The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

We present a systematic investigation on an improved variant of the N-acyl-Pictet–Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N–H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure–activity relationships in this chemotype.


Synthesis details and analytical data: General Procedure A -Protection with an ethoxycarbonyl group
In a manner similar to a procedure in [1], the appropriate arylethylamine or phenol (1.0 equiv) was dispersed/dissolved in dry CH2Cl2 and cooled to −20 °C, followed by dropwise addition of NEt3 (1.5-3.5 equiv) and ethyl chloroformate (1.3-2.5 equiv).
The reaction mixture was refluxed for 4-72 h, before water was added. The mixture was extracted thrice with CH2Cl2, the combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification was accomplished by flash column chromatography (FCC) or recrystallization to yield carbamates and carbonates.

General Procedure B -Wittig reaction
In a manner similar to a procedure in [1], (methoxymethyl)triphenylphosphonium chloride (1.2 equiv) was suspended in dry THF under nitrogen and cooled to −4 °C, before LDA (1 equiv) was added dropwise. The mixture was stirred for 30 min at −4 °C, followed by slow, dropwise addition of a solution of the appropriate aldehyde (1.0 equiv) in dry THF. The solution was stirred for 2 h at 0 °C, then poured on brine and extracted thrice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by FCC to give desired cis/trans-enol ethers. Due to limited stability, the products are stored at −18 °C.

General Procedure C -N-Acyl Pictet-Spengler reaction
In a manner similar to a procedure in [1], carbamate (1.0 equiv) and enol ether (1.0-1.2 equiv) were dissolved in dry dichloromethane, 4 Å molecular sieves (1.00 g per 20 mL solvent) was added and the mixture was cooled to 0 °C, before TFA (10-11 equiv) was added dropwise. The mixture was allowed to warm to rt and stirred for 18-90 h, before the molecular sieves was removed by filtration. Saturated aqueous NaHCO3 solution was added. The mixture was extracted thrice with CH2Cl2, the combined organic layers were washed with 10% aqueous citric acid and brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification was accomplished by FCC or recrystallization to yield desired racemic tetrahydroisoquinolines.

General Procedure D -Lithium alanate reduction
In a manner similar to a procedure in [1], LiAlH4 (7-12 equiv) was suspended under nitrogen in 8 mL dry THF and a solution of the carbamate (1.0 equiv) in 8 mL dry THF S4 was added dropwise, and the suspension was refluxed for 3-20 h. The mixture was cooled to 0 °C and a saturated solution of Na2SO4 was added in small portions under vigorous stirring over 30 min. Water was added and the mixture was extracted thrice with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification was accomplished by FCC to give tertiary amines.

S13
The reaction was completed after 12 h and the crude product was purified by FCC using hexanes/ EtOAc (EtOAc up to 40%) yielding the desired tetrahydroisoquinoline (5d, 141 mg, 0.307 mmol, 35%) as a yellow oil. 1
However, this published method gave 2a in only 35 % yield, in a mixture with a byproduct.