Design, synthesis, and characterization of SO2-containing azabicyclo[3.n.1]alkanes: promising building blocks for drug discovery.

A set of novel SO2-containing azabicyclo[3.n.1]alkanes has been synthesized by the double-Mannich annulation of of the corresponding monocyclic S-ketones. These compounds have been rationally designed as 3D-shaped, conformationally restricted SO2-containing building blocks for drug discovery.

[1]  David S. Wishart,et al.  DrugBank: a knowledgebase for drugs, drug actions and drug targets , 2007, Nucleic Acids Res..

[2]  E. Carreira,et al.  Four-membered ring-containing spirocycles: synthetic strategies and opportunities. , 2014, Chemical reviews.

[3]  Matthew W D Perry,et al.  Designing novel building blocks is an overlooked strategy to improve compound quality. , 2015, Drug discovery today.

[4]  M. Brimble,et al.  Efficient Synthesis of the Azabicyclo[3.3.1]nonane Ring System in the Alkaloid Methyllycaconitine Using Bis(alkoxymethyl)alkylamines as Aminoalkylating Agents in a Double Mannich Reaction , 2005 .

[5]  E. Carreira,et al.  Synthesis of azaspirocycles and their evaluation in drug discovery. , 2010, Angewandte Chemie.

[6]  C. Marson,et al.  New and unusual scaffolds in medicinal chemistry. , 2011, Chemical Society reviews.

[7]  N. Sach,et al.  Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction. , 2011, Organic letters.

[8]  A. Mann Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry , 2008 .

[9]  Robert D. M. Davies,et al.  Cubanes in medicinal chemistry: synthesis of functionalized building blocks. , 2014, Organic letters.

[10]  E. M. Holt,et al.  Synthesis, Stereochemical, and Conformational Studies of Selected 3,7-Diheterabicyclo[3.3.1]nonan-9-ols: X-Ray Diffraction Analyses of 7-Benzyl-9-phenyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-ol and 7-Benzyl-9-(4- N,N′ -dimethylaminophenyl)-3-thia-7-azabicyclo[3.3.1]nonan-9-ol, a Rare Stable Chair–Boat Fo , 2007 .

[11]  K. Berlin,et al.  1H NMR spectroscopy in the study of the three-dimensional structure of 7-alkoxyalkyl-3-thia-7-azabicyclo-[3.3.1]nonan-9-ones and some of their derivatives , 2008 .

[12]  E. Carreira,et al.  Construction of multifunctional modules for drug discovery: synthesis of novel thia/oxa-azaspiro[3.4]octanes. , 2013, Organic letters.

[13]  S. Purser,et al.  Fluorine in medicinal chemistry. , 2008, Chemical Society reviews.

[14]  M. Brimble,et al.  Use of bis-(aminol) ethers derived from N-(S)-(−)-α-methylbenzylamine in reactions with resorcinarenes and double Mannich reactions , 2005 .

[15]  A. Tolmachev,et al.  An entry into hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide derivatives. , 2011, The Journal of organic chemistry.

[16]  R. Lazzara,et al.  3,7,9-Triheterabicyclo[3.3.2]decan-10-ones : an unusual family of heterocycles obtained from 3,7-diheterabicyclo[3.3.1]nonan-9-ones , 1993 .

[17]  A. William,et al.  A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3-iodobicyclo[1.1.1]pentane. , 2014, Organic letters.

[18]  Channa K. Hattotuwagama,et al.  Lead-oriented synthesis: a new opportunity for synthetic chemistry. , 2012, Angewandte Chemie.

[19]  V. Yu,et al.  Synthesis and structure of 7-alkoxyalkyl-3-thia-7-zabicyclo[3.3.1]nonan-9-ones and several of their derivatives , 2006 .

[20]  S.L. Carney,et al.  Drug Discovery Today: Technologies (2007) volume 4 issues 3/4. , 2007, Drug discovery today. Technologies.

[21]  C. Humblet,et al.  Escape from flatland: increasing saturation as an approach to improving clinical success. , 2009, Journal of medicinal chemistry.

[22]  W. Hagmann,et al.  The many roles for fluorine in medicinal chemistry. , 2008, Journal of medicinal chemistry.

[23]  E. Carreira,et al.  Synthesis of novel azaspiro[3.4]octanes as multifunctional modules in drug discovery. , 2011, Organic letters.

[24]  E. M. Holt,et al.  Synthesis, conformational analysis, and antiarrhythmic properties of 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonan-9-one, 7-benzyl-3-thia-7-azabicyclo[3.3.1]nonane hydroperchlorate, and 7-benzyl-9-phenyl-3-thia-7-azabicyclo[3.3.1]nonan-9-ol hydroperchlorate and derivatives: single-crystal X-ray diffracti , 1984, Journal of medicinal chemistry.

[25]  E. M. Holt,et al.  Isolation and single-crystal X-ray diffraction analysis of N-benzyl-3-thia-7-azabicyclo [3.3.1]-nonan-9,9-diol perchlorate, a novel hydrate formed from reaction of N-benzyl-3-thia-7-azabicyclo [3.3.1]-nonan-9-one with perchloric acid , 1984 .