Solid-Phase Synthesis and Combinatorial Technologies

Figure 3.36.

The formation of 3.83 was highly sensitive to experimental conditions, and the use of previously reported protocols for SP intramolecular cyclizations to hydantoins failed. The most abundant isolated side-product was the acid urea 3.100, derived from basic hydrolysis of the ester function; this finding led to the successful validation of an anhydrous cyclative cleavage protocol using five equivalents of potassium t-butox- ide in anhydrous THF at RT under an Ar atmosphere for 1 hr (Fig. 3.38). Compound 3.83 was isolated in a satisfactory overall 20% yield (12 steps).

Exploitation of the SP route: Four steps were identified to build a combinatorial SP route to 3.83-inspired libraries (Fig. 3.39):

•Coupling of 3.91 with various allyl alcohols M1;

•Reductive amination of deprotected 3.92-like with aldehydes M2;

•Reaction of 3.98-like with primary amines M3;

•Acylation or reductive amination of deprotected 3.95-like with acylating agents M4 or aldehydes M5.

A set of fully characterized representative compounds was reported (see for example structures 3.101–3.106, Fig. 3.40); the synthesis of >1000-member libraries was

O N

NH 3.100

Figure 3.38.

3.5.5 SPS of Prostaglandin E1 (PGE1) analogues (30).

Rationale of the project:

•Prostaglandins are an under-exploited, well known class of biologically active compounds for many clinical applications;

•Rationally designed prostaglandin analogues can be tailored towards specific receptors; an example is 3.107 (Fig. 3.41), a potential binder to prostaglandin EP3 receptor inspired by the structures of known EP3 binders PGE1 (3.108), PGE1 methyl ester (3.109) and sulprostone (3.110);

•The rigid, substituent-orienting prostaglandin core is an ideal scaffold for combinatorial library generation;

•An assessed protocol amenable to high throughput synthesis of prostaglandins does not exist;

•The full combinatorial exploitation of 3.107 requires a solid, assessed SP synthetic method to build the prostaglanding scaffold and to generate an SP library;

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 127

Figure 3.40.

• This method should then be adjustable for SPS of other tailored prostaglandins.

Target selection and synthetic strategy in solution: Compound 3.107 represents an example of EP3-targeted prostaglandins to be tested on in vitro assays; other compounds were similarly designed based on 3.108 and 3.109 (vide infra). The main structural drivers of the project were the replacement of the carboxylic function of 3.108 to increase bioavailability and affinity compared to the ester 3.109, and to use decorating side-chains either identical or inspired by EP3-active known compounds; thus, general structure 3.111 can be seen as the project target. Retrosynthesis from 3.107 selected the easily accessible key intermediates 3.112–3.116 (Fig. 3.42); the extensive knowledge about prostaglandin synthesis in solution and previous SP assessments for similar compounds (31) prompted the authors to move directly to SPS.

SP synthetic strategy to 3.107: The designed SP synthetic scheme (Fig. 3.43) supported the intermediate 3.112 via its free hydroxyl function, built the precursor of the

128 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

O

O

N

H

O

HO

3.107 OH

O

O

3.108 R = H

3.109 R = Me

Figure 3.41.

first chain through Suzuki coupling with 3.114 (3.118) and then built the second chain through 1,4 conjugate addition of 3.116 on an α,β-unsaturated system obtained after hydroxyl deprotection and oxidation (3.119). Conversion of the N-acylsulfonamido group to the desired carboxamide as in 3.107 was planned through N-cyanomethyla- tion (as for safety-catch linkers, Section 1.2.5) and substitution with amine 3.115 to give the resin-bound prostaglandin 3.121.

Supporting the hydroxyl function of 3.112 solved the issue of protecting this group during the synthesis; protecting groups other than TMTt (vide infra) were not necessary. This scheme did not prevent the use of PS resins, while a careful evaluation of available linkers was requested: stability to basic, nucleophilic and mild acidic conditions was requested, as was a clean cleavage protocol to recover pure materials with no contamination from cleavage reagents. Commercially available, fluoride-labile polystyrene diethyl silyl resin (PS-DES) (32) theoretically satisfies the above requisites, and was selected by the authors. The mild acidic cleavage requested by TMTt should have caused only a negligible loss of loading, while the most common dimethoxytrityl (DMTt) protection would have significantly affected the SPS performance.

SP chemistry assessment: Compound 3.112 was supported onto PS-DES using standard conditions which proceed through chlorination of the resin and in situ reaction with 3.112; moisture was excluded from the reaction mixture and a good loading was obtained (>75%, Fig. 3.44). Suzuki coupling to give 3.118 employed standard conditions; terminal alkene 3.114 was converted in situ to the alkyl 9-BBN reagent (step c).

Na+ O

Figure 3.42.

TMTt deprotection was performed in extremely careful conditions (1 min stirring at rt, five cycles, extensive washing) to avoid the cleavage of the DES linker; oxidation with Dess-Martin reagent was performed successfully to give 3.123 (Fig. 3.44).

The 1,4 conjugate addition resulted extremely sensitive to experimental conditions. The detailed procedure reported in Fig. 3.45 gave good overall yields, and represented the best compromise among low temperatures (lower amounts of released material from the support, higher stereocontrol, but negligible resin swelling and reaction rates) and high temperatures and extended reaction times (good swelling and reaction rates, but loss of material and formation of other stereoisomers). Thiophene as an auxiliary

132 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

3.115

O HO

3.107OH

Figure 3.46.

Exploitation of the SP route: The focused nature of this library restricted the modifications to the assessed SP route to two functionalities of 3.107 (Fig. 3.47):

•R2 was imposed as A (as for 3.107) or B by addition of the respective cuprates (see the project rationale);

•Compound 3.117 was reacted with 3.114, then transformed on SP as seen for 3.107 and diversified with amines R3R4NH to give 3.125 (twenty amides, route a);

•Alternatively, compound 3.117 was reacted with terminal alkenes 3.113 to provide compounds 3.127 (six representatives, route b).

The 26 fully characterized representatives were obtained in moderate to good yields. Several general comments are worth mentioning:

1.The focused set of substituents was perfectly suited for the selected and assessed SP route;