Total syntheses of macleanine and lycoposerramine-S

Abstract

Total syntheses of fawcettimine-class Lycopodium alkaloids having an imino bridge between C5 and C13 were accomplished. Fawcettimine was first prepared in 10 steps from a known compound, and the characteristic structures, including the imino bridge, were constructed via the formation of a bridgehead imine.

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Hundreds of alkaloids have been isolated from Lycopodium species.¹ These alkaloids can be classified into several groups on the basis of their core structure. Among these groups, the fawcettimine-class is a major group of Lycopodium alkaloids (Fig. 1).² Fawcettimine has a cis-hydrindane core to which a nine-membered ring containing a nitrogen atom is fused. The nitrogen atom on the nine-membered ring forms a hemiaminal with a carbonyl function on the cis-hydrindane core, resulting in the formation of two heterocycles, a piperidine and an azepane. As minor constituents of the fawcettimine class, three alkaloids that have an imino bridge between C5 and C13 have been isolated.³ Although various total syntheses toward fawcettimine have been reported,⁴ synthetic efforts toward these alkaloids with the imino bridge are limited. Only two synthetic studies toward lycoposerramines-A and S ⁵ and one total synthesis of lycoposerramine-S have been reported.⁶ However, no synthetic study on macleanine has thus far been reported. Herein we disclose our effort to synthesize fawcettimine-class alkaloids with an imino bridge between C5 and C13, resulting in the total syntheses of macleanine and lycoposerramine-S.

Fig. 1 Structures of selected fawcettimine-class Lycopodium alkaloids.

We first planned the synthesis of macleanine, which has an aminal moiety in the structure. Aminals can be prepared via dehydrative condensation of a ketone or an aldehyde with two amines. This process involves the formation of an imine as an intermediate. In the synthesis of macleanine, the imine must be formed at a bridgehead position (Scheme 1a).⁷ Additional strain caused by the bicyclo[2.2.1] system appeared to introduce difficulties.⁸ To avoid the formation of strained bridgehead imines, we planned the synthetic route as shown in Scheme 1b. Thus, the sequential formation of C–N bonds via an intramolecular addition of a secondary amine moiety to an imine (I), followed by an intramolecular S_N2 reaction (II), could construct the structure of macleanine without forming a bridgehead imine. The requisite substrate would be prepared from fawcettimine.

Scheme 1 Synthetic plan toward macleanine.

We synthesized fawcettimine on the basis of our synthesis of huperzine Q,⁹ starting from the known enone 1 (Scheme 2).^4p A Diels–Alder reaction of 1 with siloxydiene 2 produced the bicyclic compound 3, which was converted into enone 5via a three-step sequence involving the introduction of a phenylthio group, oxidation into a sulfoxide, and sulfoxide elimination under thermal conditions.¹⁰ After the sequential cleavage of the tert-butyloxycarbonyl (Boc) and tert-butyldiphenylsilyl (TBDPS) groups, a Mitsunobu reaction of the resultant hydroxy nosylamide formed a nine-membered ring,¹¹ affording the tricyclic compound 7. Nucleophilic epoxidation with hydrogen peroxide under basic conditions afforded epoxyketone 8, which was subjected to ring contraction mediated by trimethylsilyl triflate (TMSOTf) as a Lewis acid to afford keto aldehyde 9.^12,13 The nosyl and formyl groups were cleaved simultaneously by treatment with benzenethiol under basic conditions to yield fawcettimine.

Scheme 2 Preparation of fawcettimine.

With a sufficient amount of fawcettimine in hand, we next attempted our planned synthesis of macleanine (Scheme 3).¹⁴ The Birch reduction of fawcettimine stereoselectively produced alcohol 10,⁹ and then the hemiaminal moiety was cleaved by a reaction with allyl chloroformate (AllocCl). The resultant ketone 11 was transformed into its oxime ether. Attempted mesylation of the secondary alcohol moiety in 12, to our surprise, produced methoxylamine 15. In this transformation, the mesylate formed in situ might be attacked by the oxime ether moiety to form the N-methoxyiminium ion 14, which was then trapped by water. Removal of the Alloc group with a palladium catalyst in dichloromethane and acetic acid afforded the pentacyclic aminal 16. Reductive cleavage of the N–O bond with zinc in aqueous acetic acid produced macleanine.

Scheme 3 Transformation of fawcettimine into macleanine.

These results show that the aminal formation via an iminium ion proceeded more smoothly than expected,¹⁵ and led to more concise syntheses of the related alkaloids (Scheme 4). Thus, the conversion of fawcettimine into the corresponding oxime ether 17,¹⁶ followed by hydrogenation with platinum oxide (Adams catalyst) in acetic acid at room temperature, furnished macleanine in good yield.¹⁷ In addition, the reduction of oxime ether 17 with sodium cyanoborohydride in acetic acid, followed by reductive methylation, afforded tetracyclic amine 18, which could be converted into lycoposerramine-S via cleavage of the N–O bond.

Scheme 4 Synthesis of fawcettimine-class alkaloids with an imino bridge.

In our synthesis, the additional bridge in the 2-azabicyclo[3.3.1] system might facilitate the formation of a bridgehead imine. Maier and Schleyer evaluated the stability of bridgehead double bonds using the olefinic strain energy (OS),¹⁸ which is related to the heat of hydrogenation of the olefins by a constant difference. According to their report, the OS of bicyclo[3.3.1]non-1-ene (19a) is 15.2 kcal mol⁻¹, whereas that of olefin 19b, which has an additional ethylene bridge in the bicyclic system, is 12.5 kcal mol⁻¹ (Table 1). These results indicate that the additional bridge lowers the strain. Unfortunately, the OS of olefin 19c has not been reported. However, density functional theory (DFT) calculations have shown that olefins 19b and 19c have approximately the same heats of hydrogenation: −38.6 kcal mol⁻¹ and −38.4 kcal mol⁻¹, respectively; thus, olefin 19c is also less strained than bicyclo[3.3.1]non-1-ene (19a). The heats of hydrogenation of the imines were also calculated, and comparing them revealed the same tendency; an additional bridge lowered the heat of hydrogenation, indicating that imine 20c is less strained than imine 20a.¹⁹

Table 1 Olefinic strain energies (OS) of bridgehead olefins and imines^a

	19a	19b	19c	20a	20c
a All energies are in kcal mol^−1. b Ref. 18a. The energies are calculated using Allinger's MM1 force field program. c B3PW91/6-311+G(d,p). d Not available. e Energy relative to the calculated heat of hydrogenation of olefin 19a. f Energy relative to the calculated heat of hydrogenation of imine 20a.
OS^b	15.2	12.5	NA^d	—	—
|ΔOS|	0	2.7	NA^d	—	—
	–41.6	–38.6	–38.4	–30.7	–26.3
	0	3.0^e	3.2^e	0	4.4^f

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In conclusion, we achieved total syntheses of the fawcettimine-class alkaloids macleanine and lycoposerramine-S via the formation of a bridgehead imine. We also showed that an additional bridge in the 2-azabicyclo[3.3.1] system could facilitate the formation of the bridgehead imine.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by JSPS KAKENHI (Grant Number JP23H02602) and by the Research Support Project for Life Science and Drug Discovery [Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)] from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP23ama121044.

References

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ob01065a

‡ These authors contributed equally.

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