Synthetic Studies on Ecteinascidin-743:  Constructing a Versatile Pentacyclic Intermediate for the Synthesis of Ecteinascidins and Saframycins

Abstract

[reaction: see text] The asymmetric synthesis of a highly functionalized pentacyclic tetrahydroisoquinoline relevant to the ecteinascidin, saframycin, safracin, and renieramycin family of antitumor alkaloids is described.

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

“…A similar reaction sequence was developed independently by Williams and coworkers. [8,14] Besides the complexity and thus the unpredictability of the sequence, the key issue that needed to be addressed to validate this approach was the regioselectivity of the cyclization (at C19 versus C15 of 6). We planned to assemble the key intermediate 6 by acylation of the tetrahydroisoquinoline 7 with the known amino acid 8.…”

“…Removal of the N-Boc functionality from the acid-sensitive compound 12 according to the procedure described by Sakaitani and Ohfune [18a] followed by cleavage of the silyl ether furnished the free aminophenol 13 in 84 % overall yield. After much experimentation, the Pictet-Spengler reaction between 13 and benzyloxyacetaldehyde (14) provided the 1,3-cis tetrahydroisoquinoline 15 in 91 % yield as a single diastereomer (d.r. > 30:1).…”

Ring Expansions of β-Lactams and β-(thio)lactones

“…This strategy involves the reductive opening/elimination of the C3-C4 β-lactam fragment followed by spontaneous Pictet-Spengler cyclization. Scheme 35 shows the construction of the pentacyclic framework from previously synthesized compounds 131 and 132 [48,49]. First, amino acid 132 was converted into the corresponding acid chloride by reaction with oxalyl chloride.…”

Cycloadditions with StereoselectiveCNBond Formation in Total Syntheses

“…More recently, Williams and co-workers employed a Staudinger [2þ2] cycloaddition of the highly oxygenated benzaldimine 17 to Evans-Sj€ ogren ketene 16 during the total synthesis of (-)-cribrostatin 4 (22,Scheme 41.4), a tetrahydroisoquinoline antitumoral antibiotic, isolated from the blue sponge Haliclona cribicutis. 12,13 In this project, the formed cis-b-lactam served as a temporary inducer of chirality for the C1 stereocenter and as an enal precursor. The cycloaddition of imine 17 to the ketene 16 generated from acid chloride 15 in the conditions described by Evans and Sjögren resulted in the recovery of the desired cis-b-lactam 18 as one diastereomer.…”