Organocatalytic asymmetric hydrophosphination of α,β-unsaturated aldehydes: Development, mechanism and DFT calculations

Article abstract of DOI:10.1002/adsc.200800277

The development and mechanism of the highly chemo- and enantioselective organocatalytic hydrophosphination reaction of α,β-unsaturated aldehydes is presented. The reactions are catalyzed by protected chiral diarylprolinol derivatives and give access to op

Full text of DOI:10.1002/adsc.200800277

FULL PAPERS
DOI: 10.1002/adsc.200800277
Organocatalytic Asymmetric Hydrophosphination of
a,b-Unsaturated Aldehydes: Development, Mechanism
and DFT Calculations
Ismail Ibrahem,a Peter Hammar,b Jan Vesely,a Ramon Rios,a Lars Eriksson,c
and Armando Córdovaa,*
a
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 196 91 Stockholm, Sweden
Fax : (+46) 815-4908; e-mail: acordova@organ.su.se or acordova1a@netscape.net
Department of Theoretical Chemistry, School of Biotechnology, The Royal Institute of Technology, 196 91 Stockholm,
b
Sweden
c
Department of Structural Chemistry, The Arrhenius Laboratory, Stockholm University, 196 91 Stockholm, Sweden
Received: May 6, 2008; Published online: July 24, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The development and mechanism of the investigated. The origin of the high enantioselectivity
highly chemo- and enantioselective organocatalytic for the reaction with diphenylphosphine as the nucle-
hydrophosphination reaction of a,b-unsaturated al- ophile is investigated by density functional theory
dehydes is presented. The reactions are catalyzed by calculations.
protected chiral diarylprolinol derivatives and give
access to optically active phosphine derivatives in Keywords: asymmetric catalysis; chiral phosphines;
high yields with upto 99% ee. The organocatalytic DFT calcuations; hydrophoshination; organocataly-
addition of other phosphorus nucleophiles was also sis; a,b-unsaturated aldehydes
Introduction
based on catalytic asymmetric synthesis.[7,8] For exam-
ple, Togni has reported a highly enantioselective HP
Optically active compounds with a chiral phosphorus- reaction catalyzed by a Lewis acid.[7]
carbon bond such as phosphines and phosphonates
Organocatalysis is a rapidly growing research sub-
are very important for chemical applications.[1–3] For field within the area of asymmetric catalysis.[9] In this
example, chiral phosphines are highly valuable ligands context, asymmetric aminocatalysis has proven to be
for metal-catalyzed asymmetric transformations[1] and a powerful procedure for the enantioselective trans-
can be utilized as nucleophilic catalysts for organoca- formations of carbonyl compounds.[9,10] This type of
talytic transformations such as the Morita–Baylis– catalysis is based on enamine,[10e] iminium,[10d,f] singly
Hillman reaction.[2] Chiral phosphonates are, for ex- occupied molecular orbital (SOMO)[11] or nucleophilic
ample, important as precursors of optically active amine activation[10a,12] and combinations thereof.[9–12]
phosphonic acids and can be used as pharmaceuticals Iminium activation of enals has been successfully
and pesticides.[3]
demonstrated in Michael-type b-functionalizations for
Chiral phosphines are generally prepared by resolu- carbon,[13] hydrido,[14] sulfur,[15] nitrogen[16] and oxygen
tion, employment of stoichiometric amounts of chiral nucleophiles,[17] and should be a suitable strategy for
auxiliaries and the use of enantiopure substrates.[4] the addition of P nucleophiles to activated olefins.
Thus, it is highly desirable to developmore efficient
Based on this research and our previous experience in
catalytic methods for the enantioselective synthesis of organocatalysis,[18] we envisioned a direct route to
optically active compounds with a chiral carbon atom functionalized optically active compounds 3 with a
[5]
À
À
having a P C bond. In this context, the asymmetric chiral carbon atom having a P C bond by amine-cata-
hydrophosphination (AHP)[6] of trivalent phosphine lyzed stereoselective reactions between phosphorus
compounds with a P H bond to electron-deficient nucleophiles 2 and enals 1 [Eq. (1)]. However, there
olefins provides a direct route to useful chiral mole- are inherent difficulties in this type of transformation
cules with a P C bond such as ligands for asymmetric due to the reversibility of the nucleophilic attack and
À
À
catalysis. However, there are only a few methods
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Ismail Ibrahem et al.
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competition between 1,2- and 1,4-addition to the enal Catalyst Screen
(Scheme 1).[3f,8b]
The catalyst screen was performed with cinnamic al-
dehyde 1a as the acceptor and diphenylphosphine 2a
as the trivalent phosphorus source in chloroform
(Table 1). The corresponding b-formylphosphine 3a
were not air stable. Hence, we decided to reduce the
b-formylphosphine 3a in situ with NaBH4 to furnish
the air- and more stable phosphine borane alcohol de-
rivative 4a. Moreover, the deprotection of phosphine
boranes can be readily accomplished.[23]
Scheme 1. Difficulties encountered when attempting addi-
tion of P nucleophiles to enals.
The screen showed that all the chiral amines 6–12
Notably, during our initial studies, Melchiorre and catalyzed the AHP of enal 1a with high efficiency and
co-workers disclosed the first chiral organic base-cata- chemoselectivity. No 1,2-addition product was ob-
lyzed AHP of nitrostyrenes that proceed with good served and the corresponding product 3a was formed
enantioselectivity.[19] Our group[20a] and Melchior- with 0–56% ee at room temperature. Proline 6, di-
reꢁs[20b] grouphave recently simultaneously reported
ACHTREaUNG mine 7 and prolinol 8 catalyzed the reaction with
the first direct enantioselective hydrophosphination of poor enantioselectiviy (0–14% ee). MacMillanꢁs cata-
a,b-unsaturated aldehydes.[20] After our reports, lyst 9 was more efficient and catalyzed the reaction
Terada et al.[21a] as well as Wang[21b] and co-workers with higher stereoselectivity (entry 4). To our delight,
presented a chiral amine-catalyzed asymmetric phos- diarylprolinols 10, 11 and 12 were highly efficient and
phonylation (AP) of nitrostyrenes.[21] Moreover, Jør- complete conversion was achieved within 60 min and
gensen and co-workers reported an elegant organoca- the enantioselectivity of the AHP was moderate (38–
talytic AP of enals.[22] In this paper, we describe our 56% ee, entries 5–8). Notably, the reaction was signifi-
findings, including the scope, density functional cantly accelerated by the addition of benzoic acid (10
theory (DFT) calculations and mechanism of the cata- mol%), which promotes the formation of the iminium
lytic addition of trivalent phosphorus compounds to intermediate shown in Eq. (1) (entry 8). Under these
unmodified a,b-unsaturated aldehydes with a focus conditions the reaction was completed within 10 min.
on the AHP transformation.
However, the enantioselectivity of the reaction de-
creased.
Results and Discussion
Organic Acid Additive Screen
In our initial experiments, we performed an extensive
screening of catalysts and different suitable phospho- The significant acceleration of the protected chiral di-
rus sources 2 for the asymmetric addition to enals 1 arylprolinol-catalyzed reactions by benzoic acid en-
[Eq. (2)]. We decided to focus on the AHP reaction couraged us to perform a screen of different organic
since it would be a direct catalytic route to functional- acids for their ability to improve the efficiency and
ized optically active b-formyl- and g-hydroxyphos- enantioselectivity of the reaction. Thus, the influence
phines and derivatives thereof [Eq. (3)].
of the addition of different acid additives to the AHP
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Organocatalytic Asymmetric Hydrophosphination of a,b-Unsaturated Aldehydes
FULL PAPERS
Table 1. Catalyst screen for the reaction between 1a and
2a.[a]
Table 2. Organic acid additive screen for the chiral amine
11- and 12-catalyzed reaction between 1a and 2a.[a]
Entry Additive
T
t
Conversion ee
[8C] [min] [%][b]
[%][c]
1
2
3
4
5
6
none
r.t.
r.t.
r.t.
r.t.
60
10
10
120
30
20
>99
>99
>99
traces
70
50
38
40
2
26
18
PhCO2H
2-FC6H4CO2H
CH3CO2H
2-NO2C6H4CO2H r.t.
2,5-
(NO2)2C6H3CO2H
2-FC6H4CO2H
none
2-FC6H4CO2H
2-FC6H4CO2H
r.t.
>99
Entry Catalyst T [8C] t [min] Conversion [%][b] ee [%][c]
7
8
9
10
4
r.t.
4
À10 60
20
60
20
>99
>99[d]
>99[d]
45
83
56[d]
73[d]
79
1
2
3
4
5
6
7
8
6
7
8
9
10
11
12
11
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
60
60
60
60
60
60
60
10
53
55
59
81
>99
>99
>99
>99[d]
0
14
12
18
38
50
56
38[d]
[a]
Experimental conditions: A mixture of 1a (0.25 mmol),
acid (10 mol%) and catalyst (20 mol%) in CHCl3
(1.0 mL) was flushed with argon. Next, 2a (0.30 mmol)
was added and the reaction mixture stirred at the tem-
perature for the time indicated. In situ reduction of 3a
with NaBH4 gave the corresponding g-alcohol 4a.
Conversion into product 3a as determined by NMR anal-
ysis.
[a]
Experimental conditions: A mixture of 1a (0.25 mmol)
and catalyst (20 mol%) in CHCl3 (1.0 mL) was flushed
with argon. Next, 2a (0.30 mmol) was added and the re-
action mixture stirred at the temperature for the time in-
dicated. In situ reduction of 3a with NaBH4 gave the cor-
responding g-alcohol 4a.
Conversion into product 3a as determined by NMR anal-
ysis.
Determined by chiral-phase HPLC analysis.
Benzoic acid (10 mol%) was added. TMS=trimethyl-
silyl.
[b]
[c]
[d]
Determined by chiral-phase HPLC analysis.
Reaction performed with catalyst 12 (20 mol%).
[b]
without considerably affecting the efficiency (en-
tries 7, 9 and 10). The highest enantioselectivity was
achieved at 48C whereby chiral amines 11 and 12 cat-
alyzed the formation of 3a after 20 min in full conver-
sion with 83 and 79% ee, respectively (entries 7 and
[c]
[d]
of enal 1a in the presence of catalysts 11 and 12 was 9). It should be mentioned that the lower enantiose-
investigated (Table 2).
lectivity at room temperature might be due to an un-
We found that the use of benzoic acid derivatives selective background reaction between 2a and 1a.[8b]
significantly increased the reaction rate. The use of 2-
fluorobenzoic acid (10 mol%, pKa of 3.27 in H2O)
gave the best result without affecting the enantiose- Solvent Screen
lectivity at room temperature (entry 3). In compari-
son, the use of 2-nitrobenzoic acid (pKa =2.17 in We also performed a solvent screen and found that
H2O) and benzoic acid (pKa =4.20 in H2O) decreased the AHP reaction was possible in all solvents investi-
the stereoselectivity. Thus, we decided to further opti- gated. The fastest reaction rate was achieved in
mize the reaction conditions by using 2-fluorobenzoic CHCl3 and the highest enantioselectivity was ob-
acid as the additive. Moreover, 4-nitrobenzoic acid served in toluene followed by CHCl3 and Et2O
(pKa =3.44 in H2O) is also a very good additive.[20b] (Table 3, entries 1–3). The reaction rate in toluene
Hence, the pKa of the acid additive was an important was similar to the one in CH2Cl2. The reaction was
factor. To our delight, decreasing the reaction temper- slower and moderate enantioselectivity was observed
ature increased the enantioselectivity of the reaction in CH3CN and THF.
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Table 3. Solvent screen.[a]
Table 4. Screen for the reaction between 1a and different
phosphorus compounds 2.[a]
Entry Solvent T [8C] t [min] Conversion [%][b] ee [%][c]
1
2
3
4
5
6
7
8
9
CHCl3
toluene
Et2O
CH3CN r.t.
CH3CN 4
CH2Cl2
DMF
THF
4
4
4
20
20
45
240
120
20
120
120
240
>99
62
83
84
55
81
38[d]
56
45[d]
24
4
4
4
r.t.
69
24
76
n.d.
42
Entry Catalyst 2 Product T
t
Conversion ee
[8C] [h] [%][b]
[%][c]
32
THF
60[d]
46[d]
1
2
3
4
5
6
7
11
11
11
11
12
11
12
2a 4a
4
0.33 >99
83
[a]
Experimental conditions: A mixture of 1a (0.25 mmol), 2-
fluorobenzoic acid (10 mol%) and catalyst 11 (20 mol%)
in CHCl3 (1.0 mL) was flushed with argon. Next, 2a
(0.30 mmol) was added and the reaction mixture stirred
at the temperature for the time indicated. In situ reduc-
tion of 3a with NaBH4 gave the corresponding g-alcohol
4a.
Conversion into product 3a as determined by NMR anal-
ysis.
Determined by chiral-phase HPLC analysis.
No 2-fluorobenzoic acid was added. n.d.=not deter-
mined.
2b 4ab
2c 4ac
2d 4ab
2d 4ab
2e 4ac
2f 4af
r.t. 48
r.t. 48
<5
0
n.d.
n.d.
14
4
24 45[d
r.t. 24 46[d]
24
r.t. 24 47[d]
10
4
0
n.d.
12
[a]
[b]
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 reac-
tion mixture stirred at the temperature for the time indi-
cated. In situ reduction of 3 with NaBH4 gave the corre-
sponding g-alcohol 4.
Conversion into product 3 as determined by NMR analy-
sis.
Determined by chiral-phase HPLC analysis.
2-Fluorobenzoic acid (100 mol%) was added. TMS=tri-
methylsilyl.
[c]
[d]
[b]
[c]
[d]
Nucleophile Screen
We also screened different phosphorus compounds 2
for their ability to be used as nucleophiles in the
chiral amine-catalyzed stereoselective conjugate addi-
tion to enal 1a (Table 4).
We found that the asymmetric conjugate additions
only gave the corresponding product when com-
pounds with a trivalent P atom were used as nucleo-
philes. The organocatalytic reaction with phoshine 2a
exhibited the highest stereoselectivity. The use of the
pentavalent P compounds 2b and 2c did not furnish
the corresponding phoshonates 2ab and 2ac, respec-
tively. This is due to the lower nucleophilicity of these
compounds. Moreover, the equilibrium of the phos-
Scheme 2. One-pot asymmetric synthesis of b-phosphine
oxide acid 13c.
phonate with its phosphite form lowers the pKa as the corresponding phosphonates 4ab and 4af were fur-
compared to the diarylphosphine 2a, which favors the nished with low enantioselectivity. Thus, the organo-
reversible reaction after the initial addition stepand
catalytic asymmetric addition of P nucleophiles to
regenerates the starting materials (Scheme 3). The enals can also be used for the synthesis of phospho-
chiral amine-catalyzed reactions with phosphites 2d–f nates. We decided not to further optimize these re-
were successful when trialkyl phosphites such as 2d sults since an elegant report appeared which describes
and 2f were employed as nucleophiles. In these cases, this reaction using catalysts 11 and 12.[22]
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Organocatalytic Asymmetric Hydrophosphination of a,b-Unsaturated Aldehydes
FULL PAPERS
Scope of the Reaction
cess. Thus, initial decomposition of 3d followed by
1,2-addition of the liberated phosphine and subse-
On the basis of the results from the catalyst, acid ad- quent oxidation by air gave unexpectedly 14d as the
ditive and solvent screens, we decided to investigate crystalline side product.
the catalytic AHP of enals 1 with diphenylphosphine
2a in CHCl3 at 48C utilizing amines 11 and 12 as the
catalysts, respectively (Table 5).
Mechanistic Considerations
The organocatalytic AHP were highly chemo- and
enantioselective and the corresponding formylphos- The mechanism of the organocatalytic AHP reaction
phines 3 were converted in situ to the corresponding is shown in Scheme 3. Thus, iminium activation of
alcohols 4 or phosphine oxides 5 by in situ reduction enal 1 is followed by enantioselective conjugate addi-
or oxidation, respectively. For example, aldehydes 5a– tion of the P nucleophile to the unshielded face of the
j were isolated in high yields and b-phosphine alco- iminium intermediate I (Si-face when R=Ar; Re-face
hols 4b–j were isolated with upto 99% ee. The reac- when R=alkyl). This stepis reversible and it is im-
tion was efficient and highly enantioselective for a,b- portant that the proton gets abstracted in order to
unsaturated aldehydes 1 with both aliphatic and aro- avoid racemization or low conversion. In fact, our ex-
matic functionalities. Having an electron-donating perimental results showed that the enantioselectivity
groupon the aromatic moiety of the enal decreased
of the reaction can dropat prolonged reaction times.
the ee of the reaction under our reaction conditions Next, interconversion of the in situ generated enam-
(entry 9). Moreover, the a,b-unsaturated aldehyde 1a ine to the iminium intermediate II followed by hy-
was also converted in one-pot to the corresponding b- drolysis gives the corresponding b-formylphosphine 3
diphenylphosphoryl acid 13 in 65% yield with 92% ee and releases the catalyst. We believe that the acid ad-
(Scheme 2, Figure 1).
ditive has an important role in accelerating the cata-
These phosphine oxide derivatives can be readily lytic cycle by facilitating the formation of iminium in-
converted to the hydrophosphines by reduction with termediates I and II. This will also push the equilibri-
silanes.[24] The absolute configuration of the phospho- um towards product formation. As discussed above
rus-containing compounds was 2S (R=Ar) as estab- (see Table 4), it was essential that the P nucleophile
lished by X-ray analysis of a single crystal of diphos- had a trivalent phosphorus in order to achieve prod-
phine oxide derivative 14d (Figure 1).[25] This com- uct formation. The similar mechanism for the AP of
pound was formed as a side product from the isolated a,b-unsaturated aldehydes is depicted in Scheme 4.
pure compound 3d during the slow crystallization pro- The difference is that irreversible nucleophilic substi-
Table 5. Scope of the organocatalytic AHP.[a]
Entry
Catalyst
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
11
11
12
12
12
12
Ph
5a
5b
5c
5d
5e
5f
85
87
79
78
85
70
83
99
92
90
98
91
4-NO2C6H4
4-ClC6H4
4-BrC6H4
2-Naph
7
12
5g
72
95
8
9
10
11
12
11
3-NO2C6H4
4-MeOC6H4
3-BrC6H4
5h
5i
5j
84
67
86
98
76
83
[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, 2a (0.30 mmol) was added and the reaction mixture stirred for 20 min at
48C. In situ reduction of 3 with NaBH4 gave the corresponding g-alcohol 4.
Yield of isolated pure product aldehyde 5 after in situ oxidation of 3 with I2.
Determined by chiral-phase HPLC analysis.
[b]
[c]
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Scheme 4. Proposed catalytic cycle for the AP reaction.
Scheme 3. Proposed catalytic cycle for the AHP reaction.
tution by the benzoic acid derivative drives the reac-
tion forward after the initial reversible stereoselective
P conjugate attack.[22] Thus, when the R3 groupof the
P nucleophile in Scheme 4 is equal to an aryl group
the substitution does not occur and no product is
formed (see Table 4).
We also performed DFT calculations on the chiral
amine 11 catalyzed AHP of enals. In order to verify
the conformation of the ground state of the catalyst-
iminium intermediate and reduce the number of tran-
sition states to consider for the phosphination, we ini-
tially optimized the iminium conformations shown in
Figure 2.
We found that the E-isomer Ia is lowest in energy.
For the catalyst studied, diphenylprolinol derivative
11, there are three rotamers Ia–c regarding the bulky
groupof the amine catalyst 11, which all lie within
2.4 kcalmolÀ1 (Figure 2). All rotamers are expected to
give similar shielding of the iminium ion, which is
why only the lowest of these rotamers is considered
further for the other conformations and transition
states. The Z-isomer II is higher by 3.5 kcalmolÀ1
(2.0 kcalmolÀ1 with solvation correction). This corre-
lates well with the work of DinØr et al. who calculated
this difference to 1.4 kcalmolÀ1 using 2-pentenal as
the enal and chiral prolinol 12 as the catalyst.[16e] The
cis-conformations of type III are considerably higher,
E-III has an energy of 5.2 (4.8) kcalmolÀ1 relative to
E-trans-Ia, while Z-IV is 12.3 (11.6) kcalmolÀ1 higher
in energy. In Figure 3, the optimized transition states
for the stereointroducing stepare shown. For the
most accessible iminium conformer (Ia) we have con-
sidered the attack by diphenylphosphine on the un-
shielded as well as the shielded face. The attack on
Figure 1. ORTEP pictures of the crystalline diphosphine
oxide compound 14d (top) and acid 13c (bottom).
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Organocatalytic Asymmetric Hydrophosphination of a,b-Unsaturated Aldehydes
FULL PAPERS
Figure 2. Conformations of catalyst-iminium intermediate. Values in the label are energies relative to Ia, in kcalmolÀ1 (solva-
tion corrected energy in parentheses).
Figure 3. Transition state structures for the phosphination. Values in the label are energies relative to TS-S1a, in kcalmolÀ1
À
(solvation corrected energy in parentheses). The P C distances are given in Š.
the unshielded face, TS-S1a, leads to the observed as compared to the optimal TS-S1a due to higher
2S-product, and is indeed lowest in energy among all steric effects between the phenyl groups of the P nu-
À
transition states located (Figure 3). The forming P C cleophile and the cinnamyl moiety of the imminium
bond in TS-S1a is 2.32 Š. We have also located all complex. The P C distances of these transition states
À
transition states obtained by different rotations of are almost the same (2.33 Š). The attack on the
phosphine 2a. The two less favored rotameric transi- shielded face of the iminium complex Ia, TS-R1a, is
tion states TS-S1b and TS-S1c are 0.6 (0.2) kcalmolÀ1 higher in energy by 1.5 (2.9) kcalmolÀ1 due to the
and 1.2 (1.3) kcalmolÀ1 higher in energy, respectively, steric repulsion with the bulky group of the catalyst
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Ismail Ibrahem et al.
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À
11. In this transition state the P C distance is also stereoselectivity originated from a combination of the
slightly longer (2.36 Š). The other transition states orientations of the iminium complexes, with E-trans-
TS-R1b and TS-R1c of the rotameric possibilities of Ia being the most favored, and efficient steric shield-
the Re-facial attack on iminium complex Ia are 3.1 ing of Re-face (R=Ar) of this iminium complex by
(2.4) and 3.3 (2.9) kcalmolÀ1, respectively, higher in the bulky chiral group of the protected diarylprolinol
energy as compared to TS-S1a. The Z-iminium con- catalysts.
former II and the cis-conformer III of the catalyst-
iminium complex both expose the Re-face, which
upon attack gives the corresponding minor 2R-enan- Experimental Section
tiomer product. In order to verify that the unshielded
attack on these iminium intermediates have higher Computational Study
transition states energies compared to transition state
TS-S1a, we also investigated these possibilities. The
In order to rationalize the enantioselectivity, we have per-
formed DFT calculations on the chiral iminium complexes
R-transition state involving cis-III-iminium intermedi-
ate, TS-R2, was found to be 6.1 kcalmolÀ1 (4.5 with
solvation added) less favored than TS-S1a. One other
transition state rotamer was optimized, also having
similar energy, 6.6 (6.6) kcalmolÀ1, in agreement with
III being 5 kcalmolÀ1 higher in energy. This hence
rules out these transition states as viable options. The
transition state TS-R3 of the Z-iminium II complex
was found to be 4.2 kcalmolÀ1 higher in the gas phase.
However, when the effect of solvation in the form of
a dielectric continuum is added, the energy difference
decreases to only 2.1 kcalmolÀ1, which is less than TS-
R1a–c. Thus, TS-R3 has a competitive energy, indicat-
ing that increasing the bulkiness of the catalyst would
not increase the enantiomeric excess significantly.
This is confirmed by the experimental data in Table 1
where the enantioselectivity for the AHP reaction
was not increased when using the more bulky catalyst
10 as compared to catalyst 11. The Si-facial attack in
as well as the phosphine addition transition states. All calcu-
lations were performed using the B3LYP functional[26] im-
plemented in Gaussian 03.[27] Geometries were optimized
with 6–31G
ACHTREUNG
more accurate basis set 6–311+G
AHCTREUNG
zero point vibrational energies from frequency calculations,
also confirming the nature of the stationary points. The
effect of solvation was treated as a single point correction to
the final energy obtained from polarizable continuum
model, CPCM,[28] calculation with the smaller basis set on
the optimized structures, specifying CHCl3 as solvent.
Typical Experimental Procedure for the the
Optimized Organocatalytic AHP Reactions
To a stirred solution of catalyst (20 mol%) and 2-fluoroben-
zoic acid (10 mol%) in CHCl3 (1.0 mL) at 48C, was added
0.25 mmol (1.0 equiv) of a,b-unsaturated aldehyde 1. The
reaction mixture was then flushed with Ar, and 0.3 mmol
(1.2 equiv.) of diphenylphosphine was added. The reaction
mixture was stirred at 48C for the time reported in Table 2.
Next, the product was oxidized or reduced in situ. Thus,
1.5 equiv. of I2 in 2%H2O in pyridine (1.2 mL) were added.
The crude mixture was purified by column chromatography
to afford the pure phosphine oxide aldehydes 5. In order to
determine the ee, the crude material was reduced in situ by
NaBH4 in MeOH, and the crude product was purifed by
column chromatography to afford the corresponding phos-
phine alcohol derivatives 4.
TS-S2, which leads to the S-product but is shielded by
À1
the bulky groupis raised by 5.2 (5.6) kcalmol
as
compared to TS-S1a due to both the Z-conformation
sterics and the apparent proximity of the attacking
phosphine 2a to the bulky chiral groupof the catalyst.
Transition states involving the Z-iminium IV was not
considered since this structure is considerably higher
in energy.
Typical Experimental Procedure for the Direct
Enantioselective Catalytic Hydrophosphination of
a,b-Unsaturated Aldehydes and in situ Oxidation to
Acid
Conclusions
In summary, we report the development and mecha-
nism of the chemo- and enantioselective organocata-
To a stirred solution of catalyst (20 mol%) and 2-fluoroben-
lytic hydrophosphination of a,b-unsaturated alde- zoic acid (10 mol%) in CHCl3 (1.0 mL) at 48C, was added
0.25 mmol (1.0 equiv.) of a,b-unsaturated aldehyde. The re-
action mixture was then flushed with Ar, and 0.3 mmol
(1.2 equiv.) of diphenylphosphine was added. The reaction
mixture was stirred at 48C for the time reported in Table 2.
Next, isobutene (0.1 mL), tert-butanol (0.4 mL), H2O
(0.2 mL) KH2PO4 (54.4 mg, 4 mmol), and NaClO2 (36 mg,
4 mmol) were added sequentially. The reaction mixture was
allowed to reach room temperature and was stirred over-
night. The crude material was purified by column chroma-
tography (pentane/ethyl acetate mixtures) to afford the de-
hydes. The catalytic AHP of enals was highly enantio-
selective and efficiently catalyzed by simple chiral
pyrrolidine derivatives. The corresponding phosphine
derivatives such as g-alcohols 4 and aldehydes 5 were
isolated in high yields with upto 99% ee. Our study
revealed that trivalent phosphorus nucleophiles were
essential in order to achieve product formation. Ex-
tensive DFT calculations of the AHP reaction gave
the lowest energy transition state TS-S1a and re-
vealed the origins of the enantioselectivity. The high sired acid.
1882
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1875 – 1884

Organocatalytic Asymmetric Hydrophosphination of a,b-Unsaturated Aldehydes
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Acknowledgements
We thank Prof. Jacek Stawinski for valuable discussions. We
gratefully acknowledge the Swedish National Research Coun-
cil, Wenner-Gren Foundation, Magn Bergvall Foundation,
and Carl Trygger Foundation for financial support.
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