Manganese-proline derived new catalyst system for the enantioselective synthesis of α-hydroxyphosphonates and α-aminophosphonates

Article abstract of DOI:10.1016/j.tetlet.2017.02.088

A novel manganese/proline-derived catalyst system is reported for the stereoselective synthesis of α-hydroxyphosphonates and α-aminophosphonates. The reaction proceeded smoothly under mild reaction conditions with efficient reaction times. The resulting p

Full text of DOI:10.1016/j.tetlet.2017.02.088

Accepted Manuscript
Manganese-proline derived new catalyst system for the enantioselective syn-
thesis of α-hydroxy phosphonates and α-amino phosphonates
Hyun Lim, Vicklyn Datilus, Rania Teriak, Prianka Chohan, Parminder Kaur
PII:
S0040-4039(17)30274-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.088
TETL 48699
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
30 January 2017
23 February 2017
27 February 2017
Please cite this article as: Lim, H., Datilus, V., Teriak, R., Chohan, P., Kaur, P., Manganese-proline derived new
catalyst system for the enantioselective synthesis of α-hydroxy phosphonates and α-amino phosphonates,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.088
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Title: Manganese-proline derived new catalyst system for the
enantioselective synthesis of α-hydroxy phosphonates and α-amino
phosphonates
Hyun Lim,# Vicklyn Datilus,# Rania Teriak, Prianka Chohan and Parminder
Kaur *
College of Science and Health, Department of Chemistry, William Paterson
University, 300 Pompton Road, Wayne, NJ 07470, United States
#co-authors contributed equally
Corresponding Author’s Email: kaurp6@wpunj.edu, Tel: (973)-720-2706
Abstract: A novel manganese/proline-derived catalyst system is reported for the
stereoselective synthesis of α-hydroxyphosphonates and α-aminophosphonates.
The reaction proceeded smoothly under mild reaction conditions with efficient
reaction times. The resulting products were obtained with high yields and good
enantioselectivities (up to 83% ee).
Introduction
In the past two decades, a tremendous amount of research has been done on
organophosphorous compounds, especially phosphate esters, because of their
significant importance in processes such as photosynthesis, carbohydrate/lipid
metabolism and the nitrogen cycle. In addition, these compounds also act as
pesticides, herbicides, plant growth regulators, anti-thrombotic agents1-12 and
precursors for variety of other biologically important organophosphorous
compounds.13-17
Among these compounds, α-hydroxyphosphonates and α-aminophosphonates
are two important classes because of their anti-bacterial,14-15 anti-viral and other
biological properties.10 Both α-hydroxyphosphonates and α-aminophosphonates
also behave as potent inhibitors for a variety of enzymes such as HIV-protease,4-
7,10
polymerase and serine esterases18 as well as have anti-proliferative
properties for tumor cells.19 However, most of the time, one of the enantiomer

was found to be more active for these properties than the other and hence
synthesis of stereochemically pure compound is highly desired.15, 18, 19
The most direct and economical method for the C-P bond formation is the
addition of dialkylphosphite to carbonyl compounds, widely known as Pudovik
reaction.20a Various methods and catalysts have been developed in the past for
the synthesis of stereochemically pure derivatives20-32 including the use of Al
(salen), Al (saleyen) and Al-Schiff base catalysts.20b-22 Feng and co-workers
reported the highly efficient Lewis-acid catalyzed phosphonate synthesis in
presence of Ti(OiPr)4 as catalysts.29 It was later reported that lanthanide salts
can also act as potential catalysts for this transformation.24
Despite the great progress in the area, the development of new methodologies
using less complex chiral catalyst system is still highly desirable. Spilling and
group has extensively been involved in the enantioselective synthesis of α-
hydroxyphosphonates and has recently published a very comprehensive review
on the topic.33 Spilling and group has achieved the asymmetric synthesis of α-
hydroxyphosphonates and several other substituted phosphonates using
different elegant catalytic systems and has achieved the product with great %ee.
35 In one of their studies, they reported the Titanium alkoxide-diol based catalyst
system for the asymmetric phosphonylation of aldehydes and achieved upto
70%ee which upon enzymatic kinetic resolution gave >99% purity of the
product.35c Spillling and group also reported the non-racemic allylic hydroxy
phosphonate synthesis using olefin cross metathesis using the second
generation Grubbs catalyst.35e
Our group has been involved in developing simpler catalytic system for
common organic transformations34 and in our continuing effort to achieve that,
we would like to report herein a new Manganese-proline derived chiral catalytic
system for the asymmetric carbon–phosphorus bond formation via the addition of
various dialkylphosphites onto different aldehydes and imines. The reaction was
carried out under simple reaction conditions and the products were obtained in
good yields and moderate enantioselectivities.

Results and Discussion
The reaction optimization was done using benzaldehyde 9a (1.00 mmol) as the
model substrate (Scheme 1) and was treated with diethylphosphite (1.20 mmol)
and lithium carbonate as base and chiral catalyst 6 (10 mol%) to give the
corresponding α-hydroxyphosphonates. For the first reaction, manganese
chloride (12 mol%) was used as the metal source. The reaction was stirred at
room temperature and was constantly monitored by TLC (hexane:EtOAc, 8:2,
v⁄v) before it was quenched with saturated ammonium chloride solution at
completion after 24 h. The product 10a was isolated in good yield (72%) and
moderate enantioselectivity (ee% = 62).
Further attempts were made to enhance the yield and enantioselectivity of the
reaction. A series of different metals salts of Mn, Fe, Ni, and Zn was first tested.
Iron, nickel and zinc salts were not proven to be very effective. However, cobalt
bromide (yield: 66% and %ee = 58) and manganese chloride (yield: 72% and
%ee = 62) gave some promising results.
To further improve the enantioselectivity, a series of proline-derived ligands was
then tested and the results for the screening have been summarized in Scheme
1. Also, it was found during the screening of the metal salts that manganese
bromide (12 mol%) is a better choice than manganese chloride (12 mol%) to
carry out this reaction (Table 1).
It was found that the use of ligands 1-5 had poor to moderate effect on the
enantioselectivity of the reaction and with ligands 1-3, no significant stereocontrol
was observed (Scheme 1). While designing and choosing these ligands, it was
anticipated that the presence of the trans-hydroxyl group would increase the
coordination with the metal ion and hence would show a better stereocontrol and
prove to be a better catalytic system (particularly in case of 4 and 5, Scheme 1).
But surprisingly only 24%ee and 37%ee of the product was obtained
respectively. However, when ligand 6 was used, 71% ee was observed instead.
The presence of a free amine group is anticipated to coordinate with the metal
center well and help in achieving the desired transition state or intermediate to
carry out the reaction. Based on these optimizations, 6 was chosen to be the
ligand of choice. A series of solvents such as THF, acetonitrile, DMF, 1,4-

dioxane and dichloromethane was also screened and it was found that both
anhydrous THF and anhydrous acetonitrile worked extremely well under the
optimized conditions.
A variety of bases were tested next under the same reaction conditions and the
results are listed in Table 1. K2CO3, n-BuLi, LiHMDS, and triethylamine are some
of the bases that were tested but it was found that the best results were obtained
with Li2CO3 (Table 1, entry 10). At last, we screened the chiral ligand with
different bases and manganese salts to find the best combination and we
concluded that the catalyst 6 (10 mol%) along with MnBr2 (12 mol%) and Li2CO3
(1 equiv) in anhydrous THF gave the best results (Table 1, entry 10).
Scheme 1. Screening of different chiral catalysts.
Table 1. Optimization of chiral ligand, base and metal source for the asymmetric
synthesis of α-hydroxyphosphonates using benzaldehydea

Entry
Chiral
Mn
Base
Yield%b %Eec
Ligand source
1
1
2
3
4
5
6
6
6
6
6
6
6
6
6
Mn(OAc)2 Li2CO3
Mn(OAc)2 Li2CO3
Mn(OAc)2 Li2CO3
Mn(OAc)2 Li2CO3
Mn(OAc)2 Li2CO3
Mn(OAc)2 Li2CO3
44
41
36
28
31
49
72
58
49
78
58
59
48
33
25
12
19
23
28
62
21
19
71
23
49
62
14
2
3
4
5
6
7
MnCl2
MnCO3
MnSO4
MnBr2
MnBr2
MnBr2
MnBr2
MnBr2
Li2CO3
Li2CO3
Li2CO3
Li2CO3
K2CO3
TEA
8
9
10
11
12
13
14
n-BuLi
LiHMDS 42
aAll reactions were carried out at room temperature with aldehyde (1equiv), Mn salt (12 mol%), chiral ligand (10 mol%),
base (1 equiv) and dialkylphosphite (1.2 equiv) in anhydrous THF for 24 h. bCombined yields of both isomers.
cEnantioselectivity was determined by chiral HPLC analysis: OD-H Chiralpak column (7:3 hexane:IPA).
After the optimal conditions were obtained, various aldehydes (9a-9i) and imines
(12a-12e) were tested to examine the substrate scope of the methodology. As
summarized in Table 2, substituents on the phenyl rings of aldehydes and imines
have some effect on both the yield and the enantioselectivity of the product.
Moderate to good yields were obtained in the case of 4-tolyladehyde (9c) and 4-
bromo benzaldehyde (9e) (entry 3 & 5, Table 2). On the contrary, in presence of
an electron-withdrawing group such as 4-nitrobenzaldehyde (9f) (entry 6, Table
2), the yield declined significantly and poor enantioselectivity (42%) was
obtained. Also, in case of 2-nitrobenzaldehyde, no product was obtained at all
and the aldehyde was recovered after the reaction. Similar reaction trends were
observed with different imines that were tested under the same reaction
conditions and the results are summarized in Table 4.
Table 2. Enantioselective synthesis of α-hydroxyphosphonates using various

aldehydesa
Entry
R
Product Yield%b
Ee%c
71
58
67
59
54
43
nr
1
H (9a)
10a
10b
10c
10d
10e
10f
78
82
89
75
92
63
nr
2
2-Me (9b)
4-Me (9c)
2-F (9d)
3
4
5
2-Br (9e)
4-NO2 (9f)
2-NO2 (9g)
1-Naphthyl (9h)
2-furyl (9i)
6
7
10g
10h
10i
8
65
64
62
73
43
56
9
10
Cinnamaldehyde (9j) 10j
aAll reactions were carried out at room temperature with aldehyde (1equiv), Mn salt (12 mol%), chiral ligand (10 mol%),
base (1 equiv) and dialkylphosphite (1.2 equiv) in anhydrous THF for 24 h. bCombined yields of both isomers.
cEnantioselectivity was determined by chiral HPLC analysis: OD-H Chiralpak column (7:3 hexane:IPA).
Table 3. Screening of different dialkyl phosphitesa
Entry
R
R’
Product
Yield%b
Ee%c
1
2
3
4
5
6
Me (8b)
i-Pr(8c)
Ph(8d)
Bn(8e)
i-Pr(8c)
Ph(8d)
11a
11b
11c
11d
11e
11f
H
85
78
62
75
86
62
61
46
56
65
48
38
H
H
H
4-Me
4-Me

aAll reactions were carried out at room temperature with aldehyde (1equiv), Mn salt (12 mol%), chiral ligand (10 mol%),
base (1 equiv) and dialkylphosphite (1.2 equiv) in anhydrous THF for 24 h. bCombined yields of both isomers.
cEnantioselectivity was determined by chiral HPLC analysis: OD-H Chiralpak column (7:3 hexane:IPA).
Finally, a series of dialkyl phosphites including dimethyl (8b), diisopropyl (8c),
diphenyl (8d), and dibenzyl phsophites (8e) was tested (Table 3). All the five
dialkyl phosphites were tested with benzaldehyde (9a) and it was found that the
best result was obtained with diethyl phosphite (entry 1, Table 2). However, a
poor reaction profile was achieved when diphenyl phosphite was used for
carrying out the reaction (Table 3).
Table 4. Enantioselective synthesis of α-aminophosphonates using different
iminesa
Entry
R
Product
13a
Yield%b
65
Ee%c
52
1
2
3
4
5
H (12a)
2-Me (12b)
4-NO2 (12c)
4-Br (12d)
4-F (12e)
13b
72
71
13c
58
23
13d
68
49
13e
63
45
aAll reactions were carried out at room temperature with imine (1equiv), Mn salt (12 mol%), chiral ligand (10 mol%), base
(1 equiv) and dialkylphosphite (1.2 equiv) in anhydrous THF for 24 h. bCombined yields of both isomers.
cEnantioselectivity was determined by chiral HPLC analysis: OD-H Chiralpak column (7:3 hexane:IPA).
To further test the substrate scope of the new catalytic system, a series of imines
(12a-12e) was also tested under the same conditions (Table 4). However,
comparatively lower product yields were observed when the reaction was carried
out with various imines vs aldehydes. Also, better yields and selectivities were
observed in the presence of the electron-donating group (entry 2&4, Table 4)

compare to the electron-withdrawing group (entry 3, Table 4).
As shown in Scheme 2, the absolute configuration of α-hydroxyphosphonates
(10a) was determined by comparing the literature [α]20D of 10a with the observed
one.35 After comparing the values, it was found that the new chiral center has an
R-configuration. Similar results were obtained for the α-aminophosphonates and
it was found that all the products have R configuration too.
Lit. [α]20D = -20.5 (c 2.0 in CHCl3) assigned as “S” configuration35
Obs. [α]20D = +32.8 (c 1.49 in CHCl3) for “R” configuration
Scheme 2. Absolute configuration determination of the product
Conclusion
Chiral ligand 6 was found to be an effective catalyst for the enantioselective
synthesis of α-hydroxyphosphonates/α-aminophosphonates. The reaction was
carried out under mild conditions by using the appropriate manganese-proline
derived system and dialkylphosphite in anhydrous THF. The products were
obtained in high chemical yields and moderate to good enantioselectivities.
Decreased product yields and poor enantioselectivities were obtained in
presence of electron-withdrawing groups on aldehdyes and imines. The absolute
configuration was determined by comparing the optical rotation with the known
phosphonates. It was also observed that the presence of various substitutions on
the chiral ligands/catalysts has significant effect on the asymmetric induction.
The study to further improve the structure of the chiral ligand to achieve better
selectivity is underway.
Acknowledgments
We would like to thank the Department of Chemistry, College of Science and
Health, William Paterson University (WPU) for providing the start-up funds to
Prof. Kaur. We would also like to thank WPU for providing the necessary facilities
to carry out this study. P.C. would like to thank Center for Research, Summer
Award from William Paterson University. V.D., H.L., and R.K. would like to thank

Garden State–Louis Stokes Alliance for Minority Participation (GS-LSAMP) for
the financial support.
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