Enantioselective organocatalytic hydrophosphination of α,β- unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200700916

Keeping it simple: Optically active phosphine derivatives can be obtained in high yields and in up to 99% ee by using simple chiral amines to catalyze the hydrophosphination of α,β-unsaturated aldehydes (see scheme, green sphere = chiral group). The synth

Full text of DOI:10.1002/anie.200700916

Angewandte
Chemie
DOI: 10.1002/anie.200700916
Organocatalysis
Enantioselective Organocatalytic Hydrophosphination of
a,b-Unsaturated Aldehydes**
Ismail Ibrahem, Ramon Rios, Jan Vesely, Peter Hammar, Lars Eriksson, Fahmi Himo, and
Armando Córdova*
Chiral phosphines are highly valuable ligands for metal-
catalyzed enantioselective transformations[1] and can be used
as catalysts in organocatalytic reactions.[2] They are generally
prepared by resolution—by employing stoichiometric
amounts of chiral auxiliaries or enantiopure substrates.[3]
Thus, there is an important need for the development of
more efficient catalytic methods.[4] The asymmetric hydro-
phosphination (AHP)[5] of trivalent phosphine compounds
within the field of organocatalysis[10] for the enantioselective
transformation of carbonyl compounds. In this context,
iminium activation[11a] has been successfully demonstrated in
Michael-type b-functionalizations for carbon-,[11] hydrido-,[12]
sulfur-,[13] nitrogen-,[14] and oxygen nucleophiles.[15] On the
basis of this research and the importance of developing AHP
reactions, we envisioned a direct route to functionalized
optically active b-formyl- and g-hydroxyphosphines and
derivatives thereof by amine-catalyzed stereoselective reac-
tions between trivalent phosphine compounds and enals
[Eq. (1), gray sphere = chiral group]. However, there are
inherent difficulties in this type of transformation because of
the reversibility of the nucleophilic attack and competition
between 1,2- and 1,4-addition to the enal (Scheme 1).
À
with a P H bond to electron-deficient olefins provides a
direct route to useful chiral phosphine ligands containing
different chemical functionalities. However, there are only a
few catalytic asymmetric methods for this transformation;[6–8]
for example, Togni and co-workers reported a highly enan-
tioselective reaction catalyzed by a Lewis acid,[6] and, during
our initial studies,
Melchiorre and co-
workers reported an
elegant AHP of nitro-
styrenes catalyzed by
a chiral organic base
that proceeds with
good enentioselectiv-
ity.[8]
Aminocatalysis
has proven to be a
powerful procedure[9]
Herein we present the highly chemo- and enantioselective
organocatalytic b-hydrophosphination of a,b-unsaturated
aldehydes.
[*] I. Ibrahem, Dr. R. Rios, Dr. J. Vesely, Prof. Dr. A. Córdova
Department of Organic Chemistry
The Arrhenius Laboratory
Stockholm University
106 91 Stockholm (Sweden)
Fax: (+46)815-4908
E-mail: acordova1a@netscape.net
E-mail: acordova@organ.su.se
Prof. Dr. L. Eriksson
Department of Structural Chemistry
The Arrhenius Laboratory
Stockholm University
Scheme 1. Difficulties encountered when attempting AHP of enals.
106 91 Stockholm (Sweden)
P. Hammar, Prof. Dr. F. Himo
Department of Theoretical Chemistry
The Royal Institute of Technology
ALBANOVA
After extensive screening of catalysts and different
suitable phosphine sources for the AHP of cinnamic aldehyde
(1a), we found that diphenylphosphine (2a) had the right
properties to achieve product formation. Some of the results
from the screening of the reaction conditions and catalysts for
the enantioselective reaction of enal 1a and 2a in CHCl3 are
shown in Table 1.[16] The corresponding b-formylphosphine
3a was reduced in situ with NaBH4 to the air-stable alcohol
derative 4a to facilitate the purification process as well as to
generate a more stable product.[17]
106 91 Stockholm (Sweden)
[**] We thank Prof. Jacek Stawinski for valuable discussions. We
gratefully acknowledge the Swedish National Research Council,
Wenner-Gren Foundation, Magn Bergvall Foundation, and Carl
Trygger Foundation for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Catalyst screen for the reaction between 1a and 2a.[a]
these results we decided to inves-
tigate the enantioselective AHP of
enals
1 with diphenylphosphine
(2a) catalyzed by amine 11 and 12
under these conditions (Table 2).
The organocatalytic AHP reac-
tions were highly chemo- and enan-
tioselective and the corresponding
formylphosphines 3 were converted
in situ into the corresponding alco-
hols 4 or phosphine oxides 5 by
in situ reduction or oxidation,
respectively. For example, b-phos-
phine alcohols 4b–4g were isolated
with 90–99% ee. The reaction was
efficient and highly enantioselective
Entry
Catalyst
T [8C]
t [min]
Conv [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
6
7
8
9
10
11
12
11
11
12
11
RT
RT
RT
RT
RT
RT
RT
RT
4
60
60
60
60
60
60
60
53
55
59
>99
81
>99
>99
>99[d]
>99[d]
>99[d]
45[d]
0
14
12
38
18
50
56
10[d]
20[d]
20[d]
60[d]
40[d]
83[d]
73[d]
79[d]
9
10
11
4
À10
for a,b-unsaturated aldehydes
1
with either aliphatic or aromatic
functional groups. Moreover, the
a,b-unsaturated aldehydes 1 could
also be converted in a one-pot
reaction into the corresponding b-
[a] Experimental conditions: A mixture of 1a (0.25 mmol) and catalyst (20 mol%) in CHCl3 (1.0 mL) was
flushed with argon. Next, 2 (0.30 mmol) was added and the reaction mixture stirred at the temperature
for the time indicated. In situ reduction of 3a with NaBH4 gave the corresponding g-alcohol 4a.
[b] Conversion into product 3a as determined by NMR analysis. [c] Determined by chiral-phase HPLC
analysis. [d] 2-Fluorobenzoic acid (10 mol%) was added. TMS=trimethylsilyl.
phosphine
oxide
acids
13
(Scheme 2). For example, b-phos-
phine oxide carboxylic acid 13c was
obtained in 65% yield and 92% ee.
If desired, the phosphine oxide
derivatives can be readily converted
into the hydrophosphines by reduc-
tion with silanes.[19] The absolute
configuration of the phosphorus-
containing compounds was 2S
(R = Ar), as established by X-ray
We found that chiral amines 6–12 catalyzed the AHP of
enal 1a with high efficiency and with ee values ranging from
0–56% ee. Chiral protected diarylprolinols 7, 11,[18] and
12[11j,g,13a,c,15a] were the most efficient catalysts under our
reaction conditions and mediated
analysis of a single crystal of the diphosphine oxide derivative
14d (Figure 1),[20] which was formed by decomposition of the
isolated pure phosphine oxide aldehyde 3d after more than
16 h at room temperature.
the formation of 3a with high
chemoselectivity (entries 4, 6, and
7). Notably, we found that the
reaction was significantly acceler-
ated by the addition of a benzoic
acid additive, which probably pro-
moted the formation of the imi-
nium ion. Of the benzoic acids
Table 2: Scope of the organocatalytic AHP.[a]
Entry
Catalyst
R
Prod.
Yield [%][b]
ee [%][c]
tested,
2-fluorobenzoic
acid
1
2
3
4
5
11
11
12
12
12
Ph
4a
4b
4c
4d
4e
85
87
79
78
85
83
99
92
90
98
(10 mol%) gave the best results
without significantly affecting the
enantioselectivity (entry 8). Under
these conditions, chiral amine 11
catalyzed the asymmetric forma-
tion of 3a with 83% ee and com-
plete conversion at 48C within
20 minutes (entry 9). Decreasing
the temperature to À108C did not
improve the enantioselectivity and
reduced the efficiency of the reac-
tion (entry 11). On the basis of
4-NO2C6H4
4-ClC6H4
4-BrC6H4
2-Naph
6
12
4 f
70
91
7
12
4g
72
95
[a] Experimental conditions: A mixture of 1 (0.25 mmol), 2-fluorobenzoic acid (10 mol%), and catalyst
11 or 12 (20 mol%) in CHCl3 (1.0 mL) was flushed with argon. Next, 2 (0.30 mmol) was added and the
reaction mixture stirred for 20 min at 48C. Next, in situ reduction of 3 with NaBH4 gave the
corresponding alcohol 4. [b] Yield of isolated pure product aldehyde 5 after in situ oxidation of 3 with I2.
[c] Determined by chiral-phase HPLC analysis.
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Si facial attack. The Z-iminium ion was previously found to be
less stable than the E-iminium ion.[14e] We have calculated that
the different transition states for the phosphine attack on the
Z-iminium ion have 3–5 kcalmolÀ1 higher energies than those
formed by attack on the E-iminium ion, and are not
considered further here. This finding is also in accordance
with previous conjugate additions catalyzed by catalysts 11
and 12.[13–15]
Scheme 2. One-pot asymmetric synthesis of b-phosphine oxide acid
13c.
In summary, we have reported the unprecedented exam-
ple of a highly chemo- and enantioselective organocatalytic
hydrophosphination of a,b-unsaturated aldehydes. The reac-
tion is catalyzed efficiently by simple chiral pyrrolidine
derivatives and gives the corresponding phosphine derivatives
To shed more light on the origin of the enantioselectivity
we performed density functional theory (DFT) calculations
À
on the P C bond-forming step. The calculations were
[21]
performed using the Gaussian 03software package
the B3LYP functional.[22]
Geometries were optimized
with the 6-31G(d,p) basis
set, and characterized with
frequency calculations. Final
energies were obtained with
the larger basis set 6-311 + G-
(2d,2p) and corrected for zero
point effects obtained from
the frequency calculations.
The effect of solvation in
CHCl3 was calculated using
and
a
polarizable
conductor
model (CPCM).[23] As a rep-
resentative case for the cal-
culations, we considered the
reaction of diphenylphos-
phine (2a) with the iminium
species formed from cinnamic
aldehyde (1a) and catalyst 11
Figure 2. Optimized transition-state structures for phosphine attack on an E-iminium ion. TS-S arises from
attack on the unshielded face of the iminium ion and has lower energy than when the attack is on the
shielded face (TS-R). Relative energies [kcalmolÀ1] in the gas phase (in parentheses) and solvated [in
brackets] are given. Distances are in ꢀngstroms.
(Figure 2).[24] The transition state leading to the S product
(TS-S) was calculated to have the lowest energy. The attack
takes place at the face of the E-iminium ion that is not
shielded by the bulky group of the catalyst. The attack on the
shielded face of the E-iminium ion (TS-R), which yields the
2R product, is 1.5 kcalmolÀ1 higher in energy (2.9 kcalmolÀ1
including solvation effects). Although the energy difference
suggests a somewhat higher enantioselectivity than the one
observed experimentally for this specific reaction, it is
qualitatively in agreement with the experimental findings
and supports the prediction that the bulky group of 11 shields
the Re face (R = Ar)[25] of the E-iminium ion, which leads to
in high yields and in up to 99% ee. The synthetic utility of the
novel catalytic AHP was exemplified by the one-pot asym-
metric synthesis of b-phosphine oxide acids. DFT calculations
showed that the lowest energy transition state led to the
S product. Mechanistic studies, synthetic applications of this
transformation, as well as development of other enantiose-
lective AHP reactions based on this concept are ongoing.
Received: February 28, 2007
Published online: May 11, 2007
Keywords: aldehydes · asymmetric synthesis ·
.
conjugate addition · organocatalysis · phosphanes
[1] a) Asymmetric Catalysis on Industrial Scale. Challenges,
Approaches, and Solutions (Ed.: H.-U. Blaser, E. Schmidt),
Wiley-VCH, Weinheim, 2004; b) K. V. L. CrØpy, T. Imamoto,
Top. Curr. Chem. 2003, 229, 1.
[2] For reviews on the use on phosphine catalyzed reactions, see
a) X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res. 2001, 34, 535; b) J. L.
Methot, W. R. Roush, Adv. Synth. Catal. 2004, 346, 1035.
[3] a) B. Wiese, G. Knühl, D. Flubacher, J. W. Prieß, B. Ulriksen, K.
Brödner, G. Helmchen, Eur. J. Org. Chem. 2005, 3246, and
references therein; b) K. M. Pietrusiewicz, M. Zablocka, Chem.
Rev. 1994, 94, 1375; c) W. Tang, X. Zhang, Chem. Rev. 2003, 103,
3029.
Figure 1. ORTEP picture of the crystalline di(phosphine oxide) com-
pound 14d.
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[4] For recent examples, see a) B. Join, D. Mimieu, O. Delacroix, A.-
c) R. Rios, H. Sunden, I. Ibrahem, G.-L. Zhao, L. Eriksson, A.
Córdova, Tetrahedron Lett. 2006, 47, 8547; d) S. Brandau, E.
Maerten, K. A. Jørgensen, J. Am. Chem. Soc. 2006, 128, 14986.
[14] For selected references, see a) Y. K. Chen, M. Yoshida, D. W. C.
MacMillan, J. Am. Chem. Soc. 2006, 128, 9328; b) I. Ibrahem, R.
Rios, J. Vesely, G.-L. Zhao, A. Córdova, Chem. Commun. 2006,
849; c) H. SundØn, R. Rios, I. Ibrahem, G.-L. Zhao, L. Eriksson,
A. Córdova, Adv. Synth. Cat. 2007, DOI: 10.1002/
adsc.200600513; d) J. Vesely, I. Ibrahem, R. Rios, G.-L. Zhao,
Y. Xu, A. Córdova, Tetrahedron Lett. 2007, 48, 2193; e) P. DinØr,
M. Nielsen, M. Marigo, K. A. Jørgensen, Angew. Chem. 2007,
119, 2029 – 2033; Angew. Chem. Int. Ed. 2007, 46, 1983– 1987;
f) J. Vesely, I. Ibrahem, G.-L. Zhao, R. Rios, A. Córdova, Angew.
Chem. 2007, 119, 792; Angew. Chem. Int. Ed. 2007, 46, 778.
[15] For selected references, see a) S. Bertelsen, P. DinØr, R. L.
Johansen, K. A. Jørgensen, J. Am. Chem. Soc. 2007, 129, 1536;
b) T. Govender, L. Hojabri, F. M. Moghaddam, P. I. Arvidsson,
Tetrahedron: Asymmetry 2006, 17, 1763; c) H. SundØn, I.
Ibrahem, G.-L. Zhao, L. Eriksson, A. Córdova, Chem. Eur. J.
2007, 13, 574.
C. Gaumont, Chem. Commun. 2006, 3249; b) C. Scriban, D. S.
Glueck, J. Am. Chem. Soc. 2006, 128, 2788; c) V. S. Chan, I. C.
Stewart, R. G. Bergman, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 2786.
[5] a) M. Tanaka, Top. Curr. Chem. 2004, 232, 25; b) “Hydrophos-
phination and related reactions”: D. K. Wicht, D. S. Glueck in
Catalytic Heterofunctionalizations (Eds.: A. Togni, H. Grütz-
macher), Wiley-VCH, Weinheim, 2001.
[6] a) A. D. Sadow, A. Togni, J. Am. Chem. Soc. 2005, 127, 17012;
b) A. D. Sadow, I. Haller, L. Fadini, A. Togni, J. Am. Chem. Soc.
2004, 126, 14704.
[7] I. Kovacik, D. K. Wicht, N. S. Grewal, D. S. Glueck, C. D.
Incarvito, I. A. Guzei, A. L. Rheingold, Organometallics 2000,
19, 950.
[8] G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, A. Mazzanti, L.
Sambri, P. Melchiorre, Chem. Commun. 2007, 722.
[9] For example, see a) B. List, Chem. Commun. 2006, 819; b) M.
Marigo, K. A. Jørgensen, Chem. Commun. 2006, 2001; c) D.
Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. 2007, 119,
1590; Angew. Chem. Int. Ed. 2007, 46, 1570.
[10] a) P. I. Dalko, L. Moisan, Angew. Chem. 2001, 113, 3840; Angew.
Chem. Int. Ed. 2001, 40, 3726; b) R. O. Duthaler, Angew. Chem.
2003, 115, 1005; Angew. Chem. Int. Ed. 2003, 42, 975; d) P. I.
Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248; Angew. Chem.
Int. Ed. 2004, 43, 5138; c) A. Berkessel, H. Gröger, Asymmetric
Organocatalysis, Wiley-VCH, Weinheim, 2004.
[16] Chiral amine 11 catalyzed the AHP in CH3CN, THF, toluene,
and DMF with similar enantioselectivity (26–45% ee), but with
lower efficiency.
[17] Deprotection of the phosphine borane can be readily accom-
plished, see Ref. [3a] and a) J. McNulty, Y. Zhou, Tetrahedron
Lett. 2004, 45, 407; b) H. Brisset, Y. Gourdel, P. Pellon, M.
Le Corre, Tetrahedron Lett. 1993, 34, 4523.
[11] For selected examples, see a) K. A. Ahrendt, C. J. Borths,
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 4243;
b) A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc.
2002, 124, 2458; c) R. K. Kunz, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 3240; d) N. A. Paras, D. W. C. MacMillan,
J. Am. Chem. Soc. 2001, 123, 4370; e) W. S. Jen, J. J. M. Wiener,
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 9874; f) N.
Halland, P. S. Aburell, K. A. Jørgensen, Angew. Chem. 2004,
116, 1292; Angew. Chem. Int. Ed. 2004, 43, 1272; g) S. Brandau,
A. Landa, J. Franzen, M. Marigo, K. A. Jørgensen, Angew.
Chem. 2006, 118, 4411; Angew. Chem. Int. Ed. 2006, 45, 4305;
h) N. Halland, T. Hansen, K. A. Jørgensen, Angew. Chem. 2003,
115, 5105; Angew. Chem. Int. Ed. 2003, 42, 4955; i) N. Halland,
P. S. Aburel, K. A. Jørgensen, Angew. Chem. 2003, 115, 685;
Angew. Chem. Int. Ed. 2003, 42, 661; j) A. Carlone, S. Cabrera,
M. Marigo, K. A. Jørgensen, Angew. Chem. 2007, 119, 1119;
Angew. Chem. Int. Ed. 2007, 46, 1101, and references therein;
k) H. Gotoh, R. Masui, H. Ogino, M. Shoji, Y. Hayashi, Angew.
Chem. 2006, 118, 7007; Angew. Chem. Int. Ed. 2006, 45, 6853;
l) S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975.
[18] a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen,
Angew. Chem. 2005, 117, 804; Angew. Chem. Int. Ed. 2005, 44,
794; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew.
Chem. 2005, 117, 4284; Angew. Chem. Int. Ed. 2005, 44, 4212.
[19] a) R. Shintani, W.-L. Duan, T. Nagano, A. Okada, T. Hayashi,
Angew. Chem. 2005, 117, 4687; Angew. Chem. Int. Ed. 2005, 44,
4611, and references therein; b) K. Vandyck, B. Matthys, M.
Willen, K. Robeyns, L. Van Meervelt, J. van der Eycken, Org.
Lett. 2006, 8, 363.
[20] CCDC-637922 contains 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.
[21] Gaussian 03, Revision D.01, M. J. Frisch, et al. Gaussian, Inc.,
Wallingford CT, 2004.
[22] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785;
b) A. D. Becke, Phys. Rev. A 1988, 38, 3098; c) A. D. Becke, J.
Chem. Phys. 1992, 96, 2155; d) A. D. Becke, J. Chem. Phys. 1992,
97, 9173; e) A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
[23] a) V. Barone, M. Cossi, J. Phys. Chem. A 1998, 102, 1995; b) M.
Cossi, N. Rega, G. Scalmani, and V. Barone, J. Comput. Chem.
2003, 24, 669.
[24] For a seminal example of DFT calculations on the concept of
iminium activation, see C. Allemann, R. Gordillo, F. R. Clem-
ente, P. H.-Y. Cheong, K. N. Houk, Acc. Chem. Res. 2004, 37,
558.
[12] For selected examples, see a) J. W. Yang, M. T. Hechevarria
Fonseca, N. Vignola, B. List, Angew. Chem. 2005, 117, 110;
Angew. Chem. Int. Ed. 2005, 44, 108; b) S. G. Guellet, J. B. Tuttle,
D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127, 3 2; c) S.
Mayer, B. List, Angew. Chem. 2006, 118, 4299; Angew. Chem.
Int. Ed. 2006, 45, 4193; d) R. M. Wilson, W. S. Jen, D. W. C.
MacMillan, J. Am. Chem. Soc. 2005, 127, 11616; e) G.-L. Zhao,
A. Córdova, Tetrahedron Lett. 2006, 47, 7417.
[25] In the case of enals with an aliphatic R group, this is the Si face;
see also A. Carlone, G. Bartoli, M. Bosco, L. Sambri, P.
[13] For selected examples, see a) M. Marigo, T. Schulte, J. Franzen,
K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 15710; b) W.
Wang, H. Li, J. Wang, L. Zu, J. Am. Chem. Soc. 2006, 128, 10354;
Melchiorre,
Angew.
Chem.
2007,
DOI:
10.1002/
ange.200700754; Angew. Chem. Int. Ed. 2007, DOI: 10.1002/
anie.200700754.
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