Pancratistatin - Total Synthesis

Total Synthesis

The first total synthesis of racemic (+/-) Pancratistatin was proposed by Samuel Danishefsky and Joung Yon Lee, which involved a very complex and long (40 steps) total synthesis. According to both Danishefsky and Joung, there were several weak steps in this synthesis that gave rise to a disappointing low synthetic yield. Amongst the most challenging issues, the Moffatt transposition and theorthoamide problem, which required a blocking maneuver to regiospecifically distinguish the C, hydroxyl group for rearrangement were considered to be the severe cases. However, both Danishevsky and Yon Lee stated that their approach towards the PST total synthesis was not out of merit and believed that their work would interest other medicinal scientists to construct a much more practical and efficient way for PST total synthesis.

The work of Danishevsky and Joung provided the foundation for another total synthesis of PST, which was propounded by Li,M. in 2006. This method employed a more sophisticated approach, starting out with the pinitol 30 that its stereocenters are exactly the same as the ones in the C-ring of Pancratistatin. Protection of the diol functions of compound 30 gave compound 31. The free hydroxyl of this was subsequently substituted by an azide to give 32. After removal of the silyl function, a cyclic sulfate was installed to obtain product 33. The Staudinger reaction gave the free amine 34 from azide 33. The coupling reaction between 34 and 35 gave compound 36 with a moderate yield. Methocymethyl protection of both the amide and the free phenol gave compound 37. Treatment of this latter product with t-BuLi followed by addition of cerium chloride gave compound 38. Full deprotection of 38 by BBr3 and methanol afforded pancratistatin 3 in 12 steps from commercially available pinitol with an overall yield of 2.3% 20.

a: TIPDSCl2, imidazole, DMAP, DMF, 24%. b: DMP, p-TsOH, acetone, 81%. c: PPh3, DEAD, CH3SO3H, CH2Cl2, 0 °C to r.t. then NaN3, DMF, 60 °C, 72%. d: TBAF, THF, 0 °C to r.t., 100%. e: SOCl2, Et3N, CH2Cl2, 0 °C. f: NaIO4, RuCl3, aq CH3CN, 87% (more than two steps). g: PPh3, aq THF, 0 °C to r.t., 94%. h: Et2O, 35, 0 °C, 64%. i: K2CO3, MOMCl,DMF, 84%. j: t-BuLi, CeCl3, ultrasound, THF, −78 °C to r.t., 72%. k: BBr3, CH2Cl2, −78 °C to 0 °C, 1 hour then MeOH, −78 °C to 0 °C, 2 hours, 52%.

• Total Synthesis of racemic Pancratistatin

• The abstract of the Stereocontrolled synthesis of Pancratistatin

• Pancratistatin and Narciclasine

• Streocontrolled synthesis of pancratistatin

A very recent approach to a stereocontrolled Pancratistatin synthesis was accomplished by Sanghee Kim from the National University of Seoul, in which claisen rearrangement of dihydropyranethlyene and a cyclic sulfate elimination reaction were employed 21. This reaction has proven to be very highly efficient as it produced an 83% overall synthetis yield. (Proved by H and 13C NMR).

The B ring of the phenanthridone (three membered nitrogen hetrocyclic ring) is formed using the Bischler-Napieralski reaction. The n precursor 3 with its stereocenters in the C ring is stereoselectively synthesized from the cis-disubstituted cyclohexene 4. The presence of unsaturated carbonyl in compound 4 suggested the use of a Claisen rearrangement of 3,4-dihydro-2H-pyranylethylene.

The synthesis starts with the treatment of 6 with excess trimethyl phosphate. This reaction provides phosphate 7 in 97% yield. Using Honer-Wadsworth-Emmons reaction between 7 ands acrolein dimmer 8 in the presence of LHMDS in THF forms (E)-olefin 5 with very high stereoselectivity in 60% yield. Only less than 1% of (Z)-olefin was detected in the final product. The Claisen rearrangement of dihydropyranethylene forms the cis-distributed cyclohexene as a single isomer in 78% yield.

The next step of the synthesis involves the oxidation of aldehyde of compound 4 using NaClO2 to the corresponding carboxylic acid 9 in 90% yield. Iodolactonization of 9 and subsequent treatment with DBU in refluxing benzene gives rise to the bicyclic lacytone in 78% yield. Mthanolysis of lactone 10 with NaOMe forms a mixture of hydroxyl ester 11 and its C-4a epimer (Pancratistatin numbering). Saponification of the methyl ester 11 with LiOH was followed by a Curtius rearrangement of the resulting acid 12 with diphenylphosphoryl azide in refluxing toluene to afford isocyanate intermediate, which its treatment with NaOMe/MeOH forms the corresponding carbamate 13 in 82% yield.

The next steps of the synthesis involve the regioselevtive elimination of C-3 hydroxyl group and subsequent unsaturation achieved by cyclic sulfate elimination. Diol 16 needs to be treated with thionyl chloride and further oxidation with RuCl3 provides the cyclic sulfate 17 in 83% yield. Treatment of cyclic sulfate with DBU yields the desired allylic alcohol 18 (67% yield).

Reaction with OsO4 forms the single isomerlization 19 in 88% yield. Peracetylation of 19 (77% yield) accompanied by Banwell’s modified Bischler-Napieralski forms the compound 20 with a little amount of isomer 21 ( 7:1 regioselectivity). The removal of protecting groups with NaOMe/MeOH forms Pancratistatin in 83%.