Retrosynthetic analysis

Retrosynthetic analysis is a technique for solving problems in the planning of organic syntheses. This is achieved by transforming a target molecule into simpler precursor structures without assumptions regarding starting materials. Each precursor material is examined using the same method. This procedure is repeated until simple or commercially available structures are reached. E. J. Corey formalized this concept in his book The Logic of Chemical Synthesis.

Quotes

• During the first half of this century most syntheses were developed by selecting an appropriate starting material, after a trial and error search for commercially available compounds having a structural resemblance to the target of synthesis. Suitable reactions were then sought for elaboration of the chosen starting material to the desired product. Synthetic planning in most instances was strongly dependent on an assumed starting point. In the fall of 1957 I came upon a simple idea which led to an entirely different way of designing a chemical synthesis. In this approach the target structure is subjected to a deconstruction process which corresponds to the reverse of a synthetic reaction, so as to convert that target structure to simpler pecursor structures, without any assumptions with regard to starting materials. Each of the precursors so generated is then examined in the same way, and the process is repeated until simple or commercially available structures result. This “retrosynthetic” or “antithetic” procedure constitutes the basis of a general logic of synthetic planning which was developed and demonstrated in practice over the ensuing decade.
  • E. J. Corey, "The Logic of Chemical Synthesis: Multistep Synthesis of Complex Carbogenic Molecules (Nobel Lecture)". Angewandte Chemie International Edition in English 30 (5): 455–465.

• The construction of a synthetic tree by working backward from the target molecule (TM) is called retrosynthetic analysis or antithesis. The symbol ⇒ signifies a reverse synthetic step and is called a transform. The main transforms are disconnections, or cleavage of C-C bonds, and functional group interconversions (FGI). Retrosynthetic analysis involves the disassembly of a TM into available starting materials by sequential disconnections and functional group interconversions. Structural changes in the retrosynthetic direction should lead to substrates that are more readily available than the TM. Synthons are fragments resulting from disconnection of carbon-carbon bonds of the TM. The actual substrates used for the forward synthesis are the synthetic equivalents (SE). Also, reagents derived from inverting the polarity (IP) of synthons may serve as SEs.
  • George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 1. Synthetic Design

• Heterolytic retrosynthetic disconnection of a carbon-carbon bond in a molecule breaks the TM into an acceptor synthon, a carbocation, and a donor synthon, a carbanion. In a fomal sense, the reverse reaction – the formation of a C-C bond – then involves the union of an electrophilic acceptor synthon and a nucleophilic donor synthon.
  • George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 1. Synthetic Design

• Computer programs are available that suggest possible disconnections and retrosynthetic pathway. Such programs utilize the type of systematic analysis outlined above to identify key bonds for disconnection and plausible functional group inter-conversions.
  • George S. Zweifel and Michael H. Nantz, Modern Organic Synthesis (2006), Ch. 1. Synthetic Design