Nucleophilic additions to cyclic nitrones en route to iminocyclitols - Total syntheses of DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, nectrisine, and radicamine B

Article abstract of DOI:10.1002/ejoc.200800098

Highly diastereoselective nucleophilic additions to cyclic nitrones derived from L-malic acid and D-arabinose have been used for the construction of enantiomerically pure polyhydroxylated pyrrolidines. The synthetic strategy adopted was based on an oxidat

Full text of DOI:10.1002/ejoc.200800098

FULL PAPER
DOI: 10.1002/ejoc.200800098
Nucleophilic Additions to Cyclic Nitrones en Route to Iminocyclitols – Total
Syntheses of DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, Nectrisine, and
Radicamine B
Pedro Merino,*[a] Ignacio Delso,[a,b] Tomás Tejero,[a] Francesca Cardona,[b]
Marco Marradi,[a,b] Enrico Faggi,[a,b] Camilla Parmeggiani,[a,b] and Andrea Goti*[b]
Keywords: Iminocyclitols / Pyrrolidines / Nitrones / Nucleophilic addition / Nitrogen heterocycles
Highly diastereoselective nucleophilic additions to cyclic
nitrones derived from -malic acid and -arabinose have
substituted polyhydroxylated pyrrolidines have been pre-
pared with abundant configurational diversity. The use of ap-
propriate substrates and reagents allowed for approaches to
DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, nectrisine and rad-
icamine B. Several analogues of these compounds with in-
verted configuration at one or more stereocenters were also
prepared.
L
D
been used for the construction of enantiomerically pure poly-
hydroxylated pyrrolidines. The synthetic strategy adopted
was based on an oxidation/reduction protocol involving hy-
droxylamine/nitrone pairs and demonstrates the use of rea-
gent- and substrate-derived stereocontrol. In most cases re-
actions took place with total diastereoselectivity and in quan-
titative yield, with no purification being necessary. By this
strategy, 2-(hydroxymethyl)-, 2-(aminomethyl)-, and 2-aryl-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tivities of DMDP and its analogues make them attractive
targets for synthesis.[9] Of particular interest are several de-
oxy derivatives bearing lipophilic groups instead of the “us-
ual” hydroxymethyl group at their 2-positions, several of
which show potent α--fucosidase inhibitory activity.[10] Im-
portant members of this subclass of compounds are aniso-
mycin, deoxyanisomycin, and analogues.[11]
The biological activities of iminocyclitols are due to the
structural similarity of the corresponding protonated com-
pounds under physiological conditions with the flattened
half-chair conformation found for the transition structures
involved in the mechanism of glycosidases (Figure 1).[12] In
the particular case of the N-acetyl-β-hexosaminidases, im-
portant enzymes involved in osteoarthritis, the participation
of the neighboring C-2 acetamido group of the substrate
has been suggested.[13] Investigating this hypothesis, Wong
and co-workers[14] found that N-acetyl-2-(aminomethyl)imi-
nocyclitol 2 and its structural analogues are potent inhibi-
tors of N-acetyl-β-hexosaminidases, and hence are expected
to have potential as chondrotherapeutic agents.[15] Closely
Introduction
A great variety of alkaloids possessing polyhydroxylated
pyrrolidine structures, otherwise known as iminocyclitols,
have been isolated from natural sources, including plants
and microorganisms,[1] and many of them are powerful in-
hibitors of biologically important enzymes such as glycosid-
ases and other enzymes closely associated with the metabo-
lism of N-linked glycoproteins.[2] Because of that biological
activity, iminocyclitols might constitute powerful tools
against cancer,[3] viral infections,[4] or diabetes.[5] Naturally
occurring DMDP (1), a fairly widespread secondary metab-
olite first isolated from Derris elliptica (Leguminosae)[6] and
since then found in microorganisms and plant species of
quite unrelated families,[7] together with its unnatural syn-
thetic analogues, are known to be selective inhibitors of gly-
cosidases and have proved to have potential for use as anti-
viral and anticancer therapeutic drugs, as well as immuno-
modulators.[8] Such a diverse array of potentially useful ac-
[a] Laboratorio de Síntesis Asimétrica, Departamento de Química
Orgánica, Instituto de Ciencia de Materiales de Aragón, Uni- related derivatives of 2 bearing lipophilic aliphatic or aro-
versidad de Zaragoza, CSIC,
matic amides attached to C1 have been found to inhibit β-
50009 Zaragoza, Aragón, Spain
glucosidase in the nanomolar range.[16] Simpler synthetic
Fax: +34-976-762075
E-mail: pmerino@unizar.es
analogues of 2 are also inhibitors of several glycosidases, as
reported by Vogel.[17] Other syntheses of polyhydroxylated
2-(aminomethyl)pyrrolidines have been reported by Jäger[18]
and Correia.[19] Several of these compounds have also been
used as ligands, forming chelates with a variety of metals
including vanadium,[20] gold,[21] zinc,[22] palladium,[23]
[b] Dipartimento di Chimica Organica Ugo Schiff and Hetero-
BioLab, Università di Firenze, associated with ICCOM-CNR,
via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39-055-4573531
E-mail: andrea.goti@unifi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 2929–2947
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P. Merino, A. Goti et al.
FULL PAPER
nickel,[24] ruthenium,[25] platinum,[26] rhodium,[27] titanium, versity.[38] As a continuation of our interest in the use of
and zirconium,[28] that served as catalysts in a variety of nitrones as versatile synthetic intermediates[39] here we de-
enantioselective reactions such as homocoupling of boronic scribe in detail a concise, efficient, and stereochemically
acids[29] and hydrogenation.[30] Platinum complexes of 2- flexible approach to the preparation of a wide variety of
(aminomethyl)pyrrolidines have also been evaluated against polyhydroxylated pyrrolidines. The viability of this strategy
several human cancer lines[26b] and their DNA-binding was confirmed by the preparation of DMDP and analogues
properties have been studied.[26c]
including 6-deoxy-DMDP, DAB-1, CYB-3, and nectrisine,
of 2-(aminomethyl)pyrrolidines, and of 2-arylpyrrolidines,
including radicamine B.[40]
Results and Discussion
Synthetic Plan
We opted to take advantage of the availability of a vari-
able set of protected hydroxylated cyclic nitrones that can
easily be prepared from carbohydrates and other natural
sources,[41] thus providing the configuration(s) of one or
more stereogenic centers of the pyrrolidine ring as derived
from the chiral pool precursor. To obtain the target com-
pounds we adopted the synthetic plan illustrated in
Scheme 1, where nitrone A serves as electrophile in nucleo-
philic addition reactions. The additions would be expected
to be highly stereoselective, according to our previous ex-
perience,[33a] by virtue of the presence of vicinal stereogenic
centers that should discriminate between the two faces of
the nitrone.
Figure 1. Polyhydroxylated pyrrolidines as inhibitors of glycosid-
ases.
An unusual variety of natural polyhydroxylated pyrroli-
dines possessing an aromatic ring at C-2 of the pyrrolidine
system have recently attracted great attention both from
synthetic and from biological points of view. Among these
compounds are codonopsine (3a) and codonopsinine
(3b),[31] isolated from Codonopsis clematidea and displaying
hypotensive activity,[32] the synthesis of the latter having
been recently reported by us.[33] Radicamines A (4a) and B
Scheme 1. Synthetic plan.
In order to introduce suitable groups we have chosen as
(4b) have been isolated[34] from Lobelia chinensis, a plant nucleophiles hydroxymethyl anion synthetic equivalents,[42]
used in Chinese folk medicine, and syntheses of their cyanide (as an aminomethyl synthon equivalent),[43] and
enantiomers (as a result of a misassignment of the naturally Grignard reagents.[44] To gain access to other isomers an
occurring compounds) have recently been reported.[35] oxidation/reduction protocol was implemented for the hy-
Other 2-aryliminocyclitols such as 5a and 5b have been droxylamines B obtained immediately after the nucleophilic
shown to be inhibitors of nucleoside hydrolase and phos- addition step. The route involved oxidation of compounds
phorylase enzymes with inhibition constants in the picomo- B to nitrones C, followed by stereoselective reduction to
lar range.[36] Several syntheses of these compounds have epimeric hydroxylamine D.
been reported.[37]
Finally, further elaboration of intermediates B and D
Among the structural variations of five-membered imi- would allow the obtention of the target polyhydroxylated
nocyclitols reported in the literature,[1,2] relatively limited pyrrolidines. It should be pointed out that the oxidation of
attention has been devoted to the obtainment of structural B to furnish C may allow regioselectivity to be accounted
analogues with different configurations, particularly at C- for, since two possible isomers can be formed, it being pos-
2 and/or C-5, from common starting materials. Usually, a sible to some extent to predict the major one. This feature,
particular synthesis has been designed for each isomer to combined with a suitable study on the reduction scheme,
be prepared, without addressing possible stereochemical di- gives our approach great flexibility, which should make it
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Iminocyclitols from Cyclic Nitrones
possible to play around with a wide panel of substrates, higher yield (see below). In each case the reaction took
leading to an abundant variety of configurational combina- place smoothly, the only exception being the addition of 9
tions.
to 6 (Table 1, Entry 1). Only one diastereoisomer, as de-
tected by 400 MHz H NMR, was obtained in the cases of
1
additions to nitrones 6 and 7 (Table 1, Entries 1–3). Al-
though excellent selectivity was also observed for nitrone 8,
it was possible in this case to identify the minor isomer,
which was obtained in 5% yield.[49] This slight decrease in
selectivity might arise from the fluxionality of the O-benzyl
groups, which could, to some extent, interfere with the ap-
proach of the nucleophile to the less hindered face.[50]
Contrary to what has been found for acyclic α-alkoxy
nitrones,[38c] stereocontrol of the nucleophilic additions to
cyclic derivatives cannot be achieved by use of Lewis ac-
ids.[39,43a] In order to gain access to C-2 epimers of hydrox-
Synthesis of DMDP and Structural Analogues
The starting nitrones 6–8 used for this study were pre-
pared from -malic acid, for nitrone 6,[45] and from -arabi-
nose for nitrones 7[46] and 8[47] (Scheme 2).
Scheme 2. Synthesis of cyclic nitrones.
Methoxymethyl- and benzyl-protected (hydroxymethyl)-
lithium derivatives 9 and 10, generated in situ from the cor-
responding tributyltin derivatives as described,[48] were cho-
sen as the synthetic equivalents of the hydroxymethyl anion.
The results of the nucleophilic additions of these reagents
to nitrones 6–8, illustrated in Scheme 3, are summarized in
Table 1.
Scheme 3. Addition of protected hydroxymethyllithium derivatives.
Table 1. Nucleophilic additions of LiCH2ORЈ to nitrones 6–8.[a,b]
Entry Nitrone RЈ
Hydroxylamine
cis/trans[c,d]
% Yield[e]
1
2
3
4
6
6
7
8
MOM
Bn
MOM
Bn
11
12
13
14
Յ5:95
Յ5:95
Յ5:95
5:95
35
80
70
71
[a] All reactions were carried out in THF at –80 °C. [b] 1.25 equiv.
of LiCH2ORЈ were used. [c] Measured by 1H NMR in the crude
isolated mixture. [d] With reference to the relative configuration
between substituents at C-2 and C-3 of the pyrrolidine ring. [e] Iso-
lated yield after column chromatography.
For nitrones 6 and 7, the OMOM derivative 9 was to be
preferred (Table 1, Entries 1 and 3) in view of the potential
for further deprotection in only one step under acidic con-
ditions. For the same reason (simultaneous hydrogenolysis
of all benzyl ethers), the OBn reagent 10 was used with
nitrone 8. The addition of 10 to 6 (Table 1, Entry 2) was
carried out to provide the corresponding product in a Scheme 4. Oxidation and reduction of cyclic hydroxylamines.
Eur. J. Org. Chem. 2008, 2929–2947
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2931

P. Merino, A. Goti et al.
ylamines 12–14 it was then necessary to apply an oxidation Table 2. Reduction of nitrones 15, 16a, and 17.
FULL PAPER
(to nitrone) and reduction (to hydroxylamine) sequence,
which had been successfully used in our laboratories for
the synthesis of substituted prolines.[40,51] The oxidation of
hydroxylamine 12 with manganese(IV) oxide[52] took place
regioselectively, affording nitrone 15 (Scheme 4). On the
other hand, the oxidation of hydroxylamine 13 showed
lower regioselectivity, furnishing a 2:1 mixture of nitrones
16a and 16b (Scheme 4). Because of its C2 symmetry, no
regioselectivity issue applied for the oxidation of hydroxyl-
amine 14, which afforded nitrone 17 quantitatively. All oxi-
dations were found to be clean and quantitative, no purifi-
cation of the obtained nitrones being necessary after con-
ventional workup.
Entry
Nitrone
Hydride[a]
cis/trans[b,c]
% Yield
1
2
3
4
5
6
15
15
NaBH4
-selectride
NaBH4
-selectride
NaBH4
-selectride
Ն95:5[e]
Ն95:5[e]
Ն95:5[f]
Ն95:5[f]
57:43[g]
Ն95:5[g]
100
100
66[d]
66[d]
100
100
16a
16a
17
17
[a] NaBH4/MeOH 2 h, 0 °C; -selectride: THF, –80 °C, 14 h. [b]
Measured by 1H NMR in the crude isolated mixture. [c] With refer-
ence to the relative configuration between substituents at C-2 and
C-3 in the pyrrolidine ring. [d] Isolated yield after column
chromatography. [e] With reference to 18:12. [f] With reference to
19:13. [g] With reference to 20:14.
The observed regioselectivity was in agreement with the
model previously proposed by some of us.[45a,53] According duction with -selectride was found to be completely selec-
to this model, the oxidation should occur preferentially at tive towards the expected isomer. The absolute configura-
the side where a β-alkoxy group (to nitrogen) is present and tions of the newly created stereogenic centers in hydroxyl-
if the α-hydrogen atom to be abstracted can be oriented in amines 12–14 and 18–20 were unambiguously ascertained
an antiperiplanar disposition with respect to the β-alkoxy by 1D NOE and 2D NOESY and COSY NMR experi-
group. This orientation allows an electron-donating hyper- ments, which unequivocally showed the expected interac-
conjugative effect (σC–H Ǟσ*C–O) responsible for favoring tions between the protons of the pyrrolidine ring. For com-
1
the abstraction of the corresponding proton in the oxi- pound 14 both the H and 13C spectra only showed signals
dation process. Thus, the oxidation of hydroxylamine 12 consistent with the presence of a symmetry plane in the
took place only on the side where two β-alkoxy groups are molecule.
present.
The target polyhydroxylated pyrrolidines were finally ob-
For hydroxylamine 13, a proton at both C-2 and C-5 can tained by concomitant reduction and deprotection of the
be accommodated antiperiplanar to a β-alkoxy substituent precursor hydroxylamines. Compounds 12–14 and 18–20
(Figure 2). The preferential formation of 16a is due to the were subjected to hydrogenolysis under hydrogen (20 atm)
presence of an additional α-alkoxy group at the C-2 exocy- in concd. HCl/methanol and in the presence of Pearlman’s
clic chain, which can be more easily oriented into the ap- catalyst (10%) to give the corresponding hydrochlorides in
propriate conformation with 2-H than 5-Hantiperiplanar with nearly quantitative yields. Thus, the hydrochloride of CYB-
the α-alkoxy group at C-4.[54] The obtainment of 16a as 3 21[56] and its C-2 epimer 22[56,57] were obtained in 80%
the major regioisomer may also result from the generally overall yield from nitrone 6. Hydrochlorides 23[58] and 24[58]
preferred formation of the more substituted ketonitrone were obtained in 70% overall yield from nitrone 7, and the
with respect to its regioisomeric aldonitrone when hydroxyl- hydrochloride of DMDP 1·HCl[9] and its C-2 epimer 25[59]
amines with different degrees of substitution at C-α and C- were obtained from nitrone 8 in 71% overall yield
αЈ are oxidized.[55]
(Scheme 5).
The complete deprotection and reduction of 14 allowed,
as in the other cases, an easy manipulation of the final com-
pound as the corresponding hydrochloride 1·HCl, which
proved to be stable at 25 °C for months without appreciable
decomposition. Nevertheless, in order to compare the spec-
troscopic and physical properties of DMDP with those re-
ported in the literature, the obtained hydrochloride was also
characterized as the free base after deposition onto a
DOWEX 50W8–200 exchange resin and elution with
NH4OH in MeOH (3 ). Since there has been some contro-
Figure 2. Antiperiplanar 2-H/OMOM conformation in 13.
The reduction of nitrones 15, 16a, and 17 (Scheme 4) was versy about the presence of hydrochloride salts and free
carried out with sodium borohydride and -selectride as bases with other isomers,[60] it is worth pointing out that a
listed in Table 2. In each case the reaction was quantitative, trivial analysis of the 1H NMR showed more deshielded
showing excellent diastereoselectivity.
signals for the hydrochlorides than for the free bases. In
Both sodium borohydride in methanol at 0 °C (Table 2, addition, the typical signal corresponding to ammonium
Entries 1 and 3) and -selectride in THF at –80 °C (Table 2, species is seen at 7–8 ppm in the spectrum of 1·HCl (as a
Entries 2, 4, and 6) gave only one isomer, the only exception consequence of the high symmetry around the nitrogen
being the reduction of 17 with NaBH4 (Table 2, Entry 5). atom), thus unequivocally confirming the presence of the
In this case, attempts to increase the selectivity by lowering hydrochloride salt. Also, the elemental analyses fully agree
the temperature resulted in no reaction. Fortunately, the re- with both hydrochloride and free salt. The analytical and
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Iminocyclitols from Cyclic Nitrones
and α-mannosidase, isolated from Angylocalyx sp. (Leg-
uminosae),[62,63] was obtained in high yield (86%) by direct
hydrogenation of nitrone 8 with Pd/C in HCl/MeOH
(Scheme 6).
Scheme 6. Syntheses of DAB-1 and nectrisine.
Nectrisine (28, also known as FR-900483), isolated from
the fungus Nectria lucida F-4490 (Ascomycetes),[64] is an
inhibitor of glucosidase and mannosidase, also possessing
immunostimulating properties. Deoxygenation of nitrone 8
to provide imine 27 was achieved by a modification of a
reported procedure.[65] Only the addition of triphenylphos-
phane (10 mol-%) to trimethylphosphite in triethylamine al-
lowed 27[66] to be afforded in good yield. Debenzylation of
27 with BCl3,[66] in order to preserve the imine function-
ality, gave nectrisine 28, which was found to be unstable in
D2O solution,[67] affording hydrated derivatives. On the
other hand, 13C NMR spectroscopic data of the crude com-
pound were in agreement with those reported in the litera-
ture.[68]
The synthesis of 6-deoxy-DMDP (30), an inhibitor of
β-mannosidase, β-galactosidase, and α-fucosidase isolated
from Angylocalyx sp. (Leguminosae),[69] was achieved
through quantitative and complete stereoselective addition
of methylmagnesium bromide to nitrone 8 (Scheme 7). As
expected, the Grignard reagent reacted with the cyclic
nitrone at the less hindered face, opposite the C-3 OBn sub-
stituent, to afford hydroxylamine 29 quantitatively. Hydro-
genation of 29 with Pd/C (10%) in HCl/MeOH, followed
Scheme 5. Hydrogenation/deprotection of protected hydroxyl-
amines.
spectroscopic data of 1 were in agreement, the NMR spec-
troscopic data being an exact match with those previously
reported.[61]
It was also found that direct treatment of nitrones 15 and
16a under the same hydrogenolytic conditions gave pyrroli-
dines 22 and 24, respectively, also in quantitative yields
(Scheme 5). Overall, it was found that the direct hydrogena-
tion of ketonitrones was the more efficient route, providing
22 and 24 in overall yields of 80% and 70%, respectively,
in three steps from the starting nitrones 6 and 7. The hydro-
genation of nitrone 17 was less selective, however, probably
because of the presence of the benzyloxy group at C-4, af-
fording a mixture of 1·HCl and 25, which were formed in
32% and 68% yields, respectively.
Nitrone 8 is also itself a direct precursor of polyhy-
droxylated pyrrolidines of interest. DAB-1 26, a potent in-
hibitor of α-glucosidases, α--arabinosidase, β-glucosidase, Scheme 7. Synthesis of 6-deoxy-DMDP.
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P. Merino, A. Goti et al.
FULL PAPER
by elution through DOWEX WX8–200 with ammonium the C-3 substituent could be detected by 1H NMR
hydroxide (6%), furnished the free amine 30 in 87% overall (Scheme 8). Since attempts to invert the stereocontrol in the
yield over two steps.
hydrocyanation of nitrones had been unsuccessful,[43a] we
focused our attention on the oxidation/reduction protocol
described above to obtain epimeric hydroxylamines at C-2.
This was accomplished by oxidation of 31–33 to nitrones
34–36 with manganese(IV) oxide[52] as described above, fol-
lowed by stereoselective reduction with sodium borohyd-
ride. The oxidation and reduction were found to be com-
pletely regio- and stereoselective, respectively. Presumably,
the regioselectivity of the reaction was controlled by conju-
gation of the incipient nitrone functionality with the cya-
nide moiety, so that the oxidation was directed solely
towards the cyanide side. The relative stereochemistry of all
pyrrolidine substituents in 31–33[43a] and 37–39, and thus
the absolute configurations of the new stereogenic centers,
was confirmed by 2D NMR (NOESY and COSY) experi-
ments and X-ray analysis in the case of 32.[43a]
Synthesis of 2-(Aminomethyl)pyrrolidines
Nitrones 6–8 were converted into the corresponding α-
cyano hydroxylamines 31–33 by treatment with trimethyl-
silyl cyanide in methanol (Scheme 8). In our previous study
on hydrocyanation of cyclic nitrones,[43a] we described the
reaction in dichloromethane as a solvent, providing the cor-
responding O-(trimethylsilyl) derivatives. Under these con-
ditions an activating agent was needed,[43a,70] as well as an
additional desilylation step also being necessary.[71] We have
now improved the process: in methanol as solvent, trimeth-
ylsilyl cyanide was slowly converted in situ into HCN,[72]
which reacted smoothly with nitrones, no additive being
necessary,[73] to provide the free hydroxylamine in a single
step.
It was next attempted to apply the palladium-catalyzed
hydrogenation/deprotection methodology used for the syn-
thesis of 1 and 21–25 in Scheme 5 to the synthesis of 2-
(aminomethyl)pyrrolidines. When compounds 31–33 and
37–39 were subjected to hydrogenolysis under hydrogen
(150 bar) in HCl in MeOH (1 ), the corresponding dihy-
Scheme 8. Synthesis of 2-cyano-N-hydroxypyrrolidines.
All the reactions took place with quantitative yields, and
with no purification of the obtained free hydroxylamines
being necessary. The selectivity of each reaction was com-
plete, and only the isomer showing a trans disposition to Scheme 9. Synthesis of 2-(aminomethyl)pyrrolidines.
2934 Eur. J. Org. Chem. 2008, 2929–2947
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Iminocyclitols from Cyclic Nitrones
drochlorides 40–41, 42–43,[39a] 44, and 45 were obtained in
quantitative yield (Scheme 9). Similar results were obtained
when a more direct approach to 41, 43, and 45 was at-
tempted. Catalytic hydrogenation, under the above condi-
tions, of nitrones 34–36 afforded the target compounds in
quantitative yield and with complete stereoselectivity as de-
1
termined by 400 MHz H NMR spectroscopy. Overall, it is
worth noting that all the processes described above and re-
lating to the synthesis of 2-(aminomethyl)pyrrolidines 40–
45 from nitrones 6–8 are clean and quantitative, both the
intermediates and the final iminocyclitols being obtained
analytically pure (as demonstrated by their spectra and ele-
mental analyses) from crude reaction mixtures without any
need for separation or purification.
Synthesis of 2-Aryl-substituted Polyhydroxylated
Pyrrolidines
These compounds are a unique subset of iminocyclitols
possessing four contiguous stereogenic centers, with the
presence of an aryl group adjacent to the nitrogen atom (C-
2) distinguishing this group from the larger class of polyhy-
droxylated pyrrolidines. In light of the above features, we
turned our attention to the construction, in a stereoselective
fashion starting from nitrone 8, of all possible 2-phenyl-
substituted polyhydroxylated pyrrolidines with different
configurations at C-2 and C-5. According to the synthetic
plan outlined in Scheme 1, the most evident approach was
the addition of the corresponding aryl Grignard rea-
gents.[74]
Scheme 10. Synthesis of protected 1-hydroxy-2-phenylpyrrolidines.
Table 3. Regioselective oxidation of hydroxylamine 46.
Entry Oxidant
T [°C]
t [h]
48/47 ratio[a] % Yield[b]
The nucleophilic addition of phenylmagnesium bromide
to 8 gave the expected all-trans hydroxylamine 46 with com-
plete selectivity and in quantitative yield (Scheme 10). We
next tried oxidation of 46 to apply the protocol for inverting
configuration at C-2. The oxidation of 46 with activated
manganese(IV) oxide[52] as described above afforded re-
gioisomeric nitrones 47 and 48 in a 1:1.4 ratio. Presumably,
this lack of regioselectivity is due to the presence of the
phenyl group, which favored, to an appreciable extent and
through a conjugative effect, the formation of nitrone 47,
in spite of the absence of a proton at C-2 to be positioned
antiperiplanar with respect to the C-3 benzyloxy substitu-
ent. Thus, the virtual lack of selectivity was the result of
contrasting effects of the C-2 phenyl group (conjugation)
and the C-5 benzyloxymethyl group (hyperconjugative ef-
fect to antiperiplanar 2-H), favoring the formation of 47
1
2
3
4
5
6
7
8
MnO2
MnO2
MnO2
MnO2
MnO2
HgO
HgO
PDC
KMnO4
TBHP
UHP[c]
Oxone
TEMPO
25
0
–20
–60
80
0
80
0
0
0
0
0
–60
0.5
0.5
24
24
0.5
25
0.5
0.5
0.5
1
1.4
1.7
2.6
2.7
1.0
1.3
1.2
1.4
1.8
1.7
2.6
3.8
6.7
100
100
100
70
90
100
100
90
100
100
40
9
10
11
12
13
24
24
3
100
100
[a] Measured by 1H NMR in the crude isolated mixture. [b] Isolated
yield after column chromatography. [c] UHP: urea hydroperoxide
complex used in the presence of
a catalytic amount of
Na2WO4·H2O.
and 48, respectively. An investigation of other oxidants was ide as the oxidant (Table 3, Entries 6 and 7). We therefore
then undertaken in an effort to improve the regioselectivity decided to check other typical oxidants employed in the
of the oxidation. The results of this study are summarized synthesis of nitrones[40a] at 0 °C; lower temperatures usually
in Table 3.
led to poor conversions and low chemical yields. Oxidation
Evidence of thermodynamic control[75] of the oxidation with potassium permanganate[76] (Table 3, Entry 9) and
reaction was provided when the process was performed at tert-butyl hydroperoxide[77] (Table 3, Entry 10) afforded re-
different temperatures. While at low temperature a more se- sults similar to those obtained with MnO2, showing a slight
lective reaction was found (Table 3, Entries 1–4), on carry- preference for regioisomer 48. Increased regioselectivity ra-
ing out the oxidation at 80 °C a complete lack of selectivity tios were found with urea/hydrogen peroxide complex[78] in
was observed (Table 3, Entry 5). Similar results, although the presence of a catalytic amount of sodium tungstate[79]
with slight differences, were obtained with mercury(II) ox- (Table 3, Entry 11) and oxone (Table 3, Entry 12).
Eur. J. Org. Chem. 2008, 2929–2947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2935

P. Merino, A. Goti et al.
FULL PAPER
The best result was obtained with TEMPO in dichloro- were their reduction and complete deprotection. These were
methane as a solvent (Table 3, Entry 13), which gave rise to each accomplished in one step to afford 2-phenylpyrrolidine
a 1:6.7 ratio of isomers 47 and 48. After separation by hydrochlorides 53–56 in quantitative yield, in all cases, by
MPLC, both nitrones 47 and 48 were subjected to reduction catalytic hydrogenation (Scheme 11).[81]
in order to obtain the corresponding hydroxylamines. The
reduction of 47 was more difficult than expected, with the
compound proving resistant to attack by both sodium
borohydride and lithium aluminium hydride even at room
temperature after 4 h, and only unchanged starting material
was recovered from the reaction. It thus appeared that the
C-2 phenyl group made the nitrone carbon of 47 simply too
sterically hindered and/or weakly electrophilic to react with
nucleophiles. However, upon treatment with a coordinating
reducing agent such as DIBAH, nitrone 47 did react, pro-
viding a 92:8 mixture of hydroxylamines 49 and 46. After
chromatographic purification compound 49 was obtained
in 81% isolated yield. On the other hand, the reduction of
48 with sodium borohydride afforded an almost equimolar
mixture of hydroxylamines 50 and 46. A rather more selec-
tive reduction was achieved with -selectride at –80 °C,
which furnished 50 in 96% yield and as a single dia-
stereomer as observed by 400 MHz 1H NMR spectroscopy.
In order to gain access to the last diastereomeric hydrox-
ylamine (involving the configurations at C-2 and C-5), the
regioselective oxidation at C-5 of 49 was now required. This
was accomplished in 90% yield with TEMPO at –60 °C,
which was selected as the oxidant of choice on the basis of
the results reported in Table 3 for the oxidation of 46. Un-
der these conditions, nitrones 51 and 47 were obtained in
Scheme 11. Synthesis of 2-phenyl-substituted polyhydroxylated
pyrrolidines.
1:3 ratio. The lower regioselectivity ratio with respect to the
oxidation of 46 was expected, in view of the fact that 2-H
in 49 can be accommodated in an antiperiplanar fashion to
the vicinal benzyloxy group. Surprisingly, reduction of 51
with -selectride at –80 °C afforded hydroxylamine 49 as the
only product of the reaction, thus providing evidence of an
opposite steric preference with respect to nitrone 48, the
With nitrone 8 to hand and the above strategy assessed,
it was necessary to prepare the required Grignard reagent
in order to synthesize radicamine B. A previous synthesis
of the enantiomer of this compound by the same strategy
has been reported very recently.[35] Nitrone 8 was thus
transformed into hydroxylamine 57 by treatment with 4-
benzyloxyphenylmagnesium bromide[82] (Scheme 12).
only structural difference being the configuration of the N-
hydroxy pyrrolidine ring at C-2. After several attempts we
found that the reduction of 51 with an excess of coordinat-
ing DIBAH (6 equiv.) provided 52 in 81% isolated yield and
with complete diastereofacial selectivity (single dia-
1
stereoisomer by 400 MHz H NMR). The observed differ-
ence in selectivity between -selectride and DIBAH can be
interpreted in terms of the hydride delivery. Whereas re-
duction with -selectride would be expected to proceed at
the less hindered face through external delivery of the hy-
dride, reduction with excess of a coordinating reagent such
as DIBAH could invert the selectivity through coordination
of the reagent by the less hindered face and a further exter-
nal delivery of hydride from a second molecule of reagent
by the opposite face.[80]
Scheme 12. Synthesis of radicamine B.
The absolute configurations of hydroxylamines 46, 49,
50, and 52 were confirmed by 2D NOESY and COSY
Consistently with the addition of phenylmagnesium bro-
NMR experiments. All the observed signal enhancements mide described above, the reaction showed complete dia-
(and their absence) were consistent with the configurations stereofacial selectivity, affording the all-trans compound 57.
depicted in Scheme 10.
This configuration was also established by 2D NMR experi-
The diastereomeric hydroxylamines 46, 49, 50, and 52 ments (NOESY and COSY). Finally, natural radicamine B
having been synthesized, the next transformations required was obtained by catalytic hydrogenolysis to provide its pure
2936
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Eur. J. Org. Chem. 2008, 2929–2947

Iminocyclitols from Cyclic Nitrones
(–80 °C) solution of the stannane derivative of 9 (0.760 g, 2 mmol)
in anhydrous THF (15 mL). The resulting solution was stirred for
6 min, at which point a cooled (–80 °C) solution of 6 (0.126 g,
0.8 mmol) in THF (5 mL) was added over a period of 5 min by
cannula. After 15 min at –80 °C the reaction was quenched with
satd. aq. NH4Cl (1 mL) and the reaction mixture was allowed to
warm to room temperature. The reaction mixture was treated with
additional satd. aq. NH4Cl (20 mL) and diethyl ether (30 mL). The
organic layer was separated, and the aqueous layer was extracted
with diethyl ether (2ϫ30 mL). The combined organic extracts were
washed with brine, dried (MgSO4), filtered, and evaporated under
reduced pressure to give a crude product, which was purified by
radial chromatography (hexane/EtOAc, 2:1). (65.4 mg, 35%); oil.
hydrochloride 4b·HCl, isolated in quantitative yield
(Scheme 12). In order to allow comparisons with the litera-
ture data, this compound was deposited onto a DOWEX
W8–200 exchange resin column and eluted with NH4OH
(1 ) to afford 4b as the free base, which showed physical
and spectroscopic data identical to those reported for the
natural compound[34] and for the enantiomer,[35] in this case
with the exception of the opposite sign of optical rotation.
Conclusions
1
[α]2D5 = +53 (c = 0.23, CHCl3). H NMR (400 MHz, CDCl3): δ =
The diastereoselective synthetic methodology reported
above has allowed the preparation of several families of
polyhydroxylated pyrrolidines and their variants with great
versatility. The complete diastereoselectivity found in nucleo-
philic additions to cyclic nitrones and the possibility of
configurational inversion at the newly created stereocenter,
through an oxidation/reduction protocol, makes this meth-
odology complementary to other Lewis-acid-tunable nucle-
ophilic additions to acyclic nitrones. The approach was used
to synthesize several 2-(hydroxymethyl)-, 2-(aminomethyl)-,
and 2-aryl-substituted polyhydroxylated pyrrolidines en-
antiospecifically, offering a new route to such systems com-
peting with previously reported strategies. Finally, the work
provided access to the naturally occurring alkaloids
DMDP, 6-deoxy-DMDP, DAB-1, CYB-3, nectrisine and
radicamine B, as well as to several structural analogues. The
total synthesis of other natural polyhydroxylated pyrroli-
dines and analogues by this methodology is under investiga-
tion in our laboratories.
1.16 [s, 9 H, C(CH3)3], 1.61–1.78 (m, 1 H, 4-Ha, 1.93–2.18 (m, 1
H, 4-Hb), 3.03 (q, J = 9.5 Hz, 1 H, 2-H), 3.23 (dt, J = 10.3, 2.2 Hz,
1 H, 5-Ha), 3.36 (s, 3 H, OCH2OCH3), 3.69 (dd, J = 10.3, 5.1 Hz,
1 H, CH2OMOM), 3.79 (dd, J = 10.3, 2.9 Hz, 1 H, 5-Hb), 3.97
(dq, J = 8.1, 3.7 Hz, 1 H, 3-H), 4.65 (s, 2 H, OCH2OCH3) ppm.
13C NMR (100 MHz, CDCl3): δ = 28.4 [C(CH3)3], 31.3 (C-4), 55.4
(OCH2OCH3), 56.5 (C-5), 65.2 (C-2), 69.6 (CH2OMOM), 73.6 (C-
3), 73.8 [C(CH3)3], 97.0 (OCH2OCH3) ppm. C11H23NO4 (233.26):
calcd. C 56.63, H 9.94, N 6.00; found C 56.49, H 10.05, N 5.89.
(2R,3S)-2-(Benzyloxymethyl)-3-(tert-butoxy)-1-hydroxypyrrolidine
(12): Butyllithium (3.2 mL of a 1.6  solution in hexanes, 2 mmol)
was slowly added by syringe under argon to a cooled (–80 °C) solu-
tion of the stannane derivative of 10 (0.850 g, 2 mmol) in anhy-
drous THF (15 mL). The resulting solution was stirred for 6 min,
at which point a cooled (–80 °C) solution of 6 (0.126 g, 0.8 mmol)
in THF (5 mL) was added by cannula over a period of 5 min. After
15 min at –80 °C the reaction was quenched with satd. aq. NH4Cl
(1 mL) and the reaction mixture was allowed to warm to room
temperature. The reaction mixture was treated with additional satd.
aq. NH4Cl (20 mL) and diethyl ether (30 mL). The organic layer
was separated, and the aqueous layer was extracted with diethyl
ether (2ϫ30 mL). The combined organic extracts were washed
with brine, dried (MgSO4), filtered, and evaporated under reduced
pressure to give a crude product, which was purified by radial
Experimental Section
General Methods: The reaction flasks and other glass equipment
were heated overnight in an oven at 130 °C and assembled in a
stream of Ar. All reactions were monitored by TLC on silica gel
60 F254; the positions of the spots were detected with UV light
(254 nm) or by spraying with one of the following staining systems:
methanolic sulfuric acid (50%), ethanolic phosphomolybdic acid
(5%), or iodine. Preparative centrifugally accelerated radial thin-
layer chromatography (radial chromatography) was performed with
a Chromatotron® Model 7924 T (Harrison Research, Palo Alto,
CA, USA) and with solvents that were distilled prior to use; the
rotors (1 or 2 mm layer thickness) were coated with silica gel Merck
grade type 7749, TLC grade, with binder and fluorescence indicator
(Aldrich 34,644–6) and the eluting solvents were delivered by the
pump at a flow-rate of 0.5–1.5 mL min–1. Column chromatography
was carried out in a Büchi 800 MPLC system with silica gel SDS
60 microns. Melting points were uncorrected. 1H and 13C NMR
spectra were recorded on Bruker Avance 400 or 500 instruments or
on a Varian Mercury 400 in the stated solvent. Chemical shifts are
reported in ppm (δ) relative to CHCl3 (δ = 7.26 ppm) in CDCl3.
Optical rotations were measured on a Perkin–Elmer 241 polarime-
ter or on a JASCO DIP-370 polarimeter. Elemental analysis were
performed on a Perkin–Elmer 240B microanalyzer or with a Per-
kin–Elmer 2400 instrument.
chromatography (hexane/EtOAc, 2:1). 0.178 g, 80%; oil. [α]2D5
=
1
+34 (c = 1.06, CHCl3). H NMR (400 MHz, CDCl3): δ = 0.05 [s,
9 H, C(CH3)3], 1.61 (dddd, J = 12.9, 9.0, 3.2, 2.5 Hz, 1 H, 4-Ha),
1.89–2.03 (m, 1 H, 4-Ha), 2.72–2.79 (m, 1 H, 2-H), 2.93 (c, J =
9.6 Hz, 1 H, 5-Ha), 3.18 (ddd, J = 9.6, 8.0, 2.3 Hz, 1 H, 5-Hb), 3.51
(dd, J = 9.9, 4.3 Hz, 1 H, CH2OBn), 3.63 (J = 10.0, 3.1 Hz, 1 H,
CH2OBn), 3.92 (ddd, J = 8.3, 7.3, 3.7 Hz, 1 H, 3-H), 4.41 (d, J =
11.9 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.9 Hz, 1 H, CH2Ph), 7.17–
7.32 (m, 15 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.4
[C(CH3)3], 31.3 (C-4), 56.6 (C-4), 67.3 (CH2OBn), 69.6 (C-3), 73.4
(CH2Ph), 73.5 (C-2), 73.8 [C(CH3)3], 127.7 (Ar), 128.1 (Ar), 128.3
(Ar), 138.1 (Ar) ppm. C16H25NO3 (279.34): calcd. C 68.79, H 9.02,
N 5.01; found C 68.84, H 9.27, N 4.86.
(2S,3S,4R)-1-Hydroxy-3,4-(isopropylidenedioxy)-2-[(methoxymeth-
yloxy)methyl]pyrrolidine (13): Treatment of a solution of the stan-
nane derivative of 9 (0.760 g, 2 mmol) with nitrone 7 (0.126 g,
0.8 mmol), as described above for nitrone 6 to give 11, afforded
pure 13 (0.131 g, 70%) as an oil. [α]2D5 = –9 (c = 0.695, MeOH). 1H
NMR (400 MHz, CDCl3): δ = 1.34 [s, 3 H, C(CH3)2], 1.54 [s, 3 H,
C(CH3)2], 3.18 (dd, J = 11.0, 3.9 Hz, 1 H, 5-Ha), 3.32 (q, J =
4.5 Hz, 1 H, 2-H), 3.40 (s, 3 H, OCH2OCH3), 3.55 (dd, J = 11.0,
5.7 Hz, 1 H, 5-Ha), 3.76 (dd, J = 10.3, 4.5 Hz, 1 H, CH2OMOM),
3.83 (dd, J = 10.3, 4.5 Hz, 1 H, CH2OMOM), 4.58 (dd, J = 6.7,
4.5 Hz, 1 H, 3-H), 4.67 (s, 2 H, OCH2OCH3), 4.73–4.65 (m, 1 H,
4-H), 6.35 (br. s, 1 H, NOH) ppm. 13C NMR (100 MHz, CDCl3):
(2R,3S)-3-(tert-Butoxy)-1-hydroxy-2-[(methoxymethoxy)methyl]pyr-
rolidine (11): Butyllithium (3.2 mL of a 1.6  solution in hexanes,
2 mmol) was slowly added by syringe under argon to a cooled
Eur. J. Org. Chem. 2008, 2929–2947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2937

P. Merino, A. Goti et al.
FULL PAPER
δ = 4.6 [C(CH3)2], 26.9 [C(CH3)2], 55.4 (OCH2OCH3), 63.1 (C-5), J = 8.9 Hz, 1 H, 2-H), 4.19–4.08 (m, 2 H, CH2OMOM), 4.59 (s, 2
65.4 (CH2OMOM), 71.7 (C-2), 77.3 (C-4), 80.2 (C-3), 96.8 (OCH2- H, OCH2OCH3), 4.85 (d, J = 6.1 Hz, 1 H, 3-H), 5.21 (d, J =
OCH3), 112.8 [C(CH3)2] ppm. C10H19NO5 (233.21): calcd. C 51.49, 6.1 Hz, 1 H, 4-H), 6.92 (s, 1 H, 5-H) ppm. 13C NMR (100 MHz,
H 7.21, N 6.00; found C 51.66, H 8.39, N 5.90.
CDCl3): δ = 25.8 [C(CH3)2], 27.3 [C(CH3)2], 55.5 (OCH3), 63.7
(CH2OMOM), 76.7 (C-2), 78.9 (C-3 or C-4), 79.0 (C-3 or C-4),
96.6 (OCH2OCH3), 111.8 [C(CH3)2], 133.3 (C-5) ppm. C10H17NO5
(231.19): calcd. C 51.94, H 7.41, N 6.06; found C 51.90, H 7.53, N
6.11.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2,5-bis(benzyloxymethyl)-1-hy-
droxypyrrolidine (14): Treatment of a solution of the stannane de-
rivative of 10 (0.850 g, 2 mmol) with nitrone 8 (0.334 g, 0.8 mmol),
as described above for nitrone 6 to give 12, afforded pure 14
(0.306 g, 71%); oil. [α]2D5 = +21 (c = 0.25, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 3.51 (m, 2 H, 2-H), 3.63 (dd, J = 9.6,
6.2 Hz, 2 H, CH2OBn), 3.78 (dd, J = 9.6, 4.8 Hz, 2 H, CH2OBn),
4.00 (dd, J = 3.7, 1.5 Hz, 2 H, 3-H), 4.43 (d, J = 11.8 Hz, 2 H,
CH2Ph), 4.49 (d, J = 11.8 Hz, 2 H, CH2Ph), 4.50 (d, J = 12.1 Hz,
2 H, CH2Ph), 4.54 (d, J = 12.1 Hz, 2 H, CH2Ph), 6.04 (s, 1 H,
OH), 7.34–7.20 (m, 20 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 62.6 (CH2OBn), 64.4 (C-2), 66.5 (CH2Ph), 68.2 (CH2Ph), 78.6
(C-3), 122.4 (Ar), 122.6 (Ar), 123.2 (Ar), 132.9 (Ar), 133.0
(Ar) ppm. C34H37NO5 (539.59): calcd. C 75.67, H 6.91, N 2.60;
found C 75.52, H 6.83, N 2.87.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2,5-bis(benzyloxymethyl)-3,4-di-
hydro-2H-pyrrole 1-Oxide (17): The oxidation of 14 (1.078 g,
2 mmol), as described above for hydroxylamine 12 to give 15, af-
forded pure 17 (1.075 g, 100%) as an oil. [α]2D5 = –38 (c = 0.96,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.72 [dd, J = 3.3,
10.1 Hz, 1 H, (C(5)H)CH2OBn], 3.87 [dd, J = 10.1, 5.8, Hz, 1 H,
(C(5)H)CH2OBn], 3.94–3.99 (m, 1 H, 5-H), 4.14 (dd, J = 2.9,
1.7, Hz, 1 H, 4-H), 4.25 [dt, J = 14.4, 1.3, Hz, 1 H, C(2)CH2OBn],
4.35 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.39 (d, J = 11.9 Hz, 1 H,
CH2Ph), 4.41 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.47 (d, J = 11.7 Hz,
1 H, CH2Ph), 4.47 (s, 2 H, CH2Ph), 4.48 (d, J = 12.0 Hz, 1 H,
CH2Ph), 4.53 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.59 [d, J = 14.4 Hz,
1 H, C(2)CH2OBn], 4.68 (s, 1 H, 3-H), 7.13–7.28 (m, 20 H,
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.4 (CH2Ph), 66.8
[C(2)HCH2OBn], 71.6 [C(2)CH2OBn], 72.1 (CH2Ph), 73.5
(CH2Ph), 73.6 (CH2Ph), 78.2 (C-5), 78.9 (C-4), 83.4 (C-3), 127.0
(Ar), 127.6 (Ar), 127.7 (Ar), 127.9 (Ar), 128.0 (Ar), 128.0 (Ar),
128.1 (Ar), 128.4 (Ar), 128.5 (Ar), 128.5 (Ar), 137.2 (Ar), 137.2
(Ar), 137.5 (Ar), 137.7 (Ar), 143.9 (C-2) ppm. C34H35NO5 (537.58):
calcd. C 79.95, H 6.56, N 2.61; found C 79.88, H 6.73, N 2.90.
(S)-5-(Benzyloxymethyl)-4-tert-butoxy-3,4-dihydro-2H-pyrrole 1-
Oxide (15): Activated manganese(IV) oxide (2.09 g, 2.4 mmol) was
added portionwise to a cooled (0 °C) solution of 12 (0.56 g,
2 mmol) in CH2Cl2 (30 mL). After 15 min of stirring at 0 °C the
reaction mixture was allowed to warm to room temperature and
stirring was continued until complete disappearance of the starting
material (TLC, ca. 2 h). The reaction mixture was then filtered
through a pad of Celite and anhydrous MgSO4, and the resulting
filtrate was evaporated under reduced pressure to give 15 (0.554 g,
100%), which did not need further purification; oil. [α]2D5 = –78, (c
1.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.14 [s, 9 H,
C(CH3)3], 1.84 (dddd, J = 12.2, 8.7, 4.9, 3.0 Hz, 1 H, 3-Ha), 2.23
(dddd, J = 13.7, 9.2, 7.7, 6.2 Hz, 1 H, 3-Hb), 3.72 (ddd, J = 13.8,
9.3, 4.9 Hz, 1 H, 2-Ha), 3.96–4.05 (m, 1 H, 2-Hb), 4.07 (d, J =
12.7 Hz, 1 H, CH2OBn), 4.45 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.52
(d, J = 11.7 Hz, 1 H, CH2Ph), 4.60 (d, J = 12.7 Hz, 1 H, CH2OBn),
4.76 (d, J = 7.4 Hz, 1 H, 4-H), 7.25 (m, 5 H, Ph) ppm. 13C NMR
(100 MHz, CDCl3): δ = 28.2 [C(CH3)3], 28.5 (C-3), 61.0 (CH2OBn),
61.7 (C-2), 71.8 (C-4), 73.7 (CH2Ph), 74.9 [C(CH3)3], 127.9 (Ar),
128.0 (Ar), 128.4 (Ar), 137.7 (Ar), 144.0 (C-5) ppm. C16H23NO3
(277.32): calcd. C 69.29, H 8.36, N 5.05; found C 69.40, H 8.48, N
4.93.
(2S,3S)-2-(Benzyloxymethyl)-3-(tert-butoxy)-1-hydroxypyrrolidine
(18): Sodium borohydride (0.151 g, 4 mmol) was added to a cooled
(0 °C) solution of nitrone 15 (0.277 g, 1 mmol) in MeOH (6 mL),
and stirring was continued for an additional 2 h, at which point
satd. aq. NH4Cl (10 mL) was added. The resulting mixture was
treated with diethyl ether (15 mL), the organic layer was separated,
and the aqueous layer was extracted with diethyl ether (2ϫ15 mL).
The combined organic extracts were washed with brine, dried
(MgSO4), and evaporated under reduced pressure to give pure 18
(0.279 g, 100%) as an oil. [α]2D5 = +23 (c = 0.973, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.11 {s, 9 H, [C(CH3)3]}, 1.70 (dtd, J =
12.1, 8.8, 4.7 Hz, 1 H, 4-Ha), 2.18 (dddd, J = 13.4, 8.9, 7.6, 3.2 Hz,
4-Hb), 2.68 (c, J = 9.4 Hz, 1 H, 5-Ha), 2.95 (q, J = 6.4 Hz, 1 H, 2-
H), 3.38 (ddd, J = 10.3, 8.4, 3.2 Hz, 1 H, 5-Hb), 3.70 (dd, J = 9.2,
6.3 Hz, 1 H, CH2OBn), 3.76 (dd, J = 9.3, 6.5 Hz, 1 H, CH2OBn),
4.17 (dt, J = 7.0, 3.4 Hz, 1 H, 3-H), 4.51 (s, 2 H, CH2Ph), 7.27–
7.39 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.2
[C(CH3)3], 31.9 (C-4), 54.4 (C-5), 66.8 (CH2OBn), 66.9 [C(CH3)3],
68.2 (C-2), 70.3 (C-3), 72.4 (CH2Ph), 126.5 (Ar), 126.7 (Ar), 127.3
(Ar), 137.1 (Ar) ppm. C16H25NO3 (279.34): calcd. C 68.79, H 9.02,
N 5.01; found C 68.88, H 9.15, N 5.27.
(3aR,6aS)-6-[(Methoxymethoxy)methyl]-2,2-dimethyl-4,6a-dihydro-
3aH-[1,3]dioxolo[4,5-c]pyrrole 5-Oxide (16a) and (3aS,4S,6aR)-4-
[(Methoxymethoxy)methyl]-2,2-dimethyl-4,6a-dihydro-3aH-[1,3]di-
oxolo[4,5-c]pyrrole 5-Oxide (16b): The oxidation of 13 (0.466 g,
2 mmol), as described above for hydroxylamine 12 to give 15, af-
forded a 2:1 mixture of compounds 16a and 16b, which were sepa-
rated by column chromatography (EtOAc/MeOH, 20:1).
Compound 16a: 0.305 g, 66%; oil. [α]2D5 = +1 (c = 0.91, MeOH). 1H
NMR (400 MHz, CDCl3): δ = 1.38 [s, 3 H, C(CH3)2], 1.41 [s, 3 H,
C(CH3)2], 3.38 (s, 3 H, OCH3), 4.08 (dd, J = 14.9, 2.0 Hz, 1 H, 2-
Ha), 4.19 (dd, J = 14.9, 6.2 Hz, 1 H, 2-Hb), 4.31 (d, J = 14.5 Hz, 1
H, CH2OMOM), 4.69 (s, 2 H, OCH2OCH3), 4.71 (d, J = 14.5 Hz,
1 H, CH2OMOM), 4.84 (td, J = 6.4, 2.0 Hz, 1 H, 4-H), 5.40 (d, J
= 6.4 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 25.6
[C(CH3)2], 27.1 [C(CH3)2], 55.5 (OCH3), 59.6 (C-5), 68.1 (CH2O-
MOM), 71.7 (C-4), 80.5 (C-3), 96.9 (OCH2OCH3), 112.1 [C-
(CH3)2], 142.6 (C-2) ppm. C10H17NO5 (231.19): calcd. C 51.94, H
7.41, N 6.06; found C 51.84, H 7.62, N 6.13.
(2R,3S,4R)-1-Hydroxy-3,4-(isopropylidenedioxy)-2-[(methoxy-
methoxy)methyl]pyrrolidine (19): The reduction of nitrone 16a
(0.231 g, 1 mmol) as described above for nitrone 15 to give 18 af-
forded pure 19 (0.233 g, 100%) as an oil. [α]2D5 = –73 (c = 0.13,
1
MeOH). H NMR (400 MHz, CDCl3): δ = 1.29 [s, 3 H, C(CH3)2],
1.45 [s, 3 H, C(CH3)2], 2.73 (dd, J = 11.0, 3.3 Hz, 1 H, 5-Ha), 2.83
(ddd, J = 8.1, 5.3, 4.5 Hz, 1 H, 2-H), 3.39 (s, 3 H), 3.52 (d, J =
11.1 Hz, 1 H, 5-Hb), 3.85 (dd, J = 9.6, 5.3 Hz, 1 H, CH2OMOM),
3.93 (dd, J = 9.6, 8.1 Hz, 1 H, CH2OMOM), 4.68 (s, 2 H, OCH2-
OCH3), 4.69–4.66 (m, 2 H, 3-H and 4-H), 6.17 (s, NOH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 24.3 [C(CH3)2], 25.8 [C(CH3)2], 55.3
(OCH3), 62.5 (C-5), 65.1 (CH2OMOM), 70.2 (C-2), 77.0 (C-3 and
Compound 16b: 0.157 g, 34%; white solid; m.p. 50–52 °C. [α]2D5
=
1
+6 (c = 0.29, MeOH). H NMR (400 MHz, CDCl3): δ = 1.38 [s, 3
H, C(CH3)2], 1.46 [s, 3 H, C(CH3)2], 3.33 (s, 3 H, OCH3), 3.84 (d, C-4), 96.8 (OCH2OCH3), 110.9 [C(CH3)2] ppm. C10H19NO5
2938
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2929–2947

Iminocyclitols from Cyclic Nitrones
(233.21): calcd. C 51.49, H 8.21, N 6.00; found C 51.62, H 8.13, N
6.19.
(2R,3S,4R)-3,4-Dihydroxy-2-(hydroxymethyl)pyrrolidine Hydrochlo-
ride (24): The hydrogenation of 16 (0.231 g, 1 mmol) or 19 (0.233 g,
1 mmol), as described above for nitrone 12 to give 21, afforded pure
24 (0.170 g, 100%) as a white solid; m.p. 156–158 °C (ref.[58e] m.p.
157–159 °C). [α]2D5 = +20 (c = 0.32, H2O) [ref.[58e] [α]2D5 = +21 (c =
0.70, H2O)]. 1H NMR (400 MHz, D2O): δ = 3.11 (dd, J = 12.1,
7.3 Hz, 1 H, 5-Ha), 3.42 (dd, J = 12.1, 7.3 Hz, 1 H, 5-Hb), 3.63 (dt,
J = 8.3, 4.0 Hz, 1 H, 2-H), 3.78 (dd, J = 12.1, 8.3 Hz, 1 H,
CH2OH), 3.88 (dd, J = 12.1, 4.0 Hz, 1 H, CH2OH), 4.24 (t, J =
4.0 Hz, 1 H, 3-H), 4.38 (td, J = 7.3, 4.0 Hz, 1 H, 4-H) ppm. 13C
NMR (100 MHz, D2O): δ = 47.1 (C-5), 57.7 (CH2OH), 62.5 (C-2),
69.8 (C-3 or C-4), 70.0 (C-3 or C-4) ppm. C5H12ClNO3 (169.57):
calcd. C 35.41, H 7.13, N 8.26; found C 35.26, H 7.14, N 8.22.
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2,5-bis(benzyloxymethyl)-1-
hydroxypyrrolidine (20): A cooled (–80 °C) solution of 17 (0.538 g,
1 mmol) in anhydrous THF (10 mL) was treated dropwise under
argon with -Selectride (2 mL of a 1  solution in hexanes,
2 mmol). After stirring for 2 h at –80 °C the reaction mixture was
warmed to 0 °C, at which point satd. aq. NH4Cl (5 mL) was added.
The resulting mixture was treated with diethyl ether (15 mL), the
organic layer was separated, and the aqueous layer was extracted
with diethyl ether (2ϫ15 mL). The combined organic extracts were
washed with brine, dried (MgSO4), and evaporated under reduced
pressure without exceeding 20 °C to give pure 20 (0.540 g, 100%)
as an oil. This compound could not be characterized since it proved
to be rather unstable, being oxidized immediately to the precursor
nitrone 17. Because of this it was used immediately in the next step
without any purification.
(2R,3R,4R,5R)-3,4-Dihydroxy-2,5-bis(hydroxymethyl)pyrrolidine
Hydrochloride (1, DMDP): The hydrogenation of 14 (0.540 g,
1 mmol), as described above for hydroxylamine 12 to give 21, af-
forded pure 1 (0.2 g, 100%) as a white solid; m.p. Ͼ150 °C (dec.).
1
[α]2D5 = +48 (c = 0.32, H2O). H NMR (400 MHz, D2O): δ = 3.44–
(2R,3S)-2-(Hydroxymethyl)-3-hydroxypyrrolidine Hydrochloride
(21, CYB-3): A solution of hydroxylamine 12 (0.277 g, 1 mmol) in
methanol (10 mL) was treated with Pd(OH)2-C (15 mg) and a solu-
tion of HCl in methanol (1 ). The resulting mixture was stirred
under hydrogen (20 atm) for 6 h. The catalyst was eliminated by
filtration through a pad of Celite, the filtrate was treated with HCl
(3 ) in methanol, and the resulting solution was stirred at room
temperature for an additional 10 min. The solvent was eliminated
under reduced pressure to afford pure 21 (0.153 g, 100%) as a white
solid; m.p. 110–112 °C (ref.[56c] m.p. 108–112 °C). [α]2D5 = +43 (c =
0.10, H2O) [ref.[56c] [α]2D5 = +46.5 (c = 0.10, H2O)]. 1H NMR
(500 MHz, D2O): δ = 1.93–2.03 (m, 1 H, 4-Ha), 2.22 (dddd, J =
3.50 (m, 2 H, 2-H), 3.76 (dd, J = 12.7, 5.7 Hz, 2 H, CH2OH), 3.84
(dd, J = 12.7, 3.7 Hz, 2 H, CH2OH), 3.96–4.01 (m, 2 H, 3-H) ppm.
13C NMR (100 MHz, D2O): δ = 57.8 (CH2OH), 62.4 (C-2), 74.2
(C-3) ppm. C6H14ClNO4 (199.63): calcd. C 36.10, H 7.07, N 7.02;
found C 36.32, H 7.21, N 7.17.
In order to allow comparisons with the literature data an analytical
sample of the free amine was obtained by passing the hydrochloride
through a Dowex 50WX8 ion-exchange resin. Elution with ammo-
nia in methanol (3 ) afforded, after evaporation, the free base of
1 as a white solid: m.p. 114–117 °C (ref.[9d] m.p. 115–117 °C). [α]2D5
= +53 (c = 0.95, H2O) [ref.[9d] [α]D = +55.4 (c = 1.3, H2O)]. 1H
14.1, 8.3, 8.0, 6.0 Hz, 1 H, 4-Hb), 3.36–3.49 (m, 2 H, 5-Ha, 5-Ha), NMR (400 MHz, D2O): δ = 2.92–2.99 (m, 2 H, 2-H), 3.53 (dd, J
3.57 (dt, J = 7.3, 4.0 Hz, 2-H), 3.67 (dd, J = 12.4, 7.3 Hz, CH2OH), = 11.9, 4.3 Hz, 2 H, CH2OH), 3.61 (dd, J = 11.9, 6.3 Hz, 2 H,
3.84 (dd, J = 12.4, 4.3 Hz, 1 H, CH2OH), 4.33 (dt, J = 6.0, 4.0 Hz, CH2OH), 3.72–3.77 (m, 2 H, 3-H) ppm. 13C NMR (100 MHz,
3-H) ppm. 13C NMR (125 MHz, D2O): δ = 31.1 (C-4), 43.1 (C-5),
D2O): δ = 61.5 (C-2), 61.6 (CH2OH), 77.5 (C-3) ppm. C6H14ClNO4
57.6 (CH2OH), 66.3 (C-2), 70.0 (C-3) ppm. C5H12ClNO2 (153.58): (199.59): calcd. C 44.16, H 8.03, N 8.58; found C 43.87, H 8.05, N
calcd. C 39.09, H 7.87, N 9.12; found C 38.86, H 7.95, N 8.90. 8.53.
(2R,3R)-2-(Hydroxymethyl)-3-hydroxypyrrolidine Hydrochloride (2S,3R,4R,5R)-2,5-Bis(hydroxymethyl)-3,4-dihydroxypyrrolidine
(22): The hydrogenation of 15 (0.277 g, 1 mmol) or 18 (0.279 g,
1 mmol), as described above for hydroxylamine 12 to give 21, af-
forded pure 22 (0.153 g, 100 %) as a white solid; m.p. Ͼ150 °C
(dec.) (ref.[57b] m.p. 220 °C). [α]2D5 = +12 (c = 0.25, MeOH) [ref.[57b]
[α]2D5 = –12.7 (c = 0.2, MeOH)]. 1H NMR (400 MHz, D2O): δ =
2.03 (dddd, J = 13.9, 7.5, 3.4, 1.5 Hz, 1 H, 4-Ha), 2.20 (dddd, J =
Hydrochloride (25): The hydrogenation of 20 (0.540 g, 1 mmol), as
described above for hydroxylamine 12 to give 21, afforded pure 25
(0.2 g, 100%) as a white solid; m.p. Ͼ150 °C (dec.). [α]2D5 = –5 (c =
0.75, MeOH) [ref.[59] [α]D = –3.4 (c = 1.0, MeOH)]. 1H NMR
(400 MHz, D2O): δ = 3.49 (ddd, J = 8.4, 4.6, 3.6 Hz, 1 H, 2-H),
3.70–3.92 (m, 5 H, 5-H, CH2OH), 3.98 (dd, J = 3.6, 2.2 Hz, 1 H,
14.0, 9.4, 9.2, 4.6 Hz, 1 H, 4-Hb), 3.33–3.50 (m, 2 H, 5-Ha, 5-Ha), 3-H), 4.16 (dd, J = 3.6, 2.2 Hz, 1 H, 4-H) ppm. 13C NMR
3.57 (ddd, J = 8.8, 4.9, 3.7 Hz, 2-H), 3.81 (dd, J = 12.1, 8.5 Hz,
CH2OH), 3.94 (dd, J = 12.2, 4.9 Hz, 1 H, CH2OH), 4.49–4.53 (m,
(100 MHz, D2O): δ = 56.7 (CH2OH), 59.1 (CH2OH), 62.9 (C-5),
66.6 (C-2), 74.3 (C-4), 75.8 (C-3) ppm. C6H14ClNO4 (199.59):
1 H, 3-H) ppm. 13C NMR (100 MHz, D2O): δ = 32.6 (C-4), 43.2 calcd. C 36.10, H 7.07, N 7.02; found C 35.83, H 7.15, N 6.86.
(C-5), 57.6 (CH2OH), 65.2 (C-2), 69.8 (C-3) ppm. C5H12ClNO2
(2R,3R,4R)-3,4-Dihydroxy-2-(hydroxymethyl)pyrrolidine (26, DAB-
(153.58): calcd. C 39.09, H 7.87, N 9.12; found C 38.91, H 7.89, N
1): A solution of nitrone 8 (0.430 g, 1.03 mmol) in methanol (8 mL)
9.06.
was treated with Pd/C (420 mg) and concentrated HCl (4 drops).
(2S,3S,4R)-3,4-Dihydroxy-2-(hydroxymethyl)pyrrolidine Hydrochlo-
ride (23): The hydrogenation of 13 (0.233 g, 1 mmol), as described
above for hydroxylamine 12 to give 21, afforded pure 23 (0.169 g,
100%) as a white solid; m.p. 128–130 °C (ref.[58e] m.p. 124–126 °C).
[α]2D5 = –52 (c = 0.41, H2O) [ref.[58e] [α]2D5 = –52.0 (c = 0.6, H2O)].
1H NMR (400 MHz, D2O): δ = 3.36 (d, J = 12.8 Hz, 1 H, 5-Ha),
3.50 (dd, J = 12.8, 4.0 Hz, 1 H, 5-Hb), 3.63 (ddd, J = 8.3, 5.8,
3.5 Hz, 1 H, 2-H), 3.81 (dd, J = 12.6, 5.8 Hz, 1 H, CH2OH), 3.97
(dd, J = 12.6, 3.5 Hz, 1 H, CH2OH), 4.20 (dd, J = 8.3, 4.0 Hz, 1
H, 3-H), 4.38 (m, 1 H, 4-H) ppm. 13C NMR (100 MHz, D2O): δ =
The resulting mixture was stirred under hydrogen for 15 h. The
catalyst was eliminated by filtration through a pad of Celite, and
the filtrate was then concentrated under reduced pressure and
passed through a short pad of Dowex WX8–200, with elution with
water, MeOH, and finally with a NH4OH solution (6%). Concen-
tration of the fractions eluted with NH4OH afforded a brown oil
(135 mg, 98% yield). [α]2D3 = +5.6 (c = 0.285, H2O) [ref.[63] [α]D
=
1
+6.3 (c = 1, H2O)]. H NMR (400 MHz, D2O): δ = 2.74 (dd, J =
12.3, 3.9 Hz, 1 H, 5-Ha), 2.90 (m, 1 H, 2-H), 3.02 (dd, J = 12.2,
5.7 Hz, 1 H, 5-Hb), 3.55 (dd, J = 11.5, 6.4 Hz, 1 H, CH2OH), 3.63
49.7 (C-5), 58.1 (CH2OH), 61.9 (C-2), 69.5 (C-4), 71.2 (C-3) ppm. (dd, J = 11.5, 4.9 Hz, 1 H, CH2OH), 3.73 (dd, J = 5.7, 3.6 Hz, 1
C5H12ClNO3 (169.57): calcd. C 35.41, H 7.13, N 8.26; found C H, 3-H), 4.03 (dt, J = 5.7, 3.9 Hz, 1 H, 4-H) ppm. 13C NMR
35.18, H 7.16, N 8.20.
(50 MHz, D2O): δ = 49.6 (C-5), 61.0 (CH2OH), 64.4 (C-2), 76.4
2939
Eur. J. Org. Chem. 2008, 2929–2947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

P. Merino, A. Goti et al.
FULL PAPER
(C-4), 78.0 (C-3) ppm. C5H11NO3 (133.12): calcd. C 45.10, H 8.33,
N 10.52; found C 44.82, H 8.11, N 10.23.
mixture was stirred under hydrogen at room temperature for 16 h.
The catalyst was eliminated by filtration through a pad of Celite,
and the filtrate was then passed through a Dowex 50WX8 ion-
exchange resin. Elution with ammonia in methanol (3 ) afforded
pure 30 (0.41 g, 87%) as a syrup after evaporation. [α]2D0 = +44.4
(c = 0.71, MeOH) [ref.[69a] [α]D = +26.2 (c = 1.1, MeOH)] for the
natural compound, [α]D = +42.9 (c = 0.72, MeOH) for the synthetic
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-
2H-pyrrole (27): Triphenylphosphane (75 mg, 0.30 mmol) was
added to a solution of nitrone 8 (285 mg, 0.68 mmol) in a mixture
of trimethyl phosphite and TEA (10:1, 20 mL), and the mixture
was heated at reflux for 4 h. After evaporation under reduced pres-
sure, purification by flash column chromatography (eluent petro-
leum ether/EtOAc, 1.5:1) afforded pure 27 (170 mg, 62%) as an oil.
1
compound. H NMR (400 MHz, D2O): δ = 1.06 (d, J = 6.4 Hz, 3
H, CH3), 2.83 (dq, J = 8.2, 6.4 Hz, 1 H, 5-H), 2.92 (td, J = 6.6,
4.9 Hz, 1 H, 2-H), 3.51–3.45 (m, 2 H, CH2, 4-H), 3.55 (dd, J =
11.4, 4.9 Hz, 1 H, CH2), 3.69 (t, J = 7.0 Hz, 1 H, 3-H) ppm. 13C
NMR (50 MHz, D2O): δ = 17.4 (CH3), 55.7 (C-5), 61.5 (C-2), 62.5
(CH2), 78.2 (C-3), 82.7 (C-4) ppm. C6H13NO3 (147.14): calcd. C
48.97, H 8.90, N 9.52; found C 48.59, H 9.02, N 9.78.
[α]2D2 = –10.4 (c = 0.76, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
3.58 (dd, J = 9.8, 6.3 Hz, 1 H, CH2OH), 3.79 (dd, J = 9.8, 4.5 Hz,
1 H, CH2OH), 4.14 (t, J = 3.8 Hz, 1 H, 3-H), 4.18–4.21 (m, 1 H,
2-H), 4.59–4.66 (m, 7 H, CH2Ph, 4-H), 7.23–7.40 (m, 15 H, Ar),
7.64 (d, J = 2.34 Hz, 1 H, 5-H) ppm. 13C NMR (50 MHz, D2O): δ
= 71.1 (C-6), 72.1 (CH2Ph), 72.4 (CH2Ph), 73.4 (CH2Ph), 76.9 (C- (2R,3S)-3-tert-Butoxy-1-hydroxypyrrolidine-2-carbonitrile (31): Tri-
2), 84.5 (C-3), 90.7 (C-4), 127.6 (Ar), 127.7 (Ar), 127.8 (Ar), 127.9
(Ar), 128.0 (Ar), 128.2 (Ar), 128.3 (Ar), 128.4 (Ar), 128.5 (Ar),
137, 4 (Ar), 137.8 (Ar), 138.1 (Ar), 165.9 (C-5) ppm. C26H27NO3
(401.45): calcd. C 77.78, H 6.78, N 3.49; found C 77.58, H 6.56, N
3.31.
methylsilyl cyanide (0.100 g, 1 mmol) was added under argon to a
solution of nitrone 6 (0.157 g, 1 mmol) in MeOH (10 mL). The
resulting solution was stirred at room temperature for 10 h, at
which point the solvent was rotatory evaporated, without exceeding
35 °C, to give the pure hydroxylamine 31 (0.184 g, 100%), which
did not need further purification. White solid; m.p. 127–129 °C.
(2R,3R,4R)-2-(Hydroxymethyl)-3,4-dihydro-2H-pyrrole-3,4-diol (28,
Nectrisine): A solution of BCl3 in CH2Cl2 (1 , 1.75 mL) was added
under nitrogen at –78 °C to a solution of 27 (0.1 g, 0.25 mmol) in
dry CH2Cl2 (0.5 mL). The mixture was stirred for 3 h, while the
temperature was raised to –40 °C. Then, a saturated aqueous solu-
tion of NaHCO3 was added until neutral pH was reached. The
solvent was evaporated under reduced pressure, and the residue
was taken up with AcOEt (10 mL) and stirred for 10 min. After
decantation, this procedure was repeated three times. The com-
bined organic phases were concentrated, affording a white solid
that was purified by flash column chromatography (eluent EtOAc/
MeOH, 2:1) to afford pure 28 (22 mg, 67% yield) as an oil. 13C
[α]2D5 = +20 (c = 1.00, CHCl3). H NMR (400 MHz, CDCl3): δ =
1
1.14 [s, 9 H, C(CH3)3], 1.69 (ddt, J = 13.4, 3.7, 8.6 Hz, 1 H, 4-Ha),
2.22 (dq, J = 13.4, 8.6 Hz, 1 H, 4-Hb), 3.07 (dt, J = 11.7, 8.6 Hz,
1 H, 5-Ha), 3.18 (ddd, J = 11.7, 8.9, 3.7 Hz, 1 H, 5-Hb), 3.58 (d, J
= 5.9 Hz, 1 H, 2-H), 4.33 (ddd, J = 8.9, 5.9, 3.7 Hz, 1 H, 3-H),
7.41 (s, 1 H, –NOH) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.1
(CH3), 31.6 (C-4), 56.2 (C-5), 67.7 (C-2), 73.3 (C-3), 74.9 [C-
(CH3)3], 117.8 (CN) ppm. C9H16N2O2 (184.21): calcd. C 58.67, H
8.75, N 15.21; found C 58.73, H 8.90, N 15.14.
(2S,3S,4R)-1-Hydroxy-3,4-(isopropylidenedioxy)pyrrolidine-2-
carbonitrile (32): The hydrocyanation of 7 (0.157 g, 1 mmol), as de-
NMR (50 MHz, D2O): δ = 61.3 (t), 76.8 (d), 78.3 (d), 83.4 (d), scribed above for nitrone 6 to give 31, afforded pure 32 (0.184 g,
170.6 (d) ppm. Nectrisine (28) was found to be unstable in D2O
100%) as a white solid; m.p. 110–112 °C. [α]2D5 = +22 (c = 0.695,
MeOH). 1H NMR (400 MHz, CDCl3): δ = 1.27 (s, 3 H, CH3), 1.44
(s, 3 H, CH3), 3.15 (dd, J = 11.4, 4.8 Hz, 1 H, 5-Ha), 3.42 (d, J =
11.4 Hz, 1 H, 5-Hb), 4.20 (s, 1 H, 2-H), 4.70–4.80 (m, 2 H, 3-H
and 4-H), 6.18 (s, 1 H, NOH) ppm. 13C NMR (100 MHz, CDCl3):
δ = 24.3 (CH3), 25.8 (CH3), 60.5 (C-5), 62.9 (C-2), 76.1 (C-4), 80.1
(C-3), 112.6 [C(CH3)2], 114.8 (CN) ppm. C8H12N2O3 (184.16):
calcd. C 52.17, H 6.57, N 15.21; found C 52.04, H 6.54, N 15.30.
solution, due to formation of hydrated derivatives.[68]
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-hydroxy-
5-methylpyrrolidine (29): Methylmagnesium bromide (3 mL of a 3 
solution in THF, 3 mmol) was added dropwise under argon to a
cooled (0 °C) solution of nitrone 8 (0.418 g, 1 mmol) in anhydrous
THF (10 mL). The resulting solution was stirred at 0 °C for 3 h, at
which point the reaction was quenched with satd. aq. NH4Cl
(10 mL). The reaction mixture was diluted with diethyl ether
(10 mL), the organic layer was separated, and the aqueous layer
was extracted with diethyl ether (2ϫ10 mL). The combined or-
ganic extracts were washed with brine (20 mL), dried with MgSO4,
and filtered, and the solvent was eliminated under reduced pressure.
The crude product was purified by column chromatography (hex-
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-1-hydroxy-
pyrrolidine-2-carbonitrile (33): The hydrocyanation of 8 (0.417 g,
1 mmol), as described above for nitrone 6 to give 31, afforded a
crude product that was purified by column chromatography (hex-
ane/EtOAc, 4:1) to give pure 33 (0.444 g, 100%) as an oil. [α]2D5
+9 (c = 1.08, CHCl3). H NMR (400 MHz, CDCl3): δ = 3.32 (dt,
J = 3.5, 7.0 Hz, 1 H, 5-H), 3.59 (dd, J = 10.6, 3.5 Hz, 1 H,
=
1
ane/EtOAc, 4:1) to give pure 29 (0.434 g, 100%) as an oil. [α]2D4
–12.5 (c = 0.135, CDCl3). H NMR (400 MHz, CDCl3): δ = 1.26 CH2OH), 3.76 (dd, J = 10.6, 3.5 Hz, 1 H, CH2OH), 3.97 (dd, J =
=
1
(d, J = 6.4 Hz, 3 H, CH3), 3.37–3.40 (m, 1 H, 5-H), 3.51–3.55 (m,
1 H, CH2OBn), 3.62 (dd, J = 9.6, 6.5 Hz, 1 H, CH2OBn), 3.72–
6.7, 2.3 Hz, 1 H, 4-H), 4.19 (t, J = 2.4 Hz, 1 H, 3-H), 4.25 (d, J =
1.9 Hz, 1 H, 2-H), 6.51–6.42 (m, 4 H, CH2Ph), 6.54 (d, J = 11.7 Hz,
3.76 (m, 2 H, 3-H, 4-H), 3.90 (dd, J = 4.1, 3.1 Hz, 1 H, 2-H), 4.45– 1 H, CH2Ph), 6.59 (d, J = 12.2 Hz, 1 H, CH2Ph), 6.81 (s, 1 H,
4.56 (m, 6 H, CH2Ph), 4.95 (br. s, 1 H, OH), 7.25–7.37 (m, 15 H,
OH), 7.30 (m, 15 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ =
Ar) ppm. 13C NMR (50 MHz, CDCl3): δ = 11.7 (CH3), 62.3 (C-5), 61.3 (C-2), 66.3 (C6), 69.5 (C-5), 72.2 (CH2Ph), 72.3 (CH2Ph), 73.4
67.2 (C-4), 69.4 (CH2OBn), 69.7 (CH2OPh), 71.1 (CH2OPh), 71.4 (CH2Ph), 81.3 (C-4), 83.7 (C-3), 115.8 (CN), 127.9 (Ar), 128.0 (Ar),
(CH2OPh), 81.8 (C-2), 85.0 (C-3), 125.4–126.8 (15 C, Ar), 135.3– 128.0 (Ar), 128.1 (Ar), 128.1 (Ar), 128.4 (Ar), 128.5 (Ar), 128.5
135.6 (3 C, Ar) ppm. C27H31NO4 (433.49): calcd. C 74.80, H 7.21,
N 3.23; found C 74.78, H 6.91, N 3.44.
(Ar), 128.8 (Ar), 136.6 (Ar), 137.4 (Ar), 137.5 (Ar) ppm.
C27H28N2O4 (444.47): calcd. C 72.95, H 6.35, N 6.30; found C
73.05, H 6.28, N 6.48.
(2R,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-methylpyrrol-
idine (6-Deoxy-DMDP, 30): A solution of hydroxylamine 29
(0.141 g, 0.32 mmol) in methanol (20 mL) was treated with Pd/C
(10%, 170 mg), and concd. HCl (6 drops) was added. The resulting
(S)-4-tert-Butoxy-5-cyano-3,4-dihydro-2H-pyrrole 1-Oxide (34):
The oxidation of 31 (0.368 g, 2 mmol), as described above for hy-
droxylamine 12 to give 15, afforded pure 34 (0.364 g, 100%) as a
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Eur. J. Org. Chem. 2008, 2929–2947

Iminocyclitols from Cyclic Nitrones
1
white solid; m.p. 78–80 °C. [α]2D5 = +17 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 1.27 [s, 9 H, C(CH3)3], 2.19 (dddd, J =
13.6, 9.0, 5.3, 3.2 Hz, 1 H, 3-Ha), 2.65 (dddd, J = 14.0, 9.1, 7.6,
6.5 Hz, 1 H, 3-Hb), 3.95 (dddd, J = 15.0, 9.4, 5.5, 0.6 Hz, 1 H, 2-
Ha), 4.26 (dddd, J = 14.9, 8.9, 6.5, 1.8 Hz, 1 H, 2-Hb), 4.99 (dddd,
J = 5.0, 2.3, 1.1, 0.5 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz,
[α]2D5 = –130 (c = 0.695, MeOH). H NMR (300 MHz, CDCl3): δ
= 1.33 (s, 3 H, CH3), 1.55 (s, 3 H, CH3), 2.77 (dd, J = 11.4, 4.4 Hz,
1 H, 5-Ha), 3.49 (s, 1 H, 2-H), 3.55 (d, J = 11.4 Hz, 1 H, 5-Hb),
4.72–4.79 (m, 2 H, 3-H and 4-H), 5.98 (br. s, 1 H, NOH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 24.8 (CH3), 25.9 (CH3), 61.7 (C-5),
63.6 (C-2), 76.6 (C-4), 76.7 (C-3), 112.8 [C(CH3)2], 115.7
CDCl3): δ = 28.7 (C-3), 30.0 (CH3), 62.8 (C-2), 71.5 [C(CH3)3], 75.5 (CN) ppm. C8H12N2O3 (184.16): calcd. C 52.17, H 6.57, N 15.21;
(C-4), 111.0 (CN), 120.2 (C-5) ppm. C9H14N2O2 (182.20): calcd. C found C 52.31, H 6.43, N 15.30.
59.32, H 7.74, N 15.37; found C 59.48, H 7.90, N 15.21.
(2S,3R,4R,5R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-1-hydroxy-
pyrrolidine-2-carbonitrile (39): The reduction of 36 (0.442 g,
1 mmol), as described above for hydroxylamine 34 to give 37, af-
forded pure 39 (0.444 g, 100%) as an oil. [α]2D5 = +11 (c = 0.27,
(3aR,6aS)-6-Cyano-2,2-dimethyl-4,6a-dihydro-3aH-[1,3]dioxolo[4,5-
c]pyrrole 5-Oxide (35): The oxidation of 32 (0.368 g, 2 mmol), as
described above for hydroxylamine 12 to give 15, afforded pure 35
(0.364 g, 100%) as a white solid; m.p. 128–130 °C. [α]2D5 = –90 (c =
0.535, MeOH). 1H NMR (400 MHz, CDCl3): δ = 1.41 (s, 3 H,
CH3), 1.49 (s, 3 H, CH3), 4.18 (dtd, J = 15.6, 1.2, 0.6 Hz, 1 H, 2-
Ha), 4.29 (dd, J = 15.7, 6.4 Hz, 1 H, 2-Hb), 4.99 (dddd, J = 6.2,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 3.03 (c, J = 5.4 Hz, 1
H, 5-H), 3.54 (dd, J = 10.0, 5.6 Hz, 1 H, CH2OBn), 3.59 (dd, J =
10.0, 5.4 Hz, 1 H, CH2OBn), 3.76 (d, J = 5.2 Hz, 1 H, 4-H), 3.95
(s, 2 H, 2-H and 3-H), 4.29 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.34 (d,
J = 11.8 Hz, 1 H, CH2Ph), 4.47 (s, 2 H, CH2Ph), 4.48 (d, J =
12.0 Hz, 1 H, CH2Ph), 4.60 (d, J = 12.0 Hz, 1 H, CH2Ph), 7.08–
7.33 (m, 15 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.1
(C-2), 68.7 (C-6), 71.8 (CH2Ph), 71.9 (C-5), 72.6 (CH2Ph), 73.4
(CH2Ph), 79.7 (C-4), 81.7 (C-3), 116.3 (CN), 127.7 (Ar), 127.8 (Ar),
127.9 (Ar), 128.0 (Ar), 128.2 (Ar), 128.4 (Ar), 128.5 (Ar), 128.6
(Ar), 136.6 (Ar), 137.2 (Ar), 137.8 (Ar) ppm. C27H28N2O4 (444.47):
calcd. C 72.95, H 6.35, N 6.30; found C 73.14, H 6.21, N 6.57.
4.9, 1.4, 0.6 Hz, 1 H, 3-H), 5.45 (d, J = 6.1 Hz, 1 H, 4-H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 25.7 (CH3), 27.1 (CH3), 69.1 (C-2),
73.0 (C-3), 79.3 (C-4), 110.4 (CN), 113.4 [C(CH3)2], 118.4 (C-
5) ppm. C8H10N2O3 (182.14): calcd. C 52.74, H 5.53, N 15.38;
found C 52.68, H 5.64, N 15.50.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-cyano-3,4-di-
hydro-2H-pyrrole 1-Oxide (36): The oxidation of 33 (0.888 g,
2 mmol), as described above for hydroxylamine 12 to give 15, af-
forded pure 36 (0.885 g, 100%) as an oil. [α]2D5 = –35 (c = 2.50,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 3.71 (dd, J = 3.2,
10.4 Hz, 1 H, CH2OBn), 4.01 (dd, J = 10.4, 4.9 Hz, 1 H, CH2OBn),
4.07–4.11 (m, 1 H, 2-H), 4.40 (dd, J = 3.6, 2.0 Hz, 1 H, 3-H), 4.50
(d, J = 11.8 Hz, 1 H, CH2Ph), 4.51 (d, J = 12.0 Hz, 1 H, CH2Ph),
4.55 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.59 (d, J = 12.0 Hz, 1 H,
CH2Ph), 4.65 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.76 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.84 (dd, J = 2.0, 0.6 Hz, 4-H), 7.10–7.35 (m, 15 H,
Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 65.7 (CH2OBn), 72.1
(CH2Ph), 72.2 (CH2Ph), 73.6 (CH2Ph), 79.3 (C-3), 79.5 (C-2), 82.0
(C-4), 111.1 (CN), 118.0 (C-5), 127.8 (Ar), 128.0 (Ar), 128.1 (Ar),
128.4 (Ar), 128.5 (Ar), 128.7 (Ar), 136.4 (Ar), 136.5 (Ar), 137.1
(Ar) ppm. C27H26N2O4 (442.45): calcd. C 73.28, H 5.92, N 6.33;
found C 73.41, H 5.78, N 6.49.
(2R,3S)-2-(Aminomethyl)-3-hydroxypyrrolidine Dihydrochloride
(40): The hydrogenation of 31 (0.184 g, 1 mmol), as described above
for hydroxylamine 12 to give 21, afforded pure 40 (0.189 g, 100%)
as a white solid; m.p. Ͼ150 °C (dec.). [α]2D5 = +23 (c = 0.30, H2O).
1H NMR (500 MHz, D2O): δ = 2.00 (ddddd, J = 14.3, 8.3, 5.9, 4.9,
0.6 Hz, 1 H, 4-Ha), 2.26 (dddd, J = 13.9, 8.4, 7.8, 6.0 Hz, 1 H, 4-
Hb), 3.19 (dd, J = 13.9, 7.3 Hz, 2 H, CH2NH2), 3.40–3.44 (m, 2 H,
5-Ha, 5-Hb), 3.69 (dt, J = 7.0, 4.9 Hz, 1 H, 2-H), 4.37 (c, J = 5.0 Hz,
1 H, 3-H) ppm. 13C NMR (125 MHz, D2O): δ = 30.8 (C-4), 38.4
(CH2NH2), 43.9 (C-5), 62.2 (C-2), 72.2 (C-3) ppm. C5H14Cl2N2O
(189.07): calcd. C 31.76, H 7.46, N 14.81; found C 31.60, H 7.60,
N 14.78.
(2S,3S)-2-(Aminomethyl)-3-hydroxypyrrolidine Dihydrochloride
(41): The hydrogenation of 34 (0.182 g, 1 mmol) or 37 (0.184 g,
1 mmol), as described above for hydroxylamine 12 to give 21, af-
forded pure 41 (0.189 g, 100 %) as a white solid; m.p. Ͼ150 °C
(2S,3S)-3-tert-Butoxy-1-hydroxypyrrolidine-2-carbonitrile (37): So-
dium borohydride (76 mg, 2 mmol) was added portionwise to a co-
oled (0 °C) solution of nitrone 34 (0.182 g, 1 mmol) in MeOH
(6 mL). The reaction mixture was stirred for an additional hour
and satd. aq. NH4Cl (5 mL) was added. After stirring for 15 min
the reaction mixture was diluted with diethyl ether (20 mL). The
organic layer was separated, and the aqueous layer was extracted
with diethyl ether (2ϫ20 mL). The combined organic extracts were
washed with brine, dried with MgSO4, and filtered, and the solvent
was eliminated under reduced pressure to give pure 37 (0.184 g,
100%), which did not need further purification; oil. [α]2D5 = +23 (c
= 0.97, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 1.21 [s, 9 H,
C(CH3)3], 1.86 (dddd, J = 12.1, 8.4, 8.3, 4.6 Hz, 1 H, 4-Ha), 2.25
(dtd, J = 12.8, 8.2, 4.5 Hz, 1 H, 4-Hb), 2.87 (dt, J = 10.1, 8.3 Hz,
1 H, 5-Ha), 3.37 (ddd, J = 9.9, 9.0, 4.6 Hz, 1 H, 5-Hb), 3.88 (d, J
= 6.7 Hz, 1 H, 2-H), 4.30 (ddd, J = 7.9, 6.8, 4.7 Hz, 1 H, 3-H) ppm.
13C NMR (50 MHz, CDCl3): δ = 27.4 [C(CH3)3], 31.3 (C-4), 54.7
(C-5), 64.4 (C-2), 68.3 (C-3), 74.5 [C(CH3)3], 115.6 (CN) ppm.
C9H16N2O2 (184.21): calcd. C 58.67, H 8.75, N 15.21; found C
58.73, H 8.92, N 15.11.
(dec.). [α]2D5 = +66 (c = 1.0, H2O). H NMR (400 MHz, D2O): δ =
1
2.03 (dddd, J = 14.3, 7.7, 3.5, 1.5 Hz, 1 H, 4-Ha), 2.16 (dtd, J =
14.0, 9.9, 4.2 Hz, 1 H, 4-Hb), 3.26–3.54 (m, 4 H, 5-Ha, 5-Hb and
CH2NH2), 3.72 (dt, J = 6.6, 3.5 Hz, 1 H, 2-H), 4.53 (dd, J = 4.0,
1.5 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz, D2O): δ = 31.7 (C-
4), 35.4 (C-5 or CH2NH2), 43.5 (C-5 or CH2NH2), 59.9 (C-2), 69.0
(C-3) ppm. C5H14Cl2N2O (189.07): calcd. C 31.76, H 7.46, N 14.81;
found C 31.54, H 7.62, N 14.73.
(2S,3S,4R)-2-(Aminomethyl)-3,4-dihydroxypyrrolidine Dihydrochlo-
ride (42): The hydrogenation of 32 (0.184 g, 1 mmol), as described
above for hydroxylamine 12 to give 21, afforded pure 42 (0.204 g,
100%) as a white solid; m.p. Ͼ150 °C (dec.). [α]2D5 = –19 (c = 0.33,
MeOH). 1H NMR (400 MHz, D2O): δ = 3.23 (dd, J = 13.2, 1.2 Hz,
1 H, 5-Ha), 3.31 (dd, J = 13.9, 5.7 Hz, 1 H, CH2NH2), 3.36 (dd, J
= 14.0, 7.5 Hz, 1 H, CH2NH2), 3.43 (dd, J = 13.2, 4.1 Hz, 1 H, 5-
Hb), 3.60 (dd, J = 9.4, 7.6, 6.1 Hz, 1 H, 2-H), 4.04 (dd, J = 9.5,
4.0 Hz, 1 H, 3-H), 4.18 (dt, J = 4.1, 1.0 Hz, 1 H, 4-H) ppm. 13C
NMR (100 MHz, D2O): δ = 40.3 (CH2NH2), 51.8 (C-5), 58.6 (C-
2), 70.3 (C-4), 75.5 (C-3) ppm. C5H14Cl2N2O2 (205.06): calcd. C
29.28, H 6.88, N 13.66; found C 28.48, H 6.95, N 13.42.
(3aS,4R,6aR)-5-Hydroxy-2,2-dimethyltetrahydro-3aH-[1,3]dioxolo-
[4,5-c]pyrrole-4-carbonitrile (38): The reduction of 35 (0.182 g,
1 mmol), as described above for hydroxylamine 34 to give 37, af-
forded pure 38 (0.184 g, 100%) as a white solid; m.p. 144–145 °C;
(2R,3S,4R)-2-(Aminomethyl)-3,4-dihydroxypyrrolidine Dihydrochlo-
ride (43): The hydrogenation of 35 (0.182 g, 1 mmol) or 38 (0.184 g,
Eur. J. Org. Chem. 2008, 2929–2947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2941

P. Merino, A. Goti et al.
FULL PAPER
1 mmol), as described above for hydroxylamine 12 to give 21, af-
forded pure 43 (0.204 g, 100 %) as a white solid; m.p. Ͼ150 °C
72.0 (CH2Ph), 73.5 (CH2Ph), 74.1 (C-5), 83.6 (C-3), 87.6 (C-4),
127.6 (Ar), 127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8
(Ar), 128.1 (Ar), 128.2 (Ar), 128.4 (Ar), 128.4 (Ar), 128.4 (Ar),
137.9 (Ar), 138.1 (Ar), 138.2 (Ar), 139.5 (Ar) ppm. C32H33NO4
1
(dec.). [α]2D5 = –5 (c = 0.38, MeOH). H NMR (400 MHz, D2O): δ
= 3.20 (dd, J = 13.2, 6.1 Hz, 1 H, 5-Ha), 3.38 (dd, J = 13.2, 5.6 Hz,
1 H, 5-Hb), 3.42 (dd, J = 12.6, 6.6 Hz, 1 H, CH2NH2), 3.53 (dd, J (495.55): calcd. C 77.55, H 6.71, N 2.83; found C 77.79, H 6.92, N
= 12.6, 7.1 Hz, 1 H, CH2NH2), 3.85 (q, J = 6.8 Hz, 1 H, 2-H),
4.35–4.45 (m, 2 H, 3-H and 4-H) ppm. 13C NMR (100 MHz, D2O):
δ = 36.6 (C-5), 48.2 (CH2NH2), 57.2 (C-2), 69.8 (C-3 or C-4), 70.0
(C-3 or C-4) ppm. C5H14Cl2N2O2 (205.06): calcd. C 29.28, H 6.88,
N 13.66; found C 28.97, H 6.95, N 13.42.
3.10.
(2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-phenyl-3,4-di-
hydro-2H-pyrrole 1-Oxide (47) and (2R,3R,4R)-3,4-Bis(benzyloxy)-
5-(benzyloxymethyl)-2-phenyl-3,4-dihydro-2H-pyrrole 1-Oxide (48):
The oxidation of 46 (0.495 g, 1 mmol), as described above for hy-
droxylamine 34 to give 37, afforded a 1 :1.4 mixture of nitrones 47
and 48, which were separated by column chromatography (hexane/
EtOAc, 3:2).
(2R,3R,4R,5R)-2-(Aminomethyl)-5-(hydroxymethyl)-3,4-dihydroxy-
pyrrolidine Dihydrochloride (44): The hydrogenation of 33 (0.444 g,
1 mmol), as described above for hydroxylamine 12 to give 21, af-
forded pure 44 (0.235 g, 100 %) as a white solid; m.p. Ͼ150 °C
1
Compound 47: 0.207 g, 42%; oil. [α]2D2 = –13 (c = 1.5, CHCl3). H
1
(dec.). [α]2D5 = +43 (c = 1.43, H2O). H NMR (400 MHz, D2O): δ
NMR (400 MHz, CDCl3): δ = 4.03 (dd, J = 9.9, 3.7 Hz, 1 H,
CH2OBn), 4.10 (dd, J = 9.9, 6.5 Hz, 1 H, CH2OBn), 4.32 (ddd, J
= 3.5, 2.3, 6.1 Hz, 1 H, 2-H), 4.36 (dd, J = 2.2, 1.1 Hz, 1 H, 3-H),
4.50 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.56 (d, J = 11.1 Hz, 1 H,
CH2Ph), 4.58 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.62 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.63 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.68 (d, J =
11.9 Hz, 1 H, CH2Ph), 5.20 (s, 1 H, 4-H), 7.22 (dd, J = 3.0, 6.6 Hz,
2 H), 7.28–7.45 (m, 18 H, Ar) ppm. 13C NMR (100 MHz, CDCl3):
δ = 67.8 (CH2OBn), 70.5 (CH2Ph), 71.5 (CH2Ph), 73.6 (CH2Ph),
76.4 (C-3), 79.4 (C-2), 84.5 (C-4), 127.7 (Ar), 127.8 (Ar), 127.9
(Ar), 128.1 (Ar), 128.1 (Ar), 128.1 (Ar), 128.2 (C-5), 128.4 (Ar),
128.4 (Ar), 128.5 (Ar), 128.6 (Ar), 130.5 (Ar), 137.0 (Ar), 137.1
(Ar), 137.7 (Ar), 139.8 (Ar) ppm. C32H31NO4 (493.54): calcd. C
77.87, H 6.33, N 2.84; found C 77.92, H 6.53, N 2.72.
= 3.42 (dd, J = 13.9, 6.2 Hz, 1 H, CH2NH2), 3.54 (dd, J = 13.9,
6.8 Hz, 1 H, CH2NH2), 3.62 (ddd, J = 8.8, 4.9, 2.4 Hz, 1 H, 5-H),
3.76 (dd, J = 12.1, 8.8 Hz, 1 H, CH2OH), 3.90 (dd, J = 12.1, 4.8 Hz,
1 H, CH2OH), 4.02 (dt, J = 6.6, 3.6 Hz, 1 H, 2-H), 4.05 (dd, J =
2.7, 1.7 Hz, 1 H, 4-H), 4.27 (dd, J = 3.5, 1.4 Hz, 1 H, 3-H) ppm.
13C NMR (100 MHz, D2O): δ = 35.4 (CH2NH2), 58.7 (C-2), 59.3
(CH2OH), 68.3 (C-5), 74.5 (C-3), 75.6 (C-4) ppm. C6H16Cl2N2O3
(235.07): calcd. C 30.65, H 6.86, N 11.92; found C 30.50, H 6.93,
N 11.70.
(2S,3R,4R,5R)-2-(Aminomethyl)-5-(hydroxymethyl)-3,4-dihydroxy-
pyrrolidine Dihydrochloride (45): The hydrogenation of 36 (0.442 g,
1 mmol) or 39 (0.444 g, 1 mmol), as described above for hydroxyl-
amine 12 to give 21, afforded pure 45 (0.235 g, 100%) as a white
1
solid; m.p. Ͼ150 °C (dec.). [α]2D5 = +43 (c = 1.43, H2O). H NMR
Compound 48: 0.286 g, 58%; oil. [α]2D1 = +12 (c = 3.0, CHCl3). H
1
(400 MHz, D2O): δ = 3.54 (dd, J = 13.9, 6.2 Hz, 1 H, CH2NH2),
3.54 (dd, J = 13.9, 6.8 Hz, 1 H, CH2NH2), 3.62 (ddd, J = 8.8, 4.9,
2.4 Hz, 1 H, 5-H), 3.76 (dd, J = 12.1, 8.8 Hz, 1 H, CH2OH), 3.90
(dd, J = 12.1, 4.8 Hz, 1 H, CH2OH), 4.02 (dt, J = 6.6, 3.6 Hz, 1
H, 2-H), 4.05 (dd, J = 2.7, 1.7 Hz, 1 H, 4-H), 4.27 (dd, J = 3.5,
1.4 Hz, 1 H, 3-H) ppm. 13C NMR (100 MHz, D2O): δ = 35.4
(CH2NH2), 58.7 (C-2), 59.3 (CH2OH), 68.3 (C-5), 74.5 (C-3), 75.6
(C-4) ppm. C6H16Cl2N2O3 (235.07): calcd. C 30.65, H 6.86, N
11.92; found C 30.89, H 7.01, N 11.83.
NMR (400 MHz, CDCl3): δ = 4.15 (dd, J = 2.3, 1.2 Hz, 1 H, 3-
H), 4.42 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.48 (td, J = 14.1, 1.3 Hz,
1 H, CH2OBn), 4.51 (d, J = 11.5 Hz, 1 H, CH2Ph), 4.64 (s, 2 H,
CH2Ph), 4.67 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.72 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.76 (d, J = 14.6 Hz, 1 H, CH2OBn), 4.86 (s, 1 H,
4-H), 4.99 (s, 1 H, 2-H), 7.21–7.25 (m, 2 H, Ar), 7.27–7.41 (m, 18
H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.8 (CH2OBn),
71.9 (CH2Ph), 72.6 (CH2Ph), 73.7 (CH2Ph), 83.0 (C-4), 83.4 (C-2),
83.9 (C-3), 127.8 (Ar), 127.9 (Ar), 128.0 (Ar), 128.1 (Ar), 128.1
(Ar), 128.1 (Ar), 128.2 (Ar), 128.5 (Ar), 128.6 (Ar), 128.6 (Ar),
128.9 (Ar), 129.0 (Ar), 135.3 (Ar), 136.8 (Ar), 137.4 (Ar), 137.5
(Ar), 143.6 (C-5) ppm. C32H31NO4 (493.54): calcd. C 77.87, H 6.33,
N 2.84; found C 77.99, H 6.29, N 2.90.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-hydroxy-
5-phenylpyrrolidine (46): Phenylmagnesium bromide (6 mL of a 1 
solution in THF, 6 mmol) was added dropwise to a cooled (0 °C)
solution of nitrone 8 (0.836 g, 2 mmol) in anhydrous THF. After
stirring for 3 h at 0 °C the reaction was quenched with satd. aq.
NH4Cl (20 mL). The reaction mixture was diluted with diethyl
ether (20 mL), the organic layer was separated, and the aqueous
layer was extracted with diethyl ether (2ϫ20 mL). The combined
organic extracts were washed with brine (20 mL), dried with
MgSO4, and filtered, and the solvent was eliminated under reduced
pressure to afford pure 46 (0.990 g, 100%), which did not need
further purification. White solid; m.p. 80–82 °C (lit.[35b] value for
the enantiomer m.p. 81–82 °C). [α]2D4 = –15 (c = 0.15, CHCl3)
[lit.[35b] value for the enantiomer [α]2D4 = +16.8 (c = 2.5, CHCl3)].
1H NMR (500 MHz, CDCl3): δ = 3.72–3.77 (m, 1 H, 5-H), 3.78
(dd, J = 9.0, 7.4 Hz, 1 H, CH2OBn), 3.91 (dd, J = 9.1, 4.0 Hz, 1
(2R,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-hydroxy-
5-phenylpyrrolidine (49): DIBAH (1 mL of a 1  solution in tolu-
ene, 1 mmol) was added dropwise under argon to a cooled (–80 °C)
solution of nitrone 47 (0.493 g, 1 mmol) in anhydrous THF
(20 mL). The resulting solution was stirred at –80 °C for 4 h, at
which point the reaction mixture was quenched with water (1 mL)
and allowed to warm to room temperature. The reaction mixture
was partitioned between satd. aq. NH4Cl (25 mL) and diethyl ether
(30 mL). The organic layer was separated, and the aqueous layer
was extracted with diethyl ether (2ϫ250 mL). The combined or-
ganic extracts were washed with brine (20 mL), dried with MgSO4,
and filtered, and the solvent was eliminated under reduced pressure
H, CH2OBn), 4.06 (dd, J = 7.3, 3.4 Hz, 1 H, 4-H), 4.12 (dd, J = to afford the crude product, which showed a 92:8 ratio of dia-
3.3, 2.8 Hz, 1 H, 3-H), 4.24 (d, J = 7.3 Hz, 1 H, 5-H), 4.32 (d, J =
stereomers by 1H NMR. Purification of the crude product by radial
11.8 Hz, 1 H, CH2Ph), 4.36 (d, J = 11.8 Hz, 1 H, CH2Ph), 4.51 (d, chromatography (hexane/EtOAc, 4:1) gave pure 49 (0.401 g, 81%)
J = 12.0 Hz, 1 H, CH2Ph), 4.56 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.59 as an oil. [α]2D2 = –28 (c = 1.1, CHCl3). 1H NMR (500 MHz,
(d, J = 12.0 Hz, 1 H, CH2Ph), 4.61 (d, J = 12.0 Hz, 1 H, CH2Ph), CDCl3): δ = 3.26 (q, J = 5.5 Hz, 1 H, 2-H), 3.79 (dd, J = 10.0,
4.85 (s, 1 H, NOH), 7.13 (dd, J = 6.5, 2. 5 Hz, 2 H, Ar), 7.23–7.42
5.4 Hz, 1 H, CH2OBn), 3.84 (dd, J = 10.0, 5.5 Hz, 1 H, CH2OBn),
(m, 16 H, Ar), 7.46 (dd, J = 7.4, 1.6 Hz, 2 H, Ar) ppm. 13C NMR 3.95 (dd, J = 5.9, 1.5 Hz, 1 H, 3-H), 3.90 (dd, J = 5.7, 1.5 Hz, 1
(125 MHz, CDCl3): δ = 66.8 (CH2OBn), 68.8 (C-2), 71.7 (CH2Ph), H, 4-H), 3.96 (d, J = 11.9 Hz, 1 H, CH2Ph),4.01 (d, J = 11.9 Hz,
2942
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Iminocyclitols from Cyclic Nitrones
1 H, CH2Ph), 4.25 (d, J = 6.0 Hz, 1 H, 5-H), 4.48 (d, J = 11.8 Hz,
1 H, CH2Ph), 4.52 (d, J = 11.9 Hz, 1 H, CH2Ph), 4.62 (d, J =
12.0 Hz, 1 H, CH2Ph), 4.66 (d, J = 12.0 Hz, 1 H, CH2Ph), 5.01 (s,
1 H, NOH), 6.93 (dd, J = 6.4, 3.0 Hz, 2 H, Ar), 7.23 (dd, J = 4.9,
1.7 Hz, 1 H, Ar), 7.27–7.41 (m, 14 H, Ar),7.53 (d, J = 6.9 Hz, 1 H,
Ar) ppm. 13C NMR (125 MHz, CDCl3): δ = 70.2 (CH2OBn), 71.6
(2S,3R,4R,5S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-hydroxy-
5-phenylpyrrolidine (52): DIBAH (3 mL of a 1  solution in tolu-
ene, 3 mmol) was added dropwise under argon to a cooled (–80 °C)
solution of nitrone 51 (0.247 g, 0.5 mmol) in anhydrous THF
(10 mL). The resulting solution was stirred at –80 °C for 16 h, at
which point the reaction mixture was quenched with water (1 mL)
(C-2), 71.7 (CH2Ph), 72.1 (CH2Ph), 73.4 (CH2Ph), 74.8 (C-5), 82.5 and allowed to warm to room temperature. The reaction mixture
(C-4), 83.2 (C-3), 127.6 (Ar), 127.6 (Ar), 127.6 (Ar), 127.7 (Ar), was partitioned between satd. aq. NH4Cl (25 mL) and diethyl ether
127.8 (Ar), 127.8 (Ar), 127.9 (Ar), 128.1 (Ar), 128.2 (Ar), 128.4
(Ar), 128.4 (Ar), 129.2 (Ar), 136.9 (Ar), 137.7 (Ar), 138.0 (Ar),
138.3 (Ar) ppm. C32H33NO4 (495.55): calcd. C 77.55, H 6.71, N
2.83; found C 77.48, H 6.80, N 2.68.
(30 mL). The organic layer was separated, and the aqueous layer
was extracted with diethyl ether (2ϫ20 mL). The combined or-
ganic extracts were washed with brine (20 mL), dried with MgSO4,
and filtered, and the solvent was eliminated under reduced pressure
to afford the crude product, which was purified by radial
chromatography (hexane/EtOAc, 4:1) to give pure 52 (0.223 g,
90%) as an oil. [α]2D1 = +38 (c = 0.50, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 3.88–3.95 (m, 2 H, 2-H, CH2OBn), 2.98–4.03 (m, 1
H, CH2OBn), 3.99 (d, J = 11.3 Hz, 1 H, CH2Ph), 4.09 (d, J =
11.5 Hz, 1 H, CH2Ph), 4.21–4.27 (m, 2 H, 5-H, 3-H), 4.57–4.67 (m,
4 H, CH2Ph), 4.69 (d, J = 6.7 Hz, 1 H, 4-H), 6.88–6.93 (m, 2 H,
Ar), 7.19–7.24 (m, 2 H, Ar), 7.29–7.39 (m, 14 H, Ar), 7.42–7.47
(m, 2 H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 65.5
(CH2OBn), 65.6 (C-2), 72.2 (CH2Ph), 72.6 (CH2Ph), 73.4 (C-5),
73.6 (CH2Ph), 82.4 (C-4), 82.9 (C-3), 127.5 (Ar), 127.5 (Ar), 127.6
(Ar), 127.7 (Ar), 127.9 (Ar), 127.9 (Ar), 128.1 (Ar), 128.4 (Ar),
128.4 (Ar), 129.9 (Ar), 137.3 (Ar), 137.7 (Ar), 138.3 (Ar), 138.4
(Ar) ppm. C32H33NO4 (495.55): calcd. C 77.55, H 6.71, N 2.83;
found C 77.48, H 6.52, N 2.96.
(2S,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-1-hydroxy-
5-phenylpyrrolidine (50): -Selectride (1.5 mL of a 1  solution in
hexanes, 1.5 mmol) was added dropwise under argon to a cooled
(–80 °C) solution of nitrone 48 (0.493 g, 1 mmol) in anhydrous
THF (20 mL). The resulting solution was stirred at –80 °C for 16 h,
at which point the reaction mixture was quenched with water
(1 mL) and allowed to warm to room temperature. The reaction
mixture was partitioned between satd. aq. NH4Cl (25 mL) and di-
ethyl ether (30 mL). The organic layer was separated, and the aque-
ous layer was extracted with diethyl ether (2ϫ250 mL). The com-
bined organic extracts were washed with brine (20 mL), dried with
MgSO4, and filtered, and the solvent was eliminated under reduced
pressure to afford the crude product, which was purified by radial
chromatography (hexane/EtOAc, 4:1) to give pure 50 (0.476 g,
96%) as an oil. [α]2D2 = +14 (c = 0.835, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 3.56 (dt, J = 7.3, 5.4 Hz, 1 H, 2-H), 3.86–
3.93 (m, 3 H, CH2OBn, 5-H, 4-H), 4.03 (dd, J = 9.1, 7.9 Hz, 1 H,
CH2OBn), 4.14 (dd, J = 6.7, 1.8 Hz, 1 H, 3-H), 4.31 (d, J =
11.7 Hz, 1 H, CH2Ph), 4.37 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.60 (d,
J = 11.8 Hz, 1 H, CH2Ph), 4.61 (s, 2 H, CH2Ph), 4.64 (d, J =
11.8 Hz, 1 H, CH2Ph), 5.08 (s, 1 H, NOH), 7.12–7.15 (m, 2 H, Ar),
7.26–7.46 (m, 16 H, Ar), 7.47–7.52 (m, 2 H, Ar) ppm. 13C NMR
(100 MHz, CDCl3): δ = 68.1 (CH2OBn), 69.4 (C-2), 71.9 (CH2Ph),
72.2 (CH2Ph), 73.5 (CH2Ph), 77.4 (C-5), 80.3 (C-3), 88.0 (C-4),
127.6 (Ar), 127.7 (Ar), 127.7 (Ar), 127.7 (Ar), 127.8 (Ar), 127.8
(Ar), 127.8 (Ar), 128.1 (Ar), 128.3 (Ar), 128.4 (Ar), 128.6 (Ar),
137.7 (Ar), 138.2 (Ar), 138.2 (Ar), 140.3 (Ar) ppm. C32H33NO4
(495.55): calcd. C 77.55, H 6.71, N 2.83; found C 77.62, H 6.54, N
2.79.
(2R,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-phenylpyrrol-
idine Hydrochloride (53): A solution of hydroxylamine 46 (0.248 g,
0.5 mmol) in methanol (6 mL) was treated with Pd(OH)2-C (50 mg)
and concentrated HCl (0.5 mL). The resulting mixture was stirred
under hydrogen (5 atm) for 4 h. The catalyst was eliminated by fil-
tration through a pad of Celite, and the filtrate was evaporated
under reduced pressure to afford pure 53 (0.123 g, 100%) as a white
solid; m.p. Ͼ 150 °C (dec.). [α]2D5 = +57 (c = 1.105, H2O). 1H NMR
(400 MHz, D2O): δ = 3.63 (ddd, J = 8.2, 5.5, 4.1 Hz, 1 H, 2-H),
3.83 (dd, J = 13.3, 6.3 Hz, 1 H, CH2OH), 3.88 (dd, J = 13.3, 4.5 Hz,
1 H, CH2OH), 4.11 (t, J = 7.5 Hz, 1 H, 3-H), 4.39 (d, J = 9.9 Hz,
1 H, 5-H), 4.43 (dd, J = 10.0, 6.9 Hz, 1 H, 4-H), 7.37–7.47 (m, 5
H, Ar) ppm. 13C NMR (100 MHz, D2O): δ = 58.1 (CH2OH), 61.9
(C-2), 63.2 (C-5), 73.7 (C-3), 77.5 (C-4), 128.3 (Ar), 128.5 (Ar),
130.3 (Ar), 131.3 (Ar) ppm. C11H16ClNO3 (245.67): calcd. C 53.77,
H 6.56, N 5.70; found C 53.82, H 6.49, N 5.83.
(2S,3R,4R)-3,4-Bis(benzyloxy)-5-(benzyloxymethyl)-2-phenyl-3,4-di-
hydro-2H-pyrrole 1-Oxide (51): TEMPO (2 mmol) was added to a
cooled (–60 °C) solution of hydroxylamine 49 (0.496 g, 1 mmol) in
anhydrous CH2Cl2 (20 mL). The resulting solution was stirred for
48 h, at which point the solvent was evaporated under reduced
pressure to give a 1:3 mixture of nitrones 51 and 47. Purification
of the mixture by radial chromatography (hexane/EtOAc, 3:2) af-
forded pure 51 (0.173 g, 23%) as an oil. [α]2D2 = –86 (c = 0.53,
(2R,3R,4R,5S)-3,4-Dihydroxy-2-(hydroxymethyl)-5-phenylpyrrol-
idine Hydrochloride (54): The hydrogenation of 49 (0.248 g,
0.5 mmol), as described above for hydroxylamine 46 to give 53,
afforded pure 54 (0.123 g, 100%) as a white solid; m.p. Ͼ150 °C
1
(dec.). [α]2D5 = +78 (c = 0.535, H2O). H NMR (400 MHz, D2O): δ
= 3.64 (ddd, J = 8.4, 4.8, 3.5 Hz, 1 H, 2-H), 3.85 (dd, J = 12.2,
8.6 Hz, 1 H, CH2OH), 3.95 (dd, J = 12.2, 5.0 Hz, 1 H, CH2OH),
4.11 (dd, J = 3.4, 1.3 Hz, 1 H, 3-H), 4.37 (dd, J = 3.3, 1.2 Hz, 1
H, 4-H), 4.85 (d, J = 3.3 Hz, 1 H, 5-H), 7.34–7.40 (m, 5 H,
Ar) ppm. 13C NMR (100 MHz, D2O): δ = 59.4 (CH2OH), 64.8 (C-
5), 67.5 (C-2), 75.9 (C-3), 76.6 (C-4), 127.5 (Ar), 128.9 (Ar), 129.1
(Ar), 130.3 (Ar) ppm. C11H16ClNO3 (245.67): calcd. C 53.77, H
6.56, N 5.70; found C 53.86, H 6.52, N 5.59.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 4.08 (s, 2 H, CH2Ph),
4.31 (dd, J = 6.6, 2.4 Hz, 1 H, 3-H), 4.46 (ddd, J = 14.4, 2.3, 1.1 Hz,
1 H, CH2OBn), 4.62 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.65 (d, J =
11.7 Hz, 1 H, CH2Ph), 4.66 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.71 (d,
J = 11.6 Hz, 1 H, CH2Ph), 4.80 (dd, J = 14.4, 0.9 Hz, 1 H,
CH2OBn), 4.96 (dt, J = 2.1, 1.1 Hz, 1 H, 4-H), 5.42 (tdd, J = 6.4,
2.4, 1.3 Hz, 1 H, 2-H), 6.87–6.92 (m, 2 H, Ar), 7.22–7.45 (m, 18
H, Ar) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.5 (CH2OBn),
72.4 (CH2Ph), 72.9 (CH2Ph), 73.7 (CH2Ph), 79.4 (C-3), 79.8 (C-4), (2S,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-phenylpyrrol-
83.3 (C-2), 127.9 (Ar), 128.0 (Ar), 128.0 (Ar), 128.0 (Ar), 128.0
(Ar), 128.1 (Ar), 128.4 (Ar), 128.4 (Ar), 128.5 (Ar), 128.6 (Ar),
idine Hydrochloride (55): The hydrogenation of 50 (0.248 g,
0.5 mmol), as described above for hydroxylamine 46 to give 53,
128.9 (Ar), 129.7 (Ar), 131.4 (Ar), 136.7 (Ar), 137.4 (Ar), 137.5 afforded pure 55 (0.122 g, 100%) as a white solid; m.p. Ͼ150 °C
1
(Ar), 143.4 (C-5) ppm. C32H31NO4 (493.54): calcd. C 77.87, H 6.33,
N 2.84; found C 77.79, H 6.234, N 2.89.
(dec.). [α]2D5 = +45 (c = 0.41, H2O). H NMR (400 MHz, D2O): δ
= 3.86–3.96 (m, 3 H, 2-H, CH2OH), 4.35 (t, J = 3.3 Hz, 1 H, 3-
Eur. J. Org. Chem. 2008, 2929–2947
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2943

P. Merino, A. Goti et al.
FULL PAPER
H), 4.41 (d, J = 5.9 Hz, 1 H, 5-H), 4.49 (dd, J = 5.9, 3.1 Hz, 1 H,
(C-4), 116.1 (Ar), 122.8 (Ar), 130.2 (Ar), 157.0 (Ar) ppm.
C11H16ClNO4 (261.66): calcd. C 50.48, H 6.16, N 5.35; found C
4-H), 7.40–7.50 (m, 5 H, Ar) ppm. 13C NMR (100 MHz, D2O): δ
= 56.9 (CH2OH), 62.9 (C-2), 67.6 (C-5), 74.5 (C-3), 79.8 (C-4), 50.39, H 6.38, N 5.24.
128.5 (Ar), 129.4 (Ar), 130.0 (Ar), 132.1 (Ar) ppm. C11H16ClNO3
(245.67): calcd. C 53.77, H 6.56, N 5.70; found C 53.70, H 6.66, N
5.53.
In order to allow comparisons with the literature data an analytical
sample of the free amine was obtained by passing the hydrochloride
through a Dowex 50WX8 ion-exchange resin. Elution with ammo-
nia in methanol (3 ) afforded the free base of 4b (61 mg, 90%) as
a syrup after evaporation: [α]2D5 = +74 (c = 0.1, H2O) [lit.[35b] value
for the enantiomer [α]2D5 = –72.7 (c = 0.17, H2O)]. 1H NMR
(400 MHz, D2O): δ = 2.85–2.93 (m, 1 H, 2-H), 3.36 (dd, J = 11.1,
7.5 Hz, 1 H, CH2OH), 3.42–3.57 (m, 3 H, 3-H, 5-H, CH2OH), 3.75
(t, J = 8.3 Hz, 1 H, 4-H), 6.38 (d, J = 8.3 Hz, 2 H, Ar), 6.93 (d, J
= 8.4 Hz, 2 H, Ar) ppm. 13C NMR (100 MHz, D2O): δ = 62.3 (C-
2), 63.5 (CH2OH), 63.8 (C-5), 78.4 (C-3), 82.9 (C-4), 118.7 (Ar),
126.1 (Ar), 128.8 (Ar), 165.6 (Ar) ppm. C11H15NO4 (225.20): calcd.
C 58.66, H 6.71, N 6.22; found C 58.71, H 6.59, N 6.14.
(2S,3R,4R,5S)-3,4-Dihydroxy-2-(hydroxymethyl)-5-phenylpyrrol-
idine Hydrochloride (56): The hydrogenation of 52 (0.248 g,
0.5 mmol), as described above for hydroxylamine 46 to give 53,
afforded pure 56 (0.123 g, 100%) as a white solid; m.p. Ͼ150 °C
(dec.). [α]2D5 = +27 (c = 0.08, H2O). H NMR (500 MHz, D2O): δ
1
= 3.90 (dd, J = 12.0, 8.2 Hz, 1 H, CH2OH), 3.98 (dd, J = 12.1,
5.1 Hz, 1 H, CH2OH), 3.98–4.06 (m, 1 H, 2-H), 4.30–4.34 (m, 1 H,
5-H), 4.46 (dd, J = 4.3, 1.3 Hz, 1 H, 3-H), 4.81–4.85 (s, 1 H, 4-H),
7.34–7.43 (m, 5 H, Ar) ppm. 13C NMR (75 MHz, D2O): δ = 58.3
(CH2OH), 62.5 (C-2), 64.0 (C-4), 75.0 (C-3), 77.4 (C-5), 127.8 (Ar),
128.8 (Ar), 131.3 (Ar) ppm. C11H16ClNO3 (245.67): calcd. C 53.77,
H 6.56, N 5.70; found C 53.88, H 6.38, N 5.90.
Supporting Information (see also the footnote on the first page of
1
this article): H, 13C NMR and nOe spectra of new compounds.
(2R,3R,4R,5R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-5-[4-(ben-
zyloxy)phenyl]pyrrolidine (57): A freshly prepared THF solution of
4-(benzyloxy)phenylmagnesium bromide[35b] (2 mmol) was added
dropwise under argon to a cooled (0 °C) solution of nitrone 8
(0.209 g, 0.5 mmol) in anhydrous THF (10 mL). The resulting solu-
tion was stirred at 0 °C for 2 h, at which point the reaction was
quenched with satd. aq. NH4Cl (10 mL).The reaction mixture was
diluted with diethyl ether (20 mL). The organic layer was separated,
and the aqueous layer was extracted with diethyl ether (2ϫ20 mL).
The combined organic extracts were washed with brine (20 mL),
dried with MgSO4, and filtered and the solvent was eliminated un-
der reduced pressure to afford the crude product, which was taken
up in 1:1 hexane/diethyl ether. The resulting white solid was filtered
off and dried to give pure 57 (0.268 g, 89%) as a white solid; m.p.
130–131 °C (lit.[35b] value for the enantiomer 131 °C). [α]2D5 = –19
(c = 1.0, CHCl3) [lit.[35b] value for the enantiomer [α]2D5 = +18 (c =
Acknowledgments
For their support of our programs we thank: the Spanish Ministry
of Science and Education (Madrid, Spain. Projects CTQ2004-0421
and CTQ2007-67532-C02-01), the European Regional Develop-
ment Fund and Government of Aragon (Zaragoza, Spain), and the
Ministero dellЈUniversità e della Ricerca (Italy). One of us (I. D.)
also thanks the Gobierno de Aragon for a pre-doctoral grant. The
Socrates/Erasmus exchange programme is also acknowledged for
grants to I. D., E. F. and C. P.
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1
0.55, CHCl3)]. H NMR (500 MHz, CDCl3): δ = 3.71–3.75 (m, 1
H, 2-H), 3.79 (dd, J = 9.2, 7.3 Hz, 1 H, CH2OBn), 3.91 (dd, J =
9.2, 4.2 Hz, 1 H, CH2OBn), 4.08 (dd, J = 7.2, 3.4 Hz, 1 H, 4-H),
4.13 (t, J = 3.2 Hz, 1 H, 3-H), 4.22 (d, J = 7.2 Hz, 1 H, 5-H), 4.35
(d, J = 11.8 Hz, 1 H, CH2Ph), 4.39 (d, J = 11.8 Hz, 1 H,
CH2Ph),4.53 (d, J = 12.0 Hz, 1 H, CH2Ph),4.58 (d, J = 12.0 Hz, 1
H, CH2Ph), 4.61 (d, J = 11.2 Hz, 1 H, CH2Ph), 4.63 (d, J =
11.9 Hz, 1 H, CH2Ph), 5.09 (s, 2 H, CH2Ph), 6.98 (d, J = 8.7 Hz,
1 H, Ar), 7.11–7.14 (m, 2 H, Ar), 7.24–7.52 (m, 20 H, Ar) ppm.
13C NMR (125 MHz, CDCl3): δ = 66.9 (CH2OBn), 68.8 (C-2), 70.0
(CH2Ph), 71.7 (CH2Ph), 72.0 (CH2Ph), 73.4 (CH2Ph), 73.4 (C-5),
83.6 (C-3), 87.4 (C-4), 114.8 (Ar), 127.5 (Ar), 1267.6 (Ar), 127.6
(Ar), 127.7 (Ar), 127.7 (Ar), 128.0 (Ar), 128.1 (Ar), 128.2 (Ar),
128.4 (Ar), 128.4 (Ar), 128.6 (Ar), 129.6 (Ar), 131.6 (Ar), 137.1
(Ar), 137.9 (Ar), 138.1 (Ar), 138.2 (Ar), 158.5 (Ar) ppm.
C39H39NO5 (601.66): calcd. C 77.85, H 6.53, N 2.33; found C
77.54, H 6.47, N 2.44.
(2R,3R,4R,5R)-3,4-Dihydroxy-2-(hydroxymethyl)-5-(4-hydroxy-
phenyl)pyrrolidine (Radicamine B) Hydrochloride (4b): The hydro-
genation of 57 (0.181 g, 0.3 mmol), as described above for hydrox-
ylamine 12 to give 21, afforded pure 4b (79 mg, 100%) as a white
solid; m.p. Ͼ150 °C (dec.). [α]2D5 = +81 (c = 0.25, H2O). H NMR
1
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(400 MHz, CDCl3): δ = 3.59 (ddd, J = 8.4, 5.5, 4.0 Hz, 1 H, 2-H),
3.82 (dd, J = 12.7, 5.7 Hz, 1 H, CH2OH), 3.87 (dd, J = 12.8, 3.9 Hz,
1 H, CH2OH), 4.09 (t, J = 7.7 Hz, 1 H, 3-H), 4.32 (d, J = 10.2 Hz,
1 H, 5-H), 4.39 (dd, J = 10.2, 7.4 Hz, 1 H, 4-H), 6.88 (d, J = 8.6 Hz,
2 H, Ar), 7.33 (d, J = 8.6 Hz, 2 H, Ar) ppm. 13C NMR (100 MHz,
D2O): δ = 58.2 (CH2OH), 61.5 (C-2), 62.8 (C-5), 73.6 (C-3), 77.1
2944
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2929–2947

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2946
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2929–2947

Iminocyclitols from Cyclic Nitrones
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Received: January 27, 2008
Published Online: April 29, 2008
Eur. J. Org. Chem. 2008, 2929–2947
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