A Convenient Synthesis of A-Ring-Functionalized Podolactones. Revision of the Structure of Wentilactone B

Article abstract of DOI:10.1021/ol0257070

(Matrix Presented) A new route to podolactones functionalized in the A ring has been achieved. Two key steps were employed in this synthesis, the construction of the bicyclic skeleton via a Mn(III)-mediated radical cyclization and the transformation of this bicyclic intermediate into the tetracyclic podolactone skeleton through a Pd (II)-mediated bislactonization of the corresponding conjugate diene. The reported synthesis of 3β-hydroxy-13,14,15,-16-tetranorlabda-7,9(11)-dien-(19,6β),(12,17)- diolide (1) let us reassign the structure of wentilactone B, for which structure 1 was wrongly reported.

Full text of DOI:10.1021/ol0257070

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1379-1382
A Convenient Synthesis of
A-Ring-Functionalized Podolactones.
Revision of the Structure of
Wentilactone B
Alejandro F. Barrero,* Mar´ıa M. Herrador, Jose´ F. Qu´ılez del Moral, and
Mo´nica V. Valdivia
Department of Organic Chemistry, Institute of Biotechnology, UniVersity of Granada,
AVda. FuentenueVa, 18071 Granada, Spain
afbarre@goliat.ugr.es
Received February 12, 2002
ABSTRACT
A new route to podolactones functionalized in the A ring has been achieved. Two key steps were employed in this synthesis, the construction
of the bicyclic skeleton via a Mn(III)-mediated radical cyclization and the transformation of this bicyclic intermediate into the tetracyclic podolactone
skeleton through a Pd (II)-mediated bislactonization of the corresponding conjugate diene. The reported synthesis of 3â-hydroxy-13,14,15,-
16-tetranorlabda-7,9(11)-dien-(19,6â),(12,17)-diolide (1) let us reassign the structure of wentilactone B, for which structure 1 was wrongly reported.
Podolactones are nor- or bisnorditerpenic compounds isolated
from different plants of the genus Podocarpus1 and from
filamentous fungi.2 These molecules present a wide range
of biological activities, with antitumor, insecticidal, anti-
feedant, allelopathic, and fungicide activities deserving
special attention.3 With respect to this antifungal activity, it
is worth mentioning that some of these compounds have
shown promising results against Candida albicans and the
dimorphic fungus Histoplasma capsulatum, which causes one
of the most severe mycoses.3e Recently, the production of
terpenoid lactones from Oidiodendrum griseum,4 and its use
as an antiinflammatory in the treatment of IL-1 (interleukin-
1) and TNF (tumor necrosis factor)-mediated diseases has
been described. Since we have previously reported the
synthesis of podolactones with no functionalization in the
A ring,5 we aimed to complete the access to most of these
natural dilactones by seeking a methodology to prepare 3â-
hydroxy derivatives, compounds whose preparation has only
been reported once.6 Here we describe the synthesis of 3â-
(1) In Dictionary of Terpenoids; Connolly, J. D., Hill, R. A. Eds.;
Chapman & Hall: London, U.K., 1991; Vol. 2, pp 853-857.
(2) (a) Andersen, N. R.; Rasmunsen, P. R. Tetrahedron Lett. 1984. (b)
Dorner, J. W.; Cole, R. J.; Springer, J. P.; Cox, R. H.; Cutler, H.; Wicklow,
D. T. Phytochemistry 1980, 19, 1157. (c) Ellestad, G. A.; Evans, R. H.;
Kunstmann, M. P.; Lancaster, J. E.; Morton, G. O. J. Am. Chem. Soc. 1970,
92, 5483.
(3) (a) Hembree, J. A.; Chang, C.; McLaughlin, J. L.; Cassady, J. M.;
Watts, D. J.; Wenkert, E.; Fonseca, S. F.; De Paiva Campello, J.
Phytochemistry 1979, 18, 1691. (b) Singh, P.; Russell, G. B.; Hayashi, Y.;
Gallagher, R. T.; Fredericksen, S. Entomol. Exp. Appl. 1979, 25, 121. (c)
Zhang, M.; Ying, B. P.; Kubo, I. J. Nat. Prod. 1992, 55, 1057. (d) Mac´ıas,
F. A.; Simonet, A. M.; Pacheco, P. C.; Barrero, A. F.; Cabrera, E.; Jime´nez-
Gonza´lez, D. J. Agric. Food Chem. 2000, 48, 3003. (e) Hosoe, T.; Nozawa,
K.; Lumley, T. C.; Currah, R. S.; Fukushima, K.; Takizawa, K.; Miyaji,
M.; Kawai, K. Chem. Pharm. Bull. 1999, 47, 1591.
(4) Ichikawa, K.; Ikunaka, M.; Kojima, N.; Nishida, H.; Yoshikawa, N.
European Patent 0 933 273 A1, 1999.
(5) Barrero, A. F.; Qu´ılez del Moral, J. F.; Cuerva, J. M.; Cabrera, E.;
Jime´nez-Gonza´lez, D. Tetrahedron Lett. 2000, 41, 5203.
(6) To our knowledge, only one A-ring-functionalized podolactone,
(()3â-hydroxynagilactone F, has been previously synthesized. This syn-
thesis was reported by de Groot et al. in less than 0.1% yield: Reuvers, J.
T. A.; de Groot, A. J. Org. Chem. 1986, 51, 4594.
10.1021/ol0257070 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/23/2002

hydroxy-13,14,15,16-tetranorlabda-7,9(11)-dien-(19,6â),(12,-
17)-diolide (1), a structure that was wrongly attributed to
wentilactone B.2b
mixture could only be separated as the diol derivatives 7
and 8). Allylic oxidation of 4 with SeO2 gave a mixture of
5 and 6, which was converted by treatment with LAH to
diols 7 and 8 in a 4:1 ratio favorable to the E,E isomer.
Regioselective chlorination of 7 yielded the corresponding
chloride 9.8 Alkylation of the dianion of ethyl 2-methyl-
acetoacetate with 9 afforded 79% of acyclic precursor 10.
Oxidative free-radical cyclization of 10 using a 2:1 molar
The retrosynthetic planning for 1 is shown in Figure 1.
This scheme includes as key steps the radical cyclization of
9
ratio of Mn(OAc)3 and Cu(OAc)2 in deaerated AcOH
provided 68% of bicyclic 11.10
Following the same process as described for 7, compound
8 was converted into the corresponding E,Z acyclic precursor.
As expected,11 no bicyclic compound was obtained upon
treatment of this precursor with Mn(III).
The remaining steps for the synthesis of 1 are shown in
Scheme 2. Oxidation of 11 with PDC in DMF followed by
Scheme 2a
Figure 1. Retrosynthetic analysis of 3â-hydroxy-13,14,15,16-
tetranorlabda-7,9(11)-dien-(19,6â),(12,17)-diolide (1).
the acyclic precursor and the 1,4-regioselective oxidation of
the appropriate conjugated diene in the presence of Pd(II)
complexes.7
The preparation of the bicyclic intermediate 11 is sum-
marized in Scheme 1. Bromination of commercially available
geraniol (2) with PBr3 afforded bromide 3, which upon
treatment with KCN and subsequent hydrolysis and esteri-
fication furnished 4 as a mixture of geometrical isomers (this
Scheme 1a
a Regents and conditions: (a) (i) PDC, DMF, 24 h; (ii) CH2N2,
ether, 75% in two steps; (b) (i) NaBH4, MeOH, 0 °C, 15 min, 91%;
(ii) ClOAc, DMAP, 20 h, 95%; (c) (i) O3, CH2Cl2, -78 °C, 20
min; (ii) PPh3, -78 °C f rt, 2 h, 91%; (d) (i) PhSeCl, EtOAc, 60
h, (ii) H2O2, Py, CH2Cl2, 0 °C f rt, 15 min, 77%; (e) Tebbe’s
reagent, THF, 0 °C, 17 min, 69%; (f) NaSCH2CH2CH3, DMF, 50
°C, 26 h, 95%; (g) Pd(OAc)2, p-benzoquinone, HOAc, acetone, 18
h, 78% of 19 based on the amount of 17 in the mixture of 17 and
18; (h) (i) LDA, -78 °C, THF, 20 min; (ii) TMSCl 20 min; (iii)
PhSeCl, -60 °C, THF, 45 min; (iv) H2O2, Py, CH2Cl2, 30 s, 40
°C, 36%.
CH2N2 treatment yielded methyl ester 12, which was
converted to acetate 13 after standard transformations.
a Regents and conditions: (a) (i) PBr3, t-BuOMe, 0 °C, 25 min;
(ii) KCN, DMSO, 2 h, 80%; (b) (i) KOH 25%, MeOH, 90 °C, 9 h;
(ii) CH2N2, ether, 0 °C, 5 min, 68% of 3 and 4 (ratio 4:1) in two
steps; (c) SeO2, t-BuOOH, CH2Cl2, 5 °C, 6 h, 65%; (d) LAH, THF,
0 °C f rt, 12 h, 86% of 7 and 8 (ratio 4:1); (e) (i) NCS, DMS,
CH2Cl2, 0 °C, 2.5 h, 85%; (f) CH3COCHCH3COOEt, NaH, n-BuLi,
THF, 2.5 h, 79%; (g) Mn(OAc)3‚2H2O, Cu(OAc)2‚H2O, HOAc,
68%
(7) (a) Ba¨ckvall, J. E.; Bystro¨m, S. E.; Nordberg, R. E. J. Org. Chem.
1984, 49, 4619. (b) Ba¨ckvall, J. E. In Metal-Catalyzed Cross-Coupling
Reactions; Stang, P.. Diederich, F., Eds.; Wiley-VCH: Weinham, 1998;
pp 339-385.
(8) Corey, E. J.; Kim, C. U.; Takeda, M. Tetrahedron Lett. 1972, 13,
5203.
(9) Oxidative radical cyclization of polyenes with Mn(III) and Cu(II)
has been widely used in the synthesis of policyclic compounds. For recent
examples see: (a) Yang, D.; Xu, M. Org. Lett. 2001, 3, 1785 and references
therein. For a review, see: (b) Snider, B. B. Chem. ReV. 1996, 96, 339.
1380
Org. Lett., Vol. 4, No. 8, 2002

Ozonolysis of 13 furnished ketone 14 in high yield, which
upon treatment with PhSeCl in EtOAc and oxidation with
H2O2 provided conjugated ketone 15. In a noteworthy
transformation, 15 was chemoselectively methylenated by
exposure to Tebbe reagent12 to afford 16. Subsequent
saponification with sodium propanethiolate afforded the
mixture of the desired dicarboxylic compound 17 and
monoester 18 (1:1.4 ratio). Regioselective bislactonization
of 17 took place when the mixture was subjected to the
presence of substoichiometric Pd(II) (25%) and p-benzo-
quinone in a mixture of acetic acid and acetone as solvent
(Figure 2).13 Ester 18 could be recovered and recycled.
Professor Dorner allowed us to record high-resolution NMR
spectra for this compound, whose analysis both confirmed
the wrong assignation of the natural product structure and
let us relocate the hydroxyl group in the 2R-position. This
reassignment is confirmed by comparison of the newly
recorded NMR data of wentilactone B with those of 2R-
hydroxynagilactone F (20) (Table 1).14
Table 1. 1H NMR of 1, Wentilactone B, and
2R-Hydroxynagilactone F (20)a
H
1
wentilactone Bb
20
1R
1â
2
3R
3â
5
6
7
11
2.15-1.65 m
2.15-1.65 m
2.15-1.65 m
3.79 m
1.82 dd (4.9, 13.5) 1.95
2.09 t (13.5)
4.11 m
2.24t (13.0)
4.11 m
1.54 dd (7.0, 13.5) 1.59 dd (7.0, 14.0)
2.41 dd (9.0, 13.5) 2.45 dd (9.0, 14.0)
2.18 d (4.1)
5.22 bt (4.0)
6.36 m
2.15 d (5.2)
1.95 d (5.0)
5.18 td (1.6, 4.9)
6.35 dd (1.6, 5.0)
5.74 d (1.7)
5.08 bt (1.5, 5.0)
6.20 dd (1.5, 5.0)
5.83 d (1.6)
5.72 d (1.8)
17R 4.97 d (13.8)
4.95 d (13.5)
17â 5.08 dt (1.9, 13.8) 5.04 dt (1.9, 13.5) 4.87 d (1.8)
18
20
1.53 s
0.92 s
1.38 s
1.22 s
1.42 s
1.28 s
a Coupling constant in hertzs are given in brackets. b Newly recorded
data.
Figure 2. Proposed mechanism for the bislactonization of 14.
With the ultimate aim of achieving enantioselective
syntheses of the target compounds, we also studied the
diastereoselectivity of the cyclization step using (-)-8-
phenylmentol as a chiral auxiliary.15 Preparation of the chiral
acyclic precursor is depicted in Scheme 3.
Introduction of the C9-C11 unsaturation proceeded, via
the corresponding silyl ketene acetal, after syn elimination
of the 11R-phenilselenoxide intermediate by treatment with
hydrogen peroxide. It is worth mentioning that under the
reaction conditions the free hydroxyl group at C-3 remained
unaltered, surely as a result of the formation of hydrogen
bonding between the hydroxyl hydrogen atom and the
carbonyl oxygen atom of the ester group at C4.
Scheme 3a
Surprisingly, the NMR data of our synthetic 1 do not
match with those reported for natural podolactone wentilac-
tone B, to which the same chemical structure was assigned2b.
The kind donation of a sample of wentilactone B by
(10) The cyclization of 10 to give 11 in 58% yield has been previously
reported by Zoretic et al. in their synthesis of d,l-norlabdane oxide: Zoretic,
P. A.; Haiquan, F.; Ribeiro, A. A. J. Org. Chem. 1998, 63, 4779.
(11) Radical cyclization has been described to proceed with total
stereoselectivity. Furthermore, in works published by us and others, double
bonds with Z configuration have been reported not to react with free
radicals: (a) Barrero, A. F.; Cuerva, J. M.; Herrador, M. M.; Valdivia, M.
V. J. Org. Chem. 2001, 66, 4074. (b) Julia, M. Acc. Chem. Res. 1971, 4,
386.
(12) In Handbook of Reagents for Organic Synthesis. Reagents, Auxil-
iaries, and Catalysts for C-C Bond Formation; Coates, R. M., Denmark,
S. E., Eds.; John Wiley & Sons Ltd: Chichester, 1999; pp 180-184.
(13) (a) Although few examples of intramolecular nucleophilic attack
of a carboxylate to conjugate dienes leading to a monolactone have been
described (Jonasson, C.; Ro¨nn, M.; Ba¨ckvall, J. E. J. Org. Chem. 2000, 67,
2122), this bislactonization process has been successfully applied only once
before by our group in the synthesis of oidiolacone C: Barrero, A. F.;
Arseniyadis, S.; Qu´ılez del Moral, J. F.; Herrador, M. M.; Valdivia, M.;
Jime´nez, D. J. Org. Chem. 2002, in press. (b) Ba¨ckvall, J. E.; Granberg, K.
L.; Andersson, P. G.; Gatti, R.; Gogoll, A. J. Org. Chem. 1993, 58, 5445.
a Regents and conditions: (a) DMAP, toluene, reflux, 75%; (b)
NaH, n-BuLi, THF, 9, 2.5 h, 80%; (c) Mn(OAc)3‚2H2O, Cu(OAc)2‚
H2O, HOAc, 7.5 h, 45%.
Transesterification of ethyl 2-methylacetoacetate (21) with
(-)-8-phenylmentol (22) in the presence of DMAP afforded
(14) Kubo, I.; Himejina, M.; Ying, B. P. Phytochemistry 1991, 30, 1469.
Org. Lett., Vol. 4, No. 8, 2002
1381

°C in HOAc, the induced selectivity is low (25 and 26 were
obtained in 2:1 ratio). However, if the reaction is carried
out in MeOH at 0 °C the selectivity increases, and a 6.5:1
mixture of diastereomers is obtained.
The determination of the stereochemistry for the cycliza-
tion compounds has been realized on the grounds of the
spatial disposition of the two more favorable chairlike
transition states (Figure 3). The assignment of 25 as major
diastereomer has been made considering the steric interaction
in TS2 between the methyl substituent on the double bond
and the 6-CH2 group of the menthyl moiety.15a
In conclusion, with the synthesis of 3â-hydroxy-13,14,-
15,16-tetranorlabda-7,9(11)-dien-(19,6â),(12,17)-diolide (1)
we have described a new access to 3â-hydroxypodolactones,
which together with the recent syntheses reported by our
group widens the range of podolactone types available by
chemical synthesis. The asymmetric version of this synthesis
has also been investigated. This work has also allowed us
to reassign the structure of natural wentilactone B.
Figure 3. Proposed charlike transition states for free radical
cyclization of 24.
23. As described for the formation of the racemic acyclic
precursor, alkylation of the dianion of 23 with 9 afforded
79% of 24. When the radical cyclization is achieved at 25
Acknowledgment. This research was supported by the
Spanish Direccio´n General de Investigacio´n Cient´ıfica y
Te´cnica (DGESIC; Proyecto PB 98-1365).
(15) (-)-8-Phenylmenthol has been reported both to induce a good
diastereomer ratio and to proceed with high yield in Mn(III)-based
asymmetric radical cyclization of related â-keto esters; see: (a) Yang, D.;
Ye, X.-Y.; Xu, M. J. Org. Chem. 2000, 65, 2208. (b) Zhang, Q.-W.; Mohan,
R. M.; Cook, L.; Kazanis, S.; Peisach, D.; Foxman, B. M.; Snider, B. B..
J. Org. Chem. 1993, 58, 7640. (c) Zoretic, P. A.; Weng, X.; Biggers, M.
S.; Caspar, M. L.; Davis, D. G. Tetrahedron Lett. 1992, 33, 2637.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new compounds. This
material is available free of charge at http://pubs. acs.org.
OL0257070
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Org. Lett., Vol. 4, No. 8, 2002