Azanorbornadienes as Thiol-Reactive Cleavable Linkers

Abstract

Azanorbornadienes (ZNDs), prepared from pyrroles, undergo Michael reaction with thiols followed by retro-Diels−Alder (rDA) cleavage to release the starting pyrrole and a thiomaleate. Somewhat less reactive in this regard than furan-derived oxanorbornadienes, ZNDs have an additional point of variability at the pyrrole nitrogen center. Sulfonylated ZNDs were far more stable toward rDA cleavage than acylated analogues. tert-Butoxycarbonyl examples were much less reactive with thiols, rendering the rDA step slower than the initial conjugate addition.

Ylidenenorbornadiene Carboxylates: Experimental Kinetic Analysis of a Nucleophile-Induced Fragmentation Reaction

“…Based on the consistent observation of pyrrole, even with excess acetylene, Finn and co-workers suggest the reversibility of the cycloaddition of azanorbornadiene systems under similar conditions. 26 These two results indicate that YND systems exhibit a higher stability than ZNDs and would likely offer different fragmentation kinetics.…”

“…Previous work pioneered by the Finn group has recently highlighted [4 + 2] cycloadditions between furan or pyrrole dienes with acetylene dicarboxylate dienophiles, which are exergonic in the formation of oxa- and azanorbornadienes, ONDs − and ZNDs, respectively (Scheme ). These systems are then “switched on” by a nucleophile (thiol, amine, or phosphine) stimulus, and the fragmentation of the adduct is favored via a retro-[4 + 2] cycloaddition.…”

“…Model substrate 4a was prepared via a conjugate addition with beta -mercaptoethanol (BME). However, unlike the OND and ZND systems with the BME nucleophile, , YND–BME adducts provided a complex mixture of four diastereomers 4a:d1–4 (Scheme ). Presumably, this is because: (1) YNDs have increased steric hindrance at the top of the norbornadiene bridge, lessening the preference for an exo -face attack of the thiol nucleophile, and (2) YNDs lack a H-bond acceptor (O or N) that could potentially direct either the thiol nucleophile or the addition of the proton during the conjugate addition reaction.…”

“…The ratio of diastereomers was determined by integrations of the alkene proton signals in the 1 H NMR spectrum in CDCl 3 (Figure S1). The structural assignment of diastereomers 4a:d1–4 was realized based on three factors: (1) the rapid disappearance of the 1 H NMR signal assigned to 4a:d2 in conjunction with the consequent appearance of the vinyl proton 1 H NMR signal of the thioether-fumarate trans -5 ; (2) the ratio of thioether-maleate:thioether-fumarate ( cis -5 : trans -5 ) isomers at the end of kinetic trials; and (3) the assumption that the major diastereomer 4a:d1 , present at 60%, is the syn-exo diastereomer since syn-exo isomers are the only isomers observed in the OND and ZND systems with BME nucleophiles. , (For a more thorough explanation of the 1 H NMR analysis, see the Supporting Information).…”