Determination of the absolute structure of albaconol

Article abstract of DOI:10.1016/j.tet.2008.03.050

The concise synthesis of (8aR)-(-)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison of the sign of specific rotation of between synthet

Full text of DOI:10.1016/j.tet.2008.03.050

Tetrahedron 64 (2008) 5147–5149
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Determination of the absolute structure of albaconol
,
b
b
a,
*
Mikio Fujii a , Sadayuki Ishii , Ryota Saito , Hiroyuki Akita
*
a Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
b Faculty of Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The concise synthesis of (8aR)-(ꢀ)-albaconol (1) from (8aR)-albicanol (2) obtained from the lipase-
assisted asymmetric acetylation of rac-2, was achieved in 45% overall yield (eight steps). By comparison
of the sign of specific rotation of between synthetic (8aR)-(ꢀ)-albaconol (1) and natural (þ)-albaconol
(1), the absolute structure of natural (þ)-1 was determined to be 1R,2R,4aS,8aS configuration.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 18 February 2008
Received in revised form 13 March 2008
Accepted 14 March 2008
Available online 18 March 2008
Keywords:
(8aR)-Albaconol
Natural product synthesis
Structure elucidation
1. Introduction
OH
OAc
Lipase PL
O
O
Albaconol (1) was isolated from the fresh fruiting bodies of the
basidiomycetes Albatrellus confluens,1 and acts as weak antagonists
for human vanilloid-receptor (VR1) without agonistic effect.2
Albaconol (1) inhibits significantly the growth of human tumor cell
lines in vitro, and stimulates DNA cleavage, stabilizes and increases
the topo II-mediated DNA cleavable complex because of inhibition
the religation activity of topo II in a dose-dependent manner.3
Structure of 1 was determined by spectral analysis, including
2D-NMR spectroscopy, but the absolute structure of 1 was not
determined yet.1 Albaconol (1) possesses the skeleton of drimane-
type sesquiterpenoids, which is directly connected to a resorcinol
moiety. On the other hand, lipase-assisted resolution of racemic
albicanol (ꢁ)-2 was reported to give (8aS)-acetate 3 (56%, 67% ee)
and (8aR)-2 (38%, >99% ee) by us.4 Herein we report the first syn-
thesis of (8aR)-1 from (8aR)-2, and determination of the absolute
structure of natural albaconol (1) based on chiral synthesis of
(8aR)-1 (Scheme 1).
8a
rac-2
+
H
H
(8aR)-2
(38%, >99%ee)
(8aS)-3
(56%, 67%ee)
Scheme 1.
overall yield from (8aR)-4. Dihydroxylation of the exo-olefin part
of (8aR)-7 using OsO4/K3Fe(CN)6 gave stereoselectively the desired
diol (8aR)-8 (83% yield), which is corresponding to the dihydr-
oxylation product from less-hindered b-side. The relative config-
uration of C(2)-position in (8aR)-8 could be S, because the present
(8aR)-8 was finally converted to the enantiomer of natural alba-
conol (8aS)-1 as mentioned later on. Monotosylation of (8aR)-8
gave selectively primary tosylate (8aR)-9 (94% yield), which was
treated with LiAlH4 to afford tertiary alcohol (8aR)-10 in 96% yield.
Finally, (8aR)-10 was treated with pyridinium p-toluenesulfonate
(PPTS) in the presence of ethylene glycol to afford (8aR)-albaconol
(1) in 80% yield (Scheme 2). In this case, PPTS was used as weak
acid to avoid formation of ether linkage between phenolic hy-
droxyl group and C(2)-carbon. The physical data (mp 212–213 ꢂC,
1H and 13C NMR) of the synthetic (8aR)-1 were identical with
those (mp 212–214 ꢂC and 1H and 13C NMR) of natural albaconol
(1). The specific rotation {[a]2D3 ꢀ58.9 (c 1.15, MeOH)} of synthetic
(8aR)-1 was in accord with that {[a]2D3 þ63.8 (c 0.4, MeOH)} of
natural albaconol (1)1 except for the sign of the specific rotation.
From these evidences, the absolute structure of natural albaconol
(1) was determined as shown in Figure 1.
2. Synthesis of (8aR)-albaconol (1)
Dess–Martin oxidation of (8aR)-albicanol (2)4 gave a (8aR)-
albicanal (4) in 92% yield, which was treated with an anion 5
obtained by reaction of 3,5-di-O-methoxymethyltoluene5 with
n-BuLi to afford a diastereomeric mixture of (8aR)-6. Acetylation of
(8aR)-6 followed by the Birch reduction provided (8aR)-7 in 82%
* Corresponding authors. Tel.: þ81 047 472 1805; fax: þ81 047 476 6195.
E-mail address: akita@phar.toho-u.ac.jp (H. Akita).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.050

5148
M. Fujii et al. / Tetrahedron 64 (2008) 5147–5149
OMOM
Li
MOMO
CHO
1) AcCl, Pyr
DMAP
Dess-Martin
reagent
MOMO
HO
5
(8aR)-2
OMOM
MOMO
H
NaHCO3 / CH2Cl2
92%
2) Li, liq. NH3
3 steps 82%
H
H
(8aR)-4
(8aR)-6
MOMO
MOMO
OsO4
OH
OH
K3Fe(CN)6
TsCl, Pry
OMOM
OMOM
OH
OMOM
OTs
83%
94%
H
H
(8aR)-7
(8aR)-8
(8aR)-9
MOMO
HO
LiAlH4
PPTS
HOCH2CH2OH
80%
OMOM
OH
OH
OH
Et2O
96%
H
H
(8aR)-10
(8aR)-1
Scheme 2.
4'
HO
8a
FT/IR 4100 spectrometer. Optical rotations were measured with
a JASCO DIP-370 digital polarimeter. For column chromatography,
silica gel (Kieselgel 60) was employed.
1'
OH
OH
4.2. 1-{[(1R,4aR,8aR)-Decahydro-2-methylene-5,5,8a-
trimethylnaphthalen-1-yl]methyl}-2,6-di-O-methoxy-
methyl-4-methylbenzene (7)
H
albaconol (1)
Figure 1.
(1) To a solution of (8aR)-2 (0.955 g, 4.3 mmol) in CH2Cl2
(65.0 mL) were added NaHCO3 (5.89 g, 70.1 mmol) and Dess–Martin
reagent (3.15 g, 7.43 mmol) at 0 ꢂC and the reaction mixture was
stirred for 2 h at rt. The reaction mixture was directly subjected
to chromatography on silica gel [100 g, n-hexane/AcOEt¼200:1] to
give (8aR)-4 (0.871 g, 92% yield) as a colorless oil. Compound
(8aR)-4: 1H NMR: d 0.87 (3H, s), 0.89 (3H, s), 1.03 (1H, dd, J¼12.6,
2.8 Hz), 1.15 (3H, s), 1.17–1.28 (2H, m), 1.38–1.50 (3H, m), 1.54–1.66
(2H, m), 1.69–1.75 (1H, m), 2.05–2.13 (1H, m), 2.37–2.49 (2H, m),
4.50 (1H, br s), 4.92 (1H, br s), 9.87 (1H, d, J¼4.8 Hz). 13C NMR:
d 16.0, 18.7, 21.9, 23.1, 33.4, 33.5, 36.7, 39.0, 39.9, 41.9, 54.0,
67.9, 109.2, 145.0, 205.7. (2) To a solution of 3,5-di-O-methoxy-
methyltoluene (2.53 g, 11.9 mmol) in dried THF (15 mL) was added
n-butyl lithium (4.35 mL, 11.3 mmol, 2.6 M in n-hexane) at 0 ꢂC and
the resulting mixture was stirred for 1 h at the same temperature to
generate anion 5. A solution of (8aR)-4 (0.871 g, 3.95 mmol) in THF
(2 mL) was added to the solution of anion 5 at 0 ꢂC and the reaction
mixture was stirred for 3 h. The mixture was poured into water
and extracted with ethyl acetate. The organic layer was dried over
sodium sulfate and evaporated under reduced pressure. The resi-
due was purified by silica gel column chromatography [silica gel
(50 g), n-hexane/ethyl acetate (10:1)] to afford crude product 6
(1.48 g). (3) To a solution of crude 6 in pyridine (30 mL) were added
acetic anhydride (4.0 g, 40 mmol) and 4-N,N-dimethylaminopyr-
idine (96.6 mg, 0.79 mmol), and the reaction mixture was stirred
for 13 h at rt. The mixture was poured into water and extracted with
ethyl acetate. The organic layer was dried over sodium sulfate and
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography [silica gel (50 g), n-hexane/ethyl
3. Conclusion
The reaction of (8aR)-albicanal (4) derived from (8aR)-albicanol
(2) with 4-(3,5-di-O-methoxymethyl)tolyl anion 5 gave a dia-
stereomeric mixture of (8aR)-6, which was subjected to consecu-
tive acetylation and Birch reduction to afford the exo-olefin (8aR)-7.
Stereoselective dihydroxylation of (8aR)-7 followed by consecutive
monotosylation and LiAlH4 reduction provided the protected
albaconol (8aR)-10, which was deprotected to give (8aR)-albaconol
(1). Overall yield of (8aR)-1 from (8aR)-albicanol (2) was 45% in
eight steps. By comparison of the sign of specific rotation of be-
tween synthetic (8aR)-(ꢀ)-albaconol (1) and natural (þ)-albaconol
(1), the absolute configuration of natural (þ)-1 was determined to
be 1R,2R,4aS,8aS.
4. Experimental
4.1. General
All melting points were measured on a Yanaco MP-3S melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on JEOL AL-400 spectrometer in CDCl3. 2D-NMR mea-
surement (COSY, HMQC, HMBC, NOESY) of (8aR)-(ꢀ)-albaconol (1)
was carried out by means of JEOL ECP-500 NMR spectrometer in
acetone-d6. High-resolution mass spectra (HRMS) were obtained
with a JEOL JMS-AM II 50. IR spectra were recorded with a JASCO

M. Fujii et al. / Tetrahedron 64 (2008) 5147–5149
5149
acetate (20:1)] to afford the corresponding acetate (1.93 g). A
solution of the acetate in THF (0.5 mL) was added to Li (0.275 g,
40 mmol) in liq. ammonia (ca. 20 mL) at ꢀ78 ꢂC and the reaction
mixture was stirred for 3 h. The mixture was warmed up to rt and
the residue was purified by silica gel column chromatography
[silica gel (50 g), n-hexane/ethyl acetate (20:1)] to afford (8aR)-7
(1.36 g, 3.27 mmol, 82% yield) from (8aR)-4. Compound (8aR)-7:
colorless plates [from n-hexane/ethyl acetate (20:1)]. Mp: 88–
89 ꢂC. [a]D20 þ33.5 (c 0.60, CHCl3). 1H NMR: d 0.81 (6H, s), 0.85 (3H,
s), 1.08–1.62 (7H, m), 1.65–1.72 (1H, m), 1.83–1.93 (2H, m), 2.25 (3H,
s), 2.20–2.32 (1H, m), 2.54 (1H, br d, J¼10.8 Hz), 2.70 (1H, dd, J¼3.4,
13.2 Hz), 2.83 (1H, dd, J¼9.6, 13.2 Hz), 3.48 (6H, s), 4.67 (1H, s), 4.98
(2H, d, J¼8.8 Hz), 5.14 (2H, d, J¼8.8 Hz), 6.54 (2H, s), 7.32 (2H, d,
J¼8.0 Hz), 7.81 (2H, d, J¼8.0 Hz). 13C NMR: d 15.5, 18.1, 18.5, 19.1,
21.3, 21.5, 21.7, 33.1, 33.3, 37.1, 38.8, 39.3, 41.5, 56.2, 56.2 (2C), 59.5,
71.8, 74.4, 94.4 (2C), 108.5 (2C), 117.2, 128.0 (2C), 129.6 (2C), 133.1,
137.3, 144.5, 155.1 (2C). IR (CCl4): 3545, 2925, 1610, 1585, 1174, 1153.
Anal. for C33H48O8S: C, 65.54; H, 8.00%. Found: C, 65.07; H, 7.91%.
4.5. 1-{[(1S,2S,4aR,8aR)-Decahydro-2-hydroxy-2,5,5,8a-
tetramethylnaphthalen-1-yl]methyl}-2,6-di-O-
methoxymethyl-4-methylbenzene (10)
To a solution of (8aR)-9 (0.200 g, 0.331 mmol) in ether (10 mL)
was added LiAlH4 (38 mg, 1 mmol) at rt and the resulting mixture
was refluxed for 6 h. Ice-cold water (0.2 mL), aq sodium hydroxide
(1 M, 0.2 mL), and Celite 545 (1 g) were added to the mixture and
the resulting mixture was filtrated through a pad of Celite 545 and
the residue was washed with ether. The filtrate was evaporated
under reduced pressure. The residue was purified by silica gel
column chromatography [silica gel (10 g), n-hexane/ethyl acetate
(2:1)] to afford (8aR)-10 (0.180 g, 0.234 mol, 94% yield). Compound
(8aR)-10: colorless oil. [a]2D0 ꢀ13.0 (c 0.65, CHCl3). 1H NMR: d 0.72–
0.92 (1H, m), 0.74 (3H, s), 0.83 (3H, s), 0.94 (3H, s), 1.07 (1H, dt,
J¼4.4, 13.2 Hz), 1.17–1.33 (3H, m), 1.27 (3H, s), 1.38 (1H, dt, J¼3.6,
13.0 Hz), 1.46–1.63 (2H, m), 1.72 (1H, t, J¼5.4 Hz), 1.80–1.88 (2H, m),
2.26 (3H, s), 2.71 (1H, dd, J¼5.2, 14.4 Hz), 2.86 (1H, dd, J¼5.0,
14.4 Hz), 3.03 (1H, br), 3.48 (6H, s), 5.17 (4H, s), 6.56 (2H, s). 13C
NMR: d 15.0, 18.6, 18.7, 20.3 21.6, 21.7, 23.6, 33.3, 33.5, 39.1, 39.6,
41.9, 44.3, 56.3 (2C), 56.4, 60.4, 76.7, 94.5 (2C), 108.7 (2C), 118.7,
136.9,155.3 (2C). IR (CCl4): 3564, 2923,1610,1584. HREIMS calcd for
(1H, s), 5.14 (2H, d, J¼6.8 Hz), 5.16 (2H, d, J¼6.8 Hz), 6.54 (2H, s). 13
C
NMR: d 14.2, 19.3, 19.4, 21.7, 21.8, 24.6, 33.6, 33.8, 38.6, 38.8, 40.4,
42.4, 55.2, 56.0, 56.2 (2C), 94.5 (2C), 106.3, 108.7 (2C), 117.6, 136.6,
155.9 (2C). IR (CCl4): 2925, 1611, 1585, 1153, 1046. HREIMS calcd for
C
26H40O4: 416.2927, found: 416.2931.
4.3. 1-{[(1S,2S,4aR,8aR)-Decahydro-2-hydroxy-2-hydroxyl-
methyl-5,5,8a-trimethylnaphthalen-1-yl]methyl}-
2,6-di-O-methoxymethyl-4-methylbenzene (8)
A solution of (8aR)-7 (0.200 g, 0.48 mmol) in tert-butyl alcohol
(10 mL) was added to a mixture of potassium osmate dihydrate
(0.03 mmol), K3Fe(CN)6 (0.984 g, 3.0 mmol), and potassium car-
bonate (0.414 g, 3.0 mmol) in water (10 mL) and the resulting
mixture was stirred for 2 days at rt. Ice-cooled aq sodium sulfite
(10%) was added to the mixture and the mixture was extracted with
ethyl acetate twice. The organic layers were combined, dried over
sodium sulfate, and evaporated under reduced pressure. The resi-
due was purified by silica gel column chromatography [silica gel
(10 g), n-hexane/ethyl acetate (2:1)] to afford (8aR)-8 (0.180 g,
0.400 mmol, 83% yield) and recovered starting material (30 mg,
15%). Compound (8aR)-8: colorless oil. [a]2D0 ꢀ26.5 (c 0.78, CHCl3).
1H NMR: d 0.71 (1H, dt, J¼3.6,13.6 Hz), 0.76 (3H, s), 0.81 (3H, s), 0.87
(3H, s),1.03 (1H, dt, J¼3.6,13.6 Hz),1.07–1.31 (4H, m),1.42–1.63 (2H,
m), 1.81 (1H, br d, J¼12.8 Hz), 1.89 (1H, t, J¼7.4 Hz), 2.24 (3H, s), 2.31
(1H, br d, J¼12.4 Hz), 2.68 (1H, dd, J¼3.2, 14.6 Hz), 2.86 (1H, dd,
J¼6.4, 14.6 Hz), 3.46 (6H, s), 3.57 (1H, d, J¼9.6 Hz), 3.75 (1H, d,
J¼9.6 Hz), 5.15 (4H, s), 6.54 (2H, s). 13C NMR: d 15.2, 18.1, 18.5, 19.7,
21.5, 21.7, 33.2, 33.4, 37.2, 38.6, 39.4, 41.7, 56.3 (2C), 56.4, 59.5, 63.3,
75.8, 94.5 (2C), 108.5 (2C), 117.7, 137.2, 155.1 (2C). IR (CCl4): 3503,
2925, 1610, 1584, 1153, 1044. HREIMS calcd for C26H42O5: 450.2981,
found: 450.2976.
C26H42O5: 434.3032, found: 434.3035.
4.6. (8aR)-Albaconol (1)
To a solution of (8aR)-10 (75.0 mg 0.123 mmol) and ethylene
glycol (0.1 mL) in ethanol (3 mL) was added pyridinium p-tolu-
enesulfonate (30.0 mg, 0.12 mmol) and the resulting mixture was
stirred for 2 days at 50 ꢂC. The mixture was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography [silica gel (10 g), n-hexane/ethyl acetate (1:1)] to
afford (8aR)-1 (47.9 mg, 0.138 mmol, 80% yield). Compound (8aR)-1:
colorless needles. Mp 212–213 ꢂC (from ethyl acetate) (lit.1 mp 212–
214 ꢂC). [a]2D3 ꢀ58.9 (c 1.15, MeOH) (lit.1 [a]2D3 þ63.8 (c 0.40, MeOH)).
1H NMR (acetone-d6): d 0.57 (1H, td, J¼13.2, 3.6 Hz), 0.82 (3H, s),
0.85 (3H, s), 0.98 (3H, s), 0.89–0.96 (1H, m), 1.06 (1H, td, J¼13.2,
4.0 Hz), 1.06–1.15 (2H, m), 1.30 (3H, s), 1.25–1.45 (3H, m), 1.48–1.60
(5H, m), 1.88–1.97 (2H, m), 2.02–2.19 (3H, m), 2.17 (3H, s), 2.45 (1H,
d, J¼15.2 Hz), 3.02 (1H, dd, J¼5.6, 15.2 Hz), 5.00 (1H, s), 6.10 (2H, s),
8.56 (2H, s). 13C NMR (acetone-d6): d 15.4, 18.7, 19.0, 21.1, 21.2, 21.9,
24.4, 33.7, 33.8, 38.5, 40.0, 42.6, 44.6, 57.1, 61.4, 75.5, 108.6 (2C),
114.1, 136.6, 156.6 (2C). IR (CCl4): 3345, 2924, 1584. HREIMS calcd
for C22H34O3: 346.2508, found: 346.2366.
4.4. 1-{[(1S,2S,4aR,8aR)-Decahydro-2-hydroxy-2-tosyl-
oxylmethyl-5,5,8a-trimethylnaphthalen-1-yl]methyl}-
2,6-di-O-methoxymethyl-4-methylbenzene (9)
To a solution of (8aR)-8 (0.176 g, 0.391 mmol) in pyridine (3 mL)
was added p-toluenesulfonyl chloride (0.224 g,1.17 mmol) at rt. The
resulting mixture was stirred for 4 h at rt. The mixture was added to
ice-cold water and extracted with ethyl acetate twice. The organic
layers were combined and dried over sodium sulfate and evapo-
rated under reduced pressure. The residue was purified by silica gel
column chromatography [silica gel (10 g), n-hexane/ethyl acetate
(4:1)] to afford (8aR)-9 (0.225 g, 0.373 mmol, 94% yield). Compound
(8aR)-9: colorless oil. [a]2D0 ꢀ16.2 (c 1.07, CHCl3). 1H NMR: d 0.69
(3H, s), 0.78 (3H, s), 0.81 (3H, s), 0.74–0.87 (2H, m), 1.04 (1H, dd,
J¼3.2, 13.2 Hz), 1.15 (1H, dd, J¼3.4, 13.2 Hz), 1.22–1.56 (4H, m), 1.79–
1.90 (2H, m), 2.09 (1H, br d, J¼13.4 Hz), 2.24 (3H, s), 2.41 (3H, s),
2.63 (1H, dd, J¼6.4, 14.6 Hz), 2.77 (1H, dd, J¼5.2, 14.6 Hz), 2.92 (1H,
br), 3.44 (6H, s), 4.27 (1H, d, J¼10 Hz), 4.41 (1H, d, J¼10 Hz), 5.12
References and notes
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5. This compound was obtained by the reaction of commercially available
5-methylresorcinol with methoxymethyl chloride (MOM-Cl) in the presence of
diisopropylethylamine.