Diastereoselection in the Formation of Spirocyclic Oxindoles by the Intramolecular Heck Reaction

Diastereoselective double Heck cyclizations of cyclohexene diamides 1 and 3 form contiguous quaternary
stereocenters, with diastereoselection being controlled by the trans-diol protecting group. In this, the
first in a series of two papers, the origin of diastereoselection in the first ring-closure step of these reactions
is examined. Nine simplified analogues of 1 and 3 were synthesized and cyclized to discern what structural
features are required to realize high diastereoselection in the first intramolecular Heck reaction. These
studies show that high stereoselection (>20:1) does not arise from a single structural feature:  it is seen
only in substrates that contain both a trans-acetonide and a tertiary amide substituent at C2. Two subtle
factors appear to be involved:  (1) Avoidance of eclipsing interactions between the forming C−C bond
and the pseudoaxial hydrogen atom at C6 and between the pseudoequatorial hydrogen atom at C6 and
the carbonyl carbon of the forming spirooxindole. (2) The vinylic amide substituent that is not involved
in the insertion event preferentially adopts a perpendicular conformation, placing the sterically bulky
NR2 over the alkene π bond. syn-Pentane-like interactions between this substituent and the C3 of the
cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce
a highly diastereoselective process.