Glycosylation-induced and Lewis acid-catalyzed asymmetric synthesis of β-N-glycosidically linked α-aminophosphonic acids derivatives

Article abstract of DOI:10.1002/adsc.200800406

The diastereospecific formation of β-N-glycosidically linked α-aminophosphonic acids derivatives has been achieved with high yield via a Mannich-type reaction. The reaction was performed by using O-pivaloylated galactosylamine 1 as a chiral template and boron trifluoride diethyl etherate as a catalyst in THF. Imines 3 of aromatic compounds and diethyl phosphite were converted to N-galactosyl α-aminoalkylphosphonate 4, giving ratios of diastereomers higher than 19:1. This procedure provides a rapid access to biologically important galactosyl α-aminophosphonic acids derivatives.

Full text of DOI:10.1002/adsc.200800406

FULL PAPERS
DOI: 10.1002/adsc.200800406
Glycosylation-Induced and Lewis Acid-Catalyzed Asymmetric
Synthesis of b-N-Glycosidically Linked a-Aminophosphonic
Acids Derivatives
Yadan Wang,a Fei Wang,a Yangyun Wang,a Zhiwei Miao,a,b,* and Ruyu Chena
a
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, Peopleꢀs Republic
of China
Fax : (+86)-22-2350-2351; e-mail: miaozhiwei@nankai.edu.cn
Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University,
b
Beijing 100084, Peopleꢀs Republic of China
Received: June 30, 2008; Published online: October 2, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800406.
Abstract: The diastereospecific formation of b-N-gly- a-aminoalkylphosphonate 4, giving ratios of diaste-
cosidically linked a-aminophosphonic acids deriva- reomers higher than 19:1. This procedure provides a
tives has been achieved with high yield via a Man- rapid access to biologically important galactosyl a-
nich-type reaction. The reaction was performed by aminophosphonic acids derivatives.
using O-pivaloylated galactosylamine 1 as a chiral
template and boron trifluoride diethyl etherate as a Keywords: a-aminophosphonic acids; asymmetric
catalyst in THF. Imines 3 of aromatic compounds synthesis; carbohydrate auxiliaries; Lewis acid catal-
and diethyl phosphite were converted to N-galactosyl ysis; Mannich-type reaction
Introduction
(Figure 1).[7] The sugar moieties of glycopeptides
define their biological activity, and thus the potential
a-Aminophosphonic and -phosphinic acids are the of carbohydrates for the development of new drugs is
phosphorus analogues of a-aminocarboxylic acids, being explored. Linking peptides to carbohydrates
and therefore have biological importance both in can improve the activity and selectivity of various ef-
themselves and as building blocks for peptides.[1] fects.[8,9]
Phosphonopeptides are a class of unnatural peptides,
The configuration at the a-carbon atomin the a-
which act as antagonists and compete with their car- aminophosphinic acid derivatives plays a decisive role
boxylic counterparts for the active sites of enzymes in the biological properties of these types of com-
and other cell receptors.[1,2] Several phosphonopepti- pound,[10] as it does similarly in a-aminocarboxylic
des show antibiotic effects, others have been recog- and -phosphonic acids.[11] Typical examples for the
nized as herbicides. On the basis of these biological preparation of optically active a-aminophosphonic
effects a number of asymmetric syntheses of a-amino-
phosphonic acids derivatives have been developed
during the past two decades.[3] Carbohydrates are val-
uable as enantiomerically pure starting materials in
chiral pool syntheses of many chiral natural products
and drugs.[4] The polyfunctionality of carbohydrates is
useful for binding or coordinating a substrate.[5] Car-
bohydrate derivatives are efficient auxiliaries for ste-
reodifferentiation in many stereoselective chiral syn-
theses.[5,6] Synthetic N- and O-linked glycoaminophos-
phonic acid derivatives are analogous to those found
in naturally occurring carbohydrates linked glycosidi-
cally to the a-amino acid of a peptide or a protein tween carbohydrate and peptides
Figure 1. a-O-Glycosidic and b-N-glycosidic linkages be-
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Yadan Wang et al.
FULL PAPERS
acids derivatives include the addition of a dialkyl
phosphite or its lithiumsalt to an imine bearing a
chiral auxiliary with or without Lewis acid catalysis,
respectively.[12] However, studies on the synthesis and
configuration of b-N-linked glycoaminophosphonic
derivatives, which are formal a-aminophosphonic
acids derivatives, are rare.[12d] Herein, we present an
asymmetric and efficient synthesis of a-aminophos-
phonates in which O-pivaloylated galactosylamine
serves as the stereodifferentiating auxiliary and
BF3·Et2O as the catalyst.
Results and Discussion
The Mannich-type reaction is one of the important
methods of synthesis of a-aminoalkylphosphonic
acids and derivatives.[3] Chiral auxiliaries proved to be
good to excellent in inducing asymmetry on the imine
carbon atomresulting in enantiopure a-aminophos-
phinates. Lewis acid catalysts are required for induc-
tion of the enantioselectivity in the phosphorylation
reaction.[13] One very versatile carbohydrate of the
Scheme 1. Reagents and conditions: (a) i-PrOH, 2–3 drops
of acetic acid, roomtemperature, 0.5 h; (b) 1.5 equiv.
HP(O)
2.5–4 h; (c) 0.5M NaOMe/MeOH, roomtemperature, 2 d,
001”7
(732), H+.
A
AHCTREUNG
chiral tool is the pivalyl-protected d-galactosylald- in the presence of CuBr or CuI in THF, the reaction
ACHTREUNG
chiral auxiliary has already been used in diastereose- ride in THF was used, the Mannich-type reaction of
lective Strecker,[15] Ugi,[16] Mannich,[17] and tandem the imines 3 with diethyl phosphite proceed at +48C
Mannich–Michael reactions.[18]
to roomtemperature to give the N-galactosyl-a-ami-
The synthesis of b-N-glycosidically linked a-amino- noalkylphosphonate 4 as a mixture of four diastereo-
phosphonates started with the condensation of aryl al- mers in low yield. The results summarized in Table 1
dehyde 2 and 2,3,4,6-tetra-O-pivaloyl-b-d-galactopyr- show that besides the two b-configurated diastereo-
anosylamine 1. The formation of the corresponding mers 4, the two a-configurated diastereomers 4 were
N-galactosylaldimines 3[14b] proceeded smoothly at obtained at the same time.
roomtepmerature under dehydrating conditions.
The reaction of the N-galactosylaldimines 3 with di-
Higher temperatures and longer reaction times led ethyl phosphite required activation by Lewis acids.
preferentially to the formation of the undesired con- Compared with SnCl4 and AlCl3, the best result was
jugated enamines. In a Lewis acid-catalyzed Mannich- obtained when BF3·Et2O in THF at roomtemperature
type reaction the aldimines 3 were reacted with dieth- was used (Table 1). When equimolar or higher than
yl phosphite to form N-galactosyl a-aminoalkyl- equimolar amounts of BF3·Et2O were used at room
phosphonate 4 (Scheme 1). Removal of the protecting temperature, the reactions were finished within four
groups proved initially troublesome due to the high hours with very high yields (Table 1, entries 6–8). The
stability of the pivalate group under basic conditions. ratios of diastereomers ranged between 9:1 and 19:1
The preferred conditions that were found involved with preponderance of the bS-configurated diastereo-
use of a freshly prepared solution of sodiummethox-
mer 4. The pure diastereomers were isolated in high
ide in a mixture of methanol and THF. Under these yields by simple crystallization of the crude products
conditions, the amount of deglycosylation was mini- 4 from n-hexane and diethyl ether. As a rule, the re-
mized, and no loss of anomeric purity was ob- action catalyzed by BF3·Et2O showed the higher ste-
served.[19]
reoselectivity. The crude products 4 only contained a
Under these conditions, the Schiff bases 3 of aro- few percent of the corresponding a-anomeric isomers
matic aldehydes are obtained in crystalline form. The presumably produced by a Lewis acid-catalyzed
amount of the corresponding a-anomer can be re- anomerization of the b-anomeric isomers. The ratio of
stricted to less than 4%, and imines 3 of aliphatic al- diastereomers 4 was determined by 31P NMR analysis.
dehydes cannot be isolated in crystalline formby this
Among other Lewis acids tested, CuBr and CuI both
method. Furthermore, aliphatic imines undergo applied in THF at roomtemperature, cannot catalyze
anomerization at temperatures above À108C. Being this reaction (Table 1, entries 2 and 3). And also the
of relatively low reactivity, the aldimines 3 do not reaction cannot work if CHCl3 or toluene is used as
react with diethyl phosphite at low temperature. Also slovent (Table 1, entries 16 and 17).
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Asymmetric Synthesis of b-N-Glycosidically Linked a-Aminophosphonic Acids Derivatives
Table 1. Survey of the conditions for the formation of 4a according to Scheme 1.[a]
FULL PAPERS
Entry Lewis acid (equi.v) Solvent Reaction time Yields [%][b] Ratio of aS:bR:bS:aR diastereomers of 4 de [%][d]
1
2
3
4
5
6
7
8
–
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CHCl3
3 days
3 days
3 days
3.5 days
4 h
4 h
4 h
4 h
4 h
3 ays
2.5 days
3 days
3 days
3 days
3 days
1 day
n.r.[c]
n.r.
trace
7
60
95
>99
>99
87
85
75
31
82
78
80
n.r.
n.r.
–
–
–
–
–
–
CuBr (1)
CuI (1)
ZnCl2 (1)
25.0:11.1:63.3:0.6
10.7:9.3:80.0:0
10.4:5.7:83.9:0
9.8:5.8:84.4:0
9.6:5.2:85.2:0
9.0:6.9:84.1:0
9.8:6.8:83.4:0
7.3:9.7:83.0:0
7.2:27.0:65.8:0
12.3:5.4:82.3:0
9.2:2.7:88.1:0
11.4:4.3:84.3:0
–
77
81
89
88
90
86
86
81
46
89
94
91
–
BF3·Et2O (0.5)
BF3·Et2O (1)
BF3·Et2O (1.5)
BF3·Et2O (2)
BF3·Et2O (2.5)
SnCl2·2 H2O (1)
AlCl3 (1)
AlCl3 (0.5)
SnCl4 (0.5)
SnCl4 (1)
9
10
11
12
13
14
15
16
17
SnCl4 (1.5)
BF3·Et2O (2)
BF3·Et2O (2)
PhCH3 1 day
–
–
[a]
Unless otherwise noted all the reactions were performed with 0.5 mmol of 3, 0.75 mmol diethyl phosphite in 5 mL solvent
at roomtemperature.
[b]
[c]
[d]
Determined from the crude product by 31P NMR.
No reaction.
Ref.[20]
To further demonstrate the scope and flexibility of tained by simple recrystallization from n-hexane and
the present optimized conditions, a wide range of dif- diethyl ether. In order to determine the absolute con-
ferent aldehydes were then successfully examined figuration of the main isomer of the diethyl phosphite
with this methodology (Table 2). As expected, a addition to N-galactosylaldimines 3, a single crystal
number of N-galactosyl-a-aminoalkylphosphonates
4a–h were prepared in a Mannich-type reaction. The
reaction was conducted in THF at roomtemperature
under mild conditions, in the presence of 2.0 equiv. of
BF3·Et2O, and the products 4 were obtained in high
yields. Based on these experiments, it was found that
the rates of the reaction of the electron-poor aromatic
aldehydes were a little bit higher than those of the
electron-rich aromatic aldehydes.
After flash chromatography (petroleum ether:ethyl
acetate, 2:1) N-galactosyl a-aminoalkylphosphonates
4a–h were isolated in high yields and high stereoselec-
tivity. The diastereomeric ratio of 4 was determined
by 31P NMR fromthe 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 phosphonate, the four anomeric diaste-
reomers have the bS, bR, aR and aS configurations.
Diastereomerically pure compounds 4a–h were ob- with 20% probability displacement ellipsoids.
Figure 2. ORTEP presentation of the crystal structure of 4e,
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Table 2. The Mannich-type reaction of N-(2,3,4,6-tetra-O-pivaloylated-d-galactosyl)aldimines 4a–h at roomtemperature.
Entry
Product
R
Time [h]
Yield [%][a]
Ratio of aS:bR:bS:aR diastereomers[b]
de [%][c]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
p-NO2
p-Br
p-F
o-Br
p-Cl
p-CH3
p-OCH3
H
4
3
88
85
82
90
82
85
80
87
9.6:5.1:85.2:0
88
88
86
62
86
84
77
80
8.2:4.0:85.8:2.0
8.4:4.4:84.5:2.7
10.3:12.0:70.7:7.0
8.2:3.8:84.8:3.2
8.0:5.2:83.8:3.0
7.0:8.1:81.4:3.5
4.3:4.7:85.7:5.3
2.5
3.5
3
3.5
3
2.5
[a]
After purification by chromatography and recrystallization.
Diastereomeric ratio determined from the crude product by 31P NMR.
Ref.[20]
[b]
[c]
X-ray diffraction study of 4e was performed.[21] The ured diastereomer of 4 can be rationalized by an
molecular structure of 4e is shown in Figure 2, and attack of diethyl phosphite fromthe si side of N-gal-
the structure shows that the absolute configuration of actosylaldimines 3. In the transition state (Figure 3),
a-aminoalkyl phosphonate main product can be as- the boron atomhas tetracoordination of which the
signed as S.
sites are occupied by the imine nitrogen and carbonyl
The possible mechanism for the reactions is shown oxygen (C-2) of the pivaloyloxy group respectively,
in Figure 3. The preferred formation of the S-config- and one of the three fluorines maybe removed when
diethyl phosphite was introduced. According to this
retionalization, the SN2ꢀ-type attack of diethyl phos-
phite fromthe back side of the imine is initiated.
Based on these results, the OH moiety of the diethyl
phosphite is suggested to play an important role in
determining the high enantioselectivity, since the re-
quired tautomeric equilibrium between the P(V)
phosphinic and the P(III) phosphonous forms is still
G
available. The mechanism indicates that the Piv4Gala
group plays a significant role in controling the regio-
and diastereoselective addition of diethyl phosphite
to N-galactosylaldimines 3.
Conclusions
We have found a procedure in which a highly diaste-
reoselective addition of diethyl phosphite occurs onto
the N-galactosylaldimines 3 to give N-galactosyl a-
aminoalkylphosphonate 4 in high yields and high dia-
stereoselectivity. O-Pivaloylated galactosylamine is an
effective chiral template in this Mannich-type reac-
tion. Boron trifluoride can forma tetra-coordination
intermediate that induces the S configuration at the
Ca center by attack at the si side of the C=N plane of
the imine carbon atom. The deprotection of N-galac-
tosyl a-aminoalkylphosphonate 4 under mild condi-
Figure 3. Plausible reaction mechanism.
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Asymmetric Synthesis of b-N-Glycosidically Linked a-Aminophosphonic Acids Derivatives
FULL PAPERS
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General Procedure for the Synthesis of N-(2,3,4,6-
Tetra-O-pivaloyl-d-galactosyl)-aldimines 3
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Glycosidically Linked a-Aminophosphonic Acid
Derivatives 4
A solution of N-galactosylaldimine 3 (0.5 mmol) in THF
(5 mL) was cooled to 08C, and diethyl phosphite (0.104 g,
0.75 mmol) and BF3·Et2O (0.142 g, 1.0 mmol) were added.
The mixture was stirred for 4 h at room temperature. Then
an aqueous saturated solution of sodiumbicarbonate
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Acknowledgements
We thank the Committee of Science and Technology of Tian-
jin (07JCZDJC04800), the Research Foundation for the Doc-
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and Nankai University (J02044 to Z. W. Miao) for financial
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Adv. Synth. Catal. 2008, 350, 2339 – 2344