Synthesis of ent-gabosine E from d-mannose by intramolecular nitrone-olefin cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2009.09.154

Intramolecular nitrone-olefin cycloaddition in a mannose template followed by N-O cleavage, quaternization of the resulting amine, and finally oxidative elimination of the amino group affords, after deprotection, ent-gabosine E in enantiomerically pure form.

Full text of DOI:10.1016/j.tetlet.2009.09.154

Tetrahedron Letters 50 (2009) 6916–6918
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Synthesis of ent-gabosine E from D-mannose by intramolecular nitrone–olefin
cycloaddition
*
Christos I. Stathakis, Maria N. Athanatou, John K. Gallos
Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki GR 541 24, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular nitrone–olefin cycloaddition in a mannose template followed by N–O cleavage, quatern-
ization of the resulting amine, and finally oxidative elimination of the amino group affords, after depro-
tection, ent-gabosine E in enantiomerically pure form.
Received 21 August 2009
Revised 11 September 2009
Accepted 25 September 2009
Available online 1 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The name ‘gabosines’ has been given to a group of 14 carba-sug-
ars isolated from Streptomyces strains.1 The majority are diastereo-
isomeric 4,5,6-trihydroxy-2-cyclohexenones with an additional
methyl, hydroxymethyl, or acetoxymethyl group at the 2- or 3-
positions (Fig. 1), and exhibit a variety of biological activities such
as antiprotozoal activity, DNA binding properties, and enzyme
inhibition. Related natural products include the glyoxylase I inhib-
itor COTC2 (Fig. 1) isolated from Streptomyces filipensis, the plant
growth factor streptol,1c its diastereoisomer MK76073 isolated
from Curvularia eragrostidis which possesses herbicidal activity,
the antibiotic rancinamycins,4a and numerous structurally related
natural products.4 Furthermore, gabosine-like compounds are con-
stituents of complex entities such as acarbose and/or have been
used as intermediates for the synthesis of biologically interesting
compounds.
oxidative elimination of hydroxyamine 2, which could be obtained
by N–O bond cleavage in bicyclic isoxazolidine 3. The latter is the
intramolecular cycloadduct of the nitrone derived from the sugar
template 4, which in turn is easily prepared from a hexose. Thus,
following this route and assuming that no epimerization would oc-
cur during the reaction sequence, the absolute configurations of
the C-2, C-3, and C-4 chiral centers of the starting sugar should
be transferred to the C-4, C-5, and C-6 positions of the final gabo-
sine. Importantly, this sequence gives us the opportunity to selec-
tively protect the three secondary hydroxy groups, allowing
oxidation of the fourth hydroxyl as necessary. It is also worth not-
ing that the stereoselectivity of the cycloaddition reaction is of less
O
O
As a consequence, a number of synthetic approaches toward
gabosines and related compounds have been reported in the liter-
ature,5 usually starting from carbohydrates or quinic acid. Despite
the existence of these synthetic methods for converting sugars into
gabosines, a general route starting from a monosaccharide leading
O
O
HO
HO
HO
HO
Me
HO
HO
Me
HO
HO
Me
R
OH
gabosine B
OH
OH
gabosine F
OH
gabosine A
R = OAc, gabosine D
R = OH, gabosine E
to
a 4,5,6-trihydroxy-2-hydroxymethyl-2-cyclohexenone with
transfer of chirality to the products and allowing the synthesis of
any of its diastereoisomers, is needed. Such general methods exist
only for gabosines with a 3-hydroxymethyl5i or 2-methyl5k substi-
tuent. Whilst investigating a general synthetic scheme to gabo-
sines with a 3-hydroxymethyl substituent, we considered that
our recent work6 on the synthesis of chiral cyclopentenones might
be useful and applicable in this case.
O
O
O
O
HO
HO
HO
R
O
R
HO
OH
R = OH, gabosine C
R = H, gabosine N
HO
OH
R = OAc, gabosine G
R = H, gabosine H
R = OH, gabosine I
HO
OH
COTC
Starting from a hexose, a carbocyclic ring with a hydroxymethyl
group could be prepared by an intramolecular nitrone–olefin
cycloaddition and further manipulation of the cycloadduct
(Scheme 1). The installation of an enone group in protected gabo-
sine 1 could be accomplished by quaternization and subsequent
O
O
OH
O
HO
Me
OH
Me
HO
HO
HO
OH
HO
OH
gabosine J
OAc
HO
gabosine L
HO
HO
OH
gabosine K
OH
gabosine O
* Corresponding author. Tel.: +30 2310 997714; fax: +30 2310 997679.
E-mail address: igallos@chem.auth.gr (J.K. Gallos).
Figure 1. Structure of known isolated gabosines.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.154

C. I. Stathakis et al. / Tetrahedron Letters 50 (2009) 6916–6918
6917
importance, since the newly formed stereocenters are subse-
quently destroyed.
group was selectively protected using TBSOTf to give compound
12 in 77% overall yield (two steps). Quaternization of the amino
group of 12 followed by oxidative elimination led to protected
ent-gabosine E 13. This method has been used previously by us,6
and others12 for the regioselective formation of an enone function-
ality. Finally, the protecting groups were removed from 13 with
BBr3 and the expected ent-gabosine E 14 was obtained in 85% yield
with spectroscopic data in good agreement with those reported for
gabosine E.1a,13
Unfortunately, the minor cycloadduct 10 did not give 14 when
we applied the same reaction sequence. Attempted oxidation of
the free secondary hydroxy group after N–O bond scission to 15,
protection of the primary hydroxy group and quaternization of
the amine did not give ent-gabosine, evidently because the H and
Me3N groups are not anti-disposed for elimination, a fact that con-
firmed the assigned structure of 10.
In summary, we have prepared enantiomerically pure ent-gabo-
sine E in 11 steps and 12% overall yield starting from commercially
available methyl a-D-mannopyranoside, using generally applicable
reactions and procedures. In addition, interesting new aminocycli-
tols, such as 11 and 15, are prepared as intermediates. Similarly,
starting from other hexoses, diasteroisomers of 14 may be pre-
pared and work in this direction is in progress.
D
-Mannose was the starting material of choice, which would re-
sult in ent-gabosine E by transfer of its chirality to the final prod-
uct, applying the above-mentioned methodology. Using the
standard protection–deprotection manipulations, commercially
available methyl
a-D-mannopyranoside 5 was converted into the
known compound 6 according to the literature7 (Scheme 2). Next,
the free primary hydroxy group was subjected to Swern oxidation
and Wittig reaction to give the known template 7.8 Acetal hydroly-
sis was achieved by the treatment of 7 with H2SO4 and Ac2O fol-
lowed by hydrolysis of the intermediate acetate with EtONa in
EtOH to give 8 in excellent yield. This intermediate was able to un-
dergo the intramolecular nitrone cycloaddition upon condensation
with MeNHOH.9 After some experimentation, we found that the
treatment of MeNHOHꢀHCl with EtONa/EtOH for 30 min, followed
by addition to 8 gave the respective nitrone, which without isola-
tion, afforded upon stirring for 24 h, the two cycloaddition prod-
ucts 9 and 10 in 80% combined yield and in a 2:1 ratio. It is
interesting to note that when pyridine was used as the solvent
and base in the reaction of 8 with MeNHOHꢀHCl, partial epimeriza-
tion of the C-2 (sugar numbering) stereocenter took place. The two
products 9 and 10 were separated by chromatography and their
structures were elucidated by COSY and NOE experiments.10,11
The N–O bond of the major cycloadduct 9 was then cleaved
using a standard procedure (Zn, AcOH) and the primary hydroxy
References and notes
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R.; Uhr, H.; Wink, J.; Zeek, A. Liebigs Ann. Chem. 1993, 241–250; (b) Tang, Y.-Q.;
Maul, C.; Höfs, R.; Sattler, I.; Grabley, S.; Feng, X.-Z.; Zeek, A.; Thiericke, R. Eur. J.
Org. Chem. 2000, 149–153; (c) Höfs, R.; Scoppe, S.; Thiericke, R.; Zeek, A. Eur. J.
Org. Chem. 2000, 1883–1887.
O
OH
BnO
BnO
BnO
BnO
OR
OR
2. Huntley, C. F. M.; Hamilton, D. S.; Creighton, D. J.; Ganem, B. Org. Lett. 2000, 2,
3143–3144. and references therein.
NHMe
3. Song, C.; Jiang, S.; Singh, G. Synlett 2001, 1983–1985. and references therein.
4. Selected publications: (a) Arjona, O.; Borallo, C.; Iradier, F.; Medel, R.; Plumet, J.
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K.; Ogasawara, K. Chem. Commun. 1999, 2197–2198.
OBn
OBn
1
2
5. (a) Mirza, S.; Molleyeres, L.-P.; Vasella, A. Helv. Chim. Acta 1985, 68, 988–996;
(b) Tatsuda, K.; Yasuda, S.; Araki, N.; Takahashi, M.; Kamiya, Y. Tetrahedron Lett.
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N.; Fanefjord, M.; Hansen, F. G.; Jensen, N. M. E.; Madsen, R. Eur. J. Org. Chem.
OH
O
BnO
BnO
BnO
OH
OBn
O
N
Me
BnO
OBn
3
4
Scheme 1. Retrosynthetic analysis of gabosine.
OH
HO
HO
HO
OH
O
O
O
BnO
BnO
iv, v
BnO
BnO
vi
i, ii, iii
OMe
BnO
BnO
OMe
OBn
BnO
OR
+
O
O
N
N
HO
OH
BnO
7, R = Me
8, R = H
OBn
Me
Me
OBn
OBn
10 (minor)
6
5
9 (major)
vii, viii
vii, viii
O
O
OH
OH
HO
HO
BnO
BnO
BnO
BnO
BnO
BnO
OH
xi
OTBS
OR
NHMe
OR
NHMe
ix, x
OH
ent -gabosine E
OBn
13
OBn
OBn
14,
15, R = H
16, R = TBS
11, R = H
12, R = TBS
Scheme 2. Reagents and conditions: (i) TrCl, pyridine, 20 °C, 24 h, 84%; (ii) BnCl, NaH, DMF, 20 °C, 12 h, 90%; (iii) H2SO4, MeOH (abs), 20 °C, 1 h, 84%; (iv) (COCl)2, DMSO, Et3N,
DCM, ꢁ60 °C then Ph3P+CH3Brꢁ, n-BuLi 1.6 M in hexanes, THF, ꢁ70 °C, 1 h, 72%; (v) H2SO4, Ac2O, 0 °C, 10 min, then EtONa, EtOH, 0 °C, 10 min, 91%; (vi) MeNHOH.HCl, EtONa,
EtOH, then 20 °C, 24 h, 80%; (vii) Zn, AcOH, reflux, 1 h; (viii) TBSOTf, 2,6-lutidine, CH2Cl2, ꢁ78 °C, 45 min, 77% for 12, 80% for 16; (ix) excess MeI, K2CO3, THF, 24 h; (x) Dess–
Martin periodinane, CH2Cl2, 20 °C, 30 min, 80% from 12; and (xi) BBr3, CH2Cl2, ꢁ78 °C, 45 min, 85%.

6918
C. I. Stathakis et al. / Tetrahedron Letters 50 (2009) 6916–6918
2009, 396–402; (k) Mac, D. H.; Samineni, R.; Petrignet, J.; Srihari, P.;
3.94 (dd, J = 10.8, 3.2 Hz, 1H), 4.07 (t, J = 6.8 Hz, 1H), 4.33 (d, J = 12.0 Hz,
1H), 4.36 (d, J = 12.0 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz,
1H), 4.48 (d, J = 12.0 Hz, 1H), 4.73 (d, J = 12.0 Hz, 1H), 7.25–7.40 (m, 15H);
Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Commun. 2009, 4117–4119.
6. (a) Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem. Soc., Perkin Trans. 1 1994,
613–614; (b) Gallos, J. K.; Damianou, K. C.; Dellios, C. C. Tetrahedron Lett. 2001,
42, 5769–5771; (c) Gallos, J. K.; Stathakis, C. I.; Kotoulas, S. S.; Koumbis, A. E. J.
Org. Chem. 2005, 70, 6884–6890; (d) Stathakis, C. I.; Gallos, J. K. Tetrahedron Lett.
2008, 49, 6804–6806.
7. (a) Borén, H. B.; Eklind, K.; Garegg, P. J.; Lindberg, B.; Pilotti, Å. Acta Chem. Scand.
1972, 4143–4146; (b) Jaramillo, C.; Chiara, J.-L.; Martin-Lomas, M. J. Org. Chem.
1994, 59, 3135–3141.
8. (a) Aurrecoechea, J. M.; López, B.; Arrate, M. J. Org. Chem. 2000, 65, 6493–6501;
(b) Aurrecoechea, J. M.; Arrate, M.; Gil, J. H.; López, B. Tetrahedron 2003, 59,
5515–5522.
9. (a) Shing, T. K. M.; Elsley, D. A.; Gillhouley, J. G. J. Chem. Soc., Chem. Commun.
1989, 1280–1282; (b) Peet, N. P.; Huber, E. W.; Farr, R. A. Tetrahedron 1991, 47,
7537–7550; (c) Koumbis, A. E.; Gallos, J. K. Curr. Org. Chem. 2003, 7, 585–628;
(d) Bashiardes, G.; Cano, C.; Mausé, B. Synlett 2005, 1425–1428; (e) 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, 3145–3148; (f) Shing, T. K. M.; Wong, W. F.;
Ikeno, T.; Yamada, T. Chem. Eur. J. 2009, 15, 2693–2707.
10. The proton signal assignment of diastereoisomers 9 and 10 was made by H,H-
COSY experiments. Significant NOE enhancements were observed between the
two bridged protons (3a-H and 7a-H) as well as between 3a-H and 4-H in
compound 9, whereas no considerable enhancement was shown between 7-H
and 7a-H. On the other hand, in compound 10, an NOE enhancement was
observed between 7-H and 3a-H, but no significant enhancements between the
two bridged protons (3a-H and 7a-H) as well as between the couples 3a-H, 4-H
and 7-H, 7a-H were evident.
13C NMR (CDCl3, 75 MHz)
d 47.5, 49.4, 67.7, 68.2, 69.5, 71.9, 73.2, 73.7,
74.8, 79.6, 80.4, 127.7, 127.9, 128.1, 128.4, 128.6, 137.7, 138.0, 138.1;
HRMS m/z 476.2438 [C29H34NO5 (M+H)+ requires 476.2431]. Compound 12:
oil,
[a
]
D
;
ꢁ12.7 (c 1.5, CHCl3); IR (neat film) 3325 cmꢁ1 1H NMR (C6D6,
400 MHz, some peaks are broad due to conformer interconversion) d 0.11
(s, 3H), 0.12 (s, 3H), 1.01 (s, 9H), 2.17 (s, 3H), 2.34 (br m, 1H, 6-H), 3.07
(br m, 1H), 3.95 (dd, J = 10.4, 3.2 Hz, 1H), 4.04 (m, 4H), 4.23 (br, 1H), 4.49
(d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.64
(d, J = 12.0 Hz, 1H), 4.75 (d, J = 12.0 Hz, 1H), 4.81 (d, J = 12.0 Hz, 1H), 7.05–
7.40 (m, 15H); 13C NMR (CDCl3, 100 MHz) d ꢁ5.4, 18.2, 25.9, 34.7, 39.9,
58.7, 61.3, 69.6, 72.5, 72.9, 73.3, 75.9, 76.4, 80.2, 127.4, 127.5, 127.8,
128.3, 138.7, 138.8, 139.1; HRMS m/z 592.3469 [C35H50NO5Si (M+H)+
requires 592.3453]. Compound 13: oil, [
a
]
D
ꢁ91.1 (c 1.2, CHCl3); IR (neat
film) 1680 cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
d 0.08 (s, 3H), 0.09 (s, 3H),
0.93 (s, 9H), 3.96 (dd, J = 8.0, 3.2 Hz, 1H), 4.36 (m, 3H), 4.44 (br s, 1H),
4.69 (d, J = 11.2 Hz, 1H), 4.72 (d, J = 12.0 Hz, 2H), 4.79 (d, J = 12.0 Hz, 1H),
4.81 (d, J = 12.0 Hz, 1H), 4.91 (d, J = 11.2 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H),
7.25–7.40 (m, 15H); 13C NMR (CDCl3, 100 MHz) d ꢁ5.5, ꢁ5.45, 18.3, 25.9,
59.5, 72.2, 72.5, 73.2, 74.0, 78.8, 80.3, 127.7 (two peaks), 127.8, 128.0,
128.3 (two peaks), 128.4, 137.8, 138.1, 138.2, 138.6, 138.9, 196.4; HRMS
m/z 559.2882 [C34H43O5Si (M+H)+ requires 559.2874]. Compound 16: oil; IR
(neat film) 3325 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 0.11 (s, 3H), 0.12 (s,
;
3H), 0.90 (s, 9H), 2.05 (m, 1H), 2.60 (s, 3H), 3.13 (t, J = 10.8 Hz, 1H), 3.76
(m, 3H), 3.87 (dd, J = 10.5, 7.5 Hz, 1H), 4.03 (d, J = 8.7 Hz, 1H), 4.12 (dd,
J = 10.8, 4.5 Hz, 1H), 4.27 (d, J = 11.1 Hz, 1H), 4.43 (d, J = 11.1 Hz, 1H), 4.44
(d, J = 12.0 Hz, 2H), 4.58 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 7.20–
7.40 (m, 15H); 13C NMR (CDCl3, 100 MHz) d ꢁ5.8, ꢁ5.7, 18.1, 25.8, 33.9,
42.0, 60.1, 64.5, 67.6, 71.5, 71.9, 73.2, 73.9, 76.5, 77.8, 127.8, 128.0 (two
peaks), 128.1, 128.2, 128.4 (two peaks), 128.5, 128.8, 137.4, 137.7, 137.8;
HRMS m/z 592.3460 [C35H50NO5Si (M+H)+ requires 592.3453].
11. Selected data. Compound 9: oil,
[
a
]
D
ꢁ54.2 (c 1.0, CHCl3); IR (neat film)
3500 (br) cmꢁ1 1H NMR (CDCl3, 400 MHz)
;
d 2.66 (s, 3H, Me), 2.70 (m,
1H, 6-H), 3.15 (m, 2H, 1-H), 3.79 (dd, J = 5.2, 4.0 Hz, 1H), 3.85 (dd, J = 6.4,
2.8 Hz, 1H), 3.89 (dd, J = 5.2, 2.8 Hz, 1H), 4.06 (t, J = 8.0 Hz, 1H), 4.11 (dd,
J = 7.2, 6.4 Hz, 1H), 4,20 (br s, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.52 (d,
J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1H), 4.64 (d, J = 12.0 Hz, 1H), 4.68 (d,
J = 12.0 Hz, 1H), 4.72 (d, J = 12.0 Hz, 1H), 7.25-7.40 (m, 15H); 13C NMR
(CDCl3, 75 MHz) d 44.6, 44.8, 66.8, 67.2, 68.3, 72.6, 73.2 (two peaks), 75.4,
76.1, 79.5, 127.6, 127.7 (two peaks), 127.8, 127.9, 128.3, 128.4, 128.5,
137.8, 138.5, 138.7; HRMS m/z 476.2440 [C29H34NO5 (M+H)+ requires
12. (a) Jiang, S.; Singh, G.; Wightman, R. H. Tetrahedron Lett. 1994, 35, 5505–5508;
(b) van Boggelen, M. P.; van Dommelen, B. F. G. H.; Singh, G. Tetrahedron Lett.
1995, 36, 1899–1902; (c) Jiang, S.; McCullough, K. J.; Mekki, B.; Singh, G.;
Wightman, R. H. J. Chem. Soc., Perkin Trans.
1 1997, 1805–1814; (d) van
Boggelen, M. P.; van Dommelen, B. F. G. A.; Jiang, S.; Singh, G. Tetrahedron 1997,
53, 16897–16910.
476.2431]. Compound 10: oil, [
(br) cmꢁ1 1H NMR (CDCl3, 400 MHz) d 2.10 (br s, 1H), 2.69 (m, 1H), 2.83
(t, J = 10.8 Hz, 1H), 2.85 (s, 3H), 3.69 (t, J = 3.2 Hz, 1H), 3.83 (m, 3H, 2-H),
a
]
D
ꢁ48.7 (c 0.9, CHCl3); IR (neat film) 3500
;
13. For ent-gabosine E 14, ½a D20
ꢂ
ꢁ145.7 (c 0.35, MeOH) [for gabosine E lit.1a
[a]
D
+148 (c 0.85, MeOH) and +152 (c 1.0, H2O)].