Highly enantioselective and anti -diastereoselective catalytic intermolecular glyoxylate-ene reactions: Effect of the geometrical isomers of alkenes

Article abstract of DOI:10.1021/acs.orglett.5b01151

An efficient method for the synthesis of homoallylic alcohols with high enantioselectivities and anti-diastereoselectivities via an In(III)-catalyzed intermolecular glyoxylate-ene reaction has been developed. The geometrical isomers of alkenes were shown to have different reactivities. Only the isomers of the alkenes having a proton β-cis to the substituent reacted in this catalytic system.

Full text of DOI:10.1021/acs.orglett.5b01151

Letter
pubs.acs.org/OrgLett
Highly Enantioselective and Anti-Diastereoselective Catalytic
Intermolecular Glyoxylate−Ene Reactions: Effect of the Geometrical
Isomers of Alkenes
Xiang Zhang,† Min Wang,† Ran Ding,† Yun-He Xu,*,† and Teck-Peng Loh*,†,‡
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
S
* Supporting Information
ABSTRACT: An efficient method for the synthesis of
homoallylic alcohols with high enantioselectivities and anti-
diastereoselectivities via an In(III)-catalyzed intermolecular
glyoxylate−ene reaction has been developed. The geometrical
isomers of alkenes were shown to have different reactivities.
Only the isomers of the alkenes having a proton β-cis to the
substituent reacted in this catalytic system.
reaction between glyoxylates and trisubstituted alkenes with
high anti-diastereoselectivities and enantioselectivities (Scheme
1). This study also revealed the different reactivities of the
geometrical isomers of the alkenes used in this reaction.
To achieve this goal, the model reaction between (E)-but-2-
en-2-ylbenzene (1a) and ethyl glyoxylate was first carried out to
test the enantioselectivity and diastereoselectivity of this
glyoxylate−ene reaction. The catalytic system of In(OTf)3−
omoallylic alcohols are important building blocks for the
Hsynthesis of natural products and biologically active
compounds.1 Among the many methods available, the
intermolecular carbonyl−ene reaction2 is probably one of the
best methods for the construction of C−C bonds due the ease of
obtaining the starting materials as well as the atom-economic
nature of the reaction. Since the first report by Yamamoto on the
use of aluminum BINOL complex for the highly catalytic
enantioselective carbonyl−ene reaction,3 many groups have also
developed different catalytic systems that afford high enantiose-
lectivies. Elegant work by Mikami on the use of Ti−BINOL
complex,4 Evans’ Cu−Box5 and Sc−Box6 complex systems,
Jacobsen’s Cr−Schiff complex,7 Rawal′s Co−Salen complex,8
Feng’s Ni−N′N′-dioxide complex,9 and other systems have also
been shown to be effective.10−12 The use of an organocatalyst has
also been recently reported by Macmillan’s group.13 In most of
these cases, the enantioselective ene reactions studied involved
the use of 1,1-disubstituted olefins. In contrast, only sporadic
examples of diastereoselective and enantioselective intermolec-
ular carbonyl−ene reactions using trisubstituted olefins to
construct two or more stereogenic centers have been reported.14
For this reaction to be a method of choice for the stereochemical
construction of complex molecules, it is essential to access all the
possible stereoisomers. While Evans6 has reported a highly
enantioselective syn-selective carbonyl−ene reaction, a general
method for the highly enantioselective anti-diastereoselective
carbonyl−ene using simple trisubstituted alkenes is not available.
In light of our continuing interest in chiral indium complex
catalyzed asymmetric ene reactions,15 herein we report an
indium-catalyzed intermolecular asymmetric glyoxylate−ene
Scheme 1. Transition-Metal-Catalyzed Diastereoselective
Carbonyl−Ene Reaction
Received: April 20, 2015
Published: May 12, 2015
© 2015 American Chemical Society
2736
DOI: 10.1021/acs.orglett.5b01151
Org. Lett. 2015, 17, 2736−2739

Organic Letters
Letter
PyBox developed previously for the carbonyl−ene reaction
(entry 1) was first examined. Fortunately, the desired product 3a
could be obtained with good enantioselectivity (ee = 92%) albeit
with only 26% yield. Considering the lower reactivity of
trisubstituted alkenes as compared with 1,1-disubstituted olefins,
a stronger Lewis acid catalyst is required. Therefore, the cationic
indium catalysts generated in situ from different InX3 and
AgSbF6 were explored (Table 1, entries 2−5). As expected, the
With the optimized reaction conditions in hand, different
glyoxylates were screened to examine the ester substituent effect
for this asymmetric glyoxylate−ene reaction. It was found that
glyoxylates with linear ester substituents such as methyl, ethyl,
and n-butyl groups could furnish the products in high yields with
good enantioselectivities and diastereoselectivities. When bulky
isopropyl glyoxylate was used, a 93% ee product could be
obtained along with a decreased diastereoselectivity and yield
(Table 2, entry 3).
a
Table 1. Optimization of the Reaction Conditions
a d
Table 2. Screening of Various Glyoxylates −
a
Reactions were carried on 0.3 mmol scale of 2 with 2.0 equiv of
olefins in 3.0 mL of anhydrous DCE for 48 h at room temperature.
b
c
d
Isolated yield. The dr ratios were determined by 1H NMR. The ee
values of the major product were determined by chiral-phase HPLC
analysis.
a
Unless noted otherwise, reactions were carried out on a 0.3 mmol
Therefore, ethyl glyoxylate was chosen to test the scope of the
trisubstituted alkenes. The results are shown in Table 3. In most
cases, the desired homoallylic alcohol products could be obtained
in moderate to good yields with high diastereoselectivities and
enantioselectivities. Various substituents on the phenyl ring of
alkenes were also investigated. The results showed that both the
electron-donating and the electron-deficient groups were well
tolerated in the substrates to give the corresponding products in
good yields and diastereoselectivities and enantioselectivities.
More importantly, the homoallylic alcohols with halide atoms
such as F, Cl, Br, and even I on the phenyl ring all could be
obtained in reasonable to high yields and good stereoselectivities.
When (E)-2-(but-2-en-2-yl)naphthalene was used in the
reaction, an excellent dr ratio (98:2) along with a 95% ee
product could be observed. Next, the steric effect of the
trisubstituted alkenes with changing R2 and R3 groups was
examined. When the R2 was a propyl group, the reaction
proceeded smoothly and afforded the desired product in a
slightly decreased yield but with high diastereoselectivity (99:1)
and enantioselectivity (96% ee). Meanwhile, the selectivities
were also good when R3 was changed to an ethyl group.
Furthermore, when cyclopentenylbenzene was employed in this
reaction, the product 3r could be obtained in 75% yield with an
excellent enantioselectivity and a slightly diminished dr ratio
(88:12). To our delight, this reaction was not only limited to
scale of 2b with 2.0 equiv of olefins in 3.0 mL of anhydrous DCE for
b
c
48 h at room temperature. Isolated yield. The values of dr were
d
1
determined by H NMR. The ee values of the major products were
e
determined by chiral-phase HPLC analysis. The reaction ran at 0 °C.
5 mol % of InCl3, 6 mol % of PyBox, and 10 mol % of AgSbF6 were
f
used.
“counterion effect”16 greatly enhanced the reaction’s efficiency.
Among the indium halides, both InCl3 and InBr3 were found to
afford the desired products with good enantioselectivities (95%,
92% respectively), while a better diastereoselectivity was
observed in the presence of InCl3 (Table 1, entry 3). When
other ligands were examined in this reaction, it was found that
ligand d afforded the product in the highest diastereoselectivity
(95:5) but with lower enantioselectivity (Table 1, entry 8).
Taking the influence of acidity due to the “non-coordinating”
anion into account, diverse silver salts were also evaluated (Table
1, entries 11−13). The results indicated that the AgSbF6 was
more effective at controlling the enantioselectivity and
diastereoselectivity. Finally, either lowering the temperature or
reducing the catalyst loading greatly decreased the product yield,
without damaging the enantioselectivity. As a result, the
optimized reaction conditions were set as follows: 10 mol % of
InCl3, 20 mol % of AgSbF6, and 12 mol % of Pybox ligand in the
solvent of DCE at room temperature.
2737
DOI: 10.1021/acs.orglett.5b01151
Org. Lett. 2015, 17, 2736−2739

Organic Letters
Letter
a d
aromatic-substituted alkene derivatives; the 1-methylcyclohex-1-
ene was also successfully converted into the corresponding
homoallylic alcohol in good yield with 97% ee and 94:6 dr.
Finally, to understand this diastereoselective glyoxylate−ene
reaction pathway, the influence of the steric configuration of
olefins was investigated (Scheme 2). Only the alkene with E-
Table 3. Screening of Different Trisubstituted Alkenes −
Scheme 2. Control Experiments To Investigate the Stereo
Effect of Trisubstituted Alkenes for Ene Reaction
configuration 1a could give the desired product in a high yield
and excellent diastereoselectivity and enantioselectivity. When
the Z-isomer Z-1a′ was applied in the reaction, only a 17% yield
of product was obtained. Interestingly, the product ee and dr
were the same as the reaction using E-1a. We envisage that this
reaction proceeds via the E-isomer. Indeed, when pure Z-1a′ was
subjected under the same reaction conditions, the isomerized E-
1a was obtained in 21% yield. Next, we used the rigid cyclic
alkene 1t with no proton in the β-cis substituent. As expected, no
desired product was obtained, further confirming the need to
have a proton in the β-cis substitutent for this glyoxylate−ene
reaction to proceed.
The anti-relative configuration of the diastereomers was
confirmed by converting one of the products 3b to the
corresponding tetrahydropyran derivative 5 (refer to below).17
1
The long-range H coupling interaction between the methyl
group in the axial position and the indicated proton was
identified via 2D NMR spectroscopy analysis. To account for this
observed selectivity, we proposed that this indium-catalyzed
intermolecular ene reaction proceeded via an endo transition
state.5b
a
Unless noted otherwise, the reactions were carried out under the
b
c
standard reaction conditions. Isolated yield. The dr ratios were
determined by H NMR The ee values of the major products were
d
1
In conclusion, we have developed a simple and efficient
method for the synthesis of homoallylic alcohols with high
determined by chiral-phase HPLC analysis.
2738
DOI: 10.1021/acs.orglett.5b01151
Org. Lett. 2015, 17, 2736−2739

Organic Letters
Letter
(c) Zheng, K.; Yin, C. K.; Liu, X. H.; Lin, L. L.; Feng, X. M. Angew. Chem.,
Int. Ed. 2011, 50, 2573−2577.
enantioselectivities and anti-diastereoselectivities via an In-
catalyzed intermolecular glyoxylate−ene reaction. The geo-
metrical isomers of the alkenes were found to have a profound
effect on the reactivity of the reaction. In this asymmetric
carbonyl−ene reaction, the presence of a proton β-cis to the
substituent of the alkene is essential for the high reactivity. This
study provides useful information for the design of other ene-
type reactions using specific heterosubstituted olefins to obtain
homoallylic alcohols in high enantio- and anti-diastereoselectiv-
ities.
(10) (a) Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem. 1998, 63,
2133−2143. (b) Kezuka, S.; Ikeno, T.; Yamada, T. Org. Lett. 2001, 3,
́
1937−1939. (c) Koh, J. H.; Larsen, A. O.; Gagne, M. R. Org. Lett. 2001,
3, 1233−1236. (d) Rueping, M.; Theissmann, T.; Kuenkel, A.; Koenigs,
R. M. Angew. Chem., Int. Ed. 2008, 47, 6798−6801. (e) Qian, C.; Wang,
L. Tetrahedron: Asymmetry 2000, 11, 2347−2357. (f) Terada, M.; Soga,
K.; Momiyama, N. Angew. Chem., Int. Ed. 2008, 47, 4122−4125.
(g) Yuan, Y.; Zhang, X.; Ding, K. L. Angew. Chem., Int. Ed. 2003, 42,
5478−5480.
(11) (a) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059−
4062. (b) Aikawa, K.; Kainuma, S.; Hatano, M.; Mikami, K. Tetrahedron
Lett. 2004, 45, 183−185. (c) Hatano, M.; Mikami, K. J. Am. Chem. Soc.
2003, 125, 4704−4705. (d) Mikami, K.; Kawakami, Y.; Akiyama, K.;
Aikawa, K. J. Am. Chem. Soc. 2007, 129, 12950−12951.
(12) (a) Truong, P. M.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int.
Ed. 2014, 53, 6468−6472. (b) Xu, X. C.; Wang, X. C.; Liu, Y.; Doyle, M.
P. J. Org. Chem. 2014, 79, 12185−12190.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS). The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01151.
(13) Comito, R. J.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc.
2013, 135, 9358−9361.
AUTHOR INFORMATION
(14) See refs 4c,d, 5b, 7a, and 11a,b.
■
(15) (a) Zhao, J.-F.; Tsui, H.-Y.; Wu, P.-J.; Lu, J.; Loh, T.-P. J. Am.
Chem. Soc. 2008, 130, 16492−16493. (b) Zhao, Y.-J.; Li, B.; Tan, L.-J. S.;
Shen, Z.-L.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 10242−10244.
(c) Zhao, J. F.; Tan, B. H.; Zhu, M. K.; Tjan, T. B.W.; Loh, T. P. Adv.
Synth. Catal. 2010, 352, 2085.
(16) (a) Zhao, J.-F.; Tjan, T. B. W.; Tan, B.-H.; Loh, T.-P. Org. Lett.
2009, 11, 5714−5716. (b) Zhao, J.-F.; Tjan, T. B. W.; Loh, T.-P.
Tetrahedron Lett. 2010, 51, 5649−5652.
(17) Zheng, K.; Liu, X. H.; Qin, S.; Xie, M. S.; Lin, L. L.; Hu, C. W.;
Feng, X. M. J. Am. Chem. Soc. 2012, 134, 17564−17573.
Corresponding Authors
*E-mail: xyh0709@ustc.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, U.K., 1991. (b) Mikami, K.;
Terada, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. III, Chapter
32. (c) Hornberger, K. R.; Hamblet, C. L.; Leighton, J. L. J. Am. Chem.
Soc. 2000, 122, 12894−12895. (d) Nicolaou, K. C.; Kim, D. W.; Baati, R.
Angew. Chem., Int. Ed. 2002, 41, 3701−3704. (e) Felpin, F. X.; Lebreton,
J. J. Org. Chem. 2002, 67, 9192−9199.
(2) For a general review of the ene reaction, see: (a) Clarke, M. L.;
France, M. B. Tetrahedron 2008, 64, 9003−9031. (b) Mikami, K.;
Shimizu, M. Chem. Rev. 1992, 92, 1021−1050. (c) Berrisford, D. J.;
Bolm, C. Angew. Chem., Int. Ed. 1995, 34, 1717−1719. (d) Mikami, K.;
Terada, M.; Narisawa, S.; Nakai, T. Synlett 1992, 255−265. (e) Mikami,
K. Pure Appl. Chem. 1996, 68, 639−644.
(3) Maruoka, K.; Hoshino, Y.; Shirasaka, Y. H.; Yamamoto, H.
Tetrahedron Lett. 1988, 29, 3967−3970.
(4) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1989, 111,
1940−1941. (b) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc.
1990, 112, 3949−3954. (c) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc.
1993, 115, 7039−7040. (d) Mikami, K.; Yajima, T.; Terada, M.; Kato,
E.; Maruta, M. Tetrahedron: Asymmetry 1994, 6, 1087−1090.
(e) Mikami, K.; Tomoko, Y.; Takasaki, T.; Matsukawa, S.; Terada,
M.; Uchimaru, T.; Maruta, M. Tetrahedron 1996, 52, 85−98.
(5) (a) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.; Tregay,
S. W. J. Am. Chem. Soc. 1998, 120, 5824−5825. (b) Evans, D. A.; Tregay,
S. W.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T. J. Am. Chem. Soc. 2000,
122, 7936−7943.
(6) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2005, 127, 8006−8007.
(7) (a) Ruck, R. T.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 2882−
2883. (b) Ruck, R. T.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2003, 42,
4771−4774. (c) Grachan, M. L.; Tudge, M. T.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2008, 47, 1469−1472. (d) Rajapaksa, N. S.; Jacobsen, E.
N. Org. Lett. 2013, 15, 4238−4241.
(8) Hutson, G. E.; Dave, A. H.; Rawal, V. H. Org. Lett. 2007, 9, 3869−
3872.
(9) (a) Zheng, K.; Shi, J.; Liu, X.; Feng, X. M. J. Am. Chem. Soc. 2008,
130, 15770−15771. (b) Zheng, K.; Yang, Y.; Zhao, J. N.; Yin, C. K.; Lin,
L. L.; Liu, X. H.; Feng, X. M. Chem.Eur. J. 2010, 16, 9969−9972.
2739
DOI: 10.1021/acs.orglett.5b01151
Org. Lett. 2015, 17, 2736−2739