Synthesis of α-Acyloxynitrones and Reactivity towards Samarium Diiodide

Article abstract of DOI:10.1002/ejoc.201600478

Upon treatment of fructose-derived nitrone 1 with samarium diiodide, with the aim of inducing its umpolung and coupling with electrophiles, an unexpected β-elimination of the benzyloxy group at C-1 was observed, yielding nitrone 2. The mechanism and scope

Full text of DOI:10.1002/ejoc.201600478

DOI: 10.1002/ejoc.201600478
Full Paper
Samarium Diiodide and Keto Nitrones
Synthesis of α-Acyloxynitrones and Reactivity towards
Samarium Diiodide
Emilie Racine,[a] Olga N. Burchak,[a] and Sandrine Py*[a]
Abstract: Upon treatment of fructose-derived nitrone 1 with and 4 from D-fructose; their synthesis demonstrates that acyl-
samarium diiodide, with the aim of inducing its umpolung and protected nitrones can be prepared efficiently by intramolecular
coupling with electrophiles, an unexpected ꢀ-elimination of the N-alkylation of sugar-derived oximes, a strategy previously de-
benzyloxy group at C-1 was observed, yielding nitrone 2. The veloped only for ether- or ketal-protected cyclic nitrones. Nitro-
mechanism and scope of this transformation were investigated, nes 3 and 4 underwent fast ꢀ-elimination upon treatment with
from nitrone 1 and from five other α-alkoxy or α-acyloxy nitro- SmI2. Contrastingly, no ꢀ-elimination occurred with nitrones 5–
nes. This paper describes the preparation of new nitrones 3 7, suggesting a specific behavior of endocyclic keto nitrones.
Introduction
Samarium diiodide has been widely used as a reducing agent
in organic synthesis since the seminal works of Kagan et al.[1]
and Molander et al.,[2] highlighting its utility for selective trans-
formations of carbonyl-containing compounds. Highly efficient
C–C bond forming processes have been developed[3] and ap-
plied to the synthesis of structurally complex molecules.[4] The
SmI2-promoted chemistry of imines and their derivatives, al-
though developed to a lesser extent, have also attracted some
attention.[5] In particular, nitrones and sulfonylimines have
proven to be excellent substrates for reductive cross-coupling
reactions yielding vicinal amino alcohols[6] and γ-amino acid
derivatives.[7] Interestingly, the SmI2-promoted cross-coupling
Scheme 1. Synthetic approach to polyhydroxylated pyrrolizidines from carbo-
hydrate-derived nitrones.
of carbohydrate-derived nitrones[8] with alkyl acrylates allowed
straightforward syntheses of highly functionalized polyhydroxy-
lated pyrrolizidines as illustrated by the total syntheses of (+)-
treated under the previously described conditions for SmI2-pro-
moted reductive coupling with unsaturated esters, none of the
[8a]
hyacinthacine A2 and (+)-australine[8d] (Scheme 1).
In continuation of our work in this field, we considered the
construction of polyhydroxylated indolizidines by SmI2-induced
reductive cross-coupling of α,ꢀ-unsaturated esters and six-
membered-ring nitrones (Scheme 2). Such nitrones have been
scarcely used in synthesis compared to their five-membered
ring analogues[9] and have sometimes been reported to be un-
stable.[10] However, the work of van den Broek[11] suggested
that six-membered-ring keto nitrones would exhibit better sta-
bility than the corresponding aldo nitrones. Indeed, we showed
that nitrone 1, synthesized from the cheap and easily available
expected coupling product was isolated; only nitrone 2 was
produced (Scheme 2).[13]
D
-fructose, is stable during storage and can be used in the syn-
thesis of iminosugars.[12] Surprisingly, when this nitrone was
Scheme 2. Unexpected reactivity of nitrone 1 under SmI2-induced reductive
coupling conditions.
[a] Univ. Grenoble Alpes, DCM, CNRS, DCM,
38000 Grenoble, France
E-mail: sandrine.py@univ-grenoble-alpes.fr
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600478.
The formation of nitrone 2 was explained by an SmI2-medi-
ated two-electron reduction of nitrone 1 resulting in a dianion,
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followed by ꢀ-elimination of the benzyloxy group to produce
an unprecedented samarium enaminolate.[13] This result was un-
expected, as a number of α-alkoxy nitrones had been previously
treated under similar conditions without occurrence of this ꢀ-
elimination process.[8,14] It should be mentioned, however, that
Fisera and co-workers have reported two examples of such
eliminations in exocyclic α-alkoxy aldo nitrones.[15]
Intrigued by the scope of this elimination and with the aim
of isolating derivatives of the putative samarium enaminolate
intermediates and deciphering their reactivity, we undertook a
study of the reactivity of α-alkoxy and α-acyloxy nitrones to-
wards SmI2. For this purpose, nitrones 3–7 were synthesized
and treated with SmI2, to compare their capacities for ꢀ-elimi-
nation vs. reductive coupling with electrophilic partners. The
effect of the nature of the eliminated group was investigated,
as well as the role of cyclic structures vs. acyclic ones (Figure 1).
Scheme 3. Synthesis of nitrone 1 from tetrabenzyl D-fructopyranose.
readily mesylated to afford 8 (94 %, 3:2 mixture of isomers).
However, the overall efficiency of the synthesis of keto nitrone
1 was somewhat limited by the fluoride-promoted cyclization
step, in which only the (E) isomer of oxime 8 was transformed
into the desired nitrone 1; the (Z) isomer was solely desilylated
into Z-9.[23] It appears that in Z-9 the nucleophilic lone pair of
electrons on the nitrogen atom is not well oriented for cycliza-
tion. This is in contrast with previous results obtained with silyl-
oximes derived from aldoses, where nitrones were obtained in
high yields from mixtures of isomers, with no by-products iso-
lated.[8a,9] Attempts to improve the yield of isolated 1 using
various fluoride sources to induce cyclization from 8 are re-
ported in Table 1.
Figure 1. Nitrones prepared for this study.
Results and Discussion
First, tetrabutylammonium difluorotriphenylsilicate[24] (TBAT)
was used to transform 8 into nitrone 1, in the presence of mo-
Preparation of Nitrones
Among the synthetic approaches to prepare endocyclic nitro- lecular sieves, in refluxing THF.[25] Under these conditions, 1 was
nes, oxidation of pyrrolidines and piperidines using hydrogen isolated in 46 % yield, along with 31 % desilylated oxime Z-
peroxide in the presence of catalysts,[16] dimethyldioxirane,[11] 9. Heating of the reaction mixture for 24 h to induce oxime
Davis oxaziridine,[10e,17] or methyltrioxorhenium[18] suffers from isomerization followed by N-alkylation did not lead to a better
poor regioselectivity. Similarly, the oxidation of N-hydroxy- yield of 1 (Table 1, Entry 2). Under these conditions, O-cyclized
pyrrolidines and N-hydroxypiperidines using HgO[19] or product 10 (30 %) was formed as a side-product. Tetrabutylam-
[20]
MnO2
generally yields mixtures of regioisomers. As carbo- monium fluoride, a cheaper fluoride source, was next used at
hydrates exhibit a “masked” carbonyl group at their anomeric lower temperatures, and afforded good overall yields of desilyl-
position, the most practical approach to prepare carbohydrate- ation, but again both 1 and Z-9 were isolated (Table 1, Entries 3
derived endocyclic nitrones involves intramolecular N-alkylation and 4). Finally, tetrabutylammonium fluoride adsorbed onto sil-
of oximes as a key step, as first described by Holzapfel and ica gel[26] was found to be a convenient reagent for promoting
Crous.[21] This method has been used to prepare five-mem- the desired cyclization of 8 to 1 (Table 1, Entries 5 and 6), as it
bered-ring nitrones from most of the available pentoses and allowed easy workup (simple filtration and evaporation of the
hexoses.[9] However, although a number of aldo nitrones have solvent). However, significant amounts of oxime Z-9 or oxaze-
been prepared by this method, its extension to the preparation pine 10 contaminated the desired nitrone 1; heating of the
of keto nitrones remained unexplored. A few years ago, we de- reaction mixture favoured the undesired O-cyclization of Z-9 to
scribed the synthesis of nitrone
1
from
D
-fructose 10 over oxime isomerization (Table 1, Entry 6).
Since no trace of E-9 was detected from these reactions
-fruc- (fluoride-induced desilylation of 8) it was postulated that E-9
topyranose was prepared in high yield (92 %) by treatment of cyclized spontaneously into nitrone 1 and that the latter could
the protected -fructo hemiketal with O-(tert-butyldiphenylsi- be prepared more efficiently if Z-9 isomerised to E-9. However,
(Scheme 3).[12]
The tert-butyldiphenylsilyl ketoxime of tetra-O-benzyl-
D
D
lyl)hydroxylamine,[22] in the presence of a catalytic amount of attempts to induce isomerization of oxime Z-9 failed. At-
pyridinium para-toluenesulfonate (PPTS). Water removal from tempted thermal isomerization in protic solvents,[27] photo-
the reaction mixture by azeotropic distillation was found neces- chemical isomerization in dichloromethane or acetonitrile,[29] or
sary to achieve good yields. Under these conditions, a 3:2 mix- treatment of Z-9 with AlCl3 in anhydrous dichloromethane[28]
ture of (E)/(Z)-isomeric oximes was isolated; this mixture was all led to decomposition of the starting oxime.
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Table 1. Effect of the fluoride source on the desilylation/cyclization of mesyl silyloximes 8.
Entry
Reagent (equiv.)
TBAT (1.1)
Conditions
4 Å MS, THF, 65 °C, 30 min
Global yield [%]
1 [%]
46
9 [%]
31
Z-10 [%]
1
2
3
4
5
6
77
70
86
80
91
81
–
30
–
–
–
TBAT (1.3)
TBAF·3H2O (1.2)
4 Å MS, THF, 65 °C, 24 h
THF, r.t., 1.5 h
THF, 0 °C, 1 h
THF, r.t., 14 h
toluene, 110 °C, 5 h
40
52
49
51
37
–
34
31
40
13
1
M
TBAF in THF (1.1)
TBAF/silica gel (2.0)
TBAF/silica gel (1.2)
31
Nitrones 3 and 4 were also prepared from inexpensive
fructose, but using a different protecting-group strategy. Syn- along with 30 % of unprotected oxime Z-14. The global yield
thesis of nitrone 3, in which the C-1-hydroxy protection is differ- for nitrone 3 from -fructose (8 steps) is thus 12 %, and is satis-
D
-
cyclization. Nitrone 3 was isolated in 59 % yield from this step,
D
entiated from the other hydroxy groups, started with formation fying when one considers the high availability and renewability
of the 1,2:4,5-bis(isopropylidene) derivative[30] and subsequent of this starting material.
regioselective acidic deprotection of the C-4- and C-5-OH moie-
Nitrone 4 was synthesized by a shorter route (Scheme 5).
It is worth noting that, although several carbohydrate-derived
nitrones have been prepared from substrates protected as
benzyl, tert-butyl or silyl ethers, nitrones protected by acyl
groups are very scarce.[34] The synthesis of 4 started with the
ties to furnish 11 (Scheme 4).[31]
formation of 1,3,4,5-tetra-acetyl-
-fructopyranose (15),[35] which
D
was then iodinated at C-6 using conditions described by Fellahi
and Morin.[36] With linear iodide 16 in hand, the corresponding
O-(tert-butyldimethylsilyl) ketoxime 17 was readily prepared in
only 3 h (86 % yield). Surprisingly, in this case the (E) isomer
was highly predominant [(E)/(Z) = 9:1]. As a consequence, the
next step, a fluoride-induced cyclization to nitrone 4, was high-
yielding (90 %). No trace of unreacted Z-oxime was detected as
a by-product. Thus, peracetylated nitrone 4 was prepared in
only 4 steps and with an overall yield of 20 % from D-fructose.
Next, nitrones 5,[37] 6[38] and 7[39] were prepared according to
established literature procedures.
Scheme 4. Synthesis of nitrone 3.
Free hydroxy groups were protected as benzyl ethers, the
second isopropylidene group was hydrolyzed in aqueous acetic
acid at 110 °C,[32] and 12 was then obtained by easy acylation
of the C-1 primary OH group with pivaloyl chloride.[33] Forma-
tion of the protected oxime at C-2, was effected by treating 12
with O-(tert-butyldimethylsilyl)hydroxylamine in the presence of
a catalytic amount of pyridinium para-toluenesulfonate under
dehydrating conditions at 110 °C for 20 h. The primary alcohol
at C-6 was then converted into a leaving group by mesylation,
prior to treatment with silica-supported tetrabutylammonium
fluoride. Again, the efficiency of nitrone formation upon treat-
ment of 13 with fluoride sources was decreased by the lack
of isomerization of the oxime Z-14 and its reluctance towards
Scheme 5. Synthesis of nitrone 4.
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Reactivity of Nitrones 1 and 3–7 in the Presence of SmI2
When nitrone 1 was initially treated with excess SmI2 (4 equiv.)
at –78 °C in the presence of ethyl acrylate (1.4 equiv.) and water
(8 equiv.) to induce reductive coupling,[7] nitrone 2 was isolated
as the sole product in 88 % yield (see Scheme 2).[13] Under simi-
lar conditions, but in the absence of water, nitrone 1 was also
converted into nitrone 2. Even when cyclopentanone was intro-
duced as the electrophilic coupling partner with nitrone 1 (re-
ductive coupling of aliphatic nitrones with aldehydes and ket-
ones are generally faster than with acrylic acid derivatives[40]
)
nitrone 2 was again the sole product. It thus appeared that
elimination of the benzyloxy group at C-1 is a fast process, com-
peting with reductive cross-couplings. After optimization, it was
found that at –40 °C, nitrone 1 was converted into 2 (86 %
yield) using 2.2 equiv. of SmI2 and no additive in only 15 min
(Scheme 6).
Scheme 7. Proposed mechanism for the SmI2-mediated ꢀ-elimination from
nitrone 1.
Scheme 6. Reactivity of nitrone 1 upon treatment with SmI2.
Mechanistically, the transformation of nitrone 1 into nitrone
2 compares to the well-known SmI2-mediated reduction of α-
heterosubstituted carbonyl compounds.[41] It is generally admit-
ted that reductions of α-alkoxy and α-epoxy ketones involve
reduction of a carbonyl to a ketyl radical as the first step. The
latter can then undergo radical elimination to a samarium enol-
ate,[42] or can be further reduced by SmI2 to a dianion, from
which elimination of the α-alkoxy group would form the same
samarium enolate.
Scheme 8. Tandem ꢀ-elimination/aldol reaction from nitrone 1.[13]
Similarly, elimination of the benzyloxy group at C-1 of ni- niscent of metalated N-oxy enamines, and the latter are often
trone 1 probably proceeds via an enaminolate intermediate unstable species, known to undergo various rearrangements.[43]
(Scheme 7). If a radical elimination was occurring [Scheme 7, We thus envisaged the preparation of derivatives that could
Equation (1)] only 1 equiv. of SmI2 would be sufficient to fully be isolated and characterized, with the aim of studying their
convert nitrone 1 into nitrone 2. However, when nitrone 1 was reactivity trends. However, our attempts to trap samarium en-
treated with 1.1 equiv. of SmI2 at –78 °C, nitrone 2 was isolated aminolates in situ by O-silylation using excess TMSCl/Et3N,
in only 32 % yield, and 40 % of nitrone 1 was recovered. Con- TBDPSCl/Et3N, TBDMSOTf/Et3N,[44] TBDPSCl/AgOTf/Et3N[45] or by
versely, upon treatment of 1 with 2.2 equiv. of SmI2 nitrone 2 O-acylation with acetyl chloride or 3,5-dinitrobenzoyl chloride
was isolated in 81 % yield. These results favor a 2-electron re- all failed [Scheme 7, Equation (5)]. Upon treatment of nitrone 1
duction mechanism and formation of an enaminolate interme- with SmI2 (2.5 equiv.) in THF at low temperature, followed by
diate through anionic elimination [Scheme 7, Equation (2)] introduction of a trapping agent and slow warming to room
which is strongly supported by unambiguous deuterium incor- temperature only nitrone 2 was isolated; characterization of any
poration upon introduction of D2O (8 equiv.) in the reaction N-oxy enamine intermediate was not possible. We thus endeav-
mixture [formation of D
-
2 in 70 % yield, Scheme 7, Equa- ored to determine the structural factors involved in N-oxy ena-
tion (3)]. Formation of the proposed samarium(III) enaminolate mine formation from various α-substituted nitrones.
is also supported by the development of a tandem ꢀ-elimina-
tion/aldolization reaction from nitrone 1, in which a C–C bond
forms in place of the eliminated benzyloxy group [Scheme 7,
Equation (4) and Scheme 8].[13]
Nitrones 3 and 4 were chosen to assess the influence of
the leaving group at C-1 on SmI2-promoted elimination. It was
expected that the acyloxy groups would be better leaving
groups than the benzyloxy moiety.[41d] When 3 was treated
As this process occurs under extremely mild conditions, we with 2.2 equiv. of SmI2 in THF at –40 °C, nitrone 2 (50 %) was
decided to investigate the scope of samarium enaminolate in- isolated again as the main product, although in lower yield
termediates in synthesis. These species have not been studied (Scheme 9). In the same manner, peracetylated nitrone 4 under-
yet and could reveal themselves as key intermediates in the α- went efficient ꢀ-elimination at C-1 under similar conditions to
functionalization of nitrones. However, these species are remi- yield nitrone 18 in 72 % yield. ꢀ-Elimination of benzyloxy or
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acetoxy groups at C-3 was never detected in experiments per-
Exocyclic α-alkoxy nitrone 5 was thus treated with SmI2 at
formed with endocyclic nitrones. The rate of elimination (evalu- –40 °C in the absence of both water and an electrophilic part-
ated visually by the colour change of the blue SmI2 solution to ner, with the aim of isolating the corresponding ꢀ-eliminated
yellow upon oxidation of SmII to SmIII) was very fast in all cases nitrone (Scheme 12). However, no trace of this product was
(45 min is the time during which SmI2 was slowly added to the detected, and only starting nitrone 5 was recovered at low tem-
starting nitrones).
perature. The same nitrone 5 was isolated as the major product
along with unidentified products if the reaction mixture was
allowed to warm to room temperature. Similarly, α-alkoxy ni-
trone 6 failed to undergo ꢀ-elimination and ring opening upon
treatment with SmI2 in THF at –40 °C, and the starting material
was completely recovered (Scheme 12).
Scheme 9. SmI2-mediated ꢀ-elimination from nitrones 3 and 4.
Nitrone 5 was used in our group in a formal synthesis of (S)-
vigabatrin, a selective and irreversible inhibitor of GABA-amino-
transferase.[14a] The synthetic approach involved a high-yielding
(81 %) reductive coupling of 5 with methyl acrylate upon treat-
ment with SmI2 (Scheme 10). During this work no trace of ꢀ-
elimination product was detected regardless of the inclusion of
water (8 equiv.) as an additive. This result contrasts those re-
ported by Fisera and co-workers, who isolated ꢀ-elimination
Scheme 12. Reactivity of nitrones 5, 6 and 7 in the presence of SmI2.
Nitrone 7 was next tested as an example of a non-endocyclic
product 20 as the major product of nitrone 19 under similar keto nitrone, twice heterosubstituted at both α-positions. Al-
conditions, as well as substantial amounts of the ꢀ-elimination though structurally resembling nitrone 5, this substrate could
product 23 from nitrone 22 (Scheme 11).[15]
in principle have afforded, upon SmI2-promoted ꢀ-elimination,
Scheme 10. SmI2-mediated reductive coupling of nitrone 5 with methyl acrylate, used for the formal synthesis of (S)-vigabatrin.[14a]
Scheme 11. ꢀ-Elimination reactions reported by Fisera and co-workers.[15]
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Scheme 13. Proposed conformation for selective reductive ꢀ-elimination in endocyclic nitrones.
two different products resulting from C-1 (benzyloxy) or C-3 Experimental Section
(ketal) elimination. However, treatment of 7 with SmI2 in THF
General Experimental: Reactions were performed under Schlenk
conditions or a positive pressure of dry argon in oven- or flame-
dried glassware equipped with a magnetic stir bar. Standard inert-
gas techniques were used in handling all air- and moisture-sensitive
reagents. THF and toluene were freshly distilled from sodium,
CH2Cl2, acetonitrile, pyridine and triethylamine were distilled from
CaH2, acetone from K2CO3, DMF from 4 Å molecular sieves. Zinc
chloride was sublimated prior to use. Purchased reagents were used
without purification. Reactions were monitored by thin layer chro-
matography (TLC) using commercial aluminum-backed silica gel
plates. TLC spots were viewed under ultraviolet light and by heating
the plate after treatment with either a 1 % ethanolic solution of
phosphomolybdic acid or a 3 % solution of potassium permanga-
nate in 10 % aqueous potassium hydroxide (w/v). Product purifica-
tion by gravity column chromatography was performed using silica
gel 60 (70–230 mesh). Infrared (IR) spectra were recorded with a
Fourier transform spectrometer as neat films, or as a thin film of a
dichloromethane solution of the compound on sodium chloride
discs. The data are reported in reciprocal centimeters (cm–1) and
are described as following: br. (broad), s (strong), m (medium), w
(from –40 °C to –10 °C) for 1 h gave a complex mixture of
products from which only the starting nitrone (25 %) could be
identified.
These results show that the rate of SmI2-mediated ꢀ-elimina-
tion of alkoxy substituents in nitrones strongly depends on the
structure of the substrates, rather than the nature of the leaving
group. We hypothesize that elimination occurs readily and re-
gioselectively when the nitrones are reduced to dianionic spe-
cies that exhibit a conformation in which a vicinal C–O σ-bond
adopts an antiperiplanar alignment with the p-orbital of the
intermediate carbanion generated α to their nitrogen atom
(Scheme 13). This could explain why clean elimination was only
observed on exocyclic substituents, and why it was never ob-
served with α-alkoxy substituents on the cyclic moieties includ-
ing the nitrone functionality (endocyclic keto nitrones).[8,14]
However, the efficiency and regioselectivity of this reaction do
not extend to nitrones 5–7, from which ꢀ-elimination products,
if formed, are not isolated following treatment with SmI2.
1
(weak). H and 13C NMR spectra were recorded in CDCl3. Chemical
shifts for 1H spectra are values from tetramethylsilane in CDCl3 (δ =
0.00 ppm). Chemical shifts for 13C spectra are values from CDCl3
1
(δ = 77.16 ppm). H NMR spectra are reported as follows: chemical
Conclusions
shift (ppm), multiplicity (br.: boad; s: singlet; d: doublet; t: triplet; q:
quadruplet; m: multiplet), coupling constants [Hz] and integration.
Mass spectra (MS) were recorded with an ion-trap spectrometer
using DCI (ammonia/isobutane, 63:37) or with an ESI spectrometer.
High-resolution mass spectra (HRMS) were recorded at the LCOSB,
UMR 7613, Université Pierre et Marie Curie, Paris. Elemental analyses
were performed at the Service d'Analyse Elementaire du Départe-
ment de Chimie Moléculaire, Grenoble.
We report herein the synthesis of α-alkoxy- and α-acyloxy-sub-
stituted nitrones and the study of their reactivity in the pres-
ence of SmI2. This study aimed to define the scope of the re-
gioselective elimination reaction associated with tandem ꢀ-
elimination/aldol reactions with six-membered endocyclic nitro-
nes such as 1.[13] The ꢀ-elimination was shown to occur readily
with nitrones 3 and 4, demonstrating that not only benzyl
ethers, but also pivaloyl and acetyl esters, eliminate promptly
upon treatment with samarium diiodide. The mechanism of this
transformation involves a samarium enaminolate intermediate,
generated from a double electron transfer from samarium di-
(4R,5S,6R)-4,5,6-Tris(benzyloxy)-3-[(benzyloxy)methyl]-4,5,6,7-
tetrahydro-1,2-oxazepine (10): A solution of mesylates 8 (100 mg,
0.12 mmol) in distilled toluene (5 mL) was heated to 110 °C, then
TBAF on silica gel (145 mg, 0.145 mmol) was added. The reaction
mixture was stirred for 5 h (until complete consumption of 8), then
iodide to the nitrones. This intermediate was identified by deu- it was filtered and the solid was washed with THF. The filtrate was
teration and by reaction with carbonyl compounds,[13] but
concentrated under vacuum. Purification of the obtained residue by
chromatography on silica gel (pentane/AcOEt, 4:1 to 0:1) afforded
could not be characterized by O-trapping. It was anticipated
that such an enaminolate may find applications in synthesis, as
its reactivity would compare with those of both enamines and
enolates. However, the ꢀ-elimination reaction observed in nitro-
nes 1, 3, and 4 does not extend to α-alkoxy-substituted nitro-
nes 5–7. Further studies will be needed to delineate what fea-
tures in the α-heterosubstituted nitrones favour the regioselect-
ive ꢀ-elimination over their reductive coupling with electro-
philic partners.
oxazepine 10 (20 mg, 31 %), oxime Z-9[12] (9 mg, 13 %) and nitrone
1[12] (24 mg, 37 %) as pale yellow oils. Compound 10: [α]2D0 = –34.0
(c = 1.03, CHCl ). MS (ESI): m/z = 538 [M + H]+. IR: ν = 3085 (m),
˜
3
3063 (m), 3028 (m), 2924 (s), 2864 (s), 1727 (w), 1606 (w), 1493 (s),
1454 (s), 1354 (m), 1207 (m), 1090 (s) cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 3.96–4.08 (m, 4 H), 4.13 (d, J = 12.6 Hz, 1 H), 4.18 (d, J =
12.6 Hz, 1 H), 4.49 (d, J = 11.9 Hz, 1 H), 4.55 (d, J = 11.9 Hz, 1 H),
4.59–4.72 (m, 8 H), 7.21–7.32 (m, 20 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 69.7, 69.9, 72.6, 73.0, 73.4, 73.7, 75.7, 77.1, 77.4, 127.8–
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128.6, 137.7, 137.9, 138.3, 138.4, 172.6 ppm. HRMS (ESI): calcd. for
C34H36NO5 [M + H]+ 538.2593; found 538.2592.
13C NMR (100 MHz, CDCl3): δ = 57.8, 61.3, 64.9, 66.1, 71.6, 71.7, 71.8,
72.2, 73.3, 73.5, 74.3, 74.3, 74.6, 75.7, 75.8, 97.3, 98.0, 127.8–128.7,
137.1, 137.5, 138.1, 138.3, 138.4 ppm.
1,2:4,5-Di-O-isopropylidene-ꢀ-
propane (2.50 mL, 20.0 mmol) was added at 0 °C to a solution of
-fructose (6.00 g, 33.3 mmol) in acetone (110 mL). The mixture
D-fructopyranose: 2,2-Dimethoxy-
3,4,5-Tri-O-benzyl-1-O-pivaloyl-ꢀ-
D-fructopyranose (12): 3,4,5-
D
Tri-O-benzyl-ꢀ- -fructopyranose (1.85 g, 4.1 mmol) was dissolved in
D
was stirred at 0 °C for 15 min, then HClO4 (70 % in water, 2.33 mL,
16.3 mmol) was added. The mixture was stirred at 0 °C for 6 h, then
NH4OH (28 % in water, 1.60 mL) was added, and the mixture was
concentrated under vacuum. A viscous oil was obtained, which was
dissolved in CH2Cl2 (70 mL). The organic solution was washed twice
with brine (30 mL). The organic phase was dried with MgSO4, then
concentrated under vacuum. A pure white powder (4.51 g,
17.3 mmol, 52 %) was obtained after crystallization from hexane
(50 mL). This powder exhibited spectroscopic data identical to those
pyridine (19 mL), and freshly distilled pivaloyl chloride (0.61 mL,
4.9 mmol) was added. The solution was stirred at room temperature
for 18 h. The mixture was concentrated under vacuum, then CH2Cl2
(200 mL) was added. The organic phase was washed with a 5 %
aqueous HCl solution (100 mL), then water (300 mL) and with a 5 %
NaHCO3 aqueous solution (100 mL). It was then dried with MgSO4
and concentrated under vacuum to give a syrup, which upon col-
umn chromatography on silica gel (pentane/AcOEt, 6:1 to 0:1)
yielded 12 (1.85 g, 84 %, α/ꢀ = 2:3) as a white solid. M.p. 102–
103 °C. [α]2D0 = –40 (c = 1.0, CHCl3). MS (ESI): m/z = 557 [M + Na+].
reported in the literature.[30] IR: ν = 3457 (br.), 3056 (m), 2985 (s),
˜
2938 (s), 1455 (s), 1367 (s) cm–1
.
13C NMR (75 MHz, CDCl3): δ = 26.1,
IR: ν = 3427 (br.), 3027 (w), 2966 (m), 2926 (m), 2866 (m), 1728 (s),
˜
1449 (m), 1284 (m) 1154 (s), 1090 (s) cm–1
.
1H NMR (400 MHz,
26.4, 26.6, 28.1, 60.9, 70.6, 72.5, 73.5, 77.4, 104.7, 109.6, 112.0 ppm.
1,2-O-Isopropylidene-ꢀ- -fructopyranose (11): 1,2:4,5-Di-O-iso-
propylidene-ꢀ- -fructopyranose (1.21 g, 4.6 mmol) was dissolved in
CDCl3): δ = 1.21 (s, 9 H), 3.54 (d, J = 3.6 Hz, 0.38 H), 3.72–3.80 (m,
1.75 H), 3.86–3.93 (m, 2 H), 3.98–4.11 (m, 2 H), 4.17–4.24 (m, 1 H),
4.32 (d, J = 11.5 Hz, 0.38 H), 4.43–4.68 (m, 4.24 H), 4.73 (d, J =
12.5 Hz, 0.62 H), 4.84 (d, J = 12.0 Hz, 0.38 H), 5.00 (d, J = 10.5 Hz,
0.62 H), 7.13–7.15 (m, 0.8 H), 7.25–7.40 (m, 14.1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 27.3, 27.4, 38.9, 39.0, 57.6, 60.8, 65.1, 65.6,
71.1, 71.6, 71.8, 71.9, 73.0, 73.5, 74.4, 74.6, 75.2, 75.7, 96.7, 97.5,
127.7–128.8, 137.2, 137.5, 138.0, 138.2, 138.3, 177.7, 178.2 ppm.
C32H38O7 (534.65): calcd. C 71.89, H 7.17; found C 71.63, H 7.28.
D
D
AcOH (75 % in water, 18 mL). The solution was stirred at 45 °C for
4 h. The mixture was concentrated under vacuum to give a syrup.
Dissolution in MeOH, treatment with DOWEX 1X8 (OH– form) until
pH 9, then fitration gave a residue, which upon column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 9:1 to 7:3) yielded 11 (1.02 g,
98 %) as a white powder that exhibited spectroscopic data in ac-
cordance with those reported in the literature.[32] M.p. 118–119 °C;
ref.[32] 122–123 °C. IR: ν = 3397 (br.), 2924 (m), 1385 (m), 1221 (m),
˜
3,4,5-Tetra-O-benzyl-1-O-pivaloyl-D-fructose O-(tert-Butyldi-
1178 (m), 1081 (s) cm–1
.
13C NMR (75 MHz, CDCl3): δ = 26.4, 26.5,
phenylsilyl)oxime: O-(tert-Butyldiphenylsilyl)hydroxylamine
(254 mg, 0.9 mmol) and pyridinium p-toluenesulfonate (9 mg,
30 mol-%) were added to a solution of 12 (100 mg, 0.2 mmol) in
dry toluene (3 mL). The reaction mixture was heated in a Dean–
Stark apparatus at reflux temperature for 20 h. The mixture was
then cooled and washed with a saturated aqueous solution of NaH-
CO3 (2 mL). The aqueous phase was extracted three times with Et2O
(5 mL). The organic layers were dried with MgSO4 and concentrated
under vacuum to give a residue, which upon column chromatogra-
phy on silica gel (pentane/AcOEt, 9:1 to 1:1) yielded the title oxime
[109 mg, 75 %, (E)/(Z) = 3:2] as an oil. MS (ESI): m/z = 788 [M + H+].
64.2, 69.1, 69.4, 72.1, 72.2, 105.9, 112.1 ppm.
3,4,5-Tri-O-benzyl-1,2-O-isopropylidene-ꢀ-D-fructopyranose:
THF (25 mL) was added to sodium hydride (5.98 g of a 60 % suspen-
sion in oil, 149.7 mmol). A solution of 11 (5.52 g, 25.0 mmol) in
DMF (86 mL) was added to the suspension of NaH at 0 °C. The
suspension was stirred at room temperature for 15 min, then tetra-
butylammonium iodide (cat.) and benzyl bromide (17.80 mL,
149.7 mmol) were added. The mixture was stirred at room tempera-
ture for 9 h. After addition of methanol (30 mL) and water (30 mL),
the phases were separated. The aqueous phase was extracted three
times with Et2O (50 mL). The organic layer was dried with MgSO4,
then concentrated to give a residue which upon column chroma-
tography on silica gel (pentane/AcOEt, 1:0 to 0:1), afforded the title
compound (9.52 g, 77 %) as a white powder that exhibited spectro-
scopic data in accordance to those reported in the literature.[32] M.p.
74–75 °C; ref.[32] 81–82 °C. [α]D20 = –103.2 (c = 1.0, CH2Cl2); ref.[46]
[α]D = –98.5 (c = 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 1.42
(s, 3 H), 1.47 (s, 3 H), 3.72–3.83 (m, 3 H), 3.88–4.01 (m, 4 H), 4.58–
4.77 (m, 5 H), 5.03 (d, J = 11.5 Hz, 1 H), 7.23–7.40 (m, 15 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.3, 27.2, 61.5, 71.7, 72.0, 72.2, 73.6,
75.4, 75.5, 80.3, 106.0, 111.9, 127.6–128.5, 138.4, 138.6, 138.7 ppm.
C30H34O6 (490.59): calcd. C 73.45, H 6.99; found C 72.99, H 7.11.
IR: ν = 3562 (br.), 3419 (m), 3067 (w), 3024 (w), 2959 (m), 2933 (m),
˜
2855 (m), 1732 (s), 1454 (m), 1389 (m), 1194 (s), 1146 (s), 1107 (s),
1
1064 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 0.87 (s, 3 H), 1.03 (s,
3 H), 1.04 (s, 3 H), 1.07 (s, 9 H), 1.89 (dd, J = 3.0 and 9.0 Hz, 0.4 H),
2.02–2.06 (m, 0.6 H), 3.24–3.28 (m, 0.6 H), 3.52–3.72 (m, 2 H), 3.78–
3.83 (m, 0.4 H), 3.97 (t, J = 6.9 Hz, 0.6 H), 4.07–4.76 (m, 8 H), 4.96
(d, J = 15.0 Hz, 0.4 H), 5.15 (d, J = 14.0 Hz, 0.6 H), 5.34 (d, J =
3.0 Hz, 0.4 H), 7.09–7.35 (m, 21 H), 7.58–7.62 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.5, 27.1, 27.3, 27.4, 38.9, 57.7, 60.0, 60.4,
61.6, 71.3, 71.6, 71.7, 73.3, 74.4, 75.6, 75.7, 77.4, 78.8, 79.0, 79.3, 80.5,
82.3, 127.5–130.0, 133.0, 133.2, 133.4, 135.8, 137.3, 138.4, 159.4,
161.2, 177.7, 178.0 ppm. C48H57NO7Si (788.07): calcd. C 73.16, H
7.30, N 1.78; found C 73.02, H 7.71, N 1.51.
3,4,5-Tri-O-benzyl-ꢀ-
D-fructopyranose: 3,4,5-Tri-O-benzyl-1,2-O-
isopropylidene-ꢀ- -fructopyranose (9.5 g, 19.3 mmol) was dissolved
D
3,4,5-Tetra-O-benzyl-6-O-(methylsulfonyl)-1-O-pivaloyl-D-fruc-
in AcOH (80 % in water, 193 mL). The solution was stirred at 110 °C
for 1 h. The mixture was concentrated under vacuum, then co-evap-
orated four times with cyclohexane (200 mL) to give a syrup, which
upon column chromatography on silica gel (pentane/AcOEt, 6:1 to
0:1) yielded the title compound (7.21 g, 83 %, α/ꢀ = 1:2) as a white
tose O-(tert-Butyldiphenylsilyl)oxime (13): To a solution of the
above-described oxime (1.79 g, 2.3 mmol) in CH2Cl2 (10 mL) placed
at 0 °C, were added successively triethylamine (0.47 mL, 3.4 mmol)
and mesyl chloride (0.21 mL, 2.7 mmol). The solution was stirred at
room temperature for 18 h, and water (30 mL) was added. The
powder that exhibited spectroscopic data in accordance with those aqueous layer was extracted twice with AcOEt (50 mL). The organic
reported in the literature.[32] M.p. 73–74 °C. [α]D20 = –36.0 (c = 1.0, phase was washed with a saturated solution of NaHCO3 (20 mL),
CHCl3), ref.[32] (for α/ꢀ = 1:4) [α]D = –40.2 (c = 1.0, CHCl3). MS (ESI):
dried with MgSO4 and concentrated under vacuum to give a resi-
m/z = 473 [M + Na+]. IR: ν = 3440 (br.), 3028 (m), 2924 (m), 2877 due, which upon column chromatography on silica gel (pentane/
˜
(m), 1497 (m), 1454 (s), 1359 (m), 1202 (m), 1124 (s), 1090 (s) cm–1
.
AcOEt, 6:1 to 3:1) yielded 13 [1.75 g, 89 %, (E)/(Z) = 3:1] as a pale
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yellow oil. MS (ESI): m/z = 888 [M + Na+]. IR: ν = 3426 (w), 3066 (w),
(s, 3 H), 2.15 (s, 3 H), 3.46 (br. s, 1 H), 3.78 (dd, J = 1.5 and 13.0 Hz,
1 H), 4.02 (d, J = 12.0 Hz, 1 H), 4.15–4.27 (m, 2 H), 5.32–5.38 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.7, 20.8, 21.1, 61.8, 66.7,
68.2, 68.4, 69.2, 96.4, 170.1, 170.2, 170.5, 171.2 ppm.
˜
3029 (w), 2955 (m), 2930 (m), 2853 (m), 1730 (s), 1452 (m), 1358 (s),
1
1173 (s), 1108 (s) cm–1. H NMR (400 MHz, CDCl3): δ = 0.90 (s, 3 H),
1.04 (s, 3 H), 1.05 (s, 3 H), 1.08 (s, 9 H), 2.64 (s, 0.75 H), 2.68 (s, 2.25
H), 3.48–3.52 (m, 0.75 H), 3.79–3.83 (m, 0.25 H), 3.91 (t, J = 6.5 Hz,
0.75 H), 4.05–4.72 (m, 10 H), 4.98 (d, J = 15.0 Hz, 0.25 H), 5.17 (d,
J = 14.0 Hz, 0.75 H), 5.34 (d, J = 3.0 Hz, 0.25 H), 7.04–7.40 (m, 21 H),
7.59–7.64 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.5, 27.1,
27.3, 27.4, 37.4, 37.6, 38.9, 57.8, 61.5, 68.3, 68.6, 71.7, 72.1, 72.2, 73.5,
74.4, 75.4, 75.5, 77.1, 77.7, 78.5, 79.1, 81.5, 127.8–128.7, 130.0, 130.1,
132.9, 133.2, 135.7, 135.8, 137.4, 137.5, 137.9, 159.4, 161.1,
177.9 ppm. C49H59NO9SSi (866.15): calcd. C 67.95, H 6.87, N 1.62;
found C 67.68, H 7.19, N 1.64.
1,3,4,5-Tetra-O-acetyl-6-deoxy-6-iodo-D-arabino-hex-2-ulose
(16): Imidazole (1.54 g, 22.7 mmol) and freshly distilled chlorodi-
phenylphosphine (2.4 mL, 13.4 mmol) were added to a solution of
15 (3.60 g, 10.3 mmol) in distilled toluene (80 mL). The mixture was
stirred at 60 °C for 1 h, then iodine (3.40 g, 13.4 mmol) was added,
and the mixture was stirred at 60 °C for 14 h. The mixture was
washed with a saturated aqueous solution of NaHCO3, then iodine
was added until a dark organic phase was obtained. The aqueous
phase was extracted three times with toluene (80 mL), and the
organic layers were washed with a saturated aqueous solution of
Na2S2O3, dried with MgSO4, then concentrated under vacuum to
give a residue, which upon column chromatography on silica gel
(3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-(pivaloyloxymethyl)-3,4,5,6-
tetrahydropyridine 1-Oxide (3): To a solution of mesyloximes 13
(1.73 g, 2.0 mmol) in distilled THF (50 mL) was added TBAF on silica
gel (2.40 g, 2.40 mmol) at 0 °C. The reaction mixture was stirred at (pentane/AcOEt, 3:1 to 1:1) yielded 16 (2.62 g, 55 %) as a yellow
room temperature for 14 h. The mixture was filtered, and the solid
was washed with THF. The filtrate was concentrated under vacuum.
Purification of the obtained residue by chromatography on silica
gel (pentane/AcOEt, 3:1 then 1:1) afforded pure nitrone 3 (635 mg,
59 %) as a yellow oil and oxime Z-14 (376 mg, 30 %) as a pale
yellow oil. Nitrone 3: [α]2D0 = –82.0 (c = 1.0, CHCl3). MS (ESI): m/z =
solid that exhibited spectroscopic data in accordance with those
reported in the literature.[36] M.p. 109–110 °C; ref.[36] 110 °C. [α]2D0
=
+32.0 (c = 1.00, CH2Cl2); ref.[36] [α]D20 = +35.0 (c = 1.0, CH2Cl2). MS
(ESI): m/z = 481 [M + Na+]. IR: ν = 2937 (w), 1745 (s), 1424 (m), 1363
˜
(s), 1211 (s), 1046 (m) cm–1. H NMR (300 MHz, CDCl3): δ = 2.09 (s,
1
6 H), 2.15, (s, 3 H), 2.17 (s, 3 H), 3.22 (dd, J = 6.0 and 11.5 Hz, 1 H),
3.40 (dd, J = 3.5 and 11.5 Hz, 1 H), 4.67 (d, J = 17.5 Hz, 1 H), 4.85–
532 [M + H]+. IR (neat): ν = 3432 (w), 3059 (m), 3024 (m), 2972 (m),
˜
2868 (m), 1727 (s), 1588 (m), 1450 (s), 1137 (s), 1094 (s), 1059 (s) 4.97 (m, 2 H), 5.43 (d, J = 2.0 Hz, 1 H), 5.54 (dd, J = 2.0 and 8.5 Hz,
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.12 (s, 9 H), 3.79–3.83 (m, 1
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 3.7, 20.5, 20.6, 20.7, 21.0,
H), 3.84–3.93 (m, 1 H), 4.01–4.12 (m, 2 H), 4.28 (d, J = 4.0 Hz, 1 H),
4.37–4.52 (m, 5 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.80 (d, J = 13.5 Hz, 1
H), 5.16 (d, J = 15.0 Hz, 1 H), 7.08–7.10 (m, 2 H), 7.18–7.30 (m, 13
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.4, 39.0, 59.2, 59.7, 70.7,
72.4, 72.8, 73.7, 74.0, 77.2, 127.8–128.7, 137.4, 137.5, 137.8, 140.5,
177.8 ppm. HRMS (ESI): calcd. for C32H38NO6 [M + H]+ 532.2694;
found 532.2692.
67.0, 69.1, 71.5, 74.1, 169.4, 169.7, 169.8, 170.1, 197.9 ppm.
1,3,4,5-Tetra-O-acetyl-6-deoxy-6-iodo-D-fructose O-(tert-Butyl-
diphenylsilyl)oxime (17): O-tert-(Butyldiphenylsilyl)hydroxylamine
(177 mg, 0.7 mmol), MgSO4 (300 mg) and pyridinium p-toluene-
sulfonate (cat.) were added to a solution of 16 (100 mg, 0.2 mmol)
in dry toluene (3 mL). The reaction mixture was heated at reflux
temperature for 3.5 h. The mixture was concentrated under vac-
uum, dissolved in Et2O (10 mL), then washed successively with a
(3R,4R,5R)-3,4,5-Tri-O-benzyl-6-O-(methylsulfonyl)-1-O-pival-
oyl-
D
-fructose Oxime (Z-14): [α]2D0 = –12.2 (c = 1.0, CHCl3). MS (ESI): saturated aqueous solution of NaHCO3 (10 mL) and brine (10 mL).
m/z = 650 [M + Na+]. IR: ν = 3393 (br.), 3028 (m), 2968 (m), 2933 The aqueous phases were extracted twice with Et2O (10 mL). The
˜
(m), 2868 (m), 1732 (s), 1450 (m), 1354 (s), 1172 (s) cm–1 1H NMR organic layers were dried with MgSO4 and concentrated under vac-
.
(400 MHz, CDCl3): δ = 1.18 (s, 9 H), 2.87 (s, 3 H), 3.82–3.86 (m, 1 H),
4.08 (dd, J = 4.5 and 6.5 Hz, 1 H), 4.32–4.41 (m, 3 H), 4.55–4.70 (m,
uum to give a residue, which upon column chromatography on
silica gel (pentane/AcOEt, 9:1 to 3:1) yielded oxime 17 [134 mg,
5 H), 4.78 (d, J = 14.5 Hz, 1 H), 4.92 (d, J = 14.5 Hz, 1 H), 5.09 (d, J = 86 %, (Z)/(E) = 1:9] as a white powder. M.p. 99–101 °C. [α]2D0 = +23.0
4.0 Hz, 1 H), 7.25–7.35 (m, 15 H) ppm. 13C NMR (75 MHz, CDCl3): (c = 1.00, CHCl3). MS (ESI): m/z = 734 [M + Na+]. IR: ν = 2924 (w),
δ = 27.3, 37.5, 38.9, 61.6, 69.3, 72.5, 73.4, 74.5, 75.5, 77.5, 77.6, 78.6,
˜
1
2855 (w), 1735 (s), 1424 (m), 1372 (m), 1215 (s), 1107 (w) cm–1. H
127.9–128.6, 137.1, 137.5, 137.7, 156.1, 178.1 ppm. C33H41NO9S NMR (300 MHz, CDCl3): δ = 1.07 (s, 9 H), 1.80 (s, 3 H), 1.83 (s, 3 H),
(627.75): calcd. C 63.14, H 6.59, N 2.24; found C 62.99, H 6.86, N
2.21.
2.09 (s, 3 H), 2.20 (s, 3 H), 3.22 (dd, J = 6.0 and 11.5 Hz, 1 H), 3.41
(dd, J = 3.5 and 11.5 Hz, 1 H), 4.84–4.93 (m, 1 H), 5.13 (d, J = 16.0 Hz,
1 H), 5.24 (d, J = 16.0 Hz, 1 H), 5.50 (dd, J = 3.0 and 7.5 Hz, 1 H),
5.64 (d, J = 3.0 Hz, 1 H), 7.33–7.44 (m, 6 H), 7.58–7.63 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 4.1, 19.4, 20.3, 20.4, 20.8, 27.1, 59.1,
69.0, 69.3, 71.6, 127.7, 127.8, 129.8, 129.9, 132.9, 133.0, 135.5, 135.6,
155.9, 169.3, 169.5, 169.6, 169.9 ppm. C30H38INO9Si (711.62): calcd.
C 50.64, H 5.39, N 1.97; found C 51.02, H 5.39, N 1.76.
1,3,4,5-Tetra-O-acetyl-ꢀ-
(25.5 mL, 277.5 mmol) was added to a mixture of
D
-fructopyranose (15): Acetic anhydride
-fructose (5.00 g,
D
27.8 mmol) and anhydrous zinc chloride (750 mg, 5.6 mmol). The
mixture was stirred at 0 °C for 16 h, then cooled to –20 °C for 15 h.
The precipitate was filtered, then rinsed with cold Et2O to give 15
as a white powder (3.51 g, 36 %) that exhibited spectroscopic data
identical to those reported in the literature.[36] The mother liquor
was washed with a saturated aqueous solution of NaHCO3. The
aqueous phase was extracted with CH2Cl2, then the organic phases
(3R,4R,5R)-3,4,5-Tris(acetoxy)-2-(acetoxymethyl)-3,4,5,6-tetra-
hydropyridine 1-Oxide (4): To a solution of oxime 17 (130 mg,
0.2 mmol) in distilled THF (5 mL) was added TBAF on silica gel
were dried, filtered and concentrated under vacuum to give an oil, (360 mg, 0.4 mmol) at 0 °C. The reaction mixture was stirred at
which crystallized at 4 °C. The crystals were washed with Et2O. Filtra- room temperature for 14 h. The mixture was filtered, and the solid
tion afforded 15 as a white powder (1.14 g, 12 %) that exhibited
was washed with THF. The filtrate was concentrated under vacuum.
spectroscopic data in accordance with those reported in the litera- Purification of the obtained residue by chromatography on silica
ture.[36] M.p. 128–129 °C; ref.[36] 128–129 °C. [α]2D0 = –84.0 (c = 1.5, gel (pentane/AcOEt, 1:1 then 0:1) afforded pure nitrone 4 (56 mg,
CHCl3); ref.[36] [α]D20 = –82.0 (c = 1.5, CHCl3). MS (ESI): m/z = 371 90 %) as a yellow oil. [α]2D0 = –7.2 (c = 1.00, CHCl3). MS (ESI): m/z =
[M + Na+]. IR: ν = 3422 (br.), 2976 (w), 1744 (s), 1361 (w), 1229 (s)
368 [M + Na+]. IR: ν = 3472 (br.), 2950 (w), 2924 (m), 1747 (s), 1592
˜
˜
1
cm–1. H NMR (300 MHz, CDCl3): δ = 1.99 (s, 3 H), 2.10 (s, 3 H), 2.13
(w), 1435 (m), 1364 (m), 1208 (s), 1056 (m) cm–1. 1H NMR (300 MHz,
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CDCl3): δ = 2.02 (s, 3 H), 2.06 (s, 9 H), 3.99 (dd, J = 7.0 and 15.5 Hz,
1 H), 4.17 (br. dd, J = 4.0 and 16.0 Hz, 1 H), 4.88 (d, J = 16.5 Hz, 1
H), 5.15 (d, J = 16.5 Hz, 1 H), 5.23–5.30 (m, 1 H), 5.40–5.49 (m, 1 H),
5.81 (d, J = 5.0 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.5,
20.6, 20.6, 20.7, 59.4, 59.6, 64.7, 65.5, 67.2, 139.0, 169.1, 169.5, 169.6,
170.1 ppm. C14H19NO9 (345.31): calcd. C 48.70, H 5.55, N 4.06; found
C 48.71, H 5.97, N 3.98.
[2]
[3]
(3R,4R,5R)-3,4,5-Tris(benzyloxy)-2-methylpiperidine 1-Oxide
(2): To a solution of carefully deoxygenated nitrone 3 (118 mg,
[4]
[5]
0.22 mmol) in THF (2.5 mL) a 0.1
M solution of SmI2 (4.9 mL,
0.49 mmol) was added under argon at –40 °C. The reaction was
performed at –40 °C for 45 min. A saturated aqueous solution of
Na2S2O3 (2 mL), a saturated aqueous solution of NaHCO3 (2 mL)
and AcOEt (10 mL) were then added. The phases were separated,
then the aqueous phase was extracted twice with AcOEt (20 mL).
The organic phase was washed with brine, then dried with MgSO4
and concentrated under vacuum to give a residue, which upon col-
umn chromatography on silica gel (AcOEt then AcOEt/MeOH, 9:1)
yielded 2 (48 mg, 50 %) as a pale yellow oil. [α]2D0 = –54.0 (c = 1.00,
CHCl3). MS (ESI): m/z = 432 [M + H]+. IR: ν = 3029 (m), 2869 (m),
˜
1612 (m), 1446 (s), 1198 (s), 1071 (s) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 2.02 (s, 3 H), 3.86 (dd, J = 1.9 and 4.6 Hz, 1 H), 3.94 (br. d, J =
17.0 Hz, 1 H), 4.03–4.16 (m, 3 H), 4.50 (d, J = 11.5 Hz, 1 H), 4.52–
4.66 (m, 4 H), 4.73 (d, J = 12.0 Hz, 1 H), 7.21–7.23 (m, 2 H), 7.28–
7.38 (m, 13 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 16.0, 58.8, 71.0,
71.9, 72.7, 73.9, 74.1, 76.8, 127.9–128.7, 137.2, 137.5, 137.8,
143.5 ppm. C27H29NO4 (431.53): calcd. C 75.16, H 6.78, N 3.25; found
C 74.89, H 6.80, N 3.14.
[6]
(3R,4R,5R)-3,4,5-Tris(acetoxy)-2-methylpiperidine 1-Oxide (18):
To a solution of carefully deoxygenated nitrone 4 (20 mg,
0.06 mmol) in THF (0.5 mL) a 0.1
M solution of SmI2 (1.27 mL,
0.13 mmol) was added under argon at –40 °C. The reaction was
performed at –40 °C for 45 min. A saturated aqueous solution of
Na2S2O3 (2 mL), a saturated aqueous solution of NaHCO3 (2 mL)
and AcOEt (2 mL) were then added. The phases were separated,
and the aqueous phase was extracted twice with AcOEt (20 mL).
The organic phase was dried with MgSO4 and concentrated under
vacuum to give a residue, which upon column chromatography on
silica gel (AcOEt/MeOH, 1:0 then 8:1) yielded 18 (12 mg, 72 %) as a
pale yellow oil. [α]2D0 = –9.8 (c = 1.00, CHCl3). MS (ESI): m/z = 288
[M + H]+. IR (solution in CH2Cl2): ν = 3436 (br.), 2929 (m), 2855 (m),
˜
[7]
1753 (s), 1597 (m), 1432 (m), 1367 (s), 1211 (s), 1046 (s) cm–1
.
1H
NMR (400 MHz, CDCl3): δ = 2.08 (s, 6 H), 2.11 (s, 3 H), 2.14 (s, 3 H),
4.03 (dd, J = 5.0 and 16.0 Hz, 1 H), 4.15–4.24 (m, 1 H), 5.26 (dd, J =
2.6 and 6.5 Hz, 1 H), 5.49–5.52 (m, 1 H), 5.81 (d, J = 6.1 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 15.0, 20.7, 20.8, 20.9, 59.8,
65.3, 68.0, 68.8, 141.1, 169.8 ppm.
Acknowledgments
This work was supported by the Centre National de la Recher-
che Scientifique (CNRS), the Université Joseph Fourier and the
Agence Nationale pour la Recherche (grant ANR-05-JCJC-0130-
01). E. R. is grateful to the French Ministry of Education, Re-
search and Technology (MENRT) for a doctoral fellowship.
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Keywords: Nitrones · Samarium Diiodide · ꢀ-Elimination ·
Reactivity · Organic Synthesis · Regioselectivity · Cross-
coupling · Carbohydrates
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Received: April 15, 2016
Published Online: ■
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Full Paper
Samarium Diiodide and Keto
Nitrones
The synthesis of novel acyl-protected
D
-fructose-derived keto nitrones is de-
scribed. The latter reacted readily with
SmI2 to regioselectively eliminate one
of their α-substituents through forma-
tion of an original samarium–enamin-
olate intermediate. However, the effi-
ciency and selectivity of this process
does not extend to non-endocyclic α-
heterosubstituted nitrones.
E. Racine, O. N. Burchak,
S. Py* ................................................... 1–11
Synthesis of α-Acyloxynitrones and
Reactivity towards Samarium Diiod-
ide
DOI: 10.1002/ejoc.201600478
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