Amino acid based diastereoselective synthesis of fucosamines

Article abstract of DOI:10.1016/S0957-4166(02)00376-2

Enantiomerically pure (+)-D-fucosamine 1, (+)-N-methyl-D-fucosamine 2 and (+)-3-O-methyl-D-fucosamine 3 (elsaminose) have been synthesised from known building blocks derived from natural amino acids. Direct and diastereoselective construction of the key intermediate 8 was accomplished by a highly syn,anti-selective aldol reaction between lithiated Schoellkopf's bis-lactim ether 7 and the 1,3-dioxolane-4-carboxaldehyde 5. Elaboration of the common intermediate required optional methylation, selective hydrolysis of the bis-lactim ether in the presence of an isopropylidene ketal, lactonization and partial reduction of the carboxylic group.

Full text of DOI:10.1016/S0957-4166(02)00376-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1535–1549
Amino acid based diastereoselective synthesis of fucosamines
Mar´ıa Ruiz,* Vicente Ojea 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 19 June 2002; accepted 17 July 2002
Abstract—Enantiomerically pure (+)-D-fucosamine 1, (+)-N-methyl-D-fucosamine 2 and (+)-3-O-methyl-D-fucosamine 3
(elsaminose) have been synthesised from known building blocks derived from natural amino acids. Direct and diastereoselective
construction of the key intermediate 8 was accomplished by a highly syn,anti-selective aldol reaction between lithiated
Scho¨llkopf’s bis-lactim ether 7 and the 1,3-dioxolane-4-carboxaldehyde 5. Elaboration of the common intermediate required
optional methylation, selective hydrolysis of the bis-lactim ether in the presence of an isopropylidene ketal, lactonization and
partial reduction of the carboxylic group. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
The most direct synthetic routes to 2-amino sugars
usually involve the stereoselective functionalization of
glycals which, in turn, can be prepared from natural
carbohydrates or by Lewis acid catalyzed diene–alde-
hyde cyclocondensation.10 Stereoselective amination of
carbocycles which are accessible by enzymatic dihy-
droxylation of aromatic compounds has also been used
in the asymmetric synthesis of 2-amino sugars.11
Another commonly employed strategy relies on the
diastereoselective elongation of acyclic homochiral pre-
cursors. Thus, organometallic addition to serine-derived
aldehydes12 or Julia olefination of glyceraldehydes,13
followed by diastereoselective dihydroxylation consti-
tute efficient examples of this methodology. Amino-
homologation of aldehydes by coupling of their
nitrones with metalated thiazoles14 and aldol reaction
of chiral glycine imines15 provided other straightfor-
ward approaches to the stereocontrolled construction
of the 2-amino sugar skeleton.
Amino sugars are an important class of carbohydrates
which are ubiquitous in nature and, in the form of
glycoproteins, oligosaccharides, or glycolipids, play a
fundamental role in various molecular recognition pro-
cesses.1 Furthermore, amino sugars are essential units
in other compounds of biological interest as aminogly-
coside, macrolide, anthracycline and cyclopeptide
antibiotics.2 2-Amino-2-deoxyhexoses are the most
commonly occurring amino sugars and constitute inte-
gral components of bioactive natural products of sig-
nificant
N-acetyl-
pharmacological
importance.3
Thus,
D-galactosamine is a constituent of the human
breast tumor (Globo-H) antigen oligosaccharide,4
whereas N-acetyl-
derivatives of
D
-glucosamine and other N-acyl
D
-galactosamine are present in
tunicamycin, a potent inhibitor of glycosyltransferases.5
Additionally,
galactose) is
D
-fucosamine (2-amino-2,6-dideoxy-D-
a
common component of bacterial
polysaccharides6 and its 3-O-methyl and N-methyl
derivatives are present in elsamicin A7 and
neocarzinostatin8 antibiotics, respectively. These carbo-
hydrate residues seem to be critical in conferring opti-
mum activity to both antibiotics.9
In this area, as part of a project directed towards an
efficient synthesis of bioactive amino polyol deriva-
tives,16 we have recently developed a convergent
approach to 2-amino-2-deoxyhexoses, where the
stereoselective construction of the sugar backbone
relied on an aldol reaction using derivatives of natural
amino acids as chiral auxiliaries and building blocks.
Thus, in this paper we report in full details the applica-
Despite the ubiquity of 2-amino sugars in nature, the
available methods for the preparation of such struc-
tures in enantiomerically pure form are few in number.
tion of such methodology to the synthesis of
D-
fucosamine
1 and its N-methyl and 3-O-methyl
derivatives (2 and 3, respectively).17 Although carbohy-
* Corresponding author. Tel.: +34-981167000; fax: +34-981167065;
e-mail: ruizpr@udc.es
drate-based syntheses of these biologically significant
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00376-2

1536
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
amino sugars have been described,18 to the best of our
knowledge, only N-methyl- -fucosamine has been pre-
adducts 8, 9, and 10 in a combined yield of 69% (see
Scheme 2).
D
pared, previously to this work, by other asymmetric,
amino acid-based, approach.12a In formulating the syn-
thetic plan, we recognized that the three targeted sugars
would originate through reduction of a common poly-
Integration of the pairs of doublets corresponding to
1
the isopropyl groups in the H NMR spectrum of the
mixture of adducts revealed high asymmetric induction
in the formation of both new stereocenters, the ratio
8/9/10 being ca. 50:3.3:<1. Thus, at low temperature,
the aldol addition of 7 to 5 is highly stereoselective, and
the facial discrimination delivered by aldehyde 5, with a
methyl group at the b-position and trans to the car-
bonyl group, is higher than that reported by Scho¨llkopf
for cyclohexylidene glyceraldehyde.25f This trend is in
agreement with the results obtained in the addition of
other nucleophiles to similar 1,3-dioxolane-4-
carboxaldehydes23c and also in double stereodifferenti-
ating additions of lithium enolates to b-alkoxy
aldehydes.30 However, the product distribution of the
aldol reaction between 5 and 7 was found to be
markedly dependent on the reaction temperature. When
the addition was performed at 0°C a different mixture
of aldol adducts was obtained in similar yield, but
containing adducts 8/10/11 in a 7:3:1 ratio.
hydroxylated a-amino acid derived from
D-galactonic
acid. In this way, disconnection at the C(2)ꢀC(3) bond
makes key intermediate 4 accessible via a syn-aldol19
reaction between a chiral glycine equivalent and a
C4-building block with the required configuration at
positions 4 and 5 (see Scheme 1).20 As the addition of
organometallic reagents to 1,3-dioxolane-4-carboxalde-
hyde systems generally proceed with anti selectivity,21
the aldehyde 5, readily available from
L
-threonine,22
was sought as an appropriate precursor.23 On the other
hand, of the various chiral glycine equivalents,24 we
found Scho¨llkopf’s bis-lactim ethers (like 6) to be very
attractive, due to the high syn-selectivity shown by
these reagents in aldol-type reactions.25 We anticipated
a highly selective formation of the desired 2,3-syn-3,4-
anti configuration in the key step of the synthesis, as the
hydroxyaldehyde 5 and the azaenolate derived from 6
would form a matched pair,26 and their coupling in the
aldol reaction should proceed with double asymmetric
induction.
Separation of the major components of the mixtures
could be achieved by flash chromatography to provide
products of high purity, with diastereomeric excess
higher than 98%. Evidence supporting the relative
configuration on adducts was obtained by NMR analy-
ses. For compounds 8 and 9, the H-6 resonance appears
2. Results and discussion
5
near to 3.93 ppm, as a triplet with J(H3,H6) close to
2.1. Azaenolate aldol addition to dioxolane-
carboxaldehyde
3.5 Hz, which is general of the trans relationship of
substituents at the pyrazine ring. Conversely, the NMR
spectrum of adduct 10 shows the absorption corre-
sponding to H-6 at similar l, as a double doublet with
According to the literature,22
L-threonine was converted
5
into (4S)-trans-2,2,5-trimethyl-1,3-dioxolane-4-carbox-
aldehyde (−)-5, while (3S)-2,5-diethoxy-3-isopropyl-3,6-
dihydropyrazine, (+)-6 was prepared from glycine and
valine.27,28 A high degree of stereoselection in the aldol
addition was essential for a successful execution of our
strategy. Nevertheless, taking into account that sub-
strate 5 and reagent 6 should form a matched pair, the
reactivity of the more accessible but usually less selec-
tive lithium salt of the Scho¨llkopf’s bis-lactim ether was
examined.16,25 Thus, slow addition of freshly distilled29
5 over a solution of 1.2 equiv. of 7 at −78°C in THF
led, after quenching, aqueous workup, and removal of
side products by flash chromatography, to a mixture of
a J(H3,H6) of 6.0 Hz, which is typical of a cis rela-
tionship at the bis-lactim ring.31 The assignment of the
relative configurations for adduct 8 (3,1%-syn-1%,2%-anti ),
for adduct 9 (3,1%-anti-1%,2%-syn), and for adduct 10
(3,1%-anti-1%,2%-anti ), was made on the basis of X-ray
1
structure determination or analysis by H NOE differ-
ence spectroscopy of their cyclic derivatives, as will be
described below. Absolute configurations follow from
the use of aldehyde 5, as there is ample precedent.22,23
6
EtO
(-)-5, THF, 1 h
1.
2.
N
NH Cl aq
4
EtO
Li
3
N
N
OEt
OH
1´
N
2´
OEt
(69%)
O
O
O
OH
OH NH2
2
HO
7
HO
NHR1
CO2H
8
3
OR2
OH
syn
4
1, R1 = R2 = H
EtO
EtO
EtO
2, R1 = Me, R2 = H
3, R1 = H, R2 = Me
N
N
N
OEt
N
N
N
OEt
OEt
OH
10
OEt
OH
11
O
N
O
5
O
O
O
O
O
O
N
OH
4
O
OEt
9
(-)-5
(+)-6
Scheme 2. Addition of lithiated bis-lactim ether 7 to aldehyde
(−)-5.
Scheme 1. Retrosynthetic approach to fucosamines.

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1537
OEt
Furthermore, stereochemical assignment for major
HCl 0.25 N
EtOH
NHR
CO2Et
O
adduct 8 was unambiguously confirmed through its
conversion into natural amino sugars of known
configuration (vide infra).
N
O
O
O
N
(80%)
OMe
OR OEt
Na2CO3
CbzCl
(99%)
NaH, MeI
(95%)
13: R = H
14: R = Cbz
The stereochemical course of the addition of azaenolate
7 to aldehyde 5 can be rationalised by extending the
proposal of Roush,32 which combines the Zimmerman–
Traxler transition state model33 and the non-Anh
model34 for 1,2-asymmetric induction. In this manner,
an initial lithium–carbonyl coordination to form an
intermediate complex should be followed by the rate-
determining reorganisation through competitive six-
membered transition states. The chair-like transition
structure pro-8, with lk topology arising from the inter-
action between the Re faces of the azaenolate and the
carbonyl moieties, would be favoured with respect to
other diastereomeric transition structures due to the
minimisation of the steric interactions between the iso-
propyl and ethoxy groups of the bis-lactim and the
equatorial aldehyde substituents (see Fig. 1). In addi-
tion, an anticlinal relationship between the a-alkoxy
and carbonyl groups, determining a non-Anh confor-
mation for the aldehyde moiety, could reduce the unfa-
vourable g+g− double gauche interaction with one of the
bis-lactim nitrogen atoms. In agreement with this quali-
tative transition state model, ab initio molecular orbital
calculations (at the B3LYP/6-31+G*//HF/6-31G* level)
showed a chair-like, non-Anh conformation as the most
stable transition structure, being preferred by more
than 2.1 kcal/mol to the competitive ones.35
8: R = H
12: R = Me
OR
O
TFA, H2O
(88%)
O
14
MeO
NHCbz
DMIPSCl
imidazole
(99%)
15: R = H
16: R = DMIPS
Scheme 3. Synthesis of elsaminose: transformation of adduct
8 into the intermediate lactone 16.
the isopropylidene ketal required some experimenta-
tion: treatment of a solution of 12 in THF with TFA at
room temperature led to an intractable mixture, while
the reaction with aqueous 0.25N HCl or Dowex
50WX8 (H+ form) under the same conditions resulted
in a complete hydrolysis to the corresponding galac-
tonic acid, which was isolated in low yield. Eventually,
a clean conversion of 12 to the desired amino ester was
accomplished employing 0.25N HCl in EtOH at room
temperature, and thus, amino ester 13 could be isolated
in good yield after removal of the chiral auxiliary by
flash chromatography. In order to avoid the manipula-
tion of compounds with the a-amino aldehyde function,
of well documented configurational instability,36 we
decided to postpone the partial reduction of the car-
boxyl group until the lactonization of 13 was achieved.
Thus, quantitative protection of the amino group of 13
as a benzylcarbamate under standard conditions was
followed by the hydrolysis of the isopropylidene ketal
(of 14) in acidic media, which led to the simultaneous
formation of the desired lactone 15 in high yield. Treat-
ment of lactone 15 with isopropyldimethylsilyl chloride
(DMIPSCl) in the presence of imidazole then afforded
the corresponding silyl ether 16 in excellent yield.
2.2. Synthesis of 2-amino-2,6-dideoxy-3-O-methyl-D-
galactose (elsaminose, 3)
Conversion of adduct 8 into 2-amino-2,6-dideoxy-3-O-
methyl- -galactose 3 required methylation of the free
D
hydroxyl group, removal of the chiral auxiliary, and
partial reduction of the carboxylic group. Attempts to
obtain the methylated adduct 12 (see Scheme 3) by
quenching the aldol reaction with methyl iodide were
unsuccessful. Thus, after 24 h at room temperature and
aqueous workup, only traces of 12 were isolated, along
with the adduct 8 and the 3-methyl derivative of the
Scho¨llkopf’s reagent that was present in excess during
the aldol addition. Methylation was finally accom-
plished in high yield by treatment of 8 with sodium
hydride and methyl iodide. Selective hydrolysis of the
pyrazino moiety of methyl ether 12 in the presence of
In order to allow the stereochemical assignment of the
minor adducts, compounds 9 and 10 were also trans-
formed into the cyclic derivatives 20 and 24 (see
Scheme 4). As was previously observed for other aldol
adducts derived from Scho¨llkopf’s reagents,25c the
hydrolysis of the pyrazino moiety of compounds 9 and
10 required the protection of the hydroxyl group to
proceed with acceptable yields. Thus, after benzylation
of 9 and 10, the selective hydrolysis of the intermediates
17 and 21 with 0.25N HCl in EtOH led to the corre-
sponding amino esters 18 and 22. Subsequent forma-
tion of the benzylcarbamates 19 and 23 was followed
by the TFA-catalysed lactonization, to afford com-
pounds 20 and 24 in good yields. The IR spectra of
compounds 15, 16, 20, and 24 included bands at 1775,
1785, 1770, and 1760 cm−1, respectively, clearly indicat-
ing the formation of g-lactones in these cyclizations.
THF
H
THF
H
Li
N
O
O
EtO
H
O
H
H
N
g+g−
OEt
pro-8
Figure 1. Proposed transition state model for the addition of
7 to 5.

1538
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
OEt
OEt
Partial reduction of the lactone with the required configu-
ration and a final deprotection step were necessary to
complete the synthesis of elsaminose. Although no reac-
tion was observed when lactone 15 was treated with 2.5
equiv. of DIBALH in THF or CH2Cl2 at low temperature,
the use of a 2:1 mixture of toluene/THF as solvent gave
rise to lactols 25+27, along with unreacted starting
material and alcohol 28, which were isolated in 43, 28 and
7% yields, respectively (see Scheme 5). Attempts to
improve the conversion of 15 to the lactols using a larger
excess of DIBALH resulted in increased over-reduction
to the alcohol 28. Although hydrogenation of the mixture
of pyranose and furanose anomers 25+27 afforded
elsaminose with acceptable efficiency (16% yield for the
seven steps), better yields were obtained by performing
the reduction of the fully protected lactone. Thus, when
16 was treated with 2.0 equiv. of DIBALH in toluene/
THF (2:1) at low temperature, a 65% conversion to a 2:1
mixture of furanoses 26 was achieved. As the undesirable
reduction to the alcohol was not observed in this case,
the yield of 26 could be increased to 85% by subjecting
recovered starting material to these reduction conditions.
Finally, deprotection of 26 by catalytic hydrogenation in
acidic media allowed, after chromatography on acidic
ion-exchange resin, the isolation of the free amino sugar
in a global yield of 31% over eight steps from the starting
building blocks. Treatment of 3 with HCl and purification
by reversed-phase flash chromatography afforded
elsaminose as its hydrochloride salt 29 in almost quanti-
tative yield. Analysis of the 1H NMR spectrum (500 MHz,
D2O) of 29 showed the presence of a 2:1 mixture of a-
and b-pyranoses, with vicinal coupling constants charac-
teristic for the galacto configuration. The specific rotation
value determined for 29 was in good agreement with that
reported in the literature: [h]2D2=+92.1 (c 0.6, H2O), (lit.
[h]D=+85.3 (c 1.1, H2O)).18d
N
O
N
O
O
O
N
N
OR OEt
OR OEt
NaH, BnBr
(75%)
NaH, BnBr
(77%)
9: R = H
17: R = Bn
10: R = H
21: R = Bn
HCl 0.25 N
EtOH
(67%)
(81%)
NHR
CO2Et
NHR
CO2Et
O
O
O
O
OBn
OBn
Na2CO3
CbzCl
(82%)
Na2CO3
18: R = H
19: R = Cbz
22: R = H
23: R = Cbz
CbzCl
(82%)
(86%)
TFA, H2O
(81%)
OH
OH
O
O
O
O
BnO
NHCbz
BnO
NHCbz
20
24
Scheme 4. Transformation of adducts 9 and 10 into lactones
20 and 24.
1
In contrast to 15, the H NMR spectra of lactones 16,
20and24showedapatternofsignalssuitableforthestudy
of their conformation and relative stereochemistry by 1H
NOE difference spectroscopy. After corroborating the 1H
NMR assignments by COSY experiments, the analysis of
the sets of observed NOEs confirmed the formation of
g-lactones and allowed assignment of the relative configu-
ration of the stereogenic centers formed in the aldol
reaction (see Fig. 2).37–43 Thus, the stereochemistry of
lactone 16, derived from the major aldol adduct 8, was
determined as 3,4-trans-4,5-trans, while lactones 20 and
24 showed a3,4-cis-4,5-cis- and3,4-cis-4,5-trans-configu-
ration, respectively.
DIBALH
-78 ºC
15 or 16
OR
O
OH
O
OH
HO
MeO
OH
HO
MeO
OH
MeO
NHCbz
NHCbz
NHCbz
25: R = H
26: R = i-PrMe2Si
28
27
H2, Pd/C
HCl 0.25 N
O
HO
MeO
OH
25+27 or 26
(85 or 87%)
NH2. X
3: X = -
29: X = HCl
Scheme5. Transformationoflactones15and16intoelsaminose
3.
2.3. Synthesis of
D
-fucosamine and N-methyl-D-
fucosamine 1 and 2
Figure 2. PM3-optimized minimum energy conformations
locatedformodelsofg-lactones16, 20and24(MMXforcefield),
showing characteristic NOEs.
Conversion of key intermediate 8 to fucosamines 1 and
2 required the removal of the chiral auxiliary and partial
reduction of the carboxylate, in addition to an

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1539
optional and selective monomethylation of the amino
group. After the protection of the hydroxyl group at
position 1%, the selective hydrolysis of the pyrazino
moiety in the presence of the isopropylidene ketal
should give rise to intermediates capable of undergoing
the N-monomethylation. Using the conditions previ-
ously developed for the preparation of lactones 20 and
24, the benzylation of 8, followed by selective hydroly-
sis of the pyrazino moiety of 30, gave the amino ester
31 in high yield (see Scheme 6). After protection of the
amino group of 31 as the benzylcarbamate, cyclization
in acidic media led to lactone 33, which was isolated in
high yield as a colorless solid. Upon crystallisation on a
ligroin/ether mixture, lactone 33 yielded crystals
amenable to X-ray structure determination, allowing
the confirmation of its 2,3-trans-3,4-trans-stereochem-
istry. The fully protected lactone 34 was obtained by
O-silylation of 33.
ate a benzhydryl secondary amine and subsequent
reductive methylation47 enabled the isolation of the
monomethylamine 37. Treatment of this compound in
aqueous acidic media resulted in rapid hydrolysis of the
isopropylidene ketal, but proceeded slowly to the lac-
tone 38. Complete lactonization of the corresponding
g,d-dihydroxy ester, with the bulky N-methyl-N-
diphenylmethylamino group at the a-position, required
prolonged reaction times. Silylation of the secondary
hydroxyl group of compound 38 afforded the fully
protected N-methylated lactone 39 in excellent yield.
OR
O
NR1R2
CO2Et
TFA, H2O
(81%)
O
O
O
Ph
Ph
BnO
N
OBn
Ph2CN
p-TsOH
(81%)
imidazole
DMIPSCl
(94%)
31: R1 = R2 = H
36: R1+ R2 = CPh2
38: R = H
39: R = DMIPS
CH2O
EtO
37: R1 = Me, R2 = CHPh2
HCl 0.25 N
N
NaBH3CN
(82%)
NR1R2
O
EtOH
N
O
OEt
OR
CO2Et
Scheme 7. Synthesis of N-methyl-D-fucosamine: N-mono-
methylation of intermediate 31 and lactonization.
(88%)
O
O
OBn
31: R1 = R2 = H
32: R1 = H, R2 = Cbz
Na2CO3
CbzCl
(98%)
NaH
BnBr
(85%)
Completion of the synthesis of fucosamines 1 and 2
followed the same reaction sequence as described for
elsaminose. Partial reduction of lactones 34 and 39 led
to the mixtures of furanoses 40 and 41, respectively,
within combined yields higher than 80% (see Scheme 8).
Finally, deprotection of lactols by catalytic hydrogena-
tion in acidic media allowed, after chromatography on
acidic ion-exchange resin, the isolation of the free
amino sugars 1 and 2, with 28 and 19% overall yields,
8: R = H
30: R = Bn
TFA, H2O
OR
(85%)
DMIPSO
O
O
O
O
BnO
NHCbz
NHCbz
35
DMIPSCl
imidazole
(95%)
33: R = H (X-ray)
34: R = DMIPS
respectively. The hydrochloride salt of
D-fucosamine
was prepared to make comparisons with the reported
physical and spectral data. Optical rotations for both
amino sugars were in good agreement with those
Scheme 6. Synthesis of
D-fucosamine: transformation of
reported:
D
-fucosamine hydrochloride: [h]2D3=+76.1
adduct 8 into the intermediate lactone 34.
(final, c 0.6, H2O), (lit [h]2D5=+81.0 (final, c 0.2,
H2O))18c; N-methyl- -fucosamine: [h]2D3=+69.0 (final, c
D
For the synthesis of N-methyl-D-fucosamine, we stud-
0.1, H2O), (lit [h]2D5=+73.1 (final, c 0.1, H2O)).8b 1H
NMR spectral data obtained for both fucosamines were
also in accordance with the literature values.6,12a
ied the direct methylation of carbamates 32 and 34.
Attempts to achieve the N-methylation of 32 under the
conditions described by Cheung and Benoiton44 for the
preparation of N-methylated a-amino acids (NaH,
MeI, THF, 5°C, 15 h) resulted in recovered starting
material, while higher reaction temperatures and pro-
longed reaction times led only to decomposition prod-
ucts. Treatment of lactone 34 with sodium hydride and
methyl iodide (THF, −15°C, 15 min) led to the exclu-
sive formation of the butenolide 35 by syn-elimination45
of the 4-benzyloxy group. These disappointing results
led us to examine a slightly longer, but ultimately
practical route for N-monomethylation of the interme-
diate 31, based on the reduction of its O’Donnell’s
Schiff base followed by reductive methylation of the
corresponding secondary amine (Scheme 7).12a Thus,
the imino ester 36 was obtained in good yield by
treatment of amino ester 31 with diphenylketimine and
anhydrous p-TsOH acid as catalyst.46 Reduction of the
Schiff base under anhydrous acidic conditions to gener-
H2, Pd/C
HCl 0.25 N
DIBALH
-78 ºC
DMIPSO
O
OH
1 or 2
34 or 39
(87%)
(86 or 91%)
BnO
NR1R2
40: R1 = H, R2 = Cbz
41: R1 = Me, R2 = CHPh2
Scheme 8. Synthesis of
D-fucosamine and N-methyl-D-
fucosamine from lactones 34 and 39.
3. Conclusion
We have developed a practical, chemically efficient, and
diastereoselective synthesis of -fucosamine 1 and its
D

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M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
N-methyl and 3-O-methyl derivatives (2 and 3, respec-
tively), three amino sugars not readily available from
natural sources. Direct and diastereoselective construc-
tion of the common key intermediate 8, with the com-
plete backbone and the proper stereochemical
configuration, was accomplished by a syn,anti-aldol
type reaction between Scho¨llkopf’s bis-lactim ether 6
and the 1,3-dioxolane-4-carboxaldehyde 5, both derived
from natural amino acids. One of the attractive features
of the present approach to 2-deoxy-2-aminosugars lay
in its inherent flexibility since a variety of 2-aminopoly-
ols could be available by simply altering the stereo-
chemistry or the pattern of substitution in the starting
aldehyde. Additionally, the syntheses require rather
inexpensive reagents, require straightforward reaction
conditions, and the overall yields for the targeted sug-
ars were high and compare well or favourably with
those in the literature.
the aldehyde (−)-5 (3.3 g, 22.9 mmol) in THF (25 mL)
was added dropwise over a period of 40 min. After
stirring at −78°C for 1 h, the reaction was quenched
with saturated aqueous NH4Cl. The crude reaction
mixture was warmed to room temperature, and the
solvent was removed in vacuo. The resulting material
was diluted with water and extracted with EtOAc. The
combined organic layers were dried (Na2SO4) and evap-
orated, and the residue was purified by gradient flash
chromatography (silica gel, EtOAc/hexanes, 1:9–1:3) to
yield pure 8 (5.2 g, 64%) and pure 9 (348 mg, 4%).
When the addition was carried out at 0°C, starting
from 1 g of 5, pure 8 (632 mg, 26%) and pure 10 (472
mg, 19%) along with a 3:1 mixture of adducts 8/11 (624
mg, 25%) were obtained after column chromatography.
4.2.1. (3R,6S,1%R,2%S,3%R)-Adduct 8. Colorless oil: Rf
0.48 (silica gel, EtOAc/hexanes, 1:2.3); [h]2D2=+14.5 (c
1
1.5, CH2Cl2); H NMR (CDCl3) l 0.76 (d, J=6.9 Hz,
3H), 1.02 (d, J=6.9 Hz, 3H), 1.29 (t, J=6.9 Hz, 3H),
1.30 (t, J=6.9 Hz, 3H), 1.39 (d, J=5.9 Hz, 3H), 1.41 (s,
3H), 1.44 (s, 3H), 1.67 (d, J=9.3 Hz, 1H), 2.20 (dsp,
J=6.9, 3.7 Hz, 1H), 3.77 (dd, J=8.6, 7.2 Hz, 1H), 3.97
(t, J=3.7 Hz, 1H), 4.00–4.30 (m, 7H); 13C NMR
(CDCl3) l 14.2, 17.2, 19.1, 19.8, 27.0, 27.6 (CH3), 32.5,
56.4 (CH), 61.0, 61.1 (CH2), 61.3, 72.9, 77.0, 81.1 (CH),
108.4 (C), 161.3, 166.6 (CꢁN); IR (film) w 3460, 2995,
1690, 1380, 1300, 1230, 1030 cm−1; FABMS m/z 357
(MH+, 97). Anal. calcd for C18H32N2O5: C, 60.65; H,
9.05; N, 7.86. Found: C, 60.56; H, 9.09; N, 7.65%.
4. Experimental
4.1. General methods
All moisture-sensitive reactions were performed under
an argon atmosphere using oven-dried glassware.
Reagents and solvents were purchased and used with-
out further purification unless otherwise stated. THF
and toluene were distilled from sodium/benzophenone.
CH2Cl2 and CH3CN were distilled from calcium
hydride. Reactions were monitored by thin-layer chro-
matography carried out on 0.25 mm E. Merck silica gel
plates (60F-254) using UV light as visualising 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 60 and RP-18
(both 230–400 mesh) were used for liquid chromatogra-
phy separations and Dowex 50WX8 resin (100–200
mesh) for ion-exchange chromatography. Melting
points are uncorrected. IR spectra were obtained as
liquid film or as KBr pellets. Unless otherwise indi-
4.2.2. (3R,6S,1%S,2%S,3%R)-Adduct 9. Colorless oil: Rf
0.40 (silica gel, EtOAc/hexanes, 1:4); [h]2D2=+8.9 (c 1.0,
1
CH2Cl2); H NMR (CDCl3) l 0.68 (d, J=6.9 Hz, 3H),
1.02 (d, J=6.9 Hz, 3H), 1.20–1.35 (m, 15H), 2.26 (dsp,
J=6.9, 3.3 Hz, 1H), 3.27 (d, J=10.0 Hz, 1H), 3.42 (dd,
J=8.5, 1.5 Hz, 1H), 3.85 (dd, J=4.9, 1.5 Hz, 1H), 3.88
(t, J=3.3 Hz, Hz, 1H), 4.00–4.22 (m, 6H); 13C NMR
(CDCl3) l 14.2, 16.5, 17.0, 19.0, 26.5, 27.4 (CH3), 31.5,
58.7 (CH), 60.6, 60.7 (CH2), 60.9, 69.0, 73.4, 81.6 (CH),
108.4 (C), 160.5, 163.8 (CꢁN); IR (film) w 2977, 1695,
1237 cm−1; FABMS m/z 357 (MH+, 100). Anal. calcd
for C18H32N2O5: C, 60.65; H, 9.05; N, 7.86. Found: C,
60.32; H, 9.27; N, 7.80%.
1
cated, H NMR spectra were recorded at 200 MHz and
13C NMR spectra were recorded at 50 MHz with
broad-band 1H decoupling at 25°C. Recognition of
methyl, methylene, methine, and quaternary carbon
nuclei in 13C spectra rests on the J-modulated spin-echo
4.2.3. (3S,6S,1%R,2%S,3%R)-Adduct 10. Colorless oil: Rf
0.36 (silica gel, EtOAc/hexanes, 1:4); [h]2D2=+62.4 (c
sequence. H or 13C assignments were confirmed with
1
1
the aid of homonuclear or heteronuclear two-dimen-
sional experiments. FABMS spectra were recorded
using thioglycerol as a matrix. High-resolution FAB
mass spectra were obtained using 3-nitrobenzyl alcohol
as a matrix. Elemental analyses were performed at
Servicios Xerais de Apoio a´ Investigacio´n of Universi-
dade da Corun˜a.
1.0, CH2Cl2); H NMR (CDCl3) l 0.74 (d, J=6.8 Hz,
3H), 1.07 (d, J=6.8 Hz, 3H), 1.20–1.40 (m, 15H), 2.41
(dsp, J=6.8, 3.7 Hz, 1H), 2.95 (brd, 1H), 3.55 (t, J=7.7
Hz, 1H), 3.90 (dd, J=6.0, 3.7 Hz, 1H), 3.95–4.25 (m,
7H); 13C NMR (CDCl3) l 14.2, 17.1, 19.4, 19.5, 26.7,
27.2 (CH3), 31.1, 57.9, 60.4 (CH), 60.5, 60.7 (CH2),
73.7, 75.8, 80.8 (CH), 108.2 (C), 159.6, 164.0 (CꢁN); IR
(film) w 3500, 2995, 1690, 1370, 1230 cm−1; FABMS m/z
357 (MH+, 100). Anal. calcd for C18H32N2O5: C, 60.65;
H, 9.05; N, 7.86. Found: C, 60.60; H, 9.27; N, 7.88%.
4.2. 2,5-Diethoxy-3,6-dihydro-3-(1-hydroxy-2,3-iso-
propylidenedioxybutyl)-6-isopropylpyrazines, 8, 9 and
10
4.3. General procedure for the protection of the
hydroxyl group of adduct 8
A solution of n-BuLi (2.5 M in hexane, 11.3 mL, 28.3
mmol) was added to a stirred solution of the bis-lactim
ether (+)-6 (6 g, 28.3 mmol) in THF (160 mL) at −78°C
and the mixture was stirred for 1 h. Then, a solution of
A solution of adduct 8 (2.2 g, 6.18 mmol) in THF (30
mL) was added to a stirred suspension of NaH (210

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1541
mg, 80% dispersion in mineral oil, 7.0 mmol) in THF
(60 mL) at 0°C. After 30 min, MeI (1.9 mL, 30.5 mmol)
was added, and the resulting solution was stirred at
room temperature for a further 12 h. The reaction
mixture was cooled to 0°C and quenched by the addi-
tion of CH3OH (2 mL). The solvents were removed in
vacuo and the resulting material was diluted with water
and extracted with EtOAc. The combined organic lay-
ers were dried (Na2SO4) and evaporated and the residue
was purified by gradient flash chromatography (silica
gel, EtOAc/hexane, 1:18–1:9) to yield 12 (2.17 g, 95%)
as a colorless oil.
mmol), according to the general procedure, but n-
Bu4NI (0.1 equiv.) and BnBr (2.0 equiv.) were added
instead of MeI. Purification by gradient flash chro-
matography (silica gel, EtOAc/hexane, 1:19–1:12)
afforded 21 (386 mg, 77%) as a colorless oil: Rf 0.34
(silica gel, EtOAc/hexanes, 1:9); [h]2D3=+26.1 (c 1.0,
1
CH2Cl2); H NMR (CDCl3) l 0.75 (d, J=6.7 Hz, 3H),
1.05 (d, J=6.7 Hz, 3H), 1.20–1.35 (m, 15H), 2.25
(dsp, J=6.7, 4.3 Hz, 1H), 3.81 (dd, J=6.0, 4.3 Hz,
1H), 3.85–4.07 (m, 3H), 4.07–4.30 (m, 4H), 4.31 (dd,
J=6.0, 3.0 Hz, 1H), 4.57 (d, J=11.7 Hz, 1H), 4.73 (d,
J=11.7 Hz, 1H), 7.28–7.37 (m, 5H); 13C NMR
(CDCl3) l 14.2, 14.3, 17.8, 19.6, 19.8, 26.7, 27.1
(CH3), 31.6, 56.7, 60.4 (CH), 60.5, 60.6, 73.0 (CH2),
76.1, 80.6, 81.9 (CH), 107.9 (C), 127.6, 128.0, 128.2
(aromatic CH), 138.0 (aromatic C), 160.4, 163.6
(CꢁN); IR (film) w 2980, 1700, 1360, 1250 cm−1;
FABMS m/z 447 (MH+, 100). Anal. calcd for
C25H38N2O5: C, 67.24; H, 8.58; N, 6.27. Found: C,
67.45; H, 8.27; N, 6.09%.
4.3.1. (3R,6S,1%R,2%S,3%R)-2,5-Diethoxy-3,6-dihydro-3-
(2,3-isopropylidenedioxy-1-methoxybutyl)-6-isopropyl-
pyrazine, 12. Following the general procedure, adduct 8
(2.2 g, 6.18 mmol) gave 12 (2.17 g, 95%) as a colorless
oil: Rf 0.66 (silica gel, EtOAc/hexanes, 1:9); [h]2D2=−
41.2 (c 2.7, CH2Cl2); 1H NMR (CDCl3) l 0.68 (d,
J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 1.26 (t, J=7.1
Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.37 (d, J=5.9 Hz,
3H), 1.42 (s, 3H), 1.43 (s, 3H), 2.30 (dsp, J=6.8, 3.4
Hz, 1H), 3.34 (s, 3H), 3.78 (dd, J=8.1, 1.9 Hz, 1H),
3.92 (dd, J=8.2, 8.1 Hz, 1H), 3.96 (dd, J=3.4, 3.5 Hz,
1H), 4.08–4.32 (m, 6H); 13C NMR (CDCl3) l 14.2,
14.4, 16.5, 19.1, 19.6, 27.1, 27.5 (CH3), 31.5 (CH), 56.3,
60.2, 60.4 (CH, OCH3), 60.6, 60.7 (CH2), 76.1, 80.4,
83.7 (CH), 108.2 (C), 161.4, 163.8 (CꢁN); IR (film) w
2950, 1700, 1380, 1370, 1230, 1100, 1040 cm−1; FABMS
m/z 371 (MH+, 100). Anal. calcd for C19H34N2O5: C,
61.60; H, 9.25; N, 7.56. Found: C, 61.83; H, 9.21; N,
7.56%.
4.3.4. (3R,6S,1%R,2%S,3%R)-3-(1-Benzyloxy-2,3-isopropyl-
idenedioxybutyl)-2,5-diethoxy-3,6-dihydro-6-isopropyl-
pyrazine, 30. Prepared from adduct 8 (1.6 g, 4.49
mmol), according to the general procedure, but n-
Bu4NI (0.1 equiv.) and BnBr (2.0 equiv.) were added
instead of MeI. The crude material was purified by
flash chromatography (silica gel, EtOAc/hexanes, 1:16)
to give 30 (1.70 g, 85%) as a colorless oil: Rf 0.62 (silica
gel, EtOAc/hexanes, 1:9); [h]2D2=−65.2 (c 1.5, CH2Cl2);
1H NMR (CDCl3) l 0.69 (d, J=6.8 Hz, 3H), 1.06 (d,
J=6.8 Hz, 3H), 1.23–1.35 (m, 9H), 1.41 (s, 3H), 1.44 (s,
3H), 2.32 (dsp, J=6.8, 3.6 Hz, 1H), 3.91 (t, J=3.6 Hz,
1H), 3.98–4.41 (m, 8H), 4.44 (d, J=11.0 Hz, 1H), 4.51
(d, J=11.0 Hz, 1H), 7.20–7.40 (m, 5H); 13C NMR
(CDCl3) l 14.2, 14.4, 16.4, 19.2, 19.9, 27.1, 27.5 (CH3),
31.3, 56.5, 60.3 (CH), 60.6, 73.7 (CH2), 75.9, 80.6, 81.2,
(CH), 108.2 (C), 127.7, 128.0, 128.2 (aromatic CH),
138.0 (aromatic C), 161.4, 163.6 (CꢁN); IR (film) w
2980, 2960, 1690, 1370, 1240 cm−1; FABMS m/z 447
(MH+, 29), 169 (100). Anal. calcd for C25H38N2O5: C,
67.24; H, 8.58; N, 6.27. Found: C, 67.47; H, 8.44; N,
6.18%.
4.3.2. (3R,6S,1%S,2%S,3%R)-3-(1-Benzyloxy-2,3-isopropylid-
enedioxybutyl) - 2,5 - diethoxy - 3,6 - dihydro - 6 - isopropyl-
pyrazine, 17. Prepared from adduct 9 (300 mg, 0.84
mmol), according to the general procedure, but n-
Bu4NI (0.1 equiv.) and BnBr (2.0 equiv.) were added
instead of MeI. Purification by gradient flash chro-
matography (silica gel, EtOAc/hexanes, 1:19–1:12)
afforded 17 (282 mg, 75%) as a colorless oil: Rf 0.60
(silica gel, EtOAc/hexanes, 1:4); [h]2D2=−13.3 (c 0.7,
1
CH2Cl2); H NMR (CDCl3) l 0.65 (d, J=6.9 Hz, 3H),
1.03 (d, J=6.9 Hz, 3H), 1.25 (t, J=6.9 Hz, 3H), 1.27 (t,
J=7.1 Hz, 3H), 1.36 (d, J=5.6 Hz, 3H), 1.42 (s, 3H),
1.43 (s, 3H), 2.40 (dsp, J=6.9, 3.3 Hz, 1H), 3.69 (dd,
J=7.7, 2.0 Hz, 1H), 3.82 (t, J=3.3 Hz, 1H), 3.90–4.25
(m, 7H), 4.60 (d, J=11.7 Hz, 1H), 4.80 (d, J=11.7 Hz,
1H), 7.20–7.50 (m, 5H); 13C NMR (CDCl3) l 14.2,
16.4, 19.1, 19.5, 27.1, 27.4 (CH3), 30.7, 57.4, 60.2 (CH),
60.7 (CH2), 73.9 (CH), 74.4 (CH2), 83.5, 83.8 (CH),
108.0 (C), 127.3, 128.0, 128.1 (aromatic CH), 138.06
(aromatic C), 159.7, 165.0 (CꢁN); IR (film) w 2948,
1734, 1672, 1378, 1332, 1095 cm−1; FABMS m/z 447
(MH+, 100). Anal. calcd for C25H38N2O5: C, 67.24; H,
8.58; N, 6.27. Found: C, 67.27; H, 8.27; N, 6.02%.
4.4. General procedure for the hydrolysis of the bis-
lactim ether
A solution of compound 12 (1.76 g, 4.75 mmol) in
EtOH (60 mL) and 0.25N HCl (38 mL) was stirred at
room temperature for 5 h. Then the solution was
diluted with water (40 mL) and concentrated to half its
initial volume. The aqueous solution was made basic
(pHꢀ10) by the addition of NaHCO3 followed by
concentrated ammonia. The aqueous layer was
extracted with CH2Cl2 (7×50 mL) and the combined
organic layers were dried (Na2SO4) and evaporated.
The crude mixture of ethyl valinate and amino ester 13
was purified by flash chromatography (silica gel,
EtOAc) to yield amino ester 13 (995 mg, 80%) as a
colorless oil.
4.3.3. (3S,6S,1%R,2%S,3%R)-3-(1-Benzyloxy-2,3-isopropylid-
enedioxybutyl) - 2,5 - diethoxy - 3,6 - dihydro - 6 - isopropyl-
pyrazine, 21. Prepared from adduct 10 (400 mg, 1.12

1542
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
4.4.1. Ethyl (2R,3R,4S,5R)-2-amino-4,5-isopropylidene-
dioxy-3-methoxyhexanoate (13). Following the general
procedure, compound 12 (1.76 g, 4.75 mmol) gave 13
(995 mg, 80%) as a colorless oil: Rf 0.56 (silica gel,
EtOAc); [h]2D2=−15.0 (c 1.9, CH2Cl2); 1H NMR
(CDCl3) l 1.32 (t, J=6.8 Hz, 3H), 1.37 (d, J=6.0 Hz,
3H), 1.40 (s, 3H), 1.42 (s, 3H), 1.63 (brs, 2H), 3.36 (s,
3H, OCH3), 3.7–3.8 (m, 3H), 4.1 (quintuplet, J=6.0
Hz, 1H), 4.24 (q, J=6.8 Hz, 2H); 13C NMR (CDCl3) l
14.0, 19.2, 27.1, 27.5 (CH3), 54.7 (CH), 59.4 (OCH3),
61.1 (CH2), 76.2, 80.2, 83.6 (CH), 108.3 (C), 174.6
(CꢁO); IR (film) w 3000, 1740, 1090 cm−1; FABMS m/z
262 (MH+, 100). Anal. calcd for C12H23NO5: C, 55.16;
H, 8.87; N, 5.36. Found: C, 54.91; H, 8.57; N, 5.61%.
2H), 4.22 (dq, J=7.0, 2.0 Hz, 2H), 4.46 (d, J=11.3 Hz,
1H), 4.55 (d, J=11.3 Hz, 1H), 7.20–7.40 (m, 5H); 13C
NMR (CDCl3) l 14.2, 19.6, 27.1, 27.5 (CH3), 55.3
(CH), 61.2, 73.6 (CH2), 76.4, 80.6, 81.6 (CH), 108.4 (C),
127.9, 128.0, 128.4 (aromatic CH), 137.4 (aromatic C),
175.1 (CꢁO); IR (film) w 3392, 3337, 2984, 2934, 1736,
1378, 1216 cm−1; FABMS m/z 338 (MH+, 100). Anal.
calcd for C18H27NO5: C, 64.07; H, 8.07; N, 4.15.
Found: C, 64.28; H, 7.96; N, 4.14%.
4.5. General procedure for the protection of the amino
group as N-benzylcarbamate
A solution of amino ester 13 (800 mg, 3.06 mmol),
Na2CO3 (324 mg, 3.06 mmol) and NaHCO3 (261 mg,
3.11 mmol) in dioxane (32 mL) and H2O (32 mL) at
0°C was treated with CbzCl (0.5 mL, 3.49 mmol). The
mixture was stirred at room temperature for 1 h, and
then was concentrated to half its initial volume and
extracted with Et2O. The combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The crude
material was purified by flash chromatography (silica
gel, EtOAc/hexanes, 1:6–1:3) to give 14 (1.20 g, 99%) as
a colorless oil.
4.4.2. Ethyl (2R,3S,4S,5R)-2-amino-3-benzyloxy-4,5-iso-
propylidenedioxyhexanoate, 18. Prepared from com-
pound 17 (260 mg, 0.58 mmol) following the general
procedure. The crude material was purified by flash
chromatography (silica gel, EtOAc) to give 18 (131 mg,
67%) as a colorless oil: Rf 0.41 (silica gel, EtOAc/hex-
anes, 2:1); [h]D22=−13.3 (c 1.0, CH2Cl2); 1H NMR
(CDCl3) l 1.15 (d, 3H, J=6.1 Hz, 3H), 1.24 (t, J=7.1
Hz, 3H), 1.34 (s, 6H), 2.23 (brs, 2H), 3.58–3.66 (m, 1H),
3.71 (dd, J=8.2, 3.0 Hz, 1H), 3.80–3.93 (m, 1H),
4.05–4.23 (m, 3H), 4.55 (d, J=11.7 Hz, 1H), 4.69 (d,
J=11.7 Hz, 1H), 7.28–7.33 (m, 5H); 13C NMR (CDCl3)
l 14.1, 17.6, 26.7, 27.3 (CH3), 55.8 (CH), 61.1, 73.2
(CH2), 72.6, 78.0, 82.3 (CH), 108.5 (C), 127.8, 127.9,
128.4 (aromatic CH), 137.6 (aromatic C), 173.4 (CꢁO);
IR (film) w 3390, 3330, 2980, 2934, 1736, 1380, 1214
cm−1; FABMS m/z 338 (MH+, 90). Anal. calcd for
C18H27NO5: C, 64.07; H, 8.07; N, 4.15. Found: C,
64.42; H, 7.96; N, 4.21%.
4.5.1. Ethyl (2R,3R,4S,5R)-2-[N-(benzyloxycarbonyl)-
amino]-4,5-isopropylidenedioxy-3-methoxyhexanoate, 14.
Following the general procedure, amino ester 13 (800
mg, 3.06 mmol) gave 14 (1.20 g, 99%) as a colorless oil:
Rf 0.37 (silica gel, EtOAc/hexanes, 1:4); [h]2D2=−5.3 (c
1
2.7, CH2Cl2); H NMR (CDCl3) l 1.29 (t, J=7.1 Hz,
3H), 1.31 (d, J=6.0 Hz, 3H), 1.38 (s, 6H), 3.36 (s, 3H),
3.54 (dd, J=8.3, 7.0 Hz, 1H), 3.77 (dd, J=8.3, 1.5 Hz,
1H), 4.06 (dq, J=7.0, 6.0 Hz, 1H), 4.24 (q, J=7.1 Hz,
2H), 4.62 (dd, J=9.5, 1.5 Hz, 1H), 5.29 (s, 2H), 5.50
(brd, J=9.5 Hz, 1H), 7.28–7.4 (m, 5H); 13C NMR
(CDCl3) l 14.0, 19.3, 26.9, 27.3 (CH3), 54.4 (CH), 59.5
(OCH3), 61.5, 66.9 (OCH2), 76.0, 80.2, 82.8 (CH), 108.7
(C), 127.5, 127.9, 128.4 (aromatic CH), 136.3 (aromatic
C), 156.3, 171.4 (CꢁO); IR (film) w 2980, 1730, 1500,
1250, 1200 cm−1; FABMS m/z 396 (MH+, 100). Anal.
calcd for C20H29NO7: C, 60.74; H, 7.39; N, 3.54.
Found: C, 60.84; H, 7.35; N, 3.44%.
4.4.3. Ethyl (2S,3R,4S,5R)-2-amino-3-benzyloxy-4,5-iso-
propylidenedioxyhexanoate, 22. Prepared from com-
pound 21 (350 mg, 0.78 mmol) following the general
procedure. The crude material was purified by flash
chromatography (silica gel, EtOAc) to give 22 (214 mg,
81%) as a colorless oil: Rf 0.43 (silica gel, EtOAc/hex-
anes, 1:1); [h]2D6=−4.0 (c 1.1, CH2Cl2); 1H NMR
(CDCl3) l 1.20–1.40 (m, 12H), 1.82 (brs, 2H), 3.75–3.92
(m, 2H), 3.98 (dd, J=7.2, 6.0 Hz, 1H), 4.02–4.30 (m,
3H), 4.56 (d, J=11.4 Hz, 1H), 4.68 (d, J=11.4 Hz,
1H), 7.29–7.40 (m, 5H); 13C NMR (CDCl3) l 14.1,
19.4, 26.5, 27.2 (CH3), 55.0 (CH), 60.1, 72.4 (CH2),
76.4, 79.5, 82.3 (CH), 108.4 (C), 128.0, 128.4 (aromatic
CH), 137.4 (aromatic C), 172.7 (CꢁO); IR (film) w 2934,
1730, 1380, 1250 cm−1; FABMS m/z 338 (MH+, 47),
306 (100). Anal. calcd for C18H27NO5: C, 64.07; H,
8.07; N, 4.15. Found: C, 63.95; H, 8.32; N, 4.23%.
4.5.2. Ethyl (2R,3S,4S,5R)-3-benzyloxy-2-[N-(benzyl-
oxycarbonyl)amino] - 4,5 - isopropylidenedioxyhexanoate,
19. Prepared from amino ester 18 (100 mg, 0.30 mmol)
following the general procedure. The crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:6) to give 19 (116 mg, 82%) as a
colorless oil: Rf 0.35 (silica gel, EtOAc/hexanes, 1:6);
1
4.4.4. Ethyl (2R,3R,4S,5R)-2-amino-3-benzyloxy-4,5-iso-
propylidenedioxyhexanoate, 31. Prepared from com-
pound 30 (1.5 g, 3.36 mmol) following the general
procedure. The crude material was purified by flash
chromatography (silica gel, EtOAc) to give 31 (1.0 g,
88%) as a colorless oil: Rf 0.43 (silica gel, EtOAc/hex-
anes, 1:1); [h]D24=−20.7 (c 1.1, CH2Cl2); 1H NMR
(CDCl3) l 1.30 (t, J=7.0 Hz, 3H), 1.33 (d, J=5.9 Hz,
3H), 1.39 (s, 3H), 1.42 (s, 3H), 1.67 (brs, 2H), 3.75 (d,
J=1.9 Hz, 1H), 3.82 (t, J=7.6 Hz, 1H), 3.97–4.10 (m,
[h]2D1=−5.4 (c 0.5, CH2Cl2); H NMR (CDCl3) l 1.11
(d, J=6.0 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 1.39 (s,
6H), 3.52 (dd, J=8.2, 2.6 Hz, 1H), 3.79 (dd, J=4.3, 2.6
Hz, 1H), 4.10–4.20 (m, 1H), 4.23 (q, 2H, J=7.1 Hz,
2H), 4.50 (d, J=11.7 Hz, 1H), 4.77 (d, J=11.7 Hz,
1H), 4.89 (dd, J=8.7, 4.3 Hz, 1H), 5.13 (s, 2H), 6.17
(brd, J=8.7 Hz, 1H), 7.29–7.40 (m, 10H); 13C NMR
(CDCl3) l 14.2, 17.2, 26.5, 27.4 (CH3), 55.0 (CH), 61.6,
66.9, 71.7 (CH2), 72.4, 73.6, 82.6 (CH), 109.1 (C), 128.0,
128.2, 128.4 (aromatic CH), 136.4, 137.1 (aromatic C),

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1543
156.6, 170.0 (CꢁO); IR (film) w 3343, 2962, 1728, 1689,
1549, 1260, 1089, 1020 cm−1; FABMS m/z 472 (MH+,
10), 181 (100). Anal. calcd for C26H33NO7: C, 66.22; H,
7.05; N, 2.97. Found: C, 65.82; H, 7.10; N, 2.97%.
3.54–3.61 (m, 1H), 4.03 (dq, J=6.2, 1.3 Hz, 1H), 4.14
(q, J=7.1 Hz, 2H), 4.30–4.40 (m, 2H), 4.66 (d, J=10.8
Hz, 1H), 4.83 (d, J=10.8 Hz, 1H), 7.12–7.18 (m, 2H),
7.25 (s, 5H), 7.27–7.46 (m, 6H), 7.70–7.74 (m, 2H); 13C
NMR (CDCl3) l 14.1, 19.2, 26.6, 27.3 (CH3), 61.0
(CH2), 68.7 (CH), 74.8 (CH2), 75.2, 81.4, 81.7 (CH),
108.1 (C), 127.6, 128.0, 128.2, 128.4, 128.9, 130.4 (aro-
matic CH), 136.2, 138.1, 139.4 (aromatic C), 170.5,
171.9 (CꢁO, CꢁN); IR (film) w 3000, 1745, 1625, 1450,
1370, 1250, 700 cm−1; FABMS m/z 502 (MH+, 27), 206
(95), 193 (87), 165 (100). Anal. calcd for C31H35NO5: C,
74.23; H, 7.03; N, 2.79. Found: C, 73.87; H, 6.72; N,
2.70%.
4.5.3. Ethyl (2S,3R,4S,5R)-3-benzyloxy-2-[N-(benzyl-
oxycarbonyl)amino] - 4,5 - isopropylidenedioxyhexanoate,
23. Prepared from amino ester 22 (180 mg, 0.53 mmol)
following the general procedure. The crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:9) to give 23 (206 mg, 82%) as a
colorless oil: Rf 0.50 (silica gel, EtOAc/hexanes, 1:3);
1
[h]2D1=−1.4 (c 1.2, CH2Cl2); H NMR (CDCl3) l 1.23–
1.34 (m, 12H), 3.59 (t, J=8.1 Hz, 1H), 3.90 (dq, J=6.2,
1.0 Hz, 1H), 4.02 (dd, J=8.1, 2.2 Hz, 1H), 4.05–4.03
(m, 2H), 4.49 (d, J=11.1 Hz, 1H), 4.84 (d, J=11.1 Hz,
1H), 5.00 (dd, J=9.2, 2.2 Hz, 1H), 5.16 (s, 2H), 5.55
(brd, J=9.2 Hz, 1H), 7.30–7.41 (m, 10H); 13C NMR
(CDCl3) l 14.1, 19.1, 26.3, 27.3 (CH3), 54.0 (CH), 61.5,
67.2, 71.8 (CH2), 77.0, 80.0, 80.8 (CH), 108.7 (C), 128.0,
128.2, 128.4, 128.5 (aromatic CH), 136.1, 137.0 (aro-
matic C), 156.5, 169.8 (CꢁO); IR (film) w 3340, 2980,
1730, 1500 cm−1; FABMS m/z 472 (MH+, 7), 181 (74),
165 (100). Anal. calcd for C26H33NO7: C, 66.22; H,
7.05; N, 2.97. Found: C, 66.46; H, 7.18; N, 3.08%.
4.5.6. Ethyl (2R,3R,4S,5R)-3-benzyloxy-4,5-isopropyli-
denedioxy - 2 - [N - methyl - N - (diphenylmethyl)amino]-
hexanoate, 37. Schiff base ester 36 (250 mg, 0.50 mmol)
in anhydrous CH3CN (8 mL) was added to solid
NaBH3CN (51 mg, 0.81 mmol), and glacial HOAc was
added to keep the pH near to neutrality. After the
reduction was complete (15 min by TLC, silica gel,
EtOAc/hexanes, 1:4), 37% aqueous formaldehyde (0.78
mL, 9.7 mmol) and additional NaBH3CN (190 mg, 3.0
mmol) were added. The resulting exothermic reaction
was allowed to cool to room temperature and glacial
HOAc was added until the solution was neutral to wet
pH paper. After 4 h, the reaction mixture was diluted
with Et2O and then washed with aqueous saturated
NaHCO3 and then H2O. The organic layer was dried
(Na2SO4) and concentrated. The crude material was
purified by flash chromatography (silica gel, EtOAc/
hexanes, 1:12) to give 37 (212 mg, 82%) as a white
solid: Rf 0.50 (silica gel, EtOAc/hexanes, 1:9); mp 86–
87°C; [h]2D4=+77.1 (c 1.9, CH2Cl2); 1H NMR (CDCl3) l
1.21 (d, J=5.9 Hz, 3H), 1.31 (t, J=7.1 Hz, 3H), 1.36 (s,
3H), 1.49 (s, 3H), 2.55 (s, 3H), 3.68 (d, J=6.1 Hz, 1H),
3.91 (dd, J=7.9, 6.6 Hz, 1H), 4.10–4.34 (m, 4H), 4.69
(d, J=11.1 Hz, 1H), 4.83 (d, J=11.1 Hz, 1H), 5.00 (s,
1H), 7.10–7.50 (m, 15H); 13C NMR (CDCl3) l 14.4,
19.2, 26.9, 27.3, 36.8 (CH3), 59.7 (CH2), 60.1, 74.6
(CH), 74.8 (CH2), 75.0, 81.0, 81.4 (CH), 107.8 (C),
126.7, 127.3, 127.5, 127.8, 128.2, 128.3, 128.4, 128.9
(aromatic CH), 138.4, 142.1, 144.0 (aromatic C), 171.4
(CꢁO); IR (KBr) w 3000, 1730, 1500 cm−1; FABMS m/z
518 (MH+, 7), 168 (45), 167 (100). Anal. calcd for
C32H39NO5: C, 74.25; H, 7.59; N, 2.71. Found: C,
74.12; H, 7.28; N, 2.70%.
4.5.4. Ethyl (2R,3R,4S,5R)-3-benzyloxy-2-[N-(benzyl-
oxycarbonyl)amino] - 4,5 - isopropylidenedioxyhexanoate,
32. Prepared from amino ester 31 (700 mg, 2.08 mmol)
following the general procedure. The crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:4) to give 32 (961 mg, 98%) as a
colorless oil: Rf 0.35 (silica gel, EtOAc/hexanes, 1:4);
1
[h]2D1=−14.6 (c 1.0, CH2Cl2); H NMR (CDCl3) l 1.28
(t, J=7.0 Hz, 3H), 1.28 (d, J=5.8 Hz, 3H), 1.37 (s,
3H), 1.39 (s, 3H), 3.62 (t, J=7.6 Hz, 1H), 3.94–4.10 (m,
2H), 4.15–4.30 (m, 2H), 4.42 (d, J=11.0 Hz, 1H), 4.56
(d, J=11.0 Hz, 1H), 4.70 (dd, J=8.3, 1.0 Hz, 1H), 5.15
(s, 2H), 5.56 (brd, J=9.5 Hz, 1H), 7.20–7.40 (m, 10H);
13C NMR (CDCl3) l 14.1, 19.5, 26.9, 27.3 (CH3), 54.7
(CH), 61.7, 67.1, 73.7 (CH2), 75.8, 80.2, 82.5 (CH),
108.7 (C), 128.1, 128.3, 128.5 (aromatic CH), 136.1,
136.7 (aromatic C), 156.4, 171.4 (CꢁO); IR (film) w
3439, 3343, 2984, 2936, 1728, 1501, 1212, 1062 cm−1;
FABMS m/z 472 (MH+, 13), 181 (100). Anal. calcd for
C26H33NO7: C, 66.22; H, 7.05; N, 2.97. Found: C,
66.23; H, 7.25; N, 2.97%.
4.5.5. Ethyl (2R,3R,4S,5R)-3-benzyloxy-4,5-isopropyli-
denedioxy - 2 - [N - (diphenylmethylene)amino]hexanoate,
36. Benzophenone imine (0.25 mL, 1.49 mmol), amino
ester 31 (381 mg, 1.13 mmol) and anhydrous p-TsOH
(63 mg) in dry CH2Cl2 (15 mL) were stirred under an
argon atmosphere at room temperature for 14 h. The
reaction mixture was poured into aqueous saturated
NaHCO3 and extracted with CH2Cl2. The combined
organic layers were washed with H2O, dried (Na2SO4)
and concentrated. The crude material was purified by
flash chromatography (silica gel, EtOAc/hexanes, 1:11)
to give 36 (458 mg, 81%) as a colorless oil: Rf 0.40
(silica gel, EtOAc/hexanes, 1:4); [h]2D5=+91.4 (c 0.8,
4.6. General procedure for lactonization
A solution of compound 14 (1.17 g, 2.96 mmol) in
THF/H2O (6:1) (28 mL) at 0°C was treated with TFA
(24 mL) and stirred at room temperature for 3 h. The
solvents were removed in vacuo and the crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:1) to give lactone 15 (808 mg, 88%)
as a white solid.
4.6.1. (3R,4R,5S,1%R)-3-[N-(Benzyloxycarbonyl)-amino]-
5-(1-hydroxyethyl)-4-methoxytetrahydrofuran-2-one, 15.
Following the general procedure, 14 (1.17 g, 2.96
mmol) gave 15 (808 mg, 88%) as a white solid; Rf 0.23
1
CH2Cl2); H NMR (CDCl3) l 1.20 (d, J=6.1 Hz, 3H),
1.26 (t, J=7.1 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H),

1544
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
(silica gel, EtOAc/hexanes, 2:3); mp 89–90°C (CH2Cl2/
hexanes); [h]2D0=−28.2 (c 1.7, CH2Cl2); 1H NMR
(CDCl3) l 1.33 (d, J=6.4 Hz, 3H, CH3CH), 3.10 (brs,
1H, OH), 3.45 (s, 3H, OCH3), 4.00 (m, 1H, H-1%),
4.07–4.15 (m, 2H, H-4, H-5), 4.46 (m, 1H, H-3), 5.14
(s, 2H, CH2Ph), 5.87 (brd, J=8.6 Hz, 1H, NH), 7.35
(s, 5H, ArH); 13C NMR (CDCl3) l 19.3 (CH3), 57.5,
58.1 (OCH3, C-3), 67.1 (CH), 67.6 (CH2), 81.9, 84.7
(CH), 128.2, 128.3, 128.6 (aromatic CH), 135.6 (aro-
matic C), 156.0, 172.9 (CꢁO); IR (KBr) w 3300, 1775,
1700, 1540 cm−1; FABMS m/z 310 (MH+, 25), 266
([M−CO2]H+, 100). Anal. calcd for C15H19NO6: C,
58.25; H, 6.19; N, 4.53. Found: C, 57.95; H, 5.86; N,
4.52%.
4.6.4. (3R,4R,5S,1%R)-4-Benzyloxy-3-[N-(benzyloxycar-
bonyl)amino]-5-(1-hydroxyethyl)tetrahydrofuran-2-one,
33. Prepared from compound 32 (650 mg, 1.38 mmol)
following the general procedure. The crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 2:3) to give 33 (452 mg, 85%) as a
colorless solid. Crystallization from ligroin/ether
afforded colorless needles: Rf 0.50 (silica gel, EtOAc/
hexanes, 1:1); mp 97–99°C; [h]2D4=−23.6 (c 1.0,
1
CH2Cl2); H NMR (CDCl3) l 1.32 (d, J=6.4 Hz, 3H),
2.10 (brs, 1H), 3.8–4.00 (m, 1H), 4.10–4.21 (m, 1H),
4.32 (brt, J=6.1 Hz, 1H), 4.40–4.75 (m, 3H), 5.11 (d,
J=12.2 Hz, 1H), 5.18 (d, J=12.2 Hz, 1H), 5.6 (brd,
J=8.5 Hz, 1H), 7.32 (s, 5H), 7.35 (s, 5H); 13C NMR
(CDCl3) l 19.3 (CH3), 57.9, 67.0 (CH), 67.5, 72.4
(CH2), 79.9, 84.7 (CH), 128.0, 128.2, 128.4, 128.6 (aro-
matic CH), 135.8 (aromatic C), 155.9, 172.6 (CꢁO); IR
(KBr) w 3544, 3414, 2985, 1789, 1710, 1505, 1250, 1128
cm−1; FABMS m/z 386 (MH+, 10), 342 ([M−CO2]H+,
100). Anal. calcd for C21H23NO6: C, 65.44; H, 6.02; N,
3.63. Found: C, 65.32; H, 6.04; N, 3.65%.
4.6.2. (3R,4S,5S,1%R)-4-Benzyloxy-3-[N-(benzyloxycar-
bonyl)amino]-5-(1-hydroxyethyl)tetrahydrofuran-2-one,
20. Prepared from 19 (70 mg, 0.15 mmol) following
the general procedure. The crude material was purified
by flash chromatography (silica gel, EtOAc/hexanes,
1:1) to give 20 (47 mg, 81%) as a white solid: Rf 0.30
(silica gel, EtOAc/hexanes, 1:3); mp 167–169°C
(EtOH); [h]2D3=−53.4 (c 0.9, acetone); 1H NMR
([D6]acetone) l 1.13 (d, J=6.3 Hz, 3H, CH3CH),
4.08–4.2 (m, 1H, H-1%), 4.13 (d, J=2.7 Hz, 1H, OH),
4.38 (dd, J=7.0, 3.8 Hz, 1H, H-5), 4.50 (dd, J=5.0,
3.8 Hz, 1H, H-4), 4.52 (d, J=11.3 Hz, 1H, CH2Ph),
4.57 (d, J=11.3 Hz, 1H, CH2Ph), 4.91 (dd, J=8.5, 5.0
Hz, 1H, H-3), 5.13 (d, J=12.5 Hz, 1H, CH2Ph), 5.19
(d, J=12.5 Hz, 1H, CH2Ph), 7.00 (brd, J=8.5 Hz,
1H, NH), 7.26–7.44 (m, 10H, ArH); 13C NMR
([D6]acetone) l 18.7 (CH3), 56.3, 65.9 (CH), 67.2, 74.8
(CH2), 77.4, 85.7 (CH), 128.5, 128.6, 128.7, 128.8,
129.1, 129.2 (aromatic CH), 137.9, 138.5 (aromatic C),
157.0, 174.0 (CꢁO); IR (KBr) w 3400, 3300, 1770,
1690, 1500 cm−1; FABMS m/z 386 (MH+, 10), 342
([M−CO2]H+, 100); HRFABMS calcd for C21H23NO6:
(M+H)+ 386.1604. Found: 386.1607.
4.6.5. X-Ray crystallographic data of lactone 33. X-Ray
crystal analysis was performed on a Siemens Smart
CCD diffractometer with Moka radiation (u=0.71073
,
A). Crystallographic data (excluding structure factors)
for this structure have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary
publication no. CCDC-175830. Copies of the data can
be obtained free of charge on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44)
1223-336-033;
e-mail:
deposit@ccdc.cam.ac.uk).
C21H23NO6; M=385.4; colorless needles; crystal
dimensions=0.50×0.35×0.30
P212121; orthorhombic;
mm;
a=5.6870(7)
space
group
,
A,
b=
3
,
,
,
11.4549(13) A, c=30.439(3) A; V=1982.9(4) A ; Z=4;
T=298(2) K; zcalcd=1.291 Mg m−3; v=0.095 mm−1;
reflections total: 14106, unique: 4930 (Rint 0.0685),
observed: 2695 (I>2|(I)); R indices (all data), R1=
0.1243, wR2=0.1126; final R indices (I>2|(I)), R1=
0.0530, wR2=0.0935; GOF=0.998.
4.6.3. (3S,4R,5S,1%R)-4-Benzyloxy-3-[N-(benzyloxycar-
bonyl)amino]-5-(1-hydroxyethyl)tetrahydrofuran-2-one,
24. Prepared from 23 (100 mg, 0.21 mmol) following
the general procedure. The crude material was purified
by flash chromatography (silica gel, EtOAc/hexanes,
1:1) to give 24 (70 mg, 86%) as a white solid: Rf 0.40
(silica gel, EtOAc/hexanes, 1:1.8); mp 90–91°C
(CH2Cl2/hexanes); [h]2D1=+4.3 (c 1.4, CH2Cl2); 1H
NMR (CDCl3) l 1.25 (d, J=6.5 Hz, 3H, CH3CH),
2.93 (brs, 1H, OH), 3.9 (dq, J=6.5, 2.7 Hz, 1H, H-1%),
4.22 (d, J=6.0 Hz, 1H, H-4), 4.29 (d, J=2.7 Hz, 1H,
H-5), 4.54 (d, J=11.8 Hz, 1H, CH2Ph), 4.60 (d, J=
11.8 Hz, 1H, CH2Ph), 5.02 (dd, J=8.9, 6.0 Hz, 1H,
H-3), 5.10 (d, J=12.1 Hz, 1H, CH2Ph), 5.16 (d, J=
12.1 Hz, 1H, CH2Ph), 5.53 (brd, J=8.9 Hz, 1H, NH),
7.23–7.38 (m, 10H, ArH); 13C NMR (CDCl3) l 19.4
(CH3), 52.7, 67.4 (CH), 67.4, 72.4 (CH2) 76.4, 86.5
(CH), 127.9, 128.1, 128.2, 128.5, 128.6 (aromatic CH),
135.9, 136.5 (aromatic C), 156.3, 174.5 (CꢁO); IR
(KBr) w 3400, 3240, 1760, 1700 cm−1; FABMS m/z 386
(MH+, 10), 342 ([M−CO2]H+, 100). Anal. calcd for
C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C,
65.54; H, 6.02; N, 3.62%.
4.6.6. (3R,4R,5S,1%R)-4-Benzyloxy-5-(1-hydroxyethyl)-
3-[N-methyl-N-(diphenylmethyl)amino]tetrahydrofuran-
2-one, 38. Prepared from compound 37 (163 mg, 0.31
mmol) following the general procedure. Lactonization
required 16 h of stirring at room temperature. The
crude material was purified by flash chromatography
(silica gel, EtOAc/hexanes, 1:3) to give 38 (108 mg,
81%) as a colorless oil: Rf 0.37 (silica gel, EtOAc/hex-
anes, 1:3); [h]D22=+12.1 (c 0.9, CH2Cl2); 1H NMR
(CDCl3) l 1.26 (d, J=6.5 Hz, 3H), 2.4 (s, 3H), 3.15
(brs, 1H), 3.85 (dq, J=6.5, 2.4 Hz, 1H), 3.96 (dd,
J=6.6, 2.4 Hz, 1H), 4.04 (d, J=7.9 Hz, 1H), 4.60 (t,
J=7.5 Hz, 1H), 4.75 (d, J=11.2 Hz, 1H), 5.04 (d,
J=11.2 Hz, 1H), 5.41 (s, 1H), 7.15–7.61 (m, 15H); 13C
NMR (CDCl3) l 19.3 (CH3), 36.1 (NCH3), 66.4, 66.7
(CH), 72.8 (CH2), 73.1 76.1, 84.0 (CH), 127.4, 127.6,
127.9, 128.0, 128.2, 128.5, 128.7, 129.0 (aromatic CH),
137.4, 141.0, 141.8 (aromatic C), 172.0 (CꢁO); IR
(film) w 3300, 3414, 1765, 1495, 1450 cm−1; FABMS
m/z (%): 431 (M+, 20), 167 (100). Anal. calcd

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1545
for C27H29NO4: C, 75.15; H, 6.77; N, 3.25. Found: C,
75.26; H, 6.82; N, 3.35%.
4.7.3. (3R,4R,5S,1%R) - 4 - Benzyloxy - 5 - [1 - (isopropyl-
dimethylsilanyloxy)ethyl)] - 3 - [N - methyl - N - (diphenyl-
methyl)amino]tetrahydrofuran-2-one, 39. Prepared from
lactone 38 (100 mg, 0.23 mmol) following the general
procedure. The crude material was purified by flash
chromatography (silica gel, EtOAc/hexanes, 1:13) to
give 39 (116 mg, 94%) as a colorless oil: Rf 0.5 (silica
gel, EtOAc/hexanes, 1:9); [h]2D2=+8.5 (c 2.7, CH2Cl2);
1H NMR (CDCl3) l 0.07 (s, 3H), 0.09 (s, 3H), 0.70–
0.91 (m, 1H), 0.91–1.04 (m, 6H), 1.26 (d, J=6.7 Hz,
3H), 2.40 (s, 3H), 3.90–4.05 (m, 3H), 4.49 (dd, J=8.0,
6.6 Hz, 1H), 4.70 (d, J=11.3 Hz, 1H), 5.11 (d, J=11.3
Hz, 1H), 5.42 (s, 1H), 7.20–7.56 (m, 15H); 13C NMR
(CDCl3) l −3.8, −3.5 ((CH3)2Si), 14.7, 15.5, 19.8
((CH3)2CHSi, CH3CH), 35.9 (NCH3), 66.3, 66.6 (CH),
72.4 (CH2), 72.8, 75.8, 83.9 (CH), 127.9, 127.5, 128.2,
128.5, 128.6, 128.7 (aromatic CH), 137.0, 142.0, 143.0
(aromatic C), 172.7 (CꢁO); IR (film) w 2960, 1775, 1450
cm−1; FABMS m/z 531 (M+, 4), 530 (20), 167 (100).
Anal. calcd for C32H41NO4Si: C, 72.28; H, 7.77; N,
2.63. Found: C, 72.45; H, 7.72; N, 2.70%.
4.7. General silylation procedure
A solution of lactone 15 (470 mg, 1.52 mmol) and
imidazole (207 mg, 3.04 mmol) in THF (25 mL) was
treated with isopropyldimethylsilyl chloride (0.30 mL,
1.91 mmol) and stirred at room temperature for 3 h.
The solvent was removed in vacuo and the residue was
dissolved in CH2Cl2, washed with water, dried
(Na2SO4) and concentrated in vacuo. Flash chromatog-
raphy (silica gel, EtOAc/hexanes, 1:6–1:4) of the crude
material gave lactone 16 (615 mg, 99%) as a colorless
oil.
4.7.1. (3R,4R,5S,1%R)-3-[N-(Benzyloxycarbonyl)-amino]-
5-[1-(isopropyldimethylsilanyloxy)ethyl)]-4-methoxytetra-
hydrofuran-2-one, 16. Following the general procedure
lactone 15 (470 mg, 1.52 mmol) gave lactone 16 (615
mg, 99%) as a colorless oil: Rf 0.50 (silica gel, EtOAc/
1
hexanes, 1:4); [h]D22=−34.1 (c 1.0, CH2Cl2); H NMR
4.7.4.
(5S,1%R)-3-[N-(Benzyloxycarbonyl)amino]-5-[1-
(CDCl3) l 0.09 (s, 6H; (CH3)2Si), 0.70–0.90 (m, 7H,
(CH3)2CHSi), 1.27 (d, J=6.9 Hz, 3H, CH3CH), 3.45 (s,
3H, OCH3), 3.90 (t, J=5.8 Hz, 1H, H-4), 4.00–4.10 (m,
1H, H-1%), 4.10–4.17 (m, 1H, H-5), 4.50 (dd, J=8.5, 5.8
Hz, 1H, H-3), 5.16 (s, 2H, CH2Ph), 5.30 (brd, J=8.5
Hz, 1H, NH), 7.36 (s, 5H, ArH); 13C NMR (CDCl3) l
−3.7, −3.6 ((CH3)2Si), 14.6, 16.8, 19.4 ((CH3)2CHSi,
CH3CH), 57.3, 57.8 (CH, OCH3), 67.4 (CH2), 67.9,
82.4, 85.3 (CH), 128.1, 128.2, 128.5 (aromatic CH),
135.7 (aromatic C), 155.7, 172.5 (CꢁO); IR (film) w
3340, 2950, 2860, 1785, 1720, 1420, 1250 cm−1; FABMS
m/z 410 (MH+, 42), 366 ([M−CO2]H+, 100). Anal. calcd
for C20H31NO6Si: C, 58.65; H, 7.63; N, 3.42. Found: C
58.95, H; 7.31; N, 3.25%.
(isopropyldimethylsilanyloxy)ethyl)]-5H-furan-2-one, 35.
Sodium hydride (8 mg, 60% dispersion in mineral oil,
0.21 mmol) was added to a solution of lactone 34 (68
mg, 0.14 mmol) and MeI (0.07 mL, 1.12 mmol) in dry
THF (5 mL) at −15°C. After the reaction was complete
(15 min by TLC, silica gel, EtOAc/hexanes, 1:4),
MeOH (0.3 mL) was added and the reaction mixture
was concentrated in vacuo. The residue was diluted
with H2O and extracted with CH2Cl2. The organic layer
was dried (Na2SO4) and concentrated, and the crude
material was purified by flash chromatography (silica
gel, EtOAc/hexanes, 1:6) to give 35 (36 mg, 68%) as a
colorless oil: Rf 0.57 (silica gel, EtOAc/hexanes, 1:4);
1
[h]2D4=−5.1 (c 0.8, CH2Cl2); H NMR (CDCl3) l 0.08
(s, 6H), 0.70–1.0 (m, 7H), 1.16 (d, J=6.3 Hz, 3H), 3.97
(quintuplet, J=6.3 Hz, 1H), 4.9 (dd, J=5.8, 2.0 Hz,
1H), 5.2 (s, 2H), 7.04 (brd, J=9.2 Hz, 1H), 7.10–7.40
(m, 6H); 13C NMR (CDCl3) l −4.0, −3.8 ((CH3)2Si),
14.6, 16.7, 19.4 ((CH3)2CHSi, CH3CH), 67.8 (CH2),
68.7, 84.8, 123.9 (CH), 126.9 (C), 128.2, 128.6, 128.7
(aromatic CH), 135.0 (aromatic C), 153.0, 169.0 (CꢁO);
IR (film) w 2954, 1768, 1738, 1666, 1536, 1320, 1216
cm−1; FABMS m/z 378 (MH+, 28), 334 ([M−CO2]H)+,
18), 181 (100). Anal. calcd C19H27NO5Si: C, 60.45; H,
7.21; N, 3.71. Found: C, 60.58; H, 6.96; N, 3.49%.
4.7.2. (3R,4R,5S,1%R)-4-Benzyloxy-3-[N-(benzyloxycar-
bonyl)amino] - 5 - [1 - (isopropyldimethylsilanyloxy)ethyl)-
]tetrahydrofuran-2-one, 34. Prepared from lactone 33
(440 mg, 1.14 mmol) following the general procedure.
The crude material was purified by flash chromatogra-
phy (silica gel, EtOAc/hexanes, 1:4) to give 34 (525 mg,
95%) as a colorless oil: Rf 0.38 (silica gel, EtOAc/hex-
anes, 1:4); [h]D22=−26.7 (c 1.0, CH2Cl2); 1H NMR
(CDCl3) l 0.03 (s, 3H), 0.06 (s, 3H), 0.70–0.96 (m, 7H),
1.26 (d, J=6.4 Hz, 3H), 3.91–4.12 (m, 1H), 4.10 (t,
J=5.4 Hz, 1H), 4.21–4.25 (m, 1H), 4.50–4.60 (m, 1H),
4.55 (d, J=11.9 Hz, 1H), 4.76 (d, J=11.9 Hz, 1H), 5.13
(d, J=12.2 Hz, 1H), 5.21 (d, J=12.2 Hz, 1H), 5.21
(brd, 1H), 7.31 (s, 5H), 7.37 (s, 5H, ArH); 13C NMR
(CDCl3) l −3.7, −3.6 ((CH3)2Si), 14.6, 16.8, 19.4
((CH3)2CHSi, CH3CH), 57.6 (CH), 67.4 (CH2), 67.9
(CH), 71.9 (CH2), 79.9, 85.6 (CH), 128.1, 128.3, 128.5
(aromatic CH), 135.8, 136.9 (aromatic C), 155.7, 172.5
(CꢁO); IR (film) w 3340, 2953, 2865, 1789, 1722, 1515,
1254 cm−1; FABMS m/z 486 (MH+, 5), 442 ([M−
CO2]H+, 17), 181 (100). Anal. calcd for C26H35NO6Si:
C, 64.30; H, 7.26; N, 2.88. Found: C, 63.95; H, 7.04; N,
2.88%.
4.8. General procedure for the DIBALH reduction
DIBALH (1.5 M solution in toluene, 2 mL, 3.0 mmol)
was added dropwise to a stirred solution of lactone 16
(592 mg, 1.45 mmol) in toluene/THF (2:1) (45 mL) at
−78°C. After stirring for 6 h at −78°C, the reaction was
quenched with cold CH3OH (2 mL). Then, an ice-cold
aqueous saturated NH4Cl solution (8 mL) was slowly
added, and the suspension was allowed to reach to
room temperature. The mixture was extracted with
EtOAc and the combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The crude mate-

1546
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
rial was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:6–1:3) to give lactols 26 (385 mg,
65%; 85% based on recovered starting material) and
starting lactone 16 (186 mg, 31%) unchanged in [h]D.
((CH3)2CHSi, CH3CH), 57.7, 57.9, 58.3, 60.5 (CH,
OCH3), 66.9, 67.0 (CH2), 68.7, 68.8, 85.0, 86.9, 87.0,
87.9, 96.1, 102.2 (CH), 128.1, 128.3, 128.4 (aromatic
CH), 136.2 (aromatic C), 155.4, 155.7 (CꢁO); IR (film)
w 2960, 1720, 1260, 1100, 1020 cm−1; FABMS m/z 394
([M−H2O]H+, 100). Anal. calcd for C20H33NO6Si: C,
58.37; H, 8.08; N, 3.40. Found: C, 58.64; H, 7.88; N,
3.18%.
4.8.1. 2-[N-(Benzyloxycarbonyl)amino]-2,6-dideoxy-3-O-
methyl-D-galactose, 25 and 27 and alcohol 28. Prepared
from lactone 15 (300 mg, 0.97 mmol) following the
general procedure but using 2.5 equiv. of DIBALH.
The crude material was purified by flash chromatogra-
phy (silica gel, EtOAc/hexanes, 2:3 to EtOAc) to give a
7:3:1 mixture of lactols 25 and 27 (130 mg, 43%),
starting lactone 15 (84 mg, 28%) unchanged in [h]D and
alcohol 28 (21 mg, 7%). Data for 25 and 27: colorless
oil: Rf 0.33 (silica gel, EtOAc/hexanes, 3:1); [h]2D4=+2.7
4.8.3.
3-O-Benzyl-2-N-(benzyloxycarbonyl)amino-2,6-
-galactofuranose,
dideoxy-5-O-(isopropyldimethylsilyl)-
D
40. Prepared from lactone 34 (140 mg, 0.29 mmol)
following the general procedure. The crude material
was purified by flash chromatography (silica gel,
EtOAc/hexanes, 1:4–1:3) to give lactols 40 (95 mg, 67%,
86% based on recovered starting material) as a colorless
oil and starting lactone 34 (40 mg, 29%). Data for 40:
Rf 0.40 (silica gel, EtOAc/hexanes, 1:1.8); [h]2D0=−54.1
1
(c 0.7, CH2Cl2); H NMR (CDCl3) l (7:3:1 anomeric
mixture) 1.21 (d, J=6.4 Hz, 9H), 1.27 (d, J=6.4 Hz,
21H), 1.29 (d, J=6.3 Hz, 3H), 3.35–3.45 (m, 44H),
3.76–3.90 (m, 11H), 4.00–4.35 (m, 22H), 5.00–5.38 (m,
33H), 5.45 (brd, J=6.8 Hz, 1H), 5.79 (brd, J=9.2 Hz,
1
(c 2.5, CH2Cl2); H NMR (CDCl3) l (1.5:1 anomeric
mixture) 0.07 (s, 6H), 0.14 (m, 9H), 0.72–0.94 (m,
17.5H), 1.24 (d, J=6.4 Hz, 3H), 1.27 (d, J=6.4 Hz,
4.5H), 3.66–3.92 (m, 4H), 3.99 (dd, J=1.5, 1.1 Hz,
1.5H), 4.14 (t, J=2.1 Hz, 1H), 4.31–4.43 (m, 3.5H),
4.53 (dd, J=7.7, 1.8 Hz, 2.5H), 4.8 (d, J=12.0 Hz,
2.5H), 5.10–5.30 (m, 7.5H), 5.36 (brd, J=8.0 Hz, 1.5H),
5.36 (brd, J=8.0 Hz, 1H), 7.20–7.45 (m, 25H); 13C
NMR (CDCl3) l (1.5:1 anomeric mixture) −4.1, −4.0,
−3.7 ((CH3)2Si), 14.2, 14.6, 16.7, 19.9, 20.1
((CH3)2CHSi, CH3CH), 58.8, 61.1 (CH), 66.9, 67.0
(CH2), 68.3, 68.4 (CH), 71.4, 71.7 (CH2), 82.3, 83.5,
87.6, 88.0, 96.3, 102.3 (CH), 127.8, 128.0, 128.2, 128.4,
128.5, 128.6 (aromatic CH), 136.3, 136.7, 137.6 (aro-
matic C), 155.4, 155.6 (C−O); IR (film) w 2965, 1485,
1478, 1260 cm−1; FABMS m/z 470 ([M−H2O]H+, 20),
181 (100). Anal. calcd for C26H37NO6Si: C, 64.04; H,
7.65; N, 2.87. Found: C, 64.35; H, 7.46; N, 2.56%.
7H), 5.95 (brd, J=8.6 Hz, 3H), 7.30–7.40 (m, 55H); 13
C
NMR (CDCl3) l (7:3:1 anomeric mixture) 16.4, 19.6,
19.9 (CH3), 50.1, 54.9, 57.7, 57.9, 59.7, 60.5 (CH,
OCH3), 66.9, 67.2 (CH2), 67.6, 68.1, 70.4, 78.4, 80.1,
84.7, 86.0, 87.6, 92.1, 95.5, 96.4, 102.2 (CH), 128.1,
128.3, 128.4 (aromatic CH), 135.9, 136.3 (aromatic C),
155.9, 156.6, 157.8 (C−O); IR (film): w=3330, 2950,
1700, 1540, 1260, 1200 cm−1; FABMS m/z 312 (MH+,
22), 294 ([M−H2O]H+, 82), 241 (100). Anal. calcd for
C15H21NO6: C, 57.87; H, 6.80; N, 4.50. Found: C,
57.99; H, 6.80; N, 4.73%. Data for 28: colorless oil: Rf
0.25 (silica gel, EtOAc); [h]2D3=−17.7 (c 2.0, CH2Cl2);
1H NMR (CDCl3) l 1.27 (d, J=5.9 Hz, 3H), 3.23 (brd,
J=8.8 Hz, 1H), 3.42–3.54 (m, 1H), 3.50 (s, 3H), 3.55–
3.70 (m, 3H), 3.75–4.00 (m, 1H), 4.00–4.20 (m, 1H),
5.11 (s, 2H), 5.37 (brd, J=9.2 Hz, 1H), 7.35 (s, 5H); 13
C
NMR (CDCl3) l 20.5 (CH3), 52.8, 60.4 (CH, OCH3),
63.0 (CH2), 66.2 (CH), 67.3 (CH2), 77.6, 80.4 (CH),
128.1, 128.3, 128.6 (aromatic CH), 136.1 (aromatic C),
157.7 (CꢁO); IR (film) w 3382, 2948, 1694, 1519, 1260,
1051 cm−1; FABMS m/z 314 (MH+, 20), 270 (100).
Anal. calcd for C15H23NO6: C, 57.50; H, 7.40; N, 4.47.
Found: C, 57.19; H, 7.35; N, 4.14%.
4.8.4. 3-O-Benzyl-2,6-dideoxy-5-O-(isopropyldimethyl-
silyl)-2-[N-methyl-N-(diphenylmethyl)amino]-D-galacto-
furanoses, 41. Prepared from lactone 39 (80 mg, 0.15
mmol) following the general procedure. The crude
material was purified by flash chromatography (silica
gel, EtOAc/hexanes, 1:6) to give lactols 41 (62 mg, 77%,
91% based on recovered starting material) as a colorless
oil and starting lactone 39 (14 mg, 18%). Data for 41:
Rf 0.35 (silica gel, EtOAc/hexanes, 1:4); [h]2D4=−33.0 (c
4.8.2. 2-N-[(Benzyloxycarbonyl)amino]-2,6-dideoxy-5-O-
(isopropyldimethylsilyl)-3-O-methyl-D-galactofuranose,
26. Prepared from lactone 16 (592 mg, 1.45 mmol)
following the general procedure. The crude product was
purified by flash chromatography (silica gel, EtOAc/
hexanes, 1:6–1:3) to give lactols 26 (385 mg, 65%, 85%
based on recovered starting material) as a colorless
solid and starting lactone 16 (186 mg, 31%) unchanged
in [h]D. Data for 26: Rf 0.26 (silica gel, EtOAc/hexanes,
1:3); mp 61–62°C; [h]2D2=−22.4 (c 2.9, CH2Cl2); 1H
NMR (CDCl3) l (1.5:1 anomeric mixture) 0.07 (s, 3H),
0.08 (s, 3H), 0.15 (s, 4.5H), 0.16 (s, 4.5H), 0.80–1.03 (m,
17.5H), 1.27 (d, J=6.4 Hz, 4.5H), 1.29 (d, J=6.3 Hz,
3H), 3.42 (s, 4.5H), 3.45 (s, 3H), 3.40–3.55 (m, 1H),
3.62–3.68 (m, 2.5H), 3.85–3.97 (m, 2.5H), 4.00–4.11 (m,
1H), 4.20–4.33 (m, 3H), 5.08–5.24 (m, 7.5H), 5.35 (brd,
J=8.5 Hz, 1.5H), 5.84 (brd, J=8.5 Hz, 1H), 7.32–7.43
(m, 12.5H); 13C NMR (CDCl3) l (1.5:1 anomeric mix-
ture) −3.8, −3.6 ((CH3)2Si), 14.3, 14.6, 16.7, 20.0, 20.1
1
2.4, CH2Cl2); H NMR (CDCl3) l (1:1 anomeric mix-
ture) 0.01–0.20 (m, 12H), 0.80–0.11 (m, 14H), 1.28 (d,
J=3.7 Hz, 3H), 1.27 (d, J=3.8 Hz, 3H), 2.32 (s, 3H),
2.43 (s, 3H), 3.49 (dd, J=6.8, 4.7 Hz, 1H), 3.57 (dd,
J=4.7, 2.2 Hz, 1H), 3.89–4.12 (m, 3H), 4.27 (dd,
J=6.8, 4.7 Hz, 1H), 4.40 (dd, J=6.8, 4.7 Hz, 1H),
4.60–4.90 (m, 6H), 5.10 (brs, 1H), 5.20 (brd, J=4.5 Hz,
1H), 5.57 (brs, 1H), 7.20–7.60 (m, 30H); 13C NMR
(CDCl3) l (1:1 anomeric mixture) −3.8, −3.7, −3.5
((CH3)2Si), 14.7, 16.8, 16.9, 20.2, 20.4 ((CH3)2CHSi,
CH3CH), 35.7, 36.7 (NCH3), 61.1, 67.6, 69.3 (CH), 71.8
(CH2), 72.4, 73.4, 74.4, 78.3, 81.0, 84.4, 86.3, 96.1, 97.6
(CH), 126.8, 126.9, 127.2, 127.7, 128.0, 128.4 (aromatic
CH), 138.0, 138.1, 141.7, 142.2, 142.4 (aromatic C); IR
(film) w 2960, 1490, 1470, 1260 cm−1; FABMS m/z 533
(MH+, 9), 532 (14), 167 (100). Anal. calcd for

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1547
C32H43NO4Si: C, 72.00; H, 8.12; N, 2.62. Found: C,
72.28; H, 8.15; N, 2.44%.
J=10.9, 3.3 Hz, 1H), 4.23 (q, J=6.6 Hz, 1H), 5.39 (d,
J=3.6 Hz, 1H); H NMR (D2O) l (for b-anomer) 1.24
1
(d, J=6.6 Hz, 3H), 3.09 (dd, J=10.9, 8.6 Hz, 1H),
3.74–3.82 (m, 2H), 3.84 (dd, J=10.9, 3.3 Hz, 1H), 4.84
(d, J=8.6 Hz, 1H); 13C NMR (D2O) l (anomeric
mixture) 16.5, 52.0, 55.3, 67.5, 70.5, 71.3, 71.8, 72.3,
90.2, 93.9; FABMS m/z 164 (MH+, 49), 146 ([M−
H2O]H+, 69), 57 (100).
4.9. General procedure for the final deprotection
A mixture of lactols 26 (100 mg, 0.24 mmol) in THF (8
mL) and 0.25N HCl (4 mL) was stirred with 10% Pd/C
(10 mg) under H2 (1 atm) for 6 h at room temperature.
The catalyst was removed by filtration through a short
pad of Celite, and the filtrate was concentrated in
vacuo. The crude product was dissolved in 1 M NaOH
(2 mL) and loaded onto a column (1.5×7.0 cm) of
Dowex-50WX8 (H+ form), the column was washed
with H2O, and the product was eluted with a 1%
aqueous NH3 solution. Evaporation of the solvent gave
free amino sugar 3 as a pale yellow solid (37 mg, 87%).
4.9.3. N-Methyl-D-fucosamine, 2. Prepared from lactols
41 (53 mg, 0.10 mmol) following the general procedure.
The crude product was dissolved in 1 M NaOH (1 mL)
and loaded onto a column (1.5×7.0 cm) of Dowex-
50WX8 (H+ form), the column was washed with H2O,
and the product was eluted with MeOH/3 M NH4OH/
H2O (2:5:3).8b,12a Evaporation of the solvent followed
by purification by reversed-phase flash chromatography
(RP-18, H2O) afforded free amino sugar 2 as a colorless
solid (15 mg, 87%): Rf 0.60 (silica gel, n-BuOH/AcOH/
H2O, 1:1:1); mp 158–162°C (dec.) (lit. mp 158–161°C
(dec.));8b [h]D25=+69.0 (final, c 0.1, H2O) (lit. [h]2D5=
+73.1 (final, c 0.1, H2O)).8b A mixture of pyranose and
4.9.1.
2-Amino-2,6-dideoxy-3-O-methyl-D-galactose
hydrochloride, 29. Deprotection of lactols 26 (100 mg,
0.24 mmol) following the general procedure gave free
amino sugar 3 as a pale yellow solid (37 mg, 87%).
Treatment of 3 with 0.25N HCl until pH 2, and purifi-
cation by reversed-phase flash chromatography (RP-18,
H2O) afforded 29 in an almost quantitative yield. Data
for 29: pale yellow oil: Rf 0.34 (silica gel, n-BuOH/
AcOH/H2O, 12:3:5); [h]2D2=+92.1 (c=0.6, H2O) (lit.
[h]D=+85.3 (c=1.1, H2O));18d a 1.4:1 (a/b) anomeric
mixture was observed in D2O solution. For a-anomer:
1H NMR (500 MHz, D2O, 25°C) l 1.01 (d, J=6.6 Hz,
3H, CH3CH), 3.21 (dd, J=11.0, 3.8 Hz, 1H, H-2), 3.22
(s, 3H, OCH3), 3.54 (dd, J=11.0, 3.0 Hz, 1H, H-3),
3.91 (d, J=3.0 Hz, 1H, H-4), 4.00 (q, J=6.6 Hz, 1H,
H-5), 5.17 (d, J=3.8 Hz, 1H, H-1); 13C NMR (125
MHz, D2O, 25°C) l 16.6 (C-6), 50.9 (C-2), 56.8
(OCH3), 67.0 (C-4), 67.4 (C-5), 76.5 (C-3), 90.2 (C-1).
1
furanose anomers was observed in D2O solution. H
NMR (D2O) l (major anomer) 1.21 (d, J=6.5 Hz, 3H),
2.67 (s, 3H), 3.03 (dd, J=11.0, 3.5 Hz, 1H), 3.75 (m,
1H), 3.92 (dd, J=11.0, 3.0 Hz, 1H), 4.18 (q, J=6.5 Hz,
1H), 5.48 (d, J=3.5 Hz, 1H); 13C NMR (D2O) l (major
anomers) 16.6, 32.7, 34.7, 59.1, 62.3, 67.2, 68.6, 71.8,
72.1, 89.8, 96.7; FABMS m/z 178 (MH+, 99), 160
([M−H2O]H+, 94).
Acknowledgements
1
For b-anomer: H NMR (500 MHz, D2O, 25°C) l 1.06
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. We also thank Dr. M. A.
Maestro for resolving the X-ray structure. The authors
are indebted to Centro de Supercomputacio´n of Galicia
for providing the computer facilities.
(d, J=6.4 Hz, 3H, CH3CH), 2.90 (dd, J=11.0, 8.6 Hz,
1H, H-2), 3.22 (s, 3H, OCH3), 3.35 (dd, J=11.0, 3.0
Hz, 1H, H-3), 3.60 (q, J=6.4 Hz, 1H, H-5), 3.87 (d,
J=3.0 Hz, 1H, H-4), 4.63 (d, J=8.6 Hz, 1H, H-1); 13C
NMR (125 MHz, D2O, 25°C) l 16.7 (C-6), 54.1 (C-2),
57.1 (OCH3), 66.4 (C-4), 72.3 (C-5), 79.4 (C-3), 94.0
(C-1); IR (film) w 3410, 1630, 1200 cm−1; FABMS m/z
178 (MH+, 42), 160 ([M−H2O]H+, 100).
References
4.9.2.
D-Fucosamine, 1. Prepared from lactols 40 (50
mg, 0.10 mmol) following the general procedure. The
crude product was dissolved in 1 M NaOH (2 mL) and
loaded onto a column (1.5×7.0 cm) of Dowex-50WX8
(H+ form), the column was washed with H2O, and the
product was eluted with a 1% aqueous NH3 solution.
Evaporation of the solvent gave free amino sugar 1 as
a pale yellow solid (14 mg, 87%). Treatment of 1 with
1 M HCl until pH 2 and purification by reversed-phase
flash chromatography (RP-18, H2O) afforded
fucosamine hydrochloride as a colorless solid in an
almost quantitative yield: Rf 0.35 (silica gel, n-BuOH/
AcOH/H2O, 12:3:5); mp 175–178°C (dec.) (lit. mp 174–
176°C (dec.));18c [h]D23=+76.1 (final, c 0.6, H2O) (lit.
[h]D25=+81.0 (final, c 0.24, H2O));18c a mixture of a/b
1. Essentials of Glycobiology; Varki, A.; Cummings, R.;
Esko, J.; Freeze, H.; Hart, G.; Marth, J., Eds.; Cold
Spring Harbor Laboratory Press: Cold Spring Harbor,
New York, 1999.
2. Mallams, A. K. In Carbohydrate Chemistry; Kennedy, J.
F., Ed. The Carbohydrate-Containing Antibiotics;
Clarendon Press: Oxford, 1988; pp. 73–133.
3. (a) Gijsen, H. J. M.; Qiao, L.; Fitz, W.; Wong, C.-H.
Chem. Rev. 1996, 96, 443–473; (b) Danishefsky, S. J.;
Roberge, J. Y. Pure Appl. Chem. 1995, 67, 1647–1662; (c)
Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21–123.
4. For a leading reference, see: Park, T. K.; Kim, I. J.; Hu,
S.; Bilodeau, M. T.; Randolph, J. T.; Kwon, O.; Dan-
ishefsky, S. J. J. Am. Chem. Soc. 1996, 118, 11488–11500.
5. Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38,
2300–2324.
1
anomers 1.5:1 was observed in D2O solution. H NMR
(D2O) l (for a-anomer) 1.20 (d, J=6.6 Hz, 3H), 3.39
(dd, J=10.9, 3.6 Hz, 1H), 3.80 (m, 1H), 4.05 (dd,

1548
M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
6. Aono, R.; Uramoto, M. Biochem. J. 1986, 233, 291–294
20. For conceptually related approaches to amino sugars or
amino polyols based on aldol-type reactions of polyhy-
droxylated aldehydes with glycine, see: (a) Fujii, M.;
Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046–104;
(b) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G.
Synlett 1999, 1333–1350; (c) Kazmaier, U.; Grandel, R.
Eur. J. Org. Chem. 1998, 1833–1840; (d) Vassilev, V. P.;
Uchiyama, T.; Kajimoto, T.; Wong, C.-H. Tetrahedron
Lett. 1995, 36, 4081–4084; (e) Banfi, L.; Cardani, S.;
Potenza, D.; Scolastico, C. Tetrahedron 1987, 43, 2317–
2322. See also Ref. 15a.
21. Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23,
556–569 and references cited within.
22. Servi, S. J. Org. Chem. 1985, 50, 5865–5867 the corre-
sponding methyl ester is commercially available from the
Aldrich Chemical Company.
and references cited therein.
7. Structure: (a) Sugawara, K.; Tsunakawa, M.; Konishi,
M.; Kawaguchi, H.; Krishnan, B.; Cung-heng, H.;
Clardy, J. J. Org. Chem. 1987, 52, 996–1001. Antitumor
activity of elsamicin A (elsamitrucin; BMY-28090): (b)
Constanza, M. E.; Weiss, R. B.; Henderson, I. C.; Nor-
ton, L.; Berry, D. A.; Cirrincione, C.; Winer, E.; Wood,
W. C.; Frei, E., III; McIntyre, O. R.; Schilsky, R. L. J.
Clin. Oncol. 1999, 17, 1397–1406; (c) Vaquero, A.; Portu-
gal, J. Eur. J. Biochem. 1998, 251, 435–442 and references
cited therein.
8. (a) Smith, A. L.; Nicolau, K. C. J. Med. Chem. 1996, 39,
2103–2117; (b) Edo, K.; Akiyama, Y.; Saito, K.; Mizu-
gaki, M.; Koide, Y.; Ishida, N. J. Antibiot. 1986, 39,
1615–1619.
9. For elsamicin A, see: (a) Alhambra, C.; Luque, F. J.;
Portugal, J.; Orozco, M. Eur. J. Biochem. 1995, 230,
555–566 and references cited therein; (b) Uesugi, M.;
Sekida, T.; Matsuki, S.; Sugiura, Y. Biochemistry 1991,
30, 6711–6715. For neocarzinostatin, see: (c) Myers, A.
G.; Liang, J.; Hammond, M. Tetrahedron Lett. 1999, 40,
5129–5133; (d) Myers, A. G.; Kort, M. E.; Hammond,
M. J. Am. Chem. Soc. 1997, 119, 2965–2972; (e) Myers,
A. G.; Harrington, P. M.; Kwon, B.-M. J. Am. Chem.
Soc. 1992, 114, 1086–1087.
23. 2,2,5-Trimethyl-1,3-dioxolane-4-carboxaldehyde
has
proven to be a useful chiral synthon for the diastereo-
selective synthesis of carbohydrates. See, for instance: (a)
Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.;
Pedrini, P. J. Org. Chem. 1989, 54, 693–702; (b) Fuganti,
C.; Grasselli, P.; Pedrocchi-Fantoni, G. J. Org. Chem.
1983, 48, 909–910 and references cited therein. For the
cyclohexylidene analogue, see: (c) Roush, W. R.; Adam,
M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem. Soc.
1986, 108, 3422–3434, and references cited therein.
10. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int.
24. Williams, R. M. Synthesis of Optically Active a-Amino
Acids; Baldwin, J. E.; Magnus, P. D., Eds.; Organic
Chemistry Series, Pergamon: Oxford, 1989; Vol. 7.
25. (a) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima,
M.; Hanada, K. J. Am. Chem. Soc. 1998, 120, 908–919;
(b) Bold, G.; Allmendinger, T.; Herold, P.; Moesch, L.;
Scha¨r, H.-P.; Duthaler, R. O. Helv. Chim. Acta 1992, 75,
865–882; (c) Groth, U.; Scho¨llkopf, U.; Tiller, T. Tetra-
hedron 1991, 47, 2835–2842; (d) Gelb, M. H.; Lin, Y.;
Pickard, M. A.; Song, Y.; Vederas, J. C. J. Am. Chem.
Soc. 1990, 112, 4932–4942; (e) Scho¨llkopf, U.; Barden-
hagen, J. Liebigs Ann. Chem. 1987, 393–397; (f) Grauert,
M.; Scho¨llkopf, U. Liebigs Ann. Chem. 1985, 1817–1824;
(g) Scho¨llkopf, U.; Nozulak, J.; Grauert, M. Synthesis
1985, 55–56; (h) Scho¨llkopf, U.; Nozulak, J.; Groth, U.
Tetrahedron 1984, 40, 1409–1417; (i) Scho¨llkopf, U. Pure
Appl. Chem. 1983, 55, 1799–1806; (j) Scho¨llkopf, U.;
Groth, U.; Gull, M.-R.; Nozulak, J. Liebigs Ann. Chem.
1983, 1133–1151; (k) Scho¨llkopf, U.; Groth, U.; Hartwig,
W. Liebigs Ann. Chem. 1981, 2407–2418.
Ed. Engl. 1996, 35, 1380–1419.
11. (a) Pitzer, K.; Hudlicky, T. Synlett 1995, 803–805; (b)
Lehmann, J.; Moritz, A. Liebigs Ann. Chem. 1991, 937–
940.
12. (a) Sames, D.; Polt, R. J. Org. Chem. 1994, 59, 4596–
4601; (b) Golebiowski, A.; Jurczak, J. Synlett 1993, 241–
245.
13. Ermolenko, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc.,
Perkin Trans. 1 2000, 2465–2473.
14. Dondoni, A.; Franco, S.; Junquera, F.; Mercha´n, F. L.;
Merino, P.; Tejero, T.; Bertolasi, V. Chem. Eur. J. 1995,
1, 505–520.
15. (a) Mukaiyama, T.; Miwa, T.; Nakatsuka, T. Chem. Lett.
1982, 145–148; (b) Nakatsuka, T.; Miwa, T.;
Mukaiyama, T. Chem. Lett. 1981, 279–282.
16. (a) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M.
Tetrahedron: Asymmetry 2002, 13, 795–799; (b) Ruiz, M.;
Ojea, V.; Quintela, J. M. Synlett 1999, 204–206; (c) Ruiz,
M.; Ruanova, T. M.; Ojea, V.; Quintela, J. M. Tetra-
hedron Lett. 1999, 40, 2021–2024.
17. Part of this work was already presented as preliminary
communications: (a) Ojea, V.; Ruiz, M.; Quintela, J. M.
Synlett 1997, 83–84; (b) Ruiz, M.; Ojea, V.; Quintela, J.
M. Tetrahedron Lett. 1996, 37, 5743–5746.
18. Syntheses of fucosamine: (a) Carreira, E. M.; Hong, J.;
Du Bois, J.; Tomooka, C. S. Pure Appl. Chem. 1998, 70,
1097–1103; (b) Lehmann, J.; Reutter, W.; Scho¨ning, D.
Chem. Ber. 1979, 112, 1470–1472; (c) Zehavi, U.; Sharon,
N. J. Org. Chem. 1964, 29, 3654–3658. Synthesis of
3-O-methyl-fucosamine: (d) Perry, M. B.; Daoust, V.
Can. J. Chem. 1974, 52, 3251–3255. Syntheses of N-
methyl-fucosamine: (e) Kaneko, T.; Takahashi, K.;
Hirama, M. Heterocycles 1998, 47, 91–96. See also Refs.
8b and 18a.
26. Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
27. cyclo-[L-Val-Gly] was obtained as described by Rose et
al. Treatment of this compound with triethyloxonium
tetrafluoroborate allowed the preparation of the 2,5-
diethoxy pyrazine derivative. See Rose, J. E.; Leeson, P.
D.; Gani, D. J. Chem. Soc., Perkin Trans. 1 1995, 157–
165. Alternatively, both enantiomers of the related 2,5-
dimethoxy-3-isopropyl-3,6-dihydropyrazine
can
be
synthesized28 or purchased from E. Merck.
28. Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321–327.
29. As pure aldehyde 5 has proven to be elusive,22 probably
due to hydration or polymerization, it was distilled just
before use.
19. In this work we use the syn/anti nomenclature according
to Masamune convention. See: Masamune, S.; Kaiho, T.;
Garvey, D. S. J. Am. Chem. Soc. 1982, 104, 5521–5523.
30. (a) Evans, D. A.; Yang, M. G.; Dart, M. J.; Duffy, J. L.
Tetrahedron Lett. 1996, 37, 1957–1960; (b) Evans, D. A.;

M. Ruiz et al. / Tetrahedron: Asymmetry 13 (2002) 1535–1549
1549
Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 37,
8537–8540.
38. PCMODEL version 5. Molecular Modelling Software,
from Serena Software, Bloomington, IN 47402, USA.
http://www.serenasoft.com/.
39. Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1977, 99,
4899–4907.
40. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart,
J. J. P. J. Am. Chem. Soc. 1985, 107, 3902–3909.
41. Stewart, J. J. P. J. Comp. Chem. 1989, 10, 221–264.
42. MOPAC 93. Stewart, J. J. P.; Fujitsu Limited, Tokyo,
Japan, 1993.
43. Rotamers for 16 and 24 (not shown in Fig. 2), within 0.7
and 1.1 kcal/mol of the PM3 global minima, can better
account for the observed NOEs between methyl groups
and protons at C-4, showed with dashed arrows in Fig. 2
and characteristic for g-lactones.
31. See, for instance: Busch, K.; Groth, U. M.; Ku¨hnle, W.;
Scho¨llkopf, U. Tetrahedron 1992, 48, 5607–5618.
32. Roush, W. R. J. Org. Chem. 1991, 56, 4151–4157.
33. Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc.
1957, 79, 1920–1923.
34. Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987,
109, 3353–3361.
35. Ruiz, M.; Ojea, V.; Quintela, J. M. Tetrahedron: Asym-
metry 2002, submitted
36. Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–
164.
37. Minimun energy conformations for models of all possible
g- and d-lactones derived from adducts 8, 9 and 10 (with
the alkyl chain of the alkoxy and silyl ether groups
reduced to methyl and proton, respectively) were located
using the MMX force field as implemented in
PCMODEL.38 The geometries of the most important
conformers were fully optimized semiempirically, using
the MNDO,39 AM140 and PM341 Hamiltonians included
in MOPAC 93.42 It is worth noting that models for
g-lactones showed lower heats of formation than the
corresponding d-isomers (the differences being higher
than 3 kcal/mol), and thus, according to semiempirical
calculations the cyclization step gave rise, exclusively, to
the thermodynamic lactones.
44. Cheung, S. T.; Benoiton, N. L. Can. J. Chem. 1977, 55,
906–910.
45. Related b-eliminations have been observed for furanones
and pyranones derived from glucosaminic acid and other
sugar lactones, see: (a) Bru¨ckner, R. Chem. Commun.
2001, 141–152; (b) Varela, O. Pure Appl. Chem. 1997, 69,
621–626.
46. O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47,
2663–2666.
47. Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37,
1673–1674.