The catalytic asymmetric claisen rearrangement (CAC) in natural product synthesis: Synthetic studies toward (-)-ecklonialactone B

Article abstract of DOI:10.1055/s-2007-982563

A catalytic asymmetric Claisen rearrangement (CAC) in concert with a ring-closing metathesis (RCM) has been utilized in the enantioselective synthesis of the C10-C18 segment of ecklonialactone B. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982563

LETTER
1683
The Catalytic Asymmetric Claisen Rearrangement (CAC) in Natural Product
Synthesis: Synthetic Studies Toward (–)-Ecklonialactone B
Synthetic Studies
T
oward (–)-E
W
cklonialactone
B
ang,a Agnès Millet,b Martin Hiersemann*a
a
Universität Dortmund, Fachbereich Chemie, Lehrbereich Organische Chemie, Otto-Hahn-Str. 6, 44227 Dortmund
Fax +49(231)46336148; E-mail: martin.hiersemann@uni-dortmund.de
b
Technische Universität Dresden, Fachrichtung Chemie, Organische Chemie, Bergstraße 66, 01062 Dresden
Received 3 May 2007
by removing the epoxide and C18. Subsequent utilization
of a ring-closing metathesis transformation and of a redox
transformation provides the a-keto ester 4. The following
disconnection rests on the CAC retron present in 4 and
provides the achiral E,Z-configured allyl vinyl ether 5.
The final simplification takes advantage of the availability
of an olefination transformation for the diastereoselective
synthesis of 2-alkoxycarbonyl-substituted allyl vinyl
ethers as 5 from the known phosphonoacetate 6.7b
Abstract: A catalytic asymmetric Claisen rearrangement (CAC) in
concert with a ring-closing metathesis (RCM) has been utilized in
the enantioselective synthesis of the C10–C18 segment of ecklonia-
lactone B.
Key words: total synthesis, natural products, asymmetric catalysis,
pericyclic reactions, Lewis acids
(–)-Ecklonialactone B (EB, 1), is a carbocyclic C18-oxy-
lipin of marine origin that has been isolated from the
brown algae Ecklonia stolonifera1 and Egregia menziessi2
(Scheme 1).3 EB is a member of a larger family of
ecklonialactones that are distinguished by the number and
position of double bonds in the macrolactone ring.4,5 Fur-
thermore, the cyclopentane segment of ecklonialactones
may either be epoxidized (as in EB) or trans-dihydroxylat-
ed at the C12/C13 position. The relative configuration of
ecklonialactone A (D6,9), EA, has been established by crys-
tal structure analysis.1 By chemical correlation, it was
demonstrated that EB (D9) possesses the same relative
configuration as EA.1 The absolute configuration of EA
was later deduced from its chiroptical properties and con-
ferred to EB based on the similar negative optical rotation
values of EA and EB.2
O
18
18
H
H
1
O
OH
15
13
11
12
H
OBn
O
O
10
10
H
(–)-ecklonialactone B (1)
2, this letter
O
OMe
O
OMe
16
15
16
15
O
OH
11
OBn
OBn
11
3
4
As part of a program aimed at the exploration of the scope
and limitations of the recently developed catalytic asym-
metric Claisen rearrangement (CAC)6 in natural product
synthesis,7 EB (1) was identified as a worthwhile target
molecule. Specifically, the proof of the assigned absolute
configuration, which has important biosynthetic implica-
tions,2 as well as the study of potential biological
activities3 of 1 and its derivatives appear appealing. In this
letter, we report an 11-step synthesis (8% overall yield) of
the enantiomerically pure cyclopentanoid 2, the key build-
ing block in the total synthesis of EB (1).
CAC
O
O
CO2Me
O
(MeO)2P
16
16
OMe
15
O
11
BnO
11
OBn
(E,Z)-5
6
Scheme 1 Retrosynthesis of (–)-ecklonialactone B (1)
The synthesis of the allyl vinyl ether (E,Z)-5 is summa-
rized in Scheme 2. Nucleophilic ring opening of tetra-
hydrofurane by the phenyl selenide anion, that was
generated from diphenyl diselenide (7) and lithium alumi-
num hydride (LAH)8 followed by Parikh–Doering oxida-
tion,9 provided the aldehyde 8. Horner–Wadsworth–
Emmons olefination10 of the aldehyde 8 utilizing the 2-
allyloxy-substituted trimethyl 2-phosphonoacetate 67b
afforded the allyl vinyl ether 9 as a mixture of vinyl ether
double-bond isomers. Subsequent oxidation of the
selenide to the selenoxide induced a thermal elimination11
which provided the required allyl vinyl ether 5 as an
Our retrosynthetic analysis of EB (1) is depicted in
Scheme 1. It is apparent that the molecular complexity of
1 materializes at the highly substituted cyclopentane moi-
ety, which features five contiguous stereogenic carbon at-
oms, and that the cyclopentanoid 2 represents an
advanced building block toward EB (1). The first retrosyn-
thetic simplification converts 2 into the cyclopentanoid 3
SYNLETT 2007, No. 11, pp 1683–1686
0
3
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-982563; Art ID: G14107ST
© Georg Thieme Verlag Stuttgart · New York

1684
Q. Wang et al.
LETTER
1. LAH, THF
r.t., 1 h; reflux, 12 h
2. O3S·pyridine, Et3N
DMSO, CH2Cl2, r.t.
7.5 mol% 10
HOCH2CF3, CH2Cl2
r.t., 3 d
CO2Me
O
(E,Z)-5
PhSe
(PhSe)2
O
2+
(600 mg)
BnO
7
8 (55%)
O
O
–
(3R,4R)-4
92%
dr > 95:5 (NMR)
99% ee (HPLC)
2 SbF6
N
N
6, LDA, THF
–78 °C to r.t.
Cu
t-Bu
t-Bu
H2O OH2
(S,S)-10
SePh
BnO
K[(sec-Bu)3BH]
THF, –100 °C
CO2Me
CO2Me
O
OH
DDQ, CH2Cl2
aq pH 7 buffer
r.t., 42 h
H2O2, NaHCO3
THF, r.t., 3 d
O
O
BnO
O
CO2Me
13 (72%, unoptimized)
5
9
(81%, E:Z = 6:1)
(70%, E:Z = 6:1)
OH
1 mol% 12
DCE
40 °C, 5 h
BnO
preparative HPLC
(2R,3R,4R)-11
91%
dr > 95:5 (NMR)
(E,Z)-5
CO2Me
OH
Scheme 2 Synthesis of allyl vinyl ether (E,Z)-5
N
N
BnO
Mes
Mes
Ph
Cl
Cl
3 (82%)
Ru
PCy3
E:Z = 6:1 mixture of double-bond isomers. The diastereo-
mers were conveniently separable by preparative HPLC.12
Efforts to utilize 3-butenal for the olefination were unsuc-
cessful.13
12
Scheme 3 The sequence of two stereodifferentiating reactions and
a ring-closing metathesis provides enantiomerically pure 3
The pivotal sequence for the generation of the two stereo-
genic carbon atoms C11 and C15 as well as the cyclopen-
tene moiety from an acyclic precursor is depicted in
Scheme 3. The chosen route to the key building block 3
hinges upon the methodology recently developed in our
laboratory.6,7 The CAC of the allyl vinyl ether (E,Z)-5 in
the presence of the chiral Lewis acid {Cu[(S,S)-tert-Bu-
The sequence required for the conversion of cyclopen-
tenoid 3 into the C10–C18 segment 2 of EB (1) is depicted
in Scheme 4.
Reduction of 3 to the diol 14 followed by one-step
epoxidation20 enabled the introduction of the yet missing
C18. Copper-mediated ring opening of the epoxide 16
with methyl magnesium bromide provided the alcohol
17.21 The diastereoselective epoxidation of the cyclo-
pentanoid 17 employing meta-chloroperbenzoic acid
(MCPBA) provided the desired C10–C18 segment 222 of
EB (1) along with its diastereomer 18.23 The diastereomers
were easily separable by flash chromatography. NOE
studies on both diastereomers unambiguously support the
assignment of the relative configuration. Efforts aimed at
14
box]}(H2O)2(SbF6)2 (10) afforded the a-keto ester
(3R,4R)-415 as single stereoisomer based on NMR and
HPLC analysis. The absolute configuration of 4 was as-
signed based on the previously established stereochemical
course of the CAC.6,7 Judging from our experience with
structurally related allyl vinyl ethers, the CAC of (E,Z)-5
was unexpectedly slow requiring 7.5 mol% of 12 and 3
days reaction time to proceed to completion. Neverthe-
less, the chemo- and stereoselectivity of this catalytic
asymmetric C–C-connecting transformation is impressive
and reproducible, even on a synthetically useful scale.
Studies are underway to further optimize the reaction
conditions.
O
O
S
LiBH4, THF
0 °C, 2 h
N
N
15
3
OH
NaH, THF
0 °C, 30 min
then 15
OH
BnO
14 (94%)
In accordance with previous work from our laboratory, re-
duction of the a-keto ester 4 with K-selectride provided
the a-hydroxy ester (2R,3R,4R)-11 as a single diastereo-
mer based on NMR analysis (Scheme 3).6b,7b The config-
uration of the newly generated stereogenic carbon atom
C2 may be explained by the Cram–Felkin–Anh model.16
Oxidative cleavage17 of the benzyl ether in 11 followed by
in situ lactonization provided the corresponding d-lactone
13. NOE studies on the d-lactone 13 support the assign-
ment of the relative configuration. The ring-closing meta-
thesis of the diene 11 was catalyzed by the second-
generation Grubbs catalyst18 (12) at slightly increased
temperature to afford the cyclopentenoid 3.19
1 h, r.t.
0.5 equiv CuI, THF
10 equiv MeMgBr
–30 °C, 30 min
0 °C, 1 h
O
then 16
–30 °C, 3 h
OH
BnO
BnO
O
17 (92 %)
MCPBA
16 (80%)
O
Na2HPO4
CH2Cl2, r.t., 7 h
+
OH
OH
18 (26%)
BnO
BnO
2 (66%)
Scheme 4 Introduction of the C18 methyl group and epoxidation of
the cyclopentene double bond
Synlett 2007, No. 11, 1683–1686 © Thieme Stuttgart · New York

LETTER
Synthetic Studies Toward (–)-Ecklonialactone B
1685
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653.
(14) Evans, D. A.; Burgey, C. S.; Paras, N. A.; Vojkovsky, T.;
Tregay, S. W. J. Am. Chem. Soc. 1998, 120, 5824.
(15) Synthesis of (3R,4R)-4
the improvement of the diastereoselectivity of the epoxi-
dation are ongoing.
In summary, we have once again demonstrated the power
of the catalytic asymmetric Claisen rearrangement (CAC)
of 2-alkoxycarbonyl-substituted allyl vinyl ethers in nat-
ural product synthesis. The CAC provides access to stere-
oisomerically pure acyclic a-keto esters. Various
functional groups are tolerated. The strategic positioning
of double bonds allows access to cyclic building blocks
for the total synthesis of enantiomerically pure carbo-
cyclic natural products. Work aimed at the completion of
the total synthesis of EB (1) is currently underway and will
be reported in due course.
A stock solution of {Cu[(S,S)-tert-Bu-box]}(H2O)2(SbF6)2
(10) in CF3CH2OH (1 mL, 0.1 M, 86 mg, 0.1 mmol, 0.05
equiv) was dissolved in CH2Cl2 (5 mL). The allyl vinyl ether
(E,Z)-5 (0.59 g, 2.0 mmol, 1 equiv) was then added and the
solution was stirred over night at r.t. At this point, additional
{Cu[(S,S)-tert-Bu-box]}(H2O)2(SbF6)2 (0.5 mL, 0.1 M in
CF3CH2OH, 43 mg, 0.05 mmol, 0.025 equiv) was added.
The reaction mixture was stirred for 3 d at r.t. and then
concentrated under reduced pressure. The catalyst was
removed by filtering the crude product mixture through a
short path silica gel column. Subsequent flash
chromatography (hexane–EtOAc, 50:1) afforded the a-keto
ester 4 (0.54 g, 1.8 mmol, 92%) as a light yellow oil. TLC:
Rf = 0.72 (hexane–EtOAc, 5:1). 1H NMR (400 MHz,
CDCl3): d = 2.32–2.36 (m, 2 H), 2.83 (ddd, J1 = 19.1 Hz,
J2 = 9.5 Hz, J3 = 4.8 Hz, 1 H), 3.32 (dd, J1 = J2 = 9.7 Hz, 1
H), 3.39–3.47 (m, 2 H), 3.54 (s, 3 H), 4.27 (d, J = 12.1 Hz, 1
H), 4.31 (d, J = 12.1 Hz, 1 H), 4.90–4.97 (m, 2 H), 5.13–5.17
(m, 2 H), 5.52 (ddd, J1 = 17.4 Hz, J2 = J3 = 9.5 Hz, 1 H), 5.64
(dddd, J1 = 17.1 Hz, J2 = 10.0 Hz, J3 = 7.1, J4 = 7.0 Hz, 1 H),
7.19–7.31 (m, 5 H). 13C NMR (100 MHz, CDCl3): d = 34.7
(CH2), 48.2 (CH), 48.2 (CH), 52.4 (CH3), 72.5 (CH2), 72.6
(CH2), 117.2 (CH2), 118.9 (CH2), 127.5 (3 × CH), 128.2 (2
× CH), 134.7 (CH), 135.4 (CH), 137.3 (C), 161.2 (C), 194.7
(C). IR (in substance): 3080-2860, 1730, 1640 cm–1. Anal.
Calcd for C18H22O4: C, 71.5; H, 7.3. Found: C, 71.5; H, 7.1.
Acknowledgment
Financial support by the DFG is gratefully acknowledged.
References and Notes
(1) Kurata, K.; Taniguchi, K.; Shiraishi, K.; Hayama, N.;
Tanaka, I.; Suzuki, M. Chem. Lett. 1989, 267.
(2) Todd, J. S.; Proteau, P. J.; Gerwick, W. H. J. Nat. Prod.;
1994, 57, 171.
(3) For a review on oxylipins, see: Gerwick, W. H. Chem. Rev.
1993, 93, 1807.
(4) Kurata, K.; Taniguchi, K.; Shiraishi, K.; Suzuki, M.
Phytochemistry 1993, 33, 155.
(5) Ecklonialactones have also been isolated from the brown
alga Eisenia bicyclis, see: Kousaka, K.; Ogi, N.; Akazawa,
Y.; Fujieda, M.; Yamamoto, Y.; Takada, Y.; Kimura, J.
J. Nat. Prod. 2003, 66, 1318.
(6) (a) Abraham, L.; Czerwonka, R.; Hiersemann, M. Angew.
Chem. Int. Ed. 2001, 40, 4700. (b) Abraham, L.; Körner,
M.; Schwab, P.; Hiersemann, M. Adv. Synth. Catal. 2004,
346, 1281. (c) Abraham, L.; Körner, M.; Hiersemann, M.
Tetrahedron Lett. 2004, 45, 3647.
(7) (a) Pollex, A.; Hiersemann, M. Org. Lett. 2005, 7, 5705.
(b) Körner, M.; Hiersemann, M. Synlett 2006, 121.
(8) (a) Haraguchi, K.; Tanaka, H.; Hayakawa, H.; Miyasaka, T.
Chem. Lett. 1988, 17, 931. (b) Haraguchi, K.; Tanaka, H.;
Miyasaka, T. Synthesis 1989, 434; in our experiments, it was
beneficial to replace the originally used solvent 1,4-dioxane
by THF.
25
[a]D +46.8 (c 0.68, CHCl3).
(16) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191.
(17) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885. (b) Horita, K.; Yoshioka, T.; Tanaka, T.;
Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986, 42, 3021.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
(19) Synthesis of 3
Diene 11 (36.4 mg, 0.12 mmol, 1 equiv) was dissolved in
DCE (2.5 mL) in a septum-sealed round-bottomed flask. The
flask was twice evacuated (20 mbar, 2 min) and ventilated
with argon. The Grubbs catalyst 12 (1.0 mg, 1.2 mmol, 0.01
equiv) was then added to the solution and the flask was again
twice evacuated and ventilated with argon. The reaction
mixture was then stirred for 5 h at 40 °C. Silica gel (120 mg)
was subsequently added and the heterogeneous mixture was
stirred for several minutes. The solid was then removed by
filtration and the solvents were evaporated at reduced
pressure. The crude product was purified by flash
chromatography (hexane–EtOAc, 20:1 to 10:1) to afford the
cyclopentenoid 3 (27.6 mg, 0.10 mmol, 84%) as a light
yellow oil. TLC: Rf = 0.17 (hexane–EtOAc, 5:1). 1H NMR
(400 MHz, CDCl3): d = 2.32 (ddd, J1 = 15.9 Hz, J2 = 6.0 Hz,
J3 = 2.1 Hz, 1 H), 2.41 (ddd, J1 = 15.1 Hz, J2 = J3 = 6.3 Hz,
1 H), 2.51 (ddd, J1 = 15.8 Hz, J2 = J3 = 2.3 Hz, 1 H), 2.96–
2.98 (m, 1 H), 3.20 (dd, J1 = J2 = 8.7 Hz, 1 H), 3.51 (dd,
J1 = 8.8 Hz, J2 = 5.0 Hz, 1 H), 3.66 (s, 3 H), 4.10 (d, J = 6.8
Hz, 1 H), 4.50 (d, J = 12.2 Hz, 2 H), 4.55 (d, J = 12.2 Hz, 1
H), 5.50 (ddd, J1 = 3.8 Hz, J2 = J3 = 1.9 Hz, 1 H), 5.70 (dd,
J1 = 5.5 Hz, J2 = 2.3 Hz, 1 H), 7.25–7.35 (m, 5 H). 13C NMR
(100 MHz, CDCl3): d = 35.7 (CH2), 45.9 (CH), 48.8 (CH),
52.0 (CH3), 73.2 (CH2), 73.5 (CH2), 74.0 (CH), 127.7 (3 ×
CH), 128.4 (2 × CH), 130.1 (CH), 130.9 (CH), 137.6 (C),
174.4 (C). IR (in substance): 3445, 3060–2855, 1738 cm–1.
Anal. Calcd for C16H20O4: C, 69.5; H, 7.3. Found: C, 69.3;
H, 7.6. [a]D25 –58.9 (c 0.56, CHCl3).
(9) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505.
(10) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G.
Chem. Ber. 1959, 92, 2499. (b) Wadsworth, W. S.;
Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
(c) Paquet, F.; Sinay, P. J. Am. Chem. Soc. 1984, 106, 8313.
(d) Paquet, F.; Sinay, P. Tetrahedron Lett. 1984, 25, 3071.
(e) Pawlak, J. L.; Berchtold, G. A. J. Org. Chem. 1987, 52,
1765. (f) Lesuisse, D.; Berchtold, G. A. J. Org. Chem. 1988,
53, 4992.
(11) (a) Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem.
Soc. D 1970, 86. (b) Sharpless, K. B.; Young, M. W.; Lauer,
R. F. Tetrahedron Lett. 1973, 14, 1979. (c) Reich, H. J.;
Reich, I. L.; Renga, J. M. J. Am. Chem. Soc. 1973, 95, 5813.
(12) Preparative HPLC: Nu 50-7, 32 × 250 mm, heptane–EtOAc
(95:5), 20 mL/min, tR (E,Z)-5 = 25 min, tR (Z,Z)-5 = 22 min,
baseline separation with 100 mg/injection.
(13) Though the synthesis of 3-butenal has been reported in the
literature, the isomerization to crotonic aldehyde could not
be prevented. For the preparation of 3-butenal, see:
Synlett 2007, No. 11, 1683–1686 © Thieme Stuttgart · New York

1686
Q. Wang et al.
LETTER
(20) Hicks, D. R.; Fraser-Reid, B. Synthesis 1974, 203.
(21) (a) Huynh, C.; Derguini-Boumechal, F.; Linstrumelle, G.
Tetrahedron Lett. 1979, 20, 1503. (b) Cink, R. D.; Forsyth,
C. J. J. Org. Chem. 1995, 60, 8122.
3.41 (m, 2 H), 3.53 (dd, J1 = 9.3 Hz, J2 = 9.1 Hz, 1 H), 3.81
(dd, J1 = 9.1 Hz, J2 = 4.5 Hz, 1 H), 4.15 (OH, 1 H), 4.54 (d,
J = 12.1 Hz, 1 H), 4.62 (d, J = 12.1 Hz, 1 H), 7.26–7.29 (m,
5 H). 13C NMR (100 MHz, CDCl3): d = 9.2 (CH3), 28.0
(CH2), 32.4 (CH2), 44.7 (CH), 45.6 (CH), 55.6 (CH), 59.1
(CH), 71.5 (CH2), 73.5 (CH2), 75.8 (CH), 127.8 (3 × CH),
128.4 (2 × CH), 137.0 (C). IR (in substance): 3430, 3090–
2875, 1715 cm–1. Anal. Calcd for C16H22O2: C, 73.3; H, 8.5.
Found: C, 72.9; H, 8.6. [a]D25 –55.1 (c 0.55, CHCl3).
(23) The stereochemical result of the epoxidation may be
explained by assuming a favorable hydroxyl directed
(12Si,13Si)-attack of the peracid, see: (a) Hoveyda, A. H.;
Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307; and
literature cited therein. Alternatively and or additionally, the
(12Si,13Si)-approach of the peracid from the face opposite to
the benzyloxymethyl group on C11 should be favorable. For
recent peracid epoxidations of highly substituted
(22) Synthesis of 2
To a solution of the olefin 17 (79.6 mg, 0.32 mmol, 1 equiv)
in CH2Cl2 (12 mL) was added Na2HPO4 (137.7 mg, 0.97
mmol, 3 equiv) and MCPBA (77% purity, 108.7 mg, 0.49
mmol, 1.5 equiv) at 0 °C. The reaction mixture was then
stirred for 7 h at r.t. and subsequently quenched with sat. aq
Na2SO3 solution. The layers were separated and the aq phase
was extracted three times with CH2Cl2. The combined
organic phases were dried with MgSO4 and concentrated
under reduced pressure. Flash chromatography (hexane–
EtOAc, 20:1 to 10:1) afforded the epoxide 2 (56 mg, 0.21
mmol, 66%) and its diastereomer 18 (22 mg, 0.08 mmol,
26%). TLC (hexane–EtOAc, 2:1): Rf(18) = 0.41, Rf(2) =
0.31.
cyclopentenoids in the context of the total synthesis of
oxylipins, see for example: (b) Ghosh, S.; Sinha, S.; Drew,
M. G. B. Org. Lett. 2006, 8, 3781. (c) Miyaoka, H.; Hara,
Y.; Shinohara, I.; Kurokawa, T.; Yamada, Y. Tetrahedron
Lett. 2005, 46, 7945.
Compound 2: 1H NMR (400 MHz, CDCl3): d = 0.92 (dd,
J1 = J2 = 7.4 Hz, 3 H), 1.26 (ddq, J1 = 14.2, J2 = 7.3 Hz,
J3 = 7.1 Hz, 1 H), 1.41 (ddd, J1 = 13.9 Hz, J2 = 9.1 Hz,
J3 = 0.7 Hz, 1 H), 1.47–1.59 (m, 2 H), 2.12–2.19 (m, 2 H),
3.26 (ddd, J1 = 8.5 Hz, J2 = 8.3 Hz, J3 = 1.9 Hz, 1 H), 3.40–
Synlett 2007, No. 11, 1683–1686 © Thieme Stuttgart · New York

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