Trienes, Stille coupling

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

The total synthesis of (+)-mycotrienol was accomplished by J. Panek and co-workers using a Pd -catalyzed Stille coupling reaction to incorporate the ( , , )-triene unit with simultaneous macrocyclization. After macrocyclization, the aromatic core was oxidized with CAN and the protecting groups were removed to provide the natural product. 

White applied the alkenyl-alkenyl coupling of 8 with dienyl stannane 9 under standard conditions, for the bnild np of the triene fragment of polycavernoside A (10), a lethal toxin of a red alga (Scheme 5.4.3).32 It is noteworthy that this Stille coupling was efficiently performed as the last step of the synthesis, nsing the full glycosidated aglycon 8 as the electrophilic partner. 

Retrosynthetic analysis of disorazole Cl suggested that the cyclodimerization of acid 67 would be a viable synthetic route. This was accomplished by addition of trimethylstannane 65 to a solution of dieneyl iodide 66 via a Stille coupling in the presence of a catalytic amount of Pd(CH3CN)Cl2 to give triene 67 in 76% yield [14]. 

Double Stille couplings are valuable for symmetrical compounds like p-carotene 226. The symmetrical bis-tributylstannyl-pentaene 224 is coupled at both ends to the iodo-triene 223 in one step with catalyst 225 to give an excellent yield of P-carotene 226 with full control over E/Z stereochemistry.35... 

The final steps to complete the total synthesis required stereoselective construction of the triene side chain and global deprotection. After extensive experimentation, it was found that the Pd(PPh3)4/ CuCl/LiCl-promoted modified Stille coupling conditions" were quite suitable for the construction... 

In 2006, Bout and Suffert combined Stille coupling with a preceding intramolecular alkyne insertion into a vinylic palladium bond and developed a new application of the 4-exo-dig cyclocarbopalladation of acyclic y-bromopropargylic diols 120 [48] (Scheme 6.30). This strategy is an efficient route to cyclobutanediol derivatives 121. The efficiency of the reaction is improved greatly by the use of brief microwave irradiation at 130 °C. Further 6ii-electrocyclization occurred, providing new bicyclic systems 123 instead of trienes 122, when the reaction was conducted in the presence... 

Scheme 28 Synthesis of dienes and trienes via Stille coupling...

Another palladium-catalysed process that has proven utility for cyclic structures is the Stille coupling between organostannanes and aiyl or vinyl halides/triflates. Specifically for the macrocyclic framework, this chemistry was applied to the preparation of cyclic trienes (102) with defined geometry (Scheme 11.11) that were intermediates for transannular Diels-Alder reactions. The intramolecular Stille reaction also has been efficiently conducted on solid phase to form 104, an advanced intermediate in the synthesis of (S)-zearalenone, from 103 by a cyclization-release strategy. ... 

In the presence of in, V -generated palladium(O) species, an electrophilic 7t-allyl complex 228 is formed, which is readily engaged in an intramolecular carbometallation (Scheme 57). The resulting vinylpalladium species then undergoes a Stille-type cross-coupling to provide a triene.232... 

The examples discussed in this paper demonstrate that Pd-catalyzed coupling reactions can be successfully utilized in the convergent (modular) synthesis of vitamin D-active compounds. The new synthetic routes open an efficient and highly selective access to a variety of vitamin D analogs. While reliable methods exist today for the construction of the triene system and for the synthesis of the ring A precursors, the search for efficient total synthetic approaches to the CD building blocks still remain a challenging task for the future. 

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