Stereoselective syntheses of rolliniastatin 1, rollimembrin, and membranacin

Article abstract of DOI:10.1021/ja0526867

A radical cyclization of β-alkoxyvinyl sulfoxides-Pummerer rearrangement-allylation protocol was successfully applied to the synthesis of the threol cis/threol cis/erythro bis-oxolane moiety in rolliniastatin 1 (1), rollimembrin (2), and membranacin (3).

Full text of DOI:10.1021/ja0526867

Published on Web 06/28/2005
Stereoselective Syntheses of Rolliniastatin 1, Rollimembrin,
and Membranacin
Gyochang Keum,†,‡ Cheol Hee Hwang,† Soon Bang Kang,‡ Youseung Kim,‡ and
Eun Lee*,†
Contribution from the Department of Chemistry, College of Natural Sciences, Seoul National
UniVersity NS60, Seoul 151-747, Korea, and Biochemicals Research Center, Korea Institute of
Science and Technology, Seoul 130-650, Korea
Received April 26, 2005; E-mail: eunlee@snu.ac.kr
Abstract: A radical cyclization of â-alkoxyvinyl sulfoxides-Pummerer rearrangement-allylation protocol
was successfully applied to the synthesis of the threo/cis/threo/cis/erythro bis-oxolane moiety in rolliniastatin
1 (1), rollimembrin (2), and membranacin (3).
Rolliniastatin 1 (1), rollimembrin (2), and membranacin (3)
are Annonaceous acetogenins isolated from the seeds of Rollinia
mucosa and Rollinia membranacea (Figure 1).1 Annonaceous
acetogenins are a large family of natural products that have been
described as potent in vitro inhibitors of the mitochondrial
respiratory chain complex I. Rolliniastatin 1 (1) (the murine
P388 lymphocytic leukemia test (PS), 28% life extension at 0.25
mg/kg, and ED50 4.5 × 10-5 µg/mL) and the more active
rollimembrin (2) and membranacin (3) belong to the most potent
subgroup featuring a dihydroxy bis-oxolane moiety with a threo/
cis/threo/cis/erythro relative configuration.2
Compared to other Annonaceous acetogenins which are
popular targets for total synthesis,3 there has been limited
Figure 1. Rolliniastatin 1, rollimembrin, and membranacin.
synthetic activities toward this important subgroup: synthesis
of 2 has not been reported yet, and we find in the literature
only one synthesis of 1 by Koert4 and a recent synthesis of 3.5
Radical cyclization reactions of â-alkoxyacrylates and â-alkox-
yvinyl ketones6 are now well-known to produce cis-2,5-
disubstituted oxolane and cis-2,6-disubstituted oxane rings.
Recently, double stereocontrol in the radical cyclization of
â-alkoxyvinyl sulfoxides was discussed in the preparation of
oxolane products,7 and we intended to examine the efficacy of
these reactions in a stereocontrolled synthesis of 1, 2, and 3.
† Seoul National University NS60.
‡ Korea Institute of Science and Technology.
(1) (a) Pettit, G. R.; Cragg, G. M.; Polonsky, J.; Herald, D. L.; Goswami, A.;
Smith, C. R.; Moretti, C.; Schmidt, J. M.; Weisleder, D. Can. J. Chem.
1987, 65, 1433-1435. (b) Saez, J.; Sahpaz, S.; Villaescusa, L.; Hoc-
quemiller, R.; Cave´, A.; Cortes, D. J. Nat. Prod. 1993, 56, 351-356. (c)
Gonza´lez, M. C.; Tormo, J. R.; Bermejo, A.; Zafra-Polo, M. C.; Estornell,
E.; Cortes, D. Bioorg. Med. Chem. Lett. 1997, 7, 1113-1118. (d) Bermejo,
A.; Figade`re, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes,
D. Nat. Prod. Rep. 2005, 22, 269-303. For introduction on Annonaceous
acetogenins in general, read the following reviews. (e) Alali, F. Q.; Liu,
X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504-540. (f) Rupprecht,
J. K.; Hui, Y.-H.; McLaughlin, J. L. J. Nat. Prod. 1990, 53, 237-278.
(2) For further studies on the bioactivity of rolliniastatin 1 and related
compounds, see: Royo, I.; DePedro, N.; Estornell, E.; Cortes, D.; Pela´ez,
F.; Tormo, J. R. Oncol. Res. 2003, 13, 521-528.
(4) Koert, U. Tetrahedron Lett. 1994, 35, 2517-2520.
(5) Head, G. D.; Whittingham, W. G.; Brown, R. C. D. Synlett 2004, 1437-
1439.
(3) For more recent examples of synthetic efforts, see: (a) Nattrass, G. L.;
D´ıez, E.; McLachlan, M. M.; Dixon, D. J.; Ley, S. V. Angew. Chem., Int.
Ed. 2005, 44, 580-584. (b) Zhang, Q.; Lu, H.; Richard, C.; Curran, D. P.
J. Am. Chem. Soc. 2004, 126, 36-37. (c) Crimmins, M. T.; She, J. J. Am.
Chem. Soc. 2004, 126, 12790-12791. (d) Han, H.; Sinha, M. K.; D’Souza,
L. J.; Keinan, E.; Sinha, S. C. Chem.sEur. J. 2004, 10, 2149-2158. (e)
Prestat, G.; Baylon, C.; Heck, M.-P.; Grasa, G. A.; Nolan, S. P.;
Mioskowski, C. J. Org. Chem. 2004, 69, 5770-5773. (f) Cecil, A. R. L.;
Hu, Y.; Vicent, M. J.; Duncan, R.; Brown, R. C. D. J. Org. Chem. 2004,
69, 3368-3374. (g) Zhu, L.; Mootoo, D. R. J. Org. Chem. 2004, 69, 3154-
3157. (h) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2004,
69, 1993-1998. (i) Strand, D.; Rein, T. Org. Lett. 2005, 7, 199-202. (j)
Makabe, H.; Hattori, Y.; Kimura, Y.; Konno, H.; Abe, M.; Miyoshi, H.;
Tanaka, A.; Oritani, T. Tetrahedron 2004, 60, 10651-10657. (k) Makabe,
H.; Miyawaki, A.; Takahashi, R.; Hattori, Y.; Konno, H.; Abe, M.; Miyoshi,
H. Tetrahedron Lett. 2004, 45, 973-977.
(6) For selected examples of stereoselective radical cyclization reactions of
â-alkoxyacrylates and â-alkoxyvinyl ketones in natural product syntheis,
see: (a) Kang, E. J.; Cho, E. J.; Lee, Y. E.; Ji, M. K.; Shin, D. M.; Chung,
Y. K.; Lee, E. J. Am. Chem. Soc. 2004, 126, 2680-2681. (b) Song, H. Y.;
Joo, J. M.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Kwak, H. S.; Park, J. H.;
Lee, E.; Hong, C. Y.; Jeong, S.; Jeon, K.; Park, J. H. J. Org. Chem. 2003,
68, 8080-8087. (c) Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.;
Lee, E. J. Am. Chem. Soc. 2002, 124, 14655-14662. (d) Lee, E.; Choi, S.
J.; Kim, H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son, S. H.; Lim, S. M.;
Jang, W. S. Angew. Chem., Int. Ed. 2002, 41, 176-178. (e) Lee, E.; Park,
C. M.; Yun, J. S. J. Am. Chem. Soc. 1995, 117, 8017-8018. For more
examples on oxacycle synthesis via radical cyclization, read the following
review. (f) Lee E. In Radicals in Organic Synthesis, Vol. 2: Applications;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; pp 303-
333.
(7) Keum, G.; Kang, S. B.; Kim, Y.; Lee, E. Org. Lett. 2004, 6, 1895-1897.
9
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J. AM. CHEM. SOC. 2005, 127, 10396-10399
10.1021/ja0526867 CCC: $30.25 © 2005 American Chemical Society

Rolliniastatin 1, Rollimembrin, and Membranacin
A R T I C L E S
Scheme 1. Retrosynthetic Analysis 1
Figure 2. Crystal structure of 9.
Scheme 2. Synthesis of Oxolane Intermediate 11
In retrosynthetic analysis, oxolanyl sulfoxide E was to be
prepared from (E)-â-alkoxyvinyl (S)-sulfoxide precursor F
(matched case)7 via stereoselective radical cyclization. Bis-
oxolane derivative C was envisaged to arise via a second
stereoselective radical cyclization of (E)-â-alkoxyvinyl (S)-
sulfoxide D (matched case), which may be obtained from
intermediate E. Homoallylic alcohol B prepared from C may
serve as a pivotal intermediate for 1 and 2 via cross metathesis
reaction with terminal olefin A (m ) 7 or 5) (Scheme 1).
Butane-1,4-diol (4) was monosilylated, and the corresponding
aldehyde was converted into an unsaturated ester via modified
Knoevenagel condensation8 with monomethyl malonate. Sharp-
less asymmetric dihydroxylation9 provided hydroxy lactone 5
(86% ee) in high yield. Lithium aluminum hydride reduction
of 5, benzylidene acetal formation, desilylation, and regiose-
lective tosylation led to secondary alcohol 6. Reaction of 6 with
ethynyl p-tolyl (S)-sulfoxide (7)10 in the presence of N-
methylmorpholine followed by iodide substitution resulted in
the formation of (E)-alkoxyvinyl (S)-sulfoxide 8, which was
purified by crystallization. When 8 was treated with tributyl-
stannane in the presence of triethylborane at -20 °C in toluene,
cis-2,5-disubstituted oxolanyl product 9 was obtained in 95%
yield (d.r. ) 88:1).11 A pure sample of 9 was obtained in 93%
yield after recrystallization, and the structure was confirmed
by X-ray crystallographic studies (Figure 2). Radical cyclization
of 8 in the presence of 1-ethylpiperidinium hypophosphite
(EPHP) and triethylborane in ethanol at room temperature12 also
proceeded efficiently to yield 9 (d.r. ) 26:1). Aldehyde 10 was
then obtained from sulfoxide 9 via Pummerer rearrangement
reaction13 and hydrolysis. When aldehyde 10 was allowed to
react with n-decylmagnesium bromide, a 2:1 mixture of products
was obtained favoring the erythro derivative 1114 (Scheme 2).
TBS-protection of the secondary hydroxyl group in 11,
benzylidene acetal deprotection, and regioselective tosylation
furnished tosylate 12. Treatment of 12 with ethynyl p-tolyl (S)-
sulfoxide (7) in the presence of N-methylmorpholine resulted
in the formation of (E)-alkoxyvinyl (S)-sulfoxide 13 in 54%
yield with 22% recovery of the starting material 12. The yield
of 13 did not improve under a variety of different conditions.
Iodide substitution of 13 and low temperature radical cyclization
proceeded smoothly to yield bis-oxolane product 14 efficiently.
Aldehyde 15 was prepared from sulfoxide 14 via Pummerer
rearrangement, and homoallylic alcohol 16 was obtained ste-
reoselectively from 15 via reaction with allyltributylstannane
in the presence of magnesium bromide etherate (Scheme 3).
The original scheme provided homoallylic alcohol 16 in a
stereoselective manner, but it was plagued by the low conversion
of 12 to 13 and the low selectivity in the conversion of 10 to
11. Realizing difficulty in overcoming the intrinsic steric
hindrance problems, it was decided to pursue an alternative route
to intermediate 16. Oxolanyl sulfoxide K was to be prepared
from (E)-â-alkoxyvinyl (R)-sulfoxide precursor L (matched
(8) (a) Yamanaka, H.; Yokoyama, M.; Sakamoto, T.; Shiraishi, T.; Sagi, M.;
Mizugaki, M. Heterocycles 1983, 20, 1541-1544. (b) Harcken, C.;
Bru¨ckner, R. New J. Chem. 2001, 25, 40-54.
(9) Torneiro, M.; Still, W. C. Tetrahedron 1997, 53, 8739-8750.
(10) Kosugi, H.; Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org. Chem.
1987, 52, 1078-1082.
(11) Use of ethynyl p-tolyl (R)-sulfoxide (19) in the present synthetic sequence
yielded the corresponding oxolanyl product in 98% yield, but the stereo-
selectivity was lower (mismatched, d.r. ) 16:1).
(13) Sugihara, H.; Tanikaga, R.; Kaji, A. Synthesis 1978, 881.
(14) The expected major product was the threo product via chelation model,
but the erythro product 11 was the major product in this case.
(12) Lee, E.; Han, H. O. Tetrahedron Lett. 2002, 43, 7295-7296.
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A R T I C L E S
Keum et al.
Scheme 3. Synthesis of Bis-Oxolane Intermediate 16
Scheme 5. Synthesis of Bis-Oxolane Intermediate 26
Scheme 4. Retrosynthetic Analysis 2
Oxidative cleavage of the double bond in 23 and reduction-
tosylation provided hydroxy tosylate 24, which was converted
into (E)-â-alkoxyvinyl (S)-sulfoxide 25 via reaction with 7 and
iodide substitution. Radical cyclization proceeded uneventfully
to yield bis-oxolane 26 in high yield (Scheme 5).
When aldehyde 27, which was obtained from 26 via Pum-
merer rearrangement reaction, was allowed to react with
n-decylmagnesium bromide, the major product was the threo
derivative. The epimeric mixture favoring (81:19) the erythro
derivative 2816 was obtained via Swern oxidation-L-Selectride
reduction sequence. TBS-protection, benzyl deprotection, and
Swern oxidation provided aldehyde 15 in good yield, from
which homoallylic alcohol 16 was prepared following the
established procedure. The crucial cross metathesis reaction of
16 was carried out in dichloromethane at 45 °C in the presence
of 4 equiv of terminal olefin 30 and 10 mol % of the first-
generation Grubbs catalyst 29: 79% yield of the cross metathesis
reaction product 31 was obtained after supplementary addition
of 10 mol % of the catalyst. Rolliniastatin 1 (1) was prepared
from 31 via diimide reduction of the double bond, oxidation-
elimination of the phenylthio group, and TBS-deprotection. Use
of an alternative terminal olefin 33 (4 equiv) in the cross
metathesis reaction of 16 in the presence of the second-
generation Grubbs catalyst 32 (10 mol %) led to the product
34 in 74% yield, which was converted to rollimembrin (2) via
the established three-step sequence (Scheme 6). Use of 1 equiv
of 33 led to 46% yield of 34 accompanied by 28% yield of the
homodimer of 16, and 57% of 34 and 19% of the homodimer
were obtained when 2 equiv of 33 was used.
case) via stereoselective radical cyclization. Bis-oxolane deriva-
tive H was envisaged to arise via a second stereoselective
radical cyclization of (E)-â-alkoxyvinyl (S)-sulfoxide I (matched
case), which may be obtained from homoallylic alcohol J
(Scheme 4).
Hydroxy tosylate 18 was prepared from D-malic acid (17)
via a known five-step sequence. Reaction of 18 with ethynyl
p-tolyl (R)-sulfoxide (19) in the presence of N-methylmorpholine
produced the corresponding (E)-â-alkoxyvinyl (R)-sulfoxide,
which was converted into iodide 20 via substitution reaction.
Radical cyclization of 20 proceeded stereoselectively (d.r. )
99:1) to give cis-2,5-disubstituted oxolane product 21. Aldehyde
22 which was obtained from 21 via Pummerer rearrangement
reacted with allyltributylstannane in the presence of magnesium
bromide etherate, and homoallylic alcohol 23 was obtained in
high stereoselectivity (>99:1).15
(15) Synthesis of ent-23 was reported in ref 7.
(16) Use of the intermediates 27 and 28 was reported in ref 4.
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10398 J. AM. CHEM. SOC. VOL. 127, NO. 29, 2005

Rolliniastatin 1, Rollimembrin, and Membranacin
A R T I C L E S
Scheme 6. Synthesis of Rolliniastatin 1 (1) and Rollimembrin (2)
Scheme 7. Synthesis of Butenolide Segments
Scheme 8. Synthesis of Membranacin (3)
Terminal olefin 3017 was prepared from phenylthiolactone
37, and iodide 36 derived from (R)-glycidyl tosylate (35)
(Scheme 7). A similar reaction sequence provided terminal olefin
33 from (R)-epichlorohydrin (38).18
For synthesis of membranacin (3), terminal olefin 41 was
prepared from 37 and bromide 40 (Scheme 8). A cross olefin
metathesis reaction of 16 and 41 provided intermediate 42,
which was converted into membranacin (3) via the three-step
sequence.
In this synthesis, a radical cyclization of â-alkoxyvinyl
sulfoxides-Pummerer rearrangement-allylation protocol was
successfully applied to the synthesis of the threo/cis/threo/cis/
erythro dihydroxy bis-oxolane moiety in 1, 2, and 3. Expeditious
synthesis was achieved via an allylation-olefin cross metathesis
protocol for coupling two major fragments. The modular
approach employed in the present synthesis is selective and
efficient and can easily be adapted to analogue synthesis.
Acknowledgment. This work was supported by a grant from
MarineBio21, Ministry of Maritime Affairs and Fisheries, Korea,
and a grant from the Center for Bioactive Molecular Hybrids
(Yonsei University) and KOSEF. A Brain Korea 21 graduate
fellowship grant to C.H.H. is gratefully acknowledged.
Supporting Information Available: Experimental procedures
(34 pages, print/PDF), 1H and 13C NMR spectra of the
compounds (38 pages, print/PDF), and X-ray crystallographic
structure of 9 (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) For preparation of a lower homologue of 30, see: Avedissian, H.; Sinha,
S. C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org.
Chem. 2000, 65, 6035-6051.
(18) For a reported use of 37 and 38 for similar purposes, see: Schaus, S. E.;
Brånalt, J.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 4876-4877.
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