Synthesis of a Series of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles from an L -Erythrose-Derived Nitrone and Alkoxyallenes

Article abstract of DOI:10.1002/ejoc.201301406

Two different lithiated alkoxyallenes and the enantiopure L-erythrose-derived cyclic nitrone (+)-3 were used as precursors for the preparation of novel bicyclic 2H-1,2-oxazine derivatives, which were formed as single diastereomers. A highly stereoselective hydroboration/oxidation sequence provided key substrates that were suitable for the synthesis of a series of polyhydroxylated bicyclic N-heterocycles, including unique 5-oxaindolizidines such as 8 and 12. Depending on the protecting groups installed, a straightforward ring-opening/recyclization protocol allowed the preparation of the corresponding pyrrolizidines bearing two, three or four free hydroxy groups. By inversion of the order of reaction steps, the synthesis of novel isomeric azabicyclo[3.2.0]heptane derivatives that are the lower homologues of pyrrolizidines and indolizidines were achieved. The prepared novel polyhydroxylated compounds were examined for their property as glycosidase inhibitors, but none of the compounds showed noteworthy activity. The use of lithiated alkoxyallenes and L-erythrose-derived nitrone allowed the synthesis of enantiopure bicyclic 1,2-oxazine derivatives as key intermediates. Their straightforward conversions led to a series of enantiopure polyhydroxylated oxaindolizidines, pyrrolizidines and novel bicyclic compounds incorporating an azetidine ring.

Full text of DOI:10.1002/ejoc.201301406

FULL PAPER
DOI: 10.1002/ejoc.201301406
Synthesis of a Series of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
from an -Erythrose-Derived Nitrone and Alkoxyallenes
L
Marcin Jasin´ski,[a][‡] Elena Moreno-Clavijo,[b][‡‡] and Hans-Ulrich Reissig*[a]
Dedicated to Professor Dr. Peter Metz on the occasion of his 60th birthday
Keywords: Allenes / Nitrogen heterocycles / Fused-ring systems / Diastereoselectivity / Samarium / 1,2-Oxazines
Two different lithiated alkoxyallenes and the enantiopure
erythrose-derived cyclic nitrone (+)-3 were used as precur-
L
-
ring-opening/recyclization protocol allowed the preparation
of the corresponding pyrrolizidines bearing two, three or four
sors for the preparation of novel bicyclic 2H-1,2-oxazine de- free hydroxy groups. By inversion of the order of reaction
rivatives, which were formed as single diastereomers. A
highly stereoselective hydroboration/oxidation sequence
provided key substrates that were suitable for the synthesis
of a series of polyhydroxylated bicyclic N-heterocycles, in-
steps, the synthesis of novel isomeric azabicyclo[3.2.0]hept-
ane derivatives that are the lower homologues of pyrrolizid-
ines and indolizidines were achieved. The prepared novel
polyhydroxylated compounds were examined for their prop-
cluding unique 5-oxaindolizidines such as 8 and 12. De- erty as glycosidase inhibitors, but none of the compounds
pending on the protecting groups installed, a straightforward
showed noteworthy activity.
tion patterns, we turned our attention to nitrones of the l-
erythrose series (Figure 1).
Introduction
The high synthetic potential of enantiomerically pure
3,6-dihydro-2H-1,2-oxazine derivatives for the preparation
of functionalized compounds has been demonstrated in a
series of recent publications dealing with N- and O-hetero-
cyclic carbohydrate mimetics, neuraminic acid derivatives,
and other natural products and their analogues.[1] A variety
of 2H-1,2-oxazines is easily accessible by [3+3]-cyclization
of lithiated alkoxyallenes and nitrones and, in the case of
enantiomerically pure carbohydrate-derived precursors, the
reaction generally proceeds in a highly stereoselective fash-
ion.[2] Because the stereochemical outcome could be diversi-
fied either by the use of additives (suitable Lewis acid as
a precomplexing agent)[2c] or appropriately functionalized
substrates (chelation due to free hydroxy groups of the
nitrone),[2d] both possible diastereomers are often readily
accessible. In our search for 1,2-oxazines with new substitu-
Figure 1. l-Erythrose-derived nitrone equivalent 1 and nitrones 2
and 3.
Whereas compound 1, which can be regarded as a
masked nitrone, yielded enantiopure amino- and aza-sugar
derivatives in a few relatively simple steps including key ad-
dition of lithiated alkoxyallenes,[2d] the use of 2, bearing a
removable carbohydrate-derived chiral auxiliary, enabled
the synthesis of various 1,2-oxazine derivatives lacking a
substituent at the nitrogen atom.[3] In light of the fact that
additions of lithiated alkoxyallenes described for selected
five-membered[2b] and six-membered[4] cyclic nitrones occur
with excellent anti stereoselectivity, l-erythrose-originated
nitrone (+)-3 should be an ideal candidate for the prepara-
tion of enantiopure bicyclic 1,2-oxazine derivatives and,
therefore, a platform that should open several options for
the synthesis of more complex structures. According to de-
tailed studies on monocyclic 1,2-oxazines, functionalization
of the electron-rich enol ether double bond should be
possible in a highly stereoselective manner. For instance,
cyclopropanation,[5] bromination,[6] and the more exten-
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
http://www.bcp.fu-berlin.de/chemie/chemie/forschung/
OrgChem/reissig/index.html
[b] Departamento de Química Orgánica, Facultad de Química,
Universidad de Sevilla,
Prof. García González 1, 41012 Seville, Spain
[‡] Present address: Department of Organic and Applied Chemis-
try, University of Łódz´,
Tamka 12, 91-403 Łódz´, Poland
[‡‡] Responsible for glycosidase inhibition tests
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301406.
442
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Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
sively studied hydroxylation[1h,2d,3,7] reactions are well docu-
mented. In the latter case, the hydroboration/oxidation pro-
tocol led to enantiopure 5-hydroxy-1,2-oxazines, which
could be subsequently converted into pyrrolidine[7a] and
azetidine[7b] derivatives depending on the step sequence, as
shown in Figure 2. By applying these methodologies to bi-
cyclic 1,2-oxazines, the corresponding azabicyclic analogues
should be accessible in a straightforward manner.
Scheme 1. Synthesis of bicyclic 1,2-oxazine 5 by addition of
lithiated methoxyallene to l-erythrose-derived nitrone (+)-3:
(a) lithiated methoxyallene (2.8 equiv.), THF, –78 °C, 2 h; (b) Et2O,
MgSO4, room temp., 36 h.
nitroso-ene fragmentation of bicyclic intermediate 4 as pre-
viously observed and discussed for the allenyl-hydroxyl-
amines derived from acyclic nitrones.[2c]
The novel bicyclic 1,2-oxazine 5 reacted cleanly with
BH3·THF complex; however, the use of a higher excess of
hydroboration reagent (6.0 equiv.) was necessary for com-
plete conversion. After a standard oxidative workup, the
desired hydroxylated 1,2-oxazine derivative 7 was isolated
as the only product in excellent yield (Scheme 2). Further
acid-induced removal of the acetonide moiety provided the
tetrahydroxylated bicyclic product 8 as the monomethyl
ether. As shown in Scheme 2, the synthesis of the respective
C-3 epimer (epi-8) was possible by an oxidation/reduction
sequence, by analogy to previous studies on hydroxylated
1,2-oxazines.[1h] Thus, treatment of 7 with Dess–Martin
periodinane followed by reduction of the crude ketone by
the bulky L-Selectride afforded epi-7 in moderate yield
(51%) and excellent diastereoselectivity. Deprotection pro-
vided bicyclic 1,2-oxazine epi-8 in good yield. The hydroxyl-
ated pyrrolidine derivative 9 was efficiently prepared as its
hydrochloride through reductive ring-opening of 8 by
hydrogenolysis using palladium on charcoal as catalyst.
Figure 2. General strategies for the synthesis of pyrrolidine and az-
etidine derivatives by exploiting 2H-1,2-oxazines as key substrates.
In this report, the reactions of (+)-(3R,4S)-3,4-isopropyl-
idenedioxypyrroline 1-oxide [(+)-3] with two model allenes
bearing methoxy or 2-(trimethylsilyl)ethoxy (TMSEO) sub-
stituents, leading to novel bicyclic 1,2-oxazine derivatives,
are described. Their hydroxylations followed by further
transformations into “izidine alkaloid”[8] analogues by ex-
ploiting the two reactive sites of the 2H-1,2-oxazine skel-
eton (enol ether moiety and N–O bond) are also discussed.
Results and Discussion
The starting nitrone (+)-3 was prepared in 54% overall
yield from the corresponding O-isopropylidene-l-erythrose
by the method of Goti and co-workers, based on condensa-
tion with hydroxylamine and subsequent esterification with
methanesulfonyl chloride.[9] The required l-erythronolactol
was readily synthesized in a one-pot procedure from com-
mercial l-arabinose according to a literature report.[10] The
reactions of (+)-3 were conducted by using an excess of
lithiated methoxyallene (typically ca. 3 equiv.), at –78 °C in
tetrahydrofuran, and delivered the corresponding allenyl-
hydroxylamine 4 in excellent diastereoselectivity as depicted
in Scheme 1. However, unstable adduct 4 could not be iso-
lated in pure form, because upon stirring with the drying ii. NaOH, H2O2, –10 °C to room temp., overnight; (b) Dess–Martin
periodinane (3.1 equiv.), CH2Cl2, room temp., 48 h; (c) L-Se-
agent MgSO4 in dilute ethereal solution it slowly cyclized
within 36 h to furnish the desired bicyclic 1,2-oxazine 5.
Purification by short-column chromatography enabled iso-
24 h.
lation of the pure product as a colorless crystalline material
Scheme 2. Synthesis of polyhydroxylated 1,2-oxazines 8, epi-8, and
pyrrolidine 9 via hydroxylated 1,2-oxazine 7. Reagents and condi-
tions: (a) i. BH3·THF (6.0 equiv.), THF, –30 °C to room temp., 3 h;
lectride, THF, –78 °C, 3 h; (d) 0.5 n HCl, MeOH, room temp.,
30 min; (e) H2, Pd/C, MeOH, satd. methanolic HCl, room temp.,
in high yields (80%) on a gram scale (up to 3 g).
To prepare the fully deprotected analogue of 8, lithiated
In all experiments, small amounts (usually ca. 5–10%) of TMSE-allene was used as the starting material, which, after
a complex mixture of isomeric diene aldoximes 6 [(E)/(Z)- reaction with (+)-3, delivered the expected bicyclic product
alkenes in a 94:6 ratio, each existing as a ca. 2:1 mixture of 10 (Scheme 3). Subsequent installation of the hydroxy
(E)/(Z)-aldoximes] were isolated as the more polar frac- group followed by exhaustive deprotection afforded the de-
tion.[11] Compounds 6 were formed as a result of a retro- sired tetrahydroxylated derivative 12 in high overall yield
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M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
(59%). The final step was achieved by using acidic ion ex- the desired pyrrolizidines (35–45%). Further attempts to
change resin DOWEX-50. Although the acetonide cleavage optimize the reaction conditions with respect to tempera-
proceeded smoothly within a few hours, complete removal ture and dilution gave no improved results.
of the TMSE protecting group required a prolonged reac-
tion time of 3 d at slightly enhanced temperatures (50 °C).
Scheme 4. Ring opening/recyclization strategy to pyrrolizidine de-
rivatives of type 15. Reagents and conditions: (a) NaH, BnBr,
DMF, 0 °C to room temp., overnight; (b) TBSCl, imidazole,
DMAP, CH2Cl2, 0 °C to room temp., 6 h; (c) SmI2, THF, room
temp., 3 h; (d) MsCl (1.1 equiv.), pyridine, 0 °C to room temp.,
24 h.
Scheme 3. Synthesis of tetrahydroxylated hexahydropyrrolo[1,2-
b][1,2]oxazine derivative 12 by use of lithiated 2-(trimethylsilyl)-
ethoxyallene. Reagents and conditions: (a) lithiated TMSE-allene
(3.0 equiv.), THF, –78 °C, 3 h, then MgSO4, room temp., 36 h;
(b) i. BH3·THF (5.9 equiv.), THF, –30 °C to room temp., 3 h;
ii. NaOH, H2O2, –10 °C to room temp., overnight; (c) DOWEX-
50, EtOH, 50 °C, 3 d.
The deprotection/functionalization steps of the hydroxy
groups present in the pyrrolizidines of type 15 are summa-
rized in Scheme 5. As expected, treatment of 15a by meth-
anolic HCl afforded dihydroxypyrrolizidine 16a, which was
obtained as a colorless crystalline material, but which suf-
fered rapid decomposition at room temperature as well as in
the presence of moisture. To our surprise, freshly prepared
compound 16a also underwent degradation during an at-
tempted debenzylation reaction, presumably due to the
cleavage of C–N bonds. For instance, not only the use of
reactive Raney-Ni but also milder reducing agents, for ex-
ample, hydrogen gas (Pd/C, balloon pressure) or catalytic
hydrogen-transfer reagents[17] (ammonium formate/Pd cata-
lyst) led to complex mixtures of inseparable products. Thus,
the desired trihydroxypyrrolizidine 16b was prepared from
15b by simultaneous acid-mediated removal of both the
acetonide moiety and the tert-butyldimethylsilyl group.
Because the polyhydroxylated azabicyclic compounds
containing quinolizidine, indolizidine, and pyrrolizidine
scaffolds are widely distributed in nature and exhibit a vari-
ety of biological activities, including antimicrobial, analge-
sic, and strong glycosidase inhibition properties,[12] highly
functionalized and easily accessible bicyclic 1,2-oxazines
such as 8 and 12 (which are formally 5-oxaindolizidine ana-
logues) should also be considered as potentially bioactive
compounds (see below). On the other hand, synthetically
challenging but highly attractive structures of simple izidine
alkaloids result in a constantly growing number of strate-
gies employed for the construction of their skeletons.[12b,13]
For example, elegant syntheses of loline, swainsonine, am-
phorogynine C, australine, lentiginosine as well as other
pyrrolizidine and indolizidine analogues have recently been
reported.[14] Similarly, the carbapenem family and related
classes of antibiotics that contain an azabicyclo[3.2.0]hept-
ane motif has been the focus of particular interest.[15] For
this reason, we concentrated on hydroxylated 1,2-oxazine
derivatives 7 and 11 as potentially useful substrates in the
synthesis for such N-bridged bicyclic compounds and, in
particular, for fused pyrrolidine and azetidine rings.
As depicted in Scheme 4, the free hydroxy group of 1,2-
oxazine 7 could easily be converted into benzyl ether 13a
or silyl ether 13b to afford suitably protected substrates for
an anticipated ring-opening/recyclization protocol (Fig-
ure 2). According to previous reports on chemoselective N–
O bond cleavage of tetrahydro-2H-1,2-oxazine derivatives
and also other heterocycles,[1f,1h,7,16] treatment of 13a,b with
an excess of samarium diiodide cleanly furnished the de-
sired amino alcohols 14a,b almost quantitatively. Subse-
quent mesylation of the primary hydroxy group followed by
spontaneous SN2-type ring-closure afforded the pyrrolizid-
Scheme 5. Deprotection/functionalization of the hydroxy groups in
15a,b: Reagents and conditions: (a) 1 n HCl, MeOH, room temp.,
32 h; (b) DOWEX-50, EtOH, 50 °C, 24 h; (c) Ac2O, Et3N, DMAP,
room temp., 24 h.
The assignments and the relative configurations at the
ine derivatives 15a and 15b in acceptable yields of 60 and newly generated stereogenic centers at C-6, C-7 and C-7a
64%, respectively. Although in both cases the use of of 15b were established on the basis of the 1H NMR spectra
1.1 equiv. of MsCl gave the desired products 15, ac- of the parent compound supported by NMR analysis of its
companied not only by small amounts of N,O-dimesylated peracetylated analogue 16c. The anti attack of the lithiated
compounds derived from 14 (ca. 15–20%) but also by traces alkoxyallene (with respect to the acetonide moiety) followed
of starting material (up to 15%), the use of a higher excess by hydroboration from the sterically less hindered top side
of MsCl (Ͼ1.3 equiv.) significantly diminished the yield of should place the 7-H/7a-H/1-H atoms in a relative cis/trans
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Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
orientation. The coupling constants of J = 2.9 Hz and J = in the presence of weaker bases such as triethylamine and
1.8 Hz observed for 7-H/7a-H (16b and 16c, respectively) pyridine no conversion could be observed even after weeks,
and the coupling constant of J = 7.1 Hz noted for 7a-H/1- in the case of the strong bases (tBuOK or NaH), rapid de-
H (both compounds) was consistent with that assumption. gradation of the acetonide group was observed.
Finally, the fully deprotected tetrahydroxylated pyrroliz-
idine 20 was prepared in moderate overall yield (39%) in an
analogous four-step sequence by starting from 1,2-oxazine
derivative 11 (Scheme 6). As expected, the presence of the
acid-labile TMSE substituent derived from the starting
allene enabled exhaustive deprotection of all OH groups in
one step by using DOWEX ion-exchange resin in nearly
quantitative yield. A significant resistance of the TBDPS
group under the conditions applied was observed. After 4 d
at 65 °C, along with desired product 20, ca. 10% of the
respective intermediate still bearing the TBDPS group was
found in the mother liquor. Stirring of the mixture in the
presence of the ion-exchange resin for an additional 2 d af-
forded pure pyrrolizidine 20, which is a known inhibitor of
moderate activity specific towards Rhizopus mold amylo-
glucosidase.[18]
Scheme 7. Preparation of mesylates 24a,b: Reagents and condi-
tions: (a) SmI2, THF, room temp., 3 h; (b) MsCl, Et3N, CH2Cl2,
0 °C to room temp., 30 min; (c) HCO2NH4, Pd/C, MeOH, reflux,
1.5 h; (d) H2 (balloon pressure), Pd/C, MeOH, room temp., over-
night; (e) TBSCl, imidazole, DMAP, CH2Cl2, 0 °C to room temp.,
24 h.
As a result of these failures, we changed the strategy and
attempted to install the mesyl group first and then re-
ductively cleaved the 1,2-oxazine ring. After the mesyl
group was introduced to 7, the respective ester 22a was then
subjected to Pd-catalyzed N–O bond cleavage as depicted
in Scheme 7. Either under hydrogen or by using ammonium
formate as a source for catalytic hydrogen transfer, the de-
sired product 23a could be prepared in good yields (71 and
63%, respectively). However, a significant deacceleration of
the reaction progress, very likely due to a poisoning pro-
cesses, required high loadings of the palladium catalyst (up
to 30 mol-%) in both experiments. It should be noted that
an attempted synthesis of 23a by treatment of 22a with sa-
marium diiodide resulted in complete degradation of the
Scheme 6. Synthesis of tetrahydroxylated pyrrolizidine 20. Reagents
and conditions: (a) TBDPSCl, imidazole, DMAP, CH2Cl2, 0 °C to
room temp., 20 h; (b) SmI2, THF, room temp., 3 h; (c) MsCl
(1.1 equiv.), pyridine, 0 °C to room temp., overnight; (d) DOWEX-
50, EtOH, 65 °C, 6 d.
In analogy to the methodology applied for monocyclic mesylate. This observation is consistent with recent reports
1,2-oxazines (Figure 2), precursors of type 24 should also on SmI2-promoted deprotections of tosylamides and their
be suitable for conversion into bicyclic azetidine deriva- respective esters.[21] To decrease the polarity and to simplify
tives.[19] The key steps are ring opening, subsequent regiose- the purification of the cyclization product, the free hydroxy
lective silylation, mesylation and recyclization to the four- group of 23a was protected to afford TBS ether 24a in good
membered ring. Treatment of 7 with SmI2 afforded expected yield.
pyrrolidine 21 in high yield (Scheme 7). However, the at-
It is also worth mentioning that, similar to the other tri-
tempted selective silyl protection of the terminal hydroxy cyclic hexahydro-1,2-oxazine derivatives (7, epi-7, 11, 13a,
group was difficult. For example, reaction of 21 with stoi- and 13b), the NMR spectra of mesylates 22a,b recorded at
chiometric amounts of TBSCl provided a complex mixture room temperature show two sets of signals attributed to the
of the two monosilylated products (65%, ca. 1:1) along with 1,2-oxazine ring, which is very likely due to the rigidity
the disilylated derivative (17%) and unconsumed starting caused by the acetonide moiety. For this reason, the NMR
material (9%). An attempted separation of the desired re- spectra of all the compounds mentioned above were mea-
gioisomer by column chromatography was not successful. sured at 80 °C (coalescence points at ca. 60 °C) as [D6]-
Similarly, the more bulky TBDPSCl reagent yielded an in- DMSO solutions.
separable mixture of both possible mono(silyl ethers) (com-
The crucial ring closure leading to enantiopure azetidine
bined yield 91%, ca. 1:1 ratio). The observed unexpected derivative 25a was found to be highly sensitive to the
enhanced nucleophilicity of the secondary hydroxy group applied reaction temperature. No cyclization could be ob-
may result from activation due to its close proximity to the served by heating 24a in pyridine at 65 °C for 3 d, whereas
pyrrolidine nitrogen atom. An attempted preparation of the higher temperatures (above 100 °C) resulted in significant
monosilylated derivative of 21 by base-induced migration decomposition of the starting material, and only traces of
of the TBS group[20] in 14b was also unsuccessful. Whereas the desired product could be detected. As shown in
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M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
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Scheme 8, running the reaction at 90 °C for 60 h provided The findings described here nicely supplement our recently
the target compound 25a in a moderate yield of 38%, iso- published approach to the pyrrolizidine alkaloids casuarine
lated as analytically pure sample after a single chromato- and australine.[24]
graphic purification. Subsequent deprotection on an ion ex-
change resin afforded polyhydroxylated derivative 26a as a
Experimental Section
stable crystalline solid. As expected for the more strained
1
heterocyclic system, in the H NMR spectrum of 26a the
General Methods: Reactions were generally performed under argon
in flame-dried flasks. Solvents and reagents were added by using a
syringe. Solvents were purified with an MB SPS-800-dry solvent
system. Freshly distilled pyridine and triethylamine were stored
over KOH under argon. Other reagents were purchased and used
as received without further 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 600, AVIII 700) or JOEL (ECX 400,
Eclipse 500) instruments. Chemical shifts are reported relative to
TMS or solvent residual peaks [1H: δ = 0.00 ppm (TMS), δ =
2.50 ppm ([D6]DMSO), δ = 3.31 ppm (CD3OD), δ = 7.26 ppm
(CDCl3); 13C: δ = 39.5 ppm ([D6]DMSO), δ = 49.0 ppm (CD3OD),
δ = 77.0 ppm (CDCl3)]. Integrals are in accordance with assign-
ments, and coupling constants J are given in Hz. All 13C NMR
spectra are proton-decoupled. For detailed peak assignments, 2D
spectra were measured (COSY, HMQC, HMBC). IR spectra were
measured with a Nexus FTIR fitted with a Nicolet Smart Dura-
Sample IR ATR spectrometer, an AVATAR 320 FTIR Nicolet IR
spectrometer, or with an FTIR NEXUS spectrometer (as KBr pel-
lets). MS and HRMS analyses were performed with a Varian Ion-
spec QFT-7 instrument (ESI-FT ICRMS) or with a Finnigan
MAT-95 instrument. Elemental analyses were obtained with a Va-
rio EL or a Vario EL III (Elementar Analysensysteme GmbH) in-
strument. Melting points were determined in capillaries with a
Reichert apparatus (Thermovar) or with a MEL-TEMP II appara-
tus (Aldrich) and are uncorrected. Optical rotations ([α]D) were de-
termined with a Perkin–Elmer 241 polarimeter at the temperatures
given.
signals of the azetidine protons 5-H and 7-H adjacent to
the bridged nitrogen atom were found at lower field (e.g.,
in comparison to the isomeric pyrrolizidine 16b; 26a: δ =
3.84 ppm, dd, J5H–6H = 1.1 Hz, J5H–1H = 5.4 Hz; 16b: δ =
3.77 ppm, td, J ≈ 3.9, 6.5 Hz).
Scheme 8. Synthesis of enantiopure polyhydroxylated azabi-
cyclo[3.2.0]heptane derivatives 26: Reagents and conditions:
(a) pyridine, 90 °C, 60 h; (b) DOWEX-50, EtOH, 50 °C, 24 h (for
25a), 70 °C, 20 h (for 25b).
The final synthesis of tetrahydroxy-substituted derivative
26b was accomplished in an analogous manner. After
alcohol 11 was converted into the corresponding mesylate
24b in an overall yield of 65% (Scheme 7), subsequent cycli-
zation reaction provided azetidine derivative 25b (43%
yield; Scheme 8). The surprisingly high stability of the final
product allowed us to run the deprotection step at even
higher temperatures (70 °C), and after 20 h, 26b was iso-
lated as a single product in almost quantitative yield.
Compounds 8, epi-8, 9, 12, 16b, 26a, and 26b prepared in
this investigation were tested for their glycosidase inhibitor
activity as 1 mm methanolic or aqueous solutions towards
eleven commercially available enzymes.[22] Unfortunately,
none of the examined compounds showed meaningful in-
hibition.
(4aS,5R,6S)-5,6-Isopropylidenedioxy-4-methoxy-4a,5,6,7-tetra-
hydro-2H-pyrrolo[1,2-b][1,2]-oxazine (5): Lithiated methoxyallene
was generated under dry argon by treating a solution of methoxy-
allene (1.35 g, 1.50 mL, 19.3 mmol) in anhydrous tetrahydrofuran
(100 mL) with nBuLi (2.5 m in hexane; 6.6 mL, 16.5 mmol) at
–40 °C. After 5 min, a solution of nitrone (+)-3 (0.93 g, 5.92 mmol)
in tetrahydrofuran (50 mL) was added slowly at –78 °C. The mix-
ture was stirred at this temperature for 2 h, and then quenched by
the addition of water. The mixture was warmed to room temp.,
then extracted with diethyl ether (3ϫ 75 mL), and the organic layer
was stirred with MgSO4 for 36 h. After cyclization of the primarily
formed allenyl adduct was complete (TLC monitoring; hexane/
ethyl acetate, 4:1; p-anisaldehyde stain), the solvents were removed
under reduced pressure. The crude mixture was purified by
chromatography (SiO2; hexane/acetone, 6:1) to give 1,2-oxazine 5
(1.07 g, 80%, first eluted) as a colorless solid and a mixture of
dienes 6 (87 mg, 6%, second eluted) as a pale-yellow oil. Additional
purification of 6 by column chromatography (SiO2; hexanes/acet-
one, 6:1) gave the major diene (53 mg, 4%) as an inseparable mix-
ture of (E)- and (Z)-aldoximes (ca. 2:1 ratio) as a colorless semi-
solid.
Conclusions
Our methodology, which exploits enantiomerically pure
bicyclic 2H-1,2-oxazines, offers excellent and flexible access
to highly functionalized 5-oxaindolizidine and pyrrolizidine
derivatives. In addition, new bicyclic compounds incorpo-
rating an azetidine moiety could be prepared for the first
time. The reliable key steps are highly stereoselective ad-
dition of suitably substituted lithiated alkoxyallenes to an l-
erythrose-derived nitrone (+)-3, subsequent hydroboration/
oxidation and reductive ring-opening followed by ring clo-
sure. Although single steps had to be optimized, the overall
sequences are straightforward and efficient, clearly demon-
strating the practicability of this approach to novel enantio-
pure polyhydroxylated N-heterocycles. These are of interest
as biologically active compounds, for example as glycosi-
dase inhibitors and inflammatory agents.[23] The described
concept should have general importance, because other
Data for 1,2-Oxazine 5: M.p. 61–62 °C; [α]2D2 = +91.9 (c = 1.04,
1
CHCl3). H NMR (CDCl3, 500 MHz): δ = 1.35, 1.54 (2 s, 6 H, 2
Me), 3.09 (dd, J = 6.4, 14.1 Hz, 1 H, 7-H), 3.54 (dd, J ≈ 1.7, 5.3 Hz,
1 H, 4a-H), 3.64 (s, 3 H, OMe), 3.70 (dd, J = 6.3, 14.1 Hz, 1 H, 7-
enantiopure nitrones may be employed instead of (+)-3. H), 4.12 (dd, J = 4.5, 14.4 Hz, 1 H, 2-H), 4.42 (dt, J ≈ 1.7, 14.4 Hz,
446 Eur. J. Org. Chem. 2014, 442–454
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
1 H, 2-H), 4.75 (dd, J = 1.5, 4.5 Hz, 1 H, 3-H), 4.78 (dd, J = 5.3,
in 0.5 n HCl in MeOH (6 mL) and stirred at room temp. for
7.1 Hz, 1 H, 5-H), 5.10 (q, J ≈ 6.5 Hz, 1 H, 6-H) ppm. 13C NMR 30 min. The reaction was quenched by the addition of an excess of
(CDCl3, 126 MHz): δ = 24.8, 27.3 (2 q, 2 Me), 54.8 (q, OMe), 62.1 solid NaHCO3, and the mixture was stirred for 30 min, then filtered
(t, C-7), 66.0 (t, C-2), 70.8 (d, C-4a), 82.1 (d, C-6), 85.2 (d, C-5), through Celite and purified by flash chromatography (short pad of
91.5 (d, C-3), 115.3 (s, OCO), 152.7 (s, C-4) ppm. IR (ATR): ν =
silica gel; dichloromethane/methanol, 9:1) to give triol 8 (182 mg,
˜
1
3020–2840 (=C–H, C–H), 1675 (C=C), 1230, 1200, 1070 95%) as a thick colorless oil. [α]2D2 = +44.3 (c = 1.15, MeOH). H
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C11H18NO4 [M + H]+
NMR (CD3OD, 500 MHz): δ = 2.79 (dd, J = 5.5, 13.0 Hz, 1 H, 7-
228.1236; found 228.1235. C11H17NO4 (227.3): calcd. C 58.14, H H), 2.89 (dd, J = 3.4, 8.4 Hz, 1 H, 4a-H), 3.43 (br. t, J ≈ 3.5 Hz, 1
7.54, N 6.16; found C 58.16, H 7.59, N 6.15.
H, 4-H), 3.49 (s, 3 H, OMe), 3.60 (br. t, J ≈ 3.6 Hz, 1 H, 3-H), 3.61
(dd, J = 6.5, 13.0 Hz, 1 H, 7-H), 3.66 (dd, J = 3.9, 12.2 Hz, 1 H,
2-H), 4.02 (dd, J = 2.6, 12.2 Hz, 1 H, 2-H), 4.24 (br. q, J ≈ 6.4 Hz,
1 H, 6-H), 4.44 (br. t, J ≈ 7.0 Hz, 1 H, 5-H) ppm. 13C NMR
(CD3OD, 126 MHz): δ = 57.0 (q, OMe), 62.7 (t, C-7), 66.0 (d, C-
3), 68.0 (d, C-6), 70.2 (d, C-4a), 70.4 (d, C-5), 70.5 (t, C-2), 78.4
Data for (4S,5R,1ЈE)-5-(2Ј-Methoxybuta-1Ј,3Ј-dienyl)-2,2-dimethyl-
[1,3]dioxolane-4-carbaldehyde (E,Z)-Oxime (6): [α]2D2 = +27.4 (c =
0.69, CHCl ). IR (film): ν = 3375 (OH), 3105–2840 (=C–H, C–
˜
3
H), 1650, 1590 (C=C, C=N), 1220, 1050 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C11H17NNaO4 [M + Na]+ 250.1050; found
250.1067. 1H NMR (CDCl3, 600 MHz): δ [(E)-aldoxime (major)]
= 1.36, 1.46 (2 s, 6 H, 2 Me), 3.60 (s, 3 H, OMe), 4.45 (br. d, J =
9.1 Hz, 1 H, 1Ј-H), 4.56 (dd, J = 6.3, 7.8 Hz, 1 H, 4-H), 5.06 (dd,
J = 6.3, 9.1 Hz, 1 H, 5-H), 5.23 (dd, J = 1.4, 11.1 Hz, 1 H, 4Ј-HA),
5.65 (br. dd, J = 1.4, 17.0 Hz, 1 H, 4Ј-HB), 6.39 (dd, J = 11.1,
17.0 Hz, 1 H, 3Ј-H), 7.31 (d, J = 7.8 Hz, 1 H, CH=N), 8.12 (br. s,
1 H, OH) ppm. 13C NMR (CDCl3, 151 MHz): δ [(E)-aldoxime
(major)] = 25.5, 28.1 (2 q, 2 Me), 54.7 (q, OMe), 74.5 (d, C-5), 76.2
(d, C-4), 95.0 (d, C-1Ј), 109.4 (s, C-2), 117.8 (t, C-4Ј), 127.4 (d, C-
3Ј), 148.7 (d, C=N), 156.4 (s, C-2Ј) ppm. 1H NMR (CDCl3,
600 MHz): δ [(Z)-aldoxime (minor)] = 1.34, 1.47 (2 s, 6 H, 2 Me),
3.51 (s, 3 H, OMe), 4.48 (br. d, J = 9.5 Hz, 1 H, 1Ј-H), 5.12–5.18
(m, 2 H, 4-H, 5-H), 5.21 (dd, J = 1.8, 11.0 Hz, 1 H, 4Ј-HA), 5.62
(br. dd, J = 1.8, 17.1 Hz, 1 H, 4Ј-HB), 6.46 (dd, J = 11.0, 17.1 Hz,
1 H, 3Ј-H), 6.77 (d, J = 5.5 Hz, 1 H, CH=N), 8.24 (br. s, 1 H,
OH) ppm. 13C NMR (CDCl3, 151 MHz): δ [(Z)-aldoxime (minor)]
= 25.3, 28.0 (2 q, 2 Me), 54.5 (q, OMe), 72.6 (d, C-4), 74.2 (d, C-
5), 96.4 (d, C-1Ј), 109.1 (s, C-2), 117.0 (t, C-4Ј), 127.4 (d, C-3Ј),
150.0 (d, C=N), 156.1 (s, C-2Ј) ppm.
(d, C-4) ppm. IR (ATR): ν = 3520–3220 (O–H), 2985–2830 (C–H),
˜
1085 (C–O) cm–1. HRMS (ESI-TOF): calcd. for C8H16NO5 [M +
H]+ 206.1028; found 206.1033.
(1ЈR,2S,2ЈR,3R,4S)-2-(2Ј,3Ј-Dihydroxy-1Ј-methoxypropyl)pyrrol-
idine-3,4-diol Hydrochloride (9): A stirred suspension of Pd on char-
coal (10%, 134 mg, 0.13 mmol) in MeOH (15 mL) was saturated
with hydrogen for 1 h. A solution of compound 8 (130 mg,
0.63 mmol) in MeOH (6 mL) was then added, followed by addition
of a saturated methanolic HCl solution (0.8 mL). The mixture was
stirred under hydrogen at normal pressure at room temp. for 24 h.
Filtration through a pad of Celite and solvent removal in vacuo
yielded 9 (150 mg, 94%) as a colorless oil. [α]2D2 = +60.9 (c = 1.12,
MeOH). 1H NMR (CD3OD, 500 MHz): δ = 3.27 (br. d, J ≈
12.4 Hz, 1 H, 5-H), 3.46 (dd, J = 2.7, 12.4 Hz, 1 H, 5-H), 3.55 (s,
3 H, OMe), 3.68 (dd, J = 5.9, 10.9 Hz, 1 H, 3Ј-H), 3.70 (mc, 1 H,
1Ј-H), 3.73 (dd, J = 6.1, 10.9 Hz, 1 H, 3Ј-H), 3.95 (dd, J = 4.0,
8.1 Hz, 1 H, 2-H), 4.06 (dt, J ≈ 2.9, 5.9 Hz, 1 H, 2Ј-H), 4.30–4.34
(m, 2 H, 3-H, 4-H) ppm. 13C NMR (CD3OD, 126 MHz): δ = 51.8
(t, C-5), 60.0 (q, OMe), 63.0 (d, C-2), 64.1 (t, C-3Ј), 72.2 (d, C-2Ј),
73.8, 73.9 (2 d, C-3, C-4), 78.1 (d, C-1Ј) ppm. IR (ATR): ν = 3535–
˜
(3R,4R,4aR,5R,6S)-5,6-Isopropylidenedioxy-4-methoxy-hexa-
hydropyrrolo[1,2-b][1,2]oxazin-3-ol (7): To a solution of 1,2-oxazine
5 (1.25 g, 5.50 mmol) in anhydrous THF (180 mL), a solution of
BH3·THF (1 m in THF, 33 mL, 33 mmol) was added at –30 °C. The
solution was warmed to room temp. and stirred for 3 h, then cooled
to –10 °C, and aq. NaOH (2 m, 68 mL) followed by H2O2 (30%,
22 mL) were added. Stirring at room temp. was continued over-
night. After addition of satd. aq. Na2S2O3 solution, the layers were
separated, the aqueous layer was extracted with Et2O (3ϫ 100 mL),
the combined organic layers were dried with MgSO4, filtered, and
the solvents were removed under reduced pressure. The crude prod-
uct was purified by flash chromatography (silica gel; hexane/ethyl
acetate, 1:2) to give alcohol 7 (1.24 g, 92%) as a viscous colorless
3250 (O–H), 2990–2820 (C–H), 1210 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C8H18NO5 [M – Cl]+ 208.1185; found 208.1193.
(3S,4R,4aR,5R,6S)-5,6-Isopropylidenedioxy-4-methoxy-hexa-
hydropyrrolo[1,2-b][1,2]oxazin-3-ol (epi-7): To a solution of 7
(266 mg, 1.08 mmol) in CH2 Cl2 (2.5 mL), Dess–Martin
periodinane (1.44 g, 3.40 mmol) was added and the mixture was
stirred at room temp. for 48 h. The reaction was quenched by the
addition of satd. Na2S2O3 solution (3.0 mL), and the resulting mix-
ture was stirred for an additional 45 min, then diluted with Et2O
(10 mL), washed with H2O (10 mL), and the organic layer was
dried with Na2SO4. After filtration and removal of the solvents
under reduced pressure, the respective 1,2-oxazinone derivative
(215 mg, 81%) was isolated as a creamy semisolid and used for the
next step without purification.
1
oil. [α]2D2 = +89.5 (c = 1.16, CHCl3). H NMR ([D6]DMSO, 80 °C,
500 MHz): δ = 1.31, 1.47 (2 s, 6 H, 2 Me), 2.73 (dd, J = 5.7, 7.3 Hz,
1 H, 4a-H), 2.75 (dd, J = 4.7, 10.4 Hz, 1 H, 7-H), 3.22 (br. t, J ≈
7.0 Hz, 1 H, 4-H), 3.50 (s, 3 H, OMe), 3.54–3.49 (m, 2 H, 2-H, 3-
H), 3.56 (dd, J = 6.0, 10.4 Hz, 1 H, 7-H), 3.80 (br. q, J ≈ 7.9 Hz, 1
H, 2-H), 4.69 (dd, J = 5.7, 7.0 Hz, 1 H, 5-H), 4.75 (ddd, J = 4.7,
6.0, 7.0 Hz, 1 H, 6-H), 5.01 (br. d, J = 4.0 Hz, 1 H, OH) ppm. 13C
NMR ([D6]DMSO, 80 °C, 126 MHz): δ = 25.6, 27.7 (2 q, 2 Me),
58.7 (q, OMe), 59.3 (t, C-7), 68.7 (d, C-3), 70.6 (t, C-2), 72.1 (d,
C-4a), 77.5 (d, C-6), 80.7 (d, C-5), 81.0 (d, C-4), 113.5 (s,
Data for the Isolated Crude (4R,4aS,5R,6S)-5,6-Dihydroxy-5,6-O-
isopropylidene-4-methoxy-tetrahydropyrrolo[1,2-b][1,2]oxazin-3-one:
1H NMR (CDCl3, 500 MHz): δ = 1.37, 1.51 (2 s, 3 H each, 2 Me),
3.06 (dd, J = 6.4, 14.0 Hz, 1 H, 7-H), 3.41 (br. t, J ≈ 5.3 Hz, 1 H,
4a-H), 3.56 (s, 3 H, OMe), 3.72 (dd, J = 6.3, 14.0 Hz, 1 H, 7-H),
4.08 (d, J = 5.9 Hz, 1 H, 4-H), 4.12, 4.34 (2 d, J = 16.2 Hz, 1 H
each, 2-H), 4.90 (mc, 1 H, 5-H), 5.06 (br. dd, J ≈ 6.4, 12.9 Hz, 1 H,
6-H) ppm. 13C NMR (CDCl3, 126 MHz): δ = 25.0, 27.3 (2 q, 2
Me), 58.9 (q, OMe), 62.0 (t, C-7), 76.0 (d, C-4a), 76.3 (t, C-2),
81.0 (d, C-6), 82.6 (d, C-4), 86.5 (d, C-5), 115.3 (s, OCO), 206.7 (s,
OCO) ppm. IR (ATR): ν = 3460 (O–H), 2990–2860 (C–H), 1375,
˜
1212, 1105, 1040 (C–O) cm–1. HRMS (ESI-TOF): calcd. for
C11H19NNaO5 [M + Na]+ 268.1155; found 268.1164. C11H19NO5
(245.3): calcd. C 53.87, H 7.81, N 5.71; found C 53.94, H 7.90, N
5.60.
C=O) ppm. IR (ATR): ν = 2985–2830 (C–H), 1750 (C=O), 1210,
˜
1055 (C–O) cm–1. HRMS (ESI-TOF): calcd. for C11H17NNaO5 [M
+ Na]+ 266.1004; found 266.0998.
(3R,4R,4aS,5R,6S)-4-Methoxy-hexahydropyrrolo[1,2-b][1,2]oxaz- To a solution of this 1,2-oxazinone (215 mg, 0.88 mmol) in THF
ine-3,5,6-triol (8): Compound 7 (230 mg, 0.94 mmol) was dissolved (9 mL), L-Selectride (1 m in THF, 1.33 mL, 1.33 mmol) was added
Eur. J. Org. Chem. 2014, 442–454
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
447

M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
dropwise at –78 °C. The mixture was stirred at this temperature for
3 h, the reaction was quenched by the addition of H2O (8 mL).
The mixture was warmed to room temp., extracted with Et2O (3ϫ
10 mL), and the combined organic layers were dried (Na2SO4). Af-
ter filtration, the solvents were removed, and the crude product was
purified by flash column chromatography (silica gel; hexane/ethyl
acetate, 1:2) to give epi-7 (136 mg, 62%) as a colorless solid. M.p.
4) ppm. IR (ATR): ν = 3010–2830 (=C–H, C–H), 1675 (C=C),
˜
1210, 1070 (C–O) cm– 1 . HRMS (ESI-TOF): calcd. for
C15H27NNaO4Si [M + Na]+ 336.1607; found 336.1592.
(3R,4R,4aR,5R,6S)-5,6-Isopropylidenedioxy-4-[2-(trimethylsilyl)-
ethoxy]hexahydropyrrolo[1,2-b][1,2]oxazin-3-ol (11): According to
the typical procedure described for the hydroboration of 5, com-
pound 10 (200 mg, 0.64 mmol) in anhydrous THF (20 mL) was
treated with BH3·THF (1M in THF, 3.8 mL, 3.8 mmol) and, after
oxidative workup, the resulting crude product was purified by
chromatography on a short silica gel column (hexane/ethyl acetate,
1:1) to give pure 11 (175 mg, 83%) as a viscous colorless oil. [α]2D2
= +83.5 (c = 1.01, CHCl3). 1H NMR ([D6]DMSO, 80 °C,
500 MHz): δ = 0.02 (s, 9 H, SiMe3), 0.90 (ddd, J = 2.6, 6.0, 9.4 Hz,
2 H, CH2SiMe3), 1.26, 1.42 (2 s, 3 H each, 2 Me), 2.71–2.74 (m, 2
H, 4a-H, 7-H), 3.28 (br. t, J ≈ 6.4 Hz, 1 H, 4-H), 3.43–3.53 (m, 3
H, 2-H, 3-H, 7-H), 3.69–3.80 (m, 3 H, 2-H, 4-OCH2), 4.68 (dd, J
= 5.5, 7.0 Hz, 1 H, 5-H), 4.70–4.74 (m, 1 H, 6-H), 4.87 (br. d, J ≈
4.4 Hz, 1 H, OH) ppm. 13C NMR ([D6]DMSO, 80 °C, 126 MHz):
δ = –1.6 (q, SiMe3), 17.9 (t, CH2SiMe3), 24.7, 26.7 (2 q, 2 Me),
58.5 (t, C-7), 66.7 (t, 4-OCH2), 67.7 (d, C-3), 69.4 (t, C-2), 71.4 (d,
C-4a), 76.8 (d, C-6), 77.3 (d, C-4), 80.0 (d, C-5), 112.5 (s,
1
45–46 °C. [α]2D2 = +69.2 (c = 1.22, CHCl3). H NMR ([D6]DMSO,
80 °C, 500 MHz): δ = 1.26, 1.42 (2 s, 3 H each, 2 Me), 2.72 (dd, J
= 4.7, 9.8 Hz, 1 H, 7-H), 3.00 (dd, J = 5.4, 8.6 Hz, 1 H, 4a-H),
3.26 (dd, J = 3.3, 8.6 Hz, 1 H, 4-H), 3.36 (s, 3 H, OMe), 3.51 (dd,
J = 6.1, 9.8 Hz, 1 H, 7-H), 3.70–3.72 (m, 2 H, 2-H), 3.86 (dq, J ≈
3.3, 6.4 Hz, 1 H, 3-H), 4.40 (br. d, J ≈ 4.8 Hz, 1 H, OH), 4.42 (dd,
J = 5.4, 7.1 Hz, 1 H, 5-H), 4.62–4.66 (m, 1 H, 6-H) ppm. 13C NMR
([D6]DMSO, 80 °C, 126 MHz): δ = 25.6, 27.6 (2 q, 2 Me), 56.5 (q,
OMe), 58.7 (t, C-7), 63.6 (d, C-3), 68.7 (d, C-4a), 71.2 (t, C-2), 76.6
(d, C-6), 78.4 (d, C-4), 80.6 (d, C-5), 113.5 (s, OCO) ppm. IR
(ATR): ν = 3465 (O–H), 2985–2830 (C–H), 1210, 1110, 1060
˜
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C11H19NNaO5 [M +
Na]+ 268.1155; found 268.1165. C11H19NO5 (245.3): calcd. C 53.87,
H 7.81, N 5.71; found C 53.79, H 7.85, N 5.75.
(3S,4R,4aS,5R,6S)-4-Methoxy-hexahydropyrrolo[1,2-b][1,2]oxazine-
3,5,6-triol (epi-8): By a procedure similar to that applied for the
reaction of 7, compound epi-7 (80 mg, 0.33 mmol) was treated with
0.5 n HCl in MeOH (2 mL) and stirred at room temp. for 30 min.
After standard workup, the crude product was purified on a short
pad of silica gel (dichloromethane/methanol, 9:1) to give epi-8
(56 mg, 84%) as a colorless solid. Melting range 148–155 °C. [α]2D2
= +17.8 (c = 1.34, MeOH). 1H NMR (CD3OD, 500 MHz): δ =
2.85 (dd, J = 5.7, 12.8 Hz, 1 H, 7-H), 3.19 (dd, J = 5.0, 8.6 Hz, 1
H, 4a-H), 3.51 (s, 3 H, OMe), 3.60 (br. t, J ≈ 4.1 Hz, 1 H, 4-H),
3.62 (dd, J = 6.6, 12.8 Hz, 1 H, 7-H), 3.74 (dd, J = 3.9, 11.4 Hz, 1
H, 2-H), 3.88 (dd, J = 7.9, 11.4 Hz, 1 H, 2-H), 3.95 (dt, J ≈ 3.8,
7.7 Hz, 1 H, 3-H), 4.10 (br. t, J ≈ 7.9 Hz, 1 H, 5-H), 4.26 (br. dt, J
≈ 6.4, 6.7 Hz, 1 H, 6-H) ppm. 13C NMR (CD3OD, 126 MHz): δ =
57.9 (q, OMe), 63.5 (t, C-7), 64.9 (d, C-3), 69.0 (d, C-6), 70.5 (d,
OCO) ppm. IR (ATR): ν = 3435 (O–H), 2990–2855 (C–H), 1250,
˜
1095, 1065, 1040 (C–O) cm–1. HRMS (ESI-TOF): calcd. for
C15H29NNaO5Si [M + Na]+ 354.1702; found 354.1697.
(3R,4R,4aS,5R,6S)-Hexahydropyrrolo[1,2-b][1,2]oxazine-3,4,5,6-
tetraol (12): To a solution of compound 11 (142 mg, 0.43 mmol) in
EtOH (8.0 mL) was added acidic ion exchange resin DOWEX-50
(557 mg; washed several times with EtOH before use). The suspen-
sion was vigorously stirred at 50 °C for 3 d, and then decanted.
The resin was washed with three portions of ammonia in methanol
solution (7 n, ca. 2.5 mL each), and the organic layers were com-
bined. After evaporation of the solvents, compound 12 (80 mg,
98%) was isolated as a colorless oil, which solidified upon standing
in the refrigerator. M.p. 112–115 °C. [α]2D2 = +42.3 (c = 1.21,
MeOH). 1H NMR (CD3OD, 500 MHz): δ = 2.76 (br. d, J = 5.4 Hz,
1 H, 4a-H), 2.77 (dd, J = 5.7, 12.1 Hz, 1 H, 7-H), 3.50 (br. dt, J ≈
3.6, 5.4 Hz, 1 H, 3-H), 3.61 (dd, J = 6.6, 12.1 Hz, 1 H, 7-H), 3.63
(dd, J = 5.5, 12.0 Hz, 1 H, 2-H), 3.77 (br. t, J ≈ 5.0 Hz, 1 H, 4-H),
4.06 (dd, J = 3.5, 12.0 Hz, 1 H, 2-H), 4.24 (br. q, J ≈ 6.4 Hz, 1 H,
6-H), 4.31 (br. t, J ≈ 7.0 Hz, 1 H, 5-H) ppm. 13C NMR (CD3OD,
126 MHz): δ = 63.3 (t, C-7), 69.2 (d, C-6), 70.4 (d, C-3), 71.8 (t,
C-2), 71.9* (d, C-4, C-5), 73.9 (d, C-4a) ppm; *higher intensity. IR
C-4a), 71.3 (t, C-2), 71.7 (d, C-5), 78.8 (d, C-4) ppm. IR (ATR): ν
˜
= 3540–3180 (O–H), 2950–2840 (C–H), 1110 (C–O) cm–1. HRMS
(ESI-TOF): calcd. for C8H15NNaO5 [M + Na]+ 228.0848; found
228.0843. C8H15NO5 (205.2): calcd. C 46.82, H 7.37, N 6.83; found
C 46.87, H 7.28, N 6.83.
(4aS,5R,6S)-5,6-Isopropylidenedioxy-4-[2-(trimethylsilyl)ethoxy]-
4a,5,6,7-tetrahydro-2H-pyrrolo[1,2-b][1,2]oxazine (10): By a pro-
cedure similar to that applied for methoxyallene, lithiated TMSE-
allene was generated by treating a solution of freshly distilled 2-
(trimethylsilyl)ethoxyallene (2.71 g, 17.4 mmol) in anhydrous THF
(150 mL) with nBuLi (2.5 m in hexane, 5.95 mL, 14.9 mmol) and
(neat): ν = 3545–3250 (O–H), 2995–2860 (C–H), 1060 (C–O) cm–1.
˜
HRMS (ESI-TOF): calcd. for C7H13NNaO5 [M + Na]+ 214.0691;
found 214.0679.
(3R,4R,4aR,5R,6S)-3-Benzyloxy-5,6-isopropylidenedioxy-4-meth-
then with nitrone (+)-3 (780 mg, 4.96 mmol) in THF (45 mL) for oxy-hexahydropyrrolo[1,2-b][1,2]oxazine (13a): A solution of com-
3 h. After typical workup, the resulting organic layer was stirred pound 7 (355 mg, 1.45 mmol) in DMF (15 mL) was added to NaH
with MgSO4 for 36 h. The crude product was purified by
chromatography on silica gel (hexane/ethyl acetate, 8:1) to give
spectroscopically pure bicyclic product 10 (1.12 g, 72%) as a pale-
yellow oil. [α]2D2 = +62.0 (c = 1.00, CHCl3). 1H NMR (CDCl3,
500 MHz): δ = 0.04 (s, 9 H, SiMe3), 1.02–1.13 (m, 2 H, CH2SiMe3),
1.33, 1.52 (2 s, 3 H each, 2 Me), 3.06 (dd, J = 6.4, 13.9 Hz, 1 H,
7-H), 3.53 (br. dd, J ≈ 1.4, 5.0 Hz, 1 H, 4a-H), 3.66 (dd, J = 6.2,
13.9 Hz, 1 H, 7-H), 3.82–3.91 (m, 2 H, 4-OCH2), 4.10 (dd, J = 4.4,
(60% in mineral oil, 94 mg, 2.35 mmol) at 0 °C. Benzyl bromide
(250 μL, 358 mg, 2.10 mmol) was added, and the solution was
stirred at room temp. overnight. H2O (15 mL) was added, the aque-
ous layer was extracted with Et2O (3ϫ 25 mL), and the combined
organic layers were dried with MgSO4. After filtration, the solvent
was removed in vacuo. The crude product was purified by column
chromatography (silica gel; hexane/ethyl acetate, 1:1) to give 13a
(393 mg, 81%) as a colorless oil. [α]2D2 = +46.3 (c = 1.74, CHCl3).
14.4 Hz, 1 H, 2-H), 4.40 (dt, J ≈ 1.7, 14.4 Hz, 1 H, 2-H), 4.68 (dd, 1H NMR ([D6]DMSO, 80 °C, 500 MHz): δ = 1.30, 1.47 (2 s, 6 H,
J = 1.3, 4.4 Hz, 1 H, 3-H), 4.75 (dd, J = 5.0, 7.0 Hz, 1 H, 5-H),
5.06 (q, J ≈ 6.5 Hz, 1 H, 6-H) ppm. 13C NMR (CDCl3, 126 MHz):
δ = –1.4 (q, SiMe3), 17.1 (t, CH2SiMe3), 24.9, 27.3 (2 q, 2 Me),
2 Me), 2.80 (dd, J = 4.3, 11.1 Hz, 1 H, 7-H), 2.86 (br. t, J ≈ 5.8 Hz,
1 H, 4a-H), 3.44–3.51 (m, 2 H, 3-H, 4-H), 3.48 (s, 3 H, OMe), 3.58
(dd, J = 5.9, 11.1 Hz, 1 H, 7-H), 3.68 (dd, J = 6.4, 11.8 Hz, 1 H,
61.8 (t, C-7), 64.7 (t, 4-OCH2), 65.8 (t, C-2), 70.7 (d, C-4a), 81.9 2-H), 3.96 (dd, J = 3.8, 11.8 Hz, 1 H, 2-H), 4.66 (s, 2 H, Bn), 4.76–
(d, C-6), 85.0 (d, C-5), 91.6 (d, C-3), 114.9 (s, OCO), 151.4 (s, C- 4.81 (m, 2 H, 5-H, 6-H), 7.31–7.35, 7.37–7.41 (2 m, 5 H, Ph) ppm.
448
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 442–454

Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
13C NMR ([D6]DMSO, 80 °C, 126 MHz): δ = 25.6, 27.7 (2 q, 2 H), 3.71 (d, J = 13.2 Hz, 1 H, 6-H), 3.77 (dd, J = 1.8, 6.0 Hz, 1 H,
Me), 58.5 (q, OMe), 59.9 (t, C-7), 68.0 (t, C-2), 71.8 (t, Bn), 72.2
1Ј-H), 3.80–3.84 (m, 1 H, 2Ј-H), 3.93 (mc, 1 H, 4-H), 4.32 (dd, J =
(d, C-4a), 75.6 (d, C-3), 78.1 (d, C-6), 78.6 (d, C-4), 80.9 (d, C-5), 5.0, 11.0 Hz, 1 H, 3Ј-H), 4.40 (dd, J = 3.9, 11.0 Hz, 1 H, 3Ј-H),
113.9 (s, OCO), 128.08, 128.12, 128.5, 139.2 (3 d, s, Ph) ppm. IR
4.69 (s, 2 H, Bn), 4.69–4.72 (m, 1 H, 6a-H), 4.84 (dd, J = 0.8,
5.9 Hz, 1 H, 3a-H), 7.28–7.40 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 23.9, 26.2, 36.9, 37.6 (4 q, 2 Me, NMs,
OMs), 54.3 (t, C-6), 61.4 (q, OMe), 66.3 (t, C-3Ј), 67.6 (d, C-4),
73.4 (t, Bn), 77.6 (d, C-2Ј), 80.5 (d, C-6a), 81.1 (d, C-3a), 84.4 (d,
C-1Ј), 111.7 (s, C-2), 128.0, 128.2, 128.4, 137.2 (3 d, s, Ph) ppm. IR
(ATR): ν = 3085–2830 (=C–H, C–H), 1210, 1105, 1050
˜
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C18H26NO5 [M + H]+
336.1811; found 336.1811.
(2ЈR,3ЈR,3aR,4R,6aS)-4-(2Ј-Benzyloxy-3Ј-hydroxy-1Ј-methoxy-
propyl)-2,2-dimethyl-tetrahydro[1,3]dioxolo[4,5-c]pyrrole (14a): To a
solution of samarium diiodide (ca. 0.1 m in THF, 10 mL, ca.
1.0 mmol), a solution of 13a (116 mg, 0.35 mmol) in degassed THF
(30 mL) was added dropwise at room temp. The mixture was stirred
for 3 h, then the reaction was quenched by the addition of satd.
aq. sodium potassium tartrate solution (15 mL), and extracted with
diethyl ether (3ϫ 25 mL). The combined organic layers were dried
(MgSO4), filtered, and the solvents removed under reduced pres-
sure to give spectroscopically pure 14a as a pale-yellow oil. Fil-
tration through a short silica gel pad (dichloromethane/methanol,
15:1) gave 14a (103 mg, 89%) as a colorless oil. [α]2D2 = +26.0 (c =
1.04, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 1.31, 1.45 (2 s, 6 H,
2 Me), 2.92 (dd, J = 4.2, 13.4 Hz, 1 H, 6-H), 3.04 (d, J = 13.4 Hz, 1
H, 6-H), 3.21 (dd, J = 6.1, 7.7 Hz, 1 H, CHOMe), 3.26 (d, J =
7.9 Hz, 1 H, 4-H), 3.39 (br. s, 2 H, NH, OH), 3.46 (s, 3 H, OMe),
3.58 (dt, J ≈ 4.2, 5.9 Hz, 1 H, CHOBn), 3.73 (ddd, J = 4.1, 12.4,
16.0 Hz, 2 H, CH2OH), 4.65, 4.69 (2 d, J = 11.5 Hz, 2 H, Bn), 4.69
(t, J ≈ 4.7 Hz, 1 H, 6a-H), 4.75 (br. d, J ≈ 5.7 Hz, 1 H, 3a-H), 7.29–
7.25, 7.38–7.31 (2 m, 5 H, Ph) ppm. 13C NMR (CDCl3, 126 MHz):
δ = 24.0, 26.3 (2 q, 2 Me), 52.4 (t, C-6), 60.1 (q, OMe), 60.6 (t, C-
3Ј), 66.4 (d, C-4), 72.5 (t, Bn), 81.3 (d, C-1Ј), 81.6 (d, C-6a), 81.9
(d, C-2Ј), 83.0 (d, C-3a), 111.1 (s, C-2), 127.7, 127.9, 128.3, 138.3
(ATR): ν = 3060–2835 (=C–H, C–H), 1330 (S=O), 1175, 1150
˜
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C20H31NNaO9S2 [M +
Na]+ 516.1332; found 516.1341.
(1R,2S,6R,7R,7aS)-6-Benzyloxy-7-methoxypyrrolizidine-1,2-diol
(16a): A solution of 15a (99 mg, 0.31 mmol) in MeOH (0.5 mL)
was added to a methanolic HCl solution (1M, 4 mL), and the mix-
ture was stirred at room temp. overnight. Solid NaHCO3 (420 mg)
was then added, and stirring was continued for 30 min. The mixture
was filtered through Celite, the solvent was removed in vacuo, and
the product was purified by flash chromatography (silica gel;
dichloromethane/methanol, 9:1) to give pure 16a (84 mg, 97%) as
colorless crystals. Melting range 118–124 °C. [α]2D2 = +51.2 (c =
0.64, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 2.93 (d, J =
12.6 Hz, 1 H, 5-H), 3.01 (dd, J = 3.3, 11.3 Hz, 1 H, 3-H), 3.23 (dd,
J = 4.1, 12.6 Hz, 1 H, 5-H), 3.35 (s, 3 H, OMe), 3.43 (d, J =
11.3 Hz, 1 H, 3-H), 3.52 (br. dd, J ≈ 0.9, 7.7 Hz, 1 H, 7a-H), 3.92
(mc, 1 H, 7-H), 4.04 (mc, 1 H, 6-H), 4.17 (dd, J = 4.1, 7.7 Hz, 1 H,
1-H), 4.23 (t, J ≈ 3.2 Hz, 1 H, 2-H), 4.50, 4.57 (2 d, J = 11.8 Hz, 1
H each, Bn), 5.14 (br. s, 2 H, OH), 7.25–7.36 (m, 5 H, Ph) ppm.
13C NMR (CDCl3, 126 MHz): δ = 57.2 (q, OMe, and t, C-5; over-
lapping signal), 60.7 (t, C-3), 71.6 (t, Bn), 72.8 (d, C-2), 73.1 (d, C-
7a), 75.9 (d, C-1), 83.7 (d, C-6), 86.3 (d, C-7), 127.5, 127.9, 128.5,
(3d, s, Ph) ppm. IR (ATR): ν = 3475–3245 (O–H, N–H), 3030–
˜
2830 (=C–H, C–H), 1460, 1210, 1065 (C–O) cm–1. HRMS (ESI-
TOF): calcd. for C18H28NO5 [M + H]+ 338.1967; found 338.1967.
137.4 (3 d, s, Ph) ppm. IR (ATR): ν = 3500–3155 (O–H), 3085–
˜
2825 (=C–H, C–H), 1105, 1050 (C–O) cm–1. HRMS (ESI-TOF):
calcd. for C15H22NO4 [M + H]+ 280.1549; found 280.1540.
(1R,2R,6S,7R,7aR)-2-Benzyloxy-6,7-isopropylidenedioxy-1-meth-
oxypyrrolizidine (15a): To a solution of amino alcohol 14a (175 mg,
0.52 mmol) in anhydrous pyridine (14 mL), methanesulfonyl chlor-
ide (65 mg, 0.57 mmol, 44 μL) was added at 0 °C. After stirring at
room temp. for 24 h, 5% aq. CuSO4 solution (14 mL) was added.
The mixture was extracted with Et2O (3ϫ 15 mL each), the com-
bined extracts were dried with MgSO4, and the solvents were re-
moved in vacuo. The crude product mixture was separated by col-
umn chromatography (silica gel; dichloromethane/methanol, 30:1)
to furnish the N,O-dimesylated product (56 mg, 22%, first eluted)
and pyrrolizidine 15a (99 mg, 60%, second eluted) as colorless oils.
(3R,4R,4aR,5R,6S)-3-(tert-Butyldimethylsiloxy)-5,6-isopropylidene-
dioxy-4-methoxy-hexahydropyrrolo[1,2-b][1,2]oxazine (13b): To a
solution of alcohol 7 (983 mg, 4.01 mmol) in anhydrous CH2Cl2
(20 mL) were added at 0 °C imidazole (1.16 g, 17.0 mmol) and
DMAP (98 mg, 0.80 mmol, 20 mol-%) followed by TBSCl (1.22 g,
8.02 mmol) in CH2Cl2 (10 mL). The mixture was allowed to reach
room temp. and stirred for 6 h. CH2Cl2 (20 mL) was then added
followed by H2O (35 mL), and the layers were separated. The aque-
ous layer was extracted with CH2Cl2 (3ϫ 15 mL), the combined
organic layers were washed with brine, dried with Na2SO4, then
filtered, and the solvents were removed under reduced pressure.
Purification by flash column chromatography (silica gel; hexane/
Data for Compound 15a: [α]2D2 = +56.0 (c = 1.08, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.32, 1.53 (2 s, 3 H each, 2 Me), 2.90 (dd,
J = 2.4, 12.9 Hz, 1 H, 3-H), 3.11 (dd, J = 4.9, 11.7 Hz, 1 H, 5-H),
3.24–3.28 (m, 2 H, 3-H, 5-H), 3.35 (mc, 1 H, 7a-H), 3.39 (s, 3 H,
OMe), 3.70 (dd, J = 2.9, 5.8 Hz, 1 H, 1-H), 4.00 (dt, J ≈ 2.9, 5.6 Hz,
1 H, 2-H), 4.51 (s, 2 H, Bn), 4.71 (dd, J = 1.9, 6.1 Hz, 1 H, 7-H),
4.78–4.81 (m, 1 H, 6-H), 7.27–7.36 (m, 5 H, Ph) ppm. 13C NMR
(CDCl3, 126 MHz): δ = 24.9, 26.3 (2 q, 2 Me), 57.2 (t, C-3), 57.6
(q, OMe), 59.9 (t, C-5), 71.6 (t, Bn), 75.9 (d, C-7a), 81.2 (d, C-6),
83.9 (d, C-7), 85.5 (d, C-2), 89.2 (d, C-1), 111.8 (s, OCO), 127.5,
ethyl acetate, 3:1) gave 13b (1.43 g, 99%) as a colorless oil. [α]2D2
=
+68.5 (c = 0.93, CHCl3). 1H NMR ([D6]DMSO, 80 °C, 600 MHz):
δ = 0.08, 0.11, 0.90 (3 s, 2ϫ 3 H, 9 H, TBS), 1.27, 1.44 (2 s, 6 H,
2 Me), 2.72–2.78 (m, 2 H, 4a-H, 7-H), 3.21 (br. t, J ≈ 6.5 Hz, 1 H,
4-H), 3.46 (s, 3 H, OMe), 3.49 (dd, J = 7.1, 11.6 Hz, 1 H, 2-H),
3.53–3.57 (m, 1 H, 7-H), 3.63 (td, J ≈ 4.3, 6.4 Hz, 1 H, 3-H), 3.81
(dd, J = 4.2, 11.6 Hz, 1 H, 2-H), 4.72–4.75 (m, 2 H, 5-H, 6-H) ppm.
13C NMR ([D6]DMSO, 80 °C, 151 MHz): δ = –5.29, –5.28, 17.2,
25.2 (2 q, s, q, TBS), 24.5, 26.6 (2 q, 2 Me), 57.6 (q, OMe), 58.7
(t, C-7), 68.8 (d, C-3), 69.7 (t, C-2), 71.4 (d, C-4a), 76.8, 79.7 (2 d,
127.7, 128.4, 137.8 (3 d, s, Ph) ppm. IR (ATR): ν = 3090–2815
˜
(=C–H, C–H), 1210, 1110, 1055 (C–O) cm–1. HRMS (ESI-TOF):
calcd. for C18H26NO4 [M + H]+ 320.1856; found 320.1863.
C-5, C-6), 80.3 (d, C-4), 112.7 (s, OCO) ppm. IR (KBr): ν = 2980–
˜
2820 (=C–H, C–H), 1255, 1120, 1050 (C–O) cm–1. HRMS (EI):
calcd. for C17H33NO5Si [M]+ 359.2128; found 359.2132.
C17H33NO5Si (359.5): calcd. C 56.79, H 9.25, N 3.90; found C
56.89, H 9.31, N 3.69.
Data for (2ЈR,3ЈR,3aR,4R,6aS)-4-(2Ј-Benzyloxy-3Ј-methylsulf-
onyloxy-1Ј-methoxypropyl)-2,2-dimethyl-5-methylsulfonyl-tetra-
1
hydro[1,3]dioxolo[4,5-c]pyrrole: [α]2D2 = –32.4 (c = 1.07, CHCl3). H
NMR (CDCl3, 500 MHz): δ = 1.28, 1.46, 2.96, 3.05, 3.53 (5 s, 3 H
each, 2 Me, NMs, OMs, OMe), 3.64 (dd, J = 4.5, 13.2 Hz, 1 H, 6-
(2ЈR,3ЈR,3aR,4R,6aS)-4-[2Ј-(tert-Butyldimethylsiloxy)-3Ј-hydroxy-
1Ј-methoxypropyl]-2,2-dimethyl-tetrahydro[1,3]dioxolo[4,5-c]pyrrole
Eur. J. Org. Chem. 2014, 442–454
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
449

M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
(14b): By a procedure similar to that applied to the reaction of 13a,
compound 13b (286 mg, 0.79 mmol) was added to a solution of
196 mg, 1.92 mmol) were added and the resulting heterogeneous
mixture stirred at room temp. for 24 h. H2O (4 mL) was added,
samarium diiodide (ca. 0.1 m in THF, 24 mL, ca. 2.4 mmol). After and the mixture was extracted with diethyl ether (3ϫ 3 mL). The
standard workup, the crude product was purified by flash
chromatography (silica gel washed with 1% Et3N in dichlorometh-
ane before use; dichloromethane/methanol, 20:1) to give 14b
(275 mg, 96%) as a colorless solid. M.p. 71–73 °C. [α]2D2 = +12.3 (c
combined organic layers were dried (MgSO4), filtered, and the sol-
vents were removed in vacuo. The resulting crude product was puri-
fied by chromatography with a short column (SiO2; ethyl acetate)
to give 16c (42 mg, 85%) as a colorless oil. [α]2D2 = +22.9 (c = 0.82,
1
1
= 1.17, CHCl3). H NMR (CDCl3, 600 MHz): δ = 0.11, 0.12, 0.91
CHCl3). H NMR (CDCl3, 600 MHz): δ = 2.052, 2.053, 2.07 (3 s,
(3 s, 2ϫ 3 H, 9 H, TBS), 1.31, 1.46 (2 s, 6 H, 2 Me), 2.93 (dd, J =
3 H each, 3 OAc), 2.82 (br. d, J ≈ 13.4 Hz, 1 H, 5-H), 3.09 (dd, J
4.2, 13.3 Hz, 1 H, 6-H), 3.05 (d, J = 13.3 Hz, 1 H, 6-H), 3.12 (br. t, = 4.6, 11.6 Hz, 1 H, 3-H), 3.26 (dd, J = 2.9, 11.6 Hz, 1 H, 3-H),
J ≈ 6.6 Hz, 1 H, 1Ј-H), 3.28 (br. d, J ≈ 7.0 Hz, 1 H, 4-H), 3.43 (s, 3.37 (s, 3 H, OMe), 3.40 (dd, J = 9.0, 13.4 Hz, 1 H, 5-H), 3.48 (dd,
3 H, OMe), 3.54 (br. s, 2 H, NH, OH), 3.61 (dd, J = 5.0, 11.9 Hz,
1 H, 3Ј-H), 3.67 (dd, J = 3.6, 11.9 Hz, 1 H, 3Ј-H), 3.79 (ddd, J =
3.6, 5.0, 6.3 Hz, 1 H, 2Ј-H), 4.68–4.70 (m, 1 H, 6a-H), 4.73 (dd, J
= 0.9, 5.7 Hz, 1 H, 3a-H) ppm. 13C NMR (CDCl3, 151 MHz): δ =
–4.8, –4.6, 18.1, 25.9 (2 q, s, q, TBS), 24.1, 26.4 (2 q, 2Me), 52.5
J = 1.8, 7.1 Hz, 1 H, 7a-H), 3.77 (mc, 1 H, 7-H), 5.14 (dt, J ≈ 1.9,
4.0 Hz, 1 H, 6-H), 5.17 (dd, J = 4.6, 7.1 Hz, 1 H, 1-H), 5.44 (td, J
≈ 3.1, 4.6 Hz, 1 H, 2-H) ppm. 13C NMR (CDCl3, 151 MHz): δ =
20.6, 20.8, 21.0 (3 q, 3 Ac), 57.6 (t, C-5), 57.81 (q, OMe), 57.83 (t,
C-3), 71.5 (d, C-7a), 72.9 (d, C-2), 74.6 (d, C-1), 78.7 (d, C-6), 87.1
(t, C-6), 60.1 (q, OMe), 64.0 (t, C-3Ј), 66.2 (d, C-4), 74.8 (d, C-2Ј), (d, C-7), 169.8, 170.2, 170.3 (3 s, 3 C=O) ppm. IR (film): ν = 2985–
˜
81.7 (d, C-6a), 82.7 (d, C-1Ј), 82.9 (d, C-3a), 111.1 (s, C-2) ppm.
2850 (C–H), 1740 (C=O), 1375, 1230, 1105 (C–O) cm–1. HRMS
IR (KBr): ν = 3430 (O–H), 3250 (N–H), 2980–2855 (C–H), 1045 (ESI-TOF): calcd. for C14H22NO7 [M + H]+ 316.1396; found
˜
(C–O) cm–1. HRMS (EI): calcd. for C17H35NO5Si [M]+ 361.2284;
found 361.2285. C17H35NO5Si (361.5): calcd. C 56.47, H 9.76, N
3.87; found C 56.51, H 9.79, N 3.72.
316.1402. C14H21NO7 (315.3): calcd. C 53.33, H 6.71, N 4.44;
found C 53.34, H 6.50, N 4.27.
(3R,4R,4aR,5R,6S)-3-(tert-Butyldiphenylsiloxy)-5,6-isopropylidene-
dioxy-4-[2-(trimethylsilyl)ethoxy]-hexahydropyrrolo[1,2-b][1,2]oxaz-
ine (17): To a solution of alcohol 11 (190 mg, 0.57 mmol) in anhy-
drous CH2Cl2 (10 mL) were added at 0 °C imidazole (118 mg,
1.73 mmol) and DMAP (14 mg, 0.11 mmol) followed by TBDPSCl
(315 mg, 0.30 mL, 1.15 mmol) in CH2Cl2 (10 mL). The mixture was
allowed to reach room temp. and stirred overnight, then CH2Cl2
(15 mL) was added followed by H2O (25 mL), and the layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 ϫ
10 mL), the combined organic phases were washed with brine,
dried with Na2SO4, filtered, and the solvents were removed under
reduced pressure. Filtration through a silica gel pad (petroleum
ether/ethyl acetate, 8:1) followed by purification by column
chromatography (silica gel; dichloromethane then ethyl acetate)
gave 17 (272 mg, 83%) as a colorless oil. [α]2D2 = +7.1 (c = 1.09,
(1R,2R,6S,7R,7aR)-2-(tert-Butyldimethylsiloxy)-6,7-isopropylidene-
dioxy-1-methoxypyrrolizidine (15b): According to the procedure de-
scribed for compound 14a, to a solution of freshly prepared amino
alcohol 14b (853 mg, 2.36 mmol) in anhydrous pyridine (90 mL),
methanesulfonyl chloride (297 mg, 2.59 mmol, 201 μL) was added
at 0 °C, and the mixture was stirred at room temp. for 1 d. After
workup, the crude mixture was separated by column chromatog-
raphy (silica gel; 0.7% triethylamine in ethyl acetate) to give pyrrol-
izidine 15b (520 mg, 64%) as a pale-yellow oil. [α]2D2 = +41.7 (c =
1.57, CHCl3). 1H NMR (CDCl3, 600 MHz): δ = 0.05, 0.07, 0.87 (3
s, 2 ϫ 3 H, 9 H, TBS), 1.32, 1.52 (2 s, 3 H each, 2 Me), 2.63 (dd,
J = 2.7, 12.1 Hz, 1 H, 3-H), 3.17 (dd, J = 5.4, 11.9 Hz, 1 H, 5-H),
3.23 (dd, J = 4.8, 12.1 Hz, 1 H, 3-H), 3.29 (dd, J = 2.0, 11.9 Hz, 1
H, 5-H), 3.36 (mc, 1 H, 7a-H), 3.39 (s, 3 H, OMe), 3.54 (mc, 1 H,
1-H), 4.00 (dt, J ≈ 2.8, 4.7 Hz, 1 H, 2-H), 4.69 (dd, J = 2.6, 6.0 Hz,
1 H, 7-H), 4.79 (td, J ≈ 2.2, 5.7 Hz, 1 H, 6-H) ppm. 13C NMR
(CDCl3, 151 MHz): δ = –5.0, –4.8, 17.9, 25.7 (2 q, s, q, TBS), 25.3,
27.3 (2 q, 2 Me), 57.6 (q, OMe), 60.9 (t, C-3), 61.1 (t, C-5), 75.5
(d, C-7a), 78.1 (d, C-2), 81.4 (d, C-6), 84.4 (d, C-7), 91.3 (d, C-1),
1
CHCl3). H NMR ([D6]DMSO, 80 °C, 600 MHz): δ = –0.04 (s, 9
H, SiMe3), 0.74 (ddd, J = 6.0, 9.5, 14.0 Hz, 1 H, CH2SiMe3), 0.79
(ddd, J = 6.5, 9.7, 14.0 Hz, 1 H, CH2SiMe3), 1.07 (s, 9 H, tBu),
1.27, 1.43 (2 s, 6 H, 2 Me), 2.75 (dd, J = 5.2, 11.8 Hz, 1 H, 7-H),
2.83 (br. t, J ≈ 5.8 Hz, 1 H, 4a-H), 3.45–3.52 [m, 3 H, 4-OCH2 (2
H), 4-H], 3.55 (dd, J = 6.2, 11.9 Hz, 1 H, 2-H), 3.58 (td, J ≈ 6.5,
9.3 Hz, 1 H, 7-H), 3.64 (dd, J = 3.3, 11.9 Hz, 1 H, 2-H), 3.67 (td,
J ≈ 3.5, 5.1 Hz, 1 H, 3-H), 4.83 (dd, J = 6.0, 12.4 Hz, 1 H, 6-H),
5.00 (br. t, J ≈ 6.7 Hz, 1 H, 5-H), 7.40–7.49, 7.63–7.65, 7.67–7.69
(3 m, 10 H, TBDPS) ppm. 13C NMR ([D6]DMSO, 80 °C,
151 MHz): δ = –1.9 (q, SiMe3), 17.6 (t, CH2SiMe3), 18.3, 26.3 (s,
q, tBu), 24.4, 26.7 (2 q, 2 Me), 59.7 (t, C-7), 66.3 (t, C-2), 68.7 (d,
C-3), 69.3 (t, 4-OCH2), 71.7 (d, C-4a), 76.4 (d, C-4), 77.7 (d, C-6),
80.2 (d, C-5), 113.0 (s, OCO), 127.20, 127.25, 129.38, 129.41, 132.6,
112.0 (s, OCO) ppm. IR (KBr): ν = 2980–2820 (C–H), 1255, 1110,
˜
1070 (C–O) cm–1. HRMS (EI): calcd. for C17H33NO4Si [M]+
343.2179; found 343.2185.
(1R,2S,6R,7R,7aS)-7-Methoxypyrrolizidine-1,2,6-triol (16b): By a
procedure analogous to that applied to compound 12, pyrrolizidine
15b (82 mg, 0.24 mmol) and DOWEX-50 (310 mg) in EtOH (5 mL)
were stirred at 50 °C for 24 h to give 16b (43 mg, 95%) as a viscous
1
colorless oil. [α]2D2 = +43.6 (c = 0.79, MeOH). H NMR (CD3OD,
600 MHz): δ = 2.63 (dd, J = 4.4, 11.5 Hz, 1 H, 5-H), 2.97 (dd, J =
4.2, 11.2 Hz, 1 H, 3-H), 3.11 (dd, J = 2.5, 11.2 Hz, 1 H, 3-H), 3.13
(dd, J = 4.8, 11.5 Hz, 1 H, 5-H), 3.26 (dd, J = 2.9, 7.1 Hz, 1 H,
7a-H), 3.40 (s, 3 H, OMe), 3.63 (mc, 1 H, 7-H), 4.14 (dd, J = 4.4,
7.1 Hz, 1 H, 1-H), 4.18–4.21 (m, 2 H, 2-H, 6-H) ppm. 13C NMR
(CD3OD, 151 MHz): δ = 57.8 (q, OMe), 60.8 (t, C-5), 61.3 (t, C-
3), 73.90 (d, C-7a), 73.93 (d, C-2), 76.9 (d, C-1), 77.6 (d, C-6), 90.7
132.9, 134.81, 134.83 (4 d, 2 s, 2 d, TBDPS) ppm. IR (KBr): ν =
˜
3070–2845 (=C–H, C–H), 1250, 1205, 1115, 1050 (C–O) cm–1
.
HRMS (FAB): calcd. for C31H48NO5Si2 [M + H]+ 570.3071; found
570.3085. C31H47NO5Si2 (569.9): calcd. C 65.34, H 8.31, N 2.46;
found C 65.12, H 8.22, N 2.41.
(2ЈR,3ЈR,3aR,4R,6aS)-4-{2Ј-(tert-Butyldiphenylsiloxy)-3Ј-hydroxy-
1Ј-[2-(trimethylsilyl)ethoxy]propyl}-2,2-dimethyl-tetrahydro[1,3]di-
oxolo[4,5-c]pyrrole (18): By a procedure similar to that applied to
the reaction of 13a, compound 17 (230 mg, 0.41 mmol) was added
to a solution of samarium diiodide (ca. 0.1 m in THF, 13 mL, ca.
(d, C-7) ppm. IR (KBr): ν = 3570–3230 (O–H), 2970–2825 (C–H),
˜
1090 (C–O) cm–1. HRMS (EI): calcd. for C8H15NO4 [M]+
189.1001; found 189.1006.
(1R,2S,6R,7R,7aR)-1,2,6-Triacetoxy-7-methoxypyrrolizidine (16c): 1.3 mmol). After standard workup, the crude product was purified
To pyrrolizidine 16b (30 mg, 0.158 mmol) in anhydrous triethyl-
amine (2 mL), DMAP (2.0 mg, 0.016 mmol) and Ac2O (181 μL,
by flash chromatography (silica gel washed with 1 % Et3N in
dichloromethane before use; dichloromethane/methanol, 20:1) to
450
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 442–454

Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
give 18 (205 mg, 89%) as a colorless oil. [α]2D2 = –19.6 (c = 0.43,
CHCl3). H NMR (CDCl3, 600 MHz): δ = –0.07 (s, 9 H, SiMe3),
0.71–0.80 (m, 2 H, CH2SiMe3), 1.09 (s, 9 H, tBu), 1.31, 1.48 (2 s,
(1ЈR,2R,2ЈR,3R,4S)-2-(2Ј,3Ј-Dihydroxy-1Ј-methoxypropyl)-3,4-iso-
propylidenedioxypyrrolidine (21): To a solution of samarium diiod-
ide (ca. 0.1 m in THF, 25 mL, ca. 2.5 mmol), a solution of 7
1
6 H, 2 Me), 2.94 (dd, J = 4.2, 12.8 Hz, 1 H, 6-H), 2.98 (d, J = (200 mg, 0.81 mmol) in THF (10 mL) was added dropwise at room
12.8 Hz, 1 H, 6-H), 3.18 (ddd, J = 6.3, 9.4, 10.8 Hz, 1 H, 1Ј-OCH2), temp. The mixture was stirred for 3 h, then the reaction was
3.26 (br. t, J ≈ 5.2 Hz, 1 H, 1Ј-H), 3.34 (ddd, J = 6.6, 9.4, 10.2 Hz, quenched by the addition of satd. aq. sodium potassium tartrate
1 H, 1Ј-OCH2), 3.40 (br. d, J ≈ 5.3 Hz, 1 H, 4-H), 3.59 (dd, J =
4.9, 11.8 Hz, 1 H, 3Ј-H), 3.64 (dd, J = 3.8, 11.8 Hz, 1 H, 3Ј-H),
3.85 (td, J ≈ 4.0, 4.7 Hz, 1 H, 2Ј-H), 4.65–4.68 (m, 1 H, 6a-H), 4.74
(dd, J = 1.0, 5.8 Hz, 1 H, 3a-H), 7.36–7.45, 7.71–7.75 (2 m, 10 H,
TBDPS) ppm. 13C NMR (CDCl3, 151 MHz): δ = –1.4 (q, SiMe3),
18.9 (t, CH2SiMe3), 19.3, 27.1 (s, q, tBu), 24.1, 26.5 (2 q, 2 Me),
53.0 (t, C-6), 62.8 (t, C-3Ј), 65.3 (d, C-4), 68.5 (t, 1Ј-OCH2), 73.5
(d, C-2Ј), 82.0 (d, C-6a), 82.1 (d, C-1Ј), 82.9 (d, C-3a), 110.9 (s, C-
2), 127.71, 127.72, 129.86, 129.93, 133.1, 133.9, 135.8, 136.1 (4 d,
solution (30 mL), and extracted with ethyl acetate (3ϫ 30 mL). The
combined organic layers were dried (MgSO4), filtered, and the sol-
vents were removed under reduced pressure. The resulting crude
product was filtered through a short silica gel plug (dichlorometh-
ane/methanol, 9:1) to give 21 (147 mg, 74%) as a viscous colorless
1
oil. [α]2D2 = –4.5 (c = 1.17, CHCl3). H NMR (CDCl3, 500 MHz):
δ = 1.28, 1.42 (2 s, 3 H each, 2 Me), 2.85 (dd, J = 3.8, 13.9 Hz, 1
H, 5-H), 3.05–3.09 (m, 2 H, 5-H, 1Ј-H), 3.33 (d, J = 10.9 Hz, 1 H,
2-H), 3.40 (s, 3 H, OMe), 3.69 (dd, J = 6.7, 11.4 Hz, 1 H, 3Ј-H),
2 s, 2 d, TBDPS) ppm. IR (KBr): ν = 3550–3380 (N–H, O–H), 3.73 (dd, J = 4.5, 11.4 Hz, 1 H, 3Ј-H), 3.81 (br. s, 3 H, 2 OH, NH),
˜
3070–2850 (=C–H, C–H), 1110, 1090, 1060, 1040 (C–O) cm–1
.
3.94 (dt, J ≈ 4.4, 6.5 Hz, 1 H, 2Ј-H), 4.60 (d, J = 5.5 Hz, 1 H, 3-
H), 4.70 (d, J = 5.5 Hz, 1 H, 4-H) ppm. 13C NMR (CDCl3,
126 MHz): δ = 23.8, 26.1 (2 q, 2 Me), 51.8 (t, C-5), 58.5 (q, OMe),
62.9 (t, C-3Ј), 66.7 (d, C-2), 71.3 (d, C-2Ј), 76.6 (d, C-1Ј), 81.5 (d,
HRMS (FAB): calcd. for C31H50NO5Si2 [M + H]+ 572.3228; found
572.3241.
(1R,2R,6S,7R,7aR)-2-(tert-Butyldiphenylsiloxy)-6,7-isopropylidene-
dioxy-1-[2-(trimethylsilyl)ethoxy]pyrrolizidine (19): According to
the general procedure described for compound 14a, to a solution
of freshly prepared amino alcohol 18 (190 mg, 0.33 mmol) in anhy-
drous pyridine (13 mL) was added methanesulfonyl chloride
(42 mg, 0.36 mmol, 28 μL) in pyridine (2 mL) at 0 °C, and the mix-
ture was stirred at room temp. overnight. After workup, the crude
product was separated by filtration through a short silica gel col-
umn (hexane/diethyl ether, 2:3) and purified by column chromatog-
raphy (silica gel; pentane/triethylamine, 20:1) to afford pyrrolizidine
19 (99 mg, 54%) as a colorless oil. [α]2D2 = +10.7 (c = 1.55, CHCl3).
1H NMR (CDCl3, 600 MHz): δ = –0.07 (s, 9 H, SiMe3), 0.71–0.80
(m, 2 H, CH2SiMe3), 1.06 (s, 9 H, tBu), 1.35, 1.53 (2 s, 3 H each,
2 Me), 2.73 (dd, J = 2.0, 12.5 Hz, 1 H, 3-H), 3.07 (dd, J = 4.6,
12.5 Hz, 1 H, 3-H), 3.20 (td, J ≈ 6.4, 9.6 Hz, 1 H, 1-OCH2), 3.26–
3.35 [m, 4 H, 1-OCH2 (1 H), 5-H (2 H), 7a-H], 3.65 (mc, 1 H, 1-
H), 4.20 (dt, J ≈ 2.3, 4.6 Hz, 1 H, 2-H), 4.77 (dd, J = 2.8, 6.0 Hz,
1 H, 7-H), 4.87 (ddd, J = 2.9, 4.6, 5.9 Hz, 1 H, 6-H), 7.36–7.40,
7.42–7.45, 7.60–7.63, 7.65–7.67 (4 m, 10 H, TBDPS) ppm. 13C
NMR (CDCl3, 151 MHz): δ = –1.4 (q, SiMe3), 18.4 (t, CH2SiMe3),
19.0, 27.0 (s, q, tBu), 25.4, 27.4 (2 q, 2 Me), 60.8, 60.9 (2 t, C-3,
C-5), 67.1 (t, 1-OCH2), 76.6 (d, C-7a), 79.3 (d, C-2), 81.5 (d, C-6),
84.4 (d, C-7), 89.2 (d, C-1), 112.0 (s, OCO), 127.73, 127.75, 129.90,
129.92, 133.32, 133.34, 135.77, 135.84 (4 d, 2 s, 2 d, TBDPS) ppm.
C-4), 84.2 (d, C-3), 110.9 (s, OCO) ppm. IR (KBr): ν = 3470–3280
˜
(O–H, N–H), 2995–2860 (C–H), 1225, 1140, 1045 (C–O) cm–1
.
HRMS (ESI-TOF): calcd. for C11H22NO5 [M + H]+ 248.1498;
found 248.1494.
(3R,4R,4aR,5R,6S)-5,6-Isopropylidenedioxy-4-methoxy-3-methyl-
sulfonyloxy-hexahydropyrrolo[1,2-b][1,2]oxazine (22a): To a solution
of 7 (1.58 g, 6.44 mmol) in anhydrous dichloromethane (100 mL)
and triethylamine (2.75 g, 27.1 mmol, 3.79 mL), methanesulfonyl
chloride (1.13 g, 9.85 mmol, 0.76 mL) was added dropwise at 0 °C,
and the mixture was stirred at room temp. for 30 min. After
quenching with H2O (150 mL), the layers were separated, the aque-
ous layer was extracted with dichloromethane (2ϫ 35 mL), and the
combined organic phases were dried with MgSO4. The mixture was
filtered, the solvents were removed under reduced pressure, and
the crude product was purified by flash chromatography (silica gel;
hexane/ethyl acetate, 1:1) to give 22a (1.98 g, 95%) as a colorless
solid. M.p. 84–86 °C. [α]2D2 = +85.0 (c = 1.31, CHCl3). 1H NMR
([D6]DMSO, 80 °C, 600 MHz): δ = 1.30, 1.46 (2 s, 3 H each, 2 Me),
2.82 (dd, J = 4.7, 11.1 Hz, 1 H, 7-H), 2.90 (t, J ≈ 6.2 Hz, 1 H, 4a-
H), 3.22, 3.50 (2 s, 3 H each, OMs, OMe), 3.57 (t, J ≈ 6.2 Hz, 1 H,
4-H), 3.60 (dd, J = 6.2, 11.1 Hz, 1 H, 7-H), 3.79 (dd, J = 6.8,
12.0 Hz, 1 H, 2-H), 4.05 (dd, J = 4.1, 12.0 Hz, 1 H, 2-H), 4.53 (td,
J ≈ 4.6, 6.2 Hz, 1 H, 3-H), 4.69 (t, J ≈ 6.6 Hz, 1 H, 5-H), 4.78 (td,
J ≈ 5.6, 6.2 Hz, 1 H, 6-H) ppm. 13C NMR ([D6]DMSO, 80 °C,
151 MHz): δ = 24.6, 26.7 (2 q, 2 Me), 37.6 (q, OMs), 57.5 (q, OMe),
58.8 (t, C-7), 67.4 (t, C-2), 71.5 (d, C-4a), 75.5 (d, C-3), 76.9 (d, C-
4, C-6; higher intensity), 79.6 (d, C-5), 113.1 (s, OCO) ppm. IR
IR (KBr): ν = 3080–2810 (C–H), 1250, 1110, 1075 (C–O) cm–1.
˜
HRMS (FAB): calcd. for C31H48NO4Si2 [M + H]+ 554.3122; found
554.3125. C31H47NO4Si2 (553.9): calcd. C 67.22, H 8.55, N 2.53;
found C 67.31, H 8.54, N 2.62.
(KBr): ν = 3020–2890 (C–H), 1360 (S=O), 1180, 1100, 1050
˜
(C–O) cm–1. HRMS (ESI-TOF): calcd. for C12H22NO7S [M + H]+
324.1117; found 324.1116. C12H21NO7S (323.4): calcd. C 44.57, H
6.55, N 4.33; found C 44.61, H 6.45, N 4.36.
(1R,2S,6R,7R,7aS)-Pyrrolizidine-1,2,6,7-tetraol (20): Analogously
to the synthesis of 12, pyrrolizidine 19 (150 mg, 0.27 mmol) and
DOWEX-50 (350 mg) in EtOH (6 mL) were stirred at 65 °C for 6 d
to give 20 (47 mg, 99%) as a colorless semisolid. [α]2D2 = +29.4 (c
(1ЈR,2R,2ЈR,3R,4S)-2-(3Ј-Hydroxy-1Ј-methoxy-2Ј-methylsulfonyl-
= 0.75, MeOH) [ref.[18] +31.0 (c = 0.9, MeOH)]. 1H NMR oxypropyl)-3,4-isopropylidenedioxypyrrolidine (23a): To a suspen-
(CD3OD, 600 MHz): δ = 2.63 (dd, J = 4.4, 11.5 Hz, 1 H, 5-H),
2.95 (dd, J = 4.3, 11.1 Hz, 1 H, 3-H), 3.11 (dd, J = 3.5, 11.1 Hz, 1
H, 3-H), 3.21 (dd, J = 4.6, 11.5 Hz, 1 H, 5-H), 3.24 (dd, J = 3.3,
6.1 Hz, 1 H, 7a-H), 3.95 (t, J ≈ 3.6 Hz, 1 H, 7-H), 4.07 (td, J ≈ 4.0,
4.5 Hz, 1 H, 6-H), 4.16 (dd, J = 4.3, 6.1 Hz, 1 H, 1-H), 4.19 (td, J
≈ 3.8, 4.3 Hz, 1 H, 2-H) ppm. 13C NMR (CD3OD, 151 MHz): δ =
60.5 (t, C-5), 61.1 (t, C-3), 73.5 (d, C-2), 76.3 (d, C-7a), 76.7 (d, C-
sion of 22a (1.19 g, 3.68 mmol) in methanol (13 mL), Pd on char-
coal (10 %, 1.08 g, 1.05 mmol) followed by ammonium formate
(2.60 g, 41.2 mmol, added in two equal portions, the second after
ca. 45 min) were added, and the mixture was heated to reflux until
the starting material was no longer visible on TLC (typically ca.
1.5 h). The mixture was cooled to room temp. and diluted with
dichloromethane (30 mL), then filtered through Celite, and the sol-
vents were removed under reduced pressure. The resulting oil was
purified by flash chromatography through a short silica gel plug
(dichloromethane/methanol, 15:1) to give 23a (847 mg, 71%) as a
1), 79.4 (d, C-6), 80.8 (d, C-7) ppm. IR (KBr): ν = 3420–3190 (O–
˜
H), 2995–2840 (C–H), 1110, 1090, 1040 (C–O) cm–1. HRMS (EI):
calcd. for C7H13NO4 [M]+ 175.0845; found 175.0847.
Eur. J. Org. Chem. 2014, 442–454
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
451

M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
FULL PAPER
pale-yellow oil, which was used for the next step without further
purification. An analytically pure sample was obtained by ad-
(3S,4R,5S,6S,7S)-7-Hydroxymethyl-6-methoxy-1-azabicyclo[3.2.0]-
heptane-3,4-diol (26a): By a procedure analogous to that applied to
ditional chromatography (silica gel; dichloromethane/methanol, compound 12, azetidine 25a (70 mg, 0.20 mmol) and DOWEX-50
20:1) as a colorless oil. [α]2D2 = +24.0 (c = 0.97, CHCl3). H NMR
(CDCl3, 600 MHz): δ = 1.32, 1.46 (2 s, 3 H each, 2 Me), 2.88 (dd,
J = 3.9, 13.7 Hz, 1 H, 6-H), 3.10 (d, J = 13.7 Hz, 1 H, 6-H), 3.10
(260 mg) in EtOH (3 mL) were stirred at 50 °C for 24 h to give 26a
1
(37 mg, 96%) as colorless crystals. M.p. 164–167 °C (dec.). [α]2D2
=
1
+30.3 (c = 0.44, MeOH). H NMR (CD3OD, 600 MHz): δ = 2.66
(s, 3 H, OMs), 3.22–3.27 (m, 2 H, 1Ј-H, 4-H), 3.38 (br. s, 2 H, OH, (dd, J = 9.3, 12.7 Hz, 1 H, 2-H), 3.22 (dd, J = 6.7, 12.7 Hz, 1 H,
NH), 3.48 (s, 3 H, OMe), 3.90 (d, J = 3.8 Hz, 2 H, 3Ј-H), 4.71–
4.73 (m, 2 H, 2Ј-H, 6a-H), 4.75 (d, J = 5.6 Hz, 1 H, 3a-H) ppm.
13C NMR (CDCl3, 151 MHz): δ = 24.0, 26.3 (2 q, 2 Me), 38.5 (q,
OMs), 52.2 (t, C-6), 60.2 (q, OMe), 61.6 (t, C-3Ј), 66.2 (d, C-4),
2-H), 3.27 (s, 3 H, OMe), 3.66 (dd, J = 3.9, 12.4 Hz, 1 H, 7-CH2),
3.69 (dd, J = 5.4, 6.1 Hz, 1 H, 6-H), 3.71 (dd, J = 7.0, 12.4 Hz, 1
H, 7-CH2), 3.77 (td, J ≈ 3.9, 6.5 Hz, 1 H, 7-H), 3.84 (dd, J = 1.1,
5.4 Hz, 1 H, 5-H), 3.96 (dd, J = 1.1, 4.6 Hz, 1 H, 4-H), 4.40 (ddd,
79.1 (d, C-1Ј), 81.7 (d, C-6a), 82.8 (d, C-3a), 85.0 (d, C-2Ј), 111.3 J = 4.6, 6.7, 9.3 Hz, 1 H, 3-H) ppm. 13C NMR (CD3OD,
(s, OCO) ppm. IR (KBr): ν = 3440–3320 (O–H, N–H), 2985–2835
151 MHz): δ = 50.8 (t, C-2), 56.7 (q, OMe), 60.6 (t, 7-CH2), 68.4
(d, C-7), 74.9 (d, C-3), 75.1 (d, C-5), 75.4 (d, C-4), 77.5 (d, C-
˜
(C–H), 1350 (S=O), 1210, 1170, 1040 (C–O) cm–1. HRMS (FAB):
calcd. for C12H24NO7S [M + H]+ 326.1273; found 326.1266. 6) ppm. IR (KBr): ν = 3620–3290 (O–H), 2995–2820 (C–H), 1130,
C12H23NO7S (325.4): calcd. C 44.30, H 7.12, N 4.30; found C
44.28, H 6.98, N 4.12.
˜
1120, 1105, 1060, 1035 (C–O) cm–1. HRMS (ESI-TOF): calcd. for
C8H16NO4 [M + H]+ 190.1079; found 190.1086. C8H15NO4 (189.2):
calcd. C 50.78, H 7.99, N 7.40; found C 50.52, H 8.03, N 7.42.
(1ЈR,2R,2ЈR,3R,4S)-2-[3Ј-(tert-Butyldimethylsiloxy)-1Ј-methoxy-2Ј-
methylsulfonyloxypropyl]-3,4-isopropylidenedioxypyrrolidine (24a):
According to the general protocol for the silyl ether synthesis, crude
amino alcohol 23a (587 mg, 1.80 mmol) was treated with TBSCl
(0.57 g, 3.77 mmol) in the presence of imidazole (273 mg,
4.01 mmol), and DMAP (23 mg, 0.19 mmol) in anhydrous dichlo-
romethane (40 mL) for 24 h. After standard workup and purifica-
tion by chromatography on a short silica gel column (dichloro-
methane/methanol, 40:1), compound 24a (666 mg, 80%) was iso-
(1ЈR,2R,2ЈR,3R,4S)-2-{3Ј-(tert-Butyldimethylsiloxy)-2Ј-methylsulf-
onyloxy-1Ј-[2-(trimethylsilyl)ethoxy]propyl}-3,4-isopropylidenedi-
oxypyrrolidine (24b): In analogy to the reaction sequence described
for 24a, compound 11 (169 mg, 0.51 mmol) in dichloromethane
(10 mL) was treated with triethylamine (218 mg, 2.15 mmol,
0.30 mL) and methanesulfonyl chloride (89 mg, 0.78 mmol, 60 μL),
and the mixture was stirred at room temp. for 30 min. After
workup and filtration through a short silica gel column (petroleum
ether/ethyl acetate, 3:1), 22b (199 mg, 95%) was isolated as a color-
less oil. [α]2D2 = +71.1 (c = 0.67, CHCl3). 1H NMR ([D6]DMSO,
80 °C, 600 MHz): δ = 0.03 (s, 9 H, SiMe3), 0.93 (t, J = 7.9 Hz, 2
H, CH2SiMe3), 1.29, 1.45 (2 s, 3 H each, 2 Me), 2.82 (dd, J = 4.8,
11.4 Hz, 1 H, 7-H), 2.90 (t, J ≈ 6.2 Hz, 1 H, 4a-H), 3.21 (s, 3 H,
OMs), 3.60 (dd, J = 6.1, 11.4 Hz, 1 H, 7-H), 3.67 (t, J ≈ 5.9 Hz, 1
H, 4-H), 3.72–3.82 (m, 3 H, 2-H, 4-OCH2), 4.05 (dd, J = 4.0,
12.2 Hz, 1 H, 2-H), 4.49 (td, J ≈ 4.2, 6.0 Hz, 1 H, 3-H), 4.69 (t, J
≈ 6.7 Hz, 1 H, 5-H), 4.79 (dt, J ≈ 5.7, 6.1 Hz, 1 H, 6-H) ppm. 13C
NMR ([D6]DMSO, 80 °C, 151 MHz): δ = –1.8 (q, SiMe3), 17.7 (t,
CH2SiMe3), 24.7, 26.7 (2 q, 2 Me), 37.7 (q, OMs), 59.1 (t, C-7),
66.8 (t, 4-OCH2), 67.4 (t, C-2), 71.8 (d, C-4a), 74.5 (d, C-4), 75.7 (d,
1
lated as a colorless oil. [α]2D2 = +18.6 (c = 2.27, CHCl3). H NMR
(CDCl3, 600 MHz): δ = 0.09, 0.10, 0.90 (3 s, 2ϫ 3 H, 9 H, TBS),
1.32, 1.46 (2 s, 3 H each, 2 Me), 2.16 (br. s, 1 H, NH), 2.88 (dd, J
= 4.2, 13.4 Hz, 1 H, 6-H), 3.05 (d, J = 13.4 Hz, 1 H, 6-H), 3.09 (s,
3 H, OMs), 3.21 (br. d, J ≈ 6.7 Hz, 1 H, 4-H), 3.39 (dd, J = 4.3,
6.7 Hz, 1 H, 1Ј-H), 3.51 (s, 3 H, OMe), 3.89 (dd, J = 5.5, 11.1 Hz,
1 H, 3Ј-H), 3.97 (dd, J = 5.9, 11.1 Hz, 1 H, 3Ј-H), 4.65 (dd, J =
1.2, 5.8 Hz, 1 H, 3a-H), 4.70–4.72 (m, 1 H, 6a-H), 4.82 (td, J ≈ 4.7,
5.6 Hz, 1 H, 2Ј-H) ppm. 13C NMR (CDCl3, 151 MHz): δ = –5.4
(enhanced signal), 18.2, 25.8 (q, s, q, TBS), 24.2, 26.5 (2 q, 2 Me),
38.4 (q, OMs), 52.9 (t, C-6), 60.7 (q, OMe), 61.8 (t, C-3Ј), 65.9 (d,
C-4), 79.2 (d, C-1Ј), 82.4 (d, C-6a), 82.6 (d, C-2Ј), 83.1 (d, C-3a),
111.4 (s, C-2) ppm. IR (KBr): ν = 3335 (N–H), 2990–2840 (C–
˜
C-3), 77.1 (d, C-6), 79.8 (d, C-5), 113.1 (s, OCO) ppm. IR (KBr): ν
˜
H), 1360 (S=O), 1175, 1090 (C–O) cm–1. HRMS (FAB): calcd. for
C18H38NO7SSi [M + H]+ 440.2138; found 440.2138.
= 2990–2870 (C–H), 1365 (S=O), 1180, 1105, 1050 (C–O) cm–1.
HRMS (FAB): calcd. for C16H32NO7SSi [M + H]+ 410.1669; found
410.1664.
(3S,4R,5R,6S,7S)-7-(tert-Butyldimethylsiloxymethyl)-3,4-isopropyl-
idenedioxy-6-methoxy-1-azabicyclo[3.2.0]heptane (25a): A solution
of mesylate 24a (560 mg, 1.27 mmol) in anhydrous pyridine
(20 mL) was heated at 90 °C for 60 h. The solvent was removed
under reduced pressure and the resulting brown oil was purified
by chromatography (silica gel; pentane/triethylamine, 9:1) to give
analytically pure azetidine derivative 25a (166 mg, 38%) as a color-
less oil. [α]2D2 = +10.3 (c = 0.31, CHCl3). 1H NMR (CDCl3,
600 MHz): δ = 0.086, 0.089, 0.92 (3 s, 2ϫ 3 H, 9 H, TBS), 1.32,
1.47 (2 s, 3 H each, 2 Me), 2.86 (dd, J = 4.6, 13.4 Hz, 1 H, 2-H),
To a stirred solution of Pd on charcoal (10%, 80 mg, 0.08 mmol,
saturated with hydrogen for 1 h) in MeOH (4 mL), a solution of
22b (199 mg, 0.49 mmol) in MeOH (2 mL) was added, and the mix-
ture was stirred under hydrogen (balloon pressure) at room temp.
for 24 h. Filtration through a pad of Celite and purification by
flash chromatography (silica gel; ethyl acetate/methanol, 12:1) af-
forded 23b (150 mg, 75%) as a pale-yellow oil, which was used in
the next step without further purification. [α]2D2 = +12.9 (c = 1.25,
3.29 (s, 3 H, OMs), 3.45 (dd, J = 6.8, 13.4 Hz, 1 H, 2-H), 3.64 (dd, CHCl3). 1H NMR (CDCl3, 600 MHz): δ = 0.02 (s, 9 H, SiMe3),
J = 4.3, 12.1 Hz, 1 H, 7-CH2), 3.73 (mc, 1 H, 7-H), 3.77 (dd, J =
2.4, 12.1 Hz, 1 H, 7-CH2), 3.87 (t, J ≈ 5.2 Hz, 1 H, 6-H), 4.02 (br. d,
J ≈ 4.5 Hz, 1 H, 5-H), 4.56 (dd, J = 1.0, 6.0 Hz, 1 H, 4-H), 4.94
(td, J ≈ 4.9, 6.3 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3, 151 MHz):
δ = –5.58, –5.55, 18.4, 25.9 (2 q, s, q, TBS), 25.5, 27.5 (2 q, 2 Me),
54.1 (t, C-2), 56.3 (q, OMe), 60.6 (t, 7-CH2), 66.8 (d, C-7), 73.9 (d,
C-5), 77.0 (d, C-6), 83.5 (d, C-3), 85.2 (d, C-4), 112.4 (s,
0.94–0.99 (m, 2 H, CH2SiMe3), 1.32, 1.46 (2 s, 3 H each, 2 Me),
2.91 (dd, J = 4.1, 13.6 Hz, 1 H, 6-H), 3.09 (d, J = 13.6 Hz, 1 H, 6-
H), 3.10 (s, 3 H, OMs), 3.17 (br. s, 2 H, OH, NH), 3.26 (d, J =
8.4 Hz, 1 H, 4-H), 3.38 (dd, J = 6.2, 8.4 Hz, 1 H, 1Ј-H), 3.47–3.53,
3.72–3.78 (2 m, 2 H, 1Ј-OCH2), 3.91 (d, J = 3.7 Hz, 2 H, 3Ј-H),
4.69–4.75 (m, 3 H, 2Ј-H, 3a-H, 6a-H) ppm. 13C NMR (CDCl3,
151 MHz): δ = –1.4 (q, SiMe3), 18.9 (t, CH2SiMe3), 24.0, 26.4 (2
OCO) ppm. IR (film): ν = 2985–2855 (C–H), 1250, 1210, 1160, q, 2 Me), 38.7 (q, OMs), 52.3 (t, C-6), 61.4 (t, C-3Ј), 66.1 (d, C-4),
˜
1130, 1055 (C–O) cm–1. HRMS (FAB): calcd. for C17H34NO4Si [M 70.1 (t, 1Ј-OCH2), 77.1 (d, C-1Ј), 81.6 (d, C-6a), 82.8 (d, C-3a),
+ H]+ 344.2257; found 344.2258. C17H33NO4Si (343.5): calcd. C 84.7 (d, C-2Ј), 111.4 (s, OCO) ppm. IR (KBr): ν = 3490–3315
˜
59.44, H 9.68, N 4.08; found C 59.46, H 9.84, N 4.09.
(O–H, N–H), 2990–2860 (C–H), 1350 (S=O), 1250, 1170, 1060
452
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 442–454

Synthesis of Enantiopure Polyhydroxylated Bicyclic N-Heterocycles
(C–O) cm–1. HRMS (FAB): calcd. for C16H34NO7SSi [M + H]+
412.1825; found 412.1831.
for C7H14NO4 [M + H]+ 176.0923; found 176.0913. C7H13NO4
(175.2): calcd. C 47.99, H 7.48, N 8.00; found C 47.86, H 7.51, N
7.89.
According to the general protocol for silylation, freshly prepared
23b (150 mg, 0.36 mmol) was treated overnight with TBSCl
(108 mg, 0.71 mmol) in the presence of imidazole (57 mg,
0.81 mmol) and DMAP (6 mg, 0.05 mmol) in anhydrous dichloro-
methane (8 mL). After aqueous workup, drying (Na2SO4), and pu-
rification by column chromatography (silica gel; petroleum ether/
ethyl acetate, 1:1), 24b (174 mg, 91%) was isolated as a colorless
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of all compounds.
Acknowledgments
1
oil. [α]2D2 = +6.8 (c = 1.11, CHCl3). H NMR (CDCl3, 600 MHz):
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 acknowledge support by Prof. Inmaculada Robina and the
Ministerio de Ciencia e Innovación of Spain (project CTQ2012-
31247).
δ = 0.01 (s, 9 H, SiMe3), 0.085, 0.089, 0.90 (3 s, 2ϫ 3 H, 9 H,
TBS), 0.93–0.98 (m, 2 H, CH2SiMe3), 1.32, 1.46 (2 s, 3 H each, 2
Me), 2.04 (br. s, 1 H, NH), 2.88 (dd, J = 4.2, 13.4 Hz, 1 H, 6-H),
3.02 (d, J = 13.4 Hz, 1 H, 6-H), 3.08 (s, 3 H, OMs), 3.21 (br. d, J
≈ 6.9 Hz, 1 H, 4-H), 3.46 (dd, J = 4.4, 6.9 Hz, 1 H, 1Ј-H), 3.55–
3.59, 3.74–3.80 (2 m, 2 H, 1Ј-OCH2), 3.88 (dd, J = 5.5, 11.0 Hz, 1
H, 3Ј-H), 3.96 (dd, J = 6.2, 11.0 Hz, 1 H, 3Ј-H), 4.65 (dd, J = 1.2,
5.8 Hz, 1 H, 3a-H), 4.69–4.71 (m, 1 H, 6a-H), 4.80 (td, J ≈ 4.4,
5.8 Hz, 1 H, 2Ј-H) ppm. 13C NMR (CDCl3, 151 MHz): δ = –5.44,
–5.41, 18.2, 25.8 (2 q, s, q, TBS), –1.4 (q, SiMe3), 19.1 (t,
CH2SiMe3), 24.2, 26.5 (2 q, 2Me), 38.5 (q, OMs), 53.0 (t, C-6),
61.7 (t, C-3Ј), 65.9 (d, C-4), 70.3 (t, 1Ј-OCH2), 77.1 (d, C-1Ј), 82.4
(d, C-6a), 82.7 (d, C-2Ј), 83.2 (d, C-3a), 111.3 (s, OCO) ppm. IR
[1] Reviews: a) M. Brasholz, H.-U. Reissig, R. Zimmer, Acc.
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(KBr): ν = 3385 (N–H), 2960–2855 (C–H), 1360 (S=O), 1250, 1175,
˜
1085 (C–O) cm–1. HRMS (FAB): calcd. for C22H48NO7SSi2 [M +
H]+ 526.2690; found 526.2685.
(3S,4R,5R,6S,7S)-7-Hydroxymethyl-1-azabicyclo[3.2.0]heptane-
3,4,6-triol (26b): A solution of 24b (860 mg, 1.63 mmol) in an-
hydrous pyridine (25 mL) was heated at 90 °C for 60 h. After the
solvent was removed in vacuo, the resulting oil was purified by
chromatography (silica gel; hexane/triethylamine, 20:1) to provide
25b (301 mg, 43%) as a colorless oil. [α]2D2 = +10.0 (c = 1.36,
CHCl3). 1H NMR (CDCl3, 600 MHz): δ = 0.01 (s, 9 H, SiMe3),
0.08, 0.92 (2 s, 6 H, 9 H, TBS), 0.89–0.92 (m, 2 H, CH2SiMe3),
1.32, 1.46 (2 s, 3 H each, 2 Me), 2.86 (dd, J = 4.8, 13.4 Hz, 1 H,
2-H), 3.41 (dt, J ≈ 7.8, 9.0 Hz, 1 H, 6-OCH2), 3.46 (dd, J = 6.8,
13.4 Hz, 1 H, 2-H), 3.48 (dt, J ≈ 8.2, 9.0 Hz, 1 H, 6-OCH2), 3.64
(dd, J = 4.3, 12.0 Hz, 1 H, 7-CH2), 3.73 (mc, 1 H, 7-H), 3.77 (dd,
J = 2.4, 12.0 Hz, 1 H, 7-CH2), 3.93 (t, J ≈ 5.4 Hz, 1 H, 6-H), 4.03
(br. d, J ≈ 5.0 Hz, 1 H, 5-H), 4.55 (dd, J = 1.0, 6.0 Hz, 1 H, 4-
H), 4.93 (td, J ≈ 4.9, 6.3 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3,
151 MHz): δ = –5.57, –5.53, 18.4, 25.9 (2 q, s, q, TBS), –1.3 (q,
SiMe3), 18.3 (t, CH2SiMe3), 25.6, 27.5 (2 q, 2Me), 54.2 (t, C-2),
60.7 (t, 7-CH2), 66.2 (t, 6-OCH2), 67.3 (d, C-7), 74.3 (d, C-5), 75.0
(d, C-6), 83.4 (d, C-3), 85.3 (d, C-4), 112.4 (s, OCO) ppm. IR (film):
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˜
(C–O). HRMS (ESI-TOF): calcd. for C21H44NO4Si2 [M + H]+
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A solution of 25b (263 mg, 0.61 mmol) in EtOH (8 mL) was stirred
with DOWEX-50 (780 mg) at 70 °C for 20 h to give 26b (104 mg,
97%) as colorless crystals. M.p. 198–201 °C (dec.). [α]2D2 = +28.0 (c
1
= 0.55, MeOH). H NMR (CD3OD, 600 MHz): δ = 2.66 (dd, J =
9.7, 12.7 Hz, 1 H, 2-H), 3.23 (dd, J = 6.9, 12.7 Hz, 1 H, 2-H), 3.66
(dd, J = 3.6, 12.6 Hz, 1 H, 7-CH2), 3.70 (dd, J = 7.1, 12.6 Hz, 1
H, 7-CH2), 3.76 (td, J ≈ 3.6, 6.9 Hz, 1 H, 7-H), 3.85 (br. d, J ≈
5.8 Hz, 1 H, 5-H), 3.93 (dd, J = 5.8, 6.7 Hz, 1 H, 6-H), 3.94 (br. d,
J ≈ 4.6 Hz, 1 H, 4-H), 4.40 (ddd, J = 4.6, 6.9, 9.7 Hz, 1 H, 3-
H) ppm. 13C NMR (CD3OD, 151 MHz): δ = 50.5 (t, C-2), 60.2 (t,
7-CH2), 68.5 (d, C-6), 70.8 (d, C-7), 74.7 (d, C-3), 75.0 (d, C-4),
77.8 (d, C-5) ppm. IR (KBr): ν = 3590–3100 (O–H), 2990–2850 (C–
˜
H), 1130, 1095, 1065, 1050 (C–O) cm–1. HRMS (ESI-TOF): calcd.
Eur. J. Org. Chem. 2014, 442–454
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
453

M. Jasin´ski, E. Moreno-Clavijo, H.-U. Reissig
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Received: September 14, 2013
Published Online: November 19, 2013
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