Lipase-catalyzed resolution of 5-acetoxy-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene. Application to the synthesis of (+)-(3R,4S)-cis-4-hydroxy-6-deoxyscytalone, a metabolite isolated from Colletotrichum acutatum

Article abstract of DOI:10.1016/j.tet.2009.02.054

(+)-cis-4-Hydroxy-6-deoxyscytalone, a natural product bio-synthesized by Colletotrichum sp., has been prepared and its absolute configuration confirmed as 3R,4S, the key step being a kinetic racemic resolution of a cis-diol easily obtained from commercial 1,2,3,4-tetrahydronaphthalen-1,5-diol. Four lipases and different reaction conditions were tested in order to obtain the best yield and enantiomeric excess. Confirmation of absolute configuration was made by NMR using a single-derivatization low-temperature procedure and MPA as the auxiliary reagent.

Full text of DOI:10.1016/j.tet.2009.02.054

Tetrahedron 65 (2009) 3392–3396
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Lipase-catalyzed resolution of 5-acetoxy-1,2-dihydroxy-1,2,3,4-
tetrahydronaphthalene. Application to the synthesis of (þ)-(3R,4S)-cis-4-
hydroxy-6-deoxyscytalone, a metabolite isolated from Colletotrichum acutatum
*
´
´
´
Daniel Jimenez-Teja, Mourad Daoubi, Isidro G. Collado, Rosario Hernandez-Galan
´
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias, UCA, Polıgono Rio San Pedro s/n, 11510 Puerto Real, Cadiz, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
(þ)-cis-4-Hydroxy-6-deoxyscytalone, a natural product bio-synthesized by Colletotrichum sp., has been
prepared and its absolute configuration confirmed as 3R,4S, the key step being a kinetic racemic reso-
lution of a cis-diol easily obtained from commercial 1,2,3,4-tetrahydronaphthalen-1,5-diol. Four lipases
and different reaction conditions were tested in order to obtain the best yield and enantiomeric excess.
Confirmation of absolute configuration was made by NMR using a single-derivatization low-temperature
procedure and MPA as the auxiliary reagent.
Received 5 November 2008
Received in revised form 20 February 2009
Accepted 20 February 2009
Available online 27 February 2009
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
4-Hydroxy-6-deoxyscytalone
Trihydroxytetralone
Kinetic resolution
Biocatalysis
Absolute configuration
Colletotrichum acutatum
1. Introduction
deoxyscytalone (1) was isolated.9 This metabolite, also named 3,
4-dihydro-3,4,8-trihydroxy-1(2H)-naphthalenone and cis-3,4,8-
The phytopathogen genus Colletotrichum (teleomorph Glomer-
ella), is an important post-harvest pathogen. This is a widespread
pathogen that causes anthracnose disease. Colletotrichum can affect
a wide variety of tropical and subtropical plants such as avocado,
strawberry, tomato, cereals, legumes, vegetables, etc. The fungi not
only affect plants, but also stored fruit and plant materials. The
symptoms of anthracnose are stunted growth and chlorosis and the
appearance of dark and necrotic spots and yellow-orange masses of
spores on plant tissue. The fungi affect leaves, petioles, crowns, rots,
flowers, blight, fruits, and buds, ultimately killing the plant.1 This
pathogen can be found in many areas around the whole world.
Colletotrichum is the cause of important losses in France,2 Australia,
southern Europe, Spain,3 Norway,4 and Finland5 and C. acutatum
has also been detected in Israel6 and California.7 Moreover legal
issues are involved as Colletotrichum acutatum is a quarantine
organism on strawberries in the EU (EC Directive 77/93).
trihydroxytetralone, is a phytotoxic substance, which was first
isolated from Pyricularia oryzae by Iwasaki et al. in 1972.10,11 This
substance stunts the growth of rice seedlings at high concentra-
tions but can also stimulate the growth of seedlings at low con-
centrations after 24 h. 3,4,8-Trihydroxytetralone was also isolated
from Ceratocystis fimbriata coffe12 in 1996 and Fusidium sp.13 in
´
2002 and from endophytic Colletotrichum gloeosporioides by Inacio
et al. in 2006.14 The antifungal activity displayed by 1 was similar
to that exhibited by the positive control nystatin.14
4-Hydroxy-6-deoxyscytalone is an important melanin bio-
synthetic intermediate in fungi. Several studies involving melanin-
deficient mutants and inhibitors (i.e., tricyclazole) have shown that
melanin plays an important role in fungi virulence.15 Melanin-de-
ficient mutant strains were less aggressive than their wild
counterparts.
The configuration of (þ)-1 was proposed as 3R,4S by comparing
the rotation sign with those of (þ)-isosclerone whose configuration
was assigned as S by interpretation of the optical rotatory disper-
sion of isosclerone dibenzoate.16 However, the validity of that as-
signment has been called into question even by its own authors.13
The great deal of confusion found in the bibliography about the
stereochemistry of 1 where we found (ꢀ)-cis-4-hydroxy-6-deoxy-
scytalone represented as 3R,4S14 prompted us to address the
problem of obtaining it from an easily available compound. In this
Colletotrichum species produce phytotoxic metabolites, which
induce symptoms similar to those of the pathogens themselves.8
In the course of our search for bioactive compounds from the
phytopathogen fungus C. acutatum, the metabolite 4-hydroxy-6-
* Corresponding author. Tel.: þ34 956 016371; fax: þ34 956 016193.
´
´
E-mail address: rosario.hernandez@uca.es (R. Hernandez-Galan).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.054

D. Jime´nez-Teja et al. / Tetrahedron 65 (2009) 3392–3396
3393
OAc
5
OH
8
O
4
1
6
7
7
6
1
4
3
2
2
3
OH
OR
OAc
OH
b,e,f
b,e,f
OH
OH
8
5
a, (b,) c
d
6
1a
OH
+
OH
O
OAc
OH
OH
OH
OH
3 R=H
4 R=Ac
2
4b
1b
OH
OH
Scheme 1. Synthetic route to (þ)- and (ꢀ)-cis-4-hydroxy-6-deoxyscytalone. (a) Benzene–TsOH,
D
; (b) Ac2O–Py; (c) OsO4–NMO–tBuO2H–H2O–Py, 110 ꢂC; (d) vinyl acetate–TBME–
PSL; (e) CrO3–Py; (f) K2CO3–MeOH.
article we report on its preparation using a biocatalytic racemic
resolution of a cis-diol, easily obtained from a commercial 1,2,3,4-
tetrahydronaphthalen-1,5-diol and the confirmation of its absolute
configuration by NMR.
Table 1
Results of lipase mediated acetylation at room temperature for 48 h
Sub Lipase Products
Residual alcohol
E
6
5
ee (%) Yielda (%) ee (%) Yielda (%) ee (%) Yielda (%)
2. Results and discussion
4
3
CRL
AK
PSL
44
11
15
32
1
36
19
95
70
20
34
37
3.4b
6.2
Our initial approach to the preparation of 1 was based on the
synthetic route shown in Scheme 1. (ꢁ)-cis-1,2,5-Trihydroxy-
1,2,3,4-tetrahydronaphthalene (3) and (ꢁ)-cis-5-acetoxy-1,2-dihy-
droxy-1,2,3,4-tetrahydronaphthalene (4) were prepared from
commercially available 1,2,3,4-tetrahydronaphthalene-1,5-diol (2),
by elimination of the hydroxyl group using p-TsOH, acetylation
(only for the synthesis of 4) and then dihydroxylation under stan-
dard conditions (catalytic OsO4–NMO). The lipase mediated kinetic
resolution of 3 and 4 was then studied by testing different lipases,
substrates, and reaction conditions.
100
19
>400
6
8
CRL
AK
PSL
44
89
>99
11
8
12
57
53
39
15
23
48
4.8
93
>99
7
6
30b
81.7b
a
Isolated yield.
Calculated considering ee of compound 6 as eep.
b
PSL. Also, mono-acetylated and fully acetylated compounds 8 and 7
were obtained with AK and PSL.
Based on the best value of selectivity obtained (E>400), we
chose 4 as the starting material and lipase PS to carry out a reaction
conditions’ study with the aim of attaining the best yield with the
highest enantioselectivity possible.
Four lipases: PS (PSL) and AK Amano, Candida rugosa (CRL) and
porcine pancreas lipases (PPL), and two different substrates 3 and 4
were tested (Scheme 2).
Temperature, time, and the effect of tert-butylmethyl ether
(TBME) as a solvent on the enantiomeric excesses and conversion
were evaluated. The reaction was carried out at room temperature
(rt) and at 48 ꢂC, which is the optimum reaction temperature for
PSL, and with and without TBME for 72 h. The results shown in
Table 2 indicate that temperature accelerates the kinetics of
enzymes yielding di- and triacetylated compound in excellent ee.
In view of the results shown in Tables 1 and 2, the best enan-
tiomeric excess was obtained under the initial conditions but in
a poor yield. So we used initial conditions to obtain enantiomeri-
cally pure 6 and 8 in order to determine its absolute configuration
and chose 48 ꢂC, 72 h, and TBME as the best conditions for
continuing the synthetic route. Under these conditions we obtained
di- and triacetylated compounds with an overall yield of 46% and
excellent enantiomeric excess and recovered starting material
enriched in 95% ee.
OR
OR3
AcO
OH
OR2
Lipase
OR1
OH
3 R=H
4 R=Ac
5 R1=R3=Ac, R2=H
6 R1=H, R2= R3=Ac
6a R1=(R)-MPA, R2= R3=Ac
6b R1=(S)-MPA, R2= R3=Ac
7 R1=R2=R3=Ac
8 R1=R3=H, R2=Ac
8a R1=(R)-MPA, R2=Ac, R3=H
Scheme 2. Kinetic resolution of 3 and 4.
PPL was rejected as a possible catalyst due to the slow conver-
sion observed. Results obtained with the other three enzymes are
shown in Table 1. Enantiomeric excess (ee) were measured by HPLC
fitted with a chiral column.
The best results were obtained with PSL, which was highly se-
lective under the initial testing conditions. Different results were
obtained depending on the substrate and the lipase used. CRL was
not completely regioselective on substrate 4 leading to compounds
5 and 6 in low yields while lipases AK and PS showed different
regioselectivity yielding 5 and 6, respectively. Although the yield
obtained using PSL was lower than that obtained with lipase AK,
stereoselectivity was significantly better.
In accordance with the Kazlauskas empirical rule for secondary
alcohols,17 1S,2R-6 and 7 along with unreacted alcohol 4 highly
enriched in enantiomer 1R,2S should be obtained. All attempts to
Table 2
Results of PSL-mediated acetylation of diol 4 for 72 h
Residual alcohol
6
7
ee
(%)
Yielda
(%)
ee Yielda E1
(%) (%)
ee
(%)
Yielda E2
(%)
Similar behavior was observed with the three enzymes starting
from triol 3. The same regioselectivity was observed in all cases
yielding in majority the product of acetylation in both the phenol
and the hydroxyl group on C-2 position ranging from low enan-
tioselectivities (44%) when CRL was used to very high (99.96%) with
rt, TBME
84
95
38
30
37
47
35
98 29
91 38
87 39
70 33
>400
90.5 >99
1.9
16.3 99
d
d
48 ꢂC, TBME
rt, solvent free
8
d
>400
>400
d
48 ꢂC, solvent free 88
11
a
Isolated yield.

3394
D. Jime´nez-Teja et al. / Tetrahedron 65 (2009) 3392–3396
assign the absolute configuration of compound 6 were unsuccess-
ful. Treatment of 6 with R (ꢀ) and S (þ)-MPA led to the securing of
the corresponding R and S-MPA esters 6a and 6b, respectively. 1H
NMR spectra of both compounds were compared but the signals of
neighboring protons to the ester group in the diastereoisomeric
derivatives were too close to be distinguished (small DdRS) and we
therefore decided to use the single-derivatization low-temperature
procedure.18 The NMR spectrum of 6a was recorded at ꢀ70 ꢂC and
compared with that recorded at 25 ꢂC but the signals were again to
close to be distinguished. Confirmation of absolute configuration
was finally made using single-derivatization low-temperature
procedure on compound 8. Compound 8 was treated with R
(ꢀ)-MPA leading to the corresponding R-MPA ester 8a. Comparison
of the chemical shifts in 1H NMR spectra taken both at 25 ꢂC and at
ꢀ70 ꢂC showed that DdT1T2 value for H2, H-3a, and H-3b was 0.08,
0.11, and 0.09 ppm, respectively, while the DdT1T2 for H-7 and H8
was ꢀ0.08 and ꢀ0.06 ppm. Application of Riguera’s rule18 showed
a 1S,2R configuration for esterified product 8a and hence for
compound 8. This stereochemistry coincides with that predicted by
the Kazlauskas’ rule for transesterification reactions catalyzed by
lipases.
(187.5 mL). The mixture was stirred for 12 h at room temperature
under nitrogen atmosphere. The mixture was then washed with
distilled water. The organic layer was dried over anhydrous Na2SO4
and concentrated in a rotary evaporator. The residue was purified by
column chromatography using EtOAC–hexane (30%) as an eluent to
give 7,8-dihydronaphthalen-1-ol in 82.82% yield. IR (film): nmax
;
3390.18, 1574.03, 1463.49, 1279.80, 808.17 cmꢀ1 1H NMR (CDCl3,
400 MHz)
d
(ppm): 2.17 (2H, m), 2.67 (2H, t, J¼8.3 Hz), 5.86 (1H, m),
6.28 (1H, ddd, J¼1.6, 3.3, 9.5 Hz), 6.46 (1H, d, J¼7.4 Hz), 6.58 (1H, d,
J¼7.9 Hz), 6.84 (1H, t, J¼8.2 Hz), 7.15 (1H, s, OH); 13C NMR (CDCl3,
100 MHz) d (ppm): 19.5 (1C, t), 22.5 (1C, t),114.5 (1C, d), 118.9 (1C, d),
120.6 (1C, s), 126.7 (1C, d), 127.6 (1C, d), 128.5 (1C, d), 135.3 (1C, s),
152.2 (1C, s); EIMS m/z: 146 (Mþ, 73), 144 (100), 126 (90), 115 (85).
4.1.2. 1-Acetoxy-7,8-dihydronaphthalene
7,8-Dihydronaphthalen-1-ol (86.2 mg, 0.59 mmol) and acetic
anhydride (60 mg, 0.59 mmol, 55
mL) were dissolved in dry pyri-
dine (330 L) and the mixture was stirred for 26 h at room tem-
m
perature. The excess of acetic anhydride was then eliminated with
cyclohexane and acetone and evaporated in a rotary evaporator.
The residue was purified by column chromatography using EtOAC–
hexane (10%) as an eluent to give 1-acetoxy-7,8-dihydronaph-
thalene in 89.83% yield. IR (film): nmax 2929.78, 1763.94,
Compound 6 and residual alcohol 4, highly enriched in enan-
tiomer 1R,2S, were acetylated under standard conditions (Ac2O, Py).
Triacetylated compounds were oxidized in position 1 with CrO3 and
acetic acid. Deprotection with K2CO3 and ethanol gave a very poor
yield, leading to the two enantiomers of cis-4-hydroxy-6-deoxy-
scytalone. Comparison of specific rotations of natural and synthetic
triacetylated derivative of 1 allows us to confirm the absolute con-
figuration for (þ)-cis-4-hydroxy-6-deoxyscytalone as 3R,4S.
1206.90 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d (ppm): 2.30 (3H, s), 2.30
(2H, m), 2.65 (2H, t, J¼8.2 Hz), 6.05 (1H, dt, J¼4.7, 9.7 Hz), 6.48 (1H,
d, J¼9.7 Hz), 6.88 (1H, dd, J¼1.2, 8.2 Hz), 6.92 (1H, d, J¼7.4 Hz), 7.15
(1H, dd, J¼7.4, 8.2 Hz); 13C NMR (CDCl3,100 MHz)
d (ppm): 20.5 (1C,
t), 20.6 (1C, q), 22.2 (1C, t), 120.5 (1C, d), 123.7 (1C, d), 126.7 (1C, d),
126.9 (1C, s), 127.2 (1C, d), 128.9 (1C, d), 135.6 (1C, s), 147.7 (1C, s),
169.1 (1C, s); EIMS m/z: 164 (Mþ, 78), 122 (85), 43 (100).
3. Conclusions
4.1.3. (ꢁ)-cis-5-Acetoxy-1,2-dihydroxy-1,2,3,4-
tetrahydronaphthalene (4)
Preparation of enantiomerically pure (þ) and (ꢀ)-cis-4-hy-
droxy-6-deoxyscytalone allowed us to confirm the absolute stereo-
chemistry of (þ)-cis-4-hydroxy-6-deoxyscytalone proposed by
Krohn et al.13 for natural product obtained from Colletotrichum sp.
The absolute stereochemistry was established via the trans-
esterification kinetic resolution of racemic diol (ꢁ)-4 and con-
firmed by NMR using a single-derivatization low-temperature
procedure. The optimal conditions for kinetic racemic resolution
have been established.
1-Acetoxy-7,8-dihydronaphthalene (100.6 mg, 0.53 mmol), tri-
methylamine-N-oxide (82.35 mg, 0.74 mmol), pyridine (100
and osmium tetroxide 2.5 wt % solution in 2-methyl-2-propanol
(45
L) were dissolved in H2O–tBuOH 1:1 (2 mL) in a 5 mL flask.
mL),
m
The mixture was refluxed at 100 ꢂC and stirred for 48 h. The
mixture was then diluted with 10 mL of 10% NaHSO3 and stirred at
room temperature for 1 h. The crude was extracted with AcOEt
and the organic layers were dried over anhydrous Na2SO4 and
concentrated in a rotary evaporator. The residue was purified by
column chromatography using AcOEt–hexane (30%) as an eluent
to give (ꢁ)-4 in 51.84% yield. IR (film): nmax 3385.6, 2936.8, 1735.5,
4. Experimental section
4.1. General
1215.13 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d (ppm): 1.89 (1H, m),
2.00 (1H, m), 2.30 (3H, s), 2.52 (1H, ddd, J¼17.5, 8.8, 6.5 Hz), 2.79
(1H, dt, J¼17.5, 5.8 Hz), 3.98 (1H, dt, J¼9.8, 3.7 Hz), 4.67 (1H, d,
J¼3.7 Hz), 6.96 (1H, dd, J¼1.4, 8.0 Hz), 7.25 (1H, t, J¼7.8 Hz), 7.36
IR spectra were recorded on a Perkin–Elmer FT-IR System
Spectrum BX spectrophotometer. 1H and 13C NMR spectra were
taken with an Inova-400 MHz instrument and mass spectra were
determined with a Voyager (Termoquest) spectrometer. Air sensi-
tive reactions were run under an argon atmosphere. Solvents were
distilled by normal methods (THF was dried over sodium–benzo-
phenone, CH2Cl2 was dried over CaCl2). TLC was performed on
Merck Kieselgel 60 F254, 0.2 mm thick Silica gel 60PF254 (60–100
mesh, Merck) was used for column chromatography. HPLC was
performed with a Hitachi/Merck L-6270 apparatus equipped with
a UV–vis detector (L 4250) and a differential refractometer detector
(RI-71) using a silica gel column (Hibar 60, 7 m, 1 cm wide, 25 cm
long). Chemical products were obtained from Fluka or Aldrich. All
solvents used were freshly distilled. Enantiomeric excesses were
determined by means of HPLC analyses on a chiral column
(Chiralcel OD, Daicel, Japan).
(1H, d, J¼7.8 Hz); 13C NMR (CDCl3, 100 MHz)
d (ppm): 20.8 (1C, q),
21.0 (1C, t), 25.3 (1C, t), 68.9 (1C, d), 69.6 (1C, d), 121.5 (1C, d),
127.2 (1C, d), 127.6 (1C, d), 128.7 (1C, s), 138.4 (1C, s), 148.4 (1C, s),
169.4 (1C, s); EIMS m/z: 222 (Mþ, 0.01), 204 (12), 180 (36), 162
(91), 136 (97), 43 (100).
4.1.4. (ꢁ)-cis-1,2,3,4-Tetrahydronaphthalene-1,2,5-triol (3)
Following the procedure described above for dihydroxylation,
7,8-dihydronaphthalen-1-ol was treated with osmium tetroxide–
trimethylamine-N-oxide yielding 3 in 73.5% yield. IR (film): nmax
3385.65, 1215.33, 1057.18 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d (ppm):
1.27 (1H, m), 1.47 (1H, m), 1.99 (1H, m), 2.32 (1H, dt, J¼17.5, 5.6 Hz),
2.90 (2H, s, OH), 3.35 (1H, dt, J¼2.3, 10.2 Hz), 4.02 (1H, d, J¼3.9 Hz),
6.14 (1H, br d, J¼7.8 Hz), 6.34 (1H, d, J¼7.8 Hz), 6.41 (1H, t,
J¼7.8 Hz); 13C NMR (CDCl3, 100 MHz)
d (ppm): 21.5 (1C, t), 25.9 (1C,
4.1.1. 7,8-Dihydronaphthalen-1-ol
1,2,3,4-Tetrahydronaphthalene-1,5-diol (1 g, 6 mmol) and p-tol-
uene sulfonic acid (420 mg, 2.2 mmol) were dissolved in dry benzene
t), 69.5 (1C, d), 70.2 (1C, d), 113.7 (1C, d), 121.4 (1C, d), 123.8 (1C, s),
126. 7 (1C, d, C-7), 139.2 (1C, s, C-8a), 154.6 (1C, s, C-5); EIMS m/z:
162 (Mþꢀ18, 61), 131 (12), 120 (100), 91 (21), 69 (21).

D. Jime´nez-Teja et al. / Tetrahedron 65 (2009) 3392–3396
3395
4.2. General procedure for lipase-catalyzed kinetic resolution
at room temperature
and then for another 15 min at 100 ꢂC. The solvent was removed
under reduced pressure and ice–water (10 mL) was added. The
organic layers were extracted with Et2O (3ꢃ5 mL), washed with
H2O (15 mL), dried over dry Na2SO4, filtered, and concentrated in
a rotary evaporator providing a crude product. The residue was
Starting material (0.255 mmol), the lipase (68.04 mg), vinyl ac-
etate (813 mg, 9.4 mmol, 870 mL), and TBME (1.3 mL) were mixed
and stirred for the period of time detailed in Table 2 at room
temperature or 48 ꢂC. TBME was omitted in solvent-free reactions.
The lipase was then filtered and the solvent evaporated in a ro-
tary evaporator. The residue was purified by column chromatog-
raphy using AcOEt–hexane (30%) as an eluent to give the
diacetylated product. The yields are summarized in Table 2.
purified by chromatography using AcOEt–hexane 15:85 as an elu-
23
ent to give (þ)-3,4,8-triacetoxytetralone in 65% yield. [
a
]
þ95.30
D
(c 0.345, CHCl3); IR (film): nmax 3021.98, 1746.5, 1693.7, 1241.55,
1218.37, 1196.67 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
d
(ppm): 2.03
(3H, s), 2.10 (3H, s), 2.37 (3H, s), 2.87 (1H, ddd, J¼0.7, 4.2, 17.4 Hz),
3.03 (1H, dd, J¼9.2, 17.4 Hz), 5.51 (1H, ddd, J¼2.9, 4.7, 9.2 Hz), 6.29
(1H, d, J¼2.9 Hz), 7.13 (1H, dd, J¼1.2, 7.8 Hz), 7.40 (1H, dd, J¼0. 8,
4.2.1. (þ)-2,5-Diacetoxy-1-hydroxy-1,2,3,4-tetrahydro-
7.8 Hz), 7.61 (1H, t, J¼7.8 Hz); 13C NMR (CDCl3)
d: 20.8 (1C, q), 20.9
naphthalene (6)
(1C, q), 21.0 (1C, q), 40.4 (1C, t), 67.9 (1C, d), 69.5 (1C, d), 124.0 (1C,
s),125.1 (1C, d), 127.2 (1C, d), 135.0 (1C, d),139.3 (1C, s), 150.1 (1C, s),
169.6 (1C, s), 170.0 (1C, s), 170.2 (1C, s), 192.4 (1C, s); EIMS m/z: 320
(Mþ, 48), 162 (84), 144 (100), 133 (79), 43 (91).
23
[
a]
þ23.94 (c 1.697, CHCl3); IR (film): nmax 3368.6, 2947.94,
D
1734.9, 1718.15, 1260.06 cmꢀ1; 1H NMR (CDCl3, 400 MHz)
d (ppm):
1.94 (1H, m), 2.11 (3H, s), 2.26 (1H, m), 2.30 (3H, s), 2.63 (1H, dt,
J¼7.2, 17.6 Hz), 2.77 (1H, dt, J¼6.2, 17.6 Hz), 4.85 (1H, br s), 5.18 (1H,
dt, J¼3.1, 9.6 Hz), 6.99 (1H, dd, J¼1.2, 7.8 Hz), 7.26 (1H, t, J¼7.8 Hz),
(ꢀ)-3,4,8-Triacetoxytetralone was obtained from (ꢀ)-7, follow-
23
ing the same procedure. [
a
]
ꢀ93.48 (c 0.525, CHCl3).
D
7.38 (1H, d, J¼7.8 Hz); 13C NMR (CDCl3, 100 MHz)
d (ppm): 20.8 (1C,
q), 20.9 (1C, t), 21.2 (1C, q), 22.3 (1C, t), 68.9 (1C, d), 72.2 (1C, d),
121.6 (1C, d), 127.0 (1C, d), 127.2 (1C, d), 128.3 (1C, s), 138.0 (1C, s),
148.4 (1C, s), 169.1 (1C, s), 170.6 (1C, s); EIMS m/z: 264 (Mþ, 0.02),
246 (3), 204 (18), 162 (100), 144 (71), 133 (66), 77 (29), 43 (75).
4.2.5. (þ)-(3R,4S)-cis-4-Hydroxy-6-deoxyscytalone (1)
3,4,8-Triacetoxytetralone (100 mg, 0.37 mmol) was dissolved in
methanol (2 mL) containing a few drops of water and then K2CO3
(168 mg, 1.22 mmol) was added and the mixture stirred at room tem-
perature for 2 h. The reaction mixture was concentrated to remove
methanol, diluted with water (5 mL), and extracted with AcOEt
(3ꢃ5 mL). The crude product was purified by column chromatography
with hexane–AcOEt (30:70) as the eluent to give 1 in a very poor yield.
The 1H NMR was identical with that of the natural product.
4.2.2. (þ)-2-Acetoxy-1,5-dihydroxy–1,2,3,4-tetrahydro-
naphthalene (8)
23
[
a]
þ14.15 (c 1.75, CHCl3); IR (film): nmax 3450.32, 2935.56,
D
1736.21, 1214.40 cmꢀ1 1H NMR (CDCl3, 400 MHz)
; d (ppm): 1.95
(1H, m), 2.11 (3H, s), 2.28 (1H, m), 2.68 (1H, m), 2.86 (1H, dt, J¼17.4,
5.8 Hz), 4.81 (1H, d, J¼3.1 Hz), 5.16 (1H, dt, J¼9.9, 3.1 Hz), 6.70 (1H,
d, J¼7.8 Hz), 7.02 (1H, d, J¼7.81 Hz), 7.10 (1H, t, J¼7.81 Hz); 13C NMR
4.2.6. Acetylation of natural (þ)-(3R,4S)-cis-4-hydroxy-6-
deoxyscytalone (1)
(CDCl3, 100 MHz)
d
(ppm): 20.7 (1C, t), 21.3 (1C, q), 22.2 (1C, t), 22.2
Compound 1 (4 mg, 0.0206 mmol), obtained from the fermen-
(1C, q), 68.6 (1C, d), 72.6 (1C, d), 114.3 (1C, d), 121.5 (1C, d), 122.6
(1C, s), 127.2 (1C, d), 137.5 (1C, s), 153.0 (1C, s), 170.8 (2C, s); EIMS
m/z: 222 (Mþ, 1), 204 (0.5), 162 (100), 144 (74), 133 (71),43 (79).
tation broth of C. acutatum,9 and acetic anhydride (6.28 mg,
0.062 mmol, 6 mL) were dissolved in dry pyridine (100 mL) and the
mixture was stirred for 24 h at room temperature. The excess of
acetic anhydride was eliminated with cyclohexane and acetone and
evaporated in a rotary evaporator. The residue was purified by
column chromatography using EtOAc–Hex (10%) as an eluent to
4.2.3. 1,2,5-Triacetoxy-1,2,3,4-tetrahydronaphthalene (7)
2,5-Diacetoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene
(100 mg, 0.38 mmol) and acetic anhydride (38.64 mg, 0.38 mmol,
35 L) were dissolved in dry pyridine (212 L) and the mixture was
(6)
give the fully acetylated natural product in a 92.13% yield. (þ)-3,4,8-
23
m
m
Triacetoxytetralone: [
a
]
þ97.13, the spectral data were identical
D
stirred for 26 h at room temperature. The excess of acetic anhydride
was then eliminated with cyclohexane and acetone and evaporated
in a rotary evaporator. The residue did not need any purification
with that previously described for synthetic compound.
4.2.7. 2,5-Diacetoxy-1,2,3,4-tetrahydronaphthyl 1-(R)-a-
and 7 was obtained in 100% yield. 1,2,5-Triacetoxy-1,2,3,4-tetrahy-
methoxyphenylacetate (6a)
23
dronaphthalene ((þ)-7): [
a]
þ119 (c 1.025, CHCl3); IR (film): nmax
(þ)-2,5-Diacetoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene
D
2949.40, 1742.8, 1370.36, 1248.9, 1217.10, 1202.28 cmꢀ1
;
1H NMR
(6) (5 mg, 0.033 mmol), EDC (6.5 mg, 0.036 mmol, 1.1 equiv), DAMP
(CDCl3, 400 MHz) (ppm): 1.94 (1H, m), 2.00 (3H, s), 2.05 (3H, s),
d
(catalytic amount), and R (ꢀ)-
a-methoxyphenylacetic acid (R-MPA)
2.15 (1H, m), 2.28 (3H, s), 2.63 (1H, ddd, J¼6.8, 9.6, 17.6 Hz), 2.84
(1H, ddd, J¼4.7, 5.8, 17.6 Hz), 5.19 (1H, dt, J¼3.1, 10.9 Hz), 6.13 (1H, d,
J¼3.1 Hz), 6.98 (1H, dd, J¼1.3, 7.8 Hz), 7.14 (1H, d, J¼7.8 Hz), 7.18
(5 mg, 0.03 mmol) were dissolved in dry DCM (1 mL) and the
mixture was stirred under Ar atmosphere for 3 h at room temper-
ature. The solvent was then evaporated in a rotary evaporator and
the residue purified by HPLC using AcOEt–hexane (20%) as an el-
(1H, t, J¼7.8 Hz); 13C NMR (CDCl3, 100 MHz)
d (ppm): 20.7 (1C, q),
1
20.9 (2C, q), 21.5 (1C, t), 22.4 (1C, t), 68.8 (1C, d), 69.5 (1C, d), 122.3
(1C, d), 127.2 (1C, d), 127.6 (1C, d), 129.0 (1C, s), 134.6 (1C, s), 148.6
(1C, s), 169.0 (1C, s), 170.3 (1C, s), 170,43 (1C, s); EIMS m/z: 306
(0.01), 204 (38), 162 (100), 144 (100), 133 (80), 43 (72).
uent to give 6a in 76.3% yield. H NMR (CDCl3, 400 MHz, 25 ꢂC)
d
(ppm): 1.90 (3H, s, C2–OAc), 1.96 (1H, m, H-3a), 2.17 (1H, m, H-3b),
2.30 (3H, s, C5–OAc), 2.63 (1H, m, H-4a), 2.840(1H, dt, J¼17.4, 5.5 Hz,
0
H-4b), 3.41 (3H, s, C2 –OMe), 4.77 (1H, s, H-2 ), 5.24 (1H, dt, J¼10.8,
1,2,3,4-Tetrahydro-1,2,5-triacetoxynaphthalene ((ꢀ)-7) was
3.3 Hz, H-2), 6.14 (1H, d, J¼3.3 Hz, H-1), 6.76 (1H, br d, J¼7.4 Hz, H-
6), 6.96 (1H, dd, J¼8.0, 1.2 Hz, H-8), 7.07 (1H, t, J¼7.8 Hz, H-7), 7.31
obtained from residual alcohol 5, following the same procedure.
23
0
[a]
ꢀ121.52 (c 1.025, CHCl3).
and 7.40 (2H, m and 3H, m, C2 –Ph).
D
4.2.4. 3,4,8-Triacetoxytetralone
4.2.8. 2,5-Diacetoxy-1,2,3,4-tetrahydronaphthyl 1-(S)-a-
To a stirred solution of (þ)-1,2,5-triacetoxy-1,2,3,4-tetrahy-
dronaphthalene (7) (100 mg, 0.32 mmol) in glacial acetic acid
(1.5 mL) at 5–10 ꢂC in an ice bath was added dropwise over 15 min
a solution of CrO3 (95 mg, 0.96 mmol) in AcOH (1 mL). The resulting
dark brown solution was stirred for 15 min at room temperature
methoxyphenylacetate (6b)
(þ)-2,5-Diacetoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene
(6) was treated with S (ꢀ)-
a
-methoxyphenylacetic acid (S-MPA)
following the procedure described above for 6a yielding 6b in 75.8%
yield. IR and 1H NMR were almost identical tothose described for 6a.

3396
D. Jime´nez-Teja et al. / Tetrahedron 65 (2009) 3392–3396
4.2.9. 2-Acetoxy-5-hydroxy-1,2,3,4-tetrahydronaphthyl 1-(R)-
References and notes
a
-methoxyphenylacetate (8a)
(þ)-2-Acetoxy-1,5-dihydroxy-1,2,3,4-tetrahydronaphthalene
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(8) was treated with S (ꢀ)-
a-methoxyphenylacetic acid (S-MPA)
following the procedure described above for 6a yielding 8a in
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d
(ppm):
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1.780 (1H, m, H-3a), 1.942 (1H, m, H-3b), 2.24 (3H, s, C2–OAc),
2.563 (1H, m, H-4a), 2.772 (1H, d0dd, J¼18.0, 3.0, 1.6 Hz, H-4b), 3.34
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(3H, s, C2 –OMe), 4.64 (1H, s, H-2 ), 4.920 (1H, dt, J¼11.6, 3.2 Hz, H-
2), 6.07 (1H, d, J¼3.2 Hz, H-1), 6.934 (1H, dd, J¼8.0, 1.2 Hz, H-6),
7.067 (1H, br d, J¼7.2 Hz, H-8), 7.161 (1H, t, J¼7.6 Hz, H-7), 7.32
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0
and 7.25 (2H, m and 3H, C2 –Ph); (CD2Cl2–CS2 (1:4), 400 MHz,
´
´
´
´
9. Mancilla, G.; Jimenez-Teja, D.; Femenıa-Rios, M.; Macıas-Sanchez, A. J.; Collado,
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ꢀ70 ꢂC)
d (ppm): 1.691 (1H, m, H-3a), 1.830 (1H, m, H-3b), 2.32
(3H, s, C2–OAc), 2.530 (1H, m, H-4a), 2.752 (1H,m, H-4b), 3.32 (3H,
0
0
s, C2 –OMe), 4.68 (1H, s, H-2 ), 4.841 (1H, dt, J¼12.0, 3.2 Hz, H-2),
6.08 (1H, d, J¼3.2 Hz, H-1), 6.963 (1H, dd, J¼8.0, 1.2 Hz, H-6), 7.130
(1H, br d, J¼8.0 Hz, H-8), 7.242 (1H, t, J¼8.0 Hz, H-7), 7.32 (5H, m,
0
14. Ina´cio, M. L.; Silva, G. H.; Teles, H. L.; Revisan, H. C. T.; Cavalheiro, A. J.; Bolzani,
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This work was kindly supported by the Spanish Science and
´
technology Ministry and in part by the Junta de Andalucıa through
projects AGL2006-13401-C02-01 and PAI05-FQM-00489. D.J.-T.
´
thanks the Foundation Ramon Areces for a studentship.