Exploring nitrone chemistry: Towards the enantiodivergent synthesis of 6-substituted 4-hydroxypipecolic acid derivatives

Article abstract of DOI:10.1002/ejoc.200800348

A methodology for the stereoselective preparation of all-cis 6-substituted 4-hydroxypipecolic acid derivatives using nitrone chemistry, involving both nucleophilic additions and cycloadditions, is presented. The N-benzyl nitrone derived from 1,2-di-O-isop

Full text of DOI:10.1002/ejoc.200800348

FULL PAPER
DOI: 10.1002/ejoc.200800348
Exploring Nitrone Chemistry: Towards the Enantiodivergent Synthesis of
6-Substituted 4-Hydroxypipecolic Acid Derivatives
Pedro Merino,*[a] Vanni Mannucci,[a] and Tomás Tejero[a]
Keywords: Pipecolic acids / Piperidines / Nitrones / Nucleophilic Addition / Cycloaddition / Cope rearrangement /
Allylation
A methodology for the stereoselective preparation of all-cis
6-substituted 4-hydroxypipecolic acid derivatives using
nitrone chemistry, involving both nucleophilic additions and
cycloadditions, is presented. The N-benzyl nitrone derived
substituent at the 6-position. The resulting N-alkenyl nitro-
nes underwent stereoselective intramolecular 1,3-dipolar cy-
cloaddition reactions to provide the immediate precursors of
the target compounds. The selectivity observed in the intra-
molecular cycloaddition was dictated by both the steric pref-
erence and the electronic nature of the substrate, which pro-
moted a hitherto unknown aza-Cope rearrangement of the
N-alkenyl nitrone. The chiral induction exerted by the diox-
from 1,2-di-O-isopropylidene-D-glyceraldehyde was shown
to undergo stereocontrolled allylation reactions to provide
enantiomerically pure homoallyl hydroxylamines. Further
transformation of these substrates into N-alkenyl nitrones
was achieved in high yields and regioselectivities by oxi- olane moiety as well as its synthetic equivalence with the
dation with manganese(IV) oxide. The oxidation reaction is
thermodynamically controlled and directed by a phenyl
group which became the 6-substituent. A transoximation re-
action of the intermediate N-alkenyl-C-phenyl nitrone was
needed to add versatility to the methodology by varying the
carboxy group provided the basis for the enantiodivergency
achieved in the synthesis of 6-substituted (2R,4S,6R)-4-hy-
droxypipecolic acids and their enantiomers.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
and Tetraberlinia (Leguminosae: Caesalpiniodeae).[7] In
particular, (2S,4S)-hydroxypipecolic acid (1) was isolated
from Acacia species and the (2S,4R) isomer 2 was obtained
from the leaves of Calliandra pittieri and Strophantus scan-
deu.[8] Compound 2 is also a constituent of antibiotics such
as virginiamicin S[9] as well as a key intermediate in the
synthesis of NMDA receptor antagonists[10] and the HIV
protease inhibitor palinavir.[11] 4-Oxygenated pipecolic ac-
ids have also been used as key intermediates in the synthesis
of several constrained amino acids and peptidomimetics.[12]
Pipecolic acids 1 and 2 have been synthesized from dihy-
dropyridones,[13] amino acid derived N-acyliminium ions,[14]
imines,[15] vinylglycinols,[16] and nitrones.[17] Davies et al. re-
ported the stereoselective synthesis of all four stereoisomers
of 4-hydroxypipecolic acids.[18] A protected derivative of 2
served to prepare (2S,4R)-4-aminopipecolic acid (3).[19]
Compounds 3 and 4, isolated from Strophantus scandeus
(Apocinacea)[20] and Calliandra haematocephala (Leg-
uminosae),[21] are representative of endocyclic-Nα/exocyclic-
Nγ basic constrained amino acids. Other 4-aminopipecolic
acids have been prepared through catalytic imino-Diels–
Alder reactions of 2-aminodienes.[22] (2S,3S)-3-Hydroxypi-
pecolic acid and its enantiomer have been prepared starting
from - and -glyceraldehyde imines, respectively.[23] The
(2R,3R) isomer has also been synthesized from methyl man-
delate as the chiral source.[24] The cis-(2S,3R) and (2S,3R)
derivatives have been obtained by enzymatic resolution.[25]
Introduction
The synthesis of polysubstituted piperidine derivatives is
still a challenging field of ongoing interest as demonstrated
by very recent publications.[1] Several synthetic methodolo-
gies have been applied so far and the subject of the synthe-
sis of piperidines has been covered in several dedicated re-
views.[2] In the domain of piperidines, pipecolic acid deriva-
tives have been widely used as chiral intermediates for the
synthesis of drugs,[3] unnatural amino acids and peptides[4]
and several pipecolic acid containing natural products.[5]
For this reason, the study of synthetic methods directed
towards the preparation of enantiomerically pure pipecolic
acid derivatives has attracted much attention in recent
years.[6] Of particular interest are pipecolic acid derivatives
bearing hydroxy or amino groups. Because of their struc-
tural diversity and interesting functionalities, some interest
has been directed towards devising strategies for the synthe-
sis of such compounds. Several 4- and 5-hydroxypipecolic
acids have been isolated from the leaves of species of Bikinia
[a] Laboratorio de Síntesis Asimétrica, Departamento de Química
Orgánica, Instituto de Ciencia de Materiales de Aragón, Uni-
versidad de Zaragoza, CSIC
50009 Zaragoza, Aragón, Spain
Fax: +34-976-762075
E-mail: pmerino@unizar.es
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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P. Merino, V. Mannucci, T. Tejero
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Several syntheses of 3-hydroxypipecolic acids have been re-
ported because of their importance in biologically active
molecules.[26] 5-Hydroxypipecolic acids, available from
trans-4-hydroxyproline,[27] have recently been used as inter-
mediates in the preparation of chimeric peptide nucleic
acids[28] and (+)-epiquinamide.[29]
Scheme 1. Retrosynthetic analysis for 6-substituted 4-hydroxy-
pipecolic acid derivatives.
The introduction of additional substituents at the 6-posi-
tion in 4-hydroxypipecolic acids and their derivatives gives
an entry to a variety of natural alkaloids of biological im-
portance.[30] The synthesis of several isomers of 6-substi-
tuted 4-hydroxypipecolic acids 5 have been reported start-
ing from suitable precursors depending on the desired iso-
mer.[31] Only in one case has a diastereodivergent reduction
of 4-oxo derivatives allowed the preparation of C-4 epimeric
6-substituted (2R,6S)-4-hydroxypipecolic acids.[32] In this
paper we describe in detail the enantiodivergent synthesis of
6-substituted (2S,4R,6R)-4-hydroxypipecolic acids and their
enantiomers by using a strategy based on nitrone chemistry
that involves both nucleophilic additions and 1,3-dipolar
cycloaddition reactions.
give versatility to the methodology it will also be necessary
to develop a suitable procedure for exchanging the phenyl
group with other radicals. As discussed in this work (see
below), this is possible through a transoximation reaction.
The last steps towards the targeted pipecolic acid deriva-
tives 5 involves the reduction of the N–O bond by standard
procedures and transformation of the dioxolane ring into
the carboxy group, as we[36] and others[37] have previously
described. In this way, one could take advantage of the loss
of the chiral dioxolane unit because, by preparing the anti
isomer 8b, the enantiomer of 5 would be expected, thus
achieving an enantiodivergent approach from nitrone 9.[38]
Synthesis of Homoallyl Hydroxylamines
Results and Discussion
We decided first to study the allylation reaction of
nitrone 9 with a series of allyl metals and Lewis acids, with
the expectation that the reaction could be stereocon-
Synthetic Plan
Our approach to the synthesis of 6-substituted deriva- trolled.[35a] In spite of the numerous studies on the al-
tives (2S,4R,6R)-5 is illustrated by the retrosynthetic analy- lylation of imines, the allylation of nitrones has scarcely
sis depicted in Scheme 1 and envisaged the use of N-benzyl- been investigated.[39] In order to evaluate the influence of
1,2-di-O-isopropylidene--glyceraldehyde nitrone 9, which the protecting groups on stereofacial discrimination, nitro-
can be easily obtained in a multigram scale from protected nes 10 and 11, in addition to 9, were also considered
-glyceraldehyde[33] as the starting material.
(Scheme 2, Table 1).
As shown in Scheme 1 the stereoselective allylation of
The reaction protocol involved of the slow addition of a
nitrone 9 could allow the preparation of hydroxylamine syn- solution of nitrone to a solution of the corresponding allyl
8a. Work from this laboratory has previously shown that metal derivative. In the case of reactions carried out in the
nucleophilic addition to 9 could be stereocontrolled by the presence of Lewis acids, the nitrone complex was preformed
appropriate use of Lewis acids.[34] Based on these previous by admixing the Lewis acid and nitrone in the stated solvent
observations it can be assumed that the corresponding anti for 5 min at room temperature, later subjecting it to a speci-
isomer 8b will also be available.[35] Elaboration of the fied temperature for sequential addition to the allyl metal
homoallyl hydroxylamines would then involve oxidation of solution. The reaction progress was easily monitored by
the hydroxyamino moiety and intramolecular cycloaddition TLC analysis, and purification of the crude product by
of the resulting alkenyl nitrone 7. The phenyl substituent at flash chromatography and determination of the dia-
the site of oxidation is of particular interest as this is re- stereomeric ratio by NMR spectroscopy provided assess-
quired for directing the oxidation to the aldo nitrone 7. To ment of the efficiency of the reaction.
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Nitrone Chemistry
Whereas the reaction in the absence of any additive
(Table 1, entry 1) led to an almost equimolar mixture of
isomers, the addition of 1 equiv. of TMEDA (Table 1 en-
try 2) or TMSOTf (Table 1, entry 3) proved to be more ef-
ficient. However, the best syn selectivity was obtained in the
presence of Zn2Br (Table 1, entry 4). In accord with our
previous studies on nucleophilic addition to nitrones,[34] the
reaction was also carried out in the presence of TiCl4
(Table 1, entry 5), Et2AlCl (Table 1, entry 6) and BF3·Et2O
(Table 1, entry 7), typical Lewis acids that promote anti ad-
dition. However, only a very slight inversion of the selectiv-
ity was observed. In addition, lower chemical yields were
obtained. This behaviour was not observed with nitrone 10
(Table 1, entries 18–20), which also afforded syn-12a even
in the presence of diethylaluminium chloride. Nitrone 11
(Table 1, entries 24–26) exhibited stereocontrol of the reac-
tion, but with lower diastereoselectivities, and therefore is
not synthetically useful. On the other hand, an acceptable
50% chemical yield was obtained with allyltributyltin in the
presence of 1.0 equiv. of trimethylsilyl triflate (Table 1, en-
try 8), a modest anti selectivity also being achieved. Gratify-
ingly, when the reaction was carried out in the presence of
boron trifluoride etherate (Table 1, entry 9), excellent anti
selectivity and chemical yield were obtained. Although in
this case stereocontrol of the reaction was achieved
(Table 1, entries 4 and 9), we tested the commercially avail-
Scheme 2. Allylation of -glyceraldehyde nitrones.
First, the addition of allyllithium, prepared in situ from
allyltriphenyltin and phenyllithium,[40] to nitrone 9 was
tested.
Table 1. Stereocontrolled allylation of -glyceraldehyde nitrones 9–11.
Entry
Nitrone
M[a]
Lewis acid[b]
Solvent T [°C]
t [h]
Hydroxylamine[c] syn/anti[d]
Yield [%][e]
1
2
3
4
5
6
7
8
9
9
Li
none
none
TMSOTf
ZnBr2
TiCl4
Et2AlCl
BF3·Et2O
TMSOTf
BF3·Et2O
none
TMSOTf
ZnBr2
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
Et2O
Et2O
Et2O
Et2O
Et2O
THF
–80
–80
–80
–80
–80
–80
–80
25
25
–50
0
–50
0
–50
–50
–50
–50
–80
–80
–80
0
–50
–50
–80
–80
–80
0
1
1
1
1
1
1
1
72
72
8
2
8
3
8
8
8
10
1
1
1
2
8
8
1
1
1
2
8
8
55:45
71:29
81:19
90:10
37:63
52:48
44:56
31:69
Յ 5:95
76:24
45:55
Ͼ95:5
17:83
45:55
55:45
35:65
5:95
86
90
50
75
43
64
69
50
90
100
70
100
43
78
80
90
90
86
87
80
78
93
85
90
80
86
100
90
90
90
Li[f]
9
Li
Li
Li
Li
8
9
8
9
8
9
8
9
Li
8
9
S-nBu3
S-nBu3
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
Li
Li
Li
MgBr
MgBr
MgBr
Li
8
9
9
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
9
8
9
8
9
8
9
TiCl4
8
9
Ti(iPrO)2Cl2
Ti(iPrO)4
Et2AlCl
BF3·Et2O
none
ZnBr2
Et2AlCl
none
ZnBr2
BF3·Et2O
none
ZnBr2
Et2AlCl
none
ZnBr2
Et2AlCl
BF3·Et2O
8
9
8
9
8
9
8
10
10
10
10
10
10
11
11
11
11
11
11
11
12
12
12
12
12
12
13
13
13
13
13
13
13
72:28
76:24
64:36
74:26
91:9
8:92
60:40
61:39
37:63
62:38
69:31
48:52
29:71
Li
Li
MgBr
MgBr
MgBr
MgBr
–50
0
–50
8
2
8
[a] 2.0 equiv. of organometallic reagent were used. [b] 1.0 Equiv. of Lewis acid was used. [c] In the text, a series refers to syn compounds
1
and b series refers to anti compounds. [d] Measured by H NMR of isolated crude mixtures. [e] Isolated yield after column chromatog-
raphy. [f] 1.0 equiv. of TMEDA was added.
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P. Merino, V. Mannucci, T. Tejero
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able allylmagnesium bromide as a more advisable and easy-
The stereochemical course of the allylation reaction was
to-handle reagent.[41] The addition of such a reagent to 9 at attributed to different conformations depending on the
–50 °C in the absence of any additive (Table 1, entry 10) or Lewis acid employed. No proof was found for the existence
in the presence of TMSOTf (Table 1, entry 11) provided of α- or β-chelation between the nitrone and the Lewis
syn-8a in good yield but only modest diastereoselectivity. A acids. Although chelated models can be invoked to explain
change of solvent or reduction of the reaction temperature the Lewis acid dependent stereocontrol,[45] further NMR
did not lead to better results. On the other hand, the reac- studies confirmed that nitrone 9 coordinated to the Lewis
tion in the presence of Zn2Br (Table 1, entry 12) proved to acids as a monodentate ligand.[46] From these experiments
be quantitative and only the syn isomer 8a could be de- we believe that the nature of the Lewis acid plays a crucial
tected in the crude product by 400 MHz NMR spec- role in stabilizing different conformations, leading to oppo-
troscopy. In an effort to invert the stereochemical course site diastereomers through classical Houk[47] models A and
of the reaction with the same reagent, several Lewis acids, B in which either the oxygen atom or the methylene group
including TiCl4 (Table 1, entry 13), Ti(iPrO)2Cl2 (Table 1, can act as the large group, respectively (Figure 1).
entry 14), Ti(iPrO)4 (Table 1, entry 15), Et2AlCl (Table 1,
entry 16) and BF3·Et2O (Table 1, entry 17) were tested. In
most cases only modest selectivities were obtained. How-
ever, by using 1.0 equiv. of BF3·Et2O, essentially complete
anti selectivity (ds Ͼ 95%) with 90% yield was obtained.
Similar results were observed with nitrones 10 (Table 1, en-
tries 21–23) and 11 (Table 1, entries 27–30). Even though
lower selectivities were obtained, some stereocontrol was
still present. Hence, complete stereocontrol of the allylation
reaction was achieved with nitrone 9 by using allylmagne-
sium bromide and by changing the Lewis acid from Zn2Br
to BF3·Et2O. Under these conditions multigram quantities
(1–5 g) of enantiomerically pure syn-8a and anti-8b could
be obtained without loss of selectivity.[42]
The structures of 8a and 8b were assigned by comparison
of their physical and spectroscopic properties, including op-
Figure 1. Models for the allylation of -glyceraldehyde nitrones.
tical rotations, with previously prepared compounds.[41] The
configurations of hydroxylamines 12 and 13 were deter-
mined by using the chemical correlation method. The ad-
duct 12a was transformed through a transacetalization re-
action into 8a (Scheme 3). Compounds 8a and 13a were
Synthesis of N-Alkenyl Nitrones and Intramolecular 1,3-
Dipolar Cycloaddition Reactions
converted into the known[43] compound 14 by catalytic hy-
drogenation. In this way, the hydroxyamino and α-alkoxy
groups of adducts 12a and 13a were unequivocally found
to exist in a syn orientation. In the diastereomers 12b and
13b, these groups adopt an anti orientation. The stereo-
divergent allylation of nitrone 9 was also ascertained and its
utility demonstrated[44] by synthesizing both enantiomers of
allylglycine, as described in a preliminary communica-
tion.[35a]
Hydroxylamines 8a and 8b were subjected to MnO2 oxi-
dation,[48] which provided nitrones 15 and 16, respectively,
in quantitative yield (Scheme 4). The Z configuration of the
Scheme 3. Structural assignment of homoallyl hydroxylamines.
Scheme 4. Synthesis of N-alkenyl nitrones.
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Nitrone Chemistry
nitrone was confirmed by NOESY experiments, which
showed for both 15 and 16 an interaction between the azo-
methine proton of the nitrone functionality and the proton
attached to the Cα atom of the nitrogen atom. This assign-
ment was confirmed for 15 by a single-crystal X-ray analy-
sis (Figure 2).[49] Our method provided ready access to N-
alkenyl-C-phenyl nitrones, which are precursors of the cor-
responding 4-hydroxy-6-phenylpipecolic acids (see below).
The fact that only the C-phenyl nitrones were formed in the
oxidation reactions is a consequence of the driving force
exerted by the phenyl group, which favours the formation
of the more stable aldo nitrone instead of the keto nitrone
17 (not observed in any case).
Scheme 5. Intramolecular cycloaddition reactions of nitrones 15
and 16.
This cycloaddition reaction revealed an intriguing aspect.
From the intramolecular cycloaddition reactions of nitrones
15 and 16, and according to their configuration, only cy-
cloadducts 20 and 21 (from 15) and 23 and 24 (from 16)
Figure 2. ORTEP drawing of the X-ray structure corresponding to were expected. The major compounds 20 and 23 arose from
15 (ellipsoids drawn at the 50% probability level).
intramolecular attack at the Re face of the syn nitrones 15
and 16, respectively. The minor compounds 21 and 24 were
formed by attack at the Si face of the same nitrones. Only
As explained in the synthetic plan (see above) we needed
these products were expected, in principle, because in all
to be able to prepare different C-alkyl- and C-aryl-N-alk-
cases, for steric reasons, only the endo approach of the
enyl nitrones in order to gain access to different 6-substi-
double bond to the two diastereotopic faces of the nitrone
tuted 4-hydroxypipecolic acids. Starting with other N-sub-
is allowed. In principle there are two possible explanations
stituted nitrones instead of 9 would have two significant
for the formation of cycloadducts 22 and 25: i) the nitrone
15 epimerizes to 16 and then this compound isomerizes[53]
drawbacks: i) complete stereocontrol of the allylation reac-
to the corresponding (E)-nitrone,[54] which could lead to ad-
duct 22 (the same applies to 16: epimerization to 15 and
isomerization to the (E)-nitrone could explain the forma-
tion of 25) or ii) a 2-aza-Cope rearrangement takes place
to form nitrone 26 from 15 and 27 from 16 (Scheme 6).
Intramolecular cycloaddition of these rearranged nitrones
should afford cycloadducts 20 and 22 (from 26) and 23 and
25 (from 27).
tion could not be guaranteed as different substrates would
be used and ii) the oxidation reaction in the case of N-
alkyl-substituted hydroxylamines could afford mixtures of
regioisomeric N-alkenyl nitrones. For these reasons we de-
cided to carry out a transhydroximation[50] of nitrone 16,
which led to the formation of the free hydroxylamine 18.
This compound can be condensed with an aldehyde to give
C-(substituted)-N-alkenyl nitrones, which can be converted,
as discussed below, into the corresponding 6-substituted 4-
hydroxypipecolic acids. As an example, compound 18 was
condensed with n-propanal under typical conditions to
yield nitrone 19 in 86% isolated yield (Scheme 4).
The intramolecular 1,3-dipolar cycloaddition of N-alk-
enyl nitrones has been employed before to obtain cyclic ni-
trogen derivatives,[51] many of which form a part of natural
product structures such as alkaloids.[52] The intramolecular
cycloaddition of nitrone 15 proceeded quantitatively in tol-
uene at 100 °C to give, unexpectedly, the three adducts 20,
21 and 22 in a 75:5:20 ratio, respectively. Similarly, heating
nitrone 16 afforded, also quantitatively, the adducts 23, 24
and 25 in an 82:5:13 ratio, respectively (Scheme 5). All of
these cycloadducts were separated by radial chromatog-
raphy and fully characterized.
Scheme 6. Intramolecular cycloaddition reactions of nitrones 15
and 16.
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Compounds 20 and 23 should be formed by endo attack 400-MHz NMR spectroscopy. The compound obtained
on the Si faces of nitrones 26 and 27, respectively. The un- should be formed by endo attack of the double bond on the
expected adducts 22 and 25 should be formed by endo at- Re face of the nitrone 19. Of course compound 31 could
tack on the Re faces of nitrones 26 and 27, respectively.[55] also be formed by endo attack on the Si face of the re-
These assumptions were discerned by analyzing the stereo- arranged nitrone 30. In this case we think that there is no
chemical course of the reaction. Thus, the epimerization/ reason for ruling out the 2-aza-Cope rearrangement. How-
isomerization route is negligible as the first process should ever, it cannot strictly be demonstrated for 19 as no other
occur in opposite senses, that is, from 15 and 16, which cycloadducts were detected in the reaction mixture.
contradicts the basic rules of thermodynamics. In addition,
if partial epimerization (or even isomerization) took place
a cross-mixture of products from the syn and anti series
should be obtained. Moreover, other diastereomers should
also have been observed. Such a contamination of dia-
stereomers was not detected at all in either case.[55]
The 2-aza-Cope rearrangement[56] has previously been
reported for iminium salts[57] and for nitrones protonated
or coordinated to Lewis acids,[58] which actually were oxy-
iminium salts. The thermal rearrangement of nitrones has
also been suggested[59] but never demonstrated because of
the use of racemic products that prevent discrimination be-
tween the rearrangement and E/Z isomerization processes
(see below). We have reported the preliminary results of the
2-aza-Cope rearrangement of nitrones 15 and 16, including
a theoretical study.[60] It was observed that the activation
energies for the aza-Cope rearrangement are very similar to
those of the cycloaddition processes, which explains why
nitrones 26 and 27 were not detected in the course of the
reactions. In order to confirm the above hypothesis we syn-
thesized nitrones 26 and 27 in an alternative way. As their
preparation by a homochiral route would not be easy we
decided to prepare them as a diastereomeric mixture by
condensation of racemic hydroxylamine 29 (obtained from
the addition of allylboronate 28 to benzaldoxime)[59a] with
1,2-di-O-isopropylidene--glyceraldehyde (Scheme 7).
Scheme 8. Intramolecular cycloaddition reaction of nitrone 19.
The structures of cycloadducts 20–25 and 31 were deter-
mined by a combination of X-ray crystallography and
NMR techniques. The stereochemistries of compounds 20
and 25 was proven by single-crystal X-ray analysis (see Fig-
ures 3 and 4).[49]
Scheme 7. Synthesis of nitrones 26 and 27.
Unfortunately, nitrones 26 and 27 could not be separated
and careful column chromatography under a variety of con-
ditions was in vain; only enriched mixtures were obtained.
Nevertheless, when these mixtures were subjected to cyclo-
addition conditions (toluene, 110 °C, sealed tube) identical
results were observed[61] to those obtained separately from
nitrones 15 and 16, which confirms the connection between
the nitrone pairs 15/26 and 16/27 through a reversible 2-
aza-Cope thermal rearrangement. As expected, nitrones 15
and 16 could not be detected during the course of these
Figure 3. ORTEP drawings of the X-ray structures of 20 and 25
showing ellipsoids at the 50% probability level.
The NMR signals of all the adducts were assigned by
experiments and only the final adducts 20 and 23 were ob- COSY and HSQC (or HMQC) 2D-NMR experiments. The
tained preferentially in diastereomeric ratios of 75 and 82%, NOE difference spectra of the adducts were compared for
respectively.
complete structural assignment (Figure 4). For compounds
The intramolecular cycloaddition of 19 afforded the cy- 20, 23 and 31, correlations of 2-H with both 3en-H and 6-
cloadduct 31 (Scheme 8) as the only isomer, as detected by H as well as those found between 6-H and 5en-H, and 5en-
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Nitrone Chemistry
Synthesis of Pipecolic Acid Derivatives
Having in hand enantiomerically pure cycloadducts 20
and 23 we pursued the synthesis of 4-hydroxy-6-phenylpipe-
colic acids. From compounds 20 and 23, two key operations
should be performed: i) reduction of the N–O bond to form
the 4-hydroxypiperidine skeleton and ii) unmasking of the
carboxylic group by oxidation of the dioxolane moiety. Bi-
cyclics 20 and 23 were first reduced with Zn in acetic acid
to furnish piperidines 32 and 33 in 94 and 96% yields,
respectively (Scheme 9). By carrying out the reaction at am-
bient temperature over 4 h the integrity of the dioxolane
moiety was completely maintained. With the aim of estab-
lishing an orthogonal protection protocol, compound 32
was converted into O-silyl derivatives 34 and 35. Although
the formation of the O-(tert-butyldimethylsilyl) derivative
took place in 85% yield under conventional conditions
(TBSCl; 2,6-lutidine), protection as the O-(tert-butyldi-
phenylsilyl) derivative proved to be more difficult. Indeed,
by using TBDPSCl in the presence of imidazole, triethyl-
Figure 4. NOE relationships of cycloadducts 20–25 and 31.
H and 3en-H allowed us to assign the exo,exo configuration amine or DMAP,[62] compound 35 was isolated in a low
(further confirmed by X-ray analysis of 20). For com- yield (at best 25%). In contrast, by carrying out the reaction
pounds 21 and 25, no correlation was observed between 6- in the presence of silver nitrate,[63] the same compound was
H and 5en-H. These data, together with the interactions obtained in quantitative yield. Nitrogen protection in 34
shown in Figure 1, suggest that the C-6 substituent is in an and 35 allowed us to isolate the trifluoroacetamido deriva-
endo disposition. As discussed above, the configuration of tives 36 and 37 in good yields. At ambient temperature the
25 was confirmed by X-ray analysis. Similarly, the observed 1H and 13C NMR spectra of these compounds showed an
correlations for 22 and 24 as well as the lack of correlation equilibrium between amide rotamers, but on heating to
between 2-H and 3en-H indicate an endo orientation of the 55 °C coalescence was observed although in the case of 36
substituent at C-2.
broad signals were still present.
Scheme 9. Synthesis of pipecolic acid derivatives (route 1).
Eur. J. Org. Chem. 2008, 3943–3959
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3949

P. Merino, V. Mannucci, T. Tejero
FULL PAPER
To transform the dioxolane ring into a carboxylic acid,
In order to differentiate oxygen and nitrogen protecting
we needed to subject compounds 36 and 37 to acidic condi- groups, compound 35 was benzoylated. An excess of ben-
tions. Unfortunately, treatment of 36 with p-toluenesulfonic zoyl chloride (2.5 equiv.) was needed, which also indicates
acid in methanol resulted in a very sluggish reaction and steric hindrance at the nitrogen atom. Under these condi-
only complex mixtures were obtained. Subjecting 37 to the tions the fully protected derivative 41 was obtained in 77%
same reaction conditions resulted in the recovery of 35 in yield. The same protocol was applied to 33; after silylation
86% isolated yield. From these experiments we concluded and benzoylation, compound 45 was isolated in 73% overall
that the O-(tert-butyldimethylsilyl) and, more disappoint- yield (two steps). Finally, unmasking of the carboxy group
ingly, N-trifluoroacetyl protecting groups were not compati- was carried out by one-pot oxidation of the dioxolane ring
ble with the required conditions for unmasking the carboxy by using periodic acid in diethyl ether.[70] The resulting in-
group. We also attempted an initial N-(tert-butoxycarbonyl) termediate amino aldehyde was oxidized in situ with so-
protection of compound 33. However, after several dium chlorite under neutral conditions.[71] Esterification of
attempts, only the O-Boc derivative 38 was isolated in 40% the carboxylic acid 42 with trimethylsilyldiazomethane fur-
yield.[64] We then turned our attention to the amide group nished the targeted, fully protected (2R,4S,6S)-4-silyloxy-6-
to protect the nitrogen atom. Attempts at chemoselective phenylpipecolic acid 43. Similarly, transformation of 45 into
N-benzoylation of 32 and 33 only led to dibenzoylated ad- ent-43 was carried out in 61% overall yield. As expected,
ducts 39 and 40, which were obtained in good yields when physical and spectroscopic properties of this compound
an excess of benzoyl chloride was employed. As before for were identical to those of its enantiomer with the only ex-
1
compounds 36 and 37, the H and 13C NMR spectra of 39 ception the sign of the optical rotation. Thus, the enantiodi-
and 40 showed a complexity characteristic of compounds vergent synthesis of 43 and ent-43 has been achieved in 32
presenting slow conformational equilibria.
and 30% overall yields (nine steps) from the starting nitrone
Indeed, previous studies with N-acyl-4-acetyl-2,6-di- 9.
phenylpiperidines showed two preferential conforma-
With the aim of simplifying the synthetic process we also
tions[65] due to a pseudo-allylic A(1,3) strain. Allylic A(1,3) considered the possibility of unmasking the carboxy group
strain[66] can feature in N-acylpiperidines due to the partial before reducing the N–O bond in cycloadducts 20 and 23.
double bond character of the amide N–CO bond. It has Bicyclic amino ester 46 was synthesized from 20 by the
been known for some time that a ring substituent at the 2- above-mentioned sequence featuring oxidative cleavage of
position of N-acylpiperidines preferentially adopts a pseu- the dioxolane ring and oxidation of the emerging aldehyde
doaxial arrangement.[67] Such a conformational preference (Scheme 10). The complete protocol took place with a rela-
has been found in nature to be related to biological ac- tively low yield of 43%, presumably due to the presence of
tivity[68] and it has also been used to predict a high level a nucleophilic nitrogen atom, which might lead to undesired
of asymmetric induction in several chemical reactions.[69] oxidation byproducts. Zinc-mediated cleavage of the N–O
Following from these considerations, conformation A for bond afforded methyl ester 47, which was differentially pro-
2,6-disubstituted N-acyl-4-hydroxypiperidines, like those
considered in this work, should present unfavourable steric
interactions between the amide moiety and the adjacent
substituents (Figure 5). The two conformations B and C
should be preferred. These conformational preferences
serve to explain both the difficulty in protecting the nitro-
gen atom as a Boc derivative and the observed lability of
the trifluoroacetamido group.
Figure 5. Preferred conformations for 2,5-disubstituted N-acyl-4-
hydroxypiperidine.
Scheme 10. Synthesis of pipecolic acid derivatives (route 2).
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Eur. J. Org. Chem. 2008, 3943–3959

Nitrone Chemistry
tected to furnish 43. Application of the same reaction se- ogy should thus be of general utility for the preparation
quence to 23 provided ent-43 via bicyclic ent-46 and pipec- of a large number of polysubstituted 4-hydroxypiperidines
olic acid ent-47. By this route compounds 43 and ent-43 (including 2,3,5,6-tetrasubstituted 4-hydroxypiperidines if
were obtained in 23 and 27% overall yields from nitrone 9 substituted allylic compounds are considered) and provides
in nine steps. The approach depicted in Scheme 10 provided a highly stereoselective route to the preparation of highly
the target compounds in lower overall yields than that illus- substituted 4-hydroxypipecolic acids.
trated in Scheme 9. Nevertheless, the initial unmasking of
the carboxy group in 46 and its enantiomer offers the pos-
sibility of introducing acid-sensitive protecting groups in 47 Experimental Section
and ent-47 that could not be used for protecting 32 and 33.
The two routes can be defined as being complementary as
the first provides access not only to pipecolic acid deriva-
General Methods: The reaction flasks and other glass equipment
were heated in an oven at 130 °C overnight and assembled in a
stream of Ar. All reactions were monitored by TLC on silica gel
tives but also to substituted piperidines because of the dif-
ferent synthetic elaborations that can be achieved with the
dioxolane ring.
60 F254; the positions of the spots were detected with 254 nm UV
light or by spraying with one of the following staining systems:
50% methanolic sulfuric acid, 5% ethanolic phosphomolybdic acid
and iodine. Preparative centrifugally accelerated radial thin-layer
chromatography (radial chromatography) was performed with a
Chromatotron® Model 7924 T instrument (Harrison Research,
Palo Alto, CA, USA) and with solvents that were distilled prior to
use; the rotors (1 or 2 mm layer thickness) were coated with silica
gel Merck grade type 7749, TLC grade, with binder and fluores-
cence indicator and the eluting solvents were delivered by the pump
at a flow-rate of 0.5–1.5 mL min–1. Column chromatography was
carried out with a MPLC system (max. pressure: 40 bar) using 5–
60 micron silica gel. Melting points are uncorrected. 1H and 13C
NMR spectra were recorded with Bruker 300, 400 and 500 instru-
ments in CDCl3 unless otherwise indicated. Chemical shifts are re-
ported in ppm (δ) relative to CHCl3 (δ = 7.26 ppm) in CDCl3 and
coupling constants are given in Hz. Optical rotations were mea-
Conclusions
The combination of two typical reactions of nitrones,
that is, nucleophilic addition and cycloaddition chemistry,
has allowed the development of an enantiodivergent strat-
egy directed towards the synthesis of all-cis orthogonally
protected 6-substituted 4-hydroxypipecolic acids. The meth-
odology involves the stereocontrolled allylation of N-ben-
zyl-1,2-di-O-isopropylidene--glyceraldehyde nitrone 9, oxi-
dation of the resulting hydroxylamines and stereoselective
intramolecular cycloaddition of the thus formed N-alkenyl
nitrones. During the course of the research, experimental sured at 25 °C on a Perkin-Elmer 241 or Jasco polarimeter. Ele-
mental analyses were performed with a Perkin-Elmer 240B micro-
analyzer. -Glyceraldehyde nitrone 9 was prepared as described
previously.[33] Nitrones 10 and 11 were prepared by condensation
of the corresponding protected -glyceraldehyde with N-benzylhy-
droxylamine following the same procedure reported for 9.
evidence for a thermal 2-aza-Cope rearrangement of nitro-
nes was found. The final steps of the synthetic methodology
required the use of suitable protecting groups due to the
particular structural features of the 2,4,6-trisubstituted pi-
peridine precursor of the target compounds.
Allylation of Nitrones. General Procedure: A Lewis acid (1.0 equiv.),
where appropriate, was added to a solution of the nitrone
(1.0 equiv.) in the stated solvent (Table 1), and the mixture stirred
for 5 min at ambient temperature and then cooled to the stated
temperature (Table 1). The corresponding allylic metal (2.0 equiv.)
was added and the reaction mixture was stirred at the correspond-
ing temperature until no more nitrone (TLC) was observed (see
Table 1). Saturated aq. NH4Cl was added and the resulting mixture
was diluted with diethyl ether. The organic layer was separated and
the aqueous layer extracted with diethyl ether. The combined or-
ganic extracts were dried (MgSO4), filtered and evaporated to fur-
nish the crude product, which was purified by radial chromatog-
raphy.
Taking into account the fact that the starting nitrone is
easily prepared by condensation of an aldehyde and an N-
substituted hydroxylamine, which, in turn, is obtained by
reduction of the corresponding oxime formed by condensa-
tion of an aldehyde and hydroxylamine hydrochloride, it
can be concluded that the primary raw materials of 6-sub-
stituted 4-hydroxypipecolic acids are two aldehydes, an allyl
reagent and hydroxylamine, the latter being the source of
the nitrogen atom and the hydroxy group (Scheme 11).
(2S,3R)-3-(Benzylhydroxyamino)-1,2-di-O-isopropylidenehex-5-
ene-1,2-diol (8a): Rf (hexane/ethyl acetate, 4:1) = 0.48; white solid,
m.p. 79–80 °C. [α]2D0 = +13 (c = 1.70, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.48–7.20 (m, 5 H), 5.98–5.81 (m, 1 H), 5.25–5.00 (m,
Scheme 11. General approach to 6-substituted 4-hydroxypipecolic
acid derivatives.
3
3 H), 4.50–4.38 (m, 1 H), 4.15–3.95 (m, 3 H), 3.82 (t, J = 8.1 Hz,
1 H), 3.05–2.95 (m, 1 H), 2.62–2.40 (m, 1 H), 2.38–2.25 (m, 1 H),
1.46 (s, 3 H), 1.41 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
138.2, 136.3, 129.1, 128.4, 127.2, 116.5, 108.6, 75.6, 66.8, 65.6, 61.1,
30.8, 26.6, 25.5 ppm. C16H23NO3 (277.36): calcd. C 69.29, H 8.36,
N 5.05; found C 69.57, H 8.34, N 5.07.
The major benefits of this synthetic approach include
large amounts of the intermediate N-alkenyl nitrones, less
than three days work, a very stereoselective two-step se-
quence from -glyceraldehyde nitrone, efficient isolation of
the product in an enantiomerically pure form and the ease
of their conversion into different C-substituted nitrones
(2S,3S)-3-(Benzylhydroxyamino)-1,2-di-O-isopropylidenehex-5-ene-
1,2-diol (8b): Rf (hexane/ethyl acetate, 4:1) = 0.47; white solid, m.p.
through a typical transoximation protocol. This methodol- 74–75 °C. [α]2D0 = –8 (c = 0.84, CHCl3). 1H NMR (300 MHz,
Eur. J. Org. Chem. 2008, 3943–3959
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3951

P. Merino, V. Mannucci, T. Tejero
CDCl3): δ = 7.34–7.22 (m, 5 H), 6.11–5.95 (m, 1 H), 5.25–5.05 (m, Transacetalization of 12a: A solution of 12a (0.095 g, 0.3 mmol) in
FULL PAPER
3
2 H), 5.00 (br., 1 H), 4.35 (q, 3J = 6.5 Hz, 1 H), 4.11 (dd, J = 8.5,
acetone (15 mL) was treated with p-TsOH (2 mg) and MgSO4 (1 g)
and the resulting mixture was stirred at ambient temperature for
16 h. The reaction mixture was then filtered and the solvents evapo-
2
2
6.5 Hz, 1 H), 3.98 (d, J = 13.4 Hz, 1 H), 3.85 (d, J = 13.4 Hz, 1
H), 3.79 (dd, J = 8.5, 6.5 Hz, 1 H), 2.93–2.77 (m, 1 H), 2.72–2.55
3
(m, 1 H), 2.55–2.40 (m, 1 H), 1.43 (s, 3 H), 1.37 (s, 3 H) ppm. 13C rated to dryness. The residue was purified by radial chromatog-
NMR (75 MHz, CDCl3): δ = 138.1, 137.0, 129.5, 128.2, 127.2, raphy (hexane/ethyl acetate, 4:1) to furnish pure 8a. The physical
116.0, 108.9, 75.8, 68.3, 67.9, 60.3, 30.8, 26.6, 25.4 ppm.
16H23NO3 (277.36): calcd. C 69.29, H 8.36, N 5.05; found C
69.52, H 8.22, N 4.88.
and spectroscopic properties of this compound were identical to
those observed for the same product prepared by allylation of
nitrone 9 as described above.
C
(2S,3R)-3-(tert-Butoxycarbonylamino)hexane-1,2-diol 14 from 8a: A
solution of 8a (0.069 g, 0.25 mmol) in methanol (10 mL) was
treated with p-TsOH (5 mg) and stirred at ambient temperature for
6 h. The reaction mixture was then neutralized with Amberlyst ba-
sic ion-exchange resin and filtered. The filtrate was then treated
with Pd(OH)2/C (24 mg) and di-tert-butyl dicarbonate (0.109 g,
0.5 mmol) and the mixture stirred under hydrogen at ambient tem-
perature and 2000 psi. After 24 h the reaction mixture was filtered
through a pad of Celite, which was washed with methanol. The
filtrate was evaporated and the residue was purified by flash
chromatography on silica gel (hexane/ethyl acetate, 2:1) to afford
pure 14 (48 mg, 83%) as a white solid; m.p. 63–65 °C. [α]2D0 = –14
(2S,3R)-3-(Benzylhydroxyamino)-1,2-di-O-cyclohexylidenehex-5-
ene-1,2-diol (12a): Rf (hexane/ethyl acetate, 4:1) = 0.55; oil. [α]2D0
=
–10 (c = 3.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.28–7.16
2
3
(m, 5 H), 5.96 (ddt, J = 17.2, J = 10.1, 7.1 Hz, 1 H), 5.08 (ddt,
2J = 17.2, J = 1.8, 1.2 Hz, 1 H), 5.00 (d, J = 10.1 Hz, 1 H), 4.71
(br., 1 H), 4.26 (q, J = 6.6 Hz, 1 H), 4.03 (dd, J = 8.3, 6.4 Hz, 1
H), 3.92 (d, J = 13.4 Hz, 1 H), 3.81–3.74 (m, 2 H), 2.81 (q, J =
6.5 Hz, 1 H), 2.59 (dt, J = 14.4, J = 6.8 Hz, 1 H), 2.42 (dt, J =
14.4, 3J = 6.2 Hz, 1 H), 1.61–1.45 (m, 8 H), 1.39–1.27 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.3, 137.2, 129.3,
128.4, 127.3, 116.1, 109.5, 75.8, 88.3, 68.1, 60.1, 36.4, 35.0, 31.1,
25.3, 24.1, 23.9 ppm. C19H27NO3 (317.42): calcd. C 71.89, H 8.57,
N 4.41; found C 72.01, H 8.39, N 4.47.
3
3
3
3
2
3
2
3
2
(c = 0.21, CHCl3) {lit.:[43] [α]2D0 = –12 (c = 1, CHCl3)}. H NMR
1
3
(400 MHz, CDCl3): δ = (400 MHz, CDCl3): δ = 4.65 (br. d, J =
(2S,3S)-3-(Benzylhydroxyamino)-1,2-di-O-cyclohexylidenehex-5-
5.3 Hz, 1 H); 3.64–3.70 (m, 2 H), 3.44–3.52 (m, 2 H), 2.48 (br. s, 2
H), 1.43–1.55 (m, 4 H), 1.48 (s, 9 H), 0.98 (t, 3J = 7.2 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 155.0, 80.0, 72.5, 64.3, 51.7,
34.8, 28.7, 19.2, 13.4 ppm. C11H23NO4 (233.31): calcd. C 56.63, H
9.94, N 6.00; found C 56.59, H 10.04, N 5.89.
ene-1,2-diol (12b): Rf (hexane/ethyl acetate, 4:1) = 0.54; oil. [α]2D0
=
+8 (c = 1.75, CHCl3). 1H NMR (400 MHz, CDCl3): δ = (400 MHz,
CDCl3): 7.42–7.37 (m, 2 H), 7.37–7.31 (m, 2 H), 7.31–7.25 (m, 1
H), 5.93 (ddt, 2J = 17.1, 3J = 10.1, 7.0 Hz, 1 H), 5.13 (dt, 2J = 17.1,
3J = 1.5 Hz, 1 H), 5.08 (d, 3J = 10.1 Hz, 1 H), 4.44 (q, 3J = 6.2 Hz,
(2S,3R)-3-(tert-Butoxycarbonylamino)hexane-1,2-diol 14 from 13a:
A solution of 13a (0.104 g, 0.25 mmol) in methanol (10 mL) was
treated with Pd(OH)2/C (24 mg) and di-tert-butyl dicarbonate
(0.109 g, 0.5 mmol), and the mixture was stirred under hydrogen at
ambient temperature and 2000 psi. After 24 h the reaction mixture
was filtered through a pad of Celite, which was washed with meth-
anol. The filtrate was evaporated and the residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate, 2:1) to
afford pure 14 (52 mg, 90%). The physical and spectroscopic prop-
erties of this compound were identical to those observed for the
same product prepared from 8a as described above.
3
3
1 H), 4.07 (s, 2 H), 4.02 (t, J = 6.2 Hz, 1 H), 3.81 (t, J = 6.1 Hz,
3
2
3
1 H), 3.00 (q, J = 6.4 Hz, 1 H), 2.51 (dt, J = 14.7, J = 6.8 Hz,
1 H), 2.32 (dt, 2J = 14.7, 3J = 6.7 Hz, 1 H), 1.70–1.56 (m, 8 H),
1.46–1.38 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.5,
136.3, 129.0, 128.3, 127.2, 116.5, 109.4, 75.4, 66.6, 65.9, 61.1, 36.2,
35.0, 31.2, 25.2, 24.1, 24.0 ppm. C19H27NO3 (317.42): calcd. C
71.89, H 8.57, N 4.41; found C 71.77, H 8.49, N 4.37.
(2S,3R)-3-(Benzylhydroxyamino)-1,2-di-O-benzylhex-5-ene-1,2-diol
(13a): Rf (hexane/ethyl acetate, 4:1) = 0.63; oil. [α]2D0 = –5 (c = 1.18,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = (400 MHz, CDCl3): δ
= 7.28–7.14 (m, 15 H), 5.91 (ddt, 2J = 17.2, 3J = 10.1, 7.1 Hz, 1
(R,Z)-N-Benzylidene-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-en-
1-amine Oxide (15): Activated manganese(IV) oxide (0.65 g,
7.6 mmol) was added in portions to an ice-cooled solution of hy-
droxylamine 8a (1.75 g, 6.3 mmol) in dichloromethane (100 mL).
The reaction was stirred for 8 h at 0 °C. The solution was then
filtered through anhydrous sodium sulfate and concentrated under
reduced pressure. The NMR analysis of the crude product revealed
the presence of only one regioisomer. The crude product was puri-
fied by flash chromatography (hexane/ethyl acetate, 4:1; Rf = 0.13)
to give pure 15 (1.73 g, 100%); white solid, m.p. 104–105 °C. [α]2D0
= –30 (c = 0.72, methanol). 1H NMR (300 MHz, CDCl3): δ = 8.32–
8.24 (m, 2 H), 7.48–7.38 (m, 3 H), 7.36 (s, 1 H), 5.85–5.68 (m, 1 H),
5.20 (ddt, 2J = 16.9, 3J = 2.6, 1.3 Hz, 1 H), 5.10 (d, 3J = 10.1 Hz, 1
3
3
H), 5.07–4.92 (m, 2 H), 4.64 (d, J = 11.4 Hz, 1 H), 4.51 (d, J =
2
11.4 Hz, 1 H), 4.48 (s, 2 H), 3.92 (d, J = 13.5 Hz, 1 H), 3.84 (d,
2J = 13.5 Hz, 1 H), 3.81 (q, J = 5.2 Hz, 1 H), 3.71 (dd, J = 9.9,
3
3
5.1 Hz, 1 H), 3.64 (dd, 3J = 9.9, 4.7 Hz, 1 H), 2.94 (q, J = 6.1 Hz,
3
2
3
2
3
1 H), 2.62 (dt, J = 13.8, J = 6.8 Hz, 1 H), 2.38 (dt, J = 13.8, J
= 6.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.6,
138.5, 138.0, 137.8, 129.0, 128.4, 128.3, 128.2, 127.8, 127.7, 127.6,
127.5, 127.1, 115.7, 79.3, 73.5, 72.4, 71.3, 67.0, 60.9, 30.8 ppm.
C27H31NO3 (417.54): calcd. C 77.67, H 7.48, N 3.35; found C
77.52, H 7.37, N 3.43.
(2S,3S)-3-(Benzylhydroxyamino)-1,2-di-O-benzylhex-5-ene-1,2-diol
(13b): Rf (hexane/ethyl acetate, 4:1) = 0.62; oil. [α]2D0 = –20 (c =
0.37, CHCl3). 1H NMR (400 MHz, CDCl3): δ = (400 MHz,
CDCl3): δ = 7.28–7.12 (m, 15 H), 5.76–5.62 (m, 1 H), 4.97–4.89
3
3
H), 4.61 (q, J = 6.6 Hz, 1 H), 4.18 (ddd, J = 8.5, 6.4, 0.9 Hz, 1
H), 3.95–3.81 (m, 2 H), 2.96–2.82 (m, 1 H), 2.28–2.16 (m, 1 H),
1.44 (s, 3 H), 1.36 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
134.8, 132.2, 130.0, 129.9, 128.5, 128.0, 118.5, 109.1, 78.3, 74.9,
65.8, 32.1, 26.4, 24.8 ppm. C16H21NO3 (275.34): calcd. C 69.79, H
7.69, N 5.09; found C 70.02, H 7.76, N 4.98.
3
3
(m, 2 H), 4.69 (dd, J = 11.5 Hz, 1 H), 4.59 (br., 1 H), 4.47 (d, J
= 11.5 Hz, 1 H), 4.42 (d, J = 11.9 Hz, 1 H), 4.37 (d, 3J = 11.9 Hz,
3
1 H), 4.01 (d, 2J = 13.2 Hz, 1 H), 3.80–3.74 (m, 1 H), 3.72–3.65
(m, 3 H), 2.94–2.87 (m, 1 H), 2.57–2.39 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 138.4, 138.3, 138.1, 136.5, 129.6, 129.0, (S,Z)-N-Benzylidene-1-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-
128.3, 128.1, 127.7, 127.6, 127.5, 127.0, 121.3, 116.8, 78.9, 73.3,
73.2, 71.2, 64.8, 60.6, 28.4 ppm. C27H31NO3 (417.54): calcd. C
77.67, H 7.48, N 3.35; found C 77.62, H 7.43, N 3.39.
en-1-amine Oxide (16): Oxidation of hydroxylamine 8b (1.75 g,
6.3 mmol) as described above for 8a afforded nitrone 16 (1.73 g,
100 %) after purification by flash chromatography (hexane/ethyl
3952
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Nitrone Chemistry
3
acetate, 4:1; Rf = 0.24); white solid, m.p. 38–39 °C. [α]2D0 = +18 (c
7.22–7.14 (m, 1 H), 4.95 (t, J = 4.8 Hz, 1 H), 4.26 (q, 3J = 6.9 Hz,
1
3
3
= 1.71, MeOH). H NMR (300 MHz, CDCl3): δ = 8.20–8.12 (m, 1 H), 3.99 (dd, J = 8.1, 6.9 Hz, 1 H), 3.93 (dd, J = 8.3, 4.8 Hz, 1
2 H), 7.38–7.26 (m, 4 H), 5.71 (ddt, J = 17.1, J = 10.1, 7.2 Hz, 1 H), 3.72 (dd, 3J = 8.1, 6.9 Hz, 1 H), 3.18 (td, J = 7.6, 4.8 Hz, 1
2
3
3
2
3
2
H), 5.11 (d, J = 17.1 Hz, 1 H), 4.99 (d, J = 10.1 Hz, 1 H), 4.46
H), 2.15 (dd, J = 11.8, 3J = 8.3 Hz, 1 H), 2.05–1.94 (m, 1 H), 1.75
(dt, J = 7.4, 5.6 Hz, 1 H), 4.00 (dd, J = 8.9, 6.1 Hz, 1 H), 3.90 (dd, 2J = 11.8, J = 8.0 Hz, 1 H), 1.68–1.57 (m, 1 H), 1.41 (s, 3 H),
3
3
3
(dd, 3J = 8.9, 4.9 Hz, 1 H), 3.81–3.72 (m, 1 H), 2.90–2.74 (m, 1 H),
1.33 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.7, 128.4,
2.61–2.49 (m, 1 H), 1.34 (s, 3 H), 1.28 (s, 3 H) ppm. 13C NMR
126.9, 126.8, 109.3, 78.7, 77.2, 70.5, 69.9, 65.7, 42.7, 34.8, 26.7,
(75 MHz, CDCl3): δ = 135.1, 132.9, 130.3, 129.8, 128.5, 128.3, 25.1 ppm. C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N 5.09;
118.5, 109.6, 77.7, 75.8, 66.3, 33.4, 26.7, 25.0 ppm. C16H21NO3 found C 69.88, H 7.76, N 5.03.
(275.34): calcd. C 69.79, H 7.69, N 5.09; found C 69.68, H 7.65, N
21: Yield: 0.031 g (5%). Rf (hexane/ethyl acetate, 4:1) = 0.30; white
5.13.
solid, m.p. 148–149 °C. [α]2D0 = +31 (c = 0.07, CHCl3). 1H NMR
N-{(S)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]but-3-enyl}hydroxyl-
amine (18): A well-stirred and cooled (0 °C) solution of hydroxyl-
amine hydrochloride (0.051 g, 0.73 mmol) in methanol (5 mL) was
sequentially treated with NaOH (0.029 g, 0.73 mmol) and AcOH
(0.044 g, 0.734 mmol). The resulting solution was stirred for 15 min
after which time the nitrone 16 (0.185 g, 0.67 mmol) was added.
The resulting mixture was stirred at room temperature for 24 h and
then concentrated under reduced pressure. The crude product was
purified by radial chromatography (hexane/ethyl acetate, 4:1; Rf =
0.19) to give pure 18 (0.112 g, 90%); oil. [α]2D0 = +4 (c = 2.49,
CHCl3). 1H NMR (500 MHz, CDCl3): δ = 6.27 (br., 1 H), 5.82
(ddt, 2J = 17.1, 3J = 10.2, 7.2 Hz, 1 H), 5.15 (d, 2J = 17.1 Hz, 1
(400 MHz, CDCl3): δ = 7.47–7.42 (m, 2 H), 7.37–7.33 (m, 2 H),
3
7.27–7.21 (m, 1 H), 5.05–5.00 (m, 1 H), 4.61 (t, J = 6.5 Hz, 1 H),
3
3
4.28 (dt, J = 8.5, 6.9 Hz, 1 H), 4.14 (dd, J = 8.0, 6.3 Hz, 1 H),
3
3
3.77 (t, J = 7.6 Hz, 1 H), 3.58 (ddd, J = 10.0, 8.5, 6.3 Hz, 1 H),
2.19–2.08 (m, 3 H), 1.50 (s, 3 H), 1.40 (s, 3 H), 1.26 (dd, J = 11.2,
2
3J = 6.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.9,
128.4, 126.9, 126.7, 110.0, 80.4, 75.4, 67.9, 67.7, 62.9, 43.3, 35.3,
26.7, 25.4 ppm. C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N
5.09; found C 69.74, H 7.65, N 5.03.
22: Yield: 0.126 g (20%). Rf (hexane/ethyl acetate, 4:1) = 0.33; white
solid, m.p. 94–96 °C. [α]2D0 = –34 (c = 0.23, CHCl3). 1H NMR
3
(300 MHz, CDCl3): δ = 7.47–7.29 (m, 5 H), 5.03 (t, J = 5.0 Hz, 1
3
3
H), 5.13 (d, J = 10.2 Hz, 1 H), 4.21 (q, J = 6.4 Hz, 1 H), 4.08 (t,
H), 4.75 (dd, 3J = 10.2, 6.4 Hz, 1 H), 4.13 (dd, 3J = 8.0, 6.5, 5.7 Hz,
3J = 7.6 Hz, 1 H), 3.86 (t, 3J = 7.6 Hz, 1 H), 3.01 (dt, 3J = 8.8,
3
3
1 H), 3.97 (dd, J = 8.5, 6.5 Hz, 1 H), 3.64 (dd, J = 8.5, 5.7 Hz, 1
2
3
2
4.8 Hz, 1 H), 2.37 (dt, J = 14.2, J = 5.2 Hz, 1 H), 2.26 (dt, J =
14.2, 3J = 8.4 Hz, 1 H), 1.42 (s, 3 H), 1.36 (s, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 134.6, 118.2, 108.7, 76.0, 66.9, 62.4, 32.3,
26.4, 25.2 ppm. C9H17NO3 (187.24): calcd. C 57.73, H 9.15, N 7.48;
found C 57.84, H 9.03, N 7.36.
3
H), 3.17 (td, J = 8.0, 5.5 Hz, 1 H), 2.47–2.34 (m, 1 H), 1.75 (dd,
2J = 11.6, 3J = 6.4 Hz, 1 H), 1.62 (dd, 2J = 11.6, 3J = 8.0 Hz, 1
H), 1.58–1.49 (m, 1 H), 1.33 (s, 3 H), 1.26 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 136.5, 128.6, 128.5, 127.6, 109.3, 81.3, 77.4,
70.2, 65.7, 62.3, 36.5, 35.7, 26.5, 25.1 ppm. C16H21NO3 (275.34):
calcd. C 69.79, H 7.69, N 5.09; found C 69.93, H 7.80, N 5.11.
(S,Z)-1-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-N-propylidenebut-3-en-
1-amine Oxide (19): Hydroxylamine 18 (0.050 g, 0.27 mmol) and
anhydrous magnesium sulfate (0.033 g, 0.27 mmol) were added to
a well-stirred solution of propionaldehyde (0.021 mL, 0.29 mmol)
in dichloromethane (4 mL) and the resulting mixture was stirred at
room temperature for 4 h. The mixture was filtered and the filtrate
evaporated under reduced pressure to yield the crude product
which was purified by chromatography on silica gel (hexane/ethyl
acetate, 4:1; Rf = 0.17) to afford the corresponding pure nitrone 19
(0.053 g, 86%); oil. [α]2D0 = –5 (c = 1.59, CHCl3). 1H NMR
Intramolecular 1,3-Dipolar Cycloaddition of Nitrone 16: The intra-
molecular cycloaddition of nitrone 16 (0.63 g, 2.3 mmol) was car-
ried out as described above for 15. The NMR analysis of the crude
product revealed the presence of the three regioisomeric cycload-
ducts 23, 24 and 25 in an 82:5:13 ratio, respectively. Purification
by radial chromatography of the crude product afforded the pure
cycloadducts.
23: Yield: 0.516 g (82%). Rf (hexane/ethyl acetate, 4:1) = 0.54; white
solid, m.p. 76–77 °C. [α]2D0 = +54 (c = 1.28, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.29–7.25 (m, 2 H), 7.24–7.21 (m, 2 H),
3
2
(500 MHz, CDCl3): δ = 6.63 (t, J = 5.8 Hz, 1 H), 5.70 (ddt, J =
17.2, 3J = 10.1, 7.3 Hz, 1 H), 5.16 (dd, 2J = 17.2, 3J = 1.2 Hz, 1
H), 5.09 (d, J = 10.1 Hz, 1 H), 4.47 (ddd, J = 7.9, 5.9, 5.3 Hz, 1
3
3
3
3
7.17–7.10 (m, 1 H), 4.91 (t, J = 4.9 Hz, 1 H), 4.09 (dd, J = 8.6,
3
3
H), 4.06 (dd, J = 9.0, 6.2 Hz, 1 H), 3.86 (dd, J = 9.0, 4.8 Hz, 1
3
5.9 Hz, 1 H), 3.92 (dd, J = 8.6, 4.7 Hz, 1 H), 3.90–3.80 (m, 2 H),
H), 3.57 (ddd, 3J = 10.7, 8.1, 3.3 Hz, 1 H), 2.77 (ddd, 2J = 14.4, J
3
3
2
3
2.89 (td, J = 8.5, 4.0 Hz, 1 H), 2.07 (dd, J = 11.8, J = 8.4 Hz, 1
H), 1.96–1.86 (m, 2 H), 1.76 (dd, 2J = 11.8, 3J = 7.8 Hz, 1 H), 1.35
(s, 3 H), 1.25 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.7,
128.4, 126.8, 126.5, 109.0, 79.4, 78.6, 70.1, 70.0, 68.8, 42.4, 36.8,
27.1, 25.2 ppm. C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N
5.09; found C 69.81, H 7.75, N 5.22.
= 10.7, 7.3 Hz, 1 H), 2.58–2.52 (m, 1 H), 2.51–2.42 (m, 2 H), 1.41
(s, 3 H), 1.34 (s, 3 H), 1.09 (t, 3J = 7.6, 3 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 141.5, 133.1, 118.5, 109.7, 76.3, 75.6, 66.4,
33.3, 26.9, 25.1, 19.6, 10.0 ppm. C12H21NO3 (227.30): calcd. C
63.41, H 9.31, N 6.16; found C 63.20, H 9.25, N 6.26.
Intramolecular 1,3-Dipolar Cycloaddition of Nitrone 15: Nitrone 15
(0.63 g, 2.3 mmol) was dissolved in toluene (20 mL) and the corre-
sponding solution was heated with stirring at 110 °C for 72 h in a
sealed tube. After this time the solution was concentrated under
reduced pressure. The NMR analysis of the crude product revealed
the presence of the three regioisomeric cycloadducts 20, 21 and 22
in a 75:5:20 ratio, respectively. The crude mixture was purified by
radial chromatography to give the corresponding pure cycload-
ducts.
24: Yield: 0.031 g (5%). Rf (hexane/ethyl acetate, 4:1) = 0.45; white
solid, m.p. 140–141 °C. [α]2D0 = –51 (c = 0.09, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.45–7.38 (m, 2 H), 7.37–7.29 (m, 2 H),
3
3
7.28–7.19 (m, 1 H), 5.04 (t, J = 5.2 Hz, 1 H), 4.57 (dd, J = 8.3,
3
3
4.6 Hz, 1 H), 4.43 (ddd, J = 8.2, 6.5, 3.6 Hz, 1 H), 4.16 (dd, J =
8.2, 6.5 Hz, 1 H), 3.66 (t, 3J = 8.2 Hz, 1 H), 3.55 (ddd, J = 9.7,
5.9, 3.6 Hz, 1 H), 2.20 (dd, J = 11.2, J = 8.3 Hz, 1 H), 2.16–2.00
(m, 2 H), 1.69 (dd, J = 11.2, J = 5.9 Hz, 1 H), 1.47 (s, 3 H), 1.42
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.3, 128.4, 126.7,
126.6, 110.0, 81.2, 73.4, 68.4, 68.1, 64.3, 43.5, 33.0, 26.4, 25.9 ppm.
C16H21NO3 (275.34): calcd. C 69.79, H 7.69, N 5.09; found C
3
2
3
2
3
20: Yield: 0.472 g (75%). Rf (hexane/ethyl acetate, 4:1) = 0.38; white
solid, m.p. 98–99 °C. [α]2D0 = –34 (c = 0.41, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.33 (m, 2 H), 7.32–7.27 (m, 2 H), 69.65, H 7.58, N 5.13.
Eur. J. Org. Chem. 2008, 3943–3959
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3953

P. Merino, V. Mannucci, T. Tejero
FULL PAPER
25: Yield: 0.081 g, 13%). Rf (hexane/ethyl acetate, 4:1) = 0.50; white
2.65 (tdd, 3J = 7.9, 6.4, 4.5 Hz, 1 H), 1.92–1.84 (m, 1 H), 1.74 (dd,
2J = 11.4, 3J = 7.7 Hz, 1 H), 1.71 (dd, 2J = 11.4, 3J = 7.8 Hz, 1
solid, m.p. 80–81 °C. [α]2D0 = +83 (c = 0.11, CHCl3). 1H NMR
3
(300 MHz, CDCl3): δ = 7.46–7.30 (m, 5 H), 5.08 (t, J = 5.1 Hz, 1 H), 1.58 (dq, 2J = 13.8, 3J = 7.5 Hz, 1 H), 1.52–1.44 (m, 1 H), 1.42
3
3
2
3
H), 4.68 (dd, J = 10.1, 6.5 Hz, 1 H), 4.14 (dd, J = 8.3, 6.1 Hz, 1
(s, 3 H), 1.34 (s, 3 H), 1.25 (dq, J = 13.8, J = 7.1 Hz, 1 H), 0.95
H), 3.95 (dt, 3J = 9.0, 6.1 Hz, 1 H), 3.56 (dd, J = 8.3, 6.1 Hz, 1 (t, 3J = 7.4, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 108.9,
3
H), 2.91 (ddd, 3J = 8.6, 8.2, 4.7 Hz, 1 H), 2.40–2.26 (m, 1 H), 2.01–
79.3, 78.7, 69.9, 69.5, 68.7, 39.4, 36.8, 29.5, 27.2, 25.2, 11.2 ppm.
C12H21NO3 (227.30): calcd. C 63.41, H 9.31, N 6.16; found C
63.37, H 9.45, N 6.08.
2
3
2
1.90 (m, 1 H), 1.82 (dd, J = 11.9, J = 6.5 Hz, 1 H), 1.76 (dd, J
= 11.9, 3J = 8.0 Hz, 1 H), 1.29 (s, 3 H), 1.25 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 135.9, 128.7, 128.5, 128.0, 108.9, 82.0,
78.6, 70.4, 68.6, 62.4, 38.6, 35.0, 26.7, 25.3 ppm. C16H21NO3
(275.34): calcd. C 69.79, H 7.69, N 5.09; found C 70.00, H 7.96, N
5.07.
(2R,4S,6S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-phenylpiper-
idin-4-ol (32): Compound 20 (0.450 g, 1.63 mmol) was taken up in
70% aq. acetic acid (10 mL) and Zn powder (2.120 g, 32.6 mmol)
was added portionwise to the resulting suspension. The resulting
(؎)-N-Hydroxy-1-phenylbut-3-en-1-amine (29): A solution of mixture was stirred at room temperature for 4 h, filtered and the
benzaldoxime (3.634 g, 30 mmol) and 2-allyl-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (28) (3.70 g, 33 mmol), synthesized as de-
scribed by Hoffmann and Endesfelder,[59a] in carbon tetrachloride
(50 mL) was heated at reflux for 7 h. The reaction mixture was
diluted with diethyl ether (100 mL) and 1  HCl (100 mL). The
organic layer was separated and the aqueous layer was extracted
with diethyl ether (3ϫ20 mL). The aqueous layer was cooled in an
ice bath and adjusted to pH 10 by addition of 6  aqueous KOH,
and extracted with diethyl ether (3ϫ50 mL). The combined or-
ganic extracts were washed with brine, dried with magnesium sul-
fate and concentrated under reduced pressure. The crude product
was purified by flash chromatography (hexane/ethyl acetate, 4:1; Rf
solid washed with water. The filtrate was neutralized by the ad-
dition of 5  NaOH and then extracted with dichloromethane
(3ϫ50 mL). The combined organic extracts were washed sequen-
tially with a saturated aq. solution of EDTA and brine. The organic
layer was separated, dried with magnesium sulfate, filtered and
evaporated under reduced pressure. The resulting crude product
was purified by radial chromatography (hexane/ethyl acetate, 4:1;
Rf = 0.1) to give pure 32 (0.424 g, 94%); white solid, m.p. 124–
125 °C. [α]2D0 = –45 (c = 0.62, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.45–7.40 (m, 2 H), 7.38–7.32 (m, 2 H), 7.31–7.25 (m,
3
1 H), 4.11–4.00 (m, 2 H), 3.85 (tt, J = 10.8, 4.5 Hz, 1 H), 3.77–
3
3.69 (m, 2 H), 2.79 (ddd, J = 10.9, 8.2, 2.3 Hz, 1 H), 2.29 (br., 1
1
= 0.48) to afford pure 29 (3.525 g, 72%); oil. H NMR (400 MHz,
H), 2.13 (ddt, 2J = 11.9, 3J = 4.5, 2.2 Hz, 1 H), 1.82 (ddt, 2J =
2
3
3
CDCl3): δ = 7.42–7.28 (m, 5 H), 5.74 (dddd, J = 16.7, J = 10.1,
11.9, J = 4.5, 2.2 Hz, 1 H), 1.65–1.45 (m, 2 H), 1.40 (s, 3 H), 1.35
7.9, 6.3 Hz, 1 H), 5.15–5.05 (m, 2 H), 4.05 (t, J = 7.1 Hz, 1 H), (s, 3 H), 1.23 (q, 3J = 11.2 Hz, 1 H) ppm. 13C NMR (100 MHz,
3
2.57 (dt, 2J = 14.8, 3J = 7.7 Hz, 1 H), 2.46 (dt, 2J = 14.8, 3J = CDCl3): δ = 143.5, 128.3, 127.3, 126.7, 109.2, 79.0, 68.8, 66.5, 59.0,
6.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 140.8, 134.5,
128.5, 127.7, 127.6, 117.9, 66.1, 38.1 ppm. C10H13NO (163.22):
calcd. C 73.59, H 8.03, N 8.58; found C 73.69, H 8.07, N 8.77.
58.5, 43.3, 36.7, 26.7, 25.3 ppm. C16H23NO3 (277.36): calcd. C
69.29, H 8.36, N 5.05; found C 69.16, H 8.59, N 5.23.
(2S,4R,6R)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-phenylpiper-
idin-4-ol (33): The reduction of 23 (0.500 g, 1.82 mmol), as de-
scribed for 20 in the synthesis of 32, gave after purification by ra-
dial chromatography (hexane/ethyl acetate, 4:1; Rf = 0.10) pure 33
(S,Z)-N-{[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methylene}-1-phenyl-
but-3-en-1-amine Oxide (26) and (R,Z)-N-{[(S)-2,2-Dimethyl-1,3-di-
oxolan-4-yl]methylene}-1-phenylbut-3-en-1-amine Oxide (27):
Amine 29 (0.326 g, 2 mmol) and anhydrous magnesium sulfate (0.485 g, 96%); white solid, m.p. 98–99 °C. [α]2D0 = +33 (c = 0.84,
(0.241 g, 2 mmol) were added to a well-stirred solution of 1,2-di-
O-isopropylidene--glyceraldehyde[72] (0.260 g, 2 mmol) in dichlo-
romethane (15 mL) and the stirring was maintained at room tem-
CHCl3). 1H NMR (400 MHz, [D6]acetone): δ = 7.34–7.16 (m, 5
H), 4.10–3.99 (m, 2 H), 3.92 (t, 3J = 6.1 Hz, 1 H), 3.72 (tt, 2J =
11.4, 3J = 4.3 Hz, 1 H), 3.61 (dd, 2J = 11.4, 3J = 2.2 Hz, 1 H), 2.96
perature for 4 h. The mixture was filtered and the filtrate evapo- (dt, 2J = 11.4, 3J = 2.9 Hz, 1 H), 2.19 (br., 1 H), 2.02 (ddt, J =
2
3
2
3
rated under reduced pressure to yield the crude product, which was
purified by flash chromatography (hexane/ethyl acetate, 4:1; Rf =
0.08) to afford a 1:1 mixture of nitrones 26 and 27 (0.485 g, 88%)
11.7, J = 4.3, 2.1 Hz, 1 H), 1.94 (ddt, J = 11.7, J = 4.3, 2.0 Hz,
3
1 H), 1.36–1.28 (m, 1 H), 1.32 (s, 3 H), 1.30 (s, 3 H), 1.01 (q, J =
11.5 Hz, 1 H) ppm. 13C NMR (100 MHz, [D6]acetone): δ = 146.7,
129.6, 129.3, 128.0, 110.7, 80.2, 70.0, 66.7, 60.4, 57.5, 46.3, 39.1,
27.4, 26.1 ppm. C16H23NO3 (277.36): calcd. C 69.29, H 8.36, N
5.05; found C 69.19, H 8.43, N 4.92.
1
that could not be separated by chromatographic methods; oil. H
NMR (400 MHz, CDCl3; mixture of diastereoisomers): δ = 7.52–
3
3
7.34 (m, 10 H), 7.03 (d, J = 4.5 Hz, 1 H), 7.00 (d, J = 4.7 Hz, 1
H), 5.83–5.67 (m, 2 H), 5.27–5.06 (m, 6 H), 4.81 (dd, 3J = 9.0,
(2R,4S,6S)-4-tert-Butyldimethylsiloxy-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-6-phenylpiperidine (34): 2,6-Lutidine (0.535 g, 5 mmol)
was added to a cooled (0 °C) solution of 32 (0.277 g, 1 mmol) in
anhydrous dichloromethane (10 mL) under argon. The resulting
mixture was cooled to –40 °C and tert-butyldimethylsilyl triflate
(0.793 g, 3 mmol) was added through a syringe. After 5 min of stir-
ring at –40 °C, the reaction mixture was warmed slowly to room
temperature. Then the reaction was quenched with saturated aq.
ammonium chloride (10 mL). The organic layer was separated,
washed with brine, dried with magnesium sulfate, filtered and evap-
orated under reduced pressure. The crude product was filtered
through a short pad of silica gel (hexane/ethyl acetate, 4:1; Rf =
0.17) to give pure 34 (0.333 g, 85%); oil. [α]2D0 = +10 (c = 1.2,
3
3
5.8 Hz, 1 H), 4.77 (dd, J = 9.4, 5.4 Hz, 1 H), 4.43 (dd, J = 8.6,
3
3
7.2 Hz, 1 H), 4.37 (dd, J = 8.7, 7.1 Hz, 1 H), 3.88 (dd, J = 8.6,
3
5.9 Hz, 1 H), 3.77 (dd, J = 8.7, 5.8 Hz, 1 H), 3.28–3.16 (m, 2 H),
2.74–2.62 (m, 2 H), 1.44 (s, 3 H), 1.43 (s, 3 H), 1.39 (s, 3 H), 1.38
(s, 3 H) ppm.
Intramolecular 1,3-Dipolar Cycloaddition of Nitrone 19: The intra-
molecular cycloaddition of nitrone 19 (0.053 g, 0.23 mmol) was
carried out as described above for 15. The NMR analysis of the
crude product revealed the presence of cycloadduct 31 as the only
product of the reaction. Purification by radial chromatography
(hexane/ethyl acetate, 4:1; Rf = 0.73) of the crude product afforded
1
pure 31 (0.050 g, 95%) as an oil. [α]2D0 = +5 (c = 0.47, CHCl3). H
3
1
NMR (500 MHz, CDCl3): δ = 4.85 (t, J = 4.9 Hz, 1 H), 4.18 (dd,
CHCl3). H NMR (400 MHz, CDCl3, 55 °C): δ = 7.49–7.17 (m, 5
3
3J = 8.6, 6.0 Hz, 1 H), 4.00 (dd, J = 8.6, 4.7 Hz, 1 H), 3.90 (ddd,
H), 4.10–3.94 (m, 2 H), 3.82–3.55 (m, 4 H), 2.18 (br., 1 H), 2.2–
1.86 (m, 2 H), 1.66–1.44 (m, 2 H), 1.37 (s, 1.5 H), 1.36 (s, 1.5 H),
3
3J = 9.3, 6.0, 4.7 Hz, 1 H), 2.78 (ddd, J = 9.3, 7.9, 4.2 Hz, 1 H),
3954
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3943–3959

Nitrone Chemistry
3
2
1.32 (s, 1.5 H), 1.31 (s, 1.5 H), 1.30–1.18 (m, 1 H), 0.88–0.84 (m, 9 (t, 3J = 6.5 Hz, 1 H), 3.29 (t, J = 7.5 Hz, 1 H), 2.49 (dt, J = 12.8,
H), 0.06–0.03 (m, 3 H), 0.02–0.01 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, 55 °C): δ = 143.4, 128.3, 127.6, 126.3, 109.3,
3J = 6.6 Hz, 1 H), 2.20 (ddd, 2J = 12.8, 3J = 7.6, 4.2 Hz, 1 H),
2.05–1.92 (m, 1 H), 1.37 (s, 3 H), 1.37–1.27 (m, 1 H), 1.11 (s, 3 H),
79.9, 70.6, 67.1, 59.6, 58.1, 44.2, 37.5, 26.7, 26.6, 25.1, 19.4, –4.7, 1.08 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 158.1, 140.2,
–4.9 ppm. C22H37NO3Si (391.62): calcd. C 67.47, H 9.52, N 3.58; 135.8, 135.6, 133.5, 133.4, 130.1, 130.0, 128.0, 127.9, 127.8, 126.9,
found C 67.32, H 9.33, N 3.70.
126.7, 116.8, 109.8, 75.7, 67.5, 65.1, 57.5, 53.8, 49.6 35.2, 27.1, 26.3,
25.2, 19.1 ppm. C34H40F3NO4Si (611.77): calcd. C 66.75, H 6.59,
N 2.29; found C 66.69, H 6.45, N 2.33.
(2R,4S,6S)-4-tert-Butyldiphenylsiloxy-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-6-phenylpiperidine (35): Pyridine (0.171 g, 2.16 mmol)
and silver nitrate (0.08 g, 0.473 mmol) were added sequentially to
a well-stirred solution of 32 (0.120 g, 0.43 mmol) in anhydrous
dichloromethane (5 mL). After 10 min of stirring, tert-butyldiphen-
ylsilyl chloride (0.155 g, 0.56 mmol) was added and stirring was
maintained for 18 h. After this time the solution was filtered trough
a short pad of Celite®, diluted with dichloromethane (10 mL),
washed with saturated aq. CuSO4 (15 mL) and water (15 mL),
dried with anhydrous magnesium sulfate, filtered and evaporated
under reduced pressure. The crude product was purified by radial
chromatography (hexane/ethyl acetate, 4:1; Rf = 0.59) to afford
pure 35 (0.222 g, 100%); oil. [α]2D0 = +8 (c = 1.04, CHCl3). 1H NMR
(400 MHz, CDCl3, 55 °C): δ = 7.79–7.68 (m, 4 H), 7.52–7.24 (m,
tert-Butyl (2S,4R,6R)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-
phenylpiperidin-4-yl Carbonate (38): Boc2O (0.746 g, 3.42 mmol)
was added to a well-stirred solution of 33 (0.315 g, 1.14 mmol) in
dioxane (30 mL) and the resulting solution was stirred for 48 h,
after which time the solvent was removed under reduced pressure.
The NMR analysis of the crude revealed the presence of the start-
ing material and the product. After purification by radial
chromatography (hexane/ethyl acetate, 4:1), compounds 33
(0.189 g, 60%) and 38 (0.172 g, 40%) were obtained.
1
38: Rf (hexane/ethyl acetate, 4:1) = 0.13; oil. H NMR (400 MHz,
CDCl3): δ = 7.42–7.37 (m, 2 H), 7.37–7.31 (m, 2 H), 7.30–7.24 (m,
1 H), 4.74 (tt, 2J = 11.2, 3J = 4.2 Hz, 1 H), 4.17–4.07 (m, 2 H),
3
11 H), 4.02–3.91 (m, 2 H), 3.84 (tt, J = 10.7, 4.5 Hz, 1 H), 3.54
3
2
3
3.99 (dd, J = 6.8, 6.0 Hz, 1 H), 3.76 (dd, J = 11.5, J = 2.2 Hz,
2
3
3
(dd, J = 11.5, J = 2.1 Hz, 1 H), 3.47 (dd, J = 7.4, 6.4 Hz, 1 H),
2
3
2
1 H), 3.10 (ddd, J = 11.8, J = 5.2, 2.2 Hz, 1 H), 2.23 (ddt, J =
3
2.54 (ddd, J = 10.4, 8.0, 1.8 Hz, 1 H), 2.51 (br., 1 H), 2.07–2.00
(m, 1 H), 1.69 (q, J = 11.4 Hz, 1 H), 1.53–1.45 (m, 1 H), 1.36 (s,
3
2
3
11.8, J = 4.2, 2.2 Hz, 1 H), 2.14 (ddt, J = 11.5, J = 4.2, 2.2 Hz,
3
1 H), 1.75 (br., 1 H), 1.54 (q, 2J = 11.6 Hz, 1 H), 1.49 (s, 9 H), 1.39
3 H), 1.34 (s, 3 H), 1.36–1.24 (m, 1 H), 1.10 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 144.0, 135.7, 135.6, 134.4, 134.1,
129.7, 129.6, 128.3, 127.6, 127.5, 127.2, 126.8, 109.1, 79.1, 70.7,
65.5, 59.1, 58.5, 43.8, 37.0, 26.9, 26.8, 25.3, 19.0 ppm. C32H41NO3
(487.67): calcd. C 74.52, H 8.01, N 2.72; found C 74.49, H 7.94, N
2.62.
(s, 3 H), 1.37 (s, 3 H), 1.25 (q, J = 11.6 Hz, 1 H) ppm. 13C NMR
2
(100 MHz, CDCl3): δ = 152.8, 143.7, 128.5, 127.4, 126.6, 109.0,
82.1, 78.4, 74.4, 65.1, 58.8, 55.2, 40.4, 33.4, 27.8, 26.4, 25.2 ppm.
C
21H31NO5 (377.48): calcd. C 66.82, H 8.28, N 3.71; found C
66.99, H 8.17, N 3.59.
(2R,4S,6S)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-phenyl-N-
benzoylpiperidin-4-yl Benzoate (39): Benzoyl chloride (0.133 g,
0.95 mmol) was added to a cooled (0 °C) solution of 32 (0.120 g,
0.43 mmol) in pyridine (2 mL). The resulting solution was stirred
at room temperature for 4 h after which time the reaction was
quenched with saturated aq. CuSO4 (2 mL) and extracted with
dichloromethane (3ϫ10 mL). The combined organic extracts were
washed sequentially with water (30 mL), 5 % HCl (30 mL), 5%
NaOH (30 mL) and brine (30 mL). The organic layer was sepa-
rated, dried with magnesium sulfate and evaporated under reduced
pressure. The crude product was purified by radial chromatography
(hexane/ethyl acetate, 4:1; Rf = 0.10) to give pure 39 (0.177 g, 85%);
oil. [α]2D0 = –65 (c = 1.87, methanol). 1H NMR (400 MHz, CDCl3):
δ = 7.58–7.45 (m, 4 H), 7.44–7.27 (m, 6 H), 7.22–7.10 (m, 5 H),
6.10 (br., 1 H), 5.46–5.41 (m, 1 H), 4.31–4.22 (m, 1 H), 4.22 (br., 1
(2R,4S,6S)-4-tert-Butyldimethylsiloxy-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-6-phenyl-N-(trifluoroacetyl)piperidine (36): pyridine
(0.073 g, 0.93 mmol) and TFAA (0.097 mL, 0.62 mmol) were added
sequentially to a stirred solution of 34 (0.120 g, 0.31 mmol) in an-
hydrous dichloromethane (2 mL) and the resulting solution was
stirred for 3 h. After this time saturated aq. sodium hydrogen car-
bonate (5 mL) was added and the resulting mixture was extracted
with diethyl ether (3ϫ15 mL). The combined organic extracts were
washed with saturated aq. CuSO4 (45 mL) and brine (45 mL). The
organic layer was separated, dried with magnesium sulfate, filtered
and the solvent removed under reduced pressure. The crude prod-
uct was purified by radial chromatography (hexane/ethyl acetate,
4:1; Rf = 0.88) to give pure 36 (0.136 g, 90%). The NMR analysis
revealed the presence of several conformers; only signals corre-
sponding to the major one are given; oil. [α]2D0 = –61 (c = 1.09,
3
H), 3.40 (t, J = 6.0 Hz, 1 H), 3.06–2.94 (m, 2 H), 2.32–2.21 (m, 1
1
2
CHCl3). H NMR (400 MHz, CDCl3, 55 °C): δ = 5.72–5.52 (br. s,
H), 2.09–1.99 (m, 1 H), 1.57 (d, J = 14.9 Hz, 1 H), 1.19 (s, 3 H),
0.97 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.2, 165.7,
140.5, 136.7, 133.1, 129.4, 129.3, 129.2, 128.2, 128.1, 127.9, 126.9,
126.6, 126.3, 109.4, 75.6, 67.4, 66.7, 30.8, 30.1, 26.4, 25.1 ppm (C-
2 and C-6 of the piperidine cycle could not be detected probably
due to the formation of a conformational equilibrium). C30H31NO5
(485.57): calcd. C 74.21, H 6.43, N 2.88; found C 74.50, H 6.57, N
2.89.
1 H), 4.34–4.19 (m, 1 H), 4.15–4.05 (m, 2 H), 3.94–3.85 (m, 1 H),
3.42–3.33 (m, 1 H), 2.53–2.41 (m, 1 H), 2.29–2.20 (m, 1 H), 2.16–
2.05 (m, 1 H), 1.45–1.36 (m, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.0, 143.6, 128.2, 127.5, 126.4, 114.1, 109.6, 76.1,
67.8, 65.5, 57.9, 54.1, 46.5 34.9, 27.2, 26.4, 25.0, 19.0, –4.9,
–5.1 ppm. C24H36F3NO4Si (487.63): calcd. C 59.11, H 7.44, N 2.87;
found C 59.36, H 7.40, N 2.91.
(2R,4S,6S)-4-tert-Butyldiphenylsiloxy-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-6-phenyl-N-(trifluoroacetyl)piperidine (37): The protec-
tion of 35 (0.160 g, 0.31 mmol), as described above for 34 in the
synthesis of 36, using pyridine (0.073 g, 0.93 mmol) and TFAA
(0.097 mL, 0.62 mmol) afforded pure 37 (0.167 g, 88%) after purifi-
cation by radial chromatography (hexane/ethyl acetate, 4:1; Rf =
0.75); oil. [α]2D0 = –56 (c = 1.33, CHCl3). 1H NMR (400 MHz,
(2S,4R,6R)-2-[(S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-6-phenyl-N-
benzoylpiperidin-4-yl Benzoate (40): The reaction of 33 (0.120 g,
0.43 mmol), as described for 32 in the synthesis of 39, gave, after
purification by radial chromatography (hexane/ethyl acetate, 4:1; Rf
= 0.13), pure 40 (0.180 g, 86%); oil. [α]2D0 = +60 (c = 1.20, meth-
anol). 1H NMR (400 MHz, CDCl3): δ = 7.73–7.65 (m, 2 H), 7.44–
7.10 (m, 13 H), 5.66 (br., 1 H), 5.48–5.41 (m, 1 H), 4.42 (br., 1 H),
CDCl3): δ = 7.70–7.65 (m, 2 H), 7.62–7.55 (m, 2 H), 7.53–7.35 (m, 4.14–4.00 (m, 1 H), 3.69 (br., 2 H), 2.90 (d, 2J = 14.7 Hz, 1 H),
8 H), 7.33–7.22 (m, 3 H), 5.52 (br., 1 H), 4.45–3.95 (m, 3 H), 3.86
2.41 (d, 2J = 14.1 Hz, 1 H), 2.34–2.23 (m, 1 H), 2.03 (dt, 2J = 14.7,
Eur. J. Org. Chem. 2008, 3943–3959
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3955

P. Merino, V. Mannucci, T. Tejero
3J = 5.6 Hz, 1 H), 1.10 (br., 3 H), 0.82 (s, 3 H) ppm. 13C NMR 7.62–7.57 (m, 2 H), 7.56–7.51 (m, 2 H), 7.48–7.22 (m, 14 H), 4.91
FULL PAPER
3
3
(100 MHz, CDCl3): δ = 173.2, 166.0, 141.2, 136.3, 132.9, 130.1, (dd, J = 8.2, 4.7 Hz, 1 H), 4.46 (dd, J = 8.6, 5.2 Hz, 1 H), 4.21–
2
3
129.6, 129.5, 128.7, 128.2, 128.1, 127.0, 126.5, 126.0, 109.2, 75.6,
67.7, 67.4, 29.6, 29.1, 26.5, 24.5 ppm (C-2 and C-6 of the piperidine
cycle could not be detected, probably due to the formation of a
conformational equilibrium). C30H31NO5 (485.57): calcd. C 74.21,
H 6.43, N 2.88; found C 74.38, H 6.60, N 2.72.
4.13 (m, 1 H), 3.80 (s, 3 H), 2.38 (ddd, J = 14.4, J = 8.2, 5.6 Hz,
2
3
2
1 H), 2.29 (ddd, J = 14.4, J = 8.6, 6.0 Hz, 1 H), 2.12 (ddd, J =
3
2
3
14.4, J = 7.5, 4.8 Hz, 1 H), 2.04 (ddd, J = 14.4, J = 7.4, 5.2 Hz,
1 H), 0.92 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.1,
172.9, 143.0, 135.7, 135.6, 135.5, 133.6, 133.5, 130.2, 129.8, 129.7,
128.3, 128.2, 127.7, 127.6, 126.9, 126.8, 126.6, 65.2, 56.5, 55.1, 52.4,
38.8, 34.3, 26.7, 19.0 ppm. C36H39NO4Si (577.79): calcd. C 74.84,
H 6.80, N 2.42; found C 74.64, H 6.66, N 2.35.
(2R,4S,6S)-N-Benzoyl-4-tert-butyldiphenylsiloxy-2-[(S)-2,2-di-
methyl-1,3-dioxolan-4-yl]-6-phenylpiperidine (41): The reaction of
35 (0.516 g, 1 mmol), as described for 32 in the synthesis of 39,
gave, after purification by radial chromatography (hexane/ethyl ace-
tate, 4:1; Rf = 0.26), pure 41 (0.477 g, 77%); oil. [α]2D0 = –82 (c =
1.81, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.70–7.66 (m, 2
H), 7.64–7.60 (m, 2 H), 7.55–7.48 (m, 3 H), 7.47–7.40 (m, 5 H),
7.38–7.30 (m, 7 H), 7.27–7.21 (m, 1 H), 5.90 (br., 1 H), 4.41–4.31
(2S,4R,6R)-4-tert-Butyldiphenylsiloxy-2-[(S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]-6-phenylpiperidine (44): The reaction of 33 (0.277 g,
1 mmol), as described for 32 in the synthesis of 35, afforded after
purification by radial chromatography (hexane/ethyl acetate, 4:1; Rf
= 0.62) pure 44 (0.490 g, 74%); oil. [α]2D0 = +45 (c = 0.84, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.63–7.55 (m, 4 H), 7.39–7.25
(m, 6 H), 7.24–7.19 (m, 4 H), 7.18–7.12 (m, 1 H), 3.99 (t, 3J =
3
(m, 2 H), 4.06 (br., 1 H), 3.70 (dd, J = 7.6, 6.2 Hz, 1 H), 2.98 (t,
3J = 7.9 Hz, 1 H), 2.58 (dt, 2J = 14.1, 3J = 5.2 Hz, 1 H), 2.22 (ddd,
2J = 14.1, 3J = 7.7, 3.8 Hz, 1 H), 1.80 (ddd, 2J = 13.8, 3J = 7.7,
4.4 Hz, 1 H), 1.32–1.25 (m, 1 H), 1.28 (s, 3 H), 1.09 (s, 3 H), 1.04
(s, 9 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 172.9, 141.5,
137.0, 135.8, 135.5, 133.5, 133.3, 130.0, 129.9, 128.9, 128.0, 127.8,
127.7, 127.6, 126.8, 126.8, 126.3, 109.2, 76.0, 67.4, 65.5, 55.7, 50.9,
34.4, 34.0, 27.0, 26.4, 25.2, 19.0 ppm. C39H45NO4Si (619.87): calcd.
C 75.57, H 7.32, N 2.26; found C 75.51, H 7.39, N 2.22.
3
3
7.0 Hz, 1 H), 3.91 (td, J = 6.6, 3.8 Hz, 1 H), 3.85 (dd, J = 7.0,
3
2
6.2 Hz, 1 H), 3.69 (tt, J = 10.6, 4.4 Hz, 1 H), 3.39 (dd, J = 11.5,
3J = 2.4 Hz, 1 H), 2.73 (ddd, 2J = 11.9, 3J = 3.7, 2.4 Hz, 1 H), 1.86
2
3
2
3
(ddt, J = 12.2, J = 4.4, 2.2 Hz, 1 H), 1.70 (ddt, J = 11.9, J =
2
4.4, 2.2 Hz, 1 H), 1.63 (br., 1 H), 1.44 (q, J = 11.5 Hz, 1 H), 1.24
(s, 6 H), 1.08 (q, J = 11.5 Hz, 1 H), 0.96 (s, 9 H) ppm. 13C NMR
2
(100 MHz, CDCl3): δ = 144.6, 135.8, 134.4, 134.3, 129.7, 129.6,
128.4, 127.6, 127.2, 126.7, 108.7, 78.7, 71.1, 65.0, 59.0, 55.1, 44.6,
37.3, 27.0, 26.5, 25.3, 19.1 ppm. C32H41NO3Si (515.76): calcd. C
74.52, H 8.01, N 2.72; found C 74.77, H 8.14, N 2.90.
(2R,4S,6S)-N-Benzoyl-4-tert-butyldiphenylsiloxy-6-phenylpiper-
idine-2-carboxylic Acid (42): H5IO6 (0.180 g, 0.79 mmol) was added
to a well-stirred solution of 41 (0.477 g, 0.77 mmol) in diethyl ether
(10 mL) and the resulting suspension was stirred at room tempera-
ture for 4 h. After this time the mixture was filtered through a short
pad of silica gel and the filtrate was evaporated under reduced pres-
sure. The crude product was taken up in acetonitrile (3 mL) and
then added to a cooled (0 °C) and freshly prepared solution of
NaH2PO4 (0.022 g, 0.183 mmol) and sodium chlorite (0.099 g,
1.10 mmol) in water (2 mL). The resulting mixture was stirred for
5 min after which time H2O2 30 % (0.077 mL, 0.82 mmol) was
added. The stirring was maintained for an additional hour at 0 °C
after which time Na2SO3 (0.007 g, 0.05 mmol) was added. After
5 min of stirring the solution was acidified to pH 2–3 with 10%
HCl. The resulting solution was diluted with dichloromethane
(30 mL) and saturated aq. ammonium chloride. The organic layer
was separated, washed with brine (3ϫ50 mL), dried with magne-
sium sulfate, filtered and evaporated at reduced pressure. The crude
product was purified by radial chromatography (hexane/ethyl ace-
tate, 4:1; Rf = 0.07) to give pure 42 (0.282 g, 65%); oil. [α]2D0 = –6
(2S,4R,6R)-N-Benzoyl-4-tert-butyldiphenylsiloxy-2-[(S)-2,2-di-
methyl-1,3-dioxolan-4-yl]-6-phenylpiperidine (45): The reaction of
44 (0.382 g, 0.74 mmol), as described for 35 in the synthesis of 41,
afforded after purification by radial chromatography (hexane/ethyl
acetate, 4:1; Rf = 0.37) pure 45 (0.367 g, 80%); oil. [α]2D0 = +39 (c
= 0.79, CHCl3). 1H NMR (400 MHz, CDCl3, 55 °C): δ = 7.78–7.66
(m, 4 H), 7.52–7.20 (m, 14 H), 7.18–7.13 (m, 2 H), 5.44 (t, 3J =
2
7.0 Hz, 1 H), 4.30–4.13 (m, 3 H), 3.68–3.54 (m, 2 H), 2.49 (dt, J
= 14.4, J = 7.3 Hz, 1 H), 2.25–2.15 (m, 1 H), 2.08–1.99 (m, 1 H),
3
2
3
1.94 (dt, J = 13.5, J = 6.6 Hz, 1 H), 1.21 (s, 3 H), 1.19 (s, 3 H),
1.11 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3, 55 °C; mixture of
conformers): δ = 173.1, 142.3, 137.1, 136.0, 135.9, 134.2, 134.1,
133.5, 130.2, 129.9, 129.8, 129.1, 128.5, 128.2, 127.7, 127.6, 127.1,
126.9, 126.0, 109.4, 77.5, 67.4, 66.7, 54.4, 35.4, 32.7, 29.7, 27.1,
26.7, 25.3, 19.2 ppm. C39H45NO4Si (619.87): calcd. C 75.57, H
7.32, N 2.26; found C 75.46, H 7.28, N 2.41.
1
Methyl (2S,4R,6R)-N-Benzoyl-4-tert-butyldiphenylsiloxy-6-phenyl-
piperidine-2-carboxylate (ent-43): Starting from 45 (0.367 g,
0.59 mmol) and applying, sequentially, the methodologies used to
synthesize 42 and 43, pure ent-43 (0.198 g, 58%) was obtained; oil.
[α]2D0 = –39 (c = 0.83, CHCl3). The Rf, m.p. and NMR data were
identical to those found for its enantiomer 43.
(c = 0.42, CHCl3). H NMR (500 MHz, CDCl3): δ = 8.80 (br., 1
H), 7.78–7.52 (m, 5 H), 7.50–7.30 (m, 12 H), 7.29–7.19 (m, 3 H),
3
3
4.97 (t, J = 5.9 Hz, 1 H), 4.43 (dd, J = 9.6, 5.4 Hz, 1 H), 4.22–
4.14 (m, 1 H), 2.41 (ddd, 2J = 14.6, 3J = 6.8, 5.6 Hz, 1 H), 2.33
(dt, 2J = 14.6, 3J = 7.9 Hz, 1 H), 2.19–2.08 (m, 2 H), 0.99 (s, 9
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 176.5, 173.7, 142.7,
135.8, 135.7, 135.6, 135.4, 133.8, 133.7, 130.4, 129.9, 129.8, 128.4,
127.8, 127.7, 127.0, 126.9, 126.7, 65.4, 57.3, 55.4, 38.7, 33.8, 26.8,
19.0 ppm. C35H37NO4Si (563.76): calcd. C 74.57, H 6.62, N 2.48;
found C 74.44, H 6.78, N 2.42.
Methyl (2R,4S,6S)-6-Phenyl-7-oxa-1-azabicyclo[2.2.1]heptane-2-
carboxylate (46): Starting from 20 (0.6 g, 2.18 mmol) and applying
the methodology used to synthesize 43, pure 46 was obtained after
radial chromatography (hexane/ethyl acetate, 4:1; Rf = 0.38); white
Methyl (2R,4S,6S)-N-Benzoyl-4-tert-butyldiphenylsiloxy-6-phenyl- solid, m.p. 88–89 °C. [α]2D0 = –6 (c = 1.49, CHCl3). 1H NMR
piperidine-2-carboxylate (43): Compound 42 (0.282 g, 0.50 mmol)
was dissolved in methanol (5 mL) and treated with TMSCHN2
(0.75 mmol) under vigorous stirring. After 3 h the solvent was elim-
inated under reduced pressure and the resulting crude product was
purified by radial chromatography (hexane/ethyl acetate, 4:1; Rf =
0.33) to give pure 43 (0.260 g, 90%); oil. [α]2D0 = –14 (c = 1.24,
(400 MHz, CDCl3): δ = 7.35–7.30 (m, 2 H), 7.26–7.20 (m, 2 H),
3
3
7.17–7.12 (m, 1 H), 5.00 (t, J = 4.9 Hz, 1 H), 3.89 (dd, J = 8.3,
3
5.0 Hz, 1 H), 3.69 (s, 3 H), 3.64 (dd, J = 8.6, 4.7 Hz, 1 H), 2.32
(dtd, 2J = 11.9, 3J = 4.8, 2.7 Hz, 1 H), 2.13 (dd, 2J = 11.9, 3J =
2
3
8.3 Hz, 1 H), 2.00–1.93 (m, 1 H), 1.90 (dd, J = 11.9, J = 8.6 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.5, 143.2, 128.4,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.72–7.66 (m, 2 H), 127.0, 126.7, 78.7, 70.1, 68.3, 52.6, 42.4, 36.5 ppm. C13H15NO3
3956
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3943–3959

Nitrone Chemistry
Q. R. Li, O. P. Zee, Y. H. Jung, Tetrahedron Lett. 2007, 48,
6258–6261.
a) M. P. G. Buffat, Tetrahedron 2004, 60, 1701–1729; b) P. M.
Weintraub, J. S. Sabol, J. M. Kane, D. R. Borcherding, Tetrahe-
dron 2003, 59, 2953–2989; c) S. Laschat, T. Dickner, Synthesis
2000, 1781–1813; d) F. X. Felpin, J. Lebreton, Curr. Org. Synth.
2004, 1, 83–109.
a) Y. Chen, J. A. Porco Jr, J. S. Panek, Org. Lett. 2007, 9, 1529–
1532; b) S. Gupta, B. C. Das, C. E. Schafmeister, Org. Lett.
2005, 7, 2861–2864; c) M. A. R. C. Bulusu, P. Waldstatten, T.
Tricotet, C. Rochais, A. Steck, M. Bacher, Tetrahedron Lett.
2004, 45, 5833–5836; d) C. Agami, F. Bisaro, S. Comesse, S.
Guesne, C. Kadouri-Pouchot, R. Morgentin, Eur. J. Org.
Chem. 2001, 2385–2389.
a) C. M. Boot, T. Amagata, K. Tenney, J. E. Compton, H. Pie-
traszkiewicz, F. A. Valeriote, P. Crews, Tetrahedron 2007, 63,
9903–9914; b) J. Zheng, R. Wen, X. Luo, G. Lin, J. Zhang, L.
Xu, L. Guo, H. Jiang, Bioorg. Med. Chem. Lett. 2006, 16, 225–
227; c) H. Muramatsu, H. Mihara, M. Yasuda, M. Ueda, T.
Kurihara, N. Esaki, Biosci. Biotechnol. Biochem. 2006, 70,
2296–2298; d) W. Maison, A. Lutzen, M. Kosten, I. Schlem-
minger, O. Westerhoff, W. Saak, J. Martens, J. Chem. Soc. Per-
kin Trans. 1 2000, 1867–1871.
a) M. Sani, G. Fossati, F. Huguenot, M. Zanda, Angew. Chem.
Int. Ed. 2007, 46, 3526–3529; b) R. E. Looper, M. T. C. Runne-
gar, R. M. Williams, Tetrahedron 2006, 62, 4549–4562.
a) A. Fadel, N. Lahrache, J. Org. Chem. 2007, 72, 1780–1784;
b) P. Etayo, R. Badorrey, M. D. Diaz-de-Villegas, J. A. Galvez,
Synlett 2006, 2799–2803; c) F. Lenda, F. Guenoum, B. Tazi,
N. B. Larbi, H. Allouchi, J. Martinez, F. Lamaty, Eur. J. Org.
Chem. 2005, 326–333; for reviews, see: d) F. Couty, Amino Ac-
ids 1999, 16, 297–320; e) C. Kadouri-Pouchot, S. Comesse,
Amino Acids 2005, 29, 101–130.
(233.26): calcd. C 66.94, H 6.48, N 6.00; found C 66.75, H 6.44, N
5.99.
[2]
[3]
Methyl (2R,4S,6S)-4-Hydroxy-6-phenylpiperidine-2-carboxylate
(47): The reduction of 46 (0.030 g, 0.13 mmol), as described for 20
in the synthesis of 32, gave, after purification by radial chromatog-
raphy (hexane/ethyl acetate, 4:1; Rf = 0.25), pure 47 (0.029 g, 95%);
white solid, m.p. 128–129 °C. [α]2D0 = –24 (c = 0.11, CHCl3). 1H
NMR (400 MHz, CDCl3): δ = 7.34–7.30 (m, 2 H), 7.30–7.24 (m, 2
2
3
H), 7.24–7.18 (m, 1 H), 3.80 (tt, J = 11.0, J = 4.5 Hz, 1 H), 3.67
(s, 3 H), 3.63 (dd, 2J = 11.4, J = 2.3 Hz, 1 H), 3.47 (dd, 2J = 11.8,
3
3J = 2.6 Hz, 1 H), 2.35 (ddt, J = 12.1, J = 4.5, 2.4 Hz, 1 H), 2.07
2
3
2
3
2
(ddt, J = 12.1, J = 4.5, 2.3 Hz, 1 H), 1.96 (br., 2 H), 1.45 (td, J
= 11.5, 3J = 3.3 Hz, 1 H), 1.40 (td, 2J = 11.5, 3J = 3.3 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.5, 142.9, 128.6,
127.6, 126.8, 69.3, 59.1, 57.4, 52.2, 43.1, 37.6 ppm. C13H17NO3
(235.28): calcd. C 66.36, H 7.28, N 5.95; found C 66.48, H 7.13, N
5.78.
[4]
Methyl (2S,4R,6R)-6-Phenyl-7-oxa-1-azabicyclo[2.2.1]heptane-2-
carboxylate (ent-46): Starting from 23 (0.6 g, 2.18 mmol) and ap-
plying the methodology used to synthesize 43, pure ent-46 (0.276 g,
54%) was obtained. [α]2D0 = +6 (c = 1.42, CHCl3). The Rf, m.p. and
NMR data were identical to those found for its enantiomer 46.
[5]
[6]
C
13H15NO3 (233.26): calcd. C 66.94, H 6.48, N 6.00; found C
66.82, H 6.49, N 6.05.
Methyl (2S,4R,6R)-4-Hydroxy-6-phenylpiperidine-2-carboxylate
(ent-47): Starting from ent-46 (0.030 g, 0.13 mmol) and applying
the methodology used to synthesize 32, pure ent-47 (0.029 g, 95%)
was obtained. [α]2D0 = +24 (c = 1.05, CHCl3). The Rf, m.p. and
NMR data were identical to those found for its enantiomer 47.
[7]
[8]
G. C. Kite, J. J. Wieringa, Biochem. System. Ecol. 2003, 31,
279–292.
C
13H17NO3 (235.28): calcd. C 66.36, H 7.28, N 5.95; found C
66.45, H 7.49, N 5.86.
a) J. T. Romeo, L. A. Swain, A. B. Bleecker, Phytochemistry
1983, 22, 1615–1620; b) V. W. Schenk, H. R. Schutte, Flora
1963, 153, 426–443.
H. Vanderhaeghe, G. Janssen, F. Compernolle, Tetrahedron
1971, 27, 2687–2688.
a) P. L. Ornstein, D. D. Schoepp, M. B. Arnold, J. D. Leander,
D. Lodge, J. W. Paschal, T. Elzey, J. Med. Chem. 1991, 34, 90–
97; b) S. J. Hays, T. C. Malone, G. Johnson, J. Org. Chem. 1991,
56, 4084–4086.
Supporting Information (see also the footnote on the first page of
this article): Full analysis of the stereochemical course of the intra-
molecular cycloadditions and 1H and 13C NMR spectra of the new
compounds.
[9]
[10]
Acknowledgments
[11]
a) J. Gillard, A. Abrham, P. C. Anderson, P. L. Beaulieu, T.
Bogri, Y. Bousquet, L. Grenier, I. Guse, P. Lavalle, J. Org.
Chem. 1996, 61, 2226–2231; b) P. L. Beaulieu, P. Lavalle, A.
Abraham, P. C. Anderson, C. Boucher, Y. Bousquet, J.-S. Du-
ceppe, J. Gillard, V. Gorys, C. Grand-Maitre, L. Grenier, Y.
Guindon, I. Guse, L. Plamondon, F. Soucy, S. Valois, D.
Wernic, C. Yoakim, J. Org. Chem. 1997, 62, 3440–3448; c) R.
Badorrey, C. Cativiela, M. D. Diaz-de-Villegas, J. A. Galvez,
Tetrahedron 2002, 58, 341–354.
a) A. S. Golubev, H. Schedel, G. Radics, J. Sieler, K. Burger,
Tetrahedron Lett. 2001, 42, 7941–7944; b) B. Bellier, S. da Nas-
cimiento, H. Meudal, E. Gincel, B. P. Roques, C. Garbay, Bi-
oorg. Med. Chem. Lett. 1998, 8, 1419–1424.
a) C. A. Brooks, D. L. Comins, Tetrahedron Lett. 2000, 41,
3551–3553; b) J. Marin, C. Didierjean, A. Aubry, J.-R. Casimir,
J.-P. Briand, G. Guichard, J. Org. Chem. 2004, 69, 130–141.
F. P. J. T. Rutjes, J. J. N. Veerman, W. J. N. Meester, H. Hiem-
stra, H. E. Shoemaker, Eur. J. Org. Chem. 1999, 1127–1135.
A. Kulesza, A. Mieczkowski, J. Jurczak, Tetrahedron: Asym-
metry 2002, 13, 2061–2069.
This study was supported by the Spanish Ministry of Science and
Education and European Regional Development Fund (Madrid,
Spain, project CTQ2007-67532-C02-01) and the Aragon Regional
Government (Zaragoza, Spain). V. M. thanks the Spanish Minis-
terio de Educación y Ciencia (MEC) for a predoctoral grant. Prof.
Larry Falvello (University of Zaragoza) is gratefully acknowledged
for suggestions in relation to the X-ray analyses. Dr. Ignacio Delso
and Dr. Pilar Romero are also acknowledged for exploratory work
and NMR assistance, respectively.
[12]
[13]
[1] a) J. F. Bower, T. Riis-Johannessen, P. Szeto, A. J. Whitehead,
T. Gallagher, Chem. Commun. 2007, 728–730; b) L. A. Gan-
don, A. G. Russel, T. Guvelli, A. E. Brodwolf, B. M. Kairuki,
N. Spencer, J. S. Snaith, J. Org. Chem. 2006, 71, 5198–5207; c)
R. M. de Figuereido, R. Frohlich, M. Christmann, J. Org.
Chem. 2006, 71, 4147–4154; d) A. Takemiya, J. F. Hartwig, J.
Am. Chem. Soc. 2006, 128, 6042–6043; e) S. Minakata, Y. Mor-
ino, Y. Oderatoshi, M. Komatsu, Org. Lett. 2006, 8, 3335–3337;
f) Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian, R. A.
Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066–9073; g) N.
Girard, J.-P. Hurvois, Tetrahedron Lett. 2007, 48, 4097–4099;
h) X. Han, R. A. Widenhoefer, Angew. Chem. Int. Ed. 2006,
45, 1747–1749; i) F. E. Michael, B. M. Cochran, J. Am. Chem.
Soc. 2006, ##128##71, 1529–1532; j) I. S. Kim, C. B. Ryu,
[14]
[15]
[16]
[17]
[18]
M. Sabat, C. R. Johnson, Tetrahedron Lett. 2001, 42, 1209–
1212.
F. Cordero, S. Bonollo, F. Machetti, A. Brandi, Eur. J. Org.
Chem. 2006, 3235–3241.
F. A. Davies, T. Fang, B. Chao, D. M. Burns, Synthesis 2000,
2106–2112.
Eur. J. Org. Chem. 2008, 3943–3959
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3957

P. Merino, V. Mannucci, T. Tejero
FULL PAPER
[19]
and added slowly by cannula to the cooled solution of allyl-
magnesium bromide.
R. Badorrey, C. Cativiela, M. D. Diaz-de-Villegas, R. Diez,
J. A. Galvez, Eur. J. Org. Chem. 2002, 3763–3767.
Homoallyl hydroxylamines 8a and 8b have also been employed
for the synthesis of vinyl isoxazolidines in a novel Pd-catalyzed
heterocyclization procedure, see: P. Merino, T. Tejero, V. Man-
nucci, G. Prestat, D. Madec, G. Poli, Synlett 2007, 944–948.
A. Dondoni, S. Franco, F. L. Merchan, P. Merino, T. Tejero,
F. Machetti, F. Cordero, F. DeSarlo, A. M. Papini, M. C. Al-
caro, A. Brandi, Eur. J. Org. Chem. 2004, 2928–2935.
W. Schenk, H. R. Shutte, K. Mothes, Flora 1962, 152, 590–609.
M. Marlier, G. Dardenne, J. Casimir, Phytochemistry 1979, 18,
479–481.
J. Barluenga, M. A. Fernandez, F. Aznar, C. Valdes, Tetrahe-
dron Lett. 2002, 43, 8159–8163.
a) S. K. Chattopadhyay, T. Biswas, T. Biswas, Tetrahedron Lett.
2008, 49, 1365; b) L. Battistini, F. Zanardi, G. Rassu, P. Spanu,
G. Pelosi, G. G. Fava, M. B. Ferrari, G. Casiraghi, Tetrahedron:
Asymmetry 1997, 8, 2975–2987.
[20]
[21]
[43]
[44]
[22]
[23]
[45]
[46]
Tetrahedron Lett. 1992, 33, 5475–5478.
P. Merino, T. Tejero, unpublished results; see also ref.
[34b]
We
[24]
[25]
[26]
M. Haddad, M. Larcheveque, Tetrahedron Lett. 2001, 42,
5223–5225.
have also studied the allylation of nitrones theoretically by
using ab initio methods, see ref.[35b]
J. D. Scott, R. M. Williams, Tetrahedron Lett. 2000, 41, 8413–
8416.
S. D. Koulocheri, P. Magiatis, A.-L. Skaltsounis, S. A. Harou-
tounian, Tetrahedron 2002, 58, 6665–6671, and references cited
therein.
J.-C. Jung, M. A. Avery, Tetrahedron: Asymmetry 2006, 17,
2479–2486.
P. S. Shirude, V. A. Kumar, K. N. Ganesh, Tetrahedron Lett.
2004, 45, 3085–3088.
M. A. Wijdeven, P. N. M. Botman, R. Wijtmans, H. E. Shoe-
maker, F. P. J. T. Rutjes, R. H. Blaauw, Org. Lett. 2005, 7,
4005–4007.
a) R. Chenevert, M. Dickman, J. Org. Chem. 1996, 61, 3332–
3341; b) H. Acherki, C. Alvarez-Ibarra, S. Guzman-Fernandez,
M. L. Quiroga-Feijoo, Tetrahedron: Asymmetry 2004, 15, 693–
697.
a) C. Agami, S. Comesse, C. Kadouri-Puchot, J. Org. Chem.
2000, 65, 4435–4439; b) R. Chenevert, M.-P. Morin, J. Org.
Chem. 1999, 64, 3178–3180.
[47]
a) M. N. Paddon-Row, N. G. Rondan, K. N. Houk, J. Am.
Chem. Soc. 1982, 104, 7162–7166; b) Y.-D. Wu, K. N. Houk,
J. Am. Chem. Soc. 1987, 109, 908–910.
S. Cicchi, M. Marradi, A. Goti, A. Brandi, Tetrahedron Lett.
2001, 42, 6503–6505.
[48]
[49]
[27]
[28]
[29]
CCDC-633434 (for 15), -633435 (for 20), and -633436 (for 25)
contain the supplementary crystallographic data. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
This reaction has been described previously for nitrones to pro-
vide free hydroxylamines. For selected examples, see: a) H. Tok-
uyama, T. Kuboyama, A. Amano, T. Yamashita, T. Fukuyama,
Synthesis 2000, 1299–1304; b) O. Tamura, K. Gotanda, J.
Yoshino, Y. Morita, R. Terashima, M. Kikuchi, T. Miyawaki,
N. Mita, M. Yamashita, H. Ishibashi, M. Sakamoto, J. Org.
Chem. 2000, 65, 8544–8551; c) S. K. Patel, K. Murat, S. Py, Y.
Vallee, Org. Lett. 2003, 5, 4081–4084; the same type of reaction
has been reported using ionic liquids: d) D. Li, F. Shi, S. Guo,
Y. Deng, Tetrahedron Lett. 2004, 45, 265–268.
[50]
[30]
[31]
[32]
[33]
[34]
[51]
S. Carbonell, C. Fayet, J. Gelas, Y. Troin, Tetrahedron Lett.
2000, 41, 8293–8296.
P. Merino, S. Franco, F. Merchan, T. Tejero, Tetrahedron:
Asymmetry 1997, 8, 3489–3496.
a) P. Merino in Science of Synthesis (Ed.: A. Padwa), Georg
Thieme, Stuttgart, 2004, pp. 511–580; b) P. Merino, S. Franco,
F. Merchan, T. Tejero, Synlett 2000, 442–454; c) P. Merino,
Compt. Rend. Chim. 2005, 8, 775–788.
For recent examples, see: a) T. K. M. Shing, W. F. Wong, T.
Ikeno, T. Yamada, Org. Lett. 2007, 9, 207–209; b) G. L. Ellis,
I. A. O’Neil, V. E. Ramos, S. B. Kalindjian, A. P. Chorlton,
D. J. Tapolczay, Tetrahedron Lett. 2007, 48, 1687–1690; c)
T. K. M. Shing, A. W. F. Wong, T. Ikeno, T. Yamada, J. Org.
Chem. 2006, 71, 3253–3263; d) P. Padar, M. Hornyak, M.
Forgo, Z. Kele, G. Paragi, N. M. Howarth, L. Kovacs, Tetrahe-
dron 2005, 61, 6816–6823; e) M. Marradi, A. Brandi, A. de Me-
ijere, Synlett 2006, 1125–1127.
A. Padwa, W. H. Pearson (Eds.) Synthetic applications of 1,3-
dipolar cycloaddition chemistry towards heterocycles and natural
products, Wiley, New York, 2002.
For theoretical studies on the E/Z isomerization of C-alkoxy-
carbonyl and C-hetaryl nitrones, see: a) P. Merino, J. Revuelta,
T. Tejero, U. Chiacchio, A. Rescifina, G. Romeo, Tetrahedron
2003, 59, 3581–3592; b) P. Merino, T. Tejero, U. Chiacchio, G.
Romeo, A. Rescifina, Tetrahedron 2007, 63, 1448–1458. An-
other theoretical study on the mechanism of the E/Z isomeriza-
tion of nitrones is underway in our laboratories.
The E/Z isomerization of nitrones has been invoked by several
authors to explain the products obtained, see: a) M. T. Rispens,
E. Keller, B. de Lange, R. W. J. Zijlstra, B. L. Feringa, Tetrahe-
dron: Asymmetry 1994, 5, 607–615; b) P. Merino, J. Revuelta,
T. Tejero, U. Chiacchio, A. Rescifina, G. Romeo, Tetrahedron
2003, 59, 3581–3592.
For a complete analysis of all the possible adducts that could
be formed, considering all the possibilities of epimerization,
isomerization and rearrangement see the Supporting Infor-
mation.
For reviews on aza-Cope rearrangements, see: a) R. P. Lutz,
Chem. Rev. 1984, 84, 205–247; b) S. Blechert, Synthesis 1989,
71–82.
a) K. M. Brummond, J. Lu, Org. Lett. 2001, 3, 1347–1349; b)
Z. D. Aron, L. E. Overman, Org. Lett. 2005, 7, 913–916; c) M.
Sugiura, C. Mori, S. Kobayashi, J. Am. Chem. Soc. 2006, 128,
11038–11039.
[35]
[36]
For a preliminary communication on the allylation of α-alkoxy
and α-amino nitrones, see: a) P. Merino, I. Delso, V. Mannuci,
T. Tejero, Tetrahedron Lett. 2006, 47, 3311–3314; for the ad-
dition of lithiated allyl phenyl sulfone to 10, see: b) P. Merino,
V. Mannucci, T. Tejero, Tetrahedron 2005, 61, 3335–3347.
a) P. Merino, E. Castillo, S. Franco, F. L. Merchan, T. Tejero,
J. Org. Chem. 1998, 63, 12301–12322; b) P. Merino, J. A. Mates,
J. Revuelta, T. Tejero, U. Chiacchio, G. Romeo, D. Iannazzo,
R. Romeo, Tetrahedron: Asymmetry 2002, 13, 173–190.
For a similar use of the dioxolane ring in the synthesis of 4-
oxopipecolic acids, see: G. Galley, B. Ziemer, M. Pätzel, J.
Prakt. Chem. 1998, 340, 551–556.
For the enantiodivergent synthesis of α-amino acids through
stereocontrolled Grignard nucleophilic additions to 10 follow-
ing the same principle, see: P. Merino, E. Castillo, S. Franco,
F. L. Merchan, T. Tejero, J. Org. Chem. 1998, 63, 2371–2374.
For reviews on allylation of imines and related compounds, see:
a) H. Ding, G. K. Friestad, Synthesis 2005, 2815–2829; b) P.
Merino, T. Tejero, I. Delso, V. Mannucci, Curr. Org. Synth.
2005, 2, 479–498.
D. Seyferth, M. A. Weiner, Org. Synth. 1961, 41, 30–33; D. Sey-
ferth, M. A. Weiner, Org. Synth., Collect. 1973, 5, 452–455.
The reaction of allylmagnesium bromide with 10 has been de-
scribed previously. However, only the direct allylation was re-
ported and an almost equimolar mixture of syn- and anti-13b
was obtained: D. D. Dhavale, L. Gentilucci, M. G. Piazza, C.
Trombini, Liebigs Ann. Chem. 1992, 1289–1295.
When the reactions were carried out on the 10–20 mmol scale,
the solution of precomplexed nitrone was precooled to –50 °C
[52]
[53]
[37]
[38]
[54]
[55]
[39]
[40]
[41]
[56]
[57]
[42]
[58]
P. G. M. Wuts, Y.-W. Jung, J. Org. Chem. 1998, 63, 1957–1965.
3958
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3943–3959

Nitrone Chemistry
[59] a) R. W. Hoffmann, A. Endesfelder, Liebigs Ann. Chem. 1986,
1823–1826; b) A. Varlamov, V. Kouznetsov, F. Zubkov, A.
Chernyshev, O. Shurupova, L. Y. V. Mendez, A. P. Rodriguez,
J. R. Castro, A. J. Rojas-Romero, Synthesis 2002, 771–783.
[60] P. Merino, T. Tejero, V. Mannucci, Tetrahedron Lett. 2007, 48,
3385–3388. A complete theoretical study of thermal 2-aza-
Cope rearrangement of nitrones is underway in our laboratory
and will be reported in due course.
[61] Analyses were performed by comparison of the HPLC chroma-
tograms of the corresponding isolated reaction mixtures.
[62] These conditions, however, have been reported for the O-si-
lylation of 4-hydroxypiperidines, ee: M. K. S. Vink, C. A.
Schortinghuis, J. Luten, J. H. van Maarseeven, H. E. Shoe-
maker, H. Hiemstra, F. P. J. T. Rutjes, J. Org. Chem. 2002, 67,
7869–7871.
[63] R. K. Bhatt, K. Chauhan, P. Wheelan, J. R. Falck, R. C. Mur-
phy, J. Am. Chem. Soc. 1994, 116, 5050–5056.
[64] A number of different conditions for introducing the Boc
group were assayed with both 32 and 33. In the case of 32,
unreacted starting compound was recovered in all cases.
[65] K. Pandiarajan, A. Manimekalai, N. Kalaiselvi, Magn. Reson.
Chem. 1997, 35, 372–378.
[67]
[68]
[69]
P. Beak, N. J. Zajdel, J. Am. Chem. Soc. 1984, 106, 1010–1018.
R. H. Hoffmann, Chem. Rev. 1989, 89, 1841–1860.
a) D. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int.
Ed. Engl. 1996, 35, 2708–2748; b) J. F. Dellaria, B. D. Santasi-
ero, J. Org. Chem. 1989, 54, 3916–3926; c) B. H. Norman, J. S.
Kroin, J. Org. Chem. 1996, 61, 4990–4998; d) N. Anthony, R. P.
Gomez, W. J. Holtz, J. S. Murphy, R. G. Ball, T. J. Lee, Tetrahe-
dron Lett. 1995, 36, 3821–3824; e) J. D. Brown, M. A. Foley,
D. A. Comins, J. Am. Chem. Soc. 1988, 110, 7445–7447; f) S.
Hanessian, W. A. van Otterlo, I. Nilsson, U. Bauer, Tetrahedron
Lett. 2002, 43, 1995–1998; g) S. Hanessian, M. Seid, I. Nilsson,
Tetrahedron Lett. 2002, 43, 1991–1994; h) M. Muller, A.
Schoenfelder, B. Didier, A. Mann, C. G. Wermuth, Chem.
Commun. 1999, 683–684.
[70] a) C. Kuhn, E. Roulland, J.-C. Madelmont, C. Monneret, J.-C.
Florent, Org. Biomol. Chem. 2004, 2, 2028–2039; b) W. L. Wu,
Y. L . Wu , J. Chem. Soc., Chem. Commun. 1993, 821–822.
[71] a) G. A. Kraus, B. J. Roth, J. Org. Chem. 1980, 45, 4825–4830;
b) B. O. Lindgren, T. Nilsson, Acta Chem. Scand. 1973, 27,
888–890.
[72] C. R. Schmid, J. D. Bryant, Org. Synth. 1993, 72, 6–13.
Received: April 4, 2008
Published Online: June 10, 2008
[66] For reviews, see: a) F. Johnson, Chem. Rev. 1968, 68, 375–413;
b) R. H. Hoffmann, Angew. Chem. Int. Ed. Engl. 1992, 31,
1124–1134.
Eur. J. Org. Chem. 2008, 3943–3959
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3959