Macrocyclization step

As outlined in Sect. 2, various classes of concave acids and bases may be synthesized in gram quantities. But the syntheses are multistep sequences and the yields are often limited by the macrocyclization steps. Therefore, for a practical use, these reagents are quite expensive and recovery and recycling is necessary. 

The intramolecular mechanism, illustrated on the left-hand side of Figure 6.8, is based on four separate operations [52]. (a) Destabilization of the stable translational isomer light excitation of the photoactive unit P (step 1) is followed by the transfer of an electron from the excited state to the Al station, which is encircled by the macrocycle (step 2) with the consequent deactivation of this station such a photoinduced electron-transfer process has to compete with the intrinsic decay of P (step 3). (b) Ring displacement the ring moves from the reduced station Ah to A2 (step 4), a step that has to compete with the back electron-transfer process from Ah (still encircled by the macrocycle) to the oxidized photoactive unit P+ (step 5). This is the most difficult requirement to meet in the intramolecular mechanism, (c) Electronic reset a back electron-transfer process from the free reduced station Ah to P+ (step 6) restores the electron-acceptor power to the Al station, (d) Nuclear reset as a consequence of the electronic reset, back movement of the ring from A2 to Al takes place (step 7). 

Although there were several syntheses of host 17, the yields were often low and the synthetic steps were irreproducible. The first synthesis of host 17 was pursued by Marlon Cowart.26b A convergent pathway in which two Troger s base halves were coupled in the macrocyclic step was used (Scheme 1). There were problems associated with this synthesis the two Troger s base pieces were obtained from two different precursors, the yields in the Troger s base formation and macrocyclization step were low, and the deprotection step was irreproducible. 

The macrocyclization step involving the two bifunctional compounds 2 and 3 is performed under high-dilution conditions. For this reaction there is a need to use a specially adapted apparatus illustrated in Fig. 5.3. The crucial features of this reaction are the precision addition funnels which have to deliver the solutions at a low and constant rate and the vigorous stirring ensured by a high-speed motor and by the creased flask. 

The bicyclization step is accomplished under identical conditions to the first macrocyclization step, the base being in this case added triethylamine. The reduction of the bicyclic amide 6 has to be realized with diborane (LiAlH4 cleaves the macrobicyclic system). Note that there is no need to isolate the intermediate aminoborane 7 the crude mixture obtained after... 

Even tris- and tetrakis-adducts of C6o were accessible in a regioselective way by sequential tether-directed macrocyclization steps. A clipping reaction starting from mono-adduct 40 with two tether-linked malonate residues thus yielded tris-adduct ( )-41 (Scheme 1.5).125 Under the assumption that both m-xylylene tethers enforce the expected cis-2 addition, the C2-symmetry of... 

The MALDI-TOF monitored SP preparation of lysobactin, a natural cyclopeptide antibiotic, on PS resin bearing the Rink amine linker 1.6 has been reported (141). The SPS scheme is shown in Fig. 1.21. The classical peptide coupling steps, the allyl deprotection (see Section 1.3.5), and the macrocyclization step were all monitored by MALDI-TOF, and the purity of the products was also determined using this technique. The presence of small impurities in compounds 1.56-1.61 was easily detected, and the reaction conditions for the key deprotection of 1.59 and cyclization of 1.60 were rapidly optimized. A total yield of 15% was obtained after HPLC purification of released 1.62 (lysobactin). 

The macrocyclization step proceeds at 80 °C at moderate dilution conditions because tin exerts a template effect in the course of the reaction, so that good yields are already obtained in 10 M solutions. If, on the contrary, the reaction temperature is increased to 140 °C, the yield of monomer 80 is drastically reduced in favor of higher molecular, linear oligomers, an effect which can be attributed to the cancellation of the template effect. 

Li et al. reported on the total synthesis of cembrene C from geraniol (137) or trans, frani-famesol (91) by using the titantium-induced intramolecular coupling of the dicarbonyl precursor keto enal 176 as the key macrocyclization step (Scheme 6-17). 

By carefully designing the structure of bifunctional substrates, Wessjohann developed a fourfold Ugi-4CR for the syntheses of large ring-size macrocycles. Thus, the reaction of diamine 67, cyclopropane-1,1-dicarboxylic acid (72), isopropylamine and formaldehyde afforded 48-membered macrocycle 73 in 49% yield (Scheme 21). It is appropriate to note herein that a yield of 49% corresponds to an approximately 96% calculated yield for each individual bond-forming process, including the macrocyclization step. 

An impressive threefold Ugi reaction using carefully designed trifunctional building blocks has been subsequently developed by Wessjohann (Scheme 22). This reaction unified eight components (74, 75, three equivalents each of formaldehyde and isopropylamine) via twelve reactions including two macrocyclization steps in a one-pot fashion to produce hemicryptophane 76 in 44% yield [99, 100]. 

Control experiment indicated that template effect (in the presence of different metal salts) [108] was not operating for this transformation. The presence of NH function in 86 that could potentially form a H-bond with oxazole ring, thus preorganizing the cyclization precursor [109], was not an obligation. Indeed, compound 86 (R = H) and 87 (R = Et, Fig. 2) was obtained in essentially identical yield. Aliphatic diamines are suitable substrates, as cyclophane 88 and 89 can be prepared in reasonable yield. It is interesting to note that a 47% yield of 89 meant 88% yield per chemical bond created, including the macrocyclization step. 

The synthesis of the pyrrole-pyridine-containing expanded porphyrins 4.196 and 4.197 was reported by Bell, et al. in 1993. These macrocycles, termed torands because of their rigid torroidal structure, were prepared via an elaborate linear synthesis, part of which is shown in Scheme 4.6.4. The key macrocyclization step in the synthesis involves the pyrolysis of the bis(semicarbazone) 4.195 to afford torand 4.196 in up to 69% yield. This torand may then be dehydrogenated with... 

C.S. Wilcox and his research team designed and synthesized chiral water-soluble cyclophanes based on carbohydrate precursors. These compounds are also dubbed as glycophanes and they are potentially valuable enzyme models. The key macrocyclization step utilized the Glaser coupling and the reaction was carried out in a thermal flow reactor at 80 °C in 67% yield. 

The total synthesis of the potent anticancer macrocyclic natural product lasiodiplodin was achieved in the laboratory of A. Furstner. The key macrocyclization step was carried out by the alkene metathesis of a styrene derivative, which was prepared in excellent yield via an intermolecular Heck reaction between an aryl triflate and high-pressure ethylene gas. 

One of the key steps during the first total synthesis of (-)-aspinolide B by A. de Meijere and co-workers was the NHK reaction to form the ten membered lactone ring. The precursor for this key macrocyclization step was prepared by forming an ester from a three-carbon monoprotected diol fragment and a seven-carbon vinyl iodide fragment. Deprotection of the primary alcohol and its subsequent oxidation afforded the desired vinyl iodide aldehyde precursor. Exposure of this precursor to 15 equivalents of CrCl2 doped with 0.5% of NiCb at high dilution in DMF afforded the desired diastereomer in a 1.5 1 ratio. 

The total synthesis of the diarylheptanoid garugamblin 1 was achieved by M. Nogradi et al. using the modified Wurtz coupiing as the key macrocyclization step. The dibromide was treated with sodium metal at room temperature in the presence of TPE to afford the desired macrocycle in moderate yield. The N-0 bond of the isoxazole ring was cleaved under the reaction conditions. 

The stereocontrolled total synthesis of (-)-macrolactin A, a 24-membered macrolide, was achieved by J.P. Marino and co-workers/ The key macrocyclization step was carried out using the Yonemitsu modification of the Yamaguchi macroiactonization. In this procedure, the mixed anhydride is added to the highly dilute solution of DMAP rapidly (in one portion) at room temperature. The final step of the total synthesis was the removal of the protecting groups under acidic condition. 

Scheme 1.21). Transformation of ester 103 into acid chloride 104 then set the stage for the novel macrocyclization step. Deprotonation of 104 induced an intramolecular Wittig condensation followed by immediate loss of HCl to produce allenic lactone 105 in 42% yield. Subsequent [4 + 2] cycloaddition of diene 100 with 105 gave cyclohexene 106 in 55% yield. Aromatization of 106 under basic conditions then afforded a 50% yield of lasiodiplodin (90). 

While the completion of the synthesis awaits the outcome of the above studies, the critical macrocyclization step has been demonstrated in a model. Thus, this approach provides much promise of efficiently creating the macrolide antibiotics. 

The synthetic plan followed by the authors is presented in Scheme 24 which shows strategic bond formations in the retrosynthetic sense. For the construction of 181, a ketophosphonate aldehyde condensation was used as the macrocyclization step which led to compound 182, an ester derived from hydroxyaldehyde 183 and ketophosphonate acid 184. The remaining C-C bond formations are indicated on 183 and 184, which then conducted to the key building blocks 127,185-188. The authors took advantage of hidden symmetry elements which led them to select both enantiomers of xylose and tartaric acid as chiral starting materials and/or chiral auxiliaries. 

The synthesis of larger [njcatenanes with >3 is a fascinating challenge for preparative organic chemistry. A prerequisite for the formation of oligocatenanes is to find appropriate ditopic host macrocycles that can bind two guests from the other catenane wheels in a subsequent macrocyclization step. So far, catenanev with up to seven... 

A lengthy synthesis of the parent dodecahydrohexaaza-kekulene (1, r =R = H) was reported by Ransohoff and Staab. - The final, macrocyclization step apparently gave the torand in 3% yield as a sparingly soluble solid. 

In 2004, Myers and Haidle reported a convergent and modular total synthesis of cytochalasin B (1088) and the [lljcytochalasan L-696,474 (1139) (742), using a late-stage macrocyclization step involving an intramolecular Horner-Wadsworth-Emmons olefination. Their strategy is applicable for the synthesis of cytochalasans of different ring sizes, as exemplified by these two total syntheses. Both macrolactone and macrocarbocyclic cytochalasans can lead back retrosyntheticaUy to the same precursors. The synthesis of the tricyclic isoindolone precursor to cytochalasin B (1088) and L-696,474 (1139) is shown in Scheme 14.1. 

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