Accessing Polycyclic Terpenoids from Zerumbone via Lewis Acid Catalyzed Synthetic Strategies

Key words

zerumbone - zerumbone epoxide - zerumbal - zerumbenone - Lewis acid catalysis - cyclization - polycyclic terpenoids

Natural-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]

Scheme 1 Epoxidation of zerumbone

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.

Scheme 2 Lewis acid catalyzed transformation of zerumbone epoxide 1

Table 1 Optimization of Lewis Acid Catalyzed Transformation of Zerumbone Epoxide 1 with Indole^a

Entry	Lewis acid	Solvent	Temp (°C)	Yield (%)b
				3a	3a′
1	Yb(OTf)3	CH3CN	RT	NR	NR
2	Yb(OTf)3	CH3CN	80	29	5
3	Sc(OTf)3	CH3CN	80	65	25
4	In(OTf)3	CH3CN	80	29	trace
5	Cu(OTf)2	CH3CN	80	40	trace
6	Hf(OTf)4	CH3CN	80	40	10
7	La(OTf)3	CH3CN	80	32	trace
8	Zn(OTf)2	CH3CN	80	trace	trace
9	Sn(OTf)2	CH3CN	80	32	trace
10	Sn(OTf)2	DMF	153	trace	trace
11	Sn(OTf)2	THF	66	32	trace
12	Sn(OTf)2	DCE	83	32	trace
13	Sn(OTf)2	toluene	110	38	trace

^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.

Table 2 Generality of Lewis Acid Catalyzed Transformation of Zerumbone Epoxide 1 with Indoles 2 ^a

Entry	R1	R2	Products		Yield (%)b
					3	3′
1	H	H	3a	3a′	65	25
2	H	5-CH3	3b	3b′	33	22
3	H	5-Br	3c	3c′	27	23
4	H	5-NO2	3d	3d′	32	20
5	H	5-CHO	3e	3e′	31	20
6	H	5-CN	3f	3f′	31	11
7	H	5-F	3g	3g′	20	15
8	H	5-OH	3h	3h′	NR	NR
9	H	5-NH2	3i	3i′	NR	NR
10	H	5-OCH3	3j	3j′	35	20
11	H	7-CH3	3k	3k′	37	15
12	H	6-CH3	3l	3l′	34	13
13	H	5-Cl	3m	3m′	25	18
14	2-Ph	H	3n	3n′	25	23
15	2-CHO	H	3o	3o′	NR	NR
16	2-COOH	H	3p	3p′	NR	NR
17	3-CH3	H	3q	3q′	NR	NR

^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.

Scheme 3 CuAAC of zerumbone azide 4a with phenylacetylene (5a)

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).

Table 3 Substrate Scope of CuAAC of Zerumbone Azide 4a with Alkynes^a

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).

Table 4 Optimization of Lewis Acid Catalyzed Transformation of Triazole­-Appended Zerumbone 6a with Indole

Entry	Lewis acid	Solvent	Temp (°C)	Yield (%)b
1	Sc(OTf)3	CH3CN	RT	NR
2	Sc(OTf)3	CH3CN	80	38
3	In(OTf)3	CH3CN	80	45
4	Cu(OTf)2	CH3CN	80	NR
5	Hf(OTf)4	CH3CN	80	trace
6	La(OTf)3	CH3CN	80	NR
7	Zn(OTf)2	CH3CN	80	23
8	Yb(OTf)3	CH3CN	80	38
9	Ag(OTf)	CH3CN	80	NR
10	AlCl3	CH3CN	80	50
11	AlCl3	DMF	153	trace
12	AlCl3	THF	66	NR
13	AlCl3	DCE	83.5	NR
14	AlCl3	toluene	110	NR

^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.

Table 5 Scope of Lewis Acid Catalyzed Transformation of Triazole-Appended­ Zerumbone 6a with Indoles 2 ^a

Entry	R	Product	Yield (%)b
1	H	7a	50
2	5-CH3	7b	30
3	5-Br	7c	43
4	5-NO2	7d	39
5	5-CHO	7e	32
6	5-OCH3	7f	40
7	7-CH3	7g	39
8	6-CH3	7h	41
9	5-Cl	7i	37
10	5-F	7j	35
11	5-CN	7k	33
12	5-NH2	7l	NR
13	5-OH	7m	NR

^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.

Scheme 4 Allylic oxidation of zerumbone

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.

Scheme 5 Lewis acid catalyzed interrupted Nazarov cyclization of zerumbal 8 with indole

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.

Table 6 Optimization of Lewis Acid Catalyzed Transformation of Zerumbal 8 with Indole^a

Entry	Lewis acid	Solvent	Temp (°C)	Yield (%)b
1	Sc(OTf)3	CH3CN	RT	44
2	Sc(OTf)3	CH3CN	80	20
3	In(OTf)3	CH3CN	RT	81
4	Cu(OTf)2	CH3CN	RT	trace
5	Fe(OTf)3	CH3CN	RT	trace
6	La(OTf)3	CH3CN	RT	NR
7	Zn(OTf)2	CH3CN	RT	NR
8	Yb(OTf)3	CH3CN	RT	trace
9	AlCl3	CH3CN	RT	80
10	BF3·OEt2	CH3CN	RT	NR
11	In(OTf)3	CH3CN	80	78
12	In(OTf)3	DCE	RT	trace
13	In(OTf)3	DCE	80	75
14	In(OTf)3	THF	RT	trace
15	In(OTf)3	DMSO	RT	NR
16	In(OTf)3	DCE/toluene	RT	trace

^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]).

Table 7 Scope of Lewis Acid Catalyzed Transformation of Zerumbal 8 with Indoles 2 ^a

Entry	R1	R2	Product	Yield (%)b
1	H	H	10a	81
2	2-Ph	H	10b	73
3	2-CHO	H	10c	NR
4	3-CHO	H	10d	NR
5	H	5-CHO	10e	71
6	H	5-NO2	10f	82
7	H	5-CN	10g	78
8	H	5-CH3	10h	62
9	H	5-OCH3	10i	64
10	H	5-F	10j	74
11	H	5-Cl	10k	75
12	H	5-NH2	10l	NR
13	H	5-OH	10m	NR
14	H	6-CH3	10n	63

^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.

Figure 1 Single-crystal X-ray crystal structure of compound 10g

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]).

Scheme 6 Lewis acid catalyzed interrupted Nazarov cyclization of zerumbenone 9 with indole

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.

Table 8 Optimization Studies of Lewis Acid Catalyzed Interrupted Nazarov Cyclization of Zerumbenone 9 with Indole^a

Entry	Lewis acid	Solvent	Temp (°C)	Yield (%)b,c
1	Sc(OTf)3	CH3CN	RT	NR
2	Sc(OTf)3	CH3CN	80	85
3	AlCl3	CH3CN	RT	NR
4	AlCl3	CH3CN	80	65
5	In(OTf)3	CH3CN	80	79
6	Fe(OTf)3	CH3CN	80	73
7	La(OTf)3	CH3CN	80	66
8	Zn(OTf)2	CH3CN	80	80
9	BF3·OEt2	CH3CN	80	NR
10	Sc(OTf)3	DCE	80	60
11	Sc(OTf)3	THF	80	trace
12	Sc(OTf)3	DMSO	80	NR
13	Sc(OTf)3	toluene	80	NR
14	Sc(OTf)3	CH3CN	RT	NR

^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).

Table 9 Scope and Generality of Lewis Acid Catalyzed Interrupted Nazarov Cyclization of Zerumbenone 9 with Indoles^a

Entry	R1	R2	Product	Yield (%)b,c
1	H	H	11a	85
2	2-Ph	H	11b	trace
3	2-COOH	H	11c	NR
4	H	5-CN	11d	50
5	H	5-CHO	11e	35
6	H	5-NO2	11f	56
7	H	5-OCH3	11g	55
8	H	5-CH3	11h	50
9	H	5-F	11i	53
10	H	5-Cl	11j	45
11	H	5-Br	11k	20
12	H	5-NH2	11l	NR
13	H	5-OH	11m	NR

^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.

Scheme 7 Plausible mechanism for Lewis acid catalyzed transannular cyclization of zerumbone epoxide

Scheme 8 Plausible mechanism for Lewis acid catalyzed transannular cyclization of zerumbal and zerumbenone

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 (CDCl_3­, 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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: R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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; R_f = 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.

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