Strained bicyclic

Strained bicyclic compounds can be obtained e.g. when cyclopropenes are used as dipolarophiles. Reaction of 3,3-dimethylcyclopropene 7 with diazomethane 4 gives the heterobicyclic cycloaddition product 8 in 85% yield ... 

The strained bicyclic carbapenem framework of thienamycin is the host of three contiguous stereocenters and several heteroatoms (Scheme 1). Removal of the cysteamine side chain affixed to C-2 furnishes /J-keto ester 2 as a possible precursor. The intermolecular attack upon the keto function in 2 by a suitable thiol nucleophile could result in the formation of the natural product after dehydration of the initial tetrahedral adduct. In a most interesting and productive retrosynthetic maneuver, intermediate 2 could be traced in one step to a-diazo keto ester 4. It is important to recognize that diazo compounds, such as 4, are viable precursors to electron-deficient carbenes. In the synthetic direction, transition metal catalyzed decomposition of diazo keto ester 4 could conceivably furnish electron-deficient carbene 3 the intermediacy of 3 is expected to be brief, for it should readily insert into the proximal N-H bond to... 

In 1980, a Merck group disclosed the results of a model study which amply demonstrated the efficiency with which the strained bicyclic ring system of thienamycin can be constructed by the carbene insertion cyclization strategy.12 Armed with this important precedent, Merck s process division developed and reported, in the same year, an alternative route to carbene precursor 4.13 Although this alternative approach suffers from the fact that it provides key intermediate 4, and ultimately thienamycin, in racemic form, it is very practical and is amenable to commercial scale production. The details of this interesting route are presented in Schemes 4-6. 

The strained bicyclic core of the antitumor antibiotic ncocarzinostatin was constructed by this method23. 

Small (three- and four-membered) cyclic sulfoxides, or strained bicyclic sulfoxides, appear to be particularly good candidates for the photoextrusion process. For example,... 

The resulting carbene complex 41b bears a hetero substituent and shows activity in the ring-opening/cross metathesis of strained bicyclic alkenes and... 

From the kinetic viewpoint the polymerizability of 61 is considered to be higher than that of e-caprolactam, which is polymerized usually at temperatures above 135 °C63,64 Thermodynamically, the polymerization of 61 appears to be more favored than that of a-pyrrolidone, for which no polymerization is observed in THF63-65 The higher polymerizability of 61 may be attributed not only to its highly strained bicyclic structure but also to the activation of the anion 66 by the... 

The short lifetimes of carbon-centered monoradicals are generally reduced in the case of diradicals due to their propensity to form covalent bonds. It has been suggested that stable diradicals may be observable from highly strained bicyclic molecules where the TS for inversion is a diradical. Unfortunately, only persistent diradicals have been obtained in this way. Akin to this approach, in a recent attempt to generate the oxyallyl diradical, Sorensen and co-workers synthesized two substituted bicyclobutanones hoping to stretch and homolytically break the central bond using bulky substituents, which would also stabilize the diradical. Though the bicyclobutanones did not yield the desired oxyallyl derivative, the X-ray structures showed... 

Dioxabicyclo[2.2.1]heptane naturally assumed the role of the principal target molecule. It represented a considerable synthetic challenge, for not only is it a strained bicyclic molecule containing the weak and labile 0—0 bond, but it is also a di(secondary-alkyl) peroxide which is the most difficult type to make by classical procedures 12). New synthetic methods of exceptional mildness were clearly needed to solve this problem. In the course of the development of such techniques and from a desire to establish their scope, a variety of saturated bicyclic peroxides have been obtained in addition to 2,3-dioxabicyclo[2.2.1]heptane. The question of how substitution patterns and ring sizes affect the reactivity of bicyclic peroxides has further served to broaden interest in the subject. 

The bicyclic peroxide 11 was prepared via diimide reduction of the endoperoxide derived from spirocyclopentadiene (Eq. 8)21>. As before, at elevated temperature the labile endoperoxide rearranges into diepoxide and ketoepoxide,22) but diimide reduction at —78 °C allows trapping leading to the highly strained bicyclic peroxide 11. 

Studies on the biosynthesis of prostaglandins revealed that a strained bicyclic bis(secondary-alkyl) peroxide was not only a key intermediate, but could survive the biological conditions long enough to be isolated, albeit in minute amounts. This was a startling discovery in that no simple bicyclic peroxides of the same type were known, clearly for reasons of preparative difficulty. The prostaglandin connection focused attention upon this missing class of peroxides and stimulated... 

Strained bicyclic sulfonium salts are important reactive intermediates and undergo subsequent transformations often with high levels of regio- and stereoselectivity. Various research groups have reported evidence for the formation of [4.1.0] 7, [3.2.0] 8, [3.1.0] 9, and [2.2.1] 10 bicyclic sulfonium salts as reactive intermediates. 

Borst et al. <2005CEJ3631> conducted a study on the synthesis of strained bicyclic phosphirane and phosphirene iron-tetracarbonyl complexes (Scheme 11). It was shown that, depending on the ring size of the resulting heterocycle, electrophilic phosphinidene [Ri-PrNP=Fe(CO)4] could be trapped intramolecularly with both double and triple bonds (compounds 146-150). The phosphinidene addition was found to be reversible at room temperature and when using phenylacetylene as solvent, exchange between phenylacetylene and the phosphinidene group took place. Compound 151 was isolated as the dimer, compound 152. 

In contrast to the above general scheme (p. 66), the strained bicyclic cyclopro-penone 4047 is attacked by hydroxide ion at both three-ring sites (C3 and C1 2 ) resulting in formation of acid 320 and 1,2-diketone 321 in a ratio of 2 3,... 

Our approach to the synthesis of model compounds, suited for the generation of carbenes, which are bound to the bridgehead of a strained bicyclic system, used the facile synthesis of [n.l.ljpropellanes, which we developed some years ago. Starting from substituted allyl chlorides 35, dibromocarbene addi-... 

The intermolecular reaction of alkynes with acylcarbene complexes normally yields cyclopropenes [587,1022,1060-1062]. Because of the high reactivity of cyclopropenes, however, in some of these reactions unexpected products can result. In particular intramolecular cyclopropanations of alkynes, which would lead to highly strained bicyclic cyclopropenes, often yield rearrangement products of the latter. In many instances these products result from a transient vinylcarbene complex, which can be formed by two different mechanisms (Figure 4.3). 

While for CTOCri.v-O1,02-cyclohexanediolate>21 the carbinolic protons are pairwise magnetically equivalent (Fig. 4), the strained bicyclic structure in the [CrO(l,2-cyclopentanediolate)2] complex leads to a local inequivalence of all carbinolic protons (Table II). 

Although it is generally accepted that the exo approach to norbomene is favored over the endo, the magnitude of the AAE is rarely measurable experimentally unless some fraction of the endo product can be detected. The exo approach to norbomene is favored over the endo orientation by nearly 3 kcalmol for both PFA and DMDO, while the exo TS for benzonorbomadiene is favored by nearly 5 kcalmol (Figure 27). The preferred exo approach does not appear to result from steric interactions. It is of particular interest that the AE for norbomene is only 0.9 kcalmol greater than that for cyclohexene despite the SE = 19.2 kcalmol" for the strained bicyclic alkene. Thus, in the absence of twist-strain we observe little rate enhancement due to strain energy. 

Most of the highly unsaturated monocyclic eight-membered heterocycles contain one or two nitrogen atoms and have been obtained by bond reorganization processes from strained bicyclic or polycyclic precursors. Although several of the less substituted compounds without stabilizing substituents are highly labile substances, 1,4-dihydro-1,4-diazocines qualify as dihetera[8]annulenes and display distinct aromatic properties. 

Theorists believe that the symmetry of the n system is imposed by the framework of a bonds. Bond alternation in the n system can be forced by the fusion of strained bicyclic rings [248] such as in [4]phenylene [249], tricyclobutabenzene [250], or trisbicyclo[2.1.1]-hexabenzene [251] ... 

Alkenes participate readily in oxymercuration with increasing alkyl-substitution resulting in decreasing reactivity.489,491,492 The oxymercuration of alkenes is usually an anti process.493 195 Exceptions are strained bicyclic olefins, such as norbomene495,496 [Eq. (6.83)],497 and frans-cyclooctene and frans-cyclononene.494... 

Aryl azides react with olefins to give 1,2,3-A2-triazolines.201-203 Whereas unactivated olefins are sluggish toward aryl azides, strained bicyclic systems, on the contrary, are particularly reactive.204-208 The rate of phenyl azide addition to a series of olefins parallels the heat of hydrogenation (Table Vffl).107 This thermodynamic parameter is a measure for the degree of strain associated with these molecules.200 Bicyclo[2.2.1]hep-tenes, such as norbomene (37), react readily at room temperature, and the addition occurs at the less hindered exo side (39).,06 1°7 210 211 A striking example of the increased... 

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