SOLID PHASE ORGANIC SYNTHESIS

PREPARATION OF ORGANOMETALLIC COMPOUNDS • Usually generated on insoluble supports only as synthetic intermediates, and not as target molecules... • Reaction of resin-bound organolithium

SOLID PHASE ORGANIC SYNTHESIS

PREPARATION OF ORGANOMETALLIC

COMPOUNDS

• Usually generated on insoluble supports only

as synthetic intermediates, and not as target molecules

• Highly versatile reagents

Group I and II Organometallic Compounds

• Metallated, cross-linked polystyrene reacts smoothly with a wide range of electrophiles

• Lithiation of polystyrene-bound arenes and heteroarenes

Group I and II Organometallic Compounds

• Halogen-metal exchange

Group I and II Organometallic Compounds

Transmetallation and direct Lithiation

Group III Organometallic Compounds

• Reaction of resin-bound organolithium compounds with chlorosilanes

• Hydrosilylation of resin- bound alkenes

Group IV Organometallic Compounds

Group IV Organometallic Compounds

• Hydrolyses of organometallic compounds

Preparation of Alkanes by Hydrogenation

and Reduction

Preparation of Alkanes by Hydrogenation

and Reduction

Preparation of Alkanes by Carbon-Carbon

Bond Formation

C-Alkylations have been performed with:

• Support-bound carbon nucleophiles: boranes, organozinc and organomagnesium compounds

• Support-bound carbon electrophiles: benzyl, allyl, and aryl halides or triflates

• Addition of radicals to alkenes

• Friedel-Crafts alkylation

Coupling Reactions with Group I Organometallic Compounds

Coupling Reactions with Group I Organometallic Compounds

Coupling Reactions with Group II Organometallic Compounds

Coupling Reactions with Boranes

Coupling Reactions with Boranes

Coupling Reactions with Arylpalladium

Compounds

The Heck reaction

Alkylations with Alkyl Radicals

The highest yields are usually obtained when:

• Electron-rich radicals (alkyl radicals, substituted radicals) add to acceptor-substituted alkenes

heteroatom-• when electron-poor radicals add to electron-rich double bonds

Alkylations with Electron-poor Radicals

Alkylations with Alkyl Radicals

• Similarly, the β-elimination of resin-bound leaving groups has been used as a cleavage strategy for the

Preparation of Alkenes by β-Elimination

Preparation of Alkenes by β-Elimination

Preparation of Alkenes by Carbonyl

Olefination

By Wittig Reaction

By Wittig Reaction

By Wittig Reaction

By Aldol and Related Condensations

By Aldol and Related Condensations

Preparation of Alkenes by C-Vinylation

The Heck, Stille, and Suzuki couplings

Synthesis of tetrahydroisoquinolines

diversification reaction

diversification reaction divide

Parallel Library Synthesis

• Optimization of 12 reactions provides 9 compounds

• The library members are spatially separated, so this technique can

be used for solution as well as solid phase synthesis

Split-pool Synthesis

• Optimization of 6 reactions leads to 9 compounds

• Each library member must be compartmentalized (each compound on its own bead) to allow pooling of the library

split diversification pool

reaction

Ellman, J et al J Am Chem Soc., 1995, 117, 3306.

An Example of Split-Pool Synthesis

O

NHBoc SnMe3

9X

O

NHBoc SnMe3

O

NHBoc SnMe3

O

NHBoc SnMe3

3X

3X

3X

1) Pd2dba3, 2) TFA

1) Pd2dba3, 2) TFA

1) Pd2dba3, 2) TFA

Cl Me O

Cl O

3X

O

NH2O

3X

NH2

O Me

O

NH2

O Me

O

NH2

O

F O

NHFmoc

F O

2) piperidine

O

NH

O Me

O

NH2

O

NH2O

NH2

O

NH

O Me

O

NH2

O

NH2O

Ellman, J et al J Am Chem Soc., 1995, 117, 3306.

Overview of the Entire Split-Pool Library

Pd2dba3,

TFA

F O

35 Amino Acids

16 Alkylating Agents

Split-Pool step:

H N O

R1

O N

O

H N O

R1

HO O

NH

R2

18 iodides

Example of the Efficiency of the Split-pool Strategy

amplification in the number of compounds