Introduction

C19-diterpene alkaloids are a class of natural products present in the plants of the genera Aconitum and Delphinium, and many exhibit pharmacologically important biological activities.1 The structures of talatisamine and puberuline C are depicted in Scheme 1a as representative examples. The intricately fused hexacyclic ABCDEF-ring system of the C19-diterpene alkaloids has inspired chemists to invent synthetic methods for their assembly,2, 3, 4, 5, 6 culminating in the full chemical construction of several members of this family.7, 8, 9, 10, 11 Recently, we successfully synthesized the ABCDE-ring system12 of talatisamine and the ABCDEF-ring system13 of puberuline C based on our development of a new radical-based strategy. In these synthetic studies, a C11-bridgehead radical of the AE-ring moiety undergoes cyclization with the C-ring enone to form a seven-membered B-ring. The success of the intramolecular C11-radical addition led us to explore its intermolecular version, because intermolecular multicomponent reactions generally ensure more convergent, and thus more efficient, approaches to complex molecular architectures.14, 15, 16, 17, 18, 19 Here we report the three-component coupling reaction between the bicyclic AE-ring, the 5-membered C-ring and the C6-8 carbon chain to assemble the ACE-ring substructure 4a with the correct C4,11-quaternary and C10-tertiary carbons in a single step (Scheme 1b).

Results and discussion

We previously realized a three-component reaction between 2a, 3b and O,Te-acetal 5 using a reagent combination of Et3B and O2 (Scheme 1c).20, 21 Treatment of O,Te-acetal 5 with Et3B/O2 generated the highly reactive bridgehead radical species D22, 23, 24, 25, 26 that sequentially coupled with α,β-unsaturated ketone 2a and aldehyde 3b via a radical–polar crossover mechanism to provide adduct 6. This method intermolecularly connected the three simple units with stereoselective installation of the three new stereocenters, and thus significantly increased the molecular complexity in a single step.

To explore efficient strategies for synthesizing the C19-diterpene alkaloids, we decided to construct the ACE-ring system 4a with the C6-8 carbon chain by employing the radical–polar three-component reaction (Scheme 1b). We planned to assemble the structure of 4a from the azabicyclo[3.3.1]nonane AE-ring 1, 5-membered C-ring 2a and the C6-8 carbon chain 3a. Et3B/O2-promoted C-I bond cleavage of 1 would produce the nucleophilic C11-bridgehead radical A that would add to the electron-deficient double bond of C-ring 2a, leading to Ba.27, 28 Then, radical Ba would be captured by Et3B to form boron enolate Ca29 that would undergo the aldol reaction with aldehyde 3a.30, 31, 32 Hence, the one-pot radical and polar additions were expected to afford 4a possessing the correct C4,11-quaternary and C10-tertiary carbon centers of the C19-diterpene alkaloids, such as talatisamine and puberuline C (highlighted by small circles).

Before investigating the key coupling reactions, we prepared the optically active AE-ring 1 from 2-(methoxycarbonyl)cyclohexanone (7) (Scheme 2). Bromination of 7, followed by exchange of the bromide of 8 with iodide using NaI, led to 9. The resultant 9 underwent the double Mannich reaction in the presence of formaldehyde and ethyl amine, giving rise to the azabicyclo[3.3.1]nonane structure (±)-10 as the racemate.33 The methyl ester and the ketone groups of (±)-10 were in turn simultaneously reduced with DIBAL-H (diisobutylaluminium hydride) to the primary and secondary hydroxy groups of (±)-11 (dr at C5=1:1). Then, the racemic (±)-11 was subjected to enzymatic resolution to obtain enantio-enriched (−)-11. Although (±)-11 possesses two potentially reactive hydroxy groups for the enzymatic acylation, screening of enzymes and acylating reagents permitted us to realize the chemo- and enantioselective functionalization of the C18-primary hydroxy group. Namely, treatment of diol (±)-11 (dr at C5=1:1) with Candida rugosa lipase34, 35, 36 and vinyl butyrate in i-Pr2O at 28 °C provided (−)-11 (39% yield) along with (+)-12 having a C18-butyrate group (39% yield). The C4,11-absolute configurations of (−)-11 were elucidated by NMR experiments of derivatives of 4a (Table 1, see Supplementary Information for details). To determine the enantiomeric ratio of the C5-diastereomeric mixtures (−)-11 and (+)-12, the corresponding C5-ketone 13a/b was prepared separately from these compounds, and then analyzed with the chiral HPLC. Acetylation of the C18-hydroxy group of (−)-11, and subsequent Dess–Martin oxidation of the C5-hydroxy group provided 13a and 13b in a 9:1 enantiomeric ratio. On the other hand, basic hydrolysis of the butyrate of (+)-12 was followed by acetylation and oxidation to afford 13a and 13b in a 1:5.5 ratio. Finally, compound (−)-11 (er=9:1) was converted to the requisite AE-ring fragment 1 in two steps; site-selective methyl ether formation by the action of Me3O•BF4 and 2,6-di-tert-butylpyridine, and 2-azaadamantane N-oxyl (AZADO)-catalyzed C5-oxidation in the presence of CuCl.37

Table 1 The two- and three-component radical coupling reactions of 1
Full size table

To evaluate the reactivity of AE-ring iodide 1 as a radical precursor, we first examined the formation of the corresponding radical A and subsequent addition to the cyclopentenone derivatives (2a–c) (Table 1). Upon treatment of 1 and cyclopentenone 2b with Et3B and O2 in CH2Cl2 at room temperature, the C-I bond at the congested bridgehead position was homolytically cleaved to generate bridgehead radical A that reacted with 2b to furnish 14b in 65% yield (dr at C10=1:1, entry 1). When the enantiopure cyclopentenone derivatives 2a and 2c38 were used under the same conditions (entries 2 and 3), the radical reaction of 1 occurred from the opposite side of the preexisting tert-butyldimethylsilyl (TBS)-oxy and acetonide groups, providing 14a (51%) and 14c (52%), respectively, in a C11-stereospecific and C10-stereoselective manner. Thus, the sterically cumbersome bond between the C11-quaternary and C10-tertiary carbon atoms of 14a-c were intermolecularly connected under mild conditions, corroborating the potent reactivity of radical A.

The bridgehead radical reaction was next extended to the radical–polar crossover three-component reactions. Et3B/O2 successfully promoted the reaction between iodide 1, chiral cyclopentenone 2a and benzaldehyde (3b) in CH2Cl2 at room temperature to afford adduct 4b in a C8,9,10-stereoselective manner (53%, entry 4). (Trimethylsilyl)propynal (3a) participated in the coupling with 1 and 2a in the presence of Et3B and O2 to selectively yield 4a (55%, dr at C8=4:1, entry 5). No radical reaction to the triple bond of 3a or 4a was observed, showing the high chemoselectivity of the present method. Moreover, acid/base-sensitive aldehyde 3c with the β-silyloxy group functioned as an effective electrophile to provide 4c (52%, dr at C8=2.9:1, entry 6). The newly generated C8,9,10-stereochemistry of coupling products 4a-c was consistent, and determined by extensive NMR experiments using their derivatives (see Supplementary Information for details). Significantly, the C9-substituted ACE-ring systems 4a–c with the two quaternary carbons (C4,11) and one tertiary carbon (C10) of the C19-diterpene alkaloids were built in a single operation in neutral media at room temperature. In contrast to the successful formation of 4a–c, the three-component adduct 4d was obtained from 1, 2c and 3b in only 10% yield, and the two-component adduct 14c was mainly generated in 36% yield (entry 7). The distinct behavior of 2a and 2c indicated that the C-ring structure influenced the efficiency of the aldol reaction.

The reaction mechanism of the selective generation of 4b and 14c from 2a and 2c, respectively, is outlined in Scheme 3. Addition of bridgehead radical A to 2a from the opposite side of the TBS-oxy group installs the C10-stereochemistry. After the formation of boron enolate Ca, aldehyde 3b approaches from the less hindered face to avoid the bulky AE-ring, and forms the boron-chelating 6-membered transition state Ea, from which the C8,9-stereochemistry of 4b is established.39, 40 In the case of 2c, the radical reaction of 2c and the radical termination of Et3B occurred similarly to 2a, producing Cc. The approach of 3b toward one face of the enolate Cc, however, is blocked by the AE-ring, and the approach toward the other face is hindered by the acetonide-protected 1,2-diol. Because of the structural differences in the Y,Z-functionalities between Ec and Ea, the aldol reaction via Ec becomes less efficient compared with Ea. As a result, the yield of the three-component coupling adduct 4d is significantly decreased, and hydrolysis of Cc mainly occurs to produce the two-component adduct 14c.

In conclusion, we investigated the two- and three-component reactions of 1, and realized the expeditious assembly of the functionalized ACE-ring substructure 4a of the C19-diterpene alkaloids by applying the radical–polar crossover reaction. AE-ring 1, C-ring 2a and C6-8 chain 3a were coupled to generate 4a using Et3B and O2 through formation of the bridgehead radical from iodide 1, radical addition to cyclopentenone 2a and polar addition of the resultant boron enolate to aldehyde 3a. Remarkably, this operationally simple reaction enabled connection of the hindered C10-11 and C8-9 bonds, and installation of the C8,9,10-stereocenters under mild conditions in a single step. As the thus obtained 4a bears the C4,11-quaternary and C10-tertiary carbon centers, and the C6-8 chain of the C19-diterpene alkaloids, the compound would function as a valuable advanced intermediate for their total syntheses.

Experimental procedures

General methods

All reactions sensitive to air or moisture were carried out under argon atmosphere in dry solvents under anhydrous conditions, unless otherwise noted. THF, CH2Cl2 and Et2O were purified by Glass Contour solvent dispensing system (Nikko Hansen, Osaka, Japan). All other reagents were used as supplied unless otherwise stated. Analytical TLC was performed using E. Merck Silica gel 60 F254 precoated plates (Merck, Darmstadt, Germany). Preparative TLC was performed using E. Merck Silica gel 60 F254 precoated plates with 0.50 mm thickness. Flash chromatography was performed using 40–50 μm Silica Gel 60N (Kanto Chemical, Tokyo, Japan), 40–100 μm Silica Gel 60N (Kanto Chemical), 100–210 μm Silica Gel 60N (Kanto Chemical) and 32–53 μm Silica gel BW-300 (Fuji Silysia Chemical, Aichi, Japan). Optical rotations were measured on a JACSO P-200 Digital Polarimeter at room temperature using the sodium D line (JASCO, Tokyo, Japan). IR spectra were recorded on a JASCO FT/IR-4100 spectrometer. 1H- and 13C-NMR spectra were recorded on a JEOL JNM-ECX-500 (500 MHz), a JNM-ECA-500 (500 MHz) or a JNM-ECS-400 (400 MHz) spectrometer (JEOL, Tokyo, Japan). Chemical shifts were reported in ppm on the δ scale relative to CHCl3 (δ=7.26 for 1H NMR), CDCl3 (δ=77.0 for 13C NMR), C6D5H (δ=7.16 for 1H-NMR) and C6D6 (δ=128.0 for 13C-NMR) as internal references. Signal patterns are indicated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak. The numbering of compounds corresponds to that of natural product. Electrospray ionization mass spectra were measured on a JEOL JMS-T100LP or a Bruker microTOF II instrument.

Iodide (±)-10

Br2 (200 μl, 7.96 mmol) was added to a solution of 7 (1.13 g, 7.24 mmol) in Et2O (4.8 ml) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. Then, saturated aqueous NaHCO3 (5 ml) was added. The resulting mixture was extracted with Et2O (5 ml × 3), and the combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated to afford the crude bromide 8. The crude 8 was divided into three equal parts. One-third of the crude 8 was used in the next iodination.

NaI (470 mg, 3.13 mmol) was added to a solution of one-third of the above crude bromide 8 (2.41 mmol) in acetone (4.8 ml) at room temperature. The reaction mixture was stirred at room temperature for 1.5 h. Then, the reaction mixture was filtered through a pad of Celite and the filter cake was washed with acetone. The resultant solution was concentrated to afford the crude 9 that was used in the next reaction without further purification.

Aqueous EtNH2 (70% in water, 465 μl, 7.23 mmol) was added to a solution of the above crude 9 in MeOH (8.0 ml) and aqueous HCHO (37% in water, 2.3 ml, 28.9 mmol) at 0 °C over 3 h. The reaction mixture was warmed to 45 °C and stirred for 5 h. After the mixture was cooled to room temperature, H2O (16 ml) was added. The resultant mixture was extracted with EtOAc (8 ml × 3), and the combined organic layers were washed with brine (5 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (100 g, hexane/EtOAc 50:1 to 5:1) to afford iodide (±)-10 (703 mg, 2.00 mmol). The yield was determined to be 83% yield over 3 steps based on one-third amount of the starting compound 7: pale yellow oil; IR (film) ν 2969, 2949, 2932, 2811, 1739, 1731, 1454, 1435, 1292, 1259, 1224, 1208, 1175, 1131, 1112, 1098, 1090 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.11 (3H, t, J=7.3 Hz, NCH2CH3), 1.51 (1H, m), 2.30 (1H, dddd, J=14.2, 6.4, 2.3, 2.3 Hz), 2.43 (2H, m, NCH2CH3), 2.57 (1H, m), 2.80 (1H, m), 2.99 (1H, dddd, J=13.7, 5.9, 2.3, 2.3 Hz), 3.03 (1H, dd, J=11.9, 2.3 Hz, NCHAHB), 3.16 (1H, m, NCHAHB), 3.18 (1H, m), 3.30 (1H, dd, J=11.9, 2.3 Hz, NCHAHB), 3.74 (1H, dd, J=8.7, 2.8 Hz), 3.76 (3H, s, OMe); 13C NMR (100 MHz, CDCl3) δ 12.6, 24.4, 36.6, 49.4, 50.3, 52.5, 56.2, 59.0, 61.2, 71.6, 170.5, 203.1; HRMS (ESI) calcd for C12H18INO3Na [M+Na]+ 374.0224, found 374.0225.

Diol (±)-11

DIBAL-H (1.0 M in hexane, 9.2 ml, 9.2 mmol) was added to a solution of (±)-10 (536 mg, 1.53 mmol) in THF (15 ml) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 30 min. Then, saturated aqueous NH4Cl (10 ml), saturated aqueous potassium sodium tartrate (15 ml) and EtOAc (15 ml) were successively added. After being stirred at room temperature for 1 h, the resultant mixture was extracted with EtOAc (10 ml × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (40 g, hexane/EtOAc 50:1 to 5:1) to afford a 1:1 C5-diastereomeric mixture of diol (±)-11 (431 mg, 1.33 mmol) in 87% yield: yellow oil; IR (film) ν 3403, 2970, 2925, 2809, 1471, 1452, 1394, 1327, 1291, 1227, 1146, 1076, 1025, 959, 943 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.03 (3H × 1/2, t, J=6.8 Hz, N(CH2CH3), 1.04 (3H × 1/2, t, J=7.2 Hz, N(CH2CH3), 1.32–1.50 (2H and 1H × 1/2, m), 1.44–1.48 (1H × 1/2, m), 2.03–2.10 (1H, m), 2.23–2.40 (3H, m), 2.54 (1H × 1/2, d, J=9.2 Hz), 2.58–2.93 (5H and 1H × 1/2, m), 2.97 (1H × 1/2, dd, J=8.7 1.9 Hz), 3.18 (1H, m), 3.34 (1H, m), 3.43 (1H × 1/2, d, J=8.7 Hz), 3.48 (1H × 1/2, d, J=9.2 Hz), 3.59 (1H × 1/2, dd, J=9.2, 1.8 Hz), 3.88 (1H × 1/2, s), 3.89 (1H × 1/2, s); 13C NMR (100 MHz, CDCl3) δ 12.5 (1C × 1/2), 12.6 (1C × 1/2), 24.8 (1C × 1/2), 25.3 (1C × 1/2), 25.4 (1C × 1/2), 33.9 (1C), 38.9 (1C × 1/2), 42.3 (1C × 1/2), 45.9 (1C × 1/2), 51.2 (1C × 1/2), 51.7 (1C × 1/2), 53.0 (1C × 1/2), 60.4 (1C × 1/2), 62.5 (1C × 1/2), 63.4 (1C × 1/2), 69.0 (1C × 1/2), 70.3 (1C × 1/2), 70.9 (1C × 1/2), 80.3 (1C), 81.1 (1C × 1/2); HRMS (ESI) calcd for C11H21INO2 [M+H]+ 326.0611, found 326.0622.

Diol (−)-11 and butyrate (+)-12

Lipase from C. rugosa (1009 U mg−1, 1.27 g) and vinyl butyrate (1.2 ml, 9.7 mmol) were successively added to a solution of diol (±)-11 (1.27 g, 3.91 mmol) in i-Pr2O (40 ml) at 28 °C. The reaction mixture was stirred at 28 °C for 1 h. Then, the mixture was filtered through a pad of Celite with Et2O. After the filtrate was concentrated, brine (15 ml) was added. The resultant solution was extracted with EtOAc (15 ml × 3), and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (30 g, hexane/EtOAc 50:1 to 1:1) to afford a 1:1 C5-diastereomeric mixture of diol (−)-11 (491 mg, 1.51 mmol) and a 1.7:1 C5-diastereomeric mixture of butyrate (+)-12 (632 mg, 1.54 mmol) in 39% and 39% yields, respectively. The enantiopurity of (−)-11 and (+)-12 was evaluated by the chiral HPLC analysis of compound 13 derived from (−)-11 and (+)-12, respectively (see Scheme 2). The enantiomeric ratio (er) of 13a/13b from (−)-11 was 9:1 and that from (+)-12 was 1:5.5. The analytical detail was described in the Supplementary Information. Diol (−)-11: yellow oil; [α]D23 −3.5 (c 1.00, CHCl3). Butyrate (+)-12: [α]D26 8.0 (c 1.00, CHCl3); IR (film) ν 3500, 2966, 2931, 2875, 2807, 1739, 1454, 1416, 1384, 1304, 1261, 1181, 1132, 1081, 1048, 1091, 991 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.95 (3H × 5/8, t, J=7.4 Hz, COCH2CH2CH3), 1.03 (3H × 3/8, t, J=7.3 Hz, NCH2CH3), 1.33 (1H × 3/8, m), 1.42-1.46 (2H × 5/8, m), 1.67 (2H, qt, J=7.4, 7.4 Hz, COCH2CH2CH3), 1.77 (1H, m), 2.19–2.33 (5H, m), 2.40 (1H × 3/8, d, J=11.0 Hz, NHAHB), 2.55 (1H × 5/8, d, J=11.0 Hz, NHAHB), 2.56–2.70 (1H, m), 2.72–2.90 (3H, m), 2.95 (1H × 5/8, d, J=11.0 Hz, NHAHB), 3.19 (1H × 5/8, s, H-5), 3.56 (1H × 5/8, d, J=11.0 Hz, NHAHB), 3.74-3.80 (1H and 1H × 3/8, m), 4.06 (1H × 5/8, d, J=11.0 Hz, H-18a), 4.10 (1H × 3/8, d, J=11.0 Hz, H-18a); 13C NMR (125 MHz, C6D6) δ 12.5, 12.6, 13.77, 13.79, 18.7, 18.8, 25.5, 25.7, 25.8, 33.8, 36.1, 36.2, 39.4, 41.9, 42.1, 46.6, 51.4, 51.8, 53.6, 60.8, 61.8, 63.0, 63.1, 69.36, 69.39, 69.9, 76.9, 78.2, 173.1, 173.2; HRMS (ESI) calcd for C15H27INO3 [M+H]+ 396.1030, found 396.1017.

Iodide 1

Me3O•BF4 (564 mg, 3.81 mmol) was added to a solution of a 1:1 C5-diastereomeric mixture of diol (−)-11 (620 mg, 1.91 mmol) and 2,6-di-tert-butylpyridine (1.3 ml, 5.7 mmol) in CH2Cl2 (38 ml) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 2 h. Then, saturated aqueous NaHCO3 (20 ml) was added. The resultant mixture was extracted with EtOAc (15 ml × 3), and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (30 g, hexane/EtOAc 50:1 to 5:1) to afford the crude methyl ether that was used in the next reaction without further purification.

CuCl (227 mg, 2.29 mmol) and AZADO (87.2 mg, 573 μmol) were successively added to a solution of the above crude methyl ether, DMAP (93.3 mg, 764 μmol) and 2,2′-bipyridine (59.7 mg, 382 μmol) in CH3CN (9.6 ml) at room temperature. The reaction mixture was stirred at room temperature for 15 min. Then, saturated aqueous Na2S2O3 (10 ml) was added. The resultant mixture was extracted with Et2O (10 ml × 3), and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (20 g, hexane/EtOAc 80:1 to 10:1) to afford iodide 1 (309 mg, 916 μmol) in 48% yield over 2 steps: colorless oil; [α]D22 −0.59 (c 1.00, CHCl3); IR (film) ν 2973, 2925, 2894, 2807, 1727, 1452, 1385, 1348, 1318, 1289, 1235, 1202, 1164, 1112, 1020, 965, 935 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.09 (3H, t, J=7.3 Hz, NCH2CH3), 1.44 (1H, m), 1.75 (1H, ddd, J=13.3, 13.3, 2.3 Hz), 2.34–2.40 (4H, m), 2.74 (1H, ddd, J=13.3, 13.3, 2.3 Hz), 2.97 (1H, m), 3.09 (1H, d, J=11.0 Hz), 3.18 (1H, m), 3.31–3.37 (2H, m), 3.34 (3H, s, OMe), 3.44 (1H, d, J=9.6 Hz), 3.73 (1H, dd, J=11.0, 2.3 Hz); 13C NMR (100 MHz, CDCl3) δ 12.6, 24.6, 37.5, 49.8, 50.3, 51.6, 59.2, 59.4, 61.9, 71.7, 76.2, 207.3; HRMS (ESI) calcd for C12H20INO2 [M+Na]+ 360.0431, found 360.0432.

General procedure A: two-component radical coupling reaction Compound 14b

Et3B (0.99 M in hexane, 370 μl, 370 μmol) was added to a solution of cyclopentenone 2b (31 μl, 370 μmol) and iodide 1 (41.3 mg, 123 μmol) in CH2Cl2 (250 μl) at 0 °C over 30 min. The mixture was warmed to room temperature under air and stirred for 30 min. Then, saturated aqueous NaHCO3 (2 ml) was added. The resultant mixture was extracted with EtOAc (2 ml × 3), and the combined organic layers were passed through a pad of silica gel with EtOAc. After the filtrate was concentrated, the residue was purified by flash column chromatography on silica gel (4 g, hexane/EtOAc 100:1 to 1:1) to afford a 1:1 C10-diastereomeric mixture of 14b (23.4 mg, 79.8 μmol) in 65% yield: [α]D26 −0.43 (c 1.00, CHCl3); IR (film) ν 2957, 2930, 1731, 1710, 1459, 1362, 1330, 1208, 1165, 1112, 1058 cm−1; 1H NMR (500 MHz, CDCl3) δ 1.08 (3H × 1/2, t, J=6.9 Hz, NCH2CH3), 1.09 (3H × 1/2, t, J=6.9 Hz, NCH2CH3), 1.40–1.50 (1H, m), 1.63–1.70 (1H, m), 1.73–1.80 (2H, m), 1.95-2.07 (2H, m), 2.10-2.19 (2H, m), 2.21–2.27 (1H, m), 2.29–2.42 (7H, m), 2.72–2.90 (1H, m), 2.92 (1H × 1/2, dd, J=11.0, 1.8 Hz, NHAHB), 3.01 (1H × 1/2, dd, J=11.0, 1.8 Hz, NHAHB), 3.14 (1H × 1/2, dd, J=11.5 Hz, NHAHB), 3.17 (1H × 1/2, dd, J=11.5 Hz, NHAHB), 3.29 (1H × 1/2, d, J=9.2 Hz, H-18a), 3.30 (1H × 1/2, d, J=9.2 Hz, H-18a), 3.34 (3H, s, OMe), 3.38 (1H, d, J=9.2 Hz, H-18b); 13C NMR (125 MHz, CDCl3) δ 12.56, 12.57, 20.36, 20.37, 20.53, 20.54, 23.4, 23.7, 35.9, 36.3, 36.41, 36.42, 36.52, 36.53, 38.5, 38.7, 39.5, 39.8, 40.9, 41.2, 50.8, 50.9, 51.1, 52.3, 59.2, 59.3, 61.5, 61.6, 63.2, 63.6, 212.5, 212.6, 218.5, 218.7; HRMS (ESI) calcd for C17H27NO3Na [M+Na]+ 316.1883, found 316.1880.

Compound 14a

According to the general procedure A, a 9.1:1 mixture of 14a and the diastereomer presumably originated from the minor enantiomer of 1 (25.7 mg, 60.7 μmol) was obtained in 51% yield by using cyclopentenone 2a (enantiopure, 75.8 mg, 359 μmol), iodide 1 (er=9:1, 40.1 mg, 119 μmol) and Et3B (0.99 M in hexane, 360 μl, 360 μmol) in CH2Cl2 (240 μl). The crude was purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 1:1). [α]D26 23.0 (c 1.00, CHCl3); IR (film) ν 2950, 2929, 2895, 2808, 1747, 1707, 1470, 1389, 1361, 1254, 1204, 1164, 1112, 1007, 979, 940, 908 cm−1; 1H NMR (400 MHz, CDCl3) peaks of the major isomer: δ 0.03 (3H, s, CH3 of TBS), 0.07 (3H, s, CH3 of TBS), 0.86 (9H, s, t-Bu of TBS), 1.09 (3H, t, J=7.3 Hz, NCH2CH3), 1.46 (1H, m), 1.65–1.82 (2H, m), 2.15–2.28 (5H, m), 2.33 (1H, d, J=7.8 Hz), 2.36 (2H, q, J=7.3 Hz, NCH2CH3), 2.58 (1H, d, J=11 Hz, NCHAHB), 2.70 (1H, dd, J=17.8, 7.4 Hz), 2.84 (1H, m), 2.95 (1H, dd, J=11.0, 2.3 Hz, NCHAHB), 3.14 (1H, ddd, J=11.4, 1.8, 1.8 Hz, NCHAHB), 3.32 (1H, d, J=9.6 Hz, H-18a), 3.33 (3H, s, OMe), 3.37 (1H, d, J=9.6 Hz, H-18b), 4.50 (1H, dd, J=6.0, 6.0 Hz, H-12); 13C NMR (100 MHz, CDCl3) peaks of the major isomer: δ −4.7, −3.9, 12.8, 17.7, 20.4, 25.7, 37.9, 40.3, 40.6, 49.3, 50.4, 50.8, 51.4, 52.0, 59.6, 62.3, 62.8, 70.9, 76.0, 216.1, 217.2; HRMS (ESI) calcd for C23H41NO4SiNa [M+Na]+ 446.2697, found 446.2708.

Compound 14c

According to the general procedure A, a 14:1 mixture of 14c and the diastereomer presumably originated from the minor enantiomer of 1 (23.4 mg, 64.0 μmol) was obtained in 52% yield by using cyclopentenone 2c (enantiopure, 56.8 mg, 368 μmol), iodide 1 (er=9:1, 41.4 mg, 123 μmol) and Et3B (0.99 M in hexane, 370 μl, 370 μmol) in CH2Cl2 (250 μl). The crude was purified by flash column chromatography on silica gel (4 g, CH2Cl2 to CH2Cl2/EtOAc 10:1). [α]D22 -65.0 (c 1.00, CHCl3); IR (film) ν 2979, 2934, 2810, 1757, 1706, 1453, 1381, 1242, 1210, 1157, 1112, 1041, 1004, 976 cm−1; 1H NMR (500 MHz, CDCl3) peaks of the major isomer: δ 1.10 (3H, t, J=7.5 Hz, NCH2CH3), 1.33 (3H, s, acetonide), 1.43 (3H, s, acetonide), 1.50 (1H, m), 1.67 (1H, ddd, J=12.6, 12.6, 6.3 Hz), 1.81 (1H, ddd, J=13.2, 13.2, 6.3 Hz), 1.97 (1H, m), 2.04 (1H, m), 2.22 (1H, m), 2.38–2.45 (3H, m), 2.53 (1H, d, J=11.5 Hz, NCHAHB), 2.63 (1H, dd, J=19.5, 10.3 Hz), 2.67 (1H, m), 2.76 (1H, d, J=11.5 Hz, NCHAHB), 2.97 (1H, dd, J=11.5, 1.7 Hz, NCHAHB), 3.09 (1H, dd, J=11.5, 1.2 Hz, NCHAHB), 3.26 (1H, d, J=9.8 Hz, H-18a), 3.32 (3H, s, OMe), 3.36 (1H, d, J=9.8 Hz, H-18b), 4.61 (1H, d, J=6.9 Hz, H-12), 4.68 (1H, d, J=6.9 Hz, H-13); 13C NMR (100 MHz, CDCl3) peaks of the major isomer: δ 12.6, 19.6, 24.7, 26.9, 37.2, 37.8, 38.9, 45.7, 50.2, 51.2, 51.7, 59.6, 62.2, 63.0, 75.8, 79.65, 79.68, 111.8, 212.8, 217.4; HRMS (ESI) calcd for C20H31NO5Na [M+Na]+ 388.2094, found 388.2088.

General procedure B: three-component coupling reaction Compound 4b

Et3B (0.99 M in hexane, 350 μl, 350 μmol) was added to a solution of cyclopentenone 2a (enantiopure, 75.4 mg, 355 μmol), aldehyde 3b (36 μl, 350 μmol) and iodide 1 (er=9:1, 39.9 mg, 118 μmol) in CH2Cl2 (240 μl) at 0 °C over 30 min. The reaction mixture was warmed to room temperature under air and stirred for 30 min. Then, saturated aqueous NaHCO3 (2 ml) was added. The resultant mixture was extracted with EtOAc (2 ml × 3), and the combined organic layers were passed through a pad of silica gel with EtOAc. After the filtrate was concentrated, the residue was purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 1:1) to afford 4b (33.2 mg, 62.7 μmol) in 53% yield: colorless oil; [α]D26 3.13 (c 1.00, CHCl3); IR (film) ν 3462, 2952, 2928, 2894, 2857, 2807, 1708, 1472, 1456, 1388, 1253, 1172, 1113, 1061 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.11 (3H, s, CH3 of TBS), 0.19 (3H, s, CH3 of TBS), 0.94 (9H, s, t-Bu of TBS), 0.98 (3H, t, J=6.9 Hz, NCH2CH3), 1.34-1.38 (1H, m), 1.44-1.53 (2H, m), 1.61 (1H, ddd, J=12.0, 12.0, 6.3 Hz), 1.68 (1H, br d, J=10.9 Hz), 2.12-2.19 (5H, m), 2.34 (1H, d, J=18.9 Hz), 2.36 (1H, m), 2.64 (1H, dd, J=11.4, 1.8 Hz), 2.64-2.74 (2H, m), 3.02 (1H, dd, J=11.4, 1.4 Hz), 3.13 (1H, d, J=9.6 Hz, H-18a), 3.33 (3H, s, OMe), 3.39 (1H, d, J=9.6 Hz, H-18b), 4.43 (1H, d, J=6.0 Hz), 4.48 (1H, s), 4.92 (1H, d, J=7.8 Hz), 7.29-7.38 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) δ −4.6, 12.5, 17.8, 20.0, 25.7, 37.3, 37.4, 49.6, 50.3, 51.2, 52.1, 55.3, 56.7, 59.5, 62.1, 63.1, 71.1, 76.0, 76.3, 127.2, 127.8, 128.2, 141.2, 216.4, 220.4; HRMS (ESI) calcd for C30H47NO5SiNa [M+Na]+ 552.3116, found 552.3117.

Compound 4a

According to the general procedure B, C8(S)-4a (29.0 mg, 52.7 μmol) and C8(R)-4a (7.4 mg, 13.5 μmol) were obtained in 44% and 11% yields, respectively, by using cyclopentenone 2a (enantiopure, 76.7 mg, 361 μmol), aldehyde 3a (53 μl, 361 μmol), iodide 1 (er=9:1, 40.6 mg, 120 μmol) and Et3B (0.99 M in hexane, 370 μl, 370 μmol) in CH2Cl2 (240 μl). The crude was purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). C8(S)-4a: [α]D26 −0.11 (c 1.00, CHCl3); IR (film) ν 3454, 2955, 2929, 2897, 2857, 2809, 2175, 1743, 1709, 1472, 1462, 1388, 1361, 1286, 1251, 1172, 1112, 1066, 1006, 976 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s, CH3 of TBS), 0.13 (3H, s, CH3 of TBS), 0.16 (9H, s, CH3 of TMS), 0.86 (9H, s, t-Bu of TBS), 1.09 (3H, t, J=6.8 Hz, NCH2CH3), 1.49 (1H, m), 1.66 (1H, m), 1.87 (1H, m), 2.02 (1H, m), 2.22-2.41 (7H, m), 2.54 (1H, d, J=11.0 Hz, NCHAHB), 2.81 (2H, dd, J=18.3, 5.5 Hz), 3.01 (1H, d, J=11.0 Hz, NCHAHB), 3.13 (1H, d, J=11.0 Hz, NCHAHB), 3.26 (1H, d, J=9.6 Hz, H-18a), 3.32 (3H, s, OMe), 3.36 (1H, d, J=9.2 Hz, H-18b), 3.70 (1H, s, OH), 4.43 (1H, d, J=5.5 Hz, H-12), 4.66 (1H, d, J=7.8 Hz, H-8); 13C NMR (100 MHz, CDCl3) δ −4.7, −4.5, −0.2, 12.7, 17.7, 20.0, 25.6, 37.4, 38.9, 49.1, 50.4, 51.3, 52.3, 55.3, 55.5, 59.6, 62.2, 63.8, 65.3, 71.0, 75.9, 91.0, 103.6, 216.7, 218.6; HRMS (ESI) calcd for C29H51NO5Si2Na [M+Na]+ 572.3198, found 572.3192. C8(R)-4a: [α]D25 5.21 (c 1.00, CHCl3); IR (film) ν 3441, 2955, 2929, 2898, 2857, 2810, 2172, 1743, 1713, 1471, 1459, 1389, 1250, 1173, 1113, 1065 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s, CH3 of TBS), 0.14 (3H, s, CH3 of TBS), 0.16 (9H, s, CH3 of TMS), 0.87 (9H, s, t-Bu of TBS), 1.08 (3H, t, J=7.3 Hz, NCH2CH3), 1.25 (1H, s, OH), 1.45, (1H, m), 1.71 (1H, m), 1.94 (1H, m), 2.13 (1H, m), 2.23-2.44 (7H, m), 2.49 (1H, d, J=11.0 Hz, NCHAHB), 2.69 (1H, m), 2.80 (1H, dd, J=19.2, 6.4 Hz), 2.88 (1H, dd, J=11.0, 1.8 Hz, NCHAHB), 3.12 (1H, dd, J=11.0, 1.4 Hz, NCHAHB), 3.29 (1H, d, J=9.6 Hz, H-18a), 3.32 (3H, s, OMe), 3.34 (1H, d, J=9.6 Hz, H-18b), 4.39 (1H, d, J=4.4 Hz, H-12), 4.70 (1H, d, J=7.8 Hz, H-8); 13C NMR (125 MHz, CDCl3) δ −4.8, −4.5, −0.2, 12.6, 17.7, 20.4, 25.7, 37.4, 38.5, 49.0, 50.3, 51.3, 52.4, 55.2, 55.3, 59.6, 62.0, 63.6, 65.2, 70.8, 75.8, 77.3, 103.6, 217.0, 218.4, one 13C peak was not observed; HRMS (ESI) calcd for C29H51NO5Si2Na [M+Na]+ 572.3198, found 572.3200.

Compound 4c

According to the general procedure B, a 2.9:1 C8-diastereomeric mixture of 4c (39.2 mg, 64.0 μmol) was obtained in 52% yield by using cyclopentenone 2a (enantiopure, 78.4 mg, 369 μmol), aldehyde 3c (69.5 mg, 369 μmol), iodide 1 (er=9:1, 41.5 mg, 123 μmol) and Et3B (0.99 M in hexane, 380 μl, 380 μmol) in CH2Cl2 (250 μl). The crude was purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). [α]D26 2.48 (c 1.00, CHCl3); IR (film) ν 3471, 2953, 2930, 2892, 2857, 2810, 1740, 1470, 1387, 1362, 1295, 1254, 1188, 1171, 1006, 973, 938 cm−1; 1H NMR (400 MHz, CDCl3) peaks of the major isomer: δ 0.04 (6H, s, CH3 of TBS × 2), 0.06 (3H, s, CH3 of TBS), 0.11 (3H, s, CH3 of TBS), 0.87 (18H, s, t-Bu of TBS × 2), 1.06 (3H, t, J=7.3 Hz, NCH2CH3), 1.42–1.44 (1H, m), 1.60–1.80 (3H, m), 1.93 (1H, m), 2.02–2.06 (1H, m), 2.13 (1H, s), 2.20–2.37 (6H, m), 2.47 (1H, d, J=11.0 Hz, NCHAHB), 2.67–2.73 (1H, m), 2.82 (1H, m), 2.96 (1H, d, J=11.0 Hz, NCHAHB), 3.14 (1H, dd, J=11.4, 1.8 Hz, NCHAHB), 3.26 (1H, d, J=10.1 Hz, H-18a), 3.31 (3H, s, OMe), 3.35 (1H, d, J=9.6 Hz, H-18b), 3.80 (2H, m), 3.84 (1H, s, OH), 4.02-4.05 (1H, m), 4.40 (1H, m); 13C NMR (100 MHz, CDCl3) δ −5.5 (2C × 3/4), -5.4 (2C × 1/4), −4.8 (1C × 1/4), -4.7 (1C × 3/4), -4.4 (1C × 1/4), −4.3 (1C × 3/4), 12.61 (1C × 3/4), 12.64 (1C × 1/4), 17.7 (1C), 18.20 (1C × 1/4), 18.21 (1C × 3/4), 20.2 (1C × 3/4), 20.4 (1C × 1/4), 25.66 (3C × 1/4), 25.69 (3C × 3/4), 25.9 (3C × 3/4), 26.0 (3C × 1/4), 36.5 (1C), 37.2 (1C × 1/4), 37.5 (1C × 3/4), 39.0 (1C × 3/4), 50.0 (1C × 1/4), 50.1 (1C × 3/4), 50.2 (1C × 1/4), 50.3 (1C × 3/4), 51.2 (1C × 1/4), 51.3 (1C × 3/4), 53.1 (1C × 1/4), 53.2 (1C × 3/4), 55.9 (1C × 3/4), 56.5 (1C × 1/4), 56.6 (1C × 3/4), 59.5 (1C), 61.3 (1C × 1/4), 61.5 (1C × 3/4), 62.1 (1C × 3/4), 62.4 (1C × 1/4), 63.3 (1C × 3/4), 63.5 (1C × 1/4), 70.8 (1C), 73.0 (1C × 1/4), 73.2 (1C × 3/4), 75.8 (1C × 1/4), 75.9 (1C × 3/4), 216.8 (1C × 3/4), 217.7 (1C × 3/4), 218.1 (1C × 1/4), 221.0 (1C × 1/4), two 13C peaks of the minor diastereomer were not observed; HRMS (ESI) calcd for C32H61NO6Si2Na [M+Na]+ 634.3930, found 634.3943.

Compound 4d

According to the general procedure B, a 3.6:1 mixture of 14c and 4d (22.3 mg, 44.9 μmol for 14c, 12.5 μmol for 4d) was obtained by using cyclopentenone 2c (enantiopure, 57.8 mg, 375 μmol), aldehyde 3b (38 μl, 370 μmol), iodide 1 (er=9:1, 42.1 mg, 125 μmol) and Et3B (0.99 M in hexane, 380 μl, 380 μmol) in CH2Cl2 (250 μl). The crude was purified by flash column chromatography on silica gel (4 g, CH2Cl2/EtOAc 100:1 to 5:1). The yields were calculated to be 36% for 14c and 10% for 4d, respectively. A small amount of the mixture was repurified by flash column chromatography to obtain pure 4d for characterization. [α]D25 9.1 (c 0.60, CHCl3); IR (film) ν 3491, 2974, 2934, 2812, 1736, 1705, 1455, 1382, 1243, 1207, 1156, 1114, 1042, 915 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, t, J=7.5 Hz, NCH2CH3), 1.20–1.32 (3H, m), 1.35 (3H, s, acetonide), 1.45–1.49 (1H, m), 1.59 (3H, s, acetonide), 1.77 (1H, br s, OH), 2.04–2.07 (1H, m), 2.25–2.30 (2H, m), 2.33–2.40 (1H, m), 2.49 (1H, d, J=10.3 Hz, H-9), 2.85–2.87 (2H, m), 2.86 (1H, d, J=11.5 Hz), 3.19 (1H, d, J=9.8 Hz, H-18a), 3.29 (3H, s, OMe), 3.31 (1H, d, J=9.8 Hz, H-18b), 4.00 (1H, s), 4.65-4.69 (2H, m, H-12 and H-13), 4.75 (1H, d, J=10.3 Hz, H-8), 7.26–7.37 (5H, m, aromatic); 13C NMR (100 MHz, CDCl3) δ 12.3, 14.1, 18.4, 22.3, 24.1, 26.5, 37.2, 49.9, 51.0, 51.7, 56.5, 59.5, 61.7, 62.4, 76.0, 79.4, 80.2, 111.5, 127.7, 128.2, 128.3, 140.3, 216.1, 217.4; HRMS (ESI) calcd for C27H37NO6Na [M+Na]+ 494.2513, found 494.2497.

scheme 1

(a) Structures of the C19-diterpene alkaloids, talatisamine and puberuline C. (b) Plan for assembly of the AE-ring, C-ring and C6-8 carbon chain of the C19-diterpene alkaloids by the three-component coupling reaction. (c) Previously developed radical–polar crossover three-component coupling reaction.

scheme 2

Synthesis of optically active AE-ring fragment 1. Reagents and conditions: (a) Br2, Et2O; (b) NaI, acetone; (c) aq HCHO, aq EtNH2, MeOH, 45 °C, 83% (3 steps); (d) DIBAL-H, THF, 87%, (dr at C5=1:1); (e) lipase from Candida rugosa, vinyl butyrate, i-Pr2O, 28 °C, 39% for (−)-11 (dr at C5=1:1), 39% for (+)-12 (dr at C5=1.7:1); (f) Me3O•BF4, 2,6-di-tert-butylpyridine, CH2Cl2; (g) AZADO, DMAP, 2,2’-bipyridine, CuCl, air, CH3CN, 48% (2 steps); (h) Ac2O, pyridine, 100% from (−)-11; (i) Dess–Martin reagent, CH2Cl2, 80%, 13a: 13b=9: 1; (j) 1M KOH, MeOH, 73% from (+)-12; (k) Ac2O, pyridine, 100%; (l) Dess–Martin reagent, CH2Cl2, 84%, 13a: 13b=1: 5.5.

scheme 3

Rationale of the different reactivity between 2a and 2c, and the stereoselectivity of the three-component coupling reaction.