Suzuki macrocyclization

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. 

Nicolaou and coworkers recently employed an intramolecular Suzuki macrocyclization reaction in their total synthesis of the antibiotic... 

Danishefsky has reported the total synthesis of epothilone 490 (129) via an intramolecular Suzuki macrocyclization of alkenyl boronic ester 130 bearing a terminal alkenyl iodide group [104]. The corresponding alkenyl boronate fragment was prepared by alkenyl boronate cross-metathesis as reported by Grubbs (Scheme 3.69) [105,106]. 

Z-vinyl iodide was obtained by hydroboration and protonolysis of an iodoalkyne. The two major fragments were coupled by a Suzuki reaction at Steps H-l and H-2 between a vinylborane and vinyl iodide to form the C(ll)-C(12) bond. The macrocyclization was done by an aldol addition reaction at Step H-4. The enolate of the C(2) acetate adds to the C(3) aldehyde, creating the C(2)-C(3) bond and also establishing the configuration at C(3). The final steps involve selective deprotonation and oxidation at C(5), deprotection at C(3) and C(7), and epoxidation. 

For the domino transition metal-catalyzed synthesis of macrocycles, conditions must be found for two distinct cross-coupling reactions, of which one is inter- and the other intramolecular. For this purpose, Zhu s group [115] has developed a process of a Miyura arylboronic ester formation followed by an intramolecular Suzuki reaction to give model compounds of the biphenomycin structure 6/1-232 containing an endo-aryl-aryl bond. 

K. Tomono, A. Mugishima, T. Suzuki, H. Goto, H. Uedal, T. Nagail, and J. Watanabe, Interaction between cycloamylose and various drugs, J. Inclusion Phenom. Macrocyclic Chem., 44 (2002) 267-279. 

Other Pd cross-coupling reactions such as Heck [52] and Suzuki [53] reactions have also been used for macrocyclizations. The main drawback for Pd catalyzed macrocylization is the yield, that is often somewhat disappointing if compared with other established methods. Also, the introduction of the required coupling components (e.g., trialkyltin group, vinylic iodide) can be difficult in some compounds. In other cases, Pd-catalyzed side reactions such as double bond migration or allylic activation can occur. 

The group of Samuel Danishefsky at the Sloan-Kettering Institute for Cancer Research in New York has also been active in the synthesis of the natural epothilones and biologically active analogs. One of these syntheses also uses the olefin metathesis reaction (not shown). The synthesis in Scheme 13.51 uses an alternative approach to create the macrocycle. One of the key steps is a Suzuki coupling carried out at step H-(l,2) between a vinylborane and vinyl iodide. The macrocyclization is an aldol addition reaction at step H-4. The enolate of the acetate adds to the aldehyde, creating the C(2)-C(3) bond of the macrolactone and also establishing the stereocenter at C-3. 

As for the biaryl ether containing macrocycles, an array of bioactive macrocycles with an endo aryl-aryl bond exist in nature. A new palladium catalyzed reaction has been recently developed in which bis(pinacolato)diborane(4) mediated the process to reach such a structural motif. The reaction consists of a domino process involving a Miyaura s arylboronic ester synthesis and an intramolecular Suzuki-coupling. Synthesis of a bicyclic A-B-O-C ring system of RP-66453 273, a neurotensine receptor antagonist, with an endo aryl-aryl and an endo aryl-aryl ether bond was described (Scheme 53).141... 

In comparison with the fabrication of alkynyl- or alkenyl-linked multicomponent assemblies, there are few examples dedicated to aryl-Pcs. Such attempts are mainly based on Suzuki or Stille couplings. Hence, Odobel et al. [80] reported the construction of a Pc macrocycle carrying a trimethyltin function, thus allowing... 

Umehara T, Kawai H, Fujiwara K, Suzuki T (2008) Entropy- and hydrolytic-driven positional switching of macrocycle between imine- and hydrogen-bonding stations in rotaxane-based molecular shuttles. J Am Chem Soc 130 13981-13988... 

Key reactions of the total synthesis of the vancomycin aglycon presented by Nicolaou and coworkers [4-6] are a Suzuki coupling [15] for the synthesis of the M(5-7) unit (Scheme 5) and the triazene method, described recently for the construction of macrocyclic biaryl ethers (Scheme 6) [16]. 

A novel macrocyclization reaction was developed based on a domino Miyaura boration intramolecular Suzuki crosscoupling sequence in the laboratory of J. Zhu. " This strategy was applied in the synthesis of biaryl-containing macrocycles. The diiodide substrate was dissolved in degassed DMSO, and then the catalyst and the base were added. Successful macrocyclization required extensive experimentation, and the authors determined that the concentration and the nature of the base were the two most important factors. Interestingly, potassium carbonate is not suitable as a base in the Miyaura boration, since it tends to give biaryl by-products, but in this particular macrocyclization reaction it proved to be completely ineffective because the reaction failed to take place. 

A formal total synthesis of oximidine II was achieved by G.A. Molander et al., using an intramoiecuiar Suzuki-type cross-coupiing between an alkenyl potassium trifluoroborate and an alkenyl bromide to construct the highly strained, polyunsaturated 12-membered macrolactone core of the natural product. " The stability of potassium trifluoroborates was exploited in order to establish the best conditions for the macrocyclization. 

Carbonnelle, A.-C., Zhu, J. A Novel Synthesis of Biaryl-Containing Macrocycles by a Domino Miyaura Arylboronate Formation Intramolecular Suzuki Reaction. Org. Lett. 2000, 2, 3477-3480. 

Molander, G. A., Dehmel, F. Formal Total Synthesis of Oximidine II via a Suzuki-Type Cross-Coupling Macrocyclization Employing Potassium Organotrifluoroborates. J. Am. Chem. Soc. 2004, 126, 10313-10318. 

Suzuki coupling has been used in tandem with Stille coupling. The boronic ester analog of (44) has been coupled to provide (46g).49 Similarly, the boronic ester (48) was coupled with (45b) to afford (49), which then was coupled with an analogous diiodo-derivative to give a shape-persistent bis-tpy macrocycle (Scheme 8). 0... 

Intramolecular coupling of 120 having an aryl iodide group and a vinylstannane group accomplished the total synthesis of (-)-zealarenone (99) (Scheme 19) [77]. The first total synthesis of macrolactin A (124) was efficiently accomplished based on the Stille reaction of 122 for both stereospecific construction of the diene moieties and closure of the 24-membered macrocyclic ring [78]. The key precursor 122 was synthesized via two Stille couplings and Mitsunobu esterification. An alternative route to the dimethyl ether 125 was reported by cyclization of 123, which was prepared by the Stille and Suzuki couplings followed by DCC-DMAP esterification... 

T.- - J from bis(pinacolato)diboron s-a. r.iied macrocycle representing n r r.imolecular Suzuki coupling rs.T -. Mage of development. 

Kanbara, T., Suzuki, Y. and Yamamoto, T. (2006) New proton-sponge-Uke macrocyclic compound synergistic hydrogen bonds of aminopyridine. European Journal of Organic Chemistry, 3314—3316. 

Fig. 16 (a) macrocyclic lactone synthesis by cyclorelease via a sulfur ylide and (b) macrocyclization via intramolecular Suzuki-... 

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