A Multifaceted Phosphate Tether: Application to the C1−C14 Subunit of Dolabelides A−D

Joshua D. Waetzig, Paul R. Hanson
2008 Organic Letters  
A phosphate tether approach to the C1-14 subunit of dolabelide is described. The phosphate tether serves a multifaceted role mediating several processes, including (i) diastereotopic differentiation via RCM, (ii) selective CM by imparting Type III behavior to the exocyclic olefin, (iii) regioselective hydrogenation, and (iv) regioselective Pd(0)-catalyzed reductive opening of the bicyclic phosphate. Overall, this strategy uses orthogonal protecting-and leaving-group properties innate to
more » ... e esters to rapidly assembly the titled subunit. In 1995, isolation and structural characterization of two new 22-membered macrolides, dolabelides A (1) and B, 1 from the sea hare Dolabella auricularia were reported. Isolation of dolabelides C and D, 2 24-membered macrolides, was achieved from the same source. Cytotoxicity studies of dolabelides A-D revealed promising results against cervical cancer HeLa-S 3 cells with IC 50 values of 6.3, 1.3, 1.9, and 1.5 μg/mL, respectively. Synthetic studies toward various subunits of dolabelide have recently been reported. 3 These efforts include synthesis of protected intermediates of the C1-C14 subunit, with Leighton and co-workers reporting the properly acetylated C1-C14 fragment and completing the only total synthesis of dolabelide D in 2006. 4 Key features common among the dolabelide family are 11 stereogenic centers, eight of which bear oxygen, and two E-configured trisubstituted olefins. Other attributes possessed by this family of molecules include 1,3-anti-diol fragments found at C7/ C9 and C19/C21, along with an accompanying 1,3-syn-diol at C9/C11 and polypropionate fragments at C1/C4 and C22/23. The endgame strategy for ring closure was envisioned to hinge on a key ring-closing metathesis (RCM) of the C14/C15-trisubstitued olefin following a precedent set by Leighton and co-workers. 4 Preceding this macrocyclization is a simple esterification connecting the C1 carboxylic acid and C23 alcohol, thus coupling the C1-C14 (2) and C15-C30 (3) subunits of dolabelide. The stereochemical complexity and known biological activity of the dolabelide family present a worthy and formidable challenge. In this regard, we herein report the use of a multifaceted phosphate tether toward the synthesis of the C1-C14 subunit of dolabelide. The cornerstone for the title work hinged on recent studies, countering historical views, which have revealed a functionally active phosphate triester tether 5 within the P-chiral bicyclic phosphate 5 (Scheme 1). 6 These studies also revealed selective cleavage pathways operative through displacement reactions at carbon (S N 2, S N 2′) and phosphorus, ultimately affording multipositional activation, which extends throughout the bicyclic framework. Overall, rapid access to advanced polyol synthons was attained, thus providing impetus for this study. 5 Retrosynthetic analysis shows that assembly of the C1-C14 (2) portion can be achieved via a Grignard addition into the C11 aldehyde, which is accessed by regioselective hydride opening phanson@ku.edu.
doi:10.1021/ol7025944 pmid:18062695 pmcid:PMC2640944 fatcat:2aaqbc4465dy7pmwc7e7f7fzym