Chiral tetraaminophosphonium salt-mediated asymmetric direct henry reaction

Article abstract of DOI:10.1021/ja075152+

Chiral tetraaminophosphonium salts 1 possessing the phosphorus-centered [5.5]-spirocyclic core have been designed and synthesized in a single step from l-valine-derived diamine. The three-dimensional molecular structure was successfully verified by the si

Full text of DOI:10.1021/ja075152+

Published on Web 09/20/2007
Chiral Tetraaminophosphonium Salt-Mediated Asymmetric Direct Henry
Reaction
Daisuke Uraguchi, Sawako Sakaki, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya UniVersity, Nagoya 464-8603, Japan
Received July 11, 2007; E-mail: tooi@apchem.nagoya-u.ac.jp
Quaternary phosphonium salts are widely employed in organic
synthesis and normally regarded as the precursors of ylides, the
reagents developed by Georg Wittig for carbonyl olefination.1,2
Despite the prevailing applications as stoichiometric reagents and
ionic liquid solvents, however, the challenges associated with the
catalytic use of phosphonium salts are rather limited.3 Especially,
chiral, nonracemic phosphonium salts have received little attention
and were left behind in the evolution of asymmetric organic
molecular catalysis.3b,4
Figure 1. X-ray crystal structure of (M,S)-3a (all calculated hydrogens
and solvent molecules are omitted for clarity).
Tetraaminophosphonium salts bearing four primary amino groups
[(RNH)4P+X-, 1] have been studied as broad-spectrum biocides,5
and also used as precursors of P-1 phosphazenes in organic
chemistry.6 In contrast to phosphorus acid esters, the amino series
are generally insusceptible to the P-N bond cleavage by a
nucleophilic anion, such as a halide, and thus the salts are relatively
stable even in the presence of excess anions. It is noteworthy that
deprotonation from a nitrogen of 1 generates triaminoiminophos-
phorane, which is known as a nucleophilic component of aza-Wittig
reaction as well as a strongly basic reagent.7-9 In addition, the
secondary interaction between the cation and anion moieties of 1
via double hydrogen-bonding has been documented.6a,d Although
the judicious combination of these characteristics would provide a
new and fruitful opportunity for the design and utilization of chiral
phosphonium salts as a catalyst for synthetically relevant, stereo-
selective transformations, this possibility has remained unexplored.
Herein, we disclose the development and application of a chiral
tetraaminophosphonium chloride of type 3, demonstrating its
inherent potential to exert efficient asymmetric catalysis.
diastereomer) was successfully verified by a single-crystal X-ray
diffraction analysis, thus establishing its (M,S) configuration (Figure
1). Importantly, the chloride anion is located in proximity to two
of the N-H protons, being able to interact with them via double
hydrogen-bonding.12 The two diazaphosphacycles linked through
the P(V) center are nearly perpendicular, and this conformational
information is transmitted to each substituent, creating an attractive
chiral environment around the anion.
With the exact structure of 3a in hand, we next focused on the
evaluation of its own ability as a catalytic stereocontroller for
valuable carbon-carbon bond-forming reactions. For this purpose,
we chose a Henry reaction13,14 as an ideal probe on the basis of the
following considerations: (1) nitroalkanes would be deprotonated
by triaminoiminophosphorane (I)7,9d generated in situ from 3 and
a strong base, such as KOtBu; (2) since nitronate anions are
bidentate hydrogen-bonding acceptors, the resulting chiral phos-
phonium nitronate could form a structured ion pair (II), allowing
the highly stereoselective addition to aldehydes (Figure 2). Pre-
liminary 31P NMR studies revealed that the original signal of the
phosphonium salt (M,S)-3a at δ 34.7 ppm in DMF underwent a
downfield shift to δ 47.1 ppm upon the addition of KOtBu at
-40 °C, and it shifted upfield back to δ 37.9 ppm by the subsequent
treatment with nitromethane.15 This observation suggests that
the iminophosphorane of type I can indeed be derivatized from
3 and could promote a Henry reaction in a manner illustrated in
Figure 2.
Scheme 1. Molecular Design and Synthesis of Chiral
Tetraaminophosphonium Salts 3
Our tactics for the molecular design was to introduce a
phosphorus-centered [5.5]-spirocyclic core using the readily ac-
cessible chiral 1,2-diamine 210 as the requisite subunit (Scheme
1). The advantage of this structural motif is that the directions of
not only the alkyl and geminal aromatic substituents on the rigid
diazaphosphacycles but also the N-H protons would be rigorously
regulated, making it feasible to fully appreciate the intrinsic
hydrogen-bonding capability for anion recognition. The actual
synthesis of the desired P-spirocyclic aminophosphonium salt 3
was implemented in a single step from L-valine-derived diamine 2
and phosphorus pentachloride.6a Interestingly, 3 was obtained as a
diastereomeric mixture on the phosphorus stereogenic center.
Purification by simple silica gel column chromatography and single
recrystallization fortunately gave the major diastereomer in an
essentially pure form.11 The three-dimensional molecular structure
of the chiral P-spiro tetraaminophosphonium salt 3a (major
Figure 2. Working hypothesis for the phosphonium salt 3-mediated
asymmetric direct Henry reaction.
In the experiments to examine this hypothesis, (M,S)-3a was
initially neutralized in the presence of nitromethane (4a) by the
treatment with a solution of KOtBu in THF at -78 °C for 30 min,
and then benzaldehyde was successively added. As expected, the
9
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J. AM. CHEM. SOC. 2007, 129, 12392-12393
10.1021/ja075152+ CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Effect of Aromatic Substituent (Ar) of 3 and Scope of the
Acknowledgment. This paper is dedicated to the memory of
Professor Yoshihiko Ito. We gratefully acknowledge Dr. Jun-ichi
Ito (Nagoya Univ.) for his kind support of the X-ray crystallographic
analysis. This work was partially supported by a Grant-in-Aid for
Scientific Research on Priority Areas "Advanced Molecular Trans-
formation of Carbon Resources" from the Ministry of Education,
Culture, Sports, Science and Technology, Japan and Nagase Science
and Technology Foundation.
Nitroalkanesa
entry
(M,S)-3
4 (R1)
yieldb (%)
drc (anti:syn)
eed (%)
1
2
3
4
5
6
7e
3a
3b
3c
3d
3d
3d
3d
H (4a)
4a
86
36
84
90
93
78
90
89
45
88
94
97
96
97
Supporting Information Available: Representative experimental
procedures, physical characterization data of (M,S)-3a-d including the
X-ray analysis, and the details of the low-temperature NMR study;
crystallographic data for (M,S)-3a (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
4a
4a
Me (4b)
Et (4c)
4b
>19:1
13:1
>19:1
a See Supporting Information for details. b Isolated yield. c Determined
by 1H NMR analysis of crude reaction mixtures. d Determined by chiral
HPLC analysis. Enantiomeric excess of anti isomer (entries 5-7). e Reaction
was performed for 48 h with 1 mol % of (M,S)-3d/KOtBu.
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entry
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drc (anti:syn)
eed (%)
1
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o-F-C6H4
p-F-C6H4
p-Cl-C6H4
p-Me-C6H4
1-naphthyl
2-furyl
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a See Supporting Information for details. b Isolated yield. c Determined
by 1H NMR analysis of crude reaction mixtures. d Enantiomeric excess of
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reaction proceeded smoothly even at -78 °C to furnish the
corresponding nitro alcohol 5 (R1 ) H) in 86% yield with 89% ee
(entry 1, Table 1). Here, we found that the choice of the aromatic
substituent (Ar) on the diazaphosphacycle of 3 had a significant
effect on the catalyst efficiency (entries 1-4). While the use of
(M,S)-3b having m-xylyl groups caused a substantial decrease in
the reactivity and selectivity (entry 2), the p-tolyl substitution [(M,S)-
3c] scarcely affected the performance of the catalyst (entry 3).
Eventually, introduction of an electron-deficient p-trifluorometh-
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enantioselectivities was attained (entries 5-6). It should be added
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detrimental effect on the selectivity albeit a longer reaction time
was required (entry 7).
Further investigation of the ability of (M,S)-3d to control the
relative and absolute configurations was conducted with nitroethane
(4b) as a representative nucleophilic component and various
aldehydes, and these results are summarized in Table 2. A virtually
complete stereochemical control was achieved with a series of
aromatic aldehydes including fused and heteroaromatic ones (entries
1-6). Notably, R,â-unsaturated and aliphatic aldehydes also
appeared to be good candidates (entries 7-9), which clearly
demonstrated the broad generality of this asymmetric direct Henry
protocol.
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and references therein.
In conclusion, we have designed a chiral tetraaminophosphonium
salt 3 possessing the P-spirocyclic structure, and its potential as an
organic molecular catalyst has been demonstrated in the application
to the asymmetric direct Henry reaction. We believe that the present
study offers a new axis of chiral onium salt catalyses.
(15) See Supporting Information for details of the NMR experiment.
JA075152+
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J. AM. CHEM. SOC. VOL. 129, NO. 41, 2007 12393