Total synthesis of eupomatilones 4 and 6: Structurally rearranged and atropisomerically fluxional lignan natural products

Article abstract of DOI:10.1021/ol048333e

(Chemical Equation Presented) A convergent and diastereocontrolled total synthesis of eupomatilones 4 and 6 is reported and was based on a diastereoselective hydroboration/ oxidation sequence and a convergent Lipshutz biarylcuprate cross-coupling reaction. The structure of eupomatilone 6 is revised.

Full text of DOI:10.1021/ol048333e

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4025-4028
Total Synthesis of Eupomatilones 4 and
6: Structurally Rearranged and
Atropisomerically Fluxional Lignan
Natural Products
Robert S. Coleman* and Srinivas Reddy Gurrala
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
coleman@chemistry.ohio-state.edu
Received August 20, 2004
ABSTRACT
A convergent and diastereocontrolled total synthesis of eupomatilones 4 and 6 is reported and was based on a diastereoselective hydroboration/
oxidation sequence and a convergent Lipshutz biarylcuprate cross-coupling reaction. The structure of eupomatilone 6 is revised.
The structurally novel lignans eupomatilones 1-7 were
isolated in 1991 by Carroll and Taylor from the indigenous
Scheme 1
Australian shrub Eupomatia bennettii, co-occurring with a
structurally diverse set of related lignan natural products.1
The normally dimeric â-cinnamic acid carbon skeleton has
undergone an unprecedented rearrangement that involves
cleavage of a carbon-aryl bond. As proposed by Carroll
and Taylor,2 the spirocyclohexadienone skeleton of eupodi-
enone precursor 1 undergoes hemiketal formation to afford
2, which fragments to lactone 3 (Scheme 1). All six carbons
of the side chains of the cinnamic acid precursors end up
attached to just one of the aromatic rings. The eupomatilones
equilibrate about the biaryl axis, which is stereogenic for
eupomatilones 6 and 7. This rotation is slow on the NMR
1
There have been two reports of synthetic approaches to
eupomatilone 6.3,4 In this paper, we report the total synthesis
of eupomatilones 4 and 6 and correct the structure of
eupomatilone 6 (Figure 1).
time scale, and two isomers are observed by both H and
13C NMR for eupomatilones 6 and 7. The hydrogens on the
trimethoxyphenyl ring of eupomatilone 4 are diastereotopic.
The atropdiastereomers are inseparable, and the coalescence
temperature was found to be 97-102 °C.2
(3) (a) Hutchison, J. M.; Hong, S.-p.; McIntosh, M. C. J. Org. Chem.
2004, 69, 4185. (b) Hong, S.-p.; McIntosh, M. C. Org. Lett. 2002, 4, 19.
(4) Gurjar, M. K.; Cherian, J.; Ramana, C. V. Org. Lett. 2004, 6,
317.
(1) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1615.
(2) Carroll, A. R.; Taylor, W. C. Aust. J. Chem. 1991, 44, 1705.
10.1021/ol048333e CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

Figure 1. Reported structures of the eupomatilones.
These agents share a fluxional biaryl axis and a γ-lactone
bearing two or three stereogenic carbons. A synthetic strategy
was developed (Scheme 2) that was based on a Lipshutz
occurred regioselectively6 to afford the o-bromoaldehyde 11,
which was methylated (Me2SO4, K2CO3, acetone, 56 °C) to
afford 8.
Construction of the eupomatilone side chain (Scheme 4)
relied on addition of (E)-2-methyl-2-buten-1-ylmagnesium
bromide to aldehyde 8 (THF, -78 °C, 1.5 h), which provided
Scheme 2
Scheme 4
a 1:1 mixture of syn and anti adducts 12 in 95% yield. The
undesired anti adduct was converted to the desired syn adduct
by Mitsunobu inversion with p-nitrobenzoic acid7 (Ph3P,
DIAD, THF, 0-25 °C) and hydrolysis (K2CO3, MeOH, 25
°C), which resulted in an overall yield for conversion of 8
to 12 of 73%. Alternatively, 12 could be produced as a 95:5
syn/anti mixture in 92% yield8 by addition of the analogous
indium reagent9 to aldehyde 8. The alcohol of 12 was
protected as the tert-butyldimethylsilyl ether (t-BuMe2SiOTf,
2,6-lutidine, CH2Cl2, -78 °C, 20 min) to afford 13.
We implemented the methodology of Lipshutz for biaryl
coupling,10 which involves low temperature formation of a
mixed biarylcuprate and oxidation of this species to form
the carbon-carbon biaryl bond. This reaction is less sensitive
to steric or electronic features of the aromatic systems
oxidative biarylcuprate cross-coupling of 6 with 7 and a
subsequent diastereocontrolled hydroboration/oxidation se-
quence on the alkene of 5. Starting from commercially
available 7, readily constructed 8, and (E)-1-bromo-2-methyl-
2-butene (9), these natural products were synthesized in an
efficient and stereocontrolled manner.
Aldehyde 8 was synthesized from 5-hydroxypiperonal
(10)5 (Scheme 3). Bromination (NBS, dioxane, 15 °C)
(5) Jacob, P., III; Shulgin, A. T. Synth. Commun. 1981, 11, 969.
(6) (a) Fujisaki, S.; Eguchi, H.; Omura, A.; Okamoto, A.; Nishida, A.
Bull. Chem. Soc. Jpn. 1993, 66, 1576. (b) Pearson, D. E.; Wysong, R. D.;
Breder, C. V. J. Org. Chem. 1967, 32, 2358.
Scheme 3
(7) (a) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59,
234. (b) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(8) Coleman, R. S.; Raao, A. M. Unpublished observations.
(9) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831.
(10) (a) Lipshutz, B. H.; Siegmann, K.; Garcia, E. J. Am. Chem. Soc.
1991, 113, 8161. (b) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser, F.
J. Am. Chem. Soc. 1993, 115, 9276. (c) Lipshutz, B. H.; Kayser, F.; Maullin,
N. Tetrahedron Lett. 1994, 35, 815. (d) Lipshutz, B. H.; Liu, Z.-P.; Kayser,
F. Tetrahedron Lett. 1994, 35, 5567.
4026
Org. Lett., Vol. 6, No. 22, 2004

compared to palladium-mediated processes. We have em-
ployed this reaction in a stereocontrolled synthesis of the
natural products calphostin A and phleichrome.11
In the present case (Scheme 5), aryl bromide 13 was
converted to the aryllithium reagent 14 (t-BuLi, MeTHF, -78
matilone 4 in 92% yield for the two-step sequence. Eupo-
matilone 4 was synthesized in eight steps from known 7 and
10 in 33% overall yield. The 1H NMR spectrum of synthetic
eupomatilone 4 was identical with that reported for the
natural product.2
The origin of the diastereoselection in the hydroboration
of 17 is detailed in Scheme 7. In the lowest energy
Scheme 5
Scheme 7
conformation (MM3) about the sp2-sp3 bond, the allylic
hydrogen is eclipsed with the alkene in order to minimize
A1,3 strain. The least sterically congested approach by 9-BBN
is from the side of the allylic methyl group, giving a new
stereogenic center wherein the methyl groups are anti. This
model has precedent in several related contexts.13
Total synthesis of eupomatilone 6 proceeded from aryl
bromides 1914 and commercially available 22 (Scheme 8).
°C), and subsequently to the lower order cyanocuprate 15
(CuCN, MeTHF, -40 °C). Aryl bromide 7 was similarly
converted to aryllithium 16 (t-BuLi, MeTHF, -78 °C), which
was added to cyanocuprate 15 (-125 °C, 30 min) to form a
biarylcuprate species. Treatment with oxygen (-125 °C, 3
h) affected conversion to the biaryl system 17 in modest
yield.
Scheme 8
Hydroboration of 17 (9-BBN, THF, 0-25 °C, 12 h)
followed by oxidation (NaOH, H2O2, 0-25 °C, 3 h) afforded
primary alcohol 18 in essentially quantitative yield, with
complete control of diastereoselectivity (Scheme 6). Depro-
Scheme 6
Cuprate coupling of the corresponding aryllithium reagents
20 and 23 under previously described conditions afforded
biphenyl 24. Following reaction conditions used in the total
(12) (a) Einhorn, J.; Einhorn, C.; Ratajczak, F.; Pierre, J. L. J. Org. Chem.
1996, 61, 7452. (b) Kamal, A.; Sandbhor, M.; Shaik, A. A. Tetrahedron:
Asymmetry 2003, 14, 1575,
tection of the silyl ether of 18 (n-Bu4NF, THF, 25 °C, 3 h)
and oxidation of the primary alcohol (TEMPO, NCS, n-Bu4-
NI, CH2Cl2/1:1 0.05 M K2CO3/0.5 M NaHCO3, 25 °C, 1
h)12 was accompanied by lactonization and afforded eupo-
(13) (a) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1994, 629. (b) Coutts, L. D.; Cywin, C. L.; Kallmerten, J. Synlett 1993,
696. (c) Bernsmann, H.; Fro¨lich, R.; Metz, P. Tetrahedron Lett. 2000, 41,
4347. (d) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tetrahedron
2002, 58, 1983. (e) Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129.
(14) Prepared from 2-bromo-3,4,5-trimethoxybenzaldehyde (cf. Molan-
der, G. A.; George, K. M.; Monovich, L. G. J. Org. Chem. 2003, 68, 9533)
as described for the preparation of 13.
(11) Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1994, 116, 8795.
Coleman, R. S.; Grant, E. B. J. Am. Chem. Soc. 1995, 117, 10889.
Org. Lett., Vol. 6, No. 22, 2004
4027

synthesis of eupomatilone 4, hydroboration/oxidation of the
alkene of 24 afforded the corresponding primary alcohol
(42% for two steps). Fluoride-mediated desilylation and
selective oxidation of the primary alcohol afforded γ-lactone
McIntosh and co-workers,3 whose reported synthesis of 5-epi-
eupomatilone 6 should now be regarded as a synthesis of
3,5-bis-epi-eupomatilone 6 (29).
1
25, supposedly eupomatilone 6. However, the H NMR
Scheme 10
spectrum of synthetic 25 did not match the data published
for eupomatilone 6,2 differing slightly in the chemical shifts
of and coupling constants between C3-H and C4-H. Our
spectral data matched that obtained by Gurjar and co-
workers4 in their synthesis of this putative structure of
eupomatilone 6.
We had inadvertently synthesized the correct structure of
eupomatilone 6 during studies on the oxidation/lactone
formation sequence (Scheme 9). Oxidation of alcohol 26 with
Scheme 9
Attempts to alter the diastereoselectivity of the hydro-
boration of 24 using rhodium catalysis15 were unproductive,
producing a 4:3 mixture of diastereomers 30 and 31 (Scheme
11). Although a stereocontrolled route from 24 to 31, and
Scheme 11
thence to eupomatilones 3 and 6, has not been achieved, this
is beyond the intended scope of this work. The total synthesis
of eupomatilone 6 has been achieved by a serendipitous route
involving base-induced epimerization.
pyridinium dichromate (CH2Cl2, 25 °C, 3 h, 85%) afforded
the corresponding aldehyde, which cyclized to lactol 27 after
fluoride-mediated deprotection of the silyl ether (THF, 25
°C, 6 h). Compound 27 was produced as a mixture of
diastereomers, presumably from epimerization of the inter-
mediate aldehyde under basic reaction conditions. Lactol to
lactone oxidation (CH2Cl2, 25 °C, 2 h, 90%) afforded a 1:3
mixture of 25 and its epimer 28, which could be separateds
with difficultysby preparative TLC. The 1H NMR spectrum
of pure 28 proved identical with that published for eupoma-
tilone 6.2
Acknowledgment. This work was supported by a grant
from the National Cancer Institute (R01 CA 91904).
Supporting Information Available: Experimental pro-
cedures and spectral characterization of intermediates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL048333E
Our synthesis of 25 (Scheme 8) produced 3-epi-eupoma-
tilone 6, whereas the structure of the natural product must
possess a trans relationship of the C3 and C4 methyl groups,
as in 28 (Scheme 10). This result changes the work of
(15) (a) Burgess, K.; Cassidy, J.; Ohlmeyer, M. J. J. Org. Chem. 1991,
56, 1020. (b) Burgess, K.; van der Donk, W. A.; Westcott, S. A.; Marder,
T. B.; Baker, R. T.; Calabrese, J. C. J. Am. Chem. Soc. 1992, 114, 9350.
(c) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042. (d) Evans,
D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1988, 110, 6917.
4028
Org. Lett., Vol. 6, No. 22, 2004