Cooperative Rh/Chiral Phosphoric Acid Catalysis toward the Highly Stereoselective (3 + 3)-Cycloannulation of Carbonyl Ylides and Indolyl-2-methides.

A stereoselective (3 + 3)-cycloannulation of in situ generated carbonyl ylides with indolyl-2-methides has been developed furnishing oxa-bridged azepino[1,2-a]indoles within one synthetic step. This process is enabled by cooperative rhodium and chiral phosphoric acid catalysis to produce both transient intermediates in separate catalytic cycles. The products comprising three stereogenic centers were obtained with good stereoselectivity and yields and display valuable heterocyclic complexity.

Cooperative Catalysis for the Highly Diastereo- and Enantioselective [4+3]-Cycloannulation of ortho-Quinone Methides and Carbonyl Ylides.

We describe herein a highly diastereo- and enantioselective [4+3]-cycloannulation of ortho-quinone methides and carbonyl ylides to furnish functionalized oxa-bridged dibenzooxacines with excellent yields and stereoselectivity in a single synthetic step. The combination of rhodium and chiral phosphoric acid catalysis working in concert to generate both transient intermediates in situ provides direct access to complex bicyclic products with two quaternary and one tertiary stereogenic centers. The products may be further functionalized into valuable and enantiomerically highly enriched building blocks.

Phosphoric Acid Catalyzed [4 + 1]-Cycloannulation Reaction of ortho-Quinone Methides and Diazoketones: Catalytic, Enantioselective Access toward cis-2,3-Dihydrobenzofurans.

A highly straightforward route to enantiomerically highly enriched cis-2,3-dihydrobenzofurans has been achieved via addition of α-diazocarbonyl compounds to in situ generated o-QMs catalyzed by a chiral Brønsted acid. This catalytic strategy provides a direct access to 2,3-dihydrobenzofurans in high yields and with up to 91:9 dr and 99:1 er at ambient temperature. Moreover, a unique phenonium-type rearrangement accounts for product formation with an inverted 2,3-substitution pattern.

(R)-DM-SEGPHOS-Ag(I)-Catalyzed Enantioselective Synthesis of Pyrrolidines and Pyrrolizidines via (1,3)- and Double (1,3)-Dipolar Cycloaddition Reactions.

An efficient diastereo- and enantioselective route to access a wide range of highly substituted pyrrolidine and pyrrolizidine derivatives has been described via (1,3)- and double (1,3)-dipolar cycloaddition reactions catalyzed by the (R)-DM-SEGPHOS-Ag(I) complex. The reactions proceed smoothly at ambient temperature, affording a variety of pyrrolidines and pyrrolizidines in high yields (up to 93%) with up to 99:1 dr and excellent enantioselectivities (up to 98% ee) without any additives. The newly synthesized pyrrolidine and pyrrolizidine derivatives contain four and seven contiguous stereogenic centers, respectively. Moreover, the synthetic utility of enantioenriched products has been demonstrated by transforming them into various synthetically useful advanced intermediates.

Enantioselective Hydrophosphonylation of in Situ Generated N-Acyl Ketimines Catalyzed by BINOL-Derived Phosphoric Acid.

An efficient route to pharmacologically interesting isoindolinone-based α-amino phosphonates is described via asymmetric hydrophosphonylation of in situ generated ketimines catalyzed by BINOL-derived phosphoric acid. The reaction proceeds smoothly at ambient temperature affording a variety of α-amino phosphonates with a quaternary stereogenic center embedded in isoindolinone motif in high yields with excellent enantiomeric ratios (up to 98.5:1.5 er). Several interesting transformations of the products into valuable synthetic intermediates are also depicted.

Ag(I)-Catalyzed Indolization/C3-Functionalization Cascade of 2-Ethynylanilines via Ring Opening of Donor-Acceptor Cyclopropanes.

A AgSbF6-catalyzed cascade involving the ring opening of donor-acceptor cyclopropanes (DACs) preceded by the cyclization of N-protected 2-ethynylaniline is described. The method discloses a step-economy route to 2,3-disubstituted indole, where a Ag catalyst is found to trigger the cascade by activating both alkyne and DACs. Various functionalities at different ends of both substrates offer rapid access to 2,3-disubstituted indole derivatives in one pot in good to excellent yields. Elaboration of the cascade product to useful intermediates is also depicted.

Asymmetric Syntheses of Medicinally Important Isoindolinones (S)-PD 172938, (R)-JM 1232, and Related Structures.

A unified approach for the asymmetric syntheses of medicinally important isoindolinones (S)-PD 172938 and (R)-JM 1232 has been accomplished via a Cu(I)-PYBOX-diPh catalyzed highly enantioselective (up to 99% ee) alkynylation/lactamization sequence in a one-pot fashion. The overall sequence involves one C-C and two C-N bond forming events in one pot starting from inexpensive starting material in ambient reaction conditions.

Approach to Isoindolinones, Isoquinolinones, and THIQs via Lewis Acid-Catalyzed Domino Strecker-Lactamization/Alkylations.

A one-pot, three-component synthesis of widely substituted isoindolinones and isoquinolinones, featuring a Lewis acid-catalyzed efficient Strecker reaction and lactamization sequence, affording products in good to high yields is reported. The method has also been extended to the synthesis of tetrahydroisoquinolines (THIQs) in high yields.

Ni(II)-Catalyzed Highly Stereo- and Regioselective Syntheses of Isoindolinones and Isoquinolinones from in Situ Prepared Aldimines Triggered by Homoallylation/Lactamization Cascade.

An efficient route to isoindolinones and isoquinolinones has been achieved via a domino Ni-catalyzed homoallylation/lactamization from in situ prepared imines, derived from o-formyl benzoates and o-formyl arylacetates, with conjugated dienes promoted by diethylzinc. The reaction proceeds smoothly at room temperature for a variety of aldehydes, amines, and dienes. The method involves one C-C and two C-N bond forming events under operationally simple conditions.

Unified Approach to Isoindolinones and THIQs via Lewis Acid Catalyzed Domino Mukaiyama-Mannich Lactamization/Alkylations: Application in the Synthesis of (±)-Homolaudanosine.

A novel and efficient synthesis of a variety of isoindolinones and tetrahydroisoquinolines via a Lewis acid catalyzed domino Mukaiyama-Mannich lactamization/alkylation is achieved. This transformation comprises a sequential formation of three new bonds through a one-pot, three-component procedure to afford product in moderate to high yields. A concise synthesis of (±)-homolaudanosine (2b) has been achieved using this method.

An Efficient Entry to syn- and anti-Selective Isoindolinones via an Organocatalytic Direct Mannich/Lactamization Sequence.

An organocatalytic direct Mannich-lactamization sequence for the syntheses of pharmacologically important enantioenriched isoindolinones is reported. The method utilizes simple α-amino acids to deliver syn- and anti- selective isoindolinones with remarkably high enantioselectivity (up to >99% ee) in good to excellent yields and diastereomeric ratios. The overall sequence involves one C-C and two C-N bond forming events in one pot starting from inexpensive starting material.

A general catalytic route to isoindolinones and tetrahydroisoquinolines: application in the synthesis of (±)-crispine A.

An unprecedented highly efficient Lewis acid catalyzed one-pot cascade has been demonstrated as a general catalytic system for the synthesis of diversely substituted isoindolinones and tetrahydroisoquinolines. The cascade effects one C-C and two C-N bond-forming events in one pot. Several interesting transformations of the products into valuable synthetic intermediates are featured with the successful total synthesis of (±)-crispine A.

Asymmetric alkynylation/lactamization cascade: an expeditious entry to enantiomerically enriched isoindolinones.

An unprecedented Cu(I)-pybox-diPh-catalyzed highly enantioselective (up to >99% ee) alkynylation/lactamization cascade has been developed as a general catalytic system for the synthesis of diversely substituted isoindolinones of immense biological importance. The cascade effects one C-C and two C-N bond-forming events in one reaction vessel under operationally simple, additive-free reaction conditions in good to excellent yields. The methodology was further extended to the synthesis of tetrahydroisoquinoline scaffolds common to several biologically active natural products in a two-step sequence with remarkable selectivity (up to 94% ee).