A common strategy for the synthesis of (+)-gabosine N, (+)-gabosine O, and some carbapyranoses using a Nozaki-Hiyama-Kishi reaction and RCM

Article abstract of DOI:10.1016/j.tetasy.2010.05.041

Stereoselective synthesis of carbasugars (+)-gabosine N 1 and (+)-gabosine O 2, carba-α-l-rhamnose 17, and carba-6-deoxy-α-l-talose 18 by using a Nozaki-Hiyama-Kishi (NHK) reaction and ring-closing metathesis.

Full text of DOI:10.1016/j.tetasy.2010.05.041

Tetrahedron: Asymmetry 21 (2010) 930–935
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Tetrahedron: Asymmetry
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A common strategy for the synthesis of (+)-gabosine N, (+)-gabosine O, and some
carbapyranoses using a Nozaki–Hiyama–Kishi reaction and RCM
*
J. Prasada Rao, B. Venkateswara Rao
Organic III division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective synthesis of carbasugars (+)-gabosine N 1 and (+)-gabosine O 2, carba-a-L-rhamnose 17,
Received 6 April 2010
Accepted 21 May 2010
Available online 19 June 2010
and carba-6-deoxy-
a-L-talose 18 by using a Nozaki–Hiyama–Kishi (NHK) reaction and ring-closing
metathesis.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
been reported by Singh et al.12 while the perbenzoyl derivative of
carba-6-deoxy-a-L
-talose has been reported by Redlich et al.13 Ret-
Carbasugars1 are analogues of monosaccharides, in which the
ring oxygen is replaced with methylene group2, and have attracted
considerable interest as inhibitors of glycosidases. Glycosidase en-
zymes are involved in numerous biological processes and their
inhibition has enormous potential for the treatment of many dis-
eases.3 Gabosines isolated from Streptomyces strains belong to
the sub class of carbasugars known as ketocarbasugars.4 Gabosines
exhibit a variety of biological activities such as antiprotozoal, DNA
binding properties, and enzyme inhibition.5 Fifteen different gabo-
sines have been isolated which possess the trihydroxy methyl
(hydroxymethyl) cyclohexenone or cyclohexanone skeleton in
common (Fig. 1). Due to their interesting biological activities and
fascinating structural features, they have attracted the attention
of many synthetic chemists and biologists.6,7 Furthermore gabo-
sines can be considered as chemical precursors of 6-deoxy-carba
pyranose derivatives which are known for the inhibition of
oligosaccharide processing enzymes.8 Recently a new class of com-
pounds called ampelomins A–G (polyoxygenated methyl cyclo-
hexanoids) were isolated from Ampelomyces fungus (Fig. 2),
which has glycosidase inhibition and antibacterial activities.9
These compounds can also be considered as reduced forms of
gabosines.
rosynthetic analysis of gabosine N and gabosine O (Scheme 1) re-
vealed that the hydroxyl groups at C4, C5, and C6 can be obtained
from D-ribose. For instance, one carbon homologation at C-1 and
propenyl group introduction at C-5 on compound 5 will give the
RCM precursor 4 which can be elongated to the cyclohexene core
3 of gabosines. The key aspect of the synthesis is to find the stere-
oselectivity at the newly generated stereogenic center in 4 during
the nucleophilic addition of propenyl unit.
2. Results and discussions
Based on the above-described retro synthetic plan, the synthe-
sis of (+)-gabosine N and (+)-gabosine O started from 5-O-tert-
butyldimethylsilyl-2,3-O-isopropylidene-
D-ribofuranose
5
as
shown in Scheme 2. One carbon homologation of the lactol 5 affor-
ded the olefin compound 6 using a Wittig reaction.14 The second-
ary hydroxy group of 6 was protected as MOM ether using
methoxy methyl chloride to give 7. Deprotection of the silyl group
in compound 7 gave 8, which was followed by oxidation of the
resultant alcohol under Swern conditions gave the
aldehyde.
a-alkoxy
Nucleophilic addition on the
a-alkoxy aldehyde with 2-bromo
propene under Nozaki–Hiyama–Kishi conditions15 in DMF gave
anti alcohol 10 as the major product along with 9 in a ratio of
3.8:1. When the addition was carried out under Grignard condi-
tions in THF at ꢀ78 °C interestingly syn alcohol 9 was obtained
as a major compound along with 10 in the ratio of 4:1, both iso-
mers could be separated by column chromatography. The reversal
of stereoselectivities in the above-mentioned case can be explained
as follows (Fig. 3);16 Generally during the NHK reaction, the nucle-
ophile undergoes addition via non-chelated Felkin–Anh model,17
whereas in the case of the Grignard addition, chelation of the mag-
Recently our group has been involved in the development of
new strategies for the synthesis of carbasugars by using ring-clos-
ing metathesis10 and a Tebbe-mediated cascade reaction.11 As part
of this program we reported the synthesis of (ꢀ)-gabosine C using
NHK-RCM strategy.7f In continuation, we herein report a short, effi-
cient, and common strategy for the synthesis of (+)-gabosine N 1,
(+)-gabosine O 2, carba-
-talose 18. Earlier few syntheses for gabosine N and gabosine O
have been reported.6 The synthesis of carba-b-
-rhamnose has
a-L-rhamnose 17, and carba-6-deoxy-a-
L
D
nesium ion with the
to give syn isomer 9 as the major product.
a-alkoxy group allowed nucleophilic addition
* Corresponding author. Tel.: +91 40 27193003; fax: +91 40 27193003.
E-mail addresses: venky@iict.res.in, drb.venky@gmail.com (B.V. Rao).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.041

J. P. Rao, B. V. Rao / Tetrahedron: Asymmetry 21 (2010) 930–935
931
O
O
O
O
HO
HO
HO
HO
HO
HO
HO
HO
R
R
OH
OH
OH
OH
gabosine C (R=OH)
gabosine N (R=H)
gabosine D (R=OAc)
gabosine E (R=OH)
gabosine B
gabosine A
O
O
O
O
HO
HO
HO
HO
HO
HO
OH
R
OH
HO
HO
OH
OH
gabosine J
OH
gabosine O
gabosine G (R= OAC)
gabosine H (R=H)
gabosine I (R=OH)
gabosine L
Figure 1. Gabosine family.
OH
OH
OH
O
HO
HO
HO
HO
O
OH
OH
ampelomin B
ampelomin A
ampelomin C
ampelomin D
HO
OH
OH
OH
O
O
OH
HO
HO
OH
OH
ampelomin F
OH
ampelomin G
ampelomin E
Figure 2. Ampelomins A–G.
O
O
OH
TBSO
OMOM
O
HO
HO
HO
MOMO
OH
HO
HO
O
O
O
O
O
O
OH
OH
1
5
2
3
4
Scheme 1. Retrosynthetic analysis.
The diene mixture of 9 and 10 was subjected to ring-closing
metathesis using Grubb’s 2nd generation catalyst18 in toluene at
reflux to give cyclohexene derivative 3. The allylic alcohol in com-
pound 3 was oxidized with PDC to yield the enone derivative 11.
Global deprotection of MOM and isopropylidene in compound 11
was achieved with AmberlystÒ 15 in THF/H2O (2:1) to give (+)-
gabosine N 1 as a white solid whose physical and spectral data
were identical with the reported values.6d Hydrogenation of 11
gave 12. Global deprotection of MOM and isopropylidene group
in 12 was achieved with AmberlystÒ 15 to give (+)-gabosine O 2
as a white solid whose physical and spectroscopic data were iden-
tical with the reported values.6a,d
bal deprotection of 15 and 16 with aq 6 M HCl in methanol gave
carbapyranoses 1712 and 18.13 The spectroscopic and physical data
of 17 were identical with the reported values, thus confirming the
configuration of the newly generated stereogenic centre in 9. Fur-
thermore, it also confirms the configuration of the hydroxyl group
generated by propenyl addition in 10 and 18.
3. Conclusions
In conclusion, we have developed a diversity-oriented general
strategy for the synthesis of (+)-gabosine N, (+)-gabosine O, and
carbapyranoses by using nucleophilic addition on
a-alkoxy alde-
hyde under NHK and Grignard conditions followed by ring-closing
We extended this strategy for the synthesis of 6-deoxy carbasu-
metathesis.
gars, such as carba-a-L-rhamnose 17 and carba-6-deoxy-a-L-talose
18 (Scheme 3); these compounds resemble the structures of ampe-
lomins (Fig. 2). Diene 9 and 10 were independently subjected to
ring-closing metathesis using Grubb’s 2nd generation catalyst in
toluene at reflux to give cyclohexene derivatives 13 and 14. Stere-
oselective reduction of the double bond in 13 and 14 was achieved
with hydrogenation using PtO2 as a catalyst to give 15 and 16. Glo-
4. Experimental
TLC was performed on Merck Kiesel gel 60, F254 plates (layer
thickness 0.25 mm). Column chromatography was performed on
silica gel (60–120 mesh) using ethyl acetate and hexane mixture

932
J. P. Rao, B. V. Rao / Tetrahedron: Asymmetry 21 (2010) 930–935
TBSO
i
TBSO
ii
HO
OMOM
O
TBSO
OH
OMOM
O
O
iii
OH
O
O
O
O
O
O
7
6
8
5
OMOM
O
HO
O
vi
vii
iv
v
R
R'
O
MOMO
O
MOMO
O
HO
O
OH
O
O
OH
1
R'= H and R= OH 9
R'= OH and R= H 10
11
3
O
O
ix
viii
MOMO
HO
O
OH
O
OH
12
2
Scheme 2. Synthesis of (+)-gabosine N and (+)-gabosine O. Reagents and conditions: (i) Ph3P@CH2, THF, ꢀ78 °C to rt, 4 h, 76%; (ii) MOM-Cl, DIPEA, cat. DMAP, CH2Cl2, ꢀ15 °C
to rt, 12 h, 93%; (iii) TBAF, THF, 4 h, 95%; (iv) (a) (COCl)2, DMSO, CH2Cl2, Et3N, ꢀ78 °C, 2 h; (b) 2-bromo propene, CrCl2, cat. NiCl2, DMF, 12 h, 72% or 2-bromo propene, Mg, THF,
ꢀ78 °C, 4 h, 85%; (v) 10 mol % Grubbs catalyst 2nd generation, toluene, reflux, 12 h, 85%; (vi) PDC, CH2Cl2, 4 Å MS, 12 h, 82%; (vii) AmberlystÒ 15, THF/H2O (2:1), 70 °C, 5 h,
75%; (viii) H2, Pd/C, MeOH, 1 h, 95%; (ix) AmberlystÒ 15, THF/H2O (2:1), 70 °C, 5 h, 85%.
plet), number of proton(s), and coupling constant(s) J (Hz). 13C
Br
Mg
NMR chemical shifts are expressed in ppm. Optical rotations were
measured with a Horiba-SEPA-300 digital polarimeter. Accurate
mass measurement was performed on a Q STAR mass spectrometer
(Applied Biosystems, USA).
O
O
MOMO
H
O
O
H
MOMO
O
4.1. (R)-5-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
8,8,9,9-tetramethyl-2,4,7-trioxa-8-siladecane 7
O
H
H
Nu
Nu
Cram's chelated model where the
nucleophile is organo magnesium
Felkin-Anh model where the
To an ice-cooled stirred solution of alcohol
6 (2.08 g,
nucleophile is organochromium
6.88 mmol) in CH2Cl2 (20 mL) were added DIPEA (4.5 mL,
34.44 mmol), MOM-Cl (1.1 mL, 13.77 mmol), and DMAP (5 mg).
The reaction mixture was allowed to warm to room temperature
and then stirred for 12 h. The reaction mixture was extracted with
CH2Cl2 (3 ꢁ 30 mL) and water (30 mL). The combined organic lay-
ers were washed with brine (20 mL) and dried over Na2SO4, and
the solvent was concentrated under reduced pressure. The crude
product was purified by column chromatography using ethyl ace-
tate/petroleum ether (1:19) to afford compound 7 (2.2 g, 93%) as
Figure 3. Felkin–Anh and Cram model.
as eluant. Melting points were determined on a Fisher John’s melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RX-1 FT-IR system. 1H NMR and 13C NMR spec-
tra were recorded using a Varian Gemini-200 MHz and 400 MHz or
a Bruker Avance-300 MHz spectrometer. 1H NMR data are ex-
pressed as chemical shifts in parts per million (ppm) followed by
multiplicity (s-singlet; d-doublet; t-triplet; q-quartet; m-multi-
a liquid. ½a 2D8
¼ ꢀ5:6 (c 0.92, CHCl3); IR (neat) mmax 2930, 1464,
ꢂ
1373, 1215, 836 cmꢀ1
;
1H NMR (200 MHz, CDCl3): 0.06 (s, 3H),
OH
HO
OMOM
HO
HO
ii
i
iii
HO
MOMO
MOMO
O
O
O
O
HO
O
O
O
15
OH
17
9
13
OMOM
OH
HO
HO
HO
ii
i
iii
HO
O
O
MOMO
MOMO
O
HO
O
O
OH
18
10
16
14
Scheme 3. Synthesis of carbapyranoses. Reagents and conditions: (i) 10 mol % Grubbs catalyst 2nd generation, toluene, reflux, 12 h, 85%; (ii) (a) H2, PtO2, MeOH, 4 h, 90%; (b)
aq 6 M HCl, MeOH, rt, 80%.

J. P. Rao, B. V. Rao / Tetrahedron: Asymmetry 21 (2010) 930–935
933
0.91 (s, 9H), 1.34 (s, 3H), 1.45 (s, 3H), 3.36 (s, 3H), 3.45–3.57 (m,
1H), 3.73 (dd, 1H, J = 3.9, 10.9 Hz), 3.91 (dd, 1H, J = 2.7, 10.9 Hz),
4.26 (dd, 1H, J = 6.2, 8.2 Hz), 4.57–4.66 (m, 1H), 4.62 (d, 1H,
J = 7.0 Hz), 4.70 (d, 1H, J = 7.0 Hz), 5.21 (d, 1H, J = 10.1 Hz), 5.34
(d, 1H, J = 17.2 Hz), 5.83–6.03 (m, 1H); 13C NMR (75 MHz, CDCl3)
d ꢀ5.1, 18.7, 25.6, 26.2, 28.0, 56.1, 63.7, 76.6, 77.9, 78.9, 97.2,
108.7, 117.9, 134.7; ESI/MS (m/z) 369 (M++Na); HRMS calcd for
for 12 h, the reaction mixture was diluted with ether (30 mL) poured
into water (20 mL), and extracted with ether repeatedly. The com-
bined extracts were dried (Na2SO4) and concentrated. Purification
by silica gel column chromatography using ethyl acetate/hexane
(12:1) as the eluant provided alcohol 9 (15%) and 10 (57%) as yellow
color oils in the ratio of 1:3.8 (0.42 g, 72%).
4.3.1. (1R,2S)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan
C17H34O5NaSi 369.2073, found 369.2063.
-4-yl)-1-(methoxymethoxy)-3-methylbut-3-en-2-ol 9
½
a 2D8
ꢂ
¼ ꢀ19:1 (c 1.52, CHCl3); IR (neat) mmax 3332, 2924, 1649,
4.2. (R)-2-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-
(methoxymethoxy)ethanol 8
1455, 1215, 1076 cmꢀ1 1H NMR (400 MHz, CDCl3): 1.34 (s, 3H),
;
1.47 (s, 3H), 1.78 (s, 3H), 2.88 (d, 1H, J = 6.2 Hz, OH), 3.37 (s, 3H),
3.74 (dd, 1H, J = 4.2, 6.2 Hz), 4.16–4.22 (m, 2H), 4.58 (t, 1H,
J = 6.8 Hz), 4.62 (q, 2H, J = 6.2 Hz), 4.92 (s, 1H), 5.03 (s, 1H), 5.24
(d, 1H, J = 10.4 Hz), 5.33 (d, 1H, J = 17.1 Hz), 5.97–6.06 (m, 1H);
13C NMR (75 MHz, CDCl3) d 19.0, 25.1, 27.7, 56.3, 74.3, 77.6, 78.6,
79.0, 97.9, 108.4, 112.7, 118.4, 134.7, 144.3; ESI/MS (m/z) 295
(M++Na); HRMS calcd for C14H24O5Na 295.1521, found 295.1510.
To an ice-cooled stirred solution of silyl compound 7 (2.0 g,
5.78 mmol) in THF (10 mL) was added TBAF (8.7 mL, 1 M solution
in THF, 8.67 mmol). The reaction mixture was allowed to warm to
room temperature, and then stirred for 4 h. The reaction was
quenched with saturated NaHCO3 solution (20 mL) and the reaction
mixture was extracted with ethyl acetate (3 ꢁ 75 mL). The com-
bined organic fractions were collected and washed with water and
brine, then dried over Na2SO4 and concentrated under reduced pres-
sure. The crude product was purified by column chromatography
using ethyl acetate/petroleum ether (1:4) to afford compound 8
4.3.2. (1R,2R)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan
-4-yl)-1-(methoxymethoxy)-3-methylbut-3-en-2-ol 10
½
a 2D8
ꢂ
¼ þ5:1 (c 1.4, CHCl3); IR (neat) mmax 2923, 1647, 1457,
1076 cmꢀ1 1H NMR (400 MHz, CDCl3): 1.32 (s, 3H), 1.47 (s, 3H),
;
(1.27 g, 95%) as a viscous liquid. ½a D28
ꢂ
¼ þ76:1 (c 0.86, CHCl3); IR
1.81 (s, 3H), 3.41 (s, 3H), 3.60 (d, 1H, J = 8.4 Hz, OH), 3.66 (dd, 1H,
J = 3.1, 8.9 Hz), 4.09 (dd, 1H, J = 5.7, 8.9 Hz), 4.21 (dd, 1H, J = 3.1,
8.3 Hz), 4.52–4.58 (m, 3H), 4.93 (s, 1H), 4.99 (s, 1H), 5.20 (d, 1H,
J = 10.4 Hz), 5.31 (d, 1H, J = 17.2 Hz), 5.85–5.95 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 19.4, 25.3, 27.9, 56.5, 74.5, 77.1, 79.1, 83.3,
99.0, 108.5, 113.7, 117.6, 134.6, 143.9; ESI/MS (m/z) 295 (M++Na).
(neat) mmax 3454, 2935, 1645, 1375, 1035 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 1.34 (s, 3H), 1.46 (s, 3H), 3.11 (br s, 1H), 3.41
(s, 3H), 3.45–3.49 (m, 1H), 3.57 (dd, 1H, J = 5.8, 11.2 Hz), 3.79 (d,
1H, J = 11.7 Hz), 4.08 (dd, 1H, J = 6.8, 8.8 Hz), 4.59 (dd, 2H, J = 6.8,
10.7 Hz), 4.62 (dd, 1H, J = 5.8, 6.8 Hz), 5.19 (dt, 1H, J = 2.0, 10.7 Hz),
5.33 (dt, 1H, J = 2.0, 17.5 Hz), 5.81–5.89 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 24.9, 27.3, 55.6, 63.1, 76.6, 78.3, 80.4, 97.2,
108.4, 117.1, 133.5; ESI/MS (m/z) 255 (M++Na); HRMS calcd for
4.4. General procedure for Ring-Closing Metathesis
C
11H20O5Na 255.1208, found 255.1197.
To the solution of diene 10 (0.3 g, 1.10 mmol) in toluene
(44 mL), Grubbs’ 2nd generation catalyst (0.093 g, 0.110 mmol)
was added at room temperature and the reaction mixture was re-
fluxed for 12 h. Toluene was removed under vacuum, and applied
for column chromatography using ethyl acetate/hexane (1:4) as
eluant provided cyclohexenol 3 as an oily compound (0.23 g, 85%).
4.3. (S)-2-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
2-(methoxymethoxy)acetaldehyde
To a stirred solution of oxalyl chloride (0.9 mL, 10.3 mmol) in
dry CH2Cl2 (10 mL) under nitrogen atmosphere was added DMSO
(1.5 mL, 20.7 mmol) slowly at ꢀ78 °C and stirred for 30 min at
the same temperature. Then alcohol 8 (1.2 g, 5.17 mmol) in dry
CH2Cl2 (10 mL) was added slowly over 10 min and stirred for a fur-
ther 2 h after which Et3N (4.3 mL, 31.03 mmol) was added. The
temperature was slowly raised to room temperature over 20 min
and the reaction mixture was diluted with CH2Cl2 (100 mL). The
organic layer was washed with water and brine, and dried over
anhydrous Na2SO4. The solvent was removed on a rotary evapora-
tor to give an aldehyde, which was used as such for the next reac-
tion without any purification.
4.4.1. (3aS,4R,5S,7aS)-4-(Methoxymethoxy)-2,2,6-trimethyl-
3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-5-ol 13
½
a 2D8
ꢂ
¼ þ27:6 (c 1.23, CHCl3); IR (neat) mmax 3620, 2923, 1647,
1461, 1035 cmꢀ1 1H NMR (300 MHz, CDCl3): 1.33 (s, 3H), 1.34
;
(s, 3H), 1.82 (d, 3H, J = 1.1 Hz), 3.3 (br s, 1H, OH), 3.5 (s, 3H),
3.48–3.53 (m, 1H), 4.27–4.31 (m, 1H), 4.45–4.50 (m, 1H), 4.53
(m, 1H), 4.81 (d, 1H, J = 7.2 Hz), 4.84 (d, 1H, J = 7.2 Hz), 5.30 (m,
1H); 13C NMR (75 MHz, CDCl3) d 18.7, 26.7, 27.7, 56.0, 69.0, 73.9,
75.5, 82.8, 97.8, 109.6, 121.8, 136.7; ESI/MS (m/z) 267 (M++Na);
HRMS calcd for C12H20O5Na 267.1208, found 267.1207.
Procedure for Grignard reaction: To the solution of isopropenyl
magnesium bromide prepared from Mg (0.26 g, 10.86 mmol) and
2-bromopropene (0.76 mL, 8.7 mmol) in THF (10 mL) was added
the solution of aldehyde (0.5 g, 2.17 mmol) in THF over 10 min at
ꢀ78 °C under nitrogen. After stirring for 4 h at room temperature,
the mixture was poured into saturated NH4Cl (50 mL) and ex-
tracted with ethyl acetate (3 ꢁ 50 mL). The collected organic layers
were combined, washed with water, brine, and then dried over
Na2SO4, concentrated under reduced pressure and purified through
column chromatography (hexane/ethyl acetate, 12:1) to afford the
corresponding alcohol 9 (68%)and 10 (17%) as yellow oils in a ratio
of 4:1 (0.51 g, 85% for two steps).
Procedure for Nozaki–Hiyama–Kishi reaction: A mixture of CrCl2
(1.33 g, 8.69 mmol) and a catalytic amount of NiCl2 (0.028 g,
0.217 mmol) in dry DMF (7 mL) was stirred at 25 °C for 10 min under
a nitrogen atmosphere. A solution of aldehyde (0.5 g, 2.17 mmol) in
DMF (5 mL) followed by 2-bromo propene (0.76 mL, 8.69 mmol)
was added at 25 °C successively. After stirring at room temperature
4.4.2. (3aS,4R,5R,7aS)-4-(Methoxymethoxy)-2,2,6-trimethyl-
3a,4,5,7a-tetrahydrobenzo[d][1,3]dioxol-5-ol 14
½
a 2D8
ꢂ
¼ ꢀ82:4 (c 1.2, CHCl3); IR (neat) mmax 3620, 2923, 1641,
1461, 1036 cmꢀ1 1H NMR (300 MHz, CDCl3): 1.35 (s, 3H), 1.43
;
(s, 3H), 1.89 (dd, 3H, J = 1.1, 1.5 Hz), 3.05 (d, 1H, J = 10.9 Hz, OH),
3.46 (s, 3H), 3.73 (dd, 1H, J = 2.3, 4.1 Hz), 3.96 (dd, 1H, J = 4.1,
10.6 Hz), 4.49–4.52 (m, 1H), 4.53–4.58 (m, 1H), 4.76 (d, 1H,
J = 7.2 Hz), 4.9 (d, 1H, J = 7.2 Hz), 5.36–5.40 (m, 1H); 13C NMR
(75 MHz, CDCl3) d 21.0, 26.5, 28.0, 55.8, 68.4, 72.0, 73.9, 75.5,
95.1, 110.6, 121.4, 137.3; ESI/MS (m/z) 267 (M++Na).
4.5. (3aS,4S,7aS)-4-(Methoxymethoxy)-2,2,6-trimethyl-3a,4
-dihydrobenzo[d][1,3]dioxol-5(7aH)-one 11
To a solution of alcohol 3 (0.1 g, 0.41 mmol) in CH2Cl2 (5 mL),
PDC (0.385 g, 1.02 mmol) was added at 0 °C. After stirring at rt
for 12 h., the reaction mixture was filtered through a Celite pad,

934
J. P. Rao, B. V. Rao / Tetrahedron: Asymmetry 21 (2010) 930–935
washed with CH2Cl2. Filtrate and washings were combined and
concentrated to a syrup and applied for column chromatography
using ethyl acetate/hexane (1:5) as the eluant to give cyclohexe-
tion mixture was filtered and the filtrate was concentrated under
reduced pressure to give a syrup, which was purified by column
chromatography using ethyl acetate/hexane (1:5) as the eluant to
none 11 as syrup (0.081 g, 82%). ½a D28
ꢂ
¼ ꢀ61:0 (c 0.8, CHCl3); IR
give 15 in 90% yield as a syrup. ½a D28
ꢂ
¼ þ3:0 (c 0.23, CHCl3); IR
(neat) mmax 2927, 1706, 1516, 1031 cmꢀ1
;
1H NMR (300 MHz,
(neat) mmax 3620, 2919, 1464, 1177 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): 1.34 (s, 1H), 1.41 (s, 1H), 1.85 (s, 3H), 3.47 (s, 3H), 4.44–
4.47 (m, 1H), 4.79–4.83 (m, 2H), 4.86 (d, 1H, J = 7.2 Hz), 4.99 (d,
1H, J = 7.2 Hz), 6.32–6.35 (m, 1H); 13C NMR (75 MHz, CDCl3) d
15.5, 26.9, 27.8, 56.0, 72.7, 74.8, 77.6, 96.5, 111.2, 125.9, 139.0,
195.1; ESI/MS (m/z) 265 (M++Na); HRMS calcd for C12H18O5Na
265.1051, found 265.1044.
CDCl3): 1.06 (d, 3H, J = 6.04 Hz), 1.25–1.37 (m, 2H), 1.32 (s, 3H),
1.51 (s, 3H), 1.79 (dd, 1H, J = 6.8, 10.6 Hz), 2.93 (br s, 1H), 3.43–
3.48 (m, 2H), 3.46 (s, 3H), 4.07–4.15 (m, 1H), 4.42 (dd, J = 4.1,
3.7 Hz), 4.81 (s, 2H); 13C NMR (75 MHz, CDCl3) d 17.8, 26.1, 28.5,
32.8, 36.2, 55.8, 73.4, 74.1, 76.2, 82.1, 97.6, 109.2; ESI/MS (m/z)
269 (M++Na); HRMS calcd for C12H22O5Na 269.1364, found
269.1369.
4.6. (3aS,4S,6R,7aS)-4-(Methoxymethoxy)-2,2,6-
trimethyltetrahydrobenzo[d][1,3]dioxol-5(6H)-one 12
4.10. (3aS,4R,5R,6R,7aS)-4-(Methoxymethoxy)-2,2,6-
trimethylhexahydrobenzo[d][1,3]dioxol-5-ol 16
Compound 11 (0.05 g, 0.206 mmol) was taken in to methanol
(2 mL) and to it was added Pd/C (10 mg). The flask was then purged
with H2 and hydrogenated at room temperature for 1 h. The reac-
tion mixture was filtered and the filtrate was concentrated under
reduced pressure to give a syrup, which was purified by column
chromatography ethyl acetate/hexane (1:5) as the eluant to give
Compound 16 was obtained from compound 14 (0.07,
0.28 mmol) according to the procedure described for the afore-
mentioned compound 15 in 90% yield. ½a D28
ꢂ
¼ ꢀ39:8 (c 0.2, CHCl3);
IR (neat) mmax 3620, 2921, 1647, 1037 cmꢀ1
;
1H NMR (300 MHz,
CDCl3): 1.06 (d, 3H, J = 7.06 Hz), 1.25–1.28 (m, 1H), 1.34 (s, 3H),
1.38–1.43 (m, 1H), 1.55 (s, 3H), 1.57–1.64 (m, 1H), 2.63 (d, 1H,
J = 7.1 Hz), 3.45 (s, 3H), 3.66 (dd, 1H, J = 3.7, 4.7 Hz), 3.80–3.84
(m, 1H), 4.12–4.15 (m, 1H), 4.34 (dd, 1H, J = 3.7, 4.7 Hz), 4.77 (d,
1H, J = 7.1 Hz), 4.87 (d, 1H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3)
d 17.7, 26.2, 28.9, 30.5, 31.7, 55.8, 71.0, 74.0, 74.5, 75.6, 94.8,
109.6; ESI/MS (m/z) 269 (M++Na).
cyclohexane derivative 12 (0.048 g, 95%). ½a D28
ꢂ
¼ ꢀ36:6 (c 0.7,
CHCl3); IR (neat) mmax 2979, 1728, 1377, 1213, 1023 cmꢀ1
;
1H
NMR (300 MHz, CDCl3): 1.26 (d, 3H, J = 6.8 Hz), 1.30 (s, 3H), 1.40
(s, 3H), 1.97–2.08 (m, 1H), 2.28–2.49 (m, 2H), 3.39 (s, 3H), 4.34
(d, 1H, J = 4.5), 4.54–4.61 (m, 1H), 4.68–4.74 (m, 3H); 13C NMR
(75 MHz, CDCl3) d 16.9, 24.0, 26.3, 31.3, 39.8, 55.9, 73.3, 76.9,
78.2, 95.6, 109.5, 207.5; ESI/MS (m/z) 267 (M++Na); HRMS calcd
for C12H20O5Na 267.1208, found 267.1210.
4.11. 5a-Carba-a-L-rhamnopyranose 17
4.7. (+)-Gabosine N 1
Compound 15 was taken in methanol (2 mL), to this solution at
room temperature was added aq 6 M HCl (1.5 mL). This mixture
was stirred for 12 h at room temperature. After completion of the
reaction, the solvent was removed under vacuum. Purification by
silica gel flash chromatography using MeOH/chloroform (1:20) as
the eluant provided alcohol 17 as a white solid in 80% yield. Mp:
To the solution of protected gabosine 11 (0.05 g, 0.206 mmol) in
THF (2 mL) and H2O (1 mL), AmberlystÒ-15 resin (40 mg) was
added and refluxed at 70 °C for 5 h. The reaction mixture was fil-
tered and the filtrate was concentrated under reduced pressure
to give a syrup, which was purified by column chromatography
to give (+)-gabosine N 1 in 75% yield as a white solid. Mp: 180–
159–162 °C; ½a 2D8
ꢂ
¼ ꢀ5:4 (c 0.7, CH3OH) {lit.12 for enantiomer
½
a 2D8
ꢂ
¼ þ7:0 (c 1.1, CH3OH)}; IR (neat) mmax 3356, 2295, 1456,
181 °C; ½a 2D8
ꢂ
¼ þ172 (c 0.2, CH3OH) {lit.6d, ½a D28
ꢂ
¼ þ180 (c 0.15,
1054 cmꢀ1 1H NMR (300 MHz, CD3OD): 1.07 (d, 3H, J = 6.4 Hz),
;
CH3OH)}; IR (neat) mmax 3422, 2923, 1684, 1363, 1055 cmꢀ1
;
1H
1.3–1.41 (m, 1H), 1.49–1.61 (m, 2H), 3.26–3.31 (m, 2H), 3.60–
3.70 (m, 1H), 3.98 (br s, 1H); 13C NMR (75 MHz, CD3OD) d 18.5,
35.3, 36.3, 70.7, 75.1, 76.2, 76.3; ESI/MS (m/z) 185 (M++Na); HRMS
calcd for C7H14O4Na 185.0789, found 185.0791.
NMR (300 MHz, CD3OD): 1.80 (dd, 3H, J = 1.5, 2.2 Hz), 4.22 (d,
1H, J = 1.9 Hz), 4.32–4.37 (m, 1H), 4.52–4.59 (m, 1H), 6.46–6.50
(m, 1H); 13C NMR (75 MHz,) d 15.3, 69.2, 76.7, 77.7, 134.6, 145.9,
200.3; ESI/MS (m/z) 181 (M++Na); HRMS calcd for C7H10O4Na
181.0476, found 181.0468.
4.12. Carba-6-deoxy-a-L-talose 18
4.8. (+)-Gabosine O 2
Compound 18 was obtained from compound 16 (0.03,
0.12 mmol) according to the procedure described for the afore-
mentioned compound 17 as a yellow color oil in 80% yield.
Gabosine
O was obtained from compound 12 (0.05 g,
0.205 mmol) in 85% yield as a white solid according to the proce-
dure described for (+) gabosine N. Mp: 105–107 °C; ½a D28
¼ þ17:5
ꢂ
½
a 2D8
ꢂ
¼ ꢀ2:58 (c 1.1, CH3OH), IR (neat) mmax 3356, 2295, 1456,
(c 0.1, CH3OH) {lit.6d
[a]D = +20.0 (c 0.3, CH3OH)}; IR (neat) mmax
1054 cmꢀ1 1H NMR (300 MHz, CD3OD): 1.03 (d, 3H, J = 6.0 Hz),
;
3422, 1715, 1349, 1033 cmꢀ1 1H NMR (300 MHz, CD3OD): 1.03
;
1.39–1.68 (m, 3H), 3.41 (dd, 1H, J = 2.6, 3.0 Hz), 3.48–3.58 (m,
1H), 3.65 (br s, 1H), 3.92 (br s, 1H); 13C NMR (75 MHz, CD3OD) d
17.8, 31.4, 33.6, 71.2, 71.7, 76.1, 76.2; ESI/MS (m/z) 185 (M++Na);
HRMS calcd for C7H14O4Na 185.0789, found 185.0792.
(d, 3H, J = 6.6 Hz), 1.82 (q, 1H, J = 12.5 Hz), 1.96–2.07 (m, 1H),
2.46–2.60 (m, 1H), 4.14–4.18 (m, 1H), 4.18–4.22 (m, 1H), 4.25–
4.28 (m, 1H); 13C NMR (75 MHz, CD3OD) d 14.0, 37.9, 39.7, 69.5,
76.9, 78.2, 212.6; ESI/MS (m/z) 183 (M++Na); HRMS calcd for
C7H12O4Na 183.0633, found 183.0630.
Acknowledgments
4.9. (3aS,4R,5S,6R,7aS)-4-(Methoxymethoxy)-2,2,6-
trimethylhexahydrobenzo[d][1,3]dioxol-5-ol 15
J.P.R. thanks CSIR (New Delhi) for fellowship and Dr. G. V.
Ramana for fruitful discussions. We would like to thank Dr. J. S. Ya-
dav, Dr. A. C. Kunwar, and Dr. T. K. Chakraborty for their constant
support and encouragement; we also thank DST (SR/S1/OC-14/
2007), New Delhi for financial assistance.
Compound 13 (0.1 g, 0.41 mmol) was taken into methanol
(5 mL) and to it was added PtO2 (10 mg). The flask was then purged
with H2 and hydrogenated at room temperature for 4 h. The reac-

J. P. Rao, B. V. Rao / Tetrahedron: Asymmetry 21 (2010) 930–935
935
56, 209–220; (i) Banwell, M. G.; Bray, A. M.; Wong, D. J. New J. Chem. 2001, 25,
1351–1354; (j) Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000, 40, 3509–
3512; (k) Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron Lett. 2000, 41,
2031–2034; (l) Lubineau, A.; Billault, I. J. Org. Chem. 1998, 63, 5668–5671; (m)
Tatsuda, K.; Yasuda, S.; Araki, N.; Takahashi, M.; Kamiya, Y. Tetrahedron Lett.
1998, 39, 401–402; (n) Lygo, B.; Swiatyj, M.; Trabsa, H.; Voyle, M. Tetrahedron
Lett. 1998, 35, 4197–4200; (o) Mirza, S.; Molleyeres, L.-P.; Vasella, A. Helv. Chim.
Acta 1985, 68, 988–996.
References
1. (a) Arjona, O.; Gomez, A. M.; Lopez, J. C.; Plumet, J. Chem. Rev. 2007, 107, 1919–
2036; (b) Plumet, J.; Gomez, A. M.; Lopez, J. C. Mini-Rev. Org. Chem. 2007, 4, 201.
2. (a) McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1966, 31, 1516–1521;
(b) Suami, T.; Ogawa, S. Adv. Carbohydr. Chem. Biochem. 1990, 48, 21–90.
3. (a) Asano, N. Glycobiology 2003, 13, 93R; (b) de Melo, E. B.; Gomes, A. S.;
Carvalho, I. Tetrahedron 2006, 62, 10277–10302.
4. (a) Tatsuta, K.; Tsuchiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H. J. Antibiot.
1974, 27, 579–586; (b) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hamman, P.;
Hutter, K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993,
241–250.
8. Wilcox, C. S.; Gaudino, J. J. J. Am. Chem. Soc. 1986, 108, 3102–3104.
9. Zhang, H.; Xue, J.; Wu, P.; Xu, L.; Xie, H.; Wei, X. J. Nat. Prod. 2009, 72, 265–269.
10. (a) Ramana, G. V.; Rao, B. V. Tetrahedron Lett. 2006, 47, 4441–4444; (b) Ramana,
G. V.; Rao, B. V. Tetrahedron Lett. 2003, 44, 5103–5105.
11. Mishra, G. P.; Ramana, G. V.; Rao, B. V. Chem. Commun. 2008, 29,
3423–3425.
12. (a) Maudru, E.; Sing, G.; Wightman, R. H. Chem. Commun. 1998, 1505–1506; (b)
Shrivastava, R. K.; Maudru, E.; Singh, G.; Wightman, R. H.; Morgan, K. M.
Beilstein J. Org. Chem. 2008, 4, 43–50.
13. The prebenzoyl derivative of 18 was reported by Redlich, H.; Sudau, W.;
Szardenings, A. K.; Vollerthum, R. Carbohydr. Res. 1992, 226, 57–78.
14. Kumar, D. N.; Rao, B. V.; Ramanjaneyulu, G. S. Tetrahedron: Asymmetry 2005, 16,
1611–1614.
15. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–
5646; (b) Takai, K.; Tagashira, M.; Kuroda, K.; Oshima, K.; Utimoto, K.; Nozaki,
H. J. Am. Chem. Soc. 1986, 108, 6048–6050.
16. (a) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191–1224; (b) Guillarme, S.; Ple,
K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem. Rev. 2006, 106, 2355–2403.
17. (a) Furstner, A. Chem. Rev. 1999, 99, 991–1045; (b) Wei, A.; Kishi, Y. J. Org.
Chem. 1994, 59, 88.
5. Tang, Y.-Q.; Maul, C.; Hofs, R.; Sttler, I.; Grabley, S.; Feng, X.-Z.; Zeeck, A.;
Thiericke, R. Eur. J. Org. Chem. 2000, 149–153.
6. For the synthesis of gabosine N and gabosine O: (a) Shing, T. K. M.; So, K. H.;
Kwok, W. S. Org. Lett. 2009, 11, 5070–5073; (b) Monard, R. N.; Fanefjord, M.;
Hansen, F. G.; Jensen, N. M. E.; Madsen, R. Eur. J. Org. Chem. 2009, 396–402; (c)
Carreno, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.; Urbano, A. Chem. Eur. J.
2007, 13, 1064–1077; (d) Alibes, R.; Bayon, P.; de March, P.; Figueredo, M.;
Font, J.; Marjanet, G. Org. Lett. 2006, 8, 1617–1620.
7. For the synthesis of other gabosines: (a) Shing, T. K. M.; Cheng, H. M. Synlett
2010, 142–144; (b) Stathakis, C. I.; Athanatou, M. N.; Gallos, J. K. Tetrahedron
Lett. 2009, 50, 6916–6918; (c) Shing, T. K. M.; Cheng, H. M. Org. Biomol. Chem.
2009, 7, 5098–5102; (d) Mac, D. H.; Samineni, R.; Petrignet, J.; Srihari, P.;
Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. Commun. 2009, 4117–4119; (e)
Shing, T. K. M.; Cheng, H. M. J. Org. Chem. 2007, 72, 6610–6613; (f) Ramana, G.
V.; Rao, B. V. Tetrahedron Lett. 2005, 46, 3049–3051; (g) Shinada, T.; Fuji, T.;
Ohtani, Y.; Yoshida, Y.; Ohfune, Y. Synlett 2002, 1341–1343; (h) Takahashi, T.;
Yamakoshi, Y.; Okayama, K.; Yamada, J.; Ge, W.; Koizumi, T. Heterocycles 2002,
18. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.