Diastereoconvergent Synthesis of trans-5-Hydroxy-6-Substituted-2-Piperidinones by Addition–Cyclization–Deprotection Process

Abstract

A diastereoselective one-pot approach to access trans-5-hydroxy-6-substituted-2-piperidinones by an addition-cyclization-deprotection process has been developed, in which the stereogenic center at the C-6 position was solely controlled by α-OTBS group. The utility of this transformation is demonstrated by the asymmetric synthesis of the enantiomer of (-)-CP-99,994.

Synthesis of Enantiopure Mixed Alkyl-Aryl Vicinal Diamines by the Diaza-Cope Rearrangement: A Synthesis of (+)-CP-99,994

“…An NK1 receptor antagonist, CP-99,994 has been synthesized by several research groups within 10–20 synthetic steps. − Recently, Bhat reported an efficient 4-step synthesis of (+)-CP-99,994 from l -ornithine in an overall yield of 40% . However, this method provides other cis -disubstituted piperidines with 74–92% de.…”

“…Ivory solid (356 mg, 92% yield); 1 H NMR (400 MHz, DMSO- d 6 ): δ ppm 7.86 (d, J = 7.6 Hz, 1H), 7.51–7.36 (m, 3H), 7.08–7.04 (m, 2H), 6.84–6.78 (m, 2H), 6.76–6.69 (m, 2H), 6.67–6.63 (m, 2H), 5.58 (s, 1H), 4.53 (d, J = 8.6 Hz, 1H), 4.46 (d, J = 8.6 Hz, 1H); 13 C NMR (100 MHz, DMSO- d 6 ): δ ppm 156.9, 156.8, 139.2, 132.8, 129.6, 129.4, 129.1, 128.6, 128.2, 128.1, 127.8, 127.4, 123.9, 123.8, 118.4, 118.3, 116.1, 115.9, 71.1, 66.3, 64.5; HRMS (ESI) m / z : [M+H] + calcd for C 21 H 20 ClN 2 O 2 367.1213, Found 367.1213; [α] D −2.4 ( c 1.0, DMSO).…”

“…Yellow oil (75.8 mg, 82% yield); 1 H NMR (400 MHz, CDCl 3 ): δ ppm 12.95 (s, 1H), 12.68 (s, 1H), 8.31 (s, 1H), 8.30 (s, 1H), 7.31–7.24 (m, 2H), 7.20–7.12 (m, 2H), 6.94–6.88 (m, 2H), 6.84–6.77 (m, 2H), 4.91 (d, J = 9.0 Hz, 1H), 3.83 (m, 1H), 1.70–1.51 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ ppm 167.9, 167.3, 161.0, 160.9, 133.2, 132.8, 132.2, 131.9, 119.1, 119.0, 118.4, 118.2, 117.1, 117.0, 73.6, 68.6, 25.9, 10.6; 19 F NMR (376 MHz, CDCl 3 ): δ ppm −140.5 (dd, J = 22.4, 7.8 Hz, 2F), −153.6 (t, J = 20.9 Hz, 1F), −160.5 (td, J = 22.1, 8.2 Hz, 2F); The enantiopurity was confirmed by HPLC analysis (Chiralpak IB column, 2% isopropanol in hexanes, 0.5 mL/min); ( S , S )- 5l t R = 10.2 min, ( R , R )- 5l t R = 11.2 min; HRMS (ESI) m / z : [M+H] + calcd for C 24 H 20 F 5 N 2 O 2 463.1445, Found: 463.1449; [α] D −186.3 ( c 1.0, CHCl 3 ).…”

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

“…The stereoselective synthesis of trans-5-hydroxy-6-substituted-2-piperidinones was also reported by the group of Wei, taking advantage of the addition of Grignard reagents to N-tert-butanesulfinyl α-alkoxy aldimines 126 [124]. In this one-pot approach, a successive nucleophilic addition-cyclization-desulfinylation took place, leading directly to piperidinones 127.…”

Copper Promoted Oxidative Coupling of SnAP Hydrazines and Aldehydes to Form Chiral 1,4,5‐Oxadiazepanes and 1,2,5‐Triazepanes

“…Saturated nitrogen heterocycles have attracted considerable attention due to their wide range of pharmacological activities . A number of modern methods are devoted to their construction and impressive progress in hydroamination, C–H functionalization, α ‐lithiation, or annulation methodologies have improved access to these structures. To this end, our group has introduced SnAP (Sn (tin) amine protocol) reagents, and SLAP (silicon amine protocol) reagents for the one‐step transformation of aldehydes and ketones to saturated, substituted, N‐unprotected aza‐heterocycles as thiomorpholines, morpholines, piperazines, piperidines, pyrrolidines, medium‐sized rings, and spirocycles.…”