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Synthesis 2024; 56(02): 346-356
DOI: 10.1055/a-2186-7034
paper

Examination of Diels–Alder/Tsuji–Trost Route towards Kopsia Alkaloids

Ekaterina A. Zhigileva
a   Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., Moscow 117997, Russian Federation
b   Lomonosov Moscow State University, Leninskie Gory 1 (3), Moscow 119991, Russian Federation
,
Marina V. Molchanova
a   Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., Moscow 117997, Russian Federation
b   Lomonosov Moscow State University, Leninskie Gory 1 (3), Moscow 119991, Russian Federation
,
Pavel N. Solyev 
c   Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences, 32 Vavilova St., Moscow 119991, Russian Federation
,
Alexander A. Korlyukov
d   Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow 119334, Russian Federation
e   Pirogov Russian National Research Medical University, Ostrovitianov 1, Moscow 117997, Russian Federation
,
Mikhail S. Baranov 
a   Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., Moscow 117997, Russian Federation
e   Pirogov Russian National Research Medical University, Ostrovitianov 1, Moscow 117997, Russian Federation
,
Andrey A. Mikhaylov  ∗
a   Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 16/10 Miklukho-Maklaya St., Moscow 117997, Russian Federation
› Author Affiliations

The authors gratefully acknowledge support from the Russian Science Foundation, grant No. 21-73-00165.
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Abstract

A reaction sequence of Diels–Alder cycloaddition and Tsuji–Trost allylation was examined in terms of its application to the synthesis of kopsinine and the related Kopsia alkaloids. Results of the studies in two synthetic directions are presented herein: 1) synthesis of the properly substituted diene, required for the Diels–Alder step; and 2) model studies and optimization of the key reaction sequence in the absence of side-chain. Details on the challenging introduction of the side-chain into tetrahydrocarboline ketone and its silylation, resulting in rare but unproductive vinylogous Claisen cyclization, and the successful Mannich/Mukaiyama aldol sequence are disclosed in the first direction. In the second direction, the endo-selective Diels–Alder reaction with allyl acrylate and Tsuji–Trost allylation providing incorrect stereochemistry are disclosed. Interaction of both dienes with an alkyne provides carbazoles via Alder–Rickert reaction.


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Key words

alkaloids - total synthesis - Diels–Alder reaction - Tsuji–Trost allylation - Alder–Rickert reaction

Terpene indole alkaloids represent a large group of plant natural products, the biological activity for members of which has been known since antiquity.[1] Based on the modern classification, monoterpene derivatives, produced biosynthetically from tryptophane and seco-loganine, could be divided in three subgroups: Corynanthe, Iboga, and Aspidosperma.[2] Corynanthe alkaloids retain the initial seco-loganine carbon skeleton connectivity, while the other two groups have undergone rearrangements. Kopsia (Apocynaceae) species produce highly congested Aspidosperma alkaloids such as kopsine (1), kopsinine (2), kopsijasmine (3), and kopsijasminilam (4), etc. (Figure [1]).[3] Being related to vincristine[4] and rhazinilam,[5] [6] these compounds are mostly searched for cytotoxic and antitumor activities (including co-action with vincristine to overcome resistance[7]), as well as for a number less-profound activities, such as anti-inflammatory, and antirheumatoid effects.[8]

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Figure 1 Selected Kopsia alkaloids

Cage polycyclic architecture of Kopsia and Aspidosperma alkaloids with a number of quaternary centers, including contiguous ones, have attracted a great deal of attention from the synthetic community.[9] [10] [11] Since the first total synthesis of aspidospermine by Stork in 1963,[12] they have become model objects for development of synthetic methods.

Kopsinine (2), a hexacyclic alkaloid with three quaternary stereocenters, is one of such benchmark structures. Among other methods used for its synthesis, such as electrophilic and radical cyclization, Claisen rearrangement, Fischer indole synthesis, and Michael addition,[13] [14] Diels–Alder cycloaddition is an outstanding tool to construct quaternary centers (Scheme [1, a]).[15] Its capacities could be illustrated with two notable examples: 1) Boger’s approach,[16] utilizing [4+2]/retro-[4+2]/[3+2]-reactivity of oxadiazoles to construct 5 out of 6 cycles of target structure, and 2) double Diels–Alder strategy of MacMillan,[17] based on tandem organocatalytic cycloaddition of propiolaldehyde to form tetracyclic core, followed by earlier developed Diels–Alder of vinyl sulfone.[18]

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Scheme 1 Diels–Alder reaction in the formation of quaternary stereocenters of kopsinine (2)

Diels–Alder reaction such as the cycloaddition #2 in MacMillan’s synthesis readily provides central bicyclo[2.2.2]octane fragment but has a disadvantage of necessary removal of the activating sulfone group. The more straightforward approach should exploit a doubly activated diene, consisting of indole double bond conjugated with enolate or enamine, and acrylate dienophile. Moreover, common endo-selectivity of the Diels–Alder reaction would provide three out of five stereocenters of kopsinine (2). However, such cycloadditions are much underdeveloped.[19] [20] [21] Only the group of Nishida investigated exo-selective [4+2] cycloaddition of conjugated enolates under catalysis of chiral Ho complexes (Scheme [1, b]),[22] and Jia very recently investigated endo-selective reaction of indole-derived chlorinated dienes, which resulted in a series of synthesized kopsane alkaloids.[23] The latter work demonstrates high efficiency of set-up of Diels–Alder step early in synthetic strategy, which can be further employed for other representatives of Kopsia alkaloids.

In this work, we examined the direct Diels–Alder reaction of the silyl enolate analogous to Harada’s but proceeding with endo-selectivity with focus on successive hypothetic intramolecular Tsuji–Trost allylation of the formed silyl enolate[24] and successive total synthesis of kopsinine (2) (Scheme [1, c]). The suggested Tsuji–Trost allylation differs from the most common intramolecular variants[25] [26] [27] [28] due to connection via carboxylate tether, cleaved in the course of the reaction. Although there are several precedents of such connection strategy described in literature,[29–31] the verity of intramolecular nature of such process and its stereochemical outcome of such reaction are still unclear.

Realization of the idea was started with elaboration of the synthetic approach towards diene 5a, containing side-chain, required for the synthesis of kopsinine (2). Introduction of the side-chain for the ketone, such as compound 6 (Scheme [2]), is described in literature[32] [33] [34] but in all cases requires indirect methods: either C–H oxidation of the tetrahydrocarboline, prepared from 4-substituted cyclohexanone via Fischer synthesis, or via assistance of auxiliary carboxylate function in α-position to carbonyl. Direct Michael addition of lithium enolates or enamines to ethyl acrylate does not proceed, probably due to poor energetics.[35] [36]

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Scheme 2 Synthesis of substituted tetrahydrocarboline 6

In this work, we developed an alternative indirect procedure for the preparation of ketone 6 from the Boc-protected tricyclic ketone 7, which is readily available by Fischer synthesis from phenylhydrazine and cyclohexan-1,3-dione (Scheme [2]).[37] This procedure consists of 1) formation of silyl enolate 5b using conventional method, 2) reaction of the latter with methylene malonate under Sc(OTf)3 catalysis[38] to afford diester 8, and 3) decarboxylation under Krapcho conditions.[39] During the latter step, the Boc-protecting group had fallen off and thus its reinstallation was required, which was performed without isolation of the reaction intermediate.

Ketone 6, synthesized in this way, was subjected to silylation under action of usual TBSOTf/Et3N system (Scheme [3]). Surprisingly, an unexpected product was obtained. Based on NMR analysis, which evidenced several magnetically inequivalent protons (indicating presence of at least one asymmetric center) and retention of the ketone carbonyl (198.7 ppm in 13C NMR spectrum), it was assigned as the tetracyclic silylated hemiketal 9. Stereochemistry of the chiral oxa-quaternary carbon was further established by single-crystal X-ray diffraction analysis. Formation of such product proceeds presumably via deprotonation of the more accessible γ-position and following vinylogous Claisen condensation of the so-formed homo-enolate.[40] [41] Alternative conditions for silylation, such as deprotonation with LDA, followed by quenching with TBSCl, or use of less hindered bases (pyridine, 2,6-lutidine, etc.) did not provide required silyl enol 5a. In view of these results, at this point we had to revise the synthetic scheme.

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Scheme 3 Unexpected vinylogous Claisen condensation upon silylation of the ketone 6. X-ray structure for compound 9 is depicted with thermal ellipsoids at the 50% probability level. Hydrogen atoms are omitted for clarity.

The second most widely used approach to prepare silyl enols is Mukaiyama–Michael addition.[42] [43] [44] [45] For this purpose, preparation of Michael acceptor 10 was required (Scheme [4]). Direct Mannich reaction of the ketone 7 was accompanied with a number of side processes, such as protective group cleavage, hydroxymethylation, etc. It turned out more convenient to perform the same transformation on the unprotected compound 11. The reaction proceeded rather cleanly, although the indole nitrogen additionally underwent partial hydroxymethylation, forming enone 12. Cleavage of this substituent followed by installment of Boc-group provided the desired Michael acceptor 10 in 45% yield over 3 steps. Addition of silyl ketene acetal to it resulted in target silyl enol 5a, which turned out to be tentatively unstable. We were unable to purify it by column chromatography, however, its structure was reliably confirmed by 1H, 13C, HSQC NMR, as well as high-resolution mass spectrometry.

Silyl enolate 5a, obtained as above, was tested in Diels–Alder reaction with allyl acrylate. However, we were unable to observe any reaction neither under thermal activation conditions (up to 180 °C, heating in mesitylene), nor under catalysis with Lewis acids such as Yb(OTf)3, Sc(OTf)3, or Cu(OTf)2. In order to reveal the conditions for the cycloaddition, we shifted our focus to the model reactions with the simpler derivative 5b (Scheme [5]). Heating with 1.5–5 equivalents of acrylate dienophiles, namely ethyl, allyl, and cinnamyl acrylates in toluene and, in particular, o-xylene, resulted in the formation of the bridged products 13 in relatively good yields (56–77%) and diastereoselectivity (dr 3.2:1–4.6:1). endo-Isomer was separated by column chromatography, which granted further study of allyl transfer in the compound 13bb.

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Scheme 4 Successful Mannich/Mukaiyama–Michael approach towards silyl enol ether 5a
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Scheme 5 Diels–Alder cycloaddition of silyl enolates 5

To further establish reactivity (and prove at least the plausibility of any Diels–Alder reaction of the substituted dienolate 5a), a reaction of dienolates 5 with a more reactive alkyne dienophile – ethyl propiolate – was carried out. As one could expect, it proceeded as Alder–Rickert reaction[46] [47] [48]: after initial [4+2] cycloaddition a rapid retro-[4+2] extrusion of ethylene occurred, which provided carboline-type products 14 and 15 (Scheme [5]).[49] In case of the diene 5a it took 6 hours reflux in xylene to give deprotected 14a in rather disappointing 36% yield. Diene 5b, in turn, reacted faster – in 3 hours it gave 12% of deprotected product 14b and 47% of the primary Alder–Rickert product 15b. Cleavage of Boc protective group could occur both in the reaction solution, as well as on column chromatography – analysis of the reaction mixtures revealed that products 14 and 15 were both present before the chromatography, and the amount of 14 increased upon isolation. Thus, diene 5a is shown to be reactive enough to participate in Diels–Alder reaction, but the conditions for the reaction with acrylate dienophiles are yet to be found.

Following the lead idea of the project, an interaction of the allyl derivative endo-13bb with Pd(OAc)2/Xanthphos at 80 °C in DMF was studied (Scheme [6]).[24] [50] It resulted in the formation of single stereoisomer of α-allylated ketone 16 in 83%, containing a free acid group. Careful analysis of the reaction mixture allowed to isolate after chromatography minute amounts of intermolecular allyl transfer product 17a (ca. 3% yield). It is noteworthy, that cinnamyl derivative endo-13bc remained intact under the same conditions (except for partial silyl enol cleavage).

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Scheme 6 Tsuji–Trost allyl transfer for derivative endo-13bb. X-ray structure for compound 18 is depicted with thermal ellipsoids at the 50% probability level. Hydrogen atoms are omitted for clarity.

The stereochemistry and the structure of the product 16 were hard to determine. Usual NMR as well as NOESY-analysis were complicated because of the broadening of signals due to Boc-group conformational dynamics. Thus, we performed methylation to prove carboxylic group formation with MeI/K2CO3, which gave product 17b in 92% yield. Deprotection and X-ray crystal structure analysis of the formed compound 18 revealed that allyl group entered from the opposite face to carboxylate in the bicyclic system. Both formation of side-product 17a and stereochemistry of the allylation reaction indicate that the reaction proceeds intermolecularly. Indeed, under the same conditions derivative endo-13ba with ethyl group could be reacted with allyl acetate to provide analogous product 17c in 53% yield (Scheme [7]). Thus, it became the dead end in the proposed synthesis of kopsinine. However, this strategy might be used in the synthesis of truncated kopsinine analogues with alternative (epi)-stereochemistry, which is supported by our primary results on oxidative cleavage/reductive amination but require additional investigation with different protection group at indole nitrogen atom.

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Scheme 7 Intermolecular Tsuji–Trost allylation of derivatives 13ba

In conclusion, in this work a reaction sequence of Diels–Alder cycloaddition and intramolecular Tsuji–Trost allylation were examined. Since the common silylation reaction turned out inapplicable, an original approach towards sterically congested tetrahydrocarbazole silyl dienol ether was developed. Although the required Diels–Alder reaction proceeds with the desired endo-selectivity, it could be implemented only for simplified derivatives. The following Tsuji–Trost reaction provides undesired stereochemistry of the newly established stereocenter, which leads to revision of the synthetic strategy but opens opportunities for synthesis of truncated epi-derivatives.

All reactions were performed in round-bottom flasks fitted with rubber septa. Reactions sensitive to air and/or moisture were performed under a positive pressure of argon. Air- and moisture-sensitive liquids were transferred by syringe. Analytical TLC was performed using aluminum plates pre-coated with silica gel (silica gel 60 F254, Merck or Sorbfil). TLC plates were visualized by exposure to 254 nm ultraviolet light (UV) or were stained by submersion in acidic ethanolic solution of vanillin followed by brief heating (vanillin) or submersion in aqueous KMnO4 solution followed by extensive washing with H2O. Flash column chromatography was carried out on silica gel (60 Å, 230–400 mesh, Merck). All solvents for chromatography and extractions were technical grade and distilled prior use. All reagents were obtained from commercial suppliers (Sigma-Aldrich, Acros Organics, Fluorochem, ABCR, DALCHEM) and were used without further purification.

NMR spectra were recorded using Bruker Fourier 300 and Bruker Avance II 700 instruments at indicated temperature. Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances), coupling constant (J) in hertz (Hz), integration. Proton chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to residual protium in the NMR solvents (CHCl3, δ = 7.26; CD3SOCD2H: δ = 2.50; CD3COCD2H: δ = 2.05). Carbon chemical shifts are expressed in parts per million (ppm, δ scale) and are referenced to the carbon resonances of the NMR solvents (CDCl3, δ = 77.16; DMSO-d 6: δ = 39.51 ppm; acetone-d 6; δ = 29.84). High-resolution mass spectra were recorded on a Bruker micrOTOF-Q II mass spectrometer using electrospray ionization (ESI-TOF). Melting points were determined on Kofler melting point apparatus and are uncorrected.

X-ray crystallographic studies were carried out with Bruker D8 Quest diffractometer in Center for molecular composition studies of INEOS RAS. The most important details of crystallographic studies can be found in the Supporting Information.


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2,3-Dihydro-1H-carbazol-4(9H)-one (11)[51]

Cyclohexan-1,3-dione (6.35 g, 57 mmol, 1 equiv.) and phenylhydrazine hydrochloride (8.22 g, 57 mmol, 1.0 equiv.) were dissolved in a mixture of H2O (140 mL) and EtOH (50 mL) and degassed with vigorous flow of argon bubbling through the solution. The reaction mixture was cooled to 0 °C. Then a solution of NaOAc·3H2O (7.72 g, 57 mmol, 1.0 equiv.) in H2O was added dropwise to the above prepared solution. Yellowish oil almost immediately started to precipitate. After stirring for 30 min, the mixture was kept in a freezer (–20 °C). After 1 h at this temperature, the resulting oil was solidified by scratching with spatula. The orange crystalline precipitate was collected by filtration, washed with minimum amount of cold 20% aq EtOH and dried in vacuum desiccator over KOH (10 Torr) for 45 min to give crude hydrazone (ca. 11.4 g). The prepared hydrazone was then dissolved in TFA (70 mL). The resulting deep blue solution was heated under reflux for 8 h. Then 4/5 of TFA was distilled out and the resulting black viscous solution was poured into ice H2O, and stirred for 10 min to form a greenish precipitate. The solid was filtered from the cold solution, washed with cold H2O and dried on air. Recrystallization from MeOH (30–50 mL) provided pure tetrahydrocarbazole derivative 11 as beige crystals; yield: 5.82 g (31 mmol, 55%); mp 220–222 °C (MeOH); Rf = 0.18 (hexane/EtOAc 1:1).

1H NMR (700 MHz, 303 K, DMSO-d 6): δ = 11.82 (s, 1 H), 7.95 (dd, J = 7.5, 1.8 Hz, 1 Н), 7.39 (d, J = 7.8 Hz, 1 Н), 7.16 (td, J = 7.6, 1.8 Hz, 1 H), 7.13 (t, J = 7.3 Hz, 1 Н), 2.96 (t, J = 6.2 Hz, 2 Н), 2.42 (t, J = 6.4 Hz, 2 Н), 2.12 (pent, J = 6.3 Hz, 1 H).


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tert-Butyl 4-Oxo-3,4-dihydro-1H-carbazole-9(2H)-carboxylate (7)[37]

DMAP (10 mg, 0.1 mmol, 5 mol%) was added to a stirred suspension of dihydrocarbazole 11 (305 mg, 1.6 mmol, 1 equiv.) and Boc2O (395 mg, 1.8 mmol, 1.1 equiv.) in CH2Cl2 (5 mL). Gas evolution and rapid dissolution of the starting material were observed. After 1 h, the clear solution was concentrated on a rotary evaporator and the solid residue was subjected to column chromatography on silica gel (eluent: hexane/EtOAc 10:1 → 5:1), which furnished protected carbazole 7 as fine off-white crystals; yield: 465 mg (1.6 mmol, 99%); mp 147–148 °C (hexane/EtOAc); Rf = 0.51 (hexane/EtOAc 1:1)

1H NMR (700 MHz, 303 K, CDCl3): δ = 8.30–8.27 (m, 1 Н), 8.10–8.06 (m, 1 Н), 7.34–7.30 (m, 2 H), 3.31 (t, J = 6.2 Hz, 2 Н), 2.58 (t, J = 6.4 Hz, 2 Н), 2.23 (pent, J = 6.3 Hz, 1 H), 1.71 (s, 9 H).


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tert-Butyl 4-(tert-Butyldimethylsilyloxy)-1H-carbazole-9(2H)-carboxylate (5b)

TBSOTf (1.5 mL, 1.76 g, 6.7 mmol, 1.2 equiv.) was added dropwise at 0 °C to a stirred solution of the ketone 7 (1.58 g, 5.5 mmol, 1 equiv.) and Et3N (1.2 mL, 0.84 g, 8.3 mmol, 1.5 equiv.) in CH2Cl2 (16 mL). The resulting clear solution was stirred at 0 °C for 1 h and poured into a separatory funnel with Et2O (120 mL) and H2O (60 mL). The organic layer was separated and washed with brine (60 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Further drying in high vacuo (0.5 Torr) provided pure silyl enolate 5b as a white solid of sufficient purity; yield: 2.15 g (5.4 mmol, 97%). The product can be purified from silicon impurities by recrystallization from hexane; yield: 1.88 g (4.7 mmol, 85% in 2 crops); white crystals; mp 80–82 °C (hexane); Rf = 0.58 (hexane/EtOAc 5:1, decomposed on silica gel).

1H NMR (300 MHz, 298 K, CDCl3): δ = 8.22–8.08 (m, 1 H), 8.02–7.92 (m, 1 H), 7.29–7.19 (m, 2 H), 4.84 (t, J = 4.6 Hz, 1 H), 3.19 (t, J = 9.1 Hz, 2 H), 2.49 (td, J = 9.1, 4.6 Hz, 2 H), 1.70 (s, 9 H), 1.06 (s, 9 H), 0.29 (s, 6 H).

13C{1H} NMR (75 MHz, 298 K, CDCl3): δ = 150.5, 147.9, 138.0, 136.1, 126.5, 123.2, 122.8, 120.8, 115.7, 115.4, 97.9, 84.0, 28.4 (3 ×), 26.3 (3 ×), 23.5, 23.4, 18.7, –4.0 (2 ×).

HRMS (ESI): m/z [M + H+] calcd for C23H34NO3Si: 400.2302; found: 400.2299.


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Dimethyl 2-Methylenemalonate[52]

Di-isopropylammonium trifluoroacetate (12.3 g, 57 mmol, 1.05 equiv.), dimethyl malonate (7.20 g, 54 mmol, 1 equiv.), and paraformaldehyde (3.42 g, 114 mmol, 2.10 equiv.) were dissolved in THF (75 mL) in a three-necked flask, equipped with a reflux condenser. Trifluoroacetic acid (0.46 mL, 0.65 g, 6 mmol, 0.1 equiv.) was added at rt and the reaction mixture was brought to reflux. After 2 h, an additional portion of paraformaldehyde (3.42 g, 114 mmol, 2.10 equiv.) was added and the reflux was continued for 6 h. After that, the mixture was cooled to rt and concentrated on a rotary evaporator. The crude mixture was dissolved in Et2O (100 mL) and filtered through a short pad of Celite. The Et2O layer was transferred to a separatory funnel and washed with aq 1 M HCl (2 × 50 mL). Without washing with brine, the organic layer was dried [Na2SO4 (great excess)], concentrated on a rotary evaporator and subjected to fraction vacuum distillation. The fraction with bp 108–110 °C/12 Torr was collected, providing pure dimethyl methylenemalonate; yield: 3.55 g (25 mmol, 47%). The product could be stored in a freezer for at least one month without degradation; colorless viscous liquid; bp 108–110 °C/12 Torr.

1H NMR (300 MHz, 303 K, CDCl3): δ = 6.58 (s, 2 H), 3.84 (s, 6 H).

13C{1H} NMR (75 MHz, 303 K, CDCl3): δ = 164.5 (2 ×), 135.4, 134.3, 52.7 (2 ×).


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Dimethyl 2-((9-(tert-Butoxycarbonyl)-4-oxo-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl)malonate (8)

Sc(OTf)3 (73 mg, 0.2 mmol, 5 mol%) was added to a stirred solution of silyl enolate 5b (1.20 g, 3.0 mmol, 1 equiv.) and dimethyl methylenemalonate (0.56 g, 3.9 mmol, 1.3 equiv.) in dichloroethane (15 mL) at rt. The reaction mixture was stirred for 12 h, then concentrated on a rotary evaporator. The oily residue was subjected to column chromatography on silica gel (eluent hexane/EtOAc 4:1 → 3:1) to give diester 8 as a white solid; yield: 0.73 g (1.7 mmol, 57%); mp 112–113 °C (hexane/EtOAc); Rf = 0.19 (hexane/EtOAc 3:1) along with the desilylated product 7 (0.16 g (0.06 mmol, 18%) as a white solid.

1H NMR (700 MHz, 303 K, CDCl3): δ = 8.29–8.23 (m, 1 H), 8.11–8.06 (m, 1 H), 7.33–7.30 (m, 2 H), 3.91 (dd, J = 8.8, 6.0 Hz, 1 H), 3.76 (s, 3 H), 3.74 (s, 3 H), 3.44 (dt, J = 18.9, 4.9 Hz, 1 H), 3.25 (ddd, J = 18.9, 9.5, 5.2 Hz, 1 H), 2.58–2.47 (m, 2 H), 2.32 (dq, J = 13.4, 4.7 Hz, 1 H), 2.08 (ddd, J = 13.8, 8.8, 4.9 Hz, 1 H), 2.04 (dddd, J = 13.8, 10.2, 9.5, 4.9 Hz, 1 H), 1.71 (s, 9 H).

13C{1H} NMR (75 MHz, 298 K, CDCl3): δ = 196.7, 170.2, 170.0, 151.2, 149.9, 136.2, 125.8, 125.1, 124.5, 121.5, 116.8, 115.3, 85.6, 52.7 (2 ×), 50.0, 43.9, 29.7, 29.4, 28.3 (3 ×), 25.3.

HRMS (ESI): m/z [M + H+] calcd for C23H28NO7: 430.1860; found: 430.1863.


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tert-Butyl 3-(3-Methoxy-3-oxopropyl)-4-oxo-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate (6)

A solution of diester 8 (300 mg, 0.70 mmol, 1 equiv.), NaCl (82 mg, 1.40 mmol, 2.0 equiv.), and H2O (25 μL, 25 mg, 1.40 mmol, 2.0 equiv.) in DMSO (5 mL) was heated to 180 °C for 2.5 h. Then the reaction mixture was allowed to cool to rt, poured into a separatory funnel with EtOAc (20 mL) and H2O (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with H2O (10 mL) and brine (30 mL), dried (Na2SO4) and concentrated on a rotary evaporator. The oily residue was dissolved in CH2Cl2 (5 mL) and directly subjected to the next step by treating with Boc2O (228 mg, 1.05 mmol, 1.5 equiv.) and DMAP (4 mg, 0.03 mmol, 5 mol%). The reaction mixture was stirred overnight (8 h) and concentrated on a rotary evaporator. The oily residue was subjected to column chromatography on silica gel (eluent: hexane/EtOAc 10:1 → 3:1) to give ester 6; yield: 185 mg (0.50 mmol, 71%); white crystals; mp 70–72 °C (hexane/EtOAc); Rf = 0.23 (hexane/EtOAc 3:1).

1H NMR (700 MHz, 303 K, CDCl3): δ = 8.29–8.25 (m, 1 H), 8.10–8.06 (m, 1 H), 7.35–7.29 (m, 2 H), 3.68 (s, 3 H), 3.44 (dt, J = 18.8, 5.1 Hz, 1 H), 3.25 (ddd, J = 18.8, 9.1, 5.2 Hz, 1 H), 2.61–2.48 (m, 3 H), 2.32 (dq, J = 13.8, 5.0 Hz, 1 H), 2.25 (ddt, J = 13.8, 8.5, 6.8 Hz, 1 H), 2.04 (dtd, J = 13.8, 9.3, 5.1 Hz, 1 H), 1.87 (ddt, J = 13.8, 8.5, 6.6 Hz, 1 H), 1.71 (s, 9 H).

13C{1H} NMR (75 MHz, 298 K, CDCl3): δ = 197.0, 174.1, 151.3, 149.9, 136.1, 125.9, 125.0, 124.5, 121.6, 116.8, 115.3, 85.5, 51.7, 45.6, 32.0, 29.0, 28.3 (3 ×), 25.1, 25.0.

HRMS (ESI): m/z [M + H+] calcd for C21H26NO5: 372.1805; found: 372.1801.


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tert-Butyl (6S*,7S*,10R*)-7-((tert-Butyldimethylsilyl)oxy)-7-methoxy-11-oxo-6,7,8,9,10,11-hexahydro-5H-6,10-methanocycloocta[b]indole-5-carboxylate (9)

TBSOTf (102 μL, 117 mg, 0.44 mmol, 1.1 equiv.) was added dropwise at 0 °C to a stirred solution of the ketone 6 (150 mg, 0.40 mmol, 1 equiv.) and Et3N (73 μL, 53 mg, 0.53 mmol, 1.3 equiv.) in CH2Cl2 (2.5 mL). The resulting clear solution was stirred at 0 °C for 1.5 h and poured into a separatory funnel with Et2O (20 mL) and aq 1 M NaHCO3 (10 mL). The organic layer was separated and washed with brine (10 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Column chromatography on silica gel (eluent: hexane/EtOAc 10:1 → 5:1) provided bridged polycycle 9; yield: 120 mg (0.25 mmol, 61%); white crystals; mp 70–72 °C (hexane/EtOAc); Rf = 0.43 (hexane/EtOAc 3:1). Crystals, suitable for X-ray diffraction analysis were obtained by slow diffusion of hexane in CH2Cl2 solution of 9.

It is presumed that an alternative diastereomer might be forming in the reaction (dr 4.5:1), but it could not be isolated in a pure form.

1H NMR (300 MHz, 303 K, CDCl3): δ = 8.47–8.17 (m, 1 H), 8.10–7.89 (m, 1 H), 7.39–7.28 (m, 2 H), 4.86 (t, J = 3.1 Hz, 1 H), 3.44 (s, 3 H), 2.62 (pent, J = 3.3 Hz, 1 H), 2.40 (dq, J = 12.9, 3.1 Hz, 1 H), 2.14 (dt, J = 12.9, 2.9 Hz, 1 H), 2.03–1.82 (m, 2 H), 1.77–1.71 (m, 2 H), 1.72 (s, 9 H), 0.66 (s, 9 H), 0.09 (s, 3 H), –0.04 (s, 3 H).

13C{1H} NMR (75 MHz, 298 K, CDCl3): δ = 198.7, 154.8, 150.2, 136.8, 125.2, 125.0, 124.4, 121.7, 119.5, 115.5, 99.6, 85.4, 48.4, 42.1, 36.0, 33.8, 32.7, 28.5 (3 ×), 26.2, 26.0 (3 ×), 18.1, –2.4, –2.7.

HRMS (ESI): m/z [M + H+] calcd for C27H40NO5Si: 486.2670; found: 486.2672.


#

tert-Butyl 3-Methylene-4-oxo-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate (10)

Morpholine (48 μL, 48 mg, 0.55 mmol, 0.5 equiv.) was added to a stirred solution of ketone 11 (207 mg, 1.12 mmol, 1 equiv.) and paraformaldehyde (50 mg, 1.65 mmol, 1.5 equiv.) in AcOH (3 mL). The reaction mixture was brought to reflux. Then every 30 min (5 times) an additional portion of paraformaldehyde (50 mg, 1.65 mmol, 1.5 equiv.) was added. After 3 h of reflux (9 equiv. of paraformaldehyde altogether), the reaction mixture was allowed to cool down and poured into a mixture of EtOAc (50 mL) and H2O (30 mL). The two-phase system was filtered through a short pad of Celite and poured into a separatory funnel. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4) and concentrated on a rotary evaporator.

The semisolid residue (containing ca. 50% N-hydroxymethyl derivative 12) was dissolved in THF (1.5 mL). Then H2O (0.5 mL) and NaOH (220 mg, 5.60 mmol, 5 equiv.) were added. The reaction mixture was stirred at rt for 2.5 h, then poured into a separatory funnel with H2O (50 mL) and EtOAc (50 mL). The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4) and concentrated on a rotary evaporator.

Finally, the solid residue was dissolved in CH2Cl2 (5 mL). Boc2O (269 mg, 1.23 mmol, 1.1 equiv.) and DMAP (13 mg, 0.11 mmol, 0.1 equiv.) were added and the reaction mixture was stirred overnight (10 h). Concentration on a rotary evaporator, followed by column chromatography on silica gel (eluent: hexane/EtOAc 10:1 → 7:1) provided the pure enone 10; yield: 150 mg (0.51 mmol, 45% over 3 steps); white crystals; mp 151–153 °C (hexane/EtOAc); Rf = 0.55 (hexane/EtOAc 3:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 8.45–8.28 (m, 1 H), 8.08 (ddt, J = 6.3, 4.1, 2.0 Hz, 1 H), 7.40–7.29 (m, 2 H), 6.13 (q, J = 1.4 Hz, 1 H), 5.41 (q, J = 1.7 Hz, 1 H), 3.42 (t, J = 6.5 Hz, 2 H), 2.95 (tt, J = 6.5, 1.4 Hz, 2 H), 1.71 (s, 9 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 185.1, 152.0, 149.9, 143.2, 136.3, 126.1, 125.2, 124.6, 122.0, 119.5, 118.2, 115.3, 85.7, 31.3, 28.3 (3 ×), 26.3.

HRMS (ESI): m/z [M + H+] calcd for C18H20NO3: 298.1438; found: 298.1435.


#

tert-Butyl 3-(3-Methoxy-3-oxopropyl)-4-oxo-1,2,3,4-tetrahydro-9H-carbazole-9-carboxylate (12)

Intermediate hydroxymethylated enone 12 could be isolated by column chromatography on silica gel after the 1st step of synthesis of the compound 10 (eluent: hexane/EtOAc 1:1 → EtOAc); white crystals; mp 195–197 °C (EtOAc); Rf = 0.51 (EtOAc).

1H NMR (300 MHz, DMSO-d 6): δ = 8.08 (dd, J = 6.8, 2.0 Hz, 1 H), 7.63 (dd, J = 7.1, 1.5 Hz, 1 H), 7.32–7.18 (m, 2 H), 6.61 (t, J = 7.2 Hz, 1 H), 5.92 (d, J = 2.4 Hz, 1 H), 5.56 (d, J = 7.2 Hz, 2 H), 5.42 (q, J = 1.8 Hz, 1 H), 3.16 (t, J = 6.4 Hz, 2 H), 2.93 (t, J = 6.4 Hz, 2 H).

13C{1H} NMR (75 MHz, DMSO-d 6): δ = 182.5, 152.5, 144.1, 136.8, 124.7, 123.0, 122.4, 120.6, 118.1, 112.7, 110.9, 65.9, 30.3, 21.6.

HRMS (ESI): m/z [M + H+] calcd for C14H14NO2: 228.1019; found: 228.1015.


#

O-Methyl-O′-tert-butyldimethylsilylketene Acetal[53]

n-BuLi (2.4M in hexanes; 15.0 mL, 36 mmol, 1.2 equiv.) was added dropwise to a solution of i-Pr2NH (5.5 mL, 3.94 g, 39 mmol, 1.3 equiv.) in anhyd THF (50 mL) at 0 °C. The flask was maintained at 0 °C for 20 min, then cooled to –78 °C. MeOAc (2.4 mL, 2.22 g, 30 mmol, 1 equiv.) was then added dropwise during 5 min. The reaction mixture was stirred for 30 min at –78 °C, followed by dropwise addition of DMPU (5.8 mL, 6.14 g, 48 mmol, 1.6 equiv.) over 5 min, followed by dropwise addition of a solution of TBSCl (6.77 g, 45 mmol, 1.5 equiv.) in THF (10 mL) over 10 min. The reaction mixture was stirred for an additional 30 min at –78 °C, then slowly allowed to warm to rt over a 1 h period. The reaction mixture was poured into a mixture of H2O (100 mL) and hexane (200 mL). The hexane layer was washed with brine (100 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Distillation in vacuo afforded pure O-methyl-O′-tert-butyldimethylketene acetal; yield: 3.40 g (18 mmol, 68%); easy-flowing colorless liquid; bp 98–105 °C/100 Torr.

1H NMR (300 MHz, 303 K, CDCl3): δ = 3.53 (s, 3 H), 3.23 (d, J = 2.6 Hz, 1 H), 3.10 (d, J = 2.6 Hz, 1 H), 0.93 (s, 9 H), 0.17 (s, 6 H).

13C{1H} NMR (75 MHz, CDCl3): δ = 162.5, 60.3, 55.2, 25.8 (3 ×), 18.3, –4.6 (2 ×).


#

tert-Butyl 4-(tert-Butyldimethylsilyloxy)-3-(3-methoxy-3-oxopropyl)-1,2-dihydro-9H-carbazole-9-carboxylate (5a)

TBSOTf (4 μL, 4.5 mg, 0.02 mmol, 10 mol%) was added at –84 °C (EtOAc­/liquid N2 bath) to a stirred solution of O-methyl-O′-tert-butyldimethylketene acetal (55 μL, 0.25 mmol, 1.5 equiv.) and enone 10 (50 mg, 0.17 mmol, 1 equiv.) in CH2Cl2 (2 mL). The reaction mixture was stirred at the same temperature for 1.5 h, then it was quenched at –84 °C (EtOAc/liquid N2 bath) with slow addition of concd aq NaHCO3 solution (100 μL). After additional stirring at –84 °C for 15 min, the mixture was poured into a separatory funnel with Et2O (20 mL) and H2O (20 mL) and immediately shaken. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated on a rotary evaporator to give silyl enol ether 5a (ca. 100 mg, ca. 81% pure, major impurity – TBSOH, colorless oil, decomposed on silica gel), which was used immediately in cycloaddition reaction.

Note: For successful preparation of silyl enol ether 5a it is important to quench the reaction in exactly the same way as described. Trace impurities of acid would irreversibly hydrolyze the silyl derivative into ketone 6.

1H NMR (300 MHz, 300 K, CDCl3): δ = 8.12–7.99 (m, 1 H), 7.86–7.66 (m, 1 H), 7.24–7.12 (m, 2 H), 3.67 (s, 3 H), 3.14 (t, J = 8.7 Hz, 2 H), 2.67–2.57 (m, 2 H), 2.48–2.37 (m, 2 H), 2.35 (t, J = 8.7 Hz, 2 H), 1.68 (s, 9 H), 1.08 (s, 9 H), –0.00 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 174.1, 150.5, 141.6, 136.2, 136.0, 126.5, 123.2, 122.4, 121.1, 116.4, 115.4, 112.8, 84.0, 51.7, 32.6, 28.4 (3 ×), 28.3, 26.1 (3 ×), 25.5, 23.3, 18.4, –3.9 (2 ×).

HRMS (ESI): m/z [M + H+] calcd for C27H40NO5Si: 486.2670; found: 486.2675 (very weak).


#

Allyl Acrylate[54]

A mixture of methyl acrylate (40 mL, 33.9 g, 394 mmol, 2.3 equiv.), allyl alcohol (12 mL, 10.0 g, 172 mmol, 1 equiv.), pTsOH·H2O (1.6 g, 9 mmol, 5 mol%), and hydroquinone (2.1 g, 19 mmol, 10 mol%) was gently heated to reflux in a distillation apparatus to keep the vapor condensing in the Vigreux column. After 30–45 min, the first drops of the methyl acrylate/MeOH azeotrope started to distill (bp 55–65 °C/760 Torr). The distillation was continued, keeping the rate of several drops per min, for 6–8 h, during which most of the azeotrope was distilled. Then the temperature was raised, resulting in distillation of methyl acrylate itself (bp 80 °C/760 Torr), followed by small fraction of mixed acrylates (bp 85–110 °C/760 Torr). Last, the pure allyl acrylate distilled, having a bp 121–122 °C/760 Torr; yield: 10.2 g (91 mmol, 53%); colorless liquid.

1H NMR (300 MHz, 303 K, CDCl3): δ = 6.44 (dd, J = 17.3, 1.5 Hz, 1 H), 6.15 (dd, J = 17.3, 10.5 Hz, 1 H), 5.96 (ddt, J = 17.2, 10.4, 5.7 Hz, 1 H), 5.85 (dd, J = 10.5, 1.5 Hz, 1 H), 5.35 (dd, J = 17.2, 1.6 Hz, 1 H), 5.26 (dd, J = 10.4, 1.3 Hz, 1 H), 4.67 (d, J = 5.7 Hz, 2 H).

13C{1H} NMR (75 MHz, 303 K, CDCl3): δ = 166.0, 132.2, 131.1, 128.4, 118.4, 52.7.


#

Cinnamyl Acrylate[55]

Maleic anhydride (686 mg, 7.0 mmol, 1 equiv.), cinnamyl alcohol (1126 mg, 8.4 mmol, 1.2 equiv.), and Ph3P (183 mg, 0.7 mmol, 10 mol%) were heated at reflux for 18 h. Then the reaction mixture was cooled down to rt, concentrated on a rotary evaporator and subjected to column chromatography on silica gel (eluent: hexane/EtOAc 5:1) to provide pure cinnamyl acrylate; yield: 750 mg (4.0 mmol, 57%); colorless oil; Rf = 0.70 (hexane/EtOAc 3:1).

1H NMR (300 MHz, 303 K, CDCl3): δ = 7.39 (d, J = 7.3 Hz, 2 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.25 (t, J = 7.0 Hz, 1 H), 6.68 (dd, J = 15.9, 1.3 Hz, 1 H), 6.45 (dd, J = 17.3, 1.5 Hz, 1 H), 6.31 (dt, J = 15.9, 6.4 Hz, 1 H), 6.16 (dd, J = 17.3, 10.4 Hz, 1 H), 5.85 (dd, J = 10.4, 1.5 Hz, 1 H), 4.82 (dd, J = 6.4, 1.3 Hz, 2 H).


#

Diels–Alder Cycloaddition with Ethyl Acrylate

Silyl enol ether 5b (1.31 g, 3.3 mmol, 1 equiv.) and ethyl acrylate (1.8 mL, 1.64 g, 16.4 mmol, 5.0 equiv.) in o-xylene (6 mL) were heated to reflux for 6 h. After this time, the reaction mixture was allowed to cool down and evaporated. Column chromatography of the yellowish oily residue on silica gel (eluent: hexane/EtOAc 20:1 → 15:1 → 10:1) provided a mixture of diastereomers 13ba (1.26 g, 2.5 mmol, 77%, dr 3.3:1) as a colorless oil. Second chromatography of 400 mg sample on silica gel (eluent: hexane/EtOAc 20:1 → 15:1) allowed the separation of isomers endo-13ba (285 mg, 93% recovery) and exo-13ba (75 mg, 81% recovery).


#

9-(tert-Butyl) 1-Ethyl (1R*,3R*,9aR*)-4-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (endo-13ba)

White crystals; mp 94–95 °C (pentane); Rf = 0.42 (hexane/EtOAc 10:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 7.99 and 7.55 (2 br m, 1 H), 7.50 (d, J = 7.5 Hz, 1 H), 7.05 (t, J = 7.9 Hz, 1 H), 6.92 (t, J = 7.4 Hz, 1 H), 3.85 and 3.58 (2 br s, 1 H), 3.81 (q, J = 7.1 Hz, 2 H), 2.83 and 2.58 (2 br s, 1 H), 2.71 (pent, J = 3.0 Hz, 1 H), 1.90 (dq, J = 12.9, 3.7 Hz, 1 H), 1.78 (ddd, J = 12.6, 9.7, 2.7 Hz, 1 H), 1.62 (s, 11 H), 1.41–1.28 (m, 1 H), 1.09–0.98 (m, 9 H), 0.88 (t, J = 7.1 Hz, 3 H), 0.27 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 173.0, 152.2, 145.7, 144.3, 126.5, 125.9, 122.5, 122.2, 115.1 (2×), 81.1, 69.1, 60.6, 44.5, 36.5, 30.2, 28.7 (3 ×), 28.5, 25.9 (3 ×), 24.0, 18.2, 14.0, –3.3, –3.6.

HRMS (ESI): m/z [M + H+] calcd for C28H42NO5Si: 500.2827; found: 500.2832.


#

9-(tert-Butyl) 1-Ethyl (1S*,3R*,9aR*)-4-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (exo-13ba)

White crystals; mp 114–115 °C (pentane); Rf = 0.32 (hexane/EtOAc 10:1).

1H NMR (700 MHz, 303 K, CDCl3): δ = 7.68 (br s, 1 H), 7.56 (dd, J = 7.5, 1.4 Hz, 1 H), 7.10 (td, J = 7.8, 1.4 Hz, 1 H), 6.98 (td, J = 7.5, 1.0 Hz, 1 H), 4.30 (dq, J = 10.8, 7.2 Hz, 1 H), 3.97 (dq, J = 10.8, 7.2 Hz, 1 H), 3.30 (br t, J = 11.1 Hz, 1 H), 2.68 (pent, J = 3.0 Hz, 1 H), 2.47 (ddd, J = 11.1, 5.2, 2.1 Hz, 1 H), 1.97 (ddd, J = 12.5, 5.2, 2.4 Hz, 1 H), 1.93 (dddd, J = 12.5, 10.1, 4.5, 2.6 Hz, 1 H), 1.68 (tt, J = 11.4, 3.5 Hz, 1 H), 1.57 (s, 9 H), 1.55–1.51 (m, 1 H), 1.28–1.21 (m, 1 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.04 (s, 9 H), 0.24 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 174.5, 152.4, 147.6, 143.1, 126.5, 125.4, 122.6, 122.5, 118.5, 116.1, 81.8, 70.4, 60.9, 47.3, 36.5, 30.5, 28.5 (3 ×), 25.9 (3 ×), 24.8, 24.4, 18.2, 14.1, –3.3, –3.4.

HRMS (ESI): m/z [M + H+] calcd for C28H42NO5Si: 500.2827; found: 500.2831.


#

Diels–Alder Cycloaddition with Allyl Acrylate

Silyl enol ether 5b (500 mg, 1.25 mmol, 1 equiv.) and allyl acrylate (702 mg, 6.27 mmol, 5.0 equiv.) in o-xylene (3 mL) were heated to reflux for 6 h. After this time, the reaction mixture was allowed to cool down and evaporated. Column chromatography of the yellowish oily residue on silica gel (eluent: hexane/EtOAc 20:1 → 15:1 → 10:1) allowed the separation of the isomers endo-13bb (372 mg, 0.73 mmol, 58%) and exo-13bb (88 mg, 0.17 mmol, 14%).


#

1-Allyl 9-(tert-Butyl) (1R*,3R*,9aR*)-4-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (endo-13bb)

White crystals; mp 74–75 °C (pentane); Rf = 0.60 (hexane/EtOAc 3:1).

1H NMR (800 MHz, 303 K, CDCl3): δ = 7.99 and 7.52 (2 br s, 1 H), 7.50 (d, J = 7.0 Hz, 1 H), 7.04 (br t, J = 7.9 Hz, 1 H), 6.91 (t, J = 7.4 Hz, 1 H), 5.57–5.51 (br m, 1 H), 5.06 (dd, J = 17.2, 1.5 Hz, 1 H), 5.00 (d, J = 10.3 Hz, 1 H), 4.25 (ddt, J = 12.9, 6.2, 1.3 Hz, 1 H), 4.21 (br dd, J = 12.9, 5.9 Hz, 1 H), 3.90 and 3.61 (2 br s, 1 H), 2.83 and 2.58 (2 br s, 1 H), 2.70 (pent, J = 2.9 Hz, 1 H), 1.89 (dq, J = 12.6, 4.7 Hz, 1 H), 1.80 (ddd, J = 12.6, 9.7, 2.6 Hz, 2 H), 1.68–1.60 (m, 11 H), 1.51–1.46 (m, 1 H), 1.05 (s, 9 H), 0.26 (s, 3 H), 0.26 (s, 3 H).

13C{1H} NMR (201 MHz, 303 K, CDCl3): δ = 172.7, 152.2, 145.7, 144.3, 132.4, 126.5, 125.9, 122.5, 122.3, 118.5, 118.1, 115.3, 81.2, 69.2, 65.6, 44.7, 36.6, 31.0, 30.4, 28.7 (3 ×), 26.0 (3 ×), 24.1, 18.2, –3.2, –3.4.

HRMS (ESI): m/z [M + H+] calcd for C29H42NO5Si: 512.2827; found: 512.2827.


#

1-Allyl 9-(tert-Butyl) (1S*,3R*,9aR*)-4-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (exo-13bb)

White crystals; mp 90–92 °C (pentane); Rf = 0.55 (hexane/EtOAc 3:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 7.67 (br d, J = 8.2 Hz, 1 H), 7.57 (dd, J = 7.5, 1.4 Hz, 1 H), 7.10 (td, J = 7.8, 1.4 Hz, 1 H), 6.98 (t, J = 7.4 Hz, 1 H), 5.94 (ddt, J = 16.5, 11.0, 5.7 Hz, 1 H), 5.29 (dd, J = 17.2, 1.7 Hz, 1 H), 5.19 (dt, J = 10.4, 1.4 Hz, 1 H), 4.79 (ddt, J = 13.5, 5.8, 1.5 Hz, 1 H), 4.41 (dd, J = 13.5, 5.6 Hz, 1 H), 3.32 (ddd, J = 13.4, 10.0, 3.8 Hz, 1 H), 2.69 (pent, J = 2.8 Hz, 1 H), 2.54 (ddd, J = 11.2, 5.2, 2.0 Hz, 1 H), 2.04–1.87 (m, 2 H), 1.76–1.48 (m, 12 H), 1.05 (s, 9 H), 0.25 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 174.1, 152.4, 147.5, 143.9, 132.7, 126.5, 125.4, 122.6, 122.5, 118.4, 117.7, 116.1, 81.8, 70.4, 65.8, 47.2, 36.5, 30.5, 28.6 (3 ×), 25.9 (3 ×), 24.7, 24.4, 18.2, –3.3, –3.4.

HRMS (ESI): m/z [M + H+] calcd for C29H42NO5Si: 512.2827; found: 512.2828.


#

Diels–Alder Cycloaddition with Cinnamyl Acrylate

Silyl enol ether 5b (140 mg, 0.35 mmol, 1 equiv.) and cinnamyl acrylate (132 mg, 0.70 mmol, 2.0 equiv.) in o-xylene (5 mL) were heated to reflux for 5 h. After this time, the reaction mixture was allowed to cool down and evaporated. Column chromatography of the brown oily residue on silica gel (eluent: hexane/EtOAc 20:1 → 15:1 → 10:1) allowed the separation of the isomer endo-13bc (70 mg, 0.12 mmol, 34%, 90%+ purity) and a mixture of endo-13bc/exo-13bc (45 mg, 0.17 mmol, 22%, dr 1.2:1).


#

9-(tert-Butyl) 1-Cinnamyl (1S*,3R*,9aR*)-4-((tert-Butyldimethylsilyl)oxy)-2,3-dihydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (endo-13bc)

Colorless oil; Rf = 0.29 (hexane/EtOAc 5:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 8.06–7.16 (m, 7 H), 6.95 (td, J = 7.8, 1.5 Hz, 1 H), 6.86 (t, J = 7.4 Hz, 1 H), 6.38 (d, J = 15.9 Hz, 1 H), 5.99–5.68 (br m, 1 H), 4.75–4.28 (br m, 2 H), 3.91 and 3.60 (2 br s, 1 H), 2.83 and 2.57 (2 br s, 1 H), 2.69 (pent, J = 2.9 Hz, 1 H), 1.91 (dq, J = 12.1, 4.0 Hz, 1 H), 1.84–1.73 (m, 1 H), 1.65–1.24 (m, 12 H), 1.03 (s, 9 H), 0.25 (s, 3 H), 0.24 (s, 3 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 172.9, 152.2, 145.7, 136.4, 134.3, 128.5 (2 ×), 127.9, 126.9 (2 ×), 126.6, 123.4, 122.5, 122.2, 115.2, 81.2, 69.2, 65.5, 44.5, 36.5, 30.3, 28.6 (br, 4 ×), 26.0 (3 ×), 23.9, 18.2, –3.3, –3.5. Three quaternary carbons are not seen due to spectrum broadening.

HRMS (ESI): m/z [M + H+] calcd for C35H46NO5Si: 588.3140; found: 588.3129.


#

Ethyl 4-((tert-Butyldimethylsilyl)oxy)-3-(3-methoxy-3-oxopropyl)-9H-carbazole-1-carboxylate (14a)

Silyl enol ether 5a (ca. 80 mg, 0.165 mmol, 1 equiv.) and ethyl propiolate (0.17 mL, 162 mg, 1.65 mmol, 10 equiv.) in o-xylene (2 mL) were heated at reflux for 6 h. Then the reaction mixture was allowed to cool down and evaporated. Column chromatography on silica gel (eluent: hexane/EtOAc 20:1 → 10:1) of the brown oily residue provided carbazole 14a; yield: 27 mg (0.059 mmol, 36%); colorless oil; Rf = 0.41 (hexane/EtOAc 5:1)

1H NMR (300 MHz, 300 K, CDCl3): δ = 9.90 (br s, 1 H), 8.26 (d, J = 7.9 Hz, 1 H), 7.90 (s, 1 H), 7.48–7.35 (m, 2 H), 7.20 (ddd, J = 8.1, 6.8, 1.4 Hz, 1 H), 4.45 (q, J = 7.1 Hz, 2 H), 3.67 (s, 3 H), 3.17–3.04 (m, 2 H), 2.73–2.59 (m, 2 H), 1.46 (t, J = 7.1 Hz, 3 H), 1.15 (s, 9 H), 0.19 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 173.6, 167.3, 153.9, 141.7, 139.4, 129.8, 125.8, 123.5, 122.2, 121.8, 119.4, 110.7, 106.3, 60.8, 51.7, 35.5, 26.1 (3 ×), 26.0, 18.8, 14.7, –2.6 (2 ×).

HRMS (ESI): m/z [M + H+] calcd for C25H34NO5Si: 456.2201; found: 456.2200.


#

Ethyl 4-((tert-Butyldimethylsilyl)oxy)-9H-carbazole-1-carboxylate (14b) and 9-(tert-Butyl) 1-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-9H-carbazole-1,9-dicarboxylate (15b)

Silyl enol ether 5b (74 mg, 0.185mmol, 1 equiv.) and ethyl propiolate (0.19 mL, 182 mg, 1.85 mmol, 10 equiv.) in o-xylene (2 mL) were heated at reflux for 3 h. Then the reaction mixture was allowed to cool down and evaporated. Column chromatography on silica gel (eluent hexane/EtOAc 20:1 → 15:1) of the brown oily residue provided carbazole 14b (10 mg, 82% pure, 0.022 mmol, 12%) and 15b (39 mg, 0.083 mmol, 45%) both as colorless oils.


#

Ethyl 4-((tert-Butyldimethylsilyl)oxy)-9H-carbazole-1-carboxylate (14b)

Colorless oil; Rf = 0.41 (hexane/EtOAc 5:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 9.97 (br s, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.47 (t, J = 7.9 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 7.25 (d, J = 7.3 Hz, 1 H), 6.65 (d, J = 8.5 Hz, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.46 (t, J = 7.1 Hz, 3 H), 1.12 (s, 9 H), 0.42 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 167.5, 156.6, 142.8, 139.0, 129.2, 125.7, 122.8, 122.7, 122.1, 120.1, 115.4, 110.7, 105.6, 60.6, 26.1 (3 ×), 18.7 (2 ×), –3.5 (2 ×).

HRMS (ESI): m/z [M + H+] calcd for C21H28NO3Si: 370.1833; found: 370.1834.


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9-(tert-Butyl) 1-Ethyl 4-((tert-Butyldimethylsilyl)oxy)-9H-carbazole-1,9-dicarboxylate (15b)

Colorless oil; Rf = 0.39 (hexane/EtOAc 5:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 8.31 (dd, J = 7.7, 1.4 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.73 (d, J = 8.6 Hz, 1 H), 7.45 (ddd, J = 8.6, 7.3, 1.4 Hz, 1 H), 7.35 (td, J = 7.5, 1.1 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 4.39 (q, J = 7.1 Hz, 2 H), 1.67 (s, 9 H), 1.39 (t, J = 7.2 Hz, 3 H), 1.10 (s, 9 H), 0.40 (s, 6 H).

13C{1H} NMR (75 MHz, 300 K, CDCl3): δ = 167.7, 154.4, 151.4, 139.2, 138.8, 129.3, 126.6, 124.9, 123.1, 122.7, 118.7, 115.1, 115.0, 112.3, 84.4, 60.9, 28.3 (3 ×), 26.1 (3 ×), 18.7, 14.4, –3.6 (2 ×).

HRMS (ESI): m/z [M + Na+] calcd for C26H35NO5SiNa: 492.2177; found: 492.2185.


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(1S*,3S*,4aR*,9aR*)-4a-Allyl-9-(tert-butoxycarbonyl)-4-oxo-1,2,3,4,4a,9-hexahydro-3,9a-ethanocarbazole-1-carboxylic Acid (16) and 9-(tert-Butyl) 1-Allyl (1S*,3S*,4aR*,9aR*)-4a-Allyl-4-oxo-2,3,4,4a-tetrahydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (17a)

A solution of endo-13bb (87 mg, 0.17 mmol, 1 equiv.) and Xantphos (8 mg, 0.01 mmol, 8 mol%) in DMF (2 mL) was degassed with a flow of argon (needle inserted into solution) for 5 min. Then Pd(OAc)2 (2 mg, 0.01 mmol, 5 mol%) was added. The resulting pale brown solution was heated to 90 °C (submersion of the reaction flask into a preheated silicon oil bath) for 3 h. Then the resulting black reaction mixture was allowed to cool down and poured into mixture of aq 0.1 M HCl (20 mL) and Et2O (30 mL). The aqueous layer was extracted with Et2O (10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Column chromatography on silica gel (eluent: hexane/EtOAc 5:1 → 1:1) of the brown residue provided allylic aster 17a (2 mg, 5 × 10–3 mmol, 3%) and carboxylic acid 16 (56 mg, 0.14 mmol, 83%) as colorless white solids.


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16

White solid; mp 78–79 °C (hexane/EtOAc); Rf = 0.12 (hexane/EtOAc 1:1).

1H NMR (800 MHz, 303 K, CDCl3): δ = 8.42–7.45 (br m, 2 H), 7.34 (d, J = 7.5 Hz, 1 H), 6.97 (t, J = 7.4 Hz, 1 H), 6.81 (t, J = 7.4 Hz, 1 H), 5.52 (dddd, J = 16.9, 10.0, 7.1, 6.5 Hz, 1 H), 4.91 (d, J = 10.0 Hz, 1 H), 4.67 (d, J = 16.9 Hz, 1 H), 3.45–7.57 (br m, 2 H), 2.49 (pent, J = 2.7 Hz, 1 H), 2.47 (dd, J = 13.9, 6.5 Hz, 1 H), 2.43–2.36 (m, 2 H), 2.32 (dd, J = 13.9, 3.4 Hz, 7 H), 2.29–2.22 (m, 1 H), 2.01 (dq, J = 13.5, 2.3 Hz, 1 H), 1.97 (ddd, J = 13.9, 11.3, 2.4 Hz, 1 H), 1.60 (s, 9 H).

13C{1H} NMR (201 MHz, 303 K, CDCl3): δ = 210.1, 177.6, 153.0, 142.6, 132.3, 130.1, 127.9, 125.1, 122.6, 118.9, 116.0, 82.1, 72.5, 59.4, 42.2, 41.1, 28.7 (3 ×), 28.2, 25.2. Two carbons too broad to be detected due to dynamic process.

HRMS (ESI): m/z [M + H+] calcd for C23H28NO5: 398.1962; found: 398.1969.


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17a

White semi-solid; Rf = 0.39 (hexane/EtOAc 3:1).

1H NMR (700 MHz, 303 K, CDCl3): δ = 7.96–7.42 (br m, 2 H), 7.13 (br s, 1 H), 6.94 (t, J = 7.4 Hz, 1 H), 5.68 (br s, 1 H), 5.55 (dddd, J = 17.2, 10.3, 7.7, 6.6 Hz, 1 H), 5.16–5.08 (m, 2 H), 4.93 (d, J = 10.1 Hz, 1 H), 4.68 (br d, J = 16.7 Hz, 1 H), 3.84 (dd, J = 13.1, 6.0 Hz, 1 H), 3.50–3.20 (br m, 2 H), 3.02–2.62 (br m, 1 H), 2.59–2.21 (m, 6 H), 2.05–1.95 (m, 2 H), 1.63 (s, 9 H).

13C{1H} NMR (201 MHz, CDCl3): δ = 209.8, 172.5, 152.9, 142.7, 132.3, 132.3, 132.0, 128.0, 127.8, 125.6, 125.1, 122.9, 122.7, 119.0, 118.4, 115.8, 81.9, 66.3, 66.0, 59.9, 59.4, 43.6, 42.4, 42.2, 41.4, 41.3, 29.9, 28.7 (3 ×), 28.5, 26.9, 25.9, 25.8, 25.5, 22.8. Several signals are very weak or not seen due to low amount of the material and dynamic processes; there is also duplication of selected signals because of rotamers.

HRMS (ESI): m/z [M + H+] calcd for C26H32NO5: 438.2275; found: 438.2269.


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9-(tert-Butyl) 1-Methyl (1S*,3S*,4aR*,9aR*)-4a-Allyl-4-oxo-2,3,4,4a-tetrahydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (17b)

A solution of the carboxylic acid 16 (79 mg, 0.20 mmol, 1 equiv.), MeI (25 μL, 57 mg, 0.40 mmol, 2.0 equiv.), and K2CO3 (55 mg, 0.40 mmol, 2.0 equiv.) in DMF (0.5 mL) was stirred for 2 h at r.t. Then the resulting reaction mixture was added to a mixture of H2O (20 mL) and Et2O (30 mL). The aqueous layer was extracted with Et2O (10 mL). The combined organic phases were washed with H2O (10 mL) and brine (20 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Column chromatography on silica gel (eluent: hexane/EtOAc 5:1 → 3:1) provided ester 17b as colorless needles; yield: 75 mg (0.18 mmol, 92%); white crystals; mp 150–151 °C (hexane/EtOAc); Rf = 0.34 (hexane/EtOAc 1:1).

1H NMR (300 MHz, 303 K, CDCl3): δ = 7.89 and 7.46 (2 br s, 1 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.13 (t, J = 7.9 Hz, 1 H), 6.93 (t, J = 7.5 Hz, 1 H), 5.54 (ddt, J = 17.1, 10.1, 7.2 Hz, 1 H), 4.92 (dd, J = 10.2, 1.8 Hz, 1 H), 4.67 (dd, J = 17.1, 1.8 Hz, 1 H), 3.45 and 3.21 (2 br s, 1 H), 2.98 and 2.65 (2 br s, 1 H), 2.92 (s, 3 H), 2.56–2.35 (m, 5 H), 2.36–2.20 (m, 1 H), 2.06–1.92 (m, 2 H), 1.63 (s, 9 H).

13C NMR (75 MHz, 303 K, CDCl3): δ = 210.0, 173.4, 173.2, 153.3, 142.7, 142.0, 132.3, 130.4, 127.9, 125.5, 124.9, 122.7, 119.0, 115.6, 82.1, 81.8, 72.4, 59.8, 59.3, 51.9, 43.3, 42.2, 41.3, 28.7 (3 ×), 28.4, 26.9, 25.3. Several signals are broad or duplicated due to dynamic processes.

HRMS (ESI): m/z [M + H+] calcd for C24H30NO5: 412.2118; found: 412.2115.


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(1S*,3S*,4aR*,9aR*)-4a-Allyl-4-oxo-1,2,3,4,4a,9-hexahydro-3,9a-ethanocarbazole-1-carboxylic Acid (18)

A solution of Boc-protected indole 16 (35 mg, 88 μmol, 1 equiv.) in CH2Cl2/TFA (0.9 mL, 8:1 mixture) was stirred for 3 h at r.t. Then solvents were evaporated in vacuo and the residue was subjected to column chromatography on silica gel (eluent: hexane/EtOAc 1:1 → 1:2) to afford deprotected indole 18 (21 mg, 71 μmol, 81%) as white plates. Sample for X-ray diffraction analysis was grown by slow evaporation of saturated acetone solution; white crystals; mp 184–185 °C (acetone); Rf = 0.09 (EtOAc).

1H NMR (800 MHz, 300 K, acetone-d 6): δ = 7.16 (dd, J = 7.6, 1.3 Hz, 1 H), 6.89 (td, J = 7.6, 1.3 Hz, 1 H), 6.63–6.47 (m, 2 H), 5.69 (ddt, J = 17.1, 10.2, 7.0 Hz, 1 H), 4.84 (dd, J = 10.2, 2.0 Hz, 1 H), 4.67 (dt, J = 17.1, 1.8 Hz, 1 H), 2.75 (dd, J = 11.3, 3.8 Hz, 1 H), 2.49 (d, J = 7.0 Hz, 2 H), 2.40–2.35 (m, 1 H), 2.34–2.28 (m, 3 H), 2.09–1.99 (m, 3 H). NH and CO2H protons were too broad to be detected.

13C{1H} NMR (201 MHz, 303 K, acetone-d 6): δ = 211.1, 174.8, 151.1, 134.8, 130.7, 128.1, 125.8, 118.9, 117.6, 112.3, 71.5, 60.9, 47.5, 43.4, 39.8, 30.3, 27.8, 25.9.

HRMS (ESI): m/z [M + H+] calcd for C18H20NO3: 298.1438; found: 298.1433.


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9-(tert-Butyl) 1-Ethyl (1S*,3S*,4aR*,9aR*)-4a-Allyl-4-oxo-2,3,4,4a-tetrahydro-3,9a-ethanocarbazole-1,9(1H)-dicarboxylate (17c)

A solution of endo-13ba (100 mg, 0.20 mmol, 1 equiv.), allyl acetate (24 mg, 0.24 mmol, 1.2 equiv.), and Xantphos (9 mg, 0.02 mmol, 8 mol%) in DMF (3 mL) was degassed with a flow of argon (needle inserted into solution) for 5 min. Then Pd(OAc)2 (2 mg, 0.01 mmol, 5 mol%) was added. The resulting pale brown solution was heated to 90 °C (submersion of the reaction flask into a preheated silicon oil bath) for 3 h. Then the resulting black reaction mixture was allowed to cool down and poured into a mixture of aq 0.1 M HCl (20 mL) and Et2O (30 mL). The aqueous layer was extracted with Et2O (10 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4) and concentrated on a rotary evaporator. Column chromatography on silica gel (eluent: hexane/EtOAc 5:1 → 1:1) of the brown residue provided allylated product 17c as colorless needles; yield: 45 mg (0.11 mmol, 53%); white crystals; mp 114–116 °C (hexane/EtOAc); Rf = 0.40 (hexane/EtOAc 5:1).

1H NMR (300 MHz, 300 K, CDCl3): δ = 7.99–7.35 (br m, 2 H), 7.12 (t, J = 8.0 Hz, 1 H), 6.92 (t, J = 7.4 Hz, 1 H), 5.53 (ddt, J = 17.2, 10.3, 7.2 Hz, 1 H), 4.91 (d, J = 10.3 Hz, 1 H), 4.66 (d, J = 17.2 Hz, 1 H), 3.52–3.10 (m, 2 H), 3.07–2.54 (m, 2 H), 2.58–2.14 (m, 6 H), 2.13–1.87 (m, 2 H), 1.62 (s, 9 H), 1.00 (t, J = 7.1 Hz, 3 H).

13C NMR (201 MHz, 303 K, CDCl3): δ = 210.0, 209.8, 173.2, 172.8, 153.1, 153.0, 142.7, 142.0, 132.3, 130.6, 130.2, 127.9, 127.8, 125.5, 124.9, 122.7, 122.5, 118.9, 115.5, 82.1, 81.7, 72.3, 61.3, 60.9, 59.8, 59.3, 43.5, 42.3, 42.2, 41.4, 41.3, 28.7 (3 ×), 28.5, 28.4, 27.0, 25.9, 25.4, 13.8, 13.5. Most signals are duplicated due to presence of 2 rotameric forms.

HRMS (ESI): m/z [M + H+] calcd for C25H32NO5: 426.2275; found: 426.2276.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

A. A. Korlyukov acknowledges Ministry of Science and Higher Education of the Russian Federation (Contract No. 075-03-2023-642) for employing the equipment of Center for molecular composition studies of INEOS RAS in X-ray crystallographic study.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2186-7034.
  • Supporting Information

Corresponding Author

Andrey A. Mikhaylov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences
16/10 Miklukho-Maklaya St., Moscow 117997
Russian Federation   

Publication History

Received: 04 September 2023

Accepted after revision: 05 October 2023

Accepted Manuscript online:
05 October 2023

Article published online:
06 November 2023

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Zoom Image
Figure 1 Selected Kopsia alkaloids
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Scheme 1 Diels–Alder reaction in the formation of quaternary stereocenters of kopsinine (2)
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Scheme 2 Synthesis of substituted tetrahydrocarboline 6
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Scheme 3 Unexpected vinylogous Claisen condensation upon silylation of the ketone 6. X-ray structure for compound 9 is depicted with thermal ellipsoids at the 50% probability level. Hydrogen atoms are omitted for clarity.
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Scheme 4 Successful Mannich/Mukaiyama–Michael approach towards silyl enol ether 5a
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Scheme 5 Diels–Alder cycloaddition of silyl enolates 5
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Scheme 6 Tsuji–Trost allyl transfer for derivative endo-13bb. X-ray structure for compound 18 is depicted with thermal ellipsoids at the 50% probability level. Hydrogen atoms are omitted for clarity.
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Scheme 7 Intermolecular Tsuji–Trost allylation of derivatives 13ba