A Metathetic Approach to [5/5/6] Aza-Tricyclic Core of Dendrobine, Kopsanone, and Lycopalhine A Type of Alkaloids

Abstract

A concise synthetic approach to [5/5/6] tricyclic pyrrolidine core of dendrobine is reported. This methodology relies on the construction of β-hydroxylactams by NaBH₄-I₂ reduction followed by reaction of allylsilane with the aid of Lewis acid to generate alkenyl lactams in good yields. Further, ring-opening metathesis (ROM) followed by ring-closing metathesis (RCM) were used to assemble the [5/5/6] aza-tricyclic skeleton of dendrobine. This short synthetic route has been expanded to assemble tricyclic [5/5/8] system with pentenylboronic acid.

Key words

dendrobine - [5/5/6] aza-tricyclic - metathesis - allylation - NOE - BF₃·OEt₂

The total synthesis of alkaloids has been considered as a challenging task in organic synthesis.[1a] Alkaloids such as dendrobine (1), kopsanone (2), and lycopalhine A (3) contain the [5/5/6] aza-tricyclic core as a common structural element. Dendrobine (1), a tetracyclic pyrrolidine alkaloid isolated from the Dendrobium nobile plant, shows analgesic and antipyretic activity.[1] Dendrine (4) and mubironine C (5) are structurally related alkaloids to dendrobine (1), originated from similar orchid species.[2] Kopsinidines 6–8 and kopsanone (2) are monoterpenoid alkaloids isolated from Kopsia officinalis plant that exhibits anti-inflammatory, antirheumatic, and cholinergic effects.[3] Interestingly, lycopalhine A (3) is a hexacyclic lycopodium alkaloid isolated from Palhinhaea cernua plant, a family of lycopodiaceae.[4] Total synthesis of these pyrrolidine-based alkaloids have gained considerable interest in recent years due to their unique structural features and a wide range of biological activities (Figure [1]).

Figure 1 Alkaloids containing [5/5/6] aza-tricyclic core

Synthesis of tricyclic [5/5/6] pyrrolidine unit is not a trivial task. Previously, this pyrrolidine-based [5/5/6] tricyclic core has been assembled by a lengthy synthetic sequence in moderate yields. Recently, Chen and co-workers have disclosed the [5/5/6] aza-tricyclic Kende intermediate towards asymmetric synthesis of dendrobine in seven steps in 15% overall yield (Scheme [1a]).[5] In 2018, Williams and Trauner have reported the synthesis of 5-deoxymubironine C in eight steps in 7% overall yield (Scheme [1b]).[6]

Here, we have developed a simple and stereoselective metathesis strategy to synthesize [5/5/6] pyrrolidine aza-tricyclic core, which produced more than 50% overall yield in a stereoselective manner (Scheme [1c]). Further, we expanded this strategy to assemble [5/5/8] aza-tricyclic core successfully. The methodology reported to pyrrolidine cores may be useful in generating compounds suitable for material science and bioactive targets.

Our synthesis starts with the preparation of known ­endo-Diels–Alder (DA) adducts 9a–d,[7] which on reduction with NaBH₄-I₂ system[8] at room temperature in CH₂Cl₂–MeOH gave the hydroxyl derivatives 10a–d in good yields as a pure diastereomer (Scheme [2]). We found that electron-withdrawing groups (CN, Br) at para-position produce excellent yields of 10b and 10c, whereas electron-donating group (Me) gave moderate yields. The stereochemistry of 10 was confirmed by NOE experiment. Recently, Bergens and co-workers have reported an enantioselective catalytic hydrogenation of amides and imides through base-catalyzed bifunctional addition. They assigned the stereochemistry of the hydroxyl group with the aid of single crystal X-ray analysis data of the corresponding carbamate derivative.[9] Further, addition of allylsilane via N-acyliminium ions is one of the mostly used methodology to synthesize functionalized lactams.[10] Thus, allylation of 10 with allyl TMS was accomplished in the presence of BF₃·OEt₂ at –78 °C to deliver the allyl derivative 11 in good yield with a β-selectivity (Scheme [2]).

Scheme 1 (a) Earlier reported asymmetric pathway to dendrobine; (b) Previously reported azomethine ylide pathway to 5-deoxymubironine C; (c) Proposed metathetic approach to [5/5/6] aza-tricyclic core

Scheme 2 Synthesis of α-allyl precursor 11. ^a Crystal XRD of 11c with thermal ellipsoids drawn at 50% probability level. ^b Crystal XRD of 11d with thermal ellipsoids drawn at 50% probability level.

The stereochemistry of allyl derivative 11 was derived by attack of allyl TMS on acyliminium ion from less hindered side as proposed in the mechanism (Scheme [3]) and the stereochemistry was confirmed by NOE study and further supported by single-crystal X-ray diffraction studies.[11]

Scheme 3 Possible mechanism for allylation

We have studied the allylation sequence at different temperatures (–78 °C to rt) to improve the yield and found that this reaction gave stereocontrolled product 11 even at 0 °C and also at room temperature in excellent yields (Table [1]).

Table 1 Reaction Conditions of Allylation of 10

Entry	Compound	R	Catalyst	Temp (°C)	Time (h)	Conversion (%)a
1	10b	CN	BF3·OEt2	–78	15	73
2	10d	Me	BF3·OEt2	–78	15	47
3	10c	Br	BF3·OEt2	–78	15	65
4	10c	Br	BF3·OEt2	–40	14	78
5	10c	Br	BF3·OEt2	–20	15	97
6	10c	Br	BF3·OEt2	0	8	98
7	10c	Br	BF3·OEt2	rt	6	100
8	10c	Br	TiCl4	0	8	40
9	10c	Br	CF3CO2H	0	8	45
10	10c	Br	SiCl4	0	8	0

^a Percentage of conversion of allylation is based on the ¹H NMR data.

Scheme 4 Synthesis of aza-tricyclic core 13 using metathesis strategy

Further, α-allyl derivatives 11b and 11c were subjected to metathesis using Grubbs 1st, 2nd generation and Hoveyda–Grubbs 1st and 2nd catalysts under different conditions.[12] Unfortunately, we did not observe the ring-rearrangement metathesis (RRM) product 13 under these ­conditions (Table [2]); however, we found the ring-opening metathesis (ROM) products 12b and 12c. Later, these were again subjected to the ring-closing metathesis (RCM) using G-II catalyst at room temperature to deliver the desired aza-tricyclic derivatives 13b and 13c in 84% and 76% yield, respectively (Scheme [4]).[12]

Table 2 Reaction Optimization of ROM of 11b

Entry	Catalyst (mol%)	Solvent/temp/time	Yield of 12b (%)a
1	G-I (5 mol%)	CH2Cl2/rt/12 h	34
2	G-I (10 mol%)	CH2Cl2/rt/12 h	26
3	G-I (10 mol%)	toluene/reflux/8 h	28
4	G-II (5 mol%)	CH2Cl2/rt/12 h	25
5	GH-I (5 mol%)	CH2Cl2/rt/12 h	72
6	GH-I (5 mol%)	toluene/reflux/8 h	70
7	GH-II (5 mol%)	CH2Cl2/rt/12 h	36

^a Isolated yield.

Along similar lines, the hydroxy derivative 10b was treated with allyl bromide in the presence of NaH to furnish the O-allyl derivative 14 in 98% yield.[13] Further, this O-allyl derivative 14 was subjected to ROM to yield the compound 15, which on treatment with G-I and G-II catalysts did not produce the expected ring-closure product 16 (Scheme [5]).

Scheme 5 Synthesis of the compound 15 (70% of conversion from 14 to 15 by ¹H NMR analysis). ^a Yield is based on the recovery of 30% starting material.

NOE Study

We have performed the NOE studies of compounds 10, 11, 12, and 14 to establish the relative stereochemistry of alkyl and vinyl side chains. For example, H_d proton of cyclic CH_d=CH moiety shows strong NOE correlation with H_a of CH_a–NPh of compounds 10, 11, and 14. Additionally, methylene protons (H_j, H_k) of CH₂=CH exhibit NOE correlation with the H_g of bridged CH₂ in compound 14. These results indicated that the stereochemistry of hydroxyl group of 10 is assigned as β-orientation. Similarly, methylene protons (H_h and H_i) of allyl group exhibit strong NOE with the bridge protons (H_b and H_c) in compound 11 and H_a of CH_a–NPh of the compound 12 shows NOE correlation with H_d of vinylic CH_d=CH₂ group of 12. These observations support the stereochemistry of allyl group of 11 as β (Figure [2]).

Figure 2 NOE correlation of the compounds 10, 11, 12, and 14

We have expanded this methodology to synthesize [5/5/8] tricyclic derivative 19, which is difficult to assemble by conventional methods. Addition of unsaturated boronic acid such as pentenylboronic acid to N-acyliminium ions in the presence of Lewis acid, for example, BF₃·OEt₂, copper triflate, and Ca(II) catalysts, is not reported.[14] [15] [16] [17]

Thus, the hydroxy derivative 10 was treated with pentenylboronic acid in the presence of BF₃·OEt₂ at –78 °C to deliver the pentenyl derivative 17 in 58% yield. This derivative 17 was further subjected to ROM using GH-I catalyst followed by RCM using G-II catalyst to obtain the corresponding aza-tricyclic analogue 19 in good yield (Scheme [6]).[12]

Scheme 6 Synthesis of compound 19 (65% of conversion from 17 to 18 by ¹H NMR analysis). ^a Yields are based on recovery of 35% starting material.

All commercially available reagents were used without further purification and the reactions involving air-sensitive catalysts or reagents were performed in degassed solvents. Moisture-sensitive materials were transferred by using syringe-septum technique and the reactions were maintained under N₂ atmosphere. Analytical TLC was performed on glass plates (7.5 × 2.5 cm) coated with Acme’s silica gel GF 254 (containing 13% CaSO₄ as a binder) by using a suitable mixture of EtOAc and PE for development. Column chromatography was performed by using Acme’s silica gel (100–200 mesh) with an appropriate mixture of EtOAc and PE. The coupling constants (J) are given in hertz (Hz) and chemical shifts are denoted in parts per million (ppm) downfield from internal standard TMS. Standard abbreviations are used to denote spin multiplicities. IR spectra were recorded on Nicolet Impact-400 FT-IR spectrometer. NMR spectra were generally recorded on a Bruker (AvanceTM 400 or AvanceTM III 500) spectrometer operating at 400 or 500 MHz for ¹H and 100.6 or 125.7 MHz for ¹³C nuclei. The high-resolution mass spectrometric (HRMS) measurements were carried out using a Bruker (Maxis Impact) or Micromass Q-ToF spectrometer.

endo-Imides 9a–d;[7] General Procedure

The known endo-imides 9a–d were prepared following the literature procedure.[7]

Compound 9a

Off-white solid; mp 143.9–144.9 °C[18a]; R_f  = 0.35 (20% EtOAc/hexane).

¹H and ¹³C NMR spectra of compound 9a matched with the literature reported values.[7]

Compound 9b

White solid; mp 169–172 °C[18b]; R_f  = 0.39 (20% EtOAc/hexane).

¹H and ¹³C NMR spectra of compound 9b matched with the literature reported values.[7]

Compound 9c

White solid; mp 153.4–154.6 °C[18a]; R_f  = 0.38 (20% EtOAc/hexane).

¹H and ¹³C NMR spectra of compound 9c matched with the literature reported values.[7]

Compound 9d

Off-white solid; mp 158.2–158.6 °C[18a]; R_f  = 0.36 (20% EtOAc/hexane).

¹H and ¹³C NMR spectra of compound 9d matched with the literature reported values.[7]

β-Hydroxyl Lactams 10; General Procedure

The respective imide 9 (1 mmol, 1 equiv) was dissolved in CH₂Cl₂–MeOH (1:1, 20 mL) and I₂ (catalytic amount) was added at rt under N₂ atmosphere. Later, the resultant solution was stirred for 15 min at rt; NaBH₄ (5 mmol, 5 equiv) was added and the mixture was allowed to stir for 8–12 h at rt. After completion of the reaction, solvents were removed under reduced pressure. The residue was diluted with CH₂Cl₂, washed with H₂O (2 × 30 mL), and concentrated to obtain the desired compound as a pure diastereomer.

Compound 10a

Pale yellow liquid yield: 820 mg (81%) starting from 1.0 g of 9a; R_f  = 0.32 (30% EtOAc/hexane).

IR (neat): 2946, 2931, 1687, 1551, 1392, 822, 771 cm^–1.

¹H NMR (CDCl₃, 500 MHz): δ = 7.45–7.33 (m, 4 H), 7.26–7.19 (m, 1 H), 6.25 (dd, J = 5.40, 2.60 Hz, 1 H), 6.16 (dd, J = 5.45, 2.55 Hz, 1 H), 4.97 (d, J = 7.20 Hz, 1 H), 3.38–3.31 (m, 2 H), 3.26 (br s, 1 H), 2.88 (d, J = 7.35 Hz, 1 H), 2.75 (dd, J = 8.25, 4.25 Hz, 1 H), 1.62 (dd, J = 8.55, 1.30 Hz, 1 H), 1.44 (dd, J = 8.50 Hz, 1 H).

¹³C NMR (CDCl₃, 125 MHz): δ = 175.2 (C), 137.1 (C), 136.7 (CH), 133.4 (CH), 129.3 (CH), 126.8 (CH), 124.6 (CH), 87.1 (CH), 51.4 (CH₂), 49.6 (CH), 46.5 (CH), 45.9 (CH), 45.30 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₅H₁₅NO₂Na: 264.0996; found: 264.0993.

Compound 10b

White solid; yield: 744 mg (93%) starting from 800 mg of 9b; mp 161.1–165.7 °C; R_f  = 0.30 (30% EtOAc/hexane).

IR (neat): 2925, 2228, 1683, 1510, 1392, 1304, 842, 760 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.70 (d, J = 8.76 Hz, 2 H), 7.60 (d, J = 8.72 Hz, 2 H), 6.17 (dd, J = 5.64, 2.80 Hz, 1 H), 6.09 (dd, J = 5.60, 2.92 Hz, 2 H), 5.00 (s, 1 H), 3.38–3.30 (m, 2 H), 3.28 (br s, 1 H), 2.76 (dd, J = 8.28, 4.24 Hz, 1 H), 1.62 (d, J = 8.60 Hz, 1 H), 1.42 (d, J = 8.68 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 175.5 (C), 141.5 (C), 136.5 (CH), 133.5 (CH), 133.1 (CH), 122.4 (CH), 118.7 (C), 108.8 (C), 86.5 (CH), 51.4 (CH₂), 49.9 (CH), 46.7 (CH), 46.4 (CH), 45.4 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₆H₁₄N₂O₂Na: 289.0947; found: 289.0946.

Compound 10c

White solid; yield: 890 mg (89%) starting from 1.0 g of 9c; mp 186.1–188.3 °C; R_f  = 0.29 (30% EtOAc/hexane).

IR (neat): 2922, 1689, 1516, 1429, 989, 770 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.43 (dt, J = 8.84, 2.04 Hz, 2 H), 7.30 (dt, J = 8.88, 2.04 Hz, 2 H), 6.17 (dd, J = 5.64, 2.96 Hz, 1 H), 6.09 (dd, J = 5.56, 2.88 Hz, 1 H), 4.85 (d, J = 6.32 Hz, 1 H), 3.61 (d, J = 8.08 Hz, 1 H), 3.31 (br t, J = 1.26 Hz, 1 H), 3.27–3.20 (m, 2 H), 2.70 (ddd, J = 8.52, 4.24, 0.76 Hz, 1 H), 1.60 (dt, J = 8.55, 1.52 Hz, 1 H), 1.38 (d, J = 8.52 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 175.7 (C), 136.4 (CH), 133.5 (CH), 132.1 (CH), 125.4 (CH), 119.7 (C), 87.2 (CH), 51.4 (CH₂), 49.6 (CH), 46.6 (CH), 46.1 (CH), 45.3 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₅H₁₄BrNO₂Na: 342.0099; found: 342.0100.

Compound 10d

White solid; yield: 455 mg (57%) starting from 800 mg of 9d; mp 104.8–106.5 °C; R_f  = 0.30 (30% EtOAc/hexane).

IR (neat): 2933, 1684, 1515, 1405, 1321, 842, 761 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.23 (d, J = 8.40 Hz, 2 H), 7.14 (d, J = 8.24 Hz, 2 H), 6.22 (dd, J = 5.52, 2.78 Hz, 1 H), 6.13 (dd, J = 5.56, 2.78 Hz, 1 H), 4.88 (s, 1 H), 3.37–3.17 (m, 4 H), 2.71 (dd, J = 8.40, 4.14 Hz, 1 H), 2.32 (s, 3 H), 1.59 (d, J = 8.48 Hz, 1 H), 1.40 (d, J = 8.48 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 175.1 (C), 136.7 (C), 136.6 (CH), 134.5 (C), 133.4 (CH), 129.8 (CH), 124.7 (CH), 87.3 (CH), 51.4 (CH₂), 49.5 (CH), 46.5 (CH), 45.8 (CH), 45.2 (CH), 21.1 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₆H₁₇NO₂Na: 278.1153; found: 278.1151.

β-Allyl Lactams 11b–d and Lactam 17; General Procedure

BF₃·OEt₂ (4 mmol for 1 mmol of 10, 4 equiv) was added to a solution of the respective β-hydroxyl lactam derivative 10b–d (1 mmol, 1 equiv) at the given temperature (Table [1]) and the mixture was stirred for 15 min under N₂ atmosphere. Next, allyl TMS or pentenylboronic acid (4 mmol for 1 mmol of 10, 4 equiv) was added to the solution and allowed to stir for 1 h at the same temperature. The mixture was brought to rt over 4–8 h and the stirring was continued for 2 h at rt. After completion of reaction, the mixture was quenched and washed with H₂O (2 × 25 mL). The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to obtain the desired compound as a pure isomer. The crude product was purified by column chromatography.

Compound 11b

White solid; yield: 140 mg (73%) starting from 250 mg of 10b (yield based on 30% recovered starting material); mp 105.8–108.2 °C; R_f  = 0.55 (20% EtOAc/hexane).

IR (neat): 2935, 2222, 1692, 1508, 1385, 1295, 915, 763 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.62 (d, J = 8.56 Hz, 2 H), 7.55–7.51 (m, 2 H), 6.19 (s, 2 H), 5.74–5.62 (m, 1 H), 5.18–5.02 (m, 2 H), 3.79 (dt, J = 7.72, 5.30 Hz, 1 H), 3.34 (br s, 1 H), 3.29 (dd, J = 9.16, 9.14 Hz, 1 H), 3.14 (br s, 1 H), 2.65 (ddd, J = 9.16, 2.52 Hz, 1 H), 2.38–2.30 (m, 1 H), 2.25–2.16 (m, 1 H), 1.61 (d, J = 8.50 Hz, 1 H), 1.43 (d, J = 8.50 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 175.1 (C), 141.7 (C), 137.6 (CH), 133.6 (CH), 133.1 (CH), 132.2 (CH), 123.0 (CH), 119.6 (CH₂), 118.8 (C), 108.3 (C), 61.1 (CH), 51.1 (CH₂), 51.0 (CH), 46.8 (CH), 46.0 (CH), 40.7 (CH), 38.2 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₉H₁₈N₂ONa: 313.1312; found: 313.1311.

Compound 11c

White solid; yields starting from 300 mg (0.874 mmol) of 10c are mentioned in Table [1]; mp 106.1–110.6 °C; R_f = 0.57 (20% EtOAc/hexane).

IR (neat): 2930, 1689, 1491, 1387, 1290, 826 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.44 (d, J = 8.76 Hz, 2 H), 7.17 (d, J = 8.76 Hz, 2 H), 6.21 (s, 2 H), 5.74–5.60 (m, 1 H), 5.12 (d, J = 10.12 Hz, 1 H), 5.06 (dd, J = 17.08, 1.38 Hz, 1 H), 3.68–3.61 (m, 1 H), 3.31 (s, 1 H), 3.23 (dd, J = 9.24, 9.14 Hz, 1 H), 3.10 (d, J = 3.10 Hz, 1 H), 2.61 (qt, J = 10.56, 2.22 Hz, 1 H), 2.33–2.24 (m, 1 H), 2.20–2.10 (m, 1 H), 1.59 (d, J = 8.38 Hz, 1 H), 1.41 (d, J = 8.44 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 174.6 (C), 137.5 (CH), 136.6 (C), 133.6 (CH), 132.5 (CH), 132.1 (CH), 125.8 (CH), 119.2 (CH₂), 61.9 (CH), 51.0 (CH₂), 50.6 (CH), 46.6 (CH), 45.6 (CH), 40.8 (CH), 38.3 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₈H₁₈BrNONa: 366.0464; found: 366.0461.

Compound 11d

Colorless liquid; yield: 107 mg (47%) starting from 300 mg of 10d (yield based on 30% recovered starting material); R_f  = 0.55 (20% EtOAc/hexane).

IR (neat): 2927, 1688, 1395, 915, 816 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.17–7.10 (m, 4 H), 6.28–6.21 (m, 2 H), 5.77–5.65 (m, 1 H), 5.16–5.04 (m, 2H), 3.60 (dt, J = 7.88, 2.74 Hz, 1 H), 3.36–3.30 (m, 1 H), 3.23 (dd, J = 9.33, 9.16 Hz, 1 H), 3.12–3.07 (m, 1 H), 2.61 (qd, J = 10.56, 2.24 Hz, 1 H), 2.31 (s, 3 H), 2.30–2.25 (m, 1 H), 2.21–2.05 (m, 1 H), 1.60 (dt, J = 8.44, 1.56 Hz, 1 H), 1.42 (d, J = 8.44 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 174.7 (C), 137.5 (CH), 136.1 (C), 134.9 (C), 133.6 (CH), 133.0 (CH), 129.7 (CH), 124.8 (CH), 118.8 (CH₂), 62.4 (CH), 51.0 (CH₂), 50.5 (CH), 46.7 (CH), 45.6 (CH), 40.9 (CH), 38.5 (CH₂), 21.1 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₉H₂₁NONa: 302.1515; found: 302.1515.

Compound 17

Colorless liquid; yield: 100 mg (58%) starting from 150 mg of 10c; R_f  = 0.50 (20% EtOAc/hexane).

IR (neat): 2926, 2857, 1691, 1484, 1384, 914 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.44 (d, J = 8.16 Hz, 2 H), 7.31 (d, J = 8.3 Hz, 2 H), 6.21 (s, 1 H), 6.12 (s, 1 H), 5.80–5.66 (m, 1 H), 5.03–4.90 (m, 2 H), 4.72 (s, 1 H), 3.43–3.27 (m, 4 H), 3.19 (s, 1 H), 2.76 (br s, 1 H), 2.06 (q, J = 6.90 Hz, 1 H), 1.70–1.53 (m, 4 H), 1.46 (d, J = 8.60 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 175.4 (C), 137.9 (CH), 136.9 (C), 136.8 (CH), 136.7 (CH), 133.2 (CH), 132.1 (CH), 125.6 (C), 125.2 (CH), 119.5 (C), 115.3 (CH₂), 92.7 (CH), 64.7 (CH₂), 51.5 (CH₂), 49.8 (CH), 46.1 (CH), 45.6 (CH), 43.3 (CH), 30.3 (CH₂), 28.9 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₂₁H₂₂N₂ONa: 341.1625; found: 341.1624.

Compound 14

NaH (60% dispersed in paraffin, 115 mg, 4.7 mmol, 5 equiv) was washed with anhyd PE (2 × 20 mL) and dried under N₂ before being suspended in anhyd THF (20 mL). To this suspension, was added compound 10b (300 mg, 0.94 mmol) and stirred for 10 min at rt. After the reaction mixture was cooled to 0 °C, allyl bromide (0.45 mL, 2.82 mmol, 3 equiv) was added and allowed to stir for overnight at rt. After the completion of reaction, THF was removed and the residue was suspended in EtOAc (30 mL). The suspension was washed with H₂O (2 × 20 mL), the organic layer was separated, and dried (Na₂SO₄). Solvents were removed under reduced pressure to obtain the compound 14 as a pure product; yield: 330 mg (98%); colorless liquid; R_f  = 0.35 (30% EtOAc/hexane).

IR (neat): 2972, 2223, 1708, 1508, 1385, 1064, 841, 748 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.65–7.60 (m, 2 H), 7.59–7.54 (m, 2 H), 6.15 (s, 1 H), 6.06 (d, J = 2.89 Hz, 1 H), 5.88–5.76 (m, 1 H), 5.23 (d, J = 17.16 Hz, 1 H), 5.15 (d, J = 10.40 Hz, 1 H), 4.87 (s, 1 H), 3.95 (d, J = 5.52 Hz, 2 H), 3.37–3.30 (m, 2 H), 3.18 (s, 1 H), 2.84–2.77 (m, 1 H), 1.52 (dd, J = 61.50, 8.48 Hz, 2 H).

¹³C NMR (CDCl₃, 125 MHz): δ = 175.6 (C), 141.7 (C), 136.5 (CH), 133.3 (CH), 133.2 (CH), 132.8 (CH), 122.4 (CH), 118.6 (C), 117.8 (CH₂), 108.6 (C), 91.4 (CH), 66.2 (CH₂), 51.4 (CH₂), 49.9 (CH), 46.2 (CH), 45.5 (CH), 42.8 (CH).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₉H₁₈N₂O₂Na: 329.1259; found: 329.1260.

Ring-Opening Metathesis; General Procedure

The respective compound 11, 17, or 14 was dissolved in an anhyd solvent (7 mM, CH₂Cl₂, or toluene) and degassed with N₂ followed by ethylene for about 20 min. To this, was added Grubbs catalyst (5 mol% or 10 mol%) and stirred (as described in Table [2] conditions) under ethylene atmosphere. Solvent was removed and the crude product was purified by column chromatography to obtain the desired product.

Compound 12b

Colorless liquid; yields starting from 70 mg of 11b (0.22 mmol) are given in Table [2]; R_f  = 0.6 (20% EtOAc/hexane).

IR (neat): 2925, 2227, 1703, 1509, 1386, 1295, 920, 760 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.63 (s, 4 H), 6.10–5.98 (m, 1 H), 5.94–5.82 (m, 1 H), 5.63–5.49 (m, 1 H), 5.26–4.93 (m, 6 H), 4.24 (pent, J= 3.04 Hz, 1 H), 3.22 (t, J = 8.68 Hz, 1 H), 2.96–2.82 (m, 2 H), 2.75 (td, J = 11.20, 2.64 Hz, 1 H), 2.34–2.15 (m, 2 H), 1.96–1.87 (m, 1 H), 1.45 (q, J = 12.45 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 173.7 (C), 141.7 (C), 137.5 (CH), 133.1 (CH), 131.7 (CH), 122.8 (CH), 120.0 (CH₂), 117.1 (CH₂), 115.1 (CH₂), 108.3 (C) 58.5 (CH), 51.6 (CH), 47.3 (CH), 46.4 (CH), 42.7 (CH), 37.7 (CH₂), 35.2 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + H]⁺ calcd for C₂₁H₂₂N₂O: 319.1804; found: 319.1805.

Compound 12c

Colorless liquid; yield: 48 mg (63%) from 70 mg of 11c (0.19 mmol); R_f  = 0.6 (20% EtOAc/hexane).

IR (neat): 2923, 1702, 1641, 1490, 1291, 916, 757 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.47 (dt, J = 8.84, 2.04 Hz, 2 H), 7.31 (dt, J = 8.78, 2.07 Hz, 2 H), 6.13–6.04 (m, 1 H), 5.97–5.86 (m, 1 H), 5.64–5.51 (m, 1 H), 5.65–5.51 (m, 6 H), 4.14 (dt, J = 6.52, 3.24 Hz, 1 H), 3.19 (t, J = 8.74 Hz, 1 H), 2.94–2.83 (m, 2 H), 2.74 (td, J = 8.48, 3.16 Hz, 1 H), 2.30–2.13 (m, 2 H), 1.92 (dt, J = 12.36, 5.89 Hz, 1 H), 1.50 (q, J = 12.45 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 173.2 (C), 137.9 (CH), 137.7 (CH), 136.6 (C), 132.2 (CH), 132.1 (CH), 125.4 (CH), 119.6 (CH₂), 118.9 (C), 116.8 (CH), 114.8 (CH), 59.1 (CH), 51.4 (CH), 47.2 (CH), 46.4 (CH), 42.9 (CH), 37.7 (CH₂), 35.3 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + H]⁺ calcd for C₂₀H₂₂BrNO: 394.0777; found: 394.0775.

Compound 18

Colorless liquid; yield: 45 mg (91%) from 70 mg of 17 (0.22 mmol) (yield based on 35% recovered starting material); R_f  = 0.6 (20% ­EtOAc/hexane).

IR (neat): 2937, 1691, 1491, 1385, 1292, 827, 757 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.49–7.44 (m, 2 H), 7.40–7.36 (m, 2 H), 6.19–6.10 (m, 1 H), 5.97–5.89 (m, 1 H), 5.75–5.66 (m, 1 H), 5.24–5.04 (m, 6 H), 3.34–3.23 (m, 3 H), 2.94–2.84 (m, 2 H), 2.80 (t, J = 8.60 Hz, 1 H), 2.00 (q, J = 7.15 Hz, 2 H), 1.95–1.87 (m, 1 H), 1.70–1.64 (m, 1 H), 1.59–1.53 (m, 2 H), 1.39 (q, J = 12.52 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 173.5 (C), 137.9 (CH), 137.5 (CH), 137.3 (CH), 136.8 (C), 132.3 (CH), 132.1 (CH), 125.3 (CH), 125.1 (CH), 119.4 (C), 117.1 (CH₂), 115.2 (CH₂), 115.1 (CH₂), 91.1 (CH), 65.3 (CH₂), 50.5 (CH), 47.0 (CH), 45.8 (CH), 45.2 (CH), 35.0 (CH₂), 30.2 (CH₂), 28.8 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₂₃H₂₆N₂ONa: 369.1935; found: 369.1937.

Compound 15

Colorless liquid; yield: 68 mg (89%) from 100 mg of 14 (yield based on 30% recovered starting material); R_f  = 0.45 (30% EtOAc/hexane).

IR (neat): 2863, 2227, 1713, 1499, 1400, 1058, 932, 761 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.74–7.69 (m, 2 H), 7.66–7.60 (m, 2 H), 6.20–6.09 (m, 1 H), 5.96–5.86 (m, 1 H), 5.84–5.73 (m, 1 H), 5.36 (d, J = 1.00 Hz, 1 H), 5.25–5.07 (m, 6 H), 3.90 (dt, J = 5.52, 1.32 Hz, 2 H), 3.31 (t, J = 8.10 Hz, 1 H), 3.00–2.84 (m, 3 H), 1.98–1.86 (m, 1 H), 1.37 (q, J = 12.46 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 173.8, 141.7, 137.0, 133.3, 133.0, 122.5, 118.7, 117.9, 117.5, 115.4, 108.8, 90.0, 66.7, 50.5, 47.1, 45.1, 34.9, 29.8.

HRMS (ESI, Q-ToF): m/z [M + H]⁺ calcd for C₂₁H₂₂N₂O₂: 357.4083; found: 357.4085.

Ring-Closing Metathesis; General Procedure

The respective compound 12 or 18 was dissolved in an anhyd solvent (7 mM, CH₂Cl₂ or toluene) and degassed with N₂ followed by ethylene for about 20 min. To this, Grubbs 2nd generation catalyst (G-II, 5 mol%) was added and stirred for 5 h at rt under ethylene atmosphere. Solvents were removed and purified by column chromatography to obtain the desired product.

Compound 13b

Colorless liquid; yield: 30 mg (84%) starting from 40 mg of 12b; R_f  = 0.48 (20% EtOAc/hexane).

IR (neat): 2876, 2219, 1717, 1476, 990, 755 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.69–7.63 (m, 2 H), 7.39–7.34 (m, 2 H), 6.01–5.93 (m, 1 H), 5.83–5.66 (m, 2 H), 5.08 (dt, J = 16.92, 1.30 Hz, 1 H), 4.97 (dt, J = 10.20, 2.48 Hz, 1 H), 3.87 (td, J = 10.44, 3.80 Hz, 1 H), 3.36–3.23 (m, 1 H), 3.15 (dd, J = 11.76, 6.92 Hz, 1 H), 2.86–2.75 (m, 1 H), 2.61–2.50 (m, 2 H), 2.44–2.34 (m, 1 H), 2.09–2.00 (m, 1 H), 1.80–1.69 (m, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 176.7 (C), 141.9 (C), 139.0 (CH), 132.9 (CH), 131.5 (CH), 125.9 (CH), 123.5 (CH), 118.9 (C), 115.2 (CH₂), 108.5 (C), 57.3 (CH), 51.4 (CH), 50.7 (CH), 45.0 (CH), 40.2 (CH), 38.2 (CH₂), 30.2 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₉H₁₈N₂ONa: 313.1316; found: 313.1318. 

Compound 13c

Colorless liquid; yield: 28 mg (76%) starting from 40 mg of 12c; R_f  = 0.50 (20% EtOAc/hexane).

IR (neat): 2925, 2853, 1714, 1490, 992, 762 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 7.49 (d, J = 8.68 Hz, 2 H), 7.11 (d, J = 8.72 Hz, 2 H), 5.99–5.92 (m, 1 H), 5.85–5.73 (m, 2 H), 5.08 (dt, J = 16.96, 1.25 Hz, 1 H), 4.99 (dt, J = 10.28, 1.16 Hz, 1 H), 3.81 (td, J = 14.52, 3.38 Hz, 1 H), 3.33–3.23 (m, 1 H), 3.11 (dd, J = 11.88, 6.96 Hz, 1 H), 2.83–2.73 (m, 1 H), 2.55–2.48 (m, 1 H), 2.47–2.34 (m, 2 H), 2.08–2.02 (m, 1 H), 1.79–1.72 (m, 1 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 176.9 (C), 139.3 (CH), 136.8 (C), 132.1 (CH), 131.5 (CH), 126.1 (CH), 125.7 (CH), 114.9 (CH₂), 57.8 (CH), 51.6 (CH), 50.7 (CH), 44.9 (CH), 40.1 (CH), 38.3 (CH), 30.2 (CH₂).

HRMS (ESI, Q-ToF): m/z [M + Na]⁺ calcd for C₁₈H₁₈BrNONa: 366.0461; found: 366.0464.

Compound 19

Colorless liquid; yield: 13 mg (62%) starting from 25 mg of 18; R_f  = 0.46 (20% EtOAc/hexane).

IR (neat): 2923, 2857, 1710, 1491, 1384, 1286, 1074, 915 cm^–1.

¹H NMR (CDCl₃, 500 MHz): δ = 7.53–7.47 (m, 2 H), 7.41–7.34 (m, 2 H), 5.26–5.19 (m, 1 H), 5.18–5.06 (m, 2 H), 4.39–4.09 (m, 1 H), 3.84–3.37 (m, 2 H), 3.26–3.24 (m, 1 H), 3.01–2.84 (m, 2 H), 2.77 (t, J = 8.91 Hz, 1 H), 2.08–1.89 (m, 2 H), 1.54–1.28 (m, 6 H).

¹³C NMR (CDCl₃, 100 MHz): δ = 173.1, 137.3, 136.9, 136.0, 132.3, 125.3, 125.2, 119.7, 118.1, 117.1, 115.3, 114.2, 85.1, 50.2, 50.0, 49.4, 46.7, 45.1, 34.9.

HRMS (ESI, Q-ToF): m/z [M + H]⁺ calcd for C₂₀H₂₂BrNO: 394.0775; found: 394.0776.

Acknowledgment

SK thanks the DST for the award of a J. C. Bose fellowship (SR/S2/JCB-33/2010). We thank Dr. Saidulu Todeti for the preparation of the compound 9b. We also thank Ms. Saima Ansari and Mr. Darshan Mhatre, Dept. of Chemistry, IIT Bombay for collecting the crystal data. SK is thankful to Praj industries for supporting the award of Pramod Chaudhari Chair Professor (Green Chemistry).

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