Total Synthesis of (+)-Erogorgiaene Using Lithiation–Borylation Methodology, and Stereoselective Synthesis of Each of Its Diastereoisomers

Abstract

A short (8 steps) synthesis of (+)-erogorgiaene in 44% overall yield from p-methylacetophenone is described. Key steps include lithiation/borylation-protodeboronation to build up the molecule and control the stereochemistry at C1 and C4. The C11 stereochemistry was similarly set up by using lithiation/borylation methodology. The use of a mixed, unhindered borane in the lithiation/borylation reaction proved critical to success in the reaction of the tetralone-derived carbamate to control the C4 stereochemistry. The power of the reagent controlled methodology is illustrated in the stereocontrolled synthesis of all of the diastereomers of (+)-erogorgiaene.

Catalytic activation of carbon–carbon bonds in cyclopentanones

“…c , Applications in asymmetric total syntheses of terpenoids. It is known that α-tetralone ( 2b ) is an intermediate for accessing erogorgiaene 20,21 , ( R )-ar-himachalene 22 and (−)-heliophenanthrone 23 in three to seven steps (shown at the bottom). However, enantioselective preparation of α-tetralones with a C4 stereocentre is non-trivial and generally requires many steps 22 (top left, pale grey).…”

“…3c). For example, α-tetralone ( 2b ) is a known intermediate for accessing erogorgiaene 20,21 , ( R )-ar-himachalene 22 and (−)-heliophenanthrone 23 in three to seven steps; however, enantioselective preparation of α-tetralones with a C4 stereocentre is non-trivial and generally requires many steps 22 . Given that optically enriched 3-arylcyclopentanones can be synthesized in a single step from asymmetric conjugate addition between cyclopentenone and arylboronic acids 24 , using the C–C activation approach we isolated α-tetralone ( ( R )-2b ) in 64% yield over two steps, with 94.5% chirality transfer.…”

Total Synthesis and Stereochemical Assignment of Actinoranone

“…At this stage, all that remained to transform 19 to the desired product 1 was the protection of allylic alcohol 19 as its tert‐ butyldimethylsilyl ether and cleavage of the tert ‐butyl ester followed by an intramolecular Friedel–Crafts cyclization as described for 3 . Unfortunately, the attempted Friedel–Crafts cyclization of either 20 or 21 could not be effected to give rise to 1 , presumably due to the sensitive nature of the allylic silyloxy system.…”

Reagent-Controlled Lithiation–Borylation

“…The natural product (+)-erogorgiaene 51 and its diastereoisomers have all been synthesized using two lithiation-borylation-protodeboronation sequences as key steps [35]. As outlined in Scheme 14, lithiation-borylation of enantioenriched benzylic carbamate 52 with the ester-functionalized boronic ester 53 gave the tertiary organoboron 54 that was subjected to the protodeboronation protocol to give 55 in excellent yield and complete stereospecificity.…”