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1.
Org Lett ; 25(48): 8590-8595, 2023 Dec 08.
Article in English | MEDLINE | ID: mdl-38009850

ABSTRACT

The direct, asymmetric conjugate addition of unactivated α-branched nitroalkanes is developed based on the combined use of chiral amine/ureidoaminal bifunctional catalysts and a tunable acrylate template to provide tertiary nitrocompounds in 55-80% isolated yields and high enantioselectivity (e.r. up to 96:4). Elaboration of the ketol moiety in thus obtained adducts allows a fast entry to not only carboxylic and aldehyde derivatives but also nitrile compounds and enantioenriched 5,5-disubstituted γ-lactams.

2.
Chem Rec ; 23(11): e202300164, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37350363

ABSTRACT

Chiral Brønsted base (BB) catalyzed asymmetric transformations constitute an important tool for synthesis. A meaningful fraction of these transformations proceeds through transiently generated enolate intermediates, which display quite versatile reactivity against a variety of electrophiles. Some years ago, our group became interested in developing BB-catalyzed asymmetric reactions of enolizable carbonyl substrates that involve π-extended enolates in which, besides control of reaction diastereo and enantioselectivity, the site-selectivity control is an additional issue in most cases. In the examples covered in this account the opportunities deployed, and the challenges posed, by these methods are illustrated, with a focus on the generation of quaternary carbon stereocenters. In the way, new bifunctional BB catalysts as well as achiral templates were developed that may find further applications.

3.
Org Biomol Chem ; 21(23): 4833-4845, 2023 Jun 14.
Article in English | MEDLINE | ID: mdl-37249037

ABSTRACT

Aminocatalytic asymmetric conjugate addition of aldehydes to Michael acceptors is a well established C-C bond forming methodology. However, various acrylic-type acceptors, including acrylic acid derivatives and acrolein, remain reluctant. Here we demonstrate that the internal H-bonding self-activation in α'-hydroxy enones allows them to react smoothly with enolizable aldehydes using commercially available aminocatalysts to afford adducts in good yields and high enantioselectivity. Straightforward conversion of the ketol moiety of these adducts into aldehyde, ketone and carboxylic acid functionalities offers an indirect, unified entry to products derived from acrolein, alkyl-vinyl ketones and acrylates, respectively.

4.
J Org Chem ; 88(2): 972-987, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36630318

ABSTRACT

The catalytic, enantio- and diastereoselective addition of hydantoin surrogates II to "rigidified" vinylidene bis(sulfone) reagents is developed, thus overcoming the inability of commonly employed ß-substituted vinylic sulfones to react. Adducts are transformed in enantioenriched 5,5-disubstituted hydantoins through hydrolysis and reductive desulfonylation processes providing new structures for eventual bioassays. Density functional theory studies that rationalize the observed reactivity and stereoselectivity trends are also provided.

5.
Org Lett ; 25(1): 125-129, 2023 01 13.
Article in English | MEDLINE | ID: mdl-36579971

ABSTRACT

The production of chiral pyrrolodiketopiperazines under organocatalytic conditions demonstrates the capacity of bicyclic acylpyrrol lactims to perform as pronucleophiles in direct carbon-carbon bond forming reactions. The good performance of ureidoaminal-derived Brønsted bases in the Michael addition to nitroolefins affords these heterocyclic scaffolds with high skeleton diversity.


Subject(s)
Carbon , Catalysis , Stereoisomerism
6.
Angew Chem Int Ed Engl ; 61(13): e202113504, 2022 03 21.
Article in English | MEDLINE | ID: mdl-34717037

ABSTRACT

Planar chirality is one of the most fascinating expressions of chirality, which is exploited by nature to lock three-dimensional chiral conformations and, more recently, by chemists to create new chiral reagents, catalysts, and functional organic materials. Nevertheless, the shortage of procedures able to induce and secure asymmetry during the generation of these unique chiral entities has dissuaded chemists from exploiting their structural properties. This Minireview intends to illustrate the limited but remarkable catalytic methods that have been reported for the production of planar chirality in strained molecules and serve as a source of inspiration for the development of new unconventional procedures, which are expected to appear in the near future.


Subject(s)
Stereoisomerism , Catalysis , Molecular Conformation
7.
Chemistry ; 27(40): 10226-10246, 2021 Jul 16.
Article in English | MEDLINE | ID: mdl-33961323

ABSTRACT

Catalyst-controlled functionalization of unmodified carbonyl compounds is a relevant operation in organic synthesis, especially when high levels of site- and stereoselectivity can be attained. This objective is now within reach for some subsets of enolizable substrates using various types of activation mechanisms. Recent contributions to this area include enantioselective transformations that proceed via transiently generated noncovalent di(tri)enolate-catalyst coordination species. While relatively easier to form than simple enolate congeners, di(tri)enolates are ambifunctional in nature and so control of the reaction regioselectivity becomes an issue. This Minireview discusses in some detail this and other problems, and how noncovalent activation approaches based on metallic and metal free catalysts have been developed to advance the field.


Subject(s)
Carboxylic Acids , Metals , Catalysis
8.
J Org Chem ; 86(11): 7757-7772, 2021 06 04.
Article in English | MEDLINE | ID: mdl-33998227

ABSTRACT

Here we report the highly enantio- and syn-selective synthesis of ß-hydroxy α-amino acids from glycine imine derivatives under Brønsted base (BB) catalysis. The key of this approach is the use of benzophenone-derived imine of glycine o-nitroanilide as a pronucleophile, where the o-nitroanilide framework provides an efficient hydrogen-bonding platform that accounts for nucleophile reactivity and diastereoselectivity.


Subject(s)
Amino Acids , Glycine , Aldehydes , Catalysis , Molecular Structure , Schiff Bases , Stereoisomerism
9.
Chemistry ; 27(7): 2483-2492, 2021 Feb 01.
Article in English | MEDLINE | ID: mdl-33034390

ABSTRACT

The high tendency of α-amino aldehydes to undergo 1,2-additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α-amino aldehydes. Herein, it is demonstrated that the chemistry of α-amino aldehydes may be expanded beyond these limits by documenting the first direct α-alkylation of α-branched α-amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo- and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α-amino aldehyde is key for reaction stereocontrol.


Subject(s)
Acids/chemistry , Aldehydes/chemistry , Alkalies/chemistry , Alkenes/chemistry , Catalysis , Hydrogen Bonding , Hydrogen-Ion Concentration , Molecular Structure , Stereoisomerism
10.
Chemistry ; 27(1): 20-29, 2021 Jan 04.
Article in English | MEDLINE | ID: mdl-32667706

ABSTRACT

N,N-Diacylaminals are flexible molecular scaffolds that have commonly been utilized as amide surrogates in peptidomimetics. The singularities of this motif as an N-acyl imine equivalent and as hydrogen-bond donor have recently opened new synthetic opportunities, especially in the field of asymmetric catalysis. This concept article highlights this diverse synthetic potential and provides the elements necessary for further developments.

11.
Angew Chem Int Ed Engl ; 58(40): 14250-14254, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31368176

ABSTRACT

A catalyst-driven one-pot reaction sequence is developed for the enantio- and diastereoselective synthesis of tetrasubstituted cyclohexenes from simple unsaturated ketones or thioesters. The method involves a tertiary amine/squaramide-catalyzed α-selective addition of transiently generated trienolates to nitroolefins, subsequent base-catalyzed double bond isomerization, and an intramolecular (vinylogous) 1,6-addition reaction, a rare key carbocyclization step that proceeded with essentially perfect stereocontrol.

12.
Chemistry ; 25(53): 12431-12438, 2019 Sep 20.
Article in English | MEDLINE | ID: mdl-31318987

ABSTRACT

A bifunctional amine/squaramide catalyst promoted direct aldol addition of an hydantoin surrogate to pyridine 2-carbaldehyde N-oxides to afford adducts bearing two vicinal tertiary/quaternary carbons in high diastereo- and enantioselectivity (d.r. up to >20:1; ee up to 98 %) is reported. Acid hydrolysis of adducts followed by reduction of the N-oxide group yields enantiopure carbinol-tethered quaternary hydantoin-azaarene conjugates with densely functionalized skeletons. DFT studies of the potential energy surface (B3LYP/6-31+G(d)+CPCM (dichloromethane)) of the reaction correlate the activity of different catalysts and support an intramolecular hydrogen-bond-assisted activation of the squaramide moiety in the transition state of the catalytic reaction.

13.
Chemistry ; 25(41): 9701-9709, 2019 Jul 22.
Article in English | MEDLINE | ID: mdl-31087692

ABSTRACT

In this study, the unique capacity of bifunctional Brønsted bases to generate α-branched ketone dienolates and control both site- and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented. We demonstrate that by using selected chiral tertiary amine/squaramide catalysts, the reactions of ß,γ-unsaturated cycloalkanones proceed through the dienolate Cα almost exclusively and provide all-carbon quaternary cyclic ketone adducts in good yields with very high enantioselectivities. A minor amount (<5 %) of γ-addition is observed when nitroolefins are used as electrophiles. The parent acyclic ketone dienolates proved to be less reactive under these conditions, and thus still constitute a challenging class of substrates. Quantum chemical calculations correctly predict these differences in reactivity and explain the observed site-specificity and enantioselectivity.

14.
Chemistry ; 25(17): 4390-4397, 2019 Mar 21.
Article in English | MEDLINE | ID: mdl-30652365

ABSTRACT

Various sets of enolizable alkynyl ketones (including methyl ynones with α-aryl, α-alkenyl, and α-alkoxy groups) were able to react smoothly with nitroolefins with the assistance of bifunctional Brønsted base/H-bond catalysts to provide adducts with two consecutive tertiary stereocenters in a highly diastereo- and enantioselective fashion. Further transformation of the obtained adducts into optically active acyclic and polycyclic molecules, including some with intricate carbon skeletons, was also demonstrated.

15.
Chemistry ; 24(45): 11554-11558, 2018 Aug 09.
Article in English | MEDLINE | ID: mdl-29917275

ABSTRACT

The potential of ß-alkoxy α-keto amides as pronucleophiles in the enantioselective Mannich type reaction with p-nosyl imines is presented. The proper combination of ß-alkoxy α-keto amides and a squaramide-based Brønsted base catalyst produced highly enantioenriched Mannich adducts, which may be transformed into functionalized amino diols.

16.
Chemistry ; 24(28): 7217-7227, 2018 May 17.
Article in English | MEDLINE | ID: mdl-29575281

ABSTRACT

A new method for the enantioselective synthesis of 5,5-disubstituted (quaternary) hydantoins was developed on the basis of an organocatalytic Michael reaction approach involving the use of 2-benzylthio-3,5-dihydroimidazol-4-ones as key hydantoin surrogates. The method is general with respect to the substitution pattern at the hydantoin N1 (alkyl, aryl, acyl), N3 (aryl), and C5 (linear/branched alkyl, aryl) positions and affords essentially single diastereomeric products with enantioselectivities higher than 95 % ee in most cases. Among the bifunctional Brønsted base/H-bond catalysts examined, a known squaramide-tertiary amine catalyst and a newly prepared squaramide-tertiary amine catalyst provide the highest selectivity so far with either nitroolefins or vinyl ketones as the acceptor components. Kinetic measurements support a first-order rate dependence on both reaction partners, the donor template and the Michael acceptor, whereas competitive 1 H NMR spectroscopy experiments reveal the high ability of the template for catalyst binding.

17.
Chemistry ; 24(15): 3893-3901, 2018 Mar 12.
Article in English | MEDLINE | ID: mdl-29446501

ABSTRACT

The catalyst-controlled enantioselective direct addition reaction of enolizable esters and related carboxylic acid derivatives to π electrophiles remains a difficult synthetic transformation. In this study, the suitability of α-hydroxy ketones as ester equivalents capable of being activated by bifunctional Brønsted base catalysts in the context of conjugate addition reactions to nitroolefins is demonstrated. The scope of the reaction, which affords the corresponding Michael adducts with very high stereoselectivity (diastereomeric ratio (d.r.) ≥95:5, up to 99 % enantiomeric excess (ee)), and its limitations are explored, as is the aftermath elaboration of adducts into densely functionalized enantioenriched products.

18.
J Am Chem Soc ; 139(43): 15308-15311, 2017 11 01.
Article in English | MEDLINE | ID: mdl-29023111

ABSTRACT

The catalytic asymmetric α-functionalization of prochiral barbituric acids, a subtype of pseudosymmetric 1,3-diamides, to yield the corresponding 5,5-disubstituted (quaternary) derivatives remains essentially unsolved. In this study 2-alkylthio-4,6-dioxopirimidines are designed as key 1,3-diamide surrogates that perform exceedingly in amine-squaramide catalyzed C-C bond forming reactions with vinyl ketones or Morita-Baylis-Hillmann-type allyl bromides as electrophiles. Mild acid hydrolysis of adducts affords barbituric acid derivatives with an in-ring quaternary carbon in unprecedented enantioselectivity, offering valuable materials for biological evaluations.


Subject(s)
Barbiturates/chemistry , Barbiturates/chemical synthesis , Bromides/chemistry , Catalysis , Hydrolysis , Ketones/chemistry , Stereoisomerism
19.
Chemistry ; 23(54): 13332-13336, 2017 Sep 27.
Article in English | MEDLINE | ID: mdl-28869315

ABSTRACT

We report the first diastereo- and enantioselective formal Mannich reaction of 2-pyridyl acetates which gives rise to α- and ß-functionalized 2-substituted pyridines. Key for success is the previous azaarene N-oxide formation enabling α-carbon deprotonation by a mild bifunctional Brønsted base and subsequent reaction with N-Boc imines under almost perfect stereocontrol.

20.
J Am Chem Soc ; 139(36): 12524-12532, 2017 09 13.
Article in English | MEDLINE | ID: mdl-28783369

ABSTRACT

Substantial progress has been made toward the development of metal-free catalysts of enantioselective transformations, yet the discovery of organic catalysts effective at low catalyst loadings remains a major challenge. Here we report a novel synergistic catalyst combination system consisting of a peptide-inspired chiral helical (thio)urea oligomer and a simple tertiary amine that is able to promote the Michael reaction between enolizable carbonyl compounds and nitroolefins with excellent enantioselectivities at exceptionally low (1/10 000) chiral catalyst/substrate molar ratios. In addition to high selectivity, which correlates strongly with helix folding, the system we report here is also highly amenable to optimization, as each of its components can be fine-tuned separately to increase reaction rates and/or selectivities. The predictability of the foldamer secondary structure coupled to the high level of control over the primary sequence results in a system with significant potential for future catalyst design.

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