Total synthesis of (-)-ecklonialactone B

Article abstract of DOI:10.1021/ol4028418

The total synthesis of (-)-ecklonialactone B as well as the 9,10-dihydro derivative by two different strategies is reported. The catalytic asymmetric Claisen rearrangement of Gosteli-type allyl vinyl ethers delivered elaborated α-keto ester building blocks. Ring-closing metatheses, including a notable diastereotopos-differentiating variant, a B-alkyl Suzuki-Miyaura cross-coupling reaction and a regio- and diastereoselective last-step epoxidation are key contributors.

Full text of DOI:10.1021/ol4028418

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of (ꢀ)-Ecklonialactone B
Julia Becker, Lena Butt, Valeska von Kiedrowski, Elisabeth Mischler, Florian Quentin,
and Martin Hiersemann*
€
Fakultat Chemie und Chemische Biologie, Technische Universitat Dortmund,
44227 Dortmund, Germany
€
martin.hiersemann@udo.edu
Received October 3, 2013
ABSTRACT
The total synthesis of (ꢀ)-ecklonialactone B as well as the 9,10-dihydro derivative by two different strategies is reported. The catalytic asymmetric
Claisen rearrangement of Gosteli-type allyl vinyl ethers delivered elaborated R-keto ester building blocks. Ring-closing metatheses, including a
notable diastereotopos-differentiating variant, a B-alkyl SuzukiꢀMiyaura cross-coupling reaction and a regio- and diastereoselective last-step
epoxidation are key contributors.
The oxylipins (ꢀ)-ecklonialactone A (1) and B (3) have
been isolated from the brown algae Ecklonia stolonifera
by Kurata et al. and Egregia menziessi by Gerwick et al.
(Figure 1).1,2 The constitution and configuration of (ꢀ)-1
was deduced from NMR experiments, X-ray crystallogra-
phy, and analysis of the chiroptical properties of a deriva-
tive. The structural assignment of (ꢀ)-3 was deduced from
the close similarity of the NMR data of (ꢀ)-1 and (ꢀ)-3
and further evidenced by the experimental observation
that hydrogenation of (ꢀ)-1 as well as (ꢀ)-3 afforded
(þ)-2.1 An initial report on the enantioselective synthesis
of the cyclopentanoid segment of (ꢀ)-3 by our group was
subsequently followed by the disclosure of the total synth-
Our retrosynthetic reasoning is summarized in Figure 1.
A last-step regio- and diastereoface-differentiating epox-
idation of thediene4wasenvisionedinordertocircumvent
the presence of the labile oxirane already at an early stage
of the synthetic sequence toward (ꢀ)-3.4 Subsequent retro-
synthetic dismantling of the 14-membered lactone of 4
leads to the chiral cyclopentenoid building block 5 which,
in turn, was envisioned to be accessible from the achiral
Gosteli-type allyl vinyl ether (E,Z)-6.5
The experimental realization of the planning is illu-
strated in Scheme 1. Catalytic asymmetricGosteliꢀClaisen
rearrangement (CAGC)6ꢀ8 of (E,Z)-69 on gram scale
delivered the R-keto ester 8 which was subjected to highly
diastereoselective K-Selectride reduction to afford the
eses of (ꢀ)-1 and (ꢀ)-3 by Hickmann, Alcarazo, and
3,4
€
€
Furstner. Furstner’s synthesis required a longest linear
sequence of 13 steps, avoided any protecting group trans-
formation, and relied on a ring-closing alkyne metathesis
for the formation of the 14-membered lactone.
(5) (a) Gosteli, J. Helv. Chim. Acta 1972, 55, 451–460. (b) Rehbein, J.;
Hiersemann, M. J. Org. Chem. 2009, 74, 4336–4342. (c) Rehbein, J.;
Leick, S.; Hiersemann, M. J. Org. Chem. 2009, 74, 1531–1540.
(6) For a recent review on catalyzed Claisen rearrangements, see:
Rehbein, J.; Hiersemann, M. Synthesis 2013, 45, 1121–1159.
(7) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew. Chem.,
€
(1) Kurata, K.; Taniguchi, K.; Shiraishi, K.; Hayama, N.; Tanaka, I.;
Suzuki, M. Chem. Lett. 1989, 267–270.
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Int. Ed. 2001, 40, 4700–4703. (b) Abraham, L.; Korner, M.; Schwab, P.;
Hiersemann, M. Adv. Synth. Catal. 2004, 346, 1281–1294. (c) Abraham,
€
L.; Korner, M.; Hiersemann, M. Tetrahedron Lett. 2004, 45, 3647–3650.
(8) For the synthesis of [Cu{(S,S)-tert-Bu-box}(tfe)2](SbF6)2, see:
Jaschinski, T.; Hiersemann, M. Org. Lett. 2012, 14, 4114–4117.
(9) Prepared in 7 steps (19%)from cis-2-butene-1,4-diol including the
separation of vinyl ether double bond isomers by preparative HPLC;
see ref 3.
(3) Wang, Q.; Millet, A.; Hiersemann, M. Synlett 2007, 1683–1686.
€
(4) (a) Hickmann, V.; Alcarazo, M.; Furstner, A. J. Am. Chem. Soc.
2010, 132, 11042–11044. (b) Hickmann, V.; Kondoh, A.; Gabor, B.;
€
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r
10.1021/ol4028418
XXXX American Chemical Society

Scheme 1. Synthesis of 12,13-Desepoxy Ecklonialactone
Figure 1. Retrosynthesis.
R-hydroxy ester 9.10ꢀ12 Reductive homologation was ac-
complished by a two-pot reaction sequence: initial LAH
reduction afforded the corresponding diol which was
isolated and characterized and subsequently converted to
the corresponding oxirane using 1-tosyl imidazole (TsIm)
and NaH. In situ ring opening of the epoxide employing
MeMgBr and CuI, thereafter, provided the alcohol 10.13,14
Having assembled the unusual stereotriad of the acyclic
1,5-diene 10, subsequent ring-closing metathesis (RCM)
using the Grubbs catalyst 11a15 (0.005 equiv) delivered the
desired building block 5. Progressing to the bicyclic diene 4
then required assembly of the 14-membered lactone that
included the isolated Z-configured double bond.
Accordingly, the secondary hydroxyl group was pro-
tected,16 the benzyl ether reductively was cleaved,17 the unpro-
tected primary alcohol was oxidized,18 and the resulting
aldehyde was subjected to a Wittig-type olefination19 to
(10) Brown, C. A. J. Am. Chem. Soc. 1973, 95, 4100–4102.
afford the vinyl iodide 12 in excellent overall yield (4 steps,
88%) and a synthetically useful diastereoselectivity (Z:E >
10:1). SuzukiꢀMiyaura cross-coupling20 between the
vinyl iodide 12 and a B-alkyl borate complex, in situ
prepared from the alkyl bromide 13,21 t-BuLi, and
B-MeO-9-BBN, and subsequent silyl ether cleavage then
delivered the diol 14 in a robust 80% yield as a Z:E > 10:1
mixture of double bond isomers. Regioselective two-step
oxidation22,23 of 14 provided the corresponding hydroxy
acid which was subjected to a Yamaguchi lactonization24
which furnished the desired 12,13-desepoxy ecklonialac-
tone 4.
€
(11) Korner, M.; Hiersemann, M. Org. Lett. 2007, 9, 4979–4982.
(12) Despite being very robust in terms of diastereoselectivity, the
reduction is hampered by limited scalability. Attempts to utilize the
CoreyꢀBakshiꢀShibata protocol, as described in ref 12a, led to inferior
yields or diastereoselectivities, depending on the configuration of the
MeCBS catalyst. (a) Gille, A.; Hiersemann, M. Org. Lett. 2010, 12,
5258–5261. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551–5553.
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(14) The reaction conditions for the telescoped process were carefully
optimized and controlled, including the screening of various copper
salts; however, slightly inconsistent yields and the addition of an excess
of CuI (5 equiv) and MeMgBr (10 equiv) were inevitable in our hands.
(15) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956.
€
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hedron Lett. 1986, 27, 6369–6372. (b) Johnson, C. R.; Braun, M. P.
J. Am. Chem. Soc. 1993, 115, 11014–11015. (c) Schnabel, C.; Hiersemann,
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J. Chem. Soc., Chem. Commun. 1987, 1625–1627.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Regio- and Diastereoselective Epoxidation
Figure 2. Revised retrosynthesis based on diastereotopos-differ-
entiating RCM.
The synthesis of the Gosteli-type allyl vinyl ether 19 by
an aldol condensation approach is outlined in Scheme 3.29
Etherification of 2,4-pentadienol 20 followed by carbo-
diimide-mediated esterification30 furnished the acetate 21
which was subjectedto a stepwise aldol condensation using
4-phenylselenylbutanal31 as a synthetic equivalent for
3-butenal to afford the phenylselenides 22 (Z:E = 3:2)
which were separated by preparative HPLC. Oxidation of
the selenides (E,E)- as well as (Z,E)-22 triggered elimina-
tion32 to provide the Gosteli-type allyl vinyl ethers (E,E)-
and (Z,E)-19. Subsequent CAGC of (Z,E)-19 delivered the
R-keto ester (S)-23 which could serve as a building block
for the total synthesis of (þ)-ecklonialactone B.
With the diene 4 in hand, opportunities for a regio- and
diastereoselective epoxidation of the C12/C13 double
bond were explored (Scheme 2). An initial attempt using
m-CPBA (1 equiv) was highly regioselective. However, the
undesired diastereomer 15 was obtained exclusively. This
outcome was not unexpected considering the result of
Hickmann who obtained the same (12Re,13Si)-diastereo-
face differentiation (dr = 7:1) using the corresponding
enyne.25 Taking advantage of the intrinsic (12Re,13Si)-
nucleophilicity of the diene 4, a two-step procedure was
then employed to finalize the synthesis. Thus, subjecting
the diene 4 to NBS (1 equiv) in aqueous acetone followed
by treatment of the isolated and purified bromohydrin
intermediate with Ag2O in toluene at reflux furnished
(ꢀ)-3 whose NMR data matched thosereported byKurata
The implementation of the projected nine-step synthetic
sequence from (E,E)-19 to (ꢀ)-ecklonialactone B (3) is
outlined in Scheme 4. CAGC of (E,E)-19 to the R-keto
ester (R)-23 and subsequent reduction by K-Selectride
afforded the R-hydroxy ester 24. The crucial diastereotopos-
differentiating RCM was best performed using the
HoveydaꢀGrubbs catalyst33 (11b, 0.01 equiv) at ambient
temperature; we were pleased to discover that the trans-
1,2-disubstituted cyclopentenoid 25 was thus isolated in
very good yield and diastereoselectivity (g95:5 according
to NMR analysis). Reductive homologation of 25 to the
corresponding secondary alcohol was followed by an
esterification using the Yamaguchi protocol which deliv-
ered the triene 26. We then turned our attention to devising
conditions that would enable the much desired Z-selective
RCM of 27 to afford 12,13-desepoxy ecklonialactone (4).
Disappointingly, however, and despite the screening of
€
as well as Furstner. At this point, we decided to carry the
synthetic material toward the non-natural (þ)-9,10-dihydro
ecklonialactone B (2) whose partial synthesis from the
natural ecklonialactones A and B had been reported by
Kurata.26 Accordingly, (ꢀ)-3 was hydrogenated using
Adam’s catalyst27 to afford (þ)-2 whose spectroscopic
data were in accordance with those reported.
In pursuit of a streamlined synthetic sequence we next
implemented a revised retrosynthesis which hinged on the
success of a Z-selective RCM for the ring closure of the
macrolactone 4 from the triene 16 and a diastereotopos-
differentiating RCM28 for formation of the 1,2-trans-
disubstituted cyclopentenoid 17 from the R-hydroxy ester
18 (Figure 2); 18 would be accessible by a sequence of
enantio- and diastereoselective transformations from the
Gosteli-type allyl vinyl ether (E,E)-19.
(29) Hiersemann, M. Synthesis 2000, 1279–1290.
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Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Synthesis of Gosteli-Type Allyl Vinyl Ethers and
Catalytic Asymmetric Claisen Rearrangement
Scheme 4. Synthesis of (þ)-9,10-Dihydro Ecklonialactone B
different commercial Ru-based catalysts and conditions,
from which in our hands the StewartꢀGrubbs catalyst34
(11c) was best-performing in terms of yield, the diene 4 was
isolated as mixture of Δ9,10 double bond isomers (E:Z =
1ꢀ4:1, depending on the catalyst and conditions).35 Con-
version to the oxirane was then performed as described
above and proceeded without affecting the ratio of Δ9,10
double bond isomers. Subsequent hydrogenation of the
resulting E/Z-mixture of 3 delivered (þ)-2 whose spectral
properties matched those reported by Kurata and those of
the synthetic (þ)-2 from our initial synthesis (Scheme 2).
In conclusion, the catalytic asymmetric Claisen rearran-
gement of the Gosteli-type allyl vinyl ethers 6 and 19
allowed the strategic positioning of double bonds within
the chiral acyclic R-keto esters 8 and 23. Subsequent
RCM furnished the cyclopentenoid building blocks 5
and 17 whose availability enabled the total synthesis of
(ꢀ)-ecklonialactone B (3) (longest linear sequence of
23 steps, 2% overall yield) as well as of the non-natural
(þ)-9,10-dihydro ecklonialactone B (2) (protecting-group-
free, longest linear sequence of 17 steps, 4% overall yield)
via an E/Z-mixture of (ꢀ)-3.
Acknowledgment. This research was made possible
€
by financial support from the Technische Universitat
Dortmund. A generous gift of L-tert-leucine by Evonik
Degussa GmbH is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data, copies of 1H and 13
C
(35) The search for catalysts that support the selective RCM to
macrocyclic 1,2-disubstituted Z-cycloalkenes is ongoing; see: (a) Wang,
C.; Yu, M.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.;
Hoveyda, A. H. Chem.;Eur. J. 2013, 19, 2726–2740. (b) Marx, V. M.;
Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2012, 135,
94–97.
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX