Aldehydes as Building Blocks

Hartmann and co-workers have described the synthesis of a series of potent and selective inhibitors of aldosterone synthase (CYP11B2), in which the key synthetic step was a Wittig reaction using various heterocyclic aldehydes (Scheme 1). The isoquinoline adduct was a potent and selective inhibitor of CYP11B2. The successful inhibition of CYP11B2 has been proposed as a strategy for treatment of congestive heart failure and myocardial fibrosis.¹

4-(1-Pyrrolidino)benzaldehyde was reported as a key building block in the synthesis of an improved inhibitor of NS5B polymerase of the hepatitis C virus (Scheme 2).² The product from this substrate displayed significant improvement in the potency of the original HTS lead compound (Figure 1).

Professor Jørgensen’s group reported an asymmetric formal synthesis of (–)-paroxetine, a selective serotonin reuptake inhibitor used in the treatment of anxiety and other psychological disorders.³ The key step involved the organocatalytic conjugate addition of dibenzyl malonate to trans-4-fluorocinnamaldehyde (Scheme 3). Similarly, Wang’s research group has used the Jørgensen organocatalyst in a tandem Michael-aldol reaction to furnish chiral thiochromenes in excellent yields (Scheme 4).⁴