corresponding chiral alcohols with excellent enantioselec-
tivities. In these reactions, a strong base such as KOtBu is
required for activating the catalysts. Because KOtBu isalso
a good promoter for the oxa-Michael cyclization,8eꢀk we
envisioned the asymmetric hydrogenation of arylketones 1
bearing an R,β-unsaturated ester group catalyzed by the
Ir-SpiroPAP catalyst (4)10c,d or RuCl2-(SDPs)(DPEN)
(5)11 to generate chiral hydroxy enoates 2, which would
undergo an oxa-Michael cyclization to afford chiral 2,6-
cis-disubstituted tetrahydropyrans 3 in a one-pot process
(Scheme 1). In this communication, we report our initial
studies on the development of a tandem process involving
asymmetric ketone hydrogenation and base-promoted
oxa-Michael cyclization to produce chiral 2,6-cis-disubsti-
tuted tetrahydropyrans in high yields with excellent en-
antioselectivities (up to 99.9% ee) and cis-selectivities (cis/
trans ratios up to 99:1). This highly efficient one-pot
process was used for the enantioselective total synthesis
of (ꢀ)-centrolobine.
Figure 1. Selected bioactive natural products containing one or
more chiral cis-2,6-disubstituted tetrahydropyran units.
Over the past decades, considerable effort has been
devoted to the development of efficient methods for con-
structing chiral 2,6-cis-disubstituted tetrahydropyran units
for the synthesis of natural products containing a tetra-
hydropyran motif.6 The intramolecular oxa-Michael addi-
tion, also referred to as oxa-Michael cyclization, is one
such method.7 However, most reported syntheses of opti-
cally pure 2,6-cis-disubstituted tetrahydropyrans using this
method required preinstalled chiral centers on the oxy-
anion groups.8 Although the transition-metal-catalyzed
asymmetric hydrogenation of ketones is a highly efficient
and straightforward method for the preparation of chiral
alcohols,9 the enantioselective synthesis of chiral 2,6-cis-
disubstituted tetrahydropyrans via consecutive asym-
metric ketone hydrogenation and oxa-Michael cyclization
has not been reported in the literature, to the best of our
knowledge.
Scheme 1. Tandem Process for the Construction of Chiral
2,6-cis-Disubstituted Tetrahydropyrans
Recently, we found that chiral iridium10 and ruthenium
complexes11 bearing a chiral spiro ligand efficiently cata-
lyze the hydrogenation of a wide range of ketones to the
Acrylate-containing arylketones 1 were easily prepared
from δ-valerolactone in three steps, including a Hornerꢀ
WadsworthꢀEmmons reaction,12 in good to high yields
(see Supporting Information). We then used (E)-ethyl
7-(4-methoxyl)-7-oxohept-2-enoate (1a) as a substrate to
optimize the conditions for the hydrogenation/cyclization
reaction (Table 1). When the reaction was performed with
iridium catalyst (R)-4 in EtOH under 10 atm of H2 at room
temperature for 4 h in the presence of KOtBu, the desired
2,6-disubstituted tetrahydropyran 3a (ethyl ester) was
obtained in good yield (85%) and excellent enantioselec-
tivity (95% ee) with high cis-selectivity (cis/trans = 96:4,
entry 1),13 albeit accompanied by an approximately
8% yield of the undesired overhydrogenated product ethyl
7-hydroxy-7-(4-methoxyphenyl)-heptanoate. When RuCl2-
(SDPs)(DPEN) ((Sa,RR)-5a) was used as the catalyst
(7) For a recent review on oxa-Michael reactions, see: Nising, C. F.;
€
Brase, S. Chem. Soc. Rev. 2008, 37, 1218.
(8) For selected recent papers including creation of chiral cis-2,6-
tetrahydropyrans via oxa-Michael cyclization, see: (a) Kanematsu, M.;
Yoshida, M.; Shishido, K. Angew. Chem., Int. Ed. 2011, 50, 2618. (b)
Fuwa, H.; Noto, K.; Sasaki, M. Org. Lett. 2011, 13, 1820. (c) Park, H.;
Kim, H.; Hong, J. Org. Lett. 2011, 13, 3742. (d) Kanematsu, M.;
Yoshida, M.; Shishido, K. Tetrahedron Lett. 2011, 52, 1372. (e) Sabitha,
G.; Reddy, S. S. S.; Yadav, J. S. Tetrahedron Lett. 2011, 52, 2407. (f)
Fuwa, H.; Saito, A.; Sasaki, M. Angew. Chem., Int. Ed. 2010, 49, 3041.
(g) Fuwa, H.; Yamaguchi, H.; Sasaki, M. Org. Lett. 2010, 12, 1848. (h)
Hiebel, M.-A.; Pelotier, B.; Piva, O. Tetrahedron Lett. 2010, 51, 5091. (i)
Dong, C.-G.; Henderson, J. A.; Kaburagi, Y.; Sasaki, T.; Kim, D.-S.;
Kim, J. T.; Urabe, D.; Guo, H.; Kishi, Y. J. Am. Chem. Soc. 2009, 131,
ꢀ
15642. (j) Ferrie, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.; Reymond,
S.; Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864. (k) Takahashi,
S.; Hongo, Y.; Tsukagoshi, Y.; Koshino, H. Org. Lett. 2008, 10, 4223.
(9) Ohkuma, T.; Noyori, R. In Handbook of Homogeneous Hydro-
genation, Vol. 3; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH:
Weinheim, 2007; p 1105.
(10) (a) Xie, J.-B.; Xie, J.-H.; Liu, X.-Y.; Kong, W.-L.; Li, S.; Zhou,
Q.-L. J. Am. Chem. Soc. 2010, 132, 4538. (b) Xie, J.-B.; Xie, J.-H.; Liu,
X.-Y.; Zhang, Q.-Q.; Zhou, Q.-L. Chem.;Asian J. 2011, 6, 899. (c) Xie,
J.-H.; Liu, X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem.,
Int. Ed. 2011, 50, 7329. (d) Xie, J.-H.; Liu, X.-Y.; Xie, J.-B.; Yang, X.-H.;
Zhou, Q.-L. Angew. Chem., Int. Ed. 2012, 51, 201.
i
(KOtBu, 50 atm of H2, PrOH, room temperature), 3a
(isopropyl ester) wasobtainedin96%yieldand98%ee(cis/
trans = 96:4, entry 2), and none of the overhydrogenated
(12) (a) Edmunds, A. J. F.; Arnold, G.; Hagmann, L.; Schaffner, R.;
Furlenmerier, H. Bioorg. Med. Chem. Lett. 2000, 10, 1365. (b) Shindo,
M.; Matsumoto, K.; Sato, Y.; Shishido, K. Org. Lett. 2001, 3, 2029.
(13) The cis/trans selectivity of the reaction was very low (ca. 63:37)
when the hydrogenation was completed; however, it increased to 96:4
after removal of the solvent slowly (6ꢀ10 h) in vacuo at room
temperature.
(11) (a) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan, B.-M.;
Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (b) Xie,
J.-H.; Liu, S.; Huo, X.-H.; Cheng, X.; Duan, H.-F.; Fan, B.-M.; Wang,
L.-X.; Zhou, Q.-L. J. Org. Chem. 2005, 70, 2967.
B
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