Construction of Carbocycles

Reaction (7.13) shows the simplest and most popular type of hex-5-en-l-yl radical cyclization mediated by (TMS)3SiH. Thus, a 50 mmol solution of 5-hexenyl bromide and silane in the reported conditions leads to a 24 1 ratio of cyclized vs uncyclized products [6]. Similar results were obtained by replacing the bromide with isocyanide [7]. 

Using this procedure for the secondary isocyanide 7 (Reaction 7.14), the desired product was isolated after workup in 78% yield as a 4.6 1 mixture of 

The behaviour of a series of methyl substituted hept-6-en-l-yl radicals, generated from the corresponding iodides with (TMS)3SiH and AIBN in benzene at 80 °C, has been investigated too. The low regioselectivity and poor stereoselectivities observed for these reactions are not unexpected given the conformational flexibility inherent in the hept-6-en-l-yl radical [24]. 

A convenient route to triquinanes is based on a strategy of silyl radical addition to conjugated dienes to form allylic type radicals and their subsequent intramolecular addition to C=C double bonds. By exposure of 10 to (TMS)3SiH and AIBN at 80 °C (Reaction 7.16) the triquinane 11 is obtained with an unoptimized 51 % yield [26]. 

Cyclization of secondary alkyl radicals can occur with a, (S-alkynyl esters, such as 12, and proceeds with high stereoselectivity to give predominantly (Z)-exocyclic alkenes at low temperature upon reaction with (TMS)3SiH (Reaction 7.17) [28]. 

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The intramolecular Hiyama reaction is excellently suited for the construction of carbocyclic and heterocyclic ring systems of different size. In most examples, problems of induced diastereoselectivity are involved (Sections 1.3.3.3.9.2.2. and D.2.3.). In the total synthesis of the antitumor germacranolide ( )-costunolide from ( ,.E)-farnesol, the correctly substituted ( , )-cyclodecadiene moiety was constructed by an intramolecular Hiyama reaction22. 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

It is noteworthy that, based on the sulfoxide- sulfenic acid rearrangement, the readily accessible 1,3-dithiolane systems (316) may be utilized (equation 116) as an efficient entry into the 1,4-dithiane series303, including the construction of carbocyclic fused systems304. The oxidation of the dithienes 318 to the corresponding sulfoxides (319 and 320) and sulfones is a simple, straightforward process. 

The majority of sequential radical reactions deal with cyclizations as the key steps. The constructions of carbocycles, oxygen, and nitrogen heterocycles using (TMSlsSiH as a mediator are many and represents the expansion and importance of these synthetic approaches. For example, Nicolaou and coworkers found that (TMSlsSiH serves as a superior reagent in the radical-based approach toward the synthesis of azadirachtin, an antifeedant agent currently used as an insecticide, and in other related systems. ° ° Here below we collected a number of reactions mostly from the recent work in the area of intramolecular reactions. 

In the construction of carbocycles, five-membered ring formation has been used for preparing fused cyclic compounds, such as functionalized diquinanes. ° The reaction of 36 with (TMSlsSiH furnished the expected product 37 in 80% yield and in a or.fi ratio of 82 18, as the result of a kinetic controlled reaction (Reaction 43). 

The popular methodology for the construction of carbocyclic ring consists of the intramolecular aldol condensation of properly activated monosugars. This may be exemplified by transformation of 73 into the dicarbonyl derivative 74 which, upon treatment with base (or acid), provided the desired carbocycle (Fig. 26).39 Other differently substituted derivatives were also prepared by this approach.40... 

A different mode of fragmentation of the lactone ring in 35 occurred to give butyrolactone 38 when anhydrous lithium alkoxides were used in place of metal hydroxides under aqueous conditions (Scheme 10). It is noteworthy that 36, 37 and 38 (R = H) are all formed without racemization. Although we are only in the early stages of development of the chemistry of iodolactones 35, it is already clear that there is considerable potential for utilization of the butenolides derived from 35 as scaffolds for construction of carbocyclic and heterocyclic ring... 

Another way to approach the enantioselective construction of carbocycles is to start with a readily-available carbohydrate. Gloria Rassu of the Insituto di Chimica Biomolecolare del CNR, Sassari, and Giovanni Casiraghi of the University di Parma report (J. Org. Chem. 68 5881, 2003) that the lactone 8 undergoes smooth aldol condensation to give the highly-substituted, and... 

Usually, (he construction of carbocyclic rings requires the preparation of highly functionalized intermediates. Youquan Deng of the Lanzhou Institute of Chemical Physics reports (Tetrahedron Lett. 48 2I91, 2003) that simple acid-mediated equilibration of l-dodecene 12 gives a remarkably efficient conversion to cyclododecane 13. The authors speculate that the peculiar thermodynamic stability of 13 favors this transformation. 

Grant, T. N., Modified Nazarov Reactions and Ring Expansion Chemistry Useful Methodologies for the Construction of Carbocyclic and Heterocyclic Compounds, Ph. D. dissertation, Univ. Alberta, Edmonton, AB, 2008. 

Aminocarbafuranoses have been widely utilized as building blocks for the construction of carbocyclic nucleosides whose heterocyclic base is forged... 

Details have been published of the pyridine-type molecule approach for the construction of carbocyclic compounds,11 in particular ( )-D-homo-oestrone. Treatment of (39) with toluene-p-sulphonic acid in hot benzene for one minute gave12 compound (40) of the elusive A8(9)-structure further reaction led to the expected oestrapentaene (41) from which by suitable reduction procedures 8aH-, 9 8H,14j3H-, 8aH,14 3H-, and 9/3H-oestrone methyl ethers were obtained. The well known compound (42) on electrocatalytic reduction13 (palladinized platinium... 

Participation by aromatic rings is also possible and there are now several examples of electro M]ic aromatic substitution involving Pummerer intermediates. Equation (20), the alkylation of benzene with dimethyl sulfoxide in trifluoroacetic anhydride, illustrates the process in its inq>lest foim. As widi al-kenes, reaction with aromatics has been more widely exploit in intramolecular versions for the construction of carbocycles and heterocycles. In many cases the sulfoxide precursor is of the keto variety, thus ensuring regiospecificity in the point of cyclization. Equation (21) (formation of a six-monber carbocycle), equation (22) (formation of a six-membered sulfur heterocycle), equation (23) (formation of a six-membered nitrogen heterocycle) and equation (24) (formation of a seven-membered nitrogen, sulfur heterocycle) provide illustrations of the versatility of diis form of intramolecular aromatic alkylation. 

It is probably superfluous to say that radical reactions are suitable for the construction of carbocycles. What is working to achieve carbohydrate ring closure is obviously suitable to form... 

Piers, E., Romero, M. A. Intramolecular CuCI-Mediated Oxidative Coupling of Alkenyltrimethylstannane Functions An Effective Method for the Construction of Carbocyclic 1,3-Diene Systems. J. Am. Chem. Soc. 1996, 118, 1215-1216. 

A semipinacol rearrangement in tandem with a cyclization has been shown to be a powerful method for the construction of carbocyclic rings. Here the cyclization is initiated by an acetal function and terminated by a semipinacol rearrangement (Scheme 25). In some cases, the cyclization has been found to be stereospecific at the acetal center (equation 48), and up to four chiral centers can be generated in a single step (equation 49). Highly substituted tetrahydrofurans are obtained from cyclic acetals (Scheme 26), and stereoselective tetrahydrofuran annelations are possible using bicyclic acetals (Scheme 27). ... 

The Hosomi-Sakurai reaction is a powerful method for conjugate allylation of a,fi-unsaturated ketones [425], In the presence of TiCl4 the allylation occurs smoothly at the y-position of allylsilanes and the / -position of a, -unsaturated ketones. This highly regioselective process has been widely used for introduction of functionalized carbon chains and construction of carbocycles in natural product synthesis [6, 426]. When TBAF is used as catalyst, both conjugate addition and 1,2-addition occur competitively [333]. The fluoride ion-catalyzed procedure is, however, effec-... 

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