Journal of the American Chemical Society
Communication
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O−C−N−C dihedral angle of 180°. Furthermore, the catalyzed
DA reaction is predicted to have a lower activation barrier than
the background reaction (Figures S5 and S6). A postulated
reaction pathway is illustrated in Scheme 4. Reaction of acid
chloride 1a with (−)-BTM forms acylammonium salt 6 that
undergoes endo-selective intermolecular DA with diene 2b to
form an initial, catalyst-bound cycloadduct 7. The presumed
tetrahedral intermediate 8 then enters a shuttle deprotonation
cycle in which catalytic 2,6-lutidine relays its proton to
stoichiometric K3PO4 and undergoes intramolecular lactoniza-
tion to form 3e and regenerate the catalyst.
In summary, we have unveiled a new and versatile family of
chiral dienophiles, α,β-unsaturated acylammonium salts, that
undergo enantioselective and stereodivergent DAL organo-
cascades rapidly generating complex and stereochemically
diverse scaffolds. This scalable process proceeds under mild
conditions, provides excellent relative and absolute stereo-
control, and utilizes readily prepared dienes, commodity acid
chlorides, and commercially available organocatalysts. A
prominent feature of the described methodology is the use of
a DA reaction to initiate an organocascade; a strategy with
limited precedent.18 The utility of the DAL was demonstrated
by conversion of the derived bicyclic lactones to several core
structures of natural products constituting formal syntheses in
some cases. Computational results suggest kinetic preference
for an endo TS with enantiocontrol ascribed to stereoelectronic
and conformational preferences of the acylammonium salt
dienophiles. Further applications and mechanistic investigations
are underway to delineate the scope of this methodology.
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ASSOCIATED CONTENT
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S
* Supporting Information
Experimental and characterization details for all new com-
pounds, computational data, crystallographic data, HPLC
traces, and NMR spectra. This material is available free of
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AUTHOR INFORMATION
■
Corresponding Author
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from NSF (CHE-1112397 to D.R.; CHE-030089 with
XSEDE to D.J.T.) and the Robert A. Welch Foundation (A-
1280 to D.R.), ACS PRF (52801-ND4 to D.J.T.), and partial
support from NIH (GM 052964 to D.R.) and the U.S.
Department of Education (GAANN Fellowship to B.M.H), is
gratefully acknowledged. Drs. Nattamai Bhuvanesh and Joe
Reibenspies (Center for X-ray Analysis, TAMU) secured
structural data, and Dr. Bill Russell (Laboratory for Biological
Mass Spectrometry, TAMU) provided mass data.
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