexanone, which was subjected to a dehydration with MsCl-pyridine to give enone 20. Stereoselective reduction under Luche's conditions afforded the β-alcohol 21. After protection of the hydroxy group, debenzoylation and subsequent protection with TBDMSOTf-lutidine afforded 23. Deprotection of the MPM ether of 23 provided the β-alcohol 24, which was oxidized with m-CPBA to yield the epoxide 25 efficiently in a highly diastereoselective manner. The remaining hydroxy group was protected as an MPM ether to give 26. The subsequent introduction of a hydroxymethyl group by nucleophilic opening of the epoxide afforded the diol 27 in good yield. Deprotection of 27 and successive benzylation afforded 28, which was deprotected with DDQ and then mesylation provided the mesylate 29. The fully-benzylated mesylate 29 was subjected to hydrogenolysis using 1 atm of H 2 and Pd(OH) 2 in MeOH to generate the deprotected mesylate 30. Finally, treatment of 30 with aqueous NaOH afforded the cyclophellitol C3-epimer.

Conclusions
We have presented a facile synthesis of cyclophellitol and its C3-epimer utilizing Ferrier-II reaction mediated by PdCl 2 . This method enables not only the synthesis of various diastereomers of cyclophellitol but also application of the new strategy for the regioselective hydroxymethylation reaction of highly oxygenated cyclohexanes.

Acknowledgements
We thank Misses J. Shimode, M. Kitsukawa, and A. Tonoki for spectroscopic measurements. The generous financial support for this research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Fujisawa Foundation, Hayashi Memorial Foundation for Female Natural Scientists, and Uehara Memorial Foundation are gratefully acknowledged.

General
Melting points were determined with a Yanagimoto micro melting point apparatus and are uncorrected. IR spectra were measured with a JASCO FT/IR-8000 spectrometer. HRFAB-MS were recorded with a JEOL SX-102A. 1 H-NMR and 13 C-NMR spectra were recorded at 600 MHz with a JEOL GSX-600 spectrometer using tetramethylsilane (TMS) as the internal standard. Chemical shifts were reported in ppm downfield from TMS. Optical rotations were measured with a JASCO DIP-370 in a 1-dm cell. Analytical and preparative TLC was conducted on precoated TLC plates (silica gel 60 F 254 , Merck). Column chromatography was performed using Merck silica gel 60 N (100-210 µm). All anhydrous solvents were purified according to standard methods.