Total Synthesis of Heilonine from the Wieland–Miescher Ketone by Mingji Dai (JACS, 2024)

Heilonine is an alkaloid isolated in 1989 from Fritillaria ussuriensis and belongs to the structurally interesting family of veratrum alkaloids. Within this group, cyclopamine is noted for its biological activity and teratogenic effects. Veratrum alkaloids have been synthesised several times before; however, the synthetic route to heilonine was only established once in 2021. In their recent work, Mingji Dai and his research group from Emory University (Atlanta, USA) reported a new total synthesis involving fewer than 13 steps in the Journal of the American Chemical Society.

In their synthetic strategy (see Fig. 1), heilonine (1) is expected to be obtained from compound 2 through late-stage deoxygenation. In their key reaction, cyclopentenone 2 is anticipated to be generated from the Nazarov cyclisation of precursor 3. The Nazarov precursor is then divided into two equally complex fragments, 4 and 5, which can both be synthesised in a few steps from literature-known compounds.

Figure 1: Retrosynthetic approach for the synthesis of heilonine (1) by Mingji Dai and research group.

Synthesis of Fragment 4 from Wieland-Miescher Ketone

As shown in Figure 2, the Wieland-Miescher Ketone 6 was first selectively protected to form 7. The authors opted to follow a recent one-step protocol [2] for the oxidation at the gamma position, yielding 8 in 45% yield. Subsequently, keto-enol tautomerisation produced 9 with a yield of 56%. Using a bulky reduction reagent, both ketone groups were reduced from the sterically less hindered side, followed by acidic workup to deprotect the acetonide. TBS protection then afforded keto diol 10. The enol was trapped as a triflate using Comins' reagent, and palladium-catalyzed coupling with the Me₃Sn dimer afforded coupling partner 4.

Figure 2: Synthesis of fragment 4 in 7 steps from Wieland-Miescher Ketone 6.

Synthesis of Coupling Partner 5

After synthesising the western fragment 4, its coupling partner 5 needed to be synthesised. The route (see Fig. 3) began with literature-known compounds 12 and 13. Boc-directed lithiation of 13 was followed by transmetallation and Negishi coupling with 12. The subsequent deprotection yielded 14 in a total yield of 52%. A stereoselective reduction was carried out using Crabtree's catalyst, achieving complete diastereoselectivity. Next, [Pd]-catalysed oxidative carbonylative C–H lactamization produced 16 in very good yield. Finally, the iodide required for coupling was introduced by NIS in a [Rh]-catalysed C–H iodination. Deoxygenation using BH₃ afforded the final fragment 5 in six steps from 12 and 13.

Figure 3: Synthesis of eastern fragment 5 by C-H functionalisation.

Fragment Coupling and Nazarov Cyclisation

To complete the total synthesis, fragments 4 and 5 were coupled, as shown in Figure 4, by Stille carbonylation. This set the required structural motif for the Nazarov cyclisation. Photochemical conditions and in situ epimerisation yielded compound 2 in good yields and moderate diastereoselectivity. Fortunately, the stereocenter could be established by another epimerisation step using iPr2NH. Next, ketone 2 was reduced, and Barton-McCombie reaction yielded the deoxygenated product. Final acidic deprotection liberated heilonine (1) in 86% yield.

Figure 4: Completion of total synthesis using Nazarov cylisation.

In conclusion, Mingji Dai and his research group successfully described the synthesis of heilonine (1) in 13 steps (longest linear synthesis). Key features of this total synthesis include the C–H functionalisation leading to the Nazarov precursor and the subsequent cyclisation.

Published in: Yuan Jin, Sovanneary Hok, John Bacsa, Mingji Dai J. Am. Chem. Soc. 2024, 146, 3, 1825–1831. doi: 10.1021/jacs.3c13492