A Novel and Highly Stereoselective Intramolecular Formal [3+3] Cycloaddition Reaction of Vinylogous Amides Tethered withα,β-Unsaturated Aldehydes: A Formal Total Synthesis of (+)-Gephyrotoxin

Abstract

We have been exploring reactions of b-diketo equivalents 1 with a,b-unsaturated iminium salts 2 for the construction of heterocycles such as 3 (Scheme 1). [1±3] These reactions involve a sequence consisting of a Knoevenagel condensation followed by a six p-electron electrocyclic ring-closure, [4] thereby constituting a stepwise formal [33] cycloaddition [5±7] in which two s bonds are formed, along with a new stereocenter Scheme 1.[33] Cycloaddition reactions of vinylogous amides and a,bunsaturated iminium salts. Reagents and conditions: a) EtOAc/toluene 1:2, 150 8C, 15 ± 30 h, 76 ± 80 %; TBS tert-butyldimethylsilyl. adjacent to the heteroatom. This cycloaddition protocol can be classified as a sequential anionic ± pericyclic strategy for which the significance in natural product synthesis has been elegantly summarized by Tietze and Beifuss. [8] Our recent work on the use of vinylogous amides in this formal cycloaddition [1] has allowed us to envision an intramolecular version of this reaction. Since the vinylogous amide 1, which contains a functionalized tether, provided the formal cycloadduct 3 in good yields, [1] it is conceivable that the vinylogous amides 4, which are tethered with an a,b-unsaturated iminium ion, may lead to piperidinyl heterocycles 5, attractive as intermediates in the syntheses of natural alkaloids (Scheme 1). We report herein the first stereoselective intramolecular formal [33] cycloaddition reaction by using vinylogous amides that are tethered with iminium ions, and its application in a formal total synthesis of ()-gephyrotoxin. [9±11] Based on our previous studies, the formation of the a,bunsaturated iminium salt prior to the addition of a b-diketo nucleophile is crucial to the regio-and chemoselectivity of the intermolecular formal cycloaddition reaction. [1, 2a] Conditions and protocols that generate a,b-unsaturated iminium salts in the presence of the b-diketo nucleophile lead to low yields of the desired products, and/or to synthetically less useful byproducts resulting from various competing reaction pathways. [7b±e] However, the enal precursor to a,b-unsaturated iminium ions in the intramolecular variant also contains a vinylogous amide. Thus, controlling the extent of iminium ion formation before competing reactions take place is a major challenge.To demonstrate the feasibility of an intramolecular formal [33] cycloaddition, the vinylogous amides 6 and 7 were prepared [12,13] and treated with piperidine (2.0 equiv) and Ac 2 O (2.0 equiv) in EtOAc/toluene (1:2; concentration of vinylogous amides: 0.03 ± 0.30 m) at 858C for 1 h (Scheme 2). These are the standard reaction conditions that have been consistently employed for the formation of iminium salts. [1,2] Subsequent heating at 150 8C in a sealed tube led to the isolation of the desired heterocycles 8 and 9 in yields of 80 and 68 %, respectively. Furthermore, the chiral vinylogous amide 10 [12] led to the desired tricycle 11 in 55 % yield as a single diastereomer under the same reaction conditions. The stereochemistry of...