Total synthesis and complete assignment of the stereostructure of a cytotoxic bromotriterpene polyether (+)-aurilol

Article abstract of DOI:10.1021/ja050123p

The plane structure and partial stereochemistry of a cytotoxic bromotriterpene polyether (+)-aurilol (1), isolated from the sea hare Dolabella auricularia, were mainly elucidated by NMR methods; however, determination of the entire stereochemistry has not been reached. Although there have also been many other types of triterpene polyethers, it is often difficult to determine their stereostructures even by the current highly advanced spectroscopic methods, especially in acyclic systems including quaternary carbon centers such as C10-C11, C14-C15, and C18-C19 in 1. In this paper, we report that the total assignment of the incomplete stereostructure of (+)-aurilol (1) to the structural formula 2 has been accomplished through its first asymmetric total synthesis featuring the highly regio- and stereocontrolled biogenetic-like A-D ether ring formations. Copyright

Full text of DOI:10.1021/ja050123p

Published on Web 04/02/2005
Total Synthesis and Complete Assignment of the Stereostructure of a
Cytotoxic Bromotriterpene Polyether (+)-Aurilol
Yoshiki Morimoto,* Yoshihiro Nishikawa, and Mamoru Takaishi
Department of Chemistry, Graduate School of Science, Osaka City UniVersity,
Sumiyoshi-ku, Osaka 558-8585, Japan
Received January 8, 2005; E-mail: morimoto@sci.osaka-cu.ac.jp
Chart 1. Structures of Aurilol
A bromotriterpene polyether aurilol (1) was isolated from the
sea hare, Dolabella auricularia, by Yamada et al. in 1998 and
exhibited cytotoxicity against HeLa S3 cells with IC50 of 4.3 µg/
mL (Chart 1).1 Although the plane structure and partial stereo-
chemistry of 1 were elucidated by spectroscopic and chemical
analyses, determination of the entire stereochemistry has not been
reached. There have also been many other types of triterpene
polyethers (oxasqualenoids);2 however, it is often difficult to
determine their stereostructures even by the current highly advanced
spectroscopic methods, especially in acyclic systems including
quaternary carbon centers such as C10-C11, C14-C15, and C18-
C19 in 1. In such cases, it is effective to predict and synthesize the
possible stereoisomers.3 1 also possesses a synthetically challenging
2,8-dioxabicyclo[5.4.0]undecane A,B ring system with a bromine
atom at the neopentylic position and 1,3-diaxial dimethyl substit-
uents on the B ring. These contexts have made oxasqualenoids,
including bromotriterpene polyethers,4 attractive targets for many
synthetic organic chemists.3 In this paper, we report that the total
assignment of the incomplete stereostructure of (+)-aurilol (1) to
2 has been achieved through its first asymmetric total synthesis
featuring biogenetic-like regioselective ether ring formations to
secure the stereochemical pathway.
In the course of our structural studies on oxasqualenoids, which
could biogenetically be derived by epoxide-opening cyclizations
of squalene polyepoxides,3b,4b we predicted the unknown stereo-
chemistry to be erythro configuration as shown in 2. In the
retrosynthetic analysis of 2, we planned to straightforwardly
construct all of the A-D ether rings by biogenetic-like cyclizations.
The oxepane A ring would be constructed by 7-endo-trig5 bromo-
etherification of the corresponding trishomoallylic alcohol, and the
B-D rings would be formed by 6-endo-tet, 5-exo-tet, and 5-exo-
tet5 epoxide openings of the corresponding bishomoepoxy alcohols,
respectively (vide infra).
The synthesis of target molecule 2 began with SEM protection
of the hydroxy group in the known optically active epoxy alcohol
3 (98% ee)6 (Scheme 1). Selective deprotection of the TBDMS
ether in 4 and Sharpless’ epoxidation7 of the allylic alcohol 5 using
L-(+)-DET afforded diepoxide 6. The C ring formation from 6
under the alkaline condition stereoselectively proceeded via a
regioselective 5-exo-tet epoxide opening of the intermediate A to
provide triol 7 in 88% yield.8 The following sequence, (1)
mesylation; (2) epoxidation; (3) chain extension with the C10 unit
8;9 and (4) desulfurization,3b uneventfully yielded diol 9 from 7.
Shi’s epoxidation of 9 catalyzed by chiral ketone 1010 diastereo-
selectively gave labile bishomoepoxy alcohol 11. Treatment of 11
with a protic acid underwent a regioselective 5-exo-tet cyclization
to produce diol 12 in 98% yield.11
of the SEM ether in 12 afforded triol 13, from which diene 15 was
derived by the same sequence as that of 7 to 9 except for employing
sulfide 14.12 Shi’s epoxidation of the diene 15 with ent-10,10
enantiomeric to 10, proceeded in a regioselective manner to provide
monoepoxide 16 with the terminal alkene intact. The construction
of the desired B ring was regioselectively carried out by treating
the bishomoepoxy alcohol 16 with TIPSOTf and 2,6-lutidine in
CH3NO2 at 0 °C for 20 min. The unprecedented 6-endo-tet
cyclization promoted by a silyl triflate against Baldwin’s rule5 would
be very stimulating14 because Brønsted acid-catalyzed cyclizations
for these types of bishomoepoxy alcohols, such as 11, generally
afford 5-exo-tet regioselectivity, regardless of the relative configura-
tions of the tertiary alcohol-epoxide substrates.11
After removal of the TIPS group in 17, cross metathesis of
olefin 18 with 2-methyl-2-butene using Grubbs’ catalyst 1915
produced alkene 20 in 90% yield.16 After many attempted experi-
mentations,17 it has been found that (CF3)2CHOH with high polarity
and non-nucleophilicity18 is the solvent of choice to successfully
form the A ring. The regio- and stereoselective 7-endo-trig
bromoetherification of 20 was brought about under the optimal
condition to give the A,B-ring system 21,19 wherein removal of
the acetonide, finally furnished the target molecule 2. The spectral
characteristics (1H and 13C NMR) of the synthetic 2, [R]19 +4.5
D
(c 0.21, CHCl3), were identical to those reported for the natural
product, [R]30D +4.6 (c 0.41, CHCl3).1 Thus, it has been found that
the hitherto unknown relative configuration of (+)-aurilol (1) is
erythro as indicated in 2.
In conclusion, we have accomplished the first asymmetric
total synthesis of a cytotoxic bromotriterpene polyether (+)-aurilol
(4.74% overall yield in 21 steps from 3) featuring the highly
regio- and stereocontrolled biogenetic-like A-D ether ring for-
mations. The total synthesis has realized the total assignment of
the incomplete stereostructure of aurilol (1), which is difficult
to determine the stereochemistry otherwise. Application of this
synthetic strategy to other bromotriterpene polyethers is in
progress.
With the highly stereocontrolled 12 in hand, we embarked on
the elaboration of the formidable A,B-ring system. Deprotection
9
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J. AM. CHEM. SOC. 2005, 127, 5806-5807
10.1021/ja050123p CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Total Synthesis of Target Molecule 2a
a Reaction conditions: (a) SEMCl, i-Pr2NEt, CH2Cl2, 0 °C to room temperature, 12 h, 99%; (b) Bu4NF, THF, 0 °C, 1 h, 100%; (c) t-BuO2H, Ti(Oi-Pr)4,
L-(+)-DET, MS 4A, CH2Cl2, -25 °C, 16 h (>20:1); (d) 1 M aq NaOH, 1,4-dioxane, reflux, 5 h; (e) MsCl, Py, CH2Cl2, 0 °C to room temperature, 1 h; (f)
K2CO3, MeOH, rt, 15 min; (g) 8, BuLi, TMEDA, THF, -78 °C, 1 h; (h) Na, i-PrOH, THF, reflux, 4 h; (i) 10, Oxone, (MeO)2CH2/CH3CN/H2O, pH 10.5,
0 °C, 2 h (>15:1); (j) CSA, CH2Cl2, rt, 10 min; (k) Bu4NF, THF, reflux, 30 h, 92%; (l) 14, BuLi, TMEDA, THF, -78 °C, 1 h; (m) ent-10, Oxone,
(MeO)2CH2/CH3CN/H2O, pH 10.5, 0 °C, 2 h (>10:1); (n) TIPSOTf, 2,6-lutidine, CH3NO2, 0 °C, 20 min; (o) Bu4NF, THF, 0 °C to room temperature, 15
h, 100%; (p) 19, 2-methyl-2-butene, reflux, 12 h; (q) 2.5 equiv of NBS, MS 4A, (CF3)2CHOH, 0 °C, 10 min (>10:1); (r) 80% aq AcOH, rt, 14 h.
0 °C, 15 h, 80% (98% ee); (2) Me2C(OMe)2, CSA, CH2Cl2, 0 °C, 2 h,
Acknowledgment. This research was financially supported by
97%; (3) K2CO3, MeOH, rt, 4 h, 98%; (4) (PhS)2, Bu3P, THF, rt, 4 h,
96%.
the Novartis Foundation (Japan) for the Promotion of Science.
(10) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc.
Supporting Information Available: Characterization data for 2-7,
9, 11-13, 15-18, 20, and 21, and experimental procedures for synthesis
of 2 (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
1997, 119, 11224-11235.
(11) For many similar examples implementing 5-exo-tet cyclizations, see: (a)
Hanessian, S.; Cooke, N. G.; DeHoff, B.; Sakito, Y. J. Am. Chem. Soc.
1990, 112, 5276-5290. (b) Hashimoto, M.; Harigaya, H.; Yanagiya, M.;
Shirahama, H. J. Org. Chem. 1991, 56, 2299-2311. (c) Ujihara, K.;
Shirahama, H. Tetrahedron Lett. 1996, 37, 2039-2042. (d) Towne, T.
B.; McDonald, F. E. J. Am. Chem. Soc. 1997, 119, 6022-6028. (e)
Morimoto, Y.; Iwai, T.; Yoshimura, T.; Kinoshita, T. Bioorg. Med. Chem.
Lett. 1998, 8, 2005-2010. (f) Xiong, Z.; Corey, E. J. J. Am. Chem. Soc.
2000, 122, 4831-4832.
(12) The sulfide 14 was prepared from the known (E)-6-acetoxy-4-methyl-4-
hexenal (ref 13) by the following sequence: (1) Ph3PdCH2, 0 °C, 1 h,
99%; (2) K2CO3, MeOH, rt, 30 min, 95%; (3) (PhS)2, Bu3P, THF, rt, 4 h,
93%.
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