Cycloadditions of the Oxyallyl Cation

Scheme 3.22 Formal intramolecular [3+2] cycloaddition of the oxyallyl cation intermediate.

The construction of tetracyclic substrate 25 has been achieved by the intramolecular cycloaddition of a furan tethered (n = l) to a cycloalkanone using conditions related to those developed by Fohlisch, Eq. 15 [42,43]. As the ring size of the oxyallyl cation increased, products arising from cycloaddition via the less strained exo transition state predominated. Cycloadducts with n = 6,8 have also been successfully prepared as a mixture of stereo isomers [43 b]. 

The dipolar cycloaddition of 2-oxyallyl cations is also a process that has been exploited for the synthesis of substituted furans and polycyclic materials, for example it can be made the means for the introduction of acylmethyl groups at the furan 2-position." ... 

Hoffmann s cycloaddition (67) of the oxyallyl cation 272, generated from 2,4-dibromopentan-2-one with LeGoff s zinc-copper couple (68). Hydrogenation followed by Baeyer-Villiger oxidation gave the lactone 274, with C-2, C-3 and C-6 correctly set up. Methanolysis gave a single hydroxyester,... 

There have been several examples of good stereocontrol in 4+3 cycloaddition reactions. For instance, it is known that cyclopentenyl and cyclohexenyl oxyallylic zwitterions bearing a stereogenic center react preferentially with dienes from the face opposite to the substituent. One of the precedents from our laboratory is the intramolecular reaction of ketones 50 and 52 (Scheme 15). Treatment of these ketones with LDA/TfCl afforded the corresponding a-chloroketones, which reacted intramolecularly with the tethered furans to yield cycloadducts 51a,b and 53a,b upon treatment with base. The endo isomers (51a, 53a) dominated in both cases. Only those products derived from the transition states having furans approach the least hindered faces of the oxyallylic cations were produced. 

The sensitivity of S to electrophilic reagents proved to be a complication when an attempt was made to perform cycloaddition with the oxyallyl cation, which had worked well with phosphole oxides. The reagent attacked on S, presumably to give a spirophosphorane, such as (177), which rearranged to leave oxygen on phosphorus as in (178) (Scheme 38) (31% <75T53 . Other products... 

The cycloaddition of 2-oxyallyl cations to dienes is now a well established procedure for the synthesis of seven-membered rings. An extensive mechanistic study by Hoffmann and his co-workers has now shown that the reaction proceeds via a stepwise mechanism.A new procedure for the generation of these species involves the treatment of a -chlorotrimethylsilyl enol ethers [e.g. (203)] with silver ions. ... 

Hoffmann" and Noyori later developed and popularized the analogous higher order [4+ 3]-cycloaddition of an oxyallyl cation equivalent and 1,3-dienes as an attractive method for the formation of historically difficult-to-access seven-membered rings. The oxyallyl cations are typically generated from the reduction of a,a -dihalo ketone derivatives, often generating symmetric cations. Subsequent addition to both cyclic and acyclic dienes produces the bicyclo[3.2.1]oct-6-en-3-ones, meso compounds that have found wide use in organic syntheses. ... 

Addition of the oxyallyl intermediate using a tethered alkene can produce new C-C bonds with ease. When short tethers are used, the formation of a second C-C bond can be seen by way of a formal [3+2]cycloaddition onto the oxyallyl cation. West and coworkers [26] were the first to demonstrate this behavior (Scheme 3.22). The Nazarov cydization of substrate 99 generates the first ring 102 via the standard conrotatory cydization. The intermediate 102 is poised to undergo an endo-mode cationic cydization to produce bicyclic compound 103. At this point. 

The trapping of the oxyallyl cation by the alkene in a formal [3+2] fashion is not the only cycloaddition possible by this method. The oxyallyl cation, in the presence of a 1,3-butadiene, undergoes a [4+3] cycloaddition. West and coworkers [27] reported cases of cascade-interrupted Nazarov/intramolecular [4+3] cycloadditions in 1999, a representative example of which is depicted in Scheme 3.23. Thus, tetraenone 104 was subjected to FeClj at low temperature to produce a mixture of stereoisomeric tetracyclic products 105 and 106 in 98% yield. The initially formed oxyallyl cation 107 generates these two diastereomeric products by way of putative endo and exo-mode cycloaddition transition states, 107-endo and 107-exo, respectively. 

These earliest examples of the use of enolsUane derivatives as precmsors of oxyallyl cations showcased the advantages of this approach. In these cycloadditions, the counterion M of the oxyallyl cation was known to be the silyl group and could be expected to be relatively robust... 

The furan nucleus undergoes cycloadditions with oxyallyl cations to produce compounds with the oxabicyclo[3.2.1]octene skeleton. Various research groups have found new ways of generating the oxyallyl cation and have also defined the types of substituted furans which undergo reaction. Reviews on this reaction have covered the literature up to 1987 [24-26]. The mechanism of the cycloaddition has been discussed in detail by Hoffmann [26]. 

Recently, Lautens, Aspiotis and Colucci extended the [4+3] cycloaddition methodology to include the diastereoselective intermolecular cycloaddition between an oxyallyl cation and a chiral furan [45]. The best results were obtained employing furan 26 bearing a free hydroxyl group in the 2-position, reacting with excess 1,3-dibromopentanone in the presence of diethyl zinc. Under the optimized conditions, up to 80% yield of the crystalline oxabicyclo[3.2.1]octene 27 was obtained with a diastereoselectivity of a 19 1. The other product was the minor diastereomer 28, Eq. 17. 

This looks as though each of the C—C bonds is independently the result of both HOMO/LUMO interactions, with an endo selectivity as well. In the presence of dienes, these species behave as allyl cations (see p. 259) and undergo clean [4 + 2] cycloadditions, as in the reaction of the oxyallyl 6.372 giving the tricyclic ketone 6.373, which is similar to the diene 6.369. Normally, oxyallyls are in equilibrium by disrotatory electrocyclic ring closures with cyclopropanones and with allene oxides, but the presence of the five-membered ring in these particular examples makes these pathways counter-thermodynamic. 

The intramolecular 4+3 cycloaddition reactions of cyclopentenyl oxyallylic cations have been studied and developed in our laboratory for quite some time. Our group appreciates the power of cyclic oxyallylic cations such as 31 that allow us to perform a 4+3 cycloaddition reaction to create a product that is a formal 4+(3+m) cycloadduct (32) (Scheme 10). So does Fred West s group. 

The lack of diastereoselectivity in the intramolecular 4+3 cycloaddition reactions of cyclopentenyl oxyallylic cations with tethered butadienes has prohibited the application of this methodology to the synthesis of natural produets. Therefore, the development of stereocontrol in cycloadditions of this type is of great significance. Our study in this area was conducted in the context of the synthesis of (+)-dactylol. 

The synthesis of seven-membered rings from furans and a,a -dibromoketones via oxyallyl intermediates is well known. It was reported that this reaction occurs quite easily when water is used as solvent <97TL8031>. In a study on the influence of steric and electronic effects on a function attached at C-2 of furans in the yield and diastereoselectivity of [4 + 3] cycloaddition reactions with oxyallyl cations it was found that in almost all cases a c/x-diastereospecificity and a high endo diastereoselectivity is obtained <97T11669>. A tandem Peterson olefination-[4 + 3] cycloaddition reaction with furans has been reported <97JOC1578 97TL386l>. For an intramolecular [4 -t- 3] cycloaddition see <97JOC6051>. The first asymmetric [4 + 3]... 

Phosphole oxides also participate in a cycloaddition reaction with oxyallyl cations <75T53>, a process that gives rise to novel phosphatropolone structures. Preformed 1,2,5-triphenylphosphole oxide gave a derivative of the 8-phosphabicyclo(3.2.1]octan-6-ene-3-one ring system ((157), 91%). The oxyallyl cation (156) was prepared from a,a -dibromodibenzylketone and Nal in acetonitrile (Scheme 31). 

A convenient method for the formation of 2-oxyallyl cations has been developed from ketones and applied to both inter- and intramolecular cycloaddition reactions. The ketone is converted to the intermediate a-chloroketone, from which the 2-oxyallyl cation is formed with lithium perchlorate. For example, intramolecular cycloaddition of the 2-oxyallyl cahon generated from the cyclic ketone 194, gave the exo adduct 195 as the major stereoisomer (3.128). 

Another intermediate for which a cycloaddition product provides convincing evidence is the oxyallyl cation. This compound can be made from a,a -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

The intramolecular aza-[4 + 3] cycloaddition reactions of aza-oxyallylic cations with furans provided macrocyclic furans (13S1825). The [4 + 3] cycloaddition products of 2-chlorocyclopentanones with furans were prone... 

Cycloadditions and Rearrangements. The addition of 2-oxyallyl cations to furan provides a route to oxabicyclo[3,2,l]octanes complementary to the cycloaddition of cyclopropanones to furan. Careful experimental studies have led to yields of preparative importance both with furan and with cyclopentadiene. Following the route to azabicyclo-octanes, dipolar addition to the pyrylium betaine (99) affords oxa-analogues (Scheme 23). Also reported are the addition of fiiran to 1-cyanonaphthalene, the formation of various cycloadducts of tropone and tropolone (Scheme 24), and the phototransformations of (100) (Scheme 25) and (101) (Scheme 26). Thermal addition gives (102) from (103) and similarly other 8-oxabicyclo-octanes are prepared from acyclic precursors. ... 

A noteworthy observation is the lack of [4+3] or [3+2] cycloaddition products when using cyclic dienes to trap the oxyallyl intermediate. Indeed, the use of furan or 1,3-cyclohexadiene 125 gave only alkylation product 126. One can assume that significant steric hindrance between these dienes and the oxyallyl cation in the [4+3]- and [3+2] cycloaddition transition states would prevent these transformations from occurring and favor the Friedel-Crafts alkylation process. 

---