Development of a General, Sequential, Ring-Closing Metathesis/Intramolecular Cross-Coupling Reaction for the Synthesis of Polyunsaturated Macrolactones

Abstract

A general strategy for the construction of macrocyclic lactones containing conjugated Z,Z-1,3-diene subunits has been is described. The centerpiece of the strategy is a sequential ring-closing metathesis that forms an unsaturated siloxane ring followed by an intramolecular cross-coupling reaction with a pendant alkenyl iodide. A highly modular assembly of the various precursors allowed the preparation of unsaturated macrolactones containing 11-, 12-, 13-and 14-membered rings. Although the ring closing metathesis process proceeded uneventfully, the intramolecular cross-coupling required extensive optimization of palladium source, solvent, fluoride source and particularly fluoride hydration level. Under the optimal conditions (including syringe pump high dilution), the macrolactones were produced in 53-78% yield as single stereoisomers. A benzo fused 12-membered ring macrolactone containing an E,Z-1,3-diene unit was also prepared by the same general strategy. The E-2-styryl iodide was prepared by a novel Heck reaction of an aryl nonaflate with vinyltrimethylsilane followed by iododesilylation with ICl.

The Synthesis of Macrocycles for Drug Discovery

“…232 In a final example, Denmark has described a detailed study on a tandem RCM/Si-assisted Pd cross-coupling reaction sequence that led to unsaturated macrolactones 128 (Scheme 11.15) through the intermediacy of siloxane 127. 233 The typically difficult 11-to 14-membered ring sizes could be accessed under the optimized conditions, which included a hydrated fluoride ion activator. High dilution conditions were not required and this process was adapted to provide benzo-fused products as well.…”

“…330,331 Specifically, reaction of the bis-functionalized substrates with appropriate diactivated reagents were utilized to form cyclic carbonates (231), sulphites (232), phosphates (233), sulphides (234), amines (235,236) and malonates (237) with ring sizes of 15-19 members. Although yields were generally modest, these sequences do provide a route to impart significant diversification to a single functionalized precursor.…”

Sequential Processes in Palladium‐Catalyzed Silicon‐Based Cross‐Coupling

“…[xxx] The resulting cyclic alkenylsilyl ether 52 undergoes facile cross-coupling reactions with aryl iodides under very mild conditions to furnish substituted alkenyl secondary homoallylic alcohols 53 with exclusive Z -configuration (Scheme 13). [xxxia,d] …”

“…Remarkably, despite the unfavorable entropic and enthalpic factors, [xxxii] even 12-membered rings bearing a cis,cis -1,3-diene unit have been constructed through this strategy (Scheme 14). [xxxia,b] Similarly, macrolactones bearing a cis,cis -1,3-diene, 59 , can be prepared via this sequence. Alhtough the RCM of vinylsilyl ether 57 proceeds uneventfully under the conditions previously developed, the intramolecular cross-coupling of cyclic silyl ethers 58 requires some modification of parameters to prevent an undesired side-reaction (an intramolecular transesterification through the base-promoted attack of the secondary alcohol of lactone 59 ).…”

Conditions for a Rh(I)-catalyzed [2+2+1] cycloaddition reaction with methyl substituted allenes and alkynes

“…The temperature of this reaction was increased to 110 °C to limit exposure time of the product to the rhodium catalyst, resulting in only a slight increase in the yield of dienone 10a (entry 4). Decreasing the concentration of the reaction further was accomplished by adding a solution of alleneyne 8a in toluene dropwise over 1.5 h to a preheated solution of [Rh(CO) 2 Cl] 2 in toluene with a final concentration of 0.01 M. 15 Upon completion of the addition, the reaction is stirred for an additional 15 min until allene-yne 8a was no longer visible by TLC. Dienone 10a was afforded in 81% yield with no byproduct observed (entry 5).…”