Synthesis and Reactive Intermediates

Grubbs (I) Structure

abbreviate cyclohexanes as -Cy

Grubbs (II) Structure

same as Grubbs I but one PCy₃ is an N-heterocyclic carbene which is a better sigma donor, so catalyst is more stable and more reactive

Why are the Grubbs reagents precatalysts?

PCy₃ has to be lost to generate the active 14e catalyst

Why is RCM efficient even though it is an equilibrium?

Ring Closing Metathesis

two terminal CH₂ groups leave together as ethene → Le Chatelier - gas is leaving so equilibrium shifts forward

This is why terminal alkenes are necessary

Rules for RCM

• Grubbs II catalyst (2 mol%)

• DCM, r.t.

• functional group tolerant → alkene specific

• Only for rings >=5

How to achieve cross metathesis

With two electronically identical terminal alkenes, RCM leads to R1=R2, R1=R1, and R2=R2.

• Make one alkene electron rich - plain alkyl, and one with an EWG (ester, ketone, sulfone, halide)

• Electron rich alkene dimerises fast but also reverses quickly, R1=R2 reacts but will not reverse as its kinetically irreversible

• EWG alkene dimer barely forms, too slow

• System accumulates R1=R2

Why does Cross Metathesis lead to trans stereochemistry?

In the cyclobutane intermediate, R and the EWG substituents sit on opposite corners of the ring, and point opposite directions to avoid steric hindrance.

When the alkene is formed these substituents sit trans

How does ROCM work?

• strained (>6 or =4) ring and excess electron poor alkene

• produced bis-functionalised linear product driven by strain

What are the three main uses of silicon?

1. Silyl enol ethers (enolates in a bottle) alkene + OH where the H is protected by SiR₃

2. Nucleophilic enhancement of alkenes/arenes

3. Protecting groups for alcohols or alkynes

What determines the position of the double bond in the synthesis of SEE from ketones?

kinetic (1) vs thermodynamic (2) product

1. Low temperature prevents equilibrium, strong bulky base (LDA) which targets most accessible H = outer H producing terminal DB

2. R.t., weak base (Et₃N) so ketone is not deprotonated directly, ketone is silylated on oxygen, then base picks up the H which will lead to the most subtituted (stable) alkene.

What is TMSCl?

tetramethylsilyl chloride

Me₃SiCl

Si-Cl bond can attacked by a nucleophile, e.g. oxygen which displaces Cl

How to make a SEE from enone

R₂CuLi (Gilman Reagent) does 1,4-conjugate addition with R group added to alkene and lithium enolate at O (O-, Li+)

Oxygen attacks Si to form strong Si-O bond → SEE

What is a Gilman Reagent?

R₂CuLi

Cu coordinates with alkenes to do 1,4 CA on enones

What is TBAF?

Bu₄N⁺ F^-

F ions can attack Si to form Si-F (strongest bond ever)

How do SEEs react?

1. Reform enolate (O^-) with TBAF or MeLi + THF then react with R-X at the alpha carbon to create alkylated ketone

2. Alkylation, R-Cl, TiCL₄, forms a carbocation, the electron rich alkene of the SEE attacks and TMS is lost due to the Lewis acid. Forms

Structure of mCPBA

Good for oxidations, can lose terminal O (weak O-O bond), and regenerate to form carboxylic acid tail

What is Rubottom oxidation?

alpha hydorxylation of SEEs

SEE reacts with mCPBA to form 3-chlorobenzoic acid (protected by TMS) and an alpha-hydroxyketone

What is a tosyl (Ts) group

tosylhydrazine used in the shapiro reaction to convert a ketone to a vinyl silane

What is a vinyl silane?

TMS attached to a C=C, have e/z geometry and are stereospecific

What is the Shapiro reaction?

a ketone is transformed into a vinyl silane

tosylhydrazine + H⁺ with ketone forms tosylhydrazone

loss of N₂ drives the reaction thermodynamically

How can you substitute an alkenyl silane with another R group?

dilithiated intermediate is stable at r.t.p.

if you add an R-X the R group will be added

you then need a 3rd eq. of BuLi to deprotonate and form the alkene

What is unique about vinyl silane reactivity?

TMS group stabilises positive charge on the beta carbon

Results in the replacement of TMS with E⁺ due to a stable intermediate and retained geometry

Why is stereochemistry retained with reactions of alkenyl silanes?

• Double bond attacks the electrophile from above or below the plane

• Electrophile bonds to the TMS carbon to form an sp3 centre (positive charge on beta carbon stabilised)

• TMS substituent rotates the shortest distance in order to align with the empty p orbital on the + carbon

• TMS only leaves when this alignment is achieved

• a new pi bond forms, and E⁺ is where TMS was

What is THF?

tetrahydrofuran

solvent

What is TBDMS-OR?

tert-butyldimethylsilyl

protecting group

What is TIPS-OR

protection group

What is TBAF?

Source of Fluoride ions

deprotection of silyl ethers

What is TBDPS-OR?

protecting group

What is DHP?

used to install THP (protecting agent) for alcohols and amines

What is TFA?

Trifluoroacetic acid

deprotects t-BOC groups

What is DCC?

Dicyclohexylcarbodiimide

Enables formation of esters under mild conditions

What is HOBt?

Helps with peptide synthesis

What is DEAD?

Reagent in the Mitsunobu reaction

What is CBS?

Reagent allows prochiral products

What is Moschers acid chloride?