Synthesis of the New Furo[3,2-h]isoquinoline Alkaloid, TMC-120B from Aspergillus ustus

Abstract

A total synthesis of a new furo[3,2-h]isoquinoline alkaloid TMC120-B (2), isolated from Aspergillus ustus together with two related compounds, has been completed in sixteen steps. The key step is the synthesis of the appropriate 3,7,8-trisubstituted isoquinoline framework (23) based on a thermal electrocyclic reaction of the 1-aza 6p p-electron system involving the benzene double bond. In addition, the microwave assisted electrocyclic reaction of this system was newly performed.

A Concise Total Synthesis of the Fungal Isoquinoline Alkaloid TMC-120B

“…The total synthesis of 1 was then finalized using an aldol con-densation between 8 and acetone under acidic conditions at a 35% yield. Comparison of NMR spectroscopic data with that of previous reports and isolation from natural extracts confirmed the identity of 1 [1,13].…”

“…This enabled alkylation of the phenol with ethyl bromoacetate to give the second key intermediate 9 in 73% yield. Instead of a Dieckmann condensation [21] and decarboxylation sequence to form the final furanone ring as previously reported, [12][13][14] cyclization was realized using an intramolecular Friedel-Crafts acylation [22]. Hydrolysis to the carboxylic acid and subsequent conversion to the corresponding acid chloride was achieved with sodium hydroxide (NaOH) and thionyl chloride (SOCl 2 ), followed by the addition of aluminum trichloride to assemble the complete scaffold of TMC-120B (1) in 79% yield over two steps.…”

“…The first total synthesis of 1 was reported by With renewed interest in the biological properties of 1, a need for convenient access to this natural product has emerged [3]. The first total synthesis of 1 was reported by Hibino et al in 2003 and consisted of 17 steps from 2,4-dihydroxybenzaldehyde (3) with an overall yield of 1.5% [12,13]. In 2012, the same group reported an improved total synthesis of 1 in 11 steps starting from methyl β-resorcylate (5) with an overall yield of 2.9% (Scheme 1) [14].…”

“…Moreover, in the first total synthesis, the isoquinoline framework 2 was constructed from 3 in 11 steps (7% overall yield), improved by the same group by constructing 4 from 5 in seven steps (16% overall yield); in our work, we simplified the synthesis of isoquinoline framework 6 into three steps (52% overall yield). 3) with an overall yield of 1.5% [12,13]. In 2012, the same group reported an improved total synthesis of 1 in 11 steps starting from methyl β-resorcylate (5) with an overall yield of 2.9% (Scheme 1) [14].…”

A new synthesis of the benzo[c]phenanthridines nornitidine, noravicine, and isodecarine, based on a microwave-assisted electrocyclic reaction of the aza 6π-electron system

“…[18][19][20][21] Nitidine (1e) is a potent inhibitor of topoisomerase II. 21 In our laboratory, we have focused on the construction of fused pyridine ring systems, such as furoisoquinoline, 22 phenanthridine, 23 b-carboline, 24 and azaanthraquinone alkaloids, 25 using a microwave-assisted electrocyclic reaction of the aza 6p-electron system. Here, we describe a new and versatile synthesis of benzo[c]phenanthridine alkaloids, using the microwave-assisted electrocyclic reaction of the aza 6p-electron system to induce bond formation between the C4b and N5-positions 13 in the tetracyclic benzo[c]phenanthridine nucleus (Fig.…”