- A dimethylzinc/diphenylphosphinoylimine approach to the asymmetric synthesis of the calcimimetic agent NPS R-568
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An asymmetric synthesis of the calcimimetic agent NPS R-568 using a (1R,2S)-N-benzylephedrine-promoted addition of dimethylzinc to a diphenylphosphinoylimine derived from 3-methoxybenzaldehyde is described. The enantiomeric ratio of the key amine fragment was determined to be 93:7 (86% ee), favoring the (R)-enantiomer by derivatization and chiral stationary phase HPLC analysis.
- Banerjee, Sucharita,Smith, Brad,Hitchcock, Shawn R.
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experimental part
p. 105 - 109
(2012/06/18)
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- A stereo-controlled synthesis of 2,4-dimethyl-4-hydroxy-16- phenylhexadecanoic acid 1,4-lactone and its PPAR activities
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A novel class of natural PPAR agonists, 2,4-dimethyl-4-hydroxy-16- phenylhexadecanoic acid 1,4-lactone (1), were discovered in marine natural product libraries. The synthesis of 1 was accomplished starting from vinylmethyl ketone. Ring formation of the α,γ dialkyl γ-lactone was achieved via the stereo-controlled reaction of a ketyl radical anion with a chiral methacrylate. In the PPAR agonistic assay, the most potent of the four stereoisomers had EC50 values of 12 μM for mPPARα, 9 μM for mPPARδ and >100 μM for mPPARγ.
- Ko, Jaeyoung,Hwang, Hoosang,Chin, Jungwook,Hahn, Dongyup,Lee, Jaehwan,Yang, Inho,Shin, Kyoungjin,Ham, Jungyeob,Kang, Heonjoong
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scheme or table
p. 6017 - 6019
(2010/11/17)
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- Enantiospecific Stereodivergent Synthesis of trans- and cis-N(2), 3-Dimethyl- 4-phenyl-1, 2, 3, 4-tetrahydroisoquinolines
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The acid-promoted cyclizations of a range of N-benzylethanolamines (derived from pseudoephedrine or ephedrine) give the corresponding trans-N(2), 3-dimethyl-4-phenyl-1, 2, 3, 4- tetrahydroisoquinolines with high levels of diastereoselectivity and in good yields of isolated product. The cyclizations of the corresponding chromium tricarbonyl complexes are rendered completely stereoselective. Acidpromoted cyclization of N-(3′, 4′- dimethoxybenzyl) ephedrine and its chromium tricarbonyl complex occur with complementary diastereoselectivities to give trans- and cis-N(2), 3-dimethyl-4- phenyl-6, 7-dimethoxy-1, 2, 3, 4-tetrahydro- isoquinoline, respectively, in >99:1 d.r. The latter is consistent with a "double inversion" mechanism, which involves neighboring group participation by the chromium tricarbonyl moiety followed by rearomatization to give the corresponding cis-tetrahydroisoquinoline with overall retention of configuration.
- Coote, Steven J.,Davies, Stephen G.,Fletcher, Ai M.,Roberts, Paul M.,Thomson, James E.
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experimental part
p. 589 - 604
(2010/08/07)
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- N-Pyridylmethylephedrine derivatives in the catalytic asymmetric addition of diethylzinc to aldehydes and diphenylphosphinoylimines
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N-Pyridylmethyl-substituted Ephedra derivatives were synthesized by either direct alkylation or reductive alkylation of (1R,2S)-norephedrine, (1S,2S)-pseudo norephedrine, and (1R,2S)-ephedrine. These derivatives were then employed in asymmetric addition reactions with diethylzinc and aldehydes and diphenylphosphinoylimines. The use of the diastereomers from the Ephedra family allowed for a systematic evaluation of the contribution of the N-pyridylmethyl.
- Banerjee, Sucharita,Groeper, Jonathan A.,Standard, Jean M.,Hitchcock, Shawn R.
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scheme or table
p. 2154 - 2161
(2010/03/03)
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- Development of a solid-phase 'asymmetric resin-capture-release' process: Application of an ephedrine chiral resin in an approach to γ- butyrolactonest
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The potential of a solid-phase asymmetric resin-capture-release strategy for high-throughput synthesis has been evaluated. Fukuzawa's Sm(II)-mediated, asymmetric approach to γ-butyrolactones was selected to illustrate the feasibility of such a process. α,β-Unsaturated esters immobilised on an ephedrine chiral resin have been applied in an asymmetric approach to γ-butyrolactones. Lactone products are obtained in moderate isolated yields with selectivities up to 96% ee. In addition, we have shown that the ephedrine resin can be conveniently recovered and recycled although in some cases lower yields were obtained on reuse of the chiral resin. A short synthesis of a moderate DNA-binding microbial metabolite using asymmetric resin-capture-release is also described.
- Kerrigan, Nessan J.,Hutchison, Panee C.,Heightman, Tom D.,Procter, David J.
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p. 2476 - 2482
(2007/10/03)
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- Diastereoselectivity in the reduction of α-oxy- and α-amino-substituted acyclic ketones by polymethylhydrosiloxane
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Diastereoselectivity in the reduction of α-alkoxy-, α-acyloxy-, and α-alkylamino-substituted ketones with polymethylhydrosiloxane (PMHS) in the presence of fluoride ion catalysis was investigated. High syn-selectivity was observed in the reduction of α-alkoxy, α-acyloxy, and α-dialkylamino ketones. Reduction of α-monoalkylamino ketone proceeded in anti-selective manner with moderate selectivity. The observed selectivity is explained based on Felkin-Anh and Cram-chelate models.
- Nadkarni, Durgesh,Hallissey, James,Mojica, Carlos
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p. 594 - 596
(2007/10/03)
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- Stereoselective formation and rearrangement of morpholinium ylides derived from copper carbenoids
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Amino diazoacetoacetates 4a-e and 7a,b were prepared from readily available amino alcohols and subjected to copper-catalyzed carbene-transfer reaction. Substrates 4c-e furnished the morpholin-2-ones 5c-e in good yield via the corresponding cyclic ammonium ylides, albeit with poor diastereoselectivity. Substrates 4a,b failed to provide the corresponding morpholinones, perhaps as a result of steric congestion. Cyclic substrates 7a,b underwent conversion to bicyclic morpholinones 8 and 9 in good yield and with moderate to good diastereoselectivity. This result is rationalized via control of the transiently stereogenic ammonium center of the intermediate bicyclic ylides.
- Glaeske, Kevin W.,Naidu,West
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p. 917 - 920
(2007/10/03)
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- Synthesis of N-(dialkylaminoalkyl)alcohols by homogeneously catalyzed hydrogenolysis of cyclic N,O-acetals
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The homogeneously catalyzed hydrogenation of 1,3-oxazolidines affording unsymmetrically substituted 2-N-(dialkylamino)ethanols is reported showing for the first time that Rh(I) catalysts based on chelating diphosphines can be advantageous for this reaction.
- Tararov, Vitali I.,Kadyrov, Renat,Riermeier, Thomas H.,B?rner, Armin
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p. 375 - 380
(2007/10/03)
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- The Reductive Cleavage of Cyclic Aminol Ethers to N,N-Dialkylamino-derivatives: Modifications to the Eschweiler-Clarke Procedure
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The reductive cleavage of cyclic aminol ethers to give N-alkylamino-derivatives in very high yields can be achieved using chlorotrimethylsilane in the presence of sodium cyanoborohydride: in the case of cyclic aminol ethers derived from formaldehyde the Eschweiler-Clarke reaction can be carried out in formic acid heated under reflux in the absence of formaldehyde.
- Page, Philip C. Bulman,Heaney, Harry,Rassias, Gerasimos A.,Reignier, Serge,Sampler, Edward P.,Talib, Salem
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p. 104 - 106
(2007/10/03)
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- Reactions of aldehydes with diethylzinc catalysed by polymer-supported ephedrine and camphor derivatives: Comparisons of enantiomeric excesses achieved with various supports: Optimisation of support parameters to enable high enantiomeric excesses to be obtained
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The reactions of benzaldehyde with diethylzinc catalysed by PS ephedrine or camphor derivatives have been investigated in some depth in order to identify the crucial factors necessary to successfully prepare PS chiral catalysts for such reactions. The most important factor is found to be a favourable interaction of the polymer matrix with the reaction solvent so that the polymer will dissolve or swell to allow the other reactants easy access to the catalytic sites. Accordingly toluene is a better reaction solvent than hexane. The ephedrine-derived catalytic groups reduce the solubility of the linear polymers in toluene and, almost certainly, the swelling properties of the crosslinked polymers. Thus, of the polymers investigated the better linear ones had ca. 1.5 mmol per g of catalyst sites and the better insoluble ones were 1% crosslinked gels with ca. 1.0 mmol per g of catalyst sites. Site-site interactions and microenvironmental effects do not appear to play a major role in these PS reaction systems. For the reaction of benzaldehyde with diethylzinc, using the best linear PS ephedrine derivatives 10f, 10g or 11e affords 1-phenylpropanol (1) with 83-88% enantiomeric excesses (ee)s of the (R)-enantiomer; using the best linear PS camphor derivative 21 affords the alcohol 1 with a 98% ee of the (S)-enantiomer; using the best crosslinked PS ephedrine derivative 12a affords the alcohol 1 with a 78-81% ee and using the best crosslinked PS camphor derivative 22 affords alcohol 1 with a 97% ee of the (S)-enantiomer. These values are close to those obtained using analogues of non-polymeric catalysts under similar reaction conditions.
- Sung, David W. L.,Hodge, Philip,Stratford, Peter W.
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p. 1463 - 1472
(2007/10/03)
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- Application of the Mitsunobu reaction to ephedrines and some related amino alcohols. Aspects of intramolecular participation of the amino group
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Inversion of configuration at the benzylic hydroxyl group of (1S,2S)-pseudoephedrine (2) to afford (1R,2S)-ephedrine is known to be a difficult process.The Mitsunobu reactions of 1 and 2 might offer a route to achieve such inversions.In fact Mitsunobu reactions on 1 and 2 are known to proceed via aziridines formed on intramolecular SN2 substitution by the amine functionality.The Mitsunobu reactions of N-methylated and N-benzylated ephedrines have been found to proceed via the corresponding aziridinium ions.These aziridinium ions can be opened (SN2 substitution) by nucleophiles like phthalimide and thiols.Intramolecular participation in 2 can be avoided by use of the tert-butyloxycarbonyl-(BOC) or benzyloxycarbonyl- (CBZ) protected derivatives.Mitsunobu reactions on these derivatives lead to inversion of configuration at the benzylic hydroxyl center.In contrast the BOC and CBZ derivatives of 1 are deprotected under Mitsunobu conditions.The Mitsunobu reactions of threo (1S,2S)-2-amino-1,3-propanediol have also been examined.An attempt to achieve protection by reaction with dimethylformamide dimethyl acetal led to the more substituted 2-oxazoline as established by X-ray crystallography.The desired inversion of configuration of the benzylic hydroxylic group was eventually achieved by protection of the amino substituent as the phthalimide and protection of the primary hydroxyl group as the tosylate.
- Poelert, Martin A.,Hulshof, L. A.,Kellogg, Richard M.
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p. 355 - 364
(2007/10/02)
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- Reaction of alkyl sulfoxides and phenylphosphinic acid with amines. Alternative reagents for secondary amines N-alkylation
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Phenylphosphinic acid and dialkylsulfoxides are found to be alternative reagents for respectively the reducing reagent (formic acid) and the alkylating reagent (aldehyde) currently used for secondary amines N-alkylation. Primary amines do not react with this system, but phenylglycine is decarboxilated to benzylamine.
- Chauvin
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p. 1425 - 1428
(2007/10/02)
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- Polymer-Assisted Asymmetric Reactions. 4. Polymer-Bound Ephedrine, Its Use and Limitations in Supported LiAlH4 Reductions
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A cross-linked polystyrene resin containing (1R,2S)-(-)-ephedrine moieties bound through nitrogen to some of its p-methylene-substituted aromatic rings is a useful regenerable chiral auxiliary in the enantioselective reduction of acetophenone by the chiral polymer-bound complexes of lithium aluminium hydride and an added achiral phenol.Evidence is presented to explain the capacity-dependent behavior of the polymer in the formation of chiral complexes and its effect on the enantioselectivity of the reduction of acetophenone.At high capacities, both unbound achiral and m ultiply bound chiral complexes are formed while numerous chiral ligands appear to be inaccessible to the hydride; under such conditions the enantioselectivity of the reaction is poor.In contrast, at low capacities corresponding to 8-10percent substitution of the styrene repeating units, the polymer-bound chiral moieties can act independently from one another and are fully accessible to the hydride.The reduction then proceeds with a high enantioselectivity, comparable to that of similar small chiral molecules.This mechanism is consistent with and explains the phenomena observed with other polymer-supported hydride reagents.
- Frechet, Jean M. J.,Bald, Edward,Lecavalier, Pierre
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p. 3462 - 3467
(2007/10/02)
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