Synthesis of the tricyclic indole alkaloids, dilemmaones A and B

Abstract

Dilemmaones A-C are naturally occurring tricyclic indole alkaloids possessing a unique hydroxymethylene or methoxymethylene substituent at the C2 position of the indole core and a C6-C7 fused cyclopentanone. Dilemmaone B has been prepared in 5 steps from 5-methylindan-1-one, and dilemmaone A has been prepared in 3 steps from a common precursor, 6-bromo-5-methyl-7-nitroindan-1-one. In both syntheses, key steps include a Kosugi-Migita-Stille cross coupling and a reductive cyclization using hydrogen gas and a transition metal catalyst.

Graphical Abstract

Introduction

In 1997, a variety of sponge specimens were collected off the coast of Cape Town, South Africa in order to explore the biomedical potential of South African marine invertebrates. During preliminary cytotoxicity screening, an extract of a mixed collection of sponges was selected for investigation. A bioassay directed fractionation of the crude extract led to the isolation of a sphingolipid as the active metabolite. Subsequent ¹H NMR investigation of the inactive fractions led to the structural elucidation of dilemmaones A (1), B (2) and C (3) (Figure 1.).¹ These indole alkaloids were originally named based upon the dilemma surrounding their sponge source. However, a process of elimination suggested that one of the sponges in the mixed collection, Ectyonanchora flabellata, is the source of the dilemmaones.

Figure 1.

Structures of the dilemmaones.

The functional group dense structures of dilemmaones A-C are unusual. To the best of our knowledge, no other 2-hydroxymethylene- or 2-methoxymethylene-substituted indoles have been isolated and fully characterized to date. In addition to the three dilemmaones, eighteen related 6,8-dimethyl-cyclopenta[g]indole natural products have been reported to date. These include the trikentrins (4-8, Figure 2), a family of compounds displaying antibacterial activity that were first isolated by Capon et al from the marine sponge Trikentrion flabelliforme.² The structurally similar herbindoles were isolated from the Australian sponge Axinella sp. by Scheuer et al (9-11)³ and very recently from Trikentrion flabelliforme by Salib and Molinski (12, Figure 2).⁴ Herbindoles possess both cytotoxic and antifeedant properties.

Figure 2.

Structures of trikentrins (4-8) and herbindoles (9-12).

Subsequently, the related trikentramides have all been isolated from sponges belonging to the genus Trikentrion (Figure 3).⁵

Figure 3.

Structures of trikentramides (13-21).

Two related compounds are monomargine (22) and monomarginine (23), cytotoxic lactams isolated from Monocarpia marginalis (Figure 4).⁶ These 6,7-annulated compounds possess the indanone-like framework also seen in the dilemmaones.

Figure 4.

Structures of monomargine and monomarginine.

The interesting biological profiles of the trikentrins, herbindoles, and trikentramides combined with their uncommon structural motifs have made them attractive targets for total synthesis. The significant challenges associated with the construction of these complex systems are reflected in the many distinct approaches that have been reported for the racemic⁷, ⁸ and enantioselective total syntheses.⁹, ¹⁰ To date, there has been no reported synthesis of any member of the dilemmaone family, despite their skeletal resemblance to the trikentrins and herbindoles. Hence, a route to the dilemmaones was envisioned which involves a palladium catalyzed, carbon monoxide mediated, reductive cyclization as the key step.¹¹ Herein we report the first total syntheses of dilemmaones A and B.

Results and Discussion

Retrosynthetically, dilemmaone B (2) can be constructed from the palladium-catalyzed reductive cyclization of the 2-nitrostyrene 24. Compound 24 may arise from a Kosugi-Migita-Stille cross coupling between an aryl halide (26) and vinyl stannane 25. Arylindanone 26 could be fashioned through the manipulation of commercially available 2,3-dihydro-5-methylinden-1-one (27).

For the synthesis of dilemmaone B, 6-amino-5-methylindan-1-one (28) was prepared in two steps from commercially available 5-methylindan-1-one (27) according to Pinna et al (Scheme 2).¹² In order to install the nitro group present in the reductive cyclization precursor 24 (Scheme 1), a direct nitration of 28 to intermediate 31 was attempted. Lemaire et al have reported a one-step nitration of several anilines using 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (34)¹³ as the nitronium ion source.¹⁴ Utilizing Lemaire’s protocol, aniline 28 was seemingly converted to nitroaniline 31 in good yield. An electrophilic aromatic substitution was confirmed by the presence of only one aromatic proton by ¹H NMR. However, no molecular ion or protonated molecular ion was observed by HRMS of the presumed nitration product, 31. Instead, the HRMS spectrum surprisingly displayed two equally intense peaks at m/z 240 and 242, indicating the presence of a bromine atom. Thus, it was determined that aniline 28 was brominated by 33 to give bromoindanone 34 in 59% isolated yield (Scheme 2). The dual reactivity of 33, nitration or bromination, has previously been demonstrated.¹⁵ Iranpoor and Firouzabadi have also reported a nitration of free aromatic amines using a triphenylphosphine-bromine-silver nitrate reagent system.¹⁶ Interestingly, treatment of aniline 28 with PPh₃-Br₂-AgNO₃ also produced the undesired bromoindanone 34 as the sole reaction product in comparable yield (Scheme 2).

Scheme 2.

Unexpected bromination of aniline 28.

Scheme 1.

Retrosynthetic route to dilemmaone B.

After the failure of a direct nitration of aniline 28, a more traditional route to nitroaniline 31 was envisioned via a protection-nitration-deprotection sequence. Aniline 28 was first converted to acetanilide 29 in good yield using acetyl chloride in the presence of triethyl amine (Scheme 3). Nitration of 29 initially proved to be problematic. However, after some optimization of the reaction conditions, the most effective and concise procedure was the use of fuming HNO₃ and concentrated H₂SO₄ at a reaction temperature of −20 °C for 90 min.

Scheme 3.

Initial synthetic approach to dilemmaone B.

With nitroindanone 30 in hand, deprotection to 2-nitroaniline 31 was attempted using a procedure reported by Pouli et al.¹⁷ These conditions afforded nitroaniline 31, however, the reactions were highly inconsistent, with yields ranging from 5-84%. Conversion of 31 to the corresponding iodide or bromide also proved challenging. Sequential diazotization-iodination of aromatic amine 31 furnished iodoindanone 32, but we were unable to prepare the corresponding bromoindanone from 31 using a similar methodology. With iodoindanone 32 in hand, Kosugi-Migita-Stille cross-coupling with (E)-3-(tributylstannyl)-2-propen-1-ol (25)¹⁸ was attempted. Under all reaction conditions screened, only starting material 32 was isolated. Since iodoindanone 32 proved to be an unsuitable candidate for the preparation of cyclization precursor 24, a different approach was envisioned.

The second iteration toward dilemmaone B sought to install an aromatic halogen prior to nitration, thus avoiding the more circuitous five-step route from 27 involving a protection-deprotection protocol. To that end, various conditions were screened in an attempt to access bromoindanone 35. Diazotization of aniline 28 followed by addition of copper bromide proceeded smoothly to afford desired bromoindanone 35 (Scheme 4). The overall three-step yield of 35 from 5-methylindan-1-one (27) was, in our hands, 37%. In an effort to directly convert commercially available 27 to 35, bromination with Br₂-AlCl₃ was attempted, however, only the undesired isomer 36 was observed under the reaction conditions (Scheme 5, Conditions A). However, when 27 was treated with N-bromosuccinimide (NBS) in sulfuric acid, conditions previously employed in our laboratory,¹⁹ both the desired bromoindanone 35 and its regioisomer 36 were obtained in 32% and 41% isolated yields, respectively. The isomers were readily separated by chromatography. Although the yields of the desired product 35 were similar either by a bromination of 5-methylindanone (27) (Scheme 5) or in three steps from 27 via aniline 28 (Schemes 2 and 4), the former approach was more direct.

Scheme 4.

Synthesis of intermediate 35 via diazotation- bromination of 28.

Scheme 5.

Synthesis of intermediate 35 by direct bromination of 27.

Nitration of 35 using fuming HNO₃ and concentrated H₂SO₄ gave, as expected, two isomeric products (Scheme 6). The desired nitroindanone 38 was isolated as the major product (64%) and the isomer 37 as the minor product (17%). Nitroindanone 38 was then subjected to a Kosugi-Migita-Stille cross coupling with (E)-tributyl(3-hydroxy-1-propenyl)stannane (25).²⁰ Upon optimization, we were gratified to find that cyclization precursor 24 could be obtained cleanly in 55% yield. Compound 24 was then subjected to reductive cyclization conditions previously developed in our laboratories.²¹ In the event, compound 24 was treated with carbon monoxide in the presence of a catalytic amount of bis(dibenzylidene)acetone palladium, 1,10-phenanthroline, and 1,2-bis(diphenylphophino)propane. A number of related palladium-ligand combinations were examined including palladium diacetate - triphenylphosphine.²² However, all attempts to form dilemmaone B were unsuccessful only resulting in recovery of starting material (24).

Scheme 6.

Second synthetic approach to dilemmaone B.

Theorizing that the free alcohol or the electron withdrawing effect of the ketone could affect the cyclization, compound 38 was first converted to 2-nitrostyrene derivative 40 in 80% yield via a Kosugi-Migita-Stille cross coupling with (E]-tributyl(3-methoxy-1-propenyl)stannane (39)²³ (Scheme 7). However, cyclization of 40 using a palladium diacetate - triphenyl phosphine catalyst system in the presence of carbon monoxide did again fail. Finally, compound 40 was treated with trimethyl orthoformate under acidic conditions in an attempt to isolate the corresponding dimethylacetal. Surprisingly the corresponding methoxyindene (41) was isolated in place of the acetal in low yield. Surmising that this unexpected product was sufficiently altered in its electronics from compound 24, derivative 41 was subjected to reductive cyclization conditions. Upon examination of the crude ¹H NMR, no indole product (42) was observed. Rather, chemical shifts indicated conversion back to indanone 40. Based upon these results, the free alcohol or electronics of the system were likely not the reason for the lack of reactivity under palladium catalyzed, carbon monoxide mediated conditions.

Scheme 7.

Synthesis and attempted cyclization of derivative 41.

In an effort to effect cyclization by alternative methods, both 2-nitrostyrene derivatives, 24 and 40, were subjected to an array of other reductive cyclizations conditions. Thus, in addition to cyclization conditions described above, TiCl₃-promoted reductive cyclization,²⁴ diborane-mediated deoxygenation,²⁵ and a modified Cadogan-Sundberg cyclization²⁶ were attempted. In all cases, cyclization to the desired indole was never observed, but rather starting material 24 or 40 was recovered in various amounts. It is plausible that the substrates are too sterically encumbered to undergo reductive cyclization. This is supported by the lack of examples of reductive cyclizations of 3,6-disubstituted-2-nitrostyrenes to give 4,7-disubstituted indoles, using a variety of reducing agents. The only previously described sterically encumbered starting material successfully cyclized to form the corresponding indole is methyl 3-(3,6-dibromo-4,5-dimethoxy-2-nitrophenyl)propanoate. This transformation was achieved under modified Cadogan-Sundberg conditions using triphenyphosphine and a catalytic amount of MoO₂Cl₂(dmf)₂ under microwave heating.²⁷

Due to the steric encumbrance of the dilemmaone core being unavoidable, and our proposed late-stage cyclization of 2-nitrostyrene 24 having thus been ruled out as a possible mean of access, an alternate pathway was envisioned. Compound 24 was transformed into epoxide 43 using 4 equivalents of 3-chloroperbenzoic acid (3-CPBA, Scheme 8). It was anticipated that treatment of 43 with Pd/C and H₂ would not only result in a reduction of the nitro group to the corresponding amine or hydroxylamine, but also a subsequent epoxide ring-opening and elimination to afford the desired product, dilemmaone B (2). To the best of our knowledge, this type of transformation has only been reported once in the literature.²⁸ Our first attempt did afford an indole from 43, however, the ¹H NMR chemical shifts were similar but not in complete agreement with the shifts reported by Faulkner et al for dilemmaone B. The structure of the isolated indole product 44 was determined to be the N-hydroxy analog of dilemmaone B (Scheme 8), the product derived from incomplete reduction of the nitro group to a hydroxylamine. Additionally, 46% of unreacted starting material 43 was also isolated.

Scheme 8.

Synthesis of derivative 44 via sequential epoxidation-reductive cyclization.

Encouraged by this result, we examined this reductive cyclization for its viability toward the synthesis of dilemmaone B. As our first attempt had yielded 27% of the N-hydroxy derivative (44) and had not run to completion, the reaction was performed at a slightly elevated temperature (50 °C, Table 1, entry 2). In this case, the reaction proceeded to completion, but the only product isolated was N-hydroxyindole 44, in a somewhat higher yield. N-Hydroxyindoles have been shown to be readily deoxygenated using Pd/C-H₂ (pCO = 1 atm) at ambient temperature.²⁹ Thus, N-hydroxyindole (44) was treated with H₂ (2.7 atm) in the presence of Pd/C and the reaction was carefully monitored by TLC. It was observed that starting material had been completely converted to dilemmaone B (2) in 27% yield after 2 h (Table 1, entry 3). The successful formation of dilemmaone B from N-hydroxyindole 44 suggests that a one pot reductive cyclization to give 44 followed by deoxygenation to afford dilemmaone B (2) should be possible using the conditions described in entry 3. However, after complete consumption of the starting material, it was found that over-reduction had occurred, resulting in the formation of 2,4-dimethylindole derivative 45 (Table 1, entry 4). Reductive transformations of 2-hydroxymethylindoles to give 2-methylindoles have been described using platinum black under 2.7 atm of H₂ in methanol.³⁰

Table 1.

Reductive cyclizations to give dilemmaone B (2), 44, or 45.

Entrya		Catalyst	Time	2	44	45
1b	43	Pd/C (0.02 equiv Pd)	16 h	-	27% (50%)c	-
2	43	Pd/C (0.02 equiv Pd)	16 h	-	37%	-
3	44	Pd/C (0.05 equiv Pd)	2 h	27%	-	-
4	43	Pd/C (0.05 equiv Pd)	16 h	-	-	16%
5	43	PtO2 (0.02 eauiv)	3 h	48%	-	-

^aAll reactions were performed in EtOH under 2.7 atm of H₂ using Pd/C (10 mol% Pd) at 50 °C unless otherwise noted. The starting material was completely consumed. Yields reported are isolated yields after chromatography. See experimental section for details.

^bReaction performed at ambient temperature.

^cBased on recovered starting material.

In an effort to obtain dilemmaone B (2) directly from the epoxide precursor, a different reducing agent was selected. Upon subjecting 43 to PtO₂ and H₂ (pCO = 2.7 atm) at 50 °C, we were gratified to find that dilemmaone B was obtained in 48% isolated yield after 3 h. Neither N-hydroxyindole 44 nor 2,5-dimethylindole 45 were observed (Table 1, entry 5).

It is worth noting that, while the identities of N-hydroxyindole 44 and dilemmaone B (2) can be confirmed and differentiated via ¹H NMR analysis in CDCl₃, their solubilities are poor in CDCl₃ and thus splitting patterns are unclear. Conversely, both compounds are readily soluble in DMSO-d₆, however, their ¹H NMR chemical shifts are strikingly similar in this solvent, necessitating structural confirmation by ¹H-¹⁵N gHMBCAD experiments (See supplemental materials. Dilemmaone B (2) exhibits a ¹H-¹⁵N correlation between the ¹H resonance at 11.30 ppm and the ¹⁵N peak at −246.6 ppm. No correlation is seen between the ¹H peak of N-hydroxyindole 44 at 11.30 ppm and its ¹⁵N resonance at −199.0 ppm. Full characterization data for both compounds can be found in the experimental section.

Synthesis of Dilemmaone A

With the synthesis of dilemmaone B successfully completed, we turned our attention to dilemmaone A (1), which differs in structure only at the C2 position with the presence of a 2-methoxymethyl rather than a 2-hydroxymethyl substituent. Epoxidation of 40 proceeded smoothly to furnish compound 46 in 51% yield (Scheme 9). Cyclization precursor 46 was then subjected to reductive conditions using both Pd/C and PtO₂.

Scheme 9.

Synthesis of dilemmaone A.

a) Pd/C (0.02 equiv Pd), 2.7 atm H₂, EtOH, 16 h, 50 °C. 30%.

b) PtO₂ (0.02 equiv), 2.7 atm H₂, EtOH, 4 h, 50 °C. 25%.

Interestingly, both conditions led to clean conversion of epoxide 45 to dilemmaone A (1) in comparable yields. While Pd/C (0.02 equiv) consistently led to the production of N-hydroxyindole 44 while attempting to form dilemmaone B, the same conditions fully reduced precursor 45 to dilemmaone A, and the corresponding N-hydroxyindole was not observed. While the use of PtO₂ worked cleanly toward the production of both dilemmaones A and B, it seems that the use of Pd/C is marginally more effective for the reductive cyclization of epoxide 45.

Conclusions

Dilemmaones A and B can be efficiently prepared from 2,3-dihydro-5-methylinden-1-one (27), with both syntheses featuring a Kosugi-Migita-Stille coupling and an interesting one-pot reductive cyclization using H₂ and either a Pd/C or PtO₂ catalyst. Dilemmaone B (2) was synthesized in 5 steps with an overall yield of 4.0 %. From a common intermediate 6-bromo-5-methyl-7-nitroindan-1-one (38), dilemmaone A (1) was synthesized in 3 additional steps with an overall yield of 12.2 %. The !H NMR data in CDCl₃ for synthetic dilemmaone A and B and the compounds isolated by Faulkner et al from the sponge Ectyonanchora flabellata are almost identical. The range in difference in ¹H NMR chemical shifts between isolated and synthetic material was 0.07 ppm (−0.01 to 0.06 ppm) and 0.13 ppm (−0.12 to 0.01) for dilemmaone A (1) and dilemmaone B (2), respectively. Due to their low solubility in CDCl3, the synthetically prepared alkaloids were fully characterized by ¹H and ¹³C NMR in DMSO-d₆. Probably due to the very limited amount of dilemmaone 2 isolated, Faulkner et al did not observe any of the seven quaternary ¹³C NMR resonances. It should be noted that while the melting point for synthetic 1 was only slightly higher compared to the isolated compound, the melting point of synthetic 2 was twenty degrees higher compared to isolated 2.

As the scope of reductive cyclization of 2-nitrostyrene derived epoxides using either Pd/C or PtO₂ has not yet been explored, studies are ongoing in our laboratory to determine its versatility.

Experimental Section

General Procedures.

NMR spectra were determined in CDCl₃ or DMSO-d₆ at 400 or 600 MHz (¹H NMR) and at 100 or 151 MHz (¹³C NMR). ¹⁵N NMR chemical shifts were determined in DMSO-d₆ at 60.6 MHz via ¹H-¹⁵N gHSQCAD experiments. The chemical shifts are expressed in δ values relative to SiMe₄ (0.0 ppm, ¹H and ¹³C) or CDCl₃ (77.0 ppm, ¹³C) internal standards. The multiplicity of each resonance observed in the ¹H NMR spectra are reported as, br = broad; s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. Hexanes and ethyl acetate (EtOAc) were distilled prior to use. Tetrahydrofuran (THF) was purified/dried via two consecutive columns composed of activated alumina and Q5 catalyst on a Glass Contours solvent purification system. Toluene and 1,4-dioxane were purified/dried via two consecutive columns composed of activated alumina on a Glass Contours solvent purification system. N-bromosuccinimide (NBS) was recrystallized prior to use. Chemicals prepared according to literature procedures have been footnoted the first time discussed in the Results and Discussion section; all other reagents were obtained from commercial sources and used as received. Solvents were removed from reaction mixtures and products on a rotary evaporator at water aspirator pressure. Melting points are uncorrected.

N-(5-Methyl-1-oxo-1H-indan-6-yl)acetamide (29).

To a solution of 28 (4.62 g, 28.7 mmol) in dichloromethane (DCM, 100 mL) was added triethylamine (3.19 g, 31.5 mmol) at ambient temperature. After 15 min, ethanoyl chloride (2.70 g, 34.4 mmol) was added drop wise and the reaction mixture was stirred for 22 h at ambient temperature. The crude reaction mixture was washed with water (2 × 100 mL) and brine (100 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc) to give 29 (4.86 g, 23.9 mmol, 84%) as a tan solid. mp = 221-223 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.99 (s, 1H), 7.33 (s, 1H), 6.98 (br s, 1H), 3.07 (t, J = 4.8 Hz, 2H), 2.68 (t, J = 5.4 2H), 2.35 (s, 3H), 2.23 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 206.1, 168.6, 152.4, 138.9, 135.9, 135.2, 128.4, 119.2, 36.6, 25.3, 24.0, 18.9; IR (ATR) 3310, 1691, 1656, 1527, 864 cm⁻¹; HRMS (ESI) calculated for C₁₂H₁₄NO₂ (M+H₊) 204.1019, found 204.1019.

N-(5-Methyl-7-nitro-1-oxo-1H-indan-6-yl)acetamide (30).

Fuming nitric acid (10 mL) was stirred at −20 °C for 5 min, 25 drops of H₂SO₄ (conc.) was added and the resulting mixture was stirred at −20 °C for 20 min. This mixture was added drop wise to 29 (1.00 g, 4.92 mmol), cooled to −20 °C and stirred at the same temperature for 1.5 h. Water (20 mL) and saturated NH4G (aqueous, 20 mL) was sequentially added and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with H₂O (3 × 50 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (EtOAc) to afford 30 (860 mg, 3.46 mmol, 70%) as a white solid. mp = 225-227 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.53 (s, 1H), 7.17 (br s, 1H), 3.14 (t, J = 6.0 Hz, 2H), 2.79 (t, J = 6.3 Hz, 2H), 2.39 (s, 3H), 2.18 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 200.4, 168.9, 154.6, 146.3, 142.4, 130.7, 126.7, 126.1, 36.8, 25.3, 23.2, 19.5; IR (ATR) 3347, 1718, 1673, 1536, 782 cm⁻¹; HRMS (ESI) calculated for C₁₂H₁₃N₂O₄ (M+H⁺) 249.0870, found 249.0871.

6-Amino-5-methyl-7-nitroindan-1-one (31).

A solution of 30 (140 mg, 0.56 mmol) and 5 M HCl (aqueous, 10 mL) in absolute ethanol (15 mL) was heated at reflux for 18 h. The ethanol was removed in vacuo and the resulting aqueous solution was made alkaline (pH 8-9) with a saturated NaOH solution (aqueous). The solution was extracted with DCM (3 × 20 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes/EtOAc, 1:1) to afford 31 (98 mg, 0.48 mmol, 84%) as a bright yellow solid. mp = 229-231 °C; ¹H NMR (600 MHz, CDCl₃ + DMSO-d₆) δ 7.31 (s, 1H), 5.10 (br s, 2H), 2.98 (t, J = 5.6 Hz, 2H), 2.73 (t, J = 5.7 Hz, 2H), 2.32 (s, 3H); ¹³C NMR (151 MHz, CDCl₃-DMSO-d₆) δ 199.6, 143.9, 139.2, 133.5, 129.8, 127.5, 127.0, 35.8, 23.3, 17.8; IR (ATR) 3460, 3362, 1689, 1634, 1518, 1313, 887 cm⁻¹; HRMS (ESI) calculated for C₁₀H₁₁N₂O₃ (M+H⁺) 207.0764, found 207.0764.

6-Iodo-5-methyl-7-nitroindan-1-one (32).

To an ice cold solution of 31 (21 mg, 0.10 mmol) in HCl (conc., 1 mL) was added drop wise a solution of sodium nitrite (8 mg, 0.11 mmol) in H₂O (1 mL). After 30 min of at 0 °C, the resulting mixture was added drop wise to a solution of potassium iodide (50 mg, 0.30 mmol) in H₂O (1 mL) at ambient temperature. After 16 h at ambient temperature, the mixture was extracted with DCM (3 × 20 mL). The combined organic phases were washed in sequence with 10% NaOH (aqueous, 20 mL), 5% NaHCO₃ (aqueous, 20 mL), and H₂O (20 mL) before being dried (MgSO₄), filtered, and concentrated in vacuo. The resulting dark yellow residue was purified by chromatography (hexanes/EtOAc, 9:1 then 8:2) to afford 32 (20 mg, 0.063 mmol, 63%) as an off-white solid. mp = 173-175 °C; *H NMR (400 MHz, CDCl₃) δ 7.29 (s, 1H), 3.00 (t, J = 6.0 Hz 2H), 2.75 (t, J = 6.6 Hz, 2H), 2.61 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 201.8, 156.8, 150.4, 136.1, 131.6, 125.8, 107.3, 36.9, 31.1, 24.5; IR (ATR) 2923, 1694, 1432, 1149, 871 cm⁻¹; HRMS (ESI, negative mode) calculated for C₁₀H₇INO₃ (M-H⁻) 315.9471, found 315.9479.

6-Amino-7-bromo-5-methylindan-1-one (34).

2,3,5,6-Tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (33)¹³ (2.13 g, 4.55 mmol) was added to a solution of 28 (733 mg, 4.55 mmol) in ethanoic acid (5 mL). The resulting solution was stirred for 4 h at ambient temperature and then poured into a 10% NaHCO₃ solution (aqueous, 15 mL). The resulting suspension was extracted with DCM (3 × 30 mL) and the combined organic phases were washed with H₂O (2 × 30 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The resulting residue was purified by chromatography (hexanes/EtOAc, 8:2) to afford 34 (640 mg, 2.66 mmol, 59%) as a brown solid. mp=177-179 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.11 (s, 1H), 4.26 (br s, 2H), 2.95 (t, J = 5.7 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 204.2, 147.4, 142.4, 132.5, 131.2, 126.7, 103.6, 37.4, 23.8, 19.2; IR (ATR) 3378, 3352, 1688, 1621, 1469, 1318, 871 cm⁻¹; HRMS (ESI) calculated for C₁₀H₁₁BrNO (M+H⁺) 240.0024, found 240.0018.

6-Bromo-5-methylindan-1-one (35).

A solution of 28 (100 mg, 0.62 mmol) in 48% HBr (aqueous, 500 μL), H₂O (1 mL), and 1,4-dioxane (500 μL) was heated at reflux for 20 min. The resulting solution was cooled to ambient temperature and placed in an ice bath. A solution of NaNO₂ (40 mg, 0.62 mmol) in H₂O (1 mL) was added dropwise, and the resulting orange solution was stirred at 0 °C for 20 min. This solution was added drop wise to a solution of CuBr (100 mg, 0.68 mmol) in 48% HBr (aqueous, 500 μl) and H₂O (1 mL) at 0 °C, during which time the evolution of gas was observed. The resulting dark red-brown solution was warmed to ambient temperature and stirred for 16 h. Saturated NaHCO₃ (aqueous) was slowly added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with H₂O (10 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes/EtOAc 8:2) to afford 35 (104 mg, 0.46 mmol, 75%) as an orange solid.

6-Bromo-5-methylindan-1-one (35) and 4-bromo-5-methylindan-1-one (36).

Compound 27 (2.00 g, 13.7 mmol) was added to H₂SO₄ (conc., 15 mL) at ambient temperature. N-bromosuccinimide (NBS, 3.05 g, 17.1 mmol) was added in portions, and the resulting orange solution was stirred at ambient temperature for 3 h. The reaction was quenched by addition of ice and the solution was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated NaHCO₃ (aqueous, 15 mL) and brine (15 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes/EtOAc, 9:1 then 7:3) to afford, in order of elution, 35 (973 mg, 4.33 mmol, 32%) as an orange solid and 36 (1.26 g, 5.61 mmol, 41%) as a pale orange solid.

Analytical data for 35: mp = 114-116 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.36 (s, 1H), 3.05 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 6.2 Hz, 2H), 2.48 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 205.1, 154.0, 144.9, 136.7, 128.6, 127.4, 124.3, 36.5, 25.3, 23.9; IR (ATR) 1702, 1597, 1432, 1379, 1171, 884 cm⁻¹; HRMS (ESI) calculated for C₁₀H₁₀BrO (M+H⁺) 224.9915, found 224.9918.

Analytical data for 36: mp = 65-68 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.61 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 3.07 (t, J = 5.8 Hz, 2H), 2.73 (t, J = 6.0 Hz, 2H), 2.51 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 205.8, 155.4, 145.1, 136.8, 130.2, 124.1, 122.0, 36.4, 27.5, 23.1; IR (ATR) 1702, 1595, 1258, 1116, 1038, 808 cm⁻¹; HRMS (ESI) calculated for C₁₀H₁₀BrO (M+H⁺) 224.9915, found 224.9917.

4-Bromo-5-methylindan-1-one (36).

A solution of 27 (500 mg, 3.42 mmol) in DCM (4 mL) was added drop wise over 30 min to a suspension of aluminum trichloride (910 mg, 6.84 mmol) in DCM (4 mL). To the resulting solution was added dropwise a solution of Br₂ (190 μL, 3.76 mmol) in DCM (4 mL). The dark red-orange solution was heated at 50 °C for 22 h. The solution was cooled to ambient temperature and water (5 mL) was slowly added. The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by chromatography (hexanes/EtOAc 9:1) to afford 36 (92 mg, 0.41 mmol, 12%) as a pale orange solid.

6-Bromo-5-methyl-4-nitroindan-1-one (37) and 6-Bromo-5-methyl-7-nitroindan-1-one (38).

Compound 35 (1.52 g, 6.77 mmol) was treated with fuming HNO₃ (15 mL) and conc. H₂SO₄ (40 drops) as described for 30 (−20 °C, 90 min). Purification by chromatography (hexanes/EtOAc, 7:3 then EtOAc) gave, in order of elution, 37 (317 mg, 1.18 mmol, 17%) as an off-white solid and 38 (1.15 g, 4.30 mmol, 64%) as an orange solid. Analytical data for 37: mp = 145 °C (sublimation); ¹H NMR (600 MHz, CDCl₃) δ 8.11 (s, 1H), 3.18 (t, J = 5.8 Hz, 2H), 2.78 (t, J = 6.1 Hz, 2H), 2.56 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 202.6, 149.3, 145.7, 137.8, 137.3, 130.1, 126.2, 35.9, 23.8, 19.6; IR (ATR) 3069, 1712, 1527, 1356, 1241, 1199, 1161 cm⁻¹; HRMS (ESI) calculated for C₁₀H₉BrNO₃ (M+H⁺) 271.9766, found 271.9748.

Analytical data for 38: mp = 137-138 °C; ¹H NMR (600 MHz, CDCl₃) δ 7.51 (s, 1H), 3.12 (t, J = 5.8 Hz, 2H), 2.79 (t, J = 6.1 Hz, 2H), 2.57 (s, 3H); ¹³C NMR (151 MHz, CDCl₃-DMSO-d₆) δ 199.7, 154.7, 147.0, 145.4, 129.7, 126.3, 114.1, 36.3, 25.0, 23.9; IR (ATR) 2928, 1704, 1599, 1538, 1431, 1375, 1309, 1165, 887, 801 cm⁻¹; HRMS (ESI) calculated for C₁₀H₉BrNO₃ (M+H⁺) 271.9766, found 271.9745.

6-(3-Hydroxy-1-propenyl)-5-methyl-7-nitroindan-1-one (24).

To an oven-dried flask equipped with a condenser was added 38 (688 mg, 2.56 mmol), PdCl₂(PPh₃)₂ (36 mg, 0.05 mmol) and PPh₃ (27 mg, 0.10 mmol), and the system was purged with N₂. 1,4-dioxane (anhydrous, 15 mL) was added via syringe, and the solution was stirred at ambient temperature. (E)-3-(Tributylstannyl)-2-propen-1-ol (25)¹⁸ (1.15 g, 3.33 mmol) dissolved in 1,4-dioxane (5 mL) was added via syringe and the solution was heated at 110 °C for 120 h. After allowing the mixture to cool to ambient temperature, water (20 mL) was added and the solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (3 × 30 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes/EtOAc, 2:8) to afford 24 (345 mg, 1.40 mmol, 55%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃, HO not observed) δ 7.42 (s, 1H), 6.51 (d, J = 16.2 Hz, 1H), 6.06 (dt, J = 16.2, 4.6 Hz, 1H), 4.31 (br s, 2H), 3.13 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.43 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 201.2, 154.8, 146.3, 144.0, 137.2, 129.3, 128.1, 125.1, 120.5, 62.7, 36.5, 25.2, 21.3; IR (ATR) 3409, 2924, 1710, 1614, 1536, 1381, 1314, 1124, 1022 cm⁻¹; HRMS (ESI) calculated for C₁₃H₁₄NO₄ (M+H⁺) 248.0923, found 248.0928.

6-(3-Methoxy-1-propenyl)-5-methyl-7-nitroindan-1-one (40).

To an oven-dried flask equipped with a cold water condenser were added 38 (601 mg, 2.23 mmol), PdCl₂(PPh₃)₂ (32 mg, 0.05 mmol), and PPh₃ (24 mg, 0.09 mmol), and the system was purged with N₂. 1,4-dioxane (anhydrous, 15 mL) was added via syringe, and the solution was stirred at ambient temperature. (E)-Tributyl(3-methoxy-1-propenyl)stannane (39)²³ (1.05 g, 2.90 mmol) in 1,4-dioxane (anhydrous, 7 mL) was added via syringe and the solution was heated to 110 °C for 120 h. The resulting reaction mixture was cooled to ambient temperature and H₂O (20 mL) was added. The solution was extracted with EtOAc (3 × 30 mL) and the combined organic phases were washed with brine (3 × 30 mL), dried (MgSO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (hexanes/EtOAc 1:1) to afford an approximately 10:1 ratio of E- to Z-40 (467 mg, 1.79 mmol, 80%) as an orange solid. Analytical data of the major isomer from the mixture. mp = 109-113 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.42 (s, 1H), 6.48 (d, J = 16.3 Hz, 1H), 5.99 (dt, J =16.3, 5.0 Hz, 1H), 4.05 (dd, J = 5.0, 1.8 Hz, 2H), 3.39 (s, 3H), 3.13 (t, J = 5.8 Hz, 2H), 2.74 (t, J = 6.0 Hz, 2H), 2.43 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 200.9, 154.8, 146.2, 134.9, 131.9, 129.3, 128.2, 125.2, 122.0, 72.2, 58.3, 36.5, 25.2, 21.4; IR (ATR) 2929, 1716, 1615, 1539, 1441, 1382, 1315, 1186, 1120 cm⁻¹; HRMS (ESI) calculated for C₁₄H₁₆NO₄ (M+H⁺) 262.1074, found 262.1084. Partial analytical data of non-overlapping signals of the minor isomer from the mixture. ¹H NMR (400 MHz, CDCl₃) δ 6.26 (d, J = 14.4 Hz, 1H), 5.75 (m, 1H), 3.33 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 72.6, 57.9.

3-Methoxy-5-(3-methoxy-1-propen-1-yl)-6-methyl-4-nitroind-1-ene (41).

To a solution of 40 (101 mg, 0.39 mmol) in MeOH (3 mL) was added p-toluenesulfonic acid (3 mg, 0.02 mmol) followed by trimethyl orthoformate (84 μL, 0.77 mmol). The resulting solution was stirred at ambient temperature for 16 h before being diluted with EtOAc (5 mL) and NaOH (aqueous, 1M, 5 mL). The mixture was extracted with EtOAc (3 × 10 mL), and the combined organic phases were dried (MgSO₄), filtered, and concentrated in vacuo. Purification by chromatography (hexanes/EtOAc 7:3 then 1:1) gave, in order of elution, 41 (13 mg, 0.05 mmol, 12%) as a viscous yellow oil and 40 (11 mg, 0.04 mmol, 11%). ¹H NMR (600 MHz, CDCl₃) δ 7.30 (s, 1H), 6.53 (d, J = 16.3 Hz, 1H), 5.94 (dt, J = 16.2, 5.4 Hz, 1H), 5.35 (t, J = 2.4 Hz, 1H), 4.07-4.05 (m, 2H), 3.79 (s, 3H), 3.38 (s, 3H), 3.30 (d, J = 2.3 Hz, 2H), 2.36 (s, 3H); ¹³C NMR (151 MHz, CDCl₃) δ 156.2, 143.8, 135.0, 133.3, 128.0, 126.9, 126.8, 124.2, 110.0, 100.0, 72.6, 58.0, 57.3, 33.6, 20.6; IR (ATR) 2927, 1712, 1613, 1533, 1379, 1116 cm⁻¹; HRMS (ESI) calculated for C₁₅H₁₈NO₄ (M+H⁺) 276.1236, found 276.1232.

6-(1,2-Epoxy-3-hydroxypropyl)-5-methyl-7-nitroindan-1-one (43).

Compound 24 (340 mg, 1.40 mmol) was dissolved in DCM (10 mL), and the solution was cooled to 0 °C. 3-Chloroperoxybenzoic acid (3-CPBA, 70-75%/wt, 1.38 g, 5.60 mmol) was added in portions. The resulting suspension was warmed to ambient temperature and stirred for 16 h. The reaction mixture was quenched by slow addition of saturated Na₂SO₃ (aqueous, 10 mL) and diluted with DCM (5 mL), then washed with saturated NaHCO₃ (aqueous, 10 mL) and brine (10 mL). The organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo. The resulting residue was purified by chromatography (EtOAc) to afford 43 (268 mg, 1.02 mmol, 74%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (s, 1H), 4.09 (s, 1H), 4.02 (d, J = 13.4 Hz, 1H), 4.02 (d, J = 13.2, 1H), 3.85 (t, J = 14.9 Hz, 1H), 3.19 (s, 1H), 3.13 (t, J = 5.9 , 3H), 2.76 (t, J = 5.8 Hz, 2H), 2.57 (s, 3H), 1.63 (t, J = 6.8 Hz, 1H); ¹³C NMR (151 MHz, CDCl₃) δ 200.8, 155.9, 147.0, 144.0, 130.0, 126.1, 125.3, 60.5, 59.2, 51.5, 36.5, 25.2, 20.1; IR (ATR) 3419, 2927, 1713, 1618, 1541, 1372, 1309, 1121, 903 cm⁻¹; HRMS (ESI) calculated for C₁₃H₁₄NO₅ (M+H⁺) 264.0866, found 264.0876.

6,7-Dihydro-2-(hydroxymethyl)-4-methylcyclopent[g]-(N-hydroxy)indol-8(1H)-one (44).

To a thick-walled pressure tube was added 43 (84 mg, 0.32 mmol) and Pd/C (10%-Pd, 7 mg, 0.006 mmol). Absolute EtOH (3 mL) was added and the resulting suspension was charged with hydrogen gas (2.7 atm). The reaction mixture was heated at 50 °C for 12 h. The solution was cooled to ambient temperature and filtered through Celite. The Celite was washed with hot absolute ethanol and the filtrate was concentrated in vacuo. The residue was purified by chromatography (hexanes/EtOAc, 1:1) affording 44 (27 mg, 0.12 mmol, 37%) as a yellow solid. mp = 164-166 °C; ¹H NMR (400 MHz, DMSO-d₆/CDCl₃) δ 11.70 (br s, 1H), 6.87 (s, 1H), 6.39 (s, 1H), 4.98 (t, J = 5.8 Hz, 1H), 4.73 (d, J = 5.6 Hz, 2H), 3.26-3.22 (m, 2H), 2.77-2.73 (m, 2H), 2.55 (s, 3H); ¹H NMR (400 MHz, CDCl₃) δ 12.17 (s, 1H), 6.88 (s, 1H), 6.39 (s, 1H), 4.86 (d, J = 6.6 Hz, 2H), 3.39 (t, J = 5.1 Hz, 2H), 2.84-2.79 (m, 2H), 2.57 (s, 3H), 2.23 (t, J = 6.6 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆/CDCl₃) δ 206.8, 153.1, 140.4, 135.3, 125.6, 121.1, 118.4, 116.6, 95.2, 54.3, 35.5, 27.0, 18.7; ¹⁵N NMR (60.8 MHz, DMSO-d₆) δ - 199.0; IR (ATR) 3350, 2925, 1614, 1367, 1299, 1158, 1076, 1006 cm⁻¹; HRMS (ESI) calculated for C₁₃H₁₄NO₃ (M+H⁺) 232.0968, found 232.0978.

6,7-Dihydro-2,4-dimethylcyclopent[g]indol-8(1H)-one (45).

Treatment of 43 (58 mg, 0.22 mmol) with Pd/C (10% Pd, 12 mg, 0.011 mmol) in absolute ethanol (3 mL) under 2.7 atm of H₂, as described for 44 (50 °C, 16 h), gave after chromatography (hexanes/EtOAc, 1:1) 45 as a pale-orange viscous oil. ¹H NMR (600 MHz, CDCl₃) δ 9.30 (br s, 1H), 6.93 (s, 1H), 6.27 (s, 1H), 3.19 (t, J = 5.4 Hz, 2H), 2.71 (t, J = 5.5 Hz, 2H), 2.58 (s, 3H), 2.48 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 206.7, 151.4, 138.7, 135.0, 130.3, 128.1, 119.2, 117.7, 99.0, 36.5, 26.6, 19.7, 13.6; IR (ATR) 3327, 2921, 1678, 1633, 1554, 1298 cm⁻¹; HRMS (ESI) calculated for C₁₃H₁₄NO (M+H⁺) 200.1075, found 200.1070.

Dilemmaone B (2).

Treatment of 44 (17 mg, 0.074 mmol) with Pd/C (10%-Pd, 4 mg, 0.004 mmol) in EtOH (3 mL) under 2.7 atm of H₂, as described for 45 (50 °C, 2 h), gave after chromatography (hexanes/EtOAc, 2:8) 2 (4 mg, 0.02 mmol, 27%) as an off-white solid.

Alternative method: Treatment of 43 (126 mg, 0.48 mmol) with PtO₂ (3 mg, 0.010 mmol) in EtOH (3 mL) under 2.7 atm H₂, as described for 45 (50 °C, 3 h), gave after chromatography (hexanes/EtOAc, 2:8) 2 (49 mg, 0.23 mmol, 48%) as an off-white solid. mp = 188-190 °C; ¹H NMR (400 MHz, CDCl₃, broad signals observed due to low solubility in CDCl₃) δ 9.70 (1H), 6.97 (1H), 6.49 (1H), 4.87 (2H), 3.21 (2H), 2.73 (2H), 2.60 (3H), 2.04 (1H); ¹H NMR (600 MHz, DMSO-d₆) δ 11.33 (br s, 1H), 6.94 (s, 1H), 6.43 (s, 1H), 5.09 (t, J = 6.0 Hz, 1H), 4.61 (d, J = 6.1 Hz, 2H), 3.13 (t, J = 5.4 Hz, 2H), 2.62 (t, J = 5.5 Hz, 2H), 2.53 (s, 3H); ¹³C NMR (151 MHz, DMSO-d₆) δ 204.7, 151.4, 140.8, 138.1, 129.4, 127.3, 119.3, 117.2, 98.1, 56.6, 35.9, 26.0, 19.2; ¹⁵N NMR (60.8 MHz, DMSO-d₆) δ −246.6; IR (ATR) 3376, 2851, 1634., 1556, 1439, 1299, 1233, 1125, 1025 cm⁻¹; HRMS (ESI) calculated for C₁₃H₁₄NO₂ (M+H⁺) 216.1019, found 216.1028.

6-(1,2-Epoxy-3-methoxypropyl)-2,3-dihydro-5-methyl-7-nitroinden-1-one (46).

Treatment of a solution of 40 (220 mg, 0.84 mmol) in DCM (5 mL) with m-CPBA (70-75%/wt, 830 mg, 3.36 mmol), as described for 43, gave after chromatography (hexanes/EtOAc 2:8) 46 (119 mg, 0.43 mmol, 51%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (s, 1H), 3.95 (d, J = 1.8 Hz, 1H), 3.77(dd, J = 11.7, 2.8 Hz, 1H), 3.54 (dd, J = 11.7, 4.8 Hz, 1H), 3.42 (s, 3H), 3.18-3.10 (m, 3H), 2.77-2.70 (m, 2H), 2.56 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 216.0, 200.5, 186.8, 155.9, 147.2, 130.0, 126.0, 125.2, 71.2, 59.4, 57.7, 51.4, 36.5, 25.2, 20.2; IR (ATR) 2929, 1714, 1618, 1541, 1449, 1371, 1309, 1110, 907 cm⁻¹; HRMS (ESI) calculated for C₁₄H₁₆NO₅ (M+H⁺) 278.1028, found 278.1025.

Dilemmaone A (1).

Method A (Scheme 8): 46 (88 mg, 0.32 mmol) was treated with Pd/C (10% Pd, 7 mg, 0.006 mmol) and EtOH (3mL) under 2.7 atm H₂ as described for 2 (50 °C, 16 h) to afford after purification (hexanes/EtOAc, 1:1) 1 (22 mg, 0.10 mmol, 30%) as an off-white solid.

Method B (Scheme 8): 46 (119 mg, 0.43 mmol) was treated with PtO₂ (2 mg, 0.009 mmol) and EtOH (3 mL) under 2.7 atm of H₂ as described for 2 (50 °C, 4 h) to afford after chromatography (hexanes/EtOAc, 1:1) 1 (25 mg, 0.11 mmol, 25%) as an off-white solid. mp = 151-154 °C; ¹H NMR (400 MHz, CDCl₃) δ 9.52 (br s, 1H), 6.95 (s, 1H), 6.50 (s, 1H), 4.61 (s, 2H), 3.37 (s, 3H), 3.21 (t, J = 5.6 Hz, 2H), 2.72 (t, J = 5.5 Hz, 2H), 2.59 (s, 3H); ¹H NMR (600 MHz, DMSO-d₆) δ 11.59 (s, 1H), 6.95 (s, 1H), 6.52 (s, 1H), 4.54 (s, 2H), 3.28 (s, 3H), 3.12 (t, J = 5.6 Hz, 2H), 2.62 (t, J = 5.6 Hz, 2H), 2.54 (s, 3H); ¹³C NMR (151 MHz, DMSO-d₆) δ 204.6, 152.1, 138.4, 136.3, 129.5, 127.3, 119.5, 117.3, 100.4, 66.4, 57.2, 35.9, 26.1, 19.3; ¹⁵N NMR (60.8 MHz, DMSO-d₆) δ −241.2 ppm; IR (ATR) 3339, 1658, 1560, 1294, 1129, 971, 793, 708 cm⁻¹; HRMS (ESI) calculated for C₁₄H₁₆NO₂ (M+H⁺) 230.1181, found 230.1174.

Highlights.

• Total syntheses and structure corroboration of dilemmaones A-B