Polycyclic systems cycloadditions

Gratifyingly, when compound 24 is refluxed in a solution of toluene at 110°C, it undergoes quantitative [4+2] cycloaddition to polycyclic system 25. The indicated stereochemistry of 25 was anticipated on the basis of the trans,trans geometry of the phenyl-diene system in precursor 24 and the presumed preference for an exo transition state geometry. These assumptions were vindicated by the eventual conversion of 25 to endiandric acids A (1) and B (2). 

When (62) was treated with ethyl vinyl ether the cycloadduct (63) is afforded. If (62) is reacted with electron donating dienophiles such as allyl alcohols, transesterification and intramolecular cycloaddition occurs in the presence of a catalytic amount of distannoxane catalyst to give cis-fused polycyclic systems such as (64) <96T733>. 

In this section, those reactions in which the ylide is attached by a tether to the dipolaraphile resulting in an intramolecular cycloaddition will be discussed. To date, such a strategy has proved to be one of the less investigated aspects of azomethine ylide chemistry. However, intramolecular azomethine ylide technology, when combined with the excellent stereocontrol offered by cycloaddition reactions, allows for the rapid construction of complex polycyclic systems from relatively simple precursors. Consequently, it represents a highly attractive synthetic protocol that makes it a candidate for further investigation in the coming years. 

An attractive approach toward the preparation of polycyclic systems containing a thiophene ring involves the intramolecular [3 - - 2] cycloaddition of thiocarbonyl ylides. A number of representative examples were reported using mesoionic compounds. Gotthardt et al. (151) used l,3-dithiolium-4-olates such as 89 bearing an olefinic side chain. Upon heating to 120 °C in xylene, the polycyclic tetrahy-drothiophene 90 was formed (Scheme 5.33). 

Substituted 7-pyrones are versatile synthetic precursors. There is strong precedent for the metalation4 and bromination5 of the 7-position, which allows 7-pyrones to be used in alkylation and aldol reactions and makes them attractive intermediates in the synthesis of polyacetate and spiroketal containing natural products.6 They can also be used as cycloaddition substrates in the construction of complex polycyclic systems as West has demonstrated.7 Furthermore, 7-pyrones have been used by Wender in an oxidopyrilium-alkene cycloaddition, a key reaction in his synthesis of phorbol.8... 

Further reactions that are highly suited to the synthesis of cyclohexane derivatives, such as cycloaddition processes, 1,3-dipolar additions, and Diels-Alder cyclizations, have been used extensively. In the latter set, carbohydrate-based dienes or dienophiles have been employed and, in addition, intramolecular processes have provided highly suitable means of synthesizing complex polycyclic systems. 

This cycloaddition can be performed with either the amino acid, the aldehyde, or the electron-poor alkene linked to the support. Intramolecular azaallyl anion cycloadditions have been used to prepare polycyclic systems on solid phase (Entries 5 and 7, Table 15.5). 

Support-bound pyridines and partially saturated pyridines can be valuable synthetic intermediates, enabling various types of chemical transformation. Piperidinones can be prepared on cross-linked polystyrene by the addition of organometallic reagents to tetrahydropyridinones (Entry 10, Table 15.23). 1,2-Dihydropyridines are electron-rich dienes that can undergo Diels-Alder reaction with electron-poor dienophiles. Diels-Alder cycloaddition of support-bound 1,2-dihydropyridines has been used to prepare nitrogen-containing polycyclic systems (Entry 12, Table 15.23). 

Polycyclic Systems via l-MCR and Intramolecular Diels-Alder Cycloaddition... 

A selective sampling of the photochemical cycloaddition and cyclization chemistry of 2H-azirines has been outlined in this chapter. Some photochemical sequences increase molecular complexity more than others, but each seems to provide complex heterocyclic structures in a very efficient manner. Indeed, many of these photoreactions rapidly construct hetero-polycyclic systems that are difficult to produce in other ways. In contrast to their photochemical behavior, the major thermal reaction of 2H-azirines generally involves C(2)-N bond cleavage to form vinyl nitrenes which further react by either insertion into an adjacent C-H bond or else undergo addition across a neighboring rc-bond. The 27i-electrons of the carbon-nitrogen double bond of 2H-azirines can also participate in thermal symmetry-allowed [4- -2]-cycloadditions with a variety of substrates. It is clear from the above discussion that the chemistry of 2H-azirines is both mechanistically complex and... 

The intramolecular variant of the hetero-Diels-Alder cycloaddition is attractive since it allows the stereochemistry of the products to be controlled at four centers or even more, if substituents in the bridging chain are considered. Following the experimental procedures devised for inter-molecular cycloaddition, a number of bicyclic and polycyclic systems have been prepared with the... 

The overall sequence of carbenoid generation/ylide formation/[3-l-2]-cycloaddition or rearrangement was explored in the synthesis of a series of 1,3-triazine derivatives. Thus, 1,3-dipolar cycloaddition of the pyridinium ylide derived from 2-(3-diazo-2-oxopropylthio)pyridine gives a 1,3-thiazine ring incorporated into the polycyclic system (Scheme 21) (93JOC1144). 

Hart and Ghosh [43] have explored the 7-exo aryl and vinyl radical cyclizations for the construction of polycyclic systems as part of their tandem cycloaddition-radical cyclization strategies for polycycles. Treatment of the bromides 177-179 with BujSnH and AIBN furnished the tetra- and pentacyclic compounds 180-182 via stereoselective 7-exo trig cyclizations. 

Tethering the ene and yne reaction partners for Pauson-Khand cycloaddition was first conceived as a way to improve simultaneously the effective reactivity of simple alkene moieties and to provide access to a wider variety of bi- and polycyclic systems. Indeed, well over 100 examples of such cycloadditions have been published, mostly involving reactions of derivatives of 1,6-heptenyne to give bicyclo[3.3.0]oct-l-en-3-ones [cf. Eq. (37)] together with a smaller number of 1,7-octenynes, which afford bicyclo[4.3.0]non-l (9)-en-8-ones [81 c, 117]. The use of dry-state conditions [118] or additives such as amine oxides [119] has virtually revolutionized this field the cycloaddition shown in Eq. (52) is completed in 15 minutes( ) when promoted by NMO. 

Finally, 1,3-cycloadditions have been coupled with radical cyclizations to quickly assemble polycyclic systems, as in the conversion of betaine 415 to benzyne cycloadduct 416 and thence to aminoketone 417. ... 

The [4+2] cycloaddition is certainly one of the most important reactions in organic chemistry, and many books and reviews are dedicated to this topic [54]. In particular, Diels-Alder reaction of (hetero)dienes with (hetero)dienophiles is extensively used at the early stages of numerous syntheses to establish a structural scaffold which is then usually further elaborated toward more complex target structures. The [4+2] cycloaddition is usually an efficient method with predictably high regio and stereoselectivity as such it can enable the synthesis of highly functionalized polycyclic systems. 

Cascade reactions of substituted 1,2,4-triazines are of great interest as simple ways to a dramatic increase in molecular complexity, from planar 1,2,4-triazine unit into a polycyclic system. Indeed, in this multistep process, the diallylamine and cyclopentanone react first in situ to give the corresponding enamine, which undergoes an inverse electron demand cycloaddition reaction with 1,2,4-triazine to give an intermediate dihydropyridine compound. A spontaneous intramolecular Diels-Alder reaction between the allyl moiety and the dihydropyridine gives the tetracyclic compound (Scheme 99) <2004JA12260>. 

In all cases, cycloadditions were observed across both C=C-N02 fragments to give polycyclic systems 154 containing two pyrrolidine rings. The reactions proved... 

Another example of a,j8-imsaturated carbonyl compoimds is provided by p-quinones. Carbonyl yhdes engage p-quinones in a manner reminiscent of their reaction with o ,)S-unsaturated carbonyl compoimds [97,132]. For example, the reaction of 56 with p-benzoquinone yielded to the novel oxa-bridged polycyclic systems 150-152 through stereoselective C=0 and C=C bond additions (Scheme 47). The formation of 150 through tandem cyclization-cycloaddition-Michael addition is quite interesting as four C-O bonds and one C-C bond are formed in a single synthetic step [133]. 

Especially when combining two or more pericyclic reactions with each other, the outcome is highly efficient and could be almost qualified as miraculous, as each cycloaddition event could introduce a new ring, two new covalent bonds, and up to four new contiguous asymmetric centers in one step. Moreover, great progress has been achieved in the intramolecular and asymmetric pericyclic reactions recently, which provide highly effective approaches for the rapid elaboration of complex polycyclic systems. Some prominent total syntheses achieved based on pericyclic MBFTs will be exemplified below. 

Intramolecular trapping of trimethylmethanepalladium complexes affords a useful [3 + 2] cycloaddition strategy which could well be applied to the synthesis of polycyclic systems in which at least one ring is pentacyclic (Scheme 27). ... 

An intramolecular version of this cycloaddition has been developed by the same authors for the preparation of polycyclic systems 122 [157] and 123 (single diastereomers) [158] (Scheme 18). The latter compound has been converted into... 

Intramolecular Cycloaddition of Nonconjugated Enediynes of a Higher Order as a Route to Functionalized Condensed Polycyclic Systems... 

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