Hyrtiosanes from labdanes: (-)-Hyrtiosal from sclareol

Article abstract of DOI:10.1055/s-2002-33332

(-)-Hyrtiosal and its C-16 epimer have been prepared from sclareol in moderate yield. The absolute configuration of natural product (-)-hyrtiosal has being determined.

Full text of DOI:10.1055/s-2002-33332

PAPER
1523
Hyrtiosanes from Labdanes: (–)-Hyrtiosal from Sclareol
Hyrtiosanes
fr
i
L
ab
l
danes:
a
(–)-Hyrtios
r
al
f
rom
SclareB
ol asabe,*a Alberto Diego,a David Díez,a Isidro S. Marcos,a Faustino Mollinedo,b Julio G. Uronesa
a
Departimento de Química Orgánica, Universidad de Salamanca, Plaza de los Caídos 1–5, 37008 Salamanca, Spain
Fax +34(923)294574; E-mail: pbb@usal.es
b
Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
Received 18 December 2001; revised 8 May 2002
In the synthesis of ent-cheilanthenediol Heissler et al.4 de-
scribed the rearrangement of an epoxide on a tricyclic
skeleton to an ent-hyrtiosal derivative using lithium di-
isobutyl-n-butylaluminium hydride in refluxing toluene.
In our case the rearrangement of 1 was done with
BF3 Et2O to give aldehyde 2 in 96% yield by the mecha-
nism shown in Scheme 2. The absolute configuration of 2
was confirmed by X-ray analysis of its derivative 5, as
will be shown later.
Abstract: (–)-Hyrtiosal and its C-16 epimer have been prepared
from sclareol in moderate yield. The absolute configuration of na-
tural product (–)-hyrtiosal has being determined.
Key words: terpenoids, labdanes, hyrtiosal, sclareol, natural prod-
ucts, coupling, antitumor agents
Hyrtiosal, a new sesterterpenoid possessing a novel ar-
rangement of a tricarbocyclic skeleton of unknown abso-
lute stereochemistry was isolated1 from the okinawan
marine sponge Hyrtios erectus. This compound inhibited
the proliferation of KB cells in vitro. Hyrtiosal possesses
a new carbon skeleton that was called hyrtiosane (Figure).
Recently, we reported the synthesis and absolute configu-
ration of hyrtiosal.2
-
-
+
O
-
BF3
O
BF3
O
+
BF3
CHO
+
CO2Me
CO2Me
CO2Me
CO2Me
2
1
Scheme 2
24
The synthesis of sesterterpene hyrtiosal was planned via
the introduction of a furan ring to aldehyde 8 (Scheme 3).
Therefore, at the outset, homologation of compound 2 was
required.
13
23
12
11
CHO
H
22
1
4
OH
16
18
14
17
25
9
10
8
7
19
5
3
O
H
Before the homologation was attempted it was necessary
to protect the aldehyde functionality in 2 using a dithioac-
etal, and in turn to transform the methyl ester into an alde-
hyde.
21
20
(–)-Hyrtiosal
Hyrtiosane skeleton
Figure
As shown in Scheme 3 the following reactions were car-
ried out. Treatment of 2 with ethylendithiol led to com-
pound 3. Reduction of 3 to the aldehyde did not take place
in one step; it was necessary to use DIBALH reduction to
give alcohol 4 in an excellent 94% yield. The subsequent
oxidation of 4 to give 5 could be done either with CrO3 in
pyridine5 or by tetrapropylammonium perruthenate
(TPAP) oxidation.6 The first oxidation gave 61% yield of
the required aldehyde 5 and 11% of a mixture 1:1 of sul-
foxides 6a,b. In the second oxidation, the yield to alde-
hyde 5 dropped to 45%, and the sulfoxides were obtained
in 27% yield.
According to the biosynthetic model for hyrtiosal pro-
posed by Iguchi et al1 from a cheilanthane skeleton, our
synthetic strategy starts from epoxide 1, itself synthesized
from methyl isoanticopalate obtained from sclareol3
(Scheme 1). This constitutes a new route to compounds
with the hyrtiosane skeleton from a compound with a lab-
dane skeleton (sclareol).
O
12
16
11
20
17
1
CO2Me
14
m-CPBA/DCM,
9
CO2Me
15
10
5
4
3
7
H
Aldehyde 5 was crystallized in hexane–benzene and its
absolute configuration was determined by X-ray analy-
sis,7 confirming its stereochemistry, as well as that of al-
dehyde 2.
10 °C,12 h, 71%
H
1
Methyl isoanticopalate
19
18
Scheme 1
Treatment of aldehyde 5 with (methoxymethyl)triphe-
nylphosphonium chloride using NaHMDS as base8 led to
a 1:4 mixture of inseparable enol ethers 7a,b in a 92%
yield. Treatment of 7a,b with p-TsOH gave the homolo-
gated aldehyde 8 in a 98% yield.
Synthesis 2002, No. 11, Print: 22 08 2002.
Art Id.1437-210X,E;2002,0,11,1523,1529,ftx,en;E08601SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1524
P. Basabe et al.
PAPER
S
conditions gave a 3:7 mixture of 11 and 12 in 86% yield.
However, when the deprotection of 9 and 10 was carried
out with [bis(trifluoroacetoxy)iodo]benzene,10 there was
no epimerization but the yield dropped to 15% in both cas-
es.
16
12
13
CHO
11
S
20
17
1
14
a
COOMe
9
COOMe
10
8
7
15
S
5
87%
3
4
H
H
3
19
2
18
O
b
94%
S
8
a
S
S
24
S
CH2OH
CHO
S
S
12
c
11
22
H
S
H
23
OH
17
4
1
4
OH
6a/6b
11%
+
S
14
18
H
H
16
S
S
16
19
10
8
7
12
15
13
5
11
3
25
O
20
O
17
H
1
4
15
S
14
H
44%
9
10 32%
21
20
9
10
d
8
7
OMe
CHO
15a
b
3 : 7
b
5
15%
c
3
15%
c
92%
3 : 1
89%
OH
H
86%
7a/7b
H
5
19
18
CHO
H
CHO
H
61%
e
OH
98%
S
S
+
O
O
H
H
12
11
CHO
15
( Hyrtiosal)
15a
H
Scheme 4 a) BuLi, 3-bromofuran, THF, –78 ºC, 1 h.; b) Hg(ClO4)2,
CaCO3, THF, H2O, r.t., 10 min.; c) PhI(O2CCF3)2, MeOH–H2O 99:1,
r.t., 10 min.
8
Scheme 3 a) Ethanedithiol, DCM, r.t.; b) DIBAL, DCM, –78 ºC, 1
h.; c) CrO3, pyridine, r.t., 0.25 h [or TPAP, N-methylmorpholine N-
oxide (NMO), DCM, r.t.; 5: 45%, 6a,b: 27%]; d) Ph3P=CHOMe,
NaHMDS, THF, –78 ºC, 1 h.; e) acetone, p-TsOH, r.t.
In order to assure no epimerization at C-16 during depro-
tection whilst keeping high yields, acetylation of the hy-
droxy group was planned Scheme 5. Acetylation of
compound 10 with Ac2O–pyridine gave 13, in quantita-
tive yield. After treatment with Hg(ClO4)2 this led to alde-
hyde 14 in 75% yield. This compound was transformed
under basic conditions into aldehyde 12. The physical
properties of compound 12 were identical to those of (–)-
hyrtiosal. As the stereochemistry of (–)-hyrtiosal has been
determined by Iguchi et al.1 by two dimensional NOESY
experiments, corroborated by our NOE studies, the stereo-
chemistry of 10 is established as the one of compound 9
shown in Scheme 4.
Once obtained it was necessary to couple aldehyde 8 with
an organometallic species. In this regard, 3-lithiofuran
was chosen due to its reactivity towards aldehydes. Gen-
eration of the organometallic reagent was done by treat-
ment of 3-bromofuran with BuLi. This was then reacted
with aldehyde 8 to give a 4:3 mixture of furano derivatives
9 and 10 (Scheme 4) that were separated by column chro-
matography. The stereochemistry of both compounds was
determined later on.
For the deprotection of the aldehyde different reagents
were tested. Treatment of 9 with Hg(ClO4)2 gave a 3:1
mixture of 11 and 12 in 89% yield, that were separated by
column chromatography. Treatment of 10 in the same
9
The same reaction sequence, as described in Scheme 5 has
been followed with the other alcohol 9 giving 15, 16 and
11 epimers on C-16 of 13, 14 and 12, respectively.
S
S
S
S
OH
OAc
H
H
a
quantitative
O
O
H
H
13
10
75%
b
CHO
H
CHO
H
OH
OAc
c
99%
O
O
H
H
12
14
Scheme 5 a) Ac2O, pyridine, r.t.; b) Hg(ClO4)2,CaCO3, THF, H2O, r.t., 0.1 h.; c) K2CO3, MeOH (2%), r.t., 2 h.
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Hyrtiosanes from Labdanes: (–)-Hyrtiosal from Sclareol
1525
13C NMR (50 MHz, CDCl3): = 172.6 (C-15), 62.1 (C-12), 60.3
(C-14), 56.9 (C-13), 56.4 (C-5), 51.0 (CO2Me), 50.3 (C-9), 41.9 (C-
3), 40.4 (C-7), 39.5 (C-1), 37.3 (C-10), 36.1 (C-8), 33.5 (C-18), 33.1
(C-4), 21.8 (C-11), 21.7 (C-19), 22.4 (C-16), 18.4 (C-2, C-6), 15.8
(C-17), 15.1 (C-20).
EIMS: m/z (%) = 334 (M)+ (36), 319 (80), 301 (71), 205 (53), 191
(64), 177 (91), 143 (73), 123 (68), 95 (75), 81 (100), 69 (80).
The antitumor activity of the compounds 11 and 12 was
evaluated in a number of human tumor cell lines by mea-
suring the metabolic activity of viable cells by the XTT
assay. The following cell lines were examined: HL-60
(human acute leukemia), HeLa (human cervix carcino-
ma), HT-29 (human colon carcinoma), and A549 (human
lung carcinoma). Both compounds exert an antiprolifera-
tive effect on human tumor cells, derived from leukemia
and solid tumors, with an IC50 value ranging between 2.4
and 16.2 M. Both compounds have similar IC50 values
against a number of human tumor cell lines, suggesting a
similar antineoplastic activity. Leukemic cells seem to be
slightly more sensitive to the antiproliferative action of
both compounds. Within solid tumor cell lines, HeLa cells
were slightly more sensitive to the action of 12 and 11,
suggesting a certain higher sensitivity of cervix carcinoma
to the antiproliferative action of these compounds. Com-
pound 11 showed a slightly higher antineoplastic activity
against HeLa cells than 12.
HRMS (EI): m/z calcd for C21H34O3 (M)+: 334.2508; found:
334.2511.
Methyl 13S-11(12 13)-abeo-12-Oxoisoanticopal-15-oate (2)
To a stirred solution of 1 (367.1 mg, 1.1 mmol) in anhyd benzene (8
mL) at 0 °C, was added BF3 Et2O (5 mL) under argon. The mixture
was heated up to 60 °C over 1 h and was poured into H2O (8 mL).
This solution was removed by extraction with Et2O (3 100 mL).
The organic layer was washed with aq NaHCO3 (10%, 3 25 mL)
and H2O (3 25 mL), dried (Na2SO4) and concentrated under re-
duced pressure to give 2.
Yield: 356 mg (96%); colorless solid; [ ]D20 –10.3 (c 0.94, CHCl3).
IR (neat): 2850, 1740, 1730, 1450, 1390, 1190 cm–1.
1H NMR (200 MHz, CDCl3): = 9.46 (1 H, s, H-12), 3.62 (3 H, s,
CO2Me), 2.80 (1 H, s, H-14), 2.03 (1 H, dt, J = 12.0, 3.2, H-7A),
1.94 (1 H, dd, J = 12.0, 5.6, H-11A), 1.65–1.37 (9 H, m), 1.35 (3 H,
s, Me-16), 1.32–0.90 (3 H, m), 1.12 (3 H, s, Me-18), 0.88 (3 H, s,
Me-17), 0.85 (3 H, s, Me-19), 0.82 (3 H, s, Me-20).
13C NMR (50 MHz, CDCl3): = 202.7 (C-12), 171.6 (C-15), 59.9
(C-14), 57.7 (C-9), 57.1 (C-5), 52.6 (C-13), 50.9 (CO2Me), 45.1 (C-
8), 42,3 (C-3), 40.5 (C-7), 40.0 (C-1), 36.8 (C-10), 33.4 (C-18), 33.0
(C-11), 32.9 (C-4), 21.2 (C-19), 18.9 (C-2), 20.6 (C-16), 18.1 (C-6),
16.7 (C-17), 15.7 (C-20).
In this paper a simple route for the synthesis of (–)-hyr-
tiosal from methyl isoanticopalate has been described,
having stated the absolute configuration. This methodolo-
gy paves the way for the transformation of labdanes to
hyrtiosanes.
Unless otherwise stated, all chemicals were purchased as the high-
est purity commercially available and were used without further pu-
rification. Mps were determined with a Kofler hot stage mp
apparatus and are uncorrected. IR spectra were recorded on a
FABMS: m/z (%) = 335 (M + H)+ (8), 303 (24), 245 (6), 191 (10),
154 (100), 107 (51), 69 (78).
1
BOMEM 100 FT IR spectrophotometer. H and 13C NMR spectra
were performed in CDCl3 and referenced to the residual peak of
CHCl3 at = 7.26 and = 77.0 for 1H and 13C, respectively, using a
Bruker WP-200 SY and a Bruker DRX 400 MHz. Chemical shifts
are reported in , ppm and coupling constants (J) are given in Hz.
MS were performed in a VG-TS 250 spectrometer at 70 eV ionizing
voltage. Mass spectra are presented as m/z (% rel. int.). HRMS were
recorded in a VG Platform spectrometer using electronic impact
(EI) or fast atom bombardment (FAB) technique. Optical rotations
were determined in a Perkin-Elmer 241 polarimeter in 1 dm cells.
Et2O, THF and benzene were distilled from sodium, and pyridine
and CH2Cl2 were distilled under argon from CaH2.
HRMS (FAB): m/z calcd for C21H35O3 (M + H)+: 335.2585; found:
335.2583.
Methyl 13S-11(12 13)-abeo-12-Ethylenedithiaisoanticopal-15-
oate (3)
To a solution of 2 (367 mg, 1.1 mmol) in anhyd CH2Cl2 (8 mL) was
added 1,2-ethanedithiol (0.14 mL, 1.65 mmol) and BF3 Et2O (0.03
mL) under argon. After the solution was stirred for 12 h at r.t., aq
NaHCO3 (10%, 5 mL) was added and the aq layer was extracted
with Et2O (3 100 mL). The organic layer was washed with brine
(3 25 mL), dried (Na2SO4) and concentrated under reduced pres-
sure. Flash chromatography (hexane–EtOAc, 95:5) provided 3.
Yield: 393.7 mg (87%); colorless oil; [ ]D20 –12.7 (c 0.6, CHCl3).
IR (neat): 2930, 1736, 1458, 1433, 1389, 1159 cm–1.
1H NMR (400 MHz, CDCl3): = 4.85 (1 H, s, H-12), 3.62 (3 H, s,
CO2Me), 3.32–3.10 (4 H, m, SCH2CH2S), 2.47 (1 H, s, H-14), 1.80
(1 H, dt, J = 12.0, 3.2, H-7A), 1.73 (1 H, dt, J = 12.0, 5.6, H-11A),
1.68–1.37 (8 H, m), 1.39 (3 H, s, Me-16), 1.36–0.88 (4 H, m), 1.01
(3 H, s, Me-18), 0.86 (3 H, s, Me-17), 0.84 (3 H, s, Me-19), 0.82 (3
H, s, Me-20).
Methyl 12 ,13 -Epoxyisoanticopal-15-oate (1)
To an ice cooled solution of methyl isoanticopalate (7.0 g, 22.3
mmol) in anhyd CH2Cl2 (500 mL), was added MCPBA (7.0 g, 40.6
mmol) and the flask was stoppered with a drying tube containing
CaCl2. After being stirred for 12 h, the solution was diluted with
Et2O (600 mL) and washed successively with aq Na2SO3 (10%,
3
100 mL), aq NaHCO3 (6%, 3 100 mL) and H2O (3 100 mL).
The organic layer was dried (Na2SO4) and concentrated under re-
duced pressure. The residue was purified by silica gel chromatogra-
phy (hexane–EtOAc, 95:5) to give 1.
13C NMR (100 MHz, CDCl3): = 172.5 (C-15), 68.0 (C-12), 62.7
(C-14), 59.9 (C-9), 57.4 (C-5), 50.8 (CO2Me), 48.1 (C-13), 46.2 (C-
8), 42.4 (C-3), 40.8 (C-1), 40.0 (C-7), 39.1 and 38.5 (SCH2CH2S),
36.9 (C-10), 36.3 (C-11), 33.4 (C-18), 33.0 (C-4), 27.0 (C-16), 21.2
(C-19), 18.9 (C-2), 18.2 (C-6), 17.1 (C-17), 15.6 (C-20).
EIMS: m/z (%) = 410 (M)+ (8), 305 (22), 153 (44), 105 (78), 77
(100).
Yield: 5.3 g (71%); colorless solid; mp 155–157 °C (crystals were
obtained from hexane–Et2O); [ ]D20 –23.0 (c 0.85, CHCl3).
IR (neat): 1740, 1450, 1320, 1200, 1170, 1110, 1010 cm–1.
1H NMR (200 MHz, CDCl3): = 3.67 (3 H, s, CO2Me), 3.05 (1 H,
br s, H-12), 2.47 (1 H, s, H-14), 2.02 (1 H, dd, J = 14.8, 4.8, H-11A),
1.80–1.68 (2 H, m), 1.65–1.42 (4 H, m), 1.35–1.13 (4 H, m), 1.29 (3
H, s, Me-16), 1.07 (3 H, s, Me-17), 0.97 (1 H, dd, J = 12.4, 4.8, H-
9), 0.97–0.80 (2 H, m), 0.89 (3 H, s, Me-20), 0.83 (3 H, s, Me-18),
0.80 (3 H, s, Me-19).
HRMS (EI): m/z calcd for C23H38O2S2 (M)+: 410.2313; found:
410.2317.
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York

1526
P. Basabe et al.
PAPER
13S-11(12 13)-abeo-12-Ethylenedithiaisoanticopal-15-ol (4)
To a solution of 3 (211 mg, 0.5 mmol) in anhyd CH2Cl2 (9 mL) was
added a solution of DIBALH in toluene (1.6 N, 0.7 mL, 1.02 mmol)
under argon at –78 °C. The solution was stirred for 1 h, quenched
by addition of MeOH (5 mL) and H2O (5 mL), and extracted with
Et2O (3 100 mL). The organic layer was washed with H2O (3 30
mL), dried (Na2SO4) and evaporated under reduced pressure to give
4.
IR (neat): 2930, 1709, 1456, 1387, 1044 cm–1.
1H NMR (400 MHz, CDCl3): = 9.91 (1 H, d, J = 3.2, H-15), 4.77
(1 H, s, H-12), 3.30–3.10 (4 H, m, SCH2CH2S), 2.20 (1 H, d, J = 3.2,
H-14), 1.90 (1 H, dt, J = 12.0, 2.8, H-7A), 1.71 (1 H, dd, J = 12.0,
5.6, H-11A), 1.67–1.10 (10 H, m), 1.54 (3 H, s, Me-16), 1.04 (3 H,
s, Me-18), 0.98–0.80 (2 H, m), 0.85 (3 H, s, Me-17), 0.84 (3 H, s,
Me-19), 0.81 (3 H, s, Me-20).
13C NMR (100 MHz, CDCl3): = 205.8 (C-15), 68.1 (C-12), 67.9
(C-14), 59.7 (C-9), 57.3 (C-5), 47.7 (C-8), 47.2 (C-13), 42.4 (C-3),
40.7 (C-7), 40.0 (C-1), 39.1 and 38.6 (SCH2CH2S), 37.8 (C-11),
36.9 (C-10), 33.4 (C-18), 33.0 (C-4), 26.0 (C-16), 21.2 (C-19), 18.5
(C-2), 18.2 (C-6), 17.6 (C-17), 15.7 (C-20).
EIMS: m/z (%) = 380 (M)+ (1), 352 (15), 275 (6), 134 (8), 105
(100).
HRMS (EI): m/z calcd for C22H36OS2 (M)+: 380.2208; found:
380.2207.
20
Yield: 180 mg (94%); colorless oily residue; [ ]D –12.6 (c 0.52,
CHCl3).
IR (neat): 3418, 2947, 1458, 1387, 1277, 1022 cm–1.
1H NMR (400 MHz, CDCl3): = 4.81 (1 H, s, H-12), 3.74 (1 H, dd,
J = 11.2, 8.4, H-15A), 3.60 (1 H, dt, J = 11.2, 5.6, H-15B), 3.27–3.14
(4 H, m, SCH2CH2S), 1.83 (1 H, dt, J = 12.0, 2.8, H-7A), 1.72 (1 H,
dt, J = 12.0, 5.6, H-11A), 1.63 (1 H, dt, J = 8.4, 5.6, H-14), 1.61–
1.30 (9 H, m), 1.30–1.15 (2 H, m), 1.18 (3 H, s, Me-16), 1.00–0.80
(2 H, m), 0.83 (3 H, s, Me-18), 0.80 (3 H, s, Me-19), 0.79 (6 H, s,
Me-20 and Me-17).
13C NMR (100 MHz, CDCl3): = 68.1 (C-12), 60.5 (C-9), 60.3 (C-
15), 59.3 (C-14), 57.5 (C-5), 47.3 (C-13), 45.1 (C-8), 42.4 (C-3),
41.5 (C-7), 40.1 (C-1), 38.8 and 38.5 (SCH2CH2S), 37.2 (C-11),
36.7 (C-10), 33.4 (C-18), 33.0 (C-4), 24.4 (C-16) 21.2 (C-19), 18.9
(C-2), 18.3 (C-6), 16.2 (C-17), 15.9 (C-20).
6a
1H NMR (400 MHz, CDCl3): = 9.88 (1 H, d, J = 2.4, H-15), 4.24
(1 H, s, H-12), 3.66 [1 H, ddd, J = 17.3, 12.5, 5.3, S(O)–CHA], 3.48–
3.30 [2 H, m, S(O)–CHB and S–CHB], 2.93 (1 H, ddd, J = 17.3,
14.4, 6.0, S–CHA), 2.19 (1 H, d, J = 2.4, H-14), 2.05 (1 H, dd,
J = 13.0, 6.1, H-7A), 1.90–1.59 (7 H, m), 1.56 (3 H, s, Me-16), 1.50–
1.10 (4 H, m), 1.09 (3 H, s, Me-18), 0.98–0.80 (2 H, m), 0.89 (3 H,
s, Me-17), 0.87 (3 H, s, Me-19), 0.83 (3 H, s, Me-20).
EIMS: m/z (%) = 382 (M)+ (2), 245 (35), 191 (10), 105 (100), 69
(100).
HRMS (EI): m/z calcd for C22H38OS2 (M)+: 382.2364; found:
382.2389.
6b
1H NMR (400 MHz, CDCl3): = 9.86 (1 H, d, J = 2.4, H-15), 4.20
(1 H, s, H-12), 3.61 [1 H, ddd, J = 16.3, 12.0, 4.8, S(O)–CHA], 3.48–
3.30 [2 H, m, S(O)–CHB and S–CHB], 2.83 (1 H, ddd, J = 16.3,
12.5, 6.6, S–CHA) 2.18 (1 H, d, J = 2.4, H-14), 2.05 (1 H, dd,
J = 13.0, 6.1, H-7A), 1.90–1.59 (7 H, m), 1.52 (3 H, s, Me-16), 1.50–
1.10 (4 H, m), 1.09 (3 H, s, Me-18), 0.98–0.80 (2 H, m), 0.88 (3 H,
s, Me-17), 0.86 (3 H, s, Me-19), 0.83 (3 H, s, Me-20).
13S-11(12 13)-abeo-12-Ethylenedithia-15-isoanticopalal (5)
and 13S-11(12 13)-abeo-12-(2-Oxo)ethylenedithia-15-isoanti-
copalal (6)
Method A
To a stirred solution of 4 (716 mg, 1.88 mmol) in anhyd CH2Cl2 (19
mL) with 4 Å molecular sieves, were added NMO (460 mg, 3.4
mmol) and TPAP (64 mg, 0.18 mmol). The mixture was stirred for
1 h, then the solution was diluted with EtOAc (250 mL), filtered
through a short pad of silica gel and Celite, and the solvent was
evaporated to provide an oily residue. Column chromatography (sil-
ica gel; benzene) gave starting material (56.9 mg), compound 5
(324.1 mg, 45%) as a colorless solid, and an unseparated 1:1 mix-
ture of 6a,b as a colorless solid (198.9 mg, 27%). The ratio of the
last compounds was calculated by integration of the signals in the
1H NMR for hydrogens H-12 and H-15.
6a,b
IR (neat): 2940, 1717, 1458, 1387, 1045 cm–1.
13C NMR (100 MHz, CDCl3): = 204.2/203.5 (C-15), 90.9 (C-12),
69.2/70.3 (C-14), 60.0 (C-9), 57.3 (C-5), 47.7 (C-8), 47.2 (C-13),
42.2 (C-3), 40.7/40.6 (C-7), 40.1/40.0 (C-1), 38.0/57.2
(SCH2CH2S), 31.3 (C-11), 36.9 (C-10), 33.4 (C-18), 33.0 (C-4),
26.4/25.1 (C-16), 21.2 (C-19), 18.5/18.4 (C-2), 18.1 (C-6), 17.7 (C-
17), 15.8 (C-20).
EIMS: m/z (%) = 396 (M)+ (15), 352 (7), 191 (13), 105 (55), 84
Method B
(100).
To a solution of pyridine (3.0 mL, 37.5 mmol) in anhyd CH2Cl2 (44
mL) was added CrO3 (1.7 g, 17.4 mmol). The mixture was stirred
for 15 min and then was added a solution of 4 (1.1 g, 2.9 mmol) in
CH2Cl2 (3 mL). The mixture was stirred at r.t. for 15 min. Then the
solution was diluted with EtOAc (100 mL) and filtered. The solid
residue was washed with EtOAc (3 50 mL) and the combined or-
ganic layers were washed successively with aq NaOH (4%, 3 30
mL), aq HCl (2 N, 3 30 mL), aq NaHCO3 (10%, 3 30 mL) and
brine (3 30 mL), dried (Na2SO4) and evaporated to give a solid
residue. The purification by silica gel chromatography (benzene)
gave firstly 5 (672 mg, 61%), starting material (153 mg), and an un-
separated 1:1 mixture of a colorless solid 6a,b (132 mg, 11%). The
ratio obtained for 6a,b in this reaction was identical to the one ob-
tained by method A.
HRMS (EI): m/z calcd for C22H36O2S2 (M)+: 396.2157; found:
396.2161.
(E/Z)-15a-homo-13S-11(12 13)-abeo-12-Ethylenedithia-
15,15a-ene-15-methoxyisoanticopalane (7a,b)
To a suspension of methoxymethyltriphenylphosphonium chloride
(1.5 g, 4.4 mmol) in anhyd THF (2.5 mL) under argon, was added a
solution of NaHMDS in THF (1 M; 4.4 mL, 4.4 mmol) at –78 °C.
The solution was stirred for 15–20 minutes and 5 (731 mg, 1.9
mmol) was added diluted in THF (3 mL) via cannula. The solution
was stirred for 1 h until no starting material remained. The solution
was quenched by addition of sat. aq NH4Cl (5 mL) and extracted
with Et2O (3 100 mL). The organic layer was washed with H2O
(3 30 mL), dried (Na2SO4) and evaporated to provide a solid res-
idue. Column chromatography (hexane–benzene, 8:2 and 1:1) gave
an unseparated mixture of 7a,b (E/Z, 1:4). The 1:4 ratio was estab-
lished by integration of the signals for H-15 and H-15a.
5
20
Mp 137 °C (crystals were obtained from hexane–benzene); [ ]D
+17.03 (c 1.18, CHCl3).
Yield: 724 mg (92%); colorless oil.
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Hyrtiosanes from Labdanes: (–)-Hyrtiosal from Sclareol
1527
7a
aq NH4Cl (2 mL) and extracted with Et2O (3 100 mL). The ethe-
real extracts were washed with H2O (3 30 mL) and brine (3 30
mL), dried (Na2SO4) and evaporated to provide an oily residue.
Flash chromatography (benzene) gave 9 and 10.
1H NMR (400 MHz, CDCl3): = 6.18 (1 H, d, J = 12.4, H-15), 4.71
(1 H, s, H-12), 4.67 (1 H, dd, J = 12.4, 10.4, H-15a), 3.55 (3 H, s,
MeO), 3.35–3.05 (4 H, m, SCH2CH2S), 2.58 (1 H, d, J = 10.4, H-
14), 1.85–1.20 (12 H, m), 1.17 (3 H, s, Me-16), 0.98–0.80 (2 H, m),
0.83 (3 H, s, Me-18), 0.81 (3 H, s, Me-17), 0.80 (3 H, s, Me-19),
0.79 (3 H, s, Me-20).
9
Yield: 148 mg, (44%); pale yellow oil; [ ]D20 +10.2 (c 1.26, CHCl3).
IR (neat): 3440, 2920, 1462, 1385, 1159, 1022, 874 cm–1.
7b
1H NMR (400 MHz, CDCl3): = 7.41 (1 H, s, H-19), 7.39 (1 H, s,
H-25), 6.42 (1 H, s, H-18), 4.81 (1 H, s, H-12), 4.73 (1 H, dd,
J = 9.0, 4.2, H-16), 3.27–3.14 (4 H, m, SCH2CH2S), 1.92 (1 H, ddd,
J = 13.2, 9.0, 4.2, H-15A), 1.82–1.21 (15 H, m), 1.16 (3 H, s, Me-
24), 1.00–0.88 (2 H, m), 0.89 (3 H, s, Me-20), 0.85 (6 H, s, Me-21
and Me-23), 0.82 (3 H, s, Me-22).
1H NMR (400 MHz, CDCl3): = 6.01 (1 H, d, J = 6.4, H-15), 4.78
(1 H, s, H-12), 4.36 (1 H, dd, J = 10.4, 6.4, H-15a), 3.55 (3 H, s,
MeO), 3.35–3.05 (4 H, m, SCH2CH2S), 2.58 (1 H, d, J = 10.4, H-
14), 1.85–1.20 (12 H, m), 1.17 (3 H, s, Me-16), 0.98–0.80 (2 H, m),
0.83 (3 H, s, Me-18), 0.81 (3 H, s, Me-17), 0.80 (3 H, s, Me-19),
0.79 (3 H, s, Me-20).
13C NMR (100 MHz, CDCl3): = 143.2 (C-19), 139.0 (C-25),
129.7 (C-17), 108.4 (C-18), 68.4 (C-12), 65.6 (C-16), 59.7 (C-9),
57.3 (C-5), 55.2 (C-14), 46.4 (C-13), 45.6 (C-8), 42.4 (C-3), 41.6
(C-7), 40.1 (C-1), 38.1 and 38.9 (SCH2CH2S), 36.7 (C-10), 35.4 (C-
15), 35.1 (C-11), 33.4 (C-20), 33.0 (C-4), 24.8 (C-24), 21.2 (C-21),
19.0 (C-2), 18.3 (C-6), 16.1 (C-23), 15.8 (C-22).
FABMS: m/z (%) = 463 (M + H)+ (3), 445 (3), 307 (19), 245 (9),
154 (100), 107 (28), 77 (27).
HRMS (FAB): m/z calcd for C27H43O2S2 (M + H)+: 463.2704;
found: 463.2701.
7a,b
IR (neat): 2920, 1659, 1462, 1381, 1271, 1109 cm–1.
13C NMR (100 MHz, CDCl3): = 147.3 (C-15), 104.0 (C-15a), 68.7
(C-12), 59.4 (C-9, MeO), 57.6 (C-5), 55.5 (C-14), 47.0 (C-13), 46.9
(C-8), 42.5/42.4 (C-3), 40.2 (C-1), 39.2 (C-7), 39.0/38.2
(SCH2CH2S), 36.8 (C-10), 36.2 (C-11), 33.5 (C-18), 33.1 (C-4),
23.4 (C-16), 21.2 (C-19), 18.8 (C-2), 18.3 (C-6), 16.5 (C-17), 15.7
(C-20).
EIMS: m/z (%) = 408 (M)+ (8), 308 (14), 271 (9), 245 (9), 205 (10),
155 (18), 105 (23).
HRMS (EI): m/z calcd for C24H40OS2 (M)+: 408.2520; found:
408.2523.
10
Yield: 106 mg (32%); pale yellow oil; [ ]D20 –12.8 (c 0.42, CHCl3).
IR (neat): 3435, 2940, 1385, 1022 cm–1.
15a-homo-13S-11(12 13)-abeo-12-Ethylenedithia-15-isoanti-
copalal (8)
1H NMR (400 MHz, CDCl3): = 7.41 (1 H, s, H-19), 7.39 (1 H, s,
H-25), 6.48 (1 H, s, H-18), 4.79 (1 H, t, J = 6.7, H-16), 4.73 (1 H, s,
H-12), 3.18–3.07 (4 H, m, SCH2CH2S), 1.91 (1 H, ddd, J = 12.9,
7.0, 6.5, H-15A), 1.86–1.65 (5 H, m), 1.60–1.25 (9 H, m), 1.16 (3 H,
s, Me-24), 1.10–0.90 (3 H, m), 0.88 (3 H, s, Me-20), 0.83 (3 H, s,
Me-21), 0.82 (3 H, s, Me-23), 0.81 (3 H, s, Me-22).
13C NMR (100 MHz, CDCl3): = 143.2 (C-19), 139.8 (C-25),
128.6 (C-17), 108.8 (C-18), 68.2 (C-12), 65.3 (C-16), 59.6 (C-9),
57.3 (C-5), 55.1 (C-14), 46.8 (C-13), 45.6 (C-8), 42.4 (C-3), 41.7
(C-7), 40.0 (C-1), 38.9 and 38.2 (SCH2CH2S), 36.7 (C-10), 35.4 (C-
15), 35.1 (C-11), 33.4 (C-20), 33.0 (C-4), 25.0 (C-24), 21.2 (C-21),
19.0 (C-2), 18.3 (C-6), 16.2 (C-23), 15.8 (C-22).
To a stirred solution of 7a,b (394 mg 0.97 mmol) in acetone and
H2O (20 mL, 99:1) was added p-TsOH (48 mg, 0.23 mmol). After
8 h, the solution was poured into H2O (5 mL) and extracted with
Et2O (3 100 mL). The organic layer was washed with aq NaHCO3
(10%, 3 30 mL) and H2O (3 30 mL), dried (Na2SO4) and con-
centrated by rotatory evaporation to give 8.
Yield: 376 mg (98%); colorless oil; [ ]D20 –23.8 (c 0.64, CHCl3).
IR (neat): 2930, 1724, 1464, 1385, 1275, 910, 733 cm–1.
1H NMR (400 MHz, CDCl3): = 9.71 (1 H, dd, J = 4.0, 1.5, H-15),
4.76 (1 H, s, H-12), 3.36–3.08 (4 H, m, SCH2CH2S), 2.64 (1 H, ddd,
J = 15.7, 5.0, 1.5, HA-15a), 2.38 (1 H, ddd, J = 15.7, 9.3, 4.0, HB-
15a), 2.04 (1 H, dd, J = 9.3, 5.0, H-14), 1.73 (1 H, dd, J = 12.0, 5.6,
H-11A), 1.70–1.13 (11 H, m), 1.11 (3 H, s, Me-16), 1.02–0.85 (2 H,
m), 0.83 (3 H, s, Me-18), 0.82 (3 H, s, Me-19), 0.81 (3 H, s, Me-17),
0.80 (3 H, s, Me-20).
FABMS: m/z (%) = 463 (M + H)+ (2), 445 (10), 307 (18), 245 (9),
191 (26), 154 (100), 105 (26), 69 (31).
HRMS (FAB): m/z calcd for C27H43O2S2 (M+H)+: 463.2704; found:
463.2699.
13C NMR (100 MHz, CDCl3): = 203.1(C-15), 68.1 (C-12), 59.3
(C-9), 57.4 (C-5), 53.6 (C-14), 46.4 (C-13), 45.4 (C-8), 42.4 (C-3),
42.3 (C-15a), 40.9 (C-7), 40.1 (C-1), 39.0 and 38.4 (SCH2CH2S),
36.7 (C-10), 36.3 (C-11), 33.4 (C-18), 33.0 (C-4), 24.1 (C-16), 21.2
(C-19), 18.8 (C-2), 18.3 (C-6), 16.3 (C-17), 15.8 (C-20).
EIMS: m/z (%) = 394 (M)+ (1), 289 (12), 245 (100), 191 (7), 149
(18), 105 (80).
13S,16R-19,25-Epoxy-17(25),18-diene-16-hydroxyhyrtiosan-
12-al (11) and 13S,16S-19,25-Epoxy-17(25),18-diene-16-hy-
droxyhyrtiosan-12-al (12)
Method A
To a stirred solution of the dithiolanyl alcohol 9 (42 mg, 0.09 mmol)
in THF and H2O (2 mL, 99:1) was added CaCO3 (11 mg) and aq
Hg(ClO4)2 (2 M; 0.07 mL, 0.14 mmol) dropwise. The mixture was
stirred for 10 min and then was diluted with Et2O (20 mL) and fil-
tered through a short pad of silica gel and a Celite column to give a
mixture of both hydrohyaldehydes 12 and 11. Column chromatog-
raphy (benzene) afforded the hyrtiosal 12 (7 mg, 22%) and epi-hyr-
tiosal 11 (22 mg, 67%) both as colorless solids.
HRMS (EI): m/z calcd for C23H38OS2 (M)+: 394.2364; found:
394.2368.
13S,16R-12-Ethylenedithia-19,25-epoxy-17(25),18-dienehyr-
tiosan-16-ol (9) and 13S,16S-12-Ethylenedithia-19,25-epoxi-
17(25),18-dienehyrtiosan-16-ol (10)
To a solution of 3-bromofuran (0.1 mL, 1.1 mmol) in anhyd THF
(2.5 mL) was added a solution of BuLi in hexane (1.6 M, 0.68 mL,
1.1 mmol) at –78 °C under argon. The solution was stirred for 10
min and 8 (288 mg, 0.7 mmol) was added diluted in THF (3 mL) via
cannula. After 1 h the reaction was quenched by addition of a sat.
Experimental for 10 (100 mg, 0.22 mmol); yields 11 (23 mg, 29%)
and 12 (48 mg, 57%).
11
[ ]D20 –27.1 (c 1.15, CHCl3).
IR (neat): 2930, 1717, 1458, 1387, 1022 cm–1.
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York

1528
P. Basabe et al.
PAPER
1H NMR (400 MHz, CDCl3): = 9.32 (1 H, s, H-12), 7.38 (1 H, s,
H-25), 7.33 (1 H, s, H-19), 6.39 (1 H, s, H-18), 4.49 (1 H, dd,
J = 8.6, 6.1, H-16), 1.83–1.28 (13 H, m), 1.21 (3 H, s, Me-24), 1.19–
0.87 (4 H, m), 0.86 (3 H, s, Me-20), 0.85 (3 H, s, Me-21), 0.83 (3 H,
s, Me-23), 0.82 (3 H, s, Me-22).
13C NMR (100 MHz, CDCl3): = 204.9 (C-12), 143.5 (C-19),
140.0 (C-25), 128.2 (C-17), 108.0 (C-18), 65.4 (C-16), 60.3 (C-9),
57.4 (C-5), 52.2 (C-13), 50.4 (C-14), 44.6 (C-8), 42.4 (C-3), 40.1
(C-1 and C-7), 36.8 (C-10), 33.8 (C-11), 33.4 (C-20, C-15), 33.0 (C-
4), 21.2 (C-21), 18.9 (C-24), 18.8 (C-2), 18.2 (C-6), 16.4 (C-23),
15.6 (C-22).
13C NMR (50 MHz, CDCl3): = 170.7 (MeCO2), 143.2 (C-19),
141.7 (C-25), 124.3 (C-17), 109.7 (C-18), 68.5 (C-12), 67.5 (C-16),
59.7 (C-9), 57.4 (C-5), 54.9 (C-14), 46.8 (C-13), 45.9 (C-8), 42.7
(C-7), 42.1 (C-3), 40.3 (C-1), 39.2 and 38.4 (SCH2CH2S), 37.0 (C-
10), 35.9 (C-11 and C-15), 33.6 (C-20), 33.3 (C-4), 25.0 (C-24),
21.6 (MeCO2), 21.5 (C-21), 19.3 (C-2), 18.6 (C-6), 16.3 (C-23),
16.0 (C-22).
EIMS: m/z (%) = 504 (M)+ (2), 444 (20), 339 (14), 245 (100), 149
(24), 105 (44).
HRMS (EI): m/z calcd for C29H44O3S2 (M)+: 504.2738; found:
504.2742.
FABMS: m/z (%) = 387 (M + H)+ (2), 369 (23), 307 (13), 245 (7),
154 (100), 107 (37), 69 (37).
HRMS (FAB): m/z calcd for C25H39O3 (M+H)+: 387.2899; found:
387.2893.
13S,16S-19,25-Epoxy-17(25),18-dien-16-acetoxyhyrtiosan-12-al
(14)
Compound 13 (20 mg, 0.04 mmol) was treated with Hg(ClO4)2 in
similar conditions used for the formation of 11/12, Method A, yield-
ing after column chromatography (CHCl3) 14.
12
[ ]D20 –62.2 (c 0.74, CHCl3).
Yield: 14 mg (75%); colorless solid; [ ]D20 –58.8 (c 0.25, CHCl3).
IR (neat): 2930, 1717, 1458, 1387 cm–1.
IR (KBr): 1719, 1458, 1389, 1250, 1157, 1026, 876, 822, 795, 725
cm–1.
1H NMR (400 MHz, CDCl3): = 9.46 (1 H, s, H-12), 7.36 (2 H, s,
H-25, H-19), 6.37 (1 H, s, H-18), 4.42 (1 H, t, J = 7.2, 6.0, H-16),
1.98 (1 H, dd, J = 8.0, 6.4, H-14), 1.90 (1 H, dd, J = 12.8, 6.0, H-
11A), 1.73 (1 H, dt, J = 12.4, 3.2, H-7A), 1.70–1.02 (12 H, m), 1.19
(3 H, s, Me-24), 1.02–0.85 (2 H, m), 0.87 (3 H, s, Me-20), 0.86 (3
H, s, Me-21), 0.85 (3 H, s, Me-23), 0.83 (3 H, s, Me-22).
1H (400 MHz, CDCl3): = 9.35 (1 H, s, H-12), 7.40 (1 H, s, H-19),
7.37 (1 H, s, H-25), 6.35 (1 H, s, H-18), 5.69–5.62 (1 H, m, H-16),
2.03 (3 H, s, MeCO2), 1.98–1.18 (15 H, m), 1.14 (3 H, s, Me-24),
1.05–0.82 (2 H, m), 0.90 (3 H, s, Me-20), 0.86 (3 H, s, Me-21), 0.85
(3 H, s, Me-23), 0.83 (3 H, s, Me-22).
13C NMR (100 MHz, CDCl3): = 205.6 (C-12), 143.2 (C-19), 138.7
(C-25), 129.2 (C-17), 108.4 (C-18), 64.2 (C-16), 60.3 (C-9), 57.4
(C-5), 52.8 (C-13), 48.1 (C-14), 44.5 (C-8), 42.4 (C-3), 40.2 (C-1
and C-7), 36.58 (C-10), 33.7 (C-15), 33.6 (C-11), 33.4 (C-20), 33.0
(C-4), 21.2 (C-21), 19.1 (C-24), 18.8 (C-2), 18.2 (C-6), 16.5 (C-23),
15.6 (C-22).
13C NMR (100 MHz, CDCl3): = 203.7 (C-12), 170.3 (MeCO2),
143.2 (C-19), 140.8 (C-25), 124.5 (C-17), 108.7 (C-18), 66.7 (C-
16), 60.1 (C-9), 57.2 (C-5), 52,3 (C-13), 48.8 (C-14), 44.6 (C-8),
42.3 (C-3), 40.7 (C-7), 40.1 (C-1), 36.8 (C-10), 33.5 (C-11), 33.4
(C-20), 33.0 (C-4), 30.6 (C-15), 21.2 (MeCO2 and C-21), 19.1 (C-
24), 18.8 (C-2), 18.2 (C-6), 16.3 (C-23), 15.6 (C-22).
FABMS: m/z (%) = 387 (M + H)+ (2), 369 (36), 307 (13), 245 (8),
EIMS: m/z (%) = 428 (M)+ (9), 385 (6), 368 (32), 245 (100), 191
191 (9), 154 (100), 91 (55), 69 (46).
(25), 137 (44), 69 (76).
HRMS (FAB): m/z calcd for C25H39O3 (M+H)+: 387.2899; found:
HRMS (EI): calcd for C27H40O4 (M+): 428.2927; found: 428.2967.
387.2902.
Compound 12; Saponification of 14
Method B
A solution of 14 (5 mg, 0.012 mmol) in MeOH (1 mL) was treated
with methanolic K2CO3 (2.5%; 1 mL) and stirred for 2 h. After-
wards the reaction was quenched with H2O (2 mL) and the MeOH
was evaporated. The aqueous layer was extracted with Et2O (3 20
mL) and the organic layer was washed with H2O (3 10 mL), dried
(Na2SO4), and concentrated under reduced pressure to yield 12.
To a stirred solution of dithiolanyl alcohol 9 (91 mg, 0.20 mmol) in
aq MeOH (2.5 mL, 99:1) was added PhI(O2CF3) (27 mg, 0.1 mmol).
The mixture was stirred for 10 min until no starting material re-
mained, and then quenched by addition of aq NaHCO3 (10%, 3 50
mL) and extracted into Et2O (3 150 mL). The organic layer was
washed with H2O (3 50 mL), dried (Na2SO4) and evaporated to
give a solid residue. Column chromatography (benzene) yielded
epi-hyrtiosal 11 (11 mg, 15%) as a colorless solid.
Yield: 5 mg (99%).
13S,16R-12-Ethylenedithia-19,25-epoxy-17(25),18-dien-16-ace-
toxyhyrtiosane (15)
Experimental for 10 (107 mg, 0.23 mmol); yield 12 (13 mg, 15%).
Compound 9 (11 mg, 0.02 mmol) was acetylated in the same condi-
tion described for 13, giving 15 in quantitative yield.
Yield: 12 mg (100%); colorless oil; [ ]D20 +25.5 (c 0.40, CHCl3).
13S,16S-12-Ethylenedithia-19,25-epoxy-17(25),18-dien-16-ace-
toxyhyrtiosane (13)
To a solution of 10 (19.1 mg, 0.04 mmol) in pyridine (0.5 mL) was
added Ac2O (1 mL). The solution was stirred overnight and then
was added onto ice. The solution was extracted with Et2O (3 50
mL) and the organic extracts were washed successively with aq HCl
(2 N; 3 25 ml), aq NaHCO3 (3 25 mL) and H2O (3 25 mL),
dried (Na2SO4) and evaporated to yield 13.
Yield: 20 mg (100%); [ ]D20 –14.6 (c 0.50, CHCl3).
IR (neat): 1738, 1458, 1373, 1240, 1022, 874, 797, 733 cm–1.
1H NMR (200 MHz, CDCl3): = 7.49 (1 H, s, H-25), 7.39 (1 H, t,
J = 18.0, H-19), 6.50 (1 H, s, H-18), 5.87 (1 H, dd, J = 9.0, 6.6, H-
16), 4.68 (1 H, s, H-12), 3.30–3.05 (4 H, m, SCH2CH2S), 2.04 (3 H,
s, MeCO2), 1.98–1.02 (15 H, m), 1.14 (3 H, s, Me-24), 0.98–0.80 (2
H, m), 0.91 (3 H, s, Me-20), 0.83 (3 H, s, Me-21), 0.82 (3 H, s, Me-
23), 0.81 (3 H, s, Me-22).
IR (neat): 1740, 1458, 1371, 1238, 1022, 874 cm–1.
1H NMR (200 MHz, CDCl3): = 7.46 (1 H, s, H-25), 7.38 (1 H, s,
H-19), 6.42 (1 H, s, H-18), 5.80 (1 H, dd, J = 9.1, 5.7, H-16), 4.77
(1 H, s, H-12), 3.32–3.06 (4 H, m, SCH2CH2S), 2.06 (3 H, s,
MeCO2), 1.88–1.08 (15 H, m), 1.17 (3H, s, Me-24), 1.02–0.84 (2 H,
m), 0.85 (3 H, s, Me-20), 0.83–0.81 (9 H, 3 s, Me-21, Me-22 and
Me-23).
13C NMR (50 MHz, CDCl3): = 170.4 (MeCO2), 143.0 (C-19),
140.8 (C-25), 125.0 (C-17), 108.8 (C-18), 67.9 (C-12), 67.3 (C-16),
59.9 (C-9), 57.3 (C-5), 55.2 (C-14), 46.9 (C-13), 45.3 (C-8), 42.4
(C-7), 41.3 (C-3), 40.0 (C-1), 39.1 and 38.2 (SCH2CH2S), 36.7 (C-
10), 34.7 (C-11 and C-15), 33.4 (C-20), 33.0 (C-4), 25.2 (C-24),
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Hyrtiosanes from Labdanes: (–)-Hyrtiosal from Sclareol
1529
21.3 (MeCO2), 21.2 (C-21), 18.9 (C-2), 18.3 (C-6), 16.2 (C-23),
15.7 (C-22).
Acknowledgments
Financial support for this work came from the Spanish CICYT
(PB97-1323,) and from grant 1FD97-2018-C02-01 from the Euro-
pean Commission and Comisión Interministerial de Ciencia y Tec-
nología and Junta de Castilla y León (Spain) (SA 48/97). The
authors thank also Dr. A. M. Lithgow, Dr Cesar Raposo and Dr A.
Jimenez for the NMR, mass spectra and X-ray analysis, respective-
ly, and to E. San Vicente and M. C. Esteban-Hernandez for excel-
lent technical assistance during the biological tests.
EIMS: m/z (%) = 504 (M)+ (1), 444 (6), 329 (19), 245 (100), 191
(12), 143 (18), 69 (39).
HRMS (EI): m/z calcd for C29H44O3S2 (M)+: 504.2738; found:
504.2640.
13S,16R-19,15-Epoxy-17(25),18-dien-16-acetoxyhyrtiosan-12-
al (16)
Compound 15 (12 mg, 0.02 mmol) was treated with Hg(ClO4)2 in
similar conditions used for 11/12, Method A, yielding after column
chromatography (CHCl3) 16.
References
Yield: 7 mg (77%); colorless solid; [ ]D20 –3.0 (c 0.40, CHCl3).
(1) Iguchi, K.; Shimada, Y.; Yamada, Y. J. Org. Chem. 1992,
57, 522.
(2) Basabe, P.; Diego, A.; Diez Martin, D.; Marcos, I. S.;
Urones, J. G. Synlett 2000, 1807.
(3) Urones, J. G.; Marcos, I. S.; Basabe, P.; Gómez, A.; Estrella,
A.; Lithgow, A. M. Nat. Prod. Lett. 1994, 5, 217.
(4) Jean, T.; Heissler, D. Synlett 1995, 607.
(5) Ratcliffe, R.; Rodehost, R. J. Org. Chem. 1970, 35, 4000.
(6) Griffith, W. P.; Ley, S. V.; Withcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625.
(7) Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 145607. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK; fax: +44(0)1223336033;
e-mail: deposit@ccdc.cam.ac.uk.
(8) Paquette, L. A.; Bulman-Page, P. C.; Pansegrau, P. D.;
Wiedeman, P. E. J. Org. Chem. 1988, 53, 1450.
(9) (a) Bernardi, R.; Ghiringhelli, D. J. Org. Chem. 1987, 52,
5021. (b) Lipshutz, B. H.; Moretti, R.; Crow, R. Tetrahedron
Lett. 1989, 30, 15.
IR (KBr): 2938, 1738, 1715, 1391, 1366, 1238, 1018, 941, 874, 799
cm–1.
1H (400 MHz, CDCl3): = 9.33 (1 H, s, H-12), 7.41 (1 H, s, H-25),
7.39 (1 H, s, H-19), 6.38 (1 H, s, H-18), 5.54 (1 H, dd, J = 9.2, 6.0,
H-16), 2.00 (3 H, s, MeCO2), 1.92–1.36 (14 H, m), 1.25 (3 H, s, Me-
24), 1.18–0.90 (3 H, m), 0.88 (3 H, s, Me-20), 0.84 (3 H, s, Me-21),
0.83 (3 H, s, Me-23), 0.80 (3 H, s, Me-22).
13C NMR (100 MHz, CDCl3): = 204.0 (C-12), 170.1 (MeCO2),
143.2 (C-19), 141.6 (C-25), 123.8 (C-17), 108.5 (C-18), 67.4 (C-
16), 60.1 (C-9), 57.3 (C-5), 52.3 (C-13), 49.5 (C-14), 44.7 (C-8),
42.3 (C-3), 40.1 (C-7, C-1), 36.7 (C-10), 33.7 (C-11), 33.4 (C-20),
33.0 (C-4), 30.6 (C-15), 21.3 (MeCO2), 21.2 (C-21), 18.9 (C-24),
18.8 (C-2), 18.2 (C-6), 16.4 (C-23), 15.6 (C-22).
EIMS: m/z (%) = 428 (M)+ (10), 386 (24), 368 (43), 325 (7), 245
(100), 191 (28), 123 (48), 69 (84).
HRMS (EI): m/z calcd for C27H40O4 (M+): 428.2927; found:
428.2937.
Compound 11; Saponification of 16
Compound 16 (12 mg, 0.05 mmol) was treated under the same con-
ditions used for the saponification of 14, yielding 11.
(10) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
Yield: 11 mg (99%).
Synthesis 2002, No. 11, 1523–1529 ISSN 0039-7881 © Thieme Stuttgart · New York