Synthesis of Pharmaceuticals + Natural Products Flashcards
What two molecules form amides?
Carboxylic acids and an amine
What reagent is commonly added during an amide formation reaction and why? Name some examples.
Coupling agents (DCC, CDI, T3P), acyl chlorides are difficult to handle (reactive) so coupling agents mean carboxylic acids can be used.
What is a downside to using DCC?
Urea formed which is difficult to remove
What is an upside to using CDI?
CO2 and imidazole former which are easy to remove
What does T3P require to use?
2x Pyridine as a base
When should amide disconnections be done in an RSA?
Always first
What is the product of a reductive amination?
A secondary or tertiary amine
What are the reagents and pH for reductive amination?
Amine, ketone (or aldehyde), gentle borohydride species, AcOH. pH 6
What species is formed during reductive amination?
An imine
Why is pH 6 used in reductive amination?
Below pH 4 the amine starting material will protonate and not react.
Above pH 7 OH isnt protonated to form H2O as a good LG
Why is a gentle borohydride like STAB used instead of NaBH4 in reductive amination?
1) NaBH4 can reduce the ketone (or aldehyde) to an alcohol before the from the imine
2) NaBH4 is destroyed and cannot function with AcOH
What type of reaction is the amination of an alkyl halide (or alkyl sulfonate)?
Sn2
What condtions does amiantion of an alkyl halide require?
Weakly Basic - Cs2CO3, K2CO3 or Et3N
What is REALLY important to consider during an amination reaction?
Inversion of any stereogenic centres! Sn2 rxn! Only use sulfonates - much easier to introduce chirality into alcohols than alkyl halides
True or False? For an amination, the alkyl halide can be primary, secondary or tertiary?
FALSE - too much steric crowding for a tertiary to be able to be used
Why does over-reaction of during amination occur and how can it be overcome?
The inducive effect makes the amine more reactive (nucleophillic). Introducing steric crowding decreases this
When the product has a stereogenic centre what SM should be used and why?
Sulphonate! Much easier to introduce chirality into alcohols than alkyl halides
TRUE or FALSE - Sn2 amination is impossible with an aromatic halide?
TRUE - nucleophile cannot approach from the correct angle to attack
Nucleophilic aromatic substitution (SnAr) is possible as long as what is on the aromatic ring?
An EWG
Why is F usually a bad LG, and why is it a good LG during SnAr?
Usually bad because of the strong C-F bond, but good during SnAr as the RDS is the addition step which is dependant on a large delta+ charge
What is the regioselectivity during amination of aromatic halides?
The LG must be ortho- or para- to the EWG
The amination of halopyridines is similar to which other reaction?
Amination of aromatic halides (SnAr). The nitrogen acts as the EWG
What is the regioselectivity in the amination of halopyridines reaction?
LG must be at the 2 or 4 position to allow the negative charge to be places on the heteroatom
What SM and reaction conditions does Buchwald-Hartwig amination require?
Aromatic halide, amine, Pd precat, a phosphine and NaOtBu
For Buchwald-Hartwig amination, what differs when using a primary amine to a secondary amine?
Primary: Pd2(dba)3, BrettPhos. Pd doesnt need to be reduced
Secondary: Pd(OAc)2, RuPhos. Pd needs to be reduced from Pd2 to Pd0
What are the steps during the catalytic cycle of a Buchwald-Hartwig amination?
1) Oxidative addition
2) Ligand Substitution
3) Deprotonation
4) Reductive Elimination
Why are Buchwald-Hartwig amination reactions much more versitile SnAr reactions?
1) Works with EWG and EDG substituents
2) Can work at any point on the ring
What reagents are used for amidation of aromatic halides?
Aromatic Iodide, amide, CuI, DMEDA, K3PO4 (base)
What type of amides work well for Cu-mediated amidation?
Cyclical amides - works well with EDG and EWG substituents
What is the product in a Suzuki-Miyaura reaction?
Two coupled aromatic rings
What are the SMs in a Suzuki-Miyaura reaction?
Aromatic halide
Aromatic boronic acid OR Aromatic pinacolate ester
What base is used in a Suzuki-Miyaura reaction?
Na2CO3 aqueous –> generates OH-
What are the steps in a Suzuki-Miyaura catalytic cycle?
1) Oxidative addition
2) Ligand Substitution
3) Transmetallation
4) Reductive Elimination
What are the two methods for synthesizing boronic acids/pinacolate esters? When should one be used and not the other?
1) Lithiation - HARSH CONDITIONS (uses n-BuLi) not compatible with some functional groups
2) Miyaura Borylation - MIDLER CONDITIONS
What is the key mechanistic difference between a Suzuki-Miyaura coupling with a boronic acid, and with a pinacolate ester?
Hydroxide (OH-) attacks empty p-orbital on B, forming a charge AND THEN the charged complex attacks the Pd centre and removes the halide
Does α-functionalisation of cyclic amines require harsh or mild conditions?
Very harsh - sBuLi, TMEDA, -78c
sBuLi is one of the strongest bases
Why is TMEDA required for the α-functionalisation of cyclic amines?
As it coordinates to sBuLi to make it more reactive
Why are diastereoisomers formed when using TMEDA for α-functionalisation of cyclic amines?
TMEDA is not chiral
Negishi cross coupling can be used for which reaction?
α-functionalisation of cyclic amines
In Negishi cross coupling some of the SM is said to be “sacrificial”, why is this?
Two molecules of the organozinc reagent bind to the Pd pre-catalyst and couple to each other to form active Pd0 catalyst
What are the steps in the Negishi catalytic cycle?
1) Oxidative addition
2) Transmetallation
3) Reductive Elimination
When should Negishi cross-coupling be used?
α-functionalisation of cyclic amines with an aromatic halide
Why is sparteine or a sparteine surrogate used in place of TMEDA?
Sparteine is chiral while TMEDA is not, allowing asymmetric induction into the product in the α-functionalisation of cyclic amines
TRUE or FALSE? (-)-sparteine leads to lithiation of the back proton?
TRUE - S product formed
TRUE or FLASE (+)-sparteine surrogate leads to lithiation of the back proton?
FALSE - lithiation of the front proton –> R product formed
Before α-functionalisation can occur, what MUST be done first?
The amine MUST BE PROTECTED! Boc2O (Boc anhydride)
What are the SMs in the Fischer indole synthesis?
Aromatic hydrazine, ketone OR aldehyde
What are the keys steps in a Fischer Indole synthesis?
1) Formation of an enamine
2) [3,3]-sigmatropic rearrangement
3) Rearomatiscation
What are the regioselectivity issues to be considered during a Fischer indole synthesis?
1) Hydrazine should be symmetrical otherwise regioisomers formed
2) Ketone (aldehyde) should be symmetrical OR with only one position that can react
What are the 2 steps involved in the benzimidazole formation?
1) Formation of amide
2) Cyclisation to give product
With attempting to form sulfur and oxygen analogues of benzimidazole, how do we know that the S or O wont attack the acyl chloride in the first step?
Nitrogen is more nucleophilic and will always attack the acyl chloride first to form the amide
What are the SMs when forming a tetrazole?
A nitrile and sodium azide in Nh4Cl (ammonium chloride)
What type of reaction occurs in the formation of a tetrazole?
[1,3]-dipolar cycloaddition
