A novel synthesis of noviose and its C-(4) epimer

Article abstract of DOI:10.1016/S0040-4039(02)00500-2

An efficient and stereoselective synthetic route has been developed to both noviose and its C-(4) epimer, thus providing a platform for the investigation of the structure-activity relationships (SAR) involving the methoxy group of noviose.

Full text of DOI:10.1016/S0040-4039(02)00500-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3141–3144
A novel synthesis of noviose and its C-(4) epimer
David W. Gammon,* Roger Hunter* and Seanette Wilson
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Received 7 January 2002; revised 28 February 2002; accepted 8 March 2002
Abstract—An efficient and stereoselective synthetic route has been developed to both noviose and its C-(4) epimer, thus providing
a platform for the investigation of the structure–activity relationships (SAR) involving the methoxy group of noviose. © 2002
Elsevier Science Ltd. All rights reserved.
DNA gyrase is a member of an essential class of
proteins known as type II topoisomerases and plays a
major role in DNA replication, recombination and the
control of gene expression.1 Since it is a crucial enzyme
in prokaryotes and is not found in eukaryotes, it is an
attractive target for drug design. DNA gyrase is made
up of two proteins, A and B, with the active molecule
being an A2B2 heterotetramer.2 The gyrase B protein,
containing the ATP binding site,3 is targeted by the
coumarin antibiotics of which novobiocin, 1, cloro-
biocin, 2 and coumermycin A1, 3, are members.4
the C-3 amino-position of the coumarin as well as the
C-3% amino-position and the C-5% position of the sugar
noviose.6
The crystal structure of the complex between novo-
biocin and a 24 kD N-terminal fragment of DNA
gyrase B protein has been solved7 and reveals that the
5%,5%-methyl groups of the sugar component of novo-
biocin sit in a pocket close to hydrophobic amino acid
residues. The 4%-methoxy group sits in a similar hydro-
phobic cleft.7b The important role played by the 5%,5%-
methyl groups in the antibacterial activity of coumarin
antibiotics has been reported,8 but little appears to be
documented on the interaction between the 4%-OCH3 of
noviose and gyrase B. In order to study this interaction
a novel divergent route to noviose as well as its C-(4)
epimer has been developed and is the subject of this
communication.
These coumarins are naturally occurring compounds
originally isolated from Streptomyces species that have
been shown to be active against Gram-positive bacteria.
As potential pharmaceuticals, they suffer from numer-
ous shortcomings including poor solubility in water,
toxicity and side effects, as well as the rapid develop-
ment of coumarin-resistant organisms,5 and thus have
not found widespread use. In order to overcome these
shortfalls, numerous derivatives of novobiocin have
been synthesised, the modifications being focused on
Previously, noviose has been synthesised in enantiomer-
ically pure form from
-arabinose11 as well as from (1S,4R)-4-acetoxy-5,5-
D L
-glucose,9 -rhamnose10 and
L
Keywords: coumarin antibiotics; noviose.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00500-2

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D. W. Gammon et al. / Tetrahedron Letters 43 (2002) 3141–3144
dimethyl-2-cyclopenten-1-ol.12 None of these routes,
however, directly accesses the C-4 epimer of noviose.
failure to do this resulted in very low yields. The scene
was now set for transformation to the pyranose ring.
This has now been achieved by employing
D-ribose as
Double debenzylation proceeded in 99% yield to afford
diol 8, which was then oxidatively cyclised under Swern
conditions (2 equiv.) to the lactone 9, via the lactol.
Reduction with DIBAL-H afforded the crystalline b-
lactol 1016 as the major anomer in 67% yield. Mono-
oxidation to the desired lactol was always complicated
by over-oxidation to the lactone. A single-crystal X-ray
the chiral starting material with a diastereoselective
reduction using K-Selectride® as a key step.
The synthesis of the C-4 epimer of noviose is outlined
in Scheme 1.
isopropylidene-
D
-Ribose was converted to methyl-2,3-O-
-ribofuranose by treatment with excess
D
methanol in the presence of concentrated sulfuric acid,
followed by addition of acetone to the reaction mix-
ture.13 Subsequent oxidation using RuO2·H2O and
NaIO4,14 followed by esterification using K2CO3 and
MeI yielded the known ester, 2, [h]D −67.8 (c 1.28,
CHCl3) {lit.15 [h]D −72.7 (c 2.0, CHCl3)} in 88% yield
over the two steps.
4
structure determination (Fig. 1) confirmed the C1 chair
conformation as well as the configuration of the
anomeric position as b. Finally, hydrolysis of acetonide
10 using EtOH:CF3CO2H:H2O (90:9:1) afforded the
C-(4) epimer of noviose, 11, as a mixture of anomers, in
95% yield.
The synthesis of noviose is summarised in Scheme 2.
Swern oxidation of the free hydroxyl group of 6
afforded ketone 12, mp 43–45°C (from hexane), [h]D
+31.7 (c 1.2, CHCl3) in 85% yield. The diastereoselec-
tivity of the reduction of 12 with various reducing
The introduction of the gem-dimethyl groups of
noviose was achieved by performing a double Grignard
reaction on the ester using MeMgI to afford 3 in 92%
yield. The tertiary hydroxyl group of 3 was then pro-
tected as its benzyl ether 4 in 92% yield by first reflux-
ing with NaH for 1 h to ensure formation of the anion
n
before adding the BnBr and Bu4NI. In order to reduce
to the ribitol, 4 was completely hydrolysed in aqueous
acid and then treated with acetone and concentrated
sulphuric acid to reform the 2,3-acetonide in 62% over-
all yield. Reduction with LiAlH4 afforded a high yield
of diol 5, which underwent chemoselective primary
protection to form benzyl ether 6 in 98% yield. Methyl-
ation of the remaining secondary hydroxyl group of 6
to form 7 proved to be difficult using standard condi-
tions owing to steric hindrance imposed by the cis-rela-
tionship between the substituents of the dioxolane ring.
Methylation was eventually achieved in high yield by
first refluxing a solution of 6 in THF with NaH for 2 h
before adding dry MeI. As with the benzylation of 3,
Figure 1. X-Ray crystal structure of lactol 10.
Scheme 1. Reagents and conditions: (a) i. MeOH, H2SO4, 0°C; ii. acetone, H2SO4, 0°C to rt, 80%; (b) i. RuO2·H2O, aq. NaIO4
(10% m/v), acetonitrile/CCl4 (1:1); ii. K2CO3, MeI, DMF, rt, 88%; (c) MeMgI (2 equiv.), ether, reflux, 92%; (d) NaH, BnBr,
nBu4NI, THF, reflux, 92%; (e) i. HCl (1 M), dioxane, 60°C; ii. acetone, H2SO4, 0°C, 62%; (f) LiAlH4, THF, 0°C, 84%; (g) NaH
(1.1 equiv.), BnBr (1.1 equiv.), THF, rt, 98%; (h) NaH, THF, reflux, then MeI, rt, 97%; (i) Pd/C, H2, EtOH, 99%; (j) (COCl)2
(2 equiv.), DMSO (4 equiv.), Et3N, CH2Cl2, 72%; (k) DIBAL-H, toluene, −78°C, 67%; (l) EtOH:CF3COOH:H2O (90:9:1), 80°C,
95%.

D. W. Gammon et al. / Tetrahedron Letters 43 (2002) 3141–3144
3143
Scheme 2. Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, 85%; (b) K-Selectride®, toluene, 0°C to rt, 72%; (c) NaH,
,
THF, reflux, then MeI, rt, 85%; (d) Pd/C, H2, EtOH, 94%; (e) TPAP (cat.), NMO, 4 A sieves, CH2Cl2, 91%; (f) DIBAL-H, THF,
−78°C, 89%; (g) EtOH:CF3CO2H:H2O (90:9:1), 80°C; 92%.
agents is outlined in Table 1. The desired product was
obtained by treating 12 with K-Selectride® in toluene at
0°C and allowing the reaction to warm to room
temperature.
chelates to the carbonyl prior to the delivery of the
hydride.17
Methylation and debenzylation of the reduced product
13 afforded the diol 14 in excellent yield (80% over two
steps).
The observed stereoselectivity may be rationalised using
the Felkin–Ahn model (Fig. 2a) in which the hydride is
delivered to the less hindered face of the lowest energy
non-chelated conformation. By comparison, reduction
with DIBAL-H and L-Selectride® may be explained by
Houk’s model (Fig. 2b) in which the metal (Al or Li)
In this series, TPAP oxidation using NMO as co-
oxidant18 proved to be the method of choice to furnish
the lactone, 15, in 91% yield, which upon reduction
with DIBAL-H yielded a mixture of a- and b-lactols,
16, as well as the acyclic aldehyde in 89% yield. Depro-
tection of the acetonide, under standard conditions,
afforded the cyclic noviose 17 as a mixture of anomers
in 92% yield. Table 2 summarises the 1H NMR data for
lactones 9 and 15 and shows the differences in the
Table 1. Observed stereoselectivity for various reducing
agents
Reducing agent
Yield (%)
3S
3R
4
conformation of the chair forms with 9 being C1 and
LiAlH4, THF, 0°C
\95
\95
\95
72
1
2
B1
1
1
DIBAL-H, toluene, rt
\99
4
B1
15 being C4.
L-Selectride®, toluene, −78°C
K-Selectride®, toluene, 0°C to rt
\99
In conclusion, an efficient, high-yielding and stereo-
selective synthesis of noviose and its C-(4) epimer has
been developed from a relatively inexpensive and read-
ily available starting material. Easy access to both C-(4)
epimers now sets the scene for SAR studies related to
coumarin antibiotics.
Acknowledgements
We thank the National Research Foundation, Pretoria,
for research funding.
Figure 2. (a) Felkin–Ahn model; (b) Houk’s model with
DIBAL-H.
Table 2. Selected H NMR dataa for lactones 9 and 15
1
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