Total Synthesis of Calothrixin B via an Intramolecular Baylis‐Hillman Cyclization/6π Electrocyclization/Dehydro‐aromatization Sequence and a Specific Oxidative Quinone Formation

Abstract

A short total synthesis of bioactive alkaloid calothrixin B have been accomplished with atom and step economy from commercially available starting materials. The key cyclization involved a Baylis−Hillman/6π electrocyclization/dehydroaromatiz‐ation sequence to construct the pentacyclic skeleton. Reduction of the resulting lactam followed by oxidation led to the characteristic quino[4,3‐b]carbazole framework. This intermediate underwent a direct oxidation with high regioselectivity to yield the final product.magnified image

Synthesis of Cytotoxic Quino[4,3-b]carbazole Frameworks through an Intramolecular Diels–Alder Reaction

“…Mp: 160−162 °C; 1 H NMR (300 MHz, CDCl 3 ): δ 8.17 (dd, J 1 = 9.0 Hz, J 2 = 4.5 Hz, 1 H), 7.89−7.81 (m, 3 H), 7.78−7.70 (m, 3 H), 7.66− 7.61 (m, 1 H), 7.55−7.47 (m, 3 H), 7.42−7.35 (m, 3 H), 7.18 (td, J 1 = 8.4 Hz, J 2 = 2.7 Hz, 1 H), 7.12 (dd, J 1 = 8.4 Hz, J 2 = 2.4 Hz, 1 H), 7.04 (td, J 1 = 9.0 Hz, J 2 = 2.4 Hz, 1 H), 6.75 (s, 1 H), 6.65 (dd, J 1 = 9.3 Hz, J 2 = 2.7 Hz, 1 H), 4.37 (s, 2 H), 1.63 (t, J = 2. 1 Hz,3 H) = 3.7 Hz),133.9,133.2,131.4,(d,J C−F = 9.7 Hz),129.2,128.9,128.3,128.2,128.0,126.8,120.33,120.30,116.8 (d, ), 82.7, 72.6, 42.4, 3.3…”

“…Mp: 104−106 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 8.15−8.08 (m, 1 H), 7.75 (d,J = 7.6 Hz,2 H),1 H),3 H),2 H),6.85 (d,J = 3.1 Hz,1 H),4 H),3.77 (d,J = 22.2 Hz, 2 H), 1.30 (t, J = 7.0 Hz, 6 H) ppm; 13 C{ 1 H} NMR (75 MHz, CDCl 3 ): δ 138. 4, 136.8, 133.7, 131.1, 131.0, 129.5, 129.1, 126.2, 124.4, 123.8, 120.6, 114.9, 112.6, 112.5, 77.4, 62.45, 62.37, 26.0 (d, J C−P = 141.7 Hz), 16.32, 16.24 Diethyl ((5-Fluoro-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)phosphonate 9b.…”

“…Subsequent removal of solvent in vacuo gave phosphonate ester 9b (4.3 g, 74%) as a thick brown liquid. 1 H NMR (300 MHz, CDCl 3 ): δ 8.06 (dd, J 1 = 9.3 Hz, J 2 = 4.5 Hz, 1 H), 7.73 (d,J = 8.1 Hz,2 H),1 H),2 H) Diethyl ((5-Chloro-1-(phenylsulfonyl)-1H-indol-2-yl)methyl)phosphonate 9c. The Michaelis-Arbuzov reaction of 5chloro-2-bromomethylindole 6c (4.5 g, 11.78 mmol) with triethyl phosphite (2.0 mL, 17.67 mmol) was performed at reflux under N 2 for 3 h. After consumption of the bromo compound (monitored by TLC), the reaction mass was poured over crushed ice containing conc.…”

“…The Wittig−Horner reaction of phosphonate ester 9a (3.5 g, 8.59 mmol) using 4-fluoro-2-nitrobenzaldehyde 10b (1.7 g, 10.31 mmol) in the presence of NaH (0.51 g, 12.89 mmol) in dry THF at 0 °C for 30 min followed by workup using the above-mentioned general procedure A afforded 2-(4-fluoro-2-nitrostyryl) indole 11b (2.9 g, 80%) as a bright yellow solid. Mp: 170−172 °C; 1 H NMR (300 MHz, CDCl 3 ): δ 8.26 (d,J = 8.1 Hz,1 H),4 H),9 H),6.86 (s,1 H) 148.3, 138.7, 138.2, 137.8, 133.9, 130.6 (d, = 3.7 Hz),126.2,126.2,125.5,124.4,124.3,124.3,121.2,120.9,115.4,112.3 (d, 9, 138.4, 137.8, 137.6, 134.2, 133.9, 133.6, 130.9, 129.9, 129.8, 129.1, 126.5, 125.9, 125.5, 124.9, 124.5, 124.4, 121.2, 115.3, 111. ), 148.2, 140.6, 137.9, 134.0, 133.4, 132.3, 131.2 (d, 10.5 Hz),129.2,128.81,128.78,127.9,126.6,124.8,123.7,116.5 , 1 H), 7.80−7.60 (m, 5 H), 7.45−7.30 (m, 5 H), 7.06−7.99 (m, 2 H), 6.86−6.77 (m, 1 H) ppm; 13 C{ 1 H} NMR (75 MHz, CDCl 3 ): δ 161 9b (3.9 g, 9.17 mmol) using 4-chloro-2-nitrobenzaldehyde 10c (2.0 g, 11.01 mmol) in the presence of NaH (0.55 g, 13.76 mmol) in dry THF at 0 °C for 30 min followed by workup using the abovementioned general procedure A afforded 2-(4-chloro-2-nitrostyryl) indole 11f (3.0 g, 71%) as a bright yellow solid. Mp: 200−202 °C; 1 H NMR (300 MHz, CDCl 3 ): δ 8.14 (dd, J 1 = 9.0 Hz, J 2 = 4.5 Hz, 1 H 148.2, 140.2, 137.9, 134.6, 134.0, 133.6, 131.1 (d, = 9.7 Hz),130.8,129.8,129.2,…”

Total Synthesis and Structural Revision of the 6,11-Epoxyisodaucane Natural Sesquiterpene Using an Anionic 8π Electrocyclic Reaction

“…Electrocyclic reactions have long been used as powerful methods for constructing the carbocyclic moieties in natural products . To date, a number of natural product syntheses that use 6π electrocyclization, 8π electrocyclization, or cationic 4π electrocyclization (e.g., Nazarov cyclization) as key steps have been reported. However, anionic 8π electrocyclization chemistry for the formation of seven-membered carbocycles appears not to have been developed …”