Understand the Specific Regio- and Enantioselectivity of Fluostatin Conjugation in the Post-Biosynthesis

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 6; p. 815
• Main Authors: Wang, Yuanqi, Zhang, Changsheng, Zhao, Yi-Lei, Zhao, Rosalinda, Houk, Kendall N
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.05.2020; MDPI
• Subjects: Biosynthesis; conjugation, regioselectivity; Density Functional Theory; Fluorenes - chemistry; Fluorenes - metabolism; fluostatin; Health aspects; Molecular Structure; Observations; Polyketides - chemistry; Polyketides - metabolism; Statins; Stereoisomerism; stereoselectivity; π–π stacking interaction; Japan; conjugation, regioselectivity; stereoselectivity; fluostatin; π–π stacking interaction
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10060815

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 nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST anion. In particular, the significant π-π 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 ( ) 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 π-π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.