Formal total synthesis of histrionicotoxin alkaloids via Hg(OTf)₂-catalyzed cycloisomerization and SmI₂-induced ring expansion

Abstract

The efficient formal total synthesis of histrionicotoxin alkaloids was achieved. In this process, two key reactions were used to construct a core 1-azaspiro[5.5]undecane framework common to histrionicotoxins: a mercuric triflate (Hg(OTf)₂)-catalyzed cycloisomerization of a linear substrate, which was developed in our laboratory, and a samarium iodide (SmI₂)-mediated ring expansion.

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Introduction

(−)-Histrionicotoxin 283A (HTX-283A, 1, Fig. 1) is an azaspirocyclic histrionicotoxin alkaloid that was first isolated from skin extracts of the Colombian poison arrow frog Dendrobates histrionicus in 1971 by Witkop et al.¹ It exhibits highly selective inhibition of nicotinic acetylcholine receptors. Since Witkop et al. separated a mixture of six alkaloids including 1 from the skin extracts of 1110 frogs, other members of this alkaloid family have also been identified. In 1992, (−)-histrionicotoxin 235A (HTX-235A, 2) was also isolated as a major constituent by Spande et al. from the other poison frog Dendrobates auratus.² The bioactivities have led to its use as important probes in neurophysiology. Establishing an efficient synthetic pathway for histrionicotoxin alkaloids is essential to investigate the development of new biological tools and the structure–activity relationships in more detail.

Fig. 1 Chemical structures of (−)-HTX-283A (1) and (−)-HTX-235A (2).

Regarding the structural features, compound 1 has a unique chemical structure characterized by a core spiropiperidine structure and two cis-enyne side chains. The core spirocyclic skeleton of 1 is conserved in 2, but the two side cis-enyne groups are replaced by allylic and vinylic groups. The spirocyclic skeleton structure of histrionicotoxin alkaloids has prompted many synthetic organic chemists to promote the total syntheses so far.³ In this contribution, we intended to realize the efficient construction of the core 1-azaspiro[5.5]undecane skeleton common to histrionicotoxin alkaloids based on ring expansion of a 1-azaspiro[4.5]decane one that could be formed in a stereoselective manner from a linear substrate by our original Hg(OTf)₂-catalyzed cycloisomerization reaction⁴ (Fig. 1). In this letter, we report the formal synthesis of histrionicotoxins via two key steps: Hg(OTf)₂-catalyzed cycloisomerization and SmI₂-mediated ring expansion reactions.

Results and discussion

The retrosynthetic analysis of histrionicotoxin alkaloids is shown in Scheme 1. The spirocyclic ring compound 3 has been converted into histrionicotoxins via introduction of an allylic group by Tokuyama et al.³ⁱ Therefore, we planned to synthesize the 1-azaspiro[5.5]undecane skeleton 3 by applying a SmI₂-mediated ring expansion reaction, reported by Honda et al.,⁵ to 1-azaspiro[4.5]decane skeleton 4, which would be derived from spirocyclic compound 5. Compound 5 would be constructed by the key Hg(OTf)₂-catalyzed cycloisomerization reaction of linear ynone 6, which would be prepared through acylation of sulfone 8 with pyrrolidinone 7, derived from L-glutamic acid according to the known method.⁶ Compound 8 would be synthesized by alkylation of a lithium acetylide of alkyne 9 with commercially available 1,3-diiodopropane (10).

Scheme 1 Retrosynthetic analysis of histrionicotoxins.

The total synthesis commenced with the known silyl ether 9, derived from commercially available 3-butyn-1-ol (Scheme 2).⁷ Alkylation of a lithium acetylide of 9 with 1,3-diiodopropane (10) followed by sulfonylation of the iodo moiety gave sulfone 8. After acylation of an α-anion of 8 with the known pyrrolidinone 7, the cyclization precursor 6 was prepared through SmI₂-mediated desulfonylation.⁸

Scheme 2 Synthesis of the cyclization precursor 6.

We examined the Hg(OTf)₂-catalyzed cycloisomerization reaction of precursor 6 as the first key reaction (Table 1). As expected, the reaction proceeded in a stereoselective manner to provide the desired spirocyclic product 5 in an isolated yield of 58%, along with a minor diastereomer 11 (11% and 12%), when 6 was allowed to react with Hg(OTf)₂ (5 and 10 mol%) in MeCN at 0 °C (entries 1 and 2, respectively). Increasing the catalyst loading to 20 mol% afforded a better yield (67%) of 5 (entry 3). When the catalyst loading was increased to 30 and 50 mol%, the yield of 5 decreased to 52% and 38%, respectively (entries 4 and 5). The reaction at −20 °C resulted in a decrease in the yield of 11 (trace) (entry 6). When the reaction solution was gradually warmed to room temperature from −20 °C, the result was the same as that in entry 3 (entry 7). Finally, the effect of reaction temperature was examined (entries 8–10). Entry 9 showed the best conditions (cat. 20 mol%, −30 °C) in terms of the yield of 5. Lowering the temperature resulted in a gradual decrease in the yield of 11. Stereochemical assignments of 5 and 11 were achieved by their NOESY spectra; see (ESI†). The reaction mechanism, which we propose at present, is shown in Table 1.

Table 1 Optimization of the cycloisomerization of cyclization precursor 6

Entry	Hg(OTf)2 (mol%)	Temp. (°C)	Yield^a (%)
			5	11
a Isolated yield.
1	5	0	58	11
2	10	0	58	12
3	20	0	67	11
4	30	0	52	11
5	50	0	38	17
6	10	−20	67	Trace
7	20	−20 to 0	69	17
8	20	−20	73	7
9	20	−30	77	6
10	20	−40	53	3

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The aminoketal A would be formed through a 6-exo-dig intramolecular oxymercuration to the alkyne π-electron activated by coordination of Hg(OTf)₂ followed by nucleophilic addition of the nitrogen function. The intermediate A could be cleaved by protonation with the generated TfOH to give an iminium ion intermediate B or C. The construction of a carbocycle via Ferrier-type cyclization would provide the desired spirocyclic product 5 with regeneration of the catalyst. Considering the chair-like transition states B and C, the desired 5 would be diastereoselectively obtained by way of the more stable transition state B without steric repulsion with a benzyloxymethyl group as outlined in Table 1. The by-product 11 would be produced through C.⁹

According to Procter's conditions,¹⁰ treatment of spirocyclic product 5 with SmI₂ in the presence of H₂O and triethylamine afforded the desired eq-alcohol 12 as a major diastereomer (58%), along with ax-alcohol 12 (40%) (Scheme 3).¹¹ The undesired ax-12 was oxidized with Dess–Martin periodinane (DMP) for the recycling use.¹² After MOM protection of a hydroxy group in eq-12, a benzylic group was removed by hydrogenolysis using Pd/C. After a hydroxy group was converted into a carboxylic acid through one-pot oxidation using 1,5-dimethyl-nor-AZADO (DMN-AZADO) and NaClO₂,¹³ the esterification using MeI and Cs₂CO₃ afforded ester 14. Deprotection of a TBDPS group using tetrabutylammonium fluoride (TBAF) provided the desired alcohol 15.

Scheme 3 Synthesis of alcohol 15.

The formal total syntheses of histrionicotoxins were completed from 15 as outlined in Scheme 4. After a vinylic group was constructed by Nishizawa–Grieco elimination,^3i,14 deprotection of MOM and Boc groups afforded vinyl alcohol 16. The conformation of the spirocycle in 16 was assigned based on the NOESY spectra; see ESI.† The TBDPS protection of a hydroxy group in 16 provided silyl ether 4. Compound 4 was further converted into 1-azaspiro[5.5]undecane 3 in high yield through the key SmI₂-mediated ring expansion reaction in the presence of HMPA and pivalic acid.⁵ It is the first example that the SmI₂-mediated radical ring expansion was applied for constructing such a complex system as a 1-azaspiro[5.5]undecane skeleton of histrionicotoxins. Compound 3 is a key intermediate in the total synthesis of histrionicotoxin alkaloids, (−)-HTX-283A (1) and (−)-HTX-235A (2), by Tokuyama's group.³ⁱ The spectral data (¹H- and ¹³C-NMR) and the optical rotation of our synthetic 3 were consistent with those reported for the previous synthetic compound.³ⁱ It has been reported that compound 3 can be transformed to (−)-1 via (−)-2.³ⁱ

Scheme 4 Formal synthesis of histrionicotoxin alkaloids.

Conclusions

In summary, the combination of Hg(OTf)₂-catalyzed cycloisomerization and SmI₂-mediated ring expansion reactions made it possible to efficiently construct a 1-azaspiro[5.5]undecane framework of histrionicotoxin alkaloids. The synthetic efficiency of key intermediate 3 (15% overall yield and 15 steps based on the known silyl ether 9) was demonstrated in comparison with Tokuyama's method³ⁱ (5% overall yield and 14 steps based on the readily available ketodiester and benzylamine). Our synthetic method will be useful to synthesize HTXs and the derivatives as biological probes.

Experimental

General procedures

¹H-NMR spectra were recorded in deuteriochloroform on Bruker Biospin Avance 300 nanobay (300 MHz), JEOL JNM-ECZ400S or Bruker Biospin Avance III HD 400 (400 MHz), and Bruker Biospin Avance III HD 600 (600 MHz) spectrometers. ¹³C-NMR spectra were measured in deuteriochloroform on Bruker Biospin Avance 300 nanobay (75 MHz), JEOL JNM-ECZ400S or Bruker Biospin Avance III HD 400 (100 MHz), and Bruker Biospin Avance III HD 600 (150 MHz) spectrometers. Chemical shifts were reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (CDCl₃: 7.26 ppm for ¹H-NMR, 77.0 ppm for ¹³C-NMR). Splitting patterns were designated as “s, d, t, q, and m” to indicate “singlet, doublet, triplet, quartet, and multiplet,” respectively. IR spectra were recorded on a JASCO FT/IR-4100 spectrophotometer by the attenuated total reflection (ATR) method, unless otherwise noted. High-resolution mass spectra were obtained on a JEOL AccuTOF LC-plus JMS-T100LP (DART). Optical rotations were determined on a JASCO DIP-370 digital polarimeter. Mp are uncorrected and were recorded on a Yanagimoto micro melting point apparatus. Analytical TLC was carried out by precoated silica gel (Merck TLC plates silica gel 60 F254). Flash column chromatography was performed with Merck silica gel 60 (particle size 63–200 μm), Wakogel® 60N (particle size 38–100 μm), and KANTO silica gel 60N (particle size 40–50 μm). All reactions were performed in oven-dried glassware. Tetrahydrofuran (THF) was distilled over sodium metal/benzophenone ketyl. Acetonitrile (MeCN), dichloromethane (CH₂Cl₂), and triethylamine (Et₃N) were distilled over calcium hydride. Hexamethylphosphoric triamide (HMPA), N,N′-dimethylpropyleneurea (DMPU), and N,N-dimethylformamide (DMF) were distilled over calcium hydride under reduced pressure. Methanol (MeOH) was distilled from Mg(OMe)₂.

Experimental procedures

Sulfone 8. To a solution of 9 (ref. 7) (2.10 g, 6.81 mmol) in THF (14 mL) was added dropwise nBuLi (8.86 mL, 5.68 mmol, 1.56 M in hexane) at −78 °C under a nitrogen atmosphere, and the solution was stirred for 30 min. After DMPU (1.60 mL, 13.3 mmol) was added to the solution, the mixture was stirred for 15 min. To the solution of a lithium acetylide of 9 in THF was added a solution of 1,3-diiodopropane (10) (8.07 g, 27.3 mmol) in THF (14 mL) at −20 °C, and the solution was allowed to warm to room temperature and stirred for 10 h. After the reaction was quenched with a saturated aqueous solution of NH₄Cl, the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (toluene/hexane, 10 : 90) on silica gel to give a mixture including a desired mono-iodide, which was used in the next reaction without further purification.

To a solution of the mixture including a desired mono-iodide in DMF (68 mL) was added NaSO₂Ph (1.68 g, 10.2 mmol) at room temperature under a nitrogen atmosphere, and the solution was stirred for 5 h. After the reaction was quenched with H₂O, the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 30 : 70) on silica gel to give 8 (2.24 g, 4.56 mmol, 67% in 2 steps) as a colorless oil: R_f = 0.58 (EtOAc/hexane, 30 : 70); ¹H-NMR (300 MHz, CDCl₃) δ 7.91–7.85 (2H, m), 7.70–7.58 (5H, m), 7.56–7.48 (2H, m), 7.47–7.34 (6H, m), 3.69 (2H, t, J = 7.1 Hz), 3.22–3.12 (2H, m), 2.42–2.33 (2H, m), 2.28–2.19 (2H, m), 1.85 (2H, quintet, J = 7.3 Hz), 1.03 (9H, s); ¹³C-NMR (75 MHz, CDCl₃) δ 139.0, 135.5, 133.7, 133.6, 129.7, 129.3, 128.0, 127.7, 79.0, 78.6, 62.6, 55.2, 26.7, 22.8, 22.1, 19.2, 17.6; IR (ATR) 3070, 3051, 2997, 2956, 2931, 2857, 1769, 1588, 1508, 1472, 1447, 1428, 1388, 1362, 1308, 1261, 1152, 1111, 1089, 1059, 1025, 915, 822, 800 cm⁻¹; DART-HRMS calcd for C₂₉H₃₅O₃SSi [(M + H)⁺] 491.2076, found 491.2078.

Preparation of a THF solution of SmI₂. To a slurry of Sm metal powder (1.50 g, 9.98 mmol) in THF (50 mL) was added CH₂I₂ (450 μL, 5.60 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 h. The resulting solution was directly used to effect the following reductive reactions.

Ynone 6 (ref. 8). To a solution of 8 (252 mg, 826 μmol) in THF (6.1 mL) at −78 °C was added dropwise nBuLi (1.60 M in hexane, 862 μL, 1.38 mmol) under a nitrogen atmosphere, and the solution was stirred for 30 min. A solution of 7 (ref. 6) (749 mg, 1.53 mmol) in THF (1.7 mL) was added to the solution, and the solution was stirred at −78 °C for 35 h. After the reaction was quenched with a saturated aqueous solution of NH₄Cl, the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was subjected to flash column chromatography (EtOAc/hexane, 10 : 90) on silica gel to afford a mixture including a desired sulfone, which was used in the next reaction without further purification.

To a solution of the mixture including a desired sulfone in THF (6.0 mL) and MeOH (4.0 mL) was added SmI₂ (15.0 mL, 1.50 mmol, 0.100 M in THF) at −78 °C under a nitrogen atmosphere, and the solution was stirred for 1 h. The reaction was quenched with a saturated aqueous solution of NaHCO₃, and the mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexane, 30 : 70) on silica gel to provide 6 (404 mg, 617 μmol, 75% in 2 steps) as a colorless oil: R_f = 0.37 (EtOAc/hexane, 30 : 70); [α]²⁵_D −12.3 (c 2.31, CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ 7.72–7.64 (4H, m), 7.46–7.26 (11H, m), 4.74 (1H, br d, J = 11.3 Hz), 4.52 (1H, d, J = 11.9 Hz), 4.46 (1H, d, J = 12.0 Hz), 3.73 (2H, t, J = 7.1 Hz), 3.71 (1H, m), 3.44 (2H, d, J = 4.0 Hz), 2.52–2.36 (6H, m), 2.14 (2H, td, J = 7.0, 2.3 Hz), 1.92–1.61 (4H, m), 1.42 (9H, s), 1.05 (9H, s); ¹³C-NMR (75 MHz, CDCl₃) δ 210.1, 155.7, 138.0, 135.5, 133.6, 129.6, 128.4, 127.64, 127.61, 127.57, 80.4, 79.2, 77.7, 77.2, 73.1, 72.2, 62.8, 49.9, 41.5, 39.3, 28.3, 26.7, 26.1, 22.9, 22.8, 19.2, 18.1; IR (ATR) 3371, 3070, 3049, 3031, 2956, 2932, 2894, 2858, 1712, 1589, 1499, 1473, 1453, 1428, 1389, 1365, 1246, 1221, 1171, 1111, 1059, 1028, 915, 823 cm⁻¹; DART-HRMS calcd for C₄₀H₅₄NO₅Si [(M + H)⁺] 656.3771, found 656.3789.

Spiroketone 5 and its diastereomer 11 (Table 1, entry 9)⁴. To a solution of 6 (42.7 mg, 65.2 μmol) in MeCN (1.3 mL) was added a solution of Hg(OTf)₂ (6.5 mg, 13.0 μmol) in MeCN (650 μL) at −30 °C under a nitrogen atmosphere, and the solution was stirred for 1 h at −30 °C. After the reaction was quenched with a saturated aqueous solution of NaHCO₃, the mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 10 : 90) on silica gel to give 5 (32.8 mg, 50.0 μmol, 77%) and 11 (2.6 mg, 3.97 μmol, 6%) as each colorless oil. 5: R_f = 0.58 (EtOAc/hexane, 30 : 70); [α]²⁶_D −15.9 (c 0.34, CHCl₃); ¹H-NMR (600 MHz, CDCl₃, 25 °C, two rotamers in a 4 : 1 ratio) δ 7.68–7.61 (4H, m), 7.42–7.21 (11H, m), 4.55 (0.2H, d, J = 12.0 Hz), 4.51 (1.6H, s), 4.49 (0.2H, d, J = 12.0 Hz), 4.20 (0.2H, br s), 4.01 (0.8H, br s), 3.84 (0.8H, dd, J = 10.2, 1.8 Hz), 3.69 (1H, td, J = 9.2, 4.6 Hz), 3.55 (0.2H, d, J = 4.7 Hz), 3.53–3.44 (2H, m), 3.36 (0.8H, dd, J = 8.9, 7.5 Hz), 3.30 (0.2H, d, J = 9.8 Hz), 2.96 (0.8H, td, J = 13.6, 4.2 Hz), 2.62 (0.2H, td, J = 13.4, 4.2 Hz), 2.36–2.22 (1.8H, m), 2.21–1.99 (1.2H, m), 1.93–1.63 (5.2H, m), 1.61–1.53 (0.8H, m), 1.52–1.38 (2H, m), 1.38 and 1.36 (total 9H, each s), 1.03 (9H, s); ¹³C-NMR (150 MHz, CDCl₃, 25 °C, two rotamers in a 4 : 1 ratio) δ 210.9, 210.0, 153.3, 152.9, 138.5, 138.2, 135.49, 135.45, 134.1, 133.9, 133.84, 133.82, 129.43, 129.42, 129.36, 129.3, 128.3, 128.2, 127.6, 127.5, 127.4, 127.3, 80.2, 79.4, 73.0, 71.2, 70.8, 70.3, 69.4, 63.2, 62.8, 59.7, 59.1, 54.3, 52.4, 42.0, 41.8, 37.7, 36.8, 33.7, 32.4, 28.5, 28.4, 27.0, 26.84, 26.80, 26.6, 26.3, 25.8, 21.5, 19.1; IR (ATR) 3070, 3048, 3032, 2956, 2929, 2858, 1712, 1688, 1589, 1541, 1472, 1455, 1428, 1388, 1364, 1317, 1298, 1254, 1219, 1171, 1111, 1072, 1029, 999, 973, 941, 909, 886, 866, 823, 772 cm⁻¹; DART-HRMS calcd for C₄₀H₅₄NO₅Si [(M + H)⁺] 656.3771, found 656.3773. 11: R_f = 0.53 (EtOAc/hexane, 30 : 70); [α]²⁴_D −8.0 (c 0.87, CHCl₃); ¹H-NMR (600 MHz, CDCl₃, 25 °C, two rotamers in a 5 : 1 ratio) δ 7.68–7.60 (4H, m), 7.42–7.25 (11H, m), 4.56 (0.83H, d, J = 12.1 Hz), 4.53, 4.51 (each 0.17H, d, J = 12.1 Hz), 4.50 (0.83H, d, J = 12.1 Hz), 4.15 (0.17H, br s), 3.98 (0.83H, br t, J = 7.0 Hz), 3.91 (0.83H, d, J = 9.7 Hz), 3.87 (0.17H, dd, J = 10.1, 2.1 Hz), 3.69 (0.17H, m), 3.67–3.55 (1.83H, m), 3.55–3.44 (1H, m), 3.37 (0.17H, m), 3.25 (0.83H, t, J = 8.9 Hz), 3.02 (0.17H, td, J = 13.5, 4.3 Hz), 2.73 (0.83H, td, J = 13.3, 4.0 Hz), 2.42–2.17 (2.17H, m), 2.15–2.02 (0.83H, m), 1.97–1.33 (8H, m), 1.42 and 1.37 (total 9H, each s), 1.03 (1.53H, s), 1.02 (7.47H, s); ¹³C-NMR (150 MHz, CDCl₃, 25 °C, two rotamers in a 5 : 1 ratio) δ 210.5, 209.5, 153.2, 152.9, 138.3, 138.1, 135.54, 135.52, 134.13, 134.10, 134.07, 133.9, 129.6, 129.4, 128.4, 128.3, 127.7, 127.64, 127.59, 127.53, 127.50, 80.2, 79.6, 73.2, 71.0, 70.7, 70.5, 70.4, 62.83, 62.75, 58.2, 57.8, 52.4, 52.1, 41.5, 41.4, 32.2, 30.6, 28.4, 26.9, 26.8, 25.7, 25.3, 24.5, 23.8, 21.9, 21.4, 19.18, 19.16; IR (ATR) 3069, 3049, 3030, 2959, 2931, 2857, 1712, 1688, 1588, 1473, 1455, 1428, 1366, 1306, 1256, 1169, 1110, 1026, 975, 955, 908, 854, 823, 804 cm⁻¹; DART-HRMS calcd for C₄₀H₅₄NO₅Si [(M + H)⁺] 656.3771, found 656.3771.

Alcohols eq-12 and ax-12 (SmI₂-mediated reduction)¹⁰. To a solution of 5 (133 mg, 203 μmol) in THF (2.0 mL) were added H₂O (66.0 μL, 3.66 mmol) and Et₃N (510 μL, 3.66 mmol). After SmI₂ (12.0 mL, 1.20 mmol, 0.100 M in THF) was added to the solution at room temperature under a nitrogen atmosphere, the mixture was stirred for 6 h. After the reaction was quenched with a saturated aqueous solution of NaHCO₃, the resulting mixture was extracted with EtOAc (×3). The organic extracts were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 10 : 90) on silica gel to provide eq-12 (77.4 mg, 118 μmol, 58%) and ax-12 (54.1 mg, 82.2 μmol, 40%) as each colorless oil: eq-12: R_f = 0.54 (EtOAc/hexane, 30 : 70); [α]²⁶_D −15.1 (c 1.40, CHCl₃); ¹H-NMR (600 MHz, CDCl₃, 25 °C, two rotamers in a 2 : 1 ratio) δ 7.71–7.63 (4H, m), 7.46–7.36 (6H, m), 7.36–7.23 (5H, m), 4.75 (0.33H, br s), 4.54 (0.67H, d, J = 13.0 Hz), 4.49 (0.67H, d, J = 11.6 Hz), 4.47 (0.33H, d, J = 12.0 Hz), 4.46 (0.33H, d, J = 12.1 Hz), 4.23 (0.67H, d, J = 3.1 Hz), 4.10 (0.33H, m), 3.91 (0.67H, m), 3.77 (0.33H, dt, J = 10.2, 4.1 Hz), 3.72–3.65 (0.67H, m), 3.61 (0.67H, td, J = 10.0, 3.7 Hz), 3.57 (0.33H, m), 3.56 (0.33H, td, J = 9.3, 2.5 Hz), 3.49 (0.67H, dd, J = 8.9, 3.1 Hz), 3.45 (0.33H, dd, J = 8.9, 7.7 Hz), 3.43–3.32 (1H, m), 3.29 (0.67H, t, J = 8.5 Hz), 2.77 (0.67H, br t, J = 7.4 Hz), 2.39 (0.67H, td, J = 13.2, 4.2 Hz), 2.37 (0.33H, m), 2.16 (0.33H, td, J = 12.9, 3.6 Hz), 2.10–1.99 (1H, m), 1.99–1.88 (1H, m), 1.88–1.53 (7H, m), 1.45–1.16 (2H, m), 1.38 (3H, s), 1.26 (6H, s), 1.07 (3H, s), 1.04 (6H, s); ¹³C-NMR (150 MHz, CDCl₃, 25 °C, two rotamers in a 2 : 1 ratio) δ 153.5, 152.6, 138.6, 138.3, 135.64, 135.59, 135.56, 133.0, 132.6, 132.5, 129.94, 129.90, 129.72, 129.67, 128.4, 128.3, 127.8, 127.7, 127.6, 127.44, 127.39, 79.9, 79.0, 73.11, 73.06, 73.0, 71.5, 70.7, 68.9, 68.3, 65.1, 64.6, 59.0, 58.6, 50.0, 47.3, 37.9, 36.8, 35.1, 35.0, 33.4, 31.8, 31.4, 31.1, 28.5, 28.3, 26.8, 26.7, 26.0, 20.58, 20.56, 19.0, 18.9; IR (ATR) 3435, 3070, 3048, 3032, 2956, 2929, 2858, 1688, 1589, 1541, 1472, 1455, 1428, 1388, 1364, 1317, 1298, 1254, 1219, 1171, 1111, 1072, 1029, 999, 973, 941, 909, 886, 866, 823, 772, 736, 700 cm⁻¹; DART-HRMS calcd for C₄₀H₅₆NO₅Si [(M + H)⁺] 658.3928, found 658.3935. ax-12: R_f = 0.67 (EtOAc/hexane, 30 : 70); [α]²⁷_D −26.3 (c 0.82, CHCl₃); ¹H-NMR (600 MHz, CDCl₃, 25 °C, two rotamers in a 3 : 1 ratio) δ 7.70–7.62 (4H, m), 7.47–7.22 (11H, m), 4.57 (0.25H, d, J = 12.0 Hz), 4.53 (0.75H, d, J = 12.1 Hz), 4.48 (0.25H, d, J = 12.0 Hz), 4.50 (0.75H, d, J = 11.9 Hz), 4.18 (1H, br d, J = 2.4 Hz), 4.12 (0.25H, m), 3.94 (0.75H, m), 3.82–3.71 (1H, m), 3.71–3.60 (1H, m), 3.60 (0.25H, dd, J = 9.0, 3.3 Hz), 3.50 (0.75H, dd, J = 8.8, 3.1 Hz), 3.39 (0.25H, t, J = 8.5 Hz), 3.24 (0.75H, t, J = 8.8 Hz), 2.81 (1H, m), 2.49 (0.75H, td, J = 13.0, 3.2 Hz), 2.44 (0.25H, m), 2.25 (0.75H, br s), 2.10 (0.25H, br s), 1.89–1.75 (3H, m), 1.75–1.53 (5H, m), 1.53–1.28 (2H, m), 1.39 (2.25H, s), 1.32 (6.75H, s), 1.05 (2.25H, s), 1.04 (6.75H, s); ¹³C-NMR (150 MHz, CDCl₃, 25 °C, two rotamers in a 3 : 1 ratio) δ 153.7, 152.8, 138.7, 138.4, 135.6, 135.5, 133.3, 133.2, 129.80, 129.78, 129.74, 129.71, 128.4, 128.3, 127.8, 127.73, 127.71, 127.6, 127.5, 127.4, 127.3, 79.5, 78.8, 73.02, 72.98, 71.3, 70.7, 68.9, 68.6, 67.1, 66.7, 63.7, 63.5, 58.5, 58.1, 43.1, 41.1, 39.3, 38.4, 34.2, 33.1, 33.0, 32.6, 29.3, 29.0, 28.6, 28.5, 26.9, 26.81, 26.79, 26.2, 19.03, 19.01, 18.7, 18.6; IR (ATR) 3485, 3070, 3049, 3031, 2957, 2929, 2858, 1673, 1473, 1454, 1428, 1388, 1364, 1322, 1253, 1219, 1169, 1108, 1081, 1028, 996, 940, 908, 858, 823, 805, 772, 735, 700 cm⁻¹; DART-HRMS calcd for C₄₀H₅₆NO₅Si [(M + H)⁺] 658.3928, found 658.3942.

Alcohols eq-12 and ax-12 (NaBH₄ reduction). To a solution of 5 (15.7 mg, 24.0 μmol) in MeOH (480 μL) was added NaBH₄ (9.1 mg, 240 μmol) at 0 °C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature over 2 h. After the reaction was quenched with H₂O, the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 10 : 90) on silica gel to provide eq-12 (2.8 mg, 3.96 μmol, 16%) and ax-12 (9.8 mg, 14.9 μmol, 62%) as each colorless oil.

Spiroketone 5 from alcohol ax-12. To a solution of ax-12 (75.8 mg, 115 μmol) in CH₂Cl₂ (1.2 mL) were added NaHCO₃ (92.2 mg, 1.10 mmol) and DMP (146 mg, 345 μmol) at room temperature under a nitrogen atmosphere. After the solution was stirred for 50 min, the reaction was quenched with a saturated aqueous solution of NaHCO₃, and the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (EtOAc/hexane, 10 : 90) on silica gel to give 5 (74.0 mg, 113 μmol, 98%) as a colorless oil.

Methoxymethyl ether 13. To a solution of eq-12 (105 mg, 160 μmol) in CH₂Cl₂ (3.2 mL) were added DIPEA (264 μL, 1.60 mmol) and MOMCl (121 μL, 1.60 mmol) at 0 °C under a nitrogen atmosphere. After the mixture was allowed to warm to room temperature, the solution was stirred for 17 h. After the reaction was quenched with a saturated aqueous solution of NH₄Cl, the resulting mixture was extracted with CH₂Cl₂ (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 10 : 90) on silica gel to afford 13 (112 mg, 160 μmol, quant.) as a colorless oil: R_f = 0.62 (EtOAc/hexane, 30 : 70); [α]²³_D −27.6 (c 0.66, CHCl₃); ¹H-NMR (300 MHz, CDCl₃, 25 °C, two rotamers in a 2 : 1 ratio) δ 7.69–7.60 (4H, m), 7.43–7.25 (11H, m), 4.57 (0.67H, d, J = 7.0 Hz), 4.53 (0.33H, d, J = 7.3 Hz), 4.50 (2H, s), 4.46 (0.67H, d, J = 6.8 Hz), 4.44 (0.33H, d, J = 7.3 Hz), 4.10 (0.33H, br s), 3.95–3.76 (1.67H, m), 3.66–3.51 (1.33H, m), 3.51–3.40 (1H, m), 3.30 (3H, s), 3.25 (0.67H, m), 3.16 (1H, td, J = 10.2, 4.4 Hz), 2.50 (0.67H, quintet, J = 5.3 Hz), 2.37 (0.67H, td, J = 12.7, 3.5 Hz), 2.20–2.03 (0.66H, m), 2.03–1.50 (8H, m), 1.45–1.08 (3H, m), 1.34 (3H, s), 1.23 (6H, s), 1.022 (3H, s), 1.015 (6H, s); ¹³C-NMR (75 MHz, CDCl₃, 25 °C, two rotamers in a 2 : 1 ratio) δ 153.3, 152.6, 138.7, 138.4, 135.5, 134.3, 134.20, 134.18, 129.4, 129.3, 128.4, 128.3, 127.6, 127.53, 127.50, 127.4, 95.6, 95.4, 80.8, 80.5, 79.7, 78.9, 73.0, 71.5, 70.7, 68.3, 67.7, 64.82, 64.77, 59.1, 58.5, 55.5, 55.4, 44.7, 42.8, 37.8, 36.9, 33.5, 32.7, 32.10, 32.07, 32.04, 32.02, 28.5, 28.3, 26.91, 26.88, 26.6, 26.1, 20.5, 20.4, 19.2; IR (ATR) 3069, 3046, 3030, 2954, 2929, 2883, 2858, 2822, 1688, 1636, 1589, 1541, 1473, 1455, 1428, 1388, 1371, 1364, 1318, 1300, 1254, 1172, 1143, 1105, 1078, 1038, 998, 939, 915, 884, 863, 823, 805 cm⁻¹; DART-HRMS calcd for C₄₂H₆₀NO₆Si [(M + H)⁺] 702.4190, found 702.4196.

Ester 14 (ref. 13). To a solution of 13 (40.6 mg, 57.8 μmol) in MeOH (1.2 mL) was added 10% Pd/C (200 mg, 493 wt%) at room temperature under a hydrogen atmosphere, and the solution was stirred for 4 h. After the mixture was filtered with a pad of Celite, the pad was washed with MeOH. The filtrate was concentrated under reduced pressure to afford a mixture including a desired alcohol, which was used in the next reaction without further purification.

DMN-AZADO (9.2 mg, 55.3 μmol), NaClO₂ (81.9 mg, 906 μmol), and NaOCl (5.2 mg, 69.9 μmol) were added to a solution of the mixture including a desired alcohol in MeCN (600 μL) and phosphate buffer (pH 6.8, 190 μL) at room temperature under a nitrogen atmosphere. The mixture was stirred for 22 h, and the reaction was quenched with H₂O. After the resulting mixture was extracted with CHCl₃, the organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. A mixture including a desired carboxylic acid was directly used in the following reaction.

To a solution of the mixture including a desired carboxylic acid in DMF (1.2 mL) were added Cs₂CO₃ (13.3 mg, 40.8 μmol) and MeI (4.3 μL, 69.0 μmol) at room temperature under a nitrogen atmosphere. After the solution was stirred for 9 h, the reaction was quenched with a saturated aqueous solution of Na₂CO₃. After the resulting mixture was extracted with EtOAc (×3), the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Purification by flash silica gel column chromatography (EtOAc/hexane, 5 : 95) afforded 14 (29.7 mg, 46.4 μmol, 80% in 3 steps) as a colorless oil: R_f = 0.41 (EtOAc/hexane, 30 : 70); [α]²³_D −21.7 (c 0.45, CHCl₃); ¹H-NMR (300 MHz, CDCl₃, 25 °C, two rotamers in a 3 : 1 ratio) δ 7.68–7.61 (4H, m), 7.45–7.30 (6H, m), 4.55 (0.75H, d, J = 7.0 Hz), 4.51 (0.25H, d, J = 7.1 Hz), 4.44 (1H, d, J = 7.1 Hz), 4.28 (0.25H, dd, J = 8.5, 4.6 Hz), 4.11 (0.75H, dd, J = 7.9, 6.3 Hz), 3.90 (1H, m), 3.71 (0.75H, s), 3.70 (2.25H, s), 3.58 (1H, m), 3.29 (0.75H, s), 3.28 (2.25H, m), 3.12 (1H, m), 2.78–2.63 (0.5H, m), 2.49 (0.75H, ddd, J = 10.1, 6.2, 3.1 Hz), 2.27 (0.75H, td, J = 13.5, 5.0 Hz), 2.16–1.86 (2H, m), 1.83–1.45 (6H, m), 1.37–1.14 (3H, m), 1.34 (2.25H, s), 1.25 (6.75H, s), 1.03 (2.25H, s), 1.02 (6.75H, s); ¹³C-NMR (75 MHz, CDCl₃, 25 °C, two rotamers in a 3 : 1 ratio) δ 174.0, 173.9, 153.6, 152.2, 135.49, 135.47, 134.5, 134.3, 134.2, 134.1, 129.44, 129.41, 129.39, 129.36, 127.6, 127.52, 127.50, 127.47, 95.5, 95.2, 80.5, 80.4, 80.1, 79.6, 69.3, 68.4, 64.82, 64.80, 61.64, 61.59, 55.5, 55.4, 52.0, 51.8, 44.9, 43.1, 35.0, 33.3, 32.6, 32.2, 32.12, 32.06, 31.9, 30.3, 28.4, 28.0, 27.4, 27.3, 26.9, 26.6, 20.6, 19.2, 19.1; IR (ATR) 3071, 3051, 2950, 2931, 2888, 2859, 2822, 1749, 1701, 1685, 1624, 1590, 1577, 1569, 1558, 1541, 1522, 1507, 1497, 1489, 1473, 1457, 1429, 1389, 1376, 1364, 1327, 1297, 1272, 1257, 1197, 1177, 1146, 1133, 1110, 1082, 1040, 1008, 999, 941, 915, 881, 857, 824, 805 cm⁻¹; DART-HRMS calcd for C₃₆H₅₄NO₇Si [(M + H)⁺] 640.3670, found 640.3657.

Alcohol 15. To a solution of 14 (36.1 mg, 56.4 μmol) in THF (282 μL) was added TBAF (63.2 μL, 63.2 μmol, 1.00 M in THF) at 0 °C under a nitrogen atmosphere. After the mixture was allowed to warm to room temperature, the mixture was stirred for 23 h. After the reaction was quenched with a saturated aqueous solution of NH₄Cl, the resulting mixture was extracted with EtOAc (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 70 : 30) on silica gel to afford 15 (22.6 mg, 56.3 μmol, quant.) as a colorless oil: R_f = 0.19 (EtOAc/hexane, 50 : 50); [α]²⁴_D −29.7 (c 0.58, CHCl₃); ¹H-NMR (300 MHz, CDCl₃, 25 °C, two rotamers in a 4 : 1 ratio) δ 4.81 (0.2H, d, J = 7.1 Hz), 4.78 (0.8H, d, J = 7.1 Hz), 4.62 (0.2H, d, J = 7.2 Hz), 4.59 (0.8H, d, J = 7.1 Hz), 4.39 (0.2H, m), 4.26 (0.8H, m), 3.72 (3H, s), 3.62 (1H, br s), 3.42 (0.6H, s), 3.38 (2.4H, s), 3.23 (1H, m), 3.04 (1H, br s), 2.86 (0.8H, ddd, J = 8.4, 6.1, 2.3 Hz), 2.50 (0.2H, ddd, J = 8.8, 6.0, 2.2 Hz), 2.27 (0.8H, td, J = 13.0, 3.7 Hz), 2.21–2.03 (2.2H, m), 1.94–1.65 (6H, m), 1.65–1.45 (2H, m), 1.31 (1H, m), 1.38 (9H, s); ¹³C-NMR (75 MHz, CDCl₃, 25 °C, two rotamers in a 4 : 1 ratio) δ 173.9, 173.7, 153.8, 152.8, 95.00, 94.97, 81.1, 80.3, 79.8, 79.5, 69.9, 69.0, 63.0, 62.9, 61.9, 61.8, 56.1, 55.9, 52.0, 51.9, 46.8, 45.2, 34.5, 32.8, 32.0, 31.8, 31.7, 31.6, 31.3, 29.8, 28.5, 28.2, 27.1, 26.6, 20.6; IR (ATR) 3463, 2975, 2950, 2931, 2887, 2868, 2824, 1748, 1700, 1684, 1559, 1541, 1520, 1507, 1474, 1456, 1437, 1391, 1365, 1328, 1295, 1276, 1255, 1198, 1175, 1146, 1131, 1120, 1101, 1037, 942, 916, 879, 854, 792 cm⁻¹; DART-HRMS calcd for C₂₀H₃₆NO₇ [(M + H)⁺] 402.2492, found 402.2501.

Olefin 16 (ref. 14). To a solution of 15 (15.5 mg, 38.6 μmol) in THF (800 μL) were added nBu₃P (48.0 μL, 195 μmol) and 2-nitrophenylselenocyanate (43.4 mg, 191 μmol) at room temperature under a nitrogen atmosphere. After the mixture was stirred for 12 h, mCPBA (77%, 71.0 mg, 317 μmol) was added to the solution at 0 °C. The mixture was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with a saturated aqueous solution of Na₂S₂O₃, and the resulting mixture was extracted with CHCl₃. The organic extracts were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo to afford a mixture including a desired olefin, which was used in the next reaction without further purification.

To a solution of the mixture including a desired olefin in CH₂Cl₂ (800 μL) was slowly added TFA (200 μL) at 0 °C under a nitrogen atmosphere. After the mixture was allowed to warm to room temperature, the solution was stirred for 12 h. After the reaction was quenched with a saturated aqueous solution of NaHCO₃, the resulting mixture was extracted with CHCl₃ (×3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. Purification by flash silica gel column chromatography (MeOH/CHCl₃, 10 : 90) afforded 16 (9.0 mg, 37.6 μmol, 98% in 2 steps) as a colorless oil: R_f = 0.50 (MeOH/CHCl₃, 10 : 90); [α]²⁷_D −49.3 (c 0.90, CHCl₃); ¹H-NMR (600 MHz, CDCl₃) δ 5.73 (1H, dt, J = 16.9, 10.0 Hz), 5.17 (1H, dd, J = 17.0, 1.4 Hz), 5.16 (1H, dd, J = 10.1, 1.7 Hz), 3.85 (1H, dd, J = 8.8, 5.6 Hz), 3.80 (1H, m), 3.75 (3H, s), 2.38 (1H, dd, J = 9.1, 2.7 Hz), 2.19 (1H, m), 1.94 (1H, m), 1.88–1.78 (3H, m), 1.73–1.61 (2H, m), 1.56 (1H, dt, J = 13.5, 4.3 Hz), 1.46 (1H, dt, J = 14.0, 3.8 Hz), 1.25 (1H, m); ¹³C-NMR (150 MHz, CDCl₃) δ 175.2, 136.7, 118.8, 72.4, 65.8, 58.7, 52.4, 51.7, 36.0, 34.4, 30.3, 28.9, 18.0; IR (ATR) 3282, 3074, 3005, 2930, 2856, 1736, 1699, 1635, 1507, 1456, 1438, 1356, 1339, 1327, 1284, 1260, 1232, 1206, 1153, 1117, 1092, 1074, 1032, 996, 968, 921, 901, 869, 856, 808 cm⁻¹; DART-HRMS calcd for C₁₃H₂₂NO₃ [(M + H)⁺] 240.1600, found 240.1560.

Silyl ether 4. To a solution of 16 (18.6 mg, 77.7 μmol) in CH₂Cl₂ (1.6 mL) were added TBDPSCl (200 μL, 769 μmol) and imidazole (48.6 mg, 714 μmol) at room temperature under a nitrogen atmosphere. After the solution was stirred for 17.5 h, the reaction was quenched with a saturated aqueous solution of NH₄Cl. After the resulting mixture was extracted with MeOH/CHCl₃ (10 : 90) (×3), the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (MeOH/CHCl₃, 2 : 98) on silica gel to afford 4 (35.8 mg, 74.9 μmol, 96%) as a colorless oil: R_f = 0.44 (MeOH/CHCl₃, 2 : 98); [α]²⁶_D −35.1 (c 0.40, CHCl₃); ¹H-NMR (600 MHz, CDCl₃) δ 7.72–7.64 (4H, m), 7.46–7.33 (6H, m), 5.50 (1H, dt, J = 17.0, 10.0 Hz), 5.07 (1H, dd, J = 10.2, 2.0 Hz), 5.02 (1H, d, J = 16.8 Hz), 3.76 (1H, t, J = 7.5 Hz), 3.70 (1H, m), 3.68 (3H, s), 2.20 (1H, t, J = 8.2 Hz), 1.94 (1H, m), 1.87 (1H, m), 1.74 (1H, m), 1.60–1.43 (3H, m), 1.43–1.12 (4H, m), 1.05 (9H, s); ¹³C-NMR (150 MHz, CDCl₃) δ 175.4, 137.3, 136.02, 135.97, 135.5, 134.5, 134.0, 129.6, 129.5, 127.5, 127.4, 118.8, 74.0, 64.5, 59.1, 51.9, 57.3, 37.4, 33.0, 32.3, 28.8, 27.0, 19.5, 19.2; IR (ATR) 3373, 3071, 3050, 2998, 2932, 2892, 2858, 1737, 1639, 1540, 1523, 1510, 1458, 1429, 1361, 1311, 1282, 1254, 1200, 1158, 1109, 1086, 1029, 1002, 919, 885, 822, 793 cm⁻¹; DART-HRMS calcd for C₂₉H₄₀NO₃Si [(M + H)⁺] 478.2777, found 478.2811.

Lactam 3 (ref. 3i). To a solution of 4 (13.4 mg, 28.0 μmol) in THF (560 μL) were HMPA (98.0 μL, 563 μmol) and pivalic acid (14.2 mg, 139 μmol). After the solution was cooled to 0 °C, SmI₂ (1.40 mL, 140 μmol, 0.100 M in THF) was added to the solution under a nitrogen atmosphere, and the solution was allowed to warm to room temperature over 2.5 h. After the reaction was quenched with a saturated aqueous solution of NaHCO₃, the resulting mixture was extracted with CHCl₃ (×3). The organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc/hexane, 50 : 50) on silica gel to give 3 (10.9 mg, 24.3 μmol, 87%) as a colorless oil: R_f = 0.25 (MeOH/CHCl₃, 2 : 98); [α]²⁸_D −57.1 (c 0.55, CHCl₃); ¹H-NMR (300 MHz, CDCl₃) δ 7.74–7.64 (4H, m), 7.47–7.34 (6H, m), 5.47 (1H, dt, J = 16.9, 10.1 Hz), 4.97 (1H, dd, J = 10.2, 1.8 Hz), 4.83 (1H, dd, J = 16.8, 1.4 Hz), 3.88 (1H, br s), 2.40–2.15 (3H, m), 1.93 (1H, m), 1.82–1.56 (3H, m), 1.56–1.22 (7H, m), 1.14 (9H, s); ¹³C-NMR (75 MHz, CDCl₃) δ 170.9, 136.0, 135.9, 135.1, 133.5, 133.3, 129.9, 129.7, 127.64, 127.60, 118.7, 74.3, 56.7, 55.7, 34.2, 33.2, 31.0, 29.1, 27.1, 19.0, 16.5, 16.0; IR (ATR) 3358, 3207, 3071, 3048, 2932, 2857, 1659, 1589, 1463, 1428, 1406, 1391, 1363, 1335, 1283, 1220, 1184, 1165, 1110, 1084, 1071, 1025, 994, 957, 936, 919, 875, 841, 822, 795 cm⁻¹; DART-HRMS calcd for C₂₈H₃₈NO₂Si [(M + H)⁺] 448.2672, found 448.2682.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financially supported by the Astellas Foundation and the JGC-S Scholarship Foundation (Nikki Saneyoshi Scholarship).

Notes and references

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11. The reduction of a carbonyl moiety in spirocyclic product 5 was performed using various reduction methods. When compound 5 was allowed to react with NaBH₄, the undesired ax-12 was obtained as a major isomer (62%), along with the desired eq-12 (16%). The use of Super-Hydride® (lithium triethylborohydride) also gave ax-12 (76%). In the borohydride reduction of 5, an equatorial hydride attack could predominate as a result of avoiding the axial alkyl group. In the ¹H NMR spectrum of a major rotamer of ax-12, the coupling pattern of C8-H at 4.18 ppm was observed as a doublet with J = 2.4 Hz, showing an equatorial proton. When using Bouveault–Blanc reduction, compound eq-12 was stereoselectively obtained, but the yield was very low (22%). The reduction of 5 under Birch conditions afforded a debenzylated compound of eq-12 in low yield (<30%). The Corey–Bakshi–Shibata (CBS) asymmetric reduction resulted in the recovery of the starting material. The Luche reduction gave eq-12 as a major product (59%, ax-12: 30%).
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14. P. A. Grieco, S. Gilman and M. Nishizawa, J. Org. Chem., 1976, 41, 1485–1486.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c8ra02011f

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