.
Angewandte
Communications
Experimental Section
A solution of a ligand 4h (0.03 mmol, 10 mol%) and (CuOTf)2·PhMe
complex (0.03 mmol, 10 mol%) in dry chloroform (3 mL) was stirred
at 08C for 30 min under a nitrogen atmosphere. An aldehyde
(0.3 mmol) and an aromatic amine (0.3 mmol) were added, and the
resulting mixture was stirred for an additional 15 min. An alkyne
(0.45 mmol) was then added at the same temperature, and the
reaction mixture was allowed to warm to 258C. After completion of
the reaction (monitored by TLC), the mixture was concentrated in
vacuo and purified over silica gel by column chromatography (15–
40% EtOAc in hexane) to afford products in up to 98% yield with up
to > 99% ee.
Scheme 7. Synthetic elaboration to enantiomerically enriched THIQs.
The absolute configuration of the products was unambig-
uously assigned as “S” on the basis of the X-ray crystal
structures of compounds 5y (CCDC 1000307) and 8a
(CCDC 1000308; see the Supporting Information).
Received: May 7, 2014
Revised: July 23, 2014
Published online: && &&, &&&&
Finally, the usefulness of this process was highlighted by
partial hydrogenation of the triple-bond functionality of 5c
(97% ee) to give 10, which underwent reductive ozonolysis to
afford the hydroxymethyl derivative 11 with 93% ee. Com-
pound 11 could serve as an advanced intermediate for the
synthesis of 1a–c. Furthermore, complete hydrogenation of
5o followed by oxidative cleavage of the N-PMP group[28] in
the presence of CAN afforded enantiomerically enriched 12
in 85% yield over two steps (Scheme 8).
Keywords: alkynylation · domino reactions · isoindolinones ·
synthetic methods · tetrahydroisoquinolines
.
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Scheme 8. Synthetic elaboration to important intermediates. CAN=ceric
ammonium nitrate, EA=ethyl acetate.
In conclusion, we have reported the first highly enantio-
selective one-pot alkynylation/lactamization cascade as a new
entry to a wide range of isoindolinones. The operational
simplicity of the method and its amenability to gram-scale
synthesis, as well as the straightforward access it provides to
enantiomerically enriched isoindolinones with unprecedented
levels of enantioselectivity (up to > 99% ee) under additive-
free conditions, makes our strategy highly viable. Further-
more, its application is illustrated in the synthesis of optically
pure THIQs (up to 94% ee) in a two-step procedure. The
usefulness of the methodology has also been demonstrated by
cleavage of the N-PMP group and by exploiting the reactivity
of the triple bond. This concise and flexible synthetic route
offers ample opportunity for its application in the synthesis of
complex natural products, which is currently being pursued in
our laboratory.
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therein.
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4
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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