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1.
Org Biomol Chem ; 22(28): 5734-5738, 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-38953694

ABSTRACT

Rhodium-catalyzed [3 + 2] annulation of diazoenals and N-alkyl imines resulted in N-alkyl-pyrrole-3-carbaldehyde derivatives. The reaction involves thermal 6π-electrocyclization and aromatization of a new class of enal-azomethine ylides (EAYs). The EAYs derived from dihydroisoquinoline and 2H-azirine gave fused-pyrrole and pyridine derivatives, respectively. The synthetic importance of pyrrole products has been demonstrated by one-step synthesis of the biologically relevant pyrrolo[3,2-c]quinoline scaffold as well as pyrrolo[2,1-a]isoquinoline which is a core structure of lamellarin alkaloids.

2.
JACS Au ; 4(6): 2099-2107, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38938806

ABSTRACT

Reported herein are the bench stable (2E,4E)-diazohexa-2,4-dienals (diazodienals) and their unprecedented polycyclization with aldimine and arylamines enabled by Rh(II)/Brønsted acid relay catalysis. This scalable and atom-economical reaction provides direct access to the biologically important azatricyclo[6.2.1.04,11]undecane fused polycycles having six-contiguous stereocenters. Mechanistic studies revealed that polycyclization proceeds through an unusual triple-nucleophilic cascade initiated by aldimine attack on remote Rh-carbenoid, 6π-electrocyclization of aza-trienyl azomethine ylide, stereoselective aza-Michael addition via iminium activation, and inverse electron-demand intramolecular aza Diels-Alder reaction. The π-π secondary interactions play a crucial role in the preorganization of reactive intermediates for the pericyclic reactions and, hence, the overall efficiency of the polycyclization.

3.
Org Lett ; 26(16): 3463-3468, 2024 Apr 26.
Article in English | MEDLINE | ID: mdl-38625754

ABSTRACT

Herein, we report a new Rh(II)/Sc(III)-catalyzed [3+3] annulation between diazoenals and α-mercapto ketones for the direct synthesis of 4-formyl-2H-thiopyrans. The reaction proceeds via protic sulfonium ylides derived from highly electrophilic Rh-enalcarbenoids, followed by regioselective intramolecular aldol condensation. Further studies revealed that 4-formyl-2H-thiopyrans are novel precursors for unstudied 2H-thiopyran-2-ones and 4H-thiopyran-4-ones. The 4H-thiopyran-4-ones were obtained via a novel O2/Et3N-mediated oxidative deformylation. This methodology was applied to the short synthesis of structurally complex pyrimidine-fused 2H-thiopyran via cascade Schmidt, Ritter, and intramolecular cyclization reactions.

4.
Chemistry ; 30(19): e202303862, 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38165004

ABSTRACT

Novel rhodium-catalyzed [3+3] annulations of diazoenals and α-amino ketones has been disclosed here. The reactivity of diazoenals has been switched from carbenoid to vinylogous NH-insertion by altering acyclic to cyclic α-amino ketones. In this direction, we report an efficient strategy to synthesize 1,2-dihydropyridines (DHPs) and fused 1,4-oxazines. Mechanistic investigation revealed that the formyl group is necessary for carbenoid [3+3] annulation and the cyclohexyl group is the dictating factor for vinylogous NH- insertion. The synthetic utility of 1,2-dihydropyridines was demonstrated by synthesizing piperidine, pyrido[1,2-a]indole, and 2-pyridone scaffolds. Further, structural diversification of fused 1,4-oxazines resulted in the short synthesis of hexahydroquinolin-2(1H)-ones, hexahydro quinolines and tetrahydroquinolinones via ring opening rearrangement and a new oxidative deformylation, respectively.

5.
Org Lett ; 24(21): 3850-3854, 2022 Jun 03.
Article in English | MEDLINE | ID: mdl-35587254

ABSTRACT

Herein, we report a simple method for functionalized enals involving enal-transfer reaction of water-soluble N-methoxypyridazinium salts. This open-flask reaction proceeds under mild aqueous basic conditions through [2,3]-sigmatropic rearrangement of propargyl/allyl sulfur-ylides derived from in situ-generated Rh-(E)-enalcarbene. Various synthetically challenging allene- and allyl-functionalized (E)-enals with a γ-C(sp3) quaternary center were obtained in good to high yields. InCl3-catalyzed cascade cyclization of allenyl-enal and aniline gave a valuable pyrrolo[1,2-a]quinoline motif.

6.
Angew Chem Int Ed Engl ; 57(19): 5433-5437, 2018 05 04.
Article in English | MEDLINE | ID: mdl-29536602

ABSTRACT

A dirhodium carboxylate catalyzed [1+1+3] annulation reaction of diazoenals and vinyl azides that gives synthetically important enal-functionalized 1-pyrroline derivatives was developed. The reaction involves a novel rhodium-catalyzed olefination of diazoenals with vinyl azides via electrophilic enal carbenoids, resulting in a new class of enal acrylates. The annulation reaction was used for the direct synthesis of valuable deuterated 1-pyrrolines. Structural diversification of the enal-functionalized 1-pyrrolines resulted in the biologically important pyrrolidine-fused oxaziridine, amino acid derivatives, and a 6-azabicyclo[3.2.1]octane motif present in polycyclic alkaloids.

7.
Chem Commun (Camb) ; 52(94): 13699-13701, 2016 Nov 17.
Article in English | MEDLINE | ID: mdl-27819079

ABSTRACT

An efficient AgOTf catalyzed tandem intramolecular transannulation of ((2-alkynyl)aryl)cyclopropyl ketones leading to the 2,3-dihydronaphtho[1,2-b]furans has been developed. The reaction features a regioselective alkyne hydration, cyclopropylketone-2,3-dyhydrofuran rearrangement, and benzannulation. The methodology gives direct access to the tricyclic core structure of biologically important 2,3-dihydronaphtho[1,2-b]furan natural products.

8.
Chem Commun (Camb) ; 52(34): 5812-5, 2016 Apr 30.
Article in English | MEDLINE | ID: mdl-26992045

ABSTRACT

A novel Rh(ii)/Brønsted acid catalyzed tandem benzannulation of oxindoles with enaldiazo carbonyls led to the formation of valuable 1-hydroxy-2-acylcarbazoles. This reaction is proposed to involve a formal insertion of a rhodium enalcarbenoid into an oxindole sp(2) C-O bond, an oxa-Michael addition, Friedel-Crafts reaction and a semipinacol type 1,2-carbonyl migration.

9.
Angew Chem Int Ed Engl ; 55(27): 7831-5, 2016 06 27.
Article in English | MEDLINE | ID: mdl-26949079

ABSTRACT

A novel rhodium-catalyzed dienamine activation of diazoenals resulted in a new class of γ-functionalized donor-acceptor dienamines. The synthetic utility of these dienamines has been demonstrated in a cooperative rhodium(II)/Brønsted acid and gold(I)-catalyzed direct [3+3] annulation of enaldiazo ketones with N-propargyl anilines, thus leading to highly substituted enal-functionalized 1,4-oxazines. The reaction is proposed to involve dienamine activation through the diacceptor rhodium enalcarbenoid NH-insertion and a gold-catalyzed intramolecular site-selective 6-exo-dig heterocyclization. The methodology was applied to the efficient synthesis of structurally complex [1,4]oxazino[4,3-a]quinolone, which is present in the antibacterial agent PNU-286607.

10.
Org Biomol Chem ; 14(24): 5569-73, 2016 Jun 28.
Article in English | MEDLINE | ID: mdl-26964882

ABSTRACT

A novel rhodium catalyzed pyridannulation of 3-substituted indoles with diazoenals furnished privileged pyrido[1,2-a]indoles. The reaction is proposed to involve a [4 + 2]-annulation of the diacceptor rhodium enalcarbenoid via C-2 functionalization of the indole. The utility of the methodology was demonstrated with a short synthesis of the tetrahydropyrido[1,2-a]indole core, present in a large number of biologically important polycyclic indole alkaloids.

11.
Org Lett ; 17(23): 5878-81, 2015 Dec 04.
Article in English | MEDLINE | ID: mdl-26588048

ABSTRACT

Pyridazine N-oxides are used for the first time as precursors of metallocarbenes. These nitrogen-rich heterocycles led to the discovery of a novel acceptor and donor-acceptor enalcarbenoids. The synthetic utility of these metallocarbenes was demonstrated in the rhodium-catalyzed denitrogenative transannulation of pyridazine N-oxides with pyrroles to the valuable alkyl, 7-aryl, and 7-styryl indoles. The transannulation strategy was applied to the synthesis of a potent anticancer agent.


Subject(s)
Antineoplastic Agents/chemical synthesis , Cyclic N-Oxides/chemistry , Indoles/chemical synthesis , Methane/analogs & derivatives , Pyridazines/chemistry , Rhodium/chemistry , Antineoplastic Agents/chemistry , Catalysis , Indoles/chemistry , Methane/chemistry , Molecular Structure , Nitrogen/chemistry , Pyrroles/chemical synthesis
12.
Org Biomol Chem ; 12(43): 8641-5, 2014 Nov 21.
Article in English | MEDLINE | ID: mdl-25247844

ABSTRACT

An efficient Rh(II) carboxylate and Brønsted acid catalyzed direct π-extension of indoles to 4-substituted carbazoles is developed. The reaction involves a regioselective C-3 functionalization of indole by a rhodium enalcarbenoid and a Brønsted acid assisted cyclocondensation. In addition a twofold regioselective π-extension of pyrroles to 4,8-disubstituted carbazoles has also been developed. The utility of the methodology was demonstrated with the synthesis of analogues of an hepatitis C virus replication inhibitor and a secreted phospholipase A2 (sPLA2) inhibitor.


Subject(s)
Antiviral Agents/chemical synthesis , Carbazoles/chemical synthesis , Carboxylic Acids/chemistry , Indoles/chemistry , Phospholipase A2 Inhibitors/chemical synthesis , Rhodium/chemistry , Antiviral Agents/pharmacology , Carbazoles/pharmacology , Catalysis , Hepacivirus/drug effects , Hepacivirus/physiology , Molecular Structure , Phospholipase A2 Inhibitors/pharmacology , Phospholipases A2/metabolism , Pyrroles/chemistry , Stereoisomerism , Virus Replication/drug effects
13.
Org Lett ; 16(14): 3700-3, 2014 Jul 18.
Article in English | MEDLINE | ID: mdl-24988365

ABSTRACT

The design of a synergistic rhodium(II) carboxylate and BINOL phosphoric acid catalyzed efficient multicomponent reaction of enaldiazo compounds, arylamines, and aryl aldehydes leading to the first transition-metal-catalyzed direct synthesis of valuable α-pyrrolylbenzylamines is disclosed. The reaction is proposed to involve a transient ammonium ylide of a new class of electrophilic rhodium enalcarbenoid, its regioselective Mannich reaction, and a cyclocondensation cascade. The methodology was used in a highly diastereoselective synthesis of a binaphthyl based chiral pyrrole.


Subject(s)
Benzylamines/chemical synthesis , Carboxylic Acids/chemistry , Pyrroles/chemical synthesis , Rhodium/chemistry , Aldehydes/chemistry , Benzylamines/chemistry , Catalysis , Molecular Structure , Phosphoric Acids/chemistry , Pyrroles/chemistry , Stereoisomerism
14.
Angew Chem Int Ed Engl ; 53(16): 4076-80, 2014 Apr 14.
Article in English | MEDLINE | ID: mdl-24590818

ABSTRACT

Disclosed herein is the design of an unprecedented electrophilic rhodium enalcarbenoid which results from rhodium(II)-catalyzed decomposition of a new class of enaldiazo compounds. The synthetic utility of these enalcarbenoids has been successfully demonstrated in the first transition-metal-catalyzed [4+2] benzannulation of pyrroles, thus leading to substituted indoles. The new benzannulation has been applied to the efficient synthesis of the natural product leiocarpone as well as a potent adipocyte fatty-acid binding protein inhibitor.


Subject(s)
Indoles/chemistry , Pyrroles/chemistry , Rhodium/chemistry , Catalysis , Molecular Structure , Stereoisomerism
15.
J Org Chem ; 74(20): 7707-14, 2009 Oct 16.
Article in English | MEDLINE | ID: mdl-19761213

ABSTRACT

Three closely related analogues of epoxomicin have been synthesized. Allene-derived spirodiepoxides were key intermediates. Spirodiepoxide formation and stereochemical dependence on solvent, oxidant, and allene structure were cataloged. The facial selectivity of the first epoxidation of 1,3-disubstituted and trisubstituted allenes was found to be >20:1 with dimethyldioxirane in chloroform. For stereogenic allenes, the facial selectivity of the second oxidation is dependent primarily on allene structure and secondarily on solvent and oxidant. For the acyclic systems evaluated this ratio was as high as 8:1. A conformational model is advanced to account for these observations.


Subject(s)
Spiro Compounds/chemistry , Models, Chemical , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Stereoisomerism
16.
Org Lett ; 8(5): 823-6, 2006 Mar 02.
Article in English | MEDLINE | ID: mdl-16494450

ABSTRACT

A one-pot procedure for the conversion of carboxylic acids to N-acyl sulfonamides, via thio acid/azide amidation, is presented. The method is compatible with acid- and base-sensitive amino acid protection. N-Acyl sulfonamide synthesis on solid support, peptide thio acid/sulfonazide coupling, and N-alkyl amide synthesis via selective cleavage of sulfonyl from an N-alkyl-N-acyl sulfonamide are also reported.


Subject(s)
Amides/chemistry , Azides/chemistry , Carboxylic Acids/chemistry , Sulfonamides/chemical synthesis , Amides/classification , Amino Acids/chemistry , Molecular Structure , Peptides/chemistry , Sulfonamides/chemistry
17.
J Am Chem Soc ; 126(47): 15348-9, 2004 Dec 01.
Article in English | MEDLINE | ID: mdl-15563139

ABSTRACT

The first use of the spirodiepoxide functional group in total synthesis, a study culminating in an efficient synthesis of the potent proteasome inhibitor epoxomicin, is described. Spirodiepoxides derived from allenes by oxidation are shown to give syn disubstituted ketones and their derivatives, including ortho ester, oxazoline, azido epoxide, as well as sulfonamide-, amide-, and azide-containing hydroxy ketones.


Subject(s)
Epoxy Compounds/chemistry , Oligopeptides/chemical synthesis , Spiro Compounds/chemistry
18.
J Am Chem Soc ; 125(26): 7754-5, 2003 Jul 02.
Article in English | MEDLINE | ID: mdl-12822965

ABSTRACT

A new amide synthesis strategy based on a fundamental mechanistic revision of the reaction of thio acids and organic azides is presented. The data demonstrate that amines are not formed as intermediates in this reaction. Alternative mechanisms proceeding through a thiatriazoline intermediate are suggested. The reaction has been applied to the preparation of simple and architecturally complex amides that are difficult to access using conventional methods. The reaction is chemoselective, effective for unprotected substrates, and compatible with aprotic and protic solvents, including water.


Subject(s)
Amides/chemical synthesis , Azides/chemistry , Sulfhydryl Compounds/chemistry
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