CHEM 3100 / Section 2: Retrosynthesis and Protecting Groups

As discussed in the lectures, differentiate the three primary types of organic syntheses: linear synthesis, convergent synthesis, and retrosynthesis.

As discussed in the lectures, differentiate the three primary types of organic syntheses: linear synthesis, convergent synthesis, and retrosynthesis.

1. Linear synthesis: Forward process, constructing from simpler compounds to build a complex molecule.

2. Convergent synthesis: Multiple compounds are built separately and then combined in a final step.

3. Retrosynthesis: Backward process, deconstructing from complex molecule to simpler compounds or commercially available starting materials.

Why are linear and convergent synthesis generally not as good as retrosynthesis?

• Efficiency: Decreasing yields with each step.

• Flexibility: Each step depends on the previous one.

What are Dr. Walsh’s two “rules” when it comes to retrosynthesis?

• Never cut benzene.

• Never cut cyclic systems.

Before getting into retrosynthesis, define these terms:

• Transformation.

• Retrosynthetic cut or disconnection.

• Synthons.

• Synthetic equivalents.

• Transformation: A reaction of changing a molecule, either going either forward or backward.

• “Retrosynthetic cut” or disconnection: Breakage of a bond, converting a molecule into a possible starting material.

• Synthons: A generalized fragment, usually an ion, produced by a

  disconnection, which cannot itself be used, often because it is too unstable

• Synthetic equivalent: A reagent carrying out the function of a synthon.

What are the three considerations for using protecting groups (PGs) for functional groups (FGs)?

• Nature of the functional group requiring protecting group.

• Conditions for stability of protecting group.

• Conditions for removal of protecting group.

In total synthesis, it is a bad idea to carry through reactive _________. If you have a functional group in your final product, you don’t want your functional group in your ____ step in your 20-step synthesis.

In total synthesis, it is a bad idea to carry through reactive intermediates. If you have a functional group in your final product, you don’t want your functional group in your first step in your 20-step synthesis.

In total synthesis, it’s a much better idea to keep _____ intermediates as ________ intermediates. Keep the reactive stuff towards the end.

In total synthesis, it’s a much better idea to keep reactive intermediates as protected intermediates. Keep the reactive stuff towards the end.

You don’t need to take your protecting group on and off _________.

You don’t need to take your protecting group on and off immediately.

Name the four primary protecting groups for alcohols, as discussed in lectures.

• Tetrahydropyran group. (THP).

• Allyl groups.

• Methoxymethyl (MOM).

• Silyl ethers.

How to install THP?

Any acid stronger than a hydroxy group, optimally p-TsOH.

How to install allyl groups?

Use allyl bromide and a base, optimally potassium bicarbonate.

How to remove allyl group?

Use tetrakis(triphenylphosphine) palladium.

How to install MOM?

MOM itself and base, optimally NEt₃.

How to remove MOM?

An acid, optimally p-TsOH.

Why are silyl ethers used instead of regular carbon ethers?

It is difficult to cleave the ether bond, as carbon is not a good leaving group.

What are the four silyl ethers that we have discussed so far? Order them in increasing reactivity to install and remove and briefly explain why.

• TIPS. (least reactive)

• TBDMS.

• TES.

• TMS. (most reactive)

Sterics - as reactivity increases, less steric hinderance is involved, and better chance at installation (Oxygen attack) and removal (Fluoride attack).

How to install any of the silyl ethers?

Silyl ether and base, optimally NEt₃.

How to remove any of the silyl ethers?

Any fluoride source, optimally TBAF.

Why would you use TBAF to remove silyl ethers?

Si-F bond is very strong.

Generally, what are the three amino-PGs?

• Phthalimide.

• A carbamate commonly called Boc.

• A carbamate commonly called Fmoc.

How would you install phthalimide on an amino group?

Phthalimide itself and a base, optimally sodium carbonate.

How would you remove phthalimide on an amino group?

Hydrazine.

How would you install Boc on an amino group?

Use Boc₂ and a base, optimally sodium bicarbonate.

How would you remove Boc from an amino group?

Use an acid, optimally trifluoroacetic acid.

How would you install Fmoc on an amino group?

Fmoc-Cl and a base, optimally sodium bicarbonate.

How would you remove Fmoc on an amino group?

*Piperidine.

How would you protect and install a PG on a diol group? On that note, how would you remove it?

Use a carbonyl and proton source. Reversible for deprotection.

How would you install a dithioacetal on a carbonyl group efficiently?

Use dithioacetal themselves and some acid, optimally BF₃.

How would you remove a dithioacetal on a carbonyl group?

Use Raney Ni.

What are the two ways of protecting carboxyls?

• Via oxazoline.

• Via OBO.

How would you protect a carboxyl via oxazoline?

How would you deprotect a carboxyl via oxazoline?

How would you protect a carboxyl via OBO?

How would you deprotect a carboxyl via OBO?