Organocatalytic Enantioselective Pictet–Spengler Approach to Biologically Relevant 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline Alkaloids

Abstract

A general procedure for the synthesis of 1-benzyl-1,2,3,4-tetrahydroisoquinolines was developed, based on organocatalytic, regio- and enantioselective Pictet-Spengler reactions (86-92% ee) of N-(o-nitrophenylsulfenyl)-2-arylethylamines with arylacetaldehydes. The presence of the o-nitrophenylsulfenyl group, together with the MOM-protection in the catechol part of the tetrahydroisoquinoline ring system, appeared to be a productive combination. To demonstrate the versatility of this approach, 10 biologically and pharmaceutically relevant alkaloids were prepared using (R)-TRIP as the chiral catalyst: (R)-norcoclaurine, (R)-coclaurine, (R)-norreticuline, (R)-reticuline, (R)-trimemetoquinol, (R)-armepavine, (R)-norprotosinomenine, (R)-protosinomenine, (R)-laudanosine, and (R)-5-methoxylaudanosine.

Occurrence of Enantioselectivity in Nature: The Case of (S)‐Norcoclaurine

“…In 2013, a ruthenium‐catalyzed double‐bond isomerization combined with an enantioselective Pictet‐Spengler type cyclization was envisaged for the synthesis of enantiopure THIQs . Hiemstra and colleagues have just reported a general enantioselective approach to the synthesis of 1‐benzyl‐1,2,3,4‐THIQs through a BINOL‐phosphoric acid [( R )‐TRIP]‐catalyzed asymmetric Pictet‐Spengler reaction. The innovation is represented by the introduction of a moderately strong electron‐withdrawing group on the nitrogen atom of the phenylethylamine.…”

Chiral Thioureas Promote Enantioselective Pictet–Spengler Cyclization by Stabilizing Every Intermediate and Transition State in the Carboxylic Acid-Catalyzed Reaction

“…18–20 The enzymes catalyzing these transformations have been scrutinized by the structural biology and enzymology communities, 3,16,17,21–23 and parallel attention has been devoted to the development of small molecule catalysts for stereocontrolled Pictet–Spengler reactions. 24–35 …”

Design and Use of de novo Cascades for the Biosynthesis of New Benzylisoquinoline Alkaloids

“…[12][13][14] In addition, their incorporation into enzymatic and chemoenzymatic cascades to give THIAs in high yields and stereoselectivity has demonstrated their potential in sustainable synthesis. [20][21][22] Synthetic biology has provided an ew approach to BIA biosynthesis in recent years.I ndeed, the reconstruction of BIA pathways in microorganisms,s uch as E. coli or S. cerevisiae,w ith bacterial or plant enzymes has enabled the production of BIAs through fermentation in vivo (Scheme 1A), although racemic NCS products were noted in an umber of cases. [19] Thes tructural complexity of many BIAs also means that chemical synthesis through multistep procedures are not viable on an industrial scale.…”

“…Overall the reactions demonstrate that EfTyrDC is an extremely efficient and versatile decarboxylase that provides anovel route to 14, 15, 17,and 18. [16] Thed opamine formed was converted into 2-(3,4-dihydroxyphenyl)-acetaldehyde (22)by CvTAma nd addition of TfNCS gave (S)-21 in 53 %y ield of isolated product (98 %y ield by analytical HPLC) and more than 97 % ee. [16,17,39,40] Initially,t hree cascades were developed using l-tyrosine (4,2 .5 mm ;T able 2, entries 1-3).…”

“…[19] Thes tructural complexity of many BIAs also means that chemical synthesis through multistep procedures are not viable on an industrial scale. [20][21][22] Synthetic biology has provided an ew approach to BIA biosynthesis in recent years.I ndeed, the reconstruction of BIA pathways in microorganisms,s uch as E. coli or S. cerevisiae,w ith bacterial or plant enzymes has enabled the production of BIAs through fermentation in vivo (Scheme 1A), although racemic NCS products were noted in an umber of cases. [23][24][25][26][27][28][29] Additionally, such heterologous pathways can also be achieved by combining enzymes into cascade reactions in vitro (Scheme 1B).…”