Macrocycles enantioselective synthesis

It should be mentioned that conditions have been found recently to obtain C4-symmetrical tetraethers 115 directly from resorcinol monoethers by condensation with aldehydes. The regular incorporation in the macrocyclic skeleton was confirmed for one example by X-ray analysis.224 However, in contrast to Heaney s enantioselective synthesis, the racemic mixture of the two enantiomers is formed in this case. 

Nishioka, T., Iwabuchi, Y, Irie, H., and Hatakeyama, S., Concise enantioselective synthesis of (-t)-aspicilin based on a ruthenium catalyzed olefin metathesis reaction. Tetrahedron Lett.. 39, 5597, 1998. Williams, D.R., and Clark, M.P., The macrocyclic domain of phorboxazole A. A stereoselective synthesis of the Cj-Cjj macrolactone. Tetrahedron Lett., 40, 2291. 1999. 

Since cis-3, trans-3, and trans-2 bis-adducts of 50 with identical addends are chiral as a result of inherently chiral functionalization patterns [10, 44-46], it was of interest to explore whether Bingel macrocyclizations with bismalonates bridged by non-racemic tethers would provide an enantioselective synthesis of these compounds. An overall enantioselective synthesis of optically active Cgg bis-adducts had been achieved previously by asymmetric Sharpless bis-osmylation [77] however, this sequential bis-func-tionalization lacks the regioselectivity of the Bingel macrocyclization, and therefore requires tedious regioisomer separations. 

Knopff O, Kuhne J, Fehr C. Enantioselective intramolecular aldol addition/dehydration reaction of a macrocyclic diketone synthesis of the musk odorants (/f)-muscone and (R,Z)-5-muscone. Augew. Chem. Int. Ed. 2007 46 1307-1310. 

Liao, X. and Xu, X. (2000) Studies towards the total synthesis of methyl isosartortuoate enantioselective synthesis of a precursor of the macrocycle. Tetrahedron Lett., 41, 4641-4644. 

Scheme 1. Catalytic enantioselective aldehyde alkylation affords the chiral macrocyclic alcohol 3 in Oppolzer s total synthesis of muscone (1993).

An enantioselective biomimetic synthesis of longithorone A was accomplished on the basis of proposed biosynthesis. " The syntheses of two [12]-paracyclophanes 105 and 107 are realized by applying ene-yne metatheses macrocyclization to 104 and 106, which are synthesized from the common substrate 103. Longtholone A is constructed using intermolecular and transannular Diels-Alder reactions followed by oxidation (Scheme 40). 

The macrocyclic chemistry of tetradentate Schiff base complexes has been known for long time. However, the successful use of such a complex as an enantioselective catalyst in epoxidation reactions is a relatively recent finding. In these reactions complex 9.9 or an analogue is used. One of the possible routes for the synthesis of intermediate 9.2 of Table 9.1 involves the use of a similar catalyst. While complex 9.9 works well with unfunctionalized alkenes, for the epoxidation of allylic alcohols, dialkyl tartarates, 9.10, are the preferred ligands. As we shall see, the mechanisms of epoxidation in these two cases are different. Also for the tartarate-based system titanium is the metal of choice (see Section 9.3.3). 

The first total synthesis of sarcophytol A (3), which was reported by Takayanagi et al. in 1990, ° was achieved in a highly stereo- and enantioselective manner starting from , -famesol (91) it included (1) a newly developed Z-selective (Z > 35 1) Horner-Emmons reaction with a phosphonate nitrile, (2) modified cyanohydrin macrocyclization, and (3) enantioselective (93% ee) reduction of macrocyclic ketone 100 as its key steps (Scheme 6-1). 

In the laboratory of J. Zhu, the synthesis of the fully functionalized 15-membered biaryl-containing macrocycle of RP 66453 was accomplished. One of the key steps in their approach was Corey s enantioselective alkylation of a glycine template with a structurally complex biaryl benzyl bromide. This benzyl bromide was prepared from the corresponding benzyl mesylate via the Finkelstein reaction using lithium bromide in acetone. 

Martinez-Diaz et al. have reported the synthesis of chiral podands and macrocycles based on 1,2,4-triazole (Figure 64) [89]. They have observed enantioselective transportation of chiral ammonium cations through supported liquid membranes. 

White, J.D., Tiller, T., Ohba, Y, Porter, W.J., Jackson, R.W., Wang, S., and Hanselmann, R., Total synthesis of rutamycin B via Suzuki macrocyclization, J. Chem. Soc., Chem. Commun., 19, 1998. Lafontaine, J.A., Provencal, D.P., Gardelli, C., and Leahy, J.W., The enantioselective total synthesis of the antitumor macrolide natural product rhizoxin D, Tetrahedron Lett., 40, 4145, 1999. 

Kilbum et al/ described the synthesis and peptide binding properties of some macrocyclic compounds containing a diamidopyridine unit as a carboxylic acid binding site (see Figure 16). Complexation studies in CDClj solution with N-protected (Z or B oc) amino acids or dipeptides were characterized by free association energies of up to 23 kJ/mol, but rather small enantioselectivity (max. AAG 4 kJ/mol). 

Both enantiomers of 1,1 -bi-2-naphthol are widely used for various applications 1) chiral inducing agents for catalytic, asymmetric reactions such as the Diels-Alder reacfion,2 ene reaction,3 or as Lewis acids 2) enantioselective reduction of ketones 3) synthesis of chiral macrocycles and other interesting compounds. Previously... 

Scheiper, B. Glorius, E Leitner, A. Fiirstner, A. Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotin. Proc. Natl. Acad. Sci. 2004, 101, 11960-11965. 

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