Highly enantioselective conjugate additions of phosphites to α β-unsaturated N-acylpyrroles and imines: A practical approach to enantiomerically enriched amino phosphonates3

Article abstract of DOI:10.1002/chem.200901901

The first highly enantioselective phosphonylation of αβ- unsaturated N-acylpyrroles has been developed. Excellent yields (91-99%) and enantioselectivities (up to >99% enantiomeric excess (ee)) were observed for a broad spectrum of both phosphites and N-ac

Full text of DOI:10.1002/chem.200901901

FULL PAPER
DOI: 10.1002/chem.200901901
Highly Enantioselective Conjugate Additions of Phosphites to a,b-
Unsaturated N-Acylpyrroles and Imines: A Practical Approach to
Enantiomerically Enriched Amino Phosphonates
Depeng Zhao,[a] Yuan Wang,[a] Lijuan Mao,[a] and Rui Wang*[a, b]
Abstract: The first highly enantioselec-
tive phosphonylation of a,b-unsaturat-
ed N-acylpyrroles has been developed.
Excellent yields (91–99%) and enan-
tioselectivities (up to >99% enantio-
meric excess (ee)) were observed for a
broad spectrum of both phosphites and
N-acylpyrroles under mild conditions.
In particular, when diethyl phosphite
was employed to test the scope of the
N-acylpyrroles, almost optically pure
products (98 to >99% ee) were ob-
tained for 20 examples of N-acylpyr-
roles. Moreover, optically pure a-sub-
stituted b- or g-amino phosphonates
can be obtained by several simple
transformations of the pyrrolyl phos-
phonates. The versatility of the N-acyl-
pyrrole moiety makes the phosphorus
adducts powerful chiral building blocks
that enable the synthesis of various
phosphonate-containing
compounds.
Finally, the present strategy can also be
applied to the asymmetric hydrophos-
phonylation of N-acylimines with high
enantioselectivities (93 to >99% ee).
Keywords: asymmetric catalysis
·
hydrophosphonylation Michael
·
addition · phosphonates · synthetic
methods
Introduction
sen and co-workers[5] reported an organocatalytic enantiose-
lective phosphonylation of a,b-unsaturated aldehydes. And
recently, we[6] described the first enantioselective 1,4-addi-
tion of phosphite to a,b-unsaturated ketones by using a di-
nuclear zinc catalyst.[7] However, there is still high demand
in both academia and industry for the asymmetric phospha-
Michael reaction of a,b-unsaturated esters or their surro-
gates,[8] since these moieties can be readily converted to var-
ious functional groups. To achieve this goal, Quirion and co-
workers[9] employed chiral amides and phosphonate salts to
synthesize amidophosphonates (Scheme 1a). Unfortunately,
the scope is limited and a catalytic version is still required.
Herein, we report the first conjugate addition reactions of
phosphites to a,b-unsaturated N-acylpyrroles catalyzed by a
dinuclear zinc catalyst. Significantly, this new catalytic asym-
metric phospha-Michael reaction afforded consistently ex-
The catalytic asymmetric synthesis of optically active phos-
phonates provokes continuing interest because such com-
pounds are usually precursors of many biologically active
and pharmaceutically important molecules.[1] The direct ad-
dition of phosphite to electrophiles is, without a doubt, one
of the most powerful methods to provide such compounds.
Indeed, numerous studies have been focused on the asym-
metric hydrophosphonylation of aldehydes,[2] imines,[2] and
nitroalkenes[3] in recent decades. In contrast, the asymmetric
conjugate additions of phosphites to a,b-unsaturated car-
bonyl compounds are still challenging and have been much
less developed. To the best of our knowledge, there are only
two catalytic examples presented to date.[4] In 2007, Jørgen-
[a] Dr. D. Zhao, Y. Wang, L. Mao, Prof. R. Wang
State Key Laboratory of Applied Organic Chemistry and Institute of
Biochemistry and Molecular Biology School of Life Sciences
Lanzhou University, Lanzhou 730000 (China)
Fax : (+86)931-891-2567
E-mail: wangrui@lzu.edu.cn
[b] Prof. R. Wang
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Kowloon (Hong Kong)
E-mail: bcrwang@polyu.edu.hk
Scheme 1. a) Chiral auxiliary-induced asymmetric phospha-Michael reac-
tion of a,b-unsaturated ester surrogates. b) Catalytic protocol for asym-
metric hydrophosphonylation of a,b-unsaturated ester surrogates.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901901.
Chem. Eur. J. 2009, 15, 10983 – 10987
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
10983

Table 2. Examination of the scope of phosphites.
cellent enantioselectivities with a wide scope for both phos-
phites and N-acylpyrroles.
Results and Discussion
Entry[a]
2
R
Product
Time [h]
Yield [%][b]
ee [%][c]
Recently, a,b-unsaturated N-acylpyrroles developed by Shi-
basaki and co-workers have proven to be highly reactive,
monodentate ester surrogates.[10] Importantly, these com-
pounds display similar reactivity to a,b-unsaturated ke-
tones[10,11] and the N-acylpyrrole moiety of the adducts can
be readily converted to the alcohol, aldehyde/ketone, or car-
boxylic acid derivatives.[12] On the other hand, we recently
successfully carried out the phospha-Michael reaction of
a,b-unsaturated ketones through a bifunctional mode of cat-
alysis and we assumed that this strategy may also be applied
to a,b-unsaturated N-acylpyrroles. That is, one metal of the
catalyst functions as a Lewis acid to bind with the ester sur-
rogate and another metal functions as a Brønsted base to
activate the phosphite (Scheme 1b).
To test this assumption, the reaction of the N-acylpyrrole
1a with diethyl phosphite (2a) in THF in the presence of
4 ꢁ molecular sieves and 20 mol% catalyst was chosen as a
model. We were pleased to find that N-acylpyrrole was
stable enough in the catalytic system, such that the addition
reaction proceeded in high yield and enantioselectivity
(Table 1, entry 1). A solvent screen indicated that the reac-
tion was able to tolerate a series of solvents. In particular,
toluene gave the best yield and enantioselectivity (Table 1,
entry 5). Thus, toluene was used for further optimization of
the reaction conditions. When the catalyst loading was de-
creased to 10 mol%, the yield and enantioselectivity were
both slightly affected.
1
2
3
4
5
2a
2b
2c
2d
2e
Et
3a
12
12
12
24
24
99
93
98
95
96
>99
95
>99
97
Me
nPr
iPr
Ph
3ba
3ca
3da
3ea
92
[a] Unless otherwise noted, reactions were carried out with 1a
(0.25 mmol) and 2 (1.5 equiv) in toluene (2.5 mL) at room temperature.
[b] Yield of the isolated product. [c] The enantiomeric excess was deter-
mined by HPLC analysis (see the Supporting Information).
action in high yields and enantioselectivities (Table 2, en-
tries 1–4). Among the phosphites tested, linear alkyl phos-
phites 2a and 2c gave the best yields and enantioselectivi-
ties (>99% ee). Interestingly, we found that diaryl phos-
phite 2e was also amenable to the present catalysis system
(Table 2, entry 5). By comparison, phosphites 2d and 2e
with bulkier substituents were found to react more slowly
and therefore longer reaction times were required.
The scope of the a,b-unsaturated N-acylpyrroles was then
investigated by using commercially available 2a. As sum-
marized in Table 3, the reaction was able to tolerate a broad
range of substrates. For b-aryl-N-acylpyrroles, the adducts
could be obtained in almost optically pure form, irrespective
of the electronic nature or position of the substituents on
the phenyl ring (Table 3, entries 1–6 and 10–14). Good re-
sults were also observed for various b-heteroaryl-N-acylpyr-
roles (Table 3, entries 7–9) and b-alkyl-N-acylpyrroles
(Table 3, entries 16–20). Interestingly, the reaction proceed-
ed stereoselectively and regioselectively with diene 1o and
despite the prolonged reaction time required, exclusive for-
mation of the Michael adduct was observed (Table 3,
entry 15). Importantly, when the phospha-Michael addition
reaction was performed on a larger scale the yield and enan-
tioselectivity were not significantly affected (Table 3,
entry 21).
Having established the optimal reaction conditions, we
then examined a series of phosphites. As shown in Table 2,
all dialkyl phosphites examined underwent the addition re-
Table 1. Optimization of the phospha-Michael reaction of 1a and 2a.
The synthetic utility of the phosphorous adducts was dem-
onstrated by the following transformations (Scheme 2): The
pyrrolyl phosphonates 3 can be easily transformed into
methyl esters 4 in the presence of sodium methoxide in
methanol. Reactions of pyrrolyl phosphonates 3a with a pri-
mary or secondary amine gave the corresponding amides in
good yields. Amide 6 can be further converted to g-amino
phosphonate 7 by reduction. It should be noted that phos-
phonate 3a can be directly hydrolyzed by using NaOH to
the corresponding carboxylic acid 8, which can then be
transformed into b-amino phosphonate[13] 9 by the well-es-
tablished literature procedure.[14]
Entry[a] L [mol%] Et2Zn [mol%] Solvent Yield [%][b] ee [%][c]
1
2
3
4
5
6
20
20
20
20
20
10
40
40
40
40
40
20
THF
Et2O
hexane 89
CH2Cl2 84
toluene 99
toluene 90
84
94
98
99
98
99
>99
98
Interestingly, the present strategy can also be applied to
the asymmetric hydrophosphonylation of imines. To date,
several organocatalysts including chiral thiourea deriva-
tives,[15] cinchona alkaloids,[16] and chiral phosphoric acids,[17]
[a] All reactions were carried out with 1a (0.25 mmol) and 2a
(0.375 mmol, 1.5 equiv) in solvent (2.5 mL) at room temperature for 12 h.
[b] Yield of the isolated product. [c] The enantiomeric excess was deter-
mined by HPLC analysis on a Chiralpak AD-H column.
10984
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Chem. Eur. J. 2009, 15, 10983 – 10987

Highly Enantioselective Conjugate Additions of Phosphites
FULL PAPER
Table 3. Examination of the scope of a,b-unsaturated N-acylpyrroles.
ment of a highly enantioselective and efficient catalytic
system for this reaction.
In light of the similarity in structure between N-acyl-
AHCTUNGTREGiNNUN mines and chalcones, we speculated that the present
method could be extended to the use of N-acylimines as
substrates. Thus, N-acylimine 10a was employed to examine
the hypothesis under typical reaction conditions. It seems
that the strategy was indeed effective for the hydrophospho-
nylation reaction (99% ee, 90% yield), however, the enan-
tioselectivities were not reproducible. This problem was
solved by using Me2Zn instead of Et2Zn to form the catalyst.
In addition, it was found that 4 ꢁ molecular sieves were not
essential to achieve a good result for this reaction.
Under the modified reaction conditions (10 mol% of L/
Me2Zn in toluene at room temperature), the scope of the
imines was then examined. We were pleased to find that the
reaction showed particularly high reactivity for all imines in-
vestigated and reactions were complete within 15 min. Aro-
matic imines possessing substituents with differing electronic
properties showed similar reactivity and enantioselectivity
(Table 4, entries 1–9). Moreover, the condensed-ring imine
10j and the aliphatic imine 10k were also excellent sub-
strates for the present system (Table 4, entries 10 and 11). It
should be noted that this method provided the highest aver-
age enantioselectivities of the asymmetric hydrophosphony-
lation of imines to date.
Entry[a]
1
R
Product
Yield
[%][b]
ee
[%][c]
1[d]
2
3
4
5
6
7
8
9
10
11[e]
12
13
14
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
99
99
99
96
98
96
99
99
94
94
94
96
95
97
>99 (S)
>99
>99
>99
>99
98
>99
>99
>99
99
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
2-furyl
2-thienyl
3-thienyl
3-MeOC6H4
2-MeOC6H4
4-NO2C6H4
1-naphthyl
2-naphthyl
98
98
98
>99
15[f]
1o
3o
91
96
>99
>99
16
1p
3p
17
18
19
1q
1r
1s
1t
nPr
iPr
3q
3r
3s
3t
93
99
98
92
98
98
99
98
CH
(CH3)2CHCH2
Ph
N
20
G
>99
>99
21[g]
1a
3a
Finally, the product 11a can be readily converted into the
corresponding amino phosphonic acid 12 (Scheme 3). The
benzoyl and ester groups were removed by treating 11a
[a] Unless otherwise noted, reactions were carried out with 1 (0.25 mmol)
and 2a (0.375 mmol, 1.5 equiv) in 2.5 mL toluene at room temperature
for 12 h. [b] Yield of the isolated product. [c] The enantiomeric excess
was determined by HPLC analysis. [d] The absolute configuration of 3n
was determined as S by chemical correlation (see the Supporting Infor-
mation) and the rest of the products were assigned by analogy. [e] Re-
action time: 18 h. [f] Reaction time: 36 h. [g] Reaction performed on a
10 mmol scale.
Table 4. Examination of the scope of imines.
Entry[a]
10
R
Product
Yield
[%][b]
ee
[%][c]
1[d]
2
3
10a
10b
10c
Ph
11a
11b
11c
91
91
91
>99 (R)
>99
>99
4-MeC6H4
4-MeOC6H4
4
10d
11d
87
99
5
6
7
8
9
10
10e
10 f
10g
10h
10i
3-MeOC6H4
2-FC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-naphthyl
11e
11 f
11g
11h
11i
85
88
91
91
88
88
96
98
99
98
97
98
Scheme 2. Synthetic utility of pyrrolyl phosphonates 3. a) NaOMe,
MeOH, 08C, 10 min; b) piperidine, THF, reflux, 80%; c) NH2Bn, THF,
reflux, 91%; d) BH3·SMe2, THF, 08C–reflux, 79%; e) NaOH, MeOH,
H2O, RT, 2 h, 93%; f) (PhO)2PON3, Et3N, toluene, tBuOH, reflux, 48 h,
48%. Bn=benzyl, Boc=tert-butoxycarbonyl.
10j
11j
11[e]
10k
11k
87
93
[a] Unless otherwise noted, reactions were carried out with 10
(0.25 mmol) and 2a (1.5 equiv) in toluene (2.5 mL) at RT. [b] Yield of
the isolated product. [c] The enantiomeric excess was determined by
HPLC analysis. [d] The absolute configuration of 11a was determined as
R by chemical correlation (see the Supporting Information) and the rest
of the products were assigned by analogy. [e] The reaction was performed
at 08C.
as well as metal catalysts, such as Shibasakiꢂs heterobimetal-
ACTHNUTRGNEUNG
lic complexes,[18] chiral aluminium(III),[19] and chiral
scandium
tion. However, there is still a great need for the develop-
ACHTUNGTRENNUNG
(III)[20] have been successfully utilized for this reac-
Chem. Eur. J. 2009, 15, 10983 – 10987
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10985

R. Wang et al.
General procedure for asymmetric hydrophosphonylation of N-acyl-
AHCTUNGERTGiNNUN mines: Dimethylzinc (0.167 mL, 1.2m in toluene, 0.2 mmol) was added
to a stirred solution of L (64 mg, 0.1 mmol) in toluene (1.83 mL) under
an argon atmosphere and the mixture was stirred at room temperature
for 0.5 h to generate the zinc catalyst (~0.05m). The resulting solution of
catalyst (0.5 mL, 0.025 mmol) was added to a stirred solution of 10
(0.25 mmol) and 2a (48 mL, 0.375 mmol) in toluene (2 mL) in one portion
at room temperature under an argon atmosphere. After stirring at the
same temperature for 15 min, the reaction was quenched with a saturated
aqueous solution of NH4Cl. The mixture was extracted with CH2Cl2 and
the organic layer was washed with brine, dried over Na2SO4, and concen-
trated under vacuum. The residue was purified by silica gel column chro-
matography (petroleum ether/ethyl acetate 4:1 to 1:2) to give 11a (91%
yield, >99% ee). The optical purity was determined by HPLC on a Chir-
alpak AD-H column (hexane/2-propanol=90:10, flow rate=
Scheme 3. Synthesis of a-aminophosphonic acid.
with concentrated HCl to give the desired product in 96%
yield.[21]
1.0 mLminÀ1
,
t
minor =12.1 min,
t
major =10.8 min); [a]2D0 =À19 (c=1.0,
Conclusion
CHCl3); 1H NMR (300 MHz, CDCl3): d=7.95–7.80 (m, 3H), 7.59 (d, J=
6.0 Hz, 2H), 7.47 (t, J=7.5 Hz, 1H), 7.42–7.28 (m, 5H), 5.79 (dd, J=
21.2, 9.5 Hz, 1H), 4.23–4.02 (m, 2H), 4.01–3.86 (m, 1H), 3.79–3.64 (m,
1H), 1.27 (t, J=7.5 Hz, 3H), 1.10 (t, J=7.1 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d=166.9 (d, J=7.5 Hz), 135.2, 133.8, 131.6, 128.5 (d,
J=1.5 Hz), 128.3, 128.27 (d, J=5.3 Hz), 128.0 (d, J=2.3 Hz), 127.4, 63.3
(d, J=6.8 Hz), 63.0 (d, J=7.5 Hz), 50.5 (d, J=153.8 Hz), 16.4 (d, J=
6.0 Hz), 16.1 (d, J=6.0 Hz) ppm; 31P NMR (121 MHz, CDCl3): d=
+21.5 ppm; IR (neat): n˜ =3277, 2986, 1650, 1539, 1244, 1026, 699,
562 cmÀ1; HRMS (ESI): m/z calcd for C18H22NO4P: 348.1359 [M+H]+;
found: 348.1349.
We have achieved the first highly enantioselective phospho-
nylation of a,b-unsaturated N-acylpyrroles. Excellent yields
and enantioselectivities (up to >99% ee) were observed for
a broad spectrum of both phosphites and N-acylpyrroles
under mild conditions. Moreover, optically pure a-substitut-
ed b- or g-amino phosphonates can be obtained by several
simple transformations of the pyrrolyl phosphonates. The
versatility of the N-acylpyrrole moiety makes the phospho-
rus adduct a powerful chiral building block for the synthesis
of various phosphonate-containing compounds. Finally, the
present strategy can also be applied to the asymmetric hy-
drophosphonylation of imines in high efficiency (<15 min)
and enantioselectivities (93 to >99% ee). Further applica-
tions of this methodology to the synthesis of biologically
and pharmaceutically interesting targets are in progress in
our laboratory.
Acknowledgements
We are grateful for the grants from the National Natural Science Founda-
tion of China (20525206, 20621091, 90813012 and 20772052), the National
S & T Major Project of China (2009ZX09503–017) and the Chang Jiang
Program of the Ministry of Education of China for financial support.
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Experimental Section
General procedure for asymmetric hydrophosphonylation of a,b-unsatu-
rated N-acylpyrroles: Diethylzinc (0.1 mL, 1m in toluene, 0.1 mmol) was
added to a stirred solution of L (32 mg, 0.05 mmol) in toluene (0.5 mL)
under an argon atmosphere. The mixture was then stirred at room tem-
perature for 30 min to generate the zinc catalyst. The resulting solution
of catalyst was added to a stirred mixture of 4 ꢁ molecular sieves
(100 mg, dried at 2008C under vacuum for 12 h), 1a (52 mg, 0.25 mmol),
and 2a (48 mL, 0.375 mmol) in toluene (2 mL) at 08C under an argon at-
mosphere. After the addition, the mixture was allowed to warm slowly to
room temperature over 12 h. The reaction was quenched with aqueous
HCl (1m) and extracted with CH2Cl2. The organic layer was washed with
saturated NaHCO3 and brine, dried over Na2SO4, and concentrated
under vacuum. The residue was purified by silica gel column chromatog-
raphy (petroleum ether/ethyl acetate 7:1 to 1:2) to give 3a (99% yield,
>99% ee). The optical purity was determined by HPLC on a Chiralpak
AD-H column (hexane/2-propanol=90:10, flow rate=1.0 mLminÀ1
,
t
minor =11.5 min, tmajor =12.3 min); [a]2D0 =À31 (c=1.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.48–7.38 (m, 2H), 7.38–7.21 (m, 5H), 6.27 (t, J=
2.4 Hz, 2H), 4.18–4.00 (m, 2H), 3.98–3.79 (m, 2H), 3.77–3.60 (m, 1H),
3.60–3.43 (m, 2H), 1.29 (t, J=7.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H) ppm;
13C NMR (75 MHz, CDCl3): d=167.7 (d, J=18.0 Hz), 135.1 (d, J=
6.8 Hz), 129.1 (d, J=6.0 Hz), 128.6 (d, J=2.3 Hz), 127.6 (d, J=3.0 Hz),
119.0, 113.3, 63.2 (d, J=7.5 Hz), 62.1 (d, J=7.5 Hz), 39.5 (d, J=
140.3 Hz), 35.5, 16.3 (d, J=6.0 Hz), 16.1 (d, J=5.3 Hz) ppm; 31P NMR
(121 MHz, CDCl3): d=+27.3 ppm; IR (neat): n˜ =2983, 2927, 1719, 1284,
1052, 967, 747, 558 cmÀ1; HRMS (ESI): m/z calcd for C17H22NO4P:
336.1359 [M+H]+; found: 336.1353.
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Highly Enantioselective Conjugate Additions of Phosphites
FULL PAPER
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Received: July 9, 2009
Published online: September 8, 2009
Chem. Eur. J. 2009, 15, 10983 – 10987
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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10987