A method for synthesizing chiral lactams from chiral oxaziridines in continuous flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the oxaziridines using the Booker-Milburn flow system provides conversion to the chiral lactams in good yield and short residence times. Application of this chemistry toward the synthesis of a chiral bicyclic lactam is described.
Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam
Manager, Custom Synthesis Group at Vertex Pharmaceuticals
– Present (16 years 7 months)Boston, MA
– Supervised 10 chemists (6 Ph.D., 2 M.S., 2 B.S)
– Synthesized starting materials, intermediates, and preclinical tox lots for medicinal chemistry on
multigram to kilogram scale.
– Synthesized standards for various assays
– Performed kilo-scale enzymatic reactions
– Used flow chemistry on kilo scale
– Worked with several outsourcing firms in Europe and Asia
– Designed and updated an internal group website used to communicate with stakeholders
– Experienced with DOE and reaction optimization
– (3 years 11 months)Cambridge, MA
– Supervised 4 chemists (2 M.S., 2 B.S.)
– Managed a lead generation team that synthesized hundreds of very potent and selective heterocyclic leads on several kinase programs including JNK3, GSK3, LCK, SYK, and JAK3.
– Chemistry Head of the p38 2nd-generation program.
– Designed and synthesized very potent and selective inhibitors of p38
– Designed synthetic routes for previously unknown substitution patterns on pyridine
– Made presentations to external collaborators on the program.
– Produced two clinical candidates that were substantially more potent and had much better physical
properties than the 1st-generation inhibitors.
– Filed several patents concerning the 1st-generation compounds and related scaffolds
– (2 years 2 months)Atlanta, GA
– Designed and researched a proposal to use Pummerer chemistry to synthesize furans and to apply
the methodology to lignin synthesis
– Authored and investigated a proposal to synthesize 2-aminofurans using Pummerer or diazo
chemistry and to use them to make highly substituted anilines, phenols, indoles, and the general
framework found in the Amaryllidaceae, Erythrina, Lycopodium, and Aspidospermina classes of
– Designed the synthetic strategy for indole synthesis using a vinylogous Pummerer rearrangement.
– Authored and supervised the research on a proposal to use Pummerer chemistry to synthesize
aromatic glides that can be used to make complex polycyclic systems.
– Supervised two graduate students working on the 2-aminofuran project and one graduate student on the vinylogous Pummerer project.
– (6 years)Muscle Shoals, AL
– Synthesized potential urease inhibitors in gram to several hundred gram quantities using high
temperature and high pressure equipment
– Performed gas-phase reactions in fluidized bed reactors containing transition-metal catalysts to find
an efficient industrial process for making dicyandiamide
– Characterized compounds and analyzed their decomposition kinetics using 1H and 31P NMR, HPLC,
– Authored and researched a proposal to modify urea crystal morphology in fluid fertilizers
– Developed software for receiving and analyzing data from various instrumentation.
Synthesized heterocyclophanes and studied their binding interactions with small neutral molecules in nonaqueous media. Complexation studies were performed with 1H , 13C, variable temperature, and 2D NMR, UV spectroscopy, and X-ray diffraction.
///////John E. Cochran, vertex, Chiral Bicyclic Lactam