Enantioselective Synthesis of Natural Polyoxygenated Cyclohexanes and Cyclohexenes from [(p‐Tolylsulfinyl)methyl]‐p‐quinols

Abstract

Exploitation of the beta-hydroxysulfoxide fragment present in a number of enantiomerically pure (SR)- and (SS)-[(p-tolylsulfinyl)methyl]-p-quinols allowed chemo- and stereocontrolled conjugate additions of different organoaluminium reagents to the cyclohexadienone moiety. The same fragment was also shown to act as an efficient chiral masking carbonyl group, after oxidation to sulfone and retroaddition in basic medium, with elimination of methyl p-tolyl sulfone. Through the use of both transformations as key steps, enantiocontrolled syntheses of different natural products-such as the two enantiomers of dihydroepiepoformin, (-)-gabosine O, (+)-epiepoformin, (-)-theobroxide and (+)-4-epigabosine A (an epimer of the natural product gabosine A)-has been achieved. The presence of the beta-hydroxy sulfone moiety makes the cyclic structures rigid, allowing a number of stereoselective transformations such as carbonyl reductions, enone epoxidations or cis-dihydroxylations, en route to the natural structures. The observed selectivities were dependent on the particular substitution in each substrate, providing evidence of a strong influence of remote groups on the preferred approach of the reactants to the reactive conformations. An advanced precursor of natural (+)-harveynone was also synthesized, but the isolation of the natural product was not possible because of the instability of the corresponding enone, containing a triple bond, under the basic conditions necessary to eliminate the beta-hydroxy sulfone. This demonstrated that the limitations of the use of the beta-hydroxy sulfoxide as a chiral protecting carbonyl group were dependent on the relative stabilities of the final targets in the presence of the required base.

Divergent Approach to Gabosines and Anhydrogabosines: Enantioselective Syntheses of (+)‐Epiepoformin, (+)‐EpoKformin, (+)‐Gabosine A, and Gabosines B and F

“…When this sequence of reactions was applied to (4 S )‐ 6 , the dextrorotatory enantiomer of epiepoformin was furnished, [ α ] D = +315 ( c = 1.1, EtOH) 28. The conversion of (+)‐epiepoformin into (–)‐theobroxide and (+)‐4‐epigabosine A was described previously 23b…”

“…Formally, regioselective hydrolysis of the epoxide in (+)‐epiepoformin or (–)‐epoformin could deliver (+)‐gabosine A, whereas the corresponding antipode, which is equally available through our approach, would deliver the naturally occurring enantiomer. However, it was described that hydrolysis of the epoxide in epiepoformin was a troublesome transformation that could only be achieved by treatment with aqueous sodium acetate in 45 % yield;23b furthermore, this reaction delivered 4‐epigabosine A, an epimer of the natural product. In view of this precedent, for the synthesis of gabosine A, we decided to assay the hydrolysis of the epoxide with a former intermediate lacking the conjugated C–C double bond; it was thought that the higher flexibility could benefit the desired transformation.…”

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

“…We found this transformation to be completely diastereoselective, and an X-ray diffraction study [58] of the product confirmed our hypothesis regarding the facial selectivity, as the hydride was delivered to the convex face. An analogous reaction occurs when 2a is treated with AlMe 3 , affording the 1,2-addition product (Scheme 3) [59–63]. …”

Enantioselective Synthesis of Natural Epoxyquinoids

“…In Carreño's synthesis of (+)-epiepoformin (2) and (-)theobroxide (21) [112,113] the key step involved a stereocontrolled conjugated addition of trimethylaluminium to a chiral sulfoxide-pquinol [114] in order to introduce the required asymmetry (scheme 25). p-Benzoquinone dimethylmonoacetal (163) reacted with the lithium anion of (R)-methyl-p-tolylsulfoxide, and then was subjected to hydrolysis of the acetal to afford sulfoxide 164.…”