Synthesis of pyrrolidine homoazasugars and 3,4-dihydroxy-5- hydroxymethylprolines using aldol additions of metalated bislactim ethers to 2,4-O-ethylidene-d-erythroses

Article abstract of DOI:10.1039/b902366f

A strategy for the synthesis of 2,5-dideoxy-2,5-iminohexitols and 2,5-dideoxy-2,5-iminoglyconic acids is described by using diastereoselective aldol additions of metalated bislactim ethers to 2,4-O-ethylidene-d-erythroses and intramolecular N-alkylation a

Full text of DOI:10.1039/b902366f

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Volume 7 | Number 11 | 7 June 2009 | Pages 2225–2468
ISSN 1477-0520
FULL PAPER
Vicente Ojea et al.
Synthesis of pyrrolidine
homoazasugars and 3,4-dihydroxy-
5-hydroxymethylprolines using aldol
additions of metalated bislactim
PERSPECTIVE
C.-Y. Wu, P.-H. Liang and C.-H. Wong
New development of glycan arrays

PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of pyrrolidine homoazasugars and 3,4-dihydroxy-5-
hydroxymethylprolines using aldol additions of metalated bislactim
ethers to 2,4-O-ethylidene-D-erythroses†
Olga Blanco, Cristina Pato, Mar´ıa Ruiz* and Vicente Ojea*
Received 4th February 2009, Accepted 3rd March 2009
First published as an Advance Article on the web 27th March 2009
DOI: 10.1039/b902366f
A strategy for the synthesis of 2,5-dideoxy-2,5-iminohexitols and 2,5-dideoxy-2,5-iminoglyconic acids is
described by using diastereoselective aldol additions of metalated bislactim ethers to
2,4-O-ethylidene-D-erythroses and intramolecular N-alkylation as key steps. The nature of the metal
fragment of the azaenolate and the b-alkoxy protecting group for the erythrose moiety were varied to
modulate the level and the direction of the asymmetric induction in the aldol addition. The contrasting
stereochemical results of the tin(II)-mediated aldol reactions have been rationalized with the aid of
density functional theory calculations (B3LYP/cc-pVDZ-PP). DFT calculations indicate that
boat-shaped transition structures that allow the formation of a stabilizing hydrogen bond can account
for the unusual anti,syn-stereoselectivity of the aldol addition to b-protected 2,4-O-ethylidene-
erythroses. In the addition to the “unprotected” 2,4-O-ethylidene-erythrose, the preference for
chair-shaped transition structures in which the erythrose moiety is involved in a six-membered chelate
ring is consistent with the experimentally observed syn,anti-stereochemical outcome. The preparative
utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis
of glycosidase inhibitors 2,5-dideoxy-2,5-iminogalactitol and 2,5-dideoxy-2,5-imino-D-glucitol
(DGADP and DGDP) and 3,4-dihydroxy-5-hydroxymethylprolines (2,5-dideoxy-2,5-imino-L-gulonic
acid and 2,5-dideoxy-2,5-imino-L-galactonic acid) that may be useful for glycosidase and glycuronidase
inhibition.
Introduction
Imino sugars are powerful and specific inhibitors of glycosidases
and glycosyltransferases due to their mimicry of the transition
state of the enzymatic reactions. Accordingly, they are useful tools
for the study of the biological functions of oligosaccharides and
constitute an excellent platform for the development of new drugs
against diabetes, cancer metastasis and viral infections.1 To date,
Fig. 1
several piperidine imino sugars have already reached the market or
are undergoing clinical trials.2 Piperidine imino acids, a particular
have gained special importance. Homoazasugars present high
subset of the imino sugar family, also have a similarly appealing
pharmacological potential. For example, naturally occurring 2,6-
dideoxy-2,6-imino-L-gulonic acid (1)3 inhibits a-D-glucosidases,4
and its diastereoisomer with L-galacto configuration 2 is a
potent inhibitor of a-galactosidases (Fig. 1).5 Both acids can be
also considered as 1,5-dideoxy-1,5-imino analogues of glycuronic
acids and have been shown to act as competitive inhibitors of
b-D-glucuronidases, a-L-iduronidases or galacturonidases.5,6,7,8
Pyrrolidine imino sugars have also shown promising biological
activity. Among them, those having a hydroxymethyl group or
a polyhydroxylated carbon chain linked to the carbon adjacent
to nitrogen, the so-called homoazasugars (aza-C-glycosides),
stability towards chemical and enzymatic degradation, usually
retain the same type of enzymatic inhibition activity of the lower
homologues and, in some cases, exhibit higher selectivity and
potency. In particular, 2,5-dideoxy-2,5-imino-D-glucitol (DGDP,
see 3 in Fig. 2) and its C-4 epimer, 2,5-dideoxy-2,5-iminogalactitol
(DGADP, 4), are potent inhibitors of several galactosidases and
glucosidases9 and, consequently, significant efforts have been
devoted to their synthesis.10,11,12 Imino acids of the pyrrolidine
family are likewise interesting. As polyhydroxylated proline deriva-
tives, they are key constituents of natural bioactive molecules,13
useful building blocks for the construction of peptide-mimetics
with improved pharmacological profile,14 and also have been
shown as efficient organocatalysts in asymmetric synthesis.15,16
Despite their synthetic utility17 and potential as glycosidase and
glycuronidase inhibitors, routes to five-membered imino acids of
the homoazasugar family (2,5-dideoxy-2,5-iminoglyconic acids),
like 5 and 6, are notably scarce in the literature. Thus, only very
recently, Lundt, Wrodnigg et al. have reported the synthesis of
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, Universi-
dade da Corun˜a, Campus da Zapateira s/n, 15071 A Corun˜a, Spain. E-mail:
ojea@udc.es; Fax: +34 981167065; Tel: +34 981167000
† Electronic supplementary information (ESI) available: Computational
details, Cartesian coordinates and absolute energies for the models re-
ported and NMR spectra of new compounds. See DOI: 10.1039/b902366f
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been commonly used in stereoselective synthesis,22 and their
reactions with different nucleophilic reagents were reported to
afford moderate to high anti-selectivity.23
In contrast with these precedents, we have recently found that
tin(II)-mediated aldol reaction between bislactim ether (R)-10
and matched 3-O-silylated-D-erythrose ethylidene 11a takes place
with an unusual stereochemical course and affords adduct 12a,
with 3,1¢-anti-1¢,2¢-syn configuration, with high selectivity (see
Scheme 2 and Table 1, entry 1).24 Due to the potential effect
that the tin(II) counterion and the silyl group may have on
the stereoselection of the aldol addition, we were interested in
evaluating the influence of different metal fragments and b-alkoxy
protecting groups on the process. Thus, in this paper, we report
the dependence of the level and the sense of the asymmetric
induction of the aldol reaction on the nature of the metallic
counterion of the azaenolate and on the b-alkoxy protecting group
for the D-erythrose ethylidene derivative. To gain more insight
into the origins of the stereoinduction, we have also carried
out computational studies of the diastereomeric pathways, and
Fig. 2
2,5-dideoxy-2,5-imino-L-gulonic acid (5) by ring closure of 2-
amino-6-bromo-2,6-dideoxy-D-1,4-mannonolactone.10a
In this area, our group has developed a general methodology
for the synthesis of piperidine imino sugars, which involves the
aldol reaction between metalated bislactim ethers and tetrose
acetonides as the key step.18 In an earlier paper we have shown
the flexibility of this strategy and reported its application to the
synthesis of the pyrrolidine homoazasugar DGDP.19 Herein we
present a further extension of our aldol-based methodology for
the synthesis of the pyrrolidine homoazasugar DGADP and also
introduce its applicability for the synthesis of five-membered imino
acids of the homoazasugar family. Thus, in this paper we also
report novel routes to 2,5-dideoxy-2,5-imino-L-gulonic acid (5)
and the previously unknown 2,5-dideoxy-2,5-imino-L-galactonic
acid (6).
In formulating the synthetic plan, we recognized that poly-
hydroxy amino esters 7 might be valuable key intermediates,
since the targeted five-membered imino acids would originate by
cyclization, via nucleophilic substitution of an activated hydroxyl
group (see Scheme 1). In addition, the corresponding homoaza-
sugars would be accessible by simple reduction of the carboxylic
acid function. We envisaged preparing key intermediates 7 by
stereocontrolled aldol additions between metalated bislactim
ethers 8 and suitably protected tetrose derivatives 9. Bislactim
ethers were sought as appropriate precursors, as aldol additions
of metalated bislactims to matched a-alkoxyaldehydes have been
reported to proceed with high levels of syn,anti-selectivity,20 which
has been rationalized by invoking chair-like pericyclic transition
structures21 with Felkin-Anh or Cornforth-like conformations
for the aldehyde moiety. Moreover, 2,4-alkylidene-tetroses have
Scheme 2 Legend: a, P = TBDPS; b, P = Bn; c, P = H; d, P = Ms.
Table 1 Aldol additions of M+10- to D-erythrose ethylidenes 11a-c
D-erythrose
(R)-10
equiv
yield ratiob
additive (equiv) (%)a
12/13/14
entry
ethylidene (P)
1
2
3
4
5
11a (TBDPS)
11b (Bn)
1.2
1.5
1.5
1.5
1.5
SnCl2 (1.5)
—
80c
75d
86d
73d
81d
92:–:08
50:37:13
72:28:–
69:31:–
10:66:24
11b (Bn)
SnCl2 (1.9)
SnCl2 (3.8)
Ti(OiPr)2Cl2
(1.9)
11b (Bn)
11b (Bn)
6
11b (Bn)
1.5
Ti(OiPr)2Cl2
(3.8)
83d
10:65:25
7
8
11b (Bn)
11c (H)
1.5
3.2
ZnCl2 (1.9)
SnCl2 (3.8)
8d
36:64:–
06:94:–
88e
a Isolated yield of mixtures of diastereomeric adducts, after flash chro-
1
matography. b Determined by integration of the H NMR spectra of the
crude mixtures. c Data obtained from reference 19. d Reaction conducted
at -78 ◦C in THF. e Reaction conducted from -78 to 0 ◦C in THF.
Scheme 1
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transition-state models consistent with the stereoselectivity of the
aldol additions are also put forward. Finally, we describe the
efficient transformation of the addition products into the targeted
homoazasugars and 2,5-dideoxy-2,5-iminoglyconic acids that may
result in useful pharmacological tools for the study of glycosidase
and glycuronidase inhibition.
the lower steric requirement and the different electronic nature of
the benzyl group in 11b with respect to the tert-butyldiphenylsilyl
one in 11a led to an increased trans-selectivity and a markedly
reduced anti,syn-stereoselection in the reaction with SnCl+10-.
Prompted by the moderate stereoselectivity achieved in the
reaction of SnCl+10- and the benzylated aldehyde 11b, we tested
the addition process in the presence of other metallic counterions.
Thus, we prepared the zinc(II) and the titanium(IV) azaenolates
from Li+10- and ZnCl2 or Ti(OiPr)2Cl2 (in THF at -78 ◦C for 1 h),
prior to the addition of 11b. Switching the metal of the azaenolate
from lithium or tin(II) to zinc(II) or titanium(IV) changed the
stereochemical outcome of the process, and thus, additions to the
benzylated aldehyde took place with moderate syn,anti-selectivity
in both cases. In this manner, by using Ti(OiPr)2Cl+10-, the
reaction with 11b was also complete under the standard conditions
(4 h at -78 ◦C) and furnished a mixture of adducts 12b/13b/14b
in a 10:66:24 ratio, with 81% yield (see Table 1, entry 5). Neither
the selectivity nor the yield could be significantly changed when
this reaction was performed with a larger excess of Ti(OiPr)2Cl2
(see entry 6). In a different manner, the reaction of the zinc(II)
azaenolate resulted in a very low conversion to products, which
could not be increase◦d with longer reaction times or higher
temperatures (12 h at 0 C). Thus, by using ZnCl+10-, the reaction
with 11b gave a mixture of adducts 12b/13b in a 36:64 ratio that
was isolated in 8% yield (see entry 7). Finally, all the mixtures of
the addition products could be separated by flash chromatography,
and the benzylated adducts 12b and 13b were isolated as single
diastereoisomers in yields up to 62% and 53%, respectively.
To further explore the effect of the b-protecting group on the
stereochemical outcome of the aldol addition, 2,4-O-ethylidene-
D-erythrose (11c),22 with an “unprotected” hydroxyl group, was
found attractive. As was previously found for the azaenolate
additions to erythrose acetonides with an “unprotected” g-
hydroxyl group,18a,b we reasoned that an initial deprotonation of
11c by the azaenolate M+10- would lead to an oxyanion at the b-
position, which should be able to coordinate with the metal cation
to form a temporary ring that could enhance 1¢,2¢-anti-selectivity
in the subsequent aldol addition. To this end, aldehyde 11c was
added to a solution of 3.8 equiv of SnCl+10- at -78 ◦C. As the
addition was not observed at this temperature, the reaction mixture
was gradually warmed to 0 ◦C. Reaction was completed 4 h later,
and after quenching with NaHCO3, aqueous work-up and removal
of the excess of (R)-10 by chromatography, a mixture of adducts
12c/13c was obtained in 88% yield. Integration of the 1H NMR of
this mixture revealed a 6:94 ratio between adducts 12c and 13c (see
Table 1, entry 8). Thus, with the use of the matched “unprotected”
erythrose ethylidene, addition of the tin(II) azaenolate proceeded
in the expected way, with remarkable 3,6-trans-3,1¢-syn-1¢,2¢-anti-
stereoselection. In this manner, the major adduct 13c could be
obtained with high purity (d.e. higher than 98%) and 83% yield
after purification by flash chromatography.
Results and discussion
1. Aldol additions of metalated bislactim ethers to
2,4-O-ethylidene-D-erythroses
To investigate the effect of the b-alkoxy protecting groups in the
addition of metalated bislactim ethers to the erythrose ethylidenes,
we decided to employ the aldehydes 11b and 11c (see Scheme 2).
A benzyl group was selected to protect the b-oxygen atom due
to its common use in synthesis design and its significant steric
and electronic differences with the tert-butyldiphenylsilyl group
that was used in our previous work. On the basis of the complete
azaenolate control (and syn-selectivity) reported by Scho¨llkopf
and Kobayashi in the reactions of tin(II), zinc(II) or titanium(IV)
salts of bislactim ethers with either matched or mismatched poly-
hydroxylated aldehydes,20b,e we decided to examine the behaviour
of the corresponding metalated azaenolates M+10- as the aldol
counterparts of the erythrose derivatives.
Consequently, 3-O-benzyl-2,4-O-ethylidene-D-erythrose was
readily obtained from D-glucose, following the reported
procedure.25 The benzylated aldehyde 11b underwent stereose-
lective aldol additions of metalated azaenolates M+10-, in an
analogous fashion to that previously reported for the 3-O-tert-
butyldiphenylsilyl derivative 11a. Thus, slow addition of n-BuLi
to a solution of bislactim ether (R)-10 in THF at -78 ◦C was
followed 1 h later by the addition of freshly distilled benzylated
aldehyde 11b. Reaction took place within 4 h, and after quenching
with NH4Cl, aqueous workup, and removal of the excess of
(R)-10 by chromatography,26 a mixture containing adducts 3,6-
trans-3,1¢-anti-1¢,2¢-syn 12b, 3,6-trans-3,1¢-syn-1¢,2¢-anti 13b and a
3,6-cis diastereoisomer 14b was isolated in 75% combined yield.
Integration of the pairs of doublets corresponding to the isopropyl
groups in the 1H NMR spectrum of this mixture revealed a
50:37:13 ratio between adducts 12b/13b/14b (see Table 1, entry
2). The yield and the stereoselectivity of this aldol addition could
be increased by using the tin(II) azaenolate, as previously reported
for other aldol reactions with bislactim ethers.18a,20b To this end,
the lithium azaenolate was allowed to react with SnCl2 for 1 h
to produce the transmetalated azaenolate SnCl+10-, prior to the
addition of the aldehyde 11b. Reaction of the tin(II) azaenolate
was also complete within 4 h at -78 ◦C and, after quenching
with NaHCO3, aqueous workup, and removal of the excess of
(R)-10, led to a mixture of adducts 12b/13b in a 72:28 ratio
with 86% yield (see entry 3). Attempting to further improve
the diastereoselectivity of the process we also performed the
reaction of SnCl+10 and 11b in the presence of an excess of
SnCl2,27 but in this condition the diastereomeric ratio between
12b/13b was almost unchanged and the yield was lower (see
entry 4). It should be noticed that adducts 12a,b, with an unusual
anti,syn-configuration, were obtained as the major products in the
additions of the tin(II) azaenolate SnCl+10- to either the silylated
or the benzylated erythrose derivatives 11a and 11b. Nevertheless,
Evidence supporting the relative configurations of the addition
products was obtained from NMR analysis and chemical corre-
lation. For the 3,6-trans diastereoisomers (12b,c and 13b,c) the
H-6 resonance appears between 3.86 and 4.08 ppm, as a triplet
5
with J(H-3,H-6) close to 3.5 Hz, which is general of the trans
relationship of substituents at the bislactim ethers. Conversely,
the 1H NMR spectrum of adduct 14b shows the absorption
corresponding to H-6 at 3.97 ppm, as a doublet of doublets with
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a 5J(H-3,H-6) of 6.0 Hz, which is typical of a 3,6-cis relationship
at the bislactim ethers.28 Furthermore, the configurations of the
major adducts were unambiguously confirmed through their
conversion into known pyrrolidine alkaloids. Thus, adducts 12b,c
were transformed into DGDP and adducts 13b,c were used in the
preparation of DGADP, as will be described below (see Schemes 2,
4 and 5).
In summary, the experimental results obtained in the additions
of metalated bislactim ethers to erythrose ethylidenes indicate that
the level and the direction of the stereoinduction is markedly
dependent on the presence of a free or a protected b-hydroxyl
group. With the use of tin(II) azaenolates, addition to the
“unprotected” erythrose ethylidenes takes place with high syn,anti-
stereoselection, while additions to the b-protected erythrose
derivatives results in an unusual anti,syn-stereoselectivity. Finally,
this unusual stereochemical result was found to be characteristic
for the reactions with lithium and tin(II) azaenolates, and could
be reverted to the expected one by switching the metal fragment
to titanium(IV).
are in line with the experimental values encountered in the tin(II)-
mediated aldol additions of Scho¨llkopf’s bislactim ethers.18a,19
We first analyzed the reaction of SnCl+10- and the benzy-
lated erythrose ethylidene 11b. Pericyclic TSs connecting the
intermediate complex 15b to the corresponding aldolates with
either cis,anti,anti, cis,syn,syn, trans,anti,syn or trans,syn,anti
configuration were grouped into four diastereomeric pathways
designated as caa, css, tas and tsa, respectively. In each di-
astereomeric pathway, different geometries were constructed and
subjected to optimization, considering (1) boat-like and chair-
like conformations for the pericyclic ring29 (denoted “B” and
“C”, respectively), (2) Felkin-Anh,30 modified-Cornforth,31 and
non-Anh32 conformations for the erythrose moiety (denoted “F”,
“M” and “N”, respectively, see Fig. S2 of the ESI), and (3)
R and S configurations for the tetrahedral tin(II) cation. Most
stable diastereomeric TSs located for the reorganization of the
benzylated complex 15b were analogous to those previously
computed from the silylated intermediate 15a.19 In agreement with
the experimental result, the trans,anti,syn-diastereomeric pathway
offered the lowest energy profile for the reaction between SnCl+10-
and 11b. The most favourable TS, designated as tas-BNb, was
characterized by a boat-like conformation for the pericyclic ring
and a non-Anh conformation for the erythrose moiety. In the
trans,syn,anti-diastereomeric pathway, the most stable TS was tsa-
CMb, which showed chair-like and Cornforth-like conformations
for the pericyclic ring and the erythrose moiety, respectively, and
was calculated to be 0.6 kcal mol-1 higher in energy than tas-BNb
(see Fig. 3). Other competitive TSs in the cis-pathways were also
calculated higher in energy (see Fig. S3 of the ESI). In tas-BNb, the
distance between the oxygen atom at a-position of the erythrose
moiety and one of the methoxy hydrogen atoms of the bislactim
2. Models for diastereoselective aldol additions of tin(II)
azaenolates of bislactim ethers to erythrose ethylidenes
We have studied the kinetically controlled tin(II)-mediated aldol
additions of bislactim ethers to glyceraldehyde and erythrose
acetonides by computational methods, and reported that these
reactions proceed by the exothermic formation of an intermediate
complex which subsequently reorganizes to the diastereomeric
aldolates in the rate-determining step, through competitive six-
membered, pericyclic transitions structures (TSs). We analyze
herein the extension of this model to the reactions of SnCl+10-
with “unprotected” and benzylated erythrose ethylidenes 11b and
11c (see Scheme 3) and show that DFT calculations provide
some insight to rationalize the contrasting stereochemical results.
Since these reactions are performed under conditions of kinetic
control, the analysis can be performed from comparison of the
competing TSs for the reorganization step, in which the new
stereocenters are formed. To this end, geometry optimizations
were performed using the B3LYP procedure with the cc-pVDZ
basis set and a small-core relativistic pseudopotential (PP) for Sn.
Single point energy calculations were performed at the B3LYP/cc-
pVTZ-PP level in THF solution using the PCM method (see
Computational methods and ESI for further details). We reported
in early contributions that this computational methodology has
performed well in providing predictions of diastereoselectivity that
˚
ether was 2.26 A, indicating the presence of a hydrogen bond
interaction (represented as a doted line in Fig. 3). The magnitude
of this interaction was assessed by natural bond order (NBO)
analysis of the optimized structure. Thus, in tas-BNb, the energy
associated with oxygen lone pair donation into the C–H s* is 1.8
kcal mol-1. This interaction was not present in the competing TSs,
and therefore could contribute to the unusual preference for the
trans,anti,syn-pathway.
Fig. 3 Chem3D representations of the most favoured TSs located in
the gas phase (at B3LYP/cc-pVDZ-PP level) for the reaction between
azaenolate SnCl+10- and benzylated erythrose ethylidene 11b. Relative
energies in THF (at B3LYP(SCRF)/cc-pVTZ-PP level using the PCM
method) are shown in parentheses in kcal mol-1. Distances are in
angstroms. The hydrogen atoms are omitted for clarity except at chiral
and reaction centers.
We next studied the reaction of SnCl+10- and the “unprotected”
erythrose ethylidene 11c. The most stable TS located in the
rearrangement of the intermediate complex 15c was found in
Scheme 3
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the trans,syn,anti-diastereomeric pathway, also in agreement with
the experimental result. This TS was designated as tsa-CMc,
and was characterized by the presence of two pseudotetrahedral,
tricoordinated tin(II) cations, a chair-like conformation for the
pericyclic ring, and a Cornforth-like one for the erythrose moiety,
which was also involved in a six-membered chelate ring (see Fig. 4).
Thus, in tsa-CMc, the carbonyl oxygen acts as a bidentate ligand,
which binds to the tin(II) cation of the azaenolate and also to
the tin(II) cation of the erythrose moiety. The most stable TS
in the trans,anti,syn-pathway was tas-BNc, which showed a 6,8
ring system, boat-like conformation for the pericyclic ring and
non-Anh conformation for the erythrose moiety. The additional
eight-membered ring in tas-BNc originates from the interaction
of the chlorine of the tin(II) azaenolate with the tin(II) cation of
the erythrose moiety. Although tas-BNc showed a hydrogen bond
interaction between the oxygen atom at a-position of the erythrose
moiety and one of the methoxy hydrogens of the bislactim ether,
it was calculated 4.4 kcal mol-1 higher in energy than tsa-CMc.
Other competitive TSs in the cis-pathways were also computed
higher in energy (see Fig. S4 in the ESI).
3. Transformation of aldol adducts into proline derivatives and
pyrrolidine homoazasugars
Conversion of the aldol adducts 12c and 13c into the targeted
polyhydroxylated proline derivatives required, in addition to the
removal of the chiral auxiliary, a selective activation of the
hydroxyl group at C-3¢ that would enable the cyclization by
intramolecular N-alkylation. To this end, additional amounts of
the required diols were obtained by catalytic hydrogenation of
the benzylated adducts 12b and 13b. Thus, heating of 12b or
13b with ammonium formate and palladium catalyst in MeOH
furnished 12c and 13c in high yield (see Scheme 2). By following
our recently reported methodology,19 diols 12c and 13c were
efficiently transformed into gulonate 17 and galactonate 20,
respectively, as depicted in Schemes 2 and 4. In this manner,
treatment of diol 12c with MsCl, Et3N and a catalytic amount of
dimethylaminopyridine in CH2Cl2 at 0 ◦C led to the regioselective
mesylation of the equatorial hydroxyl group at position 3¢, and
afforded the mesylate 12d in good yield.33 Conversely treatment of
diol 13c in the same conditions gave rise to a mixture of mesylate
13d along with the corresponding dimesylated derivative, in a
3:1 ratio and 88% combined yield (see Scheme 2). Nevertheless,
tosylation of 13c by treatment with TsCl, Ag2O and a catalytic
amount of KI in toluene at rt was completely regioselective at
equatorial hydroxyl group and gave 18 in 91% yield (see Scheme 4).
As was previously observed for other bislactim ether derivatives
with free hydroxyl groups, protection of mesylate 12d and tosylate
18 was necessary to achieve acceptable yields in the hydrolysis
of the bislactim ethers. In this way, reaction of 12d and 18 with
sodium hydride and benzyl bromide in the presence of a catalytic
amount of tetrabutylammonium iodide led to the corresponding
benzyl ethers 16 and 19 in good yields. Selective hydrolysis of
the bislactim ether ring in the presence of the ethylidene acetal
was achieved on the benzyl ethers 16 and 19 with 0.25 M HCl in
MeOH at room temperature. Under these conditions, cyclization
of the amino mesylate intermediate to afford the corresponding
Fig. 4 Chem3D representations of the most favoured TSs located in
the gas phase (at B3LYP/cc-pVDZ-PP level) for the reaction between
azaenolate SnCl+10- and “unprotected” erythrose ethylidene 11c. Relative
energies in THF (at B3LYP(SCRF)/cc-pVTZ-PP level using the PCM
method) are shown in parentheses in kcal mol-1. Distances are in
angstroms. The hydrogen atoms are omitted for clarity except at chiral
and reaction centers.
In summary, the computational models reproduce the sense
and degree of stereoselection in the reactions of SnCl+10- with
the erythrose ethylidenes 11a-c. When the b-oxygen atom of the
aldehyde is protected, trans,anti,syn TSs were favoured over the
trans,syn,anti-counterparts, and the calculated energy gap between
the competitive TSs was greater for the silylated derivatives (1.2
kcal mol-1, see ref. 19) than for the benzylated ones (0.6 kcal
mol-1, see Fig. 3) in agreement with the experimentally observed
ratios (see Table 1). Calculations indicate that the unusual anti,syn-
selectivity in the aldol additions to the b-protected erythrose
ethylidenes originate from the kinetic preference for boat-shaped
TSs in which a stabilizing hydrogen-bond exists between the a-
oxygen atom of the erythrose and an alkoxy hydrogen of the
bislactim ether. Conversely, the enhanced syn,anti-stereoselectivity
in the addition of the tin(II) azaenolate to “unprotected” erythrose
ethylidene can be explained in terms of the preference for chair-
shaped TSs in which the erythrose moiety is involved in a six-
membered chelate ring. Thus, in this case, DFT calculations
indicate that chelation may play a key role in both activating the
“unprotected” erythrose ethylidene towards the aldol addition and
also directing facial selectivity.
Scheme 4 Reagents and conditions: i. NaH, BnBr, Bu4NI, THF. ii. 0.25 M
HCl/MeOH 1:3, rt. iii. (a) 0.25 M HCl/THF 1:1, H2, Pd/C, rt; (b) 1 M
HCl, D. iv. TsCl, Ag2O, KI, toluene, rt. v. (a) 0.25 M HCl/MeOH 1:3, rt;
(b) DMSO, Et3N, D.
2314 | Org. Biomol. Chem., 2009, 7, 2310–2321
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©

gulonate 17 was observed. On the other hand, complete cyclization
of the corresponding amino tosylate intermediate to galactonate
20 required heating in DMSO, in the presence of Et3N as auxiliary
base. Finally, deprotection of 17 and 20 by catalytic hydrogenation
and hydrolysis in hydrochloric acid, followed by purification by
ion-exchange and reversed-phase chromatography, furnished 2,5-
dideoxy-2,5-imino-L-gulonic acid (5) and 2,5-dideoxy-2,5-imino-
L-galactonic acid (6) in high yields.
Pyrrolidine homoazasugars DGADP and DGDP were readily
accessible from the gulonate 17 and galactonate 20, respectively,
as depicted in Scheme 5. Reduction of the ester group in 17 and 20
by treatment with lithium triethylborohydride proceeded cleanly,
and gave the protected homoazasugars 21 and 22 in excellent
yields. Thus, under the conditions employed for the deprotection
of the prolinates, 21 and 22 gave rise to DGDP and DGADP,
respectively, in high yields after ion-exchange and reversed-phase
chromatography. Specific rotations and spectral data obtained
for imino acid 5, DGDP and DGADP were consistent with the
literature values.10,11
were purchased and used without further purification unless
otherwise stated. Ti(OiPr)2Cl2 was prepared in situ by reaction
of equimolecular amounts of TiCl4 and Ti(OiPr)4 in THF at room
temperature.34 THF was distilled from sodium/benzophenone,
CH2Cl2 was distilled from calcium hydride and toluene and
Et3N were distilled from sodium. Reactions were monitored
by thin-layer chromatography carried out on 0.25 mm silica
gel plates (60F-254) using UV light as visualizing agent and
cerium sulfate/ammonium molybdate in 10% sulfuric acid or
ninhydrin in a 3% HOAc/n-BuOH solution as developing agents.
E. Merck Silica gel and RP-18 (both 230–400 mesh) were used for
liquid chromatography separations and Dowex 50W-X8 resin (H+
form, 100–200 mesh) was used for ion-exchange chromatography.
Melting points, determined with a Bibby SM3P apparatus, are
uncorrected. IR spectra were recorded on a Bruker Vector 22
spectrometer. 1H NMR and 13C NMR spectra were recorded
on Bruker AVANCE spectrometers (300 MHz or 500 MHz).
Coupling constants were measured in Hz. Chemical shifts were
given in d (ppm) relative to internal CDCl3 (d 7.27), to HOD in
1
D2O (d 4.79) or to Me4Si in MeOD (d 0.00) for H, relative to
internal CDCl3 (d 77.0) for 13C. 1H or 13C assignments were made
on the basis of NOESY, COSY, HSQC and HMBC experiments.
In 1H NMR assignments, dsp stands for double septuplet.
FABMS spectra were recorded on a Thermo Finnigan MAT95XP
spectrometer using thioglycerol as a matrix. Optical rotations were
taken at the NaD-line using a Jasco DIP-1000 polarimeter. [a]D
Values are given in units 10-1 deg cm2 g-1. Elemental analyses
were performed at Servizos Xerais de Apoio a´ Investigacio´n of
Universidade da Corun˜a.
Scheme 5 Reagents and conditions: i. LiEt3BH, THF, 0 ◦C. ii. (a) 0.25 M
HCl/THF 1:1, H2, Pd/C, rt; (b) 1 M HCl, D.
Synthetic intermediates
3-[3-Benzyloxy-2,4-ethylidenedioxybutyl-1-hydroxy]-3,6-dihy-
dro-6-isopropyl-2,5-dimethoxypyrazine (12b and 13b). A solution
of n-BuLi (2.5 M in hexane, 0,4 mL, 1.0 mmol) was added to
a stirred solution of Scho¨llkopf’s bislactim ether 10 (176 mg,
0.96 mmol) in THF (6 mL) at -78 ◦C and the mixture was stirred
for 1 h. Then, a 0.5 M solution of the additive (SnCl2, Ti(OiPr)2Cl2
or ZnCl2) in THF (1.9 or 3.8 equiv) was added dropwise. The
mixture was stirred for 1 h, and a solution of freshly distilled
aldehyde 11b (150 mg, 0.63 mmol) ◦in THF (1 mL) was added
dropwise. After being stirred at -78 C for 4 h, the reaction was
quenched with aqueous saturated NaHCO3 solution. The crude
reaction mixture was warmed to rt. The solids were removed by
filtration and the filtrate was concentrated in vacuo. The resulting
material was diluted with water and extracted with ether. The
combined organic layers were dried (Na2SO4) and evaporated,
and the residue was purified by flash chromatography (silica gel,
EtOAc/hexanes 1:6) to yield the corresponding addition products
12b and 13b.
Conclusions
Stereoselective aldol additions of bislactim ethers to matched
2,4-O-ethylidene-erythroses coupled with an intramolecular N-
alkylation step gave an easy access to the synthesis of biologically
active homoazasugars (DGADP and DGDP) and 3,4-dihydroxy-
5-hydroxymethylprolines 5 and 6 with potential glycuronidase
inhibition activity. It has been shown that the stereochemical
outcome of these aldol additions can be modulated (1) by varying
the metal fragment of the azaenolate or (2) with the presence of a
free or a protected b-hydroxyl group at the erythrose ethylidene. An
additional interesting feature of the described methodology lays in
its inherent flexibility, since a variety of pyrrolidine homoazasug-
ars and 2,5-iminoglyconic acids could become accessible by simply
altering the stereochemistry or the chain length in the starting
aldehyde. The combined experimental/theoretical investigations
of the aldol additions of metalated bislactim ethers to matched
and mismatched 2,4-O-ethylidene-threoses and their adaptation
to the synthesis of biologically active compounds are currently
underway.
(3S,6R,1¢R,2¢S,3¢R)-3-[3-Benzyloxy-2,4-ethylidenedioxybutyl-
1-hydroxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxypyrazine (12b):
colorless oil; Rf = 0.45 (silica gel, EtOAc/hexanes 1:3); [a]24
D
+13.5 (c 0.6 in CH2Cl2); (Found: C, 62.93; H, 7.69; N, 6.58. Calc.
for C22H32N2O6: C, 62.84; H, 7.67; N, 6.66%); nmax/cm-1 2943,
1695, 1239, 1094; dH (300 MHz, CDCl3) 0.70 (3H, d, J = 6.9),
1.07 (3H, d, J = 6.9), 1.23 (3H, d, J = 5.0), 2.29 (1H, dsp, J = 6.8
and 3.4), 3.38 (1H, t, J = 10.5), 3.47 (1H, d, J = 9.6), 3.51 (1H,
dd, J = 9.3 and 1.2), 3.70 (3H, s), 3.74 (3H, s), 3.73–3.81 (1H,
Experimental
All moisture-sensitive reactions were performed under an argon
atmosphere using oven-dried glassware. Reagents and solvents
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2310–2321 | 2315
©

m), 3.87 (1H, t, J = 3.4), 4.10 (1H, dd, J = 10.7 and 5.2), 4.18
(1H, ddd, J = 9.5, 6.5 and 1.3), 4.37 (1H, dd, J = 6.5 and 3.8),
4.56 (1H, q, J = 5.0), 4.58 (1H, AB system, J = 11.6), 4.68 (1H,
AB system, J = 11.6), 7.29–7.38 (5H, m), dC (75 MHz, CDCl3)
16.5 (CH3), 19.1 (CH3), 20.4 (CH3), 31.4 (CH), 52.5 (CH3), 52.6
(CH3), 57.7 (CH), 61.1 (CH), 68.2 (CH), 68.5 (CH), 69.1 (CH2),
72.8 (CH2), 79.7 (CH), 98.4 (CH), 127.7 (CH), 128.4 (CH), 138.2
(C), 161.8 (C), 163.8 (C); FABMS (thioglycerol) m/z 421 (MH+,
100). HRMS 421.2334. C22H33N2O6 requires 421.2339.
6.8), 1.07 (3H, d, J = 6.8), 1.22 (3H, d, J = 5.0), 2.30 (1H, dsp,
J = 6.8 and 3.4), 3.20–3.50 (2H, m), 3.67–3.75 (1H, m), 3.72 (6H,
s), 3.87 (1H, t, J = 3.4), 3.98–4.05 (2H, m), 4.32 (1H, dd, J = 6.2
and 3.4), 4.62 (1H, q, J = 5.0); dC (75 MHz, CD3OD) 16.9 (CH3),
19.8 (CH3), 20.9 (CH3), 32.1 (CH), 53.2 (CH3), 53.6 (CH3), 59.9
(CH), 61.9 (CH), 62.0 (CH), 71.0 (CH), 72.1 (CH2), 82.1 (CH),
100.1 (CH), 164.3 (C), 166.9 (C). FABMS (thioglycerol) m/z 331
(MH+, 100%). HRMS 331.1882. C15H27N2O6 requires 331.1869.
(3S,6R,1¢S,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1,3-dihydro-
xy]-3,6-dihydro-6-isopropyl-2,5-dimethoxypyrazine (13c): white
solid; m.p. 155 ◦C; Rf = 0.50 (silica gel, EtOAc/hexanes 1:1);
(3S,6R,1¢S,2¢S,3¢R)-3-[3-Benzyloxy-2,4-ethylidenedioxybutyl-
1-hydroxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxypyrazine (13b):
colorless oil; Rf = 0.55 (silica gel, EtOAc/hexanes 1:3); [a]24
[a]22 -24.7 (c 1.0 in CH2Cl2); (Found: C, 54.69; H, 7.66; N, 8.61.
D
D
-37.5 (c 1.0 in CH2Cl2); (Found: C, 62.77; H, 7.71; N, 6.87. Calc.
for C22H32N2O6: C, 62.84; H, 7.67; N, 6.66%); nmax/cm-1 2943,
1697, 1236, 1091; dH (300 MHz, CDCl3) 0.72 (3H, d, J = 6.9),
1.05 (3H, d, J = 6.9), 1.33 (3H, d, J = 5.0), 2.26 (1H, dsp, J = 6.8
and 3.5), 3.10 (1H, d, J = 5.8), 3.48 (1H, t, J = 10.1), 3.70 (3H,
s), 3.72–3.78 (1H, m), 3.76 (3H, s), 3.87–3.93 (1H, m), 4.00 (1H, t,
J = 3.5), 4.22–4.28 (3H, m), 4.57 (1H, AB system, J = 11.4), 4.61
(1H, AB system, J = 11.4), 4.72 (1H, q, J = 5.0), 7.29–7.38 (5H,
m); dC (75 MHz, CDCl3) 16.8 (CH3), 19.1 (CH3), 20.5 (CH3), 31.7
(CH), 52.4 (CH3), 52.6 (CH3), 55.6 (CH), 60.9 (CH), 68.4 (CH2),
72.0 (CH2), 73.4 (CH), 74.7 (CH2), 76.1 (CH), 98.8 (CH), 128.0
(CH), 128.2 (CH), 128.6 (CH), 137.1 (C), 162.0 (C), 165.5 (C);
FABMS (thioglycerol) m/z 421 (MH+, 100).
Calc. for C15H26N2O6: C, 54.53; H, 7.93; N, 8.48%); nmax/cm-1 3399,
3152, 1698, 1228, 1196, 1079, 1042, 1007; dH (300 MHz, CDCl3)
0.70 (3H, d, J = 6.8), 1.08 (3H, d, J = 6.8), 1.5 (3H, d, J = 5.1),
2.10 (1H, brd, J = 4.6), 2.32 (1H, dsp, J = 6.8 and 3.5), 3.44 (1H,
t, J = 10.7), 3.54 (1H, dd, J = 8.9 and 3.1), 3.73 (3H, s), 3.76 (3H,
s), 3.85 (1H, ddd, J = 10.1, 9.0 and 5.5), 4.08 (1H, t, J = 3.5), 4.15
(1H, brd, J = 3.6), 4.22 (1H, dd, J = 10.7 and 5.5), 4.41–4.43 (1H,
m), 4.73 (1H, q, J = 5.1), 6.81 (1H, brs), dC (75 MHz, CDCl3) 16.5
(CH3), 19.1 (CH3), 20.5 (CH3), 31.6 (CH), 52.9 (CH3), 53.4 (CH3),
56.5 (CH), 59.5 (CH), 60.7 (CH), 70.0 (CH2), 73.4 (CH), 83.1
(CH), 98.6 (CH), 160.5 (C), 167.6 (C); FABMS (thioglycerol) m/z
331 (MH+, 100). HRMS 331.1876. C15H27N2O6 requires 331.1869.
(3S,6R,1¢R,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1-hydroxy-3-
methanesulfonyloxy ] - 3, 6 - dihydro - 6 - isopropyl - 2, 5 - dimethoxy -
pyrazine (12d). A solution of diol 12c (340 mg, 1.03 mmol), Et3N
(0.28 mL, 2.02 mmol) and DMAP (21 mg, 0.17 mmol) in CH2Cl2
(15 mL) at 0 ◦C was treated with MsCl (0.12 mL, 1.55 mmol) and
the mixture was stirred for 2 h at rt. The solvent was evaporated
and the residue was purified by flash chromatography (silica gel,
EtOAc/hexanes 2:3) to give mesylate 12d (386 mg, 92%) as a
3-[2,4-Ethylidenedioxybutyl-1,3-dihydroxy]-3,6-dihydro-6-iso-
propyl-2,5-dimethoxypyrazine (12c and 13c). A solution of n-
BuLi (2.5 M in hexane, 5.5 mL, 13.75 mmol) was added to a stirred
solution of Scho¨llkopf’s bislactim ether 10 (2.42 g, 13.14 mmol)
◦
in THF (60 mL) at -78 C and the mixture was stirred for 1 h.
Then, a 0.5 M solution of SnCl2 (2.96 g, 15.62 mmol) in THF
was added dropwise. The mixture was stirred for 1 h, and a
solution of aldehyde 11c (600 mg, 4.11 mmol) in THF (11 mL)
was added dropwise. The reaction mixture was gradually warmed
colorless oil; Rf = 0.50 (silica gel, EtOAc/hexanes 1:1); [a]23
D
-22.5 (c 1.0 in CH2Cl2); (Found: C, 47.15; H, 7.03; N, 6.58;
S, 7.71. Calc. for C16H28N2O8S: C, 47.05; H, 6.91; N, 6.86; S,
7.85%); nmax/cm-1 2952, 2873, 1697, 1382, 1245, 1180 and 995; dH
(300 MHz, CDCl3) 0.71 (3H, d, J = 6.7), 1.07 (3H, d, J = 6.7),
1.25 (3H, d, J = 5.0), 2.27 (1H, dsp, J = 6.7 and 3.5), 3.15 (3H, s),
3.56–3.78 (2H, m), 3.70 (3H, s), 3.76 (3H, s), 3.89 (1H, t, J = 3.5),
3.95–4.01 (1H, m), 4.33–4.43 (2H, m), 4.58 (1H, q, J = 5.0), 4.74
(1H, ddd, J = 14.6, 9.8 and 5.3); dC (75 MHz, CDCl3) 16.6 (CH3),
19.1 (CH3), 20.2 (CH3), 31.6 (CH), 37.4 (CH3), 52.6 (CH3), 52.7
(CH3), 56.3 (CH), 61.3 (CH), 67.6 (CH), 68.5 (CH2), 68.9 (CH),
78.1 (CH), 99.0 (CH), 161.1 (C), 164.0 (C). FABMS (thioglycerol)
m/z 409 (MH+, 100%). HRMS 409.1652. C16H29N2O8S requires
409.1645.
◦
to 0 C for 4 h and quenched with aqueous saturated NaHCO3
solution. The solids were removed by filtration and the filtrate
was concentrated in vacuo. The resulting material was diluted
with water and extracted with ether. The combined organic layers
were dried (Na2SO4) and evaporated, and the residue was purified
by flash chromatography (silica gel, EtOAc/hexanes 1:1) to yield
adduct 12c (70 mg, 5%) and adduct 13c (1.12 g, 83%).
Compounds 12c and 13c were also prepared by hydrogenation
of 12b and 13b respectively: A solution of adduct 12b or 13b
(1 equiv) in MeOH (15 mL/mmol) was added to a mixture of
HCO2NH4 (2.4 equiv) and 10% Pd/C (75% w/w). The mixture
was heated to 70 ◦C in a sealed flask for 1.5 h. The solids
were removed by filtration through a short pad of Celite and
the filtrate was concentrated in vacuo, and the residue was
purified by flash chromatography (silica gel, EtOAc/hexanes 2:3)
to give the corresponding diols. Hydrogenation of compound 12b
(314 mg, 0.75 mmol) gave 210 mg of 12c (85%). Hydrogenation of
compound 13b (210 mg, 0.5 mmol) gave 146 mg of 13c (89%).
(3S,6R,1¢R,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1,3-dihydro-
xy]-3,6-dihydro-6-isopropyl-2,5-dimethoxypyrazine (12c): color-
Mesylation of diol 13c. A solution of diol 13c (100 mg,
0.30 mmol), Et3N (0.083 mL, 0.60 mmol) and DMAP (6 mg,
0.05 mmol) in CH2Cl2 (5 mL) at 0 ◦C was treated with MsCl
(0.025 mL, 0.33 mmol) and the mixture was stirred for 12 h at
rt. The solvent was evaporated and the residue was purified by
flash chromatography (silica gel, MeOH/CH2Cl2 1:19) to give
monomesylate 13d (79 mg, 65%) along with dimesylated derivative
(33 mg, 23%).
(3S,6R,1¢S,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1-hydroxy-3-
methanesulfonyloxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxy-
pyrazine 13d: colorless oil; Rf = 0.25 (silica gel, MeOH/CH2Cl2
1:19); [a]25D -18.3 (c 1.0 in CH2Cl2); (Found: C, 47.01; H, 6.99; N,
less oil; Rf = 0.35 (silica gel, EtOAc/hexanes 1:1); [a]22 -4.1
D
(c 1.0 in CH2Cl2); (Found: C, 54.28; H, 8.06; N, 8.52. Calc. for
C15H26N2O6: C, 54.53; H, 7.93; N, 8.48%); n max/cm-1 3429, 2951,
1749, 1239 and 1206; dH (300 MHz, CD3OD) 0.69 (3H, d, J =
2316 | Org. Biomol. Chem., 2009, 7, 2310–2321
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The Royal Society of Chemistry 2009
©

6.68; S, 7.91. Calc. for C16H28N2O8S: C, 47.05; H, 6.91; N, 6.86; S,
7.85%); n max/cm-1 2946, 2872, 1696, 1349, 1237, 1174, 1134, 1112,
1052, 1002; dH (300 MHz, CDCl3) 0.74 (3 H, d, J = 6.8), 1.03 (3 H,
d, J = 6.8), 1.33 (3 H, d, J = 5.0), 2.11 (1 H, d, J = 10.6), 2.23 (1 H,
dsp, J = 6.8 and 3.8), 3.08 (3 H, s), 3.64 (1 H, dd, J = 11.1 and
9.9), 3.73 (3 H, s), 3.74 (3 H, s), 3.93–3.99 (1 H, m), 4.01 (1 H, t,
J = 3.8), 4.19 (1 H, ddd, J = 10.3, 8.1 and 2.1), 4.26 (1 H, dd, J =
3.6 and 2.2), 4.40 (1 H, dd, J = 11.1 and 5.5), 4.64 (1 H, td, J = 9.5
and 5.5), 4.73 (1 H, q, J = 5.0); dC (75 MHz, CDCl3) 17.0 (CH3),
19.0 (CH3), 20.4 (CH3), 32.3 (CH), 38.3 (CH3), 52.7 (CH3), 52.8
(CH3), 55.2 (CH), 61.3 (CH), 68.3 (CH2), 72.7 (CH), 73.4 (CH),
75.6 (CH), 98.8 (CH), 161.6 (C), 167.0 (C). FABMS (thioglycerol)
m/z 409 (MH+, 100%). HRMS 409.1645. C16H29N2O8S requires
409.1645.
(MH+, 16%), 242 (100). HRMS 499.2094. C23H35N2O8S requires
499.2114.
Methyl 3-benzyloxy-4,6-ethylidenedioxy-2,5-dideoxy-2,5-imino-
D-gulonate (17). A solution of compound 16 (265 mg, 0.53 mmol)
in MeOH (13 mL) and 0.25 M HCl (4.25 mL, 1.06 mmol) was
stirred at rt for 9 h. Then, the solution was diluted with water
(10 mL) and concentrated to one-third its initial volume. The
aqueous solution was made basic (pH ~ 10) by the addition of
NaHCO3 followed by concentrated ammonia. The aqueous layer
was extracted with CH2Cl2 (7 ¥ 12 mL) and the combined organic
layers were dried (Na2SO4) and evaporated. The crude was purified
by flash chromatography (silica gel, EtOAc) to give gulonate 17
(134 mg, 82%) as a colorless oil; Rf = 0.35 (silica gel, EtOAc);
[a]19 +22.6 (c 0.8 in CH2Cl2); (Found: C, 62.71; H, 6.75; N,
D
(3S,6R,1¢S,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1,3-dime-
thanesulfonyloxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxypy-
razine: white solid; m.p. 129–130 ◦C; Rf = 0.45 (silica gel,
4.60. Calc. for C16H21NO5: C, 62.53; H, 6.89; N, 4.56%); nmax/cm-1
2910, 1739 and 1109; dH (500 MHz, CDCl3) 1.25 (3H, d, J =
5.0, CHCH3), 2.60 (1H, brs, NH), 3.11 (1H, m, 5-H), 3.78 (3H, s,
OCH3), 3.89 (1H, d, J = 2.1, 2-H), 3.98 (1H, dd, J = 12.5 and
2.4, 6-H), 4.04 (1H, d, J = 2.1, 3-H), 4.08 (1H, d, J = 2.1, 4-
H), 4.18 (1H, d, J = 12.5, 6¢-H), 4.59 (1H, AB system, J = 11.9,
CH2Ph), 4.64 (1H, q, J = 5.0, CH3CH), 4.68 (1H, AB system, J =
11.9, CH2Ph), 7.28–7.38 (5H, m, Ph); dC (75 MHz, CDCl3) 21.0
(CH3CH), 52.4 (OCH3), 55.4 (C-5), 65.5 (C-6), 66.7 (C-2), 71.7
(CH2Ph), 79.4 (C-4), 87.9 (C-3), 97.6 (CHCH3), 127.7 (CH), 127.8
MeOH/CH2Cl2 1:19); [a]25 +8.5 (c 0.5 in CH2Cl2); nmax/cm-1
D
2960, 1705, 1676, 1336, 1248, 1168, 1135, 1060, 1010; dH
(300 MHz, CDCl3) 0.68 (3 H, d, J = 6.8), 1.06 (3 H, d, J =
6.9), 1.35 (3 H, d, J = 5.0), 2.33 (1 H, dsp, J = 6.9 and 3.3), 2.99
(3 H, s), 3.15 (3 H, s), 3.75 (6 H, s), 3.77 (1 H, dd, J = 11.4 and 9.0),
3.99 (1 H, t, J = 3.6), 4.33 (1 H, dd, J = 8.5 and 6.1), 4.44–4.50
(1 H, m), 4.55 (1 H, dd, J = 11.4 and 5.1), 4.80 (1 H, q, J = 5.0),
4.87 (1 H, td, J = 8.8 and 5.1), 5.08 (1 H, dd, J = 6.1 and 3.0); dC
(75 MHz, CDCl3) 16.4 (CH3), 19.1 (CH3), 20.4 (CH3), 31.4 (CH),
38.4 (CH3), 38.8 (CH3), 52.7 (CH3), 52.9 (CH3), 55.3 (CH), 60.7
(CH), 67.8 (CH2), 71.3 (CH), 75.7 (CH), 80.7 (CH), 98.8 (CH),
159.8 (C), 165.4 (C). FABMS (thioglycerol) m/z 487 (MH+, 49%),
391 (100%). HRMS 487.1418. C17H31N2O10S2 requires 487.1420.
=
(CH), 128.4 (CH), 137.4 (C), 172.0 (C O). FABMS (thioglycerol)
m/z 308 (MH+, 77%), 154 (100). HRMS 308.1500. C16H22NO5
requires 308.1498.
(3S,6R,1¢S,2¢S,3¢R)-3-[2,4-Ethylidenedioxybutyl-1-hydroxy-3-
p-toluenesulfonyloxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxy-
pyrazine (18). A solution of diol 13c (750 mg, 2.27 mmol), Ag2O
(789 mg, 3.40 mmol), KI (75 mg, 0.45 mmol) and TsCl (477 mg,
2.50 mmol) in toluene (30 mL) was stirred for 11 h at rt. The
reaction mixture was filtrated through a short pad of Celite, the
filtrate was concentrated in vacuo and the residue was purified
by flash chromatography (silica gel, EtOAc/hexanes 1:4) to give
tosylate 18 (1.0 g, 91%) as a white solid; Rf = 0.50 (silica gel,
EtOAc/hexanes 3:7); m.p. 48–50 ◦C; [a]27D +3.4 (c 1.0 in MeOH);
(Found: C, 54.83; H, 6.47; N, 5.65; S, 6.90. Calc. for C22H32N2O8S:
C, 54.53; H, 6.66; N, 5.78; S, 6.62%); nmax/cm-1 3553, 2945, 1698,
1365, 1238, 1176; dH (300 MHz, CDCl3) 0.72 (3H, d, J = 6.9),
1.04 (3H, d, J = 6.9), 1.30 (3H, d, J = 5.0), 2.23 (1H, dsp, J = 6.9
and 3.6), 2.30 (1H, d, J = 8.9), 2.45 (3H, s), 3.56 (1H, dd, J = 11.1
and 9.7), 3.69 (3H, s), 3.73 (3H, s), 3.94–4.00 (2H, m), 4.05–4.10
(2H, m), 4.13 (1H, dd, J = 11.0 and 5.2), 4.19 (1H, dd, J = 3.6
and 2.7), 4.65–4.73 (1H, m), 4.70 (1H, q, J = 5.0), 7.34 (2H, d,
J = 8.2), 7.82 (2H, d, J = 8.2); dC (75 MHz, CDCl3) 16.9 (CH3),
19.0 (CH3), 20.4 (CH3), 21.7 (CH3), 32.0 (CH), 52.5 (CH3), 52.6
(CH3), 55.4 (CH), 61.1 (CH), 67.6 (CH2), 72.4 (CH), 72.8 (CH),
76.6 (CH), 98.7 (CH), 128.1 (CH), 129.8 (CH), 133.3 (C), 145.2
(C), 161.7 (C), 166.1 (C); FABMS (thioglycerol) m/z 485 (MH+,
100). HRMS 485.1976. C22H33N2O8S requires 485.1958.
(3S,6R,1¢R,2¢S,3¢R)-3-[1-Benzyloxy-2,4-ethylidenedioxybutyl-
3-methanesulfonyloxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxy-
pyrazine (16). A solution of mesylate 12d (340 mg, 0.83 mmol)
in THF (2 mL) was added to a stirred suspension of NaH (60%
dispersion in mineral oil, 40 mg, 1.0 mmol) in THF (10 mL) at
0 ◦C. After 1 h, NBu4I (107 mg, 0.30 mmol) and BnBr (0.12 mL,
1.0 mmol) were added, and the resulting solution was stirred
at rt for 3 h. The reaction mixture was cooled to 0 ◦C and
quenched by the addition of CH3OH (2.5 mL). The solvents were
removed in vacuo and the resulting material was diluted with
water and extracted with CH2Cl2. The combined organic layers
were dried (Na2SO4) and evaporated and the residue was purified
by flash chromatography (silica gel, EtOAc/hexanes 1:3) to give
compound 16 (291 mg, 70%) as a colorless oil; Rf = 0.40 (silica
gel, EtOAc/hexanes 1:2); [a]22 +13.7 (c 1.0 in CH2Cl2); (Found:
D
C, 55.48; H, 6.69; N, 5.73; S, 6.52. Calc. for C23H34N2O8S: C, 55.41;
H, 6.87; N, 5.62; S, 6.43%); nmax/cm-1 1691, 1357, 1237, 1176 and
1098; dH (300 MHz, CDCl3) 0.69 (3H, d, J = 6.8), 1.08 (3H, d, J =
6.8), 1.31 (3H, d, J = 5.0), 2.35 (1H, dsp, J = 6.8 and 3.2), 2.89
(3H, s), 3.59 (1H, t, J = 10.5), 3.71 (3H, s), 3.72 (3H, s), 3.85–3.96
(3H, m), 4.41 (1H, dd, J = 10.8 and 5.4), 4.55 (1H, dd, J = 5.7
and 3.6), 4.64 (1H, q, J = 5.0), 4.66 (1H, AB system, J = 11.0),
4.73 (1H, AB system, J = 11.0), 4.95 (1H, ddd, J = 14.8, 9.6 and
5.4), 7.26–7.42 (5H, m); dC (75 MHz, CDCl3) 16.4 (CH3), 19.2
(CH3), 20.3 (CH3), 30.9 (CH), 38.3 (CH3), 52.6 (CH3), 52.7 (CH3),
55.9 (CH), 60.4 (CH), 68.3 (CH2), 69.2 (CH), 72.8 (CH2), 77.4
(CH), 77.5 (CH), 99.4 (CH), 127.7 (CH), 128.1 (CH), 128.3 (CH),
137.9 (C), 161.9 (C), 165.0 (C). FABMS (thioglycerol) m/z 499
(3S,6R,1¢R,2¢S,3¢R)-3-[1-Benzyloxy-2,4-ethylidenedioxybutyl-
3-p-toluenesulfonyloxy]-3,6-dihydro-6-isopropyl-2,5-dimethoxy-
pyrazine (19). A solution of tosylate 18 (927 mg, 1.90 mmol) in
THF (10 mL) was added to a stirred suspension of NaH (60%
dispersion in mineral oil, 93 mg, 2.3 mmol) in THF (28 mL)
at 0 ◦C. After 1 h, NBu4I (249 mg, 0.67 mmol) and BnBr
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Org. Biomol. Chem., 2009, 7, 2310–2321 | 2317
©

(0.27 mL, 2.3 mmol) were added, and the resulting solution
was stirred at rt for 3 h. The reaction mixture was cooled to
0
solvents were removed in vacuo and the resulting material was
diluted with water and extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4) and evaporated and the residue
was purified by flash chromatography (silica gel, EtOAc/hexanes
vacuo and the residue was diluted with water and extracted with
EtOAc. The combined organic layers were dried (Na2SO4) and
evaporated, and the crude was purified by flash chromatography
(silica gel, MeOH/CH2Cl2 1:20), to give pyrrolidine 21 (123 mg,
90%) as a colorless oil; Rf = 0.30 (silica gel, MeOH/CH2Cl2 1:20),
◦C and quenched by the addition of MeOH (6 mL). The
[a]22 +35.1 (c 0.8 in CH2Cl2); (Found: C, 64.39; H, 7.57; N, 5.11.
D
Calc. for C15H21NO4: C, 64.50; H, 7.58; N, 5.01%); nmax/cm-1 3277,
2990, 2862 and 1069; dH (500 MHz, CDCl3) 1.32 (3H, d, J = 5.0,
CHCH3), 2.71 (1H, brs, NH), 3.11 (1H, brs, 2-H), 3.35–3.37 (1H,
m, 5-H), 3.73 (1H, d, J = 2.7, 4-H), 3.74–3.80 (2H, m, 6-H and
6¢-H), 4.00 (1H, dd, J = 12.5 and 2.5, 1-H), 4.15 (1H, d, J =
12.5, 1¢-H), 4.17 (1H, d, J = 2.7, 3-H), 4.57 (1H, AB system, J =
11.8, CH2Ph), 4.61 (1H, AB system, J = 11.8, CH2Ph), 4.69 (1H,
q, J = 5.0, CH3CH), 7.28–7.37 (5H, m); dC (75 MHz, CDCl3)
21.0 (CH3CH), 55.1 (C-2), 63.3 (C-6), 66.4 (C-1), 66.9 (C-5),
72.0 (CH2Ph), 80.1 (C-3), 86.8 (C-4), 97.9 (CHCH3), 127.6 (CH),
127.8 (CH), 128.5 (CH), 137.8 (C). FABMS (thioglycerol) m/z
280 (MH+, 88%), 154 (78), 147 (89), 136 (100). HRMS 280.1546.
C15H22NO4 requires 280.1549.
1:9) to give compound 19 (1.0 g, 91%) as a white solid; Rf =
◦
0.35 (EtOAc/hexanes 1:9); m.p. 79–81 C; [a]27 +32.7 (c 1.0 in
D
CH2Cl2); (Found: C, 60.79; H, 6.69; N, 4.95; S, 5.53. Calc. for
C29H38N2O8S: C, 60.61; H, 6.66; N, 4.87; S, 5.58%); nmax/cm-1
1694, 1361, 1191, 1176, 1071; dH (300 MHz, CDCl3) 0.66 (3H, d,
J = 6.8), 1.04 (3H, d, J = 6.8), 1.31 (3H, d, J = 5.0), 2.26 (1H, dsp,
J = 6.8 and 3.3), 2.39 (3H, s), 3.55 (1H, dd, J = 11.3 and 8.9), 3.62
(3H, s), 3.71 (3H, s), 3.85 (1H, t, J = 3.3), 4.03–4.12 (3H, m), 4.31
(1H, dd, J = 3.9 and 1.5), 4.36 (1H, d, J = 11.0), 4.63 (1H, d, J =
11.0), 4.71 (1H, q, J = 5.0), 4.77–4.84 (1H, m), 7.17 (2H, d, J =
8.3), 7.21–7.33 (5H, m), 7.65 (2H, d, J = 8.3); dC (75 MHz, CDCl3)
16.4 (CH3), 19.1 (CH3), 20.5 (CH3), 21.6 (CH3), 31.1 (CH), 52.2
(CH3), 52.4 (CH3), 55.6 (CH), 60.3 (CH), 67.4 (CH2), 73.0 (CH),
73.2 (CH2), 76.1 (CH), 80.6 (CH), 98.4 (CH), 127.4 (CH), 127.7
(CH), 128.1 (CH), 128.1 (CH), 129.6 (CH), 134.0 (C), 138.1 (C),
144.7 (C), 161.7 (C), 164.3 (C); FABMS (thioglycerol) m/z 575
(MH+, 100). HRMS 575.2429. C29H39N2O8S requires 575.2427.
4-Benzyloxy-1,3-ethylidenedioxy-2,5-dideoxy-2,5-imino-D-gala-
ctitol (22). LiEt3BH (1 M in THF, 1.20 mL, 1.20 mmol)
was dropwise added to a solution of galactonate 20 (123 mg,
0.40 mmol) in THF (6 mL) at 0 ◦C and the mixture was stirred at
this temperature for 1 h. The reaction mixture was quenched by
the addition of aqueous saturated NH4Cl solution, the solvents
were removed in vacuo and the residue was diluted with water
and extracted with EtOAc. The combined organic layers were
dried (Na2SO4) and evaporated, and the crude was purified by
flash chromatography (silica gel, MeOH/CH2Cl2 1:20), to give
pyrrolidine 22 (99 mg, 89%) as a colorless oil; Rf = 0.25 (silica gel,
Methyl 3-benzyloxy-4,6-ethylidenedioxy-2,5-dideoxy-2,5-imino-
D-galactonate (20). A solution of compound 19 (941 mg,
1.64 mmol) in MeOH (50 mL) and 0.25 M HCl (13 mL, 3.2 mmol)
was stirred at rt for 9 h. Then, the solution was diluted with
water (50 mL) and concentrated to one-third its initial volume.
The aqueous solution was made basic (pH ~ 10) by the addition
of NaHCO3 followed by concentrated ammonia. The aqueous
layer was extracted with CH2Cl2 (7 ¥ 12 mL) and the combined
organic layers were dried (Na2SO4) and evaporated. The residue
was dissolved in DMSO (19 mL), Et3N (0.45 mL, 3.2 mmol)
was added and the mixture was heated to 70 ◦C for 1.5 h. The
reaction mixture was cooled to rt, diluted with brine and extracted
with EtOAc. The combined organic layers were dried (Na2SO4)
and evaporated. The crude was purified by reversed-phase flash
chromatography (RP-18, MeOH/H2O 1:1) to give galactonate 20
(302 mg, 60%) as a colorless oil; Rf = 0.15 (silica gel, AcOEt);
MeOH/CH2Cl2 1:20), [a]27 -66.7 (c 1.0 in CH2Cl2); (Found: C,
D
64.44; H, 7.62; N, 5.10. Calc. for C15H21NO4: C, 64.50; H, 7.58; N,
5.01%); nmax/cm-1 2879, 1408, 1155, 1080; dH (300 MHz, CDCl3)
1.38 (3H, d, J = 5.0), 2.75 (1H, brs), 2.83 (2H, brs), 3.35–3.48 (1H,
m), 3.70 (1H, dd, J = 11.6 and 4.0), 3.92 (1H, dd, J = 11.7 and
2.4), 3.98 (1H, dd, J = 12.3 and 2.3), 4.05–4.25 (3H, m), 4.49 (1H,
AB system, J = 11.7), 4.70 (1H, AB system, J = 11.7), 4.73 (1H,
q, J = 5.0), 7.27–7.36 (5H, m); dC (75 MHz, CDCl3) 21.1 (CH3),
53.3 (CH), 60.7 (CH), 60.8 (CH2), 66.5 (CH2), 72.5 (CH2), 74.3
(CH), 82.1 (CH), 97.8 (CH), 127.6 (CH), 127.9 (CH), 128.5 (CH),
137.8 (C); FABMS (thioglycerol) m/z 280 (MH+, 100). HRMS
280.1553. C15H22NO4 requires 280.1549.
[a]25 +10.3 (c 1.0 in CH2Cl2); (Found: C, 62.35; H, 6.94; N, 4.57.
D
Calc. for C16H21NO5: C, 62.53; H, 6.89; N, 4.56%); nmax/cm-1 1737,
1206, 1102, 955; dH (300 MHz, CDCl3) 1.40 (3H, d, J = 5.1), 2.68
(1H, brs), 3.81 (3H, s), 3.98 (1H, dd, J = 12.4 and 2.5), 4.00 (1H,
d, J = 9.0), 4.05 (1H, dd, J = 3.8 and 2.1), 4.12 (1H, dd, J = 12.4
and 0.8), 4.23 (1H, dd, J = 9.0 and 3.8), 4.65 (1H, AB system,
J = 12.6), 4.71 (1H, AB system, J = 12.6 4.69), (1H, q, J = 5.1),
7.29–7.36 (5H, m); dC (75 MHz, CDCl3) 21.1 (CH3), 52.1 (CH3),
53.9 (CH), 61.7 (CH), 65.8 (CH2), 72.5 (CH2), 74.8 (CH), 82.0
(CH), 97.8 (CH), 127.5 (CH), 127.7 (CH), 128.3 (CH), 137.8 (C),
171.1 (C); FABMS (thioglycerol) m/z 308 (MH+, 100). HRMS
308.1487. C16H22NO5 requires 308.1498.
Targeted pyrrolidine derivatives
2,5-Dideoxy-2,5-imino-D-glucitol (DGDP, 3). A solution of
pyrrolidine 21 (86 mg, 0.31 mmol) in THF (5 mL) and 0.25 M
HCl (3 mL, 0.75 mmol) was stirred with 10% Pd/C (18 mg) under
H2 (1 atm) for 12 h at rt. The catalyst was removed by filtration
through a short pad of Celite and the filtrate was concentrated
in vacuo. The residue was dissolved in HCl 1 M (3 mL) and the
◦
mixture was heated to 100 C for 1 h. The reaction mixture was
concentrated in vacuo and the residue was diluted with 1% aqueous
NH3 solution and was evaporated again. The residue was purified
by ion-exchange chromatography (Dowex 50W-X8, H+ form,
elutingwith2%aqueous NH3 solution)followedbyreversed-phase
flash chromatography (RP-18, using H2O as eluent) to give DGDP
(48 mg, 96%) as a white solid; m.p. 136–138 ◦C (from H2O), (lit.,10d
m.p. 138–140 ◦C); Rf = 0.20 (silica gel, BuOH/AcOH/H2O
4-Benzyloxy-1,3-ethylidenedioxy-2,5-dideoxy-2,5-imino-D-glu-
citol (21). LiEt3BH (1 M in THF, 1.5 mL, 1.5 mmol) was
dropwise added to a solution of gulonate 17 (150 mg, 0.49 mmol) in
THF (9 mL) at 0 ◦C and the mixture was stirred at this temperature
for 1 h. The reaction mixture was quenched by the addition of
aqueous saturated NH4Cl solution, the solvents were removed in
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©

◦
12:3:5), [a]22 +24.2 (c 0.7 in H2O), (lit.,10d [a]D +25.1 (c 1.5 in
mixture was heated to 100 C for 1 h. The reaction mixture was
D
H2O)); (Found: C, 44.34; H, 8.12; N, 8.43. Calc. for C6H13NO4: C,
44.16; H, 8.03; N, 8.58%); nmax/cm-1 3274, 3272, 3198, 2905, 1318
and 1033; dH (300 MHz, D2O) 3.14 (1H, app q, J = 5.3), 3.44
(1H, app q, J = 6.0), 3.69–3.91 (4H, m), 3.93 (1H, dd, J = 5.0
and 2.8), 4.17 (1H, dd, J = 5.0 and 2.8); dC (75 MHz, D2O) 62.8
(CH2), 64.1 (CH), 64.9 (CH2), 68.1 (CH), 80.1 (CH), 81.8 (CH).
FABMS (thioglycerol) m/z 164 (MH+, 100%). HRMS 164.0920.
C6H14NO4 requires 164.0923.
concentrated in vacuo and the residue was diluted with 1% aqueous
NH3 solution and was evaporated again. The residue was purified
by ion-exchange chromatography (Dowex 50W–X8, H+ form,
eluting with 2% aqueous NH3 solution) followed by reversed-
phase flash chromatography (RP-18, using H2O as eluent) to give
imino acid 6 (76 mg, 87%) as a white solid; Rf = 0.10 (silica
◦
gel, BuOH/AcOH/H2O 12:3:5); m.p. 228 C (decomp.); [a]26
D
+47.1 (c 0.5 in H2O); (Found: C, 40.72; H, 6.37; N, 7.87. Calc.
for C6H11NO5: C, 40.68; H, 6.26; N, 7.91%); nmax/cm-1 3196, 3113,
1624, 1559, 1132, 1019; dH (500 MHz, D2O) 3.82–3.90 (1H, m),
3.92–3.97 (2H, m), 4.15 (1H, d, J = 5.3), 4.46–4.56 (2H, m); dC
(125 MHz, D2O) 57.4 (CH2), 60.8 (CH), 62.7 (CH), 70.1 (CH),
70.6 (CH), 170.2 (C); FABMS (thioglycerol) m/z 178 (MH+, 100).
HRMS 178.0719. C6H12NO5 requires 178.0715.
2,5-Dideoxy-2,5-iminogalactitol (DGADP, 4). A solution of
pyrrolidine 22 (45 mg, 0.16 mmol) in THF (2.5 mL) and 0.25 M
HCl (1.6 mL, 0.4 mmol) was stirred with 10% Pd/C (9 mg) under
H2 (1 atm) for 12 h at rt. The catalyst was removed by filtration
through a short pad of Celite and the filtrate was concentrated
in vacuo. The residue was dissolved in HCl 1 M (2 mL) and the
◦
mixture was heated to 100 C for 1 h. The reaction mixture was
concentrated in vacuo and the residue was diluted with 1% aqueous
NH3 solution and was evaporated again. The residue was purified
by ion-exchange chromatography (Dowex 50W-X8, H+ form,
eluting with 2% aqueous NH3 solution) followed by reversed-
phase flash chromatography (RP-18, using H2O as eluent) to give
DGADP (23 mg, 88%) as colorless oil; Rf = 0.25 (silica gel,
BuOH/AcOH/H2O 12:3:5); (Found: C, 44.22; H, 8.10; N, 8.62.
Calc. for C6H13NO4: C, 44.16; H, 8.03; N, 8.58%); nmax/cm-1 3303,
1668, 1190, 1126; dH (300 MHz, D2O) 3.28–3.46 (2H, m), 3.72
(2H, dd, J = 11.5 and 6.3), 3.83 (2H, dd, J = 11.5 and 5.4),
4.34 (2H, d, J = 5.7); dC (75 MHz, D2O) 60.2 (CH2), 63.6 (CH),
72.4 (CH); FABMS (thioglycerol) m/z 164 (MH+, 100). HRMS
164.0919. C6H14NO4 requires 164.0923.
Computational
Electronic structure calculations were performed using the Kohn–
Sham formulation of the density functional theory (DFT) with
the hybrid exchange functional of Becke35 and the Lee, Yang,
and Parr correlation functional36 (B3LYP) and the cc-pVDZ
basis set37 with a small-core relativistic pseudopotential for Sn38
(referred to as B3LYP/cc-pVDZ-PP level). All transition struc-
tures were obtained by unconstrained optimization and frequency
calculations have been performed to check the presence of a
single negative eigenvalue in their diagonalized force constant
matrices. The associated eigenvectors were inspected with the
aid of the visualization program GaussView 3.0 to confirm that
they correspond to the expected reaction coordinate. All the
intermediate complexes have positive defined Hessian matrices.
All the energies reported are free energies and thus contain zero-
point energy corrections (using frequencies scaled by 0.97)39 and
thermal and entropy effects at reaction temperature (195 or 273
K) and 1 atm pressure calculated at B3LYP/cc-pVDZ-PP level.
Finally, single point energy calculations considering solvent effects
were computed at B3LYP(SCRF)/cc-pVTZ-PP level for the gas-
phase stationary points using the self-consistent reaction field
method40 based on the polarizable continuum model of Tomasi’s
group41 with a permittivity of 7.52 for THF. All optimizations
and frequency calculations reported in this article were performed
using Gaussian03 program package.42 cc-pVDZ-PP and cc-pVTZ-
PP basis sets and ECP parameters for Sn were obtained from Basis
Set Exchange (BSE) software and the EMSL Basis Set Library
(https://bse.pnl.gov/bse/portal).43 NBO delocalization energies
were calculated using second-order perturbation theory with the
NBO 3.1 program44 as implemented in Gaussian03 program
package. See ESI for further details.
2,5-Dideoxy-2,5-imino-L-gulonic acid (5). A solution of gu-
lonate 17 (238 mg, 0.77 mmol) in THF (15 mL) and 0.25 M HCl
(15 mL, 3.75 mmol) was stirred with 10% Pd/C (24 mg) under
H2 (1 atm) for 12 h at rt. The catalyst was removed by filtration
through a short pad of Celite and the filtrate was concentrated
in vacuo. The residue was dissolved in HCl 1 M (2 mL) and the
◦
mixture was heated to 100 C for 1 h. The reaction mixture was
concentrated in vacuo and the residue was diluted with 1% aqueous
NH3 solution and was evaporated again. The residue was purified
by ion-exchange chromatography (Dowex 50W-X8, H+ form,
eluting with 4% aqueous NH3 solution) followed by reversed-
phase flash chromatography (RP-18, using H2O as eluent) to give
imino acid 5 (131 mg, 96%) as a white solid; Rf = 0.10 (silica gel,
◦
BuOH/AcOH/H2O 12:3:5); m.p. 216–217 C (decomp.), (lit.,10a
◦
m.p. 216 C (decomp)); [a]24 -13.5 (c 1.0 in H2O), (lit.,10a [a]20
D
D
EQ/S -14.3 (c 1.0 in H2O)); (Found: C, 40.49; H, 6.52; N, 7.86.
Calc. for C6H11NO5: C, 40.68; H, 6.26; N, 7.91%); nmax/cm-1 3443,
3183, 1631, 1564, 1347, 1058; dH (500 MHz, D2O + DCl) 3.96–4.06
(3 H, m), 4.32 (1 H, dd, J = 3.0 and 1.6), 4.37 (1 H, brs), 4.62 (1 H,
brs); dC (75 MHz, D2O + DCl) 58.1 (CH2), 64.9 (CH), 67.1 (CH),
75.1 (CH), 79.1 (CH), 170.5 (C); FABMS (thioglycerol) m/z 178
(MH+, 100%). HRMS 178.0710. C6H12NO5 requires 178.0715.
Acknowledgements
2,5-Dideoxy-2,5-imino-L-galactonic acid (6). A solution of
galactonate 20 (150 mg, 0.49 mmol) in THF (10 mL) and 0.25 M
HCl (10 mL, 2.50 mmol) was stirred with 10% Pd/C (15 mg) under
H2 (1 atm) for 12 h at rt. The catalyst was removed by filtration
through a short pad of Celite and the filtrate was concentrated
in vacuo. The residue was dissolved in HCl 1 M (2 mL) and the
We gratefully acknowledge the financial support of Ministerio
de Ciencia y Tecnolog´ıa (BQU2003–00692) and Xunta de Galicia
(PGIDIT05BTF10301PR). The authors are indebted to Centro de
Supercomputacio´n de Galicia (CESGA) for providing computer
facilities. O. B. thanks Xunta de Galicia for an “Isidro Parga
Pondal” position at Universidade da Corun˜a.
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 2310–2321 | 2319
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