Unified Asymmetric Synthesis of Aryltetralin Lactone Cyclolignans via Conformation-Assisted Radical C–H Cyclization

Abstract

Aryltetralin lactones featuring vicinal stereogenic centers at their ring junctions are important scaffolds in pharmacologically relevant cyclolignans. Currently, the direct and efficient assembly of tetracyclic core scaffolds from simple acyclic precursors is challenging. Herein, we developed a conformation-assisted radical-initiated iodocarbocyclization of C­(sp3)–H bonds in 5-alkenylmalonates. This was followed by lactonization for the direct assembly of aryltetralin lactone scaffolds. Nine aryltetralin lactone cyclolignans were successfully produced by unified asymmetric total syntheses. This methodology shows potential for advancing both medicinal chemistry and biological research.

Natural products are vital for the development of new drugs for comprehensive cancer treatment. Aryltetralin lactone cyclolignans are a subset of natural lignan compounds that are primarily isolated from the rhizomes and roots of the Podophyllum species (Scheme A). These compounds exhibit a wide range of pharmacological activities and have anticancer, insecticidal, antifungal, antiviral, anti-inflammatory, neurotoxic, and immunosuppressive effects. , Consequently, they have been investigated in chemical synthesis and structural modification for the development of anticancer drugs. For instance, etoposide (2) and teniposide (3) are structural analogs of podophyllotoxin (1) and act as topoisomerase II inhibitors during the late S and early G2 stages of the cell cycle for microtubule assembly. Currently, aryltetralin lactone cyclolignans are currently used in clinical settings to treat multiform glioblastoma and small cell lung cancer. − Structurally, the aryltetralin lactone lignans are characterized by a tetracyclic fused-ring skeleton that includes a tricyclic tetrahydronaphtho­[2,3-c]­furan-1­(3H)-one motif (A, B, and C rings) and four consecutive chiral centers in the B ring (Scheme A). Structure–activity relationships and mechanistic studies have revealed that subtle modifications to the relative stereochemistry and the aromatic rings (A and D rings) of the parent podophyllotoxin scaffolds can greatly affect the inhibitory activity. −

1. Background and Our Working Hypothesis .

^a (A) Representative examples of stereodivergent aryltetralin lignans. (B) Representative previously reported synthetic strategies. (C) I₂-mediated C­(sp ³ )-H carbolactonization of 4-alkenylmalonates. (D) Limitations of I₂-mediated C­(sp ³)-H carbolactonization of 5-alkenylmalonates. (E) Conformation-assisted I₂-mediated radical C­(sp ³ )-H iodocarbocyclization and lactonization of 5-alkenylmalonates (this work).

With their tetracyclic structures and biological activities, aryltetralin cyclolignans are attractive targets for synthetic and medicinal chemists. − Extensive research has led to significant advances in the collective total synthesis of aryltetralin lactone cyclolignans through the stepwise incorporation of ring systems (Scheme B). The first modular synthesis of racemic cyclolignans was accomplished by Maimone et al. and used a novel palladium-catalyzed C­(sp3)–H arylation reaction to modify the D-ring. Renata et al. and Fuchs et al. developed attractive chemoenzymatic total syntheses of (−)-podophyllotoxin and related lactone cyclolignans, leveraging nonheme dioxygenase-catalyzed intramolecular oxidative cyclization to form the B-ring. Gao et al. used a titanium-mediated asymmetric photoenolization/Diels–Alder cycloaddition to forge the B-ring and complete the total syntheses of cyclic ether cyclolignans aglacins A, B, and E. Lu et al. performed an enantioselective hydrogenation of tetrasubstituted olefin within the B-ring, enabling the modular and diverse de novo synthesis of cyclolignans. More recently, Zhang et al. developed an enantioselective Oshima–Utimoto reaction to establish the C-ring and accomplished the stereodivergent total syntheses of (−)-podophyllotoxin and 11 structural congeners. Even though these advances are significant, straightforward construction of the tetracyclic core from simple acyclic starting materials to synthesize aryltetralin lactone cyclolignans is still challenging. −

From the viewpoint of efficiency and practicality in total synthesis, oxidative radical cyclization of the C­(sp3)–H bond is one of the most attractive methods for constructing structurally complex molecular scaffolds. − Conventional methods for oxidative radical carbolactonization typically rely on stoichiometric transition-metal oxidants. , Transition-metal-free access to fused [4.3.0]-bicyclic γ-lactones from alkenylmalonates is challenging. Although the I₂-mediated ionic carbolactonization of 4-alkenylmalonates − (Scheme C) proceeds efficiently via a kinetically favored anionic cyclization, this strategy is not feasible for 5-alkenylmalonates (Scheme D) due to the competing pathways of α-iodination , and decomposition. We postulated that it may be possible to leverage the intrinsic conformational bias − of 5-alkenylmalonate derivatives to enable a successful oxidative radical process. Herein, we developed a conformationally directed carbolactonization of 5-alkenylmalonates via sequential I₂-mediated radical C­(sp3)–H cyclization and lactonization to provide a straightforward assembly of aryltetralin lactone lignans.

The proposed synthetic strategy is illustrated in Scheme E. Malonate anion H was generated by treating G under basic conditions. Although α-iodination of the malonate anion H delivers iodomalonate I, we anticipated that the strong nucleophilic enolate H would be regenerated from iodomalonate I , in the presence of iodide. Comparative analysis of the oxidation potentials of malonate anion H [E­(P•/P^–) = +0.03 V vs SCE] and I₂ (E­[I₂/I^–] = +0.60 V vs SCE) demonstrated that single electron transfer was thermodynamically favorable for the generation of malonate radical J. The vicinal disubstituent effect of the two aryl groups (Ar¹ and Ar²) in intermediate J may enhance the rate of conformationally directed − 6-exo-trig iodocarbocyclization through radical cyclization to produce intermediate K. This might trigger the formation of cyclic iodinated intermediate L, which may drive the equilibrium between H and I in favor of regeneration of H. Consequently, intermediate L can undergo lactonization to afford structurally distinct lactones M and N, both of which serve as pivotal intermediates for the unified synthesis of the aryltetralin-type lactone cyclolignan scaffold for antineoplastic drug discovery.

The feasibility of this carbolactonization reaction was examined. Racemic compound 7a, which was easily accessed in two steps (see SI for details), was prepared and used as a model substrate to optimize the reaction conditions. The effects of the base, iodide source, additive, solvent, and temperature on the reaction were investigated (Table ). The optimized reaction conditions of NaHMDS (1.0 equiv), I₂ (1.0 equiv), and 15-crown-5 (2.0 equiv) in PhMe at 0 °C for 2 h effectively promoted regioselective iodocarbocyclization. After lactonization at 120 °C for 12 h, the corresponding lactones 8a and 9a were obtained in a 64% combined yield with a 2.6:1.0 diastereomeric ratio (¹H NMR analysis) (entry 1, Table ). Notably, the relative configuration of 8a was determined by X-ray crystallographic analysis (CCDC 2418450, see the SI for details). The use of NaHMDS for deprotonation of the malonic ester played a critical role in the cyclization reaction. The results obtained with other bases (NaH, LiHMDS, and KHMDS; entries 2–4, Table ) were inferior. Additionally, replacing the electrophilic iodine reagent with NIS led to the formation of an iodomalonate but no cyclized products (entry 5, Table ). Without 15-crown-5, the anticipated tetracyclic aryltetralins 8a and 9a were obtained in an overall yield of 61% with a 1.1:1.0 diastereomeric ratio (entry 6, Table ). Finally, the effects of the solvent and temperature were evaluated; however, the reactivity and stereoselectivity did not increase compared with those obtained under the standard conditions (entries 7–10, Table ).

1. Selected Optimization Results .

Entry	Deviation from standard conditions	Ratio (8a:9a)	Yield (%)
1	None	2.6:1.0	64
2	NaH instead of NaHMDS	2.3:1.0	33
3	LiHMDS instead of NaHMDS	1.1:1.0	55
4	KHMDS instead of NaHMDS		trace
5	NIS instead of I2		0
6	no 15-crown-5	1.1:1.0	61
7	Et2O instead of PhMe	2.1:1.0	50
8	THF instead of PhMe	2.6:1.0	32
9	–30 °C instead of 0 °C	2.6:1.0	63
10	25 °C instead of 0 °C	2.1:1.0	52

^aStandard reaction conditions: 7a (0.20 mmol), I₂ (0.20 mmol), NaHMDS (0.20 mmol), 15-crown-5 (0.4 mmol), PhMe, 0 °C, 2 h; then 120 °C for 12 h.

^bDetermined by ¹H NMR analysis.

^cIsolated yield. PhMe, toluene; LiHMDS, lithium bis­(trimethylsilyl)­amide; NaHMDS, sodium bis­(trimethylsilyl)­amide; KHMDS, potassium bis­(trimethylsilyl)­amide; and NIS, N-iodosuccinimide.

With the optimal conditions established, the carbolactonization reaction was evaluated for preparing a small library of structural analogs to 8a and 9a (Table ). Remarkably, the reaction went to completion with a broad range of different C7′-substituted substrates to deliver the aryltetralin lactones (Table ). The desired products were obtained in good yields when the iodolactonization was performed with different ester groups (8b and 8c) and substituents at C3′, C4′, and C5 (8d-8k). However, when the aryl group at C7′ was substituted at C2′ and C6′ with methoxy or methyl groups (8l-8n), the yield decreased slightly, presumably because of steric hindrance. We also investigated construction of vicinal quaternary centers at C8 and C8′ with a methyl group at C8 (8o). The relative configuration of 8o was determined by X-ray crystallographic analysis (CCDC 2418451, see SI for details). The desired cyclization proceeded in a moderate yield. A substrate bearing a n-butyl group at C7 gave 8p in an overall yield of 44% with a diastereomeric ratio of 4.5:1.0 (¹H NMR analysis) without any α-iodination byproduct. When the substituent at C7′ was replaced with a bulky t-butyl group, the product 8q was obtained in 41% yield as a single diastereoisomer (diastereomeric ratio > 20:1, ¹H NMR analysis). In our opinion, the orientation of the t-butyl group is hypothesized to substantially regulate the favorable conformation of the transition state in radical cyclization.

2. Scope of Fused-Ring [4,3,0]-γ-Lactones,

^aStandard conditions: 7 (0.20 mmol), I₂ (0.20 mmol), NaHMDS (0.20 mmol), 15-crown-5 (0.4 mmol), PhMe, 0 °C, 2 h; then 120 °C for 12 h.

^bIsolated yield; d.r. was determined by ¹H NMR analysis.

^c 7 (0.20 mmol), I₂ (0.20 mmol), NaHMDS (0.20 mmol), 15-crown-5 (0.4 mmol), PhMe, 25 °C, 2 h; then 120 °C for 12 h.

Notably, in the absence of an aryl group at C7′ or on the A ring (substrates 7r and 7s, respectively), the iodocarbocyclization proceeded only when the reaction temperature was increased to 25 °C. This was presumably because of the lack of assistance from vicinal disubstituent effects.

To better understand the mechanism, we investigated the following aspects of the iodocarbocyclization of 5-alkenylmalonates: whether the iodide ion-promoted equilibrium between α-iodinated malonates and malonate anions involved in the iodocarbocyclization reaction, whether the cyclization occurred through a radical-mediated process or an ionic mechanism, and whether the vicinal disubstituent effect influenced the reactivity of the cyclization reaction.

Initially, when compound 12c was subjected to the reaction with the addition of NaI and 15-crown-5, the desired iodocarbocyclization products 10c (54% yield) and 11c (24% yield) were obtained. None of the cyclization products were detected without the addition of NaI, which suggested that there might be an equilibrium between iodomalonates and malonate anions during the iodocarbocyclization reaction (Scheme A).

2. Mechanistic Investigations .

^a (A) Iodocarbocyclization of iodomalonate 12c. (B) Radical-clock and -trapping experiments. (C) Chiral retention of the cyclization reaction. (D) The influence of the vicinal disubstituent effect on the reaction processes. (E) Energy barrier (ΔG ^‡) of radical cyclization for different substrates.

Subsequently, when the vinylcyclopropane derivative 13 was subjected to the standard reaction conditions, it gave cyclized products 14 and 15 via a sequence of radical ring-opening , and iodination reactions (Scheme B). No reaction occurred without the addition of I₂. Meanwhile, when compound 16 was reacted with NaI and 15-crown-5, the desired iodocarbocyclization products 14 (35% yield) and 15 (18% yield) were obtained. Additionally, the TEMPO-trapped complex was detected when the reaction of compound 7c was conducted in the presence of a stoichiometric amount of TEMPO (see the SI for details). These results strongly suggested that a malonate radical intermediate was cyclized with the alkene moiety during the oxidative iodocarbocyclization. To further probe the mechanism (Scheme C), the retention of chirality when converting 5-alkenylmalonates to tetracyclic lactones was investigated. Optically active (+)-7c (99% enantiomeric excess, see the SI for details) was transformed in 62% combined yield without loss of enantiomeric excess to the corresponding highly enantioenriched (−)-8c and (+)-9c under standard carbolactonization conditions. The retention of stereochemistry allowed for the use of our oxidative radical cyclization methodology for the asymmetric synthesis of aryltetralin lactone cyclolignans.

Next, when the aryl groups were absent, no cyclization products were observed when the oxidative iodocarbocyclization reactions of compounds 7r, 7s, and 7t were conducted at 0 °C (Scheme D). These observations suggested that the iodocarbocyclization rate acceleration may be attributed to the vicinal disubstituent effect of the two aryl groups. To elucidate this, we evaluated the energy barrier of radical cyclization for different substrates using density functional theory calculations (Scheme E). The results indicated that the energy barrier increased as the aryl groups decreased in compounds 7a, 7r, 7s, and 7t, which corroborated the relationship between the vicinal substituent effect and reactivity. The efficiency of this radical cyclization relies on the in situ generated acyclic 5-alkenylmalonate radical adopting a favorable conformation, dictated by the vicinal disubstituent effect, which facilitates 6-exo-trig cyclization over competing iodination.

Furthermore, we also considered the diastereoselectivity in the radical cyclization step. For reactant 7a, The free energy discrepancy of the transiton states lead to syn- and anti-isomers 10a and 11a is 0.6 kcal/mol, thus a modest diastereomeric ratio of about 2.6:1 could be obtained. In contrast, the bulky t-butyl group in 7q induces a significant energy difference of 1.4 kcal/mol by preferentially stabilizing the transition state to syn-isomer 10q, thereby achieving excellent diastereoselectivity (d.r. > 20:1) (see Figure S15 in the SI for details).

After successfully synthesizing (−)-8c, we investigated decarboxylation, C–H oxidation, and epimerization for the divergent asymmetric synthesis of Podophyllum lignans (Scheme A). Initially, the decarboxylation with the assistance of Raney nickel gave (−)-deoxyepiisopicropodophyllotoxin (18) in 80% yield. Diastereoselective epimerization at C8′ in 18 under treatment with KOH gave (+)-deoxyisopodophyllotoxin (6). Benzylic oxidation of 6 and 18 with CrO₃•3,5-DMP or N-Bromosuccinimide resulted in oxidative aromatization instead of regioselective oxidation at C7 and led to the formation of dehydrodeoxypodophyllotoxin (19). Therefore, to avoid the oxidative aromatization of B-ring, the decarboxylation at C8′ should be performed subsequent to the benzylic oxidation at C7. To access the corresponding natural products with a higher level of oxidation at C7, the benzylic oxidation of (−)-8c with CrO₃•3,5-DMP gave ketone 20 in 68% yield, which was converted by decarboxylation into (−)-isopicropodophyllone (5) in 78% yield. Subsequent chemo- and diastereoselective ketone reduction at C7 and transesterification gave (−)-8-epi-neopodophyllotoxin (22) in 60% yield.

3. Collective Asymmetric Total Syntheses of Aryltetralin Lactone Cyclolignans.

To further illustrate the versatile synthetic utility of this stereodivergent assembly strategy, the remaining two kinds of C8/C8′ stereoisomers were successfully prepared from (+)-9c (Scheme B). Using the established sequence, we accomplished the asymmetric total syntheses of (−)-podophyllotoxin (1), (+)-epipicropodophyllotoxin (4), (+)-deoxypicropodophyllin (23), (−)-deoxypodophyllotoxin (24), (−)-podophyllone (25), and (−)-picropodophyllone (27). The structure of 27 was confirmed by X-ray crystallographic analysis (CCDC 2418449, see the SI for details).

In summary, we developed a radical cyclization of C­(sp3)–H bonds in 5-alkenylmalonates and subsequent lactonization for efficient synthesis of the tetracyclic core structure inherent to aryltetralin lactone cyclolignans. The keys to success were 1) iodide ion-promoted regeneration of malonate anions from iodomalonates, 2) formation of malonate radicals via the I₂-mediated oxidation of malonate anions, and 3) conformation-assisted 6-exo-trig radical cyclization of the malonate radical onto the alkene. Notably, the reaction provided an aryltetralin lactone bearing two continuous all-carbon quaternary carbon centers. This reaction was successfully applied to the collective asymmetric total syntheses of nine aryltetralin lactone lignans in two–four steps from the common intermediate (+)-7c. This method produces medically significant natural product scaffolds in a streamlined and efficient manner.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.5c01176.

• Experimental procedures and spectral data for all new compounds (PDF)

R.Y. discovered as well as developed the reaction and designed the experiments. R.Y., X.W., R.Z., and J.H. ran the experiments. L.Z. conducted the computations. J.H. directed the project. L.Z. and J.H. wrote the manuscript.

The authors declare no competing financial interest.