An enantioselective approach to (−)-aphanorphine featuring a stereoselective oxidative amidation

Abstract

A formal enantioselective synthesis of (2)-aphanorphine (91% ee), that culminates with the preparation of (+)-O-methyl aphanorphine, was achieved. The methodology involves the diastereoselective synthesis of a key 3,5-disubstituted pyrrolidinone intermediate by the intramolecular oxidative amidation of a suitably functionalized a-hydroxy pentenoic acid derivative. A late-stage N-formyl protection, which functions as a latent N-methyl group, is utilized as a simple alternative to a protecting group switch and subsequent N-methylation strategy implemented in all other syntheses of aphanorphine related to the present approach.Aphanorphine (1) 1 is an alkaloid that shares structural features with the analgesic benzomorphan alkaloids eptazocine (3), pentazocine (4) and morphine (5, Fig. 1). This structural resemblance and the synthetically intriguing 3-benzazepine ring system and quaternary stereocenter have all contributed to significant interest in the synthesis of aphanorphine, 2-4 which continues to be a popular target for showcasing new methodology leading to the benzazepine motif. We describe here a synthesis of (+)-O-methyl aphanorphine (2), an immediate synthetic precursor of (2)-aphanorphine.Our interest in aphanorphine stems from our studies on the enantioselective synthesis and applications of a-alkyl a-hydroxy acid derivatives as intermediates to biologically relevant motifs and natural products. 5 We therefore envisaged an a-hydroxy acid based route to aphanorphine as detailed in Scheme 1. The strategy utilizes a stereoselective, intramolecular C-N bond formation as a pivotal step in the synthesis of a key pyrrolidine intermediate. A cyclative Friedel-Crafts alkylation in this pyrrolidine is used, as in previous aphanorphine syntheses, 2a,3a,4f for constructing the bridged benzazepine motif in aphanorphine. The precursor of the pyrrolidine is obtained by a cross metathesis reaction of an enantiomerically enriched a-hydroxy pentenoic acid derivative which, in turn, is obtained by asymmetric allylation of a chiral pyruvate (Scheme 1).Initially, we chose to explore the synthesis of a suitably substituted N-methyl pyrrolidinone as a precursor to the functionalized pyrrolidine motif in aphanorphine. The motivation for this approach was twofold: 1) several substituted N-methyl pyrrolidinones are natural products 6 or motifs in bioactive molecules, 7 and the present study could potentially provide methodology for their synthesis as well; and 2) the starting material for the pyrrolidinone based approach, the a-hydroxy N-methyl amide (R)-8 5f (Scheme 2) is directly obtained by our asymmetric allylation protocol 5f employing an ephedrine-derived chiral pyruvamide. Furthermore, the intramolecular Friedel-Crafts alkylation (Scheme 1) of the N-methyl pyrrolidine, obtained from the pyrrolidinone, could potentially provide the aphanorphine framework. Our studies therefore commenced with (R)-8 (92% ee) which was prepared by the asymmetric allylation of an ephedrine and pyruvic acidderived morpholinone 6 as shown in Sche...

Synthesis of (±)-Aphanorphine Using Rh-Catalyzed Cyclohydrocarbonylation

“…As a possible candidate for bioactivity investigation and an intriguing structure for methodology development, aphanorphine has attracted synthetic chemists’ interest to develop various approaches to its synthesis. These approaches can be generally classified as follows (Scheme ): (1) Friedel–Crafts alkylation of a tertiary carbocation at the C ring with an electron-rich aromatic A ring contributes the largest portion among these approaches. − (2) Similar strategies include radical-initiated coupling or Pd-catalyzed Heck reaction of an aryl halide with an olefin or enol at the C ring. − (3) Transannular substitution in the benzazepine moiety can produce the B and C ring in one step. With suitable arrangements, intramolecular substitution allows formation of a bicyclo[3.2.1] system from a 7-membered ring intermediate. − (4) Preparation of suitable tetraline or dihydronaphthalene derivatives followed by construction of the C ring. − In addition, Grainger et al reported a dithiacarbamate initiated radical cyclization to build the B and C ring followed by construction of the aromatic A ring, which does not belong to those shown above .…”

Total synthesis of dehaloperophoramidine using a highly diastereoselective Hosomi–Sakurai reaction

“…Subsequent Lewis acid catalysed epoxide opening followed by trapping with allylsilane was predicted to lead to 5 with the approach of the allyl nucleophile occurring from the opposite face to the allyl group that is already present. This reaction, which we refer to as a modified Hosomi-Sakurai reaction, 11 has been used in natural product synthesis, 12 but to the best of our knowledge has not been used in the construction of contiguous all-carbon quaternary centres. Alternative approaches to lactam 4 involving the early development of the allyl group in 6 or alkylation of a C11-based ester were explored but were either ultimately unsuccessful or led to significantly longer reaction sequences (data not shown).…”

“…This reaction was robust and scalable with 62 g of 6 being prepared in a single batch and without the need for purification by column chromatography at any stage. Ketone 6 could be resolved by treatment with (R)-tert-butanesulfinamide (12) to generate the readily separable diastereomeric imines 13 and 14 (Scheme 3). This approach was inspired by the reported resolution of a ketone-containing intermediate en route to epiboxidine.…”