Angewandte
Chemie
DOI: 10.1002/anie.200902328
Synthetic Methods
Enantioselective Allylation, Crotylation, and Reverse Prenylation of
À
Substituted Isatins: Iridium-Catalyzed C C Bond-Forming Transfer
Hydrogenation**
Junji Itoh, Soo Bong Han, and Michael J. Krische*
3-Substituted 3-hydroxy-oxindoles appear as substructures
within a fascinating array of natural products, including the
convulutamydines,[1a,b] maremycins,[1c,d] donaxaridines,[1e,f]
dioxibrassinins,[1g,h,i] celogentin K,[1j] hydroxyglucoisatisins,[1k]
and TMC-95A-D (Figure 1).[1l] Whereas catalytic asymmetric
account, we report that activated ketones in the form of
substituted isatins are subject to highly enantioselective
carbonyl allylation, crotylation, and reverse prenylation,
constituting a convenient synthesis of optically enriched 3-
substituted 3-hydroxy-oxindoles.
Our initial studies focused on the allylation of N-benzyl
isatin (1a). Using the cyclometalated C,O-benzoate gener-
ated in situ from [{Ir(cod)Cl}2], biphep (biphep = 2,2’-bis(di-
phenylphosphino)biphenyl), and 4-chloro-3-nitrobenzoic
acid,[14b] the coupling of allyl acetate (1000 mol%) to 1a at
1008C in tetrahydrofuran (0.2m) delivered the tertiary
homoallyl alcohol 2a in 42% yield upon isolation. At lower
loadings of allyl acetate (200 mol%) and with further
optimization of reaction temperature, time, and concentra-
tion, the yield of homoallyl alcohol 2a was increased to 77%.
An assay of chelating chiral phosphine ligands was under-
taken, which revealed dramatic enhancement in the level of
asymmetric induction at lower reaction temperatures. How-
ever, lower temperatures also diminished conversion. This
impasse was resolved by increasing the loading of isopropanol
from 200 mol% to 400 mol%, which enabled conversion of
N-benzyl isatin (1a) to the homoallyl alcohol 2a in 73% yield
and 91% enantiomeric excess using cth-(R)-p-phos (cth-(R)-
p-phos = (R)-(+ )-2,2’,6,6’-tetramethoxy-4,4’-bis(diphenyl-
phosphino)-3,3’-bipyridine) as the ligand. Notably, under
analogous reaction conditions employing our initially dis-
closed iridium catalyst modified by 3-nitrobenzoic acid,[14a,b]
2a was obtained in 61% yield and 90% enantiomeric excess.
These data further illustrate how catalyst performance is
enhanced through structural variation of the C,O-benzoate
moiety. Data pertaining to the optimization of the catalytic
enantioselective allylation of N-benzyl isatin (1a) is tabulated
in the Supporting Information.
Optimal reaction conditions identified for the conversion
of N-benzyl isatin (1a) to the hydroxy oxindole 2a were
applied to substituted isatins 1a–1g (Table 1). To our delight,
the products of ketone allylation, 2a–2g, were produced in
moderate to excellent yields upon isolation (65–92%) with
uniformly high levels of optical enrichment (91–96% ee). The
absolute stereochemical assignments of the adducts 2a–2g
are based upon that determined for the 5-bromo derivative 2b
by single-crystal X-ray diffraction analysis using the anom-
alous dispersion method.
Given these favorable results, the crotylation of substi-
tuted isatins 1a–1g was attempted under identical conditions
employing a-methyl allyl acetate as the crotyl donor
(Table 2). The products of ketone crotylation, 3a–3g, were
produced in moderate to excellent yields upon isolation (64–
Figure 1. Examples of naturally occurring 3-substituted 3-hydroxy-oxin-
doles.
additions to isatins are known,[2–6] highly enantioselective
catalytic allylation, crotylation, and reverse prenylation of
isatins have remained elusive. In the course of developing
À
hydrogen-mediated C C couplings beyond hydroformyla-
tion,[7–15] chiral ortho-cyclometalated iridium C,O-benzoates
were found to catalyze highly enantioselective carbonyl
allylation,[14a,b] crotylation,[14c] and reverse prenylation[12d]
under transfer-hydrogenation conditions. In contrast to clas-
sical allylation procedures which employ stoichiometric
organometallic reagents,[16] transfer-hydrogenation protocols
exploit allyl acetate, a-methyl allyl acetate, and 1,1-dimethyl-
allene as precursors to transient allyl–, crotyl–, and prenyl–
metal intermediates, respectively.[12,14a–c] To further evaluate
the scope of this emergent methodology, catalytic enantiose-
lective additions to ketones were explored.[17,18] In this
[*] Dr. J. Itoh, S. B. Han, Prof. M. J. Krische
University of Texas at Austin
Department of Chemistry and Biochemistry
1 University Station-A5300, Austin, TX 78712-1167 (USA)
Fax: (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
[**] Acknowledgements are made to Merck, the Robert A. Welch
Foundation, the American Chemical Society Green Chemistry
Institute Pharmaceutical Roundtable, and the NIH (RO1-
GM069445) for partial support of this research. Dr. Oliver Briel of
Umicore is thanked for the generous donation of [{Ir(cod)Cl}2].
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 6313 –6316
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6313