The total synthesis of the annonaceous acetogenin 10-hydroxyasimicin

Article abstract of DOI:10.1002/anie.200462264

Orthogonal and modular templating is an effective basis for the preparation of the biologically active annonaceous acetogenin 10-hydroxyasimicin (1). The versatile tartrate-derived 2,3-butanediacetal building block together with a highly diastereoselectiv

Full text of DOI:10.1002/anie.200462264

Communications
Natural Products Synthesis
The Total Synthesis of the Annonaceous
Acetogenin 10-Hydroxyasimicin**
Gillian L. Nattrass, Elena Dꢀez,
Matthew M. McLachlan, Darren J. Dixon, and
Steven V. Ley*
tether that could temporarily link two BDA-protected
alkenol building blocks 2 (BDA = 2,3-butanediacetal) of, in
principle, any desired stereochemical arrangement.[12] The
tether could then induce stereocontrol during the critical ring-
closing metathesis (RCM) to give compound 3.[13] Subsequent
Sharpless asymmetric dihydroxylation and chemoselective
cleavage of the tether would afford 4.[14] Intramolecular
displacement by the unmasked hydroxy groups of the
desymmetrized bistosylate 4 would yield the bis-THF unit 5.
Late-stage Sonogashira coupling of the terminal alkyne 6 and
the butenolide 7 (constructed through a hetero-Diels–Alder
(HDA) reaction to install the 1,5-stereochemical relationship
and mask the butenolide double bond simultaneously, as
reported in our synthesis of muricatetrocin C)[10] would
The annonaceous acetogenins comprise a class of almost 400
natural products that exhibit a remarkably broad spectrum of
biological activity. They function as insecticides, fungicides,
herbicides, and, perhaps most importantly, in vivo antitumor
agents and have been shown to overcome resistance in
multidrug-resistant tumors.[1] Structurally, the acetogenins are
characterized by a long lipophilic tail, a central polyoxy-
genated core, and a terminal a,b-unsaturated g-lactone. The
structural diversity in this family arises principally from
variations in the stereochemistry and connectivity of the
polyoxygenated central core, which can consist of one or more
tetrahydrofuranyl (THF) rings or, occasionally, a tetra-
hydropyranyl (THP) ring with various patterns of
hydroxylation. These variations and the stereochemical
consequences give rise to an impressive molecular
diversity within the family. Owing to their biological
activity and limited availability from natural sources,
these compounds have attracted worldwide attention
and have become the targets for total synthesis for a
number of research groups,[2–9] including our own.[10]
The majority of publications to date have focused on
the synthesis of individual members of the family that
suit a particular reaction type or stereochemical out-
come. Motivated by the bioactivity of the annonaceous
acetogenins, we embarked on a project to develop a
more general route that utilizes an orthogonal and
modular templating approach to provide access to many
members in the series. Herein we describe the first
successful synthesis of 10-hydroxyasimicin (1),[11] which
contains a bis-THF motif in the central core.
The crucial component in the synthesis of any of
these natural products is the stereoselective preparation
of the polyoxygenated central fragment. 10-Hydroxya-
simicin bears adjacent bis-THF rings flanked by two
hydroxy groups with a threo,trans,threo,trans,threo ster-
eochemistry. Our synthetic strategy to this oxygenated
arrangements (Scheme 1) hinged upon the design of a
Scheme 1. Proposed synthetic route to 10-hydroxyasimicin (1). Ts=p-toluene-
sulfonyl, MOM=methoxymethyl.
[*] G. L. Nattrass, E. Dꢀez, M. M. McLachlan, D. J. Dixon,
Prof. Dr. S. V. Ley
complete the carbon skeleton. Finally, selective hydrogena-
tion and global deprotection would furnish the natural
product 1 (Scheme 1).
Synthesis of fragment 2 began from (S,S)-dimethyl-d-
tartrate, which was readily converted into the monoprotected
diol 8 in three steps according to a previously established
procedure (Scheme 2).[12] Subsequent tosylation of 8 and
treatment of the corresponding tosyl derivative with allyl-
magnesium bromide in the presence of CuBr afforded 2 in
multigram quantities after deprotection with TBAF.
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB21EW (UK)
Fax: (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
[**] We thank the Commonwealth Scholarship Commission in the
United Kingdom for funding (G.L.N.), the EU for a Marie Curie
Fellowship (E.D.), GlaxoSmithKline (M.M.M.), Novartis for a
research fellowship (S.V.L.), and Pfizer Global Research and
Development for unrestricted funding towards the work.
580
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DOI: 10.1002/anie.200462264
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Angewandte
Chemie
tion with phosphonate 15, which afforded an
E,E diene exclusively.[20] Exhaustive reduction of the
E,E diene with the Pearlman catalyst then afforded
saturated ester 12 in 94% yield (Scheme 4). To
generate the last stereocenter, further chain extension
to propargylic ketone 13 was required. To this end
ketone 13 was obtained by conversion of the saturated
ester into the Weinreb amide,[21] which was then
Scheme 2. Synthesis of alkenol 2. a) Reference [12]; b) NEt3, TsCl, DMAP,
CH2Cl2, 1.5 h, room temperature, 99%; c) allylMgBr, CuBr, Et2O, 8 h, 08C,
84%; d) TBAF, THF, 5 h, 08C, 100%. DMAP=4-(dimethylamino)pyridine,
TBAF=tetrabutylammonium fluoride.
The next step in the synthesis involved the development
of a suitable template to link the two alkenol molecules
together in order to proceed with an intramolecular meta-
thesis reaction. As mentioned earlier, we required a tether-
ing unit that could adjust the conformation of the macro-
cycle to control the stereoselectivity during the RCM
reaction.[13] The chosen tethering template should behave as
a “molecular workbench” and help orientate the olefin so
that one face is preferentially available for attack during a
syn-stereoselective dihydroxylation reaction.[14] Further-
more, the tether would play the role of a protecting group
upon cleavage of the macrocycle to enable desymmetriza-
tion of the core. Hence the unit had to be dissymmetric to
allow orthogonal cleavage upon completion of the dihy-
droxylation. On top of this, a dissymmetric tethering unit
would enable us to attach different BDA-protected alkenol
units sequentially to produce acetogenins with alternative
stereochemistries at the core.[15] To put these concepts into
effect, a differentiated arene with orthogonal substituents
was chosen, as we could fine-tune the macrocycle ring size
simply by varying the substitution pattern of the aryl
system. 4-Bromomethylbenzoyl chloride was found to give
the best results and was used in all subsequent investiga-
tions.[16]
Coupling of alkenol 2 with 4-bromomethylbenzoyl
chloride in the presence of KHMDS gave the doubly
loaded para-linked diene 9 in 69% yield. Subsequent
treatment of 9 with a second-generation Grubbs catalyst[17]
in dichloromethane at reflux delivered the intramolecular
metathesis product in excellent yield, exclusively as the
E adduct. Sharpless asymmetric dihydroxylation of the
olefin with AD-mix-a afforded the diol in a diastereomeric
ratio of 16:1 favoring the desired S,S product (Scheme 3).[18]
Treatment of the diol with TsCl in pyridine afforded the
ditosylated compound 10 in 90% yield.
Scheme 3. Synthesis of bis-THF framework 5. a) KHMDS, THF, 5 h, ꢀ78!08C,
69%; b) second-generation Grubbs catalyst, CH2Cl2, 1 h, reflux, 99%; c) AD-mix-a,
MeSO2NH2, NaHCO3, tBuOH/H2O (1/1), 96 h, 08C!RT, 96% (S,S/R,R 16:1);
d) TsCl, pyridine, 20 h, 08C!RT, 90%; e) NaOMe, MeOH, 44 h, room temperature,
93%; f) DMSO, (COCl)2, CH2Cl2, ꢀ788C; NEt3, ꢀ788C!RT, 98%;
g) CH3(CH2)8PPh3Br, nBuLi, THF, 7 h, ꢀ78!08C, 69%; h) TFA/H2O (2:1), 5 min
(repeat twice), room temperature; i) K2CO3, MeOH, 3.5 h, reflux, 80% over two
steps; j) MOMCl, Hꢁnig base, DMAP, CH2Cl2, 18 h, 08C!RT, 78%; k) Pd/C,
HCO2ꢀNH4+, MeOH, 2 h, reflux, 79%. HMDS=hexamethyldisilazide,
DMSO=dimethyl sulfoxide, TFA=trifluoroacetic acid.
treated with the lithium derivative of trimethylsilylacetylene
followed by desilylation with TBAF to give 13 in 60% yield
over the two steps.[22] Diastereoselective oxazaborolidine-
catalyzed (CBS)[23] reduction gave 6 in 78% yield, with an
excellent ratio favoring the desired isomer (44:1).
The macrocycle was opened by treatment of 10 with
sodium methoxide in methanol at room temperature to afford
the primary alcohol.[19] Swern oxidation and a subsequent
Wittig reaction installed the nine-membered carbon side-
chain terminus as the Z olefin 4. Removal of the BDA groups
followed by an intramolecular Williamson cyclization with
potassium carbonate as the base led to the formation of the
bis-THF core 11 in 80% yield over the two steps. Finally,
protection of the free secondary alcohols with MOMCl,
followed by parallel reduction of the double bond and
debenzylation under transfer-hydrogenation conditions com-
pleted the synthesis of fragment 5 (Scheme 3).
With the synthesis of fragment 6 completed, we now
turned our attention to the synthesis of butenolide 7 in
preparation for the final coupling reaction. Diene 17 was
synthesized in seven steps from 1,4-butanediol according to a
previously established procedure (Scheme 5).[10] As in our
synthesis of muricatetrocin C, the 1,5-stereochemical rela-
tionship in the butenolide moiety was installed through the
HDA reaction with nitrosobenzene at 08C which afforded an
inseparable 7:3 mixture of regioisomers favoring the desired
Fragment 5 was further elaborated by Dess–Martin
oxidation, followed by Horner–Wadsworth–Emmons olefina-
adduct 18.[24] The N O bond was cleaved by using freshly
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man catalyst afforded the free alcohol. Oxidation of
the released primary alcohol with TPAP,[26] fol-
lowed by one-carbon homologation, according to
the Takai procedure,[27] provided the vinyl iodide 20
as a mixture of isomers (3.7:1 ratio favoring the
E geometry) in 59% yield over two steps. Subse-
quent elimination of the trifluoroacetamide group
in the presence of DBU in acetonitrile at 08C
afforded fragment 7 without epimerization of the
butenolide methyl substituent (Scheme 5).
Sonogashira cross-coupling of vinyl iodide 7
with the propargylic alcohol 6 proceeded smoothly
to produce the skeleton 14 in 86% yield
(Scheme 4).[28] The enyne functional group was
reduced selectively over the butenolide double
bond by using the Wilkinson catalyst to afford the
protected acetogenin in 74% yield. Final global
deprotection with BF3·Et2O in methyl sulfide
afforded 1 as a colorless wax in 68% yield. The
spectroscopic data for synthetic
1
(1H NMR,
13C NMR, IR, MS, and specific rotation)[29] were
in excellent agreement with those reported for
naturally occurring 10-hydroxyasimicin (1).[11]
In conclusion, the successful synthesis of 10-
hydroxyasimicin (1) demonstrates the potential of
the template approach to the oxygenated core of
the acetogenins in an efficient and easily adapted
manner. This route provides an efficient method for
the construction of the bis-THF moiety incorporat-
Scheme 4. Synthesis of 10-hydroxyasimicin (1). a) DMP, NaHCO3, CH2Cl2, 1 h, 08C!RT,
95%; b) 15, NaHMDS, THF, 18 h, ꢀ788C!RT, 81%; c) Pd(OH)2/C, H2, THF, 1 h, room
temperature, 94%; d) Me(MeO)NH·HCl, iPrMgCl, THF, 1.5 h, ꢀ108C, 82%; e) trimethylsilyl-
acetylene, nBuLi, THF, 1 h, ꢀ78!08C; f) TBAF, THF, 20 min, ꢀ208C, 60% over two steps;
g) (S)-16, BH3·Me2S, THF, 1 h, ꢀ358C, 78% (S/R 44:1); h) [Pd(PPh3)2Cl2], CuI, NEt3, 45 min,
room temperature, 86%; i) [Rh(PPh3)3Cl], H2, benzene/EtOH (1:1), 23 h, room temperature,
74%; j) BF3·OEt2, Me2S, 20 min, room temperature, 68%. DMP=Dess–Martin periodinane.
prepared [Mo(CO)3(MeCN)3] in the presence of water at
room temperature.[25] Protection of the resultant secondary
hydroxy group as a MOM ether enabled the separation of the
regio- and stereoisomers through flash-column chromatog-
raphy, thus avoiding the need for the laborious preparative
HPLC separation required in the previous synthesis of
muricatetrocin C. Subsequent hydrogenation over catalytic
palladium and protection of the amine as the trifluoroaceta-
mide afforded compound 19. Debenzylation with the Pearl-
ing a tether that enhances the stereochemical outcome of the
RCM step and enables desymmetrization of the central
fragment for further chain extension. The TBS-protected diol
building block 8, arising from (R,R,S,S)-2,3-BDA-protected
(S,S)-dimethyl-d-tartrate, and the highly diastereoselective
HDA approach to the butenolide unit are usefully employed
in this new synthesis of an acetogenin natural product.
Further applications of these general approaches will be
employed in the preparation of other members of the
acetogenin series in due course.
Received: October 11, 2004
Published online: December 13, 2004
Keywords: metathesis · natural products · templating effect ·
.
total synthesis
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Angew. Chem. Int. Ed. 2005, 44, 580 –584
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583

Communications
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[29] Spectroscopic data for synthetic 1, a colorless wax: [a]2D5 = + 16
(c = 0.25 in CHCl3, lit. [11] [a]2D2 = + 17.3 in CHCl3); 1H NMR
(400 MHz; CDCl3): d = 7.18 (d, J = 1.3 Hz, 1H; 35-H), 5.05 (qd,
J = 6.8, 1.4 Hz, 1H; 36-H), 3.86 (m, 5H; 16-H, 19-H, 20-H, 23-
H), 3.60 (m, 1H; 10-H), 3.41–3.38 (m, 2H; 15-H, 24-H), 2.53
(dddd, J = 15.2, 3.2, 1.5, 1.5 Hz, 1H; 3a-H), 2.40 (dddd, J = 15.1,
8.3, 1.2, 1.2 Hz, 1H; H-3b), 1.97 (m, 8H; 17-H, 18-H, 21-H, 22-
H), 1.70–1.26 (m, 36H; 5–9-H, 1–14-H, 25–33-H), 1.43 (d, J =
6.7 Hz, 3H; 37-H), 0.88 ppm (t, J = 6.7 Hz, 3H; 34-H); 13C NMR
(125 MHz; CDCl3): d = 174.6 (C1), 151.8 (C35), 131.2 (C2), 83.2,
83.1 (C16, C23), 81.81, 81.75 (C19, C20), 78.0 (C36), 74.1, 74.0
(C15, C24), 71.7 (C10), 69.9 (C4), 37.34 (C5), 37.3 (C11), 37.2
(C9), 33.41, 33.36, 33.32 (C3, C14, C25), 31.9 (C32), 29.71, 29.61,
29.60, 29.59, 29.47, 29.32 (C6–C8, C12, C13, C26–C31), 29.0
(C21, C18), 28.3 (C17, C22), 25.64, 25.62, 25.5 (C6–C8, C12, C13,
C26–C31), 22.7 (C33), 19.1 (C37), 14.1 ppm (C34); IR (thin
ꢀ1
=
film): n˜max = 3404 br (OH), 2924, 2853 (CH), 1753 (C O) cm
;
HRMS: calcd for C37H66O8Na [M+Na]+: 661.4650; found:
661.4651.
584
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2005, 44, 580 –584