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Enantioinversion in the Gold(I)-catalyzed Hydroalkoxylation of Allenes: Previously developed chiral phosphoramidite ligands comprising a TADDOL-related acyclic backbone have proven successful in asymmetric gold catalysis. While extending their applicability to the intramolecular hydroalkoxylation, a striking case of enantioinversion was observed: the sense of induction in the cyclization of allenol 1 to tetrahydrofuran 2 can be swapped from (S) to (R) solely by changing either the solvent or the temperature or the escorting counterion, while using the very same chiral gold complex C3. The perplexing phenomenon of enantioinversion, in which a single chiral source delivers either enantiomer of a given product, is not uncommon. However, the understanding of its origins at the molecular level is quite limited. Moreover, the present case seemed particularly remarkable, since it represents the first reported example in which three different parameters are able to trigger a significant switch. Thus, a combined experimental and computational approach was conducted to gain insight into the underlying mechanism. Preparative studies including thorough screenings, Eyring plots and NMR experiments in combination with DFT calculations provided a plausible mechanistic scenario. The major reason for the enantioinversion was found in the existence of two competing pathways: a pathway where proto-deauration is rate-determining favors the (S)-product, whereas an alternative outlet involving assisted proto-deauration preferably produces the (R)-product; such assistance can be provided either by a protic solvent, a coordinating counterion or a second substrate molecule. Consequently, the reaction free energy profile gains a significant entropic component that can ultimately dictate the stereochemical course.
This case study represents the first example, which explains the unusual effect of enantioinversion at the molecular level. The results highlight the importance of considering the entropy in the analysis of a multi-step reaction mechanism.
Studies Toward the Total Synthesis of Chagosensine: The selective and consecutive functionalization of alkynes was investigated in the context of a challenging total synthesis program. The marine polyketide chagosensine, isolated in 2003 from the Red Sea calcareous sponge Leucetta chagosensis in Israel, was deemed an ideal target for the application of a sequence of ring closing alkyne metathesis (RCAM), trans-hydrostannylation and tin/chloride exchange to install the unique (Z,Z)-chlorodiene motif within a highly decorated macrocycle. An additional obstacle to this endeavor was posed by the unsecured structure assignment of the natural product, whose synthesis had not been tackled before. After the successful preparation of the required building blocks, the original endgame strategy was studied. However, RCAM could not be achieved, presumably due to the highly strained enyne macrocycle. Attempted ring closing diene-ene metathesis to circumvent such macrocyclic enynes did not succeed either. An alternative strategy based on the construction of an acyclic enyne was hampered by inefficient Sonogashira cross coupling and unfeasible hydrometalations.
Despite enormous efforts and catalyst development, conventional approaches such as RCAM, RCM and cross coupling strategies failed in this complex environment with an exceptionally high density of potentially coordinating functional groups. A remedy was found in the functionalization of the alkyne prior to fragment assembly: the intricate chlorodiene-containing macrolactone was finally accessed by bis-metalation of the northern domain followed by selective Stille coupling with the southern sector and subsequent macrolactonization. Thus, the synthesis of the sophisticated intermediate by this forth route sets the stage for the completion of the first total synthesis of chagosensine.
