Access to both enantiomers of α-chloro-β-keto esters with a single chiral ligand: Highly efficient enantioselective chlorination of cyclic β-keto esters catalyzed by chiral copper(II) and zinc(II) complexes of a spiro-2,2'-bischroman-based bisoxazoline ligand

Article abstract of DOI:10.1002/adsc.201200088

The spiro-2,2'-bichroman-based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)- and zinc(II)-catalyzed asymmetric chlorinations of cyclic β-keto esters with N-chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α-chloro-β-keto esters in excellent yields in 5-30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities. Copyright

Full text of DOI:10.1002/adsc.201200088

FULL PAPERS
DOI: 10.1002/adsc.201200088
Access to Both Enantiomers of a-Chloro-b-keto Esters with
a Single Chiral Ligand: Highly Efficient Enantioselective
Chlorination of Cyclic b-Keto Esters Catalyzed by Chiral
Copper(II) and Zinc(II) Complexes of a Spiro-2,2’-bischroman-
Based Bisoxazoline Ligand
Jie Li,a Wei Pan,a Zheng Wang,a Xumu Zhang,a,b and Kuiling Dinga,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: kding@mail.sioc.ac.cn
Department of Chemistry and Chemical Biology, Center of Molecular Catalysis, Rutgers, The State University of New
b
Jersey, 610 Taylor, Piscataway, New Jersey 08854, USA
Received: February 3, 2012; Revised: April 1, 2012; Published online: July 2, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200088.
Abstract: The spiro-2,2’-bichroman-based chiral bi- flate complexes of a single SPANbox ligand demon-
soxazoline ligands (SPANbox) were found to be strated complementary results to each other with re-
highly efficient in copper(II)- and zinc(II)-catalyzed spect to the enantioselection, affording both anti-
asymmetric chlorinations of cyclic b-keto esters with podes of the chlorinated product enantiomers with
N-chlorosuccinimide (NCS) as the chlorination re- good to excellent optical purities.
agent, to give the corresponding a-chloro-b-keto
esters in excellent yields in 5–30 min with ee values Keywords: asymmetric catalysis; bisoxazolines;
up to 97%. The copper(II) triflate and zinc(II) tri- chlorination; a-chloro-b-keto esters; copper; zinc
Introduction
and bromination) of b-keto esters in 2000, using iso-
lated chiral Ti-TADDOLato complexes as the cata-
Chiral a-halo carbonyl compounds are versatile syn- lysts.[6] Following this pioneering work, a number of
thetic intermediates for further stereospecific transfor- catalytic systems based on chiral Lewis acidic com-
mations and important structural motifs in biological- plexes of Cu(II),[7] Ni(II),[8] Cu(I),[9] Co(II),[10] or
ly active molecules.[1] Catalytic asymmetric electro- Zn(II)[11] have been found to be effective catalysts for
philic a-halogenation of carbonyl compounds can pro- asymmetric a-chlorination of 1,3-dicarbonyl com-
vide a direct access to enantioenriched a-halo carbon- pounds, which can form reactive enolates by chelation
yl compounds, and thus has gained considerable with the metal centers. The organocatalytic enantiose-
interests in recent years.[2] Several strategies based on lective a-chlorination of this type of substrates has
Lewis acid catalysis[3] or organocatalysis[4] have been also been recently developed by the groups of Bartoli,
successfully developed over the past decade for the Feng, and Dꢁaz-de-Villegas, respectively, using chiral
stereocontrolled construction of carbon halogen amines,[12] N,N’-dioxides,[13] or amino diol deriva-
À
bonds adjacent to either one or two carbonyl groups, tives[14] as the catalysts for the enolate generation.
with the most significant progresses being made in the High enantioselectivities have been achieved for the
area of a-fluorination reactions.[5] On the other hand, a-chlorination of 1,3-dicarbonyl compounds in some
the catalytic enantioselective a-chlorination reactions cases, but the protocols incorporating cheap chlorinat-
of carbonyl compounds have been relatively less ex- ing reagents, mild conditions, and excellent yields
plored, and catalytic systems with synthetically useful remain scarce. Herein, we report a highly efficient a-
enantioselectivities (>90% ee) and general substrate chlorination of cyclic b-keto esters by N-chlorosuc-
adaptability are still rare. In this regard, Hintermann
ACHTUNGTRENcNUNG inimide (NCS) using Cu(II) or Zn(II) complexes of
and Togni disclosed the first example of catalytic chiral spiro-2,2’-bichroman-based[15,16] bisoxazoline li-
asymmetric a-chlorination (also involving fluorination gands[17] (SPANbox 1,[18] Figure 1) as the catalysts.
1980
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1980 – 1986

Access to Both Enantiomers of a-Chloro-b-keto Esters with a Single Chiral Ligand
Table 1. Screening of Lewis acids in the catalytic enantio-
AHCTUNGTRENNUNG
selective chlorination of b-keto ester 2a.[a]
Entry Lewis acid
Time
[min]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
None
Sc(OTf)3
La(OTf)3
InCl3
InBr3
20
5
5
5
5
5
5
5
5
5
5
5
70
rac.
rac.
rac.
G
>99
>99
>99
>99
>99
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
G
10 (À)
10 (À)
3 (À)
rac.
2 (+)
10 (+)
56 (À)
86 (À)
21 (+)
84 (À)
33 (+)
85 (+)
rac.
In
Mg
Fe(OAc)2
Ni(ClO4)2·6H2O
CuOTf·0.5C6H6
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Figure 1. Chiral spiro bisoxazoline ligands (SPANbox 1)
used in this study.
E
9
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
Cu
Cu
Cu
Cu
Zn
Zn
ACHTUNGTRENNUNG
A
AHCTUNGTRENNUNG
N
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Under mild conditions, most of the reactions were ac-
complished in 5 min to afford the a-chloro-b-keto
esters in almost quantitative yields with good to high
enantioselectivities. Notably, the SPANbox complexes
of Cu(II) and Zn(II) are found to be complementary
to each other in the sense of asymmetric induction,
and both antipodes of the chlorinated product enan-
tiomers can be readily accessed using a single chiral
ligand simply by switching the metal salt from
5
5
5
[a]
Reaction conditions: 2a (0.1 mmol), Lewis acid
(10 mol%), 1a (18 mol%), NCS (1.2 equiv.), dichlorome-
thane solvent (0.75 mL), room temperature. Ad=1-ada-
mantyl.
Yield of the isolated product.
Determined by chiral HPLC.
[b]
[c]
CuACHTUNGTRENNUNG(OTf)2 to ZnACHTUNGTRENNUNG(OTf)2, or vice versa.
Results and Discussion
cupric salts and Zn
15). The identity of the anions also plays a prominent
The chiral spiro-bisoxazoline ligands SPANbox role in the catalysis. For instance, the catalyst generat-
ACHTUNGERTN(NUNG OTf)2 are exceptions (entries 10–
1 (Figure 1) were synthesized by following our previ- ed from CuACTHNURTGNENG(U OTf)2 and (S,R,S)-1a gave the product
ously published procedure.[18] As an initial investiga- (À)-3a with an ee value of 86% (entry 11), whereas
tion of the reaction, a number of commercially avail- changing the anion of the cupric salt to either acetate
able Lewis acidic metal salts in combination with or perchlorate led to an erosion in enantioselectivity
SPANbox ligand (S,R,S)-1a were examined as the po- or even a change in stereochemistry (entries 12 and
tential catalysts for the enantioselective chlorination 14). Similar behaviors can also be found in Zn(II)-
of a cyclic b-keto ester, 1-adamantyl 1-oxo-2,3-dihy- mediated reactions (entries 15 vs. 16). Most interest-
dro-1H-indene-2-carboxylate (2a). The reactions were ingly, the (S,R,S)-1a/ZnACTHNUTRGNEUNG(OTf)2 catalyst combination
performed in dichloromethane at room temperature afforded the (+)-3a in 85% ee, but with a complete
in the presence of a catalytic amount of Lewis acid reversal of enantioselectivity with respect to that of
(10 mol%) and the chiral ligand (S,R,S)-1a (S,R,S)-1a/CuACTHNUTRGENUG(N OTf)2 under the otherwise identical
(18 mol%), using NCS (1.2 molar equiv.) as the chlori- conditions (entries 15 vs. 11). In consideration of their
nating agents (Table 1). Clearly, 2a is a highly enoliza- complementary nature in asymmetric inductions, both
ble substrate, which readily underwent an uncatalyzed (S,R,S)-1a/CuACTHNUTRGNEN(UG OTf)2 and (S,R,S)-1a/ZnCAHTUGNTREN(NUGN OTf)2 catalyst
background reaction in the absence of any Lewis acid combinations were employed in subsequent reaction
to afford a racemic product 3a (entry 1). In all cases, studies.
the presence of a catalytic amount of Lewis acid
A general survey of the reaction conditions was
(10 mol%) was found to significantly accelerate the subsequently conducted for the enantioselective
reactions, however, the enantioselectivities varied chlorination of 2a, using the complexes generated in
widely (0–86% ee) depending on the salt used. While situ from (S,R,S)-1a and CuACTHNUTRGENN(UG OTf)2 or ZnACHTUGNTNER(NUGN OTf)2 as the
the majority of the examined metal salts only gave 3a catalyst, respectively. The reactions were typically per-
in nil or modest ee values (entries 1–9 and 16), some formed by treatment of a solution of 2a with an elec-
Adv. Synth. Catal. 2012, 354, 1980 – 1986
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1981

Jie Li et al.
Table 2. Screening of ligands 1a–h for CuACHTGNURETN(NUNG OTf)2- or ZnACTHGNUTRENNUG
(OTf)2-catalyzed enantioselective chlorination of b-keto ester 2a.[a]
FULL PAPERS
Entry
Ligand
3a [Cu(II)/1]
Yield [%][b]
3a [Zn(II)/1]
Yield [%][b]
ee [%][c]
ee [%][c]
1
2
3
4
5
6
7
8
U
>99
99
91
>99
>99
>99
>99
>99
90
>99
99
>99
99
>99
>99
90 (À)
15 (+)
73 (À)
rac.
71 (À)
25 (À)
rac.
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
88 (+)
14 (À)
66 (+)
rac.
79 (+)
rac.
24 (+)
29 (+)
10 (+)
6 (+)
49 (+)
7 (+)
29 (+)
4 (+)
2 (+)
rac.
9
69 (À)
9 (À)
43 (À)
rac.
10
11
12
13
14
15
35 (À)
rac.
3 (À)
[a]
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
[b]
[c]
trophilc chlorinating agent (1.2 equiv.), generally propanol (HFIP, 1.0 equiv.) was found to have a bene-
NCS, in the presence of a catalytic amount of ligand ficial effect on the enantioselectivity, leading to an en-
(S,R,S)-1a together with Cu
Zn(OTf)2 (10 mol%). Many reaction parameters were Supporting Information). Finally, a screening of reac-
found to have an influence on the reactivity and/or tion conditions for (S,R,S)-1a/Zn(OTf)2-catalyzed
ACHTUNGRTEN(NUGN OTf)2 (10 mol%) or hancement of ee value of 3a to 90% (Table S6 in the
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
enantioselectivity of the catalysis, including the metal chlorinations of 2a (Table S7–Table S11 in the Sup-
to ligand molar ratio, solvent, catalyst concentration, porting Information) revealed a behavior somewhat
temperature, additive, as well as the chlorinating parallel to that of 1a/CuACTHNUTRGNEUNG(OTf)2 catalysis. In this case,
agent (for details, see Table S1–Table S11 in the Sup- the reaction was found to be best conducted in 1,2-di-
porting Information). As a result, the reaction per- chloroethane (DCE) at 608C for 5 min, using NCS as
formed in dichloromethane at room temperature with the chlorine source and with a metal to ligand molar
a catalyst concentration of 0.13 mM and a metal to ratio of 1:2.2, to give a quantitative yield of (+)-3a in
ligand molar ratio of 1:1.8 was found to be beneficial 95% ee (entry 2, Table S11 in the Supporting Informa-
for the (S,R,S)-1a/CuACHTNUTRGNE(NUG OTf)2-catalyzed chlorination of tion).
2a,[19] giving a quantitative yield of (À)-3a in 5 min
In order to identify the optimal ligand(s), the li-
with an ee value of 86% (entry 4, Table S1 in the Sup- brary of chiral SPANbox ligands (S,R,S)- and (S,S,S)-
porting Information). A deviation from these condi- 1 was screened for the chlorination of 2a catalyzed by
tions led to some loss in enantioselectivity (Table S1– CuACTHNUGTRENNUG(OTf)2 or ZnACHTUTGNREN(NUGN OTf)2, respectively. The reactions
Table S4 in the Supporting Information). Further were conducted at room temperature in CH2Cl2 [for
scrutiny of some electrophilic chlorinating agents re- Cu(II)] or DCE [for Zn(II)] using NCS as the chlor-
vealed that NCS was still the best one in terms of ine source, and the results are summarized in Table 2.
both activity and enantioselectivity for the Cu(II)-cat- While almost all the catalyst combinations were
alyzed reaction (Table S5 in the Supporting Informa- highly active in this reaction (>99% yield in 5 min),
tion). Some common additives were examined for the ee values of the chlorinated product 3a varied
(S,R,S)-1a/Cu
ACHTUNGTRENNUNG(OTf)2-catalyzed chlorination as well, widely (0–90%) depending on the ligand structure. It
among which the weak Brønsted acid hexafluoro-2- is noteworthy that for each SPANbox ligand, the
1982
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1980 – 1986

Access to Both Enantiomers of a-Chloro-b-keto Esters with a Single Chiral Ligand
CuACHTUNGTRENNUNG(OTf)2- and ZnCAHTUNGTERN(NGUN OTf)2-mediated reaction demon- indanyl, or tert-butyl-substituted ligands (S,R,S)-1f–h
strated an enantioselectivity level parallel to each and (S,R,S)-1d only led to poor enantioselectivities
other, but always with the opposite sense of chiral in- (entries 7, 11, 13, and 15). In these cases the sterically
duction (columns 4 vs. 6 in Table 2). In addition, the encumbering oxazolyl substituents might hinder or in-
match or mismatch of the chiralities on the spiro hibit the substrate coordination and hence prevent its
backbone (axial) and oxazolinyl (central) moieties of activation, presumably as a result of steric congestion
1 was found to have a considerable impact on the caused by their proximity to the catalytic metal
asymmetric induction of the catalysis. The reactions center. Overall, (S,R,S)-1a was found to be optimal in
with (S,R,S)-1 generally afforded the product 3a with terms of enantioselectivity for both Cu
ee values higher than those obtained using their corre- Zn
sponding (S,S,S)-counterparts (entries 1 vs. 2, 3 vs. 4, 5 or (+)-antipodes of 3a, respectively, both in high ee
ACHTUNGRTENN(UNG OTf)2- and
(OTf)2-catalyzed chlorination of 2a, providing (À)-
vs. 6, 9 vs. 10, 11 vs. 12, and 13 vs. 14, respectively), in- values (entry 1).
dicating that (S,R,S) should be the matched pair for
both Cu(OTf)2- and Zn(OTf)2-catalyzed reactions. Fi- NCS was extended to a variety of cyclic b-keto ester
nally, the substituents on the oxazolinyl moieties of substrates 2a–m, using Cu(OTf)2/A(S,R,S)-1a or
the (S,R,S)-1 were also found to have a significant Zn(OTf)2/A(S,R,S)-1a as the catalyst under their re-
Therefore, the enantioselective chlorination with
A
ACHTUNGTRENNUNG
A
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
effect on the enantioselectivity. For instance, the reac- spective optimized reaction conditions. As shown in
tions involving phenyl-substituted ligand (S,R,S)-1a Table 3, most of the reactions were completed in 5–
afforded 3a with high ee values (entry 1), whereas 10 min under mild conditions, to afford the chlorinat-
sterically more bulky 1-naphthyl-, 2-naphthyl-, cis-1,2- ed products in good to excellent yields (82 to >99%).
(OTf)2-catalyzed asymmetric chlorination of b-oxo esters 2a–m.[a]
Table 3. ACHTUNGTRENNUNG(S,R,S)-1a complex of CuACHTUNTRGEG(NNUN OTf)2- or ZnACHTUNGTRENNUGN
Entry
Product
3 [Cu(II)/1a]
Yield [%][b]
3 [Zn(II)/1a]
Yield [%][b]
ee [%][c]
90 (À)
ee [%][c]
94[f] (+)
1
2
3
4
5
6
>99
>99[d]
>99
82
99[f]
90[d](À)
74 (À)
64 (À)
63 (À)
81 (À)
81 (À)
>99[f]
>99
83[f] (+)
28 (+)
[g]
[g]
–
–
[g]
[g]
99
–
–
89
>99
>99
90 (+)
89 (+)
7
98
Adv. Synth. Catal. 2012, 354, 1980 – 1986
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1983

Jie Li et al.
FULL PAPERS
Table 3. (Continued)
Entry
Product
3 [Cu(II)/1a]
Yield [%][b]
3 [Zn(II)/1a]
ee [%][c]
92 (À)
Yield [%][b]
ee [%][c]
96 (+)
8
98
97
84
>99
9
84 (À)
63 (À)
82 (À)
99
95 (+)
90[f] (+)
92 (+)
10
>99f)
>99
11
12
99
98[e]
75[e] (À)
97 (À)
>99[f]
81[f] (+)
92 (+)
13[h]
85
80
[a]
Unless otherwise specified, all reactions were performed for 5 min with 2a–l (0.1 mmol) using NCS (1.2 equiv.) as the
chlorinating agent, in the presence of the catalyst geneated in situ by mixing of Cu(OTf)2 (10 mol%) with ligand
1 (18 mol%) in CH2Cl2 (0.75 mL), or Zn(OTf)2 (10 mol%) with ligand 1 (22 mol%) in DCE (0.75 mL), respectively. The
reactions with Cu(OTf)2 were carried out at room temperature in the presence of HFIP (1.0 equiv.) as the additive,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
whereas the reactions involving Zn
Yield of the isolated product.
Determined by chiral HPLC.
ACHTUNGRTEN(NUNG OTf)2 were performed at 608C.
[b]
[c]
[d]
[e]
[f]
Cu
Reaction time: 10 min.
Zn(OTf)2 (5 mol%) and (S,R,S)-1a (11 mol%).
ACHTUNGTRENNUNG(OTf)2 (5 mol%) and (S,R,S)-1a (9 mol%).
ACHTUNGTRENNUNG
[g]
[h]
Not examined.
Reaction time: 30 min.
A general trend with respect to the enantioselectivity only modest ee values (see the Supporting Informa-
is clearly discernible for both Cu(II)- and Zn(II)-cata- tion). These results suggested that the SPANbox
lyzed chlorination of 2-carboxylate indanones 2a–e, (S,R,S)-1a complexes of CuACTHNUTRGENN(UG OTf)2 and ZnACHTUGNTERN(NUGN OTf)2 can
i.e., the sterically bulkier ester substituents (1-ada- show complementary results to each other in the
mantyl or t-Bu) generally impart higher enantioselec- chlorination reactions,[20] presumably as a result of
tivity in the chlorinated products 3a–e (entries 1 and 2 a change in the coordination geometry in the copper
vs. 3-5). Remarkably, Cu
Zn(OTf)2/A(S,R,S)-1a were found to afford the oppo-
(S,R,S)-1a and and zinc catalysts.[21]
ACHUTGTNRNENUG(OTf)2/ACHTUNGTRENNUGN
N
CHTUNGTRENNUNG
site enantiomers in the chlorination of of adamantyl
b-keto esters 2a and 2f–l, with good to high ee values Conclusions
(63–96%) being attained in the chlorinated products
(entries 1 and 6–12). Excellent results have also been SPANbox complexes of CuACTHNUTRGENN(UG OTf)2 and ZnACHTUGNTERN(NUGN OTf)2 were
obtained for the chlorination of cyclopentanone deriv- found to be highly efficient catalysts for enantioselec-
ative 2m (entry 13). In the case of tert-butyl 2-methyl- tive chlorination of cyclic b-keto esters using the com-
3-oxo-3-phenylpropanoate, a more challenging acyclic mercially available NCS as the cheap chlorinating
b-keto ester, the chlorination product was obtained in agent, affording the chlorinated products in good to
good yields after a prolonged time (12 h), but with excellent yields (82 to >99%) with high enantioselec-
1984
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ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1980 – 1986

Access to Both Enantiomers of a-Chloro-b-keto Esters with a Single Chiral Ligand
References
tivity (up to 97% ee) in 5–30 min under mild condi-
tions. Intriguingly, Cu(II)- and Zn(II)-catalyzed reac-
tions with a single SPANbox ligand produce the
chlorinated products with opposite enantioselection in
good to high enantiopurity, indicating that both anti-
podes of the chlorinated b-keto ester enantiomers can
be readily accessed by simply switching the zinc(II)
and copper(II) salts in the present system. These fea-
tures suggest that the method can potentially be ex-
tended to asymmetric reactions involving the use of
other nucleophiles.
[1] a) N. D. Kimpe, R. Verhꢃ, The Chemistry of a-Halo-
AHCTUNGTREGkNNUN etones, a-Haloaldehydes, and a-Haloimines, John
Wiley & Sons, New York, 1988; b) G. Thomas, Medici-
nal Chemistry: An Introduction, 2nd edn., John Wiley
& Sons, Chichester, 2007.
[2] For a highlight, see: a) M. Oestreich, Angew. Chem.
2005, 117, 2376–2379; Angew. Chem. Int. Ed. 2005, 44,
2324–2327. For reviews, see: b) H. Ibrahim, A. Togni,
Chem. Commun. 2004, 1147–1155; c) S. France, A.
Weatherwax, T. Lectka, Eur. J. Org. Chem. 2005, 475–
479.
[3] For a review, see: A. M. R. Smith, K. K. Hii, Chem.
Rev. 2011, 111, 1637–1656.
[4] For a review, see: G. Guillena, D. J. Ramon, Tetrahe-
Experimental Section
dron: Asymmetry 2006, 17, 1465–1492.
General Procedure for CuACHTNUTRGENNG(U OTf)2/SPANbox-Catalyzed
Enantioselective Chlorination of b-Keto Esters
[5] For reviews: a) J. A. Ma, D. Cahard, Chem. Rev. 2004,
104, 6119–6146; b) S. Lectard, Y. Hamashima, M. So-
deoka, Adv. Synth. Catal. 2010, 352, 2708–2732; c) T.
Furuya, A. S. Kamlet, T. Ritter, Nature 2011, 473, 470–
477.
[6] a) L. Hintermann, A. Togni, Helv. Chim. Acta 2000, 83,
2425–2435; b) H. Ibrahim, F. Kleinbeck, A. Togni,
Helv. Chim. Acta 2004, 87, 605–610; c) L. Hintermann,
M. Perseghini, A. Togni, Beilstein J. Org. Chem. 2011,
7, 1421–1435.
[7] a) M. Marigo, N. Kumaragurubaran, K. A. Jørgensen,
Chem. Eur. J. 2004, 10, 2133–2137; b) M. Frings, C.
Bolm, Eur. J. Org. Chem. 2009, 4085–4090. For an ex-
ample of Cu(II)-catalyzed enantioselective gem-chloro-
fluorination of active methylene compounds, see: c) K.
Shibatomi, A. Narayama, Y. Soga, T. Muto, S. Iwasa,
Org. Lett. 2011, 13, 2944–2947.
To an anhydrous dichloromethane solution (0.75 mL) of
copper(II) triflate (3.6 mg, 0.01 mmol) and the SPANbox
ligand 1a (11.2 mg, 0.018 mmol) in a 5-mL Schlenk tube was
added b-keto ester 2 (0.1 mmol), and the resulting mixture
was stirred under argon at room temperature for 0.5 h.
HFIP (11 mL, 0.1 mmol) was injected into the tube, and the
mixture was stirred further for 10 min at room temperature
before the chlorinating agent NCS (15.9 mg, 0.12 mmol) was
added. After completion of the reaction as indicated by
TLC analysis (5–10 min), the solvent was evaporated under
vacuum and the residue was purified by column chromatog-
raphy on silica gel with petroleum ether/ethyl acetate (20:1)
as the eluent. The ee value of the a-chloro-b-keto ester 3
was determined by chiral HPLC.
[8] a) N. Shibata, J. Kohno, K. Takai, T. Ishimaru, S. Naka-
mura, T. Toru, S. Kanemasa, Angew. Chem. 2005, 117,
4276–4279; Angew. Chem. Int. Ed. 2005, 44, 4204–4207;
b) K. Shibatomi, Y. Tsuzuki, S. Iwasa, Chem. Lett.
2008, 37, 1098–1099.
[9] a) M.-H. Qi, F.-J. Wang, M. Shi, Tetrahedron: Asymme-
try 2010, 21, 247–253; b) J. J. Jiang, J. A. Huang, D.
Wang, Z. L. Yuan, M. X. Zhao, F. J. Wang, M. Shi,
Chirality 2011, 23, 272–276.
General Procedure for ZnACHTNUTRGENNG(U OTf)2/SPANbox-Catalyzed
Enantioselective Chlorination of b-Keto Esters
Zinc(II) triflate (1.8 mg, 0.005 mmol) and the SPANbox
ligand 1a (6.8 mg, 0.011 mmol) were dissolved in anhydrous
1,2-dichloroethane (0.37 mL) in a 5-mL Schlenk tube, and
the solution was stirred at 608C under argon for 1 h. The b-
keto ester 2 (0.1 mmol) was added, and the resulting mix-
ture was stirred further at 608C for 0.5 h before the chlori-
nating agent NCS (15.9 mg, 0.12 mmol) was added. The re-
action mixture was stirred at this temperature for a short
period (ca. 5 min) until TLC indicated the completion of the
reaction. The solvent was evaporated under vacuum and the
residue was purified by column chromatography on silica
gel with petroleum ether/ethyl acetate (20:1) as the eluent.
The ee value of the a-chloro-b-keto ester 3 was determined
by chiral HPLC.
[10] M. Kawatsura, S. Hayashi, Y. Komatsu, S. Hayase, T.
Itoh, Chem. Lett. 2010, 39, 466–467.
[11] Chiral bisoxazoline complexes of Zn(II) have been
used in enantioselective chlorination and fluorination
of b-keto phosphonates, a class of closely related che-
lating carbonyl substrates. See: L. Bernardi, K. A. Jør-
gensen, Chem. Commun. 2005, 1324–1326.
[12] G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Mel-
chiorre, L. Sambri, Angew. Chem. 2005, 117, 6375–
6378; Angew. Chem. Int. Ed. 2005, 44, 6219–6222.
[13] Y. Cai, W. Wang, K. Shen, J. Wang, X. Hu, L. Lin, X.
Liu, X. Feng, Chem. Commun. 2010, 1250–1252.
[14] P. Etayo, R. Badorrey, M. D. Dꢁaz-de-Villegas, J. A.
Gꢄlvez, Adv. Synth. Catal. 2010, 352, 3329–3338.
[15] The spiro-2,2’-bichroman motif has been used by van
Leeuwen and co-workers for the construction of bis-
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (Nos. 20972176, 21172237, 21121062), the
Major Basic Research Development Program of China (No.
2010CB833300), and the Chinese Academy of Sciences is
gratefully acknowledged.
AHCTUNGTREGpNNUN hosphine ligands (SPANphos) that are prone to trans-
ligation as well as some modular diamine ligands, for
leading works, see: a) Z. Freixa, M. S. Beentjes, G. D.
Adv. Synth. Catal. 2012, 354, 1980 – 1986
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1985

Jie Li et al.
FULL PAPERS
Batema, C. B. Dieleman, G. P. F. van Strijdonck,
J. N. H. Reek, P. C. J. Kamer, J. Fraanje, K. Goubitz,
P. W. N. M. van Leeuwen, Angew. Chem. 2003, 115,
1322–1325; Angew. Chem. Int. Ed. 2003, 42, 1284–1287;
b) Z. Freixa, P. C. J. Kamer, M. Lutz, A. L. Spek,
P. W. N. M. van Leeuwen, Angew. Chem. 2005, 117,
4459–4462; Angew. Chem. Int. Ed. 2005, 44, 4385–4388;
c) C. Jimꢃnez-Rodrꢁguez, F. X. Roca, C. Bo, J. Benet-
Buchholz, E. C. Escudero-Adꢄn, Z. Freixa, P. W. N. M.
van Leeuwen, Dalton Trans. 2006, 268–278; d) X. Sala,
E. J. Garcꢁa Suꢄrez, Z. Freixa, J. Benet-Buchholz,
P. W. N. M. van Leeuwen, Eur. J. Org. Chem. 2008,
6197–6205. Very recently, we developed a catalytic
asymmetric synthesis of aromatic spiroketals, which
provided a facile synthesis of enantiopure analogous
SPANphos: e) X. Wang, Z. Han, Z. Wang, K. Ding,
Angew. Chem. 2012, 124, 960–964; Angew. Chem. Int.
Ed. 2012, 51, 936–940.
[18] Very recently, the Zn(II) complexes of this class of li-
gands have been shown to be highly efficient in the cat-
alytic asymmetric hydroxylation of b-keto esters, see: J.
Li, G. Chen, Z. Wang, R. Zhang, X. Zhang, K. Ding,
Chem. Sci. 2011, 2, 1141–1144.
[19] The importance of metal/ligand ratios in copper-bisoxa-
zoline catalysis has been demonstrated for other sys-
tems, for examples, see: a) R. Rasappan, M. Hager, A.
Gissibl, O. Reiser, Org. Lett. 2006, 8, 6099–6102; b) A.
Schꢅtz, R. Rasappan, M. Hager, A. Gissibl, O. Reiser,
Chem. Eur. J. 2008, 14, 7259–7265; c) M. Hager, S.
Wittmann, A. Schꢅtz, F. Pein, P. Kreitmeier, O. Reiser,
Tetrahedron: Asymmetry 2010, 21, 1194–1198. In these
studies, an excess of ligands was shown to have a detri-
mental effect on the catalysis. Even when an excess of
ligand 1a is used for the present catalysis using
ZnACHTNUGTRENNUG(OTf)2 or CuACHTUGNTREN(NUNG OTf)2 salt, our previous study on
a mechanistically related hydroxylation of keto esters
using the same zinc catalyst (ref.[18]) suggested the cata-
lytically active species in the chlorination reaction
should be a 1:1 M/L species. The mass spectrum of Cu-
[16] The spiro backbone has been recognized as one type of
the privileged structures for chiral ligand construction:
a) A. S. C. Chan, W. H. Hu, C. C. Pai, C. P. Lau, Y. Z.
Jiang, A. Q. Mi, M. Yan, J. Sun, R. L. Lou, J. G. Deng,
J. Am. Chem. Soc. 1997, 119, 9570–9571; b) M. A.
Arai, M. Kuraishi, T. Arai, H. Sasai, J. Am. Chem. Soc.
2001, 123, 2907–2908; c) T. Tsujihara, K. Takenaka, K.
Onitsuka, M. Hatanaka, H. Sasai, J. Am. Chem. Soc.
2009, 131, 3452–3453; d) Y. Fu, J.-H. Xie, A.-G. Hu, H.
Zhou, L.-X. Wang, Q.-L. Zhou, Chem. Commun. 2002,
480–481; e) S.-F. Zhu, Y. Cai, H. Mao, J.-H. Xie, Q.-L.
Zhou, Nat. Chem. 2010, 2, 546–551; f) Z. Han, Z.
Wang, X. Zhang, K. Ding, Angew. Chem. 2009, 121,
5449–5453; Angew. Chem. Int. Ed. 2009, 48, 5345–5349;
g) K. Shibatomi, T. Muto, Y. Sumikawa, A. Narayama,
S. Iwasa, Synlett 2009, 241–244; h) K. Shibatomi, A.
Narayama, Y. Soga, T. Muto, S. Iwasa, Org. Lett. 2011,
13, 2944–2947. For reviews, see: i) Privileged Chiral Li-
gands and Catalysts, (Ed.: Q.-L. Zhou), Wiley-VCH:
Weinheim, 2011; j) J.-H. Xie, Q.-L. Zhou, Acc. Chem.
Res. 2008, 41, 581–593; k) G. B. Bajracharya, M. A.
Arai, P. S. Koranne, T. Suzuki, S. Takizawa, H. Sasai,
Bull. Chem. Soc. Jpn. 2009, 82, 285–302; l) K. Ding, Z.
Han, Z. Wang, Chem. Asian J. 2009, 4, 32–41.
AHCTUNGRTEGNUN(N OTf)2/1a also indicated the presence of an 1:1 species
along with a significant amount of free ligand 1a (see
the Supporting Information), indicating an equilibra-
tion of the species in the precatalyst solution. Presuma-
bly, an excess of ligand is required to suppress the
background reaction promoted by ligand-free and un-
selective metal centers.
[20] Similar behavior has been observed in bisoxazoline
complexes-catalyzed asymmetric fluorination of keto
esters, where the choice of the metal salt Cu or Ni has
been shown to afford opposite enantioselectivity, see:
N. Shibata, T. Ishimaru, T. Nagai, J. Kohno, T. Toru,
Synlett 2004, 1703–1706.
[21] Assuming tetracoordinated modes adopted by SPAN-
box metal enolate intermediates for Cu
Zn(OTf)2-mediated catalysis might account for their
complementary nature in enantioselection. The reac-
tion involving Cu(OTf)2 is likely to proceed via
square-planar SPANbox-Cu-enolate intermediate,
whereas the one with Zn(OTf)2 should favor the forma-
ACHTUNGRTEN(NUNG OTf)2- or
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
a
AHCTUNGTRENNUNG
tion of a tetrahedral SPANbox-Zn-enolate intermediate
[17] Bisoxazoline ligands (Box) are one type of the most
versatile chiral inducers in various transition metal-cat-
alyzed asymmetric reactions, for reviews, see: a) A. K.
Ghosh, M. Packiarajan, J. Cappiello, Tetrahedron:
Asymmetry 1998, 9, 1–45; b) H. A. McManus, P. J.
Guiry, Chem. Rev. 2004, 104, 4151–4202; c) G. Desimo-
ni, G. Faita, K. A. Jørgensen, Chem. Rev. 2006, 106,
3561–3651.
as a result of filled d orbitals (d10) in Zn(II). Chiral bis-
AHCTUNGTREGoNNUN xazoline metal-bound substrates with these two geo-
metries can afford opposite selectivity, since rotation of
a coordinated substrate by 908 moves its accessible face
from the shielded into the unshielded region, and vice
versa. For an excellent review, see: R. Rasappan, D.
Laventine, O. Reiser, Coord. Chem. Rev. 2008, 252,
702–714.
1986
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1980 – 1986