Synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer via fluorocyclisation of tryptophan-containing dipeptides

Abstract

The synthesis of 10b-fluorinated analogues of protubonine A and its 11a-epimer was accomplished using fluorocyclisation of tryptophan-containing dipeptides with N-fluoro-2,4,6-trimethylpyridinium triflate to 3a-fluoropyrrolo[2,3-b]indoles as a key step. Acetylation of the indole nitrogen and the following diketopiperazine formation gave the 10b-fluorinated analogues of protubonine A and its 11a-epimer.

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Introduction

Organofluorine compounds have fascinated medicinal chemists ever since 9α-fluorocortisol was reported to have much higher biological activity than cortisol.¹ An extensive number of fluorine-containing pharmaceuticals have been developed to date,² some of which have become blockbusters.³ The growing interest in organofluorine compounds in medicinal chemistry stemmed from the unique properties of fluorine atom(s). Fluorine has the highest electronegativity and the smallest van der Waals radius next to hydrogen.^2a,4 The C–F bond is far stronger than C–H, C–O and C–X (X = Cl, Br and I) bonds.^2a,4 Therefore, incorporation of fluorine atom(s) into bioactive molecules often produces dramatic changes in their chemical, physical and pharmacological properties.^2a,5 For example, when a hydrogen in molecules is replaced with a fluorine, the fluorinated molecules often have different reactivity from the parent fluorine-free ones, although the replacement has little effect on recognition of the molecules by proteins.^2a,5 Replacement of a hydroxy group with a fluorine can also be utilised for producing isosteric analogues.^2a,5 Introduction of multiple fluorine atoms often increases lipophilicity.^2a,5

Protubonine A is a pyrroloindole alkaloid with a diketopiperazine (DKP) structure, which was isolated by Ahn and Oh in 2011 from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF-5044 (Fig. 1).⁶ The absolute configuration of protubonine A was originally determined to be 3S,5aR,10bR,11aR, as shown in Fig. 1 as 1.⁶ Interestingly, 1 has an unnatural (R)-configuration in the tryptophan moiety and would be derived biosynthetically from D-tryptophan and L-leucine. Since D-amino acids reportedly play important roles in exhibiting various biological functions,⁷ we were interested in the potential biochemical importance of this rare pyrroloindole alkaloid having an (R)-configuration.⁸

Fig. 1 Structures of 11a-epi-protubonine A (1), protubonine A (2) and their fluorinated analogues 3 and 4.

As a part of our studies on the design, synthesis and biological evaluation of fluorine-containing bioactive compounds,⁹ we recently reported a versatile procedure for a fluorocyclisation reaction of tryptamines 5 with N-fluoro-2,4,6-trimethylpyridinium triflate (7), obtaining the corresponding 3a-fluoropyrrolo[2,3-b]indoles 6 (Scheme 1).¹⁰ Since the replacement of the 10b-hydroxy group of 1 with a fluorine would generate a useful analogue for understanding the biochemical behaviour of 1, we envisaged application of our fluorocyclisation reaction to the synthesis of the 10b-fluorinated analogue 3 of 1. However, unfortunately, after we started our synthesis of 3, de Lera and co-workers reported that in actuality, protubonine A is represented by 2 and has a 3S,5aR,10bR,11aS configuration.¹¹ In this paper, we report the synthesis of a 10b-fluorinated analogue of originally proposed protubonine A (3) and that of the revised one (4) via fluorocyclisation of tryptophan derivatives with 7 as a key step.

Scheme 1 Fluorocyclisation reaction of tryptamines 5 with N-fluoro-2,4,6-trimethylpyridinium triflate (7).

Results and discussion

Our simple retrosynthetic analysis is illustrated in Scheme 2. Opening the DKP ring of 3 leads to dipeptide 8, which includes 3a-fluoropyrrolo[2,3-b]indole 9 and N-carbobenzyloxy(Cbz)-L-leucine (10). The fluoropyrroloindole 9 would be formed by our reported fluorocyclisation of N-Cbz-D-tryptophan methyl ester (11). Since 3 includes an unnatural D-amino acid, the DKP ring of 3 has a trans-relationship between the C-3 and C-11a positions, in contrast to the cis-relationship of the generally observed DKP ring in natural products. This suggests that construction of the trans-DKP ring of 3 is easier than that of natural cis-DKPs.¹² In addition, 8 contains a proline structure in its dipeptide system. It is well-known that the DKP forming reaction of dipeptides containing proline as a C-terminal residue is generally much faster than that of other dipeptides.¹² On the basis of these two considerations, we planned to form the DKP ring at the final stage in our synthesis.¹³ Moreover, we were very interested in the stereoselectivity of the fluorocyclisation of 11 relative to the selenocyclisation and bromocyclisation of similar tryptophan derivatives with N-(phenylseleno)phthalimide¹⁴ and N-bromosuccinimide,^14d,15 respectively.

Scheme 2 Retrosynthetic analysis of the 10b-fluorinated analogue 3 of 11a-epi-protubonine A.

Our synthesis commenced from D-tryptophan (12) shown in Scheme 3. Protected tryptophan 11 was prepared in excellent yield by esterification of 12 with thionyl chloride in anhydrous methanol, followed by protection of the primary amino group with benzyl chloroformate in the presence of sodium bicarbonate. Fluorocyclisation of 11 according to our reported procedure,¹⁰ which employed 1.5 equiv. of 7 in anhydrous THF at 60 °C for 8.5 h, yielded an inseparable mixture of diastereomeric fluoropyrroloindoles 13a and 13b in an 83% yield. Unfortunately, no diastereoselectivity (dr: ca. 1 : 1) was observed. Acetylation of the mixture of 13a and 13b with acetic anhydride (Ac₂O) and pyridine was rather slow and required 2 days at 60 °C to produce fully protected fluoropyrroloindoles 14a and 14b in an 82% yield. Although separation of 14a and 14b by silica gel column chromatography proved difficult, small amounts of pure 14a and 14b were isolated to estimate their stereochemistries by ¹H NMR spectroscopic analysis (Fig. 2). Taniguchi and Hino reported that the ¹H chemical shifts of ester methyl protons of 16a and 16b were quite different.¹⁶ Owing to the shielding effect of the indole ring, the ester methyl protons of 16a, having an anti relationship between the H-3a and CO₂Me group, appeared at a higher field (δ_H 3.11 ppm) compared with the ester methyl protons of 16b (δ_H 3.63 and 3.72 ppm) that have a syn relationship. Thus, the stereochemistry of 14a and 14b was assigned by comparing the chemical shifts of the ester methyl protons of the two isomers. The product having the ester methyl protons appeared at a higher field (δ_H 3.09 ppm) is to be the anti-isomer 14a, whereas another product having them appeared at a lower field (δ_H 3.43 and 3.78 ppm) is to be the syn-isomer 14b. Removal of the Cbz groups of the mixture of 14a and 14b with hydrogen gas and a Pd/C catalyst gave 8-acetylfluoropyrroloindoles 15a and 15b in 45% and 43% yields, respectively. However, condensation of either 15a or 15b with 10, in the presence of coupling agents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and O-(6-chlorobenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, resulted in the recovery of the starting material. Hydrogenation of a mixture of 13a and 13b to remove their Cbz groups was unsuccessful, producing a complex mixture.

Scheme 3 Attempted synthesis of dipeptide 8.

Fig. 2 Estimation of stereochemistry of fluoropyrroloindoles 14a,b. (a) Two methyl signals were observed because of the presence of the rotamers, (b) ref. 16.

We subsequently attempted fluorocyclisation of dipeptide 18 as an alternative route to 3 (Scheme 4). Condensation of D-tryptophan methyl ester (17) with 10 in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), 1-hydroxybenzotriazole (HOBt) and N-methylmorpholine (NMM) produced 18 in an 83% yield. Since 18 has a bulky leucine moiety at the nucleophilic nitrogen atom, we were concerned that the reactivity of 18 for fluorocyclisation might decrease. Fortunately, fluorocyclisation of 18 with 1.5 equiv. of 7 at 60 °C proceeded smoothly, generating a mixture of the corresponding fluoropyrroloindoles 20a and 20b in an 84% yield. Again, no diastereoselectivity (dr: ca. 1 : 1) was observed. In contrast to the high stereoselectivity of the selenocyclisation¹⁴ and bromocyclisation^14d,15 of tryptophan derivatives, the fluorocyclisation of 18 showed no stereoselection. This unfortunate result can be rationalized by the formation of indolenine intermediates such as 19.^14a Owing to the difficulty of the separation of 20a and 20b, we attempted separation and determination of their stereochemistry after acetylation. Treatment of the mixture of 20a and 20b with Ac₂O and pyridine at 60 °C for 42 h afforded an inseparable mixture of 8 and 21 (8 : 21 = ca. 2 : 1) in a 65% yield and a substantial amount (<22%) of unreacted 20b. This suggested a significant difference in the reactivity of 20a and 20b. When acetylation of the mixture of 20a and 20b was stopped after 3 h, ca. 17 : 1 mixture of 8 and 21 was obtained in a 45% yield, and 20b was recovered in a 47% yield. Acetylation of pure 20b was accomplished by a longer reaction (50 h) to generate pure 21 in a 52% yield accompanied with a 41% recovery of the starting material 20b. The stereochemistry of 8 and 21 was determined by a comparison of the ¹H NMR spectra of both isomers. Since the ester methyl protons of 8 appeared at a higher field (δ_H 3.21 ppm) compared with those of 21 (δ_H 3.70 and 3.83 ppm), 8 was determined to be the anti-isomer and 21 the syn-isomer. When 8 was treated with Pd/C under a hydrogen atmosphere, deprotection and subsequent DKP formation occurred smoothly after 4 h as expected, yielding the desired 10b-fluorinated analogue 3 in a 50% yield. On the other hand, a similar reaction of 21 was faster, requiring only 2 h to generate the 5a,10b-epimer of 3 (22) in a higher yield (78%).

Scheme 4 Synthesis of 10b-fluorinated analogue 3 and 5a,10b-epimer 22.

Finally, we applied the procedure to synthesise 4 (Scheme 5). Fluorocyclisation of N-Cbz-L-Leu-L-Trp-OMe (23)¹⁷ with 7 gave the corresponding fluoropyrroloindoles 24a and 24b (24a : 24b = ca. 1 : 1) in a 77% yield. Acetylation of the mixture of 24a and 24b for 4 h generated ca. 30 : 1 mixture of 25a and 25b in a 49% yield, and 24b was recovered in a 43% yield. Recrystallisation of the mixture of 25a and 25b from hexane and dichloromethane gave 25a in pure form. Recovered 24b was acetylated again for 50 h to give pure 25b (52%) accompanied with a 22% recovery of 24b. The stereochemistry of 25a and 25b was determined by the ¹H NMR spectroscopic analysis. Catalytic hydrogenation of 25b fortunately produced the desired 10b-fluorinated analogue 4 in an 87% yield. A similar reaction of 25a required longer reaction time (5 h) to generate the 5a,10b-epimer 26 in an 86% yield.

Scheme 5 Synthesis of 10b-fluorinated analogue 4 and 5a,10b-epimer 26.

Conclusions

We succeeded in synthesising the 10b-fluorinated analogue of originally proposed protubonine A (3) and that of the revised one (4) using our fluorocyclisation as a key step. Treatment of 18 with 7 at 60 °C generated 20a and 20b in high yields, although no stereoselectivity was observed. Acetylation of 20a and 20b produced 8 and 21, respectively. The stereochemistry of 8 and 21 was easily determined by ¹H NMR spectroscopic analysis. Deprotection and following trans-DKP formation of 8 and 21 under hydrogenation conditions proceeded smoothly to produce 3 and its 5a,10b-epimer 22, respectively. Synthesis of 4 and its 5a,10b-epimer 26 was accomplished by similar synthetic procedure. A difference in reactivity between the diastereomers was observed both during acetylation and the subsequent DKP formation.

Experimental

General

Melting points were determined using a Yanaco micro melting point apparatus and are uncorrected. Optical rotations were determined using a JASCO P-2100 polarimeter. Infrared (IR) spectra were recorded using a JEOL FT/IR-460Plus spectrometer. All NMR spectra were recorded using a JEOL ECX-400P or JEOL ECA-500II spectrometers. Proton (¹H) NMR spectra were recorded at 400 or 500 MHz. Carbon-13 (¹³C) NMR spectra were recorded using the broadband proton decoupling at 100 or 126 MHz. Fluorine-19 (¹⁹F) NMR spectra were recorded at 376 or 470 MHz. All chemical shifts, δ, are stated in units of parts per million (ppm), relative to a standard. For ¹H NMR, the reference point is TMS (= 0.00 ppm). For ¹³C NMR, the reference point is CDCl₃ (= 77.0 ppm). For ¹⁹F NMR, the reference point is CFCl₃ (= 0.00 ppm). High and low resolution electron ionization (EI) mass spectra were recorded using a JEOL JMS-GCmate II spectrometer. Values are reported as a ratio of mass to charge (m/z). Column chromatography was performed on Nacalai Tesque Silica Gel 60 PF₂₅₄ (0.005–0.050 mm), Kanto chemical silica gel 60N (0.040–0.050 mm) or Merck 9385 silica gel 60 (0.040–0.063 mm). Thin layer chromatography was performed on Merck 5715 silica gel 60 F₂₅₄ or Merck 5554 silica gel 60 F₂₅₄.

N-Benzyloxycarbonyl-D-tryptophan methyl ester (11). D-Tryptophan (1.22 g, 6.00 mmol) was dissolved in anhydrous MeOH (20 mL) and thionyl chloride (1.30 mL, 18.0 mmol) was added to the solution at 0 °C. After stirring at room temperature for 15 h, the mixture was concentrated under reduced pressure. The residue was purified by recrystallization from MeOH/Et₂O to give D-tryptophan methyl ester hydrochloride (1.45 g, 95%) as a colourless crystalline solid.

To a solution of D-tryptophan methyl ester hydrochloride (1.01 g, 3.95 mmol) in 1,4-dioxane/H₂O (1/1, 19 mL) were added NaHCO₃ (1.16 g, 13.8 mmol) and benzyl chloroformate (0.560 mL, 3.95 mmol) at room temperature. After stirring for 3.5 h, the mixture was extracted twice with EtOAc. The combined organic layers were washed with 5% aq. HCl, water and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give 11 (1.29 g, 92%) as a pale yellow viscous oil. [α]²⁵_D −46.2 (c 1.0 in CHCl₃). ν_max (neat)/cm⁻¹ 3410, 3360, 3059, 3034, 2952, 2850, 1741, 1709, 1510, 1456, 1438, 1341, 1265, 1215, 1059, 1027, 1011, 741, 699. δ_H (400 MHz, CDCl₃) 3.26 (1H, dd, J = 15.1, 5.5 Hz), 3.28 (1H, dd, J = 15.1, 5.5 Hz), 3.63 (3H, s), 4.70 (1H, dt, J = 7.8, 5.5 Hz), 5.05 (1H, d, J = 12.4 Hz), 5.10 (1H, d, J = 12.4 Hz), 5.39 (1H, br d, J = 7.8 Hz), 6.85 (1H, br d, J = 1.4 Hz), 7.07 (1H, td, J = 7.3, 1.4 Hz), 7.15 (1H, td, J = 7.3, 1.4 Hz), 7.20–7.33 (6H, m), 7.50 (1H, br d, J = 7.3 Hz), 8.28 (1H, br s). δ_C (100 MHz, CDCl₃) 27.8 (s), 52.3 (s), 54.4 (s), 66.8 (s), 109.5 (s), 111.2 (s), 118.4 (s), 119.5 (s), 122.0 (s), 122.9 (s), 127.4 (s), 128.0 (s), 128.1 (s), 128.4 (s), 136.0 (s), 136.1 (s), 155.8 (s), 172.4 (s). MS (EI) m/z 353 ([M + H]⁺), 352 ([M]⁺). HRMS (EI) calcd for C₂₀H₂₀N₂O₄ ([M]⁺): 352.1423, found 352.1424.

(2R,3aRS,8aSR)-3a-Fluoro-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylic acid 1-benzyl 2-methyl ester (13a and 13b). To a solution of 11 (1.06 g, 3.00 mmol) in anhydrous THF (300 mL) was added 7 (1.30 g, 4.50 mmol) at room temperature. After stirring at 60 °C for 8.5 h, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 4/1) to give an inseparable mixture of 13a and 13b (13a : 13b = ca. 1 : 1, 926 mg, 83%) as a pale yellow viscous oil. Each of 13a and 13b was observed as a mixture of two rotamers (13a: ca. 7 : 10 ratio, 13b: ca. 7 : 10 ratio) in ¹H and ¹⁹F NMR. δ_H (400 MHz, CDCl₃) 2.61–3.04 (4H, m), 3.17 (30/17H, s), 3.28 (21/17H, s), 3.60 (30/17H, s), 3.79 (21/17H, s), 4.47 (10/17H, dd, J = 8.7, 4.6 Hz), 4.53 (7/17H, dd, J = 8.7, 4.6 Hz), 4.66–4.87 (2H, m), 5.03–5.30 (5H, m), 5.53 (7/17H, d, J = 17.4 Hz), 5.56 (10/17H, d, J = 17.4 Hz), 5.73 (7/17H, dd, J = 22.0, 3.2 Hz), 5.76 (10/17H, dd, J = 22.0, 3.2 Hz), 6.59–6.69 (2H, m), 6.75–6.85 (2H, m), 7.19–7.41 (14H, m). δ_F (376 MHz, CDCl₃) −139.2 (7/17F, m), −139.7 (7/17F, br t, J = 16.2 Hz), −139.8 (10/17F, m), −141.4 (10/17F, br t, J = 16.6 Hz). MS (EI) m/z 371 ([M + H]⁺), 370 ([M]⁺), 350 ([M − HF]⁺).

(2R,3aR,8aS)-8-Acetyl-3a-fluoro-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylic acid 1-benzyl 2-methyl ester (14a) and (2R,3aS,8aR)-8-acetyl-3a-fluoro-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylic acid 1-benzyl 2-methyl ester (14b). To a solution of a mixture of 13a and 13b (13a : 13b = ca. 1 : 1, 198 mg, 0.535 mmol) in acetic anhydride (2.10 mL) was added pyridine (0.130 mL, 1.60 mmol) at room temperature. After stirring at 60 °C for 48 h, the mixture was diluted with CHCl₃. The mixture was then washed with sat. aq. NaHCO₃, water, 5% aq. citric acid, water and brine. The resulting organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 3/1) to give a mixture of 14a and 14b (14a : 14b = ca. 1 : 1, 180 mg, 82%) as a pale yellow amorphous solid. Each of 14a and 14b gave the following data after partial separation by silica gel column chromatography (eluent: hexane/EtOAc = 3/1) and recrystallisation from hexane/CH₂Cl₂.

14a. Colourless crystalline solid. Mp 153–154 °C (from hexane/CH₂Cl₂). [α]²⁵_D −80.8 (c 1.0 in CHCl₃). ν_max (KBr)/cm⁻¹ 3033, 3002, 2956, 1761, 1736, 1707, 1675, 1604, 1478, 1467, 1422, 1389, 1361, 1335, 1311, 1285, 1248, 1217, 1197, 1172, 1139, 1094, 1061, 1022, 924, 768, 756, 727, 707. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 5 ratio) 2.19 (1/2H, br s), 2.65 (5/2H, br s), 2.90–3.02 (2H, m), 3.09 (3H, br s), 4.75 (1H, br d, J = 6.0 Hz), 5.16 (2H, s), 6.13 (1H, br d, J = 11.5 Hz), 7.16 (1H, t, J = 7.3 Hz), 7.26–7.38 (6H, m), 7.42–7.46 (1H, m), 8.06 (1H, br s). δ_C (100 MHz, CDCl₃, major rotamer) 23.5 (s), 37.1 (br s), 52.2 (s), 59.3 (d, J = 5.8 Hz), 67.9 (s), 80.6 (d, J = 32.6 Hz), 102.2 (d, J = 207.0 Hz), 119.3 (s), 124.3 (s), 124.6 (s), 126.6 (d, J = 21.1 Hz), 127.9 (s), 128.4 (s), 128.6 (s), 132.2 (d, J = 3.8 Hz), 135.4 (s), 144.8 (s), 154.0 (s), 170.0 (s), 170.9 (br s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 5 ratio) −142.7 (1/6F, br s), −143.0 (5/6F, br s). MS (EI) m/z 413 ([M + H]⁺), 412 ([M]⁺). HRMS (EI) calcd for C₂₂H₂₁FN₂O₅ ([M]⁺): 412.1434, found 412.1430.

14b. Colourless needles. Mp 110–112 °C (from hexane/CH₂Cl₂). [α]²⁵_D +148.5 (c 1.0 in CHCl₃). ν_max (KBr)/cm⁻¹ 3063, 3037, 2980, 2952, 1743, 1708, 1676, 1480, 1418, 1385, 1357, 1343, 1291, 1215, 1179, 1044, 974, 917, 785, 761, 742, 699. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2.5 ratio) 2.08 (6/7H, br s), 2.63–2.72 (22/7H, m), 3.01 (1H, dd, J = 12.4, 7.3 Hz), 3.43 (15/7H, br s), 3.78 (6/7H, br s), 4.07 (1H, dd, J = 10.1, 7.3 Hz), 4.88 (4/7H, br s), 5.15 (20/21H, s), 5.17 (10/21H, s), 6.09 (1H, br s), 7.22 (1H, t, J = 7.3 Hz), 7.33 (5H, br s), 7.44–7.50 (2H, m), 7.95 (2/7H, br s), 8.11 (5/7H, br s). δ_C (100 MHz, CDCl₃, major rotamer) 23.7 (s), 35.2 (d, J = 26.8 Hz), 52.4 (s), 58.7 (s), 67.8 (s), 80.2 (d, J = 36.4 Hz), 100.8 (d, J = 205.1 Hz), 119.7 (s), 123.9 (s), 124.9 (s), 126.9 (d, J = 20.1 Hz), 128.4 (s), 128.5 (s), 128.7 (s), 132.3 (d, J = 2.9 Hz), 135.0 (s), 143.8 (s), 153.0 (s), 170.8 (s), 171.4 (s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2.5 ratio) −142.0 (2/7F, br s), −142.4 (5/7F, br s). MS (EI) m/z 413 ([M + H]⁺), 412 ([M]⁺). HRMS (EI) calcd for C₂₂H₂₁FN₂O₅ ([M]⁺): 412.1434, found 412.1428.

(2R,3aR,8aR)-8-Acetyl-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (15a) and (2R,3aS,8aS)-8-acetyl-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (15b). To a solution of a mixture of 14a and 14b (14a : 14b = ca. 1 : 1, 113 mg, 0.274 mmol) in MeOH (0.6 mL) was added 10% palladium on carbon (23 mg) at room temperature. After stirring under 3–4 atm of hydrogen for 2 h, the mixture was filtered through a small pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 2/3) to give 15a (34 mg, 45%) and 15b (33 mg, 43%).

15a. Pale yellow viscous oil. [α]²⁵_D +19.0 (c 0.93 in CHCl₃). ν_max (neat)/cm⁻¹ 3344, 3001, 2952, 2853, 1740, 1666, 1606, 1483, 1467, 1436, 1396, 1356, 1317, 1294, 1218, 1144, 1092, 1053, 1021, 944, 914, 850, 836, 760, 736. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) 2.37 (2H, br s), 2.47 (1H, br s), 2.56–3.01 (3H, m), 3.42 (2H, br s), 3.47 (1H, br s), 4.12–4.18 (1H, m), 5.49 (2/3H, br d, J = 18.8 Hz), 5.68 (1/3H, br d, J = 22.0 Hz), 7.15 (1H, t, J = 7.8 Hz), 7.40 (1H, t, J = 7.8 Hz), 7.49 (1H, br d, J = 7.8 Hz), 8.22 (1H, br d, J = 7.8 Hz). δ_C (100 MHz, CDCl₃, major rotamer) 23.7 (s), 39.9 (d, J = 31.6 Hz), 52.3 (s), 59.3 (s), 83.1 (d, J = 30.7 Hz), 105.2 (d, J = 197.4 Hz), 117.7 (s), 123.8 (s), 124.5 (s), 125.9 (s), 131.6 (d, J = 39.3 Hz), 143.4 (br s), 168.7 (s), 172.3 (s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) −136.9 (2/3F, td, J = 18.4, 9.5 Hz), −137.8 (1/3F, td, J = 20.4, 13.5 Hz). MS (EI) m/z 279 ([M + H]⁺), 278 ([M]⁺), 258 ([M − HF]⁺), 219 ([M − CO₂Me]⁺). HRMS (EI) calcd for C₁₄H₁₅FN₂O₃ ([M]⁺): 278.1067, found 278.1067.

15b. Colourless viscous oil. [α]²⁵_D +49.3 (c 0.67 in CHCl₃). ν_max (neat)/cm⁻¹ 3330, 2955, 2927, 2853, 1740, 1668, 1605, 1483, 1468, 1393, 1357, 1312, 1287, 1252, 1217, 1199, 1180, 1136, 1092, 1064, 1032, 1013, 957, 916, 820, 799, 762. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 4 ratio) 2.35 (12/5H, s), 2.48 (3/5H, s), 2.64–2.81 (2H, m), 3.27 (4/5H, br s), 3.62 (1/5H, br s), 3.78 (3H, s), 3.71–3.88 (1H, m), 5.66 (4/5H, br d, J = 18.8 Hz), 5.85 (1/5H, br d, J = 19.7 Hz), 7.17 (1H, dd, J = 7.8, 7.3 Hz), 7.40–7.53 (2H, m), 8.27 (1H, br d, J = 7.8 Hz). δ_C (100 MHz, CDCl₃, major rotamer) 24.0 (s), 42.5 (d, J = 30.7 Hz), 52.6 (s), 59.0 (s), 83.3 (d, J = 29.7 Hz), 107.0 (d, J = 197.9 Hz), 117.4 (s), 124.3 (s), 124.4 (s), 126.9 (d, J = 23.0 Hz), 131.9 (s), 143.6 (d, J = 2.9 Hz), 169.4 (s), 172.8 (s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 4 ratio) −138.6 to −138.7 (4/5F, br m), −139.5 (1/5F, br s). MS (EI) m/z 279 ([M + H]⁺), 278 ([M]⁺), 258 ([M − HF]⁺), 219 ([M − CO₂Me]⁺). HRMS (EI) calcd for C₁₄H₁₅FN₂O₃ ([M]⁺): 278.1067, found 278.1070.

N-(Benzyloxycarbonyl)-L-leucyl-D-tryptophan methyl ester (18). To a solution of D-tryptophan methyl ester (17) (1.40 g, 6.40 mmol), obtained by neutralisation of its hydrochloride, and N-carbobenzyloxy-L-leucine (2.04 g, 7.70 mmol) in anhydrous DMF (32 mL) were added HOBt (1.04 g, 7.70 mmol), EDC·HCl (1.48 g, 7.70 mmol) and NMM (0.94 mL, 8.30 mmol) at 0 °C. After stirring for 18 h, the mixture was diluted with sat. aq. NaHCO₃ and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 3/2) to give 18 (2.47 g, 83%) as a colourless crystalline solid. Mp 133–134 °C (from hexane/CHCl₃). [α]²⁵_D −51.9 (c 0.75 in CHCl₃). ν_max (KBr)/cm⁻¹ 3410, 3392, 3320, 2957, 2930, 2871, 1755, 1739, 1689, 1656, 1533, 1457, 1439, 1351, 1341, 1321, 1267, 1230, 1217, 1112, 1050, 1022, 743, 698. δ_H (400 MHz, CDCl₃) 0.84 (3H, d, J = 6.0 Hz), 0.85 (3H, d, J = 6.0 Hz), 1.36–1.45 (1H, m), 1.50–1.60 (2H, m), 3.26 (1H, dd, J = 15.1, 5.5 Hz), 3.30 (1H, dd, J = 15.1, 5.5 Hz), 3.64 (3H, s), 4.16–4.21 (1H, m), 4.87–4.91 (1H, m), 5.04 (1H, d, J = 12.4 Hz), 5.10 (1H, br d, J = 7.3 Hz), 5.11 (1H, d, J = 12.4 Hz), 6.60 (1H, br d, J = 7.3 Hz), 6.90 (1H, br s), 7.09 (1H, ddd, J = 7.8, 6.9, 0.9 Hz), 7.16 (1H, ddd, J = 8.2, 6.9, 0.9 Hz), 7.30 (2H, dt, J = 8.2, 0.9 Hz), 7.31–7.36 (4H, br m), 7.50 (1H, br d, J = 7.8 Hz), 7.95 (1H, br s). δ_C (100 MHz, CDCl₃) 21.6 (s), 22.9 (s), 24.6 (s), 27.4 (s), 41.3 (s), 52.4 (s), 52.6 (s), 53.6 (s), 67.0 (s), 109.5 (s), 111.2 (s), 118.4 (s), 119.6 (s), 122.1 (s), 123.0 (s), 127.4 (s), 128.1 (s), 128.2 (s), 128.5 (s), 136.0 (s), 136.2 (s), 156.1 (s), 172.0 (s), 172.2 (s). MS (EI) m/z 466 ([M + H]⁺), 465 ([M]⁺). HRMS (EI) calcd for C₂₆H₃₁N₃O₅ ([M]⁺): 465.2264, found 465.2263.

(2R,3aRS,8aSR)-1-[(2S)-2-Benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (20a and 20b). To a solution of 18 (931 mg, 2.00 mmol) in anhydrous THF (200 mL) was added 7 (868 mg, 3.00 mmol) at room temperature. After stirring at 60 °C for 7.5 h, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with water and brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 3/1) to give an inseparable mixture of 20a and 20b (20a : 20b = ca. 1 : 1, 814 mg, 84%) as a colourless viscous oil. Each of 20a and 20b was observed as a mixture of two rotamers (20a: ca. 1 : 1 ratio, 20b: ca. 1 : 2 ratio) in ¹H and ¹⁹F NMR. δ_H (400 MHz, CDCl₃) 0.77 (3/2H, d, J = 6.4 Hz), 0.87 (5H, d, J = 6.4 Hz), 0.93 (2H, d, J = 6.4 Hz), 0.97 (1H, d, J = 6.4 Hz), 1.00 (5/2H, d, J = 6.4 Hz), 1.43–1.80 (6H, m), 2.55–3.11 (4H, m), 3.14 (3/2H, s), 3.28 (3/2H, s), 3.73 (1H, s), 3.83 (2H, s), 4.24 (1/2H, td, J = 9.6, 3.2 Hz), 4.31 (2/3H, td, J = 9.6, 3.7 Hz), 4.58 (1/2H, td, J = 9.6, 5.0 Hz), 4.64 (1/3H, dd, J = 8.7, 4.6 Hz), 4.88 (1/3H, td, J = 10.1, 5.5 Hz), 4.90–5.40 (29/3H, m), 5.62 (1H, dd, J = 17.4, 7.3 Hz), 5.83 (2/3H, dd, J = 25.2, 4.1 Hz), 5.90 (1/3H, dd, J = 22.0, 5.5 Hz), 6.64 (2/3H, d, J = 7.8 Hz), 6.65 (1/2H, d, J = 7.8 Hz), 6.78 (1/2H, t, J = 7.8 Hz), 6.821 (1/3H, d, J = 7.8 Hz), 6.824 (2/3H, t, J = 7.8 Hz), 6.96 (1/3H, t, J = 7.8 Hz), 7.20–7.37 (15H, m). δ_F (376 MHz, CDCl₃) −131.6 (1/3F, q, J = 20.2 Hz), −138.1 to −138.2 (1/2F, m), −141.8 (1/2F, br dd, J = 17.5, 11.3 Hz), −145.0 (2/3F, ddd, J = 32.8, 25.6, 17.5 Hz). MS (EI) m/z 483 ([M]⁺), 463 ([M − HF]⁺).

(2R,3aR,8aR)-8-Acetyl-1-[(2S)-2-benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (8) and (2R,3aS,8aS)-8-acetyl-1-[(2S)-2-benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (21).
Method A. To a solution of a mixture of 20a and 20b (20a : 20b = ca. 1 : 1, 169 mg, 0.350 mmol) in acetic anhydride (1.40 mL) was added pyridine (0.085 mL, 1.05 mmol) at room temperature. After stirring at 60 °C for 42 h, the mixture was diluted with CHCl₃. The mixture was then washed with sat. aq. NaHCO₃, water, 5% aq. citric acid, water and brine. The resulting organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 3/1) to give a mixture of 8 and 21 (8 : 21 = ca. 2 : 1, 120 mg, 65%) and 20b (containing small amounts of unidentified side products, 37 mg, <22%).
Method B. Acetylation of a mixture of 20a and 20b (20a : 20b = ca. 1 : 1, 193 mg, 0.400 mmol) with acetic anhydride (1.60 mL) and pyridine (0.100 mL, 1.24 mmol) at 60 °C for 3 h gave a mixture of 8 and 21 (8 : 21 = ca. 17 : 1, 95 mg, 45%) and 20b (91 mg, 47%). Compound 20b (86 mg, 0.178 mmol) was acetylated again with acetic anhydride (1.00 mL) and pyridine (0.0600 mL, 0.742 mmol) at 60 °C for 50 h to generate 21 (49 mg, 52%) and 20b (35 mg, 41%).

8. Colourless needles. Mp 166–167 °C (from hexane/CH₂Cl₂). [α]²⁵_D −113.1 (c 0.5 in CHCl₃). ν_max (KBr)/cm⁻¹ 3374, 2959, 2871, 1717, 1687, 1673, 1509, 1477, 1468, 1456, 1419, 1386, 1339, 1321, 1285, 1255, 1226, 1212, 1171, 1142, 1128, 1096, 1058, 1038, 1021, 960, 919, 842, 805, 782, 762, 700. δ_H (400 MHz, CDCl₃) 0.76 (3H, d, J = 6.4 Hz), 0.88 (3H, d, J = 6.4 Hz), 1.43–1.51 (1H, m), 1.58–1.68 (2H, m), 2.61 (3H, s), 2.98 (1H, td, J = 12.8, 8.7 Hz), 3.16 (1H, d, J = 12.8 Hz), 3.21 (3H, s), 4.16–4.22 (1H, m), 5.07 (1H, d, J = 12.4 Hz), 5.12 (1H, d, J = 12.4 Hz), 5.28 (1H, br d, J = 8.7 Hz), 5.48 (1H, br d, J = 8.7 Hz), 6.31 (1H, br d, J = 12.4 Hz), 7.17 (1H, dd, J = 7.8, 7.3 Hz), 7.31–7.45 (7H, m), 8.06 (1H, br d, J = 8.2 Hz). δ_C (100 MHz, CDCl₃) 21.1 (s), 23.3 (s), 23.5 (s), 24.4 (s), 37.7 (d, J = 29.7 Hz), 40.9 (s), 50.3 (s), 52.5 (s), 59.9 (d, J = 5.8 Hz), 67.3 (s), 79.8 (d, J = 32.6 Hz), 102.0 (d, J = 204.2 Hz), 119.4 (s), 124.5 (d, J = 6.7 Hz), 124.6 (s), 126.3 (d, J = 22.0 Hz), 128.0 (s), 128.3 (s), 128.6 (s), 132.2 (d, J = 2.9 Hz), 135.8 (s), 145.0 (d, J = 3.8 Hz), 156.5 (s), 169.7 (s), 171.0 (s), 174.3 (s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 16 ratio) −142.4 (1/17F, br s), −143.9 (16/17F, br t, J = 12.2 Hz). MS (EI) m/z 526 ([M + H]⁺), 525 ([M]⁺). HRMS (EI) calcd for C₂₈H₃₂FN₃O₆ ([M]⁺): 525.2275, found 525.2271.

21. Colourless crystalline solid. Mp 157–158 °C (from hexane/CH₂Cl₂). [α]²⁵_D +28.9 (c 0.25 in CHCl₃). ν_max (KBr)/cm⁻¹ 3242, 3033, 2994, 2953, 2868, 1749, 1703, 1685, 1672, 1607, 1539, 1479, 1469, 1415, 1389, 1317, 1294, 1260, 1219, 1179, 1051, 995, 941, 781, 758, 741, 700. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 3 ratio) 0.71–0.97 (3H, br m), 0.89 (3H, d, J = 6.4 Hz), 1.21–1.44 (1H, br m), 1.49–1.80 (2H, br m), 2.19–2.79 (4H, br m), 2.80–3.29 (1H, br m), 3.60–4.10 (1H, br m), 3.70 (3/4H, br s), 3.83 (9/4H, br s), 4.58–5.33 (4H, br m), 6.08 (3/4H, br s), 6.83 (1/4H, br s), 7.15–7.59 (35/4H, br m), 7.97 (1/4H, br s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 3 ratio) −144.2 (3/4F, br s), −144.4 (1/4F, br s). MS (EI) m/z 526 ([M + H]⁺), 525 ([M]⁺). HRMS (EI) calcd for C₂₈H₃₂FN₃O₆ ([M]⁺): 525.2275, found 525.2281.

20b. Colourless crystalline solid. Mp 49–51 °C (dec.). [α]²⁵_D +150.4 (c 0.4 in CHCl₃). ν_max (KBr)/cm⁻¹ 3396, 3331, 2956, 2871, 1749, 1714, 1653, 1618, 1523, 1486, 1472, 1437, 1322, 1301, 1257, 1219, 1187, 1094, 1058, 922, 753, 698. δ_H (400 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) 0.87 (2H, d, J = 6.4 Hz), 0.93 (2H, d, J = 6.4 Hz), 0.97 (1H, d, J = 6.4 Hz), 1.00 (1H, d, J = 6.4 Hz), 1.53–1.60 (1H, m), 1.65–1.78 (2H, m), 2.54–2.70 (1H, m), 2.79 (1/3H, ddd, J = 19.2, 14.2, 4.6 Hz), 2.97 (2/3H, dd, J = 17.4, 14.2 Hz), 3.72 (1H, s), 3.83 (2H, s), 4.32 (2/3H, td, J = 9.6, 3.7 Hz), 4.64 (1/3H, dd, J = 8.7, 4.6 Hz), 4.88 (1/3H, ddd, J = 10.1, 8.7, 5.5 Hz), 5.02 (2/3H, d, J = 12.4 Hz), 5.08 (2/3H, d, J = 12.4 Hz), 5.12 (1/3H, d, J = 11.9 Hz), 5.16 (1/3H, d, J = 11.9 Hz), 5.25–5.41 (8/3H, m), 5.82 (2/3H, dd, J = 25.7, 4.1 Hz), 5.90 (1/3H, dd, J = 22.4, 5.5 Hz), 6.63 (2/3H, d, J = 7.8 Hz), 6.820 (2/3H, t, J = 7.8 Hz), 6.823 (1/3H, d, J = 7.3 Hz), 6.96 (1/3H, t, J = 7.3 Hz), 7.21 (2/3H, t, J = 7.8 Hz), 7.26–7.36 (19/3H, m). δ_C (100 MHz, CDCl₃, major rotamer) 21.4 (s), 23.4 (s), 24.2 (s), 40.5 (s), 41.4 (d, J = 31.6 Hz), 50.3 (s), 53.0 (s), 60.1 (s), 67.1 (s), 84.1 (d, J = 27.8 Hz), 106.7 (d, J = 195.1 Hz), 110.5 (s), 119.4 (s), 123.4 (s), 126.5 (d, J = 24.0 Hz), 127.9 (s), 128.2 (s), 128.5 (s), 131.2 (s), 136.0 (s), 148.3 (d, J = 4.8 Hz), 156.2 (s), 171.7 (s), 173.5 (s). δ_F (376 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) −131.6 (1/3F, q, J = 20.7 Hz), −145.0 (2/3F, ddd, J = 32.8, 25.2, 17.5 Hz). MS (EI) m/z 484 ([M + H]⁺), 483 ([M]⁺), 463 ([M − HF]⁺). HRMS (EI) calcd for C₂₆H₃₀FN₃O₅ ([M]⁺): 483.2169, found 483.2157.

(3S,5aR,10bR,11aR)-6-Acetyl-10b-fluoro-6,10b,11,11a-tetrahydro-3-(2-methylpropyl)-2H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(3H,5aH)-dione (3). To a solution of 8 (109 mg, 0.207 mmol) in MeOH (0.4 mL) was added 10% palladium on carbon (22 mg) at room temperature. After stirring under 3–4 atm of hydrogen for 4 h, the mixture was filtered through a small pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 2/3) to give 3 (37 mg, 50%) as a colourless crystalline solid. Mp 182–183 °C (from hexane/CH₂Cl₂). [α]²⁵_D +27.3 (c 0.50 in CHCl₃). ν_max (KBr)/cm⁻¹ 3286, 2960, 2931, 2874, 1686, 1480, 1468, 1418, 1385, 1330, 1292, 1185, 1146, 1096, 1061, 1040, 937, 771, 759. δ_H (400 MHz, CDCl₃) 0.91 (3H, d, J = 6.4 Hz), 0.97 (3H, d, J = 6.4 Hz), 1.63 (2H, dd, J = 7.8, 6.4 Hz), 1.71 (1H, septet, J = 6.4 Hz), 2.55 (3H, s), 2.92 (1H, ddd, J = 18.8, 14.2, 10.5 Hz), 3.37 (1H, dt, J = 14.2, 4.6 Hz), 3.77 (1H, td, J = 7.8, 4.6 Hz), 4.52 (1H, dd, J = 10.5, 4.6 Hz), 5.96 (1H, d, J = 12.4 Hz), 6.68 (1H, br d, J = 4.6 Hz), 7.17 (1H, dd, J = 7.8, 7.3 Hz), 7.39 (1H, tt, J = 7.8, 1.8 Hz), 7.47 (1H, dt, J = 7.3, 1.8 Hz), 8.00 (1H, br d, J = 7.8 Hz). δ_C (100 MHz, CDCl₃) 21.1 (s), 22.9 (s), 24.3 (s), 24.5 (s), 32.3 (d, J = 30.7 Hz), 41.3 (s), 55.8 (d, J = 4.8 Hz), 56.0 (s), 81.3 (d, J = 33.6 Hz), 100.9 (d, J = 201.3 Hz), 118.8 (s), 124.9 (s), 125.0 (d, J = 2.9 Hz), 127.6 (d, J = 22.0 Hz), 132.1 (d, J = 2.9 Hz), 142.8 (d, J = 3.8 Hz), 167.4 (s), 167.8 (s), 170.4 (s). δ_F (376 MHz, CDCl₃) −138.4 (1F, br t, J = 15.3 Hz). MS (EI) m/z 359 ([M]⁺). HRMS (EI) calcd for C₁₉H₂₂FN₃O₃ ([M]⁺): 359.1645, found 359.1637.

(3S,5aS,10bS,11aR)-6-Acetyl-10b-fluoro-6,10b,11,11a-tetrahydro-3-(2-methylpropyl)-2H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(3H,5aH)-dione (22). To a solution of 21 (49 mg, 0.0930 mmol) in MeOH (0.4 mL) was added 10% palladium on carbon (10 mg) at room temperature. After stirring under 3–4 atm of hydrogen for 2 h, the mixture was filtered through a small pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/EtOAc = 2/3) to give 22 (26 mg, 78%) as colourless needles. Mp 214–216 °C (from hexane/CH₂Cl₂). [α]²⁵_D +212.6 (c 0.20 in CHCl₃). ν_max (KBr)/cm⁻¹ 3233, 3161, 2968, 2932, 2871, 1685, 1669, 1645, 1483, 1466, 1437, 1392, 1330, 1294, 1200, 1146, 1090, 1060, 1037, 820, 793, 757. δ_H (400 MHz, CDCl₃) 0.92 (3H, d, J = 6.4 Hz), 0.94 (3H, d, J = 6.4 Hz), 1.50–1.75 (3H, m), 2.62 (3H, s), 2.75 (1H, dt, J = 13.7, 12.4 Hz), 3.07 (1H, dd, J = 12.4, 5.5 Hz), 3.92–4.02 (2H, m), 6.37 (1H, d, J = 13.3 Hz), 7.04 (1H, br d, J = 2.8 Hz), 7.26 (1H, dd, J = 7.8, 7.3 Hz), 7.46–7.52 (2H, m), 8.17 (1H, br d, J = 7.8 Hz). δ_C (100 MHz, CDCl₃) 21.3 (s), 22.9 (s), 23.8 (s), 24.2 (s), 40.0 (d, J = 29.7 Hz), 43.9 (s), 55.7 (s), 58.2 (d, J = 5.8 Hz), 79.8 (d, J = 32.6 Hz), 102.0 (d, J = 204.2 Hz), 119.0 (s), 124.2 (s), 125.3 (d, J = 2.9 Hz), 126.0 (d, J = 22.0 Hz), 132.4 (d, J = 2.9 Hz), 144.5 (d, J = 3.8 Hz), 166.45 (s), 166.49 (s), 170.9 (s). δ_F (376 MHz, CDCl₃) −144.6 (1F, br t, J = 13.5 Hz). MS (EI) m/z 359 ([M]⁺). HRMS (EI) calcd for C₁₉H₂₂FN₃O₃ ([M]⁺): 359.1645, found 359.1652.

(2S,3aRS,8aSR)-1-[(2S)-2-Benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (24a and 24b). Fluorocyclisation of N-Cbz-L-Leu-L-Trp-OMe (23)¹⁷ (349 mg, 0.75 mmol) with 7 (325 mg, 1.13 mmol) in anhydrous THF (75 mL) at 60 °C for 7 h in a similar manner to that of 18 gave an inseparable mixture of 24a and 24b (24a : 24b = ca. 1 : 1, 279 mg, 77%) as a colourless viscous oil. Each of 24a and 24b was observed as a mixture of two rotamers (24a: ca. 1 : 2 ratio, 24b: ca. 1 : 4 ratio) in ¹H and ¹⁹F NMR. δ_H (500 MHz, CDCl₃) 0.88 (3/5H, d, J = 6.3 Hz), 0.941 (2H, d, J = 6.3 Hz), 0.944 (3/5H, d, J = 6.3 Hz), 0.97 (2H, d, J = 6.3 Hz), 1.00 (12/5H, d, J = 6.9 Hz), 1.01 (12/5H, d, J = 6.9 Hz), 1.02 (1H, d, J = 6.3 Hz), 1.06 (1H, d, J = 6.3 Hz), 1.35–1.86 (6H, m), 2.63–3.13 (4H, m), 3.17 (2H, s), 3.31 (1H, s), 3.747 (3/5H, s), 3.754 (12/5H, s), 4.38–4.43 (13/15H, m), 4.47 (4/5H, t, J = 8.0 Hz), 4.55 (4/5H, td, J = 9.2, 5.7 Hz), 4.64 (2/3H, br d, J = 8.0 Hz), 4.65 (1/5H, br d, J = 9.2 Hz), 4.70 (1/3H, td, J = 9.7, 4.6 Hz), 4.77 (1/3H, br d, J = 4.0 Hz), 4.996 (1/3H, br d, J = 9.2 Hz), 5.001 (1/3H, br d, J = 9.2 Hz), 5.02 (2/3H, d, J = 12.6 Hz), 5.06 (2/3H, d, J = 12.6 Hz), 5.10 (1/3H, d, J = 12.0 Hz), 5.11 (2/5H, s), 5.12 (4/5H, d, J = 12.0 Hz), 5.13 (1/3H, d, J = 12.0 Hz), 5.15 (4/5H, d, J = 12.0 Hz), 5.26 (1/5H, br d, J = 9.2 Hz), 5.31 (2/3H, br s), 5.33 (4/5H, br d, J = 9.2 Hz), 5.41 (1/5H, br d, J = 9.2 Hz), 5.43 (2/3H, br d, J = 9.2 Hz), 5.59 (2/3H, d, J = 17.8 Hz), 5.81 (4/5H, dd, J = 18.9, 2.3 Hz), 5.87 (1/5H, dd, J = 25.8, 4.0 Hz), 5.97 (1/3H, dd, J = 17.8, 4.0 Hz), 6.49 (4/5H, br d, J = 2.3 Hz), 6.61 (4/5H, d, J = 8.0 Hz), 6.63 (2/3H, d, J = 8.0 Hz), 6.66 (1/5H, d, J = 8.0 Hz), 6.77 (2/3H, t, J = 8.0 Hz), 6.81 (1/3H, d, J = 8.0 Hz), 6.83 (4/5H, t, J = 8.0 Hz), 6.84 (1/5H, t, J = 8.0 Hz), 6.93 (1/3H, t, J = 8.0 Hz), 7.18–7.39 (14H, m). δ_F (470 MHz, CDCl₃) −133.3 to −133.4 (1/3F, m), −140.8 to −141.0 (5/3F, m). MS (EI) m/z 483 ([M]⁺), 463 ([M − HF]⁺).

(2S,3aS,8aS)-8-Acetyl-1-[(2S)-2-benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (25a) and (2S,3aR,8aR)-8-acetyl-1-[(2S)-2-benzyloxycarbonylamino-4-methylpentanoyl]-3a-fluoro-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid methyl ester (25b). Acetylation of a mixture of 24a and 24b (24a : 24b = ca. 1 : 1, 224 mg, 0.463 mmol) with acetic anhydride (1.85 mL) and pyridine (0.110 mL, 1.39 mmol) at 60 °C for 4 h in a similar manner to that of 20a and 20b gave a mixture of 25a and 25b (25a : 25b = ca. 30 : 1, 120 mg, 49%) and 24b (97 mg, 43%). Compound 24b (76 mg, 0.157 mmol) was acetylated again with acetic anhydride (0.63 mL) and pyridine (0.0380 mL, 0.472 mmol) at 60 °C for 50 h to generate 25b (43 mg, 52%) and 24b (17 mg, 22%). The data of pure 25a was obtained after recrystallisation of the mixture of 25a and 25b from hexane and dichloromethane.

25a. Colourless needles. Mp 131–132 °C (from hexane/CH₂Cl₂). [α]²³_D +27.5 (c 0.5 in CHCl₃). ν_max (KBr)/cm⁻¹ 3414, 2952, 1726, 1677, 1670, 1513, 1480, 1468, 1419, 1385, 1343, 1321, 1287, 1224, 1172, 1142, 1097, 1062, 1040, 1028, 775, 751, 698. δ_H (500 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) 0.93–0.96 (6H, br m), 1.34–1.38 (2/3H, br m), 1.52–1.80 (7/3H, br m), 2.44 (1H, br s), 2.63 (2H, br s), 2.75–3.20 (2H, br m), 3.06 (2H, br s), 3.18 (1H, br s), 4.38 (2/3H, br t, J = 8.6 Hz), 4.61 (2/3H, br d, J = 8.6 Hz), 4.99–5.37 (4H, br m), 6.19 (2/3H, br d, J = 12.0 Hz), 7.03 (1/3H, br d, J = 8.0 Hz), 7.14–7.47 (8H, br m), 8.03 (2/3H, br d, J = 6.3 Hz). δ_C (126 MHz, CDCl₃, major rotamer) 21.6 (s), 23.4 (s), 23.7 (s), 24.4 (s), 37.6 (d, J = 31.2 Hz), 43.0 (s), 50.4 (s), 52.8 (s), 59.3 (d, J = 4.8 Hz), 66.9 (s), 80.4 (d, J = 32.4 Hz), 101.5 (d, J = 203.9 Hz), 119.3 (s), 124.6 (d, J = 12.0 Hz), 125.6 (s), 128.0 (s × 2), 128.1 (s), 128.4 (s), 132.3 (s), 136.1 (s), 145.1 (s), 155.5 (s), 169.0 (s), 171.2 (s), 172.8 (s). δ_F (470 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 2 ratio) −143.7 (2/3F, br s), −143.8 (1/3F, br s). MS (EI) m/z 526 ([M + H]⁺), 525 ([M]⁺). HRMS (EI) calcd for C₂₈H₃₂FN₃O₆ ([M]⁺): 525.2275, found 525.2275.

25b. Colourless crystalline solid. Mp 56–59 °C (from hexane/CHCl₃). [α]²³_D −67.2 (c 0.75 in CHCl₃). ν_max (KBr)/cm⁻¹ 3385, 2956, 2871, 1752, 1721, 1683, 1608, 1520, 1481, 1468, 1416, 1370, 1326, 1288, 1281, 1257, 1246, 1214, 1174, 1043, 778, 760, 740, 699. δ_H (500 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 3 ratio) 0.60 (3/4H, d, J = 6.3 Hz), 0.71 (3/4H, d, J = 6.3 Hz), 0.83–0.90 (1/4H, m), 1.02 (9/4H, d, J = 6.9 Hz), 1.08 (9/4H, d, J = 6.9 Hz), 1.19–1.35 (1/2H, m), 1.45–1.51 (3/4H, m), 1.65–1.70 (3/4H, m), 1.83 (3/4H, septet, J = 6.9 Hz), 2.43 (9/4H, s), 2.62 (3/4H, td, J = 12.6, 11.5 Hz), 2.63 (3/4H, s), 2.77 (1/4H, td, J = 13.2, 9.7 Hz), 2.95 (3/4H, dd, J = 12.6, 6.9 Hz), 3.19 (1/4H, dd, J = 13.2, 8.6 Hz), 3.72 (9/4H, s), 3.77 (3/4H, s), 4.01 (3/4H, dd, J = 11.5, 6.9 Hz), 4.08 (1/4H, td, J = 8.6, 5.2 Hz), 4.17 (1/4H, br t, J = 8.6 Hz), 5.00–5.07 (7/2H, m), 5.35 (1/4H, br d, J = 9.2 Hz), 6.13 (1/4H, d, J = 9.2 Hz), 6.64 (3/4H, d, J = 8.0 Hz), 7.09 (3/4H, d, J = 8.0 Hz), 7.22–7.49 (8H, m), 8.02 (1/4H, br d, J = 8.0 Hz). δ_C (126 MHz, CDCl₃, major rotamer) 22.1 (s), 23.0 (s), 23.4 (s), 24.9 (s), 33.7 (d, J = 26.4 Hz), 42.4 (s), 50.2 (s), 52.4 (s), 59.0 (d, J = 3.6 Hz), 66.6 (s), 77.7 (d, J = 33.6 Hz), 100.2 (d, J = 205.1 Hz), 119.5 (s), 124.7 (s), 125.7 (s), 127.9 (s), 128.0 (s), 128.4 (s), 129.1 (d, J = 21.6 Hz), 132.1 (d, J = 2.4 Hz), 136.7 (s), 143.4 (d, J = 3.6 Hz), 155.4 (s), 170.5 (s), 171.8 (s), 174.9 (s). δ_F (470 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 3 ratio) −144.3 (3/4F, br t, J = 10.3 Hz), −144.8 (1/4F, br t, J = 11.4 Hz). MS (EI) m/z 526 ([M + H]⁺), 525 ([M]⁺). HRMS (EI) calcd for C₂₈H₃₂FN₃O₆ ([M]⁺): 525.2275, found 525.2261.

24b. Colourless crystalline solid. Mp 45–47 °C (dec.) (from hexane/CH₂Cl₂). [α]²⁵_D −178.5 (c 0.5 in CHCl₃). ν_max (KBr)/cm⁻¹ 3317, 2956, 2871, 1752, 1717, 1698, 1654, 1618, 1541, 1523, 1474, 1437, 1320, 1259, 1216, 1190, 1177, 1121, 1095, 1057, 749, 698. δ_H (500 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 4 ratio) 0.86 (3/5H, d, J = 6.3 Hz), 0.93 (3/5H, d, J = 6.3 Hz), 0.99 (12/5H, d, J = 6.9 Hz), 1.00 (12/5H, d, J = 6.9 Hz), 1.35 (1/5H, ddd, J = 14.3, 9.7, 4.0 Hz), 1.52 (1/5H, ddd, J = 14.3, 9.7, 4.6 Hz), 1.61–1.71 (8/5H, m), 1.77–1.85 (1H, m), 2.60–2.79 (9/5H, m), 2.98–3.05 (1/5H, m), 3.73 (12/5H, s), 3.74 (3/5H, s), 4.41 (1/5H, td, J = 9.7, 4.0 Hz), 4.45 (4/5H, t, J = 8.0 Hz), 4.56 (4/5H, td, J = 9.2, 5.7 Hz), 4.63 (1/5H, br d, J = 8.0 Hz), 5.08 (2/5H, s), 5.11 (4/5H, d, J = 12.6 Hz), 5.13 (4/5H, d, J = 12.6 Hz), 5.37 (1/5H, br d, J = 4.0 Hz), 5.55 (1/5H, d, J = 9.2 Hz), 5.63 (4/5H, d, J = 9.7 Hz), 5.81 (4/5H, dd, J = 18.9, 2.3 Hz), 5.85 (1/5H, dd, J = 25.5, 4.0 Hz), 6.54 (4/5H, br d, J = 2.3 Hz), 6.59 (4/5H, d, J = 8.0 Hz), 6.64 (1/5H, d, J = 8.0 Hz), 6.82 (1H, br t, J = 8.0 Hz), 7.19–7.22 (1H, m), 7.28–7.34 (6H, m). δ_C (126 MHz, CDCl₃, major rotamer) 22.1 (s), 23.1 (s), 24.3 (s), 38.6 (d, J = 31.2 Hz), 42.0 (s), 50.9 (s), 52.5 (s), 59.5 (s), 67.4 (s), 80.9 (d, J = 30.0 Hz), 107.5 (d, J = 199.1 Hz), 110.6 (s), 119.5 (d, J = 2.4 Hz), 123.81 (s), 123.85 (d, J = 22.8 Hz), 128.0 (s), 128.3 (s), 128.6 (s), 131.9 (d, J = 2.4 Hz), 135.9 (s), 149.4 (d, J = 4.8 Hz), 156.8 (s), 170.6 (s), 172.8 (s). δ_F (470 MHz, CDCl₃, a mixture of two rotamers in ca. 1 : 4 ratio) −140.8 to −140.9 (4/5F, m), –140.8 to −141.0 (1/5F, m). MS (EI) m/z 484 ([M + H]⁺), 483 ([M]⁺). HRMS (EI) calcd for C₂₆H₃₀FN₃O₅ ([M]⁺): 483.2169, found 483.2151.

(3S,5aR,10bR,11aS)-6-Acetyl-10b-fluoro-6,10b,11,11a-tetrahydro-3-(2-methylpropyl)-2H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(3H,5aH)-dione (4). Deprotection and subsequent DKP formation of 25b (42 mg, 0.080 mmol) using 10% palladium on carbon (8 mg) in MeOH (1.0 mL) at room temperature for 1.5 h in a similar manner to those of 8 gave 4 (25 mg, 87%) as a colourless crystalline solid. Mp 93–96 °C (from hexane/CHCl₃). [α]²²_D −244.6 (c 0.40 in CHCl₃). ν_max (KBr)/cm⁻¹ 3246, 2959, 2930, 2871, 1685, 1480, 1467, 1408, 1384, 1351, 1332, 1295, 1284, 1179, 1158, 1143, 1104, 1092, 1061, 1045, 925, 767, 755. δ_H (500 MHz, CDCl₃) 0.92 (3H, d, J = 6.3 Hz), 1.00 (3H, d, J = 6.3 Hz), 1.58 (1H, ddd, J = 14.4, 9.8, 5.2 Hz), 1.72–1.80 (1H, m), 2.01 (1H, ddd, J = 14.4, 9.8, 3.5 Hz), 2.65 (3H, s), 2.79 (1H, td, J = 12.6, 12.1 Hz), 3.07 (1H, dd, J = 12.6, 6.3 Hz), 3.97–4.01 (2H, m), 6.24 (1H, d, J = 12.1 Hz), 6.58 (1H, s), 7.24 (1H, t, J = 7.5 Hz), 7.46–7.52 (2H, m), 8.13 (1H, br d, J = 8.0 Hz). δ_C (126 MHz, CDCl₃) 21.1 (s), 23.3 (s), 23.8 (s), 24.3 (s), 37.8 (d, J = 30.0 Hz), 39.0 (s), 53.1 (s), 58.8 (d, J = 6.0 Hz), 79.8 (d, J = 32.4 Hz), 101.7 (d, J = 205.1 Hz), 119.3 (s), 124.1 (s), 125.2 (d, J = 2.4 Hz), 126.2 (d, J = 22.8 Hz), 132.4 (d, J = 3.6 Hz), 144.5 (d, J = 3.6 Hz), 166.5 (s), 167.5 (s), 170.9 (s). δ_F (470 MHz, CDCl₃) −144.9 (1F, br t, J = 11.9 Hz). MS (EI) m/z 359 ([M]⁺). HRMS (EI) calcd for C₁₉H₂₂FN₃O₃ ([M]⁺): 359.1645, found 359.1653.

(3S,5aS,10bS,11aS)-6-Acetyl-10b-fluoro-6,10b,11,11a-tetrahydro-3-(2-methylpropyl)-2H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(3H,5aH)-dione (26). Deprotection and subsequent DKP formation of 25a (53 mg, 0.100 mmol) using 10% palladium on carbon (11 mg) in MeOH (1.0 mL) at room temperature for 5 h in a similar manner to those of 8 gave 26 (31 mg, 86%) as a colourless crystalline solid. Mp 105–106 °C (from hexane/CH₂Cl₂). [α]²⁵_D −15.5 (c 0.40 in CHCl₃). ν_max (KBr)/cm⁻¹ 3227, 3120, 2959, 2937, 2871, 1689, 1680, 1673, 1480, 1468, 1406, 1385, 1334, 1293, 1184, 1042, 938, 769, 755. δ_H (500 MHz, CDCl₃) 0.89 (3H, d, J = 6.3 Hz), 0.90 (3H, d, J = 6.3 Hz), 1.42 (1H, ddd, J = 14.3, 9.7, 5.2 Hz), 1.56–1.65 (1H, m), 1.91 (1H, ddd, J = 14.3, 9.7, 4.0 Hz), 2.58 (3H, s), 2.91 (1H, ddd, J = 17.8, 14.3, 10.9 Hz), 3.51 (1H, ddd, J = 14.3, 3.4, 1.7 Hz), 3.90 (1H, dd, J = 9.7, 4.0 Hz), 4.50 (1H, dd, J = 10.9, 3.4 Hz), 5.62 (1H, s), 5.98 (1H, d, J = 11.5 Hz), 7.19 (1H, t, J = 7.5 Hz), 7.42 (1H, dddd, J = 8.6, 7.5, 2.3, 1.2 Hz), 7.52 (1H, br d, J = 7.5 Hz), 7.99 (1H, br d, J = 8.6 Hz). δ_C (126 MHz, CDCl₃) 21.1 (s), 23.0 (s), 24.2 (s), 24.5 (s), 30.9 (d, J = 30.0 Hz), 37.7 (s), 53.5 (s), 57.5 (d, J = 6.0 Hz), 80.8 (d, J = 33.6 Hz), 101.2 (d, J = 201.5 Hz), 118.9 (s), 125.0 (d, J = 2.4 Hz), 125.1 (s), 127.3 (d, J = 21.6 Hz), 132.2 (d, J = 3.6 Hz), 142.9 (d, J = 4.8 Hz), 167.9 (s), 168.1 (s), 170.2 (s). δ_F (470 MHz, CDCl₃) −138.5 (1F, br t, J = 14.1 Hz). MS (EI) m/z 359 ([M]⁺), 339 ([M − HF]⁺). HRMS (EI) calcd for C₁₉H₂₂FN₃O₃ ([M]⁺): 359.1645, found 359.1638.

Notes and references

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3. D. O'Hagan, J. Fluorine Chem., 2010, 131, 1071–1081.
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Footnote

† Electronic supplementary information (ESI) available: NMR spectra of new compounds. See DOI: 10.1039/c4ra08741k

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