P-Chirogenic Diaminophosphine Oxide: A New Class of Chiral Phosphorus Ligands for Asymmetric Catalysis

Article abstract of DOI:10.1021/ja031792a

We successfully synthesized a novel P-chirogenic diaminophosphine oxide 4, which was applied to catalytic enantioselective construction of quaternary carbon centers using Pd-catalyzed asymmetric allylic substitution with various β-keto esters (up to 99% yield, 94% ee). Preliminary mechanistic studies indicated that two molecules of 8 coordinate to the Pd metal in a monodentate fashion, resulting in the formation of Pd complex 9 (Pd:8 = 1:2), which functions as the active species. Copyright

Full text of DOI:10.1021/ja031792a

Published on Web 03/06/2004
P-Chirogenic Diaminophosphine Oxide: A New Class of Chiral Phosphorus
Ligands for Asymmetric Catalysis
Tetsuhiro Nemoto,† Takayoshi Matsumoto,† Takamasa Masuda,† Tsukasa Hitomi,†
Keiichiro Hatano,‡ and Yasumasa Hamada*,†
Graduate School of Pharmaceutical Sciences, Chiba UniVersity, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan, and
Faculty of Pharmaceutical Sciences, Nagoya City UniVersity, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received December 17, 2003; E-mail: hamada@p.chiba-u.ac.jp
Scheme 1. Synthesis of Diaminophosphine Oxide 4a
Considerable effort has been devoted to the design and synthesis
of various types of chiral ligands.1 From a practical point of view,
stable, inexpensive, and easily accessible ligands are desirable.
Secondary phosphine oxides and phosphonic acid derivatives exist
in equilibrium between the pentavalent forms (RR′P(dO)H) and
trivalent tautomeric forms (RR′POH).2,3 Secondary phosphine
oxides have been utilized as air- and moisture-stable ligand
precursors in Pt- and Pd-catalyzed reactions, wherein the tautomeric
phosphinous acids coordinate to the metal center through a
phosphorus atom.4 The first application of P-chirogenic secondary
phosphine oxide to iridium-catalyzed asymmetric hydrogenation
was recently reported.5 Intensive examination of the ligand structure,
however, might be hampered by the difficult optical resolution by
preparative chiral HPLC. These aspects prompted us to develop a
a Reagents and conditions: (a) aniline, DMSO, room temperature, 1 h;
new class of chiral phosphorus ligands. We report a novel
(b) aniline, WSCI, DMF, room temperature, 24 h; (c) Pd-C (2 mol %),
P-chirogenic diaminophosphine oxide that can be utilized for
catalytic asymmetric carbon-carbon bond forming reactions to
construct quaternary carbon centers.
H2, 2-propanol-DMF, room temperature, 6 h; (d) benzoyl chloride, NEt3,
THF, room temperature, 1 h; (e) LiAlH4, THF, reflux, 13 h; (f) PCl3, NEt3,
toluene, -78 °C to room temperature, 16 h, then SiO2, H2O, AcOEt, room
temperature, 18 h.
Cyclic diaminophosphine oxides (diazaphosphole oxides) pre-
pared from asymmetric diamines possess a stereogenic center on
the phosphorus atom.6 Triaminophosphines are reactive under
aqueous acidic conditions, giving the corresponding diaminophos-
phine oxides via an SN2 type process.2 Thus, we expected that
optically active triamines derived from aspartic acid would be ideal
precursors of the desired asymmetric diamine. Our ligand synthesis
started with the known acid anhydride 1 (Scheme 1).7 Nucleophilic
opening of 1, followed by condensation with aniline, yielded the
corresponding dianilide, which was transformed into triamide 2 in
83% overall yield. After reduction of all of the amide groups, the
obtained triamine 3 was reacted with phosphorus trichloride to
afford the corresponding triaminophosphine, which was converted
into diaminophosphine oxide 4 by treatment with SiO2 in wet
AcOEt.8 The absolute structure of 4 was unequivocally determined
by X-ray crystal structure analysis.
With an optically pure P-chirogenic diaminophosphine oxide 4
in hand, we attempted to use 4 as a chiral phosphorus ligand.
Catalytic enantioselective synthesis of a quaternary carbon center
is a formidable challenge in organic synthesis.9 Pd-catalyzed
asymmetric allylic substitution using prochiral nucleophiles is one
of the most straightforward approaches toward this end.10 We first
examined asymmetric allylic substitution of cinnamyl acetate 5a
with ethyl 2-oxo cyclohexane carboxylate 6a (Table 1). With the
use of 2.5 mol % of (η3-C3H5PdCl)2 and 10 mol % of 4, the reaction
proceeded in the presence of N,O-bis(trimethylsilyl)acetamide
(BSA)11 to afford 7a in 53% ee, even though the yield was only
10%. Encouraged by this result, we investigated the effect of the
additive and the amount of BSA and 6a in detail. Zn(OAc)2 was
Table 1. Asymmetric Allylic Substitution of 5a with 6a
run
additive
x (equiv)
y (equiv)
yieldb
eec
1
2
3
4
5
6
7
3.0
3.0
3.0
3.0
3.0
3.0
4.0
1.25
1.25
1.25
1.25
1.25
1.5
10%
53%
99%
81%
80%
86%
99%
53% ee
8% ee
LiOAc
Mg(OAc)2‚4H2O
Zn(OAc)2‚2H2O
Zn(OAc)2
Zn(OAc)2
Zn(OAc)2
66% ee
89% ee
91% ee
91% ee
92% ee
1.5
a The absolute configuration was determined to be S; see the Supporting
Information for details. b Isolated yield. c Determined by HPLC analysis.
the best additive for asymmetric induction, and 4 equiv of BSA
and 1.5 equiv of 6a to 5a gave the best reactivity.
Having developed efficient conditions, we further examined the
scope and limitation of different substrates (Table 2). When 0.5-5
mol % of the catalyst was employed, asymmetric substitution of
both γ-aryl and γ-alkyl substituted-allyl acetates 5a-f using
prochiral nucleophiles with a six-membered ring (runs 1-5, 9-15)
proceeded smoothly at room temperature to provide the corre-
sponding products in good yield with good to high enantioselectivity
(80-94% ee).12 In addition, this reaction system was also effective
for nucleophiles with five-, seven-, and eight-membered rings (runs
6-8), resulting in the formation of quaternary carbon centers with
modest to good enantioselectivity (72-85% ee). To the best of our
† Chiba University.
‡ Nagoya City University.
9
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J. AM. CHEM. SOC. 2004, 126, 3690-3691
10.1021/ja031792a CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Proposed Structure of the Active Species
Table 2. Asymmetric Allylic Substitution Using Various Substrates
Acknowledgment. This work was financially supported in part
by a Grant-in-Aid for Scientific Research (B) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental procedures,
characterization of the products, other data, and discussions (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
a Isolated yield. b Determined by HPLC analysis. c 2 mol % of the Pd
catalyst was used. d 1 mol % of the Pd catalyst was used. e 0.5 mol % of
the Pd catalyst was used. f 5 mol % of the Pd catalyst was used. g Xylenes
was used as a solvent. h 12.5 mol % of 4 was used. i See the Supporting
Information for details.
References
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New York, 2000.
(2) Barton, D.; Ollis, W. D. In ComprehensiVe Organic Chemistry; Sutherland,
I. O., Ed.; Pergammon Press: Oxford, 1979; Vol. 2, Part 10.
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A. M.; Bright, T. A.; Jones, R. A. J. Coord. Chem. 1987, 16, 45. (c)
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(6) Synthesis and application of chiral diaminophosphine oxides derived from
symmetrical chiral diamines, see: (a) Koeller, K. J.; Spilling, C. D.
Tetrahedron Lett. 1991, 32, 6297. (b) De la Cruz, A.; Koeller, K. J.; Rath,
N. P.; Spilling, C. D.; Vasconcelos, I. C. F. Tetrahedron 1998, 54, 10513.
(7) John, W. D.; Young, G. T. J. Chem. Soc. 1954, 2870.
(8) Diaminophosphine oxide 4 is an air- and moisture-stable solid. See the
Supporting Information for details of the conversion of 3 to 4.
(9) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(10) (a) Hayashi, T.; Kanehira, K.; Tsuchiya, H.; Kumada, M. J. Chem. Soc.,
Chem. Commun. 1982, 1162. (b) Hayashi, T.; Kanehira, K.; Hagihara,
T.; Kumada, M. J. Org. Chem. 1988, 53, 113. (c) Sawamura, M.; Nagata,
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B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879.
(e) Kuwano, R.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 3236. (f) Trost, B.
M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727. (g) Brunel, J. M.;
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knowledge, this is the first asymmetric catalysis using diamino-
phosphine oxide as a chiral ligand.
Typical bases other than BSA did not promote the reaction. 31
P
NMR studies revealed that pentavalent 4 (chemical shift: 10.9 ppm)
first reacts with BSA to provide trivalent 8 (chemical shift: 109.0
ppm). To gain preliminary insight into the catalyst structure and
reaction mechanism, we performed several mechanistic studies.13
When the catalyst was prepared in different Pd-ligand ratios [Pd:
4 ) 1:1 and 1:1.5 (Pd, 2 mol %; substrate, 5a and 6a)], there was
a remarkable decrease in the reactivity without any loss of
enantioselectivity (2 h, no reaction; and 2 h, 34%, 93% ee,
respectively), as compared to the case of the best ratio (2 h, 89%,
93% ee). Kinetic studies were performed, and the reaction rate had
a first-order dependency on the catalyst. Moreover, there was a
positive nonlinear effect in this reaction. From these observations,
Pd complex 9 (Pd:8 ) 1:2) is proposed to be the active species,
where two molecules of 8 coordinate to the Pd metal in a
monodentate fashion (Scheme 2).14 On the other hand, there was a
significant decrease in both the reactivity and the selectivity with
the use of N-acetylated ligand 11 [2h, 37%, 79% ee (Pd, 2 mol %;
substrate, 5a and 6a)], indicating that nitrogen atoms on the sidearms
should have an important role in the catalytic activity, as well as
the enantiofacial discrimination of prochiral nucleophiles.15
In conclusion, we developed a novel chiral ligand precursor,
P-chirogenic diaminophosphine oxide, which is activated to trivalent
phosphorus ligand in situ by BSA-induced tautomerization. This
unique property was successfully applied to catalytic asymmetric
synthesis of quaternary carbon centers. Further studies using a
structurally optimized ligand are in progress.
(11) For review, see: El Gihani, M. T.; Heaney, H. Synthesis 1998, 357.
(12) Reaction using simple allyl acetate gave less satisfactory results [cat. 5
mol %, keto ester 6g, 48 h, 24%, 63% ee, absolute configuration S].
(13) See the Supporting Information for details.
(14) No signal was observed in the 31P NMR measurement of the reaction
mixture, which might indicate that several complexes exist in a fast
equilibrium.
(15) At the present stage, we speculate that the nitrogen atoms might fix the
nucleophiles in the appropriate position through secondary ligand substrate
interaction mediated by Zn metal. For the secondary ligand substrate
interaction, see ref 10a-c.
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