Serendipitous Discovery of a New Method for the Catalytic Synthesis of Indole-fused Benzazepanes

We report here on our investigations into the application of 1,5-hydride transfer cyclization mechanisms to the synthesis of 2,3-disubstituted benzofurans and indoles. We found that PtI4 in MeCN at 120 ºC was indeed capable of activating the alkyne, however, the expected 2,3-disubstituted indole product was not observed. Instead we isolated an indolyl-3-benzazepane via an unexpected intramolecular Steven’s rearrangement/ring expansion. While this transformation has been previously reported our method may prove to have increased substrate scope and more practical reaction conditions. Further studies are underway to optimize the reaction conditions and to fully explore the scope and mechanism of the transformation

Catalytic Coupling of Arene C–H Bonds and Alkynes for the Synthesis of Coumarins: Substrate Scope and Application to the Development of Neuroimaging Agents

C–H bond functionalization offers strategically novel approaches to complex organic compounds. However, many C–H functionalization reactions suffer from poor compatibility with Lewis basic functional groups, especially amines, which are often essential for biological activity. This study describes a systematic examination of the substrate scope of catalytic hydroarylation in the context of complex amino coumarin synthesis. The choice of substrates was guided by the design and development of the next generation of fluorescent false neurotransmitters (FFNs), neuroimaging probes we recently introduced for optical imaging of neurotransmission in the brain. Comparison of two mild protocols using catalytic PtCl₄ or Au­(PPh₃)­Cl/AgSbF₆ revealed that each method has a broad and mutually complementary substrate scope. The relatively less active platinum system out-performed the gold catalyst with indole substrates lacking substitution at the C-3 position and provided higher regioselectivity in the case of carbazole-based substrates. On the other hand, the more active gold catalyst demonstrated excellent functional group tolerance, and the ability to catalyze the formation of strained, helical products. The development of these two protocols offers enhanced substrate scope and provides versatile synthetic tools required for the structure–activity examination of FFN neuroimaging probes as well as for the synthesis of complex coumarins in general

Gold-Catalyzed Dearomative Spirocyclization of Aryl Alkynoate Esters

Aryl alkynoate esters undergo gold-catalyzed spirocyclization under mild conditions, affording spirolactones in high yields. This approach obviates the need for stoichiometric halogenating reagents typically employed for alkyne activation in related transformations. Water was found to play a critical role in governing the product selectivity. Anhydrous conditions lead selectively to coumarin products, as has previously been observed for aryl alkynoate esters, while the addition of 1 equiv of water leads selectively to spirocycle formation

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

C–H Bond Functionalization via Hydride Transfer: Formation of α-Arylated Piperidines and 1,2,3,4-Tetrahydroisoquinolines via Stereoselective Intramolecular Amination of Benzylic C–H Bonds

We here report a study of the intramolecular amination of sp³ C–H bonds via the hydride transfer cyclization of <i>N</i>-tosylimines (HT-amination). In this transformation, 5-aryl aldehydes are subjected to <i>N</i>-toluenesulfonamide in the presence of BF₃·OEt₂ to effect imine formation and HT-cyclization, leading to 2-arylpiperidines and 3-aryl-1,2,3,4-tetrahydroisoquinolines in a one-pot procedure. We examined the reactivity of a range of aldehyde substrates as a function of their conformational flexibility. Substrates of higher conformational rigidity were more reactive, giving higher yields of the desired products. However, a single substituent on the alkyl chain linking the <i>N</i>-tosylimine and the benzylic sp³ C–H bonds was sufficient for HT-cyclization to occur. In addition, an examination of various arenes revealed that the electronic character of the hydridic C–H bonds dramatically affects the efficiency of the reaction. We also found that this transformation is highly stereoselective; 2-substituted aldehydes yield <i>cis</i>-2,5-disubstituted piperidines, while 3-substituted aldehydes afford <i>trans</i>-2,4-disubstituted piperidines. The stereoselectivity is a consequence of thermodynamic control. The pseudoallylic strain between the arene and tosyl group on the piperidine ring is proposed to rationalize the greater stability of the isomer with the aryl ring in the axial position. This preferential placement of the arene is proposed to affect the observed stereoselectivity

Chemical Synthesis of the β‑Subunit of Human Luteinizing (hLH) and Chorionic Gonadotropin (hCG) Glycoprotein Hormones

Human luteinizing hormone (hLH) and human chorionic gonadotropin (hCG) are human glycoprotein hormones each consisting of two subunits, an identical α-subunit and a unique β-subunit, that form noncovalent heterodimers. Structurally, β-hCG shares a high degree of sequence similarity with β-hLH, including a common N-glycosylation site at the N-terminus but differs mainly in the presence of an extended C-terminal portion incorporating four closely spaced O-linked glycans. These glycoproteins play important roles in reproduction and are used clinically in the treatment of infertility. In addition, the role of hCG as a tumor marker in a variety of cancers has also attracted significant interest for the development of cancer vaccines. In clinical applications, these hormones are administered as mixtures of glycoforms due to limitations of biological methods in producing homogeneous samples of these glycoproteins. Using the powerful tools of chemical synthesis, the work presented herein focuses on the highly convergent syntheses of homogeneous β-hLH and β-hCG bearing model glycans at all native glycosylation sites. Key steps in these syntheses include a successful double Lansbury glycosylation en route to the N-terminal fragment of β-hCG and the sequential installation of four O-linked glycosyl-amino acid cassettes into closely spaced O-glycosylation sites in a single, high-yielding solid-supported synthesis to access the C-terminal portion of the molecule. The final assembly of the individual glycopeptide fragments involved a stepwise native chemical ligation strategy to provide the longest and most complex human glycoprotein hormone (β-hCG) as well as its closely related homologue (β-hLH) as discrete glycoforms

Gold-Catalyzed Dearomative Spirocyclization of <i>N</i>‑Aryl Alkynamides for the Synthesis of Spirolactams

A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of <i>N</i>-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au­(PPh₃)Cl and AgOTf in dichloroethane at 50–80 °C leads to selective spirocyclization, furnishing the products in yields of 35–87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the <i>para</i>-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a <i>para</i>-methoxy group leads to trace amounts of the desired spirolactams, the <i>para</i>-<i>tert</i>-butoxy or <i>para</i>-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity