Chemo and enantioselective addition of grignard reagents to ketones and enolizable
ketimines
Ortiz, Pablo
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Publication date: 2017
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Ortiz, P. (2017). Chemo and enantioselective addition of grignard reagents to ketones and enolizable ketimines. University of Groningen.
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Summary
Chiral α-tertiary alcohols and amines are a widespread motif in biologically active compounds, both natural and man-made. Due to their importance several strategies have been designed to synthesize them, among which the most straightforward and explored one is the asymmetric addition of nucleophiles to ketones and ketimines. For the introduction of an alkyl or aryl chain organometallic reagents are needed. For long time organozinc reagents have been the reagents of choice for this transformation. Grignard reagents, in spite of having more desirable properties (lower cost, higher availability, less pyrophoricity and higher atom efficiency) could not be used for the asymmetric addition to ketones and imines due to their high reactive profile, which made the catalysis imposible. Moreover, enolization and reduction were major issues. In 2012 it was discovered in our group a catalytic system based on Cu(I) and a chiral diphosphine ligand that allowed the catalytic enantioselective 1,2-alkylation of enones, and later the alkylation of aryl alkyl ketones and acylsilanes.
Chapter 2 describes the use of this catalytic system for the first catalytic asymmetric
alkylation of (di)(hetero)aryl ketones. Chiral α-tertiary diarylmethanols are extensively present in drugs, and their asymmetric synthesis has been pursued by arylation of aryl alkyl ketones. The development of the complementary methodology, the alkylation of (di)(hetero)aryl ketones posed several problems: the low reactivity of the substrates, the competing reduction, the difficult enantiodiscrimination due to the similarity of the enantiotopic faces, and finally the instability of some products and their tendency to undergo elimination. Despite these great difficulties moderate to good yields and enantioselectivities could be achieved in this new approach for the synthesis of these valuable molecules.
Chapter 3 covers the Brook rearrangement/stereospecific trapping of α-tertiary
silylated allylic alcohols, obtained by the catalytic asymmetric alkylation of
acylsilanes. Upon treatment with Et2Zn the zinc alkoxide is formed, Brook
rearrangement takes place, and the chiral carbanion formed is trapped by a carbonyl electrophile with full transfer of chirality. In order to explain this surprising stereospecificity of the sequence a concerted mechanism is proposed in which the carbonyl electrophile plays a key role: it first triggers the Brook rearrangement and then it is attacked by the nascent carbanion in a chair-like transition state.
Chapter 4 continiues with the Brook rearrangement of α-tertiary silylated alcohols,
but this time the starting point is a benzylic hydroxysilane. Interestingly and contrary to benzylic substrates discussed in chapter 3, the benzylic system behaved in a completely different way: Alkali metals were needed to triger the rearrangement, and all attemps to stereospecifically trap carbon electrophiles failed, leading to the racemic product. This can be attributed to the fast racemization of the carbanion, which is not configurationally stabilized. Protons could be trapped with full retention of chirality when catalytic amount of base (LiOtBu) was used, probably because it took place in a concerted manner from the pentacoordinate silicon intermediate. The Brook rearrangement proceed with invertion of configuration.
Summary
Chiral α-tertiary alcohols and amines are a widespread motif in biologically active compounds, both natural and man-made. Due to their importance several strategies have been designed to synthesize them, among which the most straightforward and explored one is the asymmetric addition of nucleophiles to ketones and ketimines. For the introduction of an alkyl or aryl chain organometallic reagents are needed. For long time organozinc reagents have been the reagents of choice for this transformation. Grignard reagents, in spite of having more desirable properties (lower cost, higher availability, less pyrophoricity and higher atom efficiency) could not be used for the asymmetric addition to ketones and imines due to their high reactive profile, which made the catalysis imposible. Moreover, enolization and reduction were major issues. In 2012 it was discovered in our group a catalytic system based on Cu(I) and a chiral diphosphine ligand that allowed the catalytic enantioselective 1,2-alkylation of enones, and later the alkylation of aryl alkyl ketones and acylsilanes.
Chapter 2 describes the use of this catalytic system for the first catalytic asymmetric
alkylation of (di)(hetero)aryl ketones. Chiral α-tertiary diarylmethanols are extensively present in drugs, and their asymmetric synthesis has been pursued by arylation of aryl alkyl ketones. The development of the complementary methodology, the alkylation of (di)(hetero)aryl ketones posed several problems: the low reactivity of the substrates, the competing reduction, the difficult enantiodiscrimination due to the similarity of the enantiotopic faces, and finally the instability of some products and their tendency to undergo elimination. Despite these great difficulties moderate to good yields and enantioselectivities could be achieved in this new approach for the synthesis of these valuable molecules.
Chapter 3 covers the Brook rearrangement/stereospecific trapping of α-tertiary
silylated allylic alcohols, obtained by the catalytic asymmetric alkylation of
acylsilanes. Upon treatment with Et2Zn the zinc alkoxide is formed, Brook
rearrangement takes place, and the chiral carbanion formed is trapped by a carbonyl electrophile with full transfer of chirality. In order to explain this surprising stereospecificity of the sequence a concerted mechanism is proposed in which the carbonyl electrophile plays a key role: it first triggers the Brook rearrangement and then it is attacked by the nascent carbanion in a chair-like transition state.
Chapter 4 continiues with the Brook rearrangement of α-tertiary silylated alcohols,
but this time the starting point is a benzylic hydroxysilane. Interestingly and contrary to benzylic substrates discussed in chapter 3, the benzylic system behaved in a completely different way: Alkali metals were needed to triger the rearrangement, and all attemps to stereospecifically trap carbon electrophiles failed, leading to the racemic product. This can be attributed to the fast racemization of the carbanion, which is not configurationally stabilized. Protons could be trapped with full retention of chirality when catalytic amount of base (LiOtBu) was used, probably because it took place in a concerted manner from the pentacoordinate silicon intermediate. The Brook rearrangement proceed with invertion of configuration.
Chapter 5 describes the addition of organomagnesium compounds to
diphenyphosphinyl protected diarylimimes, allowing the access to α-trisubstituted diarylmethylamines. (Hetero)aryl and allyl Grignard reagents were suitable nucleophiles and the undesired β-hydride elimination from alkylmagnesium bromides could be circumvented using dialkylmagnesium reagents. Both the substrate and the reagents scope were broad and the products were obtained in high yields, through fast and clean reactions that translated into easy purifications or no need of them at all. It consitutes the first general strategy for the synthesis of these type of compounds and more advantageous than the previous examples which employed trialkyl aluminium reagents. The main drawback is the unfeasibility to deprotect the products because of the tendency towards elimination.
Chapter 6 outlines the direct synthesis of enolizable N-sulfonyl ketimines using
microwave irradiation. N-sulfonyl ketimines are commonly used in organic chemistry but all the methods reported in the literature require more than one step. The methodology developed affords the desired product in just one step of one hour, in synthetically useful yields and starting from commercially available ketones. Ti(OEt)4 working as a catalyst and dehydrating agent and microwave
irradiation allowing 150 °C temperature are key elements for the fast transformation.
Chapter 7 describes the catalytic asymmetric alkylation of enolizable N-sulphonyl
ketimines using Grignard reagents, affording the products in excellent yields and enantioselectivities. Asymmetric alkylation of acyclic ketimines is a considerable
challenge and in the literature there are only three reports of methylation and ethylation of a small set of activated ketimines. By using highly reactive Grignard reagents the need of activated substrates has been overcome and the competing reaction pathways, including substrate enolization, substrate reduction via β-hydride transfer, and non-catalyzed addition (commonly observed with Grignard reagents), have been avoided thanks to a highly chemoselective chiral copper/diphosphine catalyst system.
Chapter 8 presents the NMR experiments carried out to determine the solution
structure of Grignard reagents in tBuOMe and CH2Cl2 at conditions typical of their
use in asymmetric catalysis (-78 °C, 0.15-0.5 M). Through the use of 1H NMR,
NOESY and DOSY experiments the Grignard reagents were determined to be monomeric and closely coordinated to two molecules of solvent (Et2O if the
Grignard was diluted in CH2Cl2 and tBuOMe if it was prepared/diluted in tBuOMe).
It was also observed that the transition to the dialkylmagnesium compounds is more difficult in CH2Cl2 as compared with Et2O, which could have implications in
the catalysis.
Chapter 9 gives a personal perspective on overcoming the limitations of
organometallic reagents. Some of the most important recent advances are discussed, alongside with ideas that were tested in the lab inspired by them.
Chapter 5 describes the addition of organomagnesium compounds to
diphenyphosphinyl protected diarylimimes, allowing the access to α-trisubstituted diarylmethylamines. (Hetero)aryl and allyl Grignard reagents were suitable nucleophiles and the undesired β-hydride elimination from alkylmagnesium bromides could be circumvented using dialkylmagnesium reagents. Both the substrate and the reagents scope were broad and the products were obtained in high yields, through fast and clean reactions that translated into easy purifications or no need of them at all. It consitutes the first general strategy for the synthesis of these type of compounds and more advantageous than the previous examples which employed trialkyl aluminium reagents. The main drawback is the unfeasibility to deprotect the products because of the tendency towards elimination.
Chapter 6 outlines the direct synthesis of enolizable N-sulfonyl ketimines using
microwave irradiation. N-sulfonyl ketimines are commonly used in organic chemistry but all the methods reported in the literature require more than one step. The methodology developed affords the desired product in just one step of one hour, in synthetically useful yields and starting from commercially available ketones. Ti(OEt)4 working as a catalyst and dehydrating agent and microwave
irradiation allowing 150 °C temperature are key elements for the fast transformation.
Chapter 7 describes the catalytic asymmetric alkylation of enolizable N-sulphonyl
ketimines using Grignard reagents, affording the products in excellent yields and enantioselectivities. Asymmetric alkylation of acyclic ketimines is a considerable
challenge and in the literature there are only three reports of methylation and ethylation of a small set of activated ketimines. By using highly reactive Grignard reagents the need of activated substrates has been overcome and the competing reaction pathways, including substrate enolization, substrate reduction via β-hydride transfer, and non-catalyzed addition (commonly observed with Grignard reagents), have been avoided thanks to a highly chemoselective chiral copper/diphosphine catalyst system.
Chapter 8 presents the NMR experiments carried out to determine the solution
structure of Grignard reagents in tBuOMe and CH2Cl2 at conditions typical of their
use in asymmetric catalysis (-78 °C, 0.15-0.5 M). Through the use of 1H NMR,
NOESY and DOSY experiments the Grignard reagents were determined to be monomeric and closely coordinated to two molecules of solvent (Et2O if the
Grignard was diluted in CH2Cl2 and tBuOMe if it was prepared/diluted in tBuOMe).
It was also observed that the transition to the dialkylmagnesium compounds is more difficult in CH2Cl2 as compared with Et2O, which could have implications in
the catalysis.
Chapter 9 gives a personal perspective on overcoming the limitations of
organometallic reagents. Some of the most important recent advances are discussed, alongside with ideas that were tested in the lab inspired by them.
