Qo

2) MeONa, MeOH, rt, 18 h C02Me 3) CH2N2, Et20, rt, 0.5 h

CQ2Me

C02Me

2) MeONa, MeOH, rt, 18 h C02Me 3) CH2N2, Et20, rt, 0.5 h

CQ2Me

C02Me

C02Me C02Me

C02Me C02Me

Scheme 4.10. Synthesis of macrocycles by Soucy et al. [121].

Arylhydrazides can serve as safety-catch linkers for C-terminal carboxylic acid, amide, or ester functionalities. The cleavage proceeds via an oxidation with copper(II) and subsequent cleavage of the diazenyl moiety by means of a nucleo-phile (Scheme 4.11) [119].

1) solid phase Fmoc peptide synthesis q

Nu Peptide

TentaGel X = NH,0

Scheme 4.11. Detachment of peptides from hydrazide resins by Millington et al. [119].

Silyl Linkers

The electronic and steric properties of silicon compounds have been used in many applications for the design and use of new linker types (Table 4.6). The different applications can be divided as follows:

1 Direct attachment of building blocks on silylated resins: linker for alcohols [19, 20], traceless linkers for arenes (Sect. 4.5.5).

2 Use of the b-silicon effect for elimination reactions: e.g. the SEM (2-trimethylsi-lylethoxymethyl) linker [21].

3 Silylated benzhydryl linkers: [69, 122].

74 | 4 Linkers for Solid-phase Synthesis Tab. 4.6. Overview of silyl linkers.

Structure

Reference Possible structures achievable

[123] Alcohols; cleavage with

(Tetrabutylammonium fluoride) TBAF [21] Alcohols

[124] Traceless linking of arenes

XSiWH' Br 95

[125] Traceless linking of arenes

[126] Traceless linking of arenes

[127-129] Traceless linking of arenes;

cleavage with fluoride f.NHR

f.NHR

SAL linker (20)

[55] Amides; cleavage with 90% TFA, scavenger o^if T 1

SAC linker (21)

SiMe3

BHA or methyl polystyrene

Pbs linker ("silico Wang linker") (98)

[122] Carboxylic acids; cleavage with

TBAF

BHA or methyl polystyrene

Ramage linker (15)

O SiMe3

Ramage linker (15)

O SiMe3

SiMe3 SEM linker (99)

[52, 53] Carboxylic acids; cleavage with TBAF

[21] Alcohols; cleavage with TBAF

SiMe3 32

SiMe3 32

[67, 69] Estes; cleavage with TBAF or Cs2CO3 [69]

The robustness of silicon linkers against basic and organometallic reagents makes them especially suitable for solid-phase organic synthesis. Cleavage can be affected by electrophiles such as protons (trifluoroacetic acid; TFA). A special feature of silyl linkers is their sensitivity to fluoride ions, which makes them ideally orthogonal (Sect. 4.3.8) to various other functionalities present in the molecule. The fine-tuning of electronic and steric properties is possible by using different substituents on the silicon atom (trimethylsilyl vs. tert-butyldimethylsilyl).

The first traceless linkers (Sect. 4.5.5) for arenes were described independently by Ellman and coworkers [125, 130] and Chenera et al. [124] (see Scheme 4.60) in the 1990s using silyl linkers. This linker type was used in Ellman's synthesis of a benzodiazepine library, which is a milestone in the solid-phase synthesis of small organic molecules (Scheme 4.12). The synthesis of the linker involves a lithiumhalogen exchange and, after chlorosilane attachment, coupling with an aryl halide. As the silyl arene might be cleaved in the unwanted direction to give silylated arenes, further improvement led to the development of a germanium linker [131], which gives rise to the formation of pure material (Sect. 4.5.5, see Scheme 4.61). In addition, cleavage of these linkers can be accomplished by electrophiles other than protons to yield halogenated residues, thus rendering this linker into a multiple cleavage linker system [see 379] (Sect. 4.5.6). The range of electrophiles is limited, since only small, reactive electrophiles (e.g. iodine, bromine, and chlorine) react to give the desired products.

Me Me

NHPg SnMe3

Me Me

R1 R1

100 101 102

Scheme 4.12. Synthesis of a benzodiazepine library using silyl linker [131].

The silicon-based linkers, which are commercially available [132], were developed further by several groups [133] and have been used in the synthesis of various systems for the traceless detachment ofvarious arenes and heteroarenes [126128, 133-143]. They are also suitable as traceless linkers for allyl silanes to give alkenes [144] (Sect. 4.5.5).

A recent traceless application was demonstrated in the synthesis of chrome-nones (104) [145]. In this case, a mild cyclization method was used to circumvent a premature cleavage for the support (Scheme 4.13). Similarly, heteroarenes are also accessible [128] (Scheme 4.14).

Other linkers having silyl fragments are the silyl acid linker (SAC linker 21) [56], the silyl amide linker (SAL linker 20) [55], the Pbs linker (''silico Wang linker'') (98) [122], the Ramage silyl linker (15) [52], the SEM linker (99) [21], and silylated benzhydryl linkers (32) [69].

Was this article helpful?

0 0

Post a comment