The structure and stereochemistry of gabosine K: Syntheses of 7-O-acetylstreptol and 7-O-acetyl-1-epi-streptol

Article abstract of DOI:10.1055/s-0029-1218540

Gabosine K, whose structure was erroneously assigned previously as 7-O-acetyl-4-epi-streptol, has been synthesized for the first time from D-glucose via a key carbocyclization strategy, intramolecular direct aldol reaction of a 2,6-diketone, in 15 steps with 13.5% overall yield. In the same manner, (+)-7-O-acetyl-streptol has been constructed for NMR spectral comparison. The structure, relative and absolute configurations of (-)-gabosine K are now revised and established as (-)-7-O-acetyl-1-epi-streptol, that is, (1R,2S,3S,4R)-tetrahydroxy-5-acetoxymethy lcyclohex-5-ene. Since the specific rotation of the natural product is not available, the absolute configuration of natural gabosine K is either (-)-7-O-acetyl-1-epi-streptol or its enantiomer. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218540

142
LETTER
The Structure and Stereochemistry of Gabosine K: Syntheses of 7-O-Acetyl-
streptol and 7-O-Acetyl-1-epi-streptol
S
ynthese
s
of 7-
O
o
-Acetylstre
n
ptol and 7-
O
y
-Acetyl-1-epi-strep
K
tol . M. Shing,* Hau M. Cheng
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 18 September 2009
RO
HO
AcO
HO
HO
HO
Abstract: Gabosine K, whose structure was erroneously assigned
previously as 7-O-acetyl-4-epi-streptol, has been synthesized for
the first time from D-glucose via a key carbocyclization strategy, in-
tramolecular direct aldol reaction of a 2,6-diketone, in 15 steps with
13.5% overall yield. In the same manner, (+)-7-O-acetyl-streptol
has been constructed for NMR spectral comparison. The structure,
relative and absolute configurations of (–)-gabosine K are now re-
vised and established as (–)-7-O-acetyl-1-epi-streptol, that is,
(1R,2S,3S,4R)-tetrahydroxy-5-acetoxymethylcyclohex-5-ene.
Since the specific rotation of the natural product is not available, the
absolute configuration of natural gabosine K is either (–)-7-O-
acetyl-1-epi-streptol or its enantiomer.
OH
O
O
HO
OH
HO
OH
HO
OH
2 (–)-gabosine G
3 R = H, MK7607
4 R = OAc (misassigned
1 (–)-gabosine I,
valienone
as gabosine K)
7
RO
HO
AcO
HO
5
3
6
1
4
OH
OH
OH
2
HO
HO
OH
Key words: carbasugars, carbohydrates, stereoselective synthesis,
aldol reactions, natural products
5
6
R = H, streptol
R = OAc
7 7-O-acetyl-1-epi-streptol,
(–)-gabosine K
Figure 1 Structures of gabosines
Gabosines are a group of natural products, isolated from
Streptomyces strains, that share a common multihydroxy-
lated cyclohexanone or hexenone skeleton.1,2 These sec-
ondary metabolites have been demonstrated to exhibit
bioactivities such as antibiotic,1 anticancer,2 and weak
DNA binding properties.3 Gabosine C and its crotonyl es-
ter COTC were isolated in 19744 whereas gabosines A to
K were isolated in 1993.1 In 2000, three more gabosines
were also reported.3 Our previous work has furnished ga-
bosine I (1) and G (2) from d-D-gluconolactone via a Hor-
ner–Wadsworth–Emmons olefination as the key step, and
established the absolute configuration of (–)-gabosine G
(2, Figure 1).5 Gabosine I (1) is identical to valienone,6 an
intermediate for the biosynthesis of validamycin A.7 To
product, and could be 7-O-acetyl-1-epi-streptol (7). Our
reasoning has proven to be correct.
The present work reports the first and stereoselective syn-
thesis of (–)-7-O-acetyl-1-epi-streptol (7) from D-glucose
with spectral data identical to those reported for the natu-
ral gabosine, thereby confirming the relative and absolute
configurations of (–)-gabosine K as compound 7. This
work also reports a stereoselective synthesis of 7-O-ace-
tylstreptol (6) for NMR spectral comparison. Our con-
struction of hydroxylated carbacycles involves an
intramolecular direct aldol reaction of sugar-derived 2,6-
diketones.
date, the structure and the stereochemistry of gabosine K In our previous investigation, b-allylic alcohol 12 and a-
was assigned as 7-O-acetyl-4-epi-streptol (4),1 on the ba- allylic alcohol 13 were prepared from D-glucose in 11
steps with 20% overall yield and 9 steps with 25% overall
yield, respectively, using an intramolecular direct aldol
cyclization of diketone 8 to cyclohexanone 9 as the key
step (Scheme 1).13,14 Conversion of 13 into 7-O-acetyl-
streptol (6) is straightforward and hence protection of 13
with TBSCl afforded silyl ether 14 from which the isopro-
pylidene group was selectively removed to give diol 15 in
a good yield. Regioselective acetylation of the primary al-
cohol in 15 furnished acetate 16. Acid hydrolysis then
provided (+)-7-O-acetylstreptol (6) that was thus synthe-
sized from D-glucose in 13 steps with 15.9% overall
yield.15
sis of its NMR spectral data which are closely related to
those of (+)-streptol (5), a plant-growth inhibitor.8,9
In 2000, Mehta and coworkers disclosed a synthesis of ra-
cemic 4.10 However, the spectral data (1H NMR, 13C
NMR) of synthetic 4 were similar but different from those
of natural gabosine K, hence the structure of gabosine K
needs to be revised. The deacetylated 4 is known as (+)-
MK7607 (3), an effective herbicide.11,12 We reason that
(+)-streptol (5) is likely the biosynthetically carbonyl-
reduction product of valienone (1), then it is feasible that
gabosine K could be derived from the other reduction
The transformation of the allylic alcohol 12 is shown in
Scheme 2. Silylation of the free alcohol in 12 provided si-
lyl ether 17. Selective hydrolysis of the terminal isopropy-
lidene group in 17 gave diol 18 that was subjected to
SYNLETT 2010, No. 1, pp 0142–0144
Advanced online publication: 02.12.2009
DOI: 10.1055/s-0029-1218540; Art ID: W14809ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

LETTER
Syntheses of 7-O-Acetylstreptol and 7-O-Acetyl-1-epi-streptol
143
OH
O
O
O
O
HO
HO
O
L-proline
DMSO
POCl3
O
O
6 steps
pyridine
O
OH
99%
intramolecular
direct aldol
reaction
O
O
O
O
HO
OH
MeO
OMe
MeO
OMe
D-glucose
9
8
O
O
O
a) NaBH4, MeOH
CeCl3⋅7H2O
K2CO3
MeOH
O
OAc
O
O
O
OH
b) Ac2O, DMAP
Et3N, CH2Cl2
82%
99%
O
O
O
O
O
O
MeO
OMe
MeO
OMe
MeO
OMe
12, 11 steps,
20% overall yield
from D-glucose
10
11
K-Selectride
THF, –78 °C, 99%
O
O
O
O
HO
TBSCl
imidazole
OH
OTBS
HO
OTBS
CH2Cl2
95%
80% AcOH
88%
O
O
O
O
O
O
MeO
OMe
MeO
OMe
MeO
OMe
13, 9 steps,
25% overall yield
from D-glucose
14
15
AcO
HO
AcO
HO
AcCl, 2,4,6-collidine
CH2Cl2, –30 °C
TFA, H2O
OTBS
CH2Cl2
OH
94%
81%
O
O
MeO
OMe
HO
OH
16
6
Scheme 1 Synthesis of 7-O-acetylstreptol (6)
accord with the literature values,1 and the 13C NMR data
O
HO
of 7 have perfect match with those of natural gabosine K
(Table 2). The H NMR spectrum of 7 in acetone-d6 re-
TBSCl
imidazole
1
O
OTBS
HO
OTBS
CH2Cl2
100%
80% AcOH
84%
12
veals all the coupling constants and the large J values
(J1,2 = 7.4 Hz, J2,3 = 10.1 Hz, and J3,4 = 7.4 Hz) indicate
that H1, H2, H3, and H4 are in pseudo-axial orientation
(Figure 2). Therefore, the absolute configuration of (–)-
gabosine K (7) {[a]D20 –47.9 (c 0.52, MeOH)} is now es-
tablished as 1R,2S,3S,4R.
O
O
O
O
MeO
OMe
MeO
OMe
17
18
AcO
AcCl
2,4,6-collidine
CH2Cl2, –30 °C
AcO
HO
HO
OTBS
TFA, H2O
CH2Cl2
H6
1.4 Hz
OH
O
O
H2
92%
86%
MeO
OMe
H4
7.4 Hz
10.1 Hz
H3
7.4 Hz
HO
OH
OH
H1
AcO
HO
OH
H6
H4
H2
H1
_
19
( )-gabosine K (7)
HO
Scheme 2 Synthesis of (–)-gabosine K [7-O-acetyl-1-epi-streptol (7)]
AcO
HO
H3
OH
OH
(–)-gabosine K (7)
regioselective acetylation to provide acetate 19. Removal
of the acid-labile blocking groups furnished 7-O-acetyl-1-
epi-streptol (7) in a good yield.15
The spectral data (1H NMR, 13C NMR) of racemic 4,10
(+)-7-O-acetylstreptol (6) and 7-O-acetyl-1-epi-streptol
(7) are compared with those1 of natural gabosine K.15 The
1H NMR spectral data of 7 in MeOH-d4 (Table 1) are in
HO
Figure 2 Conformation of 7 in acetone-d6
To conclude, (–)-gabosine K [7-O-acetyl-1-epi-streptol
(7)] was synthesized from D-glucose in 15 steps with
13.5% overall yield using an intramolecular direct aldol
Synlett 2010, No. 1, 142–144 © Thieme Stuttgart · New York

144
T. K. M. Shing, H. M. Cheng
LETTER
Table 1 Comparison of 1H NMR Spectral Data of Natural Gabosine K with Those of Synthetic 4, 6, and 7a
Compd 410
Compd 6
Compd 7
Natural gabosine K1
2.06 (s)
2.07 (s)
2.06 (s)
2.06 (s)
3.87–3.90 (m)
4.23–4.27 (m)
4.60 (d, J = 13.5 Hz)
4.70 (d, J = 13.5 Hz)
5.75–5.85 (m)
3.44 (dd, J = 10.1, 4.2 Hz)
3.71 (dd, J = 10.1, 7.3 Hz)
3.94 (dd, J = 7.3, 0.7 Hz)
4.18 (d, J = 4.6 Hz)
4.57 (d, J = 13.3 Hz)
4.76 (d, J = 13.3, 0.8 Hz)
5.80–5.82 (m)
3.35–3.42 (m)
4.04–4.08 (m)
4.52 (d, J = 13.5 Hz)
4.72 (d, J = 13.2 Hz)
5.59 (d, J = 1.2 Hz)
3.39 (m, J = 8, 6.5 Hz)
4.04–4.18 (m)
4.53 (d, J = 13.5 Hz)
4.73 (d, J = 13.5 Hz)
5.59 (m)
a Chemical shift in ppm in MeOH-d4.
Table 2 Comparison of 13C NMR Spectral Data of Natural Ga-
bosine K with Those of Synthetic 4, 6, and 7a
Chinese University of Hong Kong and by a Direct Grant from The
Chinese University of Hong Kong. The provision of a Croucher
Senior Research Fellowship (to T.K.M.S.) is also acknowledged.
Compd 410
20.8
Compd 6
19.2
Compd 7
20.7
Natural gabosine K1
20.8
64.8
73.0
73.5
77.1
77.5
128.8
136.2
172.5
References and Notes
(1) Bach, G.; Breiding-M, S.; Grabley, S.; Hammann, P.;
Huetter, K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A.
Liebigs Ann. Chem. 1993, 3, 241.
(2) (a) Huntley, C. F. M.; Hamilton, D. S.; Creighton, D. J.;
Ganem, B. Org. Lett. 2000, 2, 3143. (b) Kamiya, D.;
Uchihata, Y.; Ichikawa, E.; Kato, K.; Umezawa, K. Bioorg.
Med. Chem. Lett. 2005, 15, 1111.
65.8
63.5
64.8
67.4
66.0
73.0
68.0
70.9
73.5
70.7
71.9
77.1
(3) Tang, Y. Q.; Maul, C.; Hofs, R. Eur. J. Org. Chem. 2000, 1,
70.9
72.4
77.5
149.
128.2
137.2
172.5
124.4
137.9
171.0
128.8
136.2
172.5
(4) Tatsuta, K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.;
Umezawa, H.; Naganawa, H. J. Antibiot. 1974, 27, 579.
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(6) Sedmera, P.; Halada, P.; Pospísil, S. Magn. Reson. Chem.
2009, 47, 519.
(7) (a) Mahmud, T. Curr. Opin. Chem. Biol. 2009, 13, 161.
(b) Mahmud, T.; Lee, T. S.; Floss, H. G. Chem. Rec. 2001,
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a Chemical shift in ppm in MeOH-d4.
(8) Isogai, A.; Sakuda, S.; Nakayama, J.; Watanabe, S.; Suzuki,
S. Agric. Biol. Chem. 1987, 51, 2277.
(9) For a synthesis of (+)-streptol, see: Mehta, G.; Pujar, S.;
Ramesh, S. S.; Slam, K. Tetrahedron Lett. 2005, 46, 3373.
(10) Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000, 41,
3509.
reaction of 2,6-diketone 8 as the key step. However, the
specific rotation of natural gabosine K has not been re-
ported and a recent communication with Prof. Zeeck1 con-
firms that the rotation value is not available. As a
consequence, the absolute configuration of the natural
product is either (–)-gabosine K (7) or its enantiomer.
(11) Nobuji, Y.; Noriko, C.; Takashi, M.; Shigeru, U.; Kenzou,
H.; Michiaki, I. JP 06306000, 1994.
(12) For recent syntheses of (+)-MK7607 and C-1 epimer, see
(a) Lim, C.; Baek, D. J.; Kim, D.; Youn, S. W.; Kim, S. Org.
Lett. 2009, 11, 2583. (b) Grondal, C.; Enders, D. Synlett
2006, 3507.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(13) Shing, T. K. M.; Cheng, H. M.; Wong, W. F.; Kwong,
C. S. K.; Li, J.; Lau, C. B. S.; Leung, P. S.; Cheng, C. H. K.
Org. Lett. 2008, 10, 3145.
(14) Shing, T. K. M.; Cheng, H. M. Org. Lett. 2008, 10, 4137.
(15) For details, see Supporting Information.
Acknowledgment
This work was supported by a Strategic Investment Scheme admi-
nistered by the Center of Novel Functional Molecules of The
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