(2013) The intramolecular Buchner reaction of α-diazo-β-ketonitriles : development and application to the total synthesis of (+)-Salvileucalin B. Dissertation (Ph.D.), California Institute of Technology.
Asymmetric dearomatization methods are underdeveloped and significant potential for chemical synthesis. Therefore, the development of new catalytic and enantioselective dearomatization methods such as that recently reported by Buchwald and co-workers will set the bar for further applications in the total synthesis of complex molecules (). The authors found that a palladium(0) complex bearing the chiral P,N ligand 286 catalyzed asymmetric, intramolecular dearomatization of naphthalene derivatives such as 287 to produce the fused tetracyclic indolenine 288 (83% yield, 92%ee) which contains two contigous nonaromatic rings proximal to a quaternary stereocenter. Indolenine 288 was further functionalized at C2 by highly diastereoselective addition of methyllithium (d.r. 9:1) and directly protected on the indoline nitrogen to deliver tetracyclic product 289 in 62% overall yield and 99%ee. This elegant work should inspire future studies in the area of transition-metal-catalyzed, enantioselective dearomatization.
ChemInform Abstract: Diastereoselective Total Synthesis of ..
In a recent synthesis of the immunosuppressive polyketide dalesconol B (40), Snyder and co-workers employed oxidative dearomatization as part of a clever tandem process (). In this sequence, finetuning of the two phenol protecting groups and the acid sources were required for the sequence of Friedel–Crafts cyclizations. Indeed, in such complex syntheses of polyphenolic structures, stabilized carbocations from retro-Friedel–Crafts or skeletal rearrangements may occur and generate multiple polycyclic structures. Hydrogenation of substrate 134 delivered the isolable free phenol 135. The latter compound was first treated with TFA producing carbocation 136 thereby triggering intramolecular Friedel–Crafts alkylation to 137 in a controlled manner. Subsequent oxidation of naphthol 137 in the same reaction vessel using PIDA afforded 138 which initiated oxidative dearomatization and assembly of the polycyclic dalesconol precursor 139 in 32%overall yield. This remarkable access to the complex heptacyclic core structure through tandem Friedel–Crafts/oxidative dearomatization paved the way for the total synthesis of dalesconol B after a few additional steps.
A Modular Synthesis of Salvileucalin B Structural Domains
The total synthesis of the sesquiterpenoid sinularene (59) from the coral Sinularia mayi  started from alcohol 56, which was converted to bicyclic 57 in nine steps. Trans-divinylcyclopropane 57 was then subjected to high temperature DVCPR conditions furnishing bridged bicycle 58. Trans-cis isomerization of the vinyl moiety had to take place prior to the rearrangement to access the required boat transition state of the rearrangement. Intermediate 58 was converted to the natural product 59 in four additional steps.
“A Modular Synthesis of Salvileucalin B ..
Quideau and co-workers developed an efficient route to masked ortho-benzoquinones (MOBs) in chiral, nonracemic form through the λ3-iodane (PIDA)-mediated ortho-oxidative dearomatization of catechols. The methodology was successfully applied to the asymmetric total synthesis of the bis(monoterpene) (+)-biscarvacrol (36; ). During this synthesis, the authors demonstrated the utility of a chiral tether for the diastereoselective spiroketalization of resorcinol 114. A chairlike iodine(III) intermediate 115, which may be stabilized by orbital interactions between the iodine and spiro-carbon atom, was proposed to explain the stereochemical outcome of the reaction and production of (S,S)-MOB diastereomer 116. The addition of methyl Grignard to ketone 116 from the less hindered face was found to be highly diastereoselective (d.r. >95:5) and afforded alcohol 117 in 54% yield over two steps. The ketal auxiliary was finally removed under acidic conditions which initiated spontaneous and regioselective cyclodimerization of ortho-quinol intermediate 118 to furnish (+)-biscarvacrol (36) as the major stereoisomer (86% ee).