Combo chemistry (2)

Question 1

Solid phase synthesis

Answer 1

• A substrate molecule is temporarily attached to an insoluble polymer bead via a linker
• Chemical transformations are carried out upon the substrate
• The modified substrate is released from the polymer by specific chemical conditions
• The polymer together with the bound substrate is easily removed from the reaction by FILTRATION
• Facilitates multistage chemistry by cutting down the work of isolating intermediate

Question 2

Solid phase synthesis

We need

Answer 2

1. A cross-linked, insoluble polymeric material that is inert to the condition of synthesis
2. Some means of linking the substrate to this solid phase that permits selective cleavage of the final product
3. A chemical protection strategy to allow selective protection and deprotection of reactive groups

Question 3

The solid support- The resin

Answer 3

• An insoluble polymer that
  
  • Swells in the presence of the reaction solvent-increase the volume of pores within the resin which allows access to functional groups within the resin increasing its capacity to perform chemistry
  • Is inert to the reaction conditions
• Common resins include
  
  • Polystyrene cross-linked with 1% Divinyl benzene to give the polymer structural rigidity and to render it insoluble
  • Tentagel resin- polyethene glycol attached to polystyrene through an ether linkage

Question 4

The solid support- the resin

Answer 4

• Simple cross-linked polystyrene has good swelling characteristics in solvents of low to medium polarity (aliphatic hydrocarbons to dichloromethane)
• Polar, protic solvents, such as alcohols and water, do not swell such resins, and accessibility to all reaction sites may be comprimised
• Hence such supports are most suitable for chemistry performed in solvents for low to medium polarity
• Tentage- type resins (polystyrene-oxyethylene) graft co-polymers were developed to allow the use of reactions in polar solvents

Question 5

The solid support- the linker

Answer 5

• The linker for attaches the organic molecule to the polymeric support it must
  
  • Survive the conditions of the synthesis
  • Be readily cleaved from the resin without destroying the synthesised molecule once the reaction is complete

Question 6

The linker- Merrifield resin

Answer 6

• The original resin designed for peptide synthesis
  
  • Provides a handle for anchoring carboxylic acids
• The carbonyl group is attached by the nucleophillic displacement of the chloride with a cesium carboxylate salt in DMF
• After synthesis is complete, the carboxylic acid or peptide is usually detached by exposure to HF (very aggressive)

Question 7

The linker- Wang resin

Answer 7

• Wang resin is an improvement upon Merrifield resin
  
  • Carboxylic acids are attached to the solid support by esterification using a coupling agent
• The cleavage step is milder than in the Merrifield case
• The mesomeric effect of the oxygen atom at the para position of the benzene ring results in an increase in electron density at the carbonyl group of the acid, allowing this to be cleaved with 50% TFA in dichloromethane rather than neat HF

Question 8

The linker- Rink (amide) linker

Answer 8

• Preferred for generating primary carboxamide by solid phase chemistry
• The starting material is attached to the linker as carboxylic acid and after synthetic modification is cleaved from the resin with TFA
• The greater acid sensitivity is a consequence of the two additional electron donating methoxy groups

Question 9

Traceless linkers

Answer 9

• Silicone-based linkers are the most common
  
  • Leave no memory of attachment to the solid support
  • The silicon-carbon bond is cleaved by acid (Proto-desilylation) to leave no clue as to the point of resin attachment

Question 10

Solid phase synthesis

Advantages

Answer 10

• Easier purification- just filter
• Can use excess reagents to drive reactions to completion
• Stabilisation of reactive substances
• Stimulation of high dilution (site isolation)
• Easy synthesis of mixtures (mix and split)
• Automation easy

Question 11

Solid phase synthesis

Disadvantages

Answer 11

• Linker required
• Cleavage conditions required
• 2 extra steps cf solution phase (attach/cleave)
• Reinventing chemistry
• Difficult to monitor
• Small quantities
• Expensive

Question 12

Solution phase synthesis

Advantages

Answer 12

• Known chemistry
• Short development phase
• No loading or cleaving (saves 2 steps)
• Easier to monitor than solid phase
• Large quantities possible
• Cheaper (no expensive resins)

Question 13

Solution phase synthesis

Disadvantages

Answer 13

• Automated purification
• Short syntheses only
• Automation less straightforward compared with solid phase especially if chromatographic purification of intermediate compounds is required

Question 14

The choice: solid phase or solution phase

Answer 14

• How many compounds are required
• How soon are the compounds are required
• How pure should the compounds be
• What scale
• Does the chemistry already exist
• How many steps
• What automation is available
• How much money do you have

Question 15

Solid or solution phase

Answer 15

Question 17

Purity issues

Traditional vs Modern synthesis

Answer 17

• Traditional
  
  • Purity requirement >99.5%
  • 1 Chemist
  • 50 compound per year
• Modern
  
  • Purity requirements >50%
  • 1 Chemist + ROBOT
  • Thousands of compounds per year

Question 18

What do chemists do all day

Answer 18

*

Question 19

Compound purity choices

Biological assay

Answer 19

• Difficult, expensive low-throughput
• Automated high-throughput

Question 20

Compound purity requirements

Answer 20

• Must use very pure compounds (Small number)
• Can use crude compounds (large number)

Question 21

Compound purity choices

Answer 21

• Will the pitential by-products and residual starting materials interfere with the bio-assay
• NO
  
  • Can use crude compounds
  • Easier to automate
• YES
  
  • Must purify
  • More difficult to automate

Question 22

Automated/Combinatorial solution phase synthesis

Answer 22

• Is it possible to have the best of both worlds => Polymer supported reagents and scavenger resins
  
  • The main advantage of solid supported synthesis is the somple (And easy to automate) filtration process between each synthetic step
  • This can be applied to solution phase chemistry if the reagents and catalysts are bound to the solid phase rather than the substrates or by-products can be captured by scavenger resins
  • the reactions take place in solution using a reagent attached to solid phase, and the resulting products are separated by filtering the reaction mixtures after completion
  • The filtrate contains the desired product

Question 23

Automated/Combinatorial solution phase synthesis

Answer 23

Question 24

Example of the use of a scavenger resin

Answer 24