Intramolecular S..l Reactions

When the nucleophilic centre and the nucleofugal group are in ra-position, the photo-stimulated reaction gives ultimately the ring closure product by an intermolecular followed by an intramolecular S l reaction. Thus, the reaction of the enolate ion of co- m-bromophenyl)-3,3-dimethylalkan-2-one (325) in liquid ammonia gives [m-m] cyclopha-dienones (326) (equation 194)340. 

The second step of the synthetic sequence is relatively straightforward. The exocyclic olefin is protonated in trifluoroacetic acid to form the tertiary carbocation, which cyclizes by an intramolecular S l reaction to give the final product. 

The intramolecular S l reactions of substrates that have both a nucleophUic center and a leaving group give an interesting example of a ring closure reaction. An example of this is the synthesis of oxindoles by the intramolecular cyclization of N-alkyl-N-acyl-o-haloanihnes in the presence of LDA in THF or KNHj in liquid ammonia ... 

The key step in the synthesis of the azaphenanthrene alkaloid eupoulauramine 19 (56% yield) is an intramolecular S l reaction, followed by in situ stilbene photocychzation and further methylation Eq. (47.41). >s... 

Similar cyclization reactions to polychlorodibenzodioxins have been reported under irradiation of the sodium salt of the conjugate base of perchloro-u-phenoxyphenol in methanol in the presence of a sensitizer and excess triethylamine. Photodecomposition of the conjugate base of perchloro-0-phenoxyphenol in methanol reveals a small amount of cyclization, while irradiation in methanol in the presence of a 10-fold excess of triethylamine increase the quantum yield of cyclization by 17-fold. These results were interpreted in terms of an ET to the substrate to from a radical dianion, which reacts through an intramolecular S l mechanism347. 

The stereospecific intramolecular isomerization of a-phenylallyl esters in aprotic solvents might conceivably be a concerted S i reaction with a cyclic transition state (1) instead of an S l reaction involving a tight ion pair intermediate. If so, structural and solvent effects on reactivity require that the... 

Intramolecular reactions have been successfully applied to the syntheses of five-membered rings through biaryl C—C bond formation as the key step. In this sense, the synthesis of a series of substituted 9Ef-carbazoles 105 by the photostimulated S l reaction of diaryl-amine anions 104 as starting substrates was performed in liquid ammonia or DMSO (Eq. 10.36) [81]. Furthermore, when Af,Af -bis(2-bromophenyl)biphenyl-4,4 -diamine was treated with f-BuOK in DMSO and irradiated, 3,3 -bi(9//-carbazole) 106 was achieved in 67% isolated yield (Eq. 10.36) [81] ... 

Polyphosphoric acid is a commonly used catalyst for this reaction however, in some cases a mixture of hydrogen bromide/acetic acid gives better results. Acylation of the S-phenyl-, V-(4-tolyl)- or S-(l-naphthyl)-substituted thiobenzenepyruvic acids 3a-c affords the corresponding dibenzo[A,/]thiepins in satisfactory yields, while reaction of the S-(4-methoxyphenyl) or S-(2-naphthyl) derivatives fails to provide any thiepin.60 The intramolecular Friedel-Crafts acylation of 2-(arylsulfanyl)benzeneacetic acids also yields the corrresponding dibenzothiepins in this case the use of hydrogen fluoride sometimes results in purer products.38 The applicability of this method is restricted to the synthesis of stable bisannulated thiepins. 

Scheme 45 summarizes Mori s synthesis of the male-produced sex pheromone [(l ,3 ,7S)-3-methyl-a-himachalene (31)] of the sandfly (Lutzomyia longipalpis) in Jacobina, Brazil [70]. This sandfly is the vector of Leishmania chagasU the causative protozoan parasite of visceral leishmaniasis in South America. The key-steps of the synthesis of 31 were the asymmetric methylation of A to give C via B and the intramolecular Diels-Alder reaction of D to give E. 

With chiral racemic oxiranes one enantiomer reacts faster than the other the degree of kinetic resolution is very high for L-valine/alanine-based dialkoxydihydropyrazines. For example, in the reaction of one equivalent of (2.S )-2,5-dihydro-2-isopropyl-3,6-dimethoxy-5-methyl-pyrazine (1, R1 = CH3) with two equivalents of fW-(//,/ )-2,3-dimethyloxirane (R2,R4 = CH3 R = H) virtually only the (2//,3/ )-oxirane enantiomer reacts with the lithiated dihydropyrazine to give exclusively the (l /, 2/, 2 / )-configuratcd adduct i.e., (2/ ,5S)-2,5-dihydro-5-isopropyl-3,6-dimethoxy-2-[(l/ ,2/ )-2-(2-methoxyethoxymethoxy)-l-methylpropyl]-2-methylpyrazine, entry 7. Likewise, kinetic resolution (intramolecular) occurs upon reaction with rac-7-oxabicy-clo[4.1.0]heptane (entry 8). 

A major source of acceleration in enzymic reactions is approximation, that is to say, the bringing together of two or more reactants in the active site. Once the reagents are in contact, the subsequent reaction is intra- rather than intermolecular. Comparisons of the rates of intermolecular and intramolecular reactions are, however, difficult because the rate constants for bimolecular reactions have the units of M "1 s-1, whereas rate constants for unimolecular reactions have the units of s l. The best one can do in comparing them is to state the molarity at which the reactants would have to be present in the bimolecular reaction to achieve the rate of the unimolecular process when the effective molarity is large-say 1000 M or more-one has some measure of the power of approximation to accelerate chemical reaction. 

Hydrolase-catalyzed domino reactions incorporating a resolution and a subsequent cycloaddition reaction have been described [95-97]. This constitutes an attractive approach to complex synthetic intermediates. For example, the l-(3-methyl-2-furyl)]propanol roc-93 reacts with ethoxyvinyl methyl fumarate (94) catalyzed by Lipase LIP (from Pseudomonas aeruginosa) to furnish a dienophilic fumarate ester, which spontaneously undergoes an intramolecular Diels-Alder reaction with the furan moiety furnishing exclusively the syn-adduct, the oxabicy-clohexene 95 in excellent along with the remaining alcohol S-96 (Scheme 4.31) [95]. A similar approach has been used for a procedure that includes a series of domino reactions that includes dynamic kinetic resolution of the 3-vinylcyclohex-... 

The Bu OK.-promoted reaction of 4-chlorobut-2-yn-l-ol (11) with nitroalkenes (12) gives 3-vinylidenetetrahydrofurans (14) in good yields with complete dia-stereoselectivity.12 It is supposed that oxa-Michael addition to form the intermediate (13) is followed by intramolecular S 2 substitution. 

It has been suggested307 that the observed thermal rearrangement of the bicyclo[2.2.2]- to the bicyclo[3.2.1]-octadiene skeleton in tricyclic lactams, viz. (265)—s- (266), is consistent with an intramolecular Diels-Alder reaction in which a zwitterion is formed by the migration of one vinyl group from C(l) to C(5) of the lactam moiety (see Scheme 62). It has been shown308 that the 7r-facial selectivity of the Diels-Alder reaction of 1,3-dienes (267) having an attached stereogenic centre can be... 

The 5,6-dihydro-2 -deoxyuridin-6-yl was generated specifically by photolyzing the respective tertiary butyl ketone (Carter and Greenberg 2003). It reacts fast with 2-mercaptoethanol [reaction (150) k = 8.8 x 106dm3 mol-1 s 1] and noticeably slower with 2,5-dimethyltetrahydrofurane (31 dm3 mol1 s ). In the presence of 02, 6-hydroxy-5,6-dihydro-dUrd is the major product [reactions (151) and (152)]. Interestingly, 2-dRL is also formed under such conditions which is believed to be formed by an intramolecular C(l )-H abstraction via a six-membered transition state [reaction (153) for this type of reaction see also Chap. 8.6],... 

To the best of our knowledge only one example of diastereoselective intramolecular Ugi reaction employing a ketoacid is known [80]. The condensation of acid 89 with (S)-l-phenylethylamine proved to be stereoselective, giving a mixture of the four possible diastereoisomers 90 in a 42 42 8 8 ratio, with the trans stereoisomers pre-... 

Akai S, Tanimoto K et al (2004) Lipase-catalyzed domino dynamic kinetic resolution of racemic 3-vinylcyclohex-2-en-l-ols/Intramolecular Diels-Alder reaction one-pot synthesis of optically active polysubstituted decalins. Angew Chem Int Ed 43 1407-1410... 

Although the asymmetric total syntheses developed by Nicolaou and by Shair provide easy routes to enantiomerically pure CP compounds, the target molecules (+)-CP-263,114 (ent-1) and (—)-CP-225,917 (ent-2) are only the enantiomers of the natural occurring phomoidrides. After the establishment of the absolute configuration of the CP molecules by chemical synthesis, the focus of synthetic interest is the asymmetric total syntheses of (—)-CP-263,114 (1) and (-l-)-CP-225,917 (2). The first total synthesis furnishing (—)-CP-263,114 (1) as the correct enantiomer has recently been reported by Fukuyama et al. [23]. As the stereoselectivitydetermining step, an intramolecular Diels-Alder reaction was chosen, similar to that in Nicolaou s synthesis (Figure 11). The Diels-Alder precursor 42 is prepared in four easy... 

Fig. 11. Fukugama s asymmetric synthesis of (-(-CP-263,114 intramolecular Diels—Alder reaction and formation of the maleic acid anhydride moiety. DBU = l,8-diazabicyclo[5.4.0]undec-7-ene, NIS = N-iodosuccinimide.

S CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Dennis P. Curran. Intramolecular 1,3-Dipolar Cycloaddition Chemistry, Albert Padwa and Allen M. Schoffstall. Stereochemical and Synthetic Studies of the Intramolecular Diels-Alder Reaction, William R. Roush. Thermal Reaction of Cyclopropenone Ketals, Key Mechanistic Features, Scope and Application of the Cycloaddition Reactions of Cyclopropenone Ketals and p - Delocalized Singlet Vinyl Carbenes Three Carbon 1,1-/1,3-Dipoles, Dale L. Boger and Christine E. Brotherton-Pleiss. Index. 

De Keukeleire, D., He, S.-L., Blakemore, D., and Gilbert, A. (1994) Intramolecular photocydoaddition reactions of 4-phenoxybut-l-enes. Journal of Photo-... 

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