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8/14/2019 Solid Phase Chemistry Ready

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Solid Phase Chemistry

Presented By

Amod S.Patil

M.Pharm

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OUTLINE

Introduction : What it is?

Basic theme

Comparison with solution phase

Resins

Linkers

Noncovalentsolid-phase organic synthesis

Microwave assisted peptide synthesis

References

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INTRODUCTION: What it is?

In chemistry ,solid phase synthesis is a method in which

molecules are bound on bead & synthesised step by step in a

reactant solution .

In this method, building blocks are protected at all reactive

functional group. The two functional groups that are able to

participate in the desired reaction between building blocks

in the solution and on the bead can be controlled by the

order of deprotection.

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The Nobel Prize in Chemistry 1984

--for his development of methodology

for chemical synthesis on a solidmatrix

Robert Bruce Merrifield

Rockefeller University

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SOLID PHASE PEPTIDE SYNTHESIS

Bruce Merrifield published in 1963

Nobel Prize in Chemistry in 1984The idea:

T

P

AA1 RXanchoring

T

P

AA1 R

deprotection

P

AA1 R

T

P

AA2

coupling (-H2

O)T

P

AA2

P

AA1 R5


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T

P

AA2

P

AA1 R deprotection

coupling

repetitivecycle

T

P

AAn

P

AA2

P

AA1 R

AAn AA2 AA1

cleavage+

final deprotection

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Comparison with solution phase synthesis

Solution phase Solid phase

time consuming

manual

side chain protecting groups for

Lys, Asp, Glu, (Cys)

coupling: less than 90% conversion

purification after each steps

large scale

cheap

fast

synthesizer(or manual)

side chain protecting groups for

all functional groups

coupling: over 99.5% conversion

purification at the end

rather small scale

expensive

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Can be functionalised.

Chemical stability (it must be inert to all applied chemicals).

Mechanical stability (it shouldnt brake under stirring).

It must swell extensively in the solvents used for the synthesis.

RESINS

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Peptide-resin bond should be stable during the synthesis.

Peptide-resin bond can be cleaved effectively at the end of the

synthesis.

It is typical for all supports that they are used in beaded form as

spherical microparticles available in a choice of size distributions.

The beads diameter usually lie in the range of 80-200m.

The no. of functional groups per mass of dry support is termed as

Loading capacity .

Commercial products with rough capacity between 0.2-1.5mmole/g or

100pmol/bead

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Names Structure Feature

1.Crosslinked geltype Polystyrene(GPS):

2. Polyamide Resins

3.TentaGel Resins

Good swelling property inmedium to low polarity solvants.

Improved solvation properties in

polar & aprotic solvants.

This is grafted type ofcopolymers.

Examples of resins


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Linkers

The group that joins the substrate to the resin bead is anessential part of solid phase synthesis.

The linker is a specialised protecting group, in that much

of the time, the linker will tie up a functional group, only

for it to reappear at the end of the synthesis. The linker must not be affected by the chemistry used to

modify or extend the attached compound. And finally the

cleavage step should proceed readily and in a good yield.

The best linker must allow attachment and cleavage in

quantitative yield.

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Type

Carboxylic acidlinkerse.g. 1.Merrifieldresin

2. Wang linker

Structure Clevagecondition

Hydrogen fluoride

Trifluoroacetic acid

Examples of Linkers


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Solid phase Organic Synthesis Without Using Any

Solvent

These type of synthesis involves direct reaction between

two solid molecules without using any solvent.

For example-

Formation of Ethers from Alcohols:- Treatment of alcohol with p-

toluene sulphonic acid ( TsOH ) in solid state by keeping the

powdered mixture 1:1 at R.T. for 10 min. gives the corresponding

ethers in 94-98% yields.

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R'

OH

TsOH

Solid

O

R' R'

Alcohol Ether 94-98%


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Noncovalentsolid-phase organic synthesis

Noncovalent solid-phase organic synthesis or NC-SPOS is a

form of Solid phase synthesis where by the organic substrate is

bonded to the solid phase not by a covalent bond but by other

chemical interactions. This bond may consist of an induceddipole interaction between a hydrophobic matrix and a

hydrophobic anchor.

As long as the reaction medium is hydrophilic (polar) in nature

the anchor will remain on the solid phase. Switching to a non polar solvent releases the organic substrate

containing the anchor.

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For example, the hydrophobic matrix is RP silica gel and

the anchor is attached to it & this system is subjected to a

sequence of organic reactions.


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Microwave assisted solid phase synthesis

Application of microwave irradiation in organic reactions

has added a new dimention to solid phase synthesis

In these the reactants are dissolved in suitable solvant like

water, alcohol, methylene chloride etc. & the solution is

stirred with a suitable adsorbant or solid support like silica

gel, allumina or phyllosilicate

After stirring, the solvant is removed & the dried support

on which the reactants have been adsorbed are used for

carrying out the reaction under microwave irradiation.

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Examples

Saponification of esters:

Hindered esters which takes 5 hrs under classical heating

with alkali can be easily saponified under microwave

irradiation using KOH aliquat

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R OR'

O1) KOH Aliquat

mw 4 -10 min

2) HCl

R OH

O

+ R'OH


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REDUCTIONS :

Sodium borohydride has been extensively used as a

reducing agent. The solid state reduction with NaBH4

requires longer time & use of solvents slow down the

reaction. A microwave irradiation reaction has been

developed for the reduction of aldehydes & ketones

using alumina supported NaBH4in short time.

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O

R'R

NaBH4

allumina

R CH

OH

R'

mw


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Microwave assisted peptide synthesis

However, SPPS has disadvantage of intermolecular aggregation, steric

hindrance from protecting groups. As a result, standard amino acid cycle

times range from 30 minutes to 2 hours and incomplete deprotection and

coupling reactions are still common. Traditionally, solid phase peptide

synthesis (SPPS) has been performed at room temperature and been a very

time consuming process.

In an effort to speed this process, nitrogen bubbling and vortex mixing

have been applied to increase deprotection and coupling reaction rates.

Elevated temperature up to 60C causes thermal disruption of peptide

aggregation.

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Unlike conventional heating, microwave energy directly activates

any molecule with a dipole moment and allows for rapid heating atthe molecular level.

Microwave energy has also been successfully used to increase the

rate of peptide coupling.


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REFERENCES:

Patrick Grahm L. An introduction to Medicinal Chemistry Third

edition 2005, oxford university press page no. 299-305

Fassina Giorgio, Stanislav Miertus, Combinatorial chemistry &

applications, second edition 2005,Tylor & Francis page no.89-102 www.wikipedia.com

http://www.combichemistry.com

Ahluwalia V.K. Kidwai M. New Trends In Green Chemistry,

Second edition, Anamaya publishers New Delhi , page no. 60-72, 213.

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