Exo-tet cyclization

The formation and the hydrolysis of acyclic and cyclic acetals have been studied in rather great detail [91]. Several reviews on this topic are available [92] and some comments have been made [13] concerning the carbohydrate series. We have shown in Schemes 1,2, and 3 that a common feature of this reaction seems to be the intermediacy of an oxocarbenium ion. However, the cyclization of such an intermediate has been questioned more recently [93] in the light of the Baldwin s rules for ring closure [94]. At least for the five-membered ring, an SN2-type displacement mechanism far the protonated form (B) of die hemiacetal (A) (favorable 5-exo-tet cyclization) has been proposed rather than the unfavorable 5-endo-trig cyclization of the oxocarbenium ion (C) (Scheme 5). Except when the formation of the enol ether (D) is structurally impossible, the intermediacy of such a compound remains feasible. 

Attack of a nucleophile on the /1-silyl carbocation 127 or the cyclic siliconium ion 128 leads to desilylation and formation of the Sakurai product. When nucleophilic attack is disfavoured by steric hindrance at the silicon, competing intramolecular attack by the enolate becomes important. This 5-exo-tet cyclization gives the trimethylsilylcyclopentane product with high stereospecificity, the trimethylsilyl group having undergone a 1,2 shift. 

In a complementary approach, the stereocontrolled [4-exo-tet] cyclization of enolates (71) in which the nucleophilic species attack from the C4-position of the p-lactam ring to be formed has been reported [77] (Scheme 17). B3LYP/6-311+ +G calculations showed that the enolates (71) are preferred with respect to enolates (72) thus resulting in the formation of (3-lactams (3S,4)-(73). 

Despite the variation in rate we have described for this type of reaction, exo-tet cyclizations have no stereoelectronic problems the lone pair and the C-X a (X is the leaving group) can overlap successfully irrespective of ring size. The ring closures in Table 42.2 all fall into this categoiy. 

A simple and efficient stereoselective synthesis of 4-hydroxyalkyl-l,2-oxazetidines 31 is based on the addition of -lithiated aryloxiranes 29 to aryl nitrones and subsequent 4-exo-tet cyclization of the corresponding intermediates 30 (Scheme 19) <2006OL3923>. 

Preparative Methods (1) is easily made by cy clization of commercially available A-Cbz-r-serine (4) under modified Mit-sunobu conditions, using a preformed complex of dimethyl azodicarboxylate (DMAD) and Triphenylphosphine (eq 1). The reaction proceeds via hydroxy group activation, and labeling studies show that the 3-hydroxy group is lost in a 4-exo-tet cyclization mechanism. The p-lactone must be separated quickly from the reaction mixture, and a slight excess of DMAD improves the yield because unreacted triphenylphosphine can cause polymerization. The Boc (f-butoxycarbonyl) analog (2) is prepared similarly, and the p-toluenesulfonate (tosylate) salt (3) is synthesized from (2) by acidic cleavage. ... 

Note that the 5-(enolendo)-exo-tet cyclization shown below is a disfavored ringclosing alkylation. 

Step 2. Chemoselective reduction of the a-alkoxy ester Step 4. Ester enolate alkylation (5-exo-tet cyclization)... 

The total synthesis of balanol, a fungal metabolite was accomplished by K.C. Nicolaou et al. For the construction of the central hexahydroazepine ring, they have utilized a 7-exo-tet cyclization. The substitution reaction between the mesylate of the primary alcohol and the Cbz-protected amine was effected by a slight excess of base to produce the desired 7-membered ring in high yield. 

Hydroxymethyl phosphinate 105 was prepared in three steps from hydroxymethyl-//-phosphinic acid 115 [102]. //-Phosphinic acid 115 was silylated to give the P ° intermediate, which reacted in a silyl-Arbusov reaction with the bromoacetyl derivative of aspartic acid to give 116. A deprotective step using hydrogen afforded phosphinic acid 105. From intermediate 116, cyclic phosphinic acid 106 was also accessible in two steps. First, a 5-exo-tet cyclization under... 

Fig. 1.2b) classes wherein an enolizable nucleophile (commonly an enamine, nitronate or 1,3-dicarbonyl) cyclizes onto an sp carbon. Enolexo-exo-tet cyclizations (Fig. 1.2c) are less common however, and tend to occur predominantly in cyclopropanation reactions. Indeed, alkylations using secondary amine catalysis are difficult under standard organocatalytic conditions owing to problems associated with the alkylation of the catalyst itself, although various methods have been adopted to address this. Finally, exo-trig cyclizations of heteroatoms onto sp centres (Fig. 1.2d) are a useful way of constructing enantiopnre heterocycles. 

Selective epoxidation of polyene compound has also achieved with ent 2, the enantiomer of ketone 2. In Morimoto s total synthesis of polyether (+)-aurilol, Shi epoxidation was utilized twice, with ketone 2 and ent-2, respectively." Epoxidation of 79 with ketone 2 gave epoxide 80 with high diastereoselectivity. Epoxide 80 underwent acid catalyzed 5-exo-tet cyclization to produce tetrahydrofuran 81 with the desired stereochemistry. Subsequently, diene 82 was selectively epoxidized with ent-2 only at the trisubstituted olefin to give epoxide 83. Epoxides 80 and 83 played important roles in setting stereocenters in the final product. 

The desired 2-aminoquinoxaline 262 could be obtained after the aerobic oxidation of R Pathway II). Under these conditions, 6-exo-dig cyclization would predominantly take place over 5-exo-tet cyclization presumably due to a better orbital orientation between HOMO and LUMO, which led to the exclusive formation of 2-aminoquinoxalines 262. Although this transformation was previously reported in literamre (Ricciardi and Joullie 1986 Hu et al. 2010), it should be noted that this transformation is operationally very simple and displayed a very broad substrate scope from aromatic aldehydes, heteroaromatic aldehydes, to more challenging aliphatic aldehydes. 

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