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Total Synthesis of (±)-Allocolchicine and Its Analogues Using CoCatalyzed Alkyne [2 + 2 + 2]-Cyclotrimerization Dinesh J. Paymode†,‡ and Chepuri V. Ramana*,†,‡ †

Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India

‡

S Supporting Information *

ABSTRACT: The total synthesis of (±)-allocolchicine has been completed by employing cobalt-catalyzed alkyne [2 + 2 + 2]-cyclotrimerization as the key reaction. The essential diyne has been synthesized from easily available 3,4,5-trimethoxybenzaldehyde following simple chemical transformations. In general, the cycloaddition gave a mixture of C(9) and C(10) isomers thus allowing the synthesis of both allocolchicine and its C(10)-carboxylate. Because this cycloaddition was employed at the penultimate stage, it allowed the synthesis of various analogues having the diverse functionality at C(9) and/or C(10) of ring C.

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INTRODUCTION

In 1820, colchicine was first isolated by Pelletier and Caventou from the meadow saffron Colchicum autumnale.1 Colchicine is the first and most studied drug against acute gout and familial Mediterranean fever, where it arrests the formation of the mitotic spindle in the cell by binding with microtubules thus resulting in microtubule depolymerization.2 Along with this, it is useful in the treatment of chronic myelocytic leukemia and other types of cancers.3 Unfortunately, its toxicity has caused limitation in the treatment of human neoplasm and has proved ineffective in therapeutic studies.4 It was observed that the prominent activity of colchicine primarily depends on the size of ring C and substituents present on ring C.5 Later, compounds having modifications of ring C, such as natural allocolchicine (1) and allied allocolchicinoids, like methyl ester of N-acetyl colchicinol (NSC 51046), N-acetylcolchicinol, and its dihydrogenphosphate (ZD 6126), possessing a 6−7−6 carbocyclic framework, showed good activity with reduced toxicity compared to that of the 6−7−7 tricylic system present in colchicine (Figure 1).3,6 This reduced toxicity and the structural features have led to an interest in the development of synthetic protocols to enable allocolchicine (1) and its analogues as promising tubulin-binding agents. In this context, developments of modular synthetic approaches that provide an easy access to a variety of ring C-modified allocolchicinoids are highly desirable. Interestingly, till date, there is only one report on the total synthesis of allocolchicine (1) by Wulff’s group and one formal synthesis report by Fagnou’s group. Wulff and co-workers used a Diels−Alder reaction for C ring construction.7 On the other hand, Fagnou’s group documented the Pd-catalyzed intramolecular direct arylation to install the B ring of allocolchicine.8 Coming to the other allocolchicinoids that are currently in clinical trials, Maudet’s9 report on the synthesis of N© 2017 American Chemical Society

Figure 1. Colchicine, allocolchicine, and related pharmaceutically important allocolchicinoids.

acetylcolchicinol using modified Ziegler Ullmann coupling, Hanna’s10 enyne ring-closing metathesis (RCM) and Diels− Alder aromatization for B and C ring construction, synthesis of NSC 51046 by Green’s11 group employing an intramolecular Nicholas reaction for B ring construction, as well as synthesis of NSC 51046 by DeShong’s12 group employing the siloxane coupling-ring expansion protocol are the remarkable examples in this regard. Moreover, Norman’s group developed an approach for the synthesis of 6-oxa-allocolchicinoids by [2 + 2 + 2]-cycloaddition as well as synthesized various allocolchicine analogues with pyridine C ring through Received: July 12, 2017 Accepted: August 24, 2017 Published: September 8, 2017 5591

DOI: 10.1021/acsomega.7b00980 ACS Omega 2017, 2, 5591−5600

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excellent yields (Scheme 2). Initially, the introduction of the alkyne unit on 5 was attempted by following a sequence of

intermolecular Vollhardt diyne-nitrile cyclotrimerization in another report.13 We have recently documented the synthesis of a library focused on the cyclopropyl allocolchicinoids that have shown equipotent tubulin-binding ability when compared to the natural allocolchicine (1).14 A large number of C ringmodified analogues of this cyclopropyl allocolchicinoids could be realized by virtue of using the alkyne [2 + 2 + 2]cyclotrimerization15,16 as the key reaction and importantly as the final event in our adopted approach. Given its simplicity and realization of a large number of analogues, especially with substituent alteration on ring C, we realized that adopting a similar cyclotrimerization approach will address the total synthesis of allocolchicine as well as the synthesis of ring Cmodified allocolchicinoids. In this article, we document the successful total synthesis of (±)-allocolchicine (1) employing Co-catalyzed alkyne [2 + 2 + 2]-cyclotrimerization for the simultaneous construction of rings B and C and the synthesis of several ring-modified allocolchicinoids.17

Scheme 2. Preparation of the Building Block Propargyl Chloride 3

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RESULTS AND DISCUSSION Our retrosynthetic disconnections for (±)-allocolchicine (1) are summarized in Scheme 1. Keeping the alkyne [2 + 2 + 2]-

formylation and Ohira−Bestmann alkynylation reactions. The formylation of 5 proceeded smoothly by using dichloromethylmethyl ether in the presence of TMSOTf to afford aldehyde 6 in admirable yield. Strangely, the attempts for alkynylation of 6 either by the Ohira−Bestmann reagent18 or by the Corey− Fuchs reaction19 were unsuccessful, probably due to the steric hindrance. This led us to opt for an alternative route for the preparation of 3, where we intended to employ Sonogashira cross-coupling at an elevated temperature to introduce the alkyne unit opted for previous synthesis.14 Accordingly, 5 was first subjected for oxidative cleavage by using KMnO4 and NaIO4 to get aldehyde, which was carried further for reduction to get alcohol and then protection of the resulting free −OH as its acetate to obtain 7 in 70% yield over four steps (Scheme 3). The iodination of 7 with I2/ Ag(CF3CO2) in CHCl3 gave the requisite iodo compound 8 with 94% yield. The intended Sonogashira coupling of 8 with trimethylsilylacetylene proceeded smoothly in the presence of PdCl2(PPh3)2 (2 mol %), copper iodide (20 mol %), and PPh3 (20 mol %) in DMF/diethyl amine (1:2) at 80 °C and provided the required coupling product 9 in 86% yield. Following this, one-pot alkynyl−TMS as well as acetate group deprotection using K2CO3 in methanol gave the desired alkynol 10. The oxidation of alkynol 10 proceeded smoothly with Dess−Martin periodinane (DMP)20 in CH2Cl2 to provide the aldehyde intermediate. Our next concern was the α-chlorination of an aldehyde and installation of the second alkyne unit. The treatment of this aldehyde with N-chlorosuccinimide (NCS) in the presence of L-proline in acetonitrile followed by the subjection of the resulting α-chloroaldehyde immediately for alkynylation using the Ohira−Bestmann reagent and K2CO3 in methanol provided the diyne 3 with 45% yield over three steps. At this point, we had the cyclization precursor diyne 3, the building block for the key cyclotrimerization reaction. With this, we began our efforts for the installation of the amine functionality at the C(7) center. To achieve this, we sought to explore the possibility of the nucleophilic substitution of chlorine by the amination reagent. The displacement of the chloro group in diyne 3 was carried out with p-methoxybenzyl amine in the presence of Cs2CO3 in CH3CN to obtain the diyne 11 in moderate yield. Subsequent acetyl protection with acetic anhydride gave the key intermediate diyne 2 (Scheme 3). With the fully elaborated diyne 2 having the required basic arrangement of all components, we proceeded toward the

Scheme 1. Retrosynthetic Analysis of (±)-Allocolchicine (1)

cyclotrimerization reaction as the key reaction, the simultaneous disconnection of the rings B and C led to the identification of diyne 2 as the key intermediate. PMB protection of the N−Ac group could avoid any complications associated with the free amide during the cyclotrimerization. An SN2 displacement of the corresponding propargyl chloride 3 with PMB-amine has been planned to introduce the amine functional group. The synthesis of propargyl chloride 3 was intended from commercially available 3,4,5-trimethoxybenzaldehyde by the Grignard reaction for side-chain elongation, followed by Sonogashira coupling to introduce the aryl alkyne unit, followed by the sequence of proline-catalyzed αchlorination on the side chain, and the subsequent Ohira− Bestmann alkynylation reaction. The synthesis commenced with the Grignard addition of but3-enylmagnesium bromide to 3,4,5-trimethoxybenzaldehyde and subsequent deoxygenation of the resulting benzyl alcohol 4 in the presence of Et2O·BF3 and Et3SiH to afford 5 in 5592


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Scheme 3. Total Synthesis of (±)-Allocolchicine (1) and Its C(10) Regioisomer 1a

Table 1. Scope of the [2 + 2 + 2]-Cyclotrimerization of Diyne 2 and Various Alkynes

in 1:2 proportion in 79% combined yield over two steps. Both (±)-allocolchicine (1) and its C(10) regioisomer 1a were characterized by 1H and 13C NMR, and the spectral data matched entirely with earlier reports.7,10b Having synthesized target allocolchicine (1) and established the feasibility of the cobalt-catalyzed alkyne [2 + 2 + 2]cyclotrimerization reaction, we turned our attention to the synthesis of its analogues having variations at C(9) and C(10) of ring C. Table 1 shows the scope of the Co-catalyzed alkyne

construction of the aromatic ring of allocolchicine (1) using the intended [Co]-mediated cyclotrimerization reaction.21 After optimization of the reaction, the cyclotrimerization of diyne 2 with methyl propiolate was realized successfully in the presence of 20 mol % CpCo(CO)2 catalyst under light (200 W bulb) in toluene and resulted in an inseparable mixture of regioisomers, which were consequently subjected to PMB deprotection by using trifluoroacetic acid/CH2Cl2 (2:1) to afford easily separable (±)-allocolchicine (1) and its C(10) regioisomer 1a 5593


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[2 + 2 + 2]-cyclotrimerization reaction of diyne 2 with easily available symmetric as well as asymmetric alkynes. With acetylene, the cyclotrimerization reaction proceeded effectively in a sealed tube to afford 1b in 77% yield. However, the reaction with bis(trimethylsilyl)acetylene did not provide the desired product. Similarly, the reaction was carried out with symmetric alkynes like dimethyl acetylenedicarboxylate, 4octyne, and the diacetate of butyne diol and provided the corresponding allocolchicinoids in good yields. In the case of asymmetric alkynes, the cyclotrimerization resulted in inseparable regioisomeric mixtures, but the regioisomers were easily separated by column chromatography after PMB deprotection and were characterized by two-dimensional NMR spectroscopy. In the reaction of diyne 2 with methyl 3-phenylpropiolate, the major regioisomer 1h was observed in 62% yield, whereas the minor regioisomer could not be isolated. These numbers of analogues having different functionality at the C ring show the importance and flexibility of our synthetic strategy (Table 1). The NMR spectra of allocolchicine and other analogues revealed that these compounds exist as an equilibrium mixture of two atropisomers. It has been reported earlier that in the case of colchicine and other colchicinoids, the conformational equilibrium is solvent-dependent and also depends on the nature of the substituents present on ring B.6c,7,22 It has been seen that deacetamidocolchicine, in which C(7) is a methylene, exists in solution as a 1:1 mixture of both the atropisomers.23 However, when colchicine’s seven-member tropolone ring is replaced with an aromatic phenyl ring, as in allocolchicinoids, the structural features controlling the equilibrium of atropisomers are less clear. In this regard, few groups have studied conformational equilibria of modified allocolchicinoids in various solvents.3,7 However, a detailed study of the atropisomerism of allocolchicine (1) has not been revealed yet. To probe in this direction, the 1H NMR of allocolchicine (1) and its regioisomer 1a has been recorded in different solvents. As shown in Table 2, in nonpolar solvents like

Figure 2. Key coupling constants for atropisomers of allocolchicinoids.

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CONCLUSIONS In summary, the total synthesis of (±)-allocolchicine has been completed by employing simple starting compounds and Cocatalyzed alkyne [2 + 2 + 2]-cyclotrimerization to construct the central 6−7−6 tricyclic framework. To demonstrate the flexibility of our approach, a good number of ring C-modified allocolchicinoids with varying substituents at C(9) and/or C(10) have been synthesized. The effects of various solvents on the atropisomerism present in allocolchicinoids were studied in detail. Currently, work in the direction of asymmetric synthesis of allocolchicine and the accessing of various C-ring-modified allocolchicine analogues and their screening for tubulin-binding affinity and as antimitotic agents are in progress, and the results will be reported in due course.

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EXPERIMENTAL SECTION General Information. Air- and/or moisture-sensitive reactions were carried out in anhydrous solvents under an atmosphere of argon in oven-dried glassware. All anhydrous solvents were distilled prior to use: CH2Cl2, toluene, and DMF from CaH2; methanol from Mg cake; tetrahydrofuran (THF) on Na/benzophenone; and acetonitrile over P2O5. Commercial reagents were used without purification. Column chromatography was carried out by using silica gel (60−120, 100−200, and 230−400 mesh). 1H NMR and 13C NMR chemical shifts are reported in ppm relative to chloroform-d (δ = 7.25) or TMS, and coupling constants (J) are reported in hertz (Hz). The following abbreviations have been used to designate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and b = broad. The multiplicity of carbons has been assigned with the help of DEPT spectra. High resolution mass spectra (HRMS) were recorded on a Q Exactive Hybrid Quadrupole Orbitrap Mass Spectrometer, where the mass analyzer used for analysis is orbitrap. 1-(3,4,5-Trimethoxyphenyl)pent-4-en-1-ol (4). A suspension of Mg (3.22 g, 132.52 mmol) and catalytic iodine (50 mg) in dry THF (350 mL) was treated with 4-bromobut-1-ene (13.45 mL, 132.52 mmol) at 0 °C, and the contents were stirred at room temperature for 1 h. To this, a solution of the 3,4,5-trimethoxybenzaldehyde (20.00 g, 101.94 mmol) in THF (50 mL) was added slowly at 0 °C, and the mixture was stirred for another 2 h at room temperature. The reaction mixture was quenched with saturated NH4Cl (200 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extract was dried (Na2SO4) and concentrated, and the resulting crude residue was purified by silica gel column chromatography (20 → 35% EtOAc in pet. ether) afforded 4 (23.7 g, 92%) as a colorless oil. Rf = 0.4 (40% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.71−1.91 (m, 2H), 2.05−2.19 (m, 2H), 3.80 (s, 3H), 3.83 (s, 6H), 4.60 (dd, J = 5.8, 7.6 Hz, 1H), 4.95−5.08 (m, 2H), 5.82 (ddt, J = 6.4, 10.2, 17.1 Hz, 1H), 6.53 (s, 2H);

Table 2. Ratio of Atropisomers of Allocolchicine (1) and Its Regioisomer 1a in Various Solvents sr. no.

solvents

1

1a

1. 2. 3. 4. 5. 6.

chloroform-d1 dichloromethane-d2 benzene-d6 acetone-d6 methano-d4 pyridine-d5

10:2.3 10:1.7 10:1.2 10:0 10:0 10:0

10:2.5 10:2.2 10:1.7 10:0 10:0 10:0

chloroform-d1, dichloromethane-d2, and benzene-d6, the atropisomer mixture was observed in varying proportions. In polar solvents, like acetone-d6, methanol-d4, and pyridine-d5, only a single atropisomer was observed with both 1 and 1a. This study indicated clearly a solvent-dependent conformational equilibrium in the case of allocolchicine (1) and its isomer 1a. Also, the comparison of variation of this ratio in 1 and 1a revealed that the substituent position on the ring C has some nominal effect on the ratio of the conformational isomers. The observed large coupling constants, J6,7 = 12.2 Hz and J6′,7 = 6.7 Hz for H-C(7) of 1 and J6,7 = 12.2 Hz and J6′,7 = 7.2 Hz for H-C(7) of 1a, revealed their conformers as (aS,7S);(aR,7R) in methanol-d4 solvent (Figure 2).22 5594


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C NMR (50 MHz, CDCl3): δ 30.1 (t), 38.0 (t), 55.9 (q, 2C), 60.7 (q), 74.1 (d), 102.5 (d, 2C), 114.9 (t), 136.9 (s), 138.1 (d), 140.5 (s), 153.1 (s, 2C) ppm; HRMS (m/z) [M + Na]+ calculated for C14H20O4Na 275.1254; found 275.1251. 1,2,3-Trimethoxy-5-(pent-4-en-1-yl)benzene (5). To a cooled (0 °C) solution of the alcohol 4 (23.00 g, 91.16 mmol) in anhydrous CH2Cl2 (400 mL), triethylsilane (18.93 mL, 118.51 mmol) and boron trifluoride diethyl etherate (16.88 mL, 136.74 mmol) were added slowly one by one and stirring was continued at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (200 mL), and the aqueous layer was extracted with CH2Cl2 (2 × 300 mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (10 → 15% EtOAc in pet. ether) gave 5 (20.3 g, 94%) as a colorless oil. Rf = 0.4 (15% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.70 (quint, J = 7.5 Hz, 2H), 2.09 (q, J = 7.3 Hz, 2H), 2.56 (t, J = 7.3 Hz, 2H), 3.81 (s, 3H), 3.84 (s, 6H), 4.94−5.08 (m, 2H), 5.83 (ddt, J = 6.7, 10.2, 17.1 Hz, 1H), 6.38 (s, 2H); 13C NMR (50 MHz, CDCl3): δ 30.6 (t), 30.3 (t), 35.7 (t), 55.9 (q, 2C), 60.8 (q), 105.1 (d, 2C), 114.8 (t), 135.8 (s), 138.2 (s), 138.5 (d), 153.0 (s, 2C) ppm; HRMS (m/z) [M + H]+ calculated for C14H21O3 237.1485; found 237.1483. 2,3,4-Trimethoxy-6-(pent-4-en-1-yl)benzaldehyde (6). To a solution of the olefin 5 (1.00 g, 4.23 mmol) in anhydrous CH2Cl2 (30 mL), dichloromethylmethyl ether (0.50 mL, 5.50 mmol) was added and cooled to 0 °C. After 10 min, trifluoromethanesulfonate (0.84 mL, 4.65 mmol) was added slowly to the reaction mixture and stirred at the same temperature for 10 min. Completion of the reaction was confirmed by thin-layer chromatography (TLC); thereafter, the reaction was quenched with saturated NaHCO3 solution (10 mL), the aqueous layer was extracted with CH2Cl2 (2 × 50 mL), and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography (10 → 20% EtOAc in pet. ether) gave 6 (1.05 g, 94%) as colorless oil. Rf = 0.6 (20% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.60 (quint, J = 7.7 Hz, 2H), 2.12 (q, J = 7.2 Hz, 2H), 2.91 (t, J = 7.7 Hz, 2H), 3.83 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 4.91− 5.06 (m, 2H), 5.83 (ddt, J = 6.6, 10.4, 17.1 Hz, 1H), 6.48 (s, 1H), 10.35 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 30.4 (t), 33.7 (t, 2C), 55.9 (q), 60.8 (q), 62.3 (q), 109.6 (d), 114.5 (t), 120.8 (s), 138.7 (d), 139.7 (s), 142.6 (s), 157.6 (s), 158.4 (s), 190.7 (d) ppm; HRMS (m/z) [M + H]+ calculated for C15H21O4 265.1434; found 265.1428. 4-(3,4,5-Trimethoxyphenyl)butyl Acetate (7). To a solution of olefin 5 (20.00 g, 84.63 mmol) in 1,4-dioxane/ water (9:1, 400 mL), KMnO4 (14.71 g, 93.10 mmol) was added and the contents were stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was filtered through a celite pad and the crude was extracted with EtOAc (3 × 300 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum. The crude was used for the next step, as such without purification. To a solution of the above crude product in CH2Cl2/water (9:1, 400 mL), NaIO4 (18.10 g, 84.63 mmol) was added at room temperature. The reaction mixture was stirred for 2 h at room temperature. The reaction mixture was partitioned between water and CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (2 × 300 mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced 13

pressure. The crude was used in the next step without further purification. A solution of the above product in methanol (300 mL) was treated with NaBH4 (3.20 g, 84.63 mmol) at 0 °C. The reaction was stirred for 3 h at room temperature and quenched with saturated ammonium chloride (200 mL) and extracted with EtOAc (3 × 300 mL). The combined organic extract was dried (Na2SO4) and concentrated, and the resulting crude was used for the next step, as such without purification. To a cooled solution of the above crude in CH2Cl2 (300 mL), NEt3 (11.78 mL, 84.63 mmol), catalytic 4-dimethylaminopyridine (DMAP), and Ac2O (8.00 mL, 84.63 mmol) were added and the contents were stirred at room temperature for 4 h. The reaction mixture was partitioned between water and CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (2 × 300 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum. The resulting crude residue purified by silica gel column chromatography (10 → 15% EtOAc in pet. ether) afforded 7 (16.7 g, 70%) as a colorless sirup. Rf = 0.4 (15% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.63−1.70 (m, 4H), 2.04 (s, 3H), 2.54−2.61 (m, 2H), 3.81 (s, 3H), 3.84 (s, 6H), 4.08 (t, J = 6.4 Hz, 2H), 6.38 (s, 2H); 13C NMR (50 MHz, CDCl3): δ 21.0 (q), 27.8 (t), 28.2 (t), 35.9 (t), 56.0 (q, 2C), 60.8 (q), 64.3 (t), 105.1 (d, 2C), 136.0 (s), 137.8 (s), 153.1 (s, 2C), 171.2 (s) ppm; HRMS (m/ z) [M + H]+ calculated for C15H23O5 283.1540; found 283.1535. 4-(2-Iodo-3,4,5-trimethoxyphenyl)butyl Acetate (8). A solution of ester 7 (7.50 g, 26.56 mmol) in CHCl3 (150 mL) is cooled to 0 °C and treated with (CF3CO2)Ag (7.63 g, 34.53 mmol). The reaction mixture was stirred for 10 min, and then I2 (8.09 g, 31.88 mmol) was added portionwise to the solution. The reaction was continued for 6 h at room temperature and then partitioned between water and CHCl3, and the aqueous layer was extracted with CH2Cl2 (2 × 100 mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5 → 20% EtOAc in pet. ether) to give iodo compound 8 (9.2 g, 94%) as pale yellow sirup. Rf = 0.6 (20% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.62− 1.72 (m, 4H), 2.04 (s, 3H), 2.53 (t, J = 7.3 Hz, 2H), 3.84 (s, 6H), 3.85 (s, 3H), 4.11 (t, J = 6.1 Hz, 2H), 6.61 (s, 1H); 13C NMR (50 MHz, CDCl3): δ 20.9 (q), 26.6 (t), 28.1 (t), 40.5 (t), 56.0 (q), 60.6 (q), 60.8 (q), 64.2 (t), 108.5 (d), 140.2 (s), 140.3 (s, 2C), 152.9 (s), 153.4 (s), 171.1 (s) ppm; HRMS (m/z) [M + Na]+ calculated for C15H21IO5Na 431.0326; found 431.0317. 4-(3,4,5-Trimethoxy-2-((trimethylsilyl)ethynyl)phenyl)butyl Acetate (9). A mixture of iodo compound 8 (3.00 g, 7.35 mmol), trimethylsilylacetylene (3.14 mL, 22.05 mmol), PPh3 (385 mg, 1.47 mmol), Pd(PPh3)2Cl2 (258 mg, 0.37 mmol), and CuI (280 mg, 1.47 mmol) was dissolved in dry DMF (7 mL) and Et2NH (15 mL) in an airtight sealed tube. The reaction mixture was heated at 80 °C for 16 h. Then, it was cooled to room temperature and partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resulting crude residue was purified by silica gel column chromatography (5 → 15% EtOAc in pet. ether) and afforded 9 (2.4 g, 86%) as a yellow oil. Rf = 0.5 (15% EtOAc in pet. ether); 1 H NMR (200 MHz, CDCl3): δ 0.24 (s, 9H), 1.64−1.71 (m, 4H), 2.03 (s, 3H), 2.68−2.73 (m, 2H), 3.81 (s, 3H), 3.84 (s, 3H), 3.94 (s, 3H), 4.08 (t, J = 6.0 Hz, 2H), 6.46 (s, 1H); 13C 5595


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NMR (50 MHz, CDCl3): δ 0.0 (q, 3C), 21.0 (q), 26.9 (t), 28.4 (t), 34.5 (t), 55.9 (q), 61.0 (q, 2C), 64.4 (t), 99.6 (s), 100.9 (s), 107.8 (d), 109.9 (s), 140.0 (s), 141.5 (s), 153.7 (s), 155.2 (s), 171.2 (s) ppm; HRMS (m/z) [M + H]+ calculated for C20H31O5Si 379.1935; found 379.1931. 4-(2-Ethynyl-3,4,5-trimethoxyphenyl)butan-1-ol (10). To a solution of alkyne 9 (6.00 g, 15.85 mmol) in methanol (200 mL), K2CO3 (6.57 g, 47.55 mmol) was added and stirred for 4 h at room temperature. The reaction mixture was diluted with water and EtOAc, and the crude product was extracted by using EtOAc (3 × 100 mL). Then, it was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The purification of residue by silica gel chromatography (30 → 45% EtOAc in pet. ether) gave alcohol 10 (3.73 g, 89%) as colorless sirup. Rf = 0.3 (40% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 1.62−1.68 (m, 4H), 2.75 (t, J = 7.3 Hz, 2H), 3.37 (s, 1H), 3.68 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 3.94 (s, 3H), 6.49 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 26.7 (t), 32.3 (t), 34.2 (t), 55.9 (q), 61.0 (q), 61.2 (q), 62.6 (t), 78.3 (s), 83.3 (d), 107.8 (d), 108.6 (s), 139.9 (s), 141.9 (s), 153.9 (s), 155.4 (s) ppm; HRMS (m/z) [M + H]+ calculated for C15H21O4 265.1434; found 265.1435. 1-(3-Chloropent-4-yn-1-yl)-2-ethynyl-3,4,5-trimethoxybenzene (3). A solution of alkynol 10 (500 mg, 1.89 mmol) in CH2Cl2 (20 mL) was treated with Dess−Martin periodinane (962 mg, 2.27 mmol) for 2 h at room temperature. The reaction mixture was quenched with saturated Na2S2O3 (10 mL) and then with saturated NaHCO3 (10 mL). The crude was extracted with CH2Cl2 (2 × 50 mL) from the aqueous layer. The combined organic extract was dried (Na2SO4) and concentrated, and the resulting crude residue was used immediately for the next step, as such without purification. A solution of the above product in acetonitrile (20 mL) was reacted with L -proline (65 mg, 0.57 mmol) and Nchlorosuccinimide (253 mg, 1.89 mmol) at 0 °C. The reaction was stirred for 1 h at room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (2 × 50 mL); the combined organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude was used for the next step without further purification. To a cooled solution of the above crude in methanol (40 mL), Ohira−Bestmann reagent (400 mg, 2.08 mmol) and K2CO3 (314 mg, 2.27 mmol) were added and the contents were stirred at room temperature for 5 h. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc (2 × 30 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum. The resulting crude residue was purified by silica gel column chromatography (5 → 15% EtOAc in pet. ether) and afforded 3 (239 mg, 45%) as pale yellow oil. Rf = 0.6 (15% EtOAc in pet. ether); 1H NMR (200 MHz, CDCl3): δ 2.27 (q, J = 7.5 Hz, 2H), 2.63 (d, J = 2.4 Hz, 1H), 3.37 (dt, J = 1.1, 8.1 Hz, 2H), 3.40 (s, 1H), 3.83 (s, 3H), 3.85 (s, 3H), 3.95 (s, 3H), 4.47 (dt, J = 2.3, 6.7 Hz, 1H), 6.52 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 31.3 (t), 39.0 (t), 47.3 (d), 56.0 (q), 61.0 (q), 61.3 (q), 74.6 (d), 77.8 (s), 81.7 (s), 84.0 (d), 108.3 (d), 108.9 (s), 139.4 (s), 140.4 (s), 154.0 (s), 155.7 (s) ppm; HRMS (m/ z) [M + H]+ calculated for C16H18ClO3 293.0939; found 293.0939. 5-(2-Ethynyl-3,4,5-trimethoxyphenyl)-N-(4methoxybenzyl)pent-1-yn-3-amine (11). To a solution of diyne 3 (250 mg, 0.85 mmol) in acetonitrile (15 mL), pmethoxybenzyl amine (0.17 mL, 1.28 mmol) and Cs2CO3 (834

mg, 2.53 mmol) were added at room temperature and stirred for 48 h. The reaction mixture was concentrated, and the resulting crude material was dissolved in EtOAc (60 mL), washed with water (50 mL), dried (Na2SO4), and concentrated in vacuum. The purification of residue by silica gel column chromatography (25 → 40% EtOAc in pet. ether) gave diyne 11 (205 mg, 61%) as yellow oil. Rf = 0.3 (40% EtOAc in pet.); 1 H NMR (500 MHz, CDCl3): δ 1.90−2.02 (m, 2H), 2.36 (d, J = 2.1 Hz, 1H), 2.86−2.95 (m, 2H), 3.35 (s, 1H), 3.38 (dt, J = 1.8, 6.7 Hz, 1H), 3.74 (d, J = 12.5 Hz, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 3.94 (s, 3H), 3.96 (d, J = 12.8 Hz, 1H), 6.50 (s, 1H), 6.85 (d, J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H); 13 C NMR (125 MHz, CDCl3): δ 31.2 (t), 36.3 (t), 48.8 (d), 50.6 (t), 55.3 (q), 56.0 (q), 61.0 (q), 61.2 (q), 71.9 (d), 78.1 (s), 83.6 (d), 85.2 (s), 108.1 (d), 108.8 (s), 113.8 (d, 2C), 129.5 (d, 2C), 132.0 (s), 140.1 (s), 141.1 (s), 153.9 (s), 155.5 (s), 158.7 (s) ppm; HRMS (m/z) [M + H]+ calculated for C24H28NO4 394.2013; found 394.2012. N-(5-(2-Ethynyl-3,4,5-trimethoxyphenyl)pent-1-yn-3yl)-N-(4-methoxybenzyl)acetamide (2). To a cooled solution of diyne 11 (200 mg, 0.51 mmol) in CH2Cl2 (10 mL), Et3N (85 mL, 0.61 mmol), catalytic DMAP, and Ac2O (72 mL, 0.76 mmol) were added and the contents were stirred at room temperature for 4 h. The reaction mixture was partitioned between water and CH2Cl2, and the aqueous layer was extracted with CH2Cl2 (2 × 300 mL). The combined organic layer was dried (Na2SO4) and concentrated under vacuum. The resulting crude residue was purified by silica gel column chromatography (35 → 50% EtOAc in pet. ether) and afforded 2 (206 mg, 93%) as yellow sirup. Rf = 0.3 (50% EtOAc in pet. ether); 1H NMR (500 MHz, CDCl3): δ 1.90−1.96 (m, 2H), 1.98 (s, 3H), 2.29 (d, J = 2.4 Hz, 1H), 2.71−2.77 (m, 1H), 2.84−2.90 (m, 1H), 3.37 (s, 1H), 3.78 (s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 3.94 (s, 3H), 4.53 (d, J = 17.1 Hz, 1H), 4.68 (d, J = 17.1 Hz, 1H), 5.58 (dt, J = 2.1, 8.8 Hz, 1H), 6.47 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 22.5 (q), 31.3 (t), 34.7 (t), 46.7 (d), 48.5 (t), 55.3 (q), 56.0 (q), 61.0 (q), 61.3 (q), 73.5 (d), 78.1 (s), 81.7 (d), 83.7 (s), 107.9 (d), 108.7 (s), 114.1 (d, 2C), 127.5 (d, 2C), 129.9 (s), 140.1 (s), 140.4 (s), 154.0 (s), 155.5 (s), 158.8 (s), 171.3 (s) ppm; HRMS (m/z) [M + H]+ calculated for C26H30NO5 436.2118; found 436.2115. General Procedure for Alkyne [2 + 2 + 2]-Cyclotrimerization. The diyne 2 (1 equiv) and alkyne (2.5 equiv) were placed in a screw-capped pressure tube and dissolved in anhydrous toluene (2 mL), which was then evacuated and back-filled with argon. To the reaction vessel, CpCo(CO)2 (20 mol %) was added. The solution was then stirred under light (200 W) until consumption of the starting material. The reaction mixture was cooled to room temperature and the crude filtered through Celite pad and concentrated, and the crude product was subjected to N-PMB group deprotection. A solution of the above crude product in CH2Cl2/trifluoroacetic acid (1:2, 6 mL) was stirred at room temperature until the complete disappearance of the starting compound, as indicated by TLC. After completion, the solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography (230−400 mesh) to afford the corresponding cyclotrimerization product. (±)-Allocolchicine (1). The reaction of diyne 2 (30 mg, 0.069 mmol) with methyl propiolate was carried out by following a given general procedure for cyclotrimerization. The mixture of the two regioisomers was separated in 1:2 5596


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3H), 4.96 (d, J = 7.6 Hz, 1H), 5.00−5.05 (m, 1H), 6.34 (s, 1H), 7.14 (s, 1H), 8.30 (dd, J = 1.5, 8.0 Hz, 1H), 8.66 (d, J = 1.1 Hz, 1H). 1 H NMR (500 MHz, acetone-d6): δ 1.93 (s, 3H), 1.94−1.95 (m, 1H), 2.12−2.18 (m, 1H), 2.31−2.31 (m, 1H), 2.55 (dd, J = 6.1, 13.4 Hz, 1H), 3.54 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.89 (s, 3H), 4.74−4.79 (m, 1H), 6.79 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.92 (dd, J = 8.2, 1.7 Hz, 1H), 8.05 (d, J = 1.1 Hz, 1H). 1 H NMR (500 MHz, methanol-d4): δ 1.98−2.02 (m, 1H), 2.04 (s, 3H), 2.18−2.25 (m, 1H), 2.33−2.41 (m, 1H), 2.59 (dd, J = 6.1, 13.4 Hz, 1H), 3.56 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 3.93 (s, 3H), 4.73 (dd, J = 7.2, 12.2 Hz, 1H), 6.80 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.99 (dd, J = 8.0, 1.5 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H). 1 H NMR (500 MHz, pyridine-d5): δ 2.14−2.17 (m, 4H), 2.34−2.37 (m, 1H), 2.50−2.56 (m, 2H), 3.70 (s, 3H), 3.83 (s, 3H), 3.86 (s, 3H), 3.95 (s, 3H), 5.28−5.33 (m, 1H), 6.80 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 8.22 (dd, J = 1.5, 8.0 Hz, 1H), 8.54 (d, J = 1.5 Hz, 1H), 9.21 (d, J = 7.6 Hz, 1H) ppm. HRMS (m/z) [M + H]+ calculated for C22H26NO6 400.1755; found 400.1750. N-((11aR)-9,10,11-Trimethoxy-6,7-dihydro-5Hdibenzo[a,c][7]annulen-5-yl)acetamide (1b). The reaction of diyne 2 (40 mg, 0.092 mmol) with acetylene was carried out by following the given general procedure for cyclotrimerization. The allocolchicinoid 1b (24 mg, 77%) was obtained as white solid. Rf = 0.3 (70% EtOAc in pet. ether); major atropisomer: 1 H NMR (400 MHz, CDCl3): δ 1.76−1.83 (m, 1H), 2.05 (s, 3H), 2.29−2.35 (m, 1H), 2.40−2.47 (m, 2H), 3.51 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 4.80−4.86 (m, 1H), 5.86 (d, J = 6.9 Hz, 1H), 6.56 (s, 1H), 7.27−7.28 (m, 1H), 7.30−7.33 (m, 2H), 7.46−7.50 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 23.3 (q), 30.5 (t), 39.7 (t), 49.3 (d), 56.1 (q), 61.1 (q), 61.3 (q), 107.5 (d), 122.0 (d), 124.9 (s), 126.5 (d), 127.2 (d), 130.2 (d), 134.4 (s), 134.7 (s), 138.8 (s), 141.3 (s), 151.2 (s), 152.7 (s), 169.4 (s) ppm. HRMS (m/z) [M + H]+ calculated for C20H24O4N 342.1700; found 342.1693. Dimethyl (11aR)-5-Acetamido-9,10,11-trimethoxy6,7-dihydro-5H-dibenzo[a,c][7]annulene-2,3-dicarboxylate (1c). The reaction of diyne 2 (40 mg, 0.092 mmol) with dimethyl acetylenedicarboxylate was carried out by the following given general procedure for cyclotrimerization. The allocochicinoid 1c (34 mg, 81%) was obtained as white solid. Rf = 0.3 (80% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 1.84−1.91 (m, 1H), 2.09 (s, 3H), 2.25− 2.30 (m, 1H), 2.43−2.53 (m, 2H), 3.59 (s, 3H), 3.93 (s, 6H), 3.95 (s, 6H), 4.86−4.92 (m, 1H), 6.01 (d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 7.65 (s, 1H), 7.90 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 23.2 (q), 30.2 (t), 39.4 (t), 49.4 (d), 52.6 (q), 52.7 (q), 56.1 (q), 61.3 (q), 61.4 (q), 107.8 (d), 123.2 (s), 123.3 (d), 130.2 (s), 130.4 (s), 131.1 (d), 134.6 (s), 137.7 (s), 141.5 (s), 142.4 (s), 151.3 (s), 153.7 (s), 168.0 (s, 2C), 168.6 (s) ppm. HRMS (m/z) [M + H]+ calculated for C24H28O8N 458.1809; found 458.1802. N-((11aR)-9,10,11-Trimethoxy-2,3-dipropyl-6,7-dihydro-5H-dibenzo[a,c][7]annulen-5-yl)-acetamide (1d). The reaction of diyne 2 (40 mg, 0.092 mmol) with 4-octyne was carried out by the following given general procedure for cyclotrimerization. The allocochicinoid 1d (28 mg, 72%) was obtained as white solid. Rf = 0.3 (60% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 0.94−1.02 (m, 6H), 1.61−1.65 (m, 5H), 2.05 (s, 3H), 2.39−2.44 (m, 2H),

proportion. The minor regioisomer allocholchicine (1) (7 mg, 25%) was obtained as a white solid. Rf = 0.2 (70% EtOAc in pet. ether). Spectral Data of (±)-Allocolchicine (1). Major Atropisomer. 1H NMR (500 MHz, CDCl3): δ 1.84−1.85 (m, 1H), 2.10 (s, 3H), 2.24−2.27 (m, 1H), 2.43−2.47 (m, 2H), 3.54 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 3.94 (s, 3H), 4.87 (br s, 1H), 6.10 (br s, 1H), 6.59 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.97−7.99 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 23.2 (q), 30.2 (t), 39.3 (t), 49.1 (d), 52.0 (d), 55.9 (q), 61.1 (q, 2C), 107.6 (d), 123.5 (d), 123.8 (s), 127.5 (d), 128.5 (s), 130.2 (d), 134.5 (s), 139.2 (s), 139.4 (s), 141.2 (s), 151.1 (s), 153.2 (s), 167.1 (s), 169.5 (s) ppm. Major Atropisomer. 1H NMR (500 MHz, CD2Cl2): δ 1.81− 1.87 (m, 1H), 2.02 (s, 3H), 2.18−2.25 (m, 1H), 2.38−2.45 (m, 1 H), 2.49 (dd, J = 6.7, 12.9 Hz, 1H), 3.57 (s, 3H), 3.88 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.71−4.76 (m, 1H), 5.95 (d, J = 7.6 Hz, 1H), 6.62 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.95− 7.97 (m, 2H). Major Atropisomer. 1H NMR (500 MHz, benzene-d6): δ 1.37−1.39 (m, 1H), 1.50 (s, 3H), 2.03−2.11 (m, 1H), 2.15− 2.24 (m, 2H), 3.42 (s, 3H), 3.49 (s, 3H), 3.57 (s, 3H), 3.82 (s, 3H), 4.97 (d, J = 8.0 Hz, 1H), 5.06−5.11 (m, 1H), 6.32 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 8.0, 1.1 Hz, 1H), 8.25 (s, 1H). 1 H NMR (400 MHz, acetone-d6): δ 1.95 (s, 3H), 2.09−2.11 (m, 1H), 2.14−2.19 (m, 1H), 2.31−2.40 (m, 1H), 2.57 (dd, J = 6.1, 12.8 Hz, 1H), 3.55 (s, 3H), 3.85 (s, 3H), 3.90 (s, 6H), 4.75−4.82 (m, 1H), 6.81 (s, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 8.07 (s, 1H). 1 H NMR (400 MHz, methanol-d4): δ 1.95−2.01 (m, 1H), 2.05 (s, 3H), 2.16−2.24 (m, 1H), 2.31−2.37 (m, 1H), 2.59 (dd, J = 6.1, 12.8 Hz, 1H), 3.55 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 4.73 (dd, J = 6.7, 12.2 Hz, 1H), 6.79 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H). 1 H NMR (500 MHz, pyridine-d5): δ 2.14 (s, 3H), 2.16−2.19 (m, 1H), 2.30−2.35 (m, 1H), 2.52−2.57 (m, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H), 3.97 (s, 3H), 5.37−5.41 (m, 1H), 6.79 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H), 9.38 (d, J = 8.0 Hz, 1H) ppm; HRMS (m/z) [M + H]+ calculated for C22H26NO6 400.1755; found 400.1751. Allocolchicine 10-Carboxylate 1a. The major regioisomer 1a (15 mg, 54%) was obtained as a white solid. Rf = 0.3 (80% EtOAc in pet. ether). Spectral Data of 1a. Major Atropisomer. 1H NMR (400 MHz, CDCl3): δ 1.80−1.86 (m, 1 H), 2.07 (s, 3H), 2.23−2.30 (m, 1H), 2.45−2.50 (m, 2H), 3.57 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 3.94 (s, 3H), 4.83−4.89 (m, 1H), 5.86 (d, J = 7.4 Hz, 1H), 6.58 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 8.00 (d, J = 7.8 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 23.3 (q), 30.3 (t), 39.5 (t), 49.5 (d), 52.1 (d), 56.1 (q), 61.2 (q), 61.3 (q), 107.6 (d), 122.4 (d), 124.0 (s), 128.4 (d), 128.6 (s), 131.5 (d), 134.5 (s), 134.7 (s), 141.4 (s), 144.2 (s), 151.3 (s), 153.1 (s), 167.2 (s), 169.2 (s) ppm. Major Atropisomer. 1H NMR (500 MHz, CD2Cl2): δ 1.81− 1.87 (m, 1H), 2.01 (s, 3H), 2.20−2.26 (m, 1H), 2.38−2.45 (m, 1H), 2.46−2.51 (m, 1H), 3.58 (s, 3H), 3.89 (s, 6H), 3.90 (s, 3H), 4.69−4.75 (m, 1H), 5.86 (d, J = 7.2 Hz, 1H), 6.62 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.96 (dd, J = 1.7, 8.2 Hz, 1H), 8.08 (d, J = 1.5 Hz, 1 H). Major Atropisomer. 1H NMR (500 MHz, benzene-d6): δ 1.36−1.37 (m, 1H), 1.55 (s, 3H), 2.05−2.11 (m, 1H), 2.14− 2.23 (m, 2H), 3.44 (s, 3H), 3.51 (s, 3H), 3.52 (s, 3H), 3.78 (s, 5597


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2.46 (m, 2H), 2.93−3.02 (m, 2H), 3.54 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H), 3.92 (s, 3H), 4.84 (quint, J = 7.3 Hz,1H), 5.81 (d, J = 8.1 Hz, 1H), 6.54 (s, 1H), 7.09 (s, 1H), 7.99 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 14.1 (q), 22.9 (t), 23.4 (q), 30.4 (t), 34.0 (t), 34.4 (t), 39.6 (t), 49.2 (d), 51.8 (q), 56.1 (q), 61.2 (q), 61.3 (q), 107.6 (d), 124.0 (s), 124.7 (d), 127.6 (s), 131.9 (s), 132.5 (d), 134.6 (s), 141.3 (s), 142.8 (s), 143.7 (s), 151.3 (s), 152.9 (s), 168.1 (s), 169.2 (s) ppm. HRMS (m/z) [M + H]+ calculated for C26H34O6N 456.2381; found 456.2371. Methyl (11aR)-5-Acetamido-9,10,11-trimethoxy-3phenyl-6,7-dihydro-5H-dibenzo[a,c][7]-annulene-2-carboxylate (1h). The reaction of diyne 2 (60 mg, 0.138 mmol) with methyl 3-phenylpropiolate was carried out by the following given general procedure for cyclotrimerization. The mixture of two regioisomers were separated. The major regioisomer 1 h (39 mg, 62%) was obtained as pale yellow oil. Rf = 0.3 (60% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 1.78−1.84 (m, 1H), 2.02 (s, 3H), 2.32−2.36 (m, 1H), 2.42−2.50 (m, 2H), 3.63 (s, 3H), 3.64 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 4.87−4.93 (m, 1H), 5.81 (d, J = 8.1 Hz, 1H), 6.57 (s, 1H), 7.22 (s, 1H), 7.34−7.41 (m, 5H), 7.97 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 23.3 (q), 30.4 (t), 39.7 (t), 49.3 (d), 51.9 (q), 56.1 (q), 61.2 (q), 61.3 (q), 107.7 (d), 123.7 (s), 124.8 (d), 127.2 (d), 128.0 (d, 2C), 128.5 (d, 2C), 128.9 (s), 131.9 (d), 133.6 (s), 134.6 (s), 141.3 (s), 141.4 (s), 141.5 (s), 142.4 (s), 151.3 (s), 153.1 (s), 168.8 (s), 169.4 (s) ppm. HRMS (m/z) [M + H]+ calculated for C28H30O6N 476.2068; found 476.2061.

2.49−2.55 (m, 1H), 2.59−2.65 (m, 4H), 3.50 (s, 3H), 3.88 (s, 3H), 3.91 (s, 3H), 4.77−4.84 (m, 1H), 5.78 (d, J = 8.6 Hz, 1H), 6.54 (s, 1H), 6.95 (s, 1H), 7.27 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 14.1 (q), 14.4 (q), 23.5 (q), 24.3 (t), 24.4 (t), 30.7 (t), 34.4 (t), 35.2 (t), 40.0 (t), 48.9 (d), 56.1 (q), 61.0 (q), 61.3 (q), 107.6 (d), 122.5 (d), 125.2 (s), 131.0 (d), 131.6 (s), 134.8 (s), 136.0 (s), 136.3 (s), 138.4 (s), 139.2 (s), 151.3 (s), 152.4 (s), 169.0 (s) ppm; HRMS (m/z) [M + H]+ calculated for C26H36NO4 426.2639; found 426.2633. (5-Acetamido-9,10,11-trimethoxy-6,7-dihydro-5Hdibenzo[a,c][7]annulene-2,3-diyl)bis(me-thylene) Diacetate (1e). The reaction of diyne 2 (40 mg, 0.092 mmol) with ester of butyne diol was carried out by the following given general procedure for cyclotrimerization. The allocochicinoid 1e (31 mg, 69%) was obtained as white solid. Rf = 0.2 (80% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 1.78−1.85 (m, 1H), 2.08 (s, 6H), 2.10 (s, 3H), 2.29−2.32 (m, 1H), 2.41−2.48 (m, 2H), 3.54 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.78−4.84 (m, 1H), 5.21 (s, 4H), 5.95 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 7.25 (s, 1H), 7.53 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 21.0 (q), 21.1 (q), 23.2 (q), 30.4 (t), 39.5 (t), 49.3 (d), 56.1 (q), 61.2 (q, 2C), 63.7 (t), 64.2 (t), 107.6 (d), 123.9 (s), 124.4 (d), 131.8 (d), 133.0 (s, 2C), 134.7 (s), 135.1 (s), 139.3 (s), 141.3 (s), 151.2 (s), 153.1 (s), 170.0 (s), 170.8 (s), 170.9 (s) ppm; 1H NMR (400 MHz, acetoned6): δ 1.95−1.96 (m, 4H), 2.06−2.07 (m, 6H), 2.15−2.22 (m, 1H), 2.30−2.38 (m, 1H), 2.53−2.57 (m, 1H), 3.59 (s, 3H), 3.85 (s, 3H), 3.89 (s, 3H), 4.75−4.80 (m, 1H), 5.19−5.26 (m, 4H), 6.79 (s, 1H), 7.48 (s, 2H), 7.73 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, acetone-d6): δ 20.9 (q, 2C), 22.9 (q), 31.2 (t), 39.9 (t), 49.4 (d), 56.4 (q), 61.1 (q), 61.4 (q), 64.2 (t), 64.6 (t), 109.0 (d), 125.1 (s), 125.5 (d), 132.1 (d), 133.7 (s), 134.3 (s), 135.8 (s), 136.1 (s),141.7 (s) 142.3 (s), 151.9 (s), 154.3 (s), 171.0 (s), 171.0 (s), 171.1 (s) ppm; HRMS (m/z) [M + Na]+ calculated for C26H31NO8Na 508.1942; found 508.1941. Methyl (11aR)-5-Acetamido-2-butyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]annulene-3-carboxylate (1f). The reaction of diyne 2 (60 mg, 0.138 mmol) with methyl 2-heptynoate was carried out by the following given general procedure for cyclotrimerization. The mixture of two regioisomers were separated. The minor regioisomer 1f (21 mg, 33%) was obtained as pale yellow oil. Rf = 0.3 (70% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 0.89−0.94 (m, 3H), 1.38 (q, J = 7.4 Hz, 2H), 1.56− 1.60 (m, 2H), 1.77−1.84 (m, 1H), 2.11 (s, 3H), 2.25−2.30 (m, 1H), 2.41−2.48 (m, 2H), 2.88−2.94 (m, 1H), 2.97−3.02 (m, 1H), 3.52 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 4.79−4.86 (m, 1H), 6.06 (d, J = 8.3 Hz, 1H), 6.56 (s, 1H), 7.40 (s, 1H), 7.72 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.0 (q), 22.7 (t), 23.2 (q), 30.5 (t), 33.9 (t), 34.0 (t), 39.4 (t), 49.1 (d), 51.9 (q), 56.1 (q), 61.2 (q), 61.3 (q), 107.8 (d), 123.9 (s), 124.5 (d), 128.0 (s), 133.1 (d), 134.7 (s), 136.1 (s), 138.3 (s), 141.4 (s), 143.0 (s), 151.3 (s), 152.2 (s), 168.5 (s, 2C) ppm. HRMS (m/z) [M + H]+ calculated for C26H34O6N 456.2381; found 456.2372. Methyl (11aR)-5-acetamido-3-butyl-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c][7]-annulene-2-carboxylate (1g). The major regioisomer 1g (21 mg, 49%) was obtained as pale yellow oil. Rf = 0.4 (70% EtOAc in pet. ether); major atropisomer: 1H NMR (400 MHz, CDCl3): δ 0.95 (t, J = 7.3 Hz, 3H), 1.42 (q, J = 7.3 Hz, 2H), 1.60−1.63 (m, 2H), 1.76−1.83 (m, 1H), 2.06 (s, 3H), 2.24−2.30 (m, 1H), 2.43−

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.7b00980. 1 H/13C NMR and HRMS spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +91 20 25902577. Fax: (+91) 20 2590 2629. ORCID

Chepuri V. Ramana: 0000-0001-5801-311X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are thankful to the CSIR for funding this project under 12 FYP ORIGIN Program (CSC0108) and UGC (New Delhi) for a research fellowship to D.J.P.

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REFERENCES

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