The Leading Question

 

 

 

The first step of the reaction involves a Lewis acid-base complexation reaction between the oxygen atom of the carbonyl group and the magnesium dication. The electrophilic oxygen atom that results is what initiates the opening of the strained cyclopropane ring. This reaction produces a planar resonance-stabilized carbocation intermediate. A double bond forms between the carbon atom that was bonded to the cyclopropane ring and the carbonyl carbon atom to form an enolate-type structure, with the magnesium atom coordinating with an oxygen atom that now has negative character. An ambient nucleophile, the enolate selectively undergoes reaction with imine 27 at the carbon atom instead of the oxygen atom, which is less nucleophilic than a carbanion.

All of the reaction sites in this concerted enolate-initiated reaction are planar sp2 carbon atoms, whether they are sigma bonds or the carbocation that formed from the previous step. Thus, the electrophile can approach from either face of the enolate, yielding a racemic mixture. The reaction mechanism above shows one possibility, the approach of the imine from above the enolate.

The reaction is a concerted cyclization in which the stereochemistry of all formed stereocenters is determined in one step, with the enolate attacking the electrophilic carbon atom of the carbon-nitrogen double bond. This compound has a resonance contributor in which the carbon atom is cationic, so it is similar in electrophilicity to a carbonyl compound. The double bond attacks back at the carbocation to complete the ring.
When the imine approaches from above the enolate, the nitrogen atom ends up above the carbocation and thus on a wedge in the drawing. Additionally, the carbon of the imine that is bonded to the phenyl group must also be above the plane, since the attack here is from the nucleophile, which is below the plane, up to the electrophile. With this substituent up, the methylene group already bonded to the enolate is pushed down to create a spirocyclic ring system.

The stereo- and regio-selectivity of this reaction is rationalized by the favorability of secondary pi orbital overlap of the phenyl group of the imine with the pi system bonded to the enolate structure. If the nitrogen atom is on the right side of the new ring, then the phenyl group is on the left in the attack so that it is placed over the _ system of the enolate. The imine must then turn clockwise to close the ring at the carbocation, causing the phenyl group to be pushed up.

According to M.P. Doyle et al, the stereoselection observed in alpha-diazocarbonyl cyclopropanations (the transformation from 25 to 26) results in the carbonyl group being trans to any “R” group on the alkene (in our case, the R group is the (E)-2-propenyl group)7. The stereoselection in this step influences the stereoselectivity of the above transformation by determining the orientation of the (E)-2-propenyl group, which in turn determines the orientations of the substituents in expanded ring structure 28.

The rhodium catalyst, a sterically large Lewis acid due to the 4 acetyl ligands, complexes with the diazo group in a _ complexation, which influences the direction of attack of the alkene due to its steric bulk. The alkene is forced to rotate so that the less substituted double bond, and thus the less sterically hindered side of the alkene approaches the complex. Thus, the rhodium catalyst imposes stereochemical limitations on the reaction. Rhodium (II) catalysts have been shown to be most effective for cyclopropanation reactions.
Approach of the imine from below the plane of the enolate gives opposite configurations at all stereocenters formed, forming the enantiomer of the compound that resulted from approach from the top. The result in either case is a spirocyclic ring that is used in latter parts of the synthesis of (-)-spirotryprostatin B.