Aldrich ChemFiles 2007, 7.8, 3.

Aldrich ChemFiles 2007, 7.8, 3.

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 very 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

Scheme 1(658103)(675180)

4-(1-Pyrrolidino)benzaldehyde was recently 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).

Scheme 2(678821)

Figure 1

Professor Jørgensen’s group has recently 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

Scheme 3(683027)

Scheme 4(683027)

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  1. Ulmschneider, S. et al. J. Med. Chem. 2005, 48, 1563.
  2. Ding, Y. et al. Bioorg. Med. Chem. Lett. 2007, 17, 841.
  3. Brandau, S. et al. Angew. Chem. Int. Ed. 2006, 45, 4305.
  4. Wang, W. et al. J. Am. Chem. Soc. 2006, 128, 10354.

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