Download Solution-Phase Combinatorial Chemistry

Solution-Phase
Combinatorial Chemistry
Introduction
• When combinatorial chemistry first emerged, the initial
focus was on solid-phase approaches due to the many
advantages.
• Solution chemistry was not regarded as being suitable
for combinatorial chemistry because of the often tedious
isolation and purification.
• It was first used for easily synthesized compound
classes [amides, sulfonamides, ureas, heterocycles
(thiazole)].
• Presently, solution-phase combinatorial synthesis is
attracting more interest because of some advantages.
Advantages
• Many more reactions are optimized in solution-phase
• All reactive groups of the starting materials are available
• No limitations of the thermal or chemical stability of the
resin
• Synthesis is shorter by one or two steps
• Reactions in solution often need considerably less time
• Reactions that involve insoluble components are
confined to solution phase
• Reactions can be followed conveniently by simple
means (TLC, NMR, UV)
• In general, the reaction volumes in relation to the amount
of product are smaller
Reactions
1. Multicomponent Condensations (MCCs)
MCCs combine two principles of organic chemistry:
Convergence and economics of atoms
a) The Ugi four-component reaction:
b) Biginelli Reaction (1893)
- catalytic amounts of acid are required
- the products are the backbones of several Cachannel blockers and antihypertensive agents (à
medicinal chemistry)
c) Hantzsch Pyridine Synthesis
- drugs derived from a pyridine template comprise
antihistamines, antiseptics and antirheumatics
d) SmCl3-Initiated MCC
2.) Acylation of Alcohols and Amines
- usually these reactions provide high yields and do not
require large excesses of starting material
(one of the most applied reaction in solution-phase
combinatorial chemistry)
3.) Sulfonation of Amines
4.) Formation of Ureas, Thioureas and Carbamates
5.) Reductive Amination
6.) Pd-Catalyzed C-C Bond Formation
7.) Hydrogenations and Reductions
8.) Cyclisation Reactions
9.) Arylation of Amines
10.) C-C Bond Formation via Condensation Reactions
…
Purification Principles
1.) Liquid-Liquid Extraction:
a) Aqueous Work-Up:
b) “Fluorous Work-Up”
- the fluorous phase consists of perfluorohydrocarbons
(e.g., perfluoro-hexanes)
- the second phase can be water or the most organic
solvents
- even three phase extraction is possible
- to dissolve organic molecules a “fluorous tag” is required
- the partition coefficient is influenced by the number of
fluorous atoms
- perflouralkylated silicium-, tin-, or phosphorous
compounds are most effective
- to decrease the strong withdrawing effect two or three
methylene groups are necessary
c) Phase Separation Techniques:
- “lollipop” methode
- adsorbation of water (Na2SO4, MgSO4)
- using a hydrophobic frit
2. Solid-Phase Extraction
a) Silica Gel and Alumina
- based on noncovalent interactions
- it`s possible to remove: many inorganic salts, amine
hydrochlorides, amines or acids
- it provides an inexpensive and easily automated
alternative to aqueous work-up
b) Ion Exchange
- charged molecules can be separated from neutral
molecules
- the interactions between the adsorbent and the
molecules can be influenced very selectively
- the ionic processes can be influenced by the ionic
strength of the solvent (pH) as well as the ionic nature of
the adsorbent
3. Covalent Scavengers
a) Solution Scavengers
- based on covalent interactions
- the scavenger reacts with the byproduct/impurity, so
that it can be separated from the product by extraction
or filtration
4. Polymer-Assisted Solution-Phase Chemistry (PASP)
- the scavenger functionality is resin-bound, so the
quenching proceeds via a covalent bond between the
unreacted starting material/impurity and the resin
- isolation of the product by filtration and rinsing
- the product can also be isolated by resin capture
Conclusions and Outlook
- new purification methods have been developed, that
offer alternatives to solid-phase approach
- the phase switch of the compounds and the separation
of the phases is the basis of automated purification
- the combination of covalent scavengers, resin capture
and solid-phase extraction may represent a highly
efficient tool for high-speed solution-phase synthesis
- these strategies may be combined with resin-bound
reagents to optimize the solution-phase synthesis
References: