O-silyl triflate-promoted addition of diethyl phosphite to chiral aldonitrones. A rapid access to complex α-amino phosphonates and their N-hydroxy derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00363-X

The addition reaction of diethyl phosphite to O-silylated N-benzyl nitrones derived from chiral α-alkoxy and N-Boc α-amino aldehydes has been studied as a stereoselective carbon-phosphorus bond forming process for the synthesis of polyhydroxylated α-amino

Full text of DOI:10.1016/S0040-4039(01)00363-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3033–3036
O-Silyl triflate-promoted addition of diethyl phosphite to chiral
aldonitrones. A rapid access to complex a-amino phosphonates
and their N-hydroxy derivatives
Carmela De Risi,a Alessandro Dondoni,b,* Daniela Perroneb and Gian Piero Pollinia,*
aDipartimento di Scienze Farmaceutiche, Universita` di Ferrara, Via Fossato di Mortara 17-19, I-44100 Ferrara, Italy
bDipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di Ferrara, Via L. Borsari 46, I-44100 Ferrara, Italy
Received 27 November 2000; accepted 28 February 2001
Abstract—The addition reaction of diethyl phosphite to O-silylated N-benzyl nitrones derived from chiral a-alkoxy and N-Boc
a-amino aldehydes has been studied as a stereoselective carbonꢀphosphorus bond forming process for the synthesis of
polyhydroxylated a-amino and a,b-diamino phosphonates. Key intermediates are the corresponding N-hydroxy a-amino
phosphonates. © 2001 Elsevier Science Ltd. All rights reserved.
a-Amino phosphonates as phosphorus isosteres of a-
amino carboxylates and isopolar analogues of a-amino
phosphates, constitute a class of compounds of current
interest owing to their use in biological studies and in
medicinal and pharmaceutical chemistry.1 Most notably
among the various methods for preparing these
compounds1,2 is that reported by Vasella and co-work-
ers employing the addition of metal phosphites or
trimethylsilyl phosphite to N-glycosyl nitrones.3 More-
over, this route represents one of the few examples of
addition of heteronucleophiles to nitrones,4 a class of
CꢁN compounds whose valuable role in synthetic
methodologies is steadily increasing.5 Recent investiga-
tions in our laboratories have been dealing with both
nitrone chemistry6 and phosphonic acid synthesis.7
These earlier studies led us to investigate the addition
of diethyl phosphite to N-benzyl nitrones derived from
chiral a-alkoxy and N-protected a-amino aldehydes.
Our nitrone–phosphite approach is complementary to
that of Vasella3 as it provides an entry to hitherto
unreported polyhydroxylated a-amino and a,b-diamino
phosphonic acids. Also N-hydroxy a-amino phospho-
nate derivatives, the primary adducts in this approach,
constitute a class of biologically important compounds8
1) TBDMSOTf
-
+
O
O
N
O
2) HP(O)(OEt)2
O
Zn, Cu(OAc)2
AcOH/H2O
P(O)(OEt)2
N(OH)Bn
P(O)(OEt)2
Bn
THF, -20 °C
NHBn
3a, b
1a, b
2a, b
O
O
O
a =
BnO
O
;
b =
:
O
Scheme 1.
Keywords: nitrones; phosphonates; enzyme inhibitors; peptide mimetics; stereoselective synthesis; aminophosphonation.
* Corresponding authors. E-mail: adn@dns.unife.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00363-X

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C. De Risi et al. / Tetrahedron Letters 42 (2001) 3033–3036
as phosphorus isosteres of the corresponding carboxylic
acids.9 The initial results of these studies are reported
below.
the a,b-diamino phosphonate 3d. The NMR spectra of
the syn-adducts 2c and 2d showed similar features to
those of the syn-hydroxylamines derived from the reac-
tion of the same nitrones 1c and 1d with various
nucleophiles.15 It has been suggested that the adducts
exist in a rigidified conformation due to hydrogen-
bonding between the N-OH and CO of N-Boc, which
leads the hydrogen atoms of the two adjacent stereo-
centers to adopt an antiperiplanar disposition. Indeed
the H NMR spectra from −40 to −55°C showed JH,H
coupling constant values between these atoms of 10.37
Hz for 2c and 10.20 Hz for 2d. Moreover, the spectra
did not change in the range of temperature between 25
and −55°C and showed a low field chemical shift for the
hydroxyamino proton at various concentrations in the
range of 7.6 and 7.9 ppm. It has to be noted that high
levels of syn-selectivity have been observed in earlier
addition reactions of organometals to N,N-diprotected
a-amino nitrones either in the absence or in the pres-
ence of pre-complexing agents.14a,15
While
a
mixture of the
D-glyceraldehyde-derived
nitrone6b 1a and diethylphosphite in anhydrous THF at
room temperature did not result in the formation of
any reaction product, treatment of 1a with 1.1 equiv. of
tert-butyldimethylsilyl triflate (TBDMSOTf)10 at −20°C
followed by the addition of the same phosphorus
reagent afforded after 10 min, the N-hydroxy a-amino
phosphonate 2a (70% yield) as a single isolated product
(Scheme 1).11 The structure of 2a as established by
X-ray crystallography12 showed the anti relationship
between the resulting N-hydroxyamino group and the
pre-existing alkoxy group. The formation of the anti-
adduct is in agreement with the stereochemical outcome
observed in earlier addition reactions of various nucle-
ophiles to 1a pre-complexed with Lewis acids.6b,13 The
removal of the hydroxy group from the nitrogen atom
of 2a was carried out by treatment with a mixture of
Zn/Cu(OAc)2 according to our earlier procedure.6d The
resulting alkoxylated N-Bn a-amino phosphonate 3a
was isolated in 60% yield by flash chromatography. The
1
3
The reactions of N-monoprotected a-amino nitrones
1e–g whose progenitors were alanine, phenylalanine
and leucine, respectively, afforded the corresponding
N-hydroxy a-amino phosphonates 2e–g in very good
yields (70–80%). Each adduct appeared by NMR analy-
sis to be constituted by a major diastereomer, more
than 95%, which was easily isolated by flash chro-
matography (Scheme 3).11 The structure of product 2g
as established by X-ray crystallography12 showed the
anti relationship between the NHBoc and N(OH)Bn
group. We observed the same stereochemical outcome
in the addition reaction of 2-lithiothiazole to the
nitrone derived from N-monoprotected serinal.14a
These results and those reported in Scheme 2 confirm
the tunable syn–anti stereoselectivity of the addition
reaction to a-amino nitrones by bis- and monoprotec-
tion of the amino group. Hence, it appeared reasonable
to assign the same configuration of 2g to the products
2e and 2f. Unfortunately, we have been unable to
transform these products into cyclic ureas for structural
assignment by NMR analysis because of their substan-
tial epimerization and decomposition. Finally, each
individual pure isomer was subjected to catalytic hydro-
genation over Pd(OH)2 in the presence of (Boc)2O and
transformed into the corresponding N-Boc protected
a,b-diamino phosphonates 3e–g in satisfactory yields
(ca. 60%).11
same procedure was repeated starting from the
L-
threose-derived nitrone6a 1b to give sequentially the
N-hydroxy a-amino phosphonate 2b (70% yield) and
the reduced product 3b (60% yield). Also in this case
the structure of the expected6 anti-adduct 2b was
assigned by X-ray crystallography.12
Successful reactions were registered also with a-amino
nitrones derived from natural a-amino acids. Thus,
treatment of the TBDMSOTf-precomplexed nitrone14
1c derived from N-Boc serinal acetonide (Garner alde-
hyde) with diethylphosphite under the same conditions
as above (THF, −20°C, 10 min) afforded exclusively the
syn-adduct 2c as a syrup, isolated in 80% yield by flash
chromatography (Scheme 2).11 The removal of both the
benzyl and hydroxy groups from the nitrogen atom of
2c with the concomitant protection of the amino group
as a tert-butyl urethane was carried out in one step by
hydrogenation over Pd(OH)2 in the presence of
(Boc)2O. The resulting N-Boc protected a,b-diamino
phosphonate 3c was isolated in 61% yield. The same
reaction sequence was applied to the prolinal-derived
nitrone 1d to give the corresponding syn-adduct 2d and
Boc
1) TBDMSOTf
2) HP(O)(OEt)2
H2, Pd(OH)2
-
+
N
O
NBoc
NBoc
(Boc)2O
N
P(O)(OEt)2
N(OH)Bn
2c, d
P(O)(OEt)2
NHBoc
3c, d
Bn
THF, -20 °C
EtOH
1c, d
NBoc
:
NBoc
NBoc
c =
;
d =
O
Scheme 2.

C. De Risi et al. / Tetrahedron Letters 42 (2001) 3033–3036
3035
1) TBDMSOTf
H2, Pd(OH)2
-
+
BocNH O
BocNH
2) HP(O)(OEt)2
BocNH
R
(Boc)2O
N
P(O)(OEt)2
P(O)(OEt)2
R
Bn
R
THF, -20 °C
EtOH
NHBoc
N(OH)Bn
2e-g
1e-g
3e-g
e, R = Me; f, R = PhCH2; g, R = Me2CHCH2
Scheme 3.
In conclusion, we have presented a method for the
stereoselective synthesis of a-amino phosphonates and
their N-hydroxy derivatives by aminophosphonation of
carbohydrate and amino acid derivatives using nitrone-
based chemistry. The method appears quite promising
for the synthesis of other compounds with a wide range
of molecular diversity in the chain and future efforts
will be made in this direction.
Franco, S.; Junquera, F.; Merchan, F. L.; Merino, P.;
Tejero, T.; Bertolasi, V. Chem. Eur. J. 1995, 1, 505; (c)
Dondoni, A.; Perrone, D. Aldrichim. Acta 1997, 30, 35;
(d) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.
L.; Merino, P.; Tejero, T. J. Org. Chem. 1997, 62, 5497;
(e) Dondoni, A.; Perrone, D.; Rinaldi, M. J. Org. Chem.
1998, 63, 9252; (f) Dondoni, A.; Perrone, D. Tetrahedron
Lett. 1999, 40, 9375.
7. (a) Simoni, D.; Invidiata, F. P.; Manferdini, M.; Lam-
pronti, I.; Rondanin, R.; Roberti, M.; Pollini, G. P.
Tetrahedron Lett. 1998, 39, 7615; (b) Barco, A.; Benetti,
S.; Bergamini, P.; De Risi, C.; Marchetti, P.; Pollini, G.
P. Tetrahedron Lett. 1999, 40, 7705; (c) Dondoni, A.;
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Acknowledgements
This research was financially supported by MURST
COFIN-98 (Italy).
8. Gouverneur, V.; Lalloz, M.-N. Tetrahedron Lett. 1996,
37, 6331.
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