Intramolecular Suzuki macrocyclization

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]. 

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. 

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... 

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. 

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. 

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

The use of the Suzuki-Miyaura reaction in the synthesis of natural products has been wide spread over the years and is well reviewed. The intramolecular Suzuki-Miyaura reaction macrocyclisation to form macrocyclic natural products has been well reviewed by Fairlamb. Interestingly the first report employing this type of approaeh for maeroeyelic formation came from the group of Miyaura and Suzuki in their synthesis of humulene (Scheme 13.23). ... 

The utility of potassium organotrifluroborate salts in natural product synthesis was demonstrated by Molander through a formal total synthesis of the macrolide oximidine II. Alkyne 68 was selectively hydroborated with di(isopropylprenyl)borane and then converted to the potassium trifluoroborate salt 69. Formation of the macrocyclic ring was achieved through intramolecular Suzuki coupling of 69, which generated 70 in a 42% yield. Intermediate 70 was transformed to 71 in two steps to complete the formal synthesis. 

Lepine R, Zhu J. Microwave-assisted intramolecular Suzuki—Miyaura reaction to macrocycle, a concise as3mimetric total synthesis of biphenomycin B. Org. Lett. 2005 7 (14) 2981-2984. 

A novel macrocyclization procedure involving ttvo distinct cross-coupling manifolds in a domino fashion has been reported by Zhu for the synthesis of bipheno-mycin model 86 [56]. Thus, treatment oflinear feis-iodide with fois(pinacol)diborane (37) in the presence of Pd(dppf)2Cl2 under defined conditions affords the biphenyl macrocyclic compound 86 in 45% yield through a Miyaura aryl boronic ester formation followed by its intramolecular Suzuki cross-coupling. The diiodide containing a free phenol function (R=H) gave the macrocycle (R=H) in only 22-25% yield under these conditions (Scheme 3.37). 

An enantioselective total synthesis of (+)-phomactin A (181) has been recently reported by Halcomb using intramolecular Suzuki coupling of a B-alkyl-9-BBN derivative to prepare the macrocycle in the final step [162,163], Thus, a regioselective hydroboration of the terminal olefin in the precursor 182 gave an internal alkyl-borane that was cyclized using modification of Johnson s conditions [164], The reaction illustrates the mildness of the Suzuki reaction since the coupling was carried out in the presence of the sensitive dihydrofuran ring (Scheme 3.95). 

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... 

Several unusual silametacyclophanes, macrocyclic cage compounds, have been prepared by multiple Pd(0)-catalyzed Suzuki coupling reactions of 9-BBN adducts of allylsilane and bromobenzene. For example, reaction of 9-BBN adduct of methyltriallylsilane and 1,3,5-tribromobenzene leads to 4-methyl-4-sila[3 - ][7] metacyclophane, 4-(2-propenyl)-4-methyl-4-sila[7]metacyclophane, which results from an intramolecular coupling of two legs of the silane and -elimination of the third leg and 4-(3-phenylpropyl)-4-methyl-4-sila[7]metacyclophane (Eq. 

A highly convergent synthesis of rutamydn B, a 26-membered lactone macrolide antibiotic has been achieved by intramolecular macrocyclization through Suzuki coupling of a linear alkenyl boronate with a terminal alkenyl iodide as the key step in high yield as reported by White et al. (Scheme 3.68) [103]. 

Scheme 3.68 Intramolecular macrocyclization via Suzuki-Miyaura coupling.

An intramolecular B-alkyl Suzuki coupling has been used to construct the core macrocyclic structure of benzolactone enamide salicylhalamide A [165], Thus, dia-stereoselective hydroboration of acyclic alkenyl iodide 183 with (dppf)PdCl2 cata-lyst/NaOH gave the macrocyclic lactone 184 in 48% yield. Because of the high dilution, a large amount of catalyst (20 mol%) was used. The steric hindrance at the ester group probably retards the cleavage of the lactone under basic conditions (Scheme 3.96). 

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