Related Experiment Video
Updated: Aug 6, 2026
05:57
Synthesizing Amino Acids Modified with Reactive Carbonyls in Silico to Assess Structural Effects Using Molecular Dynamics Simulations
Published on: April 26, 2024
Total Synthesis of Benthol A: Evidence for a Structure Revision
Guanghao Huang1, Andrea Tomio1, Thomas Varlet1
1Max-Planck-Institut für Kohlenforschung , 45470Mülheim/Ruhr, Germany.
Journal of the American Chemical Society
|July 16, 2026
Summary
The first total synthesis of marine natural product Benthol A, known for antimalaria and antiviral activities, was achieved. This synthesis revealed and corrected a structural error in the original assignment of a stereocenter.
Area of Science:
- Marine Natural Products Chemistry
- Organic Synthesis
- Medicinal Chemistry
Background:
- Benthol A is a complex marine natural product with significant antimalaria and antiviral properties.
- Its structure features a 72-carbon backbone with numerous stereocenters and alkenes, posing a significant synthetic challenge.
- Previous structural assignment relied on spectroscopic, chemical, and computational methods.
Purpose of the Study:
- To achieve the first total synthesis of Benthol A.
- To verify and potentially revise the proposed structure of Benthol A.
- To develop novel synthetic methodologies for complex molecule construction.
Main Methods:
- Total synthesis of Benthol A utilizing advanced organic chemistry techniques.
- Spectroscopic analysis (13C NMR, 3JH,H coupling) for structural elucidation and comparison.
- Gold-catalyzed spiroacetalization and Buchner-Curtius-Schlotterbeck reaction for key bond formations.
Main Results:
- Successful total synthesis of Benthol A.
- Identification of a subtle structural error in the C40 stereocenter of the originally reported structure.
- Demonstration of regiochemical control in gold-catalyzed spiroacetalization via protecting group strategy.
- Efficient coupling of complex building blocks using in situ generated diazo derivatives.
Conclusions:
- The total synthesis provides definitive structural proof of Benthol A.
- A revision of the C40 stereochemistry is proposed based on synthetic and spectroscopic evidence.
- The developed synthetic strategies offer valuable tools for the synthesis of other complex polyketides and polyethers.
More Related Videos
Related Concept Videos
01:07Structure of Benzene: Kekulé Model
In 1865, August Kekule suggested the structure of benzene according to the structural theory of organic chemistry based on the three assertions—formula of benzene is C6H6, all the hydrogens of benzene are equivalent, and each carbon must have four bonds due to its tetravalency.
He proposed that benzene has a cyclic structure of six carbon atoms attached to one hydrogen atom each, with three alternating pi bonds.
He proposed that benzene has a cyclic structure of six carbon atoms attached to one hydrogen atom each, with three alternating pi bonds.
01:13¹H NMR: Complex Splitting
A proton M that is coupled to a proton X results in doublet signals for M. However, NMR-active nuclei can be simultaneously coupled to more than one nonequivalent nucleus. When M is coupled to a second proton A, such as in styrene oxide, each peak in the doublet is split into another doublet.
Splitting diagrams or splitting tree diagrams are routinely used to depict such complex couplings. While drawing splitting diagrams, the splitting with the larger coupling constant is usually applied first.
Splitting diagrams or splitting tree diagrams are routinely used to depict such complex couplings. While drawing splitting diagrams, the splitting with the larger coupling constant is usually applied first.
01:18Structure of Benzene: Molecular Orbital Model
According to the molecular orbital (MO) model, benzene has a planar structure with a regular hexagon of six sp2 hybridized carbons. As shown in Figure 1, each carbon is bonded to three other atoms with C–C–C and H–C–C bond angles of 120°. The C–H bond length is 109 pm, and the C–C bond length is 139 pm which is midway between the single bond length of sp3 hybridized carbons (154 pm) and sp2 hybridized carbons (133 pm).
02:11Conformations of Cyclohexane
Cyclohexane does not exist in a planar form due to the high angle and torsional strain it would experience in the planar structure. Instead, it adopts non-planar chair and boat conformations.
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal tetrahedral value,...
The chair form is the most stable and derives its name from its resemblance to the “easy chair.” In the chair conformation, two carbon atoms are arranged out-of-plane — one above and one below, minimizing the torsional strain. In the chair form, the bond angle is very close to the ideal tetrahedral value,...
01:37NMR Spectroscopy of Benzene Derivatives
Simple unsubstituted benzene has six aromatic protons, all chemically equivalent. Therefore, benzene exhibits only a singlet peak at δ 7.3 ppm in the 1H NMR spectrum. The observed shift is far downfield because the aromatic ring current strongly deshields the protons. Any substitution on the benzene ring makes the aromatic protons nonequivalent, and the protons split each other. The peak is, therefore, no longer a singlet and the splitting pattern and their associated coupling constants depend...
01:20¹³C NMR: Distortionless Enhancement by Polarization Transfer (DEPT)
When proton-coupled carbon-13 spectra are simplified by a broadband proton decoupling technique, structural information about the coupled protons is lost. Distortionless enhancement by polarization transfer (DEPT) is a technique that provides information on the number of hydrogens attached to each carbon in a molecule. While the DEPT experiment utilizes complex pulse sequences, the pulse delay and flip angle are specifically manipulated. The resulting signals have different phases depending on...