Application of L-erythrose-derived nitrones in the synthesis of polyhydroxylated compounds via 3,6-dihydro-2H-1,2-oxazine derivatives

Article abstract of DOI:10.1002/ejoc.201200158

Enantiopure 3,6-dihydro-2H-1,2-oxazines were prepared by [3+3] cyclisations starting from lithiated methoxyallene and the L-erythrose-derived nitrones 1' and 3. The role of the side-chain protective group, which steers the highly selective formation of either anti- or syn-configured products, was demonstrated. A hydroboration/oxidation protocol smoothly converted 1,2-oxazine derivative syn-5 into secondary alcohol 6. After deprotection, polyhydroxylated tetrahydro-2H-1,2-oxazine 11, which can be regarded as an azasugar, was isolated. Analogous treatment of 1,2-oxazine anti-5 with the borane not only provided the expected secondary alcohol 7, but it also induced reduction of the C=C bond and ring opening. Treatment of syn-5 and anti-2 with hydrochloric acid in methanol induced deprotections and cyclisations leading to bicyclic tetrahydro-2H-1,2-oxazine derivatives. The second ring can be either a furan or a pyran ring. In the syn series, furan derivative 12 was formed exclusively, and its hydrogenolysis led to enantiopure aminofuran derivative 14. Acid-promoted rearrangement of unprotected anti-2 led to a mixture of bicyclic compounds with furan or pyran rings fused to the 1,2-oxazine core. However, when TBDPS-protected compound 20 was used it cleanly led to 1,2-oxazine 21 with a fused furan ring and then to aminofuran 22. Alternatively, the N-O bond in unprotected anti-2 was chemoselectively reduced with samarium diiodide, efficiently generating highly functionalized allylic alcohol 23. Acid-promoted cyclisation and deprotection furnished furan derivative 24. Mechanistic suggestions to explain the different outcomes of the acid-induced transformations are provided. Overall, it is demonstrated that the stereodivergent addition of lithiated alkoxyallenes to L-erythrose-derived nitrones allow flexible access to a series of enantiopure amino polyols, including aminofuran derivatives. Copyright

Full text of DOI:10.1002/ejoc.201200158

Job/Unit: O20158
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Date: 02-05-12 18:45:33
Pages: 14
FULL PAPER
DOI: 10.1002/ejoc.201200158
Application of -Erythrose-Derived Nitrones in the Synthesis of
L
Polyhydroxylated Compounds via 3,6-Dihydro-2H-1,2-oxazine Derivatives
[a,b]
Dieter Lentz,[a][‡] Elena Moreno-Clavijo,[c][‡‡] and
Hans-Ulrich Reissig*[a]
´
Marcin Jasinski,
Keywords: 1,2-Oxazines / N-Glycosyl hydroxylamines / Amino alcohols / Hydroboration / Azasugars / Furans / Lithiation /
Allenes
Enantiopure 3,6-dihydro-2H-1,2-oxazines were prepared by
[3+3] cyclisations starting from lithiated methoxyallene and
the L-erythrose-derived nitrones 1Ј and 3. The role of the
its hydrogenolysis led to enantiopure aminofuran derivative
14. Acid-promoted rearrangement of unprotected anti-2 led
to a mixture of bicyclic compounds with furan or pyran rings
fused to the 1,2-oxazine core. However, when TBDPS-pro-
tected compound 20 was used it cleanly led to 1,2-oxazine
21 with a fused furan ring and then to aminofuran 22. Alter-
natively, the N–O bond in unprotected anti-2 was chemose-
lectively reduced with samarium diiodide, efficiently gener-
ating highly functionalized allylic alcohol 23. Acid-promoted
cyclisation and deprotection furnished furan derivative 24.
Mechanistic suggestions to explain the different outcomes of
the acid-induced transformations are provided. Overall, it is
demonstrated that the stereodivergent addition of lithiated
side-chain protective group, which steers the highly selective
formation of either anti- or syn-configured products, was
demonstrated. A hydroboration/oxidation protocol smoothly
converted 1,2-oxazine derivative syn-5 into secondary
alcohol 6. After deprotection, polyhydroxylated tetrahydro-
2H-1,2-oxazine 11, which can be regarded as an azasugar,
was isolated. Analogous treatment of 1,2-oxazine anti-5 with
the borane not only provided the expected secondary alcohol
7, but it also induced reduction of the C=C bond and ring
opening. Treatment of syn-5 and anti-2 with hydrochloric
acid in methanol induced deprotections and cyclisations
leading to bicyclic tetrahydro-2H-1,2-oxazine derivatives.
The second ring can be either a furan or a pyran ring. In the
syn series, furan derivative 12 was formed exclusively, and
alkoxyallenes to L-erythrose-derived nitrones allow flexible
access to a series of enantiopure amino polyols, including
aminofuran derivatives.
thiated alkoxyallenes and carbohydrate-derived nitrones as
shown in Scheme 1.[5] Depending on the reaction condi-
tions, preferential formation either of syn-configured prod-
ucts (in the absence of additives) or of anti-configured com-
pounds (in the presence of suitable Lewis acids) is observed.
In this report we turned our attention to l-erythrose-de-
rived N-benzylhydroxylamine 1 (Scheme 2) as a promising
candidate for the preparation of 1,2-oxazines with new sub-
stitution patterns. A series of N-glycosylhydroxylamines of
this type, which are known to exist in equilibrium with the
corresponding open-chain nitrones, have been used success-
fully as reaction partners with nucleophilic reagents such as
organyllithium or Grignard reagents.[6] As expected, treat-
ment of 1/1Ј with lithiated methoxyallene proceeded
smoothly and led to the corresponding anti-configured 1,2-
oxazine with a free hydroxy group, whereas in the case of
an O-silylated nitrone derived from 1Ј a perfect switch of
stereoselectivity to a syn-configured product was observed.
Further transformations of these new 1,2-oxazine deriva-
tives exploiting the enol ether functionality – namely, hy-
droboration and acid-induced cyclisations to afford highly
substituted polyhydroxylated compounds – are also pre-
sented.
Introduction
The remarkably high synthetic potential of 3,6-dihydro-
2H-1,2-oxazine derivatives for the preparation of various
polyfunctionalized compounds has been presented in a
series of recent papers.[1] Syntheses of, for instance, enantio-
pure amino-substituted carbohydrates and sugar mi-
metics,[2] polycyclic compounds[3] and nitrogen heterocy-
cles[4] such as pyrrolidines and azetidines have been de-
scribed. These extremely versatile building blocks are easily
accessible through formal [3+3] cyclisations between li-
[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] Department of Organic and Applied Chemistry, University of
Łódz´,
Tamka 12, 91-403 Łódz´, Poland
[c] Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla,
Prof. García González 1, 41012 Seville, Spain
[‡] Responsible for X-ray crystal structure determination
[‡‡]Responsible for glycosidase inhibition tests
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200158.
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FULL PAPER
Scheme 1. Stereodivergent reactions between lithiated methoxyallene and a d-glyceraldehyde-derived nitrone leading to 3,6-dihydro-2H-
1,2-oxazines.
Scheme 2. Synthesis of N-benzylglycosylhydroxylamine 1 and reaction of its tautomer 1Ј with lithiated methoxyallene to form 1,2-oxazines
2.
served. In all reactions the first equivalent of lithiated meth-
oxyallene is consumed by deprotonation of the hydroxy
group of 1, and hence nitrone 1Ј is also formed and reacts
as the lithium alkoxide.
The role of the lithium alkoxide moiety in the formation
of the anti-configured 1,2-oxazine 2 is illustrated in Fig-
ure 1. We assume that the lithium cation intramolecularly
coordinates to the nitrone oxygen atom to form an eight-
Results and Discussion
As shown in Scheme 2, the starting masked nitrone 1 was
readily available through heating of an excess of N-benzyl-
hydroxylamine with 2,3-O-isopropylidene-l-erythrose un-
der solvent-free conditions.[6b] The latter starting material
was prepared in a one-pot fashion from l-arabinose as de-
scribed.[7] The first experiment with compound 1 was con-
ducted in accordance with the general protocol with use of
membered ring (model A). Subsequent attack of the nucleo-
lithiated methoxyallene (3.0 equiv.) at –78 °C and delivered
phile at the less hindered back side and subsequent cycli-
the expected 1,2-oxazine derivative 2 in 33% yield after 2 h,
sation then yields anti-2.[6c] In contrast, an O-protected de-
accompanied by unconsumed hydroxylamine 1. Increasing
the amount of lithiated methoxyallene to 6.0 equiv. did not
rivative of 1Ј should lead to a syn-configured product as
depicted (model B). This alternative approach is governed
improve the yield significantly (Table 1, Entries 1 and 2).
by the Felkin–Anh model, as observed for the reaction of
The reaction time was then extended to 6.5 h at the same
related glyceraldehyde-derived nitrones.[5] To test this hy-
temperature, and the desired product 2 was isolated in 52%
pothesis, TBS-protected nitrone 3 was prepared and also
yield (Entry 3). However, starting material could still be de-
treated with lithiated methoxyallene (Scheme 3).
tected in the crude mixture. These results clearly suggest
that addition of lithiated methoxyallene is limited by slow
formation of nitrone 1Ј, and so the reaction was repeated at
slightly elevated temperature (–41 °C). After 8 h, the desired
product 2 was isolated in high yield (Entry 4). In all cases,
excellent anti stereoselectivity (anti/syn ≈ 96:4) was ob-
Table 1. Optimisation of reactions between 1/1Ј and lithiated meth-
oxyallene.
Entry
Methoxyallene
[equiv.]
T
[°C]
Time
[h]
Yield [%]
1
2
1
2
3
4
3.0
6.0
6.0
6.0
–78
–78
–78
–41
2.0
2.0
6.5
8.0
55
55
43
–
33
37
52
91
Figure 1. Pathways A and B explaining the formation of anti- or
syn-configured 1,2-oxazines.
2
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l-Erythrose-Derived Nitrones in Syntheses of Polyhydroxylated Compounds
Scheme 3. Synthesis of O-silylated nitrone 3 and its transformation into 1,2-oxazines 5. (a) TBSCl (2.2 equiv.), imidazole (2.4 equiv.),
DMAP (0.05 equiv.), CH2Cl2, room temp., 3 d. (b) Ph3PCH3Br (2.3 equiv.), KOtBu (2.1 equiv.), THF, –78 °C to room temp., 3 h. (c) Lithi-
ated methoxyallene (6.0 equiv.), THF, –78 °C, 1 h.
According to the literature, the required compound 3 alized 3,6-dihydro-1,2-oxazine derivatives is also possible in
should be available from 2,3-O-isopropylidene-l-erythrose the erythrose series, with syn/anti ratios being strongly de-
in a five-step sequence (by Wittig reaction, TBS protection, pendant on the terminal hydroxy-protecting group.
C=C dihydroxylation followed by diol cleavage, and subse-
The presence of the electron-rich double bond in the 3,6-
quent condensation with N-benzylhydroxylamine) in an dihydro-2H-1,2-oxazine system opens several possibilities
overall yield of 77%.[8] In our hands, similarly to other re- for further stereoselective transformations. Results on cy-
ports,[9] the crucial Wittig reaction delivered the expected clopropanations,[10] brominations[11] and the more exten-
olefin 4 only in 60% yield. We were therefore very pleased sively studied hydroborations[4a,4c,12] have recently been
to find that the direct silylation of hydroxylamine 1 with published.
TBSCl led to a mixture in which the desired 3 was the
Because of the great interest of polyhydroxylated com-
major component. It could be isolated by simple column pounds as glycosidase inhibitors,[13] the hydroboration
chromatography in pure form and an acceptable yield of should be of particular importance. In general, treatment
43%. This direct approach to nitrones such as 3 should have of syn-configured 1,2-oxazines with BH3·THF yields, after
general importance, because it strongly facilitates access to oxidative workup, the corresponding hydroxylated com-
carbohydrate-derived nitrones. As anticipated, treatment of pounds as single diastereomers. This excellent stereocontrol
3 with lithiated methoxyallene at –78 °C smoothly yielded could be partially influenced in the presence of alkoxybor-
an inseparable mixture of the diastereomeric 1,2-oxazines 5 ane species generated in situ.[12] The introduction of a hy-
with very good syn preference. This experiment demon- droxy group at C-5 in 1,2-oxazines anti-2 and syn-5 was
strates that a stereodivergent approach to highly function- achieved under standard conditions and yielded the corre-
Scheme 4. Transformations of 1,2-oxazines syn-5 and anti-2 in a hydroboration/oxidation sequence. (a) BH3·THF (4.0 equiv.), THF,
–30 °C to room temp., 3 h, then NaOH (2 m), H2O2, –10 °C to room temp., overnight. (b) TBSCl (1.3 equiv.), imidazole (1.4 equiv.),
DMAP (5 mol-%), room temp., 16 h.
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M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
sponding alcohols
6 and 7, respectively (Scheme 4). removal of the acetonide function was achieved with ion
Whereas syn-5 (dr = 90:10) delivered the expected product exchange resin DOWEX-50 at enhanced temperature, fur-
exclusively (with respect to the major diastereomer), in the nishing the azasugar 11 in good overall yield. A dia-
case of anti-2 a complex mixture was obtained. The more stereomer of this compound should similarly be accessible
polar compounds 8 and 9 were isolated by standard column by starting with compound 7.
chromatography. From the less polar fraction, containing
mainly target compound 7, this desired product was ob- side chains, 1,2-oxazines such as syn-5 or anti-2 should be
tained after purification by HPLC in 30% yield. ideal candidates for Brønsted-acid-mediated transforma-
Because of the presence of the acetonide moieties in their
The structures of the isolated byproducts 8 and 9 clearly tions. This stereoselective approach to aminosugar deriva-
show that reduction of C=C and N–O bonds take place tives had been explored earlier by our group.[2b,14] By the
under the applied conditions. In order to examine whether general protocol, with p-toluenesulfonyl chloride in meth-
the free OH group might influence the chemoselectivity anol as a source of hydrogen chloride, transformation of
through the formation of the corresponding alkoxybor- syn-5 (dr = 90:10) furnished bicyclic compound 12 as the
anes,[12] we prepared the TBS-protected derivative of anti-2 only isolated product in an excellent 86% yield (Scheme 6).
under typical conditions. The resulting O-silylated anti-5 As expected, this compound was also formed by acid-in-
was treated with borane, followed by oxidative workup. The duced transformation of syn-2. Column chromatography
formation of a complex mixture of products related to 7–9 afforded pure 12 in 78% yield. The furanoid structure of 12
1
was observed. Only a 26% yield of the expected alcohol was was confirmed by the H NMR spectroscopic data of the
isolated; after treatment of this with TBAF under standard acetylated derivative 13, in which significant low-field shifts
conditions, 7 was obtained in 89% yield. The relative con- for the signals assigned to protons adjacent to OAc groups
figurations of 3,6-dihydro-2H-1,2-oxazine derivatives at C- could be observed. The desired aminosugar derivative 14
3 therefore seem to be a decisive factor for the observed was prepared in excellent yield by exhaustive hydrogenolysis
decreasing chemoselectivity. This observation is in full of 12 under standard conditions.
agreement with the behaviour of other anti-configured 1,2-
We then examined anti-2 under similar conditions. After
24 h, a complex mixture was found as crude product. Care-
oxazines.[4a]
With the new hydroxylated compound 6 in hand, we ful purification by chromatography allowed the isolation of
could prepare polyhydroxylated azasugar 11 by stepwise de- products 15–18 as depicted in Scheme 7. In contrast with
protection as shown in Scheme 5. Firstly, alcohol 6 was sub- the previously described cyclisation of a d-arabinose-de-
jected to hydrogen in the presence of palladium on charcoal rived anti-1,2-oxazine exclusively producing bicyclic pyr-
as catalyst to give the N-debenzylated product after a short anoid ketals (81% yield),[2b] in the case of anti-2 we ob-
reaction time (45 min). Notably, this primarily formed com- served a preference for the formation of the bicyclic furan
pound slowly underwent cleavage of the TBS group, either derivative 15 (52%). Additionally, the corresponding pyrans
during storage at room temperature in the presence of were isolated in both anomeric forms (16–18, 38%). The
methanol or on treatment with silica gel, yielding the corre- structure of cis-fused 15 was unambiguously confirmed by
sponding diol 10 in 74% yield. Complete deprotection by a single-crystal X-ray analysis (Figure 2).
In order to gain more detailed information about the
transformation, we resubjected ketal 16 to the tested condi-
tions. The formation of two more polar products was
clearly observed (TLC monitoring), and after the mixture
had been stirred for 3 d, complete conversion, exclusively
yielding fused pyran derivatives 17 and 18, was observed.
In an additional experiment, furan derivative 15 was treated
with HCl generated in situ; after 3 d at room temperature,
Scheme 5. Deprotection of 1,2-oxazine
6 leading to polyhy-
this had induced no changes in the examined sample. These
observations led to the conclusion that bicyclic furan 15
and pyran derivatives 17 and 18 are irreversibly formed un-
droxylated azasugar 11. (a) (i) H2, Pd/C, MeOH, room temp.,
45 min; (ii) MeOH, room temp., 24 h. (b) DOWEX-50, EtOH,
50 °C, 24 h.
Scheme 6. Two-step synthesis of aminofuran derivative 14 via the bicyclic 1,2-oxazine derivative 12. (a) pTsCl (0.5 equiv.), MeOH, room
temp., 1 d. (b) H2, Pd/C, MeOH, 22 h. (c) Ac2O (4.2 equiv.), Et3N (12 equiv.), DMAP (10 mol-%), CH2Cl2, room temp., 16 h.
4
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l-Erythrose-Derived Nitrones in Syntheses of Polyhydroxylated Compounds
Scheme 7. Acid-mediated cyclisation of anti-2 leading to a mixture
of bicyclic products 15–18.
Scheme 8. Cyclisation versus deprotection: a plausible explanation
for the observed formation of furan 15 and pyran derivatives 16–
18.
The desired compound 19 (Scheme 9) was finally pre-
pared by a known method with use of Ag2O as promoter[15]
in a low 38% yield. Finally, the TBDPS-protected com-
pound 20 was prepared, and under analogous conditions it
delivered the expected bicyclic furan derivative 21 in high
yield (82%), accompanied by a small amount of desilylated
compound 15 (13%). Attempted removal of the TBDPS
group by treatment with TBAF gave unsatisfactory results,
so Et3N·3HF was applied as a mildly acidic source of fluor-
ide to give the desired product 15 in 70% yield. A similar
result was observed when 21 was resubjected to anhydrous
HCl in methanol. Subsequent deprotection and simulta-
neous opening of the 1,2-oxazine ring by hydrogenolysis
furnished the desired aminofuran derivative 22 (Scheme 9).
The synthesis of aminosugar derivatives through trans-
formations of 1,2-oxazine derivatives is also possible in the
opposite order (first reduction, then cyclisation).[14] We
therefore examined anti-2 in this sequence. The reductive
N–O bond cleavage of 1,2-oxazine derivatives has recently
been studied in a series of publications[2,4a,4c,16] in which
samarium diiodide was employed as a highly chemoselec-
tive reducing agent. Compound anti-2 was treated with an
Figure 2. X-ray crystal structure of compound 15 (ellipsoids are
drawn at a 50% probability level).
der the applied conditions as a result of competitive cycli- excess of SmI2 (ca. 0.1 m solution in THF) according to
sation versus acetal cleavage as shown in Scheme 8. the general procedure. After 3 h at room temperature, the
In search of a more efficient synthesis of compound 15 starting material had been fully consumed (TLC). The cor-
a series of O-protected analogues of anti-2 was studied. In responding (E)-configured allylic alcohol 23 (Scheme 10)
the case of anti-5 complete cleavage of the TBS moiety was was formed in high yield with Ͼ95% purity, and – after
observed, and a mixture of compounds 15, 16 and 17 was filtration through a short silica gel pad – the spectroscopi-
isolated in combined 71% yield (48, 22 and 1% yields, cally pure product was isolated in 87% yield. Compound
respectively). A furan/pyran ratio slightly larger than that 23 could also be prepared by applying zinc dust in the pres-
seen in the cyclisation reaction of unprotected anti-2 was ence of hydrochloric acid, which is an alternative method
observed (ca. 3:2 and 2:1). An attempted benzylation of the for N–O bond cleavage of 1,2-oxazines.[17] Because of the
free hydroxy group of anti-2 under standard conditions was formation of several side products, careful purification was
not successful; treatment of this 1,2-oxazine with sodium necessary, and the product was isolated only in moderate
hydride in dry DMF and subsequent addition of benzyl yield (58%). In line with a more recent report on the syn-
bromide resulted in the formation of a complex mixture. thesis of vinyl-substituted aminofuran derivatives,[14] in
1
The H NMR spectrum of the crude material showed no which an allylic alcohol of type 23 was proposed as key
signals attributable to an acetonide group.
intermediate, compound 23 was subjected to acidic condi-
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M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
Scheme 9. Synthesis of aminofuran 22 via bicyclic 1,2-oxazine derivative 21. (a) Ag2O (3.0 equiv.), BnBr (1.3 equiv.), toluene, reflux, 2 d.
(b) TBDPSCl (1.4 equiv.), imidazole (1.5 equiv.), DMAP (0.05 equiv.), CH2Cl2, room temp., 36 h. (c) pTsCl (0.5 equiv.), MeOH, room
temp., 18 h. (d) Et3N·3HF (10 equiv.), THF, room temp., 36 h (70%); or pTsCl (1.1 equiv.), MeOH, room temp., 5 d (76%). (e) H2, Pd/
C, MeOH, 20 h.
Scheme 10. Transformation of anti-2 into amino furan derivative 24 by reduction/cyclisation sequences. (a) SmI2 (3.0 equiv.), THF, room
temp., 4 h. (b) Zn (5.0 equiv.), HCl (4.9 equiv.), MeOH, room temp., 16 h. (c) HCl (3 n), MeOH, room temp., 5 d. (d) Ac2O (4.3 equiv.),
Et3N (10 equiv.), DMAP (0.1 equiv.), CH2Cl2, room temp., overnight.
tions (3 n HCl in methanol). After 5 d at room temperature, tion of furan 24 at C-5 was confirmed by NOESY experi-
a single product had been formed (TLC monitoring) and ments in which a correlation peak between 2-H and the
was isolated in 87% yield. This compound was also pre- methoxy group of the 5-(methoxyethyl) substituent was ob-
pared in slightly higher yield (92%) when 23 was treated for served.
6 h with a boiling HCl/methanol solution. Surprisingly, no
characteristic vinyl signals were found in the 1H NMR spec-
trum, but two singlets at δ = 3.25 and 3.18 ppm (2ϫ 3 H)
attributable to two methoxy groups were observed. From
the NMR spectroscopic data and other analytical data, in-
cluding HRMS showing a peak at m/z = 311, the newly
formed product is proposed to be furan derivative 24
(Scheme 10). A particular preference for the formation of
the furan ring was observed again. The furan-derived struc-
ture was confirmed by acylation of both free hydroxy
1
groups present in 24. As expected, in the H NMR spec-
trum of 25 three sets of signals attributable to 3-H and the
exocyclic CH2 moiety were low-field-shifted (by ca. 0.9 and
0.7 ppm, respectively).
A possible pathway for the formation of 24 involving ad-
dition of methanol is shown in Scheme 11. After acid-pro-
moted cleavage of the acetonide moiety and subsequent eli-
mination of water, the well-stabilized allylic carbenium ion
A should be generated. Intramolecular nucleophilic attack
of the free hydroxy group could form vinylfuran derivative
26. Protonation followed by elimination of methanol could
Scheme 11. Proposed mechanism for the transformation of allylic
alcohol 23 into aminofuran derivative 24.
generate vinyl-substituted oxocarbenium ion B. This inter-
mediate could accept methanol to form exo-ethylidene de-
rivative C, and subsequent acid-induced addition of meth-
Finally, the described acid-catalysed transformation of 23
anol could finally yield product 24. This compound is un- was repeated under milder conditions with use of p-tolu-
questionably generated under thermodynamic control, and enesulfonic acid in methanol. The reaction was performed
only one diastereomer was formed. The relative configura- at 0 °C, and – after 9 h – almost complete acetonide cleav-
6
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l-Erythrose-Derived Nitrones in Syntheses of Polyhydroxylated Compounds
mentar Analysensysteme GmbH) instrument. Melting points were
age was observed, but no cyclisation products could be de-
tected at this temperature. The formation of vinylfuran 26
was observed at 25 °C, but a subsequent conversion of this
primary product into 24 occurred. From the 1H NMR spec-
tra, the maximum concentration of 26 was observed after
3 d, accompanied by the acetonide-cleaved derivative of 23
and product 24 in ca. 2:1:1 ratio. Attempted syntheses of
26 with the aid either of a less nucleophilic solvent (tri-
fluoroethanol in the presence of pTsCl) or of another pro-
measured with a Reichert apparatus (Thermovar) and are uncor-
rected. Optical rotations were determined with a Perkin–Elmer 241
polarimeter at the temperatures given. Single-crystal X-ray data
were collected with a Bruker SMART CCD diffractometer (Mo-Kα
radiation, λ = 0.71073 Å, graphite monochromator); the structure
solution and refinement were achieved by use of SHELXS-97[19]
and SHELXL-97[19] in the WINGX system.[20] CCDC-854944 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
ton source (trifluoroacetic acid in dichloromethane) gave no graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
satisfactory results.
Reaction between Lithiated Methoxyallene and 1-(N-Benzylhydrox-
Compounds 11, 14, 22 and 24 prepared in this study were
ylamino)-2,3-O-isopropylidene-1-deoxy-β-L-erythrose (1): Lithiated
examined for their glycosidase inhibitory properties
towards eleven commercially available enzymes. Unfortu-
nately, none of the compounds, tested as 1 mm solutions,[18]
showed promising inhibition.
methoxyallene was generated under dry argon by treatment of a
solution of methoxyallene (1.19 g, 1.45 mL, 17.0 mmol) in dry
tetrahydrofuran (35 mL) with nBuLi (2.5 m in hexane, 6.7 mL,
16.8 mmol) at –40 °C. After 5 min, a solution of N-benzylhydroxyl-
amine derivative 1 (0.711 g, 2.68 mmol) in tetrahydrofuran (30 mL)
was added slowly at the same temperature. The mixture was stirred
at –40 °C for 8 h and was then quenched with water. Warming up
to room temp. was followed by extraction with diethyl ether (3ϫ
45 mL) and drying of the combined extracts with MgSO4. Removal
of the solvents in vacuo yielded crude 1,2-oxazines 2 as an orange
Conclusions
The reactions between lithiated methoxyallene and either
nitrone 1Ј or its O-protected analogue 3 could be carried
out on gram scales to yield 1,2-oxazines in an anti- or syn- oil (anti-2/syn-2 = 96:4), which was purified by column chromatog-
raphy (silica gel, hexane/ethyl acetate = 1:1). The major product
anti-2 (0.818 g, 91%, Ͼ98% purity) was isolated as a light yellow
oil and the minor isomer syn-2 (18 mg, 2%) as a colourless oil.
An analytically pure sample of anti-2 was obtained after a second
chromatographic purification (silica gel, hexane/ethyl acetate = 3:1)
as a colourless liquid.
selective fashion. As observed earlier, the hydroboration
proceeded smoothly only for the syn-configured 1,2-oxazine
syn-5, which after subsequent deprotections led to azasugar
11. Acid-induced reactions of syn-2 and anti-5 depend
strongly on the protective groups present and allow the syn-
thesis of a range of aminofuran derivatives. Alternatively,
chemoselective N–O bond cleavage by samarium diiodide
was examined and – after subsequent deprotections – also
provided an aminofuran derivative. These experiments
again demonstrate the great potential of 1,2-oxazine inter-
mediates for the synthesis of cyclic or acyclic enantiopure
amino polyols. Because the starting arabinose is readily
available in both the l- and the d-series, it is clear that the
products presented in this report are also available with op-
posite absolute configurations.
(3S,4ЈR,5ЈS)-2-Benzyl-3-(5Ј-hydroxymethyl-2Ј,2Ј-dimethyl-1Ј,3Ј-di-
oxolan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-[1,2]oxazine (anti-2): [α]2D2
= +100.3 (c = 1.34, CHCl3). 1H NMR (CDCl3, 500 MHz): δ =
1.33, 1.45 (2 s, 2ϫ 3 H, 2 Me), 3.34 (ddd, J = 4.5, 8.5, 12.0 Hz, 1
H, 5Ј-CH2OH), 3.40 (d, J = 8.6 Hz, 1 H, 3-H), 3.62 (s, 3 H, OMe),
3.66 (ddd, J = 4.9, 9.5, 12.0 Hz, 1 H, 5Ј-CH2OH), 4.08, 4.12 (2 d,
J = 12.7 Hz, 1 H each, CH2Ph), 4.28–4.33 (m, 3 H, 5Ј-H, 6-H,
OH), 4.45 (br. dd, J ≈ 1.2, 15.1 Hz, 1 H, 6-H), 4.67 (dd, J = 5.5,
8.6 Hz, 1 H, 4Ј-H), 4.83 (t, J ≈ 2.8 Hz, 1 H, 5-H), 7.28–7.37 (m, 5
H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 25.6, 27.3 (2 q, 2
Me), 54.1 (q, OMe), 57.4 (t, CH2Ph), 59.3 (d, C-3), 59.7 (t,
CH2OH), 61.4 (t, C-6), 77.47 (d, C-5Ј), 77.55 (d, C-4Ј), 90.6 (d, C-
5), 108.6 (s, C-2Ј), 127.9, 128.5, 129.5, 135.2 (3 d, s, Ph), 150.4 (s,
Experimental Section
C-4) ppm. IR (ATR): ν = 3390 (O–H), 3060–2830 (=C–H, C–H),
˜
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by syringe.
Solvents were purified with an MB SPS-800-dry solvent system.
Other reagents were purchased and used as received without fur-
ther purification unless stated otherwise. Products were purified by
flash chromatography on silica gel (230–400 mesh, Merck or
Fluka). Unless stated otherwise, yields refer to analytically pure
samples. NMR spectra were recorded with Bruker (AC 250,
AC 500, AVIII 700) and JOEL (ECX 400, Eclipse 500) instruments.
Chemical shifts are reported relative to TMS or solvent residual
peaks [1H: δ = 0.00 ppm (TMS), δ = 7.26 ppm (CDCl3); 13C: δ =
77.0 ppm (CDCl3)]. Integrals are consistent with assignments, and
coupling constants are given in Hz. All 13C NMR spectra are pro-
ton-decoupled. For detailed peak assignments 2D spectra were
measured (COSY, HMQC, HMBC). IR spectra were measured
with a Nexus FT-IR spectrometer fitted with a Nicolet Smart Dura
Sample IR ATR. MS and HRMS analyses were performed with
a Varian Ionspec QFT-7 (ESI-FT ICRMS) instrument. Elemental
analyses were carried out with a Vario EL or a Vario EL III (Ele-
1675 (C=C), 1215, 1075, 1055 (C–O) cm–1. HRMS (ESI-TOF):
calcd. for C18H25NNaO5 [M + Na]+ 358.1625; found 358.1605.
C18H25NO5 (335.4): calcd. C 64.46, H 7.51, N 4.18; found C 64.38,
H 7.48, N 4.07.
(3R,4ЈR,5ЈS)-2-Benzyl-3-(5Ј-hydroxymethyl-2Ј,2Ј-dimethyl-1Ј,3Ј-di-
oxolan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-[1,2]oxazine (syn-2): [α]2D2
=
1
–65.0 (c = 1.07, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.41,
1.53 (2 s, 2ϫ 3 H, 2 Me), 2.62 (dd, J = 2.1, 9.8 Hz, 1 H, OH), 3.32
(d, J = 8.2 Hz, 1 H, 3-H), 3.47 (ddd, J = 2.1, 8.1, 11.2 Hz, 1 H, 5Ј-
CH2OH), 3.57 (s, 3 H, OMe), 3.80 (ddd, J = 3.8, 9.8, 11.2 Hz, 1
H, 5Ј-CH2OH), 4.11 (ddd, J = 3.8, 5.3, 8.1 Hz, 1 H, 5Ј-H), 4.13 (d,
J = 13.8 Hz, 1 H, CH2Ph), 4.24 (dd, J = 3.2, 14.8 Hz, 1 H, 6-H),
4.27 (d, J = 13.8 Hz, 1 H, CH2Ph), 4.39 (dt, J = 2.1, 14.8 Hz, 1 H,
6-H), 4.53 (dd, J = 5.4, 8.2 Hz, 1 H, 4Ј-H), 4.84 (t, J ≈ 2.9 Hz, 1
H, 5-H), 7.24–7.28, 7.30–7.34, 7.40–7.43 (3 m, 5 H, Ph) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 25.9, 28.2 (2 q, 2 Me), 54.3 (q,
OMe), 58.8 (t, CH2Ph), 59.0 (d, C-3), 61.6 (t, CH2OH), 63.3 (t, C-
6), 76.9 (d, C-4Ј), 78.2 (d, C-5Ј), 93.0 (d, C-5), 108.1 (s, C-2Ј), 127.2,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
128.2, 128.8, 137.4 (3 d, s, Ph), 151.0 (s, C-4) ppm. IR (ATR): ν =
For the analytical data for anti-5, see the next experiment.
˜
3470 (O–H), 3090–2835 (=C–H, C–H), 1675 (C=C), 1215, 1055
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C18H25NNaO5 [M +
Na]+ 358.1625; found 358.1640. C18H25NO5 (335.4): calcd. C 64.46,
H 7.51, N 4.18; found C 64.44, H 7.58, N 4.08.
(3S,4ЈR,5ЈS)-2-Benzyl-3-[5Ј-(tert-butyldimethylsiloxymethyl)-2Ј,2Ј-di-
methyl-1Ј,3Ј-dioxolan-4Ј-yl]-4-methoxy-3,6-dihydro-2H-[1,2]oxazine
(anti-5): Imidazole (241 mg, 3.54 mmol), DMAP (13 mg,
0.11 mmol) and TBSCl (520 mg, 3.45 mmol) in dichloromethane
(5 mL) were added dropwise at 0 °C to a solution of 1,2-oxazine
anti-2 (850 mg, 2.53 mmol) in dry dichloromethane (10 mL). The
reaction mixture was allowed to reach room temp. and stirred over-
night. Dichloromethane (15 mL) was then added, followed by water
(15 mL), and the layers were separated. The aqueous layer was ex-
tracted with three portions of dichloromethane (7 mL each), the
combined organic layers were washed with brine, dried (Na2SO4)
and filtered, and the solvents were removed. Purification by column
chromatography (silica gel, hexane/ethyl acetate = 6:1) yielded anti-
5 (958 mg, 84%) as a colourless oil. [α]2D2 = +55.7 (c = 1.00, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 0.03, 0.05, 0.88 (3 s, 2ϫ 3 H, 9
H, TBS), 1.35, 1.45 (2 s, 2ϫ 3 H, 2 Me), 3.48 (d, J = 7.2 Hz, 1 H,
3-H), 3.62 (s, 3 H, OMe), 3.61 (dd, J = 7.1, 11.2 Hz, 1 H, 5Ј-
CH2–), 3.99 (dd, J = 3.8, 11.2 Hz, 1 H, 5Ј-CH2–), 3.97, 4.03 (2 d,
J = 13.8 Hz, 2 H, CH2Ph), 4.22 (dd, J = 2.9, 15.0 Hz, 1 H, 6-H),
4.25 (ddd, J = 3.8, 6.2, 7.1 Hz, 1 H, 5Ј-H), 4.37 (br. ddd, J = 1.6,
2.1, 15.0 Hz, 1 H, 6-H), 4.61 (dd, J = 6.2, 7.2 Hz, 1 H, 4Ј-H), 4.78
(t, J ≈ 2.7 Hz, 1 H, 5-H), 7.24–7.39 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = –5.2, –5.1, 18.4, 26.0 (2 q, s, q, TBS), 25.3,
27.5 (2 q, 2 Me), 54.0 (q, OMe), 57.0 (t, CH2Ph), 60.3 (d, C-3),
61.6 (t, C-6), 62.8 (t, 5Ј-CH2–), 77.0 (d, C-4Ј), 79.0 (d, C-5Ј), 90.8
(d, C-5), 108.1 (s, C-2Ј), 127.3, 128.3, 128.8, 137.1 (3 d, s, Ph), 151.2
Synthesis of Nitrone 3: Imidazole (116 mg, 1.70 mmol), DMAP
(4.0 mg) and TBSCl (240 mg, 1.59 mmol) in dichloromethane
(10 mL) were added dropwise at 0 °C to a solution of N-benzylhy-
droxylamine derivative 1 (192 mg, 0.72 mmol) in dry dichlorometh-
ane (10 mL). The mixture was allowed to reach room temp. and
stirred for 3 d. Dichloromethane (ca. 20 mL) was then added, fol-
lowed by H2O (40 mL), and the layers were separated. The aqueous
layer was extracted with dichloromethane (3ϫ 20 mL), the com-
bined organic layers were dried (Na2SO4) and filtered, and the sol-
vents were removed in vacuo. Purification by column chromatog-
raphy (silica gel, hexane/ethyl acetate = 4:3) furnished nitrone 3
(118 mg, 43%) as a colourless oil. [α]2D2 = –138.2 (c = 1.29, CHCl3)
{ref.[8] [α]D = –106.8 (c = 1.96, CHCl3)}. 1H NMR (CDCl3,
500 MHz): δ = 0.01, 0.02, 0.87 (3 s, 9 H, 2ϫ 3 H, TBS), 1.34, 1.46
(2 s, 2ϫ 3 H, 2 Me), 3.50 (dd, J = 4.0, 11.4 Hz, 1 H, CH2OTBS),
3.65 (dd, J = 3.2, 11.4 Hz, 1 H, CH2OTBS), 4.49 (dt, J = 3.6,
7.2 Hz, 1 H, CH–O), 4.83, 4.87 (2 d, J = 13.5 Hz, 1 H each,
CH2Ph), 5.34 (dd, J = 5.5, 7.2 Hz, 1 H, N=CH–CH–O), 6.92 (d, J
= 5.5 Hz, 1 H, CH=N), 7.36–7.43 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = –5.4, –5.3, 18.2, 25.9 (2 q, s, q, TBS), 24.5,
26.7 (2 q, 2 Me), 62.3 (t, CH2OTBS), 69.0 (t, CH2Ph), 77.5 (d,
N=CH–CH–O), 78.8 (d, CH–O), 109.2 [s, O–C(Me2)–O], 128.9,
129.1, 129.3, 132.4 (3 d, s, Ph), 138.0 (d, N=CH) ppm. IR (ATR):
(s, C-4) ppm. IR (ATR): ν = 3090–2835 (=C–H, C–H), 1680
˜
ν = 3090–2855 (=C–H, C–H), 1600 (C=N), 1255, 1150, 1080 (C–
˜
(C=C), 1245, 1215, 1070 (C–O) cm–1. HRMS (ESI-TOF): calcd.
O) cm–1. HRMS (ESI-TOF): calcd. for C20H33NNaO4Si [M +
Na]+ 402.2071; found 402.2067.
for C24H39NNaO5Si [M + Na]+ 472.2490; found 472.2513.
C
24H39NO5Si (449.7): calcd. C 64.11, H 8.74, N 3.11; found C
Reaction between Lithiated Methoxyallene and Nitrone 3: Lithiated
methoxyallene was generated under dry argon by treatment of a
solution of methoxyallene (1.79 g, 2.15 mL, 25.5 mmol) in tetra-
hydrofuran (65 mL) with nBuLi (2.5 m in hexane, 9.2 mL,
23.0 mmol) at –40 °C. After 5 min, it was cooled to –78 °C, and a
solution of nitrone 3 (2.90 g, 7.64 mmol) in dry tetrahydrofuran
(30 mL) was added slowly. The mixture was stirred at this tempera-
ture for 1 h and was then quenched with water (10 mL). Warming
up to room temp. was followed by extraction with diethyl ether
(3ϫ 60 mL) and drying of the combined extracts with MgSO4.
Removal of the solvent in vacuo yielded crude product (syn-5/anti-
5 = 90:10), which was purified by column chromatography (silica
gel, hexane/ethyl acetate = 6:1) to give a 9:1 mixture of syn-5/anti-
5 as a pale yellow oil (3.02 g, 88%).
63.69, H 8.63, N 3.20.
Typical Procedure for the Hydroboration of 2H-1,2-Oxazines:
BH3·THF (1 m in THF, 4.4 mL, 4.4 mmol) was added at –30 °C to
a solution of syn-5 (490 mg, 1.09 mmol) in tetrahydrofuran
(25 mL). The solution was allowed to reach room temp. and stirred
for 3 h and was then cooled to –10 °C, and an NaOH solution (2 m,
9.0 mL) and H2O2 (30%; 3.0 mL) were added. After the mixture
had been stirred at room temp. overnight, an Na2S2O3 solution
(satd.; 20 mL) was added, the layers were separated, and the aque-
ous layer was extracted with diethyl ether (3ϫ 35 mL). The com-
bined organic phases were dried (MgSO4) and filtered, and the sol-
vents were removed under reduced pressure. The crude product was
purified by column chromatography (silica gel, hexane/AcOEt =
2:1) to give 6 as a colourless oil (288 mg, 56%).
(3R,4ЈR,5ЈS)-2-Benzyl-3-[5Ј-(tert-butyldimethylsiloxymethyl)-2Ј,2Ј-
dimethyl-1Ј,3Ј-dioxolan-4Ј-yl]-4-methoxy-3,6-dihydro-2H-[1,2]oxaz- (3R,4S,5R,4ЈR,5ЈS)-2-Benzyl-3-[5Ј-(tert-butyldimethylsiloxymeth-
ine (syn-5): [α]2D2 = –38.7 (c = 1.09, CHCl3, dr = 9:1). 1H NMR
(CDCl3, 500 MHz): δ = 0.05, 0.06, 0.89 (3 s, 2ϫ 3 H, 9 H, TBS),
1.39, 1.53 (2 s, 2ϫ 3 H, 2 Me), 3.54 (d, J = 8.0 Hz, 1 H, 3-H), 3.56
yl)-2Ј,2Ј-dimethyl-1Ј,3Ј-dioxolan-4Ј-yl]-4-methoxy-3,4,5,6-tetrahy-
1
dro-2H-[1,2]oxazinan-5-ol (6): [α]2D2 = –66.4 (c = 1.15, CHCl3). H
NMR (CDCl3, 500 MHz): δ = 0.10, 0.11, 0.92 (3 s, 2ϫ 3 H, 9 H,
(s, 3 H, OMe), 3.75 (dd, J = 6.5, 10.5 Hz, 1 H, 5Ј-CH2–), 3.92 (dd, TBS), 1.33, 1.44 (2 s, 2ϫ 3 H, 2 Me), 2.22 (d, J = 8.1 Hz, 1 H,
J = 3.8, 10.5 Hz, 1 H, 5Ј-CH2–), 4.04 (d, J = 14.3 Hz, 1 H, CH2Ph), OH), 3.42 (dd, J = 2.6, 9.2 Hz, 1 H, 3-H), 3.46 (s, 3 H, OMe), 3.59
4.15 (td, J = 3.8, 6.2 Hz, 1 H, 5Ј-H), 4.24 (br. dd, J ≈ 3.0, 14.6 Hz, (dd, J = 3.8, 10.9 Hz, 1 H, 5Ј-CH2–), 3.67 (ddd, J = 0.8, 3.0,
1 H, 6-H), 4.31 (ddd, J = 1.9, 2.6, 14.6 Hz, 1 H, 6-H), 4.37 (d, J = 12.0 Hz, 1 H, 6-H), 3.74 (mc, 1 H, 5-H), 3.79 (d, J = 15.0 Hz, 1 H,
14.3 Hz, 1 H, CH2Ph), 4.46 (dd, J = 5.8, 8.0 Hz, 1 H, 4Ј-H), 4.82 CH2Ph), 3.84 (br. t, J ≈ 3.7 Hz, 1 H, 4-H), 3.85 (dd, J = 6.3,
(t, J ≈ 2.9 Hz, 1 H, 5-H), 7.23–7.45 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = –5.27, –5.29, 18.4, 26.0 (2 q, s, q, TBS),
25.9, 27.8 (2 q, 2 Me), 54.3 (q, OMe), 59.3 (t, CH2Ph), 60.2 (d, C-
3), 63.0 (t, 5Ј-CH2-), 63.3 (t, C-6), 77.1 (d, C-4Ј), 79.0 (d, C-5Ј),
92.7 (d, C-5), 108.2 (s, C-2Ј), 126.9, 128.1, 128.7, 138.4 (3 d, s, Ph),
10.9 Hz, 1 H, 5Ј-CH2-), 4.16 (dt, J ≈ 4.1, 6.3 Hz, 1 H, 5Ј-H), 4.21
(dd, J = 2.1, 12.0 Hz, 1 H, 6-H), 4.49 (dd, J = 4.5, 9.2 Hz, 1 H, 4Ј-
H), 4.65 (d, J = 15.0 Hz, 1 H, CH2Ph), 7.21–7.43 (m, 5 H, Ph)
ppm. 13C NMR (CDCl3, 126 MHz): δ = –5.44, –5.40, 18.3, 26.0 (2
q, s, q, TBS), 25.7, 28.3 (2 q, 2 Me), 58.3 (q, OMe), 60.8 (t, CH2Ph),
61.5 (d, C-6), 63.5 (t, 5Ј-CH2–), 63.9 (d, C-4), 70.3 (t, C-3), 76.5 (d,
C-4Ј), 78.2 (d, C-5), 78.7 (d, C-5Ј), 107.6 (s, C-2Ј), 126.6, 127.9,
152.1 (s, C-4) ppm. IR (ATR): ν = 3085–2840 (=C–H, C–H), 1675
˜
(C=C), 1255, 1220, 1070 (C–O) cm–1. HRMS (ESI-TOF): calcd.
for C24H39NNaO5Si [M + Na]+ 472.2490; found 472.2483.
128.6, 138.8 (3 d, s, Ph) ppm. IR (ATR): ν = 3460 (O–H), 3085–
˜
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
l-Erythrose-Derived Nitrones in Syntheses of Polyhydroxylated Compounds
2825 (=C–H, C–H), 1095 (C–O) cm–1. HRMS (ESI-TOF): calcd.
for C24H41NNaO6Si [M + Na]+ 490.2601; found 490.2600.
C24H41NO6Si (467.7): calcd. C 61.64, H 8.84, N 2.99; found C
61.57, H 8.87, N 2.96.
= 25.4, 28.0 (2 q, 2 Me), 52.9 (t, CH2Ph), 56.4 (d, C-4), 59.0 (q,
OMe), 60.2 (t, 5Ј-CH2–), 65.3 (t, C-1), 71.4 (d, C-2), 77.2 (d, C-4Ј),
77.8 (d, C-5Ј), 82.0 (d, C-3), 108.6 (s, C-2Ј), 127.6, 128.6, 128.8,
139.0 (3 d, s, Ph) ppm. IR (ATR): ν = 3385 (OH), 3315 (N–H),
˜
3030–2825 (=C–H, C–H), 1070 (C–O) cm–1. HRMS (ESI-TOF):
calcd. for C18H30NO6 [M + H]+ 356.2073; found 356.2081.
C18H29NO6 (355.4): calcd. C 60.83, H 8.22, N 3.94; found C 60.93,
H 8.32, N 3.89.
According to the typical procedure for the hydroboration of syn-
5, compound anti-2 (247 mg, 0.74 mmol) in dry tetrahydrofuran
(10 mL) was treated with BH3·THF (1 m in THF, 3.0 mL,
3.0 mmol), and – after oxidative workup – a colourless oil was ob-
tained and purified by column chromatography (silica gel, ethyl
acetate) to give a fraction containing impure 7 (107 mg), and two
other fractions containing pure 8 (40 mg, 15%) and pure 9 (22 mg,
8%) as viscous colourless oils. A pure sample of 7 (78 mg, 30%)
was obtained by a second chromatographic separation (silica gel,
dichloromethane/methanol = 30:1) and subsequent purification by
HPLC (Nucleosil 50-5, Macherey–Nagel, 4ϫ250 mm, hexane/pro-
pan-2-ol = 9:1, flow 2 mLmin–1, 129 bar).
(3R,4S,5S,1ЈR,2ЈS)-5-Hydroxy-4-methoxy-3-(1Ј,2Ј,3Ј-trihydroxy-
propyl)-3,4,5,6-tetrahydro-2H-1,2-oxazine (11): Hydrogen was
bubbled through a stirred suspension of Pd/C (10% Pd, 86 mg) in
dry methanol (10 mL) for 1 h. A solution of 6 (210 mg, 0.45 mmol)
in methanol (2 mL) was added, and the mixture was stirred at room
temp. at normal pressure (hydrogen balloon). After 45 min, the
solution was filtered through a short pad of Celite, and the solvent
was removed to provide a colourless oil. This primarily formed
debenzylated product was kept in methanol (2 mL) for 24 h, the
solvent was removed, and the resulting oil was purified by column
chromatography (silica gel, dichloromethane/methanol = 10:1) to
(3S,4R,5S,4ЈR,5ЈS)-2-Benzyl-3-(5Ј-hydroxymethyl-2Ј,2Ј-dimethyl-
1Ј,3Ј-dioxolan-4Ј-yl)-4-methoxy-3,4,5,6-tetrahydro-2H-[1,2]oxazin-
an-5-ol (7): [α]2D2 = –40.6 (c = 1.23, CHCl3). 1H NMR ([D8]toluene,
80 °C, 500 MHz): δ = 1.24, 1.32 (2 s, 2ϫ 3 H, 2 Me), 3.13–3.19 (m,
1 H, 6-H), 3.18 (s, 3 H, OMe), 3.45 (mc, 1 H, 4-H), 3.48 (mc, 1 H,
5-H), 3.62 (dd, J = 4.7, 11.6 Hz, 1 H, 5Ј-CH2–), 3.68 (d, J =
14.7 Hz, 1 H, CH2Ph), 3.81–3.85 (m, 1 H, 3-H), 3.89 (dd, J = 7.5,
11.6 Hz, 1 H, 5Ј-CH2–), 4.08 (br. dd, J ≈ 0.9, 12.7 Hz, 1 H, 6-H),
4.13 (dt, J ≈ 5.2, 7.5 Hz, 1 H, 5Ј-H), 4.27 (dd, J = 5.7, 8.2 Hz, 1
H, 4Ј-H), 4.36 (d, J = 14.7 Hz, 1 H, CH2Ph), 7.02–7.07, 7.10–7.16,
7.28–7.33 (3 m, 5 H, Ph) ppm. 13C NMR ([D8]toluene, 80 °C,
126 MHz): δ = 25.6, 28.3 (2 q, 2 Me), 56.3 (t, CH2Ph), 58.5 (q,
OMe), 60.6 (d, C-3), 62.4 (t, 5Ј-CH2–), 64.7 (t, C-6), 65.0 (d, C-5),
75.4 (d, C-4Ј), 78.0 (d, C-4), 79.3 (d, C-5Ј), 107.7 (s, C-2Ј), 127.5,
give 10 (87 mg, 74%) as a colourless semisolid product. [α]2D2
=
1
–34.4 (c = 1.19, CHCl3). H NMR (CDCl3, 700 MHz): δ = 1.31,
1.44 (2 s, 2ϫ 3 H, 2 Me), 3.36 (mc, 1 H, 4-H), 3.47 (s, 3 H, OMe),
3.65 (dd, J = 4.9, 11.8 Hz, 1 H, CH2OH), 3.68 (dd, J = 1.8, 6.8 Hz,
1 H, 3-H), 3.72 (dd, J = 5.2, 11.8 Hz, 1 H, CH2OH), 3.78 (dd, J =
1.9, 12.2 Hz, 1 H, 6-H), 3.80 (mc, 1 H, 5-H), 4.10 (dd, J = 0.9,
12.2 Hz, 1 H, 6-H), 4.17 (dd, J ≈ 5.2, 10.7 Hz, 1 H, 5Ј-H), 4.28 (t,
J ≈ 6.4 Hz, 1 H, 4Ј-H) ppm. 13C NMR (CDCl3, 126 MHz): δ =
25.3, 27.6 (2 q, 2 Me), 54.9 (d, C-3), 58.9 (q, OMe), 61.3 (t, 5Ј-
CH2OH), 64.4 (d, C-5), 71.0 (t, C-6), 75.1 (d, C-4Ј), 76.6 (d, C-4),
77.4 (d, C-5Ј), 108.4 (s, C-2Ј) ppm. IR (ATR): ν = 3395 (O–H),
˜
3295 (N–H), 2990–2830 (C–H), 1095, 1045 (C–O) cm–1. HRMS
(ESI-TOF): calcd. for C11H21NNaO6 [M + Na]+ 286.1267; found
286.1274.
128.6, 129.1, 138.2 (3 d, s, Ph) ppm. IR (ATR): ν = 3400 (O–H),
˜
3060–2830 (=C–H, C–H), 1095, 1070, 1040 (C–O) cm–1. HRMS
(ESI-TOF): calcd. for C18H27NNaO6 [M + Na]+ 376.1731; found
376.1736.
Acidic ion-exchange resin (DOWEX-50, 390 mg, washed several
times with ethanol before use) was added to a solution of 10
(80 mg, 0.30 mmol) in ethanol (4.0 mL). The suspension was vigor-
ously stirred at 50 °C for 24 h and then decanted, the resin was
washed with three portions of ammonia in methanol solution (7 n,
ca. 3.0 mL each), and the organic layers were combined. After
evaporation of the solvents, compound 11 (48 mg, 70%) was iso-
lated as a colourless solid. M.p. 182–184 °C. [α]2D2 = –6.6 (c = 1.01,
H2O). 1H NMR (CD3OD, 400 MHz): δ = 3.36 (mc, 1 H, 4-H), 3.48
(s, 3 H, OMe), 3.61 (dd, J = 5.9, 10.4 Hz, 1 H, 3Ј-H), 3.65 (mc, 1
H, 3-H), 3.68–3.77 (m, 4 H, 6-H, 1Ј-H, 2Ј-H, 3Ј-H), 3.85 (mc, 1 H,
5-H), 4.05 (dd, J = 2.0, 12.4 Hz, 1 H, 6-H) ppm. 13C NMR (D2O/
CD3OD = 9:1, 126 MHz, 295K): δ = 56.3 (d, C-3), 57.2 (q, OMe),
62.2 (t, C-3Ј), 62.7 (d, C-5), 70.5 (t, C-6), 71.2* (t, d, C-1Ј, C-2Ј),
(3R,4R,4ЈR,5ЈS)-4-Benzylamino-4-(5Ј-hydroxymethyl-2Ј,2Ј-dimeth-
yl-1Ј,3Ј-dioxolan-4Ј-yl)-3-methoxybutanol (8): [α]2D2 = +16.9 (c =
1.21, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 1.32, 1.44 (2 s, 2ϫ
3 H, 2 Me), 1.79 (ddt, J ≈ 4.2, 6.5, 14.0 Hz, 1 H, 2-H), 1.90 (dddd,
J = 4.3, 7.6, 8.9, 14.0 Hz, 1 H, 2-H), 3.35 (dd, J = 2.3, 10.0 Hz, 1
H, 4-H), 3.47 (s, 3 H, OMe), 3.70–3.77 (m, 2 H, 5Ј-CH2–), 3.75 (d,
J = 11.8 Hz, 1 H, CH2Ph), 3.80 (ddd, J = 4.3, 6.5, 10.8 Hz, 1 H,
1-H), 3.86–3.92 (m, 2 H, 1-H, 3-H), 3.95 (dd, J = 5.7, 10.0 Hz, 1
H, 4Ј-H), 4.22 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.36 (dt, J ≈ 5.3,
9.0 Hz, 1 H, 5Ј-H), 7.25–7.35 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
126 MHz): δ = 25.3, 28.0 (2 q, 2 Me), 31.2 (t, C-2), 52.2 (t, CH2Ph),
55.7 (d, C-4), 57.5 (q, OMe), 60.4 (t, 5Ј-CH2–), 60.7 (t, C-1), 77.1
(d, C-4Ј), 77.9 (d, C-5Ј), 81.9 (d, C-3), 108.4 (s, C-2Ј), 127.6, 128.6,
76.6 (d, C-4) ppm; * higher intensity. IR (ATR): ν = 3470–3230
˜
128.7, 138.7 (3 d, s, Ph) ppm. IR (ATR): ν = 3390 (O–H), 3290
˜
(O–H, N–H), 2965–2830 (C–H), 1090 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C8H17NNaO6 [M + Na]+ 246.0954; found
246.0942. C8H17NO6 (223.2): calcd. C 43.04, H 7.68, N 6.27; found
C 43.00, H 7.48, N 6.30.
(N–H), 3060–2810 (=C–H, C–H), 1050 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C18H30NO5 [M + H]+ 340.2124; found 340.2127.
C18H29NO5 (339.4): calcd. C 63.69, H 8.61, N 4.13; found C 63.69,
H 8.60, N 4.03.
(2R,3R,4R,4ЈR,5ЈS)-4-Benzylamino-4-(5Ј-hydroxymethyl-2Ј,2Ј-di-
(4aR,6S,7R,7aR)-1-Benzyl-7-hydroxy-6-hydroxymethyl-4a-meth-
oxy-hexahydro-1H-furano[3,2-c][1,2]oxazine (12): A solution of syn-
methyl-1Ј,3Ј-dioxolan-4Ј-yl)-3-methoxybutane-1,2-diol (9): [α]2D2
=
1
+21.0 (c = 1.10, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.33, 5 (1.21 g, 2.69 mmol) in methanol (20 mL) was added to a stirred
1.43 (2 s, 2ϫ 3 H, 2 Me), 3.32 (dd, J = 2.8, 10.3 Hz, 1 H, 4-H),
3.56 (s, 3 H, OMe), 3.68–3.75 (m, 3 H, 1-H, 3-H, 5Ј-CH2–), 3.71
solution of pTsCl (260 mg, 1.36 mmol) in dry methanol (20 mL),
and the mixture was stirred at room temp. for 1 d, quenched with
(d, J = 11.6 Hz, 1 H, CH2Ph), 3.78 (dd, J = 4.8, 11.4 Hz, 1 H, 5Ј- saturated aq. NaHCO3 solution (5 mL) and extracted with dichlo-
CH2–), 3.80 (dd, J = 5.9, 11.2 Hz, 1 H, 1-H), 4.05 (ddd, J = 2.5,
4.4, 5.9 Hz, 1 H, 2-H), 4.14 (dd, J = 5.7, 10.3 Hz, 1 H, 4Ј-H), 4.29
romethane (3ϫ 25 mL). The combined organic layers were dried
with MgSO4 and filtered, and the solvents were removed under
(d, J = 11.6 Hz, 1 H, CH2Ph), 4.41 (dt, J ≈ 5.2, 9.5 Hz, 1 H, 5Ј- reduced pressure. The crude products were purified by column
H), 7.24–7.34 (m, 5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ
chromatography (silica gel, dichloromethane/methanol = 20:1) to
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
give 12 (686 mg, 86%) as a pale yellow oil. [α]2D2 = –71.1 (c = 1.05,
1065 (C–O) cm–1. HRMS (ESI-TOF): calcd. for C8H18NO5 [M +
CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 1.87 (td, J = 6.3, H]+ 208.1185; found 208.1195.
12.8 Hz, 1 H, 4-H), 2.15, 2.18 (2 mc, 1 H, 4-H), 3.08 (s, 1 H, 7a-
Acid-Mediated Cyclisation of anti-2: In a procedure similar to that
H), 3.25 (br. s, 1 H, 7-OH), 3.36 (s, 3 H, OMe), 3.76 (d, J = 14.4 Hz,
1 H, CH2Ph), 3.80 (br. td, J ≈ 2.7, 12.2 Hz, 1 H, 3-H), 3.82 (dd, J
= 2.7, 11.8 Hz, 1 H, 6-CH2-), 4.24 (br. dd, J ≈ 0.9, 12.2 Hz, 1 H,
3-H), 3.90 (dd, J = 2.1, 11.8 Hz, 1 H, 6-CH2–), 4.13 (br. s, 1 H, 7-
H), 4.23 (dd, J ≈ 2.3, 4.3 Hz, 1 H, 6-H), 4.24 (d, J = 14.4 Hz, 1 H,
CH2Ph), 7.25–7.34 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
126 MHz): δ = 30.1 (t, C-4), 48.0 (q, OMe), 59.4 (t, CH2Ph), 62.5
(t, 6-CH2–), 65.9 (t, C-3), 75.7 (d, C-7a), 75.8 (d, C-7), 88.4 (d, C-
6), 105.5 (s, C-4a), 127.4, 128.2, 129.1, 135.8 (3 d, s, Ph) ppm. IR
used for the reaction of syn-5, a solution of anti-2 (473 mg,
1.41 mmol) in methanol (12 mL) was added to a solution of pTsCl
(134 mg, 0.70 mmol) in methanol (12 mL), and the mixture was
stirred for 1 d to yield a yellow oil. The crude products were puri-
fied by column chromatography (silica gel, hexane/ethyl acetate =
3:1 gradient to 1:1) to give 16 as the first eluted fraction (142 mg,
30 %, ca. 4:1 mixture of diastereomers), 17 as second fraction
(27 mg, 6%), and a mixture of 15 and 18 (243 mg) as the last frac-
tion. The last fraction was purified by a second column chromatog-
raphy (silica gel, dichloromethane/methanol = 25:1) to afford 18
(8 mg, 2%, Ͼ95% purity) and 15 (218 mg, 52%). An additional
purification of 16 by column chromatography (silica gel, dichloro-
methane/methanol = 98:2) gave 16 (117 mg, dr = 10:1, 25%) as a
colourless oil.
(ATR): ν = 3415 (O–H), 3085–2830 (=C–H, C–H), 1060 (C–O)
˜
cm–1. HRMS (ESI-TOF): calcd. for C15H21NNaO5 [M + Na]+
318.1317; found 318.1319.
(4aR,6S,7R,7aR)-7-Acetoxy-6-acetoxymethyl-1-benzyl-4a-methoxy-
hexahydro-1H-furano[3,2-c][1,2]oxazine (13): A solution of Ac2O
(0.12 mL, 1.30 mmol) in dichloromethane (6 mL) was added drop-
wise at 0 °C to a solution of 12 (93 mg, 0.31 mmol), Et3N (0.35 mL,
3.7 mmol) and DMAP (3.8 mg) in dry dichloromethane (6 mL).
The resulting mixture was stirred at room temp. overnight and
quenched with water, the organic layer was separated, and the
aqueous layer was extracted with three portions of dichlorometh-
ane (5 mL each). The combined organic layers were dried with
Na2SO4 and filtered, and the solvent was removed under reduced
pressure. Purification by column chromatography (silica gel, hex-
ane/ethyl acetate = 2:1) yielded product 13 (114 mg, 95 %) as a
colourless solid. M.p. 73–74 °C. [α]2D2 = –93.6 (c = 1.15, CHCl3).
1H NMR (CDCl3, 500 MHz): δ = 1.86 (td, J ≈ 6.5, 13.2 Hz, 1 H,
4-H), 2.07, 2.12 (2 s, 2ϫ 3 H, 2 Ac), 2.16 (br. dd, J ≈ 2.1, 13.2 Hz,
1 H, 4-H), 3.11 (s, 1 H, 7a-H), 3.32 (s, 3 H, OMe), 3.67 (d, J =
15.3 Hz, 1 H, CH2Ph), 3.77 (td, J ≈ 2.9, 12.0 Hz, 1 H, 3-H), 3.86
(br. dd, J ≈ 5.8, 12.0 Hz, 1 H, 3-H), 4.18 (dt, J ≈ 4.1, 6.3 Hz, 1 H,
6-H), 4.28 (dd, J = 6.3, 11.5 Hz, 1 H, CH2OAc), 4.40 (d, J =
15.3 Hz, 1 H, CH2Ph), 4.49 (dd, J = 4.4, 11.5 Hz, 1 H, CH2OAc),
4.83 (br. d, J ≈ 3.3 Hz, 1 H, 7-H), 7.23–7.26, 7.29–7.35 (2 m, 5 H,
Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 20.8, 21.0 (2 ϫ q,
2ϫAc), 30.6 (d, C-4), 47.8 (q, OMe), 59.4 (t, CH2Ph), 64.1 (t,
CH2OAc), 65.6 (t, C-3), 75.1 (d, C-7a), 77.0 (d, C-7), 80.6 (d, C-
6), 105.0 (s, C-4a), 127.0, 128.1, 128.2, 137.7 (3 d, s, Ph), 170.5,
(4aS,6S,7R,7aS)-1-Benzyl-6-hydroxymethyl-4a-methoxy-hexahydro-
1H-furano[3,2-c][1,2]oxazinan-7-ol (15): Colourless crystals. M.p.
140–141 °C. Crystals suitable for X-ray analysis were obtained by
slow evaporation of the solvent from an ethyl acetate solution.
[α]2D2 = +71.5 (c = 1.61, CHCl3). 1H NMR (CDCl3, 500 MHz): δ =
1.93 (ddd, J = 6.5, 9.7, 13.4 Hz, 1 H, 4-H), 2.03 (dt, J ≈ 3.6,
13.4 Hz, 1 H, 4-H), 2.36 (br. s, 1 H, CH2–OH), 2.90 (d, J = 6.7 Hz,
1 H, 7-OH), 3.16 (d, J = 4.9 Hz, 1 H, 7a-H), 3.30 (s, 3 H, OMe),
3.72 (br. d, J ≈ 11.7 Hz, 1 H, CH2–OH), 3.76 (d, J = 14.9 Hz, 1 H,
CH2Ph), 3.81 (br. dd, J ≈ 3.7, 11.7 Hz, 1 H, CH2–OH), 3.86 (ddd,
J = 3.4, 6.5, 11.5 Hz, 1 H, 3-H), 3.90 (ddd, J = 3.8, 9.7, 11.5 Hz,
1 H, 3-H), 4.30 (dt, J ≈ 4.2, 6.4 Hz, 1 H, 6-H), 4.54 (d, J = 14.9 Hz,
1 H, CH2Ph), 4.62 (dt, J ≈ 5.2, 6.4 Hz, 1 H, 7-H), 7.23–7.27, 7.30–
7.33, 7.32–7.40 (3 m, 5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 30.8 (t, C-4), 48.4 (q, OMe), 61.4 (t, CH2Ph), 63.5 (t, –CH2OH),
65.2 (t, C-3), 70.5 (d, C-7a), 73.4 (d, C-7), 84.1 (d, C-6), 105.3 (s,
C-4a), 126.9, 128.2, 128.3, 138.1 (3 d, s, Ph) ppm. IR (ATR): ν =
˜
3410 (O–H), 3090–2830 (=C–H, C–H), 1125, 1100, 1065, 1030 (C–
O) cm–1. HRMS (ESI-TOF): calcd. for C15H22NO5 [M + H]+
296.1492; found 296.1518. C15H21NO5 (295.3): calcd. C 61.00, H
7.17, N 4.74; found C 61.06, H 7.24, N 4.74.
(4aS,7S,8R,8aS)-1-Benzyl-4a-methoxy-7,8-O-isopropylidene-hexa-
hydro-1H,3H-pyrano[3,2-c][1,2]oxazine-7,8-diol (16): [α]2D2 = +26.4
(c = 0.25, CHCl3, dr = 10:1). 1H NMR (CDCl3, 500 MHz): δ =
1.37, 1.56 (2 s, 2ϫ 3 H, 2 Me), 2.08–2.16 (m, 1 H, 4-H), 2.26 (ddd,
J = 7.0, 11.7, 14.0 Hz, 1 H, 4-H), 2.83 (d, J = 2.5 Hz, 1 H, 8a-H),
3.28 (s, 3 H, OMe), 3.58 (d, J = 13.1 Hz, 1 H, 6-H), 3.69 (dd, J =
2.0, 13.1 Hz, 1 H, 6-H), 2.26 (ddd, J = 1.8, 7.0, 11.2 Hz, 1 H, 3-H),
3.90 (ddd, J = 3.6, 11.2, 11.7 Hz, 1 H, 3-H), 3.94 (d, J = 13.7 Hz, 1
H, CH2Ph), 4.23 (dd, J = 2.0, 7.8 Hz, 1 H, 7-H), 4.29 (d, J =
13.7 Hz, 1 H, CH2Ph), 4.68 (dd, J = 2.5, 7.8 Hz, 1 H, 8-H), 7.23–
7.27, 7.29–7.33, 7.40–7.44 (3 m, 5 H, Ph) ppm. 13C NMR (CDCl3,
126 MHz): δ = 24.6, 26.2 (2 q, 2 Me), 29.3 (t, C-4), 47.8 (q, OMe),
58.4 (t, CH2Ph), 61.6 (t, C-6), 63.7 (d, C-8a), 64.3 (t, C-3), 70.6 (d,
C-8), 74.6 (d, C-7), 96.6 (s, C-4a), 110.1 [s, O–C(CH3)2–O], 127.1,
170.8 (2 s, C=O) ppm. IR (ATR): ν = 3035–2825 (=C–H, C–H),
˜
1735 (C=O), 1235, 1055, 1035 (C–O) cm–1. HRMS (ESI-TOF):
calcd. for C19H25NNaO7 [M + Na]+ 402.1529; found 402.1535.
C19H25NO7 (379.4): calcd. C 60.15, H 6.64, N 3.69; found C 60.07,
H 6.49, N 3.69.
(2S,3R,4R,5R)-4-Amino-5-(2-hydroxyethyl)-2-hydroxymethyl-5-meth-
oxy-tetrahydrofuran-3-ol (14): Hydrogen was bubbled through a
stirred suspension of Pd/C (10 % Pd, 273 mg) in dry methanol
(25 mL) for 1 h. A solution of 12 (197 mg, 0.67 mmol) in methanol
(5 mL) was added, and the mixture was stirred at room temp. at
normal pressure (hydrogen balloon). After 22 h, the solution was
filtered through a short pad of Celite, and the solvent was removed
to give spectroscopically pure product 14 (131 mg, 95%) as a light
yellow oil. [α]2D2 = –66.8 (c = 1.20, MeOH). 1H NMR (CD3OD,
500 MHz): δ = 1.94 (dt, J = 7.3, 15.5 Hz, 1 H, 5-CH2–), 2.11 (dt,
J = 4.3, 15.5 Hz, 1 H, 5-CH2–), 3.21 (br. s, 1 H, 4-H), 3.23 (s, 3 H,
OMe), 3.82 (dd, J = 4.2, 11.8 Hz, 1 H, 2-CH2OH), 3.64–3.68 (m,
2 H, 5-CH2–CH2OH), 3.77 (dd, J = 2.7, 11.8 Hz, 1 H, 2-CH2OH),
3.82 (ddd, J = 2.7, 4.2, 4.8 Hz, 1 H, 2-H), 3.87 (dd, J = 2.2, 4.8 Hz,
128.2, 128.8, 137.4 (3 d, s, Ph) ppm. IR (ATR): ν = 3095–2825
˜
(=C–H, C–H), 1120, 1100, 1055, 1025, 1005 (C–O) cm–1. HRMS
(ESI-TOF): calcd. for C18H25NNaO5 [M + Na]+ 358.1625; found
358.1686.
(4aS,7S,8R,8aS)-1-Benzyl-4a-methoxy-hexahydro-1H,3H-pyrano-
[3,2-c][1,2]oxazine-7,8-diol (17): Colourless crystals. M.p. 144–
1 H, 3-H) ppm. 13C NMR (CD3OD, 126 MHz): δ = 32.6 (t, 5- 149 °C. [α]2D2 = +78.2 (c = 1.45, CHCl3). 1H NMR (CDCl3,
CH2–), 48.1 (q, OMe), 58.0 (t, 5-CH2–CH2OH), 62.3 (t, 2- 500 MHz): δ = 1.72 (td, J ≈ 5.6, 12.6 Hz, 1 H, 4-H), 2.02 (dt, J ≈
CH2OH), 66.0 (d, C-4), 79.6 (d, C-3), 86.1 (d, C-2), 111.0 (s, C-5)
1.9, 12.6 Hz, 1 H, 4-H), 2.41 (br. s, 1 H, 8-OH), 3.16 (br. d, J ≈
ppm. IR (ATR): ν = 3450–3220 (O–H, N–H), 2965–2835 (C–H), 3.3 Hz, 1 H, 8a-H), 3.25 (s, 3 H, OMe), 3.70 (d, J = 14.7 Hz, 1 H,
˜
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
l-Erythrose-Derived Nitrones in Syntheses of Polyhydroxylated Compounds
CH2Ph), 3.74 (mc, 1 H, 7-H), 3.80 (dd, J = 1.7, 11.9 Hz, 1 H, 6-
and tert-butylchlorodiphenylsilane (683 mg, 2.49 mmol) in dichlo-
H), 3.85 (ddd, J = 1.5, 5.6, 12.0 Hz, 1 H, 3-H), 3.87 (dd, J = 2.0, romethane (60 mL) were added dropwise at 0 °C to a solution of
11.9 Hz, 1 H, 6-H), 3.96 (td, J ≈ 2.4, 12.0 Hz, 1 H, 3-H), 4.55 (br. anti-2 (588 mg, 1.75 mmol) in dry dichloromethane (80 mL). The
s, 1 H, 7-OH), 4.58 (mc, 1 H, 8-H), 5.07 (d, J = 14.7 Hz, 1 H,
mixture was allowed to reach room temp. and stirred for 36 h.
Dichloromethane (40 mL) was added followed by H2O (80 mL),
CH2Ph), 7.22–7.25, 7.28–7.36 (2 m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 34.2 (t, C-4), 47.9 (q, OMe), 61.6 (t, and the layers were separated. The aqueous layer was extracted
CH2Ph), 66.3 (t, C-3), 66.4 (t, C-6), 68.5 (d, C-8), 69.8 (d, C-8a),
70.5 (d, C-7), 97.8 (s, C-4a), 126.9, 128.2, 128.7, 138.0 (3 d, s, Ph)
with dichloromethane (3ϫ 30 mL), the combined organic layers
were washed with brine (30 mL), dried (Na2SO4) and filtered, and
the solvents were removed in vacuo. Purification by column
chromatography (silica gel, hexane/ethyl acetate = 6:1) yielded 20
(0.782 g, 78%) as a colourless solid. M.p. 82–83 °C. [α]2D2 = +37.3
ppm. IR (ATR): ν = 3370 (O–H), 3060–2830 (=C–H, C–H), 1130,
˜
1080, 1065, 1055 (C–O) cm–1. HRMS (ESI-TOF): calcd. for
C15H21NNaO5 [M + Na]+ 318.1312; found 318.1371.
1
(c = 1.37, CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.08 (s, 9 H,
(4aR,7S,8R,8aS)-1-Benzyl-4a-methoxy-hexahydro-1H,3H-pyrano-
[3,2-c][1,2]oxazine-7,8-diol (18): Colourless crystals. M.p. 194–
198 °C (decomp.). [α]2D2 = +55.2 (c = 1.00, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.58 (ddd, J = 5.3, 12.7, 14.1 Hz, 1 H, 4-
H), 2.00 (dt, J ≈ 1.6, 14.1 Hz, 1 H, 4-H), 2.64 (d, J = 2.8 Hz, 1 H,
8a-H), 2.65 (br. d, J ≈ 10.7 Hz, 1 H, 7-OH), 3.31 (s, 3 H, OMe),
3.46 (t, J ≈ 10.9 Hz, 1 H, 6-H), 3.63–3.70 (m, 1 H, 7-H), 3.71 (d, J
= 14.2 Hz, 1 H, CH2Ph), 3.73 (dd, J = 5.9, 10.9 Hz, 1 H, 6-H),
3.86 (ddd, J = 1.3, 5.3, 11.7 Hz, 1 H, 3-H), 3.95 (br. td, J ≈ 2.2,
11.7 Hz, 1 H, 3-H), 4.18 (d, J = 9.9 Hz, 1 H, 8-OH), 4.23 (dt, J ≈
2.8, 9.9 Hz, 1 H, 8-H), 4.43 (d, J = 14.2 Hz, 1 H, CH2Ph), 7.24–
7.34, 7.40–7.43 (2 m, 5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 31.3 (t, C-4), 47.7 (q, OMe), 57.4 (t, CH2Ph), 59.9 (t, C-6), 65.7
(t, C-3), 66.5 (d, C-7), 67.3 (d, C-8), 67.9 (d, C-8a), 98.1 (s, C-4a),
TBS), 1.39, 1.48 (2 s, 2ϫ 3 H, 2 Me), 3.45 (br. s, 1 H, 3-H), 3.58
(s, 3 H, OMe), 3.76 (dd, J = 7.2, 11.1 Hz, 1 H, 5Ј-CH2–), 3.77, 3.93
(2 br. d, J = 13.7 Hz, 1 H each, CH2Ph), 4.08 (br. dd, J ≈ 1.7,
15.0 Hz, 1 H, 6-H), 4.14 (dd, J = 3.3, 11.1 Hz, 1 H, 5Ј-CH2–), 4.27
(br. d, J ≈ 15.0 Hz, 1 H, 6-H), 4.37 (ddd, J = 3.3, 6.3, 7.2 Hz, 1 H,
5Ј-H), 4.61 (br. t, J ≈ 6.8 Hz, 1 H, 4Ј-H), 4.71 (t, J ≈ 2.7 Hz, 1 H,
5-H), 7.15–7.21, 7.33–7.44, 7.71–7.75 (3 m, 15 H, Ph) ppm. 13C
NMR (CDCl3, 126 MHz): δ = 19.2, 26.8 (s, q, TBS), 25.4, 27.5 (2
q, 2 Me), 54.0 (q, OMe), 56.8 (t, CH2Ph), 60.6 (d, C-3), 61.2 (t, C-
6), 63.5 (t, 5Ј-CH2–), 77.0 (d, C-5Ј), 78.9 (d, C-4Ј), 90.7 (d, C-5),
108.2 (s, C-2Ј), 127.1, 127.52, 127.54, 128.1, 128.4, 129.5*, 133.4,
133.7, 135.6, 135.7, 136.9 (6 d, 2 s, 2 d, s, Ph), 151.2 (s, C-4) ppm;
* higher intensity. IR (ATR): ν = 3070–2850 (=C–H, C–H), 1675
˜
(C=C), 1220, 1110, 1070 (C–O) cm–1. HRMS (ESI-TOF): calcd.
127.1, 128.1, 129.1, 136.9 (3 d, s, Ph) ppm. IR (ATR): ν = 3460
˜
for C34H43NNaO5Si [M + Na]+ 596.2803; found 596.2818.
(O–H), 3060–2830 (=C–H, C–H), 1140, 1060, 1045, 1030 (C–O)
cm–1. HRMS (ESI-TOF): calcd. for C15H21NNaO5 [M + Na]+
318.1312; found 318.1331.
C
34H43NO5Si (573.8): calcd. C 71.17, H 7.55, N 2.44; found C
71.22, H 7.59, N 2.60.
(4aS,6S,7R,7aS)-1-Benzyl-6-(tert-butyldiphenylsiloxymethyl)-4a-
methoxy-hexahydro-1H-furano[3,2-c][1,2]oxazinan-7-ol (21): Ac-
cording to the procedure described for the reaction of syn-5, com-
pound 20 (1.89 g, 3.29 mmol) in methanol (12 mL) was added to a
solution of pTsCl (310 mg, 1.63 mmol) in methanol (12 mL), and
the mixture was stirred for 18 h to give – after purification by col-
umn chromatography (silica gel, hexane/ethyl acetate = 5:1, then
1:1) – compounds 21 (1.45 g, 82 %) and 15 (121 mg, 13 %) as
colourless oils.
(3S,4ЈR,5ЈS)-2-Benzyl-3-(5Ј-benzyloxymethyl-2Ј,2Ј-dimethyl-1Ј,3Ј-di-
oxolan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-[1,2]oxazine (19): Ag2O
(217 mg, 0.93 mmol) was added at room temp. to a solution of anti-
2 (103 mg, 0.31 mmol) in dry toluene (2 mL), and the mixture was
stirred for 1 h. Benzyl bromide (145 mg, 0.10 mL, 0.80 mmol) was
added in two portions (0.05 mL each, the second batch was added
after 24 h), and the mixture was heated at reflux for 2 d (TLC mon-
itoring). The mixture was filtered through a short Celite pad and
washed with dichloromethane, and the solvents were removed. The
1
resulting complex mixture was purified twice by column Analytical Data for 21: [α]2D2 = +43.9 (c = 1.15, CHCl3). H NMR
chromatography on silica gel (first: hexane/ethyl acetate = 3:1; sec-
ond: dichloromethane/methanol = 19:1) to give pure 19 (50 mg,
38%) as a colourless oil. [α]2D2 = +59.2 (c = 2.50, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.09 (s, 9 H, TBS), 1.88 (ddd, J = 6.9, 9.0,
13.3 Hz, 1 H, 4-H), 2.05 (dt, J ≈ 3.6, 13.3 Hz, 1 H, 4-H), 2.42 (br.
d, J ≈ 4.5 Hz, 1 H, OH), 3.20 (d, J = 4.9 Hz, 1 H, 7a-H), 3.22 (s,
(CDCl3, 500 MHz): δ = 1.37, 1.48 (2 s, 2ϫ 3 H, 2 Me), 3.24 (d, J 3 H, OMe), 3.80 (d, J = 14.8 Hz, 1 H, CH2Ph), 3.81 (dd, J = 6.3,
= 8.2 Hz, 1 H, 3-H), 3.31 (dd, J = 8.4, 10.4 Hz, 1 H, 5Ј-CH2–), 10.5 Hz, 1 H, 6-CH2–), 3.87–3.91 [m, 3 H, 3-H (2 H), 6-CH2– (1
3.60 (s, 3 H, OMe), 3.78 (dd, J = 2.8, 10.4 Hz, 1 H, 5Ј-CH2–), 3.86, H)], 4.30 (td, J ≈ 4.8, 6.3 Hz, 1 H, 6-H), 4.63 (d, J = 14.8 Hz, 1 H,
4.01 (2 d, J = 13.4 Hz, 1 H each, NCH2Ph), 4.19 (dd, J = 3.0,
CH2Ph), 4.72 (dt, J ≈ 4.9, 6.4 Hz, 1 H, 7-H), 7.26–7.48, 7.70–7.73
15.0 Hz, 1 H, 6-H), 4.38 (br. dt, J ≈ 1.7, 15.0 Hz, 1 H, 6-H), 4.41 (2 m, 15 H, 3 Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 19.2,
(d, J = 12.4 Hz, 1 H, OCH2Ph), 4.43 (ddd, J = 2.8, 5.9, 8.4 Hz, 1
H, 5Ј-H), 4.53 (d, J = 12.4 Hz, 1 H, OCH2Ph), 4.57 (dd, J = 5.9,
8.2 Hz, 1 H, 4Ј-H), 4.76 (t, J ≈ 2.7 Hz, 1 H, 5-H), 7.24–7.33 (m, 10
26.8 (s, q, TBS), 31.5 (t, C-4), 48.2 (q, OMe), 61.2 (t, CH2Ph), 65.2
(t, 6-CH2–), 65.4 (t, C-3), 69.7 (d, C-7a), 74.8 (d, C-7), 83.0 (d, C-
6), 104.8 (s, C-4a), 126.8, 127.7, 127.8, 128.1, 128.3, 129.8, 129.9,
H, 2 Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 25.6, 27.5 (2 q, 132.9, 133.0, 135.5, 135.6, 138.3 (7 d, 2 s, 2 d, s, Ph) ppm. IR
2 Me), 53.9 (q, OMe), 56.7 (t, NCH2Ph), 59.8 (d, C-3), 60.8 (t, C- (ATR): ν = 3445 (O–H), 3075–2825 (=C–H, C–H), 1115, 1065 (C–
˜
6), 69.0 (t, 5Ј-CH2), 73.2 (t, OCH2Ph), 77.3* (d, C-4Ј, C-5Ј), 90.6
(d, C-5), 108.6 (s, C-2Ј), 127.4, 127.5, 127.7, 128.28, 128.32, 129.1,
136.6, 138.2 (6 d, 2 s, 2 Ph), 150.9 (s, C-4) ppm; * higher intensity.
O) cm–1. HRMS (ESI-TOF): calcd. for C31H39NNaO5Si [M +
Na]+ 556.2495; found 556.2513.
(2S,3R,4S,5S)-4-Amino-5-(2-hydroxyethyl)-2-hydroxymethyl-5-meth-
oxy-tetrahydrofuran-3-ol (22): According to a procedure similar to
that used for 12, hydrogenolysis of 15 (230 mg, 0.69 mmol) in the
presence of Pd/C (10% Pd, 317 mg) for 24 h yielded 22 (140 mg,
99%, 97% purity) as a colourless oil. [α]2D2 = +31.3 (c = 1.51,
CH3OH). 1H NMR (CD3OD, 500 MHz): δ = 1.98 (dt, J = 7.5,
IR (ATR): ν = 3085–2830 (=C–H, C–H), 1675 (C=C), 1365, 1215,
˜
1075 (C–O) cm–1. HRMS (ESI-TOF): calcd. for C25H31NNaO5 [M
+ Na]+ 448.2094; found 448.2116. C25H31NO5 (425.5): calcd. C
70.57, H 7.34, N 3.29; found C 70.54, H 7.34, N 3.37.
(3S,4ЈR,5ЈS)-2-Benzyl-3-(5Ј-tert-butyldiphenylsiloxymethyl-2Ј,2Ј-di-
methyl-1Ј,3Ј-dioxolan-4Ј-yl)-4-methoxy-3,6-dihydro-2H-[1,2]oxazine 15.2 Hz, 1 H, 5-CH2–), 2.13 (dt, J = 4.7, 15.2 Hz, 1 H, 5-CH2–),
(20): Imidazole (180 mg, 2.65 mmol), DMAP (12 mg, 0.10 mmol) 3.21 (s, 3 H, OMe), 3.24 (br. d, J ≈ 5.3 Hz, 1 H, 4-H), 3.55 (dd, J
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
= 7.5, 11.6 Hz, 1 H, 2-CH2–), 3.62 (dd, J = 4.7, 7.5 Hz, 2 H, 5-
CH2–CH2OH), 3.71 (dd, J = 3.4, 11.6 Hz, 1 H, 2-CH2–), 3.94 (td,
(2S,3R,4S,5S)-3-Acetoxy-2-acetoxymethyl-4-benzylamino-5-meth-
oxy-5-(2-methoxyethyl)-tetrahydrofuran (25): In a procedure similar
J = 3.4, 7.5 Hz, 1 H, 2-H), 4.29 (br. t, J ≈ 6.3 Hz, 1 H, 3-H) ppm. to that used for 12, treatment of 24 (115 mg, 0.37 mmol) with Et3N
13C NMR (CD3OD, 126 MHz): δ = 33.2 (t, 5-CH2–), 48.3 (q, (0.35 mL, 3.7 mmol), DMAP (4.5 mg, 0.037 mmol) in dry dichloro-
OMe), 58.3 (t, 5-CH2–CH2OH), 60.6 (d, C-4), 65.4 (t, 2-CH2–), methane (8 mL) and a solution of Ac2O (0.15 mL, 1.58 mmol) in
73.1 (d, C-3), 84.5 (d, C-2), 111.2 (s, C-5) ppm. IR (ATR): ν = dichloromethane (10 mL) yielded – after purification by column
˜
3480–3195 (O–H, N–H), 2960–2850 (C–H), 1095, 1035 (C–O)
chromatography (silica gel, hexane/ethyl acetate = 1:1) – compound
cm–1. HRMS (ESI-TOF): calcd. for C8H18NO5 [M + H]+ 208.1185; 25 (122 mg, 83%) as a colourless oil. [α]2D2 = +14.4 (c = 1.15,
1
found 208.1184.
CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.98 (ddd, J = 5.5, 8.0,
14.3 Hz, 1 H, 5-CH2–), 1.98, 2.10 (2 s, 2ϫ 3 H, 2 Ac), 2.13 (ddd,
J = 6.7, 8.3, 14.3 Hz, 1 H, 5-CH2–), 3.14 (d, J = 7.0 Hz, 1 H, 4-
H), 3.22, 3.24 (2 s, 2ϫ 3 H, 2 OMe), 3.44 (ddd, J = 6.7, 8.0, 9.6 Hz,
1 H, –CH2–OMe), 3.44 (ddd, J = 5.5, 8.3, 9.6 Hz, 1 H, –CH2–
OMe), 3.66, 3.82 (2 d, J = 12.9 Hz, 1 H each, CH2Ph), 4.01 (br.
dd, J ≈ 3.4, 6.3 Hz, 1 H, 2-H), 4.17 (dd, J = 4.0, 11.7 Hz, 1 H, 2-
CH2–), 4.33 (dd, J = 3.3, 11.7 Hz, 1 H, 2-CH2–), 4.99 (dd, J = 2.5,
7.0 Hz, 1 H, 3-H), 7.22–7.34 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
126 MHz): δ = 20.7, 21.0 (2 q, Ac), 31.5 (t, 5-CH2–), 47.8 (q, 5-
OMe), 51.9 (t, CH2Ph), 58.3 (q, CH2OMe), 63.3 (d, C-4), 64.1 (t,
2-CH2–), 68.1 (t, CH2OMe), 71.6 (d, C-3), 81.0 (d, C-2), 105.9 (s,
C-5), 127.1, 128.3*, 139.9 (2 d, s, Ph), 170.5, 170.8 (2 s, C=O) ppm;
(E)-(4S,4ЈR,5ЈS)-4-Benzylamino-4-(5Ј-hydroxymethyl-2Ј,2Ј-dimeth-
yl-1Ј,3Ј-dioxolan-4Ј-yl)-3-methoxybut-2-en-1-ol (23): A solution of
anti-2 (316 mg, 0.94 mmol) in degassed tetrahydrofuran (30 mL)
was added dropwise at room temp. to a solution of samarium di-
iodide (ca. 0.1 m in tetrahydrofuran, 29 mL, ca. 2.9 mmol). The
mixture was stirred for 4 h and was then quenched with satd. aque-
ous sodium potassium tartrate solution (35 mL) and extracted with
three portions of diethyl ether (40 mL each). The combined organic
layers were dried (MgSO4) and filtered, and the solvents were re-
moved under reduced pressure to give spectroscopically pure 23 as
a yellow oil in quantitative yield. Filtration through a short silica
gel pad (hexane/ethyl acetate = 1:1) yielded 23 (275 mg, 87%) as a
* higher intensity. IR (ATR): ν = 3360 (N–H), 3085–2805 (=C–H,
˜
1
colourless oil. [α]2D2 = +18.6 (c = 1.18, CHCl3). H NMR (CDCl3,
C–H), 1740 (C=O), 1225, 1065, 1035 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C20H30NO7 [M + H]+ 396.2022; found 396.2023.
C20H29NO7 (395.4): calcd. C 60.74, H 7.39, N 3.54; found C 60.73,
H 7.39, N 3.65.
500 MHz): δ = 1.30, 1.38 (2 s, 2ϫ 3 H, 2 Me), 3.55 (d, J = 12.0 Hz,
1 H, CH2Ph), 3.61 (dd, J = 3.6, 11.6 Hz, 1 H, 5Ј-CH2–), 3.66 (d, J
= 12.0 Hz, 1 H, CH2Ph), 3.66 (s, 3 H, OMe), 3.74 (dd, J = 9.8,
11.6 Hz, 1 H, 5Ј-CH2–), 3.88 (d, J = 10.0 Hz, 1 H, 4-H), 4.01 (dd,
J = 7.7, 12.1 Hz, 1 H, 1-H), 4.13 (dd, J = 8.6, 12.1 Hz, 1 H, 1-H),
4.22 (dd, J = 6.3, 10.0 Hz, 1 H, 4Ј-H), 4.42 (ddd, J = 3.6, 6.3,
9.8 Hz, 1 H, 5Ј-H), 5.25 (br. t, J ≈ 8.2 Hz, 1 H, 2-H), 7.24–7.35 (m,
5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz): δ = 24.5, 27.2 (2 q,
2 Me), 50.9 (t, CH2Ph), 54.9 (q, OMe), 55.5 (d, C-4), 56.9 (t, C-1),
60.7 (t, 5Ј-CH2–), 76.4 (d, C-4Ј), 77.9 (d, C-5Ј), 101.7 (d, C-2), 108.1
(s, C-2Ј), 127.7, 128.7*, 137.8 (2 d, s, Ph), 155.9 (s, C-3) ppm;
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra of all synthesized
compounds.
Acknowledgments
Support of this work by the Foundation for Polish Science (post-
doctoral fellowship to M. J.), the Deutsche Forschungsgemein-
schaft, and Bayer Healthcare is most gratefully acknowledged. We
also thank Prof. I. Robina and the Ministerio de Ciencia e Innova-
ción (CTQ2008-01565) for supporting E. M.-C., and M. Royer (vis-
iting student from the École Nationale Supérieure de Chimie de
Lille) for his experimental help. Help by Dr. R. Zimmer and valu-
able discussions during the preparation of the manuscript are grate-
fully acknowledged.
* higher intensity. IR (ATR): ν = 3455–3250 (O–H, N–H), 3065–
˜
2830 (=C–H, C–H), 1660 (C=C), 1210, 1045 (C–O) cm–1. HRMS
(ESI-TOF): calcd. for C18H27NNaO5 [M + Na]+ 360.1781; found
360.1799.
(2S,3R,4S,5S)-4-Benzylamino-2-hydroxymethyl-5-methoxy-5-(2-
methoxyethyl)-tetrahydrofuran-3-ol (24): A solution of 23 (118 mg,
0.35 mmol) in methanol (3 mL) was treated with HCl in methanol
(3 n, 5 mL) and stirred at room temp. for 5 d. After quenching
with satd. NaHCO3 (8 mL), it was extracted with three portions of
dichloromethane (5 mL each). The combined organic layers were
dried (MgSO4) and filtered, and the solvents were removed under
reduced pressure. The crude product was purified on a short pad
of silica gel (dichloromethane/methanol = 25:1) to give 24 (95 mg,
87%) as a colourless oil. [α]2D2 = +10.2 (c = 1.05, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.88 (dt, J ≈ 4.7, 14.7 Hz, 1 H, 5-CH2–),
2.19 (ddd, J = 5.6, 8.8, 14.7 Hz, 1 H, 5-CH2–), 2.89 (br. s, 3 H, 2
OH, NH), 3.14 (d, J = 5.9 Hz, 1 H, 4-H), 3.18 (s, 3 H, CH2OMe),
3.25 (s, 3 H, 2-OMe), 3.28–3.38 (m, 2 H, CH2OMe), 3.62 (dd, J =
2.5, 12.0 Hz, 1 H, 2-CH2–), 3.73 (d, J = 12.8 Hz, 1 H, CH2Ph),
3.75 (dd, J = 2.8, 12.0 Hz, 1 H, 2-CH2–), 3.94 (d, J = 12.8 Hz, 1
H, CH2Ph), 4.04 (mc, 1 H, 2-H), 4.06 (dd, J = 2.3, 5.9 Hz, 1 H, 3-
H), 7.23–7.27, 7.30–7.38 (2 m, 5 H, Ph) ppm. 13C NMR (CDCl3,
126 MHz): δ = 30.9 (t, 5-CH2–), 47.7 (q, 5-OMe), 52.0 (t, CH2Ph),
58.4 (q, CH2OMe), 63.0 (t, 2-CH2–), 63.5 (d, C-4), 68.2 (t,
–CH2OMe), 70.7 (d, C-3), 86.8 (d, C-2), 107.3 (s, C-5), 127.1, 128.3,
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84, 23–36; b) F. Pfrengle, H.-U. Reissig, Chem. Soc. Rev. 2010,
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128.5, 139.9 (3 d, s, Ph) ppm. IR (ATR): ν = 3500–3295 (O–H, N–
˜
H), 3060–2810 (=C–H, C–H), 1105, 1050, 1025 (C–O) cm–1
.
HRMS (ESI-TOF): calcd. for C16H26NO5 [M + H]+ 312.1811;
found 312.1797. C16H25NO5 (311.4): calcd. C 61.72, H 8.09, N
4.50; found C 61.66, H 8.16, N 4.45.
12
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
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[18] The tests were performed under standard conditions in water/
methanol solutions (100:1.7).
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Received: February 9, 2012
Published Online: ᭿
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13

Job/Unit: O20158
/KAP1
Date: 02-05-12 18:45:33
Pages: 14
M. Jasin´ski, D. Lentz, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
Heterocyclic Chemistry
M. Jasin´ski, D. Lentz, E. Moreno-Clavijo,
H.-U. Reissig* ................................. 1–14
Application of l-Erythrose-Derived Nitro-
nes in the Synthesis of Polyhydroxylated
Compounds via 3,6-Dihydro-2H-1,2-ox-
azine Derivatives
Depending on the protection of the starting
l-erythrose-derived nitrone, the addition of
lithiated methoxyallene leads to the forma-
tion either of anti- or of syn-configured 1,2-
oxazine derivatives. Subsequent hydrobor-
ation also proceeds with excellent stereo-
selectivity. The high synthetic value is dem-
onstrated by conversion of the resulting in-
termediates into amino polyols.
Keywords: 1,2-Oxazines / N-Glycosyl hy-
droxylamines / Amino alcohols / Hydro-
boration / Azasugars / Furans / Lithiation /
Allenes
14
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