Polymer Supported Proline-Based Organocatalysts in Asymmetric Aldol Reactions: A Review

The use of proline-based organocatalysts has acquired significant importance in organic synthesis, especially in enantioselective synthesis. Proline and its derivatives are proven to be quite effective chiral organocatalysts for a variety of transformations including the aldol reaction, which is considered as one of the important C-C bond forming reactions in organic synthesis. The use of chiral organocatalysts has several advantages over its metal-mediated analogues. Subsequently, a large number of highly efficient proline-based organocatalysts including polymer-supported chiral analogues have been identified for aldol reaction. The use of polymer-supported organocatalysts exhibited remarkable stability under the reaction conditions and offered the best results particularly in terms of its recyclability and reusability. These potential benefits along with its economic and green chemistry advantages have led to the search for many polymer-supported proline catalysts. In this review, recent developments in exploring various polymer immobilized proline-based chiral organocatalysts for asymmetric aldol reactions are described.

Recent advancement and novel application of organocatalyzed aldol condensation reactions: A comprehensive review

Background: Aldol reactions play an important role in the development of organic synthesis-owing to their critical importance for the forming of carbon-carbon bonds while concurrently one or two chiral centers come into being. In the modern scenario, the Aldol condensation reaction has arisen as perhaps the most significant reaction for the formation of novel medicinal agents exhibits promising pharmacological activities. Objective: The purpose of this study is to present newer synthetic approaches through Aldol condensation reaction for the synthesis of diverse scaffolds to explore the promising various types of biological activities. Methods: Aldol condensation concerns the nucleophilic addition reaction of a ketone enolate to an aldehyde to form aldol or β- hydroxy ketone. Occasionally, the aldol addition product losing water molecule yields an α, β-unsaturated ketone. Results: Results showed that amino acids and all lengths of peptides are utilized as chiral catalysts. As of now, the arrangement of catalysts that have been accounted for is intensely one-sided towards proline. This is to some degree because of its exceptional status among the normally happening amino acids as an auxiliary amine and to its restricted underlying adaptability. Conclusion: The present study thus provides useful insight concerning the promising coherent way for the synthesis of prolinamide analogue of proline, through a direct asymmetric aldol condensation reaction. Thus, the current study summarizes various Aldol condensation reactions for the synthesis of novel agents as well as their promising pharmacological importance.

New Mechanistic Approach in the Enamine-Based Asymmetric Organocatalysis

During the course of my research in asymmetric organocatalysis the inversion of enantioselectivity was observed in the asymmetric aldol reactions of acetone with different aldehydes catalyzed by amphiphilic proline derivatives in aqueous media varying only achiral components. It was not possible to explain the explored dual stereocontrol with the existing models, therefore I proposed a new mechanism for asymmetric aldol reactions catalyzed by l-amino acid derivatives in aqueous media and explained the explored phenomenon of inversion of enantioselectivity with different structures of micelle-stabilized transition state described as a metal-free version of the Zimmermann-Traxler model with explicit participation of a water molecule. Contrary to the existing models, according to the proposed mechanism the formation of new bonds proceeds directly in the transition state stabilized by a water molecule without the additional step of product iminium ion hydrolysis. The proposed mechanism has universal character, it is consistent with experimental results and general theoretical conceptions and it is applicable to all enamine-based asymmetric organocatalytic reactions carried out not only in aqueous, but in organic media as well, because the initial step of catalytic cycle, which involves the formation of an enamine from the carbonyl compound and proline (derivative), liberates one water molecule.

Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

<p>Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role. Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable. A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.</p>

Mechanistic Investigation of 1,5-Anti Stereoinduction in Aldol Reactions

<p>Peloruside A (+)-1 is a novel secondary metabolite isolated from a New Zealand marine sponge (Mycale hentscheli) by Northcote and West of Victoria University. Because it has a polyketide backbone, aldol reactions have been widely employed for its total synthesis. Aldol reactions displaying 1,5-anti stereoinduction mediated by the C₁₅ stereocenter (according to peloruside A numbering) have proven useful for the synthesis of the C₁₁–C₁₂ bond of peloruside A and analogues. This project is the continuation of Stocker's and Turner's studies on the excellent stereoinduction of 2 in boron-mediated aldol reactions. The relative stereochemistry of the corresponding aldol product is consistence with the expectations of Kishi's C database for a 1,5-anti product. Furthermore, the diphenylsilyl acetal tethered eight-membered ring of 2 has proven to be essential for its stereoinduction, while the homoallylic oxygen does not appear to play a significant role. Although 1,5-anti aldol reactions have been used frequently in the syntheses of polyketidederived natural products, the underlying mechanism for the 1,5-anti-stereoinduction remains inconclusive. Three models have been proposed, including Hoberg's π-stacking model, Goodman's hydrogen-bonding model, and a modification of Abiko's diborylated model. The underlying mechanism for the stereoinduction of 2 was investigated using variable temperature NMR, 1D NOESY and 1D ROESY experiments. It was found that Hoberg's and Abiko's models are not able to explain the stereoinduction of 2 and that Goodman's model used for explaining the transition states of the aldol reaction of β-trimethylsilyloxy methyl ketones is also not suitable. A modification of Goodman's model has been proposed to explain the excellent 1,5-anti stereoinduction of 2. While attempts to couple 2 and 3 to a variety of bulky aldehydes bearing groups with different steric and electronic factors in boron-mediated aldol reactions were unsuccessful, the reaction of 3 with 4-bromobenzaldehyde using TiCl₄ and DIPEA afforded an excellent yield (>99%) of the aldol product. This revealed the six-membered ring in the TS of the boron-mediated aldol reaction is too compact for 2 and 3. However, it was found that 2 is incompatible with TiCl₄. Key questions regarding the 1,5-anti-stereoinduction of 2 have been answered and a modified procedure for the NMR investigation of an aldol reaction is described in this thesis.</p>

Studies Towards the Synthesis of Peloruside A

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>

Studies Towards the Synthesis of Peloruside A

<p>In the search for new treatments for cancer, advances in biology have provided targets for the destruction of cancer cells. One such structure the microtubule, a protein required for cell division, has been the target of many successful anticancer agents including the multi-million dollar earning Taxol [trademark] (paclitaxel) and the epothilones, currently in late-stage clinical trials. More recently it has been shown that peloruside A 1, a secondary metabolite isolated from the New Zealand marine sponge Mycale hentscheli, prevents cell division by stabilising microtubules, and thus offers promise as a novel anticancer agent. However, due to its limited natural abundance, significant quantities of peloruside A can only be obtained through chemical synthesis. A retrosynthetic analysis of peloruside A divided the molecule into four key fragments: a) the commercially available C-l to C-2 benzyloxy acetic acid fragment; b) the C-3 to C-7 fragment; c) the C-8 to C-11 fragment and d) the remaining C-12 to C-24 portion of the macrocycle and side chain. The C-3 to C-7 and C-8 to C-11 fragments combine to form a key intermediate pyranose ring. This thesis however, addresses the synthesis of two of these key fragments, namely the C-8 to C-11 and C-12 to C-24 fragments. An efficient synthesis of the C-8 to C-11 fragment of peloruside A, starting from commercially available pantolactone, has been developed. This synthesis proceeds in good overall yield, and has been successfully reproduced on the multigram scale. The significant portion of this thesis, however, is dedicated to the synthesis of the C-12 to C-24 fragment. After our initial strategy proved unviable, a short, facile method for the synthesis of the C-12 to C-24 fragment, involving the formation of a bis-silyl ether, was developed. The protocol for its desired coupling, via a boron_mediated, remote 1,5-anti-induction aldol reaction has also been established. These and subsequent studies provided valuable insight into the origin of 1,5-anti induction in boron-mediated aldol reactions.</p>