Efficient synthesis of (2R,3S)- and (2S,3S)-2-amino-1,3,4-butanetriols through stereodivergent hydroxymethylation of D-glyceraldehyde nitrones

Article abstract of DOI:10.1016/S0040-4039(01)02191-8

The nucleophilic addition of two alkoxymethyllithium derivatives to three D-glyceraldehyde derived nitrones has been investigated. The diastereofacial selectivity of the reaction could be controlled by the appropriate use of Lewis acids as precomplexing a

Full text of DOI:10.1016/S0040-4039(01)02191-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 459–462
Efficient synthesis of (2R,3S)- and
(2S,3S)-2-amino-1,3,4-butanetriols through stereodivergent
hydroxymethylation of
D-glyceraldehyde nitrones
Pedro Merino,* Santiago Franco, Francisco L. Merchan, Julia Revuelta and Tomas Tejero
Departamento de Quimica Organica, Facultad de Ciencias-ICMA, Universidad de Zaragoza, E-50009 Zaragoza, Aragon, Spain
Received 16 November 2001; accepted 19 November 2001
Abstract—The nucleophilic addition of two alkoxymethyllithium derivatives to three
D-glyceraldehyde derived nitrones has been
investigated. The diastereofacial selectivity of the reaction could be controlled by the appropriate use of Lewis acids as
precomplexing agents of the nitrones. The obtained syn and anti adducts were further converted into C-4 building blocks and
b-hydroxy-a-aminoacids. © 2002 Elsevier Science Ltd. All rights reserved.
oxy)methyllithium 3b, easily available from the corre-
Optically active 2-amino-1,3,4-butanetriols (ABTs) 1
find application as C-4 building blocks for the synthesis
of a variety of biologically interesting compounds, as
Inaba and co-workers have recently pointed out.1 Sev-
eral studies have been aimed at preparing differentially
protected ABTs in chiral non-racemic forms.1,2 How-
ever, to the best of our knowledge, no approaches have
addressed the stereodivergent synthesis of syn and anti
compounds.
sponding alkoxymethyl tributylstannanes.4
Nitrones 2 were prepared by condensation of the corre-
sponding protected
D-glyceraldehyde with N-benzylhy-
droxylamine, following our previously described
procedure for nitrone 2a.5 This nitrone was chosen as
the reference substrate for our investigation. The fol-
lowing standard reaction conditions were employed to
screen the efficiency of the Lewis acids as stereocon-
trolling agents: in situ formation of an excess (2.5
equiv.) of the alkoxymethyllithium derivative at low
temperature (−80°C), following the reported proce-
dures,4 and addition of a THF solution of nitrone (1.0
equiv.), in the presence or absence of additives. The
reaction mixture was maintained at −80°C for 15 min
and then stopped by adding saturated aqueous ammo-
nium chloride. After extractive work-up the hydroxyl-
amines 4–9 (Scheme 2) were obtained. The results from
these experiments are given in Table 1.
Recent work from our laboratory has demonstrated the
utility of Lewis acid controlled nucleophilic addition to
nitrones for the stereocontrolled formation of nitro-
genated compounds.3 In continuation of these studies,
we envisaged that addition of a hydroxymethylanion to
D
-glyceraldehyde derived nitrones 2 will provide a
direct route to compounds 1 (Scheme 1). As suitable
synthetic equivalents of the hydroxymethylanion we
chose (methoxymethoxy)methyllithium 3a and (benzyl-
OH
OR1
O
N
HO
R1O
OH
Bn
HO
*
NH2
OH
2
NH2
LiCH2OR2
CH2OH
1
3
Scheme 1.
* Corresponding author. E-mail: pmerino@posta.unizar.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02191-8

460
P. Merino et al. / Tetrahedron Letters 43 (2002) 459–462
see
Table 1
OR1
OR1
N
OR1
O
N
R1O
R1O
R1O
LiCH2OR2
OR2
OH
OR2
OH
Bn
N
3a R2=MOM
3b R2= Bn
2a-c
Bn
Bn
4a-9a
4b-9b
OBn O
O
O
O
O
N
;
;
2:
O
O
BnO
N
N
Bn
Bn
Bn
2a
2b
2c
Scheme 2.
Table 1. Diastereoselective addition of a-alkoxymethyllithium derivatives 3 to nitrones 2a
Entry
Nitrone
a-Alkoxy methyllithium
Additiveb
Hydroxylaminec
Syn:antid
Yield %e
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2c
2c
3a
3a
3a
3a
3b
3b
3b
3b
3a
3a
3b
3b
3a
3a
3b
3b
None
TMSOTf
ZnBr2
Et2AlCl
None
TMSOTf
ZnBr2
Et2AlCl
None
Et2AlCl
None
Et2AlCl
None
Et2AlCl
None
4
4
4
4
5
5
5
5
6
6
7
7
8
8
9
9
90:10
88:12
80:20
5:95
86:14
88:11
80:20
5:95
90:10
30:70
85:15
32:68
58:42
45:55
60:40
45:55
72
58
77
80
70
61
75
81
64
73
66
70
64
72
65
70
9
10
11
12
13
14
15
16
Et2AlCl
a All reactions were carried out at −80°C using an excess (2.5 equiv.) of 3.
b The nitrone was previously treated with the additive (1.0 equiv.) at ambient temperature for 5 min.
c a and b series refer to syn and anti compounds, respectively.
d Determined by NMR analysis of the crude reaction mixture.
e Isolated yields of diastereomeric mixtures after radial-centrifugally accelerated chromatography.
and 5, respectively, by transketalization.7 The experi-
mental findings listed in Table 1 are in good agreement
with previous data reported by us5 and by others,8
which showed that a reversal of stereoselectivity
occurred when Et2AlCl was used as a precomplexing
Addition of a-alkoxymethyllithium 3a to nitrone 2a
resulted in an acceptable degree of syn selectivity (entry
1) which was slightly decreased when the nitrone was
previously treated with either TMSOTf (entry 2) or
ZnBr2 (entry 3). A complete reversal of diastereoselec-
tivity was achieved precomplexing the nitrone with
Et2AlCl (entry 4). The same behavior was observed for
the organolithium 3b (entries 5–8), thus revealing that
the sense of the diastereofacial selectivity is strictly
dependent on the nature of the precomplexing agent
(and on its presence). In fact, similar results were
obtained with nitrone 2b (entries 9–12), although a
remarkable decrease of the anti isomer was observed in
the reaction carried out in the presence of Et2AlCl. In
agent in nucleophilic additions to
nitrones.
D-glyceraldehyde
With respect to their synthetic utility, syn and anti
hydroxylamines 4 and 5 may be considered immediate
precursors of syn and anti ABTs 1. Catalytic hydro-
genation, in the presence of Boc2O, of 4a,b and 5a,b
gave the orthogonally protected ABTs 10a,b and 11a,b,
respectively (Scheme 3).9
contrast,
nitrone
2c
displayed
unsatisfactory
diastereoselectivities (entries 13–16). The relative
configuration assignement of the obtained hydroxyl-
amines was carried out with pure compounds,6 with
the only exception of hydroxylamines 8 and 9, which
were not separated, due to the poor selectivity
observed. Thus, configuration of hydroxylamines 4 and
5 was established by chemical correlation as discussed
below. Hydroxylamines 6 and 7 were converted into 4
In order to prove the configuration of the hydroxyl-
amines and to illustrate further useful transformations,
compounds 11 were debenzylated and in situ oxidized
with ruthenium(IV) oxide to afford, after esterification,
methyl esters 12 which had been previously prepared.10
The overall yields for compounds 12a and 12b, from
the nitrone 2a, were 39.5 and 41%, respectively. The
stereochemistry of compounds 10 was confirmed by the

P. Merino et al. / Tetrahedron Letters 43 (2002) 459–462
461
O
O
O
ii
i
O
O
O
CO2Me
NHBoc
12a
OR
OR
NHBoc
(for R=Bn)
70%
90-94%
N(OH)Bn
Cl
OH
OH
4a R = MOM
R = Bn
10a R = MOM
R = Bn
11a
HO
5a
NH3
13
O
O
O
ii
i
O
O
O
CO2Me
OR
N(OH)Bn
OR
NHBoc
(for R=Bn)
72%
88/95%
NHBoc
4b R = MOM
R = Bn
10b R = MOM
R = Bn
11b
12b
5b
Scheme 3. Reagents and conditions: (i) H2, Pd(OH)2-C, MeOH, Boc2O, rt, 1500 psi, 24 h; (ii) (1) Na, NH3(l); (2) RuO2, NaIO4,
CH3CN:CCl4:H2O, then CH2N2, Et2O.
complete deprotection (10% HCl–MeOH, 10°C, 6 h) of
10b into the hydrochloride 13. This compound showed
the same physical and spectroscopic properties (except
for the sign of the optical rotation) that those described
for its enantiomer,11 thus also confirming the assigned
stereochemistry to hydroxylamines 4.
4. R2=MOM: (a) Danheiser, R. L.; Romines, K. R.;
Koyama, H.; Gee, S. K.; Johnson, C. R.; Medich, J. R.
Org. Synth. 1992, 71, 133–139; (b) Johnson, C. R.;
Medich, J. R.; Danheiser, R. L.; Romines, K. R.;
Koyama, H.; Gee, S. K. Org. Synth. 1992, 71, 140–145.
R2=Bn: Still, W. C. J. Am. Chem. Soc. 1978, 100,
1481–1486.
5. Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetra-
hedron: Asymmetry 1997, 8, 3489–3496.
6. Selected data (solvent for optical rotations: CHCl3) for
4a: [h]2D0=+6 (c 0.40); 4b: [h]D20=−24 (c 0.31); 5a: [h]2D0=
+2 (c 0.33); 5b: [h]D20=−8 (c 0.29); 6a: [h]2D0=−14 (c 0.76);
6b: [h]2D0=−16 (c 0.52); 7a: [h]D20=−7 (c 0.34); 7b: [h]2D0=
−4 (c 0.20).
The present method provides a convenient asymmetric
synthesis of either diastereoisomer of differentially pro-
tected ABTs desired by choosing the appropriate Lewis
acid. Throughout this study, we also showed that ABTs
are also an effective entry to b-hydroxy-a-aminoacids.
Applications of this methodology for the synthesis of
biologically interesting nitrogenated compounds are
under investigation.
7. Treatment of acetone solutions of hydroxylamines 6 and
7
with catalytic amounts of p-toluensulfonic acid
afforded, after 8 h, the corresponding hydroxylamines 4
and 5, in ca. 80% yield.
8. (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632–634; (b)
Fiumana, A.; Lombardo, M.; Trombini, C. Tetrahedron
1997, 53, 11721–11730.
Acknowledgements
Financial support was provided by Ministerio de Cien-
cia y Tecnologia (Madrid, Spain. Project PB97-1014)
and Diputacion General de Aragon (Zaragoza, Spain,
project PO79/99-C).
9. Data for 10a: [h]2D0=+7 (c 0.39, CHCl3); 1H NMR
(CDCl3, 300 MHz, 328 K) l 1.32 (s, 3H), 1.41 (s, 3H),
1.43 (s, 9H), 3.34 (s, 3H), 3.54 (dd, 1H, J=7.3, 9.8 Hz),
3.58 (dd, 1H, J=5.4, 9.8 Hz), 3.72 (dd, 1H, J=6.8, 8.0
Hz), 3.81 (m, 1H), 4.00 (dd, 1H, J=6.5, 8.0 Hz), 4.32 (dt,
1H, J=2.4, 6.5 Hz), 4.60 (s, 2H), 4.74 (bs, 1H). 13C
NMR (CDCl3, 75.5 MHz, 328 K) l 25.0, 26.3, 28.3, 50.3,
55.3, 66.1, 67.5, 74.1, 79.7, 96.5, 109.4, 154.8. Compound
10b: [h]2D0=+3 (c 0.45, CHCl3); 1H NMR (CDCl3, 300
MHz, 328 K) l 1.30 (s, 3H), 1.37 (s, 3H), 1.41 (s, 9H),
3.33 (s, 3H), 3.58 (m, 1H), 3.76 (m, 2H), 3.88 (dd, 1H,
J=6.4, 8.5 Hz), 3.99 (dd, 1H, J=5.3, 8.5 Hz), 4.08 (dt,
1H, J=5.9, 7.3 Hz), 4.58 (s, 2H), 4.82 (bs, 1H). 13C
NMR (CDCl3, 75.5 MHz, 328 K) l 25.4, 26.6, 28.3, 52.9,
55.2, 67.1 (2C), 75.4, 79.5, 96.8, 109.3, 155.5. Compound
11a: [h]2D0=+2 (c 0.51, CHCl3); 1H NMR (CDCl3, 300
MHz, 328 K) l 1.33 (s, 3H), 1.40 (s, 3H), 1.42 (s, 9H),
3.49 (t, 1H, J=9.1 Hz), 3.54 (dd, 1H, J=5.9, 9.3 Hz),
3.72 (dd, 1H, J=7.3, 8.1 Hz), 3.88 (m, 1H), 3.99 (dd, 1H,
J=6.4, 8.1 Hz), 4.36 (dt, 1H, J=2.4, 6.8 Hz), 4.50 (d,
1H, J=11.7 Hz), 4.54 (d, 1H, J=11.7 Hz), 4.80 (bd, 1H,
J=8.8 Hz), 7.28 (m, 5H). 13C NMR (CDCl3, 75.5 MHz,
328 K) l 25.0, 26.3, 28.3, 50.3, 66.2, 70.0, 73.1, 74.2, 79.6,
References
1. For a complete list of references concerning preparation
and synthetic applications of ABTs see: Inaba, T.;
Yamada, Y.; Abe, H.; Sagawa, S.; Cho, H. J. Org. Chem.
2000, 65, 1623–1628 and references cited therein. During
the preparation of this manuscript Kwon and Ko
reported the stereoselective preparation of (2S,3S)-2-
amino-1,3,4-butanetriol, see: Kwon, S. J.; Ko, S. Y. J.
Org. Chem. 2001, 66, 6833–6835.
2. (a) Delle Monache, G.; Misiti, D.; Zappia, G. Tetra-
hedron: Asymmetry 1999, 10, 2961–2973; (b) Fadnavis, N.
W.; Sharfuddin, M.; Vadivel, S. K. Tetrahedron: Asym-
metry 2001, 11, 691–693.
3. For an account, see: Merino, P.; Franco, S.; Merchan, F.
L.; Tejero, T. Synlett 2000, 442–454.

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P. Merino et al. / Tetrahedron Letters 43 (2002) 459–462
109.2, 127.5, 127.6, 128.4, 138.0, 155.9. Compound 11b:
10. Selected data (solvent for optical rotations: CHCl3) for
12a: [h]2D0=−64 (c 0.50); 12b: [h]2D0=−34 (c 0.22). For a
previous preparation and full data of 12a and 12b see
Ref. 5. Compound 12b had been previously described:
Kirschbaum, B.; Stahl, U.; Jager, V. Bull. Soc. Chim.
Belg. 1994, 103, 425–432.
1
[h]2D0=+7 (c 0.46, CHCl3); H NMR (CDCl3, 300 MHz,
328 K) l 1.33 (s, 3H), 1.38 (s, 3H), 1.42 (s, 9H), 3.55 (dd,
1H, J=3.4, 9.3 Hz), 3.73 (dd, 1H, J=2.9, 9.3 Hz), 3.80
(m, 1H), 3.90 (dd, 1H, J=5.9, 8.8 Hz), 4.00 (dd, 1H,
J=6.4, 8.8 Hz), 4.14 (dt, 1H, J=5.9, 7.3 Hz), 4.49 (d,
1H, J=11.7 Hz), 4.52 (d, 1H, J=11.7 Hz), 4.94 (bd, 1H,
J=8.3 Hz), 7.29 (m, 5H). 13C NMR (CDCl3, 75.5 MHz,
328 K) l 25.6, 26.8, 28.4, 52.6, 67.1, 69.5, 73.4, 75.5, 79.7,
109.4, 127.7, 127.8, 128.5, 138.2, 155.7.
11. Selected data for 13: [h]2D0=−15 (c 0.32, MeOH); lit. for
the enantiomer:12 [h]2D0=+14 (c 0.32, MeOH).
12. Dequeker, E.; Compernolle, F.; Toppet, S.; Hoornaert,
G. Tetrahedron 1995, 51, 5877–5890.