Diels-Alder Reactivity of Allenylboronic Acid Pinacol Ester and Related Dienophiles: Mechanistic Studies and Distortion/Interaction-Activation Strain Model Analysis.

A DFT study of the Diels-Alder reactions of vinylboronic acid pinacol ester, allenylboronic acid pinacol ester, methyl acrylate, and methyl 2,3-butadienoate with cyclopentadiene has been performed. Competitive mechanisms for the reactions of the carboxylic esters have been fully investigated, and similar results to those previously found for the organoboron compounds were obtained. Moreover, reactivity and selectivity patterns were correctly reproduced. The distortion/interaction-activation strain energy model analysis provided a rationale to explain the experimental outcome of the studied [4 + 2] cycloadditions. While the regioselectivity of the allenyl compounds and the relative reactivity of the boronic and carboxylic esters appear to originate from electronic effects that arise from orbital overlap and correlate with the energies of the vacant orbitals of the dienophiles, the lower reactivity of the allenes relative to the vinyl compounds may be due to the distortion of the dienophiles.

Theoretical Study of the Borono-Mannich Reaction with Pinacol Allenylboronate.

A density functional theory study of the mechanism of the Borono-Mannich reaction using benzylamine and piperidine as representative examples of primary and secondary amines with pinacol allenylboronate is presented. The study shows that both reactions progress through coordination between the boron and the phenolic oxygen. Ring size strain and hydrogen bond activation appear to determine the observed divergent regioselectivity. In the case of benzylamine, the eight-membered ring transition structure that leads to the propargylamine exhibits a hydrogen bond between the hydrogen attached to the nitrogen and the phenolic oxygen (γ-attack), whereas for piperidine a hydrogen bond between the hydrogen on the imine carbon and one of the oxygens of the pinacol group was observed in the six-membered ring transition structure toward the allenylamine (α-attack).

Theoretical Study of the BF3-Promoted Rearrangement of Oxiranyl N-Methyliminodiacetic Acid Boronates.

The mechanism of the rearrangement of oxiranyl N-methyliminodiacetyl (MIDA) boronates in dicholoromethane has been extensively investigated with density functional theory. Several reaction pathways were examined. Our results revealed that the most-favorable mechanisms for the BF3-promoted rearrangement of 2-phenyl oxiranyl MIDA boronate (1) and 1-phenyl oxiranyl MIDA boronate (24) comprise two steps: ring opening of the epoxide to a carbocation intermediate followed by migration of a MIDA-boryl group (for the reaction of 1) and hydrogen (for the reaction of 24), to give the same BF3-coordinated α-boryl aldehyde in both cases. The first step of the ring opening of the epoxide is the rate-determining step of these reactions. In the rearrangement step for the reaction of 1, the MIDA-boryl group migrates easily, probably because of its electron-rich sp3-hybridized boron center. For 24, the most-favorable pathway involves a rare boryl-substituted carbocation. The course of these reactions is mainly controlled by electronic effects, although steric effects are also significant. The higher energy barrier calculated for the unsubstituted oxiranyl MIDA boronate (31) explains the lack of reactivity in the studied BF3-promoted rearrangement.

A genome-wide regulatory framework identifies maize pericarp color1 controlled genes.

Pericarp Color1 (P1) encodes an R2R3-MYB transcription factor responsible for the accumulation of insecticidal flavones in maize (Zea mays) silks and red phlobaphene pigments in pericarps and other floral tissues, which makes P1 an important visual marker. Using genome-wide expression analyses (RNA sequencing) in pericarps and silks of plants with contrasting P1 alleles combined with chromatin immunoprecipitation coupled with high-throughput sequencing, we show here that the regulatory functions of P1 are much broader than the activation of genes corresponding to enzymes in a branch of flavonoid biosynthesis. P1 modulates the expression of several thousand genes, and ∼1500 of them were identified as putative direct targets of P1. Among them, we identified F2H1, corresponding to a P450 enzyme that converts naringenin into 2-hydroxynaringenin, a key branch point in the P1-controlled pathway and the first step in the formation of insecticidal C-glycosyl flavones. Unexpectedly, the binding of P1 to gene regulatory regions can result in both gene activation and repression. Our results indicate that P1 is the major regulator for a set of genes involved in flavonoid biosynthesis and a minor modulator of the expression of a much larger gene set that includes genes involved in primary metabolism and production of other specialized compounds.

A hydrogen bond rationale for the enantioselective ß-alkenylboration of enones catalyzed by O-monoacyltartaric acids.

DFT calculations suggest that O-monoacyl L-tartaric acids catalyze the asymmetric conjugate alkenylboration of enones through transition structures that are stabilized by hydrogen-bonding interactions. Formation of a five-membered acyloxyborane is proposed. The hydrogen of the free carboxy group derived from the catalyst interacts with the carbonyl group of the cyclic acyloxyborane, stabilizing the transition structure and reducing the flexibility of the system. Additional stabilizing nonclassical CH···O hydrogen-bond interactions seem to determine the observed enantioselectivity.

Reactivity and selectivity of boron-substituted alkenes in the Diels-Alder reaction with cyclopentadiene. A study of the electron charge density and its Laplacian.

The effect of the nature of the boron moiety upon the reactivity and the selectivity of a variety of vinylboron dienophiles (1-12) in the Diels-Alder (DA) reaction was investigated using density functional theory and the quantum theory of atoms in molecules. The calculated reactivity of the dienophiles decreases in the order vinylborane (1) > dihalovinylboranes (2-4) > dialkylvinylboranes (5-7) ≈ vinyl boronic acid (8) > vinylboronates (9, 10) > vinyl MIDA boronate (11) ≈ vinyltrifluoroborate (12). The DA reactions of 1-7 were slightly endo-selective due to the stronger C6-B secondary orbital interaction in the endo transition structures (TSs) evaluated by the C6|B delocalization index. In the TSs of 5 and 7, a combination of electronic and steric factors reduce the endo selectivity. The moderate exo selectivity calculated for the DA reactions of boronates 8-11 was attributed mainly to the hydrogen bond between the oxygen atom of boronate moieties and one of the acidic hydrogens of the methylene of cyclopentadiene in the exo TSs, which also reduces the ability of the oxygen lone pairs to donate electron density into the vacant boron orbital. Interestingly, the cooperative effect between the two hydrogen bonds in the exo TS of the DA reaction of vinyltrifluoroborate (12) determines the almost exclusive exo selectivity predicted for this DA reaction. We propose that the relative reactivities of the dienophiles can be estimated by the charge density (ρr) and its Laplacian (∇(2)ρr) at the (3,+1) critical point in the topology of ∇(2)ρr, evaluated at the reactant molecules in the ground state. The profiles of the several topological parameters along the reaction are affected by the nature of the substituents attached to the boron atom and by the mode of addition (endo and exo) in the DA reactions.

Theoretical investigation of the Diels-Alder reactions of unsaturated boronates.

The Diels-Alder reactions of simple unsaturated boronates have been investigated using computational methods and the results were compared with those for the analogue dihalo- and dialkylboranes. Our results indicate that the activating effect of the boronate moiety is small. All the studied reactions are concerted normal electron-demand Diels-Alder reactions with asynchronous transition structures and weak [4 + 3] C-B secondary orbital interactions, which explains the low experimental reactivity. Both electronic and steric effects contribute to give the observed low stereo- and regioselectivities.

[4 + 3] and [4 + 2] mechanisms of the Diels-Alder reactions of vinylboranes: an analysis of the electron charge density distribution.

The Diels-Alder (DA) reactions of isoprene with vinylborane, dimethylvinylborane and dichlorovinylborane have been studied using density functional theory and the quantum theory of atoms in molecules. We evaluated the topological properties of the transition structures (TSs) and the evolution of such properties along the reaction paths. In accordance with previous studies, our results indicate that the endo TSs of the reaction with vinylborane present high [4 + 3] character, while the exo TSs and all the TSs of the reactions with dimethylvinylborane and dichlorovinylborane have [4 + 2] character. The higher charge concentration between the diene and the dienophile appears to account for the greater stabilization of the [4 + 3] TSs. The [4 + 3] structure turns into the [4 + 2] structure through a conflict mechanism in which the C1 and B atoms compete to become attached to C6. The C6-B interaction, present from early steps of the reaction until beyond the TSs, plays a key role in facilitating the formation of the new σ-bonds. The [4 + 3] and [4 + 2] mechanisms for the DA reactions of boron-substituted dienophiles may be distinguished by analyzing the profile of the ellipticity at the C1-C6 bcp along the course of the reaction.

Mechanistic insights into the BINOL-derived phosphoric acid-catalyzed asymmetric allylboration of aldehydes.

BINOL-derived phosphoric acids catalyze the asymmetric allylboration of aldehydes. DFT and QM/MM hybrid calculations showed that the reaction proceeds via a transition state involving both a hydrogen-bonding interaction from the catalyst hydroxyl group to the pseudoaxial oxygen of the cyclic boronate and a stabilizing interaction from the phosphoryl oxygen of the catalyst to the formyl hydrogen of the aldehyde. These interactions lower the energy of the transition structure and provide extra rigidity to the system. This mechanistic pathway is consistent with the experimentally observed enantioselectivity except in one case. We have used our model's predictions to guide our own experimental work. The conflict is resolved in favor of our calculations.

Application of the multi-standard methodology for calculating 1H NMR chemical shifts.

Gauge including atomic orbitals (GIAO) (1)H NMR chemical shift calculations have been performed for 66 organic compounds at 72 different levels of theory using the multi-standard approach (MSTD) previously developed for (13)C NMR. This straightforward computational technique involves the combination of methanol and benzene as standards. The studied methodology has been shown to predict (1)H NMR chemical shifts efficiently at different levels of theory.

Allenylboronic Acid Pinacol Ester: A Selective Partner for [4 + 2] Cycloadditions.

We have studied the reaction of allenylboronic acid pinacol ester with cyclopentadiene with experimental and computational methods. The reaction occurred efficiently with complete Diels-Alder periselectivity and regioselectivity at the proximal double bond. The concerted mechanism for the observed transformation was computed to be favored over competitive addition to the distal double bond, [3,3]-sigmatropic rearrangements, and stepwise radical mechanism. This unprecedented Diels-Alder reaction enables the construction of synthetically versatile boron-substituted cycloadducts.

A facile microwave-assisted Diels-Alder reaction of vinylboronates.

The Diels-Alder reaction of vinylboronates can be easily performed using microwave irradiation giving excellent yields of the cycloadducts. Pinacol vinylboronate was the reagent of choice due to its stability towards hydrolysis, operational simplicity and yields of Diels-Alder products. To the best of our knowledge, this is the first example of microwave-assisted Diels-Alder reaction of boron-substituted dienophiles. Subsequent in situ oxidation of the cycloadducts with alkaline hydrogen peroxide afforded the alcohols efficiently.

Synthetic and computational studies on the tricarboxylate core of 6,7-dideoxysqualestatin H5 involving a carbonyl ylide cycloaddition-rearrangement.

Reaction of diazodiketoesters 17 and 28 with methyl glyoxylate in the presence of catalytic rhodium(II) acetate generates predominantly the 6,8-dioxabicyclo[3.2.1]octanes 29 and 30, respectively. Acid-catalysed rearrangement of the corresponding alcohol 31 favours, at equilibrium, the 2,8-dioxabicyclo[3.2.1]octane skeleton 33 of the squalestatins-zaragozic acids. Force field calculations on the position of the equilibrium gave misleading results. DFT calculations were correct in suggesting that the energy difference between 31 and 33 should be small, but did not always suggest the right major product. Calculation of the NMR spectra of the similar structures could be used to assign the isomers with a high level of confidence.

A multi-standard approach for GIAO (13)C NMR calculations.

The influence of the reference standard employed in the calculation of (13)C NMR chemical shifts was investigated over a large variety of known organic compounds, using different quantum chemistry methods and basis sets. After detailed analysis of the collected data, we found that methanol and benzene are excellent reference standards for computing NMR shifts of sp(3)- and sp-sp(2)-hybridized carbon atoms, respectively. This multi-standard approach (MSTD) performs better than TMS in terms of accuracy and precision and also displays much lower dependence on the level of theory employed. The use of mPW1PW91/6-31G(d)//mPW1PW91/6-31G(d) level is recommended for accurate (13)C NMR chemical shift prediction at low computational cost.

Asymmetric allylboration reactions with Soderquist's chiral 10-substituted-9-borabicyclo[3.3.2]decanes: a theoretical study.

Chiral B-allyl-10-substituted-9-borabicyclo[3.3.2]decanes are highly efficient reagents for the enantioselective allylboration of adehydes and ketones. In this study, we use DFT calculations to rationalize the experimentally observed reactivity and selectivity. Calculations correctly reproduced the experimental reactivity trends and enantioselectivities. Our results suggest that the origin of the facial selectivity relies strongly on steric effects.

Remarkable Reactivity of Boron-Substituted Furans in the Diels-Alder Reactions with Maleic Anhydride.

The reactivity of boron-substituted furans as dienes in the Diels-Alder reaction with maleic anhydride has been investigated. Gratifyingly, the furans with boryl substituents at C-3 gave the exo cycloadduct exclusively with excellent yields. In particular, the potassium trifluoroborate exhibited outstanding reactivity at room temperature. Theoretical calculations suggested that the trifluoroborate group is highly activating and also that the thermodynamics is the main factor that determines whether the products can be obtained efficiently or not.

Theoretical study of the asymmetric conjugate alkenylation of enones catalyzed by binaphthols.

To rationalize the experimental results observed in the asymmetric conjugate addition of alkenylboronates to enones catalyzed by binaphthols and shed light into the factors controlling the rate, the selectivity, and the substituent effects of this process, a theoretical DFT study has been performed. The calculations suggest the catalytic cycle is finely balanced. Reversible exchange of methoxy ligands gives rise to the binaphthol-derived alkenylboronate, which is highly Lewis acidic and strongly coordinates to the enone carbonyl in a reversible fashion, lowering the energy barrier for the subsequent conjugate addition step. The key asymmetric step goes through a sofalike transition structure in which the boron atom is strongly bound to the carbonyl oxygen and lies in the plane of the enone moiety. A steric clash between one of the iodine atoms of the ligand and one face of the enone seems to be responsible for the facial discrimination. The alternative reaction channel in which only one methoxy ligand of the alkenylboronate is exchanged was investigated too and was computed to be disfavored. The [4 + 2] and the [4 + 3] pathways for the competitive hetero-Diels-Alder reaction were also found to be disfavored relative to the conjugate alkenylboration. In addition, the effects of substitution on the enone and the alkenylboronate have been evaluated. Calculations correctly reproduced the experimental reactivity trends and enantiomeric ratios.

Alkylhalovinylboranes: a new class of Diels-Alder dienophiles.

The Diels-Alder reactions of alkylhalovinylboranes have been investigated theoretically and experimentally. Alkylhalovinylboranes presented higher reactivity than the corresponding dialkylvinylboranes. Although endo/exo selectivities were high for the reactions with cyclopentadiene, facial selectivities for the chiral analogues were low. Our results demonstrate that the replacement of an alkyl group on the boron atom by a halogen increases the dienophilicity considerably.

Mechanistic insights into the catalytic asymmetric allylboration of ketones: Brønsted or Lewis acid activation?

Binaphthol ligands promote the enantioselective addition of allylboronates to ketones. In this study, we use DFT calculations to establish the identity of the reacting chiral species. Our results show that a cyclic Lewis acid-activated boronate is the most reactive species on the basis of calculated energy barriers, and it is only this species that leads to the correct enantiomer. The stereoinduction can be rationalized in terms of the competing chairlike transition structures.