Strategies for the Total Synthesis of Clavicipitic Acid

Abstract

Clavicipitic acid is an ergot alkaloid, which was isolated from Claviceps strain and Claviceps fusiformis. Its unique tricyclic azepinoindole skeleton has attracted synthetic chemists, and various strategies have been developed for its total synthesis. These strategies can be generally categorized into two types based on the synthetic intermediates, namely, 4-substituted gramine derivatives and 4-substituted tryptophan derivatives. This Minireview summarizes the reported total syntheses from the point of these two key intermediates.

Regioselective Direct C‐Alkenylation of Indoles

“…Activation of the four different positions in the benzene ring of indoles is only known through the presence of a close directing group or exploiting intramolecular reactions . The insertion of alkenyl moieties at C‐4 is particularly important for the preparation of central intermediates for the synthesis of biologically active compounds such as clavicipitic acid . Depending on the nature of the group present at C‐3, a suitable N‐protection with a sterically hindered group which shields the C‐2 position may be advisable.…”

“…[66] The insertion of alkenyl moieties at C-4 is particularly important for the preparation of centrali ntermediates for the synthesis of biologicallya ctive compounds such as clavicipitic acid. [67] Depending on the nature of the group present at C-3, as uitable Nprotection with as terically hindered group which shields the C-2 positionm ay be advisable.F or the FM 4-alkenylation of varioust ryptophan derivatives, the N-TIPS protection has been revealed as particularly effective (Scheme 24). [68] The obtained results are satisfactory with mosto ft he electron-pooro lefins tested and with styrene.…”

Total synthesis, biosynthesis and biological profiles of clavine alkaloids

“…38 This section will briefly highlight two distinct approaches to synthesize enantiomerically pure clavicipitic acid ( 1 ), which has recently been the subject of a comprehensive review. 39 As with aurantioclavine, a central challenge for any synthesis of clavicipitic acid is the formation of the seven-membered ring, and this is reflected in the focus on strategies for the diastereoselective annulation of the azepine.…”

Concise Syntheses of Hyrtioreticulins C and D via a C-4 Pictet–Spengler Reaction: Revised Signs of Specific Rotations

“…Changing Et 3 N to DIEA resulted in an increase in diastereoselectivity (entries 9 and 10, up to 15:1). Our methodology could afford rapid access to azepinoindoles in contrast to the previous approaches …”