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Scott D. Rychnovsky - One of the best experts on this subject based on the ideXlab platform.
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Stereochemical Outcomes in Reductive Cyclizations To Form Spirocyclic Heterocycles
Organic letters, 2015Co-Authors: Matthew A Perry, Richard R. Hill, Justin J. Leong, Scott D. RychnovskyAbstract:Reductive Lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.
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Stereochemical Outcomes in Reductive Cyclizations To Form Spirocyclic Heterocycles
2015Co-Authors: Matthew A. Perry, Justin J. Leong, Richard R. Hill, Scott D. RychnovskyAbstract:Reductive Lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product
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Trianion Synthon Approach to Spirocyclic Heterocycles.
ChemInform, 2013Co-Authors: Matthew A Perry, Richard R. Hill, Scott D. RychnovskyAbstract:A general strategy to construct spirocyclic heterocycles is developed with the key step being a Reductive Lithiation and cyclization of a nitrile phosphate to form the spirocyclic pyrrolidine, piperidine, or tetrahydrofuran ring.
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Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons
The Journal of organic chemistry, 2012Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott D. RychnovskyAbstract:Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a Reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent Reductive Lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.
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Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons
2012Co-Authors: Matthew A. Perry, Matthew D Morin, Brian W Slafer, Scott D. RychnovskyAbstract:Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a Reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent Reductive Lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis
Theodore Cohen - One of the best experts on this subject based on the ideXlab platform.
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Fundamental Difference in Reductive Lithiations with Preformed Radical Anions versus Catalytic Aromatic Electron‐Transfer Agents: N,N‐Dimethylaniline as an Advantageous Catalyst
Angewandte Chemie (International ed. in English), 2015Co-Authors: Nicole Kennedy, Peng Liu, Theodore CohenAbstract:The Reductive Lithiation of phenyl thioethers, or alkyl chlorides, by either preformed aromatic radical anions or by lithium metal and an aromatic electron-transfer catalyst, is commonly used to prepare organolithiums. Revealed herein is that these two methods are fundamentally different. Reductions with radical anions occur in solution, whereas the catalytic reaction occurs on the surface of lithium, which is constantly reactivated by the catalyst, an unconventional catalyst function. The order of relative reactivity is reversed in the two methods as the dominating factor switches from electronic to steric effects of the alkyl substituent. A catalytic amount of N,N-dimethylaniline (DMA) and Li ribbon can achieve Reductive Lithiation. DMA is significantly cheaper than alternative catalysts, and conveniently, the Li ribbon does not require the removal of the oxide coating when DMA is used as the catalyst.
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Reductive Lithiation in the Absence of Aromatic Electron Carriers. A Steric Effect Manifested on the Surface of Lithium Metal Leads to a Difference in Relative Reactivity Depending on Whether the Aromatic Electron Carrier Is Present or Absent
The Journal of organic chemistry, 2015Co-Authors: Nicole Kennedy, Peng Liu, Theodore CohenAbstract:One of the most widely used methods of preparation of organolithium compounds is by the Reductive Lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides with either aromatic radical-anions of lithium or lithium metal in the presence of an aromatic electron-transfer catalyst. Here we present results showing that lithium dispersion can achieve Reductive Lithiation in the absence of the electron-transfer agent. This procedure is more efficient, and surprisingly, the order of reactivity of substrates is reversed depending on whether the electron-transfer agent is present or absent. For example, in the presence of a preformed radical-anion, tert-butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the absence of the radical-anion, it is just the opposite. Density functional theory calculations reveal that the exothermicity of the cleavage of the C–S bond in alkyl phenyl thioethers on the lithium surface is dependent on the size of the alkyl group,...
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Reductive Lithiation in the Absence of Aromatic Electron Carriers. A Steric Effect Manifested on the Surface of Lithium Metal Leads to a Difference in Relative Reactivity Depending on Whether the Aromatic Electron Carrier Is Present or Absent
2015Co-Authors: Nicole Kennedy, Peng Liu, Theodore CohenAbstract:One of the most widely used methods of preparation of organolithium compounds is by the Reductive Lithiation of alkyl phenyl thioethers or, usually less conveniently, alkyl halides with either aromatic radical-anions of lithium or lithium metal in the presence of an aromatic electron-transfer catalyst. Here we present results showing that lithium dispersion can achieve Reductive Lithiation in the absence of the electron-transfer agent. This procedure is more efficient, and surprisingly, the order of reactivity of substrates is reversed depending on whether the electron-transfer agent is present or absent. For example, in the presence of a preformed radical-anion, tert-butyl phenyl sulfide cleaves significantly faster than methyl phenyl sulfide, whereas in the absence of the radical-anion, it is just the opposite. Density functional theory calculations reveal that the exothermicity of the cleavage of the C–S bond in alkyl phenyl thioethers on the lithium surface is dependent on the size of the alkyl group, the smaller the alkyl group the greater the exothermicity. The increased reactivity is attributed to the smaller steric repulsion between the alkyl group and the lithium surface. The methodology includes, but may not be limited to, the lithium dispersion Reductive Lithiation of phenyl thioethers, alkyl chlorides, acrolein diethyl acetal, and isochroman
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the superiority of properly prepared lithium 1 n n dimethylaminonaphthalenide ldman over other aromatic radical anions for the generation of organolithiums by Reductive Lithiation
Tetrahedron Letters, 2010Co-Authors: Roman Ivanov, Ilan Marek, Theodore CohenAbstract:Abstract The use of lithium 1-N,N-dimethylaminonaphthalenide (LDMAN) is found to be considerably superior in yield, ease of operation, and cost to the far more widely used lithium p,p′-di-tert-butylbiphenylide (LDBB) in Reductive Lithiations by aromatic radical-anions to produce organolithium compounds, provided that careful temperature control is maintained during the generation of LDMAN. The main reason for the superiority is the great ease of separation of the aromatic byproduct dimethylaminonaphthalene by a dilute acid wash.
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organolithiums by Reductive Lithiation the catalytic aromatic method versus the use of preformed aromatic radical anions naphthalene can behave as a catalyst or an inhibitor
Tetrahedron, 2006Co-Authors: Ao Yang, Kai Deng, Heather Butela, Mary Dosch Doubleday, Theodore CohenAbstract:Abstract Two common modes, using aromatic radical-anions for Reductive Lithiation, the replacement of a C–heteroatom bond with a C–Li bond, have been compared with regard to yield and the mildness of reaction conditions required. It was found that the use of preformed radical-anions generally resulted in higher yields and milder reaction conditions than the ‘catalytic’ method in which catalytic amounts of the aromatic compound are used and the radical-anion is generated and used in situ. The one apparent exception is N -phenylaziridine, but it is shown that in this case the aromatic compound, naphthalene, is actually an inhibitor rather than a catalyst . Rational mechanistic explanations are given.
Matthew A Perry - One of the best experts on this subject based on the ideXlab platform.
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Stereochemical Outcomes in Reductive Cyclizations To Form Spirocyclic Heterocycles
Organic letters, 2015Co-Authors: Matthew A Perry, Richard R. Hill, Justin J. Leong, Scott D. RychnovskyAbstract:Reductive Lithiation and cyclization of N-Boc α-amino nitriles are often highly stereoselective. The alkyllithium intermediates are formed with varying levels of selectivity, but the alkyllithium geometry does not play a major role in the overall stereoselectivity. The final configuration is determined in the cyclization reaction, where both retention and inversion pathways are observed. Where strong thermodynamic preferences exist in the products, the kinetically controlled alkyllithium cyclization favors the more stable product.
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Trianion Synthon Approach to Spirocyclic Heterocycles.
ChemInform, 2013Co-Authors: Matthew A Perry, Richard R. Hill, Scott D. RychnovskyAbstract:A general strategy to construct spirocyclic heterocycles is developed with the key step being a Reductive Lithiation and cyclization of a nitrile phosphate to form the spirocyclic pyrrolidine, piperidine, or tetrahydrofuran ring.
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Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons
The Journal of organic chemistry, 2012Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott D. RychnovskyAbstract:Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a Reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent Reductive Lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.
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Fully Substituted Carbon Centers by Diastereoselective Spirocyclization: Stereoselective Synthesis of (+)-Lepadiformine C
Journal of the American Chemical Society, 2010Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott A Wolckenhauer, Scott D. RychnovskyAbstract:Reductive Lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on Reductive Lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
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fully substituted carbon centers by diastereoselective spirocyclization stereoselective synthesis of lepadiformine c
Journal of the American Chemical Society, 2010Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott A Wolckenhauer, Scott D. RychnovskyAbstract:Reductive Lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on Reductive Lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
Mitsuru Shindo - One of the best experts on this subject based on the ideXlab platform.
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Generation of ynolates via Reductive Lithiation using flow microreactors
Tetrahedron Letters, 2014Co-Authors: Satoshi Umezu, Toshiya Yoshiiwa, Manabu Tokeshi, Mitsuru ShindoAbstract:Abstract A new method has been developed for the generation and subsequent reaction of ynolates in a micro flow reactor system. This new procedure allowed for ynolates to be prepared at 0 °C or ambient temperature within 1 min via a Reductive Lithiation reaction, whereas the corresponding batch processes generally require low temperature control and extended reaction times of up to 1 h. The resulting ynolates were applied to the olefination of carbonyl compounds, with the reactions reaching completion in a much shorter reaction time in the continuous flow reactor than the batch reactor. These results highlight the practical utility of the ynolate reaction, and represent the first reported example of the use of lithium naphthalenide in a flow microreactor, which would contribute to progress of the flash chemistry.
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practical synthesis of ynolate anions naphthalene catalyzed Reductive Lithiation of α α dibromo esters
Tetrahedron Letters, 2001Co-Authors: Mitsuru Shindo, Ryoko Koretsune, Wakako Yokota, Kotaro Itoh, Kozo ShishidoAbstract:Abstract Reductive Lithiation of α,α-dibromo esters using lithium naphthalenide afforded ester dianions leading to ynolate anions in good yields. Naphthalene-catalyzed Reductive Lithiation was also accomplished. This is a convenient, economical and practical method for the preparation of ynolate anions.
Matthew D Morin - One of the best experts on this subject based on the ideXlab platform.
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Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons
The Journal of organic chemistry, 2012Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott D. RychnovskyAbstract:Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a Reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent Reductive Lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis.
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Total Synthesis of Lepadiformine Alkaloids using N-Boc α-Amino Nitriles as Trianion Synthons
2012Co-Authors: Matthew A. Perry, Matthew D Morin, Brian W Slafer, Scott D. RychnovskyAbstract:Lepadiformine A, B, and C were synthesized in an enantiomerically pure form using a Reductive cyclization strategy. N-Boc α-amino nitriles were deprotonated and alkylated with enantiomerically pure dibromides to afford the first ring. The products were manipulated to introduce phosphate leaving groups, and subsequent Reductive Lithiation followed by intramolecular alkylation formed the second ring with high stereoselectivity. The third ring was formed by intramolecular displacement of a mesylate by the deprotected amine. Lepadiformine A and B contain a hydroxymethyl group adjacent to the amine. This appendage was introduced in a sequence using a Polonovski–Potier reaction as the key step. The synthetic strategy is stereoselective and convergent and demonstrates the utility of N-Boc α-amino nitriles as linchpins for alkaloid synthesis
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Fully Substituted Carbon Centers by Diastereoselective Spirocyclization: Stereoselective Synthesis of (+)-Lepadiformine C
Journal of the American Chemical Society, 2010Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott A Wolckenhauer, Scott D. RychnovskyAbstract:Reductive Lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on Reductive Lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.
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fully substituted carbon centers by diastereoselective spirocyclization stereoselective synthesis of lepadiformine c
Journal of the American Chemical Society, 2010Co-Authors: Matthew A Perry, Matthew D Morin, Brian W Slafer, Scott A Wolckenhauer, Scott D. RychnovskyAbstract:Reductive Lithiation of N-Boc α-amino nitriles generated α-amino alkyllithium reagents with unexpected selectivity. The intermediate radical prefers to align with the nitrogen lone pair, and this interaction leads to an A1,3-strain effect that biases the conformation of the radical. In cyclohexane rings with α-substituents the net effect is an inversion of configuration on Reductive Lithiation. In the presence of a tethered electrophile the alkyllithium cyclizes to produce a spiro compound, again with inversion of configuration. The overall result is retention of configuration in the cyclization reaction. The same overall selectivity is found with α-oxygen alkyllithium cyclizations, but in this case both steps proceed with retention. The difference can be explained by careful consideration of the intermediate geometries. The α-amino spirocyclization was utilized in a concise and stereoselective synthesis of lepadiformine C.