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. 2017 Jun 14;139(23):8029-8037.
doi: 10.1021/jacs.7b03943. Epub 2017 May 31.

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

Eileen G Burke  1 , Brian Gold  1 , Trish T Hoang  1 , Ronald T Raines  1 , Jennifer M Schomaker  1
Affiliations

Fine-Tuning Strain and Electronic Activation of Strain-Promoted 1,3-Dipolar Cycloadditions with Endocyclic Sulfamates in SNO-OCTs

Eileen G Burke et al. J Am Chem Soc. .

Abstract

The ability to achieve predictable control over the polarization of strained cycloalkynes can influence their behavior in subsequent reactions, providing opportunities to increase both rate and chemoselectivity. A series of new heterocyclic strained cyclooctynes containing a sulfamate backbone (SNO-OCTs) were prepared under mild conditions by employing ring expansions of silylated methyleneaziridines. SNO-OCT derivative 8 outpaced even a difluorinated cyclooctyne in a 1,3-dipolar cycloaddition with benzylazide. The various orbital interactions of the propargylic and homopropargylic heteroatoms in SNO-OCT were explored both experimentally and computationally. The inclusion of these heteroatoms had a positive impact on stability and reactivity, where electronic effects could be utilized to relieve ring strain. The choice of the heteroatom combinations in various SNO-OCTs significantly affected the alkyne geometries, thus illustrating a new strategy for modulating strain via remote substituents. Additionally, this unique heteroatom activation was capable of accelerating the rate of reaction of SNO-OCT with diazoacetamide over azidoacetamide, opening the possibility of further method development in the context of chemoselective, bioorthogonal labeling.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Strain and electronic effects on rate and selectivity of strain-promoted 1,3-dipolar-alkyne cycloadditions.
Figure 2
Figure 2
Calculated free energies [M06-2X/6-311+G(d,p) level of theory with an IEFPCM solvent model for water (radii = UFF)] of activation (kcal/mol) of the lowest energy TSs for cycloaddition of methyl azide with alkynes containing various propargylic and homopropargylic substituents either without an endocyclic sulfonyl group (A) or containing an endocyclic sulfonyl group (B). (C) Starting alkyne geometries with selected bond lengths given in ångstroms and angles in degrees. Hybridizations were obtained from NBO analyses for the sulfur bonding orbitals in S–X and S–Y bonds. Black = carbon; white = hydrogen; blue = nitrogen; red = oxygen; yellow = sulfur. (D) Distortion/interaction analysis. For a full analysis and further computational details, see Table S6 in the Supporting Information. aThe syn-TS is preferred, where syn refers to the relationship of the azide methyl group relative to the C–X bond.
Figure 3
Figure 3
(A) Free energies of activation (kcal/mol) of the lowest energy TSs for cycloadditions of methyl azide with alkynes containing various propargylic and homopropargylic substituents. Geometries were optimized at the M06-2X/6-311+G(d,p) level of theory with an IEFPCM solvent model for water (radii = UFF). Inset: ΔΔG‡ relative to X = Y = CH2 and distortion/interaction analysis. For a full analysis and further details, see Table S6 in the Supporting Information. (B) Starting alkyne geometries with selected bond lengths given in ångstroms and angles in degrees. Hybridizations were obtained from NBO analysis and are given for sulfur bonding orbitals in S–X and S–Y bonds. Black = carbon; white = hydrogen; blue = nitrogen; red = oxygen; yellow = sulfur.
Figure 4
Figure 4
Chemoselectivity in the reaction of strained cycloalkynes with two different 1,3-dipoles.
Figure 5
Figure 5
Conjugation of maleimide–SNO-OCT to P19C RNase 1, followed by the 1,3-dipolar cycloaddition of azide–PEG3–biotin.
Scheme 1
Scheme 1
Strained Heterocycles from Silylated Allenes
Scheme 2
Scheme 2
Synthesis of 19
See this image and copyright information in PMC

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