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IX. RESINS AND LINKERS FOR GENERATION OF OTHER FUNCTIONS

IX. RESINS AND LINKERS FOR GENERATION OF OTHER FUNCTIONS

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Figure 15



85]. A further extension to this concept was (dimethylsilyl)propionic acid

linker 75 used for the solid-phase synthesis of aryl-containing organic

compounds [86]. The linker was cleaved smoothly with TFA and has been

used for the synthesis of compounds which involved alkylation, acylation,

and Mitsunobu reactions.

Silicon linker 76 was used for direct loading of aromatic compounds to supports for the assembly of pyridine-based tricyclics (Scheme

39) [87]. Following the initial coupling of an aromatic bromide to the

resin by halogen/metal exchange in the presence of tert-butyl lithium, a



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 39



series of reactions including TFA deprotection of Boc, alkylation under

strong basic condition, SnCl2 reduction, and ring cyclization were

performed. The final tricyclic products were released from the polymer

via basic fluoride (Bu4N+-F) in THF at room temperature. A similar

trialkylsilane linker was synthesized from Merrifield resin in two steps

[88].

Piperazine linker 77 was treated with propargyltriphenylphosphine

bromide to provide a resin-bound Wittig reagent (Scheme 40) [89]. Base

treatment followed by aldehyde addition produced a resin-bound 2-aminobutadiene which was implemented in [4+2] cycloadditions. Alternatively,

treatment with 3% TFA in CH2Cl2 released a,h-unsaturated methylketones in high yields.



Scheme 40



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 41



Acetal handle 78 synthesized from Merrifield resin and 4-hydroxybenzaldehyde was applied to the solid-phase synthesis of carbohydrates

and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was

initially anchored to the support to form a cyclic acetal. A ring opening

reaction with DIBAL generated a resin-bound alcohol which was

converted to the corresponding triflate for N-alkylation with 4-vinyloxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxacephams from the support.

Aryl hydrazide-based linker 79 was developed as a traceless handle

that released products under mild oxidative conditions (Scheme 42) [91].

Polymeric bound p–iodophenylhydrazide was subjected to a variety of

Pd0-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille).

Oxidation with Cu(OAc)2 in MeOH and pyridine released the final

products in 50–96% yield.

A traceless linker for solid-phase homo- and hetero-Diels-Alder

reactions was based upon resin bound quinodimethane precursors



Scheme 42



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Scheme 43



(Scheme 43) [92]. Reaction of dienophiles such as 4-nitrobenzaldehyde

with linker 80 at high temperature gave Diels-Alder products. Dihydropyrans were released from the support by Bronsted or Lewis acid-nucleophile combinations in moderate to good yield with stereoselectivity for the

anti isomer.



X. CONCLUSION

The past decade witnessed a renaissance in drug discovery due to the

emergence of solid-phase synthesis. Initially, the solid supports and linkers

used for the repetitive process of biomolecule assembly applied to the

construction of small molecule libraries and scaffolds were required to

contain a carboxylic acid or amide in order to anchor to the polymeric

support. Thus, the linkers from solid-phase peptide synthesis such as Rink,

Wang, and PAL were commonly employed in the synthetic strategy. As

new bond-forming reactions have been adapted for solid phase as well as

the construction of novel lead compounds, synthetic pathways are requiring additional handles that release compounds into solution upon various

cleavage conditions and provide additional functionality at the anchoring

position. In a retrosynthetic analysis of a library, one should plan the

anchoring strategy as it relates to the functionality of the molecule as well

as to insure that the cleavage conditions are compatible with the synthetic

scheme. Although there are now a plethora of linkers that have been

described in the literature, novel handles still provide medicinal chemists

the tools to expand molecular diversity with the ultimate reward of

discovering a new drug candidate.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Appendix A. HANDLES AND DERIVATIZED

SOLID SUPPORTS



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.



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