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Development of Enantioenriched Cyclic Allene Precursor via Stereoselective Derivatization of α-Silylcyclohexenones

  • 최명수 (Choi Myungsoo, 아주대학교 일반대학원)

초록/요약

The cyclic allene, first identified by Wittig in 1966, is a highly reactive intermediate with significant strain energy, similar to aryne, yet it is distinctively advantageous for its inherent chirality, attributable to its asymmetric axis, making it an advantageous building block in the synthesis of complex compounds. Despite the seminal discovery of cyclic allene by Wittig, the compound has received comparatively less attention over an extended period, especially when contrasted with aryne. The chiral sp3 carbon ring, synthesized through organic reactions of cyclic allene, serves as a versatile backbone for various bioactive molecule derivatives, maintaining the unique chirality of cyclic allene. The potential utility of cyclic allene as a building block for constructing stereochemically complex and structurally diverse compounds, especially for substances with a three-dimensional structure, is explored. Previous studies relied on racemic mixture of cyclic allene precursors obtained through chiral Supercritical fluid chromatography (SFC) separation to isolate single enantiomer. However, this approach demands diverse conditions suitable for different forms of cyclic allene precursors, necessitating numerous chiral columns and incurring substantial efforts and costs to establish a chiral SFC system. Due to the inherent high strain energy in cyclic allene, it is commonly employed in precursor, functionalized a silyl and triflate group. The in situ generation of cyclic allene is facilitated using F– sources, actively participating in the reactions. In our study, we employed SAMP ((S)-2-(methoxymethyl)pyrrolidine-1-amine)), developed by Enders and Corey in 1966, as a chiral auxiliary to synthesize enantioenriched cyclic allene precursors. Starting from commercially affordable L- proline, the synthesis of SAMP ((S)-2-(methoxymethyl-l)pyrrolidine-1-amine) involves a six step process, with the only purification requirement occurring during the final step through distillation. We successfully formed a single diastereomer through condensation and silylation reactions between SAMP and cyclohexanone, synthesizing a cyclic allene precursor with 99% enantiomeric excess (ee) optical purity. In 2018, Garg group's research highlights the key role of α-substituents in controlling racemization energy and driving stereoretentive reactions in cyclic allene. Therefore, we functionalize the α-position of cyclohexanone derivatives with various substituents to synthesize cyclic allene precursors with high optical purity.

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목차

1. Introduction 1
2. Result and Discussion 9
2.1. Synthesis of SAMP ((S)-2-(methoxymethyl)pyrrolidine-1-amine)) 9
2.2. Synthesis of Enantioselective Cyclic Allene Precursors via Cyclohexanones 10
2.3. Synthesis of Enantioselective Cyclic Allene Precursors via α-Functionalized Cyclohexanones 11
2.4. Detour of Approach 1 for Synthesis of Enantioenriched Cyclic Allene Precursor: 2-Methylcyclohexanone as Starting Material 15
2.4.1. Optimization of The Condensation Reaction (Challenge 2) 16
2.4.2. Optimization of The Silylation Reaction (Challenge 3) 19
2.4.3. Optimization for Ozonolysis Step (Challenge 4) 21
2.5. Synthesis of Enantioselective Cyclic Allene Precursors via γ-Functionalized Cyclohexanones 23
3. Conclusion 25
4. Experiment Section 27
4.1. General Information 27
4.2. General procedure for synthesis of SAMP 28
4.3. Procedure for synthesis of cyclic allene precursor 31
4.4. Procedure for recycling of SAMP 33
4.5. Procedure for synthesis of methyl-substituted cyclic allene precursor 33
4.6. General Procedure for Synthesis of Enantioselective Cyclic Allene Precursors via γ-Functionalized Cyclohexanones 36
4.7. Analytical HPLC data of cyclic allene precursor 38
4.8. Analytical data of the products 42
4.9. NMR Spectra of the Products 52
5. Reference 66

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