Diastereoselective Nucleophilic Addition Research Articles

Diastereoselective Addition of PhSCF2SiMe3 to Chiral N-tert-Butanesulfinyl Ketimines Derived from Isatins: Synthesis of Enantioenriched gem-Difluoromethylenated Spiro-pyrrolidinyl and Spiro-piperidinyl Oxindoles.

A convenient and efficient synthetic strategy to prepare enantioenriched gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles is described. Fluoride-mediated diastereoselective nucleophilic addition of PhSCF2SiMe3 to chiral N-tert-butanesulfinyl ketimines derived from isatins was a key step and provided diastereomeric adducts, which were readily separable. Removal of the chiral sulfinyl group followed by structural manipulation afforded chiral gem-difluoromethylenated spiro-pyrrolidinyl and spiro-piperidinyl oxindoles.

Total Synthesis and Antibacterial Investigations of 1-Hydroxyboivinianin A.

Synthetic investigations of natural products has been instrumental in the development of novel antibacterial small molecules. 1-hydroxyboivinianin A, a lactone containing phenolic bisabolane isolated from marine sediment, has reported antibacterial activity against the aquatic pathogen Vibrio harveyi. The total synthesis of 1-hydroxyboivinianin A and its enantiomer was completed in a six-step sequence in 42 % overall yield. The synthesis leveraged a key diastereoselective nucleophilic addition with chiral imidazolidinone to establish the benzylic tertiary alcohol and intramolecular Horner-Wadsworth Emmons to furnish the lactone. Both enantiomers were found to have negligible antibacterial activity against a panel of gram-positive and negative bacteria and minimal antifungal activity against phytopathogens. Investigations of a possible in vitro lactone hydrolysis to produce an inactive linear acid led to the discovery of a spontaneous cyclization, suggesting the lactone is resistant to hydrolysis and the lactone is not degrading to produce an inactive species.

Diastereoselective Phosphonylation of Chiral Cyclic Imines for the Synthesis of Phosphoproline Derivatives

AbstractWe report here the first diastereoselective synthesis of (2S,5R)‐5‐methyl‐5‐(phosphono)‐proline, a phosphoproline derivative from L‐pyroglutamic acid. The main feature of this methodology is the transformation of L‐pyroglutamic acid into chiral cyclic imines as a versatile intermediate followed by diastereoselective nucleophilic addition of trialkyl phosphites or diethyl phosphite in the presence of PhB(OH)2, Ph2P(O)OH, (PhO)2P(O)OH, Ph(H)P(O)OH and TiCl4. N‐Cbz Cleavage with simultaneous hydrolysis of phosphonate and carboxylate esters in the quaternary cyclic α‐aminophosphonate, gave the target compound.

Cobalt-Catalyzed C-H Activation and [3 + 2] Annulation with Allenes: Diastereoselective Synthesis of Indane Derivatives.

An unprecedented bidentate directing-group-assisted cobalt-catalyzed oxidative C-H activation of aryl hydrazones followed by a syn-diastereoselective [3 + 2] annulation reaction has been achieved, employing allenes as the annulation partners. The selective 2,3-migratory insertion of allenes with arylcobalt(III) species and the subsequent intramolecular diastereoselective nucleophilic addition of η1-allylcobalt onto the imine resulted in [3 + 2] annulation over the alternative [4 + 2] annulation. Furthermore, the oxidative annulation obviates the need for stoichiometric metal oxidants and proceeds under aerobic conditions.

Enantio‐ and Diastereoselective Nucleophilic Addition of N‐tert‐Butylhydrazones to Isoquinolinium Ions through Anion‐Binding Catalysis

AbstractA highly enantio‐ and diastereoselective thiourea‐catalyzed dearomatization of isoquinolines employing N‐tert‐butylhydrazones as neutral α‐azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high‐yielding transformations provide appealing dihydroisoquinoline derivatives.

Enantio- and Diastereoselective Nucleophilic Addition of N-tert-Butylhydrazones to Isoquinolinium Ions through Anion-Binding Catalysis.

A highly enantio- and diastereoselective thiourea-catalyzed dearomatization of isoquinolines employing N-tert-butylhydrazones as neutral α-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

Synthesis of Quaternary Carbon Stereogenic Centers by Diastereoselective Conjugate Addition of Boron-Stabilized Allylic Nucleophiles to Enones.

A method for the site-selective and diastereoselective conjugate addition of boron-stabilized allylic nucleophiles to α,β-unsaturated ketones is disclosed. Transformations involve easily prepared γ,γ-disubstituted allyldiboron reagents and proceed in the presence of a fluoride activator at 80 °C. Reactions proceed with a wide variety of enones and allyldiboron reagents efficiently to deliver ketone products that contain otherwise difficult-to-access vicinal β-tertiary and γ-quaternary carbon stereogenic centers and an alkenylboron moiety. The utility of the method is highlighted by several transformations, including cross-coupling and carbocyclizations.

Construction of Highly Functionalized Piperazinones via Post-Ugi Cyclization and Diastereoselective Nucleophilic Addition

A novel method for the generation of uniquely functionalized piperazinones by utilizing post-Ugi functionalization is described. The method involves an Ugi reaction with aminoacetaldehyde dimethyl acetal, followed by acid-mediated cyclization to generate the iminium precursor that was subjected to nucleophilic addition in a diastereoselective manner. The method was also employed to synthesize trans-dragmacidine C and praziquantel-like molecules.

Debenzylative Cycloetherification as a Synthetic Tool in the Diastereoselective Synthesis of 3,6-Disubstituted Hexahydro-2H-furo[3,2-b]pyrroles, PDE1 Enzyme Inhibitors with an Antiproliferative Effect on Melanoma Cells.

Two series of novel chiral hexahydro-2H-furo[3,2-b]pyrroles, 4-(7,8-dimethoxyquinazolin-4-yl) series A and 4-(6,7- dimethoxyquinazolin-4-yl) series B, were synthesized in enantiomerically pure form and evaluated for their inhibitory effects on phosphodiesterase 1 (PDE1) and phosphodiesterase 4 (PDE4) as well as for their inhibitory activity on cell proliferation in A375 melanoma and 3T3 fibroblast cells in vitro. Key steps of synthesis were (i) diastereoselective nucleophilic addition of vinylmagnesium bromide to N-allylimine derived from conveniently protected d-glyceraldehyde, (ii) ring-closing metathesis, (iii) debenzylative cycloetherification, and (iv) aromatic nucleophilic substitution. Some of the obtained compounds were proven to be active as inhibitors of PDE1 isoforms, with IC50 values in the high nanomolar/low micromolar concentration range, and showed antiproliferative activity on A375 melanoma cells.

Highly Diastereoselective Synthesis of Cyclic α‐Aminophosphonic and α‐Aminophosphinic Acids from Glycyl‐l‐Proline 2,5‐Diketopiperazine

This paper describes the first diastereoselective synthesis of cyclic α‐aminophosphonic and α‐amino phosphonic acids from glycyl‐l‐proline 2,5‐diketopiperazine (S)‐6 prepared according to the usual peptide coupling procedures. The highlights of this contribution is the chemoselective reduction of the carbamate‐imide activated carbonyl group in the N‐Boc 2,5‐diketopiperazine (S)‐11 to generate the unstable hemiaminals (1R,8aS)‐12 and (1S,8aS)‐13, followed by the highly diastereoselective nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to the chiral carbenium ion (S)‐5. Acid hydrolysis of the phosphonate and phosphinate functionalities with simultaneous cleavage of the tert‐butyl carbamate protecting group led to the target compounds. The high diastereoselectivity in the nucleophilic addition of trivalent phosphorus to the chiral carbenium ion (S)‐5 is in agreement with our precedent reports.

Synthesis of the N-Acyl Amycolose Moiety of Amycolamicin and Its Methyl Glycosides.

The N-acyl amycolose moiety incorporated in amycolamicin, a broad-spectrum antibacterial natural product produced by soil actinomycetes, and its two anomeric methyl glycosides have been synthesized enantioselectively each in 12 steps from a known methyl ( R)-lactate derivative by exploiting a diastereoselective nucleophilic addition of a p-methoxybenzyloxy-substituted vinyllithium reagent to an α,β-bisalkoxy ketone intermediate to provide the corresponding tertiary alcohol as a single diastereomer. The three sugar derivatives are known as cytotoxic degradation products of amycolamicin.

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

AbstractA catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C−H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.

Enantioselective Access to 1H-Isoindoles with Quaternary Stereogenic Centers by Palladium(0)-Catalyzed C-H Functionalization.

A catalytic enantioselective method for the synthesis of chiral 1H-isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)-catalyzed C-H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H-isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.

Chemoselective, Isomerization‐Free Synthesis of N‐Acylketimines from N–H Imines

AbstractN‐Acylketimines were synthesized through a ruthenium‐catalyzed generation of N–H ketimines from secondary azides and subsequent acylation with mixed anhydrides under mild conditions. The synthetic scope was broad to give N‐acylimines having various functional groups, including those with aliphatic groups that are prone to tautomerization to the corresponding enamides. In addition, various acyl moieties were accommodated. The synthetic utility of this chemoselective imine generation was illustrated by a highly diastereoselective nucleophilic addition of a Grignard reagent to a cyclic N‐acylimine.magnified image

Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid.

5-Nor stemmadenine alkaloids, isolated from the genus Tabernaemontana, display a range of bioactivity. 16-Hydroxy-16,22-dihydroapparicine, the active component of an extract from the Tabernaemontana sp. (dichotoma, elegans, and divaricate), exhibited potent antimalarial activity, representing the first such report of the antimalarial property of 5-nor stemmadenine alkaloids. We, therefore, decided to attempt the total synthesis of the compound to explore its antimalarial activity and investigate structure and bioactivity relationships. As a result, we completed the first total synthesis of 16-hydroxy-16,22-dihydroapparicine, by combining a phosphine-mediated cascade reaction, diastereoselective nucleophilic addition of 2-acylindole or methylketone via a Felkin–Anh transition state, and chirality transferring intramolecular Michael addition. We also clarified the absolute stereochemistries of the compound. Furthermore, we evaluated the activity of the synthetic compound, as well as that of some intermediates, all of which showed weak activity against chloroquine-resistant Plasmodium falciparum (K1 strain) malaria parasites.

Sulfur-containing derivatives from (1R)-(−)-myrtenal designed as chiral ligands

New chiral sulfur-containing derivatives were prepared in the diastereoselective nucleophilic additions of thiophenols to the commercially available (1R)-(−)-myrtenal. The newly synthesized 3-phenylsulfanyl derivatives containing an aldehyde functionality were successfully transformed into enantiopure compounds with S, Se and N-donor atoms and applied as chiral ligands in palladium-catalyzed asymmetric allylic alkylations (Tsuji–Trost reaction) providing products with enantioselectivities of up to 75% ee.

A Stereoselective Synthesis of Lentiginosine.

A concise stereoselective synthesis of (-)-lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline N-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-lentiginosine can be synthesized by the same method but starting from l-tartaric acid.

ChemInform Abstract: Highly Diastereoselective Addition of Chiral H‐Phosphonate to tert‐Butylsulfinyl Aldimines: A Convenient Approach to (R)‐α‐Aminophosphonic Acids.

Abstract A highly diastereoselective nucleophilic addition of chiral H -phosphonate, derived from a readily available TADDOL auxiliary, to ( S )- N - tert -butylsulfinyl aldimines is reported. The reaction proceeds at room temperature in the presence of potassium carbonate and yields the corresponding aliphatic, aromatic and heteroaromatic α-aminophosphonates with dr >95:5. Subsequent simultaneous removal of both chiral auxiliaries leads to the desired α-aminophosphonic acids in very good yields with an ( R )-configuration at the stereogenic α carbon.

Highly diastereoselective addition of chiral H-phosphonate to tert-butylsulfinyl aldimines: a convenient approach to (R)-α-aminophosphonic acids

A highly diastereoselective nucleophilic addition of chiral H-phosphonate, derived from a readily available TADDOL auxiliary, to (S)-N-tert-butylsulfinyl aldimines is reported. The reaction proceeds at room temperature in the presence of potassium carbonate and yields the corresponding aliphatic, aromatic and heteroaromatic α-aminophosphonates with dr >95:5. Subsequent simultaneous removal of both chiral auxiliaries leads to the desired α-aminophosphonic acids in very good yields with an (R)-configuration at the stereogenic α carbon.

1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine

Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.