Concise and Efficient Synthesis of Calothrixin B

Abstract

A convergent synthesis of the naturally occurring alkaloid Calothrixin B is presented, which used a regioselective hetero-Diels-Alder reaction between a "push-pull" 2-aza-diene and a N-protected 3-bromo-9H-carbazole-1,4-dione to construct the five-ring skeleton of the molecule. Protection of the indole motif with a benzyl group was unattractive for delivery of sufficient target material because the removal of the protecting group had not been high yielding. We therefore elected to temporarily protect the indole motif with a more labile benzyloxycarbonyl group. Accordingly, the synthesis of calothrixin B proceeded in 17% overall yield over 9 steps from the commercially available 1,2,3,9-tetrahydro-4H-carbazol-4-one.

Iodine-catalyzed aromatization of tetrahydrocarbazoles and its utility in the synthesis of glycozoline and murrayafoline A: a combined experimental and computational investigation

“…However, protection of the hydroxyl motif of 7 by the alkyl group meant that compatible conditions could not be established. Sissouma 16 proposed the total synthesis of Calothrixin B without protection of the indole nitrogen using enolate formation, followed by dehydrogenation. We thought that enolation of substrate 6 followed by oxidative dehydrogenation with molecular iodine could achieve product 8.…”

Total synthesis of calothrixins A and B via oxidative radical reaction of cyclohexenone with aminophenanthridinedione

“…Finally, the debenzylation of compound 13 was carried out by following a previously reported literature procedure using AlCl 3 and anhydrous benzene to furnish calothrixin B ( 2 ) in 40 % yield. 12b In order to improve the yield of this step, we attempted other debenzylation reaction conditions such as H 2 in the presence of Pd/C or Pd black/HCOONH 4 . But, these reactions resulted in lower yields than what we obtained with AlCl 3 .…”

“…4-9 The first total synthesis of calothrixins was reported by Kelly, using an o -lithiation strategy. 10 Several other syntheses of calothrixins have also been reported exploring different synthetic strategies such as metallations, 11 hetero Diels-Alder, 12 Friedel-Crafts acylation reaction, 11a, 13 etc. A few other syntheses of calothrixins have also been reported.…”

Synthesis of Thiazolo- and 7,8-Dihydrothiazolo[4,5-e]benzoisoxazoles

“…of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Scheme 2). 25 In the absence of DDQ, a mixture of 4 and 5 (25:75, respectively) was obtained. A common characteristic of 4 in the subsequent N -acylation reaction is the low nucleophilicity of the thiazol-2-amine functionality, which dictates the use of high temperature and an excess of acylating agent.…”