Thermally cleavable safety-catch linkers for solid phase chemistry

Article abstract of DOI:10.1016/S0040-4039(00)00807-8

Safety-catch linkers based on the sulfoxide/selenoxide syn elimination have been developed. Clean and efficient oxidation of the sulfide to the sulfoxide was achieved with the homogeneous oxidising system comprising of hexafluoroisopropanol (HFIP) and hydrogen peroxide. Elimination of the sulfoxide was only possible with the most activated of substrates, while the selenoxide underwent cleavage under much milder conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00807-8

Tetrahedron Letters 41 (2000) 5287±5290
Thermally cleavable safety-catch linkers for solid
phase chemistry
Helen E. Russell,a Richard W. A. Lukeb and Mark Bradleya,*
aDepartment of Chemistry, University of Southampton, High®eld, Southampton SO17 1BJ, UK
bAstraZeneca Pharmaceuticals, Mereside, Alderley Park, Maccles®eld, Cheshire SK10 4TG UK
Received 5 April 2000; accepted 16 May 2000
Abstract
Safety-catch linkers based on the sulfoxide/selenoxide syn elimination have been developed. Clean and
ecient oxidation of the sul®de to the sulfoxide was achieved with the homogeneous oxidising system
comprising of hexa¯uoroisopropanol (HFIP) and hydrogen peroxide. Elimination of the sulfoxide was
only possible with the most activated of substrates, while the selenoxide underwent cleavage under much
milder conditions. # 2000 Elsevier Science Ltd. All rights reserved.
Solid phase synthesis usually requires the use of a linker1 to attach the compound of interest to
the solid support. This linker must be stable to the synthetic conditions used to prepare the target
compound but should be cleavable under relatively mild conditions at the end of the synthesis to
yield the target molecule. Safety-catch linkers2 6 require some pre-determined activation step
prior to ®nal compound cleavage. The advantage of this class of linkers is that the cleavage step
may be e€ected under very mild conditions, possibly with the product being cleaved directly into
an aqueous solution for immediate biological screening,7 9 while the ultimate cleavage process
does not have to be orthogonal to the preceding synthesis.
Here we describe the synthesis of linkers cleaved by sulfoxide and selenoxide pericyclic elim-
ination reactions10 (Scheme 1). We also describe a versatile, homogeneous solid phase oxidation
method for the selective oxidation of thioethers to sulfoxides. This follows initial reports by
Michels11 in 1976, who co-polymerised 4-styreneselenol with 1,4-divinylbenzene to generate
seleno-PS resin which was then used for the introduction of unsaturation into carbonyl com-
pounds. More recent reports by ourselves in the area of sulfoxide linkers12 and a variety of other
solid phase selenium based chemistries have also been published by a number of groups.13
The synthetic methodology was developed using t-butyl-p-bromomethylbenzoate (1), synthesised
in two steps from p-toluoyl chloride in 74% overall yield.14 This allowed preliminary studies to be
carried out in solution prior to resin attachment. Thus, bromide 1 was alkylated with thiourea or
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00807-8

5288
Scheme 1. (a) Thiourea or selenourea (1 equiv.), EtOH, 65ꢀC, quantitative; (b) 4% aq. NaOH, RBr (1.2 equiv.),
EtOH:water (1:1) or 20% aq. NaOH, TEBA; then 1.1 equiv. R-Br, 60ꢀC, 33±60%; (c) TFA, DCM (thio analogue),
HCO2H, (seleno analogue), 85±100%; (d) aminomethyl polystyrene resin, DIC, HOBt, DMF; (e) H2O2, HFIP, DCM
(2:1); (f) dioxane, re¯ux, (sulfoxide only)
selenourea in re¯uxing EtOH for 7 h, to give the isothiouronium/isoselenouronium salts (2a,b),
respectively, in quantitative yields. These salts were subsequently hydrolysed with 4% aq. NaOH,
then alkylated in situ to give the desired thio/seleno ethers 3a,b, ready for solid phase attachment
or solution chemistry. Oxidation of the thioether 4a to the sulfoxide 5a was achieved in very good
yield using an excess of H2O2 in 1,1,1,3,3,3-hexa¯uoroisopropanol/DCM (2:1) as previously
described.15
There was no evidence of over-oxidation to the sulfone (reactions on the solid phase were
monitored both by gel phase 13C NMR and analysis following cleavage of model compounds
attached to the solid phase via the Rink linker) thus allowing a very controlled solid phase
synthesis of the sulfoxides. The HFIP was not just acting as an acid catalyst since the addition
of other acids led to mixtures of both sulfones and sulfoxides and thus it may be that HFIP
co-ordinates the sulfoxide thereby preventing over-oxidation to the sulfone.15
Initially the indenones 8a,b were viewed as suitable synthetic targets, since the precursors 7a,b
were highly activated towards elimination (Scheme 2). Thus 6a,b were prepared from 2 and
2-bromo-2-methylindanone in yields of 27 and 22%, respectively, and coupled to aminomethyl
polystyrene resin (negative ninhydrin test). Compound 7a was thermally eliminated to give pre-
dominantly the exo-indenone 8a (the ratio of exo/endo indenones was 13:1 by reverse phase
Scheme 2. (a) DIC, HOBt, DMF; (b) 30% aq. H2O2, HFIP, DCM (2:1); (c) compound 7a: 100oC, dioxane; compound
7b, room temperature

5289
HPLC, Fig. 1) in excellent purity (>95% by HPLC) and in reasonable puri®ed yields (45% based on
initial resin loading). The identity of the indenones 8a,b were con®rmed by comparison with pre-
synthesised standards which were prepared according to literature methods.16,17 The dominance
of the exo isomer was surprising based on literature expectations.18
Figure 1. Crude RP-HPLC analysis of indenone elimination from 7a
Numerous other thioethers were prepared in an analogous manner. However upon oxidation
and thermolysis using a range of solvents (dioxane, toluene, N-methylformamide) no unsaturated
products were obtained. A typical example was 4-{[(3-phenylpropyl)sul®nyl]methyl}benzoate
which was re¯uxed in MeOH, dioxane or N-methylformamide (bp 199ꢀC), but in no case was the
desired elimination product obtained. Since Moghaddam19 had successfully obtained allylbenzene
in 30% yield using an analogous system and had increased the yield by the use of microwaves, a
purpose designed microwave reactor with a CO2 cooled condenser was used. Unfortunately, the
only product obtained in this reaction was the phenyl disul®de. It was clear that the sulfoxide
linkers could only be used for highly activated substrates and thus the analogous seleno-ether based
linker constructs were prepared. The selenium indanone conjugates were prepared in an identical
manner (Schemes 1 and 2), except for the use of formic acid to remove the tert-butyl ester from 3b
(TFA led to the reductive cleavage of the C±Se bond to give methylindanone). The indenones were
prepared in a straightforward manner (Scheme 2) following oxidation with hydrogen peroxide
and thermal elimination. The selenol was also alkylated with 3-bromopropanol, which was ester-
i®ed with Fmoc-Phe-OH to give 9 (Scheme 3). Oxidation and elimination gave the allyl ester
Fmoc-Phe-OAllyl 10 with a purity of 96% in 31% yield based on initial resin loading.
Scheme 3. NaIO4, dioxane:water (1:1), 0ꢀC, ®ltered, add dioxane, 18 h, 20ꢀC
An alternative method of direct attachment was also successful (Scheme 4). Thus aminomethyl
TentaGel resin was reacted with bromoacetic acid/DIC (25% BrC13H2CO2H was used for reaction
analysis by 13C NMR),20 the bromide was displaced with selenourea, the isoselenouronium salt
hydrolysed (NaOH) and the resulting selenol immediately alkylated. The use of 2-bromo-2-
methylindanone as the alkylating agent and oxidation (NaIO4) as previously described led to a
21:1 ratio of the exo:endo indenones in 32% isolated overall yield based on the starting loading of
the aminomethyl TentaGel resin.

5290
Scheme 4. (a) BrCH2CO2H, DIC, DCM; (b) selenourea, EtOH, 2% then 10% aq. NaOH; (c) 2-bromo-2-methylinda-
none, Cs2CO3, DMF
In summary, we have developed a series of linker constructs which can be cleaved by oxidation
followed by elimination. In the case of the sulfoxides this process requires an activated substrate
and relatively high temperatures, while in the case of selenoxides much reduced temperatures are
required and much less activated materials are required. One particularly useful new prospect is a
method of synthesising peptide allyl esters by solid phase synthesis.
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