A concise enantioselective synthesis of iminosugar derivatives

Article abstract of DOI:10.1039/b516352h

The concise de novo synthesis of amino- and iminosugar derivatives is presented; the four stereocenters of the iminosugar derivatives are created in two-steps with high chemoselectivity and excellent enantioselectivity. The Royal Society of Chemistry 2006

Full text of DOI:10.1039/b516352h

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A concise enantioselective synthesis of iminosugar derivatives{
Wei-Wei Liao, Ismail Ibrahem and Armando Co´rdova*
Received (in Cambridge, UK) 17th November 2005, Accepted 22nd December 2005
First published as an Advance Article on the web 10th January 2006
DOI: 10.1039/b516352h
manipulations. However, amino acid catalysis has not yet been
applied to the synthesis of iminosugars.
The concise de novo synthesis of amino- and iminosugar
derivatives is presented; the four stereocenters of the iminosugar
derivatives are created in two-steps with high chemoselectivity
and excellent enantioselectivity.
Triggered by the importance and pharmaceutical activity of
iminosugars, we became interested in finding a short enantioselec-
tive route for their preparation based on asymmetric catalysis.
Thus, we envisioned an expeditious amino- and iminosugar
synthesis based on one-pot tandem organocatalytic asymmetric
Mannich–Wittig-olefination reactions utilizing an a-oxyaldehyde
as the aldehyde component followed by diastereoselective
hydroxylation [eqn (1)].
Glycobiology is a rapidly growing research area uncovering
multiple biological processes wherein carbohydrates play a major
role. Moreover, this research area is also used in the finding of
selective carbohydrate based inhibitors with different therapeutic
areas.1 Among these, glycosidase inhibitors are the most
important,2 being extensively studied in the treatment of metabolic
disorders such as diabetes3 and Gaucher disease4 and as antiviral
or anticancer agents.5,6 An important type of glycosidase inhibitor
are sugar-like compounds with an easily protonated basic N-atom
replacing the ring oxygen atom of the carbohydrate (iminosugars).
There is a plethora of approaches to their synthesis and they
usually rely on monosaccharide transformations.2c,7 Moreover, the
development of efficient catalytic enantioselective methods for the
preparation of iminosugars constitutes an important active area of
research.8 However, existing catalytic enantioselective routes
usually require extensive protective group strategies and more
than six steps.
ð1Þ
Herein, we describe the short de novo synthesis of amino- and
iminosugar derivatives, where the newly formed stereocenters are
created in two-steps with high stereocontrol.
Organocatalysis is a rapidly growing research field in organic
synthesis.9 In this context, amino acid catalysis was recently added
to the synthetic repertoire of carbohydrate synthesis.10 For
example, organocatalysis has been employed to the de novo
synthesis of aldoses and ketoses.11 Organocatalysis has the
advantages of being highly selective and reducing synthetic
In initial experiments, we investigated the possibility of
developing a one-pot tandem organocatalytic Mannich–(Horner–
Wittig–Emmons) (HWE) reaction (Table 1). Thus, we reacted
a-benzyloxyacetaldehyde 1a (3 equiv.) with p-anisidine (1 equiv.) in
the presence of a catalytic amount of (S)-proline (30 mol%) in
DMF.12 After 48 h of stirring at room temperature, LiBr
(2.2 equiv.), the alkyl diethylphosphonoacetate (2.2 equiv.) and
DBU (2.2 equiv.) were added to the reaction mixture. The reaction
was quenched after 1.5 h and the desired orthogonally protected
vicinal amino alcohols 2a and 2b where isolated in 64 and 51%
yield, respectively, with 4:1 dr and 95% ee.
Table 1 One-pot asymmetric assembly of 2a and 2b
Encouraged by these results we investigated our tandem
catalytic asymmetric Mannich–HWE protocol for a set of different
aldehyde donors and acceptors (Table 2). In all cases tested, the
desired p-methoxyphenyl (PMP) protected vicinal amino alcohols
2a–2e were furnished with good to high dr [4:1–(>19):1 dr] and
high enantiomeric excesses (95–96% ee).
Entry
R
Product
Yield (%)a
Drb
Ee (%)c
1
2
a
Me
Et
2a
2b
64
51
4:1
4:1
95
95
The one-pot tandem organocatalytic asymmetric Mannich–
HWE reaction protocol is readily performed with other donor and
acceptor aldehydes than protected a-oxyaldehydes,13 which allows
for structural variation at the C-6 and C-4 positions of the
products 2. For example, the PMP protected chiral amine 2d was
assembled in an asymmetric manner in 88% yield with >19:1 dr
and 96% ee (Entry 4). We next assembled in an asymmetric
manner the desired galactolactam 4a with excellent stereocontrol
(Scheme 1). Thus, tandem catalytic asymmetric Mannich–HWE
Isolated yield of the pure products after silica-gel chromatography.
syn:anti ratio as determined by NMR analyses. Determined by
chiral-phase HPLC analyses, Bn = benzyl, PMP = p-methoxyphenyl.
b
c
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm
University, Sweden. E-mail: acordova1a@netscape.net;
acordova@organ.su.se; Fax: +46 8 15 49 08; Tel: +46 8 162479
{ Electronic supplementary information (ESI) available: Experimental
procedures. See DOI: 10.1039/b516352h
674 | Chem. Commun., 2006, 674–676
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Table 2 One-pot tandem catalytic Mannich–HWE reactions
Scheme 2 Reagents and conditions: [a] i. p-anisidine, (S)-proline, DMF,
rt, ii. (Ph)3PLCH2COOMe, DMF, rt, 56% for 2e; [b] AcOH, MeOH,
reflux, 82% for 5. [c] cat. OsO4, NMO, acetone–H2O 9:1, rt, 80% for 4b.
Entry
R
R1
Product Yield (%)a Drb
Ee (%)c
1
2
3
4
a
CH2OBn OBn 2a
64
45
51d
88
4:1
10:1
10:1
95
96
96
CO2Et
CO2Et
p-ClC6H4 Me
OBn 2c
OBn 2c
2d
.19:1 96
Isolated yield of the pure products after silica-gel chromatography.
syn:anti ratio as determined by NMR analyses. Determined by
Scheme 3 Reagents and conditions: [a] p-anisidine, (S)-proline, LiOEt,
(1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide, DMF, rt, 31%
for 6.
b
c
chiral-phase HPLC analyses, Bn = benzyl, PMP = p-methoxyphenyl.
Preformed imine was used as the acceptor.
d
The catalytic asymmetric Mannich reaction of 1a was also
linked with Wittig olefination to furnish protected vicinal amino
alcohol 2e with a 4:1 Z:E (2e: 92% ee; 2a: 95% ee) ratio (Scheme 2).
The subsequent ring-closure of 2e was followed by catalytic
diastereoselective dihydroxylation of lactam 5 to furnish the
desired gulolactam 4b as a single diastereomer with high
enantiomeric excess (92% ee).
Scheme 1 Reagents and conditions: [a] p-anisidine, (S)-proline, DBU,
LiCl, (EtO)2POCH2COOMe, DMF, rt, 64% for 2a; [b] cat. OsO4, NMO,
acetone–H2O 9:1, rt, 67% for 3a; [c] AcOH, MeOH, reflux, 74% for 4a.
Thus, iminosugar derivatives with a gulose configuration can
also be prepared in few chemical manipulations. Moreover, the
one-pot catalytic asymmetric Mannich–Wittig reaction can also be
applied to the synthesis of other excellent precursors of
iminosugars. For example, starting from aldehyde 1a chiral
protected aldehyde 6 was asymmetrically assembled exclusively
as the trans-isomer with 90% ee in one-pot (Scheme 3).
reaction with protected glycoaldehyde 1a gave 2a, which was
catalytically dihydroxylated14 to furnish galactonic acid 3a. The
subsequent ring-closure of 3a yielded the desired galactolactam 4a
with 95% ee (Scheme 1).
In addition, we also asymmetrically assembled other galactonic
acids than 3a. Thus, catalytic diastereoselective dihydroxylation of
the chiral vicinal amino alcohols 2 furnished the corresponding
orthogonally protected 5-deoxy-5-aminogalactonic acids 3a–3c in
good yield with good dr (6:1–8:1 dr) and high ees (95–96% ee)
(Table 3).
The PMP protective groups of galactolactams 7a and 7b were
readily removed with CAN (cerium ammonium nitrate) to yield
the corresponding galactolactams 8a and 8b, respectively
(Scheme 4).
Comparison of the known galactolactam 8a with the literature
established that the absolute and relative stereochemistry of the
iminosugar was that of (+)-D-galactolactam ([a]2D5 = +62.0 (c = 0.1,
CHCl3); literature [a]2D5 = +68.0 (c = 0.38, CHCl3)15). Thus,
starting the de novo synthesis with (S)-proline asymmetrically
assembles the corresponding D-iminosugars with excellent stereo-
selectivity. This is in accordance with established transition state
theory for proline-catalyzed Mannich reactions.12,13
The dihydroxylation of a,b-unsaturated ester 2d proceeded with
moderate diastereoselectivity. Thus, the size of the C-4 substituent
of the chiral amines 2 was important in the shielding of the Re-face
of the olefinic bond. The galactonic acids 3 are structurally varied
at the C-6, and C-4 positions, which makes them highly modular
chiral synthons and scaffolds for the synthesis of polyhydroxylated
compounds.
In summary, we have developed a short protocol for the de novo
synthesis of amino- and iminosugar derivatives. The new
stereocenters are set in two steps: a one-pot catalytic asymmetric
Mannich–HWE or Mannich–Wittig olefination reaction and a
Table 3 Catalytic conversion of chiral a,b-unsaturated esters 2 to
galactonic acids
Entry
R
R1
R2 Product Yield (%)a Drb Ee (%)c
1
2
3
4
a
CH2OBn OBn Me 3a
CH2OBn OBn Et 3b
CO2Et OBn Me 3c
p-ClC6H4 Me Me 3d
67
71
74
86
7:1 95
8:1 95
6:1 96
2:1 96
Isolated yield of the pure products after silica-gel chromatography.
syn:anti ratio as determined by NMR analyses. Determined by
chiral-phase HPLC analyses, Bn = benzyl, PMP = p-methoxyphenyl.
Scheme 4 Reagents and conditions: [a] BnBr, NaH, n-Bu4NI, THF, 0–
4 uC, 34% for 7a; [b] Ac2O, cat. DMAP, CH2Cl2, rt, 96% for 7b. [c] CAN,
CH3CN–H2O 9:1, 0 uC, 36% for 8a and 40% for 8b.
b
c
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subsequent catalytic diastereoselective dihydroxylation. For exam-
ple, orthogonally protected galactolactams were prepared with
high stereoselectivity. The short synthetic protocol allows for
structural variation at the C-4, and C-6 positions of the
iminosugar. Thus, both enantiomeric forms of several natural as
well as non-natural iminosugars can be prepared in few steps,
which reduces extensive protective group manipulations and the
generation of waste products. We are currently applying our
synthetic methodology in the asymmetric assembly of several novel
enzyme inhibitors as well as linking the one-pot tandem
asymmetric Mannich–Wittig reaction with other catalytic asym-
metric oxidations.
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Council, Carl-Trygger Foundation, Lars-Hierta Foundation and
Wenner-Gren Foundation for financial support.
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676 | Chem. Commun., 2006, 674–676
This journal is ß The Royal Society of Chemistry 2006