An overview on Aspidospermidine:

Figure 1: (+)-aspidospermidine

Aspidospermidine, a dream molecule for many of the synthetic organic chemists is a complex naturally occurring a molecule that belongs to the Aspidosperma family. It was first isolated from the plant Plameria rubra.¹ 

Plameria rubra

Aspidospermidine constitutes one structurally a unique class having pentacyclic {[6.5.6.6.5] ABCDE ring system} frameworks with contiguous cis-stereocenters at C-7, C-21, and C-20 (all-carbon quaternary) as a common structural feature.

Synthetic Wheel

In 1991 Kunesch and co-workers have shown that the treatment of vinylogous amide 2 with n-BuLi and p-TsCl resulted in the formation of the N-tosyl derivative 3 in 92% yield. Exposure of the former to potassium hydride and lithium iodide and subsequently to ethyl iodide gave in 52% of compound 4. And after the treatment of LAH, they have achieved aspidospermidine.

Scheme 1: Kunesch and co-workers (1991)

Mild acid hydrolysis of enol ether led to the recovery (89%) of Penta-cycle 3. Exhaustive reduction of the dicarbonyl compound 4 with LiAlH₄ produced the diamine (65%) and alcohol (20%). Platinum-assisted hydrogenation of the highly resistant double bond of olefin furnished (±) aspidospermidine with 82% yield.

Rubiralta and co-workers in 1996 have shown a fascinating synthetic approach towards aspidospermidine to show the synthetic application of 2-(1,3-dithian-2-yl)indoles. 

Scheme 2: Rubiralta and co-workers(1996)

A tandem conjugate addition-alkylation reaction starting from indolyldithiane, 3-methylene lactam and EtI followed by treatment of DIBAL-H forms the required tetracyclic core. After that debenzylation of compound 5 with Me₂S and BF₃.Et₂O and obtained amino alcohol. After some synthetic manipulation, they have achieved (±)-aspidospermidine.

In 1997 Schultz and co-workers have shown the elegant approach towards the synthesis of enantioenriched aspidospermidine via the highly diastereoselective potassium in ammonia reduction ethylation (EtI) of the chiral 2-(trimethylsilyl)benzamide to give 1,4-cyclohexadiene is the key step in asymmetric syntheses of (-)-aspidospermidine.

Scheme 3: Schultz and co-workers(1997)

Cyclohexadiene was converted to cyclohexanone, which provided the butyrolactone 6 required for the synthesis of aspidospermidine.The conversion of 8 to (-)-aspidospermidine (1) was best carried out as described by Harley-Mason in 40% H₂SO₄ to give 9. Finally, they achieved the synthesis of (-)-aspidospermidine by the treatment of LiAlH₄.

Aube and co-workers utilized a challenging intra-molecular Schmidt reaction to form a tricyclic lactam which is the key intermediate for their synthesis. 

Scheme 4: Aube and co-workers (2000)

The preparation of enantiomerically enriched enone was a deracemizing imine alkylation protocol as introduced by d’Angelo. The synthesis was then completed by invoking Stork’s classic Fischer-indolization to afford (+)-aspidospermidine with >99% enantiomeric excess. 

An iodoazide radical cascade cyclization strategy has been used by Murphy and co-workers as the key step in a formal synthesis of aspidospermidine. 

Scheme 5: Murphy and co-workers (2000)

Specifically, this step generated the alkaloid’s B- and E-rings in the ethylidene functionalized tetracycle 10. In turn, this was converted into pentacycle 11, a known advanced synthetic precursor of aspidospermidine.

Heathcock and Toczko reported a racemic synthesis of aspidospermidine in which the key complexity-generating step was the TFA-mediated intramolecular cascade cyclization of precursor  12

Scheme 6: Heathcock and Toczko(2000)

to give tetracyclic intermediate 13 in high yield. To afford the final ring closure, chloroacetamide 12 was converted to the correspondimg iodide. Treatment with silver triflate yilded pentacyclic 14 which gave (±)-aspidospermidine upon reduction with LiAlH₄.

Marino and co-workers reported an enantioselective synthesis of (+)-aspidospermidine in which boc-protected aniline was treated with cuprate-reagent to form the substituted lactone 15 which underwent ring opening with pyrrolidine to achieve the aldehyde.

Scheme 7: Marino and co-workers(2002)

Then the subsequent intramolecular aldol followed by the treatment with mixed anhydride protocol gave chloroamide 16.After that, via an intramolecular alkylation cascade reaction, tricyclic core was achieved. The enone 17 was installed with a modified Saegusa reaction followed by deprotection of the boc-group. The synthesis of (+)-aspidospermidine was completed by Wolff-Kishner reduction followed by the treatment of LAH.

Zard and co-workers in 2006 reported a 5-exo/6-endo radical cascade cyclization from amidyl radical to provide the tricyclic system 20 which would later be converted to aspidospermidine via the well-known Fisher-Indole reaction. 

Scheme 8: Zard and co-workers(2006)

The route to tricyclic core began with the Birch reduction with Li/NH₃ and alkylation the ester 18  to yield a lactol 19. Radical precursor was treated with ACCN and tribytyltin hydride to achieve the tricyclic amine.

A Tandem Asymmetric was utilized Suzuki and Tomioka in 2008 Conjugate Addition-Alkylation reaction for the construction of a quaternary carbon centre. Oxidative cleavage of olefin 21 yielded a lactol which upon oxidation gave d-lactone.

Scheme 9: Suzuki and Tomioka(2008)

The remaining transformations were a modification of the Harley-Mason’s protocol. Sulfuric acid treatment of 23 induced Pictet-Spengler cyclization followed by LiAlH₄ reduction in THF completed the synthesis of (-)-aspidospermidine 1 in 37% yield.

A novel domino Michael/Mannich/N-alkylation sequence to access the tetrahydrocarbazole framework of the Aspidospermidine was introduced by Zhao and co-workers. 

Scheme 10: Zhao and co-workers (2013)

In this synthetic approach, they have utilized ring-closing metathesis (RCM) to form the D-ring with Hoveyda-Grubbs 2^nd generation catalyst followed by Bosch-Rubiralta spirocyclization for the C-ring.

A highly efficient, redox-free Pd(II)-catalyzed tandem cyclization reaction initiated by intramolecular aminopalladation of alkynes followed by nucleophilic addition to nitriles was developed by Han and Lu in 2014. 

Scheme 11: Han, Lu and co-workers (2014)

This method has provided a versatile approach for the synthesis of six- to eight-membered ring-fused indoles in one step and has also shown advantages in the formal synthesis of (±)-aspidospermidine.

An efficient and highly stereoselective intramolecular [3 + 2] cycloaddition of nonstabilized azomethine ylide generated from a

Scheme 12: Pandey and co-workers (2016)

designed bicyclic aminal precursor was reported by Pandey and co-workers for the synthesis of both (-)- and (+) octahydropyrroloquinolinone.

Cho and co-workers have shown that a base-catalyzed intramolecular aza-Michael reaction, in situ trapping of the resulting enolate, and

Scheme 13: Cho and co-workers (2016)

subsequent C-N coupling with phenyl hydrazide afforded the key ene-hydrazides, which were cyclized to give the desired regioselective indole alkaloid products.

A novel asymmetric intramolecular Cu-Catalyzed Propargylic Substitution reaction was utilized by Carreira and co-workers in a very nice way to synthesize (+)-aspidospermidine. In their synthesis they have shown that propargylation of a pyrrole as the asymmetry-generating step yielded compound 7 which upon lithiation with n-BuLi

Scheme 14: Carreira and co-workers (2017)

and quenching with CO₂ followed by reduction, they afforded compound 20 with 91% yield. After that an intramolecular Fridel-Craft alkylation gave the desired tricyclic core. The end game of this synthesis was the Fischer-Indolization which was well established.

In 2019, Chang,Song and co-workers have shown a palladium catalysed decarboxylative allylation towards the synthesis of (+)-aspidospermidine. In which they have used tert-Butyl PHOX ligand for

Scheme 15: Chang, Song, and co-workers (2019)

an enatioenriched decarboxylative allylation reaction. After that the more important reaction of this sequence was the reductive ammination reaction in presence of BnNH₂ and AcOH to form the D-ring. The total synthesis of (+)-aspidospermidine was accomplished by the selective acylation of the piperidine nitrogen followed by the reduction with LiAlH₄.
In summary, in this overview, we can observe that aspidospermidine is a very important and interesting molecule to synthetic organic chemists. There are lots of reports which show various important strategies. Although lots of work have already done in this field but there are opportunities to study on the field of Aspidospermidine.