1,3-Dipolar cycloadditions of N-benzyl-2,3-O-isopropylidene-D- glyceraldehyde nitrone to methoxyallene - Control of site- and diastereoselectivity of isoxazolidine formation by Lewis acids

Article abstract of DOI:10.1002/ejoc.200700724

The siteselectivity of cycloadditions of the D-glyceraldehyde-derived nitrone 1 and methoxyallene (2) is strongly influenced by Lewis acids. The uncatalyzed reaction results in the formation of isomeric isoxazolidines 3a-3d and 4a-4c, whereas in the prese

Full text of DOI:10.1002/ejoc.200700724

FULL PAPER
DOI: 10.1002/ejoc.200700724
1,3-Dipolar Cycloadditions of N-Benzyl-2,3-O-isopropylidene- -glyceraldehyde
D
Nitrone to Methoxyallene – Control of Site- and Diastereoselectivity of
Isoxazolidine Formation by Lewis Acids
[a,b]
[b]
[a]
ˇ
ˇ
Lubor Fisera, and Hans-Ulrich Reißig*
Branislav Dugovic,
Keywords: Methoxyallene / Nitrone / 1,3-Dipolar cycloaddition / Lewis acids / Isoxazolidines
The siteselectivity of cycloadditions of the
D
-glyceraldehyde-
giving rise to both diastereomeric isoxazolidines 3,4Ј-anti-4
or 3,4Ј-syn-4, just by employing different Lewis acids. The
redox ring-opening of isoxazolidines 4 using Murahashi’s
protocol yields α-methylene-β-amino acid esters 5a,b and
7a,b.
derived nitrone 1 and methoxyallene (2) is strongly influ-
enced by Lewis acids. The uncatalyzed reaction results in the
formation of isomeric isoxazolidines 3a–3d and 4a–4c,
whereas in the presence of different Lewis acids exclusive
formation of 4-methylene-substituted isoxazolidines 4a–4d is
observed. Furthermore, the diastereofacial selectivity of the
methoxyallene addition to nitrone 1 can be controlled, thus
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Over the years, nitrones have become important building
blocks in organic synthesis.[1] Recently, we have published
that nitrones are excellent electrophiles for nucleophilic ad-
ditions of lithiated alkoxyallenes which give rise to the for-
mation of 3,6-dihydro-2H-1,2-oxazines A (Scheme 1).[2]
These heterocycles are extremely versatile intermediates for
the synthesis of several classes of enantiopure compounds
such as hydroxylated pyrrolidines and azetidines as well as
amino polyols.[3]
On the other hand, 1,3-dipolar cycloadditions[4] of nitro-
nes to alkenes are well established reactions by which isox-
azolidines are formed, often with a high degree of stereo-
chemical control.[1a,1b] However, allenes as dipolarophiles
Scheme 1. Nucleophilic addition of lithiated methoxyallene to
nitrones leading to 1,2-oaxzines A and cycloaddition pathways pro-
viding isoxazolidiines B or C.
have attracted less attention in this type of reactions.[5]
A
possible reason could be that unsymmetrically substituted
allenes possess two different double bonds capable of un-
dergoing 1,3-dipolar cycloadditions. Therefore besides re-
gio-, diastereo- and enantioselectivity, also siteselectivity of
the reaction has to be considered (Scheme 2). The forma-
tion of sixteen isomeric isoxazolidines is conceivable, if
nitrones react with monosubstituted allenes. In the litera-
ture are so far only few examples on 1,3-dipolar cycload-
ditions of alkoxyallenes to nitrones.[5b,5c]
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-83855367
E-mail: hans.reissig@chemie.fu-berlin.de
[b] Institute of Organic Chemistry, Catalysis and Petrochemistry,
Slovak University of Technology,
Scheme 2. Site- and regioselectivity in 1,3-dipolar cycloadditions of
nitrones with monosubstituted allenes (stereoisomers are not
shown).
81237 Bratislava, Slovak Republic
Eur. J. Org. Chem. 2008, 277–284
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
277

B. Dugovicˇ, L. Fisˇera, H.-U. Reißig
FULL PAPER
Employment of Lewis acids has extensively been studied
during the last two decades, in order to control regio-, dia-
stereo- as well as enantioselectivity of 1,3-dipolar cycload-
ditions of nitrones.[6] However, the catalytic effect of Lewis
acids on the siteselectivity of nitrone cycloadditions to all-
enes has not been investigated. In the case of a thermal
nitrone to methoxyallene cycloaddition it was suggested
that the expected 4-methylene-substituted isoxazolidine of
type B rearranged under the experimental conditions and a
4-methoxymethylene-substituted isoxazolidine of type C
was formed exclusively.[5b] A 4-methylene-substituted isox-
azolidine of type B was obtained exclusively in an intramo-
lecular 1,3-dipolar cycloaddition of an allene with a nitro-
ne.[5c] Our objective was to access highly substituted
enantiopure isoxazolidines of general structure B. We re-
port herein the first Lewis-acid-promoted cycloadditions of
d-glyceraldehyde-derived nitrone 1 and methoxyallene (2).
Nitrone 1 is an easily accessible and important chiral C3
building block. By its reaction with strong nucleophiles
both diastereomeric hydroxylamine derivatives (anti and syn
compounds) are accessible in the presence or absence of
Lewis acids.[1c]
Scheme 3. 1,3-Dipolar cycloadditions of d-glyceraldehyde-derived
nitrone 1 with methoxyallene (2).
It has been found, that nitrones are activated for cycload-
ditions to electron-rich alkenes by coordination to Lewis
acids.[7d] Several Lewis acids have been screened in this
study (Table 1, entries 2–7). The cycloaddition between 1
and 2 performed in the presence of equimolar amounts of
AlMe3 in CH2Cl2 was accelerated compared to the uncata-
lyzed reaction (Table 1, entry 2), moreover, in the crude re-
action mixture only 4-methylene-substituted isoxazolidines
4a–4d were detected (56% yield). A similar result was ob-
tained using 1 equiv. of Et2AlCl in CH2Cl2 (Table 1, entry
3). Compared to the AlMe3-promoted reaction, a slightly
Results and Discussion
Due to its enol ether substructure methoxyallene (2) can lower yield (50%) was obtained, but in this particular ex-
be regarded as an electron-rich π-system. Several reports periment a lower excess of methoxyallene was used.
were recently published dealing with Lewis-acid-catalyzed or
Jørgensen et al. have found that the (BINOL)-AlMe
-promoted nitrone cycloadditions to electron-rich alkenes. complexes catalyze 1,3-dipolar cycloadditions of C-aryl-
Whereas cycloadditions of simple achiral nitrones bearing substituted nitrones with vinyl ethers.[7d] In our case, use of
C-aryl substituents were accelerated in the presence of sub- 0.2 equiv. of the (R)-(BINOL)-AlMe complex resulted in a
stoichiometric amounts of catalyst,[7] equimolar amounts of siteselectivity very similar to the uncatalyzed reaction. Bet-
Lewis acids were required in the case of carbohydrate-de- ter results were obtained in the presence of 1.0 equiv. of
rived nitrones.[8] Therefore, we decided to study the 1,3-di- (R)- or (S)-(BINOL)-AlMe complex, respectively (Table 1,
polar cycloadditions of d-glyceraldehyde-derived nitrone 1 entries 4 and 5). In both cases only isoxazolidines 4 were
with 2 in the absence and presence of Lewis acids. The re- formed in 44% or 45% yield. Other Lewis acids such as
sults are summarized in the Table 1. First, the thermal cy- ZnI2 and TMSOTf were also found to be efficient (Table 1,
cloaddition of nitrone 1 and methoxyallene (2) has been entries 6 and 7). Whereas the ZnI2-promoted cycloaddition
performed. Nitrone 1 reacted with 2 (Scheme 3) in CH2Cl2 afforded isoxazolidines 4a–4d in the highest isolated yield
at ambient temperature over 72 h to give a mixture of seven (72%), this reaction resulted in a disappointingly poor dia-
of the sixteen theoretically possible isoxazolidines 3a–3d stereoselectivity (Table 1, entry 6). The highest rate acceler-
and 4a–4c in 56% overall yield (Table 1, entry 1). Both pos- ation was achieved in the reaction with trimethylsilyl triflate
sible site-isomers have been formed, with 4-methoxymethyl- (TMSOTf) as promoter in CH2Cl2 at –78 to –65 °C. The
ene-substituted isoxazolidines 3 being moderately predomi- consumption of nitrone 1 was complete within 1 h and al-
nant (3/4 = 77:23).
lowed isolation of 4a–4d in 61% yield (Table 1, entry 7).
Table 1. 1,3-Dipolar cycloadditions of d-glyceraldehyde-derived nitrone 1 with methoxyallene (2).
Lewis acid
Conditions[a]
Products[b]
Ratio[c] 4a/4b/4c/4d
% Yield[d]
1
2
3
4
5
6
7
–
r.t., 72 h[e]
3a–3d,[f] 4a–4c (77:23)
26:17:57:–
69:7:22:2
55:8:32:5
n.d.
n.d.
17:5:61:17
2:5:65:28
56
56
50
44
45
72
61
AlMe3
Et2AlCl
(R)-(BINOL)–AlMe
(S)-(BINOL)–AlMe
ZnI2
0 to 8 °C, 50 h[g]
4a–4d
4a–4d
4a–4d
4a–4d
4a–4d
4a–4d
0 to 8 °C, 51 h
0 °C to room temp., 27 h
0 °C to room temp., 27 h
0 °C to room temp., 22 h
–78 to –65 °C, 1 h
TMSOTf
[a] 5 equiv. of methoxyallene (2), 1 equiv. of Lewis acid and CH2Cl2 as solvent were used. [b] Based on 1H NMR spectra of crude
products. [c] Determined by HPLC. [d] Cumulative yield of isolated mixture of isoxazolidines. [e] 2.5 equiv. of methoxyallene (2) were
employed. [f] Ratio of 3a/3b/3c/3d = 43:35:8:14. [g] 10 equiv. of methoxyallene (2) were used.
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Controlled Isoxazolidine Formation
FMO theory fails to predict the siteselectivity of the un- strongly increases its electrophilicity from 0.98 to 1.93 eV.
catalyzed reaction. DFT[9] calculations (Table 2) suggest A difference of electrophilicity Δω of the reagent pair has
that the HOMO of methoxyallene is located at the enol been used as a measure of the polar character of cycload-
ether moiety, whereas its LUMO is at the terminal double ditions.[10,11a] The Δω for the reaction between nitrone 1
bond. According to the calculated FMO energy gaps, and methoxyallene has a low value (0.31 eV), thus indicat-
the favoured cycloadduct should be the result of a ing that the corresponding cycloaddition will have a low
LUMOnitrone–HOMOmethoxyallene interaction (ΔE
5.41 eV); this separation is smaller than that of the other moted cycloaddition of 1-AlMe3 and 2 has a value of Δω
combination: LUMOmethoxyallene–HOMOnitrone (ΔE = 1.26 eV. This increase of Δω suggests a more polar pro-
=
polar character. On the other hand, the Lewis-acid-pro-
=
6.19 eV). Therefore, on the basis of simple FMO theory just cess with lower activation energy for the Lewis-acid-pro-
regarding the energies of frontier orbitals, methoxyallene (2) moted reaction. The large increase of Δω for the catalyzed
is expected to undergo the 1,3-dipolar cycloaddition in pref- reaction, accounts for the acceleration of the inverse elec-
erence across the more substituted double bond and to pro- tron-demand cycloaddition. The increased electrophilic
duce the 4-methylene-5-methoxy-substituted isoxazolidines character of the nitrone could also lead to a change of
4, which contradicts the experimentally observed siteselec- mechanism:[11d] as a consequence of the large electrophilic
tivity (3/4 = 77:23, Table 1, entry 1). The same disagreement activation of the nitrone upon coordination of AlMe3, the
of the theoretically predicted and the observed siteselectiv- mechanism of the reaction changes from a concerted asyn-
ity in methoxyallene cycloadditions towards nitrones has chronous cycloaddition with a low polar character to a con-
been reported by Padwa et al.[5b] These authors suggested certed highly asynchronous cycloaddition or even to a step-
that the 4-methylene-5-methoxy-substituted isoxazolidine wise addition with a large polar character.
of type B undergoes a facile rearrangement to give 4-meth-
Interestingly, the Lewis acids not only change the sitese-
oxymethylene-substituted isoxazolidines of type C. A sim- lectivity of cycloadditions of 1 and 2, they also considerably
ilar transformation did not occur in our case. After re- influence the diastereoselectivity (Table 1, entries 2, 6 and
fluxing pure isomer 4c in toluene for 24 h, no traces of 4- 7). Precomplexation of nitrone 1 with AlMe3 led to prefer-
methoxymethylene-substituted isoxazolidines 3 were ob- ential formation of 3,4Ј-anti-4a,b (3,4Ј-anti-4a,b/3,4Ј-syn-
served. Hence, the uncatalyzed reaction is apparently con- 4c,d = 76:24). On the other hand, using TMSOTf resulted
trolled by more subtle electronic and by steric effects.
in a reversal of diastereoselectivity giving 3,4Ј-syn-4c,d al-
most exclusively as major isomers (3,4Ј-anti-4a,b/3,4Ј-syn-
4c,d = 7:93). The facial selectivity seems to depend strongly
on the chelating properties of the Lewis acids. The mono-
dentate TMSOTf strongly favours the 3,4Ј-syn products 4c/
4d, as expected by the pathway A in Scheme 4 according to
the Houk model.[13] Bidentate Lewis acids such as AlEt2Cl
or AlMe3 can additionally coordinate to the oxygen of the
dioxolane ring in α- and/or β-position.[14] A β-chelated
structure (pathway B, Scheme 4) is preferably adopted in
the case of AlMe3, which results in a 3,4Ј-anti stereorela-
Table 2. Energies of FMOs (in eV) and global indexes: electronic
chemical potential (μ, au), chemical hardness (η, au), and global
electrophilicity (ω, in eV) of nitrone 1, nitrone-AlMe3 complex 1-
AlMe3 and methoxyallene (2).
HOMO
–5.98
LUMO
μ
η
ω
1
–0.54
–1.85
0.20
–0.1200
–0.1703
–0.1056
0.1999
0.2044
0.2262
0.98
1.93
0.67
1-AlMe3 –7.42
2
–5.95
The siteselectivity in the presence of AlMe3 is in agree- tionship (formation of 4a/4b).[14] We can not offer a simple
ment with the prediction and the cycloaddition is controlled explanation for the cis/trans selectivity in these cycload-
by the LUMOnitrone complex–HOMOmethoxyallene interaction ditions which is determined by the preference for one of
(ΔE = 4.10 eV; LUMOmethoxyallene–HOMOnitrone complex
7.62 eV).
=
the two face-to-face approaches of the two prochiral units
(methoxyallene and nitrone).
Recent studies devoted to Diels–Alder[10] and 1,3-dipolar
cycloadditions[11] have shown that the global indexes de-
fined in the context of DFT[12] are a powerful tool to under-
stand the behaviour of polar cycloadditions. This model de-
termines the charge transfer pattern and decides which of
the partners is acting as nucleophile or electrophile in polar
processes. It can also anticipate a concerted pathway in
those cases where the electrophilicity/nucleophilicity differ-
ence is small.[10,11a] According to this model nitrones are
generally classified as moderate electrophiles within the
electrophilicity index ω scale and therefore, they can
undergo both normal electron-demand (HOMOnitrone
–
–
LUMOdipolarophile) or inverse electron-demand (LUMOnitrone
HOMOdipolarophile) cycloadditions.[11a] Nitrone 1 has an
electrophilicity value ω = 0.98 eV, that also classifies it as
Scheme 4. Pathways of Lewis-acid-promoted cycloadditions of
moderate electrophile. Coordination of nitrone 1 to AlMe3 nitrone 1 with methoxyallene.
Eur. J. Org. Chem. 2008, 277–284
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279

B. Dugovicˇ, L. Fisˇera, H.-U. Reißig
FULL PAPER
The relative configuration of C-3 and C-4Ј of isoxazolid- ture of isomers) at room temperature. This process can be
ines 3a–3c, 4a and 4c was assigned only tentatively, taking explained by an intramolecular Michael addition of the
into account already known stereoselectivities of nitrone 1 amine moiety, followed by a reverse Michael elimination.[21]
in additions of nucleophiles[1c] and of other cycload- Interestingly, a similar transformation was not observed in
ditions.[15] Assignment of 3,5-trans and 3,5-cis or E- and Z- the case of 3,4Ј-anti-5a. N-Allylation of 4 with allyl bromide
configuration is based on NOE measurements of the iso- was not successful, probably due to the steric reasons. Reac-
lated isoxazolidines 3a–3c, 4a and 4c, respectively.
tions of the more reactive allyl triflate with dia-
α-Methylene-β-amino acid derivatives[16] are most di- stereomerically pure 3,4Ј-anti-3,5-cis-4a or 3,4Ј-syn-3,5-
rectly accessible via aza-Morita–Baylis–Hillman reac- trans-4c followed by N–O bond cleavage by base treatment
tions.[17] However, this approach is very substrate depend- led to the formation of the desired N-allyl-N-benzyl-α-
ent and a variety of specific reaction conditions are known methylene-β-amino acid ester 3,4Ј-anti-7a and 3,4Ј-syn-7b
for the synthesis of this class of compounds. Therefore, the in moderate 39% and 36% yields, respectively.[22]
preparation of highly functionalized α-methylene-β-amino
acids is still demanding and the development of alternative
methods is an attractive objective in organic synthesis.[18]
A
Conclusions
variety of reductive isoxazolidine ring-opening methods
have been reported, which generate β-amino acids or related
derivatives.[19] In our case we have used the redox ring-
opening of isoxazolidines first reported by Murahashi et
al.[20a] and further employed by others including our groups
for the cleavage of N–O heterocycles.[3f,7c,8,20b–20d] Both dia-
stereomers of the corresponding N,N-disubstituted-α-meth-
ylene-β-amino acid ester 5 and 7 were prepared starting
from appropriate isoxazolidines 4 and methyl triflate or al-
lyl triflate, respectively (Scheme 5). Treatment of dia-
stereomeric mixtures of isoxazolidines 3,4Ј-anti-4a,b and
3,4Ј-syn-4c,d with MeOTf in acetonitrile at 0 °C smoothly
afforded the expected N-benzyl-N-methylisoxazolidinium
salts. For the subsequent N–O bond cleavage with triethyl-
amine prolonged reaction times were required. Low tem-
perature was also crucial, in particular for the transforma-
tion of 3,4Ј-syn-4c,d into 3,4Ј-syn-5b, while α-methylene-β-
amino acid ester 3,4Ј-syn-5b underwent further conversion
into the thermodynamically more stable product 6 (1:1 mix-
We have studied the first 1,3-dipolar cycloadditions of
d-glyceraldehyde-derived nitrone 1 and methoxyallene (2).
In the absence of Lewis acid this reaction proceeded essen-
tially unselective to the terminal and to the alkoxysubsti-
tuted double bond of methoxyallene, affording seven iso-
meric isoxazolidines 3a–3d and 4a–4c out of sixteen theore-
tically possible. We have demonstrated that in the presence
of Lewis acids siteselectivity of the cycloaddition was
strongly enhanced with the exclusive formation of 4-methyl-
ene-substituted isoxazolidines 4a–4d. Furthermore, the dia-
stereofacial selectivity of the methoxyallene addition to the
nitrone 1 could be controlled by the nature of the Lewis
acid. Precomplexation of nitrone 1 with AlMe3 gave access
to isoxazolidines with relative configuration 3,4Ј-anti-4a,b,
whereas 3,4Ј-syn-4c,d were obtained predominantly in the
presence of TMSOTf. The redox ring-opening of isoxazol-
idines 4 by treatment with reactive alkylating agents such
as methyl or allyl triflate resulted in conversion into syn-
thetically valuable α-methylene-β-amino acid esters 5a,b
and 7a,b.
Experimental Section
General Methods: Reactions were generally performed under argon
in flame-dried flasks, and the components were added by syringe.
The starting materials, the d-glyceraldehyde-derived nitrone 1,[23]
methoxyallene[24] and allyl triflate,[25] were prepared according to
literature procedures. All other chemicals are commercially avail-
able and were used without further purification. Dichloromethane
and acetonitrile were distilled from calcium hydride and stored over
molecular sieves (4 Å). Products were purified by flash chromatog-
raphy (FLC) on silica gel (230–400 mesh, Merck). Preparative
HPLC was carried out on a Nucleosil 50–5 column and detected
with a Knauer variable UV-detector (λ = 255 nm) and a Knauer
refractometer. Unless stated otherwise, yields refer to analytically
1
pure samples. Isomer ratios were determined by HPLC. H NMR
spectra [TMS (δ = 0.00 ppm) as internal standard] and 13C NMR
spectra [CDCl3 (δ = 77.0 ppm) as internal standard] were recorded
on Jeol Eclipse 500 (500 MHz) and Bruker AC 250 (250 MHz) in-
struments in CDCl3 solution. Integrals are in accordance with as-
signments; coupling constants are given in Hz. IR spectra were
measured with an FTIR spectrometer Nicolet 5 SXC and 205 (Per-
kin–Elmer). MS and HRMS analyses were performed on Finnigan
MAT 711 (EI, 80 eV, 8 kV), MAT CH7A (EI, 80 eV, 3 kV) instru-
Scheme 5. Redox ring-opening of isoxazolidines 4a–4d by treat-
ment with alkylating agents and base.
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Controlled Isoxazolidine Formation
ments. The elemental analyses were recorded with “Elemental-Ana-
lyzer” (Vario EL). Optical rotations ([α]D) were determined with
Perkin–Elmer 141 or Perkin–Elmer 241 polarimeters at the tem-
peratures given.
All calculations were carried out using PC GAMESS software.[9]
Energies of FMOs were obtained from singlepoint DFT calcula-
tions using a B3LYP/6-31G* basis set on HF/3-21G*-optimized
structures. Global indexes: electronic chemical potential μ, chemi-
cal hardness η, and global electrophilicity ω of nitrone 1, nitrone–
AlMe3 complex (1-AlMe3), and methoxyallene (2) were calculated
according to ref.[11a]
290.13892. C17H23NO4 (305.4): calcd. C 66.86, H 7.59; N 4.59;
found C 66.90, H 7.59, N 4.54.
(3S,4E)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-(meth-
oxymethylene)isoxazolidine (3b): Colourless wax. Rf = 0.14 (EtOAc/
hexane, 15:85). [α]D = +20.5 (c = 1.06, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 1.25, 1.32 [2 s, 3 H each, OC(CH3)2O], 3.63
(s, 3 H, OCH3), 3.80 (d, J = 12.7 Hz, 1 H, NCH2Ph), 3.83–3.85
(m, 1 H, 3-H), 3.89, 3.91 (2 dd, J = 6.3, 9.4 Hz, 1 H each, 5Ј-H),
4.06 (d, J = 12.7 Hz, 1 H, NCH2Ph), 4.12 (td, J = 6.3, 8.1 Hz, 1
H, 4Ј-H), 4.38 (ddd, J = 1.5, 2.1, 10.7 Hz, 1 H, 5-H), 4.53 (ddd, J
= 0.7, 1.8, 10.7 Hz, 1 H, 5-H), 6.22 (dt, J = 1.5, 1.8 Hz, 1 H, =CH),
7.22–7.26, 7.29–7.32, 7.38–7.40 (3 m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 25.5, 26.5 [2 q, OC(CH3)2O], 59.9 (q,
OCH3), 60.6 (t, NCH2Ph), 66.4, 66.5 (2 t, C-5, C-5Ј), 67.0 (d, C-
3), 76.3 (d, C-4Ј), 109.1 (s, C-2Ј), 115.4 (s, C-4), 127.2, 128.2, 129.3,
Uncatalyzed Cycloaddition: A solution of nitrone 1 (0.500 g,
2.13 mmol) and methoxyallene (2, 0.44 mL, 5.3 mmol, 2.5 equiv.)
in CH2Cl2 (5 mL) was stirred 72 h at room temp. Volatile compo-
nents were evaporated in vacuo. Preparative HPLC of the residue
allowed isolation of isoxazolidines 3a (72 mg, 11%), 3b (119 mg,
18%), 3c (20 mg, 3%), 4a (21 mg, 3%), 4c (56 mg, 9%) and a mix-
ture of diastereomers 3a–3d (66 mg, 10%) and 4a–4c (12 mg, 2%).
136.7 (3 d, s, Ph), 141.4 (d, =CH) ppm. IR (film): ν = 3085 –2845
˜
(=C–H, C–H), 1700 (C=C) cm–1. MS (EI, 80 eV): m/z (%) = 305
(Ͻ1) [M+], 290 (Ͻ1) [M – CH3]+, 204 (33) [M – C5H9O2]+, 101 (4)
[C5H9O2]+, 91 (100) [C7H7]+. HRMS: (EI, 80 eV) calcd. for
C16H20NO4 290.13922 [M – CH3]+; found 290.13839. C17H23NO4
(305.4): calcd. C 66.86, H 7.59, N 4.59; found C 66.74, H 7.73, N
4.46.
AlMe3-Promoted Reaction: The reaction was carried out under an
argon atmosphere. To a stirred solution of nitrone 1 (0.500 g,
2.13 mmol) in CH2Cl2 (5 mL), was added AlMe3 (2 m in hexanes,
1.1 mL, 1 equiv.) at 0 °C and stirring was continued at the same
temperature for 1 h. A solution of methoxyallene (2, 1.77 mL,
21.3 mmol, 10 equiv.) in CH2Cl2 (5 mL) was added in seven por-
tions during 12 h. The temperature was kept between 0 and 8 °C
until nitrone 1 was consumed (50 h). The reaction was quenched
by addition of MeOH (2 mL) followed by filtration through silica
gel and washing with EtOAc/hexane, 1:1. Solvents were evaporated
in vacuo and after preparative HPLC of the residue pure isoxazol-
idines 4a (240 mg, 37%), 4c (82 mg, 13%) and a mixture of dia-
stereomers 4a–4d (36 mg, 6%) were isolated.
(3R,4E)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-(meth-
oxymethylene)isoxazolidine (3c): Colourless oil. Rf = 0.20 (EtOAc/
hexane, 15:85). [α]D = –38.0 (c = 1.03, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 1.33, 1.42 [2 s, 3 H each, OC(CH3)2O], 3.63
(s, 3 H, OCH3), 3.83 (d, J = 12.9 Hz, 1 H, NCH2Ph), 3.89 (mc, 2
H, 5Ј-H, 3-H), 3.98 (d, J = 12.9 Hz, 1 H, NCH2Ph), 4.00 (dd, J =
6.4, 8.4 Hz, 1 H, 5Ј-H), 4.24 (dt, J = 5.7, 6.4 Hz, 1 H, 4Ј-H), 4.40
(ddd, J = 1.7, 1.8, 10.5 Hz, 1 H, 5-H), 4.51 (ddd, J = 0.8, 1.8,
10.5 Hz, 1 H, 5-H), 6.23 (q, J = 1.8 Hz, 1 H, =CH), 7.24–7.37 (m,
5 H, Ph) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.4, 26.5 [2 q,
OC(CH3)2O], 59.9 (q, OCH3), 61.4 (t, NCH2Ph), 66.5 (d, C-3), 66.6
(t, C-5Ј), 66.9 (t, C-5), 76.1 (d, C-4Ј), 109.3 (s, C-2Ј), 116.3 (s, C-
4), 127.4, 128.3, 129.1, 137.1 (3 d, s, Ph), 141.1 (d, =CH) ppm. IR
TMSOTf-Promoted Reaction: The reaction was carried out under
an argon atmosphere. To a stirred solution of nitrone 1 (1.00 g,
4.25 mmol) in CH2Cl2 (20 mL), was added TMSOTf (0.82 mL,
4.3 mmol, 1 equiv.) at –78 °C. After 20 min, methoxyallene (2,
1.77 mL, 21.3 mmol, 5 equiv.) was added dropwise. The tempera-
ture was allowed to increase to –65 °C during 1 h. The mixture
was again cooled to –78 °C and quenched by addition of 20 mL of
saturated NaHCO3. After warming up to room temp., the mixture
was extracted with Et2O, dried with Na2SO4 and volatile compo-
nents were evaporated. Preparative HPLC the of residue allowed
isolation of pure isoxazolidines 4a,b (71 mg, 5%), 4c (483 mg,
37%), 227 mg (17%) of a mixture of 4d/4c (92:8) and 27 mg (2%)
of a mixture of all diastereomers 4a–4d.
(film): ν = 3090 –2840 (=C–H, C–H), 1705 (C=C) cm–1. MS (EI,
˜
80 eV): m/z (%) = 305 (1) [M+], 290 (3) [M – CH3]+, 204 (100)
[M – C5H9O2]+, 101 (6) [C5H9O2]+, 91 (167) [C7H7]+. C17H23NO4
(305.4): calcd. C 66.86, H 7.59; N 4.59; found C 66.57, H 7.15, N
4.52.
(3R,4Z)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-(meth-
oxymethylene)isoxazolidine (3d): 1H NMR (500 MHz, CDCl3): δ =
1.31, 1.36 [2 s, 3 H each, OC(CH3)2O], 3.34 (dbr, J = 8.7 Hz, 1 H,
3-H), 3.61 (dd, J = 4.8, 8.7 Hz, 1 H, 5Ј-H), 3.69 (s, 3 H, OCH3),
3.72 (d, J = 12.5 Hz, 1 H, NCH2Ph), 3.95 (ddd, J = 4.8, 6.2, 8.7 Hz,
1 H, 4Ј-H), 4.03 (d, J = 12.5 Hz, 1 H, NCH2Ph), 4.04 (dd, J = 6.2,
8.7 Hz, 1 H, 5Ј-H), 4.49 (ddd, J = 1.6, 2.5, 12.3 Hz, 1 H, 5-H), 4.70
(ddd, J = 0.6, 2.5, 12.3 Hz, 1 H, 5-H), 6.16 (dt, J = 0.9, 2.5 Hz, 1
H, =CH), 7.27–7.37 (m, 5 H, Ph) ppm. 13C NMR (125 MHz,
CDCl3): δ = 25.2, 27.0 [2 q, OC(CH3)2O], 60.1 (q, OCH3), 60.3 (t,
NCH2Ph), 66.3 (t, C-5Ј), 67.9 (d, C-3), 67.9 (t, C-5), 76.2 (d, C-4Ј),
109.2 (s, C-2Ј), 116.1 (s, C-4), 127.6, 128.4, 129.2, 136.6 (3 d, s, Ph),
141.4 (d, =CH) ppm.
(3S,4Z)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4-(meth-
oxymethylene)isoxazolidine (3a): Colourless oil. Rf = 0.30 (EtOAc/
hexane, 15:85). [α]D = +5.6 (c = 1.00, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 1.28, 1.32 [2 s, 3 H each, OC(CH3)2O], 3.60 (dd, J =
7.2, 8.6 Hz, 1 H, 5Ј-H), 3.66 (s, 3 H, OCH3), 3.64–3.66 (m, 1 H, 3-
H), 3.77 (d, J = 12.5 Hz, 1 H, NCH2Ph), 4.00 (dd, J = 6.3, 8.6 Hz,
1 H, 5Ј-H), 4.09 (d, J = 12.5 Hz, 1 H, NCH2Ph), 4.13 (ddd, J =
6.0, 6.3, 7.2 Hz, 1 H, 4Ј-H), 4.39 (ddd, J = 1.7, 2.5, 12.5 Hz, 1 H,
5-H), 4.68 (ddd, J = 0.7, 2.5, 12.5 Hz, 1 H, 5-H), 6.14 (dt, J = 1.1,
2.5 Hz, 1 H, =CH), 7.24–7.38 (m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 25.6, 26.5 [2 q, OC(CH3)2O], 60.1 (q,
OCH3), 60.4 (t, NCH2Ph), 66.1 (t, C-5Ј), 66.5 (d, C-3), 66.6 (t, C-
5), 76.7 (d, C-4Ј), 108.9 (s, C-2Ј), 115.0 (s, C-4), 127.5, 128.4, 129.2,
(3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-meth-
oxy-4-methyleneisoxazolidine (4a): Colourless oil. Rf = 0.48
1
(EtOAc/hexane, 15:85). [α]D = –132.0 (c = 1.02, CHCl3). H NMR
(500 MHz, CDCl3): δ = 1.34, 1.38 [2 d, J = 0.5 Hz, 3 H each,
OC(CH3)2O], 3.35 (s, 3 H, OCH3), 3.64 (td, J = 2.3, 5.3 Hz, 1 H,
3-H), 4.00 (d, J = 14.0 Hz, 1 H, NCH2Ph), 4.02, 4.04 (2 dd, J =
136.6 (3 d, s, Ph), 141.4 (d, =CH) ppm. IR (film): ν = 3085 (–2850,
˜
=C–H, C–H), 1700 (C=C) cm–1. MS (EI, 80 eV): m/z (%) = 305
(Ͻ1) [M+], 290 (2) [M – CH3]+, 274 (Ͻ1) [M – CH3O]+, 204 (60) 6.4, 8.4 Hz, 1 H each, 5Ј-H), 4.29 (d, J = 14.0 Hz, 1 H, NCH2Ph),
[M – C5H9O2]+, 101 (3) [C5H9O2]+, 91 (100) [C7H7]+. HRMS: (EI, 4.41 (dt, J = 5.3, 6.4 Hz, 1 H, 4Ј-H), 5.24–5.25 (m, 2 H, 5-H,
80 eV) calcd. for C16H20NO4 290.13922 [M – CH3]+; found =CH2), 5.37 (dd, J = 1.0, 2.3 Hz, 1 H, =CH2), 7.24–7.27, 7.30–
Eur. J. Org. Chem. 2008, 277–284
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281

B. Dugovicˇ, L. Fisˇera, H.-U. Reißig
FULL PAPER
7.34, 7.40–7.42 (3 m, 5 H, Ph) ppm. 13C NMR (125 MHz, CDCl3): in water and extracted with hexane, dried with Na2SO4 and concen-
δ = 25.1, 26.5 [2 q, OC(CH3)2O], 54.8 (q, OCH3), 63.2 (t, trated in vacuo. For purification FLC on silica gel (EtOAc/hexane,
NCH2Ph), 65.9 (t, C-5Ј), 66.9 (d, C-3), 77.0 (d, C-4Ј), 102.2 (d, C- 15:85) was employed.
5), 109.3 (s, C-2Ј), 111.5 (t, =CH2), 127.2, 128.2, 128.7, 137.3 (3 d,
Methyl 3-[Benzyl(methyl)amino]-2,3-dideoxy-2-methylene-4,5-O-(1-
methylethylidene)-D-erythro-pentanoate (5a): According to the ge-
s, Ph), 148.8 (s, C-4) ppm. IR (film): ν = 3090 –2830 (=C–H, C–
˜
H), 1675 (C=C), 1605, 1585 [C=C (Ph)] cm–1. MS (EI, 80 eV): m/z
(%) = 305 (7) [M+], 290 (5) [M – CH3]+, 274 (2) [M – OCH3]+,
246 (Ͻ1) [M – C2H3O2]+, 216 (2) [C14H18NO]+, 204 (51) [M –
C5H9O2]+, 101 (8) [C5H9O2]+, 91 (100) [C7H7]+. HRMS: (EI,
80 eV) calcd. for C17H23NO4 305.16272; found 305.16377.
C17H23NO4 (305.4): calcd. C 66.86, H 7.59, N 4.59; found C 66.89,
H 7.68, N 4.59.
neral procedure above, the mixture was treated with MeOTf at 0 °C
for 4.5 h and then with Et3N at 0 to 4 °C for 7 d. After FLC 60 mg
(57%) of 5a (yellow oil) was isolated. Rf = 0.52 (EtOAc/hexane,
15:85). [α]D = +51.1 (c = 1.09, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 1.35, 1.37 [2 s, 3 H each, OC(CH3)2O], 2.08 (s, 3 H,
NCH3), 3.50, 3.53 (2 d, J = 13.5 Hz, 1 H each, NCH2Ph), 3.79 (s,
3 H, COOCH3), 3.85 (d, J = 9.6 Hz, 1 H, 3-H), 4.01, 4.20 (2 dd, J
= 6.0, 8.4 Hz, 1 H each, 5-H), 4.50 (td, J = 6.0, 9.6 Hz, 1 H, 4-H),
5.78 (br. s, 1 H, =CH2), 6.58 (d, J = 0.8 Hz, 1 H, =CH2), 7.21–7.26
(m, 3 H, Ph), 7.28–7.31 (m, 2 H, Ph) ppm. 13C NMR (125 MHz,
CDCl3): δ = 25.6, 26.8 [2 q, OC(CH3)2O], 37.8 (q, NCH3), 52.0 (q,
COOCH3), 59.2 (t, NCH2Ph), 68.7 (t, C-5), 65.1 (d, C-3), 75.1 (d,
C-4), 109.3 [s, OC(CH3)2O], 126.9, 128.2 (2 d, Ph), 128.3 (t, =CH2),
128.4, 135.5, 139.5 (d, 2 s, Ph, C-2), 168.1 (s, COOCH3) ppm. IR
(3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-meth-
oxy-4-methyleneisoxazolidine (4b): The following characteristic sig-
nals can be unambiguously assigned: 1H NMR (250 MHz, CDCl3):
δ = 1.31, 1.38 [2 s, 3 H each, OC(CH3)2O], 3.45 (s, 3 H, OCH3),
4.36 (d, J = 12.6 Hz, 1 H, NCH2Ph), 5.33–5.34 (m, 1 H, 5-H),
5.54–5.56 (m, 2 H, =CH2) ppm.
(3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-meth-
oxy-4-methylenesoxazolidine (4c): Colourless oil. Rf = 0.40 (EtOAc/
hexane, 15:85). [α]D = +178.4 (c = 1.09, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 1.32, 1.36 [2 d, J = 0.5 Hz, 3 H each,
OC(CH3)2O], 3.37 (s, 3 H, OCH3), 3.55 (td, J = 2.2, 7.1 Hz, 1 H,
3-H), 3.91 (dd, J = 7.1, 8.3 Hz, 1 H, 5Ј-H), 4.07 (dd, J = 6.4, 8.3 Hz,
1 H, 5Ј-H), 4.08 (d, J = 13.9 Hz, 1 H, NCH2Ph), 4.24 (td, J = 7.1,
6.4 Hz, 1 H, 4Ј-H), 4.27 (d, J = 13.9 Hz, 1 H, NCH2Ph), 5.20 (br.
s, 1 H, 5-H), 5.25, 5.35 (2 dd, J = 1.3, 2.2 Hz, 1 H each, =CH2),
7.24–7.27, 7.30–7.33, 7.40–7.41 (3 m, 5 H, Ph) ppm. 13C NMR
(125 MHz, CDCl3): δ = 25.1, 26.5 [2 q, OC(CH3)2O], 54.9 (q,
OCH3), 62.2 (t, NCH2Ph), 66.5 (t, C-5Ј), 68.5 (d, C-3), 76.0 (d, C-
4Ј), 102.4 (d, C-5), 109.2 (s, C-2Ј), 112.0 (t, =CH2), 127.2, 128.2,
(film): ν = 3105–2795 (=C–H, C–H), 1720 (C=O), 1625 (C=C),
˜
1600, 1585 [C=C (Ph)] cm–1. MS (EI, 80 eV): m/z (%) = 319 (3)
[M+], 304 (6) [M – CH3]+, 288 (Ͻ1) [M – OCH3]+, 218 (64) [M –
C5H9O2]+, 101 (5) [C5H9O2]+, 91 (100) [C7H7]+. C18H25NO4
(319.4): calcd. C 67.69, H 7.89; N 4.39; found C 67.54, H 7.93, N
4.40.
Methyl 3-[Benzyl(methyl)amino]-2,3-dideoxy-2-methylene-4,5-O-(1-
methylethylidene)-D-threo-pentanoate (5b): According to the general
procedure above, the mixture was treated with MeOTf at 0 °C for
3.75 h and then with Et3N at 0 to 4 °C for 3 d. After FLC 79 mg
(75%) of 5b (yellowish oil) was isolated. Rf = 0.43 (EtOAc/hexane,
15:85). [α]D = –33.5 (c = 0.98, CHCl3). 1H NMR (500 MHz,
CDCl3): δ = 1.40, 1.43 [2 s, 3 H each, OC(CH3)2O], 2.24 (s, 3 H,
NCH3), 3.57 (dd, J = 7.2, 8.2 Hz, 1 H, 5-H), 3.60 (d, J = 13.5 Hz,
1 H, NCH2Ph), 3.77 (s, 3 H, COOCH3), 3.79 (dd, J = 1.0, 8.8 Hz,
1 H, 3-H), 3.80 (d, J = 13.5 Hz, 1 H, NCH2Ph), 3.98 (dd, J = 6.4,
8.2 Hz, 1 H, 5-H), 4.62 (ddd, J = 6.4, 7.2, 8.8 Hz, 1 H, 4-H), 5.57
(t, J = 1.0 Hz, 1 H, =CH2), 6.31 (d, J = 1.0 Hz, 1 H, =CH2), 7.20–
7.23, 7.27–7.33 (2 m, 5 H, Ph) ppm. 13C NMR (125 MHz, CDCl3):
δ = 25.5, 26.7 [2 q, OC(CH3)2O], 37.5 (q, NCH3), 52.1 (q, CO-
OCH3), 59.3 (t, NCH2Ph), 65.0 (d, C-3), 67.5 (t, C-5), 75.4 (d, C-
4), 109.7 [s, OC(CH3)2O], 126.2 (t, CH2), 126.7, 128.1, 128.7, 138.0,
129.1, 136.8 (3 d, s, Ph), 148.2 (s, C-4) ppm. IR (film): ν = 3090
˜
–2830 (=C–H, C–H), 1675 (C=C), 1605, 1585 [C=C (Ph)] cm–1.
MS (EI, 80 eV): m/z (%) = 305 (6) [M+], 290 (5) [M – CH3]+, 274
(2) [M – OCH3]+, 247 (1) [M – C3H6O]+, 216 (1) [C14H18NO]+, 204
(54) [M – C5H9O2]+, 101 (6) [C5H9O2]+, 91 (100) [C7H7]+. HRMS:
(EI, 80 eV) calcd. for C17H23NO4 305.16272; found 305.16355.
C17H23NO4 (305.4): calcd. C 66.86, H 7.59, N 4.59; found C 66.77,
H 7.42, N 4.55.
(3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-5-meth-
1
oxy-4-methyleneisoxazolidine (4d): H NMR (500 MHz, CDCl3): δ
139.8 (3 d, 2 s, Ph, C-2), 167.7 (s, COOCH ) ppm. IR (Film): ν =
˜
= 1.27, 1.32 [2 s, 3 H each, OC(CH3)2O], 3.47 (s, 3 H, OCH3), 3.60
(dd, J = 7.0, 8.6 Hz, 1 H, 5Ј-H), 3.80–3.82 (m, 1 H, 3-H), 3.99 (dd,
J = 6.3, 8.6 Hz, 1 H, 5Ј-H), 4.08 (d, J = 12.7 Hz, 1 H, NCH2Ph),
4.13 (dt, J = 6.3, 7.0 Hz, 1 H, 4Ј-H), 4.40 (d, J = 12.7 Hz, 1 H,
NCH2Ph), 5.30 (dt, J = 1.5, 2.8 Hz, 1 H, 5-H), 5.51, 5.57 (2 t, J =
1.5 Hz, 1 H each, =CH2), 7.25–7.28, 7.31–7.34, 7.38–7.39 (3 m, 5
H, Ph) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.5, 26.3 [2 q,
OC(CH3)2O], 55.9 (q, OCH3), 64.1 (t, NCH2Ph), 65.9 (t, C-5Ј),
68.1 (d, C-3), 76.7 (d, C-4Ј), 106.0 (d, C-5), 109.0 (s, C-2Ј), 114.6
(t, =CH2), 127.4, 128.3, 129.1, 137.0 (3 d, s, Ph), 148.4 (s, C-4)
ppm.
3
3105–2790 (=C–H, C–H), 1720 (C=O), 1650 (C=C), 1600, 1585
[C=C (Ph)] cm–1. MS (EI, 80 eV): m/z (%) = 319 (7) [M+], 304 (19)
[M – CH3]+, 288 (Ͻ1) [M – OCH3]+, 218 (50) [M – C5H9O2]+, 101
(4) [C5H9O2]+, 91 (100) [C7H7]+. C18H25NO4 (319.4): calcd. C
67.69, H 7.89; N 4.39; found C 67.15, H 7.38, N 4.32.
Methyl (2E/2Z)-2-{[Benzyl(methyl)amino]methyl-3-[(4S)-2,2-di-
methyl-1,3-dioxolan-4-yl]}acrylate (6): 1H NMR (500 MHz,
CDCl3): δ = 1.39, 1.45, 1.46 [3 s, 3 H, 1.5 H each, OC(CH3)2O],
2.12, 2.17 (2 s, 1.5 H each, NCH3), 3.05 (dd, J = 1.1, 13.8 Hz, 0.5
H, 1Ј-H), 3.20 (d, J = 12.8 Hz, 0.5 H, 1Ј-H), 3.27 (dd, J = 0.9,
12.8 Hz, 0.5 H, 1Ј-H), 3.33 (td, J = 1.1, 13.8 Hz, 0.5 H, 1Ј-H), 3.43,
3.46, 3.54, 3.55 (4 d, J = 13.0, 13.2 Hz, 0.5 H each, NCH2Ph), 3.61
(dd, J = 6.8, 8.3 Hz, 0.5 H, 5-H), 3.62 (dd, J = 7.3, 8.5 Hz, 0.5 H,
5-H), 3.74, 3.75 (2 s, 1.5 H each, COOCH3), 4.18 (dd, J = 6.5,
8.2 Hz, 0.5 H, 5-H), 4.31 (dd, J = 6.8, 8.3 Hz, 0.5 H, 5-H), 4.93
(ddd, J = 6.5, 7.3, 8.5 Hz, 0.5 H, 4-H), 5.17 (q, J = 6.8 Hz, 0.5 H,
4-H), 6.21 (td, J = 1.1, 6.8 Hz, 0.5 H, 3-H), 6.81 (dd, J = 0.9,
8.5 Hz, 0.5 H, 3-H), 7.28 (m, 5 H, Ph) ppm. 13C NMR (125 MHz,
CDCl3): δ = 25.5, 25.7, 26.6 [3 q, OC(CH3)2O], 41.7, 42.0 (2 q,
NCH3), 51.7, 52.0 (2 q, COOCH3), 52.4, 59.5 (2 t, C-1Ј), 61.9, 62.5
N-Methylation and Redox Cleavage of Isoxazolidines: The corre-
sponding isoxazolidine 4 (as diastereomeric mixture of 3,5-cis/3,5-
trans, 0.100 g, 0.33 mmol) was dissolved in acetonitrile (2 mL). The
solution was treated with methyl triflate (0.041 mL, 0.36 mmol,
1.1 equiv.) at 0 °C and the resulting mixture was stirred at 0 °C for
the time given in the individual experiments until the starting mate-
rial was consumed. The mixture was then treated with triethyl-
amine (0.137 mL, 0.98 mmol, 3 equiv.) and stirred for the given
time until the isoxazolidinium salt disappeared (tlc control). After
all volatile components had been removed the residue was dissolved
282
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 277–284

Controlled Isoxazolidine Formation
(2 t, NCH2Ph), 68.9, 69.7 (2 t, C-5), 72.5, 73.9 (2 d, C-4), 109.6, OCH3]+, 244 (90) [M – C5H9O2]+, 91 (100) [C7H7]+. C20H27NO4
109.9 [2 s, OC(CH3)2O], 127.0, 127.1, 128.1, 128.2, 128.9, 129.1,
131.8, 132.4, 138.7, 138.9 (6 d, 4 s, C-2, Ph), 142.1, 142.7 (2 d, C-
3), 167.2, 167.6 (2 s, COOCH3) ppm.
(345.4): calcd. C 69.54, H 7.88; N 4.05; found C 69.37, H 7.70, N
3.92.
N-Allylation and Redox Cleavage of Isoxazolidines: Freshly pre-
pared allyl triflate (1 m in CCl4, 0.43 mL, 1.5 equiv., filtered from
AgI) was added at 0 °C under an argon atmosphere to a stirred
CH2Cl2 solution of the corresponding isoxazolidine 4a or 4c
(0.100 g, 0.33 mmol), the temperature was raised and stirring con-
tinued for 2 h at room temp. Solvents were evaporated, the residue
was dissolved in CHCl3 (5 mL), Et3N (0.09 mL, 0.7 mmol, 2 equiv.)
was added and the mixture was heated 30 min at 50 °C. After all
volatile materials had been removed the residue was dissolved in
water and extracted with hexane, dried with Na2SO4 and concen-
trated in vacuo. For purification FLC on silica gel (CH2Cl2/EtOAc/
hexane = 30:3.5:66.5) was employed.
Acknowledgments
Support of this work by the Deutsche Forschungsgemeinschaft
(DFG), the Alexander von Humboldt Stiftung (fellowship for
B. D.), the Fonds der Chemischen Industrie and the Schering AG
is most gratefully acknowledged.
[1] For reviews on 1,3-dipolar cycloadditions of nitrones see: a)
J. J. Tufariello in 1,3-Dipolar Cycloaddition Chemistry (Ed.: A.
Padwa), Wiley-Interscience, New York, 1984, vol. 2, chapter 9,
pp. 83–168; b) R. C. F. Jones, J. N. Martin in The Chemistry of
Heterocyclic Compounds, vol. 59: Synthetic Applications of 1,3-
Dipolar Cycloaddition Chemistry Toward Heterocycles and Nat-
ural Products (Eds.: A. Padwa, W. H. Pearson), John Wiley &
Sons, New York, 2002, chapter 1, pp. 1–81; for reviews on nu-
cleophilic additions to nitrones see: c) P. Merino, S. Franco,
F. L. Merchán, T. Tejero, Synlett 2000, 442–454; d) F. Cardona,
A. Goti, Angew. Chem. 2005, 117, 8042–8045; Angew. Chem.
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[3] a) R. Pulz, T. Watanabe, W. Schade, H.-U. Reißig, Synlett 2000,
983–986; b) R. Pulz, A. Al-Harrasi, H.-U. Reißig, Synlett 2002,
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Methyl 3-[Allyl(benzyl)amino]-2,3-dideoxy-2-methylene-4,5-O-(1-
methylethylidene)-
(39%) of 7a (colourless oil) and 14 mg (14%) of starting isoxazolid-
ines 4a,b were isolated. Rf = 0.51 (EtOAc/hexane, 10:90). [α]D
D-erythro-pentanoate (7a): After FLC 44 mg
=
1
+81.4 (c = 1.00, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.30,
1.31 [2 s, 3 H each, OC(CH3)2O], 2.91 (tdd, J = 1.2, 7.8, 14.2 Hz,
1 H, NCH2), 3.18 (tdd, J = 1.7, 5.1, 14.2 Hz, 1 H, NCH2), 3.33,
3.79 (2 d, J = 14.0 Hz, 1 H each, NCH2Ph), 3.79 (s, 3 H, CO-
OCH3), 3.84 (d, J = 9.8 Hz, 1 H, 3-H), 3.85, 4.13 (2 dd, J = 6.2,
8.4 Hz, 1 H each, 5-H), 4.51 (td, J = 6.2, 9.8 Hz, 1 H, 4-H), 5.11
(dddd, J = 1.2, 1.7, 1.9, 10.1 Hz, 1 H, CH=CH2), 5.15 (dddd, J =
1.2, 1.7, 1.9, 18.0 Hz, 1 H, CH=CH2), 5.75 (d, J = 1.0 Hz, 1 H, 2-
CH2), 5.75 (dddd, J = 5.1, 7.8, 10.1, 18.0 Hz, 1 H, CH=CH2), 6.54
(d, J = 1.0 Hz, 1 H, 2-CH2), 7.21–7.32 (m, 5 H, Ph) ppm. 13C
NMR (125 MHz, CDCl3): δ = 25.7, 26.7 [2 q, OC(CH3)2O], 52.0
(q, COOCH3), 54.0 (t, N-CH2), 54.6 (t, NCH2Ph), 61.5 (d, C-3),
68.8 (t, C-5), 75.0 (d, C-4), 109.2 [s, OC(CH3)2O], 117.5 (t,
CH=CH2), 126.9, 128.2, 128.5 (3 d, Ph), 128.8 (t, 2-CH2), 136.0,
136.6 (2 s, Ph, C-2), 139.8 (d, CH=CH2), 168.1 (s, COOCH3) ppm.
IR (film): ν = 3085–2815 (=C–H, C–H), 1720 (C=O), 1640, 1625
˜
(C=C), 1600, 1585 [C=C (Ph)] cm–1. MS (EI, 80 eV): m/z (%) =
345 (Ͻ 1) [M+], 330 (3) [M – CH3]+, 314 (Ͻ1) [M – OCH3]+, 244
(100) [M – C5H9O2]+, 91 (65) [C7H7]+. C20H27NO4 (345.4): calcd.
C 69.54, H 7.88; N 4.05; found C 69.52, H 7.97, N 3.98.
Methyl 3-[Allyl(benzyl)amino]-2,3-dideoxy-2-methylene-4,5-O-(1-
methylethylidene)-
of 7b (colourless oil) and 42 mg (42%) of unreacted starting isox-
azolidine 4c were isolated. Rf = 0.51 (EtOAc/hexane, 10:90). [α]D
D-threo-pentanoate (7b): After FLC 41 mg (36%)
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=
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1
–31.3 (c = 1.02, CHCl3). H NMR (500 MHz, CDCl3): δ = 1.38,
1.42 [2 s, 3 H each, OC(CH3)2O], 3.08, 3.40 (2 tdd, J = 1.5, 6.4,
14.1 Hz, 1 H each, NCH2), 3.56 (dd, J = 7.4, 8.2 Hz, 1 H, 5-H),
3.65 (d, J = 13.9 Hz, 1 H, NCH2Ph), 3.74 (s, 3 H, COOCH3), 3.85
(d, J = 13.9 Hz, 1 H, NCH2Ph), 3.90 (dd, J = 0.8, 8.3 Hz, 1 H, 3-
H), 3.93 (dd, J = 6.4, 8.2 Hz, 1 H, 5-H), 4.58 (ddd, J = 6.4, 7.4,
8.3 Hz, 1 H, 4-H), 5.07 (tdd, J = 1.5, 2.3, 10.1 Hz, 1 H, CH=CH2),
5.13 (tdd, J = 1.5, 2.3, 16.6 Hz, 1 H, CH=CH2), 5.58 (s, 1 H, 2-
CH2), 5.84 (tdd, J = 6.4, 10.1, 16.6 Hz, 1 H, CH=CH2), 6.25 (d, J
= 0.8 Hz, 1 H, 2-CH2), 7.19–7.21, 7.25–7.28, 7.31–7.33 (3 m, 5 H,
Ph) ppm. 13C NMR (125 MHz, CDCl3): δ = 25.4, 26.6 [2 q,
OC(CH3)2O], 52.0 (q, COOCH3), 53.6 (t, N-CH2), 54.1 (t,
NCH2Ph), 60.9 (d, C-3), 67.7 (t, C-5), 76.0 (d, C-4), 109.5 [s,
OC(CH3)2O], 116.8 (t, CH=CH2), 126.1 (t, 2-CH2), 126.6, 128.0,
128.7, 137.0, 139.0 (3 d, 2 s, Ph, C-2), 140.3 (d, CH=CH2), 167.9
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˜
3
(C=O), 1640, 1625 (C=C), 1600, 1585 [C=C (Ph)] cm–1. MS (EI,
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Eur. J. Org. Chem. 2008, 277–284
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
283

B. Dugovicˇ, L. Fisˇera, H.-U. Reißig
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Received: August 2, 2007
Published Online: October 30, 2007
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 277–284