Macrocyclization total synthesis reactions

An example of the efficient formation of an electron-deficient double bond by RCM was disclosed by a Japanese group in a novel total synthesis of the macrosphelides A (209) and B (208) (Scheme 41) [100]. When the PMB-pro-tected compound 204 was examined as a metathesis substrate, the ring closure did not proceed at all in dichloromethane using catalysts A or C. When the reaction was carried out using equimolar amounts of catalyst C in refluxing 1,2-dichloroethane, the cyclized product 205 was obtained in 65% yield after 5 days. On the other hand, the free allylic alcohol 206 reacted smoothly at room temperature leading to the desired macrocycle 207 in improved yield. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

A Mitsunobu process simultaneously coupled the enyne acid fragment 4 to /J-lactam 10 and inverted the CIO stereochemistry to the required (S)-configured ester 11 in 93% yield. A deprotection provided alcohol 12, the key /J-lactam-based macrolactonization substrate, which, under conditions similar to those reported by Palomo for intermolecular alcoholysis of /J-lactams (Ojima et al, 1992, 1993 Palomo et al, 1995), provided the desired core macrocycle 13 of PatA 13 (Hesse, 1991 Manhas et al, 1988 Wasserman, 1987). Subsequent Lindlar hydrogenation gave the required E, Z-dienoate. A Stille reaction and final deprotection cleanly provided (-)-PatA that was identical in all respects to the natural product (Romo etal, 1998 Rzasaef al, 1998). This first total synthesis confirmed the relative and absolute configuration of the natural product and paved the way for synthesis of derivatives for probing the mode of action of this natural product. 

RCM-based macrocyclization reactions as they potentially sequester the catalyst in an unproductive form. A recent total synthesis of gloeosporone 86 addresses this aspect and describes a simple, yet efficient way to overcome this limitation [31]. 

Initial efforts in the ring-dosing metathesis approach were attempted with substrates 34 and 35. However, after employing a variety of catalysts and experimental conditions, no cydized systems (36 or 37) were obtained. Other substrates were prepared to further probe this unexpected failure however, no observable reaction was realized. Model systems later suggested that die dense functionality between C3 and C8 was the culprit for lack of macrocycle formation. Eventually a second generation Cl2-03 RCM (not shown here) approach was developed [26] which yielded mixtures of C12-C13 Z/E isomers that were used in early SAR studies. [26b] However, since the separation of products was so difficult, we did not seriously pursue this route for total synthesis. 

Reaction (7.61) shows an example of macrocyclization which represents the key step in the total synthesis of the macrolide (—)-zearalenone [71]. 

Grasillas, A. Perez-Castells, J. Macrocyclization by ring-closing metathesis in the total synthesis of natural products Reaction conditions and limitations. Angew. Chem. Int. Ed. 2006,45, 6086-6101. 

The structural similarity between claenone (42) and stolonidiol (38) enabled Yamada to exploit an almost identical strategy for the total synthesis of (-)-stolonidiol (38) [40]. A short retrosynthetic analysis is depicted in Fig. 12. An intramolecular HWE reaction of 68 was successfully applied for the macrocyclization. The highly substituted cyclopentanone 69 was made available by a sequence that is highlighted by the sequential Michael-Mi-chael addition between the enolate 53 and the a, -unsaturated ester 70 followed by a retro-aldol addition. However, as is the case for the claenone (42) synthesis, the synthesis of stolonidiol (38) is characterized by numerous functional and protecting group transformations that are a consequence of Yamada s synthetic strategy. 

More recently, Aitken and coworkers described a short and convergent formal total synthesis of cyclotheonamide C using a process that involves a Passerini reaction, amine deprotection, and an acyl migration (PADAM sequence. Scheme 22) [90]. The key linear pentapeptide 22e is obtained by a Passerini reaction of isocyanide a, Fmoc-amino aldehyde b, and Boc-dipeptide acid e followed by Fmoc removal and consequently 0,N-acyl migration [91]. The macrocyclization was achieved with TBTU and HOBt after Boc and fBu removal in good yield (52%) to furnish intermediate f. 

Trost succeeded in formal total synthesis of roseophilin. Macrocyclic compound 118 is synthesized from enyne 117 by platinum-catalyzed skeletal reorganization reaction and is converted into 119, which is further converted into pyrrole derivative 120 (Scheme 43). ... 

Hayward CM, Yohannes D et al (2002) Total synthesis of rapamycin via a novel titanium-mediated aldol macrocyclization reaction. J Am Chem Soc 115 9345-9346... 

Along with diene and diyne metathesis, ene-yne metathesis has also been employed to form macrocycles. This type of metathesis is performed with the catalysts used for olefin metathesis, and the yields are improved in the presence of ethylene, which forms the highly reactive [Ru]=CH2 species. Shair and coworkers took advantage of this reaction twice in the course of their total synthesis of longithorone A [40]. When ene-ynes 51 and 52 are treated with ruthenium complex G1 under an atmosphere of... 

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]. 

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). 

The closure of the macrocyclic ring by means of an intramolecular 8 2 reaction is a straightforward approach, and sulfur-stabilized carbanion alkylation has been successfully applied in the synthesis of 14-membered cembranoids. The synthesis of nephthenol (40) and cembrene A (59) is an example of this methodology. In Li and Yue s report, the total synthesis of ( )-sarcophytol M (17) was achieved from ger-aniol (137) through 12 steps and in 8.9% overall yield with an intramolecular nucleophilic addition of a sulfur-stabilized carbanion to a ketone as a key step. This example is the first of the closure of a macrocyclic ring with the intramolecular nucleophihc addition of a sulfur-stabilized carbanion to a ketone (Scheme 6-7). 

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