A concise and chemoenzymatic synthesis of (-)-gabosine A, a carba-sugar enone from Streptomycetes

Article abstract of DOI:10.1039/b106419c

The title compound 1 has been prepared, for the first time, in six steps and a completely stereo-controlled fashion from the cis-1,2-dihydrocatechol 3. The starting material is a readily available and enantiopure compound that can be obtained in large qua

Full text of DOI:10.1039/b106419c

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A concise and chemoenzymatic synthesis of (Ô)-gabosine A, a
carba-sugar enone from Streptomycetes
Martin G. Banwell,*a Andrew M. Brayb and David J. Wonga
a Research School of Chemistry, Institute of Advanced Studies, T he Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb=rsc.anu.edu.au
b Mimotopes Pty L td, 11 Duerdin Street, Clayton, V ictoria 3168, Australia
L e t t e r
Received (in Montpellier, France) 19th July 2001, Accepted 21st August 2001
First published as an Advance Article on the web 15th October 2001
The title compound 1 has been prepared, for the Ðrst time, in
six steps and a completely stereo-controlled fashion from the
cis-1,2-dihydrocatechol 3. The starting material is a readily
available and enantiopure compound that can be obtained in
large quantity ¿ia toluene dioxygenase (TDO) mediated di-
hydroxylation of iodobenzene.
5 react with OsO ),17 which contributes to the complexity of
4
the process. The TBDPS protecting group migration associ-
ated with the conversion 4 ] 6 was not detected initially but
revealed through subsequent chemistry. In particular, after
selective protection of the newly introduced and cis-related
hydroxyl groups as the corresponding TBDMS ethers, so as
to a†ord tris(silyl ether) 7, the remaining free hydroxyl group
was subject to oxidation under Swern conditions. Spectro-
scopic analysis of the ensuing product 8 (ca. 10% ex. 6) estab-
lished, inter alia, that the carbonyl moiety was not conjugated
([)-Gabosine A (1)1 is one of more than a dozen structurally
related and generally base-sensitive compounds1h4 isolated by
Zeeck and others during chemical screening of di†erent Strep-
tomycetes strains for new secondary metabolites. Although
such carba-sugars are similar in their molecular architectures
to shikimic acid, biosynthetic studies5 have revealed that their
origins are distinct and involve a pentose phosphate pathway
with the carbonÈcarbon double bond (l
1748 cm~1) and
max
led to the conclusion that the structure of this ketone is as
illustrated.
In an e†ort to circumvent the difficulties described above
the readily prepared TBDPS derivative 918 of compound 3
was converted (Scheme 2), by previously established
procedures18 and via triol 10, into the acetonide 11 (78%
overall yield from 3). The success of this sequence, as com-
pared with the equivalent shown in Scheme 1, derives, at least
in part, from the strong di†erence in nucleophilicity between
the two double bonds within compound 9. As a consequence,
only the non-halogenated double bond is subject to di-
hydroxylation. Oxidation of compound 11 to the correspond-
ing ketone 12 (85%) proceeded smoothly under Swern
conditions and the presence of a conjugated cyclohexenone
with cyclisation of
a heptulose phosphate intermediate.
Certain of the gabosines exhibit plant growth regulating
e†ects,6 DNA-binding properties4 and/or anti-bacterial behav-
iour,2 while congener 2 [([)-COTC], which was isolated from
the culture broth of Streptomyces griseoporeus by Umezawa
and co-workers,7 acts as a glyoxalase I inhibitor and, as such,
has potential as a tumour-selective anti-cancer agent.8 As a
consequence of their unusual structures and promising bio-
logical proÐles, these carba-sugars have been the subject of
various synthetic studies9h15 but a route to the title com-
pound 1 has not been reported to date. Consequently, we now
describe a concise (six step) and chemoenzymatic synthesis of
([)-gabosine A from the cis-1,2-dihydrocatechol 3, a material
readily prepared in large quantity and enantiopure form by
toluene dioxygenase mediated dihydroxylation of iodoben-
zene.16
Like congener 3, diol 4 is readily prepared by analogous
means although now from toluene and this latter metabolite
seemed the more obvious precursor to target 1. Indeed, our
initial studies were focussed on exploiting compound 4 for this
purpose. While the sterically less hindered C-1 hydroxyl group
within diol 4 could be selectively protected as the correspond-
ing TBDPS ether (Scheme 1), reaction of product 5 with OsO
4
under the UpJohn conditions a†orded a complex mixture of
products from which only the triol 6 (7%) could be isolated.
No doubt there is a lack of selectivity associated with this
dihydroxylation reaction (viz. both double bonds within diene
Scheme 1 Reagents and conditions: (i) TBDPSCl (1.1 mol equiv.),
imidazole (3.2 mol equiv.), CH Cl , 18 ¡C, 1.5 h; (ii) OsO (cat.),
2
2
4
NMMNO (1.5 mol equiv.), acetoneÈH O (1 : 1 v/v), 60 ¡C, 1 h; (iii)
2
TBDMSOTf (2 mol equiv.), Et N (3 mol equiv.), CH Cl , [78 to
3
2 2
18 ¡C, 1 h; (iv) oxalyl chloride (5 mol equiv.), DMSO (10 mol equiv.),
[78 ¡C, 1 h, then Et N (10 mol equiv.), [78 to [10 ¡C, 0.5 h.
3
DOI: 10.1039/b106419c
New J. Chem., 2001, 25, 1351È1354
1351
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

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were carried out in electron-impact mode and on a VG
Micromass 7070F double-focussing spectrometer. Thin layer
chromatographic analyses were carried out on aluminium-
backed 0.2 mm thick silica gel 60 GF
plates supplied by
254
Merck while Ñash chromatographic puriÐcations were con-
ducted according to the method of Still et al.22 using Merck
silica gel 60 (230È400 mesh) as adsorbent. All solvents and
common reagents were puriÐed by established procedures.23
Syntheses
(1S,2R,3R,6R)-6-{ [(1,1-Dimethylethyl)diphenylsilyl]oxy}-
5-methylcyclohex-4-ene-1,2,3-triol (6). (1,1-Dimethylethyl)-
diphenylsilyl chloride (TBDPSCl; 2.42 g, 8.82 mmol) was
added, dropwise, to a magnetically stirred solution of the diol
4 (1.01 g, 8.02 mmol) and imidazole (1.75 g, 25.65 mmol) in dry
CH Cl (15 ml) maintained at 18 ¡C under a nitrogen atmo-
2
2
sphere. Stirring was continued for a further 1.5 h, then the
reaction mixture was poured into water (20 ml). The separated
aqueous phase was extracted with CH Cl (3 ] 20 ml) and the
2
2
combined organic extracts were washed with NaCl (1 ] 80 ml
of a saturated solution) before being dried (MgSO ), Ðltered
4
and concentrated under reduced pressure to give the TBDPS
Scheme 2 Reagents and conditions: (i) TBDPSCl (1.1 mol equiv.),
imidazole (3 mol equiv.), CH Cl , 18 ¡C,
7
h; (ii) OsO (cat.),
ether 524 (2.92 g, 99%) as a pale yellow oil. HRMS: m/z
2
2
4
NMMNO (1.3 mol equiv.), acetoneÈH O (3 : 1 v/v), 0È4 ¡C, 30 h; (iii)
364.1864 (M~`); C
H
O Si requires 364.1859; d 7.73È7.67
2
23 28
2
H
2,2-dimethoxypropane (neat), p-TsOH (cat.), 18 ¡C, 3 h, then Et N
(0.27 mol equiv.); (iv) oxalyl chloride (2.5 mol equiv.), DMSO (5 mol
(complex m, 4H), 7.48È7.36 (complex m, 6H), 5.78È5.72
(complex m, 1H), 5.68È5.66 (complex m, 1H), 5.49È5.45
(complex m, 1H), 4.47È4.45 (complex m, 1H), 3.79 (dd, J \ 5.6
and 5.5 Hz, 1H), 2.67 (d, J \ 5.1 Hz, 1H, OH), 1.87 (s, 3H,
CH ), 1.09 (s, 9H, 3 ] CH ); m/z 364 (M~`, 7), 346 [(M
3
equiv.), [78 ¡C, 1 h, then Et N (5.2 mol equiv.), [78 to [10 ¡C, 0.5
3
h; (v) MeMgCl (2.2 mol equiv.), FeCl (10 mol.%), NMP (9 mol
3
equiv.), THF, 0 ¡C, 0.5 h; (vi) HCl (trace of 2 M aq. solution), meth-
anol, 18 ¡C, 96 h, then (Me N) S`F SiMe ~ (4.8 mol equiv.), THF,
2
3
2
3
3
3
18 ¡C, 0.5 h.
[ H O)`, 1], 307 (5), 289 (76), 229 (100), 199 (96), 77 (30).
This unstable material was used immediately in the next
2
moiety within this product was readily discerned spectro-
scopically (l 1705 cm~1). The necessary replacement of
step of the reaction sequence. Osmium tetroxide (3 ml of a 2.5
wt% solution in 2-methylpropan-2-ol) was added to a mag-
netically stirred solution of compound 5 (2.92 g, 8.02 mmol)
and N-methylmorpholine-N-oxide (NMMNO; 1.41 g, 12.03
mmol) in a mixture of acetoneÈwater (120 ml of a 3 : 1 v/v
mixture) maintained at 0 ¡C. The resulting solution was heated
at 60 ¡C for 1 h, then cooled and poured into sodium metabi-
sulÐte (100 ml of a 20 wt% aq. solution). The resulting mixture
was extracted with CH Cl (6 ] 200 ml) and the combined
max
iodine by a methyl group was attempted at this point.
However, all e†orts to e†ect such a conversion (viz. 12 ] 13)
using palladium(0) catalysed cross-coupling reactions with
tetramethyltin, dimethylzinc or methylmagnesium chloride
failed. In stark contrast, reaction of compound 12 with 2.2
mol equiv. of methylmagnesium chloride in the presence of
iron(III) chloride under the very mild conditions (0 ¡C) devel-
oped by Cahiez and Avedissian19 proved highly e†ective and
provided, in just 0.5 h, target 13 in 94% yield. Treatment of
the latter compound with methanolic HCl at room tem-
perature for extended periods then gave gabosine A (1) (85%).
The synthetic sample of ([)-gabosine A proved identical, as
judged by appropriate spectroscopic comparisons, with
material obtained by Zeeck and co-workers.1 In particular,
2
2
organic extracts dried (MgSO ), Ðltered and concentrated
4
under reduced pressure to a†ord a dark brown oil. Subjection
of this material to Ñash chromatography (silica gel, 3 : 2 v/v
ethyl acetateÈhexane elution) and concentration of the appro-
priate fractions (R 0.4) a†orded the triol 6 (231 mg, 7%) as a
f
clear colourless oil. [a] [ 86 (c 0.7 in CHCl ); HRMS: m/z
D
3
362.1706 (M [ 2 H O)~`; C
H
O Si requires 362.1702; l
2
23 26
2
max
the optical rotations of the synthetic M[a] [ 131 (c \ 0.27 in
3400, 2956, 2930, 1110 cm~1; d 7.73È7.61 (complex m, 4H),
D
methanol)N and natural M[a] [ 132 (c \ 1 in methanol)N
D
H
7.49È7.39 (complex m, 6H), 5.53 (d, J \ 4.3 Hz, 1H), 4.40 (m,
materials were in excellent agreement.
1H), 4.18 (d, J \ 3.8 Hz, 1H), 4.12 (m, 1H), 3.80 (m, 1H), 2.61
(br s, 1H, OH), 1.41 (s, 3H, CH ), 1.06 (s, 9H, 3 ] CH ); d
The present study serves to emphasize the utility of cis-1,2-
dihydrocatechols like 3 as starting materials in chemical syn-
thesis and their potential as versatile precursors to the bio-
logically signiÐcant gabosines and related carba-sugars.
Furthermore, the capacity for replacement of the iodine atom
within intermediates such as the a-iodoenone 12 by carbon-
based groups other than simple methyl (and especially under
the mild cross-coupling conditions deÐned above)20 o†ers the
possibility for accessing a wide range of carba-sugars, includ-
ing the interesting anti-mitotic agent tricholomenyn B.21
Work aimed at pursuing such possibilities is now underway in
our laboratories.
3
3
C
137.3 (C), 135.9 (CH), 135.8 (CH), 133.2 (C), 132.6 (C), 129.9
(CH), 129.7 (CH), 127.7 (CH), 127.5 (CH), 124.9 (CH), 72.5
(CH), 70.2 (CH), 69.2 (CH), 66.3 (CH), 27.0 (CH ), 21.4 (CH ),
3
3
2
19.7 (C); m/z 362 [(M [ 2 H O)~`, 5], 323 M[M [ (H O
] C H )]`, 41N, 245 (63), 227 (40), 199 (100).
2
4
9
(1S,2R,5R,6S)-5,6-Bis-{ [(1,1-dimethylethyl)dimethyl-
silyl]oxy}-2-{ [(1,1-dimethylethyl)diphenylsilyl]oxy}-3-methyl-
cyclohex-3-enol (7). (1,1-Dimethylethyl)dimethylsilyl triÑuoro-
methanesulfonate (TBDMSOTf; 85 mg, 0.32 mmol) was
added dropwise to a magnetically stirred solution of triol 6 (64
mg, 0.16 mmol) and Et N (49 mg, 0.48 mmol) in CH Cl (5
3
2 2
ml) maintained at [78 ¡C under a nitrogen atmosphere. The
reaction mixture was allowed to warm to 18 ¡C over ca. 0.5 h,
then stirred at this temperature for a further 0.5 h. The
resulting solution was poured into sodium carbonate (10 ml of
a saturated aqueous solution) and diluted with CH Cl (5 ml).
Experimental
1H and 13C NMR spectra were recorded on a Varian Gemini
300 spectrometer using deuterochloroform as solvent. Infrared
spectra were recorded using KBr plates on either a PerkinÈ
Elmer 683 or 1800 FTIR instrument. Mass spectral analyses
2
2
The separated aqueous phase was extracted with CH Cl
2
2
1352
New J. Chem., 2001, 25, 1351È1354

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(3 ] 10 ml) and the combined organic extracts were dried
as a light yellow oil. d 7.78È7.38 (complex m, 10H), 6.62 (d,
H
(MgSO ), Ðltered and concentrated under reduced pressure to
J \ 5.5 Hz, 1H), 5.65 (dd, J \ 9.6 and 3.5 Hz, 1H), 5.54 (dd,
4
a†ord a pale yellow oil. Subjection of this material to Ñash
J \ 9.6 and 5.5 Hz, 1H), 4.51 (m, 1H), 4.08 (d, J \ 6.0 Hz, 1H),
2.80 (br m, 1H), 1.09 (br s, 9H). This unstable material was
used immediately in the next step of the reaction sequence.
chromatography (silica gel, 1 : 10 v/v ethyl acetateÈhexane
elution) and concentration of the appropriate fractions (R 0.6)
f
a†orded the title alcohol 7 (58 mg, 58%) as a clear, colourless
oil. [a] [ 92 (c 0.9 in CHCl ); HRMS: m/z 569.2942 (M
(3aR,4R,5S,7aR)-4-{ [(1,1-Dimethylethyl)diphenylsilyl]oxy}-
3a,4,5,7a-tetrahydro-6-iodo-2,2-dimethyl-1,3-benzodioxol-5-ol
(11). Osmium tetroxide (4.0 ml of a 2.5 wt% solution in 2-
methylpropan-2-ol, 0.47 mmol) was added, dropwise, to a
magnetically stirred solution of alcohol 9 (3.84 g, 8.06 mmol)
and N-methylmorpholine-N-oxide (1.22 g, 10.4 mmol) in
acetoneÈwater (200 ml of a 3 : 1 v/v mixture) maintained at
0 ¡C. The resulting solution was warmed to 4 ¡C, stirred at this
temperature for 30 h, then treated with sodium metabisulÐte
(100 ml of a 20% w/v aq. solution). After 1 h the reaction
mixture was concentrated under reduced pressure and the
residue thus obtained was partitioned between diethyl ether
(500 ml) and NaCl (300 ml of a 50% w/v aq. solution). The
separated aqueous phase was extracted with diethyl ether
(2 ] 500 ml) and the combined ethereal fractions were washed
with HCl (500 ml of a 10% v/v aq. solution), then brine
D
3
[ C H )`; C
H
O Si requires 569.2939; l
2954, 2929,
4
9
31 49
4
3
max
2983, 2857, 1103, 1070, 1047, 879, 835, 776, 701 cm~1; d
H
7.71È7.66 (complex m, 4H), 7.46È7.34 (complex m, 6H), 5.24
(m, 1H), 4.46È4.42 (complex m, 2H), 4.08È4.05 (complex m,
1H), 3.86 (dd, J \ 5.6 and 3.9 Hz, 1H), 2.70 (br s, 1H, OH),
1.50 (s, 3H, CH ), 1.11 (s, 9H, 3 ] CH ), 0.88 (s, 9H, 3 ] CH ),
3
3
3
0.71 (s, 9H, 3 ] CH ), 0.06 (s, 6H, 2 ] CH ), [0.01 (s, 3H,
3
3
CH ), [0.08 (s, 3H, CH ); d 136.1 (CH), 136.0 (CH), 133.5
3
3
C
(C), 133.1 (C), 130.0 (CH), 129.9 (CH), 127.7 (CH), 127.6 (CH),
126.3 (CH), 73.1 (CH), 71.9 (CH), 71.5 (CH), 67.3 (CH), 27.2
(CH ), 26.2 (CH ), 25.8 (CH ), 20.6 (CH ), 19.6 (C), 18.4 (C),
3
3
3
3
18.1 (C), [4.3 (CH ), [4.6 (CH ), [5.1 (CH ), (two signals
3
3
3
4
obscured or overlapping); m/z 569 [(M [ C H )`, 40] 452
9
(82), 437 (57), 73 (100).
(2R,5R,6R)-5,6-Bis-{ [(1,1-dimethylethyl)dimethylsilyl]oxy}-
2-{ [(1,1-dimethylethyl)diphenylsilyl]oxy}-3-methylcyclohex-3-
enone (8). Dimethyl sulfoxide (52 mg, 0.67 mmol) was added,
dropwise, to a magnetically stirred solution of oxalyl chloride
(43 mg, 0.34 mmol) in dry CH Cl (4 ml) maintained at
(1 ] 500 ml) before being dried (MgSO ), Ðltered and concen-
4
trated under reduced pressure to a†ord the triol 1018 (4.00 g,
98%) as a tan-coloured oil. This unstable material was used
immediately in the next step of the reaction sequence.
p-TsOH (8 mg, 0.421 mmol) was added to a magnetically
stirred solution of triol 10 (4.00 g, 7.84 mmol) in dry 2,2-di-
methoxypropane (50 ml) maintained at 18 ¡C under a nitrogen
atmosphere. After 3 h the reaction mixture was treated with
2
2
[78 ¡C under an atmosphere of nitrogen. After 0.5 h, a solu-
tion of alcohol 7 (42 mg, 0.067 mmol) in CH Cl (3 ml) was
2
2
added, dropwise, to the reaction mixture. After a further 1 h, a
solution of Et N (68 mg, 0.67 mmol) in CH Cl (2 ml) was
Et N (300 ll, 2.15 mmol) and the resulting mixture concen-
3
2
2
3
added dropwise and the resulting homogenous solution
stirred at [78 ¡C for 20 min, then for a further 10 min at
[10 ¡C. The reaction mixture was then diluted with CH Cl
trated under reduced pressure. The residue so-formed was dis-
solved in diethyl ether (300 ml) then washed with NaOH
(1 ] 90 ml of a 1 M aq. solution) and water (1 ] 90 ml). The
2
2
(20 ml) and sodium bicarbonate (20 ml of a saturated aqueous
solution). The separated aqueous phase was extracted with
CH Cl (3 ] 40 ml) and the combined organic extracts
separated aqueous phase was dried (MgSO ), Ðltered and con-
4
centrated under reduced pressure and the residue subjected to
Ñash chromatography (silica gel, 1 : 10 v/v ethyl acetateÈ
hexane elution) to a†ord, after concentration of the appropri-
2
2
washed with brine (2 ] 100 ml), dried (MgSO ), Ðltered and
4
concentrated under reduced pressure to a†ord a pale yellow
ate fractions (R 0.3), the title acetonide 1118 (3.67 g, 85%) as a
f
oil. Subjection of this material to Ñash chromatography (silica
gel, 1 : 10 v/v ethyl acetateÈhexane elution) and concentration
of the appropriate fractions (R 0.5) a†orded ketone 8 (41 mg,
clear, colourless oil. [a] ]19 (c 1.4 in CHCl ); HRMS: m/z
D
3
535.0800 (M [ CH )`; C
H
IO Si requires 535.0802; l
3
24 28
4
max
3556, 2932, 1428, 1131, 1113, 1052 cm~1; d 7.73È7.62
f
H
98%) as a clear, colourless oil. [a] [41 (c 2.4 in CHCl );
(complex m, 4H), 7.49È7.38 (complex m, 6H), 6.53 (m, 1H),
D
3
HRMS: m/z 624.3488 (M~`); C
H
O Si requires 624.3486;
4.48 (m, 1H), 4.29 (dd, J \ 5.4 and 3.5 Hz, 1H), 4.20 (app t,
J \ ca. 5.4 Hz, 1H), 4.06È4.02 (complex m, 1H), 2.40 (d,
J \ 8.6 Hz, 1H), 1.26 (s, 3H, CH ), 1.23 (s, 3H, CH ), 1.09 (s,
35 56
4 3
l
2929, 2856, 1748, 1472, 1428, 1361, 1256, 1112, 837, 779,
max
702 cm~1; d 7.71È7.67 (complex m, 4H), 7.44È7.32 (complex
H
3
3
m, 6H), 5.40 (d, J \ 3.0 Hz, 1H), 4.84 (s, 1H), 4.41 (d, J \ 3.2
9H, 3 ] CH ); d 137.1 (CH), 136.0 (CH), 135.6 (CH), 132.3
3
C
Hz, 1H), 4.36 (m, 1H), 1.55 (s, 3H, CH ), 1.09 (s, 9H, 3 ] CH ),
(C), 130.2 (CH), 130.1 (CH), 128.1 (CH), 127.9 (CH), 109.8 (C),
104.9 (C), 75.2 (CH), 73.8 (CH), 72.2 (CH), 71.8 (CH), 27.6
(CH ), 26.9 (CH ), 26.1 (CH ), 19.4 (C), (one signal obscured
or overlapping); m/z 536 and 535 [(M [ CH )`, \1 and
\1], 436 and 435 (21 and 50), 199 [(C
3
3
3
0.84 (s, 9H, 3 ] CH ), 0.80 (s, 9H, 3 ] CH ), 0.04 (s, 3H, CH ),
3
3
0.03 (s, 3H, CH ), [0.01 (s, 3H, CH ), [0.08 (s, 3H, CH ); d
3
3
3
C
3
3
3
204.5 (C), 136.3 (CH), 136.1 (CH), 133.6 (C), 132.9 (C), 129.7
(CH), 127.5 (CH), 127.4 (CH), 126.5 (CH), 78.8 (CH), 74.4
(CH), 72.2 (CH), 27.0 (CH ), 25.9 (CH ), 25.8 (CH ), 20.2
3
H
SiO)~`, 100].
12 11
3
3
3
(CH ), 19.8 (C), 18.2 (C), [4.5 (CH ), [4.8 (CH ), [4.9
(CH ), (four signals obscured or overlapping); m/z 624 (M~`,
4), 567 [(M [ C H )`, 69], 539 (12), 435 (36), 275 (63), 73
(3aR,4R,7aR)-4-{ [(1,1-Dimethylethyl)diphenylsilyl]oxy}-
3a,7a-dihydro-6-iodo-2,2-dimethyl-1,3-benzodioxol-5(4H)-one
(12). Dimethyl sulfoxide (200 ll, 2.81 mmol) was added, drop-
wise, to a magnetically stirred solution of oxalyl chloride (118
ll, 1.35 mmol) in dry CH Cl (4 ml) maintained at [78 ¡C
3
3
3
3
4
9
(100).
2
2
(1S, 6S)-6-{ [(1,1-Dimethylethyl)diphenylsilyl]oxy}-2-
under a nitrogen atmosphere. After 0.5 h a solution of com-
iodocyclohexa-2,4-dien-1-ol (9). (1,1-Dimethylethyl)diphenyl-
silyl chloride (3.96 ml, 15.2 mmol) was added dropwise to a
magnetically stirred solution of diol 3 (3.30 g, 13.8 mmol) and
imidazole (2.83 g, 41.6 mmol) in dry CH Cl (70 ml) main-
pound 11 (300 mg, 0.545 mmol) in dry CH Cl (3 ml) was
2
2
added dropwise to the reaction mixture. After a further 1 h a
solution of Et N (392 ll, 2.81 mmol) in CH Cl (1 ml) was
3
2 2
added and the resulting homogeneous solution was stirred at
[78 ¡C for 20 min and then for a further 10 min after
warming to [10 ¡C. The reaction mixture was then diluted
with CH Cl (20 ml) and NaHCO (20 ml of a saturated aq.
2
2
tained at 18 ¡C under a nitrogen atmosphere. Stirring was
continued for 7 h, then the reaction mixture was poured into
water (90 ml). The separated aqueous layer was extracted with
CH Cl (2 ] 100 ml) and the combined organic layers were
2
2
3
solution). The separated organic phase was washed with water
2
2
washed with NaCl (1 ] 100 ml of a 50% v/v aq. solution)
(2 ] 20 ml) and brine (2 ] 20 ml), then dried (MgSO ), Ðltered
4
before being dried (MgSO ), Ðltered and concentrated under
and concentrated under reduced pressure to yield the title
4
reduced pressure to give the title compound 918 (6.40 g, 97%)
compound 12 (269 mg, 90%) as a clear colourless oil. [a]
D
New J. Chem., 2001, 25, 1351È1354
1353

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]9.4 (c 5.0 in CHCl ); HRMS: m/z 533.0643 (M [ CH )`;
15.6 (CH , 7-CH ); m/z 158 (M~`, 2), 140 (31), 111 (79), 98
3
3
3
(100), 70 (74).
3
C
H
IO Si requires 533.0645; l
2932, 1705, 1223, 1113,
24 26
4
max
1069 cm~1; d 7.70È7.66 (complex m, 2H), 7.59È7.56 (complex
H
m, 2H), 7.46È7.35 (complex m, 7H), 4.77 (m, 1H), 4.44 (m, 2H),
Acknowledgements
We thank the Institute of Advanced Studies for Ðnancial
support and the Australian Research Council for providing an
APA(I) (to D. J. W.).
1.29 (s, 3H, CH ), 1.27 (s, 3H, CH ), 1.06 (s, 9H, 3 ] CH ); d
3
3
3
C
188.8 (C), 151.6 (CH), 135.9 (CH), 132.4 (C), 131.9 (C), 130.1
(CH), 130.0 (CH), 127.8 (CH), 127.7 (CH), 111.7 (C), 102.9 (C),
78.2 (CH), 73.6 (CH), 72.2 (CH), 27.7 (CH ), 26.8 (CH ), 26.6
3
3
(CH ), 19.4 (C) (one peak due to sp2-hybridised carbon
3
obscured or overlapping); m/z 534 and 533 [(M [ CH )`, ca.
3
Notes and references
1 and 1], 492 and 491 (20 and 36), 434 and 433 (20 and 34),
406 and 405 (20 and 40), 307 and 306 (36 and 100), 199
1
G. Bach, S. Breiding-Mack, S. Grabley, P. Hammann, K.
Huetter, R. Thiericke, H. Uhr, J. Wink and A. Zeeck, L iebigs
Ann. Chem., 1993, 241 (gabosines AÈK).
Gabosine C was Ðrst isolated by Umezawa and co-workers (K.
Tatsuta, T. Tsuchiya, N. Mikami, S. Umezawa, H. Umezawa and
H. Naganawa, J. Antibiot., 1974, 27, 579) and designated as
KD16-U1.
[(C
H
SiO)~`, 30].
12 11
2
(3aR,4R,7aR)-4-{ [(1,1-Dimethylethyl)diphenylsilyl]oxy}-
3a,7a-dihydro-2,2,6-trimethyl-1,3-benzodioxol-5(4H)-one (13).
A solution of methyl magnesium chloride (160 lL of a 3 M
solution in THF, 0.48 mmol) was added, dropwise, to a mag-
netically stirred solution of a-iodoenone 12 (120 mg, 0.22
mmol) and iron(III) chloride (4 mg, 0.02 mmol) in a mixture of
THF (5 ml) and N-methylpyrrolidinone (NMP; 195 mg, 1.97
mmol) maintained at 0 ¡C under a nitrogen atmosphere. The
resulting mixture was stirred at this temperature for a further
0.5 h, then diluted with water (10 ml). The reaction mixture
was extracted with CH Cl (3 ] 10 ml) and the organic
3
4
Recent synthetic studies (G. Metha and S. Lakshminath, T etra-
hedron L ett., 2000, 41, 3509) indicate that the structure of gabo-
sine K needs to be revised.
Y.-Q. Tang, C. Maul, R. Hoefs, I. Sattler, S. Grabley, X.-Z. Feng,
A. Zeeck and R. Thiericke, Eur. J. Org. Chem., 2000, 149
(gabosines L, N and O).
5
6
R. Hofs, S. Schoppe, R. Thiericke and A. Zeeck, Eur. J. Org.
Chem., 2000, 1883.
S. Grabley, J. Wink, P. Hammann, C. Giani, K. Huetter and A.
Zeeck (Hoechst A. G., Fed. Rep. Ger.), PCT Int. Appl., PIXXD2
WO 8912038, 1989; S. Grabley, J. WInk, P. Hammann, C. Giani,
K. Huetter and A. Zeeck, Chem. Abstr., 1990, 113, 22211y.
T. Takeuchi, H. Chimura, M. Hamada and H. Umezawa, J. Anti-
biot., 1975, 28, 737.
(a) H. Chimura, H. Nakamura, T. Takita, T. Takeuchi, H.
Umezawa, K. Kato, S. Saito, T Tomisawa and Y. Iitaka, J. Anti-
biot., 1975, 28, 743; (b) Y. Sugimoto, H. Suzuki, H. Yamaki, T.
Nishimura and N. Tanaka, J. Antibiot., 1982, 35, 1222; (c) K. T.
Douglas and S. Shinkai, Angew. Chem., 1985, 97, 32.
S. Mirza, L.-P. Molleyres and A. Vasella, Helv. Chim. Acta, 1985,
68, 988 [([)-gabosine C and ([)-COTC ex. D-glucose].
2
2
extracts were combined, dried (MgSO ), Ðltered and concen-
4
trated under reduced pressure to a†ord a light yellow oil. Sub-
jection of this material to Ñash chromatography (silica gel,
1 : 10 v/v ethyl acetateÈhexane elution) and concentration of
the appropriate fractions (R 0.3) a†orded the title enone 13
7
8
f
(90 mg, 94%) as a colourless oil. [a] [30 (c 0.8 in CHCl );
D
3
O Si requires
4
HRMS: m/z 421.1831 (M [ CH )`; C
H
3
25 29
421.1835; l
2931, 2858, 1705, 1112, 1066, 702 cm~1; d
max
H
7.75È7.64 (complex m, 4H), 7.44È7.32 (complex m, 6H), 6.43
(dq, J \ 3.9 and 0.7 Hz, 1H), 4.81È4.77 (complex m, 1H), 4.44È
4.40 (complex m, 1H), 4.31 (d, J \ 6.3 Hz, 1H), 1.77 (dd,
J \ 1.5 and 1.4 Hz, 3H, CH ), 1.34 (s, 3H, CH ), 1.25 (s, 3H,
9
10 H. Takayama, K. Hayashi and T. Koizumi, T etrahedron L ett.,
1986, 27, 5506 [([)-COTC ex. 2-methoxyfuran and (S)-S-
menthyl 3-(3-triÑuoromethylpyrid-2-ylsulÐnyl)acrylate].
11 (a) T. K. M. Shing and Y. Tang, T etrahedron, 1990, 46, 6575; (b)
C. F. M. Huntley, H. B. Wood and B. Ganem, T etrahedron L ett.,
2000, 41, 2031 [([)-COTC ex. ([)-quinic acid].
3
3
3
CH ), 1.11 (s, 9H, 3 ] CH ); d 196.1 (C), 136.2 (C), 136.1
3
C
(CH), 136.0 (CH), 133.0 (C), 132.9 (C), 129.8 (CH), 129.7 (CH),
127.5 (CH), 127.4 (CH), 110.8 (C), 78.8 (CH), 75.2 (CH), 71.5
(CH), 27.8 (CH ), 26.9 (CH ), 26.5 (CH ), 19.5 (C), 15.9 (CH ),
12 B. Lygo, M. Swiatyj, H. Trabsa and M. Voyle, T etrahedron L ett.,
1994, 35, 4197 [(])-gabosines C and E ex. D-ribose].
13 A. Lubineau and I. Billault, J. Org. Chem., 1998, 63, 5668 [([)-
gabosine I ex. D-glucose].
3
3
3
3
(one signal obscured or overlapping); m/z 421 [(M [ CH )`,
1], 379 (42), 321 (100), 293 (78), 227 (45), 199 (49).
3
14 K. Tatsuta, S. Yasuda, N. Araki, M. Takahashi and Y. Kamiya,
T etrahedron L ett., 1998, 39, 401 [([)-gabosine C and ([)-COTC
ex. D-ribonic acid c-lactone].
(4R,5R,6S)-4,5,6-Trihydroxy-2-methyl-2-cyclohexen-1-one
[(Ô)-gabosine A, 1]. HCl (1 drop of a conc. aq. solution) was
added to a magnetically stirred solution of compound 13 (12
mg, 0.027 mmol) in methanol (2 ml) maintained at 18 ¡C under
a nitrogen atmosphere. The resulting mixture was stirred at
this temperature for 96 h, then concentrated under reduced
pressure to a†ord a light yellow oil. 1H NMR analysis of this
oil suggested the presence of a ca. 1 : 2 mixture of the target
compound 1 and its 6-TBDPS ether so it was dissolved in
THF (3 ml), then tris(dimethylamino)sulfonium diÑuorotri-
methylsilicate25 (35 mg, 0.13 mmol) was added in portions.
The resulting mixture was stirred at 18 ¡C for 0.5 h, then con-
centrated under reduced pressure to a†ord a pale yellow oil
that was subject to Ñash chromatography (silica gel, 1 : 10 v/v
methanolÈchloroform elution). Concentration of the appropri-
15 See citation in ref. 3 [(^)-gabosine B ex. DielsÈAlder derived
norborane].
16 For a comprehensive and up-to-date commentary on the pro-
duction and synthetic utility of cis-1,2-dihydrocatechols, see: T.
Hudlicky, D. Gonzalez and D. T. Gibson, Aldrichimica Acta,
1999, 32, 35.
17 For related examples where this is deÐnitely so, see: (a) M. Bro-
vetto, V. Schapiro, G. Cavalli, P. Padilla, A. Sierra, G. Seoane, L.
Suescun and R. Mariezcurrena, New J. Chem., 1999, 23, 549; (b)
M. G. Banwell, A. M. Bray, A. J. Edwards and D. J. Wong, New
J. Chem., 2001, 25, 3.
18 M. G. Banwell, C. De Savi, D. C. R. Hockless, S. Pallich and K.
G. Watson, Synlett, 1999, 885.
19 G. Cahiez and H. Avedissian, Synthesis, 1998, 1199.
20 For a useful commentary on the synthetic utility of a-iodoenones,
see: M. W. Miller and C. R. Johnson, J. Org. Chem., 1997, 62,
1582 and references cited therein.
ate fractions (R 0.3) then gave gabosine A (1) (3.7 mg, 85%) as
f
a pale yellow oil. [a] [131 (c 0.27 in methanol); HRMS: m/z
D
158.0582 (M~`); C H
O
requires 158.0579; l
3292, 2919,
21 L. Garlaschelli, E. Magistrali, G. Vidari and O. Zu†ardi, T etra-
7
10
4
max
hedron L ett., 1995, 36, 5633.
1686 cm~1; j
(methanol) 222 nm (e 7200); d (600 MHz)
max
H
22 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
23 D. D. Perrin and W. L. F. Amarego, PuriÐcation of L aboratory
Chemicals, Pergamon Press, Oxford, 3rd edn., 1988.
24 S. V. Ley and F. Sternfeld, T etrahedron, 1989, 45, 3463.
25 A. K. Scheidt, H. Chou, B. C. Follows, S. R. Chemler, S. D.
Co†ey and W. R. Roush, J. Org. Chem., 1998, 63, 6436.
6.75 (qd, J \ 1.5 and J \ 5.6 Hz, 1H, H-3), 4.38 (m, 1H,
3, 7
3, 4
H-4), 4.32 (d, J \ 10.0 Hz, 1H, H-6), 3.73 (dd, J \ 10.0
6, 5 5, 6
and J \ 4.0 Hz, 1H, H-5), 1.82 (dd, J \ 1.5 and J
5, 4 7, 3 7, 4
0.9 Hz, 1H, 7-CH ); d \ 200.5 (C, C-1), 143.0 (CH, C-3),
\
3
C
136.9 (C, C-2), 75.1 (CH, C-6), 73.9 (CH, C-5), 67.4 (CH, C-4),
1354
New J. Chem., 2001, 25, 1351È1354