A number of syntheses targeting commercially available drugs have been reported, which demonstrate the utility and effectiveness of supported reagents for the rapid and efficient preparation of drug-like scaffolds. The introduction of Sildenafil45 4 for the treatment of male erectile dysfunction has been incredibly successful, resulting in it becoming one of the largest selling globally marketed prescription drugs.46 Sildenafil acts by inhibiting the phosphodiesterase enzyme PDE5, which is the main phosphodiesterase present in the smooth muscle of the corpus cavernosum. Upon sexual stimulus, nitric oxide is released from nerve terminals in the corpus cavernosum. The nitric oxide activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), causing the intracellular levels of cGMP within the smooth muscle cells of the penis to increase. In healthy tissue, the elevated cGMP is returned to basal levels by the action of the PDE5 enzyme. Inhibition of the PDE5 enzyme prevents the breakdown of cGMP and thus potentiates the smooth muscle relaxation. This increases the blood flow in the cavernosum causing an erection.47
The polymer-assisted synthesis48 to Sildenafil (Scheme 2) follows a precedented route,45,49 which concludes with the convergent coupling of the two key fragments 5 and 6. These fragments were prepared using PASP techniques, without the need for column chromatography, the former in a two-step sequence and the latter utilising seven different transformations. Fragment 5 was found to be contaminated with approximately 10% of the to-esterified material 7, which could be removed in the subsequent catch-and-release step. Notably by using a catch-and-release strategy in the penultimate amide-coupling step, this transformation acts as an in-line purification step while concomitantly activating the acid group to nucleophilic attack. Introduction of 6, followed by scavenging with isocyanate resin to remove any unre-acted amine, cleanly yielded the amide. Assembly of the pyrimidine ring system is performed using microwave heating to effect the rapid dehydration of 8. A simple removal of the water formed during the cyclisation step was achieved with MgSO4
Scheme 2 Reagents and conditions: (a) PyBrOP, DMF; (b) (i) 6, THF, (ii) THF; (c) EtOH/NaOEt, MW10 min, 120 °C
and the subsequent evaporation of the solvent gave a quantitative yield of Sildenafil 4. This convergent synthetic pathway is clearly amenable to library production.
Rosiglitazone 9, an agonist of peroxisome proliferator activated receptor-y (PPARy), is a recently introduced antihyperglycemic thiazolidinedione effective in the treatment of noninsulin dependant diabetes mellitus (type II diabetes).50 A seven-step synthesis was developed (Scheme 3), which utilised supported reagents in combination with in-line SPE purifications.51 The introduction of the pyridine moiety provided a convenient molecular handle by which to purify the molecule throughout the synthesis. Notably, the overall yield (46%) for this synthesis was higher than the yield reported in the initial shorter solution-phase synthesis (31%).52
The synthesis of chiral drug molecules has only recently been reported using a supported reagent approach. Although many supported reagents systems have been reported for use in enantioselective reactions, the paucity of the enantioselectivity achieved has prevented their extensive application in synthesis. A single isomer of the drug Salmeterol53,54 10, a potent and long-acting P2 adrenoceptor agonist,55 has been prepared via a chiral auxiliary approach (Scheme 4). The key chiral reduction of
Scheme 3 Reagents and conditions: (a) ethyl iodoacetate, DMF, rt, 93% (or ethyl iodoacetate, K2CO3, DMF, 90 °C, 96%); (b) MeNH2, THF, 100%; (c) (i) BH3:THF, 65 °C, (ii) Et-NH, (iii) SCX-2, 84% overall; (d) 2-fluoropyridine, 120 °C, 82%; (e) THF, D, 86%; (f) (i) 2,4-thiazolidinedione, PhMe, 88 °C, (ii) SCX-2, 99%; (g) H2, 1,4-diox-ane, 80 °C, 82%
ketone 11 to alcohol 12 is dependent upon the introduction of the (S)-phenylglycinol functionality. Treatment of 11 with calcium chloride at 0 °C followed by the addition of PS-borohydride resin delivered the desired amino alcohol 12 as a 10:1 mixture of diastereoisomers favouring the desired (^)-alcohol. A single recrystallisation afforded diastereomerically pure material. It is hypothesised on the basis of 1H NMR shift studies that the reduction proceeds via a chelated intermediate 13 where the phenyl substituent points away from the crowded centre. The approach of the reducing agent then occurs preferentially from the convex face of the complex. From here, introduction of the long liphophilic chain and selective removal of the chiral auxiliary and ace-tonide-protecting group affords (^)-Salmeterol 10 in >97% ee.
Attack from top face hindered
Attack from top face hindered
Phenyl points away from crowded centre
Scheme 4 Reagents and conditions: (a) Me2NCH2I, CH2Cl2; (b) Ac2O, toluene, 80 °C; (c) CH2Cl2; (d) 1N HBr. THF 1:1, 75 °C; (e) CH2Cl2, CH3CH(CH2)OCH3; (f) THF, NH2CH(Ph)CH2OH; (g) (i) CaCl2, MeOH; (ii2 MeOH; (h) (i) Ph(CH2)4O(CH2)5 CHO, 5% AcOH, CH2Cl2; (ii) CH2Cl2; (i) (i) Pd(OH)2, H2, EtOAc; (ii) SCX-2
Was this article helpful?