The chemistry of cyclopropylmethyl and related radicals

Abstract

Ring opening of the cyclopropylmethyl radical (1) gives the but-3-enyl radical (2) with a rate constant at 37 "C of 1.2 x lo8 sl .The cyclopropylmethyl carbanion also undergoes ring opening giving the but-3-enyl anion. The rate of this process is very much slower than that of the corresponding radical and has been estimated to be about 9.5 x l o p 5 s -l at -24"C.2 Unlike the corresponding cations, cyclopropylmethyl radicals do not rearrange to cyclobutane derivatives.The rapidity of the ring opening of the cyclopropylmethyl radical has resulted in the widespread use of cyclopropane rings as a probe of reaction mechanism both in chemical and enzymecatalysed reactions. This is only a valid probe if the ring opening of the cyclopropylmethyl radical is more rapid than any competing reactions. For this reason it is essential to have a sound appreciation of the factors which control rates of ring opening of substituted cyclopropylmethyl radicals. As will be demonstrated, hypersensitive radical probes can be used, i.e. substituted cyclopropylmethyl radicals which ring open much faster than the parent cyclopropylmethyl radical.The variation in the rate of ring opening with substituents either at the radical centre or on the cyclopropane ring will be discussed in this review along with the regioselectivity of the ring opening process. Examples of the application of cyclopropylmethyl radical ring opening to the study of enzyme mechanisms and to synthetic methodology will also be discussed. Characteristics of the RearrangementThe parent cyclopropylmethyl radical contains ca. 1 15 kJ molof strain and hence homolytic cleavage of the C,-C, bond to give a but-3-enyl radical is highly exothermic. EPR studies show that the preferred conformation of the radical is bisected, (3).3(3) Derek Nonhebel received his B.Sc. degree from King's College, University of London in 1954 and his D. Phil.jrom the University of Oxford where he worked under the supervision o j the late Prof. W. A . Waters, F.R.S. He was elected a Fellow of the Royal Society of Edinburgh in 1982. His research interests centre on various aspects of radical chemistry. He has co-authored two books on radical chemistry.

Enantioselective synthesis of (−)-paeonilide

“…The retro synthetic analysis (Scheme 7) of the target compound 5 does not start from a chiral starting material in contrast to the published diastereoselective synthesis, but employs commercially available 3-furoic acid (59). The chiral information is introduced by a copper(I)-catalyzed cyclopropanation reaction using a chiral bis(oxazoline) ligand to yield the bi-cycle 58.…”

“…By choosing commercially available 3-furoic acid (59) as starting material for the planned synthesis of (-)-Paeonilide (5) a protection of the free carboxylic acid by esterification proved to be necessary to avoid unwanted side reactions. 42 The ester was formed under strongly acidic conditions, i.e.…”

“…Although this hypothesis has yet to be proven, it gives an explanation for the lower enantioselectivity of this cyclopropanations and makes the way for further optimization. In order to increase the steric repulsion, more bulky ester groups could be introduced into the 3-furoic acid (59) to enable a screening process.…”

“…[59][60][61][62] The main reason for the broad interest in this special moiety is the reactivity of cyclopropanes, which is usually associated with electron-donating and/or electron-accepting substituents. (92), vicinal (93), 1,3-dipolar synthon (94).…”

Stereospecific Synthesis of Carbanucleotides Designed for Antisense Methodology.

“…Moreover, the assignment of the syn-and anti-configuration to the isomers of ketal 21 was also possible by NOE difference spectroscopy, since the enhancement by 23.5% of the intensity of the resonance signal at 1.77 ppm assigned to HÀC(3) of the tricycle observed on irradiation at HÀC (8) Unfortunately, however, reductive cleavage of the cyclopropane ring, which was attempted by catalytic hydrogenation of the mixture of syn-and anti-stereoisomers of 11 (both as racemates), was not regioselective: the reaction product consisted of a mixture of the desired 5-oxonorbornane-2-acetate rac-12a and its isomer rac-12b in a ratio of roughly 1 : 1 (Scheme 2). In view of this difficulty, we next attempted a regioselective cleavage of the cyclopropane ring in consideration of the well-known tendency of cyclopropylmethyl radicals to isomerize, yielding butene radicals [22]. As a matter of fact, rearrangement of the cyclopropylmethyl radical 22, derived from 11, may produce the two radicals 23 and 24, 23 being homoconjugated with the carbonyl group of the norbornanone skeleton (Scheme 4).…”