*3.4. Iodocyclopropanation of Vindoline* (**4**)

Vindoline (**4**) (228 mg, 0.50 mmol) was dissolved in dichloromethane (20 mL) and under an Ar at 0 ◦C 1.28 mL (1.28 mmol in 1 *M* hexane solution) of diethylzinc, it was injected to the solution. Then 394 mg (1.00 mmol) of iodoform was added and the reaction mixture was stirred for 30 min at 0 ◦C and then for 6 h at room temperature. After allowing the solution to stand overnight, the addition of diethylzinc (1.28 mL) and iodoform (394 mg) was repeated at 0 ◦C. After stirring for 7 h at room temperature, the reaction mixture was filtered and the filtrate was diluted with dichloromethane (30 mL) and washed with water (100 mL). The aqueous phase was extracted with dichloromethane (5 × 60 mL) and the combined organic phase was dried over magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was separated by preparative TLC (dichloromethane-methanol 19:1) and 28 mg (9%) of product (**10**) was isolated. Mp 116−117 ◦C.

TLC (dichloromethane-methanol 20:1); *Rf* = 0.75.

IR (KBr) 2963, 1742, 1615, 1502, 1231, 1039 cm<sup>−</sup>1.

1H NMR (499,9 MHz, CDCl3) *δ* (ppm) 0.68 (t, *J* = 7.3 Hz, 3H, H3-18), 0.93 (dd, *J* = 9.2, 4.3 Hz, 1H, H-15), 0.99 (dq, *J* = 14.3, 7.3 Hz, 1H, Hx-19), 1.52–1.57 (m, 1H, H-14), 1.89 (dq, *J* = 14.3, 7.3 Hz, 1H, Hy-19), 2.21–2.31 (m, 7H, Hx-3, H2-6, C(17)-OC(O)C*H3*, H-21), 2.32–2.41 (m, 1H, Hx-5), 2.63 (s, 3H, N(1)-C*H3*), 3.13 (dd, *J* = 4.3, 3.7 Hz, 1H, H-22), 3.23–3.35 (m, 1H, Hy-5), 3.42–3.50 (m, 1H, Hy-3), 3.56 (s, 1H, H-2), 3.78 (s, 3H, C(11)-OC*H3*), 3.81 (s, 3H, C(16)-COOC*H3*), 5.53 (s, 1H, H-17), 6.07 (d, *J* = 2.3 Hz, 1H, H-12), 6.30 (dd, *J* = 8.2, 2.3 Hz, 1H, H-10), 6.83 (d, *J* = 8.2 Hz, 1H, H-9), 8.03 (br, 1H, C(16)-O*H*).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) -9.5 (C-22), 8.1 (C-18), 22.4 (C(17)-OC(O)*C*H3), 24.3 (C-14), 29.0 (C-15), 34.5 (C-19), 38.6 (N(1)-*C*H3), 42.1 (C-20), 44.6 (C-6), 52.2 (C-3), 52.3 (C-7), 52.4 (C(16)-COO*C*H3), 53.3 (C-5), 55.4 (C(11)-O*C*H3), 69.7 (C-21), 76.5 (C-17), 78.9 (C-16), 83.8 (C-2), 95.9 (C-12), 105.0 (C-10), 122.5 (C-9), 125.5 (C-8), 153.6 (C-13), 161.2 (C-11), 171.2 (C(17)-O*C*(O)CH3), 171.9 (C(16)-*C*OOCH3).

HRMS: M + H = 597.14664 (C26H34O6N2I, Δ = 1.7 ppm). HR-ESI-MS-MS (CID = 35%) (rel. int. %): 537(100); 505(1); 477(2); 441(1); 381(3); 362(2); 188(2).

#### *3.5. Iodocyclopropanation of 10-Bromovindoline* (**7**)

The compound 10-Bromovindoline (**7**) (268 mg, 0.50 mmol) was dissolved in dichloromethane (20 mL) and under Ar at 0 ◦C with 1.28 mL (1.28 mmol in 1 *M* hexane solution) of diethylzinc being injected into the solution. Then 394 mg (1.00 mmol) of iodoform was added and the reaction mixture was stirred for 30 min at 0 ◦C and then for 8 h at room temperature. After allowing the solution to stand overnight, the addition of diethylzinc (1.28 mL) and iodoform (394 mg) was repeated at 0 ◦C. After stirring for 6 h at room temperature, the reaction mixture was filtered and the filtrate was diluted with dichloromethane (30 mL) and washed with water (100 mL). The aqueous phase was extracted with dichloromethane (5 × 60 mL) and the combined organic phase was dried over magnesium sulfate, filtered and the filtrate was evaporated to dryness. The crude product was separated by preparative TLC (dichloromethane-methanol 19:1) and 74 mg (22%) of product (**11**) was isolated. Mp > 350 ◦C.

TLC (dichloromethane-methanol 20:1); *Rf* = 0.86.

IR (KBr) 3444, 2927, 1740, 1228, 742 cm<sup>−</sup>1.

1H NMR (499,9 MHz, CDCl3) *δ* (ppm) 0.71 (t, 3H, *J* = 7.3 Hz, H3-18), 0.93 (dd, *J* = 9.2, 4.3 Hz, 1H, H-15), 0.93–1.01 (m, 1H, Hx-19), 1.54–1.58 (m, 1H, H-14), 1.89 (dq, *J* = 14.6, 7.3 Hz, 1H, Hy-19), 2.22–2.27 (m, 4H, Hx-3, H2-6, H-21), 2.27 (s, 3H, C(17)-OC(O)C*H3*), 2.32–2.39 (m, 1H, Hx-5), 2.64 (s, 3H, N(1)-C*H3*), 3.10 (t, *J* = 4.3 Hz, 1H, H-22), 3.24–3.30 (m, 1H, Hy-5), 3.43–3.47 (m, 1H, Hy-3), 3.57 (s, 1H, H-2), 3.81 (s, 3H, C(16)-COOC*H3*), 3.88 (s, 3H, C(11)-OC*H3*), 5.51 (s, 1H, H-17), 6.09 (s, 1H, H-12), 7.05 (s, 1H, H-9), 8.01 (br, 1H, C(16)-O*H*).

13C NMR (125.7 MHz, CDCl3) *δ* (ppm) -9.7 (C-22), 8.1 (C-18), 22.4 (C(17)-OC(O)*C*H3), 24.2 (C-14), 28.9 (C-15), 34.7 (C-19), 38.7 (N(1)-*C*H3), 42.1 (C-20), 44.5 (C-6), 52.17 (C-3), 52.22 (C-7), 52.5 (C(16)-COO*C*H3), 53.1 (C-5), 56.3 (C(11)-O*C*H3), 69.6 (C-21), 76.3 (C-17), 78.7 (C-16), 83.8 (C-2), 94.5 (C-12), 100.1 (C-10), 126.2 (C-9), 126.4 (C-8), 152.8 (C-13), 156.7 (C-11), 171.2 (C(17)-O*C*(O)CH3), 171.7 (C(16)-*C*OOCH3).

HRMS: M + H = 675.05411 (C26H33O6N2BrI, Δ = –2.9 ppm). ESI-MS-MS (CID = 35%) (rel. int. %): 615(100); 555(2); 459(1).

## *3.6. Attempted Dichlorocyclopropanation of Vindoline* (**4**)

Vindoline (**4**) (256 mg, 0.56 mmol) and TEBAC (9 mg, 0.04 mmol) were dissolved in chloroform (1.4 mL), then a solution of sodium hydroxide (0.6 g, 15.00 mmol) in water (0.6 mL) was added dropwise to the reaction mixture, and stirred at room temperature for 2 h. The pH of the reaction mixture was adjusted to 7 using 1 M hydrochloric acid. Water was added and the mixture was extracted with chloroform. The combined organic phase was washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative TLC (dichloromethane-methanol 20:1) and 24 mg (9%) of product (**13**) [20−22] was obtained.

#### *3.7. Attempted Dichlorocyclopropanation of Vinblastine* (**1**)

Vinblastine (**1**) (120 mg, 0.15 mmol) was dissolved in chloroform (0.4 mL), TEBAC (3 mg, 0.013 mmol) was added, and 200 mg (5.00 mmol) of NaOH in water (0.2 mL) was added dropwise. After stirring at room temperature for 2 h, the pH of the reaction mixture was neutralized using 1 M hydrochloric acid. Water (20 mL) was added and the mixture was extracted with chloroform (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 20 mg (16%) of product (**15**) was obtained. Mp 205−207 ◦C.

TLC (dichloromethane-methanol 10:1); *Rf* = 0.60.

IR (KBr) 3470, 2964, 1740, 1669, 1614, 1501, 1461, 1371, 1227, 1040, 742 cm<sup>−</sup>1.

1H NMR (799.7 MHz, CDCl3) *δ* (ppm) 0.39 (t, *J* = 7.5 Hz, 3H, H3-18'), 0.82 (t, *J* = 7.4 Hz, 3H, H3-18), 0.91 (dd, *J* = 13.8, 12.3 Hz, 1H, Hx-15'), 1.06 (dq, *J* = 14.7, 7.5 Hz, 1H, Hx-19'), 1.36 (dq, *J* = 14.4, 7.4 Hz, 1H, Hx-19), 1.46 (dd, *J* = 13.8, 3.4 Hz, 1H, Hy-15'), 1.66 (dq, *J* = 14.7, 7.5 Hz, 1H, Hy-19'), 1.83 (dq, *J* = 14.4, 7.4 Hz, 1H, Hy-19), 1.99–2.05 (m, 1H, H-14'), 2.11 (s, 3H, C(17)-OC(O)C*H3*), 2.14 (ddd, *J* = 14.0, 8.7, 7.4 Hz, 1H, Hx-6), 2.30 (br d, *J* = 16.5 Hz, 1H, Hx-17'), 2.43 (d, *J* = 4.9 Hz, 1H, Hx-21'), 2.44–2.47 (m, 1H, Hx-5), 2.48 (dd, *J* = 13.2, 11.2 Hz, 1H, Hx-3'), 2.55–2.56 (m, 1H, Hy-21'), 2.62–2.66 (m, 2H, H-21, Hy-6), 2.66 (s, 3H, N(1)-C*H3*), 2.79–2.83 (m, 1H, Hx-3), 3.01–3.09 (br m, 1H, Hy-17'), 3.15–3.20 (m, 1H, Hx-6'), 3.31–3.35 (m, 1H, Hy-5), 3.37–3.42 (m, 2H, Hx-5', Hy-3), 3.50–3.61 (m, 2H, Hy-6', Hy-5') overlapped with 3.56 (br s, 3H, C(16')-COOC*H3*), 3.73 (s, 1H, H-2), 3.80 (s, 3H, C(16)-COOC*H3*), 3.81 (s, 3H, C(11)-OC*H3*), 3.84–3.87 (m, 1H, Hy-3'), 5.28–5.31 (m, 1H, H-15), 5.52 (s, 1H, H-17), 5.87 (ddd, *J* = 10.4, 4.8, 0.8 Hz, 1H, H-14), 6.11 (s, 1H, H-12), 6.65 (s, 1H, H-9), 7.10–7.14 (m, 2H, H-10', H-12'), 7.16–7.19 (m, 1H, H-11'), 7.35 (br s, 1H, N(4')-C*H*O), 7.51–7.53 (m, 1H, H-9'), 7.95 (br, 1H, NH-1'), 9.85 (br, 1H, C(16)-O*H*).

13C NMR (201.1 MHz, CDCl3) *δ* (ppm) 8.4 (C-18'), 8.5 (C-18), 21.2 (C(17)-OC(O)*C*H3), 24.9 (C-19'), 25.1 (C-6'), 28.8 (br, C-14'), 30.9 (C-19), 38.5 (N(1)-*C*H3), 39.1 (C-17'), 42.6 (C-15'), 42.7 (C-20), 43.6 (C-6), 49.5 (C-5'), 50.5 (C-3), 51.37 (C-5), 51.40 (C-3'), 52.2 (C(16)-COO*C*H3), 52.4 (C(16')-COO*C*H3), 53.3 (C-7), 54.5 (C-21'), 55.7 (C(11)-O*C*H3), 56.4 (br, C-16'), 58.7 (C-20'), 66.4 (C-21), 76.6 (C-17), 79.7 (C-16), 84.0 (C-2), 94.0 (br, C-12), 110.8 (C-12'), 111.1 (br, C-7'), 117.6 (C-9'), 119.3 (C-10'), 120.0 (br, C-10), 122.5 (C-11'), 123.8 (br, C-8), 124.6 (C-14), 125.3 (C-9), 128.3 (C-8'), 129.9 (C-15), 133.0 (br, C-2'), 135.3 (br, C-13'), 153.3 (C-13), 157.9 (C-11), 163.4 (N(4')-*C*HO), 171.0 (C(17)-O*C*(O)CH3), 171.8 (C(16)-*C*OOCH3), 174.4 (br, C(16')-*C*OOCH3).

HRMS: M + Na = 839.41764 (C45H60O10N4Na, Δ = –3.0 ppm). ESI-MS-MS (CID = 35%, rel. int. %): 821(12), 779(100), 761(4), 747(4), 677(7), 570(45).
