Total Synthesis of Dimeric HPI Alkaloids

Abstract In this paper, we report a full account of the synthesis of dimeric hexahydropyrroloindole alkaloids and its analogues. The key feature of our new strategy is the novel catalytic copper (10 %) mediated intramolecular arylations of o-haloanilides followed by intermolecular oxidative dimerization of the resulting oxindoles in one pot. This sequential reaction leads to the key intermediates for the synthesis of (+)-chimonanthine, (+)-folicanthine, (−)-calycanthine and (−)-ditryptophenaline. Graphical Abstract In the presence of catalytic amount of cuprous iodide (10 %), an intramolecular arylation of o-haloanilides followed by an intermolecular oxidative dimerization of the resulting oxindoles leads to a common intermediate for the synthesis of (+)-chimonanthine, (+)-folicanthine and (−)-calycanthine. Based on this cascade sequence, we also developed a flexible strategy towards the asymmetric syntheses of dimeric HPI alkaloids (−)-ditryptophenaline and its analogues. Electronic supplementary material The online version of this article (doi:10.1007/s13659-016-0092-8) contains supplementary material, which is available to authorized users.


Introduction
The hexahydropyrroloindole (HPI) structure-unit presents in a large class of natural products isolated from plants, microorganisms and fungi (for selected reviews and book chapters, see: [1][2][3][4][5][6][7][8]). Representative natural product of this family is physostigmine (Fig. 1, 1) which was isolated from the seeds of the calabar bean plant and is currently used to treat myasthenia gravis, glaucoma, Alzheimers disease, delayed gastric emptying and orthostatic hypotension [5,7]. There are a number of alkaloids containing more than one HPI unit and some of them contain a unique vicinal C3a-C3a 0 quaternary carbon center [1,4]. The stereocontrol synthesis of the congested all-carbon quaternary stereocenters in these alkaloids presents a formidable challenge [9][10][11][12][13][14][15][16]. In 1999, Overman and his team completed the first enantioselective synthesis of dimeric alkaloid (?)-calycanthine ( Fig. 1, 4) and (-)-chimonanthine ( Fig. 1, 2) [17]. Utilization of the same strategy, they also successfully synthesized a number of other dimeric and oligomeric HPI alkaloids [17][18][19][20][21][22][23][24][25][26][27]. In 2007, Mavassaghi reported a reductive radical dimerization strategy for the syntheses of dimeric HPI alkaloids ( Fig. 1) [28,29]. Based on this reductive dimerization reaction, a number of important works have been published towards the syntheses of dimeric HPI alkaloids (for selected syntheses of dimeric HPI alkaloids employed Movassaghi's reductive dimerization, see: [30][31][32][33][34][35][36][37]). Prompted by the success of reductive dimerization strategies, studies on the oxidative dimerization of tryptamine and tryptophan derivatives have been revived and syntheses of natural HPI alkaloids, especially chimonanthine, folicanthine and ditryptophenaline, have been achieved by a number of research groups (oxidative dimerization of tryptamine and tryptophan derivatives as the key steps for the syntheses of dimeric HPI alkaloids before 2007: ). Careful examination of literature related to the total syntheses of dimeric HPI alkaloids, we found that tryptamine or tryptophan derivatives were used frequently as starting materials , few examples had been documented by application of non-indole and/or non-oxindole starting materials [59]. To some extent, utilization of tryptamine and tryptophan derivatives as starting materials might limited the access of structurally diverse dimeric analogues. Therefore, it is of importance to develop alternative approaches towards the synthesis of the target dimeric HPI natural molecules as well as its analogues for the interests of medicinal chemistry.
A major focus of our research group is the use of metal mediated sequential reactions to assemble the key structure units of the target molecules [60][61][62][63]. Our synthesis of the HPI alkaloids initiated in the early 2008. We successfully developed a sequential reaction for the synthesis of mesembrine [60] and esermethole [61] using palladium chemistry. In 2012, we developed a copper catalyzed arylation of o-bromoanilides assisted by a remote sulfinylamide or carbamate auxiliary [62]. Very recently, we established a novel copper catalyzed asymmetric arylationoxidative dimerization of o-haloanilide derivatives (Scheme 1) to construct the vicinal C3a-C3a 0 all carbon quaternary stereocenters required for the synthesis of dimeric HPI compounds [64]. In this paper, we report our full accounts of new strategy towards the synthesis of (?)chimonanthine, (?)-folicanthine, (-)-calycanthine, (-)ditryptophenaline and its analogues.

Results and Discussion
The syntheses of dimeric HPI alkaloids began in the early 1960, and after endeavours of many research groups, the bio-inspired oxidative dimerization reaction of tryptamine and tryptophan derivatives has been developed to be a powerful method for the construction of dimeric HPI alkaloids 64]. In comparison with oxidative dimerization of tryptamine and tryptophan derivatives, however, few oxidative dimerizations of oxindole derivatives have been reported [65][66][67][68][69][70][71][72][73][74]. To the best of our knowledge, only five papers reported direct oxidative dimerization of oxindoles derivatives. Except for the method established by Rodrigo which provided the dimeric intermediate in 61 % overall yield and good diastereoselectivity (dl:meso isomers = 53:8, Scheme 2) [67], other methods unfortunately suffered from low yields [65] or Scheme 1 Sequential process for natural product synthesis poor diastereoselectivity [66,68,69]. Before we conducted this research, no asymmetric oxidative dimerization of oxindoles had been developed to form the vicinal C3-C3 0 all-carbon quaternary centers.
Recently, we disclosed an asymmetric synthesis of debromoflustramine and its analogues through a copper mediated arylation followed by oxindole-alkylation [62]. We envisioned that this copper catalysed cyclization process (Scheme 1) might be applied to the synthesis of dimeric HPI alkaloids indicated in Fig. 1. A retrosynthetic analysis is outlined in Scheme 3. Key to our new strategy is to develop a sequential reaction that combines metal catalysed arylation with an in situ oxidative dimerization of the resulting oxindole intermediates (Scheme 3, converting 12 to 13). Based on this new sequential process, we would be able to synthesize the dimeric HPI alkaloids starting from o-haloanilide 12. The amides (12) bearing a chiral sulfinyl amide unit [(S) or (R)-tert-butanesulfinamide] could be synthesized according to our previous procedure. We were curious to know whether the key intermediates (13,Scheme 3), containing the vicinal C3-C3 0 all-carbon quaternary centers required for dimeric HPI alkaloids, could be formed diastereoselectively in a one-pot manner by a copper catalyzed arylation of o-haloanilide (12) followed by an oxidative dimerization of the newly generated oxindole intermediates in the presence of a suitable oxidant. Our synthesis started from commercially available obromoaniline and c-butyrolactone, and (S)-(-)-tert-butanesulfin-amide was used to introduce the nitrogen atom and also served as a chiral auxiliary. Amide 12a was synthesized in 68 % overall yield in six steps according to our previous procedure [62] (Scheme 4). Amide 12b was also prepared from 17a in a 97 % yield. With amides (12a and 12b) in hand, we next began to explore the key copper mediated sequential arylation-dimerization of o-bromoanilides, in the hope that the oxidative dimerization might also be effected by copper salts in an efficient and economic ''one pot'' operation.
The initial experiment was conducted with amide 12b under our previous optimized reaction condition [62], namely LiN(SiMe 3 ) 2 and CuI in THF at reflux (Table 1, entry 1). This condition unfortunately gave a complex mixture, with the isolated product being N-benzyl-o-bromoaniline (18, 16 % yield). After several unsuccessful experiments, we finally found that the desired sequential reaction could be realized smoothly in toluene (Table 1, entry 6). Arylation of sulfinamide 12b with catalytic amount of cuprous iodide (10 % eq.) and lithium bis(trimethylsilyl)amide (2.0 eq.) in toluene, followed by oxidation with anhydrous tert-butylhydroperoxide resulted in dimeric diastereomers (13a ? 13b, as a 5:1 mixture of diastereoisomers in 78 % yield, and 13c: the meso isomer in 7 % yield). We also isolated small amount of the C3hydroxy-oxindole (19). Although a number of oxidants could be used to generate the desired dimeric product (13a ? 13b), anhydrous tert-butyl hydroperoxide proved to be the best additive for this sequential arylation-oxidative dimerization. Next we carried out the sequential procedure with amide 12a under the optimized reaction condition. The dimeric diastereomers (13d ? 13e, as a mixture of diastereoisomers) were obtained in 71 % yield, we also isolated the meso isomer 13f in 8 % yield (Table 1, entry  10). In order to know whether the oxidative dimerization was promoted solely by tert-butyl hydroperoxide, we conducted an arylation with tris(dibenzylideneacetone)dipalladium [Pd 2 (dba) 3 ] [61] followed by oxidation with t-BuOOH. It was noteworthy that only C3-hydroxy-2-oxindole product (19 , Table 1, entry 11, as a mixture of diastereomers at C3 position, Scheme 5) was obtained. We next carried out arylation with Pd 2 (dba) 3 without addition of t-BuOOH and successfully obtained oxindole 19a in 61 % yield. The oxindole (19a) was then subjected to oxidation in the presence of LiN(SiMe 3 ) 2 and t-BuOOH (see Scheme 5) and provided C3-hydroxy-2-oxindole (19) as the sole product.
The fact that no dimerization products (13a, 13b or 13c) formed in the absence of a copper salt suggests that the copper(II) ion, rather than tert-butyl hydroperoxide, plays the role of oxidizing the carbanion to a radical in the dimerization process. Tert-butyl hydroperoxide just serves as an oxidant to convert copper(I) to copper(II) in the oxidative dimerization process. Next, we came to the issue of determining diastereoselectivity induced by remote tert-butanesulfinamide moiety. Although the major product (13a and 13b) of this reaction was an unseparatable mixture of diastereoisomers (C3S-C3 0 S and C3R-C3 0 R) by silica gel column chromatography, the ratio could be readily determined by proton nuclear magnetic resonance ( 1 H-NMR; 84:16, see Electronic supplementary material). The enantioselectivity for the formation of vicinal C3-C3 0 quaternary carbon center was also determined after oxidation of the tert-butylsulfinyl group with 3-chloroperbenzoic acid (m-CPBA) in dichloromethane. A 66 % enantioselective excess was recorded (see Electronic supplementary material for chiral HPLC analysis) under our optimum reaction condition (Table 1, entry 6). The enantioselectivity for compounds 13d and 13e was also determined after oxidation of the tertbutylsulfinyl group with 3-chloroperbenzoic acid (m-CPBA) and relatively low enantioselective excess (35 %) was observed. To the best of our knowledge, this is the first example of copper catalyzed sequential arylation-dimerization of an o-bromoanilide, a high-yield procedure and also the first asymmetric oxidative dimerization of an oxindole derivative with good diastereoselectivity (dr [10:1) and enantioselectivity (ee = 66 %). The absolute stereochemistry was late confirmed by the total synthesis of (?)-chimonanthine (Scheme 10). A working hypothesis was proposed for prediction of C3-C3 0 configuration in Scheme 6. p-p Stack (for a review for p-p.stack in asymmetric synthesis, see: [75,76]) might play important role for the enantioselectivity as well as diastereoselectivity.
In order to access the starting material for the synthesis of ditryptophenaline, we started the synthesis of amide 12c (Scheme 7). Nucleophilic addition of vinyl magnesium bromide to aldimine 17a unfortunately provided two isolatable diastereisomers (20a and 20b) in a ratio of 3.4-1 (see Scheme 7). This problem was soon fixed by addition of Grignard reagent to aldimine 17c, a surrogate prepared from o-iodoaniline. Better diastereoselectivity (dr = 10:1, see Scheme 7) was obtained by 1,2-addition of vinyl magnesium bromide to o-iodoanilide 17c. After benzylation, we obtained 12c in 58 % yield in six steps from iodoaniline. The absolute configuration for the newly generated chiral center of compound 12c was deduced by Cram's chelation model [77] and late confirmed by X-ray crystallography (Schemes 8, 9) and our total synthesis of (-)-ditryptophenaline (Scheme 11).
We next conducted the arylation-oxidative dimerization reaction with substrate 12c under the optimized condition. This reaction afforded the dimerization products in good yield, and all dimeric diastereomers were isolated by silica gel column chromatography, with the desired isomer (21a) being obtained as the major product and in a 50 % yield (Scheme 8). It was noteworthy that this sequential arylation-oxidative dimerization process could be conducted on multi-gram scale in the presence of only catalytic amount of cuprous iodide (10 %). In order to determine the absolute configuration of compound 21a, we converted it to sulfonyl ester 23 and successfully obtained a suitable crystal for X-ray crystallography. The absolute configuration was confirmed by X-ray crystallography with Mo Ka radiation (Scheme 9).
In conclusion, we have developed the first copper catalyzed arylation-oxidative dimerization of o-haloanilides with a remote assistance of an intramolecular sulfinyl amide unit. Based on this method, a general synthetic strategy has been successfully established for the total synthesis of chimonanthine, folicanthine, calycanthine and ditryptophenaline. This copper catalyzed sequential arylation-oxidative dimerization should find further application in the synthesis of HPI alkaloids as well as its medicinally interesting analogues.

Synthesis of Compound 16a
To a mixture of cesium carbonate (17.43 g, 53.5 mmol, 1.5 eq.) in acetonitrile (90 mL) and N,N-dimethylformamide (DMF, 45 mL) at 0°C was added dropwise a solution of amide 15a (9.20 g, 35.7 mmol) in acetonitrile (10 mL) and DMF (5 mL). Benzyl bromide (6.4 mL, 53.5 mmol, 1.5 eq.) was then added. The resulting mixture was allowed to stir at room temperature for 8 h. After filtration through a short column of silica gel and washed with ethyl acetate (180 mL), the combined organic phases were concentrated under reduced pressure and the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 1:1) to afford alcohol 16a (11.86 g, 96 %) as a colorless oil.

Synthesis of Compound 11a
Alcohol 16a (11.86 g, 34.1 mmol) was dissolved in dichloromethane (120 mL). To this solution, a powder of Dess-Martin periodinane (21.67 g, 51.1 mmol, 1.5 eq.) was added. The resulting mixture was then stirred at room temperature for 6 h. After filtration through a short column of silica gel and washed with ethyl acetate (150 mL), the combined organic phases were concentrated under reduced pressure and the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 3:1) to afford aldehyde 11a (

Synthesis of Compound 17b
To a solution of aldehyde 11a (5.85 g, 16.8 mmol) in toluene (60 mL) was added a powder of (S)-(-)-tert-butanesulfinamide (4.1 g, 33.7 mmol, 2.0 eq.) and KHSO 4 (4.56 g, 33.7 mmol, 2.0 eq.). The resulting mixture was stirred at 45°C for 3 h. After filtration through a short column of silica gel and washed with ethyl acetate (80 mL), the combined organic phases were concentrated under reduced pressure and the residue was flash chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 3:1) to afford the sulfinyl imine (17a: 7.36 g, 97 %) as colorless syrup. The sulfinyl imine was re-dissolved in anhydrous methanol (60 mL) and the resulting solution was cooled to 0°C. A powder of sodium borohydride (1.87 g, 49.2 mmol, 3.0 eq.) was added in small portion over a period of 30 min. The resulting mixture was then allowed to stir at 0°C for 4 h. After which, a saturated solution of NH 4 Cl (20 mL) was introduced and the resulting mixture was concentrated (ca. 20-30 mL). The mixture was diluted with water (100 mL) and extracted with ethyl acetate (4 9 50 mL). The combined organic phases were washed with brine (60 mL) and dried over anhydrous sodium sulfate. After removal of the solvent, the crude products were chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 1:2) to provide sulfinamide 17b (6.6 g, 89 %) as a white solid.

Synthesis of Compound 12a
To a mixture of sodium hydride (60 % in mineral oil, 1.22 g, 30.5 mmol, freshly washed with anhydrous hexane three times under nitrogen) in anhydrous THF (50 mL) at 0°C was added a solution of sulfonamide 17b (10.6 g, 23.5 mmol) in THF (50 mL) via syringe. After stirring at 0°C for 30 min, methyl iodide (1.9 mL, 30.6 mmol) was added. The resulting mixture was then stirred at room temperature for 15 h under nitrogen. A powder of NH 4 Cl (1.62 g, 30.0 mmol) was added and the mixture was stirred for 10 min. After concentrated under reduced pressure, the residue was diluted with water (100 mL) and extracted with ethyl acetate (3 9 50 mL). The combined organic phases were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 1:1) to afford the product (12a: 10

Synthesis of Compound 12b
To a mixture of sodium hydride (60 % in mineral oil, 1.32 g, 33 mmol, 1.5 eq., freshly washed with anhydrous

Synthesis of Compound 15b
2-Iodoaniline (21.9 g, 100.0 mmol) was dissolved in toluene (300 mL) under nitrogen. To this mixture, a solution of trimethylaluminum in toluene (2.0 M, 60 mL, 120 mmol, 1.2 eq.) was added dropwise at 0°C. The resulting mixture was then stirred at room temperature for 45 min, after which, c-butyrolactone (9.2 mL, 120 mmol, 1.2 eq.) was added via syringe and the reaction mixture was stirred at room temperature overnight. The solidified mixture was then cooled to 0°C and HCl (1 N, 360 mL) was added slowly. After 1 h, the resulting mixture was extracted with ethyl acetate (4 9 150 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After removal of the solvent, the crude products were chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 1:2) to provide amide 15b (

Synthesis of Compound 17c
To a solution of aldehyde 11b (19.7 g, 50 mmol) in THF (200 mL) was added a powder of (S)-(-)-tert-butanesulfinamide (12.1 g, 100 mmol, 2.0 eq.) and Ti(OEt) 4 (22.8 g, 100 mmol, 2.0 eq.). The resulting mixture was stirred at 60°C under nitrogen for 12 h. The reaction mixture was then cooled to room temperature and treated with saturated NaCl aqueous solution (100 mL) for 1 h. After filtration through a short column of Celite and washed with ethyl acetate (80 mL), the combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvent under reduced pressure, the residue was flash chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 3:1) to afford the sulfinyl imine (17c: 22.85 g, 92 %) as a pale yellow syrup.

Synthesis of Compound 20c
A solution of imine 17c (19.8 g, 40 mmol) in dichloromethane (200 mL) was stirred at -78°C for 10 min. To this mixture was added slowly a solution of vinyl magnesium bromide in THF (1.0 M, 60 mL, 60 mmol, 1.5 eq.). The reaction mixture was then stirred at -78°C for 5 h before warming up to room temperature. Saturated NH 4 Cl aqueous solution (80 mL) was introduced and the resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with water (150 mL) and extracted with dichloromethane (3 9 100 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 . After filtration and concentrated, the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 2:1) to afford the major amide (20c: 16.35 g, 78 %) as a yellow syrup. Further elution with solvents (petroleum ether 60-90°C:ethyl acetate = 1:2) provided the minor sulfinamide 20d (1.64 g, 7.8 %) as a pale yellow oil.  13

Synthesis of Compound 12c
To a mixture of sodium hydride (60 % in mineral oil, 1.87 g, 46.7 mmol, 1.5 eq., freshly washed with anhydrous hexane three times under nitrogen) in anhydrous THF (50 mL) at 0°C was added a solution of sulfonamide 20c (16.3 g, 31.1 mmol) in THF (150 mL) via syringe. After stirring at 0°C for 10 min, benzyl bromide (5.5 mL, 46.7 mmol, 1.5 eq.) was added. The resulting mixture was then stirred at 0°C for 2 h, then at room temperature for 12 h under nitrogen. A powder of NH 4 Cl (2.7 g, 50.0 mmol) was added and the mixture was stirred for 10 min. After concentrated under reduced pressure, the residue was diluted with water (150 mL) and extracted with ethyl acetate (3 9 100 mL). The combined organic phases were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 2:1) to afford the product (11b: 18.1 g, 95 %) as a pale yellow oil.  13  A mixture of copper iodide (CuI, 133.3 mg, 0.7 mmol, 0.1 eq.) and bromoanilide 12b (3.78 g, 7.0 mmol) in anhydrous toluene (140 mL) was degassed and purged with argon (three times). A solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 14 mL, 14 mmol, 2.0 eq.) was added and the resulting mixture was stirred at 80°C (oil bath) under argon for 5 h. After cooling to room temperature then to 0°C, a solution of anhydrous t-BuOOH (degassed and purged with argon, *3.0 M in toluene, 3.5 mL, 10.5 mmol, 1.5 eq.) was added. The reaction mixture was allowed to stir at 0°C under argon for 3 h. Saturated aqueous solution of NH 4 Cl (8 mL) was added. After 30 min, the mixture was diluted with water (100 mL). The aqueous phase was extracted with ethyl acetate (3 9 60 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvents, the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 2:1 ? 1:1 ? 1:2) to afford the major product (13a ? 13b, as a mixture of C3-C3a diastereomers, 2.51 g, 78.1 %) as pale yellow syrup. Further elution afforded the minor product (13c: meso-isomer, 0.23 g, 7.2 %) as a pale yellow oil, which was characterized after removal of the tert-butylsulfinyl group (13d). *The anhydrous tert-butylhydroperoxide (t-BuOOH) in toluene (ca. *3.0 M) was prepared by the following procedure: 70 % aqueous solution of t-BuOOH (40.6 mL, density = 0.93 g/mL) was added to toluene (46 mL) and the resulting water (ca. 10 mL) was separated and back-extracted with toluene (2 9 10 mL). The combined organic phases were then dried over anhydrous sodium sulfate. After filtration, the resulting solution was kept with 4 Å molecular sieve and could be used for this reaction without further purification.

Synthesis of Compound 21a
To a mixture of copper iodide (CuI, 190 mg, 1.0 mmol, 0.1 eq.) and o-iodoanilide 12c (6.14 g, 10.0 mmol) in anhydrous toluene (200 mL) was added a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 20 mL, 20 mmol, 2.0 eq.). The resulting mixture was degassed and purged with argon (three times). The reaction mixture was then allowed to stir at 60°C (oil bath) under argon for 5 h. After cooling to room temperature then to 0°C, a solution of anhydrous t-BuOOH (degassed and purged with argon, *3.0 M in toluene, 5.0 mL, 15 mmol, 1.5 eq.) was added. The reaction mixture was then stirred at 0°C under argon for 3 h. Saturated aqueous solution of Na 2 S 2 O 3 (10 mL) was added followed by saturated aqueous solution of NH 4 Cl (10 mL). After 30 min, the resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 9 100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvents, the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 2:1 ? 1:1 ? 1:2) to afford the major product (21a, 2.42 g, 50 %) as a pale yellow syrup. Further elution afforded the meso-isomer (21c, characterized after removal of tert-butylsulfinyl group, 0.205 g, 4.2 %), followed by minor product (21b, characterized after removal of the tert-butylsulfinyl group, 0.40 g, 8.2 %) as a pale yellow oil.  2 9 9H, s). 13  Sulfinamide (21b: 400 mg, 0.41 mmol) was dissolved in methanol (6 mL). To this mixture was added an aqueous solution of HCl (4 N, 0.31 mL, 1.23 mmol, 3 eq.). The resulting mixture was allowed to stir at room temperature under nitrogen for 1 h. The reaction mixture was then treated with saturated aqueous solution of sodium bicarbonate (*8 mL) and concentrated under reduced pressure. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3 9 10 mL), the combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 2:1) to afford the diamine (21d) (290 mg, 92 %) as yellow oil.  Sulfinamide (21c: 205 mg, 0.21 mmol) was dissolved in methanol (6 mL). To this mixture was added an aqueous solution of HCl (4 N, 0.16 mL, 0.63 mmol, 3 eq.). The resulting mixture was allowed to stir at room temperature under nitrogen for 1 h. The reaction mixture was then treated with saturated aqueous solution of sodium bicarbonate (*4 mL) and concentrated under reduced pressure. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3 9 5 mL), the combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvent, the residue was chromatographed on silica gel (petroleum ether 60-90°C:ethyl acetate = 1:2) to afford the diamine (21e) (145 mg, 91 %) as yellow syrup.  2 9 1H, brs). 13

Synthesis of Compound 22
A solution of 21a (485 mg, 0.5 mmol) in dichloromethane and methanol (20 mL, 1:1 mixture) was cooled to -78°C (dry ice-acetone bath). Ozone was then passed through the solution for 10 min. The reaction progress was monitored by TLC. Sodium borohydride (189 mg, 5 mmol, 10 eq.) was added. The reaction mixture was then gradually warmed up to room temperature under argon at stirration overnight. Saturated aqueous solution of NH 4 Cl (10 mL) was added. The resulting mixture was diluted with water (20 mL) and extracted with dichloromethane (3 9 20 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 . After removal of the solvents, the residue was  13

Synthesis of Compound 26
Diamine 25 (369 mg, 0.5 mmol) in anhydrous 1,2-dichloroethane (15 mL) was stirred with a solution of a-chloroethyl chloroformate (ACE-Cl, 0.54 mL, 5 mmol, 10.0 eq.) at 0°C for 2 h, then at room temperature for 1 h. After which, the reaction mixture was allowed to stir at 80°C (oil bath) for 12 h. After removal of the solvents, the residue was diluted with methanol (15 mL) and stirred at 70°C (oil bath) for 3 h. The resulting mixture was concentrated under reduced pressure and diluted with dichloromethane (5 mL), ice (*10 g) and saturated aqueous solution of NaHCO 3 (10 mL). The mixture was then extracted with dichloromethane (3 9 15 mL), and the combined organic phases was dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (dichloromethane:MeOH:NH 3

Synthesis of (?)-Chimonanthine
To a solution of liquid ammonia (freshly distilled and collected by Birch condenser, acetone-dry ice, 50-60 mL) at -78°C was added sodium metal (ca. 124 mg, 5.4 mmol, 10 eq.). A solution of chimonanthine precursor (27, 284 mg, 0.54 mmol) in anhydrous THF (10 mL) was added to this dark blue solution of liquid ammonia. After stirring at -78°C for 15 min, a powder of NH 4 Cl (433 mg, 8.1 mmol) was added in one portion followed by saturated aqueous solution of NH 4 Cl (5 mL). The resulting mixture was allowed to evaporate in fume hood. The residue was then diluted with water (20 mL) and extracted with dichloromethane (3 9 20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure and the crude product was chromatographed on silica gel (CH 2 Cl 2 :MeOH:NH 3

Synthesis of (?)-Folicanthine
To a solution of amine 2 (35 mg, 0.1 mmol) in acetonitrile (3 mL) was added a solution of formalin (37 % HCHO in water, 39 lL, 0.52 mmol, 5.2 eq.) and sodium triacetoxyborohydride [NaBH(OAc) 3 , 110 mg, 0.52 mmol]. The resulting mixture was then stirred at room temperature under argon for 1 h. The mixture was then treated with a solution of methanol in dichloromethane saturated with ammonia (ca. 5 mL, CH 2 Cl 2 :MeOH = 95:5). After stirring for 5 min, the mixture was concentrated and the residue was chromatographed on silica gel (dichloromethane: methanol:NH 3