A Novel Straightforward Synthesis of Enantiopure Tetrahydroisoquinoline Alkaloids

Abstract

A novel, direct,and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.

Studies on the Diastereoselective Intramolecular Pauson–Khand Reaction on Regioisomeric Chiral Perhydrobenzoxazines Derived from (–)‐8‐Aminomenthol

“…The reaction took place only if the solution was saturated with CO previous to the addition of the catalyst, and the yield was highly dependent on the catalyst loading. In the presence of 5 mol-% of Co 2 (CO) 8 , a mixture of diastereoisomers was obtained in only 20 % yield, but the yield increased to 85 % when using 10 mol-% of the catalyst, although no diastereoselection was observed in any case (Table 1, Entries 6 & 7).…”

“…Pauson-Khand reaction of 2-vinyl-3-propargylperhydrobenzoxazines. Complete disappearance of the starting compound was observed when an equimolar mixture of 2a and Co 2 (CO) 8 was heated in refluxing toluene for 2 h, but a lot of decomposition products were formed and only 28 % of cyclization diastereoisomers 3a and epi-3a was isolated as a 2:3 mixture (Table 1, Entry 1). The yield was improved to 45-50 % when an equimolar mixture of 2a and Co 2 (CO) 8 in DCM and NMO or trimethylamine N-oxide (TMANO, 6 equiv.)…”

“…clizations, [8] and now we reasoned that this structure could act as a chiral template in diastereoselective intramolecular PKRs. The attachment of a vinyl substituent at C-2 and a propargyl group at the nitrogen atom of the perhydrobenzoxazine nucleus allows the construction of chiral 1,6-enynes, which could lead to pirrolyl cyclopentenone derivatives diastereoselectively.…”

Isolation and X-ray Crystal Structure of Tetrahydroisoquinoline Alkaloids from Calycotome Villosa Subsp. intermedias

“…Alkaloids 1 and 2 were isolated in a crystalline form and completely characterized. [13][14][15][16][17][18][19] allowed identification of alkaloid 1 as the known compound (R)-1-hydroxymethyl-7-8-dimethoxy-1,2,3,4-tetrahydroisoquinoline (named calycotomine).…”

Enzymatic resolution of tetrahydroisoquinoline derivatives in batch and continuous-flow systems

“…103 To determine the stereochemistry of the homocalycotomine enantiomers, enantiomeric triisopropylsilyl-1-(2-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (177) was prepared from the enantiomeric alcohol 2, according to the method described by Tietze and co-workers. 6 The with a combination of the batch and a CF system.…”