High stereocontrol in the allylation of chiral non-racemic α-alkoxy and α-amino nitrones

Article abstract of DOI:10.1016/j.tetlet.2006.03.004

The stereocontrolled addition of allylic metals to chiral non-racemic nitrones promoted by the addition of Lewis acids is described. Whereas for α-alkoxy nitrones the stereocontrol depends on the Lewis acid used as an activator, for α-amino nitrones the d

Full text of DOI:10.1016/j.tetlet.2006.03.004

Tetrahedron Letters 47 (2006) 3311–3314
High stereocontrol in the allylation of chiral non-racemic
a-alkoxy and a-amino nitrones
Pedro Merino,* Ignacio Delso, Vanni Mannucci and Tomas Tejero
Laboratorio de Sintesis Asimetrica, Departamento de Quı´mica Orga´nica, Instituto de Ciencia de Materiales de Aragon,
Facultad de Ciencias, Universidad de Zaragoza, Consejo Superior de Investigaciones Cientificas,
E-50009 Zaragoza, Aragon, Spain
Received 6 February 2006; revised 25 February 2006; accepted 1 March 2006
Available online 24 March 2006
Dedicated to the memory of Professor Marcial Moreno-Manas
˜
Abstract—The stereocontrolled addition of allylic metals to chiral non-racemic nitrones promoted by the addition of Lewis acids
is described. Whereas for a-alkoxy nitrones the stereocontrol depends on the Lewis acid used as an activator, for a-amino nitrones
the diastereofacial course of the reaction depends on the protection of the a-amino group. The successful implementation of the
methodology is represented by the enantiodivergent synthesis of D- and L-allylglycine.
Ó 2006 Elsevier Ltd. All rights reserved.
The reaction of allylic organometallics with imines and
related compounds is a useful method for preparing syn-
thetically important nitrogen-containing compounds.1,2
Despite numerous studies of imine additions,3 the most
significant ones reported by Yamamoto and co-work-
ers,4 other substrates such as oximes, nitrones or hydra-
zones have not received much attention.2 The use of a
nitrone as the electrophile in the allylation reaction is
an attractive approach because (i) the product of the
reaction, a hydroxylamine, contains a nitrogen in an
intermediate oxidation state, (ii) the presence of the nit-
rone oxygen atom can facilitate the use of Lewis acids to
modulate both reactivity and selectivity and (iii) if neces-
sary, it is easy to transform the hydroxyamino group
into the corresponding homoallylamine by reductive
methods (Scheme 1).
In the course of our research, we need to prepare highly
functionalized homoallylic hydroxylamines in an enantio-
merically pure form. The trimethylsilyltriflate catalyzed
addition of allylsilane to nitrones was first described
by Wuts and Jung.5 This reaction as well as the addition
of allylmagnesium chloride have successfully been ap-
plied by Trombini et al.6 towards the synthesis of 3,5-
substituted isoxazolines. However, with chiral non-race-
mic a-alkoxy nitrones derived from sugars, such as N-
benzyl-D-glyceraldehyde nitrone 1a the reaction took
place only with moderate selectivity.7 In spite of a fur-
ther report in which the use of Lewis acids enhanced
the reactivity of the nitrones,8 a synthetically viable acy-
clic stereocontrol of allylation of a-alkoxy nitrones has
not yet been reported. In our continuing efforts to devel-
op stereocontrolled additions to nitrones, we have found
that the addition of several nucleophiles to a-alkoxy and
a-amino nitrones can be stereodirected by the use of
appropriate substrates and additives.9 Prompted by
these results and the desirable synthetic properties of
homoallyl hydroxylamines, herein we report our explo-
ration on the addition of several allylic organometals
to a-alkoxy and a-amino nitrones 1a–f. These nitrones
were readily prepared from the corresponding aldehyde
and N-benzylhydroxylamine.10 All these compounds are
stable solid products that can be stored for long time.
N#
NH#
M
R1
R1
L.A.
N#: NR, NNR2, NOR, N+(O-)R
Scheme 1.
*
The allylation of nitrone 1a was investigated first
(Scheme 2). We exhaustively examined the dependence
Corresponding author. Tel./fax: +34 976 762075; e-mail: pmerino@
unizar.es
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.004

3312
P. Merino et al. / Tetrahedron Letters 47 (2006) 3311–3314
X
X
X
H
M
see Table 1
N
N
N
O
Bn
HO
Bn
HO
Bn
M = Li, MgBr
1a-f
syn 2a-f
anti 3a-f
OBn
NHBoc
H
O
O
O
NBoc
H
BnO
H
H
H
H
tBuPh2SiO
O
O
O
O
BnO
N
N
N
N
N
O
N
O
Bn
O
Bn
O
Bn
O
Bn
Bn
O
Bn
1a
1b
1c
1d
1e
1f
Scheme 2. Allylation of nitrones 1a–f (enantiomers are shown for 2e–f and 3e–f).
Table 1. Allylation of nitrones 1 produced via Scheme 1
Entry
Nitrone
Ma
Additiveb
Solvent
T (°C)
Time (h)
syn:anti
Yieldc (%)
1
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1d
1d
1d
1e
1e
1e
1e
1f
Li
Li
Li
Li
Li
Li
Li
SnBu3
SnBu3
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
Li
None
TMEDA
ZnBr2
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
CH2Cl2
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
Et2O
THF
Et2O
Et2O
Et2O
THF
Et2O
Et2O
À80
À80
À80
À80
À80
À80
À80
25
1
1
1
1
1
1
1
72
72
2
8
2
8
3
8
8
3
8
3
3
10
2
1
1
1
2
8
2
8
1
1
1
2
8
8
2
4
2
1
2
8
8
1
2
55:45
71:29
90:10
37:63
52:48
44:56
81:19
>5:95
31:69
53:47
76:24
88:12
>96:4
17:83
45:55
55:45
32:68
35:65
30:70
17:83
5:95
45:55
60:40
61:39
37:63
62:38
69:31
48:52
29:71
72:28
76:24
64:36
74:26
91:9
86
90
75
43
64
69
50
90
92
100
100
100
100
43
78
80
86
90
35
40
90
70
90
80
86
100
90
90
90
86
87
80
78
93
85
TiCl4
Et2AlCl
BF3ÆEt2O
TMSOTf
BF3ÆEt2O
TMSOTf
None
None
ZnBr2
ZnBr2
TiCl4
Ti(iPrO)2Cl2
Ti(iPrO)4
Et2AlCl
Et2AlCl
BF3ÆEt2O
BF3ÆEt2O
BF3ÆEt2O
TMSOTf
None
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
25
0
À50
0
À50
0
À50
À50
0
À50
0
0
À50
0
À80
À80
À80
0
Li
Li
ZnBr2
Et2AlCl
None
MgBr
MgBr
MgBr
MgBr
Li
ZnBr2
À50
Et2AlCl
BF3ÆOEt2
None
ZnBr2
Et2AlCl
None
ZnBr2
BF3ÆOEt2
None
ZnBr2
BF3ÆOEt2
None
None
ZnBr2
BF3ÆOEt2
None
None
0
À50
À80
À80
À80
0
À50
À50
0
Li
Li
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
Li
MgBr
MgBr
MgBr
Li (3.0)
MgBr (3.0)
8:92
38:62
92:8
10:90
>95:5
>95:5
>95:5
>95:5
20:80
10:90
100
100
100
89
100
94
92
75
81
À50
0
À80
0
À50
À50
À80
0
1f
a An excess of 2.0 equiv was used.
b 1.0 equiv was used in all cases.
c Isolated yield after purification of the mixture of adducts.

P. Merino et al. / Tetrahedron Letters 47 (2006) 3311–3314
3313
of both the diastereoselectivity and the yield of the reac-
tion, on the temperature, solvent, allylic reagent and
Lewis acid.11 The results are collected in Table 1.
Mukaiyama’s aldehyde. Good ds values and chemical
yields again were found for this nitrone (entries 37–39)
and a complete stereocontrol was obtained by moving
from zinc(II) bromide to boron trifluoride etherate.
With allyllithium (prepared from allyltriphenyltin and
phenyllithium12) mixtures of syn and anti compounds
were formed (entries 1–8). Only when ZnBr2 was used
as an additive the syn hydroxylamine was obtained pref-
erentially. On the other hand, by changing the Lewis
acids only a slight reversal of selectivity could be ob-
tained. When using allyltributyltin, the reaction only
worked if activated with BF3ÆOEt2 and trimethylsilyltri-
flate (entries 9 and 10) and needed 3 days to go on com-
pletion. In both cases, the anti adduct was obtained
preferentially, the best results being observed with the
former; in that case the anti isomer was obtained as
the only product of the reaction in an excellent chemical
yield. For the reactions with commercially available
allylmagnesium bromide the diastereomeric ratio of the
products 2a–3a depended more strongly on the reaction
conditions (entries 11–23). Thus, in the absence of any
additive (entries 11 and 12), the reaction proceeded
smoothly to give mixtures of adducts in which the syn
isomer was the major component. The addition of
zinc(II) bromide as a promoter of the reaction notably
increased the amount of the syn isomer and at low
temperature (entry 14) an almost total syn selectivity
was obtained in quantitative yield after 8 h. The ques-
tion as to whether a reversal of the stereochemistry could
be achieved, as in other nucleophilic additions developed
in our laboratory,9 was examined by using titanium,
boron and aluminium derived Lewis acids. With tita-
nium additives (entries 15–17) only moderate anti selec-
tivities were obtained. In the case of titanium(IV)
chloride, which afforded the best result the chemical
yield dropped to 45%, probably due to the competitive
acetonide hydrolysis promoted by the Lewis acid. Simi-
lar results were obtained with diethyl aluminium chlo-
ride (entries 18 and 19), which afforded moderate
values of anti selectivity even at low temperature. On
the other hand, by using boron trifluoride etherate as
an additive (entries 20–22) a complete reversal of the dia-
stereofacial selectivity was observed, and at À50 °C in
THF as a solvent, an excellent ds value was obtained.
The low chemical yield observed at 0 °C might be due
to the acetonide hydrolysis. The use of a TMSOTF as
a promoter (entry 23) did not improve these results.
Thus it seems that the diastereofacial selectivity ob-
served strongly depends not only on the Lewis acid but
also on the allylic organometallic reagent. To evaluate
the influence of the protecting groups in the substrate
we took our best systems and applied them to acyclic nit-
rone 1b (entries 24–30). In this case, although a trend in
stereocontrol is observed, the results are rather moderate
and they cannot be considered as synthetically useful.
On the other hand, with nitrone 1c, which possess a cyc-
lic system vicinal to the nitrone functionality, excellent
values of stereocontrol were obtained. Whereas the
addition in the presence of zinc(II) bromide (entry 35)
afforded the syn isomer in 91% dr, the same reaction
carried out in the presence of boron trifluoride etherate
(entry 36) furnished the anti isomer in 92% dr. We
then extended the study to nitrone 1d, derived from
Attempts to extend this methodology to a-amino nitro-
nes led to completely different results. As outlined in
previous papers,13 the selectivity of nucleophilic addi-
tions to a-amino nitrones are not influenced by Lewis
acids but by the protection of the a-amino group. As ex-
pected, allylation of nitrone 1e furnished the syn isomer
in excellent yields, whatever the Lewis acid is used
(entries 40–43).14 However, switching to monoprotected
nitrone 1f proved beneficial since this afforded a mixture
of adducts with a dr of 9:1, the anti adduct being the
major isomer.
We also attempted the addition of samarium and
indium allyl derivatives following the reported proce-
dures by Prajapati15 and Kumar,16 respectively. Unfor-
tunately, we did not observe any reaction after several
days. This behaviour might be due to the less reactivity
generally observed for alkyl nitrones with respect to aryl
nitrones like those used in the cited reports.
The dr’s were determined by both NMR spectroscopy
and HPLC. The configuration of the obtained isomers
was unambiguously assigned by comparison with litera-
ture data for 2a and 3a,7a and following our previously
published rule17 for hydroxylamine 2e. Assignment of
the other hydroxylamines was made by chemical corre-
lation through their conversion into known com-
pounds.18 In addition, the configurations for all
compounds were in good agreement with COSY,
NOESY and HMQC experimental data.
Further demonstration of the diastereodivergency of
the process was achieved by the transformation of
O
O
O
O
O
O
N
N
HO
Bn
HO
Bn
2a
3a
(88%)
(89%)
i
i
O
O
N
N
Boc
Bn
Boc
Bn
4
6
(72%)
(76%)
ii
ii
HO2C
HO2C
NHBoc
5
NHBoc
ent-
5
Scheme 3. Reagents and conditions: (i) Zn, AcOH, 70 °C; then Boc2O,
dioxane, rt. (ii) Li, NH3 (liq); then p-TosOH, MeOH; then NaIO4,
SiO2, CH2Cl2; then TEMPO, [bis(acetoxy)iodo]benzene, MeCN–H2O.

3314
P. Merino et al. / Tetrahedron Letters 47 (2006) 3311–3314
5. Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53,
1957–1965.
diastereomeric hydroxylamines 2a and 3a into enantio-
meric protected derivatives of allylglycine (Scheme 3).
Deoxygenation of the hydroxyamino function, N-pro-
tection and further transformation of the dioxolane ring
into a carboxyl group,19 afforded 5 and ent-5 in good
overall yields.
6. (a) Lombardo, M.; Spada, S.; Trombini, C. Eur. J. Org.
Chem. 1998, 2361–2364; (b) Gianotti, M.; Lombardo, M.;
Trombini, C. Tetrahedron Lett. 1998, 39, 1643–1646; (c)
Mancini, F.; Piazza, M. G.; Trombini, C. J. Org. Chem.
1991, 56, 4246–4252.
7. (a) Dhavale, D. D.; Gentilucci, L.; Piazza, M. G.;
Trombini, C. Liebigs Ann. Chem. 1992, 1289–1295; (b)
Dhavale, D. D.; Jachak, S. M.; Karche, N. P.; Trombini,
C. Tetrahedron 2004, 60, 3009–3016.
8. Fiumana, A.; Lombardo, M.; Trombini, C. J. Org. Chem.
1997, 62, 5623–5626.
9. (a) Merino, P. C.R. Acad. Sci., Ser. IIc: Chim. 2005, 8,
775–778; (b) Merino, P.; Franco, S.; Merchan, F. L.;
Tejero, T. Synlett 2000, 442–454.
10. Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.;
Merino, P.; Tejero, T. Synth. Commun. 1994, 24, 2537–
2550.
11. Typical procedure: To a solution of nitrone (1.0 equiv) in
the indicated solvent and temperature (see Table 1),
1.0 equiv of Lewis acid was added. After 5 min, 2.0 equiv
of the allylic metal was added and the reaction mixture
was stirred until no more nitrone (TLC) was observed. A
saturated aq solution of NH4Cl was added and the
resulting mixture was diluted with diethyl ether. The
organic layer was separated, dried (MgSO4) and evapo-
rated to furnish the crude product, which was purified by
radial chromatography.
In this letter we have described the successful applica-
tion of Lewis acids to control the diastereofacial selectiv-
ity in allylation reactions of chiral non-racemic a-alkoxy
nitrones. We have also demonstrated the utility of the
methodology by preparing N-Boc-L-allylglycine and its
enantiomer. The effect of the Lewis acid in the stereo-
chemical course of the allylation reaction is a matter
of interest, and further studies are in progress.
Acknowledgements
We thank the Ministerio de Educacion y Ciencia (MEC,
Project CTQ2004-0421), and the Regional Government
of Aragon (DGA) for financial support. I.D. and V.M.
thanks DGA and MEC, respectively, for pre-doctoral
grants. Hortensia Rico, Michael Roessler and Sasha
Schaeffer are acknowledged for exploratory work.
12. Seyferth, D.; Weiner, M. A. Org. Synth. 1973, 5, 452
(freely available on the Internet).
References and notes
13. (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. J.
Org. Chem. 1998, 63, 5627–5630; (b) Merino, P.; Lanaspa,
A.; Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry
1998, 9, 629–646. See also Ref. 9 and references cited
therein.
14. Merino, P.; Tejero, T. Tetrahedron 2001, 57, 8125–8128.
15. Laskar, D. D.; Prajapati, D.; Sandhu, J. S. Tetrahedron
Lett. 2001, 42, 7883–7886.
16. Kumar, H. M. S.; Anjaneyulu, S.; Reddy, E. J.; Yadav,
J. S. Tetrahedron Lett. 2000, 41, 9311–9314.
17. Merino, P.; Franco, S.; Gascon, J. M.; Merchan, F. L.;
Tejero, T. Tetrahedron: Asymmetry 1999, 10, 1861–
1865.
1. Ding, H.; Friestad, G. K. Synthesis 2005, 2815–2829.
2. Merino, P.; Tejero, T.; Delso, J. I.; Mannucci, V. Curr.
Org. Synth. 2005, 2, 479–498.
3. For recent and representative examples see: (a) Shimizu,
M.; Kimura, M.; Watanabe, T.; Tamaru, Y. Org. Lett.
2005, 7, 637–640; (b) Smitha, G.; Miriyala, B.; William-
son, J. S. Synlett 2005, 839–841; (c) Vilaivan, T.; Wino-
tapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J.
Org. Chem. 2005, 70, 3464–3471; (d) Foubelo, F.; Yus, M.
Tetrahedron: Asymmetry 2004, 15, 3823–3825; (e) Lee,
C.-L. K.; Ling, H. Y.; Loh, T.-P. J. Org. Chem. 2004, 69,
7787–7789.
4. (a) Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004,
69, 3562–3564, and references cited therein; For a review
see: (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93,
2207–2293.
18. All compounds gave satisfactory elemental analysis and
their structure was identified by NMR spectroscopy.
19. Merino, P.; Castillo, E.; Franco, S.; Merchan, F. L.;
Tejero, T. J. Org. Chem. 1998, 63, 2371–2374.