Three-Step Catalytic Asymmetric Total Syntheses of 13-Methyltetrahydroprotoberberine Alkaloids

Abstract

(S,R)-N-PINAP was identified to be the chiral ligand for highly enantioselective CuI-catalyzed reaction of tetrahydroisoquinolines (THIQs), alkynes, and 2-bromobenzaldehyde derivatives. This enables us to accomplish the first asymmetric total synthesis of 12 natural 13-methyltetrahydroprotoberberine (13-MeTHPB) alkaloids in only three catalytic steps with 47-64% overall yields. In addition, the Pd-catalyzed reductive Heck cyclization was successfully extended to three Pd-catalyzed domino reactions (Heck/Suzuki, Heck/Sonogashira, and Heck/Heck), which greatly expands the synthetic utility of this catalytic strategy and allows expeditious access to 13-substituted tetrahydroprotoberberines for further bioactivity evaluation.

Gold Catalyzed Photoredox C1‐Alkynylation of N‐Alkyl‐1,2,3,4‐tetrahydroisoquinolines by 1‐Bromoalkynes with UVA LED Light

“…[10,13] The intra-or intermolecular coupling of the radical species generated in this manner were subsequently shown to produce a variety of synthetically valuable targets. [4,5] The proposed radical formation step is also shown to differ from that delineated in a previous study and this work exploring the dimeric Au(I)-mediated reactions of 1-iodoalkynes, which were found to occur via an oxidative quench pathway. To our knowledge, the analogous Au 2 (I,I)-catalyzed photoredox reactions involving radical species III and IV generated from the respective N-heterocycle and alkynyl halide to effect C(sp 3 )ÀC(sp) bond formation has so far remained unrealized.…”

“…In contrast to our earlier findings disclosed in Table 1, entry 10 showing that 3 aa could be obtained in 82% when the molar ratio of 1 a:2 a = 4:1, this led us to believe that the present reaction might occur by a reductive quench pathway. [10h] This was further supported by results furnished on repeating these reactions once more but with (iodoethynyl) benzene 2 m in place of 2 a (entries [3][4][5]. [10h] This was further supported by results furnished on repeating these reactions once more but with (iodoethynyl) benzene 2 m in place of 2 a (entries [3][4][5].…”

“…[5] As shown in Scheme 2, treating 3 ea with 10% mol of Pd(PPh 3 ) 4 in DMF and water (1:1 v/v) at 100 8C for 2 h was found to give the nitrogen-containing tetracyclic adduct 4 in 87% yield. [5] As shown in Scheme 2, treating 3 ea with 10% mol of Pd(PPh 3 ) 4 in DMF and water (1:1 v/v) at 100 8C for 2 h was found to give the nitrogen-containing tetracyclic adduct 4 in 87% yield.…”

“…[8][9][10]16] With the reaction of substrates 1 a and 2 a as a representative example, this could initially involve the exciplex species V of the dinuclear gold(I) complex being generated as it absorbs the UVA LED light. 1 a (4) + 2 m (1) --31 11 5 1 a (1) + 2 m (4) --20 77 As a result, this delivers the nitrogencentered THIQ radical cation species VIa and [Au I ÀAu 0 ] + complex VIIa.…”

“…[1][2][3][4][5][6] The nitrogen-containing heterocycle is also a versatile building block in organic synthesis and drug discovery programs. [1][2][3][4][5][6] The nitrogen-containing heterocycle is also a versatile building block in organic synthesis and drug discovery programs.…”