Highly Stereoselective Total Syntheses of (±)‐Chelidonine and of (±)‐Norchelidonine by an Intramolecular o‐Quinodimethane/Nitrostyrene‐Cycloaddition

Abstract

Conversion of 2‐bromomethylstyrene 22 and benzocyclobutenyl carbamate 28 to the benzophenanthridine alkaloids (±)‐chelidonine (1, five steps, 25% from 28) and to (±)‐norchelidonine (2, six steps, 24% from 28) are described. The key step 29 → 31 involves a highly regio‐ and stereocontrolled intramolecular Diels‐Alder reaction of the (E)‐quinodimethane 30.

Concise Enantioselective Total Syntheses of (+)‐Homochelidonine, (+)‐Chelamidine, (+)‐Chelidonine, (+)‐Chelamine and (+)‐Norchelidonine by a PdII‐Catalyzed Ring‐Opening Strategy

“…The spectroscopic properties of the synthetic material were in agreement with those of the natural product 2g. 14d Regioselectively ring‐opening epoxide intermediate 52 with H 2 O in the presence of a catalytic amount of BiCl 3 gave diol 53 in 86 % yield. Heating diol 53 with LiAlH 4 reduced the carbamate group to the methylamine to give (+)‐chelamine ( 5 ) in 93 % yield.…”

“…(+)‐Chelidonine (4) :14d Following the procedure to prepare (+)‐homochelidonine ( 2 ), the addition of LiAlH 4 (9 mg, 0.24 mmol) to epoxide 52 (30 mg, 0.06 mmol) in 1,4‐dioxane (1.5 mL) gave after work‐up and column chromatography (50 % EtOAc in hexane) (+)‐chelidonine ( 4 ) (18 mg, 88 %) as a white solid. M.p.…”

“…These include racemic syntheses of homochelidonine,13 chelamidine,13c chelidonine,14 chelamine14e and norchelidonine 14a. d An asymmetric synthesis of the B/C hexahydrobenzo[ c ]phenanthridine basic skeleton has also been described 15…”

The Diels-Alder Reaction in Total Synthesis

“…Upon heating 141 in refluxing o ‐xylene, reversible conrotatory ring opening indeed furnished a highly reactive o ‐quinodimethane ( 142 ) that immediately engaged the pendent alkyne moiety in a productive Diels–Alder union to afford polycyclic system 143 in 73 % overall yield which served as the progenitor of the targeted natural product. Significantly, Oppolzer and Robbiani optimized this cyclobutene‐opening methodology72b to achieve greatly enhanced yields of 143 . They also further extended this insightful Diels–Alder approach to heterocyclic systems by using tethered imines as substrates, thus paving the way for a plethora of subsequent applications 73…”

Biosynthetic Relationships and Total Syntheses of Naturally Occurring Benzo[c]Phenanthridine Alkaloids

“…The latter was reacted with silver nitrate in the presence of iodine afforded β‐nitrostyrene derivative 49 d , which under elevated temperature furnished inverse‐Diels‐Alder product 49 f via the intermediacy of 49 e . Next, the replacement of the nitro group by an oxo group was carried out by treatment with TiCl 3 , and sodium methoxide to afford ketone 49 g (Scheme ) –. The unstable ketone 49 g was reduced with AlH 3 to furnish (±)‐chelidonine ( 18 a ).…”