RSS-Feed abonnieren
DOI: 10.1055/s-0039-1690840
Accessing Polycyclic Terpenoids from Zerumbone via Lewis Acid Catalyzed Synthetic Strategies
Publikationsverlauf
Received: 23. Dezember 2019
Accepted after revision: 05. Februar 2020
Publikationsdatum:
27. März 2020 (online)
Abstract
We herein disclose an effective strategy for the synthesis of [5.3.0] and [6.3.0] fused polycyclic terpenoids, which are important structural elements of natural products and biologically active compounds. The method comprises of Lewis acid catalyzed interrupted Nazarov cyclization of zerumbone derivatives such as zerumbone epoxide, triazole-appended zerumbone, zerumbal, and zerumbenone with a wide substrate scope with different indoles. Zerumbone epoxide furnished [5.3.0] and [6.3.0] fused structurally diverse sesquiterpenoids and all other zerumbone derivatives furnished the [6.3.0] fused motifs.
#
Key words
zerumbone - zerumbone epoxide - zerumbal - zerumbenone - Lewis acid catalysis - cyclization - polycyclic terpenoidsNatural-product-based drug discovery, especially phytochemical-focused drug development programs, holds an undeniable position in the present drug research scenario.[1] [2] [3] [4] [5] [6] In between 1999–2013, only 34% of FDA approved drugs were from natural product origin.[7] Even though natural products have high structural diversity and biological activity, further structural modifications are needed in many cases to develop novel scaffolds with specific properties. The structural reconstruction of natural products (NPs) delivers highly relevant molecular changes, which provide insights into the bioactivities and structure–activity relationships against specific targets that are critical for the exploration of a still-unknown chemical space.
Our group mainly focuses on the phytochemical investigation of medicinal plants from Western Ghats of India[8] and the utilization of naturally abundant molecules to generate structurally diverse bioactive molecules. Zingiber zerumbet Smith is one among such plants having natural moieties showing interesting biological activities.[9] Zerumbone, the marker compound present in the rhizome oil of this tropical ginger,[10] comprises 3% of its dry weight. It is a crystalline achiral 11-membered monocyclic sesquiterpene with a flexible skeleton structure with a conjugated dienone part and an isolated olefin part. Within the last few decades, the diverse reactivity of zerumbone was extensively explored by various research groups. Mainly Kitayama and co-workers established various synthetic modifications of zerumbone, including transannular ring contraction,[11] cyclization,[12] regio- and diastereoselective conjugate additions,[13] various regiospecific ring cleavage reactions,[14] ring expansion reaction,[15] asymmetric epoxidation, and so forth.[16]
Our interest in zerumbone chemistry began in 2013 with the report on transition metal catalyzed 1,4-conjugate addition of boronic acids to zerumbone.[17a] In the very next year, we reported a new synthetic methodology for Pd-catalyzed decarboxylative reactions of arenecarboxylic acid with zerumbone.[17b] Later we described the metal-free trans-aziridation of zerumbone and the evaluation of their antidiabetic properties.[17c] In the same year, our group reported the synthesis of zerumbone pendant derivatives via a palladium-catalyzed Tsuji–Trost coupling reaction for the first time.[17d] Recently we have utilized Lewis acid chemistry for the synthesis of [5.7.0], [5.8.0], and [5.8.3] ring-fused structurally diverse natural sesquiterpenoids.[17e] In continuation of our interest in the Lewis acid catalyzed transformations of zerumbone towards highly functionalized sesquiterpenoids, we have extended our work to other zerumbone derivatives, such as zerumbone epoxide and synthetically prepared triazole-linked zerumbone, zerumbal, and zerumbenone, where zerumbone epoxide is a naturally occurring humulene epoxide, a component of Zingiber zerumbet Smith, and have been reported as precursors for many naturally relevant fused cyclic sesquiterpenoid motifs.[11] [12]
We hypothesized that, just like zerumbone, the zerumbone epoxide could also be activated with a Lewis acid, resulting in transannular cyclization reactions leading to the formation of structurally diverse motifs. We already observed the same while doing the zerumbone activation reactions.[17e] With this concept in mind, we synthesized the epoxide 1 by following a reported procedure in which mCPBA selectively reacted at the isolated double bond of zerumbone (Z) to afford 97% of zerumbone epoxide 1 (Scheme [1]).[16] The structure of the epoxide was confirmed by using various spectroscopic techniques and in comparison with previous reports.
a Reaction conditions: 1 (1.0 equiv), 2a (1.0 equiv), Lewis acid (30 mol%), H2O (10.0 equiv), solvent (2.0 mL), 5 h.
b NR = no reaction.
We initiated our studies[17e] with the reaction of zerumbone epoxide and indole as nucleophile in the presence of water and Yb(OTf)3 at room temperature. The reaction after 5 hours at 80 °C afforded a mixture of [5.3.0] (3a) and [6.3.0] (3a′) fused ring systems (Scheme [2]). The structures of the products were confirmed by various spectroscopic techniques and the stereochemistry of the molecules were confirmed from NOE methods; this was similar to our own previous reports.[17e]
On the basis of the structural analysis of the product, we confirmed that the transformation of zerumbone epoxide to 3a′ had taken place via an interrupted Nazarov cyclization followed by a nucleophilic attack of indole, but the isodaucane system 3a was formed via an interrupted Nazarov cyclization followed by a pinacol–pinacolone rearrangement of the diol formed through the epoxide ring opening. A similar type of rearrangement was reported by Luu et al. in 1981, where they reported the acid-catalyzed transannular cyclization of zerumbone epoxide to bicyclic derivatives.[12]
The reaction conditions were optimized further by examining various Lewis acids, solvents, and temperatures (Table [1]). From the optimization studies, the best conditions were found to consist of a combination of zerumbone epoxide 1 (1.0 equiv), indole 2a (1.0 equiv), Sc(OTf)3 (30 mol%), and water (10 equiv) in MeCN (2.0 mL) at 80 °C for 5 hours; this led to the products being isolated in yields of 65% for 3a and 25% for 3a′.
With the optimal conditions in hand, we checked the scope and generality of this reaction with indoles 2 featuring both electron-withdrawing and -donating substituents. The results are summarized in Table [2]. In almost all cases (entries 1–7 and 10–13), except in the case of hydroxy- and amino-substituted indoles (entries 8 and 9), the reactions proceeded smoothly and were completed within 5 hours at 80 °C. Indoles bearing electron-donating and -withdrawing groups afforded comparable yields. In the case of substituted indoles, formation of two more side products resulted; these include polymerized products of indole and indole–acetonitrile products.
a Reaction conditions: 1 (1.0 equiv), 2 (1.0 equiv), Sc(OTf)3 (30 mol%), H2O (10.0 equiv), CH3CN (2 mL), 80 °C, 5 h.
b NR = no reaction.
We also checked the reactivity of C2-substituted indoles (Table [2], entries 14–16); with 2-phenylindole, we obtained the expected products 3n and 3n′ in 25% and 23% yield, but 2-formylindole and indole-2-carboxylic acid failed to afford the corresponding products, possibly due to the lower nucleophilicity at the C3 position. Reaction with C3-substituted indole also failed to afford the expected products (entry 17).
Next, the scope of this reaction was explored with various nucleophiles such as pyrrole, thiophene, imidazole, sulfonamide, oxazolidine, and pyrazole, but the expected products were not obtained under the optimized conditions.
Our next aim was to check the feasibility of Nazarov cyclization on zerumbone derivatives (functionalized at the isolated double bond). Triazole is an important class of nitrogen-containing heterocycles prevalent in many pharmaceuticals, agrochemicals, and so on.[18] These compounds exhibit various biological activities, such as antimicrobial, antiviral, anti-histaminic, anti-tubercular, etc., and this has attracted various research groups to develop promising synthetic approaches towards these heterocycles.[19] The synthesis of these bioactive motifs can be achieved via the click chemistry approach.[20] Herein, we describe the synthesis of triazole-linked zerumbone derivatives.
We commenced our investigation with the synthesis of azido zerumbone derivative 4a via the activation of the allylic methyl group of zerumbone by using N-bromosuccinimide, followed by azidation using sodium azide, which furnished the product in 56% overall yield[21] (Scheme [3]). Azide 4a was subsequently treated with phenylacetylene (5a; 1.5 equiv), in the presence of CuI (20 mol%) as catalyst, and by using DIPEA (3.0 equiv) as the base in acetonitrile (2 mL) at room temperature for 2 hours. The reaction afforded the corresponding triazole-linked product 6a in 44% yield (Scheme [3]). The structure and stereochemistry of the product was confirmed by various spectroscopic techniques such as 1H NMR, 13C NMR, and HRMS analysis.
The scope of the reaction was checked with various aromatic as well as aliphatic alkynes (Table [3]). Variously substituted alkynes reacted smoothly with 4a affording the corresponding triazole-linked products 6a–f in moderate to good yields (Table [3]). The reaction with propargyl alcohol (5e) gave the highest yield of 89% (entry 5), but the reaction with propargyl bromide (5g) failed (entry 7).
 |
|||
|
Entry |
Alkyne |
Product |
Yield (%)b |
|
1 |
 |
6a |
44 |
|
2 |
 |
6b |
41 |
|
3 |
 |
6c |
36 |
|
4 |
 |
6d |
38 |
|
5 |
 |
6e |
89 |
|
6 |
 |
6f |
48 |
|
7 |
 |
6g |
NR |
a Reaction conditions: 4a (1.0 equiv), alkyne (1.5 equiv), CuI (20 mol%), DIPEA (3.0 equiv), CH3CN (2.0 mL), RT, 2 h.
b NR = no reaction.
To check our Nazarov cyclization hypothesis, we started our investigations with the reaction of 6a with the external nucleophile indole 2a in the presence of various Lewis acids as catalyst in different solvents at 80 °C for 12 hours (Table [4]). From the optimization studies, the best conditions were found to consist of a combination of 6a (1.0 equiv), indole 2a (1.0 equiv), and AlCl3 (5 mol%), in CH3CN at 80 °C for 12 hours, delivering the triazole-appended [6.3.0] fused product 7a in 50% yield (entry 10).
a Reaction conditions: 6a (1.0 equiv), 2a (1.0 equiv), Lewis acid (5 mol%), solvent (2.0 mL), 12 h.
b NR = no reaction.
With the optimal conditions in hand, we investigated the scope of reaction with substituted indoles 2 (Table [5]). Indoles bearing both electron-donating and electron-withdrawing groups afforded the corresponding products in moderate to good yields.
a Reaction conditions: 6a (1.0 equiv), 2 (1.0 equiv), AlCl3 (5 mol%), CH3CN (2.0 mL), 80 °C, 12 h.
b NR = no reaction.
Next, we turned our attention to the oxidation reactions of zerumbone (Z). In 2016, Kumar et al. reported the allylic oxidation of the isolated olefin of Z when using selenium dioxide (Scheme [4]).[22] They synthesized new zerumbone–bicarbonyl analogues by selective oxidation of the methyl at C13, leading to an aldehyde (zerumbal, 8) and a ketone (zerumbenone, 9) with an exocyclic double bond between the C13 and C6 positions.
With our persistent curiosity in constructing polycyclic frameworks, here also we checked the possibility of Lewis acid catalyzed cyclization reactions of the bicarbonyl zerumbone derivatives 8 and 9. Reaction of zerumbal 8 with indole (1.0 equiv) in the presence of In(OTf)3 (5 mol%) in acetonitrile at room temperature resulted in the formation of the 6–3 ring-fused system 10a in 81% yield (Scheme [5]), eventuated via the same interrupted Nazarov cyclization followed by nucleophilic attack, as described earlier. The structure and the stereochemistry were confirmed using various spectroscopic techniques.
In the detailed optimization studies, the catalytic activity of different Lewis acids and the effect of different solvents and conditions for the reaction were studied; it was found out that the reaction with In(OTf)3 (5 mol%) at room temperature in acetonitrile (2.0 mL) for 12 hours under an argon atmosphere gave the best yield of 81% for 10a (Table [6], entry 3). Since zerumbal contains two carbonyl groups, we also performed the reaction with 2.0 equivalents of indole, but no desired product was obtained.
a Reaction conditions: 8 (1.0 equiv), 2a (1.0 equiv), Lewis acid (5.0 mol%), solvent (2 mL), 12 h.
b NR = no reaction.
To extend the scope and generality of the synthetic methodology, we carried out the reaction with different substituted indoles and the results are listed in Table [7]. We first studied the effect of substitution at the C2 position of indole (10b, 10c). Interestingly, 2-phenylindole delivered the expected product (entry 2) but 2-formylindole failed (entry 3). Further, we checked the possibility of C2 activation using C3-substituted indoles (10d). Only a trace amount of the desired product was obtained (entry 4). A detailed substrate scope was checked with C5- and C6-substituted indoles (10e–n); the products were obtained in similar yield, which indicates that substitutions have no effect on the outcome of the reaction. The final confirmation of the structure and stereochemistry was obtained from a single-crystal X-ray structure of compound 10g (Figure [1]).
a Reaction conditions: 8 (1.0 equiv), 2 (1.0 equiv), In(OTf)3 (5.0 mol%), CH3CN (2.0 mL), RT, 12 h.
b NR = no reaction.
In the case of zerumbenone, we also started our investigations with Sc(OTf)3 as the Lewis acid. To our dismay, the reaction failed to proceed at room temperature. We noticed that when the reaction temperature was increased to 80 °C, a diastereoisomeric mixture (1:0.8) of a [6.3.0] ring-fused system appended to two indole moieties was formed, probably via an interrupted Nazarov cyclization and allylic carbocation formation (Scheme [6]).
We have carried out detailed optimization studies for the formation of the bis-indole derivative with different Lewis acids, solvents, and reaction conditions. All the Lewis acid tested furnished the desired product in good yield, but Sc(OTf)3 emerged as the best Lewis acid in CH3CN at 80 °C under an argon atmosphere, with 85% yield (Table [8], entry 2). The structure of the product was established using various spectroscopic techniques such as 1H, 13C, and other 2-D NMR techniques and finally by HRMS analysis.
a Reaction conditions: 9 (1.0 equiv), 2a (2.0 equiv), Lewis acid (5.0 mol%), solvent (2 mL), 12 h.
b NR = no reaction.
c Diastereoisomers obtained.
With the optimum reaction condition in hand, we checked the feasibility of the reaction with different indoles; the results are listed in Table [9]. The substrate scope was tested with different indoles, both with electron-withdrawing and electron-releasing groups, which afforded the products in similar yields In the case of 2-phenyl indole (entry 2), only a trace amount of product was obtained, possibly due to the steric hindrance. Indole-2-carboxylic acid failed to form the product (entry 3), possibly due to the lower nucleophilicity furnished by the carboxylic group at the C3 position. Like in the previous case, here also C5-substituted aminoindole and hydroxyindole failed to deliver the product (entries 12 and 13).
a Reaction conditions: 9 (1.0 equiv), 2 (2.0 equiv), Sc(OTf)3 (5mol%), CH3CN (2.0 mL), 80 °C, 12 h.
b NR = no reaction.
c Diasteroisomers (1:0.8).
A plausible mechanism for the trans-annular cyclization is shown in Scheme [7]. The mechanism of formation of 3a′ can be explained by path A which follows the Nazarov-type cyclization pathway (path A; Scheme [7]). Initially, the Lewis acid coordinates to the carbonyl oxygen atom of Z, thereby creating an allylic carbocation intermediate C2 . Then, the carbocation is trapped by an external nucleophile (indole), followed by tautomeric rearrangement to afford the product 3a′ (Scheme [7]). Product 3a′ again undergoes ring opening by a water molecule to afford the diol intermediate C4 , which upon pinacol–pinacolone rearrangement affords product 3a, which is a [5.3.0] fused ring system.
The formation of 4a follows the same mechanistic pathway as 3a′, but for 5a, there is an interrupted Nazarov cyclization followed by conjugate addition of the nucleophile which results in the formation of the bis-indole derivative (Scheme [8]).
In conclusion, we have described a straightforward method for the preparation of polycyclic terpenoid systems from the naturally abundant sesquiterpene zerumbone. Lewis acid catalyzed transannular cyclization of zerumbone derivatives furnished [5.3.0] and [6.3.0] fused ring systems via interrupted Nazarov cyclization. Zerumbone epoxide delivered biologically relevant [5.3.0] and [6.3.0] systems, while all other derivatives, such as triazole-appended zerumbone derivatives, zerumbenone, and zerumbal furnished [6.3.0] fused sesquiterpenoid motifs. Furthermore, the synthetic scope of the polycyclics prepared were tested with a wide variety of substrates, which gave moderate to good yields. Further, the biological evaluation of various scaffolds is in progress in our laboratory, and will be reported in due course.
All chemicals were of the best grade commercially available and were used without further purification. All solvents were purified according to standard procedures; anhydrous solvents were obtained according to literature methods and stored over molecular sieves. Analytical TLC was performed with Merck TLC Silica gel F254 coated on aluminum sheets. Gravity column chromatography was performed using 100–200 or 230–400 mesh silica gel and mixtures of hexane–EtOAc were used for elution. Melting points were determined on a Buchi melting point apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a Bruker AMX 500 spectrophotometer (CDCl3, CCl4 or their mixtures were used as solvent). Chemical shifts δ of the 1H and 13C NMR spectra were referenced against SiMe4 (δ = 0.0) or the signal of the NMR solvent. ESI-HRMS spectra were recorded at 60,000 resolution by using a Thermo Scientific Exactive mass spectrometer. IR spectra were recorded on a Bruker FT-IR alpha spectrophotometer.
#
Preparation of [5.3.0] and [6.3.0] Fused Cyclic Products 3 and 3′ from Zerumbone Epoxide 1; General Procedure
Zerumbone epoxide 1 (1.0 equiv), indole 2 (1.0 equiv), Sc(OTf)3 (30 mol%), and H2O (10.0 equiv) were placed in a reaction tube. CH3CN (2 mL) was added and the reaction mixture was stirred at 80 °C for 5 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, 230–400 mesh, hexane–EtOAc) to yield the product.
#
3-(1H-Indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-carbaldehyde (3a)
Yield: 49 mg (65%); brown pasty mass; Rf = 0.37 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3360, 2961, 2927, 1731, 1691, 1621, 1459, 1370, 1340, 1263, 1158, 1102, 1012, 653, 590 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.46 (s, 1 H), 8.15 (s, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 2.0 Hz, 1 H), 3.40 (d, J = 11.0 Hz, 1 H), 2.25–2.21 (m, 2 H), 2.14–2.05 (m, 2 H), 1.88 (d, J = 15.5 Hz, 1 H), 1.74 (dd, J 1 = 14.5, J 2 = 7 Hz, 1 H), 1.57 (d, J = 15.5 Hz, 1 H), 1.50 (dd, J 1 = 23.0, J 2 = 12.0 Hz, 2 H), 1.17 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.88 (s, 3 H), 0.65 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 218.1, 206.1, 136.6, 126.4, 122.4, 122.1, 119.5, 119.1, 115.8, 111.4, 59.2, 50.8, 50.5, 49.5, 49.0, 47.7, 36.6, 33.1, 32.7, 27.3, 25.3, 21.5, 12.2.
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO2: 352.22711; found: 352.22712.
#
6-(1H-Indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3a′)
Yield: 19 mg (25%); brown pasty mass; Rf = 0.28 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3337, 2964, 2930, 1696, 1574, 1464, 1437, 1376, 1340, 1262, 1141, 1104, 1074, 750, 650 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.21 (t, J = 7.0 Hz, 1 H), 7.15 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 1.5 Hz, 1 H), 3.68 (d, J = 5.0 Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1 H), 2.41–2.37 (m, 1 H), 2.33 (dd, J 1 = 14.0, J 2 = 7.2 Hz, 1 H), 2.17–2.12(m, 2 H), 2.05 (d, J = 11.5 Hz, 1 H), 1.87–1.84 (m, 1 H), 1.75 (dd, J 1 = 17.5, J 2 = 7.5 Hz, 1 H), 1.63 (s, 3 H), 1.23 (dd, J 1 = 13.0, J 2 = 5.0 Hz, 2 H), 1.12 (d, J = 7.0 Hz, 3 H), 1.04 (s, 3 H), 1.02 (s, 3 H), 0.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 214.6, 134.7, 133.8, 131.0, 130.2, 129.9, 128.3, 112.1, 53.5, 52.4, 49.4, 49.3, 48.3, 41.2, 40.3, 39.6, 34.1, 31.2, 29.7, 25.1, 20.3, 18.8, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO2: 352.22711; found: 352.22712.
#
1,4,4,6-Tetramethyl-3-(5-methyl-1H-indol-3-yl)-2-oxodecahydroazulene-6-carbaldehyde (3b)
Yield: 26 mg (33%); brown viscous liquid; Rf = 0.35 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3370, 2962, 2927, 1730, 1691, 1583, 1460, 1374, 1343, 1265, 1155, 1102, 920, 795, 735, 621 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.47 (s, 1 H), 7.98 (br s, 1 H), 7.29 (d, J = 0.5 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.99 (dd, J 1 = 7.0, J 2 = 1.0 Hz, 1 H), 6.91 (d, J = 2.0 Hz, 1 H), 3.38 (d, J = 11.0 Hz, 1 H), 2.44 (s, 3 H), 2.23–2.20 (m, 2 H), 2.19–2.09 (m, 2 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.75–1.72 (m, 2 H), 1.56–1.43 (m, 2 H), 1.16 (d, J = 7.0 Hz, 3 H), 1.08 (s, 3 H), 0.89 (s, 3 H), 0.67 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.6, 205.9, 134.8, 129.2, 124.3, 122.2, 121.0, 119.3, 110.8, 59.6, 52.3, 49.8, 48.7, 47.9, 39.7, 34.2, 31.1, 29.8, 25.4, 21.6, 20.0, 19.0, 13.0, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H31NNaO2: 388.22525; found: 388.22638.
#
1a,4,7,7-Tetramethyl-6-(5-methyl-1H-indol-3-yl)decahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3b′)
Yield: 17 mg (22%); brown viscous liquid; Rf = 0.18 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3386, 2924, 2855, 1701, 1577, 1458, 1377, 1263, 1180, 1099, 1071, 796, 708, 644, 622 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.80 (br s, 1 H), 7.60 (s, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 7.00 (dd, J 1 = 8.0, J 2 = 1.2 Hz, 1 H), 6.88 (d, J = 2.0 Hz, 1 H), 3.12 (d, J = 11.0 Hz, 1 H), 2.73 (d, J = 11.0 Hz, 1 H), 2.59 (d, J = 7.0 Hz, 1 H), 2.46 (s, 3 H), 2.07–1.99 (m, 2 H), 1.91 (dd, J 1 = 14.0, J 2 = 6.5 Hz, 2 H), 1.77–1.73 (m, 2 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 1.26 (s, 3 H), 1.10 (d, J = 7.0 Hz, 1 H), 1.03 (d, J = 7.0 Hz, 1 H), 0.95 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 214.6, 123.7, 120.3, 119.0, 116.2, 110.5, 62.8, 60.9, 50.8, 50.0, 49.9, 47.0, 45.3, 37.9, 36.7, 36.6, 35.0, 30.8, 29.9, 25.7, 23.5, 21.5, 19.8, 18.5, 14.3.
HRMS (ESI): m/z [M + Na]+ calcd for C24H31NNaO2: 388.22525; found: 388.22632.
#
3-(5-Bromo-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-carbaldehyde (3c)
Yield: 25 mg (27%); brown viscous liquid; Rf = 0.27 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3346, 2964, 2930, 1730, 1688, 1457, 1375, 1266, 1154, 1104, 884, 795, 734, 702, 636, 614 cm–1.
1H NMR (500 MHz, CDCl3): δ = δ 9.47 (s, 1 H), 8.29 (br s, 1 H), 7.61 (d, J = 1.0 Hz, 1 H), 7.22 (dd, J 1 = 8.5, J 2 = 1.5 Hz, 1 H), 7.13 (d, J = 8.5 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 3.33 (d, J = 11.0 Hz, 1 H), 2.22–2.18 (m, 1 H), 2.14–2.10 (m, 2 H), 1.89 (d, J = 15.0 Hz, 1 H), 1.74 (dd, J 1 = 15.0, J 2 = 6.5 Hz, 1 H), 1.58–1.49 (m, 2 H), 1.25 (d, J = 7.0 Hz, 2 H), 1.18 (d, J = 6.5 Hz, 3 H), 1.08 (s, 3 H), 0.87 (s, 3 H), 0.62 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 217.1, 206.1, 135.2, 128.1, 125.0, 123.7, 121.5, 115.3, 112.9, 59.4, 50.8, 50.5, 49.4, 48.9, 47.9, 36.6, 33.1, 27.1, 25.5, 21.4, 14.2, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28BrNNaO2: 452.12011; found: 452.12076.
#
6-(5-Bromo-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3c′)
Yield: 21 mg (23%); brown viscous liquid; Rf = 0.18 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3357, 2962, 2929, 1703, 1573, 1457, 1364, 1287, 1226, 1101, 884, 797, 753, 703, 647 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.28 (br s, 1 H), 7.89 (d, J = 12.0 Hz, 1 H), 7.26 (t, J = 4.0 Hz, 1 H), 7.17 (d, J = 8.5 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 3.59 (t, J = 5.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.52–2.38 (m, 1 H), 2.36–2.25 (m, 2 H), 2.12 (d, J = 11.5 Hz, 1 H), 1.96–1.80 (m, 2 H), 1.79–1.71 (m, 1 H), 1.65 (s, 2 H), 1.61–1.50 (m, 2 H), 1.13 (s, 3 H), 1.04 (s, 7 H), 0.99 (d, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 206.1, 135.2, 128.1, 125.0, 123.7, 121.5, 115.3, 112.9, 60.4, 59.4, 50.8, 50.5, 49.5, 48.9, 47.9, 36.6, 33.1, 27.1, 25.5, 21.3, 14.2, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28BrNNaO2: 452.12011; found: 452.12076.
#
1,4,4,6-Tetramethyl-3-(5-nitro-1H-indol-3-yl)-2-oxodecahydroazulene-6-carbaldehyde (3d)
Yield: 27 mg (32%); yellow pasty mass; Rf = 0.33 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3335, 2961, 2928, 1728, 1696, 1623, 1519, 1470, 1373, 1332, 1248, 1106, 914, 816, 739, 651 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.48 (s, 1 H), 8.51 (s, 1 H), 8.11 (dd, J 1 = 9.0, J 2 = 2.0 Hz, 1 H), 8.00–7.95 (m, 1 H), 7.37 (d, J = 9.0 Hz, 1 H), 7.13 (d, J = 2.0 Hz, 1 H), 3.44 (d, J = 11.0 Hz, 1 H), 3.19–3.05 (m, 1 H), 2.95–2.74 (m, 1 H), 2.66–2.45 (m, 1 H), 2.26–2.20 (m, 1 H), 2.13–2.11 (m, 1 H), 1.93 (d, J = 15.0 Hz, 1 H), 1.26 (d, J = 3.0 Hz, 2 H), 1.19 (d, J = 6.5 Hz, 3 H), 1.09 (s, 3 H), 0.91 (s, 3 H), 0.64 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 217.4, 205.9, 141.9, 139.4, 133.5, 130.2, 125.3, 118.1, 116.6, 111.4, 59.6, 50.7, 50.5, 49.3, 48.9, 47.9, 44.8, 40.2, 39.7, 36.6, 33.0, 30.9, 27.0, 25.5, 23.3, 21.3, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28N2NaO4: 419.19468; found: 419.19461.
#
1a,4,7,7-Tetramethyl-6-(5-nitro-1H-indol-3-yl)decahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3d′)
Yield: 17 mg (20%); yellow viscous liquid; Rf = 0.24 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3077, 2963, 2926, 1728, 1624, 1575, 1520, 1471, 1432, 1376, 1334, 1305, 1262, 1142, 1074, 898, 749, 721, 669 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.74 (dd, J 1 = 15.0, J 2 = 2.0 Hz, 1 H), 8.51 (s, 1 H), 8.15–8.11 (m, 1 H), 7.57 (s, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 3.69 (d, J = 6.0 Hz, 1 H), 2.64 (dd, J 1 = 11.5, J 2 = 4.5 Hz, 1 H), 2.49 (dd, J 1 = 10.0, J 2 = 3.0 Hz, 1 H), 2.41–2.36 (m, 1 H), 2.32–2.27 (m, 2 H), 2.23 (d, J = 11.5 Hz, 1 H), 1.94–1.88 (m, 5 H), 1.81 (dd, J 1 = 13.0, J 2 = 8.0 Hz, 3 H), 1.65–1.60 (m, 1 H), 1.49–1.39 (m, 1 H), 1.26 (s, 3 H), 1.09 (s, 6 H), 1.00 (d, J = 12.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 219.5, 134.7, 133.8, 130.2, 129.8, 128.3, 68.6, 64.2, 54.9, 52.8, 48.9, 41.7, 39.4, 34.1, 30.9, 29.4, 28.6, 21.3, 18.1, 14.1.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28N2NaO4: 419.19468; found: 419.19447.
#
3-(6-Formyl-3,6,8,8-tetramethyl-2-oxodecahydroazulen-1-yl)-1H-indole-5-carbaldehyde (3e)
Yield: 25 mg (31%); brown viscous liquid; Rf = 0.32 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3333, 2961, 2929, 1714, 1679, 1612, 1576, 1459, 1365, 1267, 1175, 1100, 896, 811, 735, 663 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.03 (s, 1 H), 9.48 (s, 1 H), 8.36 (br s, 1 H), 8.09 (s, 1 H), 7.75 (dd, J 1 = 8.5 Hz, J 2 = 1.5 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 2.0 Hz, 1 H), 3.46 (d, J = 11.5 Hz, 1 H), 2.26–2.23 (m, 2 H), 2.26–2.23 (m, 2 H), 2.21–2.10 (m, 2 H), 1.92 (d, J = 15.5 Hz, 1 H), 1.79–1.74 (m, 1 H), 1.28–1.25 (m, 2 H), 1.18 (d, J = 6.5 Hz, 3 H), 1.15–1.14 (m, 1 H), 1.08 (s, 3 H), 0.90 (d, J = 7.0 Hz, 3 H), 0.65 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.8, 206.0, 192.3, 140.0, 129.6, 123.9, 118.1, 111.9, 59.6, 50.4, 49.3, 48.9, 47.9, 36.6, 33.0, 27.1, 25.5, 21.3, 12.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO3: 380.22202; found: 380.22328.
#
3-(3,3,6,8a-Tetramethyl-5-oxodecahydro-2H-cyclopenta[5,6]-cycloocta[1,2-b]oxiren-4-yl)-1H-indole-5-carbaldehyde (3e′)
Yield: 16 mg (20%); brown pasty mass; Rf = 0.29 (EtOAc–hexane, 3:7).
IR (neat): 3335, 2961, 2929, 1714, 1612, 1562, 1464, 1365, 1267, 1175, 1100, 896, 811, 735, 663 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.06 (s, 1 H), 8.40 (s, 1 H), 8.33 (d, J = 11.0 Hz, 1 H), 8.07 (t, J = 1.5 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.43 (d, J = 7.5 Hz, 1 H), 3.72 (d, J = 5.5 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.53–2.43 (m, 1 H), 2.39 (t, J = 6.0 Hz, 1 H), 2.32–2.28 (m, 1 H), 2.21–2.13 (m, 1 H), 2.09–2.03 (m, 1 H), 1.91 (d, J = 5.5 Hz, 1 H), 1.41 (d, J = 5.5 Hz, 1 H), 1.25 (d, J = 7.5 Hz, 2 H), 1.13 (s, 3 H), 1.07 (s, 6 H), 1.02 (d, J = 8.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 217.1, 192.5, 139.9, 133.7, 130.2, 129.8, 128.3, 122.5, 111.9, 53.3, 52.1, 50.1, 49.4, 48.6, 48.4, 31.1, 30.7, 29.7, 20.5, 18.7, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO3: 380.22202; found: 380.22333.
#
3-(6-Formyl-3,6,8,8-tetramethyl-2-oxodecahydroazulen-1-yl)-1H-indole-5-carbonitrile (3f)
Yield: 25 mg (31%); brown viscous liquid; Rf = 0.52 (EtOAc–hexane, 3:7).
IR (neat): 3325, 2962, 2931, 2220, 1728, 1691, 1619, 1469, 1370, 1265, 1173, 1102, 809, 736, 640 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.47 (s, 1 H), 8.52 (br s, 1 H), 7.87 (s, 1 H), 7.38 (d, J = 1.5 Hz, 1 H), 7.35 (d, J = 0.5 Hz, 1 H), 7.06 (d, J = 2.5 Hz, 1 H), 3.39 (d, J = 11.5 Hz, 1 H), 2.20–2.09 (m, 5 H), 1.92 (d, J = 15.5 Hz, 1 H), 1.18–1.74 (m, 1 H), 1.54–1.49 (m, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 1.14 (s, 3 H), 1.09 (s, 3 H), 0.89 (s, 3 H), 0.61 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.4, 204.9, 137.2, 125.1, 124.2, 123.9, 123.6, 115.8, 111.3, 101.9, 58.4, 49.7, 49.5, 48.5, 46.9, 35.6, 31.9, 31.9, 25.9, 24.5, 20.2, 11.2.
HRMS (ESI): m/z [M + Na]+ calcd for C24H28N2NaO2: 399.20485; found: 399.20572.
#
3-(3,3,6,8a-Tetramethyl-5-oxodecahydro-2H-cyclopenta[5,6]-cycloocta[1,2-b]oxiren-4-yl)-1H-indole-5-carbonitrile (3f′)
Yield: 9 mg (11%); brown viscous liquid; Rf = 0.41 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3330, 2961, 2927, 2220, 1729, 1621, 1459, 1370, 1340, 1263, 1158, 1102, 1012, 653, 640 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.43 (br s, 1 H), 8.15 (d, J = 13.0 Hz, 1 H), 7.44–7.42 (m, 1 H), 7.40 (s, 1 H), 7.14 (dd, J 1= 10.5, J 2 = 1.5 Hz, 1 H), 3.64 (dd, J 1= 8.5, J 2 = 5.0 Hz, 1 H), 2.65 (d, J = 11.5 Hz, 1 H), 2.55–2.43 (m, 2 H), 2.34 (dd, J 1= 11.0, J 2 = 5.0 Hz, 1 H), 2.31–2.24 (m, 2 H), 2.19 (d, J = 11.5 Hz, 1 H), 2.05 (d, J = 10.5 Hz, 1 H), 1.89 (d, J = 3.5 Hz, 1 H), 1.44–1.39 (m, 1 H), 1.25 (s, 3 H), 1.05 (s, 6 H), 1.00 (d, J = 9.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.5, 143.4, 137.9, 133.5, 130.9, 129.1, 122.9, 111.8, 52.1, 49.6, 47.7, 41.5, 40.0, 29.7, 20.6, 17.6, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C24H28N2NaO2: 399.20485; found: 399.20517.
#
3-(5-Fluoro-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-carbaldehyde (3g)
Yield: 16 mg (20%); brown viscous liquid; Rf = 0.43 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3350, 2964, 2931, 2874, 1792, 1629, 1580, 1486, 1457, 1375, 1292, 1233, 1168, 936, 843, 794, 735, 700 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.46 (s, 1 H), 8.33 (s, 2 H), 7.40 (dd, J 1 = 12.0, J 2 = 8.5 Hz, 1 H), 7.15 (s, 1 H), 6.90 (d, J = 9.5 Hz, 1 H), 3.33 (d, J = 11.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.49–2.41 (m, 1 H), 2.35–2.29 (m, 1 H), 2.21 (dd, J 1 = 13.5, J 2 = 7.0 Hz, 1 H), 1.88 (d, J = 14.0 Hz, 1 H), 1.76–1.72 (m, 1 H), 1.57 (d, J = 13.5 Hz, 1 H), 1.50–1.47 (m, 2 H), 1.07 (s, 3 H), 1.04 (s, 3 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.9, 206.4, 134.6, 133.5, 130.1, 129.8, 128.2, 123.1, 123.0, 116.7, 53.3, 52.2, 49.4, 48.8, 48.6, 48.3, 41.1, 40.1, 39.6, 34.0, 30.9, 29.7, 25.4, 20.3, 18.8, 13.2, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28FNNaO2: 392.20018; found: 392.20019.
#
6-(5-Fluoro-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3g′)
Yield: 12 mg (15%); brown viscous liquid; Rf = 0.40 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3366, 2964, 2932, 1728, 1580, 1486, 1458, 1375, 1236, 1167, 1101, 936, 844, 796, 734, 700, 614 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.30 (br s, 1 H), 8.08 (s, 1 H), 7.41 (dd, J 1= 8.5, J 2 = 6.5 Hz, 1 H), 7.21 (dd, J 1= 8.5, J 2 = 4.0 Hz, 1 H), 6.93 (t, J = 9.0 Hz, 1 H), 3.58 (d, J = 5.0 Hz, 1 H), 2.71 (dd, J 1= 21.0, J 2 = 11.5 Hz, 1 H), 2.53–2.39 (m, 1 H), 2.33–2.28 (m, 2 H), 2.10 (d, J = 11.5 Hz, 1 H), 1.88 ( d, J = 11.0 Hz, 1 H), 1.73 (dd, J 1= 17.0, J 2 = 7.5 Hz, 1 H), 1.55–1.49 (m, 2 H), 1.11 (s, 3 H), 1.09–0.95 (m, 9 H).
13C NMR (125 MHz, CDCl3): δ = 216.2, 134.7, 133.7, 133.0, 130.2, 129.8, 128.3, 122.9, 112.0, 111.9, 52.2, 50.0, 49.4, 48.6, 48.3, 41.1, 39.6, 34.0, 31.1, 29.7, 20.3, 18.8, 13.2.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28FNNaO2: 392.20018; found: 392.20019.
#
3-(5-Methoxy-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-carbaldehyde (3j)
Yield: 28 mg (35%); brown viscous liquid; Rf = 0.84 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3360, 2962, 2930, 1733, 1689, 1625, 1583, 1485, 1459, 1374, 1295, 1264, 1214, 1172, 1032, 925, 799, 735, 698, 632 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.46 (s, 1 H), 8.04 (br s, 1 H), 7.22–7.19 (m, 2 H), 6.99 (s, 1 H), 6.87–6.83 (m, 2 H), 3.85 (s, 3 H), 3.36 (d, J = 11.0 Hz, 1 H), 2.18 (t, J = 9.0 Hz, 2 H), 2.12–2.09 (m, 2 H), 2.06 (d, J = 10.0 Hz, 1 H), 1.89 (d, J = 15.5 Hz, 1 H), 1.76–1.72 (m, 1 H), 1.59–1.52 (m, 1 H), 1.49–1.46 (m, 2 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.88 (s, 3 H), 0.66 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 218.3, 206.2, 153.9, 131.8, 126.9, 123.1, 115.5, 112.0, 111.8, 101.7, 59.2, 50.8, 50.4, 49.2, 49.0, 47.7, 36.6, 33.0, 32.8, 27.3, 25.4, 21.5, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C24H31NNaO3: 404.22016; found: 404.22034.
#
6-(5-Methoxy-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3j′)
Yield: 16 mg (20%); brown viscous liquid; Rf = 0.82 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3362, 2961, 2930, 1729, 1625, 1583, 1485, 1459, 1372, 1296, 1214, 1170, 1038, 912, 832, 800, 731, 696, 645 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.05 (br s, 1 H), 7.26 (s, 1 H), 7.21 (s, 1 H), 6.99 (s, 1 H), 6.86 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.62 (d, J = 4.0 Hz, 1 H), 2.72 (d, J = 11.5 Hz, 1 H), 2.40–2.37 (m, 1 H), 2.35–2.30 (m, 1 H), 2.18–2.13 (m, 2 H), 1.91–1.83 (m, 2 H), 1.77–1.70 (m, 2 H), 1.64 (s, 3 H), 1.52–1.48 (m, 1 H), 1.13 (s, 3 H), 1.03 (d, J = 4.0 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 215.5, 154.3, 133.6, 130.2, 129.8, 128.3, 121.7, 113.1, 112.0, 101.2, 55.9, 52.0, 49.8, 49.4, 48.8, 41.1, 39.7, 34.3, 31.1, 29.8, 20.1, 19.0, 13.0, 12.8.
HRMS (ESI): m/z [M + Na]+ calcd for C24H31NNaO3: 404.22016; found: 404.22034.
#
1,4,4,6-Tetramethyl-3-(7-methyl-1H-indol-3-yl)-2-oxodecahydroazulene-6-carbaldehyde (3k)
Yield: 27 mg (37%); brown viscous liquid; Rf = 0.64 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3368, 2960, 2924, 2854, 1733, 1689, 1617, 1458, 1375, 1266, 1156, 1102, 782, 738, 703 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.46 (s, 1 H), 8.08 (s, 1 H), 7.98 (d, J = 8.0 Hz, 2 H), 7.03–6.98 (m, 2 H), 3.40 (d, J = 11.0 Hz, 1 H), 2.47 (d, J = 4.5 Hz, 1 H), 2.44 (s, 3 H), 2.23 (d, J = 10.0 Hz, 2 H), 2.08 (d, J = 13.5 Hz, 2 H), 1.88 (d, J = 15.0 Hz, 1 H), 1.74 (d, J = 7.5 Hz, 1 H), 1.56 (s, 1 H), 1.47 (d, J = 11.0 Hz, 1 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.07 (s, 3 H), 0.89 (s, 3 H), 0.67 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 218.2, 206.2, 134.7, 133.7, 131.1, 130.2, 129.8, 128.3, 122.8, 122.1, 120.5, 119.8, 116.9, 59.2, 50.5, 49.7, 49.0, 47.7, 36.6, 27.3, 25.3, 21.5, 16.6, 12.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO2: 366.24276; found: 366.24302.
#
1a,4,7,7-Tetramethyl-6-(7-methyl-1H-indol-3-yl)decahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3k′)
Yield: 12 mg (15%); brown viscous liquid; Rf = 0.61 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3366, 2962, 2930, 1724, 1617, 1457, 1436, 1372, 1230, 1160, 1070, 784, 741 702, 673, 646 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.01 (br s, 11 H), 7.62 (t, J = 8.5 Hz, 1 H), 7.07 (t, J = 7.0 Hz, 1 H), 7.03 (d, J = 6.5 Hz, 1 H), 6.99 (d, J = 12.0 Hz, 1 H), 3.67 (d, J = 3.0 Hz, 1 H), 2.71 (d, J = 11.5 Hz, 1 H), 2.46 (s, 3 H), 2.42–2.36 (m, 2 H), 2.31 (dd, J 1= 15.0, J 2 = 7.0 Hz, 1 H), 2.19 (dd, J 1= 16.0, J 2 = 4 Hz, 1 H), 2.13 (d, J = 12.5 Hz, 1 H), 2.05 (s, 1 H), 1.86 (d, J = 10.5 Hz, 1 H), 1.74 (d, J = 13.5 Hz, 2 H), 1.26 (s, 6 H), 1.04 (d, J = 3.0 Hz, 3 H), 1.02 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.6, 136.1, 123.1, 120.8, 120.3, 120.1, 117.4, 116.9, 52.4, 49.4, 48.9, 48.8, 48.3, 41.0, 34.3, 31.1, 20.1, 19.0, 16.5, 13.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO2: 366.24276; found: 366.24302.
#
1,4,4,6-Tetramethyl-3-(6-methyl-1H-indol-3-yl)-2-oxodecahydroazulene-6-carbaldehyde (3l)
Yield: 27 mg (34%); brown viscous liquid; Rf = 0.78 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3370, 2962, 2930, 1733, 1690, 1630, 1548, 1459, 1375, 1339, 1156, 1101, 1032, 912, 800, 733, 648 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.45 (s, 1 H), 8.01 (br s, 1 H), 7.99 (s, 1 H), 7.08 (d, J = 13.0 Hz, 1 H), 6.80 (s, 1 H), 3.36 (d, J = 11.0 Hz, 1 H), 2.71–2.67 (m, 1 H), 2.43 (s, 3 H), 2.22–2.16 (m, 2 H), 2.10 (d, J = 12.0 Hz, 2 H), 1.88 (s, 1 H), 1.76–1.71 (m, 1 H), 1.57 (s, 1 H), 1.48 (d, J = 11.0 Hz, 1 H), 1.16 (d, J = 6.5 Hz, 3 H), 1.06 (s, 3 H), 0.87 (s, 3 H), 0.65 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.7, 206.3, 137.0, 131.9, 124.2, 121.6, 121.2, 118.7, 111.4, 103.5, 59.2, 50.8, 50.5, 49.6, 49.0, 47.7, 36.6, 33.1, 32.6, 27.3, 25.3, 21.7, 12.2.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO2: 366.24276; found: 366.24334.
#
1a,4,7,7-Tetramethyl-6-(6-methyl-1H-indol-3-yl)decahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3l′)
Yield: 10 mg (13%); brown viscous liquid; Rf = 0.89 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3275, 2978, 2930, 1702, 1605, 1479, 1443, 1368, 1224, 1166, 1105, 1011, 860, 736, 650 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.92 (br s, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 9.0 Hz, 2 H), 6.91 (d, J = 8.0 Hz, 1 H), 3.57 (d, J = 4.5 Hz, 1 H), 2.64 (d, J = 11.5 Hz, 1 H), 2.37 (s, 3 H), 2.32–2.28 (m, 1 H), 2.25 (dd, J 1= 8.5, J 2= 7.0 Hz, 1 H), 2.18–2.09 (m, 1 H), 2.07–2.02 (m, 1 H), 1.97 (d, J = 11.4 Hz, 1 H), 1.78 (d, J = 6.2 Hz, 1 H), 1.69–1.64 (m, 2 H), 1.26 (s, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.95 (d, J = 6.0 Hz, 9 H).
13C NMR (125 MHz, CDCl3): δ = 216.6, 137.0, 132.5, 124.1, 121.7, 120.4, 119.3, 116.3, 111.1, 52.6, 52.3, 50.5, 49.4, 48.8, 48.2, 41.0, 39.7, 35.2, 34.3, 31.2, 29.8, 21.7, 20.1, 19.0, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H32NO2: 366.24276; found: 366.24334.
#
3-(5-Chloro-1H-indol-3-yl)-1,4,4,6-tetramethyl-2-oxodecahydroazulene-6-carbaldehyde (3m)
Yield: 21 mg (25%); brown pasty mass; Rf = 0.56 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3337, 2963, 2922, 1708, 1689, 1629, 1574, 1433, 1289, 1259, 1139, 1105, 1073, 896, 802, 752, 703, 672 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.47 (s, 1 H), 8.24 (br s, 1 H), 8.08 (t, J = 2.0 Hz, 1 H), 7.59–7.57 (m, 1 H), 7.46 (d, J = 2.0 Hz, 1 H), 6.91 (d, J = 2.5 Hz, 1 H), 3.34 (d, J = 11.5 Hz, 1 H), 2.69–2.64 (m, 1 H), 2.34–2.32 (m, 1 H), 2.30–2.28 (m, 1 H), 2.14–2.10 (m, 2 H), 1.89 (d, J = 15.5 Hz, 1 H), 1.77–1.72 (m, 1 H). 1.56–1.46 (m, 1 H), 1.20–1.25 (m, 1 H), 1.18 (d, J = 7.0 Hz, 3 H), 1.08 (s, 3 H), 0.88 (s, 3 H), 0.63 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.0, 209.1, 144.4, 135.4, 133.8, 133.1, 130.5, 127.8, 68.4, 66.1, 58.3, 51.9, 50.0, 48.3, 37.0, 36.8, 34.1, 29.8, 25.5, 24.2, 18.6, 14.3.
HRMS(ESI): m/z [M + H]+ calcd for C23H29ClNO2: 386.18813; found: 386.18806.
#
6-(5-Chloro-1H-indol-3-yl)-1a,4,7,7-tetramethyldecahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3m′)
Yield: 15 mg (18%); brown pasty mass; Rf = 0.53 (EtOAc–hexane, 3.5:6.5).
IR (neat): 3337, 2963, 2922, 1708, 1629, 1581, 1486, 1460, 1362, 1291, 1222, 1184, 1102, 937, 799, 754, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.16 (s, 1 H), 8.02–7.97 (m, 1 H), 7.59 (ddd, J 1 = 8.0, J 2 = 2.0, J 3 = 1.0 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.19–7.12 (m, 1 H), 3.60 (d, J = 5.0 Hz, 1 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.54–2.39 (m, 1 H), 2.37–2.30 (m, 1 H), 2.30–2.26 (m, 1 H), 2.24 (d, J = 11.5 Hz, 1 H), 2.11 (d, J = 11.5 Hz, 1 H), 2.09–1.99 (m, 1 H), 1.93–1.82 (m, 1 H), 1.74 (dd, J 1 = 12.5, J 2= 8.5 Hz, 1 H), 1.59–1.50 (m, 1 H), 1.13 (s, 3 H), 1.06 (m, 9 H).
13C NMR (125 MHz, CDCl3): δ = 214.6, 134.7, 133.8, 131.2, 129.9, 128.3, 112.1, 53.5, 52.4, 49.4, 49.4, 41.2, 40.3, 39.6, 34.1, 31.2, 29.7, 25.1, 20.3, 18.8, 13.1.
HRMS (ESI): m/z [M + H]+ calcd for C23H29ClNO2: 386.18813; found: 386.18806.
#
1,4,4,6-Tetramethyl-2-oxo-3-(2-phenyl-1H-indol-3-yl)decahydroazulene-6-carbaldehyde (3n)
Yield: 23 mg (25%); colorless liquid; Rf = 0.58 (EtOAc–hexane, 2.5:7.5).
IR (neat): 3369, 2926, 2858, 1730, 1690, 1457, 1339, 1161, 1073, 923, 765, 742, 703 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.36 (s, 1 H), 8.08 (s, 1 H), 7.57 (d, J = 7.0 Hz, 1 H), 7.45 (dd, J 1 = 13.0, J 2 = 5.5 Hz, 3 H), 7.41 (d, J = 7.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.08 (t, J = 7.5 Hz, 1 H), 3.57 (d, J = 11.5 Hz, 1 H), 2.60–2.50 (m, 1 H), 2.27 (dd, J 1 = 16.0, J 2= 9.0 Hz, 1 H), 2.08 (dd, J 1= 13.5, J 2 = 7.0 Hz, 2 H), 2.02–1.96 (m, H), 1.86–1.72 (m, 1 H), 1.70 (d, J = 15.0 Hz, 1 H), 1.42 (dd, J 1 = 13.0, J 2 = 7.6 Hz, 1 H), 1.26 (s, 3 H), 1.23 (d, J = 6.5 Hz, 3 H), 1.09 (d, J = 6.5 Hz, 1 H), 0.99 (s, 3 H), 0.40 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 219.9, 206.0, 128.9, 128.8, 128.4, 122.2, 119.7, 119.4, 111.4, 57.3, 51.2, 50.6, 49.7, 48.9, 47.9, 36.4, 33.0, 31.6, 27.3, 25.1, 21.5, 12.6.
HRMS (ESI): m/z [M + H]+ calcd for C29H34NO2: 428.25841; found: 428.25792.
#
1a,4,7,7-Tetramethyl-6-(2-phenyl-1H-indol-3-yl)decahydro-5H-cyclopenta[5,6]cycloocta[1,2-b]oxiren-5-one (3n′)
Yield: 21 mg (23%); colorless liquid; Rf = 0.55 (EtOAc–hexane, 2.5:7.5).
IR (neat): 3369, 2927, 2874, 1730, 1607, 1456, 1338, 1371, 1310, 1160, 913, 843, 737, 702, 652 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.12 (s, 1 H), 7.58 (dd, J 1 = 8.0, J 2 = 1.3 Hz, 2 H), 7.50–7.45 (m, 2 H), 7.44–7.41 (m, 3 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.21–7.18 (m, 1 H), 7.14–7.10 (m, 1 H), 3.87 (d, J = 9.0 Hz, 1 H), 2.54 (dd, J 1 = 9.0, J 2 = 7.0 Hz, 1 H), 2.46 (d, J = 11.5 Hz, 1 H), 2.40–2.32 (m, 1 H), 2.27–2.22 (m, 1 H), 1.97 (s, 2 H), 1.81 (d, J = 11.0 Hz, 3 H), 1.67 (d, J = 11.0 Hz, 1 H), 1.59 (d, J = 2.0 Hz, 1 H), 1.20 (d, J = 7.0 Hz, 3 H), 1.06 (dd, J 1 = 7.0, J 2 = 2.5 Hz, 1 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.83 (s, 3 H), 0.51 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 217.5, 136.4, 132.9, 128.9, 128.8, 128.4, 122.2, 119.7, 119.4, 111.3, 52.9, 50.6, 49.6, 48.9, 36.4, 33.1, 31.7, 29.7, 27.4, 21.6, 12.6.
HRMS (ESI): m/z [M + Na]+ calcd for C29H33NNaO2: 450.24090; found: 450.24222.
#
(2E,6Z,10E)-6-(Azidomethyl)-2,9,9-trimethylcycloundeca-2,6,10-trienone (4a)
Allylic bromination of zerumbone: NBS (1.0 mmol) was added to a solution of zerumbone (0.92 mmol) and CH3CN/H2O (1:1, 15 mL), and the mixture was stirred vigorously at RT for 1 min. H2O (30 mL) was poured into the solution, which was filtrated immediately, and washed with H2O several times; this afforded 7-bromo-2,9,9-trimethyl-6-methylenecycloundeca-2,10-dienone as a colorless solid.
Azidation: NaN3 (1.0 mmol) and Cs2CO3 (5 mol%) were added to a solution of 7-bromo-2,9,9-trimethyl-6-methylenecycloundeca-2,10-dienone (0.67 mmol) in DMF (20 mL) at RT and the mixture was stirred for 12 h. The progress of the reaction was monitored by TLC (hexane–EtOAc, 3:2). The DMF solution was extracted with CH2Cl2 (3 × 30 mL) and the combined organic extracts were washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, and concentrated on a rotary evaporator. Chromatography (silica gel, hexane–EtOAc, 2:1) afforded 4a.
Yield: 245 mg (56%); colorless viscous liquid; Rf = 0.71 (EtOAc–hexane, 3:7).
IR (neat): 2960, 2924, 2854, 2095, 1653, 1451, 1386, 1364, 1265, 1105, 968, 903, 831, 777, 698, 631 cm–1.
1H NMR (500 MHz, CDCl3): δ = 6.00 (s, 1 H), 5.96 (t, J = 7.0 Hz, 1 H), 5.76 (d, J = 8.0 Hz, 1 H), 5.50 (t, J = 8.5 Hz, 1 H), 4.06 (br s, 1 H), 3.44 (br s, 1 H), 2.69 (s, 1 H), 2.55–2.21 (m, 5 H), 1.79 (s, 3 H), 1.25 (s, 3 H), 1.11 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.0, 159.3, 148.4, 138.9, 138.6, 129.0, 127.4, 57.8, 48.8, 43.1, 38.3, 29.3, 25.8, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H21N3NaO: 282.15823; found: 282.15758.
#
Triazole-Linked Zerumbones 6; General Procedure
Zerumbone azide 4a (1.0 equiv), the appropriate alkyne (1.5 equiv), CuI (20 mol%) as catalyst, and DIPEA (3 equiv) as base were weighed in a reaction tube. CH3CN (2 mL) was added and the mixture was allowed to stir at RT for 2 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, 100–200 mesh, hexane–EtOAc).
#
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]cycloundeca-2,6,10-trienone (6a)
Yield: 31 mg (44%); white solid; Rf = 0.42 (EtOAc–hexane, 3:7); mp 189–190 °C.
IR (neat): 3432, 3058, 2970, 2928, 2858, 2119, 1709, 1647, 1430, 1363, 1266, 1224, 1047, 973, 898, 739, 611, 557 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.84–7.76 (m, 2 H), 7.70 (s, 1 H), 7.44–7.41 (m, 2 H), 7.35–7.27 (m, 1 H), 6.05 (d, J = 16.5 Hz, 1 H), 6.03–5.94 (m, 1 H), 5.85 (d, J = 16.5 Hz, 1 H), 5.63–5.60 (m, 1 H), 4.81 (br s, 1 H), 5.06 (br s, 1 H), 2.56–2.42 (m, 2 H), 2.28–2.14 (m, 3 H), 1.90–1.86 (m, 1 H), 1.79 (s, 3 H), 1.29 (s, 3 H), 0.93 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.4, 158.9, 148.6, 148.2, 139.0, 133.6, 131.7, 130.4, 128.9, 128.3, 127.7, 125.7, 119.3, 47.8, 42.3, 37.7, 34.7, 24.3, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27N3NaO: 384.20518; found: 384.20580.
#
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-p-tolyl-1H-1,2,3-triazol-1-yl)methyl]cycloundeca-2,6,10-trienone (6b)
Yield: 30 mg (41%); pale yellow solid: Rf = 0.48 (EtOAc–hexane, 3:7); mp 205–208 °C.
IR (neat): 3407, 3138, 2959, 2925, 2861, 1716, 1647, 1497, 1453, 1364, 1268, 1223, 1183, 1108, 1075, 1064, 973, 908, 820, 734, 699, 660 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.70 (d, J = 8.5 Hz, 2 H), 7.61 (s, 1 H), 7.21 (d, J = 7.5 Hz, 2 H), 6.03 (d, J = 16.5 Hz, 1 H), 6.00–5.98 (m, 1 H), 5.82 (d, J = 16.5 Hz, 1 H), 5.61–5.58 (m, 1 H), 5.06–5.03 (m, 1 H), 4.79 (br s, 1 H), 2.55–2.41 (m, 2 H), 2.40 (s, 3 H), 2.38–2.04 (m, 4 H), 1.87 (s, 3 H), 1.33 (s, 3 H), 1.16 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.0, 158.6, 148.3, 139.1, 138.0, 133.8, 131.5, 129.5, 127.8, 125.6, 118.7, 47.8, 42.3, 37.7, 34.8, 29.7, 29.4, 24.3, 21.3, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C24H29N3NaO: 398.22083; found: 398.22180.
#
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-phenethyl-1H-1,2,3-triazol-1-yl)methyl]cycloundeca-2,6,10-trienone (6c)
Yield: 27 mg (36%); amorphous viscous solid; Rf = 0.27 (EtOAc–hexane, 3:7).
IR (neat): 3425, 2960, 2927, 2105, 1644, 1453, 1368, 1268, 1218, 1053, 749, 701, 558 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.27–7.24 (m, 3 H), 7.19–7.14 (m, 2 H), 6.99 (s, 1 H), 6.02 (d, J = 16.5 Hz, 1 H), 6.00–5.96 (m, 1 H), 5.77 (d, J = 16.5 Hz, 1 H), 5.55–5.52 (m, 1 H), 4.97–4.90 (m, 1 H), 4.69–4.66 (m, 1 H), 3.05–2.97 (m, 4 H), 2.42–2.37 (m, 1 H), 2.32–2.26 (m, 2 H), 2.10–2.07 (m, 3 H), 1.81 (s, 3 H), 1.27 (s, 3 H), 1.13 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 202.9, 158.5, 148.2, 147.6, 141.0, 139.0, 133.9, 131.1, 128.5, 128.4, 127.7, 126.1, 120.6, 47.5, 42.2, 37.7, 35.5, 34.7, 27.5, 24.3, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C25H31N3NaO: 412.23648; found: 412.24168.
#
(2E,6Z,10E)-6-[(4-Benzyl-1H-1,2,3-triazol-1-yl)methyl]-2,9,9-trimethylcycloundeca-2,6,10-trienone (6d)
Yield: 27 mg (38%); pale yellow liquid; Rf = 0.28 (EtOAc–hexane, 3:7).
IR (neat): 3410, 2185, 1645, 1454, 1362, 1267, 1210, 1054, 752, 712, 554 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.31–7.21 (m, 5 H), 7.12 (s, 1 H), 6.02 (d, J = 16.5 Hz, 1 H), 6.00–5.97 (m, 1 H), 5.79 (d, J = 16.5 Hz, 1 H), 5.56–5.29 (m, 1 H), 4.96 (br s, 1 H), 4.71 (br s, 1 H), 4.08–4.05 (m, 2 H), 2.46–2.44 (m, 2 H), 2.24–2.06 (m, 4 H), 1.79 (s, 3 H), 1.29 (s, 3 H), 1.16 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.5, 159.0, 148.7, 148.1, 139.0, 138.9, 133.6, 131.5, 128.6, 128.4, 127.6, 126.5, 121.2, 47.6, 42.2, 37.7, 34.7, 32.2, 29.3, 24.3, 24.0, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C24H29N3NaO: 398.22083; found: 398.21868.
#
(2E,6Z,10E)-6-[(4-(Hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl]-2,9,9-trimethylcycloundeca-2,6,10-trienone (6e)
Yield: 54 mg (89%); colorless solid; Rf = 0.45 (EtOAc–hexane, 3:7); mp 152–154 °C.
IR (neat): 3417, 2960, 2928, 2127, 1641, 1442, 1268, 1223, 1122, 1047, 1010, 971, 755, 699, 557, 538 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.48 (s, 1 H), 6.05 (d, J = 16.5 Hz, 1 H), 6.02–5.99 (m, 1 H), 5.80 (d, J = 16.5 Hz, 1 H), 5.62–5.59 (m, 1 H), 5.04–4.96 (m, 1 H), 4.80 (s, 2 H), 4.76–4.75 (m, 1 H), 2.47–2.41 (m, 2 H), 2.28–2.27 (m, 1 H), 2.20–2.19 (m, 3 H), 1.83 (s, 3 H), 1.26 (s, 3 H), 1.15 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.4, 158.8, 148.5, 139.0, 133.5, 131.8, 127.7, 121.3, 56.6, 47.6, 42.2, 37.7, 34.7, 24.3, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C18H25N3NaO2: 338.18445; found: 338.18424.
#
(2E,6Z,10E)-2,9,9-Trimethyl-6-[(4-pentyl-1H-1,2,3-triazol-1-yl)methyl]cycloundeca-2,6,10-trienone (6f)
Yield: 33 mg (48%); colorless viscous liquid; Rf = 0.42 (EtOAc–hexane, 3:7).
IR (neat): 3438, 2958, 2930, 2863, 2097, 1646, 1460, 1366, 1267, 1217, 1048, 971, 780, 558 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.21 (s, 1 H), 6.04 (d, J = 16.5 Hz, 1 H), 6.02–6.00 (m, 1 H), 5.82 (d, J = 16.5 Hz, 1 H), 5.60–5.56 (m, 1 H), 4.99 (br s, 1 H), 4.74 (br s, 1 H), 2.72–2.68 (m, 2 H), 2.52–2.23 (m, 4 H), 2.18–2.04 (m, 2 H), 1.88 (s, 3 H), 1.82–1.64 (m, 2 H), 1.40–1.20 (m, 7 H), 1.14 (s, 3 H), 0.92–0.86 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 203.2, 158.9, 148.8, 148.5, 138.9, 133.9, 131.2, 127.6, 120.2, 47.5, 42.2, 37.6, 34.7, 31.4, 29.6, 29.3, 29.1, 25.6, 24.3, 24.0, 22.4, 14.0, 12.0.
HRMS (ESI): m/z [M + Na]+ calcd for C22H33N3NaO: 378.25213; found: 378.25278.
#
Triazole-Appended [6.3.0] Fused Cyclic Products 7; General Procedure
Triazole-appended zerumbone 6a (1.0 equiv), indole 2 (1.0 equiv), and AlCl3 (5 mol%) were placed in a reaction tube. CH3CN (2 mL) was added and the reaction mixture was stirred at 80 °C for 5 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, 100–200 mesh, hexane–EtOAc).
#
(E)-3-(1H-Indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7a)
Yield: 33 mg (50%); brown viscous liquid; Rf = 0.66 (EtOAc–hexane, 2:3).
IR (neat): 3327, 2959 2928, 2869, 1730, 1619, 1459, 1338, 1265, 1224, 1077, 1048, 764, 737, 696 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.0 Hz, 2 H), 7.84 (s, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.48 (d, J = 7.0 Hz, 1 H), 7.43 (s, 1 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.14 (d, J = 7.0 Hz, 1 H), 7.09 (t, J = 8.0 Hz, 1 H), 6.71 (s, 1 H), 5.93 (dd, J 1 = 6.5, J 2 = 10 Hz, 1 H), 5.06 (d, J = 14.0 Hz, 1 H), 4.75 (d, J = 14.0 Hz, 1 H), 3.53 (d, J = 3.5 Hz, 1 H), 2.58–2.52 (m, 1 H), 2.41–2.34 (m, 3 H), 2.26–2.20 (m, 2 H), 2.05–2.02 (m, 1 H), 1.95–1.85 (m, 2 H), 1.25 (s, 6 H), 0.92 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.8, 148.1, 136.9, 136.2, 130.7, 129.8, 129.1, 128.5, 126.2, 126.1, 122.4, 121.3, 119.7, 119.6, 116.7, 110.9, 59.0, 48.0, 46.4, 43.7, 39.7, 38.5, 34.9, 31.9, 29.7, 29.3, 24.8, 22.7, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C31H35N4O: 479.28054; found: 479.27464.
#
(E)-1,4,4-Trimethyl-3-(5-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7b)
Yield: 20 mg (30%); colorless viscous liquid; Rf = 0.69 (EtOAc–hexane, 2:3).
IR (neat): 3332, 2957, 2925, 2856, 1732, 1623, 1464, 1372, 1265, 1224, 1181, 1078, 1048, 975, 917, 798, 765, 737, 696 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.5 Hz, 2 H), 7.83 (s, 2 H), 7.56 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.06 (d, J = 4.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.64 (s, H), 5.92 (t, J = 8.0 Hz, 1 H), 5.06 (d, J = 13.5 Hz, 1 H), 4.98 (d, J = 14.0 Hz, 1 H), 3.49 (s, 1 H), 2.54–2.51 (m, 2 H), 2.43 (s, 3 H), 2.39–2.33 (m, 3 H), 2.22 (d, J = 5.0 Hz, 1 H), 1.94–1.85 (m, 3 H), 1.26 (s, 6 H), 0.92 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.9, 148.1, 134.5, 130.7, 129.8, 129.1, 128.9, 128.5, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3, 110.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 15.0, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C32H37N4O: 493.29619; found: 492.29605.
#
(E)-3-(5-Bromo-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7c)
Yield: 33 mg (43%); brown viscous liquid; Rf = 0.33 (EtOAc–hexane, 3:7).
IR (neat): 3331, 2958, 2926, 2856, 1732, 1613, 1459, 1362, 1265, 1222, 1149, 1077, 1048, 976, 884, 797, 764, 735, 695, 655 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.92 (s, 1 H), 7.90–7.87 (m, 2 H), 7.85 (s, 1 H), 7.65 (s, 1 H), 7.52 (d, J = 6.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 6.78 (s, 1 H), 5.99–5.89 (m, 1 H), 5.05 (d, J = 14.0 Hz, 1 H), 5.00 (d, J = 14.0 Hz, 1 H), 3.44 (d, J = 3.5 Hz, 1 H), 2.57 (t, J = 13.0 Hz, 1 H), 2.39–2.34 (m, 2 H), 2.27–2.14 (m, 3 H), 2.09–1.99 (m, 1 H), 1.94–1.87 (m, 2 H), 1.26 (s, 3 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.2, 148.0, 136.6, 134.9, 130.5, 129.2, 129.8, 128.5, 128.0, 126.0, 125.2, 122.8, 122.2, 120.1, 112.9, 112.5, 59.1, 47.8, 46.5, 39.6, 38.5, 34.8, 29.7, 22.8, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C31H34BrN4O: 557.19105; found: 557.19170.
#
(E)-1,4,4-Trimethyl-3-(5-nitro-1H-indol-3-yl)-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7d)
Yield: 28 mg (39%); yellow viscous liquid; Rf = 0.30 (EtOAc–hexane, 3:7).
IR (neat): 3348, 2959, 2920, 2851, 1710, 1623, 1520, 1469, 1361, 1332, 1267, 1222, 1092, 1048, 975, 912, 815, 766, 733, 698, 649 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.62 (br s, 1 H), 8.53 (s, 1 H), 8.10 (d, J = 9.0 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 2 H), 7.72 (s, 1 H), 7.43 (d, J = 7.0 Hz, 2 H), 7.38 (d, J = 9.0 Hz, 1 H), 7.35 (d, J = 7.0 Hz, 1 H), 7.20 (s, 1 H), 5.63–5.55 (m, 1 H), 4.92 (d, J = 15.0 Hz, 1 H), 4.80 (d, J = 14.5 Hz, 1 H), 3.02 (d, J = 5.5 Hz, 1 H), 2.50–2.44 (m, 1 H), 2.26–2.22 (m, 1 H), 2.14–2.10 (m, 2 H), 2.06–2.03 (m, 2 H), 1.93–1.86 (m, 2 H), 1.26 (s, 3 H), 0.89 (d, J = 7.0 Hz, 1 H), 0.82 (s, 3 H), 0.36 (s, 3 H)..
13C NMR (125 MHz, CDCl3): δ = 218.6, 148.0, 141.7, 138.8, 136.4, 130.4, 128.9, 128.3, 127.8, 127.5, 126.4, 125.7, 119.8, 117.6, 115.9, 111.3, 56.6, 52.6, 39.8, 38.0, 35.1, 30.9, 29.7, 22.9, 21.9, 21.5, 15.0, 10.9.
HRMS (ESI): m/z [M + H]+ calcd for C31H34N5O3: 524.26562; found: 524.265760.
#
(E)-3-(3,9,9-Trimethyl-2-oxo-6-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbaldehyde (7e)
Yield: 22 mg (32%); brown viscous liquid; Rf = 0.82 (EtOAc–hexane, 2:3).
IR (neat): 3317, 2958, 2927, 2871, 1735, 1690, 1627, 1578, 1465, 1367, 1316, 1226, 1177, 1078, 1048, 974, 920, 810, 766, 697, 625 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.96 (s, 1 H), 7.82 (s, 1 H), 7.81 (s, 1 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.69 (s, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.36 (t, J = 7.0 Hz, 1 H), 7.28 (t, J = 7.0 Hz, 1 H), 5.76 (t, J = 8.5 Hz, 1 H), 4.89 (d, J = 14.0 Hz, 1 H), 4.83 (d, J = 14.0 Hz, 1 H), 3.51 (d, J = 3.5 Hz, 1 H), 2.93 (t, J = 16.0 Hz, 1 H), 2.84 (d, J = 5.5 Hz, 1 H), 2.79–2.75 (m, 1 H), 2.64–2.60 (m, 1 H), 2.27 (d, J = 6.0 Hz, 1 H), 2.24 (d, J = 6.5 Hz, 1 H), 2.10–2.01 (m, 1 H), 1.87–1.83 (m, 2 H), 1.59 (s, 3 H), 0.95 (s, 3 H), 0.86 (s, 3 H), 0.59 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 209.0, 192.2, 148.2, 138.4, 136.3, 130.4, 129.2, 128.9, 128.3, 127.1, 126.0, 125.7, 119.3, 111.7, 58.8, 47.1, 46.6, 39.2, 38.5, 38.3, 30.0, 28.3, 27.8, 22.4, 12.1, 8.2.
HRMS (ESI): m/z [M + Na]+ calcd for C32H34N4NaO2: 529.25795; found: 529.25932.
#
(E)-3-(5-Methoxy-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7f)
Yield: 28 mg (40%); blackish viscous liquid; Rf = 0.69 (EtOAc–hexane, 3:7).
IR (neat): 3398, 2958, 2928, 2869, 1732, 1626, 1583, 1485, 1464, 1371, 1292, 1263, 1215, 1174, 1051, 912, 799, 766, 735, 696, 619 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.90 (d, J = 7.0 Hz, 2 H), 7.86 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.47 (d, J = 7.0 Hz, 1 H), 7.31 (s, 1 H), 7.23 (d, J = 2.5 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 6.80 (dd, J 1 = 8.5, J 2 = 2.0 Hz, 1 H), 6.68 (s, 1 H), 6.03–5.89 (m, 1 H), 5.07 (d, J = 13.5 Hz, 1 H), 4.99 (d, J = 14.0 Hz, 1 H), 3.87 (s, 3 H), 3.46 (d, J = 3.5 Hz, 1 H), 2.54 (d, J = 13.5 Hz, 1 H), 2.43–2.31 (m, 2 H), 2.23 (dd, J 1 = 10, J 2 = 5.0 Hz, 2 H), 1.99–1.80 (m, 2 H), 1.29 (dd, J 1 = 8.0, J 2 = 3.0 Hz, 2 H), 1.26 (d, J = 1.0 Hz, 3 H), 0.93 (d, J = 3.5 Hz, 3 H), 0.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 218.9, 154.2, 148.1, 136.8, 129.8, 129.2, 128.5, 126.6, 126.1, 122.0, 112.9, 111.7, 101.1, 58.9, 55.9, 48.2, 46.2, 38.5, 35.1, 31.4, 29.6, 29.4, 22.9, 11.9.
HRMS (ESI): m/z [M + Na]+ calcd for C35H36N4NaO2: 531.27360; found: 531.27363.
#
(E)-1,4,4-Trimethyl-3-(7-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7g)
Yield: 27 mg (39%); colorless viscous liquid; Rf = 0.69 (EtOAc–hexane, 2:3).
IR (neat): 3334, 2956, 2923, 2868, 1727, 1625, 1462, 1340, 1225, 1191, 1076, 1048, 910, 802, 765, 732, 695, 648 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.5 Hz, 2 H), 7.83 (s, 1 H), 7.56 (s, 1 H), 7.51 (t, J = 7.0 Hz, 2 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.29 (br s, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.64 (s, 1 H), 5.92 (t, J = 8.0 Hz, 1 H), 5.06 (d, J = 13.5 Hz, 1 H), 4.98 (d, J = 14.0 Hz, 1 H), 3.49 (s, 3 H), 2.57–2.51 (m, 2 H), 2.37 (s, 3 H), 2.35–2.31 (m, 3 H), 2.25–2.17 (m, 2 H), 1.94–1.85 (m, 3 H), 1.25 (s, 3 H), 0.92 (s, 3 H), 0.91 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.2, 148.1, 134.5, 130.7, 129.8, 129.1, 128.9, 128.4, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3, 110.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C32H37N4O: 493.29619; found: 493.29605.
#
(E)-1,4,4-Trimethyl-3-(6-methyl-1H-indol-3-yl)-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7h)
Yield: 28 mg(41%); colorless viscous liquid; Rf = 0.69 (EtOAc–hexane, 2:3).
IR (neat): 3338, 2958, 2930, 2863, 1719, 1625, 1460, 1366, 1267, 1217, 1048, 971, 780, 558 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.81 (d, J = 7.0 Hz, 1 H), 7.76 (s, 2 H), 7.62 (d, J = 5.0 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.51 (s, 1 H), 7.46–7.41 (m, 2 H), 7.36 (t, J = 7.5 Hz, 2 H), 6.89 (s, 1 H), 6.00 (t, J = 16.0 Hz, 1 H), 4.97 (d, J = 14.0 Hz, 1 H), 4.90 (d, J = 13.5 Hz, 1 H ), 3.42 (s, 1 H), 2.48 (s, 1 H), 2.36 (d, J = 4.0 Hz, 1 H), 2.34 (s, 3 H), 2.26 (d, J = 7.5 Hz, 2 H), 2.15 (d, J = 5 Hz, 2 H), 1.98 (d, J = 10.5 Hz, 1 H), 1.53–1.46 (m, 2 H), 1.05 (s, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.83 (d, J = 6.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 216.2, 148.1, 134.5, 130.7, 129.8, 129.1, 128.9, 128.5, 126.5, 126.1, 124.0, 121.4, 119.7, 119.2, 116.3, 110.6, 59.0, 48.0, 46.3, 38.6, 34.9, 31.9, 29.7, 29.4, 22.7, 21.5, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C32H37N4O: 493.29610; found: 493.29701.
#
(E)-3-(5-Chloro-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7i)
Yield: 26 mg (37%); brownish viscous liquid; Rf = 0.63 (EtOAc–hexane, 2:3).
IR (neat): 3332, 2930, 2871, 1731, 1627, 1463, 1368, 1224, 1076, 1048, 908, 799, 764, 730, 694, 648, 614 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.0 Hz, 2 H), 7.85 (s, 1 H), 7.76 (s, 1 H), 7.49 (d, J = 7.5 Hz, 2 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.09 (s, 2 H), 6.82 (s, 1 H), 5.93 (t, J = 14.0 Hz, 1 H), 5.04 (d, J = 14.0 Hz, 1 H), 4.99 (d, J = 14.0 Hz, 1 H), 3.44 (d, J = 3.0 Hz, 1 H), 2.55 (t, J = 12.5 Hz, 1 H), 2.39 (t, J = 12.0 Hz, 1 H), 2.32–2.24 (m, 2 H), 2.19–2.15 (m, 1 H), 1.93–1.88 (m, 1 H), 1.62–1.57 (m, 1 H), 1.42–1.25 (m, 2 H), 0.93 (d, J = 6.5 Hz, 3 H), 0.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.2, 151.3, 148.0, 136.5, 134.6, 130.5, 129.8, 129.2, 128.6, 126.0, 125.8, 123.0, 122.6, 120.2, 119.1, 116.2, 112.1, 59.0, 51.8, 46.6, 41.2, 39.5, 38.5, 37.3, 34.8, 32.7, 29.1, 25.7, 20.2, 12.0, 7.8.
HRMS (ESI): m/z [M + H]+ calcd for C13H34ClN4O: 513.24157; found: 513.24171.
#
(E)-3-(5-Fluoro-1H-indol-3-yl)-1,4,4-trimethyl-7-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-1,3,3a,4,5,8,9,9a-octahydro-2H-cyclopenta[8]annulen-2-one (7j)
Yield: 24 mg (35%); brown viscous liquid; Rf = 0.63 (EtOAc–hexane, 2:3).
IR (neat): 3323, 2960, 2928, 2869, 2097, 1731, 1693, 1602, 1485, 1451, 1265, 1173, 1078, 937, 851, 799, 765, 738, 696, 619 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.88 (d, J = 7.0 Hz, 1 H), 7.85 (s, 1 H), 7.64 (s, 1 H), 7.51 (t, J = 7.5 Hz, 2 H), 7.44 (d, J = 11.5 Hz, 2 H), 7.08 (d, J = 4.0 Hz, 1 H), 6.88 (t, J = 8.5 Hz, 1 H), 6.81 (s, 1 H), 5.97–5.90 (m, 1 H), 5.04 (d, J = 13.5 Hz, 1 H), 5.00 (d, J = 14.0 Hz, 1 H), 3.43 (s, 1 H), 2.55 (t, J = 13.5 Hz, 1 H), 2.43–2.37 (m, 1 H), 2.34 (d, J = 8.0 Hz, 1 H), 2.25 (s, 1 H), 2.18 (d, J = 10.5 Hz, 1 H), 2.06 (d, J = 10.0 Hz, 1 H), 1.88 (d, J = 14.0 Hz, 2 H), 1.62–1.53 (m, 1 H), 1.25 (s, 6 H), 0.90 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.8, 158.9, 157.0, 148.0, 132.7, 129.8, 129.1, 128.5, 126.0, 123.1, 119.9, 111.6, 111.5, 110.9, 110.7, 104.7, 104.5, 59.1, 47.9, 46.5, 38.5, 34.9, 29.7, 22.8, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C31H34FN4O: 497.27112; found: 497.27491.
#
(E)-3-(3,9,9-Trimethyl-2-oxo-6-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbonitrile (7k)
Yield: 23 mg (33%); brown viscous liquid; Rf = 0.93 (EtOAc–hexane, 2:3).
IR (neat): 3438, 2923, 2853, 1689, 1587, 1501, 1465, 1431, 1381, 1328, 1224, 1114, 867, 804, 770, 721 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.64 (br s, 1 H), 8.19 (s, 1 H), 7.88 (t, J = 5.0 Hz, 2 H), 7.50 (t, J = 7.0 Hz, 2 H), 7.44 (t, J = 7.0 Hz, 2 H), 7.36 (d, J = 8.5 Hz, 2 H), 7.12 (s, 1 H), 5.97 (t, J = 9.5 Hz, 1 H), 5.05 (d, J = 14.0 Hz, 1 H), 5.01 (d, J = 14.0 Hz, 1 H), 3.49 (d, J = 3.0 Hz, 1 H), 2.59 (t, J = 14.0 Hz, 1 H), 2.48–2.35 (m, 2 H), 2.31–2.26 (m, 2 H), 2.14–2.10 (m, 1 H), 1.67–1.61 (m, 2 H), 1.27–1.25 (m, 1 H), 0.93 (s, 3 H), 0.91 (s, 3 H), 0.89 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.8, 148.1, 136.9, 136.2, 130.7, 129.8, 129.1, 128.5, 126.2, 126.1, 122.4, 121.3, 119.7, 119.6, 116.7, 110.9, 59.0, 47.9, 46.4, 43.7, 39.7, 38.5, 34.9, 31.9, 29.7, 29.3, 24.8, 22.7, 14.1, 12.0.
HRMS (ESI): m/z [M + H]+ calcd for C32H34N5O: 504.27579; found: 504.28834.
#
Synthesis of [6.3.0] Fused Ring System 10 from Zerumbal 8; General Procedure
Zerumbal 8 (1.0 equiv), indole 2 (1.0 equiv), and In(OTf)3 (5 mol%) were placed in a reaction tube. CH3CN (2 mL) was added and the reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, 100–200 mesh, hexane–EtOAc).
#
(E)-1-(1H-Indol-3-yl)-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10a)
Yield: 35 mg (81%); white solid; Rf = 0.20 (EtOAc–hexane, 1:4); mp 145–150 °C.
IR (neat): 3354, 2959, 2928, 2872, 1732, 1679, 1640, 1458, 1372, 1337, 1266, 1206, 1168, 1109, 1012, 739 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.50 (s, 1 H), 8.07 (br s, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.20–7.17 (m, 1 H), 7.15–7.12 (m, 1 H), 6.89 (d, J = 2.5 Hz, 1 H), 6.77–6.73 (m, 1 H), 3.60 (d, J = 4.0 Hz, 1 H), 3.00–2.96 (m, 1 H), 2.73 (t, J = 11.0 Hz, 1 H), 2.41–2.35 (m, 1 H), 2.22–2.15 (m, 4 H), 1.76–1.70 (m, 1 H), 1.52–144 (m, 1 H), 1.05 (d, J = 7.0 Hz, 3 H), 1.03 (s, 3 H), 0.97 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.0, 194.1, 152.7, 146.0, 136.4, 126.2, 122.7, 120.9, 119.9, 119.7, 116.8, 111.2, 52.1, 48.2, 47.4, 44.0, 40.9, 39.5, 35.2, 27.3, 23.2, 22.7, 12.5.
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NNaO2: 372.19398; found: 372.19468.
#
(E)-3,9,9-Trimethyl-2-oxo-1-(2-phenyl-1H-indol-3-yl)-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10b)
Yield: 67 mg (73%); white solid; Rf = 0.17 (EtOAc–hexane, 1:4); mp 215–220 °C.
IR (neat): 3350, 2961, 2931, 2336, 1736, 1681, 1640, 1459, 1374, 1281, 1207, 1168, 1112, 886, 799, 764, 670 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.43 (s, 1 H), 8.05 (br s, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 7.21–7.19 (m, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 6.81 (d, J = 2.5 Hz, 1 H), 6.70–6.67 (m, 1 H), 3.46 (d, J = 4.5 Hz, 1 H), 2.93–2.89 (m, 1 H), 2.65 (t, J = 11.5 Hz, 1 H), 2.30–2.24 (m, 1 H), 2.15–2.11 (m, 2 H), 1.68–1.63 (m, 2 H), 1.41–1.34 (m, 2 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.95 (s, 3 H), 0.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 217.4, 193.1, 151.5, 145.7, 136.5, 135.5, 133.9, 128.9, 128.6, 127.5, 121.8, 119.0, 119.0, 111.1, 109.8, 56.0, 44.8, 43.1, 40.1, 39.0, 38.3, 35.9, 26.6, 24.2, 21.8, 21.6.
HRMS (ESI): m/z [M + Na]+ calcd for C29H31NNaO2: 448.22528; found: 448.21853.
#
(E)-3-(6-Formyl-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbaldehyde (10e)
Yield: 70 mg (71%); white solid; Rf = 0.24 (EtOAc–hexane, 1:4); mp 190–194 °C.
IR (neat): 3351, 2959, 2929, 2872, 1733, 1677, 1611, 1571, 1439, 1392, 1371, 1314, 1283, 1176, 1112, 809, 735 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.23 (br s, 1 H), 9.61 (s, 1 H), 9.08 (s, 1 H), 7.96 (s, 1 H), 7.26 (d, J = 8.5 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 1 H), 6.92 (d, J = 1.5 Hz, 1 H), 6.48–6.44 (m, 1 H), 3.32 (d, J = 4.5 Hz, 1 H), 2.72–2.61 (m, 1 H), 2.51–2.47 (m, 1 H), 2.00–1.96 (m, 1 H), 1.92 (t, J = 5.0 Hz, 1 H), 1.88–1.83 (m, 1 H), 1.83–1.77 (m, 2 H), 1.50–1.44 (m, 1 H), 1.15–1.08 (m, 1 H), 0.65 (s, 3 H), 0.60 (d, J = 7.0 Hz, 3 H), 0.59 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 220.3, 198.7, 197.0, 157.1, 151.1, 145.4, 134.7, 131.7, 130.1, 129.2, 123.5, 119.8, 117.3, 57.1, 53.1, 52.6, 48.9, 45.6, 44.4, 40.3, 31.8, 27.5, 27.2, 17.0.
HRMS (ESI): m/z [M + Na]+ calcd for C24H27NNaO3: 400.18889; found: 400.18302.
#
(E)-3,9,9-Trimethyl-1-(5-nitro-1H-indol-3-yl)-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10f)
Yield: 67 mg (82%); yellow solid; Rf = 0.28 (EtOAc–hexane, 1:4); mp 210–215 °C.
IR (neat): 3324, 2958, 2923, 2852, 1723, 1671, 1624, 1516, 1469, 1373, 1370, 1252, 1205, 1168, 1105, 1047, 811, 732 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.52 (s, 1 H), 8.79 (d, J = 1.5 Hz, 1 H), 8.52 (br s, 1 H), 8.11 (dd, J 1 = 9.0, J 2 = 2.0 Hz, 1 H), 7.36 (d, J = 9.0 Hz, 1 H), 7.04 (s, 1 H), 6.79–6.75 (m, 1 H), 3.64 (d, J = 4.5 Hz, 1 H), 2.99 (dd, J 1 = 7.5, J 2 = 5.5 Hz, 1 H), 2.75 (t, J = 11.5 Hz, 1 H), 2.36–2.30 (m, 1 H), 2.22–2.17 (m, 3 H), 1.81–1.76 (m, 1 H), 1.51–1.41 (m, 2 H), 1.08 (d, J = 7.0 Hz, 3 H), 1.06 (s, 3 H), 0.97 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 214.9, 193.3, 151.7, 146.0, 141.5, 139.8, 125.9, 125.5, 118.8, 117.1, 116.8, 111.7, 52.2, 47.8, 47.4, 43.7, 40.4, 39.2, 35.2, 26.6, 22.3, 22.0, 11.8.
HRMS (ESI): m/z [M + H]+ calcd for C23H26N2HO4: 395.19726; found: 395.19089.
#
(E)-3-(6-Formyl-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulen-1-yl)-1H-indole-5-carbonitrile (10g)
Yield: 38 mg (78%); white solid; Rf = 0.24 (EtOAc–hexane, 1:4); mp 210–214 °C.
IR (neat): 3348, 2961, 2930, 2873, 2220, 1734, 1678, 1640, 1619, 1471, 1439, 1372, 1206, 1168, 1112, 810, 735, 634 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.52 (s, 1 H), 8.58 (br s, 1 H), 8.19 (s, 1 H), 7.42–7.36 (m, 2 H), 7.00 (s, 1 H), 6.79–6.75 (m, 1 H), 3.58 (d, J = 4.5 Hz, 1 H), 3.03–2.97 (m, 2 H), 2.74 (t, J = 11.5 Hz, 1 H), 2.35–2.29 (m, 1 H), 2.22–2.15 (m, 4 H), 1.78–1.73 (m, 1 H), 1.47–1.40 (m, 1 H), 1.07 (d, J = 6.5 Hz, 3 H), 1.04 (s, 3 H), 0.96 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.5, 194.1, 152.5, 146.0, 138.0, 126.2, 125.6, 125.6, 122.7, 120.6, 117.7, 112.1, 103.2, 60.4, 52.3, 47.8, 47.5, 44.0, 40.8, 39.4, 35.3, 27.3, 23.1, 22.6, 21.1, 14.2, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C24H26N2HO2: 375.20743; found: 375.20224.
#
(E)-3,9,9-Trimethyl-1-(5-methyl-1H-indol-3-yl)-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10h)
Yield: 48 mg (62%); white solid; Rf = 0.55 (EtOAc–hexane, 1:4); mp 145–147 °C.
IR (neat): 3400, 2960, 2928, 2871, 1732, 1678, 1640, 1465, 1374, 1267, 1180, 1150, 1111, 1049, 1003, 921, 796, 766, 736 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.01 (br s, 1 H), 9.52 (s, 1 H), 7.54 (d, J = 1.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 2.5 Hz, 1 H), 6.95 (s, 1 H), 6.94 (dd, J 1 = 8.5, J 2 = 1.5 Hz, 1 H), 6.91–6.87 (m, 1 H), 3.60 (d, J = 4.0 Hz, 1 H), 2.95–2.90 (m, 1 H), 2.86–2.83 (m, 2 H), 2.40 (s, 3 H), 2.31–2.29 (m, 2 H), 2.24–2.18 (m, 2 H), 1.88–1.82 (m, 1 H), 1.58–1.50 (m, 1 H), 1.06 (s, 3 H), 1.03–1.01 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 216.0, 194.0, 152.6, 146.0, 134.8, 129.3, 126.5, 124.3, 120.9, 119.3, 116.4, 110.8, 52.1, 48.2, 47.2, 44.0, 40.9, 39.5, 35.2, 27.2, 23.1, 22.7, 21.5, 12.4.
HRMS (ESI): m/z [M + H]+ calcd for C24H29NHO2: 364.22783; found: 364.22223.
#
(E)-1-(5-Methoxy-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10i)
Yield: 39 mg (64%); brown solid; Rf = 0.44 (EtOAc–hexane, 1:4); mp 170–172 °C.
IR (neat): 3383, 2958, 2930, 2872, 1733, 1678, 1638, 1584, 1485, 1457, 1374, 1287, 1214, 1173, 1032, 925, 799, 765, 736, 630 cm–1.
1H NMR (500 MHz, CDCl3): δ = 9.99 (br s, 1 H), 9.52 (s, 1 H), 7.25–7.24 (m, 2 H), 7.14 (d, J = 2.0 Hz, 1 H), 6.91–6.87 (m, 1 H), 6.76 (dd, J 1 = 8.5, J 2 = 2.5 Hz, 1 H), 3.81 (s, 3 H), 3.59 (d, J = 4.5 Hz, 1 H), 2.95–2.91 (m, 1 H), 2.85–2.81 (m, 1 H), 2.42–2.37 (m, 1 H), 2.32–2.28 (m, 2 H), 2.24–2.19 (m, 2 H), 1.87–1.83 (m, 1 H), 1.56–1.50 (m, 1 H), 1.06 (s, 3 H), 1.04–1.02 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 215.1, 193.4, 154.0, 151.9, 145.9, 132.0, 126.8, 122.5, 115.9, 112.0, 101.0, 55.0, 52.3, 48.2, 47.3, 43.8, 40.5, 39.2, 35.1, 26.6, 22.4, 22.1, 11.9.
HRMS (ESI): m/z [M + H]+ calcd for C24H29NHO3: 380.22274; found: 380.21707.
#
(E)-1-(5-Fluoro-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10j)
Yield: 49 mg (74%); white solid; Rf = 0.27 (EtOAc–hexane, 1:4); mp 214–216 °C.
IR (neat): 3367, 2960, 2928, 2872, 1732, 1678, 1640, 1582, 1487, 1457, 1375, 1285, 1207, 1172, 1091, 1014, 937, 855, 798, 764, 737, 620 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.10 (br s, 1 H), 9.37 (s, 1 H), 7.32 (dd, J 1 = 10.0, J 2 = 2.5 Hz, 1 H), 7.22–7.20 (m, 1 H), 7.11 (d, J = 2.0 Hz, 1 H), 6.78–6.74 (m, 2 H), 3.45 (d, J = 4.0 Hz, 1 H), 2.80–2.76 (m, 1 H), 2.27–2.21 (m, 1 H), 2.16–2.13 (m, 2 H), 2.10–2.03 (m, 2 H), 1.74–1.68 (m, 1 H), 1.40–1.33 (m, 1 H), 0.92 (s, 3 H), 0.88–0.87 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 215.5, 193.5, 151.9, 145.9, 133.5, 123.9, 112.3, 112.2, 109.9, 109.7, 104.1, 103.9, 52.4, 48.0, 47.1, 43.7, 40.4, 39.1, 35.2, 26.6, 22.3, 22.0, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C23H26FHNO2: 368.20276; found: 368.19702.
#
(E)-1-(5-Chloro-1H-indol-3-yl)-3,9,9-trimethyl-2-oxo-2,3,3a,4,5,8,9,9a-octahydro-1H-cyclopenta[8]annulene-6-carbaldehyde (10k)
Yield: 59 mg (75%); brown solid; Rf = 0.48 (EtOAc–hexane, 1:4); mp 210–214 °C.
IR (neat): 3347, 2960, 2930, 2872, 1732, 1678, 1625, 1578, 1518, 1470, 1373, 1330, 1108, 902, 815, 739 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.19 (br s, 1 H), 9.37 (s, 1 H), 7.65 (d, J = 2.0 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H), 6.94 (dd, J 1 = 8.5, J 2 = 2.0 Hz, 1 H), 6.77–6.74 (m, 1 H), 3.49 (d, J = 4.5 Hz, 1 H), 2.80–2.76 (m, 1 H), 2.71–2.66 (m, 1 H), 2.26–2.20 (m, 1 H), 2.17–2.15 (m, 1 H), 2.10–2.03 (m, 1 H), 1.75–1.69 (m, 1 H), 1.40–1.33 (m, 1 H), 0.92 (s, 3 H), 0.88–0.87 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 214.9, 193.3, 151.8, 145.9, 135.3, 127.7, 124.3, 123.6, 121.8, 118.8, 116.1, 112.7, 52.3, 47.8, 47.1, 43.7, 40.4, 39.2, 35.1, 26.6, 22.3, 22.0, 11.7.
HRMS (ESI): m/z [M + H]+ calcd for C23H27ClNO2: 384.17321; found: 384.16729.
#
Synthesis of [6.3.0] Fused Ring System 11 from Zerumbenone 9; General Procedure
A mixture of zerumbenone 9 (1.0 equiv), indole 2 (1.0 equiv), and Sc(OTf)3 (5 mol%) in CH3CN (2 mL) as solvent in a Schlenk tube was stirred at 80 °C for 12 h. The completion of the reaction was confirmed by TLC, after which the reaction mixture was concentrated and the crude product was purified by column chromatography (silica gel, 100–200 mesh, hexane–EtOAc), to give 11 as a diastereoisomeric mixture.
#
7-[(1H-Indol-3-yl)methyl]-3-(1H-indol-3-yl)-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione (11a)
Yield: 52 mg (85%); white solid; Rf = 0.33 (EtOAc–hexane, 3:7); mp 123–127 °C.
IR (neat): 3363, 2960, 2926, 1729, 1686, 1569, 1460, 1341, 1288, 1235, 1156, 1100, 892, 793 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.19–8.11 (m, 4 H), 7.78–7.74 (m, 2 H), 7.63–7.58 (m, 1 H), 7.36–7.29 (m, 4 H), 7.19–7.12 (m, 9 H), 7.00–6.93 (m, 4 H), 3.69 (d, J = 4.5 Hz, 1 H), 3.66 (d, J = 4.5 Hz, 1 H), 2.84–2.68 (m, 4 H), 2.60 (d, J = 11.5 Hz, 1 H), 2.45–2.41 (m, 2 H), 2.38–2.34 (m, 5 H), 1.76–1.67 (m, 3 H), 1.54–1.48 (m, 3 H), 1.07–0.99 (m, 16 H).
13C NMR (125 MHz, CDCl3): δ = 217.4, 217.0, 216.2, 215.6, 139.3, 136.6, 136.4, 136.3, 127.5, 127.4, 126.2, 126.2, 122.6, 122.5, 122.0, 121.3, 121.3, 119.8, 119.6, 119.3, 118.8, 116.3, 114.1, 113.6, 112.7, 111.3, 111.3, 56.0, 53.9, 53.8, 53.7, 52.4, 51.3, 51.0, 48.8, 48.7, 48.4, 48.3, 42.2, 41.3, 40.0, 39.8, 34.3, 33.9, 33.2, 33.2, 32.0, 31.2, 31.0, 30.4, 27.1, 21.1, 20.1, 13.2, 12.9.
HRMS (ESI): m/z [M + Na]+ calcd for C31H34N2NaO2: 489.25183; found: 489.24449.
#
3-[(1-(5-Cyano-1H-indol-3-yl)-3,9,9-trimethyl-2,7-dioxodecahydro-1H-cyclopenta[8]annulen-6-yl)methyl]-1H-indole-5-carbonitrile (11d)
Yield: 56 mg (50%); white solid; Rf = 0.28 (EtOAc–hexane, 2:3); mp 145–148 °C.
IR (neat): 3341, 2928, 2219, 1733, 1686, 1618, 1472, 1436, 1365 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.77 (br s, 1 H), 8.65 (br s, 1 H), 8.62 (br s, 1 H), 8.14 (s, 1 H), 8.10 (s, 1 H), 7.96 (s, 1 H), 7.94 (s, 1 H), 7.42–7.36 (m, 8 H), 7.16–7.11 (m, 4 H), 3.65–3.62 (m, 2 H), 2.87–2.83 (m, 1 H), 2.80–2.72 (m, 3 H), 2.65 (d, J = 7.0 Hz, 1 H), 2.38–2.33 (m, 3 H), 2.29–2.18 (m, 4 H), 2.00–1.97 (m, 2 H), 1.61–1.51 (m, 4 H), 1.08–1.03 (m, 11 H), 0.99–0.98 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 216.6, 216.2, 215.0, 214.8, 138.2, 138.0, 137.9, 127.4, 127.3, 126.2, 126.1, 125.5, 125.4, 125.0, 124.8, 124.5, 123.4, 123.3, 120.9, 120.7, 120.6, 117.2, 117.1, 114.6, 114.0, 112.3, 103.0, 102.6, 102.5, 56.0, 54.2, 53.8, 51.8, 51.4, 50.9, 48.9, 48.5, 48.4, 48.3, 42.5, 41.5, 39.6, 39.4, 33.7, 33.2, 31.1, 30.2, 28.2, 27. 3, 21.4, 20.7, 13.1, 13.0.
HRMS (ESI): m/z [M + Na]+ calcd for C33H32N4NaO2: 539.24233; found: 539.24357.
#
3-[(1-(5-Formyl-1H-indol-3-yl)-3,9,9-trimethyl-2,7-dioxodecahydro-1H-cyclopenta[8]annulen-6-yl)methyl]-1H-indole-5-carbaldehyde (11e)
Yield: 40 mg (35%); white solid; Rf = 0.65 (EtOAc–hexane, 2:3); mp 235–240 °C.
IR (neat): 3335, 2923, 2852, 2738, 1732, 1677, 1611, 1576, 1438, 1367, 1313, 1180, 1100 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.06 (s, 1 H), 10.05 (s, 1 H), 10.04 (s, 1 H), 10.04 (s, 1 H), 8.70 (br s, 2 H), 8.57 (br s, 1 H), 8.55 (br s, 1 H), 8.31 (d, J = 10.5 Hz, 2 H), 8.16 (d, J = 12.0 Hz, 2 H), 7.78–7.75 (m, 3 H), 7.46–7.43 (m, 2 H), 7.41–7.39 (m, 2 H), 7.13–7.09 (m, 3 H), 3.72–3.70 (m, 2 H), 2.92–2.87 (m, 1 H), 2.83–2.81 (m, 1 H), 2.79–2.74 (m, 2 H), 2.68 (d, J = 11.5 Hz, 1 H), 2.49–2.37 (m, 5 H), 2.31–2.27 (m, 2 H), 2.02–1.96 (m, 3 H), 1.60–1.54 (m, 4 H), 1.09–1.00 (m, 16 H).
13C NMR (125 MHz, CDCl3): δ = 216.7, 216.3, 215.2, 215.2, 192.3, 140.0, 139.8, 129.8, 129.8, 129.4, 129.3, 127.6, 127.4, 126.3, 126.2, 124.4, 123.3, 122.9, 122.8, 118.3, 118.2, 115.8, 115.1, 112.0, 111.8, 55.9, 54.0, 53.7, 52.0, 51.2, 48.8, 48.5, 48.4, 42.3, 41.4, 39.8, 39.5, 33.3, 31.1, 30.3, 29.7, 28.4, 27.3, 20.6, 20.5, 13.1, 13.0.
HRMS (ESI): m/z [M + H]+ calcd for C33H34N2O4: 545.24166; found: 545.24327.
#
1,4,4-Trimethyl-3-(5-nitro-1H-indol-3-yl)-7-[(5-nitro-1H-indol-3-yl)methyl]octahydro-1H-cyclopenta[8]annulene-2,6-dione (11f)
Yield: 40 mg (56%); yellow solid; Rf = 0.34 (EtOAc–hexane, 3:7); mp 238–245 °C.
IR (neat): 3351, 2922, 2852, 1730, 1686, 1623, 1579, 1516, 1466, 1372, 1330, 1099, 893, 813, 737 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.77 (br s, 2 H), 10.66 (br s, 2 H), 8.67 (d, J = 2.5 Hz, 1 H), 8.65 (d, J = 2.0 Hz, 1 H), 8.46 (d, J = 2.5 Hz, 1 H), 8.45 (d, J = 2.0 Hz, 1 H), 7.92–7.90 (m, 2 H), 7.90–7.89 (m, 2 H), 7.46–7.42 (m, 5 H), 7.36 (d, J = 2.0 Hz, 1 H), 7.30 (d, J = 2.0 Hz, 1 H), 3.72–3.70 (m, 2 H), 2.99–2.94 (m, 1 H), 2.89–2.85 (m, 2 H), 2.50–2.48 (m, 2 H), 2.46–2.44 (m, 1 H), 2.27–2.15 (m, 5 H), 1.80–1.74 (m, 2 H), 1.56–1.44 (m, 3 H), 0.96 (s, 2 H), 0.92–0.90 (m, 11 H), 0.84 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 215.5, 215.3, 214.0, 213.7, 141.4, 141.2, 141.2, 139.9, 139.7, 127.0, 126.0, 125.8, 125.7, 118.6, 118.5, 117.1, 117.0, 116.9, 116.6, 115.7, 115.7, 111.7, 111.6, 56.1, 53.3, 51.5, 50.6, 48.3, 48.2, 48.1, 48.0, 41.4, 39.5, 39.1, 33.1, 30.4, 29.8, 27.9, 26.9, 20.3, 20.0, 12.3, 12.2.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N4NaO6: 579.22198; found: 579.21372.
#
3-(5-Methoxy-1H-indol-3-yl)-7-[(5-methoxy-1H-indol-3-yl)methyl]-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione (11g)
Yield: 62 mg (55%); white solid; Rf = 0.37 (EtOAc–hexane, 1:3); mp 185–189 °C.
IR (neat): 3410, 2925, 2855, 2098, 1643, 1457, 1367, 1291, 1211, 1167, 1098, 1043, 792, 735 cm–1.
1H NMR (500 MHz, CDCl3): δ = 10.04 (br s, 2 H), 9.92 (br s, 2 H), 7.30–7.24 (m, 8 H), 7.16 (dd, J 1 = 17.5, J 2 = 2.5 Hz, 2 H), 7.09 (dd, J 1 = 12.5, J 2 = 2.5 Hz, 2 H), 6.80–6.78 (m, 2 H), 6.78–6.77 (m, 2 H), 3.82 (s, 3 H, OCH3), 3.82 (s, 3 H), 3.81 (d, J = 2.0 Hz, 6 H), 3.65 (d, J = 4.0 Hz, 2 H), 2.88–2.82 (m, 2 H), 2.76–2.72 (m, 1 H), 2.56–2.49 (m, 3 H), 2.38–2.24 (m, 5 H), 2.00–1.81 (m, 4 H), 1.66–1.59 (m, 1 H), 1.55–1.48 (m, 2 H), 1.05–1.02 (m, 15 H), 0.95 (d, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 215.8, 215.5, 214.7, 214.2, 154.0, 153.8, 153.8, 132.0, 132.0, 132.0, 128.1, 128.0, 126.9, 126.9, 123.9, 123.8, 122.7, 122.6, 115.7, 115.6, 112.6, 112.0, 111.9, 111.4, 111.3, 101.1, 100.5, 100.3, 56.0, 55.1, 55.0, 55.0, 53.4, 53.2, 51.9, 50.9, 50.4, 48.7, 48.7, 47.7, 47.6, 41.9, 41.3, 39.6, 39.2, 33.9, 32.6, 30.4, 29.8, 26.8, 20.3, 19.6, 12.2, 12.1.
HRMS (ESI): m/z [M + Na]+ calcd for C33H38N2NaO4: 549.27296; found: 549.26495.
#
1,4,4-Trimethyl-3-(6-methyl-1H-indol-3-yl)-7-[(6-methyl-1H-indol-3-yl)methyl]octahydro-1H-cyclopenta[8]annulene-2,6-dione (11h)
Yield: 61 mg (50%); white solid; Rf = 0.55 (EtOAc–hexane, 1:4); mp 217–225 °C.
IR (neat): 3399, 2961, 2923, 2858, 1730, 1688, 1625, 1456, 1369, 1337, 1241, 1153, 1098, 800 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.92–7.88 (m, 4 H), 7.66–7.62 (m, 2 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.17 (br s, 2 H), 7.12 (d, J = 6.0 Hz, 2 H), 6.99–6.91 (m, 7 H), 3.63 (d, J = 4.5 Hz, 2 H), 2.78–2.70 (m, 4 H), 2.53 (d, J = 12.0 Hz, 1 H), 2.46 (s, 5 H), 2.44–2.43 (m, 5 H), 2.38–2.26 (m, 7 H), 1.93–1.85 (m, 3 H), 1.51–1.44 (m, 3 H), 1.05–1.03 (m, 7 H), 1.02–1.00 (m, 7 H), 0.98 (d, J = 7.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 216.9, 216.5, 215.9, 215.3, 137.0, 136.8, 136.8, 132.5, 132.0, 131.9, 125.4, 125.3, 124.1, 124.1, 121.8, 121.8, 121.7, 121.3, 121.2, 120.4, 119.4, 119.3, 118.5, 118.5, 116.5, 113.6, 112.8, 111.2, 111.1, 111.1, 55.9, 53.9, 53.6. 52.3, 51.3, 51.0, 48.8, 48.8, 48.4, 48.2, 42.1, 41.2, 39.9, 39.8, 34.4, 33.2, 31.2, 30.3, 29.7, 29.2, 27.2, 27.1, 21.7, 21.6, 21.0, 20.0, 13.1, 12.8.
HRMS (ESI): m/z [M + Na]+ calcd for C33H38N2NaO2: 517.28313; found: 517.28496.
#
3-(5-Fluoro-1H-indol-3-yl)-7-[(5-fluoro-1H-indol-3-yl)methyl]-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione (11i)
Yield: 52 mg (53%); gummy brown solid; Rf = 0.44 (EtOAc–hexane, 3:7).
IR (neat): 3361, 3057, 2963, 2927, 1730, 1687, 1627, 1582, 1484, 1457, 1351, 1294, 1236, 1172, 1098, 935 796 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.33 (br s, 1 H), 8.32 (br s, 1 H), 8.23 (br s, 1 H), 8.21 (br s, 1 H), 7.42–7.37 (m, 2 H), 7.25–7.16 (m, 6 H), 7.01 (d, J = 2.0 Hz, 1 H), 6.99–6.98 (m, 2 H), 6.94 (d, J = 2.5 Hz, 1 H), 6.92–6.90 (m, 2 H), 3.56 (d, J = 5.0 Hz, 2 H), 2.79–2.67 (m, 5 H), 2.39–2.23 (m, 6 H), 1.94–1.88 (m, 3 H), 1.51–1.46 (m, 3 H), 1.05–0.98 (m, 16 H).
13C NMR (125 MHz, CDCl3): δ = 217.2, 216.8, 215.7, 158.9, 158.7, 158.7, 157.0, 156.9, 156.8, 133.0, 132.8, 132.7, 127.9, 127.8, 127.7, 126.6, 126.5, 126.5, 124.4, 124.4, 122.9, 122.9, 116.3, 113.8, 113.7, 113.0, 112.9, 112.0, 111.9, 111.1, 110.9, 110.6, 110.5, 110.4, 110.3, 55.9, 53.6, 52.1, 51.0, 48.7, 48.6, 48.6, 48.4, 41.3, 39.8, 39.6, 33.9, 31.2, 30.3, 28.9, 27.2, 20.2, 13.2, 13.0.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N2F2NaO2: 525.23298; found: 525.23212.
#
3-(5-Chloro-1H-indol-3-yl)-7-[(5-chloro-1H-indol-3-yl)methyl]-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione (11j)
Yield: 51 mg (45%); white solid; Rf = 0.20 (EtOAc–hexane, 1:4); mp 232–235 °C.
IR (neat): 3363, 2960, 2926, 1729, 1686, 1569, 1460, 1341, 1288, 1235, 1156, 1100, 892, 793 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.90 (br s, 2 H), 7.88 (br s, 2 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.17 (s, 2 H), 7.12 (s, 2 H), 6.97–6.94 (m, 5 H), 6.91 (d, J = 2.0 Hz, 1 H), 3.63 (d, J = 4.5 Hz, 2 H), 3.34 (d, J = 10.5 Hz, 1 H), 2.76–2.70 (m, 4 H), 2.53 (d, J = 12.0 Hz, 2 H), 2.46 (s, 5 H), 2.43 (s, 6 H), 2.36–2.30 (m, 4 H), 2.20–2.14 (m, 3 H), 1.91–1.85 (m, 2 H), 1.52–1.41 (m, 5 H), 1.05–1.03 (m, 11 H), 1.02 (s, 5 H).
13C NMR (125 MHz, CDCl3): δ = 217.4, 217.1, 216.1, 215.7, 135.0, 134.8, 134.7, 134.5, 128.5, 127.2, 125.4, 125.0, 124.2, 124.1, 122.7, 122.6, 122.2, 122.1, 119.0, 118.9, 118.1, 115.6, 115.6, 112.4, 112.3, 56.0, 52.2, 51.0, 48.5, 48.3, 41.2, 39.7, 33.9, 31.1, 30.9, 29.7, 28.8, 27.1, 20.1, 13.1.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N2Cl2NaO2: 557.17388; found: 557.16589.
#
3-(5-Bromo-1H-indol-3-yl)-7-[(5-bromo-1H-indol-3-yl)methyl]-1,4,4-trimethyloctahydro-1H-cyclopenta[8]annulene-2,6-dione (11k)
Yield: 20 mg (20%); gummy brown mass; Rf = 0.48 (EtOAc–hexane, 3:7).
IR (neat): 3417, 2960, 2926, 1730, 1685, 1614, 1544, 1455, 1399, 1369, 1331, 1236, 1156, 1099, 1051, 894, 801, 736 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.30 (br s, 2 H), 8.21 (br s, 2 H), 7.60–7.56 (m, 2 H), 7.55–7.42 (m, 3 H), 7.40–7.39 (m, 2 H), 7.21–7.19 (m, 4 H), 6.93–6.84 (m, 4 H), 3.59 (d, J = 5.0 Hz, 2 H), 2.81–2.74 (m, 2 H), 2.69–2.65 (m, 3 H), 2.46 (d, J = 12 Hz, 1 H), 2.32 (t, J = 6.0 Hz, 2 H), 2.30–2.22 (m, 3 H), 1.72–1.67 (m, 2 H), 1.53–1.47 (m, 4 H), 1.05–1.04 (m, 5 H), 1.02–0.99 (m, 6 H), 0.97–0.96 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 216.9, 216.5, 215.6, 215.2, 137.3, 137.3, 137.1, 137.0, 129.6, 126.3, 125.2, 125.1, 123.3, 123.1, 123.0, 122.9, 122.7, 121.7, 121.6, 121.0, 120.9, 120.1, 120.0, 118.3, 116.6, 116.6, 116.3, 115.7, 115.7, 115.3, 114.2, 114.2, 114.1, 113.9, 113.1, 55.8, 53.8, 53.7, 52.2, 51.1, 48.6, 48.5, 48.4, 41.2, 39.8, 39.6, 34.0, 31.9, 31.8, 31.2, 31.0, 30.3, 30.0, 29.7, 29.4, 29.3, 28.8, 27.2, 22.7, 21.2, 20.2, 13.2, 12.9.
HRMS (ESI): m/z [M + Na]+ calcd for C31H32N2Br2NaO2: 624.41700; found: 647.07138.
#
#
Acknowledgment
Authors acknowledge Dr. Jubi John for the help rendered during the preparation of the manuscript. The authors also acknowledge Mrs. Saumini Mathew and Mrs. S. Viji of CSIR-NIIST for recording the NMR and HRMS spectra. Thanks are due to Dr. Sunil Varughese, for single-crystal X-ray analysis.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690840.
- Supporting Information
- Cif File
-
References
- 1 Newman DJ, Cragg GM, Snader KM. Nat. Prod. Rep. 2000; 17: 215
- 2 Sneader W. Drug Prototypes and their Exploitation . Wiley; Chichester: 1996
- 3 Buss AD, Cox B, Waigh RD. In Burger’s Medicinal Chemistry & Drug Discovery, 6th ed., Vol. 1. Abraham DJ. Wiley-Interscience; Hoboken: 2003: 847-900
- 4 Swann J, Weatherall M. In Search of a Cure: A History of the Pharmaceutical Industry, Vol. 8. Oxford University Press; Oxford: 1990: 224-225
- 5 Grabley S, Thiericke R. Drug Discovery from Nature. Springer; Berlin: 2000: 3-37
- 6 Mann J. Murder, Magic, and Medicine, 2nd ed. Oxford University Press; Oxford: 1992: 232
- 7 Ding Y, Ding CY, Ye N, Liu Z, Wold EA, Chen H, Wild C, Shen Q, Zhou J. Eur. J. Med. Chem. 2016; 122: 102
- 8a Gopalan G, Prabha B, Joe A, Reshmitha TR, Sherin DR, Abraham B, Sabu M, Manojkumar TK, Radhakrishnan KV, Nisha P. J. Sci. Food Agric. 2019; 99: 2521
- 8b Sasikumar P, Lekshmy K, Sini S, Prabha B, Anil Kumar N, Sivan VV, Jithin MM, Jayamurthy P, Shibi IG, Radhakrishnan KV. J. Ethnopharmacol. 2019; 18: 31222
- 8c Sasikumar P, Sharathna P, Prabha B, Sunil V, Anil Kumar N, Sivan VV, Sherin DR, Suresh E, Manojkumar TK, Radhakrishnan KV. Phytochem. Lett. 2018; 26: 1
- 8d Sasikumar P, Prabha B, Reshmitha TR, Sheeba V, Pradeep AK, Rohit KR, Dhanya BP, Sivan VV, Jithin MM, Anil Kumar N, Shibi IG, Nisha P, Radhakrishnan KV. RSC Adv. 2016; 6: 77075
- 9a Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S. Chem.-Biol. Interact. 2010; 186: 295
- 9b Dai JR, Cardellina JH, McMahon JB, Boyd MR. Nat. Prod. Lett. 1997; 10: 115
- 9c Szabolcs A, Tiszlavicz L, Kaszaki J, Pósa A, Berkó A, Varga IS, Boros I, Szüts V, Lonovics J, Takács T. Pancreas 2007; 35: 249
- 9d Murakami A, Ohigashi H. Int. J. Cancer 2007; 121: 2357
- 9e Murakami A, Miyamoto M, Ohigashi H. Biofactor 2004; 21: 95
- 9f Murakami A, Takahashi M, Jiwajinda MS, Koshimizu K, Ohigashi H. Biosci., Biotechnol., Biochem. 1999; 63: 1811
- 9g Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, Kawabata K, Nakamura Y, Jiwajinda S, Ohigashi H. Int. J. Cancer 2004; 110: 481
- 10a Dev S. Tetrahedron 1960; 8: 171
- 10b Damodaran NP, Dev S. Tetrahedron Lett. 1965; 6: 1977
- 10c Dev S, Anderson JE, Cormier V, Damodaran NP, Roberts JD. J. Am. Chem. Soc. 1968; 90: 1246
- 10d Hall SR, Nimgirawath S, Raston CL, Sittatrakul A, Thadaniti S, Thirasasana N, White AH. Aust. J. Chem. 1981; 34: 2243
- 10e Farnsworth NR, Bunyapraphatsara N. Thai Medicinal Plants Recommended for Primary Health Care System . Medicinal Plants Information Center (Faculty of Pharmacy, Mahidol University); Thailand: 1992: 261
- 10f Sawada S, Yokoi T, Kitayama T. Aroma Res. 2002; 3: 34
- 11 Kitayama T, Yokoi T, Kawai Y, Hill RK, Morita M, Okamoto T, Yamamoto Y, Fokin VV, Sharpless KB, Sawada S. Tetrahedron 2003; 59: 4857
- 12a Matthes HW. D, Luu B, Ourisson G. Tetrahedron 1982; 38: 3129
- 12b Ohe K, Miki K, Yanagi S, Tanaka T, Sawada S, Uemura S. J. Chem. Soc., Perkin Trans. 2000; 1: 3627
- 12c Minassi A, Pollastro F, Chianese G, Caprioglio D, Taglialatela-Scafati O, Appendino G. Angew. Chem. Int. Ed. 2017; 56: 7935
- 12d Joshi BN, Chakravarti KK, Bhattacharyya SC. Tetrahedron 1967; 23: 1251
- 12e Chhabra BR, Kalsi PS, Dhir BS, Shirahama H, Dhillon RS. Indian J. Chem. 1985; 24: 499
- 13 Kitayama T, Okamoto T, Hill RK, Kawai Y, Takahashi S, Yonemori S, Yamamoto Y, Ohe K, Uemura S, Sawada S. J. Org. Chem. 1999; 64: 2667
- 14a Kitayama T, Yamamoto K, Utsumi R, Takatani M, Hill RK, Kawai Y, Sawada S, Okamoto T. Biosci., Biotechnol., Biochem. 2001; 65: 2193
- 14b Kitayama T, Iwabuchi R, Minagawa S, Shiomi F, Cappiello J, Sawada S, Utsumi R, Okamoto T. Bioorg. Med. Chem. Lett. 2004; 14: 5943
- 15a Kitayama T, Masuda T, Sakai K, Imada C, Yonekura Y, Kawai Y. Tetrahedron 2006; 62: 10859
- 15b Kitayama T, Iwabuchi R, Minagawa S, Sawada S, Okumura R, Hoshino K, Cappiello J, Utsumi R. Bioorg. Med. Chem. Lett. 2007; 17: 1098
- 16a Kitayama T, Masuda T, Kawai Y, Hill RK, Takatani M, Sawada S, Okamoto T. Tetrahedron: Asymmetry 2001; 12: 2805
- 16b Kitayama T, Furuya A, Moriyama C, Masuda T, Fushimi S, Yonekura Y, Kubo H, Kawai Y, Sawada S. Tetrahedron: Asymmetry 2006; 17: 2311
- 16c Kitayama T, Nagao R, Masuda T, Hill RK, Morita M, Takatani M, Sawada S, Okamoto T. J. Mol. Catal. B: Enzym. 2002; 17: 75
- 17a Ajish KR, Nayana J, Radhakrishnan KV. Synthesis 2013; 45: 2316
- 17b Ajish KR, Dhanya BP, Nayana J, Priya M, Rani B, Raghu KG, Vineetha VP, Radhakrishnan KV. Tetrahedron Lett. 2014; 55: 665
- 17c Gopalan G, Dhanya BP, Saranya J, Reshmitha TR, Baiju TV, Meenu MT, Nair MS, Nisha P, Radhakrishnan KV. Eur. J. Org. Chem. 2017; 3072
- 17d Dhanya BP, Gopalan G, Reshmitha TR, Saranya J, Sharathna P, Shibi IG, Radhakrishnan KV. New J. Chem. 2017; 41: 6960
- 17e Dhanya BP, Gopalan G, Sasikumar P, Neethu S, Meenu MT, Sharathna P, John J, Varughese S, Sabu M, Dan M, Radhakrishnan KV. Asian J. Org. Chem. 2018; 7: 471
- 18a Kharb R, Sharma PC, Yar MS. J. Enzyme Inhib. Med. Chem. 2011; 26: 1
- 18b Nguyen NT, Dang PH, Yar NX. T, Le TH, Nguyen MT. T. J. Nat. Prod. 2017; 80: 2151
- 19a Kolb HC, Sharpless KB. Drug Discov. Today 2003; 8: 1128
- 19b Brik A, Alexandratos J, Lin YC, Elder JH, Olson A, Wlodawer A, Goodsell DS, Wong CH. ChemBioChem 2005; 6: 1167
- 20 Ackermann L, Potukuchi HK, Landsberg D, Vicente R. Org. Lett. 2008; 10: 3081
- 21 Kitayama T, Nakahira M, Yamasaki K, Inoue H, Imada C, Yonekura Y, Awata M, Takaya H, Kawai Y, Ohnishi K, Murakami A. Tetrahedron 2013; 69: 10152
- 22 Kumar SC, Negi PS, Manjunatha JR, Bettadaiah BK. Food Chem. 2016; 141: 1097
-
References
- 1 Newman DJ, Cragg GM, Snader KM. Nat. Prod. Rep. 2000; 17: 215
- 2 Sneader W. Drug Prototypes and their Exploitation . Wiley; Chichester: 1996
- 3 Buss AD, Cox B, Waigh RD. In Burger’s Medicinal Chemistry & Drug Discovery, 6th ed., Vol. 1. Abraham DJ. Wiley-Interscience; Hoboken: 2003: 847-900
- 4 Swann J, Weatherall M. In Search of a Cure: A History of the Pharmaceutical Industry, Vol. 8. Oxford University Press; Oxford: 1990: 224-225
- 5 Grabley S, Thiericke R. Drug Discovery from Nature. Springer; Berlin: 2000: 3-37
- 6 Mann J. Murder, Magic, and Medicine, 2nd ed. Oxford University Press; Oxford: 1992: 232
- 7 Ding Y, Ding CY, Ye N, Liu Z, Wold EA, Chen H, Wild C, Shen Q, Zhou J. Eur. J. Med. Chem. 2016; 122: 102
- 8a Gopalan G, Prabha B, Joe A, Reshmitha TR, Sherin DR, Abraham B, Sabu M, Manojkumar TK, Radhakrishnan KV, Nisha P. J. Sci. Food Agric. 2019; 99: 2521
- 8b Sasikumar P, Lekshmy K, Sini S, Prabha B, Anil Kumar N, Sivan VV, Jithin MM, Jayamurthy P, Shibi IG, Radhakrishnan KV. J. Ethnopharmacol. 2019; 18: 31222
- 8c Sasikumar P, Sharathna P, Prabha B, Sunil V, Anil Kumar N, Sivan VV, Sherin DR, Suresh E, Manojkumar TK, Radhakrishnan KV. Phytochem. Lett. 2018; 26: 1
- 8d Sasikumar P, Prabha B, Reshmitha TR, Sheeba V, Pradeep AK, Rohit KR, Dhanya BP, Sivan VV, Jithin MM, Anil Kumar N, Shibi IG, Nisha P, Radhakrishnan KV. RSC Adv. 2016; 6: 77075
- 9a Taha MM, Abdul AB, Abdullah R, Ibrahim TA, Abdelwahab SI, Mohan S. Chem.-Biol. Interact. 2010; 186: 295
- 9b Dai JR, Cardellina JH, McMahon JB, Boyd MR. Nat. Prod. Lett. 1997; 10: 115
- 9c Szabolcs A, Tiszlavicz L, Kaszaki J, Pósa A, Berkó A, Varga IS, Boros I, Szüts V, Lonovics J, Takács T. Pancreas 2007; 35: 249
- 9d Murakami A, Ohigashi H. Int. J. Cancer 2007; 121: 2357
- 9e Murakami A, Miyamoto M, Ohigashi H. Biofactor 2004; 21: 95
- 9f Murakami A, Takahashi M, Jiwajinda MS, Koshimizu K, Ohigashi H. Biosci., Biotechnol., Biochem. 1999; 63: 1811
- 9g Murakami A, Tanaka T, Lee JY, Surh YJ, Kim HW, Kawabata K, Nakamura Y, Jiwajinda S, Ohigashi H. Int. J. Cancer 2004; 110: 481
- 10a Dev S. Tetrahedron 1960; 8: 171
- 10b Damodaran NP, Dev S. Tetrahedron Lett. 1965; 6: 1977
- 10c Dev S, Anderson JE, Cormier V, Damodaran NP, Roberts JD. J. Am. Chem. Soc. 1968; 90: 1246
- 10d Hall SR, Nimgirawath S, Raston CL, Sittatrakul A, Thadaniti S, Thirasasana N, White AH. Aust. J. Chem. 1981; 34: 2243
- 10e Farnsworth NR, Bunyapraphatsara N. Thai Medicinal Plants Recommended for Primary Health Care System . Medicinal Plants Information Center (Faculty of Pharmacy, Mahidol University); Thailand: 1992: 261
- 10f Sawada S, Yokoi T, Kitayama T. Aroma Res. 2002; 3: 34
- 11 Kitayama T, Yokoi T, Kawai Y, Hill RK, Morita M, Okamoto T, Yamamoto Y, Fokin VV, Sharpless KB, Sawada S. Tetrahedron 2003; 59: 4857
- 12a Matthes HW. D, Luu B, Ourisson G. Tetrahedron 1982; 38: 3129
- 12b Ohe K, Miki K, Yanagi S, Tanaka T, Sawada S, Uemura S. J. Chem. Soc., Perkin Trans. 2000; 1: 3627
- 12c Minassi A, Pollastro F, Chianese G, Caprioglio D, Taglialatela-Scafati O, Appendino G. Angew. Chem. Int. Ed. 2017; 56: 7935
- 12d Joshi BN, Chakravarti KK, Bhattacharyya SC. Tetrahedron 1967; 23: 1251
- 12e Chhabra BR, Kalsi PS, Dhir BS, Shirahama H, Dhillon RS. Indian J. Chem. 1985; 24: 499
- 13 Kitayama T, Okamoto T, Hill RK, Kawai Y, Takahashi S, Yonemori S, Yamamoto Y, Ohe K, Uemura S, Sawada S. J. Org. Chem. 1999; 64: 2667
- 14a Kitayama T, Yamamoto K, Utsumi R, Takatani M, Hill RK, Kawai Y, Sawada S, Okamoto T. Biosci., Biotechnol., Biochem. 2001; 65: 2193
- 14b Kitayama T, Iwabuchi R, Minagawa S, Shiomi F, Cappiello J, Sawada S, Utsumi R, Okamoto T. Bioorg. Med. Chem. Lett. 2004; 14: 5943
- 15a Kitayama T, Masuda T, Sakai K, Imada C, Yonekura Y, Kawai Y. Tetrahedron 2006; 62: 10859
- 15b Kitayama T, Iwabuchi R, Minagawa S, Sawada S, Okumura R, Hoshino K, Cappiello J, Utsumi R. Bioorg. Med. Chem. Lett. 2007; 17: 1098
- 16a Kitayama T, Masuda T, Kawai Y, Hill RK, Takatani M, Sawada S, Okamoto T. Tetrahedron: Asymmetry 2001; 12: 2805
- 16b Kitayama T, Furuya A, Moriyama C, Masuda T, Fushimi S, Yonekura Y, Kubo H, Kawai Y, Sawada S. Tetrahedron: Asymmetry 2006; 17: 2311
- 16c Kitayama T, Nagao R, Masuda T, Hill RK, Morita M, Takatani M, Sawada S, Okamoto T. J. Mol. Catal. B: Enzym. 2002; 17: 75
- 17a Ajish KR, Nayana J, Radhakrishnan KV. Synthesis 2013; 45: 2316
- 17b Ajish KR, Dhanya BP, Nayana J, Priya M, Rani B, Raghu KG, Vineetha VP, Radhakrishnan KV. Tetrahedron Lett. 2014; 55: 665
- 17c Gopalan G, Dhanya BP, Saranya J, Reshmitha TR, Baiju TV, Meenu MT, Nair MS, Nisha P, Radhakrishnan KV. Eur. J. Org. Chem. 2017; 3072
- 17d Dhanya BP, Gopalan G, Reshmitha TR, Saranya J, Sharathna P, Shibi IG, Radhakrishnan KV. New J. Chem. 2017; 41: 6960
- 17e Dhanya BP, Gopalan G, Sasikumar P, Neethu S, Meenu MT, Sharathna P, John J, Varughese S, Sabu M, Dan M, Radhakrishnan KV. Asian J. Org. Chem. 2018; 7: 471
- 18a Kharb R, Sharma PC, Yar MS. J. Enzyme Inhib. Med. Chem. 2011; 26: 1
- 18b Nguyen NT, Dang PH, Yar NX. T, Le TH, Nguyen MT. T. J. Nat. Prod. 2017; 80: 2151
- 19a Kolb HC, Sharpless KB. Drug Discov. Today 2003; 8: 1128
- 19b Brik A, Alexandratos J, Lin YC, Elder JH, Olson A, Wlodawer A, Goodsell DS, Wong CH. ChemBioChem 2005; 6: 1167
- 20 Ackermann L, Potukuchi HK, Landsberg D, Vicente R. Org. Lett. 2008; 10: 3081
- 21 Kitayama T, Nakahira M, Yamasaki K, Inoue H, Imada C, Yonekura Y, Awata M, Takaya H, Kawai Y, Ohnishi K, Murakami A. Tetrahedron 2013; 69: 10152
- 22 Kumar SC, Negi PS, Manjunatha JR, Bettadaiah BK. Food Chem. 2016; 141: 1097
