Stereodivergent Synthesis of Alkaloid (±)-223A and (±)-6-epi-223A via Rh-Catalyzed Hydroformylation Double Cyclization

Abstract

A stereodivergent approach toward total syntheses of Dendrobatid alkaloids 223A and 6-epi-223A is described. The approach features a concise construction of an indolizidine skeleton by Rh-catalyzed domino hydroformylation double cyclization and sequential stereocontrolled transformations such as reductive alkylation or anti-selective α-alkylation of the 5-oxoindolizidine. These stereoselective reactions afford the desired stereochemistry in the targets.

In 1997, Daly et al. reported the isolation of the first trisubstituted indolizidine alkaloid 223A (1), from a dendrobatid frog Dendrobates pumilio Schmidt, in Panama.¹ The strucure of alkaloid 223A was originally proposed as the structure of 6-epi-223A (6-epi-1) shown in Figure 1 and was revised as structure 1 with a cis configuration between H-6 and bridged proton H-8a, through total synthesis by Toyooka and co-workers in 2002. These dart frog poisons display blocking effects on nicotinic acetylcholine receptors,² and their use has pharmaceutical potential for neurological disorders.³ The correct introduction of the stereocenters represents the main challenge in the synthesis of the indolizidine system. Thus, various intellectual and elegant strategies were developed: Michael-type conjugate addition on a 2-piperideine system,^4,5 via an aza-Achmatowicz oxidation of a furfuryl system,⁶ amine-mediated Michael addition to ynone followed by cyclization,^7,8 trialkylsilyltin-mediated cyclization of allene,⁹ intramolecular Mannich reaction of a β-aminobutanone derivative,¹⁰ intramolecular cyclization of a homoprolinate derivative,^11,12 intramolecular Schmidt reaction followed by ring opening metathesis,¹³ and elaboration of a versatile tricyclic lactone precursor.¹⁴ These approaches can be divided into two categories: formation of the piperidine ring prior to formation of the pyrrolidine ring and vice versa. Here we describe a one-step domino approach to these two alkaloids.

Figure 1.

Revised structures of alkaloids 223A (1) and 6-epi-223A (6-epi-1).

Recently, we reported a domino Rh-catalyzed hydroformylation double cyclization process, which provides a versatile route to various azabicyclic compounds, including indolizidines and quinolizidines.¹⁵ Treatment of N-allyl 5-methyl-4-hexenamide (2a) with Rh(acac)(CO)₂ (1 mol %), BIPHEPHOS (2 mol %), and pTSA (1.0 equiv) under an atmosphere of CO and H₂ (1:1) in acetic acid at 60 °C yielded a bicyclized product as a major product, as well as a monocyclic intermediate. Subsequent treatment of the crude product with BF₃·OEt₂ in CH₂Cl₂ overnight furnished the complete formation of indolizidine 3a. The procedure was performed on a 15 mmol scale with the pressure adjusted to 20 atm to afford indolizidine 3a in 72% isolated yield as a 1.4:1 inseparable cis/trans mixture. The isopropenyl portion of 3a was converted into an acetyl group using Nicolaou’s oxidative cleavage procedure¹⁶ to produce a separable mixture of trans- and cis-ketone, which could be epimerized to the more stable trans-ketone upon treatment within DBU in CH₂Cl₂. Thus, direct treatment of the oxidative cleavage product with DBU resulted in the clean formation of trans-ketone 4a in 76% yield. With the optimized conditions in hand, treatment of 2-ethyl-substituted allylamide 2b under the bicyclization conditions afforded an inseparable diastereomeric indolizidine mixture 3b1 in 47% yield (dr ∼2:1) and a single product 3b2 in 43% isolated yield. Subjecting indolizidine 3b2 to the oxidative cleavage protocol as stated above afforded a 55% yield of ketone 4b, which was condensed with TsNHNH₂ to crystalline product tosylhydrazone 5b. The structure of 5b was confirmed unequivocally by X-ray analysis [CCDC 1939866 (Scheme 1)], which discloses the syn relationship between H-6 and bridge H-8a. The result also substantiates the syn configuration of indolizidine 3b2. Moreover, it was pleasing to learn that treatment of diastereomeric indolizidine mixture 3b1 under the oxidative cleavage conditions also gave the same ketone 4b in 50% isolated yield, presumably because of the epimerization to the most stable isomer.

Scheme 1. Synthesis of 8-Acetyl-5-oxoindolizidine 4 and X-ray Structure of Tosylhydrazone 5b.

A thioketal formation–reductive desulfurization sequence emerged as a facile procedure for converting the acetyl group into the desired ethyl group at position C-8. Several combinations of an acid (e.g., ZnCl₂, BF₃·OEt₂, or pTSA) and a dithiol (ethylene or propylene) were examined, and ZnCl₂-mediated 1,2-dithiolane formation was found to give the best result [95% yield (Scheme 2)]. Reduction of the 1,2-dithiolane moiety to the methylene group was easily accomplished by treating 6a with Raney Ni in methanol, which afforded product 7a in 95% isolated yield. However, we were finding low and unstable yields using the conditions for larger scale operations. Eventually, nickel boride,¹⁷ simply by treatment of NiCl₂ with NaBH₄ in ethanol, was found to be effective in this desulfurization to give a 97% yield of product 7a on a 4.5 mmol scale. Using the synthesis shown above, dithiolane 6b was obtained in 76% yield, and nickel boride reduction of 6b gave a 65% yield of 6,8-diethyl product 7b.

Scheme 2. Synthesis of 8-Ethyl-5-oxoindolizidine.

With a quite rigid 5-oxoindolizidine 7a in hand, we investigated the base-mediated α-alkylation conditions for the introduction of the ethyl group at position C-6, and the results are summarized in Table 1.

Table 1. Base-Mediated α-Alkylation of 5-Oxoindolizidine 7a.

			yield (%)
entry	EtI (equiv)	base	7a	7b	epi-7b	8
1	1.5	nBuLi (1.1 equiv), DIPA (1.2 equiv)	97	NDa	NDa	NDa
2	2.0	nBuLi (2.0 equiv), DIPA (2.1 equiv)	33	36	17	NDa
3	2.0	LiHMDS (2.0 equiv)	36	38	23	NDa
4	2.5	nBuLi (2.0 equiv), DIPA (2.1 equiv)	NDa	29	12	34
5	2.1	tBuLi (2.0 equiv)	NDa	NDa	92	NDa

^aNot detected.

Simple treatment with a slight excess of LDA (1.1 equiv) followed by addition of EtI (1.5 equiv) led primarily to recovered starting material 7a (entry 1). The addition of more LDA (2.0 equiv) and EtI (2.0 equiv) resulted in the formation of two diastereomeric monoalkylated products, 7b and epi-7b,¹⁸ as well as the recovery of starting material 7a (entry 2). The switch to LiHMDS (2.0 equiv) gave results similar to those of entry 2 (entry 3). The addition of more EtI (2.5 equiv) yielded two monoalkylated products, accompanied by dialkylated product 8 in 34% yield (entry 4). Fortunately, lactam 7a was successfully alkylated as a single product, epi-7b, in 92% isolated yield upon treatment with tert-BuLi (entry 5),¹⁹ probably due to a strong base-mediated irreversible deprotonation. The ¹³C NMR data of epi-7b were significantly different from those of 7b but were in agreement with those reported in the literature¹³ (see the Supporting Information for comparison). The stereoselective strong base-mediated α-alkylation not only introduced a substituent at position C-6 but also provided a stereodivergent strategy for the construction of the diastereomeric 6-substituted 5-oxoindolizidine frameworks, such as alkaloid epi-223A.

To complete the synthesis of the targets, we focused on introduction of the propyl group at position C-5 by the amide activation–reductive alkylation strategy. Attempts to activate epi-7b with Lawesson’s reagent to form thiolactam were unsuccessful, because the conditions led to significant epimerization at position C-6. Instead, we found that Huang’s one-pot protocol for reductive alkylation of lactams,²⁰ i.e., treatment within the Tf₂O/DTBMP system followed by addition of n-PrMgCl and then LiAlH₄ reduction, was effective for the conversion of indolizidine 7b into final target alkaloid 223A (1) in 48% overall yield (Scheme 3). With the same procedure, epi-7b was converted into alkaloid 6-epi-223A (6-epi-1) in 53% yield. We were pleased to find that the reactions provided complete stereoselectivity for syn addition, i.e., the cis configuration between H-5 and bridged H-8a, in both reductions. The spectroscopic data of our synthetic samples 223A (1) and 6-epi-1 were in agreement with those reported in the literature^4,6 (see the Supporting Information for ¹³C NMR comparison).

Scheme 3. Synthesis of Alkaloid 223A and Alkaloid 6-epi-223A.

To explain the observed syn selectivity in both diastereomeric products, we performed density functional theory (DFT) calculations to determine all four TS geometries in the last step during the reductive alkylation of lactams, i.e., LiAlH₄ reduction of the corresponding iminium, which determined the C-5 configuration. The substituents at positions 5, 6, and 8 were replaced with a methyl group to simplify conformation issues and minimize the calculation cost. The four TS geometries are shown in Figure 2. The results show that TS₁ is favored over TS₂ by 3.4 kcal/mol, indicating the hydride addition prefers to proceed via “syn addition” to yield the cis configuration between H-5 and H-8a, found in alkaloid 223A. The “syn addition” constitutes an axial attack involving a chairlike TS₁ and TS₃, while the “anti addition” an equatorial attack with a boat-like TS₂ and TS₄. In addition, TS₃ is favored over TS₄ by 1.1 kcal/mol, suggesting the syn addition was preferred to give the same configuration in 6-epi-1.

Figure 2.

Four TS geometries in the reductive alkylation (units of kilocalories per mole).

In conclusion, we present a concise, divergent, and protecting group free syntheses of Dendrobatid alkaloid 223A (1) and 6-epi-223A (6-epi-1). The central step in these syntheses is the Rh-catalyzed hydroformylation double cyclization, which constructs the indolizidine ring system in one step from much simpler allylamide precursors. The relative rigid indolizidine framework constitutes the origin of the observed diastereoselectivity. The DFT calculations reveal that the addition of the syn-hydride in the Tf₂O-activated reductive alkylation of the lactam involves the more stable TS, which may explain the observed cis configuration between H-5 and H-8a, in the formation of both 223A (1) and 6-epi-223A (epi-1). We are currently applying the methodology to indolizidine alkaloids, and the results will be disclosed in due course.

Experimental Section

All reactions were performed under an argon atmosphere and in an anhydrous solvent, unless otherwise stated. An oil bath was used as the heat source. The solvents and reagents have been dried or refined according to the literature procedures. The reaction flasks were dried in a 110 °C oven, allowed to cool to room temperature in a desiccator with drying agents, and assembled under an argon atmosphere. Thin layer chromatography (TLC) was performed with ultraviolet light, an iodine chamber, 10% sulfuric acid, or a 10% PMA solution. The crude product were purified by flash column chromatography on silica gel to give the isolated yield. Infrared (IR) spectra were recorded on an ATR-FTIR apparatus. Melting points were recorded on a melting point apparatus. Single-crystal X-ray analysis was carried out with an X-ray diffractometer (Bruker D8 VENTURE), and the results have been reported to the Cambridge Crystallographic Data Centre to obtain the corresponding CCDC number. All NMR spectra, i.e., ¹H, ¹³C, DEPT, gCOSY, gHSQC, and gHMBC, were recorded on a 400 or 600 MHz NMR spectrometer, which provided all necessary data for the full assignment of each compound. Chemical shifts (δ) are reported in parts per million using a residual undeuterated solvent as an internal standard. Coupling constants are in hertz. Mass spectra were recorded on a mass spectrometer with a magnetic sector as the mass analyzer, using electrospray ionization (ESI) or fast atom bombardment (FAB).

General Procedure for the Reductive Alkylation of Lactams

To a dichloromethane (15 mL) solution of lactam 7b (152 mg, 0.77 mmol, 1.0 equiv) and 2,6-di-tert-butyl-4-methylpyridine (DTBMP, 207 mg, 1.01 mmol, 1.3 equiv) in a 100 mL flask at −78 °C under argon was added triflic anhydride (0.17 mL, 1.01 mmol, 1.3 equiv). After the addition was completed, the cooling bath was removed so that the resulting solution was naturally warmed to 0 °C. After staying at the temperature for 30 min, the flask was again cooled to −78 °C. The n-PrMgCl solution (0.94 mL, 1 M in 2-MeTHF, 0.94 mmol, 1.2 equiv) was added via a syringe. The reaction mixture was allowed to be naturally warmed to room temperature for 16 h. LiAlH₄ (86 mg, 2.3 mmol, 3.0 equiv) was added, and the solution was stirred for 3 h. Upon completion of the reaction as determined by TLC analysis, a NaOH solution (20%) was slowly added until a white gel formed. The reaction mixture was subjected to filtration with a short Celite column to give a filtrate. The filtrate was concentrated to the crude product. Purification of the crude product by flash chromatography on silica gel with an EtOAc/n-hex eluant gave the title product.

rel-(5S,6S,8S,8aR)-6,8-Diethyl-5-(1-propyl)indolizidine (1, alkaloid 223A)

83 mg, 48% yield; light yellow oil; R_f = 0.47 (1:3 EtOAc/n-hex); ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.16–3.22 (m, 1H, H-3), 2.02–2.12 (m, 1H, H-8a), 1.84–1.98 (m, 3H, H-1, H-3, and H-7), 1.74–1.84 (m, 1H, H-2), 1.56–1.66 (m, 2H, H-2 and H-5), 1.36–1.54 (m, 7H, H-1, H-8, H-9, H-13 × 2, and H-14 × 2), 1.24–1.34 (m, 2H, H-6 and H-11), 1.16–1.24 (m, 1H, H-11), 0.96–1.08 (m, 1H, H-9), 0.80–0.92 (m, 10H, H-7, H-10 × 3, H-12 × 3, and H-15 × 3); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 71.4 (d), 66.8 (d), 52.0 (t), 37.7 (d), 37.2 (d), 33.4 (t), 32.4 (t), 29.2 (t), 25.9 (t), 20.4 (t), 19.1 (t), 18.3 (t), 14.5 (q), 12.4 (q), 11.0 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₅H₂₉N⁺ 223.2300, found 223.2301 (Δ = 0.4 ppm).

rel-(5S,6R,8S,8aR)-6,8-Diethyl-5-(1-propyl)indolizidine (epi-1)

99 mg, 53% yield; light yellow oil; R_f = 0.47 (1:3 EtOAc/n-hex); ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.17 (brs, 1H, H-3), 1.82–1.98 (m, 3H), 1.62–1.78 (m, 4H), 1.30–1.58 (m, 8H), 1.18–1.28 (m, 1H, H-6), 0.96–1.10 (m, 2H), 0.82–0.92 (m, 9H), 0.59 (q, J = 12.0 Hz, 1H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 69.9 (d), 67.4 (d), 52.0 (t), 42.4 (d), 40.0 (d), 35.3 (t), 33.0 (t), 28.9 (t), 26.0 (t), 24.7 (t), 20.8 (t), 17.9 (t), 14.8 (q), 11.1 (q, 2C); EI-HRMS (m/z) [M]⁺ calcd for C₁₅H₂₉N⁺ 223.2300, found 223.2308 (Δ = 3.6 ppm).

General Procedure for the Preparation of N-Allylamide Substrates

To a mixture of the corresponding acid (10.0 mmol, 1.0 equiv), EDC (2.107 g, 11.0 mmol, 1.1 equiv), and HOBt·H₂O (1.991 g, 13.0 mmol, 1.3 equiv) in CH₂Cl₂ (5.0 mL) in an ice bath was added the corresponding amine (10.0 mmol, 1.0 equiv) via a syringe. The reaction mixture was allowed to stir overnight (∼21 h) under argon. The reaction mixture was partitioned with CH₂Cl₂ (20 mL) and a saturated NaHCO₃ solution (10 mL). The organic layer was washed with a saturated NH₄Cl solution (10 mL). The aqueous solution was again extracted with CH₂Cl₂ (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure to give the crude product. Purification of the crude product by flash chromatography on silica gel, using an EtOAc/n-hexane eluant, afforded the corresponding amide in high yield.

N-Allyl-5-methyl-4-hexenamide (2a)

1.622 g, 97% yield; colorless oil; R_f = 0.60 (1:1 EtOAc/n-hex); IR (cm^–1, film) ν̅_max 3317, 3084, 2926, 2858, 1646, 1541, 1435, 1376, 1266, 988, 919, 699; ¹H NMR (400 MHz, CDCl₃) δ 6.05 (brs, 1H), 5.73–5.82 (m, 1H), 5.08–5.14 (m, 3H), 3.81 (q, J = 6.0 Hz, 2H), 2.27 (q, J = 7.2 Hz, 2H), 2.16–2.20 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.7 (s), 134.2 (d), 132.9 (s), 112.7 (d), 115.9 (t), 41.7 (t), 36.5 (t), 25.5 (q), 24.2 (t), 17.6 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₀H₁₇NO⁺ 167.1310, found 167.1314 (Δ = 2.4 ppm). The spectral data are in agreement with those reported in the literature.¹⁵

N-Allyl-2-ethyl-5-methyl-4-hexenamide (2b)

1.776 g, 91% yield; colorless oil,; R_f = 0.60 (1:1 EtOAc/n-Hex); IR (cm^–1, film) ν̅_max 3290, 3083, 2964, 1657, 1552, 1456, 1380, 1259, 1229, 987, 917, 827, 698; ¹H NMR (400 MHz, CDCl₃) δ 5.75–5.84 (m, 1H), 5.72 (brs, 1H), 5.03–5.17 (m, 3H), 3.80–3.91 (m, 2H), 2.20–2.26 (m, 1H), 2.09–2.16 (m, 1H), 1.91–1.98 (m, 1H), 1.65 (s, 3H), 1.54–1.64 (m, 1H), 1.57 (s, 3H), 1.43–1.49 (m, 1H), 0.87 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 175.3 (s), 134.5 (d), 133.4 (s), 121.7 (d), 115.9 (t), 49.8 (d), 41.6 (t), 31.2 (t), 25.7 (q), 25.4 (t), 17.7 (q), 12.1 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₂H₂₁NO⁺ 195.1623, found 195.1622 (Δ = −0.5 ppm).

General Procedure for Domino Double Cyclization

Rh(acac)(CO)₂ (2.6 mg, 1.0 mol %) and BIPHEPHOS (15.8 mg, 2.0 mol %) were dissolved in AcOH (1 mL) under argon. The resulting catalyst solution was degassed by a freezing–thawing procedure at least three times. N-Allyl amide (2, 1 mmol, 1.0 equiv) and pTSA (1.0 equiv) were placed in a 50 mL flask. The catalyst solution was transferred to the reaction flask containing the substrate by a pipet, and the total volume was adjusted to 20 mL with AcOH (0.05 M). The reaction flask was placed in a 300 mL stainless steel autoclave and pressurized with CO (2.2 atm) followed by H₂ (2.2 atm). The pressure for CO and H₂ was increased to 10 atm each as the 15 mmol substrate was used. Such an operation guaranteed the completion of the reaction. The reaction mixture was stirred at 60 °C for 16–20 h. Upon completion of the reaction as determined by TLC analysis, the gas was carefully released in a good ventilated hood and the reaction mixture was concentrated under reduced pressure to give the crude residue.

The residue was diluted with CH₂Cl₂ (∼0.2 M) and then added with BF₃·OEt₂ (2.5 equiv) to an ice bath. The solution was then stirred at room temperature for 16–20 h. Upon completion of the reaction, saturated sodium bicarbonate (amount approximately equal to that of CH₂Cl₂) was added. After separation of the organic layer, the aqueous layer was again extracted with CH₂Cl₂ (four times). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and then concentrated under reduced pressure to give the crude product. The crude product was purified by flash chromatography on silica gel using a MeOH/CH₂Cl₂ or EtOAc/n-hexane eluant to give the product.

8-(Propen-2-yl)-5-oxoindolizidine (3a)

129 mg, 72% yield (1.4:1 cis:trans); yellow oil; R_f = 0.24 (1:20 MeOH/CH₂Cl₂); ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 4.57–4.89 (m, 4H), 3.66 (ddd, J = 6.0, 6.0, 10.8, Hz, 1H), 3.44–3.60 (m, 4H), 3.33 (ddd, J = 4.8, 10.2, 10.2 Hz, 1H), 2.59 (q, J = 4.8 Hz, 1H), 2.48–2.52 (m, 1H), 2.31–2.43 (m, 3H), 1.84–2.09 (m, 6H), 1.71–1.81 (m, 12H), 1.34–1.39 (m, 1H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.3 (s), 168.7 (s), 145.0 (s), 143.1 (s), 113.0 (t), 112.1 (t), 61.8 (d), 60.5 (d), 48.4 (d), 45.2 (t), 44.7 (t), 41.0 (d), 32.3 (t), 31.3 (t), 29.1 (t), 28.3 (t), 27.2 (t), 24.8 (t), 23.6 (q), 21.9 (t), 21.6 (t), 20.0 (q). The spectral data are in agreement with those reported in the literature.¹⁵

6-Ethyl-8-(2-propenyl)-5-oxoindolizidine (3b1)

97 mg, 47% yield (dr 2:1); yellow oil; R_f = 0.55 (pure EtOAc); IR (cm^–1, film) ν̅_max 2967, 2967, 2936, 2876, 1631, 1379, 1334, 1275, 1180, 749; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 4.80 (s, 1H), 4.68 (s, 1H), 3.80 (dd, J = 11.7, 8.2 Hz, 1H), 3.62–3.74 (m, 1H), 3.49–3.61 (m, 1H), 3.38 (dd, J = 14.7, 5.8 Hz, 1H), 3.24 (d, J = 10.1 Hz, 1H), 3.01–3.22 (m, 1H), 2.74 (dd, J = 14.4, 7.1 Hz, 1H), 1.90–2.18 (m, 2H), 1.73–1.90 (m, 2H), 1.59–1.68 (m, 3H), 1.29–1.59 (m, 2H), 0.81–0.99 (m, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.3 (s, 2C), 145.5 (s, 2C), 112.7 (t, 2C), 59.9 (d), 58.4 (d), 44.2 (t), 43.2 (t), 43.1 (d), 42.7 (d), 42.2 (d), 41.6 (d), 29.2 (t), 28.1 (t), 26.3 (t), 25.6 (t), 22.9 (t), 22.7 (t), 22.6 (t), 21.9 (t), 21.6 (q), 21.4 (q), 11.9 (q), 11.8 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₃H₂₁NO⁺ 207.1623, found 207.1621 (Δ = −0.9 ppm).

rel-(6S,8R,8aR)-6-Ethyl-8-(2-propenyl)-5-oxoindolizidine (3b2)

89 mg, 43% yield; yellow oil; R_f = 0.25 (pure EtOAc); IR (cm^–1, film) ν̅_max 3439, 2966, 2936, 2877, 1729, 1621, 1459, 1375, 1250, 1057, 893, 522; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 4.83 (s, 1H), 4.81 (s, 1H), 3.53–3.60 (m, 1H), 3.44–3.50 (m, 1H), 3.60 (ddd, J = 5.2, 10.4, 10.4 Hz, 1H), 2.26–2.34 (m, 1H), 2.01–2.07 (m, 2H), 1.82–1.98 (m, 3H), 1.68 (s, 3H), 1.63–1.77 (m), 1.34–1.52 (m, 2H), 0.98 (s, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.8 (s), 145.1 (s), 112.0 (t), 61.4 (d), 45.2 (d), 45.1 (t), 41.7 (d), 32.2 (t), 30.7 (t), 25.4 (t), 22.1 (t), 19.9 (q), 12.3 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₃H₂₁NO⁺ 207.1623, found 207.1621 (Δ = −0.9 ppm).

General Procedure for Oxidative Cleavage

To the mixed solution (0.1 M, 18 mL) of acetone and water (9:1) of the alkene substrate (3a, 323 mg, 1.80 mmol, 1.0 equiv) under argon were added 2,6-dimethylpyridine (0.63 mL, 3.0 equiv), an N-methyl morpholine oxide aqueous solution (50%, 2 mL, 5 equiv), and OsO₄ (4.6 mg, 1 mol %). The solution was allowed to stir overnight (∼16 h) at 60 °C. The reaction was monitored by TLC in which the R_f value of the starting material alkene is ∼0.24 (1:20 MeOH/CH₂Cl₂), while the R_f value of the product diol is ∼0.10 in the same eluent. Upon completion of the reaction, PhI(OAc)₂ (696 mg, 1.2 equiv) was added, the mixture stirred overnight (∼20 h) at 60 °C. TLC analysis was used to follow the reaction. After the volatiles had evaporated, the resulting reaction mixture was diluted with CH₂Cl₂ (20 mL) and washed with a saturated Na₂S₂O₄ solution (30 mL). The aqueous layer was extracted three times with CH₂Cl₂ (20 mL each). The organic layer was washed with brine (10 mL), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure to give the crude product.

To the dichloromethane solution of the crude product (∼0.1 M) in an ice bath was added DBU (0.30 mL, 1.1 equiv). The resulting solution was stirred overnight (∼16 h) and then washed with a saturated NH₄Cl solution. After separation from the organic layer, the resulting aqueous solution was extracted three times with CH₂Cl₂. The organic layer was washed with brine (10 mL), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure to give the crude product. Purification of the crude product by flash chromatography on silica gel, using ethyl acetate and n-hexane as the eluant, gave the two title products.

trans-8-Acetyl-5-oxoindolizidine (4a)

248 mg, 76% yield; yellow oil; R_f = 0.37 (1:20 MeOH/CH₂Cl₂); IR (cm^–1, film) ν̅_max 3349, 2927, 1632, 1456, 1261, 1056, 749, 700; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.50–3.58 (m, 2H), 3.42 (t, J = 11.6 Hz, 1H), 2.28–2.56 (m, 3H), 2.22 (s, 3H), 2.04–2.18 (m, 2H), 1.90–1.98 (m, 1H), 1.71–1.79 (m, 2H), 1.29–1.38 (m, 1H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 208.3 (s), 167.8 (s), 59.5 (d), 53.1 (d), 44.7 (t), 32.0 (t), 30.7 (t), 29.4 (q), 24.9 (t), 22.0 (t); EI-HRMS (m/z) [M]⁺ calcd for C₁₀H₁₅NO₂⁺ 181.1103, found 181.1100 (Δ = −1.7 ppm). The spectral data are in agreement with those reported in the literature.¹⁵

rel-(6S,8S,8aR)-6-Ethyl-8-acetyl-5-oxoindolizidine (4b)

111 mg, 50% yield; yellow oil; R_f = 0.25 (pure EtOAc); IR (cm^–1, film) ν̅_max 3448, 2930, 2877, 1709, 1625, 1459, 1174, 732, 600; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.55 (ddd, J = 4.8, 11.2, 11.2 Hz, 1H), 3.32–3.48 (m, 2H), 2.46 (ddd, J = 4.8, 11.2, 11.2 Hz, 1H), 2.23–2.32 (m, 1H), 2.16 (s, 3H), 2.10–2.18 (m, 1H), 1.80–1.98 (m, 4H), 1.66–1.80 (m, 1H), 1.28–1.50 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 208.5 (s), 171.0 (s), 58.8 (d), 50.7 (d), 44.6 (t), 41.1 (d), 32.2 (t), 29.3 (q), 28.5 (t), 25.0 (t), 22.3 (t), 12.1 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₂H₁₉NO₂⁺ 209.1416, found 209.1413 (Δ = −1.4 ppm).

Tosylhydrazone Formation

rel-(6S,8S,8aR)-6-Ethyl-8-acetyl-5-oxoindolizidine Tosylhydrazone (5b, CCDC 1939886)

To a methanol solution (4 mL) of methylketone 4b (228 mg, 1.09 mmol, 1.0 equiv) under argon was added tosylhydrazide (223 mg, 1.19 mmol, 1.1 equiv). The solution was allowed to stir under reflux for 1 h. Upon completion of the reaction, the mixture was allowed to stand to cool slowly to room temperature. A large quantity of white crystals separated during that time. The resulting white crystal was isolated by being carefully washed with cold methanol and dried under vacuum. The crystal was used for X-ray analysis (131 mg, 0.31 mmol, 28%): mp 214–216 °C; R_f = 0.20 (pure EtOAc); ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 7.81 (d, J = 8.0 Hz, 2H), 7.55 (brs, 1H, NH), 7.31 (d, J = 8.4 Hz, 2H), 3.28–3.85 (m, 3H), 2.43 (s, 3H), 2.24–2.29 (m, 1H), 2.20 (ddd, J = 4.8, 10.8, 10.8 Hz, 1H), 1.91–1.99 (m, 1H), 1.81 (s, 3H), 1.71–1.87 (m, 4H), 1.60–1.70 (m, 1H), 1.23–1.41 (m, 1H), 1.18 (dddd, J = 3.6, 8.4, 8.4, 8.4 Hz, 1H), 0.95 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.3 (s), 156.4 (s), 144.2 (s), 135.2 (s), 129.4 (d), 128.1 (d), 60.0 (d), 46.1 (d), 45.0 (t), 41.4 (d), 32.0 (t), 29.6 (t), 25.2 (t), 22.3 (t), 21.5 (q), 15.1 (q), 12.2 (q); EI-HRMS (m/z) [M]⁺ calcd for [C₁₉H₂₇N₃O₃S·Na]⁺ 400.1671, found 400.1664 (Δ = −1.7 ppm).

General Procedure for the Formation of 1,3-Dithiolane

To a toluene (30 mL, 0.2 M) solution of methyl ketone 4a (989 mg, 5.45 mmol, 1.00 equiv) and anhydrous ZnCl₂ powder (1.111 g, 8.15 mmol, 1.5 equiv) in a 100 mL flask under argon was added 1,2-ethanedithiol (1.37 mL, 16.3 mmol, 3.0 equiv) via a syringe. After the flask had been fitted with a Dean-Stark trap with a water-cooled condenser, the solution was heated under reflux to remove water. Upon completion of the reaction as monitored by TLC analysis, the mixture was cooled, followed by the addition of a saturated NH₄Cl solution (20 mL). The solution was stirred for 1 h. The addition of a small quantity of water might dissolve the precipitate. After separation of the organic layer, the aqueous layer was extracted with EtOAc (4 × 20 mL). The combined organic extracts were dried over Na₂SO₄. After removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to give the crude product. Purification of the crude product by flash chromatography on silica gel, with an EtOAc/n-hex eluant, gave the title products.

trans-8-(2-Methyl-1,3-dithiolan-2-yl)-5-oxoindolizidine (6a)

1.335 g, 95% yield; yellow oil; R_f = 0.25 (pure EtOAc); IR (cm^–1, film) ν̅_max 2962, 2929, 2874, 1633, 1457, 1378, 1245, 1108, 1050, 749, 701, 609; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.40–3.52 (m, 5H), 3.21–3.29 (m, 2H), 2.38–2.43 (m, 1H), 2.23–2.36 (m, 2H), 2.13–2.19 (m, 2H), 1.86–1.92 (m, 2H), 1.64 (s, 3H), 1.59–1.72 (m, 2H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 168.5 (s), 69.1 (s), 62.1 (d), 51.6 (d), 44.4 (t), 39.9 (t), 38.1 (t), 33.9 (t), 31.4 (t), 29.9 (q), 27.4 (t), 22.3 (t); EI-HRMS (m/z) [M]⁺ calcd for C₁₂H₁₉NOS₂⁺ 257.0908, found 257.0913 (Δ = 1.9 ppm).

rel-(6S,8S,8aR)-6-Ethyl-8-(2-methyl-1,3-dithiolan-2-yl)-5-oxoindolizidine (6b)

993 mg, 76% yield; light yellow oil; R_f = 0.37 (pure EtOAc); IR (cm^–1, film) ν̅_max 3449, 2962, 2962, 2929, 2874, 1633, 1457, 1378, 1245, 1108, 1050, 749, 701, 609; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.30–3.42 (m, 2H), 3.24–3.36 (m, 3H), 3.13–3.24 (m, 2H), 2.30–2.36 (m, 1H), 2.22–2.28 (m, 1H), 2.02 (ddd, J = 4.0, 10.0, 10.0 Hz, 1H), 1.92–2.01 (m, 1H), 1.77–1.92 (m, 3H), 1.69 (s, 3H), 1.55–1.68 (m, 2H), 1.27–1.39 (m, 1H), 0.93 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.9 (s), 69.6 (s), 61.4 (d), 48.4 (d), 44.3 (t), 41.7 (d, C-6), 39.7 (t), 38.2 (t), 34.4 (t), 31.1 (t), 30.4 (q), 24.3 (t), 22.6 (t), 12.0 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₄H₂₃NOS₂⁺ 285.1221, found 285.1226 (Δ = 1.7 ppm).

General Procedure for Nickel Boride Reduction of 1,3-Dithiolane

To an ethanol (50 mL) solution of dithiolane 6a (849 mg, 3.29 mmol, 1.00 equiv) and NiCl₂·6H₂O powder (7.82 g, 32.9 mmol, 10.0 equiv) in a 100 mL flask at −50 °C under argon was added NaBH₄ (2.49 g, 65.8 mmol, 20.0 equiv) in several portions. This addition produced a large volume of gas, and the solution turned gray. After the addition was completed, the reaction mixture was stirred at room temperature. Upon completion of the reaction as monitored by TLC analysis, the mixture was subjected to filtration with a Büchner funnel to remove the dark gray solid. The filtrate was concentrated to the crude residue that was partitioned with water (30 mL) and EtOAc (30 mL). After separation of the organic layer, the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic extracts were dried over Na₂SO₄. After removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to give the crude product. Purification of the crude product by flash chromatography on silica gel, with an EtOAc/n-hex eluant, gave the title products.

trans-8-Ethyl-5-oxoindolizidine (7a)

534 mg, 97% yield; yellow oil; R_f = 0.22 (pure EtOAc); IR (cm^–1, film) ν̅_max 3417, 2963, 2933, 2877, 1599, 1493, 1459, 1345, 1324, 1051, 700; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.48–3.53 (m, 1H), 3.38–3.44 (m, 1H), 3.04 (ddd, J = 4.8, 10.0, 10.0 Hz, 1H), 2.44 (dd, J = 6.4, 18.0 Hz, 1H), 2.26 (ddd, J = 6.8, 11.6, 18.4 Hz, 1H), 2.13 (ddd, J = 6.0, 6.0, 11.6 Hz, 1H), 1.86–1.96 (m, 2H), 1.63–1.74 (m, 1H), 1.51–1.59 (m, 1H), 1.26–1.40 (m, 2H), 1.12–1.24 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 169.3 (s), 63.9 (d), 45.1 (t), 41.8 (d), 32.3 (t), 31.4 (t), 26.3 (t), 25.2 (t), 22.2 (t), 11.0 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₀H₁₇NO⁺ 167.1310, found 167.1303 (Δ = −4.2 ppm).

rel-(6S,8S,8aR)-6,8-Diethyl-5-oxoindolizidine (7b)

442 mg, 65% yield; light yellow oil; R_f = 0.40 (pure EtOAc); IR (cm^–1, film) ν̅_max 3417, 2963, 2931, 2876, 1711, 1634, 1458, 1379, 1304, 1258, 1124, 749; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.38–3.52 (m, 2H), 3.03 (ddd, J = 5.2, 10.0, 10.0 Hz, 1H), 2.19–2.28 (m, 1H), 2.18–2.26 (m, 1H), 1.78–1.94 (m, 3H, H-2), 1.62–1.76 (m, 1H), 1.48–1.60 (m, 1H), 1.22–1.48 (m, 4H), 1.11–1.22 (m, 1H, H-9), 0.94 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 172.3 (s), 63.6 (d), 45.0 (t), 41.7 (d), 38.6 (d), 32.4 (t), 30.0 (t), 25.5 (t), 25.3 (t), 22.3 (t), 12.3 (q), 11.1 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₂H₂₁NO⁺ 195.1623, found 195.1632 (Δ = 4.6 ppm).

tert-BuLi-Mediated Alkylation

rel-(6R,8S,8aR)-6,8-Diethyl-5-oxoindolizidine (epi-7b)

To a THF solution (50 mL) of lactam 7a (272 mg, 1.63 mmol, 1.0 equiv) at −78 °C was slowly added a tert-BuLi solution (1.8 M in pentane, 1.78 mL, 3.26 mmol, 2.0 equiv) via a syringe. After the addition of the base had been completed, the bath was removed, and the solution was warmed to 0 °C and then stirred in an ice bath for 30 min. The reaction mixture was again cooled to −78 °C, and EtI (0.275 mL, 3.42 mmol, 2.1 equiv) was added via a syringe. The reaction mixture was warmed gradually to room temperature in 16 h. The reaction was quenched by the addition of a saturated NH₄Cl (10 mL) solution and EtOAc (30 mL). After separation of the organic layer, the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na₂SO₄. After removal of the solid dehydrating agent, the organic layer was concentrated under reduced pressure to give the crude product. Purification of the crude product by flash chromatography on silica gel, with an EtOAc/n-hex eluant, gave a colorless oil as the title product (291 mg, 1.49 mmol, 92%): R_f = 0.34 (pure EtOAc); IR (cm^–1, film) ν̅_max 3483, 2969, 2939, 2879, 2579, 1714, 1609, 1460, 1382, 1192, 736; ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.50–3.58 (m, 1H), 3.41 (t, J = 10.4 Hz, 1H), 3.06 (ddd, J = 5.2, 10.4, 10.4 Hz, 1H), 2.16–2.22 (m, 1H), 2.09–2.14 (m, 1H), 1.89–2.05 (m, 3H), 1.64–1.73 (m, 1H), 1.45–1.60 (m, 2H), 1.35 (dddd, J = 7.0, 12.0, 12.0, 12.0 Hz, 1H), 1.12–1.27 (m, 2H), 1.05 (q, J = 12.0 Hz, 1H), 0.94 (t, J = 6.8 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 171.4 (s), 63.7 (d), 45.1 (t), 42.4 (d), 41.3 (d), 32.1 (t), 31.7 (t), 25.1 (t), 24.9 (t), 22.1 (t), 10.8 (q), 10.7 (q); ESI-HRMS (m/z) [M + H]⁺ calcd for [C₁₂H₂₁NO·H]⁺ 196.1701, found 196.1693 (Δ = −4.0 ppm).

rel-(8S,8aR)-6,6,8-Triethyl-5-oxoindolizidine (8)

Colorless oil; R_f = 0.44 (pure EtOAc); ¹H NMR (400 MHz, 25 °C, CDCl₃) δ 3.38–3.53 (m, 2H), 3.01 (ddd, J = 5.2, 10.8, 10.8 Hz, 1H), 2.11 (quintet, J = 6.0 Hz, 1H), 1.87–1.93 (m, 1H), 1.61–1.78 (m, 4H), 1.44–1.58 (m, 3H), 1.24–1.38 (m, 3H), 1.06–1.16 (m, 1H), 0.98 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 7.6 Hz, 3H), 0.78 (t, J = 7.6 Hz, 3H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 174.0 (s), 64.0 (d), 42.7 (s), 45.3 (t), 39.7 (d, C-8), 34.7 (t), 32.6 (t), 32.5 (t), 31.7 (t), 25.3 (t), 22.4 (t), 11.0 (q), 9.2 (q), 8.8 (q); EI-HRMS (m/z) [M]⁺ calcd for C₁₄H₂₅NO⁺ 223.1936, found 223.1941 (Δ = 2.2 ppm).

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.3c02366.

• (¹H and ¹³C NMR spectra of all compounds and all calculated coordinates of the TS geometries (PDF)

Author Contributions

^# J.-T.C. and W.-T.H. contributed equally to this work.

The authors declare no competing financial interest.