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Advanced Research Topics > Synthesis of Pharmaceuticals + Natural Products > Flashcards

Synthesis of Pharmaceuticals + Natural Products Flashcards

1
Q

What two molecules form amides?

A

Carboxylic acids and an amine

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2
Q

What reagent is commonly added during an amide formation reaction and why? Name some examples.

A

Coupling agents (DCC, CDI, T3P), acyl chlorides are difficult to handle (reactive) so coupling agents mean carboxylic acids can be used.

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3
Q

What is a downside to using DCC?

A

Urea formed which is difficult to remove

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4
Q

What is an upside to using CDI?

A

CO2 and imidazole former which are easy to remove

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5
Q

What does T3P require to use?

A

2x Pyridine as a base

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6
Q

When should amide disconnections be done in an RSA?

A

Always first

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7
Q

What is the product of a reductive amination?

A

A secondary or tertiary amine

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8
Q

What are the reagents and pH for reductive amination?

A

Amine, ketone (or aldehyde), gentle borohydride species, AcOH. pH 6

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9
Q

What species is formed during reductive amination?

A

An imine

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10
Q

Why is pH 6 used in reductive amination?

A

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

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11
Q

Why is a gentle borohydride like STAB used instead of NaBH4 in reductive amination?

A

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

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12
Q

What type of reaction is the amination of an alkyl halide (or alkyl sulfonate)?

A

Sn2

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13
Q

What condtions does amiantion of an alkyl halide require?

A

Weakly Basic - Cs2CO3, K2CO3 or Et3N

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14
Q

What is REALLY important to consider during an amination reaction?

A

Inversion of any stereogenic centres! Sn2 rxn! Only use sulfonates - much easier to introduce chirality into alcohols than alkyl halides

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15
Q

True or False? For an amination, the alkyl halide can be primary, secondary or tertiary?

A

FALSE - too much steric crowding for a tertiary to be able to be used

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16
Q

Why does over-reaction of during amination occur and how can it be overcome?

A

The inducive effect makes the amine more reactive (nucleophillic). Introducing steric crowding decreases this

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17
Q

When the product has a stereogenic centre what SM should be used and why?

A

Sulphonate! Much easier to introduce chirality into alcohols than alkyl halides

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18
Q

TRUE or FALSE - Sn2 amination is impossible with an aromatic halide?

A

TRUE - nucleophile cannot approach from the correct angle to attack

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19
Q

Nucleophilic aromatic substitution (SnAr) is possible as long as what is on the aromatic ring?

A

An EWG

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20
Q

Why is F usually a bad LG, and why is it a good LG during SnAr?

A

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

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21
Q

What is the regioselectivity during amination of aromatic halides?

A

The LG must be ortho- or para- to the EWG

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22
Q

The amination of halopyridines is similar to which other reaction?

A

Amination of aromatic halides (SnAr). The nitrogen acts as the EWG

23
Q

What is the regioselectivity in the amination of halopyridines reaction?

A

LG must be at the 2 or 4 position to allow the negative charge to be places on the heteroatom

24
Q

What SM and reaction conditions does Buchwald-Hartwig amination require?

A

Aromatic halide, amine, Pd precat, a phosphine and NaOtBu

25
Q

For Buchwald-Hartwig amination, what differs when using a primary amine to a secondary amine?

A

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

26
Q

What are the steps during the catalytic cycle of a Buchwald-Hartwig amination?

A

1) Oxidative addition
2) Ligand Substitution
3) Deprotonation
4) Reductive Elimination

27
Q

Why are Buchwald-Hartwig amination reactions much more versitile SnAr reactions?

A

1) Works with EWG and EDG substituents
2) Can work at any point on the ring

28
Q

What reagents are used for amidation of aromatic halides?

A

Aromatic Iodide, amide, CuI, DMEDA, K3PO4 (base)

29
Q

What type of amides work well for Cu-mediated amidation?

A

Cyclical amides - works well with EDG and EWG substituents

30
Q

What is the product in a Suzuki-Miyaura reaction?

A

Two coupled aromatic rings

31
Q

What are the SMs in a Suzuki-Miyaura reaction?

A

Aromatic halide
Aromatic boronic acid OR Aromatic pinacolate ester

32
Q

What base is used in a Suzuki-Miyaura reaction?

A

Na2CO3 aqueous –> generates OH-

33
Q

What are the steps in a Suzuki-Miyaura catalytic cycle?

A

1) Oxidative addition
2) Ligand Substitution
3) Transmetallation
4) Reductive Elimination

34
Q

What are the two methods for synthesizing boronic acids/pinacolate esters? When should one be used and not the other?

A

1) Lithiation - HARSH CONDITIONS (uses n-BuLi) not compatible with some functional groups
2) Miyaura Borylation - MIDLER CONDITIONS

35
Q

What is the key mechanistic difference between a Suzuki-Miyaura coupling with a boronic acid, and with a pinacolate ester?

A

Hydroxide (OH-) attacks empty p-orbital on B, forming a charge AND THEN the charged complex attacks the Pd centre and removes the halide

36
Q

Does α-functionalisation of cyclic amines require harsh or mild conditions?

A

Very harsh - sBuLi, TMEDA, -78c
sBuLi is one of the strongest bases

37
Q

Why is TMEDA required for the α-functionalisation of cyclic amines?

A

As it coordinates to sBuLi to make it more reactive

38
Q

Why are diastereoisomers formed when using TMEDA for α-functionalisation of cyclic amines?

A

TMEDA is not chiral

39
Q

Negishi cross coupling can be used for which reaction?

A

α-functionalisation of cyclic amines

40
Q

In Negishi cross coupling some of the SM is said to be “sacrificial”, why is this?

A

Two molecules of the organozinc reagent bind to the Pd pre-catalyst and couple to each other to form active Pd0 catalyst

41
Q

What are the steps in the Negishi catalytic cycle?

A

1) Oxidative addition
2) Transmetallation
3) Reductive Elimination

42
Q

When should Negishi cross-coupling be used?

A

α-functionalisation of cyclic amines with an aromatic halide

43
Q

Why is sparteine or a sparteine surrogate used in place of TMEDA?

A

Sparteine is chiral while TMEDA is not, allowing asymmetric induction into the product in the α-functionalisation of cyclic amines

44
Q

TRUE or FALSE? (-)-sparteine leads to lithiation of the back proton?

A

TRUE - S product formed

45
Q

TRUE or FLASE (+)-sparteine surrogate leads to lithiation of the back proton?

A

FALSE - lithiation of the front proton –> R product formed

46
Q

Before α-functionalisation can occur, what MUST be done first?

A

The amine MUST BE PROTECTED! Boc2O (Boc anhydride)

47
Q

What are the SMs in the Fischer indole synthesis?

A

Aromatic hydrazine, ketone OR aldehyde

48
Q

What are the keys steps in a Fischer Indole synthesis?

A

1) Formation of an enamine
2) [3,3]-sigmatropic rearrangement
3) Rearomatiscation

49
Q

What are the regioselectivity issues to be considered during a Fischer indole synthesis?

A

1) Hydrazine should be symmetrical otherwise regioisomers formed
2) Ketone (aldehyde) should be symmetrical OR with only one position that can react

50
Q

What are the 2 steps involved in the benzimidazole formation?

A

1) Formation of amide
2) Cyclisation to give product

51
Q

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?

A

Nitrogen is more nucleophilic and will always attack the acyl chloride first to form the amide

52
Q

What are the SMs when forming a tetrazole?

A

A nitrile and sodium azide in Nh4Cl (ammonium chloride)

53
Q

What type of reaction occurs in the formation of a tetrazole?

A

[1,3]-dipolar cycloaddition

Advanced Research Topics (2 decks)

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