Alkenes regioselectivity, intramolecular reactions

Due to the presence of these resonance forms in azomethine ylids, reaction with alkenes often leads to mixtures of regioisomeric cycloadducts. Resonance stabilizing substituents are usually employed to enhance the regioselectivity. Intramolecular reactions usually favor only one mode of addition. An example of an intermolecular reaction is taken from Williams synthesis of spirotryprostatin B,372 in which 5,6-diphenylmor-pholin-2-one (473) reacted with the aldehyde shown to give a mixture of ( )- and (Z)-azomethine ylids (474). This product was generated in situ with oxindole 475, and [3-i-2]-cycloaddition product 476 was obtained in 82% yield. 

Although the regioselectivity for the silylformylation of 1-alkynes is excellent, that of internal alkynes is low except for 2-alkynoates (vide supra). Also, in the reactions of 1-alkynes, the silyl group is always delivered to the terminal position and the formyl to the C-2 position, thus it is impossible to synthesize 3-silyl-2-alkenals, which requires opposite regioselectivity. Intramolecular directed reactions can circumvent these limitations and expand the scope of the silylformylation of alkynes. 

Use of the allylsilanes as the alkene components in the Heck reaction is illustrated in the regioselective intramolecular cyclization of 120 (equation 98)180. In addition, a high enantioselectivity of 90 %ee is obtained when the chiral phosphine (S)-BINAP is employed. The propargylsilane analog undergoes a similar reaction181. 

A similar cyclisation of an alkene derived from geranyl acetate 24 by dihydroxylation and formation of the epoxide 26 leads to a substituted cyclohexane 28. The Lewis acid ZrCU is used to open the epoxide and the alkene attacks intramolecularly 27 to give eventually the ryn-compound 28 with both substituents equatorial. The alignment of the alkene and the epoxide in a chair conformation 27a is responsible for the diastereoselectivity Note the regioselectivity the less substituted end of the alkene attacks the more substituted end of the epoxide 27. These are just two examples of the very many ordinary ionic reactions that can be used to make six-membered rings. 

As already mentioned (see Chaps. 8.2 and 8.3), the addition of an unsymmetrical enone to an unsymmetrical alkene usually affords a mixture of the possible regioisomers. This is illustrated in Sch. 10 for the reaction of cyclopentenone 28 with allylic alcohol as alkene where a mixture of eight cycloadducts is obtained. A very efficient way in controlling the regiochemical outcome for such a reaction has been proposed by Crimmins by using a siloxane as temporary tether, i.e., cyclopentenone 29 in an intramolecular reaction which now proceeds regioselectively to give first tricycle 30 and then the desired cycloadduct 31 [56]. 

As pointed out by Stork and coworkers in their definitive 1963 paper3, the reaction with electrophilic alkenes is especially successful since reaction at nitrogen is reversible. Reaction at the /2-carbon is (usually) rendered irreversible by, in the case of cyclohexanone enamines, internal proton transfer of the axial C-/2 proton to the anionic centre of the initially formed zwitterionic intermediate (34), under conditions of stereoelectronic control (Scheme 22). When this intramolecular proton transfer cannot occur in aprotic solvents, or when the product produced in protic solvents is a stronger carbon acid than adduct 35 (i.e. when Z = COR, N02), then carbon alkylation is also reversible and surprising changes in the regioselectivity of reaction may be observed (vide infra see also Section VI.D and Chapter 26). Cyclobutanes (36) and, in the case of a,/ -unsaturated... 

Sufficient information about the reaction has been gathered to allow fairly accurate predictions of yield as well as of stereo- and regioselectivity.176177 The reaction proceeds via the formation of hexacarbonylalkyne-dicobalt complexes and is remarkably tolerant of functional groups in both the alkyne and the alkene. The intramolecular Pauson-Khand reaction is an effective way of preparing bi- and polycyclic systems, and the cyclization of 1,6-heptenyne derivatives to give bicyclo[3.3.0]oct-l-en-3-ones has been the most popular application of the Pauson-Khand reaction in natural product synthesis [Eq. (17)]. 

Cycloaddition of 7-oxanorbomadiene derivatives has been reported (Scheme 247). 5-Bromo-7-azanorbomenes undergo regioselective Pauson-Khand reaction to give (168). The bromine is lost during the reaction (Scheme 248). A-Protected alkynylamides undergo intramolecular reactions with alkenes to give 2-amidocyclopentenones (Scheme 249). 

As an electrochemical reaction, Torii and co-workers demonstrated that the facile transformation of alkenes into allylic alcohols and ethers proceeded in the presence of a catalytic amount (10 mol%) of diphenyl diselenide (Scheme 15) [18]. Most of terminal co double bonds of isoprenoids undergo regioselective oxyselenenylation-deselenenylation to give frans-allylic alcohols in aqueous acetonitrile and methyl ethers in methanol. The addition of SOI salts improves chemical yields since SOI salts prevent the conversion of phenylselenenic acid (PhSeOH) into the inert phenylseleninic acid (PhSe02H) by both disproportionation and electro-oxidation. This method was also applied to intramolecular reaction to form -lactone in high yield. 

Pfaltz has examined intramolecular reactions and found that hgand, leaving group, and solvent all play a role in the regioselectivity of the cyclization and the C/O alkylation ratios. The best results were obtained with allyl carbonates in dichloromethane and the phosphinooxazoHne Hgand 29 where ees up to 87% are possible. The stereochemistry of the alkene does not affect the ee of the re-... 

A wide variety of other carbonyl compounds can give Paternb-Biichi products when irradiated with alkenes. Studies have been reported on regio-selectivity of photocycloadditions of carbonyl compounds such as thiocarbonyls [91], benzoquinones [92], diacetyls [93], and uracils [94]. A large number of intramolecular reactions have been reported, where the restraint of the reactant structure helps to give good regioselectivity. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of iJ-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P, Marino. 1975) produced cyclopentanones. Another procedure starts with a (2 + 21-cycloaddition of dichloroketene to alkenes followed by regioselective ring expansion with diazomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene. 1979 J.-P. Deprds, 1980). 

Formation of a titanacyclopentane via cyclic dimerization of ethylene was reported as early as 197644 (Scheme 17). In marked contrast with the corresponding Zr-promoted reactions discussed later in this chapter, the intramolecular version of the Ti-promoted alkene-alkene coupling reactions does not appear to have been well developed. Consequently, detailed aspects of pair -selectivity and regioselectivity still remain largely unknown. 

The nucleophiles that are used for synthetic purposes include water, alcohols, carboxylate ions, hydroperoxides, amines, and nitriles. After the addition step is complete, the mercury is usually reductively removed by sodium borohydride. The net result is the addition of hydrogen and the nucleophile to the alkene. The regioselectivity is excellent and is in the same sense as is observed for proton-initiated additions.16 Scheme 4.1 includes examples of these reactions. Electrophilic attack by mercuric ion can affect cyclization by intramolecular capture of a nucleophilic functional group, as illustrated by entries 9-11. Inclusion of triethylboron in the reduction has been found to improve yields (entry 9).17... 

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