Enantioselective Approach to 13a-Methylphenanthroindolizidine Alkaloids

Abstract

The first enantioselective approach to 13a-methylphenanthroindolizidine alkaloids is reported, featuring an efficient stereoselective Seebach's alkylation and Pictet-Spengler cyclization. The proposed and other three most probable structures were ruled out, indicating hypoestestatin 1 needs further assignment.

The Pictet-Spengler Reaction Updates Its Habits

“…Phenanthroindolizidines (50 [71,72]), phenanthroquinolizidines (51 [72]), tetrahydroprotoberberines (53 [67,68]), pyrroloisoquinolines (55 [69,70]), and diketopiperazine-fused THIQs (65 [73], vide infra) embody the tetrahydroisoquinoline skeleton, while indolizinoindoles (57 [74,75]), THBC-imidazolinediones (59 [76]), THBC-piperazinedione (61 [77,78]), the tetracyclic indole alkaloids (S)-harmicine (pyrrole-fused THBC, [66,79]), and (S)-eleagnine (1-methyl THBC, [66,80] represent the THBC-containing polyheterocycles. The additional ring can be already present in the imine substrate before the P-S reaction (type A) or can be built on the THIQ/THBC skeleton exploiting the functionality of some substituents (type B).…”

“…Palladium-catalyzed annulation of highly methoxy-substituted 2,2 -diiodobiphenyls with alkynes provided phenanthrene derivatives 49a, 49b, and 49c, which were transformed into phenanthroindolizidines (n = 1) 50a (R 1 , R 3 = OMe, R 2 = H) and 50b (R 1 , R 3 = H, R 2 = OMe), and phenanthroquinolizidine (n = 2) 51 (R 1 , R 2 = H, R 3 = OMe) by a P-S reaction (Scheme 13) [71]. Conversely, 13a-methylphenanthroindolizidine (n=1) 50c (R 1 = OMe, R 2 = R = H; Scheme 13) was obtained by an enantioselective approach, including inter alia, an efficient stereoselective Seebach's alkylation and P-S cyclization [72]. The additional ring can be an aromatic ring as in protoberberines 53 [67,68], a pyrrole nucleus as in pyrroloisoquinolines (55 [69,70]) and phenanthroindolizidines (50 [71,72]), a piperazine or a diketopiperazine fused ring, as in phenathroquinolizidines 51 [72] and THIQ analogs 65 [73].…”

“…Conversely, 13a-methylphenanthroindolizidine (n=1) 50c (R 1 = OMe, R 2 = R = H; Scheme 13) was obtained by an enantioselective approach, including inter alia, an efficient stereoselective Seebach's alkylation and P-S cyclization [72]. The additional ring can be an aromatic ring as in protoberberines 53 [67,68], a pyrrole nucleus as in pyrroloisoquinolines (55 [69,70]) and phenanthroindolizidines (50 [71,72]), a piperazine or a diketopiperazine fused ring, as in phenathroquinolizidines 51 [72] and THIQ analogs 65 [73].…”

“…Palladium-catalyzed annulation of highly methoxy-substituted 2,2′-diiodobiphenyls with alkynes provided phenanthrene derivatives 49a, 49b, and 49c, which were transformed into phenanthroindolizidines (n = 1) 50a (R1, R3 = OMe, R2 = H) and 50b (R1, R3 = H, R2 = OMe), and phenanthroquinolizidine (n = 2) 51 (R1, R2 = H, R3 = OMe) by a P-S reaction (Scheme 13) [71]. Conversely, 13a-methylphenanthroindolizidine (n=1) 50c (R1 = OMe, R2 = R3 = H; Scheme 13) was obtained by an enantioselective approach, including inter alia, an efficient stereoselective Seebach's alkylation and P-S cyclization [72]. The participation of a sulfinyl group in an ipso electrophilic aromatic substitution reaction was the key step of the syntheses of (S)-(−)-xylopinine 53a [67] and successively of (S)-(−)tetrahydropalmatine 53b and (S)-(−)-canadine 53c [68], natural products that belong to the tetrahydroprotoberberine alkaloids class (Scheme 14).…”

The First Enantioselective Approach to 13a‐Methyl‐14‐hydroxyphenanthroindolizidine Alkaloids – Synthetic Studies towards Hypoestestatin 2

“…In 2007, the first total synthesis of racemic 13a‐methylphenanthroindolizidine was reported by Ishibashi et al, in which cascade radical cyclization was used as the key step 6. Recently, we reported an enantioselective total synthesis of 13a‐methyl phenanthroindolizidine, which uses Seebach's self‐regeneration of stereochemistry (SRS) approach as the key step, and reached the conclusion that the structure of hypoestestatin 1 ( 2a ) had been misassigned 7. As a part of our ongoing research into the synthesis and biological evaluation of phenanthroindolizidine alkaloids,1d,5a,5e,8 we herein report the first enantioselective and general approach to the widely unexplored 14‐hydroxy‐13a‐methylphenanthroindolizidine alkaloids.…”