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1.
J Org Chem ; 88(15): 10881-10904, 2023 Aug 04.
Article in English | MEDLINE | ID: mdl-37441763

ABSTRACT

The synthesis of di- and trisubstituted vinyl fluorides with high isomeric purity remains a challenge for organic synthesis. While many methods exist to access these compounds, the separation of the desired isomer from the minor isomer and/or starting materials often is difficult. Herein, we report a practical method to access di- and trisubstituted vinyl fluorides via a selective Horner-Wadsworth-Emmons olefination/hydrolysis, which provides crystalline 2-fluoroacrylic acids in high (>98%) E-isomeric purity. A subsequent silver-catalyzed stereoretentive decarboxylation provides the title substances with high isomeric purity and without the need for tedious chromatography to remove the minor isomer. The process was amenable to a variety of aldehydes and ketones and provided a diverse array of di- and trisubstituted vinyl fluorides. The sequence was applied to the synthesis of antibacterial and anti-inflammatory compounds.

2.
J Am Chem Soc ; 144(35): 16171-16183, 2022 09 07.
Article in English | MEDLINE | ID: mdl-36006026

ABSTRACT

Cooperative dual catalysis is a powerful strategy for achieving unique reactivity by combining catalysts with orthogonal modes of action. This approach allows for independent control of the absolute and relative stereochemistry of the product. Despite its potential utility, the combination of N-heterocyclic carbene (NHC) organocatalysis and transition metal catalysis has remained a formidable challenge as NHCs readily coordinate metal centers. This characteristic also makes it difficult to rationalize or predict the stereochemical outcomes of these reactions. Herein, we use quantum mechanical calculations to investigate formation of γ-butyrolactones from aldehydes and allyl cyclic carbonates by means of an NHC organocatalyst and an iridium catalyst. Stereoconvergent activation of the racemic allyl cyclic carbonate forms an Ir-π-allyl intermediate and activation of an unsaturated aldehyde forms an NHC enolate, the latter of which is rate-limiting. Union of the two fragments leads to stereodetermining C-C bond formation and ultimately ring closure to generate the product lactone. Notably, CO2 loss occurs after formation of the C-C bond and Et3NH+ plays a key role in stabilizing carboxylate intermediates and in facilitating proton transfer to form the NHC enolate. The computed pathways agree with the experimental findings in terms of the absolute configuration, the enantiomer excess, and the different diastereomers seen with the (R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal the lowest energy pathway includes both an NHC ligand and a phosphoramidite ligand on the iridium center. However, the stereochemical features of this Ir-bound NHC were found to not contribute to the selectivity of the process.


Subject(s)
Heterocyclic Compounds , Iridium , 4-Butyrolactone , Aldehydes/chemistry , Catalysis , Heterocyclic Compounds/chemistry , Iridium/chemistry , Ligands , Methane/analogs & derivatives
3.
Organometallics ; 40(14): 2290-2294, 2021 Jul 26.
Article in English | MEDLINE | ID: mdl-34690402

ABSTRACT

In investigating potential control factors that would permit a palladium-catalyzed benzylic vs arene C-H activation as previously reported by our group, it was discovered that the oxidation state of the homogenous palladium species influences the selectivity of C-H activation. DFT calculations show that Pd0 and PdI preferentially activate the sp3 C-H bond in toluene, whereas PdII and PdIII preferentially activate the sp2 C-H bond. This selectivity appears to originate from the steric environment created by the ligand framework on the palladium. As the palladium oxidation state increases, the number of ligand sites increases, which decreases the energetic favorability for activation of the weaker, yet more hindered sp3 C-H bond.

4.
J Am Chem Soc ; 142(21): 9612-9624, 2020 05 27.
Article in English | MEDLINE | ID: mdl-32370493

ABSTRACT

An increasing number of examples demonstrate that the use of two mutually compatible chiral catalysts in one-pot conditions can help realize the long-cherished goal of simultaneous control of absolute and relative configurations in asymmetric catalysis. Engaging two transition metal catalysts for this goal presents a considerable degree of mechanistic challenge to control the mode of substrate activation as well as origin of enantio- and diastereoselectivities, both of which are central to the burgeoning domain of stereodivergent catalysis. We have employed density functional theory (B3LYP-D3) computations to investigate an important stereodivergent reaction between azaaryl acetamide and cinnamyl methyl carbonate. These compounds participate in the stereocontrolling C-C bond formation in the form of activated substrates, respectively, when bound to chiral Cu-Walphos and Ir-phosphoramidite catalysts. Herein, we provide the molecular origin of how all four stereoisomers of the product bearing two contiguous stereogenic centers could be accessed by changing the combinations of chiral catalysts (C1(R,Rp) or C2(S,Sp) of Cu-Walphos in conjunction with P1(R,R,R) or P2(S,S,S) of Ir-phosphoramidite catalysts). The origin of stereodivergence is identified to depend on the differences in the number and nature of noncovalent interactions (NCIs) in the stereocontrolling transition states. In particular, NCIs between the chiral catalysts (C-H···π in C1-P1 catalyst dyad and C-H···π, C-H···F, and π···π in C2-P1) in stereocontrolling transition states are found to be the differentiating factors rendering one of the four stereochemically distinct transition states to be the lowest energy one for a given catalyst combination. These molecular insights suggest that subtle modifications to the catalyst framework could be further exploited in stereodivergent catalysis.

5.
Chem Sci ; 11(1): 208-216, 2020 Jan 07.
Article in English | MEDLINE | ID: mdl-32110372

ABSTRACT

In the contemporary practice of palladium catalysis, a molecular understanding of the role of vital additives used in such reactions continues to remain rather vague. Herein, we disclose an intriguing and a potentially general role for one of the most commonly used silver salt additives, discovered through rigorous computational investigations on four diverse Pd-catalyzed C-H bond activation reactions involving sp2 aryl C-H bonds. The catalytic pathways of different reactions such as phosphorylation, arylation, alkynylation, and oxidative cycloaddition are analyzed, with and without the explicit inclusion of the silver additive in the respective transition states and intermediates. Our results indicate that the pivotal role of silver salts is likely to manifest in the form of a Pd-Ag heterobimetallic species that facilitates intermetallic electronic communication. The Pd-Ag interaction is found to provide a consistently lower energetic span as compared to an analogous pathway devoid of such interaction. Identification of a lower energy pathway as well as enhanced catalytic efficiency due to Pd-Ag interaction could have broad practical implications in the mechanism of transition metal catalysis and the current perceptions on the same.

6.
Proc Natl Acad Sci U S A ; 117(3): 1339-1345, 2020 01 21.
Article in English | MEDLINE | ID: mdl-31915295

ABSTRACT

Design of asymmetric catalysts generally involves time- and resource-intensive heuristic endeavors. In view of the steady increase in interest toward efficient catalytic asymmetric reactions and the rapid growth in the field of machine learning (ML) in recent years, we envisaged dovetailing these two important domains. We selected a set of quantum chemically derived molecular descriptors from five different asymmetric binaphthyl-derived catalyst families with the propensity to impact the enantioselectivity of asymmetric hydrogenation of alkenes and imines. The predictive power of the random forest (RF) built using the molecular parameters of a set of 368 substrate-catalyst combinations is found to be impressive, with a root-mean-square error (rmse) in the predicted enantiomeric excess (%ee) of about 8.4 ± 1.8 compared to the experimentally known values. The accuracy of RF is found to be superior to other ML methods such as convolutional neural network, decision tree, and eXtreme gradient boosting as well as stepwise linear regression. The proposed method is expected to provide a leap forward in the design of catalysts for asymmetric transformations.

7.
Chem Sci ; 9(46): 8738-8747, 2018 Dec 14.
Article in English | MEDLINE | ID: mdl-30627394

ABSTRACT

Increasing use of two chiral catalysts in cooperative asymmetric catalysis in recent years raises some fundamental questions on chiral compatibility between the catalysts, modes of activation, and relative disposition of substrates within the chiral environment of the catalysts for effective asymmetric induction. We present molecular insights into a one-pot catalytic Michael reaction cascade between a dicarbonyl compound (7-oxo-7-phenylhept-5-enal) and nitrostyrene, catalyzed by two chiral organocatalysts (proline and cinchona-thiourea), leading to a densely functionalized tetra-substituted cyclohexane product. The density functional theory (SMD(toluene)/M06-2X/6-31G**) computations helped us identify the role of the organocatalytic catalytic dyad in providing a lower energy pathway. The covalent activation of the aldehydic end by (S)-proline results in an enamine, which then adds to the noncovalently activated nitrostyrene in the first Michael addition to give a nitronate anion. The configuration at two of the four chiral centers of the product gets fixed in this step whereas that of the remaining two is determined by intramolecular cyclization between the nitronate and the enone. Important mechanistic features such as (a) a lower energy pathway as compared to a proline-only route for the formation of the syn-enamine and its participation in the first Michael addition and (b) the origin of the preferred prochiral faces in the C-C bond formation are traced to the active involvement of the cinchona-thiourea catalyst in conjunction with proline in each step of the reaction. The true cooperative action by both the catalysts is identified as enabled by a network of hydrogen bonding, and π···π stacking between the aryl ring of the cinchona-thiourea catalyst as well as other noncovalent interactions between the catalysts themselves, and that between the catalysts and substrate.

8.
J Org Chem ; 82(24): 13449-13458, 2017 12 15.
Article in English | MEDLINE | ID: mdl-29148759

ABSTRACT

Catalytic heterodimerization of ketenes can lead to important four-membered ß-lactones. A recent asymmetric organocatalytic [2 + 2] cycloaddition between methylketene (MK) and methylphenylketene (MPK) in the presence of pseudoenantiomeric cinchona catalysts (trimethylsilylquinine (TMSQ) or methylquinidine (MeQd)) provided ß-lactones with high enantio- and diastereoselectivities. We employ DFT(M06-2X) computations to understand the mechanism and the origin of stereoselectivity in this ketene heterodimerization. The mechanism is found to involve the formation of an ammonium enolate first, by the action of the quinuclidine tertiary amine of the cinchona catalyst on MK. A stepwise pathway wherein the MK-cinchona enolate (enolate-A) adds to MPK in the selectivity-determining C-C bond formation step leading to the R-Z and S-Z product respectively with TMSQ and MeQd catalysts is predicted. The inclusion of LiClO4 is found to favor the C-C bond formation transition state to the S-E isomer in the case of MeQd and the R-E isomer with TMSQ catalysts. In the most preferred transition states, more effective C-H···π (between the phenyl ring of the EPK and the catalyst) and C-H···O interactions (between the catalyst and LiClO4) are noticed than that in the higher energy analogues, underscoring the importance of noncovalent interactions in enantio- and diastereocontrol.

9.
Chem Sci ; 7(5): 3147-3153, 2016 May 01.
Article in English | MEDLINE | ID: mdl-29997806

ABSTRACT

meta-Hydroxylated cores are ubiquitous in natural products. Herein, we disclose the first template assisted meta-hydroxylation reaction. Experimental and in silico studies helped us to gain valuable mechanistic insights, including the role of the hexafluoroisopropanol (HFIP) solvent, during C-H hydroxylation. The reactive intermediates, prior to the C-H activation, have been detected by spectroscopic techniques. Additionally, the C-O bond formation has been extended to meta-acetoxylation. The preparation of a phase II quinone reductase activity inducer and a resveratrol precursor illustrated the synthetic significance of the present strategy.

10.
J Am Chem Soc ; 137(50): 15712-22, 2015 Dec 23.
Article in English | MEDLINE | ID: mdl-26599720

ABSTRACT

Accomplishing high diastereo- and enantioselectivities simultaneously is a persistent challenge in asymmetric catalysis. The use of two chiral catalysts in one-pot conditions might offer new avenues to this end. Chirality transfer from a catalyst to product gets increasingly complex due to potential chiral match-mismatch issues. The origin of high enantio- and diastereoselectivities in the reaction between a racemic aldehyde and an allyl alcohol, catalyzed by using axially chiral iridium phosphoramidites PR/S-Ir and cinchona amine is established through transition-state modeling. The multipoint contact analysis of the stereocontrolling transition state revealed how the stereodivergence could be achieved by inverting the configuration of the chiral catalysts that are involved in the activation of the reacting partners. While the enantiocontrol is identified as being decided in the generation of PR/S-Ir-π-allyl intermediate from the allyl alcohol, the diastereocontrol arises due to the differential stabilizations in the C-C bond formation transition states. The analysis of the weak interactions in the transition states responsible for chiral induction revealed that the geometric disposition of the quinoline ring at the C8 chiral carbon of cinchona-enamine plays an anchoring role. The quinolone ring is noted as participating in a π-stacking interaction with the phenyl ring of the Ir-π-allyl moiety in the case of PR with the (8R,9R)-cinchona catalyst combination, whereas a series of C-H···π interactions is identified as vital to the relative stabilization of the stereocontrolling transition states when PR is used with (8S,9S)-cinchona.

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