An easy entry to optically active α-amino phosphonic acid derivatives using phase-transfer catalysis (PTC)

Article abstract of DOI:10.1039/b807027j

The unprecedented use of phase-transfer catalysis (PTC) in an asymmetric hydrophosphonylation reaction allows the obtainment of a range of optically active α-amino phosphonic acid derivatives directly from α-amido sulfones. The Royal Society of Chemistry.

Full text of DOI:10.1039/b807027j

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An easy entry to optically active a-amino phosphonic acid derivatives
using phase-transfer catalysis (PTC)w
Francesco Fini, Gabriele Micheletti, Luca Bernardi,* Daniel Pettersen,
Mariafrancesca Fochi and Alfredo Ricci*
Received (in Cambridge, UK) 25th April 2008, Accepted 5th June 2008
First published as an Advance Article on the web 21st July 2008
DOI: 10.1039/b807027j
The unprecedented use of phase-transfer catalysis (PTC) in an
asymmetric hydrophosphonylation reaction allows the obtain-
ment of a range of optically active a-amino phosphonic acid
derivatives directly from a-amido sulfones.
Scheme 1
a-Amino phosphonic acids and their derivatives are key
compounds in medicinal chemistry.1 Often incorporated into
the considerable nucleophilicity of both the protonated and
deprotonated phosphite tautomer14 could lead to a significant
peptides a-amino phosphonic acids have shown, among
background reaction.15 An additional matter of concern in our
reaction plan was the low efficiency of deprotonated phosphites
in forming an imine from a-amido sulfones 1.11b,16
others, very promising and useful anticancer,2 anti-inflamma-
tory,2 antirheumatic,2a,3 antibacterial4 and antifungal proper-
ties.5 The striking biological activity of these a-amino acid
analogues stems in several instances from the efficient inhibi-
tion of different protease or synthetase enzymes.6
Nevertheless, confident in that a careful choice of reaction
conditions could make possible a reliable and successful
protocol for the asymmetric hydrophosphonylation of imines
using PTC, we tested the behaviour of a-amido sulfone 1a with
phosphite esters (Table 1), in combination with different
phase-transfer catalysts 4a–f (Fig. 1) easily obtained from
inexpensive (hydro)quinine.17
The nucleophilic addition of phosphite esters 2 to electron
deficient double bonds is certainly one of the most versatile
routes for the introduction of a phosphonate moiety at a
carbon atom,7 and the hydrophosphonylation of imines giving
a-amino phosphonic acid derivatives has been studied in de-
tail. Few efficient asymmetric catalytic protocols for this
transformation are currently available,8 relying on the use of
chiral Lewis acids,9 or based on organocatalytic concepts.10
Though these latter procedures give a satisfactory solution in
terms of practicability and ready applicability, they do not
appear suitable to prepare important a-amino phosphonic
acids, such as phosphoalanine (AlaP), phosphophenylalanine
(PheP), and their substituted derivatives,2–6 due to the instabil-
ity of the corresponding linear unbranched imines.10 We
envisioned that the recently developed use of a-amido sulfones
111 under phase-transfer catalysis (PTC) conditions,12 gener-
ating in situ a very reactive imine, could prevent the imine–
enamine tautomerism, responsible for the previously reported
lack of reactivity.10a However, to our knowledge no asym-
metric hydrophosphonylation reactions have been reported to
date using PTC, despite several positive features typical of this
organocatalytic method, such as the mild reaction conditions,
the environmental friendliness, the experimental simplicity
and the relatively easy scalability.13
Initial exploratory efforts directed toward the use of diethyl
phosphite 2a gave encouraging indications about the feasibi-
lity of this transformation and confirmed our expectations of
the tolerance of this system to linear, unbranched imines, as
the product 3a was obtained with very good levels of purity in
Table 1 Representative optimisation resultsa
Phosphite
Entry 2 (R)
Base
Cat. 4 (equiv.)
Conv.b
T/1C (%) (3) eec (%)
1
2
3
4
5
6
7
8
2a (Et)
2a (Et)
2a (Et)
2b (Me)
2b (Me)
2b (Me)
2b (Me)
2c (Bn)
2b (Me)
2c (Bn)
2b (Me)
4a
4b
4b
4b
4c
4d
4e
4e
4e
4e
4f
K2CO3 (5)
r.t.
r.t.
r.t.
À30
À30
À30
À30
490 (3a) 13
490 (3a) 23
K2CO3 (5)
K2CO3 (1)
CsF (5)
CsF (5)
CsF (5)
CsF (5)
45 (3a)
7
490 (3b) 67
490 (3b) 79
490 (3b) 77
490 (3b) 83
490 (3c) 80
490 (3b) 87
490 (3c) 82
490 (3b) 89
We tentatively ascribed this lack of precedents to the tauto-
meric phosphonate/phosphite equilibrium (Scheme 1), wherein
Cs2CO3 (5) À30
9d
10d
11de
KOH (3)
CsOH (1.5) À78
KOH (3)
À78
À78
Department of Organic Chemistry ‘‘A. Mangini’’, University of
Bologna, V. Risorgimento 4, 40136 Bologna, Italy.
E-mail: nacca@ms.fci.unibo.it; ricci@ms.fci.unibo.it;
Fax: +39 051 2093654; Tel: +39 0512093635
w Electronic supplementary information (ESI) available: Experimental
procedures, products characterisation and copies of the NMR spectra.
See DOI: 10.1039/b807027j
a
Conditions: 0.10 mmol 1a, 0.15 mmol 2, 0.010 mmol cat. 4, toluene
(0.05 M), base, 18–48 h. Determined by 1H NMR spectroscopy.
c
b
Determined by HPLC using a Daicel Chiralpak AD-H column.
e
0.1 M reaction. 5 mol% catalyst.
d
ꢀc
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Table 2 Reaction scopea
a-Amido
Entry sulfone 1 R
Yieldb eec
Pg Product 3 (%)
(%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
(CH3)2CHCH2 Boc 3g
(CH3)2CHCH2 Cbz 3h
CH3(CH2)5
CH3(CH2)4
CH3CH2
CH3
CH3
PhCH2
Boc 3b
Cbz 3d
Boc 3e
Cbz 3f
94d (88) 88d (34)
95
94
84
82e
93 (99) 89 (78)
83e
86f
87e
Fig. 1
93
66
84
Boc 3i
Cbz 3j
Boc 3k
Boc 3l
Cbz 3m
Boc 3n
the crude reaction mixture. These experiments showed also the
beneficial effect exerted on the enantioselectivity by a substi-
tuent at the ortho position of the benzylic moiety of the
catalyst18 (Table 1, entries 1–2, 13% vs. 23% ee). The drop
in enantioselectivity observed decreasing the amount of base
(Table 1, entry 3, 7% ee), highlighted on the other hand the
necessity of the efficient formation of the phosphite anion. A
screening of different commercially available phosphites19
identified dimethyl and dibenzyl phosphites 2b and 2c as the
most promising leads.
97 (94) 95 (84)
9
78
84
76
83
80e
79e
80f
84
10
11
12
a
1j
1k
1l
Conditions: 0.10 mmol 1, 0.15 mmol 2e (Pg = Boc), 0.30 mmol 2e (Pg
= Cbz), 0.005 mmol 4f, toluene (0.1 M), KOH (0.30 mmol), À78 1C,
60 h. Results in parenthesis refer to the opposite enantiomer, obtained
b
c
using 4g (0.010 mmol) as the catalyst. Isolated yields. Determined
d
by HPLC using a Daicel Chiralpak AD-H column. 1 mmol scale.
e
Determined after Boc deprotection and Cbz derivatisation (See
f
ESIw). Absolute configuration determined as R (See ESIw).
Decreasing the reaction temperature to À30 1C was also
found beneficial for the enantioselectivity, although the type of
inorganic base had to be carefully optimised. Using 5 equiva-
lents of CsF, catalysts 4b–e (Fig. 1) all bearing an ortho
substituent at the benzylic quinuclidinic moiety could be used
at À30 1C with dimethyl phosphite 2b (Table 1, entries 4–7),
the 2-fluoro substituted 4e giving the best asymmetric induc-
tion (Table 1, entry 7, 83% ee). Similar results were obtained
using dibenzyl phosphite 2c, although in this latter case the
inorganic base had to be changed to Cs2CO3 (Table 1, entry 8,
80% ee). The use of hydroxides allowed to perform the
reaction at lower temperature (À78 1C), giving the a-amido
dimethyl phosphonate 3b with a useful level of enantioselec-
tivity (Table 1, entry 9, 87% ee), whereas the improvement in
the case of the dibenzyl derivative 3c was less pronounced
(Table 1, entry 10, 82% ee). Pursuing the reaction with
dimethyl phosphite 2b, an additional small improvement in
the enantioselectivity was observed even at a lower catalyst
loading, when catalyst 4f, derived from hydroquinine, was
used in the reaction, (Table 1, entry 11, 89% ee).
phosphonic acid dimethyl esters 3e–n in generally good yields
and useful enantioselectivities (Table 2, entries 3–12, 66–97%
yield, 79–95% ee). The obtainment of the PAla and PPhe
precursors 3l–n (Table 2, entries 10–12), which cannot be
accessed from alkenyl imines employed by Joly and Jacobsen
to overcome the instability of linear unbranched imines,10a
well witnesses the complementarity of the present method to
previous organocatalytic reports. a-Amido sulfones derived
from aromatic aldehydes gave the corresponding products in
nearly racemic form, presumably due to a base-promoted
racemisation.
The absolute configuration of the products was determined
to be R by comparison of the optical rotation of some of the
adducts with literature values (Table 2, entries 6, 11).6a,d This
configuration, matching the stereochemistry of natural
L-a-amino acids, has been found to be useful in most applica-
tions of a-amino phosphonic acid derivatives especially as
protease inhibitors.3–6 The quasi-enantiomeric catalyst 4g
derived from hydroquinidine (Fig. 1) gave access to the
antipode of the products, though with diminished selectivities
and a rather capricious behaviour (Table 2, entries 1, 4, 8,
values in parentheses, 88–99% yield, 34–84% ee).
We then proceeded to evaluate the scope of the reaction,
using dimethyl phosphite 2b with different a-amido sulfones
1a–l under the optimised conditions. After demonstrating the
possibility of performing the reaction with 1a on a preparative
scale with similar results (Table 2, entry 1, 94% yield, 88% ee),
we investigated the tolerance of this transformation to a
change in the protecting group at the nitrogen atom. Although
a larger excess of phosphite 2b (3 equiv. vs. 1.5 equiv.)20 had to
be used to drive the reaction to completion in a reasonable
time with the N-Cbz protected a-amido sulfone 1b, the
corresponding N-Cbz a-amino phosphonic acid ester 3d could
be obtained with satisfactory results (Table 2, entry 2, 95%
yield, 84% ee). Under these conditions, several a-amido
sulfones derived from a- or b-branched (1c–f), as well as linear
unbranched aldehydes (1g–l), gave the corresponding a-amino
A salient feature of this catalytic method is the possibility of
obtaining products bearing easily removable, or useful in
peptide couplings, protecting groups at nitrogen. Indeed, with
trivial experimental procedures, these adducts can be trans-
formed either into a-amino phosphonic acids, as exemplified
by the conversion of 3b into the optically active a-amino
phosphonic acid 5, or into N-protected phosphonic acid
monomethyl esters such as 6, a known intermediate in the
assembly of phosphono-peptides inhibitors of protease
enzymes6a,b,e (Scheme 2).
ꢀc
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Scheme 2
In conclusion, the development of the first asymmetric
hydrophosphonylation using PTC, allowed to use directly
a-amido sulfones 1 in a new and straightforward protocol for
the hydrophosphonylation of imines, leading to the obtainment
of optically active a-amino phosphonic acid derivatives 3. Good
assets of the present method are the trivial experimental proce-
dures, the easy availability of substrates and catalysts, and the
complementary scope with respect to previously reported orga-
nocatalytic processes. Finally, the possibility of converting very
easily the catalytic adducts into a-amino phosphonic acids and/
or useful intermediates for the synthesis of phosphono-peptides
highlights an additional advantage associated with this strategy.
We acknowledge financial support from Consorzio CINM-
PIS and Stereoselezione in Sintesi Organica Metodologie e
Applicazioni 2005. D. P. is grateful for a post-doctoral fellow-
ship received from the Blancelor foundation, Sweden. The
financial support by the Merck-ADP grant 2007 is also grate-
fully recognised.
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14 In contrast with phosphite esters, most of the nucleophiles used
under PTC conditions (e.g. malonates) are reactive only after
deprotonation.
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19 Using cat. 4b, 5 equiv. K2CO3, r.t.: diphenyl phosphite: 0% ee;
diisopropyl phosphite: 0% ee; dimethyl phosphite: 40% ee; diben-
zyl phosphite: 37% ee.
20 The competition for the quaternary ammonium salt of the lipophilic
sulfinate anion (generated during the formation of the imine) with
the deprotonated phosphite can be the reason for the necessity of
using an excess of phosphite, and for the long reaction time (60 h).
ꢀc
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Chem. Commun., 2008, 4345–4347 | 4347