Asymmetric Total Synthesis of (-)-Phaeocaulisin A

Abstract

The therapeutic properties of Curcuma (ginger and turmeric's family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI₂), the lactone intermediate was submitted to two sequential SmI₂-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI₂, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from C. phaeocaulis─as well as their synthetic derivatives─for medicinal chemistry and drug design.

Figure 1

Guaiane-type sesquiterpenes from C. phaeocaulis and our strategy for the enantioselective synthesis of phaeocaulisin A. (a) Structurally diverse terpenoids, isolated from the rhizomes of C. phaeocaulis, exhibit enhanced anti-inflammatory activity. (b) Retrosynthetic analysis of one of the most biologically active and structurally intriguing members of the above class of guaiane-type sesquiterpene: phaeocaulisin A. The retrosynthesis builds on two SmI₂-mediated cyclizations to forge the key 1,4-diO (C3-C1) and 1,6-diO (C3-C8) patterns through an umpolung strategy. The stereocenters are highlighted; the guiding stereocenter (C12) is established in triol 11 (highlighted in red).

Scheme 1. Enantioselective Synthesis of Key Intermediates 8

Synthetic route, summarizing reagents and conditions, to enantioenriched dienoates 8: substrates for the SmI₂-mediated cyclization reactions. Cp, cyclopentadienyl; DMF, dimethylformamide; TBDPS, tert-butyldiphenylsilyl; THF, tetrahydrofuran; TMS, trimethylsilyl; DMSO, dimethyl sulfoxide; TBAF, tetrabutylammonium fluoride; DIH, 1,3-diiodo-5,5-dimethylhydantoin.

Scheme 2. Synthetic Design and Optimization of the Key SmI₂-Mediated Cyclization

Yields determined by ¹H NMR analysis using MeNO₂ as the internal standard. Asterisks denote isolated yield. (a) Postulated reactivity in the SmI₂-mediated cyclization of 8 to produce 7 through SET reduction of its ketone moiety. (b) An initial attempt using 8 Me ester afforded the undesired carboxylic acid 26 as the major product. (c) Increasing the steric bulk around the ester moiety of 8 alters the chemoselectivity of the SmI₂ reduction: design and optimization of the key SmI₂-promoted cyclization using 8tert-butyl ester as the substrate. (d) Electrochemical characterization of dienoates 8. HMPA, hexamethylphosphoramide; THF, tetrahydrofuran; TPPA, tripyrrolidinophosphoric acid triamide; 2,4,6-TTBP, 2,4,6-tri-tert-butylphenol.

Scheme 3. Completion of the Total Synthesis of (−)-Phaeocaulisin A and Structural Revision of Its Naturally Occurring Enantiomer

(a) The final steps toward the synthesis of (−)-phaeocaulisin A, featuring the two key SmI₂-mediated cyclizations and the installation of the endocyclic double bond. (b) Structural revision of the naturally occurring (+)-phaeocaulisin A based on the comparison of both the specific rotation and the CD spectrum of the synthetic and the natural sample. TPPA, tripyrrolidinophosphoric acid triamidetris(N,N-tetramethylene)phosphoric acid triamide; 2,4,6-TTBP, 2,4,6-tri-tripyrrolidinophosphoric acid triamide; 2,4,6-TTBP, 2,4,6-tri-tert-butylphenol; TFA, trifluoroacetic acid; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; THF, tetrahydrofuran; TMSOTf, trimethylsilyl trifluoromethanesulfonate; LDA, lithium diisopropylamide; DBDMH, 1,3-dibromo-5,5-dimethylhydantoin; SM, starting material.