Enantioselective formal synthesis of eurylene: Synthesis of the cis - And trans -THF fragments using oxidative cyclization

Article abstract of DOI:10.1021/ol100513y

A formal synthesis of eurylene is described, where both cis- and trans-THF-containing fragments were prepared using diastereo- and chemoselective permanganate-mediated oxidative monocyclizations of trienes.

Full text of DOI:10.1021/ol100513y

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2468-2471
Enantioselective Formal Synthesis of
Eurylene: Synthesis of the cis- and
trans-THF Fragments Using Oxidative
Cyclization
Nadeem S. Sheikh,† Carole J. Bataille,† Tim J. Luker,‡ and
Richard C. D. Brown*,†
The School of Chemistry, The UniVersity of Southampton, Highfield, Southampton
SO17 1BJ, United Kingdom, and AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough LE11 5RH, United Kingdom
rcb1@soton.ac.uk
Received March 2, 2010
ABSTRACT
A formal synthesis of eurylene is described, where both cis- and trans-THF-containing fragments were prepared using diastereo- and
chemoselective permanganate-mediated oxidative monocyclizations of trienes.
Eurylene (1) is a squalenoid natural product isolated from the
wood of the tropical Asian shrub Eurycoma longifolia, with
reported cytotoxicity against lymphocytic leukemia.1 Structural
and partial stereochemical assignments of eurylene were
established through analysis of MS and NMR data. Ultimately,
X-ray crystallography combined with the analysis of C11 and
C14 Mosher ester derivatives allowed the assignment of the
relative and absolute stereochemistry to be completed. Thus, it
was determined that eurylene contains two nonadjacently linked
2,5-bis-hydroxyalkyltetrahydrofuran (THF diol) systems, with
a combined total of eight stereogenic centers. The left segment
(C1-C12) contains an acylated trans-THF diol, whereas the
other acylated THF diol has the cis configuration. To date, three
total syntheses of eurylene have been reported.2,3
Metal-oxo-mediated oxidative cyclization reactions of
1,5-dienes permit direct stereocontrolled entry into cis-2,5-
(2) For total syntheses of eurylene (1), see: (a) Ujihara, K.; Shirahama,
H. Tetrahedron Lett. 1996, 37, 2039–2042. (b) Morimoto, Y.; Muragaki,
K.; Iwai, T.; Morishita, Y.; Kinoshita, T. Angew. Chem., Int. Ed. 2000, 39,
4082–4084. (c) Hioki, H.; Yoshio, S.; Motosue, M.; Oshita, Y.; Nakamura,
Y.; Mishima, D.; Fukuyama, Y.; Kodama, M.; Ueda, K.; Katsu, T. Org.
Lett. 2004, 6, 961–964. Synthetic studies: (d) Gurjar, M. K.; Saha, U. K.
† University of Southampton.
‡ AstraZeneca.
(1) Itokawa, H.; Kishi, E.; Morita, H.; Takeya, K.; Iitaka, Y. Tetrahedron
Lett. 1991, 32, 1803–1804.
Tetrahedron Lett. 1993, 34, 1833–1836
.
10.1021/ol100513y  2010 American Chemical Society
Published on Web 05/11/2010

disubstituted THF diol fragments found in numerous natural
products including Annonaceous acetogenins and polyethers
such as eurylene (1).4-6 However, trans-THF diol subunits
are also present in many of these natural products, and
eurylene contains both cis- and trans-THF diol motifs.
Although trans-selective oxidative cyclizations of hydroxy-
alkenes are known,8 a stereoselective method for trans-
selective oxidative cyclization of 1,5-dienes is lacking,8
leading us to consider a stereospecific method to prepare
trans-THF diols from cis-THF diols.9 Herein we describe a
formal synthesis of eurylene, where stereo- and chemose-
lective oxidative monocyclizations of trienes are used to
generate the cis- and trans-THF fragments, retaining the
electron-rich C2-C3 and C22-C23 trisubstituted alkenes.
Retrosynthetic analysis of eurylene followed a central discon-
nection to identify two major THF fragments 2 and 5 (Scheme
1), which could be manipulated to intersect with fragments 3
and 4 employed in Kodama’s published route2c or serve to
explore alternative coupling methodologies. We have reported
selective oxidative monocyclizations of trienes and dienynes
by exploiting the higher reactivity of permanganate ion toward
electron-deficient alkenes and shown how the resulting partially
oxidized products can be applied in the synthesis of Annona-
ceous acetogenins by further oxidative transformations.10 In the
present case, permanganate-mediated oxidative cyclizations of
the trienes 6 and 7 would create both THF diol systems, while
retaining the C2-C3 and C22-C23 trisubstituted alkenes
present in the target. However, for this approach to succeed,
Scheme 1. Retrosynthetic Analysis of Eurylene (1)
we needed to adapt the formally “cis-selective” permanganate
oxidative cyclization to allow access to the trans-THF system
(C6-C11) found in eurylene.
The trieneoate 9, containing the C13-C24 framework of
eurylene, was synthesized by adaptation of reported proce-
dures (Scheme 2).11 Hydrolysis of methyl ester 9, activation
(3) For selected syntheses of structurally related oxasqualenoids gla-
brescol, intricatetrol, and teurilene, see: (a) Morimoto, Y.; Iwai, T.;
Kinoshita, T. J. Am. Chem. Soc. 2000, 122, 7124–7125. (b) Xiong, Z. M.;
Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9328–9329. (c) Morimoto, Y.
Org. Biomol. Chem. 2008, 6, 1709–1719. (d) Morimoto, Y.; Okita, T.;
Takaishi, M.; Tanaka, T. Angew. Chem., Int. Ed. 2007, 46, 1132–1135. (e)
Hashimoto, M.; Harigaya, H.; Yanagiya, M.; Shirahama, H. J. Org. Chem.
1991, 56, 2299–2311. (f) Morimoto, Y.; Iwai, T.; Kinoshita, T. J. Am. Chem.
Scheme 2. Synthesis of the C13-C24 Portion of Eurylene
Soc. 1999, 121, 6792–6797
(4) For a review of diene oxidative cyclizations mediated by metal-oxo
species, see: Piccialli, V. Synthesis 2007, 2585–2607
.
.
(5) For some additional examples of oxidative cyclization of 1,5-dienes
to give cis-THF diols: MnO4-: (a) Walba, D. M.; Przybyla, C. A.; Walker,
C. B. J. Am. Chem. Soc. 1990, 112, 5624–5625. (b) Kocienski, P. J.; Brown,
R. C. D.; Pommier, A.; Procter, M.; Schmidt, B. J. Chem. Soc., Perkin
Trans. 1 1998, 9–39. (c) Cecil, A. R. L.; Hu, Y. L.; Vicent, M. J.; Duncan,
R.; Brown, R. C. D. J. Org. Chem. 2004, 69, 3368–3374. OsO4: (d) de
Champdore, M.; Lasalvia, M.; Piccialli, V. Tetrahedron Lett. 1998, 39,
9781–9784. (e) Donohoe, T. J.; Butterworth, S. Angew. Chem., Int. Ed.
2003, 42, 948–951. RuO4: (f) Lygo, B.; Slack, D.; Wilson, C. Tetrahedron
Lett. 2005, 46, 6629–6632. (g) Goksel, H.; Stark, C. B. W. Org. Lett. 2006,
8, 3433–3436
.
(6) For a selection of reviews concerning the synthesis of THFs: (a)
Jalce, G.; Franck, X.; Figadere, B. Tetrahedron: Asymmetry 2009, 20, 2537–
2581. (b) Wolfe, J. P.; Hay, M. B. Tetrahedron 2007, 63, 261–290. (c)
Harmange, J.-C.; Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711–
1754. (d) Boivin, T. L. B. Tetrahedron 1987, 43, 3309–3362
.
(7) For some examples of trans-selective oxidative cyclizations of
hydroxyalkenes by rhenium oxide, see ref 2b and: (a) Kennedy, R. M.;
Tang, S. Tetrahedron Lett. 1992, 33, 3729–3732. (b) Towne, T. B.;
McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022–6028. (c) Keinan, E.;
Sinha, S. C. Pure Appl. Chem. 2002, 74, 93–105
.
(8) Ruthenium-catalyzed oxidative cyclization of 1,5-dienes affords racemic
trans-2,5-disubstituted THF diols as minor products under certain reaction
conditions (along with the major cis-isomer): (a) Carlsen, P. H. J.; Katsuki,
T.; Martin, V. S.; Sharpless, K. B. J. Org. Chem. 1981, 46, 3936–3938. (b)
Piccialli, V.; Cavallo, N. Tetrahedron Lett. 2001, 42, 4695–4699. (c)
Albarella, L.; Musumeci, D.; Sica, D. Eur. J. Org. Chem. 2001, 997–1003.
(9) For an example of the conversion of a cis-THF diol oxidative
cyclization product to an hydroxyalkyl substituted trans-THF, see: Donohoe,
T. J.; Harris, R. M.; Williams, O.; Hargaden, G. C.; Burrows, J.; Parker, J.
J. Am. Chem. Soc. 2009, 131, 12854–12861.
Org. Lett., Vol. 12, No. 11, 2010
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of the resulting acid, and coupling with the (2S)-camphor
sultam afforded trienoyl sultam 7 in good yield ready for
the selective oxidative cyclization. We were delighted to
realize the key oxidative monocyclization of triene 7, which
delivered the desired THF diol 10 as the main isolated
product. The diastereoisomeric THF diols 10 and 11 were
separated by column chromatography to provide the major
and minor isomers in 51% and 8% isolated yields, respec-
tively. The overoxidized product 12, obtained here as a minor
component, is the major product when excess permanganate
is employed.11a Finally, borohydride reduction of the acyl-
sultam 10 afforded the triol 13, an intermediate used in the
Kodama synthesis. Spectroscopic and analytical data for 13
were consistent with those reported by Kodama.2c
but in only 25% yield. However, we were strongly encour-
aged by the observation that the parent methyl trienoate 16
gave the racemic monocyclization product 17 in excellent
yield under similar reaction conditions. These contrasting
results suggested that the bulk of the camphor sultam was
either retarding the rate of oxidation of the enoyl alkene or
impeding the subsequent cyclization reaction of the manga-
nese diester intermediate.15 Thus, in the absence of a
relatively rapid oxidative cyclization, a complex mixture of
triene oxidation products prevailed.
A number of alternative auxiliaries were investigated, the best
of which proved to be bulky cyclohexyl ester system (+)-trans-
2-(R-cumyl)cyclohexanol ((+)-TCC, Scheme 4).16,17 Oxidation
The C1-C11 fragment containing the trans-THF system
required a structurally distinct trienoic acid precursor, the
synthesis of which commenced by alkylation of methallyl
alcohol dianion with neryl chloride (14, Scheme 3).12 A two-
Scheme 4. Synthesis of the C1-C11 Fragment
Scheme 3
.
Synthesis and Oxidative Mono-cyclizations of
Trienes 16 and 6a
step MnO2-mediated oxidation of the allylic alcohol 15
secured the trienoate 16,13 which reacted directly with the
(2R)-camphor sultam in the presence of AlMe3 to give the
oxidative cyclization precursor 6a.14 Unfortunately, our initial
oxidative cyclization experiments gave mixed results; the
desired product 18 was isolated as a single diastereoisomer
(10) (a) Morris, C. L.; Hu, Y. L.; Head, G. D.; Brown, L. J.;
Whittingham, W. G.; Brown, R. C. D. J. Org. Chem. 2009, 74, 981–988.
(b) Hu, Y. L.; Brown, R. C. D. Chem. Commun. 2005, 5636–5637.
(11) (a) Brown, R. C. D.; Bataille, C. J.; Hughes, R. M.; Kenney, A.;
Luker, T. J. J. Org. Chem. 2002, 67, 8079–8085. (b) Brown, R. C. D.;
Hughes, R. M.; Keily, J.; Kenney, A. Chem. Commun. 2000, 1735–1736.
(c) Sum, F. W.; Weiler, L. Can. J. Chem. 1979, 57, 1431–1441.
(12) (a) Trost, B. M.; Dominic, M. T.; Chan, D. M. T.; Nanninga, T. N.
Org. Synth. 1984, 62, 58–66. (b) Masjedizadeh, M. R.; Dannecker-Doerig,
I.; Little, R. D. J. Org. Chem. 1990, 55, 2742–2752.
of the 8-phenylmenthol analogue 6b ultimately afforded the
desired oxidative cyclization products in 78% yield, as a
mixture of diastereoisomers (dr ) 6.7:1) that was not
separable by column chromatography on silica gel. However,
protection of the THF diol products as their bis-TMS ethers
19 and 20 rendered the diastereoismers chromatographically
separable.
2470
Org. Lett., Vol. 12, No. 11, 2010

Convertion of the protected cis-THF diol 19 to the trans-
THF motif present in eurylene was achieved through
deoxygenation at C27. Selective deprotection of the primary
silyl ether and subsequent reaction of the resulting primary
alcohol with thiocarbonyldiimidazole gave radical deoxy-
genation precursor 21. While inconsistent results were
obtained for the deoxygenation of the imidazole thioate 21
mediated by Bu3SnH, the use of (Me3Si)3SiH (TTMSS)
yielded the desired product 2b in 83% yield.18,19 We note
that ester 2b is an analogue of Kodama’s left-hand fragment
3, which has the potential to be used directly in fragment
coupling. However, in order to intersect with Kodama’s
route, thereby confirming the stereochemistry of the oxidative
cyclization product, the ester 2b was reduced using DIBALH
to afford the aldehyde 22. The formal synthesis was
completed by cleavage of the TMS protection from aldehyde
22 to secure the Kodama intermediate 23. Physical and
spectroscopic data for 23 were in agreement with those
reported by Kodama, thereby confiming the identity of the
major stereoisomer from the oxidative cyclization.
Figure 1. Model for the diastereoselective oxidative cyclization of
trieneoate 6b.
In summary, a formal synthesis of eurylene has been
achieved where both cis- and trans-THF fragments were
prepared using diastereo- and chemoselective oxidative
monocyclizations of trienes. To the best of our knowledge,
this is the first reported case of the application of perman-
ganate-mediated oxidative cyclization to the synthesis of a
trans-THF.
The sense of diastereofacial preference observed in the
oxidative cyclization is consistent with approach of the reacting
permanganate ion from the front (Re) face of the s-cis enoate
conformer (Figure 1).
(13) Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem. Soc. 1968,
90, 5616–5617.
(14) Oppolzer, W.; Kingma, A. J. HelV. Chim. Acta 1989, 72, 1337–
1345.
Acknowledgment. We thank AstraZeneca and the Uni-
versity of Southampton for studentship funding (C.J.B. and
N.S.S.), and The Royal Society for a University Research
Fellowship (R.C.D.B.).
(15) For mechanistic discussions, see: (a) Poethig, A.; Strassner, T.
Collect. Czech. Chem. Commun. 2007, 72, 715–727. (b) Wolfe, S.; Ingold,
C. F. J. Am. Chem. Soc. 1981, 103, 940–941. (c) Walba, D. M.; Wand,
M. D.; Wilkes, M. C. J. Am. Chem. Soc. 1979, 101, 4396–4397. (d) Baldwin,
J. E.; Crossley, M. J.; Lehtonen, E. M. M. J. Chem. Soc., Chem. Commun.
1979, 918–920.
Supporting Information Available: Experimental pro-
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1
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and 13C NMR spectra for all new compounds. This material
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