A Formal Synthesis of (−)-Paroxetine by Enantioselective Ring Enlargement of a Trisubstituted Prolinol

Abstract

Keywords: Dehalogenation / Paroxetine / Piperidine / Prolinol / Ring expansion A ring expansion and a radical dehalogenation have been used as the key steps in a formal total synthesis of (−)-paroxetine. The substituted piperidine ring precursor of (−)-paroxetine was generated by means of a stereoselective ring expansion of prolinol.

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para–f oxide-bridged phenylmorphan isomers

“…We attempted the ring closure of compound 15 in an analogous way to that formerly described as it is known that chloromethylpyrrolidines can be easily converted to 3-chloropiperidines with defined stereochemistry. 16 Gratifyingly, treatment of 15 with BBr 3 , followed by ammonium hydroxide, gave us a moderate yield of the known ortho-f isomer, as we anticipated from the structure of the starting material (Scheme 2). The free base was essentially identical with an authentic sample by TLC, CIMS, and 1 H-NMR, and the HCl salt had essentially the same mp as the known ortho-f isomer.…”

“…The amine displaces the chloride with formation of the aziridinium ion, which is ring opened intramolecularly by the phenoxide ion, yielding the epoxy-bridged phenylmorphan with the observed stereochemistry (for a comprehensive review of similar aziridium ion rearrangements, see Cossy and Pardo). 16 We have also examined the Mitsunobu reaction as an alternative oxide-ring closure method to obtain the ortho-e oxidebridged phenylmorphan (Fig. 1).…”

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para–f oxide-bridged phenylmorphan isomers

“…We attempted the ring closure of compound 15 in an analogous way to that formerly described as it is known that chloromethylpyrrolidines can be easily converted to 3-chloropiperidines with defined stereochemistry. 16 Gratifyingly, treatment of 15 with BBr 3 , followed by ammonium hydroxide, gave us a moderate yield of the known ortho-f isomer, as we anticipated from the structure of the starting material (Scheme 2). The free base was essentially identical with an authentic sample by TLC, CIMS, and 1 H-NMR, and the HCl salt had essentially the same mp as the known ortho-f isomer.…”

“…The amine displaces the chloride with formation of the aziridinium ion, which is ring opened intramolecularly by the phenoxide ion, yielding the epoxy-bridged phenylmorphan with the observed stereochemistry (for a comprehensive review of similar aziridium ion rearrangements, see Cossy and Pardo). 16 We have also examined the Mitsunobu reaction as an alternative oxide-ring closure method to obtain the ortho-e oxidebridged phenylmorphan (Fig. 1).…”

Chemistry of Bridged Lactams and Related Heterocycles

“…349,350 In 1970, Arata reported the synthesis of bridged lactam 225 containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme 57). 351,352 The proposed mechanism is outlined in Scheme 58, 352 and involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 .…”

“…Aziridinium ions are known to undergo regioselective ring-opening with a wide range of nucleophiles, and this type of rearrangement has been used extensively to make planar nitrogen-containing heterocycles. , In 1970, Arata reported the synthesis of bridged lactam 225 , containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme ). , The proposed mechanism is outlined in Scheme , and it involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring-opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 . Subsequently, Miyano and co-workers studied a related rearrangement in the 1-azabicyclo[3.3.1]­nonane system (Scheme ). , In their case, the reaction was carried out stepwise and the trichloromethyl analogue 227 was isolated .…”

Synthesis of Mimics of Pramanicin from Pyroglutamic Acid and Their Antibacterial Activity

“…The crude was purified via flash column chromatography on silica gel (eluent = EtOAc/PE) to give the two separate diastereomers. The 7 R and 7 S diastereomers were assigned by comparing the chemical shift values of H-6 and H-6′ with those compounds reported by Cossy et al and Beard et al…”

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para–f oxide-bridged phenylmorphan isomers

“…We attempted the ring closure of compound 15 in an analogous way to that formerly described as it is known that chloromethylpyrrolidines can be easily converted to 3-chloropiperidines with defined stereochemistry. 16 Gratifyingly, treatment of 15 with BBr 3 , followed by ammonium hydroxide, gave us a moderate yield of the known ortho-f isomer, as we anticipated from the structure of the starting material (Scheme 2). The free base was essentially identical with an authentic sample by TLC, CIMS, and 1 H-NMR, and the HCl salt had essentially the same mp as the known ortho-f isomer.…”

“…The amine displaces the chloride with formation of the aziridinium ion, which is ring opened intramolecularly by the phenoxide ion, yielding the epoxy-bridged phenylmorphan with the observed stereochemistry (for a comprehensive review of similar aziridium ion rearrangements, see Cossy and Pardo). 16 We have also examined the Mitsunobu reaction as an alternative oxide-ring closure method to obtain the ortho-e oxidebridged phenylmorphan (Fig. 1).…”

Chemistry of Bridged Lactams and Related Heterocycles

“…349,350 In 1970, Arata reported the synthesis of bridged lactam 225 containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme 57). 351,352 The proposed mechanism is outlined in Scheme 58, 352 and involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 .…”

“…Aziridinium ions are known to undergo regioselective ring-opening with a wide range of nucleophiles, and this type of rearrangement has been used extensively to make planar nitrogen-containing heterocycles. , In 1970, Arata reported the synthesis of bridged lactam 225 , containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme ). , The proposed mechanism is outlined in Scheme , and it involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring-opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 . Subsequently, Miyano and co-workers studied a related rearrangement in the 1-azabicyclo[3.3.1]­nonane system (Scheme ). , In their case, the reaction was carried out stepwise and the trichloromethyl analogue 227 was isolated .…”

Synthesis of Mimics of Pramanicin from Pyroglutamic Acid and Their Antibacterial Activity

“…The crude was purified via flash column chromatography on silica gel (eluent = EtOAc/PE) to give the two separate diastereomers. The 7 R and 7 S diastereomers were assigned by comparing the chemical shift values of H-6 and H-6′ with those compounds reported by Cossy et al and Beard et al…”

Synthesis of rac-(1R,4aR,9aR)-2-methyl-1,3,4,9a-tetrahydro-2H-1,4a-propanobenzofuro[2,3-c]pyridin-6-ol. An unusual double rearrangement leading to the ortho- and para–f oxide-bridged phenylmorphan isomers

“…We attempted the ring closure of compound 15 in an analogous way to that formerly described as it is known that chloromethylpyrrolidines can be easily converted to 3-chloropiperidines with defined stereochemistry. 16 Gratifyingly, treatment of 15 with BBr 3 , followed by ammonium hydroxide, gave us a moderate yield of the known ortho-f isomer, as we anticipated from the structure of the starting material (Scheme 2). The free base was essentially identical with an authentic sample by TLC, CIMS, and 1 H-NMR, and the HCl salt had essentially the same mp as the known ortho-f isomer.…”

“…The amine displaces the chloride with formation of the aziridinium ion, which is ring opened intramolecularly by the phenoxide ion, yielding the epoxy-bridged phenylmorphan with the observed stereochemistry (for a comprehensive review of similar aziridium ion rearrangements, see Cossy and Pardo). 16 We have also examined the Mitsunobu reaction as an alternative oxide-ring closure method to obtain the ortho-e oxidebridged phenylmorphan (Fig. 1).…”

Chemistry of Bridged Lactams and Related Heterocycles

“…349,350 In 1970, Arata reported the synthesis of bridged lactam 225 containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme 57). 351,352 The proposed mechanism is outlined in Scheme 58, 352 and involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 .…”

“…Aziridinium ions are known to undergo regioselective ring-opening with a wide range of nucleophiles, and this type of rearrangement has been used extensively to make planar nitrogen-containing heterocycles. , In 1970, Arata reported the synthesis of bridged lactam 225 , containing a [4.4.1] ring system via aziridinium rearrangement using a one-pot protocol (Scheme ). , The proposed mechanism is outlined in Scheme , and it involves the following steps: (1) tautomerization of enamine 224 to iminium ion, (2) addition of the trichloromethyl moiety, (3) formation of the aziridinium 224b , (4) regioselective nucleophilic ring-opening to the trichloroderivative 224c , and (5) hydrolysis to give the bridged lactam 225 . Subsequently, Miyano and co-workers studied a related rearrangement in the 1-azabicyclo[3.3.1]­nonane system (Scheme ). , In their case, the reaction was carried out stepwise and the trichloromethyl analogue 227 was isolated .…”

Synthesis of Mimics of Pramanicin from Pyroglutamic Acid and Their Antibacterial Activity

“…The crude was purified via flash column chromatography on silica gel (eluent = EtOAc/PE) to give the two separate diastereomers. The 7 R and 7 S diastereomers were assigned by comparing the chemical shift values of H-6 and H-6′ with those compounds reported by Cossy et al and Beard et al…”