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Fawcettimine-type Lycopodium alkaloids have attracted a vast attention of the researchers in both synthetic and medicinal chemistry discipline due to their captivating structures and vital pharmacological activities, such as acetylcholinesterase inhibition and neural cell protection. A wide variety of approaches have been developed toward their synthesis. This decade started with Yang et al. 201117 explanation of the endgame of 2010, Ramharter et al. used Heathcock-type 6-5-9 tricycle to fawcettimine. Initially, from cyclohexenone, tandem Sakurai reaction followed by oxidation with 2-iodoxybenzoic acid affords first intermediate, which was further alkylated to give second intermediate.18 Vinyl triflate formation of the less hindered carbonyl and elimination yields terminal alkyne. In next step, alkyne undergoes enyne RCM upon exposure to Grubbs second generation catalyst (Grubbs II) to give Heathcock-type 6-5-9 tricycle, which was Boc protected. Further, Yang et al. 2011 oxidised Heathcock-type 6-5-9 tricycle to its ketone derivative which was then cleaved to fawcettimine by the epimerization of the C4 stereo-centre to the thermodynamically favoured diastereomer (Figure 6).17
After this, in 2012, Pan and Williams started synthesis of Fawcettimine-type Lycopodium alkaloids fawcettimine, lycoflexine, and lycoposerramine B through efficient, unified, and stereo controlled strategy involving Diels-Alder reaction to construct the cis-fused 6,5-carbocycles with one all-carbon quaternary centre and Sharpless asymmetric dihydroxylation (Sharpless AD) of intermediate (Figure 7).19
In order to synthesize target alkaloid and also its biologically potent novel derivatives, new strategy has been established, involving proceeding through a common precursor. Huang et al. 2018 attempted the synthesis of common precursor, azaspirocycle for the further synthesis of fawcettimine alkaloids. They synthesised azaspirocycle via cascade Wacker-allylation sequence followed by a highly stereo-selective Claisen rearrangement (Figure 8).20
Synthesis of Lycopoclavamine-A, Fawcettimine-type alkaloid with a β-methyl group at C-15 and a trans-decahydroquinoline ring system at the A/D-ring junction, has been attempted by Zaimoku and Taniguchi in 2014, where they proceeded via Diels-Alder reaction.21 Recently, Kaneko et al. 2019 attempted successful asymmetric synthesis of Lycopoclavamine-A via stereoselective Pauson-Khand Reaction (PKR) and conjugate addition to construct a quaternary C-12. Reaction started with crotonamide, which in many steps including treatment with (S)-Corey-Bakshi-Shibata (CBS) reagent, formed bicyclic enedione. This was compound with Tert-Butyl Diphenyl Silyl (TBDPS) and methoxymethyl acetal (MOM) groups. Then, it was converted to tricyclic compound with only methoxymethyl acetal (MOM) group. Further, both MOM groups were removed and formed compound with two hydroxyl groups, which then converted to (Z)-enone via E1cB-like mechanism. Finally, it was converted to lycopoclavamine-A (Figure 9).22
Figure 1:
Carbon skeleton of Fawcettimine alkaloid exhibiting carbinolamine form (1a) and the keto-amine form (1b). Another analogue is fawcettidine (2).
Figure 2:
Recently isolated fawcettimine alkaloids (structures 3 to 18).
Figure 3:
Recently isolated fawcettimine alkaloids (structures 19 to 34).
Figure 4:
Recently isolated fawcettimine alkaloids (structures 35 to 41).
Figure 5:
Isolation of fawcettimine alkaloids from Lycopodiaceae/ Huperziaceae plant.
Figure 6:
Total synthesis of fawcettimine (Yang et al. 2011).
Figure 7:
Total synthesis of fawcettimine, lycoposerramine B and lycoflexine (Pan et al. 2012).
Figure 8:
Total synthesis of fawcettimine alkaloids via azaspirocycle (Huang et al. 2018).
Figure 9:
Total synthesis of Lycopoclavamine-A (Kaneko et al. 2019).
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