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TETRAHEDRON Pergamon Tetrahedron 55 (1999) 12309-12312

Diastereoselective Protonation after the Birch Reduction of Pyrroles

A. SchSfer, B. Sch~fer *

BASF AG, Hauptlaboratorium CarI-Bosch-Stral3e 38, D-67056 Ludwigshafen
Received 23 March 1999; revised 16 June 1999; accepted 20 August 1999

Abstract: Non-alkylated 3,4-dehydroprolines are obtained by diastereoselective protonation after Birch reduction of N-Boc-pyrrole carboxylic amides. Based on quantum chemical calculations the mechanism of asymmetric protonation is discussed. © 1999ElsevierScienceLtd. All rights reserved.

Key words: Birch reduction, dehydroproline,diastereoselectiveprotonation, pyrrole
The Birch reduction is one of the most convenient methods for the synthesis of partially hydrogenated aromatic and heteroaromatic compounds. The scope and limitation of this method is well documented in several reviews 1 2 3 4 and the difficulties of reducing pyrroles by this method are well known, s About two years ago, Donohoe published some first examples of reductions and alkylations of pyrrole carboxylic esters and amides. 6 Relatively little is known about asymmetric Birch reductions. In the eighties Schultz did some fundamental investigations in the case of chiral benzoic acid esters7 and amides 8 9. Magnus used this method for the synthesis of a taxane C-ring component. 1° Kinoshita 11 and later Donohoe lz used furan-2-carboxylic acid amides in diastereoselective Birch reductions with lithium in liquid ammonia. In all cases asymmetric protonation is not as selective as alkylation. Most recently Donohoe published the synthesis of alkylated 3,4-dehydroprolines. 13 In this paper we deal with the mechanism of the asymmetric protonation of an enolate resulting from Birch reduction of the electron-deficient pyrrole-2-carboxylic amide 1. Chiral as well achiral methods of syntheses of non-alkylated 3,4-dehydroproline 14 are known in literature, but all of them suffer from several disadvantages) s (S)-3,4-Dehydroproline is an unusual, natural amino acid and useful as an inhibitor of collagen synthesis le. It is also a component of phomopsin A (produced by the fungus Phomopsis leptostromiformis), which acts like Dolastatin 10 17as a potent microtubule inhibitor. 1819

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We consider the asymmetric protonation of the Li-2 complex solvated by ammonia to be the key step for the selective formation of (S. RX Boc I O OMe 2 THF was used as cosolvent in all Birch reductions. After evaporation of ammonia and filtration of lithium chloride. asymmetric protonation is more selective than methylation. the major product is (S.78 .S)-2.78 M RX de (%) 82 90 88 / 50 Li Li Na K Li NH4CI NHiCI NH4CI NH4CI Mel Finally we examined the influence of the temperature. Density functional (DFT) calculations give an approximately tetnhedral coordination of Li. The fourth position can be occupied by either the ether-O atom or a second ammonia ligand. detected by HPLC. Schafer / Tetrahedron 55 (1999) 12309-12312 The amide 1 was synthesised by methods known from the literature starting from 2-(trichloroacetyl)- pyrrole. Schdfer.78 . as shown in figure 1 for . Starting from (S)-1. B. the latter being energetically more favourable by 24 . In both cases there are two diastereomeric isomers.78 . Remarkably.27 kJ/mol (depending on the functional used in DF'I'). the solvent was removed by a rotary evaporator.S)-2 were synthesised by a propane phosphonic acid anhydride-coupling reaction 24 starting from commercially available (S)-3. Table 1: Influence of Temperature. The results using lithium and sodium are similar but the reaction with potassium failed.30 . Authentic material as well as an epimeric mixture (S. In order to get an understanding of the selectivity of the reaction.S)-2 / (R. metal and electrophile (Table 1). ~ 21 22 23 Scheme I 76-81% OMe 1 2. Metal and Electrophile T ('c) .4-dehydroproline respectively from racemic 3. and one bond to an ammonia ligand. we investigated intermediate lithium enolates by means of quantum chemical methods (see below). As expected.12310 A. with two bonds formed to the carbonyI-O atoms of the amide and ester groups in 2. The diastereoselectivity of the reaction was detected from the residue by HPLC. the selectivity decreases with increasing temperature. purified by crystallisation or chromatography and charactedsed by 1H NMR spectroscopy.S)-2. The reaction was quenched by addition of solid ammonium chloride after 1 h reaction time.4-dehydroproline.

ammonia was removed at room temperature.4 (t. a lower selectivity for the alkylation is expected.S)-N-2-(methyloxymethyl)-pyrrolidinocarbonyl)-l-(t-butyloxy-carbonyl). At the equilibrium structures. L~ Computational details All quantum chemical calculations were performed on the density functional theory (DFT) level with the Turbomole program package. The structures in figure 1 also help to rationalise the higher selectivity of protonation compared to alkylation. we calculated molecular energies with valence triple zeta basis sets 30 and one set of polarisation functions on all atoms. After filtration.S)-2 and 4.2 (right). C-DHP).4 (t. B-LYP =7 31 and B3-LYP 31 32 functionals. 24. equipped with a stirrer.42 g (60 mmol) lithium. 26.7 (q. 50 ml THF and 0.1 g 2 was obtained as a brown oil. was filled with 160 ml ammonia.5 . the pyrrolidine ring adopts a conformation which partially hinders the reacting side of the prochiral C atom. which results in a diastereoselectivity of 88 .2 % (R. t-Bu). using the B-P. The RI approximation 28 was used with the B-P and B-LYP functionals. which is in good accordance with the experimental result. After the addition of 10 g of solid ammonium chloride. so that protonation or alkylalk)n should preferably occur on the opposite side. 5p.3 (S. the solvent was removed by a rotary evaporator. 26.A. Schiller. C-Pro).2 g (20 retool) 2-((S)-N-2(methyloxymethyl)-pyrrolidinocarbonyl)-l-(t-butyloxy-carbonyl)-pyrrole((S)-1) dissolved in 20 ml THF was added at . t-Bu). Since the alkylation is sterically more demanding than the protonation. 2s ~ For the optimisation of the molecular structures we used the functionals of Becke and Perdew (B-P) 27 28 and split valence basis sets 2g with polarisation functions on non-hydrogen atoms.9 kJ/mol lower in energy. C-Pro). HPLC of the crude product (Varian. CPro). 13C NMR (D6-DMSO. since due to the coordination of the two ammonia ligands.9 (d. 250 x 4 mm. Expedmental (2): A 1 I round-bottomed flask.4 (t.5. 27.S)-2 (16 mmol.95 %.9 (t. CH3CN / H20): 79. C-Pro). Schilfer / Tetrahedron 55 (1999) 12309-12312 12311 the complex with two ammonia ligands.~3-pyrroline . Figure 1: Dlastereomeric complexes leading to (S. In the case of two ammonia ligands.78 °C. 6.3 (q. the isomer leading to (S.m. The reaction mixture was stirred for 1 h. yield: 81%). 2-((S. a dropping funnel and a reflux condenser. 45.S)-2 is 4. 5 (ppm)): 23. B. t-Bu). TMS. The coordination of the ether group or the second ammonia ligand leads to a sterical hindrance of the respective side of the prochiral C atom. 6. 52. 55. Merck Lichroapher RP 60 Select B.S~.S)-2 (left) and (R.6 (q.

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