This work is dedicated to Professor Hee-Yoon Lee (1957–2023) in memory of his scientific
contributions to the field of total synthesis.
Key words
total synthesis - securinega alkaloids - biofunctional derivatizations - hydroxyallosecurinine
- securingine F
Natural products have played a vital role in the development of new drugs.[1] Among the 185 cancer-related small-molecule drugs approved from 1981 to 2019, 62
(33.5%) were natural products or natural-product derivatives and 58 (31.4%) were synthetic
drugs with natural-product pharmacophores or natural-product-mimicking synthetic drugs.[2] Natural-product-based drug development can undoubtedly benefit from the identification
of the targets. In recent years, studies that described the syntheses of complex natural
products and of associated probes for the identification of their targets have been
reported.[3]
[4]
[5]
[6] In all these examples, the presence of a functional handle that permits anchoring
of the target-signal-enhancing moiety was essential (Scheme [1]A). Notably, the Dai group used a hydroxy group as a functional handle for the synthesis
of alkyne-based[5] and azide-based[3] natural-product chemoproteomics probes.
Scheme 1 Importance of securinega alkaloids with a handle for biofunctional derivatizations
Antibody–drug conjugates (ADCs) represent an emerging class of drugs with a wider
therapeutic index than classical chemotherapeutic agents, due to their selective drug
delivery to antigen-expressing tumor cells. Since the first approval of an ADC drug,
Mylotarg (gemtuzumab ozogamicin), by the US Food and Drug Administration (FDA), 14
ADCs have received market approval worldwide.[7] Importantly, the payloads of all of these drugs have their origins in natural-product
structures.[8] Hence, the presence of a functional handle in the payload is essential to conjugate
the linker that connects the warhead and the antibody (Scheme [1]A). On the other hand, natural products without functional handles would be relatively
more difficult to use in the aforementioned bioapplications such as target identification
and ADC (Scheme [1]A).
Securinega alkaloids have fascinated the chemical community for over six decades because
of their promising biological activities and intriguing structures.[9]
[10]
[11] They show a potent antitumor activity that is based on cytotoxicity, differentiation-induction
activity, and the reversal of multidrug-resistance activity.[12] Securinega alkaloids also exhibit nervous-system-related and cardiovascular-system-related
activities.[12] Even though a few preliminary mechanistic studies regarding the bioactivities of
these alkaloids have been reported, the exact targets for the majority of these bioactivities
have yet to be identified. Notably, Chen and co-workers reported that securinine derivatives
effectively inhibit DNA topoisomerase I (Topo I),[13]
[14] the target of the FDA-approved ADC drug Enhertu (trastuzumab deruxtecan).[15]
From a structural perspective, basic monomeric securinega alkaloids are characterized
by a fused tetracyclic core with a conjugated ester moiety and a piperidine heterocycle.
It is noteworthy that most securinega alkaloids lack a functional handle for biofunctional
derivatizations, considering that altering the electrophilic unsaturated γ-butyrolactone
moiety is not desirable because it may interact with the nucleophilic moiety of the
target (Scheme [1]B). Under these circumstances, isolations of securinega alkaloids with a hydroxy
group, such as 4α-hydroxyallosecurinine (4),[16] securingine F (5),[17] or secu’amamine A (6)[18]
[19]
[20]
[21]
[22] are notable. 4α-Hydroxyallosecurinine (4) and securingine F (5) are especially interesting entries, as their hydroxy group is located remotely from
both the unsaturated γ-butyrolactone and the N1 moieties, two probable sites for
biological activities of the natural product. Hence, building on our group’s successful
synthesis of C4-methoxylated high-oxidation-state securinega alkaloids,[23] we decided to attempt syntheses of 4α-hydroxyallosecurinine (4) and securingine F (5), structurally unique high-oxidation-state securinega alkaloids with a C4-hydroxy
group as a potential handle for biofunctional derivatizations.
Our retrosynthetic analysis of securingine F (5) and 4α-hydroxyallosecurinine (4) is shown in Scheme [2]. Securingine F (5) could be obtained from 4α-hydroxyallosecurinine (4) through N-oxidation and a subsequent 1,2-Meisenheimer rearrangement. We planned to access 4α-hydroxyallosecurinine
(4) by a 1,2-amine shift and C4-epimerization of diol 8. Diol 8 could be obtained from compound 9 through a hydrogen-atom-transfer (HAT)-mediated C2-epimerization. The tetracyclic
framework of 9 would result from an intramolecular 1,6-aza-Michael addition of the known compound
10.[23]
Scheme 2 Retrosynthetic analysis of 4α-hydroxyallosecurinine (4) and securingine F (5)
Scheme 3 The first-generation total synthesis of 4α-hydroxyallosecurinine (4) and securingine F (5)
Our synthesis commenced with a Michael addition-based stereoselective union of enone
11 and menisdaurilide derivative 12, and subsequent transformations to yield the tricyclic compound 10 by following our previously reported protocol (Scheme [3]).[23] The tert-butyl(diphenyl)silyl moiety in compound 10 was removed by reaction with TBAF to yield the allylic alcohol 13 in 80% yield. A TFA-mediated Boc-deprotection of carbamate 13 and subsequent treatment of the resulting amine intermediate with triethylamine in
methanol resulted in an intramolecular aza-1,6-conjugate addition to afford tetracyclic
compound 9 with a neosecurinane framework in 84% yield over two steps.[24]
With robust synthetic access to 9, we faced the challenge of epimerizing the C2 position of the compound. In 2020,
Ellman and co-workers reported a light-induced HAT-mediated epimerization of piperidine.[25] Our group used this transformation in the total synthesis of 4-epi-phyllanthine.[23] We envisioned that the radical-based epimerization might also be applicable to the
C2-selective epimerization of 9. To our delight, when compound 9 was irradiated with blue LEDs in the presence of 1 mol% of [Ir{dF(CF3)ppy}2(dtbpy)]PF6 [dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine; dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine] and benzenethiol for 13 hours, the C2-epimerized product 8 was obtained in 72% yield. The reaction mechanism involves the catalytic generation
of a thiol radical that reversibly abstracts the hydrogen atom at the C2 position
to set the thermodynamic equilibrium between compounds 8 and 9. Product 8, with the hydroxy group in the equatorial position, would be thermodynamically more
stable than 9, consistent with the A-value of the hydroxy group in methanol (0.9 kcal/mol). It
is worthwhile noting that prolonged exposure of compound 9 to the aforementioned reaction conditions initiated an epimerization at the C7 position.
Treatment of diol 8 with excess mesyl chloride (4 equiv) and triethylamine (8 equiv) afforded the dimesylated
intermediate 16, which underwent spontaneous intramolecular N-alkylation to give the aziridinium
ion intermediate 17. Subsequent E1cB elimination of intermediate 17 yielded the 1,2-amine-shifted product 18 in 88% yield.[24] When the mesylate derivative 18 was treated with cesium 4-nitrobenzoate, the SN2-reaction-mediated O-alkylated product 18 was obtained in 76% yield. Final methanolysis of the nitrobenzoate moiety in 19 produced the first synthetic sample of 4α-hydroxyallosecurinine (4) in 66% yield. Spectroscopic data for the synthetic 4α-hydroxyallosecurinine (4) were consistent with those of the natural sample,[16] confirming its structure.[26]
[27] Furthermore, treatment of 4α-hydroxyallosecurinine (4) with mCPBA and potassium carbonate produced securingine F (5) in 72% yield through a 1,2-Meisenheimer rearrangement.[28]
After completing the first-generation total synthesis of 4α-hydroxyallosecurinine
(4) and securingine F(5), we envisioned further streamlining of the synthetic route. We postulated that both
the 1,2-amine shift and the stereochemical inversion at the C4 site would be possible
under Mitsunobu reaction conditions. Pleasingly, when diol 8 was allowed to react with 4-nitrobenzoic acid, triphenylphosphine, and diisopropyl
azodicarboxylate (DIAD), with subsequent treatment by potassium carbonate in methanol,
4α-hydroxyallosecurinine (4) was obtained in 31% yield over the two steps (Scheme [4]).
Scheme 4 Simultaneous C4-epimerization and 1,2-amine shift of diol 8 under Mitsunobu reaction conditions
To conclude, we have successfully achieved the first total synthesis of 4α-hydroxyallosecurinine
(4) and securingine F (5). Importantly, our synthetic route features complete stereoflexibility and stereocontrollability
at both the C2 and C4 positions of the securinega framework and, therefore, various
stereochemical congeners should be synthetically accessible. Furthermore, we envisioned
coupling the newly developed strategy for the introduction of the hydroxy group at
the C4 position of the securinega skeleton with our previously established synthetic
chemistry toward various high-order and high-oxidation-state securinega alkaloids.[11] This would permit the synthesis of various complex high-order and high-oxidation-state
securinega alkaloids with a C4-hydroxy handle. Those congeners could be subjected
to biofunctional derivatizations and biological studies. Those will be the subject
of our forthcoming reports.
