Cyclization reactions stereochemistry

Throughout each chapter, clear structures, schemes, and figures accompany the text. Mechanism, reactivity, selectivity, and stereochemistry are especially addressed. Special emphasis is also placed on introducing both the logic of total synthesis and the rationale for the invention and use of important synthetic methods. In particular, we amplify the most important developments in asymmetric synthesis, catalysis, cyclization reactions, and organometallic chemistry. 

Allenylsilanes undergo intramolecular additions to appropriately positioned aldehydes, imines, conjugated esters and alkenes to afford various alkynylcyclopentane and cyclohexane derivatives (Eqs. 9.66-9.70) [66]. The reactions are promoted by SnCl4 or by thermolysis. The stereochemistry of these cyclization reactions is consistent with a concerted sigmatropic process as illustrated in Scheme 9.17. 

Cathodic cyclization reactions have supphed and continue to provide a fertile territory for the development and exploration of new reactions and the determination of reaction mechanism. Two areas that appear to merit additional exploration include the application of existing methodology to the synthesis of natural products, and, more significantly, a systematic assessment of the factors associated with the control of both relative and absolute stereochemistry. Until there is a solid foundation to which the non-electrochemist can confidently turn in evaluating the prospects for stereochemical control, it seems somewhat unlikely that electrochemically-based methods will see widespread use in organic synthesis. Fortunately, this comment can be viewed as a challenge and as a problem simply awaiting creative solution. 

One of the most synthetically useful anodic C-C bond forming reactions developed to date involves the intramolecular coupling of phenol derivatives with olefins. Yamamura has demonstrated that these reactions tend to lead to three classes of products (Scheme 22) [36]. The type of product generated depended strongly on both the nature and stereochemistry of the functional groups attached to the olefin moiety. For example, consider the two cyclization reactions illustrated in Scheme 23 [37]. In this experiment, the stereochemistry of the initial olefin substrate completely dictated the ring skeleton of the product. 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

Diethyl malonate has been proposed for use as a proton source in these cyclization reactions [124], It is not a sufficiently strong acid to protonate the radical-anion rapidly. However it irreversibly protonates the enol intermediate generated after carbon-caibon bond formation. In one case, control of stereochemistry in favour of the traHS-sunstituted five membered ring 39 was achieved by the addition of cerium(Ill) ions [124],... 

A. Kittaka, T. Asakura, T. Kuze, H. Tanaka, N. Yamada, K. T. Nakamura, and T. Miyasaka, Cyclization reactions of nucleoside anomeric radical with olefin tethered on base Factors that induce anomeric stereochemistry,/. Org. Chem., 64 (1999) 7081-7093. 

In view of the enormous impact which symmetry-based rules concerning the stereochemistry of concerted addition and cyclization reactions (Wood-ward-Hoffmann rules) have had in recent years a detailed introduction to this subject has been added. 

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

The range of monoterpenes encountered is extended considerably by cyclization reactions, and monocyclic or bicyclic systems can be created. Some of the more important examples of these ring systems are shown in Figure 5.11. Such cyclizations would not be expected to occur with the precursor geranyl diphosphate, the E stereochemistry of the double bond being unfavourable for ring formation (Figure 5.9). Neryl PP or linalyl PP, however, do have favourable stereochemistry, and either or both... 

The above described total synthesis shows the application of the (7-carbonyl radical-initiated tandem cyclization reaction for the first generation of (+)-paniculatine. With this method starting from 2-substituted-5-(R)-cyclohexenone 5 Sha and co-workers obtained 15 (=1) in 21 steps. Furthermore the HBr-salt of this alkaloid was prepared and subjected to a single X-ray analysis, which unambiguously confirmed the structure and stereochemistry of this synthetic (+)-paniculatine. 

These selection rules can also be obtained from an analysis of polyene cyclizations. If the interaction between the terminal atoms Ca and Cn is bonding (antibonding), it will favor (disfavor) the cyclization. Figure 4.5 shows how the contribution of any given MO changes as a function of the reaction stereochemistry. When p is odd (even) the conrotatory process is disfavored (favored) and the disrotatory process is favored (disfavored). Obviously, the preferred pathway can be deduced by summing the contributions of all of the occupied MOs, up to and including the HOMO ... 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

The classical theory suggests the [jts2 + n2] cyclization reaction of a singlet olefin and a ground-state olefin is a prototypical symmetry-allowed process [116]. The concerted collapse of the olefin pairs or their exciplexes produces cyclobutanes. The evidence comes from the stereochemistry of the cycloadducts. It has been... 

Electrochemically generated Co(I) species from vitamin B12 has been used as a catalyst in the radical cyclization reactions. The stereochemistry of the product contrasts with that obtained by using Bu3SnH/AIBN, and complements its synthetic usefulness139. The radical type intermediates generated in these reactions can also be trapped by neighboring multiple bonds to form cyclic products140. These processes are illustrated in Scheme 13. 

This cyclization of A to form B is truly amazing. In a single step, three rings are formed, in 71% yield, predominantly with the correct stereochemistry. And this occurs without the aid of enzymes. Although the natural process proceeds in higher yield and is more stereoselective, we see again that the enzyme does not perform magic in the case of these cyclization reactions, but simply makes a reaction that is already favorable the only reaction that occurs. 

The cyclization reaction is a typical two-stage electrophilic addition to an alkene (Chapter 20) with attack by the nucleophile at the more substituted end of the intermediate halonium ion. The iodo-nium ring opening is a stercospecific Sjsj2 and, in the simplest cases where stereochemistry can be observed, the stereochemistry of the alkene will be reproduced in the product. 

We can show that the primary alcohol is on the same side of the ring as the base by another cyclization reaction. Treatment of the related iodide with a silver (1) salt gives a new sevcn-mcmbered ring. This reaction can happen only with this stereochemistry of starting material. 

Although an energetically less favourable sp2 to sp3 carbanion transformation is involved in these processes, both aryllithium and vinyllithium cyclizations onto alkenes are successful. Moreover, cyclization reactions of vinyllithiums, rather than alkyllithiums, would also incorporate additional functionality (an alkene) into the product, allowing the preparation of alkylidenecycloalkanes with control of the alkene stereochemistry. 

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