Total synthesis of (±)-acetoxyodontoschismenol using zirconium chemistry

Abstract

The dolabellane diterpene (+/-)-acetoxyodontoschismenol has been synthesised for the first time by a short route in which a three component coupling on zirconium is used to assemble all the carbons needed for the skeleton in onepot.

Tandem Insertion of Halocarbenoids and Lithium Acetylides into Zirconacycles: A Novel Rearrangement to Zirconium Alkenylidenates by β‐Addition to an Alkynyl Zirconocene

“…The carbenoid insertion occurred very poorly and was followed by b-hydride elimination to provide an inseparable mixture of the E and Z isomers (3:1 by 13 C NMR spectroscopy) of 73 in very low yield (Scheme 13). The main product (77 %) was the protonated zirconacycle 74.…”

“…[32] Insertion of lithiated 1,1-dibromoheptane followed by lithium phenylacetylide gave compound 83 as an inseparable mixture of cis:trans ring junction isomers in the ratio of 2:1 and 53 % combined yield. The stereochemistry of cis-83 followed from the symmetry demonstrated by 13 C NMR spectroscopy, the number of signals for the core carbons being halved. Only one cis isomer was isolated, assumed to be the exo-addition product shown.…”

“…[31] Subsequent addition of lithiated 1,1-dibromoheptane and lithium phenylacetylide gave the required compounds cis-77 c and cis-77 d in 35 % and 14 % yield, respectively, and contained 3 % and 6 %, respectively, of the other isomer at the carbenoid derived quaternary centre (determined by 13 C NMR analysis). It is thought, but has not been proven, that the major isomer is the exo-addition product, the additional bulk on the exo face (c.f.…”

“…Mechanistically we would expect the addition to bis(alkynyl zirconocene) to occur on the exo face of the cis-bicycle to give exo-cis-77, but we have not proven this to be the major isomer. The ring junction stereochemistry of 77 a and b was determined on the basis of 13 C NMR analysis, the cis isomer showing degeneracy due to symmetry.…”

“…[10] Since then a wide variety of carbenoids have been used, [11] the regiochemistry of insertion into unsymmetric zirconacycles studied, [12] and the chemistry applied to natural product synthesis. [13] A reasonable mechanism for the carbenoid insertion is by initial donation of an electron pair to the 16-electron zirconium center to form an 18-electron zirconate complex 2 followed by a 1,2-metallate rearrangement [14] to give ring-expanded zirconacycle 3. A special case of carbenoid insertion into zirconacycles is that of 1-lithio-1,1-dihalo species, in which the zirconacycle ring expansion is followed by a ring closure with loss of a second halide (Scheme 2).…”