Enantioselective Formal Total Synthesis of (−)-Quinagolide

Abstract

The enantioselective formal total synthesis of (−)-quinagolide has been accomplished in a linear sequence of 8 purification steps from pyridine. The key steps are (a) organocatalyzed Diels–Alder reaction for fixing all three stereocenters on piperidine ring; (b) protecting group enabled deoxygenation of isoquinuclidine skeleton under Birch reduction condition; (c) Lewis acid (TiCl4) catalyzed intramolecular Friedel–Crafts cyclization of dicarboxylic acid; and (d) one-pot diastereoselective ketone reduction–intramolecular cyclization to form oxazolidinone which enables trans-geometry installation. During the course of the synthesis, an interesting reductive cleavage of the C–N bond in the electron-deficient isoquinuclidine skeleton under the Birch reduction conditions has been observed. This is the first synthetic effort to access the core skeleton of (−)-quinagolide.

Asymmetric Synthesis of Bridged N-Heterocycles with Tertiary Carbon Center through Barbas Dienamine-Catalysis: Scope and Applications

“…Especially, 2-azabicyclo[2.2.2]­octane, also known as isoquinuclidine, is widely present in natural products in addition to pharmaceutically active compounds ( I – IV , Scheme a) . Moreover, this structural unit has attracted significant attention as a viable synthetic precursor for many other bioactive alkaloids and drug molecules . Among the existing protocols, [4 + 2] cycloaddition between 1,2-dihydropyridines (DHPs) and dienophiles to access chiral isoquinuclidines appears as a general method .…”

Direct Amine-Catalyzed Enantioselective Synthesis of Pentacyclic Dibenzo[b,f][1,4]oxazepine/Thiazepine-Fused Isoquinuclidines along with DFT Calculations

“…In this context, 2-azabicyclo[2.2.2]­octane, an isoquinuclidine ring system, appears to be a core motif widely present in several natural products, such as catharanthine, ibogaine, caldaphinidine D, securinol A, and dioscorine ( I – V ) (Scheme a), and active pharmaceutical ingredients . Some of these natural alkaloids and their derivatives display exciting biological activities. , Furthermore, this bicyclic skeleton also serves as a feedstock to access natural products like scaffolds and marketed drug Tamiflu . Consequently, great synthetic endeavors have been continuously devoted to this valuable bicyclic unit asymmetrically .…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 7.55 (dd, J = 8.3, 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.02−6.97 (m, 1H), 6.85 (d,J = 8.3 Hz,1H),2H), 5.35 (d, J = 2.1 Hz, 1H), 4.18 (p, J = 3.0 Hz, 1H), 3.00 (q, J = 2.8 Hz, 1H), 2.60 (dt, J = 18.8, 3.0 Hz, 1H), 2.48 (dd, J = 18.8, 2.8 Hz, 1H), 2.31 (dddt, J = 13.3, 10.9, 5.5, 2.9 Hz, 1H), 2.19 (tdd,J = 11.0,4.6,3.2 Hz,1H),2.11 (dddd,J = 14.1,11.3,5.2,3.0 Hz,1H),1.83 (dddd,J = 13.2,11.1,4.7,2.2 Hz, 1H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 212. 3, 156.4, 143.7, 140.1, 138.3, 136.1, 133.1, 129.4, 122.7, 122.5, 118.9, 114.4, 87.5, 58.9, 49.2, 46.0, 45.5, 23.2, 22.5 (1S,4S,14bR) 3,4,f ]pyrido [1,2-d][1,4]oxazepin-2-one (4w). Purification with petroleum ether/EtOAc (8.5/1.5) as the eluent; yellowish solid (81 mg, 72% yield, mp = 158−160 °C); the enantiomeric ratio (er = 99:1) was determined on a Chiralpak IA column (n-hexane/2-propanol = 90/10, flow rate 0.5 mL/min), t R = 14.95 min (major), t R = 22.17 min (minor).…”

“…1 H NMR (400 MHz, CDCl 3 ) δ 1 H NMR (400 MHz, CDCl 3 ) δ 7.09−6.96 (m, 3H), 6.67 (s, 1H), 5.43 (d, J = 2.0 Hz, 1H), 4.16 (t, J = 2.9 Hz, 1H), 3.03 (q, J = 2.7 Hz, 1H), 2.56 (d,J = 18.8 Hz,1H), 2.46 (dd, J = 18.8, 2.7 Hz, 1H), 2.37 (s, 3H), 2.32−2.24 (m, 1H), 2.20 (dt, J = 10.8, 3.7 Hz, 1H), 2.17−2.06 (m, 1H), 1.83 (tdd, J = 12.2, 4.1, 2.1 Hz, 1H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 212. 6,153.5 (d,J = 251.7 Hz),143.4 (d,J = 11.9 Hz),140.1,138.8,136.9,129.6,128.5,125.3,125.2 (d,J = 7.2 Hz), 119.0 (d,J = 3.6 Hz),116.7 (d,J = 18.5 Hz),113.0,59.2,49.7,46.1,46.0,23.2,22.7,17.2 (1S,4S,14bR) 3,4,f ]pyrido [1,2-d][1,4]oxazepin-2-one (4y). Purification with petroleum ether/EtOAc (8.5/ 1.5) as the eluent; brownish solid (95 mg, 70% yield, mp = 226−229 °C); the enantiomeric ratio (er = 99:1) was determined on a Chiralpak IA column (n-hexane/2-propanol = 90:10, flow rate 0.5 mL/min), t R = 14.03 min (minor), t R = 15.51 min (major).…”

“…[α] D 25 = +8.9 (c 0.1, CH 2 Cl 2 ). (1S,4S,14bR)- 3,4,4ethanodibenzo[b,f ]pyrido [1,2-d][1,4]thiazepin-2-one (6e). Purification with petroleum ether/EtOAc (9/1) as the eluent; yellow solid (66 mg, 65% yield, mp = 216−218 °C); the enantiomeric ratio (er = 99:1) was determined on a Chiralpak IA column (n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min), t R = 10.77 min (minor), t R = 13.17 min (major).…”