From Macrocycle Dipeptide Lactams To Azabicyclo[X.Y.0]alkanone Amino Acids:  A Transannular Cyclization Route for Peptide Mimic Synthesis

Surprenant, Simon; Lubell, William D.

doi:10.1021/ol0609863

Cited by 35 publications

(31 citation statements)

References 26 publications

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“…Flow photoisomerization has provided access to functionalized trans-cyclooctenes capable of stereospecific, transannular cyclization reactions. While stereospecific, transannular cyclizations of (E)-cycloalkenes have been studied with larger ring systems, [125][126][127][128] few studies had been carried out on transcyclooctene derivatives. (E)-Thiacyclooct-4-ene has been shown to undergo acid catalyzed transannular cyclization, [129] as does the anion of (E)-4,5-epoxy-1-thiacyclooctane-1,1dioxide.…”

Section: Stereospecific Transannulation Of Trans-cyclooctenesmentioning

confidence: 99%

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Pigga

Fox

2019

Israel Journal of Chemistry

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trans-Cyclooctenes and trans-cycloheptenes have long been the subject of physical organic study, but the broader application had been limited by synthetic accessibility. This account describes the development of a general, flow photochemical method for the preparative synthesis of trans-cycloalkene derivatives. Here, photoisomerization takes place in a closed-loop flow reactor where the reaction mixture is continuously cycled through Ag(I) on silicagel. Selective complexation of the trans-isomer by Ag(I) during flow drives an otherwise unfavorable isomeric ratio toward the transisomer. Analogous photoreactions under batch-conditions are low yielding, and flow chemistry is necessary in order to obtain trans-cycloalkenes in preparatively useful yields. The applications of the method to bioorthogonal chemistry and stereospecific transannulation chemistry are described.The unusual reactivity and well-defined chiral structure of trans-cycloalkenes has made them attractive targets for synthesis for nearly 70 years. [1][2][3] For example, trans-cyclooctene possesses planar chirality and displays a high barrier to racemization (E a = 35.6 kcal/mol), [4] and the most stable "crown" conformer has an alternating sequence of equatorial and axial hydrogens that is akin to chair cyclohexane. [5][6] The double bond of trans-cyclooctene is twisted severely in the crown conformation, [7] and as a consequence the HOMO of trans-cyclooctene is relatively high in energy. [8] trans-Cycloheptene also has a rigid structure with a distorted alkene. [7] The double bonds of medium-ring trans-alkenes are twisted. [7] trans-Cycloalkenes display unusual reactivity in HOMOalkene controlled cycloaddition reactions with dienes, [9] 1,3dipoles [8] and ketenes. [10] Strained trans-cycloalkenes also serve as ligands for transition metals. [11][12][13][14][15][16] This reactivity profile has made trans-cycloalkanes interesting targets for applications in synthesis and biology.The broadest applications of trans-cycloalkenes are in the field of bioorthogonal chemistry. The inverse-electron demand Diels-Alder reaction between tetrazines and strained alkenes has a rich history in physical organic and synthetic chemistry (Figure 1). [17][18][19] In 2008, three groups described the bioorthogonal reactions of tetrazines with strained alkenes. [20][21][22] The variant introduced by our group that used trans-cyclooctene is marked by exceptionally rapid kinetics, with rate constants that can exceed 10 6 M À 1 s À 1 in the fastest cases. [23][24] With the advances including the development of fluorogenic tetrazines [25] and reactions in live cells [26] and animals, [27] the tetrazine ligation has become a widely used tool for applications that span chemical biology, biomedical imaging, and materials science. [28][29][30][31][32][33][34][35][36][37] This account describes the development of general, flow photochemical methods for the preparative synthesis of transcycloalkene derivatives and enabled applications in synthesis and bioorthogonal chemistry. Selectiv...

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Section: Stereospecific Transannulation Of Trans-cyclooctenesmentioning

confidence: 99%

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Pigga

Fox

2019

Israel Journal of Chemistry

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“…Specifically, protected lactams (Bn, Dmb) undergo transannular reactions with various electrophiles with concomitant deprotection of the resulting cyclized acylammonium moiety. 11,12 Fig. 3 Example of the mechanism of activation in the transannular reaction of olefinic cyclic amines through formation of a bromonium ion and subsequent regiospecific attack by the nitrogen.…”

Section: The Essential Classicsmentioning

confidence: 99%

“…Scheme 2 Transannular approaches to loline: (a) the reaction is high yielding and does not produce side products (b) in a single transannular reaction the olefin is activated and the Cbz group, which protects the bromonium ion from the solvent, is cleaved. 20 amination, has enabled the stereospecificity to be inverted with addition to the Re face (12).…”

Section: Alexine Alkaloidsmentioning

confidence: 99%

Azabicycles construction: the transannular ring contraction with N-protected nucleophiles

Rizzo

Harutyunyan

2014

Org. Biomol. Chem.

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Synthetic strategies are one of the most critical factors for the success of a synthetic campaign, but most importantly they are crucial for the economy and the efficiency of the sequence. Within this perspective, the synthesis of azabicyclic scaffolds, constituents of many bioactive alkaloids, can be tackled using tandem transannular ring contractions-protecting group cleavages. Commonly these reactions feature medium-sized cyclic N-protected amines that carry a potential electrophilic site. Under the correct conditions this site is activated, and the protecting group is fragmented, inducing a transannular reaction. For the first time, we review in detail this strategy's applications, which span from the assembly of small molecules to complex molecular architectures.

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“…Some of the dehydrating agents used in the process are also derivatives of HOBt 1298–1301 . In some instances, these derivatives, HBTU 1298 2002JOC1184 , 2004NAR623 , TBTU 1299 2005HCA447 , 2005HCA1040 , 2005TL6239 , 2006OL2851 , 2006TL1737 and BOP 1300 2005JA17894 , 2005JOC3660 , 2006JA3011 , 2006OL239 , 2006OL511 are used alone without addition of HOBt. Combinations of HOBt with dehydrating agents, especially DIC 2005JOC9622 , 2005TL7443 , 2006JCO150 , 2006JME1833 , 2006JME2388 , HBTU 2005AGE2534 , 2005JCO697 , 2005JOC7654 , 2005TL4053 , 2006TL2671 and BOP 2002BML2855 , 2005AGE2887 , 2005JCO703 are common reagents in solid-phase synthesis of peptides.…”

Section: Important Compounds and Applicationsmentioning

confidence: 99%

1,2,3-Triazoles

Rachwał

Katritzky

2008

Comprehensive Heterocyclic Chemistry III

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From Macrocycle Dipeptide Lactams To Azabicyclo[X.Y.0]alkanone Amino Acids: A Transannular Cyclization Route for Peptide Mimic Synthesis

Cited by 35 publications

References 26 publications

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Flow Photochemical Syntheses of trans‐Cyclooctenes and trans‐Cycloheptenes Driven by Metal Complexation

Azabicycles construction: the transannular ring contraction with N-protected nucleophiles

1,2,3-Triazoles

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