Concise total synthesis of (±)-aspidospermidine via an oxidative Hosomi–Sakurai process

Abstract

A concise total synthesis of (+/-)-aspidospermidine has been achieved in twelve steps from inexpensive 4-ethylphenol, based on an oxidative Hosomi-Sakurai reaction via the concept of "aromatic ring umpolung".

Dearomatization Strategies in the Synthesis of Complex Natural Products

“…An important example of the oxidative dearomatization of a phenolic substrate with concomittant CÀC bond formation in the context of complex total synthesis was reported by Nicolaou and co-workers in their enantioselective synthesis of (À)-platensimycin (39; Scheme 15). [42] The authors employed oxidative dearomatization with intramolecular para-spiroannulation of a pendant allylsilane [43] using hypervalent iodine activation to assemble the first two rings of the natural product. Allylsilane 129 was prepared enantioselectively using the Myers auxiliary for asymmetric alkylation.…”

“…Further treatment of acetonide 155 under acidic conditions led to diol 156 which spontaneously cyclized to give a mixture of Michael-type products 157 a and 157 b. Dearomatization by means of a Claisen rearrangement has been sparsely used in total synthesis. [52] The most impressive examples are presented in Scheme 21 wherein Theodorakis et al [53] and Nicolaou et al [54] independently demonstrated the validity of a biomimetic process [55] through Claisen rearrangement/dearomatization to access the natural product (AE )-gambogin (43). In the Theodorakis synthesis, exposure of acetylated xanthone 160 bearing reverse Oprenylated side chains to thermal conditions in polar protic solvents led to a remarkable Claisen dearomatization/Diels-Alder (CDDA) cascade.…”

Synthesis of Spirocyclic Indolenines

“…In this report, which utilised standard acetic acid catalysed conditions, only one of the two possible Fischer indolisation products was isolated; presumably the selectivity is controlled by the reaction proceeding via the more stabilised tetrasubstituted enamine 46 rather than 45 . Stork and Dolfini did not report an isolated yield for this process, but its efficacy and selectivity has been demonstrated by others since, for example, Zard and co‐workers reported the formation of 48 in 62 % yield using this procedure …”

“…[45] In this report, which utilised standard acetic acid catalysed conditions, only one of the two possible Fischer indolisation products was isolated; presumably the selectivity is controlled by the reaction proceeding via the more stabilised tetrasubstituted enamine 46 rather than 45.S tork and Dolfinid id not report an isolated Scheme2.Generalsynthetic challenges associated with spirocyclic indolenine synthesis. yield for this process, but its efficacy and selectivity has been demonstrated by others since, [46][47][48][49] for example, Zard and coworkers reported the formation of 48 in 62 %y ield using this procedure. [46] In another synthesis of af used ring system,B ird and coworkers (who were inspired by the earlier work of Georgian) [50] describedt he formation of compounds 50 and 51 to evaluate their biological properties (Scheme 7).…”

Hypervalent iodine reagents in the total synthesis of natural products

“…297 This reaction has been applied in the total synthesis of (±)-aspidospermidine, 298 and an intramolecular version was utilized in the synthesis of platensimycin. 299 Oxidative functionalization of phenols in the ortho position leads to 2,4-cyclohexadienones, which are often employed in subsequent Diels-Alder reactions.…”