Synthesis of Bisbicyclo[1.1.1]pentyldiazene. The Smallest Bridgehead Diazene

Hossain, Mohammad Tomal; Timberlake, Jack W.

doi:10.1021/jo010212u

Cited by 15 publications

(12 citation statements)

References 28 publications

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“…We envisioned securing all four quaternary stereocenters via completely stereoselective C–C bond formations following dinitrogen extrusion from the tris-diazene tetramer 10 . While the vicinal C sp3 –C sp3 quaternary stereocenters could be secured via oxidation of a mixed sulfamide intermediate, , the introduction of the remaining C sp2 –C sp3 linked stereocenters using an analogous C3a–C7′ diazene was expected to be less efficient due to competitive arene-halogenation, consistent with our previous observations . The requirement for obviating multiple oxidative N–N bond formations in complex setting as well as our desire to develop a more direct synthesis of diazenes prompted us to investigate a new aryl-alkyl diazene synthesis using hydrazines.…”

Section: Resultssupporting

confidence: 88%

Concise Synthesis of (−)-Hodgkinsine, (−)-Calycosidine, (−)-Hodgkinsine B, (−)-Quadrigemine C, and (−)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines

Lindovska

Movassaghi

2017

J. Am. Chem. Soc.

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The enantioselective total synthesis of (−)-hodgkinsine, (−)-calycosidine, (−)-hodgkinsine B, (−)-quadrigemine C, and (−)-psycholeine through a diazene-directed assembly of cyclotryptamine fragments is described. Our synthetic strategy enables multiple and directed assembly of intact cyclotryptamine subunits for convergent synthesis of highly complex bis- and tris-diazene intermediates. Photoextrusion of dinitrogen from these intermediates enables completely stereoselective formation of all C3a–C3a' and C3a–C7' carbon–carbon bonds and all the associated quaternary stereogenic centers. In a representative example, photoextrusion of three dinitrogen molecules from an advanced intermediate in a single-step led to completely controlled introduction of four quaternary stereogenic centers and guided the assembly of four cyclotryptamine monomers en route to (−)-quadrigemine C. The synthesis of these complex diazenes was made possible through a new methodology for synthesis of aryl-alkyl diazenes using electronically attenuated hydrazine-nucleophiles for a silver-promoted addition to C3a-bromocyclotryptamines. The application of Rh- and Ir-catalyzed C–H amination reactions in complex settings were used to gain rapid access to C3a- and C7-functionalized cyclotryptamine monomers, respectively, used for diazene synthesis. This convergent and modular assembly of intact cyclotryptamines offers the first solution to access these alkaloids through completely stereoselective union of monomers at challenging linkages and the associated quaternary stereocenters as illustrated in our synthesis of five members of the oligocyclotryptamine family of alkaloids.

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Section: Resultssupporting

confidence: 88%

Concise Synthesis of (−)-Hodgkinsine, (−)-Calycosidine, (−)-Hodgkinsine B, (−)-Quadrigemine C, and (−)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines

Lindovska

Movassaghi

2017

J. Am. Chem. Soc.

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“…25 Timberlake converted Wiberg’s intermediate, carboxylic acid 18 , to 44 via the Schmidt reaction. 26 During the course of their NMR studies on bridgehead-substituted polycycloalkanes, Della converted 19 to 44 via a Hofmann rearrangement with iodosobenzene. 27 Barbachyn showed that organotin species 20 could be transmetalated with n -BuLi and quenched with LiNHOMe to afford 44 .…”

Section: Direct Bicyclo[111]pentylation (“Propellerization”) Via Stmentioning

confidence: 99%

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

et al. 2017

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Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C–C and C–N bonds react with amines to allow for the “any-stage” installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release “cyclopentylation” of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral “cyclopentylation” reagents.

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“…Early approaches to BCPAs involved multistep routes using preformed BCP building blocks (derived from [1.1.1]propellane 1 , Figure b), such as acyl nitrene rearrangements − or reduction of BCP azides or hydrazines. , More recently, methods have been developed that prepare BCPAs directly from 1 by reaction with amide anions, − which can also provide access to N , C -disubstituted BCPAs (Figure b, path a). However, these processes can require elevated temperatures, restricting functional group tolerance.…”

mentioning

confidence: 99%

Twofold Radical-Based Synthesis of N,C-Difunctionalized Bicyclo[1.1.1]pentanes

et al. 2021

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Bicyclo[1.1.1]pentylamines (BCPAs) are of growing importance to the pharmaceutical industry as sp 3 -rich bioisosteres of anilines and N-tert-butyl groups. Here we report a facile synthesis of 1,3-disubstituted BCPAs using a twofold radical functionalization strategy. Sulfonamidyl radicals, generated through fragmentation of α-iodoaziridines, undergo initial addition to [1.1.1]propellane to afford iodo-BCPAs; the newly formed C−I bond in these products is then functionalized via a silyl-mediated Giese reaction. This chemistry also translates smoothly to 1,3-disubstituted iodo-BCPs. A wide variety of radical acceptors and iodo-BCPAs are accommodated, providing straightforward access to an array of valuable aniline-like isosteres.

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Synthesis of Bisbicyclo[1.1.1]pentyldiazene. The Smallest Bridgehead Diazene

Cited by 15 publications

References 28 publications

Concise Synthesis of (−)-Hodgkinsine, (−)-Calycosidine, (−)-Hodgkinsine B, (−)-Quadrigemine C, and (−)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines

Concise Synthesis of (−)-Hodgkinsine, (−)-Calycosidine, (−)-Hodgkinsine B, (−)-Quadrigemine C, and (−)-Psycholeine via Convergent and Directed Modular Assembly of Cyclotryptamines

Strain-Release Heteroatom Functionalization: Development, Scope, and Stereospecificity

Twofold Radical-Based Synthesis of N,C-Difunctionalized Bicyclo[1.1.1]pentanes

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