Asymmetric Total Syntheses of Mitragynine, Speciogynine, and 7-Hydroxymitragynine

A number of alkaloids found in Mitragyna species belonging to the Rubiaceae family have been shown to have potent biological activity such as analgesic properties. Here, we report the asymmetric total syntheses of mitragynine, speciogynine, and 7-hydroxymitragynine, which are classified as corynantheine-type monoterpenoid indole alkaloids, isolated from Mitragyna speciosa. These syntheses were accomplished within 12 steps and in >11% total yield from commercial 3-(trimethylsilyl)propanal using an organocatalytic anti-selective Michael reaction and bioinspired transformations.


Introduction
Mitragyna speciosa, which belongs to the Rubiaceae family, is endemic to the tropics of Southeast Asia, where it is called "Kratom" in Thailand and "Biak Biak" in Malaysia. 1) Traditionally, the leaf of this plant has been used to alleviate the fatigue of workers laboring in the scorching heat and as a substitute for opium. Many chemists have been fascinated by its special biological activity, and isolation and structure elucidation studies of this plant have been conducted since the 1960 s. [2][3][4][5][6] As a result, several corynantheine-type monoterpenoid indole alkaloids have been found with a methoxy group attached to the C-9 position on the indole ring ( Fig. 1).
Because of their interesting biological activity, several total syntheses of these alkaloids have been reported. 10,[17][18][19][20][21][22] Very recently, our group also achieved the total syntheses of the same class of corynantheine-type monoterpenoid indole alka-loids, corynantheidine and dihydrocorynantheine. 23) However, the efficiency of these total syntheses could be improved, specifically because the goal of previous total syntheses was to reproduce the biosynthetic transformations from strictosidine in the flask.
As shown in Chart 2, our synthesis commenced with the preparation of (R)-4-methoxy-α-cyanotryptamine (6). Synthesis of D-tryptophan derivative 13 was performed via a Lewis acid-mediated coupling reaction of 4-methoxyindole (12) with known chiral aziridine 8. 27) After several trials, Yb(OTf) 3 effectively promoted the coupling reaction and the desired 13 was obtained as a major product (1.5 equivalent (equiv.) of Yb(OTf) 3 ; room temperature (r.t.). Hydrolysis and subsequent amidation of the crude mixture of 13 gave primary amide 14 in gram quantities (39% yield over three steps). Then, amide 14 was converted to 6 via dehydration to construct a cyano group and deprotection of the Cbz group (74% yield over two steps).
With the desired synthons 6 and 7 in hand, we next attempted bioinspired transformations for the construction of a corynantheine-type scaffold (Chart 4). To prepare 9-methoxystrictosidine derivative 5, our developed diastereoselective Pictet-Spengler cyclization/reductive decyanation sequences were examined. When a mixture of 6 and 7 was treated with 50 mol% TFA in CH 2 Cl 2 at 0 °C (30 min), the desired 3Sisomer 19 was obtained as a single diastereomer in quantitative yield. 30) Reductive removal of the cyano group in 19 was performed by treatment with NaBH 3 CN in the presence of AcOH in MeOH, affording 9-methoxystrictosidine derivative 5 in excellent yield (78%).
Bioinspired transformations toward the selective synthesis of C-20R isomer (+)-speciogynine (2) were also demonstrated. After generating enamine 4 under the same conditions as for the synthesis of (−)-1, 2.0 equiv. NaBH(OAc) 3 was added in a one-pot protocol. In this case, thermodynamic controlled protonation at the C-20 position followed by reduction of a generated iminium ion afforded C-20R isomer 22 as a single diastereomer. Subsequent modification of the C-17 enol hydroxy group was carried out as in the synthesis of (−)-1, and the E1cB elimination reaction, following the formation of 23, afforded (+)-speciogynine (2) in 65% overall yield within four steps from 5.

Preparation of Compound 14
To a solution of known aziridine 8 (1.0 g, 4.25 mmol) and 4-methoxyindole (12, 1.25 g, 8.50 mmol) in CH 2 Cl 2 (17 mL) was added Yb(OTf) 3 (2.64 g, 4.25 mmol) under Ar atmosphere. The reaction mixture was stirred for 24 h at r.t. under Ar atmosphere in the dark. To the resulting mixture was added additional Yb(OTf) 3 (1.32 g, 2.13 mmol), followed by stirring for a further 48 h at r.t. The mixture was then quenched with saturated aqueous NaHCO 3 and the resulting mixture was filtered through a Celite pad, eluted with CHCl 3 . The filtrate was extracted three times with CHCl 3 . The combined organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. Flash chromatography (SiO 2 , 22-28% AcOEt/n-hexane gradient) provided an inseparable regioisomer mixture of 13 (780 mg, r.r. = 6.7 : 1). To a solution of a mixture of 13 in aqueous THF (34 mL, THF/H 2 O = 10 : 1) was added 2 M aqueous LiOH (3.06 mL, 6.12 mmol) at r.t. under Ar atmosphere. The reaction mixture was stirred for 2.5 h at r.t. before quenching with 2 M aqueous HCl (pH 2). Brine was added to the resulting mixture and the aqueous layer was extracted three times with AcOEt. The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. Obtained crude materials were dissolved in anhydrous THF (40.8 mL), then ethyl chloroformate (272 µL, 2.86 mmol) and triethylamine (853 µL, 6.12 mmol) were added at 0 °C under Ar atmosphere. The reaction mixture was stirred for 30 min at 0 °C. To the resulting mixture was added 1.0 M aqueous NH 4 Cl (3.06 mL, 3.06 mmol) at 0 °C. The reaction mixture was stirred for an additional 20 min at 0 °C. It was then quenched with saturated aqueous NaHCO 3 and the aqueous layer was extracted three times with AcOEt. The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. Flash chromatography (SiO 2 , 2%-5% MeOH/CHCl 3 gradient) afforded amide 14 (607.5 mg, 39% over three steps).

Preparation of Compound 17
To the solution of an E and Z mixture of half thioester malonate derivative 10 (500 mg, 1.85 mmol) and diphenylprolinol trimethyl silyl ether (18.0 mg, 0.0555 mmol) in Et 2 O (9.2 mL) was added n-butyraldehyde (9, 167 µL, 1.85 mmol) at 0 °C under Ar atmosphere. The reaction mixture was stirred for 40 h at 0 °C. The resulting mixture was concentrated under reduced pressure. Crude 1 H-NMR revealed that anti-adduct 16 was the main product (diastereomer ratio of 16; anti:syn = 11 : 1). The crude materials of 16 were solved to degassed THF (3.7 mL), then 10% Pd/C (197 mg, 0.185 mmol) and Et 3 SiH (886 µL, 5.55 mmol) were added at 0 °C under Ar atmosphere. The reaction mixture was stirred for 4.5 h at r.t, whereafter an additional 10% Pd/C (98.4 mg, 0.0924 mmol) and Et 3 SiH (443 µL, 2.77 mmol) were added at r.t. under Ar atmosphere. This was stirred for 5 h at r.t. before the addition of 1 M aqueous HCl (3.7 mL). The resulting mixture was stirred for a further 18 h at r.t. before filtration with a Celite pad eluted with AcOEt, and partitioned between an AcOEt layer and an aqueous layer. The aqueous layer was extracted three times with AcOEt. The combined organic layer was dried over MgSO 4 , and concentrated under reduced pressure. Flash chromatography (SiO 2 , 5%-20% AcOEt/nhexane gradient) afforded two diastereomers of dihydropyran 17 (444.5 mg, 85% over two steps, d.r. = 4 : 1).
Preparation of 9-Methoxystrictosidine Derivative 5 Acetic acid (265 µL, 4.63 mmol) and sodium cyanoborohydride (582 mg, 9.26 mmol) were added to a solution of 19 (500 mg, 0.936 mmol) in MeOH (4.6 mL) at r.t. under Ar atmosphere. The reaction mixture was stirred for 24 h at r.t. To the resulting mixture were added additional acetic acid (265 µL, 4.63 mmol) and sodium cyanoborohydride (582 mg, 9.26 mmol) under Ar atmosphere. The reaction mixture was stirred for a further 36 h at r.t. The resulting mixture was quenched with saturated aqueous NaHCO 3 solution at 0 °C. The aqueous layer was extracted three times with AcOEt. The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude materials were filtered through a short plug of amino-silica gel (SiO 2 -NH), eluted with 5% MeOH/CHCl 3 , to remove an excess amount of sodium cyanoborohydride. Flash chromatography (SiO 2 , 25% AcOEt/n-hexane then 20% MeOH/CHCl 3 ) afforded the 9-methoxystrictosidine derivative 5 (371.6 mg, 78%) with 80. 5   Ar atmosphere. The reaction mixture was stirred for 5 h at -20 °C. The resulting mixture was directly filtered through a short plug of silica gel eluted with 40% AcOEt/n-hexane. The residue of 4 was dissolved in degassed MeOH (14.6 mL) to which was added PtO 2 (150 mg, 100 wt%) at r.t. under Ar atmosphere. The resulting mixture was purged with a stream of hydrogen and the reaction mixture was stirred for 1 h at r.t. under H 2 atmosphere. The resulting mixture was filtered with a Celite pad with AcOEt, and the filtrate was concentrated under reduced pressure. The resulting residue of 20 was dissolved in degassed MeOH (14.6 mL) to which was added CH(OMe) 3 (52.7 µL, 0.481 mmol) and p-TsOH·H 2 O (211 mg, 1.11 mmol), and the mixture was stirred at 70 °C for 16 h. The resulting mixture was quenched with saturated aqueous NaHCO 3 solution, and was concentrated under reduced pressure. The aqueous layer was extracted three times with CHCl 3 . The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude materials of 21 were dissolved in dry degassed DMF (5.8 mL) to which was added t-BuOK (98.1 mg, 0.874 mmol) at 0 °C under Ar atmosphere. The reaction mixture was stirred for 45 min at r.t. under Ar atmosphere. The resulting mixture was quenched with water and the aqueous layer was extracted three times with CHCl 3 . The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. Flash chromatography (SiO 2 , 25-45% AcOEt/n-hexane gradient then 5% MeOH/CHCl 3 ) afforded (−)-mitragynine (1, 48.7 mg, 42% over four steps) and (+)-speciogynine (2, 15.2 mg, 13% over four steps). All spectral data of the obtained (−)-mitragynine (1) and (+)-speciogynine (2) were identical to those of natural products. 33,34) (−)-Mitragynine (1)  C-NMR see supporting information. Synthesis of (+)-Speciogynine (2) To a solution of 9-methoxystrictosidine derivative 5 (30 mg, 0.058 mmol) in degassed anhydrous THF (580 µL) were added acetic acid (16.7 µL, 0.291 mmol) and tetrabutylammonium fluoride (1.0 M in THF solution, 117 µL, 0.117 mmol) at -20 °C under Ar atmosphere. The reaction mixture was stirred for 5 h at -20 °C. To the resulting mixture was added sodium triacetoxyborohydride (24.7 mg, 0.117 mmol) at -20 °C. The reaction mixture was stirred for 2.5 h at -20 °C. The resulting mixture was quenched with saturated aqueous NaHCO 3 solution and the aqueous layer was extracted three times with AcOEt. The combined organic layer was washed with brine then dried over Na 2 SO 4 . The resulting residue of 22 was dissolved in degassed MeOH (2.9 mL), to which was added CH(OMe) 3 (10.5 µL, 0.0962 mmol) and p-TsOH·H 2 O (42.1 mg, 0.221 mmol), and then stirred at 70 °C for 12 h. The resulting mixture was quenched with saturated aqueous NaHCO 3 solution and then concentrated under reduced pressure. The aqueous layer was extracted three times with CHCl 3 . The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude materials of 23 were dissolved in dry degassed DMF (1.2 mL) to which was added t-BuOK (19.6 mg, 0.175 mmol) at 0 °C under Ar atmosphere. The reaction mixture was stirred for 40 min at r.t. under Ar atmosphere. The resulting mixture was quenched with water and the aqueous layer was extracted five times with CHCl 3 . The combined organic layer was dried over Na 2 SO 4 , and concentrated under reduced pressure. Flash chromatography (SiO 2 , 45% AcOEt/n-hexane) afforded (+)-speciogynine (2, 15.2 mg, 65% over four steps).