JLA Synthetic Planning

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  • Strategies in Synthetic PlanningModern Stylistic Points in Retrosynthetic Analysis

    Jen AllevaMacMillan Group Meeting

    January 8th 2014

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningDevelopment and Conceptualization of Retrosynthetic Analysis

    "By the end of this course I will be able to look at all of your retrosyntheses and know which one of youproduced it. You will all develop your own unique and recognizable style over the next few months."

    Paul Reider, Graduate Synthesis

    Common trend: Modern organic chemists have unique retrosynthetic strategies rendering their syntheseseasily recognizable to the well-read practitioner of organic chemistry

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningDevelopment and Conceptualization of Retrosynthetic Analysis

    "Retrosynthetic analysis is a problem-solving technique for transforming the structure of a synthetictarget (TGT) molecule to a sequence of progressively simpler structures along a pathway whichultimately leads to simple or commercially available starting materials for chemical synthesis."

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

    E. J. Corey, Harvard University

    Nobel Prize in Chemistry 1990

    Detailed retrosynthetic analysis and techniques

    MIT 19451950, John Sheehan Appointed as Instructor at UIUC at age 22 Earned professorship at UIUC at age 27 Moved to Harvard in 1959

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningDevelopment and Conceptualization of Retrosynthetic Analysis

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

    TargetMolecule

    Int1 Int2

    Int3 Int4

    Int5 Int6

    SM1

    SM2

    SM3 SM4

    retron

    transform: Diels-Alder

    keying elements

    Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningDevelopment and Conceptualization of Retrosynthetic Analysis

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.Hoffmann, R. W. Elements of Synthetic Planning, Springer-Verlag, Berling Heidelberg, 2009, pp 35.

    MeOH

    OH

    Me

    O

    Me Me

    O

    retron alkene keying element

    Me Me

    O

    Me

    Br Me

    O

    MeCu

    Me

    OO

    OR

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 6.

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    Enquist Jr., J. A.; Stoltz, B. M. Nature, 2008, 453, 1228.

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    MeMe

    O

    Me

    Me

    Me

    H

    H

    O

    O

    Me

    Me

    O

    O

    Me

    Me

    OO

    O

    O

    cyanthiwigin F

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    2. Lateral movement through a non-simplifying transformskeletal rearrangements, transpositions, isomerization reactions, epimerizations

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    Wipf, P.; Rector, S. R.; Takahashi, H. J. Am. Chem. Soc., 2002, 124, 14848.

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    2. Lateral movement through a non-simplifying transformskeletal rearrangements, transpositions, isomerization reactions, epimerizations

    O

    N O

    O

    OHH

    H Me

    Me

    HO

    N O

    O

    OHH

    H Me

    Me

    H

    Me

    O

    N O

    O

    OHH

    H Me

    Me

    H

    Me

    ()-tuberostemonine

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    2. Lateral movement through a non-simplifying transformskeletal rearrangements, transpositions, isomerization reactions, epimerizations

    3. Disconnections that actually increase molecular complexityprotecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds

    Thursday, January 9, 14

  • Strategies in Synthetic Planningdecreasing complexity

    The main goal of retrosynthetic analysis is to reduce the complexity of the target: How?

    1. The application of powerful transforms:forming key bonds in the molecular skeleton (i.e. CC bonds)

    aldol, Diels-Alder, intramolecular alkylations, CH activation, cross couplingsforging stereocenters through substrate control (modernly reagent control)cascade reactions

    2. Lateral movement through a non-simplifying transformskeletal rearrangements, transpositions, isomerization reactions, epimerizations

    3. Disconnections that actually increase molecular complexityprotecting groups, masking groups, activating/deactivating groups, adding functional groups or bonds

    OO

    AcOOH

    Me

    H

    MeMeMe

    O

    Me

    SePh

    MeMeMe

    O

    O PMP

    O

    O PMP

    O

    MeMe

    Me

    Me

    Shipe, W. D.; Sorensen, E. J. J. Am. Chem. Soc., 2006, 128, 7025.guanacastepene E

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningClasses of Retrosynthetic Disconnections

    Transform-Based Structure-Goal Topological Strategies

    Stereochemical Strategies Functional Group-Based Strategies

    look-ahead to powerfully simplifyingtransform or tactic

    i.e. the "Key Step"

    directed at the structure of a potentialintermediate or SM

    i.e. the branch point

    strategic analysis of correlatedbond disconnections

    i.e. rearrangementsand network analysis

    retrosynthetic strategy which clears stereocenterswith either mechanism or substrate control

    most common in modern synthesis

    reduction in molecular complexity based on theinterchange, installation and removal of functional groups

    "redox relay", directing groups, heterocycle formation

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningAcyclic Systems

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

    What to disconnect and what to preserve

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningAcyclic Systems

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

    What to disconnect and what to preserve

    Disconnect Preserve

    building block groups (alkyl, aryl)to make symmetrical fragments

    CX bonds (Cheteroatom, esters, amides, etc)

    bonds that attach rings to chains (produce the largest fragment)

    remote stereocenters (more than 3C is remote)

    either E or Z double bonds skeletal bonds proximal to remote stereocenters

    13 bonds away from functional groups

    Thursday, January 9, 14

  • Strategies in Synthetic PlanningAcyclic Systems

    Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1995, pp 38.

    What to disconnect and what to preserve

    Disconnect Preserve

    building block groups (alkyl, aryl)to make symmetrical fragments

    CX bonds (Cheteroatom, esters, amides, etc)

    bonds that attach rings to chains (produce the largest fragment)

    remote stereocenters (more than 3C is remote)

    either E or Z double bonds skeletal bonds proximal to remote stereocenters

    13 bonds away from functional groups

    O(CH2)3CO2H

    C5H11