Question

In the Kojima-Saki synthesis of \(\mathrm{PGF}_{1 \alpha}\), the relative stereochemistry at positions 8,9 , and 12 is set in the conversion of \(\mathbf{1 0}\) into \(11 .\) How is stereocontrol achieved: (i) at the 12 position relative to the 9 position in 11? (b) at the 8- position relative to the \(9-\) position in 11 ?

Short answer

Stereocontrol at position 12 relative to position 9 in 11 is achieved through asymmetric synthesis which includes use of chiral auxiliaries or catalysts, or kinetic resolution, to drive the preferred formation of one stereoisomer over the other. The stereocontrol at position 8 relative to position 9 is influenced by steric effects, where the bulkier substituent favors a certain orientation to minimize strain, thus influencing the stereochemistry at that position.

Step-by-step solution

Stereocontrol at position 12 relative to position 9

The stereocontrol at the 12 position relative to the 9 position in 11 is achieved via asymmetric synthesis. In this process, the compound is induced via a chiral auxiliary or catalyst, or by kinetic resolution, to prefer formation of one enantiomer or diastereomer over the other. Therefore, the desired stereochemistry at position 12, relative to position 9, is driven selectively by these methods.

Stereocontrol at position 8 relative to position 9

The stereocontrol at the 8 position relative to the 9 position in 11 is based on steric effects. Substituents with greater steric bulk favor the formation of certain stereoisomers over others because they can minimize the strain the bulky group causes by adopting a particular orientation. Thus, the steric effects will determine the stereochemistry at position 8, selective to position 9.

Key concepts

Stereocontrol

Stereocontrol is a crucial concept in organic chemistry, especially within asymmetric synthesis. It refers to the ability to direct the formation of specific stereoisomers—molecules that have the same molecular formula but differ in the spatial arrangement of atoms. This process is important for creating molecules with the desired properties and activities.

In the context of the Kojima-Saki synthesis of \(\mathrm{PGF}_{1 \alpha}\), stereocontrol is employed to ensure that the reaction yields a product with the correct geometry at certain positions. When focusing on a specific carbon atom's stereochemistry relative to another, chemists can influence the outcome using various techniques:

• Utilizing chiral auxiliaries or catalysts that can enhance one stereoisomer's formation over another.
• Applying steric effects to control how atoms or groups orient themselves during a chemical reaction.
• Using kinetic resolution to selectively react one enantiomer faster than the other.

All of these techniques aim to obtain the desired three-dimensional molecular structure essential for the compound's biological function.

Chiral Auxiliary

A chiral auxiliary is a prominent tool in asymmetric synthesis, designed to induce chirality into a chemical compound. Essentially, a chiral auxiliary is a molecule temporarily attached to a substrate to control the outcome of a reaction.

Here's how it works:

• The chiral auxiliary is chosen for its existing chiral center, which can influence the formation of new stereocenters when attached to the substrate.

This helper molecule sets the stage by directing the substrate to form the desired enantiomer or diastereomer.

In practice, chiral auxiliaries are removed after the desired reaction, leaving behind a product with the new stereocenter intact, while the auxiliary itself can often be recovered and reused. This method is advantageous because:

• It provides precise control over the stereochemistry of the reactions.
• It can be employed iteratively to introduce multiple stereocenters in a controlled manner.

The temporary nature of chiral auxiliaries makes them versatile and effective in managing stereochemistry during synthetic processes.

Kinetic Resolution

Kinetic resolution is a technique used in asymmetric synthesis to separate enantiomers based on their different reaction rates. This approach exploits the fact that enantiomers, despite having the same structure, can react at different rates when exposed to a chiral environment or catalyst.

In essence, one enantiomer will react faster, or more favorably, than the other, allowing for separation based on these reaction speeds. This method is particularly useful when the goal is to isolate one specific enantiomer with high purity. The primary benefits include:

• Separation of enantiomers without needing extensive purification steps post-reaction.
• The possibility to recycle or repurpose the slower-reacting enantiomer for other reactions or uses.

Kinetic resolution, therefore, is an effective strategy for achieving high selectivity at certain stages of compound synthesis. It also highlights the importance of understanding the intricate details within stereochemistry, as it capitalizes on the subtle differences that can lead to significant outcomes in chemical reactions.