Recent Advances in Monosaccharide Synthesis: A Journey into L-Hexose World

Abstract

Last years have witnessed enormous progresses in glycomic field, mainly as a consequence of the crucial role carbohydrates have shown in biological systems. While up to a few years ago attention was mainly focused on the use of easily available D-sugars, a recent interest has emerged around their L-enantiomers, as they have been found to be key components of several bioactive compounds, whether in the form of oligosaccharides, glycopeptides, terpene glycosides or other clinically useful agents. However, L-sugars (L-hexoses especially) are rather rare in nature and not easily accessi-ble from inexpensive sources. As demand for their synthesis in considerable amount and high purity is more and more pressing, intense efforts have been addressed to the development of new and general methodologies for their construction. This review covers the synthetic routes to L-hexoses, mainly those coming from the new century. Methodologies for monosaccharide assembly will comprise de novo approaches, based on carbon chain elongation, hetero Diels-Alder reac-tion, asymmetric dihydroxylation up to the most recent amino acid-catalyzed aldol addition – as well as D-sugar manipula-tion strategies, including epimerization by chemical or enzymatic methods. Application of such protocols for the construc-tion of biologically relevant oligosaccharides and natural products will be also briefly mentioned.

Full text

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Current Organic Chemistry, 2009, 13, 71-98
71
1385-2728/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.
Recent Advances in Monosaccharide Synthesis: A Journey into L-Hexose
World
Daniele D’Alonzo*, Annalisa Guaragna and Giovanni Palumbo
Dipartimento di Chimica Organica e Biochimica, Università di Napoli Federico II, via Cinthia, 4 I-80126 Napoli, Italy
Abstract: Last years have witnessed enormous progresses in glycomic field, mainly as a consequence of the crucial role
carbohydrates have shown in biological systems. While up to a few years ago attention was mainly focused on the use of
easily available D-sugars, a recent interest has emerged around their L-enantiomers, as they have been found to be key
components of several bioactive compounds, whether in the form of oligosaccharides, glycopeptides, terpene glycosides
or other clinically useful agents. However, L-sugars (L-hexoses especially) are rather rare in nature and not easily accessi-
ble from inexpensive sources. As demand for their synthesis in considerable amount and high purity is more and more
pressing, intense efforts have been addressed to the development of new and general methodologies for their construction.
This review covers the synthetic routes to L-hexoses, mainly those coming from the new century. Methodologies for
monosaccharide assembly will comprise de novo approaches, based on carbon chain elongation, hetero Diels-Alder reac-
tion, asymmetric dihydroxylation up to the most recent amino acid-catalyzed aldol addition – as well as D-sugar manipula-
tion strategies, including epimerization by chemical or enzymatic methods. Application of such protocols for the construc-
tion of biologically relevant oligosaccharides and natural products will be also briefly mentioned.
1. INTRODUCTION
In the last two decades a new key role of carbohydrates
in living organisms has emerged, as they have shown to be
major information carriers between cells and their surround-
ings, both in their free form or as glycoconjugates with pro-
teins or lipids. This finding has rapidly brought to an increas-
ing interest towards several aspects of carbohydrate chemis-
try, particularly owing to the potential use of sugars in bio-
chemical and pharmaceutical field. The need for specific
saccharides in significant amount, in order to thoroughly
understand their biological functions, has inspired modern
synthetic approaches. The demand for compounds able to
mimic natural substances by way of similar structure and/or
biological function has stimulated elaboration of innovative
preparative procedures in carbohydrate synthesis. The search
for analogues of mono- and oligosaccharides resistant to
enzymatic degradation has been also carried out. With a re-
evaluation of the importance of carbohydrates, analogously
to Proteomics and Genomics the term “Glycomics” [1] (or
“Glycobiology” [2] or “Glycoscience” [3]) has been coined
to refer to the role of carbohydrates in biological events. In
view of the various biochemical pathways and disease proc-
esses in which carbohydrates are crucially engaged – angio-
genesis [4], cancer [5], tissue repair, cardiovascular diseases
[6], immune-system function [7], microbial and viral patho-
genesis [8], just to name a few of them – the possibilities for
their use as therapeutics and diagnostics are numerous and
exciting.
Even Although up to a few years ago attention was
mainly focused on the use of common D-sugars, as their


*Address correspondence to this author at the Dipartimento di Chimica
Organica e Biochimica, Università di Napoli Federico II, via Cinthia, 4 I-
80126 Napoli, Italy; Tel/Fax: +39 081 674119;
E-mail: dandalonzo@unina.it
wide availability represented a convenient source of starting
material for biological investigations, last times have wit-
nessed an emerging interest around their L-enantiomers [9],
as they have been often recognized as components of bio-
logically relevant molecules. Especially L-hexoses (mainly in
their pyranosidic form) are key constituents of several bioac-
tive [10] oligosaccharides, antibiotics, glycopeptides and
terpene glycosides, as well as steroid glycosides and other
clinically useful agents [11]. Bleomycin A2 (1), a glycopep-
tide antibiotic with significant antitumor activity [12], con-
tains a carbohydrate moiety consisting of a ?1?2 linked 3-
O-carbamoyl-D-mannopyranose with L-gulopyranose (Fig.
1). Adenomycin (2), a nucleoside antibiotic with potential
antibacterial properties [13], is composed by L-gulosamine
as a basic subunit. L-Altrose (3) has been found to be a typi-
cal component of extracellular polysaccharides from Bu-
tyrivibrio fibrisolvens strain CF3 [14]. L-Glucose is con-
tained in natural product (-)-littoralisone (4), known as a
bioactive agent for increased NGF-induced neurite out-
growth in PC12D cells [15]. L-Mannose has been discovered
in some steroid glycosides such as 5 and its phenol deriva-
tives have been used as potent substrates for measuring the
?-L-mannosidase activity of commercial naringinase [16]. L-
Iduronic acid is a component of the disaccharide?repeating
unit of glycosaminoglycans (GAG), such as the well known
heparin (6) and heparan sulfate (7) [10b].
The increased biological and medicinal interest in un-
natural carbohydrates, the poor commercial availability of
almost all L-hexoses, along with the practical difficulties in
obtaining these compounds from natural sources, has led
chemists to develop new and convenient methods for their
production [17]. Although the pursuit of synthetic routes
already include a large number of protocols, the area of in-
vestigation is still active, because of the advent of new meth-
odologies, new concepts and the development of innovative
and general strategies, which include:

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72 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
(a) de novo approaches, in which simple molecules are
employed as starting material [18]. Depending on the condi-
tions used, strategies may be further divided in: (i) substrate-
controlled methods and (ii) catalyst-controlled methods.
(b) D-sugar elaborations by chemical or enzymatic meth-
ods, which depend on the availability of appropriate D-series
sugars as starting materials [19].
This review will focus on the most important synthetic
approaches to fully hydroxylated hexoses (especially those
belonging to L-series) developed during the new century.
Methodologies include specific or general routes generating
enantiomerically enriched or pure carbohydrates. Procedures
aimed to use such knowledge for the construction of L-
hexose-based building blocks for the synthesis of bioactive
oligosaccharides and carbohydrate-containing natural prod-
ucts will be also mentioned. For previous work about mono-
saccharide synthesis, quite a few reviews are available
[17,18b,20,21].
2. DE NOVO APPROACHES
2.1. Substrate-Controlled Methods
Substrate-controlled methods are based on interaction of
the reagent with a substrate already provided with a chiral
centre [22]. Formation of new stereogenic centres occurs by
reaction of the chiral substrate with a chiral or achiral rea-
gent at a diastereotopic site, whose stereochemistry is con-
trolled by the pre-existing stereocentre. Regarding hexose
synthesis, many brilliant solutions have been developed dur-
ing the last few years [20], thanks to ongoing efforts in the
construction of molecular building blocks via efficient and
stereoselective carbon-carbon bond-forming reactions.
2.1.1. Carbon Chain Elongation
A recent use of substrate-controlled approach has been
applied to the stereodivergent synthesis of L-hexoses using
L-ascorbic acid as starting material [23]. As depicted in
Scheme 1, the strategy comprises the following key steps: (a)
preparation of chiral aldehyde 9, readily available from L-
ascorbic acid (8); (b) synthesis of ?,?-unsaturated esters 10
with specified E or Z configuration via Wittig reaction; (c)
Sharpless asymmetric dihydroxylation (AD) of ?,?-
unsaturated esters 10 to give protected hexoses 11.
Synthesis of chiral compound 12 was carried out in two
steps from 8 by a known procedure [24] (Scheme 2); then
Mitsunobu reaction (in its chloroacetate modification [25]) at
the C-2 position of 12 provided diastereomeric ?-hydroxy
ester 13. Reduction of esters 12 and 13 (DIBAL-H or
LiBH4/Swern, DIBAL-H = diisobutylaluminium hydride) led
to aldehydes 14 and 15, respectively; Wittig-type olefination

















Fig. (1). L-Hexoses as components of bioactive molecules.
O
O
OH
OH
OH
O
NH2
O
R = H Heparin (6)
R = SO3- Heparan sulfate (7)
Bleomycin A2 (1)
L-Gulose
HO
OH
OH
O
HO
OH
L-Altrose (3)
Adenomycin (2)
HO
O
HO
O
HO
OH
L-Mannose
O
O
H3C
OH
OHC
OH
6’-Hydroxyconvallatoxin (5)
H
H
OH
OH
O
HO
O
NH
N
HN
O
N
H
Me
HO
Me
O
H
N
HOMe
H
NH
O
S
N
S
N
O
HN
S
Me
Me
O
NN
H2N
Me
H2NO
H
N
CONH2
NH2
O
O
OH
HO
OSO3-
O
L-Gulosamine
NH2
OH
OH
O
HO
H2N
OH
O
O
HO
OH
N
N
N
N
NH2
O
HO
O
OSO3-
-OOC
O
OSO3-
O
OR
-O3SHN
O
L-Iduronic acid
OH
O
OH
O
OH
O
O
O
H
H
Me
O
O
(-)-Littoralisone (4)
L-Glucose

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Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 73
finally afforded key intermediates 16-20 (diastereomers in
pairs at C-4 position).
With the four ?,?-unsaturated esters 16-20 in hand, dihy-
droxylation under Sharpless conditions [26] allowed to set
the remaining two stereogenic centers (Schemes 3-4). In
Particular, the double asymmetric synthesis was used, which
involves a reaction between an enantiomerically pure sub-
strate and an enantiomerically pure reagent [27]. In case of
olefin 16, use of dihydroquinine and dihydroquinidine phtha-
lazines (DHQ)2PHAL and (DHQD)2PHAL as ligands in AD-
mix-? and AD-mix-? reagents respectively addressed osmy-
lation towards the ?- and ?-face of the double bond, giving
diastereomers 21 and 22 after diol protection. Conversion of
ester function into formyl group, deprotection, six-membered
ring closure and acetylation yielded peracetylated hexopy-
ranosides 24 and 25 (Scheme 3).
Analogously, asymmetric dihydroxylation of olefins 17-
20 led to hexopyranosides 26-31 (Fig. 2), completing the
whole L-series.
Current studies on carbon skeleton elongation have also
led to the construction of a great deal of new heterocyclic
homologating agents, as a result of profitable investigations
in organometallic chemistry [28] (Fig. 3). In many cases,
importance of such reagents is due to their ability to work as
synthetic equivalents of several anions, resulting in powerful
tools for numerous synthetic tasks [20,29,30,31,32].
In this context, the discovery of protected (5,6-dihydro-
1,4-dithiin-2-yl)methanol 37 as a reagent capable of three-
carbon homologation [33] of electrophilic molecules by in-
troduction of a fully protected allylic alcohol moiety or an











Scheme 1. L-Hexoses from ascorbic acid.

















Scheme 2. Preparation of key intermediates 16-20 from ascorbic acid via Wittig reaction.
O
O
OHHO
OH
L-ascorbic acid (8)
OR
CHO
OR
RO
OR
OR
RO
CO2R
OR
RO
ROCHO
OR
RO
*
*
*
*
*
Sharpless AD
Wittig
olefination
1110
9
Chiral centre
fixing the
steric series
HO
O
O
OHHO
HO
OH
OCO2R
O
OH
OCO2Et
O
OH
OCHO
O
OBn
OCHO
O
OR
ClCH2COOH/Ph3P/
DIAD, then Et3N
Ref. 24
1. BnBr, Ag2O
2. LiBH4
3. Swern oxidation
1. BnBr or TBSCl
2. DIBAL-H or LiBH4/Swern
R = Et, Ref 23b-c
R = Me, Ref 23a
8
1312
14 15
R = TBS, Ref 23a
R = Bn, Ref 23b-c
O
CO2Me
O
OBn
O
CO2Me
O
OBn
OCO2Et
O
OBn
OCO2Et
O
OR
E/Z 98:2E/Z 98:2 (R = Bn)
E/Z 20:1 (R = TBS)
E/Z 1:99
E/Z 1:99
Selective
(E)- or (Z)-
Wittig
olefination
161718
19
20
Selective
(E)- or (Z)-
Wittig
olefination
65%
77% o.y.
72-85%
o.y.

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74 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
?,?-unsaturated formyl function has represented a useful and
versatile building block for the synthesis of polyhydroxy-
lated molecules [34]. Such reagent has been already used for
the elongation of a number of different substrates, leading to
several enantiopure sugar-based targets, such as C-
glycosides 38-39 [35], spirocompounds 40 [36], deoxyimi-
nosugars 41 [37], deoxysugars 42 [38] and six-membered
nucleoside analogues 43 [39] (Fig. 4).










Scheme 3. AD reaction of ?,?-unsaturated ester.








Fig. (2). Hexopyranosides 26-31 by AD reaction of olefins 17-20.









Fig. (3). Readily available heterocycles employed as synthetic equivalents.
26
L-Glc
from 17
27
L-Alt
from 17
31
L-Tal
from 20
30
L-Gul
from 20
28
L-Gal
from 18-19
29
L-Ido
from 19
O
OAc
AcO
AcO
AcO
OAc
O
OAc
AcO
AcO
OAc
OAc
O
OAc
AcO
AcO
OAc
OAc
O
OAc
AcO
AcO
OAc
OAc
O
OAc
AcO
AcO
OAc
OAc
O
OAc
AcO
AcO
OAc
OAc
S
N
SS
RLi
RCH2
O
R
R
O
R
S
NBoc
Li
O
H
N
N
H
H
OMe
O
H
or
O
or
X
R3SiO
X = O, NR, S
X
Dondoni et al.
[Ref. 20]
Corey,
Seebach et al.
[Ref. 29,30]
Casiraghi et al.
[Ref. 32]
Enders et al.
[Ref. 31]
Degl'Innocenti
et al.
[Ref. 30b]
S
S
RO
HO
H
or
O
Palumbo et al.
[Ref. 33,34]
32333435 3637
O
CO2Me
O
OBn
1. AD mix ?
(?:? = 87:13)
1. AD mix ?
(?:? = 94:6)
O
CO2Me
O
OBn
O
O
OCO2Me
O
OBn
O
O
2. DMP
2. DMP
DIBAL-H
OCHO
O
OBn
O
O
25 L-Man
1622
21
23
1. acetic acid
2. Ac2O
3. H2, Pd/C
4. Ac2O
86% o.y.
69% o.y.70%
O
OAc
OAc
AcO
AcO
AcO
24 L-All
O
OAc
OAc
OAc
AcO
AcO
same path
as for 24

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Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 75











Fig. (4). Synthetic applications of the 3-C homologating system 37.















Scheme 4. L-Altro- and L-manno-hexopyranosides from the homologating system 37.

Lately, this synthon has been exploited to open up a gen-
eral procedure for L-hexopyranose synthesis [40]. The route
was based on three-carbon homologation of 2,3-O-
isopropylidene-L-glyceraldehyde (44) [41] (Scheme 4). Cou-
pling reaction between lithium anion of 37 and glyceralde-
hyde 44 produced two diastereomers anti-45 and syn-45,
with selectivities depending on the choice of the solvent. In
an early approach, the anti-adduct was used to tune the syn-
thetic path. p-Methoxybenzyl (MPM) group removal (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone, DDQ) followed by
mild oxidation (pyridiniumchlorochromate, PCC) furnished
aldehyde 46. Treatment of the latter with Amberlyst 15 in
methanol allowed conversion of formyl group into its di-O-
methyl acetal, acetonide deprotection, and intramolecular
OH
OH
O
R
R
O
O
HO
O
HO
OH
-O2C
OH
OH
O
OH
HO
OH
HO
O
O
OMe
HO
OH
HO
O
OH
HO
OH
OH
OH
sLex mimics
Five-membered spiro-
compounds
4-Deoxy-D- and L-Hexoses
L-nucleosides
(X = O, Y = H
X = NR; Y = OH)
C-Glycosides
40
42
43
39
38
X
HO
Y
N
HO
OH
HO
1-deoxy-L-iminosugars
41
H
HO
O
OMe
OH
OH
OH
ent-42
Base
S
S
RO
37
(R = MPM)
OHC
O
O
S
S
MPMO
O
O
OH
BuLi, -78 °C
44
anti-45
48
O
BnO
OMe
AcO
Raney-Ni
BnO
OMe
HO
O
AcO
OH
1. NaH/BnBr
2. 1 eq DDQ
3. PCC/Py
S
S
O
O
O
OBn
H
1. Amberlyst 15
MeOH
2. Ac2O/Py
S
S
O
OMe
BnO
AcO
1. CF3COCH3
Oxone
2. HClO4
BnO
OMe
OH
O
HO
OH
46
47
49
L-Manno
50
L-Altro
(+ syn-45)
95%
66% o.y.
97%
o.y.
75%
82%
87% o.y.
H
OsO4N
MO

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76 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
transacetalation reaction to give bicyclic compound 47
(Scheme 4). Finally, dithioethylene bridge removal (Raney-
Ni) [42] yielded key unsaturated pyranosyl derivative 48.
Access to L-hexoses was then assessed by complementary
approaches. L-Manno- and L-altro-hexopyranosides 49 and
50 were synthesized, with a high degree of stereoselectivity,
by appropriate syn- and anti-dihydroxylation reactions of
olefin 48 [40a]. Following a similar path for syn-45, L-
epimers with gulo- and ido-configuration can be obtained.
On the other hand, synthesis of 1,6-anhydrosugar deriva-
tive 52 (Scheme 5), in turn obtained from adduct 51 by dom-
ino reaction [40b] (involving MPM deprotection, allylic al-
cohol oxidation, isopropylidene deprotection and acetalation
reactions), resulted crucial to complete the series. A well-
known feature of 1,6-anhydrosugars was exploited, namely
the fact that all stereocenters of the locked molecule are in
opposite orientation with respect to the corresponding classi-
cal pyranoside [43]. Thus, an inverse stereoselectivity in syn-
and anti-dihydroxylation reactions was observed, which led
to L-allo- and L-gluco-hexopyranosides 54 and 56 (Scheme
5).
Once more, analogous transformations carried out on
syn-45 can readily afford L-galacto- and L-talo-hexopy-
ranosides.
The procedure is stereoselective and potentially general;
also, it’s noteworthy to underline that replacement of alde-
hyde 44 with its D-enantiomer allows preparing D-series
hexoses.
2.1.2. Aldohexoses from a Synthetic Equivalent of a Dihy-
droxycyclohexadiene
An alternative substrate-controlled synthesis, virtually
leading to all eight enantiopure D- and L-aldohexoses, has
been developed [44] from the versatile cyclohexanoid build-
ing block 57 [45] (Fig. 5). The latter, which has been pre-
pared by both enzymatic [46] and chemical [47] methods,
works as a chiral synthetic equivalent of a cis-1,4-
dihydroxycyclohexane-2,5-diene (58), thus enabling stereo-
controlled manipulation of cyclohexene double bond [48].
In preliminary experiments, complementary four L- and
four D-aldohexoses were synthesized (Schemes 6-8). In ma-
jor detail, syn dihydroxylation (OsO4/NMO, NMO = N-
methylmorpholine oxide) or epoxidation (m-chloroperoxy-
benzoic acid, mCPBA) reactions carried out on starting
bromo-ether 59 opened the way to the synthesis of four cy-
clohexenols 70-73, considering the reductive cleavage
(Zn/AcOH) and the consecutive cyclohexene unmasking by
retro Diels-Alder (Ph2O/NaHCO3, Ph2O = diphenylether) as
the key steps.
Conversion of conduritols 70-73 into aldohexoses was
then carried out in a straightforward way (Schemes 7-8).
Protection of 70-71 afforded MPM ethers 74 and 77; on the
other hand, Mitsunobu protocol (PNBOH/DIAD/PPh3,
PNBOH = p-nitrobenzoic acid, DIAD = diisopropyl azodi-
carboxylate) on 70-71 followed by MPM insertion (NaOMe,
then MPMCl) gave olefins 75-76. Reductive ozonolysis of
the four cyclohexenols 74-77 (O3 then NaBH4) led to diols
78-81; finally, DDQ-based rearrangement of MPM group,
Dess-Martin oxidation and deprotection of hydroxyl groups
furnished D-aldohexoses D-mannose and D-glucose and L-
aldohexoses L-gulose and L-idose (Scheme 7).
In similar way, MPM protection of conduritols 72-73
gave ethers 86 and 89, which in turn led to the synthesis of
D-galactose and L-talose. Conversely, oxidation/reduction
(PCC, then DIBAL-H) of 72-73 enabled preparing deriva-
tives 87-88, readily leading to L-altrose and D-allose
(Scheme 8).
Although efficacy of cyclohexanoid building block 57 as
starting material for monosaccaride synthesis has been al-
ready pointed out, a more general applicability of this









Scheme 5. L-Gluco- and L-allo-hexopyranosides from 1,6-anhydrosugar derivative 52.





Fig. (5). Hexoses from a synthetic equivalent of a dihydroxycyclo-
hexadiene.
57
OPG
58
OH
L-Hexoses
PGO
Br
O
S
S
MPMO
O
O
OBn
55
1. OsO4/NMO
2. TfOTMS/MeOH
CF3COCH3
Oxone
1. KOH
2. TfOTMS
MeOH
O
O
OBn
S
S
52
DDQ (2eq)
Raney-Ni
BnO
OCH3
OH
O
HO
OH
54 L-Allo
O
O
OBn
53
BnO
OCH3
HO
56 L-Gluco
O
HO
OH
O
O
OBn
O
51
92%75%
84% o.y.
92%
93% o.y.

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Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 77
method has been suggested, since enantiomers of 70-73 may
be also accessible; indeed the authors have already reported
the preparation of the enantiomer of compound 57 [46-47].
2.2. Catalyst-Controlled Methods
One of the most significant advances in asymmetric syn-
thesis in the past decades has been represented by the use of
catalysts able to induce conversion of achiral substrates into
chiral products. The obvious benefit of asymmetric catalysis
is that only small amounts of chiral substances are needed to
generate large quantities of chiral products. The enormous
economic potential of catalytic asymmetric synthesis has
made it one of the most extensively explored research areas
[22,49]. It’s noteworthy that addition of a ligand to the cata-
lyst considerably increases the reaction rate of an already
existing catalytic transformation (ligand-accelerated cataly-
sis). In addition, the nature of ligand and its interaction with
the other components in the catalytic complex affect selec-
tivity and rate of such organic transformations [22].
2.2.1. Asymmetric Dihydroxylation
In this paragraph attention has been paid to synthetic ap-
plications deriving from the use of Sharpless asymmetric
dihydroxylation (AD) reaction, which represents one of the
most powerful tools to create enantiomerically enriched con-
tiguous chiral centres [50].
A rational use of Sharpless AD to rapidly approach enan-
tiopure hexoses in ?- or ?-lactone form has been developed
by O’Doherty and coworkers [51] (Schemes 9-10). The
method is based on two subsequent dihydroxylation reac-
tions on 2,4-dienoate esters (2E,4E)-90 (Scheme 9) or
(2Z,4E)-90 (Scheme 10), which are commercially available
or easily prepared [52]. As shown in Scheme 9, enantioselec-
tivity was attained at the initial stage of the synthesis, sub-






















Scheme 6. Preparation of cyclohexenols 70-73 from cyclohexanoid building block 59.
MOMO
Br
O
MOMO
OH
OBn
OBn
OMOM
OBn
OBn
OBn
BnO
Br
O
OBn
OBn
OH
OBn
OBn
OBn
OH
OBn
OBn
OBn
O
Br
O
BzO
Br
O
BzO
Br
O
OBOM
OBOM
OBz
OBOM
67
OBOM
OBOM
OH
OBOM
OBOM
OBOM
O
BzO
OMOM
OBz
OBz
BzO
Br
O
OBz
OBz
OMOM
OBz
OBz
OBz
OH
OBn
OBn
OBn
HCl
MeOH
DIBAL-H
1. NaOMe
2. BnBr
3. HCl
MeOH
1. HCl
2. BzCl
3. mCPBA
1. OsO4
2. NaOMe
3. BnBr
1. BF3
2. BzCl
1. Zn/AcOH
2. MOMCl
1. HCl/MeOH
2. PNBOH
DIAD
PPh3
1. OsO4
2. BnBr
3. Zn/AcOH
1. BF3
2. BOMCl
59
60
6162
63
64
65
66
68
69
70
71
72
73
1. Zn
AcOH
2. Ph2O
reflux
1. Ph2O
reflux
2. BnBr
1. Zn
AcOH
2. Ph2O
NaHCO3
reflux
80%
o.y.
88%
o.y.
99%
78% o.y.
O
Ar
87%
o.y.
97% o.y.
83%
o.y.
100%
o.y.
97% o.y.
Ph2O
NaHCO3
reflux
83%
77% o.y.
86%
90% o.y.
92%

Page 8

78 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
jecting dienoate (2E,4E)-90 to the typical Sharpless AD-mix
protocol, to afford alcohols 91-92 in good yields (89 and
80%, respectively) and good enantiomeric excess (90-92%
ee) [53]. Double bond selectivity was easily explained [54]
in terms of electron density of the ?-system (i.e. the most
electron-rich double bond reacts faster); moreover the second
double bond was loath to react because of conflicting di-
astereo-controlling issues (mismatching reagent and sub-
strate control). In addition, the use of AD-mix ? or AD-mix
? reagents provided the R- and S- configuration at C-5 posi-
tion, opening the way to the synthesis of D- and L-hexoses,
respectively.
A second osmylation reaction under slightly modified
Sharpless conditions (AD-mix-?* or AD-mix-?*, Scheme 9)
tuned on alcohols 91-92 afforded lactones 94-95. Key to the
success of this transformation was also the in situ lactoniza-
tion (Pyridine/TsOH, TsOH = p-toluenesulfonic acid) of the
initially formed polyols.
As clearly shown by the authors, from the same precursor
(2E,4E)-90, compounds ent-94 and ent-95 can be obtained
by inverting the order of addition of AD-mix reagents.
Moreover, by simply changing the dienoate double bond
geometry (i.e. using (2Z,4E) dienoate 90), the ?-lactone be-
longing to talo-series [55] (Scheme 10) was obtained with
high enantio- and diastereocontrol.
The short number of steps required and the high level of
selectivity accomplished by dienoate strategy has made this
method well suited also for total synthesis of complex targets
too. Quite a few bioactive molecules containing a pyranose
moiety have been prepared, including the antitumor macrol-
ide Apicularen A (99) [56], the syn-1,3-diol/5,6-
dihydropyran-2-one containing cyclooxygenase inhibitors
Cryptocaryolone (100), Cryptocaryolone diacetate (101),
Cryptocarya triacetate (102) and Tarchonanthuslactone (103)
[57], and the sugar moiety of the antifungal Papulacandin C
(104) [58] (Fig. 6).






















Scheme 7. Synthesis of L-Gul, D-Man, L-Ido, D-Glc from cyclohexenols 70-71.
70
OMPM
OBn
OBn
OBn
OH
OH
BnO
BnO
OBn
OMPM
CHO
O
83
BnO
BnO
OBn
O
Ar
D-Man
OMPM
OBOM
OBOM
OBOM
OH
OH
OBOM
BOMO
OBOM
MPMO
CHO
O
OBOM
BOMO
OBOM
O
Ar
L-Ido
1. PNBOH
DIAD
PPh3
2. NaOMe
3. MPMCl
OMPM
OBn
OBn
OBn
OH
OH
BnO
BnO
OBn
MPMO
CHO
O
BnO
BnO
OBn
O
Ar
L-Gul
1. Intramolecular
cyclization
(DDQ)
H2/Pd
OMPM
OBOM
OBOM
OBOM
71
OH
OH
OBOM
BOMO
OBOM
OMPM
CHO
O
OBOM
BOMO
OBOM
O
Ar
D-Glc
74
75
76
77
78
79
80
81
82
84
85
96%38% from
74
89%
o.y.
44% from
75
80%45% from
77
47% from
76
76%
o.y.
O3
NaBH4
MPMCl
H2/Pd
H2/Pd
H2/Pd
MPMCl
1. PNBOH
DIAD
PPh3
2. NaOMe
3. MPMCl
O3
NaBH4
O3
NaBH4
O3
NaBH4
2. Dess-Martin
oxidation
1. Intramolecular
cyclization
(DDQ)
2. Dess-Martin
oxidation
1. Intramolecular
cyclization
(DDQ)
2. Dess-Martin
oxidation
1. Intramolecular
cyclization
(DDQ)
2. Dess-Martin
oxidation

Page 9

Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 79
Further examples of Sharpless AD-based routes make use
of furfural (105) (Scheme 11), which has already shown to
be a valuable synthon for the assembly of numerous biologi-
cally relevant enantiopure compounds [32].
In a first approach, an integrated enantio- and diastereo-
controlled synthesis leading to all eight L-aldohexoses (as
well as their D-enantiomers) has been devised by Ogasawara
and coworkers [59]. Two key stages were pointed out: a)
Sharpless AD reaction on furfural derivative 106 followed
by Achmatowicz ring expansion [60] (mCPBA, then TsOH),
obtaining a levoglucosenone-type intermediate 108 (Scheme
11); b) conversion of compound 109 (coming from enone
108) into iodide 110 (Scheme 12); the latter could be con-
veniently used in two synthetic paths, since C-1 and C-6
positions can be reversed by suitable sugar manipulation,
with the result to obtain L-hexoses, as well as their D-
counterparts, from the same precursor (Scheme 12).
The main steps of this route are outlined in Schemes 13-
14. As already discussed, the use of 1,6-anhydrosugar-based
intermediates (such as 108) guarantees high selectivity in syn
and anti dihydroxylation reactions. Epoxidation (H2O2) of
108 and syn dihydroxylation (OsO4) of 116 respectively
yield intermediates 115 and 119, which opened the way to
















Scheme 8. Synthesis of D-Gal, L-Alt, D-All, L-Tal from cyclohex-
enols 72-73.








Scheme 10. D-Talo-?-lactone synthesis from (2Z,4E) dienoate 90.












Scheme 9. AD-based approach from dienoate (2E,4E)-90.
OMPM
OBn
OBn
OBn
73
L-Tal
OMPM
OBn
OBn
OBn
D-All
OMPM
OBn
OBn
OBn
72
D-Gal
OMPM
OBn
OBn
OBn
L-Alt
86
87
88
89
76%
31%
from 88
4 steps
4 steps
4 steps
4 steps
95%
52%
from 89
95%
80%
44%
from 86
46%
from 87
1. PCC
2. DIBAL-H
3. MPMCl
MPMCl
1. PCC
2. DIBAL-H
3. MPMCl
MPMCl
OBn
OOEt
AD-mix-?*
O
O
OBn
OH
70%, 90% ee
80%
O
O
OBn
OTBS
O
O
OBn
OH
HO
HO
1. OsO4
NMO
2. TBAF
70%
10:1 dr
D-talo-?-lactone
(2Z,4E)-90
96
97
98
TBSCl
EtO
OBn
O
EtO
OBn
O
AD-mix-?*
OH
OH
89%, 90% ee
1) AD-mix-?*
2) Py/TsOH
3) Ac2O/Py
O
O
AcO
AcO
OBn
OAc
AD-mix-? ?* = 2% OsO4, 2.1% (DHQ)2PHAL, 3eq K3Fe(CN)6,
3eq K2CO3, 1eq MeSO2NH2 in 1:1 t-BuOH/H2O
AD-mix-? ?* = 10% OsO4, 12% (DHQD)2PHAL, 6eq K3Fe(CN)6,
3eq K2CO3, 3eq NaHCO3, 1eq MeSO2NH2 in 2:1 t-BuOH/H2O
50%
o.y.
L-galacto-?-lactone
EtO
OBn
O
PMPO
92
OH
EtO
OBn
O
OPMP
OHOH
OH
AD-mix-?*
80%
1. Py/TsOH
2. Ac2O/Py
O
O
AcO
OBn
OPMP
AcO
81% o.y.
D-galacto-?-lactone
1. AD-mix-?*
2. selective
protection
80%, 92% ee
(2E,4E)-90
91
93
94
95
R
S

Page 10

80 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
the synthesis of L-galactose, L-gulose and L-idose. On the
other hand, Mitsunobu procedure (HCO2H/DIAD/PPh3 then
K2CO3) carried out on olefin 116 gave its C-4 epimer 117,
which enabled to prepare L-allose (Scheme 13).
Furthermore, SN2? reaction (MsCl then CaCO3, Ms = me-
syl) of allylic alcohol 117 (Scheme 14) led to olefins 124 and
127, which anti and syn dihydroxylation reactions afforded
anhydrosugars 126 and 128 respectively. From the last ones,
L-mannose, L-glucose, L-talose and L-altrose were synthe-
sized.
As mentioned before (Scheme 12), access to aldohexoses
belonging to D-series was also possible, as demonstrated by
the synthesis of D-glucose (Scheme 14). The latter was ob-
tained starting from 1,6-anhydrosugar 122 by a sequential
procedure consisting of 1,6-anhydro ring-opening, he-
miacetal reduction, double bond syn dihydroxylation and C-
C bond cleavage [59].
The work by Achmatowicz and Ogasawara has later in-
spired a further application of furfural-based strategy for
monosaccharide synthesis [61]. The latter relied on asym-
metric osmium chemistry carried out on vinylfuran 130
(Scheme 15). Again, depending on AD-mix-? or AD-mix-?
reagents used to generate asymmetry in the molecule, the
route enables to synthesize hexoses belonging to both steric
series.









Fig. (6). Natural product synthesis by dienoate-based strategy.










Scheme 12. Access to L- and D- aldohexoses by manipulation of enone 108.







Scheme 11. AD-based approach to enone 108 from furfural 105.
OAc OAcOAc O
O
102
Cryptocarya triacetate
OR OR O
O
O
100 Cryptocaryolone, R = H
101 Cryptocaryolone diacetate, R = Ac
HO
O
OH
O
H
N
O
O
99
(-)-Apicularen A
HO
HO
O
O
H3C
O
O
103
Tarchonanthuslactone
O
HO
HO
HO
O
O
OH
O
O
O
HO
HO
O
HO
OH
OH
O
104
Papulacandin C
109 R = OTBS
or OCH2naphthyl
110 R = I
O
OBn
OBn
OBn
O
OBn
OBn
OBn
CHO
CHOH
CHOH
OH
OH
OH
1. Zn/AcOH
2. BnBr
O3
then NaBH4
BnO
BnO
HO
L-aldohexoses
111
112
1. Deprotection
2. MsCl/LiI
CHO
CHOH
CHOH
CHOH
OH
HO
1. Zn/AcOH,
then LiAlH4
2. BnBr
CHOBn
CHOBn
OBn
OBn
OBn
113
1. OsO4
2. NaIO4
CHOBn
CHOBn
OBn
OBn
OBn
CHO
H2/Pd
D-aldohexoses
114
108
Double bond
functionalization
O
O
R
OBn
R1
OBn
R2
R1 = H, R2 = OBn
or
R1 = OBn, R2 = H
R1 = OBn
R2 = H
H2/Pd
O
CHO
O
OR
O
OR
HO
OH
O
O
RO
O
AD-mix-?
mCPBA
then
p-TsOH
R = TBS or
CH2naphthyl
105
Furfural
106
107
108

Page 11

Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 81
Aiming to test the breadth of such methodology, early
studies have been accomplished starting from diol 131, gain-
ing access to D-hexoses. In a similar manner to what previ-
ously described, pyranones 133 were prepared from alcohols
132 (Scheme 16) by Achmatowicz ring expansion
(NBS/H2O, NBS = N-bromosuccinimide) followed by he-
miacetal protection (BzCl or PivCl, Piv = pivaloyl), the axial
anomeric alcohols being selectively acylated (>20:1) at low
temperature [61c]. Hence, pyranones 133 were stereoselec-
tively reduced under Luche conditions [62] (NaBH4/CeCl3)
to afford allylic alcohols 134 as the only detectable stereoi-
somers. Syn dihydroxylation of 134 gave then D-manno-triol
135 with complete stereocontrol. Similarly, Mitsunobu reac-
tion carried out on 134 gave alcohol 136, which led to pro-
tected D-gulose 137 and D-talose 138 by respectively apply-
ing Upjohn (OsO4/NMO)
(OsO4/TMEDA, TMEDA = N,N,N,N-tetramethylethyl-
enediamine) [63] dihydroxylation conditions (Scheme 16).
The same path, developed on ent-132, enabled synthesis
of L-mannose derivative 140 (Scheme 16); likewise L-talose
and L-gulose can be prepared [61a-b].
The versatility of this method has also been proved by
the achievement of numerous synthetic tasks (Scheme 17),
including deoxysugars [64,65], iminosugars such as swain-
sonine (144) [66] and 8-epi-D-swainsonine (145) [67] and
[26] and Donohoe’s
natural products such as the bioactive pheromone daumone
(146) [68]. In addition, quite a few protocols were focused
on synthesis of biologically relevant oligosaccharide se-
quences [69], to demonstrate that de novo methodologies can
often represent a better alternative in uncommon oligosac-
charide synthesis rather than traditional approaches, starting
from natural monosaccharides. The list of molecules include
antrax tetrasaccharide (147) [70], the cardiac glycoside digi-
toxin (148) [71] and the disaccharide fragment (and its aza-
analogue) of mannopeptimycin-E (149-150) [72]. Crucial for
the successful outcome of these targets was the iterative use
of a mild palladium-catalyzed glycosylation reaction
(Pd(0)/PPh3) [61c], which efficiently provided stereocon-
trolled synthesis of ?- or ?-glycoside moieties from 141 and
their selective oligomerization (Scheme 17).
2.2.2. Diels Alder Cycloadditions
Many synthetic methods can be considered as important
processes in organic chemistry but just a few of them can
challenge the Diels Alder reaction when it comes to synthetic
utility in the formation of six-membered rings. In particular,
[4+2] hetero Diels-Alder (HDA) reactions, especially those
carried out in an asymmetric environment [73], can provide a
very efficient access to de novo stereoselective monosaccha-
ride synthesis, as they allow to synthesize highly enantio-

















Scheme 13. L-Gal, L-Ido, L-Gul and L-All from enone 108.
O
L-Gul
L-Ido
L-All
L-Gal
R = TBS or
OCH2
NaBH4
CeCl3
HCO2H/DIAD/PPh3,
then K2CO3
See
Scheme 12
See Scheme 12
1. C-2 Epimerization
(DABCO)
2. See Scheme 12
See Scheme 12
1. NaBH4
CeCl3
2. BzCl/Py
1. BF3 then H2O
2. NaOMe
3. BnBr
H2O2
NaOH
THF
108
115
116
117
121
122
123
87%
1. 3,5-(NO2)2BzCl
Py
2. OsO4
1. NaOMe
2. BnBr
87 o.y.>68%
o.y.
86%
from 116
70%
66%
from 117
O
RO
O
O
O
O
RO
O
OBz
O
O
RO
OH
O
O
RO
OH
O
O
RO
ArO
OH
OH
O
O
RO
BnO
OH
OH
O
O
RO
BnO
OBn
OBn
O
O
RO
BnO
OBn
OBn
O
O
RO
BnO
OBn
OBn
118
119
120
2. OsO4
BnBr
1. BnBr
(91%
from 108)

Page 12

82 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.
enriched carbohydrates by one-step assembly of up to three
stereogenic centres. This topic has been extensively re-
viewed in the past years [18b,21,73,74].
Research on [4+2] HDA reactions has been so far devel-
oped in two directions: on one hand, coupling reactions have
been studied between oxa-1,3-diene derivatives 151 and ho-
modienophiles like 152, leading to dihydropyrans 153; alter-
natively, reactions have been examined between substituted
1,3-dienes, such as 154, and heterodienophiles, like aldehyde
155, giving adducts 156; in both cases, 153 and 156 can be
easily functionalized to give sugars with the required stereo-
chemistry (Scheme 18).
Control of chirality in asymmetric HDA reactions has
been carried out following two main strategies: 1) use of
dienes and/or dienophiles equipped with appropriate chiral
auxiliaries (which are removed at a late stage of the synthe-
sis); 2) use of a chiral catalyst. While pioneering routes have
been developed using dienophiles bearing temporary chiral
auxiliaries [75,76], in more recent times interest has been
focused on performing catalytic enantioselective HDA reac-
tions using chiral Lewis acids [73], which is indeed the most
efficient and cheap way to approach such reactions.
Coordination of a chiral Lewis acid to carbonyl function-
ality of a dienophile or a diene activates the substrate and
provides the chiral environment that forces the contact of a
diene (or a dienophile) with the substrate from the less steri-



















Scheme 14. L-Man, L-Glc, L-Tal, L-Alt and D-Glc from 1,6-anhydrosugars 117 and 122.









Scheme 15. AD of vinylfuran.
L-Alt
L-Tal
L-Man
L-Glc
1. C-2 Epimerization
(DABCO)
2. See Scheme 12
R = TBS or
OCH2
Rearrangement
(MsCl, then CaCO3)
OH
PCC
then NaBH4
1. BF3 then H2O
2. NaOMe
3. BnBr
See
Scheme 12
1. OsO4
2. BnBr
See
Scheme 12
See Ref.
59
2. LiAlH4
3. BnBr
1. OsO4
2. NaIO4
3. H2/Pd
OBn
OBn
BnO
OBn
OBn
D-Glc
1. Zn/AcOH
117
124
127
125
128
126
129
D-Hexose path
1. PCC
2. NaOCl
3. NaBH4
CeCl3
4. BzCl
O
O
RO
OBz
O
O
O
RO
OBz
O
O
RO
OBn
OBn
BnO
O
O
RO
O
O
RO
OBn
BnO
OBn
122
O
O
RO
BnO
OBn
OBn
O
OH
OH
O
O
OH
OH
AD-mix-?
AD-mix-?
L-Hexoses D-Hexoses
130
Vinylfuran
92%ee
90%ee
steps
1. TMSCH2MgCl
2. HCl
105
131
ent-131
O
CHO
steps
Ring expansion
(NBS/H2O)
Ring expansion
(NBS/H2O)

Page 13

Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 83
cally hindered face. When a chiral Lewis acid catalyst is
designed for an asymmetric HDA reaction, many parameters
should be considered. The choice of the metal combined
with the chiral ligand is of strategical importance. Metals as
aluminium, boron, the hard early transition metals titanium
and zirconium and some lanthanide elements are oxophilic
metals and have been widely used with oxygen-containing
chiral ligands [77]. On the other hand, ligands bearing nitro-
gen as coordinating atom show broad flexibility towards
both hard and soft metals [78]; likewise phosphorous-
containing ligands are soft centres and have been very suc-
cessful when they have come in contact with soft metals
[79]. Among the existing chiral Lewis acids used as cata-
lysts, bisoxazoline copper (II) complexes have shown to be
effective for addition reactions to dicarbonyl compounds
[80]. Bisoxazoline copper (II) catalysts can promote highly
diastereo- and enantioselective HDA reactions of aldehydes
with conjugated dienes or ketones with activated dienes [81].
Independently, the groups of Evans [82] and Jørgensen
[83] showed that ?,?-unsaturated ?-ketoesters reacted with
ethyl vinyl ethers in presence of chiral bis-oxazoline cop-
per(II) catalysts 157 and 158 (Fig. 7), leading to enanti-
omerically enriched dihydropyrans.
As example, ?,?-unsaturated ?-ketoester 159 treated with
ethyl vinyl ether 160 in presence of the complex (S)-157
afforded endo-adduct 161 in satisfactory yield (60%) and
with excellent enantiomeric excess (96% ee). The latter was
then converted into ?-D-mannopyranoside 163 (Scheme 19).
Latest reports on this topic have explored new ligands
and reaction conditions to prepare convenient carbohydrate
precursors. Resuming previous results [84] carried out to
reveal influence of high pressure in HDA reactions, Jurczak
and coworkers have applied this concept to the [4+2] cy-
cloaddition [85] of 1-methoxybuta-1,3-diene (165) to gly-
coaldehyde 164 in an asymmetric environment induced by
chiral catalysts Eu(hfc)3 (Europium(III) tris[3-(heptafluoro-





















Scheme 16. D-Manno-, D-talo-, D-gulo- and L-manno-hepyranosides from alcohols 132 and ent-132.
O
O
OR1
R2O
O
OH
OR1
NaBH4
CeCl3
O
OH
OTBS
R2O
O
OH
OTBS
BzO
OH
HO
OsO4
NMO
1. NBS/H2O
2. Hemiacetal
protection
R1 = TBS, Piv
R2 = Bz, Piv
O
OH
OTBS
PivO
OsO4/NMO
OsO4/TMEDA
O
OH
OTBS
PivO
OH
HO
O
OH
OTBS
PivO
OH
HO
135
D-manno
137
D-gulo
138
D-talo
134
O
OH
OTBS
RO
O
OH
OTBS
RO
OH
HO
OsO4
NMO
140
L-manno
139
O
OH
OTBS
ent-132
1. PPh3/DEAD/PNBOH
2. Et3N/MeOH
as above
133
132
136
R = alkyl or aryl group
95%
90%
58% o.y.
80%80%
R2 = Bz
R2 = Piv

Page 14

84 Current Organic Chemistry, 2009, Vol. 13, No. 1 D’Alonzo et al.



























Scheme 17. Synthetic applications of iterative palladium-catalyzed glycosidation reaction.












Scheme 18. The hetero Diels Alder (HDA) approach.
O
HO
OH
O
O
OH
O
O
OH
O
O
H
H
OH
H
O
148
Digitoxin
O
O
R2
R2 = CH3, CH2OPG
O
O
R1
R1 = Ph, t-Bu, Ot-Bu
Nu
Pd(0)/PPh3
O
O
R2
Nu
via 143
O
O
R2
L2Pd
X
Palladium-catalyzed glycosidation reaction
142
143
141
O
OH
O
HO
HO
O
OH
O
HO
O
OH
O
HO
O
OMe
N
HO
O
OH
H
Antrax Tetrasaccharide
147
O
HO
OH
O
146
Daumone
CH3
O
OH
O
H
N
OOHN
HN
N
H
O
OH
N
HN
HN
NH
NH
NH
NH
O
O
HO
O
OH
O
OH
OH
HO
HO
O
OH
OH
O
HO
O
OH
OH
X
HO
O
149 Mannopeptimycin, X = O
150 Aza-analogue of 149, X = NH
N
HO
H
OH
OH
144
Swainsonine
145
8-epi-D-Swainsonine
N
HO
H
OH
OH
+
O
+
O
OR
O
O
D- and L-sugars
OR4
OR
O
OR2
OR
O
OR2
R1
R2
151
R1
R2
R3
R3
R1
R1
HDA
Lewis acid
sugar
elaboration
D- and L-sugars
sugar
elaboration
* *
*
*
**
HDA
Lewis acid
152
153
154
155
156

Page 15

Recent Advances in Monosaccharide Synthesis Current Organic Chemistry, 2009, Vol. 13, No. 1 85

propylhydroxymethylene)-d-camphorate], 167) and (1R,2R)-
(salen)Cr(III)BF4 (168) (Scheme 20). Application of both
catalysts afforded cycloadducts with unsatisfying enanti-
omeric excess. Indeed, Eu catalyst 167 gave, at 50 °C, cy-
cloadducts (2R,6S)- and (2S,6R)-166 with low endo-
selectivity (59% dr) and low enantiomeric excess in favour
of (2R,6S)-166. The same [4+2] cycloaddition, accomplished
in presence of Salen catalyst 168, gave cycloadducts (2S,6S)-
and (2R,6R)-166 with very high exo-selectivity (93% dr) and
better, however still not satisfactory, enantiomeric excess in
favour of (2R,6R)-166 (Table 1).
In the effort to improve such selectivity, modifications of
Cr(III) ligands have been developed [86]. Particularly, Salen-
type complexes 171-172 (Scheme 21) were employed in
reactions of 165 with alkyl glyoxylates such as 169. Applica-
tion of less active chloride complex 171b and chiral triden-
tate Cr(III)Cl 172a as catalysts afforded, in variable yields
(50-96%) along with good enantioselectivity (up to 88% ee),
2-enopyranoside cycloadducts 170 as convenient precursors
of many natural products, including D- and L-sugars (Table
2).
When catalysts (1R,2R)-171b-d were used, predomi-
nance of cycloadduct (2S,6R)-170 (L-sugar precursor) was
observed; conversely when tridentate complexes (1S,2R)-
172a-b were used, the product with opposite chirality
(2R,6S)-170 (D-sugar precursor) was formed.
2.2.3. Stereoselective Aldol Additions
The concept of asymmetric organocatalysis [87], which
makes use of simple amino acids or other chiral small mole-
cules as efficient and selective catalysts for a large variety of




Fig. (7). Cu(II) catalysts for asymmetric HDA reactions.






















Scheme 19. ?-D-mannohexopyranoside 163 by HDA of ketoester
159 and vinyl ether 160.









Scheme 20. Asymmetric HDA reactions of diene 165 with glycoaldehyde 164.

Table 1. Selectivity in Asymmetric HDA Reactions of 164/165
Ratio (%)
Endo Adducts Exo Adducts
Catalyst
Yield
(%)
(2R,6S)-166 (2S,6R)-166 (2S,6S)-166 (2R,6R)-166
167 40 32 27 20 21
168 43 4 2 38 55
N
O
Cu
X2
N
O
t-Bu
t-Bu
(S)-157; X = SbF6
(S)-158; X = OTf
O
EtO
O
OEt
OAc
BnO
+
O
OEt
OAc
BnO
O
EtO
O
OEt
OAc
BnO
1. LiAlH4
2. Ac2O/Py
92%
o.y.
1. BH3.SMe
then H2O2
NaOH
2. Ac2O/Py
O
OEt
OAc
BnO
AcO
AcO
(S)-157
60%
96% ee
35% o.y.
159160161
162163
OAc
OMe
O
RO
H
+
O
RO
OMe
H
H
+
O
RO
OMe
H
H
O
RO
OMe
H
H
O
RO
OMe
H
H
+
+
(2R,6S)-166
(2S,6R)-166
(2S,6S)-166
(2R,6R)-166
CH3
H3C
H3C
O
C3F7
O
Eu
3
NN
HH
O
O
Cr+
BF4-
168
165
164
167
Asymmetric
HDA
10 Kbar