Transannular O -heterocyclization: A useful tool for the total synthesis of Murisolin and 16,19- cis -Murisolin

Article abstract of DOI:10.1021/ol302820c

Transannular O-heterocyclization is applied as a key step in a total synthesis. This highly stereoselective and metal-free transformation introduces four stereocenters in one step. It was chosen to be the pivotal step in the synthesis of Murisolin and 16,19-cis-Murisolin, two annonaceous acetogenins. The efficiency of this synthesis is further illustrated by a stereodivergent late-stage separation of both synthetic routes.

Full text of DOI:10.1021/ol302820c

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5628–5631
Transannular O‑Heterocyclization:
A Useful Tool for the Total Synthesis
of Murisolin and 16,19-cis-Murisolin
Peter Persich, Julia Kerschbaumer, Sandra Helling, Barbara Hildmann,
€
Birgit Wibbeling, and Gunter Haufe*
€
€
€
Westfalische Wilhelms-Universitat Munster, Organisch-Chemisches Institut,
Corrensstrasse 40, D-48149 Mu€nster, Germany
haufe@uni-muenster.de
Received August 22, 2012
ABSTRACT
Transannular O-heterocyclization is applied as a key step in a total synthesis. This highly stereoselective and metal-free transformation
introduces four stereocenters in one step. It was chosen to be the pivotal step in the synthesis of Murisolin and 16,19-cis-Murisolin, two
annonaceous acetogenins. The efficiency of this synthesis is further illustrated by a stereodivergent late-stage separation of both synthetic
routes.
Annonaceous acetogenins (ACGs) belong to a class of
polyketide natural products whose structural diversity and
manifold biological activity have drawn scientific attention
since their discovery in 1982.1,2 Special interest is attracted
by the conspicuously highcytotoxicity of these compounds
which rivals that of taxol.3 Thus, ACGs might serve as
lead structures for potential drugs in e.g. cancer therapy.
Inhibition of the mitochondrial NADH dehydrogenase
complex I is thought to be the specific mode of action.4
Recentresultsshow thattheefficiencyofCa2þ chelation by
ACGs correlates with their cytotoxicity.5 Typically, their
structure consists of an unbranched C32 or C34 chain with a
terminal γ-lactone ring. Different oxygen-containing func-
tional groups are located along the carbon chain, such as
epoxides, ketones, and especially hydroxyl-flanked THF
motifs. Both moieties are active pharmacophores.4,5
Up to now, more than 500 ACGs were isolated from
Annonaceae;6 in many cases a different relative and abso-
lute configuration is the only distinction. This unique
structural diversity reveals the challenges in the synthesis
of these compounds despite their apparent simple struc-
ture. A high versatility and elegance for the introduc-
tion of stereocenters and for the connection of different
functional structure elements along the carbon chain is
desirable.
(1) Jolad, S. D.; Hoffmann, J. J.; Schram, K. H.; Cole, J. R.;
Tempesta, M. S.; Kriek, G. R.; Bates, R. B. J. Org. Chem. 1982, 47, 3151.
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Chem. 2008, 4, No. 48. (c) Bermejo, A.; Figadere, B.; Zafra-Polo, M.-C.;
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K. F.; Lee, K.-H. J. Med. Chem. 2003, 46, 3185.
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For the synthesis of the central hydroxyalkyl-flanked
THF moiety, different strategies have been developed. These
€
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J. Biol. Chem. 1999, 274, 2625. (c) Miyoshi, H. J. Bioenerg. Biomembr.
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Hocquemiller, R. ChemBioChem 2005, 6, 979. (c) Liu, H.-X.; Huang,
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r
10.1021/ol302820c
Published on Web 11/08/2012
2012 American Chemical Society

include enantioselective dihydroxylation7 or epoxidation and
adjacent epoxide opening/THF closing sequences,8 RuO4-
catalyzed oxidative cyclizations of 1,5-dienes,9 exploitation
of the chiral pool,10 the use of chiral auxiliaries,11 asymmetric
alkynylations,12 cyclizing iodoetherifications13 and oxymer-
curations14 of unsaturated alcohols, or the application of
stereoselective stannylation chemistry,15 among others.
Encouraged by our former work on different transan-
nular O-heterocyclizations16 we have chosen this type of
reaction as the pivotal step for the synthesis of Murisolin
(1)17 and its stereoisomer 16,19-cis-Murisolin (2).18 We
identified these two compounds as exemplary targets
for the development of a novel Lego-like building block
strategy and promising approach toward the total synthe-
sis of ACGs.19
best of our knowledge, it is the first application of a
transannular O-heterocyclization in total synthesis.
Scheme 1. Retrosynthetic Analysis of Murisolin (1) and
16,19-cis-Murisolin (2)
Retrosynthetically, an alkene cross-metathesis was des-
tined for the introduction of the terminal butenolide frag-
ment, whereas precursors 3 and 4 should be available from
the common intermediate 5 by stereoselective dihydrox-
ylation and cyclization. Connected to this is the late stage
separation of both synthetic routes, which minimizes the
total number of transformations. 5 was supposed to be
obtained by a Wittig reaction after BaeyerꢀVilliger oxida-
tion of bicyclic ketones 6a,b. These are accessible as a
mixture from the products of a transannular O-heterocy-
clization of cycloocta-1,5-diene (7)16dꢀf (Scheme 1). To the
In the first step, inexpensive 7 and 40% peracetic acid
were used for a highly stereoselective metal-free formal
introduction of four stereocenters. Diols 8a,b were ob-
tained as an inseparable 45:55 mixture in 92% yield.16dꢀf,20
Kinetic resolution or desymmetrization, respectively, gave
a 62:38 mixture of acetates 9a (96% ee) and 9b (76% ee)
(1H NMR of Mosher esters) by using lipase from Candida
rugosa (Scheme 2).
(7) (a) Yu, Q.; Wu, Y.; Ding, H.; Wu, Y.-L. J. Chem. Soc., Perkin
Trans. 1 1999, 1183. (b) Marshall, J. A.; Sabatini, J. J. Org. Lett. 2006, 8,
3557.
(8) (a) Hoye, T. R.; Ye, Z. J. Am. Chem. Soc. 1996, 118, 1801 and
references cited therein. (b) Makabe, H.; Tanimoto, H.; Tanaka, A.;
Oritani, T. Heterocycles 1996, 43, 2229. (c) Prestat, G.; Baylon, C.; Heck,
M.-P.; Grasa, G. A.; Nolan, S. P.; Mioskowski, C. J. Org. Chem. 2004,
69, 5770. (d) Narayan, R. S.; Borhan, B. J. Org. Chem. 2006, 71, 1416.
€
(9) (a) Goksel, H.; Stark, C. B. Org. Lett. 2006, 8, 3433. (b) Cheng, H.;
Stark, C. B. W. Angew. Chem., Int. Ed. 2010, 49, 1587.
(10) (a) Hanessian, S.; Grillo, T. A. J. Org. Chem. 1998, 63, 1049. (b)
Hu, T.-S.; Yu, Q.; Wu, Y.-L. J. Org. Chem. 2001, 66, 853.
(11) Cecil, A. L. R.; Hu, Y.; Vicent, M. J.; Duncan, R.; Brown,
R. C. D. J. Org. Chem. 2004, 69, 3368.
Scheme 2. Synthesis and Oxidative Ring Opening of Bicyclic
Precursors
(12) Maezaki, N.; Tominaga, H.; Kojima, N.; Yanai, M.; Urabe, D.;
Ueki, R.; Tanaka, T.; Yamori, T. Chem.;Eur. J. 2005, 11, 6237.
(13) Fujioka, H.; Maehata, R.; Wakamatsu, S.; Nakahara, K.;
Hayashi, T.; Oki, T. Org. Lett. 2012, 14, 1054.
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Mohapatra, S. Eur. J. Org. Chem. 2010, 6263.
(15) Marshall, J. A.; Jiang, H. Tetrahedron Lett. 1998, 39, 1493.
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Chem. 1978, 109, 575. (b) Haufe, G. Tetrahedron Lett. 1984, 25, 4365. (c)
Haufe, G.; Alvernhe, G.; Anker, D.; Laurent, A. J. Fluorine Chem. 1990,
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46, 83. (d) Hegemann, K.; Schimanski, H.; Howeler, U.; Haufe, G.
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Tetrahedron Lett. 2003, 44, 2225. (e) Hegemann, K.; Frohlich, R.; Haufe,
G. Eur. J. Org. Chem. 2004, 2181. (f) Behr, S.; Hegemann, K.; Schimanski,
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H.; Frohlich, R.; Haufe, G. Eur. J. Org. Chem. 2004, 3884.
(17) For syntheses of Murisolin, see: (a) Quinn, K. J.; Islamaj, L.;
Couvertier, S. M.; Shanley, K. E.; MacKinson, B. L. Eur. J. Org. Chem.
2010, 5943. (b) Hattori, Y.; Kimura, Y.; Moroda, A.; Konno, H.; Abe,
M.; Miyoshi, H.; Goto, T.; Makabe, H. Chem.;Asian J. 2006, 1, 894. (c)
Zhang, q.; Lu, H.; Richard, C.; Curran, D. P. J. Am. Chem. Soc. 2004,
126, 36and ref (12). Isolation:(d)Myint, S. H.;Laurens, A.;Hocquemiller,
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R.; Cave, A.; Davoust, D.; Cortes, D. Heterocycles 1990, 31, 861.
(18) For syntheses of 16,19-cis-Murisolin, see: (a) Curran, D. P.;
Zhang, Q. S.; Richard, C.; Lu, H. J.; Gudipati, V.; Wilcox, C. S. J. Am.
Chem. Soc. 2006, 128, 9561. (b) Curran, D. P.; Zhang, Q. S.; Lu, H. J.;
Gudipati, V. J. Am. Chem. Soc. 2006, 128, 9943. and refs (12), (17b, 17c).
Isolation: Woo, M. H.; Zeng, L.; Ye, Q.; Gu, Z. M.; Zhao, G. X.;
McLaughlin, J. L. Bioorg. Med. Chem. Lett. 1995, 5, 1135.
(19) Presented (in part) at the 235th ACS National Meeting, New
Orleans, April 6ꢀ10, 2008, Kerschbaumer, J.; Helling, S.; Haufe, G.
Abstracts of papers, 509-ORGAN.
(20) See also: (a) Lafont, P.; Vivant, G. French Pat. 1336187 (1963),
Chem. Abstr. 1963, 60, 2803. (b) Frazer, A. H. U.S. Pat. 3347826 (1967),
Chem. Abstr. 1968, 68, P2819. (c) Cope, A. C.; Fisher, B. S.; Funke, W.;
McIntosh, J. M.; McKervey, M. A. J. Org. Chem. 1969, 34, 2231. (d)
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Org. Lett., Vol. 14, No. 22, 2012
5629

After protecting group operations, the protected diols
10a,b were transferred into the bicyclic ketones 11a,b by in
situ deprotection and Jones oxidation. BaeyerꢀVilliger
oxidation of 11a,b leads convergently to just one single
γ-lactone 12 via lactol intermediate A. In a previous work
we revealed that intermediates of type B rearranged to
type A without loss of optical purity.16b Here, the formerly
applied reagents TFA and sodium percarbonate16f caused
additional oxidation of the benzyl group and hydrolysis of
the formed benzoyl group, whereas the milder acetic acid/
percarbonate system left the ketone moiety untouched.
Finally, formic acid and oxone were found as an appropriate
oxidizing system to obtain the desired carboxylic acid 12.
Chemoselective reductionof12 and Swern oxidation of the
formed alcohol gave aldehyde 13 as a precursor for the
following Wittig reaction to receive the Z-alkene 14 contami-
nated with 4% of the E-isomer. The following cis-dihydrox-
ylation and subsequent formation of cyclic sulfates 16a,b was
followed by the separation of the diastereomers by simple
column chromatography and hence splitting of the synthetic
routes toward Murisolin and 16,19-cis-Murisolin (Scheme 3).
Benzyl deprotection led to spontaneous cyclization and
formation of the central THF core for both natural products.
Final hydrolysis of the sulfates with 20% H2SO4 furnished
the key intermediates 17 and 18 in 67% and 83%, respec-
tively, over these three steps. Both compounds were received
with each 92% ee and the required threo-cis-threo and threo-
trans-threo relative configuration, which was confirmed by
NOE-NMR experiments21 and X-ray analysis (Figure 1).22
Figure 1. X-ray structure of compound 18.
To complete the synthesis of 1 and 2, the lactones 17 and
18 were transferred to alkenes 19 and 21 in a one-pot
DIBAL reduction and a subsequent Wittig reaction. In the
first attempt the methyl Wittig reagent was used and
terminal alkenes were obtained instead of internal alkenes
19 and 21. Unfortunately, the terminal alkenes under
went a double-bond isomerization catalyzed by 24 to form
2-alkenes resulting in a partial chain shortening during the
following cross-metathesis step with the known butenolide
bearing alkene 23.23 Therefore, the expected products 20
and 22 were isolated together with their analogues shor-
tened by one CH2 group as inseparable mixtures. The use of
internal alkenes 19 and 21 and 1,4-benzoquinone as an
additive for the metathesis24 nicely solved this problem. De-
spite this optimization, the metathesis steps remained erratic
yielding 71% or 37% of the product (Scheme 4). After final
diimide reduction25 of the internal double bond both natu-
ral products Murisolin (1) and 16,19-cis-Murisolin (2) were
obtained. For both compounds NMR and mass spectra as
well as analytical data were in agreement with those reported.26
Scheme 3. Stereodivergent Separation of the Routes towards the
Key Intermediates 17 and 18
Scheme 4. Final Steps towards Murisolin (1) and
16,19-cis-Murisolin (2)a
(21) The relative configuration of diastereomers 17 and 18 was
assigned by NOE NMR measurements, and the enantiomeric excess
was determined by chiral HPLC (see Supporting Information):
In summary, a transannular O-heterocyclization was
applied for the selective construction of stereocenters in a
5630
Org. Lett., Vol. 14, No. 22, 2012

total synthesis for the first time. By means of this key step
a synthetic access to ACGs was developed. In 18 steps
Murisolin (1) and 16,19-cis-Murisolin (2) were prepared
exemplarily in 1.6% or 0.2% overall yields. Especially key
compounds 17 and 18 are useful for the synthesis of similar
ACGs. A late stage splitting of both synthetic routes
depicts another special feature of this synthesis. Because
transannular O-heterocyclization seems to be superior to
the stepwise introduction of single stereocenters, studies
toward the synthesis of other ACGs and more complex
target molecules are ongoing. The exploitation of such a
facile and inexpensive tool in future syntheses might be an
option to metal-mediated operations.
(22) X-ray crystal structure analysis for 18: formula C21H38O4, M =
˚
3
354.51, colorless crystal 0.80 ꢁ 0.10 ꢁ 0.03 mm , a = 5.2688(2) A, b =
3
˚
˚
˚
7.4978(5) A, c = 52.7860(20) A, V = 2085.28(18) A , Fcalc = 1.129 g
cmꢀ3, μ = 0.600 cmꢀ1, empirical absorption correction (0.645 e T e
0.982), Z = 4, orthorhombic, space group P212121 (No. 19), λ = 1.54178
˚
Acknowledgment. This research was supported by the
Deutsche Forschungsgemeinschaft (DFG, Ha-2145/3-1).
J.K. is grateful to the NRW International Graduate
School of Chemistry for a stipend.
A, T = 223 K, ω and j scans, 28 582 reflections collected ((h, (k, (l),
[(sin θ)/λ] = 0.60 Aꢀ1, 3345 independent (Rint = 0.058) and 3345
˚
observed reflections [I g 2σ(I)], 228 refined parameters, R = 0.037,
2
wR = 0.105, max. residual electron density 0.12 (ꢀ0.14) e Aꢀ3, Flack
˚
parameter ꢀ0.1(2), hydrogens calculated and refined as riding atoms.
CCDC 905530 contains the supplementary crystallographic data for
compound 18. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information Available. Experimental pro-
cedures, analytical and spectral data, determination of
enantiomeric excesses, and copies of the NMR spectra of
all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(23) Avedissian, H.; Sinha, S. C.; Yazbak, A.; Sinha, A.; Neogi, P.;
Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65, 6035.
(24) Hong, S. H.; Sanders, D. P.; Lee, C. W.; Grubbs, R. H. J. Am.
Chem. Soc. 2005, 127, 17160.
(25) Hart, D. J.; Hong, W. P.; Hsu, L. Y. J. Org. Chem. 1987, 52,
4665.
(26) For a detailed comparison, see Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
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