Synthesis routes deprotection/alkylation

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

An important route for the synthesis of various functionalized TTFs utilizes the efficiency of the cyanoethyl group in protection of thiolates <19958521, 1996S407, 1997JOC4936, 1997SL1211>. Acetylacetone-substituted TTFs 736 and 737, new redox-active ligands, were prepared form the bis-cyanoethylthio TTF 735 via cyanoethyl deprotection and subsequent alkylation of the resulting thiolates with methyl iodide or 3-chloroacetylacetone (Scheme 108) <2001TL3189>. 

For the synthesis of the non-diene analogue 65, which bears a benzyl group in the terminal position (Scheme 17), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) cleavage of the p-methoxybenzyl (PMB) ether at the C15-position did not proceed in the presence of the benzyl moiety (oxidation of the methylene in allylic-benzylic-position in C23-position). Therefore, we inverted the order of the first two steps (1) DDQ deprotection on 44 and (2) nickel-catalyzed cross-coupling reaction performed on a free primary alcohol in C15 position. After this minor modification, completion of the synthesis followed the established route Suzuki-Miyaura crosscoupling reaction between alkyl iodide 73 (via its trialkylboronate species) and vinyl iodide 60 to yield 74 selective carbamate installation and final deprotection to afford DDM analogue 65. 

Fig. 1. The synthetic route to the homopiperazine compounds. Assuming that the actual synthesis would be carried out in solution phase, one would start from mono-protected homopiperazine introducing a first set of building blocks (R1 building blocks). These could come, for instance, from a set of alkyl aldehydes added via reductive amination. In a deprotection step the intermediates would be prepared for the addition of the second set of building block (R2 building blocks) to form the final products. Acylation of the secondary amine of the homopiperazine intermediate with aromatic carboxylic acids is quite common and will be used in this example (see Note 2).

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