Download (direct link):
2.4.6. Prostaglandin Synthesis
Ellman utilized the Suzuki coupling twice between a support-bound vinyl bromide and an alkyl 9-BBN derivative in a solid-phase synthesis of E- and F-series prostaglandins.91 The Suzuki reaction was performed in situ, with the hydroboration of a terminal olefin being followed by the palladium-mediated step. This sequence is attractive in library synthesis because of the wide range of suitable commercially available alkenes. The inspiration behind this chemistry was the solution-phase work of Johnson and Braun,92 where the couplings of 35 with 2-iodo-4-(silyloxy)cyclopent-2-enone 36 went well at room temperature with PdCl2(dppf)-AsPh3 as catalyst (Scheme 41). The modular chemistry demonstrated in this paper was clearly amenable to adaptation to a solid-phase strategy.
When this approach was used on solid support (Scheme 42), the (3-alkoxy ketones resulting from the coupling did not stand up well to the basic, and forcing, conditions required for complete Suzuki coupling. Hence an alternative was investigated in which the supported bromocyclopentenol 37 was coupled with the borane to generate the alkylated derivative 38, which was then functionalized at the other alkene carbon en route to the series 1 prostaglandins (i.e., with one double bond in the side chain). In a similar way, another core structure 39 was used to generate series 2 prostaglandins. In this route, one cis double bond was introduced at an early stage, and this
62 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT OH
A*r R1-9-BBN \Jjf cat. Pd(PPh3)4
Q Na2C03, THF, 65 °Ñ
/\x\ ^Br R3-9-BBN
Na2C03, THF, 65 °Ñ °N
X,Y = Î or X = H, Y = OH
was then coupled with alkyl 9-BBN derivatives. Refluxing THF was used for both couplings. No yields are given for the coupling steps, but overall yields for the prostaglandin syntheses range from 49 to 60%, implying that every step was quite efficient. This synthetic scheme illustrated that relatively complex synthetic strategies can be performed reliably on solid supports.
2.4.7. Reissert-Based Synthesis
A solid-phase Suzuki reaction has been described by Kurth et al. in their syntheses of novel isoxazolinoisoquinoline heterocycles via a traceless strategy (Scheme 43).93 The Suzuki coupling was used as an efficient means to introduce extra diversity into the pharmacophore, and a Reissert-based
2.4. SUZUKI REACTION 63
RB(OH)2, Pd(PPh3)4 DME, Na2C03(aq) -------------->80 °Ñ, 36 h
strategy was used as a resin-capture method for the immobilization of the isoquinoline in the first step of this synthesis. Surprisingly, solution-based Suzuki chemistry was ineffective for coupling boronic acids to 4-bromoi-soquinoline (perhaps due to the electron-rich nature of this bromo-enamide), but the sequence shown in Scheme 43 produced the desired product in an average yield of 66% per step. The overall yield for the sequence was reported to be significantly lower than from a direct solution-phase Suzuki reaction of 6-bromo-5,8-dimethylisoquinoline. However, the compounds released after the Reissert hydrolysis did not seem to require further purification. In solid-phase syntheses, purity is often more important than yield, especially if the objective is to prepare libraries for biological screens, so the latter result is satisfying in this respect.
2.4.8. Microwave Chemistry
Fluorous phase modifications of the Stille reaction were shown by Curran et al. to be accelerated by microwave irradiation.10 Similarly, Hallberg et al. demonstrated that such irradiation gives remarkably fast solid-phase Suzuki reactions, in the generation of biaryl units.9 Their reaction involved the coupling of a tethered (Rink amide TentaGel) aryl iodide or bromide with several boronic acids under 45 W of irradiation at 2450 MHz in sealed
64 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
vessels (Scheme 44). The reactions typically gave excellent yields (-95%) in 3.8 min. Little reactivity difference was observed between the aryl iodides and bromides, in contrast to the solution-phase reactions where the rate differences for these two substrates are significant. A simple Stille coupling with tributylphenyl tin was also reported to give 85% yield of product, with no apparent butyl transfer. Minimal decomposition of the resin polyethylene glycol was observed as a result of the microwave irradiation. The reactions could conveniently be performed on a very small scale in sealed Pyrex tubes, and a KCN-DMSO wash was used to remove precipitated palladium black.