Combo chemistry (2) Flashcards
1
Q
Solid phase synthesis
A
- 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
2
Q
Solid phase synthesis
We need
A
- A cross-linked, insoluble polymeric material that is inert to the condition of synthesis
- Some means of linking the substrate to this solid phase that permits selective cleavage of the final product
- A chemical protection strategy to allow selective protection and deprotection of reactive groups
3
Q
The solid support- The resin
A
- 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
4
Q
The solid support- the resin
A
- 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
5
Q
The solid support- the linker
A
- 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
6
Q
The linker- Merrifield resin
A
- 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)
7
Q
The linker- Wang resin
A
- 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
8
Q
The linker- Rink (amide) linker
A
- 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
9
Q
Traceless linkers
A
- 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
10
Q
Solid phase synthesis
Advantages
A
- 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
11
Q
Solid phase synthesis
Disadvantages
A
- Linker required
- Cleavage conditions required
- 2 extra steps cf solution phase (attach/cleave)
- Reinventing chemistry
- Difficult to monitor
- Small quantities
- Expensive
12
Q
Solution phase synthesis
Advantages
A
- 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)
13
Q
Solution phase synthesis
Disadvantages
A
- Automated purification
- Short syntheses only
- Automation less straightforward compared with solid phase especially if chromatographic purification of intermediate compounds is required
14
Q
The choice: solid phase or solution phase
A
- 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
15
Q
Solid or solution phase
A
16
Q
A
17
Q
Purity issues
Traditional vs Modern synthesis
A
- Traditional
- Purity requirement >99.5%
- 1 Chemist
- 50 compound per year
- Modern
- Purity requirements >50%
- 1 Chemist + ROBOT
- Thousands of compounds per year
18
Q
What do chemists do all day
A
*
19
Q
Compound purity choices
Biological assay
A
- Difficult, expensive low-throughput
- Automated high-throughput
20
Q
Compound purity requirements
A
- Must use very pure compounds (Small number)
- Can use crude compounds (large number)
21
Q
Compound purity choices
A
- 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
22
Q
Automated/Combinatorial solution phase synthesis
A
- 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
23
Q
Automated/Combinatorial solution phase synthesis
A
24
Q
Example of the use of a scavenger resin
A
