Ring B functionalization of scalarane sesterterpenes by radical relay halogenation

Article abstract of DOI:10.1016/j.tet.2007.05.048

The functionalization of the B-ring of the scalarane framework has been achieved for the first time by a radical relay halogenation (RRH) synthetic method. The known scalaranic methyl ester, which was prepared by a procedure with an overall yield higher than those reported in the literature, has been used as the starting substrate. Some theoretical considerations explaining the course of RRH reaction are also presented.

Full text of DOI:10.1016/j.tet.2007.05.048

Tetrahedron 63 (2007) 7617–7623
Ring B functionalization of scalarane sesterterpenes
by radical relay halogenation
Veaceslav Kulci¸tki, ,y Nicon Ungur,y Margherita Gavagnin,
*
Francesco Castelluccio and Guido Cimino
Istituto di Chimica Biomolecolare, CNR, Via Campi Flegrei 34, I-80078 Pozzuoli (Na), Italy
Received 15 February 2007; revised 19 April 2007; accepted 10 May 2007
Available online 17 May 2007
Abstract—The functionalization of the B-ring of the scalarane framework has been achieved for the first time by a radical relay halogenation
(RRH) synthetic method. The known scalaranic methyl ester, which was prepared by a procedure with an overall yield higher than those
reported in the literature, has been used as the starting substrate. Some theoretical considerations explaining the course of RRH reaction
are also presented.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of scalarane derivatives was focused mainly on
compounds displaying functional groups in the D-ring.
We report here our study toward the functionalization at
ring B by using a radical relay halogenation (RRH)
method. This investigation resulted in the synthesis of
scalarane compounds functionalized at the C-6 and C-7
positions.
The scalarane compounds, the first member of which was
scalaradial (1),1 are a very interesting group of natural prod-
ucts typically isolated from both marine sponges and
molluscs (Fig. 1).2 These molecules show diverse pharmaco-
logical properties including cytotoxicity, antimicrobial and
anti-inflammatory activity, platelet aggregation inhibition.3
An involvement of these sesterterpenoids in the defensive
mechanisms of sponges and molluscs has also been demon-
strated.4 The structural diversity in the scalarane family
mainly arises from the different arrangement of the oxidized
carbons C-19 and C-20, which can be involved in a cycliza-
tion process to form a five-membered ring with higher or
lower oxidation [i.e., scalarin (2)5]. The majority of natural
scalaranes are characterized by the presence of an oxygen-
ated functional group at C-12, such as scalaradial (1) and re-
lated compounds. However, a number of natural scalaranes
display additional oxygenated groups at different positions
of the tetracyclic framework [i.e., heteronemin (3),6 3-
keto-deoxoscalarin (4),7 6-keto-deoxoscalarin (5)8]. The
B-ring functionalization has also been reported for a series
of scalaranes (i.e., 6) isolated from ferns, the only report
of scalarane occurrence in plants.9
2. Results and discussion
The synthetic strategy was based on assembling the scalar-
ane skeleton, followed by a remote functionalization proce-
dure. The most convenient synthetic methodology leading
to the scalarane structure includes a C5 homologation of
the readily available manool (7), followed by a superacid-
induced cyclization11 that provides scalaranic ester (10)
(Scheme 1).
However, this sequence of transformations contains two dif-
ficult separation steps involving silver nitrate impregnated
silica gel column chromatography for the isolation of the
E-ketone 8 and E-ester 9. Taking into consideration the
fact that the formation of the scalaranic framework is not
influenced by the configuration of the D13-double bond,12
we decided to simplify the methodology starting from the
commercially available labdanic compound, sclareol (11)
(Scheme 2).
Although different synthetic pathways toward this class of
compounds have been elaborated,10 previous work on the
Keywords: Terpenoids; Cyclization; Halogenation; Scalaranes.
The C3 homologation of 11 was achieved according to the
methodology described previously.13 Treatment of 11 with
ethylacetoacetate provided the mixture of ketones 12. The
Horner olefination of ketones 12 gave the mixture of esters
* Corresponding author. Fax: +39 373 22 739954; e-mail: kulcitki@yahoo.
com
On leave from Institute of Chemistry, Moldova Academy of Sciences, str.
y
ꢀ
Academiei 3, MD-2028 Chixsinau, Republic of Moldova.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.048

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V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
AcO
HO
O
19
O
AcO
CHO 20
AcO
HO
25
14
18
CHO
O
11
23
C24
17
D
1
9
OAc
8
A
10B
3
5
6
21
22
3
1
2
HO
HO
O
O
AcO
CH2OH
AcO
O
O
OH
5
4
6
Figure 1. Representative members of scalarane family.
CO2Me
CO2Me
OH
O
7
8
9
10
Scheme 1. Synthesis of methyl 18aH-scalar-16-en-19-oate (10) from manool (7).11
OH
O
CO2Me
13
13
(MeO)2PCH2CO2Me
92%
Ref. 13
80%
1. FSO3H
OH
11
2. NaOH/EtOH
12
13
CO2Me
CO2Me
CO2H
CO2H
+
+
+
16
14
15
10 (45%)
LiAlH4
Ref. 15
19
83%
OH
CO2Me
12
20
18
1
16
9
14
OH
3
5
17
18
Scheme 2. Synthesis of methyl 18aH-scalar-16-en-19-oate (10) and methyl 18aH-scalar-16a-ol-17(20)-en-19-oate (18) from sclareol (11).
13. Superacid cyclization of this mixture, followed by alk-
aline hydrolysis, provided the desired scalarane esters 10 and
14, which were formed along with cheilanthane and rear-
ranged cheilanthane acids 15 and 16. Flash chromatography
of this mixture on Si gel provided scalaranic ester 10 in an
overall yield of 33% after four steps. To the best of our
knowledge, this is the highest overall yield of a scalarane
compound starting from a commercial product.10
remote functionalization strategy, which has been broadly
used in the field of isoprenoids.14 The characteristic feature
of these reactions is the generation of a free radical in the
molecule of the substrate, that has to contain a suitable func-
tional group playing the role of a ‘relay’ for the free radical
formation, followed by the functionalization of nearby dis-
posed C–H bond by this radical. The position of functional-
ization is governed mostly by steric factors. The ester group
of 10 can be reduced to the alcohol functionality as a radical
relay handle but, for the B-cycle functionalization of scalar-
anic skeleton, the hydroxyl group in the corresponding
The subsequent transformation of the ester 10 into a B-ring
oxidized scalarane was planned to be performed by the

V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
7619
alcohol 17 is disposed too far and cannot interact specifically
with the corresponding C–H bonds due to the steric hin-
drance of the angular methyl groups.
preventing the abstraction of H-9. So, by these consider-
ations, the RRH reaction on both substrates 19 and 20 should
only result in the abstraction of the hydrogen atom at C-5.
Optimized conformations A and B of 19 and 20 showed
the C(30)–I–C(5) angle values of 93.3ꢁ and 99.8ꢁ, respec-
tively, that is close to the linear C(5)–H–Cl–I arrangement,
provided the C–I–Cl angle equals 90ꢁ in the transition
state.17 For all conformations a slight deviation of the
abstraction protons from the C–I axis was observed (see
Fig. 2 legends).
Therefore, we decided to start from another substrate, the al-
cohol 18, obtained in two steps from ester 10,15 and to apply
a well known remote functionalization procedure, the radi-
cal relay halogenation (RRH), which was introduced by Bre-
slow and co-workers16 and used in the field of steroids. This
procedure is based on the interaction of the hydroxyl in the
substratum with an aromatic acid, containing the iodine
atom in the ring, followed by a photolytic halogenation of
the resulting ester under the action of a chlorinating agent.
As the result, the iodo-aromatic fragment forms a radical
that abstracts the hydrogen atom from a tertiary carbon suit-
ably disposed in the spatial surrounding of the molecule to
provide a chloro-derivative. The abstraction position is de-
pendent upon geometrical factors. The hydroxyl group at
C-16 in compound 18 was recognized as an excellent link
for a RRH reaction. In fact, it possesses the a-configuration,
which exactly matches the configuration of the tertiary
hydrogen atoms H-5 and H-9 in the cycle B. The abstraction
of H-5 should lead to a functionalization in the ring B,
whereas the abstraction of H-9 should result in obtaining
a functional group at ring C. Besides, after introduction of the
additional functionality by RRH, the hydroxyl and the ester
groups in cycle D could be manipulated easily to provide
the dialdehyde fragment of scalaradial 115 or other naturally
occurring scalaranes.
These theoretical observations were proven by RRH exper-
iments performed with both compounds 19 and 20, which
only gave product 21. The synthetic sequence leading to
B-cycle functionalized scalarane 23 is shown in Scheme 3.
Esterification of the secondary hydroxyl group in compound
18 proceeded smoothly with acyl chlorides of both 3-iodo-
benzoic acid and 3-iodophenylacetic acid. The acyl chlo-
rides were obtained from the corresponding acids on
treatment with an excess of thionylchloride at reflux.18 The
esterification proceeded in benzene at reflux in the presence
of pyridine. Catalytic DMF added to the reaction mixture
accelerated the reaction rate. In the case of the less reactive
3-iodobenzoylchloride a threefold excess of chloranhydride
assured almost a quantitative yield of the ester 19.
RRH reactions were performed using different chlorine
radical donors and solvent mixtures. In the case of 3-
iodobenzyl ester 19 better yields were obtained using
iodophenyldichloride19 in a mixture of dichloromethane/
tert-butanol, 2:1, under irradiation with two incandescent
lamps (100 W+200 W) for 2 h at room temperature. The
subsequent dehydrohalogenation–hydrolysis with KOH in
a dioxan/methanol mixture provided ester 21. 3-Iodophenyl-
acetic ester 20 was transformed into the same product 21
under the action of sulfuryl chloride and dibenzoylperoxide
in carbon tetrachloride at reflux for 5 h, followed by the
same dehydrohalogenation–hydrolysis procedure.
According to the conclusions made by Breslow,16,17 the sub-
stitution of a tertiary hydrogen for a chlorine atom depends
mainly on geometrical factors. First of all, in order to
achieve the transition state, there should be a match between
the distance from the hydroxyl oxygen of the substrate to the
tertiary hydrogen to be abstracted and the distance from the
same hydroxyl oxygen to the chlorine linked to the aromatic
fragment.
Molecular modeling simulations showed that, from this
point of view, both 3-iodobenzoic and 3-phenylacetic acids
meet these requirements for the abstraction of the hydrogen
at either the C-9 or C-5 position of the scalaranic skeleton.
The calculated distances in compound 18 from the oxygen
atom at C-16 to the hydrogen atom at both C-5 and C-9
The structure of compound 21 was determined by high res-
olution mass spectrometry and a detailed 2D-NMR analysis.
First of all, the molecular formula C26H40O3, deduced by the
sodiated ion peak at m/z 423 (M+Na) in the HRESIMS spec-
trum, exhibited the expected additional unsaturation degree
1
˚
are 5.93 and 4.89 A, respectively. Consequently, 3-iodoben-
with respect to the starting product 18. Analysis of H and
zoic acid (the distance O–Cl in the transition state16 is 4.3 A)
13C NMR spectra of 21 in comparison with those of
1815,20 showed that the difference was in the presence of a tri-
substituted double bond [dC 148.1 (s) and 116.4 (d); dH 5.39
(m)] in the scalarane skeleton of 21. The 1H–1H COSY spec-
trum indicated that the olefinic proton at d 5.39 (H-6) was
correlated to a methylene (H2-7) resonating at d 1.77 (m)
and 1.99 (dd, J¼17.5) linked to a quaternary carbon, accord-
ing to the position of the double bond either at C-5/C-6 or at
C-9/C-11. The expected location in the ring B was supported
by the down-field shifted 13C values of both b-methyl groups
C-21 (d 29.4 in 21, d 21.3 in 18) and C-23 (d 20.3 in 21,
d 16.2 in 18) of the scalarane framework, due to the different
steric arrangement of ring B and absence of the g-gauche
effect of C-6. All proton and carbon resonances, assigned
by 2D-NMR (1H–1H COSY, HMQC, and HMBC) experi-
ments as reported in Section 4, were in agreement with the
proposed structure 21.
˚
is a template matching better selection criteria for C-9
abstraction, while 3-iodophenylacetic acid (the distance
O–Cl in the transition state16 is 6.8 A) is more prone to
˚
abstract the hydrogen from C-5 position of the scalarane
substrate. The optimized conformations for the aromatic
ester derivatives 19 and 20 are shown in Figure 2.
The minimal total repulsion energy for all conformations
does not differ significantly, so the probability factor to
achieve C-5 or C-9 abstraction of hydrogen atoms is almost
equal. But according to Breslow,17 another requirement for
the RRH process is the possibility of obtaining a linear tran-
sition state C–H–Cl–I with a total iodine–carbon separation
˚
ꢀ5.37 A. Analysis of molecular modeling calculation data
showed that for both esters 19 and 20, it is not possible to
adopt a linear arrangement of the C(9)–H–Cl–I atoms, thus

7620
V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
A
B
9
16
9
5
16
5
3'
I
3'
I
Ester 19. C-5 abstraction of proton.
Total steric energy E=70Kcal/mol; C(5)-I=4.6Å;
C(5)-I-C(3')=93.3°;H-C(5)-I=10.3°
Ester 20. C-5 abstraction of proton.
Total steric energy E=62Kcal/mol; C(5)-I=4.3Å;
C(5)-I-C(3')=99.8°; H-C(5)-I=9.4°
C
D
9
9
16
5
16
5
3'
I
3'
I
Ester 19. C-9 abstraction of proton.
Total steric energy E=71Kcal/mol; C(9)-I=4.9Å;
C(9)-I-C(3')=65.9°; H-C(9)-I=13.6°
Ester 20. C-9 abstraction of proton.
Total steric energy E=60Kcal/mol; C(9)-I=4.4Å;
C(9)-I-C(3')=72.4°; H-C(9)-I=13.0°
Figure 2. Optimized conformations of esters 19 and 20.
CO2Me
CO2Me
O
CO2Me
O
O
O
9
16
KOH
R
R-COCl
RRH
OH
R
5
R=3-iodophenyl or
3-iodobenzyl
Cl
18
19 R=3-iodophenyl, 99%
20 R=3-iodobenzyl, 99%
CO2Me
CO2Me
CO2Me
Ac2O/Py
OH
t-BuOOH, Cul
55%
OAc
OAc
quant.
O
21 (52% from 19)
(16% from 20)
22
23
Scheme 3. Ring B functionalization of methyl 18aH-scalar-16a-ol-17(20)-en-19-oate (18) by radical relay halogenation.

V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
7621
Once its structure was proved, ester 21 was subsequently
used to functionalize the ring B of the scalaranic framework.
Accordingly, acetylation of 21 under standard conditions
(Ac2O–Py) provided the acetate 22 in quantitative yield.
The subsequent allylic oxidation of 22 was achieved in an
acceptable 55% yield using tert-butylhydroperoxide–copper
iodide procedure21 to provide the a,b-unsaturated ketone
23—a versatile substrate for further transformations.
5 g (16.23 mmol) of sclareol (11) according to the described
methodology,13 was dissolved in 230 mL of dry benzene,
trimethylphosphonoacetate (6.33 mL, 39.13 mmol) was
added, followed by a solution of NaOMe obtained from
0.9 g (39.13 mmol) of sodium dissolved in 23 mL of meth-
anol. The reaction mixture was refluxed under nitrogen for
2 h. Usual work-up provided, after Si gel flash chromato-
graphy, 4.628 g (11.99 mmol) of the mixture of esters 13,
1
which were identified by TLC and H NMR comparison
with an authentic sample of pure E-isomer 9.
3. Conclusions
4.2.2. Superacidic cyclization of the mixture of esters 13.
The mixture of esters 13 (3.978 g, 10.31 mmol) was dis-
solved in dichloromethane (35 mL) and kept at ꢂ78 ꢁC.
To this cooled solution, a solution of 2.96 mL (51.53 mmol)
of fluorosulfonic acid in 10 mL of 2-nitropropane, chilled
at the same temperature, was added dropwise. The reaction
mixture was stirred at ꢂ78 ꢁC for 25 min, then quenched
with a solution of triethylamine (16 mL, 155 mmol) in
hexane (16 mL). Usual work-up gave the crude reaction
product, which was hydrolysed by refluxing for 2 h with a
solution of 2.07 g NaOH (51.81 mmol) in 20 mL ethanol.
Usual work-up gave the crude product, which was submitted
to flash chromatography on Si gel. Elution with 3% EtOAc in
petroleum ether gave 1.8 g (4.66 mmol) of pure ester 10,
which was identified by TLC comparison with an authentic
sample.
The ring B functionalization of a sesterterpene scalarane has
been achieved by using a short and straightforward remote
functionalization procedure. The radical relay halogenation
method has been used here for the first time on terpenes. The
starting oxidized scalarane 18 has been obtained from ester
10, which has been prepared by an improved procedure in
four synthetic steps from commercially available sclareol
11. The yield of 10 after four steps reached 33% and this
is the most efficient scalarane synthesis with respect to the
literature.10 Finally, functionalized scalaranes 21–23 could
be further transformed to be used for structure–activity rela-
tionship studies. These subjects are now under consideration
in our laboratories.
4. Experimental
4.1. General procedures
4.2.3. Synthesis of alcohol 18. Alcohol 18 was obtained ac-
cording to the described methodology15 involving epoxida-
tion of ester 10, followed by Al(Oi-Pr)3-mediated epoxide
opening.
Melting points were measured on a Kofler apparatus. The IR
spectra were taken on a Bio-Rad FTS 7 spectrophotometer.
NMR experiments were recorded at ICB-NMR Service.
1D- and 2D-NMR spectra were acquired in CDCl3 (d values
are reported and referred to CHCl3 at 7.26 ppm) on a Bruker
Avance-400 operating at 400 MHz, using an inverse probe
fitted with a gradient along the Z-axis. 13C NMR were re-
corded on a Bruker DPX-300 operating at 75.5 MHz (d
values are reported to CDCl3, 77.0 ppm) using a dual probe.
Optical rotations were measured in CHCl3 on a Jasco DIP
370 polarimeter, using a 10-cm cell. Low and high resolution
ESIMS were performed on a Micromass Q-TOF MicroÔ
coupled with a HPLC Waters Alliance 2695. The instrument
was calibrated by using a PEG mixture from 200 to
1000 MW (resolution specification 5000 FWHM, deviation
<5 ppm rms in the presence of a known lock mass. Commer-
cial Merck Si gel 60 (70–230 mesh ASTM) was used for col-
umn chromatography and Merck precoated Si gel plates
were used for TLC. The chromatograms were sprayed
with 0.1% Ce(SO4)2 in 2 N H2SO4 and heated at 80 ꢁC for
5 min to detect the spots. The work-up of the reaction mix-
tures in organic solvents included exhaustive extraction
with diethyl ether and washing with water up to neutral
reaction, drying over anhydrous Na2SO4, filtration, and
removal of the solvent in vacuo. For molecular modeling
simulations the Chem3D soft was used (CS Chem3D ProÒ
Ó1999 CambridgeSoft Corporation).
4.3. Ring B functionalization of the scalaranic skeleton
4.3.1. Synthesis of 3-iodophenyl ester 19. 3-Iodobenzoic
acid (167 mg, 0.672 mmol) was treated with 1.5 mL
SOCl2 under reflux for 1 h. Cooling to room temperature
was followed by addition of three drops of DMF and reflux-
ing continued for further 30 min. Evaporation of the excess
SOCl2 under reduced pressure provided the crude acyl chlo-
ride, to which 90 mg of alcohol 18 (0.224 mmol) was added,
dissolved in 3 mL of benzene and 0.5 mL of pyridine. After
4 h of reflux, TLC showed no starting material. Usual work-
up provided the crude reaction product, which was submit-
ted to Si gel flash chromatography. Elution with 2% EtOAc
in petroleum ether provided 140 mg (0.222 mmol, 99%) of
ester 19. Colorless viscous liquid; [a]2D5 ꢂ32.4 (c 0.36,
1
CHCl3); IR nmax (liquid film) 1732, 1716 cmꢂ1. H NMR
(400 MHz) dH: 8.37 (1H, s, H-20); 7.99 (1H, d, J¼7.8 Hz,
H-60); 7.91 (1H, d, J¼7.9 Hz, H-40); 7.23 (1H, dd, J¼7.8
and 7.9 Hz, H-50); 5.66 (1H, m, H-16); 5.29 (1H, br s, H-
20a); 5.09 (1H, br s, H-20b); 3.65 (3H, s, –OMe); 3.21
(1H, s, H-18); 1.99 (1H, m, H-15a); 1.77 (1H, m, H-15b);
1.70 (2H, m, H-1a and H-7a); 1.65 (1H, m, H-2a); 1.60
(2H, m, H-6a and H-12a); 1.53 (1H, m, H-14); 1.50 (2H,
m, H2-11); 1.45 (1H, m, H-12b); 1.40 (2H, m, H-2b and
H-6b); 1.35 (1H, m, H-3a); 1.12 (1H, ddd, J¼13.3, 13.4,
and 4.0 Hz, H-3b); 1.07 (3H, s, H3-25); 0.90 (1H, br d,
J¼10.6 Hz, H-9); 0.86 (3H, s, H3-24); 0.82 (6H, s, H3-21
and H3-23); 0.81 (2H, m, H-5 and H-1b); 0.79 (3H, s, H3-
22). 13C NMR (75.5 MHz) dC: 171.4 (C-19); 163.6 (CO–
phenyl); 141.7 (C-40); 139.8 (C-17); 138.6 (C-20); 132.7
4.2. Synthesis of the scalaranic ester 18 from sclareol
(11)
4.2.1. Horner olefination of the mixture of ketones 12. The
mixture of ketones 12 (4.3 g, 13.03 mmol), obtained from

7622
V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
(C-10); 130.1 (C-50); 128.7 (C-60); 115.1 (C-20); 93.8 (C-30);
76.2 (C-16); 61.2 (C-9); 58.8 (C-18); 56.5 (C-5); 53.7 (C-
14); 51.0 (–OMe); 42.1 (C-3); 41.8 (C-7); 40.3 (C-12);
39.8 (C-1); 39.6 (C-13); 37.7 (C-8); 37.6 (C-10); 33.3 (2C,
C-4 and C-21); 27.4 (C-15); 21.3 (C-22); 18.6 (C-2); 18.1
(C-6); 17.5 (C-11); 17.1 (C-24); 16.3 (C-23); 14.2 (C-25).
HRESIMS: m/z (M+Na)+ 655.2276 (655.2260 calcd for
C33H45O4INa).
(1H, m, H-3a); 1.45 (1H, m, H-2b); 1.22 (1H, m, H-3b);
1.18 (1H, m, H-9); 1.11 (3H, s, H3-22); 1.09 (3H, s, H3-
23); 1.05 (3H, s, H3-21); 1.04 (3H, s, H3-25); 0.92 (1H, m,
H-1b); 0.85 (3H, s, H3-24). 13C NMR (75.5 MHz) dC:
171.7 (C-19); 148.1 (C-5); 145.1 (C-17); 116.4 (C-6);
111.5 (C-20); 72.9 (C-16); 57.4 (C-18); 56.1 (C-9); 50.9
(2C, –OMe and C-14); 42.6 (C-7); 41.8 (C-3); 41.1 (C-1);
39.6 (2C, C-12 and C-13); 37.8 (C-10); 36.3 (C-8); 34.8
(C-4); 33.2 (C-21); 29.4 (2C, C-15 and C-22); 20.3 (C-23);
18.9 (C-11); 18.6 (C-2); 17.9 (C-24); 13.4 (C-25). HRE-
SIMS: m/z (M+Na)+ 423.2867 (423.2875 calcd for
C26H40O3Na).
4.3.2. Synthesis of 3-iodobenzyl ester 20. 3-Iodophenyl-
acetic acid (149 mg, 0.567 mmol) was treated with SOCl2
(2 mL) under reflux for 1 h. Cooling to the room temperature
was followed by addition of three drops of DMF and reflux-
ing continued for 30 min. Evaporation of the excess SOCl2
under reduced pressure provided the crude acyl chloride,
to which 114 mg of alcohol 18 (0.284 mmol) was added, dis-
solved in 4 mL of benzene and 0.4 mL of pyridine. After 4 h
of reflux, TLC showed no starting material. Usual work-up
provided the crude reaction product, submitted to flash chro-
matography on Si gel. Elution with 3% EtOAc in petroleum
ether provided 181 mg (0.28 mmol, 99%) of ester 20. Color-
less viscous liquid; [a]2D5 ꢂ22.6 (c 0.12, CHCl3); IR nmax
(liquid film) 1747, 1732 cmꢂ1. 1H NMR (300 MHz) selected
values dH: 7.73 (1H, s, H-20); 7.63 (1H, d, J¼7.9 Hz, H-60);
7.28 (1H, d, J¼8.7 Hz, H-40); 7.06 (1H, dd, J¼7.9 and
8.7 Hz, H-50); 5.39 (1H, m, H-16); 5.17 (1H, br s, H-20a);
5.00 (1H, br s, H-20b); 3.67 (3H, s, –OMe); 3.60 (1H, d,
J¼14.2 Hz, H2a-benzyl); 3.51 (1H, d, J¼14.2 Hz, H2b-benz-
yl); 3.02 (1H, s, H-18); 0.98 (3H, s, H3-25); 0.89 (3H, s,
H3-24); 0.79 (3H, s, H3-23); 0.78 (3H, s, H3-21); 0.75 (3H,
s, H3-22). 13C NMR (75.5 MHz) dC: 171.4 (C-19); 169.5
(CO–benzyl); 140.0 (C-17); 138.5 (C-40); 136.7 (C-10);
136.2 (C-20); 130.3 (C-50); 128.7 (C-60); 114.3 (C-20);
94.4 (C-30); 75.8 (C-16); 60.8 (C-9); 58.5 (C-18); 56.0 (C-
5); 52.9 (C-14); 51.1 (–OMe); 42.2 (C-3); 41.8 (C-7); 41.4
(CH2–benzyl); 40.2 (C-12); 39.8 (C-1); 39.5 (C-13); 37.5
(C-8); 37.3 (C-10); 33.4 (2C, C-4 and C-21); 27.0 (C-15);
21.3 (C-22); 18.7 (C-2); 18.0 (C-6); 17.4 (C-11); 17.1 (C-
24); 16.3 (C-23); 14.1 (C-25). HRESIMS: m/z (M+Na)+
669.2405 (669.2417 calcd for C34H47O4INa).
4.3.4. Radical relay halogenation of ester 20. A solution of
83 mg (0.129 mmol) of ester 20 and 3.1 mg (0.013 mmol)
dibenzoylperoxide in 12 mL CCl4 was treated with
12.4 mL (0.154 mmol) SO2Cl2 and the reaction mixture re-
fluxed for 5 h. Following distillation of the solvent under re-
duced pressure provided a crude residue, which was treated
with a mixture of dioxane (1.5 mL) and 10% KOH in meth-
anol (1.5 mL) at 80 ꢁC for 1 h. Usual work-up provided the
crude product, which was submitted to flash chromato-
graphy on Si gel. Elution with 10% EtOAc in petroleum
ether provided 8 mg (0.02 mmol, 16%) of ester 21.
4.3.5. Acetylation of 21. Compound 21 (7 mg) was dis-
solved in pyridine (1 mL) and treated with acetic anhydride
(0.3 mL). After 12 h at room temperature, usual work-up
provided pure acetate 22. Colorless viscous liquid; [a]D25
ꢂ49.5 (c 0.10, CHCl3); IR nmax (liquid film) 1739 cmꢂ1
.
1H NMR (400 MHz) dH: 5.44 (1H, m, H-16); 5.39 (1H, m,
H-6); 5.20 (1H, br s, H-20a); 5.01 (1H, d, J¼0.5 Hz, H-
20b); 3.66 (3H, s, –OMe); 3.14 (1H, s, H-18); 2.05 (3H, s,
–OAc); 1.97 (1H, dd, J¼17.3 and 5.5 Hz, H-7a); 1.82 (1H,
m, H-1a); 1.80 (2H, m, H-2a and H-15a); 1.70 (1H, m, H-
15b); 1.65 (1H, m, H-7b); 1.62 (1H, m, H-12a); 1.54 (2H,
m, H2-11); 1.48 (1H, m, H-3a); 1.47 (1H, m, H-2b); 1.46
(1H, m, H-14); 1.37 (1H, m, H-12b); 1.22 (1H, m, H-3b);
1.17 (1H, m, H-9); 1.12 (3H, s, H3-22); 1.09 (3H, s, H3-
23); 1.06 (3H, s, H3-21); 1.05 (3H, s, H3-25); 0.92 (1H, m,
H-1b); 0.85 (3H, s, H3-24). 13C NMR (75.5 MHz) dC:
171.2 (C-19); 170.1 (–OAc); 149.0 (C-5); 140.2 (C-17);
116.2 (C-6); 114.4 (C-20); 74.9 (C-16); 58.4 (C-18); 56.1
(C-9); 52.0 (C-14); 51.0 (–OMe); 42.6 (C-7); 41.8 (C-3);
41.2 (C-1); 39.7 (C-12); 39.4 (C-13); 37.8 (C-10); 36.3 (C-
8); 34.8 (C-4); 33.1 (C-21); 29.3 (C-22); 27.5 (C-15); 21.5
(–OAc); 20.3 (C-23); 18.9 (C-11); 18.6 (C-2); 17.8 (C-24);
13.6 (C-25). HRESIMS: m/z (M+Na)+ 465.2958 (465.2981
calcd for C28H42O4Na).
4.3.3. Radical relay halogenation of ester 19. K2CO3
(17 mg, 0.12 mmol) was added to a deoxygenated solution
of ester 19 (15 mg, 0.024 mmol) in 2.5 mL of a mixture di-
chloromethane/tert-butanol (2:1). The resulting suspension
was treated on stirring with 9.75 mg (0.036 mmol) of iodo-
phenyldichloride.19 The reaction mixture was irradiated at
room temperature for 2 h with two filament lamps
(200 W+100 W) on stirring. Following distillation of the
solvent under reduced pressure provided a crude residue,
which was treated with a mixture of dioxane (1.5 mL) and
10% KOH in methanol (1.5 mL) at 80 ꢁC for 1 h. Usual
work-up provided the crude product, which was submitted
to flash chromatography on Si gel. Elution with 10% EtOAc
in petroleum ether provided 5 mg (0.013 mmol, 52%) of es-
ter 21. Colorless viscous liquid; [a]2D5 ꢂ50.7 (c 0.15, CHCl3);
4.3.6. Allylic oxidation of acetate 22. Compound 22 (5 mg,
0.011 mmol) was dissolved in 0.5 mL acetonitrile and
treated on stirring with a catalytic amount of CuI and
20 mL of a solution of tert-butylhydroperoxide in nonane.
After stirring for 20 h at +50 ꢁC under nitrogen, the reaction
mixture was diluted with a satd solution of Na2SO3 (5 mL)
and worked-up as usual. The crude product was submitted
to flash chromatography affording 3 mg (0.007 mmol,
58%) of keto-diester 23. Colorless viscous liquid; [a]D25
ꢂ64.9 (c 0.16, CHCl3); IR nmax (liquid film) 1738,
1
IR nmax (liquid film) 1725 cmꢂ1. H NMR (400 MHz) dH:
5.39 (1H, m, H-6); 5.06 (1H, br s, H-20a); 4.86 (1H, br s,
H-20b); 4.40 (1H, m, H-16); 3.66 (3H, s, –OMe); 3.32
(1H, s, H-18); 1.99 (1H, dd, J¼17.2 and 5.5 Hz, H-7a);
1.84 (1H, m, H-1a); 1.80 (1H, m, H-2a); 1.77 (1H, m, H-
7b); 1.70 (2H, m, H2-15); 1.63 (1H, m, H-12a); 1.60 (1H,
m, H-14); 1.52 (2H, m, H2-11); 1.48 (1H, m, H-12b); 1.47
1
1668 cmꢂ1. H NMR (400 MHz) dH: 5.76 (1H, s, H-6);
5.47 (1H, m, H-16); 5.21 (1H, br s, H-20a); 4.95 (1H,
d, J¼0.7 Hz, H-20b); 3.66 (3H, s, –OMe); 3.25 (1H, s,

V. Kulci¸tki et al. / Tetrahedron 63 (2007) 7617–7623
7623
4. Rogers, S. D.; Paul, V. J. Mar. Ecol. Prog. Ser. 1991, 77,
221.
5. Fattorusso, E.; Magno, S.; Santacroce, C.; Sica, D. Tetrahedron
1972, 28, 5993.
6. Kazlauskas, R.; Murphy, P. T.; Quinn, R. J.; Wells, R. J.
Tetrahedron Lett. 1976, 2631.
7. Miyamoto, T.; Sakamoto, K.; Amano, H.; Arakawa, Y.;
Nagarekawa, Y.; Komori, T.; Higuchi, R.; Sasaki, T.
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8. Cimino, G.; Fontana, A.; Gimenez, F.; Martin, A.; Mollo, E.;
Trivellone, E.; Zubia, E. Experientia 1993, 49, 582.
9. Kamaya, R.; Masuda, K.; Suzuki, K.; Ageta, H.; Hsu, H.-Y.
Chem. Pharm. Bull. 1996, 44, 690.
10. Ungur, N.; Kulci¸tki, V. Phytochem. Rev. 2004, 3, 401.
11. Vlad, P. F.; Ungur, N. D.; Nguen, V. T. Izv. Akad. Nauk. Ser.
Khim. 1995, 2507; [Russ. Chem. Bull. (Engl. Transl.) 1995,
44, 2404].
H-18); 2.84 (1H, m, H-15a); 2.10 (3H, s, –OAc); 2.05 (1H, dd,
J¼12.5 and 2.2 Hz, H-14); 1.96 (1H, m, H-1a); 1.87 (1H, m,
H-2a); 1.67 (1H, m, H-15b); 1.62 (2H, m, H-3a and H-12a);
1.61 (1H, m, H-9); 1.60 (3H, m, H2-11 and H-2b); 1.35 (2H,
m, H-3b and H-12b); 1.27 (3H, s, H3-23); 1.20 (3H, s, H3-
22); 1.14 (3H, s, H3-21); 1.13 (3H, s, H3-24); 1.10 (3H, s,
H3-25); 1.03 (1H, ddd, J¼13.0, 12.7, and 3.8 Hz, H-1b).
13C NMR (75.5 MHz) dC: 205.7 (C-7); 171.2 (2C, C-5 and
C-19); 169.9 (–OAc); 140.4 (C-17); 121.4 (C-6); 114.5 (C-
20); 74.7 (C-16); 58.8 (C-18); 56.4 (C-9); 51.0 (–OMe);
46.7 (C-8); 44.1 (C-14); 41.0 (C-1); 40.7 (C-3); 39.8 (C-
10); 39.4 (C-13); 38.9 (C-12); 37.2 (C-4); 32.3 (C-21);
30.1 (C-15); 28.6 (C-22); 21.5 (–OAc); 20.4 (C-23); 18.6
(C-2); 18.3 (C-11); 16.2 (C-24); 15.1 (C-25). HRESIMS:
m/z (M+Na)+ 479.2756 (479.2773 calcd for C28H40O5Na).
12. Ungur, N.; Kulci¸tki, V.; Gavagnin, M.; Castellucio, F.; Vlad,
P. F.; Cimino, G. Tetrahedron 2002, 58, 10159.
13. Vlad, P. F.; Lazurievski, G. V. Izv. Acad. Nauk MSSR 1962,
10, 67.
14. Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095.
15. Ungur, N.; Gavagnin, M.; Cimino, G. Nat. Prod. Lett. 1996,
8, 275.
16. Breslow, R. Acc. Chem. Res. 1980, 13, 170.
17. White, P.; Breslow, R. J. Am. Chem. Soc. 1990, 112, 6842.
18. Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John
Wiley and Sons: New York, NY, 1967; Vol. 1, p 287.
19. Organic Syntheses, Collective Volume 3; Horning, E. C. Ed.;
John Wiley and Sons: New York, NY, London and Sydney,
1955; p 482.
20. 13C NMR values of the pairs C-9/C-18 and C-24/C-25 of
ester 18 reported in Ref. 15 should be inverted and reassigned
as: C-9 (d 61.3), C-18 (d 57.5), C-24 (d 17.3), and C-25
(d 14.0).
Acknowledgements
Thanks are due to Mr. C. Iodice for spectrophotometric
measurements and to Mr. R. Turco for drawings. NMR
spectra were recorded at the ‘ICB-NMR Service’ the staff
of which is acknowledged. V.K. thanks ‘NATO-CNR Out-
reach Fellowship’ Program for a senior fellowship. N.U.
is grateful to ‘Short-term mobility’ CNR Program for
financial support.
References and notes
1. Cimino, G.; De Stefano, S.; Minale, L. Experientia 1974, 30,
846.
2. Blunt, J. W.; Copp, B. R.; Hu, W. P.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2007, 24, 31
and earlier articles in this series.
ꢁ
21. Salvador, J. A. R.; Sa e Melo, M. L.; Campos Neves, A. S.
Tetrahedron Lett. 1997, 38, 119.
3. Sipkema, D.; Franssen, M. C. R.; Osinga, R.; Tramper, J.;
Wijffels, R. H. Mar. Biotechnol. 2005, 7, 142.