Concise and divergent approach to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres: 3-O-Benzoyl-l-noviose and N-benzoyl-3-amino-l-noviose

Article abstract of DOI:10.1016/j.tetlet.2011.02.092

Generally applicable concise approaches to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres, represented by 5 and 6, were described. Chiral aldehyde 7 was thus prepared from dimethyl l-tartrate in five steps, and converted into 5 and 6 by emp

Full text of DOI:10.1016/j.tetlet.2011.02.092

Tetrahedron Letters 52 (2011) 2450–2453
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Concise and divergent approach to 3-O-acyl-L-noviose derivatives and their
3-amino bioisosteres: 3-O-benzoyl-L-noviose and N-benzoyl-3-amino-L-noviose
⇑
Jisheng Luo, Xiaoming Yu
Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, No.1 Xiannongtan St., Beijing 100050, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Generally applicable concise approaches to 3-O-acyl-
L-noviose derivatives and their 3-amino bioisoster-
Received 21 December 2010
Revised 27 January 2011
Accepted 22 February 2011
Available online 12 March 2011
es, represented by 5 and 6, were described. Chiral aldehyde 7 was thus prepared from dimethyl
L
-tartrate
in five steps, and converted into 5 and 6 by employing substrate induced asymmetric aldehyde or N-sul-
finyl aldimine allylation and dihydropyrane epoxidation as key steps, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Aminocoumarin
3-O-acyl-L-Noviose
Bioisostere
Novobiocin 1, clorobiocin 2, and coumermycin A1 3 (Fig. 1) are
building blocks for compound 5 and 6, respectively. Substrate
induced asymmetric addition of properly sourced allyl anion to 7
and 8 were then expected to give syn adduct 9 and 10, which
would be subsequently converted into 11 and 12. After proper
transformation of 11 and 12 into dihydropyrane derivative 13
and 14, the 2-b-OH was to be introduced by stereo-selective epox-
idation and the following in situ hydrolysis. A significant feature of
this plan is that protective group utilization was minimized and
selective acylation of the 3-OH (or 3-NH2) eased by making the
2-OH introduction the last step. However, feasibility of this plan
is largely dependent on the stereochemistry outcomes of the ally-
lation and the epoxidation steps.
members of aminocoumarin antibiotics produced by different
streptomysis species.1 Being recognized as potent DNA gyrase B
inhibitors and effective antibacterial agents for more than a half
century, these coumarin-derived molecules are conceived as valu-
able templates in searching for novel antimicrobial drugs.2
L-novi-
ose (4, Fig. 1) is a rare pyranose subunit shared by all these natural
products and has received intensive synthetic studies.3 However,
the abundance of available approaches to 4 did not result in signif-
icant advance in the chemical synthesis of aminocoumarin antibi-
otics. So far, no total synthesis has been documented, and a
possible reason is that regioselective modification of 4, that is,
installation of the 30-O-carbamyl or pyrrolylcarbonyl branch in
the molecules of 1 or 2 and 3, is not as easy as it seems.3i
The synthesis of previously unknown aldehyde 7 started with
dimethyl L-tartrate (Scheme 2). Monosilyl ether 15 was previously
A skillful semi-synthesis of 3 reported by Olson4 suggested that
-noviose derivatives bearing preexisting 3-O-acyl groups might be
prepared from the starting material using TBS triflate and 2,6-
lutidine.6 However, less expensive TBSCl and pyridine7 are used
instead in our hand, and the product was isolated in 69% yield from
the reaction in DMF. On treatment of 15 with dimethyl sulfate un-
der phase transfer condition, compound 16 was obtained in good
yield and then subjected to Grignard reaction with large excess
of methyl magnesium chloride to afford diol 17. After removal of
the TBS group in the molecule of 17, the resulting triol 18 was
oxidized with NaIO4 to deliver aldehyde 7 in excellent yield.8
Stereoselective allylation of 7 is of central importance in our
synthetic plan (Table 1). Although reagents capable of aldehyde
allylations are abundant, our choices were limited to those tolerat-
ing free hydroxyl containment in the substrate. Therefore, we first
examined the possibility of using allyl Grignard reagent to realize
the stereoselective transformation of 7 into 9. Results from the first
set of experiments (Table 1, entries 1–4) indicated that nonpolar
solvents strongly favored the formation of desired syn adduct 9,
L
more useful building blocks for this class of molecules. Moreover,
bioisosteric replacement is a widely adapted strategy in drug
discovery for acquiring new molecules with retained biological
activities but improved metabolic and physical properties.5
Accordingly, aminocoumarin bioisosteres with 30-O replaced by a
30-N, and thereby the corresponding pyranose building blocks are
of considerable interest. Based upon these ideas, we recently devel-
oped a generally applicable concise approach to 3-O-acyl-L-noviose
derivatives and their 3-amino bioisosteres represented by 5 and 6
(Fig. 1), both bearing benzoyl as model acyl group.
As depicted in Scheme 1, chiral aldehyde 7 and the correspond-
ing N-tert-butanesulfinyl aldimide 8 were designed as initial chiral
⇑
Corresponding author. Tel.: +86 10 63165259; fax: +86 10 63017577.
E-mail address: mingxyu@imm.ac.cn (X. Yu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.092

J. Luo, X. Yu / Tetrahedron Letters 52 (2011) 2450–2453
2451
Figure 1. Aminocoumarin antibiotics and L-noviose derivatives.
Table 1
Diastereoselective allylation of 7
Entry
Reagent
Solvent
T (°C)
Yieldc (9/19)d
1a
2a
3a
4a
5b
6b
7
C3H5MgBr
C3H5MgBr
C3H5MgBr
C3H5MgBr
C3H5MgBr
C3H5MgBr, CeCl3
C3H5Br, In
Et2O
Et2O
ꢀ10
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
+20
27% (1.1/1)
39% (1.5/1)
37% (4.4/1)
43% (5.5/1)
73% (4.7/1)
78% (5.2/1)
93% (4.0/1)
CH2Cl2
Toluene
Toluene
Toluene
H2O
Scheme 1. Synthetic plan for 5 and 6.
a
b
c
Addition of Grignard reagent into solution of 7.
Addition of 7 into solution of Grignard reagent.
Combined yield of 9 and 19.
d
Based on isolated products.
to a solution of 7, the instantly formed basic magnesium alkoxide
species might decompose unreacted 7. Accordingly, the same reac-
tion in toluene with reversed order of addition was carried out and
resulted in substantially improved yield and comparably good d.r.
(Table 1, entry 5). Also, by using anhydrous CeCl3 as co-reagent,10
slightly elevated yield and d.r. were observed (Table 1, entry 6). In
addition to the optimized results from the Grignard reactions, we
also examined the indium induced reductive coupling of allyl
bromide with aldehyde 7 in aqueous media.11 To our delight, the
reaction proceeding with 1.3 equiv of indium and 3 equiv of allyl
bromide at room temperature afforded 9 and 19 in a combined
yield up to 93% (Table 1, entry 7). In spite of the slightly lower
d.r., this procedure was preferred in our practical preparation of
9 for good isolated yield (74%) and convenience of operation.
With feasible approach to 9 established, this key intermediate
was converted into benzoate 20, and then subjected to OsO4 cata-
lyzed double bond cleavage using NaIO4 as real oxidant to provide
Scheme 2. Reagents and conditions: (a) TBSCl, Pyridine, DMF, 69%; (b) Me2SO4,
NaOH, n-Bu4NHSO4, CH2Cl2/H2O, 85%; (c) MeMgCl (5 equiv), THF; (d) TBAF, THF,
92% in two steps; (e) NaIO4, MeOH/H2O, 98%.
but the combined yields of 9 and 19 were unacceptably low.9 The
reason for this is that, when allyl magnesium bromide was added
2-dehydroxyl
L-noviose derivative 11. After dehydration of 11 with
methane-sulfonyl chloride and triethylamine,12 the resulting

2452
J. Luo, X. Yu / Tetrahedron Letters 52 (2011) 2450–2453
In summary, chiral aldehyde 7 was prepared from dimethyl L-
tartrate in five easy steps, and subjected to syn selective allylation
effected by Grignard reaction in nonpolar solvent or indium in-
duced reductive coupling in aqueous media to provide the key
intermediate 9, which was further converted into 3-O-benzoyl-L-
noviose 5 in four additional steps. All the reactions involved in this
synthetic sequence were carried out under mild conditions and the
overall yield of the target molecule was up to 17%. By simply diver-
sifying the acylating agent of 9, this approach is adaptable to the
preparation of a variety of 3-O-acyl-L-noviose derivatives. In a
similar manner, aldehyde 7, in combination with Ellman’s (R)-
tert-butane sulfinamide, provided a useful entrance to 3-amino
L-noviose bioisosteres, for example, 6, in an overall yield up to
13% from dimethyl -tartrate. With this model study accomplished,
L
we are now tackling the total synthesis of all three known
members of aminocoumarin family, and the preparation of their
30-amino bioisosteres as well.
Scheme 3. Reagents and conditions: (a) PhCOCl, TEA, CH2Cl2, 91%; (b) OsO4, NaIO4,
dioxane, H2O, 67%; (c)MsCl, TEA, CH2Cl2, 70%; (d) m-CPBA, CH2Cl2/H2O, 78.5%.
Acknowledgment
We are grateful for the generous financial support from
National Science Foundation of China (30772634) and the Ministry
dihydropyrane 13 was oxidized with m-CPBA and in situ hydro-
lyzed with water to afford target molecule 5 in good yield (Scheme
3). The initially worrying epoxidation of 13, however, appeared to
be highly b-selective, to a large extent owing to the presence of a
of Science and Technology of China
2009ZX09301-003).
(2009ZX09501-018,
repelling axial methyl group on
C-2 epimer was found in the reaction mixture.
a face of the substrate, since no
Supplementary data
After straightforward synthesis of 5, we moved on to embark on
preparation of the bioisosteric molecule 6 (Scheme 4). Based on the
prediction model provided by Ellman,13 (R)-tert-butanesufinamide
22 was condensed with aldehyde 7 using anhydrous copper sulfate
as water scavenger to afford N-sulfinyl aldimide 8. As it was ex-
pected, the double asymmetrically induced addition of allyl magne-
sium bromide to 8 in toluene gave the desired syn adduct 10 as a
single product in 89% yield.14 Upon removal of the N-sulfinyl group
of 10 in acidic media and subsequent N-benzoylation, the resulting
homoallylic benzamide 21 was subjected to a similar sequence
comprising double bond cleavage and dehydration to give the other
expected dihydropyrane 14. Epoxidation of this intermediate with
Davis oxidant 2315 followed by in situ hydrolysis successfully deliv-
ered compound 6, again without formation of the C-2 epimer.
Supplementary data (Experimental procedures and analytical
data. This material is available free of charge via the Internet at
http://www.elsevier.com.) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.02.092.
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