Total synthesis of apoptolidin A
Michael T Crimmins1, Hamish S Christie, Alan Long
1Venable and Kenan Laboratories of Chemistry, Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, USA. crimmins@email.unc.edu
Organic Letters
|February 10, 2009
Summary
Researchers achieved a total synthesis of apoptolidin A, a potent antitumor agent. This enantioselective synthesis utilized key glycosylations, cross-metathesis, and macrolactonization for constructing complex polypropionate and sugar units.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Chemical Synthesis
Background:
- Apoptolidin A is a potent antitumor agent with a complex polypropionate structure.
- The total synthesis of complex natural products presents significant challenges in stereocontrol and fragment coupling.
Purpose of the Study:
- To achieve a highly convergent and enantioselective total synthesis of apoptolidin A.
- To develop and apply novel synthetic methodologies for constructing complex molecular architectures.
Main Methods:
- Employing highly selective glycosylations for disaccharide and deoxyglucose attachment.
- Utilizing cross-metathesis for the incorporation of the trienoate unit.
- Executing a Yamaguchi macrolactonization to form the macrocyclic core.
- Establishing stereocenters via diastereoselective chlorotitanium enolate aldol reactions.
Main Results:
- A complete, enantioselective total synthesis of apoptolidin A was successfully achieved.
- The synthesis demonstrated the efficacy of selective glycosylations, cross-metathesis, and macrolactonization strategies.
- Precise control over twelve stereocenters was maintained throughout the synthetic route.
Conclusions:
- The developed synthetic strategy provides a viable route to apoptolidin A.
- This synthesis showcases advanced techniques in stereoselective synthesis and natural product assembly.
- The methodology may be applicable to the synthesis of related complex molecules.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
01:30Apoptosis
Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size reduction of the tissue.
01:30Production of Pharmaceuticals
Industrial insulin production uses genetically engineered E. coli expressing a proinsulin gene controlled by a tryptophan promoter and containing a methionine linker for later cleavage. The cells also carry ampicillin resistance for selective growth. Seed cultures are stored at −80 °C and production begins by thawing a small amount to inoculate starter cultures, which are progressively scaled to a 50,000-L bioreactor. In the bioreactor, E. coli grow in nutrient-rich media under sterile, tightly...
01:17The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
01:28Peptidoglycan Synthesis
Structure of PeptidoglycanPeptidoglycan is a vital structural component of the bacterial cell wall, providing mechanical strength and shape to the cell. It consists of repeating units of two sugars—N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM)—linked by β-1,4 glycosidic bonds. These sugar chains are cross-linked by short peptide chains, forming a mesh-like polymer that surrounds the bacterial plasma membrane.Cytoplasmic Phase – Precursor SynthesisPeptidoglycan biosynthesis begins in...