Synthetic Studies toward Ecteinascidin 743

Abstract

An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and Garner's aldehyde provided the protected amino diol 16, which was converted to free amine 11 in excellent yield. A Pictet-Spengler reaction between 11 and ethyl glyoxylate under carefully controlled conditions (LiCl, toluene, 1,1,1,3,3,3-hexafluoro-2-propanol, room temperature) provided the acid-sensitive tetrahydroisoquinoline (18) in high yield, which was converted to the amino alcohol 9. Enantioselective alkylation of a glycine template in the presence of a catalytic amount of chiral cinchonidium salt was the key step for the access of enantiomerically pure amino aldehyde 10. Union of the two fragments 9 and 10 via oxazolidine intermediate afforded amino nitrile 39, which upon esterification of the primary alcohol with (R)-N-(S-4,4',4' '-trimethoxyltrityl) Cys (42) afforded 43. Cyclization of 43 (1% trifluoroacetic acid in trifluoroethanol) provided compound 44 by a domino process involving (a) unmasking of the S-trimethoxytrityl group, (b) fragmentation of dioxane assisted by an electron-rich aromatic ring, and (c) formation of a 1,4-bridged 10-membered lactone via formation of a sulfide linkage. Treatment of 7, obtained in two steps from 44b, under acidic conditions (0.5% methyl sulfonic acid in acetonitrile) afforded the pentacyclic compound 51 via fragmentation of the 10-membered cyclic sulfide followed by an intramolecular Pictet-Spengler reaction.

Total Synthesis of the Marine Natural Product (−)‐Cribrostatin 4 (Renieramycin H)

“…Interestingly, and in accord with our previous observation for a related system, the treatment of 13 with ethyl glyoxylate gave the 1,3-trans isomer as the major product in 61 % yield. [13] We noticed that the trans and cis isomers are interconvertible even as a solution in CDCl 3 , and that the trans isomer always predominates after the mixture has reached equilibrium. This observation implies that the trans selectivity observed with ethyl glyoxylate is probably driven thermodynamically.…”

“…Our strategy, which features a key domino sequence [12] for the construction of pentacyclic core structure 5 from 6, is highlighted in Scheme 2. The domino sequence involving acyliminium-ion formation, loss of a proton to form the enamide, b elimination, and a phenolic Mannich cyclization led to a dead end in one of our unsuccessful approaches to Et 743, [13] but would be a very efficient way to access the present target. A similar reaction sequence was developed independently by Williams and coworkers.…”

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Syntheses of trabectedin (71) have been described by many researchers. In summary, there are three important pathways (Scheme 13): (A) combination of two fragments (I and II) via an oxazolidine intermediate, (B) acid-promoted macrocyclization via creation of carbon-sulfur bond with concomitant formation of a 10-membered ring, and (C) the intramolecular Pictet-Spengler reaction to obtain 71 [154][155][156][157]. The straightforward synthesis of 71, using 28 steps with 1.1% yield, started from L-glutamic acid as the single chiral source [158] while a 31 steps synthesis, with 1.7% yield, began from 3-methylcatechol [159].…”

Drug discovery from natural sources

“…121 It showed particularly high activity against advanced sarcomas that had relapsed or were resistant to conventional therapy. 122 …”