Efficient synthesis of direct precursors of the carbohydrate moiety of new antibacterials 6-epi-VIC-105555 and 6-epi-VIC-II

Article abstract of DOI:10.1080/07328303.2011.614982

In search for new antibiotics we have developed a novel route leading to direct precursors of the carbohydrate moieties of new promising antibacterial agents 6-epi-VIC-105555 and 6-epi-VIC-II. The presented synthetic strategy consists of using as starting material the readily available-dibenzylamino- ketoester and application of a sequence of chemical transformations on C-7: olefination or methylation, reduction, deoxygenation of the terminal alcohol, and finally hydrogenation. The desired molecules were obtained in a stereoselective fashion and with good overall yields. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/07328303.2011.614982

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Efficient Synthesis of Direct Precursors
of the Carbohydrate Moiety of New
Antibacterials 6-Epi-VIC-105555 and 6-
Epi-VIC-II
Tomasz K. Olszewski a , Fiona Serra a , Claude Grison a & Patric
Herson b
a Centre d’Ecologie Fonctionnelle et Evolutive, Unité Mixte de
Recherche 5175 , Campus CNRS, 1919 Route de Mende, 34293,
Montpellier cedex 5, France
b Université Pierre et Marie Curie Paris 6 , 4 Place Jussieu, 75252
Paris, Cedex 5, France
Published online: 21 Sep 2011.
To cite this article: Tomasz K. Olszewski , Fiona Serra , Claude Grison & Patric Herson (2011) Efficient
Synthesis of Direct Precursors of the Carbohydrate Moiety of New Antibacterials 6-Epi-VIC-105555 and
6-Epi-VIC-II, Journal of Carbohydrate Chemistry, 30:2, 94-115, DOI: 10.1080/07328303.2011.614982
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Journal of Carbohydrate Chemistry, 30:94–115, 2011
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ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2011.614982
Efficient Synthesis of Direct
Precursors of the Carbohydrate
Moiety of New Antibacterials
6-Epi-VIC-105555 and
6-Epi-VIC-II
Tomasz K. Olszewski,1 Fiona Serra,1 Claude Grison,1
and Patric Herson2
1Centre d’Ecologie Fonctionnelle et Evolutive, Unite´ Mixte de Recherche 5175,
Campus CNRS, 1919 Route de Mende, 34293 Montpellier cedex 5, France
2Universite´ Pierre et Marie Curie Paris 6, 4 Place Jussieu, 75252 Paris,
Cedex 5, France
In search for new antibiotics we have developed a novel route leading to direct pre-
cursors of the carbohydrate moieties of new promising antibacterial agents 6-epi-VIC-
105555 and 6-epi-VIC-II. The presented synthetic strategy consists of using as starting
material the readily available β-dibenzylamino-α-ketoester and application of a se-
quence of chemical transformations on C-7: olefination or methylation, reduction, de-
oxygenation of the terminal alcohol, and finally hydrogenation. The desired molecules
were obtained in a stereoselective fashion and with good overall yields.
Keywords Lincosamides; Antibacterials; Stereoselective synthesis; Azetidinium salt;
Darzens condensation
INTRODUCTION
Lincomycin 1[1] and its semisynthetic congener clindamycin 2[2] (Fig. 1) are the
most representative examples of the lincosamide class of antibacterial agents
and are used therapeutically for the treatment of mixed anaerobic and aerobic
infections, and additionally as an alternative in the treatment of patients aller-
gic to β-lactam antibiotics.[3] Lincosamides exert their antibacterial activity by
Received April 18, 2011; accepted July 31, 2011.
Address correspondence to Tomasz K. Olszewski, Centre d’Ecologie Fonctionnelle et
Evolutive, Unite´ Mixte de Recherche 5175, Campus CNRS, 1919 Route de Mende,
34293 Montpellier cedex 5, France. E-mail: tomasz.olszewski@pwr.wroc.pl
94

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
95
Figure 1: Structures of known lincosamide antibacterials.
binding to the ribosome and inhibiting bacterial protein synthesis.[4] Despite
the success of the compounds 1 and 2, finding second-generation lincosamides
with an extended antibacterial spectrum (including enterococci,[5] methicillin-
resistant Staphylococcus aureus, and clindamycin-resistant strains), an
improved side effect profile (coverage of Clostridium difficile to prohibit pseu-
domembranous colitis),[6] and superior pharmacokinetics (once-daily dosing)
is still desirable. For that reason several methods for semisynthetic modifi-
cation of lincomycin 1 and clindamycin 2 have been reported; for example,
increasing the amino acid ring size from pyrrolidine (five membered) to piperi-
dine (six membered) has resulted in a potent veterinary antibiotic pirlimycin
3,[7] and most recently substitution of the 7-hydroxy group by a methyl group
in conjunction with novel amides resulted in the discovery of VIC-II 4 and
structurally similar VIC-105555 5 (Fig. 1), both compounds showing a very
promising antibacterial activity.[8] The latter has been rapidly progressed into
preclinical development.
Synthetic work on the preparation of the antibacterial agents 1–5 has
mainly been focused on the preparation of the carbohydrate moiety (Fig. 1) that
represents the principal difficulty of the steric control in introducing two chiral
centers at C-6 and C-7 in the case of 1–3 and one chiral center at C-6 in the
case of 4–5.[9] Coupling with the appropriate carboxylic acid fragment and in-
troduction of the glycoside thiomethyl group can be considered as solved.[7,8,10]
As a part of our program aimed at developing new versatile procedures for
carbohydrate synthesis, we became interested in preparing the precursors of
the sugar moiety of the VIC-II 4 and VIC-105555 5, in light of the importance
of those compounds for development of new antibiotics. We have previously
reported on several applications of dihalogenoacetate carbanions[11] and devel-
oped a general synthesis of α-ketoesters from carbonyl compounds using potas-
sium alkyl dichloroacetates.[12] Applied to dialdosugar derivatives, the method
proved to be very convenient for the chain extension with an α-ketoester
unit[13] and to introduce a functionality at the C-6 position.[14] In this report
we describe a successful application of this protocol for the stereoselective

T.K. Olszewski et al.
96
Figure 2: Retrosynthetic analysis.
synthesis of the direct precursors of the carbohydrate moiety of new antibacte-
rial agents, 6-epi-VIC-II 4 and 6-epi-VIC-105555 5.
RESULTS AND DISCUSSION
Our synthetic strategy leading stereoselectively to compounds 6, precursors
of the carbohydrate fragments of antibiotic 6-epi-VIC-105555, and to the
molecule 7, the sugar fragment of the C-6 epimer of VIC-II, is presented in
Figure 2. In the case of the synthesis of carbohydrate 6, the synthetic strategy
consists of using as starting material the readily available β-dibenzylamino-α-
ketoester 14 and application of a sequence of chemical transformations: car-
bonyl olefination; complete reduction of a bifunctional α, β-ethylenic ester;
deoxygenation of the terminal alcohol; and finally hydrogenolysis to yield selec-
tively the desired molecule. A similar strategy can be applied for the prepara-
tion of the carbohydrate 7, the main difference being the C C bond formation
by regioselective methylation of the ketone unit of the starting material 14 in
the first step of the synthesis. The β-dibenzylamino-α-ketoester 14 was chosen
as the starting material as it can be easily synthesized as a mixture of two
epimers, that is, 14-D-glycero or 14-L-glycero. From this mixture epimer 14-D-
glycero can be isolated in pure form, although the separation is difficult.[15] In
this study, therefore, we use 14-L-glycero as starting material, as this epimer
can be much more easily obtained. Additionally, in the preparation of precur-
sor of the carbohydrate moiety of 6-epi-VIC-105555, mixture 14-L-glycero/14-
D-glycero is also tested.
Synthesis of the Direct Precursors of the Carbohydrate Moiety
of 6-epi-VIC-105555
The detailed synthetic pathway leading selectively to the precursors of the
carbohydrate moiety of 6-epi-VIC-105555 is presented in Scheme 1.
The first step of the reaction sequence is the carbonyl olefination reac-
tion of β-dibenzylamino-α-ketoester 14 with methyltriphenylphosphonium bro-
1
mide and LDA as a base.[16] In the case of epimer 14-L-glycero, H NMR, 13C

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
97
Scheme 1: Preparation of the precursors of the carbohydrate moiety of 6-epi-VIC-105555.
NMR, and X-ray analyses of the so-obtained olefin 12-L-glycero unambigu-
ously demonstrated the configurational integrity of the chiral center at C-6.[17]
When the reaction was performed using an epimeric mixture 14-L-glycero/14-
D-glycero, the lower reactivity of 14-D-glycero compared with its C-6 epimer
was observed, and that accounts for the lower yield of the reaction. Next, sev-
eral attempts to reduce the ester moiety of the olefin 12 with different reducing
agents were performed (Table 1) with the aim to obtain the compound 17. In
the case of the use of DIBAL[18] (Table 1, entry 1) or AlH3,[19] generated in situ
by addition of LiAlH4 to AlCl3 (Table 1, entry 2), the desired alcohol 17 was
isolated with low yields and gave predominantly the olefin 18, resulting from
1,4 addition followed by the elimination of the amino group. In turn, when
LiAlH4 was used as reducing agent (Table 1, entries 3–6), unexpectedly but
luckily for us, simultaneous reduction of both ester function and C C double
bond was noted, and amino alcohol 10 was isolated as the major product. The
reaction worked equally well for both, the pure epimer 12-L-glycero (Table 1,
entries 3 and 4) and the mixture of epimers 12-L-glycero/12-D-gycero (Table 1,
entries 5 and 6). It has to be noted that this transformation generates a second
chiral center on the C-7 carbon; however, since this center disappears in the

T.K. Olszewski et al.
98
Table 1: Reduction of the olefine 12 using different reducing agents
Reducing
agent
10a/
17a/
18/
Entry
12a
Yield [%]b
Yield [%]b
Yield [%]b
1
2
3
4
5
12-L-glycero
12-L-glycero
12-L-glycero
12-L-glycero
12-L-glycero/12-
D-glycero
DIBAL
LiAlH4/AlCl3
—
—
17-L-glycero/11
55
63
36
10
—
17-L-glycero/37
LiAlH4, 1.3 equiv. 10/64
LiAlH4, 1.8 equiv. 10/90
LiAlH4, 1.6 equiv. 10 / 92
—
—
—
(46/54)
6
12-L-glycero/12-
D-glycero
(40/60)
LiAlH4, 1.6 equiv. 10 / 85
—
—
aEpimeric ratio determined by 1H NMR of the crude reaction mixture.
bYield of isolated product.
next step we did not attempt to establish its absolute configuration. The ma-
jor epimer of 10 (with S configuration on the C-6) could be separated from the
mixture of four possible stereomers by careful chromatographic purification,
but its configuration on C-7 carbon remained unknown.
Having in our hands the amino alcohol 10, we preceded to further steps
of the synthesis of the precursors of the carbohydrate moiety of 6-epi-VIC-
105555, that is, the deoxygenation of the alcohol at terminal position C-8. For
that purpose the tosylation-reduction protocol was successfully applied (Sch.
1). Reaction of amino alcohol 10 with TsCl in CH2Cl2 and in the presence of
Et3N resulted in formation of azetidinium salt 19, which was isolated and its
structure unambiguously confirmed by numerous data. As it can observed in
Figure 3, the Rf (0.27 hexane/AcOEt/MeOH: 3/1/1) is in good agreement with
the polarity of the salt 19. The mass spectrometry gives a molecular peak at
100% at 480.2750, precise mass of the azetidinidium cation.
The NMR data of methylene protons carried by Ph are compatible with the
pseudo-axial and pseudo-equatorial positions on a skeleton of azetidinium type
(1H NMR: δ = 1.37 ppm and 13C NMR: δ = 3.22 ppm). They are also in good
agreement with similar structures described in the literature.[20] Additionally,

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
99
Figure 3: Characteristics of the azetidinium salt 19 (color figure available online).
the proton H-6 is more shielded in the ammonium 19 (4.49 ppm) than in the
amine 10 (3.45–3.55 ppm). The chemical shifts of C-6 confirm this analysis
(δ = 74.04 ppm for 19 and δ = 57.95 ppm for 10). Subsequent treatment of the
azetidinium salt 19 with LiAlH4 afforded the desired deoxygenated derivative
8. It has to be noted that this protocol can be performed in situ without isola-
tion of the azetidinium salt 19. Application of the tosylation-reduction protocol
to amino alcohol 10 (the major epimer with S configuration on C-6 isolated
by chromatography from the mixture of four possible stereomers) gave pure
8-L-glycero, as confirmed by X-ray analysis.[17] In turn, the use of amino alco-
hol 10 (mixture of DL-erythro/threo in ratio 36/22/36/6) as substrate afforded
the desired deoxygenated derivative 8 as a mixture of 8-D-glycero/8-L-glycero
in ratio 55/45, which could be enriched to 90% in 8-D-glycero by chromatogra-
phy. Finally, in the last step of the synthesis the amino group of 8-L-glycero
was deprotected by hydrogenation (10% Pd/C, 42 bars of H2 during 45 h at rt)
to afford, with 95% yield, the free amine 6-L-glycero, direct precursor of the
carbohydrate fragment of 6-epi VIC-105555. It can be postulated that the hy-
drogenation of the 8-D-glycero would also afford the desired free amine with
equally good yield.
Synthesis of the Carbohydrate Moiety of the C-6 Epimer of VIC-II
The success of the stereoselective preparation of the precursors of the
carbohydrate fragment of 6-epi-VIC-105555 prompted us to use a similar syn-
thetic pathway for the stereoselective preparation of the precursor of the car-
bohydrate fragment of another promising antibacterial, the 6-epi-VIC-II. The
applied protocol is depicted in Scheme 2.
The initial reaction is methylation of the β-dibenzylamino-α-ketoester 14-
L-glycero with MeLi.[21] The reaction is completely stereoselective and yields

T.K. Olszewski et al.
100
Scheme 2: Preparation of 6-epi-VIC-II.
(65%) the desired C-7 methylated tertiary alcohol 13-D-threo. This assignment
was confirmed by X-ray analysis of 11-D-threo, the product of the next step,
namely, the reduction of the 13-D-threo by means of LiAlH4.[17] Subsequently,
the deoxygenation of the alcohol at terminal position C-8 of 11-D-threo using
the, presented earlier, tosylation-reduction protocol led stereoselectively to the
desired aminoalcohol 9-L-glycero (71%). In the final step, the latter was sub-
jected for hydrogenation (10% Pd/C, 19 bars of H2 during 32 h at rt) to afford,
with 72% yield, the free amine 7-L-glycero, direct precursor of the carbohydrate
fragment of 6-epi VIC-II.
Preparation of 7-Methyl-methylthio-lincosamine 25-L-glycero,
the Carbohydrate Core of Antibiotic 6-epi VIC 10555
To demonstrate the usefulness of our precursor of the carbohydrate moiety
of new lincosamine antibiotics, we performed the complete synthesis of the car-
bohydrate core of the 6-epi-VIC-105555 25-L-glycero using a literature protocol
and amine 6-L-glycero as starting material (Sch. 3).[22]
First, the amine 6-L-glycero was protected in the form of trifluroaceti-
camide 21-L-glycero. Next, total deprotection of 21-L-glycero with aqueous TFA
was followed by acetylation and bromination with HBr in acetic acid to ob-
tain 22-L-glycero. The bromide 22-L-glycero was transformed first into 1,2-
tetraacetate, with the use of silver acetate (AgOAc) in acetic acid, and then into
β-chloride 23-L-glycero.[22] The α-thiomethyl group installation was performed

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
101
Scheme 3: Preparation of 7-methyl-methylthio-lincosamine 25-L-glycero, the carbohydrate
core of antibiotic 6-epi VIC 10555.
in the reaction of β-chloride 23-L-glycero with sodium thiomethoxide (MeSNa).
In the final step, the complete deprotection was achieved with aqueous NaOH
to obtain the desired 7-methyl-methylthio-lincosamine 25-L-glycero.
CONCLUSION
In summary, we have developed a novel route to the direct precursors of the
carbohydrate moieties of new potent antibacterial agents 6-epi-VIC-105555
and 6-epi-VIC-II. While consisting of several individual synthetic steps, the
presented route is featured with high-average yield per step and can be
employed to synthesize a carbohydrate fragment of a variety of novel lin-
cosamides, promising antimicrobial agents that warrant further study. In
addition, in order to demonstrate the usefulness of our precursors in the
synthesis of new lincosamine antibiotics we performed the complete synthe-
sis of the carbohydrate core of the 6-epi-VIC-1055555 using our precursor as
starting material.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on Bruker AC 250 MHz or Bruker
Ultrashield Plus 400 MHz spectrometers. Chemical shifts (δ) are reported in

T.K. Olszewski et al.
102
parts per million (ppm) relative to internal tetramethylsilane (Me4Si, δ 0.0)
1
for H NMR and CDCl3 (δ 77.0) for 13C NMR. Coupling constants (J) are re-
ported in hertz (Hz). Infrared spectra (IR) were recorded on a Nicolet 210 FT-IR
spectrometer and were taken as thin films or as KBr discs and only the most
representative frequencies (in cm−1) are given. Reported melting points were
measured using Electrothermal IA 9000 apparatus and are uncorrected. Op-
tical rotations were measured on a Bellingham & Stanley limited ADP 200
polarimeter. Column chromatography was performed using silica gel 60 Merck
(63–200 µm). Visualization was accomplished with UV light and exposure to
EtOH/H2SO4 36M (80/20) solution followed by heating. Preparative TLC was
performed on Merck (5535) KIESELGEL 60-F254 plates. All reactions were per-
formed under an atmosphere of dry nitrogen in oven-dried glassware. All sol-
vents for extractions and reactions were technical grade and were dried before
using standard techniques. The β-dibenzylamino-α-ketoester 14-L-glycero and
14-D-glycero were synthesized using our procedure described earlier.[15]
General Procedure for the Olefination Reaction
To the solution of methyltriphenylphosphonium bromide (788 mg,
2.2 mmol) in anhydrous THF (5.0 mL) at −78◦C was injected diisopropylamine
(29 µL, 0.21 mmol) and nBuLi (1.3 mL of 1.6 M solution in hexane). The re-
action vessel was warmed to rt during 4 h and stirred at that temperature for
an additional 1 h. After that time, the reaction mixture was again cooled down
to −78◦C and the solution of 14-L-glycero (1.163 g, 2.1 mmol) in THF (3.0 mL)
was added slowly. The resulting reaction mixture was warmed to rt and stirred
for 14 h. After that time, the solution was hydrolyzed with H2O (3.0 mL) and
sat. aq. NaCl (2.0 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined organic layers were washed
with brine (3 × 25 mL) and dried over anh. Na2SO4. After filtration of drying
agent the solvent was removed under vacuum, affording crude product that
was further purified by column chromatography.
Isopropyl 6-N,N-Dibenzylamino-6,7-dideoxy-1,2:3,4-di-
O-isopropylidene-7-methylene-L-glycero-α-D-galacto-1,
5-octopyranuronate (12-L-glycero)
A white solid (753 mg, 65%), mp 114–115◦C. Rf 0.53 (EtOAc/Hexane 1:4).
[α]D23 –53.0 (c 1.32, CH2Cl2). 1H NMR (CDCl3, 400 MHz): δH 7.39–7.11 (H Ph,
m, 10H), 6.19 (H11a, d, 1H, JH11a-H11b = 1.0 Hz), 5.72 (H1, d, 1H, JH1-H2 = 5.0
Hz), 5.29 (H11b, s, 1H), 5.04 (H9, h, 1H, JH9-H10 = 6.3 Hz), 4.61 (H5, d, 1H,
JH5-H6 = 10.9 Hz), 4.58 (H3, dd, 1H, JH3-H4 = 7.8 Hz, JH3-H2 = 2.5 Hz), 4.37
(H2, dd, 1H, JH2-H1 = 5.0 Hz, JH2-H3 = 2.5 Hz), 4.11 (H4, dd, 1H, JH4-H3 = 7.8
Hz, JH4-H5 = 1.8 Hz), 4.07 (H6, d, 1H, JH6-H5 = 10.6 Hz), 3.93 (H12, d, 2H,

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
103
J = 13.6 Hz), 3.55 (H12’, d, 2H, J = 13.6 Hz), 1.58 (CH3, s, 3H), 1.37 (CH3, s,
3H), 1.29 (CH3, s, 3H), 1.24 (H10, d, 3H, JH10-H9 = 6.3 Hz), 1.22 (H10’, d, 3H,
JH10’-H9 = 5.6 Hz), 1.21 (CH3, s, 3H). 13C NMR (CDCl3, 100 MHz): δC 167.2 (C8,
1C), 140.5 (C Ph, 2C), 137.6 (C7, 1C), 129.1, 127.7, 126.3 (CH Ph, 10C), 126.9
(C11, 1C), 109.4, 108.7 (C13, C14, 2C), 96.9 (C1, 1C), 72.1 (C4, 1C), 71.3 (C3,
1C), 70.5 (C2, 1C), 68.0 (C9, 1C), 66.8 (C5, 1C), 58.9 (C6, 1C), 54.3 (C12, C12’,
∗
2C), 26.0, 26.0, 25.2, 25.1 (CH3 4, 4C), 21.7 (C10, C10’, 2C). IR (disc, KBr) νmax
(cm−1): 1709 (CO), 1616 (C C), 1602, 1494 (C C aromatic), 1455, 1382, 1372
(C(CH3)2). HRMS calcd for C32H42NO7 (M+H)+ 552.2961. Found, 552.2964.
Isopropyl 6-N,N-Dibenzylamino-6,7-dideoxy-1,2:3,4-di-
O-isopropylidene-7-methylene-D-glycero-α-D-galacto-1,
5-octopyranuronate (12-D-glycero)
Obtained as colorless oil (413 mg, 40% as a mixture of 12-D-glycero/12-L-
glycero in ratio 63:37, from which the pure major diastereoisomer was sepa-
rated by column chromatography), using the general olefination protocol de-
scribed above, from a mixture of 14-L-glycero/14-D-glycero (26:74) (1.04 g, 1.89
1
mmol). Rf 0.53 (EtOAc/Hexane 1:4). H NMR (CDCl3, 400 MHz): δH 7.39–7.10
(H Ph, m, 10H), 6.48 (H11a, d, 1H, JH11a-H11b = 1.1 Hz), 5.52 (H11b, s, 1H),
5.42 (H1, d, 1H, JH1-H2 = 5.1 Hz), 5.11 (H9, h, 1H, JH9-H10 = 6.3 Hz), 4.67 (H4,
dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5 = 1.4 Hz), 4.63–4.55 (H3, m, 1H), 4.21 (H2, dd,
1H, JH2-H1 = 5.1 Hz, JH2-H3 = 2.2 Hz), 4.19–4.05 (H5, H6, m, 2H), 3.84 (H12, d,
2H, J = 14.1 Hz), 3.54 (H12’, d, 2H, J = 14.1 Hz), 1.39 (CH3, s, 3H), 1.36 (CH3,
s, 3H), 1.33 (H10, d, 3H, JH10-H9 = 6.4 Hz), 1.32 (CH3, s, 3H), 1.32 (H10’, d,
3H, JH10’-H9 = 6.4 Hz), 1.24 (CH3, s, 3H). 13C NMR (CDCl3, 100 MHz): δC 167.3
(C8, 1C), 140.4 (C Ph, 2C), 135.9 (C7, 1C), 129.0, 128.0, 126.7 (CH Ph, 10C),
128.9 (C11, 1C), 108.7, 108.2 (C13, C14, 2C), 96.7 (C1, 1C), 71.0, 71.0 (C3, C4,
2C), 70.8 (C2, 1C), 68.1 (C9, 1C), 66.1, 60.4 (C5, C6, 2C), 56.2 (C12, C12’, 2C),
∗
25.9, 25.8, 24.8, 24.4 (CH3 4, 4C), 21.9, 21.9 (C10, C10’, 2C). IR (disc, KBr) νmax
(cm−1): 1709 (CO), 1616 (C C), 1602, 1602 (C C aromatic), 1455, 1382, 1372
(C(CH3)2).
General Procedure for Reduction of the Olefine 12-D-Glycero/
12-L-glycero by Means of LiAlH4
To the solution of two epimers 12-L-glycero/12-D-glycero (157.0 mg, 0.27
mmol, in ratio 46/54) in Et2O (4.0 mL) at −78◦C was added slowly LiAlH4
(0.45 mL of 1M solution in Et2O) and an additional portion of Et2O (5.0 mL).
The resulting reaction mixture was stirred at −78◦C for 8 h and then at rt
for an additional 15 h. After that time, the solution was hydrolyzed with 5%
sol. aq. NaOH (0.15 mL). Next, the solution was centrifuged three times and
washed with Et2O (2 × 15 mL). The combined organic extracts were dried
over anh. Na2SO4 and after filtration of drying agent the solvent was removed

T.K. Olszewski et al.
104
under vacuum, affording crude product that was further purified by column
chromatography. The purified compound 10 (130 mg, 92%) was a mixture of
four possible diastereoisomers: 10-D-threo + 10-L-erythro (in ratio 44/2) and
10-D-erythro + 10-L-threo (in ratio 40/14).
6-N,N-Dibenzylamino-6,7-dideoxy-1,2:3,4-di-O-isopropylidene-
7-C-methyl-D-threo and L-erythro-α-D-galacto-1,5-
octopyranitol (10-D-threo and 10-L-erythro)
23
Major epimer. Colorless oil. [α]D
−70.5 (c 1.0, CH2Cl2). Rf 0.25
(EtOAc/Hexane 1:4). 1H NMR (CDCl3, 400 MHz): δH 7.48–7.17 (H Ph, m, 10H),
5.71 (H1, d, 1H, JH1-H2 = 5.3 Hz), 4.63 (H3, dd, 1H, JH3-H4 = 7.8 Hz, JH3-H2
=
2.3 Hz), 4.44 (H5, d, 1H, JH5-H6 = 9.8 Hz), 4.36 (H2, dd, 1H, JH2-H1 = 5.3
Hz, JH2-H3 = 2.5 Hz), 4.33 (H4, dd, 1H, JH4-H3 = 9.6, JH4-H5 = 1.3 Hz), 4.02
(H10, d, 2H, J = 13.4 Hz), 3.93–3.78 (H10’, m, 2H), 3.60–3.47 (H8, m, 2H),
3.18–3.08 (H6, m, 1H), 1.96–1.82 (H7, m, 1H), 1.60 (CH3, s, 3H), 1.53 (CH3, s,
3H), 1.39 (CH3, s, 3H), 1.32 (CH3, s, 3H), 0.64 (H9, d, 3H, JH9-H7 = 6.8 Hz).
13C NMR (CDCl3, 100 MHz): δC δ 140.8 (C Ph, 2C), 129.8, 128.0, 126.7 (CH
Ph, 10C), 109.1, 108.6 (C11, C12, 2C), 96.8 (C1, 1C), 72.4 (C4, 1C), 71.3 (C3,
1C), 70.3, 70.0 (C2, C5, 2C), 65.7 (C8, 1C∗), 58.4 (C6, 1C), 56.3 (C10, C10’, 2C),
36.0 (C7, 1C), 26.2, 25.9, 25.1, 24.7 (CH3 4, 4C), 16.2 (C9, 1C). IR (film, CCl4)
νmax (cm−1): 3600–3200 (OH), 1602, 1494 (C C aromatic), 1454, 1380, 1371
(C(CH3)2). HRMS calcd for C29H40NO6 (M+H)+ 498.2856. Found, 498.2858.
23
Minor epimer. Colorless oil. [α]D
–58.7 (c 1.5, CH2Cl2). Rf 0.18
(EtOAc/Hexane 1:4). 1H NMR (CDCl3, 400 MHz): δH 7.60–7.15 (H Ph, m, 10H),
5.75 (H1, d, 1H, JH1-H2 = 5.3 Hz), 4.66 (H3, dd, 1H, JH3-H4 = 8.1 Hz, JH3-H2
=
2.5 Hz), 4.41 (H2, dd, 1H, JH2-H1 = 5.3 Hz, JH2-H3 = 2.5 Hz), 4.34 (H5, dd, 1H,
JH5-H6 = 10.4 Hz, JH5-H4 = 1.8 Hz), 4.17 (H4, dd, 1H, JH4-H3 = 8.1, JH4-H5 = 1.8
Hz), 4.09–3.82 (H10, H10’, m, 4H), 3.55–3.45 (H6, m, 1H), 3.45–3.35 (H8, m,
1H), 3.13 (H8’, dd, 1H, JH8’-H8 = 10.9 Hz, JH8’-H7 = 2.3 Hz), 1.77–1.67 (H7, m,
1H), 1.59 (CH3, s, 3H), 1.52 (CH3, s, 3H), 1.40 (CH3, s, 3H), 1.31 (CH3, s, 3H),
1.18 (H9, d, 3H, JH9-H7 = 7.1 Hz). 13C NMR (CDCl3, 100 MHz): δC 129.4–126.7
(CH Ph, 10C), 109.4, 108.8 (C11, C12, 2C), 96.7 (C1, 1C), 71.5 (C4, 1C), 71.0
(C3, 1C), 70.2 (C2, 1C), 68.5 (C5, 1C), 67.4 (C8, 1C), 57.8 (C6, 1C), 57.4 (C10,
∗
C10’, 2C), 34.2 (C7, 1C), 26.2, 25.9, 25.0, 24.6 (CH3 4, 4C), 12.5 (C9, 1C).
6-N,N-Dibenzylamino-6,7-dideoxy-1,2:3,4-di-O-isopropylidene-
7-C-methyl-D-erythro and L-threo-α-D-galacto-1,5-
octopyranitol (10-D-erythro and 10-L-threo)
Major epimer. Colorless oil. Rf 0.19 (EtOAc/Hexane 1:4). 1H NMR (CDCl3,
400 MHz): δH 7.41–7.24 (Ph, m, 10H), 5.49 (H1, d, 1H, JH1-H2 = 5.1 Hz),
4.60–4.53 (H3, H4, m, 2H), 4.26 (H2, dd, 1H, JH2-H1 = 5.1 Hz, JH2-H3 = 1.7
Hz), 4.09 (H5, d, 1H, JH5-H6 = 9.9 Hz), 3.78 (H10, d, 2H, J = 13.5 Hz),

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
105
3.62–3.52 (H10’, H8, m, 4H), 3.12 (H6, dd, 1H, JH6-H5 = 9.9 Hz, JH6-H7 = 1.2
Hz), 2.39–2.28 (H7, m, 1H), 1.50 (CH3, s, 3H), 1.34 (CH3, s, 3H), 1.30 (CH3,
s, 3H), 1.24 (CH3, s, 3H), 1.07 (H9, d, 3H, JH9-H7 = 7.1 Hz). 13C NMR (CDCl3,
100 MHz): δC 139.5 (C Ph, 2C), 129.5, 128.0, 126.9 (CH Ph, 10C), 108.6, 108.5
(C11, C12, 2C), 96.7 (C1, 1C), 71.4 (C4, 1C), 70.9, 70.9 (C3, C2, 2C), 68.3 (C8,
1C), 65.9 (C5, 1∗C), 57.9 (C6, 1C), 55.1 (C10, C10’, 2C), 32.9 (C7, 1C), 25.9, 25.8,
24.8, 24.3 (CH3 4, 4C), 13.8 (C9, 1C).
Minor epimer. Colorless oil. Rf 0.18 (EtOAc/Hexane 1:4). 1H NMR (CDCl3,
400 MHz): δH 7.41–7.24 (Ph, m, 10H), 5.55 (H1, d, 1H, JH1-H2 = 5.2 Hz), 4.70
(H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.1 Hz), 4.44 (H4, dd, 1H, JH4-H3 = 8.0
Hz, JH4-H5 = 1.3 Hz), 4.32 (H2, dd, 1H, JH2-H1 = 5.2 Hz, JH2-H3 = 2.1 Hz), 4.13
(H5, d, 1H, JH5-H6 = 9.9 Hz), 3.82 (H10, d, 2H, J = 14.2 Hz), 3.68 (H10’, d,
2H, J = 13.1 Hz), 3.44 (H8, dd, 1H, JH8-H8’ = 11.1 Hz, JH8-H7 = 6.4 Hz), 3.33
(H8’, dd, 1H, JH8’-H8 = 11.1 Hz, JH8’-H7 = 4.0 Hz), 3.25 (H6, dd, 1H, JH6-H5
=
9.1 Hz, JH6-H7 = 4.1 Hz), 2.15–2.05 (H7, m, 1H), 1.56 (CH3, s, 3H), 1.44 (CH3,
s, 3H), 1.32 (CH3, s, 3H), 1.26 (CH3, s, 3H), 1.08 (H9, d, 3H, JH9-H7 = 7.3 Hz).
13C NMR (CDCl3, 100 MHz): δC 139.8 (C Ph, 2C), 128.8, 128.3, 127.3 (CH Ph,
10C), 109.0, 108.4 (C11, C12, 2C), 96.8 (C1, 1C), 72.6 (C4, 1C), 71.2 (C3, 1C),
70.6 (C2, 1C), 66.5 (C8, 1C), 65.3 (C5, 1C), 56.7 (C6, 1C), 55.7 (C10, C10’, 2C),
∗
35.5 (C7, 1C), 26.1, 26.0, 24.8, 24.5 (CH3 4, 4C), 13.3 (C9, 1C).
Preparation of the Azetidinium Salt 19
To the solution of pure major epimer (117.0 mg, 0.36 mmol, from mixture
10-D-threo and 10-L-erythro) in CH2Cl2 (6.0 mL) at rt was added neat Et3N
(0.15 mL, 1.07 mmol) and DMAP (43.0 mg, 0.36 mmol). The resulting reaction
mixture was cooled down to 0◦C and TsCl (136.0 mg, 0.71 mmol) was added.
After completion of the addition, the reaction mixture was warmed to rt and
stirred for 18 h. After that time, the solution was hydrolyzed with sat. aq. sol.
of NaHCO3 (2.0 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined organic layers were dried
over anh. Na2SO4 and after filtration of drying agent the solvent was removed
under vacuum, affording crude product that was further purified by column
chromatography, affording the desired product 19 (54.0 mg, 23%) as a pale
1
yellow oil. Rf 0.27 (EtOAc/Hexane/MeOH 1:3:1). H NMR (CDCl3, 400 MHz):
δH 7.87–7.07 (H Ph, m, 14H), 5.94 (H10a, d, 1H, JH10a-H10b = 12.5 Hz), 5.66 (H1,
d, 1H, JH1-H2 = 5.1 Hz), 4.78 (H5, dd, 1H, JH5-H6 = 10.2 Hz, JH5-H4 = 1.5 Hz),
4.70 (H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.5 Hz), 4.69–4.63 (H8, m, 1H), 4.57
(H10b, d, 1H, JH10b-H10a = 12.3 Hz), 4.53–4.45 (H6, m, 1H), 4.42 (H2, dd, 1H,
JH2-H1 = 5.1 Hz, JH2-H3 = 2.5 Hz), 4.21 (H4, dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5
=
1.7 Hz), 4.11 (H10’a, d, 1H, JH10’a-H10’b = 14.0 Hz), 4.12–4.02 (H7, m, 1H), 3.85
(H10’b, d, 1H, JH10’b-H10’a = 12.8 Hz), 3.38–3.31 (H8’, m, 1H), 2.31 (CH3 TsO-,
s, 3H), 1.60 (CH3, s, 3H), 1.49 (CH3, s, 3H), 1.34 (CH3, s, 3H), 1.27 (CH3, s,

T.K. Olszewski et al.
106
3H), 0.73 (H9, d, 3H, JH9-H7 = 6.4 Hz). 13C NMR (CDCl3, 100 MHz): δC 144.2,
138.7, 128.0, 127.8 (C Ph, 4C), 133.7, 133.5, 130.9, 130.5, 129.5, 129.3, 128.3,
126.2 (CH Ph, 14C), 109.9, 109.5 (C11, C12, 2C), 96.2 (C1, 1C), 74.0 (C6, 1C),
70.6 (C3, 1C), 70.1 (C2, 1C), 69.1 (C4, 1C), 65.1 (C5, 1C), 60.1 (C10, 1C), 63.3
∗
(C10’, 1C), 59.5 (C8, 1C), 50.6 (C7, 1C), 26.0, 25.7, 24.8, 24.0 (CH3 4, 4C), 21.3
(CH3 TsO-, 1C), 16.3 (C9, 1C). IR (film, CCl4) νmax (cm−1): 1600, 1497 (C C
aromatic), 1456, 1381 (C(CH3)2). HRMS calcd for C29H38NO5 (M)+ 480.2750.
Found, 480.2750.
Preparation of 6-N,N-Dibenzylamino-1,2:3,4-di-O-
isopropylidene-7-C-methyl-6,7,8-trideoxy-L-
glycero-α-D-galacto-1,5-octopyranose (8-L-glycero)
To the solution of azetidinium salt 19 (52.0 mg, 0.080 mmol) in Et2O/THF
(2.0 mL/3.0 mL) mixture, LiAlH4 (0.2 mL of 1M sol. in Et2O) was added at
rt and the resulting solution was stirred at that temperature for 2 h. After
that time, the reaction mixture was hydrolyzed with 5% sol. aq. NaOH (0.10
mL), centrifuged three times, and washed with Et2O (2 × 10 mL). The com-
bined organic layers were dried over anh. Na2SO4 and after filtration of drying
agent the solvent was removed under vacuum, affording crude product that
was further purified by column chromatography, affording the desired prod-
uct 8-L-glycero. White solid (38.0 mg, 99%) mp 132–133◦C. [α]D23 –81.6 (c 0.76,
CH2Cl2). Rf 0.58 (EtOAc/Hexane 1:4). 1H NMR (CDCl3, 400 MHz): δH 7.90–7.35
(H Ph, m, 10H), 5.72 (H1, d, 1H, JH1-H2 = 5.2 Hz), 4.63 (H3, dd, 1H, JH3-H4
=
7.9 Hz, JH3-H2 = 2.5 Hz), 4.38 (H2, dd, 1H, JH2-H1 = 5.2 Hz, JH2-H3 = 2.5 Hz),
4.26 (H5, dd, 1H, JH5-H6 = 10.3 Hz, JH5-H4 = 1.6 Hz), 4.19 (H4, dd, 1H, JH4-H3
= 7.9 Hz, JH4-H5 = 1.7 Hz), 3.96 (H9, d, 2H, J = 13.3 Hz), 3.83 (H9’, d, 2H, J =
12.6 Hz), 3.04 (H6, dd, 1H, JH6-H5 = 10.3 Hz, JH6-H7 = 3.1 Hz), 1.77–1.68 (H7,
m, 1H), 1.60 (CH3, s, 3H), 1.52 (CH3, s, 3H), 1.40 (CH3, s, 3H), 1.32 (CH3, s,
3H), 0.89 (H8, d, 3H, JH8-H7 = 7.2 Hz), 0.64 (H8’, d, 3H, JH8’-H7 = 6.7 Hz).13C
NMR (CDCl3, 100 MHz): δC 141.5 (C Ph, 2C), 129.8, 127.9, 126.5 (CH Ph, 10C),
109.2, 108.6 (C10, C11, 2C), 96.9 (C1, 1C), 72.3 (C4, 1C), 71.2 (C3, 1C), 70.4
(C2, 1C), 69.8 (C5, 1C), 58.3 (C6, 1C), 57.2 (C9, C9’, 2C), 28.8 (C7, 1C), 26.3,
∗
26.0, 25.1, 24.9 (CH3 4, 4C), 21.6 (C8’, 1C), 17.5 (C8, 1C). IR (film, CCl4) νmax
(cm−1): 1600, 1494 (C C aromatic), 1453, 1382, 1370 (C(CH3)2). HRMS calcd
for C29H39NO5 (M)+ 481.2828. Found, 481.2828.
Preparation of 6-N,N-Dibenzylamino-1,2:3,4-di-O-
isopropylidene-7-C-methyl-6,7,8-trideoxy-D-
glycero-α-D-galacto-1,5-octopyranose (8-D-glycero)
Prepared from the mixture of four possible diastereoisomers of amino alco-
hol 10 (38.0 mg, 0.076 mmol; composition of the mixture was 10-D-threo +

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
107
10-L-erythro and 10-D-erythro + 10-L-threo in ratio 36/6/36/22). The overall
yield, after two steps, of the purified product (a mixture of 8-L-glycero/8-D-
glycero in ratio 45/55) was 75% (28.0 mg). The sample of 8-D-glycero (en-
riched to 90% in the desired epimer) was obtained after the second chro-
23
matographic purification as colorless oil. [α]D –18.5 (c 0.65, CH2Cl2). Rf 0.56
(EtOAc/Hexane 1:8). 1H NMR (CDCl3, 400 MHz): δH 7.47–7.19 (H Ph, m, 10H),
5.51 (H1, d, 1H, JH1-H2 = 5.1 Hz), 4.61 (H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2
=
2.1 Hz), 4.51 (H4, dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5 = 1.4 Hz), 4.26 (H2, dd, 1H,
JH2-H1 = 5.1 Hz, JH2-H3 = 2.1 Hz), 4.05 (H5, dd, 1H, JH5-H6 = 10.0 Hz, JH5-H4
= 1.1 Hz), 3.77 (H9, d, 2H, J = 13.4 Hz), 3.65 (H9’, d, 2H, J = 13.4 Hz), 2.95
(H6, dd, 1H, JH6-H5 = 10.0 Hz, JH6-H7 = 2.1 Hz), 2.23–2.13 (H7, m, 1H), 1.51
(CH3, s, 3H), 1.38 (CH3, s, 3H), 1.34 (CH3, s, 3H), 1.32 (CH3, s, 3H), 0.99 (H8,
d, 3H, JH8-H7 = 7.2 Hz), 0.94 (H8’, d, 3H, JH8’-H7 = 6.9 Hz). 13C NMR (CDCl3,
100 MHz): δC 140.2 (C Ph, 2C), 129.4, 128.0, 126.8 (CH Ph, 10C), 108.6, 108.2
(C10, C11, 2C), 96.8 (C1, 1C), 71.8 (C4, 1C), 71.1 (C3, 1C), 70.7 (C2, 1C), 66.5
(C5, 1C), 59.2 (C6, 1C), 55.6 (C9, C9’, 2C), 26.3 (C7, 1C), 26.0, 25.9, 24.9, 24.5
∗
(CH3 4, 4C), 21.2 (C8, 1C), 19.8 (C8’, 1C).
Preparation of 6-Amino-1,2:3,4-di-O-isopropylidene-7-C-methyl-
6,7,8-trideoxy-L-glycero-α-D-galacto-1,5-octopyranose
(6-L-glycero), the Direct Precursor of the Carbohydrate Moiety
of 6-epi VIC-105555
To the solution of compound 8-L-glycero (27.0 mg, 0.056 mmol) in MeOH
(10.0 mL) was added 10% Pd/C (10.0 mg) and the resulting solution was stirred
under atmosphere of H2 (19 bars) for 45 h. After completion of the reaction,
the resulting mixture was filtered through a pad of Celite and the filtrate was
concentrated under reduced pressure, affording desired product, the primary
amine 6-L-glycero (16.0 mg, 95%), that does not require any further purifica-
tion. Colorless oil. [α]D23 –47.0 (c 1.15, CH2Cl2). Rf 0.28 (EtOAc/Hexane/MeOH
1
1:3:1). H NMR (CDCl3, 400 MHz): δH 5.59 (H1, d, 1H, JH1-H2 = 5.1 Hz), 4.58
(H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.3 Hz), 4.30 (H2, dd, 1H, JH2-H1 = 5.1
Hz, JH2-H3 = 2.3 Hz), 4.25 (H4, dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5 = 1.7 Hz), 3.57
(H5, dd, 1H, JH5-H6 = 7.0 Hz, JH5-H4 = 1.6 Hz), 2.89 (H6, dd, 1H, JH6-H5 = 7.0
Hz, JH6-H7 = 3.5 Hz), 1.99–1.90 (H7, m, 1H), 1.53 (CH3, s, 3H), 1.46 (CH3, s,
∗
3H), 1.33 (CH3 2, s, 6H), 1.02 (H8, d, 3H, JH8-H7 = 6.8 Hz), 0.90 (H8’, d, 3H,
JH8’-H7 = 6.8 Hz).13C NMR (CDCl3, 100 MHz): δC 109.2, 108.5 (C9, C10, 2C),
96.8 (C1, 1C), 72.0 (C4, 1C), 71.0 (C3, 1C), 70.6 (C2, 1C), 69.4 (C5, 1C), 55.6
∗
(C6, 1C), 29.0 (C7, 1C), 26.1, 26.0, 25.0, 24.3 (CH3 4, 4C), 20.5 (C8, 1C), 15.9
(C8’, 1C). IR (film, CCl4) νmax (cm−1): 3390 (NH2), 1459, 1381 (C(CH3)2). HRMS
calcd for C15H28NO5 (M+H)+ 302.1967. Found, 302.1968.

T.K. Olszewski et al.
108
Preparation of Isopropyl 6-Deoxy-6-N,N-dibenzylamino-1,2:3,4-
di-O-isopropylidene-7-C-methyl-D-threo-α-D-galacto-1,
5-octopyranuronate (13-D-threo)
To the solution of 14-L-glycero (823 g, 1.49 mmol) in Et2O (7.0 mL) at −78◦C
was gradually injected MeLi (1.0 mL of 1.6 M sol in Et2O). After the addition
was completed, the resulting reaction mixture was stirred at −78◦C for 0.75 h
and then warmed to 0◦C and stirred at that temperature for an additional 0.5
h. After that time, the reaction mixture was cooled down to −35◦C and was
hydrolyzed with sat. Et2O solution of HCl (3.0 mL) and H2O (3.0 mL). The
layers were separated and the aqueous layer was extracted with Et2O (3 × 20
mL) and CH2Cl2 (3 × 20 mL). The combined organic layers were dried over
anh. Na2SO4. After filtration of drying agent the solvent was removed under
vacuum, affording crude product that was further purified by column chro-
matography to give 13-D-threo. Colorless oil (550 mg, 65%). [α]D23 –99.3 (c 0.73,
CH2Cl2). Rf 0.45 (EtOAc/Hexane 1:4). 1H NMR (CDCl3, 400 MHz): δH 7.57–7.05
(H Ph, m, 10H), 5.68 (H1, d, 1H, JH1-H2 = 5.1 Hz), 4.75 (H9, h, 1H, JH9-H10 = 6.3
Hz), 4.59 (H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.4 Hz), 4.37–4.32 (H2, H5, m,
2H), 4.26 (H4, dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5 = 1.4 Hz), 4.20–3.70 (H12, H12’,
m, 4H), 3.59 (H6, d, 1H, JH6-H5 = 10.4 Hz), 1.57, 1.49, 1.42, 1.38, 1.27 (H11,
∗
CH3 4, 5s, 15H), 1.06 (H10, d, 3H, JH10-H9 = 6.2 Hz), 0.95 (H10’, d, 3H, JH10’-H9
= 6.3 Hz). 13C NMR (CDCl3, 100 MHz): δC 175.7 (C8, 1C), 130.7–127.0 (CH Ph,
10C), 109.1, 108.8 (C13, C14, 2C), 96.7 (C1, 1C), 73.5 (C7, 1C), 71.5 (C4, 1C),
71.0 (C3, 1C), 70.3 (C2, 1C), 68.8 (C9, 1C), 68.2 (C5, 1C), 59.8 (C6, 1C), 58.2,
∗
54.7 (C12, C12’, 2C), 26.2, 26.0, 25.0, 24.4, 23.5 (C11, CH3 4, 5C), 21.5, 21.4
(C10, C10’, 2C). IR (film, CCl4) νmax (cm−1): 3600–3300 (OH), 1720 (CO), 1602,
1495 (C C), 1453, 1380, 1372 (C(CH3)2). HRMS calcd for C32H44NO8 (M+H)+
570.3067. Found, 570.3070.
Preparation of 6-Deoxy-6-N,N-dibenzylamino-1,2:3,
4-di-O-isopropylidene-7-C-methyl-D-threo-α-D-galacto-1,
5-octopyranitol (11-D-threo)
The solution of hydroxy ester 13-D-threo (305 mg, 0.54 mmol) in Et2O
(4.0 mL) was added at 0◦C to the solution of LiAlH4 (1.1 mL of 1M sol. in Et2O).
The resulting reaction mixture was stirred at rt for 52 h. After that time, the
reaction mixture was hydrolyzed with 5% sol. aq. NaOH (0.3 mL), centrifuged
three times, and washed with Et2O (2 × 10 mL). The combined organic layers
were dried over anh. Na2SO4 and after filtration of drying agent the solvent
was removed under vacuum, affording crude product that was further purified
by column chromatography, affording 11-D-threo. White solid (192.0 mg, 70%)
mp 138–139◦C. [α]D23 –109.3 (c 0.75, CH2Cl2). Rf 0.38 (EtOAc/Hexane 1:2). 1H
NMR (CDCl3, 400 MHz): δH 7.54–7.01 (H Ph, m, 10H), 5.73 (H1, d, 1H, JH1-H2
=

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
109
5.1 Hz), 4.66 (H3, dd, 1H, JH3-H4 = 7.9 Hz, JH3-H2 = 2.5 Hz), 4.39 (H2, dd, 1H,
JH2-H1 = 5.1 Hz, JH2-H3 = 2.5 Hz), 4.32 (H5, d, 1H, JH5-H6 = 10.3 Hz), 4.17 (H4,
dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5 = 1.3 Hz), 4.20–4.07 (H8, m, 2H), 3.95 (H10a, d,
1H, JH10a-H10b = 12.4 Hz), 3.75 (H10b, d, 1H, JH10b-H10a = 12.2 Hz), 3.43 (H6, d,
1H, JH6-H5 = 10.3 Hz), 3.23 (H10’a, d, 1H, JH10’a-H10’b = 11.3 Hz), 3.17 (H10’b, d,
1H, JH10’b-H10’a = 11.3 Hz), 1.56, 1.39, 1.33, 1.19 (H9, CH3 4, 4s, 15H). 13C NMR
∗
(CDCl3, 100 MHz): δC 139.8, 138.7 (C Ph, 2C), 130.9, 130.4, 129.5, 128.7, 128.2,
127.3 (CH Ph, 10C), 109.5, 108.8 (C11, C12, 2C), 96.7 (C1, 1C), 72.2 (C4, 1C),
71.2 (C3, 1C), 70.2 (C2, 1C), 70.1 (C7, 1C), 69.6 (C10, 1C), 68.3 (C5, 1C), 57.6
∗
(C10’, 1C), 57.6 (C6, 1C), 54.8 (C8, 1C), 26.1, 26.0, 25.0, 24.3, 22.9 (C9, CH3 4,
5C). IR (disc, KBr) νmax (cm−1): 3600–3300 (OH), 1602, 1494 (C C), 1452, 1380
(C(CH3)2). HRMS calcd for C29H40NO7 (M+H)+ 514.2805. Found, 514.2807.
Synthesis of 6-N,N-Dibenzylamino-6,8-dideoxy-1,2:3,4-di-O-
isopropylidene-7-C-methyl-L-glycero-α-D-galacto-1,
5-octopyranose (9-L-glycero)
The synthesis was done in one pot, using the protocol described earlier.
The corresponding azetidinium salt 20 was not isolated but directly reduced by
means of LiAlH4 (5.0 equiv.) to furnish the desired 9-L-glycero. Starting from
11-D-threo (157.0 mg, 0.31 mmol), the overall yield, after two steps, of the pu-
23
rified product was 71% (108.0 mg). Colorless oil. [α]D –106.7 (c 0.9, CH2Cl2).
1
Rf 0.36 (EtOAc/Hexane 1:4). H NMR (CDCl3, 400 MHz): δH 7.53–7.05 (H Ph,
m, 10H), 5.72 (H1, d, 1H, JH1-H2 = 5.1 Hz), 4.64 (H3, dd, 1H, JH3-H4 = 7.8 Hz,
JH3-H2 = 2.3 Hz), 4.37 (H2, dd, 1H, JH2-H1 = 5.1 Hz, JH2-H3 = 2.4 Hz), 4.32–4.24
(H4, H5, m, 2H), 4.19–4.08 (H9, m, 2H), 3.94 (H9’a, d, 1H, JH9’a-H9’b = 12.0
Hz), 3.71 (H9’b, d, 1H, JH9’b-H9’a = 11.8 Hz), 3.17 (H6, d, 1H, JH6-H5 = 10.2 Hz),
1.56, 1.55, 1.39, 1.32, 1.19, 1.07 (C8, C8’, CH3 4, 6s, 18H). 13C NMR (CDCl3,
∗
100 MHz): δC 140.6, 139.3 (C Ph, 2C), 130.5, 129.1, 128.5, 128.0, 127.0 (CH Ph,
10C), 109.1, 108.7 (C10, C11, 2C), 96.8 (C1, 1C), 72.5 (C4, 1C), 71.1 (C3, 1C),
70.3 (C2, 1C), 69.0 (C7, 1C), 68.6 (C5, 1C), 62.9 (C6, 1C), 58.4, 54.8 (C9, C9’,
∗
2C), 29.7, 28.2, 26.2, 26.0, 25.0, 24.4 (C8, C8’, CH3 4, 6C). IR (film, CCl4) νmax
(cm−1): 3600–3200 (OH), 1487 (C C), 1456, 1384, 1370 (C(CH3)2). HRMS calcd
for C29H40NO6 (M+H)+ 498.2856. Found, 498.2856.
Preparation of 6-Amino-6,8-dideoxy-1,2:3,4-di-O-isopropylidene-
7-C-methyl-L-glycero-α-D-galacto-1,5-octopyranose
(7-L-glycero), the Direct Precursor of the Carbohydrate Moiety
of 6-epi-VIC-II
To the solution of compound 9-L-glycero (46.0 mg, 0.092 mmol) in MeOH
(6.0 mL) was added 10% Pd/C (23.0 mg) and the resulting solution was stirred

T.K. Olszewski et al.
110
under atmosphere of H2 (19 bars) for 32 h. After completion of the reaction, the
resulting mixture was filtered through a pad of Celite and the filtrate was con-
centrated under reduced pressure, affording the desired product, the primary
amine 7-L-glycero (21.0 mg, 72%) that does not require any further purifica-
tion. Colorless oil. [α]D23 –60.8 (c 1.25, CH2Cl2). Rf 0.24 (EtOAc/Hexane/MeOH
1
1:3:1). H NMR (CDCl3, 400 MHz): δH 5.58 (H1, d, 1H, JH1-H2 = 5.1 Hz), 4.58
(H3, dd, 1H, JH3-H4 = 7.9 Hz, JH3-H2 = 2.3 Hz), 4.31 (H2, dd, 1H, JH2-H1
=
5.1 Hz, JH2-H3 = 2.3 Hz), 4.23 (H4, dd, 1H, JH4-H3 = 7.9 Hz, JH4-H5 = 1.9 Hz),
3.86–3.76 (H5, m, 1H), 2.84–2.74 (H6, m, 1H), 1.53, 1.46, 1.33, 1.23, 1.13 (H8,
H8’, CH3 4, 5s, 18H). 13C NMR (CDCl3, 100 MHz): δC 109.2, 108.5 (C9, C10,
∗
2C), 96.7 (C1, 1C), 75.1 (C4, 1C), 71.3 (C7, 1C), 71.0 (C3, 1C), 70.4 (C2, 1C), 63.9
∗
(C5, 1C), 60.5 (C6, 1C), 26.6, 26.0, 26.0, 24.8, 24.2 (C8, C8’, CH3 4, 6C). IR (film,
CCl4) νmax (cm−1): 3600–3100 (OH), 1653 (NH), 1456, 1386, 1373 (C(CH3)2).
HRMS calcd for C15H28NO6 (M+H)+ 318.1917. Found, 318.1920.
Synthesis of 6-Trifluoroacetylamino-7-C-methyl-6,7,
8-trideoxy-1,2:3,4-di-O-isopropylidene-L-glycero-
α-D-galacto-1,5-octopyranose (21-L-glycero)
To a solution of amine 6-L-glycero (800 mg, 1.32 mmol) and 2,6-lutidine
(0.62 mL, 5.31 mmol) in dry CH2Cl2 (30 mL) at 0◦C was added trifluoroacetic
anhydride (TFAA) (0.28 mL, 1.98 mmol). The resulting reaction mixture was
stirred at 0◦C for 15 min and then at rt for 3 h. After that time, the reaction
was quenched with H2O (100 mL) and extracted with EtOAc (3 × 20 mL). The
layers were separated and the organic phase was washed with 1.0 N HCl (2 ×
20 mL), sat. aq. NaHCO3 (2 × 20 mL), and brine (2 × 20 mL). The combined
organic extracts were dried over anh. Na2SO4 and concentrated to give crude
21-L-glycero (colorless oil, 95%, 997 mg) that was used without purification in
1
the next step. H NMR (CDCl3, 400 MHz): δH 5.60 (H1, d, 1H, JH1-H2 = 5.0
Hz), 4.64 (H3, dd, 1H, JH3-H4 = 7.9 Hz, JH3-H2 = 2.1 Hz), 4.42 (H2, dd, 1H,
JH2-H1 = 5.2 Hz, JH2-H3 = 2.5 Hz), 4.24 (H4, dd, 1H, JH4-H3 = 8.0 Hz, JH4-H5
=
2.0 Hz), 3.64 (H5, dd, 1H, JH5-H6 = 6.9 Hz, JH5-H4 = 2.1 Hz), 2.94 (H6, m, 1H),
∗
2.01–1.93 (H7, m, 1H), 1.57 (CH3, s, 3H), 1.50 (CH3, s, 3H), 1.42 (CH3 2, s, 6H),
1.10 (H8, d, 3H, JH8-H7 = 7.0 Hz), 0.98 (H8’, d, 3H, JH8’-H7 = 6.9 Hz). MS calcd
for C17H27F3NO6 (M+H)+ 398.1. Found, 398.1.
Preparation of 6-Trifluoroacetylamino-7-C-methyl-6,7,8-trideoxy-
2,3,4-tri-O-acetyl-L-glycero-α-D-galacto-1,5-octopyranosyle
Bromide (22-L-glycero)
To a solution of 21-L-glycero (990 mg, 2.26 mmol) at 0◦C was added aqueous
TFA (80%, 20 mL) and the reaction was stirred at rt for 1 h. After that time, the
reaction mixture was concentrated and coevaporated with toluene (3 × 20 mL),

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
111
affording the desired deprotected galactose as a white solid (97%, 766 mg),
used directly in the next step. MS calcd for C11H19F3NO6 (M+H)+ 318.1.
Found, 318.1.
The solid (766 mg, 2.41 mmol) was dissolved in dry CH2Cl2 (30 mL), and
Et3N (3.36 mL, 24.1 mmol) was injected followed by addition of Ac2O (1.60 mL,
16.87 mmol) and DMAP (30 mg, 0.24 mmol). The resulting reaction mixture
was stirred at rt for 2 h, then quenched with MeOH (5 mL). Next, Et2O (50 mL)
was added and the resulting solution was washed with H2O (2 × 30 mL), 1.0 N
HCl (30 mL), sat. aq. NaHCO3 (30 mL), and brine (30 mL). The organic layer
was dried over anh. Na2SO4 and concentrated, yielding the desired acetylated
product (89%, 1.08 g). MS calcd for C19H27F3NO10 (M+H)+ 486.1. Found, 486.1.
The crude product (1.04 g, 2.13 mmol) was dissolved in dry CH2Cl2 (25
mL) and cooled down to 0◦C, and a solution of HBr in acetic acid (33%, 6.0
mL) was added. The resulting reaction mixture was stirred at 0◦C for 30 min
then warmed to rt and stirred for an additional 4 h. Next, CH2Cl2 (50 mL)
was added and the resulting solution was washed successively with a cold H2O
(2 × 10 mL), cold 50% aq. NaHCO3 (2 × 10 mL), and cold brine (30 mL). The
organic layer was dried over Na2SO4 and concentrated to yield the desired 22-
L-glycero (882 mg, 70% from 21-L-glycero). 1H NMR (CDCl3, 400 MHz): δH 5.85
(H1, d, 1H, JH1-H2 = 4.9 Hz), 4.75 (H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 1.9
Hz), 4.50–4.45 (H2, H4, m, 2H), 4.05 (H5, dd, 1H, JH5-H6 = 7.0 Hz, JH5-H4
=
1.9 Hz), 2.99 (H6, m, 1H), 2.09–1.99 (H7, m, 1H), 2.02 (CH3, s, 9H), 0.95
(H8, d, 3H, JH8-H7 = 6.9 Hz), 0.93 (H8’, d, 3H, JH8’-H7 = 7.0 Hz). MS calcd
for C17H24BrF3NO8 (M+H)+ 507.2. Found, 507.2.
Preparation of 6-Trifluoroacetylamino-7-C-methyl-6,7,8-trideoxy-
2,3,4-tri-O-acetyl-L-glycero-α-D-galacto-1,5-octopyranosyle
Chloride (23-L-glycero)
To a solution of 22-L-glycero (800 mg, 1.58 mmol) in AcOH (18 mL) at rt
AgOAc (260 mg, 1.58 mmol) was added. After 1 h reaction time, the reaction
mixture was diluted with CH2Cl2 (100 mL) and washed with H2O (20 mL),
aq. NaHCO3 (20 mL), and brine (20 mL). Organic phase was dried (Na2SO4)
and concentrated to give acetylated product as yellow oil (720 mg). The crude
product (700 mg, 1.48 mmol) was dissolved in CH2Cl2 (15 mL) and PCl5 (322
mg, 1.55 mmol) was added in one portion, followed by BF3•OEt2 (10 µL). The
resulting reaction mixture was stirred for 1 h, diluted with CH2Cl2 (30 mL),
and washed with sat. aq. NaHCO3 (20 mL) and brine (20 mL). The organic
1
layer was dried over MgSO4, yielding 23-L-glycero (657 mg, 90%). H NMR
(CDCl3, 400 MHz): δH 5.95 (H1, d, 1H, JH1-H2 = 5.2 Hz), 4.80 (H3, dd, 1H,
JH3-H4 = 7.8 Hz, JH3-H2 = 1.9 Hz), 4.51–4.44 (H2, H4, m, 2H), 4.00 (H5, dd, 1H,
JH5-H6 = 7.2 Hz, JH5-H4 = 2.0 Hz), 3.01 (H6, m, 1H), 2.11–2.05 (H7, m, 1H),

T.K. Olszewski et al.
112
2.01 (CH3, s, 9H), 0.90 (H8, d, 3H, JH8-H7 = 7.0 Hz), 0.88 (H8’, d, 3H, JH8’-H7
6.8 Hz). MS calcd for C17H24ClF3NO8 (M+H)+ 462.1. Found, 462.1.
=
Preparation of Methyl 6-Trifluoroacetylamino-7-C-methyl-6,7,
8-trideoxy-2,3,4-tri-O-acetyl-1-thio-L-glycero-α-D-
galacto-1,5-octopyranoside (24-L-glycero)
The crude 23-L-glycero (620 mg, 1.34 mmol) was dissolved in DMF (10 mL)
and HMPA (1.25 mL) was added, followed by MeSNa (280 mg, 4.02 mmol).
The resulting reaction mixture was stirred for 1 h and partitioned between
Et2O (50 mL) and 1:1 H2O:brine (20 mL). The layers were separated, and the
aqueous layer was washed with Et2O (50 mL). The combined organic phases
were dried (Na2SO4) and concentrated. The residue was dissolved in CH2Cl2
(30 mL) and treated with Et3N (1.86 mL, 13.4 mmol), Ac2O (0.88 mL, 9.40
mmol), and DMAP (16 mg, 0.13 mmol). After 1 h the reaction was quenched
with MeOH (5.0 mL) and partitioned between Et2O (15 mL) and H2O (15 mL).
The layers were separated, and the organic layer was washed with 1.0 M aq.
HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL). The combined or-
ganic phases were dried over Na2SO4 and concentrated. The crude product was
filtered through a short pad of silica gel using, as eluent, 10% EtOAc in hex-
ane. The desired 24-L-glycero was obtained after concentration of the solvent
as colorless viscous oil (318 mg, 50%). 1H NMR (CDCl3, 400 MHz): δH 5.50 (H1,
d, 1H, JH1-H2 = 5.7 Hz), 4.78 (H3, dd, 1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.1 Hz),
4.59–4.50 (H2, H4, m, 2H), 4.05 (H5, dd, 1H, JH5-H6 = 7.0 Hz, JH5-H4 = 1.8 Hz),
3.10 (H6, m, 1H), 2.20–2.12 (H7, m, 1H), 2.08 (CH3, s, 3H), 1.99 (CH3, s, 9H),
1.00 (H8, d, 3H, JH8-H7 = 7.2 Hz), 0.97 (H8’, d, 3H, JH8’-H7 = 6.8 Hz). MS calcd
for C18H27F3NO8S (M+H)+ 474.1. Found, 474.1.
Preparation of Methyl 6-Amino-7-C-methyl-6,7,8-trideoxy-1-thio-
L-glycero-α-D-galacto-1,5-octopyranoside (25-L-glycero), the
Carbohydrate Core of Antibiotic 6-epi VIC 10555
The protected 24-L-glycero (290 mg, 0.61 mmol) was dissolved in MeOH
(15 mL) and 1.0 M aq. NaOH (6.1 mL, 6.1 mmol) was added. The resulting
reaction mixture was stirred for 2 h, then acidified to pH 2 with 1.0 M aq.
HCl. After evaporation of the solvents the residue was dissolved in EtOH (10
mL) and filtered through a medium-porosity glass frit (to remove NaCl). The
filtrate was treated with Amberlite IRA-400 resin (15 mL resin bed in MeOH).
The resulting mixture was stirred at rt for 2 h and then filtered. The resin
was washed with MeOH (3 · 10 mL) and the filtrate concentrated in vacuo
1
to give the totally deprotected 25-L-glycero as white foam (138 mg, 90%). H
NMR (CD3OD, 400 MHz): δH 5.30 (H1, d, 1H, JH1-H2 = 5.7 Hz), 4.25 (H3, dd,
1H, JH3-H4 = 8.0 Hz, JH3-H2 = 2.1 Hz), 4.10–3.99 (H2, H4, m, 2H), 3.90 (H5, dd,

Efficient Synthesis of 6-epi-VIC-105555 and 6-epi-VIC-II
113
1H, JH5-H6 = 7.5 Hz, JH5-H4 = 1.9 Hz), 3.30 (H6, m, 1H), 2.89–2.79 (H7, m, 1H),
2.08 (CH3, s, 3H), 1.00 (H8, d, 3H, JH8-H7 = 7.0 Hz), 0.99 (H8’, d, 3H, JH8’-H7
6.9 Hz). MS calcd for C10H22NO4S (M+H)+ 252.1. Found, 252.1.
=
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