N-Carbamate α-aminoalkyl-p-tolylsulfones - Convenient substrates in the nitro-Mannich synthesis of secondary N-carbamate protected syn-2-amino-1-nitroalkanephosphonates

Article abstract of DOI:10.1016/j.tet.2010.10.072

An efficient one-pot synthesis of secondary N-carbamate protected syn-β-amino-α-nitroalkanephosphonates using diethyl nitromethanephosphonate and N-Boc or N-Cbz imines, generated in situ from stable N-Boc or N-Cbz α-aminoalkyl-p-tolylsulfones has been developed under PTC conditions. A model enantioselective version of this reaction is also described. Enantioselectivity up to 67% ee is achieved using a chiral thiourea catalyst derived from a cinchona alkaloid. Completely stereoselective conversion of the title compounds into partially N-carbamate protected syn-1,2- diaminoalkanephosphonates has also been elaborated.

Full text of DOI:10.1016/j.tet.2010.10.072

Tetrahedron 66 (2010) 9840e9848
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
N-Carbamate
a
-aminoalkyl-p-tolylsulfonesdconvenient substrates in the
nitro-Mannich synthesis of secondary N-carbamate protected
syn-2-amino-1-nitroalkanephosphonates
*
Roman B1aszczyk, Anna Gajda, Stefan Zawadzki, Ewelina Czubacka, Tadeusz Gajda
Institute of Organic Chemistry, Faculty of Chemistry, Technical University of Lodz, Zeromskiego St. 116, 90-924 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2010
Received in revised form 5 October 2010
Accepted 25 October 2010
Available online 29 October 2010
An efficient one-pot synthesis of secondary N-carbamate protected syn-
alkanephosphonates using diethyl nitromethanephosphonate and N-Boc or N-Cbz imines, generated in
situ from stable N-Boc or N-Cbz -aminoalkyl-p-tolylsulfones has been developed under PTC conditions.
A model enantioselective version of this reaction is also described. Enantioselectivity up to 67% ee is
achieved using a chiral thiourea catalyst derived from a cinchona alkaloid. Completely stereoselective
conversion of the title compounds into partially N-carbamate protected syn-1,2-diaminoalkane-
phosphonates has also been elaborated.
b-amino-a-nitro-
a
Keywords:
Aza-Henry reaction
Diethyl nitromethanephosphonate
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Amido sulfones
PTC reaction
Aminonitrophosphonates
1,2-Diaminoalkanephosphonates
1. Introduction
described. This prompted us to present here our contribution as a
new, practical synthesis of secondary 1-amino-2-nitroalkane-
The aza-Henry reaction,1e7 known also as the nitro-Mannich
reaction, is usually base promoted addition of nitro compounds toN-
protected imines, often beingemployed in the asymmetric synthesis
of vicinal diamines and
There are however, only isolated examples of the nitro-Mannich
approach to the preparation of -amino- -nitro- and -diamino-
and 1,2-diaminoalkanephosphonates utilizing diethyl n-
itromethanephosphonate13 (1) and N-carbamate
tolylsulfones 2 as starting materials.
a-aminoalkyl-p-
a,b
-diamino acids.1b,e,g,2,3aec,hej,l,4b,c,5d,6,8,9
2. Results and discussion
b
a
a,b
phosphonates10e12 utilizing 1-nitroalkanephosphonates and
N-protected imines as starting materials. In the late 1970s Petrov
et al.12 described the addition of nitromethane- and 1-nitro-
ethanephosphonates to N-benzylidenebenzeneamine leading to
N-phenyl analogues of aminonitrophosphonates. Recently, during
our investigations, Johnston et al.10 published a highly diastereo-
andenantioselective addition of dialkyl 1-nitroethanephosphonates
to N-Boc imines, catalyzed by chiral Brønsted acids, which allows
obtaining anti-2-amino-1-nitroethanephosphonates with a quater-
nary center next to a phosphorus atom. Until now however, the re-
It is well documented that N-Boc and N-Cbz protected a-ami-
noalkyl-p-tolylsulfones1d,14e16 2 can be considered as stable, crys-
talline, and easy to handle equivalents of N-Boc and N-Cbz imines.
Not surprisingly, nucleophilic additions of deprotonated nitro-
alkanes to N-carbamate imines generated in situ from the a-amido
sulfones, mentioned above by base-induced elimination, have re-
cently been the subject of extensive studies.4i,5a,b,d,7 In this context,
easy to perform and low demanding as far as reactions conditions
are concerned, phase transfer catalysis (PTC)1f,17 approaches to the
aza-Henry reaction seemed to be especially beneficial. After pre-
liminary experimentations, standard liquidesolid PTC conditions
using potassium carbonate as a base for simultaneous deprotona-
tion and elimination, tetrabutylammonium bromide (TBAB) as
catalyst and toluene as solvent were selected for the reaction of
diethyl nitromethanephosphonate (1) with N-carbamate protected
action of diethyl nitromethanephosphonate with N-carbamate a-
aminoalkyl-p-tolylsulfones, as convenient precursors of unstable N-
carbamate imines, leading to the title compounds has not been
* Corresponding author. Tel.: þ48 42 6313146; fax: þ48 42 6365530; e-mail
address: tmgajda@p.lodz.pl (T. Gajda).
a-aminoalkyl-p-tolylsulfones 2 (Scheme 1).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.072

R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
9841
syn-3aed and syn-3g could easily be isolated in 28e41% yields from
the mixture of 3aed and 3g via simple crystallization from carbon
tetrachloride (Table 1, entries 1e5 and 7, respectively). Pure ali-
phatic derived syn-adducts 3eef and 3h, which are formed as
viscous oils, could not be separated from the mixture either by
crystallization or chromatography.
The mother liquors of adducts 3, obtained after crystallizations,
consisted mainly of anti-diastereomers 3, and these mixtures
slowly enriched themselves in syn-3 after prolonged standing at
room temperature.
O
PGHN
R
i-ii
71 88%
(EtO)2P NO2
+
Ts
−
1
2a−h
O
O
NHPG
NHPG
1
(EtO)2P 1
(EtO)2P
+
2
R
2 R
NO2
NO2
3a h
- −
3a h
- −
syn
anti
= 53/47−64/36
/
syn anti
2 3
,
a
b
Attempted widening of the scope of the above nitro-Mannich
reaction on diethyl 1-nitroethanephosphonate,18 a homologue of 1,
was unsuccessful. Starting 1-nitroethanephosphonate was always
recovered from the reaction mixture.
PG = Boc; R = Ph ( ), -MeOC H4 ( ),
p
6
-ClC H5 (c), 2-furyl (d), Me (e), Et (f)
p
6
2 3
,
g
h
PG = Cbz; R = Ph ( ), Me ( )
Scheme 1. Reagents and conditions: (i) K2CO3 solid (5 equiv), TBAB (10 mol %), toluene,
rt, 26 h; (ii) aq KHSO4.
Determination of the relative syn/anti configuration of adducts 3
based on NMR analysis of diagnostic vicinal coupling constants
As shown in Scheme 1, a vigorously stirred mixture of 1, N-Boc
(3JHH 3JHP 3JCP) failed. In almost all of the adducts diagnostic pro-
, ,
protected
a-aminoalkyl-p-tolylsulfones 2aef (1.03 equiv), potas-
tons (H1 and H2) appeared as complex multiplets or the differences
in the values of their vicinal coupling constants 3JHH were too small
to be diagnostic. Therefore, the relative syn/anti configurations of 3
were established by conversion of selected compounds 3 into the
appropriate imidazolidine-2-thiones 5 (vide infra). However, the
phosphorus chemical shifts of 3 were consistent with the given
diastereomer. In the 31P NMR spectra of all of nitrophosphonates 3
the signals of the syn-isomers appeared 0.14e0.74 ppm upfield
relative to those of the anti-isomers (Table 1).
sium carbonate (5 equiv) and TBAB (10 mol %) in toluene afforded,
after 26 h at room temperature, the mixture of syn- and anti-ad-
ducts 3aef in good yields (79e88%) after flash chromatography.
The results are summarized in Table 1.
The results given in Table 1 indicate that adducts 3 are formed
with low and comparable syn-diastereoselectivity (syn-3aef/anti-
3aef¼56/44e64/36). The reaction also works for N-Cbz protected
a
-aminoalkyl-p-tolylsulfones 2geh as imine surrogates, for which,
Having established the synthesis of N-carbamate protected
2-amino-1-nitroalkanephosphonates 3, we focused our attention
on their conversion into partially protected 1,2-diaminoalkane-
phosphonates 4. Several 1,2-diaminoalkanephosphonic acids act
as leucine aminopeptidase inhibitors.19 However, the number of
Table 1
Diethyl
b
-amino-
a
-nitrophosphonates 3aeh prepared
Entry 3
R
PG Yielda,b (%) syn/antic syn-3 Yieldd (%) 31P NMR,
d
syn
anti
1
2
3
4
5
6
7
8
3a Ph
Boc 87
83
59/41
63/37
64/36
63/37
61/39
56/44
53/47
57/43
40e
39
41
41
d
10.36 11.02
10.08 10.79
10.10 10.76
9.88 10.55
11.09 11.27
11.00 11.29
10.17 10.93
10.67 10.81
known a,b-diaminoalkanephosphonates is limited and only a few
3b p-MeOC6H4
3c p-ClC6H4
3d 2-Furyl
3e Me
3f Et
3g Ph
routes to both racemic or enantioenriched compounds have been
88
87
88
79
reported till now.10,20,21
Sodium borohydride/nickel(II) chloride22 system in methanol
was used as the reductant of choice for the nitro group. Such re-
ductions occurred under very mild conditions, and they were shown
to proceed with retention of configuration at the stereogenic center
on the carbon atom next to the nitro group.3l,4c,h,6b,d,e,23
As shown in Scheme 2, solid NaBH4 was added at ꢀ30 ꢁC to the
solution of nitrophosphonates 3 and nickel(II) chloride hexahydrate
in methanol. The mixture was allowed to warm to 0 ꢁC, and desired
d
Cbz 71
84
28f
d
3h Me
a
All reactions were carried out on a 2 mmol scale.
Overall yield of pure syn- and anti-adducts 3aeh isolated after flash
b
chromatography.
c
Diastereomeric ratio measured by 31P NMR of the crude products.
Yields of pure syn-3, after crystallization from CCl4.
Second crop of crystals was isolated in 19% yield and consisted of anti-3a mainly
d
e
1,2-diaminophosphonates
4 were isolated in moderate yields
(syn/anti¼25/75).
(43e75%), after quenching with aq ammonium chloride followed by
flashchromatography. Theapproachmentionedaboveenablesa two-
step synthesis of secondary 1,2-diaminophosphonate esters (Table 2).
As shown in Table 2, syn-1,2-diaminophosphonates 4aed and
4g were only obtained from the reduction of pure syn-adducts
f
The mixture of syn- and anti-3g (syn/anti¼10/90) was isolated in 27% yield from
the mother liquor.
the mixtures of N-Cbz protected syn- and anti-adducts 3g and 3h
are isolated in much the same yields and with similar syn-dia-
stereoselectivity (Table 1, entries 7e8). Facile epimerization on the
carbon atom C-1, next to the nitro group, in adducts 3 and/or retro
addition/re-addition occurring under the reaction conditions, seem
to be responsible for the low diastereoselectivity of the above
mentioned reactions.y We found, additionally, that stirring the
mixture of 1 and 2a or 1, and 2g for 10 days under the same PTC
conditions, resulted, within the experimental error, in the same
diastereomeric ratios of the final adducts 3a or 3g, respectively.
The evaluation of the scope of the reaction shows that the
method is applicable to aromatic, heteroaromatic and aliphatic
O
O
NHPG
R
NHPG
R
i-ii
43−75%
(EtO)2P
(EtO)2P
NO2
NH2
3a h
−
4a h
−
3,4
3,4
a
b
PG = Boc; R = Ph ( ), -MeOC H4 ( ),
p
6
-ClC H5 (c), 2-furyl (d), Me (e), Et (f)
p
6
g
h
PG = Cbz; R = Ph ( ), Me ( )
Scheme 2. Reagents and conditions: (i) NaBH4 (10 equiv), NiCl2ꢂ6H2O (1.05 equiv),
MeOH, ꢀ30 ꢁC, 5 min, 0 ꢁC; (ii) aq NH4Cl, 0 ꢁC.
N-Boc, and N-Cbz protected a-aminoalkyl-p-tolylsulfones 2. Pure
3aed and 3g (Table 2, entries 1, 3e5, and 8, respectively). In turn,
the mixture of syn- and anti-adducts 3a and 3eeh afforded, after
reduction, the diastereomeric mixture of syn- and anti-dia-
minophosphonates 4a and 4eeh in approximately the same ratio
as starting nitro adducts 3 (Table 2, entries 2, 6e7, and 9e10, re-
spectively). These results confirm that reduction of the nitro group
y
When the solution of pure syn-3a in CDCl3 was kept in the presence of pyridine
for 4 h at room temperature, or when pure syn-3a was stirred in toluene in the
presence of K2CO3/TBAB system for 48 h at room temperature, followed by standard
work-up, epimerized mixture of syn- and anti-3a (syn/anti¼58/42) was always
formed. No formation of starting diethyl nitromethanephosphonate (1) was ob-
served in the 31P NMR spectrum of the reaction mixture, however.

9842
R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
Table 2
The stereochemistry of the imidazolidine-2-thiones 5 was
assigned by 1H and 31P NMR analysis. The values of the vicinal
coupling constants for 5a (3JHH(trans)¼6.25 Hz, 3JHH(cis)¼10.0 Hz) and
5b (3JHH(trans)¼6.36 Hz) are consistent with the observation that
trans-imidazolidine-2-thiones have smaller coupling constants
than the corresponding cis-diastereomer.26 In the 31P NMR
spectra of 5a (dP (trans/cis)¼18.46/16.42) and 5b (dP (trans/cis)¼
19.24/18.21) the signals of the trans-isomers appeared
1.03e2.04 ppm downfield relative to those of the cis-isomers.21k As
all steps of the above mentioned transformations occur with the
retention of configurations, these results confirm the assignment of
relative configuration in the parent nitro adducts 3.
1,2-Diaminophosphonates 4aeh prepared
Entry 3/4
R
PG 3 syn/anti
4
31P NMR,
Yielda (%) syn/antib syn-4 anti-4
d
1
2
3
4
5
6
7
8
9
a
a
b
c
d
e
f
g
g
h
Ph
Ph
Boc 100/0
25/75c
63
54
53
66
55
43
60
75
100/0
25/75
100/0
100/0
100/0
58/42
64/36d
100/0
16/84d
59/41
25.69 25.56
p-MeOC6H4
100/0
100/0
100/0
61/39
26.17
25.77
25.27
d
d
d
p-ClC6H4
2-Furyl
Me
Et
Ph
27.16 27.08
27.5d 27.5d
25.48 25.28
60/40
Cbz 100/0
Ph
Me
w10/90e 43
10
57/43
58
26.97 26.78
Having established the conditions of the reaction of diethyl
nitromethanephosphonate (1) with N-carbamate protected
a
Overall yield of pure syn- and anti-adducts 3aeh after flash chromatography.
Diastereomeric ratio measured by 31P NMR of the crude products.
The mixture of adducts 3a (syn/anti¼25/75), isolated from the mother liquor
b
c
a
-aminoalkyl-p-tolylsulfones 2 we next attempted the asymmetric
PTC reaction,1f,17 using cinchona alkaloid derived quaternary am-
monium salts as catalysts. Such chiral PTC catalysts were success-
fully employed in the highly stereoselective aza-Henry reactions of
simple nitroalkanes and N-protected imines generated in situ from
was used as substrate.
d
As a result of overlapping of 31P NMR signals, syn/anti ratio of diastereomeric
diaminophosphonates 4 was determined by their cyclization into trans- and cis-
imidazolidine-2-thiones 5 (31P NMR).
e
N-formyl or N-carbamate a
-aminoalkyl-arylsulfones.5a,b,d
The mixture of nitro adducts 3g (syn/anti¼w10/90), isolated from the mother
liquor, was used as substrate. As a result of relatively quick epimerization of 3g
N-tert-Butoxycarbonylamino(phenyl)methyl-p-tolylsulfone (2a)
was chosen as a model compound, and its reaction with 1 in the
presence of solid K2CO3 or Cs2CO3 was investigated using quinine-
derived catalyst 6 (Scheme 4).
However, irrespective of the base applied, model studies did not
give significant asymmetric induction under these conditions. The
major syn-3a0 was formed with low diastereoselectivity and poor
enantioselectivity (Table 3, entries 1 and 2). The enantiomeric ex-
cesses were assessed from 31P NMR spectra of the crude reaction
mixture, taking into account diagnostic chemical shifts (dP) of
diethyl syn- and anti-{(2-tert-butoxycarbonylamino)-1-[(S)-2-(6-
methoxynaphthalen-2-yl)propionylamino]-2-phenyl-ethyl}phos-
approximate ratio of diasteromer is only given.
takes place with retention of configuration on the carbon atom next
to this group and simultaneously, correlate the configuration of
1,2-diaminophosphonates 4 with parent N-carbamate protected
nitrophosphonates 3.
Relative configuration of 1,2-diaminophosphonates 4, in turn,
was assigned by conversion of the selected adducts 4 into the ap-
propriate imidazolidine-2-thiones 5 for which, relative configura-
tion could easily be determined by 31P NMR analysis of their
chemical shifts and the ring protons vicinal coupling constant (3JHH
)
in 1H NMR (Scheme 3).
As shown in Scheme 3, imidazolidine-2-thiones 5a and 5b
were prepared in 51% and 41% overallyield via standard deprotection
(TFA/CH2Cl2) of N-Boc protected syn-1,2-diamino-2-phenyl-
ethylphosphonate 4a and syn/anti-1,2-diaminobutylphosphonates
4f, followed by the conversion of free 1,2-diaminophosphonates thus
obtained into trans-imidazolidine-2-thione 5a and the mixture of
trans- and cis-imidazolidine-2-thiones 5b (trans/cis¼64/36), using
1,10-thiocarbonyldiimidazole as condensing agent in the presence of
BocHN
O
O
NHBoc
Ph
NHBoc
Ph
Base / solvent / cat*
temp., 26 h to 8 d
1
+
Ts
(EtO)2P
(EtO)2P
+
Ph
NO2
NO2
-3a'
2a
3a'
anti
-
syn
H
S
H
cat*:
ArHN
MeO
N+
N
Cl-
Ph
HO
HN
MeO
O
O
NHPG
R
H
N
i-iii
R = Ph
51%
N
N
(EtO)2P
(EtO)2P
S
6
7
; Ar = 3,5-CF3-C6H3
NH2
N
Ph
H
Scheme 4. Asymmetric aza-Henry reaction of 1 with 2a.
4a
: PG = Boc; R = Ph,
5a
(trans/
= 100/0)
cis
(
/
syn anti
= 100/0)
δP
(
= 18.46
trans)
phonates prepared by reduction of the crude nitro adducts
3a0 (NaBH4/NiCl2), followed by derivatization27 of thus formed
syn/anti-4a0 amines with (S)-Naproxen chloride [(S)-2-(6-
methoxynaphthalen-2-yl)propionyl chloride].28
4f
: PG = Boc; R = Et
O
H
N
(EtO)2P
S
i-iii
R = Et
41%
N
(S)-Naproxen chloride was proved to be a convenient chiral
derivatizing agent (CDA) for the determination of enantiomeric
purity as well as the absolute configuration assignments of diethyl
1-amino- and 2-aminoalkanephosphonates by NMR.27,29 Amida-
tion under these conditions proceeds quantitatively, and is not
Et
H
trans cis
5b
(
trans cis
/
= 64/36)
) = 19.24/18.21
δP
(
/
iv, ii-iii
23%
(
accompanied by racemization.27 The diastereomeric anisochro-
z
4g
5a
= 16/84)
nicity in naproxen amide of 4a0 was sufficiently large to estimate
the ee of the syn-isomer (dP¼21.63/22.06, Dd¼0.43). However, for
PG = Cbz; R = Ph
(syn/anti
trans/cis
= ~10/90)
δP
(
/
trans cis)
= 18.46/16.42
the anti-isomer only a broad singlet (dP¼22.38) was observed in 31
P
Scheme 3. Reagents and conditions: (i) TFA, CH2Cl2, rt,
2
h; (ii) Et3N, 1,10-thio-
NMR spectrum.
carbonyldiimidazole, CH2Cl2, rt, 24 h; (iii) aq HCl; (iv) ammonium formate (10 equiv),
10% Pd/C (cat), MeOH, rt, 2 h, Ar.
triethylamine.24 Similarly, the mixture of trans- and cis-4g (cleavage
of N-Cbz group was accomplished using ammonium formate/PdeC
system25) afforded the mixture of the appropriate trans- and cis-
imidazolidine-2-thiones 5a (trans/cis¼16/84) in 23% yield.
z
Entire derivatization (scale: 0.05 mmol) using (S)-Naproxen chloride as CDA,
followed by determination of the ee as well as the absolute configurations as-
signments were performed in an NMR tube using anhydrous CDCl3 as solvent and
pyridine as a base.

R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
9843
Table 3
The asymmetric aza-Henry reaction of 1 with N-Boc-amino(phenyl)methyl-p-tolylsulfone (2a)
Entry
Base/solvent/timea
Temperature ꢁC
cat
*
Conv. (%)
3a0 syn/antib
syne3a0/syne4a0 eec (%)
1
2
3
4
5
6
7
8
K2CO3(s)/toluene/26 h
Cs2CO3(s)/toluene/26 h
K2CO3(s)/MeCN/3d
rt
rt
rt
rt
rt
rt
0
ꢀ20
6
6
7
7
7
7
7
7
99
93
100
100
100
99
58/42
59/41
55/45
56/44
59/41
57/43
58/42
58/42
12
10
10
21
20
47
60
67
K2CO3(s)/CH2Cl2/3d
K2CO3(s)/THF/26h
K2CO3(s)/toluene/3dd,e,f
K2CO3(s)/toluene/3d
K2CO3(s)/toluene/8d
96
94g
a
Reaction conditions: scale 0.1 mmol, (c 0.1 mol/L); cat 6 (10 mol %) or cat 7 (20 mol %), base (5 equiv). Isomers 3a0, 4a0, and 3g0 have the same structure as their racemic
counterparts.
b
c
Diastereomeric ratio measured by 31P NMR of the crude products.
Calculated from the 31P NMR spectra of (S)-Naproxen amides of syn/anti-4a0 amines (dsyn¼21.63/22.06; danti¼22.38) obtained via reduction of 3a0 using NaBH4/NiCl2 system,
followed by derivatization of thus formed amines 4a0 with (S)-Nap-Cl. Absolute configurations of the major syn-isomers 3a0 and 4a0, respectively, were determined to be (1S,2S).
d
For the reaction of 1 with N-Cbz sulfone 2g the mixture of syn/anti-3g0 (syn/anti¼58/42) was obtained with 34% ee for syn-3g0 under the same reaction conditions. In turn,
only 68% conversion was obtained for the reaction conducted at 0 ꢁC for 3 days.
e
When the reaction of 1 with N-Boc sulfone 2a was repeated at rt on 1 mmol scale, pure syn-nitro adduct 3a0 and syn-diamino adduct 4a0 (47% ee) were isolated in 27% and
61% yields, respectively.
f
When the reaction of 1 with N-Boc imine, preformed independently from 2a, was repeated at room temperature without the addition of K2CO3, only in the presence of
catalyst 7, 68% conversion was obtained after 24 h (syn/anti-3a0¼56/44) and no syn-enantioselectivity was observed.
g
After 24 h only 10% conversion was observed.
Much better enantioselectivities were obtained when PTC cata-
lyst 6 was substituted for the bifunctional thiourea derived from
9-amino(9-deoxy)epiquinine30 7 in the model reaction. (Scheme 4,
Table 3, entries 3e8). Recently, thiourea-based bifunctional orga-
nocatalysts were successfully employed in nitro-Mannich reactions
of nitroalkanes with activated imines 4a,b,h,k Thus, in the reaction of
1awith 2a, in the presence of 7 (20 mol %), the mixtureof syn-3a0 and
anti-3a0 was formed with low syn-diastereoselectivity and with
moderate to good syn-enantioselectivity, the latter being highly
solvent and temperature dependent. The use of toluene gave the
highest enantioselectivity at room temperature (47% ee, Table 3,
entry 6). Lowerenantioselectivities wereobserved forothersolvents
(Table 3, entries 3e5). By lowering the reaction temperature to
ꢀ20 ꢁC, the ee was improved up to 67% for the major syn-3a0,
however at the expense of the reaction time (Table 3, entry 8). We
According to the model proposed by us29 for the Naproxen amides of
1-amino- and 2-aminoalkanephosphonates (Scheme 6), the upfield
31P NMR chemical shift, attributed to the shielding effect of the nap-
roxen naphthyl ring on the phosphorus atom, should be assigned to
aminophosphonate with configuration (1S) at C-1 stereogenic center,
whereas a minor, downfield chemical shift corresponds to configu-
ration (1R) at the same center.
In turn, bisamides syn-9a0 (dP¼21.61 (minor), 21.40 (major); ratio:
26/74) were prepared via consecutive acylation of syn-4a0 using acetic
anhydride as acetylating agent, chemoselective deprotection of Boc
group in thus obtained N-acetyl derivatives followed by derivatization
O
O
NHBoc
R
NHBoc
Ph
iii
(EtO)2P
(EtO)2P
i-ii
3a'
-
syn
NH2
HN
(S)-Nap
8a'
syn
4a'
-
-
also found that substitution of a-amido sulfone 2a for N-benzylox-
syn
δP = 21.63 (minor)
δP = 22.06 (major)
ycarbonylamino(phenyl)methyl-p-tolylsulfone (2g) resulted in the
formation of a mixture of syn/anti-3g0 (syn/anti¼58/42) with lower
syn-enantioselectivity (34% ee) compared with the analogous re-
action in which sulfone 2a was used as imine precursor (Table 3,
footnote d). However, when the addition of diethyl nitro-
methanephosphonate (1) to N-Boc imine,16c preformed in-
dependently from N-Boc-amino(phenyl)methyl-p-tolylsulfone (2a),
was repeated at room temperature in toluene without the addition
of K2CO3, only in the presence of chiral catalyst 7, the reaction was
sluggish and gave a mixtureof syn/anti-3a0 (syn/anti¼56/44) with no
syn-enantioselectivity (Table 3, footnote f). This result shows that
the catalyst 7 could only act as the chiral Brønsted acid in the re-
actions accomplished in the presence of K2CO3.
iv-v,iii
δ (S) > δ (R)
P
P
(S)-Nap
O
HN
(EtO)2P
Ph
NHAc
-9a'
Cl
syn
O
δP = 21.40 (major)
O
δ
P = 21.61 (minor)
S <
P
( )-Nap-Cl
S
R
P
δ ( ) δ (
)
Scheme 5. The absolute configuration determination of the enantioenriched syn-4a0
amines by 31P NMR spectroscopy. Reagents and conditions: (i) NaBH4 (10 equiv),
NiCl2ꢂ6H2O (1.05 equiv), MeOH, ꢀ30 ꢁC, 5 min, 0 ꢁC; (ii) aq NH4Cl, 0 ꢁC; (iii) (S)-Nap-Cl
(2.5 equiv), Pyridine/CDCl3, rt, 1 h; (iv) Ac2O (3 equiv), Et3N (3 equiv), 4 h, rt; (v) TFA/
CH2Cl2 (1:1 v/v), rt, 2 h.
The results obtained for the model reaction are encouraging,
however, to achieve better enantioselectivity further tuning of the
catalyst structure is necessary.
of free amino group using (S)-Naproxen chloride. Employing the
model mentioned above,29 (Scheme 6) the major, upfield 31P NMR
chemical shift should be assigned to aminophosphonate with con-
figuration (2S) at carbon C-2, whereas downfield one corresponds
to configuration (2R) at the same center.{ Thus, the absolute config-
urations of major stereoisomers of syn-8a0 and syn-9a0 were de-
termined to be (1S) and (2S), respectively. This allows assigning the
same configuration for parent syn-4a0 and syn-3a0.
Finally, the absolute configuration of two consecutive stereogenic
centers in the enantioenriched syn-4a0 was determined by 31P NMR
analysis using (S)-Naproxen chloride as chiral derivatizing agentx for
amidation29,31 of each stereogenic center separately (Scheme 5). As
shown in Scheme 5, nitro adducts syn-3a0 were reduced to partially
protected syn-4a0 amines, followed by derivatization with (S)-Nap-
roxen chloride27 to give the mixture of diasteromeric (S)-Naproxen
amides syn-8a0 (dP¼22.06 (major) and 21.63 (minor); ratio: 74/26).
x
{
Since the diaminoderivative syn-4a0 is a mixture of enantiomers it is enough to
As a matter of fact, the configuration at C-2 carbon atom could also be assigned
use one enantiomer of Naproxen chloride for the absolute configuration
assignment.
based on the absolute configuration at C-1 stereogenic center in syn-8a0 and rela-
tive configuration of compounds 3 and 4.

9844
R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
are uncorrected. All reagents were purchased from Fluka and
were used without further purification. Diethyl nitro-
(S)
Me
Ar
O(S)
H
O(R)H
Me(S)
Ar
methanephosphonate,13 diethyl 1-nitroethanephosphonate,18 and
R
P(O)(OEt)2
N
N
P(O)(OEt)2
R
N-Boc a
-amidoalkyl-p-tolylsulfones15 were prepared as described
H
H
H
H
previously.
S
31P NMR: δ > δ
R
4.2. Preparation of substituted diethyl N-carbamate 2-amino-
1-nitroalkanephosphonates 3aeh; general procedure
O(R)
H
(S)
Me
Ar
O
H(S)
CH2P(O)(OEt)2
Me(S)
Ar
R
N
N
H
CH2P(O)(OEt)2
H
H
R
Solid, anhydrous K2CO3 (1.40 g, 10.0 mmol) was added to a solu-
tion of diethyl nitromethanephosphonate (1, 394 mg, 2.0 mmol),
H
S
31P NMR: δ < δ
R
a
-amido sulfone (2, 2.05 mmol) and tetrabutylammonium bromide
(TBAB, 70 mg, 0.20 mmol) in anhydrous toluene (20 mL). The sus-
pension was vigorously stirred for 26 h at room temperature. The
mixture was carefully quenched with 10% aq KHSO4 (10 mL), the
organic layer separated and the aqueous phase extracted with
CH2Cl2 (3ꢂ20 mL). The combined organic phases were washed with
brine (2ꢂ10 mL), dried over MgSO4, evaporated, and subjected to
flash chromatography on silica gel (AcOEt/hexanes 5:2 or 5:3 v/v) to
give pure mixtures of syn- and anti-adducts 3aeh. Pure syn-3aed
and syn-3g were obtained after crystallization from CCl4 (Table 1).
Ar =
MeO
Scheme 6. Model for the assignment of the configuration of diethyl 1-amino- and 2-
aminoalkylphosphonates from the 31P NMR spectra of their (S)-Naproxen amides,
based on the shielding effect exerted by the anisotropy cone of the naproxen naphthyl
29
ring on the substituents in aminophosphonates
.
3. Conclusions
4.2.1. Diethyl syn-(2-tert-butoxycarbonylamino-1-nitro-2-phenylethyl)
phosphonate 3a. Crude product was purified by flash chromatogra-
phy (AcOEt/hexanes 5:2 v/v), followed by crystallization from CCl4 to
give the title compound 3a (322 mg, 40%) as a colorless solid, mp
136e139 ꢁC; [found: C, 50.73; H, 6.82; N, 6.98. C17H27N2O7P requires
C, 50.74; H, 6.76; N, 6.96%]; Rf (AcOEt/hexanes 5:2 v/v) 0.44; nmax
(ATR) 3315, 2974, 1711, 1560, 1520, 1256, 1161, 982, 699; dP (101 MHz,
CDCl3) 10.36; dH (250 MHz, CDCl3) 7.38e7.29 (m, 5HAr), 6.09e5.95 (m,
1H, NHBoc), 5.77e5.50 (m, 1H, CHNHBoc), 5.34, 5.28 (dd and br dd,
respectively, 1H, 3JHH 7.4, 5.8 Hz, 2JHP 13.0, 16.0 Hz, CHNO2, rotamers),
4.35e3.80 (m, 4H, 2CH3CH2O), 1.42, 1.41 (2s, 9H, (CH3)3C, rotamers),
1.36e1.10 (m, 6H, 2CH3CH2O); dC (63 MHz, CDCl3) 154.4 (s, C]O),
136.8 (d, 3JCP 6.4 Hz, CHCAr), 128.6, 128.3, 126.8 (s, 5CHAr), 88.4 (d, 1JCP
In conclusion, we have shown that the reaction of diethyl
nitromethanephosphonate (1) with N-Boc and N-Cbz protected
a
-aminoalkyl-p-tolylsulfones 2aeh, as stable equivalents of N-car-
bamate imines, is a convenient and efficient method for the prep-
aration of N-protected -amino- -nitrophosphonates 3geh and in
consequence also -diaminophosphonates 3aeh. Additions are
b
a
a,b
accomplished under PTC conditions and give the mixture of syn-
and anti- nitro adducts 3geh in high yields and low syn-diaster-
eoselectivity. Homologue of the nitrophosphonate 1 is unreactive
under these conditions. Crystallization of the reaction mixture
allows obtaining pure syn-3aed and syn-3g derived from the cor-
responding aromatic aldehydes, which, after the reduction by
NaBH4/NiCl2 system afford partially protected syn-1,2-dia-
minoalkanephosphonates 4aed and 4g in moderate yields. A
model catalytic, enantioselective version of this aza-Henry reaction
was only partially successful. The moderate enantioselectivity
(67%) achieved for syn-diastereomer 3a0, when bifunctional thio-
urea derived from 9-amino(9-deoxy)epiquinine 7 is used as a cat-
alyst in the presence of K2CO3. Using 31P NMR spectroscopy and
(S)-Naproxen chloride as chiral derivatizing agent the absolute
configuration of the consecutive stereogenic centers in syn-4a0
amine was determined.
2
141.1 Hz, CHNO2), 80.1 (s, (CH3)3C), 64.2 (d, JCP 6.1 Hz, 2CH3CH2O),
3
53.9 (s, CHNHBoc), 28.1 (s, (CH3)3C), 16.0, 15.9 (2d, JCP 6.0, 5.8 Hz,
2CH3CH2O).
4.2.2. Diethyl syn-[2-tert-butoxycarbonylamino-2-(4-methoxyphenyl)-
1-nitroethyl]phosphonate 3b. Crude product was purified by flash
chromatography (AcOEt/hexanes 5:2 v/v), followed by crystallization
from CCl4 to give the title compound 3b (337 mg, 39%) as a colorless
solid, mp 145e148 ꢁC; [found: C, 49.98; H, 6.63; N, 6.33. C18H29N2O8P
requires C, 50.00; H, 6.76; N, 6.48%]; Rf (AcOEt/hexanes 5:2 v/v) 0.39;
nmax (ATR) 3334, 2939, 1704, 1559, 1517, 1247, 1160, 1012, 841, 714; dP
(101 MHz, CDCl3) 10.08; dH (250 MHz, CDCl3) 7.31e6.85 (m, 4HAr),
4. Experimental
4.1. General
3
6.17 (d, 1H, JHH 9.2 Hz, NHBoc), 5.55e5.42 (m, 1H, CHNHBoc),
5.48e5.29 (m,1H, CHNO2), 4.33e3.96 (m, 4H, 2CH3CH2O), 3.78 (s, 3H,
OCH3), 1.41 (s, 9H, (CH3)3C), 1.39e1.16 (m, 6H, 2CH3CH2O); dC
3
NMR spectra were recorded on a Bruker Avance DPX 250 in-
strument at 250.13 MHz for 1H NMR, 62.90 MHz for 13C NMR, and
101.3 MHz for 31P NMR in CDCl3 solution, using either tetrame-
thylsilane as an internal and 85% H3PO4 as an external standard.
Positive chemical shifts are downfield from external 85% H3PO4 for
(63 MHz, CDCl3) 157.8 (s, C]O), 152.8 (s, CH3OCAr), 127.1 (d, JCP
6.2 Hz, CHCAr), 112.4, 126.5, (2s, 4CHAr), 86.8 (d, 1JCP 141.1 Hz, CHNO2),
78.4 (s, (CH3)3C), 62.5 (d, 2JCP 6.4 Hz, 2CH3CH2O), 53.4 (s, OCH3), 52.1
3
(br s, CHNHBoc), 26.4 (s, (CH3)3C), 14.4, 14.3 (2d, JCP 5.6 Hz,
2CH3CH2O).
31P NMR spectra. Chemical shifts (
d) are indicated in parts per
million and coupling constants (J) in hertz. For 13C NMR spectra, the
peak assignments were made with the assistance of CH-COSY and
DEPT experiments. Partially overlapped signals are assigned by
4.2.3. Diethyl syn-[2-tert-butoxycarbonylamino-2-(4-chlorophenyl)-
1-nitroethyl]phosphonate 3c. Crude product was purified by flash
chromatography (AcOEt/hexanes 5:3 v/v), followed by crystallization
from CCl4 to give the title compound 3c (358 mg, 41%) as a colorless
solid, mp 157e160 ꢁC; [found: C, 46.52; H, 5.85; N, 6.65.
C17H26ClN2O7PrequiresC,46.74;H, 6.00;N,6.41%];Rf (AcOEt/hexanes
5:2 v/v) 0.39; nmax (ATR) 3332, 2974, 1709, 1560, 1514, 1246, 1159, 1011,
867; dP (101 MHz, CDCl3) 10.10; dH (250 MHz, CDCl3) 7.35e6.85 (m,
asterisks ( ). The enantiomeric excesses (ee) were determined by
*
31P NMR spectroscopy using (S)-Naproxen chloride as chiral deri-
vatizing agent (CDA). Optical rotations were measured on a PolAAr
3001 (Optical Activity Ltd.) polarimeter. Elemental analyses were
performed on a PerkineElmer PE 2400 Analyzer. IR spectra were
measured on an IR Alpha Bruker (ATR) instrument and are reported
in cmꢀ1. Melting points were determined in open capillaries and
3
4HAr), 6.09 (br d, JHH 8.1 Hz, 1H, NHBoc), 5.60e5.48 (m, 1H,
3
2
CHNHBoc), 5.31 (br dd, JHH 7.8 Hz, JHP 13.0 Hz, 1H, CHNO2),

R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
9845
4.37e3.92 (m, 4H, 2CH3CH2O),1.41 (s, 9H, (CH3)3C),1.38e1.19 (m, 6H,
2CH3CH2O); dC (63 MHz, CDCl3) 152.8 (s, C]O), 133.8 (d, 3JCP 6.5 Hz,
CHCAr), 132.2 (CAr), 126.7, 126.3 (CHAr), 86.4 (d, 1JCP 141.0 Hz, CHNO2),
78.7 (s, (CH3)3C), 62.9, 63.8 (2d, 2JCP 6.3, 7.5 Hz, 2CH3CH2O), 51.7 (br s,
CHNHBoc), 26.4 (s, (CH3)3C), 14.4, 14.3 (2d, 3JCP 6.0 Hz, 2CH3CH2O).
7.39e7.29 (m, 10HAr), 6.40 (br d, 3JHH 9.3 Hz, 1H, NH), 5.70e5.62 (m,
1H, CHPh), 5.40 (dd, 3JHH 6.1 Hz, 2JHP 16.5 Hz, 1H, CHNO2), 5.17e5.03
(m, 2H, CH2Ph), 4.15e4.01 (m, 4H, 2CH3CH2O), 1.33e1.08 (m, 6H,
2CH3CH2O); dC (63 MHz, CDCl3) 155.3 (s, C]O), 136.3 (d, 3JCP 5.8 Hz,
CHCAr), 136.0 (s, CAr), 128.7, 128.5, 128.3, 128.0, 127.2 (s, CHAr), 88.1 (d,
1JCP 141.0 Hz, CHNO2), 67.0 (s, CH2Ph), 64.3 (d, 2JCP 6.0 Hz, 2CH3CH2O),
54.6 (s, CHNH), 16.0, 15.9 (2d, 3JCP 6.3 Hz, 2CH3CH2O).
4.2.4. Diethyl syn-(2-tert-butoxycarbonylamino-2-furan-2-yl-1-ni-
troethyl)phosphonate 3d. Crude product was purified by flash
chromatography (AcOEt/hexanes 5:2 v/v), followed by crystalliza-
tion from CCl4 to give the title compound 3d (322 mg, 41%) as
a colorless solid, mp 92e95 ꢁC; [found: C, 45.86; H, 6.42; N, 7.03.
C15H25N2O8P requires C, 45.92; H, 6.42; N, 7.14%]; Rf (AcOEt/hexanes
5:2 v/v) 0.44; nmax (ATR) 3294, 2976, 1714, 1555, 1390, 1270, 1245,
1022, 752; dP (101 MHz, CDCl3) 9.88; dH (250 MHz, CDCl3) 7.38e7.36
(m, 1H, HAr), 6.37e6.32 (m, 2HAr), 5.83e5.62 (m, 2H, CHNHBoc,
NHBoc), 5.50e5.39 (m, 1H, CHNO2), 4.33e3.95 (m, 4H, 2CH3CH2O),
1.45, 1.44 (2s, 9H, (CH3)3C; rotamers), 1.38e1.18 (m, 6H, 2CH3CH2O);
dC (63 MHz, CDCl3) 152.7 (s, C]O),147.5 (d, 3JCP 7.3 Hz, CHCAr),141.0,
108.9, 106.7 (CHAr), 84.2 (d, 1JCP 142.0 Hz, CHNO2), 78.7 (s, (CH3)3C),
4.2.8. Diethyl syn/anti-(2-benzyloxycarbonylamino-1-nitropropyl)
phosphonates 3h. Crude product was purified by flash chroma-
tography (AcOEt/hexanes 5:3 v/v) to give the title compound
3h (623 mg, 84%) as a colorless viscous oil; [found: C, 48.33; H, 6.37;
N, 7.21. C15H23N2O7P requires C, 48.13; H, 6.19; N, 7.48%]; Rf
(AcOEt/hexanes 5:2 v/v) 0.43; nmax (neat) 3285, 2983, 1718, 1555,
1245, 1012, 697, 671; dP (101 MHz, CDCl3) 10.81 (anti-3h 43%), 10.67
(syn-3h 57%); dH (250 MHz, CDCl3) 7.36e7.29 (m, 5HAr), 5.93 (d, 1H,
3JHH 8.9 Hz, NHCbz, syn), 5.84 (d, 3JHH 8.3 Hz, NHCbz, 1H, anti), 5.26
(dd, 3JHH 5.2 Hz, 2JHP 14.5 Hz, 1H, CHNO2, anti), 5.16 (dd, 3JHH 7.2 Hz,
2JHP 15.2 Hz, 1H, CHNO2, syn), 5.10, 5.05 (2s, 2H, CH2Ph, syn and
anti), 4.67e4.39 (m, 1H, CHNHCbz, syn and anti), 4.25e4.06 (m, 4H,
2CH3CH2O, syn and anti), 1.42, 1.39 (2d, 3JHH 3.0 Hz, 3H, CH3CH, syn
and anti), 1.36e1.26 (m, 6H, 2CH3CH2O, syn and anti); dC (63 MHz,
CDCl3) 153.5 (s, C]O, syn and anti),134.4, 134.3, (2s, CH2CAr, syn and
anti), 126.7, 126.4, 126.3 (3s, CHAr, syn and anti), 86.0, 84.8 (2d, 1JCP
145.0, 141.9 Hz, CHNO2, syn and anti), 65.1 (s, CH2Ph, syn and anti),
63.0, 62.7, 62.6, 62.2 (4d, 2JCP 6.7, 6.8, 7.5, 6.8 Hz, 2CH3CH2O, syn and
anti), 45.9, 45.7 (2s, CHNH, syn and anti), 16.5 (s, CH3CH, syn), 15.4
(s, CH3CH, anti), 14.4 (d, 3JCP 5.7 Hz, 2CH3CH2O, syn and anti).
2
63.1, 62.6 (2d, JCP 6.5, 7.0 Hz, 2CH3CH2O), 46.8 (s, CHNHBoc), 26.4
3
(s, (CH3)3C), 14.5, 14.2 (2d, JCP 5.7 Hz, 2CH3CH2O).
4.2.5. Diethyl syn/anti-(2-tert-butoxycarbonylamino-1-nitropropyl)
phosphonates 3e. Crude product was purified by flash chromatog-
raphy (AcOEt/hexanes 5:3 v/v) togive the title compound 3e (599 mg,
88%) as a colorless viscous oil; [found: C, 42.55; H, 7.60; N, 8.08.
C12H25N2O7P requires C, 42.35; H, 7.40; N, 8.23]; Rf (AcOEt/hexanes
5:3 v/v) 0.37; nmax (neat) 3305, 2980, 1701, 1556, 1249, 1160, 1013,
730; dP (101 MHz, CDCl3) 11.27 (anti-3e 39%), 11.09 (syn-3e 61%); dH
(250 MHz, CDCl3) 5.34e5.00 (m, 2H, CHNO2, NHBoc, syn and anti),
4.54e4.36 (m, 1H, CHNHBoc, syn and anti), 4.33e4.08 (m, 4H,
2CH3CH2O, syn and anti), 1.45e1.33 (m, 18H, 2CH3CH2O, CH3CH,
(CH3)3C, syn and anti); dC (63 MHz, CDCl3) 152.9 (br s, C]O, syn and
anti), 86.1, 84.8 (2d,1JCP 143.3,141.3 Hz, CHNO2, syn and anti), 78.3 (br
4.3. Preparation of diethyl 2-(N-carbamate) protected 1,2-
diaminoalkanephosphonates 4aeh; general procedure
Sodium borohydride (113 mg, 3.0 mmol) was added in two
portions to a cooled to ꢀ30 ꢁC solution of diethyl N-carbamate
protected 2-amino-1-nitroalkanephosphonate 3 (0.3 mmol) and
NiCl2ꢂ6H2O (71 mg, 0.3 mmol) in methanol (3 mL). The mixture
was allowed to warm up to 0 ꢁC for 10 min, quenched with satu-
rated aq NH4Cl (9 mL), and extracted with CH2Cl2 (3ꢂ15 mL). The
combined organic phases were washed with brine (5 mL), dried
over MgSO4, evaporated, and subjected to flash chromatography on
silica gel (AcOEt) to give pure adducts 4.
2
s, (CH3)3C, syn and anti), 62.9, 62.7, 62.5, 62.2 (4d, JCP 6.7, 7.0, 7.9,
6.8 Hz, 2CH3CH2O, syn and anti), 45.4 (s, CHNHBoc, syn), 45.2 (s,
CHNHBoc, anti), 26.4 (s, (CH3)3C, syn and anti), 16.5 (s, CH3CH, syn),
15.5 (s, CH3CH, anti), 14.4 (d, 3JCP 5.8 Hz, 2CH3CH2O, syn and anti).
4.2.6. Diethyl syn/anti-(2-tert-butoxycarbonylamino-1-nitrobutyl)
phosphonates 3f. Crude product was purified by flash chromatogra-
phy (AcOEt/hexanes 5:3 v/v) to give the title compound 3f (560 mg,
79%) as a colorless viscous oil; [found: C, 44.27; H, 7.72; N, 7.71.
C13H27N2O7P requires C, 44.07; H, 7.68; N, 7.91%]; Rf (AcOEt/hexanes
5:3 v/v) 0.39; nmax (neat) 2975,1716,1557,1315,1244,1162,1010, 730,
567, 464; dP (101 MHz, CDCl3) 11.29 (anti-3f 44%),11.0 (syn-3f 56%); dH
(250 MHz, CDCl3) 5.25e5.09 (m, 2H, CHNO2, NHBoc, syn and anti),
4.36e4.16 (m, 5H, 2CH3CH2O, CHNHBoc, syn and anti), 1.80e1.60 (m,
2H, CH3CH2CH, syn and anti), 1.44 (s, 9H, (CH3)3C, syn and anti),
1.41e1.31 (m, 6H, 2CH3CH2O, syn and anti), 1.00 (br t, 3JHH 7.4 Hz, 3H,
CH3CH2CH, synandanti);dC (63MHz,CDCl3)155.1,154.9(2s, C]O,syn
and anti), 86.8 (d, 1JCP 142.4 Hz, CHNO2, syn), 86.3 (d, 1JCP 145.6 Hz,
CHNO2, anti), 79.8 (br s, (CH3)3C, syn and anti), 64.9, 64.4, 64.3, 63.8
(4d, 2JCP 6.8, 5.0, 4.0, 6.9, 2CH3CH2O, syn and anti), 52.9 (s, CHNHBoc,
anti), 52.1 (s, CHNHBoc, syn), 28.1 (s, (CH3)3C, syn and anti), 25.3(d, 3JCP
4.3.1. Diethyl syn-(1-amino-2-tert-butoxycarbonylamino-2-phenyl-
ethyl)phosphonate 4a. Crude product was purified by flash chro-
matography (AcOEt) to give the title compound 4a (70 mg, 63%) as
a colorless solid, mp 108e111 ꢁC; [found: C, 54.63; H, 7.60; N, 7.30.
C17H29N2O5P requires C, 54.83; H, 7.85; N, 7.52%]; Rf (AcOEt) 0.26;
nmax (ATR) 3391, 3032, 1703, 1530, 1362, 1265, 1246, 1212, 1017, 966,
933, 860, 703; dP (101 MHz, CDCl3) 25.69; dH (250 MHz, CDCl3)
3
7.42e7.22 (m, 5HAr), 6.06 (brs, 1H, NHBoc), 5.06 (ddd, JHH 3.3,
3
8.0 Hz, JH3P 11.6 Hz, 1H, CHNHBoc), 4.22e3.99 (m, 4H, 2CH3CH2O),
2
3.40 (dd, JHH 3.3 Hz, JHP 15.6 Hz, 1H, CHNH2), 1.66 (br s, 2H,
3
CHNH2), 1.40 (s, 9H, (CH3)3C), 1.35, 1.25 (2 t, JHH 7.1 Hz, 6H,
2CH3CH2O); dC (63 MHz, CDCl3) 155.2 (s, C]O), 140.3 (d, 3JCP 4.7 Hz,
CHCAr), 128.5, 127.4, 126.6 (Car), 79.4 (s, (CH3)3C), 62.6, 62.4 (2d, 2JCP
3
3
1
5.2 Hz, CH3CH2, syn), 24.7 (d, JCP 4.3 Hz, CH3CH2, anti), 16.1 (d, JCP
6.9 Hz, 2CH3CH2O), 54.9 (br s, CHNHBoc), 53.5 (d, JCP 152.0 Hz,
6.0 Hz, 2CH3CH2O, syn and anti), 10.3 (d, 4JCP 2.9 Hz, CH3CH2).
CHNH2), 28.3 (s, (CH3)3C), 16.5, 16.3 (2d, 3JCP 6.7, 7.0 Hz, 2CH3CH2O).
4.2.7. Diethyl syn-(2-benzyloxycarbonylamino-1-nitro-2-phenylethyl)
phosphonate 3g. Crude product was purified by flash chromatogra-
phy (AcOEt/hexanes 5:2 v/v), followed by crystallization from CCl4. to
give the title compound 3g (244 mg, 28%) as a colorless solid, mp
100e103 ꢁC; [found: C, 55.16; H, 5.60; N, 6.38. C20H25N2O7P requires
C, 55.05; H, 5.77; N, 6.42%]; Rf (AcOEt/hexanes 5:2 v/v) 0.39; nmax
(ATR) 3306, 2957,1742,1555,1528,1246,1006, 813, 694; dP (101 MHz,
CDCl3) 10.93 (anti-3g 47%), 10.17 (syn-3g 53%); dH (250 MHz, CDCl3)
4.3.2. Diethyl syn-[1-amino-2-tert-butoxycarbonylamino-2-(4-me-
thoxyphenyl)-ethyl]phosphonate 4b. Crude product was purified by
flash chromatography (AcOEt) to give the title compound 4b (64 mg,
53%) as a colorless solid, mp 96e99 ꢁC; [found: C, 53.51; H, 7.82; N, 6.92.
C18H31N2O6P requires C, 53.72; H, 7.76; N, 6.96%]; Rf (AcOEt) 0.20; nmax
(ATR) 3276, 2977, 1704, 1511, 1244, 1158, 1026, 961, 767; dP (101 MHz,
CDCl3) 25.17; dH (250 MHz, CDCl3) 7.29e7.22 (m, 2HAr), 6.90e6.84 (m,
2HAr), 5.95 (br s,1H, NHBoc), 4.95 (ddd, 3JHH 3.4, 8.0 Hz, 3JHP 13.4 Hz,1H,

9846
R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
CHNHBoc), 4.21e3.98 (m, 4H, 2CH3CH2O), 3.79 (s, 3H, CH3O), 3.36 (dd,
3JHH 3.4 Hz, 2JHP 15.0 Hz, 1H, CHNH2), 1.45 (br s, 2H, NH2), 1.39 (s, 9H,
(CH3)3C), 1.34, 1.27 (2 t, 3JHH 7.1 Hz, 6H, 2CH3CH2O), dC (63 MHz, CDCl3)
158.8 (s, CH3OCAr),155.1 (s, C]O),132.2 (br s, CHCAr),127.6,113.7 (CHAr),
79.2 (s, (CH3)3C), 62.4, 62.2 (2d, 2JCP 6.9 Hz, 2CH3CH2O), 55.1 (s, CH3O),
54.3 (br s, CHNHBoc), 53.5 (d, 1JCP 151.0 Hz, CHNH2), 28.2 (s, (CH3)3C),
16.3, 16.2 (2d, 3JCP 6.6 Hz, 2CH3CH2O).
9.01; N, 8.64 %]; Rf (AcOEt) 0.30; nmax (neat) 3300, 2975, 1706, 1507,
1238, 1164, 1021, 958, 783, 558; dP (101 MHz, CDCl3) 27.5 (syn- and
anti-4f); dH (250 MHz, CDCl3) 5.23, 5.12 (2br d, JHH 8.4, 9.4 Hz, 1H,
3
CHNHBoc, syn and anti), 4.23e4.08 (m, 4H, 2CH3CH2O, syn and anti),
3.93e3.69 (m, 1H, CH3CH2CH, syn and anti), 3.17, 3.14 (2dd, 3JHH 3.6,
3.7 Hz 2JHP 15.6, 14.5 Hz, 1H, CHNH2, syn and anti), 1.80e1.49 (m, 4H,
NH2, CH3CH2CH, syn and anti),1.44 (s, 9H, (CH3)3C, syn and anti),1.35,
1.34 (2t, 3JHH 7.1 Hz, 6H, 2CH3CH2O, syn and anti), 1.00e0.90 (m, 3H,
CH3CH2CH, syn and anti); dC (63 MHz, CDCl3) 153.9 (s, C]O, syn and
anti), 77.4(s, (CH3)3C, syn and anti), 53.1, 52.2(2brs, CHNHBoc, synand
anti), 60.7, 60.1 (2br d, 2JCP 7.9 Hz, 2CH3CH2O, syn and anti), 51.0, 50.6
(2d,1JCP 144.9,148.8 Hz, CHNH2, syn and anti), 27.4 (s, (CH3)3C, syn and
4.3.3. Diethyl syn-[1-amino-2-tert-butoxycarbonylamino-2-(4-chlor-
ophenyl)-ethyl]phosphonate 4c. Crude product was purified by
flash chromatography (AcOEt) to give the title compound 4c
(81 mg, 66%) as a colorless solid, mp 111e114 ꢁC; [found: C, 50.38;
H, 7.04; N, 6.97. C17H28ClN2O5P requires C, 50.19; H, 6.94; N,
6.89%]; Rf (AcOEt) 0.26; nmax (ATR) 3273, 2931, 1703, 1532, 1247,
1212, 1161, 1012, 966, 738; dP (101 MHz, CDCl3) 25.77; dH
(250 MHz, CDCl3) 7.32e7.12 (m, 4HAr), 6.20 (br s, 1H, NHBoc), 4.94
3
anti), 24.4, 23 (2br s, CH3CH2, syn and anti), 15.5 (d, JCP 5.3 Hz,
2CH3CH2O, syn and anti), 9.9, 9.8 (2s CH3CH2, syn and anti).
4.3.7. Diethyl syn-(1-amino-2-benzyloxycarbonylamino-2-phenyl-
ethyl)phosphonate 4g. Crude product was purified by flash chro-
matography (AcOEt) to give the title compound 4g (91 mg, 75%) as
a colorless solid, mp 64e66 ꢁC; [found: C, 58.99; H, 6.66; N, 6.86.
C20H27N2O5P requires C, 59.11; H, 6.70; N, 6.89%]; Rf (AcOEt) 0.20;
nmax (ATR) 3267, 2980, 1716, 1534, 1249, 1017, 965, 790, 697, 527,
509; dP (101 MHz, CDCl3) 25.48; dH (250 MHz, CDCl3) 7.33e7.25 (m,
3
3
(ddd, JHH 3.4, 7.7 Hz, JHP 11.6 Hz, 1H, CHNHBoc), 4.13e3.93 (m,
3
2
4H, 2CH3CH2O), 3.26 (dd, JHH 3.4 Hz, JHP 16.1 Hz, 1H, CHNH2),
1.50 (br s, 2H, NH2), 1.32 (s, 9H, (CH3)3C), 1.34, 1.26 (2t, 3JHH 7.1 Hz,
6H, CH3CH2O); dC (63 MHz, CDCl3) 153.4 (s, C]O), 137.2 (br d, 3JCP
7.0 Hz, CHCAr), 131.3 (s, ClCAr), 126.7, 126.3 (2s, 2CHAr), 77.7 (s,
(CH3)3C), 60.8, 60.6 (2d, JCP 7.0 Hz, 2CH3CH2O), 52.7 (br s,
CHNHBoc), 51.5 (d, JCP 152.1 Hz, CHNH2), 26.5 (s, (CH3)3C), 14.6,
2
1
3
3
10HAr), 6.65 (br d, JHH 8.3 Hz, 1H, NHCbz), 5.15 (ddd, JHH 3.0,
3
3
14.5 (2d, JCP 6.4 Hz, 2CH3CH2O).
8.3 Hz, JHP 11.5 Hz, 1H, CHNHCbz), 5.09e5.00 (m, 2H, CH2Ph),
4.17e3.90 (m, 4H, 2CH3CH2O), 3.39 (dd, 3JHH 3.0 Hz, 2JHP 16.0 Hz,1H,
3
4.3.4. Diethyl syn-[(1-amino-2-tert-butoxycarbonylamino-2-furan-
2-yl)ethyl]phosphonate 4d. Crude product was purified by flash
chromatography (AcOEt) to give the title compound 4d (60 mg, 55%)
as a colorless solid, mp 49e52 ꢁC; [found: C, 49.53; H, 7.59; N, 7.80.
C15H27N2O6P requires C, 49.72; H, 7.51; N, 7.73%]; Rf (AcOEt) 0.26;
nmax (ATR) 3311, 2980, 1703, 1526, 1215, 1161, 1018, 953, 759; dP
(101 MHz, CDCl3) 25.27; dH (250 MHz, CDCl3) 7.36e7.35 (m, 1HAr),
CHNH2), 1.65 (br s, 2H, NH2), 1.26, 1.20 (2t, JHH 7.1 Hz, 6H,
2CH3CH2O); dC (63 MHz, CDCl3) 155.6 (s, C]O), 139.8 (d, 3JCP 5.0 Hz,
CHCAr), 136.4 (CAr), 128.3, 128.2, 127.9, 127.8, 127.3, 126.4, (CHAr),
2
66.4 (s, CH2Ph), 62.4, 62.2 (2d, JCP 9.4 Hz, 2CH3CH2O), 55.1 (s,
CHNHCbz), 53.3 (d, 1JCP 152.3 Hz, CHNH2), 16.2, 16.1 (2d, 3JCP 5.3 Hz,
2CH3CH2O).
3
6.33e6.31 (m, 1HAr), 6.27e6.25 (m, 1HAr), 5.95 (d, JHH 8.8 Hz, 1H,
4.3.8. Diethyl syn/anti-(1-amino-2-benzyloxycarbonylamino-propyl)
phosphonates 4h. Crude product was purified by flash chroma-
tography (AcOEt) to give the title compound 4h (60 mg, 58%) as
a colorless oil; [found: C, 52.53; H, 7.35; N, 8.16. C15H25N2O5P
requires C, 52.32; H, 7.32; N, 8.14%]; Rf (AcOEt) 0.14; nmax (neat)
3296, 2979, 1710, 1530, 1224, 1018, 957, 696; dP (101 MHz, CDCl3)
26.97 (syn-4h 59%), 26.78 (anti-4h 41%); dH (250 MHz, CDCl3)
7.36e7.24 (m, 5HAr, syn and anti), 6.00e5.87 (m, 1H, NHCbz, syn
and anti), 5.08 (s, 2H, CH2Ph, syn and anti), 4.15e3.97 (m, 5H,
3
3
NHBoc), 5.12 (ddd, JHH 3.7, 8.8 Hz, JHP 12.9 Hz, 1H, CHNHBoc),
3
2
4.23e3.93 (m, 4H, 2CH3CH2O), 3.53 (dd, JHH 3.7 Hz, JHP 15.6 Hz,
1H, CHNH2), 1.69 (br s, 2H, NH2), 1.44 (s, 9H, (CH3)3C), 1.33, 1.27 (2d,
3JHH 7.1 Hz, 6H, 2CH3CH2O); dC (63 MHz, CDCl3) 154.9 (s, C]O),
153.0 (d, JCP 11.1 Hz, CHCAr), 141.2, 110.1, 106.9 (CHAr), 79.4 (s,
(CH3)3C), 62.3, 62.1 (2d, JCP 7.0, 6.9 Hz, 2CH3CH2O), 51.5 (d, JCP
153.1 Hz, CHNH2), 50.1 (br s, CHNHBoc), 28.1 (s, (CH3)3C), 16.2, 16.1
3
2
1
3
(2d, JCP 4.7 Hz, 2CH3CH2O).
3
2
2CH3CH2O, CHNHCbz, syn and anti), 3.18 (dd, JHH 3.7 Hz, JHP
3
2
4.3.5. Diethyl syn/anti-(1-amino-2-tert-butoxycarbonylamino-pro-
pyl)phosphonates 4e. Crude product was purified by flash chro-
matography (AcOEt) to give the title compound 4e (40 mg, 43%) as
a colorless oil; [found: C, 46.54; H, 8.54; N, 8.80. C12H27N2O5P re-
quires C, 46.44; H, 8.77; N, 9.03%]; Rf (AcOEt) 0.29; nmax (neat) 3305,
2977, 1698, 1365, 1230, 1164, 1021, 959, 730; dP (101 MHz, CDCl3)
27.16 (syn-4e 58%), 27.08 (anti-4e 43%); dH (250 MHz, CDCl3) 5.24
(br s, 1H, NHBoc, syn and anti), 4.24e4.09 (m, 4H, 2CH3CH2O, syn
and anti), 4.08e3.83 (m, 1H, CHNHBoc, syn and anti), 3.17 (dd, 3JHH
16.1 Hz, 1H, CHNH2, anti), 3.05 (dd, JHH 3.7 Hz, JHP 15.2 Hz, 1H,
CHNH2, syn), 1.89 (br s, 2H, NH2, syn and anti), 1.41e1.15 (m, 9H,
2CH3CH2O, CH3CH, syn and anti); dC (63 MHz, CDCl3) 154.0, 153.9
(2s, C]O, syn and anti), 134.9, 134.8 (2s, CAr, syn and anti), 126.6,
126.5, 126.1 (3s, CHAr, syn and anti), 64.6 (s, CH2Ph, syn and anti),
2
60.6, 60.3 (2d, JCP 6.5, 6.1 Hz, CH3CH2O, syn and anti), 51.0 (d,
1JCP 148.5 Hz, CHNH2, syn), 50.2 (d, JCP 144.5 Hz, CHNH2, anti),
1
2
46.6 (s, CHNHCbz, syn), 46.0 (d, JCP 9.1 Hz, CHNHCbz, anti), 14.6
(d, JCP 5.7 Hz, 2CH3CH2O, syn and anti), 14.2 (s, CH3CH, syn and
3
2
3
2
3.4 Hz, JHP 15.5 Hz, 1H, CHNH2, anti), 3.09 (dd, JHH 4.4 Hz, JHP
14.9 Hz,1H, CHNH2, syn),1.77 (br s, 2H, CHNH2, syn and anti),1.44 (s,
anti).
3
9H, (CH3)3C, syn and anti), 1.35 (t, JHH 7.1 Hz, 6H, 2CH3CH2O, syn
4.4. Diethyl trans-(5-phenyl-2-thioxoimidazolidin-4-yl)
and anti), 1.26 (d, 3JHH 6.8 Hz, 3H, CH3CH, syn), 1.22 (d, 3JHH 7.0 Hz,
3H, CH3CH, anti); dC (63 MHz, CDCl3) 153.4 (s, C]O, syn and anti),
77.1(s, (CH3)3C, syn and anti), 60.5 (br s, CHNHBoc, syn and anti),
60.4, 60.2 (2d, 2JCP 7.1, 7.0 Hz, 2CH3CH2O, syn and anti), 50.9 (d, 1JCP
148.3 Hz, CHNH2, syn), 50.2 (d, 1JCP 144.1 Hz, CHNH2, anti), 26.4 (s,
(CH3)3C, syn and anti), 14.5 (d, 3JCP 5.6 Hz, 2CH3CH2O, syn and anti),
14.1 (br s, CH3CH, syn and anti).
phosphonate21k 5a
Trifluoroacetic acid (0.9 mL, 12 mmol) was added dropwise to
the solution of syn-4a, (100 mg, 0.27 mmol) in CH2Cl2 (1.5 mL).
The mixture was stirred for 1.5 h at room temperature, and the
volatile materials evaporated under reduced pressure. The oily
residue was dissolved in CH2Cl2 (1.0 mL), triethylamine (0.19 mL,
1.35 mmol) was added to the solution and the mixture was
stirred for 30 min at room temperature. Then, the solution of 1,10-
thiocarbonyldiimidazole (56 mg, 1.35 mmol) in CH2Cl2 (1.5 mL)
was added and the mixture was stirred for 24 h at room tem-
perature. Reaction mixture was diluted with CH2Cl2 (30 mL), and
4.3.6. Diethyl syn/anti-(1-amino-2-tert-butoxycarbonylamino-butyl)
phosphonates 4f. Crude product was purified by flash chromatogra-
phy (AcOEt) to give the title compound 4f (58 mg, 60%) as a colorless
oil;[found:C,48.39;H,9.26;N,8.45. C13H29N2O5PrequiresC,48.14;H,

R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
9847
washed successively with 1 M aq HCl (2ꢂ3 mL), saturated
NaHCO3 (2ꢂ3 mL), and brine (3 mL). Organic phase was dried
over MgSO4, evaporated, and subjected to flash chromatography
on silica gel (eluent: CH2Cl2/acetone 3:1 v/v) to give pure trans-
5a (43 mg, 51%) as a colorless solid, mp 151e153 ꢁC; [found: C,
49.41; H, 5.80; N, 8.69. C13H19N2O3PS requires C, 49.67; H, 6.09;
N, 8.91%]; Rf (CH2Cl2eacetone 3:1) 0.36; nmax (ATR) 3144, 2904,
1532, 1472, 1232, 1024, 780; dP (101 MHz, CDCl3) 18.46; dH
(250 MHz, CDCl3) 7.42e7.30 (m, 5H, HAr), 7.03 (br s, 2H, 2 NH),
for a sample with 47% ee). The spectroscopic data of syn-3a0 and
syn-4a0 were identical to racemic syn-3a and syn-4a.
Acknowledgements
Financial support by a grant 1T 09A 054 30 (2006e2009) from
the Ministry of Education and Science is gratefully acknowledged.
Supplementary data
3
3
5.21 (dd, JHH 6.3 Hz, JHP 20.5 Hz, 1H, CHCAr), 4.32e4.05 (m, 4H,
CH3CH2O), 4.00 (d, 3JHH 6.3 Hz, 1H, CHP), 1.35, 1.31 (2t, 3JHH 7.1 Hz,
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.10.072.
3
6H, CH3CH2O); dC (63 MHz, CDCl3) 183.2 (d, JCP 4.8 Hz, C]S),
139.9 (d, 3JCP 10.1 Hz, CHCAr), 129.0, 128.8, 126.1 (s, CHAr), 63.8 (d,
2
2JCP 6.8 Hz, CH3CH2O), 63.3 (d, JCP 7.2 Hz, CH3CH2O), 61.8 (s,
CHCAr), 61.6 (d, 1JCP 161.7 Hz, CHP), 16.5 (d, 3JCP 5.3 Hz, CH3CH2O),
References and notes
3
16.4 (d, JCP 5.7 Hz, CH3CH2O).
1. For recent reviews, see: (a) Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49,
511; (b) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151; (c) Vilaivan, T.;
Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem. 2005, 9, 1315; (d) Petrini,
M.; Torregani, E. Synthesis 2007, 159; (e) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
ꢀ
ꢀ
4.5. Diethyl trans/cis-(5-ethyl-2-thioxoimidazolidin-4-yl)
2007, 5797; (f) Marques-Lopez, E.; Merino, P.; Tejero, T.; Herrera, R. P. Eur. J. Org.
phosphonates21k 5b
ꢀ
Chem. 2009, 2401; (g) Arrayas, R. G.; Carretero, J. C. Chem. Soc. Rev. 2009, 38, 1940.
2. For recent examples, of the aza-Henry reaction using chiral betaine and gua-
nidine catalysts, see: (a) Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc.
2008, 130, 10878; (b) Lovick, H. M.; Michael, F. E. Tetrahedron Lett. 2009, 50,
1016.
A crude mixture of trans- and cis-5b was obtained in the same
way as 5a. Crude product was purified by flash chromatography
(CH2Cl2/acetone 1:1) to give the title trans- and cis-5b (29 mg,
41%) as yellow solid, mp 120e123 ꢁC; [found: C, 40.74; H, 7.38; N,
10.18. C9H19N2O3PS requires C, 40.59; H, 7.19; N, 10.52%]; Rf
(CH2Cl2/acetone 1:1) 0.45; nmax (ATR) 3163, 2967, 1523, 1225,
1011, 965, 719, 624; dP (101 MHz, CDCl3) 19.24 (trans-5b 64%),
18.21 (cis-5b 36%); dH (250 MHz, CDCl3) 7.27, 7.21 (2br s, 1H, NH,
cis), 6.83, 6.57 (2br s, 1H, NH, trans), 4.31e4.04 (m, 6H,
3. For recent examples, of the aza-Henry reaction using chiral Lewis acids and
chiral proton catalysts, see: (a) Nishiwaki, N.; Gothelf, A. S.; Knudsen, R.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992; (b) Nishiwaki, N.; Gothelf,
A. S.; Knudsen, R.; Risgaard, T.; Jørgensen, K. J. Am. Chem. Soc. 2001, 123, 5843;
(c) Knudsen, K. R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362; (d) Lee, A.
M.; Kim, W.; Lee, J.; Hyeon, T.; Kim, B. M. Tetrahedron: Asymmetry 2004, 15,
ꢀ
2595; (e) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lopez, R. Angew. Chem.,
Int. Ed. 2006, 45, 117; (f) Trost, B. M.; Lupton, D. W. Org. Lett. 2007, 9, 2023; (g)
Gao, F.; Zhu, J.; Tang, Y.; Deng, M.; Qian, C. Chirality 2006, 18, 741; (h) Anderson,
J. C.; Blake, A. J.; Howell, G. P.; Wilson, C. J. Org. Chem. 2005, 70, 549; (i)
Anderson, J. C.; Howell, G. P.; Lawrence, R. M.; Wilson, C. S. J. Org. Chem. 2005,
70, 5665; (j) Zhou, H.; Peng, D.; Qin, B.; Hou, Z.; Liu, X.; Feng, X. J. Org. Chem.
2007, 72, 10302; (k) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc.
2004, 126, 3418; (l) Singh, A.; Yoder, R. A.; Shen, B.; Johnston, J. N. J. Am. Chem.
Soc. 2007, 129, 3466; (m) Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397; (n)
Singh, A.; Johnston, J. N. J. Am. Chem. Soc. 2008, 130, 5866; (o) Rueping, M.;
Antonchick, A. P. Org. Lett. 2008, 10, 1731; (p) Davis, T. A.; Wilt, J. C.; Johnston, J.
N. J. Am. Chem. Soc. 2010, 132, 2880; (q) Hess, A. S.; Yoder, R. A.; Johnston, J. N.
Synlett 2006, 147.
4. For recent examples, of the aza-Henry reaction using chiral thioureas cata-
lysts, see: (a) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 466;
(b) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.dEur. J.
2006, 12, 466; (c) Han, B.; Liu, Q.-P.; Li, R.; Tian, X.; Xiong, X.-F.; Deng, J.-G.;
Chen, Y.-C. Chem.dEur. J. 2008, 14, 8094; (d) Wang, C.; Zhou, Z.; Tang, C. Org.
Lett. 2008, 10, 1707; (e) Wang, C.; Dong, X.; Zhang, Z.; Xue, Z.; Teng, H. J. Am.
Chem. Soc. 2008, 130, 8606; (f) Takada, K.; Nagasawa, K. Adv. Synth. Catal.
2009, 351, 345; (g) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625; (h) Robak, M. T.; Trincado, M.; Ellman, J. A. J. Am. Chem.
Soc. 2007, 129, 15110; (i) Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.;
Zhang, H.; Fu, D.; Wang, R. Adv. Synth. Catal. 2009, 351, 2096; (j) Rampalakos,
C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350, 1785; (k) Chang, Y.; Yang, J.;
Dang, Y.; Xue, Y. Synlett 2007, 2283.
3
2CH3CH2O, CH3CH2CH, trans and cis, CHP, cis), 3.83 (br d, JHH
6.4 Hz, 1H, CHP, trans), 2.03e1.77 (m, 2H, CH3CH2CH, cis),
1.75e1.61 (m, 2H, CH3CH2CH, trans), 1.36, 1.35 (2t, 6H ,
3JHH
*
7.1 Hz, 2CH3CH2O, trans and cis), 1.01 (t, 3H
, 3JHH 7.5 Hz, CH3CH2,
*
cis), 0.97 (t, 3H
*
,
3JHH 7.4 Hz, CH3CH2, trans); dC (63 MHz, CDCl3)
3
3
183.3 (d, JCP 3.7 Hz, C]S, cis), 182.2 (d, JCP 4.3 Hz, C]S, trans),
63.6 (d, JCP 6.8 Hz, CH3CH2O, trans), 63.2 (d, JCP 6.1 Hz,
2
2
2
2
CH3CH2O, trans), 63.1 (d, JCP 7.3, CH3CH2O, trans), 63.0 (d, JCP
7.4, CH3CH2O, cis), 61.1 (s, CH3CH2CH, cis), 60.0 (s, CH3CH2CH
1
1
trans), 57.8 (d, JCP 163.2 Hz, CHP, trans), 56.7 (d, JCP 157.3 Hz,
3
3
CHP, cis), 28.7 (d, JCP 10.7 Hz, CH3CH2CH, trans), 23.9 (d, JCP
7.0 Hz, CH3CH2CH, cis), 16.4, 16.3 (2br d, JCP 5.9 Hz, CH3CH2O,
3
trans and cis), 11.4 (s, CH3CH2CH, cis), 9.0 (s, CH3CH2CH, trans).
4.6. Enantioselective synthesis of diethyl syn-(1-amino-2-
tert-butoxycarbonylamino-2-phenylethyl)phosphonates 4a0
5. For recent examples, of the aza-Henry reaction using cinchona alkaloids cata-
ꢀ
lysts, see: (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem. Soc. 2005,
Solid, anhydrous K2CO3 (700 mg, 5.0 mmol) was added to the
solution of diethyl nitromethanephosphonate (1, 197 mg,
127, 17622; (b) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975; (c) Bernardi, L.; Fini, F.; Herrera,
R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62, 375; (d) Gomez-Bengoa, E.;
Linden, A.; Lopez, R.; Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem.
Soc. 2008, 130, 7955; (e) Bode, C. M.; Ting, A.; Schaus, S. E. Tetrahedron 2006, 62,
11499.
1.0 mmol),
a-amido sulfone 2a (379 mg, 1.05 mmol), and chiral
ꢀ
ꢀ
thiourea 7 (120 mg, 0.20 mmol) in anhydrous toluene (10 mL). The
suspension was vigorously stirred for 3 d at room temperature.
Then, the mixture was carefully quenched with 10% aq KHSO4
(10 mL). The organic layer was separated and the aqueous phase
was extracted with CH2Cl2 (3ꢂ15 mL). The combined organic
phases were washed with brine (2ꢂ10 mL), dried over MgSO4,
evaporated, and subjected to flash chromatography on silica gel
(AcOEt/hexanes 5:2 v/v) to give 310 mg (71%) of pure syn- and anti-
adducts 3a0 (syn/anti¼57/43). Pure enantioenriched syn-3a0
(109 mg) was obtained in 27% yield after crystallization from CCl4
(Table 3). Compound syn-3a0 (100 mg, 0.247 mmol) was subjected
to NaBH4/NiCl2 system in methanol according to the general pro-
6. For recent examples of the aza-Henry reaction using heterobimetallic catalysts,
see: (a) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001, 980; (b) Handa, S.;
Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
€
4925; (c) Yamada, K.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int.
Ed. 1999, 38, 3504; (d) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 4900; (e) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
7. For application of N-formyl and N-Carbamate protected
a-aminoalkyl-ar-
ylsulfones in the aza-Henry reaction, see: (a) Ballini, R.; Petrini, M. Tetrahedron
Lett. 1999, 40, 4449; (b) Petrini, M.; Torregiani, E. Tetrahedron Lett. 2006, 47,
3501; (c) Foresti, E.; Palmieri, G.; Petrini, M.; Profeta, M. Org. Biomol. Chem.
2003, 1, 4275; (d) Nagano, T.; Kinoshita, H. Bull. Soc. Chem. Jpn. 2000, 73, 1605;
(e) Shiraishi, Y.; Yamauchi, H.; Takamura, T.; Kinoshita, H. Bull. Soc. Chem. Jpn.
2004, 77, 2219; (f) Refs. 4i,5a,b,d.
cedure described in Section 4.3 to give, after reduction and flash
8. Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63,
9932.
20
chromatography, 56 mg (61%) of syn-4a0, [
a
]
ꢀ9.2 (c 0.15, CHCl3,
D

9848
R. Błaszczyk et al. / Tetrahedron 66 (2010) 9840e9848
9. For a recent review on the synthesis of
a
,
b
-diamino acids, see: Viso, A.; de la
21. For recent syntheses of 1,2-diaminophosphonates, see: (a) Zygmunt, J. Tetra-
hedron 1985, 41, 4979; (b) Dolence, E. K.; Roylance, J. B. Tetrahedron: Asymmetry
2004, 15, 3307; (c) Li, B.-F.; Zhang, M.-J.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2002,
Pradilla, R. F.; Garcia, A.; Flores, A. Chem. Rev. 2005, 105, 3167.
10. Wilt, J. C.; Pink, M.; Johnston, J. N. Chem. Commun. 2008, 4177.
11. Baranov, G. M.; Perekalin, V. V. Russ. Chem. Rev. 1992, 61, 1220.
12. Petrov, K. A.; Chauzov, V. A.; Bogdanov, N. N.; Agafonov, S. V. Zh. Obshch. Khim.
1979, 49, 90.
13. Petrov, K. A.; Chauzov, V. A.; Bogdanov, N. N.; Pastukhova, I. V. J. Gen. Chem.
USSR 1976, 46, 1230.
14. For recent review, see: Petrini, M. Chem. Rev. 2005, 105, 3949.
ꢀ
67, 2902; (d) Piotrowska, D. G.; Wroblewski, A. Tetrahedron 2003, 59, 8405; (e)
Dolence, E. K.; Mayer, G.; Kelly, B. D. Tetrahedron: Asymmetry 2005, 16, 1583; (f)
De Risi, C.; Dondoni, A.; Perrone, D.; Pollini, G. P. Tetrahedron Lett. 2001, 42,
3033; (g) De Risi, C.; Perrone, D.; Dondoni, A.; Pollini, G. P.; Bertolasi, V. Eur. J.
Org. Chem. 2003, 1904; (h) Studer, A.; Seebach, D. Heterocycles 1995, 40, 357; (i)
Campbell, M. M.; Carruthers, N. J. Chem. Soc., Chem. Commun. 1980, 730; (j)
Campbell, M. M.; Carruthers, N. I.; Mickel, S. J. Tetrahedron 1982, 38, 2513; (k)
B1aszczyk, R.; Gajda, T. Tetrahedron Lett. 2007, 48, 5859; (l) Louaisil, N.; Rabasso,
N.; Fadel, A. Synthesis 2007, 289; (m) Kobayashi, S.; Yazaki, R.; Seki, K.; Yama-
shita, Y. Angew. Chem., Int. Ed. 2008, 47, 5613; (n) Momo, R. D.; Fini, F.; Bernardi,
L.; Ricci, A. Adv. Synth. Catal. 2009, 351, 2283.
15. For the synthesis of N-Boc and N-Cbz protected
a-amido sulfones, see: (a)
Engeberts, J. B. F. N.; Strating, J. Recl. Trav. Chim. Pays-Bas 1964, 83, 733; (b)
Pearson, W. H.; Lindbeck, A. C.; Kampf, J. W. J. Am. Chem. Soc. 1993, 115, 2623; (c)
Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org. Chem. 1994, 59, 1238; (d)
Mecozzi, T.; Petrini, M. J. Org. Chem. 1999, 64, 8970; (e) Murry, J. A.; Frantz, D. E.;
Soheili, A.; Tillyer, R.; Grabowski, E. J.; Reider, P. J. Am. Chem. Soc. 2001, 123,
9696; (f) Bernacka, E.; Klepacz, A.; Zwierzak, A. Tetrahedron Lett. 2001, 42, 5093;
(g) Klepacz, A.; Zwierzak, A. Tetrahedron Lett. 2002, 43, 1079.
22. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1981, 29, 1159.
23. (a) Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894; (b)
Takada, K.; Takemura, N.; Cho, K.; Sohtome, Y.; Nagasawa, K. Tetrahedron Lett.
2008, 48, 1623.
16. For direct conversion of N-carbamate protected a-amido sulfones into N-car-
bamate imines, see: (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128,
6048; (b) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006,
128, 2778; (c) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964.
17. For recent reviews on asymmetric PTC, see: (a) Albanese, D. Mini-Rev. Org. Chem.
2006, 3,195; (b) Hashimoto, T.; Maruoka, K. Chem. Rev. 2007,107, 5656; (c) Ooi, T.;
Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222; (d) Maruoka, K. Org. Process Res.
Dev. 2008, 12, 679; (e) Jew, S.; Park, H. Chem. Soc. Rev. 2009, 7090.
24. Nudelman, A.; Marcovici-Mizrahi, D.; Nudelman, A.; Flint, D.; Wittenbach, V.
Tetrahedron 2004, 60, 1731.
25. Makowski, M.; Rzeszotarska, B.; Smelka, L.; Kubica, Z. Liebigs Ann. Chem. 1985,
775.
26. Davies, S. G.; Evans, G. B.; Pearce, S. Tetrahedron 1994, 50, 7521.
_
27. B1azewska, K.; Gajda, T. Tetrahedron: Asymmetry 2002, 13, 671.
28. Kazuo, N.; Shinji, Y.; Takao, A.; Keiichi, I. Synth. Commun. 1990, 20, 2033.
_
_
18. Zon, J. Synthesis 1984, 661.
19. Lejczak, B.; Kafarski, P.; Zygmunt, J. Biochemistry 1989, 28, 3549.
29. (a) B1azewska, K.; Paneth, P.; Gajda, T. J. Org. Chem. 2007, 72, 878; (b) B1azewska,
K. D.; Gajda, T. Tetrahedron: Asymmetry 2009, 20, 1337.
ꢀ
ꢀ
20. Palacios, F.; Alonso, C.; De Los Santos, J. Asymmetric Synthesis of
-Amino Phosphonates and Phosphinates and -Amino Sulfur Analogs In
Enantioselective synthesis of -amino acids; Juaristi, E., Soloshonok, V. A., Eds.;
John Wiley: Hoboken, NJ, 2005; pp 292e294.
a
-Substituted-
30. Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967.
31. For a recent paper on the absolute configuration determination of vicinal-di-
amines using NMR spectroscopy and O-methyl mandelic acid as CDA, see:
Ref. 6b.
b
b
b