Chirality transfer in Au-catalyzed cyclization reactions of monoallylic diols: Selective access to specific enantiomers based on olefin geometry

Article abstract of DOI:10.1021/ol200203k

The gold(I)-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is shown to be highly stereoselective when chiral allylic alcohols are employed. Substrates that differ only in olefin geometry provide enantiomeric products from formal S_N2′ reactions in high yields with excellent chirality transfer. The allylic alcohol stereochemistry also efficiently controls the facial selectivity when the substrates include additional stereocenters.

Full text of DOI:10.1021/ol200203k

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1330–1333
Chirality Transfer in Au-Catalyzed
Cyclization Reactions of Monoallylic
Diols: Selective Access to Specific
Enantiomers Based on Olefin Geometry
Aaron Aponick* and Berenger Biannic
Department of Chemistry, University of Florida, Gainesville, Florida 32611,
United States
aponick@chem.ufl.edu
Received January 22, 2011
ABSTRACT
The gold(I)-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is shown to be highly stereoselective when chiral allylic alcohols
are employed. Substrates that differ only in olefin geometry provide enantiomeric products from formal SN20 reactions in high yields with excellent
chirality transfer. The allylic alcohol stereochemistry also efficiently controls the facial selectivity when the substrates include additional
stereocenters.
The area of homogeneous gold catalysis continues to
progress at an extremely rapid pace with many new and
interesting advancements appearing almost daily.1 These
transformations rely on the ability of gold complexes to
activate π-bonds leading to the development of new
catalysts and selective new reactions of alkynes, allenes,
and alkenes through inspired substrate design. While
reactions of alkynes and allenes are the most prevalent
and occur under mild conditions, reactions of alkenes
typically require more forcing conditions2 and Au-cata-
lyzed reactions of this substrate class are far less
developed.3 Although the addition of heteroatoms to
prochiral olefins with a variety of nucleophiles has been
reported,4 currently Au-catalyzed alkene addition5 reac-
tions that proceed with discrimination of heterotopic
(1) For recent reviews on Au-catalysis, see: (a) Hashmi, A. S. K.;
Buhrle, M. Aldrichimica Acta 2010, 43, 27. (b) Hashmi, A. S. K. Angew.
Chem., Int. Ed. 2010, 49, 5232. (c) Shapiro, N. D.; Toste, F. D. Synlett
2010, 675. (d) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. Rev. 2008, 37,
1766. (e) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (f)
Arcadi, A. Chem. Rev. 2008, 108, 3366. (g) Gorin, D. J.; Sherry, B. D.;
Toste, F. D. Chem. Rev. 2008, 108, 3351. (h) Muzart, J. Tetrahedron
2008, 64, 5815. (i) Shen, H. C. Tetrahedron 2008, 64, 3885.
(4) For leading references, see: (a) Zhang, J. L.; Yang, C. G.; He, C. J.
J. Am. Chem. Soc. 2006, 128, 1798. (b) Liu, X. Y.; Li, C. H.; Che, C. M.
Org. Lett. 2006, 8, 2707. (c) Shi, M.; Liu, L. P.; Tang, J. Org. Lett. 2006,
8, 4043. (d) Han, X. Q.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006,
45, 1747. (e) Yang, C. G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966. (f)
Hashmi, A. S. K.; Schwarz, L.; Choi, J. H.; Frost, T. M. Angew. Chem.,
Int. Ed. 2000, 39, 2285. (g) Yao, X. Q.; Li, C. J. J. Am. Chem. Soc. 2004,
126, 6884. (h) Zhou, C.-Y.; Che, C.-M. J. Am. Chem. Soc. 2007, 129,
(2) In comparison to reactions of alkynes and allenes, elevated
temperatures and prolonged reaction times are typically required for
alkenes. For representative examples see refs 1 and 4.
~
5828. (i) Iglesias, A.; Muniz, K. Chem.;Eur. J. 2009, 15, 10563. (j)
Zhang, G.; Cui, L.; Wang, Y.; Zhang, L. J. Am. Chem. Soc. 2010, 132,
1474. (k) Melhado, A. D.; Brenzovich, W. E.; Lackner, A. D.; Toste,
F. D. J. Am. Chem. Soc. 2010, 132, 8885.
(5) For examples of selective addition to norbornene, see refs 4a, 4b,
4g, 4e. For diastereoselective reactions, see: (a) Bender, C. F.; Wide-
nhoefer, R. A. Org. Lett. 2006, 8, 5303. (b) Bender, C. F.; Widenhoefer,
R. A. Chem. Commun. 2006, 4143. (c) Li, H.; Widenhoefer, R. A. Org.
Lett. 2009, 11, 2671.
(3) Au-catalyzed cycloisomerization reactions of enynes have been
extensively reported, but the catalyst activates the alkyne component in
these substrates. For leading references, see: Jimenez-Nunez, E.; Echa-
varren, A. M. Chem. Rev. 2008, 108, 3326. Additionally, selective
addition to enantiotopic alkynes has been explored: (a) Hashmi,
A. S. K.; Hamzic, M.; Rominger, F.; Bats, J. W. Chem.;Eur. J. 2009,
15, 13318. (b) Wilckens, K.; Uhlemann, M.; Czekelius, C. Chem.;Eur.
J. 2009, 15, 13323.
r
10.1021/ol200203k
Published on Web 02/11/2011
2011 American Chemical Society

π-faces to selectively prepare chiral products have seldom
been reported. This is likely due in part to the propensity
of Au-complexes to catalyze anti-addition reactions
across π-bonds placing the ligands in a fairly distal
position from the newly formed stereocenter. Herein we
report a highly selective Au(I) catalyzed reaction of
alkenes where the absolute configuration of the product
is controlled by the olefin geometry of the substrate.
Substitution reactions of allylic alcohols (inter- and
intramolecular) have been reported using a variety of
other metal-based catalyst systems including palladium,8
platinum,9 rhodium,10 ruthenium,11 iron,12 and bis-
muth.13 For chirality transfer to be successful, a highly
organized transition state is necessary. Several mechan-
istic scenarios have been suggested including formation of
a stabilized allyl cation (Fe3þ, Bi3þ), π-allyl metal com-
plex formation (Pd0, Pt0, Rh1þ, Ru2þ), and a syn SN20
pathway (Pd2þ).8-13 Enantioselective reactions of π-allyl
metal complexes are well-known, and Uenishi has re-
ported very nice examples of chirality transfer under
Pd(II)-catalysis.8e-h In his examples, Pd(II) is proposed
to be complexed to both the olefin and alcohol of the
allylic alcohol as well as the incoming nucleophile. In
contrast to the ability of Pd(II) to form a highly coordi-
nated catalyst-substrate complex, Au(I) complexes are
known to coordinate to two ligands and prefer a linear
geometry.1 We were interested in determining if the
stereochemistry of the allylic alcohol could be transferred
to the product upon cyclization of chiral substrates even
though a linear alkene/Au(I) complex with more degrees
of freedom would be formed. Additionally, the low
loadings and functional group tolerance should allow
for a wide variety of products to selectively be formed
by changing either the olefin geometry or the absolute
configuration of the allylic alcohol.
To test this premise, monoallylic diols with the same
absolute configuration but differing in olefin geometry
were prepared by selective reduction of a common pro-
pargylic alcohol14 to both the cis- and trans-olefins.15 The
simple substrates 5 and 7 were prepared and subjected to
the reaction conditions (Table 1, entries 1 and 2). To our
delight, the tetrahydropyran 6 was isolated in high yield
with both substrates. Interestingly, the products of the
two reactions were enantiomers with only a small loss of
ee observed in the cyclization event. The scope of the
reaction was then explored and found to be fairly general,
also smoothly producing enantiomeric methylene tetra-
hydropyrans and morpholines (entries 3-6) with
Figure 1. Chirality transfer.
Recent reports from our laboratory and others have
demonstrated that heteroatom nucleophiles readily add
to the π-bond of unsaturated alcohols in Au-catalyzed
processes.6 In our systems, the reactions proceed with
concomitant loss of water and constitute a formal SN20
reaction to form substituted tetrahydropyrans.6a,b The
reaction generates a new chiral center, and due to the
ubiquity of the tetrahydropyran moiety in natural pro-
ducts,7 we were interested in exploring methods to control
the stereochemistry at the newly formed stereogenic
center. We envisioned that chirality could be transferred
from the allylic alcohol carbon to the newly formed center
and in the course of the reaction erase the stereocenter
that guided its formation (Figure 1). This process would
be advantageous because it should be possible to selec-
tively obtain either tetrahydropyran enantiomer by con-
trolling the olefin geometry, and highly functionalized
chiral allylic alcohols are readily prepared by a variety of
reliable methods.
(6) (a) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669. (b)
Aponick, A.; Biannic, B. Synthesis 2008, 3356. (c) Aponick, A.; Li, C.-
Y.; Palmes, J. A. Org. Lett. 2009, 11, 121. (d) Aponick, A.; Li, C.-Y.;
Malinge, J.; Marques, E. F. Org. Lett. 2009, 11, 4624. (e) Mukherjee, P.;
Widenhoefer, R. A. Org. Lett. 2010, 12, 1184. (f) Bandini, M.; Eichhol-
zer, A. Angew. Chem., Int. Ed. 2009, 48, 9533. (g) Lu, Y.; Fu, X.; Chen,
H.; Du, X.; Jia, X.; Liu, Y. Adv. Synth. Catal. 2009, 351, 129. (h) Shu
X.-Z.; Liu, X.-Y.; Xiao, H.-Q.; Ji, K.-Q.; Guo, L.-N.; Liang, Y.-M. Adv.
Synth. Catal. 2008, 350, 243. (i) Guo, S.; Song, F.; Liu, Y. Synlett 2007,
964. (j) Georgy, J.; Boucard, V.; Debleds, O.; Dal Zotto, C.; Campagne,
J.-M. Tetrahedron 2009, 65, 1758. (k) Kothandaraman, P.; Foo, S. J.;
Chan, P. W. H. J. Org. Chem. 2009, 74, 5947. (l) Aponick, A.; Biannic,
B.; Jong, M. R. Chem. Commun. 2010, 46, 6849. (m) Bandini, M.;
Monari, M.; Romaniello, A.; Tragni, M. Chem.;Eur. J. 2010, 16,
14272.
(7) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2010, 27, 165 and references cited therein.
(8) (a) Satoh, T.; Ikeda, M.; Miura, M.; Nomura, M. J. Org. Chem.
1997, 62, 4877. (b) Yang, S.-C.; Tsai, Y.-C. Organometallics 2001, 20,
763. (c) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968. (d)
Kinoshita, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 4085. (e)
Uenishi, J.; Ohmi, M.; Ueda, A. Tetrahedron Lett. 2005, 16, 1299. (f)
Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J. Org. Chem. 2006,
71, 4530. (g) Kawai, N.; Lagrange, J.-M.; Uenishi, J. Eur. J. Org. Chem.
2007, 2808. (h) Uenishi, J.; Vikhe, Y. S.; Kawai, N. Chem.;Asian J.
2008, 3, 473.
(9) (a) Utsunomiya, M.; Miyamoto, Y.; Ipposhi, J.; Ohshima, T.;
Mashima, K. Org. Lett. 2007, 9, 3371. (b) Mora, G.; Piechaczyk, O.;
Houdard, R.; Mezailles, N.; Le Goff, X.-F.; Le Floch, P. Chem.;Eur. J.
2008, 14, 10047. (c) Ohshima, T.; Miyamoto, Y.; Yasuhito, J.; Naka-
hara, Y.; Utsunomiya, M.; Mashima, K. J. Am. Chem. Soc. 2009, 131,
14317.
ꢀ
(10) Kabalka, G. W.; Dong, G.; Venkataiah, B. Org. Lett. 2003, 5,
893.
€
(11) (a) Zaitsev, A. B.; Gruber, S.; Pluss, P. A.; Pregosin, P. S.; Veiros;
€
Worle, M. J. Am. Chem. Soc. 2008, 130, 11604. (b) van Rijn, J. A.; Lutz,
M.; von Chrzanowski, L. S.; Spek, L. A.; Bouwman, E.; Drent, E. Adv.
Synth. Catal. 2009, 351, 1637. (c) Tanaka, S.; Seki, T.; Kitamura, M.
Angew. Chem., Int. Ed. 2009, 48, 8948.
ꢀ
(12) Guerinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808.
(13) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
€
(14) (a) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
ꢀ
2000, 122, 1806. (b) Ferrie, L.; Boulard, L.; Pradaux, F.; Bouzbouz, S.;
Reymond, S.; Capdevielle, P.; Cossy, J. J. Org. Chem. 2008, 73, 1864.
€
(15) Trans-reduction: (a) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am.
Chem. Soc. 2002, 124, 7922. (b) Trost, B. M.; Lee, D. C. J. Org. Chem.
1989, 54, 2271. Cis-reduction:(c) Shibuya, G. M.; Kanady, J. S.;
Vanderwal, C. D. J. Am. Chem. Soc. 2008, 130, 12514.
Org. Lett., Vol. 13, No. 6, 2011
1331

Interestingly, when additional stereocenters were present,
the combination of allylic alcohol stereochemistry and
olefin geometry controlled the stereochemical outcome of
the reaction overriding any inherent bias of the system to
selectively provide the cis- or trans-diastereomers 18/20 and
22/24 respectively (entries 9-12).
Table 1. Olefin Dependent Chirality Transfer
Figure 2. Predictive stereochemical mnemonic.
Analysis of the stereochemistry should provide insight
into how the allylic alcohol influences π-face discrimina-
tion and enhances olefin reactivity. In the systems studied
to date, the sense of chirality transfer is consistent. From
these data it can be seen that if the substrate is drawn as is
shown for E- and Z-25, in a position to form the tetra-
hydropyran and the trans-olefin (Figure 2), adding the
nucleophilic alcohol to the π-face syn to the allylic
hydroxyl group provides the observed products. This
mnemonic has proven to be a reliable stereochemical
predictor for reactions that provide both enantiomeric
and diastereomeric products.
Mechanistically, the reaction provides products that
result from a syn SN20 reaction.8e-h,16 Although a con-
certed mechanism with catalyst coordination to the allylic
alcohol cannot be ruled out at this point, a two-step
formal syn SN20 process with the Au-catalyst activating
the π-bond toward nucleophilic addition1 followed by
elimination of a gold hydroxide species17 is likely. The
two stereochemical elements in the products allow the
stereochemistry of each step to be determined; however,
they are interdependent. In a two-step process, both syn-
alkoxyauration/syn-β-hydroxide elimination and anti-
addition/anti-elimination are consistent with the stereo-
chemistry observed. Syn/anti or anti/syn pathways would
yield products with either opposite absolute configura-
tion or olefin geometry. To date, only trans-olefins have
been observed as products in this system.18
A probable catalytic cycle is shown in Scheme 1. The
cationic complex 27 is generated from the precatalyst
Ph3PAuCl and AgOTf. Complexation to the allylic alcohol
π-bond then forms 29 which undergoes nucleophilic attack
a Determined by HPLC. b Isolated yield. c Absolute configuration
determined by conversion to a known derivative and comparison of the
sign of the optical rotation. d Diastereomeric ratio determined by 1H
NMR. Major diastereomer shown. e Isolated yield of the major
diastereomer.
(16) Streitwieser, A.; Jayasree, E. G.; Hasanayn, F.; Leung, S. D.-H.
J. Org. Chem. 2008, 73, 9426.
(17) Gaillard, S.; Slawin, A. M. Z.; Nolan, S. P. Chem. Commun.
excellent ee transfer. With phenolic nucleophiles chirality
transfer was observed but the ee’s of the products were
lower than than the case with aliphatic alcohol nucleo-
philes (entries 7, 8). The absolute configuration of the
products was consistent, however, with the other examples.
2010, 46, 2742.
(18) Widenhoefer recently reported an amination reaction of a chiral
allylic alcohol where both enantiomer/olefin isomer combinations were
observed. See ref 6e.
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Org. Lett., Vol. 13, No. 6, 2011

Scheme 1. Probable Catalytic Cycle
Figure 3. Potential hydrogen bonding.
without any intermolecular proton transfer steps.6e Addi-
tionally, syn-processes should be disfavored because of
the preference for Au(I)-complexes to contain only two
ligands in a linear geometry.1a In comparison to other
noble metal based catalyst systems, this preference is
unique to Au(I)-complexes.20 Experiments to conclusively
distinguish between the two mechanistic scenarios are
underway and should aid in the further development of
Au-catalyzed reactions of olefins with π-facial selectivity.
In conclusion, we have demonstrated that Au-
catalyzed reactions of alkenes can exhibit a high degree
of π-facial selectivity to provide tetrahydropyrans in high
ee or de. The desired enantiomer or diastereomer can easily
be produced from a given chiral propargylic alcohol by
reduction to the correct olefin isomer and cyclization.
Applications in natural product synthesis and mechanistic
studies are underway and will be reported in due course.
forming the tetrahydropyran 30 or 31 in an anti- or
syn-addition process respectively. Loss of water and decom-
plexation regenerate the catalyst and provide the product 33.
While both syn-addition/syn-elimination and anti-
addition/anti-elimination processes lead to the correct
stereochemistry, an anti-/anti- mechanism is likely to be
preferred due to the nucleophilic addition step. Anti-
alkoxyauration involves the outer sphere attack of the
nucleophile on a catalyst π-complex, which is the role
typically invoked with gold(I) catalysts.1,19 From com-
plex 29, anti-addition would give 30 that then must lose a
proton and undergo anti-elimination to provide the trans-
olefin. It is possible that this is facilitated by hydrogen
bonding (in 34 and 35, Figure 3) and direct loss of water
Acknowledgment. We gratefully acknowledge the Her-
man Frasch Foundation (647-HF07), the donors of the
Petroleum Research Fund (47539-G1), and the James and
Ester King Biomedical Research Program (09KN-01) for
their generous support of our programs. We thank Petra
Research, Inc. for the gift of alkynes and an unrestricted
research award.
Supporting Information Available. Experimental pro-
cedures and data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(19) Recent computational studies support the anti-addition me-
chanism for addition to alkynes: Krauter, C. M.; Hashmi, A. S. K.;
Pernpointner, M. ChemCatChem 2010, 2, 1226.
€
(20) Furstner, A. Chem. Soc. Rev. 2009, 38, 3208.
Org. Lett., Vol. 13, No. 6, 2011
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