Stereoselective synthesis and relative configuration assignment of gabosine J

Article abstract of DOI:10.1021/jo300456q

The first total synthesis of (+)-gabosine J and that of the epimer at C4 of its enantiomer have been accomplished through an enantioselective approach from a common intermediate 1. These syntheses have allowed us to establish the correct relative configuration of the natural metabolite, which was originally misassigned. This work, together with our former syntheses of other gabosines and related compounds, validates enone 1 as a general synthetic precursor for this kind of carbasugars.

Full text of DOI:10.1021/jo300456q

Article
pubs.acs.org/joc
Stereoselective Synthesis and Relative Configuration Assignment
of Gabosine J
́
Miguel Angel Fresneda, Ramon Alibes, Josep Font, Pau Bayon,* and Marta Figueredo*
́
́
̀
Departament de Química, Universitat Autonoma de Barcelona, 08193 Bellaterra, Spain
S
* Supporting Information
ABSTRACT: The first total synthesis of (+)-gabosine J and
that of the epimer at C4 of its enantiomer have been accom-
plished through an enantioselective approach from a common
intermediate 1. These syntheses have allowed us to establish the
correct relative configuration of the natural metabolite, which was
originally misassigned. This work, together with our former syn-
theses of other gabosines and related compounds, validates enone
1 as a general synthetic precursor for this kind of carbasugars.
Noteworthy, most of the synthetic strategies toward gabosines
have been designed leading to one or few members of the family.
However, in the past years, we have been investigating a general,
stereodivergent, and enantioselective design (Scheme 1) in order
INTRODUCTION
Gabosines are a class of secondary metabolites isolated from
several Streptomyces strains with carbasugar structure (Figure 1).
■
Scheme 1. Stereodivergent Synthetic Strategy to Gabosines
and Related Compounds
Figure 1. Some examples of gabosines.
This family of compounds shows high structural diversity due to
differences in the unsaturation degree of the ring, the substituent
positions, and the relative and absolute configuration of their
stereogenic centers. To date, up to 14 different gabosines have
been isolated.1
Some of these metabolites display interesting bioactivities such
as antibiotic,2 antitumor,3 and DNA binding properties.1b,4 Their
promising biological activities and their challenging structural
features have triggered a number of different approaches for their
synthesis. Thus, in the past decades, the total syntheses of various
gabosines were achieved by several teams developing different
strategies. Some of them were based on Diels−Alder reactions,5
while others started from benzene derivates,6 carbohydrates,7
(−)-quinic acid,8 monoketals of cyclohexan-1,4-diones,9 or, more
recently, L-tartaric acid.10 This extensive work has contributed to
confirm the structure and absolute configuration of most gabosines,
but the structure of gabosine J has not been confirmed yet.
to accomplish a large number of syntheses starting from a common
intermediate.9b,d A crucial point of this project was the preparation of
enones (4R,6RS)- and (4S,6RS)-1 through an enzymatic resolution,
in multigram scale, with absolute stereochemical control at C4.11
We have validated our strategy by synthesizing a number of
gabosines and related compounds, among which are gabosines N
Received: March 12, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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and O, with relative cis-configuration at the C2−C3 diol unit,9b
and gabosines A, B, and F, with relative C2−C3 trans-
configuration.9d
several attempts were done by using 1H-benzotriazole-1-
methanol, as the source of formaldehyde, under basic conditions
(Table 1, entries 2−5). In those trials, we observed that the
workup protocol had a crucial influence on the yield and/or
product ratio. Thus, under the same reaction and workup
conditions as in entry 1, where the reaction quenching was
performed by addition of aqueous ammonium chloride, the total
yield increased slightly, but, along with the expected products
(−)-2 and (−)-3, a bicyclic compound (−)-4, resulting of an
intramolecular conjugated addition in (−)-3, was also isolated in
considerable amount (Table 1, entry 2). Use of LDA as the base
combined with basic workup (Table 1, entry 3) increased the
total yield but also the ratio of (−)-4 in the product mixture.
Interestingly, we observed that a quick filtrate of the reaction
mixture through a silica gel pad (Table 1, entry 4) furnished a
mixture of (−)-2 and (−)-3 in overall 76% yield with no traces of
byproduct (−)-4. An increase in the concentration of both
starting 1 and tBuOK lead to good yield and stereoselectivity
(Table 1, entry 5). The fact that this last result was not always
reproducible led us to assay a different methodology. Hence, the
hydroxymethylation was attempted with commercial 37%
formalin stabilized with methanol and tBuOK as the base
(Table 1, entry 6). Under these new reaction conditions, and
after slightly acidic workup, alcohol (−)-2 was obtained in 88%
yield as a single product. This result was totally reproducible and
made us to establish this last methodology as the one of choice to
scale up the reaction to more than 5 g of starting enone 1.
The regioselective reduction of enone (−)-2 was carried out
by reaction with NaBH4 in CH2Cl2−methanol at −10 °C
(Scheme 3) and furnished diol (−)-5 as a single stereoisomer, as
In order to increase the feasibility of enone 1 as the starting
material for the stereodivergent synthesis of gabosines, we
choose gabosine J as our next goal. Conversely to the other
gabosines previously synthesized by us, gabosine J bears a
hydroxymethyl substituent attached to the ring instead of a
methyl group, and it also displays switched functionalization at
C1 and C4 with respect to most gabosines. Moreover, to the best
of our knowledge, gabosine J has not been previously
synthesized, and no optical rotation value was described for the
metabolite isolated from natural sources.
Adjustment of our general synthetic strategy to gabosine
J (Scheme 2) required hydroxymethylation at C6, followed by
Scheme 2. Synthetic Plan for Gabosine J
switching of the hydroxyl and carbonyl group positions of the
γ-hydroxyenone moiety, and then a convenient sequence of
known steps, including dihydroxylation and oxidation of the
sulfide with concomitant elimination.
Scheme 3. Synthesis of Diols (+)-7 and (+)-8
RESULTS AND DISCUSSION
According to the plan, the hydroxymethylation of enone 1 was
first investigated. The results are summarized in Table 1.
■
a
Table 1. Hydroxymethylation Studies of Enone (4S,6RS)-1
b
entry
reagent
CH2O (g)
yield (%)
(−)-2:(−)-3:(−)-4
c
1
66
75
88
76
87
88
4.5:1:−
7.8:1:2.1
7.3:1:4.3
2.2:1:−
20.7:1:−
1:−:−
c
2
Bt−CH2OH
Bt−CH2OH
Bt−CH2OH
Bt−CH2OH
formalin−MeOH
de
,
1
it was confirmed by H NMR and 13C NMR analysis. The
3
f
4
efficient protection of the 1,3-diol as an acetal required extensive
experimentation. Treatment of (−)-5 with various reagents
under standard reaction conditions (acetone/PTSA or CuSO4,
dimethoxymethyl benzene/PTSA, dimethoxymethane/P2O5 in
CH2Cl2, dibromomethane/NaOH in DMF) gave either low
conversion or decomposition products. But the use of 2,2-
dimethoxypropane and a catalytic amount of PTSA in CH2Cl2
delivered acetonide (−)-6 in 97% yield from ketone (−)-2.
In order to achieve the ketone functionalization for gabosine J,
the acetonide (−)-6 was desilylated and the free alcohol sub-
mitted to oxidation by reaction with the Dess-Martin period-
inane. In contrast to our previous results in related compounds,
and albeit exhaustive attempts were made, we were unable to
dihydroxylate the resulting enone to the corresponding 2,3-diol.
fg
5 ,
hi
,
6
a
All reactions were performed with 0.1 M solutions of (4S,6RS)-1
b
and tBuOK in THF at −78 °C unless specified. Isolated overall
yield. Workup: aq NH4Cl. Workup: aq NaOH. LDA was used
as the base. Workup: silica gel. [(4S,6RS)-1] = 0.8 M and
[tBuOK] = 0.5 M. Workup: aq HCl. [(4S,6RS)-1] = 0.2 M and
[tBuOK] = 0.2 M.
c
d
e
f
g
h
i
Bubbling of formaldehyde (prepared in situ by cracking of
paraformaldehyde) into a solution of (4S,6RS)-1 and tBuOK in
THF at −78 °C gave a mixture of epimers (−)-2 and (−)-3 in
moderate yield (Table 1, entry 1). In order to improve this result,
B
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Table 2. Comparison of 13C NMR Data (δ) in MeOD of
(+)-14, (+)-19, and Natural Gabosine J
Consequently, we had to reconsider the sequential order of the
individual steps. Dihydroxylation of (−)-6 was easily accom-
plished under mild conditions with NMO and catalytic OsO4 in
acetone−H2O, producing a separable mixture of diols (+)-7 and
(+)-8 in 35 and 55% yield, respectively. The relative
configuration of every diol was assigned on the basis of NOE
experiments.
C1
C2
C3
C4
C5
C6
CH2
ref 1a
199.9
200.0
199.9
122.2
121.0
122.1
162.3
166.0
162.3
69.9
70.8
69.9
73.9
76.8
73.8
76.6
77.4
76.5
63.3
62.4
63.3
(+)-14
(+)-19
According to the relative configuration assigned to gabosine
J,1a the major isomer (+)-8 was the appropriate intermediate to
continue the synthesis (Scheme 4). Thus, diol (+)-8 was
With this purpose, we performed a parallel sequence starting
from diol (+)-7 that ended up with the diastereoisomeric
tetrahydroxyenone (+)-19 and was accomplished in 75% overall
yield (Scheme 5). Satisfactorily, we found a complete matching
Scheme 4. Synthesis of 4-epi-Gabosine J, (+)-14, Final Steps
Scheme 5. Synthesis of Natural Gabosine J, (+)-19, Final Steps
between the set of signals of both the 1H and 13C NMR spectra of
(+)-19 in comparison with those of natural gabosine J.1a
The final tetrahydroxyenones 14 and 19 are only soluble in
very polar solvents such as MeOH and water. In these solvents,
1
converted to the corresponding acetonide (+)-9, using the
procedure described above for the successful conversion of diol
(−)-5 into (−)-6. Subsequent removal of the silylic protection
delivered the alcohol (−)-10 in 97% yield from (+)-8.
the H NMR signals of all the protons are too close to obtain
reliable NOE data. Although epimerization of the stereogenic
centers of the intermediates 9−12 and 15−18 was never
detected, to further confirm the relative configuration of 14 and
19, we performed NOE experiments on the bisacetonides 12 and
Ketone (+)-11 was achieved in 93% yield by Dess-Martin
oxidation of (−)-10. Interestingly, we observed that long
reaction times and/or basic workup favored the production of
traces of the elimination product (+)-12. This fact prompted us
to assay the β-elimination of thiophenol, instead of the
alternative oxidation−pyrolysis protocol, in order to obtain
enone (+)-12. However, treatment of (+)-11 with DBU in
CH2Cl2 furnished a 5.3:1 mixture of (+)-12 and (+)-13,
respectively. After exhaustive study of the reaction conditions,
we discovered that by performing the reaction in a biphasic
medium (CH2Cl2−H2O), enone (+)-12 can be obtained
exclusively and in excellent yield (92%). Finally, the bisacetonide
(+)-12 was submitted to methanolysis yielding the tetrahydrox-
yenone (+)-14 with the putative structure of gabosine J.1a
However, the 1H NMR and 13C NMR spectra of (+)-14 do not
match those reported for natural gabosine J (Table 2), and
therefore, the structure assigned to the metabolite isolated from
natural sources must be corrected.
1
18 (the ultimate precursors of the final gabosines). In the H
NMR spectrum of the all cis isomer 12 in CDCl3, the signals
corresponding to the significant protons appear clearly differ-
entiated, but for the trans−cis isomer 18, it was necessary to
register the spectrum in C6D6, where the signals were better
distinguished, allowing to acquire reliable NOE data. Thus,
selective irradiation in the appropriate solvent of the signal
corresponding to H-4 shows positive NOE in the signal of H-6
for the all cis isomer 12 and no effect for the cis−trans isomer 18.
It can be hence concluded that the correct structure of the
product extracted from natural sources and named gabosine J is
that of 19. Since the specific rotation of the metabolite isolated
from Streptomyces kurssanovii (strain FH-S 1175)1a was not
described and we were unable to obtain a sample extracted from
this source, the value measured for (4R,5R,6R)-19, [α]24
=
D
+61.7 (c 1.50, MeOH), still does not permit us to establish the
absolute configuration of natural gabosine J.
C
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(dd, J = 13.9, 8.9 Hz, 1H), 1.84 (dt, J = 13.9, 2.6 Hz, 1H), 0.84 (s, 9H),
0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 206.4, 137.5,
129.4, 128.9, 128.4, 71.8, 69.1, 66.0, 56.4, 40.8, 40.0, 25.6, 17.8, −4.8,
−4.9; IR (ATR) 2953, 2928, 2856, 1472, 1252, 1119, 1101, 1065, 1003
cm−1; HRMS (ESI+) Calcd. for [C19H28O3SSi + Na+] 387.1426, found
387.1418.
(1R,4S,6R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-hydroxymethyl-
6-phenylthiocyclohex-2-enol, (−)-5. NaBH4 (51 mg, 1.35 mmol)
was added in portions to a stirred solution of enone (−)-2 (500 mg, 1.37
mmol) in MeOH (7 mL) and CH2Cl2 (7 mL) at −10 °C. After 3 h,
water (5 mL) was added to the reaction mixture, and then it was slightly
acidified by addition of 4% HCl. The organic layer was separated, and
the aqueous one was extracted with CH2Cl2 (3 × 3 mL). The combined
organic extracts were dried over MgSO4, and the solvent was removed
CONCLUSION
■
In summary, herein we have described the first and enantio-
selective total synthesis of a compound with the putative
structure of gabosine J. We have also completed the synthesis of
the natural metabolite and, hence, definitively established the
relative configuration of natural gabosine J, which is the epimer at
C4 of the originally proposed structure. It has been demonstrated
that cyclohexenone 1, which is readily prepared in multigram
scale with any desired configuration at C4, is a versatile starting
material for the synthesis of gabosines.
EXPERIMENTAL SECTION
■
under reduced pressure to furnish diol (−)-5 as a white solid (501 mg),
(4S,6R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-hydroxymethyl-
6-phenylthiocyclohex-2-enone, (−)-2. A solution of tBuOK (2.18 g,
19.4 mmol) in THF (5 mL) was slowly added to a solution of enone
(4S,6RS)-1 (5.87 g, 17.6 mmol) in THF (45 mL) at 0 °C. After stirring
for 5 min, formaldehyde (commercial 37% aqueous solution with 10−
15% MeOH, 1.5 mL, 20.1 mmol) was slowly added. The resulting
mixture was stirred for 45 min at 0 °C. Water (20 mL) was added to the
mixture, and it was slightly acidified with 4% HCl. Organics were
extracted from the mixture with CH2Cl2 (4 × 20 mL), dried over
MgSO4, and concentrated under reduced pressure. The resulting oil was
purified by flash chromatography (hexanes/AcOEt, 9:1) affording (−)-2
(5.62 g, 88%) as a yellow solid: mp 95−97 °C; [α]D20 = −122 (c 1.07,
CHCl3); Rf (hexanes/AcOEt, 5:1) 0.2; 1H NMR (400 MHz, CDCl3) δ
7.42−7.36 (m, 3H), 7.34−7.28 (m, 2H), 6.82 (dt, J = 10.3, 2.0 Hz, 1H),
5.95 (dd, J = 10.3, 2.3 Hz, 1H), 4.96 (dddd, J = 10.0, 5.4, 2.3, 2.0 Hz, 1H),
3.91 (d, J = 11.7 Hz, 1H), 3.53 (d, J = 11.7 Hz, 1H), 2.51 (dd, J = 13.9,
10.0 Hz, 1H), 2.24 (ddd, J = 13.9, 5.4, 2.0 Hz, 1H), 1.92 (br s, 1H), 0.93
(s, 9H), 0.16 (s, 3H), 0.13 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
195.0, 153.3, 137.5, 130.1, 129.1, 128.2, 127.1, 65.9, 65.7, 58.0, 40.5,
25.9, 18.2, −4.5, −4.6; IR (ATR) 3462, 2951, 2928, 2856, 1672, 1254,
1066, 1007 cm−1; HRMS (ESI+) Calcd. for [C19H28O3SSi + Na+]
387.1426, found 387.1418.
20
which was used without further purification: mp 133−136 °C; [α]D
=
1
−28 (c 1.09, CHCl3); Rf (hexanes/AcOEt, 2:1) 0.4; H NMR (400
MHz, CDCl3) δ 7.60−7.56 (m, 2H), 7.41−7.33 (m, 3H), 5.81 (m, 2H),
4.54 (m, 1H), 4.23 (s, 1H), 3.59 (d, J = 12.0 Hz, 1H), 3.44 (d, J = 12.0
Hz, 1H), 3.37−2.90 (br, 2H), 1.84 (dd, J = 14.0, 5.6 Hz, 1H), 1.61 (dd,
J = 14.0, 6.2 Hz, 1H), 0.87 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 137.2, 131.4, 129.5, 129.27, 129.25, 128.2, 70.0,
67.1, 65.5, 60.4, 35.4, 25.9, 18.1, −4.5, −4.6; IR (ATR) 3228, 2955, 2929,
2889, 2856, 1252, 1074, 1045 cm−1; HRMS (ESI+) Calcd. for
[C19H30O3SSi + Na+] 389.1583, found 389.1585.
tert-Butyl{[(4aR,6S,8aR)-2,2-dimethyl-4a-phenylthio-
4a,5,6,8a-tetrahydro-4H-1,3-benzodioxin-6-yl]oxy}dimethyl-
silane, (−)-6. A 50 mL round-bottomed flask equipped with a stir
bar was charged with (−)-5 (501 mg, 1.37 mmol), 2,2-dime-
thoxypropane (3.4 mL, 27.6 mmol), and CH2Cl2 (14 mL). The mixture
was stirred, and p-TsOH (3.1 mg, 0.016 mmol) was immediately added.
The reaction evolution was monitored by TLC (hexane/AcOEt, 2:1),
and water (6 mL) was added after all the starting material was con-
sumed. The organic layer was separated, and the aqueous one was
extracted with CH2Cl2 (3 × 4 mL). The combined organic extracts were
dried over MgSO4 and concentrated under vacuum. The product was
purified by flash chromatography (hexanes/AcOEt, 5:1), affording
(−)-6 (540 mg, 97% from (−)-2) as a white solid: mp 113−116 °C;
[α]D20 = −101 (c 1.03, CHCl3); Rf (hexanes/AcOEt, 5:1) 0.5; 1H NMR
(400 MHz, CDCl3) δ 7.63−7.59 (m, 2H), 7.37−7.31 (m, 3H), 5.73 (d,
J = 10.3 Hz, 1H), 5.65 (d, J = 10.3 Hz, 1H), 4.85 (m, 1H), 4.74 (m, 1H),
3.57 (d, J = 12.0 Hz, 1H), 3.50 (d, J = 12.0 Hz, 1H), 1.90 (ddd, J = 13.5,
6.6, 1.2 Hz, 1H), 1.59 (s, 3H), 1.49 (s, 3H), 1.44 (dd, J = 13.5, 8.8 Hz,
1H), 0.88 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 137.5, 132.2, 131.6, 129.0, 128.9, 128.2, 100.5, 73.1, 67.0
(2C), 55.3, 37.1, 29.7, 26.0, 19.6, 18.3, −4.47, −4.51; IR (ATR) 2951,
2929, 2854, 1471, 1379, 1252, 1196, 1130, 1095, 1061, 1032 cm−1;
HRMS (ESI+) Calcd. for [C22H34O3SSi + Na+] 429.1896, found
429.1894.
Diols (+)-7 and (+)-8. NMO (340 mg, 2.90 mmol) was added to a
solution of compound (−)-6 (464 mg, 1.14 mmol) in acetone (9.8 mL)
and water (1.2 mL) at room temperature. After total dissolving, OsO4
(2.5% in tBuOH, 720 μL, 0.057 mmol) was added to the reaction flask,
and the resulting mixture was stirred for 60 h. Then, aq Na2S2O3 (10%, 5
mL) was added to the reaction mixture. After 30 min stirring, the
mixture was slightly acidified by addition of 4% HCl and extracted with
CH2Cl2 (4 × 5 mL). The combined organic extracts were dried over
MgSO4, and the solvent was removed under reduced pressure.
Purification of the crude material by flash chromatography (hexanes/
AcOEt, 9:1) furnished (+)-7 (174 mg, 35%) and (+)-8 (279 mg, 55%).
(4aR,6S,7R,8S,8aR)-6-{[tert-Butyl(dimethyl)silyl]oxy}-2,2-di-
methyl-4a-phenylthiohexahydro-4H-1,3-benzodioxine-7,8-
diol, (+)-7. Data: [α]D20 = +10 (c 1.15, CHCl3); Rf (hexanes/AcOEt,
2:1) 0.2; 1H NMR (400 MHz, CDCl3) δ 7.58−7.55 (m, 2H), 7.39−7.30
(m, 3H), 4.51 (ddd, J = 9.9, 5.8, 3.1 Hz, 1H), 4.21−4.15 (m, 2H), 4.10
(d, J = 9.8 Hz, 1H), 3.56 (s, 2H), 2.61 (br s, 1H), 2.45 (br s, 1H), 1.58 (s,
3H), 1.52−1.44 (m, 2H), 1.50 (s, 3H), 0.87 (s, 9H), 0.10 (s, 3H), 0.01
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 137.6, 130.7, 129.3, 129.1,
100.9, 73.8, 73.5, 69.3, 68.0, 67.9, 51.4, 32.6, 29.7, 25.9, 19.8, 18.1,
−4.4, −4.5; IR (ATR) 3475, 2897, 2928, 2856, 1381, 1252, 1196, 1118,
During the study of this reaction, samples of ketones (−)-3 and (−)-4
were occasionally isolated.
Experimental Procedure for Entry 3 in Table 1. Triisopropyl-
amine (87 μL, 0.624 mmol) was added dropwise to a stirred solution of
n-BuLi (390 μL, 0.62 mmol) in THF (6 mL) at −10 °C. The solution
was stirred at 0 °C for 30 min and then cooled to −78 °C. Next, a
solution of enone (4S,6RS)-1 (69 mg, 0.21 mmol) in THF (2 mL) was
added dropwise, and the mixture was stirred for additional 30 min. Then,
1H-benzotriazole-1-methanol (62 mg, 0.42 mmol) in THF (4 mL) was
slowly added over a 10 min period and kept 2 h at the same temperature.
Quenching with water (10 mL) was followed by extractions with diethyl
ether (3 × 10 mL). The combined organic extracts were washed with
4 M NaOH, then dried over MgSO4, filtered, and concentrated in vacuo.
The resulting oil was purified by flash chromatography (hexanes/
AcOEt, 9:1) affording (−)-2 (39 mg, 51%), (−)-3 (5.3 mg, 7%), and
(−)-4 (23 mg, 30%).
(4S,6S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-6-hydroxymethyl-
6-phenylthiocyclohex-2-enone, (−)-3. White solid: mp 45−47 °C;
[α]D20 = −20 (c 1.01, CHCl3); Rf (hexanes/AcOEt, 5:1) 0.1; 1H NMR
(250 MHz, CDCl3) δ 7.46−7.41 (m, 2H), 7.39−7.30 (m, 3H), 6.73 (dd,
J = 10.2, 3.4 Hz, 1H), 6.01 (dd, J = 10.2, 1.4 Hz, 1H), 4.56 (dddd, J = 5.8,
5.3, 3.4, 1.4 Hz, 1H), 3.74 (d, J = 11.6 Hz, 1H), 3.59 (d, J = 11.6 Hz, 1H),
2.53 (ddd, J = 14.2, 5.3, 0.6 Hz, 1H), 2.17 (ddd, J = 14.2, 5.8, 0.6 Hz, 1H),
2.01 (br s, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 196.0, 149.5, 137.5, 129.77, 129.73, 129.0, 127.6, 65.2,
64.2, 58.4, 39.9, 25.9, 18.2, −4.51, −4.52; IR (ATR) 3421, 2953, 2928,
2856, 1672, 1471, 1254, 1101 cm−1; HRMS (ESI+) Calcd. for
[C19H28O3SSi + Na+] 387.1426, found 387.1422.
(1S,4S,7S)-7-{[tert-Butyl(dimethyl)silyl]oxy}-4-phenylthio-2-
oxabicyclo[2.2.2]octan-5-one, (−)-4. White solid: mp 53−56 °C;
[α]D20 = −10 (c 1.31, CHCl3); Rf (hexanes/AcOEt, 5:1) 0.6; 1H NMR
(360 MHz, CDCl3) δ 7.51 (m, 2H), 7.34 (m, 3H), 4.18 (m, 1H), 4.00
(m, 1H), 3.91 (dd, J = 9.4, 2.6 Hz, 1H), 3.74 (d, J = 9.4 Hz, 1H),
2.93 (dd, J = 19.5, 1.11 Hz, 1H), 2.68 (dd, J = 19.5, 3.1 Hz, 1H), 2.38
D
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1062 cm−1; HRMS (ESI+) Calcd. for [C22H36O5SSi + Na+] 463.1950,
found 463.1956.
82.5, 75.6, 73.8, 70.3, 67.6, 50.8, 35.7, 29.8, 28.4, 26.7, 19.3; IR (ATR)
3435, 2987, 2937, 2854, 1383, 1367, 1219, 1196, 1163, 1113, 1097,
1049, 1014, 1001 cm−1; HRMS (ESI+) Calcd. for [C19H26O5S + Na+]
389.1399, found 389.1403.
(4aR,6S,7S,8R,8aR)-6-{[tert-Butyl(dimethyl)silyl]oxy}-2,2-di-
methyl-4a-phenylthiohexahydro-4H-1,3-benzodioxine-7,8-
diol, (+)-8. Data: [α]D20 = +9.4 (c 1.07, CHCl3); Rf (hexanes/AcOEt,
2:1) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.63−7.60 (m, 2H), 7.40−7.31
(m, 3H), 4.38 (ddd, J = 10.8, 9.2, 4.8 Hz, 1H), 4.19 (ddd, J = 5.3, 3.4, 2.8
Hz, 1H), 3.79 (d, J = 2.8 Hz, 1H), 3.48 (s, 2H), 3.42 (ddd, J = 9.2, 6.8, 3.4
Hz, 1H), 3.20 (d, J = 5.3 Hz, 1H), 2.63 (d, J = 6.8 Hz, 1H), 1.80 (dd, J =
13.9, 4.8 Hz, 1H), 1.60 (s, 3H), 1.46 (s, 3H), 1.12 (dd, J = 13.9, 10.8 Hz,
1H), 0.86 (s, 9H), 0.15 (s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 137.6, 130.9, 129.5, 129.1, 100.6, 76.0, 74.7, 72.5, 69.5, 68.9,
52.2, 36.9, 29.6, 25.9, 19.5, 18.2, −4.17, −4.24; IR (ATR) 3446, 2928,
2854, 1381, 1248, 1119, 1065 cm−1; HRMS (ESI+) Calcd. for
[C22H36O5SSi + Na+] 463.1950, found (M + Na+) 463.1957.
The same procedure starting from acetonide (+)-15 (181 mg,
0.38 mmol) furnished (+)-16 (133 mg, 97% from (+)-7).
(3aS,4S,5aR,9aR,9bS)-2,2,8,8-Tetramethyl-5a-phenylthio-
hexahydro-3aH-[1,3]dioxolo[4,5-h][1,3]benzodioxin-4-ol,
20
(+)-16. Data: mp 98−100 °C; [α]D = +3.2 (c 1.23, CHCl3); Rf
(hexanes/AcOEt, 1:1) 0.3; 1H NMR (400 MHz, CDCl3) δ 7.59−7.55
(m, 2H), 7.40−7.31 (m, 3H), 4.66−4.58 (m, 2H), 4.37 (dd, J = 8.3, 5.5
Hz, 1H), 4.14 (d, J = 8.3 Hz, 1H), 3.58 (d, J = 12.3 Hz, 1H), 3.54 (d, J =
12.3 Hz, 1H), 2.23 (br s, 1H), 1.76 (dd, J = 14.3, 6.0 Hz, 1H), 1.56 (s,
6H), 1.49 (s, 3H), 1.42 (s, 3H), 1.38 (dd, J = 14.3, 8.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 137.8, 130.1, 129.4, 129.2, 109.5, 100.4,
76.3, 76.2, 75.5, 67.5, 65.9, 50.7, 33.8, 29.6, 28.3, 25.9, 19.3; IR (ATR)
3460, 2987, 2937, 2852, 1381, 1219, 1196, 1111, 1063, 1038 cm−1;
HRMS (ESI+) Calcd. for [C19H26O5S + Na+] 389.1399, found
389.1402.
tert-Butyl(dimethyl){[(3aS,4S,5aR,9aR,9bR)-2,2,8,8-tetra-
methyl-5a-phenylthio-hexahydro-3aH-[1,3]dioxolo[4,5-h][1,3]-
benzodioxin-4-yl]oxy}silane, (+)-9. A 25 mL round-bottomed flask
equipped with a stir bar was charged with diol (+)-8 (259 mg, 0.59
mmol), 2,2-dimethoxypropane (1.4 mL, 11.39 mmol), and CH2Cl2
(6 mL). The mixture was stirred, and p-TsOH (2.0 mg, 0.011 mmol)
was immediately added. The reaction evolution was monitored by TLC
(hexane/AcOEt, 2:1), and water (3 mL) was added after all the starting
material was consumed. The organic layer was separated, and the
aqueous one was extracted with CH2Cl2 (3 × 3 mL). The combined
organic extracts were dried over MgSO4 and concentrated under
vacuum affording (+)-9 (285 mg) as a white solid, which was used
(3aS,5aR,9aR,9bR)-2,2,8,8-Tetramethyl-5a-phenylthiotetra-
hydro-3aH-[1,3]dioxolo[4,5-h][1,3]benzodioxin-4(5H)-one,
(+)-11. Dess-Martin periodinane (15% in CH2Cl2, 1.5 mL, 0.72 mmol)
was added dropwise to a solution of alcohol (−)-10 (180 mg, 0.49
mmol) in CH2Cl2 (5 mL). The reaction mixture was stirred overnight at
room temperature. Na2S2O3 (0.1 M solution saturated with NaHCO3,
2 mL) was added, and after stirring for 1 h, the organic layer was separated,
and the aqueous one was extracted with CH2Cl2 (3 × 2 mL). The
combined organic extracts were dried over MgSO4 and concentrated
under reduced pressure. Purification of the residue by flash
chromatography (hexanes/AcOEt, 1:1) provided (+)-11 (167 mg,
93%) as a white solid: mp 161−163 °C; [α]D20 = +43 (c 1.22, CHCl3); Rf
(hexanes/AcOEt, 1:1) 0.2; 1H NMR (250 MHz, CDCl3) δ 7.67−7.61
(m, 2H), 7.38−7.29 (m, 3H), 4.73 (dd, J = 5.7, 3.5 Hz, 1H), 4.52 (d, J =
3.5 Hz, 1H), 4.38 (d, J = 5.7 Hz, 1H), 3.51 (d, J = 12.3 Hz, 1H), 3.35
(d, J = 12.3 Hz, 1H), 2.57 (d, J = 14.6 Hz, 1H), 2.19 (d, J = 14.6 Hz, 1H),
1.71 (s, 3H), 1.69 (s, 3H), 1.55 (s, 3H), 1.42 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 203.0, 138.7, 130.0, 129.6, 129.1, 113.6, 101.2, 79.7,
77.7, 72.9, 66.2, 50.7, 44.5, 29.8, 27.3, 26.4, 19.2; IR (ATR) 2987, 2935,
2883, 1728, 1383, 1254, 1223, 1196, 1157, 1111, 1066, 1024 cm−1;
HRMS (ESI+) Calcd. for [C19H24O5S + Na+] 387.1242, found
387.1235.
20
without further purification: mp 147−150 °C; [α]D = +9.0 (c 1.72,
CHCl3); Rf (hexanes/AcOEt, 2:1) 0.6; 1H NMR (400 MHz, CDCl3) δ
7.65−7.61 (m, 2H), 7.38−7.29 (m, 3H), 4.68 (ddd, J = 11.2, 6.7, 5.3 Hz,
1H), 4.36 (dd, J = 5.3, 3.4 Hz, 1H), 4.06 (d, J = 3.4 Hz, 1H), 4.00 (dd, J =
6.7, 5.3 Hz, 1H), 3.37 (d, J = 12.2 Hz, 1H), 3.30 (d, J = 12.2 Hz, 1H),
1.84 (dd, J = 13.9, 5.3 Hz, 1H), 1.71 (s, 3H), 1.67 (s, 3H), 1.46 (s, 3H),
1.39 (s, 3H), 1.15 (dd, J = 13.9, 11.2 Hz, 1H), 0.91 (s, 9H), 0.19 (s, 3H),
0.17 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 137.9, 132.0, 129.1, 128.9,
111.8, 100.9, 82.8, 75.7, 73.7, 71.0, 67.7, 50.4, 37.7, 29.9, 28.4, 26.8, 26.0,
19.3, 18.1, −4.0, −4.4; IR (ATR) 2987, 2929, 2854, 1381, 1367, 1252,
1219, 1196, 1165, 1107, 1068, 1055, 1024 cm−1; HRMS (ESI+) Calcd.
for [C25H40O5SSi + Na+] 503.2263, found 503.2257.
The same procedure starting from diol (+)-7 (163 mg, 0.37 mmol)
yielded (+)-15 (181 mg) as a white solid, which was also used without
further purification.
The same procedure starting from alcohol (+)-16 (117 mg, 0.32
mmol) yielded ketone (+)-17 (108 mg, 92%).
tert-Butyl(dimethyl){[(3aR,4S,5aR,9aR,9bS)-2,2,8,8-tetra-
methyl-5a-phenylthio-hexahydro-3aH-[1,3]dioxolo[4,5-h][1,3]-
20
(3aR,5aR,9aR,9bS)-2,2,8,8-Tetramethyl-5a-phenylthiotetra-
hydro-3aH-[1,3]dioxolo[4,5-h][1,3]benzodioxin-4(5H)-one,
benzodioxin-4-yl]oxy}silane, (+)-15. Data: mp 104−107 °C; [α]D
=
1
+16° (c 1.75, CHCl3); Rf (hexanes/AcOEt, 2:1) 0.7; H NMR (400
MHz, CDCl3) δ 7.58−7.53 (m, 2H), 7.39−7.30 (m, 3H), 4.70 (ddd, J =
9.8, 5.4, 4.6 Hz, 1H), 4.41 (t, J = 4.6 Hz, 1H), 4.30 (dd, J = 8.5, 4.6 Hz,
1H), 4.11 (d, J = 8.5 Hz, 1H), 3.62 (d, J = 12.2 Hz, 1H), 3.56 (d, J = 12.2
Hz, 1H), 1.60−1.49 (m, 2H), 1.54 (s, 3H), 1.51 (s, 3H), 1.47 (s, 3H),
1.38 (s, 3H), 0.89 (s, 9H), 0.11 (s, 3H), 0.06 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 137.1, 130.3, 129.0, 128.8, 109.0, 100.2, 77.0, 75.9, 75.2,
67.7, 66.4, 50.9, 33.7, 29.3, 28.4, 25.8, 25.7, 18.9, 18.0, −4.6, −4.7; IR
(ATR) 2987, 2929, 2856, 1381, 1250, 1219, 1124, 1047 cm−1; HRMS
(ESI+) Calcd. for [C25H40O5SSi + Na+] 503.2263, found 503.2251.
(3aR,4S,5aR,9aR,9bR)-2,2,8,8-Tetramethyl-5a-phenylthio-
hexahydro-3aH-[1,3]dioxolo[4,5-h][1,3]benzodioxin-4-ol,
(−)-10. To a solution of compound (−)-9 (285 mg, 0.59 mmol) in THF
(6 mL), TBAF (1 M in THF, 650 μL, 0.65 mmol) was added. The
reaction mixture was stirred at 60 °C until total conversion of the
starting material (monitored by TLC, hexanes/AcOEt, 1:1). The
solvent was removed under vacuum, and the product was purified by
flash chromatography (hexanes/AcOEt, 2:1) to provide alcohol (−)-10
20
(+)-17. Data: mp 123−125 °C; [α]D = +95 (c 1.22, CHCl3) Rf
(hexanes/AcOEt, 1:1) 0.6; 1H NMR (250 MHz, CDCl3) δ 7.55−7.50
(m, 2H), 7.42−7.32 (m, 3H), 4.88 (d, J = 7.5 Hz, 1H), 4.73 (t, J = 7.5 Hz,
1H), 4.14 (d, J = 7.5 Hz, 1H), 3.61 (d, J = 12.6 Hz, 1H), 3.54 (d, J = 12.6
Hz, 1H), 2.44 (d, J = 17.7 Hz, 1H), 2.22 (d, J = 17.7 Hz, 1H), 1.61 (s,
3H), 1.54 (s, 6H), 1.42 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 202.3,
138.3, 130.1, 129.5, 128.3, 111.6, 100.5, 78.2, 78.0, 76.8, 65.7, 49.4, 43.3,
29.5, 27.5, 25.3, 19.2; IR (ATR) 2987, 2937, 1728, 1682, 1373, 1217,
1196, 1159, 1105, 1061, 1010 cm−1; HRMS (ESI+) Calcd. for
[C19H24O5S + Na+] 387.1242, found 387.1232.
(3aS,9aS,9bS)-2,2,8,8-Tetramethyl-9a,9b-dihydro-3aH-[1,3]-
dioxolo[4,5-h][1,3]benzodioxin-4(6H)-one (+)-12. Ketone (+)-11
(122 mg, 0.33 mmol) was treated with DBU (10% in CH2Cl2, 0.5 mL,
0.33 mmol) in a biphasic system CH2Cl2 (7 mL)/water (7 mL) at room
temperature. Then, DBU was added (1 equiv every 2 h) until total
consumption of the starting material (monitored by TLC). After 9 h of
reaction, the mixture was slightly acidified with 4% HCl, the organic
layer was separated, and the aqueous one was extracted with CH2Cl2
(3 × 5 mL). The combined organic extracts were dried over MgSO4 and
concentrated under reduced pressure. The crude product was purified
by flash chromatography (hexanes/Et2O, 1:1) affording enone (+)-12
(78 mg, 92%) as a white solid: mp 102−105 °C; [α]D20 = +129 (c 1.73,
20
(211 mg, 97% from (+)-8): mp 178−180 °C; [α]D = −19 (c 1.12,
CHCl3); Rf (hexanes/AcOEt, 1:1) 0.1; 1H NMR (400 MHz, CDCl3) δ
7.66−7.60 (m, 2H), 7.40−7.27 (m, 3H), 4.81 (ddd, J = 11.9, 7.3, 5.0 Hz,
1H), 4.39 (dd, J = 5.2, 3.5 Hz, 1H), 4.05 (d, J = 3.5 Hz, 1H), 4.02 (dd, J =
7.3, 5.2 Hz, 1H), 3.39 (d, J = 12.2 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H),
2.76 (br s, 1H), 1.91 (dd, J = 13.7, 5.0 Hz, 1H), 1.72 (s, 3H), 1.67 (s,
3H), 1.47 (s, 3H), 1.41 (s, 3H), 1.12 (dd, J = 13.7, 11.9 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 138.0, 131.5, 129.2, 128.9, 112.3, 100.9,
1
CHCl3); Rf (hexanes/Et2O, 1:9) 0.4; H NMR (400 MHz, CDCl3) δ
5.83 (td, J = 1.9, 1.9, 1.3 Hz, 1H), 4.84 (dddd, J = 4.3, 2.4, 1.9, 1.3 Hz,
1H), 4.71 (t, J = 4.3 Hz, 1H), 4.53 (ddd, J = 16.6, 2.4, 1.9 Hz, 1H), 4.40
E
dx.doi.org/10.1021/jo300456q | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(dt, J = 16.6, 1.3 Hz,1H), 4.30 (d, J = 4.3 Hz, 1H), 1.50 (s, 3H), 1.48 (s,
3H), 1.40 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.5,
159.9, 119.8, 111.6, 101.6, 76.3, 75.0, 65.6, 61.7, 27.6, 26.3, 24.9, 23.2; IR
(ATR) 2987, 2937, 2897, 1680, 1381, 1219, 1173, 1157, 1090, 1063,
1030 cm−1; HRMS (ESI+) Calcd. for [C13H18O5 + Na+] 277.1052,
found 277.1046.
Dr. Gladis Toribio for performing some preliminary experiments
on the hydroxymethylation reaction.
REFERENCES
■
(1) (a) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hammann, P.;
Huetter, K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann.
Chem. 1993, 241−250. (b) Tang, Y.-Q.; Maul, C.; Hofs, R.; Sattler, I.;
Grabley, S.; Feng, X.-Z.; Zeeck, A.; Thiericke, R. Eur. J. Org. Chem. 2000,
149−153.
(2) Tatsua, K.; Tsushiya, T.; Mikami, N.; Umezawa, S.; Umezawa, H.;
Naganawa, H. J. Antibiot. 1974, 27, 579−586.
(3) Takeuchi, T.; Chimura, H.; Hamada, M.; Umezawa, H.; Yoshioka,
O.; Oguchi, N.; Takahashi, Y.; Matsuda, A. J. Antibiot. 1975, 28, 737−
742.
Analytical samples for the characterization of enone (+)-13 were
isolated through the study of this reaction.
(3aS,9bR)-2,2,8,8-Tetramethyl-6,9b-dihydro-3aH-[1,3]-
20
dioxolo[4,5-h][1,3]benzodioxin-4(5H)-one, (+)-13. Oil: [α]D
=
+34 (c 1.48, CHCl3); Rf (hexanes/AcOEt, 2:1) 0.3; 1H NMR (400 MHz,
CDCl3) δ 4.82 (d, J = 6.5 Hz, 1H), 4.56 (d, J = 6.5 Hz, 1H), 4.11 (d, J =
15.8 Hz, 1H), 4.04 (d, J = 15.8 Hz, 1H), 2.91 (s, 2H), 1.50 (s, 9H), 1.42
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.6, 140.5, 112.1, 104.0,
100.1, 78.5, 76.9, 61.0, 36.3, 27.6, 26.2, 25.8, 23.0; IR (ATR) 2991, 2939,
1738, 1703, 1373, 1238, 1159, 1119, 1082, 1016 cm−1; HRMS (ESI+)
Calcd. for [C13H18O5 + MeOH + Na+] 309.1314, found 309.1312.
The same procedure starting from ketone (+)-17 (91 mg, 0.25 mmol)
yielded ketone (+)-18 (59 mg, 92%) as a single compound.
(4) Maier, A.; Maul, C.; Zerlin, M.; Grabley, S.; Thiericke, R. J. Antibiot.
1999, 52, 952−959.
(5) (a) Mehta, G.; Mohal, N.; Lakshminath, S. Tetrahedron Lett. 2000,
41, 3505−3508. (b) Mehta, G.; Lakshminath, S. Tetrahedron Lett. 2000,
41, 3509−3512. (c) Takahashi, T.; Yamakoshi, Y.; Okayama, K.;
Yamada, J.; Ge, W.-Y.; Koizumi, T. Heterocycles 2002, 56, 209−220.
(6) (a) Banwell, M. G.; Bray, A. M.; Wong, D. J. New J. Chem. 2001, 25,
1351−1354. (b) Arthurs, C. L.; Raftery, J.; Whitby, H. L.; Whitehead, R.
C.; Wind, N. S.; Stratford, I. J. Bioorg. Med. Chem. Lett. 2007, 17, 5974−
5977.
(3aR,9aS,9bR)-2,2,8,8-Tetramethyl-9a,9b-dihydro-3aH-[1,3]-
20
dioxolo[4,5-h][1,3]benzodioxin-4(6H)-one (+)-18. Oil: [α]D
=
1
+131 (c 1.48, CHCl3); Rf (hexanes/AcOEt, 2:1) 0.4; H NMR (400
MHz, CDCl3) δ 5.88 (q, J = 1.5 Hz, 1H), 4.58 (m, 1H), 4.51 (dt, J = 16.1,
1.5 Hz, 1H), 4.50−4.47 (m, 2H), 4.44 (ddd, J = 16.1, 1.9, 1.5 Hz, 1H),
1.52 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H), 1.42 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 191.8, 157.7, 120.9, 110.9, 101.0, 77.8, 75.0, 69.5, 62.0,
27.4, 26.0, 25.5, 22.1; IR (ATR) 2989, 2939, 1684, 1383, 1219, 1163,
1086, 1072, 852, 781, 631 cm−1; HRMS (ESI+) Calcd. for [C13H18O5 +
Na+] 277.1052, found 277.1045.
(7) (a) Mirza, S.; Molleyres, L. P.; Vasella, A. Helv. Chim. Acta 1985, 68,
988−996. (b) Lygo, B.; Swiatyj, M.; Trabsa, H.; Voyle, M. Tetrahedron
Lett. 1994, 35, 4197−4200. (c) Lubineau, A.; Billault, I. J. Org. Chem.
1998, 63, 5668−5671. (d) Tatsuta, K.; Yasuda, S.; Araki, N.; Takahashi,
M.; Kamiya, Y. Tetrahedron Lett. 1998, 39, 401−402. (e) Ramana, G. V.;
Rao, B. V. Tetrahedron Lett. 2005, 46, 3049−3051. (f) Shing, T. K. M.;
Cheng, H. M. J. Org. Chem. 2007, 72, 6610−6613. (g) Monrad, R. N.;
Fanefjord, M.; Hansen, F. G.; Jensen, N. M. E.; Madsen, R. Eur. J. Org.
Chem. 2009, 396−402. (h) Shing, T. K. M.; So, K. H.; Kwok, W. S. Org.
Lett. 2009, 11, 5070−5073. (i) Stathakis, C. I.; Athanatou, M. N.; Gallos,
J. K. Tetrahedron Lett. 2009, 50, 6916−6918. (j) Rao, J. P.; Rao, B. V.
Tetrahedron: Asymmetry 2010, 21, 930−935.
(+)-4-epi-Gabosine J, (+)-14. To a stirred solution of compound
(+)-12 (50 mg, 0.20 mmol) in MeOH (2 mL), a drop of water and TFA
(53 μL, 0.69 mmol) were successively added. After stirring for 3 h, the
solvent was removed under reduced pressure. The oily residue was
purified by flash chromatography (CHCl3/MeOH, 9:1) to furnish
(+)-4-epi-gabosine J, (+)-14, (31.5 mg, 92%) as a white crystalline solid:
20
mp 166−169 °C; [α]D = +82 (c 0.76, MeOH); Rf (CHCl3/MeOH,
9:1) 0.1; 1H NMR (400 MHz, CD3OD) δ 6.14 (q, J = 2.0 Hz, 1H), 4.67
(dtd, J = 3.1, 2.0, 1.2 Hz, 1H), 4.48 (ddd, J = 18.2, 2.0, 1.2 Hz, 1H), 4.34
(dd, J = 3.1, 2.6 Hz, 1H) 4.28 (dt, J = 18.2, 2.0 Hz, 1H), 4.26 (d, J = 2.6
Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 200.0, 166.0, 121.0, 77.4,
76.8, 70.8, 62.4; IR (ATR) 3273, 2916, 2850, 1680, 1479, 1439, 1410,
1342, 1223, 1209, 1157, 1117, 1047 cm−1; HRMS (ESI+) Calcd. for
[C7H10O5 + Na+] 197.0426, found 197.0420.
(8) (a) Shing, T. K. M.; Tang, Y. J. Chem. Soc., Chem. Commun. 1990,
312−313. (b) Shing, T. K. M.; Tang, Y. Tetrahedron 1990, 46, 6575−
6584. (c) Huntley, C. F. M.; Wood, H. B.; Ganem, B. Tetrahedron Lett.
2000, 41, 2031−2034. (d) Shinada, T.; Fuji, T.; Ohtani, Y.; Yoshida, Y.;
Ohfune, Y. Synlett 2002, 1341−1343.
(9) (a) Carreno, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.;
̃
The same procedure starting from enone (+)-18 (30 mg, 0.12 mmol)
yielded gabosine J, (+)-19, (19 mg, 94%).
Urbano, A. Org. Lett. 2005, 7, 1419−1422. (b) Alibes
́ ́
, R.; Bayon, P.; de
March, P.; Figueredo, M.; Font, J.; Marjanet, G. Org. Lett. 2006, 8,
20
(+)-Gabosine J, (+)-19. Data: mp 113−115 °C; [α]D = +62 (c
1617−1620. (c) Carreno, M. C.; Merino, E.; Ribagorda, M.; Somoza, A.;
̃
1
1.50, MeOH); Rf (CHCl3/MeOH, 9:1) 0.1; H NMR (250 MHz,
Urbano, A. Chem.Eur. J. 2007, 13, 1064−1077. (d) Toribio, G.;
CD3OD) δ 6.10 (t, J = 1.9 Hz, 1H), 4.56 (d, J = 2.5 Hz, 1H), 4.41 (dd, J =
17.8, 1.9 Hz, 1H), 4.22 (dd, J = 17.8, 1.9 Hz, 1H), 4.21−4.16 (m, 2H);
13C NMR (63 MHz, CD3OD) δ 199.9, 162.3, 122.1, 76.5, 73.8, 69.9,
63.3; IR (ATR) 3294, 2914, 1676, 1437, 1205, 1117, 1088, 1041 cm−1;
HRMS (ESI+) Calcd. for [C7H10O5 + Na+] 197.0426, found 197.0421.
́ ́
Marjanet, G.; Alibes, R.; de March, P.; Font, J.; Bayon, P.; Figueredo, M.
Eur. J. Org. Chem. 2011, 1534−1543.
(10) Prasad, K. R.; Kumar, S. M. Synlett 2011, 11, 1602−1604.
(11) Bayon, P.; Marjanet, G.; Toribio, G.; Alibes, R.; de March, P.;
́
́
Figueredo, M.; Font, J. J. Org. Chem. 2008, 73, 3486−3491.
ASSOCIATED CONTENT
* Supporting Information
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Spectral data and copies of NMR spectra for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: marta.figueredo@uab.es; pau.bayon@uab.es.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge financial support from Direccion
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General de
Investigacion
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(Project CTQ2010-15380). We are grateful to
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dx.doi.org/10.1021/jo300456q | J. Org. Chem. XXXX, XXX, XXX−XXX