Cyclizations stepwise

The intramolecular cyclization can be favored by (i) high dilution techniques, (ii) the action of a template which forces the reacting ends together, and (ill) stepwise condensations. 

The second part of lanosterol biosynthesis is catalyzed by oxidosqualene lanosterol cyclase and occurs as shown in Figure 27.14. Squalene is folded by the enzyme into a conformation that aligns the various double bonds for undergoing a cascade of successive intramolecular electrophilic additions, followed by a series of hydride and methyl migrations. Except for the initial epoxide protonation/cyclization, the process is probably stepwise and appears to involve discrete carbocation intermediates that are stabilized by electrostatic interactions with electron-rich aromatic amino acids in the enzyme. 

As attractive as the transannular bridging of bis(thiolactones) to bicyclic bis(oxepane) frameworks is, our inability to convert the disulfide bridging product (see 25, Scheme 5) to a mmv-fused bre-vetoxin-type bis(oxepane) (see 28) necessitated the development of a modified, stepwise strategy. This new stepwise approach actually comprises two very effective methods for the construction of cyclic ethers the first of these is the intramolecular photo-induced coupling of dithioesters, and the second is the reductive cyclization of hydroxy ketones. We will first address the important features of both cyclization strategies, and then show how the combination of the two can provide an effective solution to the problem posed by trans-fused bis(oxepanes). 

Having developed effective synthetic methodology for the construction of seven-membered cyclic ethers, we were confident that the problem of the frans-fused bis(oxepane) system could now be addressed on a solid foundation. It was our hope that the breve-toxin-type bis(oxepane) system could be assembled by a stepwise strategy utilizing both photochemical dithioester and reductive hydroxy ketone cyclization methods. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Difficulties due to side reactions (cyclization) and a broad molecular weight distribution accompanying the polycondensation of active esters led to the application of methods wherein the polymers are built up stepwise. In 1968, Sakakibara et al.31) introduced the solid-phase technique using Merrifield s resin. By stepwise addition of tert-pentyloxycar-bonyl tripeptides, they have synthesized (Pro-Pro-Gly)n with n = 5, 10, 15 and 20. 

Tetraene 4 (Scheme 1.3), when treated with 40 mol % of triflic acid in methylene chloride at -23 °C for 1 h, gives the adducts 5 and 6 in a 1 1 ratio as the main reaction products. The formation of these adducts has been justified [21] by a stepwise mechanism that requires an initial reversible protonation of 4 to produce the allyl cation 7, which then cyclizes to 8 and 9 in a non-reversible process. Deprotonation of 8 and 9 gives 5 and 6, respectively. 

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

Vollhardt et al. recently reported the synthesis of hexaethynylated PAM 11 using a combined Sonogashira/Stephens-Castro approach [20]. The requisite compound for cyclization, molecule 12, was prepared in stepwise fashion from 1,2,3,4-tetrabromobenzene. Regioselective alkynylation at positions 1 and 4 afforded dibromophenyldiacetylene (13), which was then monoalkynylated at... 

No issues of stereochemistry arise until the carbon skeleton is formed, at which point all of the stereocenters are in the proper relative relationship. The structures of the successive intermediates, assuming a stepwise mechanism for the cationic cyclization, are shown below. 

Coupling of the aminomethylindole 2-558 with acrolein in a Michael manner followed by a HWE reaction with phosphonates 2-560 afforded 2-561 which cyclized under basic conditions to give the desired product 2-566 via the intermediates 2-562-2-565 in 55 % yield (Scheme 2.127). The reaction sequence was also conducted in a stepwise manner, resulting in a greatly reduced yield this clearly demonstrates again the advantage of domino strategies over conventional methods. 

Itoh and coworkers [223] have shown that fullerene derivatives as 6/2-113, which to date have been prepared in a stepwise procedure, can be obtained in a three-component domino process by treatment of diynes 6/2-109, dimethylphenylsilane 6/2-110 and fullerene (C60) in the presence of a Rh-catalyst [223]. Interestingly, using maleic anhydride as dienophile failed to give the desired cycloadduct, whereas Cso -in spite of its strong tendency to form complexes with various transition metals [224] - never suppressed the catalytic silylative cyclization step to give the diene 6/2-112 (Scheme 6/2.24). 

The reaction of trimethylsilylacetylene with triallylborane in CDCI3 proceeds stepwise and involves 1,1- and 1,2-allylboration <1968IZV1923, 1999JOM(580)234>. Vinylborane 116 readily cyclizes into compounds 117 and 118 (Scheme 49). 

While we were concerned by the potential problems with our desired reaction, particularly the poor dienophilicity of indoles and the failure of 54 to cyclize under stepwise cyclization conditions, we were nonetheless inspired to pursue this potentially direct strategy. The successes of Marko and Rosenmund in related systems (51 —> 52 and 55 —> 56, respectively), the ease of substrate synthesis, and the significant utility of the reaction products compelled us to evaluate Zincke... 

A small number of macrocycles with an odd-number of Se atoms have been reported. Both [12]aneSe3 and [20]aneSe5 involve stepwise introduction of the Se atoms, with ring closure occurring via a high dilution cyclization of NaSe(CH2)3SeNa with TsO(CH2)3 Se(CH2)3 OTs, n = 1 or 3, respectively (Scheme 3).101... 

---