Tandem Cycloaddition Chemistry of Nitroalkenes
An enduring challenge central to the mission of organic synthesis
remains: the rapid, efficient and selective construction of
complex molecules from simple components. Driven by the ever
increasing demands of synthetic efficiency, structural complexity
and stereochemical control, the invention of new reactions
and reaction strategies continues to define a frontier in organic
chemistry. From a strategic point of view, one of the most
powerful approaches for the rapid increase in molecular complexity
is the employment of sequential transformations.
The tandem [4+2]/[3+2] cycloaddition of nitroalkenes is unique
among the known tandem cycloadditions in that the intermediate
nitronate is the most reactive partner in either cycloaddition,
thus facilitating the use of simple, stable components as the
dienophiles and dipolarophiles and substituted nitroalkenes.
The modular nature of this reaction strategy imparts a great
versatility in addressing synthesis targets since major structural
and stereochemical changes in the target can be accommodated
by modification of just one reaction component. Finally, the
electronic complementarity of the two cycloaddition reactions
has permitted the extensive development of intramolecular variants
without problems of compatibility of reactants.
The spectacular structural diversity that results from the
manifold permutations of this tandem sequence can be
appreciated by color coding the three key components: (1) nitroalkene (2) dienophile and
(3) dipolarophile. The sequence involves three common
events; first, the Lewis acid activation of a [4+2] cycloaddition
of the nitroalkene with a dienophile to produce a cyclic
nitronate; second, the nitronate engages in a [3+2] cycloaddition
to construct a nitroso acetal. Thus, three subunits combine
to construct a new six-carbon unit, by assembling four bonds,
up to six contiguous stereocenters and two rings. The third
stage involves the unmasking of the nitroso acetal to reveal
the newly minted skeleton, chain or polycycle, replete with
heteroatoms and stereocenters. All four permutations of inter-
and intramolecularity of the tandem sequence have been documented.
In particular the tandem inter [4+2]/intra [3+2] sequence has
proved particularly general by virtue of the ease of construction
of the precursors and the multitude of tether attachment points.
Over the past decade we have systematically examined and
utilized new representatives of all of the key components of
the cycloaddition: nitroalkene, dienophile, dipolarophile,
Lewis acid and chiral auxiliary and have discovered new, general
methods for the unmasking of the nitroso acetals. These methodoligical
studies have allowed for the enantioselective total syntheses
of australines (e.g. 1-epiaustraline, (+)-casuarine); indolizidines
(e.g.(+)-castanospermine, mesembrine); and made significant
progress toward (+)-melodinus and daphniphylum alkaloids. In
addition, we have developed a general route to the fascinating
class of strained molecules, 1-azafenestranes which test the
limits of the theory of tetrahedral carbon.
Read the most recent review: 117,
Chapter 6
Tandem Inter[4+2] / Intra [3+2] Cycloadditions
Tandem Intra [4+2] / Intra [3+2] Cycloadditions
Azafenestranes
Applications in Total Synthesis of Pyrrolidine-Containing
Natural and Non-Natural Products
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