The long-arm effect: Influence of axially chiral phosphoramidite ligands on the diastereo- and enantioselectivity of the tandem 1,4-addition/fluorination

Article abstract of DOI:10.1002/anie.201104565

Long arm of the law: The long-armed phosphoramidite 1 was used as a catalyst for the title reaction of acyclic alkylidene β-ketoesters with dialkylzinc and fluorinating reagents. The products, containing adjacent carbon- and fluorine-substituted stereocenters, are obtained in high yield as well as diastereo- and enantioselectivity. NSFI=N-fluorobenzenesulfonimide.

Full text of DOI:10.1002/anie.201104565

Communications
DOI: 10.1002/anie.201104565
Asymmetric Catalysis
The Long-Arm Effect: Influence of Axially Chiral Phosphoramidite
Ligands on the Diastereo- and Enantioselectivity of the Tandem
1,4-Addition/Fluorination**
Lian Wang, Wei Meng, Chuan-Le Zhu, Yan Zheng, Jing Nie, and Jun-An Ma*
Dedicated to Professor Wei-Yuan Huang on the occasion of his 90th birthday
Chiral monodentate phosphoramidites provide an important
class of ligands, and enjoy high prestige in the field of
asymmetric catalysis.[1] In this context, binol-derived phos-
phoramidites have emerged as a highly versatile and readily
accessible subset of chiral ligands. Most of these ligands with
subtle structural variations at the amine moiety have been
proven to be highly effective in a wide range of asymmetric
reactions.[2] In sharp contrast to the great success of the simple
phosphoramidites A, limited progress has been made to
bond with concurrent generation of two contiguous stereo-
genic centers.[4] However, the stereocenter flanked by both
carbonyl groups may suffer potential loss of its stereochem-
ical integrity as a result of rapid epimerization. Consequently,
little progress has been made in the use of alkylidene b-
ketoesters as Michael acceptors. Only recently, two impres-
sive studies by Hird and Hoveyda,[5a] and Shizuka and
Snapper[5b] have led to the development of catalytic enantio-
selective additions of dialkylzinc and allylsilane reagents to
cyclic alkylidene b-ketoesters as mixtures of ketone/enol
tautomers, but it was not known whether these strategies were
applicable to acyclic alkylidene b-ketoesters. Herein, we
developed a novel catalytic asymmetric tandem 1,4-addition/
fluorination process by using fluorinating reagents as the
terminal electrophile. This approach not only helps solve the
longstanding problem of epimerization of the adduct, but also
introduces a fluorine-containing chiral center [Eq. (1)].
attach the bulky groups directly at the 3,3’-positions of the
binaphthol backbone.[3] In our efforts to develop superior
catalysts for new and challenging asymmetric reactions, we
considered a long-arm approach, and envisioned that intro-
duction of the bulky substituents at the 3- and 3’-position of
the binaphthol unit could positively influence the stereose-
lectivity of asymmetric transformations by narrowing the
space around the P-ligated metal center as well as relaying the
axial chirality to the reaction site. This strategy led to the
discovery of the new catalysts B, which gives access to
enantiomeric fluorinated products of a catalyzed tandem
sequence.
Owing to the unique properties of fluorinated compounds,
stereoselective construction of organofluorine molecules
under mild reaction conditions has been highly desirable in
organic and medicinal chemistry.[6] We demonstrate that, in
the presence of the new chiral ligands B, the present tandem
transformation provides a facile route to chiral fluorinated
products with adjacent carbon- and fluorine-substituted
tertiary and quaternary stereocenters, respectively, in high
yield (up to 91%) and excellent diastereo- and enantioselec-
tivity (up to 99:1 d.r., 98% ee).[7]
In a first series of experiments, six known binol-derived
monodentate phosphoramidite ligands 1a–f (Figure 1) were
screened in the copper-catalyzed tandem reaction of the
acyclic alkylidene b-ketoester 2a with N-fluorobenzenesulfo-
nimide (NFSI) as the electrophilic fluorinating reagent in
dichloromethane at 08C. The results are listed in Table 1. It
was found that all such ligands gave uniformly high diaste-
reoselectivity (entries 1–6). A moderate yield with modest
enantioselectivity could be obtained in the presence of ligand
1b (entry 2). An ethyl group in the amino moiety was found
to be optimal among other the alkyl groups (entries 1 and 3–
Conjugate addition of organometallic reagents to alkyli-
dene b-ketoesters results in the formation of a carbon–carbon
[*] L. Wang, W. Meng, C.-L. Zhu, Dr. Y. Zheng, Dr. J. Nie, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (China)
E-mail: majun_an68@tju.edu.cn
Prof. J.-A. Ma
State Key Laboratory of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071 (China)
[**] This work was supported financially by the NSFC (No. 20972110 and
21002068). We also thank Dr. Dominique Cahard (CNRS &
Universitꢀ et INSA de Rouen, France) for helpful discussions and
suggestions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104565.
9442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9442 –9446

Table 1: Screening of ligands and condition optimization for the tandem
reaction.
Entry
Ligand
Solvent
T [8C]
Yield [%][a]
d.r.[b]
ee [%][c]
With first generation ligands:
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
THF
benzene
xylene
toluene
toluene
toluene
toluene
toluene
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
50
42
37
39
40
35
58
22
30
44
40
15
60
42
55
52
60
68
60
65
81
63
93:7
96:4
96:4
96:4
96:4
92:8
95:5
95:5
95:5
97:3
97:3
98:2
98:2
93:7
92:8
95:5
97:3
98:2
97:3
98:2
98:2
97:3
30
45
20
22
29
31
70
5
55
57
74
76
76
67
74
75
74
76
76
79
84
84
9
10
11
12
13
14
15
16
17
18
19[d]
20
21[e]
22[e]
1l
1m
1m
1m
1m
1m
1m
1m
1m
1m
1m
Figure 1. Design of ligands used for screening.
6). After a systematic study of various substituents (Figure 1;
entries 7–13), we were pleased to find that ligand 1m, which
incorporates a 4-biphenyl substituent at the 3- and 3’-positions
of the binaphthyl backbone, affords the tandem product 3a in
60% yield with good enantioselecitivity (76% ee). Further
optimization of the enantioselectivity was achieved with
ligand 1m by screening different solvents and lowering the
reaction temperature (entries 14–22). Thus, the tandem
reaction of the alkylidene b-ketoester 2a could be efficiently
performed in toluene at À408C providing the fluorinated
product 3a in 81% yield with a 98:2 d.r. and 84% ee. These
results clearly validate the strategy and suggested that
additional improvement on the enantioselectivity might be
feasible by fine-tuning the substituents at the 3- and 3’-
positions of the binaphthyl bakcbone. The initial success with
the 4-biphenyl-substituted ligand 1m prompted us to design
and synthesize a second generation of the phosphoramidite
ligands containing substituted biphenyl groups. Gratifyingly,
examination on the second generation ligands in the same test
reaction revealed that the enantioselectivity can be signifi-
cantly improved from 84% ee (1m; entries 21 and 22) to
90% ee (1q) and 94% ee (1r; entries 26–27). The evolution of
the ligand 1r seems to have followed a well-defined modular
modification on the biphenyl skeleton as summarized in
Figure 1. No less remarkable is the diastereoselectivity of the
process, which amounts to greater than 99:1 d.r. for the
catalyst 1r. These results highlight the power of combining
rational design and systematic screening in catalyst develop-
ment.
À20
À40
À50
With second generation ligands:
23[e]
24[e]
25[e]
26[e]
27[e]
1n
1o
1p
1q
1r
toluene
toluene
toluene
toluene
toluene
À40
À40
70
69
84
72
81
99:1
98:2
99:1
98:2
99:1
78
82
84
90
94
À40
À40
À40
[a] Yield of isolated product. [b] Determined by 19F NMR analysis of the
crude reaction mixture. [c] The ee value was determined by HPLC
analysis using a chiral stationary phase and is given only for the major
diastereoisomer. [d] 2 mol% Cu(OTf)2 was used. [e] Reaction time was
48 h.
substituents on both the ketone and the alkylidene moieties
spanning a diverse range of sterically and electronically
different groups. The tandem reactions all proceeded
uneventfully to give the fluorinated products 3a–o in good
yields (78–91%) and high enantioselectivities (86–98% ee)
with nearly perfect diastereoselectivities (entries 1–15). Alky-
lidene b-ketoesters bearing heteroaromatic rings also fur-
nished the corresponding fluorinated products (entries 16 and
17). It is worth noting that alkyl-substituted substrates also
provided the tandem products 3r and 3s in good yields and
enantioselectivities with high diastereoselectivities (entries 18
and 19). The effect of other dialkylzinc reagents (Me2Zn,
nPr2Zn, nBu2Zn) was next probed (entries 20–22). The
ee values obtained with the Me, Et, nPr, and nBu zinc
reagents follow a rather interesting trend in their reaction
with the same substrate and seem to correlate well the size of
the alkyl groups, that is, 85% ee (Me), 94% ee (Et), 97% ee
(nPr), and 96% ee (nBu). A possible rationalization could be
With an effective chiral catalyst in hand, we next inves-
tigated the scope of the catalytic tandem reaction by employ-
ing a range of acyclic alkylidene b-ketoesters and dialkylzinc
reagents, and the results are summarized in Table 2. The
substrate scope appeared to be exceedingly broad, with aryl
Angew. Chem. Int. Ed. 2011, 50, 9442 –9446
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9443

Communications
Table 2: The scope of the copper-catalyzed asymmetric tandem reaction of the alkylidene b-ketoesters 2.
Entry
Product
Yield
[%][a]
d.r.[b]
ee
Entry
Product
Yield
[%][a]
d.r.[b]
ee
[%][c]
[%][c]
1
3a
3b
3c
3d
81
84
91
82
>99:1
94
92
96
92
12
3l
89
80
84
80
>99:1
95
88
95
93
2
3
4
>99:1
99:1
13
14
15
3m
3n
3o
>99:1
97:3
>99:1
>99:1
5
3e
87
>99:1
87
16
3p
72
82
95:5
6
3 f
3g
3h
3i
78
79
82
81
89
91
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
98
94
97
90
94
86
17
18
19
20
21
22
3q
3r
86
77
76
90
81
79
>99:1
84
84
86
85
97
96
7
96:4
8
3s
3t
>99:1
9
>99:1
>99:1
>99:1
10
11
3j
3u
3v
3k
[a] Yield of isolated product. [b] Determined by 19F NMR analysis of the crude reaction mixture. [c] The ee value was determined by HPLC analysis using
a chiral stationary phase and the absolute configuration of other adducts were assigned on the basis of analogy with study of 3a (Scheme 2).
the tendency for the larger nucleophiles to react more
stereoselectively with the enone substrate.
fluorobenzenesulfonimide afforded the fluorinated product
3a in 61% yield with moderate diastereoselectivity (75:25
d.r.; Scheme 1). These results show that the one-pot tandem
trap is crucial for the transformation stereoselectivity.[8] In
addition, decarboxylation of the addition intermediate 4 gave
the acyclic ketones 5 in high yield and without detectable loss
of enantioselectivity. The absolute configuration of the
ketone was determined by preparing known compound 5.[9]
Notably, when the addition intermediate 4, isolated by
flash filtration through a thin layer of silica gel in almost
quantitative yield with 90:10 d.r. and 97% ee, was employed
as a substrate under the current tandem reaction conditions or
in the presence of diethyl zinc, no reaction was observed.
Subjection of the intermediate 4 to sodium hydride and N-
9444 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9442 –9446

the copper-catalyzed tandem 1,4-addition/fluorination
sequence. The tandem transformation can be performed
effectively with a range of acyclic alkylidene b-ketoesters and
various dialkylzinc reagents to afford the tandem fluorinated
products with adjacent carbon- and fluorine-substituted
quaternary and tertiary stereocenters. In particular, this new
class of modular phosphorus compounds enlarges the struc-
tural diversity of the binol-derived monodentate phosphor-
amidite ligands. Additional uses of these ligands in other
unexplored asymmetric transformations are ongoing in our
laboratories and will be reported in due course.
Received: July 1, 2011
Published online: August 30, 2011
Scheme 1. Stepwise synthesis of fluorinated product 3a (96% and
75% ee are for the major and minor diastereoisomer, respectively) and
decarboxylation of the addition intermediate 4.
Keywords: asymmetric catalysis · enantioselectivity · fluorine ·
.
ligand design · tandem reactions
[1] For selected reviews, see: a) T. Jerphagnon, J.-L. Renaud, C.
Bruneau, Tetrahedron: Asymmetry 2004, 15, 2101; b) M.
van den Berg, B. L. Feringa, A. J. Minnaard in Handbook of
Homogeneous Hydrogenation (Eds.: J. G. de Vries, C. J. Elsev-
ier), Wiley-VCH, Weinheim, 2007; c) M. T. Reetz, Angew.
Chem. 2008, 120, 2592; Angew. Chem. Int. Ed. 2008, 47, 2556;
d) A. Alexakis, J. E. Bꢀckvall, N. Krause, O. Pꢁmies, M. Diꢂguez,
Chem. Rev. 2008, 108, 2796; e) C. Hawner, A. Alexakis, Chem.
Commun. 2010, 46, 7295.
[2] Recent reviews, see: a) B. L. Feringa, Acc. Chem. Res. 2000, 33,
346; b) F. Lꢃpez, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res.
2007, 40, 179; c) J. F. Teichert, B. L. Feringa, Angew. Chem. 2010,
122, 2538; Angew. Chem. Int. Ed. 2010, 49, 2486.
[3] Recent examples of monodentate phosphoramidites with bulky
substituents at the 3,3’-positions of the binol core, see: a) M. T.
Reetz, J.-A. Ma, R. Goddard, Angew. Chem. 2005, 117, 416;
Angew. Chem. Int. Ed. 2005, 44, 412; b) M. Kruck, M. P. Munoz,
H. L. Bishop, C. G. Frost, C. J. Chapman, G. Kociok-Kçhn, C. P.
Butts, G. C. Lloyd-Jones, Chem. Eur. J. 2008, 14, 7808; c) I.
Alonso, B. Trillo, F. Lꢃpez, S. Montserrat, G. Ujaque, L. Castedo,
A. Lledꢃs, J. L. Mascarꢂnas, J. Am. Chem. Soc. 2009, 131, 13020;
d) A. Z. Gonzꢄlez, F. D. Toste, Org. Lett. 2010, 12, 200; e) H.
Teller, S. Flꢅgge, R. Goddard, Alois Fꢅrstner, Angew. Chem.
2010, 122, 1993; Angew. Chem. Int. Ed. 2010, 49, 1949; f) A. Z.
Gonzꢄlez, D. Benitez, E. Tkatchouk, W. A. Goddard III, F. D.
Toste, J. Am. Chem. Soc. 2011, 133, 5500.
[4] For reviews on the metal-catalyzed conjugate addition of
organometallic reagents, see: a) A. Alexakis, C. Benhaim, Eur.
J. Org. Chem. 2002, 3221; b) A. H. Hoveyda, A. W. Hird, M. A.
Kacprzynski, Chem. Commun. 2004, 1779; c) J. Christoffers, G.
Koripelly, A. Rosiak, M. Rçssle, Synthesis 2007, 1279; d) S. R.
Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L.
Feringa, Chem. Rev. 2008, 108, 2824; e) T. Thaler, P. Knochel,
Angew. Chem. 2009, 121, 655; Angew. Chem. Int. Ed. 2009, 48,
645; f) T. Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L.
Feringa, Chem. Soc. Rev. 2009, 38, 1039.
[5] a) A. W. Hird, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127,
14988; b) M. Shizuka, M. L. Snapper, Angew. Chem. 2008, 120,
5127; Angew. Chem. Int. Ed. 2008, 47, 5049.
[6] For recent reviews, see: a) P. Kirsch, Modern Fluoroorganic
Chemistry, Wiley-VCH, Weinheim, 2004; b) Special Issue on
“Fluorine in the Life Sciences”, ChemBioChem 2004, 5, 557;
c) K. Mikami, Y. Itoh, M. Yamanaka, Chem. Rev. 2004, 104, 1;
d) R. D. Chambers, Fluorine in Organic Chemistry, Blackwell,
Oxford, UK, 2004; e) A. M. Thayer, Chem. Eng. News 2006, 84,
15; f) J.-A. Ma, D. Cahard, Chem. Rev. 2008, 108, PR1; g) K. L.
Scheme 2. Scaled-up tandem reaction and transformation of the
fluorinated product.For the X-ray crystal structure the thermal ellip-
soids are shown at 50% probability.
As expected, almost the same result was obtained when
the model tandem reaction was scaled up to the gram scale
(Scheme 2). More significantly, the presence of the b-
ketoester moiety within the fluorinated products allows
access to optically enriched alcohols with three contiguous
stereogenic centers. For example, a reduction process using
NaBH4 gives rise to the corresponding a-fluoro-b-hydrox-
yesters 6 in good yield and excellent diastereoselectivity
without racemization. Furthermore, the single stereoisomer
of 6a proved to be crystalline, thus allowing the determina-
tion of the absolute configuration of three adjacent stereo-
genic centers by means of X-ray crystallographic analysis.[10]
In combination with the above-mentioned transformation
(Scheme 1), the absolute configuration of the major stereo-
isomer 6a was determined to be 2R,3S,2’R. Thus, the absolute
configuration of the tandem fluorinated product 3a is
assigned as 2R,3S.
In summary, we have developed a promising new gen-
eration of chiral monodentate phosphoramidite ligands for
Angew. Chem. Int. Ed. 2011, 50, 9442 –9446
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9445

Communications
Kirk, Org. Process Res. Dev. 2008, 12, 305; h) J. Hu, W. Zhang, F.
Wang, Chem. Commun. 2009, 7465; i) S. Lectard, Y. Hamashima,
M. Sodeoka, Adv. Synth. Catal. 2010, 352, 2708.
[8] It should be mentioned that the reaction activity is relatively low
when CuOTf is used instead of Cu(OTf)2. For example, in the
presence of 2.5 mol% (CuOTf)2·benzene and 10 mol% ligand
1r for 120 h, the tandem product 3a was obtained in 71% yield
with > 99:1 d.r. and 89% ee.
[9] a) X. Hu, H. Chen, X. Zhang, Angew. Chem. 1999, 111, 3720;
Angew. Chem. Int. Ed. 1999, 38, 3518; b) T. Uchida, T. Katsuki,
Tetrahedron Lett. 2009, 50, 4741.
[10] The relative and absolute configuration of 6a was confirmed by
X-ray crystal structure analysis, with all fluorinated products
assigned by analogy. CCDC 809079 (6a) contains the supple-
mentary 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.
[7] For previous tandem reactions for the asymmetric synthesis of
chiral fluorinated compounds, see: a) P. C. Andrews, V. Bhaskar,
K. M. Bromfield, A. M. Dodd, P. J. Duggan, S. A. M. Duggan,
T. D. McCarthy, Synlett 2004, 791; b) Y. Huang, A. M. Walji,
C. H. Larsen, D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
15051; c) Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, M.
Sodeoka, J. Am. Chem. Soc. 2005, 127, 10164; d) J. Nie, H.-W.
Zhu, H.-F. Cui, M.-Q. Hua, J.-A. Ma, Org. Lett. 2007, 9, 3053;
e) N. T. Vo, R. D. M. Pace, F. OꢆHara, M. J. Gaunt, J. Am. Chem.
Soc. 2008, 130, 404; f) H.-F. Wang, H.-F. Cui, Z. Chai, P. Li, C.-W.
Zheng, Y.-Q. Yang, G. Zhao, Chem. Eur. J. 2009, 15, 13299;
g) H.-F. Cui, Y.-Q. Yang, Z. Chai, P. Li, C.-W. Zheng, S.-Z. Zhu,
G. Zhao, J. Org. Chem. 2010, 75, 117.
9446 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 9442 –9446