Selective hydroxyl protection of (+)-noviose via improved synthesis

Article abstract of DOI:10.1016/j.tetlet.2009.02.194

Coumarin antibiotics are biologically important molecules embedded with (+)-noviose as signature moiety. A challenging problem concerning the synthesis of these molecules and their analogues is the difficulty in selective protection of the two non-anomeri

Full text of DOI:10.1016/j.tetlet.2009.02.194

Tetrahedron Letters 50 (2009) 2317–2319
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Selective hydroxyl protection of (+)-noviose via improved synthesis
b,
Yiqiu He a,b, Jianjun Xue b, Yumei Zhou b, Junshan Yang a, , Xiaoming Yu
*
*
a Institute of Medicinal Plant Development, Chinese Academy of Medical Science & Peking Union Medical College, No. 151 Malianwa North Road, Beijing 100094, China
b Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, 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:
Coumarin antibiotics are biologically important molecules embedded with (+)-noviose as signature moi-
ety. A challenging problem concerning the synthesis of these molecules and their analogues is the diffi-
culty in selective protection of the two non-anomeric OHs of (+)-noviose. In order to provide a useful
solution to this problem, we report here a new strategy of (+)-noviose synthesis, modified from Musicki’s
Received 31 December 2008
Revised 20 February 2009
Accepted 24 February 2009
Available online 1 March 2009
previous study. Dihydrofuranone 8 was thus prepared from L-arabinose and was employed as key inter-
mediate to provide previously unknown 3-O-BOM-Noviose 9 in seven steps (40% overall yield). Com-
pound 9 was then efficiently converted into noviose 1,2-acetonide 6 (66%, two steps), which was
otherwise only available from controlled degradation of naturally occurring novobiocin 1.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Coumarin antibiotics
(+)-Noviose
Selective hydroxyl protection
L
-arabinose
Coumarin antibiotics, such as novobiocin, chlorobiocin, and cou-
8. By forming five-membered lactone ring, the carbonyl group could
then be envisioned not only as a latent site to introduce the noviose
C-5 gem-dimethyl group, but also a selective 2-OH protecting group.
Meanwhile, by taking advantage of their difference in steric hin-
drance, the primary and secondary alcohol functions presenting in
this molecule would provide a wide open window for further pro-
tecting group manipulation and finally result in selective hydroxyl
protection in the noviose molecule (Scheme 2).
marmycin A1 (1–3, Fig. 1), are potent bacterial DNA gyrase B inhib-
itors.1 Evidence also accumulated that these natural products, as
well as their simplified analogues, also represented a unique class
of Heat Shock Protein 90 (Hsp90) inhibitors.2 Therefore, practical
synthesis of these compounds and their analogues is of great impor-
tance in searching for novel anti-infectious and anticancer drugs.
Whereas the molecules of coumarin antibiotics are featured
with the presence of 3-O-acylated (+)-noviose moiety, most of
the known noviose synthetic studies merely target the unmodified
sugar.3–13 Unfortunately, direct modification to noviose usually
lacks regio-selectivity, and examples of 2- and 3-OH differently
functionalized (or protected) noviose derivatives are rarely re-
ported, except that Musicki6 obtained 3-O-acylated noviose 5 by
chromatographic separation and Olson14 prepared noviose 1,2-ace-
tonide 6 by controlled degradation of novobiocin 1. These facts
indicated that more efficient solutions to the problem of noviose
regio-selective modification are still in need. In this Letter, we re-
port a new strategy of noviose synthesis, so that the two non-ano-
meric OHs were selectively protected without ambiguity.
In order to illustrate the effectiveness of this assumption, we set
forth to the synthesis of previously unknown 3-O-BOM-noviose 9
and its subsequent conversion into noviose 1,2-acetonide 6, to
which no de novo approach is available so far. Thus, lactone 7
was prepared from L
-arabinose by repeating Musicki’s procedure6
and was heated with catalytic amount of concentrated hydrochlo-
ric acid in methanol. As it was expected, lactone 8 was isolated in
87% yield as single product. Selective primary hydroxyl protection
of 8 was then carried out with TBSCl/immidazole at 0 °C to give TBS
ether 10 in 92% yield. By subsequent BOM protection of the sec-
ondary hydroxyl group utilizing DIPEA as base and tetrabuytlam-
monium iodide as catalyst, compound 11 was isolated in 85%
yield. On treatment of 11 with excessive methyl magnesium chlo-
ride, gem-dimethyl group at C-5 was introduced to provide diol 12
in 80% yield. The newly released C-2 secondary OH was then pro-
tected as benzoate in 95% yield to form 13, and on exposure of this
precursor to iodine in methanol, diol 14 was prepared in good
yield. After 14 was subjected to PCC oxidation and the following
DIBAL-H reduction of resulted 15, 3-O-BOM-Noviose 9 was ob-
tained as 7/1 mixture of anomers based on 1H NMR (Scheme 3).
With 9 in hand, 1,2-acetonide formation was carried out in ace-
tone and 2,2-dimethoxypropane in the presence of catalytic
Our synthetic design was largely inspired by Musicki’s earlier
study, in which lactone 7 was prepared from L-arabinose and finally
converted into noviose 4 (Scheme 1).6 Instead of keeping the cis-diol
protecting acetonide group through the whole synthetic procedure,
we assume that acidic hydrolysis of this intermediate would first re-
lease the two protected hydroxyls and then trigger an intramolecu-
lar rearrangement to give thermodynamically more stable furanone
* Corresponding authors. Tel.: +86 10 63165259; fax: +86 10 63017757.
E-mail address: mingxyu@imm.ac.cn (X. Yu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.194

2318
Y. He et al. / Tetrahedron Letters 50 (2009) 2317–2319
OH
OH
OH
H
OH
O
H
N
N
O
OH
5
1
O
3
O
4
MeO
O
O
O
O
O
2
OH
HO
Cl
O
O
MeO
NH
MeO
O
O
O
1 Novibiocin
2 Clorobiocin
4 (+)-Noviose
OH
OH
O
NH2
OH
OH
OH
O
HN
H
N
H
N
O
MeO
O
O
MeO
O
O
NH
H
N
O
O
O
OH
HO
O
O
O
O
O
O
O
O
6
5
MeO
O
3
Coumamycin A1
O
OMe
O
OH
OH
NH
Figure 1. Coumarin antibiotics and known (+)-noviose derivatives.
BnO
HO
O
OH
O
Ref.6
O
OH
O
5
4
HO
1
MeO
MeO
OH
O
3
-Arabinose
L
MeO
2
OH
O
O
O
O
O
4
7
Scheme 1. Musicki’s synthesis of (+)-noviose from L-arabinose.
O
O
O
O
MeO 4
3
HO
MeO
HO
MeO
MeO
HO
5
O
O
O
2
1 OH
O
O
OR1
O
OH
7
8
O
1
MeO
R2O
OH
OH
5
4
R2O
OH
OR1
OH
OR3
O
O
MeO
MeO
MeO
R2O
23
R2O
OR3
OH
OR1
9 R2 =BOM,R 3 =H
Scheme 2. Proposed noviose synthesis resulting in selective hydroxyl protection.
O
O
O
O
MeO
OH
MeO
O
MeO
HO
MeO
HO
MeO
O
O
O
O
a
b
c
d
BOMO
OTBS
OTBS
OH
OTBS
g
BOMO
OH
12
O
8
10
11
7
MeO
BOMO
MeO
BOMO
MeO
OH
OH
OH
O
h
e
f
O
MeO
BOMO
OTBS
OH
BOMO
O
OH
OBz
OBz
14
OBz
9
13
15
Scheme 3. Reagents and conditions: (a) HCl (1 M), MeOH, reflux, 87%; (b) TBSCl, imidazole,THF, 0 °C ꢀ rt, 92%; (c) BOMOCl, DIPEA, Bu4 N+Iꢁ, THF, 0 °C ꢀ rt, 85%; (d) CH3MgCl,
THF, 0 °C, 80%; (e) BzCl, Et3 N, DMAP, CH2Cl2, 0 °C ꢀ rt, 95%; (f) I2, MeOH, rt, 90%; (g) PCC, CH2Cl2, rt, 84%; (h) DIBAL-H, CH2Cl2, ꢁ78 °C, 88%.

Y. He et al. / Tetrahedron Letters 50 (2009) 2317–2319
2319
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.02.194.
O
O
O
a
MeO
BOMO
b
O
MeO
9
HO
O
O
References and notes
16
6
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O’Brien, R.; Ladbury, J. E.; Wigley, D. B. Proteins 1997, 28, 41; (d) Maxwell, A.
Mol. Microbiol. 1993, 9, 681; (e) Reece, R. J.; Maxwell, A. CRC Crit. Rev. Biochem.
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Scheme 4. Reagents and conditions: (a) 2,2-Dimethoxy-propane, PTS, acetone, rt,
86%; (b) 1 atm H2, 10% Pd–C, THF, rt, 77% (95% based on recovered 16).
amount of PTS to give 16. After removal of the BOM group by
hydrogenolysis, target molecule 6 was isolated as colorless oil
(Scheme 4). Although Olson et al. did not provide any structural
data for 6 in their published paper, 1H NMR data gained from our
sample of 6 fit well to the required relative stereochemistry, and
the use of L-arabinose as source of all chiral centers in the molecule
of 6 leaves little doubt to the absolute configuration.15
In conclusion, we proposed that furanone 8, resulted from
acidic hydrolysis of known compound 7, is a practically useful
intermediate leading to 2- or 3-OH selectively protected noviose
derivatives, and therefore provides an effective solution to the
problem of regio-selective functional modification toward noviose.
The effectiveness of this proposal was well illustrated by the prep-
aration of previously unknown 3-O-BOM-Noviose 9 (40% yield, se-
ven steps from 8). By efficient conversion of 9 into noviose 1,2-
acetonide 6 (66%, two steps; 81% based on recovered intermedi-
ate), we were also able to accomplish the first de novo synthesis
of this synthetically versatile noviose derivative.
10. Gammon, D. W.; Hunter, R.; Wilson, S. Tetrahedron Lett. 2002, 43, 3141.
11. Yu, X. M.; Shen, G.; Blagg, B. S. J. J. Org. Chem. 2004, 69, 7375.
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15. A small sample of (+)-noviose was isolated as by-product from the reaction of
the hydrogenolysis step. Optical rotation of this sample is identical with that of
(+)-noviose prepared by repeating Laurin’s whole procedure in our laboratory,
Acknowledgments
and fits well to the previously reported data: ½a D20
ꢂ
+32.2 (c 1.0, EtOH/H2O 1:1);
This project was financially supported by Natural Science Foun-
dation of China (Approval No. 30772634) and Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, Basic Research Award (Approval No. 2006YJ02).
{lit.13 a 2D0
½ ꢂ +33.6/+27.4 (c 0.2, EtOH/H2O 1:1)}; NMR data were consistent with
those previous reported13 1H NMR (CD3OD, 600 MHz), mixture of anomers
:
8:5, d4.94 (d, J = 3.6 Hz, 1H, minor, H-1), 4.80 (d, J = 1.2 Hz, 1H, major, H-1),
3.93 (dd, J = 8.4 Hz, 3.6 Hz, 1H, minor, H-3), 3.71 (dd, J = 3.6 Hz, 1.2 Hz, 1H,
major, H-2), 3.64 (app.t, J = 3.6 Hz, 1H, minor, H-2), 3.60 (dd, J = 9.9 Hz, 3.6 Hz,
1H, major, H-3), 3.50 (s, 3H, major, OMe), 3.47 (s, 3H, minor, OMe), 3.15 (d,
J = 8.4 Hz, 1H, minor, H-4), 3.11 (d, J = 9.9 Hz, 1H, major, H-4), 1.25 (s, 3H,
minor, Me), 1.22 (s, 3H, major, Me), 1.21 (s, 3H, minor, Me), 1.08 (s, 3H, major,
Me); 13C NMR (CD3OD, 125 MHz) d95.6, 90.9, 85.8, 85.2, 78.1, 75.7, 73.8, 73.3,
72.5, 69.7, 62.1, 61.5, 29.0, 28.5, 25.1, 18.6; HRMS (ESI+) C8H16O5 calcd for
[M+Na]+ 215.0895, found 215.0895.
Supplementary data
Experimental details for the synthesis and characterization data
for key intermediates are provided. Supplementary data associated