SN2-type cyclization

The highly potent anti-HIV natural product daurichromenic acid (10-100) was synthesized by Jin and coworkers [36] using a microwave-assisted reaction of the phenol derivative 10-97 and the aldehyde 10-98 (Scheme 10.25). Normal heating gave the desired benzo[b]pyran 10-99 by a domino condensation/intramolecular SN2 -type cyclization reaction only in low yield. However, when the reaction mixture was irradiated twenty times in a microwave for 1-min intervals, 10-99 was obtained in 60% yield. This compound was then transformed into 10-100 by cleavage of the ester moiety. 

However, this method fails for 1,2-diols like (79) or (81), from which the epoxides (80) and (82) are generated (equations 28 and 29). This involves an SN2-type cyclization with retention at the secondary... 

It has been shown that P-bromocaiboxylic acids like (127) and (129) cyclize with mild base to form P-lactones like (128 equation 44) and (130 equation 45). The reaction is mostly accompanied by fragmentation to the alkene, as shown by the conversion of (131) into (132) and (133) (equation 46). In this particular example, only tranj-P-lactone (132) was found, inspite of the threo configuration of (131), which indicates an 5n1- rather than an SN2-type cyclization. 

Interestingly, the 3 chloro 1 iodopropane addition (Table 2.6, entry 9) led exclusively to pyrrolidine 37 (Scheme 2.4) none ofthe acyclic adducts was found [31]. Presumably, radical addition was followed by in situ Sn2 type cyclization. The same type ofcyclization, giving the epimeric pyrrolidine (epi 37), occurs upon ethyl addition to the 3 chlorobu tyraldehyde hydrazone (Table 2.6, entry 18). These reactions are hybrid radical ionic annulations of the C=N bond, a new class of radical polar crossover reactions [32]. 

Ma et al. reported that the palladium-catalyzed cycloisomerization of methylenecy-clopropyl ketones 109 with Nal afforded 3-furyl ketones 110, while that without Nal produced 4/7-pyrans 111 (Scheme 27.37) [48]. The former reaction proceeds via nucleophilic attack of halogen anion to the carbon-carbon double bond, followed by ring opening to form an enolate type of intermediate 112. Sn2 type cyclization and... 

We also accomplished the total synthesis of (—)-subglutinol B (7) in 2011 [12]. Our retrosynthetic plan for 7 is ouflined in Scheme 25. The target molecule 7 would be produced through an internal SN2-type cyclization of tosylate 103, which should be available from the common intermediate 98 (cf. Scheme 22) by the inversion of configuration at the C12 hydroxy group. 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

The use of the zinc-copper couple to effect the reduction of the methanesulfonate 168 with rearrangement furnished 169 (Scheme 20.34) [10]. Treatment of 168 with methylmagnesium bromide in the presence of copper(I) cyanide to induce an SN2 -type reaction produced the methylated adduct 170. The half-life of the Myers-Saito cyclization of 169 is 66 h at 37 °C, whereas that of 170 is 100 min. The faster rate of cyclization for 170 has been attributed to a steric effect favoring the requisite s-cis or twisted s-cis conformation. 

The foregoing examples of differential reactivities of rotamers may be summarized by saying that the reactivity is controlled by the steric factor. The difference in the reactivities of rotamers of 9-(2-bromomethyl-6-methyl-phenyl)fluorene (56) in SN2 type reactions falls in the same category (176). However, the substituent effect is not limited to a steric one there can be conformation-dependent electronic effects of substituents as well. A pertinent example is found in the reactivity of the bromomethyl compound (56) when the rotamers are heated in a trifluoroacetic acid solution (Scheme 10). The ap form gives rise to a cyclized product, whereas the sp form remains intact (176). The former must be reacting by participation of the it system of the fluorene ring. 

Dunitz (180) has collected X-ray crystallographic data for carbonyl compounds that possess nucleophilic atoms in proximity to C=0, and has postulated that such molecules can be used as models for the incipient transition state (reaction coordinate) for the nucleophilic addition to carbonyl compounds. Atrop-isomeric compounds have the potential, by providing a variety of such data, for understanding the incipient transition states. For example, the interaction found in the 1,4-dimethoxy-9-(2-acyloxyethyl)triptycenes (130) can be viewed as a model for SN2 type reactions where the acyloxy group is the leaving group and the methoxy is the nucleophile. In an extreme case of this sort, cyclization actually takes place. Such an example has been reported (181). 

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. 

Simple double aza-Michael reaction of divinyl ketones with primary amines was utilized to generate TV-substituted 3-phenyl-4-piperidones in good yields <07EJO4376>. In a somewhat similar mode, the diastereoselective synthesis of cyclic (3-amino esters by an Sn2 substitution-cyclization of an iodo-a,(3-unsaturated ester with (.Sj-u-mcthy 1 benzylamine was described <07OBC3614>. A combination intramolecular Michael-type addition followed by retro-Michael elimination was exploited in the generation of a phosphoryl dihydropyridone intermediate in the synthesis of /m .v-2,6-disubstitutcd 1,2,5,6-tetrahydropyridines <07JOC2046>. 

The cyclization proceeds in an SN2 -type mode of action to give the cyclobutane 23 as one single diastereoisomer. 

Analogous systems related to the models for allylsilane-acetal cyclizations have been studied. In these cases, however, cyclizadon of the acetals (105 Scheme SO) fonts the corresponding syn and anti bicyclic ethers (106). The audiors concluded diat the stereochemistry of cyclizadon of acetal models (105) is dependent upon the mechanism of activation. In the presence of TMS-OTf the acetals (105 -c) reacted through an SN2-type process, while the isopropyl acetal (105d) reacted through prior ionization to oxonium ion (107). 

Similar reactions involving an allylic fragment proceed with formation of the Sn2 type products. Indium(III) salts (InCb predominantly investigated) have been found to be effective Lewis acids to catalyze conversion of 13 at room temperature in the presence of molecular sieves. The cyclization is accompanied by elimination of hydrogen bromide, leading to the vinyl derivatives of tetrahydronaphthalene 14 and tolerates electron-withdrawing groups. 

When the intramolecular nucleophilic attack occurs to an al-lyUc alcohol, as shown in eq 11, an Sn2 type displacement takes place by Pd -catalyzed cyclization and subsequent palladium hydroxide elimination. In this case, the Pd salts are not reduced and the catalytic system works well without any reoxidant. 

Next, the bromohydrin is treated with base and an intramolecular Sn2 reaction (Chapter 17) closes the epoxide ring. This too is stereospecific and the major isomer only is shown. The mixture of epoxides is a result of the /Z-alkene mixture. Potassium carbonate is too weak a base to generate much of the alkoxide anion but the cyclization may still go this way in methanol. In Chapter 41 you will learn of an alternative type of catalysis by weak bases. 

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