Diastereoselective synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones via a nitro-Mannich/lactamization cascade

A versatile one-pot nitro-Mannich/lactamization cascade for the direct synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones has been developed. The reaction is easy to perform and broad in scope, and high levels of diastereoselectivity can be achieved.     

Synthesis of chiral isoindolinones via asymmetric propargylation/lactamization cascade

A Zn-mediated propargylation/lactamization cascade reaction with chiral 2-formylbenzoate derived N-tert-butanesulfinyl imines was realized, which provided a practical and efficient method for the synthesis of chiral isoindolinones. High diastereoselectivities (up to 97:3 dr) and good reaction yields were observed for most examined cases.     

Diastereoselective syntheses and oxygenation of silyl fulleroids

The addition of silyl diazomethane (1a-d) to fullerene C₆₀ at room temperature provided the mono-adducts, the bis- and tris-adducts of silyl fulleroid (3a-d) in moderate yields. The structures of the silyl fulleroids were characterized by mass spectroscopy, as well as ¹H and ¹³C NMR. The gated ¹H NMR and ¹³C-¹H COLOC analyses of 3a-d showed a correlation between the methine proton resonances and three fullerene carbons. These observations, as well as the ¹H NMR chemical shifts of the methine protons, suggest a remarkable diastereoselectivity, with the silyl groups located above a five-membered ring. Two transition states of the thermal nitrogen-extrusion of pyrazoline intermediate (2a) were theoretically obtained, the structures of which disclosed that the diastereoselectivity is a consequence of minimization of the repulsive interaction between the silyl groups and the N₂ moiety. The bridgehead CC double bond of the silyl fulleroid is thought to be reactive by POAV analyses. The silyl fulleroids (3a,b) were found to react with singlet oxygen to afford the silyl enol ether (9a,b) via 1,3-silyl migration of a diketone (8a,b). This is the first example of ¹O₂ oxygenation of fulleroids.     

Efficient synthesis of gamma-lactams by a tandem reductive amination/lactamization sequence

A three-component method for the synthesis of highly substituted gamma-lactams from readily available maleimides, aldehydes, and amines is described. A new reductive amination/intramolecular lactamization sequence provides a straightforward route to the lactam products in a single manipulation. The general utility of this method is demonstrated by the parallel synthesis of a gamma-lactam library.     

Diastereoselective Pictet-Spengler condensation of tryptophan with α-amino aldehydes as chiral carbonyl components

The Pictet-Spengler reaction of Trp with α-amino aldehydes derived from l and d-amino acids was studied in terms of double stereodifferentiation. The results observed for d-amino aldehydes represent ‘matched’ situation (one diastereoisomer was formed) whereas with l-amino aldehydes ‘mismatched’ (two diastereoisomers were formed). The conformation of newly formed six-membered ring was analyzed. It was found that stable conformers were different for cis and trans isomers.     

Diastereoselective synthesis of tetrasubstituted-octahydro-3,6-diazacarbazoles and tetrasubstituted-3,6-diazacarbazoles via double Pictet-Spengler reaction

Pictet-Spengler condensation of 2,5-bis(2-phenyl-1-aminoethyl)pyrrole using glacial acetic acid afforded only one diastereomer of unreported tetrasubstituted-octahydro-3,6-diazacarbazoles. These were readily dehydrogenated to tetrasubstituted-3,6-diazacarbazoles. The stereoselectivity in the Pictet-Spengler reaction has been demonstrated using single crystal X-ray analysis.     

Diastereoselective syntheses of pyrazolyl isoxazolidines via 1,3-dipolar cycloaddition

Synthesis of novel 2,3,4,5-tetrasubstituted isoxazolidine and 2,3,5-trisubstituted isoxazolidine by 1,3-dipolar cycloaddition of nitrones with electron-deficient and electron-rich olefins is described. 1,3-Dipolar cycloaddition of nitrones with β-nitrostyrene, gives exclusively endo-diastereoisomer of isoxazolidine and with ethyl vinyl ether, gives exo-diastereoisomer of isoxazolidine with de >95%. The stereochemistry of the products were assigned using extensive NMR studies.     

Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastereoselective cascade sequence

A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The viability of this approach was demonstrated by syntheses of a series of furo[2,3-b]chromene and pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids,hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.     

Diastereoselective concise syntheses of the polyhydroxylated alkaloids DMDP and DAB

A diastereoselective concise synthesis of the iminosugars DMDP and DAB is presented starting from l-xylose and affording the two alkaloids in good yields of 35% and 22% over seven and eight steps, respectively. The Petasis borono–Mannich reaction of 3,5-di-O-benzyl-l-xylofuranose with benzylamine and (E)-styrylboronic acid served as the nitrogen-introducing key step furnishing the new C–N bond in an entirely diastereoselective manner. A chemo- and regioselective O-mesylation followed by an intramolecular S_N2-cyclisation allowed the formation of the pyrrolidine ring. Ozonolysis of the styryl double bond and subsequent reduction to form the C-5 hydroxymethyl substituent followed by hydrogenolysis of the benzyl protecting groups concluded the DMDP synthesis. Furthermore, an unexpected fragmentation process during the ozonolysis reaction also gave access to the C-5 decarbinolated DMDP derivative DAB.     

Stereoselective synthesis of densely functionalized pyrrolidin-2-ones by a conjugate addition/nitro-Mannich/lactamization reaction

Copper-catalyzed conjugate addition of diorgano zinc reagents to nitroacrylate 1 followed by a subsequent nitro-Mannich reaction and in situ lactamization leads to an efficient one-pot synthesis of 1,3,5-trisubstituted 4-nitropyrrolidin-2-ones (5). The versatility of the reaction is shown for a wide range of N-p-(methoxy)phenyl protected aldimines 3 derived from alkyl, aryl, and heteroaryl aldehydes. The densely functionalized pyrrolidin-2-ones 5 are isolated as single diastereoisomers (40 examples, 33-84% yield). An enantioselective copper-catalyzed conjugate addition of diethylzinc led to highly crystalline products that could be recrystallized to enantiopurity in high yield. A range of successful chemoselective transformations were investigated, which widens the applicability of the pyrrolidn-2-ones as stereochemically pure building blocks for further organic synthesis.     

Diastereoselective syntheses of new analogues of the farnesyltransferase inhibitor RPR 130401

The access to several benzo[f]perhydroisoindolic analogues of farnesyltransferase inhibitors from a single dienic precursor is reported. An initial [4 + 2] cycloaddition between diphenylisobenzofuran6 and pyrrolines 11, 14, and 15 led to either the syn or the anti isomers, depending on the mode of activation of the cycloaddition. The syn diastereomers were isolated in 90% de under 12 kbar at room temperature, while their anti counterparts were obtained with the same selectivity by warming the reaction mixture to 110 degrees C in toluene at atmospheric pressure. Both syn and anti adducts were separately N-deprotected, and the resulting amines reacted with an activated ester derived from the acid (20) to afford the final targets (5). Two new analogues (5a and 5b) of the FT inhibitor RPR 130401 were thus synthesized in a mere three-step synthetic scheme with overall yields from 30 to 60%.     

Diastereoselective syntheses of deoxydysibetaine, dysibetaine, and its 4-epimer

(+/-)-Deoxydysibetaine 2 and 4-epi-dysibetaine 3 were prepared in a few steps from methyl pyroglutamate through a regioselective Mannich reaction at C-2. Natural (2S,4S)-dysibetaine 1, a sponge metabolite isolated from Dysidea herbacea, and (2S)-2 were synthesized from enantiopure (S)-pyroglutaminol with very high stereoselectivity. The key steps were an original formation of stereogenic quaternary center C-2 and the diastereoselective hydroxylation at C-4.     

Base-catalyzed cascade 1,6-sulfur-Michael/Henry reaction of trifluoromethyl-substituted styrylisoxazoles: Diastereoselective synthesis of tetrahydrothiophenes with a trifluoromethylated quaternary center

An effective diastereoselective [3+2] annulation of 1,4-dithiane-2,5-diol to trifluoromethyl-substituted styrylisoxazoles catalyzed by DABCO is described, giving highly functionalized tetrahydrothiophenes containing trifluoromethylated quaternary center in excellent yields and diastereoselectivities.     

Development of the Pictet-Spengler reaction catalyzed by AuCl3/AgOTf

Mild and efficient AuCl3/AgOTf-catalyzed Pictet-Spengler reactions were developed to afford in good yields a variety of tetrahydroisoquinoline and tetrahydro-beta-carboline ring systems, which constitute important motifs in biologically active natural and synthetic organic compounds.     

Diastereoselective Pd/In bimetallic inter-intramolecular (class 2) cascade reactions of allenyl-imines and aryl iodides

A new diastereoselective Pd/In bimetallic inter-intramolecular cascade reaction employing allenyl-sulfinimines and aryl iodides is described. The tert-butanesulfinyl chiral auxiliary affords chiral, highly substituted cis-pyrrolidines and piperidines.     

Diastereoselective cascade synthesis of azabicyclo[3.1.0]hexanes from acyclic precursors

The diastereoselective synthesis of azabicyclo[3.1.0]hexanes bearing different substituents on all positions of the cyclopropane ring has been achieved in moderate to good yields.     

Diastereoselective Pictet-Spengler approach for the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-one peptide turn mimics

Sixteen pyrrolo[3,2- e][1,4]diazepin-2-ones 1 were synthesized in 4-5 steps and 5-48% overall yields from 4-oxoproline 8 by a route featuring a diastereoselective Pictet-Spengler reaction to close the seven-membered diazepinone ring. Crystallographic analysis of pyrrolo[3,2- e][1,4]diazepin-2-one 1b by X-ray diffraction demonstrated that the alpha-amino acid residue adopted dihedral angle geometry similar to an ideal gamma-turn, illustrating the potential for employing these novel heterocycles as peptide turn mimics.     

Oxygen insertion in Sesamum indicum furanofuran lignans. Diastereoselective syntheses of enzyme substrate analogues

The furofuran lignans in sesame seed have an unusual oxygen insertion between their furan and aryl rings. In our continuing investigations on the isolation and characterization of the enzyme(s) involved, the diastereoselective syntheses of various substrate analogues for the oxygen insertion step were developed for future substrate specificity and inhibitor studies. This synthetic strategy also provided entry to so-called furofuranone epoxy-lignans, such as salicifoliol from Bupleurum sp., and acuminatolide from Helichrysum sp.     

Cyclic imine nitro-Mannich/lactamization cascades: a direct stereoselective synthesis of multicyclic piperidinone derivatives

An efficient nitro-Mannich/lactamization cascade of gamma-nitro esters with cyclic imines for the preparation of architecturally complex multicyclic piperidinone ring-containing structures has been developed. The reaction is broad in scope and stereoselective and may be coupled to an enantioselective nitroolefin Michael addition reaction as part of a highly enantio- and diastereoselective multicomponent process.