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.

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

References

<A NAME="RY04502ST-1">1</A> The Chemistry of Heterocyclic Compounds   Vol. 25, Part 4:  Saxton JE. John Wiley & Sons; Chichester: 1994. 

<A NAME="RY04502ST-2">2</A> Itoh T. Matsuya Y. Enomoto Y. Nagata K. Miyazaki M. Ohsawa A. Synlett  1999,  1799 

<A NAME="RY04502ST-3A">3a</A> Matsuya Y. Itoh T. Enomoto Y. Ohsawa A. Heterocycles  2000,  53:  2357 

<A NAME="RY04502ST-3B">3b</A> Itoh T. Matsuya Y. Enomoto Y. Ohsawa A. Tetrahedron  2001,  57:  7277 

<A NAME="RY04502ST-4">4</A>

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%).

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:

<A NAME="RY04502ST-5A">5a</A> Itoh T. Nagata K. Miyazaki M. Ohsawa A. Synlett  1999,  1154 

<A NAME="RY04502ST-5B">5b</A> Itoh T. Nagata K. Miyazaki M. Kameoka K. Ohsawa A. Tetrahedron  2001,  57:  8827 

<A NAME="RY04502ST-5C">5c</A> Nagata K. Itoh T. Kameoka K. Miyazaki M. Ohsawa A. Heterocycles  2001,  55:  2269 

<A NAME="RY04502ST-6">6</A>

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.

<A NAME="RY04502ST-7">7</A>

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.

<A NAME="RY04502ST-8">8</A>

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.

<A NAME="RY04502ST-9">9</A>

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

<A NAME="RY04502ST-10">10</A>

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.

<A NAME="RY04502ST-11">11</A> Tietze LF. Zhou Y. Töpken E. Eur. J. Org. Chem.  2000,  2247 

<A NAME="RY04502ST-12">12</A>

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

<A NAME="RY04502ST-13">13</A> Najera C. Yus M. Tetrahedron: Asymmetry  1999,  10:  2245 ; and references cited therein

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