Novel synthetic strategy toward abietane and podocarpane-type diterpenes from (-)-sclareol: synthesis of the antitumor (+)-7-deoxynimbidiol

Article abstract of DOI:10.1016/j.tetlet.2007.10.080

A new route to abietane and podocarpane-type terpenoids from labdane diterpenes is reported. The key step is the transformation of β-ketoester 9 into the corresponding O-acetylsalicylate ester 18, via a manganese(III)-based oxidative free-radical cyclization carried out in Ac₂O. Utilizing this, the synthesis of the antitumor (+)-7-deoxynimbidiol (5) from (-)-sclareol (11) has been achieved. (+)-Nimbidiol (6) and the natural terpenoid 20 have also been synthesized.

Full text of DOI:10.1016/j.tetlet.2007.10.080

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8930–8934
Novel synthetic strategy toward abietane and podocarpane-type
diterpenes from (ꢀ)-sclareol: synthesis of the antitumor
(+)-7-deoxynimbidiol
Enrique Alvarez-Manzaneda,a,* Rachid Chahboun,a Eduardo Cabrera,a Esteban Alvarez,a
b
c
c
´
Ramon Alvarez-Manzaneda, Mohammed Hmamouchi and Hakima Es-Samti
aDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Instituto de Biotecnologı´a, Universidad de Granada,
18071 Granada, Spain
bDepartamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Almerı´a, 04120 Almerı´a, Spain
cDepartement de Biologie, Unite´ des Substances Naturelles, Faculte´ de Medecine et Pharmacie,
Universite Mohammed V-Suissi, Rabat, Morocco
Received 12 July 2007; revised 25 September 2007; accepted 1 October 2007
Available online 22 October 2007
Abstract—A new route to abietane and podocarpane-type terpenoids from labdane diterpenes is reported. The key step is the trans-
formation of b-ketoester 9 into the corresponding O-acetylsalicylate ester 18, via a manganese(III)-based oxidative free-radical cycli-
zation carried out in Ac2O. Utilizing this, the synthesis of the antitumor (+)-7-deoxynimbidiol (5) from (ꢀ)-sclareol (11) has been
achieved. (+)-Nimbidiol (6) and the natural terpenoid 20 have also been synthesized.
Ó 2007 Elsevier Ltd. All rights reserved.
Abietane and biosynthetically related polycyclic diter-
penes constitute an important group of C ring aromatic
diterpenes.1 Abietane diterpenes show a wide range of
biological activities, for example, antibiotic,2 antivi-
ral,2a,3 antimalaria,4 antioxidant,5 cytotoxic,6 and antile-
ishmanial.7 Noteworthy among these, because of their
remarkable activities, are a number of variously oxi-
dized compounds. Representative examples of these
are taxodione (1),6a active against methicillin-resistant
Staphylococcus aureus (MRSA) and vancomycin-resis-
tant Enterococcus (VRE), the cytotoxic xanthanthusin
(2), recently isolated from Coleus xanthanthus,8 and
ferruginol (3), the gastroprotective9 and antibacterial10
activity of which has recently been reported. Podo-
carpane diterpenes are interesting metabolites from a
biosynthetic point of view, as they do not occur exten-
sively in nature. During recent years, some biologically
active podocarpane phenols have been isolated; amino-
phenol 4, a potent 5-lypoxygenase inhibitor is an
example.11 Very recently, a novel podocarpic diterpene
(+)-7-deoxynimbidiol (5), a possible probe molecule
because of its antitumor activity, has been isolated from
Calastrus hypoleucus.12 Different strategies have been
utilized to achieve the racemic synthesis of this type of
compound, including polyene cascade cyclizations
promoted by sulfenium ions,13 acid catalyzed cycli-
alkylations,14 and domino acylation–cycloalkylation
processes.15 Enantioselective syntheses of these com-
pounds have also been reported. In most cases, abietic
acid16 or podocarpic acid derivatives17 have been
utilized as starting materials. Two routes to podocar-
pane-type terpenoids from labdane diterpene have
recently been described;18,19 thus, a formal synthesis of
(+)-nimbidiol (6)20 from manool involving a Diels–
Alder cycloaddition has been achieved (see Fig. 1).18
Continuing our research into the synthesis of bioactive
compounds starting from natural diterpenes, we are
interested in developing a new route to abietane and
podocarpane-type terpenoids starting from (ꢀ)-sclareol
(11), a labdane diterpene that is very abundant in the
cultivable vegetal species Salvia sclarea. We focused
on (+)-7-deoxynimbidiol (5), whose racemic synthe-
sis through the acid catalyzed cyclialkylation of a
Keywords: Abietane diterpenoids; Podocarpane terpenoids; Oxida-
tions; Cyclizations.
*
Corresponding author. Tel./fax: +34 958 24 80 89; e-mail: eamr@
ugr.es
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.080

E. Alvarez-Manzaneda et al. / Tetrahedron Letters 48 (2007) 8930–8934
8931
OAc
OAc
O
OAc
R1
CHO
HO
O
R2
OH
(ii)
(i)
O
OH
R3
OAc
OAc
R4
R5
O
O
OH
11
13
12
1
2
3
4 R : OH; R : CH(CH ) ; R , R , R : H
1
2
3
2
3
4
5
5 R , R , R : H; R : OH; R : NH
(iii)
OR
1
4
5
2
3
2
6 RR1,, RR2:: OOHH;; RR3:, HR;,RR4, :RH5: =O
O
1
2
3
4
5
O
COOMe
Figure 1.
(v)
(vi)
homocyclogeranylcatechol has been recently reported12
and (+)-nimbidiol (6), whose synthesis has been more
extensively studied.13–15,18
14 R: Ac
15 R: H
9
10
(iv)
Scheme 2. Reagents and conditions: (i) 0.2% OsO4, NaIO4, t-BuOH,
45 °C, 3 h (90%); (ii) (a) MeMgBr, OEt2, 0 °C, 30 min (92%); (b)
CH3COCl, dimethylaniline, rt, 14 h, (92%); (iii) Collidine, reflux, 15 h
(94%); (iv) KOH, MeOH, rt, 1 h (98%); (v) Jones, acetone, 0 °C,
15 min (90%); (vi) Me2CO3, NaH, benzene, reflux, 4 h (87%).
Our planned synthetic strategy is shown in Scheme 1.
The key step is the transformation of b-ketoester 9,
obtained from 11, into the aromatic ester 8, through
an oxidative free-radical cyclization.21 The ester group
of compound 8 will allow the introduction of the isopro-
pyl group, providing the abietane skeleton of phenol 7.
The removal of the 15-hydroxy group in this intermedi-
ate, via cationic reduction or dehydration–hydrogena-
tion processes, will allow the obtention of different
abietane derivatives. Alternatively, the 15-hydroperox-
ide rearrangement will furnish the corresponding podo-
carpane derivatives, such as catechol 5.
undertaken. The manganese(III)-based oxidative free-
radical cyclization of unsaturated b-ketoesters, such as
compound 9, has been described as being suitable to
synthesize the corresponding alkyl salicylates, such as
intermediate 8 postulated in our retrosynthetic scheme
(Scheme 1); the use of Mn(OAc)3Æ2H2O and LiCl in ace-
tic acid has been described to minimize the overoxida-
tion of cyclization products, thereby improving the
yield of the resulting salicylates.21 First, we studied the
behavior of ketoester 9 under these oxidation conditions
at different temperatures and utilizing different propor-
tions of reagents: in all cases, a complex mixture of
compounds, including small quantities of the desired
methyl salicylate, was obtained.
Scheme 2 shows the synthesis of b-ketoester 9 from (ꢀ)-
sclareol (11). Treatment of acetoxyaldehyde 12, which is
obtained in high yield from 11 utilizing a modification of
our previously reported procedure,22 with MeMgBr
gave the corresponding acetoxyalcohol, which after
acetylation of the tertiary hydroxyl group led to diace-
tate 13. The exocyclic acetoxyalkene 14, together with
a small quantity of the trisubstituted regioisomer (ratio
10:1), was obtained when compound 13 was refluxed
with collidine, which was then hydrolyzed to alcohol
15. The oxidation of alcohol 15, obtained after hydro-
lysis of acetate 14, and the further treatment of the
resulting ketone 10 with Me2CO3 and NaH23 led to
ketoester 9.
In view of these results, the oxidation was essayed utiliz-
ing Ac2O as the reaction medium; this could protect the
phenolic hydroxyl group, preventing the overoxidation
side reactions. The most representative experiments are
shown in Table 1 (see Scheme 3).
Treatment of b-ketoester 9 with Mn(OAc)3Æ2H2O
(4 equiv) and LiCl (3 equiv) in Ac2O at room tempera-
ture for 12 h gave a complex mixture of compounds,
including salicylate 18 in low yield (entry 1). When the
reaction was carried out at 80–90 °C for 4 h, dichloro
derivative 16 (10%), the conjugated diene-ketoester 17
(12%) and the methyl O-acetyl salicylate 18 (52%) were
obtained (entry 2). Isolation of dichloro derivatives,
such as compound 16, has been described for the oxida-
tion with Mn(OAc)3Æ2H2O and LiCl in acetic acid;21
Next, the elaboration of the aromatic C ring of the
target compounds, starting from b-ketoester 9, was
OR
OH
OR
OH
COOMe
OH
7
8
5
O
O
Table 1. Treatment of b-ketoester 9 with Mn(OAc)3Æ2H2O (4 equiv)
and LiCl (3 equiv) in Ac2O
COOMe
OH
OH
Entry
Temperature
(°C)
Time
(h)
Products
(%)
1
2
3
rt
80–90
120
12
4
12
16 (51), 18 (9), 19 (8)
16 (10), 17 (12), 18 (8)
18 (75)
11
9
10
Scheme 1.

8932
E. Alvarez-Manzaneda et al. / Tetrahedron Letters 48 (2007) 8930–8934
O
OAc
O
OAc
OMe
OH
OH
OH
(iv)
COOMe
COOMe
(i)
COOMe
COOMe
(i)
Cl
+
Cl
16
18
9
18
20
22
(ii)
OH
+
MnIII
(v)
(ii)
O
O
O
COOMe
(iii)
COOMe
OMe
OH
OSiEt3
OMe
OH
(iii)
19
17
I
Scheme 3. Reagents and conditions: (i) Mn(OAc)3Æ2H2O (4 equiv),
LiCl (3 equiv), Ac2O (see Table 1); (ii) DBU, toluene, reflux, 12 h
(quant.); (iii) cat. H2SO4, AcOH, reflux, 3 h (87%).
21
3
23
(vii)
(vi)
OH
OH
OMe
OH
OH
OMe
as has also been reported, the conversion of this type of
dihalo compounds into the corresponding salicylates by
heating in acetic acid was not feasible, requiring the
presence of LiCl. We also observed that compound 16
remained unaltered after refluxing with p-toluenesul-
fonic acid in toluene; nevertheless, as could be expected,
this dichloro derivative was quantitatively transformed
into methyl salicylate 19 by refluxing with DBU in tolu-
ene. Isolation of diene-ketoesters, such as 17, is not very
common, which is attributed to the easy polymerization
of this type of compounds; this process would be more
difficult for the most hindered tricyclic compound 17.
Ketoester 17 was transformed in high yield into methyl
salicylate 19 after treatment with cat. H2SO4 in acetic
acid under reflux. When the treatment of ketoester 9
with Mn(OAc)3Æ2H2O (4 equiv) and LiCl (3 equiv) was
carried out in Ac2O at 120 °C for 12 h we obtained only
O-acetyl salicylate 18 in 75% yield (entry 3). It should be
emphasized that this transformation involves the use of
Ac2O as a solvent for the first time in this type of reac-
tion; the increased reaction yield utilizing this solvent
could be attributed to the obtention of an O-acetylphe-
nol which prevents the oxidation and polymerization
side reactions of phenolic compounds. This O-acetyl
derivative could be formed through the acetylation of
a manganese(III) enolate intermediate, like I,21 which
takes place at high temperature; the unsatisfactory
course of reaction at room temperature seems to sup-
port this supposition.
(viii)
O
6
24
5
Scheme 4. Reagents and conditions: (i) MeMgBr exc., Et2O, 0 °C,
15 min; dil HCl (89%); (ii) Et3SiH, CF3COOH, CH2Cl2, ꢀ40 °C,
30 min (91%); (iii) TBAF, THF, rt, 15 min (97%); (iv) MeI, K2CO3,
acetone, reflux, 12 h (93%); (v) 30% H2O2; BF3ÆOEt2, CH2Cl2, 0 °C–rt,
3 h (84%); (vi) BBr3, CH2Cl2, 0 °C, 1 h (93%); (vii) MeI, K2CO3,
acetone, reflux, 18 h (90%); (viii) Ref. 14c.
23 afforded the dimethyl derivative 24, whose trans-
formation into (+)-nimbidiol (6) has been reported
previously.14c
In summary, a new route to abietane and podocarpane-
type terpenoids from labdane diterpenes is reported. The
key step is the transformation of an unsaturated b-keto-
ester into the corresponding O-acetylsalicylate ester, via
a manganese(III)-based oxidative free-radical cycliza-
tion carried out in Ac2O. Utilizing this, the synthesis
of the antitumor (+)-7-deoxynimbidiol (5),25 starting
from (ꢀ)-sclareol (11), has been accomplished (28%
overall yield from 11). (+)-Nimbidiol (6) and the natural
15-hydroxyferruginol (20) have also been synthesized
(14% and 37% overall yields from 11, respectively).
The transformation of salicylate 18 into ferruginol (3),
7-deoxynimbidiol (5) and nimbidiol (6) is depicted in
Scheme 4. Treatment of compound 18 with an excess
of MeMgBr afforded 15-hydroxyferruginol (20), an
abietane diterpene isolated from Chamaecyparis pisif-
era.24 Treatment of this phenol with Et3SiH and
CF3COOH gave silyl ether 21, which after treatment
with TBAF in THF was converted into ferruginol (3).
Alternatively, methyl ether 22 was treated with H2O2
in the presence of BF3ÆOEt2 to give podocarpane 23, a
precursor of (+)-7-deoxynimbidiol (5). The spectro-
Acknowledgments
The authors thank Ministerio de Ciencia y Tecnologia
(Project CTQ2006-12697) and Junta de Andalucia
(PAI FQM-348) for financial support.
References and notes
1. (a) Nakano, T. In Studies in Natural Products Chemistry;
Atta-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 1989;
Vol. 4, (b) Hanson, J. R. Nat. Prod. Rep. 2004, 21, 312–
320; (c) Hanson, J. R. Nat. Prod. Rep. 2005, 22, 594–602.
scopic properties of compound 5 were identical to those
25
reported in the literature (½aꢁD +36.5, c 0.4, MeOH;
20
lit.:12 ½aꢁD +49.4, c 0.1, MeOH). Methylation of phenol

E. Alvarez-Manzaneda et al. / Tetrahedron Letters 48 (2007) 8930–8934
8933
2. (a) Batista, O.; Simoes, M. F.; Duarte, A.; Valdivia, M. L.;
De La Torre, M. C.; Rodriguez, B. Phytochemistry 1995,
38, 167–169; (b) Dellar, J. E.; Cole, M. D.; Waterman, P.
G. Phytochemistry 1996, 41, 735–738; (c) Ulubelen, A.;
Sonmez, U.; Topcu, G.; Bozok-Johansson, C. Phytochem-
istry 1996, 42, 145–147; (d) Ulubelen, A.; Topcu, G.; Eris,
C.; Sonmez, U.; Kartal, M.; Kurucu, S.; Bozok-Johans-
son, C. Phytochemistry 1994, 36, 971–974; (e) Moujir, L.;
24. Yatagai, M.; Takahashi, T. Phytochemistry 1980, 19,
1149–1151.
25. Spectroscopic properties of natural terpenoids were iden-
tical to those reported in the literature. The spectroscopic
data of compound 20 have been revised. All new
compounds were fully characterized spectroscopically
and had satisfactory high resolution mass spectroscopy
data. Selected data:
25
Gutierrez-Navarro, A. M.; San Andres, L.; Luis, J. G.
Compound 5: ½aꢁD +36.5 (c 0.4, MeOH) [lit.:12 +49.44 (c
´
1
Phytochemistry 1993, 34, 1493–1495.
0.1, MeOH)]. H NMR (500 MHz, CDCl3,) d: 0.91 (3H,
3. Tada, M.; Chiba, K.; Okuno, K.; Ohnishi, E.; Yoshii, T.
Phytochemistry 1994, 35, 539–541.
4. Achenbach, H.; Walbel, R.; Nkunya, M. H. H.; Weenen,
H. Phytochemistry 1992, 31, 3781–3784.
5. (a) Nakatani, N.; Inatani, R. Agric. Biol. Chem. 1984, 48,
2081–2085; (b) Marrero, J. G.; Andres, L. S.; Luis, J. G. J.
Nat. Prod. 2002, 65, 986–989.
6. (a) Kupchan, S. M.; Karim, A.; Marcks, C. J. Org. Chem.
1969, 34, 3912–3918; J. Am. Chem. Soc. 1968, 90, 5923–
5924; (b) Gao, J.; Han, G. Phytochemistry 1997, 44, 759–
761; (c) Jianjun, O.; Han, G. Phytochemistry 1997, 44,
759–761.
7. Tan, N.; Kaloga, M.; Radtke, O. A.; Kiderlen, A. F.;
Oksuz, S.; Ulubelen, A.; Kolodziej, H. Phytochemistry
2002, 61, 881–884.
8. Mei, S. X.; Jiang, B.; Niu, X. M.; Li, M. L.; Yang, H.;
Sun, H. D. J. Nat. Prod. 2002, 65, 633–637.
9. Rodriguez, J. A.; Theoduloz, C.; Yanez, T.; Becerra, J.;
Schmeda-Hirschmann, G. Life Sci. 2006, 78, 2503–2509.
10. Smith, E. C. J.; Williamson, E. M.; Warcham, N.; Kaatz,
G. W.; Gibbons, S. Phytochemistry 2007, 68, 210–217.
11. Oishi, T.; Otsuka, Y.; Limori, T.; Sawada, Y.; Ochi, S.
Patent JP 91-36296, 1992.
s), 0.94 (3H, s), 1.15 (3H, s), 1.28 (1H, dd, J = 12.4,
2.4 Hz), 1.35 (1H, ddd, J = 13.2, 13.2, 3.5 Hz), 1.47 (1H,
br d, J = 13.2 Hz), 1.52–1.78 (5H, m), 1.83 (1H, m), 2.15
(1H, br d, J = 12.6 Hz), 2.73 (1H, ddd, J = 16.8, 11.2,
7.3 Hz), 2.80 (1H, ddd, J = 16.8, 6.9, 1.5 Hz), 5.05 (1H, br
s), 6.52 (1H, s), 6.75 (1H, s). 13C NMR (125 MHz, CDCl3)
d: 19.3 (CH2), 19.5 (CH2), 21.8 (CH3), 25.1 (CH3), 30.0
(CH2), 33.5 (CH3), 33.6 (C), 37.6 (C), 39.3 (CH2), 41.9
(CH2), 50.7 (CH), 111.7 (CH), 115.4 (CH), 128.2 (C),
141.3 (C), 141.6 (C), 143.5 (C). HRMS (FAB) m/z calcd
for C17H24NaO2, 283.1674; found, 283.1681.
25
Compound 6: ½aꢁD +5.2 (c 1.0, CHCl3) [lit.:20 +3.4
(CHCl3)]. 1H NMR (500 MHz, CDCl3,) d: 0.92 (3H, s),
0.98 (3H, s), 1.20 (3H, s), 1.26 (1H, m), 1.46–1.56 (2H, m),
1.66 (1H, m), 1.75 (1H, m), 1.86 (1H, dd, J = 13.3,
4.0 Hz), 2.22 (1H, br d, J = 13.6 Hz), 2.60 (1H, dd,
J = 18.2, 13.6 Hz), 2.68 (1H, dd, J = 18.2, 4.1 Hz), 6.35
(1H, br s), 6.87 (1H, s), 7.50 (1H, br s), 7.70 (1H, s). 13C
NMR (125 MHz, CDCl3,) d: 19.1 (CH2), 21.5 (CH3), 23.4
(CH3), 32.7 (CH3), 33.4 (C), 36.2 (CH2), 38.1 (C), 38.2
(CH2), 41.6 (CH2), 50.0 (CH), 110.3 (CH), 113.7 (CH),
124.2 (C), 142.1 (C), 151.1(C), 152.6 (C), 200.1 (C).
HRMS (FAB) m/z calcd for C17H22NaO3, 297.1467;
found, 297.1458.
12. Xiong, Y.; Wang, K.; Pan, Y.; Sun, H.; Tu, J. Bioorg.
Med. Chem. Lett. 2006, 16, 786–789.
13. Harring, S. R.; Livinghouse, T. Tetrahedron Lett. 1989,
30, 1499–1502.
25
Compound 9: ½aꢁD ꢀ16.9 (c 0.8, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 0.69 (3H, s), 0.80 (3H, s), 0.88
(3H, s), 1.07 (1H, ddd, J = 12.7, 12.7, 4.1 Hz), 1.10–1.25
(3H, m), 1.31 (1H, dd, J = 12.7, 4.1 Hz), 1.40 (1H, br
d,J = 13.1 Hz), 1.43–1.62 (3H, m), 1.74 (1H, m), 2.09 (1H,
ddd, J = 12.9, 12.9, 5.1 Hz), 2.39 (1H, m), 2.60 (1H, dd,
J = 17.4, 3.7 Hz), 2.69 (1H, dd, J = 17.4, 10.0 Hz), 3.43
(1H, d, J = 15.3 Hz), 3.48 (1H, d, J = 15.4 Hz), 3.72 (3H,
s), 4.33 (1H, br s), 4.74 (1H, br s). 13C NMR (100 MHz,
CDCl3) d: 39.3 (C-1), 19.3 (C-2), 42.1 (C-3), 33.5 (C-4),
51.4 (C-5), 24.0 (C-6), 37.6 (C-7), 148.8 (C-8), 55.2 (C-9),
39.0 (C-10), 39.6 (C-11), 202.4 (C-12), 49.1 (C-13), 106.7
(C-14), 33.6 (C-15), 21.7 (C-16), 14.6 (C-17), 167.8
(COOMe), 52.5 (COOCH3). HRMS (FAB) m/z calcd for
C19H30NaO3, 329.2093; found, 329.2102.
14. (a) Banik, B. K.; Ghosh, S.; Ghatak, V. R. Tetrahedron
1988, 44, 6947–6955; (b) Majetich, G.; Siesel, D. Synlett
1995, 559–560; (c) Majetich, G.; Liu, S.; Fang, J.; Siesel,
D.; Zhang, Y. J. Org. Chem. 1997, 62, 6928–6951.
15. Bhar, S. S.; Ramana, M. M. V. J. Org. Chem. 2004, 69,
8935–8937.
16. For some representative examples, see: (a) Tahara, A.;
Akita, H. Chem. Pharm. Bull. 1975, 23, 1976–1983; (b)
Haslinger, E.; Michl, G. Tetrahedron Lett. 1988, 29, 5751–
5754; (c) Gigante, B.; Santos, C.; Silva, A. M.; Curto, M.
J. M.; Nascimento, M. S. J.; Pinto, E.; Pedro, M.;
Cerqueira, F.; Pinto, M. M.; Duarte, M.; Laires, A.;
Rueff, J.; GonC¸ alves, J.; Pegado, M. I.; Valdeira, M. L.
Bioorg. Med. Chem. Lett. 2003, 11, 1631–1638; (d)
Alvarez-Manzaneda, E. J.; Chahboun, R.; Bentaleb, F.;
Cabrera Torres, E.; Alvarez, E.; Haidour, A.; Ramos
1
Compound 16: H NMR (400 MHz, CDCl3) d: 0.75 (3H,
s), 0.79 (3H, s), 0.91 (3H, s), 1.04 (1H, ddd, J = 14.3, 14.3,
3.9 Hz), 1.29–1.70 (8H, m), 2.17 (1H, d, J = 14.5 Hz), 2.24
(1H, dt, J = 13.6, 2.7 Hz), 2.60 (1H, dd, J = 14.0, 2.7 Hz),
2.90 (1H, t, J = 14.0 Hz), 3.23 (1H, d, J = 14.5 Hz), 3.73
(3H, s). 13C NMR (100 MHz, CDCl3) d: 15.3 (CH3), 18.0
(CH2), 18.2 (CH2), 21.7 (CH3), 33.5 (C), 33.6 (CH3), 38.3
(CH2), 38.6 (C), 39.3 (CH2), 41.8 (CH2), 43.5 (CH2), 53.9
(CH3), 55.9 (CH), 56.5 (CH2), 58.2 (CH), 71.5 (C), 72.9
(C), 168.7 (C), 198.5 (C). HRMS (FAB) m/z calcd for
C19H28Cl2NaO3, 397.1313; found, 397.1310.
´
Lopez, J. M.; Alvarez-Manzaneda, R.; El Houssame, S.
Synlett 2004, 2701–2704.
17. Bendell, J. G.; Cambie, R. C.; Rutledge, P. S.; Woodgate,
P. D. Aust. J. Chem. 1993, 46, 1825–1843.
18. Zambrano, J. L.; Rosales, V.; Nakano, T. Tetrahedron
Lett. 2003, 44, 1859–1862.
19. Alvarez-Manzaneda, E. J.; Santiago Romera, J. L.;
Chahboun, R. J. Nat. Prod. 2006, 69, 563–566.
20. Majumder, P. L.; Maiti, D. C.; Kraus, W.; Bokel, M. K.
Phytochemistry 1987, 26, 3021–3023.
21. Snider, B. B.; Patricia, J. J. J. Org. Chem. 1989, 54, 38–46.
22. Barrero, A. F.; Alvarez-Manzaneda, E. J.; Altarejos, J.;
Salido, S.; Ramos, J. M.; Simmonds, M. S. J.; Blaney, B.
M. Tetrahedron 1995, 51, 7435–7450.
1
Compound 17: H NMR (400 MHz, CDCl3) d: 0.82 (3H,
s), 0.90 (3H, s), 0.93 (3H, s), 1.03 (1H, ddd, J = 12.7, 12.7,
4.0 Hz), 1.19 (1H, ddd, J = 13.1, 13.1, 3.9 Hz), 1.27 (1H,
dd, J = 12.3, 4.7 Hz), 1.32–1.60 (4H, m), 1.74 (1H, br d,
J = 14.5 Hz), 2.15 (1H, m), 2.39 (1H, m), 2.48 (2H,
m), 3.79 (3H, s), 6.49 (1H, br s), 7.66 (1H, s). 13C NMR
(100 MHz, CDCl3) d: 14.1 (CH3), 18.7 (CH2), 21.8
(CH3), 25.9 (CH2), 33.0 (C), 33.4 (CH3), 35.4 (C), 38.7
(CH2), 38.7 (CH2), 42.1 (CH2), 48.6 (CH), 52.3 (CH3),
23. Laube, T.; Schro¨der, J.; Stehle, R.; Seifert, K. Tetrahedron
2002, 58, 4299–4309.

8934
E. Alvarez-Manzaneda et al. / Tetrahedron Letters 48 (2007) 8930–8934
133.6 (C), 143.1 (CH), 153.6 (CH), 165.3 (C), 196.1 (C).
HRMS (FAB) m/z calcd for C19H26NaO3, 325.1780;
6.2 Hz), 6.73 (1H, s), 6.77 (1H, s), 8.50 (1H, br s). 13C
NMR (100 MHz, CDCl3) d: 38.9 (C-1), 19.4 (C-2), 41.9
(C-3), 33.7 (C-4), 50.5 (C-5), 19.5 (C-6), 30.0 (C-7), 128.5
(C-8), 151.4 (C-9), 37.9 (C-10), 113.3 (C-11), 153.6 (C-12),
126.2 (C-13), 125.8 (C-14), 76.0 (C-15), 30.4 (C-16), 30.5
(C-17), 33.5 (C-18), 24.8 (C-19), 21.8 (C-20). HRMS
(FAB) m/z calcd for C20H30NaO2, 325.2143; found,
325.2151.
found, 325.1772.
25
Compound 18: ½aꢁD +21.2 (c 0.9, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 0.92 (3H, s), 0.95 (3H, s), 1.17 (3H,
s), 1.21 (1H, ddd, J = 13.3, 13.3, 3.9 Hz), 1.30 (1H, dd,
J = 12.5, 2.1 Hz), 1.41 (1H, ddd, J = 13.2, 13.2, 3.8 Hz),
1.51 (1H, br d, J = 15.4 Hz), 1.62 (1H, m), 1.66–1.80
(2H, m), 1.90 (1H, m), 2.18 (1H, m), 2.32 (3H, s), 2.84 (1H,
ddd, J = 17.3, 11.1, 7.7 Hz), 2.96 (1H, dd, J = 17.3,
6.7 Hz), 3.83 (3H, s), 6.94 (1H, s), 7.68 (1H, s). 13C
NMR (100 MHz, CDCl3) d: 38.7 (C-1), 19.0 (C-2), 41.7
(C-3), 33.7 (C-4), 49.8 (C-5), 19.3 (C-6), 29.8 (C-7), 133.5
(C-8), 148.7 (C-9), 38.4 (C-10), 119.7 (C-11), 157.0 (C-12),
119.8 (C-13), 132.6 (C-14), 170.2 (C-15, COOMe), 33.4 (C-
16), 24.7 (C-17), 21.8 (C-20), 52.1 (COOCH3), 21.2
(OCOCH3), 165.3 (OCOCH3). HRMS (FAB) m/z calcd
for C21H28NaO4, 367.1885; found, 367.1877.
25
Compound 21: ½aꢁD +34.7 (c 1.0, CHCl3). 1H NMR
(500 MHz, CDCl3) d: 0.78 (6H, q, J = 8.0 Hz), 0.92 (3H,
s), 0.95 (3H, s), 1.01 (9H, t, J = 8.0 Hz), 1.17 (3H, d,
J = 6.9 Hz), 1.18 (3H, d, J = 6.9 Hz), 1.18 (3H, s), 1.23
(1H, ddd, J = 13.4, 13.4, 3.9 Hz), 1.34 (1H, dd, J = 12.4,
1.7 Hz), 1.38 (1H, ddd, J = 13.0, 13.0, 3.6 Hz), 1.48
(1H, br d, J = 13.1 Hz), 1.57–1.81 (3H, m), 1.86 (1H,
m), 2.14 (1H, br d, J = 12.6 Hz), 2.77 (1H, ddd, J = 16.2,
11.4, 7.2 Hz), 2.86 (1H, dd, J = 16.2, 6.3 Hz), 3.21
(1H, h, J = 6.9 Hz), 6.66 (1H, s), 6.83 (1H, s). 13C NMR
(125 MHz, CDCl3) d: 39.1 (C-1), 19.5 (C-2), 41.9
(C-3), 33.6 (C-4), 50.6 (C-5), 19.6 (C-6), 31.1 (C-7), 135.8
(C-8), 148.2 (C-9), 37.7 (C-10), 114.0 (C-11), 151.0 (C-12),
127.4 (C-13), 126.5 (C-14), 26.9 (C-15), 23.0 (C-16), 23.1
(C-17), 33.5 (C-18), 25.1 (C-19), 21.8 (C-20), 5.7
(SiCH2CH3), 7.0 (SiCH2CH3). HRMS (FAB) m/z calcd
for C26H44NaOSi, 423.3059; found, 423.3063.
25
Compound 19: ½aꢁD +27.5 (c 0.8, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 0.92 (3H, s), 0.95 (3H, s), 1.17 (3H,
s), 1.29 (1H, dd, J = 12.4, 2.2 Hz) 1.39 (1H, ddd, J = 12.9,
12.9, 3.6 Hz), 1.48 (1H, br d, J = 13.2 Hz), 1.57–1.79 (2H,
m), 1.87 (1H, m), 2.22 (1H, br d, J = 12.6 Hz), 2.76 (1H,
ddd, J = 16.6, 11.3, 7.8 Hz), 2.89 (1H, dd, J = 16.6,
6.5 Hz), 3.91 (3H, s), 6.87 (1H, s), 7.49 (1H, s). 13C
NMR (100 MHz, CDCl3) d: 38.6 (C-1), 19.0 (C-2), 41.5
(C-3), 33.6 (C-4), 49.8 (C-5), 19.2 (C-6), 29.2 (C-7), 126.4
(C-8), 159.1 (C-9), 38.5 (C-10), 112.8 (C-11), 159.3 (C-12),
109.9 (C-13), 128.9 (C-14), 170.4 (C-15, COOMe), 33.2 (C-
16), 24.3 (C-17), 21.7 (C-20), 52.0 (COOCH3). HRMS
(FAB) m/z calcd for C19H26NaO3, 325.1780; found,
325.1779.
25
Compound 23: ½aꢁD +49.8 (c 0.7, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 0.92 (3H, s), 0.95 (3H, s), 1.18 (3H,
s), 1.07 (1H, ddd, J = 13.5, 13.5, 4.1 Hz), 1.32 (1H, dd,
J = 12.4, 2.2 Hz), 1.39 (1H, ddd, J = 13.0, 13.0, 3.7 Hz),
1.48 (1H, br d, J = 13.2 Hz), 1.61 (1H, m), 1.67 (1H, m),
1.75 (1H, dt, J = 13.8, 3.4 Hz), 1.84 (1H, m), 2.21 (1H, br
d, J = 12.5 Hz), 2.75 (1H, ddd, J = 16.9, 11.3, 7.2 Hz),
2.82 (1H, ddd, J = 16.9, 7.0, 1.7 Hz), 3.85 (3H, s), 5.37
(1H, s), 6.58 (1H, s), 6.74 (1H, s). 13C NMR (100 MHz,
CDCl3) d: 39.4 (C-1), 19.3 (C-2), 41.9 (C-3), 33.6 (C-4),
50.8 (C-5), 19.6 (C-6), 30.1 (C-7), 128.4 (C-8), 142.1 (C-9),
37.8 (C-10), 107.2 (C-11), 143.4 (C-12), 144.9 (C-13), 114.4
(C-14), 33.5 (C-15), 25.1 (C-16), 21.8 (C-17), 56.3 (OCH3).
HRMS (FAB) m/z calcd for C18H26NaO2, 297.1830;
found, 297.1838.
25
25
Compound 20: ½aꢁD +26.5 (c 0.4, CHCl3); lit.:23 ½aꢁD ꢀ8.2
(c 0.73, MeOH). 1H NMR (400 MHz, CDCl3) d: 0.92 (3H,
s), 0.94 (3H, s), 1.17 (3H, s), 1.20 (1H, ddd, J = 13.4, 13.4,
3.7 Hz), 1.30 (1H, dd, J = 12.4, 2.2 Hz), 1.38 (1H, ddd,
J = 12.9, 12.9, 3.7 Hz), 1.47 (1H, br d, J = 12.2 Hz), 1.60
(1H, m), 1.63 (3H, s), 1.66 (3H, s), 1.54–1.77 (2H, m), 1.85
(1H, m), 2.20 (1H, br s), 2.22 (1H, br d, J = 12.7 Hz), 2.74
(1H, ddd, J = 16.5, 11.2, 7.5 Hz), 2.83 (1H, dd, J = 16.5,