Protecting-group-free and catalysis-based total synthesis of the ecklonialactones

Article abstract of DOI:10.1021/ja104796a

A concise and protecting-group-free total synthesis of optically pure ecklonialactones A (1) and B (2) is described. The successful route to these oxylipins isolated from various brown algae involves five transition-metal- catalyzed transformations in the longest linear sequence of 13 steps. The first chiral center was set by a rhodium-catalyzed 1,4-addition of an alkenyl boronate to the commercial butenolide 11, which was controlled by Carreira's carvone-derived diene ligand 21. Other key steps involve a ring-closing olefin metathesis effected by the ruthenium indenylidene complex 22 for the formation of the five-membered carbocycle, a vanadium-catalyzed, hydroxy-directed epoxidation, and a ring-closing alkyne metathesis (RCAM) to forge the macrocyclic ring. Because of the unusually high propensity of the oxirane of the ecklonialactones for ring-opening, this transformation was best achieved with [(Ph₃SiO)₃MoξCPh]>=OEt₂ (34) as the catalyst, which is a representative of a new generation of highly tolerant yet remarkably efficient molybdenum alkylidyne complexes. The ancillary triphenylsilanolate ligands in 34 temper the Lewis acidity of the molybdenum center and are not able to nucleophilically open the fragile epoxide ring. The final reduction of the cycloalkyne formed in the RCAM step to the required (Z)-alkene was accomplished either by Lindlar reduction or with the aid of nickel boride.

Full text of DOI:10.1021/ja104796a

Published on Web 07/16/2010
Protecting-Group-Free and Catalysis-Based Total Synthesis of the
Ecklonialactones
Volker Hickmann, Manuel Alcarazo, and Alois Fu¨rstner*
Max-Planck-Institut fu¨r Kohlenforschung, D-45470 Mu¨lheim/Ruhr, Germany
Received June 2, 2010; E-mail: fuerstner@kofo.mpg.de
featured, whereas carbohydrates, polyketides, and fatty acids are
Abstract: A concise and protecting-group-free total synthesis of
optically pure ecklonialactones A (1) and B (2) is described. The
successful route to these oxylipins isolated from various brown
algae involves five transition-metal-catalyzed transformations in
the longest linear sequence of 13 steps. The first chiral center
was set by a rhodium-catalyzed 1,4-addition of an alkenyl
boronate to the commercial butenolide 11, which was controlled
by Carreira’s carvone-derived diene ligand 21. Other key steps
involve a ring-closing olefin metathesis effected by the ruthenium
indenylidene complex 22 for the formation of the five-membered
carbocycle, a vanadium-catalyzed, hydroxy-directed epoxidation,
and a ring-closing alkyne metathesis (RCAM) to forge the
macrocyclic ring. Because of the unusually high propensity of the
oxirane of the ecklonialactones for ring-opening, this transforma-
tion was best achieved with [(Ph3SiO)3MotCPh]·OEt2 (34) as
the catalyst, which is a representative of a new generation of
highly tolerant yet remarkably efficient molybdenum alkylidyne
complexes. The ancillary triphenylsilanolate ligands in 34 temper
the Lewis acidity of the molybdenum center and are not able to
nucleophilically open the fragile epoxide ring. The final reduction
of the cycloalkyne formed in the RCAM step to the required (Z)-
alkene was accomplished either by Lindlar reduction or with the
aid of nickel boride.
currently under-represented.3 We now report a case study in the
latter arena, in which metal-catalyzed reactions play a prominent
role. Specifically, ecklonialactones A (1) and B (2) were chosen as
the targets, which are the parent members of a family of C-18
oxylipins isolated from various brown algae.4 Opening of their
epoxide ring delivers the ecklonialactones C (3) and D (4) or
eiseniahalides (5, 6) respectively, whereas the egregiachlorides (7,
8) derive from an assisted cleavage of the macrolactone.4 Further-
more, 1 and 2 are closely related to hybridalactone (9)5 and
agardhilactone (10),6 two unusual eicosanoids from red algae.
Although these oxylipins may be involved in the chemical defense
of the producing organisms against herbivores, no in-depth assess-
ment of their physiological properties has been published.7
Scheme 1a
Despite tremendous strategic and methodological advances,1 the
art and science of natural product total synthesis is still far from
mature. Even target molecules of moderate size usually impose
significant protecting group requirements on a workable synthesis
plan. As structurally unproductive steps, however, such manipula-
tions adversely affect all desirable “economies” of synthesis.2 The
pursuit of complex targets without recourse to protecting group
maneuvers was therefore recognized as a challenging yet inspira-
tional frame for chemical invention.3
a Reagents and conditions: (a) [Rh(C2H4)2Cl]2 (1.5 mol %), 21 (3.3 mol
%), SiO2 cat., 1,4-dioxane, aq. KOH, 52%, 80% ee (93% ee after recryst.);
(b) LDA, THF, -78 °C, then allyl iodide, 87%; (c) HN(OMe)Me ·HCl,
Me3Al, CH2Cl2, 0 °C f rt; (d) 22 (8 mol %), CH2Cl2, 75% (over both
steps); (e) Dess-Martin periodinane, NaHCO3, CH2Cl2, 73%; (f) 23, K2CO3,
MeOH, 75%; (g) LiHMDS, MeOTf, THF, -78 °C, 80%; (h) EtMgBr, THF,
0 °C, 93%; (i) LiBH(s-Bu)3, THF, -78 °C, 69%.
Following up on our previous investigations on prostanoids of
marine origin,8 we were committed to developing a concise entry
into the ecklonialactone series.9 Commercial butenolide 11 served
as the point of departure, undergoing a rhodium-catalyzed 1,4-
addition of alkenylboronate 12 (Scheme 1).10 Although the reaction
was only moderately selective (80% ee) when controlled by the
(-)-carvone-derived diene ligand 21,11 the optical purity of 13 could
be increased by recrystallization to a workable ee of 93%.12
Deprotonation with lithium hexamethyldisilazide (LDA) followed
by an allyl iodide quench then gave the trans-disubstituted lactone
14 in good yield. Its subsequent opening with HN(OMe)Me/Me3Al
proceeded well, but the resulting Weinreb amide 15 readily reverted
to the starting lactone; therefore, the product was exposed without
delay to the ruthenium indenylidene complex 22, previously
described by our group as a cost-effective alternative to the classical
Among the limited number of protecting-group-free total syn-
theses documented in the literature, alkaloid targets are prominently
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11042 J. AM. CHEM. SOC. 2010, 132, 11042–11044
10.1021/ja104796a  2010 American Chemical Society

C O M M U N I C A T I O N S
Grubbs catalyst.13 The ensuing ring-closing metathesis provided
cyclopentene 16 in 75% yield over two steps, which was elaborated
into enyne 18 by oxidation, Ohira-Bestmann reaction,14 and end-
capping of the resulting alkyne with a methyl group. Reaction of
18 with EtMgBr gave ketone 19, which was reduced with
L-Selectride to deliver the required alcohol segment 20.
had previously been found compatible with oxiranes.18 The
classical tungsten alkylidyne 35 failed completely, likely because
of its significant Lewis acidity,19 whereas precatalyst 33 was
unsuitable for the known propensity of the nitride function to
react with epoxides.20 Gratifyingly, however, a new generation
of molybdenum alkylidyne complexes endowed with Ph3SiO
ligands nicely solved the problem.21 Specifically, complex 34
(5 mol %) gave the desired cycloalkyne 30 in 80% yield (the
remainder being cyclic dimer). The remarkable performance of
34 is ascribed to the tempered Lewis acidity of its Mo center as
well as to the poor nucleophilicity of the peripheral silanolates.21
Lindlar reduction of 30 then completed the total synthesis of
ecklonialactone B (2).
Scheme 2a
Scheme 3a
a Reagents and conditions: (a) undec-6(Z)-en-9-ynoic acid, 31, DMAP,
CH2Cl2, 65%; (b) 34 (5 mol %), MS 5 Å, toluene, 90%; (c) P2Ni (25 mol
%), H2, EtOH, 69%.
As expected, ecklonialactone A (1), containing an additional
skipped olefin in the lipidic tether, could be obtained analogously,
although its epoxide turned out to be even more fragile (Scheme
3). Whereas RCAM of diyne 36 with complex 32 once again gave
erratic results, alkylidyne 34 furnished 37 almost quantitatively.
Given the unusual sensitivity of this particular substrate, this result
bodes well for future applications of 34 and related catalysts.21 The
final semireduction had to be effected with nickel boride rather
than by Lindlar hydrogenation. Since 1 rapidly opens to ecklonia-
lactone C (3) or eiseniachloride A (6) on treatment with aqueous
HClO4 or HCl, respectively, formal syntheses of these sister
compounds have also been accomplished.4
a Reagents and conditions: (a) 9-undecynoyl chloride, DMAP, CH2Cl2,
70%; (b) 32 (20 mol %), toluene/CH2Cl2, 80 °C, 71%; (c) dimethyl
dioxirane, acetone/CH2Cl2, -78 °C f rt, 75% (26:30 ) 3:1); (d) Lindlar
catalyst, H2, CH2Cl2, 80%; (e) VO(acac)2 (8 mol %), t-BuOOH, CH2Cl2,
94%; (f) 9-undecynoic acid, 31, DMAP, CH2Cl2, 61%; (g) 34 (5 mol %),
toluene, MS 5 Å, 80%; (h) Lindlar catalyst, H2, CH2Cl2, 90%.
Overall, the concise and protecting-group-free entry into this
unusual class of marine oxylipins features respectable levels of
atom, redox, and step economy and relies, to a notable extent, on
catalysis. It bears witness for the power of complex 34, which sets
new standards in the field of alkyne metathesis.21 In essence, it is
the ability to rigorously distinguish between alkenes and alkynes
in oxidative and reductive as well as metathetic maneuvers which
forms the chemical basis for the success of this endeavor.
From this point onward, two different routes to 2 were pursued
(Scheme 2). Esterification of 20 with 9-undecynoic acid chloride
set the stage for the macrocyclization by ring-closing alkyne
metathesis (RCAM) of diyne 24.15 This key transformation was
effected with complex 32 as precatalyst, which was activated in
situ as previously outlined.16 As expected, the catalyst rigorously
distinguished between the double- and the triple bonds in 24, thus
emphasizing the notion that alkyne and alkene metatheses are
chemically orthogonal; moreover, the labile skipped enyne motif
remained intact. Unfortunately, however, oxidation of the olefin in
product 25 with dimethyldioxirane provided a 3:1 mixture of
isomers; though separable, Lindlar reduction to the resulting (Z)-
alkenes revealed that it was the minor epoxide isomer which led
to the natural product 2.
Acknowledgment. Financial support by the MPG and the Fonds
der Chemischen Industrie is gratefully acknowledged. We thank
our analytical departments for excellent support.
Supporting Information Available: Experimental section and NMR
spectra of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
Therefore, the secondary alcohol in 20 was used to direct the
epoxidation to the R-face of the olefin. In line with a literature
precedent,5 catalytic VO(acac)2 in combination with t-BuOOH was
most effective,17 affording product 28 with five contiguous chiral
centers in 94% yield as a single isomer. Its subsequent esterification
turned out to be challenging, as the oxirane is highly prone to ring-
opening. Only the use of carbodiimide 31 escorted by a tosylate
anion gave well-reproducible results.
The unusual sensitivity of the epoxide also accounts for the
fact that the macrocyclizaton of the resulting diyne 29 with the
aid of complex 3216 gave variable yields (50-89%) and required
rather high loadings (20-40 mol %), although this precatalyst
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