Total synthesis of oidiodendrolides and related norditerpene dilactones from a common precursor: Metabolites CJ-14,445, LL-Z1271γ, oidiolactones A, B, C, and D, and nagilactone F

Article abstract of DOI:10.1021/ol901896c

An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a

Full text of DOI:10.1021/ol901896c

ORGANIC
LETTERS
2
009
Vol. 11, No. 20
640-4643
Total Synthesis of Oidiodendrolides and
Related Norditerpene Dilactones from a
Common Precursor: Metabolites
4
CJ-14,445, LL-Z1271γ, Oidiolactones A,
B, C, and D, and Nagilactone F
Stephen Hanessian,* Nicolas Boyer, Gone Jayapal Reddy, and
Beno ˆı t Desch eˆ nes-Simard
Department of Chemistry, UniVersit e´ de Montr e´ al, C.P. 6128, Succursale Centre-Ville,
Montr e´ al, Qu e´ bec, H3C 3J7, Canada
stephen.hanessian@umontreal.ca
Received August 18, 2009
ABSTRACT
An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their
diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a Morita-Baylis-Hillman
reaction, the stereocontrolled construction of a γ-lactone through bromolactonization, and an efficient catalytic Reformatsky-type reaction.
Access to CJ-14,445, LL-Z1271γ, oidiolactones A, B, C, and D, and nagilactone F was possible from a common intermediate. Structures and
stereochemistry were determined by X-ray analysis.
The family of norditerpenoid dilactones known as podola-
ctones consists of more than 70 members, exhibiting a wide
range of biological activities. The two natural sources of
podolactones are of plant or fungal origin, representing
different biosynthetic pathways, despite their seemingly
similar structures (Figure 1).
tone framework, exemplified by nagilactone F. The biological
activities of the podolactones in a host of physiologically
1
2d
and medicinally relevant areas, particularly as antifungal,
4
5
antitumoral, and antifeedant agents, have attracted attention
toward their synthesis and the study of their biogenetic
The filamentous fungi represented by Oidiodendron trun-
catum and Oidiodendron griseum produce, among others,
(2) (a) John, M.; Krohn, K.; Fl o¨ rke, U.; Aust, H.-J.; Draeger, S.; Schulz,
B. J. Nat. Prod. 1999, 62, 1218–1221. (b) For isolation of oidiolactone A,
see: Andersen, N. R.; Rasmussen, P. R.; Falshaw, C. P.; King, T. J.
Tetrahedron Lett. 1984, 25, 469–472. (c) For isolation of oidiolactone B,
see: Ellestad, G. A.; Evans, R. H., Jr.; Kunstmann, M. P. J. Am. Chem.
Soc. 1969, 91, 2134–2136. (d) For isolation of oidiolactones C and D, see:
Hosoe, T.; Nozawa, K.; Lumley, T. C.; Currah, R. S.; Fukushima, K.;
Takizawa, K.; Miyaji, M.; Kawai, K.-I. Chem. Pharm. Bull. 1999, 47, 1591–
2
the tetranorditerpene dilactones oidiolactones A-D. Pod-
3
olactones such as nagilactone F are produced from different
species of the Podocarpus plant. Unlike the oidiolactones,
podolactones originating from plants possess a carbon
branched appendage at C-14 of the bisnorditerpenoid dilac-
1
597.
(3) For isolation of nagilactone F, see: Hayashi, Y.; Yokoi, J.; Watanabe,
Y.; Sakan, T. Chem. Lett. 1972, 759–762.
(
1) (a) Barrero, A. F.; Qu ´ı lez Del Moral, J. F.; Herrador, M. M. Stud.
(4) Hembree, J. A.; Chang, C.-J.; McLaughlin, J. L.; Cassady, J. M.;
Watts, D. J.; Wenkert, E.; Fonseca, S. F.; De Paiva Campello, J.
Phytochemistry 1979, 18, 1691–1694.
Nat. Prod. Chem. 2003, 28, 453–516. (b) Banerjee, A. K.; Laya, M. S.;
Mora, H. R.; Cabrera, E. V. Curr. Org. Chem. 2008, 12, 1050–1070.
10.1021/ol901896c CCC: $40.75
Published on Web 09/24/2009
 2009 American Chemical Society

Scheme 1. Synthesis of the AB Ring System
1
1
as of nagilactone F. Imamura and co-workers utilized
abietic acid as a starting point for the synthesis of an
oidiolactone analogue. Abietic acid was also used by Hayashi
Figure 1
. Structures of naturally occurring norditerpene dilac-
tones and strategic transformations toward a common precursor
1
2
8
.
and co-workers for the semisynthesis of nagilactone F. In
spite of the importance of podolactones as biologically active
natural products, very few reports of their total synthesis
have been disclosed. An enantioselective synthesis of nagi-
lactone F and a synthesis of racemic (()-3ꢀ-hydroxy
6
interrelationships. A collection of natural and synthetic
podolactones have also been tested as allelochemicals for
their potential herbicidal activities. Recently, oidiolactone
7
13
14
nagilactone F were reported by Burke and de Groot,
respectively. Finally, a total synthesis of racemic oidiolactone
B was reported to inhibit production of human interleukin-
1
5
1
ꢀ at a concentration equal to IC50 49 nM. Antagonism of
B was reported by Welch in 1977.
such cytokines can have important effects in the treatment
of inflammatory diseases. Oidiolactone B also displays
We wish to disclose the first enantioselective total
syntheses of oidiolactones A-D and nagilactone F in an
expedient, convergent, and highly stereocontrolled manner.
A disconnective analysis illustrates key steps and the
versatility of our approach that leads to a common intermedi-
ate 8, from which the intended podolactones, as well as other
natural and synthetic analogues, can be easily accessed
8
considerable antifungal activity against opportunistic patho-
2
d
gens such as Candida albicans.
The first semisynthesis of oidiolactone B by Adinolfi and
9
co-workers was reported in 1972, soon after the elucidation
2
c
of its structure by Ellestad and co-workers. The starting
material was marrubiin, a diterpene lactone isolated from
Marrubium Vulgare, that already harbors the C-9 branched
decalin ring and the C-4-C-6 bridged γ-lactone. Barrero and
(Figure 1).
The construction of the AB ring system as a single
enantiomer was initiated from the readily available Wieland-
1
6
1
0
Miescher ketone 9 following literature reports by the
co-workers used trans-communic acid, obtained from the
cones of Juniperus communis, as a naturally occurring chiron
toward the semisynthesis of oidiolactone B and C, as well
1
7
18
Theodorakis and Danishefsky groups, which led to 10
and 11 in good overall yield (Scheme 1). Highly stereose-
lective conjugate reduction of 11 was mediated by Mg in
1
9
1
MeOH to give 12 (95:5 dr by H NMR) in an excellent
yield. Stereoselective methylation of the Li enolate at -78
(
5) Zhang, M.; Ying, B. P.; Kubo, I. J. Nat. Prod. 1992, 55, 1057–
1
062.
°
C afforded the R-methyl branched ester 13 as a single
(
6) (a) Hayashi, Y.; Takahashi, S.; Ona, H.; Sakan, T. Tetrahedron Lett.
1
968, 17, 2071–2076. (b) Kakisawa, H.; Sato, M.; Ruo, T.-i.; Hayashi, T.
J. Chem. Soc., Chem. Commun. 1973, 802–803. (c) Sato, M.; Kakisawa,
H. J. Chem. Soc., Perkin Trans. 1 1976, 2407–2413.
(11) Imamura, P. M.; dos Santos, C. Synth. Commun. 2005, 35, 2057–
2065.
(
7) Mac ´ı as, F. A.; Simonet, A. M.; Pacheco, P. C.; Barrero, A. F.;
(12) Hayashi, Y.; Matsumoto, T.; Nishizawa, M.; Togami, M.; Hyono,
Cabrera, E.; Jim e´ nez-Gonz a´ lez, D. J. Agric. Food Chem. 2000, 48, 3003–
007.
8) (a) Ichikawa, K.; Hirai, H.; Ishiguro, M.; Kambara, T.; Kato, Y.;
Kim, Y. J.; Kojima, Y.; Matsunaga, Y.; Nishida, H.; Shiomi, Y.; Yoshikawa,
N.; Huang, L. H.; Kojima, N. J. Antibiot. 2001, 54, 697–702. (b) Ichikawa,
K.; Ikunaka, M.; Kojima, N.; Nishida, H.; Yoshikawa, N. European Patent
T.; Nishikawa, N.; Uemura, M.; Sakan, T. J. Org. Chem. 1982, 47, 3428–
3433.
3
(
(13) Burke, S. D.; Kort, M. E.; Strickland, S. M. S.; Organ, H. M.; Silks,
L. A., III Tetrahedron Lett. 1994, 35, 1503–1506.
(14) Reuvers, J. T. A.; de Groot, A. J. Org. Chem. 1986, 51, 4594–
4599.
0
933 273 A1, 1999. (c) Ichikawa, K.; Inagaki, T.; Kojima, Y.; Nakamura,
T.; Nishida, H.; Ueno, Y.; Kojima, N. J. Antibiot. 2001, 54, 977–979.
9) Adinolfi, M.; Mangoni, L.; Barone, G.; Laonigro, G. Gazz. Chim.
Ital. 1973, 103, 1271–1279.
10) (a) For the synthesis of oidiolactone C, see: Barrero, A. F.;
(15) Welch, S. C.; Hagan, C. P.; White, D. H.; Fleming, W. P.; Trotter,
J. W. J. Am. Chem. Soc. 1977, 99, 549–556.
(16) Buchschacher, P.; F u¨ rst, A.; Gutzwiller, J. Org. Synth. 1990, 7,
368–372.
(
(
(17) Ling, T.; Chowdhury, C.; Kramer, B. A.; Vong, B. G.; Palladino,
M. A.; Theodorakis, E. A. J. Org. Chem. 2001, 66, 8843–8853.
(18) Waters, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem.
Soc. 2005, 127, 13514–13515.
Arseniyadis, S.; Qu ´ı lez del Moral, J. F.; Herrador, M. M.; Valdivia, M.;
Jim e´ nez, D. J. Org. Chem. 2002, 67, 2501–2508. (b) For the syntheses of
oidiolactone B and nagilactone F, see: Barrero, A. F.; S a´ nchez, J. F.;
Elmarabet, J.; Jim e´ nez-Gonz a´ lez, D.; Mac ´ı as, F.; Simonet, A. M. Tetra-
hedron 1999, 55, 7289–7304.
(19) Youn, I. K.; Yon, G. H.; Pak, C. S. Tetrahedron Lett. 1986, 27,
2409–2410.
Org. Lett., Vol. 11, No. 20, 2009
4641

γ-lactone D ring relied on a seven-step sequence (36%
1
5
overall yield) starting from the racemic acid 14. In our
synthesis, we introduced the C-14 center prior to the
γ-lactonization sequence (4 steps, 48% overall yield).
Having the fully functionalized intermediate 18 in hand,
the next challenge was the introduction of the δ-lactone
moiety between C-8 and C-9 (ring C). Many attempts to
introduce an acetic acid side-chain at C-9 in 18 were fraught
with problems involving γ-lactone ring-opening, elimination,
Scheme 2. Access to the Common Key Intermediate 19
2
8
and poor recoveries of desired material. However, an
intermolecular catalytic Reformatsky-type reaction between
enone 18 and ethyl iodoacetate in the presence of
2 3 2 2
NiCl (PPh ) and Et Zn, according to the Adrian-Snapper
2
9
protocol, led to the desired tertiary alcohol 19 as a single
isomer in excellent yield (Scheme 2). To the best of our
knowledge, this represents a seldom explored catalytic
intermolecular Reformatsky reaction in natural product
synthesis.
2
0,21
isomer (>95:5 dr) in quantitative yield.
Previously
With the expedient total synthesis of this versatile lactone
published studies have shown that alkylation of the exocyclic
Li enolate proceeds from the more accessible R-face of the
AB bicyclic system. At this juncture, the ketal 13 was
subjected to acid-catalyzed hydrolysis, and the resulting
ketone was converted to the ∆ -enone via an efficient IBX-
The recalcitrant C-19 methyl
ester hydrolysis was achieved in the presence of concd
sulfuric acid in an excellent yield over three steps to give
enone 14.
With the fully functionalized AB ring of podolactone
derivatives in hand, we focused our attention on building
the D lactone ring across C-4 and C-6 (Scheme 2). To this
end, the hydroxymethyl branch at C-8 was introduced in an
1
9, the stage was set for the introduction of appropriate
2
2
functionality to access oidiolactones A-D, as well as
nagilactone F, as shown in Scheme 3. Major difficulties arose
3
0
7,8
in the seemingly simple dehydration of ꢀ-hydroxy ester 19.
31
23,24
Eventually, treatment with the Burgess reagent yielded
unsaturated ester 20 in 79% yield. We were pleased to
observe that O-silyl deprotection mediated by triethylamine
mediated dehydrogenation.
2
5
3
2
trihydrofluoride complex (Et
3
N·3HF) led to concomitant
in situ cyclization to give biogenetic dilactone CJ-14,445
3
3
(
1). The structure and absolute stereochemistry of 1 were
confirmed by X-ray analysis.
Intermediate 20 was subjected to epoxidation with dim-
ethyldioxirane (DMDO) in the presence of 4 Å MS to afford
epoxide 21 in excellent purity and yield. As expected,
stereoselective epoxidation took place from the sterically less
hindered face of the cyclohexene ring in 20. Deprotection
26
efficient Morita-Baylis-Hillman reaction, utilizing form-
aldehyde and dimethylphenylphosphine, to give 15 in excel-
lent yield. Treatment of 15 with Br
2
followed by addition of
CO in DMF in the presence of 18-crown-6 effected
K
2
3
of the silyl group in 21 with Et
lactonization provided oidiolactone C (5) in excellent yield.
3
N·3HF followed by in situ
smooth bromolactonization and elimination to give the
corresponding tricyclic γ-lactone core 17, which was isolated
as the TES ether 18. This sequence is based on a modification
of the bromolactonization reaction developed by Welch and
co-workers. In the event, bromination of the enone acid
5 proceeded to give the labile dibromoketo acid 16.
Treatment with K CO induced dehydrohalogenation via a
trans-diaxial elimination of the bromide substituent at C-7.
The transient spiroepoxide 16′ was converted in the presence
2′ cyclization to lactone
7. The Welch group approach for the construction of the
34
The assigned absolute configuration was also firmly estab-
lished by X-ray crystallography. Mild TES deprotection of
1
5
(
27) The nonprotected allylic alcohol was necessary in this reaction,
1
thus suggesting the formation of an allylic spiroepoxide as a key intermedi-
ate. An analogous vinylogous epoxide was reported by Barrero in the semi-
synthesis of oidiolactone C (ref 10a).
2
3
(
28) Among various attempts to introduce the acetic acid side chain,
we tried inter- and intramolecular Horner-Wadsworth-Emmons olefina-
tions, Reformatsky-type cyclizations, and Mukaiyama aldol additions.
(29) Adrian, J. C., Jr.; Snapper, M. L. J. Org. Chem. 2003, 68, 2143–
of base via a facile intramolecular S
1
N
2
7
2150. Honda and co-workers also suggested the use of Wilkinson’s catalyst
[
Rh(PPh Cl], in the presence of Et
3
)
3
2
Zn (Org. Lett. 2000, 2, 2549-2551).
(
(
20) Toyota, M.; Asano, T.; Ihara, M. Org. Lett. 2005, 7, 3929–3932
.
In our case, the best results were obtained with the combination of
21) We first sought to functionalize the AB ring system using the
R-bromoacetate and Wilkinson’s catalyst in THF or R-iodoacetate and
procedure described by Theodorakis and co-workers for the enantiomer (ref
7). However, in our hands, the yield never exceeded 30% (reported 58%)
with unidentified byproducts
22) (a) Welch, S. C.; Hagan, C. P.; Kim, J. H.; Chu, P. S. J. Org.
Chem. 1977, 42, 2879–2887. (b) Welch, S. C.; Hagan, C. P. Synth. Commun.
973, 3, 29–32.
23) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am.
Chem. Soc. 2002, 124, 2245–2258
24) Previous syntheses consisted of bromination-dehydrohalogenation
ref 15) or selenoxide elimination (ref 12)
25) Reuvers, J. T. A.; Wijnberg, J. B. P. A.; de Groot, Ae. Recl. TraV.
Chim. Pays-Bas 1985, 104, 16–18.
26) Ito, H.; Takenaka, Y.; Fukunishi, S.; Iguchi, K. Synthesis 2005,
035–3038.
2 3 2
NiCl (PPh ) in DCM.
1
(30) Attempted dehydration of tertiary alcohol 19 via the mesylate, the
triflate, or the methyl carbonate failed.
.
(
(31) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26–31.
1
(32) For a review, see: McClinton, M. A. Aldrichimica Acta 1995, 28,
31–35.
(
.
(33) Sato, M.; Ruo, T.-i.; Hayashi, T.; Kakisawa, H.; Miyaki, T.;
Yamamoto, H.; Fujisawa, K. Tetrahedron Lett. 1974, 25, 2134–2136.
(34) Alternatively, the conversion of 1 to oidiolactone C can be done
in the presence of DMDO according to Barrero (ref 10a). However,
conversion to product necessitated repeated exposure to the reagent. 5 was
eventually obtained as a single isomer in 72% yield. Other epoxidation
(
(
.
(
(
3
reagents (m-CPBA, CF
3 3
CO H) were not efficient.
4642
Org. Lett., Vol. 11, No. 20, 2009

Scheme 3. Syntheses of CJ-14,445, LL-Z1271γ, Oidiolactones A-D, and Nagilactone F
2
1 with CSA in MeCN-H
2
O (1:1) gave the corresponding
exposure to TsOH and MeOH, this was in turn converted to
primary alcohol, which was oxidized with the Dess-Martin
oidiolactone B (LL-Z1271R, PR 1387, 3), in excellent yield
and good stereoselectivity (93%, 77:23 dr). Finally, our
3
5
37
periodinane reagent (DMP) leading to the aldehyde 22.
Ensuing protic-promoted lactolization generated oidiolactone
D (6), also known as CJ-14,515, in high yield as a mixture
of epimers. The synthetic product exhibited spectral data
interest turned to the synthesis of bioactive nagilactone F
(4). Whereas Barrero reported its synthesis by treatment of
hydroxylactone 2 with isopropylmagnesium bromide in 83%
yield and high stereoselectivity (90:10 dr), in our hands, this
led to low yield and moderate selectivity. To circumvent this
problem, lactol 2 was treated with isopropenylmagnesium
bromide to yield dilactone 24 in good yield and excellent
diastereoselectivity. This was in turn submitted to homoge-
neous hydrogenation in the presence of Wilkinson’s catalyst
to give nagilactone F (4).
In conclusion, concise enantioselective total syntheses of
metabolites CJ-14,445 (1) and LL-Z1271γ (2), oidiolactones
A-D (7, 3, 5, 6), and nagilactone F (4) were achieved from
a common, readily available precursor 19. Furthermore, the
total syntheses of oidiolactones A (7) and D (6) were reported
for the first time.
2
d
identical to those reported for the natural material. Treat-
ment of the lactol 6 with catalytic TsOH in MeOH provided
oidiolactone A (PR 1388, 7) and its epimer 7′ (1:1.2 ratio)
3
6
in high yield. After separation, the spectroscopic and
1
13
chiroptical data ( H NMR, C NMR, IR, [R]
D
) were identical
2b
to the reported data for natural 7. Interestingly, the ꢀ-isomer
2
d
7
2 3
′ can be hydrolyzed with K CO in MeOH or with AcOH
8
a
in aqueous THF to oidiolactone D (6).
Having successfully synthesized four naturally occurring
podolactones starting from the common intermediate 19, we
turned our attention to the efficient preparation of three other
fungal podolactones, namely, LL-Z1271γ (2), oidiolactone
B (3), and nagilactone F (4). Toward this objective, the
versatile tricyclic ester 19 was hydrolyzed under acidic
conditions, thus setting the stage for a selective DMP-
mediated oxidation to afford aldehyde 23 in quantitative
yield. We believed that biogenic lactol 2 could be accessed
from ꢀ-hydroxy ester 23 via dehydration of the tertiary
alcohol. Indeed, treatment of 23 with the Burgess reagent
Acknowledgment. We thank NSERC, FQRNT, and
Syngenta (Basel, Switzerland) for financial assistance.
Supporting Information Available: Experimental pro-
cedures, spectral data, and CIF files for 1-7, 7′, and 24.
This material is available free of charge via the Internet at
http://pubs.acs.org.
2c,9
followed by acid-catalyzed lactolization gave metabolite 2,
which was in equilibrium with its C-14 epimer. An X-ray
structure of 2 confirmed the assignment of a ꢀ-anomer. Upon
OL901896C
(
35) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
287.
36) Epoxidation of oidiolactone B (3) in the presence of m-CPBA
3
HPO , CHCl , ∆) proved particularly difficult and required a prolonged
2 4
(37) The use of catalytic concentrated H SO in MeOH, as reported by
7
Barrero (ref 10b), led to a mixture of LL-Z1227R (3) (50%), its C-14 epimer
3′ (35%), and the dimethylacetal methyl ester (15%), whereas the treatment
with HCl/MeOH, as described by Adinolfi (ref 9), gave almost quantitatively
a 1:3 mixture of LL-Z1227R and its anomer.
(
(
Na
2
4
reaction time (15% yield).
Org. Lett., Vol. 11, No. 20, 2009
4643