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Many of the greatest challenges facing society today likely have molecular solutions that await discovery. However, the process of identifying and manufacturing such molecules has remained slow and highly specialist dependent. Interfacing the fields of artificial intelligence (AI) and synthetic organic chemistry has the potential to powerfully address both limitations. The Molecule Maker Lab Institute (MMLI) brings together a team of chemists, engineers, and AI‐experts from the University of Illinois Urbana‐Champaign (UIUC), Pennsylvania State University, and the Rochester Institute of Technology, with the goal of accelerating the discovery, synthesis and manufacture of complex organic molecules. Advanced AI and machine learning (ML) methods are deployed in four key thrusts: (1) AI‐enabled synthesis planning, (2) AI‐enabled catalyst development, (3) AI‐enabled molecule manufacturing, and (4) AI‐enabled molecule discovery. The MMLI's new AI‐enabled synthesis platform integrates chemical and enzymatic catalysis with literature mining and ML to predict the best way to make new molecules with desirable biological and material properties. The MMLI is transforming chemical synthesis and generating use‐inspired AI advances. Simultaneously, the MMLI is also acting as a training ground for the next generation of scientists with combined expertise in chemistry and AI. Outreach efforts aimed toward high school students and the public are being used to show how AI‐enabled tools can help to make chemical synthesis accessible to nonexperts. [ABSTRACT FROM AUTHOR]

A novel [gamma]-selective conjugate addition of 1-silyl-substituted dienol ethers to nitroalkenes activated by Lewis acids is developed. The resulting [alpha],[beta]-unsaturated acylsilanes have undergone photoinduced protodesilylation to produce the corresponding enals, which is transformed into azepanes under appropriate reductive conditions.

The sequential rhodium-catalyzed silycarbocyclization followed by palladium-catalyzed cross-coupling reactions is described to synthesize functionalized cyclopentanes with a highly substituted exocyclic double bond. The reaction that involved 1,6-enynes and underwent silylcarbocyclization, found that if the enyne bears an electron-deficient double bond then the major side reaction, silyformation, can be suppressed by carrying out reaction under a substochiometric amount of CO.

A variety of achiral Lewis bases are found to catalyze the addition of TMSCN to the aldehydes. Among them, phosphines and amines are the most efficient catalysts and in addition several chiral amines and phosphines are examined in a catalytic, asymmetric addition of TMSCN to benzaldehyde albeit with low enantioselecitivity.

The mechanism of the catalytic, enantioselective addition of trichlorosiyl enolates to aldehydes is investigated. Determination of Arhenius activation parameter revealed that aldol addition occurs through the reversible albeit unfavorable formation of an activated complex, and natural-abundance (sup.13C) NMR kinetic isotope effect (KIE) studies have determined that the turnover limiting step is the aldol addition.

The consequences of double diastereodifferentiation in chiral Lewis base catalyzed aldol additions using chiral enoxysilanes derived from lactate, 3-hydroxyisobutyrate, and 3-hydroxybutyrate was investigated. Trichlorosilyl enolates derived from the chiral methyl and ethyl ketones were subject to aldolization in the presence of phosphoramides, and the intrinsic selectivity of these enolates and the external stereoinduction from chiral catalyst was studied.

The mechanism of the phosphoramide-catalyzed enantioselective aldol additions of trichlorosilyl enolate 1 to aldehydes is studied. The mechanism of the Lewis base-catalysed enantio-selective crossed-aldol reactions of aldehydes is proposed to involve three fundamental steps like ionization of chloride, binding of the aldehyde to the cationic silicon species and aldolization.

Chiral phosphoramide-catalyzed aldol reactions of the TMS enol ether derived from acetaldehyde with aromatic aldehydes that provides aldol products in high yield and enantioselectivity is discussed. The aldol products obtained in these cases were of R configuration.

The generality of catalytic, enantioselective alpha-additions of isocyanides to aldehydes is demonstrated. The rate of addition of the isocyanide is found to be crucial for good yields and high selectivities.

The catalytic enantioselective addition of an acetate enolate equivalent to ketones is described. The results show that methyl trichlorosilyl ketene acetal reacts with a wide range of ketones in the presence of pyridine N-oxide to afford the aldol addition products in excellent yields.

A [3 + 2] cycloaddition reaction between alkynyldimethylsilyl ethers and aryl and alkyl nitrile oxides to produce isoxazolylsilanols is developed. The cross-coupling reactions of these heterocyclic silanols with a variety of aryl iodides afford 3,4,5-trisubstituted isaxazoles.

The synthesis of (+)-brasilenyne has been described. The C(8) stereogenic center was set by a reagent-controlled asymmetric allylboration.

Chemical transformation of nitroso acetals derived from tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes have been investigated. New reduction methods were surveyed in an attempt to supplant the use of hydrogen and Raney nickel. Homogeneous catalytic hydrogenation was not successful, but samarium diiodide did effectively and selectively cleave one of the N--O bonds in a number of nitroso acetals. Acid-promoted hydrolysis of the nitroso acetals produced both [alpha]-alkoxy nitrones and hydroxamic acids selectively via expected pathways. Key words: nitroso acetals, hydroxamic acids, [alpha]-alkoxy nitrones, reduction, hydrolysis.

A systematic study of the diastereoselective alkylation of anions derived from racemic N-substituted P-alkyl 1,3,2-diazaphosphorinane 2-oxides was carried out with variation of the N-substituent. High diastereoselectivity for the methylation of a P-benzyl anion has been achieved with N-neopentyl derivative 5d. Similarly, a P-ethyl anion derived from N-neopentyl derivative 6d showed high diastereoselectivity upon benzylation. The observed difference in alkylation diastereoselectivity between P-ethyl and P-benzyl anions for various N-alkyl substituents is discussed. Key words: phosphonamide-stabilized carbanions, alkylation, asymmetric, stereoselective, organolitihium.

Enantioselective diamination of alkenes represents one of the most straightforward methods to access enantioenriched, vicinal diamines, which are not only frequently encountered in biologically active compounds, but also have broad applications in asymmetric synthesis. Although the analogous dihydroxylation of olefins is well-established, the development of enantioselective olefin diamination lags far behind. Nevertheless, several successful methods have been developed that operate by different reaction mechanisms, including a cycloaddition pathway, a two-electron redox pathway, and a radical pathway. This short review summarizes recent advances and identifies limitations, with the aim of inspiring further developments in this area. 1 Introduction 2 Cycloaddition Pathway 3 Two-Electron Redox Pathway 3.1 Pd(0)/Pd(II) Diamination 3.2 Pd(II)/Pd(IV) Diamination 3.3 I(I)/I(III) Diamination 3.4 Se(II)/Se(IV) Diamination 4 One-Electron Radical Pathway 4.1 Cu-Catalyzed Diamination 4.2 Fe-Catalyzed Diamination 5 Summary and Outlook [ABSTRACT FROM AUTHOR]

This study reports the development and application of a conformer-dependent quantitative quadrant descriptor for generating models that relate catalyst performance to catalyst structure in enantioselective transformations. The generality of these descriptors is demonstrated by using them for three different reactions: (1) copper-catalyzed, enantioselective cyclopropanation of alkenes, (2) rhodium-catalyzed enantioselective hydrogenation of α-substituted N-acyl-enamides, and (3) enantioselective addition of thiols to N-acyl imines. This work will provide researchers an interpretable steric descriptor that merges the heuristic value of quadrant models with a quantitative tool that can be used to create statistically meaningful correlations between the steric occupancy of catalyst quadrants and stereoselectivity. The low dimensionality of this descriptor, its ability to capture conformational effects and stereostructure, and its direct relationship to intuitive structural properties make it particularly well-suited for creating Quantitative Structure-Selectivity Relationships (QSSR) with smaller datasets of asymmetric reactions. [ABSTRACT FROM AUTHOR]

An efficient enantioselective total synthesis of papulacandin D by a convergent synthetic strategy is described. The reaction involves a silicon-based cross-coupling reaction to construct the key spirocyclic C-aryl glycopyranoside and an enatioselective allylation reaction using a chiral bisphosphoramide for the construction of the C7 stereocenter.