| Reference | [1]. Org Lett. 2012 Apr 20;14(8):2172-5. doi: 10.1021/ol3007277. Epub 2012 Apr 9.<br />
Construction of the azocane (azacyclooctane) moiety of the Lycopodium alkaloid lycopladine H via an intramolecular hydroaminomethylation strategy.<br />
Sacher JR(1), Weinreb SM.<br />
Author information: (1)Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.<br />
An efficient synthetic strategy has been developed for annulation of an azocane ring onto a bicyclo[2.2.2]octane scaffold via an intramolecular hydroaminomethylation protocol to generate an advanced intermediate bearing three of the four rings of the structurally unique Lycopodium alkaloid lycopladine H (1).<br />
© 2012 American Chemical Society<br />
DOI: 10.1021/ol3007277 PMID: 22486178<br />
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[2]. J Org Chem. 2019 Aug 16;84(16):9897-9906. doi: 10.1021/acs.joc.9b00979. Epub 2019 Aug 6.<br />
Electronic Donation or Steric Contraction: A Spectroscopic and Structural Analysis of Medium-Sized Constrained Rings for Potential Long-Range Hyperconjugation.<br />
Lee R(1), Bashrum B(1), Cagle EC(2), Walters J(1), Massey J(3), Zanghi M(3), Birchfield C(3), French D(2), Joy J(3), Dos Passos Gomes G(4), Wiget PA(1).<br />
Author information: (1)Department of Chemistry and Biochemistry , Samford University , 800 Lakeshore Blvd. , Birmingham , Alabama 35229 , United States. (2)Department of Chemistry , The University of Alabama at Birmingham , Birmingham , Alabama 35205 , United States. (3)Department of Biological and Environmental Sciences , Samford University , Birmingham , Alabama 35229 , United States. (4)Department of Chemistry & Biochemistry , Florida State University , Tallahassee , Florida 32306 , United States.<br />
Herein, we report the 1JCH analyses, natural bond orbital analyses, and X-ray crystal structures of a number of C, O, and N constrained tricyclic cycles. These experiments provide access into the nature of the apparent Perlin effect previously reported in constrained tricyclic cycles, as well as evidence suggesting both steric contraction and long-range hyperconjugation account for the observed 1JCH perturbations. We report a true Perlin effect of 10.9 Hz in an azocane and large steric effect resulting in Δ1JC-H = 10.9 Hz in a cyclooctane.<br />
DOI: 10.1021/acs.joc.9b00979 PMID: 31340636<br />
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[3]. Bioorg Med Chem. 2013 Apr 15;21(8):2217-2228. doi: 10.1016/j.bmc.2013.02.010. Epub 2013 Feb 19.<br />
Discovery of disubstituted piperidines and homopiperidines as potent dual NK1 receptor antagonists-serotonin reuptake transporter inhibitors for the treatment of depression.<br />
Wu YJ(1), He H(2), Bertekap R(3), Westphal R(3), Lelas S(3), Newton A(3), Wallace T(3), Taber M(3), Davis C(4), Macor JE(2), Bronson J(2).<br />
Author information: (1)Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected]. (2)Department of Neuroscience Chemistry, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. (3)Department of Neuroscience Biology, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. (4)Department of Preclinical Candidate Optimization, Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.<br />
This report describes the synthesis, structure-activity relationships and activity of piperidine, homopiperidine, and azocane derivatives combining NK1 receptor (NK1R) antagonism and serotonin reuptake transporter (SERT) inhibition. Our studies culminated in the discovery of piperidine 2 and homopiperidine 8 as potent dual NK1R antagonists-SERT inhibitors. Compound 2 demonstrated significant activity in the gerbil forced swimming test, suggesting that dual NK1R antagonists-SERT inhibitors may be useful in treating depression disorders.<br />
Copyright © 2013 Elsevier Ltd. All rights reserved.<br />
DOI: 10.1016/j.bmc.2013.02.010 PMID: 23477943<br />
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[4]. Bioorg Med Chem. 2004 Aug 15;12(16):4375-85. doi: 10.1016/j.bmc.2004.06.015.<br />
Design, synthesis, and conformational analysis of eight-membered cyclic peptidomimetics prepared using ring closing metathesis.<br />
Creighton CJ(1), Leo GC, Du Y, Reitz AB.<br />
Author information: (1)Drug Discovery Division, PO Box 776, Welsh and McKean Rds., Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA 19477-0777, USA.<br />
As part of a program to identify novel scaffolds that adopt defined secondary structure when incorporated into peptides, we have designed and prepared a library of constrained eight-membered ring lactams based upon 7-amino-8-oxo-1,2,3,6,7-pentahydroazocine-2-carboxylic acid. Ring closing metathesis (RCM) was employed as the key step, proceeding in high yields to afford the Z olefin. In this reaction sequence, the first generation benzylidene ruthenium RCM catalyst was superior to the second-generation imidazoline catalyst, which gave extensive oligomerization at higher concentrations. Conformational analysis of the 2S,7S and 2R,7S stereoisomers revealed that the 2R,7S isomer is a Type VIa beta-turn in the solid state (X-ray crystal structure) and in water (NMR analysis). The Type VIa beta-turn is relatively rare, typically bearing the cis amide bond found in proline-containing sequences. The 2S,7S diastereomer has an extended geometry of the pendent amide chains. The corresponding saturated derivatives (7-amino-8-oxoazocane-2-carboxylic acid) were also synthesized and investigated. The 2S,7S azocane bears an extended geometry and mimics the C(+) conformer of ox-[Cys-Cys], found in a variety of naturally occurring peptides. The scaffolds described here are useful for the design of constrained peptidomimics with defined secondary structure.<br />
DOI: 10.1016/j.bmc.2004.06.015 PMID: 15265489<br />
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[5]. Org Lett. 2015 Feb 20;17(4):806-8. doi: 10.1021/ol503571a. Epub 2015 Feb 6.<br />
Synthesis of the tetracyclic skeleton of the Lycopodium alkaloid lycopladine H via a pivotal double hydroformylation/intramolecular reductive amination sequence.<br />
Chauhan PS(1), Sacher JR, Weinreb SM.<br />
Author information: (1)Department of Chemistry, The Pennsylvania State University , University Park, Pennsylvania 16802, United States.<br />
A synthesis of the complete tetracyclic framework of the structurally unique Lycopodium alkaloid lycopladine H has been accomplished using a strategy involving a double alkene hydroformylation/intramolecular reductive amination to form the azocane and spiro-piperidine moieties of the natural product.<br />
DOI: 10.1021/ol503571a PMID: 25658603
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