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1.
J Org Chem ; 84(8): 4780-4795, 2019 04 19.
Article in English | MEDLINE | ID: mdl-30475616

ABSTRACT

An asymmetric synthesis of HCV NS5B nucleoside polymerase inhibitor (1) is described. This novel route features several remarkably diastereoselective and high-yielding transformations, including construction of the all-carbon quaternary stereogenic center at C-2 via a thermodynamic aldol reaction. A subsequent glycosylation reaction with activated uracil via C-1 phosphate and installation of the cyclic phosphate group using an achiral phosphorus(III) reagent followed by oxidation provides 1.


Subject(s)
Antiviral Agents/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Hepacivirus/drug effects , Hepatitis C, Chronic/drug therapy , Humans , Molecular Structure , Stereoisomerism , Viral Nonstructural Proteins/metabolism
2.
Org Lett ; 18(8): 1848-51, 2016 Apr 15.
Article in English | MEDLINE | ID: mdl-27017848

ABSTRACT

α-Aminoboronate salts are interesting examples of heteroatomic species containing adjacent nucleophilic centers. We have developed an acylation/arylation reaction using 2-bromobenzoyl chlorides as bis-electrophiles that harnesses the nucleophilicity of both positions, leading to isoindolinones. The reactions proceed under mild conditions via an intramolecular, Cu-catalyzed sp(3)-sp(2) coupling, giving products in up to 95% yield. These conditions enable arylation of α,α-disubstituted aminoboronates, which are difficult to accomplish using methods based on less abundant and more expensive transition metals.

3.
Org Lett ; 18(6): 1394-7, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26950496

ABSTRACT

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/chemistry , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
4.
Angew Chem Int Ed Engl ; 51(44): 10954-90, 2012 Oct 29.
Article in English | MEDLINE | ID: mdl-23011639

ABSTRACT

Complete control of the product of a catalytic reaction can be achieved on the basis of catalyst structure, even when the reaction conditions are nearly identical. Catalyst-controlled selectivity is well established for enantioselective catalysis but less formulated for catalytic regio-, chemo-, or product-selective reactions. This Review describes selective transformations of the same starting materials into two or more different products simply by the choice of catalyst. By collecting and highlighting examples of selective catalysis, we hope that the field will be encouraged by the progress that has been made while bringing attention to unmet needs in the design and mechanistic understanding of selective catalysts.


Subject(s)
Organic Chemicals/chemical synthesis , Catalysis , Molecular Structure , Organic Chemicals/chemistry , Stereoisomerism
6.
Org Lett ; 14(8): 2138-41, 2012 Apr 20.
Article in English | MEDLINE | ID: mdl-22475226

ABSTRACT

Acylboranes are among the most elusive boron-containing organic functional groups, a fact that has impeded development of new reactions employing them as substrates. A new synthesis of acyltrifluoroborates from benzotriazole (Bt)-based N,O-acetals has been developed. Two other routes provide acyltrifluoroborates containing alcohols, aldehydes, and carbamates. The ketone-like reactivity of the acyltrifluoroborate functional group is demonstrated, and the first X-ray structure of an acyltrifluoroborate is reported.

7.
Acc Chem Res ; 43(3): 440-54, 2010 Mar 16.
Article in English | MEDLINE | ID: mdl-20000793

ABSTRACT

Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) is a molecule with a unique history, owing to its originally misassigned structure, as well as a unique place among acylating agents, owing to its high acidity and remarkable electrophilicity. In this Account, we outline the work of our group and others toward harnessing the reactivity of Meldrum's acid derivatives in catalytic C-C bond-forming reactions. Taking advantage of the ability of Meldrum's acid to decompose to CO(2) and acetone following acyl substitution, we have shown that intramolecular Friedel-Crafts acylations can be performed under mild Lewis acidic conditions to yield a variety of benzocyclic ketones. In a further expansion of this method, a domino Friedel-Crafts acylation/alpha-tert alkylation reaction was used to complete the first total synthesis of (+/-)-taiwaniaquinol B. The unique characteristics of Meldrum's acid extend to its alkylidene derivatives, which have also proven exceptionally useful for the development of new reactions not readily accessible from other unsaturated carbonyl electrophiles. By combining the electrophilicity and dienophilicity of alkylidene Meldrum's acid with our Friedel-Crafts chemistry, we have demonstrated new domino syntheses of coumarin derivatives and tetrahydrofluorenones by conjugate additions, Diels-Alder cycloadditions, and C-H functionalizations. Additionally, we have used these powerful acceptors to allow conjugate alkenylation with functionalized organostannanes, and conjugate allylation under very mild conditions. We have also shown that these molecules permit the asymmetric formation of all-carbon quaternary stereocenters via enantioselective conjugate additions. These reactions employ dialkylzinc nucleophiles, maximizing functional group compatibility, while the presence of a Meldrum's acid moiety in the product allows a variety of postaddition modifications. A full investigation of this reaction has determined the structural factors of the alkylidene that contribute to optimal enantioselectivity. We have also used these acceptors to form tertiary propargylic stereocenters in very high enantiomeric excess by an extremely mild, Rh(I)-catalyzed addition of TMS-acetylene. Overall, we demonstrate that Meldrum's acid and its derivatives provide access to a broad range of reactivities that, combined with their ease of handling and preparation, make them ideal electrophiles.


Subject(s)
Carbon/chemistry , Dioxanes/chemistry , Acylation , Catalysis , Stereoisomerism , Transition Elements/chemistry
8.
Org Lett ; 11(22): 5346-9, 2009 Nov 19.
Article in English | MEDLINE | ID: mdl-19856944

ABSTRACT

Herein, we describe enantioselective addition of alkenyltin reagents possessing a reactive and sensitive allylic functionality not readily available to other classes of alkenyl metals. This method is enabled by the use of highly electrophilic alkylidene Meldrum's acids as acceptors and a cationic Rh(I)-diene complex as catalyst.

9.
Org Lett ; 11(9): 1919-22, 2009 May 07.
Article in English | MEDLINE | ID: mdl-19341311

ABSTRACT

Alkylidene Meldrum's acids are allylated in a conjugate fashion by allyltin nucleophiles under mild Sc(OTf)(3)-catalyzed conditions. The addition is functional group tolerant and reactions with nonracemic alkylidenes are highly diastereoselective. Allylation of alkylidenes derived from alpha-ketoesters yield all-carbon quaternary stereocenters.

10.
J Org Chem ; 73(7): 2920-3, 2008 Apr 04.
Article in English | MEDLINE | ID: mdl-18321122

ABSTRACT

4-Substituted indoles containing a variety of electrophiles and N-substituents undergo Friedel-Crafts acylation to give exclusively the products of cyclization at the 5-position of indole. These indanones and tetralones have been scarcely prepared and are subunits in natural products and analogues of potential biological significance.


Subject(s)
Indoles/chemistry , Indoles/chemical synthesis , Acylation , Cyclization , Molecular Structure , Stereoisomerism
11.
J Org Chem ; 71(26): 9899-902, 2006 Dec 22.
Article in English | MEDLINE | ID: mdl-17168619

ABSTRACT

The one-pot synthesis of tetrahydrofluorenones, the core 6-5-6 tricyclic structural motif found in norditerpenoid natural products, from alkylidene Meldrum's acids via thermal Diels-Alder/BF3.OEt2-catalyzed Friedel-Crafts acylation reactions is described. A series of tetrahydrofluorenones was assembled in good yields, and the Diels-Alder/Friedel-Crafts acylation protocol allowed modification of the substitution within the rings.


Subject(s)
Alkenes/chemistry , Dioxanes/chemistry , Fluorenes/chemical synthesis , Fluorenes/chemistry , Molecular Structure , Stereoisomerism
12.
J Org Chem ; 71(1): 409-12, 2006 Jan 06.
Article in English | MEDLINE | ID: mdl-16388672

ABSTRACT

[reaction: see text] The Yb(OTf)3-catalyzed annulation reactions of phenols with 5-alkylidene Meldrum's acids enabled the synthesis of structurally diverse heterocycles in high isolated yields. A series of 4-substituted 3,4-dihydrocoumarins, 2,2-disubstituted 4-chromanones, coumarins, and 2-substituted chromones were readily and efficiently assembled, including the naturally occurring coumarins citropten, scoparone, and ayapin. Addition of phenols to biselectrophilic 5-alkylidene Meldrum's acids proceeded through two distinct multibond-forming modes: Friedel-Crafts C-alkylation/O-acylation and Friedel-Crafts C-acylation/O-alkylation. The regioselectivity of the catalytic annulation reaction was controlled by the degree of substitution on the alkylidene moiety.


Subject(s)
Acids/chemistry , Alkenes/chemistry , Anthraquinones/chemistry , Chromones/chemistry , Coumarins/chemistry , Organometallic Compounds/chemistry , Phenols/chemistry , Ytterbium/chemistry , Catalysis , Hydrogen/chemistry , Molecular Structure
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