Efficient construction of novel α-keto spiro ketal and the total synthesis of (±)-terreinol

Article abstract of DOI:10.1016/j.tet.2005.09.068

The first total synthesis of (±)-terreinol is described. An intramolecular Pd(II)-catalyzed cycloisomerization of a 2-(1′-alkynyl) benzyl alcohol via an apparent 6-endo diagonal pathway led to the 1H-isochromene ring system, which was further converted to

Full text of DOI:10.1016/j.tet.2005.09.068

Tetrahedron 61 (2005) 11882–11886
Efficient construction of novel a-keto spiro ketal and the total
synthesis of (G)-terreinol
*
Wan-Guo Wei, Yong-Xia Zhang and Zhu-Jun Yao
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
Received 8 August 2005; revised 16 September 2005; accepted 16 September 2005
Available online 25 October 2005
Abstract—The first total synthesis of (G)-terreinol is described. An intramolecular Pd(II)-catalyzed cycloisomerization of a 2-(10-
alkynyl)benzyl alcohol via an apparent 6-endo diagonal pathway led to the 1H-isochromene ring system, which was further converted to the
desired spiro ketal via an iodine-mediated intramolecular spiro-cyclization.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Fungi have been one of the main resources of a wide variety
of complex natural products possessing attractive biological
activities.1 For example, lovastatin (mevinolin) derived
from fungus Aspergillus terreus is now used as a cholesterol
lowering agent.2 Terreinol was isolated more recently as a
novel metabolite by Marsaioli and co-workers in an effort to
screen enzymatic activity in malt extracts from cultures of
Brazilian strains of A. terreus.3a Its absolute configuration
was determined thereafter by 1H and 13C NMR experiments,
allowing assignment of the R configuration for terreinol.3b
This apparently simple molecule is structurally
distinguished by a highly oxygenated isochromene core
bearing a novel dioxa-spiro ketal. Attracted by its unique
structure and the interesting bioactivities of similar spiro-
Figure 1. Retrosynthetic analysis of (G)-terreinol.
cyclic compounds, we sought to establish an efficient route
for the synthesis of terreinol by using readily available
materials. Herein, we report our recent achievement of
the first total synthesis of (G)-terreinol, in which an
intramolecular Pd(II)-catalyzed cycloisomerization and
an intramolecular iodoetherification were employed as
key steps.
ketal core of B was to be derived from an intramolecular
haloetherification reaction, while, the 1H-isochromene ring
system of C was to be elaborated by an intramolecular
Pd(II)-catalyzed cycloisomerization of precursor D. It was
anticipated that the six-member ring would be formed
preferentially over the five-member ring. Facile removal of
the phenolic hydroxyl protections must be carefully
considered in the last step. Finally, the fully functionalized
precursor benzylalcohol derivative D could be easily
prepared from readily available starting materials, such as
aryl bromide E and terminal alkyne, by Sonogashira
coulping reaction.
2. Results and discussion
Our strategy for the synthesis of terreinol was based on two
major considerations as shown in Figure 1. First, the spiro
As outlined in Scheme 1, commencing with the com-
mercially available 2-methylresorcinol, 2-bromobenzal-
dehyde 8 was prepared using a modification of the
recently reported protocol by Porco et al.4 Accordingly,
Keywords: Aspergillus terreus; Catalyst; Iodoetherification.
*
Corresponding author. Tel.: C86 21 54925133; fax: C86 21 64166128;
e-mail: yaoz@pub.sioc.ac.cn
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.068

W.-G. Wei et al. / Tetrahedron 61 (2005) 11882–11886
11883
2-bromobenzaldehyde 8 in high yield. All these improve-
ments have the advantages of more stable intermediates,
high yield for each step, and ease of operation and
reduplication.
The functionalized cycloisomerization precursor 10 was
next prepared by a Sonogashira coupling,5 which linked aryl
bromide 8 and terminal acetylene 96 (Scheme 2). The
phenolic hydroxyls were then protected as TBS ethers 11,
Treatment of benzylaldehye 11 with NaBH4 in ethanol at
0 8C gave the corresponding benzyl alcohol 12. With this
precursor in hand, construction of the 1H-isochromene
structure by intramolecular ring-closure reaction of 12 was
investigated. Earlier studies on this type of cycloisomeriza-
tion revealed that both the substituent pattern of the
substrates and the reaction conditions could influence the
reaction leading either toward the 5-exo-dig cyclization or
the 6-endo-dig cyclization products.7 A short list of Pd(II)
catalysts (Table 1) were screened on 12 for their ability to
promote the desired 6-endo cycloisomerization. To our
delight, 10 mol% of PdCl2(PPh3)2 in 1,4-dioxane at 85 8C
worked very well and 1H-isochromene 13 was obtained as a
single isomer in satisfactory yield. It is noteworthy that the
unprotected phenolic benzylalcohol didn’t produce any
desired cycloisomerized product under such conditions.
Other Pd(II) species and conditions also gave 13, however,
in lower yields or under longer reaction times (see Table 1).
Theoretically, the five-member-ring product might be also
produced under these conditions. However, no evidence of
five-member-ring product was detected during our investi-
gations. Treatment of acetate 13 with K2CO3 in methanol
at rt afforded the corresponding alcohol 14 in high yield.
It is noteworthy that this compound was quantitatively
converted to spiro ketal 198 in CDCl3 (weakly acidic) when
left in NMR tube over 24 h.
Scheme 1. Reagents and conditions: (a) POCl3, DMF, 60 8C, 90%;
(b) Cu(NO3)2$3H2O, Ac2O, 94%; (c) Raney Nickel (50% in H2O), H2,
THF, 98%; (d) NBS (1.1 equiv), CHCl3, rt, 92%; (e) Concd HCl, THF/H2O,
NaNO2 then urea, 50% H3PO2, 89%; (f) PCC, 4 A sieves, CH2Cl2, 0 8C to
rt, 87%; (g) BBr3, CH2Cl2, K78 8C to rt, 94%.
˚
2,6-dimethoxytoluene 1 was derived from 2-methyl-
resorcinol and acylated to give aldehyde 2. Nitration of
benzaldehyde 2 was carried out with Cu(NO3)2 in acetic
anhydride to give the expected geminal diacetate 3. Raney
nickel-catalyzed reduction of the nitro group and simul-
taneously removal of the geminal diacetate were performed
in facile fashion in THF under a H2 atmosphere. Selective
bromination of the resulting 3-aminobenzyl alcohol 4 was
achieved using NBS in CHCl3 to give o-bromoaniline 5 in
excellent yield. Reductive removal of the amino group of 5
was carried out by diazotization followed by H3PO2-based
sediazotization in situ. Oxidation of the resultant 6-bromo-
Table 1. Synthesis of 1H-isochromene 13 by Pd(II)-catalyzed cycloisome-
rization of 12
2,4-dimethoxy-3-methylbenzyl alcohol
6
occurred
˚
smoothly by using PCC and 4 A molecular sieves in
anhydrous dichloromethane to afford the corresponding
benzaldehyde 7. Finally, treatment of 7 with BBr3 afforded
Entrya
Catalyst (mol%)
T (8C)
Time (h)
Product
(%)
1
2
3
4
5
6
10% PdCl2
85
85
85
85
85
85
1.0
5.0
1.5
6.0
4.0
1.5
64
14
72
68
64
60
10% Pd(OAc)2
10% PdCl2(PPh3)2
5% PdCl2(PPh3)2
5% PdI2
10% Pd(PhCN)2Cl2
a The reactions were all carried out in 1,4-dioxane as the solvent.
The final key transformation to achieve our ultimate
synthetic object was to establish the spiro ketal function-
ality. It was anticipated that an intramolecular iodo-
etherification reaction could be utilized for this key
transformation. It is well known that iodoetherification is
a powerful method for the construction of THF rings from
the corresponding g-hydroxyalkenes. This is also an
efficient method to functionalize olefinic double bonds.9
Treatment of compound 14 with 2 equiv of iodine in a
mixture of CH3CN and aq NaHCO3 (10:1, v:v) at ambient
temperature gave the desired spiro ketal 15. The iodide 15
was immediately substituted by hydroxide in situ to furnish
16 as a mixture of isomers (ca. 35:1) at rt in 86% overall
yield (from 14). Dess–Martin oxidation10 of the resulting
Scheme 2. Reagents and conditions: (a) 5 mol% Pd(PPh3)4, CuI,
4-pentynyl acetate 9, Et3N, DMF, 70 8C, 92%; (b) TBSCl, imid, DMF,
87%; (c) NaBH4, EtOH, 0 8C, 5 min, 75%; (d) 10 mol% PdCl2(PPh3)2, 1,4-
dioxane, 85 8C, 72%; (e) K2CO3, MeOH, rt, 97%; (f) HC, CDCl3, rt, 24 h,
quantitative.

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W.-G. Wei et al. / Tetrahedron 61 (2005) 11882–11886
mixture afforded 17 quantitatively as a single product.
Finally, global deprotection11 was achieved using TBAF in
THF, to give racemic terreinol in excellent yield (Scheme 3).
Data for terreinol obtained by this route were identical with
those reported for natural material.3
characterization. Mp 75–77 8C. 1H NMR (300 MHz,
CDCl3): d 6.58 (1H, s), 4.59 (2H, s), 3.72 (3H, s), 3.71
(3H, s), 3.60–2.80 (2H, br s), 2.21 (3H, s) ppm. IR (KBr):
nmax 3394, 3251, 3145, 1598, 1485, 1419, 1212, 1101, 1008,
834 cmK1. ESI-MS (m/z): 198 (MCHC). Anal. Calcd for
C10H15NO3: C, 60.90; H, 7.67; N, 7.10. Found: C, 61.06; H,
7.31; N, 7.09.
4.1.2. (3-Amino-2-bromo-4,6-dimethoxy-5-methyl-
phenyl) methanol (5). To a solution of 4 (1.0 g,
5.1 mmol) in CHCl3 (20 mL) was added NBS (990 mg,
5.6 mmol). The mixture was stirred at rt for 5 min, and then
aq Na2S2O3 solution was added to quench the reaction. The
mixture was extracted with ethyl acetate for three times and
combined organic layers were washed extensively with H2O
and finally brine. The organic extracts were dried over
Na2SO4, filtered, concentrated and the residue was purified
by silica gel column (hexane/ethyl acetateZ4:1) to afford 5
1
(1.3 g, 92%) as a pale yellowish oil. H NMR (300 MHz,
CDCl3): d 4.76 (2H, s), 4.10 (2H, br s), 3.72 (3H, s), 3.71
(3H, s), 2.50 (1H, br s), 2.17 (3H, s) ppm. IR (film): nmax
3455, 3361, 2941, 1608, 1575, 1459, 1415, 1247, 1195,
1126, 1107, 1006, 981 cmK1. HRMS (ESI, m/z) calcd for
C10H15BrNO3 (MCHC): 276.0235; found: 276.0231.
Scheme 3. Reagents and conditions: (a) I2, CH3CN, aq NaHCO3, rt, 86%;
(b) Dess–Martin periodinane, CH2Cl2, 97%; (c) TBAF, THF, rt, 98%.
3. Conclusions
4.1.3. Acetic acid 5-(2-formyl-3,5-dihydroxy-4-methyl
phenyl)pent-4-ynyl ester (10). To a mixture of 2-bromo-
benzaldehyde 8 (20 g, 86.6 mmol), alkyne 9 (13 g,
103.9 mmol), Pd(PPh3)4 (5.0 g, 4.3 mmol), CuI (840 mg,
4.4 mmol) in degassed DMF (70 mL) was added Et3N
(36 mL) under inert atmosphere. The resulting mixture was
heated and then stirred at 70 8C for about 6 h. The solvent
was removed under reduced pressure and the residue was
purified directly on silica gel column (hexane/ethyl
acetateZ5:1). The obtained crude product was then crystal-
lized from hexane and ethyl acetate, affording 10 (22 g,
In conclusion, we have disclosed the first total synthesis of
the fungal metabolite terreinol. The palladium(II)-catalyzed
cycloisomerization of 2-(10-alkynyl)benzyl alcohol 12
efficiently furnished the key precursor 1H-isochromene
13. The spiro ketal was subsequently elaborated by
iodoetherification of alcohol 14. Further investigations
including the enantioselective synthesis of the correspond-
ing spiro cycles and bioactivity studies of this novel
metabolite are currently underway.
1
92%) as a white solid. Mp 97–99 8C. H NMR (300 MHz,
4. Experimental
CDCl3): d 12.27 (1H, s), 10.16 (1H, s), 7.50 (1H, br s), 6.51
(1H, s), 4.25 (2H, t, JZ6.3 Hz), 2.56 (2H, t, JZ6.9 Hz),
2.11 (3H, s), 2.10 (3H, s), 2.01–1.92 (2H, m) ppm. 13C NMR
(100 MHz, CDCl3): d 195.0, 172.1, 163.1, 161.40, 161.36,
126.8, 114.2, 112.6, 112.2, 95.2, 63.5, 27.6, 21.0, 16.4, 7.2.
IR (KBr): nmax 3379, 1711, 1635, 1609, 1588, 1422,
4.1. General methods
1H NMR spectra were recorded at 300 or 400 MHz at
ambient temperature with CDCl3 as the solvent unless
otherwise stated. 13C NMR spectra were recorded at
100 MHz at ambient temperature with CDCl3 as the solvent
unless otherwise stated. All melting points were uncor-
rected. Infrared (IR) spectra were obtained using a Fourier
transform infrared spectrometer (FTIR). Flash column
chromatography was performed on silica gel (10–40 mm)
using a mixture of petroleum ether and ethyl acetate as the
eluent.
1367, 1303, 1251, 1139, 1107, 1049, 834, 769, 586 cmK1
.
ESI-MS (m/z): 274 (MCHC). Anal. Calcd for C15H16O5: C,
65.21; H, 5.84. Found: C, 65.18; H, 5.81.
4.1.4. Acetic acid 5-[3,5-bis(tert-butyldimethylsilanyl
oxy)-2-formyl-4-methylphenyl]pent-4-ynyl ester (11). A
mixture of phenol 10 (2.0 g, 5.9 mmol), imidazole (2.4 g,
35.5 mmol) and TBSCl (4.5 g, 29.6 mmol) in anhydrous
DMF (6.0 mL) was stirred at rt for about 4 h under N2
atmosphere. The mixture was then diluted with ethyl acetate
(100 mL) and water (30 mL). The organic layer was
separated and washed with H2O (4!30 mL), brine, dried
over Na2SO4, filtered, and concentrated. The crude product
was purified by silica gel column (hexane/ethyl acetateZ
4.1.1. (5-Amino-2,4-dimethoxy-3-methylphenyl)metha-
nol (4). A solution of 3 (8.5 g, 26.0 mmol) in 150 mL
THF was treated with Raney Nickel (50% in H2O, 10.0 g).
The resulting mixture was hydrogenated under H2 at rt and
the reaction process was monitored by TLC. After
completion of the reaction, the mixture was filtered through
Celite and washed with ethyl acetate. The filtrate was
concentrated under reduced pressure to give 4 (5.0 g, 98%)
as a pale yellow solid, which was employed in the next step
without further purification. Recrystallization of the product
from hexane and ethyl acetate afforded colorless crystal for
1
50:1) to give 11 (2.6 g, 87%) as a colorless oil. H NMR
(300 MHz, CDCl3): d 10.31 (1H, s), 6.61 (1H, s), 4.28 (2H,
t, JZ6.3 Hz), 2.59 (2H, t, JZ6.9 Hz), 2.09 (3H, s), 2.08
(3H, s), 2.07–1.98 (2H, m), 1.06 (9H, s), 1.04 (9H, s), 0.28
(6H, s), 0.15 (6H, s) ppm. 13C NMR (100 MHz, CDCl3): d
189.4, 171.0, 159.2, 157.5, 123.8, 123.1, 122.2, 118.2, 93.9,

W.-G. Wei et al. / Tetrahedron 61 (2005) 11882–11886
11885
79.2, 63.2, 27.7, 25.9 (!3), 25.7 (!3), 20.9, 18.6, 18.3,
16.6, 10.9, K3.6 (K2), K4.1 (!2) ppm. IR (film): nmax
2957, 2932, 1745, 1696, 1576, 1548, 1473, 1237, 1153, 840,
827 cmK1. HRMS (ESI, m/z) calcd for C27H45O5Si2 (MC
HC): 505.2806; found: 505.2804.
(100 MHz, CDCl3): d 157.2, 154.3, 149.2, 130.2, 118.4,
111.1, 107.5, 101.7, 64.9, 62.3, 30.2, 30.0, 25.9 (!3), 25.8
(!3), 18.5, 18.3, 11.4, K3.6 (!2), K4.2 (!2) ppm. IR
(film): nmax 3464, 2932, 2860, 1744, 1652, 1604, 1567,
1474, 1423, 1256, 1128, 1049, 973, 840, 781 cmK1
.
MALDI-FTMS (DHB, m/z) calcd for C25H44O4Si2Na
(MCNaC): 487.2676; found 487.2683.
4.1.5. Acetic acid 5-[3,5-bis(tert-butyldimethylsilanyl
oxy)-2-hydroxymethyl-4-methylphenyl]pent-4-ynyl
ester (12). To a pre-cooled solution of aldehyde 11 (1.5 g,
3.0 mmol) in ethanol (40 mL) was added NaBH4 (170 mg,
4.5 mmol) at 0 8C. 5 min later, aq NH4Cl was added slowly
to quench the reaction. The mixture was then diluted with
ethyl acetate (200 mL). The organic layer was separated and
washed with H2O and brine, dried over Na2SO4, filtered,
concentrated. The residue was purified by silica gel column
chromatography (hexane/ethyl acetateZ4:1) to give 12
(1.1 g, 75%) as a colorless oil. 1H NMR (300 MHz, CDCl3):
d 6.56 (1H, s), 4.71 (2H, d, JZ6.3 Hz), 4.24 (2H, t, JZ
6.3 Hz), 2.55 (2H, t, JZ7.2 Hz), 2.45 (1H, t, JZ6.3 Hz),
2.07 (s, 3H), 2.06 (s, 3H), 2.00–1.91 (m, 2H), 1.04 (s, 9H),
1.00 (s, 9H), 0.21 (s, 6H), 0.18 (s, 6H) ppm. 13C NMR
(100 MHz, CDCl3): d 171.1, 154.1, 152.6, 127.1, 121.8,
121.0, 116.5, 91.9, 79.6, 63.1, 58.9, 27.9, 26.1 (!3), 25.8
(!3), 20.9, 18.7, 18.3, 16.4, 11.9, K3.6 (!2), K4.2 (!
2) ppm. IR (film): nmax 3600, 2958, 2860, 1744, 1593, 1556,
1472, 1254, 1145, 1114, 898, 828, 782 cmK1. HRMS (ESI,
m/z) calcd for C27H46O5Si2Na (MCNaC): 529.2781; found
529.2774.
4.1.8. Compound 16. To a solution of alcohol 14 (80 mg,
0.17 mmol) in CH3CN (50 mL) and aq NaHCO3 (5 mL) was
added iodine (87 mg, 0.34 mmol). The mixture was stirred
at rt overnight, and then quenched by aq Na2S2O3, extracted
with ethyl acetate (3!50 mL). The combined organic
phases were washed with H2O and brine, dried over
anhydrous Na2SO4, filtered and concentrated. The residue
was purified on silica gel column (hexane/ethyl acetateZ
5:1) to give 16 (72 mg, 86%) as mixture of two isomers.
1
Data of the major isomer (70 mg): H NMR (300 MHz,
CDCl3): d 6.55 (1H, s), 4.69 (2H, s), 4.16 (1H, d, JZ
10.2 Hz), 4.05–4.00 (2H, m), 2.18–2.14 (2H, m), 2.05 (3H,
s), 2.00–1.96 (2H, m), 1.01 (18H, s), 0.22 (12H, s) ppm. 13C
NMR (100 MHz, CDCl3): d 153.8, 149.9, 132.7, 120.3,
117.7, 113.1, 107.2, 69.6, 69.4, 60.4, 34.5, 26.1 (!3), 25.8
(!3), 23.8, 18.8, 18.3, 11.4, K2.8, K3.0, K4.1,
K4.2 ppm. IR (film): nmax 3423, 2931, 2860, 1608, 1585,
1474, 1256, 1126, 1041, 904, 833, 780 cmK1. HR-MS (ESI,
m/z) calcd for C25H44O5Si2Na (MCNaC) 503.2625; found
503.2621.
4.1.6. Acetic acid 3-[6,8-bis(tert-butyldimethylsilanyl
oxy)-7-methyl-1H-2-benzopyran-3-yl]propyl ester (13).
To a mixture of 12 (120 mg, 0.24 mmol) in 1,4-dioxane
(60 mL) was added PdCl2(PPh3)2 (17 mg, 0.024 mmol)
under N2. The mixture was warmed to 85 8C and stirred at
same temperature for 4 h. The solvent was removed under
reduced pressure, and the residue was purified directly on
silica gel column (hexane/ethyl acetateZ20:1) to afford 13
(86 mg, 72%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): d 6.12 (1H, s), 5.56 (1H, s), 4.98 (2H, s), 4.13 (2H,
t, JZ6.6 Hz), 2.26 (2H, t, JZ7.5 Hz), 2.06 (3H, s), 2.03
(3H, s), 1.95–1.86 (2H, m), 1.03 (9H, s), 1.01 (9H, s), 0.20
(6H, s), 0.15 (6H, s) ppm. 13C NMR (100 MHz, CDCl3): d
171.1, 156.7, 154.3, 149.3, 130.2, 118.3, 111.2, 107.5,
101.7, 65.0, 63.9, 30.1, 26.2, 26.0 (!3), 25.8 (!3), 20.9,
18.6, 18.3, 11.4, K3.5 (!2), K4.2 (!2) ppm. IR (film):
nmax 2931, 2860, 1650, 1604, 1566, 1474, 1423, 1257, 1127,
840, 780 cmK1. MALDI-FTMS (DHB, m/z) calcd for
C27H46O5Si2Na (MCNaC): 529.2781; found 529.2761.
4.1.9. Compound 17. To a solution of alcohol 16 (58 mg,
0.12 mmol) in dichloromethane (10 mL) was added Dess–
Martin periodinane10 (76 mg, 0.18 mmol) at rt. The reaction
was stirred for 3 h and quenched by adding aq Na2S2O3 and
aq NaHCO3. Stirring was continued until the mixture turned
clear. The mixture was extracted with ethyl acetate (3!
50 mL). The combined organic layers were washed with
water and brine, dried over Na2SO4, filtered, concentrated.
Purification on silica gel column (hexane/ethyl acetateZ
1
10:1) gave 17 (56 mg, 97%) as a colorless oil. H NMR
(400 MHz, CDCl3): d 7.17 (1H, s), 5.01 (1H, d, JZ
15.4 Hz), 4.74 (1H, d, JZ15.4 Hz), 4.14–4.06 (1H, m), 4.04
(1H, dd, JZ14.6, 7.7 Hz), 2.73 (1H, dt, JZ12.9, 8.8 Hz),
2.16–2.08 (2H, m), 2.12 (3H, s), 1.88 (1H, ddd, JZ12.7, 8.1,
4.4 Hz), 1.03 (9H, s), 1.01 (9H, s), 0.234 (3H, s), 0.230 (3H,
s), 0.20 (3H, s), 0.19 (3H, s) ppm. 13C NMR (100 MHz,
CDCl3): d 188.9, 154.2, 149.7, 127.7, 127.0, 126.4, 109.8,
105.4, 70.2, 59.1, 33.1, 26.0 (!3), 25.8 (!3), 24.9, 18.7,
18.3, 12.1, K2.9, K3.3, K4.3 (!2) ppm. IR (film): nmax
2958, 2932, 1702, 1597, 1467, 1321, 1261, 1133, 1050, 886,
829, 782 cmK1. HR-MS (ESI, m/z) calcd for C25H42O5Si2-
Na (MCNaC) 501.2468; found 501.2463.
4.1.7. 3-[6,8-Bis(tert-butyldimethylsilanyloxy)-7-methyl-
1H-2-benzopyran-3-yl]propan-1-ol (14). To a solution of
13 (80 mg, 0.16 mmol) in methanol (10 mL) was added
K2CO3 (87 mg, 0.63 mmol). The whole mixture was stirred
at rt for 2 h. The mixture was then diluted with CH2Cl2
(100 mL) and saturated NH4Cl solution (20 mL). The
organic layer was separated and then washed with H2O
and brine, dried over Na2SO4, filtered, concentrated. The
residue was purified by silica gel chromatography (hexane/
ethyl acetateZ4:1) to afford alcohol 14 (71 mg, 97%) as a
4.1.10. (G)-Terreinol. A solution of compound 17 (42 mg,
0.088 mmol) in THF (10 mL) was treated with TBAF
(1.0 M in THF, 170 mL, 0.17 mmol) at rt for 10 min. The
solvent was removed under reduced pressure. The residue
was purified directly on silica gel column (hexane/ethyl
acetateZ5:1) to afford racemic terreinol (22 mg, 98%) as a
1
white wax. H NMR (400 MHz, CD3OD): d 6.97 (1H, s),
1
colorless oil. H NMR (300 MHz, CDCl3): d 6.13 (1H, s)
4.94 (1H, d, JZ15.7 Hz), 4.74 (1H, d, JZ15.7 Hz), 4.08–
4.03 (1H, m), 3.97 (1H, dd, JZ15.1, 7.6 Hz), 2.63 (1H,
dt, JZ12.8, 8.8 Hz), 2.13 (3H, s), 2.13–2.09 (1H, m),
2.04–2.00 (1H, m), 1.89 (1H, ddd, JZ12.7, 8.1,
5.58 (1H, s), 4.99 (2H, s), 3.72 (2H, t, JZ5.7 Hz), 2.29 (2H,
t, JZ7.2 Hz), 2.03 (3H, s), 1.88–1.79 (2H, m), 1.04 (9H, s),
1.01 (9H, s), 0.20 (6H, s), 0.15 (6H, s) ppm. 13C NMR

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W.-G. Wei et al. / Tetrahedron 61 (2005) 11882–11886
4.5 Hz) ppm. 13C NMR (100 MHz, CD3OD): d 191.2,
157.1, 152.8, 128.3, 123.5, 121.2, 107.1, 105.2, 71.5, 60.1,
34.2, 26.3, 9.8 ppm. IR (KBr): nmax 3405, 2509, 2075, 1690,
1438, 1353, 1119, 974 cmK1. HR-MS (ESI, m/z) calcd for
C13H14O5Na (MCNaC) 273.0739; found 273.0736.
4. Zhu, J.-L.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int.
Ed. 2004, 43, 1239–1243.
5. Fkyerat, A.; Dubin, G.-M.; Tabacchi, R. Helv. Chim. Acta
1999, 82, 1418–1422.
6. White, J. D.; Kim, T.-S.; Nambu, M. J. Am. Chem. Soc. 1997,
119, 103–111.
7. (a) Weingarten, M. D.; Padwa, A. Tetrahedron Lett. 1995, 36,
4717–4720. (b) Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara,
A.; Sakamoto, T. Tetrahedron 2001, 57, 9697–9710. (c)
Gabriele, B.; Salerno, G.; Fazio, A.; Pittelli, R. Tetrahedron
2003, 59, 6251–6259.
Acknowledgements
This work was financially supported by the Major State
Basic Research and Development Program (G2000077500),
NSFC (20432020, 20425205 and 20321202), the Chinese
Academy of Sciences (KGCX2-SW-209) and Shanghai
Municipal Commission of Science and Technology
(04DZ14901). The authors thank Dr. Terrence R. Burke,
Jr. for helpful comments.
1
8. Data for compound (19): H NMR (300 MHz, CDCl3) d 6.23
(1H, s), 4.65 (2H, s), 3.97 (2H, t, JZ6.9 Hz), 3.09 (1H, d, JZ
16.5 Hz), 2.68 (1H, d, JZ16.5 Hz), 2.15–1.82 (4H, m), 2.00
(3H, s), 0.98 (9H, s), 0.97 (9H, s), 0.17 (6H, s), 0.15 (6H,
s) ppm.
9. (a) Rousseau, G.; Robin, S. Tetrahedron 1998, 54, 13681. (b)
Harding, K. E.; Tinger, T. H. In Trost, B. M., Fleming, I., Eds.;
Comprehensive Organic Synthesis; Pergamon: Oxford, 1991;
Vol. 4, p 463. (c) Mulzer, J. In Organic Synthesis Highlights;
Mulzer, J., Altenbach, H. J., Braun, M., Krohn, K., Reissig,
H. U., Eds.; VCH: Weinheim, 1991; p 157.
References and notes
1. Simpson, T. J. Top. Curr. Chem. 1998, 195, 1.
2. Alberts, A. W.; Chen, J.; Kuron, G.; Hunt, V.; Huff, J.;
Hoffman, C.; Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.;
Patchett, A.; Monaghan, R.; Currie, S.; Stapley, E.; Albers-
Schonberg, G.; Hensens, O.; Hirshfield, J.; Hoog-steen, K.;
Liesch, J.; Springer, J. Proc. Natl. Acad. Sci. U.S.A. 1980, 77,
3957.
10. (a) Dess, B. D.; Martin, J. C. J. Org. Chem. 1983, 48,
4155–4156. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58,
2899. (c) Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.
Chem. 1999, 64, 4537–4538.
11. The O,O0-dimethyl derivative of (G)-terreinol was also
synthesized by a similar way. However, the final deprotections
were unsuccessful by using a variety of conditions.
3. (a) Macedo, F. C., Jr.; Porto, A. L. M.; Marsaioli, A. J.
Tetrahedron Lett. 2004, 45, 53–55. (b) DeMacedo, F. C., Jr.;
Marsaioli, A. J. Magn. Reson. Chem. 2005, 43, 251–255.