A New Entry to Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydro-β-carbolines Employing a Pyroglutamic Acid Derivative as a Chiral Auxiliary

Abstract

β-Carboline which was protected at N-9 by an acyl group derived from l-pyroglutamic acid reacted with allyltributyltin or silyl enol ethers in the presence of an alkyl chloroformate in a highly diastereoselective manner to give 1-substituted 1,2-dihydro-β-carbolines. The compounds were readily transformed to the corresponding asymmetric 1-substituted tetrahydro-β-carbolines that are common partial structures in a variety of indole alkaloids.

Key words

β-carboline - allyltributyltin - silyl enol ether - pyroglutamic acid - asymmetric addition - indole alkaloid

References

• 1 The Chemistry of Heterocyclic Compounds   Vol. 25, Part 4:  Saxton JE. John Wiley & Sons; Chichester: 1994. 
• 2 Itoh T. Matsuya Y. Enomoto Y. Nagata K. Miyazaki M. Ohsawa A. Synlett  1999,  1799 
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• The coordination mechanism was supposed to participate only in the reaction of β-carbolines. In the cases of isoquinoline derivatives, only the steric factor might control the stereochemistry; see:
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4

In the previous reaction which adopted N-phenylsulfonylprolinyl group as a chiral auxiliary, the addition using silyl enol ethers afforded the products in good yields but poor diastereoselectivity (<20%).

6

N-Protected l-pyroglutamic acids were readily prepared from the reaction of t-butyl l-pyroglutamate and an alkyl halide in the presence of NaH, followed by hydrolysis.

7

The compound 1 was obtained as follows: To the mixture of N-alkyl l-pyroglutamic acid (0.5 mmol) and β-carboline (0.5 mmol) in CH₂Cl₂ (1 mL) was added ethyl-(N,N′-dimethylaminopropyl)carbodiimide hydrochloride (0.6 mmol), and the mixture was reacted for 3 h at room temperature. Then the solvent was evaporated off, and the residue thus formed was chromatographed on silica gel (EtOAc) to give 9-acyl-β-carbolines 1.

8

Experimental procedure: To the CH₂Cl₂ solution (1 mL) of 9-acyl-β-carboline 1 (0.1 mmol) and allyltributyltin (0.3 mmol), 2,2,2-trichloroethyl chloroformate (0.2 mmol) was added at -40 °C under Ar atmosphere, and the reaction was continued for 24 h at the same temperature. Then 3 M aqueous KF solution was added to the solution, and the mixture was allowed to stir vigorously for 1 h. The organic layer was separated, dried over MgSO₄, and evaporated off to leave the residue, which was chromatographed on silica gel to afford the adduct 2. The compound 2 was dissolved in THF (1 mL), and treated with 1 M aqueous KOH solution (2 mL) for 30 min. Then H₂O was added to the mixture, which was extracted with CH₂Cl₂ to give pure 3. The aqueous layer was acidified with HCl and extracted with CH₂Cl₂ to afford the recovered chiral auxiliary.

9

The absolute configuration of the allyl adduct 3 was determined by the previous mentioned method; see ref. [3b]

10

In these cases, the dihydro adduct initially obtained was hydrolyzed without the isolation to give the compound 4, because of the instability of the intermediate.

12

The molecular orbital calculations were carried out using the PM3 procedure with the standard parameters, as implemented in the MOPAC2000 program.