Lipase-Catalyzed Asymmetric Synthesis of Desprenyl-carquinostatin A and Descycloavandulyl-lavanduquinocin

Abstract

The carbazole-3,4-quinone alkaloids, carquinostatin A (1) 1) and lavanduquinocin (2) 2) were isolated from Streptomyces exfoliates 2419-SVT2 and Streptomyces viridochromogenes by Seto and co-workers in 1993 and 1995, respectively. The structures of the two alkaloids were elucidated to be the same carbazole-3,4-quinone moiety by NMR spectral analyses and other spectroscopic experiments. The absolute stereochemistry of the C-11 position of the two alkaloids was the same R-configuration. Carquinostatin A (1) and lavanduquinocin (2) were also shown to be a potent neuronal cell protecting substance which exhibits a free radical scavenging activity. Total syntheses of these alkaloids have recently been developed by the Knölker group. [3][4][5][6][7][8] The transition metalmediated and -catalyzed methodologies for the construction of the carbazole framework have been efficiently employed.Throughout the course of this study, we have been interested in the synthetic development of biologically active condensed-heteroaromatic compounds, including natural products, by the thermal electrocyclic reactions of either conjugated hexatriene [9][10][11][12][13][14][15][16][17] or monoazahexatriene 18) systems incorporating one double bond from an aromatic or heteroaromatic portion. We recently reported the synthesis of the highly substituted carbazole alkaloids, carazostatin 9) and carbazoquinocins, 9,10) by the construction of the appropriate carbazole framework based on the allene-mediated electrocyclic reaction of the 6p-electron system involving the indole 2,3-bond. In the present paper, we describe the asymmetric synthesis of 6-desprenyl-carquinostatin A (6-descycloavandulyllavanduquinocin) 3, which is a common carbazole framework of both alkaloids, based on a lipase-catalyzed esterification using a racemic alcohol 6 for the determination of the absolute stereochemistry of 3. We chose the 3-ethoxy-2-methyl-1-(trifluoromethylsulfonyloxy)carbazole (4), 9,10) as a starting material, which was prepared in a six-step sequence from 3-iodoindole-2-carbaldehyde by the application of our methodology, as shown in the retrosynthetic Chart 1.The required 1-allylcarbazole 5 was prepared from the triflate 4 and allyboronic acid pinacol ester in the presence of PdCl 2 (dppf) in dimethylformamide (DMF) by the SuzukiMiyaura reaction. 19,20) An asymmetric synthesis of the core carbazole structure, 6-desprenyl-carquinostatin 3 and 6-descycloavandulyl-lavanduquinocin 3, toward a total synthesis of carquinostatin A (1) and lavanduquinocin (2)

Total Synthesis of (&plusmn;)-Carquinostatin A, and Asymmetric Total Synthesis of (<i>R</i>)-(−)-Carquinostatin A and (<i>S</i>)-(+)-Carquinostatin A

“…First, to synthesize (±)-carquinostatin A (1), the key compound, 1-acetonyl-3-ethoxy-2-methylethoxycarbazole (5), 31) which was prepared by an allene-mediated electrocyclic reaction generating from 2-ethenyl-3-propargylindole, was used as a starting material. In Chart 1, treatment of carbazole 5 with Regular Article * To whom correspondence should be addressed.…”

“…31) In accordance with this procedure, the (R)-(−)-acetate 15a (45%, [α] D −122.8°, 98%ee) and the (S)-(+)-alcohol 15b, (43%, [α] D +42°, 97%ee) were prepared from 1-acetonylcarbazole 5. These compounds, 15a and 15b were already determined to be the R-and S-configurations, respectively, using the advanced Mosher method 32,33) (Chart 3).…”

“…In summary, a novel total synthesis of (±)-carquinostatin A (1) in eight steps was established using the previously reported 1-acetonyl-3-ethoxy-2-methylcarbazole (5) 31) (50% overall yield). Although direct introduction of the prenyl group at the 6-position of carbazole failed, the desired prenyl group was converted by olefin metathesis of 6-allylcarbazole 11.…”

“…Although direct introduction of the prenyl group at the 6-position of carbazole failed, the desired prenyl group was converted by olefin metathesis of 6-allylcarbazole 11. Asymmetric syntheses of (R)-(−)-carquinostatin A (1a) and (S)-(+)-carquinostatin A (1b) starting from (R)-(−)-acetate 15a and (S)-(+)-diol 15b 31) were achieved in 57% and 75% overall yields, respectively. Another route to (R)-(−)-carquinostatine A (1a) in nine steps was established from the key compound 5 through 6-bromocarbazole 6 (22% overall yield).…”

“…1), which was prepared using an allene-mediated electrocyclic reaction. 31) In the present paper, we report a new total synthesis of (±)-carquinostatin (1), and an asymmetric total synthesis of (…”