“…0.01 M). In general, this dimerization should pose a problem in N -acyliminium ion cyclizations only when the nucleophilic partner is not sufficiently reactive, such as with the acetylene group here, or when unfavorable stereoelectronic factors exist, such as in the formation of a medium-sized ring. − …”
Section: Mechanism and Stereochemistrymentioning
confidence: 99%
“…The stereochemical course of N -acyliminium ion cyclizations has received considerable attention over the years amidst various synthetic applications, and many types of reactions afford excellent stereoselectivity. Indeed, stereochemical control has become a hallmark for N -acyliminium ion cyclizations of diverse substrates containing aromatic, heterocyclic, alkene, alkyne, and keto/enol nucleophiles. − The favorable results commonly derive from straightforward stereoelectronic factors, similar to those in related cationic π-cyclizations. − Salient control elements are (1) steric approach control of the nucleophile to the iminium species, (2) steric interactions involving substituents, and, if pertinent, (3) steric interactions in the addition of nucleophiles to the new cyclic carbocation. This section will highlight key features associated with effective stereocontrol and elaborate on aspects of the reaction mechanism.…”
Section: 3 Stereochemistry Of Cyclizations and
Mechanistic Implicationsmentioning
confidence: 99%
“…Owing to the electron-attracting properties of the carbonyl group on nitrogen, the iminium carbon is now more electron-deficient, which causes such N -acyliminium ions to be much more reactive as electrophiles than simple N -alkyliminium ions. This favorable situation has spawned a large, separate area of versatile electrophilic chemistry known as α-amidoalkylation reactions, which are expressed generically in eq 1. − Here, too, the subtype involving cyclization, i.e., the intramolecular reaction of N -acyliminium ions, has received considerable attention in organic chemistry, particularly with respect to the synthesis of alkaloid natural products. − Fortunately, nucleophiles that are relatively unreactive in the intramolecular Mannich reaction, such as unactivated benzenoids, participate effectively in cyclizations with N -acyliminum species. …”
Section: Introductionmentioning
confidence: 99%
“…Additionally, this review will not deal with cyclizations of species considered to be vinylogous N -acyliminium ions, i.e., species with a carbon−carbon double bond conjugating an acyl group to nitrogen. Under these constraints on content, we intend to provide comprehensive coverage of N -acyliminium ion cyclizations over the entire course of history. − Overall, the text portion of this review will discuss the pertinent literature through 2000, with selective coverage of information published in 2001−2002. However, the tabular portion will cover all of the pertinent literature through most of 2002 comprehensively (see section 5, Comprehensive Tabular Survey of Reactions).…”
Section: Introductionmentioning
confidence: 99%
“…A notable illustration of this viewpoint derives from the failure of iminium ion 3 to cyclize under “various conditions” (eq 3) compared to the successful N -acyliminium ion cyclization of 4 to 5 (eq 4) . In the 1960s through the 1980s, several laboratories exploited N -acyliminium ion cyclizations, especially for the synthesis of natural products. − This period also witnessed a spate of studies on diverse reactions, particularly those involving alkene and alkyne nucleophiles, thus spurring this field tremendously. The milestones of this chemistry have been presented in several review articles. − It is noteworthy that Belleau's early proposal 23 about the potential advantages of using N -acyliminium electrophiles presaged a major advance in ring formation over the next 35 yearsnamely, N -acyliminium ion cyclizations.…”
effectively in cyclizations with N-acyliminum species. Electron-attracting substituents other than N-acyl, such as N-sulfonyl, can also be employed in analogues of N-acyliminium ion reactions. However, this review will concentrate on cyclizations of the N-acyl type, encompassing groups such as alkanoyl, aroyl, carbalkoxy, and N,N-dialkylcarbamyl, with limited coverage of sulfonyl groups. Most significantly, this review will focus on intramolecular reactions of N-acyliminium ions that result in the formation of new carbon-carbon bonds, rather than new carbonheteroatom bonds. Although β-lactam synthesis based on the cyclocondensation of imines with acid halides, Bruce E. Maryanoff earned B.S. (1969) and Ph.D. (1972) degrees from Drexel University and then conducted postdoctoral studies at Princeton University, working with Prof. Kurt Mislow. He joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974 and advanced to Distinguished Research Fellow, the highest scientific position in the company. From 1976 to 1992, he principally worked on discovering drugs for treating central nervous system disorders; in 1992, he moved into cardiovascular research and presently leads the Vascular Research Team. Dr. Maryanoff is recognized for his work in organic and medicinal chemistry, especially the Wittig olefination reaction; peptides and peptidomimetics; antiepileptics and antidepressants; thrombin inhibitors; and protease-activated receptors. He discovered TOPAMAX topiramate, which is marketed worldwide for the treatment of epilepsy and is being developed for migraine headache. He has published 200 scientific papers, is an inventor on 60 U.S. patents, and has received two national awards, the ACS Heroes of Chemistry Award (2000) and the ACS Award in Industrial Chemistry (2003). Dr. Maryanoff is a Fellow in the American Association for the Advancement of Science and the Royal Society of Chemistry. Han-Cheng Zhang received B.S. and M.S. degrees in chemistry from Xiamen University, P.R.C., and served as a faculty member there for 5 years. He came to the United States and earned a Ph.D. degree in organic chemistry from Rensselaer Polytechnic Institute (1992), working with Prof. Doyle Daves. He joined the R. W. Johnson Pharmaceutical Research Institute as a Postdoctoral Scientist with Dr. Bruce Maryanoff and, after one year, as a Scientist. Dr. Zhang has worked as a medicinal chemist in the areas of G-protein-coupled receptors, proteases, and kinases to discover new drug candidates, recently leading a project that identified the first potent, selective antagonists for the thrombin receptor, proteaseactivated receptor 1. He is now at the level of Principal Scientist in Johnson & Johnson Pharmaceutical Research & Development. Dr. Zhang has published over 40 scientific papers and is an inventor on 13 U.S. patents (issued or pending). His scientific interests include the design and synthesis of novel therapeutic agents, heterocycles, stereoselective reactions, organometallic chemistry, and solid-phase organic synthesis. Judi...
“…0.01 M). In general, this dimerization should pose a problem in N -acyliminium ion cyclizations only when the nucleophilic partner is not sufficiently reactive, such as with the acetylene group here, or when unfavorable stereoelectronic factors exist, such as in the formation of a medium-sized ring. − …”
Section: Mechanism and Stereochemistrymentioning
confidence: 99%
“…The stereochemical course of N -acyliminium ion cyclizations has received considerable attention over the years amidst various synthetic applications, and many types of reactions afford excellent stereoselectivity. Indeed, stereochemical control has become a hallmark for N -acyliminium ion cyclizations of diverse substrates containing aromatic, heterocyclic, alkene, alkyne, and keto/enol nucleophiles. − The favorable results commonly derive from straightforward stereoelectronic factors, similar to those in related cationic π-cyclizations. − Salient control elements are (1) steric approach control of the nucleophile to the iminium species, (2) steric interactions involving substituents, and, if pertinent, (3) steric interactions in the addition of nucleophiles to the new cyclic carbocation. This section will highlight key features associated with effective stereocontrol and elaborate on aspects of the reaction mechanism.…”
Section: 3 Stereochemistry Of Cyclizations and
Mechanistic Implicationsmentioning
confidence: 99%
“…Owing to the electron-attracting properties of the carbonyl group on nitrogen, the iminium carbon is now more electron-deficient, which causes such N -acyliminium ions to be much more reactive as electrophiles than simple N -alkyliminium ions. This favorable situation has spawned a large, separate area of versatile electrophilic chemistry known as α-amidoalkylation reactions, which are expressed generically in eq 1. − Here, too, the subtype involving cyclization, i.e., the intramolecular reaction of N -acyliminium ions, has received considerable attention in organic chemistry, particularly with respect to the synthesis of alkaloid natural products. − Fortunately, nucleophiles that are relatively unreactive in the intramolecular Mannich reaction, such as unactivated benzenoids, participate effectively in cyclizations with N -acyliminum species. …”
Section: Introductionmentioning
confidence: 99%
“…Additionally, this review will not deal with cyclizations of species considered to be vinylogous N -acyliminium ions, i.e., species with a carbon−carbon double bond conjugating an acyl group to nitrogen. Under these constraints on content, we intend to provide comprehensive coverage of N -acyliminium ion cyclizations over the entire course of history. − Overall, the text portion of this review will discuss the pertinent literature through 2000, with selective coverage of information published in 2001−2002. However, the tabular portion will cover all of the pertinent literature through most of 2002 comprehensively (see section 5, Comprehensive Tabular Survey of Reactions).…”
Section: Introductionmentioning
confidence: 99%
“…A notable illustration of this viewpoint derives from the failure of iminium ion 3 to cyclize under “various conditions” (eq 3) compared to the successful N -acyliminium ion cyclization of 4 to 5 (eq 4) . In the 1960s through the 1980s, several laboratories exploited N -acyliminium ion cyclizations, especially for the synthesis of natural products. − This period also witnessed a spate of studies on diverse reactions, particularly those involving alkene and alkyne nucleophiles, thus spurring this field tremendously. The milestones of this chemistry have been presented in several review articles. − It is noteworthy that Belleau's early proposal 23 about the potential advantages of using N -acyliminium electrophiles presaged a major advance in ring formation over the next 35 yearsnamely, N -acyliminium ion cyclizations.…”
effectively in cyclizations with N-acyliminum species. Electron-attracting substituents other than N-acyl, such as N-sulfonyl, can also be employed in analogues of N-acyliminium ion reactions. However, this review will concentrate on cyclizations of the N-acyl type, encompassing groups such as alkanoyl, aroyl, carbalkoxy, and N,N-dialkylcarbamyl, with limited coverage of sulfonyl groups. Most significantly, this review will focus on intramolecular reactions of N-acyliminium ions that result in the formation of new carbon-carbon bonds, rather than new carbonheteroatom bonds. Although β-lactam synthesis based on the cyclocondensation of imines with acid halides, Bruce E. Maryanoff earned B.S. (1969) and Ph.D. (1972) degrees from Drexel University and then conducted postdoctoral studies at Princeton University, working with Prof. Kurt Mislow. He joined McNeil Laboratories, a Johnson & Johnson subsidiary, in 1974 and advanced to Distinguished Research Fellow, the highest scientific position in the company. From 1976 to 1992, he principally worked on discovering drugs for treating central nervous system disorders; in 1992, he moved into cardiovascular research and presently leads the Vascular Research Team. Dr. Maryanoff is recognized for his work in organic and medicinal chemistry, especially the Wittig olefination reaction; peptides and peptidomimetics; antiepileptics and antidepressants; thrombin inhibitors; and protease-activated receptors. He discovered TOPAMAX topiramate, which is marketed worldwide for the treatment of epilepsy and is being developed for migraine headache. He has published 200 scientific papers, is an inventor on 60 U.S. patents, and has received two national awards, the ACS Heroes of Chemistry Award (2000) and the ACS Award in Industrial Chemistry (2003). Dr. Maryanoff is a Fellow in the American Association for the Advancement of Science and the Royal Society of Chemistry. Han-Cheng Zhang received B.S. and M.S. degrees in chemistry from Xiamen University, P.R.C., and served as a faculty member there for 5 years. He came to the United States and earned a Ph.D. degree in organic chemistry from Rensselaer Polytechnic Institute (1992), working with Prof. Doyle Daves. He joined the R. W. Johnson Pharmaceutical Research Institute as a Postdoctoral Scientist with Dr. Bruce Maryanoff and, after one year, as a Scientist. Dr. Zhang has worked as a medicinal chemist in the areas of G-protein-coupled receptors, proteases, and kinases to discover new drug candidates, recently leading a project that identified the first potent, selective antagonists for the thrombin receptor, proteaseactivated receptor 1. He is now at the level of Principal Scientist in Johnson & Johnson Pharmaceutical Research & Development. Dr. Zhang has published over 40 scientific papers and is an inventor on 13 U.S. patents (issued or pending). His scientific interests include the design and synthesis of novel therapeutic agents, heterocycles, stereoselective reactions, organometallic chemistry, and solid-phase organic synthesis. Judi...
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