Stereodivergent syntheses at the glucose backbone

Article abstract of DOI:10.1039/b918893m

Both diastereomers of 2-C-branched carbohydrates with various functional groups are selectively available from the same malonate precursor in good yields in only a few steps. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b918893m

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Stereodivergent syntheses at the glucose backbone†
Jian Yin and Torsten Linker*
Received 10th September 2009, Accepted 18th September 2009
First published as an Advance Article on the web 5th October 2009
DOI: 10.1039/b918893m
Both diastereomers of 2-C-branched carbohydrates with
various functional groups are selectively available from the
same malonate precursor in good yields in only a few steps.
Carbohydrates play a decisive role in nature and are among the
cheapest precursors for ex-chiral pool syntheses.1 Additionally,
they find widespread applications as ligands for catalysts or as
chiral auxiliaries,2 with easily available D-glucose or D-galactose as
the most attractive starting materials. The reactions often proceed
with high stereoselectivities, however the absolute configurations
of the new stereogenic centres are predetermined by the carbohy-
drate backbone. For the synthesis of the corresponding epimers,
more expensive pseudo-enantiomeric D-arabinose or D-fucose
derivatives are required.3 On the other hand, Kunz et al. described
an interesting transformation of a D-galactose derivative, where
two epimeric dehydropiperidinones were selectively obtained by
simply changing the reaction sequence.4 Rarely, the selectivity
of reactions at the carbohydrate auxiliary was controlled by
alteration of the protecting groups or the solvents, however
considerably lower diastereomeric ratios resulted.5
Scheme 1 Methylation and subsequent decarboxylation of glucose
derivative 1.
saccharide 2 in 88% yield in analytically pure form (ESI†).
However, two epimeric methyl esters epi-3a were formed in a ratio
of 52:48 during the decarboxylation, which can be rationalized by
the drastic reaction conditions. Both isomers are easily separable
by column chromatography and show distinctive differences
in the NMR spectra. The configurations were unequivocally
assigned by the subsequent stereodivergent synthesis and by NOE
measurements (ESI†).
We have been interested in the synthesis of 2-C-branched
saccharides, which are easily available by radical addition of CH
acidic compounds to glycals in only one step, for many years.6 Mal-
onates react with especially high yields and stereoselectivities, and
the glucose derivative 1 allows various further transformations.7
Herein we describe the controlled substitution of each of the two
diastereotopic ester groups pro-S or pro-R (Fig. 1)8 by methyl, OH
or NH2 groups in only a few steps. Despite the predetermined con-
figuration of the glucose backbone, this stereodivergent synthesis9
proceeds with excellent selectivity and provides interesting
2-C-branched saccharides.
Obviously, milder conditions had to be applied for a stereoselec-
tive synthesis of 3a. Therefore, we investigated the deprotonation
of methyl ester 4, which is available from malonate 1 in 92%
yield in only one step,7a with various bases at low temperatures
and determined the diastereoselectivities of the alkylation with
iodomethane (Table 1).
Indeed, already the reaction with lithium diisopropylamide
(LDA) and subsequent methylation afforded the products
(7R)-3a and (7S)-3a in a ratio of 88:12 (entry 1). However, the
pure epimer (7R)-3a was isolated in only 30% yield, due to
the low conversion of 50%. We could improve the conversion
and yield by addition of hexamethylphosphorous triamide only
Table 1 Stereoselective synthesis of 2-C-branched carbohydrates (7R)-3
Fig. 1 Diastereotopic groups pro-S and pro-R in glucose derivative 1.
Initially, we investigated the direct alkylation of malonate 1
for the first time, to generate the new stereogenic centre after
subsequent decarboxylation (Scheme 1), which furnished high
yields at the carbohydrate backbone in our previous studies.7
Indeed, the deprotonation with sodium hydride and reaction with
iodomethane proceeded smoothly and afforded the 2-C-branched
Entry
Base
Ra
Conv. (%)b
7R:7Sb (7R)-3 (%)c
1
2
3
4
5
6
7
LDA
Me
Me
Me
Me
Me
OH
N3
50
60
90
95
>97
>97
>97
88:12
90:10
92:8
(7R)-3a (30)
(7R)-3a (42)
(7R)-3a (71)
(7R)-3a (79)
(7R)-3a (90)
(7R)-3b (82)
(7R)-3c (85)
LDA/HMPT
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
95:5
>97:3
>97:3
>97:3
Department of Chemistry, University of Potsdam, Karl-Liebknecht Str.
24-25, D-14476 Potsdam/Golm, Germany. E-mail: linker@uni-potsdam.de;
Fax: +49 331 9775056; Tel: +49 331 9775212
† Electronic supplementary information (ESI) available: Experimental
procedures and analytical data for all compounds. Determination of the
R or S configurations. See DOI: 10.1039/b918893m
a Electrophile: iodomethane, 2-sulfonyloxaziridine or trisyl azide.
b Determined by NMR spectra of the crude products. c Yield of analytically
pure product, isolated by column chromatography.
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slightly (HMPT) (entry 2). More efficient deprotonations were
realized with stronger hexamethyl-disilazides (HMDS) (entries
3–5), and already the lithium salt provided remarkably higher
conversions and stereoselectivies. Finally, the best conditions were
found with the potassium salt, since the NMR spectra indicated
full conversion and the highly selective formation of a sole epimer.
Thus, the 2-C-branched glucose derivative (7R)-3a was isolated in
90% yield in analytically pure form (entry 5, ESI†). To extend
the potential of our method, we investigated the assembly of
heteroatoms at the 7-position of the glucose backbone. Thus,
the Davis reagent10 afforded a-hydroxy ester (7R)-3b in 82% and
trisyl azide11 the azide (7R)-3c in 85% yield in only one step
(entries 6 and 7). Both reactions proceeded again with excellent
stereoselectivities, and the products were isolated in analytically
pure form.
Scheme
(7S)-3.
2
Stereoselective synthesis of 2-C-branched carbohydrates
All the main products (7R)-3 exhibit coincident coupling
constants of J2,7 = 1.8–2.1 Hz, although rotation around the
C2-C7 bond is not hindered. On the other hand, epimer (7S)-3a
less hindered convex side, but the fixation to the 1-position affords
now the 7S isomers exclusively.
shows remarkable differences in the 1H NMR spectrum with J2,7
=
In the last step of the stereodivergent synthesis, the lactone ring
had to be re-opened, which proceeds smoothly with scandium tri-
flate in methanol.7c Under such conditions, the methyl esters (7S)-
3 were isolated in good yields without epimerization (Scheme 2).
On the basis of NMR spectra, the products (7S)-3 and (7R)-3
are clearly distinguishable by characteristic coupling constants
and chemical shifts (ESI†). As additional structural proof, we
transferred the epimeric azides 3c into the known amines 8 by
Staudinger reduction (Scheme 3).14 Such amino acid derivatives 8
had to be synthesized by completely different reaction pathways,
previously.6c,15 Thus, we demonstrated not only a new concept
of stereodivergent syntheses at the glucose backbone from easily
available malonate 1, but also opened a convenient, stereoselective
and flexible access to C-glycosylated amino acids, which are of
current interest for organic chemists.6c,15,16
5.8 Hz and a shift of the methyl group by 0.3 ppm (ESI†). This
indicates consistent configurations of the new stereogenic centres
of all main products 3a–c. Finally, the R configuration of azide
3c was unequivocally determined by transformation into a known
amino acid (vide infra). The excellent stereoselectivities for all
reactions can be rationalized by ester enolate 5, which is fixed by
chelation to the 3-O-benzyl group (Fig. 2). Thus, electrophiles can
attack the bicycle only from the sterically less hindered convex
Re side. The chelation proceeds most efficiently with potassium
as counterion, explaining the best selectivities with KHMDS
(Table 1). This interpretation is in accordance with a recent study,
where the fixation of a potassium enolate to the 3-position and
not to the anomeric centre was discussed as well.12
Fig. 2 Preferred reaction of ester enolate 5.
To obtain selectively the epimeric 2-C-branched saccharides
(7S)-3, irrespective of the glucose backbone, and hence to realize
a stereodivergent synthesis, we had to develop a new concept with
no chelation-control. The covalent linking to the anomeric centre
via the 1,2-lactone 6 seemed to be especially attractive, since this
compound is available from malonate 1 in 92% yield in a one-
pot procedure.7c Furthermore, the alkylation of chiral lactones
proceeds with high selectivities and was already described for
carbohydrate 2,3-lactones.13
Scheme 3 Stereodivergent synthesis of 2-C-branched amino acid deriva-
tives 8 from malonate 1.
We applied potassium hexamethyldisilazide (KHMDS) for the
deprotonations, which allowed reactions with electrophiles at low
temperatures. Under such conditions, the substituted lactones
(7S)-7a–c were isolated in good yields and excellent stereose-
lectivities (Scheme 2). Due to the fixed bicyclic structure, the S
configuration at the new stereogenic centres of all products was
unequivocally established by J2,7 coupling constants and NOE
measurements (ESI†). Again, the high stereoselectivities can be
rationalized by the attack of the electrophiles from the sterically
In conclusion, we have shown that stereodivergent syntheses at
the glucose backbone can be realized with excellent selectivities.
Starting from an easily available 2-C-branched malonate, each of
the two diastereotopic ester groups was selectively replaced by
methyl, OH or NH2 groups in only a few steps. Our concept was
based on chelation of an ester enolate to the 3-position or lac-
tonization to the anomeric centre, respectively. For both reaction
types, the attack of electrophiles occurred exclusively from the
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sterically less hindered convex side, which afforded two epimeric
products with excellent stereoselectivities. All compounds were
isolated in good yields in analytically pure form. In contrast to
chiral auxiliaries, the newly generated stereogenic centres cannot
be cleaved off the carbohydrate. However, our method opens
interesting prospects for the stereoselective and flexible synthesis
of 2-C-branched saccharides.
119, 9377–9384; (c) T. Sommermann, B. G. Kim, K. Peters, E.-M. Peters
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This work was generously supported by the Deutsche
Forschungsgemeinschaft (Li 556/7-3).
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©