Intramolecular Cyclization During Bromination of the Quinoline Alkaloid Haplophyllidine

Bromination of the furanoquinoline alkaloid haplophyllidine by molecular bromine and N-bromosuccinimide was accompanied by intramolecular cyclization to form mixtures of new compounds containing additional penta-, hexa-, and spirocyclic rings incorporating the prenyl group of haplophyllidine. The structures and absolute configurations of the chiral centers of all four bromo-derivatives were elucidated using a combination of NMR spectroscopic methods and X-ray crystal structure analyses.

The structures of isolated 3-5 were proved by spectral methods and X-ray crystal structure analyses (XSAs). The chemical structure of 2, which was isolated as an oil, was elucidated by analyzing 1 H and 13 C NMR spectra and HSQC, HMBC, DQF-COSY, and NOESY experiments. Resonances of protons and C atoms in 1 H and 13 C NMR spectra were assigned by using HSQC and COSY experiments. The strong-field part of the 1 H NMR spectrum of 2 showed two singlets for methyls at and 4.44 (dd, J = 7.3, 6.5 Hz, H-10), which were characteristic of protons on a C atom bound to oxygen, and 3H singlets at 3.14 and 4.27 ppm for C-8 and C-4 methoxyls, respectively. The aromatic part of the spectrum had only two 1H doublets with SSCC J = 2.6 Hz at δ H 7.57 ppm (H-2) and 6.95 (H-3) that corresponded to protons of the furan ring [11].
An analysis of 13 C NMR and HSQC spectra of 2 showed 18 resonances for C atoms as seven quaternary, including five on a heteroatom; four methine; three methylene; and four methyl C atoms. The weak-field region of the 13 C NMR spectrum had resonances for three quaternary C atoms at δ 162.86 (C-1a), 158.01 (C-4), and 150.96 (C-8a) and for a protonated C atom at δ 142.90 (C-2), which was determined from an HSQC experiment of the furanopyridine motif. The aromatic range of C atoms revealed resonances of a second methine C atom at δ 104.82 (C-3) and two quaternary C atoms at δ 105.36 (C-3a) and 118. 16 (C-4a).
Resonances in 1 H and 13 C NMR spectra of 4 were assigned based on HSQC and HMBC experiments ( Table 2). Products 2 and 4 were found to be epimers at C-10. A comparative analysis of the results revealed several differences in the PMR spectra of these compounds. Protons H-9 in cyclic product 4 resonated at δ H 2.19 (dd, J = 12.0, 12.9 Hz) and 3.50 (dd, J = 12.0, 4.2 Hz) while the resonance of α-proton H-10 was shifted by 0.57 ppm to strong field. Also, the C-12 resonance of 4 was shifted (δ 18.23) as compared to that of 2 (δ 27.06). An XSA established the structure of 4 as (7R,8R,10R)-10-bromo-4,8-dimethoxy-11,11-dimethyl-5,6,7,8,10,11-hexahydro-9H-furo [2,3- The structure of 3 was established as a bromo-derivative of an oxaspiroquinoline using 2D NMR spectroscopy and an XSA. The NMR spectroscopic data showed that 3 also contained a new ring. Thus, resonances of a methyl (H 3 CO-8 at δ 3.18 ppm) and an olefin [H-10 (δ 5.35 ppm) and C-10 (δ 54.64 ppm) and C-11 (δ 74.92 ppm)] disappeared from NMR spectra of starting 1. The disappearance of the C-10=C-11 double bond in 1 was compensated by the appearance in 3 of a new fivemembered ring based on the prenyl group of 1. The lack of a methyl resonance at 3.18 ppm indicated that the new ring closed through the oxygen on C-8. Also, the multiplicities of the 7-OH and H-7 resonances were observed to change and the H-9b resonance shifted to strong field (δ 3.26→2.77 ppm). Proton H-10 in 3 resonated at δ 5.04 (1H, dd, J = 11.4, 7.1 Hz). The resonances of the other protons of oxaspiroquinoline 3 and starting 1, including two singlets from magnetically nonequivalent geminal CH 3 groups, appeared in analogous regions. The 13 C NMR spectrum of 3 had resonances at δ 85.1 (spiro C), 84.0, and 53.9 ppm that were attributed to C-8, C-11, and C-10, which resonated in starting 1 at δ 79.2, 134.1, and 119.8 ppm, respectively. It is noteworthy that cycloaddition at an exocyclic double bond is one of the methods used to synthesize spirocyclic compounds [12] although the prenyl double bond and the methoxyl O atom of haplophyllidine were involved in the formation of spirocyclic 3.

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The formation of the variously structured intramolecular cyclization products 2-5 through the action of the brominating agents in CHCl 3 provided the basis for a scheme of the reaction mechanism that explained well the experimental results using generally known concepts of the bromination mechanism of ethylene bonds (Scheme 2). The formation of two bromonium cations (A and B) is one reason for the different directions of the reactions. The presence of hydroxyl (7α-OH), methoxyl (8β-OCH 3 ), and -N= groups in 1 that stabilized carbocations formed at C-10 and C-11 led to several cyclic reaction products.
The outcome of the final cyclization step depended on the degree of localization of negative charge on the oxide atoms and on the regioisomerization of the bromonium cations (A and B). The ionic charge of the bromonium ion and the ability of a methoxyl ion to attack it (bromination method C) decreased if the polarity of the solvent was increased (DMF as compared to CHCl 3 ).
The structures of the bromination products were difficult to establish based on spectral methods, particularly NMR spectroscopy. Therefore, the structures of the obtained compounds were established using XSA analyses, which proved the structures of 3-5 and the absolute configurations of the chiral centers of the synthesized cyclic derivatives. Figure 1 shows the molecular structures of 3-5, which agreed with the absolute configurations. The Flack parameters for these compounds were 0.009(13), 0.027 (11), and 0.020 (7). The presence of the heavy Br atom in the bromination products enabled the absolute configurations to be reliably determined as 7R,8R,10S (3), 7R,8R,10R (4), and 7R,8R,10R (5). The Br atom and C-11 methyl group were disordered in 5 and exchanged places in approximately equal ratios (one of the fixed positions of the molecule is shown in Fig. 1). Therefore, the temperature factors are greater for these atoms and the Csp 3 -Csp 3 bond distances are anomalously elongated in this motif. Otherwise, the bond distances and angles fell within 3σ of the usual values [13].
The core in the molecular structures of tetrahydrofuranoquinoline derivatives 3-5 was almost planar except for ring A. Ring A in 3 adopted a 6α-sofa conformation; the oxaspiro-bonded heterocycle, a half-chair. Ring A in 4 adopted a half-chair conformation with C-6 and C-7 deviating from the plane of the other four. The condensed six-membered oxa heterocycle had a chair conformation. Ring A in 5 had another half-chair shape that was related to the deviation of C-6 and C-7 to the opposite side; the five-membered heterocycle, an envelope conformation. Scheme 2. Proposed bromination mechanism of haplophyllidine by molecular bromine and NBS in CHCl 3 .  Anomalously short van-der-Waals intermolecular contacts were not observed in crystals of the molecules. Thus, we showed that bromination of 1 by Br 2 and NBS was associated with addition of Br and intramolecular cyclization involving the prenyl double bond and the O atom of the hydroxyl or methoxyl group to form additional penta-, hexa-, and spirocyclic structures.
Bromination of 1 by NBS in CHCl 3 . A solution of 1 (0.3 g, 0.95 mmol) in CHCl 3 (5 mL) was stirred, treated with a suspension of NBS (0.2 g, 1.12 mmol) in CHCl 3 (2 mL) over 10 min, and stirred for 5 h at 20-25°C. The course of the reaction was monitored by TLC. When the reaction was finished, the solution was made basic with NH 4 OH to pH 9-10 and extracted with CHCl 3 . The solvent was distilled off. The crude product containing four compounds (R f 0.70, 0.67, 0.65, 0.50) was purified over a column of silica gel using benzine-EtOAc (100:1→100:10). One pure product (5)  Bromination of 1 by NBS in DMF. A cold (0°C) solution of 1 (0.5 g, 1.58 mmol) in DMF (5 mL) was stirred, treated with NBS (0.336 g, 1.89 mmol) over 5 min, and stirred for 4 h at 20-25°C. The course of the reaction was monitored by TLC. When the reaction was finished, the mixture was treated with ice water (5 mL). The resulting precipitate containing three compounds (R f 0.70, 0.65, 0.50) was separated and purified over a column of silica gel using benzine-EtOAc (100:1→100:10). Only 4 was isolated pure. Crystals, mp 192-194°C, R f 0.70 (benzine-EtOAc, 2:1).
Preparation of Solution of Reference Standard for HPLC. An accurate weight (1.25 mg) of reference (or test) standard was placed into a 10-mL volumetric flask, treated with EtOH (5 mL), mixed for 10 min in an ultrasound bath, diluted to the mark with the same solvent, stirred, and filtered through a 0.45-μm membrane filter.