Enynes macrocyclization

According to this hypothesis, Shair s synthesis began with the construction of the protected versions 438 and 439 of key fragments 430 and 431 as single at-ropisomers, by using for the first time enyne macrocyclization to generate the required 1,3-diene units present in both key fragments (Scheme 86). This plan... 

Pressing forward to test the operation at the heart of the entire proposed synthesis, the Shair group pleasantly discovered that the designed enyne macrocyclization reaction could be effected using... 

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-... 

Scheme 86 Regioselective enyne RCM for the synthesis of 1,3-disubstituted macrocyclic 1,3-dienes 433 and 434, main fragments in Shair s total synthesis of longithorone A [180]...

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. 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

Macrocyclic compounds are readily synthesized by enyne metathesis. RCM of enynes 17 to form 10-membered rings and smaller rings invariably gives irvo-products 18, whereas that forming 12-membered or larger rings provides OT o-products 19 (Scheme 6). 

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). ... 

The addition of thiyl radicals to alkenes or alkynes to initiate tandem sequences has also been explored. A highly stereo-controlled phenyl thiyl radical addition, 10-endo macrocyclization, termination process has been used to furnish the macrocycle (37) from the dimethylacrylic ester (36).48 In other work the vinyl radical (38) fonned from addition of a thiyl radical to an enyne gives a mixture of the three products (39)-(41) formed either by 6-exo cyclization (39), addition into the aromatic ring followed by trapping with AIBN (40), or rearomatization and fragmentation to give the sulfide (41) (Scheme 15).49... 

On the other hand, cyclization of diynes separated with a long chain catalyzed by thiolate-bridged diruthenium complexes led to endo-macrocyclic (Z)-con-jugated enynes with 10-16-membered rings [104] (Eq. 80). A butenynyl intermediate is invoked in this mechanism, probably via a vinylidene intermediate. 

M. Shair and co-workers were the first to apply the enyne metathesis for macrocyclization during the biomimetic synthesis of (-)-longithorone A." The two 16-membered paracyclophane building blocks, one diene and one dienophile component, were prepared using 50 mol% Grubbs s first-generation catalyst under 1 atm ethylene gas pressure. These components, after several additional steps, underwent two facile Diels-Alder cycloaddition reactions to afford the natural product. 

Sondheimer, F., Ben Efraim, D. A., Wolosovsky, R., Unsaturated Macrocyclic Compounds. XVII. The Prototropic Rearrangement of Linear 1,5 Enynes to Conjugated Polyenes. The Synthesis of a Series of Vinylogs of Butadiene, J. Am. Chem. Soc. 1961, 83, 1675 1681. 

Scheme 45. Ring-closing enyne metathesis to form 10-12-membered macrocycles.

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