Asymmetric total synthesis of trilobacin via organoselenium-mediated oxonium ion formation/SiO2-Promoted fragmentation

Article abstract of DOI:10.1021/ja106116v

An asymmetric total synthesis of trilobacin (1), an annonaceous acetogenin with potent anticancer activities, was accomplished wherein the construction of its erythro-bis(2,2′)-tetrahydrofuran core 2 featured a novel organoselenium-mediated oxonium ion formation/SiO₂-promoted fragmentation of α,α′-cis-oxocene 3.

Full text of DOI:10.1021/ja106116v

Published on Web 08/11/2010
Asymmetric Total Synthesis of Trilobacin via Organoselenium-Mediated
Oxonium Ion Formation/SiO2-Promoted Fragmentation
Te-ik Sohn, Mi Jung Kim, and Deukjoon Kim*
College of Pharmacy, Seoul National UniVersity, Seoul 151-742, Korea
Received July 10, 2010; E-mail: deukjoon@snu.ac.kr
Scheme 1. Retrosynthetic Plan
Abstract: An asymmetric total synthesis of trilobacin (1), an an-
nonaceous acetogenin with potent anticancer activities, was ac-
complished wherein the construction of its erythro-bis(2,2′)-tetrahy-
drofuran core 2 featured a novel organoselenium-mediated oxonium
ion formation/SiO2-promoted fragmentation of R,R′-cis-oxocene 3.
Trilobacin (1), the first known member of adjacent bis-tetrahy-
drofuran (THF) annonaceous acetogenins with a threo, trans,
erythro, cis, threo backbone, was isolated from Asmina triloba by
McLaughlin and co-workers in 1992.1 The impressive potency of
the annonaceous acetogenin against human solid-tumor cell lines,
coupled with the fascinating structure and limited availability, has
attracted considerable attention from the synthetic community.2,3
In this communication we report an asymmetric total synthesis of
trilobacin featuring a novel organoselenium-mediated oxonium ion
formation/SiO2-promoted fragmentation process for the construction
of its erythro-bis(2,2′)-THF core.
As shown in Scheme 1, our strategy focuses on the elaboration
of erythro-bis(2,2′)-THF fragment 2, and the requisite butenolide
chain would be incorporated using an existing method such as olefin
12 with Felkin-Ahn selectivity and subsequent protection of the
cross-metathesis (CM) at the indicated position to achieve the target
trilobacin (1).4 We were intrigued by the possibility that key
resulting alcohol 13 as a benzyl ether gave rise to oxocene 3 (81%, 2
steps, 15R/15S ) 34:1). This 13-step synthesis is quite efficient, and
adjacent bis-THF intermediate 2 could in turn be constructed from
we have used it to generate multigram quantities of key intermediate
3.
R,R′-cis-oxocene 3 by a novel organoselenium-mediated oxonium
ion formation/SiO2-promoted fragmentation (Vide infra). Further-
more, we were confident from previous experience5 that the
We next proceeded to address the construction of the crucial
bis(2,2′)-THF core in 2, which constitutes the keystone of our synthesis.
After some experimentation, we were delighted to find that treatment
of γ,δ-unsaturated PMB-ether 3 with PhSeCl (activated SiO213/K2CO3/
CH2Cl2/rt/24 h) produced the desired erythro-bis(2,2′)-THF 2 in 83%
yield in a stereo-, regio-, and chemoselective fashion, without the need
for prior deprotection of the PMB group.14 Upon exposure to PhSeCl,
R,R′-cis-oxocene 3 would generate dioxatricyclic oxonium ion A by
our organoselenium-based protocol, which consists of phenylseleno-
etherification and activation of the phenylselenyl group with a second
equivalent of reagent, followed by transannular ring closure as depicted
in the Scheme 3.15 A priori, nucleophilic attack by chloride at C(22),
C(19), or C(16) in oxonium ion A could produce the desired bis(2,2′)-
THF 2, 2,8-dioxabicyclo[5.2.1]decane B, or 2,5-dioxabicyclo[2.2.1]-
heptane C, respectively. The major kinetic product chloro ether B16
is in equilibrium with oxonium ion A, which undergoes SiO2-promoted
fragmentation17 to provide the desired bis(2,2′)-THF 2.18 Interestingly,
the precursor that would give rise to a derivative of oxonium ion A
that is unsubstituted at C(16) produced a 2,5-dioxabicyclo[2.2.1]heptane
related to C as the major product.
requisite oxocene substrate 3 could be synthesized from undecanal
(4) and glycolate oxazolidinone 5.
To commence the synthesis, Evans syn-aldol reaction6 of oxazoli-
dinone 5 with undecanal (4) furnished syn-aldol product 6 with the
requisite C(23)/C(24) relative stereochemistry in 74% yield (Scheme
2). Reductive cleavage of the chiral auxiliary in 6 with NaBH4 and
subsequent regioselective DIBAL-H reduction of benzylidene acetal
7, derived from the resultant 1,3-diol, afforded primary alcohol 8 (70%;
3 steps). Alcohol 8 was then smoothly transformed into R-alkoxy amide
9 in good overall yield (85%) by a three-step sequence: (1) DMSO
oxidation, (2) chelation-controlled nucleophilic addition of allyltribu-
tylstannane,7 (3) O-alkylation with N-(chloroacetyl) morpholine. Alky-
lation of 9 by successive treatment with LiHMDS and 3-butenol triflate
then furnished homoallylated product 10 as a 1.4:1 mixture of anti
and syn isomers (85%).8 We reasoned that the desired oxymethine
stereochemistry at C(16) could be secured subsequently due to the
greater stability of the incipient R,R′-cis-oxocene vs the corresponding
trans isomer.5a,9 Ring-closing metathesis (RCM)10 of diene 10 with
the first-generation Grubbs’ Ru catalyst, followed by application of
our direct ketone synthesis protocol11 to the resultant R-alkoxy
morpholine amide 11 with 5-benzyloxypentylmagnesium bromide,
yielded the desired R,R′-cis-oxocene ketone 12 in excellent overall
yield (88%, 3 steps, R,R′-cis/trans ) 17:1) after epimerization5a,9 with
aqueous KOH. Finally, L-Selectride reduction11a,12 of R-alkoxy ketone
With the requisite C(10)-C(34) segment in hand, global depro-
tection of 2 with concurrent removal of the chlorine using Raney-
Ni gave triol 14 in 92% yield (Scheme 4). Chemoselective
transformation of the primary hydroxyl group in 14 into terminal
alkene 15 by Grieco’s protocol19 (88%) set the stage for the end
9
12226 J. AM. CHEM. SOC. 2010, 132, 12226–12227
10.1021/ja106116v  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Synthesis of Key Oxocene Intermediate 3a
Scheme 4. Completion of the Synthesisa
a Reagents and conditions: (a) Raney-Ni, EtOH, reflux, 2 h, 92%; (b)
(i) o-NO2-PhSeCN, n-Oct3P, THF, rt, 30 min, (ii) 30% H2O2, THF, rt,
48 h, 88%; (c) (Cy3P)2Cl2Ru)CHPh, CH2Cl2, reflux, 6 h, then DMSO, rt,
15 h, 73% (86% BRSM); (d) TsNHNH2, NaOAc, DME, reflux, 6 h, 91%.
potential of our novel organoselenium-mediated oxonium ion
formation/SiO2-promoted fragmentation protocol to generate this
hitherto unattainable adjacent bis-THF moiety with high selectivity.
Acknowledgment. This work was supported by the NRF grant
funded by the MEST, Korea (No. 20100001710) and RIPS.
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) n-Bu2BOTf, Et3N, CH2Cl2, -78 to 0 °C,
2 h, 74%; (b) NaBH4, THF/H2O (3:1), rt, 1 h, 85%; (c) PhCH(OCH3)2, PPTS,
CH2Cl2, rt, 12 h, 90%; (d) DIBAL-H, CH2Cl2, -78 °C to rt, 3 h, 92%; (e)
SO3 ·pyridine, Et3N, CH2Cl2/DMSO (4:1), 0 °C to rt, 1.5 h; (f) allyltributyltin,
MgBr2 ·Et2O, CH2Cl2, -78 °C to rt, 2 h 86% (2 steps), syn only; (g)
ClCH2CON(CH2CH2)2O, NaH, DMF, 0 °C to rt, 2 h, 99%; (h) LiHMDS,
CH2dCHCH2CH2OTf, THF, -78 °C to rt, 15 min, 85% (88% BRSM), anti/
syn ) 1.4:1; (i) (Cy3P)2Cl2Ru)CHPh, CH2Cl2, reflux, 2 h, then DMSO, rt,
15 h, 95%; (j) BnO(CH2)5MgBr, THF, rt, 1.5 h, 97%; (k) 13 M KOH, THF/
MeOH (3:2), rt, 3 h, 95%, cis/trans ) 17:1; (l) L-Selectride, THF, -78 °C, 30
min, 86%, 15R/15S ) 34:1; (m) Bn-Br, NaH, DMF, rt, 2 h, 94%.
References
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a Reagents and conditions: (a) PhSeCl, SiO2, K2CO3, CH2Cl2, rt, 24 h, 83%.
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game to deliver the natural product. Cross-metathesis of alkene 15
with known butenolide D4b followed by a chemoselective diimide
reduction20 led to trilobacin (1), the spectral and optical rotation
data for which were in good agreement with those reported for the
natural material.
In conclusion, we have accomplished an asymmetric total
synthesis of trilobacin (1), an annonaceous acetogenin with potent
anticancer activity, in 18 steps and 14% overall yield from readily
available starting materials 4 and 5. Our synthesis illustrates the
(18) A referee suggested that C could also be formed reversibly due to
neighboring group oxonium ion activation of the C(16) Cl substituent by
the adjacent benzyloxy ether.
(19) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
(20) A small amount (∼5%) of the over-reduced product was formed.
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