Carbocyclization of carbohydrates: Diastereoselective synthesis of (+)-gabosine F, (-)-gabosine O, and (+)-4-epi-gabosine O

Article abstract of DOI:10.1021/ol902071e

Exploitation of silica gel/chloramine T mediated intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar-derived oxlmes to carbocycles furnished the first synthesis of gaboslne F from L-arablnose In 12 steps with 23% overall yield, thereby confi

Full text of DOI:10.1021/ol902071e

ORGANIC
LETTERS
2009
Vol. 11, No. 21
5070-5073
Carbocyclization of Carbohydrates:
Diastereoselective Synthesis of
(+)-Gabosine F, (-)-Gabosine O, and
(+)-4-epi-Gabosine O
Tony K. M. Shing,* King H. So, and Wun S. Kwok
Department of Chemistry and Center of NoVel Functional Molecules, The Chinese
UniVeristy of Hong Kong, Shatin, Hong Kong, China
tonyshing@cuhk.edu.hk
Received September 7, 2009
ABSTRACT
Exploitation of silica gel/chloramine T mediated intramolecular nitrile oxide-alkene cycloaddition (INOC) of sugar-derived oximes to carbocycles
furnished the first synthesis of gabosine F from L-arabinose in 12 steps with 23% overall yield, thereby confirming its absolute configuration.
Similarly, efficient syntheses of gabosine O and 4-epi-gabosine O were accomplished from D-mannose in 9 and 11 steps with 41% and 38%
overall yields, respectively, involving INOC, regioselective dehydration, and diastereoselective hydrogenation as the key steps.
Gabosines (Figure 1) belong to a family of hydroxylated
cyclohexenones and cyclohexanones that have been shown
to display interesting bioactivities such as antibiotic, anti-
cancer, and DNA binding properties.1 Since the first isolation
of gabosine C (6) from Streptomyces strains in 1974,2 15
other gabosines have been isolated. Within the family,
gabosines B (7), F (1), and O (3) are saturated cyclohex-
anones, while the others are unsaturated cyclohexenones.
Previously, our group has successfully developed a short route
to prepare unsaturated gabosines G (8) and I (9) from δ-D-
gluconolactone via a key intramolecular Horner-Wadsworth-
Emmons olefination.3 In this paper, we focus on the syntheses
of optically active gabosines with a saturated carbocycle.
(1) (a) Bach, G.; Breiding, M. S.; Grabley, S.; Hammann, P.; Hu¨tter,
K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993,
3, 241–250. (b) Huntley, C. F. M.; Hamilton, D. S.; Creighton, D. J.; Ganem,
B. Org. Lett. 2000, 2, 3143–3144. (c) Kamiya, D.; Uchihata, Y.; Ichikawa,
E.; Kato, K.; Umezawa, K. Bioorg. Med. Chem. Lett. 2005, 15, 1111–1114.
(d) Tang, Y. Q.; Maul, C.; Ho¨fs, R.; Sattler, I.; Gabley, S.; Feng, X.-Z.;
Zeeck, A.; Thiericke, R. Eur. J. Org. Chem. 2000, 1, 149–153.
(2) Tatsuta, K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H.;
Naganawa, H. J. Antibiot. 1974, 27, 579–586.
Figure 1. The gabosine family.
The first synthesis of racemic gabosine B (7) was achieved
by Mehta and Lakshminath in 14 steps from 5,5-dimethox-
10.1021/ol902071e CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

ytetrachlorocyclopentadiene, giving a mixture of rac-ga-
bosines B (7) and F (1), using the Grob-like “top-to-bottom”
fragmentation as the key step.4 Enantiopure gabosine B (7)
was constructed by Shinada et al., starting from (-)-quinic
acid and using a Mislow-Evans rearrangement as the key
step, in 15 steps with 4.3% overall yield.5 However, there is
still no report on the synthesis of enantiopure gabosine F
(1), which is the enantiomer of gabosine B (7).
Scheme 1. Synthesis of 4-epi-Gabosine O (4)
The first synthesis of gabosine O (3) was accomplished
by Figueredo et al. in 2006, using p-benzoquinone ethylene
bisketal as the starting material and an enantioselective
acetylation as the key step, in 11 stages with 0.9% overall
yield.
4-epi-Gabosine (4) was also obtained in 11 steps with an
overall yield of 4.6%.6 One year later, Carren˜o et al. reported
a new synthesis of gabosine O (3) using enantiopure (SR)-
and (SS)-[(p-tolylsulfinyl)methyl]-p-quinols as the chiral
intermediates that allowed stereocontrolled conjugate addi-
tions of organoaluminium reagents to the cyclohexadienone.
The asymmetric synthesis started from p-benzoquinone
dimethyl monoketal and furnished gabosine O (3) in 10 steps
with 13% overall yield.7
To synthesize gabosines with a saturated carbocycle,
stereoselective construction of the carbocyclic framework is
usually the key step. Previously, our group reported that silica
gel/chloramine T mediated intramolecular nitrile oxide-alkene
cycloaddition (INOC) of oximes with free hydroxy groups
derived from carbohydrates afforded hydroxylated cycload-
ducts with excellent yields.8
The configuration of the free alcohol in cycloadduct 12 was
inverted by Mitsunobu reaction11 followed by ester hydrolysis,
resulting in almost quantitative transformation with either of
the epimers 12r or 12ꢀ, or the mixture. Alcohols 13r and 13ꢀ
were therefore obtained in 49% overall yield from D-mannose
in 7 steps.
Pure isoxazoline 13r underwent hydrogenolysis with
Raney-Ni/acetic acid12 to give the corresponding hydroxy
ketone. Interestingly, not only ketone 14r but also 14ꢀ were
obtained. The longer the reaction time, the more 14ꢀ emerged
until an equilibrium was reached after 12 h where the ratio
of 14r to 14ꢀ was 6:1. The ketones appeared to epimerize
under the conditions. Pure isoxazoline 13ꢀ also underwent
hydrogenolysis and epimerization. The reaction reached
equilibrium quickly in 2 h, resulting in the same ratio of
ketones. Thus, both ketones 14r and 14ꢀ were obtained in
a ratio of 6:1 regardless of the starting material (pure 13r
or 13ꢀ or a mixture of both). It was more convenient to work
on the mixture of epimers (14r + 14ꢀ) because the
stereochemistry of C-6 would be lost in the subsequent
elimination step.
Regioselective activation of the primary alcohol followed
by elimination was then studied to access enone 15. Attempts
with activating reagents such as methanesulfonyl chloride,
triflic anhydride, TFAA, or Martin’s sulfurane were fruitless.
Re-examination of the reaction showed that the enone started
to decompose above -20 °C, indicating that the enone 15
generated had to be transformed into the next stage in one
pot at low temperature.
Exploiting this facile construction of carbocycles from
carbohydrates, we found that these INOC cycloadducts were
converted readily into the saturated gabosines in a few steps
and herein we report the first synthesis of enantiopure
gabosines F (1) from L-arabinose (2), thereby confirming its
absolute configuration. We also report efficient syntheses of
gabosine O (3) and 4-epi-gabosine O (4) from D-mannose
(5) with excellent overall yields.
The synthetic avenue toward 4-epi-gabosine O (4) is
shown in Scheme 1 and starts from D-mannose (5). Accord-
ing to our previous endeavor,8 D-mannose (5) was converted
into oxime 11 via a sequence of reactions involving aceto-
nation,9 Grignard allylation, regioselective glycol cleavage
oxidation,10 and oximation in good overall yield. The oxime
11 cyclized through a silica gel/chloramine-T mediated INOC
reaction to provide epimeric isoxazolines 12r and 12ꢀ in
65% and 14% yield, respectively.
(3) Shing, T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610–
6613.
(4) Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000, 41, 3509–3512.
(5) Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett
2002, 1341–1343.
(6) Alibe´s, R.; Bayo´n, P.; de March, P.; Figueredo, M.; Font, J.;
Marjanet, G. Org. Lett. 2006, 8, 1617–1620.
Martin’s sulfurane was chosen because it causes activation
and elimination in one pot without the addition of an external
´
(7) Carren˜o, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano,
A. Chem.sEur. J. 2007, 13, 1064–1077.
(8) Shing, T. K. M.; Wong, W. F.; Cheng, H. M.; Kwok, W. S.; So,
K. H. Org. Lett. 2007, 9, 753–756.
(11) (a) Mitsunobu, O. Synthesis 1981, 1–28. (b) Martin, S. F.; Dodge,
J. A. Tetrahedron Lett. 1991, 32, 3017–3020.
(9) Schmidt, O. T. Methods in Carbohydrate Chemistry. In Reactions
of Carbohydrates; Whistler, R. L., Wolfrom, M. L., Eds.; Academic Press
Inc.: New York, 1963; Vol. 2, pp 318-319.
(12) Curran, D. P.; Kim, B. H. Synthesis 1986, 312–315.
(13) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327–
4329.
(10) Wu, W. L.; Wu, Y. L. J. Org. Chem. 1993, 58, 3586–3588.
Org. Lett., Vol. 11, No. 21, 2009
5071

base.13 However, it is usually employed for secondary and
tertiary alcohols efficiently, while primary alcohols typically
form ether-dimers instead of the elimination product.14 In
this instance, however, when a mixture of 14r and 14ꢀ was
reacted with Martin’s sulfurane at -78 °C, the enone 15
was generated. It could be reduced smoothly and stereose-
lectively at the alkene moiety to give the corresponding
ꢀ-methyl ketone 16 via catalytic hydrogenation with Raney-
Ni at -78 °C in excellent overall yield. The desired (S)-
methyl group emerged because the ꢀ-face of 15 was hindered
by the bulky isopropylidene ring and the hydrogen could be
delivered from the less hindered R-face selectively. The
good agreement with the literature values.6,7 This is also the
first enantiospecific synthesis of Gabosine O (3), and the
overall yield was much higher than that of the previous
construction performed by Figueredo et al. (11 steps, 0.9%
overall yield) in 20066 and Carren˜o et al. (10 steps, 13%
overall yield) in 2007.7
The synthetic route toward gabosine F (1) is shown in
Scheme 3 and starts from L-arabinose (2). Our previous
Scheme 3. Synthesis of Gabosine F (1)
1
stereochemistry of ketone 16 was confirmed by H NMR
spectral analysis.15
Mild acid hydrolysis of ketone 16 afforded target 4 in a
quantitative yield and with spectral data in good agreement
with the literature values. 4-epi-Gabosine O (4) was thus
synthesized from D-mannose (5) in 11 steps with 38% overall
yield. This is the first enantiospecific synthesis of 4-epi-
gabosine O (4) with specific rotation [R] +15.6 (c 0.30,
MeOH), which is in accord with that of the previous
enantioselective synthesis {[R] +12.2 (c 0.49, MeOH)}.6 The
overall yield of our route (11 steps, 38%) was much higher
than that of the previous synthesis6 (11 steps, 4.6% overall
yield).
Using the aforesaid strategy, synthesis of natural gabosine
O (3) started from the mixture of isoxazolines 12r and 12ꢀ,
which was converted into the mixture of ketones 17r and
17ꢀ via hydrogenolysis with Raney-Ni in acetic acid (Scheme
2). The two ketones were in equilibrium and the ratio of
work8 has shown that L-arabinose (2) was transformed into
oxime 22 via a reaction sequence involving benzyl glycosi-
dation,16 diacetalization,17 hydrogenolytic debenzylation,
Grignard allylation, glycol cleavage oxidation,18 and oxi-
mation in good overall yield. The silica gel/chloramine T
mediated INOC of oxime 22 occurred to give cycloadduct
23 in 94% yield.
Scheme 2. Synthesis of Gabosine O (3) from 12
The heterocyclic ring in isoxazoline 23 was hydrogeno-
lyzed over Raney-Ni smoothly to give hydroxy ketone 24.
Regioselective acetylation19 of the primary alcohol in 24 with
collidine as base furnished acetate 25 in 87% yield. Elimina-
tion of acetic acid from R-acetoxy ketone 25 with triethy-
lamine gave the corresponding exocyclic enone 26. The
stability of this enone 26, in contrast to 15 and 18, might be
ascribed to the trans-diacetal protecting group, which
resembles a stable trans-decalin system. Catalytic hydroge-
nation over Raney nickel affored the ꢀ-methyl ketone 27.
The stereoselectivity of the hydrogenation might be attribut-
17r to 17ꢀ eventually attained 5:1, respectively. These
underwent regioselective dehydration of the primary alcohol
with Martin’s sulfurane at -78 °C to enone 18 followed by
catalytic hydrogenation with Raney-Ni to give 2,3-O-
isopropylidene gabosine O (19). The stereoselectivity of the
hydrogenation of enone 18 was rationalized in a way similar
to that of enone 15 described above.
(16) Ballou, C. E. J. Am. Chem. Soc. 1957, 79, 165–166.
(17) (a) Shing, T. K. M.; Leung, Y. C.; Luk, T. J. Org. Chem. 2005,
70, 7279. (b) For a review on 1,2-diacetals, see: Ley, S. V.; Baeschlin,
D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke, W. M. H.; Reynolds,
D. J. Chem. ReV. 2001, 101, 53.
The acetonide 19 was then hydrolyzed to afford natural
gabosine O (3) that was synthesized from D-mannose (5) in
9 steps with 41% overall yield. The specific rotation, [R]
+21.0 (c 0.07, MeOH), and the NMR spectral data are in
(18) Ogawa, S.; Sato, K.; Miyamoto, Y. J. Chem. Soc., Perkin Trans. 1
1993, 691.
(14) Paquette, L. A.; Zhao, M. J. Am. Chem. Soc. 1993, 115, 354–356.
(19) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1993, 58,
3791–3793.
(15) For details, please refer to the Supporting Information .
5072
Org. Lett., Vol. 11, No. 21, 2009

able to the “anchor effect” of the axial free R-alcohol,20
which directed the approach of the hydrogen from the R-face,
thus leading to the desired ꢀ-methyl ketone 27.
Removal of the trans-diacetal blocking group then fur-
nished the target molecule gabosine F (1). The specific
rotation, [R] +88.4 (c 0.69, MeOH) {lit. [R] +94 (c 1.0,
MeOH)}, and the NMR spectral data are in good agreement
with the literature values.1a Thus enantiopure gabosine F (1)
was synthesized for the first time from L-arabinose (2) in 12
steps with 23% overall yield, thereby confirming the absolute
configuration of the natural product.
ously. By using the same strategy, the first enantiospecific
synthesis of optically pure gabosine F (1) was achieved from
L-arabinose (2) in 12 steps with an overall yield of 23%,
thereby confirming the absolute configuration of the natural
product. All three syntheses involved an INOC reaction, a
regioselective dehydration, and diastereoselective hydrogena-
tion as the key steps. The present carbocyclization of sugar
derivatives should provide a facile and valuable entry to the
construction of enantiopure hydroxylated cyclohexanoid
natural products and pharmaceuticals.
Acknowledgment. This work was supported by a Strategic
Investment Scheme administered by the Center of Novel
Functional Molecules of The 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.
In conclusion, facile and efficient carbocyclization of
carbohydrate derivatives to provide hydroxylated cyclohex-
anones has been demonstrated by using the high-yielding
silica gel/chloramine T mediated intramolecular nitrile
oxide-alkene cycloaddition (INOC) of sugar-derived oximes
to furnish enantiospecific and efficient syntheses of gabosine
O (3) and 4-epi-gabosine O (4) from D-mannose (5) in 9
and 11 steps with 41% and 38% overall yields, respectively.
These chemical yields are superior to those reported previ-
Supporting Information Available: Additional informa-
tion, experimental procedures, and product characterization.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Sugi, Y.; Mitsui, S. Chem. Lett. 1974, 577–578.
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