Analysis of combinatorial libraries

Question 1

Direct methods used to determine active species

Answer 1

Off-bead analysis

On-bead analysis

Question 2

Off-bead analysis

Answer 2

Compound is cleaved from polymer then analysed by e.g. LCMS, NMR
Requires a highly sensitive and high throughput format

Question 3

On-bead analysis

Answer 3

Can be used to monitor the progress of a reaction

e. g. single-bead FT-IR microspectrometry
e. g. MAS NMR

Question 4

Methods for determining the active component in a split and mix combinatorial library

Answer 4

1. Deconvolution
2. Indexed library
3. Tagged library
4. Encoded sheets

Question 5

Disadvantage of deconvolution

Answer 5

Time-consuming

but still faster than synthesising all 27 species individually

Question 6

Disadvantages of indexed library

Answer 6

Wasteful of resources

Not always accurate

Question 7

Tagged library

Answer 7

Tag is used to identify compounds

i.e. each reagent has a different tag

Question 8

Disadvantage of tagged library

Answer 8

Expensive linkers required

Question 9

Disadvantage of encoded sheets

Answer 9

Logistics - can be difficult to keep track of everything that has been made

Question 10

Define multicomponent reaction

Answer 10

A reaction in which 3 or more reagents react in one pot to generate a product containing atoms from all reagents

Question 11

Why are multicomponent reactions important in the drug discovery process?

Answer 11

Can generate complexity through the combination of multiple functional groups
Diversity is easily incorporated in one step by varying the components
Often avoids deprotection steps
Efficient solid phase or solution phase syntheses are possible and high yielding
One pot reactions are ideal for automation

Question 12

Two component vs. multicomponent synthesis

Answer 12

Three component synthesis can make 8 products in 4 fewer reactions than parallel two component synthesis (8 vs. 12 reactions)

Question 13

Multicomponent vs. split-and-mix synthesis

Answer 13

Split-and-mix two component synthesis can make 8 products in 4 fewer reactions than three component synthesis (8 vs. 4 reactions)

Question 14

Advantages of parallel multicomponent synthesis vs. split and mix synthesis

Answer 14

Does not require tagging or deconvolution
Often avoids deprotection steps
More easily automated

Question 15

Disadvantages of parallel multicomponent synthesis vs. split and mix synthesis

Answer 15

Requires more steps

Question 16

Ugi reaction in combinatorial chemistry

Answer 16

High generation of diversity - all 4 components can be varied, all are commercially available, can access diverse/bespoke structures
Compatible with a large library size
Reactions can be solid or solution phase
Amenable to automated parallel synthesis

Question 17

Approaches for minimising reaction workups

Answer 17

Multicomponent one-pot reactions e.g. Ugi
Liquid-liquid phase extractions
Polymer-bound scavengers
Polymer-bound reagents or catalysts

Question 18

Liquid-liquid phase extractions

Answer 18

Involves removing excess reagents and by-products by simple acid-base aqueous extraction
Automation is possible

Question 19

Non-aqueous liquid-liquid phase extractions

Answer 19

Possible using fluorinated solvents (selectively dissolve fluorinated compounds)
Fluorous phase below organic phase

Question 20

Polymer-bound scavengers

Answer 20

Bind to/react with excess reagents

Makes purification easier - can just filter off excess reagents bound to polymer

Question 21

Polymer-bound reagents

Answer 21

Means reagents that are incompatible can be used together because the polymers cannot react with each other
e.g. acids/bases, oxidants/reductants