- The barrier to enantiomerization of N-Boc-2-lithiopyrrolidine: The effect of chiral and achiral diamines
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(-)-Sparteine and TMEDA dramatically lower both enthalpy and entropy of activation for the barrier to enantiomerization of N-Boc-2-lithiopyrrolidine in diethyl ether, whereas N,N′-diisopropylbispidine has little effect; the entropy of activation for enantiomerization is zero in the presence of TMEDA and slightly negative in the presence of sparteine; these data suggest a subtle change in mechanism of enantiomerization in the presence of TMEDA and sparteine. The Royal Society of Chemistry.
- Yousaf, Taher I.,Williams, Roger L.,Coldham, Iain,Gawley, Robert E.
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- Reactivity series for s-BuLi/diamine-mediated lithiation of N-Boc pyrrolidine: Applications in catalysis and lithiation of N-Boc piperidine
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Using competition experiments between a range of ligands and (-)-sparteine, a reactivity series for N-Boc pyrrolidine lithiation using s-BuLi/diamines has been constructed; the results indicate that the s-BuLi/(+)-sparteine surrogate complex is more reactive than s-BuLi/(-)-sparteine and this has been exploited in the selection of ligand pairs for ligand exchange catalytic asymmetric lithiation of N-Boc pyrrolidine and lithiation of N-Boc piperidine. The Royal Society of Chemistry 2006.
- McGrath, Matthew J.,Bilke, Julia L.,O'Brien, Peter
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- Dynamic resolution of N-alkyl-2-lithiopyrrolidines with the chiral ligand (-)-sparteine
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A selection of 2-lithiopyrrolidines with different N-alkyl-substituents were prepared and tested for their dynamic resolution in the presence of the chiral ligand (-)-sparteine. Good yields of the electrophile-quenched products were obtained with enantiomer ratios up to 85:15 using branched N-alkyl derivatives. The major product was shown to have the opposite absolute configuration compared with that obtained in the asymmetric deprotonation of N-Boc-pyrrolidine with (-)-sparteine. The enantioselectivity arises from a dynamic thermodynamic resolution in which the minor diastereomeric complex reacts faster with the electrophile.
- Coldham, Iain,Dufour, Samuel,Haxell, Thomas F.N.,Vennall, Graham P.
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- Synthesis and analgesic activity of hydrochlorides and quaternary ammoniums of epibatidine incorporated with amino acid ester
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Hydrochloride derivatives 5a-c and quaternary ammonium derivatives 6a-c of epibatidine incorporated with amino acid ester were synthesized and evaluated for their in vivo analgesic activity and toxicity. Among all tested compounds, compound 6c has the most potent analgesic activity. The quaternary ammonium salts 6a and 6c showed better analgesic activity than the corresponding hydrochlorides 5a and 5c. Both 5a-c and 6a-c showed significantly lower toxicity than epibatidine itself.
- Dong, Jing-Chao,Wang, Xin,Li, Run-Tao,Zhang, Hong-Mei,Cheng, Tie-Ming,Li, Chang-Ling
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- An experimental and computational study of the enantioselective lithiation of N-Boc-pyrrolidine using sparteine-like chiral diamines
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The enantioselective lithiation of N-Boc-pyrrolidine using sec-butyllithium and isopropyllithium in the presence of sparteine-like diamines has been studied experimentally and computationally at various theoretical levels through to B3P86/6-31G*. Of the (-)-cytisine-derived diamines (N-Me, N-Et, N-nBu, N-CH2t-Bu, N-iPr) studied experimentally, the highest enantioselectivity (er 95:5) was observed with the least sterically hindered N-Me-substituted diamine, leading to preferential removal of the pro-R proton i.e., opposite enantioselectivity to (-)-sparteine. The experimental result with the N-Me-substituted diamine correlated well with the computational results: at the B3P86/6-31G* level, the sense of induction was correctly predicted; the lowest energy complex of isopropyllithium/diamine/N-Boc-pyrrolidine also had the lowest activation energy (ΔH? = 11.1 kcal/mol, ΔG? = 11.5 kcal/mol) for proton transfer. The computational results with the N-iPr-substituted diamine identified a transition state for proton transfer with activation energies of ΔH? = 11.7 kcal/mol and ΔG? = 11.8 kcal/mol (at the B3P86/6-31G* level). Although comparable to (-)-sparteine and the N-Me-substituted diamine, these ΔH? and ΔG? values are at odds with the experimental observation that use of the N- iPr-substituted diamine gave no product. It is suggested that steric crowding inhibits formation of the prelithiation complex rather than increasing the activation enthalpy for proton transfer in the transition state. Three other ligands (N-H and O-substituted as well as a five-membered ring analogue) were studied solely using computational methods, and the results predict that the observed enantioselectivity would be modest at best.
- O'Brien, Peter,Wiberg, Kenneth B.,Bailey, William F.,Hermet, Jean-Paul R.,McGrath, Matthew J.
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- A readily-accessible (+)-sparteine surrogate
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A "(+)-sparteine-like" chiral diamine, readily synthesized in three steps from (-)-cytisine, has been evaluated in four different asymmetric transformations; in each case, selectivity in an enantiocomplementary fashion to (-)-sparteine was observed. Copyright
- Dearden, Michael J.,Firkin, Catherine R.,Hermet, Jean-Paul R.,O'Brien, Peter
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- An Expeditious Synthesis of Epibatidine and Analogues
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An efficient synthesis of Epibatidine and its analogues via cycloaddition of non-stabilised azomethine ylide and substituted 6-chloro-3-vinyl pyridine.
- Pandey, Ganesh,Bagul, Trusar D.,Lakshmaiah, G.
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- Evaluation of a sparteine-like diamine for asymmetric synthesis
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Evaluation of a sparteine-like diamine indicates that only the ABC rings of sparteine are required for high enantioselectivity in the lithiation-substitution of N-Boc pyrrolidine.
- Harrison,O'Brien,Porter,Smith
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- Chiral Organolithium Complexes: The Effect of Ligand Structure on the Enantioselective Deprotonation of Boc-Pyrrolidine
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The efficacies of a number of s-BuLi/chiral ligand complexes as reagents for the asymmetric deprotonation of Boc-pyrrolidine (1) to provide enantioenriched 2-lithio-Boc-pyrrolidine (2) have been evaluated by the conversion of 2 to 2-(trimethylsilyl)-Boc-pyrrolidine (3).The syntheses of new enantioenriched proline-based and bispidine ligands are described.The most effective newly examined ligands are the diproline-based diamino alcohol 20 and the α-methylbenzylamine-derived bispidine 35, which provided (S)-3 and (R)-3 with enantiomeric excesses of 72percent and 75percent, respectively.Use of the ligand (-)-isosparteine (28) resulted in lower conversions and enantioselectivities than (-)-sparteine (27).A rationale is proposed to explain the relative rates of the lithiation of 1 by s-BuLi/TMEDA, 27, or 28 complexes and the remarkable effectiveness of (-)-sparteine as the best chiral ligand examined to date.
- Gallagher, Donald J.,Wu, Shengde,Nikolic, Nikola A.,Beak, Peter
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- Dynamic kinetic resolution of N-Boc-2-lithiopyrrolidine
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Asymmetric substitution of the organolithium derived either from N-Boc-2-tributylstannylpyrrolidine by tin-lithium exchange or from N-Boc-pyrrolidine by deprotonation occurs in the presence of a commercially available chiral diamine ligand with high levels of enantioselectivity by a dynamic kinetic resolution pathway. The Royal Society of Chemistry 2005.
- Coldham, Iain,Patel, Jignesh J.,Sanchez-Jimenez, Graciela
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- Is the A-ring of sparteine essential for high enantioselectivity in the asymmetric lithiation-substitution of N-Boc-pyrrolidine?
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The simplest chiral portion of sparteine, N,N-dimethyl-2-endo- methylbispidine, was prepared and evaluated in the asymmetric lithiation-substitution of N-Boc-pyrrolidine. The results indicate that the complete A-ring of sparteine is essential for high levels of asymmetric induction. DFT-QSSR analyses of the diamine/Li+ complexes and DFT calculations of the pertinent i-PrLi/diamine/N-Boc-pyrrolidine complexes are predictive and provide complementary pictures of the stereochemical features critical to this transformation.
- Phuan, Puay-Wah,Ianni, James C.,Kozlowski, Marisa C.
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- Silylarene Hydrogenation: A Strategic Approach that Enables Direct Access to Versatile Silylated Saturated Carbo- and Heterocycles
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We report a method to convert readily available silylated arenes into silylated saturated carbo- and heterocycles by arene hydrogenation. The scope includes alkoxy- and halosilyl substituents. Silyl groups can be derivatized into a plethora of functionalities and find application in organic synthesis, materials science, and pharmaceutical, agrochemical, and fragrance research. However, silylated saturated (hetero-) cycles are difficult to access with current technologies. The yield of the hydrogenation depends on the amount of the silica gel additive. This silica effect also enables a significant improvement of a previously disclosed method for the hydrogenation of highly fluorinated arenes (e.g., to all-cis-C6H6F6).
- Wiesenfeldt, Mario P.,Knecht, Tobias,Schlepphorst, Christoph,Glorius, Frank
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supporting information
p. 8297 - 8300
(2018/06/29)
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- The search for an easily-prepared sparteine surrogate
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(?)-Sparteine has proven itself to be a highly efficient and versatile ligand. However, in recent years it has become difficult to source. In addition the (+)-enantiomer is also not readily available. Here we report a suite of chiral diamines as potential sparteine surrogates. Chiral trans-1,2-diaminocyclohexane is commercially available in both enantiomeric forms and the parent structure can be easily modified. New (and known) chiral diamines have been tested in the asymmetric silylation of N-Boc pyrrolidine, N-Boc piperidine, the α-alkylation of dimethylhydrazones and in the rearrangement of meso-epoxides. While none match the selectivity of the highly evolved natural product, there is certainly potential for this class of diamine ligands to perform in a diverse set of asymmetric transformations.
- Foley, Vera M.,Cano, Rafael,McGlacken, Gerard P.
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p. 1160 - 1167
(2016/11/04)
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- The First Modular Route to Core-Chiral Bispidine Ligands and Their Application in Enantioselective Copper(II)-Catalyzed Henry Reactions
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The first modular and flexible synthesis of core-chiral bispidines was achieved by using an "inside-out" strategy. The key intermediate, a NBoc-activated bispidine lactam, was constructed in enantiomerically pure form from a chirally modified β-amino acid and 2-(acetoxymethyl)acrylonitrile in just five steps and good 48% yield. A simple addition-reduction protocol permitted a highly endo-selective introduction of substituents and, thus, a fast and variable access to 2-endo-substituted and 2-endo,N-fused bi- and tricyclic bispidines. The new diamines were evaluated as the chiral ligands in asymmetric Henry reactions. Excellent enantioselectivities of up to 99% ee and good diastereomeric ratios of up to 86:14 were reached with a copper(II) complex modified by a 2-endo,N-(3,3-dimethylpyrrolidine)-annelated bispidine. Its performance is superior to that of the well-known bispidines (-)-sparteine and the (+)-sparteine surrogate.
- Scharnagel, Dagmar,Müller, Andreas,Prause, Felix,Eck, Martin,Goller, Jessica,Milius, Wolfgang,Breuning, Matthias
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supporting information
p. 12488 - 12500
(2015/08/25)
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- Evaluation of the chiral DIANANE backbone as ligand for organolithium reagents
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Novel endo,endo-2,5-diaminonorbonane-derived tertiary C2- symmetrical diamines were synthesized via the one-pot reductive amination of enantiomerically pure norbornane-2,5-dione. These ligands were applied to various catalytic reactions such as asymmetric deprotonation, asymmetric bromine-lithium exchange, and enantioselective addition of aryl- and allkylithium reagents to aromatic aldimines. Copyright
- Praz, Jezabel,Guenee, Laure,Aziz, Sarwar,Berkessel, Albrecht,Alexakis, Alexandre
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supporting information; experimental part
p. 1780 - 1790
(2012/07/28)
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- Silylated pyrrolidines as catalysts for asymmetric Michael additions of aldehydes to nitroolefins
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Silicon can! A convenient synthesis of enantiopure (S)-2- (diphenylmethylsilyl)pyrrolidine is described and its organocatalytic activity in asymmetric Michael reactions is demonstrated (see scheme). By using 10 mol% of this novel organocatalyst, the addition of aldehydes to nitroolefins affords products with high stereoselectivities (d.r. 97:3 and e.r. 95:5) in yields up to 99%.
- Husmann, Ralph,Joerres, Manuel,Raabe, Gerhard,Bolm, Carsten
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supporting information; experimental part
p. 12549 - 12552
(2011/02/22)
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- Diamine-free lithiation-trapping of N-Boc heterocycles using s-BuLi in THF
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A diamine-free protocol for the s-BuLi-mediated lithiation-trapping of N-Boc heterocycles has been developed. In the optimized procedure, lithiation is accomplished using s-BuLi in THF at -30 °C for only 5 or 10 min. Subsequent electrophilic trapping or transmetalation-Negishi coupling delivered a range of functionalized pyrrolidines, imidazolidines, and piperazines in 43-83% yield.
- Barker, Graeme,Obrien, Peter,Campos, Kevin R.
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supporting information; experimental part
p. 4176 - 4179
(2010/11/16)
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- Catalytic asymmetric synthesis of piperidines from pyrrolidine: Concisesynthesis of L-733,060
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Catalytic asymmetric deprotonation-aldehyde trapping-ring expansion from a 5- to a 6-ring delivers a concise route to each stereoisomer of -hydroxy piperidines starting from W-Boc pyrrolidine. The methodology is utilized in a 5-step catalytic asymmetric synthesis of the neorokinin-1 receptor antagonist, (+)-L-733,060.
- Bilke, Julia L.,Moore, Stephen P.,O'Brien, Peter,Gilday, John
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supporting information; experimental part
p. 1935 - 1938
(2009/09/25)
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- On the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine: Probing the effect of the stoichiometric ligand
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(Chemical Equation Presented) To map out the stoichiometric ligand requirements in the two-ligand catalytic asymmetric deprotonation of N-Boc pyrrolidine, 24 different ligands have been evaluated; the highest enantioselectivity (90:10 er) was obtained by using s-BuLi in the presence of 0.3 equiv of (-)-sparteine and 1.3 equiv of a cyclohexanediamine-derived ligand.
- Bilke, Julia L.,O'Brien, Peter
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p. 6452 - 6454
(2008/12/21)
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- A new sparteine surrogate for asymmetric deprotonation of N-Boc pyrrolidine
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(Chemical Equation Presented) The s-BuLi complex of a cyclohexane-derived diamine is as efficient as s-BuLi/(-)-sparteine for the asymmetric deprotonation of N-Boc pyrrolidine. This is the first example of high enantioselectivity using a non-sparteine-like diamine in such reactions. The ( S, S)-diamine is a useful (+)-sparteine surrogate and was utilized in short syntheses of (-)-indolizidine 167B and an intermediate for the synthesis of the CCK antagonist (+)-RP 66803.
- Stead, Darren,O'Brien, Peter,Sanderson, Adam
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supporting information; experimental part
p. 1409 - 1412
(2009/04/12)
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- Dynamic thermodynamic and dynamic kinetic resolution of 2-lithiopyrrolidines
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Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)-pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2- lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.
- Coldham, Iain,Dufour, Samuel,Haxell, Thomas F. N.,Patel, Jignesh J.,Sanchez-Jimenez, Graciela
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p. 10943 - 10951
(2007/10/03)
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- Development of a catalytic asymmetric variant of Hoppe's O-alkyl carbamate deprotonation methodology
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The optimisation of a ligand-exchange approach to catalytic asymmetric deprotonation of O-alkyl carbamates and subsequent electrophilic trapping (the 'Hoppe reaction') is presented. The method uses s-BuLi and sub-stoichiometric amounts of a chiral diamine [(-)-sparteine or the (+)-sparteine surrogate] in conjunction with an achiral 'regenerating' diamine (bisisopropyl bispidine) for the deprotonation and proceeds with good yields (up to 84%) and high enantioselectivity (up to 94:6 er). The first applications of this catalytic asymmetric deprotonation methodology in natural product synthesis are also described. Georg Thieme Verlag Stuttgart.
- McGrath, Matthew J.,O'Brien, Peter
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p. 2233 - 2241
(2008/02/02)
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- Catalytic asymmetric deprotonation using a ligand exchange approach
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A novel ligand exchange approach to catalytic asymmetric deprotonation-electrophilic trapping has been developed that uses 1.3 equiv of s-BuLi, 0.06-0.2 equiv of chiral diamine ((-)-sparteine or a (+)-sparteine surrogate), and 1.2 equiv of achiral bispidine. The methodology is illustrated with a range of examples and gives access to either enantiomer of useful chiral products in good yields using substoichiometric amounts of chiral diamines. Copyright
- McGrath, Matthew J.,O'Brien, Peter
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p. 16378 - 16379
(2007/10/03)
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- Synthesis of sparteine-like chiral diamines and evaluation in the enantioselective lithiation-substitution of N-(tert-butoxycarbonyl)-pyrrolidine
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Three chiral diamines were synthesised and evaluated as sparteine surrogates in the lithiation-substitution of N-(tert-butoxycarbonyl)pyrrolidine. The synthesis and attempted resolution of sparteine-like diamines {(1S*, 2R*, 8R*)-10-methyl-6,10-diazatricyclo [6.3.1.02,6]dodecane and (1S*, 2R*, 9R*)-11-methyl-7,11-diazatricyclo[7.3.1.02,7]tridecane} (via inclusion complex formation) are reported. Unfortunately, it was only possible to resolve the diazatricyclo-[7.3.1.02,7] tridecane compound. An alternative route to (1R,2S,9S)-11-methyl-7,11-diazatricyclo[7.3.1.02.7]tridecane starting from the natural product, (-)-cytisine, is described. This simple three-step route furnished gram-quantities of a (+)-sparteine surrogate. X-ray crystallography of an intermediate in the route, (1R,5S,12S)-3-methoxycarbonyl-decahydro-1,5-methanopyrido [1,2-a][1,5]diazocin-8-one, enabled the stereochemistry of all of the tricyclic diamines described in this paper to be unequivocally established. Two other diamines, starting from (S)-proline and resolved 2-piperidine ethanol, were prepared using standard methods. These diamines lacked the bispidine framework of (-)-sparteine and were found to impart vastly inferior enantioselectivity. It was concluded that, for the asymmetric lithiation-substitution of N-Boc pyrrolidine, a rigid bispidine framework and only three of the four rings of (-)-sparteine are needed for high enantioselectivity. Furthermore, it is shown that diamine (1R,2S,9S)-11-methyl-7,11-diazatricyclo [7.3.1.02,7]tridecane is the first successful (+)-sparteine surrogate.
- Hermet, Jean-Paul R.,Porter, David W.,Dearden, Michael J.,Harrison, Justin R.,Koplin, Tobias,O'Brien, Peter,Parmene, Jerome,Tyurin, Vladimir,Whitwood, Adrian C.,Gilday, John,Smith, Neil M.
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p. 3977 - 3988
(2007/10/03)
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- Synthesis of enantiopure diamine ligands related to sparteine, via scandium triflate-catalyzed imino Diels-Alder reactions
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Imino Diels-Alder reactions have been investigated as a new route to sparteine analogues. The first enantioselective synthesis of two diastereoisomeric tricyclic diamines, structurally equivalent to the ABC and BCD rings of the naturally occurring alkaloid, is reported, starting from enantiopure intermediates. The effectiveness of the diamines in the lithiation of N-Boc-pyrrolidine is discussed.
- Danieli, Bruno,Lesma, Giordano,Passarella, Daniele,Piacenti, Paola,Sacchetti, Alessandro,Silvani, Alessandra,Virdis, Andrea
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p. 7155 - 7158
(2007/10/03)
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- Stereoselective construction of X-azabicyclo[m.2.1]alkanes by [3+2]-cycloaddition of non-stabilized cyclic azomethine ylides: Synthesis of enantiopure constrained amino acids and formal total synthesis of optically active epibatidine
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A new and general strategy for the stereoselective construction of X-azabicyclo[m.2.1]alkanes has been developed by the [3+2]-cycloaddition of cyclic azomethine ylides with suitable achiral dipolarophiles. The cyclic azomethine ylides, where the whole of the ylide conjugation is in the ring, have been generated by the sequential double desilylation of the N-alkyl-α,α′-bis(trimethylsilyl) cyclic amines utilizing Ag(I)F as one electron oxidant. The structural rigidity of cyclic azomethine ylides has allowed preferential facial discrimination by the dipolarophile resulting into very good exolendo selectivity. The exolendo selectivity associated with these cycloadditions has been further exploited to access optically pure X-azabicyclo[m.2.1]alkanes by carrying out the cycloadditions with the Oppolzer's acryloyl dipolarophile. Application of this methodology is demonstrated by the construction of few constrained amino acids related to azabicyclic structural framework and the formal total synthesis of optically active epibatidine.
- Pandey, Ganesh,Laha, Joydev K,Lakshmaiah
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p. 3525 - 3534
(2007/10/03)
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- Synthesis and resolution of a novel chiral diamine ligand and application to asymmetric lithiation-substitution
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(equation presented) A short, efficient synthesis of chiral 1,5-diaza-cis-decalins (7) is presented. In the lithiation of N-Boc pyrrolidine, the ligands with the smallest most electron rich R groups (Me > Et > CH2tBu > CH2CF3 ≈ Bn) were most effective. In the asymmetric deprotonation/substitution of benzylic substrates, (R,R)-7 (R = Me, R′ = H) conferred modest selectivity. The ready availability of both enantiomers of the 1,5-diaza-cis-decalins and the ability to tune steric and electronic properties renders these compounds an attractive new class of diamine ligands.
- Li, Xiaolin,Schenkel, Laurie B.,Kozlowski, Marisa C.
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p. 875 - 878
(2007/10/03)
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- [3+2]-Cycloaddition of nonstabilized azomethine ylides, Part 9: A general approach for the construction of X-azabicyclo[m.2.1]alkanes in optically pure form by asymmetric 1,3-dipolar cycloaddition reactions
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A general strategy for the construction of X-azabicyclo[m.2.1]alkane frameworks in optically pure form is reported by the asymmetric [3+2]- cycloaddition reaction of cyclic azomethine ylides with Oppolzer's acryloyl camphor sultam.
- Pandey, Ganesh,Laha, Joydev K.,Mohanakrishnan
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p. 6065 - 6068
(2007/10/03)
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- [3 + 2] Cycloaddition of nonstabilized azomethine ylides. 7. Stereoselective synthesis of epibatidine and analogues
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Epibatidine (1) is synthesized by employing a [3 + 2] cycloaddition strategy as a key step via nonstabilized azomethine ylide 10, generated by one-electron oxidative double desilylation of N-benzyl-2,5- bis(trimethylsilyl)pyrrolidine (12). Cycloaddition of 10 with trans-ethyl-3- (6-chloro-3-pyridyl)-2-propenoate (22a) gives 26 in which the 6-chloro-3- pyridyl moiety is endo-oriented. Decarboxylation followed by debenzylation gives unnatural epimer 30 of 1. The required cycloadduct 33, in which 6- chloro-3-pyridyl moiety is exo-oriented, is obtained stereoselectively utilizing cis-ethyl-(6-chloro-3-pyridyl)-2-propenoate (22b) as dipolarophile. 30 is also converted to 1 by epimerization reaction using KO(t)Bu. An alternative route involving conjugate addition of 6-chloro-3-iodo pyridine (37) to 36, obtained by cycloaddition of 10 with ethyl propiolate, is also suggested for the stereoselective synthesis of 1. A number of substituted epibatidines (38, 39, 40, 41, and 42) are synthesized through this strategy using appropriate dipolarophiles. Formal synthesis of the N-methyl homoepibatidine 48 and its epimer 46 is suggested from the cycloaddition of homologous azomethine ylide 44, derived from 43, with 22a and 22b, respectively.
- Pandey, Ganesh,Bagul, Trusar D.,Sahoo, Akhil K.
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p. 760 - 768
(2007/10/03)
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- Copper Cyanide-Catalyzed Palladium Coupling of N-tert-Butoxycarbonyl-Protected α-Lithio Amines with Aryl Iodides or Vinyl Iodides
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Treatment of (α-aminoalkyl)lithium reagents with aryl iodides in the presence of catalytic amounts of CuCN and PdCl2(PPh3)2 or [(p-MeOC6H4)3P]4Pd affords 2-aryl substituted amines in modest to good yields. The yields can be improved by use of softer ligands such as AsPh3 and SbPh3 or by use of bis(diphenylphosphino)ferrocene (dppf). Coupled products are obtained with electron-rich aryl iodides (XArI, X = Me, OMe), and the reaction fails with electron-poor aryl iodides (XArI, X = NO2, CO2Li). Treatment of the (α-aminoalkyl)lithium reagents with vinyl iodides and Pd(0)/dppf/ CuCN afforded the coupling products in low to modest yields.
- Karl Dieter,Li, ShengJian
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p. 7726 - 7735
(2007/10/03)
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- Stereoselectivity in the Photoinduced Electron Transfer (PET) promoted intramolecular cyclisations of 1-alkenyl-2-silyl-piperidines and -pyrrolidines: Rapid construction of 1-azabicyclo[m.n.0] alkanes and stereoselective synthesis of (±)-isoretronecanol and (±)-epilupinine
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PET promoted cyclisations of 1-alkenyl-2-silyl-pyrrolidines and -piperidines 9a-d to 1-aza-bicyclo[m.n.0]alkanes have been found to be stereoselective. The five-membered ring formation gives predominantly cis products while six-membered rings are trans. Application of such cyclisations to the synthesis of (±)-isoretronecanol 22a, (±)-epilupinine 29 and related alkaloids has been demonstrated. Copyright 1996 by the Royal Society of Chemistry.
- Pandey, Ganesh,Reddy, Gottimukkula Devi,Chakrabarti, Debasish
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p. 219 - 224
(2007/10/03)
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- Sequential two-electron oxidation of α,α′-disilylmethylamines to generate non-stabilized azomethine ylide: An ideal approach for the construction of substituted and fused pyrrolidine ring systems
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α,α′-Di(trimethylsilylmethyl)amines undergo sequential double desilylation processes, by two-electron oxidation initiated either by photoinduced electron transfer (PET) or Ag(I)F, to produce non-stabilized azomethine ylides efficiently which upon trapping with appropriate dipolarophiles give the corresponding pyrrolidines. Application of this strategy to cyclic analogue for the rapid construction of biologically important 1-azabicyclo[m,3.0]alkane framework is discussed.
- Pandey, Ganesh,Lakshmaiah,Gadre, Smita R.
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- Complex induced proximity effects: Enantioselective syntheses based on asymmetric deprotonations of N-Boc-pyrrolidines
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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
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p. 3231 - 3239
(2007/10/02)
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- INDOLIZIDINE AND QUINOLIZIDINE RING FORMATION IN THE SET-PHOTOCHEMISTRY OF α-SILYLAMINES
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The scope and limitations of indolizidine and quinolizidine ring forming, SET-photoinduced, α-amino radical cyclization reactions were explored.
- Hoegy, Susan E.,Mariano, Patrick S.
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p. 8319 - 8322
(2007/10/02)
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- α-Lithioamine Synthetic Equivalents: Synthesis of Diastereoisomers from Boc Derivatives of Cyclic Amines
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Sequences of α'-lithiations and electrophilic substitutions of Boc-pyrrolidines, Boc-piperidines, and Boc-hexahydroazepines that provide compounds which are substituted adjacent to nitrigen are reported, and the pathways of the reactions are discussed.By this methodology monosubstituted 2 and disubstituted 2,4, 2,6, and 2,5 Boc-piperidines are obtained as single or separable diastereoisomers consistent with equatorial lithiations and retentive electrophilic substitution in chair conformations.Both cis and trans 2,6-disubstituted diastereoisomers can be prepared, and control of diastereoselectivity is demonstrated by syntheses of solenopsin A, a 2,6-trans-disubstituted piperidine, and of Boc-dihydropinidine, a 2,6-cis-disubstituted piperidine.In the case of 3-methoxy-Boc-piperidine elimination of methoxide occurs upon lithiation, and with cis-2,4-disubstituted Boc-piperidines the electrophile is introduced with trans stereochemistry at C-6.These reactions are suggested to involve twist boat conformations consistent with an X-ray crystal structure of 2-methyl-6-(trimethylstannyl)-4-phenyl-N-Boc-piperidine.Boc-pyrrolidine lithiates more rapidly than Boc-piperidine, provides 2-substituted products with electrophiles, and on further lithiation-substitution gives 2,5-cis- and -trans substituted products.Boc-perhydroazepine provides 2-substituted products by the sequence and on further lithiation-substitution gives 2,7-trans-disubstituted products.
- Beak, Peter,Lee, Won Koo
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p. 1109 - 1117
(2007/10/02)
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- Ag(I)F as one electron oxidant for promoting sequential double desilylation : An ideal approach to non-stabilized azomethine ylides for the rapid construction of 1-azabicyclo (m:3:0) alkanes
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A novel methodology for effecting sequential double desilylation by Ag(I)F for the generation of non-stabilized azomethine ylide and its application for the synthesis of 1-azabicyclo(m.3.0) alkane systems are described.
- Pandey, Ganesh,Lakshmaiah
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p. 4861 - 4864
(2007/10/02)
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- Stereoselectivity in the cyclisation of photoinduced electron transfer (PET) generated cyclic α -amino radicals: First general stereoselective entry to 1-azabicyclo (m:n:o) alkane systems
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Stereoselectivity in the intramolecular cyclisation of PET-generated cyclic α-amino radicals and its application to the synthesis of 1-azabicyclo (m:n:o) alkane systems is reported.
- Pandey, Ganesh,Reddy, G. Devi
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p. 6533 - 6536
(2007/10/02)
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- α-LITHIOAMINE SYNTHETIC EQUIVALENTS FROM DIPOLE-STABILIZED CARBANIONS: THE t-BOC GROUP AS AN ACTIVATOR FOR α'-LITHIATION OF CARBAMATES
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The t-Boc group activates the α'-lithiation of piperidinyl and related carbamates to give lithium reagents which add to electrophiles to provide α'-elaborated carbamates.
- Beak, Peter,Lee, Won-Koo
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p. 1197 - 1200
(2007/10/02)
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