Abstract
The chemical synthesis of molecules with closely packed atoms having their bond coordination saturated is a challenge to synthetic chemists, especially when three-dimensional control is required. The organocatalyzed asymmetric synthesis of acyclic alkenylated, alkynylated and heteroarylated quaternary carbon stereocenters via 1,4-conjugate addition is here catalyzed by 3,3´-bisperfluorotoluyl-BINOL. The highly useful products (31 examples) are produced in up to 99% yield and 97:3 er using enediketone substrates and potassium trifluoroorganoborate nucleophiles. In addition, mechanistic experiments show that the (Z)–isomer is the reactive form, ketone rotation at the site of bond formation is needed for enantioselectivity, and quaternary carbon formation is favored over tertiary. Density functional theory-based calculations show that reactivity and selectivity depend on a key n→π* donation by the unbound ketone’s oxygen lone pair to the boronate-coordinated ketone in a 5-exo-trig cyclic ouroboros transition state. Transformations of the conjugate addition products to key quaternary carbon-bearing synthetic building blocks proceed in good yield.
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Introduction
All-carbon quaternary stereocenters are an important synthetic motif found in natural products and bioactive molecules (Fig. 1) that are especially difficult to synthesize enantioselectively1,2,3,4. Successful strategies have recently been developed for cyclic systems (Fig. 2A)2,5,6,7,8,9,10; however, constructing quaternary centers in acyclic molecules remains a significant synthetic challenge due to the combination of high levels of steric congestion and greater conformational freedom11,12,13,14,15,16,17,18,19,20,21. Despite its known benefits, organocatalysis22,23,24 has been used for asymmetric quaternary center construction only a few classes of acyclic systems25,26,27,28, though asymmetric 1,4-conjugate addition for tertiary carbon synthesis is well documented29,30,31,32,33. This report details the successful organocatalytic synthesis of valuable acyclic 1,4-dicarbonyl products with vinylated and arylated quaternary centers34.
Inset shows how quaternary carbon formation applies to a synthesis86.
A Organometallic catalysis for cyclic quaternary carbon synthesis. B Organocatalytic Michael addition of nitromethane to chalcones. C The synthesis of acyclic quaternary carbons with alkenyl, alkynyl, and aryl substituents (orange “R´” substituent) via an ouroboros transition state discussed herein.
Organocatalyzed Michael additions to acyclic proquaternary substrates have been reported for nitromethane or cyanide but have otherwise been rare (Fig. 2B)35,36,37,38,39,40,41,42. A newer class of easily synthesized BINOL–derived enantioselective 1,4–addition organocatalysts have proven to be useful, recyclable, and functional group tolerant in many transformations43,44,45,46,47,48,49,50,51,52,53; however, these reactions have only produced chiral tertiary carbon centers to date. In fact, β,β–disubstituted enones were investigated for quaternary carbon formation but completely lacked reactivity54.
Results and discussion
To overcome steric deactivation via increased electrophilic activation, we looked to enones bearing additional electron-withdrawing groups. In particular, the use of 2–ene–1,4–diones (1) could allow an approach to often difficult-to-access chiral 1,4-diketones with beta quaternary carbons (Fig. 2C) and functionality for the total synthesis of natural products55,56,57. However, few precedents related to such a β-vinylation or arylation of ketones to construct quaternary centers exist58,59,60,61,62,63.
To test the diketone activation hypothesis, enediketone 1a was synthesized as a mixture of cis and trans isomers, which was then purified, and potassium styrenyl trifluoroborate was chosen as an exploratory nucleophile (Fig. 3). Unsurprisingly, the E–isomer was almost completely unreactive (<2% yield, ~77:23 er), so further experimentation was conducted with pure (Z)–enediketone. While we fully expected competing regioselectivity with addition at both alkene positions, substrate (Z)–1a reacted with superb regioselectivity with the use of typical conditions for BINOL 4–catalyzed conjugate additions9,10 to give a single product. In fact, (Z)−1a defied all initial expectations of addition at the less hindered carbon and provided quaternary carbon-bearing 1,4-diketone 3a in 99% yield and 96:4 er. A control experiment without any catalyst gave 3a from (Z)–1a in 69% yield after 18 h, indicating that a significant racemic background reaction was operative. These results suggested that two cis-disposed ketone carbonyls must be present for reactivity and may provide Z-dependent cooperative activation. We were then able to demonstrate a one-pot reaction using (E)−1a, which was first converted to the Z-form via photo-isomerization64 and then could undergo conjugate addition to provide the quaternary carbon product in good yield (79%) and the same er obtained from pure (Z)-enediketone. Such an isomerization may even have been the source of activity seen in Fig. 3A. The presence or absence of light had no effect on the reaction using pure Z-enediketone. Various BINOL derivatives were tested for increased reactivity and stereoselectivity, and the effects of solvent and temperature were also investigated, but with no improvement (See “Synthesis of BINOL-based catalysts” in the Supplementary Information).
A Nearly no reactivity was observed with the trans diketone. B The cis substrate afforded catalytic activity that produced the acyclic quaternary carbon product in high yield and with high stereoselectivity despite a significant background reaction also being operative. C Pure trans diketone or a mixture of cis and trans could be converted to cis-enriched substrate that then reacted in a similar manner to pure cis diketone. 4Å-MS 4Å molecular sieves, PhMe toluene, er enantiomeric ratio, CFL Compact Fluorescent Lightbulb.
Various enediketones showed productive reactivity with the catalytic conditions identified above. Both electron–donating and electron–withdrawing groups on the ketone’s aromatic ring provided effective reaction (3a–3e, Fig. 4). A heteroaromatic enone substituent was likewise accommodated (see 3f). However, changing the phenylketone to a methylketone resulted in the formation of product 3g with slightly reduced stereoselectivity and competing regioselectivity to form a tertiary stereocenter in 11% yield (see 5g). Despite both carbonyls being equally Lewis basic, quaternary carbon formation was still favored in a 4:1 ratio. Interestingly, moving the branching vinyl methyl from the alkyl ketone side of the alkene to the phenyl ketone side reversed the regioselectivity so that the major diastereomer of dione 5h was formed with low enantioselectivity in 63% yield. The minor diastereomer of 5h was produced along with the quaternary product in 17% yield as an inseparable 2:1 mixture. An initial regioselectivity hypothesis was that the relative locations of the phenyl and aliphatic ketones have a directing effect on the addition, where C–C bond formation is more strongly favored at the β-carbon of an aryl ketone than that of an alkyl ketone43,44,45,46,47,48,49,50,51,52,53. Based on work by Goodman and Pellegrinet44, we believed that the phenyl ketone directed an intramolecular 5-exo-trig 1,4-addition that reinforced the favored quaternary carbon formation.
Reaction yields are of purified isolated products. Enantiomeric ratios were determined by HPLC with chiral stationary phase. For 5g and 5h the stereochemistry was not determined. For 3j the use of both 20 mol % (30 h) and 40 mol % (18 h) of 4 is illustrated.
Replacing the methyl groups of 1a with ethyl groups gave improved stereoselectivity (3i) but slightly lowered the yield, likely due to an increase in steric repulsion. Changing the methyl ketone of 1a to a phenyl ketone afforded the quaternary center in 3j with moderate er; however, replacing both methyl groups with phenyls precluded reaction so triphenyl product 3k was not observed. The series 3a, 3j, and 3k shows the negative impact of increasing the size of substituents on yield. It is noteworthy that a cyclic diketone system gave the alpha quaternary center in 3l in high yield but with little enantioselectivity. Apparently, without rotation of the carbonyl-olefin bond where C–C bond formation occurs reactivity is retained, but the stereoselectivity is almost completely lost.
Various vinyl, alkynyl, and heteroaromatic nucleophiles were also examined. A few substrates gave a lower er, but use of trifluorotoluene and/or an increased loading of the catalyst improved the enantioselectivity (Fig. 5). For example, the electron rich styrenyl nucleophiles that afforded 3m and 3n originally showed a significant racemic background reaction, but increasing the catalyst loading improved the er to 80:20 and 92:8, respectively. An electron-withdrawing group on the styrene system in 3o produced a high yield and er without adjustment. Nucleophiles with alkyl chains gave the dienyl adducts 3p, 3q, and trans alkenyl 3r–3x in high yield and enantioselectivity. Having two vinyl substituents resulted in diminished enantioselectivity (see 3y and 3z), but a synthetically useful bromo vinyl borate synthesized 3aa in moderate yield and improved er. Alternatives to the vinyl nucleophilic system were also tested. Alkynyl reagents provided useful reactivity, but decreased stereoselectivity (see 3ab and 3ac). It is worth noting that the isomerization from (Z)−1a to (E)−1a occurred competitively during the formation of 3z and 3ab, which may have reduced both the yield and stereoselectivity for those reactions. The use of other strong nucleophiles, like furanyl borate, similarly formed quaternary carbons in high yield but with low enantioselectivity due to the competitiveness of the background reaction (see 3ad)65. On the other hand, a thienyl borate produced 3ae in good yield and high er.
Reaction yields are of purified isolated products, with the average of at least 2 trials presented. Enantiomeric ratios were determined by HPLC with chiral stationary phase. For 3m–n and 3s–3x, the use of 40 mol % of 4 is presented. For 3s–x and 3ae, the solvent was PhCF3. For 3aa the use 30 mol % of 4 allowed reduction of organoborate nucleophile to 1.5 equiv.
To explain (A) why only the Z-isomer was reactive and (B) why quaternary regioselectivity was favored over tertiary carbon formation, we pursued a computational investigation using substrates (Z)−1a and (E)−1a with styrenyl boronate. Based on prior mechanistic investigations relevant to tertiary carbon formation via similar catalysis47, it is likely that the potassium trifluoroborate salt dissociates fluoride and condenses with the BINOL 4 to form an activated chiral boronate ester that then coordinates to the enone carbonyl. To simplify the calculations, BINOL 4 was modelled as 3,3´-difluorobisphenol. We initially modeled the formation of the Lewis acid/Lewis base complexed boronate-ketone adduct 6, and our calculations supported Goodman’s finding44 that this complex formed as a discrete mechanistic intermediate prior to the transition state (Fig. 6). Note that this stable intermediate was taken as the zero-point reference for all other calculated geometries. Conjugate addition transition states derived from ketone-coordinated boronates with both endo and exo modes of addition66,67 were next examined (Figs. 6 and 7). Where Goodman’s work showed 6-endo cyclization (see 8c and 8e), we found that 5-exo modes68 were lower in energy for both quaternary and tertiary carbon formation (compare 8a to 8c and 8d to 8e). This new mode of reactivity is enabled by the additional ketone. Close examination of the exo transition states revealed a fascinating stabilizing effect; the ketone distal to the Lewis acid coordination not only enabled the 5-exo addition but also participated in an n→π* donation to the bound carbonyl (8a)69. This ouroboros-like activation70,71 is evidenced by the short C = O→C = O bond (1.53 Å in 8a) and the tetrahedral geometry of the carbon of the bound C = O (C16). Such interactions have been described for static protein structure72 and utilized for the synthesis of Lewis acid/base heteroaromatics69, but to our knowledge has not been proposed as a stabilizing factor in reaction catalysis73. The LUMO of the C16 carbonyl thus acts as a Lewis acid activating the planar enone for 5-exo-trig conjugate addition, lowering the LUMO energy, and the electron donation of the planar ketone to the C16 carbonyl simultaneously increases the electron density in the nucleophilic system (C28), raising the HOMO energy. Additionally, this stabilizing interaction was not accessible in the 6-endo geometries (see longer O to C distances in 8c and 8e), and we believe this to be a reason for their relatively higher energy pathways. In investigating the generation of the ouroboros stabilization, we could identify that the formation of iso-furan 7 occurred prior to C–C bond formation. Some pathways, such as that shown in Fig. 6, have 7 formed as a meta stable intermediate as a local minimum. In others, it is a shoulder or part of a continuous slope to the transition state. These calculations also showed that the (R)-biaryl introduces torsion in the coordinated system that favors 8a over 8b, giving the major observed enantiomer. In considering why reactivity is unfavorable for (E)-enediketones, several potential transitions states derived from methyl or phenyl ketone-coordinated isomers of 6 were examined, but only the transition states 8f and 8g converged reliably. Notably, ouroboros activation was not observable for any reasonable geometries corresponding to transition states derived from (E)-substrates, the 6-endo-trig transition state was thus lower in energy, and the resulting higher overall barrier explains the lack of reactivity of β-disubstituted enones in all previous studies9. Given other recent efforts that also observe such a dependence on (Z)-enone geometry25,26,27,28, ouroboros stabilization may be operative in many catalytic reactions. The poor er arising from the lack of rotation about the alkene-ketone bond in forming 3l also aligns with this hypothesis, as the carbonyl could not fully rotate out of plane to provide 5-exo reactivity, forcing it through a 6-endo transition state like 8e, which also lacks ouroboros activation and therefore has reduced stereocontrol. The decreased enantioselectivity and altered regioselectivity seen for 5g and 5h could also be due to competitive 6-endo reactivity for those substrates rather than due to Lewis basicity.
The BINOL catalyst was modelled as 3,3´-difluorobisphenol. The pre-transition state Lewis acid/Lewis base complex was defined as 0 kcal/mol and other optimized structures are reported relative that energy.
Energies are defined relative to B(Me)-Z-1a (6) in Fig. 6. A Transition state structures derived from (Z)−1a. B Transition state structures derived from (E)−1a. (Me) and (Ph) define whether the methyl ketone or phenyl ketone are bound by the Lewis acidic boron, respectively. 5-exo and 6-endo define the geometry of C–C bond formation according to Baldwin’s rules. 8b and 8d show significant ouroboros stabilization.
An examination of the calculated LUMOs in intermediate 6 and its phenylketone-coordinated isomer showed localization on the planar enone (HOMO/LUMO illustrated in the Source Data file), but the carbons undergoing nucleophilic attack (C13 or C14) bear different proportions of the LUMO74. For both isomers, C14 has significant LUMO character, leading to better HOMO/LUMO overlap, but less of the LUMO is located on C13. The relative localization of the LUMO in these structures and the relative energies of the subsequent transition states correspond to previously characterized experimental rate dependencies on the stabilization of developing cationic charge at the β-carbon of the enone in this class of conjugate additions75,76. An additional insight into the regioselectivity was obtained by examining two possible n→π* interactions in the Z-enediketone. That arising from the Ph-ketone donating into a twisted Me-ketone resulted in a 1.7 kcal/mol more stable conformation than that arising from the Me-ketone donating into a twisted Ph-ketone. The stereoelectronic and steric interactions in these conformations are also likely to be present in 8a and 8d, and the relative stability of their geometries contributing to the difference in regioisomeric transition state energies.
To demonstrate the utility of these quaternary 1,4-diketone products58,59,60,61,62,63,77, examples were transformed into key synthetic building blocks (Fig. 8). Chiral cyclopentenones (see 8), which exist widely in bioactive compounds78,79,80, could be formed in high yield and er via aldol condensation. The absolute stereochemistry of 9 was confirmed by X-ray crystallography81. Chemoselective hydrogenation reduced the benzoyl carbonyl and the alkene of 3a or 3q to form the aliphatic quaternary carbon centers in 10a and 10q, respectively, with the latter containing an otherwise difficult to access alkylated quaternary center with high er. The oxidative cleavage of the styrenyl olefin gave ketoaldehyde 11, which would be useful in recently reported pyrrolidine syntheses77,82. Non-planar heterocycle dihydropyridazine 12, a bioactive pharmacophore83,84, could be generated in good yield. Using the bromo substrate 3e to incorporate an intramolecular Heck coupling reaction gave the quinone-like derivative 1285.
The chemical synthesis of several important molecular motifs is illustrated. Examples include α-quaternary cyclopentenes (9), quaternary alkanes that are achiral (10a) or chiral and enantioenriched (10q), tricarbonyls (11), dihydropyridazines (12), and methide-quinones (13).
In conclusion, we successfully synthesized challenging quaternary centers enantioselectively from (Z)-1,4-enediketones via organocatalyzed conjugate addition. Control experiments showed that the cis-relationship of the ketones was vital to reactivity, and keto-ene bond rotation at the location of C–C bond formation was important for enantioselectivity. DFT calculations showed that the additional ketone provided 5-exo-trig reactivity and a stabilizing interaction through an n→π*cyclic ouroboros activation. The regioselectivity for quaternary carbon formation appeared to be based primarily on the greater HOMO/LUMO overlap in the formation of the quaternary carbon relative to the tertiary carbon. A broad substrate scope of chiral α-quaternary 1,4-diketones were synthesized. Further transformations to quaternary carbon-containing enantio-enriched cyclopentenones, linear hydrocarbons, dihydropyridazines, and quinone methides were demonstrated in good yield and er. These building blocks will enable synthetic endeavors in many areas.
Data availability
The experimental data generated in this study and computational procedures with optimized structures are provided in the Supplementary Information file. The molecular coordinate data generated in this study are provided in the Source Data file. All primary data files, such as.fid files for NMR spectra or coordinate files for molecular structures, are available from the corresponding author for free upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 2121715 (9). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.
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Acknowledgements
The authors are grateful for generous financial support from the NSF (grant CHE-2102282, JAM) and the Welch Foundation (grant E−1744, JAM). Professor Judy Wu at the University of Houston is thanked for aid in access to computational facilities. The computational work was completed in part with resources provided by the Research Computing Data Core at the University of Houston. We are grateful to Dr. Sasha Sundstrom and AbbVie North Chicago for aiding in the acquisition of specific rotation data.
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P.-K.P.: Conceptualization, experimental methodology development and investigation, validation of structures, writing of first draft. A.I.: computational model development and investigation, validation of transitiona states and intermediates, and electronic data curation. J.A.M.: conceptualization of project, writing and editing, project supervision, and acquisition of funding.
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Peng, PK., Isho, A. & May, J.A. Regio- and enantioselective synthesis of acyclic quaternary carbons via organocatalytic addition of organoborates to (Z)-Enediketones. Nat Commun 15, 504 (2024). https://doi.org/10.1038/s41467-024-44744-y
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DOI: https://doi.org/10.1038/s41467-024-44744-y
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