- The Configuration Stability of Chiral Lithio α-Amino Carbanions. The Effect of Li-O vs. Li-N Complexation.
-
α-Lithio pyrrolidine, as its N-t-BOC or formamidine derivative, has been generated in high enantiomeric purity via Sn-Li exchange of the enantiomerically enriched (88-95percent) α-tributylstannane derivative, 4.The alkylation of these lithio carbanions gave 2-methyl pyrrolidines as well as providing a measure of their configurational stability.It was found that the α-lithio formamidines were configurationally more stable than the t-BOC derivatives and this is attributed to, the stronger O-Li bond which weakens the adjacent C-Li bond, thus allowing configurational decay to occur more readily.This is the first report wherein a difference is observed between O-Li-C and N-Li-C configurational stability.
- Elworthy, Todd R.,Meyers, A. I.
-
-
Read Online
- Synthesis and evaluation of in vivo anti-hypothermic effect of all stereoisomers of the thyrotropin-releasing hormone mimetic: Rovatirelin Hydrate
-
We discovered the orally active thyrotropin-releasing hormone (TRH) mimetic: (4S,5S)-5-methyl-N-{(2S)-1-[(2R)-2-methylpyrrolidin-1-yl]-1-oxo-3-(1,3-thiazol-4-yl)propan-2-yl}-2-oxo-1,3-oxazolidine-4-carboxamide 1 (rovatirelin). The central nervous system (CNS) effect of rovatirelin after intravenous (iv) administration is 100-fold higher than that of TRH. As 1 has four asymmetric carbons in its molecule, there are 16 stereoisomers. We synthesized and evaluated the anti-hypothermic effect of all stereoisomers of 1, which has the (4S),(5S),(2S),(2R) configuration from the N-terminus to the C-terminus, in order to clarify the structure?activity relationship (SAR) of stereoisomers. The (4R),(5R),(2R),(2S)-isomer 16 did not show any anti-hypothermic effect. Only the (4S),(5S),(2S),(2S)-isomer 10, which has the (2S)-2-methylpyrrolidine moiety at the C-terminus showed the anti-hypothermic effect similar to 1. Stereoisomers, which have the (5R) configuration of the oxazolidinone at the N-terminus and the (2R) configuration at the middle-part, showed a much lower anti-hypothermic effect than that of 1. On the other hand, stereoisomers, which have the (4R) configuration of the oxazolidinone at the N-terminus or the (2S) configuration of the C-terminus, have little influence on the anti-hypothermic effect.
- Kobayashi, Naotake,Sato, Norihito,Sugita, Katsuji,Takahashi, Kouji,Sugawara, Tamio,Tada, Yukio,Yoshikawa, Takayoshi
-
-
- Asymmetric lithiation trapping of N -boc heterocycles at temperatures above -78°C
-
The asymmetric lithiation trapping of N-Boc heterocycles using s-BuLi/chiral diamines at temperatures up to -20°C is reported. Depending on the N-Boc heterocycle, lithiation is accomplished using s-BuLi and (-)-sparteine or the (+)-sparteine surrogate in the temperature range -50 to -20°C for short reaction times (2-20 min). Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered functionalized N-Boc heterocycles in 47-95% yield and 77:23-93:7 er. With N-Boc pyrrolidine, trapped products can be generated in ~90:10 er even at -20°C.
- Gelardi, Giacomo,Barker, Graeme,O'Brien, Peter,Blakemore, David C.
-
p. 5424 - 5427
(2013/11/19)
-
- Asymmetric synthesis of chiral cyclic amine from cyclic imine by bacterial whole-cell catalyst of enantioselective imine reductase
-
Streptomyces sp. GF3587 and 3546 were found to be imine-reducing strains with high R- and S-selectivity by screening using 2-methyl-1-pyrroline (2-MPN). Their whole-cell catalysts produced 91 mM R-2-methylpyrrolidine (R-2-MP) with 99.2%e.e. and 27.5 mM S-2-MP (92.3%e.e.) from 2-MPN at 91-92% conversion in the presence of glucose, respectively.
- Mitsukura, Koichi,Suzuki, Mai,Tada, Kazuhiro,Yoshida, Toyokazu,Nagasawa, Toru
-
experimental part
p. 4533 - 4535
(2010/11/19)
-
- LXR AND FXR MODULATORS
-
Compounds of the invention are disclosed, such as compounds of formulae LX - LXIV, and pharmaceutically acceptable salts, isomers, or prodrugs thereof, which are useful as modulators of the activity of liver X receptors (LXR) and Farnesoid X receptors (FXR), where R00, R200, R400, R500, J11, J21, G1, G21, and Q are defined herein. Pharmaceutical compositions containing the compounds and methods of using the compounds are also disclosed.
- -
-
-
- OXAZOLE DERIVATIVES AS HISTAMINE H3 RECEPTOR AGENTS, PREPARATION AND THERAPEUTIC USES
-
The present invention discloses novel aryl oxazole compounds of Formula I (I), or pharmaceutically acceptable salts thereof, which have histamine-H3 receptor antagonist or inverse agonist activity, as well as methods for preparing and using such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising compounds of Formula I as well as methods of using these compositions to treat obesity, cognitive deficiencies, narcolepsy, and other histamine H3 receptor-related diseases. Formula I (I) or a pharmaceutically acceptable salt thereof, wherein: m is independenlly at each occurrence 1, 2, or 3, Z independently represents carbon (substituted with hydrogen or the optional substituents indicated herein) or nitrogen, provided that when Z is nitrogen then R6 is not attached to Z; R1 and R2 are independently -(C1-C7) alkyl(optionally substituted with one to three halogens), or R1 and R2 and the nitrogen to which they are attached form an azetidinyl ring, a pyrrolidinyl ring, or a piperidinyl ring, wherein further the azetidinyl, pyrrolidinyl, or piperidinyl ring so formed may be optionally substituted one to three times with R5; R6 is independently at each occurrence -H, -halogen, or -CH3.
- -
-
Page/Page column 61
(2008/06/13)
-
- Process for preparing 2-methylpyrrolidine and specific enantiomers thereof
-
The invention relates to a process for preparing 2-methylpyrrolidine and, more particularly, specific enantiomers of 2-methylpyrrolidine. Novel intermediates also are described.
- -
-
-
- Process for preparing 2-methylpyrrolidine and specific enantiomers thereof
-
The invention relates to a process for preparing 2-methylpyrrolidine and, more particularly, specific enantiomers of 2-methylpyrrolidine. Novel intermediates also are described.
- -
-
-
- Complex-induced proximity effects: The effect of varying directing-group orientation on carbamate-directed lithiation reactions
-
A series of selected bicyclic carbamates in which the range of accessible angles and distances between the carbonyl group and the proton removed in an α-lithiation reaction are structurally defined have been investigated. Oxazolidinones 7-10 undergo stereoselective lithiation-substitution reactions to provide cis-18-27 and cis-31-35 as the major diastereomers. Two series of competition experiments show that the conformationally restricted carbamates 7, 10, 11, and 15 undergo lithiation via complexes more efficiently than Boc amines 4-6. These results along with semiempirical calculations suggest that a small dihedral angle and a calculated distance of 2.78 A between the carbamate carbonyl oxygen and the proton to be removed are favorable for a carbamate-directed lithiation. A series of tin-lithium exchange experiments on cis- and trans-18 and (S)-39 indicate that the configurational stability of a carbamate-stabilized organolithium species may be enhanced by restrictive geometry.
- Bertini Gross,Beak
-
p. 315 - 321
(2007/10/03)
-
- Conversion of chiral amino acids to enantiomerically pure α-methylamines
-
Enantiomerically enriched α-methylamines are obtained in high yield by Raney nickel reduction of N-Boc-protected, amino acid-derived thioethers.
- Donner
-
p. 1223 - 1226
(2007/10/02)
-
- Complex induced proximity effects: Enantioselective syntheses based on asymmetric deprotonations of N-Boc-pyrrolidines
-
Lithiation of N-Boc-pyrrolidine (6) with sec-butyllithium (s-BuLi)/(-)-sparteine (14) effects an asymmetric deprotonation to give (S)-2-lithio-N-Boc-pyrrolidine ((S)-22), which reacts with electrophiles to provide the 2-substituted N-Boc-pyrrolidines 7-11 and 13 in enantiomeric excesses which generally are >90%. In the lithiation-silylation of 6 the chiral ligand 15 gives 7 with a lower enantiomeric excess and chiral ligands 16 and 17 give 7 with lower and opposite enantiomeric excesses than that obtained with 14. Diastereoselective amplification operates in a sequential lithiation-substitution sequence to provide the conversion of (S)-2-methyl-N-Boc-pyrrolidine ((S)-10) of 95% enantiomeric excess with s-BuLi/14 to (S,S)-2,5-dimethyl-N-Boc-pyrrolidine ((S,S)-19) with >99% enantiomeric excess. Synthetic preparations of a useful chiral ligand, (R)-α,α-diphenyl-2-pyrrolidine ((R)-20), and a useful chiral auxiliary, (S,S)-2,5-dimethylpyrrolidine hydrochloride ((S,S)-21), are reported. Reactions of racemic and enantioenriched 2-lithio-N-Boc-pyrrolidine and investigation of sequential lithiations-deuterations of 6 establish the reaction pathway to be asymmetric deprotonation rather than asymmetric substitution. A rationalization for the enantioselective deprotonation is provided.
- Beak, Peter,Kerrick, Shawn T.,Wu, Shengde,Chu, Jingxi
-
p. 3231 - 3239
(2007/10/02)
-