Nickel-catalyzed intramolecular [4 + 4]-cycloadditions: a new method for the synthesis of polycycles containing eight-membered rings

Abstract

The nickel(0)-catalyzed oligomerization of 1,3-dienes holds a prominent place in the history and practice of organometallic chemistry as one of the first and most extensively studied transition-metal-catalyzed, C-C bond-forming reactions.1 In the case of buta-1,3-diene, this process selectively affords four-, six-, eight-, or twelve-membered rings, depending on catalyst ligands and reaction conditions.13 Notwithstanding its enormous synthetic potential, this chemistry has not been applied to complex molecule synthesis, due in part to the low regio-and/or stereoselectivity observed in the reactions of unsymmetrical dienes,2 the inefficiency of crossed oligomerizations,1 and the general observation that substituted dienes are far less reactive than butadiene.1 We now report a solution to these problems in the form of the first intramolecular nickel(0)-catalyzed cycloaddition and the initial study of stereoinduction in this reaction class. This investigation provides the basis for an efficient and direct [4 + 4] cycloaddition3 approach to cyclooctane-containing polycycles which are generally accessible only through multistep sequences based on fragmentation and expansion reactions.4 Illustrative of the efficacy of this method for complex polycycle synthesis, tetraene l,5 quantitatively prepared from diethyl malonate and bromopentadiene, when treated in toluene at 60 °C with 11 mol % Ni(COD)2 and 33 mol % Ph3P, gave cyclooctadienes 2a and 2b6 (19:1, respectively) in 70% yield. The products of six-membered ring formation (3) and of /3-hydride elimination (4) were also obtained in 2.6% and 12% yields, respectively. Variations in the nickel-phosphine ratio and in the ligand structure resulted in lower yields of cyclooctadiene products and preferential formation of 3 and 4. For example, reactions conducted with Ni(COD)2 and tri-o-tolyl phosphite (1:3, retí) For reviews and lead references, see: (a) Jolly, P.

The Dienyl Pauson–Khand Reaction

“…[1,2] These studies have thus far produced the first examples of transition-metal-catalyzed [4þ4] cycloadditions of bisdienes, [3] [4þ2] cycloadditions of dienynes (and diene allenes), [4] [5þ2] cycloadditions of vinylcyclopropanes and p systems, [5] and [6þ2] cycloadditions of vinylcyclobutanones and p systems.[6] Recently, we started to investigate whether these and other two-component [mþn] cycloadditions could be converted into multicomponent [mþnþo…þx)] processes through trapping of the organometallic intermediates with additional components. [7] These investigations have thus far led to the first metal-catalyzed, three-component [5þ2þ1] cycloaddition reactions based on trapping of an intermediate in the [5þ2] cycloaddition reaction with CO.…”

Toward the ideal synthesis and transformative therapies: the roles of step economy and function oriented synthesis

“…In the course of our studies on the intramolecular [4+4] cycloaddition of bis-dienes, we observed, for example, a competing process, the nickel catalyzed [4+2] cycloaddition of a diene across an alkene ( 74 , Scheme 19). 58 This was not unexpected as Reppe and others had observed this competing pathway with simple butadienes. However, its utility in complex molecule synthesis was little advanced but potentially of great value, especially if it could be controlled in an intramolecular process similar to that which we observed with the [4+4] cycloaddition.…”

“…57 In 1986, we reported the first nickel catalyzed intramolecular [4+4] cycloadditions as a strategy to overcome substitution problems and to control regio- and diastereoselectivity (Scheme 15). 58 Remarkably, the intramolecular process proved to be tolerant of diene substitution and proceeded with complete regioselectivity, high diastereoselectivity (97%) and high yield (93%), in part fueling our view that these reactions could provide “fundamentally new approaches to several structural classes including taxanes, ophiobolins, and fusicoccins”. The relationship of the cycloadduct stereochemistry and functionality to taxol is noteworthy and synthetically attractive as dihydroxylations of the double bonds would provide the B-ring oxidation pattern of this, then unsolved, target.…”

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

“…For instance, nickel-catalyzed [4 + 4], [4 + 2], and [2 + 2 + 2] cycloadditions have received considerable attention. [11,12] Over the past decade, nickel-catalyzed reductive cyclizations and couplings have evolved into a broadly useful strategy for assembling synthetically versatile substructures and complex molecules. [13] Moreover, chiral nickel complexes are becoming potential practical catalysts in enantioselective transformations.…”