A six-step synthesis of (S)-5-ethenyl-3-(1-methyl-2-pyrrolidinyl)pyridine (SIB-1508Y) from (S)-nicotine
The anti-Parkinson's agent SIB-1508Y was prepared in six steps from (S)-nicotine in 20% overall yield. The strategy involves a regioselective formylation at C-5 of a 1,4-dihydronicotine intermediate.
Enantioselective, palladium-catalyzed α-arylation of N-Boc pyrrolidine: In situ react IR spectroscopic monitoring, scope, and synthetic applications
A comprehensive study of the enantioselective Pd-catalyzed α-arylation of N-Boc pyrrolidine has been carried out. The protocol involves deprotonation of N-Boc pyrrolidine using s-BuLi/(-)-sparteine in TBME or Et2O at -78 °C, transmetalation with ZnCl2 and Negishi coupling using Pd(OAc)2, t-Bu3P-HBF4 and the aryl bromide. This paper reports several new features including in situ React IR spectroscopic monitoring of the process; use of (-)-sparteine and the (+)-sparteine surrogate to access products with opposite configuration; development of a catalytic asymmetric lithiation-Negishi coupling reaction; extension to a wide range of heteroaromatic bromides; total synthesis of (R)-crispine A, (S)-nicotine and (S)-SIB-1508Y via short synthetic routes; and examples of α-vinylation of N-Boc pyrrolidine using vinyl bromides exemplified by the total synthesis of naturally occurring (+)-maackiamine (thus establishing its configuration as (R)). In this way, the full scope and limitations of the methodology are delineated.
Barker, Graeme,McGrath, Julia L.,Klapars, Artis,Stead, Darren,Zhou, George,Campos, Kevin R.,O'Brien, Peter
experimental part
p. 5936 - 5953
(2011/10/09)
Expedient five-step synthesis of SIB-1508Y from natural nicotine
Altinicline (SIB-1508Y), an anti-Parkinson's agent, was prepared in five steps from natural nicotine in 32% overall yield via a regioselective substitution of the pyridine ring of (S)-nicotine.
Wagner, Florence F.,Comins, Daniel L.
p. 8673 - 8675
(2007/10/03)
Synthesis of nicotine derivatives from nicotine
Methods of synthesizing nicotine analogs and derivatives are described. In some embodiments the methods utilize an alkyl or aryl silyl-substituted nicotine analog intermediate. Intermediates useful for the synthesis of nicotine and nicotine analogs are al
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Page/Page column 8; 10
(2008/06/13)
The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine: A key intermediate for the preparation of SIB-1508Y
The first enantioselective synthesis of (S)-5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine is described via intramolecular hydroboration-cycloalkylation of an azido-olefin intermediate. The chiral homoallylic alcohol was efficiently synthesized by enantioselective reduction of the corresponding ketone using (+)-diisopinocamphenylchloroborane as the key reaction. The total synthesis of (S)-SIB-1508Y was achieved with an enantiomeric excess (e.e.) of 94% in ten steps and in 18% overall yield from the commercially available 5-bromo-3-pyridinecarboxylic acid.
Felpin, Francois-Xavier,Vo-Thanh, Giang,Villieras, Jean,Lebreton, Jacques
p. 1121 - 1124
(2007/10/03)
A Practical and Efficient Synthesis of the Selective Neuronal Acetylcholine-Gated Ion Channel Agonist (S)-(-)-5-Ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine Maleate (SIB-1508Y)
An efficient, high-yielding synthetic procedure for the preparation of the novel neuronal acetylcholinegated ion channel agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate [(S)-2, SIB-1508Y] is described. The key steps in the process include the lithium bis(trimethylsilyl)amide-mediated acylation of N-vinylpyrrolidinone with ethyl 5-bromonicotinate, a high-yielding sodium borohydride reduction of imine 5, and a new heteroaryl-alkyne cross-coupling protocol for the introduction of the ethyne moiety in (S)-2. The preparation of enantiomerically pure (S)-2 was accomplished via a combination of enantioselective reduction of imine 5 and crystallization of enantiomerically enriched 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine (7) as the dibenzoyl-L-tartaric acid salt.
Bleicher, Leo S.,Cosford, Nicholas D. P.,Herbaut, Audrey,Stuart McCallum,McDonald, Ian A.
p. 1109 - 1118
(2007/10/03)
(S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine maleate (SIB- 1508Y): A novel anti-Parkinsonian agent with selectivity for neuronal nicotinic acetylcholine receptors