The Viability of Nitrone–Alkene (3 + 2) Cycloadditions in Alkaloid Biosynthesis

Abstract

Although evidence has mounted in recent years for the biosynthetic relevance of [4 + 2] cycloaddition reactions, other cycloadditions have received much less attention. Herein we used density functional theory (DFT) calculations to assess the viability of nitrone-alkene (3 + 2) cycloaddition reactions proposed to occur during the biosynthesis of several alkaloid natural products (flueggines and virosaines). The results of our calculations indicate that these reactions have low enough intrinsic barriers and diastereoselectivity that they can proceed without enzymatic intervention.

Thermal and Photochemical Mechanisms for Cyclobutane Formation in Bielschowskysin Biosynthesis

“…An activation barrier of 21.6 kcal/mol for TS 4-2 translates to a computed half-life of 13 minutes in water for this ring closure, which suggests that this reaction could well occur without enzyme catalysis. 22 We considered the possibility of enzyme intervention in lowering the barrier for the cyclization of 4 to 2 through specific stabilizing interactions, which we anticipated with hydrogen-bond donating-accepting residues. The relatively apolar protein interior could, however, disfavor the increase in polarity computed to occur along the reaction coordinate (Scheme 2).…”

“…We optimized 'theozyme' transition-state models to mimic an enzyme active site, 24 in the presence of an acetate anion (a Glu/Asp mimic) activating the hemiketal O-H, and with one and two water molecules (as Ser/Thr/Tyr mimics) H-bonding to the furan-2(5H)-one. 22,25 Implicit (CPCM) solvation by diethyl ether was included to model the low dielectric constant of the protein interior. For these theozyme models, less advanced formation of the C 6 -C 12 bond takes place in the (earlier) TS, indicative of an increase in reactivity, borne out by lower computed activation barriers.…”

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

“…In particular, Diels‐Alder, that is, [4π + 2π], cycloadditions have received extensive attention, so the focus here is on several examples of less commonly proposed (3 + 2) dipolar cycloadditions (Figure ). Using SMD(water)‐M06‐2X/6‐311++G(d,p)//M06‐2X/6‐31+G(d,p) computations, Tantillo and coworkers predicted that both inter‐ and intramolecular nitrone/alkene cycloadditions proposed for formation of flueggines and virosaines have free energy barriers of approximately 20 kcal/mol . Houk and coworkers, using M06‐2X/def2‐TZVPP//M06‐2X/6‐31+G(d,p) calculations, predicted that a similar intramolecular nitrone/alkene cycloaddition proposed to be involved in lycojaponicumin biosynthesis, again has a barrier of approximately 20 kcal/mol .…”

The Securinega Alkaloids

“…As in the case of virosaine B (39), the nitrone alkene cycloaddition step was found to be energetically favored by computational methods. 90 Concerning flueggine B (47), no biogenetic pathway was proposed but one can easily speculate that this compound might result from the association of a norsecurinine unit and a bubbialine unit in position C15-C13 0 .…”