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Total Synthesis of Lissodendoric Acid A and Chemical Education Initiatives
Ippoliti Pfitzer ; Francesca Marie ;
Abstract: This dissertation describes the total synthesis of a complex natural product, lissodendoric acid A, through the innovative use of a strained cyclic allene intermediate. Strained cyclic allenes have never been previously used in total synthesis, despite being discovered shortly after other strained intermediates, such as benzyne. Cyclic allenes are useful fleeting intermediates as they are highly reactive due to their strain and have the ability to form complex, sp3 -containing molecules. These benefits, along with the ability to transfer stereochemical information, are leveraged in a key Diels–Alder cycloaddition leading to the enantioenriched azadecalin core of lissodendoric acid A and ultimately the completion of the total synthesis. Additionally, the syntheses of precursors to two other versatile strained intermediates are detailed. The synthesis of iii a key biosynthetic precursor to monoterpene indole alkaloids, as well as oxidized derivatives thereof, is also reported. Finally, initiatives toward advancing chemical education on a global scale are detailed. Chapters one and two describe the first total synthesis of the manzamine natural product lissodendoric acid A. Specifically, chapter one details a concise route to lissodendoric acid A, which proceeds via a key stereospecific Diels–Alder cycloaddition of a transient, strained azacyclic allene intermediate. Model system studies using various cyclic allene precursors are detailed, which informed the synthetic design of the enantioenriched silyl bromide used in the Diels–Alder cycloaddition en route to lissodendoric acid A. Of note, this marks the first use of a strained cyclic allene in a total synthesis. From the cycloadduct, swift late-stage manipulations of the scaffold allow for completion of the natural product. Chapter two discusses the first-generation synthesis of lissodendoric acid A, including a detailed analysis of key challenges encountered. Alterations to the synthetic strategy, which ultimately enable access to the natural product, are described. Specifically, structural modifications to the key Diels–Alder reaction partners, which allow for avoidance of difficult late-stage oxidations, are presented. Additionally, the combination of multiple late-stage reductions into one step to rapidly access the natural product is demonstrated. Chapter three describes the synthesis of silyl triflate precursors to the strained intermediates cyclohexyne and 1,2-cyclohexadiene. Cyclohexyne and 1,2-cyclohexadiene are versatile building blocks that have been used in a variety of cycloadditions to access complex, polycyclic products. The synthesis described is both concise and divergent, allowing access to precursors to both strained intermediates in an efficient and scalable manner. Chapters four and five describe the synthesis and evaluation of 8-hydroxygeraniol, a key biosynthetic precursor to all monoterpene indole alkaloids. Specifically, chapter four gives an iv account of the optimization of an efficient and highly selective oxidation reaction and subsequent deacetylation to arrive at 8-hydroxygeraniol in good yields and on large scale. Importantly, swift access to 8-hydroxygeraniol through this route enabled investigations into the enzymatic synthesis of downstream monoterpene indole alkaloids, such as those described in chapter five. Chapter five presents the fully enzymatic, one-pot synthesis of nepetalactol, starting from geraniol. 8- hydroxygeraniol and its oxidized derivatives, 8-oxogeraniol and 8-oxogeranial, were all synthesized chemically to confirm their presence in the enzymatic pathway. Chapters six and seven describe educational projects developed to improve student engagement in chemical education. Chapter six details the development and use of R/S Chemistry, an online game-like resource for students to practice assigning stereocenters. The results of a survey given to hundreds of undergraduate students who used R/S Chemistry to practice stereochemical assignments are detailed, which proved to be overwhelmingly positive. Chapter seven presents a perspective on advancing chemical education through interactive teaching tools. Multiple efforts in the area of chemical education innovation are highlighted, as well as the expansion of these resources to a global scale. These resources include interactive online learning tools, methods to help students visualize structures in 3D, and coloring and activity books for children to expand the reach of these resources to a broader audience.
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| CAS No. : | 51779-32-9 |
| Formula : | C10H19NO4 |
| M.W : | 217.26 |
| SMILES Code : | O=C(NC(OC(C)(C)C)=O)OC(C)(C)C |
| MDL No. : | MFCD00043309 |
| InChI Key : | XCAQIUOFDMREBA-UHFFFAOYSA-N |
| Pubchem ID : | 279800 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H315-H319-H335 |
| Precautionary Statements: | P261-P264-P271-P280-P302+P352-P305+P351+P338 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | With sodium hydride; In tetrahydrofuran; at 20℃; for 28h; | To a suspension of sodium hydride (1.91 g, 47.72 mmol) in anhydrous tetrahydrofuran (30 [ML)] at room temperature under nitrogen, was added a solution [OF 2-] [BROMOMETHYL-5-CHLORO-BENZONITRILE11] (10 g, 43.39 mmol) in anhydrous tetrahydrofuran (35 [ML),] followed by the dropwise addition of [DI-TERT] butyl imino dicarboxylate (10.37 g, 47.72 [MMOL)] in anhydrous tetrahydrofuran (30 [ML).] The reaction mixture was stirred at room temperature for 28 hours under nitrogen. The reaction was quenched with water (50 ml) and the solvent removed under reduced pressure. The aqueous layer was extracted with diethyl ether (3 x 100 ml), the combined organics washed with brine (50 [ML),] dried with magnesium sulfate, filtered and the solvent removed by evaporation under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient of heptane: ethyl acetate (4: 1) to give the title compound (13.45 g, 84 [%)] as a pale yellow solid. [1H-NMR] (400 MHz, [CDCI3)] : [9] = 1.46 (s, 18H), 4.98 (s, 2H), 7.28 (d, 1H), 7.53 (d, 1H), 7.61 (d, [1H).] LRMS [(APCI)] : m/z [M + H] [+] [389.] Microanalysis : Found: C, 59.37 ; H, 6.47 ; N, 7.09. [C18H23N204CI] requires C, 58. 93; H, 6.32 ; N, 7.64%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With hydrogenchloride; thionyl chloride; In N-methyl-acetamide; water; ethyl acetate; | Example 133 Synthesis of N-(2-chloro-3-nitrophenylmethyl)iminodicarboxylic acid di-t-butyl ester A mixture of the compound (1.01 g) obtained in Example 132 and thionyl chloride (50 ml) was heated under reflux for 48 h. The reaction mixture was concentrated under reduced pressure; the resulting residue was dissolved in dimethylformamide (25 ml) and added dropwise to a solution of sodium hydride (content, 60%; 0.24 g) and di-t-butyl iminodicarboxylate (1.29 g) in dimethylformamide (25 ml) at 0 C. The reaction mixture was stirred at room temperature for 1 h and stirred at 80 C. for 2 h. Water and 2 N HCl were added to the reaction mixture and extraction was performed with ethyl acetate; then, the organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=5:1) to give 1.70 g of the titled compound (yield, 82%). 1H-NMR(CDCl3) δ: 1.47(9H,s), 1.48(9H,s), 4.97(2H,s), 7.32-7.42(2H,m), 7.66-7.72(1H,m) |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile. To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
| 18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
| 18.5 g (94%) | With sodium hydroxide; In tetrahydrofuran; methanol; water; | B) Preparation of N-Boc-p-(aminomethyl)benzonitrile To a stirring suspension of sodium hydride (4.6 g, 115 mmol, 60% dispersion in oil) in tetrahydrofuran (150 mL) was added 4-(bromomethyl)benzonitrile (20.5 g, 105 mmol). To this mixture was added (slowly via an addition funnel) a solution of di-t-butyl iminodicarboxylate (25 g, 115 mmol). After stirring for 16 hours, the mixture was diluted with diethyl ether (500 mL) and washed twice with water (250 mL). The organic phase was then dried (MgSO4), filtered and concentrated to give 40.2 g of crude solid. The resulting solid (28.3 g, 85 mmol) was then dissolved in tetrahydrofuran (150 mL) and a solution of sodium hydroxide (3.4 g, 85 mmol) in methanol (300 mL) was added. After stirring overnight, the solution was concentrated to about one-half volume and water was added to promote precipitation of the product. The precipitate was filtered and dried in vacuo to give 18.5 g (94%) of a white solid. |
[ 51779-32-9 ]
[ 124796-97-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 78.3% | To a solution of di-tert-butyl iminodicarbonate (6.87 g, 31.6 mmol) in DMF (40 mL) was added t-BuOK (3.54g, 31.6 mmol). After 2 hr, a solution of ethyl 2-(chloromethyl) -5-methylnicotinate (4.5 g, 21.1 mmol) in DMF (10 ml) was added to the mixture, then stirred at 50C for 16 hr. The mixture was poured into H20 (200 mL) and extracted with EA (100 mL*3).The combined organic layers were dried over Na2504, concentrated and purified bychromatography column on silica gel using 10% of EA in PE as a eluent to give ethyl 2-((bis(tert-butoxycarbonyl)amino)methyl) -5-methylnicotinate (6.5 g, 78.3%) as a yellow solid.MS (ESI, m/e) [M+1] 394.9. |
Tags: Di-tert-butyl iminodicarboxylate | Carbamates | Organic Building Blocks | 51779-32-9
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