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II. RESINS AND LINKERS FOR CARBOXYLIC ACID GENERATION

II. RESINS AND LINKERS FOR CARBOXYLIC ACID GENERATION

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Figure 5



linker 10 (HMB) [14] contains a carbonyl group para to the ester anchor

and is activated to nucleophilic attack such as hydroxide ion and is stable

toward acid. Alkoxybenzyl derivatives with greater electron donor

strength (Fig. 6) such as SASRIN (super-acid-sensitive resin) 11 [15],

Rink acid 12 [16], and HAL (hyper-acid sensitive) 13 [17] resin allow

carboxylic acids to be cleaved using a lower acid concentration (typically



Figure 6



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



Figure 7



1–10% TFA) in DCM (dichloromethane). Linkers for carboxylic acids

have also been designed to effect cleavage via photolysis (3-nitro-4hydroxymethylbenzoic acid, ONb 14) [18] and flouridolysis (N-3 or 4)

((4-hydroxymethyl)-phenoxy-t-butylphenylsilyl)phenyl pentanedioic acid

monoamide (PBs) 15 [19] and quinonemethide-based handle 16 [20] (Fig.

7).

Fluorenone derived linker 17 prepared in two steps was coupled to

aminomethyl-PS via DIPCDI [21]. Due to the presence of an electronwithdrawing carboxamide group, the release of carboxylic acids from this

support requires strong acids, such as trifluoromethanesulfonic acid

(TFMSA) (Scheme 1). Insertion of an oxygen adjacent to the biphenyl

rings to the fluorenone scaffold provides xanthene 18 handle [22]. The

oxygen is strategically located to decrease the acid concentration required



Scheme 1



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



Scheme 2



for cleavage and carboxylic acids are released using TFA (Scheme 2). Resin

bound diazo linker 19 was synthesized starting from Wang resin and was

further oxidized to a benzyl aldehyde (Scheme 3) [23]. Carboxylic acids are

anchored to the support in a rapid, colorimetric reaction and are released

upon TFA treatment.

Photolabile linkers play an important role in solid-phase organic

synthesis (SPOS) due to their stability under both acidic and basic

conditions. The ONb photolabile linker was modified to improve cleavage rates and yields; Fmoc-Tos-OH was released in 87% yield after 23 h

(Scheme 4) [24]. Specifically, the primary alcohol was changed to a

secondary benzylic alcohol and the attachment to the resin was through

an alkyl chain as opposed to an amide function. Linker 20 was used for

the production of carboxylic acids or carbohydrates. A second example



Scheme 3



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



Scheme 4



incorporated a dithiane function to serve as a safety catch against

premature photoreaction [25–26]. A carboxylic acid functionality was

coupled to linker 21 via DIPCDI, the dithiane protecting group was

removed by an S-alkylating reagent such as methyl triflate, and release of

the molecule was accomplished with UV irradiation in THF-methanol

(Scheme 5). Based on 2-pivaloylglycerol, photolabile linker 22 was

prepared in six steps from the dimer of 1,3-dihydroxyacetone (Scheme

6) [27]. The handle was attached to TentaGel S NH2 amino resin, the

protecting groups from the hydroxyl functions were removed, and a series

of peptides were assembled. Cleavage rates were reported to be faster

than other photolabile linkers.

Silyl-based linker 23, cleaved by either basic (TBAF) or neutral

(CsF) fluoridolysis to release carboxylic acids, alcohols, or amines, was

prepared by treatment of a Grignard reagent to an aldehyde resin [28].

To demonstrate the utility of this handle, p-bromobenzoic acid was



Scheme 5



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



Scheme 6



attached to the support and cleavage was accomplished in TBAF in

DMF at 65jC or CsF in DMF at 90jC in 78% and 77% yield, respectively (Scheme 7).

Redox-sensitive resin 24 designed for solid-phase peptide synthesis

(SPPS) [29] was prepared from commercially available 2,5-dimethylbenzoquinone in seven steps [30] and loaded to a support via a Wittig

reaction. Release of the peptide occurs using two sequential mild

conditions, reduction with NaBH4 followed by TBAF-catalyzed cyclic

ether formation (Scheme 8) which provide orthogonality to acid sensitive reactions.

Allylic hydroxycrotyl-oligoethylene glyco-n-alkanoyl (HYCRON)

linker 25 was applied to the synthesis of protected peptides and glycopeptides [31]. HYCRON is stable to both acidic and basic conditions and is

compatible with Boc- and Fmoc-based chemistry. The preparation of this

novel linker is only two steps from commercially available materials.

HYCRON linker can be cleaved under neutral conditions using Pd catalyst

(Scheme 9).



Scheme 7



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



Scheme 8



III. RESINS AND LINKERS FOR GENERATION

OF AMIDE FUNCTION

Functionalized supports with amino groups such as benzhydrylamine

(BHA) 26 [32] and 4-methylbenzhydrylamine (MBHA) 3 [3] provided Cterminal amides upon HF cleavage (Fig. 2). Polyalkoxyaminobenzyl and

alkoxydiphenylamino resins such as PAL (5-(4-aminomethyl-3,5-dime-



Scheme 9



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



Figure 8



thoxyphenoxy)valeric acid) 27 [33], Rink amide support (RAM) 28 [34]

and 4-(4V-methoxyvenzhydryl)phenoxyacetic acid (Dod) linker 29 [35]

contain more electron-donating groups and were designed on the same

principles as discussed above for the hydroxymethyl supports (Fig. 8).

These three linkers are the most widely used in SPOS and require TFA for

cleavage. Xanthone-based handles XAL (xanthenyl amide linder) 30 [36]

and Seiber 31 [37] resin were designed to release amides using low

concentrations of TFA (Fig. 9). Handles which contain an aminomethyl

and o-nitrobenzyl function (Nb [nitrobenzyl] 32 [38], NBHA [nitrobenzylamine] 33 [39], and a-methyl-6-nitroveratrylamine) 34 [40] are cleaved by

photolysis and are based upon the same principles discussed for hydroxyl

resins (Fig. 10).



Figure 9



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



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