Short and efficient syntheses of gabosine I, streptol, 7-O-acetylstreptol, 1-epi-streptol, gabosine K, and carba α-d-glucose from δ-d-gluconolactone

Article abstract of DOI:10.1055/s-0030-1260547

δ-d-Gluconolactone was carbocyclized into an EOM-protected cyclohexenone in four steps involving perethoxymethylation, phosphonate anion addition, reduction, and oxidation with concomitant Horner-Wadsworth-Emmons alkenation. The stable key enone was effic

Full text of DOI:10.1055/s-0030-1260547

1318
LETTER
Short and Efficient Syntheses of Gabosine I, Streptol, 7-O-Acetylstreptol,
1-epi-Streptol, Gabosine K, and Carba-a-D-glucose from d-D-Gluconolactone
S
ynthese
s
of Ga
o
bosine I, Str
n
eptol, and 7-
y
O
-Acetylstreptol K. M. Shing,* Y. Chen, W. L. Ng
Department of Chemistry and Center of Novel Functional Molecules, The Chinese University of Hong Kong,
Shatin, Hong Kong, P. R. of China
Fax +85226035057; E-mail: tonyshing@cuhk.edu.hk
Received 10 February 2011
7
RO
HO
RO
HO
Abstract: d-D-Gluconolactone was carbocyclized into an EOM-
protected cyclohexenone in four steps involving perethoxymethyla-
tion, phosphonate anion addition, reduction, and oxidation with
concomitant Horner–Wadsworth–Emmons alkenation. The stable
key enone was efficiently transformed into gabosine I (five steps
with 65% overall yield from d-D-gluconolactone), streptol (six
steps, 54% overall yield), 7-O-acetyl-streptol (seven steps, 42%
overall yield), 1-epi-streptol (six steps, 49% overall yield), gabosine
K (seven steps, 40% overall yield), and carba-a-D-glucopyranose
(seven steps, 47% overall yield). The present chemical syntheses,
from commercially available d-D-gluconolactone, provide the high-
est overall yields of these molecules to date.
OH
O
1
3
HO
OH
HO
OH
1 R = H, gabosine I,
valienone
2 R = OAc, gabosine G
3 R = H, streptol
4 R = OAc
RO
HO
HO
5
1
HO
OH
OH
HO
OH
HO
OH
Key words: carbasugars, carbohydrates, stereoselective synthesis,
Wittig reaction, natural products
5 R = H, 1-epi-streptol
6 R = OAc, gabosine K
7 carba-α-D-glucose
Figure 1 Structures of gabosines, streptols, and carba-a-D-glucose
Gabosines are a group of natural, multihydroxylated cy-
clohexanones or hexenones, isolated from Streptomyces
strains.1,2 Gabosines A–K were isolated in 1993 and have
been demonstrated to exhibit bioactivities such as antibi-
otic,1 anticancer,2 and weak DNA-binding properties.3
Gabosine I (1) is identical to valienone,4 an intermediate
for the biosynthesis of validamycin A (Figure 1).5 The
corresponding reduction product, the a-allylic alcohol 3,
is known as (+)-streptol and is a plant-growth inhibitor.6,7
Its C-1 epimer 5 with a 7-OAc group was recently con-
firmed by us as gabosine K (6) via a synthesis involving a
key aldolization of a 2,6-diketone derived from D-
glucose.8 Saturation of the double bond in streptol (3)
furnishes carba-a-D-glucopyranose or pseudo-a-D-glu-
copyranose (7), an important sugar mimic acting as a tool
for biochemical research.9,10
so that the carbocyclized enone could be stable enough to
be elaborated into a variety of target molecules.
The present letter reports, from commercially available d-
D-gluconolactone, short, efficient, and enantiospecific
syntheses of gabosine I (1), streptol (3), 7-O-acetyl-strep-
tol (4), 1-epi-streptol (5), gabosine K (6), and carba-a-D-
glucopyranose (7) using stable ethoxymethyl (EOM)
ether for the hydroxyl protection and an intramolecular
HWE olefination12 as the key carbocyclization step. The
construction of 1-epi-streptol (5) has not been addressed
in the literature, and this paper documents its first synthe-
sis.
The synthesis of gabosine I (1) is shown Scheme 1. Glo-
bal alkylation of d-D-gluconolactone with EOM chloride
in 2,6-lutidine gave tetraether 8 in 93% yield. Nucleo-
philic addition of lithiated dimethyl methylphosphonate
to the lactone carbonyl afforded lactol 9 in 95% yield. Di-
rect oxidation of lactol 9 to the corresponding diketone
followed by HWE cyclization proved difficult, hence the
hemiacetal was reduced by borohydride to give diol 10 in
an excellent yield. Several oxidation protocols were at-
tempted, and Swern oxidation13 was found to be the most
efficient and the subsequent intramolecular HWE olefina-
tion was effected in the same pot. The olefination was
better induced by triethylamine than by diisopropylethy-
lamine (DIPEA). Addition of lithium salt14 did not im-
prove the reaction yield, beyond salting out the organic
materials. Thus enone 11 was harvested from diol 10 in
80% yield. Complete deprotection of 11 by acid hydroly-
sis smoothly provided (–)-gabosine I (1) in an excellent
Our present research is focused on the short and facile
construction of hydroxylated carbocycles from sugars
which is coined ‘carbocyclization of carbohydrates’. Our
previous work already yielded gabosine I (1) and G (2)
from d-D-gluconolactone via a Horner–Wadsworth–
Emmons (HWE) olefination as the key step, and estab-
lished the absolute configuration of (–)-gabosine G (2).11
In that synthesis, we employed a mixed acetal as the
blocking group for the hydroxyl at C-1 and C-2. However,
the mixed acetals are very acid sensitive and readily de-
composed. We therefore searched for a robust alternative
SYNLETT 2011, No. 9, pp 1318–1320
x
x.
x
x.
2
0
1
1
Advanced online publication: 29.04.2011
DOI: 10.1055/s-0030-1260547; Art ID: W05111SS
© Georg Thieme Verlag Stuttgart · New York

LETTER
Syntheses of Gabosine I, Streptol and 7-O-Acetylstreptol
1319
O
P
Li
RO
RO
EOMO
EOMO
EOMO
OMe
OMe
O
OH
O
OH
O
P
OH
NaBH4
O
P
O
EOMO
OMe
THF, –78 °C, 15 min
95%
MeOH, 96%
OMe
OMe
OMe
RO
OR
EOMO
OEOM
EOMO
OEOM
9
10
R = H, D-gluconolactone
93%
R = EOM, 8
EOMO
EOMO
HO
HO
(i) TFAA, DMSO
CH2Cl2, –78 °C
TFA, H2O
O
O
(ii) Et3N, –78 °C to r.t.
80%
r.t., 5 min, 96%
EOMO
OEOM
HO
OH
11
1, 5 steps
65% overall yield
from δ-D-gluconolactone
Scheme 1 Synthesis of gabosine I (1)
yield, identical in all respects to the one synthesized11 by lated to give gabosine K (6), identical to the one
us previously. The overall yield (65%) of the present work synthesized by us recently.8 Thus 1-epi-streptol (5) and
is far superior to our last synthesis (20.3%)11 and is the gabosine K (6) were synthesized from d-D-gluconolac-
best overall yield for the preparation of gabosine I in the tone in six and seven steps with 49% and 40% overall
literature.15,16
yield, respectively.16
The syntheses of streptol (3), 7-O-acetylstreptol (4), 1- The transformation of the allylic alcohol 12 into carba a-
epi-streptol (5), and gabosine K (6) are shown in D-glucose is shown in Scheme 3. Stereoselective hydro-
Scheme 2.16 Regio- and stereoselective hydride 1,2-re- genation with Raney nickel was believed to proceed with
duction of enone 11 with K-Selectride afforded a-alcohol an anchor effect17 of the C-1 a-hydroxy group, and the hy-
12 preponderantly whereas with NaBH4 furnished b-alco- drogen was delivered from the a-face, leading to the D-
hol 13 as the major product. Acid hydrolysis of all the gluco configuration as shown in 14 in a good yield.16
EOM ethers in 12 gave streptol (3) which was regioselec- Complete deprotection under acidic conditions furnished
tively acetylated to form 7-O-acetyl-streptol (4) in good carba-a-D-glucopyranose (7), identical in all respects to
yields. The spectral data (1H and 13C NMR) of streptol (3) the one synthesized by us previously.10b Thus, carba-a-D-
are in accord with those in the literature.4 Compound 4 glucopyranose (7) was made from d-D-gluconolactone in
was identical to 7-O-acetyl-streptol synthesized by us re- seven steps with 47% overall yield.
cently.8 Thus streptol (3) and 7-O-acetyl-streptol (4) were
To conclude, (–)-gabosine I (1), streptol (3), 1-epi-streptol
synthesized from d-D-gluconolactone in six and seven
(5), 7-O-acetylstreptol (4), gabosine K (6), and carba-a-D-
steps with 54% and 42% overall yield, respectively. On
glucopyranose (7) were synthesized from d-D-gluconolac-
tone in five to seven steps with 40–65% overall yields us-
ing an intramolecular HWE alkenation as the key step.
the other hand, acid hydrolysis of 13 provided 1-epi-strep-
tol (5) for the first time which was regioselectively acety-
EOMO
EOMO
EOMO
EOMO
EOMO
EOMO
(1) K-Selectride, –78 °C
+
O
OH
OH
(2) NaBH4, MeOH
CeCl3•7H2O
EOMO
OEOM
EOMO
OEOM
EOMO
OEOM
11
12
conditions (1) 86%
conditions (2) 9%
13
6%
82%
HO
AcO
HO
TFA, H2O
92%
AcCl, 2,4,6-collidine
CH2Cl2, –30 °C, 78%
12
13
HO
OH
OH
HO
OH
HO
OH
3
4
HO
HO
AcO
HO
TFA, H2O
89%
AcCl, 2,4,6-collidine
CH2Cl2, –30 °C, 80%
OH
OH
HO
OH
HO
OH
5
6
Scheme 2 Syntheses of streptol (3), 7-O-acetylstreptol (4), 1-epi-streptol (5), and (–)-gabosine K (6)
Synlett 2011, No. 9, 1318–1320 © Thieme Stuttgart · New York

1320
T. K. M. Shing et al.
LETTER
EOMO
EOMO
HO
HO
TFA, H2O
Raney Ni, H2
EtOH, 85%
12
OH
OH
r.t., 30 min, 96%
EOMO
OEOM
HO
OH
14
7
Scheme 3 Synthesis of carba-a-D-glucopyranose (7)
(5) (a) Mahmud, T. Curr. Opin. Chem. Biol. 2009, 13, 161.
(b) Mahmud, T.; Lee, S.; Floss, H. G. Chem. Rec. 2001, 1,
300.
(6) (a) Isogai, A.; Sakuda, S.; Nakayama, J.; Watanabe, S.;
Suzuki, A. Agric. Biol. Chem. 1987, 51, 2277. (b) Kroutil,
W.; Hagmann, L.; Schuez, T. C.; Jungmann, V.; Pachlatko,
J. P. J. Mol. Catal. B.: Enzym. 2005, 32, 247.
The present syntheses offer the shortest route to these
molecules with highest overall yields to date. It is note-
worthy that the facile and high-yielding construction of
enone 11 makes it an attractive intermediate for elabora-
tion into a wide variety of hydroxylated cyclohexenoid
natural products or molecules of pharmaceutical interest.
(7) For a synthesis of (+)-streptol, see: Mehta, G.; Pujar, S.;
Ramesh, S. S.; Islam, K. Tetrahedron Lett. 2005, 46, 3373.
(8) Shing, T. K. M.; Cheng, H. M. Synlett 2010, 142.
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A. M.; Moreno, E.; Valverde, S.; López, J. C. Tetrahedron
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by a Strategic Investment Scheme admi-
nistered by the Center of Novel Functional Molecules of The Chi-
nese University of Hong Kong and by a Direct Grant from The
Chinese University of Hong Kong.
(11) Shing, T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610.
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Synlett 2011, No. 9, 1318–1320 © Thieme Stuttgart · New York