Cycloalkene oxides

Cyclization, solvolytic, 54, 84 Cycloalkene oxides, 1-methyl, conversion to exocyclic methylene alcohols, 53, 20 Cyclobutadiene, generation in situ, 50, 23... 

Cycloalkene Oxides of Medicinal or Toxicological Interest 10.1. Introduction... 

The data in Table 10.1 suggest that the reactivity of epoxide hydrolase toward alkene oxides is highly variable and appears to depend, among other things, on the size of the substrate (compare epoxybutane to epoxyoctane), steric features (compare epoxyoctane to cycloalkene oxides), and electronic factors (see the chlorinated epoxides). In fact, comprehensive structure-metabolism relationships have not been reported for substrates of EH, in contrast to some narrow relationships that are valid for closely related series of substrates. A group of arene oxides, along with two alkene oxides to be discussed below (epoxyoctane and styrene oxide), are compared as substrates of human liver EH in Table 10.2 [119]. Clearly, the two alkene oxides are among the better substrates for the human enzyme, as they are for the rat enzyme (Table 10.1). 

The reaction of cycloalkene oxides with EH should be a priori mechanistically similar to that of acyclic analogues, except that the presence of a cycle may impose characteristic stereochemical constraints on the products. A look at Table 10.1, however, indicates that cycloalkene oxides are poorer substrates for EH than their acyclic analogues. 

A systematic study has confirmed the low activity of EHs toward cycloalkene oxides (1,2-epoxycycloalkanes, 10.123) [184], In the presence of mouse liver microsomal EH, activity was very low for cyclopentene oxide and cyclohexene oxide (10.123, n = 1 and 2, respectively), highest for cyclo-heptene oxide (10.123, n = 3), and decreased sharply for cyclooctene oxide (10.123, n = 4) and higher homologues. Mouse liver cytosolic EH showed a different structure-activity relationship in that the highest activity involved cyclodecene oxide (10.123, n = 6). With the exception of cyclohexene oxide, which exhibited an IC50 value toward microsomal EH in the p.M range, cycloalkene oxides were also very weak inhibitors of both microsomal and cytosolic EH. 

Not unexpectedly, cycloalkene oxides are equally important as alkene oxides in medicinal chemistry and drug metabolism, as illustrated below with a few selected examples. Other compounds of interest that will not be discussed here include epoxytetrahydrocannabinols and endogenous 16,17-ep-oxy steroids. 

The structure of the base will also have a significant impact on the a//3 competition, particularly for cycloalkene oxides. One of the most intriguing examples of this effect was reported by Whitesell and White in 1975. They found that the reaction of LDA with... 

The growing interest in enantioselective isomerization of meso oxiranes to allylic alcohols arises from the ready availabihty of starting materials and the synthetic value of the homochiral products. First apphed to simple meso cycloalkene oxides, this methodology has been successfully exteuded to fuuctioualized meso oxiranes, and even to the kinetic resolution of racemic oxiranes, demonstrating its potential in accessing highly advanced synthons. 

Olah et al.724 have shown that Nafion-H induces the ring opening of oxiranes under mild conditions to afford various products. Substituted oxiranes undergo hydrolysis or alcoholysis to yield 1,2-diols or 1,2-diol monoethers, when treated with Nafion-H under mild conditions in the presence of water or alcohols, respectively. Cycloalkene oxides give the corresponding trans products stereoselectively [Eq. (5.273)]. 

Isomerization of substituted styrene oxides allows the synthesis of aldehydes in high yields726 [Eq. (5.275)]. Cycloalkene oxides do not react under these conditions, whereas 2,2,3-trimethyloxirane gives isopropyl methyl ketone (85% yield). Isomerization of oxiranes to carbonyl compounds is mechanistically similar to the pinacol rearrangement involving either the formation of an intermediate carbocation or a concerted mechanism may also be operative. Glycidic esters are transformed to a-hydroxy-/3,y-unsaturated esters in the presence of Nafion-H727 [Eq. (5.276)]. 

D-Fmctose-derived ketone 50 (also available in its enantiomeric form from L-sorbose) was introduced as a catalyst for the asymmetric epoxidation of trans- and trisubstituted olefins, and as such was successful in the preparation of enantioenriched substituted cycloalkene oxides (Table 5, entries 1-5) <1996JA9806, 1997JA11224, 2001T5213>. 

Ligands of type 1 have also led to interesting results in kinetic resolutions during Cu-catalyzed reactions of dialkyIzinc with cycloalkene oxides (eq. (1)) [18] and cyclohexenones [19]. On the other hand, monophosphonites bearing a fused 1,4-dioxane ring behave moderately in the Rh-catalyzed hydrosilylation of ketones (up to ca. 56 % ee) [20] cf. Section 2.6 Finally, a phosphapallada-cyclic complex has been reported as an exceptionally fast catalyst for the hydroarylation of norbomene (TONs up to 10 °) but with low ees (< 25 %) [21]. 

Contemporaneously, Cope also reported the first examples of base-induced transannular rearrangements (C-H insertion) of medium-sized cycloalkene oxides 62 and 64 (Scheme 11) [48]. These transformations could proceed via a carbenoid species (the hthiated epoxide) and/or an a-alkoxy carbene (such as 57 in Fig. 2). 

Very recently, deprotonation-electrophile trapping of simple meso-epoxides was applied to medium-sized meso-cycloalkene oxides [77]. When cyclooctene oxide 62 is treated with s-BuLi in the presence of a diamine at -90°C, the Hthiated epoxide is stable enough to be trapped with a wide range of electrophiles, allowing the creation of carbon-heteroatom or carbon-carbon bonds [Eq. (33)]. The deprotonation is a symmetry-breaking step, and enantioselective deprotonation was successfully achieved in the presence of (-)-sparteine, leading to a range of enantio enriched functionalised epoxides 115 (in up to 86% ee). 

Dimethylaluminium amides of ( )-a-methylamine facilitated preparation of trans-2-amino-cyclohexanol and -cyclopentanol. After reaction with the appropriate cycloalkene oxide, separation of the... 

FIGURE 24.3 Chiral zinc catalyst 14 for the asymmetric, alternating copolymerization of cycloalkene oxides and CO2. 

Cheng, M. Darling, N. A. Lobkovsky, E. B. Coates, G W. Enantiomerically-enriched organic reagents via polymer synthesis Enantioselective copolymerization of cycloalkene oxides and CO2 using homogeneous, zinc-based catalysts. Chem. Commun. 2000, 2007-2008. 

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