EPC‐Synthesis of Tetrahydroisoquinolines by Diastereoselective Alkylation at the 1‐Position of Phenylalanine‐Derived Precursors. Synthesis of the Alkaloid (+)‐Corlumine

Abstract

ChemInform Abstract A series of alkylation reactions of the carboxylic acids (I), (VI), (IX) and (XI) is investigated. In the case of (I) a single diastereomer of type (III) is formed. Compounds (III) are transformed to the known title compounds (IV). Alkylation of (VI) with benzaldehyde (VII) yields a single diastereomer (VIIIa) (probably having (1R,αS) configuration) which is converted to the ester (VIIIb). Reaction of the acid (IX) with (IIa) does not yield the expected methylation product but two diastereoisomeric dimers (X). From the reaction between the acid (XI) and the aldehyde (XII) the diastereomers (XIII) are obtained and transformed to the epimers (XIVa) and (XIVb). Their stereochemistry is deduced from the fact that (XIVa) can be converted to the natural product (+)-corlumine (XIVc).

Synthesis of 1‐(m‐Hydroxybenzyl)‐Substituted 1,2,3,4‐Tetrahydroisoquinoline‐3‐carboxylic Acid Derivatives as Opioid Peptide Mimetics − Unexpected Amide Bond Cleavages under Mild Conditions

“…[5] Scheme 1. 5 (a) tBuCOCl, Et 3 N (98%); (b) H 2 , Pd/C (99%); (c) tBuLi, Ϫ78°C, 3-benzyloxybenzyl bromide (80Ϫ84%) (S)-2-Pivaloyl-Tic 4 was prepared from enantiomerically pure (S)-Tic-OBn, [6] followed by hydrogenolysis as described by Seebach.…”

“…These mild cleavage conditions are remarkable, since Seebach reported difficult pivalamide cleavages of 2-pivaloyl-1,2,3,4-tetrahydroisoquinolines. [5,8] Coupling of benzyloxycarbonyl-protected glycine (Z-Gly) to (1R,3S)-1-(m-benzyloxybenzyl)Tic-OMe 7 failed when TBTU or benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) were used as coupling reagents, but was successful when N-ethyl-NЈ-(3-dimethylaminopropyl)carbodiimide (EDC) in dichloromethane was used. The glycine-coupled compound 8 was prepared in yields of 86 to 97% after purification by flash column chromatography.…”

“…5 (a) tBuCOCl, Et 3 N (98%); (b) H 2 , Pd/C (99%); (c) tBuLi, Ϫ78°C, 3-benzyloxybenzyl bromide (80Ϫ84%) (S)-2-Pivaloyl-Tic 4 was prepared from enantiomerically pure (S)-Tic-OBn, [6] followed by hydrogenolysis as described by Seebach. [5] Direct pivaloyl protection of unprotected (S)-Tic to provide 4 was tried, but failed. 2-PivaloylTic 4 was subsequently stereoselectively alkylated [5] by use of tBuLi and m-benzyloxybenzyl bromide [7] in THF at Ϫ78°C to give (1R,3S)-1-(m-benzyloxybenzyl)-2-pivaloyl-Tic 5 in good yields (80Ϫ84%).…”

“…[5] Direct pivaloyl protection of unprotected (S)-Tic to provide 4 was tried, but failed. 2-PivaloylTic 4 was subsequently stereoselectively alkylated [5] by use of tBuLi and m-benzyloxybenzyl bromide [7] in THF at Ϫ78°C to give (1R,3S)-1-(m-benzyloxybenzyl)-2-pivaloyl-Tic 5 in good yields (80Ϫ84%). The reaction needed 3 days for completion at Ϫ78°C.…”

“…The target compound 15 was tested for its ability to displace [ 3 H]Ile 5,6 deltorphin II as a delta opioid selective ligand in rat brain homogenates, but displays very weak affinity (IC 50 ϭ 17 µ). [13] The signal transduction properties of 15 were evaluated by DPDPE-receptor-activated [ 35 S]GTPγS binding to cloned human delta receptors in C6 glioma cells, and indicated that 15 was a weak delta opioid Scheme 7.…”