One-pot biomimetic total synthesis of yuehchukene via the organocatalytic alkylation–cyclization process of a sterically encumbered α-alkyl enal

Abstract

A concise synthesis of yuehchukene has been achieved using organocatalytic Friedel–Crafts alkylation of indole to a sterically encumbered α-alkyl enal as the key step. A racemization process during the subsequent cyclization steps of the conjugate adduct to yuehchukene was observed.

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Introduction

(±)-Yuehchukene (1a), a unique dimeric indole alkaloid, has been isolated as a racemate from the roots of Murraya paniculata (L.) Jack and other related Murraya species.¹ Yuehchukene displays interesting anti-implantation activity in rats and hamsters. Due to its scarcity from natural sources, the total synthesis of this non-estrogenoid natural product has attracted much attention over recent decades. An interesting biomimetic synthesis of yuehchukene was achieved by Cheng and coworkers.² The synthetic strategy was based on the dimerization of 3-isoprenylindole, prepared from indole-3-carbaldehyde in 3 steps in 48% yield, via the intermolecular Diels–Alder cycloaddition to give yuehchukene in 4.7% overall yield.³ Later, this methodology was improved by several groups and applied in the synthesis of yuehchukene and its derivatives.⁴ Other total syntheses or approaches with organometallic reagents were also revealed, but with many reaction steps and low overall yield.⁵

Since (±)-yuehchukene occurs in nature as a racemate, at least two questions arise: (1) why do both enantiomers form in the plant? and (2) which enantiomer of yuehchukene is responsible for the biological activity? For the first question, the answer may rely on the fact that it undergoes an achiral biosynthetic pathway (intermediate) or via an achiral catalysis. For answering the second question, Ho and coworkers examined the anti-implantation activity of S-(−)- and R-(+)-camphor–yuehchukene in rats (Fig. 1).⁶ In their study, (±)-yuehchukene and R-(+)-camphor–yuehchukene were equipotent for anti-implantation, while the S-(−)-camphor–yuehchukene was almost inactive. A molecular modeling study to ascertain the isosterism of camphor–yuehchukene and yuehchukene was attempted.⁷ However, yuehchukene and camphor–yuehchukene differ in the numbers of chiral centers, since they have different scaffolds and are different compounds;⁸ the certain answer for the active enantiomer of yuehchukene remains undetermined.

Fig. 1 Select examples of yuehchukene and its derivatives.

Organocatalyzed asymmetric Michael reactions of α,β-unsaturated aldehydes have attracted much attention in the past decade and have undergone compelling advances.⁹ Nevertheless, most examples have conducted the reactions with β-alkyl-α,β-unsaturated aldehydes, yet the organocatalyzed conjugate additions with α-alkyl-α,β-unsaturated aldehydes are relatively rare due to the inherent difficulty in generating the sterically congested reaction intermediate (Scheme 1).¹⁰ Consequently, the conjugate additions to α-alkyl-α,β-unsaturated aldehydes have also been lacking and remain a compelling subject of exploration. Moreover, to the best of our knowledge, organocatalyzed asymmetric conjugate addition of α-tert-butyl-α,β-unsaturated aldehydes has not been realized. It is notable that such sterically encumbered tert-butyl structures as an α-substituent on the α,β-unsaturated aldehyde system should dramatically hamper the conjugate addition reaction due to the difficulties in activating the congested aldehyde group.

Scheme 1 Organocatalyzed asymmetric conjugate additions.

Bearing in mind the aforementioned background and in an effort to extend our general interest in organocatalytic asymmetric annulations,^11,12 we envisioned a sequence of organocatalytic reactions¹³ that might provide a useful protocol for the synthesis of yuehchukene (Scheme 1). Retrosynthetic disconnection of yuehchukene by Friedel–Craft transforms led to the indolecarbaldehyde derivative (Scheme 2). Subsequently, Michael transform disconnection of the derivative would provide another indole molecule and a commercially available 4,6,6-trimethylcyclohexa-1,3-dienecarbaldehyde. Alternatively, the commercially available 1,3-dienecarbaldehyde could be prepared from the dimerization of 3-methylbut-2-enal with L-pro or sodium hydride.¹⁴ In other words, yuehchukene, the structurally complex compound, could simply be constructed from two molecules of 3-methylbut-2-enal¹⁵ and two molecules of indoles,¹⁶ which are both naturally occurring compounds!

Scheme 2 Retrosynthetic analysis of yuehchukene (1a).

Results and discussion

At the outset of exploring feasibility, a Friedel–Crafts conjugate addition of dienecarbaldehyde (2) and indole (3a) was screened with a variety of primary amine organocatalysts (I–IV, Table 1) and trifluoroacetic acid (TFA) to obtain the conjugate addition adduct 4a (Table 1, entries 1–5). The best result was obtained in the reaction of two equivalents of 2 and indole (3a) with cat. IV–TFA (40 mol%) in CH₂Cl₂ at ambient temperature for 8 days, affording 22% yield of the Michael adduct 4a with a ratio of 86 : 14 for trans/cis; a 51% ee was observed for the adduct trans-4a (Table 1, entry 4). Notably, without the acid additive, the reaction provided no production of 4a (Table 1, entry 5). Several acid additives (A1–A12, Table 1) were screened with the catalyst IV¹⁷ in the reaction (Table 1, entries 6–17), and the optimum result was attained under the condition with (S)-A11 to give 26% of the product (trans/cis = 73 : 27) with 60% ee of the trans adduct (Table 1, entry 16). Unfortunately, the reaction with Akiyama catalyst, A12,¹⁸ did not improve the yield but yielded fewer products with recovery of ∼80% starting indole 3a, (Table 1, entry 17). The reaction with (S)-A11 in the absence of amine catalyst was completed in 5 days and afforded 20% yield of 4a and other complicated mixtures (Table 1, entry 18). The same reaction in various solvents was screened for optimization with cat. IV–TFA, e.g., toluene, CHCl₃, EtOAc, 1,4-dioxane, THF, 1,2-DCE, and i-PrOH (Table 1, entries 19–25). The reaction in ethyl acetate gave the highest enantioselective trans-4a, 56% ee, while the reaction in CHCl₃ provided the highest yield, 24% (Table 1, entries 21 and 20). Consequently, the reaction was tested with cat. IV/(S)-A11 in the combination solvent system (CH₂Cl₂/EtOAc), and the enantioselectivity of trans-4a was increased to 78% ee, which was further increased to 88% ee for the reaction under a more dilute condition, from 0.5 M to 0.35 M, and with use of the CHCl₃–EtOAc solvent system (Table 1, entries 26 and 27). Lowering the additive (S)-A11 loading to 20 mol%, increased the enantioselectivity of trans-4a to 93%, but with less yield, 11% (Table 1, entry 28). The results implied that with the lesser amount of acid, the reactions were slower but afforded the product with higher ee. Using high loading of IV/(S)-A11 (40 mol% each), the reaction further increased the ee to 96%, (Table 1, entry 29). The reaction was facilitated under microwave irradiation at 80 °C to give 24% yield of 4a in ca. 15 h, but with less ee (Table 1, entry 30).

Table 1 Screening of the catalysts, solvents and reaction conditions for the domino reaction^a

Entry	Cat./additive	Solvent	Time (days)	Yield^b (%)	dr^c anti/syn	ee^d (%)
a Unless otherwise noted, the reactions were performed with catalyst (20 mol%)–additive (40 mol%) in 0.5 M of 3a with a ratio 2/1 of 2/3a at ∼25 °C.b Isolated yields of 4a.c Determined by ^1H NMR of crude product after a short pad of silica gel chromatography.d ee of trans-4, determined by HPLC with a chiral column (Chiralpack IC).e Indole was consumed, along with small amount of 1 and other complicate mixtures.f 0.35 M of 3a was used.g 40% yield based on the recovered 3a.h Catalyst (20 mol%)–additive (20 mol%).i 22% yield based on the recovered SM.j 0.25 M of 3a was used.k Catalyst (40 mol%)–additive (40 mol%).l Reaction under microwave irradiation at 80 °C.m No amine catalyst, only Brønsted acid (S)-A11 (20 mol%), nd = not determined, na = not available.
1	I/A1	CH2Cl2	15	13	85/15	11
2	II/A1	CH2Cl2	20	∼0	na	na
3	III/A1	CH2Cl2	11	13	85/15	−32
4	IV/A1	CH2Cl2	8	22	86/14	51
5	IV/-	CH2Cl2	15	∼0	na	na
6	IV/A2	CH2Cl2	15	24	84/16	49
7	IV/A3	CH2Cl2	15	∼0	na	na
8	IV/A4	CH2Cl2	15	∼5	nd	nd
9	IV/A5	CH2Cl2	15	∼5	nd	nd
10	IV/A6	CH2Cl2	15	26	80/20	44
11	IV/A7	CH2Cl2	15	15	81/19	58
12	IV/A8	CH2Cl2	15	∼0	na	na
13	IV/A9	CH2Cl2	15	∼5	nd	nd
14	IV/A10	CH2Cl2	15	15	25/75	38
15	IV/(R)-A11	CH2Cl2	15	24	69/31	57
16	IV/(S)-A11	CH2Cl2	15	26	73/27	60
17	IV/A12	CH2Cl2	20	∼5	nd	nd
18	(S)-A11^m	CH2Cl2	5	20^e	nd	∼0
19	IV/A1	Toluene	15	19	92/8	30
20	IV/A1	CHCl3	6	24	85/15	32
21	IV/A1	EtOAc	15	15	81/19	56
22	IV/A1	1,4-Dioxane	15	15	84/16	51
23	IV/A1	THF	15	10	86/14	47
24	IV/A1	1,2-DCE	12	15	88/12	23
25	IV/A1	i-PrOH	13	22	na	0
26	IV/(S)-A11	CH2Cl2/EtOAc	15	19	52/48	78
27^f	IV/(S)-A11	CHCl3/EtOAc	15	25^g	63/37	88
28^h	IV/(S)-A11	CHCl3/EtOAc	15	11^i	70/30	93
29^j^,^k	IV/(S)-A11	CHCl3/EtOAc	15	10	70/30	96
30^f^,^l^,^h	IV/(S)-A11	CHCl3/EtOAc	0.63	24	88/12	63

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Based on the study in Table 1, it appeared that amine catalyst loading had no important effect on catalytic activity or on stereoselectivity. However, an acid co-catalyst played an important role in catalysis. The reaction with strong acids or with the amine catalyst in conjunction with an excess amount of acid accelerated the reaction to give higher yield with lower ee. For example, the reaction with the lesser amount of acid A11 was slower but afforded the product with high ee, (e.g., IV (20 mol%)–A11 (20 mol%), Table 1, entry 28). In contrast, in the reaction with a larger amount of acid A11, the reactions were faster but afforded the product with less ee, (e.g., IV (20 mol%)–A11 (40 mol%), Table 1, entry 26.) In addition, in the reaction with acid A12, yuehchukene was observed as the major product with a tiny amount of 4a, (Table 3, entry 4, vide supra).

With the optimized conditions in hand (Table 1, entries 28 and 29), the Michael reaction protocol was applied in the reaction with some indoles 3 and aldehyde 2, and the results were promising, with high enantioselectivities (Scheme 3). Apparently, with a lesser amount of acid (A11), (Method B), the reactions gave higher enantioselectivities but were slower, with recovery of ca. 50% of the starting indoles, after 15 day reaction, along with some complicated mixtures of products.

Scheme 3 Synthesis of the Michael adducts (4): (a) unless otherwise noted, the reactions were performed with catalyst–additive in 0.35 M of 3 with a ratio 2/1 of 2/3 for 15 days. (b) Isolated yields of 4. (c) Determined by HPLC with a chiral column (Chiralpack IC) for major compound, trans-4. (d) Determined by ¹H NMR of crude reaction mixture, after a short pad of silica-gel flash column chromatography to remove excess of non-polar aldehyde 2. (e) The reaction was slower; nearly 50% of indole was recovered after 15 days reaction. (f) Determined by HPLC with a chiral column (Chiralpack IA) for major compound, trans-4e.

Method A: cat.-IV (20 mol%), (S)-A11 (40 mol%), CHCl₃/EtOAc (1 : 1), ∼25 °C, 15 days.

Method B: cat.-IV (20 mol%), (S)-A11 (20 mol%), CHCl₃/EtOAc (1 : 1), ∼25 °C, 15 days.

The structure of (−)-trans-4e was ascertained by single crystal X-ray analysis (Fig. 2). Unfortunately, the X-ray crystal data of (−)-4e was not sufficient to determine the absolute configuration. The absolute configuration of these Friedel–Crafts alkylation adducts was determined to be (1S, 2R) by means of a series of calculations and comparison of the optical rotation data. The calculation of the optical rotation of (−)-trans-4a was carried out at the TDDFT/B3LYP/6-31G(d,p) level, leading to the values of −119.4. The calculated value of (−)-trans-4a was accurately predicted to have the negative sign and was close to the experimental optical rotation data, −108.5.¹⁹

Fig. 2 ORTEP diagram of the X-ray crystal structure of (−)-trans-4e: C, gray; O, red, N, blue.

Subsequently, alkylation–cyclization of adduct 4a (93% ee) toward yuehchukene (1a) was conducted by treatment with 1.5 equivalent of indole (3a) and (S)-camphor sulfonic acid, (S)-A10, in CH₂Cl₂ at ambient temperature for 10 days to give 36% yield of yuehchukene (1a), and recovery of ca. 40% of 4a. Surprisingly, the yuehchukene obtained had ∼0% ee, and the recovered 4a had 47% ee (Table 2, entry 1)! A trans/cis isomerization process was expected to occur for transforming the trans-4a to cis-1a. However, we expected at least one of the chiral centers in 4a to remain intact during the isomerization process to afford the product 1a with the retention of the enantiomeric excess. To shed some light on the racemization process, a sample of 4a with 60% ee was treated with the above reaction conditions in the absence of indole 3a for 6 days, resulting in recovery of 56% ee of 4a (Table 2, entry 2). This result indicated that the racemization process had mainly occurred during the stepwise alkylation–cyclization process, but the outcome did not arise from the self-racemization of 4a. Treatment of 4a and 3a with Akiyama catalyst, (S)-A12, in CH₂Cl₂ for 15 days provided 73% yield of yuehchukene (1a), with 21% ee. Alternatively, the reaction with (R)-A12 rendered 52% yield of 1a with 29% ee (Table 2, entries 3–4). Since the acid cyclization of enantioenriched 4a led to the racemization and provide the racemate 1a, it would be interesting to explore the feasibility of a one-pot operation of the successive Friedel–Crafts alkylation–cyclization reaction of 2 and 3a to 1a.

Table 2 Efforts towards cyclization reaction^a

Entry	ee 4a (%)	BA	Time (day)	Yield^b 1a (%)	ee^c 1a (%)	ee^d 4a (%)
a Unless otherwise noted, the reactions were performed with a ratio of 1/1.5 of 4a/3a at ambient temperature.b Isolated yields of 1.c Determined by HPLC with a chiral column (Chiralpack IA) for compound 1.d Determined by HPLC with a chiral column (Chiralpack IC) for recovered compound 4a.e Recovered 40% yield of 4a.f Indole (3a) was absent.g ∼0% recovered yield of 4a. na = not available.
1	93	(S)-A10	10	36	∼0	47^e
2^f	60	(S)-A10	6	—	—	56
3	84	(S)-A12	15	73	21	na^g
4	84	(R)-A12	15	52	29	na^g

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Reaction of 2 and 3a with 20 mol% of (R)-A12 in CH₂Cl₂ at ambient temperature for 15 days provided 17% yield of adduct 4a and 26% yield of 1a (with 5% ee, nearly racemic), (Table 3, entry 1). The same reaction conditions in toluene provided higher yield of 1a (35% yield) but nearly as a racemate, (Table 3, entry 2). Alternatively, the reactions proceeded by treatment with TFA in CHCl₃ or toluene at 60 °C for 24 h to afford 1a, in 13% and 16% yield, respectively, along with other complicated mixtures (Table 3, entries 3 and 4). The methodology was applied in the synthesis of yuehchukene derivatives 1b and 1c (Table 3, entries 5 and 6).

Table 3 One-pot synthesis of 1a from aldehyde 2 and indole (3)^a

Entry	3	Cat. (mol%)	Solvent	T (°C)	Time	Yield^b 4 (%)	Yield^b 1 (%)	ee^c 1 (%)
a Unless otherwise noted, the reactions were performed with catalyst in 0.2 M of 2.b Isolated yields of 1 or 4 along with possible side product X (∼15%) was observed.c Determined by HPLC with a chiral column (Chiralpack IA) for compound 1.d 1 equiv. of 2 and 2.5 equiv. of 3.e 1 equiv. of 2 and 2 equiv. of 3. rt = room temperature; na = not available.
1^d	3a R = H	(R)-A12 (20)	CH2Cl2	rt	15 days	17	26	5
2^d	3a R = H	(R)-A12 (20)	Toluene	rt	15 days	4	35	3
3^e	3a R = H	A1 (50)	CHCl3	60	24 h	∼0	13	na
4^e	3a R = H	A1 (50)	Toluene	60	24 h	∼0	16	na
5^e	3b R = OMe	A1 (50)	Toluene	60	24 h	∼0	14	na
6^e	3c R = Me	A1 (50)	Toluene	60	24 h	∼0	15	na

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Although the detailed mechanism of the conjugate addition is not fully understood, a postulated catalyst activation mode is proposed to account for the catalytic turn over and dual acid–base functions as depicted in Scheme 4.²⁰ Initial iminium-activation of aldehyde 2 by IV–A11 followed by the indole alkylation via the two-point binding mode (T1) or single-point coordination and cooperative catalysis (T2) to give adduct 4a with high enantioselectivity and to regenerate the catalyst IV–A11. Alternatively, in the case of excess A11 (or the reaction of A11 in the absence of amine IV), the reaction was proceed faster than the aforementioned cocktail IV–A11 catalysis, via the transition state T3 to give 4a, but with much less ee. In addition, in the condition of A12-catalysis, the majority of 4a was further reacted with additional indole, catalyzed by A12, to give yuehchukene. In an exceptional case, the reaction with IV–A12 gave very small amount of product 4a and recovered most of the starting compound. Perhaps the salt of IV–A12 is so stable and reluctant to participant the catalysis.

Scheme 4 Proposed mechanism for the Friedel–Crafts alkylation–cyclization process.

To account for the racemization during the transformation from chiral 4a to 1a, we propose a plausible mechanism (Scheme 5). Initially, nucleophilic attack of the indole toward the acid-activated trans-4a provides the cationic intermediate A, a stable intermediate which is stabilized by the resonance structure B. Subsequently, the intermediate A undergoes a disconnection rearrangement, triggered by the conjugate push–pull system of indole–indolium, affording the achiral polyene intermediate C. The lack of a suitable rigid conformation for the asymmetric induction by chiral acid permitted the successive stepwise cyclization of C and isomerization to afford the racemic 1a. Alternatively, cyclization of A toward D, following by the 1,3-H shift, led to the formation of 1a with the retention of chirality. It has to be noted that most of the conditions we attempted, vide supra, afforded 1a as a racemate or with very small amounts of ee. The results indicate that the reaction preferentially proceeded through the racemization pathway. This observation may shed a light on the fact that both enantiomeric forms of 1a have been observed in plants.

Scheme 5 Proposed mechanism for the alkylation–cyclization process.

Conclusions

In summary, we have described an organocatalytic enantioselective Friedel–Crafts alkylation of indoles to the sterically encumbered α-alkyl enal with high enantioselectivities (up to 96% ee) by a combination of a chiral Brønsted acid and a chiral Lewis base (bifunctional cinchona-derived primary amine). The structure of the conjugated adduct was illustrated by single crystal X-ray crystallographic analyses of the appropriate adduct. Particularly noteworthy is the one-pot operation of the synthesis of yuehchukene from the naturally occurring aldehyde and indole that may mimic the biosynthetic pathway. The observation of the racemization process during the cyclization steps of conjugated adduct to yuehchukene as well as the achiral Brønsted acid-catalyzed one-pot synthesis of yuehchukene provided some clues to address why yuehchukene is present in nature as a racemate.

Experimental section

All solvents were reagent grade. Chemicals were purchased from Aldrich or Acros Chemical Co. Reactions were normally carried out under argon atmosphere in glassware. Silica gel 60 (Merck Geduran Si 60, particle size 0.063–0.200 nm) was employed for flash chromatography. Melting points are uncorrected. ¹H NMR spectra were obtained in CDCl₃ unless otherwise noted at 400 MHz (Bruker DPX-400) or 500 MHz (Varian-Unity INOVA-500). ¹³C NMR spectra were obtained at 100 MHz or 125 MHz. ee values were measured by HITACHI L-2130 HPLC with HITACHI Diode Array detector L-2455 on a chiral column (chiralpak IC, 0.46 cm ID × 25 cm, particle size 5 μ; or chiralpak IA 0.46 cm ID × 25 cm, particle size 5 μ) by elution with IPA–hexane. The flow rate of the indicated elution solvent is maintained at 1.0 mL min⁻¹, and the retention time of a compound is recorded accordingly. Focused microwave irradiation was carried out at atmospheric pressure with a CEM Discover microwave reactor (5 mL reactors). The melting point was recorded on a melting point apparatus (MPA100 – Automated melting point system, Stanford Research Systems, Inc.) and is uncorrected. The optical rotation values were recorded with a Jasco-P-2000 digital polarimeter.

(1S,2R)-2-(1H-indol-3-yl)-4,6,6-trimethylcyclohex-3-enecarbaldehyde (4a)

To a solution of aldehyde 2 (102 mg, 0.68 mmol, 2 equiv.), catalyst-IV (22.1 mg, 0.068 mmol, 0.2 equiv.) and additive-(S)-A11 (47.3 mg, 0.14 mmol, 0.4 equiv.) in CHCl₃–EtOAc (1 : 1, 1 mL) was added indole 3a (40 mg, 0.34 mmol, 1 equiv.) at ∼25 °C. The resulting solution was stirred at ambient temperature for 15 days. To the reaction mixture was added Et₃N (34 mg, 0.34 mmol, 1 equiv.) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give the residue. The crude product was purified by flash column chromatography with 8% EtOAc–hexane (R_f = 0.54 for trans-4a after developing three times in 15% EtOAc–hexane and R_f = 0.51 for cis-4a after developing three times in 15% EtOAc–hexane) to afford product 4a as mixture of diastereomers (23 mg, 25% yield) as a yellow oil. Further purification of 4a provided the pure trans-4a for spectra analysis. Selected spectroscopic data for trans-4a: [α]²⁶_D − 95.5 (c 1, CHCl₃) for 88% ee of trans-4a; IR (neat): 3417, 2963, 2825, 1712, 1457, 1260, 1096, 1011, 803, 742 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.70 (d, J = 4.5 Hz, 1H), 7.96 (bs, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18–7.14 (m, 1H), 7.09–7.05 (m, 1H), 6.93 (d, J = 2.5 Hz, 1H), 5.50 (s, 1H), 4.08–4.05 (m, 1H), 2.63 (dd, J = 11.0, 4.0 Hz, 1H), 2.18 (d, J = 17.0 Hz, 1H), 1.71 (s, 3H), 1.69 (d, J = 17 Hz, 1H), 1.12 (s, 3H), 1.11 (s, 3H), ¹³C NMR (125 MHz, CDCl₃): δ 206.5 (CH), 136.7 (C), 131.7 (C), 126.4 (C), 123.0 (CH), 122.0 (CH), 121.9 (CH), 119.4 (CH), 119.2 (CH), 117.5 (C), 111.3 (CH), 60.8 (CH), 46.5 (CH₂), 33.8 (C), 32.2 (CH), 29.3 (CH₃), 23.4 (CH₃), 21.5 (CH₃); MS (m/z, relative intensity): 268 (M⁺ + 1, 20) 267 (M⁺, 100), 238 (80), 222 (39), 182 (76), 168 (77), 130 (26), 117 (44), exact mass calculated for C₁₈H₂₁NO (M⁺): 267.1623; found: 267.1624.

(1S,2R)-2-(5-methoxy-1H-indol-3-yl)-4,6,6-trimethylcyclohex-3-enecarbaldehyde (4b)

To a solution of aldehyde 2 (81.6 mg, 0.54 mmol, 2 equiv.), catalyst-IV (17.7 mg, 0.05 mmol, 0.2 equiv.) and additive-(S)-A11 (37.8 mg, 0.11 mmol, 0.4 equiv.) in CHCl₃–EtOAc (1 : 1, 0.77 mL) was added indole 3b (40 mg, 0.27 mmol, 1 equiv.) at ∼25 °C. The resulting solution was stirred at ambient temperature for 15 days. To the reaction mixture was added Et₃N (27 mg, 0.27 mmol, 1 equiv.) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give the residue. The crude product was purified by flash column chromatography with 10% EtOAc–hexane (R_f = 0.49 for trans-4b after developing three times in 15% EtOAc–hexane and R_f = 0.46 for cis-4b after developing three times in 15% EtOAc–hexane) to afford product 4b as mixture of diastereomers (24 mg, 30% yield) as yellow oil; selected spectroscopic data for trans-4b: [α]²⁶_D − 59.2 (c 1, CHCl₃) for 58% ee of trans-4b; IR (neat): 3414, 2964, 2828, 1716, 1486, 1457, 1439, 1260, 1217, 1027, 800, 756 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.70 (d, J = 4.5 Hz, 1H), 7.84 (bs, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.5 Hz, 1H), 5.49 (s, 1H), 4.04–4.00 (m, 1H), 3.83 (s, 3H), 2.60 (dd, J = 11, 4 Hz, 1H), 2.16 (d, J = 17 Hz, 1H), 1.78–1.68 (m, 1H), 1.71 (s, 3H), 1.11 (s, 3H), 1.10 (s, 3H), ¹³C NMR (125 MHz, CDCl₃): δ 206.5 (CH), 153.6 (C), 131.82 (C), 131.76 (C), 126.8 (C), 122.9 (CH), 122.7 (CH), 117.2 (C), 111.9 (CH), 111.8 (CH), 101.6 (CH), 60.6 (CH), 55.9 (CH₃), 46.5 (CH₂), 33.8 (C), 32.1 (CH), 29.3 (CH₃), 23.4 (CH₃), 21.5 (CH₃); MS (m/z, relative intensity): 298 (M⁺ + 1, 21), 297 (M⁺, 100), 268 (76), 252 (26), 212 (74), 198 (52), 147 (40), 101 (39), exact mass calculated for C₁₉H₂₃NO₂ (M⁺): 297.1729; found: 297.1728.

(1S,2R)-4,6,6-trimethyl-2-(5-methyl-1H-indol-3-yl)cyclohex-3-enecarbaldehyde (4c)

To a solution of aldehyde 2 (91.5 mg, 0.61 mmol, 2 equiv.), catalyst-IV (19.8 mg, 0.06 mmol, 0.2 equiv.) and additive-(S)-A11 (42.4 mg, 0.12 mmol, 0.4 equiv.) in CHCl₃–EtOAc (1 : 1, 0.87 mL) was added indole 3c (40 mg, 0.30 mmol, 1 equiv.) at ∼25 °C. The resulting solution was stirred at ambient temperature for 15 days. To the reaction mixture was added Et₃N (31 mg, 0.305 mmol, 1 equiv.) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give the residue. The crude product was purified by flash column chromatography with 8% EtOAc–hexane (R_f = 0.35 for trans-4c after developing two times in 15% EtOAc–hexane and R_f = 0.32 for cis-4c after developing two times in 15% EtOAc–hexane) to afford product 4c as mixture of diastereomers (23 mg, 27% yield) as yellow oil; selected spectroscopic data for trans-4c: [α]²⁶_D − 72.1 (c 0.8, CHCl₃) for 72% ee of trans-4c; IR (neat): 3375, 3012, 2963, 2825, 1719, 1543, 1484, 1466, 1369, 1317, 1205, 1157, 1021, 990, 858, 752 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.68 (d, J = 4.5 Hz, 1H), 7.84 (bs, 1H), 7.34 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 8.5, 1.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.49 (s, 1H), 4.06–4.02 (m, 1H), 2.60 (dd, J = 11.0, 4.0 Hz, 1H), 2.43 (s, 3H) 2.17–2.14 (m, 1H), 1.78–1.67 (m, 1H), 1.70 (s, 3H), 1.11 (s, 6H), ¹³C NMR (125 MHz, CDCl₃): δ 206.6 (CH), 135.0 (C), 131.6 (C), 128.4 (C), 126.6 (C), 123.7 (CH), 123.0 (CH), 122.0 (CH), 118.9 (CH), 117.0 (C), 110.9 (CH), 60.6 (CH), 46.5 (CH₂), 33.8 (C), 32.1 (CH), 29.3 (CH₃), 23.4 (CH₃), 21.62 (CH₃), 21.57 (CH₃); MS (m/z, relative intensity): 282 (M⁺ + 1, 22), 281 (M⁺, 100), 252 (92), 236 (33), 196 (75), 182 (58), 131 (35), 59 (55), exact mass calculated for C₁₉H₂₃NO (M⁺): 281.1780; found: 281.1782.

(1S,2R)-2-(6-methoxy-1H-indol-3-yl)-4,6,6-trimethylcyclohex-3-enecarbaldehyde (4d)

To a solution of aldehyde 2 (81.6 mg, 0.54 mmol, 2 equiv.), catalyst-IV (17.7 mg, 0.05 mmol, 0.2 equiv.) and additive-(S)-A11 (37.8 mg, 0.11 mmol, 0.4 equiv.) in CHCl₃–EtOAc (1 : 1, 0.77 mL) was added indole 3d (40 mg, 0.27 mmol, 1 equiv.) at ∼25 °C. The resulting solution was stirred at ambient temperature for 15 days. To the reaction mixture was added Et₃N (27 mg, 0.27 mmol, 1 equiv.) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give the residue. The crude product was purified by flash column chromatography with 10% EtOAc–hexane (R_f = 0.47 for trans-4d after developing two times in 15% EtOAc–hexane and R_f = 0.44 for cis-4d after developing two times in 15% EtOAc–hexane) to afford product 4d as mixture of diastereomers (19 mg, 23% yield) as yellow oil; selected spectroscopic data for trans-4d: [α]²⁶_D − 83.3 (c 1, CHCl₃) for 78% ee of trans-4d; IR (neat): 3369, 3015, 2963, 2825, 1718, 1484, 1466, 1317, 1205, 1156, 1021, 857, 752, 666 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.69 (d, J = 4.0 Hz, 1H), 7.80 (bs, 1H), 7.43 (d, J = 9.0 Hz, 1H), 6.81 (dd, J = 6.5, 2.0 Hz, 2H), 6.74 (dd, J = 8.5, 2.0 Hz, 1H), 5.48 (s, 1H), 4.02–3.99 (m, 1H), 3.81 (s, 3H), 2.58 (dd, J = 11.0, 4.0 Hz, 1H), 2.17–2.14 (m, 1H), 1.77–1.66 (m, 1H), 1.70 (s, 3H), 1.10 (s, 3H), 1.09 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 206.5 (CH), 156.5 (C), 137.4 (C), 131.7 (C), 123.0 (CH), 120.7 (C), 120.5 (CH), 120.0 (CH), 117.5 (C), 109.3 (CH), 94.8 (CH), 60.7 (CH), 55.7 (CH₃), 46.5 (CH₂), 33.8 (C), 32.3 (CH), 29.3 (CH₃), 23.5 (CH₃), 21.5 (CH₃), MS (m/z, relative intensity): 298 (M⁺ + 1, 21), 297 (M⁺, 100), 268 (100), 212 (61), 198 (39), 147 (38), 59 (44), exact mass calculated for C₁₉H₂₃NO₂ (M⁺): 297.1729; found: 297.1731.

(1S,2R)-2-(5,6-dimethoxy-1H-indol-3-yl)-4,6,6-trimethylcyclohex-3-enecarbaldehyde (4e)

To a solution of aldehyde 2 (68 mg, 0.45 mmol, 2 equiv.), catalyst-IV (14.3 mg, 0.04 mmol, 0.2 equiv.) and additive-(S)-A11 (30.6 mg, 0.09 mmol, 0.4 equiv.) in CHCl₃–EtOAc (1 : 1, 0.60 mL) was added indole 3e (40 mg, 0.23 mmol, 1 equiv.) at ∼25 °C. The resulting solution was stirred at ambient temperature for 15 days. To the reaction mixture was added Et₃N (23 mg, 0.23 mmol, 1 equiv.) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give the residue. The crude product was purified by flash column chromatography with 15% EtOAc–hexane (R_f = 0.30 for trans-4e after developing two times in 30% EtOAc–hexane and R_f = 0.27 for cis-4e after developing two times in 30% EtOAc–hexane) to afford product 4e as mixture of diastereomers (18 mg, 24% yield) as yellow oil. For purified trans-4e, darkkhaki solid, m.p. decomposed at 185 °C. Selected spectroscopic data for trans-4e: [α]²⁶_D − 78.2 (c 1.2, CHCl₃) for 79% ee of trans-4e; IR (neat): 3372, 2960, 1718, 1484, 1466, 1317, 1205, 1157, 1022, 755 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 9.70 (d, J = 4 Hz, 1H), 7.80 (bs, 1H), 7.01 (s, 1H), 6.82 (s, 1H), 6.79 (d, J = 2.5 Hz, 1H), 5.50 (s, 1H), 4.02–3.99 (m, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 2.56 (dd, J = 11.0, 4.5 Hz, 1H), 2.15–2.02 (m, 1H), 1.79–1.70 (m, 1H), 1.71 (s, 3H), 1.11 (s, 3H), 1.10 (s, 3H); ¹³C NMR (125 MHz, CDCl₃): δ 206.5 (CH), 147.2 (C), 144.6 (C), 131.7 (C), 130.9 (C), 123.0 (CH), 120.2 (CH), 119.1 (C), 117.4 (C), 101.2 (CH), 94.7 (CH), 60.8 (CH), 56.4 (CH₃), 56.2 (CH₃), 46.5 (CH₂), 33.8 (C), 32.1 (CH), 29.3 (CH₃), 23.4 (CH₃), 21.5 (CH₃); MS (m/z, relative intensity): 328 (M⁺ + 1, 22), 327 (M⁺, 100), 298 (99), 284 (19), 282 (16), 242 (41), 228 (28), 177 (36), 71 (32), exact mass calculated for C₂₀H₂₅NO₃ (M⁺): 327.1834; found: 327.1834.

Yuehchukene (1a)

To a solution of aldehyde 4a (15 mg, 0.06 mmol) and indole 3a (7.9 mg, 0.07 mmol, 1.2 equiv.) in CH₂Cl₂ (0.1 M, 0.56 mL) was added (S)-CSA (2.6 mg, 0.01 mmol, 0.2 equiv.) at room temperature. The resulting solution was stirred at ambient temperature for 7 days until the completion of reaction, as monitored by TLC. To the reaction mixture was added Et₃N (6 mg, 0.06 mmol) and the corresponding reaction mixture was stirred for 30 min. The reaction solution was concentrated in vacuo to give a crude residue. The crude product was purified by flash column chromatography with 8% EtOAc–hexane (R_f = 0.40 for 1a after developing three times in 15% EtOAc–hexane) to afford product 1a (15 mg, 73% yield) as amorphous white powder; m.p. 125–127 °C (decomp.) lit. 128 °C;²¹ 127;²² selected spectroscopic data for 1a:²³ IR (neat): 3410, 2963, 2906, 1454, 1415, 1260, 1114, 1008, 865, 797, 701 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 8.00 (bs, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (bs, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 7.5, 7.5 Hz, 1H), 7.15–6.99 (m, 5H), 5.68 (s, 1H), 4.56 (d, J = 8.5 Hz, 1H), 4.0 (d, J = 6.0 Hz, 1H), 3.15 (dd, J = 8.5, 7.0 Hz, 1H), 2.25 (d, J = 17.0 Hz, 1H), 1.64 (s, 3H), 1.61 (d, J = 17.0 Hz, 1H), 1.07 (s, 3H), 0.85 (s, 3H), ¹³C NMR (125 MHz, CDCl₃): δ 145.1 (C), 140.2 (C), 136.5 (C), 130.2 (C), 126.8 (C), 124.2 (C), 122.9 (CH), 122.3 (CH), 122.0 (CH), 120.52 (CH), 120.48 (CH), 119.50 (CH), 119.48 (CH), 119.4 (C), 118.4 (C), 118.2 (CH), 111.7 (CH), 111.2 (CH), 60.7 (CH), 41.0 (CH₂), 38.3 (CH), 37.6 (CH), 33.5 (C), 29.1 (CH₃), 28.9 (CH₃), 24.1 (CH₃); MS (m/z, relative intensity): 366 (M⁺, 17), 351 (8), 284 (12), 267 (82), 245 (25), 238 (58), 222 (35), 182 (91), 168 (94), 117 (62), 97 (47), 85 (82), 71 (100), 57 (100); exact mass calculated for C₂₆H₂₆N₂ (M⁺): 366.2096; found: 366.2093.

One-pot synthesis of (±)-yuehchukene (1a) from aldehyde 2 and indole (3a)

To a solution of aldehyde 2 (100 mg, 0.67 mmol) and indole 3a (156 mg, 1.33 mmol, 2 equiv.) in toluene (0.2 M, 3.3 mL) was added TFA (38 mg, 0.33 mmol, 0.5 equiv.) at room temperature. The resulting solution was heated to 60 °C and stirred at the same temperature for 24 h until the completion of reaction, as monitored by TLC. The solution was cooled to 0 °C, followed by the addition of Et₃N (67 mg, 0.66 mmol), and the corresponding reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with H₂O (10 mL). The organic reaction solution was concentrated in vacuo to give a crude residue. The crude product was purified by flash column chromatography with 8% EtOAc–hexane (R_f = 0.40 for 1a after developing three times in 15% EtOAc–hexane) to afford product 1a (40 mg, 16% yield) as white solid.

One-pot synthesis of (±)-1b from aldehyde 2 and indole 3b

To a solution of aldehyde 2 (100 mg, 0.67 mmol) and indole 3b (196 mg, 1.33 mmol, 2 equiv.) in toluene (0.2 M, 3.3 mL) was added TFA (38 mg, 0.33 mmol, 0.5 equiv.) at room temperature. The resulting solution was heated to 60 °C and stirred at the same temperature for 24 h until the completion of reaction, as monitored by TLC. The solution was cooled to 0 °C, followed by the addition of Et₃N (67 mg, 0.66 mmol), and the corresponding reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with H₂O (10 mL). The organic solution was concentrated in vacuo to give a crude residue. The crude product was purified by flash column chromatography with 10% EtOAc–hexane (R_f = 0.50 for 1b after developing two times in 20% EtOAc–hexane) to afford product 1b (30 mg, 13% yield) as yellow solid. m.p. 160 °C (decomp.). Selected spectroscopic data for 1b: IR (neat): 3403, 2947, 1586, 1484, 1211, 1034, 799, 760 cm⁻¹; ¹H NMR (500 MHz, C₆D₆): δ 7.26 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 9.0, 2.5 Hz, 1H), 6.95–7.01 (m, 3H), 6.77 (d, J = 9.0 Hz, 1H), 6.67 (bs, 1H), 6.48 (d, J = 2.0 Hz, 2H), 5.87 (s, 1H), 4.50 (d, J = 8.0 Hz, 1H), 4.05–4.10 (m, 1H), 3.59 (s, 3H), 3.39 (s, 3H), 3.17 (dd, J = 8.0, 8.0 Hz, 1H), 2.29 (d, J = 17.0 Hz, 1H), 1.66 (s, 3H), 1.59 (d, J = 17.0 Hz, 1H), 1.15 (s, 3H), 0.95 (s, 3H); ¹³C NMR (125 MHz, C₆D₆): δ 155.3 (2C), 146.7 (C), 136.2 (C), 132.2 (C), 130.2 (2C), 125.5 (C), 124.3 (CH), 123.2 (CH), 120.8 (C), 119.0 (C), 113.3 (CH), 113.0 (CH), 112.6 (CH), 111.0 (CH), 101.6 (CH), 101.4 (CH), 62.2 (CH), 55.8 (CH₃), 55.7 (CH₃), 41.8 (CH₂), 39.1 (CH), 38.2 (CH), 34.0 (C), 29.7 (CH₃), 29.6 (CH₃), 24.5 (CH); MS (m/z, relative intensity): 427 (M⁺ + 1, 31), 426 (M⁺, 100), 411 (43), 359 (56), 264 (35), 185 (45), 160 (38), 57 (54); exact mass calculated for C₂₈H₃₀N₂O₂ (M⁺): 426.2307; found: 426.2310.

One-pot synthesis of (±)-1c from aldehyde 2 and indole 3c

To a solution of aldehyde 2 (100 mg, 0.67 mmol) and indole 3c (175 mg, 1.33 mmol, 2 equiv.) in toluene (0.2 M, 3.3 mL) was added TFA (38 mg, 0.33 mmol, 0.5 equiv.) at room temperature. The resulting solution was heated to 60 °C and stirred at the same temperature for 24 h until the completion of reaction, as monitored by TLC. The solution was cooled to 0 °C, followed by the addition of Et₃N (67 mg, 0.66 mmol), and the corresponding reaction mixture was stirred for 30 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with H₂O (10 mL). The organic solution was concentrated in vacuo to give a crude residue. The crude product was purified by flash column chromatography with 8% EtOAc–hexane (R_f = 0.60 for 1c after developing two times in 15% EtOAc–hexane) to afford product 1c (40 mg, 15% yield) as yellow oil. Selected spectroscopic data for 1c: IR (neat): 3404, 2917, 1716, 1620, 1454, 1297, 1096, 798 cm⁻¹; ¹H NMR (500 MHz, C₆D₆): δ 7.54 (s, 1H), 7.41 (s, 1H), 6.98–7.16 (m, 3H), 6.81 (d, J = 8.5 Hz, 1H), 6.68 (bs, 1H), 6.51 (bs, 1H), 6.45 (d, J = 2.5 Hz, 1H), 5.88 (s, 1H), 4.52 (d, J = 8.5 Hz, 1H), 4.05–4.11 (m, 1H), 3.20 (dd, J = 8.0, 8.0 Hz, 1H), 2.48 (s, 3H), 2.31 (s, 3H), 2.26–2.28 (m, 1H), 1.65 (s, 3H), 1.56 (d, J = 16.5 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H); ¹³C NMR (125 MHz, C₆D₆): δ 146.1 (C), 139.6 (C), 135.5 (C), 130.1 (C), 129.2 (C), 128.9 (C), 128.7 (C), 125.6 (C), 124.5 (CH), 124.4 (CH), 122.64 (CH), 122.63 (CH), 120.3 (C), 119.4 (CH), 119.1 (CH), 118.9 (C), 112.1 (CH), 111.6 (CH), 62.3 (CH), 41.8 (CH₂), 39.1 (CH), 38.1 (CH), 34.0 (C), 29.8 (CH₃), 29.5 (CH₃), 24.5 (CH₃), 22.2 (CH₃), 22.1 (CH₃); MS (m/z, relative intensity): 395 (M⁺ + 1, 12), 394 (M⁺, 34), 379 (17), 248 (15), 221 (18), 207 (13), 198 (13), 149 (34), 85 (42), 71 (62), 58 (100); exact mass calculated for C₂₈H₃₀N₂ (M⁺): 394.2409; found: 394.2407.

Acknowledgements

We thank Professor Minoru Ishikura, Health Sciences University of Hokkaido, Japan, and Professor Jhy-Horng Sheu, National Sun Yat-sen University, Taiwan, for generously providing the spectra of yuehchukene. Thanks to Mr Arun Raja for his help in the experiment. We acknowledge the financial support for this study from the Ministry of Science and Technology (MOST, Taiwan) and thank the instrument center (MOST) for analyses of compounds. Thanks to Professor Wei-Ping Hu (NCCU) and Mr Chia-Chueng Chen (NCCU) for their assistance in the computational study.

Notes and references

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15. 3-Methyl-2-butenal has been isolated from Dactylanthus taylorii flower nectar, hops (Humulus Lupulus L.), and raspberry oil. (a) C. E. Ecroyd, R. A. Franich, H. W. Kroese and D. Steward, Phytochemistry, 1995, 40, 1387; (b) R. D. Hartley and C. H. Fawcett, Phytochemistry, 1968, 7, 1395; (c) M. Winter and E. Sundt, Helv. Chim. Acta, 1962, 45, 2195.
16. Indole has been isolated from more than 21 sources, including the culture of Aeromonas sp., strain CB101, leaves of Salvia divinorum, rape flower Brassica rapa, etc. For examples, (a) Z. Ma, G. Deng, R. Dai, W. Xu, L.-Y. Liu-Chen and D. Y. W. Lee, Tetrahedron Lett., 2010, 51, 5480; (b) R. Veluri, I. Oka, I. Wagner-Doebler and H. Laatsch, J. Nat. Prod., 2003, 66, 1520; (c) H. Omura, K. Honda and N. Hayashi, J. Chem. Ecol., 1999, 25, 1895.
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19. The expected value of 100% ee, derived from the observation data [α]²⁶_D − 95.5 (c 1, CHCl₃) for 88% ee of (−)-trans-4a. The calculated values of other adducts 4 also matched well with their observed values.
20. For a mechanistic rationale for the 9-amino(9-deoxy)epi cinchona alkaloids catalyzed asymmetric reactions via iminium ion activation of enones, see: A. Moran, A. Hamilton, C. Bo and P. Melchiorre, J. Am. Chem. Soc., 2013, 135, 9091–9098.
21. K. J. Henry and P. A. Grieco, J. Chem. Soc., Chem. Commun., 1993, 510.
22. (a) Y.-C. Kong, K.-F. Cheng, R. C. Cambie and P. G. Waterman, J. Chem. Soc., Chem. Commun., 1985, 47–48; (b) Y.-K. Chen, H.-F. Chung, S.-F. Lin, J.-H. Sheu and P.-J. Sung, J. Chem. Soc., Perkin Trans. 1, 1998, 1959–1965.
23. In a separate reaction, starting from 84% ee of trans-4a with (S)-A12 in CH₂Cl₂ at ∼35 °C for 15 days provided 73% yield of 1a with 21% ee. For the yuehchukene (1a) obtained (21% ee): [α]²⁶_D − 16.6 (c 1.4, CHCl₃).

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Footnote

† Electronic supplementary information (ESI) available: Experimental detail, spectroscopic characterization, HPLC analysis. CCDC 1011541. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra10222c

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