Synthesis of gabosine A and N from ribose by the use of ring-closing metathesis

Article abstract of DOI:10.1002/ejoc.200800983

A concise synthetic route is described for the synthesis of gabosine A and N. The key step uses a zinc-mediated tandem reaction where methyl 5-deoxy-5-iodo-2,3-O-isopropylidene-β-D-ribofuranoside is fragmented to give an unsaturated aldehyde which is ally

Full text of DOI:10.1002/ejoc.200800983

FULL PAPER
DOI: 10.1002/ejoc.200800983
Synthesis of Gabosine A and N from Ribose by the Use of Ring-Closing
Metathesis
Rune Nygaard Monrad,[a][‡] Mette Fanefjord,[a][‡] Flemming Gundorph Hansen,[a][‡]
N. Michael E. Jensen,[a][‡] and Robert Madsen*[a]
Keywords: Carbohydrates / Cyclitols / Metathesis / Natural products / Total synthesis
A concise synthetic route is described for the synthesis of ga-
bosine A and N. The key step uses a zinc-mediated tandem
reaction where methyl 5-deoxy-5-iodo-2,3-O-isopropylid-
bosine skeleton by ring-closing olefin metathesis. Subse-
quent protective group manipulations and oxidation gives
rise to gabosine N in a total of 8 steps from ribose while the
synthesis of gabosine A employs an additional step for in-
ene-β-D-ribofuranoside is fragmented to give an unsaturated
aldehyde which is allylated in the same pot with 3-benzo- verting a secondary hydroxy group.
yloxy-2-methylallyl bromide. The functionalized octa-1,7-
diene, thus obtained, is converted into the six-membered ga-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
The gabosines are a family of secondary metabolites iso-
lated from Streptomyces strains which share a common tri-
hydroxy(methyl)cyclohexenone/-cyclohexanone skeleton.[1]
A total of 14 different gabosines have been identified[2] and
the absolute configuration has been established for gabosine
A–F, I, L, N, and O (Figure 1). None of the 14 compounds
display any significant biological activity, but weak DNA-
binding properties have been shown for several gabosi-
nes.[1a] The biosynthesis of the gabosines occur through a
pentose phosphate pathway in which sedoheptulose 7-phos-
phate cyclizes by an aldol condensation.[3] The chemical
synthesis of the gabosines has been achieved by several stra-
tegies where the carbocyclic ring is either contained in the
starting material [i.e. p-benzoquinone, (–)-quinine, or iodo-
benzene][4] or is created by a Diels–Alder reaction[5] or by
cyclization of a carbohydrate.[6] In the latter case, the car-
bocyclization has been accomplished by an aldol condensa-
tion, a nitrile oxide cycloaddition, a Nozaki–Hiyama–Kishi
reaction, a Horner–Wadsworth–Emmons olefination and
by ring-closing olefin metathesis.
We have described a zinc-mediated tandem reaction for
converting carbohydrates into acyclic dienes that can be cy-
clized by ring-closing metathesis.[7,8] In this reaction, methyl
5-iodopentofuranosides are treated with zinc metal and al-
lylic bromides. First, a reductive fragmentation of the iodo-
Figure 1. The gabosine family of secondary metabolites.
furanoside takes place to produce an unsaturated aldehyde
which is subsequently allylated in the same pot by the al-
lylzinc reagent. In this way, the zinc metal serves a dual
purpose by promoting both the reductive fragmentation
and the subsequent allylation reaction.[7] By using this pro-
cedure, we have previously prepared several carbocyclic nat-
ural products from carbohydrates including 7-deoxypancra-
tistatin,[9] cyclophellitol,[10] and calystegine B2, B3 and
B4.[11]
[a] Center for Sustainable and Green Chemistry, Department of
Chemistry, Building 201, Technical University of Denmark,
2800 Lyngby, Denmark
Fax: +45-4593-3968
E-mail: rm@kemi.dtu.dk
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
396
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 396–402

Synthesis of Gabosine A and N from Ribose
We envisaged that the tandem reaction would also be an
effective transformation for synthesis of the gabosines as
illustrated with gabosine A and N in Figure 2. This would
require allylic bromide 1 in order to install the methyl group
in the product. Bromide 1 has not been described before,
but the corresponding 3-benzoyloxyallyl bromide has been
developed as an efficient α-hydroxyallylation agent of alde-
hydes in the presence of zinc or indium.[12] We have recently
used 3-benzoyloxyallyl bromide in the tandem reaction with
zinc for synthesis of the conduritols[13] and for chain elong-
ation of aldoses in the presence of indium.[14] On the basis
of these results we expected that the tandem reaction be-
tween 1 and the appropriate iodopentofuranoside could be
achieved to give the desired octa-1,7-diene which upon ring-
closure by metathesis would yield the gabosine skeleton.
Scheme 1. Reagents and conditions: (a) CH2Cl2, room temp. (b)
Zn, THF, H2O, 40 °C, sonication.
The tandem reaction between 1 and 2a was carried out
in a THF/H2O mixture under sonication at 40 °C. Treat-
ment of furanoside 2a with zinc for 2 h followed by addition
of bromide 1 gave 85% yield of a 2:1 mixture of dienes 3
and 4 which could be separated by silica gel chromatog-
raphy (Scheme 1). Notably, the stereochemistry at the hy-
droxy group is the same in 3 and 4 which make both com-
pounds suitable for the synthesis of gabosine N. The struc-
ture of 3 and 4 was elucidated after ring-closing metathesis
by 1H NMR and by isopropylidene formation from the cor-
responding diol. The stereochemical outcome is in accord-
Figure 2. Retrosynthesis for gabosine A and N.
Herein, we describe a short synthesis of the two epimeric
gabosines A and N by the use of a zinc-mediated tandem
reaction and ring-closing olefin metathesis.
Results and Discussion
Gabosine A and N have the same stereochemistry at two ance with our earlier observations[13] and can be rational-
hydroxy groups which will both originate from the pentose ized by the Felkin–Anh model.[17] The same mixture of 3
in the synthesis. The two natural products differ from each and 4 was obtained when the E:Z mixture of 1 was em-
other at the third hydroxy group which will be installed in ployed in the tandem reaction.
the tandem reaction (Figure 2). -Ribose has the correct
Because 3 and 4 both have the correct stereochemistry
stereochemistry at C-2 and C-3 for both gabosines and the for gabosine N several experiments were carried out to in-
corresponding methyl furanoside 2a is easy available in two vert the stereochemical outcome of the allylation in order
steps from the parent pentose (Scheme 1).[15] Bromide 1 is to prepare gabosine A by the same reaction. We have shown
prepared from methacrolein by haloacylation with benzoyl earlier that the stereochemistry in the tandem reaction can
bromide. The synthesis is carried out in the same way as be changed by using the unprotected ribofuranoside 2b[18]
the preparation of 3-benzoyloxyallyl bromide from acro- or by using indium metal[10,18] where the latter is known to
lein.[16] The kinetic product is initially formed by 1,2-ad- react by chelation control. However, treatment of 2b with
dition to the aldehyde, but slowly equilibrates to the zinc in the presence of bromide 1 did not furnish the desired
thermodynamic 1,4-addition product. The addition is diene 5. Instead, a complex mixture was obtained resulting
rather slow, but the reaction can be accelerated by adding from degradation of 2b and self-coupling of 1. When the
zinc(II) bromide as catalyst. Thus, treatment of methacro- same reaction was attempted with indium metal, self-coup-
lein with benzoyl bromide and zinc(II) bromide gave the ling of 1 was the main product and very little fragmentation
desired product in 76% yield after 2 h as a 4:3 mixture of of 2b occurred. It was therefore decided to carry out the
the E and Z isomer which could not be separated by silica fragmentation with zinc and isolate the intermediate alde-
gel chromatography. When the reaction was performed in hyde and then perform the subsequent allylation with in-
the absence of zinc(II) bromide the time for complete con- dium. Only aldehydes that are prepared by fragmentation
version increased significantly, but the yield was still accept- of protected ribofuranosides are sufficiently stable to be iso-
able and in this case only the E isomer was formed. Because lated. Hence, ribofuranosides 2a and 2c were fragmented
this isomer is crystalline and completely stable at 5 °C we with zinc followed by treatment of the corresponding alde-
favored the latter synthesis of bromide 1. Furthermore, the hydes with 1 and indium. The allylations were carried out
synthesis could be performed on a large scale and the rea- in the presence and in the absence of a Lewis acid[10] and
gent isolated without the use of flash chromatography.
in different solvent mixtures. Unfortunately, all attempts to
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397

R. Madsen et al.
FULL PAPER
obtain a decent yield of diene 5 failed. In most cases, bro- complished in a satisfying yield with PDC to furnish pro-
mide 1 only underwent self-coupling and it appears that tected gabosine 12. Finally, deprotection under acidic con-
this reaction is faster than the allylation of the aldehydes. ditions afforded gabosine N with spectral and physical data
In other cases, small amounts of dienes were obtained as in excellent accordance with those reported for the natural
diastereomeric mixtures, but the major isomers had the product.[1a,4b]
same stereochemistry as in 3 and 4. As a result, we decided
The synthesis of gabosine A could be achieved by a sim-
to abandon the tandem reaction for synthesis of diene 5 ilar sequence after inverting the hydroxy group in cyclohex-
and instead chose to invert the stereochemistry at the hy- ene 6. The inversion was carried out by initial conversion
droxy group in 3 (vide infra).
into the triflate followed by displacement with sodium ni-
The next step involved ring-closing olefin metathesis and trite in DMF to give alcohol 13 in 52% yield (Scheme 3).
was carried out with Grubbs’ 2nd generation catalyst[19] in Attempts to improve the yield by using potassium nitrite in
refluxing dichloromethane. Under these conditions the DMF or tetrabutylammonium nitrite in toluene[20] were not
major diastereomer 3 cyclized cleanly to give cyclohexene 6 successful. Alcohol 13 was converted into gabosine A by
in 97% yield (Scheme 2). However, the minor isomer 4 re- using the same four steps as employed for gabosine N. THP
acted more sluggishly and afforded the corresponding cy- protection gave acetal 14 and removal of the benzoate af-
clohexene 7 in 74% yield. The yield of 7 did not improve forded alcohol 15 which was oxidized to the corresponding
by using Grubbs’ 1st generation catalyst, Hoveyda–Grubbs’ ketone 16 in 66% overall yield from 13. Hydrolysis of the
2nd generation catalyst or by changing the solvent to re- acetal protecting groups then furnished gabosine A with
fluxing toluene.
spectral and physical data in agreement with those reported
for the natural product.[1b,4d]
Scheme 3. Reagents and conditions: (a) Tf2O, pyridine, CH2Cl2,
–20 °CǞroom temp., then NaNO2, DMF, room temp. (b) DHP,
PPTS, CH2Cl2, room temp. (c) NaOMe, MeOH, room temp. (d)
PDC, CH2Cl2, room temp. (e) AcOH, H2O, 40 °C.
Conclusions
In summary, we have developed an 8-step synthesis of
gabosine N and a 9-step synthesis of gabosine A. In both
cases, -ribose serves as the starting material and the cyclo-
hexene skeleton is created by a zinc-mediated tandem reac-
tion followed by ring-closing olefin metathesis. The results
emphasize the utility of these two reactions in the prepara-
tion of polyhydroxylated carbocyclic natural products from
carbohydrates.
Scheme 2. Reagents and conditions: (a) 10% (PCy3)(C3H4N2Mes2)-
Cl2Ru=CHPh, CH2Cl2, 40 °C. (b) K2CO3, MeOH, room temp. (c)
DHP, PPTS, CH2Cl2, room temp. (d) NaOMe, MeOH, room temp.
(e) PDC, CH2Cl2, room temp. (f) AcOH, H2O, room
temp.Ǟ40 °C.
To complete the synthesis of gabosine N the allylic posi-
tion had to be oxidized to the ketone. These experiments
were only performed with the major diastereomer 6, but
similar reactions can be envisioned from the minor isomer
7. First, diol 8 was prepared by deprotection of 6 and it
was attempted to carry out a selective allylic oxidation in
the presence of PDC, MnO2 or DDQ. However, these ex-
periments only gave the desired ketone 9 in very low yield
due to incomplete conversion or over-oxidation and it was
therefore decided to protect the homoallylic hydroxy group
in 6 prior to the oxidation. The THP group was chosen
for this purpose since it can be removed under the same
conditions as the isopropylidene acetal. Treatment of
alcohol 6 with dihydropyran gave fully protected 10 in good
yield which was followed by removal of the benzoate to give
Experimental Section
General: CH2Cl2 was dried by distillation from CaH2 while MeOH
and DMF were dried with 4-Å molecular sieves. Zinc dust (Ͻ 10
micron) was activated immediately before use: zinc (5 g) in 1  HCl
(50 mL) was stirred at room temperature for 20 min and then fil-
tered, rinsed with water and Et2O and finally dried at high vacuum
with a heat gun. Zinc(II) bromide was dried at high vacuum with
a heat gun. All other reagents were obtained from commercial
sources and used without further purification. Reactions were
monitored by TLC using aluminium plates precoated with silica
gel 60. Compounds were visualized by dipping in a solution of
allylic alcohol 11. The oxidation of 11 could now be ac- (NH4)6Mo7O24·4H2O (25 g/L) and Ce(SO4)2 (10 g/L) in 10% aque-
398
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Synthesis of Gabosine A and N from Ribose
ous H2SO4 followed by heating. Melting points are uncorrected.
Flash column chromatography was performed with E. Merck silica
gel 60 (particle size 0.040–0.063 mm). Optical rotations were mea-
sured with a Perkin–Elmer 241 polarimeter while IR spectra were
recorded with a Bruker Alpha FT-IR spectrometer. NMR spectra
5.30 (ddd, J = 1.1, 1.7, 10.4 Hz, 1 H), 5.20–5.18 (m, 1 H), 5.15 (p,
J = 1.5 Hz, 1 H), 4.71–4.65 (m, 1 H), 4.09–4.05 (m, 2 H), 2.01 (d,
J = 4.2 Hz, OH), 1.94 (s, 3 H), 1.49 (s, 3 H), 1.34 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 165.5, 140.6, 134.3, 133.3, 130.3
129.8, 128.6, 118.5, 116.1, 109.3, 79.1, 77.8, 77.5, 70.9, 28.0, 25.5,
20.3 ppm. HRMS: calcd. for C19H24O5Na [M + Na]+ 355.1516;
found 355.1530.
were recorded with a Varian Mercury 300 instrument. Residual sol-
1
vent peaks were used as internal reference in H NMR (δCHCl3
=
7.26 ppm and δCD2HOD = 3.31 ppm) while CDCl3 (δ = 77.16 ppm)
4: Rf = 0.27 (EtOAc/heptane, 1:2). [α]2D9 = –2.8 (c = 1.5, CHCl3).
and CD3OD (δ = 49.0 ppm) served as the internal standards in 13
C
IR (film): ν = 3490, 3091, 3071, 2987, 2937, 1725, 1654, 1602, 1452,
˜
NMR spectroscopy. High-resolution mass spectra were recorded at
the Department of Physics and Chemistry, University of Southern
Denmark.
1
1379, 1316, 1270, 1218, 1116, 1070, 1027, 918, 875, 712 cm–1. H
NMR (300 MHz, CDCl3): δ = 8.14–8.08 (m, 2 H), 7.58 (tt, J = 1.4,
7.4 Hz, 1 H), 7.50–7.42 (m, 2 H), 6.07 (ddd, J = 6.7, 10.4, 17.1 Hz,
1 H), 5.61 (s, 1 H), 5.46 (d, J = 17.1 Hz, 1 H), 5.32 (d, J = 10.8 Hz,
1 H), 5.07–5.02 (m, 2 H), 4.73 (t, J = 6.4 Hz, 1 H), 4.20 (dd, J =
6.1, 9.2 Hz, 1 H), 3.85 (ddd, J = 1.9, 4.7, 9.2 Hz, 1 H), 1.99 (d, J
= 4.8 Hz, OH), 1.88 (s, 3 H), 1.48 (s, 3 H), 1.28 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.3, 141.1, 133.7, 133.3, 130.1,
129.8, 128.6, 118.2, 112.9, 109.0, 78.7, 77.1, 76.2, 69.0, 28.1, 25.5,
20.1 ppm. HRMS: calcd. for C19H24O5Na [M + Na]+ 355.1516;
found 355.1521.
(E)-3-Bromo-2-methylprop-1-enyl Benzoate (1). Procedure with
ZnBr2: Benzoyl bromide (1.3 mL, 11.0 mmol) was added to a solu-
tion of freshly distilled methacrolein (770 mg, 11.0 mmol) in anhy-
drous CH2Cl2 and Et2O (1:1, 18 mL) under nitrogen. The mixture
was cooled to –20 °C followed by addition of anhydrous ZnBr2
(25 mg, 0.11 mmol). The reaction was stirred at 0 °C for 2 h and
then quenched by addition of saturated aqueous NaHCO3 (15 mL).
The aqueous solution was extracted with CH2Cl2 (3ϫ10 mL) and
the combined organic layers were dried (Na2SO4), filtered, and con-
centrated in vacuo. The residue was purified by flash column
chromatography (EtOAc/hexane, 1:20) to give 2.12 g (76%) of the
desired compound as a white crystalline mass (4:3 mixture of the
E and Z isomer).
(1S,2S,3S,6R)-3-Benzoyloxy-2-hydroxy-4,8,8-trimethyl-7,9-dioxabi-
cyclo[4.3.0]non-4-ene (6): Grubbs’ 2nd generation catalyst (151 mg,
0.18 mmol) was added to a degassed solution of diene 3 (578 mg,
1.7 mmol) in anhydrous CH2Cl2 (54 mL) under nitrogen. The solu-
tion was protected from sunlight and stirred at reflux under nitro-
gen for 4 d. The reaction was stopped by addition of charcoal
(5.52 g) and the mixture was filtered through a plug of Celite. The
filtrate was concentrated in vacuo and purified by flash column
chromatography (heptane/Et2O, 3:1) to afford the target compound
(511.5 mg, 97%) as a white solid. Rf = 0.52 (EtOAc/heptane, 1:1).
Procedure without ZnBr2: Freshly distilled methacrolein (15.0 mL,
181.7 mmol) was dissolved in anhydrous CH2Cl2 (200 mL) under
nitrogen. Benzoyl bromide (22.0 mL, 183.5 mmol) was added at
0 °C and the solution was stirred at room temperature for 10 d.
The mixture was concentrated in vacuo and the residue dissolved
in pentane. Cooling to –20 °C gave white crystals which were iso-
lated and recrystallized from pentane to afford 1 (27.8 g, 60%). Rf
[α]2D9 = +65.0 (c = 1.1, CHCl ). IR (film): ν = 3408, 3072, 2987,
˜
3
2933, 2866, 1711, 1454, 1371, 1348, 1277, 1223, 1108, 1036, 1014,
712 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.14–8.09 (m, 2 H),
7.59 (tt, J = 2.1, 7.4 Hz, 1 H), 7.49–7.42 (m, 2 H), 5.79–5.74 (m, 1
H), 5.70 (bd, J = 3.8 Hz, 1 H), 4.67–4.61 (m, 1 H), 4.45 (dd, J =
3.2, 6.5 Hz, 1 H), 4.12 (dt, J = 3.5, 6.9 Hz, 1 H), 2.47 (d, J =
6.9 Hz, OH), 1.83 (d, J = 0.8 Hz, 3 H), 1.56 (s, 3 H), 1.43 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 134.4, 133.5, 130.0,
129.8, 128.6 123.1, 110.6, 74.0, 72.0, 71.4, 67.3, 27.3, 25.9,
20.2 ppm. HRMS: calcd. for C17H20O5Na [M + Na]+ 327.1203;
found 327.1212.
= 0.19 (EtOAc/heptane, 1:10). M.p. 61–62 °C. IR (KBr): ν = 3096,
˜
2844, 2913, 1727, 1451, 1382, 1287, 1162, 1122, 704 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.14–8.08 (m, 2 H), 7.66–7.57 (m, 2 H),
7.52–7.45 (m, 2 H), 4.07 (s, 2 H), 1.98 (d, J = 1.4 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 163.2, 134.0, 133.9, 130.1, 128.9,
128.8, 119.2, 36.5, 13.2 ppm. HRMS: calcd. for C11H11BrO2Na [M
+ Na]+ 276.9835; found 276.9848.
3-Benzoyl-1,2,7,8-tetradeoxy-5,6-O-isopropylidene-2-C-methyl-
D-
allo- and - -altro-octa-1,7-dienitol (3 and 4): Activated Zn (1.21 g,
D
18.5 mmol) was added to a degassed solution of ribofuranoside
2a[15] (1.07 g, 3.4 mmol) in THF/H2O (4:1, 30 mL). The mixture
was sonicated at 40 °C under nitrogen until TLC revealed full con-
version to the aldehyde (2 h). A deoxygenated solution of bromide
1 (1.28 g, 5.1 mmol) in THF (8.0 mL) was then added in two por-
tions; one after 2 h and one after 3.5 h of sonication. After sonicat-
ing for an additional 2 h 45 min at 40 °C, the reaction mixture was
filtered through a plug of Celite and the filter cake was rinsed thor-
oughly with CH2Cl2. The filtrate was washed with saturated aque-
ous NaHCO3 (30 mL) and H2O (2ϫ30 mL). The combined aque-
ous phases were extracted with CH2Cl2 (2ϫ30 mL) and the com-
bined organic phases were dried (MgSO4), filtered, and concen-
trated in vacuo. Purification by flash column chromatography
(EtOAc/heptane, 1:5) gave dienes 3 and 4 (0.95 g, 85%) as a separa-
ble 2:1 mixture.
(1S,2S,3R,6R)-3-Benzyloxy-2-hydroxy-4,8,8-trimethyl-7,9-dioxadi-
cyclo[4.3.0]non-4-ene (7): A degassed solution of diene 4 (34 mg,
0.10 mmol) and Grubbs’ 2nd generation catalyst (7.4 mg,
0.0087 mmol) in freshly distilled CH2Cl2 (24 mL) was protected
from sunlight and stirred at reflux under argon for 3 d. The reac-
tion mixture was evaporated on Celite and purified by flash column
chromatography (heptaneǞheptane/EtOAc, 4:1) to give the de-
sired compound (23 mg, 74%) as a white solid. Rf = 0.29 (EtOAc/
heptane, 2:1). [α]2D5 = –40.4 (c = 1.0, CDCl ). IR (film): ν = 3459,
˜
3
3066, 3036, 2985, 2924, 2855, 1720, 1452, 1380, 1268, 1235, 1110,
1
1047, 1031, 712 cm–1. H NMR (300 MHz, CDCl3): δ = 8.11–8.06
(m, 2 H), 7.59 (tt, J = 2.1, 7.4 Hz, 1 H), 7.50–7.42 (m, 2 H), 5.84
(dd, J = 1.0, 8.1 Hz, 1 H), 5.57 (dq, J = 1.9, 3.3 Hz, 1 H), 4.69–
4.64 (m, 1 H), 4.56 (ddd, J = 0.7, 2.9, 5.6 Hz, 1 H), 3.97 (dt, J =
2.9, 8.1 Hz, 1 H), 2.66 (d, J = 8.1 Hz, OH), 1.78 (dd, J = 1.3,
2.6 Hz, 3 H), 1.43 (s, 3 H), 1.40 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.2, 134.6, 133.5, 130.0, 129.8, 128.6, 124.1, 109.9,
75.9, 74.1, 73.1, 71.8, 27.8, 26.5, 19.2 ppm. HRMS: calcd. for
C17H20O5Na [M + Na]+ 327.1203; found 327.1212. Deprotection
with NaOMe in MeOH gave the corresponding diol as described
below for 8. No reaction occurred when the diol was treated with
3: Rf = 0.33 (EtOAc/heptane, 1:2). [α]3D0 = –5.0 (c = 1.0, CHCl3).
IR (film): ν = 3499, 3074, 2986 2925, 2855, 1720, 1650, 1611, 1452,
˜
1373, 1318, 1270, 1218, 1110, 1070, 1027, 874, 712 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.10–8.05 (m, 2 H), 7.58 (tt, J = 1.4, 7.4 Hz,
1 H), 7.49–7.41 (m, 2 H), 6.05 (ddd, J = 7.2, 10.4, 17.4 Hz, 1 H),
5.68 (d, J = 3.1 Hz, 1 H), 5.43 (ddd, J = 1.2, 1.7, 17.2 Hz, 1 H),
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2,2-dimethoxypropane and camphorsulfonic acid at room tempera-
ture for 1 h.
H), 1.80–1.66 (m, 4 H), 1.57–1.46 (m, 6 H), 1.41 (s, 3 H), 1.39 (s,
3 H), 1.33 (s, 3 H), 1.32 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 138.6, 136.9, 121.9, 120.5, 110.8, 110.5, 99.2, 95.9, 76.4, 74.3,
74.3, 73.6, 73.6, 70.2, 69.9, 67.1, 63.1, 62.9, 30.7, 30.5, 28.2, 27.8,
26.8, 26.4, 25.4, 25.3, 21.2, 20.7, 19.7, 19.6 ppm. HRMS: calcd. for
C15H24O5Na [M + Na]+ 307.1516; found 307.1529.
(1S,2S,3S,6R)-2,3-Dihydroxy-4,8,8-trimethyl-7,9-dioxabicyclo[4.3.0]-
non-4-ene (8): K2CO3 (49 mg, 0.36 mmol) was added to a solution
of benzoate 6 (0.107 g, 0.38 mmol) in anhydrous MeOH (10 mL)
and the mixture was stirred at room temperature under nitrogen
for 3 h. The reaction was quenched with 1  HCl until neutral pH,
followed by extraction with CH2Cl2 (3ϫ15 mL). The combined or-
ganic phases were dried (MgSO4), filtered, and concentrated in
vacuo. Purification by flash column chromatography (EtOAc/hep-
tane, 1:1) gave diol 8 (50 mg, 72%) as white crystals. Rf = 0.13
(1R,2R,6R)-4,8,8-Trimethyl-3-oxo-2-tetrahydropyranyloxy-7,9-dioxa-
bicyclo[4.3.0]non-4-ene (12): PDC (0.235 g, 0.63 mmol) was added
to a solution of alcohol 11 (51 mg, 0.18 mmol) in anhydrous
CH2Cl2 (15 mL) and the mixture was stirred at room temperature
under nitrogen for 20 h. The solution was concentrated in vacuo
and purified by flash column chromatography (heptane/EtOAc,
2:1) to give 12 (36 mg, 71%) as a colorless oil and a mixture of two
(EtOAc/heptane, 1:1). [α]2D5 = +69.9 (c = 1.0, CHCl ). IR (film): ν
˜
3
= 3447, 3002, 2931, 2858, 1370, 1231, 1177, 1083, 1038, 975 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.40 (dq, J = 1.4, 2.8 Hz, 1 H),
4.55–4.50 (m, 1 H), 4.48–4.44 (m, 1 H), 3.84 (dd, J = 4.1, 11.4 Hz,
1 H), 3.77–3.69 (m, 1 H), 3.34 (d, J = 9.3 Hz, OH), 2.74 (d, J =
11.5 Hz, OH), 1.84 (t, J = 1.5 Hz, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 137.0, 122.2, 110.3, 76.7,
diastereomers. R = 0.33 (EtOAc/heptane, 1:1). IR (film): ν = 2984,
˜
f
2937, 2871, 1699, 1453, 1379, 1351, 1229, 1145, 1120, 1074, 1024,
1
971, 889 cm–1. H NMR (300 MHz, CDCl3): δ = 6.32–6.28 (m, 1
H), 4.93–4.89 (m, 1 H), 4.82–4.76 (m, 2 H), 4.56 (d, J = 2.6 Hz, 1
H), 3.92–3.84 (m, 1 H), 3.55–3.46 (m, 1 H), 1.96–1.84 (m, 3 H),
73.6, 70.5, 67.5, 28.2, 26.4, 21.0 ppm. HRMS: calcd. for 1.81 (t, J = 1.4 Hz, 3 H), 1.62–1.50 (m, 3 H), 1.37 (s, 3 H), 1.32 (s,
C10H16O4Na [M + Na]+ 223.0941; found 223.0931. Reaction with
2,2-dimethoxypropane and camphorsulfonic acid at room tempera-
ture for 40 min gave 73% yield of the corresponding bis(isopropyl-
idene) compound.
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 196.0, 139.2, 134.5,
111.7, 99.5, 78.5, 74.9, 73.2, 63.1, 30.3, 28.0, 27.2, 25.6, 19.5,
15.6 ppm. Only NMR spectroscopic data for the major dia-
stereomer are reported. HRMS: calcd. for C15H22O5Na [M +
Na]+ 305.1359; found 305.1346.
(1R,2S,3S,6R)-3-Benzoyloxy-4,8,8-trimethyl-2-tetrahydropyranyl-
oxy-7,9-dioxabicyclo[4.3.0]non-4-ene (10): DHP (0.4 mL, 4.4 mmol) Gabosine N: Ketone 12 (36 mg, 0.13 mmol) was dissolved in 80%
and PPTS (14 mg, 0.056 mmol) were added to a solution of alcohol
6 (657.7 mg, 2.16 mmol) in anhydrous CH2Cl2 (20 mL). The solu-
tion was stirred at room temperature under argon overnight. The
reaction was stopped by addition of saturated aqueous NaHCO3
until neutral pH. The phases were separated and the organic phase
was dried (MgSO4), filtered, and concentrated in vacuo. The resi-
due was purified by flash column chromatography (heptane/
EtOAc, 5:1) to give 10 (627.0 mg, 75%) as a colorless oil and a
mixture of two diastereomers. Rf = 0.44 (EtOAc/heptane, 1:1). IR
acetic acid in H2O (2.0 mL) and stirred under nitrogen for 23 h at
room temperature followed by 16 h at 40 °C. The reaction mixture
was cooled to room temperature and concentrated in vacuo to give
a residue that was purified by flash column chromatography
(EtOAc/MeOH, 99:1) to afford gabosine N (17.7 mg, 88%) as white
crystals. Rf = 0.12 (EtOAc). [α]2D5 = –150.5 (c = 0.3, CD3OD) [lit.[1a]
[α]2D0 = –152.0 (c = 0.89, H2O), lit.[4b] [α]D = –142 (c = 0.16,
MeOH)]. M.p. 174–176 °C (MeOH) [lit.[4b] 174–175 °C (MeOH),
lit.[1a] 182.5–183.3 °C]. IR (film): ν = 3427, 3308, 3244, 2943, 2925,
˜
1
(film): ν = 3070, 2981, 2939, 2873, 1715, 1452, 1369, 1270, 1232,
2851, 1680, 1408, 1343, 1197, 1132, 1044, 1022, 937, 854 cm–1. H
˜
1109, 1069, 1054, 1016, 963, 919, 709 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.13–8.06 (m, 4 H), 7.52 (tt, J = 1.4, 7.4 Hz, 2 H),
7.44–7.36 (m, 4 H), 5.82–5.78 (m, 2 H), 5.62–5.58 (m, 2 H), 4.95–
NMR (300 MHz, CD3OD): δ = 6.48 (dq, J = 1.5, 2.2 Hz, 1 H),
4.58–4.54 (m, 1 H), 4.34 (dt, J = 2.5, 3.4 Hz, 1 H), 4.23 (d, J =
2.5 Hz, 1 H), 1.81 (dd, J = 1.5, 2.2 Hz, 3 H) ppm. 13C NMR
4.89 (m, 2 H), 4.66–4.58 (m, 2 H), 4.56–4.50 (m, 2 H), 4.15 (dt, J (75 MHz, CD3OD): δ = 200.2, 145.9, 134.5, 77.7, 76.6, 69.2,
= 2.6, 4.7 Hz, 2 H), 4.00–3.84 (m, 2 H), 3.55–3.44 (m, 2 H), 1.78
(t, J = 1.3 Hz, 3 H), 1.76 (t, J = 1.4 Hz, 3 H), 1.70–1.59 (m, 8 H),
1.57 (s, 3 H), 1.55 (s, 3 H), 1.53–1.43 (m, 4 H), 1.41 (s, 3 H), 1.40
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.0, 166.9, 133.0,
132.8, 132.8, 131.5, 130.6, 130.3, 130.0, 128.4, 128.3, 126.4, 125.2,
111.0, 110.8, 97.2, 96.3, 74.5, 73.9, 73.6, 72.0, 69.8, 69.4, 69.3, 66.4,
63.0, 61.8, 30.1, 30.1, 28.3, 28.0, 26.8, 26.6, 25.5, 25.4, 20.8, 20.5,
19.5, 18.3 ppm. HRMS: calcd. for C22H28O6Na [M + Na]+
411.1778; found 411.1774.
15.3 ppm. NMR spectroscopic data are in accordance with litera-
ture values.[1a,4b] HRMS: calcd. for C7H10O4Na [M + Na]+
181.0471; found 181.0475.
(1S,2R,3S,6R)-3-Benzoyloxy-2-hydroxy-4,8,8-trimethyl-7,9-dioxabi-
cyclo[4.3.0]non-4-ene (13): A solution of alcohol 6 (1.79 g,
5.9 mmol) in freshly distilled CH2Cl2 (40 mL) under nitrogen was
cooled to –20 °C followed by addition of pyridine (2.14 mL,
26.5 mmol) and Tf2O (1.48 mL, 8.8 mmol). The reaction mixture
was slowly warmed to room temperature and after 1.5 h the reac-
tion was quenched with 2  HCl (85 mL). The phases were sepa-
rated and the aqueous phase was extracted with CH2Cl2
(2ϫ25 mL). The combined organic phases were washed with satu-
rated aqueous NaHCO3 (45 mL), dried (MgSO4), filtered, and con-
centrated in vacuo to give the crude trifluoromethanesulfonate
(2.57 g, 5.9 mmol) as a black residue, which was used directly in
the next step. The crude trifluoromethanesulfonate was redissolved
(1R,2S,3S,6R)-3-Hydroxy-4,8,8-trimethyl-2-tetrahydropyranyloxy-
7,9-dioxabicyclo[4.3.0]non-4-ene (11): Fully protected 10 (150 mg,
0.386 mmol) was dissolved in 10% NaOMe in anhydrous MeOH
(10 mL) and stirred at room temperature for 3 h. The mixture was
evaporated in vacuo and purified by flash column chromatography
(heptane/EtOAc, 3:1) to give 11 (91 mg, 83%) as a colorless oil and
a mixture of two diastereomers. Rf = 0.28 and 0.33 (EtOAc/hep-
tane, 1:1). IR (film): ν = 3529, 2983, 2937, 2874, 1440, 1371, 1227, in anhydrous DMF under nitrogen, NaNO2 (1.62 g, 23.5 mmol)
˜
1
1133, 1120, 1075, 1051, 1029, 1012, 985, 970, 814 cm–1. H NMR
(300 MHz, CDCl3): δ = 5.41–5.37 (m, 1 H), 5.34 (dq, J = 1.4,
2.8 Hz, 1 H), 4.92 (dd, J = 3.1, 4.3 Hz, 1 H), 4.77 (dd, J = 3.2,
was added and the mixture stirred at room temperature for 5.5 h.
The reaction mixture was diluted with H2O (120 mL) followed by
extraction with Et2O (5ϫ50 mL). The combined organic phases
4.5 Hz, 1 H), 4.58–4.50 (m, 2 H), 4.48–4.43 (m, 2 H), 4.02–3.92 (m, were dried (MgSO4), filtered, and concentrated in vacuo. The resi-
4 H), 3.88 (dd, J = 1.9, 4.2 Hz, 1 H), 3.82 (dd, J = 2.4, 3.9 Hz, 1 due was purified by flash column chromatography (EtOAc/heptane,
H), 3.55–3.44 (m, 2 H), 1.96–185 (m, 2 H), 1.83 (s, 3 H), 1.82 (s, 3 1:5Ǟ1:1) to give alcohol 13 (933 mg, 52%) as a slightly yellow oil.
400
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 396–402

Synthesis of Gabosine A and N from Ribose
Rf = 0.49 (EtOAc/heptane, 1:1). [α]2D5 = –12.0 (c = 2.0, CD3OD).
mixture was filtered through a plug of Celite, and concentrated in
vacuo to give a slightly yellow oil, which was purified by flash col-
umn chromatography (heptane/EtOAc, 3:1) to afford 16 (334 mg,
IR (film): ν = 3459, 3064, 3043, 2985, 2925, 2859, 1719, 1452, 1379,
˜
1
1316, 1268, 1249, 1216, 1115, 1060, 1026, 979, 907, 710 cm–1. H
NMR (300 MHz, CDCl3): δ = 8.11–8.05 (m, 2 H), 7.59 (tt, J = 1.4, 86%) as a colorless oil and a mixture of two diastereomers. Rf =
7.4 Hz, 1 H), 7.50–7.42 (m, 2 H), 5.76–5.67 (m, 2 H), 4.69–4.63 (m, 0.62 (EtOAc/heptane, 1:1). IR (film): ν = 2985, 2938, 2886, 1698,
˜
1 H), 4.21 (dd, J = 6.3, 9.0 Hz, 1 H), 3.98 (t, J = 8.9 Hz, 1 H), 1.77
1453, 1380, 1371, 1240, 1219, 1167, 1125, 1063, 1031, 977, 966, 856
1
(dd, J = 1.3, 2.7 Hz, 3 H), 1.55 (s, 3 H), 1.41 (s, 3 H) ppm. 13C cm–1. H NMR (300 MHz, CDCl3): δ = 6.54 (dq, J = 1.5, 4.2 Hz,
NMR (75 MHz, CDCl3): δ = 166.7, 139.1, 133.5, 130.0, 129.6, 1 H), 6.50–6.46 (m, 1 H), 4.98 (t, J = 3.3 Hz, 1 H), 4.87 (t, J =
128.6, 120.1, 110.6, 77.9, 74.7, 72.7, 72.3, 28.4, 26.1, 18.9 ppm.
HRMS: calcd. for C17H20O5Na [M + Na]+ 327.1203; found
327.1216.
3.2 Hz, 1 H), 4.80–4.74 (m, 2 H), 4.54–4.41 (m, 4 H), 4.13–4.03 (m,
1 H), 3.98–3.89 (m, 1 H), 3.52–3.41 (m, 2 H), 1.86 (t, J = 1.4 Hz,
3 H), 1.85 (t, J = 1.4 Hz, 3 H), 1.80–1.67 (m, 5 H), 1.61–1.52 (m,
7 H), 1.52 (s, 3 H), 1.47 (s, 3 H), 1.43 (s, 3 H), 1.40 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 197.2, 196.1, 137.5, 136.0, 135.8,
111.2, 111.1, 98.6, 97.8, 78.5, 77.7, 76.6, 71.7, 71.6, 62.2, 61.9, 30.4,
30.2, 28.1, 28.0, 26.7, 25.5, 25.4, 19.0, 18.7, 16.2, 15.9 ppm. HRMS:
calcd. for C15H22O5Na [M + Na]+ 305.1359; found 305.1368.
(1R,2R,3S,6R)-3-Benzoyloxy-4,8,8-trimethyl-2-tetrahydropyranyl-
oxy-7,9-dioxabicyclo[4.3.0]non-4-ene (14): DHP (0.5 mL, 5.5 mmol)
and PPTS (140 mg, 0.56 mmol) were added to a solution of alcohol
13 (850 mg, 2.79 mmol) in freshly distilled CH2Cl2 (60 mL). The
mixture was stirred at room temperature under nitrogen overnight.
The reaction was stopped by addition of saturated aqueous
NaHCO3 (100 mL) followed by extraction with CH2Cl2
(3ϫ50 mL). The combined organic phases were dried (MgSO4),
filtered, concentrated in vacuo and purified by flash column
chromatography (heptane/EtOAc, 9:1 Ǟ4:1) to give 14 (925 mg,
85%) as a colorless oil and a mixture of two diastereomers. Rf =
Gabosine A: Ketone 16 (52 mg, 0.184 mmol) was dissolved in 80%
acetic acid in H2O (3.0 mL) and stirred under nitrogen for 9 h at
40 °C. The reaction mixture was cooled to room temperature, con-
centrated and co-concentrated with H2O to give a residue that was
purified by flash column chromatography (EtOAc) to afford gabos-
ine A (28 mg, 96%) as a white crystalline material. Rf = 0.16
(EtOAc). [α]2D5 = –125.4 (c = 0.8, CD3OD) lit.[1b] [α]2D0 = –132 (c =
1, MeOH), lit.[4d] [α]D = –131 (c = 0.27, MeOH). M.p. 56–60 °C
0.72 (EtOAc/heptane, 1:1). IR (film): ν = 3063, 2983, 2938, 2868,
˜
1722, 1452, 1380, 1317, 1265, 1247, 1217, 1162, 1119, 1062, 1029,
1
986, 966, 869, 710 cm–1. H NMR (300 MHz, CDCl3): δ = 8.12–
(MeOH). IR (film): ν = 3354, 2955, 2924, 2862, 1684, 1448, 1236,
˜
1139, 1092, 1028 cm–1. 1H NMR (300 MHz, CD3OD): δ = 6.75
(dq, J = 1.5, 5.6 Hz, 1 H), 4.41–4.36 (m, 1 H), 4.32 (d, J = 10.0 Hz,
1 H), 3.73 (dd, J = 4.0, 10.0 Hz, 1 H), 1.82 (dd, J = 0.9, 1.3 Hz, 3
H) ppm. 13C NMR (75 MHz, CD3OD): δ = 200.4, 143.0, 136.9,
75.0, 73.9, 67.4, 15.6 ppm. NMR spectroscopic data are in accord-
ance with literature values.[1b,4d] HRMS: calcd. for C7H10O4Na [M
+ Na]+ 181.0471; found 181.0472.
8.03 (m, 4 H), 7.59–7.53 (m, 2 H), 7.48–7.40 (m, 4 H), 5.81–5.67
(m, 4 H), 5.21 (t, J = 2.6 Hz, 1 H), 4.83 (t, J = 3.3 Hz, 1 H), 4.68–
4.58 (m, 2 H), 4.29 (dt, J = 6.1, 8.3 Hz, 2 H), 4.19–4.08 (m, 3 H),
3.64–3.54 (m, 1 H), 3.46–3.37 (m, 1 H), 3.23–3.14 (m, 1 H), 1.78–
1.70 (m, 8 H), 1.62–1.58 (m, 4 H), 1.55 (s, 9 H), 1.40 (s, 3 H), 1.39
(s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4, 166.2, 139.3,
138.1, 133.4, 133.1, 130.2, 129.9, 129.8, 129.7, 128.7, 128.4, 120.9,
120.1, 110.2, 110.2, 99.0, 97.3, 78.5, 76.1, 75.6, 74.6, 73.0, 72.6,
72.6, 62.1, 61.3, 30.6, 30.5, 28.3, 28.1, 26.6, 26.5, 25.4, 25.3, 19.1,
19.0, 18.5 ppm. HRMS: calcd. for C22H28O6Na [M + Na]+
411.1778; found 411.1796.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for compounds 1, 3, 4, 6–
8, 10–16, gabosine A and N.
(1R,2R,3S,6R)-3-Hydroxy-4,8,8-trimethyl-2-tetrahydropyranyloxy-
7,9-dioxabicyclo[4.3.0]non-4-ene (15): Fully protected 14 (595 mg,
1.53 mmol) was dissolved in 10% NaOMe in anhydrous MeOH
(60 mL) and stirred at room temperature for 3 h. The mixture was
concentrated in vacuo and purified by flash column chromatog-
raphy (heptane/EtOAc, 4:1) to give alcohol 15 (393 mg, 90%) as a
colorless oil and a mixture of two diastereomers. Rf = 0.51 and
Acknowledgments
The Center for Sustainable and Green Chemistry is funded by the
Danish National Research Foundation.
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0.63 (EtOAc/heptane, 1:1). IR (film): ν = 3442, 3037, 2982, 2936,
˜
2860, 1453, 1441, 1372, 1243, 1215, 1135, 1072, 1047, 1022, 1007,
1
975, 890 cm–1. H NMR (300 MHz, CDCl3): δ = 5.54–5.45 (m, 2
H), 4.79 (dd, J = 2.6, 5.5 Hz, 1 H), 4.62–4.50 (m, 2 H), 4.40 (d, J
= 1.7 Hz, 1 H), 4.31 (t, J = 5.8 Hz, 1 H), 4.14–4.07 (m, 2 H), 4.04–
3.91 (m, 3 H), 3.87–3.80 (dd, J = 5.0, 8.5 Hz, 1 H), 3.59 (t, J =
8.5 Hz, 1 H), 3.56–3.47 (m, 2 H), 2.99 (d, J = 8.5 Hz, OH), 1.96– [2] The structure of gabosine K has not been established because
1.77 (m, 3 H), 1.87–1.85 (m, 3 H), 1.84–1.83 (m, 3 H), 1.61–1.47
(m, 9 H), 1.47 (s, 3 H), 1.43 (s, 3 H), 1.36 (s, 3 H), 1.34 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 142.1, 138.2, 120.4, 117.3,
110.0, 109.7, 102.7, 99.4, 84.3, 76.7, 75.9, 75.2, 72.7, 71.1, 70.5,
65.6, 64.0, 31.5, 30.9, 28.5, 28.2, 26.6, 26.1, 25.3, 25.1, 21.4, 20.4,
20.3, 19.0 ppm. HRMS: calcd. for C15H24O5Na [M + Na]+
307.1516; found 307.1521.
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 396–402