Total Synthesis of (+)-Azinothricin and (+)-Kettapeptin

Abstract

Asymmetric total syntheses of (+)-azinothricin and (+)-kettapeptin have been completed through a common new pathway that exploits a highly chemoselective coupling reaction between the fully elaborated cyclodepsipeptide 5 and the glycal activated esters 3 and 4 at the final stages of both respective syntheses.

Total synthesis of (+)-A83586C, (+)-kettapeptin and (+)-azinothricin: powerful new inhibitors of β-catenin/TCF4- and E2F-mediated gene transcription

“…73 Significantly, the El-Tanani group demonstrated, 51 by quantitative real-time PCR, that while 218 and 210 can markedly downregulate over-expressed Opn at 10 nM drug concentration, Scheme 28 Completion of the total synthesis of (+)-azinothricin. 55 b-catenin levels are always maintained, confirming that blockade of this protein-protein interaction with target DNA must be occurring. We have thus jointly demonstrated that small molecule disruption of the b-catenin-TCF4 protein-protein transcription-activating interaction is a viable drug intervention strategy for downregulating Opn in metastatic tumours.…”

“…The final coupling of 200 with 118 also proceeded in good yield. In fact, this particular union was one of the very best that we have so far encountered, it delivering (+)-azinothricin in 40% overall yield from the protected cyclodepsipeptide 119, 55 further vindicating the high-risk planning that we had implemented at the very outset of our programme.…”

“…60 Scheme 23 Our new second-generation synthesis of the A83586C/ kettapeptin activated ester 3. 55 pathway which now shaved ten steps off the original route to the analogous sulfone 11, and which now only required twelve steps as opposed to the previous twenty-two! Although the new pathway to 122 did significantly shorten our overall synthesis, it did nevertheless deliver a 2.3 : 1 mixture at one point in the synthesis and, in this respect, it was marginally worse than the original route to phenylsulfone 11!…”

“…55 Scheme 25 Our new second-generation pathway to dipeptide 111. 55 Having served its purpose in installing this feature, the O-isopropylidene group was detached from 176 and the liberated 1,2-diol 177 oxidatively cleaved to the acid by successive lead tetraacetate glycol fission and Pinnick oxidation 67 which gave the acid 179.…”

“…55 Scheme 25 Our new second-generation pathway to dipeptide 111. 55 Having served its purpose in installing this feature, the O-isopropylidene group was detached from 176 and the liberated 1,2-diol 177 oxidatively cleaved to the acid by successive lead tetraacetate glycol fission and Pinnick oxidation 67 which gave the acid 179. The latter thereafter had its O-benzyl ether group detached by catalytic hydrogenolysis and, following this, potassium carbonate promoted esterification of 180 with allyl iodide furnished ester 181 ready for O-triflation and S N 2 displacement with O-benzylhydroxylamine.…”