Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid

Abstract

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin-Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

Keywords: 5-Nor stemmadenine alkaloid; Antimalarial agent; Chirality transfer intramolecular Michael reaction; Diastereoselective 1,2-addition using indole nucleophile; Iminophosphorane mediated cascade reaction; Pseudo-aminal type structure.

Fig. 1

Therapeutic drugs for malaria

Fig. 2

Structure of (15S,16S)-16-hydroxy-16,22-dihydroapparicine (1)

Fig. 3

Structure of apparicine (2) and related compounds

Scheme 1

Biomimetic transformation

Scheme 2

Reported total synthesis of apparicine and conolidine

Scheme 3

Reported synthetic study of the 1-azabicyclo[4.2.2]decane skeleton

Fig. 4

Gramines (vinamidines) as versatile pseudo-aminal type compounds

Scheme 4

Designed novel phosphineimine-mediated cascade reaction

Scheme 5

Retrosynthetic analysis of key intermediate

Scheme 6

Synthesis of azidoaldehyde (23)

Scheme 7

Synthesis of proposed hydroxyapparicine (1)

Fig. 5

ROESY observations of synthetic (±)-(15S*,16S*)-1

Scheme 8

Total synthesis of (±)-(15S*,16R*)-1

Fig. 6

NOE observations of synthetic (+)-(15S*,16R*)-1

Scheme 9

Stepwise synthesis of (±)-(15S*,16R*)-1

Scheme 10

Asymmetric synthetic plan of (15S,16R)-1

Scheme 11

Asymmetric synthesis of methylketone (+)-30

Scheme 12

End game of the total synthesis of (+)-(15S, 16R)-1