CHEMICAL SCIENCE

New ideas for total synthesis of natural products


On November 10, 2022, Professor Jiang Xuefeng’s team at East China Normal University published a new study entitled “Total synthesis of (+)-asperazine A: A stereoselective domino dimerization” in the journal Chem.

This work developed a novel dominocleamine chemistry, which broke through the endo-type nitrogen heteroquaternal carbon construction that could not be achieved by tryptamine chemistry, and was successfully applied to the total synthesis of 4N dimer alkaloid family.

Heteroquaternal carbon centers are widely found in natural products and drug molecules, and the rigid and crowded spatial structure gives them important scientific significance and potential application value. For synthetic chemists, the construction of nitrogen heteroquaternal carbon centers has always been a problem, and the acquisition of nitrogen heteroquaternal carbon skeletons with high stereoselectivity is even more challenging.

Figure 1: Domino assembly strategy achieves (+)-asperazine A total synthesis

Based on the concept of “amino acid chiral induced enamine chemical construction of natural products”, Jiang Xuefeng’s research group of East China Normal University changed the exo-type chiral induction environment of tryptamine chemical flexible side chain, and used rigid chirality in the ring to induce endo-type nitrogen heteroquaternal carbon to complete the total synthesis of natural product (+)-asperazine A (Figure 1).

The authors delineated the reaction pathway and endo/exo selectivity with DFT (Figure 2). Bonded with N−I25As a reference point for calculation (0.0 kcal/mol), the dimer product Gibbs free energy variable (-52.8 kcal/mmol) is a dominant exothermic process. Electrophilic intermediates25It is captured by the attack of enamine in another monomer to construct the C3−N1′ bond and generate exo-type conformationsInt-1The energy rises by 14.1 kcal/mmol and generates the endo-type conformationInt-1The energy drop of 12.0 kcal/mmol and the barrier difference of 26 kcal/mmol contributed to the acquisition of a single endotype product. The isomeric imide cation is then captured by intramolecular anilineInt-2 (−20.5 kcal/mol), releasing protons and triggering rearrangement to the tryptophan backbone (Int-2arrive4l)。 In energy, after closing the ringInt-3-endo-exocompareInt-3-endo-endoAs low as 5.3 kcal/mol, both can obtain dimers after ring-opening aromatization4l。 The transition state structure based on DFT optimization is usedMultiwfnThe software analyzed the interactions in the IGMH system and found that the π−π packing of benzene ring and enamine stabilized the overlapping precursors and transition states of the two monomers, while there was steric hindrance exclusion between aniline and the chiral ester group of the five-membered ring in the exo conformation, so only a single highly selective endo configuration dimer product was obtained.

Figure 2: DFT depicts reaction pathways and endo/exo selectivity

By K. The distortion/interaction activation strain (DIAS) model proposed and developed by N. Houk was used to further elucidate endo/exo selectivity (Figure 3). When the two monomers are close to each other, deformation energy (blue and yellow) is also generated, and binding energy (green) is also generated, and the π− π packing of benzene ring and enamine greatly reduces the reaction energy barrier. The combined result of the three operations is the overall energy of the transition state, which is marked in red. The ENDO configuration is 13.6 kcal/mol lower than the EXO configuration, thus obtaining a single ENDO configuration product.

Figure 3: Deformation/binding energy-activation tension (DIAS) model

The “rigid chiral induced stereoselective enamine chemistry in the ring” proposed by the study changed the exo-type chiral environment induced by the flexible side chain of tryptamine chemistry, obtained the construction of endo-type nitrogen heteroquaternal carbon that could not be achieved by tryptamine chemistry, completed the domino tandem conversion, and brought inspiration for the construction of nitrogen heteroquaternal carbon in natural products. (Source: Web of Science)

Related Paper Information:https://doi.org/10.1016/j.chempr.2022.10.021



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