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ORGANIC CHEMISTRY 144 RETROSYNTHETIC ANALYSIS

The planning of a multistep synthesis is a challenging task that requires not only a thorough knowledge of synthetic reactions, but also a logical approach for disconnecting a complex target molecule. Retrosynthetic Analysis is the process of transforming a target molecule through a sequence of progressively simpler structures which leads to simple or commercially available starting materials. Synthetic Analysis is the forward planning of a synthetic pathway. For a comprehensive discussion of synthetic planning and retrosynthetic analysis, see The Logic of Chemical Synthesis by E. J. Corey and X.-M. Cheng. This handout summarizes the first section of the book. A transform is the reverse of a synthetic reaction such that when applied to the structure of a reaction product, the synthetic precursor is generated. A retron is the minimal substructural element in a molecular structure which indicates the application of a transform to generate a synthetic precursor.
Target
O

Retron
O

Transform
Robinson Annulation

Synthetic Precursors
O O

O HO O HO O Aldol

O O H O

There are thousands of transforms which can be applied in retrosynthetic analysis, but they can be grouped into classes based on their net function in retrosynthetic analysis. Structurally Simplifying Transforms create molecular simplification by disconnecting the molecular skeleton (chains or rings), functional groups, or stereogenic centers.
COOEt COOEt

+
COOEt EtOOC

Structurally Non-Simplifying Transforms may not simplify the molecular structure, but can allow the subsequent application of structurally simplifying transforms. These can connect or rearrange the molecular skeleton, interchange or transpose functional groups, or invert or transfer stereogenic centers.
OH OH COOEt COOEt

Structurally Complicating Transforms increase complexity of the molecular structure, but can again allow the subsequent application of structurally simplifying transforms.
OH OH OH OH

The use of a particular transform as the key element guiding the retrosynthetic analysis. Each of the strategies have their merits and place in synthetic planning and all should be considered for a particular problem. OH O OH Functional Group-Based Strategies . OH O Me Usnic Acid O Stereochemical Strategies .The goal of eliminating stereogenic centers as the key guiding the retrosynthetic analysis. O HO Me OH O O HO Me OH O O O HO Me . Transform-Based Strategies .The use of functional groups to guide the retrosynthetic analysis. O Diels-Alder Transform O MeO Estrone MeO Structure-Goal Strategies .STRATEGIES There are a number of strategies that can be applied when carrying out a retrosynthetic analysis. OH O OH OEt O Li OEt + .The use of a particular structure corresponding to a potential starting material or key synthetic intermediate as the guide for retrosynthetic analysis. OH + . CHO CHO O Helminthosporal (+)-Carvone Topological Strategies .The use of a particular structural subunit as eligible for disconnection or preservation to guide the retrosynthetic analysis. Most retrosynthetic analyses will encompass several of the strategies.