Synthesis of Biological Materials Flashcards by Matt Miles

What is a monosaccharide?

A single sugar unit e.g. glucose

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What is a disaccharide?

Two sugar units linked together

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What is an oligosaccharide?

More than two sugar units

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What is a carbohydrate?

Anything from monosaccharide to oligosaccharide

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What is a glycoside?

Any carbohydrate molecule with an anomeric substituent other than OH

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What is a glycoconjugate?

The general term for a carbohydrate covalently linked to another biomolecule e.g. a protein, peptide or lipid

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Why do we need to activate different amino acids when synthesising peptides?

OH- is a poor leaving group

COOH is a poor electrophile

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How does racemisation occur?

It occurs via the formation of an oxazolone intermediate, which can undergo keto-enol tautomerisation to create a non-chiral intermediate

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How can we minimise racemisation?

We can use a coupling reagent instead of activating the C-terminus.

This reduces the leaving group ability, and allows a one-pot reaction without the isolation of the activated species

Complete peptide synthesis in the C- to N- terminal direction

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How can we install a Boc protecting group?

Boc₂O + base

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How can we remove a Boc protecting group?

TFA

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How can we install an Fmoc protecting group?

Fmoc-Cl + base

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How can we install a methyl ester protecting group?

MeOH + HCl

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How can we remove an Fmoc protecting group?

Piperidine

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How can we remove a methyl ester protecting group?

NaOH, H₂O

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How can we install a benzyl ester (Bz) protecting group?

Phenylmethanol + acid

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How can we remove a benzyl ester (Bz) protecting group?

H₂, Pd/C

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How can we install an allyl ester protecting group?

Prop-2-en-1-ol + Acid

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How can we remove an allyl ester protecting group?

Pd(PPh₃)₄

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How do we install a tert-butyl ester protecting group?

Tert-butyl alcohol and acid

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How do we remove a tert-butyl ester protecting group?

TFA

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How do we install a tert-butyl ether protecting group?

Tert-butyl alcohol and acid

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How do we remove a tert-butyl ether protecting group?

Concentrated TFA or HCl

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How do we install a benzyl ether protecting group?

Phenylbromine + NaOH

How do we remove a benzyl ether protecting group?

H₂, Pd/C

How do we install a silyl ether protecting group (e.g. trimethylsilyl (TMS))

TMS-Cl + base

How do we remove a silyl ether protecting group?

TBAF

How does Solid Phase Peptide Synthesis (SPPS) work?

The peptide is immobilised on resin The reagents are in solution and can be washed away after the reaction (no further workup required) The product can be cleaved off after the synthesis is complete

In SPPS, why do we generally use Fmoc and not Boc to protect the N-terminus?

It avoids the release of the peptide during deprotection

Why do we use DIC as a coupling reagent in SPPS compared to DCC?

Using DCC creates an insoluble urea byproduct, which precipitates out of a solution. This causes issues when working with the solid support

How can we release the peptide from Merrifield resin?

Using the corrosive and toxic acid HF

How can we release the peptide from Wang resin?

Using TFA

How can we release the peptide from Sasrin resin?

Cleaving with 1% TFA

What are the advantages of SPPS?

No work-up required or any purification of intermediates Can be automated to increase efficiency

What are the limitations of SPPS?

There can be an accumulation of impurities and by-products (e.g. due to incomplete coupling reactions) Purification of the final product can be challenging A limited amount of the peptide can be released

How can we selectively protect the hydroxyl group on the C6 (primary) hydroxyl?

By using a sterically demanding protecting group e.g. triphenyl methyl ester (trityl, Tr)

What are the conditions for the selective protection of the C6 hydroxyl?

TrCl + base

What are the conditions for the deprotection of Tr?

Mild acid e.g. ethanoic acid

How can we install an acetyl ester (Ac) protecting group?

Ac₂O + pyridine

How can we remove an acetyl ester (Ac) protecting group?

NaOMe

How can we install a benzoyl ester (Bz) protecting group?

Benzoyl chloride +pyridine

How can we remove a benzoyl ester (Bz) protecting group?

NaOMe

How can we selectively protect the C4 and C6 hydroxyl groups?

Using PhCH(OMe)₂ and acid (creates a benzylidene ester)

How can we remove the benzylidene ester protecting group over the C4-C6 carbons?

H₂, Pd/C

How can we selectively protect the C6 position from a benzylidene ester?

Reducing with NaBH₄

How can we selectively protect the C4 position from a benzylidene ester?

Reducing with LiAlH₄

By what intermediate do glycosidic bonds form?

The oxocarbenium ion

How do we attach a Br to the C1 position from an unprotected sugar?

Protect with Ac (by Ac₂O + pyridine), and then react with HBr

How can bromine at the C1 position be activated?

By using Ag₂CO₃ or AgOTf

How can we attach a trichloroacetimidate group onto the C1 position?

Deprotonate the deprotected C1 hydroxyl using NaH and react with trichloroacetonitrile (with an acidic workup)

How can the trichloroacetimidate group be activated?

Using a Lewis acid such as TMSOTf

How can we attach a thioether group onto the C1 position?

React a fully protected sugar with HBr, and then add Ph-SH with Ag₂CO₃ and BF₃

How can we activate a thioether group?

Iodination with N-iodosuccinimide (NIS) + acid Methylation with Methyltriflate (MeOTf) or trimethylsilyltriflate (TMSOTf) Oxidation (e.g. mCPBA) followed by triflic anhydride (Tf₂O)

What are two reasons for the anomeric effect?

Dipole Minimisation Hyperconjugation

How does dipole minimisation lead to the anomeric effect?

In the beta-anomer, the dipoles of the endocyclic oxygen and the anomeric oxygen are partially aligned, which causes an unfavourable repulsion

How does hyperconjugation lead to the anomeric effect?

In the alpha anomer, there is orbital overlap between the axial lone electron pair on the endocyclic oxygen and the antibonding sigma* orbital of the axial C-O bond. This leads to a stabilising interaction which lowers the molecule's energy

What is neighbouring group participation?

If the protecting group on the C2 carbon is equatorial OAc, attack from above is promoted and hence the beta-anomer is formed If the protecting group on the C2 carbon is axial OAc, attack from the bottom is promoted and hence the alpha-anomer is formed

How does the choice of solvent impact the stereochemistry of the anomeric carbon?

If the solvent is nucleophilic (e.g. acetonitrile), it promotes the beta-anomer being formed as the solvent will react with the oxocarbenium ion, and then be replaced by an SN2 reaction If the solvent is non-nucleophilic, the alpha-anomer is preferred, as per the anomeric effect

How does the reactivity of the nucleophile impact the stereochemistry of the anomeric carbon?

The more reactive the nucleophile, the more likely it is to proceed by an SN2 reaction, hence not fully forming the oxocarbenium ion. This leads to the beta anomer (anomeric effect has no impact)