Solid-Phase Synthesis and Combinatorial Technologies

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 113

Exploitation of the SP route: The SP endocyclization of β-ketoesters 3.43a–f was abandoned due to results in solution. Six condensation products 3.60–3.65 were obtained from the reaction of β-ketoesters 3.30, 3.40a, 3.41a, 3.41c, 3.42a and 3.42b with bromide 3.37 with similar yields and purities than their solution counterparts (Fig. 3.23); the same experimental protocol seen for 3.38 (Fig. 3.21) was applied.

Selenium linkers provide multiple cleavage options: oxidation/elimination released the alkene 3.39 (Fig. 3.21), but radical reactions could either lead to a traceless cleavage (hydride transfer) or to the allylation of the released molecule. These cleavage protocols were validated using 3.60 and 3.64 as substrates (Fig. 3.24). Both the multiple cleavage options and the loading of decorated β-ketoester on SP could lead to diverse sets of bicyclo[3.3.1]nonan-9-ones. Post-loading transformations of the tricycle prior to the cleavage should significantly extend the scope of this SP approach.

Figure 3.23.

3.5 SOLID-PHASE SYNTHETIC STRATEGIES: SELECTED EXAMPLES 115

•The structure of 3.68 looks suited for the introduction of decorating functions in various positions to create a combinatorial library based on a natural rigid scaffold;

•The full combinatorial exploitation of 3.68 requires an assessed SP synthetic method to build the indolactam scaffold and to generate an SP library.

Target selection and synthetic strategy in solution: Several scaffold substitutions and a free primary hydroxyl as in 3.68 have potentially positive effects on biological activity. The target structure for the project was thus drawn as in Fig. 3.26 (3.69, compare with 3.68); the key synthons to 3.68 and to 3.69 are also reported (3.70–3.73, Fig. 3.26). As the solution synthesis of 3.68 was already known, its validation was not considered necessary.

SP synthetic strategy to 3.68: The advanced chiral intermediate 3.74 (Fig. 3.27), obtained with good yields and purities in solution, was selected to be anchored via a suitable linker onto SP. The primary OH function was ideal for SP anchorage, using the support as a protecting group during SP synthesis, and for the final release of the free primary alcohol 3.68. The planned SP decoration route (Fig. 3.27) was compatible with PS supports that were thus chosen. The risk of racemization for the chiral scaffold

Figure 3.26.

116 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

O

3.78

THP linker

n-Pr

Figure 3.27.

in basic conditions and the planned SP protocols selected the acid-labile tetrahydropyranyl (THP) linker (27), whose general stability and sensitivity to mild acidic conditions appeared appropriate. The use of protecting groups was not required by the designed strategy. Reductive amination of the secondary aromatic amine in 3.75 with formaldehyde/borohydride was expected to give 3.76 (resin-bound 3.68). 7-function- alization of supported indolactam 3.76 with alkynyl substituents was conceived by electrophilic iodination (3.77) and Sonogashira coupling with a terminal alkyne to give 3.78 (Fig. 3.26); this must be considered an SP representative example extendable to other metal-catalyzed C-C couplings (e.g. Suzuki, Heck, Stille).

SP chemistry assessment: The chiral intermediate 3.74 was prepared in solution with a 13-step revised strategy from protected amine 3.79 (25) (Fig. 3.28); its coupling with PS-supported THP linker gave poor loading results for unknown reasons. The problem was solved by coupling 3.74 in solution with the protected DHP derivative 3.80, then supporting 3.81 onto Merrifield resin to give 3.75 (73% yield of recovered alcohol after cleavage). Both reductive amination to 3.76 and iodination/coupling to 3.78

Figure 3.29.

• Sonogashira coupling of 3.77-like with alkynes M3.

A limited number of commercial M1–M3 representatives were reacted with the appropriate precursors and produced moderate to good yields of analogues after cleavage (Fig. 3.30). Several general comments are worth mentioning:

1.The SP route is of general use, although only similar R1–R3 groups were used in the exploitation; consequently, the use of more diverse monomers (e.g., orthogonally protected bifunctional reagents) should be recommended;

2.A large number of indolactam analogues should be achievable using commercially available M1–M3 monomers;

3.Additional derivatizations tolerated by known SAR could be conceived (e.g., N-indole derivatization), and an appropriate SP scheme designed.

3.5.4 SPS of Hexahydro-2,3a,7-Triazacyclopenta[c]Pentalene-1,3-Diones (28).

Rationale of the project:

•Pharmaceutical research craves for novel rigid polyfunctionalized scaffolds with drug-like properties exploitable via library synthesis;

O

TfO

R1 = Me (2, 43-47%); i-Pr (1, 20%); Bn (28, 11-65%)

O M1

R2 = Me (1, 20%); i-Pr (2, 43-47%); n-Bu (7, 15-53%); cyclopropyl (6, 13-52%);

H O

R2

M2

R3 = n-Pr (3, 20-43%); t-Bu (3, 15-21%); Ph (5, 11-50%); Bn (5, 10-20%);

R3

Figure 3.30.

•Among these, polyazaheterocycles are particularly appreciated, as they often recur in pharmacologically active synthetic drugs and natural products;

•Hexahydro-2,3a,7-triazacyclopenta[c]pentalene-1,3-diones such as 3.83 (Fig. 3.31) satisfy the above requirements and a reasonable synthetic scheme can be derived from previous reports (29);

•The full combinatorial exploitation of 3.83-like scaffolds requires an assessed SP synthetic method to build the tricyclic scaffold and to generate an SP library;

O

3.83

Figure 3.31.

120SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

•The cyclative cleavage approach can be applied building the hydantoin ring and simultaneously releasing in solution the pure tricycle at the end of the SPS.

Target selection and synthetic strategy in solution: The retrosynthetic study to 3.83

(Fig. 3.32) identified compounds 3.84–3.88 as the precursors to the desired nucleus; the aim of this project being the full combinatorial exploitation of a novel scaffold, an assessed SP protocol to general structures 3.89 was necessary. The synthesis in solution of related compounds (3.90a,b, Fig. 3.33; compare with 3.89, Fig. 3.32) being known (29), its adjustment to lead to 3.83 was deemed straightforward; for this reason the authors moved directly to SPS.

SP synthetic strategy to 3.83: The designed synthesis included as a final step the formation of an urea on 3.89 with simultaneous intramolecular cyclization on the carboxylic ester (Fig. 3.34); the use of an ester function to support the 3.89-like intermediate would have allowed the cyclative cleavage of the desired hexahydro- 2,3a,7-triazacyclopenta[c]pentalene-1,3-dione. The use of classical PS resins was not prevented by any of the transformations needed to give 3.83.

The cyclative cleavage determined the SP synthetic scheme (Fig. 3.35) which supported commercially available 3.84 on hydroxymethyl PS resin, built the appropriate resin-bound cycloaddition substrate 3.93 via orthogonal N-deprotection and functionalization and led to the bicycle 3.94; this was to be coupled with 3.87, deprotected and decorated with 3.88, and cyclatively cleaved to 3.83 (Fig. 3.35). The choice of the two N-protecting groups is crucial for the success of the SP scheme: the α-N-Boc on 3.84 was considered acceptable, being early removed in the SPS, but the β-N-Fmoc

R3 O

N

O N R2

R

4 X N

R1

3.83R1 = Et, R2 = p-CF3OPh, R3 = o-FBenzyl, R4 = PhNH; X = CO

3.89R1-R4 = substituted alkyls and/or aryls

Figure 3.32.

W

3.90b minor

Figure 3.33.

protection was likely to be sensitive during the SP scheme and its replacement with an acid-stable sulfonamide group was planned (Fig. 3.35). The use of a cyclative cleavage approach should have provided pure final compounds, with all the side products still anchored onto SP.

SP chemistry assessment: The designed SP route was successfully validated, using standard reaction conditions, until the formation of the cycloaddition substrate 3.93; the experimental conditions reported in Fig. 3.36 do not deserve further comments. The cycloaddition to 3.94 was thoroughly studied using a variety of Lewis acids/tertiary bases, and the best results were obtained using 10 eqs. of zinc acetate/DBU in dry acetonitrile. The yield and purity of the 3.84–3.94 conversion was unequivocably determined by cleavage of the ester and release in solution of 3.97 which was isolated in an excellent 56% yield (seven steps plus the cleavage). An unexpected advantage of the SP cycloaddition was represented by its complete regioselectivity in contrast with the results obtained with similar reactions in solution (see 3.90a,b, Fig. 3.33).

The formation of 3.95 proved to be challenging, and even an extensive assessment with various experimental protocols could not optimize the coupling of isocyanate 3.87 to an acceptable level; a clever solution was found by first coupling the hindered nitrogen of 3.94 with highly reactive and small phosgene, then coupling the imidoyl chloride 3.98 with the primary amine 3.99 (Fig. 3.37). The obtained urea 3.95 reentered the original SP scheme that led with no major problems to the final SP intermediate 3.96 (Fig. 3.37).

Figure 3.34.

122 SOLID-PHASE SYNTHESIS: SMALL ORGANIC MOLECULES

Figure 3.35.