Synthetic studies to highly functionalised B ring labdanes

Article abstract of DOI:10.1016/j.tet.2008.06.083

Several 6,7-dioxygenated (cis or trans) labdanes have been synthesised starting from sclareol. A new strategy that allows the obtention of diols α-cis as well as β-cis or trans is described. In particular, the syntheses of three natural highly functionalised labdanes in the B rings of 2, 3 and 4 with different side chains are reported. The syntheses have permitted to correct the proposed structure for one of them.

Full text of DOI:10.1016/j.tet.2008.06.083

Tetrahedron 64 (2008) 8815–8829
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic studies to highly functionalised B ring labdanes
*
´
I.S. Marcos , L. Castan˜eda, P. Basabe, D. Dıez, J.G. Urones
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias Quımicas, Universidad de Salamanca, Plaza de los Caidos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2008
Received in revised form 20 June 2008
Accepted 23 June 2008
Available online 26 June 2008
Several 6,7-dioxygenated (cis or trans) labdanes have been synthesised starting from sclareol. A new
strategy that allows the obtention of diols a-cis as well as b-cis or trans is described. In particular, the
syntheses of three natural highly functionalised labdanes in the B rings of 2, 3 and 4 with different side
chains are reported. The syntheses have permitted to correct the proposed structure for one of them.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Labdanes
Diterpenes
Sclareol
1. Introduction
HO
HO
Highly functionalised B ring labdane diterpenes are a very in-
teresting class of natural products due to the important biological
activities that some of them show.1 Being perhaps forskolin 12 the
most interesting example of all of them, as it presents cardioactive,
adenylate cyclase stimulant and hypotensive properties. As well as
forskolin, there are other functionalised labdanes in C-6 and C-7 as
2–5,3 isolated from plants, that have been used in folk medicine for
the treatment of cardiovascular diseases or as sedative, uterotonic
or repellents (Fig. 1).
In C-6 and C-7 positions can appear several oxygenated func-
tions with different stereochemistry. The side chains are differently
functionalised with Z and E double bonds, lactone rings or with
monosubstituted double bonds (Fig. 1).
Our group has been interested in the synthesis of several of
these compounds as 23a with unknown C-13 configuration and 43c
that has in the side chain a less common Z double bond in this kind
of derivatives. The structures of these compounds have been
established only by spectroscopic methods and now we want to
corroborate their structures and establish their absolute configu-
ration. Compound 33b is a highly toxic metabolite isolated from the
mucus of Trimusculus reticulatus, and it is a likely candidate to be
active in defence mechanism against depredators. Recently Morin
et al. have described the synthesis of 3 from larixol4 and established
the absolute configuration of the natural compound. Now, a new
synthesis of 3 is described by us.
O
H
HO
O
OH
OH
OH
OAc
OH
O
H
H
OAc
O
forskolin, 1
sclareol
2
CH2OH
HO
CH2OAc
O
OH
OAc
H
H
O
H
OH
OAc
O
sibiricinone B, 5
3
4
Figure 1.
Sclareol is a commercial compound that has been chosen as the
starting material. We have previously used for the synthesis of
several natural products as luffolide,5 subersic acid,6 hyrtiosal,7
chrisolic acid8 and nimbiol.9
2. Results and discussion
The synthesis of 2, 3 and 4 from sclareol was planned according
to the following retrosynthetic scheme, Scheme 1. The key
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923 294574.
E-mail address: ismarcos@usal.es (I.S. Marcos).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.083

8816
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
intermediate for the elaboration of the target compounds 2, 3 and 4
is ketone 6 from which can be elaborated the different side chains
of 2, 3 and 4 and installed the adequate functionalisation of the B
ring. Ketone 6 can be accessible from methylketone 7 obtained from
sclareol and previously used by our group.9 First of all we describe
the synthesis of intermediate 6, followed by the synthesis of 2 and
finally the syntheses of 3 and 4.
2.1. Synthesis of intermediate 6
The synthesis of 6 was done according to Scheme 2. Methyl-
ketone 7 was obtained from sclareol in an excellent yield,9 and was
transfomed into the acetylderivative 9 by reduction and ulterior
acetylation of the hydroxyderivative 8. The allylic oxidation10 of 9
with Na2CrO4 gave enone 10 from which the mixture of epimer
11
diacetylderivatives 11 was obtained by Pb(OAc)4 oxidation in
a 66% yield in two steps. The LAH reduction of 11 gave the mixture
of triols 12 and 13 (1:2.5), hardly separable by CC. Each triol is an
epimeric mixture in the side chain and can be distinguished as the
HO
O
O
hydroxyl groups of the B ring in 12 have
b-cis configuration while in
13 appear as well as cis but with configuration, as can be deduced
a
from the acetonide derivatives 12a and 13a, 1H NMR spectra. These
derivatives are obtained by reaction of the corresponding diols 12
and 13 with 2,2-DMP using p-TsOH acid as catalyst. The cis orien-
tation of the hydroxyl groups is required in both cases for the
protection to take place in the above conditions. This in agreement
with the coupling constants found for the geminal hydrogens H-6
in 12a (4.59 ppm, dd, J¼6.4 and 1.7 Hz), H-6 in 13a (4.38 ppm, dd,
J¼12.8 and 2.0 Hz) and for H-7 in 12a (4.30 ppm, d, J¼6.4 Hz), H-7
in 13a (3.79 ppm, d, J¼2.0 Hz).
OH
O
O
H
H
H
O
OAc
2
6
7
CH2OH
HO
CH2OAc
The quimioselective protection of the side chain hydroxyl group
of 12 and 13 with TBDMSCl12 gave 14 and 15, respectively. The
required isomer at this stage for the synthesis of 6 is 14, although as
will be commented later on, the isomer 15 can be transformed into
14 by inversion of the two stereogenic centres C-6 and C-7 in a high
yield. Reaction of 14 with triphosgene13 led quantitatively to the
dioxolanone 16. The TBAF14 deprotection of 16 followed by TPAP15
oxidation of the obtained hydroxyderivative 17 gave the required
ketone 6.
OH
OH
OAc
H
H
H
O
OAc
O
3
sclareol
4
Scheme 1.
HO
R1
OAc
O
d
a
OH
H
H
H
R1
R1
R1
=O
OH
OAc
sclareol
7
b
c
10
H
8
9
e
11 OAc
f
OR1
R1
OH
O
OH
O
g
i
+
R2
R2
O
O
H
O
H
R3
O
O
R1
R3
R1
12a
13a
12
H
H
OH
OH
OH
OH
OH
OH
OH
OH
16 OTBS
17 OH
j
13
h
k
14 TBS
15 TBS
6
=O
Scheme 2. Reagents and conditions: (a) Ref. 9; (b) LAH, Et2O, rt, 1 h (99%); (c) Ac2O, Py, rt, 6 h (98%); (d) Na2CrO4, Ac2O, AcOH, AcONa, C6H6, 60 ꢀC, 5 h (71%); (e) Pb(OAc)4, C6H6,
80 ꢀC, 72 h (93%); (f) LAH, Et2O, rt, 1 h (100%); (g) 2,2-DMP, p-TsOH, rt, 1 h (12a, 31%; 13a, 67%); (h) TBDMSCl, imidazole, DMF, rt, 15 h (14, 35%; 15, 55%); (i) (Cl3CO)2CO, DCM, Py,
ꢁ78 ꢀC, 1 h (100% from 14); (j) TBAF, THF, rt, 2 h (95%); (k) TPAP, NMO, sieves, DCM, rt, 1 h (96%).

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8817
OTBS
OH
OTBS
OTBS
c
OTBS
OH
b
OAc
OAc
H
H
H
OH
14
OH
O
a
d
18
20
OTBS
H
OH
15
OH
H
OAc
19
Scheme 3. Reagents and conditions: (a) Ac2O, Py, rt, 2 h (18, 81%; 19, 15%); (b) TPAP, NMO, sieves, DCM, rt, 1 h (99%); (c) LAH, Et2O, rt, 45 min (99%); (d) LAH, Et2O, rt, 1 h (96%).
The transformation of 15 into 14 can be achieved as indicated in
Scheme 3. Controlled acetylation with Ac2O in pyridine of 15 per-
mitted to obtain as major compound the monoacetylderivative 18
(81%) together with the monoacetylderivative 19 (15%) that can be
transformed back into 15. The 1H NMR spectrum for 18 shows
signal at 5.22 ppm (1H, d, J¼7.4 Hz) of H-7 geminal to the acetoxy
group in allylic position, for its multiplicity and shield. The H-7
hydrogen signal, in the 1H NMR spectrum for 19, appears as doublet
as well but more shielded at 3.95 ppm. By contrary, H-6 the geminal
hydrogen to the acetoxy group appears in 19 at 5.22 ppm (1H, dd,
J¼12.2 and 6.6 Hz). The TPAP oxidation of 18 (Scheme 3) gave
quantitatively ketone 20. In the 1H NMR spectrum of 20 by
irradiation of the signal (singlet) corresponding to the geminal
hydrogen to the acetoxy group at 5.61 ppm an NOE was observed
with the signal at 2.52 ppm corresponding to H-5, which allowed
us to verify the expected inversion of C-7, with the acetoxyl group
in the more stable equatorial position. The LAH reduction of 20 gave
the required isomer 14.
2.2. Synthesis of 2
The synthesis of 2 was achieved as shown in Scheme 4. The side
chain of 2 was completed in two different ways. In the first one the
C-13 configuration was controlled using the Sharpless asymmetric
OR1
R1
O
c
a
OR2
OR2
O
H
H
H
OR3
O
OR3
R2 R3
O
R1
R1
R2
R3
6
23 TBS
24 TBS
H
-CO-
-CO-
H
d
e
21 CO2Me
22 CH2OH
-CO-
b
H
H
25
H
f
OR1
O
HO
HO
H
i
k or l
OR1
OR1
O
O
H
H
H
OR2
R1
31 OAc OAc
OR2
O
R2
R1 R2
-CO-
R1
29
30
26
H
j
g
2
H
OAc
H
H
H
27 Ts
28
m
h
32 OAc
I
Scheme 4. Reagents and conditions: (a) (EtO)2P(O)CH2CO2Me, NaH, monoglyme, 60 ꢀC, 90 min (76%); (b) DIBAL-H, DCM, ꢁ78 ꢀC, 30 min (100%); (c) TBDMSCl, imidazole, DMF, rt,
17 h (92%); (d) (Cl3CO)2CO, DCM, Py, ꢁ78 ꢀC, 1 h (100%); (e) TBAF, THF, rt, 2 h (99%); (f) D(ꢁ)-DET, Ti(i-PrO)4, t-BuOOH, DCM, ꢁ23 ꢀC, 24 h (65%); (g) TsCl, Py, rt, 3 h (87%); (h) NaI,
Me2CO, 70 ꢀC, 3 h (86%); (i) Zn, AcOH, rt, 2 h (98%); (j) LAH, Et2O, rt, 1 h (100%); (k) Ac2O, Py, rt, 6 days (31, 96%); (l) Ac2O, Py, rt, 14 h (2, 97%); (m) AcOH, CHCl3, rt, 48 h (2, 41%; 32,
46%).

8818
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
epoxidation and in the second one by the addition of an organo-
metallic in presence of TADDOL.
The formation of 32 from 2 in mild acidic medium can be
explained by an interchange of the acetoxy group. The acetoxy is
transferred from the axial hydroxyl group at C-6 to the more stable
equatorial hydroxyl group at C-7. The spectroscopic properties of 2
were not coincident with the corresponding ones of the natural
compound isolated from Haplopappus parvifolius.3a Neither the
properties of 32 were coincident with the ones of that natural
compound. The differences in the spectroscopic properties led us to
propose for the natural compound the structure of 37 (Scheme 5)
that corresponds to the epimer at C-7, which was synthesised from
6, as shown in Scheme 5.
The Horner–Wadsworth–Emmons (HWE)16 reaction of 6 led to
21 that by DIBAL17 reduction gave triol 22. The glycol protection of
C-6 and C-7 was done as dioxolanone and not as dimethyldiox-
olane. The deprotection of the acetonides requires relatively strong
acid conditions, and the side chain functionalities were observed
not to be stable under these conditions.
In order to protect again the hydroxyl groups of the B ring, the
hydroxyl group of the side chain was protected as its silyl ether.
Reaction of 22 with TBDMSCl and imidazol in DMF gave 23 that by
reaction with trifosgene led to the carbonate derivative 24. TBAF
deprotection of 24 gave the hydroxyderivative 25. The Sharpless18
Reaction of 6 with Bu4NOAc20 in hot toluene (100 ꢀC) for 20 h
provided the monoacetylderivative 33, with inversion of the
configuration at C-7. The asymmetric addition of vinylbromide in
presence of (þ)- or (ꢁ)-TADDOL21 led after acetylation to 34 and 35,
respectively, in good yield and excellent diastereoselection (de
>99% in each case). The configuration for C-13 in 34 and 35 was
established in agreement with the chiral auxiliary stereochemistry
used in each case, corresponding to 34 the 13S configuration and to
35 the 13R configuration.
asymmetric epoxidation of 25 using
D(ꢁ)-DET produced epoxyde
26. The tosylation of the last compound with TsCl conduced to the
tosylderivative 27 that by substitution with iodide provided 28,
which by reduction with Zn in AcOH19 furnished carbonate 29 that
has the allylic functionality in the side chain. The diacetate 31 was
obtained by acetylation with acetic anhydride in pyridine at room
temperature for 6 days of triol 30, previously obtained by LAH
reduction of 29. The acetylation of 30 in the same conditions but
keeping it only for 14 h provided unexpectedly the mono-
acetylderivative 2 in quantitative yield. When the compound 2 was
left in chloroform with AcOH at room temperature for 48 h a mix-
ture of 2 (41%) and 32 (46%) was obtained that was separated by
column chromatography.
The monoacetylderivatives 36 and 37 were accessible by con-
trolled hydrolysis of the diacetylderivatives 34 and 35, respectively.
The NMR signals were assigned using bidimensional 1H/13C HMBC
and HMQC NMR experiments. The physical properties of the nat-
24
ural compound, isolated from Haplopappus parvifolius,3a
[
a]
þ30
D
(c 4.40, CHCl3), were coincident with the ones of 37, 6b-acetoxy-
22
The monoacetylderivative 2 formation, that shows the more
hindered axial hydroxyl group at C-6 esterified, can be explained
by the hydrogen bond formation between the hydroxyl group of
C-6 and the oxygen of the hydroxyl at C-7 (Fig. 2). In this manner
the more nucleophilic oxygen of C-6 reacts with the acetic
anhydride.
labda-8,14-dien-7
a
,13R-diol, [
a
]
þ27 (c 0.50, CHCl3), so in this
D
manner the structure and absolute configuration for the natural
compound were established.
2.3. Synthesis of 3 and 4
The structures of 3 and 4 differ in the stereochemistry of the side
chain double bond E and Z, respectively, and in the acid that es-
terifies the hydroxyl group at C-6, isovaleric acid for 3 or acetic for 4.
The reaction of 6 (Scheme 6) with Ph3PCHCOOEt22 heated in
toluene, provided a mixture of isomeric esters Z/E 38 and 39 in
a ratio 1:2 with excellent yield. The E isomer 21 was obtained in an
excellent yield and major diastereoselection (10:1 E:Z) when
compound 6 was submitted to the HWE reaction with methyl-
OH
H
O
O
H
H
H
H
Figure 2.
HO
HO
c
OAc
OH
H
H
OAc
OAc
36
O
b
34
a
6
OAc
H
OH
HO
HO
d
33
e
OAc
OH
H
H
OAc
35
OAc
37
Scheme 5. Reagents and conditions: (a) Bu4NOAc, Ph–Me, 100 ꢀC, 20 h (94%); (b) (i) CH2]CHMgBr, (þ)-TADDOL, THF, ꢁ85 ꢀC/ꢁ50 ꢀC/rt/ꢁ90 ꢀC, 24 h; (ii) Ac2O, Py, rt, 6 days (86%);
(c) K2CO3, MeOH, rt, 1 h (98%); (d) (i) CH2]CHMgBr, (ꢁ)-TADDOL, THF, ꢁ85 ꢀC/ꢁ50 ꢀC/ rt/ꢁ90 ꢀC, 24 h; (ii) Ac2O, Py, rt, 6 days (85%); (e) K2CO3, MeOH, rt, 1 h (100%).

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8819
22
diethyl-phosphonoacetate in monoglyme, as previously described.
The treatment of 39 with Bu4NOAc in hot toluene provided the
monoacetylderivative 40, in which the required inversion at C-7
has taken place. The DIBAL reduction of 40 gave triol 41. The se-
lective esterification of 41 with isovaleric acid in order to obtain 3
was not possible as the esterified position C-6 is the more hindered,
making necessary a process of esterification and hydrolysis.
The esterification of triol 41 was carried out by Yamaguchi23
procedure, achieving in this way the complete esterification,
a triacetoxyderivative 4, [
a
]
þ32.1 (c 0.51, CHCl3), whose physical
D
properties are identical to the ones of the natural product3b of
unknown rotation value. In order to compare the physical proper-
ties of 4 with the ones of its isomer on the side chain, compound 48
was synthesised (Scheme 6).
3. Conclusions
Starting with sclareol 1, a new route of synthesis for highly
functionalised B ring labdanes is described. In particular three
labdanes with oxygenated functions at C-6 and C-7 cis and trans
have been synthesised. A new strategy that permits the inversion of
obtaining 42, that by selective hydrolysis controlled by TLC led to 3,
22
[
a]
þ40.0 (c 1.01, CHCl3), whose physical properties are identical
D
22
to the ones described3c for the natural compound [
0.83, CHCl3).
a
]
þ38.7 (c
D
the two centres in the B ring from diols a-cis to diols b-cis, is shown.
For the synthesis of the natural compound 4 was used 38 as
intermediate. In this case, it was not possible to follow the same
strategy as for 3, that is, to invert first C-7 and then to proceed with
the esterification of C-6, as a cis–trans interconversion in the side
chain took place during the C-7 inversion process of 38 by Bu4NOAc
treatment. For this reason it was necessary to proceed by reduction
of the side chain ester and later on to do the inversion at C-7.
The DIBAL reduction of 38 gave triol 43, which by treatment
with TBDMSCl provided the silyl derivative 44. Reaction of 44 with
triphosgene gave the carbonate 45. The next step was the inversion
at C-7 that was achieved by treatment of 45 with Bu4NOAc in hot
toluene obtaining a mixture of 46 and 47. The acetylation of 47 gave
The synthesis of compound 37 has permitted to correct the
originally proposed structure for the natural product isolated from
Haplopappus parvifolius. The synthesis of 4 has allowed us to cor-
roborate the structure of the natural compound. A new synthesis of
3 is described.
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without
OR
i
OTBS
CO2Et
g
OH
O
H
O
O
H
H
OH
R
O
O
O
38
45
43
H
h
44 TBS
a
j
6
b
R1
CO2R
OR
c
OAc
OR2
O
H
H
H
OH
R
OH
O
R1
R2
Ac
H
O
R
46 TBS
47
40 CO2Et
41 CH2OH
k
39 Et
21 Me
d
H
e
m
l
OH
O
O
OAc
O
OAc
f
OH
O
OAc
H
OAc
H
H
H
O
O
OAc
OAc
O
3
42
O
48
4
Scheme 6. Reagents and conditions: (a) Ph3PCHCO2Et, Ph–Me, 120 ꢀC, 48 h (38, 19%; 39, 28%, 6, 31%); (b) (EtO)2P(O)CH2CO2Me, NaH, monoglyme, 60 ꢀC, 90 min (21, 76%); (c)
Bu4NOAc, Ph–Me, 80 ꢀC, 46 h (98%); (d) DIBAL-H, DCM, ꢁ78 ꢀC, 1 h (98%); (e) isovaleric acid, 2,4,6-trichlorobenzoyl chloride, Et3N, Ph–Me, 28 h, 80 ꢀC (100%); (f) K2CO3, MeOH, rt,
20 h (85%); (g) DIBAL-H, DCM, ꢁ78 ꢀC, 1 h (100%); (h) TBDMSCl, imidazole, DMF, 40 h (96%); (i) (Cl3CO)2CO, DCM, Py, ꢁ78 ꢀC, 1 h (100%); (j) Bu4NOAc, Ph–Me, 80 ꢀC, 46 h (46, 27%;
47, 56%); (k) TBAF, THF, rt, 90 min (90%); (l) CH3COCl, N,N-dimethylaniline, DCM, rt, 5 days (96%); (m) CH3COCl, N,N-dimethylaniline, DCM, rt, 5 days (98%).

8820
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
further purification. IR spectra were recorded on a BOMEM 100 FT-
IR or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometer. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
over Na2SO4 and evaporated to give a crude oil, which was chro-
matographed on silica gel to afford the expected compound 10
(3.91 g, 71%).
the residual peak of CHCl3 at
13C, respectively, using Varian 200 VX and Bruker DRX 400 in-
struments. Chemical shifts are reported in ppm and coupling
d 7.26 ppm and d
77.0 ppm, for 1H and
4.4.1. 13-R/S-Acetoxy-14,15-dinor-labd-8-en-7-one (10)
22
d
Rf (Hex/EtOAc 8/2)¼0.37; UV 249 nm; [
a]
þ48.2 (c 1.03,
D
constants (J) are given in hertz. MS were performed at a VG-TS 250
spectrometer at 70 eV ionising voltage. Mass spectra are presented
as m/z (% rel int.). HRMS were recorded on a VG Platform (Fisons)
spectrometer using chemical ionisation (ammonia as gas) or Fast
Atom Bombardment (FAB) technique. For some of the samples,
QSTAR XL spectrometer was employed for electrospray ionisation
(ESI). Optical rotations were determined on a Perkin–Elmer 241
polarimeter in 1 dm cells. Diethyl ether and THF were distilled from
sodium, and dichloromethane was distilled from calcium hydride
under argon atmosphere.
CHCl3); IR (film): 1737, 1663, 1374, 1242; 1H NMR
d
:4.95–4.87 (1H,
m, H-13), 2.60–0.80 (13H, m), 2.06 (3H, s, MeCOO), 1.75 (3H, s, Me-
17), 1.26 (3H, d, J¼6.2 Hz, Me-16), 1.08 (3H, s, Me-20), 0.92 (3H, s,
Me-18), 0.88 (3H, s, Me-19); 13C NMR
d: 199.7 (C-7), 170.5 (MeCOO),
166.9 (C-9), 130.3 (C-8), 70.9 (C-13), 50.4 (C-5), 41.4 (C-10), 41.0
(C-3), 36.2 (C-1), 35.3 (C-12), 35.0 (C-6), 33.0 (C-18), 32.5 (C-4), 25.1
(C-11), 21.3 (MeCOO), 19.7 (C-16), 19.6 (C-19), 18.3 (C-20), 18.7 (C-2),
11.7 (C-17); EIMS: (70 eV) m/z (%): 321 (MþHþ, 72), 260 (100), 205
(30), 135 (50).
4.5.
a-Acetoxylation of 10 with LTA to yield 11
4.2. Reduction of 7 with LiAlH4 to yield 8
To a solution of 10 (1.40 g, 4.37 mmol) in benzene (125 mL),
Pb(OAc)4 (18.4 g, 41.5 mmol) was added and the mixture was stir-
red at 80 ꢀC for 72 h. The solution was filtered washing with AcOEt
and the resulting organic layer was washed several times with
water, dried over Na2SO4 and evaporated to give a crude oil, which
was chromatographed on silica gel to afford 11 (1.53 g, 93%).
An ice cooled solution of ketone 7 (4.37 g, 16.7 mmol) in dry
Et2O (145 mL) was treated with LiAlH4 (0.94 g, 24.9 mmol) and
stirred at room temperature for 1 h. Then, the solution was cooled
to 0 ꢀC, wet EtOAc was added and the mixture filtered. The resulting
organic phase was dried over Na2SO4, filtered and evaporated
affording 8 (4.36 g, 99%).
4.5.1. 6,13-Diacetoxy-14,15-dinor-labd-8-en-7-one (11)
4.2.1. 14,15-Dinor-labd-8-en-13-R/S-ol (8)
Rf (Hex/EtOAc 7/3)¼0.53; IR (film): 1739, 1672, 1373, 1239, 1033;
22
Rf (Hex/EtOAc 9/1)¼0.15; [
a
]
þ61.8 (c 1.17, CHCl3); IR (film):
1H NMR
d: 5.80–5.60 (1H, m, H-6), 4.95–4.87 (1H, m, H-13), 2.40–
D
3346, 1460, 1387, 1374, 1118; 1H NMR
0.80 (15H, m), 1.48 (3H, s, Me-17), 1.12 (3H, d, J¼6.2 Hz, Me-16), 0.85
(3H, s, Me-20), 0.79 (3H, s, Me-18), 0.74 (3H, s, Me-19); 13C NMR
d
: 3.70 (1H, m, H-13), 2.20–
1.20 (11H, m), 2.19 (3H, s, MeCOO), 2.06 (3H, s, MeCOO), 1.76 (3H, s,
Me-17), 1.28 (3H, s, Me-20), 1.26 (3H, d, J¼6.2 Hz, Me-16), 1.04 (3H,
s, Me-18), 1.00 (3H, s, Me-19); EIHRMS: calcd for C22H34O5Na:
401.2298, found 401.2267.
d:
140.4 (C-9), 126.0 (C-8), 69.0 (C-13), 52.1 (C-5), 42.0 (C-3), 40.2 (C-
12), 39.2 (C-10), 37.3 (C-1), 33.8 (C-7), 33.4 (C-4), 33.4 (C-18), 24.3
(C-11), 23.6 (C-16), 21.9 (C-19), 20.3 (C-17), 19.7 (C-20), 19.3 (C-6),
4.6. Reduction of 11 with LiAlH4 to yield 12 and 13
19.2 (C-2); EIHRMS: calcd for
287.2361.
C18H32ONa: 287.2345, found
An ice cooled solution of 11 (98 mg, 0.26 mmol) in dry Et2O
(145 mL) was treated with LiAlH4 (33 mg, 0.85 mmol) and was
stirred at room temperature for 1 h. Then, the solution was cooled
to 0 ꢀC, wet EtOAc was added and the mixture filtered. The resulting
organic phase was dried over Na2SO4, filtered and evaporated to
give a crude oil, which was chromatographed on silica gel to afford
12 (15 mg, 19%) and 13 (42 mg, 54%).
4.3. Acetylation of 8 to yield 9
To a solution of 8 (8.80 g, 33.3 mmol) in dry pyridine (13 mL),
acetic anhydride (18 mL) was added and the mixture was stirred at
room temperature for 6 h. The reaction mixture was poured into
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and evaporated
to yield 9 (9.92 g, 98%).
4.6.1. 14,15-Dinor-labd-8-en-6
Rf (Hex/EtOAc 1/1)¼0.34; [
3358, 1459, 1375, 1265, 1125, 1021; 1H NMR (DMSO)
b,7b,13-R/S-triol (12)
22
a
]
þ63.0 (c 0.40, DMSO); IR (film):
D
d
: 4.43 (1H, d,
J¼7.8 Hz, OH), 4.36–4.32 (1H, m, OH), 4.10–4.00 (1H, m, H-7), 3.84
(1H, d, J¼2.8 Hz, OH), 3.87–3.65 (1H, m, H-6), 3.60–3.45 (1H, m, H-
13), 2.20–0.80 (11H, m), 1.57 (3H, s, Me-17), 1.26 (3H, s, Me-20), 1.15
4.3.1. Acetate of 14,15-dinor-labd-8-en-13-R/S-ilo (9)
22
Rf (Hex/EtOAc 9/1)¼0.51; [
a
]
þ54.9 (c 1.41, CHCl3); IR (film):
D
1739, 1458, 1372, 1241; 1H NMR
d
: 4.87–4.81 (1H, m, H-13), 2.10–
(3H, s, Me-19), 1.22 (3H, d, J¼7.0 Hz, Me-16), 0.89 (3H, s, Me-18); 13
C
0.70 (15H, m), 2.03 (3H, s, MeCOO), 1.55 (3H, s, Me-17), 1.21 (3H, d,
J¼6.2 Hz, Me-16), 0.92 (3H, s, Me-20), 0.87 (3H, s, Me-18), 0.82 (3H,
NMR (DMSO) d: 139.3 (C-9), 123.1 (C-8), 69.4 (C-7), 63.8 (C-13), 63.8
(C-6), 49.8 (C-5), 40.0 (C-3), 36.9 (C-1), 36.8 (C-12), 30.8 (C-10), 30.8
(C-18), 30.7 (C-4), 21.2 (C-11), 21.0 (C-19), 20.8 (C-16), 18.4 (C-20),
16.1 (C-2), 12.1 (C-17); EIHRMS: calcd for C18H32O3Na: 319.2244,
found 319.2249.
s, Me-19); 13C NMR
d: 170.9 (MeCOO), 140.1 (C-9), 126.2 (C-8), 71.7
(C-13), 52.1 (C-5), 42.0 (C-3), 39.2 (C-10), 37.2 (C-1), 36.8 (C-12),
33.8 (C-7), 33.5 (C-18), 33.5 (C-4), 23.7 (C-11), 21.9 (C-19), 21.6
(MeCOO), 20.3 (C-17), 19.9 (C-16), 19.6 (C-20), 19.3 (C-2), 19.3 (C-6);
EIHRMS: calcd for C20H34O2Na: 329.2451, found 329.2439.
4.6.2. 14,15-Dinor-labd-8-en-6
a
,7
a
,13-R/S-triol (13)
22
Rf (Hex/EtOAc 1/1)¼0.14; [
a
]
þ59.1 (c 0.64, DMSO); IR (film):
D
4.4. Oxidation of 9 with Na2CrO4 to yield 10
3358, 1459, 1375, 1265, 1125, 1021; 1H NMR
d: 3.87 (1H, d, J¼7.6 Hz,
H-7), 3.85–3.70 (2H, m, H-6 and H-13), 2.60–0.80 (11H, m),1.69 (3H,
To a solution of 9 (5.34 g, 17.5 mmol) in benzene (110 mL),
Na2CrO4 (12.4 g, 76.8 mmol), acetic anhydride (50 mL), acetic acid
(50 mL) and NaOAc (7.54 g) were added and the mixture stirred at
60 ꢀC for 5 h. Then it was cooled down to room temperature and ice
was added. The mixture was extracted with EtOAc and washed with
aqueous 6% NaHCO3, water and brine. The organic layer was dried
s, Me-17), 1.21 (3H, d, J¼6.5 Hz, Me-16),1.18 (3H, s, Me-20),1.07 (3H,
s, Me-19), 1.07 (3H, s, Me-18); 13C NMR
d: 144.1 (C-9), 126.6 (C-8),
80.2 (C-7), 74.7 (C-6), 68.8 (C-13), 54.0 (C-5), 43.8 (C-3), 42.3 (C-10),
39.3 (C-1), 37.5 (C-12), 36.6 (C-18), 33.5 (C-4), 24.6 (C-11), 23.4
(C-16), 22.4 (C-19), 21.6 (C-20), 18.9 (C-2), 14.4 (C-17); EIHRMS:
calcd for C18H32O3Na: 319.2244, found 319.2223.

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8821
4.7. Reaction of 12 and 13 with 2,2-DMP to yield 12a and 13a
14.8 (C-17), ꢁ4.2 (Me2SiCMe3), ꢁ4.5 (Me2SiCMe3); EIHRMS: calcd
for C24H46O3SiNa: 433.3108, found 433.3139.
To a solution of 12/13 (85 mg, 0.29 mmol) in Me2CO (1.20 mL)
was added 2,2-DMP (0.12 mL) and p-TsOH acid (10 mg, 0.05 mmol).
The mixture was stirred at room temperature for 1 h, then Et2O was
added and the mixture was washed with aqueous 6% NaHCO3 and
H2O. The resulting organic phase was dried over Na2SO4, filtered
and evaporated to give a crude oil, which was chromatographed on
silica gel to afford 12a (30 mg, 31%) and 13a (65 mg, 67%).
4.9. Reaction of 14 with triphosgene to yield 16
To a solution of triphosgene (26 mg, 0.09 mmol) in pyridine
(0.04 mL) and CH2Cl2 (0.60 mL) cooled at ꢁ78 ꢀC was added
another solution of 14 (36 mg, 0.09 mmol) in CH2Cl2 (0.20 mL). The
reaction mixture was stirred until it warmed up to room temper-
ature and then saturated NH4Cl solution was added. The mixture
was extracted with Et2O and washed with aqueous 2 M HCl,
aqueous 6% NaHCO3 and brine. The organic layer was dried over
Na2SO4, filtered and evaporated to afford 16 (39 mg, 100%).
4.7.1. 6
Rf (Hex/EtOAc 1/1)¼0.69; IR (film): 3400, 1458, 1377, 1366, 1236,
1216, 1126, 1022; 1H NMR
b,7b-(2,2-Propilendioxy)-14,15-dinor-labd-8-en-13-ol (12a)
d: 4.59 (1H, dd, J¼6.4 and 1.7 Hz, H-6),
4.30 (1H, d, J¼6.4 Hz, H-7), 3.85–3.75 (1H, m, H-13), 2.30–0.80 (11H,
m), 1.70 (3H, s, Me-17), 1.35 (3H, s, Me2CO), 1.34 (3H, s, Me2CO), 1.29
(3H, s, Me-20),1.22 (3H, d, J¼6.2 Hz, Me-16),1.18 (3H, s, Me-19),1.01
(3H, s, Me-18). EIHRMS: calcd for C21H36O3Na: 336.4234, found
336.4245.
4.9.1. 6b,7b-Carbonyldioxy-13-R/S-tert-butyldimethylsilyloxy-
14,15-dinor-labd-8-eno (16)
Rf (Hex/EtOAc 8/2)¼0.52; [
22
a]
þ49.7 (c 1.08, CHCl3); IR (film):
D
1802, 1374, 1168, 1137, 1038, 1017, 836, 775; 1H NMR
d: 5.15 (1H, dd,
J¼8.0 and 1.4 Hz, H-6), 4.90 (1H, d, J¼8.0 Hz, H-7), 3.72–3.83 (1H, m,
H-13), 2.30–0.75 (11H, m), 1.73 (3H, s, Me-17), 1.27 (3H, s, Me-20),
1.19 (3H, s, Me-19), 1.13 (3H, d, J¼6.1 Hz, Me-16), 1.02 (3H, s, Me-18),
4.7.2. 6
13-ol (13a)
Rf (Hex/EtOAc 8/2)¼0.13; IR (film): 3448, 1655, 1459, 1378, 1122,
1077, 1039; 1H NMR
a,7a-(2,2-Propilendioxy)-14,15-dinor-labd-8-en-
0.89 (9H, s, Me2SiCMe3), 0.05 (6H, s, Me2SiCMe3); 13C NMR
d: 155.3
d: 4.38 (1H, dd, J¼12.8 and 2.0 Hz, H-6), 3.86–
(OCOO), 149.7 (C-9), 120.4 (C-8), 79.0 (C-7), 75.0 (C-6), 68.7 (C-13),
51.6 (C-5), 42.5 (C-3), 39.3 (C-12), 38.9 (C-10), 38.5 (C-1), 34.0 (C-4),
32.8 (C-18), 25.8 (Me2SiCMe3), 24.1 (C-11), 23.6 (C-16), 23.5 (C-19),
22.3 (C-20), 18.5 (C-2), 18.0 (Me2SiCMe3), 16.1 (C-17), ꢁ4.5
(Me2SiCMe3), ꢁ4.8 (Me2SiCMe3); EIHRMS: calcd for C25H44O4SiNa:
459.29011, found 459.2917.
3.79 (1H, m, H-13), 3.79 (1H, d, J¼2.0 Hz, H-7), 2.28–0.90 (11H, m),
1.83 (3H, s, Me-17),1.25 (3H, s, Me2CO),1.25 (3H, s, Me2CO),1.22 (3H,
d, J¼6.2 Hz, Me-16), 1.17 (3H, s, Me-20), 1.16 (3H, s, Me-19), 1.15 (3H,
s, Me-18). EIHRMS: calcd for
336.4245.
C21H36O3Na: 336.4234, found
4.8. Reaction of 12 and 13 with TBDMSCl to yield 14 and 15
4.10. Reaction of 16 with TBAF to yield 17
To an ice cooled solution of 12/13 (259 mg, 0.87 mmol) in DMF
(8.7 mL), TBDMSCl (132 mg, 0.87 mmol) and imidazole (119 mg,
1.75 mmol) were added, and the mixture was stirred at room
temperature for 15 h under argon. Then, the solution was cooled to
0 ꢀC, diluted with water and extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to give a crude oil, which was
chromatographed on silica gel to afford 14 (125 mg, 35%) and 15
(196 mg, 55%).
A solution of 16 (35 mg, 0.08 mmol) in THF (1.6 mL) was treated
with TBAF (0.33 mL solution 1.0 M in THF, 0.33 mmol). After being
stirred for 2 h under argon, the reaction mixture was diluted with
water and extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to give a crude oil, which was chromatographed
on silica gel to afford 17 (25 mg, 95%).
4.10.1. 6
Rf (Hex/EtOAc 1/1)¼0.35; IR (film): 3400, 1800, 1717, 1460, 1374,
1171, 1120, 1079, 1021; 1H NMR
b,7b-Carbonyldioxy-14,15-dinor-labd-8-en-13-R/S-ol (17)
4.8.1. 13-R/S-tert-Butyldimethylsilyloxy-14,15-dinor-labd-8-ene-
d
: 5.17 (1H, dd, J¼8.0 and 1.8 Hz, H-
6
b
,7
Rf (Hex/EtOAc 1/1)¼0.74; [
3411,1472,1255, 1033, 836; 1H NMR
b
-diol (14)
6), 4.91 (1H, d, J¼8.0 Hz, H-7), 3.86–3.77 (1H, m, H-13), 2.40–0.80
22
a
]
þ43.5 (c 1.14, CHCl3); IR (film):
(11H, m), 1.74 (3H, s, Me-17), 1.22 (3H, s, Me-20), 1.20 (3H, d,
D
d
: 4.30 (1H, br s, H-7), 3.98 (1H,
J¼6.2 Hz, Me-16),1.19 (3H, s, Me-19),1.03 (3H, s, Me-18); 13C NMR
d:
br s, H-6), 3.80–3.72 (1H, m, H-13), 2.40–0.80 (11H, m), 1.71 (3H, s,
Me-17),1.35 (3H, s, Me-20),1.22 (3H, s, Me-19),1.14 (3H, d, J¼6.2 Hz,
Me-16), 0.96 (3H, s, Me-18), 0.89 (9H, s, Me2SiCMe3), 0.05 (6H, s,
155.6 (OCOO), 149.7 (C-9), 120.9 (C-8), 79.1 (C-7), 75.3 (C-6), 68.5
(C-13), 51.8 (C-5), 42.6 (C-3), 39.9 (C-12), 39.0 (C-10), 38.6 (C-1),
34.2 (C-4), 33.0 (C-18), 24.4 (C-11), 23.7 (C-19), 23.6 (C-16), 22.6
(C-20), 18.8 (C-2), 16.4 (C-17); EIHRMS: calcd for C19H30O4Na:
345.2036, found 345.2037.
Me2SiCMe3); 13C NMR
d: 144.4 (C-9), 124.9 (C-8), 73.6 (C-7), 69.2
(C-13), 68.0 (C-6), 53.2 (C-5), 43.0 (C-3), 40.1 (C-10), 40.1 (C-12),
39.6 (C-1), 34.0 (C-4), 33.8 (C-18), 26.1 (Me2SiCMe3), 24.2 (C-11),
24.2 (C-19), 23.8 (C-16), 22.1 (C-20), 19.2 (C-2), 18.3 (Me2SiCMe3),
15.0 (C-17), ꢁ4.3 (Me2SiCMe3), ꢁ4.5 (Me2SiCMe3); EIHRMS: calcd
for C24H46O3SiNa: 433.3108, found 433.3136.
4.11. Oxidation of 17 with TPAP to yield 6
To a mixture of 17 (35 mg, 0.11 mmol), N-methylmorpholine N-
oxide (NMO) (58 mg, 0.43 mmol) and molecular sieves (120 mg) in
dry CH2Cl2 (2.5 mL) at room temperature was added TPAP (3 mg,
0.01 mmol). The reaction mixture was stirred for 1 h under argon
and then it was filtered through silica gel and Celite eluting with
AcOEt. The solvent was evaporated to give a crude oil, which was
chromatographed on silica gel to afford 6 (34 mg, 96%).
4.8.2. 13-R/S-tert-Butyldimethylsilyloxy-14,15-dinor-labd-8-ene-
6
a a-diol (15)
,7
Rf (Hex/EtOAc 1/1)¼0.61; [
3365, 1472, 1255, 1038, 835; 1H NMR
22
a
]
þ33.2 (c 1.12, CHCl3); IR (film):
D
d
: 3.95–3.80 (2H, m, H-6 and
H-7), 3.80–3.72 (1H, m, H-13), 2.30–0.80 (11H, m), 1.68 (3H, s, Me-
17), 1.16 (3H, s, Me-20), 1.12 (3H, d, J¼6.2 Hz, Me-16), 1.07 (3H, s,
Me-19), 1.05 (3H, s, Me-18), 0.89 (9H, s, Me2SiCMe3), 0.05 (6H, s,
4.11.1. 6
Rf (Hex/OAcEt 1/1)¼0.64; [
1801, 1717, 1461, 1373, 1166, 1137, 1119, 1076, 1017; 1H NMR
d: 5.17
b,7b-Carbonyldioxy-14,15-dinor-labd-8-en-13-one (6)
22
Me2SiCMe3); 13C NMR
d
: 144.4 (C-9), 126.2 (C-8), 80.4 (C-7), 74.9
a
]
þ27.1 (c 0.73, CHCl3); IR (film):
D
(C-6), 69.2 (C-13), 54.0 (C-5), 43.9 (C-3), 42.4 (C-10), 39.7 (C-12),
39.4 (C-1), 33.6 (C-4), 33.6 (C-18), 26.1 (Me2SiCMe3), 24.5 (C-11),
23.8 (C-16), 22.4 (C-19), 21.6 (C-20), 18.9 (C-2), 18.3 (Me2SiCMe3),
(1H, dd, J¼8.2 and 1.0 Hz, H-6), 4.90 (1H, d, J¼8.2 Hz, H-7), 2.60–
0.80 (11H, m), 2.15 (3H, s, Me-16), 1.71 (3H, s, Me-17), 1.23 (3H, s,

8822
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
Me-20), 1.18 (3H, s, Me-19), 1.03 (3H, s, Me-18); 13C NMR
d: 207.6
0.93 (3H, s, Me-18), 0.88 (9H, s, Me2SiCMe3), 0.05 (6H, s,
Me2SiCMe3); 13C NMR
: 203.6 (C-6), 171.0 (MeCOO), 147.8 (C-9),
(C-13), 155.3 (OCOO), 148.8 (C-9), 121.7 (C-8), 78.9 (C-7), 75.1 (C-6),
51.8 (C-5), 43.5 (C-12), 42.6 (C-3), 39.1 (C-10), 38.6 (C-1), 34.1 (C-4),
33.0 (C-18), 30.0 (C-16), 23.7 (C-19), 22.5 (C-20), 21.5 (C-11), 18.8
(C-2), 16.4 (C-17); EIHRMS: calcd for C19H28O4Na: 343.1880, found
343.1896.
d
124.1 (C-8), 77.9 (C-7), 69.0 (C-13), 62.7 (C-5), 46.7 (C-10), 42.4 (C-
3), 39.8 (C-12), 39.5 (C-1), 32.5 (C-18), 32.5 (C-4), 26.1 (Me2SiCMe3),
24.6 (C-11), 23.8 (C-16), 22.3 (C-19), 21.7 (MeCOO), 20.9 (C-20), 18.7
(C-2), 18.3 (Me2SiCMe3), 15.3 (C-17), ꢁ4.2 (Me2SiCMe3), ꢁ4.5
(Me2SiCMe3); EIHRMS: calcd for C26H46O4SiNa: 473.3058, found
473.3051.
4.12. Acetylation of 15 to yield 18 and 19
To a solution of 15 (2.44 g, 5.94 mmol) in dry pyridine (10 mL),
acetic anhydride (8 mL) was added and the mixture was stirred at
room temperature for 2 h. The reaction mixture was poured into
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and evaporated
to give a crude oil, which was chromatographed on silica gel to
afford 18 (2.18 g, 81%) and 19 (0.40 g, 15%).
4.14. Reduction of 20 with LiAlH4 to yield 14
An ice cooled solution of 20 (2.15 g, 4.77 mmol) in dry Et2O
(80 mL) was treated with LiAlH4 (500 mg, 13.1 mmol) and stirred at
room temperature for 45 min. Then, the solution was cooled back to
0 ꢀC, wet EtOAc was added and the mixture filtered. The resulting
organic phase was dried over Na2SO4, filtered and evaporated
affording 14 (1.94 g, 99%).
4.12.1. 7
labd-8-en-6
Rf (Hex/EtOAc 8/2)¼0.45; [
3498, 1719, 1472, 1463, 1374, 1254, 1135, 1087, 1039, 1021, 976, 835,
774; 1H NMR
a
-Acetoxy-13-R/S-tert-butyldimethylsilyloxy-14,15-dinor-
4.15. Reaction of Horner–Wadsworth–Emmons of
6 to yield 21
a
-ol (18)
22
a]
þ7.7 (c 1.12, CHCl3); IR (film):
D
To a mixture of NaH (1.25 g 60 % in mineral oil, 31.2 mmol)
and monoglyme (4.75 mL), methyl-diethyl-phosphonoacetate
(5.70 mL) was added under argon atmosphere and the resulting
solution was stirred at room temperature 40 min. Then a solution of
6 (0.33 g, 1.03 mmol) in monoglyme (3 mL) was added via canula
and the mixture was stirred 90 min at 60 ꢀC. After that the solution
was cooled to 0 ꢀC, poured into water, extracted with Et2O and
dried over Na2SO4. The solvent was evaporated to give a crude oil,
which was chromatographed on silica gel to afford 21 (0.28 g, 76%).
d: 5.22 (1H, d, J¼7.4 Hz, H-7), 4.12–3.95 (1H, m, H-6),
3.85–3.70 (1H, m, H-13), 2.40–0.80 (11H, m), 2.14 (3H, s, MeCOO),
1.53 (3H, s, Me-17),1.15 (3H, s, Me-20),1.12 (3H, d, J¼5.8 Hz, Me-16),
1.11 (3H, s, Me-19), 1.05 (3H, s, Me-18), 0.88 (9H, s, Me2SiCMe3), 0.04
(6H, s, Me2SiCMe3); 13C NMR
d: 173.5 (MeCOO), 148.3 (C-9), 122.8
(C-8), 84.2 (C-7), 73.6 (C-6), 69.1 (C-13), 54.8 (C-5), 43.8 (C-3), 41.6
(C-10), 39.7 (C-12), 39.4 (C-1), 36.5 (C-18), 33.8 (C-4), 26.1
(Me2SiCMe3), 24.5 (C-11), 23.7 (C-16), 22.2 (C-19), 21.7 (C-20), 21.5
(MeCOO), 18.8 (C-2), 18.3 (Me2SiCMe3), 15.2 (C-17), ꢁ4.2
(Me2SiCMe3), ꢁ4.5 (Me2SiCMe3); EIHRMS: calcd for C26H48O4SiNa:
475.3214, found 475.3217.
4.15.1. Methyl 6
Rf (Hex/EtOAc 7/3)¼0.47; [
1794, 1718, 1648, 1437, 1373, 1324, 1225, 1149, 1118, 1017, 916, 733;
1H NMR
b,7b-carbonildioxi-labda-8,13E-dien-15-oate (21)
22
a]
þ69.7 (c 0.75, CHCl3); IR (film):
D
4.12.2. 6
labd-8-en-7
Rf (Hex/EtOAc 8/2)¼0.29; [
3451, 1737, 1719, 1471, 1463, 1375, 1254, 1136, 1085, 1037, 835, 774;
1H NMR
a
-Acetoxy-13-R/S-tert-butyldimethylsilyloxy-14,15-dinor-
d
: 5.68 (1H, s, H-14), 5.17 (1H, dd, J¼8.2 and 1.2 Hz, H-6),
a
-ol (19)
22
4.91 (1H, d, J¼8.2 Hz, H-7), 3.69 (3H, s, COOMe), 2.40–0.80 (11H, m),
a
]
þ54.5 (c 1.03, CHCl3); IR (film):
D
2.19 (3H, s, Me-16), 1.75 (3H, s, Me-17), 1.24 (3H, s, Me-20), 1.19 (3H,
s, Me-19), 1.03 (3H, s, Me-18); 13C NMR
d: 167.3 (C-15), 159.4 (C-13),
d
: 5.22 (1H, dd, J¼12.2 and 6.6 Hz, H-6), 3.95 (1H, d,
155.3 (OCOO), 148.5 (C-9), 121.9 (C-8), 115.4 (C-14), 78.8 (C-7), 75.1
(C-6), 51.8 (C-5), 51.1 (COOMe), 42.7 (C-3), 40.6 (C-12), 39.1 (C-10),
38.6 (C-1), 34.2 (C-4), 32.9 (C-18), 26.5 (C-11), 23.7 (C-19), 22.6
(C-20), 19.0 (C-16), 18.8 (C-2), 16.4 (C-17); EIHRMS: calcd for
J¼6.6 Hz, H-7), 3.82–3.70 (1H, m, H-13), 2.20–0.80 (11H, m), 2.13
(3H, s, MeCOO), 1.68 (3H, s, Me-17), 1.12 (3H, d, J¼5.0 Hz, Me-16),
1.11 (3H, s, Me-20),1.04 (3H, s, Me-19), 0.90 (3H, s, Me-18), 0.88 (9H,
s, Me2SiCMe3), 0.04 (6H, s, Me2SiCMe3); 13C NMR
d: 172.8 (MeCOO),
C22H32O5Na: 399.2142, found 399.2151.
145.0 (C-9), 126.6 (C-8), 78.7 (C-7), 78.6 (C-6), 69.1 (C-13), 53.0
(C-5), 43.6 (C-3), 41.9 (C-10), 39.8 (C-12), 39.6 (C-1), 36.2 (C-18),
33.3 (C-4), 26.1 (Me2SiCMe3), 24.5 (C-11), 23.8 (C-16), 22.3 (C-19),
22.1 (C-20), 22.0 (MeCOO), 18.7 (C-2), 18.3 (Me2SiCMe3), 15.3 (C-17),
ꢁ4.2 (Me2SiCMe3), ꢁ4.5 (Me2SiCMe3). EIHRMS: calcd for
4.16. Reaction of 21 with DIBAL-H to yield 22
To a solution of 21 (56 mg, 0.15 mmol) in CH2Cl2 (2.5 mL) at
ꢁ78 ꢀC, DIBAL-H (0.60 mL of solution 1.5 M in toluene, 0.90 mmol)
was added under argon. After 30 min the mixture was warmed up
to 0 ꢀC, quenched with wet Et2O and at room temperature, Et2O,
Na2SO4 (1 g) and NaHCO3 (800 mg) were added and the solution
was stirred for 1 h, filtered eluting with Et2O and EtOAc and
concentrated to afford 22 (49 mg, 100%).
C
26H48O4SiNa: 475.3214, found 475.3200.
4.13. Oxidation of 18 with TPAP to yield 20
To a mixture of 18 (2.18 g, 4.82 mmol), N-methylmorpholine
N-oxide (NMO) (1.75 g, 13.0 mmol) and molecular sieves (2.00 g) in
dry CH2Cl2 (40 mL) was added TPAP (49 mg, 0.14 mmol). The re-
action mixture was stirred at room temperature for 1 h under argon
and then was filtered through silica gel and Celite eluting with
AcOEt. The solvent was evaporated to afford 20 (2.15 g, 99%).
4.16.1. Labda-8,13E-dien-6
Rf (Hex/EtOAc 1/1)¼0.35; [
3373, 1465, 1378, 1217, 1122, 1067, 1021, 926, 734; 1H NMR
b,7b,15-triol (22)
22
a]
þ29.8 (c 0.84, CHCl3); IR (film):
D
d: 5.40
(1H, t, J¼7.0 Hz, H-14), 4.33 (1H, d, J¼4.4 Hz, H-7), 4.15 (2H, d,
J¼7.0 Hz, H-15), 4.01 (1H, br s, H-6), 2.20–0.80 (11H, m), 1.70 (6H, s,
Me-16 and Me-17), 1.33 (3H, s, Me-20),1.21 (3H, s, Me-19), 0.95 (3H,
4.13.1. 7b-Acetoxy-13-R/S-tert-butyldimethylsilyloxy-14,15-dinor-
labd-8-en-6-one (20)
22
Rf (Hex/EtOAc 8/2)¼0.61; [
a]
þ100.0 (c 0.42, CHCl3); IR (film):
s, Me-18); 13C NMR
d: 143.8 (C-9), 140.4 (C-13), 125.5 (C-8), 123.2
D
1751, 1734, 1472, 1463, 1370, 1229, 1135, 1089, 1035, 835, 774; 1H
(C-14), 73.5 (C-7), 68.0 (C-6), 59.6 (C-15), 53.2 (C-5), 43.0 (C-3), 40.1
(C-10), 40.0 (C-12), 39.6 (C-1), 34.0 (C-4), 33.8 (C-18), 26.9 (C-11),
24.2 (C-19), 22.1 (C-20), 19.2 (C-2), 16.6 (C-16), 15.1 (C-17); EIHRMS:
calcd for C20H34O3Na: 345.2400, found 345.2407.
NMR d: 5.61 (1H, s, H-7), 3.85–3.70 (1H, m, H-13), 2.52 (1H, s, H-5),
2.20–0.80 (11H, m), 2.18 (3H, s, MeCOO), 1.62 (3H, s, Me-17), 1.29
(3H, s, Me-20), 1.13 (3H, d, J¼4.8 Hz, Me-16), 0.97 (3H, s, Me-19),

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8823
4.17. Reaction of 22 with TBDMSCl to yield 23
J¼6.6 Hz, H-15), 2.30–0.80 (11H, m), 1.75 (3H, s, Me-17), 1.70 (3H, s,
Me-16), 1.23 (3H, s, Me-20), 1.19 (3H, s, Me-19), 1.03 (3H, s, Me-18);
To an ice cooled solution of 22 (56 mg, 0.17 mmol) in DMF
(2 mL) TBDMSCl (26 mg, 0.17 mmol) and imidazole (24 mg,
0.36 mmol) were added, and the mixture was stirred at room
temperature for 17 h under argon. Then, the solution was cooled to
0 ꢀC, diluted with water and extracted with Et2O. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to afford 23 (68 mg, 92%).
13C NMR
d: 155.2 (OCOO), 149.1 (C-9), 139.2 (C-13), 123.4 (C-14),
121.0 (C-8), 78.7 (C-7), 74.9 (C-6), 59.3 (C-15), 51.6 (C-5), 42.5 (C-3),
39.0 (C-1), 38.8 (C-10), 38.4 (C-12), 34.0 (C-4), 32.8 (C-18), 26.7
(C-11), 23.5 (C-19), 22.3 (C-20), 18.6 (C-2), 16.3 (C-16), 16.2 (C-17);
EIHRMS: calcd for C21H32O4Na: 371.2193, found 371.2179.
4.20. Epoxidation of Sharpless of 25 with D(L)-DET to yield 26
4.17.1. 15-tert-Butyldimethylsilyloxy-labda-8,13E-dien-
To
D
(ꢁ)-DET (85 mg, 0.41 mmol) at ꢁ23 ꢀC were added DCM
6
b
,7
Rf (Hex/EtOAc 1/1)¼0.74; [
3390, 1471, 1386, 1253, 1110, 1072, 836, 776; 1H NMR
b
-diol (23)
(2.8 mL) and Ti(iPrO)4 (0.12 mL, 0.41 mmol) under argon and the
mixture was stirred for 30 min. Then a solution of 25 (102 mg,
0.29 mmol) in CH2Cl2 (2 mL) and t-BuOOH (0.12 mL of solution
5.5 M in decane, 0.67 mmol) were added and the resulting mixture
was stirred for 24 h at this temperature. Afterwards tartaric acid
(2 mL, 10% solution) was added and it was warmed up to room
temperature and stirred until it turned to be a clear solution. It was
filtered through Celite and eluted with CH2Cl2, the solvent was
removed and the resulting residue was dissolved in Et2O (55 mL),
washed with brine, dried over Na2SO4, filtered and concentrated to
give a crude oil, which was chromatographed on silica gel to afford
26 (69 mg, 65%).
22
a]
þ31.1 (c 0.84, CHCl3); IR (film):
D
d: 5.29 (1H, t,
J¼6.2 Hz, H-14), 4.27 (1H, d, J¼4.4 Hz, H-7), 4.17 (2H, d, J¼6.2 Hz,
H-15), 3.94 (1H, dd, J¼4.4 and 1.2 Hz, H-6), 2.20–0.80 (11H, m), 1.68
(3H, s, Me-17), 1.63 (3H, s, Me-16), 1.32 (3H, s, Me-20), 1.19 (3H, s,
Me-19), 0.93 (3H, s, Me-18), 0.89 (9H, s, Me2SiCMe3), 0.05 (6H, s,
Me2SiCMe3); 13C NMR
d: 144.0 (C-9), 137.7 (C-13), 125.4 (C-8), 124.2
(C-14), 73.4 (C-7), 67.9 (C-6), 60.6 (C-15), 53.1 (C-5), 43.0 (C-3), 40.1
(C-10), 39.9 (C-12), 39.6 (C-1), 33.9 (C-4), 33.8 (C-18), 26.3
(Me2SiCMe3), 26.9 (C-11), 24.1 (C-19), 22.0 (C-20), 19.2 (C-2), 18.7
(Me2SiCMe3), 16.6 (C-16), 15.1 (C-17), ꢁ4.8 (Me2SiCMe3); EIHRMS:
calcd for C26H48O3SiNa: 459.3265, found 459.3278.
4.20.1. 13R,14R-Epoxy-6
Rf (Hex/EtOAc 1/1)¼0.23; [
3422, 1793, 1459, 1374, 1324, 1175, 1138, 1117, 1081, 1018; 1H NMR
b,7b-carbonyldioxy-labd-8-en-15-ol (26)
22
4.18. Reaction of 23 with triphosgene to yield 24
a]
þ65.5 (c 0.89, CHCl3); IR (film):
D
d
:
To a solution of triphosgene (44 mg, 0.15 mmol) in pyridine
(0.08 mL) and CH2Cl2 (0.80 mL) cooled at ꢁ78 ꢀC was added
another solution of 23 (65 mg, 0.15 mmol) in CH2Cl2 (0.70 mL). The
reaction mixture was stirred until it warmed up to room temper-
ature and then saturated NH4Cl solution was added. The mixture
was extracted with Et2O and washed with aqueous 2 M HCl,
aqueous 6% NaHCO3 and brine. The organic layer was dried over
Na2SO4, filtered and evaporated to afford 24 (69 mg, 100%).
5.16 (1H, dd, J¼8.2 and 1.2 Hz, H-6), 4.89 (1H, d, J¼8.2 Hz, H-7), 3.83
(1H, dd, J¼12.0 and 4.4 Hz, HA-15), 3.69 (1H, dd, J¼12.0 and 6.6 Hz,
HB-15), 2.98 (1H, dd, J¼6.2 and 4.4 Hz, H-14), 2.30–0.80 (11H, m),
1.72 (3H, s, Me-17), 1.32 (3H, s, Me-16), 1.22 (3H, s, Me-20), 1.17 (3H,
s, Me-19), 1.01 (3H, s, Me-18); 13C NMR
d: 155.5 (OCOO), 148.7 (C-9),
121.6 (C-8), 79.0 (C-7), 75.2 (C-6), 63.0 (C-14), 61.6 (C-15), 61.3
(C-13), 51.8 (C-5), 42.7 (C-3), 39.1 (C-10), 38.6 (C-1), 38.3 (C-12),
34.3 (C-4), 33.0 (C-18), 23.7 (C-19), 23.3 (C-11), 22.6 (C-20), 18.8
(C-2), 16.9 (C-16), 16.3 (C-17); EIHRMS: calcd for C21H32O5Na:
387.2142, found 387.2132.
4.18.1. 6b,7b-Carbonyldioxy-15-tert-butyldimethylsilyloxy-labda-
8,13E-diene (24)
22
Rf (Hex/EtOAc 7/3)¼0.65; [
a]
þ59.0 (c 1.15, CHCl3); IR (film):
4.21. Reaction of 26 with TsCl to yield 27
D
1803, 1471, 1373, 1332, 1254, 1166, 1114, 1075, 1038, 1017, 836, 776;
1H NMR
d
: 5.30 (1H, t, J¼6.2 Hz, H-14), 5.16 (1H, dd, J¼7.8 and
To an ice cooled solution of 26 (53 mg, 0.15 mmol) in pyridine
(2 mL) was added TsCl (110 mg, 0.58 mmol) and the mixture was
stirred at room temperature for 3 h. The reaction mixture was
poured into ice-water and extracted with Et2O. The combined or-
ganic layers were washed successively with aqueous 20% CuSO4
solution, aqueous 6% NaHCO3 solution and brine, dried over Na2SO4
and concentrated under reduced pressure to afford the tosylate 27
(65 mg, 87%).
1.2 Hz, H-6), 4.91 (1H, d, J¼7.8 Hz, H-7), 4.19 (2H, d, J¼6.2 Hz, H-15),
2.20–0.80 (11H, m), 1.72 (3H, s, Me-17), 1.63 (3H, s, Me-16), 1.20 (3H,
s, Me-20), 1.16 (3H, s, Me-19), 1.00 (3H, s, Me-18), 0.87 (9H, s,
Me2SiCMe3), 0.04 (6H, s, Me2SiCMe3); 13C NMR
d: 154.8 (OCOO),
148.8 (C-9), 136.1 (C-13), 124.1 (C-14), 120.5 (C-8), 78.4 (C-7), 74.5
(C-6), 59.8 (C-15), 51.1 (C-5), 42.0 (C-3), 38.6 (C-1), 38.4 (C-12), 38.3
(C-10), 33.5 (C-4), 32.3 (C-18), 26.3 (C-11), 25.5 (Me2SiCMe3), 23.0
(C-19), 21.9 (C-20), 18.1 (C-2), 17.9 (Me2SiCMe3), 15.9 (C-16), 15.7
(C-17), ꢁ5.5 (Me2SiCMe3); EIHRMS: calcd for C27H46O4SiNa:
485.3058, found 485.3067.
4.21.1. Tosylate of 13R,14R-epoxy-6
b,7
b-carbonyldioxy-labd-8-en-
15-ilo (27)
22
Rf (Hex/EtOAc 1/1)¼0.59; [
a]
þ60.4 (c 1.10, CHCl3); IR (film):
D
4.19. Reaction of 24 with TBAF to yield 25
1794,1459, 1373,1324, 1177, 1118,1097, 1018, 964, 824, 777; 1H NMR
d
: 7.80 (2H, d, J¼8.6 Hz, H-20 and H-60), 7.35 (2H, d, J¼8.6 Hz, H-30
A solution of 24 (68 mg, 0.15 mmol) in THF (3 mL) was treated
with TBAF (1 mL solution 1.0 M in THF, 1.00 mmol). After being
stirred for 2 h under argon, the reaction mixture was diluted with
water and extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure to afford 25 (51 mg, 99%).
and H-50), 5.15 (1H, dd, J¼8.2 and 1.2 Hz, H-6), 4.88 (1H, d, J¼8.2 Hz,
H-7), 4.14 (1H, dd, J¼11.8 and 5.6 Hz, HA-15), 4.09 (1H, dd, J¼11.8
and 5.2 Hz, HB-15), 3.00 (1H, dd, J¼5.6 and 5.2 Hz, H-14), 2.44 (3H,
s, Ph-Me), 2.30–0.80 (11H, m), 1.69 (3H, s, Me-17), 1.23 (3H, s, Me-
16), 1.21 (3H, s, Me-20), 1.17 (3H, s, Me-19), 1.01 (3H, s, Me-18); 13
C
NMR d
: 155.4 (OCOO), 148.5 (C-9), 145.5 (C-40), 132.8 (C-10), 130.2
(C-30), 130.2 (C-50), 128.2 (C-20), 128.2 (C-60), 121.7 (C-8), 78.9 (C-7),
75.1 (C-6), 68.5 (C-15), 61.1 (C-13), 58.9 (C-14), 51.9 (C-5), 42.7 (C-3),
39.1 (C-1), 38.7 (C-10), 38.3 (C-12), 34.2 (C-4), 33.0 (C-18), 23.7
(C-19), 23.1 (C-11), 22.6 (C-20), 21.9 (PhMe), 18.8 (C-2), 16.7 (C-16),
16.3 (C-17). EIHRMS: calcd for C28H38O7SNa: 541.2230, found
541.2221.
4.19.1. 6
Rf (Hex/EtOAc 1/1)¼0.52; [
3421, 1793, 1668, 1464, 1374, 1324, 1266, 1172, 1138, 1117, 1081, 1017,
781, 739, 714; 1H NMR
: 5.43 (1H, t, J¼6.6 Hz, H-14), 5.17 (1H, dd,
J¼7.8 and 1.2 Hz, H-6), 4.91 (1H, d, J¼7.8 Hz, H-7), 4.16 (2H, d,
b,7b-Carbonyldioxy-labda-8,13E-dien-15-ol (25)
22
a]
þ66.3 (c 1.38, CHCl3); IR (film):
D
d

8824
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
4.22. Reaction of 27 with NaI to yield 28
902, 875, 787, 739; 1H NMR
d
: 5.93 (1H, dd, J¼17.2 and 10.6 Hz, H-
14), 5.22 (1H, dd, J¼17.2 and 1.0 Hz, H-15), 5.08 (1H, dd, J¼10.6 and
1.0 Hz, H-15), 4.30 (1H, d, J¼4.4 Hz, H-7), 3.95 (1H, br s, H-6), 2.40–
0.80 (11H, m), 1.67 (3H, s, Me-17), 1.33 (3H, s, Me-16), 1.29 (3H, s,
To a solution of tosylate 27 (20 mg, 0.04 mmol) in acetone
(2.5 mL) at room temperature, NaI (27 mg, 0.18 mmol) was added.
The mixture was heated at 70 ꢀC for 3 h. The solvent was removed,
water was added and extracted with Et2O. The combined organic
layers were washed successively with 10% aqueous Na2S2O3 solu-
tion, 6% aqueous NaHCO3 solution and brine, dried over Na2SO4 and
concentrated under reduced pressure to afford 28 (16 mg, 86%).
Me-20), 1.20 (3H, s, Me-19), 0.95 (3H, s, Me-18); 13C NMR
d: 144.9
(C-14), 143.9 (C-9), 125.4 (C-8), 112.3 (C-15), 73.8 (C-13), 73.5 (C-7),
68.0 (C-6), 53.1 (C-5), 43.0 (C-3), 41.9 (C-12), 40.2 (C-10), 40.1 (C-1),
33.9 (C-18), 33.8 (C-4), 28.0 (C-16), 24.2 (C-19), 22.3 (C-11), 22.2
(C-20), 19.2 (C-2), 15.0 (C-17). EIHRMS: calcd for C20H34O3Na:
345.2400, found 345.2394.
4.22.1. 15-Iodo-13R,14S-epoxy-6b,7b-carbonyldioxy-
labd-8-ene (28)
4.25. Acetylation of 30 to yield 31 and 2
22
Rf (Hex/EtOAc 7/3)¼0.47; [
a
]
þ43.5 (c 0.98, CHCl3); IR (film):
D
1794, 1463, 1374, 1324, 1176, 1138, 1118, 1081, 1018; 1H NMR
d
: 5.16
To a solution of 30 (10 mg, 0.03 mmol) in dry pyridine (1 mL),
acetic anhydride (1 mL) was added and the mixture was stirred at
room temperature for 70 h. The reaction mixture was poured into
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and evaporated
to give a crude oil, which was chromatographed on silica gel to
afford 31 (5 mg, 40%) and 2 (5 mg, 45%).
(1H, dd, J¼8.0 and 1.2 Hz, H-6), 4.89 (1H, d, J¼8.0 Hz, H-7), 3.38 (1H,
dd, J¼8.6 and 5.2 Hz, HA-15), 3.08 (1H, dd, J¼8.6 and 5.2 Hz, H-14),
2.99 (1H, dd, J¼8.6 and 8.6 Hz, HB-15), 2.40–0.80 (11H, m), 1.73 (3H,
s, Me-17),1.31 (3H, s, Me-16),1.24 (3H, s, Me-20),1.18 (3H, s, Me-19),
1.02 (3H, s, Me-18); 13C NMR
d: 155.4 (OCOO), 148.7 (C-9), 121.6
(C-8), 78.9 (C-7), 75.1 (C-6), 64.0 (C-13), 62.7 (C-14), 51.9 (C-5), 42.7
(C-3), 39.1 (C-10), 38.7 (C-1), 38.2 (C-12), 34.2 (C-4), 33.0 (C-18),
23.7 (C-19), 23.6 (C-11), 22.6 (C-20), 18.8 (C-2), 16.4 (C-17), 15.8
(C-16), 2.4 (C-15); EIHRMS: calcd for C21H31O4INa: 497.1159, found
497.1147.
4.25.1. 6
Rf (C6H6/EtOAc 7/3)¼0.53; [
3504, 1742, 1459, 1369, 1251, 1117, 1025, 946; 1H NMR
b,7b-Diacetoxy-labda-8,14-dien-13R-ol (31)
22
a
]
þ22.3 (c 0.13, CHCl3); IR (film):
D
d
: 5.94 (1H,
dd, J¼17.4 and 10.7 Hz, H-14), 5.68 (1H, d, J¼5.2 Hz, H-7), 5.42 (1H,
dd, J¼5.2 and 0.9 Hz, H-6), 5.24 (1H, dd, J¼17.4 and 1.2 Hz, H-15),
5.10 (1H, dd, J¼10.7 and 1.2 Hz, H-15), 2.20–0.80 (11H, m), 2.07 (3H,
s, MeCOO), 2.01 (3H, s, MeCOO), 1.56 (3H, s, Me-17), 1.36 (3H, s,
Me-16), 1.31 (3H, s, Me-20), 0.97 (3H, s, Me-19), 0.96 (3H, s, Me-18);
4.23. Reduction of 28 with Zn/AcOH to yield 29
To a solution of 28 (29 mg, 0.06 mmol) in AcOH glacial (1.5 mL)
at 0 ꢀC was added activated Zny (48 mg, 0.73 mmol) and it was
stirred for 2 h. Then the mixture was filtered washing with Et2O
and the resulting organic phase was washed with aqueous 10%
Na2S2O3, aqueous 6% NaHCO3 and water. The organic layer was
dried over Na2SO4, filtered and evaporated to afford 29 (21 mg,
98%).
13C NMR
d: 170.9 (MeCOO), 170.9 (MeCOO), 145.2 (C-9), 144.8
(C-14), 122.1 (C-8), 112.4 (C-15), 73.7 (C-13), 72.9 (C-7), 66.6 (C-6),
51.5 (C-5), 43.0 (C-3), 41.9 (C-12), 40.5 (C-1), 39.9 (C-10), 33.9 (C-18),
33.6 (C-4), 28.2 (C-16), 23.3 (C-19), 22.4 (C-11), 21.6 (MeCOO), 21.6
(MeCOO), 21.1 (C-20), 19.1 (C-2), 14.5 (C-17); EIHRMS: calcd for
C
24H38O5Na: 429.2611, found 429.2599.
4.23.1. 6
Rf (Hex/EtOAc 1/1)¼0.63; [
3470, 1793, 1463, 1374, 1323, 1265, 1175, 1138, 1117, 1036, 1018, 738,
704; 1H NMR
b,7b-Carbonyldioxy-labda-8,14-dien-13R-ol (29)
22
a
]
D
þ23.8 (c 0.85, CHCl3); IR (film):
4.25.2. 6
Rf (C6H6/EtOAc 7/3)¼0.42; [
3467,1763,1461,1371,1248,1117,1025, 920; 1H NMR
b
-Acetoxy-labda-8,14-dien-7
b
,13R-diol (2)
22
a
]
D
þ10.0 (c 0.13, CHCl3); IR (film):
d
: 5.91 (1H, dd, J¼17.6 and 10.8 Hz, H-14), 5.23 (1H,
d
: 5.91 (1H, dd,
dd, J¼17.6 and 1.2 Hz, H-15), 5.16 (1H, dd, J¼8.4 and 1.2 Hz, H-6),
5.11 (1H, dd, J¼10.8 and 1.2 Hz, H-15), 4.89 (1H, d, J¼8.4 Hz, H-7),
2.40–0.80 (11H, m), 1.73 (3H, s, Me-17),1.30 (3H, s, Me-16), 1.23 (3H,
J¼17.4 and 10.6 Hz, H-14), 5.33 (1H, d, J¼4.6 Hz, H-6), 5.20 (1H, dd,
J¼17.4 and 0.9 Hz, H-15), 5.07 (1H, dd, J¼10.6 and 0.9 Hz, H-15),
4.36 (1H, d, J¼4.6 Hz, H-7), 2.13 (3H, s, MeCOO), 2.12–0.80 (11H, m),
1.51 (3H, s, Me-17), 1.36 (3H, s, Me-16), 1.28 (3H, s, Me-20), 1.18 (3H,
s, Me-20), 1.18 (3H, s, Me-19), 1.02 (3H, s, Me-18); 13C NMR
d: 155.6
(OCOO), 149.7 (C-9), 144.5 (C-14), 121.0 (C-8), 112.7 (C-15), 79.1
(C-7), 75.2 (C-6), 73.6 (C-13), 51.9 (C-5), 42.8 (C-3), 41.5 (C-12), 39.2
(C-10), 38.7 (C-1), 34.3 (C-18), 33.1 (C-4), 28.2 (C-16), 23.7 (C-19),
22.6 (C-20), 22.5 (C-11), 18.9 (C-2), 16.4 (C-17); EIHRMS: calcd for
s, Me-19), 0.93 (3H, s, Me-18); 13C NMR
d: 170.8 (MeCOO), 146.0
(C-9), 144.9 (C-14), 121.4 (C-8), 112.2 (C-15), 76.6 (C-7), 73.7 (C-13),
66.1 (C-6), 53.0 (C-5), 43.3 (C-3), 41.8 (C-12), 40.4 (C-10), 40.0 (C-1),
34.0 (C-18), 33.8 (C-4), 28.0 (C-16), 23.9 (C-19), 22.3 (C-11), 21.8
(C-20), 21.6 (MeCOO), 19.1 (C-2), 14.7 (C-17); EIHRMS: calcd for
C
21H32O4Na: 371.2193, found 371.2184.
C22H36O4Na: 387.2506, found 387.2501.
4.24. Reduction of 29 with LiAlH4 to yield 30
4.26. Acetylation of 30 to yield 31
An ice cooled solution of 29 (30 mg, 0.09 mmol) in dry Et2O
(2 mL) was treated with LiAlH4 (8 mg, 0.21 mmol) and stirred at
room temperature for 1 h. Then, the solution was cooled back to
0 ꢀC, wet EtOAc was added and the mixture filtered. The resulting
organic phase was dried over Na2SO4, filtered and evaporated
affording 30 (28 mg, 100%).
To a solution of 30 (10 mg, 0.03 mmol) in dry pyridine (1 mL),
acetic anhydride (1 mL) was added and the mixture was stirred at
room temperature for 6 days. The reaction mixture was poured into
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and concen-
trated to afford 31 (12 mg, 96%).
4.24.1. Labda-8,14-dien-6b,7b,13R-triol (30)
22
Rf (Hex/EtOAc 1/1)¼0.38; [
a]
þ27.3 (c 1.04, CHCl3); IR (film):
D
3389, 1717, 1647, 1464, 1375, 1341, 1264, 1216, 1124, 1068, 1023, 925,
4.27. Acetylation of 30 to yield 2
To a solution of 30 (10 mg, 0.03 mmol) in dry pyridine (1 mL),
acetic anhydride (1 mL) was added and the mixture was stirred at
room temperature for 14 h. The reaction mixture was poured into
y
Activation of Zn: Powder of Zn was washed four times with aqueous 5% HCl, five
times with water, five times with MeOH, six times with Et2O and then was dried
carefully under reduced pressure.

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8825
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and concen-
trated to afford 2 (11 mg, 97%).
EtOAc. The organic layer was washed successively with aqueous
2 M HCl, aqueous 6% NaHCO3 and water. The resulting solution was
then dried over Na2SO4 and evaporated to give a crude oil, which
was chromatographed on silica gel to afford 34 (18 mg, 85%).
4.28. Transacetylation of 2 to yield 32
4.30.1. 6
Rf (Hex/EtOAc 6/4)¼0.52; [
3464, 1742, 1461, 1369, 1242, 1115, 1019, 737; 1H NMR
d: 5.93 (1H,
b,7a-Diacetoxy-labda-8,14-dien-13S-ol (34)
22
a
]
þ34.3 (c 0.14, CHCl3); IR (film):
D
To a solution of 2 (11 mg, 0.03 mmol) in CHCl3 (1.00 mL), AcOH
(1 drop) was added. After 48 h the solvent was removed and the
resulting crude was chromatographed on silica gel to afford 2
(4.5 mg, 41%) and 32 (5.1 mg, 46%).
dd, J¼17.4 and 10.6 Hz, H-14), 5.30 (1H, br s, H-6), 5.24 (1H, dd,
J¼17.4 and 1.0 Hz, H-15), 5.10 (1H, dd, J¼10.6 and 1.0 Hz, H-15), 4.95
(1H, s br, H-7), 2.20–0.80 (11H, m), 2.08 (3H, s, MeCOO), 2.04 (3H, s,
MeCOO), 1.58 (3H, s, Me-17), 1.32 (3H, s, Me-16), 1.28 (3H, s, Me-20),
4.28.1. 7
Rf (Bz/EtOAc 7/3)¼0.13; [
3466, 1737, 1459, 1371, 1250, 1161, 1117, 1076, 1032, 945, 922; 1H
NMR
b
-Acetoxy-labda-8,14-dien-6
b
,13R-diol (32)
0.96 (3H, s, Me-18), 0.95 (3H, s, Me-19); 13C NMR
d: 169.7 (MeCOO),
22
a
]
þ18.4 (c 0.63, CHCl3); IR (film):
168.6 (MeCOO), 147.7 (C-9), 144.6 (C-14), 121.3 (C-8), 112.0 (C-15),
73.4 (C-13), 73.4 (C-7), 69.5 (C-6), 49.2 (C-5), 43.0 (C-3), 41.5 (C-12),
39.5 (C-10), 38.9 (C-1), 33.4 (C-4), 33.0 (C-18), 27.6 (C-16), 23.0
(C-19), 22.4 (C-11), 21.3 (MeCOO), 21.2 (MeCOO), 20.9 (C-20), 18.9
(C-2), 16.9 (C-17). EIHRMS: calcd for C24H38O5Na: 429.2611, found
429.2624.
D
d
: 5.92 (1H, dd, J¼17.4 and 10.8 Hz, H-14), 5.64 (1H, d,
J¼4.6 Hz, H-7), 5.21 (1H, dd, J¼17.4 and 1.2 Hz, H-15), 5.07 (1H, dd,
J¼10.8 and 1.2 Hz, H-15), 4.12 (1H, br s, H-6), 2.15–0.80 (11H, m),
2.07 (3H, s, MeCOO), 1.65 (3H, s, Me-17), 1.30 (3H, s, Me-16), 1.28
(3H, s, Me-20), 0.96 (3H, s, Me-19), 0.96 (3H, s, Me-18); 13C NMR
d:
172.4 (MeCOO), 144.9 (C-9), 143.5 (C-14), 125.3 (C-8), 112.2 (C-15),
73.7 (C-13), 72.5 (C-7), 69.6 (C-6), 51.7 (C-5), 43.2 (C-3), 41.8 (C-12),
40.1 (C-1), 39.9 (C-10), 33.8 (C-18), 33.5 (C-4), 28.0 (C-16), 23.3
(C-19), 22.3 (C-11), 21.8 (C-20), 21.6 (MeCOO),19.1 (C-2),14.7 (C-17);
EIHRMS: calcd for C22H36O4Na: 387.2506, found 387.2499.
4.31. Reaction of 33 with vinyl magnesium bromide/(D)-
TADDOL and acetylation to yield 35
(þ)-TADDOL (0.19 g, 0.40 mmol) was dissolved in THF (1.1 mL)
and cooled to ꢁ85 ꢀC and under argon atmosphere vinyl magne-
sium bromide (0.79 mL of solution 1.0 M in THF, 0.79 mmol) was
added. The mixture was heated to ꢁ50 ꢀC and then vinyl magne-
sium bromide (0.39 mL of solution 1.0 M in THF, 0.39 mmol) was
added, and the resulting solution was warmed up to room tem-
perature. The mixture was cooled to ꢁ90 ꢀC, a solution of 31 (17 mg,
0.05 mmol) in THF (1 mL) was added and the mixture was stirred at
this temperature for 24 h. Afterwards the reaction was quenched by
adding saturated NH4Cl solution (10 mL) and Et2O and the resulting
organic phase was washed with brine and dried over Na2SO4. The
solvent was removed to give a crude oil that was dissolved in dry
pyridine (3 mL), acetic anhydride (2 mL) was added and the mix-
ture was stirred at room temperature for 6 days. The reaction
mixture was poured into ice-water and extracted with EtOAc. The
organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3 and water. The resulting solution was then
dried over Na2SO4 and evaporated to give a crude oil, which was
chromatographed on silica gel to afford 35 (17 mg, 84%).
4.29. Reaction of 6 with Bu4NOAc to yield 33
A solution of 6 (42 mg, 0.13 mmol) in dry toluene (3 mL) was
added over Bu4NOAc (60 mg, 1.99 mmol) and the mixture was
stirred for 20 h at 100 ꢀC under argon. Then the solution was cooled
down to room temperature and AcOEt was added. The resulting
organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3, brine, dried over Na2SO4 and concentrated to
afford 33 (42 mg, 94%).
4.29.1. 7
Rf (Hex/EtOAc 6/4)¼0.56; [
3467, 1716, 1650, 1464, 1367, 1238, 1163, 1119, 1017; 1H NMR
a-Acetoxy-6b-hidroxy-14,15-dinor-labd-8-en-13-one (33)
22
a
]
þ24.3 (c 0.96, CHCl3); IR (film):
D
d
: 4.83
(1H, br s, H-7), 4.14 (1H, br s, H-6), 2.60–0.80 (11H, m), 2.17 (3H, s,
Me-16), 2.06 (3H, s, MeCOO),1.60 (3H, s, Me-17),1.29 (3H, s, Me-20),
1.18 (3H, s, Me-19), 0.91 (3H, s, Me-18); 13C NMR
d: 208.6 (C-13),
171.4 (MeCOO), 148.0 (C-9), 121.5 (C-8), 78.2 (C-7), 68.9 (C-6), 50.4
(C-5), 44.3 (C-12), 43.1 (C-3), 39.5 (C-10), 39.2 (C-1), 33.8 (C-4), 33.5
(C-18), 29.9 (C-16), 24.1 (C-19), 21.5 (C-20), 21.3 (MeCOO), 20.4
(C-11), 19.2 (C-2), 17.5 (C-17); EIHRMS: calcd for C20H32O4Na:
359.2193, found 359.2175.
4.31.1. 6
Rf (Hex/EtOAc 6/4)¼0.52; [
3457, 1742, 1461, 1448, 1369, 1242, 1122, 1076, 1020, 948; 1H NMR
b,7a-Diacetoxy-labda-8,14-dien-13R-ol (35)
22
a
]
þ52.0 (c 0.24, CHCl3); IR (film):
D
d
:
5.93 (1H, dd, J¼17.4 and 10.6 Hz, H-14), 5.30 (1H, br s, H-6), 5.24
(1H, dd, J¼17.4 and 1.0 Hz, H-15), 5.10 (1H, dd, J¼10.6 and 1.0 Hz, H-
15), 4.95 (1H, br s, H-7), 2.20–0.80 (11H, m), 2.08 (3H, s, MeCOO),
2.04 (3H, s, MeCOO), 1.58 (3H, s, Me-17), 1.32 (3H, s, Me-16), 1.28
4.30. Reaction of 33 with vinyl magnesium bromide/(L)-
TADDOL and acetylation to yield 34
(3H, s, Me-20), 0.97 (3H, s, Me-18), 0.95 (3H, s, Me-19); 13C NMR
d:
(ꢁ)-TADDOL (0.18 g, 0.38 mmol) was dissolved in THF (1.2 mL)
and cooled to ꢁ85 ꢀC and under argon atmosphere vinyl magne-
sium bromide (0.76 mL of solution 1.0 M in THF, 0.76 mmol) was
added. The mixture was heated to ꢁ50 ꢀC and then vinyl magne-
sium bromide (0.38 mL of solution 1.0 M in THF, 0.38 mmol) was
added, and the resulting solution was warmed up to room tem-
perature. The mixture was cooled to ꢁ90 ꢀC, a solution of 33
(18 mg, 0.05 mmol) in THF (1 mL) was added and the mixture was
stirred at this temperature for 24 h. Afterwards the reaction was
quenched by adding saturated NH4Cl solution (10 mL) and Et2O and
the resulting organic phase was washed with brine and dried over
Na2SO4. The solvent was removed to give a crude oil that was dis-
solved in dry pyridine (3 mL), acetic anhydride (2 mL) was added
and the mixture was stirred at room temperature for 6 days. The
reaction mixture was poured into ice-water and extracted with
169.9 (MeCOO), 169.7 (MeCOO), 147.8 (C-9), 144.5 (C-14), 121.3
(C-8), 112.1 (C-15), 73.5 (C-13), 73.4 (C-7), 69.5 (C-6), 49.2 (C-5),
43.0 (C-3), 41.4 (C-12), 39.5 (C-10), 38.9 (C-1), 33.4 (C-4), 33.0
(C-18), 27.6 (C-16), 23.0 (C-19), 22.7 (C-11), 21.5 (MeCOO), 21.2
(MeCOO), 20.9 (C-20), 18.9 (C-2), 16.9 (C-17); EIHRMS: calcd for
C24H38O5Na: 429.2611, found 429.2614.
4.32. Reaction of 34 with K2CO3/MeOH to yield 36
Compound 34 (3.4 mg, 0.01 mmol) was treated with K2CO3 in
MeOH (2%, 0.80 mL) and the mixture was stirred at room temper-
ature for 75 min. After that time, the reaction mixture was diluted
with H2O and extracted with EtOAc. The organic phase was washed
with aqueous 2 M HCl and water, dried over Na2SO4, filtered and
the solvent evaporated to afford 36 (3.0 mg, 98%).

8826
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
4.32.1. 6
b
-Acetoxy-labda-8,14-diene-7
a
,13S-diol (36)
2.17 (3H, s, Me-16),1.75 (3H, s, Me-17),1.27 (3H, t, COOCH2CH3),1.23
(3H, s, Me-20), 1.18 (3H, s, Me-19), 1.02 (3H, s, Me-18); 13C NMR
d:
22
Rf (Hex/EtOAc 6/4)¼0.23; [
a
]
D
þ14.3 (c 0.29, CHCl3); IR (film):
3435, 1738, 1460, 1375, 1241, 1103, 1020, 736; 1H NMR
d: 5.94 (1H,
165.9 (C-15), 158.1 (C-13), 154.4 (OCOO), 147.7 (C-9), 120.9 (C-8),
114.8 (C-14), 77.9 (C-7), 74.1 (C-6), 58.9 (CO2CH2CH3), 50.9 (C-5),
41.7 (C-3), 39.6 (C-12), 38.1 (C-10), 37.7 (C-1), 33.3 (C-4), 32.1 (C-18),
25.5 (C-11), 22.7 (C-19), 21.6 (C-20), 18.1 (C-16), 17.8 (C-2), 15.5
(C-17),13.6 (CO2CH2CH3); EIHRMS: calcd for C23H34O5Na: 413.2298,
found: 413.2279.
dd, J¼17.6 and 10.6 Hz, H-14), 5.26 (1H, br s, H-6), 5.24 (1H, dd,
J¼17.6 and 1.0 Hz, H-15), 5.10 (1H, dd, J¼10.6 and 1.0 Hz, H-15), 3.66
(1H, br s, H-7), 2.20–0.70 (11H, m), 2.04 (3H, s, MeCOO), 1.72 (3H, s,
Me-17), 1.31 (3H, s, Me-16), 1.25 (3H, s, Me-20), 0.99 (3H, s, Me-19),
0.99 (3H, s, Me-18); 13C NMR
d: 170.7 (MeCOO), 145.1 (C-9), 144.7
(C-14), 124.4 (C-8), 111.9 (C-15), 73.4 (C-13), 73.4 (C-6), 72.6 (C-7),
47.9 (C-5), 42.9 (C-3), 41.9 (C-12), 39.5 (C-10), 39.0 (C-1), 33.1 (C-18),
33.0 (C-4), 27.5 (C-16), 23.4 (C-19), 22.4 (C-11), 21.4 (MeCOO), 21.0
(C-20), 19.0 (C-2), 17.5 (C-17). EIHRMS: calcd for C22H36O4Na:
387.2506, found 387.2513.
4.35. Reaction of 39 with Bu4NOAc to yield 40
A solution of 39 (42 mg, 0.11 mmol) in dry toluene (4 mL) was
added over Bu4NOAc (1.03 g, 3.43 mmol) and the mixture was
stirred for 18 h at 100 ꢀC under argon. Then the solution was cooled
down to room temperature and AcOEt was added. The resulting
organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3, brine, dried over Na2SO4, filtered and
concentrated to 40 (42 mg, 98%).
4.33. Reaction of 35 with K2CO3/MeOH to yield 37
Compound 35 (9 mg, 0.02 mmol) was treated with K2CO3 in
MeOH (2%, 1.4 mL) and the mixture was stirred at room tempera-
ture for 75 min. After that time, the reaction mixture was diluted
with H2O and extracted with EtOAc. The organic phase was washed
with aqueous 2 M HCl and water, dried over Na2SO4, filtered and
the solvent evaporated to afford 37 (8 mg, 100%).
4.35.1. Ethyl 7
Rf (Hex/EtOAc 6/4)¼0.74; [
3467, 1797, 1713, 1649, 1464, 1384, 1238, 1146, 1118, 1038, 1017; 1H
NMR : 5.68 (1H, s, H-14), 4.82 (1H, br s, H-7), 4.15 (2H, q,
a-acetoxy-6b-hidroxy-labda-8,13E-dien-15-oate (40)
22
a
]
þ64.3 (c 1.02, CHCl3); IR (film):
D
d
4.33.1. 6
Rf (Hex/EtOAc 6/4)¼0.23; [
3437, 1736, 1462, 1375, 1243, 1101, 1022, 738; 1H NMR
b
-Acetoxy-labda-8,14-diene-7
a
,13R-diol (37)
COOCH2CH3), 4.13 (1H, br s, H-6), 2.30–0.80 (11H, m), 2.17 (3H, s,
Me-16), 2.06 (3H, s, MeCOO), 1.61 (3H, s, Me-17), 1.27 (3H, t,
COOCH2CH3), 1.29 (3H, s, Me-20), 1.18 (3H, s, Me-19), 0.91 (3H, s,
22
a
]
D
þ27.0 (c 0.50, CHCl3); IR (film):
d: 5.94 (1H,
dd, J¼17.6 and 10.6 Hz, H-14), 5.26 (1H, br s, H-6), 5.24 (1H, dd,
J¼17.6 and 1.2 Hz, H-15), 5.10 (1H, dd, J¼10.6 and 1.2 Hz, H-15), 3.66
(1H, br s, H-7), 2.20–0.70 (11H, m), 2.04 (3H, s, MeCOO), 1.72 (3H, s,
Me-17), 1.31 (3H, s, Me-16), 1.25 (3H, s, Me-20), 0.99 (3H, s, Me-19),
Me-18); 13C NMR
d: 169.6 (MeCOO), 165.8 (C-15), 158.3 (C-13), 147.9
(C-9), 121.4 (C-8), 114.9 (C-14), 78.3 (C-7), 68.8 (C-6), 58.8
(CO2CH2CH3), 50.5 (C-5), 43.1 (C-3), 39.6 (C-12), 39.3 (C-10), 38.7
(C-1), 33.7 (C-4), 33.4 (C-18), 24.9 (C-11), 23.9 (C-19), 21.6 (C-20),
21.3 (MeCOO), 18.7 (C-2), 18.1 (C-16), 16.9 (C-17), 13.6 (CO2CH2CH3);
EIHRMS: calcd for C24H37O5Na: 428.2599, found: 428.2419.
0.99 (3H, s, Me-18); 13C NMR
d: 170.8 (MeCOO), 145.2 (C-9), 144.6
(C-14), 124.4 (C-8), 112.0 (C-15), 73.5 (C-13), 73.4 (C-6), 72.6 (C-7),
47.9 (C-5), 42.9 (C-3), 41.8 (C-12), 39.6 (C-10), 39.0 (C-1), 33.1 (C-18),
33.0 (C-4), 27.5 (C-16), 23.4 (C-19), 22.6 (C-11), 21.6 (MeCOO), 21.0
(C-20), 19.0 (C-2), 17.5 (C-17). EIHRMS: calcd for C22H36O4Na:
387.2506, found 387.2518.
4.36. Reaction of 40 with DIBAL-H to yield 41
To a solution of 40 (39 mg, 0.10 mmol) in CH2Cl2 (1.7 mL) at
ꢁ78 ꢀC, DIBAL-H (0.40 mL of solution 1.5 M in toluene, 0.60 mmol)
was added under argon. After 30 min the mixture was warmed up
to 0 ꢀC, quenched with wet Et2O and at room temperature, Et2O,
Na2SO4 (800 mg) and NaHCO3 (650 mg) were added and the solu-
tion was stirred for 1 h, filtered eluting with Et2O and EtOAc and
concentrated to afford 41 (30 mg, 98%).
4.34. Wittig reaction of 6 to yield 38 and 39
To a solution of 6 (200 mg, 0.62 mmol) in dry toluene (42 mL),
Ph3PCHCO2Et (11 mg, 31.4 mmol) was added and the mixture was
stirred for 48 h to 120 ꢀC under argon atmosphere. Then AcOEt was
added and the resulting organic phase was washed with water and
brine and dried over Na2SO4. The solvent was evaporated to give
a crude oil, which was chromatographed on silica gel to afford 6
(62 mg, 31%), 38 (46 mg, 19%) and 39 (68 mg, 28%).
4.36.1. Labda-8,13E-dien-6
Rf (Hex/EtOAc 1/1)¼0.15; [
3376, 1719, 1460, 1371, 1222, 1128, 1063, 1029, 921, 730; 1H NMR
b,7a,15-triol (41)
22
a]
þ27.2 (c 0.93, CHCl3); IR (film):
D
d
:
5.44 (1H, t, J¼6.8 Hz, H-14), 4.25 (1H, br s, H-6), 4.17 (2H, d,
J¼6.8 Hz, H-15), 3.71 (1H, br s, H-7), 2.25–0.80 (11H, m), 1.80 (3H, s,
Me-17), 1.72 (3H, s, Me-16), 1.31 (3H, s, Me-20), 1.21 (3H, s, Me-19),
4.34.1. Ethyl 6
Rf (Hex/EtOAc 6/4)¼0.70; [
1801,1713,1649,1463,1442,1373,1323,1227,1176,1159,1038,1017;
1H NMR
b,7b-carbonyldioxy-labda-8,13Z-dien-15-oate (38)
22
a
]
D
þ54.8 (c 0.82, CHCl3); IR (film):
1.01 (3H, s, Me-18); 13C NMR
d: 169.7 (MeCOO), 146.2 (C-9), 140.0
d
: 5.64 (1H, s, H-14), 5.16 (1H, dd, J¼8.0 and 1.0 Hz, H-6),
(C-13), 124.2 (C-8), 123.0 (C-14), 76.2 (C-7), 71.7 (C-6), 59.4 (C-15),
49.3 (C-5), 42.8 (C-3), 39.4 (C-10), 39.3 (C-1), 39.3 (C-12), 33.6 (C-4),
33.4 (C-18), 26.9 (C-11), 24.1 (C-19), 21.6 (C-20), 21.2 (MeCOO), 19.0
(C-2), 17.8 (C-17), 16.4 (C-16); EIHRMS: calcd for C20H34O3Na:
345.2400, found: 345.2411.
4.91 (1H, d, J¼8.0 Hz, H-7), 4.13 (2H, q, COOCH2CH3), 2.90–2.50 (2H,
m, H-12), 2.30–0.80 (9H, m), 1.91 (3H, s, Me-16), 1.82 (3H, s, Me-17),
1.24 (3H, t, COOCH2CH3),1.24 (3H, s, Me-20),1.18 (3H, s, Me-19),1.02
(3H, s, Me-18); 13C NMR
d: 166.3 (C-15), 158.7 (C-13), 155.5 (OCOO),
149.1 (C-9), 121.9 (C-8), 116.8 (C-14), 79.2 (C-7), 75.2 (C-6), 59.8
(CO2CH2CH3), 51.9 (C-5), 42.7 (C-3), 39.2 (C-10), 38.6 (C-1), 38.5
(C-12), 34.3 (C-4), 33.1 (C-18), 26.4 (C-11), 25.1 (C-19), 23.7 (C-20),
22.7 (C-16), 18.9 (C-2), 16.4 (C-17), 14.5 (CO2CH2CH3); EIHRMS:
calcd for C23H34O5Na: 413.2298, found: 413.2310.
4.37. Reaction of 41 with isovaleric acid to yield 42
To a solution of isovaleric acid (0.16 mL, 1.50 mmol) in toluene
(0.50 mL), 2,4,6-trichlorobenzoyl chloride (0.23 mL, 1.50 mmol)
and Et3N (0.21 mL, 1.50 mmol) were added and the mixture was
stirred for 2 h at room temperature. Then 41 (24 mg, 0.07 mmol)
dissolved in toluene (0.50 mL) was added and the resulting solution
heated at 80 ꢀC for 2 h. After that, the mixture was filtered washing
with AcOEt and the organic layer obtained was washed successively
with aqueous 2 M HCl, aqueous 6% NaHCO3 and brine, dried over
4.34.2. Ethyl 6
Rf (Hex/EtOAc 6/4)¼0.70; [
1801, 1713, 1649, 1464, 1384, 1373, 1323, 1146, 1118, 1038, 1017; 1H
NMR
: 5.67 (1H, s, H-14), 5.17 (1H, dd, J¼8.0 and 1.0 Hz, H-6), 4.90
(1H, d, J¼8.0 Hz, H-7), 4.14 (2H, q, COOCH2CH3), 2.30–0.80 (11H, m),
b,7b-carbonyldioxy-labda-8,13E-dien-15-oate (39)
22
a]
þ69.9 (c 1.13, CHCl3); IR (film):
D
d

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8827
Na2SO4, filtered and concentrated to give a crude oil, which was
chromatographed on silica gel to afford 42 (42 mg, 100%).
4.40. Reaction of 43 with TBDMSCl to yield 44
To an ice cooled solution of 43 (19 mg, 0.06 mmol) in DMF (1 mL)
TBDMSCl (9 mg, 0.06 mmol) and imidazole (8 mg, 0.12 mmol) were
added, and the mixture was stirred at room temperature for 40 h
under argon. Then, the solution was cooled to 0 ꢀC, diluted with
water and extracted with AcOEt. The combined organic layers were
washed with brine, dried over Na2SO4, filtered and concentrated
under reduced pressure to afford 44 (24 mg, 96%).
4.37.1. 6
Rf (Hex/EtOAc 9/1)¼0.43; [
1742, 1581, 1548, 1371, 1291, 1122, 987, 844; 1H NMR
b,7a,15-Triisovaleryloxy-labda-8,13E-diene (42)
22
a
]
D
þ52.2 (c 0.89, CHCl3); IR (film):
d
: 5.35 (1H, t,
J¼6.9 Hz, H-14), 5.33 (1H, br s, H-6), 4.98 (1H, br s, H-7), 4.61 (2H, d,
J¼6.9 Hz, H-15), 2.36–2.00 (10H, m), 1.90–0.90 (10H, m), 1.75 (3H, s,
Me-16), 1.61 (3H, s, Me-17), 1.28 (3H, s, Me-20), 1.00 (3H, d,
J¼6.5 Hz), 0.98 (12H, d, J¼6.5 Hz), 0.97 (3H, s, Me-19), 0.96 (3H, s,
Me-18), 0.95 (3H, d, J¼6.5 Hz); 13C NMR
d: 172.5 (OCOCH2), 170.1
4.40.1. 15-tert-Butyldimethylsilyloxy-labda-8,13Z-diene-
(OCOCH2), 169.8 (OCOCH2), 147.5 (C-9), 142.3 (C-13), 121.5 (C-8),
118.1 (C-14), 73.5 (C-7), 69.6 (C-6), 61.4 (C-15), 49.1 (C-5), 44.1
(OCOCH2), 44.0 (OCOCH2), 44.0 (OCOCH2), 43.0 (C-3), 39.5 (C-10),
39.1 (C-1), 38.3 (C-12), 33.4 (C-4), 33.0 (C-18), 26.8 (C-11), 25.5
(CHMe2), 25.4 (CHMe2), 25.4 (CHMe2), 22.9 (C-19), 22.5 (CHMe2),
22.5 (CHMe2), 22.4 (CHMe2), 22.4 (CHMe2), 22.3 (CHMe2), 22.3
(CHMe2), 21.5 (C-20), 18.9 (C-2), 17.0 (C-17), 16.6 (C-16); EIHRMS:
calcd for C35H58O6Na: 597.4173, found: 597.4198.
6b b-diol (44)
,7
Rf (Hex/EtOAc 7/3)¼0.56; [
3399, 1463, 1379, 1259, 1104, 1071, 1044, 836, 805, 777; 1H NMR
22
a]
þ15.8 (c 0.92, CHCl3); IR (film):
D
d:
5.30 (1H, t, J¼6.4 Hz, H-14), 4.33 (1H, d, J¼5.0 Hz, H-7), 4.18 (2H, d,
J¼6.4 Hz, H-15), 3.99 (1H, dd, J¼5.0 and 1.0 Hz, H-6), 2.20–0.80 (11H,
m), 1.76 (3H, s, Me-17), 1.76 (3H, s, Me-16), 1.35 (3H, s, Me-20), 1.22
(3H, s, Me-19), 0.94 (3H, s, Me-18), 0.90 (9H, s, Me2SiCMe3), 0.06 (6H,
s, Me2SiCMe3); 13C NMR
d: 143.9 (C-9), 138.2 (C-13), 125.6 (C-8),
125.1 (C-14), 73.4 (C-7), 67.9 (C-6), 60.3 (C-15), 53.1 (C-5), 43.0 (C-3),
40.1 (C-10), 40.1 (C-1), 33.9 (C-4), 33.8 (C-18), 32.2 (C-12), 27.0 (C-11),
26.3 (Me2SiCMe3), 24.2 (C-19), 23.6 (C-16), 22.1 (C-20), 19.2 (C-2),
18.7 (Me2SiCMe3), 15.1 (C-17), 1.3 (Me2SiCMe3), ꢁ4.8 (Me2SiCMe3);
EIHRMS: calcd for C26H48O3SiNa: 459.3265, found: 459.3259.
4.38. Reaction of 42 with K2CO3/MeOH to yield 3
Compound 42 (24 mg, 0.04 mmol) was treated with K2CO3 in
MeOH (4%, 1.5 mL) and the mixture was stirred at room tempera-
ture for 20 h. After that time, the reaction mixture was diluted with
H2O and extracted with EtOAc. The organic phase was washed with
aqueous 2 M HCl and water, dried over Na2SO4, filtered and the
solvent evaporated to afford 3 (14 mg, 85%).
4.41. Reaction of 44 with triphosgene to yield 45
4.38.1. 6
Rf (Hex/EtOAc 6/4)¼0.23; [
3400,1732,1466,1377,1294,1260,1192,1169,1101,1008; 1H NMR
b
-Isovaleryloxy-labda-8,13E-diene-7
a
,15-diol (3)
To a solution of triphosgene (7 mg, 0.02 mmol) in pyridine
(0.01 mL) and CH2Cl2 (0.40 mL) cooled at ꢁ78 ꢀC was added an-
other solution of 44 (11 mg, 0.02 mmol) in CH2Cl2 (0.40 mL). The
reaction mixture was stirred until it warmed up to room temper-
ature and then saturated NH4Cl solution was added. The mixture
was extracted with Et2O and washed with aqueous 2 M HCl,
aqueous 6% NaHCO3 and brine. The organic layer was dried over
Na2SO4, filtered and evaporated to afford 45 (11 mg, 100%).
22
a
]
D
þ40.0 (c 1.01, CHCl3); IR (film):
d:
5.44 (1H, t, J¼6.8 Hz, H-14), 5.27 (1H, d, J¼1.4 Hz, H-6), 4.12 (2H, d,
J¼6.8 Hz, H-15), 3.67 (1H, d, J¼1.4 Hz, H-7), 2.25–0.80 (14H, m), 1.74
(3H, s, Me-17), 1.71 (3H, s, Me-16), 1.26 (3H, s, Me-20), 1.00 (3H, s,
Me-19), 1.00 (3H, s, Me-18), 0.93 (6H, d, J¼6.5 Hz, Me-24 and Me-
25); 13C NMR
d: 172.9 (OCOCH2), 145.7 (C-9), 140.1 (C-13), 124.1
(C-8), 123.0 (C-14), 73.2 (C-6), 72.6 (C-7), 59.4 (C-15), 48.0 (C-5),
44.0 (OCOCH2), 42.9 (C-3), 39.5 (C-10), 39.3 (C-1), 38.9 (C-12), 33.5
(C-4), 33.2 (C-18), 26.8 (C-11), 25.5 (CHMe2), 23.5 (C-19), 22.5
(CHMe2), 22.4 (CHMe2), 21.1 (C-20), 19.0 (C-2), 17.5 (C-17),
16.4 (C-16); EIHRMS: calcd for C25H42O4Na: 429.2975, found:
429.2995.
4.41.1. 15-tert-Butyldimethylsilyloxy-6b,7b-Carbonyldioxy-labda-
8,13Z-diene (45)
22
Rf (Hex/EtOAc 7/3)¼0.72; [
a
]
þ20.5 (c 1.00, CHCl3); IR (film):
D
1805, 1735, 1463, 1376, 1259, 1163, 1101, 1074, 1041, 1024, 804, 776;
1H NMR
d
: 5.30 (1H, t, J¼6.2 Hz, H-14), 5.17 (1H, dd, J¼7.8 and
1.2 Hz, H-6), 4.93 (1H, d, J¼7.8 Hz, H-7), 4.16 (2H, d, J¼6.2 Hz, H-15),
2.20–0.80 (11H, m), 1.78 (3H, s, Me-16), 1.76 (3H, s, Me-17),1.29 (3H,
s, Me-20), 1.20 (3H, s, Me-19), 1.04 (3H, s, Me-18), 0.90 (9H, s,
4.39. Reaction of 38 with DIBAL-H to yield 43
To a solution of 38 (26 mg, 0.07 mmol) in CH2Cl2 (2.5 mL) at
ꢁ78 ꢀC, DIBAL-H (0.30 mL of solution 1.5 M in toluene, 0.45 mmol)
was added under argon. After 1 h the mixture was warmed up to
0 ꢀC, quenched with wet Et2O and at room temperature, Et2O,
Na2SO4 (1.00 g) and NaHCO3 (0.80 g) were added and the solution
was stirred for 1 h, filtered eluting with Et2O and EtOAc and
concentrated to afford 43 (22 mg, 100%).
Me2SiCMe3), 0.06 (6H, s, Me2SiCMe3); 13C NMR
d: 154.9 (OCOO),
148.8 (C-9), 138.2 (C-13), 125.1 (C-14), 120.5 (C-8), 78.4 (C-7), 74.5
(C-6), 60.3 (C-15), 51.1 (C-5), 42.0 (C-3), 38.6 (C-1), 38.3 (C-10), 33.6
(C-18), 32.3 (C-4), 32.3 (C-12), 27.0 (C-11), 25.6 (Me2SiCMe3), 23.6
(C-16), 23.4 (C-19), 21.9 (C-20), 18.1 (C-2), 18.0 (Me2SiCMe3), 15.6
(C-17), 1.2 (Me2SiCMe3), ꢁ5.0 (Me2SiCMe3); EIHRMS: calcd for
C27H46O4SiNa: 485.3058, found: 485.3060.
4.39.1. Labda-8,13Z-dien-6
Rf (Hex/EtOAc 1/1)¼0.23; [
3366, 1463, 1377, 1261, 1095, 1020, 799; 1H NMR
b,7b,15-triol (43)
22
a
]
þ21.4 (c 1.26, CHCl3); IR (film):
D
d
: 5.39 (1H, t,
4.42. Reaction of 45 with Bu4NOAc to yield 46 and 47
J¼7.0 Hz, H-14), 4.32 (1H, d, J¼4.4 Hz, H-7), 4.13 (2H, d, J¼7.0 Hz,
H-15), 4.05–3.95 (1H, br s, H-6), 2.20–0.70 (11H, m), 1.78 (3H, s,
Me-17), 1.75 (3H, s, Me-16), 1.33 (3H, s, Me-20), 1.21 (3H, s, Me-19),
A solution of 45 (51 mg, 0.11 mmol) in dry toluene (4 mL)
was added over Bu4NOAc (1.03 g, 3.43 mmol) and the mixture was
stirred for 46 h at 80 ꢀC under argon. Then the solution was cooled
down to room temperature and AcOEt was added. The resulting
organic layer was washed successively with aqueous 2 M HCl,
aqueous 6% NaHCO3, brine, dried over Na2SO4, filtered and con-
centrated to give a crude oil, which was chromatographed on silica
gel to afford 46 (14 mg, 27%) and 47 (22 mg, 56%).
0.96 (3H, s, Me-18); 13C NMR
d: 143.9 (C-9), 140.6 (C-13), 125.8
(C-8),124.1 (C-14), 73.5 (C-7), 67.9 (C-6), 59.4 (C-15), 53.1 (C-5), 42.9
(C-3), 40.1 (C-10), 40.1 (C-1), 33.9 (C-4), 33.8 (C-18), 32.3 (C-12),
26.9 (C-11), 24.2 (C-19), 23.6 (C-16), 22.0 (C-20), 19.2 (C-2),
15.4 (C-17); EIHRMS: calcd for C20H34O3Na: 345.2400, found:
345.2416.

8828
I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
4.42.1. 7
a-Acetoxy-15-tert-butyldimethylsilyloxy-labda-8,13Z-
layer was washed successively with aqueous 2 M HCl, aqueous 6%
dien-6
Rf (Hex/EtOAc 1/1)¼0.80; [
3451, 1805, 1731, 1647, 1463, 1374, 1252, 1103, 1073, 1017, 941, 836,
776; 1H NMR
(2H, d, J¼6.0 Hz, H-15), 4.18 (1H, br s, H-6), 2.30–0.70 (11H, m), 2.08
(3H, s, MeCOO), 1.77 (3H, s, Me-16), 1.69 (3H, s, Me-17), 1.31 (3H, s,
Me-20), 1.20 (3H, s, Me-19), 0.93 (3H, s, Me-18), 0.90 (9H, s,
Me2SiCMe3), 0.07 (6H, s, Me2SiCMe3); EIHRMS: calcd for
b
-ol (46)
NaHCO3 and brine. The resulting solution was then dried over
Na2SO4, filtered and concentrated to give a crude oil, which was
chromatographed on silica gel to afford 48 (15 mg, 98%).
22
a
]
þ43.5 (c 0.20, CHCl3); IR (film):
D
d: 5.31 (1H, t, J¼6.0 Hz, H-14), 4.85 (1H, br s, H-7), 4.19
4.45.1. 6
Rf (Hex/EtOAc 7/3)¼0.45; [
1742, 1474, 1442, 1368, 1239, 1019; 1H NMR
b,7a,15-Triacetoxy-labda-8,13E-diene (48)
22
a]
þ44.8 (c 0.33, CHCl3); IR (film):
D
d: 5.35 (1H, t, J¼7.0 Hz,
H-14), 5.32 (1H, br s, H-6), 4.97 (1H, br s, H-7), 4.60 (2H, d, J¼7.0 Hz,
H-15), 2.20–0.80 (11H, m), 2.10 (3H, s, MeCOO), 2.07 (3H, s, MeCOO),
2.04 (3H, s, MeCOO), 1.74 (3H, s, Me-16), 1.62 (3H, s, Me-17), 1.28
C
28H50O4SiNa: 501.3371, found: 501.3375.
4.42.2. 7
Rf (Hex/EtOAc 7/3)¼0.45; [
3407, 1728, 1460, 1443, 1375, 1237, 1160, 1118, 1095, 1039, 1018; 1
NMR
a
-Acetoxy-labda-8,13Z-dien-6
b
,15-diol (47)
(3H, s, Me-20), 0.97 (3H, s, Me-18), 0.96 (3H, s, Me-19); 13C NMR
d:
22
a
]
þ46.7 (c 0.09, CHCl3); IR (film):
171.1 (MeCOO), 169.9 (MeCOO), 169.7 (MeCOO), 147.6 (C-9), 142.3
(C-13), 121.6 (C-8), 118.0 (C-14), 73.4 (C-7), 69.5 (C-6), 61.3 (C-15),
49.2 (C-5), 43.0 (C-3), 39.4 (C-10), 39.2 (C-1), 38.8 (C-12), 33.4 (C-4),
33.0 (C-18), 26.8 (C-11), 23.0 (C-19), 21.5 (C-20), 21.5 (MeCOO), 21.0
(MeCOO), 20.9 (MeCOO), 18.9 (C-2), 17.0 (C-17), 16.6 (C-16);
EIHRMS: calcd for C26H40O6Na: 471.2717, found: 471.2720.
D
H
d
: 5.40 (1H, t, J¼7.4 Hz, H-14), 4.84 (1H, br s, H-7), 4.16 (1H, s
ancho, H-6), 4.14 (2H, d, J¼7.4 Hz, H-15), 2.20–0.70 (11H, m), 2.07
(3H, s, MeCOO), 1.79 (3H, s, Me-16), 1.68 (3H, s, Me-17), 1.30 (3H, s,
Me-20), 1.18 (3H, s, Me-19), 0.92 (3H, s, Me-18); 13C NMR
d: 169.8
(MeCOO), 146.2 (C-9), 140.6 (C-13), 124.3 (C-8), 124.0 (C-14), 76.1
(C-7), 71.7 (C-6), 59.4 (C-15), 49.2 (C-5), 42.9 (C-3), 39.5 (C-1), 39.5
(C-10), 33.7 (C-4), 33.5 (C-18), 32.2 (C-12), 26.9 (C-11), 24.0 (C-19),
23.6 (C-16), 21.5 (C-20), 21.3 (MeCOO), 19.0 (C-2), 17.7 (C-17);
EIHRMS: calcd for C22H36O4Na: 387.2506, found: 387.2488.
Acknowledgements
The authors are gratefully acknowledged to Dr. A. Lithgow and
Dr. C. Raposo, from the NMR and Mass Spectrometry Services,
respectively, of Universidad de Salamanca and to the CICYT
(CTQ2005-04406) for financial support. L.C. is grateful to Junta de
4.43. Reaction of 46 with TBAF to yield 47
´
Castilla y Leon for a fellowship.
A solution of 46 (8 mg, 0.02 mmol) in THF (0.40 mL) was treated
with TBAF (0.40 mL solution 1.0 M in THF, 0.40 mmol). After being
stirred for 90 min under argon the reaction mixture was diluted
with water, and extracted with EtOAc. The combined organic layers
were washed with brine, dried over Na2SO4, filtered and concen-
trated under reduced pressure to afford 47 (5 mg, 90%).
References and notes
1. Hanson, J. R. Nat. Prod. Rep. 2007, 24, 1332.
2. (a) Bhat, S. V.; Bajwa, B. S.; Dornauer, H.; De Souza, N. J.; Fehlhaber, H. W.
Tetrahedron Lett. 1977, 19, 1669; (b) Hashimoto, S.; Sakata, S.; Sonegawa, M.;
Ikegami, S. J. Am. Chem. Soc. 1988, 110, 3670; (c) Corey, E. J.; Da Silva Jardine, P.;
Rohloff, J. C. J. Am. Chem. Soc. 1988, 110, 3672; (d) Hagiwara, H.; Takeuchi, F.;
Kudou, M.; Hoshi, T.; Suzuki, T.; Hashimoto, T.; Asakawa, A. J. Org. Chem. 2006,
71, 4619; (e) Shan, Y.; Wang, X.; Zhou, X.; Kong, L.; Niwa, M. Chem. Pharm. Bull.
2007, 55, 376; (f) Hagiwara, H.; Tsukagoshi, M.; Hoshi, T.; Suzuki, T.; Hashimoto,
T.; Asakawa, Y. Synlett 2008, 929.
3. (a) Zdero, C.; Bohlmann, F.; Niemeyer, M. Phytochemistry 1991, 30, 3683; (b)
Manker, D. C.; Faulkner, J. Tetrahedron 1987, 43, 3677; (c) Rovirosa, J.; Quezada,
E.; San Martı´n, A. Bol. Soc. Chil. Quim. 1992, 37, 143; (d) Boalino, M. D.; McLean,
S.; Reynolds, W. F.; Tinto, W. F. J. Nat. Prod. 2004, 67, 714.
4. Patha, K. A.; Aslaoui, J.; Morin, C. J. Org. Chem. 2005, 70, 4184.
5. Basabe, P.; Delgado, S.; Marcos, I. S.; Dı´ez, D.; Diego, A.; De Roma´n, M.; Urones,
J. G. J. Org. Chem. 2005, 70, 9480.
6. Basabe, P.; Diego, A.; Delgado, S.; Dı´ez, D.; Marcos, I. S.; Urones, J. G. Tetrahedron
2003, 59, 9173.
4.44. Acetylation of 47 to yield 4
To a solution of 47 (6 mg, 0.02 mmol) in CH2Cl2 (0.50 mL),
CH3COCl (0.12 mL, 1.50 mmol) and N,N-dimetilaniline (0.12 mL,
1.20 mmol) were added under argon atmosphere and the mixture
was stirred at room temperature for 5 days. The reaction mixture
was poured into ice-water and extracted with Et2O. The organic
layer was washed successively with aqueous 2 M HCl, aqueous 6%
NaHCO3 and brine. The resulting solution was then dried over
Na2SO4, filtered and concentrated to give a crude oil, which was
chromatographed on silica gel to afford 4 (7 mg, 96%).
7. (a) Basabe, P.; Diego, A.; Dı´ez, D.; Marcos, I. S.; Urones, J. G. Synlett 2000, 1807;
(b) Basabe, P.; Diego, A.; Dıez, D.; Marcos, I. S.; Urones, J. G.; Mollinedo, F.
´
Synthesis 2002, 1523.
8. Marcos, I. S.; Laderas, M.; Dı´ez, D.; Basabe, P.; Moro, R. F.; Garrido, N. M.; Urones,
J. G. Tetrahedron Lett. 2003, 44, 5419.
9. Marcos, I. S.; Beneitez, A.; Castan˜eda, L.; Moro, R. F.; Basabe, P.; Dı´ez, D.; Urones,
J. G. Synlett 2007, 1589.
10. (a) House, H. O. Mod. Synth. React. 1972, 280; (b) Mechoulam, R.; Luchter, K.;
Goldblum, A. Synthesis 1974, 363; (c) Salmond, W. D.; Barta, M. A.; Havens, J. L. J.
Org. Chem. 1978, 43, 2057; (d) Schlessinger, R. H.; Parson, W. H. J. Org. Chem.
1983, 48, 1146.
11. Oppolzer, W.; Sarkar, T.; Mahalanabio, K. K. Helv. Chim. Acta 1976, 59, 2012.
12. (a) Greene, T.; Wuts, P. G. M. Protective Groups in Organic S´ıntesis, 3rd ed.; Wiley:
1999; p 127; (b) Ermoleuke, L.; Sasaki, N. A.; Potier, P. J. Chem. Soc., Perkin Trans
2000, 2465; (c) Nakagawa, Y.; Irie, K.; Masuda, A.; Ohigashi, H. Tetrahedron
2002, 58, 2101.
4.44.1. 6
Rf (Hex/EtOAc 7/3)¼0.60; [
1740, 1471, 1440, 1371, 1240, 1017; 1H NMR
b,7a,15-Triacetoxy-labda-8,13Z-diene (4)
22
a]
þ32.1 (c 0.51, CHCl3); IR (film):
D
d
: 5.36 (1H, t, J¼7.0 Hz,
H-14), 5.32 (1H, br s, H-6), 4.97 (1H, br s, H-7), 4.57 (2H, d, J¼7.0 Hz,
H-15), 2.30–0.80 (11H, m), 2.09 (3H, s, MeCOO), 2.05 (3H, s,
MeCOO), 2.04 (3H, s, MeCOO), 1.82 (3H, s, Me-16), 1.65 (3H, s, Me-
17), 1.30 (3H, s, Me-20), 0.97 (3H, s, Me-19), 0.95 (3H, s, Me-18); 13
C
NMR d: 171.1 (MeCOO), 169.9 (MeCOO), 169.8 (MeCOO), 147.6 (C-9),
144.1 (C-13), 121.6 (C-8), 118.7 (C-14), 73.5 (C-7), 69.5 (C-6), 61.7
(C-15), 49.2 (C-5), 43.0 (C-3), 39.4 (C-10), 39.3 (C-1), 33.5 (C-4), 33.4
(C-18), 31.4 (C-12), 26.9 (C-11), 23.6 (C-16), 23.1 (C-19), 21.5
(MeCOO), 21.4 (C-20), 21.0 (MeCOO), 20.9 (MeCOO), 18.9 (C-2), 17.1
(C-17); EIHRMS: calcd for C26H40O6Na: 471.2717, found: 471.2722.
´
13. (a) Buro, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395; (b) Kang, S.-K.; Jeon,
J.-H.; Nam, K.-S.; Park, C.-H.; Lee, H.-W. Synth. Commun. 1994, 24, 305; (c) Greene,
T.; Wuts, P. G. M. Protective Groups in Organic Sıntesis, 3rd ed.; Wiley: 1999; p 241.
14. (a) Yokohama, K.; Sakata, J.; Kuwajima, I.; Shimizu, M.; Nakamura, E.; Noyori, R.
J. Org. Chem. 1983, 43, 932; (b) Greene, T.; Wuts, P. G. M. Protective Groups in
Organic S´ıntesis, 3rd ed.; Wiley: 1999; p 133; (c) Nicolaou, K. C.; Xu, J. Y.; Kim, S.;
Pfefferkorn, J.; Ohshima, T.; Vourloumis, D.; Hosokawa, S. J. Am. Chem. Soc. 1998,
´
4.45. Acetylation of 41 to yield 48
´
120, 866; (d) Marcos, I. S.; Escola, M. A.; Moro, R. F.; Basabe, P.; Dıez, D.;
Mollinedo, F.; Urones, J. G. Synlett 2007, 2017.
To a solution of 41 (11 mg, 0.03 mmol) in CH2Cl2 (1 mL),
CH3COCl (0.24 mL, 3.00 mmol) and N,N-dimetilaniline (0.24 mL,
2.40 mmol) were added under argon atmosphere and the mixture
was stirred at room temperature for 5 days. The reaction mixture
was poured into ice-water and extracted with Et2O. The organic
15. (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639; (b)
Dı´ez Martı´n, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Mene´ndez, J. C.; Organ,
H. H.; White, A. D. Tetrahedron 1992, 48, 7899.
16. (a) van Wyk, A. W. W.; Davies-Coleman, M. T. Tetrahedron 2007, 63, 12179; (b)
Kelly, S. E. Alkene Synthesis. Phosphorus-Stabilized Alkenation. In Comprehensive

I.S. Marcos et al. / Tetrahedron 64 (2008) 8815–8829
8829
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 1,
pp 755–782.
Balmer, E.; Germanin, A.; Jackson, W. P.; Luggo, B. J. Chem. Soc., Perkin Trans. 1
1983, 399.
17. (a) Keinan, E. Partial Reduction of Enones, Styrenes and Related Systems. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 8, pp 523–578; (b) Paquette, L. A. Reagents for Organic
20. Hanessian, S.; Tremblay, M.; Petersen, J. F. W. J. Am. Chem. Soc. 2004, 126, 6064.
21. (a) Weber, B.; Seebach, D. Tetrahedron 1994, 50, 6117; (b) Weber, B.; Seebach, D.
Angew. Chem., Int. Ed. Engl. 1992, 31, 84; (c) Corey, E. J.; Guzman-Perez, A. Angew.
Chem., Int. Ed. 1998, 37, 388; (d) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem.
, Int. Ed. 2001, 40, 92.
22. (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863; (b) Still, W. C.; Gennari,
C. Tetrahedron Lett. 1983, 24, 4405; (c) Fraser-Reid, B.; Molino, B. F.; Magdzinski,
L.; Mootoo, D. R. J. Org. Chem. 1987, 52, 4505.
Synthesis; Wiley: New York, NY, 1995; Vol. 3;
p 1908; (c) Sydorenko, S.;
Hsung, R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org. Chem. 2004, 69, 6732; (d)
Xie, Y.-P.; Li, B.-G.; Luo, Y.-G.; Chen, X.-Z.; Zhang, G.-L. Helv. Chim. Acta 2008,
91, 734.
18. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974; (b) Pfenninger,
A. Synthesis 1986, 89.
19. (a) Tsuda, K.; Ohki, G.; Suzuki, J.; Shimizu, H. Chem. Pharm. Bull. 1961, 9, 131; (b)
Carda, M.; Murga, J.; Gonza´lez, F.; Marco, J. A. Tetrahedron 1995, 51, 2755; (c)
23. (a) Hartmann, B.; Kanazawa, A. M.; Depre´s, J.-P.; Greene, A. E. Tetrahedron
Lett. 1991, 32, 5077; (b) Ball, M.; Andrews, S. P.; Wierschem, F.; Cleator, E.;
Smith, M. D.; Ley, S. V. Org. Lett. 2007, 9, 663.