A New Synthesis of Enantiopure Amine Fragment: An Important Intermediate to the Anti-HIV Drug Lenacapavir.

Herein, we describe a new seven-step approach to prepare ()-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (()-) from the inexpensive 2-(3,5-difluorophenyl)acetic acid. The key steps in the sequence include (1) the Weinreb amide-based ketone synthesis to provide an entry point to the core structure; (2) simple functional group transformations to afford the racemic amine -; and (3) dynamic kinetic resolution (DKR) to access the chiral amine ()-. This seven-step process delivered the enantiopure amine ()- in an overall isolated yield of approximately 15%.

Highly Stereospecific Cyclizations of Homoallylic Silanols.

We demonstrate that di--butylsilanols are competent nucleophiles for the intramolecular interception of palladium π-allyl species. In these reactions, allyl ethyl carbonates are the best precursors for the formation of palladium π-allyl intermediates, and [(Cinnamyl)PdCl]/BINAP is superior to other Pd salt/ligand framework combinations. Our optimized protocol is compatible with a variety of silanol substrates.

Highly Regio- and Diastereoselective Tethered Aza-Wacker Cyclizations of Alkenyl Phosphoramidates.

We present highly diastereoselective tethered aza-Wacker cyclization reactions of alkenyl phosphoramidates. "Arming" the phosphoramidate tether with 5-chloro-8-quinolinol was essential to achieving >20:1 diastereoselectivity in these reactions. The substrate scope with respect to alkenyl alcohols and phosphoramidate tether was extensively explored.

Tethered Silanoxyiodination of Alkenes.

We present the first examples of tethered silanoxyiodination reactions of allylic alcohols. The products are useful silanediol organoiodide synthons and are formed with high regioselectivity and diastereocontrol. The reaction is scalable greater than 10-fold without loss of yield or selectivity.

Tethered Silanoxymercuration of Allylic Alcohols.

We present the first examples of tethered olefin functionalization reactions using a silanol auxiliary. A range of allylic alcohols are readily condensed with di--butylsilyl bis(trifluoromethanesulfonate) to form allylic silanols. When treated with Hg(OTf) and NaHCO, these silanols easily transform into cyclic silanediol organomercurial compounds.

Metal-free spirocyclization of N-arylpropiolamides with glyoxylic acids: access to complex azaspiro-fused tricycles.

A metal-free oxidative cascade acylation and dearomatization of N-(p-methoxyaryl)propiolamides was achieved via KSO mediated decarboxylation of α-oxocarboxylic acids under operationally simple conditions to access azaspiro[4,5]-trienones in good to excellent yields. Furthermore, the utility of the protocol was illustrated in a one-pot reaction sequence consisting of Ugi-reaction/spirocyclization/aza-Michael transformation for the construction of complex tricyclic cores having quaternary spirocenters.

-arylated oxathiazinane heterocycles are convenient synthons for 1,3-amino ethers and 1,3-amino thioethers.

This communication describes a variety of nucleophilic ring openings of -arylated oxathiazinane heterocycles. We find that this reaction is compatible with phenoxides, naphthoxides, and thiolates and allows for the rapid assembly of -aryl-amino ethers and -aryl-amino thioethers. Fourteen examples are shown and a mechanistic pathway is hypothesized.

Oxidative Cyclization of Sulfamates onto Pendant Alkenes.

This communication discloses the first examples of aza-Wacker cyclizations of sulfamate esters. Within the realm of related cyclization reactions, this protocol is differential in that it forms six-membered rings in good yield and uses catalytic amounts of palladium(0) rather than palladium(II) salts. These reactions scale well, and their products are demonstrated to be valuable synthetic intermediates.

Nickel-Catalyzed Aerobic Oxidative Isocyanide Insertion: Access to Benzimidazoquinazoline Derivatives via a Sequential Double Annulation Cascade (SDAC) Strategy.

An efficient protocol for the synthesis of quinazoline derivatives through nickel-catalyzed ligand-/base-free oxidative isocyanide insertion under aerobic conditions with intramolecular bis-amine nucleophiles has been developed. A one-pot sequential double annulation cascade (SDAC) strategy involving an opening of isatoic anhydride and annulation to benzimidazole and further nickel-catalyzed intramolecular isocyanide insertion has also been demonstrated. The method is operationally simple to implement with a wide variety of substrates and represents a new approach for multiple C-N bond formations.

A metal-free cyclic iminium induced one-pot double annulation cascade: access to dihydroisoquinolinium (DHIQ) salts.

A reactive cyclic iminium induced one-pot Groebke-Blackburn-Bienayme (GBB) double annulation cascade (DAC) for the synthesis of skeletally diverse DHIQ salts has been described. The key features of this protocol are transition-metal and solvent-free, mild reaction conditions, robust method, one-step construction of two privileged heterocyclic rings, clean reaction profile and operational simplicity.

Scaffold Diversity through a Branching Double-Annulation Cascade Strategy: Iminium-Induced One-Pot Synthesis of Diverse Fused Tetrahydroisoquinoline Scaffolds.

A branching double-annulation cascade (BDAC) strategy for diverse and complex fused THIQ scaffolds via a highly reactive iminium-induced one-pot double-cyclization sequence involving Pictect-Spengler-type cyclization has been developed for the first time. The salient features of this protocol are that it allows direct and rapid access to unprecedented diverse fused THIQ skeletons, is metal/catalyst free, has a cleaner reaction profile, provides good to excellent yields, and is a convenient approach. This catalyst-free domino process facilitates the double annulation with a variety of scaffold building agents via two C-N and one C-X (X = C, N, O) bond formation in a single step under uniform reaction conditions.

Correction: Hypervalent iodine(iii)-promoted N-incorporation into N-aryl vinylogous carbamates to quinoxaline diesters: access to 1,4,5,8-tetraazaphenanthrene.

Correction for 'Hypervalent iodine(iii)-promoted N-incorporation into N-aryl vinylogous carbamates to quinoxaline diesters: access to 1,4,5,8-tetraazaphenanthrene' by A. Sagar, et al., Org.

Hypervalent iodine(iii)-promoted N-incorporation into N-aryl vinylogous carbamates to quinoxaline diesters: access to 1,4,5,8-tetraazaphenanthrene.

A novel oxidative N-incorporation strategy for synthesis of quinoxaline diesters under metal-free conditions is described for the first time. The mild reaction conditions allow for this transformation via the formation of two C(sp(2))-N bonds utilizing cheaply available NaN3 as the N-atom source. N-Aryl vinylogous carbamates in this study undergo azidation at enamino C(sp(2))-H selectively.

BF₃·OEt₂ mediated metal-free one-pot sequential multiple annulation cascade (SMAC) synthesis of complex and diverse tetrahydroisoquinoline fused hybrid molecules.

A highly efficient and distinct BF3·OEt2 mediated metal-free SMAC protocol for the synthesis of complex and diverse hybrid molecules viz. indazole fused tetrahydroisoquinolinoquinoxalines, and tetrahydroisoquinolinodiazepine has been developed. The transformation is based on sequential cascade processes involving 2H-indazole formation and deprotection Pictet-Spengler cyclization steps in one-pot fashion.