Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

Abstract

The 9-azabicyclo[3.3.1]nonane ring system is present in several insect- and plant-derived alkaloids. (−)-Adaline (1) and (+)-euphococcinine (2), found in secretions of Coccinelid beetles, and (+)-N-methyleuphococcinine (3), isolated from the Colorado blue spruce Picea pungens, are members of this alkaloid family. Their unique bicyclic system with a quaternary stereocenter, and the potent biological activity exerted by these homotropane alkaloids, make them attractive synthetic targets. This work aims briefly to review the chemical ecology of Adalia bipunctata and the recent methodologies to obtain adaline (1), euphococcinine (2), and N-methyleuphococcinine (3).

Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

“…Nitrogen-containing moieties are omnipresent in natural products, biologically active compounds and agricultural chemicals. In particular, the 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane skeletons constitute the core of many natural tropane 1 and homotropane alkaloids 2 , respectively, and analogues presenting a wide range of biological activities. For instance, tropinone, cocaine and scopolamine (Fig.…”

“…The 9-azabicyclo[3.3.1]nonane (homotropane) skeleton can be found in the structure of (–)-adaline, and (+)-euphococcinine (Fig. 1 ) 2 , two important defensive alkaloids from, respectively, the European ladybug Adalia bipunctata and the Australian ladybug Cryptolaemis montrouzieri . Moreover, N -arylated tropanes and related bicyclic aniline derivatives 3 represent a particularly attractive scaffold for medicinal chemistry as illustrated by ACP 105 4 , 5 , an orally available and potent selective androgen receptor modulator, and CFI-401870 6 , a single-digit nanomolar tyrosine threonine kinase (TTK) inhibitor (Fig.…”

Tropane and Related Alkaloid Skeletons via a Radical [3+3]-Annulation Process

“…[39][40][41][42][43][44] Secondly, in principle all three amines 1a, 2a and 3a present in solution can be easily oxidized by the Ir(III)* catalyst excited state. However, only RC1a and RC2a (calculated pKa 51.4 and 52.7 in DCE) are undergoing [1][2][3][4][5][6] deprotonation to generate α-aminoalkyl radicals. The deprotonation of the bicyclic radical RC3a (pKa 58.4) is much less favorable and no product resulting from the bicyclic radical R3a has been observed (Scheme 11B).…”

“…Unlike its natural enantiomer, unnatural (−)-ferruginine (Figure 1), is a good agonist for nicotinic acetylcholine receptor (nAchR). The 9-azabicyclo [3.3.1]nonane (homotropane) skeleton can be found in the structure of (-)adaline, and (+)-euphococcinine (Figure 1), 2 two important defensive alkaloids from, respectively, the European ladybug Adalia bipunctata and the Australian ladybug Cryptolaemis montrouzieri. Mannich reaction, 3,4 access to tropanes and related alkaloids has been the object of intense activity.…”

Four-Step Total Synthesis of (+)-Euphococcinine and (±)-Adaline

“…Several syntheses of ephococcinine were reported in the literature. 7 Most of the syntheses were based on the nitro cycloaddition reaction reported by Holmes et al, 8a while the biomimetic synthesis involving the intramolecular Mannich reaction of a suitably substituted piperidine is a practical approach. The Davis group 8b has elegantly applied this intramolecular Mannich reaction strategy for the synthesis of euphococcinine and adaline from N-sulfinyl amino ketone.…”