Cyclooctyne synthesis

Brandsma L, Verkruijsse HD (1978) An improved synthesis of cyclooctyne. Synthesis. 290... 

Problem 15.40 Show steps in the synthesis of cyclooctyne, the smallest ring with a triple bond, from C.H,OOC(CH,),COOC,H, ... 

Coordination to alkynes distorts the triple bond character nearer to that of a double bond, decreasing the linearity. Utilization of the coordination effect makes it feasible to prepare cyclic alkynes whose synthesis is difficult to achieve. Highly strained cyclooctyne can be prepared by coordination. As an example, starting from (R)-pulegone, three of the four rings of the epoxydictymene skeleton 152 were constructed by the consecutive Lewis acid-promoted Nicholas reaction of allylic silane 149 to form 150, and the intramolecular Pauson-Khand reaction of 151. The total synthesis of (+)-epoxydictymene 153 from 152 has been achieved [38]. 

Phenylazide has often been used to trap unstable cycloalkynes 1S18 2S 62> and to characterize angle strained cycloalkynes 18,89). The addition of suitable diazoalkanes to cyclooctyne (14) was applied as the first step in the synthesis of threemembered ring spirenes 223,224>. 

An additional advantage of the intramolecular protocol stems from the opportunity to prepare easily the required polyfunctional precursors via cobalt carbonyl stabilized propargyl cations. The approach based on the tandem utilization of Co-mediated alkylation and Pauson-Khand annulation was developed in Schreiber s studies to elaborate short pathways for the synthesis of polycyclic compounds. An example of the efficiency of this protocol is the two-step transformation of the acyclic precursor 409 into the tricyclic derivative 410. The cobalt-complexed acetal 409 was first transformed into the cyclooctyne derivative 411 via intramolecular reaction of the in situ generated propargyl cation 409a with the allylsilane moiety. Cyclooctyne 411 underwent smooth cycloaddition in the presence of carbon monoxide to give the target compound 410 with excellent stereoselectivity. 

Cyclooctyne (75) can be prepared according to the usual rhethods of synthesis of acetylenic compounds. For instance, oxidation of the bishydrazone of cyclooctane-1,2-dione (74) " " or debromination of 1,2-dibromocyclooctene (76) with magnesium or the photolysis of the anion of I-tosyIamino-1,2,3-triazole derivative (77) gave cyclooctyne (75). 

The formation of the allene, sometimes a serious complication in alkyne synthesis, is not a problem in this case, because 1,2-cyclooctadiene, once formed, dimerizes readily and can therefore be easily removed from cyclooctyne by distillation. 

Dihydrazones can be oxidized to alkynes with O2 (CuCl as a catalyst), HgO, ° " FsCCOaAg and Pb(OAc)4 (Scheme 61). 1-Amino-1,2,3-triazoles, which are sometimes observed as by-products in the HgO oxidation of 1,2-dihydrazones, can be oxidized with Pb(OAc)4 to give alkynes. Cyclooctyne" has been prepared and cycloheptyne and cyclohexyne" have been generated by this method (Scheme 62). The 1-tosylamino-1,2,3-triazoles can also be used as educts for alkyne synthesis the anions are decomposed to yield the corresponding alkyne, N2 and toluenesulfmate (Scheme 63). ... 

The Diels-Alder reaction of pyridinones (Scheme 4) with substituted butadienes is quite effective for the synthesis of the reduced isoquinolinones 23. Ozonolysis of the olefin provides a method for the synthesis of cA-3,4-disubstituted piperidines <97TL2295>. The high pressure Diels-Alder reaction of the pyridinone 24 with the strained cyclooctyne provides the corresponding stable, bridged tricyclic cycloadduct 25 <97H(45)15>. 

Cyclooctyne and 4-cyclooctyn-l-ol as versatile building blocks, especially, in synthesis of natural products 05EJO4231. 

The mechanism of CO substitution with phosphines in the 19-e complex Cp Mn(CO)2NO is dissociative, followed by spontaneous oxidation of the product. Trinuclear clusters containing CpRe(CO)-fiagments in combination with iron carbonyl sulfido dimers have been reported. The synthesis of CpMn(CO)2(n -cyclooctyne) and the ligand rearrangement to an allene complex within the metal coordination sphere has been investigated by NMR spectroscopy. Tc labelled esters of cytectrene carboxylic acid have been prepared by exchange with ferrocenylcarboxylic acids in the presence of carbonyl donors. ... 

Chadwick RC, Van Gyzen S, Liogier S, Adronov A (2014) Scalable synthesis of strained cyclooctyne derivatives. Synthesis 46 669-677... 

Domnin NA (1938) The triple bond in carbon rings and the probable structure of the simplest cyclic hydrocarbon of the composition C H2 .4. II. Synthesis of cyclooctyne. J Gen Chem USSR 8 851-868... 

Heber D, Rosner P, Tochtermann W (2005) Cyclooctyne and 4-cyclooctyn-l-ol versatile building blocks in organic synthesis. Fur J Org Chem 4231 247... 

Jewett JC, Bertozzi CR (2011) Synthesis of a fluorogenic cyclooctyne activated by cu-fiee click Chemistry. Org Eett 13 5937-5939... 

Looked upon as a Cu-free click reaction with no apparent toxicity issues, the SPAAC reaction would appear to have a rich future. Still, the CuAAC reaction has the advantage of synthetic convenience due to the fact that terminal alkynes can be installed in biomolecules using simple building blocks, suh as commercially available alkynoic acids, while, in contrast, the synthesis of di uorinated cyclooctyne (DIFO) requires 12 steps and the overall yield is only about 1%. Synthetically tractable cyclooctynes having the reactivities of DIFO are therefore much needed in order to expand the use of this Cu free cUck reaction as an ef cient and biocompatible tool (Codelli et al., 2008). 

Although cyclooctynes enable copper-free Click reactions, they are not compatible with bioconjugations in aqueous media, because of their hydrophobic character. Thus, Bertozzi and coworkers uncovered a new method for the synthesis of a biocompatible cyclooctyne (6,7-dimethoxyazacyclooct-4-yne = DIMAC) to detect azide-labeled biomolecules via copper-free Click chemistry. The first conjugations to biotin as well as ceU-surface glycans were arranged. 

Royzen, M., Yap, G.P.A., and Fox, J.M. (2008) A photochemical synthesis of functionalized trans-cyclooctynes driven by metal complexation. Journal of the American Chemical Society, 130,3760. 

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