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. 2015 Nov 21;13(43):10705-15.
doi: 10.1039/c5ob01572c.

Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

V V N Phani Babu Tiruveedhula  1 , Kashi Reddy Methuku  1 , Jeffrey R Deschamps  2 , James M Cook  1
Affiliations

Synthesis of aza and carbocyclic β-carbolines for the treatment of alcohol abuse. Regiospecific solution to the problem of 3,6-disubstituted β- and aza-β-carboline specificity

V V N Phani Babu Tiruveedhula et al. Org Biomol Chem. .

Abstract

A novel two step protocol was developed to gain regiospecific access to 3-substituted β- and aza-β-carbolines, 3-PBC (1), 3-ISOPBC (2), βCCt (3), 6-aza-3-PBC (4) and 6-aza-3-ISOPBC (5). These β-carbolines (1-3) are potential clinical agents to reduce alcohol self-administration, especially 3-ISOPBC·HCl (2·HCl) which appears to be a potent anti-alcohol agent active against binge drinking in a rat model of maternally deprived (MD) rats. The method consists of two consecutive palladium-catalyzed reactions: a Buchwald-Hartwig amination followed by an intramolecular Heck-type cyclization in high yield.

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Figures

Figure 1
Figure 1
Structures of 3-PBC (1), 3-ISOPBC (2), βCCt (3), 6-Aza-3-PBC (4) and 6-Aza-3-ISOPBC (5)
Figure 2
Figure 2
ORTEP view of the crystal structure of substituted carbolines 3, 9a, and 9d (Displacement ellipsoids are at the 50% level (β-carboline numbering not followed)
Scheme 1
Scheme 1. Synthesis of Substituted Carboline Analogues
Reagents and conditions: (a) Pd(OAc)2, X-Phos, Cs2CO3, toluene, 100 –140 °C, 15 – 24 h (b) Pd(OAc)2, (t-Bu)3P·HBF4, K2CO3, DMA, 120 °C, 16 h
Scheme 2
Scheme 2. Synthesis of the Carbamate Protected Analogs from Intermediate 7b
Reagents and conditions: (a) (Boc)2O, DMAP, THF, rt, 24 h; (b) Fmoc-CI, 80 °C, Microwave, 1 h; (c) Pd(OAc)2, (t-Bu)3P·HBF4, K2CO3, DMA, 120 °C, 16 h; (d) PdCI2(PPh3)2, NaOAc·3H2O, DMA, 120 °C, 14 h; (e) PdCl2(PPh3)2, NaOAc, DMA, 120 °C, 14 h
Scheme 3
Scheme 3
Retrosynthetic Analysis of 3,6-Disubstituted β-carbolines
Scheme 4
Scheme 4. Regiospecific Synthesis of β-Carbolines (1–2) and Aza-β-Carbolines (4–5)
Reagents and conditions: (a) Pd(OAc)2, rac-BINAP, Cs2CO3, toluene, 110 –140 °C, 5 – 6 h (b) Pd(OAc)2, (t-Bu)3P·HBF4, K2CO3, DMA, 120 °C, 16 h
Scheme 5
Scheme 5. Large-Scale Regiospecific Synthesis of β-Carboline 3-ISOPBC (2)
Reagents and conditions: (a) Pd(OAc)2, rac-BINAP, Cs2CO3, toluene, 110 °C, 15 h (b) Pd(OAc)2, (t-Bu)3P·HBF4, K2CO3, DMA, 120 °C, 16 h
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