Access to iminosugars by aldol additions of metalated bis-lactim ethers to L-erythrose derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00189-1

Aldol additions of metalated bis-lactim ethers derived from cyclo-[Gly-D-Val] 3A-E* to mismatched L-erythrose-derivatives 4a and 4b have been studied. Reactions of titanium(IV) and tin(II) azaenolates with the lactol derivative 4b allow direct and moderat

Full text of DOI:10.1016/S0957-4166(02)00189-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 795–799
Access to iminosugars by aldol additions of metalated bis-lactim
ethers to -erythrose derivatives
L
Mar´ıa Ruiz,* Vicente Ojea, Tania M. Ruanova and Jose´ M. Quintela
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, Universidade da Corun˜a, Campus da Zapateira, s/n, 15071 A
Corun˜a, Spain
Received 18 March 2002; accepted 19 April 2002
Abstract—Aldol additions of metalated bis-lactim ethers derived from cyclo-[Gly-D-Val] 3A–E* to mismatched L-erythrose-deriva-
tives 4a and 4b have been studied. Reactions of titanium(IV) and tin(II) azaenolates with the lactol derivative 4b allow direct and
moderate (syn,syn)- or highly (anti,anti )-selective access to polyhydroxy amino acids that have been efficiently transformed into
1-deoxy-D-gulonojirimycin or 1-deoxy-D-allonojirimycin. © 2002 Elsevier Science Ltd. All rights reserved.
Natural and synthetic alkaloid sugar mimics with a
nitrogen in the ring (iminosugars) have shown the
ability to inhibit important glycoconjugate processing
enzymes in a reversible and competitive manner.1 Gly-
cosidase inhibitors have received a great deal of atten-
tion because of their value in basic biochemical
research2 and their therapeutic potential in the treat-
ment of prominent diseases, such as viral infections,
cancer, diabetes and other metabolic disorders.3 As a
consequence, a variety of synthetic approaches have
been used to assemble this class of compounds ranging
from chemical to enzymatic methods, and employing a
wide range of starting materials from sugars to ben-
zene.1c Although, traditionally, iminosugars have been
synthesized through multistep transformations of read-
ily available carbohydrate precursors, recent interest
has increasingly focused on the synthesis of this class of
compounds from non-carbohydrate sources.4 Promi-
nent among these strategies are cycloaddition-based
routes,5a,b chemoenzymatic functionalization of carbo-
cyclic intermediates,5c,d aldolase-catalyzed condensation
reactions5e and stereoselective elongation of homochiral
short chain precursors exploiting different chemical
procedures.5f
piperidine derivatives 1 (see Scheme 1). Our strategy
relies on cyclization of the polyhydroxy amino acid
precursors 2 that can be direct and stereoselectively
prepared by aldol reactions between homochiral glycine
equivalents and readily accessible enantiopure hydroxy-
aldehydes.6 Based on this methodology, we have previ-
ously succeeded in the synthesis of 1-deoxy-
talonojirimycin and 1-deoxy- -galactonojirimycin, by
D-
D
using highly (syn,anti )-selective aldol additions of the
stannous azaenolate 3, derived from a Scho¨llkopf’s
bis-lactim ether, to matched 1,3-dioxolane-4-carbox-
aldehyde derivatives 4.7
In addition, the reactions of metalated bis-lactim ethers
with mismatched cyclohexylidene glyceraldehyde8 and
an a,b-syn-dihydroxy aldehyde,9 have been studied by
Scho¨llkopf and Kobayashi, respectively. Although the
stereochemical outcome of these additions was
markedly dependent on the metal counterpart, using
titanium(IV) or tin(II) and zinc(II) salts, the reactions
3
M
N
reductive
amination
aldol
addition
EtO
O
OEt
OR
HO
HO
H
N
HO2C
HO
Recent efforts in our laboratory directed toward the
synthesis of bioactive amino polyols led to the develop-
ment of a convergent route to the polyhydroxylated
N
NH2
OR
OH
HO
HO
OH
O
O
mismatched
pair?
4
1
2
Scheme 1. Amino acid based approach to piperidine alka-
loids.
* Corresponding author. Tel.: 34-981167000; fax: 34-981167065;
e-mail: ruizpr@udc.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00189-1

796
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 795–799
To evaluate the counterion dependence of the stereo-
chemical outcome, the lithium azaenolate 3A was
allowed to react, at −78°C in THF, with ZnCl2, SnCl2,
Ti(NEt2)3Cl, or MgBr2·OEt2, to produce the transmeta-
lated azaenolates 3B–E,8,9,16 prior to addition of the
aldehyde. Reaction of 4a with the zinc azaenolate 3B
resulted in a very low conversion to a mixture of
adducts 5a/6a/7a with almost the same ratio observed
for the lithium salt. Surprisingly, switching the metal to
Sn(II), Ti(IV) or Mg(II) did not change the stereochem-
ical course of the addition, and led to the
(trans,anti,anti )-adduct 5a as the major product with
only slightly higher selectivity.
proceeded under almost complete azaenolate control,
affording the (syn,syn)-adducts with excellent
diastereoselectivities. The high level of p-facial discrimi-
nation found in these processes prompted us to explore
the additions of metalated Scho¨llkopf’s bis-lactim
ethers to mismatched erythrose derivatives, that could
result in a stereocontrolled route to (syn,syn)-polyhy-
droxy amino acids, thus extending the applicability of
our iminosugar approach to the gulo series.10
We first examined the aldol additions of azaenolates
derived
dihydropyrazine11,12 to 4-O-benzyl-2,3-O-isopropyli-
dene-
-erythrose 4a13 (see Scheme 2). Addition of
from
(3R)-2,5-diethoxy-3-isopropyl-3,6-
L
Upon comparison with the results reported by
Kobayashi,9 it appears that the anti diastereofacial
preference of the 1,3-dioxolane-4-carboxaldehyde 4a is
reinforced by the cis-substituent,17 and the syn-selectiv-
ity characteristic for the additions of metalated bis-lac-
tims is overridden. In spite of such moderate substrate
control, the influence of the chiral azaenolate still deter-
mines the trans configuration in the two major bis-lac-
tim ethers 5a and 6a.
aldehyde 4a to 1 equiv. of azaenolates 3A–E at −78°C
in THF, afforded, after quenching and aqueous work-
up, mixtures of adducts 5a/6a/7a in good yields except
for the reaction of 3B (see Table 1). The reaction with
the lithium azaenolate 3A proceeded with very low
selectivity, giving rise to a 4.7:3.7:1.6 mixture of
adducts 5a/6a/7a.14 The configuration of the major
adduct, 5a, was determined as 3,6-trans–3,1%-anti–1%,2%-
anti, instead of the expected 3,6-trans–3,1%-syn–1%,2%-syn,
which was assigned to adduct 6a, the secondary one.15
Prompted by the unexpected change of stereochemical
control from azaenolate to aldehyde in the reactions of
3A–E with 4a, we decided to investigate the potential of
such mismatched situations for the selective construc-
tion of (anti,anti )-aminodiol fragments. For this pur-
OR
O
M
a,b
N
O
O
EtO
OEt
pose, 2,3-O-isopropylidene-L-erythrose 4b was sought
(14-88%)
N
N
as an appropriate precursor, as has been shown to react
with organometallic reagents in a highly stereoselective
fashion.18 Furthermore, reactions of organometallic
reagents with lactols are usually more selective than
reactions with the corresponding aldehydes.19 Based on
these precedents and aimed at the development of a
stereocontrolled approach to the b-galactosidase
3A-E*
4a,b
6
N
N
3
N
EtO
HO
OEt
OR
EtO
OEt
OR
EtO
HO
OEt
OR
N
N
1´
HO
inhibitor 1-deoxy-D
-allonojirimycin,20 the additions of
2´
metalated Scho¨llkopf’s bis-lactim ethers 3A–E* to the
lactol 4b were examined,21 the most salient results being
summarized in Table 2.
O
O
O
O
O
O
7a
7b
5a
5b
6a
6b
c
c
c
Scheme 2. Aldol additions of azaenolates 3A–E* to mis-
matched -erythrose derivatives 4a,b. Reagents and conditions:
L
Table 2. Selectivity and yields in the aldol additions of
metalated bis-lactims 3A–E* to mismatched lactol 4b
(a) THF, −78°C, 2 h for 4a; THF, −78–0°C, 12 h for 4b. (b)
NH4Cl or phosphate buffer. (c) H2, Pd/C, THF, rt, 6 h.
Legends. For compound 3: A, M=Li; B, M=ZnCl; C,
M=SnCl; D, M=MgBr; E, M=Ti(NEt2)3; E*, M=
Ti(OiPr)3. For compounds 5–7: a, R=Bn; b, R=H.
Case
Additive
Equiv.
Yield (%)a
5b/6b/7bb
A
B
C
C*
D
E
–
–
52
–
6.2:3.8:0.0
–:–:–
ZnCl2
SnCl2
SnCl2
MgBr2·OEt2
Ti(NEt2)3Cl
Ti(OiPr)3Cl
6.0
3.0
6.0
3.0
3.0
3.0
78
89
70
70
78
7.7:0.3:2.0
9.1:0.9:0.0
3.3:0.6:6.1
3.0:7.0:0.0
6.6:3.3:1.0
Table 1. Selectivity and yields in the aldol additions of
metalated bis-lactims 3A–E to mismatched aldehyde 4a
E*
Case
Additive
Equiv.
Yield (%)a
5a/6a/7ab
a Isolated yield of mixtures of diastereoisomers.
1
A
B
C
C*
D
E
–
–
60
14
65
65
60
60
4.7:3.7:1.6
4.6:2.8:2.5
5.7:3.8:0.5
6.5:3.1:0.3
6.4:2.2:1.4
6.4:2.7:0.9
b Ratios determined by H NMR analysis of the mixtures of adducts.
ZnCl2
SnCl2
SnCl2
MgBr2·OEt2
Ti(NEt2)3Cl
2.0
1.0
2.0
2.0
1.0
To this end, lactol 4b22 was slowly added to THF
solutions of 3 equiv. of the azaenolates 3A–E* at −78°C
and the reaction mixtures were gradually warmed to
0°C during 12 h. After quenching, aqueous work-up
and removal the excess of bis-lactim ether,23 mixtures of
diastereomeric adducts 5b/6b/7b (see Scheme 2) were
a Isolated yield of mixtures of diastereoisomers.
1
b Ratios determined by H NMR analysis of the mixtures of adducts.

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 795–799
797
isolated in good yields for all the cases except for the
reaction of 3B, that was not observed under such
conditions or with longer reaction times and higher
temperatures. The additions to the lactol 4b generally
proceeded with improved diastereoselectivity relative to
the same reactions with aldehyde 4a. In sharp contrast
to the results obtained with the aldehyde, the stereo-
chemical course of the additions to the lactol was found
to be markedly dependent on the nature of the metal
salt.15 In this way, the (trans,anti,anti )-adduct 5b was
predominantly obtained with either the lithium or the
tin azaenolates. As expected, Sn(II) azaenolate reacted
with higher diastereoselectivity and better yield than the
lithium azaenolate. Remarkably, on using an excess of
SnCl2, 5b was formed with a diastereomeric excess
higher than 80% and could be isolated with a yield of
81%.24 Surprisingly, the (cis,syn,anti )-adduct 7b was
predominantly obtained with the Mg(II) azaenolate,25
while tuning the ligand for the Ti(IV) azaenolate
enabled the modulation of the stereochemical course of
the addition. In this manner, the (trans,syn,syn)-adduct
6b was favored using Ti(NEt2)3Cl as additive, while the
(trans,anti,anti )-adduct 5b was mainly obtained with
Ti(OiPr)3Cl. It can be concluded that the diastereo-
facial preference of the lactol 4b overwhelms the stereo-
chemical bias imposed by the azaenolate in a higher
extension than previously observed for the related alde-
hyde 4a. Moderate reagent control was observed only
for the titanium azaenolate 3E in the reactions with the
lactol.
N
EtO2C
HO
H
HO
HO
H
EtO
OEt
N
c,d
N
a
b
5b
N
(98%)
(82%)
HO
(51%)
O
O
O
HO OH
O
1-deoxy-D-
allonojirimycin
O
8
9
N
EtO2C
HO
H
HO
HO
H
EtO
OEt
N
c,d
N
a
b
6b
N
(93%)
(89%)
HO
(75%)
O
O
O
HO OH
O
1-deoxy-D-
gulonojirimycin
O
10
11
N
EtO2C
HO
H
HO
HO
H
EtO
OEt
N
N
a
b
7b
N
(86%)
HO
(67%)
O
(ref. 7a)
O
O
HO OH
O
1-deoxy-L-
talonojirimycin
O
12
13
Scheme 3. Transformation of adducts 5–7b into iminosugars.
Reaction and conditions: (a) IBX, DMSO/THF (1:1), 8°C, 24
h. (b) 0.25 M HCl/EtOH (1:2), H2, Pd/C, rt, 3 h. (c) LiBEt3H,
THF, rt, 5 h. (d) Dowex-H+.
Conversion of adducts 5, 6 and 7 into 1-deoxy-
allonojirimycin,26 1-deoxy- -gulonojirimycin27 and 1-
deoxy- was straightforward,
-talonojirimycin28
involving chemoselective oxidation of the primary
hydroxyl group to enable reductive amination after
removal of the chiral auxiliary, as depicted in Scheme 3.
D-
D
tion and spectral data with those of its enantiomer,
which has been previously prepared as an intermediate
L
in the synthesis of 1-deoxy-D
-talonojirimycin.7a
In conclusion, aldol additions of metalated bis-lactim
ethers derived from cyclo-[Gly- -Val] to 2,3-O-iso-
propylidene- -erythrose allow a direct and highly
D
Debenzylation of adducts 5a, 6a, and 7a by catalytic
hydrogenation gave the corresponding diols 5b, 6b, and
7b in quantitative yields (see Scheme 1), which were
subsequently oxidized to the g-lactols 8, 10 and 12,
respectively, by using a slight modification of Corey’s
conditions.29 In this way, when a solution of com-
pounds 5b, 6b or 7b was treated with a solution of
o-iodoxybenzoic acid (IBX)30 a 62–68% conversion to
the desired lactols 8, 10 or 12 was achieved.31 Selective
hydrolysis of the bis-lactim ether in the presence of the
isopropylidene ketal and subsequent intramolecular
reductive amination were achieved in a one-pot proce-
dure. Stirring the lactols 8, 10 or 12 in a 1:2 mixture of
0.25 M HCl and EtOH under a hydrogen atmosphere
and palladium catalyst afforded the piperidine esters 9,
11 or 13 in good yields. Reduction of 9 or 11 with
LiBEt3H proceeded cleanly, as previously described for
other piperidine derivatives with acidic functions.7 Fil-
tering the crude reduction products through Dowex (H+
form) and subsequent purification by reverse-phase
flash chromatography (H2O, RP-18, 230–400 mesh)
L
(anti,anti )- or moderate (syn,syn)-selective access to
polyhydroxy amino acids that have been efficiently
transformed into 1-deoxy-
deoxy- -gulonojirimycin. Study of the corresponding
D-allonojirimycin and 1-
D
aldol additions to mismatched threose derivatives for
the synthesis of piperidine alkaloids in the ido and altro
series is currently under progress.
Acknowledgements
We gratefully acknowledge the Ministerio de Ciencia y
Tecnolog´ıa (BQU2000-0236), the Xunta de Galicia
(PGIDT00PXI10305PR) and the Universidade da
Corun˜a for financial support.
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a
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L
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isopropyl-3,6-dihydropyrazine can be synthesized12 or
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13. Aldehyde 4a was prepared from
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Lees, W. J.; Whitesides, G. M. Bioorg. Chem. 1992, 20,
173–179; (b) Liu, K. K.-C.; Kajimoto, T.; Chen, L.;
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L-rhamnose as previ-
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Anker, D. Tetrahedron 1995, 51, 1229–1244.
14. The ratios of diastereomers were determined by integra-
tion of the pairs of doublets corresponding to the isopro-
1
pyl groups in the H NMR spectra of the crude mixtures
29. Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36,
3485–3488.
of adducts.
15. The diastereomeric adducts 5/6/7 could be separated by
silica gel column chromatography and their relative
configurations were established following their conver-
30. IBX was prepared as described. See (a) Frigerio, M.;
Santagostino, M.; Sputore, S.; Palmisano, G. J. Org.
Chem. 1995, 60, 7272–7276. CAUTION: IBX has been

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 795–799
799
completely suppressed, the yield of the lactols could be
increased to 82–89% by resubjecting recovered starting
material to these oxidation conditions.
reported to detonate upon heavy impact and heating over
200°C: (b) Plumb, J. B.; Harper D. J. Chem. Eng. News
1990, July 16, 3; (c) Dess, B. D.; Martin, J. C. J. Am.
Chem. Soc. 1991, 113, 7277–7287.
32. Specific rotations and spectral data obtained for these
iminosugars were in accordance with the literature values.
31. As the overoxidation to the corresponding lactones was