En route to the total synthesis of (+)-Neopeltolide, we explored Lewis acid-assisted diastereoselective allylation of MOM-protected 3-hydroxylhexanal with β-(2,2-diethoxyethyl)-substituted (allyl)tributylstannane. The hydrated form of scandium triflate was found to be essential for attaining high 1,3-anti-diastereoselectivity (d.r. 94:6), while the use of anhydrous catalyst resulted in a modest diastereocontrol (d.r. 76:24). The preferred 1,3-anti-selectivity in this transformation can be rationalized in the framework of the Reetz chelate model of asymmetric induction. The 1,3-anti-configuration of the product was confirmed by its conversion into the known C7-C16 building block of (+)-Neopeltolide. We also report an improved protocol for the synthesis of β-(2,2-diethoxyethyl)-substituted (allyl)tributylstannane, which can be utilized as a cost-efficient bipolar isoprenoid-type C5-building block in the synthesis of natural compounds.
The
stereodivergent synthesis of cis- and trans-2,6-disubstituted tetrahydropyrans (THPs) via sodium
hexamethyldisilazide-promoted oxa-Michael cyclization of (E)-ζ-hydroxy α,β-unsaturated esters is
presented. The cyclization affords the kinetically favored trans-THPs with high stereoselectivity (dr up to 93:7) at
a low temperature (−78 °C), while the room-temperature
reaction does not produce the thermodynamically preferred cis-THPs as major products and occurs with poor stereocontrol.
The addition of tetramethylethylenediamine (TMEDA) significantly improves
the stereochemical outcome of the room-temperature cyclization and
allows attaining high cis-selectivity (dr up to 99:1).
The remarkable effect of TMEDA indicates that the sodium cation plays
an important role in controlling the stereoselectivity of the thermodynamically
driven process, that is, complexation of the cation with the cyclization
products results in diminished selectivity. DFT calculations support
this conclusion, indicating a greater difference in Gibbs energies
of sodium-free cis- and trans-enolates
compared to the respective sodium chelate complexes. The synthetic
utility of the method has been demonstrated by the formal syntheses
of (+)-Neopeltolide and (−)-Diospongin B and the total synthesis
of (−)-Diospongin A.
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