Synthetic studies toward the bicyclic peroxylactone core of plakortolides

Article abstract of DOI:10.1055/s-0030-1260959

En route to the synthesis of plakortolide E and I, we prepared a -hydroperoxy vinyl epoxide, obtained from (R)-epichlorhydrin in 13 steps and 30% yield, via chemoselective methylenation with Nysted reagent in the presence of Ti(Oi-Pr)₂Cl₂ and regioselective Mukaiyama-Isayama hydroperoxysilylation. Unexpectedly, acid-catalyzed cyclization of this peroxy epoxide occurred exclusively through a 5-exo mode to furnish a 1,2-dioxolane; this is in contrast to the behavior of hydroxy analogues. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260959

1912
LETTER
Synthetic Studies toward the Bicyclic Peroxylactone Core of Plakortolides
S
tudies towar
d
th
o
e
B
icyclic
P
e
roxylactone
d
Core of
P
lak
a
ortolides n Barnych, Jean-Michel Vatèle*
Université Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR 5246 CNRS, Equipe SURCOOF,
bât. Raulin, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
E-mail: vatele@univ-lyon1.fr
Received 11 April 2011
reochemical control at the newly formed stereogenic
Abstract: En route to the synthesis of plakortolide E and I, we pre-
centers.
pared a b-hydroperoxy vinyl epoxide, obtained from (R)-epi-
chlorhydrin in 13 steps and 30% yield, via chemoselective
methylenation with Nysted reagent in the presence of Ti(Oi-Pr)2Cl2
and regioselective Mukaiyama–Isayama hydroperoxysilylation.
Unexpectedly, acid-catalyzed cyclization of this peroxy epoxide oc-
curred exclusively through a 5-exo mode to furnish a 1,2-dioxolane;
this is in contrast to the behavior of hydroxy analogues.
In connection with our interest in exploiting the directing
effect of a double bond in the regiocontrol of intramolec-
ular cyclization of hydroxy epoxides via disfavored 5- or
6-endo-tet modes according to Baldwin’s rules,4 to pre-
pare substituted furans or pyrans,5 we wondered if this
concept could be applied to the synthesis of 1,2-dioxanes
by cyclization of b-hydroperoxy vinyl epoxides. There are
only few examples in the literature for the formation of a
1,2-dioxane ring system by cyclization of hydroperoxy
epoxides.6 This strategy of 1,2-dioxane ring forming has
been successfully applied to the synthesis of natural-prod-
uct-containing endoperoxides such as yingzhaosu C6b and
dihydroplakortin.6d,e In all cases, the cyclization proceed-
ed via a 6-exo mode following Baldwin’ rules.
Key words: cyclization, endoperoxides, hydroperoxysilylation,
plakortolides
Marine sponges of genus Plakortis and Plakinastrella are
a prolific source of cyclic peroxides, many of which ex-
hibit antifungal, antitumor, and antiparasitic activities.1
The majority of these natural products contain six-mem-
bered peroxide structure (1,2-dioxane). Plakortolides, one
of the family of secondary metabolites found in these
sponges, have an aromatic unit connected via a methylene
chain to a bicyclic 4,6-dimethyl peroxylactone ring sys-
tem.2 They differ in absolute and relative configuration at
C-3, C-4, C-6, the substitution pattern, the level of unsat-
uration, and of the chain length. A representative sample
of plakortolides is depicted in Figure 1.
The feasibility of our approach to the 4,6-dimethylper-
oxylactone framework of plakortolides, based on anti-
Baldwin cyclization of b-hydroperoxy vinylepoxides, was
tested on the structurally most simple plakortolides: pla-
kortolides E (1)7 and I (2). These two compounds were
isolated in minute amounts (3·10–4% for 2) from the
sponge plakortis sp.2c,h Plakortolide E (1) has potent and
selective activity against melanoma and breast tumor cell
lines (LC50 < 1 mM);2c no biological activity has been re-
ported for 2.
H
O
O
2
3
4
O
6
R2
O
H
O
R1
O
3
OOH
R1 = Me
R2 = (CH2)10Ph
R2 = Me
plakortolide E (1)
plakortolide I (2)
1
O
O
O
1 = (CH2)10Ph
O
R
R
R
R
1, 2
5
6
R
1 = Me
1 = Me
R2
R2
=
=
plakortolide G (3)
Ph
3
R =
Ph
8
R
Ph plakortolide O (4)
8
O
Figure 1 Representatives examples of plakortolides
O
O
O
Cl
R
R
A survey of the literature showed only one racemic syn-
thesis of a member of plakortolides: plakortolide I (2) has
been reported.3 [4+2] Photocycloaddition of singlet oxy-
gen to a diene and iodolactonization are the key steps for
the construction of the peroxylactone framework of pla-
kortolide I. A drawback of this strategy is the lack of ste-
7
8
9
Scheme 1 Retrosynthetic analysis of plakortolide E (1) and plakor-
tolide I (2)
In the retrosynthetic analysis of 1 and 2 (Scheme 1), we
took into account the low stability of the O–O bond
(DHf = –33 kcal/mol for 1,2-dioxane)8 and its susceptibil-
ity to reducing agents as well as nucleophiles and bases
(Scheme 1).9 Obviously, the hydroperoxide functionality
has to be introduced at the late stage of the synthesis.
SYNLETT 2011, No. 13, pp 1912–1916
x
x
.x
x
.2
0
1
1
Advanced online publication: 21.07.2011
DOI: 10.1055/s-0030-1260959; Art ID: D11211ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Studies toward the Bicyclic Peroxylactone Core of Plakortolides
1913
O
O
OH
O
a, b
O
c
d, e
O
OEt
Cl
Ph
Ph
10
Ph
10
10
9
8
10
7
O
OH
O
j or k
X
f
O
h, i
g
O
O
O
O
O
O
Ph
10
Ph
10
Ph
10
Ph
10
11
12
13
6
Scheme 2 Reagents and conditions: (a) Ph(CH2)9MgBr (1.3 equiv), CuCN (0.1 equiv), THF, –78 °C, 2 h; (b) NaOH (5 equiv), THF, r.t., 4 h,
79% for 2 steps; (c) ethyl propiolate (3 equiv), THF, –90 °C, n-BuLi (3 equiv), 20 min, BF3·OEt2 (3 equiv) then 8, –78 °C to r.t., 98%; (d)
Me2CuLi (3 equiv) then 10, THF, –78 °C, 0.5 h; (e) PTSA (0.1 equiv), MeOH, r.t., 4 h, 84% for 2 steps; (f) H2O2 (30%, 3.5 equiv), NaOH (6
N, 0.6 equiv), MeOH, 0 °C to r.t., 3 h, 82%; (g) DIBAL-H (1.1 equiv), toluene, –78 °C, 0.5 h, quant.; (h) NaBH4 (2 equiv), EtOH, r.t., 4 h, 95%;
(i) (COCl)2 (8 equiv), DMSO (16 equiv), CH2Cl2, –78 °C, 1 h, then Et3N (16 equiv), 50%; (j) CH2=PPh3, THF, –78 °C to r.t.; (k) CpTiMe2 (4
equiv), toluene, 80 °C, 6 h.
Among the different existing methods to incorporate the A new strategy was devised to introduce the two double
hydroperoxide group, we chose the hydroperoxysilylation bonds in a stepwise manner and was based on the ability
of alkenes developed by Mukaiyama and Isayama.10 This of titanium carbenoid reagents to effect, under mild con-
cobalt-mediated reductive oxygenation of double bonds is ditions, chemoselective methylenation of ketones in the
a particularly mild and regioselective method10a,11 which presence of esters18 (Scheme 3). A one-pot saponification
can be effected in the presence of a large number of func- of the lactone function of 11 followed by RuO4
tional groups.6b,d,e,12 Disconnection of C3–O and C1–O oxidation19 of the resulting hydroxy sodium carboxylate
within 1 and 2, guided by our strategy of 6-endo ring clos- gave, after diazomethane esterification, the keto ester 14
ing of hydroperoxy epoxide directed by a vinyl group (a in nearly quantitative yield. Monomethylenation of 14
synthetic equivalent of a carboxymethyl group), revealed turned out to be somewhat troublesome as seen in Table 1.
the vinyl epoxide 5,which itself could arise from the ep-
In the presence of methylene triphenylphosphorane or us-
oxy diene 6 via regioselective hydroperoxysilylation. Ep-
oxide 6 could originate from the unsaturated lactone 7 by
a diastereoselective epoxidation after conventional func-
tional adjustments. We believed intermediate 7 could be
prepared from commercially available (R)-epichloro-
hydrin (9) via epoxide 8.
ing the Lombardo protocol,20 only polar products were
formed (Table 1, entries 1, 2). In the latter case, Ti(III)
present in the reaction medium is known to act as a reduc-
ing agent to form pinacol-type byproducts.21 In the pres-
ence of the Tebbe reagent, compound 14 gave 15 in low
yield (Table 1, entry 3).22
Synthesis of plakortolides 1 and 2 commenced by a cop-
per-catalyzed epoxide ring opening of (R)-epichlorohy-
drin (9) with (9-phenylnonyl)magnesium bromide13
followed by treatment of the resulting chlorohydrin with
NaOH to give the epoxide 8 in 79% yield (Scheme 2).
Compound 8 was regioselectively opened with the lithium
salt of ethyl propiolate, in the presence of BF3·OEt2,14 to
provide the secondary alcohol 10 in nearly quantitative
Exposure of 14 to Petasis reagent and its catalyzed
version23 afforded about a 1:1 mixture of mono- and di-
methylenation products (Table 1, entries 4, 5). Next, we
turned our attention to another gem-bimetallic reagent: the
Nysted reagent.24 Thus, keto ester 14, treated with Nysted
reagent and TiCl4, afforded 15 in a low yield due to de-
composition (Table 1, entry 6). The use of an equal mix-
ture of TiCl4 and Ti(i-OPr)421 in combination with Nysted
reagent improved considerably the yield of 15 (Table 1,
entry 7).25 Having attained our challenging target, its
transformation to 6 was effected in 83% yield via standard
functional manipulations.
yield.
Stereoselective
addition
of
lithium
dimethylcuprate15 to the triple bond and subsequent lac-
tonization of the resulting Z-enoate with p-toluenesulfon-
ic acid in methanol at room temperature furnished the
lactone 7 in 84% overall yield. Exposure of 7 to alkaline
hydrogen peroxide in methanol gave the epoxide 11, as a
single diastereomer, in 82% yield. This trans-selective ep-
oxidation of pentenolides is well precedented.16 After
DIBAL-H reduction of 11 to lactol 12, the stage was now
set up to introduce the double bond in the a-position to the
oxirane functionality. In order to attain this goal, reduc-
tion of the lactol 12 with NaBH4 followed by Swern oxi-
dation provided the ketoaldehyde 13 in 47% overall yield.
Unfortunately, in the presence of an excess of methylene-
triphenylphosphorane or Petasis reagent,17 compound 13
led exclusively to decomposition.
The stage was thus set for the chemoselective peroxida-
tion of epoxydiene 6. The best results, in terms of yield
and chemoselectivity, were obtained by reaction of 6 with
oxygen and triethysilane in dichloroethane, in the pres-
ence of bis[2,2,6,6-tetramethylheptane-3,5-dienoate
Co(II)] [Co(thd)2]11 and by stopping the reaction at about
80% of conversion in order to avoid the bisperoxidation.
The unseparable mixture of 6 and 16, purified through a
short pad of silica gel for removing the catalyst, was treat-
ed with strongly acidic resin Amberlyst-15 which effected
cleavage of the TES group and concomitant cyclization to
afford exclusively the 5-exo-cyclized product 17 in 51%
Synlett 2011, No. 13, 1912–1916 © Thieme Stuttgart · New York

1914
B. Barnych, J.-M. Vatèle
LETTER
Table 1 Study of the Regioselective Methylenation of Keto Ester 14
methylenation
CO2Me
OMe
OMe
O
CO2Me
reagents
O
O
O
O
O
Ph
10
Ph
Ph
10
Ph
10
10
14
A
15
B
Entry Reagents
Temp (°C) Time (h) Yield of 14 (%)a
Yield of A (%) Yield of 15 (%) Yield of B (%)
b
1
2
3
4
5
6
7
Ph3P=CH2
–78 to r.t.
0 to r.t.
–78 to r.t.
80
3
–
–
–
–
–
–
b
Zn, CH2Br2, TiCl4
Cp2TiClCH2AlMe2
Cp2TiMe2
4
–
–
–
14
21
6
–
23
34
31
35
70
–
22
21
–
3c
3c
–
41
27
–
Cp2TiMe2, Cp2TiCl2 cat.
TiCl4, Nysted reagent
80
0 to 15
1
Ti(Oi-Pr)2Cl2, Nysted reagent 0 to 15
0.25
15
–
–
a Isolated yield.
b Only decomposition was observed.
c Determined by 1H NMR.
O
CO2Me
CO2Me
O
d
a–c
O
e, f
O
O
O
O
Ph
Ph
Ph
Ph
10
10
10
10
11
14
15
6
Zn
HO
O
O
O
O
g
h
OOTES
Co
BrZn
ZnBr
O
O
O
O
Ph
Ph
10
17
10
16
Nysted reagent
Co(thd)2
5
Scheme 3 Reagents and conditions: (a) NaOH (2 equiv), MeOH, r.t., 2 h, then evaporation in vacuo; (b) RuCl3 (0.05 equiv), NaIO4 (3 equiv),
K2CO3 (2 equiv), H2O, r.t., 2–3 h; (c) CH2N2 (1.2 equiv), Et2O, r.t., 10 min, 96% for 3 steps; (d) Nysted reagent (3 equiv), Ti(Oi-Pr)2Cl2 (2.5
equiv), THF, 0–15 °C, 15–20 min, 70%; (e) DIBAL-H (5 equiv), toluene, –78 °C, 40 min; (f) Ph3PMeBr (5 equiv), n-BuLi (4 equiv), THF,
0 °C then aldehyde, 30 min, 83% for 2 steps; (g) Co(thd)2 (0.1 equiv), O2 (1 atm), Et3SiH (1.2 equiv), DCE, r.t., silica gel filtration, 80% con-
version (% determined by 1H NMR); (h) Amberlyst-15 (0.5 equiv), CH2Cl2, r.t., 3 h, 51% from 6; (i) TBAF (1.3 equiv), THF, r.t., 0.5 h; (j)
Amberlyst-15 (0.5 equiv), CH2Cl2, r.t., 3 h, 17% from 6; (k) HCl (12 M, 6 equiv), MeCN, r.t., 5 h, 30% from 6.
yield.26 The structure of 17, obtained as a 1:1 mixture of epoxy ester such as 18 should undergo a cylization at the
diastereomers, was ascertained by 2D NMR experiments less hindered and more electrophilic position of the ox-
(HMBC, HSQC, NOESY). A stepwise procedure for the irane, namely at the C-2 position (Scheme 4).
formation of endoperoxide 17 involving the deprotection
of the TES group with NBu4F affording 5 and acid-pro-
O
O
COOMe
moted ring closure in the presence of Amberlyst-15 or 12
N HCl in acetonitrile27 gave 17 in lower yields than in the
one-pot reaction. As in literature precedents for hydroxy
and protected amino vinyl-cis-epoxides, the cis configura-
tion seems to disfavor the 6-endo ring closure perhaps be-
cause these systems cannot assume the planar
arrangement necessary for maximum stabilization in the
transition state, perhaps because of steric interactions.28
OMe
OMe
OOTES
HO
a
b
O
O
2
O
O
Ph
10
Ph
Ph
10
10
15
18
19a,b
Scheme 4 Reagents and conditions: (a) Co(thd)2 (0.1 equiv), O2 (1
atm), Et3SiH (2 equiv), DCE, r.t., 3–4 h, 86%; b) K2CO3 (0.3 equiv),
MeOH, 0 °C, 3 h, 75%.
Finally, we tested another strategy based on the expecta-
tions that a peroxy anion derived from a d-hydroperoxy
Regioselective hydroperoxysilylation of the gem-disub-
stituted olefin of 15 under Mukaiyama and Isayama con-
Synlett 2011, No. 13, 1912–1916 © Thieme Stuttgart · New York

LETTER
Studies toward the Bicyclic Peroxylactone Core of Plakortolides
1915
Wipf, P.; Kelly, M.; Hamann, M. T. Tetrahedron 2001, 57,
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ditions yielded a 1:1 diastereomeric mixture of the
triethylsilylperoxy ester 18 in 86% yield. Treatment of 18
with a catalytic amount of potassium carbonate gave, after
TES cleavage, again exclusively a 1,2-dioxolane deriva-
tive: 19a,b, obtained in a good yield as a mixture of dias-
tereomers, separable by preparative TLC. Compounds 19
are structurally closely related to plakinic acids of general
formula 20 (Figure 2). These natural products, isolated
from sponges of the family Plakinidae, display cytotoxic-
ity against fungal and cancer cell lines.2e,h,29
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CO2H
CO2H
R
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newly isolated plakortolides and plakortolide E. They noted
inconsistencies between the reported structure of
plakortolide E and of its 1H NMR and 13C NMR data.2c They
suggested that these data are those of seco-plakortolide E.
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Ph
9
O
O
O
O
20
20a
andavadoic acid
plakinic acids
Figure 2
In summary, during the study of plakortolide synthesis we
have shown that cyclization of b-hydroperoxy vinyl-cis-
epoxides occurred only via a 5-exo mode, unlike hydroxy
analogues, to give 1,2-dioxolanes. In this case, the vinyl
group has no directing effect. We also described a modi-
fication of the method of methylenation of Matsubara et
al., using Nysted reagent and a mixture of TiCl4 and Ti(i-
OPr)4, which allowed the chemoselective methylenation
of a keto ester in the presence of sensitive functional
groups such as epoxides. Extension of the Mukaiyama
and Isayama peroxygenation method to the diene 6 al-
lowed the introduction of the hydroperoxide function
regio- and chemoselectively. Finally, cyclization of hy-
droperoxy keto ester 18 furnished 3,5-dimethyl-1,2-diox-
olane ester, structure closely related to plakinic acid
natural product family 20. Studies are under way in our
laboratories to apply this strategy to the synthesis of some
of these members such as andavadoic acid (20a).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
B.B. thanks the ‘French Ministère de la recherche et de l’Enseigne-
ment Supérieur’ for a PhD grant.
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Synlett 2011, No. 13, 1912–1916 © Thieme Stuttgart · New York

1916
B. Barnych, J.-M. Vatèle
LETTER
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(24) (a) Tochtermann, W.; Bruhn, S.; Meints, M.; Wolff, C.;
Peters, E. M.; von Schnering, H. G. Tetrahedron 1995, 51,
1623. (b) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett
1998, 313.
(25) Procedure for the Chemoselective Methylenation of
Compound 14
filtered through a small pad of silica gel to remove metal
species, dried (Na2SO4), and concentrated in vacuo. The
residue was chromatographed on silica gel (Et2O–PE, 1:5) to
furnish 15 (0.153 g, 70%) as a colorless oil; [a]D20 –29.2 (c
1, CH2Cl2). 1H NMR (300 MHz, CDCl3): d = 1.26 (br, m, 14
H), 1.38 (s, 3 H), 1.60 (m, 2 H), 1.95 (m, 2 H), 2.35 (d, J = 15
Hz, 1 H), 2.41 (d, J = 15 Hz, 1 H), 2.59 (t, J = 8.1 Hz, 2 H),
3.37 (s, 1 H), 3.76 (s, 3 H), 4.79 (s, 1 H), 4.85 (s, 1 H), 7.16–
7.29 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 21.8, 27.6,
29.4–29.7 (6C), 31.6, 36.1, 36.3, 39.0, 52.3, 59.0, 62.2,
112.2, 125.6, 128.3 (2 C), 128.5 (2 C), 143.0, 145.3, 169.0.
IR (neat): 1646, 1736, 1757, 2854, 2927, 3026 cm–1. ESI-
HRMS: m/z calcd for C24H36NaO3 [MNa]+: 395.2557;
found: 395.2557.
(26) No 6-endo product was detected by 1H NMR of the crude
mixture.
(27) For the use of these acid conditions in the 6-endo cyclization
of epoxy alcohols, see: Chapelat, J.; Buss, A.; Chougnet, A.;
Woggon, W.-D. Org. Lett. 2008, 10, 5123.
(28) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330. (b) Ha, J. D.;
Shin, E. Y.; Chung, Y.; Choi, J.-K. Bull. Korean Chem. Soc.
2003, 24, 1567.
(29) (a) Davidson, B. S. J. Org. Chem. 1991, 56, 6722.
(b) Chen, Y.; McCarthy, P. J.; Harmody, D. K.; Schimoler-
O’Rourke, R.; Chilson, K.; Selitrennikoff, C.; Pomponi,
S. A.; Wright, A. E. J. Nat. Prod. 2002, 65, 1509.
To a stirred solution of ketone 14 (0.219 g, 0.585 mmol) in
dry THF (8 mL) was added Nysted reagent (20% in THF,
3.51 mL, 1.83 mmol), purchased from Aldrich, at 0 °C under
N2 atmosphere followed by dropwise addition of TiCl2(Oi-
Pr)2 (2. 5 equiv), prepared from TiCl4 (1 M in CH2Cl2; 0.73
mL, 0.73 mmol) and Ti(Oi-Pr)4 (0.217 mL, 0.73 mmol). The
reaction mixture was then allowed to reach 15 °C and stirred
for 15 min. The reaction mixture was cooled to 0 °C, treated
carefully with H2O (1 mL) and extracted with Et2O (5 × 8
mL). The combined organic layers were washed with sat.
Synlett 2011, No. 13, 1912–1916 © Thieme Stuttgart · New York