Total Synthesis of the Aspidosperma Alkaloid (±)-Subincanadine F via a Titanium-Mediated Intramolecular Nucleophilic Acyl Substitution (INAS) Strategy

Abstract

The total synthesis of the bridge-fused Aspidosperma indole alkaloid (±)-subincanadine F has been accomplished in seven steps. The synthetic utility of a titanium-mediated intramolecular nucleophilic acyl substitution (INAS) reaction for the construction of the bridge-fused ring system was demonstrated.

In 2002, Kobayashi and co-workers reported the isolation, structure determination, and preliminary biological properties of subincanadine F (1, Figure 1), one member of a family of monoterpenoid indole alkaloids obtained in minute quantities from the barks of the Brazilian medicinal plant Aspidosperma subincanum Mart.¹ In vitro pharmacological evaluations of subincanadine F (1) revealed cytotoxic activities against murine lymphocytic leukemia (L1210) and human epidermoid carcinoma (KB) cells lines with IC₅₀ values of 2.4 and 4.8 µg/mL, respectively.

FIGURE 1.

Representative members of the subincanadine class of indole alkaloids and stemmadenine.

Among the rich and diverse families of monoterpenoid indole alkaloids,² subincanadine F stands out as being the only known member to feature a 1-azabicyclo[4.3.1]decane bridge-fused system. Though a biogenetic mechanism rationalizing the origins of this framework has yet to be fully elucidated, one postulate put forth by Kobayashi involves a three-carbon metabolic degradation of a stemmadenine-type precursor (cf. 4, Figure 1), the proposed biosynthetic forerunner of the subincanadines.^1a The structural considerations presented by subincanadine F (1), together with its biological properties, invited us to initiate efforts directed toward its total synthesis. We also viewed the ring system of 1 as grounds on which to advance further methods for the construction of bridge-fused azabicyclic scaffolds for projected extrapolation onto broader classes of alkaloid natural products. In this Note, we describe the outcome of these initiatives.

Zhai and co-workers previously used a bridge-forming Mannich reaction to construct the C(3–14) bond of 1,³ while Li and co-workers employed a Dieckmann cyclization for C(15–20).⁴ Each synthetic route, however, required a late-stage aldol condensation to install the (E)-exo-ethenyl appendage.⁵ We envisioned that both the C(15–20) bond and the (E)-ethenyl moiety could be fashioned simultaneously through a titanium-mediated intramolecular nucleophilic acyl substitution (INAS) reaction. Specifically, 6-exo-trig ring-closure of an organotitanium species (cf. A, Scheme 1) onto the ester function at C(15) would afford the complete fused ring system of subincanadine F (1). Such an organotitanium intermediate^6,7 could be derived from the in situ complexation of alkyne 5 with a low-valent titanium reagent generated from Ti(Oi-Pr)₄ and 2 equiv of i-PrMgCl. Importantly, such a strategy would directly furnish an exo-ethenyl group having the requisite (E) geometry about the trisubstituted C(19–20) bond, thereby obviating the need for its late-stage installation.

SCHEME 1.

Retrosynthetic Analysis of Subincanadine F

We constructed intermediate 5, an N_b-butynyl derivative of Kuehne’s indoloazepine 11 (Scheme 2),⁸ from tryptamine (6), methyl chloropyruvate (7), and butynyl mesylate 8, by using a modification of Kuehne’s protocol.⁸ Thus, Pictet–Spengler condensation of 6 and 7⁹ provided (chloromethyl)tetrahydro-β-carboline adduct 9 (Scheme 2), which was briefly heated in refluxing pyridine to effect clean rearrangement with ring expansion to give indoloazepine ester 10. Reduction of the olefin in 10 using pyridine–borane complex furnished its saturated congener 11.

SCHEME 2.

Total Synthesis of Subincanadine F

Alkylation of the azepine nitrogen in 11 (Scheme 2) was achieved using butynyl mesylate 8¹⁰ and a Et₃N/K₂CO₃ base mixture to give butynyl amine 5, which after protection of the indole nitrogen provided key intermediate 12 for subsequent use in the titanium-mediated INAS reaction. After a survey of reaction parameters, the intramolecular process was best conducted under the general conditions described by Sato and co-workers involving addition of 2.2 equivalents of Ti(Oi-Pr)₄ and 4.4 equivalents of i-PrMgCl to a solution of alkyne 12 in Et₂O at −78 °C, followed by a period at −50 °C. Gradual warming to 0 °C over several hours resulted in cyclization to give the bridge-fused tetracyclic ketone 13 in 47% yield; the remaining material balance consisted of ~20% unreacted alkyne 12 and an N_b-butenyl derivative from quenching of unreacted organotitanium species A (Scheme 1). Removal of the Boc group in 13 furnished (±)-subincanadine F (1) in 92% yield, with spectral characteristics in agreement with those reported.

In summary, the total synthesis of subincanadine F (1) was accomplished in seven steps from tryptamine. Access to the unusual 1-azabicyclo[4.3.1]decane ring system was gained through a titanium-mediated ring-closing strategy employing N_b-butynyl indoloazepine ester 12 as a key intermediate. These studies underscore the emerging utility of low-valent titanium methodologies in organic synthesis and further applications in the context of alkaloid natural products are anticipated. Efforts toward the total synthesis of additional members of this structurally interesting class of indole alkaloids are currently in progress.

Experimental Section

Methyl 1-(chloromethyl)-2, 3, 4, 9-tetrahydro-1H-pyrido [3, 4-b] indole-1-carboxylate (9)

A solution of tryptamine hydrochloride (18.3 g, 93.0 mmol) and methyl chloropyruvate (14.6 g, 106.9 mmol) in MeOH (365 mL) was heated at reflux for 20 h. The cooled reaction mixture was concentrated and diluted with H₂O (270 mL). Slow addition of concentrated NH₄OH (pH>10) gave a crude solid that was filtered, rinsed with Et₂O, and recrystallized from acetone to afford 9 (24.7 g, 83% yield) as a yellow solid: mp 138–140 °C (lit.⁸ mp 137–139 °C); IR (neat) 3369, 2958, 2869, 1708, 1460, 1447, 1431, 1270, 1215, 1151, 1088, 1026, 739 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.30 (br s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 4.20 (d, J = 10.8 Hz, 1H), 3.84 (s, 3H), 3.75 (d, J = 10.8 Hz, 1H), 3.23 (dd, J = 2.6, 5.6 Hz, 1H), 3.22 (dd, J = 1.4, 5.6 Hz, 1H), 2.77 (t, J = 5.4 Hz, 2H), ¹³C NMR (125 MHz, CDCl₃) δ 172.0, 136.2, 128.3, 126.6, 122.8, 119.7, 118.7, 112.4, 111.2, 63.2, 53.2, 50.4, 40.4, 21.9; HRMS m/z calcd for [(C₁₄H₁₅N₂O₂Cl) + H]⁺ 279.0900, found 279.0894.

(E)-Methyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (10)

A solution of tetrahydro-β-carboline 9 (4.18 g, 15.0 mmol) in pyridine (23 mL) was heated at reflux for 25 min. After removal of pyridine, the residue was taken up in CH₂Cl₂, washed with H₂O, dried (Na₂SO₄), and concentrated to afford 10 (3.08 g, 85% yield) as a brown solid that was sufficiently pure for further use. An analytical sample obtained by flash chromatography (SiO₂, 50:50:1 EtOAc:hexanes:Et₃N) gave the title compound as a yellow crystalline solid: mp 152–153 °C (lit.⁴ mp 148–149 °C); IR (neat) 3449, 3354, 1641, 1592, 1433, 1291, 1249, 1136, 1065, 738 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 10.45 (br s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.11 (td, J = 1.0, 7.1 Hz, 1H), 7.07 (td, J = 0.8, 7.2 Hz, 1H), 5.23 (br s, 1H), 3.80 (s, 3H), 3.49 (q, J = 4.4 Hz, 2H), 3.12 (t, J = 4.4 Hz, 2H), ¹³C NMR (125 MHz, CDCl₃) δ 169.4, 145.9, 134.2, 131.7, 127.8, 120.4, 118.7, 116.3, 110.5, 109.3, 92.7, 51.2, 45.6, 26.5; HRMS m/z calcd for [(C₁₄H₁₄N₂O₂) + H]⁺ 243.1134, found 243.1129.

Methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (11)

To a solution of azepine 10 (3.08 g, 12.7 mmol) in formic acid (10 mL) at 0 °C was added pyridine–borane (1.48 mL 14.8 mmol). After stirring at rt for 2.5 h, the reaction mixture was cooled to 0 °C and a second portion of pyridine–borane (0.90 mL, 9.00 mmol) was added. After an additional 3.5 h at rt, the reaction mixture was cooled to 0 °C, diluted with 10% HCl, and stirred for 30 min. The mixture was basified with concentrated NH₄OH, extracted with CH₂Cl₂, washed with H₂O and brine, dried (Na₂SO₄), and concentrated. Purification of the residue by flash chromatography (SiO₂, 90:10:1 CH₂Cl₂:MeOH:NH₄OH) afforded 11 (2.18 g 70% yield) as a yellow solid: mp 135–137 °C (lit.⁸ mp 138–139 °C); IR (neat) 1724, 1461, 1434,1337, 1238, 1209, 1158, 1008, 742 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.36 (br s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 3.84 (dd, J = 2.8, 4.8 Hz, 1H), 3.71 (s, 3H), 3.59 (dd, J = 4.7, 13.8 Hz, 1H), 3.30 (ddd, J = 3.1, 5.5, 13.1 Hz, 1H), 3.23 (dd, J = 2.9, 13.7 Hz, 1H), 2.98-2.87 (m, 3H), 2.45 (br s, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 172.2, 134.8, 131.7, 128.3, 121.3, 118.9, 117.9, 113.9, 110.5, 52.0, 50.2, 49.4, 47.5, 27.4; HRMS m/z calcd for [(C₁₄H₁₆N₂O₂) + H)]⁺ 245.1290, found 245.1290.

Methyl 3-(but-2-ynyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (5)

A mixture of azepine 11 (920 mg, 3.77 mmol), but-2-ynyl methanesulfonate (8, 782 mg, 5.27 mmol), K₂CO₃ (1.04 g, 7.53 mmol), and Et₃N (0.79 mL, 5.65 mmol) in THF (21 mL) was stirred at rt for 17 h. The reaction mixture was partitioned between Et₂O and H₂O and extracted with Et₂O. The combined organic layers were washed with brine, dried (Na₂SO₄), concentrated, and the residue purified by flash chromatography (SiO₂, 65:35:1 hexanes:EtOAc:Et₃N) to afford 5 (971 mg, 87% yield) as a light yellow oil: IR (thin film) 3399, 2950, 2916, 2360, 2340, 1729, 1462, 1434, 1240, 1161, 1026 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.39 (br s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1 H), 4.04 (dd, J = 2.3, 7.0 Hz, 1H), 3.76 (s, 3H), 3.49 (q, J = 2.2 Hz, 2H), 3.30 (dd, J = 7.1, 12.9 Hz, 1H), 3.14 (dd, J = 2.4, 12.9 Hz, 1H), 2.97-2.88 (m, 4H), 1.81 (t, J = 2.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 172.3, 134.7, 132.0, 128.4, 121.5, 119.3, 118.0, 113.7, 110.7, 80.5, 74.4, 56.8, 55.3, 52.4, 49.2, 45.6, 24.4, 3.4; HRMS m/z calcd for [(C₁₈H₂₀N₂O₂) + H]⁺ 297.1603, found 297.1607.

6-tert-Butyl 5-methyl3-(but-2-ynyl)-2,3,4,5-tetrahydroazepino[4,5-b]indole-5,6(1H)-dicarboxylate (12)

To a solution of the alkylated azepine 11 (328 mg, 1.11 mmol) in THF were added Boc₂O (290 mg, 1.33 mmol) and DMAP (6.8 mg, 0.055 mmol). The reaction mixture was stirred at rt for 80 min and concentrated. Purification of the residue by flash chromatography (SiO₂, 67:33:1 hexanes:EtOAc:Et₃N) gave 12 (402 mg, 92% yield) as a yellow solid: mp 35–37 °C; IR (thin film) 2976, 2904, 2826, 2362, 2341, 1721, 1455, 1358, 1324, 1141, 1030, 845, 738 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.02 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.25 (td, J = 1.4, 7.2 Hz, 1H), 7.21 (td, J = 1.2, 7.2 Hz, 1H), 4.92 (dd, J = 2.4, 5.2 Hz, 1H), 3.70 (s, 3H), 3.60 (ddd, J = 1.0, 5.3, 13.2 Hz, 1H), 3.43 (q, J = 2.2 Hz, 2H), 3.08 (dt, J = 4.3, 12.1 Hz, 1H), 3.00 (ddd, J = 2.2, 5.1, 15.7 Hz, 1H), 2.91-2.82 (m, 2H), 2.65 (ddd, J = 2.2, 11.7, 11.7 Hz, 1H), 1.80 (t, J = 2.3 Hz, 3H), 1.62 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 171.9, 150.6, 135.5, 134.4, 129.7, 123.9, 122.4, 121.1, 117.9, 115.6, 83.9, 80.3, 74.3, 56.5, 54.1, 52.0, 49.5, 46.0, 28.1 (3C), 23.8, 3.4; HRMS m/z calcd for [(C₂₃H₂₈N₂O₄) + H]⁺ 397.2127, found 397.2130.

N_a-Boc-subincanadine F (13)

To a stirred solution of alkyne 12 (205 mg, 0.52 mmol) in Et₂O (7.0 mL) at rt was added Ti(Oi-Pr)₄ (0.35 mL, 1.16 mmol). After cooling to −78 °C, i-PrMgCl (2.0 M in THF, 1.13 mL, 2.26 mmol) was added. The reaction mixture was gradually warmed to −50 °C over 2 h, held at −50 °C for 1 h, then warmed to 0 °C over 1 h. After stirring at 0 °C for 3 h, the reaction mixture was quenched with saturated NaHCO₃, filtered through Celite, washed with brine, dried (Na₂SO₄), and concentrated. Purification of the residue by flash chromatography (SiO₂, 68:25:7:1 EtOAc:CH₂Cl₂:MeOH:NH₄OH) gave 13 (90 mg, 47% yield) as a yellow oil: IR (thin film) 2983, 2929, 2362, 2337, 2151, 2013, 1725, 1680, 1610, 1454, 1358, 1327, 1249, 1138, 1115, 835, 737 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.96 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.7 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 6.75 (q, J = 7.3 Hz, 1H), 5.04 (d, J = 4.6 Hz, 1H), 3.97 (m, 2H), 3.71 (d, J = 14.5 Hz, 1H), 3.62 (dd, J = 5.1, 14.6 Hz, 1H), 3.34 (m, 1H), 3.23 (ddd, J = 3.0, 5.7, 13.6 Hz, 1H), 2.98 (ddd, J = 3.0, 10.8, 16.7 Hz, 1H), 2.77 (ddd, J = 2.5, 5.5, 16.7 Hz, 1H), 1.78 (d, J = 7.3 Hz, 3H), 1.69 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 194.4, 150.6, 136.0, 135.9, 135.7, 135.0, 129.1, 124.0, 122.2, 120.8, 117.7, 115.3, 84.1, 54.6, 51.8, 51.3, 44.7, 28.2 (3C), 23.1, 13.5; HRMS m/z calcd for [(C₂₂H₂₆N₂O₃) + H]⁺ 367.2022, found 367.2027.

Subincanadine F (1)

To a solution of 13 (34 mg, 0.093 mmol) in CH₂Cl₂ (1.3 mL) at rt was added TFA (1.3 mL). After 75 min, the reaction mixture was basified with saturated NaHCO₃ and extracted with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄), concentrated, and the residue purified by flash chromatography (SiO₂, 63:29:8:1 EtOAc:CH₂Cl₂:MeOH:NH₄OH) to afford subincanadine F (1, 23 mg, 92% yield) as a yellow solid: mp 180 °C (dec); IR (thin film) 3397, 2916, 2366, 2237, 1682, 1622, 1455, 1342, 1246, 1180, 1146, 967, 904, 727 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.27 (br s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.9 Hz, 1H), 7.12 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.68 (q, J = 7.3 Hz, 1H), 4.06 (d, J = 16.7 Hz, 1H), 3.87 (d, J = 16.6 Hz, 2H), 3.72 (d, J = 13.8 Hz, 1H), 3.65-3.57 (m, 2H), 3.42-3.28 (m, 2H), 3.01 (ddd, J = 3.4, 10.6, 16.3 Hz, 1H), 2.85 (ddd, J = 3.1, 4.8, 16.4 Hz, 1H), 1.79 (d, J = 7.2 Hz, 3H); ¹H NMR (500 MHz, CD₃OD) δ 7.30 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.97 (t, J = 7.5 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 6.58 (q, J = 7.3 Hz, 1H), 4.10 (d, J = 16.5 Hz, 1H), 3.79 (d, J = 16.7 Hz, 1H), 3.61-3.50 (m, 1H), 3.28–3.34 (m, 2H), 3.16–3.27 (m, 2H), 2.95 (ddd, J = 3.2, 11.5, 16.4 Hz, 1H), 2.77 (ddd, J = 2.9, 4.4, 16.2 Hz, 1H), 1.77 (d, J = 7.3 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 194.8, 135.8, 135.4, 135.3, 132.9, 128.5, 121.9, 119.4, 117.9, 114.2, 110.8, 55.8, 52.1, 50.6, 49.7, 23.4, 13.7; HRMS m/z calcd for [(C₁₇H₁₈N₂O) + H]⁺ 267.1497, found 267.1497.