Highly diastereoselective addition of nitromethane anion to chiral α-amidoalkylphenyl sulfones. Synthesis of optically active α-amino acid derivatives

Article abstract of DOI:10.1039/b309211a

Optically active syn-α-amidoalkylphenyl sulfones can be prepared from chiral aldehydes in anhydrous conditions using benzenesulfinic acid. These sulfones in basic conditions give N-acylimines that react with sodium methane-nitronate to afford the corresponding nitro adducts with high anti diastereoselectivity. PM3 semiempirical calculations provide a rationale for the observed opposite stereoselectivitity. The obtained nitro derivatives undergo a Nef reaction followed by a methylation giving optically active β-hydroxy-α-amino acid and α,β-diamino acid esters in good yield. These amino acid derivatives are important building blocks for the preparation of biologically active compounds.

Full text of DOI:10.1039/b309211a

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Highly diastereoselective addition of nitromethane anion to chiral
ꢀ-amidoalkylphenyl sulfones. Synthesis of optically active ꢀ-amino
acid derivatives†
Elisabetta Foresti,a Gianni Palmieri,b Marino Petrini*b and Roberto Profetab
a Dipartimento di Chimica “G.Ciamician”, Università di Bologna, via Selmi, 2.
I-40126 Bologna, Italy
b Dipartimento di Scienze Chimiche, Università di Camerino, via S. Agostino, 1.
I-62032 Camerino, Italy. E-mail: marino.petrini@unicam.it; Fax: ϩ39 0737 402297;
Tel: ϩ39 0737 402253
Received 5th August 2003, Accepted 30th September 2003
First published as an Advance Article on the web 23rd October 2003
Optically active syn-α-amidoalkylphenyl sulfones can be prepared from chiral aldehydes in anhydrous conditions
using benzenesulfinic acid. These sulfones in basic conditions give N-acylimines that react with sodium methane-
nitronate to afford the corresponding nitro adducts with high anti diastereoselectivity. PM3 semiempirical
calculations provide a rationale for the observed opposite stereoselectivity. The obtained nitro derivatives undergo
a Nef reaction followed by a methylation giving optically active β-hydroxy-α-amino acid and α,β-diamino acid esters
in good yield. These amino acid derivatives are important building blocks for the preparation of biologically active
compounds.
by reaction of an amide or a carbamate with an appropriate
Introduction
aldehyde and sodium benzenesulfinate in the presence of formic
Imines and related derivatives occupy a central role as reactive
acid.10 Since this reaction is carried out in water as solvent,
substrates for the synthesis of functionalized amines.1 Their
the presence of acid-labile groups in the aldehyde are clearly
importance parallels that of the carbonyl group for the prepar-
incompatible with these conditions. However, we have recently
ation of hydroxy derivatives. Reactivity of imines strongly
depends upon the nature of the substituent directly linked to
the nitrogen atom. Imines bearing N-alkyl or N-aryl groups
demonstrated that α-amidoalkylphenyl sulfones can be pre-
pared in anhydrous conditions using benzenesulfinic acid in
dichloromethane without the need for other acid promoters.11
are easily prepared and stored but their reactivity towards
In this paper we report the synthesis of optically active α-amido-
alkylphenyl sulfones starting from chiral aldehydes and their
utilization for the synthesis of α-amino acid derivatives in
diastereomerically enriched form.
nucleophilic reagents is not particularly prominent.2 This lack
of reactivity dictates the utilization of powerful carbanionic
reagents that often promote enolisation rather than addition
to imino derivatives. Electron withdrawing groups on nitrogen
can suitably enhance the electrophilic character of carbon–
nitrogen double bonds. Sulfonyl,3 sulfinyl,4 as well as other
Results and discussion
N-derivatives5 have been successfully used to promote nucleo-
Optically active sulfones from chiral ꢀ-alkoxy aldehydes
philic additions in mild conditions. N-Acyl and N-carbamoyl
imines, known as amidoalkylating agents,6 are also very
As a first attempt we used (R)-2,3-O-isopropylideneglyceralde-
hyde 3,12 which features the presence of a ketal group, to obtain
active as electrophilic substrates but are too unstable to be
stored when prepared from aliphatic aldehydes since they
readily tautomerize to the corresponding enecarbamate.7
Indeed, N-acylimines 2 are usually generated in situ starting
from N-acyl-α-substituted amines 1 by a base induced elimin-
ation (Scheme 1).8
the corresponding sulfones (R,R)-5 (Scheme 2).
Scheme 2
Scheme 1
These sulfones were produced with high syn diastereo-
selectivity that has been evaluated by X-ray analysis on com-
pound 5a (Fig. 1).13 Following the general reactivity of
derivatives 1, sulfones 5 were expected to react with nucleophilic
reagents in a diastereoselective fashion giving the corresponding
adducts. Aza-Henry reaction of imines with nitronate anions
provides a rapid entry to β-nitro enamines that are amenable
to further synthetic transformations.14 Reaction of sulfones 5
with sodium methanenitronate at room temperature gave the
corresponding nitro derivatives 6 in good yield (Scheme 3).15
Among various derivatives of type 1, α-amidoalkylphenyl
sulfones (1, X = SO2Ph) have recently emerged as profitable
precursors of N-acylimines 2 in various reactions with nucleo-
philic reagents.9 These sulfonyl derivatives are usually prepared
† Electronic supplementary information (ESI) available: Compu-
tational results output for the calculated structures. Transition state
models leading to compounds 21 and 22. See http://www.rsc.org/supp-
data/ob/b3/b309211a/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 7 5 – 4 2 8 1
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semiempirical calculations16 have allowed the preferred con-
formation of reactive intermediates N-acyliminium ion 7 and
N-acylimine 8 to be established. From the structures reported in
Fig. 2 it is possible to observe that the plane of hybridisation of
the iminium group in 7 is rotated about 180Њ with respect to
the same plane of the acylimine 8. The conformation of the
iminium derivative 7 is stabilized by intramolecular electrostatic
interactions between the proton on nitrogen and the oxygen
atoms. These interactions are also apparent in the X-ray
structure of sulfone 5a (Fig. 1).
The analysis of some transition state models for the reaction
of benzenesulfinate anion with N-acyliminium ion intermediate
7 reveals that attack from the Si face requires more energy
(2.90 kcal molϪ1) than the same approach from the Re side thus
favoring the formation of (R,R)-5a (Fig. 3).
Fig. 1 X-Ray crystal structure of 5a.
Scheme 3
The nature of the carbamoyl group affects the diastereo-
selectivity of the process since sulfone 5a, which features the
N-Boc group, is practically converted into a single anti-
diastereomer 6a while sulfone 5b also produces a small amount
of the syn diastereomer. A comparison between the stereo-
chemical attributes of sulfone 5a and nitro compound 6a
immediately reveals that they present an opposite stereo-
chemistry at the newly formed stereocenter. This result is prob-
ably due to the different nature of the reactive intermediate
involved in the formation of these amido derivatives. Sulfone 5a
is prepared in acidic conditions so that an N-acyliminium ion 7
is a likely intermediate for this process. However, nitro com-
pound 6a is formed in basic conditions in which the effective
reactive species is an N-acylimine 8 (Fig. 2). Therefore, it is
evident that protonation of the nitrogen atom, as occurs in
N-acyliminium ion, would bring about a change in the
conformation of the reactive intermediate thus varying the
diastereofacial preference for the nucleophilic attack. PM3
Fig. 3 PM3 minimized structures of the transition states leading to
sulfones 5. (a) (R,R)-5a and (b) (R,S)-5a.
The minimum energy conformation for the N-acylimine
intermediate 8 shows a different arrangement of the nitrogen
atom with respect to the corresponding iminium ion 7. This
conformation closely resembles that established by the Corn-
forth model based on dipole minimization between the ketal
group C–O bond and the imino group.17 Attack of sodium
methanenitronate from the Si face is favored by 3.92 kcal molϪ1
over the addition on the Re face and leads to the formation of
(S,S)-6a (Fig. 4)
Fig. 4 PM3 minimized structures of the transition states leading to
nitro derivatives 6. (a) (S,S)-6a and (b) (S,R)-6a.
The nitro group of compound 6a can be readily converted
into a carboxylic acid by a Nef reaction using alkaline KMnO4
solutions18 giving, after a methylation, β-hydroxy-α-amino acid
esters 9 (Scheme 4).
A comparison between the literature data available for com-
pound 9a allowed us to establish the absolute configuration of
Fig. 2 PM3 lowest energy conformations for (a) N-acyliminium ion 7
and (b) N-acylimine 8.
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Scheme 4
the α-amino stereocenter for esters 9.19 It was conceivable that
other chiral aldehydes structurally related to 3 could be easily
converted into the corresponding sulfones. Aldehyde 10
obtained in a few steps from -tartaric acid20 gave sulfone 11 in
83% as single diastereomer (Scheme 5).
Scheme 6
Scheme 7
derivative 18 in 83% yield as 73 : 27 mixture of inseparable
diastereomers (Scheme 7).
Optically active sulfones from ꢀ-amino aldehydes
Stable α-amino aldehydes24 can be prepared from the corre-
sponding α-amino acids and may represent useful substrates for
the formation of α-amidoalkylphenyl sulfones. Following the
interesting results obtained with chiral aldehyde 3, we decided
to use for preliminary experiments some structurally related
α-amino aldehydes. However, every attempt to convert Garner’s
aldehyde25 19 into the corresponding sulfones using different
carbamates and reaction conditions gave only disappointing
results. Conversely, aldehyde 20 which is readily prepared from
-proline in a few steps26 reacts under the usual conditions giv-
ing sulfone 21 in 81% yield as a sole diastereomer (Scheme 8).
PM3 semiempirical calculations on intermediates 26, 27 show a
minimum energy conformation for the N-acyliminium ion 26
featured by hydrogen bonding between NH and carbonyl group
of benzyl carbamate (Fig. 5).
Scheme 5
The stereochemistry of the additional stereocenter in com-
pound 11 has been inferred assuming that aldehyde 10 has a
close similarity with glyceraldehyde 3. Reaction of sulfone 11
with sodium methanenitronate gives in high yield (85%) and
diastereoselectivity (>95 : 5) nitro compound 12, which is con-
verted into ester 13 by a Nef reaction. Polyoxamic acid ester 13
is a known intermediate in the synthesis of polyoxins, a family
of antibiotics that present a specific activity against human
fungal pathogens.20,21 The anhydrous acidic media in which the
preparation of sulfones 5, 11 takes place is unable to produce an
extensive decomposition of the dioxolanyl group at least in
the reduced time required for the sulfone formation. However,
less stable 2-phenyl-1,3-dioxane-4-carbaldehyde 14 obtained
from -malic acid22 can be converted into the corresponding
sulfone 15 only in very low yield and diastereoselectivity (25%,
dr = 60 : 40) since the dioxane ring is largely cleaved giving
benzaldehyde as expected by-product (Scheme 6).
The subsequent reaction with sodium methanenitronate
occurs with modest yield (55%) but with a better diastereo-
selectivity (dr = 80 : 20) giving nitro derivative 16. The need for
a sterically demanding cyclic structure in close proximity to the
reaction center is witnessed by the results obtained using sul-
fone 17 derived from -O-benzylacetaldehyde that has been
recently prepared by Palomo et al. as a mixture of diastereo-
mers (dr = 65 : 35).23 Reaction of sulfone 17 with the anion of
nitromethane under the usual conditions only showed a modest
diastereofacial selectivity affording the corresponding nitro
A consistent rotation of the imino group is observed for
N-acylimine 27 thus accounting for the different diastereofacial
preference in the reaction with benzenesulfinate and nitro-
methane anions respectively.27
Reaction of 21 with sodium methanenitronate gave the
corresponding nitro derivative 22 as a separable mixture
of diastereomers (9 : 1) with a marked preference for anti-22.
Following the usual Nef reaction, nitro compound 22 has
been converted into α-amino acid ester 23 in 72% yield. This
derivative is a key intermediate for the preparation of piper-
azine-2-carboxylic acids that are useful catalysts in asymmetric
reactions and are also used as chiral building blocks in the
synthesis of HIV protease inhibitors. Removal of the N-Boc
protecting group from 23 affords diamino acid ester 24 that
can be transformed into piperazine 25 by a known procedure.28
Sulfones obtained from linear α-amino aldehydes show a
trend comparable to what is observed for compound 17 in the
reaction with nitromethane anion, since they afford the
corresponding nitro derivative with low diastereoselection.29
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 7 5 – 4 2 8 1
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conceivable that a range of different nucleophilic reagents
can be profitably added to these chiral sulfones with good
diastereoselectivity thus expanding the significance of the
present procedure to the preparation of other useful synthetic
intermediates.
Experimental
1H NMR were recorded at 300 MHz on a Varian VXR300 in
CDCl3 as solvent.13C NMR were recorded at 75 MHz in CDCl3
as solvent. Optical rotations were measured on a Perkin-Elmer
241 polarimeter. Microanalyses were performed with a CHNS-
O analyzer Model EA 1108 from Fisons Instruments. IR
spectra were recorded with a Perkin-Elmer Paragon 500 FT-IR.
GLC analyses were performed on a Hewlett-Packard 5890
equipped with a capillary column of fused silica (0.32 mm ×
25 m), stationary phase SE54. Mass spectra were performed on
a Hewlett-Packard GC/MS 5970 by means of the EI technique
(70 eV). Crystals suitable for X-ray structure determination
were mounted on a Bruker AXS SMART 2000 CCD diffract-
ometer and irradiated with graphite monochromated Mo-Kα
radiation. Tetrahydrofuran was dried by refluxing it over
sodium wire and then distilled. Dichloromethane was dried
by refluxing it over calcium hydride and then distilled. All
chemicals used are commercial.
Scheme 8
Crystal structure determination of compound 5a
Crystal data. C17H25NO6S, M = 371.45, orthorhombic
system, space group P212121, a = 9.9643(4) Å, b = 11.1330(4) Å,
c = 17.3159(7) Å, V = 1920.9(1) Å3, Z = 4, ρcalc = 1.284 Mg mϪ3
,
R = 0.0358 (R2w = 0.0931) for 5339 observed reflections (214
parameters) with I > 2σI. Goodness of fit = 1.086. Flack
0.00(0.04).‡
General procedure for the preparation of phenylsulfonyl
derivatives
Carbamate 4 (6 mmol) was dissolved in dichloromethane
(30 cm3) and then benzenesulfinic acid (7.5 mmol), the
appropriate aldehyde (5 mmol) and anhydrous MgSO4 (0.5 g)
were sequentially added at room temperature. The mixture was
stirred for 2 h (16 h for compound 21) at room temperature and
then filtered over a short pad of Florisil. Removal of the solvent
afforded the crude sulfone which was purified by column
chromatography (7 : 3 hexanes–ethyl acetate).
tert-Butyl N-[(R)-1-[(4S )-2,2-dimethyl-1,3-dioxolan-4-yl]-1-
(phenylsulfonyl)methyl]carbamate 5a. Yield 75%. Mp: 135 ЊC.
[α]20D = Ϫ6.3 (c 0.85, CHCl3). Found C, 55.05; H, 6.74; N, 3.81.
Calc. for C17H25NO6S C, 54.97; H, 6.78; N, 3.77%. νmax (KBr)/
cmϪ1 3450, 1695, 1375, 1145. δH (300 MHz; CDCl3) 1.24 (s, 3H,
rotamer A), 1.26 (s, 3H, rotamer B), 1.32 (s, 3H, rotamer A),
1.40 (s, 9H, rotamer B), 1.44 (s, 9H, rotamer A), 3.74 (dd, 1H,
J = 6.6, 8.4 Hz), 5.05–4.23 (m, 2H), 4.76–5.10 (m, 1H), 5.43 (d,
1H, J = 10.3 Hz, rotamer B), 5.50 (d, 1H, J = 10.3 Hz, rotamer
A), 7.50–7.68 (m, 3H), 7.88–7.93 (m, 2H). δC (75 MHz; CDCl3)
25.1, 25.3, 26.3, 26.6 (CH3 acetal), 27.9, 28.2, 28.5, 29.5 (CH3
t-Bu), 65.7, 67.2 (CH2O), 70.7, 70.9 (CHO), 72.0, 72.1 (CHN),
81.3, 81.4 (C t-Bu), 110.3, 111.1 (OCO), 129.2, 129.3, 129.4,
Fig. 5 PM3 lowest energy conformations for (a) N-acyliminium ion 26
and (b) N-acylimine 27.
Conclusion
In conclusion, chiral cyclic carbaldehydes can be converted into
optically active α-amidoalkylphenyl sulfones generally with
enhanced syn diastereoselectivity. These sulfones react with
sodium methanenitronate giving the corresponding anti nitro
derivatives with high diastereoselectivity. This opposite stereo-
selectivity can be explained accounting for an intermediate
N-acyliminium ion for the formation of α-amidoalkylphenyl
sulfones, and a N-acylimine for the nitro derivative. The
obtained nitro compounds can be transformed into N-carb-
amoyl-α-amino acid esters by an oxidative Nef reaction using
KMnO4 followed by a methylation. By this procedure some
useful intermediates for the synthesis of biologically active
compounds can be prepared. The same synthetic strategy works
less efficiently when sulfones obtained from linear aldehydes are
used in the reaction with nitromethane anion. Preliminary
experiments with other nitro compounds reveal that they react
sluggishly with α-amidoalkylphenyl sulfones giving modest
results in terms of yield and diastereoselectivity. However it is
129.5, 134.2, 134.3, 137.3, 137.8 (C arom.), 154.2, 154.3 (C᎐O).
᎐
Benzyl
N-[(R)-1-[(4S )-2,2-dimethyl-1,3-dioxolan-4-yl]-1-
(phenylsulfonyl)methyl]carbamate 5b. Yield 70%. Mp: 90 ЊC.
[α]20D = ϩ0.6 (c 0.5, CHCl3). Found C, 59.19; H, 5.77; N, 3.41.
Calc. for C20H23NO6S C, 59.24; H, 5.72; N, 3.45%. νmax (KBr)/
cmϪ1 3380, 1695, 1375, 1145. δH (300 MHz; CDCl3) 1.40 (s, 3H),
‡ CCDC reference number 216822. See http://www.rsc.org/suppdata/
ob/b3/b309211a/ for crystallographic data in .cif or other electronic
format.
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1.42 (s, 3H), 3.75 (dd, 1H, J = 6.3, 8.7 Hz), 4.17–4.26 (m, 2H),
4.83–5.02 (m, 3H), 5.68 (d, 1H, J = 10.3 Hz), 7.18–7.70 (m, 8H),
7.85–7.96 (m, 2H). δC (75 MHz; CDCl3) 25.2, 26.3 (CH3 acetal),
67.2 (PhCH2), 67.8 (CH2O), 70.7, 71.4 (CHO), 72.0, 72.4
(CHN), 110.3 (OCO), 128.3, 128.6, 128.8, 129.3, 129.4, 129.5,
(CHNH), 66.4 (OCH), 66.7 (OCH2), 77.9 (CH2NO2), 79.8
(OCMe ), 109.9 (OCO), 155.5 (C᎐O).
᎐
3
Benzyl
N-(1S )-1-[(4S )-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
nitroethylcarbamate 6b. Yield 74%. Mp 77 ЊC. [α]20 = ϩ7.9
D
134.5, 134.7, 136.9 (C arom.), 154.3 (C᎐O).
(c 0.85, CHCl3). Found C, 55.49; H, 6.18; N, 8.60. Calc. for
C15H20N2O6 C, 55.55; H, 6.22; N, 8.64%. νmax (KBr)/cmϪ1 3420,
1700, 1650, 1550. δH (300 MHz; CDCl3) 1.33 (s, 3H), 1.44 (s,
3H), 3.90 (dd, 1H, J = 4.0, 8.8 Hz), 4.06–4.48 (m, 3H), 4.62 (dd,
1H, J = 3.3, 13.9 Hz), 4.76 (dd, 1H, J = 5.9, 13.8 Hz), 5.12 (s,
2H), 5.40 (d, 1H, J = 10.4 Hz), 7.31–7.43 (m, 5H). δC (75 MHz;
CDCl3) 25.0, 26.8 (CH3 acetal), 52.6 (CHNH), 67.3 (PhCH2),
67.7 (OCH2CH), 74.9 (OCH), 75.3 (CH2NO2), 110.7, 128.4,
᎐
tert-Butyl N-[(R)-1-[(4R,5R)-5-([1-(tert-butyl)-1,1-diphenyl-
silyl]oxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(phenyl-
sulfonyl)methyl]carbamate 11. Yield 83%. Waxy solid. [α]20
=
D
Ϫ20.8 (c 1.3, CHCl3). Found C, 63.90; H, 7.04; N, 2.22. Calc.
for C34H45NO7SSi C, 63.82; H, 7.09; N, 2.19%. νmax (film)/cmϪ1
3400, 1695, 1375, 1145. δH (300 MHz; CDCl3) 1.06 (s, 9H,
rotamer A), 1.08 (s, 9H, rotamer B), 1.23 (s, 6H, rotamer A),
1.25 (s, 6H, rotamer B), 1.44 (s, 9H), 3.71–3.90 (m, 3H), 5.01–
5.15 (m, 2H), 5.65 (d, 1H, J = 10.3), 7.38–7.56 (m, 7H), 7.60–
7.76 (m, 6H), 7.86–7.95 (m, 2H). δC (75 MHz; CDCl3) 19.4
(SiCMe3), 26.9, 27.1 (CH3 acetal), 27.2 (CH3 t-BuSi), 28.2
(CH3 t-BuO), 64.0 (CH2OSi), 70.4 (CHN), 74.2 (OCHCH2),
77.7 (OCHCH), 81.1 (OCMe3), 111.3 (OCO), 128.0, 128.1,
128.6, 128.8, 128.9 (C arom.), 154.3 (C᎐O).
᎐
tert-Butyl
N-(1S )-1-[(4S,5R)-5-([1-(tert-butyl)-1,1-di-
phenylsilyl]oxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-nitro-
ethylcarbamate 12. Yield 85%. Oil. [α]20 = Ϫ3.4 (c 1, CHCl3).
D
Found C, 62.40; H, 7.55; N, 4.97. Calc. for C29H42N2O7Si C,
62.34; H, 7.58; N, 5.01%. νmax (film)/cmϪ1 3420, 1700, 1650,
1550. δH (300 MHz; CDCl3) 1.08 (s, 9H), 1.36 (s, 3H), 1.40 (s,
3H), 1.43 (s, 9H), 3.73 (dd, 1H, J = 3.7, 11.0 Hz), 3.83 (dd, 1H,
J = 4.4, 11.0 Hz), 4.11–4.30 (m, 3H), 4.65–4.69 (m, 2H), 4.90
(d, 1H, J = 8.6 Hz), 7.35–7.50 (m, 6H), 7.68–7.78 (m, 4H).
δC (75 MHz; CDCl3) 19.4 (SiCMe3), 27.1, 27.4 (CH3 acetal),
27.6 (CH3 t-BuSi), 28.4 (CH3 t-BuO), 52.2 (CHNH), 64.1
(CH2OSi), 75.9 (CH2NO2), 76.0 (OCHCH2), 77.7 (OCHCH),
80.3 (Me3CO), 110.5 (OCO), 125.5, 128.0, 128.1, 129.3, 130.1,
129.0, 129.2, 129.5, 130.1, 134.2, 135.9 (C arom.), 154.2 (C᎐O).
᎐
tert-Butyl
N-[(2-phenyl-1,3-dioxan-4-yl)(phenylsulfonyl)-
methyl]carbamate 15. Yield 25%. Mp: 76 ЊC. Found C, 60.91;
H, 6.31; N, 3.20. Calc. for C22H27NO6S C, 60.95; H, 6.28; N,
3.23%. νmax (KBr)/cmϪ1 3450, 1695, 1375, 1145. δH (300 MHz;
CDCl3) (diastereomer A) 1.44 (s, 9H), 1.90–2.21 (m, 2H), 3.95–
4.15 (m, 2H), 4.98–5.10 (m, 1H), 5.50–5.58 (m, 1H), 5.74–5.83
(m, 1H), 6.08–6.17 (m, 1H), 7.30–7.70 (m, 8H), 7.86–7.95 (m,
2H). (diastereomer B) 1.46 (s, 9H), 1.90–2.21 (m, 2H), 4.25–
4.40 (m, 2H), 4.75–4.88 (m, 1H), 5.61–5.70 (m, 1H), 5.85–5.99
(m, 1H), 6.08–6.17 (m, 1H), 7.30–7.70 (m, 8H), 7.86–7.95 (m,
2H).
130.2, 135.8, 135.9 (C arom.), 154.1 (C᎐O).
᎐
tert-Butyl
N-[2-nitro-1-(2-phenyl-1,3-dioxan-4-yl)ethyl]-
carbamate 16. Yield 55%. Mp: 88 ЊC. [α]20 = Ϫ44.5 (c 2.1,
D
CHCl3). Found C, 57.99; H, 6.81; N, 7.97. Calc. for C17H24N2O6
C, 57.94; H, 6.86; N, 7.95%. νmax (KBr)/cmϪ1 3420, 1700, 1650,
1550. δH (300 MHz; CDCl3) (major diastereomer) 1.45 (s, 9H),
1.68–2.00 (m, 2H), 3.95 (dt, 1H, J = 3.0, 11.7 Hz), 4.01–4.17 (m,
1H), 4.21–4.40 (m, 2H), 4.63 (dd, 1H, J = 3.7, 13.5 Hz), 4.84
(dd, 1H, J = 6.6, 13.5 Hz), 5.22 (d, 1H, J = 10.4 Hz), 5.47
(s, 1H), 7.35–7.48 (m, 5H). δC (75 MHz; CDCl3) (major
diastereomer) 28.4 (CH3 t-Bu), 39.6 (CH2CH2CH), 52.9
(CHNH), 66.9 (OCH2), 74.9 (CH2NO2), 76.4 (CH2CH2CH),
80.8 (Me3CO), 101.5 (OCHO), 126.2, 128.5, 129.3, 138.0
Benzyl
(2S )-2-[(R)-1-[(tert-butoxycarbonyl)amino]-1-
(phenylsulfonyl)methyl]tetrahydro-1H-1-pyrrolecarboxylate 21.
Yield 81%. Mp: 112 ЊC. [α]20D = Ϫ50.1 (c 0.85, CHCl3). Found
C, 60.79; H, 6.40; N, 5.86. Calc. for C24H30N2O6S C, 60.74; H,
6.37; N, 5.90%. νmax (KBr)/cmϪ1 3320, 1695, 1375, 1145. δH (300
MHz; CDCl3) 1.14 (s, 9H), 1.80–2.25 (m, 2H), 2.38–2.60
(m, 1H), 3.30–3.55 (m, 2H), 4.58–4.80 (m, 2H), 5.05–5.22
(m, 3H), 6.21 (d, 1H, J = 9.2 Hz), 7.30–7.70 (m, 8H), 7.78–7.98
(m, 2H). δC (75 MHz; CDCl3) 23.6 (CH2CH2N), 28.1 (CH3
t-Bu), 29.9 (CH2CHN), 46.5 (CH2N), 55.6 (CHN), 67.5
(ArCH2), 74.0 (CHNH), 80.5 (OCMe3), 128.0, 128.3, 128.7,
(C arom.), 155.3 (C᎐O).
᎐
Benzyl N-[2-(benzyloxy)-1-(nitromethyl)propyl]carbamate 18.
Yield 83%. Oil. Found C, 63.55; H, 6.48; N, 7.76. Calc. for
C19H23N2O5 C, 63.50; H, 6.45; N, 7.79%. νmax (film)/cmϪ1 3420,
1700, 1652, 1553. δH (300 MHz; CDCl3) 1.26 (d, 3H, J = 6.2 Hz,
minor diast.), 1.29 (d, 3H, J = 6.2 Hz, major diast.), 3.70–
3.80 (m, 1H), 4.22–4.40 (m, 2H), 4.56–4.74 (m, 3H), 5.04–5.16
(m, 2H), 5.38 (d, 1H, J = 9.5 Hz, minor diast.), 5.57 (d, 1H,
J = 9.4 Hz, major diast.), 7.28–7.40 (m, 10H). δC (75 MHz;
CDCl3) (major diastereomer) 16.6 (CH3), 54.5 (CHNH),
128.9, 129.7, 134.0, 136.6, 137.5 (C arom.), 154.6 (NHC᎐O),
᎐
157.1 (NC᎐O).
᎐
General procedure for the preparation of nitro derivatives
To a stirred suspension of NaH (25 mmol) in dry THF
(15 cm3), nitromethane (25 mmol) was added dropwise at room
temperature. After stirring for 30 min, the appropriate sulfone
(5 mmol) dissolved in dry THF (8 cm3) was added and the white
suspension was stirred at room temperature for 30 min. The
reaction was quenched by addition of satd NH4Cl (8 cm3),
extracted with CHCl3 (4 × 15 cm3) and then dried over MgSO4.
The crude nitro derivative obtained after removal of the solvent
was purified by column chromatography (7 : 3 hexanes–ethyl
acetate).
67.4 (CH OC᎐O), 71.3 (CH CH), 74.8 (CH OCH), 75.2
᎐
2
3
2
(CH2NO2), 128.1, 128.2, 128.3, 128.5, 128.8, 136.4, 137.8
(C arom.), 156.0 (C᎐O).
᎐
Benzyl (2S )-2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-nitro-
ethyl]tetrahydro-1H-1-pyrrolecarboxylate 22. Yield 78%. Oil.
[α]20D = Ϫ30.1 (c 0.45, CHCl3). Found C, 58.06; H, 6.88; N, 6.96.
Calc. for C19H27N3O6 C, 58.00; H, 6.92; N, 7.00%. νmax (film)/
cmϪ1 3420, 1700, 1650, 1550. δH (300 MHz; CDCl3) 1.43 (s, 9H,
rotamer A), 1.45 (s, 9H, rotamer B), 1.80–2.22 (m, 4H), 3.31–
3.63 (m, 2H), 4.01–4.17 (m, 1H), 4.21–4.40 (m, 1H), 4.42–4.70
(m, 2H), 5.14 (s, 2H), 5.35–5.50 (m, 1H, rotamer A), 5.60–5.75
(m, 1H, rotamer B), 7.30–7.45 (m, 5H). δC (75 MHz; CDCl3)
27.1 (CH2CH2N), 28.4 (CH3 t-Bu), 47.5 (CH2N), 54.3
(CHNH), 58.7 (PhCH2O), 67.7 (CHN), 79.7 (CH2NO2), 81.8
tert-Butyl N-(1S )-1-[(4S )-2,2-dimethyl-1,3-dioxolan-4-yl]-2-
nitroethylcarbamate 6a. Yield 75%. Oil. [α]20 = Ϫ13.5 (c 1,
D
CHCl3). Found C, 49.59; H, 7.68; N, 9.70. Calc. for C12H22N2O6
C, 49.65; H, 7.64; N, 9.65%. νmax (film)/cmϪ1 3420, 1700, 1650,
1550. δH (300 MHz; CDCl3) 1.33 (s, 3H), 1.44 (s, 12H), 3.91 (dd,
1H, J = 4.4, 8.8 Hz), 4.10 (dd, 1H, J = 6.2, 8.8 Hz), 4.02–4.18
(m, 1H), 4.20–4.35 (m, 1H), 4.60 (dd, 1H, J = 3.3, 13.6 Hz), 4.74
(dd, 1H, J = 5.5, 13.6 Hz), 5.06 (d, 1H, J = 9.2 Hz). δC (75 MHz;
CDCl3) 25.3, 26.7 (CH3 acetal), 28.4 (CH3 t-Bu), 63.8
(Me C), 128.1, 128.4, 128.8, 136.5 (C arom.), 155.4 (NHC᎐O),
᎐
3
156.3 (NC᎐O).
᎐
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 7 5 – 4 2 8 1
4279

View Article Online
General procedure for the preparation of amino acid esters
(0.31 g, 0.8 mmol) was dissolved in THF (8 cm3) and 37% HCl
(4 cm3) was then added at room temperature. The mixture was
stirred for 30 min at room temperature, cooled by ice bath and
made alkaline by addition of NaOH pellets. The solution was
then extracted with ethyl acetate (4 × 10 cm3) and dried over
Na2SO4. After evaporation of the solvent at reduced pressure
the crude product was purified by column chromatography
(98 : 2 ethyl acetate–methanol) giving 0.2 g (88%) of pure
Nitro derivative (1 mmol) dissolved in tBuOH (8 cm3) was
treated with aqueous buffered KOH (0.5 M in KOH and 1.25 M
in K2HPO4, 6 cm3) at room temperature. The mixture was
stirred for 5 min and then aqueous KMnO4 (0.5 M, 2 cm3,
4 mmol) was added dropwise maintaining the temperature
below 25 ЊC by occasional cooling. After stirring at room tem-
perature for 1 h the mixture was cooled by ice bath and then
satd Na2SO3 (10 cm3) was added. The mixture was then acid-
ified with 2 M HCl until pH ∼ 5 and then extracted with ethyl
acetate (4 × 15 mL). The organic solution was dried over
MgSO4 and after evaporation of the solvent the crude acid was
obtained. The acid was dissolved in dry DMF (5 cm3) and
K2CO3 (3 mmol) and MeI (2 mmol) were sequentially added.
The mixture was stirred for 30 min and then was poured into
cold water (20 cm3). The solution was extracted with CHCl3
(4 × 15 cm3) and the organic phase was dried over MgSO4.
Evaporation of the solvent gave crude amino acid ester, which
was purified by column chromatography (6 : 4 hexanes–ethyl
acetate).
amino ester 24 as a clear oil. [α]20 = Ϫ20.7 (c 6, EtOH) [lit.28
D
[α]20 = Ϫ19.6 (c 1.03, CHCl3)]. Spectroscopic data are in
D
agreement with those reported in literature.
Acknowledgements
Financial support from University of Camerino and MIUR
(National Project “Sintesi e Reattività-attività di Sistemi
Insaturi Funzionalizzati”) is gratefully acknowledged. R.P.
thanks C.I.N.M.P.I.S (Bari) for a postgraduate fellowship.
References and notes
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2 (a) S. J. Patel and T. F. Jamison, Angew. Chem., Int. Ed., 2003, 42,
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1861; (e) S. Arrasate, E. Lete and N. Sotomayor, Tetrahedron:
Asymmetry, 2002, 13, 311–316.
3 (a) S. M. Weinreb, Top. Curr. Chem., 1997, 190, 131–184; (b) C.-S.
Ge, Y.-J. Chen and D. Wang, Synlett, 2002, 37–42; (c) X.-L. Hou,
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2002, 1487–1490; (d ) K. Y. Lee, C. G. Lee and J. N. Kim,
Tetrahedron Lett., 2003, 44, 1231–1234; (e) X. F. Zhu, J. Lan and
O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716–4717.
Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-2-[(4S )-2,2-di-
methyl-1,3-dioxolan-4-yl]ethanoate 9a. Yield 71%. Oil. [α]20
=
D
Ϫ37.3 (c 2, CHCl3) [lit.19 [α]20 = Ϫ33.5 (c 1.6, CHCl3)].
D
Spectroscopic data are in agreement with those reported in
literature.
Methyl (2R)-2-[(benzyloxy)carbonyl]amino-2-[(4S )-2,2-di-
methyl-1,3-dioxolan-4-yl]ethanoate 9b. Yield 60%. Oil. [α]20
=
D
Ϫ25.3 (c 1.2, CHCl3). Found C, 59.50; H, 6.61; N, 4.28. Calc.
for C16H21NO6 C, 59.43; H, 6.55; N, 4.33%. νmax (film)/cmϪ1
3420, 1735. δH (300 MHz; CDCl3) 1.32 (s, 3H), 1.38 (s, 3H), 3.77
(s, 3H), 4.03–4.16 (m, 2H), 4.37 (q, 1H, J = 4.4 Hz), 4.48 (dd,
1H, J = 4.4, 8.4 Hz), 5.12 (s, 2H), 5.58 (d, 1H, J = 8.4 Hz), 7.30–
7.38 (m, 5H). δC (75 MHz; CDCl3) 24.9, 26.4 (CH3 acetal), 52.7
(CH3O), 56.4 (CHNH), 65.9 (PhCH2), 67.4 (CH2OC), 76.4
(CHOC), 110.4 (OCO), 128.3, 128.4, 128.7, 136.2 (C arom.),
4 (a) J. A. Ellman, T. D. Owens and T. P. Tang, Acc. Chem. Res., 2002,
35, 984–995; (b) Z. Han, D. Krishnamurthy, P. Grover, Q. K. Fang,
D. A. Pflum and C. H. Senanayake, Tetrahedron Lett., 2003, 44,
4195–4197; (c) A. Viso, R. Fernández de la Pradilla, M. L. López-
Rodríguez, A. García and M. Tortosa, Synlett, 2002, 755–758;
(d ) P. Wipf, R. L. Nunes and S. Ribe, Helv. Chim. Acta, 2002, 85,
3478–3488; (e) Z. Han, D. Krishnamurthy, P. Grover, Q. K. Fang
and C. H. Senanayake, J. Am. Chem. Soc., 2002, 124, 7880–7881;
( f ) F. A. Davis, B. Chao and A. Rao, Org. Lett., 2001, 3, 3169–
3171.
5 Phosphinoylimines: (a) S. Matsunaga, N. Kumagai, S. Harada and
M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 4712–4713; (b) A. A.
Boezio and A. B. Charette, J. Am. Chem. Soc., 2003, 125, 1692–1693;
Nitrones: (c) M. Lombardo and C. Trombini, Synthesis, 2000, 759–
774; (d ) P. Merino, S. Franco, S. L. Merchan and T. Tejero, Synlett,
2000, 442–454.
156.0 (NHC᎐O), 170.3 (CO Me).
᎐
2
Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-2-[(4S,5R)-5-
([1-(tert-butyl)-1,1-diphenylsilyl]oxymethyl)-2,2-dimethyl-1,3-
dioxolan-4-yl]ethanoate 13. Yield 90%. Mp 87 ЊC. [α]20D = Ϫ25.2
(c 3, CHCl3). [lit.20: oil, [α]27D = Ϫ26.2 (c 1.02, CHCl3)]. Found
C, 64.68; H, 7.82; N, 2.48. Calc. for C30H47NO7Si C, 64.60; H,
7.77; N, 2.51%. νmax (KBr)/cmϪ1 3420, 1735. δH (300 MHz;
CDCl3) 1.06 (s, 9H), 1.36 (s, 3H), 1.38 (s, 3H), 1.42 (s, 9H), 3.73
(s, 3H), 3.67–3.82 (m, 2H), 4.20–4.30 (m, 2H), 4.45–4.50 (m,
1H), 5.27 (d, 1H, J = 10.4 Hz), 7.35–7.44 (m, 6H), 7.64–7.77 (m,
4H). δC (75 MHz; CDCl3) 19.4 (Me3CSi), 27.0 (CH3 t-BuSi),
27.3, 27.5 (CH3 acetal), 28.5 (CH3 t-BuO), 52.6 (CH3O), 55.7
(CHNH), 63.8 (CH2O), 78.5 (OCHCH), 78.6 (OCHCH2), 80.4
(Me3CO), 110.2 (OCO), 128.0, 129.9, 133.2, 135.1, 135.9
6 H. A. Zaugg, Synthesis, 1984, 85–110 and 181–212.
7 T. Mecozzi and M. Petrini, Synlett, 2000, 73–74.
8 N-Carbamoylimines can be also prepared by acylation of the
corresponding N-silylimines obtained from aromatic aldehydes:
(a) R. Kupfer, S. Meier and E.-U. Würthwein, Synthesis, 1984, 688–
690; (b) J. Vidal, S. Damestoy, L. Guy, J.-C. Hannachi, A. Aubry and
A. Collet, Chem. Eur. J., 1997, 3, 1691–1709; (c) B. M. Trost and
C. Jonasson, Angew. Chem., Int. Ed., 2003, 42, 2063–2066.
9 (a) M. Petrini, R. Profeta and P. Righi, J. Org. Chem., 2002, 67,
4530–4535; (b) S. Dahmen and S. Bräse, J. Am. Chem. Soc., 2002,
124, 5940–5941; (c) N. Hermanns, S. Dahmen, C. Bolm and S. Bräse,
Angew. Chem., Int. Ed., 2002, 41, 3692–3694; (d ) C. Palomo,
M. Oiarbide, A. Landa, M. C. González-Rego, J. M. García,
A. González, J. M. Odriozola, M. Martin-Pastor and A. Linden,
J. Am. Chem. Soc., 2002, 124, 8637–8643; (e) J. Zhang, C. Wei and
C.-J. Li, Tetrahedron Lett., 2002, 43, 5731–5733; ( f ) D. Enders
and S. Oberbörsch, Synlett, 2002, 471–473; (g) A. Klepacz and
A. Zwierzak, Tetrahedron Lett., 2002, 43, 1079–1080.
(C arom.), 155.3 (NHC᎐O), 170.7 (CO Me).
᎐
2
Benzyl (2S )-2-[(1R)-1-[(tert-butoxycarbonyl)amino]-2-meth-
oxy-2-oxoethyl]tetrahydro-1H-1-pyrrolecarboxylate 23. Yield
72%. Oil. [α]20 = Ϫ34.8 (c 2.5, CHCl3). Found C, 61.15; H,
D
7.14; N, 7.09. Calc. for C20H28N2O6 C, 61.21; H, 7.19; N,
7.14%. νmax (film)/cmϪ1 3420, 1735. δH (300 MHz; CDCl3) 1.43
(s, 9H), 1.80–2.05 (m, 4H), 3.30–3.68 (m, 2H), 3.76 (s, 3H),
4.25–4.37 (m, 2H), 5.13 (s, 2H), 5.65–5.75 (m, 1H), 7.30–7.43
(m, 5H). δC (75 MHz; CDCl3) 23.9 (CH2CH2N), 28.5 (CH3
t-Bu), 29.2 (CH2CHN), 47.4 (CH3O), 52.6 (CH2N), 57.7
(CHNH), 59.2 (PhCH2), 67.4 (CHN), 80.1 (Me3C), 128.1,
128.3, 128.7, 136.9 (C arom.), 165.2, 166.8 (C᎐O carb.), 171.9
(CO2Me).
᎐
10 (a) T. Mecozzi and M. Petrini, J. Org. Chem., 1999, 64, 8970–8972;
(b) A. M. Kanazawa, J.-N. Denis and A. E. Greene, J. Org. Chem.,
1994, 59, 1238–1240; (c) W. H. Pearson, A. C. Lindbeck and J. W.
Kampf, J. Am. Chem. Soc., 1993, 115, 2622–2636.
Benzyl
(2S )-2-[(1R)-1-amino-2-methoxy-2-oxoethyl]tetra-
hydro-1H-1-pyrrolecarboxylate 24. N-Boc amino ester 23
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 7 5 – 4 2 8 1
4280

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11 (a) E. Marcantoni, T. Mecozzi and M. Petrini, J. Org. Chem., 2002,
67, 2989–2994; (b) T. Mecozzi, M. Petrini and R. Profeta,
Tetrahedron: Asymmetry, 2003, 14, 1171–1178; (c) M. Mataloni,
M. Petrini and R. Profeta, Synlett, 2003, 1129–1132.
20 K. Uchida, K. Kato and H. Akita, Synthesis, 1999, 1678–1686.
21 A. K. Saksena, R. G. Lovey, V. M. Girijavallabhan and A. K.
Ganguly, J. Org. Chem., 1986, 51, 5024–5028.
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Asymmetry, 1996, 7, 3209–3246.
12 Y.-L. Zhong and T. K. M. Shing, J. Org. Chem., 1997, 62, 2622–
2624.
13 Siemens SHELXTLplus Version 5.1 (Windows NT version)
Structure Determination Package, Siemens Analytical X-Ray
Instruments Inc.,Madison, W1, 1988.
14 (a) B. Westermann, Angew. Chem., Int. Ed., 2003, 42, 151–153;
(b) J. C. Anderson, S. Peace and S. Pih, Synlett, 2000, 850–852;
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J. Org. Chem., 1998, 63, 9932–9934.
15 R. Ballini and M. Petrini, Tetrahedron Lett., 1999, 40, 4449–4452.
16 Semiempirical PM3 calculations were performed with the Spartan
ES 1.0.2, Wavefunction Inc., 18401 Von Karmen Ave., #370, Irvine,
CA 92715.
17 (a) J. W. Cornforth, M. R. H. Cornforth and K. K. Mathew,
J. Chem. Soc., 1959, 112–127; (b) M. N. Paddon-Row, N. G. Rondan
and K. N. Houk, J. Am. Chem. Soc., 1982, 104, 7162–7166; (c) B. W.
Gung and X. Xue, Tetrahedron: Asymmetry, 2001, 12, 2955–2959;
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2003, 42, 1761–1765.
23 C. Palomo, M. Oiarbide, M. C. González-Rego, A. K. Sharma,
J. M. García, A. González, C. Landa and A. Linden, Angew. Chem.,
Int. Ed., 2000, 39, 1063–1065 . α-Amido sulfone 17 reacts at Ϫ78 ЊC
with the lithium enolate of methyl acetate with very poor
diastereoselectivity, but reacts with a camphor derived lithium
enolate giving the corresponding adduct with enhanced anti
selectivity.
24 M. Reetz, Chem. Rev., 1999, 99, 1121–1162.
25 X. Liang, J. Andersch and M. Bols, J. Chem. Soc., Perkin Trans. 1,
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26 D. E. Thurston, D. S. Bose, A. S. Thompson, P. W. Howard,
A. Leoni, S. J. Croker, T. C. Jenkins, S. Neidle, J. A. Hartley and
L. H. Hurley, J. Org. Chem., 1996, 61, 8141–8147.
27 See electronic supporting information for transition state models
leading to compounds 21 and 22†.
28 S. Hanessian and R. Sharma, Heterocycles, 2000, 52, 1231–
1239.
18 (a) H. W. Pinnick, Org. React., 1990, 38, 655–792; (b) E. A. Saville-
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Asymmetry, 1997, 8, 3489–3496.
29 As an example, the α-amidoalkylphenyl sulfone obtained from
(S)-N-Boc-2-amino-3-phenylpropanal and benzyl carbamate as a
65 : 35 mixture of diastereomers, gives the corresponding nitro
derivative in low yield with a similar diastereomeric ratio (60 : 40).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 2 7 5 – 4 2 8 1
4281