Lecture 14 - Combinatorial Chemistry 2

Question 1

How does a simple well-grid array work?

Answer 1

Generally large plates of wells (think iodine+starch stuff)

In a single well:
- Well contains compound X1 in solution
- Bead is added and plate is heated causing X1 to bind to bead
- Compound Y1 is added and the plate is heated causing Y1 to bind to X1 on the bead
- Bead is removed and washed (here cycle can be repeated to create longer chains)
- Compound X1Y1 is cleaved from resin
- Compound is isolated and characterised (NMR, MS, IR etc.)

Question 2

Pin and well-grid arrays

Answer 2

• Bead is attached to the end of a pin attached to a larger unit (think of a hairbrush)
• The hairbrush is placed into the well unit in with solutions A1-3
• The well is heated, compounds bind to bead
• Resins are then washed and dipped into solutions B1-B3 and heated, etc.
• This technique is automated (automated parallel synthesis)

Question 3

Furka’s Mix and Split Technique

Answer 3

• A is bound to bead 1, B bound to bead 2, C bound to bead 3
• These are combined, mixed, and split into three new portions (added to D, E, F)
• A now exists as AD, AE, AF, same for B and C
• Combined, mixed and split again (added to G, H, I)
• A exists as ADG, ADH, ADI, AEG, AEH, AEI, AFG, AFH, AFI, same for B and C
• Produces 27 products

Question 4

Number of compounds produced in Furka’s M+S

Answer 4

No. of compounds = b^x, where b is number of compounds in stage 1, and x is the number of steps.

Question 5

What is deconvolution?

Answer 5

Deconvolution is identifying and isolating the active compound from the combinatorial library (final set of compounds)

Question 6

Micromanipulation (deconvolution)

Answer 6

• Each bead in a mixture only contains one type of substructure. The individual beads are separated and the product is cleaved and tested
• Takes a long time with large quantities

Question 7

Recursive deconvolution

Answer 7

Say the combinatorial library is 27 compounds in a reaction vessel; the vessel is split down to 4-6 smaller mixtures which are then cleaved and tested to identify and isolate the active compound.

Question 8

Sequential release equations/reactions

Answer 8

A-[RESIN]-A + Base –> A-[RESIN] + A
A-[RESIN] + Acid –> [RESIN] + A