期刊
BIOMOLECULES
卷 10, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/biom10060815
关键词
fluostatin; conjugation; regioselectivity; stereoselectivity; pi-pi stacking interaction
资金
- National Key R&D Program of China [2018YFA0901200]
- National Science Foundation of China [31970041, 31770070, 31820103003]
- SJTU JiRLMDS Joint Research Fund [MDS-JF-2019A01]
Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C-C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6-311 + G(d,p)//6-31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10'-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10') of the two reactant molecules maximizes the HOMO-LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophilep-QMand lowest unoccupied molecular orbital (LUMO) of electrophileFST(2)(-)anion. In particular, the significant pi-pi stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C-C coupling. The distortion/interaction-activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C-C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the pi-pi stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.
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