Published on Web 07/01/2010
Enantioselective Organo-SOMO Cascade Cycloadditions: A Rapid Approach
to Molecular Complexity from Simple Aldehydes and Olefins
Nathan T. Jui, Esther C. Y. Lee, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received May 18, 2010; E-mail: dmacmill@princeton.edu
Abstract: A highly selective, radical-mediated (4 + 2) coupling
reaction of aldehydes and conjugated olefins has been achieved
through asymmetric SOMO-catalysis. A radical-polar crossover
mechanism is proposed wherein olefin addition to a transient
enamine radical cation and oxidation of the resulting radical
furnishes a cation which is vulnerable to nucleophilic addition. A
range of aromatic aldehydes are shown to couple with styrenes
and dienes to provide cyclic products with high chemical ef-
ficiency, regioselectivity, and stereoselectivity.
The identification of new transformations that allow the rapid
and selective production of molecular complexity from simple
starting materials remains a preeminent goal for the chemical
sciences. The Diels-Alder reaction1 remains perhaps the archetypal
example (eq 1), a powerful technology that builds stereochemically
dense cyclohexenyl rings from simple dienes and dienophiles in a
routine and predictable fashion. Recently, we questioned whether
the mechanistic elements of SOMO-catalysis (singly occupied
molecular orbital) might be translated into a novel ring-forming
protocol that would exhibit many of the valuable characteristics
found in the Diels-Alder reaction. Herein, we describe the first
SOMO (4 + 2) cascade cycloaddition,2 a transformation that (1)
allows direct and selective access to complex cyclohexyl motifs,
(2) employs simple aldehyde and olefin substrates, (3) is catalyst
levels of enantioinduction should be possible using catalyst 1 on
the basis of 3π-electron geometry control and selective methyl group
shielding of the radical cation Si-face. Furthermore, we presumed
mediated, (4) is operationally trivial, and (5) is highly predictable
with respect to regio-, diastereo-, and enantiocontrol. We expect
that this new, stereoselective approach to carbocycle construction
that the cyclization step should be stereoselective based on the
will be of significant utility to practitioners of both natural product
kinetic preference for chairlike transition states9 wherein pseudoring
and medicinal agent synthesis.
Design Plan. Within the past three years, our laboratory has
substituents are located in equatorial orientations.
Results. After examining various single-electron oxidants,10 we
introduced a new mode of activation termed SOMO-catalysis that
found that the trisphenanthroline complexes of iron(III) bearing non-
has enabled the first direct enantioselective allylic alkylation,3
nucleophilic counterions (e.g., PF6-, AsF6-, and SbF6-, Table 1)11
enolation,4 vinylation,5 arylation,6 and carbo-oxidation7 of alde-
do indeed promote the desired cyclization reaction between 3-aryl-
hydes, all of which were previously unknown in asymmetric format.
propionaldehydes and styrene (3 equiv) with excellent levels of
enantiocontrol. Furthermore, the diastereoselectivity of the cycliza-
In the latter reaction, we demonstrated that styrenyl olefins readily
couple with transiently generated 3π-electron systems to generate
tion event appears to vary as a function of the oxidant counterion
highly reactive benzylic cations under oxidative conditions that
-
(with the largest counterion, SbF6-, being the most selective). A
possible explanation for this trend is that the stereodetermining
chairlike transition state (4) is more ordered (or later) when the
intermediate carbocation is paired with a more polarizable or
rapidly trap NO3 to afford γ-oxy-homobenzylic aldehydes.
Recently, we hypothesized that this radical-polar crossover
mechanism8 and the putative benzylic cation might provide the
design elements for a novel SOMO-cycloaddition reaction. As
detailed in eq 2, we hoped that exposure of a π-nucleophile-tethered
aldehyde to SOMO-activation using imidazolidinone catalyst 1 and
an oxidant would generate the radical cation 2, which should rapidly
engage an olefinic substrate in an enantioselective alkylation step
to produce the alkyl radical 3. Oxidative radical-polar crossover
would then furnish a carbocation that should trigger a stereoselective
π-nucleophile ring closure to deliver a complex cyclohexyl motif.
In accord with previous SOMO-studies,3-7 we presumed that high
12
-
stabilizing counterion such as SbF6
.
Having developed optimal conditions for this new cascade olefin-
addition/Friedel-Crafts sequence, we next examined the scope of
the aldehydic component. As shown in Table 2, a wide range of
electron-rich benzenes and heteroarenes (indoles, anisoles, catechols,
benzofurans) can function as suitable nucleophilic terminators to
furnish the desired cyclohexyl rings with excellent stereoselectivity
(entries 1-6, 6-20:1 dr, g92% ee). Interestingly, substrates that
9
10.1021/ja104313x 2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 10015–10017 10015