Takuri
Ozaki
and
Yuichi
Kobayashi
*
Department of Bioengineering, Tokyo Institute of Technology, Box B-52, Nagatsuta-cho 4259, Midori-ku, Yokohama 226-8501, Japan. E-mail: ykobayas@bio.titech.ac.jp
First published on 3rd February 2015
Synthesis of (−)-mesembrine was studied by using the allylic substitution for construction of quaternary carbons. The required allylic picolinate 6 (R = TBS) with the three substituents on the olefin was synthesized by hydromagnesiation of propargylic alcohol (S)-13 followed by iodination, Pd-catalyzed coupling of the resulting vinyl iodide (S)-14 with CH2CH(CH2)2MgBr and esterification with PyCO2H. The substitution proceeded stereo- and regioselectively to afford SN2′ product 9, which was transformed to keto aldehyde 29 by substitution with NsMeNH, Wacker oxidation and ozonolysis. Finally, aldol reaction and subsequent de-nosylation afforded the title compound. During the synthesis, the coupling of the vinyl iodide with alkylmetals was investigated under the Negishi conditions.
As an approach to 6 and 7, coupling of haloallylic alcohols 4, 5 or their derivatives with a 3-butenylmetal was conceived. Coupling of such secondary alcohol derivatives with alkylboranes is found in the literature,10 while that of sterically less hindered primary alcohol derivatives11 and simple alkenyl halides12,13 has been published. However, preparation of the required 3-butenylborane seemed difficult in our case. Consequently, (Z)- and (E)-iodoallylic alcohols and their derivatives 12a–c and 14, 16 were prepared by the methods14,15 delineated in Scheme 3 for a preliminary study of the coupling with model reagents of BuZnCl or BuMgBr (Scheme 4 and Table 1).
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Scheme 4 Coupling of (E)- and (Z)-iodides with Bu-M. R for 12, 17, and 18: a, H; b, TBS, c, EE. R1 and R2 for 14, 19, and 20: R1 = H, R2 = TBS. As above for 16, 21, and 22: R1 = TBS, R2 = PMB. |
Entry | Substrate | Bu-Ma (equiv.) | Catalystb (mol %) | Time (h) | Temp. | Result (ratio)c | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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a BuZnCl was prepared by mixing BuMgBr and ZnCl2. b Except Pd(PPh3)4 and PdCl2(MeCN)2 the other Pd catalysts were prepared in situ by mixing Pd2(dba)3·CHCl3 and the ligands. c The product ratios calculated by 1H NMR were given in parentheses. d Incomplete reactions at rt for 8 h (entry 5) and at rt for 17 h (entry 7). e (E)-7-(TBSO)-4-hepten-3-ol. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 | 12a | BuZnCl (4) | Pd(PPh3)4 (5) | 8 | rt | 18a + 12a | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
2 | 12a | BuZnCl (4) | Pd(AsPh3)2 (5) | 14 | rt | 18a + 12a | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3 | 12a | BuZnCl (4) | PdCl2(MeCN)2 (5) | 20 | rt | No reaction | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
4 | 12a | BuZnCl (4) | Pd(dppf) (5) | 14 | rt | No reaction | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
5 | 12b | BuZnCl (2) | Pd(PPh3)4 (5) | 20d | rt |
17b + 18b (75![]() ![]() |
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6 | 12b | BuMgBr (2) | Pd(PPh3)4 (5) | 9 | rt | 18b | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
7 | 12c | BuZnCl (2) | Pd(PPh3)4 (10) | 4 | 50 °Cd |
17c + 18c (75![]() ![]() |
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8 | 16 | BuZnCl (2) | Pd(PPh3)4 (5) | 40 | rt |
21 + 22 (90![]() ![]() |
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9 | 16 | BuZnCl (2) | Pd(DavePhos)2 (5) | 40 | rt | 21 + 22 + 16 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
10 | 16 | BuZnCl (2) | Pd(IPr)2 (5) | 40 | rt | 21 + 22 + 16 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
11 | 14 | BuZnCl (4) | Pd(PPh3)4 (5) | 18 | 50 °C |
19 + 20 (89![]() ![]() |
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12 | 14 | BuMgBr (5) | Pd(PPh3)4 (5) | 11 | 50 °C |
19 + 20 (87![]() ![]() |
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13 | 14 | BuMgBr (5) | Ni(acac)2 (20) | 11 | 50 °C | trans-Olefine |
Since protection/deprotection manipulation adds two steps in synthesis of 1, coupling of alcohol 12a with BuZnCl and Pd(PPh3)4 was investigated first. The reaction under the Negishi conditions16 produced reduction product 18a (Table 1, entry 1), indicating that dehalogenation took place predominantly. The same olefin was produced with Ni catalysts such as Ni(acac)2 and NiCl2(dppp) as well (data not shown). The use of several other Pd catalysts shown in entries 2–4 resulted in almost no reaction or reduction to 18a. We then examined coupling of TBS ether 12b, which produced the desired product 17b and reduction product 18b in a 75:
25 ratio by 1H NMR (entry 5). The reduction was predominant with BuMgBr to produce 18b (entry 6). Pd-catalyzed reaction of EE ether 12c with BuZnCl gave results similar to that of the TBS ether (entry 7).
With the above results in mind, coupling of (E)-olefin 16 with the TBS group was examined with BuZnCl and Pd(PPh3)4 to afford 21 with better product selectivity over the reduction product 22 (entry 8). A sterically less congested reaction site (C–I) of 16 might be responsible for the higher selectivity. The Pd catalysts with the DavePhos and IPr ligands retarded the reaction (entries 9 and 10). Finally, coupling of alcohol 14 with BuZnCl afforded 19 with an almost similar product selectivity to that of 16 (entry 11, cf. entry 8). Surprisingly, the use of BuMgBr produced 19 as well (entry 12, cf. entry 6). In contrast, Ni(acac)2 produced the (E)-isomer of 20 (entry 13).
In total, (E)-iodoalkenyl isomers 14 and 16 gave 19 and 21 with 87–90% product selectivity. On the other hand, 15 (the precursor of 16) was synthesized only in 33% yield by the hydromagnesiation/iodination of alcohol 11, whereas 13 possessing the TBS group was transformed to 14 in good yield. On the basis of these results, allylic picolinate 6 (R = TBS) in Scheme 2 was selected as the key intermediate for the synthesis of 1.
As delineated in Scheme 5, alcohol 23 was converted to ynone 2417 in two steps. Asymmetric hydrogen transfer18 of 24 afforded propargylic alcohol (S)-13 with 96% ee (chiral HPLC of the derived benzoate) in 93% yield. Hydromagnesiation15 of this alcohol with i-BuMgCl and Cp2TiCl2 in Et2O proceeded smoothly and the resulting vinylmagnesium species was subjected to iodination with I2 in THF to produce (S)-14 stereoselectively in 61% yield. Pd-catalyzed coupling of the iodide with 3-butenylmagnesium bromide under the conditions of Table 1, entry 12, proceeded smoothly to afford the desired product 25 in 76% yield after chromatography. Finally, esterification with 2-PyCO2H furnished the key intermediate 6 (R = TBS) in a high yield.
Among the two types of reagents for the allylic substitution (ArMgBr/Cu(acac)2, 2:
1; that is, 3
:
1 with ZnI2), the copper reagent 8 (1.5 equiv.) derived from 3,4-(MeO)2C6H3MgBr and Cu(acac)2 in a 2
:
1 ratio was investigated for the allylic substitution with 6. The substitution proceeded smoothly at −40 to −20 °C to afford 9, which upon deprotection with TBAF produced alcohol 26 in 80% yield over two steps. Absorbance corresponding to the regioisomer of 26 (structure not shown) was not detected by 1H NMR spectroscopy at the expected region (5.0–5.4 ppm) and 97% chirality transfer (CT) was determined by chiral HPLC analysis (93% ee of 26). Amination of alcohol 26 with NsMeNH19 (Ns: o-(NO2)C6H4SO2) under the Mitsunobu conditions afforded nosyl amine 27, which upon the Wacker oxidation20 produced methyl ketone 28 in 87% from alcohol 26 (two steps).
The last four-step conversion including ozonolysis of 28, aldol reaction, de-nosylation, and the addition of the free amino group to the enone was studied first using racemic olefin rac-28 prepared similarly (Scheme 6). Ozonolysis afforded keto aldehyde rac-29 in 67% yield. Subsequently, aldol reaction with LiOH in i-PrOH–CH2Cl2 (4:
1) at room temperature overnight produced enone rac-30 in 63% isolated yield. The Ns group in rac-30 was removed with the standard reagent/solvent (PhSH, Cs2CO3, MeCN) at 50 °C for 3 h to afford racemic mesembrine (rac-1). Neither the free amine rac-10 nor the PhSH adduct to the enone (structure not shown) was detected by TLC and 1H NMR. Examined next was the one-pot synthesis of rac-1 from rac-29 by adding PhSH and MeCN into the i-PrOH–CH2Cl2 solution of the aldol mixture (containing rac-30 and LiOH). However, no de-nosylation took place and the enone intermediate rac-30 was isolated. Accordingly, the crude enone isolated was exposed to PhSH and LiOH in MeCN to furnish rac-1 in 50% yield over two steps from aldehyde rac-29. These results indicated that the de-nosylation was interfered with by i-PrOH. Indeed, aldol reaction with rac-29 conducted in MeCN with Cs2CO3 was followed by reaction with PhSH to afford rac-1 in 36% yield in one pot.
Among the two-step and one-pot methods for the synthesis of rac-1 from keto aldehyde rac-29, the high yielding former method was applied to synthesis of optically active mesembrine from keto olefin 28 (Scheme 5). Thus, ozonolysis of 28 afforded crude keto aldehyde 29, which upon aldol reaction with LiOH gave enone 30. Finally, enone 30 was exposed to PhSH in MeCN at 50 °C to afford (−)-mesembrine (1) in 38% yield from 28. The yield including ozonolysis was almost comparable to that of the synthesis of racemic mesembrine (rac-1).
To a solution of the above product (320 mg, 1.07 mmol) in CH2Cl2 (10 mL) were added picolinic acid (197 mg, 1.60 mmol), Et3N (0.450 mL, 3.23 mmol), DMAP (131 mg, 1.07 mmol), and 2-chloro-1-methylpyridinium iodide (410 mg, 1.60 mmol). The mixture was stirred at rt overnight, and diluted with brine with vigorous stirring. The layers were separated and the aqueous layer was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated to give a residue, which was purified by chromatography on silica gel (hexane–EtOAc) to afford 6 (407 mg, 94%) as a pale yellow oil: Rf = 0.36 (hexane–EtOAc, 3:
1). 1H NMR (300 MHz, CDCl3) δ 0.05 (s, 6H), 0.88 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H), 1.64–1.79 (m, 1H), 1.82–1.98 (m, 1H), 2.08–2.24 (m, 4H), 2.29–2.42 (m, 1H), 2.55–2.66 (m, 1H), 3.60–3.78 (m, 2H), 4.92 (d, J = 10.2 Hz, 1H), 4.99 (d, J = 17.1 Hz, 1H), 5.37 (d, J = 9.3 Hz, 1H), 5.70–5.85 (m, 2H), 7.45 (ddd, J = 7.8, 4.8, 1.2 Hz, 1H), 7.83 (dt, J = 7.8, 1.2 Hz, 1H), 8.12 (dt, J = 7.8, 1.2 Hz, 1H), 8.77 (ddd, J = 4.8, 1.2, 1.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ −5.3 (CH3, +), 9.9 (CH3, +), 18.4 (C, −), 26.0 (CH3, +), 28.2 (CH2, −), 32.2 (CH2, −), 34.6 (CH2, −), 36.7 (CH2, −), 62.3 (CH2, −), 74.2 (CH, +), 114.7 (CH2, −), 124.9 (CH, +), 125.1 (CH, +), 126.6 (CH, +), 136.9 (CH, +), 138.1 (CH, +), 141.8 (C, −), 148.7 (C, −), 149.9 (CH, +), 164.6 (CO, −). HRMS (FAB) calcd for C23H38NO3Si [(M + H)+] 404.2621, found 404.2630.
To a solution of the above product in THF (15 mL) was added TBAF (1.0 M in THF, 2.50 mL, 2.50 mmol). The mixture was stirred at rt overnight, and diluted with saturated NH4Cl and EtOAc with vigorous stirring. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated to give a residue, which was purified by chromatography on silica gel (hexane–EtOAc) to afford 26 (379 mg, 80% from 6, 93% ee, 97% CT) as a colorless oil. The enantiomeric information was determined by HPLC analysis: Chiralcel OD-H; hexane–i-PrOH = 95/5, 1 mL min−1, 30 °C; tR (min) = 18.9 (S), 21.8 (R): Rf = 0.11 (hexane–EtOAc, 3:
1). 1H NMR (300 MHz, CDCl3) δ 1.03 (t, J = 7.5 Hz, 3H), 1.12 (t, J = 5.4 Hz, 1H), 1.73–1.94 (m, 4H), 1.97–2.17 (m, 4H), 3.51–3.62 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.88–5.02 (m, 2H), 5.52 (d, J = 15.8 Hz, 1H), 5.58 (dt, J = 15.8, 5.7 Hz, 1H), 5.70–5.85 (m, 1H), 6.74–6.87 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 14.2 (CH3, +), 26.0 (CH2, −), 28.6 (CH2, −), 37.9 (CH3, −), 40.7 (CH3, −), 45.1 (C, −), 55.77 (CH3, +), 55.81 (CH3, +), 59.7 (CH2, −), 110.6 (CH, +), 110.8 (CH, +), 114.1 (CH2, −), 119.0 (CH, +), 130.5 (CH, +), 136.0 (CH, +), 138.7 (C, −), 139.0 (CH, +), 147.2 (C, −), 148.5 (C, −). HRMS (FAB) calcd for C19H28O3 [(M)+] 304.2038, found 304.2040.
To a solution of the above mixture in aqueous DMF (DMF–H2O = 10:
1, 2.75 mL) were added PdCl2 (4.8 mg, 0.027 mmol) and CuCl (25.8 mg, 0.261 mmol). The mixture was stirred at rt under an atmosphere of O2 (balloon used) overnight, and diluted with saturated NH4Cl and EtOAc with vigorous stirring. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined extracts were washed with saturated NH4Cl and brine, dried over MgSO4, and concentrated to give a residue, which was purified by chromatography on silica gel (hexane–EtOAc) to afford 28 (116 mg, 87% from 26) as a pale yellow oil: Rf = 0.40 (hexane–EtOAc, 1
:
1). 1H NMR (300 MHz, CDCl3) δ 1.03 (t, J = 7.4 Hz, 3H), 1.95–2.18 (m, 6H), 2.10 (s, 3H), 2.25–2.33 (m, 2H), 2.85 (s, 3H), 2.95–3.03 (m, 2H), 3.86 (s, 3H), 3.88 (s, 3H), 5.44 (d, J = 15.9 Hz, 1H), 5.61 (dt, J = 15.9, 6.3 Hz, 1H), 6.77–6.82 (m, 3H), 7.52–7.74 (m, 3H), 7.83 (dd, J = 7.5, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2 (CH3, +), 26.0 (CH2, −), 30.2 (CH3, +), 31.7 (CH3, −), 34.9 (CH3, +), 36.4 (CH3, −), 38.6 (CH3, −), 44.6 (C, −), 46.6 (CH2, −), 55.8 (CH3, +), 55.9 (CH3, +), 110.5 (CH, +), 110.6 (CH, +), 119.0 (CH, +), 124.1 (CH, +), 130.6 (CH, +), 131.5 (CH, +), 131.6 (CH, +), 132.3 (C, −), 133.5 (CH, +), 134.5 (CH, +), 137.3 (C, −), 147.4 (C, −), 148.1 (C, −), 148.7 (C, −), 208.9 (CO, −). HRMS (FAB) calcd for C26H34N2O7S [(M)+] 518.2087, found 518.2079.
A mixture of the above aldehyde and LiOH (34.6 mg, 1.44 mmol) in i-PrOH–CH2Cl2 (4:
1, 15 mL) was stirred at rt overnight, and diluted with saturated NH4Cl and CH2Cl2 with vigorous stirring. The layers were separated and the aqueous layer was extracted with CH2Cl2 three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated to give enone 30, which was used for the next reaction without further purification: 1H NMR (300 MHz, CDCl3) δ 2.06–2.45 (m, 6H), 2.87 (s, 3H), 3.00–3.23 (m, 2H), 3.880 (s, 3H), 3.884 (s, 3H), 6.19 (d, J = 10.5 Hz, 1H), 6.76–6.85 (m, 3H), 7.05 (d, J = 10.5 Hz, 1H), 7.56–7.72 (m, 3H), 7.86 (dm, J = 7.2 Hz, 1H).
To a solution of the above enone in MeCN (12 mL) were added Cs2CO3 (142 mg, 0.437 mmol) and a solution of PhSH (0.030 mL, 0.292 mmol) in MeCN (3 mL) dropwise. The mixture was stirred at 50 °C for 5 h and diluted with brine and EtOAc with vigorous stirring. The layers were separated and the aqueous layer was extracted with EtOAc three times. The solution was concentrated to afford a residue, which was purified by preparative TLC (EtOAc) to afford (−)-mesembrine (1) (16.1 mg, 38% from 28) as a yellow oil: Rf = 0.17 (EtOAc). 1H NMR (300 MHz, CDCl3) δ 2.02–2.29 (m, 5H), 2.32 (s, 3H), 2.34–2.52 (m, 4H), 2.61 (d, J = 3.9 Hz, 2H), 2.95 (t, J = 3.5 Hz, 1H), 3.10–3.19 (m, 1H), 3.89 (s, 3H), 3.91 (s. 3H), 6.85 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.4, 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 35.3 (CH2, −), 36.3 (CH2, −), 38.9 (CH2, −), 40.2 (CH3, +), 40.6 (CH2, −), 47.5 (C, −), 54.9 (CH2, −), 55.9 (CH3, +), 56.0 (CH3, +), 70.4 (CH, +), 109.9 (CH, +), 110.9 (CH, +), 117.9 (CH, +), 140.2 (C, −), 147.5 (C, −), 149.0 (C, −), 211.6 (CO, −). The 1H and 13C NMR spectra were consistent with those reported.8m,x [α]20D −43.6 (c 0.76, MeOH); lit.8m [α]30D −53.0 (c 0.24, MeOH); lit.8x [α]20D +43.0 (c 0.8, MeOH) for the (+)-isomer.
Footnotes |
† This paper is dedicated to Professor Ei-ichi Negishi on the occasion of his 80th birthday. |
‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c4qo00353e |
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