*3.8. Attempt to Dichlorocyclopropanation of Vincristine* (**2**)

Vincristine (**2**) (130 mg, 0.16 mmol) was dissolved in chloroform (1 mL) and TEBAC (7 mg, 0.031 mmol) was added. Then 230 mg (5.75 mmol) of NaOH in water (0.23 mL) was added dropwise. After stirring at room temperature for 2 h, the pH of the reaction mixture was neutralized with 1 M hydrochloric acid. Water (10 mL) was added and the mixture was extracted with dichloromethane (2 × 10 mL). The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 10:1) and 49 mg (36%) of product (**17**) was obtained. Mp 233–235 ◦C (decomp.).

TLC (dichloromethane-methanol 10:1); *Rf* = 0.53.

IR (KBr) 3469, 1738, 1668, 1460, 1232, 744 cm<sup>−</sup>1.

NMR: two signal sets in a ratio of ca. 2:1 (conformational isomers due to hindered rotation of *N*-formyl group on the vindoline subunit of **2**).

Major signal set:

1H NMR (499.9 MHz, CDCl3) *δ* (ppm) 0.35–0.41 (m, 3H, H3-18'), 0.77 (br t, *J* = 7.3 Hz, 3H, H3-18), 0.97–1.06 (m, 2H, Hx-19', Hx-15'), 1.26–1.43 (m, 3H, Hx-19, Hy-19', Hy-15'), 1.59–1.69 (m, 1H, Hy-19), 1.88–1.98 (br m, 1H, H-14'), 2.01–2.08 (br m, 1H, Hx-6) overlapped with 2.07 (br s, 3H, C(17)-OC(O)C*H3*), 2.33–2.44 (m, 2H, Hx-17', Hx-21'), 2.45–2.54 (m, 2H, Hy-21', Hx-3'), 2.54–2.70 (m, 2H, Hy-6, Hx-5), 2.84–2.93 (m, 2H, Hx-3, H-21), 3.00–3.10 (br m, 1H, Hy-17'), 3.17–3.22 (m, 1H, Hx-6'), 3.35–3.43 (m, 3H, Hy-3, Hy-5, Hx-5'), 3.46–3.53 (m, 1H, Hy-6'), 3.53–3.60 (m, 1H, Hy-5'), 3.62 (s, 3H, C(16')-COOC*H3*), 3.73 (s, 3H, C(16)-COOC*H3*), 3.81 (br d, *J* = 13.7 Hz, 1H, Hy-3'), 3.89 (br s, 3H, C(11)-OC*H3*), 4.76 (br s, 1H, H-2), 5.25 (br s, 1H, H-17), 5.42–5.46 (m, 1H, H-15), 5.91–5.95 (m, 1H, H-14), 6.80 (br s, 1H, H-12), 6.93 (br s, 1H, H-9), 7.09–7.15 (m, 1H, H-10'), 7.15–7.22 (m, 2H, H-12', H-11'), 7.36 (br s, 1H, N(4')-C*H*O), 7.51–7.55 (m, 1H, H-9'), 7.94 (br, 1H, NH-1'), 8.74 (s, 1H, N(1)-C*H*O), 9.23 (br, 1H, C(16)-O*H*).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) 8.1 (C-18, C-18'), 21.1 (C(17)-OC(O)*C*H3), 24.9 (C-19'), 25.0 (C-6'), 28.7 (br, C-14'), 30.7 (C-19), 38.6 (br, C-17'), 40.3 (C-6), 42.3 (C-20), 42.5 (C-15'), 49.5 (C-5'), 49.7 (C-5), 49.9 (C-3), 51.6 (C-3'), 52.6 (C(16')-COO*C*H3), 52.9 (C(16)-COO*C*H3), 53.5 (C-7), 53.8 (C-21'), 56.1 (C(11)-O*C*H3), 56.7 (br, C-16'), 58.4 (C-20'), 65.0 (C-21), 72.6 (C-2), 77.0 (C-17), 79.8 (C-16), 94.8 (br, C-12), 111.1 (C-12'), 111.9 (C-7'), 117.7 (C-9'), 119.6 (C-10'), 122.8 (C-11'), 124.6 (C-8), 125.0 (C-14), 126.6 (br, C-10), 126.9 (C-9), 128.3 (C-8'), 129.6 (C-15), 132.1 (C-2'), 135.6 (C-13'), 141.7 (C-13), 157.7 (C-11), 160.1 (N(1)-*C*HO), 163.4 (N(4')-*C*HO), 170.5 (C(17)-O*C*(O)CH3), 170.7 (C(16)-*C*OOCH3), 173.6 (br, C(16')-*C*OOCH3).

Minor signal set:

1H NMR (499.9 MHz, CDCl3) *δ* (ppm) 0.35–0.41 (m, 3H, H3-18'), 0.64–0.70 (m, 3H, H3-18), 0.97–1.06 (m, 2H, Hx-19', Hx-15'), 1.26–1.43 (m, 3H, Hx-19, Hy-19', Hy-15'), 1.59–1.69 (m, 1H, Hy-19), 1.88–1.98 (br m, 1H, H-14'), 2.01–2.08 (br m, 1H, Hx-6), 2.10 (br s, 3H, C(17)-OC(O)C*H3*), 2.33–2.44 (m, 2H, Hx-17', Hx-21'), 2.45–2.54 (m, 2H, Hy-21', Hx-3'), 2.54–2.70 (m, 2H, Hy-6, Hx-5), 2.84–2.90 (m, 1H, Hx-3), 2.95 (br s, 1H, H-21), 3.00–3.10 (br m, 1H, Hy-17'), 3.17–3.22 (m, 1H, Hx-6'), 3.35–3.43 (m, 3H, Hy-3, Hy-5, Hx-5'), 3.46–3.53 (m, 1H, Hy-6'), 3.53–3.60 (m, 1H, Hy-5'), 3.62 (s, 3H, C(16')-COOC*H3*), 3.78 (s, 3H, C(16)-COOC*H3*), 3.81 (br d, *J* = 13.7 Hz, 1H, Hy-3'), 3.90 (br s, 3H, C(11)-OC*H3*), 4.52 (br s, 1H, H-2), 5.29 (br s, 1H, H-17), 5.42–5.46 (m, 1H, H-15), 5.92–5.96 (m, 1H, H-14), 6.86 (br s, 1H, H-9), 7.09–7.15 (m, 1H, H-10'), 7.15–7.22 (m, 2H, H-12', H-11'), 7.36 (br s, 1H, N(4')-C*H*O), 7.51–7.55 (m, 1H, H-9'), 7.80 (br s, 1H, H-12), 7.96 (br, 1H, NH-1'), 8.21 (s, 1H, N(1)-C*H*O), 9.23 (br, 1H, C(16)-O*H*).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) 7.9 (C-18), 8.1 (C-18'), 21.1 (C(17)-OC(O)*C*H3), 25.0 (C-19', C-6'), 28.7 (br, C-14'), 30.7 (C-19), 38.6 (br, C-17'), 40.0 (C-6), 42.3 (C-20), 42.4 (C-15'), 49.6 (C-5, C-5'), 50.0 (C-3), 51.7 (C-3'), 52.6 (C(16)-COO*C*H3), 52.9 (C(16')-COO*C*H3), 53.1 (C-7), 53.8 (C-21'), 56.1 (C(11)-O*C*H3), 56.7 (br, C-16'), 58.4 (C-20'), 64.3 (C-21), 74.4 (C-2), 76.0 (C-17), 81.5 (C-16), 101.7 (br, C-12), 111.1 (C-12'), 111.7 (C-7'), 117.6 (C-9'), 119.5 (C-10'), 122.7 (C-11'), 124.3 (C-8), 125.1 (C-14), 125.7 (C-9), 126.6 (br, C-10), 128.2 (C-8'), 129.6 (C-15), 132.5 (C-2'), 135.6 (C-13'), 141.6 (C-13), 157.2 (C-11), 160.5 (N(1)-*C*HO), 163.4 (N(4')-*C*HO), 170.3 (C(16)-*C*OOCH3), 170.4 (C(17)-O*C*(O)CH3), 173.7 (C(16')-*C*OOCH3).

HRMS: M + Na = 853.39557 (C45H58O11N4Na, Δ = –4.5 ppm). ESI-MS-MS (CID = 35%, rel. int. %): 835(19), 811(7), 793(100), 775(4), 733(18), 705(3).

#### *3.9. Epoxidation of 10-Bromovindoline* (**7**)

To a solution of 10-bromovindoline (**7**) (300 mg, 0.56 mmol) in methanol (5 mL) and 72% perchloric acid (0.17 mL), *m*-CPBA (306 mg, 1.37 mmol) in methanol (2 mL) was added dropwise at 0 ◦C, and the reaction mixture was stirred at reflux for 5 h. Methanol was evaporated, 10% aqueous sodium carbonate solution (20 mL) was added to the residue, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 15:1) and 70 mg (27%) of product (**19**) was obtained. Mp. 365 ◦C (decomp.).

TLC (dichloromethane-methanol 20:1); *Rf* = 0.30.

IR (KBr) 3445, 1745, 1677, 1589, 1414, 1254 cm<sup>−</sup>1.

1H NMR (499.9 MHz, CDCl3) *δ* (ppm) 0.71 (t, *J* = 7.4 Hz, 3H, H3-18), 1.47 (dq, *J* = 14.8, 7.4 Hz, 1H, Hx-19), 1.75 (dq, *J* = 14.8, 7.4 Hz, 1H, Hy-19), 2.08 (s, 3H, C(17)-OC(O)C*H3*), 2.22 (ddd, *J* = 13.6, 11.2, 5.0 Hz, 1H, Hx-6), 2.46 (ddd, *J* = 13.6, 9.0, 6.2 Hz, 1H, Hy-6), 2.74 (ddd, *J* = 11.2, 9.8, 6.2 Hz, 1H, Hx-5), 2.92–2.98 (m, 5H, H-21, N(1)-C*H3*, Hx-3), 3.48–3.54 (m, 2H, Hy-5, Hy-3), 3.82 (s, 3H, C(16)-COOC*H3*), 4.18 (s, 1H, H-2), 5.16 (s, 1H, H-17), 5.35 (br d, *J* = 10.2 Hz, 1H, H-15), 5.51 (s, 1H, H-12), 5.96 (ddd, *J* = 10.2, 5,1, 1.3 Hz, 1H, H-14), 6.38 (s, 1H, H-9).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) 7.5 (C-18), 20.8 (C(17)-OC(O)*C*H3), 31.1 (C-19), 35.3 (N(1)-*C*H3), 42.2 (C-6), 42.8 (C-20), 50.3 (C-3), 50.7 (C-5), 51.5 (C-7), 52.9 (C(16)-COO*C*H3), 66.8 (C-21), 74.7 (C-17), 79.2 (C-16), 82.1 (C-2), 94.7 (C-12), 123.8 (C-9), 124.7 (C-14), 129.4 (C-15), 157.6 (C-8), 157.9 (C-13), 170.1 (C(17)-O*C*(O)CH3), 170.6 (C(16)-*C*OOCH3), 174.6 (C-11), 180.7 (C-10).

HRMS: M + H = 457.19636 (C24H29O7N2, Δ = –1.2 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 439(23), 429(34), 415(34), 411(3), 397(100), 379(10), 369(9), 368(10), 347(6), 337(27), 295(15), 290(7), 190(7).

#### *3.10. Epoxidation of Catharanthine* (**3**)

*Method A. Without perchloric acid.* To a solution of catharanthine (**3**) (160 mg, 0.48 mmol) in dry methanol (10 mL), *m*-CPBA (184 mg, 0.82 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with 10% aqueous sodium carbonate (10 mL) and extracted with dichloromethane (3 × 10 mL). The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative

TLC (dichloromethane-methanol 4:1) and products **20** (57 mg, 34%) and **21** (62 mg, 35%) were isolated. *N*-oxide **20** is prone to rearrangement and transforms into isoxazolidine **22**, which is a stable compound.

**20** and **22**; mp 116–117 ◦C. TLC (dichloromethane-methanol 4:1); *Rf* (*N*-oxide form (**20**)) = 0.76 and *Rf* (neutral form (**22**)) = 0.90.

IR (KBr) 3378, 3185, 2960, 1735, 1460, 1435, 1237, 744 cm<sup>−</sup>1.

NMR: (chemical shifts might vary slightly with concentration, pH and the exact ratio of **20** and **22**) *N*-oxide **20**:

1H NMR (499.9 MHz, CDCl3) *δ* (ppm) 1.04 (t, *J* = 7.4 Hz, 3H, H3-18), 1.58–1.62 (m, 1H, Hx-17), 2.12–2.19 (m, 1H, Hx-19), 2.44–2.50 (m, 1H, Hy-19), 2.83–2.88 (m, 1H, Hy-17), 2.92–2.96 (m, 1H, H-14), 2.96–3.02 (m, 1H, Hx-6), 3.40–3.48 (m, 2H, Hx-3, Hy-6), 3.67 (s, 3H, C(16)-COOC*H3*), 3.74–3.79 (m, 1H, Hy-3), 3.92 (ddd, *J* = 13.2, 8.3, 1.6 Hz, 1H, Hx-5), 4.27–4.34 (m, 1H, Hy-5), 4.72–4.74 (m, 1H, H-21), 6.07–6.10 (m, 1H, H-15), 7.06–7.09 (m, 1H, H-10), 7.11–7.15 (m, 1H, H-11), 7.21–7.24 (m, 1H, H-12), 7.41–7.43 (m, 1H, H-9), 7.88 (br s, 1H, NH-1).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) 10.4 (C-18), 19.8 (C-6), 28.3 (C-19), 30.0 (C-14), 32.3 (C-17), 51.0 (C-16), 53.2 (C(16)-COO*C*H3), 73.5 (C-3), 74.4 (C-21), 76.9 (C-5), 111.1 (C-12), 111.7 (C-7), 118.2 (C-9), 120.3 (C-10), 122.8 (C-11), 124.3 (C-15), 127.4 (C-8), 133.7 (C-2), 134.9 (C-13), 145.9 (C-20), 171.5 (C(16)-*C*OOCH3).

Isoxazolidine **22**:

1H NMR (499.9 MHz, CDCl3) *δ* (ppm) 1.14 (t, *J* = 7.5 Hz, 3H, H3-18), 1.98 (dd, *J* = 14.2, 6.1 Hz, 1H, Hx-17), 2.18–2.26 (m, 1H, Hx-19), 2.26–2.30 (m, 1H, Hy-17), 2.36–2.45 (m, 1H, Hy-19), 2.58 (dd, *J* = 10.6, 5.2 Hz, 1H, Hx-3), 2.75–2.80 (m, 1H, Hx-6), 2.94–3.01 (m, 1H, Hx-5), 3.13–3.20 (m, 1H, H-14), 3.29–3.37 (m, 3H, Hy-3, Hy-5, Hy-6), 3.77 (s, 3H, C(16)-COOC*H3*), 4.53 (d, *J* = 10.0 Hz, 1H, H-15), 6.19–6.20 (m, 1H, H-21), 7.00–7.04 (m, 1H, H-10), 7.10–7.13 (m, 1H, H-11), 7.24–7.26 (m, 1H, H-12), 7.39–7.42 (m, 1H, H-9), 8.67 (br s, 1H, NH-1).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) 11.3 (C-18), 23.7 (C-6), 27.4 (C-19), 32.5 (C-17), 39.9 (C-14), 46.7 (C-16), 53.1 (C(16)-COO*C*H3), 55.5 (C-3), 55.8 (C-5), 76.6 (C-15), 110.8 (C-12), 113.6 (C-7), 118.4 (C-9), 119.5 (C-10), 121.9 (C-21), 122.7 (C-11), 127.9 (C-2), 128.0 (C-8), 135.2 (C-13), 141.5 (C-20), 174.9 (C(16)-*C*OOCH3).

HRMS:

*N*-oxide **20**:

M+H = 353.18559 (C21H25O3N2, Δ = –1.1 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 336(100), 321(7), 303(6), 294(4), 293(3), 275(2), 266(6), 229(2), 189(2), 171(2), 144(12).

Isoxazolidine **22**:

M+H = 353.18567 (C21H25O3N2, Δ = –0.9 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 335(100), 321(36), 303(36), 294(22), 293(15), 275(11), 266(38), 171(5), 144(4).

**21**; mp 146–147 ◦C. TLC (dichloromethane-methanol 4:1); *Rf* = 0.52.

IR (KBr) 3581, 3365, 2959, 1744, 1570, 1242, 774 cm<sup>−</sup>1.

1H NMR (499.9 MHz, DMSO-*d*6:CDCl3 = 1:1 + 5 *v/v*% CF3COOH) *δ* (ppm) 1.07 (t, *J* = 7.4 Hz, 3H, H3-18), 1.99–2.11 (m, 2H, Hx-17, Hx-19), 2.16–2.25 (m, 1H, Hx-6), 2.25–2.34 (m, 1H, Hy-19), 2.49–2.56 (m, 1H, Hy-6), 2.87–2.93 (m, 1H, Hy-17), 3.11–3.15 (m, 1H, H-14), 3.34–3.40 (m, 1H, Hx-3), 3.67 (s, 3H, C(16)-COOC*H3*), 3.90–3.95 (m, 1H, Hy-3), 4.14–4.29 (m, 1H, Hx-5), 4.54–4.63 (m, 1H, Hy-5), 5.59 (d, *J* = 1.4 Hz, 1H, H-21), 6.24–6.27 (m, 1H, H-15), 7.28–7.32 (m, 1H, H-10), 7.36–7.40 (m, 1H, H-11), 7.44–7.46 (m, 1H, H-12), 7.47–7.49 (m, 1H, H-9).

13C NMR (125.7 MHz, DMSO-*d*6:CDCl3 = 1:1 + 5 *v/v*% CF3COOH) *δ* (ppm) 10.2 (C-18), 26.9 (C-19), 29.0 (C-14), 30.0 (C-6), 34.6 (C-17), 52.3 (C-16), 53.3 (C(16)-COO*C*H3), 64.3 (br, C-3), 65.2 (br, C-5), 70.8 (C-21), 82.8 (C-7), 120.6 (C-12), 122.5 (C-9), 125.9 (C-15), 126.9 (C-10), 129.7 (C-11), 140.2 (br, C-8), 141.4 (C-20), 152.0 (C-13), 168.1 (C(16)-*C*OOCH3), 184.0 (C-2).

HRMS: M + H = 369.18063 (C21H25O4N2, Δ = –0.7 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 351(16), 335(9), 324(29), 307(100), 292(5), 264(14), 205(3), 187(4), 160(6).

*Method B. Using perchloric acid.* To a solution of catharanthine (**3**) (247 mg, 0.73 mmol) in methanol (10 mL) and 72% perchloric acid (0.10 mL), *m*-CPBA (184 mg, 0.82 mmol) was added at 0 ◦C, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with 10% aqueous sodium carbonate (10 mL) and extracted with dichloromethane (3x10 mL). The combined organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 10:1) and products **23** (149 mg, 58%) and **24** (30 mg, 12%) were isolated.

Compound **23**; mp 87–89 ◦C. TLC (dichloromethane-methanol 10:1); *Rf* = 0.55.

IR (KBr) 3436, 2960, 1741, 1459, 1222, 1078, 757 cm<sup>−</sup>1.

1H NMR (499.9 MHz, DMSO-*d*6) *δ* (ppm) 0.96 (t, *J* = 7.4 Hz, 3H, H3-18), 1.73 (dd, *J* = 13.2, 2.3 Hz, 1H, Hx-17), 1.75–1.83 (m, 1H, Hx-6), 1.87–1.96 (m, 2H, Hy-6, Hx-19), 2.07 (dqd, *J* = 16.1, 7.4, 2.0 Hz, Hy-19), 2.52 (dt, *J* = 8.3, 2.6 Hz, 1H, Hx-3), 2.55–2.58 (br m, 1H, H-14), 2.59 (br d, *J* = 8.3 Hz, 1H, Hy-3), 2.73–2.78 (m, 1H, Hy-17), 2.79–2.84 (m, 1H, Hx-5), 3.50 (s, 3H, C(16)-COOC*H3*), 3.61 (ddd, *J* = 14.3, 12.4, 2.3 Hz, 1H, Hy-5), 4.57 (~d, *J* = 1.1 Hz, 1H, H-21), 5.75–5.77 (m, 1H, H-15), 6.01 (d, *J* = 0.9 Hz, 1H, C(7)-O*H*), 7.18–7.22 (m, 1H, H-10), 7.28–7.32 (m, 1H, H-11), 7.33–7.36 (m, 1H, H-12), 7.36–7,39 (m, 1H,

H-9).13C NMR (125.7 MHz, DMSO-*d*6) *<sup>δ</sup>* (ppm) 11.2 (C-18), 25.9 (C-19), 30.7 (C-14), 32.9 (C-6), 39.2 (C-17), 46.7 (C-5), 47.6 (C-3), 52.0 (C(16)-COO*C*H3), 57.4 (C-16), 57.8 (C-21), 87.1 (C-7), 119.9 (C-12), 121.9 (C-9), 122.4 (C-15), 126.1 (C-10), 128.8 (C-11), 143.0 (C-8), 148.1 (C-20), 152.4 (C-13), 171.6 (C(16)-*C*OOCH3), 190.3 (C-2).

HRMS: M + H = 353.18553 (C21H25O3N2, Δ = –1.2 ppm). ESI-MS-MS (CID = 35%, rel. int. %): 335(80), 321(100), 303(3), 189(4), 171(8).

Compound **24**; mp 99–101 ◦C (decomp.). TLC (dichloromethane-methanol 10:1); *Rf* = 0.13. IR (KBr) 1730, 1693, 1618, 755 cm<sup>−</sup>1.

1H NMR (499.9 MHz, DMSO-*d*6:CDCl3 = 2:1 *(v/v*)) *δ* (ppm) 1.03 (t, *J* = 7.4 Hz, 3H, H-18), 1.71 (br d, *J* = 14.8 Hz, 1H, Hx-6), 1.95 (br d, *J* = 13.3 Hz, 1H, Hx-17), 2.06 (dqd, *J* = 16.4, 7.4, 1.6 Hz, Hx-19), 2.30–2.43 (m, 3H, Hy-19, Hy-6, Hy-17), 2.83 (br d, 1H, *J* = 10.8 Hz, Hx-3), 2.90–2.94 (m, 1H, H-14), 3.03–3.08 (m, 2H, Hy-3, Hx-5), 3.24 (s, 3H, C(16)-COOC*H3*), 4.10 (td, *J* = 12.9, 3.2 Hz, 1H, Hy-5), 4.92 (br s, 1H, H-21), 6.17 (br d, *J* = 6.4 Hz, 1H, H-15), 6.55–6.64 (br, 1H, NH-1), 6.72–6.77 (m, 1H, H-10), 6.79–6.82 (m, 1H, H-12), 7.37–7.42 (m, 1H, H-11), 7.49–7.52 (m, 1H, H-9).

13C NMR (125.7 MHz, DMSO-*d*6:CDCl3 = 2:1 (*v/v*)) *δ* (ppm) 10.7 (C-18), 23.4 (C-6), 26.5 (C-19), 28.9 (C-14), 30.3 (C-17), 44.7 (C-5), 50.3 (C-3), 51.9 (C-16), 52.0 (C(16)-COO*C*H3), 54.0 (C-21), 65.0 (C-2), 112.1 (C-12), 118.5 (C-10), 119.4 (C-8), 124.2 (C-9), 128.0 (C-15), 137.3 (C-11), 144.2 (C-20), 159.9 (C-13), 171.2 (C(16)-*C*OOCH3), 202.2 (C-7).

HRMS: M + H = 353.18512 (C21H25O3N2, Δ = –2.4 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 335(3), 321(2), 276(2), 189(100), 172(6), 160(38), 146(23).

## *3.11. Reduction of the 7-Hydroxy Derivative of Catharanthine* (**23**)

To a solution of 7-hydroxyindolenine catharanthine (**23**) (300 mg, 0.85 mmol) in methanol (20 mL), 700 mg of 10% Pd/C and NaBH4 (483 mg, 12.77 mmol) was added at 10 ◦C. The reaction mixture was stirred under an argon atmosphere for 30 min. After filtering the catalyst, a few drops of acetic acid was added, the filtrate was diluted with dichloromethane (50 mL) and washed with 10% aqueous sodium carbonate. The aqueous phase was extracted with dichloromethane (2 × 20 mL), the combined organic phase was washed with water (50 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 9:1) and catharanthine (**3**) was obtained (111 mg, 39%).

#### *3.12. Coupling of the Catharanthine Derivative* (**24**) *with Vindoline* (**4**)

Compound **24** (210 mg, 0.60 mmol) and vindoline (271 mg, 0.59 mmol) (**4**) were added to a mixture that consisted of water (21.3 mL), 1 *M* hydrochloric acid (1.1 mL) and 2,2,2-trifluoroethanol (2.2 mL). Under an argon atmosphere, FeCl3·6 H2O (802 mg, 2.97 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. At 0 ◦C, sodium borohydride (24 mg, 0.63 mmol) in water (1.9 mL) was added dropwise. After 30 min of stirring, the pH was adjusted to 8 with cc. ammonium hydroxide. The reaction mixture was extracted with dichloromethane (2 × 60 mL), the combined organic phase was washed with water (100 mL), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 6:1). A cationic vindoline trimer (**27**) (18 mg, 7%), a vindoline trimer ketone (**28**) (26 mg, 10%), and the *N*-methyl-spiro derivative of catharanthine (**29**) (24 mg, 11%) were obtained.

Compound **27**:

TLC (dichloromethane-methanol 7:1), *Rf* = 0.27.

NMR: two signal sets in a ratio of ca. 3:2 (conformational isomers). Chemical shifts vary slightly with pH, temperature, and the composition of the NMR solvent. The three vindoline subunits of **27** are denoted as A, B, and B'. The two subunits that have the same constitution (vindoline-10-yl) are called B and B'.

Major signal set:

1H NMR (799.7 MHz, CD3OD:CD3CN:D2O = 1:1:1 (*v/v*)) *δ* (ppm) 0.35 (t, *J* = 7.4 Hz, 3H, H3-18B), 0.52 (t, *J* = 7.4 Hz, 3H, H3-18B'), 0.57 (t, *J* = 7.4 Hz, 3H, H3-18A), 1.15–1.20 (m, 1H, Hx-19B'), 1.25–1.30 (m, 1H, Hx-19B), 1.47–1.53 (m, 1H, Hx-19A), 1.53–1.58 (m, 1H, Hy-19A), 1.55–1.61 (m, 1H, Hy-19B'), 1.58–1.63 (m, 1H, Hy-19B), 1.62–1.67 (m, 1H, Hx-6A), 2.02 (s, 6H, C(17B)-OC(O)C*H3*, C(17B')-OC(O)C*H3*), 2.06 (s, 3H, C(17A)-OC(O)C*H3*), 2.15–2.20 (m, 1H, Hx-6B'), 2.20–2.24 (m, 2H, Hy-6A, Hy-6B'), 2.26–2.30 (m, 2H, Hx-6B, H-21B), 2.32–2.35 (m, 1H, Hx-5B), 2.37–2.41 (m, 1H, Hy-6B), 2.54–2.58 (m, 1H, Hx-5B'), 2.64 (s, 3H, N(1B)-C*H3*), 2.65 (s, 1H, H-21B'), 2.67–2.71 (m, 1H, Hx-5A), 2.71 (s, 3H, N(1B')-C*H3*), 2.73–2.77 (m, 1H, Hx-3B), 2.85–2.89 (m, 1H, Hx-3B'), 2.94–2.98 (m, 1H, Hx-3A), 3.12 (s, 1H, H-21A), 3.28 (s, 3H, N(1A)-C*H3*), 3.30–3.34 (m, 1H, Hy-5A), 3.37–3.43 (m, 3H, Hy-5B', Hy-5B, Hy-3A), 3.45–3.53 (m, 2H, Hy-3B', Hy-3B), 3.66 (s, 1H, H-2B), 3.69 (s, 1H, H-2B'), 3.73 (s, 3H, C(11B')-OC*H3*), 3.74 (s, 3H, C(11B)-OC*H3*), 3.78 (s, 3H, C(16B')-COOC*H3*), 3.79 (s, 3H, C(16B)-COOC*H3*), 3.83 (s, 3H, C(16A)-COOC*H3*), 3.97 (s, 3H, C(11A)-OC*H3*), 4.39 (s, 1H, H-2A), 5.08 (s, 1H, H-17A), 5.08–5.11 (m, 1H, H-15B), 5.19–5.22 (m, 1H, H-15B'), 5.32 (s, 1H, H-17B'), 5.38–5.41 (s, 1H, H-15A), 5.43 (s, 1H, H-17B), 5.79–5.82 (m, 1H, H-14B), 5.87–5.90 (m, 1H, H-14B'), 5.94–5.97 (m, 1H, H-14A), 6.27 (s, 1H, H-12B), 6.36 (s, 1H, H-12B'), 6.39 (s, 1H, H-12A), 6.42 (s, 1H, H-9B'), 6.63 (s, 1H, H-9B), 7.29 (s, 1H, H-9A).

13C NMR (201.1 MHz, CD3OD:CD3CN:D2O = 1:1:1 (*v/v*)) *δ* (ppm) 7.6 (C-18A), 9.2 (C-18B), 9.5 (C-18B'), 21.0 (C(17B)-OC(O)*C*H3, C(17A)-OC(O)*C*H3, C(17B')-OC(O)*C*H3), 30.8 (C-19A), 31.9 (C-19B'), 32.7 (C-19B), 37.3 (N(1A)-*C*H3), 38.3 (N(1B')-*C*H3), 38.7 (N(1B)-*C*H3), 43.2 (C-6A), 43.3 (C-20A), 44.0 (C-6B, C-6B'), 44.1 (C-20B'), 44.4 (C-20B), 49.2 (C-5A), 50.6 (C-3A), 51.6 (C-3B'), 51.9 (C-3B, C-7A), 52.1 (C-5B'), 53.3 (C(16B')-COO*C*H3), 53.4 (C(16B)-COO*C*H3), 53.7 (C-7B), 53.8 (C-5B), 54.0 (C(16A)-COO*C*H3), 54.1 (C-7B'), 56.5 (C(11B')-O*C*H3), 57.2 (C(11B)-O*C*H3), 59.3 (C(11A)-O*C*H3), 59.4 (C-10A), 63.4 (C-21A), 67.8 (C-21B'), 69.2 (C-21B), 76.8 (C-17A), 76.9 (C-17B'), 77.0 (C-17B), 80.1 (C-16B, C-16A), 80.5 (C-16B'), 83.8 (C-2B'), 84.0 (C-2B), 84.6 (C-2A), 91.3 (C-12A), 95.1 (C-12B'), 95.5 (C-12B), 115.9 (C-10B), 116.9 (C-10B'), 124.0 (C-9B'), 126.0 (C-14B), 126.1 (C-9B), 126.2 (C-14B'), 126.4 (C-14A), 126.5 (C-8B'), 126.6 (C-8B), 130.2 (C-15A), 130.6 (C-15B, C-15B'), 132.3 (C-8A), 145.9 (C-9A), 155.3 (C-13B), 155.7 (C-13B'), 159.9 (C-11B), 160.9 (C-11B'), 169.9 (C-13A), 172.0 (C(16A)-*C*OOCH3), 172.2 (C(17A)-O*C*(O)CH3), 172.8 (C(17B')-O*C*(O)CH3), 173.0 (C(17B)-O*C*(O)CH3), 173.4 (C(16B')-*C*OOCH3), 173.7 (C(16B)-*C*OOCH3), 190.6 (C-11A).

Minor signal set:

1H NMR (799.7 MHz, CD3OD:CD3CN:D2O = 1:1:1 (*v/v*)) *δ* (ppm) 0.29 (t, *J* = 7.4 Hz, 3H, H3-18A), 0.46 (t, *J* = 7.4 Hz, 3H, H3-18B'), 0.61 (t, *J* = 7.4 Hz, 3H, H3-18B), 0.85–0.89 (m, 1H, Hx-19A), 1.09–1.14 (m, 2H, Hx-19B, Hx-19B'), 1.41–1.45 (m, 1H, Hy-19A), 1.50–1.54 (m, 1H, Hy-19B'), 1.57–1.61 (m, 1H, Hy-19B), 2.00 (s, 3H, C(17A)-OC(O)C*H3*), 2.01 (s, 3H, C(17B)-OC(O)C*H3*), 2.02 (s, 3H, C(17B')-OC(O)C*H3*), 2.07–2.11 (m, 2H, Hx-6B', Hx-6B), 2.19–2.26 (m, 3H, Hy-6B, Hx-6A, Hy-6B'), 2.43–2.47 (m, 1H, Hx-5B'), 2.47–2.51 (m, 1H, Hy-6A), 2.57 (s, 1H, H-21B'), 2.63–2.66 (m, 1H, Hx-5B), 2.68 (s, 3H, N(1B')-C*H3*), 2.72

(s, 3H, N(1B)-C*H3*), 2.77–2.80 (m, 1H, Hx-5A), 2.79–2.83 (m, 1H, Hx-3B'), 2.87 (s, 1H, H-21B), 2.90–2.96 (m, 2H, Hx-3A, Hx-3B), 2.98 (s, 1H, H-21A), 3.23 (s, 3H, N(1A)-C*H3*), 3.37–3.42 (m, 2H, Hy-5B', Hy-5B), 3.42–3.45 (m, 1H, Hy-5A), 3.44–3.49 (m, 3H, Hy-3A, Hy-3B, Hy-3B'), 3.62 (s, 3H, C(11B')-OC*H3*), 3.65 (s, 1H, H-2B'), 3.67 (s, 1H, H-2B), 3.73 (s, 3H, C(11B)-OC*H3*), 3.75 (s, 3H, C(16B)-COOC*H3*), 3.76 (s, 3H, C(16B')-COOC*H3*), 3.80 (s, 3H, C(16A)-COOC*H3*), 4.01 (s, 3H, C(11A)-OC*H3*), 4.50 (s, 1H, H-2A), 4.95 (s, 1H, H-17A), 5.19 (s, 1H, H-17B), 5.22–5.26 (m, 2H, H-15B', H-15A), 5.24 (s, 1H, H-17B'), 5.35–5.38 (m, 1H, H-15B), 5.87–5.90 (m, 1H, H-14B'), 5.90–5.93 (m, 2H, H-14A, H-14B), 6.20 (s, 1H, H-12A), 6.23 (s, 2H, H-12B, H-12B'), 6.52 (s, 1H, H-9B), 6.55 (s, 1H, H-9B'), 7.39 (br s, 1H, H-9A).

13C NMR (201.1 MHz, CD3OD:CD3CN:D2O = 1:1:1 (*v/v*)) *δ* (ppm) 7.6 (C-18A), 8.1 (C-18B), 8.7 (C-18B'), 20.8 (C(17A)-OC(O)*C*H3), 21.0 (C(17B)-OC(O)*C*H3), 21.1 (C(17B')-OC(O)*C*H3), 31.4 (C-19B), 31.6 (C-19B'), 32.1 (C-19A), 37.2 (N(1A)-*C*H3), 38.2 (N(1B)-*C*H3), 38.3 (N(1B')-*C*H3), 42.7 (C-6A), 43.4 (C-20A), 43.8 (C-20B), 43.9 (C-20B'), 44.3 (C-6B'), 44.9 (C-6B), 50.1 (C-5A), 50.7 (C-5B), 50.9 (C-3A), 51.2 (C-3B), 51.4 (C-7A), 51.6 (C-3B'), 51.9 (C-5B'), 53.2 (C(16B)-COO*C*H3), 53.3 (C(16B')-COO*C*H3), 53.9 (C(16A)-COO*C*H3), 54.1 (C-7B'), 54.4 (C-7B), 56.5 (C(11B)-O*C*H3), 56.7 (C(11B')-O*C*H3), 58.0 (C-10A), 59.5 (C(11A)-O*C*H3), 65.2 (C-21A), 66.1 (C-21B), 67.1 (C-21B'), 76.6 (C-17A), 76.9 (C-17B), 77.2 (C-17B'), 79.6 (C-16A), 80.8 (C-16B'), 81.2 (C-16B), 83.3 (C-2B), 83.4 (C-2B'), 84.9 (C-2A), 89.4 (C-12A), 94.7 (C-12B), 95.6 (C-12B'), 115.9 (C-10B), 117.3 (C-10B'), 124.3 (C-9B), 125.2 (C-8B), 125.3 (C-9B'), 125.4 (C-8B'), 125.7 (C-14B), 125.9 (C-14B'), 126.1 (C-14A), 130.1 (C-15A), 130.8 (C-15B'), 131.0 (C-15B), 132.5 (C-8A), 147.2 (br, C-9A), 154.6 (C-13B), 154.9 (C-13B'), 159.8 (C-11B), 160.7 (C-11B'), 169.9 (C-13A), 171.7 (C(17A)-O*C*(O)CH3), 172.1 (C(16A)-*C*OOCH3), 172.5 (C(17B)-O*C*(O)CH3), 172.9 (C(17B')-O*C*(O)CH3), 173.0 (C(16B)-*C*OOCH3), 173.3 (C(16B')-*C*OOCH3), 191.8 (C-11A).

HRMS: M + H = 1365.65951 (C75H93O18N6, Δ = 3.97 ppm). ESI-MS-MS (CID = 35%, rel. int. %): 1347(17), 1305(73), 1245(9), 1203(10), 1096(100), 1036(17).

Compound **28**:

TLC (dichloromethane-methanol 10:1), *Rf* = 0.35.

IR (KBr) 3433, 1749, 1619, 1289, 1207, 1151, 1025, 821 cm<sup>−</sup>1.

NMR: The three vindoline subunits of **28** are denoted as A, B, and B'. The two subunits that have the same constitution (vindoline-10-yl) are called B and B'. A minor signal set (ca. 10%) can also be detected due to conformational isomerism. The assignment of the major signal set is given below.

1H NMR (799.7 MHz, DMSO-*d6*:CD3CN:D2O = 3:1:1 (*v/v*)) *δ* (ppm) 0.30 (t, *J* = 7.3 Hz, 3H, H3-18A), 0.43 (t, *J* = 7.3 Hz, 3H, H3-18B), 0.50 (t, *J* = 7.3 Hz, 3H, H3-18B'), 0.82–0.86 (m, 1H, Hx-19B'), 0.92–0.96 (m, 1H, Hx-19A), 1.21 (dq, *J* = 15.2, 7.3 Hz, 1H, Hx-19B), 1.39–1.43 (m, 1H, Hy-19A), 1.43–1.50 (m, 2H, Hy-19B' Hy-19B), 1.91 (s, 3H, C(17A)-OC(O)C*H3*), 1.94 (s, 3H, C(17B')-OC(O)C*H3*), 1.93–1.97 (m, 1H, Hx-6B), 1.96 (s, 3H, C(17B)-OC(O)C*H3*), 2.08–2.16 (m, 3H, Hy-6B, Hx-6B', Hy-6B'), 2.16–2.20 (m, 2H, Hx-5B, Hx-6A), 2.31 (s, 1H, H-21B), 2.34–2.38 (m, 1H, Hy-6A), 2.55–2.59 (m, 2H, Hx-5A, Hx-5B'), 2.58 (s, 3H, N(1B)-C*H3*), 2.61–2.65 (m, 8H, N(1B')-C*H3*, Hx-3B, N(1A)-C*H3*, H-21A), 2.73 (br s, 1H, H-21B'), 2.79 (br d, *J* = 16.4 Hz, 1H, Hx-3A), 2.85 (br d, *J* = 16.7 Hz, 1H, Hx-3B'), 3.23–3.27 (m, 1H, Hy-5B), 3.29–3.35 (m, 2H, Hy-5A, Hy-5B'), 3.37–3.42 (m, 3H, Hy-3B', Hy-3B, Hy-3A), 3.49 (s, 1H, H-2B), 3.53 (s, 3H, C(11B)-OC*H3*), 3.55 (s, 1H, H-2B'), 3.58 (s, 3H, C(11B')-OC*H3*), 3.65 (s, 3H, C(16A)-COOC*H3*), 3.67 (s, 3H, C(16B')-COOC*H3*), 3.68 (s, 3H, C(16B)-COOC*H3*), 3.91 (s, 1H, H-2A), 4.97 (s, 1H, H-17A), 5.09 (s, 1H, H-12A), 5.10–5.12 (m, 2H, H-15A, H-17B'), 5.16 (br d, *J* = 9.6 Hz, 1H, H-15B), 5.20–5.23 (m, 2H, H-17B, H-15B'), 5.81–5.83 (m, 2H, H-14B, H-14A), 5.83–5.86 (m, 1H, H-14B'), 6.12 (s, 1H, H-12B), 6.18 (s, 1H, H-9B), 6.20 (s, 1H, H-12B'), 6.80 (s, 1H, H-9B'), 7.17 (s, 1H, H-9A).

13C NMR (201.1 MHz, DMSO-*d6*:CD3CN:D2O = 3:1:1 (*v/v*)) *δ* (ppm) 7.2 (C-18B'), 7.7 (C-18A), 8.1 (C-18B), 20.6 (C(17A)-OC(O)*C*H3), 20.77 (C(17B')-OC(O)*C*H3), 20.81 (C(17B)-OC(O)*C*H3), 30.7 (C-19B'), 30.9 (C-19B), 31.2 (C-19A), 34.4 (N(1A)-*C*H3), 38.2 (N(1B)-*C*H3), 38.8 (N(1B')-*C*H3), 42.6 (C-20A), 42.7 (C-20B'), 42.8 (C-6A), 43.0 (C-20B), 43.2 (C-6B), 44.4 (C-6B'), 50.3 (C-7A), 50.4 (C-3A), 50.5 (C-5B'), 50.6 (C-3B'), 50.9 (C-5A), 51.0 (C-3B), 51.8 (C-5B), 52.1 (C(16B')-COO*C*H3), 52.3 (C(16B)-COO*C*H3), 52.5 (C(16A)-COO*C*H3), 52.9 (C-7B), 53.1 (C-7B'), 55.3 (C(11B)-O*C*H3), 55.4 (C(11B')-O*C*H3), 59.6 (C-10A), 65.6 (C-21B'), 67.1 (C-21B), 67.2 (C-21A), 75.7 (C-17A), 76.1 (C-17B'), 76.2 (C-17B), 78.7

(C-16A), 79.5 (C-16B), 79.7 (C-16B'), 81.7 (C-2A), 82.6 (C-2B), 83.4 (C-2B'), 92.1 (C-12A), 93.8 (C-12B), 94.3 (C-12B'), 118.5 (C-10B'), 123.0 (C-10B), 123.36 (C-8B), 123.42 (C-8B'), 124.56 (C-14A), 124.67 (C-14B'), 124.73 (C-9B'), 124.88(C-9B), 124.89 (C-14B), 129.9 (C-15A), 130.3 (C-15B), 130.6 (C-15B'), 133.4 (C-8A), 140,0 (C-9A), 152.4 (C-13B), 152.6 (C-13B'), 158.3 (C-11B), 159.5 (C-11B'), 162.2 (C-13A), 170.1 (C(17A)-O*C*(O)CH3), 170.5 (C(17B')-O*C*(O)CH3), 171.1 (C(17B)-O*C*(O)CH3), 171.79 (C(16A)-*C*OOCH3), 171.83 (C(16B')-*C*OOCH3), 172.1 (C(17B)-*C*OOCH3), 199.1 (C-11A).

HRMS: [(M + 2H)/2]2+ = 676.32271 (C74H92O18N6, Δ = –0.2 ppm). ESI-MS-MS (CID = 45%, rel. int. %): 646(100), 637(14), 616(17), 595(45), 565(16), 542(39), 512(16), 457(16).

Compound **29**:

TLC (dichloromethane-methanol 7:1), *Rf* = 0.11.

1H NMR (799.7 MHz, DMSO-*d*6:CD3CN:D2O = 3:1:1 (*v/v*)) *δ* (ppm) 1.02 (t, *J* = 7.3 Hz, 3H, H3-18), 1.93–1.97 (m, 1H, Hx-6), 2.04–2.09 (m, 1H, Hx-19), 2.07–2.10 (m, 1H, Hx-17), 2.18–2.24 (m, 1H, Hy-19), 2.27–2.31 (m, 1H, Hy-17), 2.55–2.60 (m, 1H, Hy-6), 2.92–2.95 (m, 1H, Hx-3), 3.04 (s, 3H, N(4)-C*H3*), 3.14–3.16 (m, 1H, H-14), 3.23 (s, 3H, C(16)-COOC*H3*), 3.58–3.61 (m, 1H, Hx-5), 3.65–3.68 (m, 1H, Hy-3), 4.10–4.14 (m, 1H, Hy-5), 4.94 (d, *J* = 1.6 Hz, 1H, H-21), 6.41–6.44 (m, 1H, H-15), 6.80–6.84 (m, 1H, H-10), 6.87–6.90 (m, 1H, H-12), 7.48–7.50 (m, 1H, H-9), 7.50–7.53 (m, 1H, H-11).

13C NMR (201.1 MHz, DMSO-*d*6:CD3CN:D2O = 3:1:1 (*v/v*)) *δ* (ppm) 10.5 (C-18), 25.0 (C-6), 27.1 (C-19), 28.2 (C-17), 29.1 (C-14), 52.6 (C-16), 52.9 (C(16)-COO*C*H3), 55.6 (N(4)-*C*H3), 56.8 (C-5), 60.5 (C-3), 63.5 (C-2), 63.7 (C-21), 112.8 (C-12), 118.9 (C-8), 119.2 (C-10), 124.6 (C-9), 130.7 (C-15), 138.9 (C-11), 140.8 (C-20), 160.8 (C-13), 169.9 (C(16)-*C*OOCH3), 213.1 (C-7).

HRMS: M + H = 367.20122 (C22H27O3N2, Δ = –1.1 ppm). ESI-MS-MS (CID = 55%, rel. int. %): 203(100), 160(7).

#### **4. Conclusions**

Halogenated 14,15-cyclopropanovindoline derivatives were prepared by Simmons–Smith reactions with iodoform and bromoform in the presence of diethylzinc. Reactions of dichlorocarbene and catharanthine (**3**), vindoline (**4**), vinblastine (**1**) and vincristine (**2**) resulted in unexpected products. In the case of VLB (**1**), an interesting ring-opened oxirane derivative (**15**) was obtained with two different methods. Our attempt to produce epoxidized monomeric alkaloids also led to anomalous derivatives without an oxirane ring. It could have been easily noticed that the presence or absence of perchloric acid had had a crucial role in the outcome of these reactions. Eventually, we were surprised to discover two similar vindoline trimers (**27**,**28**) in the coupling reaction of vindoline (**4**) and a spiro derivative of catharanthine (**24**). Only the *O*-methylated trimeric vindoline derivative (**27**) was managed to be obtained when vindoline (**4**) was put in itself into the conditions of the formerly mentioned coupling reaction attempt without a catharanthine derivative (**24**).

**Author Contributions:** A.K., S.M., R.P. and P.K. performed the experiments; P.K. and L.H. conceived and designed the experiments; Á.S., Z.S., M.D. and C.S.J. achieved the NMR, MS and HRMS analyses and analyzed the data; A.K., Á.S., C.S.J., P.K. and L.H. wrote the paper.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors are grateful to Gedeon Richter Plc for providing *Vinca* alkaloids as a gift.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


**Sample Availability:** Samples of the compounds are not available from the authors.

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