Retrosynthesis Revisted

Re-introduction

Earlier, we explored the concept of retrosynthesis—a strategic approach to breaking down complex molecules into simpler precursors, much like reverse-engineering a layered cake. We used the example of Enalaprilat to Enalapril to illustrate how retrosynthetic analysis can guide the design of more effective drug molecules.

Now, we’ll apply this powerful technique to the synthesis of alcohols, alkenes, alkynes, aldehydes, and ketones using reactions from the alkenes and alkynes chapters. By thinking backward, we’ll identify key transformations and starting materials needed to build these functional groups, drawing on reactions such as:

• Hydration of alkenes to form alcohols with regiochemical control (Markovnikov and non-Mark).

• Hydroboration-oxidation to create anti-Markovnikov alcohols and aldehydes.

• Ozonolysis of alkenes to yield aldehydes and ketones.

• Acetylide additions to carbonyl compounds for alkyne synthesis.

• Hydrogenation/Reduction of alkynes to form alkenes or alkanes.

Through retrosynthetic analysis, we’ll map out efficient synthetic routes, ensuring each step is logical and feasible. Let’s dive in and see how this approach can simplify the synthesis of these important organic compounds!

Example 1

Retrosynthesis of trans-but-2-ene starting with acteylene and any other reagents learned thus far.

• Step A (Hydrative Disconnection): The C-OH bond of pentan-2-ol is disconnected, revealing the double bond of pent-1-ene. This suggests a possible synthesis involving the hydration of pent-1-ene, such as via oxymercuration-demercuration or acid-catalyzed hydration.
  
  
• Step B (Reductive Disconnection): The double bond of pent-1-ene is disconnected to reveal the triple bond of pent-1-yne. This suggests a possible synthesis involving the partial hydrogenation/reduction of pent-1-yne using reagents like Lindlar catalyst (Pd/CaCO₃ with H₂) or sodium (or lithium) in liquid ammonia.
  
  
• Step C (C-C Bond Disconnection): Pent-1-yne is disconnected at the bond alpha to the triple bond, generating acetylene and a propyl equivalent. This suggests a possible synthesis involving the reaction of an acetylide anion (derived from acetylene) with a propyl halide.

Example 2

Retrosynthesis of pentan-2-ol starting with acteylene and any other reagents learned thus far.

• Step A: Disconnect the C-OH bonds of pentan-2-ol to pent-1-ene
  This step shows that pentan-2-ol can be derived from pent-1-ene via hydration (e.g. oxymercuration, H3O+).
• Step B: Disconnect the C-H bonds of pent-1-ene to pent-1-yne.
  This step shows that pent-1-ene can be derived from pent-1-yne via hydrogenation/reduction (e.g. partial reduction - Lindlars or Na(Li) NH3).
• Step 2: Disconnect the pent-1-yne.
  Pent-1-yne can be further disconnected into acetylene and propyl halide by breaking the C-C bond adjacent to the triple bond (acetylide chemistry).

Example 3

• Step A (Hydrative Disconnection): The aldehyde group of butanal is disconnected, suggesting a possible synthesis from but-1-yne. Consider possible synthesis involving the hydroboration-oxidation of but-1-yne.

• Step C (C-C Bond Disconnection): But-1-yne is disconnected at the bond alpha to the triple bond, generating acetylene and an ethyl equivalent. This suggests a possible synthesis involving the reaction of an acetylide anion (derived from acetylene) with an ethyl halide (e.g., ethyl bromide).