Stereoselective synthesis of α-amino(phenyl)methyl(phenyl)phosphinic acids with O-pivaloylated D-galactoslamine as chiral auxiliary

Article abstract of DOI:10.1002/chem.200901419

Stereoselective synthesis of α-amino (phenyl)methyl(phenyl)phosphinic acids with O-pivaloylated D-galactosylamine as chiral auxiliary, was reported. 2 3 drops of acetic acid were added to a solution of amine 1 and aldehyde 2 in 2-propanol and the mixture was stirred at room temperature for about 0.5 h. A solution of N-galactosylaldimines 3 in THF was cooled to 0°C, and phosphinate 4 and SnCl₄ were added. The mixture was stirred for 2 d at room temperature. The aqueous phase was extracted with CHCl₃ and the organic layers were dried with anhydrous MgSO₄, filtered, and concentrated in vacuo to yield the crude products. A solution of compound 5 in dry methanol was treated with freshly prepared solution of HCl. Then methanol was evaporated in vacuo and the remaining residue dissolved in 0.5 M HCl and extracted with pentane. The results revealed that AlCl₃, SnCl ₄, and BF₃.OEt₂ were able to promote the addition.

Full text of DOI:10.1002/chem.200901419

DOI: 10.1002/chem.200901419
Stereoselective Synthesis of a-AminoACHTUNTGRENNUG(phenyl)methylACHUTNGTREN(NUGN phenyl)phosphinic
Acids with O-Pivaloylated d-Galactosylamine as Chiral Auxiliary
Yadan Wang,[a] Yangyun Wang,[a] Jipan Yu,[a] Zhiwei Miao,*[a, b] and Ruyu Chen*[a]
Dedicated to Professor Ruyu Chen on the occasion of her 90th birthday
a-Aminophosphonic and -phosphinic acids are the phos-
phorus analogues of a-aminocarboxylic acids, and therefore
have biological importance both in themselves and as build-
ing blocks for peptides.[1] Many natural and synthetic amino-
phosphonic acids exhibit a variety of biological properties
including enzyme inhibitors, such as synthase,[2] HIV pro-
tease,[3] renin,[4] phosphatase activity,[5] PTPases,[6] and
potent antibiotics.[7] The configuration at the a-carbon atom
in the a-aminophosphinic acids plays a decisive role in the
biological properties of these types of compound.[8] Numer-
ous optically active aminoalkylphosphonic acids have al-
ready been obtained from natural resources and by synthe-
sis. Typical examples include the addition of dialkyl phos-
phite or its lithium salt to an imine bearing a chiral auxiliary,
with or without Lewis acid catalysis, respectively.[9]
Carbohydrates are valuable as enantiomerically pure
starting materials in chiral pool syntheses of many chiral
natural products and drugs.[10] The polyfunctionality of car-
bohydrates is useful for binding or coordinating a substrate.
Carbohydrate derivatives are efficient auxiliaries for stereo-
differentiation in many stereoselective chiral syntheses.[11–12]
A notable example is the paper by Kunz, in which the use
of carbohydrates as chiral templates to promote Mannich-
type reaction and the stereoselective synthesis of a-amino-
phosphonic acid derivatives is reported.[13] The nucleophilic
addition of a dialkyl or diaryl phosphite to imines or oxoimi-
nium derivatives, the Pudovik reaction,[14] is one of the most
convenient methods for the preparation of a-aminophospho-
nates, key intermediates in the synthesis of a-aminophos-
phonic acids. Chiral auxiliaries proved to be good to excel-
lent in inducing asymmetry on the imine carbon atom result-
ing in enantiopure a-aminophosphinates. Lewis acid cata-
lysts are required for induction of the enantioselectivity in
the phosphorylation reaction.[15] Recently, we reported that
b-N-glycoside-linked a-aminophosphonic acids derivatives
can be synthesized diastereoselectively by the Lewis acid in-
duced addition of diethyl phosphite to Schiff bases of
2,3,4,6-tetra-O-pivaloyl-b-d-galactopyranosylamine
We here report on an asymmetric synthesis of a-amino-
(phenyl)methyl(phenyl)phosphinic acids in which O-pivaloy-
lated glycosylamines serve as the stereodifferentiating
auxiliaries.
The synthesis of b-N-glycoside-linked a-aminophospho-
(1).[16]
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
nates started with the condensation of amine 1 and arylalde-
hyde 2. The formation of the corresponding N-galactosylal-
dimines 3[17] proceeded smoothly at room temperature
under dehydrating conditions. Higher temperatures and
longer reaction times led preferentially to the formation of
the undesired conjugated enamines. Under these conditions,
the Schiff bases 3 of aromatic aldehydes are obtained in
crystalline form. The amount of the corresponding a-
anomer can be restricted to less than 4%, and imines 3 of
aliphatic aldehydes cannot be isolated in a crystalline form
by this method. The imines 3 and equivalent amounts of
ethyl phenylphosphinate (4) were kept at room temperature
in THF and the reaction was run until the imine was con-
sumed to furnish the eight diastereomeric N-galactosylaryl-
phosphonoglycine esters 5 in high yield. The mixture 5 was
treated with 1m hydrogen chloride in methanol at room
temperature giving the easily separable carbohydrate tem-
plate 6 and the a-aminobenzylphosphonate hydrochloride 7
in quantitative yield. Under these conditions, the amount of
deglycosylation was minimized, and no loss of anomeric
purity was observed (Scheme 1).[18]
[a] Y. Wang, Y. Wang, J. Yu, Prof. Dr. Z. Miao, Prof. Dr. R. Chen
State Key Laboratory and Institute of Elemento-Organic Chemistry
Nankai University, Weijin Road 94, Tianjin 300071 (P. R. China)
Fax : (+86)22-2350-2351
E-mail: miaozhiwei@nankai.edu.cn
[b] Prof. Dr. Z. Miao
Key Laboratory of Bioorganic Phosphorus Chemistry &
Chemical Biology (Ministry of Education)
Tsinghua University, Qinghuayuan, Beijing 100084 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901419.
9290
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Chem. Eur. J. 2009, 15, 9290 – 9293

COMMUNICATION
Table 1. Survey of the conditions for the formation of 5a according to
Scheme 1.[a]
Lewis acid
(equiv)
Solvent
t [d]
Yields
[%][b]
d.r.
N
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
–
THF
THF
THF
THF
THF
THF
THF
THF
3
3
2
2
n.r.[c]
n.r.
n.r.
n.r.
49
89
92
88
80
83
60
33
35
–
–
–
ZnCl2
CuBr (1)
CuI (1)
–
AlCl3 (1)
SnCl4 (1)
SnCl4 (1.5)
SnCl4 (2)
BF3·Et2O (1)
BF3·Et2O (1.5)
BF3·Et2O (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
SnCl4 (1.5)
–
2
>73
>85
>91
>86
>87
>88
>80
>87
>91
>90
—
2.5
2.5
2.5
1
1
1
3
3
3
3
THF
THF
Scheme 1. Synthesis of (S)-a-amino
acids 8.
ACHUTGTNREN(UNG phenyl)methylAHCTUNGTREN(NUGN phenyl)phosphinic
CH2Cl2
CH2Cl2
CHCl3
PhCH3
CH2Cl2
CHCl3
PhCH3
38
We initially investigated the reaction of O-pivaloylated N-
galactosylimine 3a (R=C6H5) with ethyl phenylphosphinate
(4) in THF without the aid of Lewis acid; no product 5a
was detected. Since the nucleophilicity of ethyl phenylphos-
phinate 4 is low and the electrophilicity of imines is only
moderate, the reaction between these compounds requires
activation by a Lewis acid to proceed. In this sense, various
Lewis acids were tested in the reaction of the N-galactosyli-
mine 3a with 4 in THF. The results revealed that AlCl3,
SnCl4, and BF3·OEt2 were able to promote the addition
(Table 1, entries 5–11). Other Lewis acids tested (e.g.,
ZnCl2, CuBr, CuI) only caused anomerization of the Schiff
base 3a, and no product of 5a was observed (Table 1, en-
tries 2–4). In addition, the reaction does not work in the ab-
sence of Lewis acid if CHCl3 or toluene is used as solvent
(Table 1, entries 16 and 17). Since SnCl4 gave the higher dia-
stereoselectivity (d.r. >91%) compared with BF3·OEt2 (d.r.
>88%), it was used in further investigations.[13] The ratio of
diastereomers 5 was determined by 31P NMR analysis.
To determine the optimal conditions, imine 3a was react-
ed with one equivalent of phosphinate 4 in the presence of
different concentrations of SnCl4 in THF at 08C for 1 h, fol-
lowed by warming to room temperature. An increase in the
concentration of Lewis acid (1.5 equiv) resulted in a higher
yield of 5a and a slight increase of the diastereoselectivity.
A further increase of the concentration (2 equiv) had no sig-
nificant effect on the yield or the selectivity. To further dem-
onstrate the scope and flexibility of the present optimized
conditions, a wide range of different aromatic aldehydes
were then successfully examined with this methodology
(Table 2). As expected, a number of N-galactosyl a-aminoal-
kylphosphonates 5a–g were prepared in a Mannich-type re-
action. The reaction was conducted in THF at room temper-
ature under mild conditions, in the presence of 1.5 equiva-
lents of SnCl4, and the products 5 were obtained in high
yields. Based on these experiments, it was found that the
rates of the reaction of the electron-poor aromatic
n.r.
n.r.
n.r.
–
–
3
3
—
—
[a] Unless otherwise noted all the reactions were performed with 3
(0.5 mmol) and diethyl phosphite (0.75 mmol) in solvent (5 mL) at room
temperature. [b] Determined from the crude product by 31P NMR spec-
troscopy. [c] No reaction. [d] Reference [12c].
Table 2. The Mannich-type reaction of imines 5a–g at room temperature.
5
R
t [h]
Yield [%][a]
d.r. [%][b]
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5 f
5g
H
p-Br
p-F
p-Cl
p-NO2
p-OCH3
p-CH3
2
2
2
2.5
3
91
86
92
84
79
82
95
>73
>82
>76
>86
>88
>74
>81
2
2
[a] After purification by chromatography and recrystallization. [b] Dia-
stereomeric ratio determined from the crude product by 31P NMR spec-
troscopy.
AHCTUNGTREGaNNNU ldehydes were nearly the same as those of the electron-rich
aromatic aldehydes. Further more, the reaction of Schiff
base 3 of aliphatic aldehydes with ethyl phenylphosphinate
4 under identical conditions did not lead to H-phosphinate
addition. Even at low temperature (À788C), only anomeri-
zation and decomposition occurred.
The ratio of the obtained diastereomers 5 was determined
by 31P NMR from the crude mixture of the reaction. It
should be noted that because of the anomeric carbon and
one stereogenic center created at the a-position of the phos-
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www.chemeurj.org
9291

Z. Miao, R. Chen et al.
phonate, the eight diastereomers are b-S,S, b-R,S, a-S,S, a-
R,S, b-S,R, b-R,R, a-S,R, and a-R,R. Diastereomerically
pure compounds 5a–d and 5 f were obtained by simple re-
crystallization from n-hexane and ethyl ether. In order to
assign the configuration of the N-galactosyl a-aminoalkyl-
phosphonate 5, a-aminophosphinate hydrochloride 7 is re-
leased from 5 with 1m HCl in methanol. The diastereomers
7 can be hydrolyzed by using concentrated hydrochloric acid
under reflux (Table 3) and the product crystallized sponta-
Scheme 2. Plausible reaction mechanism.
Table 3. Asymmetric Mannich synthesis of a-amino
nyl)phosphinic acids 8.[a]
ACHTUNGTREN(NUNG phenyl)methyl (phe-
À
the equatorial Sn Cl bond (anti to O), and they would also
lead to a more reactive anionic nucleophile. According to
this rationalization, the SN2’-type attack of phosphinate 4
from the back side of the imine is initiated. Based on the re-
sults, the OH moiety of the phosphinate 4 is suggested to
play an important role in determining the high enantioselec-
tivity, since the required tautomeric equilibrium between
the PV phosphinic and the PIII phosphonous forms is still
available. The mechanism indicates that the Piv4Gala group
plays a significant role in controlling the regio and diaste-
reoselective of ethyl phenylphosphinate to N-galactosyli-
mines 3.
R
7
t
Yield
[%][a]
8
t
Yield
[%][a]
ee
[%][b]
In conclusion, we have described a convenient and effi-
cient synthetic protocol for preparation of a-aminophos-
phinic acid derivatives in high yields and high enantiostereo-
selectivity, utilizing SnCl4 as the promoter and O-pivaloylat-
ed d-galactosylamine 1 as chiral auxiliary by means of Man-
nich-type reactions. The O-pivaloylated galactosylamine 1 is
an effective chiral template in the synthesis of chiral N-gal-
actosyl a-aminoalkylphosphonate 5. SnCl4 can form the oc-
tahedral-coordination intermediate induces the S configura-
tion at the Ca center by attack at the Si side of the C=N
[d]
[h]
1
2
3
4
5
6
7
H
p-Br
p-F
p-Cl
p-NO2
p-OCH3
p-CH3
7a
7b
7c
7d
7e
7 f
7g
2
2
2
2
2
2
2
87
90
93
78
87
95
85
8a
8b
8c
8d
8e
8 f
8g
3
3
3
3
3
3
3
88
87
82
90
93
90
91
84
78
90
94
73
88
97
[a] Isolated yield. [b] Determined by chiral HPLC analysis.
neously from propylene oxide to give the a-aminophosphin-
ic acids 8 with (À)-optical rotations (S).[19] The deprotection
reactions occurred without racemization of the a-carbon
atom.[20] Boc-a-aminophosphinic acids 9 can be easily ob-
plane of the imine carbon atom. a-AminoACHTNGUTERNNU(G phenyl)methyl
(phenyl)phosphinic acids 8 can be detached easily from the
carbohydrate template, which can be recollected.
tained by the reaction of a-amino
ACHTUNGTREN(NGNU phenyl)methyl-
ACHTUNGTRENNUNG(phenyl)phosphinic acids 8 with di-tert-butyl dicarbonate in
dichloromethane at low temperature. Treatment of com-
Experimental Section
pound 9 with trimethyl orthoformate in CH2Cl2, gave the N-
Boc ethylphenylACHTUNGTRENNUNG(benzyl)phosphinate derivatives 10, which
General procedure for the preparation of O-pivaloyiated N-galactosyl-
AHCTUNGTREGiNNUN mines 3: To a solution of amine 1 (0.515 g, 1 mmol) and aldehyde 2
(1.3 mmol) in 2-propanol (2.5 mL), 2–3 drops of acetic acid were added
and the mixture was stirred at room temperature for about 0.5 h. The ap-
pearance of a precipitate from the solution indicated the formation of 3,
after which the precipitate was filtered off, then washed with ice cold 2-
propanol and dried in vacuum, N-galactosylaldimines 3 were isolated as a
colorless solids.
were used for enantioselectivity determination by chiral
HPLC.
The proposed mechanism of this catalytic asymmetric hy-
drophosphonylation is shown in Scheme 2.[21] The preferred
formation of the S-configured diastereomer of 5 can be ra-
tionalized by an attack of ethyl phenylphosphinate from Si
side of (E)-imines 3. In the transition state, the tin should
have octahedral coordination. Two coordination sites of the
tin(IV) chloride are occupied by the imine nitrogen and the
carbonyl oxygen atoms of the (C-2) pivaloyloxy group. The
imine·SnCl4 complex maintains the H-eclipsed conforma-
tion, because chelation by the auxiliaryꢁs pivaloyl group in-
General procedure for the synthesis of b-N-glycosidic linkages in
a-aminophosphonic acid derivatives 5: A solution of N-galactosylaldi-
mines 3 (0.5 mmol) in THF (5 mL) was cooled to 08C, and phosphinate 4
(0.128 g, 0.75 mmol) and SnCl4 (0.087 mL, 0.75 mmol) were added. The
mixture was stirred for 2 d at room temperature. The mixture was hydro-
lyzed with 2m aqueous NaOH (35 mL) and the mixture was stirred at
room temperature for 5 min. The aqueous phase was extracted with
CHCl3 (3ꢂ25 mL), and the organic layers were dried with anhydrous
MgSO4, filtered, and concentrated in vacuo to yield the crude products 5,
which were purified by flash column chromatography on silica gel [petro-
À
hibits rotation along the N C* bond. Probably, the non-
bonding interaction Ph/Cl is relieved by ionic dissociation of
leum ether/ethyl acetate, 2:1ACTHNGUTERNNUG
(VV)À1] to provide pure products 5.
9292
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Chem. Eur. J. 2009, 15, 9290 – 9293

Aminophosphonic Acids
COMMUNICATION
General procedure for the synthesis of ethyl a-amino
ACHTUNGTRENNUNG(phenyl)phosphinate hydrochlorides 7: A solution of compound 5
(phenyl)methyl-
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(0.41 mmol) in dry methanol (5 mL) was treated with freshly prepared
(1m) solution of HCl (0.62 mL). The solution was stirred for 2 d (TLC
control). Then methanol was evaporated in vacuo and the remaining resi-
due dissolved in 0.5m HCl (10 mL) and extracted with pentane (3ꢂ
10 mL). The aqueous solution was evaporated to dryness and gave 7 as
colorless crystals in quantitative yield. From the pentane solution, after
drying (MgSO4) and evaporation of the solvent, the O-pivaloylated galac-
topyranose 6 was isolated as colorless crystals in quantitative yield.
[4] V. Patel, K. Rielly-Gauvin, D. E. Ryono, Tetrahedron Lett. 1990, 31,
5587–5590.
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ACHTUNGTREN(NGNU phenyl)methyl-
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ACHTUNGTRENNUNG
compound 7, and the resultant solution was heated with stirring under
reflux for 3 h. The solvent was then evaporated under vacuum to lead to
the a-aminophosphinic acid as a white solid. This material was dissolved
in refluxing ethanol and treated with propylene oxide at 70–808C to pre-
cipitate phosphinic acids acid 8 as a white crystalline powders. The prod-
uct was filtered off, washed with diisopropyl ether, and thoroughly dried
at 508C under reduced pressure and in the presence of a dehydrating
agent (P2O5).
General procedure for the synthesis of N-boc ethylphenyl-
ACHTUNGTRENNUNG(benzyl)phosphinate derivative 10 for% ee determination by chiral
HPLC: Triethylamine (0.18 mL, 0.0013 mmol) was added to an ice-cold
suspension of 8 (1 mmol) in dichloromethane (2.2 mL). Next, di-tert-butyl
dicarbonate (0.3 g, 0.0014 mol) in dichloromethane (0.11 mL) was added
over 10 min, and the mixture was stirred at 08C for overnight. The reac-
tion was discontinued by addition of saturated aqueous citric acid
(0.55 mL), and the organic phase was washed with brine (2ꢂ0.55 mL)
and water (0.55 mL). Removal (in vacuo) of solvent yielded a crude
product 9. Then trialkyl orthoformate (5 mL) was added to the crude
product 9 and the resulting mixtures were stirred at 100–1108C for 2 h,
after which time the reaction mixtures were concentrated, then dissolved
in CH2Cl2 and washed with water, the solution was evaporated to dryness
to give the crude products 10, which were purified by flash chromatogra-
phy [CH2Cl2/MeOH, 50 L (v/v)].
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Acknowledgements
We thank the Committee of Science and Technology of Tianjin
(07JCZDJC04800), the Research Foundation for the Doctoral Program
of Higher Education of China (20070055042) and Project 973 of the Min-
istry of Science and Technology of China (2007CB914800) for financial
support.
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Keywords: aminophosphonic acids · carbohydrates · chiral
auxiliaries · Mannich-type reactions · phosphorus
[19] The R enantiomer of ethyl a-benzylamino-phenylphosphinic acid is
known from the literature, and has been isolated by resolution and
by repeated crystallization from the diastereomeric mixture of its
ester; the absolute configuration was then determined by X-ray crys-
tallography, see: Yu. P. Belov, G. B. Rakhnovich, V. A. Davankov,
N. N. Godovikov, G. G. Aleksandrov, Yu. T. Struchkov, Izv. Akad.
Nauk 1980, 5, 1125.
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Received: May 27, 2009
Published online: August 5, 2009
Chem. Eur. J. 2009, 15, 9290 – 9293
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9293