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ta, K.; Ishikawa, H.; Tanaka, A.; Miyazaki, M.; Kanemitsu, T.; Itoh,
T. Heterocycles 2010, 81, 1791–1798.
Conclusion
In conclusion, we have developed a primary aminothioureaꢀ
catalyzed formal azaꢀDiels–Alder reaction of enones and cyꢀ
clic imines for the enantioselective synthesis of a variety of
stereochemically complex indoloꢀ and benzoquinolizidine
building blocks. The hydrogen bond donor and primary amine
are essential functional components of the optimal catalyst,
allowing for dual activation of the reaction components. The
application of this catalyst to the synthesis of alkaloid natural
products is the subject of ongoing research and will be pubꢀ
lished in due course.
(6) Proline catalysis of the reaction of imine 2a with three different
enones has been reported (ref. 5). High catalyst loadings (30ꢀ50
mol%) and large excess of enone (30 equiv relative to imine in two of
the reported examples) were required to achieve acceptable yields of
cyclization product.
(7) For organocatalytic cycloaddition reactions of enones to acyclic
imines, see: (a) Sundén, H.; Ibrahem, I.; Eriksson, L.; Córdova, A.
Angew. Chem., Int. Ed. 2005, 44, 4877–4880. (b) Rueping, M.; Azap,
C. Angew. Chem., Int. Ed. 2006, 45, 7832–7835. (c) Liu, H.; Cun, L.ꢀ
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(11) 2a was obtained from tryptamine in 75% overall yield over
three steps. See Supporting Information.
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ASSOCIATED CONTENT
Supporting Information. Catalyst optimization studies, complete
experimental procedures and characterization data for substrates
and FADA products, ee and dr determination, and crystallographꢀ
ic data for compounds 4ae and 5ae. This material is available free
AUTHOR INFORMATION
Corresponding Author
ACKNOWLEDGMENT
This work was supported by the NIGMS (GMꢀ43214 and P50
GMꢀ69721) and by predoctoral fellowship support to M.P.L. from
NSERC and La Fondation Baxter et Alma Ricard, to M.A.M from
Eli Lilly, and to N.S.R from Boehringer Ingelheim.
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(12) See Supporting Information for an expanded description of the
catalyst and reaction optimization studies.
(13) This type of anionꢀbinding catalysis has been invoked in other
thioureaꢀpromoted reactions of imines. See: Klausen, R. S.; Jacobꢀ
sen, E. N. Org. Lett. 2009, 11, 887–890.
(14) The excess enone can be recovered quantitatively from the reꢀ
action mixture. See Supporting Information (Scheme S8) for a prodꢀ
uct inhibition study.
(15) Proline was found to be far inferior as a catalyst for FADA reꢀ
actions involving dihydroisoquinolines. For example, reaction of
imine 6d with enone 3j (entry 4 in Table 3) with 30 mol% proline
4
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