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Article

Iron-Promoted 1,5-Substitution Reaction of Endocyclic Enyne Oxiranes with MeMgBr: A Stereoselective Method for the Synthesis of Exocyclic 2,4,5-Trienol Derivatives

by
Melih Kuş
1,†,
Cenk Omur
1,†,
Sıla Karaca
2 and
Levent Artok
1,*
1
Department of Chemistry, Faculty of Science, Izmir Institute of Technology, Urla, Izmir 35430, Türkiye
2
SOCAR Turkey R&D and Innovation Co., Aliaga, Izmir 35800, Türkiye
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Chemistry 2023, 5(4), 2682-2699; https://doi.org/10.3390/chemistry5040173
Submission received: 30 August 2023 / Revised: 21 November 2023 / Accepted: 24 November 2023 / Published: 1 December 2023
(This article belongs to the Special Issue Catalytic Organic Synthesis—a Special Issue in Honor of Professor Masahiro Miura)
Browse Figures
Versions Notes

Abstract

:
The iron-promoted 1,5-substitution reaction of endocyclic oxiranes with MeMgBr yields exocyclic 2,4,5-trienols with high diastereomeric ratios of up to 100:0. However, for the method’s success, the oxirane ring must have a trans-configuration. The reactions exhibit strong stereoselectivity concerning the methylation mode and the configuration of the resulting exocyclic double bond. Enantiomerically pure enyne oxiranes can be synthesized through Sharpless asymmetric dihydroxylation and subsequent manipulations. With these reagents, it has been possible to produce exocyclic 2,4,5-trienols in enantiopure forms. Importantly, this process maintains chirality without degradation during the center-to-axis transfer of chirality.

Graphical Abstract

1. Introduction

The combined use of iron compounds and Grignard reagents has been widely preferred in metal-mediated nucleophilic substitution [1,2,3,4,5,6,7,8,9,10] and addition [11,12,13,14,15,16,17,18,19,20] reactions. Both reagents are readily available, environmentally friendly, and relatively low in cost.
We have previously reported that the acetates of 2-en-4-yne alcohols and the conjugated enyne oxiranes undergo 1,5-substitution (SN2″) reactions with Grignard reagents in the presence of an iron compound, yielding vinyl-substituted allenes, commonly referred to as vinylallenes [10]. Vinylallenes [21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44] represent highly valuable synthetic intermediates [45,46,47] extensively utilized in various chemical processes, including electrocyclization [48,49,50], cycloaddition [35,51,52,53,54,55,56,57,58,59], cyclization [60,61,62,63,64], and isomerization [65]. Moreover, they play a significant role in the synthesis of numerous natural compounds [66,67,68,69,70]. Notably, various naturally occurring molecules feature vinylallene motifs [71,72,73] (Figure 1).
In our previous study, we observed that the method generally had low stereoselectivity [10]. An enantiomerically pure enyne acetate converted to racemic products and the reaction of enyne oxiranes resulted in products with low diastereomeric ratios (dr) (Scheme 1). Additionally, the method did not apply to endocyclic enyne acetates (Scheme 2). However, we now present evidence that, in contrast to their enyne acetate counterparts, endocyclic enyne oxiranes are suitable for the methylation method. Moreover, reactions with these reagents yield exocyclic 2,4,5-trienols with high dr levels, provided that the oxirane moiety is in the trans-configuration.

2. Materials and Methods

2.1. General

The dimethylformamide (DMF) used was dried using a solvent purification system (SPS, MBRAUN 800). The solvents, CH2Cl2 and CHCl3, were dried over a 3Å molecular sieve preactivated by heating at 400 °C for 24 h and cooled under an argon atmosphere before use. Tetrahydrofuran (THF) was distilled from benzophenone-ketyl under a nitrogen atmosphere for synthesizing starting materials. However, in metal-catalyzed reactions, THF was distilled after refluxing for at least 3 h over LiAlH4 (300–350 mg/400 mL) under high-purity grade-6 argon gas. The argon gas was passed through a KOH-P2O5 line just before use.
The synthesized enyne oxiranes were purified on triethylamine-deactivated silica gel with a mesh size of 200, while all other materials were purified on columns containing silica gel with a particle size of 35–70 μm.
Pure samples were analyzed using GC/MS, NMR, and HRMS techniques. The NMR spectra were recorded on a Varian VnmrJ 400 spectrometer using C6D6 as the NMR solvent for vinylallene products and CDCl3 for all other materials. Partial resolution of diastereomeric proton signals was achievable in the 1H-NMR spectra when recorded in C6D6. As a result, we were able to determine the diastereomeric ratios of the products using the NMR method.

2.2. Synthesis of Racemic Enyne Oxiranes

The synthesis of methoxy, benzyloxy, and silyloxy-substituted racemic endocyclic enyne oxiranes was carried out, starting from cycloalkanones (Scheme 3): to a mixture of DMF (12 mL, 153 mmol) and chloroform (80 mL) cooled to 0 °C was added PBr3 (14 mL, 138 mmol) dropwise and stirred at this temperature for 1 h. Subsequently, 60 mmol of cycloalkanone was added dropwise to this mixture, and the entire mixture was refluxed overnight. After completion, the reaction was terminated with an ice-water mixture and carefully neutralized with NaHCO3(aq). The organic phase was separated, and the aqueous phase was washed with CH2Cl2. The extract was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using silica gel column chromatography to obtain S1 as a pale-yellow oil (hexane/EtOAc; yield: n = 0, 67%; n = 1, 72%; n = 2, 74%) [74].
S1 (25 mmol), PdCl2(PPh3)2 (2 mol% Pd, 355 mg, 0.5 mmol), and CuI (2 mol%, 95 mg, 0.5 mmol) were added to a degassed solution of Et3N (50 mL) and stirred at room temperature (rt) for 10 min. A terminal alkyne (3.5 mL, 30 mmol) was then slowly added to this mixture, and the resulting mixture was magnetically stirred at rt under an inert gas. The reaction was monitored through gas chromatography (GC). After the reactant was completely consumed, the reaction was terminated by adding a saturated solution of NH4Cl(aq) and then extracted with Et2O. The combined organic phases were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude mixture was subsequently purified using silica gel column chromatography to yield endocyclic enyne aldehydes S2 as a pale-yellow oil (hexane/EtOAC; yield: R = Bu, n = 0, 88%; n = 1, 91%; n = 2, 90%; R = Ph, n = 1, 67%; R = TMS, n = 1, 92%) [75].
To a suspension of NaH (528 mg, 22 mmol) in a dry THF (50 mL) at 0 °C, triethyl phosphonoacetate (4.8 mL, 24 mmol) was added dropwise and stirred at rt for 1 h. S2 (3.8 g, 20 mmol) dissolved in 10 mL of THF was then added dropwise to this mixture at −78°C. The mixture was stirred at this temperature for 1 h and then brought to rt. The reaction was monitored using GC. The reaction was terminated upon completion by adding a saturated NH4Cl(aq) solution, extracted with Et2O, and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and purified using silica gel column chromatography to yield S3 as a colorless oil (hexane/EtOAc; R = Bu, n = 0, 77%; n = 1, 82%; n = 2, 84%; R = Ph, n = 1, 82%; R = TMS, n = 1, 81%) [76].
For the desilylation of trimethylsilyl (TMS)-substituted dienyne ester, a solution of TMS-S3 (828 mg, 3 mmol) in 10 mL of dry THF at 0 °C, was prepared. To this solution, (Bu)4NBr (1.3 equiv, 3.9 mL, 3.9 mmol, 1 M in THF) was added dropwise and stirred for 1 h. The reaction progress was monitored using TLC and was terminated by adding a saturated NH4Cl(aq) solution. The organic phase was separated, and the aqueous phase was extracted with Et2O. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was subsequently purified using silica gel column chromatography to yield the desilylated product as a pale-yellow oil (hexane/EtOAc; 92%).
To the solution of S3 (10 mmol) in dry CH2Cl2 (60 mL) cooled to −78 °C, diisopropyl aluminium hydride (DIBALH) (3 equiv, 30 mL, 1.0 M in CH2Cl2) was added dropwise and stirred at this temperature. The reaction was monitored using TLC, and upon completion, the mixture was quenched with a saturated Rochelle’s salt (sodium-potassium tartarate) solution. The quenched mixture was stirred for additional 3 h at rt. The organic phase was separated, and the aqueous phase was washed with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude mixture was purified using silica gel column chromatography to obtain S4 as a colorless oil (hexane/EtOAC; yield: R = Bu, n = 0, 81%; n = 1, 89%; n = 2, 82%; R = Ph, n = 1, 81%; R = H, n = 1, 88%) [33].
To the solution of dienynol S4 (2 mmol) in 30 mL of CH2Cl2 cooled to 0 °C, 12 mL of 25% Na2CO3(aq) solution and m-chloroperbenzoic acid (MCPBA) (762 mg, 3.4 mmol, ≤77%) were added successively. The reaction was monitored using TLC, and upon completion, the mixture was diluted with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified through column chromatography using NEt3-deactivated silica gel, and enyne oxirane S5 was obtained as a pale-yellow oil (hexane/EtOAc; yield: R = Bu, n = 0, 27%; n = 1, 83%; n = 2; 55%; R = Ph, n = 1, 75%; R = H, n = 1, 53%) [33].
The compound S5 (1 mmol) was added dropwise to the mixture of DMF (2 mL) and NaH (26.4 mg, 1.1 mmol) under an argon atmosphere at −20 °C. After stirring this mixture for 0.5 h at the same temperature, MeI (75 mL, 1.2 mmol) was added and stirred for 1 h. The reaction progress was monitored through TLC and terminated with the addition of 10 mL of water/methanol mixture (1:1). The methyl-substituted structure 1 was purified through column chromatography using NEt3-deactivated silica gel as a pale-yellow oil (hexane/EtOAc; R = Bu, 1d, n = 0, 91%; 1a, n = 1, 88%; 1e, n = 2, 82%; 1g, R = Ph, n = 1, 89%; 1f, R = H, n = 1, 88%).
A DMF (1 mL) solution of compound S5 (n = 1, 1 mmol) was added to a DMF (2 mL) solution of NaH (26.4 mg, 1.1 mmol) dropwise under an argon atmosphere at −20 °C. After stirring this mixture for 0.5 h at the same temperature, BnBr (143 μL, 1.2 mmol) was added and stirred for an additional 1 h. The reaction was monitored through TLC and terminated with the addition of 10 mL of water/methanol mixture (1:1). The benzyl-substituted structure 1b was purified through column chromatography using NEt3-deactivated silica gel as a pale-yellow oil (hexane/EtOAc; 81%).
S5 (n = 1, 234 mg, 1 mmol) was dissolved in 15 mL of CH2Cl2 under a nitrogen atmosphere. To this solution, tert-butyldimethylsilyl chloride (TBDMSCl, 1.2 equiv., 181 mg, 1.2 mmol), Et3N (1.25 equiv, 0.2mL, 1.25 mmol), and a catalytic amount of 4-dimethylaminopyridine (DMAP, 12.5 mg, 0.1 mmol) were added, respectively, and stirred for 24 h. The reaction was monitored using TLC, extracted with CH2Cl2, dried over Na2SO4, and filtered. The silyl-substituted compound 1c was purified through column chromatography using NEt3-deactivated silica gel (pale-yellow oil; hexane/EtOAc; 87%).

2.3. Synthesis of Enantiopure Trans-Enyne Oxiranes

Sharpless asymmetric dihydroxylation was the key step in synthesizing enantiopure substrates in this study [77] (Scheme 4): to a mixture of 80 mL water/tert-BuOH (1:1) at rt, 9.2 g of AD mix-β and CH3SO2NH2 (760 mg, 8 mmol) were added and stirred until the solution became clearer (about 15 min after AD mix-β was added, the mixture became a diphasic heterogeneous red mixture, but after some stirring, it became a clear, pale-red solution). Then, the mixture was cooled to 0 °C, and S3 (8 mmol) was added. The reaction flask was kept in a refrigerator at 4 °C.
When the reaction was complete (approximately 3–10 days, as determined through TLC analysis), 12 g of Na2S2O3 was added, and the mixture was stirred for 1 h at rt. The reaction medium was diluted with water, extracted using EtOAc, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude mixture was purified using silica gel column chromatography, resulting in the isolation of S8* as a white solid (hexane/EtOAc; yield: n = 0, 55%; n = 1, 78%, 96.5% ee; n = 2, 75%).
The compound S8* (4 mmol) was dissolved in a 1,4-dioxane/water mixture (40 mL, 1:1 ratio) and cooled down to 0 °C, and NaBH4 (3 equiv, 454 mg, 12 mmol) was added incrementally to the mixture. The mixture was stirred at this temperature until S8* was completely consumed, as determined through TLC. The reaction was then quenched by adding 0.1 M HCl, and the product was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified using silica gel column chromatography, yielding S9* as a white paste (hexane/EtOAc; n = 0, 80%; n = 1, 95%; n = 2, 87%).
To a solution of S9* (3.8 mmol) in 15 mL of CH2Cl2, TBDMSCl (1.2 equiv, 689 mg, 4.56 mmol), NEt3 (1.25 equiv, 0.7 mL, 4.75 mmol), and a catalytic amount of 4-dimethylaminopyridine (DMAP, 25 mg, 0.2 mmol) were added. The mixture was stirred at rt for 24 h. The reaction progress was monitored through TLC, and upon completion, the reaction mixture was diluted with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated under reduced pressure. The silylated product S10* was purified using column chromatography, resulting in a yellow oil (hexane/EtOAc; yield: n = 0, 70%; n = 1, 81%; n = 2, 77%).
The diol compound S10* (0.2 mmol) was dissolved in 1 mL of dry CH2Cl2 under an argon atmosphere. To this solution, 0.5 mg of pyridinium p-toluene sulfonate (PPTS) and trimethyl orthoacetate (1.2 equiv, 32 mL, 0.24 mmol) were added. The reaction progress was monitored using TLC, and once the reagent was completely converted, the reaction mixture was evaporated at rt under reduced pressure. The crude mixture was further evaporated using a vacuum pump for 5 min to remove volatile by-products completely. Subsequently, 1 mL of dry CH2Cl2 was added to the flask, followed by the sequential addition of NEt3 (2 mL, 10% mmol) and TMSCl (1.2 equiv, 31 mL, 0.24 mmol). The progress of the reaction was monitored using TLC, and upon depletion of the reactant, the reaction mixture was evaporated under reduced pressure at rt. In the final step of this one-pot synthesis, 1 mL of dry MeOH and K2CO3 (4 equiv, 110 mg, 0.8 mmol) were added to the crude product under an argon atmosphere, and the mixture was stirred at rt until complete conversion. The residue was purified through column chromatography using silica gel treated with NEt3 to yield the trans-configured S13* compound as a pale-yellow oil (hexane/EtOAc; yield of the three steps: n = 0, 47%; 1c*, n = 1, 63%; n = 2, 56%) [78]. The synthesis of S13* was repeated to obtain a sufficient amount of the substrate.
To a solution of S13* (0.2 mmol) in 10 mL of dry THF at 0 °C, TBAF (1.3 equiv, 0.26 mL, 0.26 mmol, 1 M in THF) was added dropwise and stirred for 1 h. The reaction was monitored using TLC and terminated with the addition of a saturated NH4Cl(aq) solution. The organic phase was separated, and the aqueous phase was extracted with Et2O. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified through column chromatography using NEt3-deactivated silica gel to yield S14* products as a pale-yellow oil (hexane/EtOAc; n = 0, 87%; n = 1, 92%; n = 2, 91%). The synthesis of S14* was repeated to obtain a sufficient amount of the substrate.
The compound S14* (1 mmol) was added dropwise to a 2 mL solution of DMF in the presence of NaH (26.4 mg, 1.1 mmol) under an argon atmosphere at −20 °C. After stirring the mixture for 0.5 h at the same temperature, MeI (75 mL, 1.2 mmol) or BnBr (1.2 mmol) was added and stirred until the reaction was complete (~1 h) as confirmed through a TLC analysis. The reaction was terminated with the addition of a 10 mL water/methanol (1:1) mixture. The resulting compound 1* was purified through column chromatography using NEt3-treated silica gel, yielding a pale-yellow oil (hexane/EtOAc; 1d*, n = 0, 91%; 1a*, n = 1, 88%; 1e*, n = 2, 82%; 1b*, 93%).

2.4. Synthesis of Enantiopure Cis-Enyne Oxiranes

A dry CH2Cl2 solution (10 mL) of S8* (1.47 g, 5 mmol, 96.5% ee), NEt3 (1.25 equiv, 0.9 mL, 6.25 mmol), and TsCl (1.2 equiv., 1.33 g, 6 mmol) was stirred 1 h under N2 at rt. Then, the reaction medium was extracted using EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified using silica gel column chromatography to obtain S15* as a pale-yellow oil (hexane/EtOAc; 97%) (Scheme 5).
In a 20 mL MeOH solution of S3* (4 mmol), NaBH4 (3 equiv, 454 mg, 12 mmol) was added in portions at 0 °C and stirred until the reduction process was complete, as determined through TLC. The reaction was terminated by adding 0.1 M HCl(aq) solution; then, it was extracted with EtOAc, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified over silica gel column chromatography to yield S16* as a white paste (hexane/EtOAC; 95% yield).
Under an inert gas atmosphere, S16* (3.8 mmol) was dissolved in dry CH2Cl2 (15 mL). Subsequently, TBDMSCl (1.2 equiv, 689 mg, 4.56 mmol), NEt3 (1.25 equiv, 0.7 mL, 4.75 mmol), and a catalytic amount of 4-dimethylamino pyridine (DMAP, 25 mg, 0.2 mmol) were added, and the reaction mixture was stirred for 24 h. The reaction was terminated using water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated under reduced pressure. The silylated product S17* was purified using silica gel column chromatography, yielding a pale-yellow oil (hexane/EtOAc; 87% yield).
For the epoxidation process, a 15 mL EtOH solution of S17* (1.44 g, 3 mmol) and K2CO3 (3 equiv, 1.24 g, 9 mmol) was stirred for 3 h at 0 °C. Upon completion, 20 mL of water was added to the reaction mixture, which was then extracted using Et2O, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified through column chromatography using NEt3-deactivated silica to obtain cis-1c* as a pale-yellow oil (hexane/EtOAc; 83% yield) [79].
In a dry THF (10 mL) solution of cis-1c* (2 mmol), TBAF (1.3 equiv, 2.6 mL, 2.6 mmol, 1 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred for 1 h, and the reaction was terminated with water, followed by its extraction using Et2O, drying over Na2SO4, filtration, and evaporation under reduced pressure. The compound S18* was isolated through column chromatography using NEt3-deactivated silica (pale-yellow oil; hexane/EtOAc; 92% yield). The methylation of the hydroxyl group was performed as described for the synthesis of 1a (colorless oil; hexane/EtOAc; 86%).
S8* (n = 1): 1H NMR (400 MHz, CDCl3) δ: 4.96 (dd, J = 6.7, 4.3 Hz, 1H), 4.35–4.21 (m, 3H), 3.04 (d, J = 6.0 Hz, 1H), 2.69 (d, J = 6.9 Hz, 1H), 2.32 (t, J = 7.0 Hz, 2H), 2.28–2.06 (m, 4H), 1.64–1.37 (m, 8H), 1.31 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 173.0, 141.5, 117.9, 95.3, 79.4, 74.4, 73.5, 62.1, 30.9, 30.6, 24.6, 22.2, 22.1, 22.0, 19.2, 14.1, 13.6; HPLC: OJ-H, hexane/IPA = 98. 0:2.0, 1.0 mL/min, 220 nm, RT1 = 9.05 (major), RT2 = 9.9 (minor), ee%: 96.5.
1a*: 1H NMR (400 MHz, CDCl3) δ: 3.88 (d, J = 2.2 Hz, 1H), 3.69 (ddd, J = 11.4, 3.0, 0.6 Hz, 1H), 3.45–3.35 (m, 1H), 3.40 (s, 3H), 3.12 (dt, J = 5.3, 2.7 Hz, 1H), 2.34 (t, J = 6.8 Hz, 2H), 2.20–2.11 (m, 2H), 2.08–1.88 (m, 1H), 1.72–1.34 (m, 9H), 0.98–0.90 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 137.3, 121.7, 94.2, 79.5, 73.0, 59.1, 56.2, 55.2, 31.6, 30.9, 22.4, 22.2, 21.9, 21.7, 19.1, 13.6; specific rotation: [ α ] D 24 = 10.3 (c = 1.165 in CHCl3); HPLC: OJ-H, hexane, 1 mL/min, 254 nm, RT1 = 8.56 (major), RT2 = 11.75 (minor), ee%: 96.7.
Cis-1a*: 1H NMR (400 MHz, CDCl3) 3.80 (d, J = 2.2 Hz, 1H), 3.69 (d, J = 11.8, 1H), 3.45–3.31 (m, 1H), 3.40 (s, 3H), 3.12 (dt, J = 5.4, 2.7 Hz, 1H), 2.34 (t, J = 6.8 Hz, 2H), 2.23–2.11 (m, 2H), 2.08–1.88 (m, 1H), 1.72–1.34 (m, 9H), 0.94 (t, J = 7.2 Hz, 3H).
1b*: 1H NMR (400 MHz, CDCl3) δ: 7.38–7.23 (m, 5H), 4.59 (q, J = 12.0 Hz, 2H), 4.01 (d, J = 2.3 Hz, 1H), 3.81 (dd, J = 11.5, 2.9 Hz, 1H), 3.47 (dd, J = 11.5, 6.0 Hz, 1H), 3.28–3.21 (m, 1H), 2.31 (t, J = 6.9 Hz, 2H), 2.19–2.05 (m, 2H), 2.01–1.87 (m, 1H), 1.73–1.29 (m, 9H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 138.0, 137.3, 128.4, 127.73, 127.70, 121.8, 94.3, 79.5, 73.2, 70.7, 56.4, 55.4, 30.94, 30.89, 22.4, 22.2, 22.0, 21.7, 19.2, 13.6; specific rotation: [ α ] D 24 = −0.97 (c = 4.11 in CHCl3); HPLC: OJ-H, hexane/IPA = 99.0:1.0, 1 mL/min, 254 nm, RT1 = 6.29 (major), RT2 = 7.69 (minor), ee%: 95.8.
1c*: 1H NMR (400 MHz, CDCl3) δ: 3.99 (d, J = 2.3 Hz, 1H), 3.87 (dd, J = 12.9, 2.9 Hz, 1H), 3.64 (dd, J = 11.9, 4.7 Hz, 1H), 3.10 (dt, J = 5.0, 2.6 Hz, 1H), 2.29 (t, J = 6.9 Hz, 2H), 2.18–2.05 (m, 2H), 2.00–1.85 (m, 1H), 1.72–1.29 (m, 9H), 0.87 (t, J = 7.2 Hz, 3H), 0.86 (s, 9H), 0.04 (s, 6H); 13C NMR (100 MHz, CDCl3) δ: 137.5, 121.4, 94.0, 79.5, 63.5, 57.0, 56.3, 30.95, 30.93, 25.8, 22.4, 22.3, 22.0, 21.7, 19.2, 18.3, 13.6, −5.35, −5.41; specific rotation: [ α ] D 24 = 11 (c = 0.22 in CHCl3) HPLC: OD-3, hexane, 1 mL/min, 254nm, RT1 = 7.025 (major), RT2 = 15.177 (minor), ee%: 97.5.
1d*:1H NMR (400 MHz, CDCl3) δ: 3.77 (d, J = 2.1 Hz, 1H), 3.71 (dd, J = 11.4, 3.0 Hz, 1H), 3.41–3.36 (m, 4H), 3.23 (dt, J = 5.3, 2.9 Hz, 1H), 2.47 (t, J = 6.7 Hz, 2H), 2.35 (t, J = 6.8 Hz, 2H), 2.18–2.08 (m, 1H), 1.83 (q, J = 7.8 Hz, 2H), 1.45 (dq, J = 37.1, 7.0 Hz, 4H), 0.90 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 143.4, 126.3, 96.4, 75.8, 72.8, 59.2, 56.4, 53.0, 37.7, 30.8, 30.6, 22.1, 21.9, 19.3, 13.6; specific rotation: [ α ] D 28 = 1.302 (c = 3.07 in CHCl3); HPLC: OJ-H, hexane/IPA = 99.0:1.0, 1 mL/min, 254 nm, RT1 = 10.80 (major), RT2 = 15.93 (minor), ee%: 98.6.
1e*:1H NMR (400 MHz, CDCl3) δ: 3.96 (d, J = 2.3 Hz, 1H), 3.74 (dd, J = 11.5, 2.8 Hz, 1H), 3.42–3.33 (m, 4H), 3.04–2.99 (m, 1H), 2.32 (d, J = 6.9 Hz, 2H), 1.96–1.82 (m, 2H), 1.74–1.66 (m, 2H), 1.56–1.24 (m, 10H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 143.7, 127.0, 95.1, 80.7, 72.8, 59.1, 55.8, 55.1, 35.7, 32.5, 30.9, 26.2, 26.1, 25.2, 21.9, 19.3, 13.6; specific rotation: [ α ] D 28 = −11.428 (c = 2.45 in CHCl3); HPLC: OJ-H, hexane/IPA = 99:1, 1 mL/min, 254 nm, RT1 = 7.94 (major), RT2 = 11.30 (minor), ee%: 94.2.
1f:1H NMR (400 MHz, CDCl3) δ: 3.99–3.93 (m, 1H), 3.72 (ddd, J = 11.4, 3.0, 1.1 Hz, 1H), 3.41–3.35 (m, 4H), 3.22–3.17 (m, 1H), 3.13 (s, 1H), 2.20–2.18 (m, 2H), 2.01–1.96 (m, 1H), 1.74–1.49 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 141.1, 120.1, 82.6, 81.1, 72.9, 59.2, 55.9, 55.3, 30.3, 22.5, 22.0, 21.5.
1g: 1H NMR (400 MHz, CDCl3) δ: 7.44–7.29 (m, 5H), 4.09 (d, J = 2.3 Hz, 1H), 3.76 (dd, J = 11.4, 3.1 Hz, 1H), 3.45 (d, J = 5.9 Hz, 1H), 3.42 (s, 3H), 3.26 (dt, J = 5.2, 2.6 Hz, 1H), 2.30 (s, 2H), 2.08–2.04 (m, 1H), 1.84–1.55 (m, 5H); 13C NMR (100 MHz, CDCl3) δ: 139.5, 131.3, 128.3, 128.1, 123.5, 121.1, 93.3, 88.3, 72.9, 59.2, 56.3, 55.5, 30.5, 22.7, 22.2, 21.6.

2.5. Iron-Catalyzed Reaction Protocol

All the glassware equipment used in the reaction were kept in an oven for 24 h at 120 °C and then cooled under an argon atmosphere before use. The catalyst precursor, Fe(acac)3, was placed in a Schlenk flask held under a 6-grade argon-filled balloon, and 2 mL of dry THF was added. After stirring the mixture for 1 min at rt, the Schlenk flask was cooled to −50 °C. The Grignard reagent (3 equiv, MeMgBr, 3 M in THF) was added to the reaction mixture dropwise and then stirred for 15 min. The enyne oxirane reagent (0.1 mmol in 1 mL dry THF) was introduced into the reaction medium via a syringe pump over 30 min. The reaction was allowed to continue after the addition of the Grignard solution was complete. Once the reaction was deemed complete as determined through TLC, it was terminated with a saturated NH4Cl solution. The mixture was then extracted using Et2O, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was purified through silica gel column chromatography (resulting in a pale-yellow oil; hexane/EtOAc). Enantiomeric excess was analyzed through HPLC using suitable chiral columns, and the diastereomeric ratios were determined with the NMR technique using C6D6 as the solvent. HRMS analyses were carried out using a Q-TOF LC/MS system.
2a*:1H NMR (400 MHz, C6D6) δ: 5.74 (d, J = 8.0 Hz, 1H), 4.67–4.57 (m, 1H), 3.18–3.10 (m, 2H), 2.99 (s, 3H, minor), 2.98 (s, 3H, major), 2.37–2.22 (m, 3H), 2.22–2.10 (m, 2H), 2.00–1.81 (m, 2H), 1.65 (s, 3H, major), 1.64 (s, 3H, minor), 1.55–1.23 (m, 8H), 0.86 (t, J = 7.3 Hz, 3H, major), 0.85 (t, J = 7.3 Hz, 3H, minor); 13C NMR (100 MHz, C6D6) δ: 197.7, 139.6, 123.7, 104.8, 98.6, 76.6, 67.0, 58.2, 34.0, 31.9, 29.8, 28.7, 26.2, 25.8, 22.3, 19.2, 13.9; M.S. (E.I. m/z): 264.2 (37.31, M+), 219.1 (36), 201.2 (26.30), 177.2 (14.85), 163.1 (29.37), 159.1 (17.87), 145.1 (51.69), 133.1 (92.06), 131 (54), 119 (45), 105 (100), 91 (88), 77 (39), 57 (21); HRMS (m/z, (M+H)+): 265.2162 (calculated), 265.2140 (found); specific rotation: [ α ] D 24 = −38.23 (c = 1.21 CHCl3); HPLC: IC, hexane/IPA = 95:5, 1 mL/min, 254 nm, RT1 = 6.14 (major), RT2 = 6.55 (minor), ee%: 95.2.
2b*:1H NMR (400 MHz, C6D6) δ 7.18–7.02 (m, 5H), 5.76 (d, J = 8.1 Hz, 1H), 4.65 (td, J = 7.8, 4.1 Hz, 1H), 4.21 (s, 2H, minor), 4.20 (s, 2H, major), 3.32–3.21 (m, 2H), 2.30–2.21 (m, 3H), 2.14–2.06 (m, 1H), 1.96–1.82 (m, 2H), 1.63 (s, 3H, major), 1.62 (s, 3H, minor), 1.53–1.16 (m, 9H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, C6D6) δ:197.7, 139.6, 138.4, 128.2, 127.5, 123.7, 104.8, 98.6, 74.3, 72.9, 67.2, 34.0, 31.9, 29.8, 28.7, 26.1, 25.7, 22.3, 19.3, 13.9; HRMS (ESI) C23H33O2 (M+Na)+: 363.2295 (calculated), 363.2280 (measured); M.S. (E.I. m/z): 340.2 (6.42, M+), 219 (15), 203 (8), 189 (13), 175.1 (8), 161 (11), 149 (10), 133 (19), 119 (20), 105 (30), 91 (100), 77 (14); specific rotation: [ α ] D 24 = −28,10 (c = 1.21 CHCl3); HPLC: IC, hexane/IPA = 95:5, 1 mL/min, 254 nm, RT1 = 6.12 (minor), RT2 = 6.55 (major), ee%: 95.8.
2c*:1H NMR (400 MHz, C6D6) δ 5.76 (d, J = 8.1 Hz, 1H, major), 5.74 (d, J = 7.6 Hz, 1H, minor), 4.56–4.49 (m, 1H), 3.56–3.49 (m, 2H, minor), 3.52–3.42 (m, 2H, major), 2.40–2.21 (m, 4H), 1.98–1.83 (m, 2H), 1.65 (s, 3H, major), 1.63 (s, 3H, minor), 1.51–1.25 (m, 9H), 0.87 (t, J = 7.3 Hz, 3H), 0.85 (s, 9H), −0.06 (s, 6H); 13C NMR (100 MHz, C6D6) δ: 197.7 (major), 197.6 (minor), 139.6 (major), 139.5 (minor), 124.0 (minor), 123.9 (major), 105.0 (minor), 104.9 (major), 98.6 (major), 98.4 (minor), 68.8 (minor), 68.7 (major), 67.3, 34.1 (major), 34.0 (minor), 31.9 (major), 31.9 (minor), 29.8 (major), 29.7 (minor), 28.8, 26.2 (minor), 26.1 (major), 25.8 (major), 25.8 (minor), 25.7, 22.3 (major), 22.2 (minor), 19.4 (major), 19.2 (minor), 18.1, 13.9, −5.7, −5.6; MS(EI m/z): 364.4 (<5, M+), 291 (26), 203 (20), 157 (30), 145 (16), 131 (23), 177 (27), 105 (19), 101 (29), 91 (40), 77.0 (17), 75 (100), 59 (26); specific rotation: [ α ] D 24 = 32.84 (c = 0.28 in CHCl3).
2d*:1H NMR (400 MHz, C6D6) δ 5.83 (dt, J = 8.2, 2.4 Hz, 1H), 4.54 (td, J = 8.0, 4.1 Hz, 1H), 3.18–3.08 (m, 2H), 2.98 (s, 3H, minor), 2.96 (s, 3H, major), 2.38 (t, J = 7.2 Hz, 2H), 2.33–2.22 (m, 1H), 2.11 (dtd, J = 10.2, 7.7, 2.6 Hz, 1H), 1.91 (td, J = 7.2, 2.2 Hz, 2H), 1.64 (s, 3H, major), 1.63 (s, 3H, minor), 1.51–1.21 (m, 7H), 0.82 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, C6D6) δ: 195.4, 142.6, 119.9, 105.7, 103.8, 76.4, 69.3, 58.2, 34.2, 31.7, 30.0, 29.8, 25.0, 22.4, 18.8, 13.8; M.S. (E.I., m/z): 250 ( <5, M+), 205 (98), 187 (46), 145 (80), 131 (53), 117 (58), 105 (77), 91 (98), 79 (63), 57 (45), 45 (47); specific rotation: [ α ] D 28 = −46.51 (c = 0.301 in CHCl3); HPLC: AS-H, hexane, 1 mL/min, 254 nm, RT1 = 24.05 (major), RT2 = 24.54 (minor), ee%: 99.3.
2e:1H NMR (400 MHz, C6D6) δ 5.83 (d, J = 8.1 Hz, 1H), 4.61 (td, J = 8.1, 4.0 Hz, 1H), 3.28–3.06 (m, 2H), 2.97 (s, 3H, minor), 2.96 (s, 3H, major), 2.31–2.18 (m, 4H), 1.90 (tq, J = 14.8, 7.3 Hz, 2H), 1.64 (s, 3H, major), 1.62 (s, 3H, minor), 1.59–1.16 (m, 11H), 0.84 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, C6D6) δ: 199.8, 142.7, 124.6, 108.2, 99.1, 76.7, 67.5, 58.2, 34.0, 33.0, 31.4, 30.2, 29.8, 29.7, 29.2, 22.4, 18.9, 13.8; M.S. (EI m/z): 278.3 (<5, M+), 147 (6), 133 (6), 117 (12), 105 (9), 91 (31), 79 (14), 67 (9), 55 (21), 45 (100); HRMS (m/z, (M+H)+: 279.2319 (calculated), 279.2327 (found); specific rotation: [ α ] D 19 = −47.61 (c = 2.16 CHCl3); HPLC: OD-3, hexane/IPA: 99.5:0.5, 1 mL/min, 254 nm, RT1 = 11.60 (major), RT2 = 12.73 (minor), ee%: 91.6.
2f: 1H NMR (400 MHz, C6D6) δ: 5.72 (d, J = 8.1 Hz, 1H), 5.10–5.03 (m, 1H), 4.64–4.56 (m, 1H), 3.15–3.06 (m, 2H), 2.96 (s, 3H), 2.33–2.17 (m, 4H), 2.13–2.01 (m, 1H), 1.51 (d, J = 7.0 Hz, 3H), 1.47–1.39 (m, 2H), 1.36–1.22 (m, 2H); 13C NMR (100 MHz, C6D6) δ: 201.3, 138.6, 124.4, 104.9, 85.0, 76.5, 66.9, 58.2, 31.4, 28.5, 25.8, 25.6, 14.6; MS (EI m/z): 208 (9), 175 (5), 163 (100), 145 (36), 121 (32), 117 (31), 105 (29), 91 (62), 79 (33) 77 (34), 55 (38).

3. Results and Discussion

The addition of the enyne oxirane 1a to a mixture of Fe(acac)3 (20%) and MeMgBr (3 equiv) in LiAlH4-dried THF via a syringe pump for over 30 min at −50 °C and further stirring for 1 h at the same temperature provided the desired product 2a in a high yield and high dr (Scheme 6). When no iron compound was present, the reaction predominantly yielded an SN2 product, with no observed formation of 2a. The configuration of the alkenyl moiety of the product was determined to be (E) through NOE studies. Using FeCl2 as the catalyst and MeMgCl as the Grignard reagent resulted in variable outcomes (see the Supplementary File). On the other hand, reactions conducted in Et2O, hexane, toluene, and DME solvents consistently yielded complex mixtures.
Encouraged by this result, we used this method to obtain enantiopure vinylallene products. This synthesis was made possible by the transfer of chirality from the center to the axial position during the reaction cycle, using enantiopure enyne oxiranes. In pursuit of this goal, we explored potential routes for direct asymmetric epoxidation methods to produce enantiopure enyne oxiranes. Unfortunately, the application of either Shi’s asymmetric epoxidation method [80,81,82] to various dienyne reagents with different functionalities on the alkenyl moiety (Scheme 7) or Sharpless’ method [83,84], a valuable technique for the asymmetric epoxidation of allylic alcohols, to alkynyldienol and bromodienol reagents (Scheme 8), all proved unsuccessful in yielding epoxide products with reasonable yields and ees.
After numerous unsuccessful attempts at direct asymmetric epoxidation, our focus shifted to indirect methods. Utilizing the Sharpless asymmetric dihydroxylation method [77], we achieved the dihydroxylation of an endocyclic diene molecule with a high ee level (Scheme 4). The substantial steric congestion on the endocyclic alkenyl moiety allowed for selective hydroxylations at the α and β positions, in contrast to the previously reported procedures typically applied to conjugated diene esters [85,86]. Subsequently, the α-hydroxyl group was selectively sulfonated, the ester functionality was modified, and finally, an intramolecular substitution process was carried out, resulting in the desired enantiopure substrate with a cis-configured oxirane moiety (Scheme 5).
It is noteworthy that the standard reaction with the cis-configured oxirane 1a* substrate resulted in the full recovery of cis-1a*. However, upon raising the reaction temperature to −20 °C, a complex mixture emerged, and the formation of the desired vinylallene product became completely imperceptible. This outcome strongly indicates that this method is exclusively effective for trans-configured enyne oxiranes. The likely explanation for this result can be attributed to steric congestion, which hinders the necessary conformers from participating in the reaction (Scheme 9).
In our pursuit, we sought a suitable method for synthesizing 1a* in the trans-configuration. Indeed, we were fortunate to observe that the Sharpless’ group achieved a successful conversion of diols to epoxides while maintaining the original configuration [80]. This method hinges on the substitution of one hydroxyl group with an inverted configuration. The process involves converting the diol into its cyclic orthoacetate form, followed by the formation of an acetate chlorohydrin via the acetoxonium ion (Scheme 4). Ultimately, through base-mediated intramolecular substitution, we were able to obtain the desired trans-epoxides with a high degree of enantiomeric excess. This method proved instrumental in synthesizing enantiomerically pure enyne oxiranes featuring five- to seven-membered ring structures.
Table 1 presents the outcomes of reactions involving various racemic and enantiopure endocyclic enyne oxiranes with MeMgBr. Typically, these reactions proceeded in an anti-mode and demonstrated a remarkable degree of center-to-axial chirality transfer. Notably, we were able to synthesize the six-membered exo-cyclic vinylallene 2a* with a commendable yield and a remarkably high ee (95.2%) This achievement was realized through the reaction of enantiopure enyne oxirane 1a* with MeMgBr (entry 1).
The Lowe–Brewster rule was employed to correlate the sign of optical rotation with the absolute configuration of allenes [87,88,89]. This correlation is supported by numerous reported allene assemblies [37,53,90,91], including those found in natural compounds as illustrated in Figure 1 [72,73,92,93,94], as well as enantiopure allenols with a chirality center [95,96].
Modifying the pendant oxygen functionality to a benzyloxy group had no discernible impact on the reaction’s outcome (entry 2). However, when a silyl protection strategy was employed, a significant decline in stereoselectivity was observed. As a consequence, the product 2c* was primarily formed through syn-mode addition, with a notably low dr (entry 3). It is likely that the diminished selectivity is attributable to steric crowding induced by the substantial size of the silyl group.
Satisfactory results can also be achieved when working with substrates featuring five- or seven-membered ring structures, although with slightly lower diastereomeric ratios (drs). These substrates led to the formation of the corresponding vinylallene products, 2d* and 2e*, with diastereomeric ratios of 90:10 and 92:8, respectively (entries 4 and 5).
Substrate 1f, having a terminal alkynyl group, was also found to be amenable to the method. Despite the presence of an acidic hydrogen atom, it underwent conversion into the corresponding vinylallene exclusively in a single diastereomeric form, as demonstrated in entry 6. In contrast, the use of a reagent with a phenyl-substituted alkynyl group resulted in the formation of complex mixtures (entry 7).
The method only applies to methyl Grignard reagents. Using other Grignard reagents, such as EtMgBr, EtMgCl, BuMgBr, PhMgBr, or BnMgCl, resulted in intricate mixtures. Only with EtMgBr and PhMgBr could the formation of corresponding vinylallenes be detected, yielding in the range of 30–40% (see the Supplementary File). The observed negative results with alkylMgBr reagents are likely due to competing β-hydride elimination from an initially formed organoiron intermediary. However, it should be noted that the methyl groups are the most prevalent alkyl substituents in natural compounds, and most small pharmaceutical products contain at least one methyl group [92,93]. Consequently, C-methylation has gained popularity as a prevalent structural modification frequently employed in medicinal chemistry [97,98,99,100,101].
While the precise reaction mechanism remains unclear, the exclusive formation of (E)-configured vinylallenes underscores the importance of the reacting compound 1 adopting the TE conformation before engaging in the reaction (Scheme 10). Otherwise, it would yield (Z)-configured vinylallenes via the TZ conformer.
A conformational analysis conducted on 1f validated that the 1f-TE conformer occupies the lowest energy state, as illustrated in Figure 2. In contrast, the 1f-TZ conformer, which would lead to the formation of the (Z)-configured 2f structure upon reaction, exhibits an energy level 20.6 kJ mol−1 higher than the 1f-TE conformer. This significant energy disparity aligns with the diastereoselectivity observed in the exocyclic alkenyl moiety’s formation, implying that the TZ conformer imposes greater steric demands on the reaction.
Based on our prior studies [10], our hypothesis suggests that the reaction involves a π-allyl iron intermediate identified as A and formed in an anti-mode (Scheme 10). This intermediate originates from compound 1, assumed to be in the TE conformation. For an effective p orbital overlap across the π-allyl ligand carbons, compound 1 should ideally assume either the TZ or TE conformation. However, the TZ conformation is less likely due to its higher energy requirement. Additionally, the inherent steric congestion in TZ impedes the penetration of organoiron clusters, thereby favoring the occurrence of the oxidative addition step in the TE conformation.
The subsequent transfer of the iron atom to the distal alkynyl carbon leads to the formation of a σ-allenyl iron complex, denoted as B, followed by reductive elimination. The introduction of acid at the conclusion of the reaction is expected to yield the desired product 2.
Notably, the nucleophilic [Fe]Me species involved in the reaction is believed to exist as large clusters [102,103], making the process particularly sensitive to steric constraints. On the other hand, the inherently more congested nature of endocyclic substrates has enhanced the method’s stereoselectivity concerning the configurations of the alkenyl and allenyl moieties, as compared to its acyclic counterparts [10].

4. Conclusions

Enantiomerically pure endocyclic enyne oxiranes were synthesized and reacted with MeMgBr in the presence of Fe(acac)3. These reactions followed a 1,5-substitution (SN2″) mechanism, exhibiting a remarkable center-to-axial chirality transfer. As a result, they exclusively produced (E)-configured exocyclic methyl-substituted vinylallenes with a high degree of enantiomeric excess and diastereomeric ratio. The largely anti-mode progression of the reactions and the conformational bias of the substrates within the reaction cycle appear to be the main reasons for the high stereoselectivity observed. The method appears to be sensitive to steric factors in both the substrate and Grignard reagent, which significantly influence the outcome.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/chemistry5040173/s1. The iron-catalyzed protocol, optimization studies, copies of NMR spectra, HPLC data, and computational details.

Author Contributions

Conceptualization, M.K. and L.A.; Methodology, M.K., C.O., S.K. and L.A.; Investigation, M.K., C.O. and S.K.; Software, S.K.; Resources, L.A.; Writing—original draft preparation, M.K., C.O. and L.A.; Writing—review and editing, L.A.; Visualization, M.K., C.O., S.K. and L.A.; Supervision, L.A.; Project administration, L.A.; Funding acquisition, L.A. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Scientific and Technological Research Council of Turkey (117Z299) and IZTECH Scientific Research Projects Coordinatorship (2017İYTE85).

Data Availability Statement

The data presented in this study are available upon request from the corresponding author and co-authors.

Acknowledgments

NMR data were acquired by the NMR center of IZTECH. HRMS analyses were performed by DAYTAM of Atatürk University. The numerical calculations reported in this paper were fully/partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Qi, L.Y.; Ma, E.L.; Jia, F.; Li, Z.P. Iron-catalyzed allylic substitution reactions of allylic ethers with Grignard reagents. Tetrahedron Lett. 2016, 57, 2211–2214. [Google Scholar] [CrossRef]
  2. Nakamura, M.; Matsuo, K.; Inoue, T.; Nakamura, E. Iron-catalyzed regio- and stereoselective ring opening of [2.2.1]- and [3.2.1]oxabicyclic alkenes with a Grignard reagent. Org. Lett. 2003, 5, 1373–1375. [Google Scholar] [CrossRef] [PubMed]
  3. Kessler, S.N.; Hundemer, F.; Backvall, J.E. A Synthesis of substituted α-allenols via iron-catalyzed cross-coupling of propargyl carboxylates with Grignard reagents. ACS Catal. 2016, 6, 7448–7451. [Google Scholar] [CrossRef] [PubMed]
  4. Kessler, S.N.; Backvall, J.E. Iron-catalyzed cross-coupling of propargyl carboxylates and Grignard reagents: Synthesis of substituted allenes. Angew. Chem. Int. Ed. 2016, 55, 3734–3738. [Google Scholar] [CrossRef] [PubMed]
  5. Domingo-Legarda, P.; Soler-Yanes, R.; Quiros-Lopez, M.T.; Bunuel, E.; Cardenas, D.J. Iron-catalyzed coupling of propargyl bromides and alkyl Grignard reagents. Eur. J. Org. Chem. 2018, 2018, 4900–4904. [Google Scholar] [CrossRef]
  6. Sun, C.L.; Furstner, A. Formal ring-opening/cross-coupling reactions of 2-pyrones: Iron-catalyzed entry into stereodefined dienyl carboxylates. Angew. Chem. Int. Ed. 2013, 52, 13071–13075. [Google Scholar] [CrossRef]
  7. Hata, T.; Bannai, R.; Otsuki, M.; Urabe, H. Iron-catalyzed regio- and stereoselective substitution of γ,δ-epoxy-α,β-unsaturated Esters and Amides with Grignard Reagents. Org. Lett. 2010, 12, 1012–1014. [Google Scholar] [CrossRef]
  8. Furstner, A.; Mendez, M. Iron-catalyzed cross-coupling reactions: Efficient synthesis of 2,3-allenol derivatives. Angew. Chem. Int. Ed. 2003, 42, 5355–5357. [Google Scholar] [CrossRef]
  9. Zhang, X.B.; Qiu, Y.A.; Fu, C.L.; Ma, S.M. Highly selective 4-alkynoic acids synthesis via iron-mediated complete inversion of stereogenic carbon center. Org. Chem. Front. 2014, 1, 247–252. [Google Scholar] [CrossRef]
  10. Taç, D.; Aytaç, I.A.; Karatavuk, A.O.; Kuş, M.; Ziyanak, F.; Artok, L. Iron-promoted 1,5-substitution (SN2″) reactions of enyne acetates and oxiranes with Grignard reagents. Asian J. Org. Chem. 2017, 6, 1415–1420. [Google Scholar] [CrossRef]
  11. Sugano, G.; Kawada, K.; Shigeta, M.; Hata, T.; Urabe, H. Iron-catalyzed δ-selective conjugate addition of methyl and cyclopropyl Grignard reagents to α,β,γ,δ-unsaturated esters and amides. Tetrahedron Lett. 2019, 60, 885–890. [Google Scholar] [CrossRef]
  12. Sherry, B.; Furstner, D. Iron-catalyzed addition of Grignard reagents to activated vinyl cyclopropanes. Chem. Commun. 2009, 7116–7118. [Google Scholar] [CrossRef]
  13. Okada, S.; Arayama, K.; Murayama, R.; Ishizuka, T.; Hara, K.; Hirone, N.; Hata, T.; Urabe, H. Iron-catalyst-switched selective conjugate addition of Grignard reagents: α,β,γ,δ-Unsaturated amides as versatile templates for asymmetric three-component coupling processes. Angew. Chem. Int. Ed. 2008, 47, 6860–6864. [Google Scholar] [CrossRef]
  14. Lu, Z.; Chai, G.B.; Ma, S.M. Iron-catalyzed highly regio- and stereoselective conjugate addition of 2,3-allenoates with Grignard reagents. J. Am. Chem. Soc. 2007, 129, 14546–14547. [Google Scholar] [CrossRef]
  15. Hata, T.; Iwata, S.; Seto, S.; Urabe, H. Iron-catalyzed synthesis of allenes from 2-alken-4-ynoates and Grignard reagents. Adv. Synth. Catal. 2012, 354, 1885–1889. [Google Scholar] [CrossRef]
  16. Fukuhara, K.; Urabe, H. Iron-catalyzed 1,6-addition of aryl Grignard reagents to 2,4-dienoates and dienamides. Tetrahedron Lett. 2005, 46, 603–606. [Google Scholar] [CrossRef]
  17. Hata, T.; Nakada, T.; Oh, Y.T.; Hirone, N.; Urabe, H. Iron-catalyzed regio- and stereoselective conjugate addition of aryl-Grignard reagents to α,β,γ,δ-unsaturated sulfones and its synthetic application. Adv. Synth. Catal. 2013, 355, 1736–1740. [Google Scholar] [CrossRef]
  18. Tindall, D.J.; Krause, H.; Furstner, A. Iron-catalyzed cross-coupling of 1-alkynylcyclopropyl tosylates and related substrates. Adv. Synth. Catal. 2016, 358, 2398–2403. [Google Scholar] [CrossRef]
  19. Huang, L.; Gu, Y.T.; Furstner, A. Iron-catalyzed reactions of 2-pyridone derivatives: 1,6-addition and formal ring opening/cross coupling. Chem. Asian J. 2019, 14, 4017–4023. [Google Scholar] [CrossRef]
  20. Chai, G.; Zeng, B.R.; Fu, C.L.; Ma, S.M. Iron-catalyzed diastereoselective synthesis of α-(methoxycarbonyl)allylsilanes. Eur. J. Org. Chem. 2013, 2013, 148–154. [Google Scholar] [CrossRef]
  21. Ziyanak, F.; Kus, M.; Alkan-Karadeniz, L.; Artok, L. Palladium-catalyzed reactions of conjugated enyne oxiranes with organoborons: A diastereoselective method of the synthesis of 2,4,5-trienol derivatives. Tetrahedron 2018, 74, 3652–3662. [Google Scholar] [CrossRef]
  22. Zhao, J.; Yu, Y.; Ma, S. Ligand effects on the Pd-catalyzed cross-coupling reaction of 3-iodoalk-2-enoates with propargyl/1,2-allenylic metallic species: An efficient regiodivergent synthesis of 2,4,5-trienoates. Chem. Eur. J. 2010, 16, 74–80. [Google Scholar] [CrossRef]
  23. Yang, M.; Yokokawa, Y.; Ohmiya, N.H.; Sawamura, M. Synthesis of conjugated allenes through copper-catalyzed γ-selective and stereospecific coupling between propargylic phosphates and aryl- or alkenylboronates. Org. Lett. 2012, 14, 816–819. [Google Scholar] [CrossRef]
  24. Wei, X.F.; Wakaki, T.; Itoh, T.; Li, H.L.; Yoshimura, T.; Miyazaki, A.; Oisaki, K.; Hatanaka, M.; Shimizu, Y.; Kanai, M. Catalytic regio- and enantioselective proton migration from skipped Enynes to allenes. Chem 2019, 5, 585–599. [Google Scholar] [CrossRef]
  25. Ucuncu, M.; Karakus, E.; Kus, M.; Akpinar, G.E.O.; Aksin-Artok, Ö.; Krause, N.; Karaca, S.; Elmacı, N.; Artok, L. Rhodium- and palladium-catalyzed 1,5-substitution reactions of 2-en-4-yne acetates and carbonates with organoboronic acids. J. Org. Chem. 2011, 76, 5959–5971. [Google Scholar] [CrossRef]
  26. Tolstikov, G.A.; Romanova, T.Y.; Kuchin, A.V. A new method for the synthesis of vinyl-and diallenes assisted by organoaluminium compounds. J. Organomet. Chem. 1985, 285, 71–82. [Google Scholar] [CrossRef]
  27. Taç, D.; Artok, L. Palladium-catalyzed coupling of 2-en-4-yne carbonates with terminal alkynes. Tetrahedron Lett. 2018, 59, 895–898. [Google Scholar] [CrossRef]
  28. Sim, S.H.; Lee, S.I.; Seo, J.; Chung, Y.K. Mercury (II) triflate-catalyzed cycloisomerization of allenynes to allenenes. J. Org. Chem. 2007, 72, 9818–9821. [Google Scholar] [CrossRef]
  29. Purpura, M.; Krause, N. Regio- and stereoselective synthesis of vinylallenes by 1,5-(SN″)-substitution of enyne acetates and oxiranes with organocuprates. Eur. J. Org. Chem. 1999, 1999, 267–275. [Google Scholar] [CrossRef]
  30. Murakami, M.; Kadowaki, S.; Matsuda, T. Molybdenum-catalyzed ring-closing metathesis of allenynes. Org. Lett. 2005, 7, 3953–3956. [Google Scholar] [CrossRef] [PubMed]
  31. Molander, G.A.; Sommers, E.M.; Baker, S.R. Palladium (0)-catalyzed synthesis of chiral ene-allenes using alkenyl trifluoroborates. J. Org. Chem. 2006, 71, 1563–1568. [Google Scholar] [CrossRef] [PubMed]
  32. Lee, S.I.; Sim, S.H.; Kim, S.M.; Kim, K.; Chung, Y.K. GaCl3-catalyzed allenyne cycloisomerizations to allenenes. J. Org. Chem. 2006, 71, 7120–7123. [Google Scholar] [CrossRef]
  33. Kuş, M.; Artok, L.; Aygün, M. Palladium-catalyzed alkoxycarbonylation of conjugated enyne oxiranes: A diastereoselective method for the synthesis of 7-hydroxy-2,3,5-trienoates. J. Org. Chem. 2015, 80, 5494–5506. [Google Scholar] [CrossRef]
  34. Krause, N.; Purpura, M. Remote stereocontrol in organocopper chemistry: Highly enantioselective synthesis of vinylallenes by 1, 5-substitution of enyne acetates. Angew. Chem. Int. Ed Engl. 2000, 39, 4355–4356. [Google Scholar] [CrossRef]
  35. Koop, U.; Handke, G.; Krause, N. Synthesis of vinylallenes by conjugate 1,6-, 1,8-, 1,10- and 1,12-addition reactions of organocuprates with acetylenic Michael acceptors and their use as dienes in intermolecular Diels-Alder reactions. Liebigs Annalen. 1996, 1996, 1487–1499. [Google Scholar]
  36. Keinan, E.; Bosch, E. Palladium-catalyzed propargylic vs. allylic alkylation. J. Org. Chem. 1986, 51, 4006–4016. [Google Scholar] [CrossRef]
  37. Karagöz, E.Ş.; Kuş, M.; Akpınar, G.E.; Artok, L. Regio-and stereoselective synthesis of 2,3,5-trienoates by palladium-catalyzed alkoxycarbonylation of conjugated enyne carbonates. J. Org. Chem. 2014, 79, 9222–9230. [Google Scholar] [CrossRef]
  38. Jiang, H.; Liu, X.; Zhou, L. First synthesis of 1-chlorovinyl allenes via palladium-catalyzed allenylation of alkynoates with propargyl alcohols. Chem. Eur. J. 2008, 14, 11305–11309. [Google Scholar] [CrossRef]
  39. Dabrowski, J.A.; Haeffner, F.; Hoveyda, A.H. Combining NHC–Cu and Brønsted base catalysis: Enantioselective allylic substitution/conjugate additions with alkynylaluminum reagents and stereospecific isomerization of the products to trisubstituted allenes. Angew. Chem. Int. Ed. 2013, 52, 7694–7699. [Google Scholar] [CrossRef]
  40. Cadran, N.; Cariou, K.; Herve, G.; Aubert, C.; Fensterbank, L.; Malacria, M.; Marco-Contelles, J. PtCl2-catalyzed cycloisomerizations of allenynes. J. Am. Chem. Soc. 2004, 126, 3408–3409. [Google Scholar] [CrossRef] [PubMed]
  41. Ben-Valid, S.; Quntar, A.A.A.; Srebnik, M. Novel vinyl phosphonates and vinyl boronates by halogenation, allylation, and propargylation of α-boryl-and α-phosphonozirconacyclopentenes. J. Org. Chem. 2005, 70, 3554–3559. [Google Scholar] [CrossRef]
  42. Ando, M.; Sasaki, M.; Miyashita, I.; Takeda, K. Formation of 2-cyano-2-siloxyvinylallenes via cyanide-induced brorok earrangement in γ-bromo-α,β,γ,δ-unsaturated acylsilanes. J. Org. Chem. 2015, 80, 247–255. [Google Scholar] [CrossRef]
  43. Akpinar, G.E.; Kus, M.; Ucuncu, M.; Karakuş, E.; Artok, L. Palladium-Catalyzed Alkoxycarbonylation of (Z)-2-En-4-yn Carbonates Leading to 2,3,5-Trienoates. Org. Lett. 2011, 13, 748–751. [Google Scholar] [CrossRef]
  44. Yu, S.H.; Gong, T.J.; Fu, Y. Three-component borylallenylation of alkynes: Access to densely boryl-substituted ene-allenes. Org. Lett. 2020, 22, 2941–2945. [Google Scholar] [CrossRef]
  45. Huang, Y.; Torker, M.S.; Li, X.H.; del Pozo, J.; Hoveyda, A.H. Racemic vinylallenes in catalytic enantioselective multicomponent processes: Rapid generation of complexity through 1,6-conjugate dditaions. Angew. Chem. Int. Ed. 2019, 58, 2685–2691. [Google Scholar] [CrossRef]
  46. Wang, K.K.; Andemichael, Y.W.; Dhumrongvaraporn, S. Regioselective synthesis of highly substituted arylsilanes by the reaction of the trimethylsilyl-substituted vinylallenones with enamines. Tetrahedron Lett. 1989, 30, 1311–1314. [Google Scholar] [CrossRef]
  47. Wu, K.M.; Midland, M.M.; Okamura, W.H. Structural effects on [1,5]-sigmatropic hydrogen shifts of vinylallenes. J. Org. Chem. 1990, 55, 4381–4392. [Google Scholar] [CrossRef]
  48. Murakami, M.; Amii, H.; Itami, K.; Ito, Y. A Remarkable effect of silyl substitution on electrocyclization of vinylallenes. Angew. Chem. Int. Ed. Engl. 1995, 34, 1476–1477. [Google Scholar] [CrossRef]
  49. López, S.; Rodríguez, J.; Rey, J.G.; de Lera, A.R. Structural effects affecting the thermal electrocyclic ring closure of vinylallenes to alkylidenecyclobutenes. J. Am. Chem. Soc. 1996, 118, 1881–1891. [Google Scholar] [CrossRef]
  50. Souto, J.A.; Pérez, M.; Silva López, C.; Álvarez, R.; Torrado, A.; de Lera, A.R. Competing thermal electrocyclic ring-closure reactions of (2Z)-hexa-2,4,5-trienals and their Schiff bases. Structural, kinetic, and computational studies. J. Org. Chem. 2010, 75, 4453–4462. [Google Scholar] [CrossRef] [PubMed]
  51. Spino, C.; Thibault, C.; Gingras, S. Stereoselective construction of tetrasubstituted exocyclic alkenes from the [4 + 2]-cycloaddition of vinylallenes. J. Org. Chem. 1998, 63, 5283–5287. [Google Scholar] [CrossRef]
  52. Ruiz, J.M.; Regas, D.; Afonso, M.M.; Palenzuela, J.A. Study of an unexpected rearrangement of the α-phenyl pyrane derivatives prepared via hetero-Diels–Alder reaction of acyclic vinyl allenes and aldehydes. J. Org. Chem. 2008, 73, 7246–7254. [Google Scholar] [CrossRef] [PubMed]
  53. Lo, V.K.Y.; Chan, Y.M.; Zhou, D.; Toy, P.H.; Che, C.M. Highly enantioselective synthesis using prolinol as a chiral auxiliary: Silver-mediated synthesis of axially chiral vinylallenes and subsequent (hetero)-Diels–Alder reactions. Org. Lett. 2019, 21, 7717–7721. [Google Scholar] [CrossRef] [PubMed]
  54. Murakami, M.; Itami, K.; Ito, Y. Catalytic asymmetric [4 + 1] cycloaddition of vinylallenes with carbon monoxide: Reversal of the induced chirality by the choice of metal. J. Am. Chem. Soc. 1999, 121, 4130–4135. [Google Scholar] [CrossRef]
  55. Murakami, M.; Itami, K.; Ito, Y. Synthesis of (vinylallene) rhodium (III) complex of planar structure: Perfect π→ σ conversion of 1,3-diene system. J. Am. Chem. Soc. 1996, 118, 11672–11673. [Google Scholar] [CrossRef]
  56. Mazumder, S.; Crandell, D.W.; Lord, R.L.; Baik, M.H. Switching the enantioselectivity in catalytic [4 + 1] cycloadditions by changing the metal center: Principles of inverting the stereochemical preference of an asymmetric catalysis revealed by DFT calculations. J. Am. Chem. Soc. 2014, 136, 9414–9423. [Google Scholar] [CrossRef]
  57. Bertrand, M.; Grimaldi, J.; Waegell, B. Diels–Alder cycloadditions of vinyl-and propenyl-allene to methyl vinyl ketone. Chem. Commun. 1968, 1141–1142. [Google Scholar] [CrossRef]
  58. Reich, J.; Eisenhart, E.K.; Whipple, W.L.; Kelly, M.J. Stereochemistry of vinylallene cycloadditions. J. Am. Chem. Soc. 1988, 110, 6432–6442. [Google Scholar] [CrossRef]
  59. Murakami, M.; Ubukata, M.; Itami, K.; Ito, Y. Rhodium-catalyzed intermolecular [4 + 2] cycloaddition of unactivated substrates. Angew. Chem. Int. Ed. 1998, 37, 2248–2250. [Google Scholar] [CrossRef]
  60. Murakami, M.; Ashida, S.; Matsuda, T. Dramatic effects of boryl substituents on thermal ring-closing reaction of vinylallenes. J. Am. Chem. Soc. 2004, 126, 10838–10839. [Google Scholar] [CrossRef]
  61. Bekele, T.; Christian, C.F.; Lipton, M.A.; Singleton, D.A. “Concerted” transition state, stepwise mechanism. Dynamics effects in C2-C6 enyne allene cyclizations. J. Am. Chem. Soc. 2005, 127, 9216–9223. [Google Scholar] [CrossRef] [PubMed]
  62. Bhunia, S.; Liu, R.S. Gold-catalyzed 1,3-addition of a sp3-hybridized C−H bond to alkenylcarbenoid intermediate. J. Am. Chem. Soc. 2008, 130, 16488–16489. [Google Scholar] [CrossRef] [PubMed]
  63. Lee, J.H.; Toste, F.D. Gold (I)-catalyzed synthesis of functionalized cyclopentadienes. Angew. Chem. Int. Ed. 2007, 46, 912–914. [Google Scholar] [CrossRef] [PubMed]
  64. Funami, H.; Kusama, H.; Iwasawa, N. Preparation of substituted cyclopentadienes through platinum (II)-catalyzed cyclization of 1,2,4-trienes. Angew. Chem. Int. Ed. 2007, 46, 909–911. [Google Scholar] [CrossRef]
  65. Delas, C.; Urabe, H.; Sato, F. Remarkably facile, unidirectional isomerization of titanated vinylallenes to cyclobutenyltitanium compounds. A practical construction of a cyclobutene framework. J. Am. Chem. Soc. 2001, 123, 7937–7938. [Google Scholar] [CrossRef]
  66. Leyes, G.A.; Okamura, W.H. Studies on vitamin D (calciferol) and its analogs. 23. Effect of 3-methyl substituents on the thermal [1,5]-and [1,7]-sigmatropic hydrogen shifts of vinylallenes. J. Am. Chem. Soc. 1982, 104, 6099–6105. [Google Scholar] [CrossRef]
  67. Posner, G.H.; Li, Z.G.; White, M.C.; Vinader, V.; Takeuchi, K.; Guggino, S.E.; Dolan, P.; Kensler, T.W. lα,25-Dihydroxyvitamin D3 analogs featuring aromatic and heteroaromatic rings: Design, synthesis, and preliminary biological testing. J. Med. Chem. 1995, 38, 4529–4537. [Google Scholar] [CrossRef]
  68. Deutsch, E.A.; Snider, B.B. Synthesis of the hexahydronaphthalene moiety of (±)-compactin (ML-236B). J. Org. Chem. 1982, 47, 2682–2684. [Google Scholar] [CrossRef]
  69. Krause, N. Synthesis of (±)-sterpurene and hydroxylated derivatives by 1,6-addition of organocuprates to acceptor-substituted enynes. Liebigs Ann. Chem. 1993, 1993, 521–525. [Google Scholar] [CrossRef]
  70. Schreiber, S.L.; Kiessling, L.L. Synthesis of the bicyclic core of the esperamicin/calichemicin class of antitumor agents. J. Am. Chem. Soc. 1988, 110, 631–633. [Google Scholar] [CrossRef]
  71. Hoffmann-Roder, A.; Krause, N. Synthesis and properties of allenic natural products and pharmaceuticals. Angew. Chem. Int. Ed. 2004, 43, 1196–1216. [Google Scholar] [CrossRef]
  72. Suzuki, T.; Watanabe, S.; Kobayashi, S.; Tanino, K. Enantioselective total synthesis of (+)-iso-A82775C, a proposed biosynthetic precursor of chloropupukeananin. Org. Lett. 2017, 19, 922–925. [Google Scholar] [CrossRef]
  73. Pan, Y.Y.; Liu, L.; Guan, F.F.; Li, E.W.; Jin, J.; Li, J.Y.; Che, Y.S.; Liu, G. Characterization of a prenyltransferase for iso-A82775C biosynthesis and generation of new congeners of chloropestolides. ACS Chem. Biol. 2018, 13, 703–711. [Google Scholar] [CrossRef]
  74. Lian, J.J.; Odedra, A.; Wu, C.J.; Liu, R.S. Ruthenium-catalyzed regioselective 1,3-methylene transfer by cleavage of two adjacent σ-carbon-carbon bonds: An easy and selective synthesis of highly subsituted benzenes. J. Am. Chem. Soc. 2005, 127, 4186–4187. [Google Scholar] [CrossRef]
  75. Sonogashira, K.; Tohda, Y.; Hagihara, N. A convenient synthesis of acetylenes: Catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes, and bromopyridines. Tetrahedron Lett. 1975, 16, 4467–4470. [Google Scholar] [CrossRef]
  76. Wadsworth, W.S.; Emmons, W.D. The utility of phosphonate carbanions in olefin synthesis. J. Am. Chem. Soc. 1961, 83, 1733–1738. [Google Scholar] [CrossRef]
  77. Sharpless, K.B.; Amberg, W.; Bennani, Y.L.; Crispıno, G.A.; Hartung, J.; Jeong, K.S.; Kwong, H.L.; Morıkawa, K.; Wang, Z.M.; Xu, D.; et al. The osmium-catalyzed asymmetric dihydroxylation: A new ligand class and a process improvement. J. Org. Chem. 1992, 57, 2768–2771. [Google Scholar] [CrossRef]
  78. Kolb, H.C.; Sharpless, K.B. A simplified procedure for the stereospecific transformation of 1,2-diols into epoxides. Tetrahedron 1992, 48, 10515–10530. [Google Scholar] [CrossRef]
  79. Shemet, A.; Sarlah, D.; Carreira, E.M. Stereochemical studies of opening of chloro vinyl epoxides: Cyclic chloronium ions as intermediates. Org. Lett. 2015, 17, 1878–1881. [Google Scholar] [CrossRef]
  80. Wu, X.Y.; She, X.G.; Shi, Y.A. Highly enantioselective epoxidation of α,β-unsaturated esters by chiral dioxirane. J. Am. Chem. Soc. 2002, 124, 8792–8793. [Google Scholar] [CrossRef]
  81. Wang, Z.X.; Shi, Y.A. pH study on the chiral ketone catalyzed asymmetric epoxidation of hydroxyalkenes. J. Org. Chem. 1998, 63, 3099–3104. [Google Scholar] [CrossRef]
  82. Frohn, M.; Shi, Y. Chiral ketone-catalyzed asymmetric epoxidation of olefins. Synthesis 2000, 2000, 1979–2000. [Google Scholar] [CrossRef]
  83. Katsuki, T.; Sharpless, K.B. The first practical method for asymmetric epoxidation. J. Am. Chem. Soc. 1980, 102, 5974–5976. [Google Scholar] [CrossRef]
  84. Hanson, R.M.; Sharpless, K.B. Procedure for the catalytic asymmetric epoxidation of allylic alcohols in the presence of molecular sieves. J. Org. Chem. 1986, 51, 1922–1925. [Google Scholar] [CrossRef]
  85. Becket, H.; Soler, M.A.; Sharpless, K.B. Selective Asymmetric Dihydroxylation of Polyenes. Tetrahedron 1995, 51, 1345–1376. [Google Scholar] [CrossRef]
  86. Matsushima, Y.; Kino, J. A versatile route to 2,4,6-trideoxy-4-aminohexoses: Stereoselective syntheses of D-vicenisamine and its epimers via iodocyclization of carbamate. Tetrahedron 2017, 73, 6831–6839. [Google Scholar] [CrossRef]
  87. Lowe, G. The absolute configuration of allenes. Chem. Commun. 1965, 411. [Google Scholar] [CrossRef]
  88. Brewster, J.H. A Useful Model of Optical Activity. I. Open Chain Compounds. J. Am. Chem. Soc. 1959, 81, 5475–5483. [Google Scholar] [CrossRef]
  89. Brewster, J.H. Helix models of optical activity. In Topics in Stereochemistry; Allinger, N., Ernest, L., Eliel, L., Eds.; Interscience: New York, NY, USA; London, UK; Sidney, Australia, 1967; Volume 2, pp. 1–172. [Google Scholar]
  90. Sasaki, M.; Kondo, Y.; Moto-ishi, T.; Kawahata, M.; Yamaguchi, K.; Takeda, K. Enantioselective synthesis of allenylenol silyl ethers via chiral lithium amide mediated reduction of ynenoyl silanes and their Diels–Alder reactions. Org. Lett. 2015, 17, 1280–1283. [Google Scholar] [CrossRef]
  91. Li, H.; Grassi, D.; Guénée, L.; Bürgi, T.; Alexakis, A. Copper-catalyzed propargylic substitution of dichloro substrates: Enantioselective synthesis of trisubstituted allenes and formation of propargylic quaternary stereogenic centers. Chem. Eur. J. 2014, 20, 16694–16706. [Google Scholar] [CrossRef]
  92. Kinnel, R.; Duggan, A.J.; Eisner, T.; Meinwald, J. Panacene: An aromatic bromoallene from a sea hare. Tetrahedron Lett. 1977, 44, 3913–3916. [Google Scholar] [CrossRef]
  93. Baumeler, A.; Brade, W.; Haag, A.; Eugster, C. Synthese von enantiomerenreinen ‘Grasshopper’-Ketonen und verwandten Verbindungen. Helv. Chim. Acta 1990, 73, 700–715. [Google Scholar] [CrossRef]
  94. Kim, G.; Kim, T.; Han, S. Total synthesis of (+)-Pestalofone A and (+)-Iso-A82775C. J. Org. Chem. 2020, 85, 6815–6821. [Google Scholar] [CrossRef]
  95. Ye, J.; Li, S.; Chen, B.; Fan, W.; Kuang, J.; Liu, J.; Liu, Y.; Miao, B.; Wan, B.; Wang, Y.; et al. Catalytic asymmetric synthesis of optically active allenes from terminal alkynes. Org. Lett. 2012, 14, 1346–1349. [Google Scholar] [CrossRef]
  96. Zhang, F.H.; Guo, X.; Zeng, X.; Wang, Z. Catalytic enantioconvergent allenylation of aldehydes with propargyl halides. Angew. Chem. Int. Ed. 2022, 61, e202117114. [Google Scholar] [CrossRef]
  97. Chen, Y.T. Recent advances in methylation: A guide for selecting methylation reagents. Chem. Eur. J. 2019, 25, 3405–3439. [Google Scholar] [CrossRef]
  98. Yan, G.B.; Borah, A.J.; Wang, L.G.; Yang, M.H. Recent advances in transition metal-catalyzed methylation reactions. Adv. Synth. Catal. 2015, 357, 1333–1350. [Google Scholar] [CrossRef]
  99. Moulay, S. C-methylation of organic substrates: A comprehensive overview. Part I. Methane as a methylating agent. Mini-Rev. Org. Chem. 2020, 17, 805–813. [Google Scholar] [CrossRef]
  100. Kuntz, K.W.; Campbell, J.E.; Keilhack, H.; Pollock, R.M.; Knutson, S.K.; Porter-Scott, M.; Richon, V.M.; Sneeringer, C.J.; Wigle, T.J.; Allain, C.J.; et al. The importance of being me: Magic methyls, methyltransferase inhibitors, and the discovery of tazemetostat. J. Med. Chem. 2016, 59, 1556–1564. [Google Scholar] [CrossRef]
  101. Barreiro, E.J.; Kummerle, A.E.; Fraga, C.A.M. The methylation effect in medicinal chemistry. Chem. Rev. 2011, 111, 5215–5246. [Google Scholar] [CrossRef]
  102. Al-Afyouni, M.H.; Fillman, K.L.; Brennessel, W.W.; Neidig, M.L. Isolation and characterisation of a tetramethyliron (III) ferrate: An intermediate in the reduction pathway of ferric salts with MeMgBr. J. Am. Chem. Soc. 2014, 136, 15457–15460. [Google Scholar] [CrossRef] [PubMed]
  103. Furstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C.W. Preparation, structure, and reactivity of nonstabilized organoiron compounds. Implications for iron-catalyzed cross coupling reactions. J. Am. Chem. Soc. 2008, 130, 8773–8787. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Some natural compounds with vinylallene moieties.
Figure 1. Some natural compounds with vinylallene moieties.
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Scheme 1. Iron-promoted reaction of acyclic enyne oxiranes and an enantiomerically pure enyne acetate with Grignard reagents.
Scheme 1. Iron-promoted reaction of acyclic enyne oxiranes and an enantiomerically pure enyne acetate with Grignard reagents.
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Scheme 2. Iron-promoted reaction of an endocyclic enyne acetate with MeMgCl.
Scheme 2. Iron-promoted reaction of an endocyclic enyne acetate with MeMgCl.
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Scheme 3. The methods applied for the synthesis of racemic endocyclic enyne oxiranes.
Scheme 3. The methods applied for the synthesis of racemic endocyclic enyne oxiranes.
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Scheme 4. The methods applied for the synthesis of enantiopure endocyclic trans-enyne oxiranes.
Scheme 4. The methods applied for the synthesis of enantiopure endocyclic trans-enyne oxiranes.
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Scheme 5. The synthesis of enantiopure endocyclic enyne oxirane cis-1a*.
Scheme 5. The synthesis of enantiopure endocyclic enyne oxirane cis-1a*.
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Scheme 6. Iron-promoted reaction of racemic 1a with MeMgBr.
Scheme 6. Iron-promoted reaction of racemic 1a with MeMgBr.
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Scheme 7. Attempts of asymmetric epoxidation using Shi’s methods.
Scheme 7. Attempts of asymmetric epoxidation using Shi’s methods.
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Scheme 8. Attempts of asymmetric epoxidation using Sharpless’ method.
Scheme 8. Attempts of asymmetric epoxidation using Sharpless’ method.
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Scheme 9. The iron-promoted reaction of cis-1a* with MeMgBr.
Scheme 9. The iron-promoted reaction of cis-1a* with MeMgBr.
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Scheme 10. Plausible mechanism.
Scheme 10. Plausible mechanism.
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Figure 2. Optimized conformers for 1f (the energy values are relative energies). Here, 1f-TE is the lowest energy conformer overall and has the potential to produce 2f with an (E)-configured exocyclic alkenyl moiety.
Figure 2. Optimized conformers for 1f (the energy values are relative energies). Here, 1f-TE is the lowest energy conformer overall and has the potential to produce 2f with an (E)-configured exocyclic alkenyl moiety.
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Table 1. Fe-promoted reactions of endocyclic enyne oxiranes and MeMgBr *.
Table 1. Fe-promoted reactions of endocyclic enyne oxiranes and MeMgBr *.
EntryEpoxide (ee%)ProductYield (%)dr/ee%
1Chemistry 05 00173 i001Chemistry 05 00173 i0028296:4/95.2
2Chemistry 05 00173 i003Chemistry 05 00173 i0047495:5/93.8
3Chemistry 05 00173 i005Chemistry 05 00173 i0066770:30/N.D.
4Chemistry 05 00173 i007Chemistry 05 00173 i0087590:10/99.3
5Chemistry 05 00173 i009Chemistry 05 00173 i0107192:8/91.6
6Chemistry 05 00173 i011Chemistry 05 00173 i01272100:0/(±)
7Chemistry 05 00173 i013Chemistry 05 00173 i014C.M.N.D.
* Performed with 0.1 mmol of 1 and 3 equiv of MeMgBr in 1 mL of dry THF at −50 °C.
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Kuş, M.; Omur, C.; Karaca, S.; Artok, L. Iron-Promoted 1,5-Substitution Reaction of Endocyclic Enyne Oxiranes with MeMgBr: A Stereoselective Method for the Synthesis of Exocyclic 2,4,5-Trienol Derivatives. Chemistry 2023, 5, 2682-2699. https://doi.org/10.3390/chemistry5040173

AMA Style

Kuş M, Omur C, Karaca S, Artok L. Iron-Promoted 1,5-Substitution Reaction of Endocyclic Enyne Oxiranes with MeMgBr: A Stereoselective Method for the Synthesis of Exocyclic 2,4,5-Trienol Derivatives. Chemistry. 2023; 5(4):2682-2699. https://doi.org/10.3390/chemistry5040173

Chicago/Turabian Style

Kuş, Melih, Cenk Omur, Sıla Karaca, and Levent Artok. 2023. "Iron-Promoted 1,5-Substitution Reaction of Endocyclic Enyne Oxiranes with MeMgBr: A Stereoselective Method for the Synthesis of Exocyclic 2,4,5-Trienol Derivatives" Chemistry 5, no. 4: 2682-2699. https://doi.org/10.3390/chemistry5040173

APA Style

Kuş, M., Omur, C., Karaca, S., & Artok, L. (2023). Iron-Promoted 1,5-Substitution Reaction of Endocyclic Enyne Oxiranes with MeMgBr: A Stereoselective Method for the Synthesis of Exocyclic 2,4,5-Trienol Derivatives. Chemistry, 5(4), 2682-2699. https://doi.org/10.3390/chemistry5040173

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