Asymmetric nazarov reaction catalyzed by chiral tris(oxazoline)/ copper(II)

Article abstract of DOI:10.1002/anie.200907266

(Figure Presented) Beverly Hills copper(II): A highly efficient catalytic asymmetric Nazarov reaction has been developed through control of the enantioselectivity of the cyclization step, affording chiral O-heterohexahydroinde-nones in excellent yields with excellent enantioselectivity and diastereoselectivity. HFIP = hexafluoro-2-propanol, B^ArF = tetrakis[3,5-bis(trifluoromethyl)phenyl] borate.

Full text of DOI:10.1002/anie.200907266

Angewandte
Chemie
DOI: 10.1002/anie.200907266
Asymmetric Catalysis
Asymmetric Nazarov Reaction Catalyzed by Chiral Tris(oxazoline)/
Copper(II)**
Peng Cao, Chao Deng, You-Yun Zhou, Xiu-Li Sun, Jun-Cheng Zheng, Zuowei Xie, and
Yong Tang*
The frequent occurrence of five-membered carbocycles in
natural products and other biologically active compounds has
provided a major impetus for the development of efficient
methods for their construction.[1] Towards this end, the
Nazarov cyclization, a stereospecific 4p electrocyclization
that converts divinyl ketones into cyclopentenones through
a conrotatory cyclization, has distinguished itself as a power-
ful tool for the synthesis of such compounds.[2] Over several
decades, great efforts have been devoted to the exploitation
of the Nazarov reaction,[3] further highlighting its synthetic
utility, as demonstrated by its increasing use in total synthe-
ses.[4] However, the asymmetric Nazarov reaction with a
catalytic amount of chiral source was not reported until the
end of 2003, probably because of the complex mechanism of
the reaction.[5] Of those catalytic asymmetric reactions
developed,[5] few examples have been reported that give
good to excellent enantiocontrol in good yields, except for
divinyl ketones that belong to type A or B (Scheme 1).
Aggarwal and Belfield developed the first asymmetric
Nazarov cyclization of type B ketones, promoted by a
stoichiometric amount of pybox/Cu2+ complex 2b, with
enantioselectivities of 44–88%.[5h] Recently, Rueping et al.
reported the first example of organocatalytic asymmetric
Narazov reactions with high enantioselectivities and moder-
ate diastereoselectivities[5a,d] using polarized alkoxy divinyl b-
ketoesters (type C) that were elegant substrates in this
transformation.[3f,m,n] To date, no highly enantioselective
version has been reported.
We found that both pybox-derived complexes 2a and 2b,
which were excellent catalysts or promoters in the enantio-
selective Nazarov reaction of type A and B substrates,[5f,h]
were not efficient for type C substrates. For example, when
alkoxy divinyl b-ketoester 1a underwent cyclization in the
presence of indane-pybox/Sc(OTf)3 2a or iPr-Pybox/CuBr2/
AgSbF6 2b, the desired product 3a was formed as the sole
product with 33% ee in 5% yield and 27% ee in 94% yield,
Scheme 1. Representative divinyl ketones used in the Nazarov
reaction.
Trauner and Liang reported the asymmetric Nazarov reac-
tions of type A divinyl ketones, catalyzed by 10 mol% of
indane-pybox/Sc(OTf)3 2a (pybox = 2,6-bis(2-oxazolin-2-
yl)pyridine) with ee values of 72–97% in good yields.[5f]
Scheme 2. Nazarov reaction of 1a catalyzed by indane-Pybox/Sc(OTf)3
and iPr-Pybox/CuII complexes.
[*] Dr. P. Cao, C. Deng, Y.-Y. Zhou, Dr. X.-L. Sun, Dr. J.-C. Zheng,
Prof. Dr. Y. Tang
respectively (Scheme 2). Compared with the planar pybox,
we envisioned that a pendant group on the box ligand[6] may
be better able to tune the three-dimensional conformation of
the catalyst–substrate complex, and subsequently improve the
enantiocontrol at the newly generated stereogenic centers
(Figure 1). Therefore, several tris(oxazoline)s[7] were synthe-
sized and were found to be excellent catalysts for the
asymmetric Nazarov cyclization of alkoxy divinyl b-ketoest-
ers, affording ee values of up to 98%. Herein, we report our
preliminary results with this catalyst system.
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P. R. China)
Fax: (+86)21-5492-5078
E-mail: tangy@mail.sioc.ac.cn
Prof. Dr. Z. Xie
Department of Chemistry, The Chinese University of Hong Kong
Shatin, New Territories, Hong Kong (China)
[**] We are grateful for the financial support from the Natural Sciences
Foundation of China (No. 20821002 and 20932008), the Major State
Basic Research Development Program (Grant No. 2006CB806105),
and the Chinese Academy of Sciences.
Tris(oxazoline)s (toxs) 4a, 4b, and 5c–d (Figure 2) are
readily available from alkylation of their corresponding
bis(oxazoline)s.[7h] As isopropyltris(oxazoline) (iPr-tox) 4a is
an efficient ligand in the asymmetric reactions of bidentate
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907266.
Angew. Chem. Int. Ed. 2010, 49, 4463 –4466
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4463

Communications
cant influence was observed when the modular box scaffold
was altered. Simply replacing iPr-box with the more rigid
indane-box led to an increase in the ee by 10%, albeit at the
cost of an 11% decline in yield (Table 1, entries 1 vs. 4).
Further studies revealed that the configuration of the chiral
pendant sidearm also had an effect on the outcome (Table 1,
entries 5 vs. 6). Fortunately, when 10 mol% of ligand 5d was
employed as the chiral source, the desired optically active
product was formed in 90% yield and 92% ee (Table 1,
entry 6).
Figure 1. Catalyst design for the asymmetric Nazarov reaction.
With the optimal combination of ligand, Lewis acid,
additive, and solvent in hand, we turned our attention to
survey the scope and limitation of the Nazarov cyclization. As
summarized in Table 2, a variety of alkoxy divinyl b-
Table 2: Asymmetric Nazarov reaction.[a]
Figure 2. Ligands used in this investigation.
Entry
1
1
R
CuII
[mol%]
t [h]
Yield
[%][b]
ee
[%][c]
malonate derivatives,[7g,i] we decided to employ 4a to optimize
the reaction conditions of model substrate divinyl b-ketoester
1a
phenyl
4-hydroxy-3,5-
dimethoxyphenyl
10
5
26
66
90
77
92
96
2[d] 1b
1a. The combination of CuCl2 and sodium tetrakis[3,5-
3[e] 1c 3,4,5-trimethoxy-
5
4 days
96
98
bis(trifluoromethyl)phenyl] borate (NaBArF
)
in tBuOMe
[8]
phenyl
with hexafluoro-2-propanol (HFIP) as an additive was found
to be the most successful among various metals, additives, and
solvents that were screened,[9] furnishing product 3a in 85%
yield and 78% ee as a single diastereomer (Table 1, entry 1).
4
5
6
1d 4-methoxyphenyl 10
18
26
26
47
80
84
87
58
96
95
93
94
1e
1 f
4-methylphenyl 10
3-methylphenyl 10
7[f] 1g 2-methylphenyl 10
8[g] 1h
9[g] 1i
4-fluorophenyl
4-chlorophenyl
3-chlorophenyl
10 (20)
10 (20)
10 (20)
50 (30) 53 (69) 93 (96)
58 (38) 46 (75) 93 (96)
70 (50) 45 (63) 91 (93)
64 (57) 77 (76) 94 (96)
10[g] 1j
11[g] 1k
12[h] 1l
Table 1: Effect of ligands on the asymmetric Nazarov cyclization.[a]
4-bromophenyl 10 (20)
cyclohexyl 10
5 days
88
78
[a] Reaction conditions: 5d/CuCl2/NaBArF (molar ratio)=0.73:1.0:2.0
(entries 1–7, 12) or 1.1:1.0:2.0 (entries 8–11), HFIP (20 mL, 0.20 mmol),
1 (0.20 mmol), tBuOMe (2.0 mL). [b] Yield of isolated product.
[c] Determined by chiral HPLC. [d] At 158C. [e] At 158C, without HFIP.
[f] 65% conversion. [g] 408C; the data in brackets are results when
20 mol% catalyst was used. [h] DCE as solvent, 50% conversion.
Entry
Ligand
d.r.[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
4a
4b
5a
5b
5c
5d
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
85
85
69
74
73
90
78
80
86
88
85
92
ketoesters that contained R groups with different electronic
and steric properties were examined. The nature of the b-aryl
substituents (R = aryl) had a limited influence on the
stereoselectivities. Excellent d.r. (> 99:1) and ee values (92–
98%) were consistently afforded (Table 2, entries 1–11),
whereas the reaction rate and yield varied according to the
nature of the aryl substituents. Electron-rich aromatic sub-
stituents improved the reaction rate and good to excellent
yields were obtained with excellent enantioselectivity, even
with 5 mol% of catalyst in some cases (Table 2, entries 2–6).
When R = 2-methylphenyl, the cyclization proceeded with
moderate conversion (Table 2, entry 7), probably owing to
steric encumbrance. The electron-poor aromatic substituents
were less reactive and moderate yields with high ee values
were obtained in the presence of 10 mol% catalyst at 408C
(Table 2, entries 8–11). Fortunately, those substrates success-
[a] Reaction conditions: CuCl2 (2.7 mg, 0.02 mmol), ligand
(0.0146 mmol), NaBArF (36.0 mg, 0.04 mmol), HFIP (20 mL,
0.20 mmol), 1a (54 mg, 0.20 mmol), tBuOMe (2.0 mL), 20 hours.
[b] Determined by 300MHz 1H NMR. [c] Yield of isolated product.
[d] Determined by chiral HPLC.
Encouraged by these preliminary results with 4a, we
further investigated the effect of several tris(oxazoline)s
(Figure 2) on the enantioselectivity of the reaction. As shown
in Table 1, ligands 4b and 5a–d all provided good enantio-
selectivities and yields under the optimized conditions.
Substitution of the isopropyloxazoline group in 4a for an
indane-oxazoline pendant group did not affect the Nazarov
process too much (Table 1, entries 1 vs. 2). However, signifi-
4464 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4463 –4466

Angewandte
Chemie
fully underwent Nazarov cyclization in the presence of
20 mol% catalyst (Table 2, entries 8–11, data in brackets).
The b-alkyl substituent was also tested and the reaction
occurred smoothly, affording the desired product in 88%
yield, albeit with 78% ee (Table 2, entry 12). In all cases, b-
keto esters 3 were isolated as single regio- and trans isomers.
To demonstrate the synthetic potential of this asymmetric
Nazarov reaction, several transformations were carried out.
As shown in Scheme 3, reactions of cyclopentenone 3e
through Michael additions, electrophilic fluorination,[5e] and
esterification/cyclization proceeded successfully in high yields
without loss of optical purity. These transformations provide a
facile method for the construction of functional cyclopente-
none derivatives. The absolute configuration of compound 6
was determined by X-ray analysis as 5S,6R.[9,10] Accordingly,
3e was assigned as having a 5S,6R configuration.
Figure 3. Energies for the intermediates in the asymmetric Nazarov
reaction. Some hydrogen atoms are omitted for clarity.
Using DFT calculations, a stereochemical model was pro-
posed to understand the high enantiocontrol exerted by the
catalyst. The mild reaction conditions, high enantioselectivity,
reasonable yields, and their utility in the construction of
quaternary stereogenic carbon centers make the present
reaction potentially highly useful in organic synthesis.
Experimental Section
Typical procedure for the asymmetric Nazarov reaction, (3a as an
example): CuCl2 (2.7 mg, 0.02 mmol), NaBArF (36.0 mg, 0.04 mmol),
and ligand 5d (7.5 mg, 0.015 mmol) were stirred in anhydrous
tBuOMe (1.0 mL) at 258C for 2 hours. HFIP (21 mL, 0.2 mmol) was
added, followed by 1a (54.5 mg, 0.2 mmol), and tBuOMe (1.0 mL).
After the reaction was complete (monitored by TLC), the mixture
was rapidly filtered through a short pad of silica gel and eluted with
EtOAc. The filtrate was concentrated under reduced pressure and the
residue was purified by flash chromatography (silica gel, petroleum
ether/ethyl acetate = 8:1) to afford the desired product 3a as liquid.
Yield: 49 mg (90%). ee: 92% (determined by HPLC: Chiralcel AD
Scheme 3. Chemical transformations of cyclopentenone 3e. DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, DMAP=4-(dimethylamino)pyridine,
NFSI=N-fluorodibenzenesulfonimide, MVK=methyl vinyl ketone.
A stereochemical model, shown in Figure 3, was devel-
oped to account for the observed enantioselectivity. In the
presence of 5d/CuII, (E)-1 is firstly isomerized to the
corresponding Z isomer as proposed by Frontier and co-
workers,[3f] followed by conrotatory annulation by either a
clockwise or an anticlockwise pathway. Using DFT calcula-
tions,[9] we found that intermediate I, formed by an anticlock-
wise conrotatory cyclization, is favored by 3.94 kJmolÀ1 over
intermediate II, which was formed by a clockwise conrotatory
cyclization, owing to steric effects (Figure 3). This result is
consistent with the absolute stereochemistry of the product
observed. To understand the role of the pendant group, DFT
calculations were performed using 5c/CuII and 5d/CuII as
models. Based on the results calculated, the sidearm might
influence the conformation of the catalytic species through
steric hindrance, leading to a discrimination between the
transition states and different enantioselectivities.[9] The exact
role of the sidearm is not clear and requires further
investigation.
column; eluent: hexane/iPrOH (70:30); 0.8 mLminÀ1; 238 nm; tR1
-
(minor) = 10 min, tR2(major) = 12 min. [a]D20 = + 176.18 (c = 0.5,
CHCl3, 92% ee). 1H NMR (300 MHz, CDCl3/TMS) d = 7.29–7.37
(m, 3H), 7.14 (d, J = 6.6 Hz, 2H), 4.24 (d, J = 1.2 Hz, 1H), 4.15–4.20
(m, 2H), 3.78 (s, 3H), 3.33 (d, J = 1.2 Hz, 1 H), 2.13–2.21 (m, 2H),
1.93–1.98 ppm (m, 2H).
Received: December 24, 2009
Revised: February 24, 2010
Published online: May 17, 2010
Keywords: asymmetric catalysis · copper · cyclization ·
.
diastereoselectivity · Nazarov cyclization
[1] For recent reviews on five-membered carbocycles, see: a) V. B.
Kurteva, C. A. M. Afonso, Chem. Rev. 2009, 109, 6809; b) S. E.
Gibson, S. E. Lewis, N. Mainolfi, J. Organomet. Chem. 2004, 689,
3873.
[2] For reviews on the Nazarov reaction, see: a) T. N. Grant, C. J.
Rieder, F. G. West, Chem. Commun. 2009, 5676; b) A. J.
Frontier, C. Collison, Tetrahedron 2005, 61, 7577; c) H. Pellissier,
Tetrahedron 2005, 61, 6479; d) M. A. Tius, Eur. J. Org. Chem.
In conclusion, we have developed a highly regio-,
diastereo-, and enantioselective asymmetric Nazarov reaction
that is catalyzed by the combination of tris(oxazoline)/CuII.
Angew. Chem. Int. Ed. 2010, 49, 4463 –4466
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4465

Communications
2005, 2193; e) M. A. Tius, Acc. Chem. Res. 2003, 36, 284; f) K. L.
A. P. Antonchick, B. J. Nachtsheim, Angew. Chem. 2007, 119,
2143; Angew. Chem. Int. Ed. 2007, 46, 2097; e) J. Nie, H.-W. Zhu,
H.-F. Cui, M.-Q. Hua, J.-A. Ma, Org. Lett. 2007, 9, 3053; f) G.
Liang, D. Trauner, J. Am. Chem. Soc. 2004, 126, 9544; g) G.
Liang, S. N. Gradl, D. Trauner, Org. Lett. 2003, 5, 4931; h) V. K.
Aggarwal, J. A. Belfield, Org. Lett. 2003, 5, 5075.
Habermas, S. E. Denmark, T. K. Jones, Org. React. 1994, 45, 1.
[3] For selected examples, see: a) P. Cordier, C. Aubert, M.
Malacria, E. Lacꢀte, V. Gandon, Angew. Chem. 2009, 121,
8913; Angew. Chem. Int. Ed. 2009, 48, 8757; b) C. J. Rieder, K. J.
Winberg, F. G. West, J. Am. Chem. Soc. 2009, 131, 7504; c) P.
Cao, X.-L. Sun, B.-H. Zhu, Q. Shen, Z. Xie, Y. Tang, Org. Lett.
2009, 11, 3048; d) A. R. Banaag, M. A. Tius, J. Org. Chem. 2008,
73, 8133; e) A. K. Basak, M. A. Tius, Org. Lett. 2008, 10, 4073;
f) W. He, I. R. Herrick, T. A. Atesin, P. A. Caruana, C. A.
Kellenberger, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 1003;
g) D. Song, A. Rostami, F. G. West, J. Am. Chem. Soc. 2007, 129,
12019; h) F. Dhoro, T. E. Kristensen, V. Stockmann, G. P. A.
Yap, M. A. Tius, J. Am. Chem. Soc. 2007, 129, 7256; i) A. R.
Banaag, M. A. Tius, J. Am. Chem. Soc. 2007, 129, 5328; j) J.
Huang, A. J. Frontier, J. Am. Chem. Soc. 2007, 129, 8060; k) T. N.
Grant, F. G. West, J. Am. Chem. Soc. 2006, 128, 9348; l) M.
Janka, W. He, I. E. Haedicke, F. R. Fronczek, A. J. Frontier, R.
Eisenberg, J. Am. Chem. Soc. 2006, 128, 5312; m) M. Janka, W.
He, A. J. Frontier, R. Eisenberg, J. Am. Chem. Soc. 2004, 126,
6864; n) W. He, X. F. Sun, A. J. Frontier, J. Am. Chem. Soc. 2003,
125, 14278; o) T. K. Jones, S. E. Denmark, Helv. Chim. Acta
1983, 66, 2377; p) T. K. Jones, S. E. Denmark, Helv. Chim. Acta
1983, 66, 2397; q) S. E. Denmark, T. K. Jones, J. Am. Chem. Soc.
1982, 104, 2642.
[6] For selected reviews on bis(oxazolines) in asymmetric catalysis,
see: a) G. C. Hargaden, P. J. Guiry, Chem. Rev. 2009, 109, 2505;
b) G. Desimoni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106,
3561; c) J. S. Johnson , D. A. Evans, Acc. Chem. Res. 2000, 33,
325; d) A. K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1; e) A. Pfaltz, Acc. Chem. Res. 1993, 26, 339.
[7] For recent reviews, see: a) L. H. Gade, S. Bellemin-Laponnaz,
Chem. Eur. J. 2008, 14, 4142; b) C. Moberg, Angew. Chem. 2006,
118, 4838; Angew. Chem. Int. Ed. 2006, 45, 4721; c) S. E. Gibson,
M. P. Castaldi, Angew. Chem. 2006, 118, 4834; Angew. Chem. Int.
Ed. 2006, 45, 4718; d) J. Zhou, Y. Tang, Chem. Soc. Rev. 2005, 34,
664; For selected examples, see: e) M. Gaab, S. Bellemin-
Laponnaz, L. H. Gade, Chem. Eur. J. 2009, 15, 5450; f) C. Foltz,
B. Stecker, G. Marconi, S. Bellemin-Laponnaz, H. Wadepohl, L.
Gade, Chem. Eur. J. 2007, 13, 9912; g) Y.-B. Kang, X.-L. Sun, Y.
Tang, Angew. Chem. 2007, 119, 3992; Angew. Chem. Int. Ed.
2007, 46, 3918; h) M.-C. Ye, B. Li, J. Zhou, X.-L. Sun, Y. Tang, J.
Org. Chem. 2005, 70, 6108; i) J. Zhou, Y. Tang, J. Am. Chem. Soc.
2002, 124, 9030.
[4] For selected examples, see: a) J. A. Malona, K. Cariou, A. J.
Frontier, J. Am. Chem. Soc. 2009, 131, 7560; b) S. Gao, Q. Wang,
C. Chen, J. Am. Chem. Soc. 2009, 131, 1410; c) A. Y. Bitar, A. J.
Frontier, Org. Lett. 2009, 11, 49; d) W. He, J. Huang, X. Sun, A. J.
Frontier, J. Am. Chem. Soc. 2008, 130, 300; e) G. O. Berger,
M. A. Tius, J. Org. Chem. 2007, 72, 6473; f) L. Wan, M. A. Tius,
Org. Lett. 2007, 9, 647; g) W. He, J. Huang, X. Sun, A. J. Frontier,
J. Am. Chem. Soc. 2007, 129, 498; h) D. R. Williams, L. A.
Robinson, C. R. Nevill, J. P. Reddy, Angew. Chem. 2007, 119,
933; Angew. Chem. Int. Ed. 2007, 46, 915.
[8] a) S.-F. Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li, Q.-L. Zhou, J. Am.
Chem. Soc. 2006, 128, 12886; b) A. Pfaltz, J. Blankenstein, R.
Hilgraf, E. Hormann, S. McIntyre, F. Menges, M. Schonleber,
S. P. Smidt, B. Wustenberg, N. Zimmermann, Adv. Synth. Catal.
2003, 345, 33; c) M. Lautens, S. Hiebert, J.-L. Renaud, J. Am.
Chem. Soc. 2001, 123, 6834; d) N. Nomura, J. Jin, H. Park, T. V.
RajanBabu, J. Am. Chem. Soc. 1998, 120, 459.
[9] For details, please see the Supporting Information.
[10] The structure was determined by X-ray analysis. CCDC 738787
(3e), 738788 (6), and 738789 (7) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[5] a) M. Rueping, W. Ieawsuwan, Adv. Synth. Catal. 2009, 351, 78;
b) K. Yaji, M. Shindo, Synlett 2009, 2524; c) I. Walz, A. Togni,
Chem. Commun. 2008, 4315; d) M. Rueping, W. Leawsuwan,
4466 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4463 –4466