Ecteinascidin 743

One of the main attractions in the chemistry of natural products, apart from facing new challenges in synthetic methodologies, is discovering a novel therapeutic agent such as ecteinascidin 743 (ET-743). This compound was isolated for the first time as pure compound from Caribbean tunicate Ecteinascidia turbinata in 1986 by Rinehart's group. This compound possess interesting properties as a potent anti-tumour agent and ET-743 is approved in Europe, Russia and South Korea for treatment of advanced soft tissue sarcoma. From synthetic chemists' point of view, ET-743 provides an interesting challenge as it has interesting molecular architecture; comprised of eight rings, including 10-membered heterocycles and 8 stereogenic centres. This interesting molecular architecture and interesting anti-tumour properties were the motivation of its first total synthesis by E. J. Corey in 1996.

After E. J. Corey's total synthesis of ET-743, it took 6 years for another total synthesis of ET-743 to be developed. A new pathway to synthesise ET-743 was developed by Fukuyama's group from Tokyo and it is based on the synthesis of pentacyclic benzyl alcohol 2 as the key intermediate.

Retrosynthetic analysis of ET-743

The tricyclic aldehyde 3 was chosen to be suitable platform for the synthesis of 2 due to intramolecular phenol substitution would give ortho position and correct oxidation level which is needed for the synthesis of the unique 10-membered sulphide heterocycle.

The synthesis of intermediate 3 was done by convergent route where the left segment (highlighted in blue) was synthesised in 7 steps while the right segment (highlighted in red) was synthesised in 8 steps.

Synthesis of 8 and 12

The synthesis of left segment 8 involved Mannich-type reaction with the chiral template 5 to give 6 as single product which then underwent phenol protection by triflate, reductive ring opening followed by silyl protection of the alcohol. The transformation of phenol to triflate is used for Me group substitution using Pd(II) coupling reaction. Then, oxidative cleavage of aminoalcohol using Pb(IV) to give imine moiety which then converted to amine 8 by hydroxylamine.

Meanwhile the synthesis of the right segment 12 was initiated by bromine-lithium exchange reaction forming organolithium reagent which then reacted with N,N'-dimethylformamide (DMF) to give the aldehyde. Then, ortho-iodo functional group was introduced by orhto-directed lithiation of dimethyl acetal followed by I₂ quenching. The simultaneous cleavage of MOM and dimethyl acetal followed by Bn protection afforded 10 which then underwent Horner-Wadsworth-Emmons reaction giving alkene 11.

Rh catalyst for asymmetric hydrogenation

The formation of 12 was done by asymmetric hydrogenation using Rh chiral catalyst affording methyl ester of 12, with high enantiomeric excess (94%), which then hydrolysed to give the carboxylic acid 12.

Synthesis of key intermediate 21

The next step of this synthesis is bringing both component into linear-synthetic route to complete the synthesis. Both components, 8 and 12, with 13 and acetaldehyde underwent Ugi reactionn to give dipeptide 14. At this stage, all the atoms required for key intermediate 3 has been brought together in a single step. After switching TBDPS with Ac group, simultaneous cleavage MOM and Boc groups giving aminophenol which then cyclised to afford the diketopiperazine 15. After protecting the phenol group using Ms proctecting group and the amide using Boc protecting group, the ring is partially reduced and the corresponding hemiaminal was dehydrated to give enamine 16 which is important for bicyclic formation. In this cyclisation, Heck reaction was used to give the bicyclic ring 17. After switching Ms group with Ac and Boc with Troc groups, epoxide formation by dimethyldioxirane followed by MeOH ring opening were used to control the stereocentre of the methoxyalcohol which underwent reduction of hemiaminal to give 19. The formed alcohol was then proctected with TBS group followed by switching Ac group with Bn. This reaction simultaneously formed lactam which then reduced to give 20. Then, the ring was opened by nucleophile attack followed protection of formed alcohol with Ac group. Deprotection of TBS group followed by Dess-Martin oxidation afforded the aldehyde group of 21 which corresponds to the key intermediate 3.

Formation of ET-743

The deprotection of Bn group to give phenol and interestingly it also triggered cyclisation which gives most of the cyclic system of ET-47. After securing the key intermediate 22, the next challenge would be the synthesis of 10-membered sulphur heterocycle. It was done by using L-cysteine derivative 23 to replace Ac protecting group and cyclised by TFA in trifluoroethanol after thiol formation by thioacetate hydrazinolysis. Then, phenol protection by Ac group secured the 10-membered sulphur heterocylces.

The final step of this total synthesis is the formation of tetrahydroisoquinoline moiety and formation of ET-743. The cleavage of Troc protecting group followed reductive alkylation formed the N-methyl functional group and then alloc and allyl group were deprotected using Pd catalyst. Then, biomimetic transamination reported by Corey followed by Pictet-Spangler reaction with amine 27 afforded related compound ET-770.

ET-743 and its related compound ET-770

Finally, ET-743 was formed by generating hemiaminal from the aminonitrile by treatment of AgNO₃ in MeCN/H₂O which gave a consistent spectral data with the structure of ET-743.

This total synthesis provides another route to synthesise ET-743 which is used as treatment for soft tissue sarcoma, as mentioned earlier, and with further several modifications this steps can be used in truly pratical scale and also be used to synthesise its analogue.

Reference

1. E. J. Corey, D. Y. Gin, and R. S. Kania, J. Am. Chem. Soc., 1996, 118, 9202-9203.
2. A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T. Kan, and T. Fukuyama, J. Am. Chem. Soc., 2002, 124, 6552-6554.