Efficient Routes to a Diverse Array of Amino Alcohol-Derived Chiral Fragments

Efficient syntheses of chiral fragments derived from chiral amino alcohols are described. Several unique scaffolds were readily accessed in 1–5 synthetic steps leading to 45 chiral fragments, including oxazolidinones, morpholinones, lactams, and sultams. These fragments have molecular weights ranging from 100 to 255 Da and are soluble in water (0.085 to >15 mM).

[1]  R. Perrone,et al.  Synthesis and absolute configuration of substituted morpholines , 1980 .

[2]  D. Erlanson.  Fragment-based lead discovery: a chemical update. , 2006, Current opinion in biotechnology.

[3]  L. Lam,et al.  ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets , 2013, Nature Medicine.

[4]  Armando Carlone,et al.  Direct catalytic synthesis of enantiopure 5-substituted oxazolidinones from racemic terminal epoxides. , 2005, Organic letters.

[5]  R. Baldwin,et al.  Asymmetric synthesis of (+)-(S,S)-reboxetine via a new (S)-2-(hydroxymethyl)morpholine preparation. , 2005, Organic letters.

[6]  F. Huet,et al.  An easy route to 4-substituted 2-oxazolidinones from prochiral-1,3-diols , 2004 .

[7]  S. Schaus,et al.  Kinetic Resolution of Terminal Epoxides via Highly Regioselective and Enantioselective Ring Opening with TMSN3. An Efficient, Catalytic Route to 1,2‐Amino Alcohols. , 1996 .

[8]  V. Tripathi,et al.  A Concise and Efficient Synthesis of Substituted Morpholines , 2014, Synthesis.

[9]  M. Terada,et al.  Kinetic resolution of racemic amino alcohols through intermolecular acetalization catalyzed by a chiral Brønsted acid. , 2015, Journal of the American Chemical Society.

[10]  Monya Baker,et al.  Fragment-based lead discovery grows up , 2012, Nature Reviews Drug Discovery.

[11]  F. Tanaka,et al.  Direct catalytic asymmetric synthesis of anti-1,2-amino alcohols and syn-1,2-diols through organocatalytic anti-Mannich and syn-aldol reactions. , 2007, Journal of the American Chemical Society.

[12]  R. Angell,et al.  Cycloadditions of 1,3-oxazolium-4-olates (isomünchnones) by rhodium(II)-induced decomposition of α-diazocarbonyl derivatives of (5R)- and (5S)-phenyloxazin-3-one as a chiral template , 1997 .

[13]  M. Batchelor,et al.  4-(1,3-Thiazol-2-yl)morpholine derivatives as inhibitors of phosphoinositide 3-kinase. , 2008, Bioorganic & medicinal chemistry letters.

[14]  C. Kashima,et al.  Synthesis and reaction of optically active morpholinones , 1988 .

[15]  Daniel P. Walker,et al.  Synthesis of (±)-6-oxa-3-azabicyclo[3.1.1]heptan-2-thione: a potential synthon for the preparation of novel heteroaryl-annulated bicyclic morpholines , 2011 .

[16]  T. Higuchi,et al.  Phase solubility techniques , 1965 .

[17]  Christine G. Espino,et al.  A Rh-Catalyzed C-H Insertion Reaction for the Oxidative Conversion of Carbamates to Oxazolidinones. , 2001, Angewandte Chemie.

[18]  S. Laschat,et al.  Ionic liquid crystals derived from amino acids. , 2013, Chemistry.

[19]  P. Hanson,et al.  Synthesis of sultam scaffolds via intramolecular oxa-Michael and diastereoselective Baylis-Hillman reactions. , 2008, Organic Letters.

[20]  Kenny K. Wong,et al.  Synthesis of analogs of (1,4)-3- and 5-imino oxazepane, thiazepane, and diazepane as inhibitors of nitric oxide synthases. , 2004, Bioorganic & medicinal chemistry letters.

[21]  Markus Schade,et al.  Assembling a Fragment Library , 2008 .

[22]  E. Carreira,et al.  Oxetanes as promising modules in drug discovery. , 2006, Angewandte Chemie.

[23]  J. Aubé,et al.  Probing Chemical Space with Alkaloid-Inspired Libraries , 2014, Nature chemistry.

[24]  C. Pittman,et al.  Selective synthesis of seven- and eight-membered ring sultams via two tandem reaction protocols from one starting material. , 2012, Organic letters.

[25]  P. Hanson,et al.  "Click, click, cyclize": a DOS approach to sultams utilizing vinyl sulfonamide linchpins. , 2009, Organic letters.

[26]  Haijun Yang,et al.  Efficient copper-catalyzed Michael addition of acrylic derivatives with primary alcohols in the presence of base. , 2013, Chemical communications.

[27]  M. White,et al.  syn-1,2-Amino alcohols via diastereoselective allylic C-H amination. , 2007, Journal of the American Chemical Society.

[28]  Diane Joseph-McCarthy,et al.  Fragment-Based Lead Discovery and Design , 2014, J. Chem. Inf. Model..

[29]  E. Hennessy.  Selective inhibitors of Bcl-2 and Bcl-xL: Balancing antitumor activity with on-target toxicity. , 2016, Bioorganic & medicinal chemistry letters.

[30]  Luis Muñoz,et al.  Carbon dioxide as a carbonylating agent in the synthesis of 2-oxazolidinones, 2-oxazinones, and cyclic ureas: scope and limitations. , 2010, The Journal of organic chemistry.

[31]  N. Turro,et al.  Highly diastereoselective dioxetane formation in the photooxygenation of enecarbamates with an oxazolidinone chiral auxiliary: steric control in the [2 + 2] cycloaddition of singlet oxygen through conformational alignment. , 2002, Journal of the American Chemical Society.

[32]  C. Murray,et al.  The rise of fragment-based drug discovery. , 2009, Nature chemistry.

[33]  B. Norman,et al.  Alkylation Studies of N-Protected-5-substituted Morpholin-3-ones. A Stereoselective Approach to Novel Methylene Ether Dipeptide Isosteres , 1996 .

[34]  A. Baeza,et al.  Enantioselective synthesis of cyanohydrin O-phosphates mediated by the bifunctional catalyst binolam-AlCl. , 2003, Angewandte Chemie.

[35]  Soyeong Kang,et al.  Enantioselective synthesis of cyclic sulfamidates by using chiral rhodium-catalyzed asymmetric transfer hydrogenation. , 2010, Organic letters.

[36]  Chemoselective catalytic conjugate addition of alcohols over amines. , 2014, Angewandte Chemie.