Total synthesis, stereochemical assignment, and biological activity of chamuvarinin and structural analogues

Article abstract of DOI:10.1002/chem.201204527

A highly stereocontrolled synthesis of (+)-chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin-Anh control), followed by the two step activatio

Full text of DOI:10.1002/chem.201204527

FULL PAPER
DOI: 10.1002/chem.201204527
Total Synthesis, Stereochemical Assignment, and Biological Activity of
Chamuvarinin and Structural Analogues
Gordon J. Florence,* Joanne C. Morris, Ross G. Murray, Raghava R. Vanga,
Jonathan D. Osler, and Terry K. Smith[a]
Abstract:
A
highly stereocontrolled
C8–C9 to introduce the terminal bute-
nolide. The inherent flexibility of our
coupling strategy led to a streamlined
synthesis with 17 steps in the longest
sequence (2.2% overall yield), in
which the key bond couplings are re-
versed. In addition, a series of structur-
al analogues of chamuvarinin have
been prepared and screened for activi-
ty against HeLa cancer cell lines and
both the bloodstream and insect forms
of Trypanosoma brucei, the parasitic
agent responsible for African sleeping
sickness.
synthesis of (+)-chamuvarinin has been
completed in 1.5% overall yield over
20 steps. The key fragment coupling re-
actions were the addition of alkyne 8
to aldehyde 7 (under Felkin–Anh con-
trol), followed by the two step activa-
tion/cyclization to close the C20–C23
2,5-cis-substituted tetrahydrofuran ring
and a Julia–Kocienski olefination at
Keywords: acetogenins
·
natural
products · stereochemistry · total
synthesis · trypanosomes
Introduction
[bis(tetrahydrofuran)]tetrahydropyran
(THF-THF-THP)
ring system spanning the C15–C28 region of the carbon
backbone.[4] Structurally, the acetogenins are classified ac-
cording to the number of tetrahydrofuran motifs they con-
tain, that is, monoTHF, bisTHF and trisTHF, and their con-
nectivity, that is, being adjacently or non-adjacently linked.
These motifs are located centrally along the 32/34-carbon
backbone and account for the vast majority of acetogenin
family members.[4] Nonclassical acetogenins containing sub-
stituted tetrahydropyran motifs are far less common and to
date only eight tetrahydropyran-containing acetogenins
have been isolated and include muconin (2),[9] bearing an
adjacently linked THP-THF ring system and mucocin (3)
with a non-adjacent THF-THP array.[10]
Given their structural diversity and potent biological pro-
files acetogenins have been the subject of intense synthetic
interest.[11] The majority of this focus has been directed to-
wards the monoTHF and adjacent bisTHF subclasses and
has resulted in the development of a range of synthetic
methodologies to effectively introduce such stereochemical
motifs. These approaches are dominated by the application
of intramolecular Williamson etherification reactions, as de-
picted in Scheme 1.[11–14] The cyclization of activated 1,4-hy-
droxysulfonate precursors of type A or 1,4-epoxyalcohols of
type B provides efficient access to the corresponding isolat-
ed monoTHF compounds of type C and D, respectively.[12]
The former approach has been readily applied in the instal-
lation of additional THF motifs in preconstructed systems.[13]
Further extension of this tactic has led to the implementa-
tion of two-directional cyclization of pseudo-C2-symmetric
activated precursors of type E and F, to assemble the char-
acteristic anti-threo-anti-configured bisTHF array of type
G,[14,15] the predominant structural motif of the adjacent
bisTHF acetogenin subclass, typified by squamocin (4).[4,16]
The Annonaceae genera of trees, shrubs and lianas are
widely found in tropical and sub-tropical regions of East
Africa and South and Central America. The crude extracts
of their bark, roots, and leaves are extensively used in tradi-
tional medicinal practices for the treatment of bacterial and
parasitic infection.[1,2] Interest in the Annonaceae intensified
with the isolation/discovery of a family of fatty-acid-derived
secondary metabolites,[3] termed the annonaceous acetoge-
nins, which currently number in excess of four hundred com-
pounds.[4] Many of these acetogenins display remarkable cy-
totoxic activity towards human cancer cell lines and a broad
spectrum of further biological properties including antifun-
gal and immunosuppressant activities. Their biological activ-
ity is primarily attributed to their inhibition of mitochondri-
al respiratory chain Complex I, of which they are amongst
the most potent inhibitors known to date.[5–7]
Isolated in 2004 by Laurens and co-workers from the root
extracts of Uvaria Chamae, chamuvarinin (1, Figure 1) dis-
played cytotoxicity towards KB 3-1 cervical cancer cell lines
with an IC50 value of 0.8 nm.[8] Chamuvarinin is unique
amongst the acetogenin family of natural products as it is
the first reported acetogenin to contain an adjacently linked
[a] Dr. G. J. Florence, J. C. Morris, Dr. R. G. Murray, Dr. R. R. Vanga,
J. D. Osler, Dr. T. K. Smith
EaStCHEM School of Chemistry
Biomedical Sciences Research Complex
University of St Andrews, North Haugh
St Andrews, KY16 9ST (UK)
Fax : (+44)1334-463808
E-mail: gjf1@st-andrews.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204527.
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Scheme 1. Application of Williamson-type etherification reactions in
acetogenin synthesis. Ms=methylsulfonyl, Ts=4-methylbenzenesulfonyl.
known acetogenins the relative configuration of the C15–
C28 region was proposed to be that given in structure 1,
bearing the unusual threo-anti-threo-syn-threo-syn adjacently
linked [bisACTHNUTRGNEUNG
(THF)]THP array.[4] Based on a common biogen-
esis and given that the majority of bioactive acetogenins
with a carbinol at C15 bear the R configuration, chamuvari-
nin should share the common 15R configuration and we
opted to target the diastereomer depicted for the synthe-
sis.[4,17,18] Herein, we provide full details of our initial syn-
thetic route,[19] a revised approach to chamuvarinin employ-
ing a reversed-coupling strategy, and report on the trypano-
cidal activity of a series of analogue structures derived from
advanced synthetic intermediates.
Figure 1. Structures of chamuvarinin (1) and representative acetogenin
family members.
Results and Discussion
Synthetic strategy: Due to the initial uncertainty surround-
ing the structure of chamuvarinin at the onset of this syn-
thetic campaign, we devised a modular synthetic strategy
based on disconnections at C8–C9 and C20–C21 that would
allow the assembly of multiple diastereomeric candidate
structures of chamuvarinin.[8a] This requirement was super-
seded by the stereochemical study by Poupon and co-work-
ers on the biosynthetic relationship between chamuvarinin
and squamocin, but our disconnection strategy remained
readily applicable to the revised structure with defined rela-
tive stereochemistry (Scheme 2).[8b,19] Attachment of the C1–
C8 aldehyde 5 containing the butenolide motif in the final
coupling enabled our primary focus to be centered on con-
firming the relative configuration of the adjacently linked
tris-tricyclic ether ring system (C15–C28) in 6. Disconnec-
tion of the central C20–C23 THF ring system in 6 gives the
C9–C20 aldehyde 7 and the C21–C34 alkyne 8,[18] in which
In common with the majority of acetogenins, chamuvari-
nin contains a butenolide moiety bearing the 36S configura-
tion. The relative stereochemistry of the central C15–C28
ether network initially proved elusive and only the relative
configuration of the C15–C19 region was proposed, present-
ing up to thirty-two possible diastereomeric variations for
the actual structure of chamuvarinin.[8a] The stereochemical
quandary initially posed by 1 was partially resolved in 2007
by Poupon and co-workersꢁ semi-synthetic study on the bio-
synthetic origin of chamuvarinin.[8b] It was initially suggested
that squamocin (4), which was co-isolated from the same
crude root extract, could be a plausible biosynthetic precur-
sor of 1 given its structural similarity. However, this proved
not to be the case and following a detailed re-evaluation of
1
the H and 13C NMR data and structural comparisons with
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Chamuvarinin and Structural Analogues
FULL PAPER
to provide 11 in 75% yield.[14j,22] Oxidation and thermal sulf-
oxide elimination (81%) was followed by cleavage of the
C8-benzyl ether with BCl3·SMe2 (91%)[23] to provide bute-
nolide 12. Dess–Martin periodinane oxidation of 12 then
completed the synthesis of C1–C8 aldehyde 5 (93%).
Synthesis of the C9–C20 subunit: As shown in Scheme 4,
the synthesis of the C9–C20 subunit 7 began with the cop-
Scheme 2. Synthetic strategy for chamuvarinin (1).
control over the C20 stereocenter would be reliant upon
Felkin–Anh induction from the carbonyl component to
enable 5-exo cyclization of the C23-hydroxyl to furnish the
2,5-syn-configured THF ring system.[13,20]
Synthesis of the C1–C8 subunit: The synthesis of the C1–C8
subunit 5 was performed in four steps from lactone 9
through an adaptation of the Marshall butenolide synthesis,
as outlined in Scheme 3.[14j] The synthesis began with alkyla-
tion of iodide 10[21] with the lithium enolate of (S)-lactone 9
Scheme 4. Synthesis of C9–C20 subunit 7: a) CH2CHCH2MgBr, CuI,
THF, ꢀ408C!RT, 82%; b) TBSCl, ImH, DMAP, DMF, RT, 98%; c) O3,
Na2CO3, CH2Cl2, ꢀ788C, 30 min; then PPh3, RT, 2 h; d) 1-phenyl-1H-tet-
razole-5-thiol, PPh3, DIAD, 08C, 98%; e) [(NH4)6Mo7O24]·4H2O, H2O2,
EtOH, 08C!RT, 99%; f) NaHMDS, DME, ꢀ788C!ꢀ508C, 86% from
14; g) TBAF, THF, 08C!RT, 85%; h) NaH, TrisIm, THF, 08C!RT,
98%; i) ADmix-b, tBuOH/H2O, 0 8C!RT; then K2CO3, MeOH, 08C!
RT, 89 %, >97:3 d.r.; j) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C, 96%;
k) (ꢁ)-CSA (20 mol%), MeOH/CH2Cl2 (1:4), 08C, 61% (recovered 22=
20% and 21=17%); l) Dess–Martin periodinane, CH2Cl2, 08C!RT,
70%. TBS=tert-butyldimethylsilyl, ImH=imidazole, DMAP=4-N,N’-di-
methylaminopyridine, DIAD=diisopropyl azodicarboxylate, NaHMDS=
sodium hexamethyldisilylazide, DME=dimethoxyethane, TBAF=tetra-
butylammonium fluoride, TrisIm=2,4,6-triisopropylbenzenesulfonyl imi-
dazole, TfO=triflate, (ꢁ)-CSA=(ꢁ)-camphorsulfonic acid, PT=phenyl
tetrazole.
Scheme 3. Synthesis of C1–C8 aldehyde 5: a) LDA, DMPU, THF,
ꢀ788C!RT, 75%; b) mCPBA, CH2Cl2, 08C; then PhMe, 1008C, 81%;
c) BCl3·SMe2, CH2Cl2, ꢀ788C!RT, 91%; d) Dess–Martin periodinane,
CH2Cl2, RT, 93%. LDA=lithium diisopropylamide, DMPU=1,3-dimeth-
yl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, mCPBA=3-chloroperbenzoic
acid, Bn=benzyl.
per(I)-promoted opening of (S)-TBS glycidol ether 13 with
allylmagnesium bromide (82%), followed by TBS ether for-
mation (TBSCl, ImH, 98%) to provide 14. Ozonolysis of 14,
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G. J. Florence et al.
with reductive PPh3 workup provided aldehyde 15 consis-
tently, which was used directly in the subsequent Julia–
Kocienski olefination reaction.[24,25] The phenyltetrazole
(PT) sulfone 16 was readily prepared in two steps from
known alcohol 17[26] through a Mitsunobu reaction (DIAD,
PPh3, 1-phenyl-1H-tetrazole-5-thiol) and catalytic MoVI oxi-
dation by using H2O2 as a co-oxidant (97% over two steps).
Deprotonation of sulfone 16 with NaHMDS in DME at
ꢀ788C, followed by addition of aldehyde 15 provided the
(E)-alkene 18 exclusively in 86% yield from 14.
With multigram quantities of 18 readily available, installa-
tion of the C16–C19 THF ring was addressed. Firstly, TBAF
deprotection of the TBS ethers in 18 gave diol 19 in 85%
yield, which was readily transformed into epoxide 20 in
98% yield by treatment with NaH and TrisIm.[27] The C15
and C16 hydroxyl stereocenters were then installed by
Sharpless asymmetric dihydroxylation[28] and the resulting
crude epoxy-diol was treated directly with K2CO3 in MeOH
to trigger 5-exo cyclization, providing the 2,5-anti-configured
THF diol 21 in 89% yield with >97:3 d.r.[29]
Attempts to selectively oxidize the primary alcohol in 21
proved unsuccessful and a two-step protecting group manip-
ulation was required to differentiate the C15 and C20 hy-
droxyl groups. Firstly, treatment of 21 with TBSOTf and 2,6-
lutidine provided 22, which underwent selective primary
silyl cleavage (CSA (20 mol%) in CH2Cl2/MeOH (4:1)) to
provide 23 in 61% yield, along with diol 21 (17%) and re-
covered starting material 22 (20%), which could be recycled
accordingly. Finally Dess–Martin oxidation of 23 provided
the C9–C20 aldehyde 7 (70%) in preparation for the cou-
pling with the C20–C21 fragment.
Scheme 5. Synthesis of C21–C34 subunit 8: a) CH2CHCH2CH2MgBr,
CuI, THF, ꢀ408C!RT, 80%; b) mCPBA, CH2Cl2, 08C!RT; then
(ꢁ)-CSA (20 mol%), RT, 73% (26=41%, 27=32%); c) (COCl)2,
DMSO, CH2Cl2, Et3N, ꢀ788C!RT, 88%; d) HCCTMS, nBuLi, THF,
ꢀ788C, 88% (29/30=12:88 d.r.); e) i) 4-BrC6H4CO2H, PPh3, DIAD, 08C;
ii) K2CO3, MeOH, RT; f) HCCTMS, (+)-(1S,2R)-N-methylephedrine, Zn-
Synthesis of the C21–C34 subunit: As shown in Scheme 5,
the synthesis of the C21–C34 subunit 8 began with the CuI-
promoted addition of homoallylmagnesium bromide[30] to
(S)-1-epoxyoctane 24[31] to afford 25 in 80% yield. Epoxida-
tion of 25 with mCPBA, followed by addition of a catalytic
amount of CSA (20 mol%), cleanly promoted the 6-exo cyc-
lization to provide syn- and anti-THP alcohols 26 (41%)
and 27 (32%), which were readily separated by column
chromatography on a multigram scale. Swern oxidation of
26 and addition of the lithium anion of trimethylsilylacety-
lene to aldehyde 28 provided (23R) and (23S)-propargylic
alcohols 29 and 30 in 88% combined yield (29:30=
12:88 d.r.).[32] Following chromatographic separation the un-
desired major (23R)-diastereomer, 30, was subjected to Mit-
sunobu inversion[33] and, following base-mediated methanol-
ysis/desilylation, gave 31 with the correct 23S configuration.
Although this three-step process provided access to 31 in
good yield, direct access to 29 from 28 was deemed prefera-
ble. This was achieved by employing the Carreira alkynyla-
tion protocol to overturn the inherent substrate bias.[34]
AHCTNUGTERNNG(UN OTf)2, Et3N, PhMe, 608C, 80% (29/30= >95:5 d.r.; g) K2CO3, MeOH,
RT, 90%; h) TBSCl, ImH, CH2Cl2, RT, 91%. TMS=trimethylsilyl.
completed the C21–C34 subunit 8 in six steps and 13%
overall yield from (S)-1-epoxyoctane 24.
Synthesis of the C9–C34 tricyclic ether core: With the C9–
C20 and C21–C34 subunits in hand, attention was now fo-
cused on their union and assembly of the central C20–C23
THF ring system (Scheme 6). In the event, treatment of
alkyne 8 with nBuLi in THF at ꢀ788C, followed by addition
of aldehyde 7 in THF at ꢀ788C provided the expected
adduct 32 in 71% yield with modest diastereoselectivity
(75:25 d.r.).[20] Gratifyingly, the level of Felkin–Anh stereo-
induction imparted by the aldehyde component could be im-
proved by performing the reaction in MTBE at ꢀ1008C,
providing 32 in 77% yield with essentially complete diaster-
eoselectivity at C20 (>95:5 d.r.).[20c,32] Reduction of the
C21–C22 alkyne under flow hydrogenation by using 5% Pt/
C at 100 bar of H2 provided 33 in 39% yield. However, di-
Thus, treatment of 28 with ZnACHTNUGRTENUNG(OTf)2/N-Me-ephedrine and
trimethylsilylacetylene provided the (23S)-alcohol 29 in
80% yield with >95:5 d.r. Basic methanolysis of the alkynyl
TMS group (90%) and subsequent protection of the C23-
hydroxyl droup in 31 as its TBS ether (TBSCl/ImH, 91%)
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Chamuvarinin and Structural Analogues
FULL PAPER
1
Figure 2. Comparative H and 13C NMR analysis of the synthetic C9–C34
intermediate 6 and natural chamuvarinin. a) Bars represent deviation in
ppm between individual proton chemical shifts observed for 6 and those
reported for the natural material (400 MHz, CDCl3); b) Bars represent
deviation in ppm between individual carbon chemical shifts observed for
6 and those reported for the natural material (100 MHz, CDCl3).
Scheme 6. Synthesis of the C9–C34 tricyclic ether intermediate 6: a) com-
pound 8, nBuLi, THF, ꢀ788C; then 7, ꢀ788C, 71%; or b) compound 8,
nBuLi, MTBE, ꢀ1008C; then 7, ꢀ1008C, 77%; c) 5% Pt/C 35 mm Cat-
Cart, H-Cube, MeOH, 1 mLminꢀ1, 100 bar H2, 39%; or d) TsNHNH2,
NaOAc, DME, H2O, 1008C, 79%; e) i) MsCl, Et3N, 0 8C; ii) TBAF, THF,
08C!RT, 90%. MTBE=methyl t-butylether.
A
give 36 in 85% yield. Finally, treatment of 36 with 1-phenyl-
1H-tetrazole-5-thiol under Mitsunobu conditions (76%) and
subsequent oxidation of the intermediate sulfide (H2O2, cat.
MoVI) provided the sulfone 34 in 76% yield.
The stage was now set for the union of 34 with the C1–C8
aldehyde 5. Thus, deprotonation of 34 with NaHMDS in
THF at ꢀ788C followed by addition of 5, with warming to
ꢀ208C over three hours provided the C1–C34 intermediate
37 in 41% yield.[24,25,36,37] Diimide reduction[14d,35] of the C8–
C9 alkene and deprotection of the C15-OTBS ether by
acidic methanolysis proceeded smoothly to provide synthetic
compound 1 in 73% yield over two steps.
The spectroscopic data obtained for the synthetic material
(1H and 13C NMR spectroscopy, IR spectroscopy and MS),
correlated fully with that of natural chamuvarinin, and the
measured specific rotation, [a]2D0 = +9.9 (c=0.1 in CHCl3),
for 1 compared with the reported data was consistent with
that of the natural material [lit. [a]D = +27 (c=0.026 in
CHCl3)].[8] However, in the absence of an authentic sample
of 1 for direct NMR spectroscopic, specific rotation and/or
HPLC comparison, additional confirmation was sought by
qualitative comparison of the biological activity of the syn-
thetic material with the reported activity of the natural ma-
terial. In screening against the HeLa cervical cancer cell
32 proved to be a superior reagent system for the alkyne re-
duction, providing 33 in 71% yield.[14d,35]
It now remained to install the central C20–C23 syn-con-
figured THF motif. This transformation was readily ach-
ieved by activation of the C20 hydroxyl group as its mesy-
late form (MsCl/Et3N), followed by treatment of the crude
reaction mixture with TBAF to promote silyl cleavage at
C15 and C23 and in situ 5-exo cyclization, providing the C9–
C34 intermediate 6 in excellent yield over two steps.[14] At
this juncture, comparison of the H and 13C NMR spectra of
6 with those of natural chamuvarinin showed them to be in
remarkably close agreement across the C15–C28 stereo-
chemical array (Figure 2), providing confidence in the rela-
tive stereochemical assignment proposed by Poupon and co-
workers.[8]
Completion of chamuvarinin: With the C9–C34 intermediate
6 in hand, our attention was directed towards the final
Julia–Kocienski coupling at C8–C9 and the completion of
chamuvarinin, as detailed in Scheme 7. This began with the
elaboration of 6 to the corresponding C9–C34 sulfone 34.
Protection of the C15 hydroxyl as its TBS ether provided 35
in 88% yield. Debenzylation at C9 proceeded smoothly to
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G. J. Florence et al.
investigate the activity displayed by 1 towards T. brucei. As
outlined in Scheme 8, our revised synthetic route uses the
common subunits from our first-generation approach and
Scheme 8. Revised coupling strategy for chamuvarinin.
maintains key disconnections at C8–C9 and C20–C21, but
reverses the order of the bond couplings. Thus, disconnec-
tion at C20–C21 gives the C1–C20 aldehyde 38 and the
C21–C34 alkyne 8. In turn, compound 38 could be assem-
bled by adaptation of the C8–C9 Julia–Kocienski olefination
developed in our initial synthesis.[19,24,25,36,37]
As shown in Scheme 9, the C9–C20 sulfone 39 was readily
prepared in three steps from intermediate 22 in 50% yield,
involving C9-debenzylation, Mitsunobu thioetherification,
and oxidation to the sulfone. The Julia–Kocienski olefina-
tion between aldehyde 5 and sulfone 39 by using NaHMDS
in THF proceeded smoothly to provide 40 in excellent yield
as a single E isomer. At this stage, selective deprotection of
the C20-TBS ether with catalytic CSA in MeOH/CH2Cl2
gave alcohol 41 in 63% yield. Dess–Martin oxidation of 41
gave C1–C20 aldehyde 38 prior to the final coupling reac-
tion with alkyne 8.
Formation of the lithium anion of alkyne 8 with nBuLi at
ꢀ1008C in MTBE, followed by addition of aldehyde 38 pro-
vided adduct 42 with 95:5 d.r., but only in a modest 29%
yield. In contrast, performing the alkynylation of 38 in THF
at ꢀ788C provided 42 in an improved yield albeit with re-
duced diastereoselectivity (56%, 75:25 d.r.).[20]
Scheme 7. Completion of chamuvarinin: a) TBSOTf, 2,6-lutidine, CH2Cl2,
ꢀ788C, 88%; b) 20% Pd(OH)2/C, H2 (1 atm), EtOH, RT, 85%;
c) 1-phenyl-1H-tetrazole-5-thiol,
PPh3,
DIAD,
08C,
76%;
d) [(NH4)6Mo7O24]·4H2O, H2O2, EtOH, 08C!RT, 76 %; e) 34, NaHMDS,
THF, ꢀ788C; then 5, THF ꢀ78!ꢀ208C, 41%; f) TsNHNH2, NaOAc,
DME, H2O, 1008C; then 3n HCl, MeOH, RT, 73% from 37.
line, synthetic compound 1 displayed low micromolar activi-
ty (ED50 =2.88ꢁ0.66 mm). Additionally, synthetic 1 dis-
played potent trypanocidal activity towards both the blood-
stream and insect form of the parasite Trypanasoma brucei,
with ED50 values of 1.37ꢁ0.08 and 1.90ꢁ0.11 mm,[38] respec-
tively, which is in line with the trypanocidal activity reported
for squamocin 4.[39]
Having established the C1–C34 carbon skeleton, all that
remained was to close the central C20–C23 THF ring and
complete our revised approach. Thus, diimide reduction[35]
of the C8-alkene and C21-alkyne in 42 provided 43 in 90%
yield. At this point, the minor diasteromer from the previ-
ous coupling reaction was readily removed by column chro-
matography. Activation of the C20-hydroxyl in 43 as its me-
Revised coupling strategy: Our initial approach to chamu-
varinin was designed to resolve the relative and stereochem-
ical configuration of chamuvarinin. Having successfully com-
pleted this primary goal,[19] we sought further strategic re-
finements in an effort to improve synthetic efficiency and
enable the synthesis of acetogenin-like analogues to further
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Chamuvarinin and Structural Analogues
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This three-step sequence only required a single chromato-
graphic purification of the final product, which was identical
to an authentic sample in all respects.[8,19] By implementa-
tion of this revised coupling strategy, we were able to im-
prove the overall step efficiency (the longest linear sequence
being 17 steps from 13, compare with 20 steps in our initial
approach), although the overall yield was only slightly im-
proved (2.2% overall yield), in part due to the challenging
C20–C21 bond construction. This revised approach also ena-
bled access to a range of advanced structural analogues,
which are detailed in the following section.
Synthesis and biological evaluation of chamuvarinin ana-
logues: Acetogenins have been the subject of intensive syn-
thetic and biological research, primarily in relation to their
development as a new generation of anti-cancer agents. In
contrast, their evaluation as potential lead compounds for
the treatment of neglected diseases, such as African sleeping
sickness, has been largely overlooked. These studies have
primarily centered on the screening of crude extracts for try-
panocidal activity,[41–43] although Hocquemiller and co-work-
ers have shown squamocin (4) to be an effective inhibitor of
the bloodstream form of T. brucei with an IC100 of 16 mm.[39]
The low-micromolar activity displayed by our synthetic ma-
terial towards both the bloodstream and procyclic forms of
T. brucei, coupled with our modular approach to the synthe-
sis of chamuvarinin, provided an ideal opportunity to access
a range of unnatural acetogenin-like analogues to assess
their trypanocidal activity.
As shown in Scheme 10, analogues 44–50 were readily
prepared from their respective protected precursors by
standard deprotection protocols. 36-epi-Chamuvarinin (51)
and 36-epi-(8E)-alkenyl analogue 52 were prepared from 34
and R-configured C1–C8 aldehyde 53[44] by utilizing our first
generation coupling strategy, as outlined in Scheme 11. As
expected, compound 51 could not be readily distinguished
from 1 by 1H and 13C NMR spectroscopy and the specific ro-
tation was of the same magnitude, but opposite polarity [51:
[a]D20 =ꢀ11.9 (c=0.52 in CHCl3); synthetic 1: [a]2D0 = +9.9
(c=0.1 in CHCl3);[19] natural 1: [a]D = +25 (c=0.026 in
CHCl3)[8]].
The synthesized compounds were tested against both the
bloodstream and procyclic forms of T. brucei and HeLa
cells,[38] as a representative mammalian cell line; the results
are summarized in Table 1. In all cases, the analogues dis-
played lower activities towards T. brucei than synthetic cha-
muvarinin, although all were essentially inactive towards
HeLa cells. The simple analogues 12 and 44 (Table 1, en-
tries 2 and 3) were devoid of any activity, as was compound
45 (Table 1, entry 4), which corresponds to the C1–C20 frag-
ment of chamuvarinin. The truncated C9–C34 analogues 46
and 47 (Table 1, entries 5 and 6) shared similar activity to-
wards bloodstream T. brucei. Incorporation of the buteno-
lide group in 48 and 49 (Table 1, entries 7 and 8) led to in-
creased trypanocidal activity compared with the truncated
C9–C34 analogue 46, but both remained essentially inactive
towards HeLa cells. Although 51 (Table 1, entry 10), bearing
Scheme 9. Revised synthesis of chamuvarinin: a) 20% Pd(OH)2/C, H2
(1 atm), EtOH, RT, 96%; b) 1-phenyl-1H-tetrazole-5-thiol, PPh3, DIAD,
08C, 64%; c) [(NH4)6Mo7O24]·4H2O, H2O2, EtOH, HMPA, 08C!RT,
81%; d) 39, NaHMDS, THF, ꢀ788C; then 5, THF, ꢀ78!ꢀ208C, 87%;
e) (ꢁ)-CSA, MeOH/CH2Cl2 (1:4), 08C, 63%; f) Dess–Martin periodi-
nane, CH2Cl2, 08C!RT, 69%; g) compound 8, nBuLi, MTBE, ꢀ1008C;
then 38, ꢀ1008C, 29%; or compound 8, nBuLi, THF, ꢀ788C; then 38,
ꢀ788C, 56%; h) TsNHNH2, NaOAc, DME, H2O, 1008C, 90%; i) i) MsCl,
Et3N; ii) 3n HCl, MeOH, RT; iii) pyridine, 708C, 57% from 43. HMPA=
hexamethylphosphoramide.
sylate (MsCl/Et3N) was followed by deprotection of the
C15- and C23-TBS ethers with 3n HCl in MeOH and expo-
sure of the crude reaction products to pyridine at reflux pro-
vided (+)-chamuvarinin in 57% yield over three steps.[13,40]
Chem. Eur. J. 2013, 19, 8309 – 8320
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8315

G. J. Florence et al.
Scheme 10. Synthesis of analogues: a) 20% Pd(OH)2/C, H2 (1 atm), EtOH, RT; b) TsNHNH2, NaOAc, DME, H2O, 1008C; c) 3n HCl, MeOH, RT.
Scheme 11. Synthesis of 36-epi-chamuvarinin: a) 34, NaHMDS, THF, ꢀ788C; then 53, THF ꢀ78!ꢀ208C, 71%; b) TsNHNH2, NaOAc, DME, H2O,
1008C; then 3n HCl, MeOH, RT, 74%; c) 3n HCl, MeOH, RT, 89%.
Table 1. Trypanocidal activity of chamuvarinin and analogues.
Conclusion
Entry
Compound[a]
T. brucei
T. brucei
HeLa
[mm]
SI[c]
2.1
A
(procyclic) [mm]
A highly stereocontrolled synthesis of (+)-chamu-
varinin has been completed by a modular coupling
strategy in 1.5% overall yield over 20 steps in the
longest linear sequence. This enabled the unambig-
uous confirmation of the relative and absolute ster-
eochemical assignment of this unique acetogenin.
Biological screening of our synthetic material
against a representative human cell line (HeLa)
provided further convincing evidence of the unam-
biguous stereochemical assignment of 1, and the
trypanocidal activity was in line with the small
number of acetogenins that have been screened
against Trypanosoma brucei. Further refinement of
our synthetic strategy led to the reversal of key
fragment couplings at C8–C9 and C20–C21, improv-
1
2
3
4
5
6
7
8
9
1
1.37ꢁ0.08
>1000
1.90ꢁ0.11
>1000
>1000
354ꢁ23
27.6ꢁ0.9
78.9ꢁ2.7
18.6ꢁ0.5
15.2ꢁ2.0
36.5ꢁ4.1
>100
2.88ꢁ0.66
12
44
45
46
47
48
49
50
51
52
>1000
>1000
–
528ꢁ19.6
>1.9
0.23
>1.4
>1.9
>7
5.5
>2.7
–
575ꢁ35
132ꢁ14
69.7ꢁ2.5
51.0ꢁ3.8
13.5ꢁ0.8
27.3ꢁ2.0
36.7ꢁ2.9
>100
>100
>100
151ꢁ7.4
>100
>100
>100
10
11
>100
9.6ꢁ1.1
18.9ꢁ2.8
>10
[a] For structures see Scheme 9; [b] BSF=bloodstream form; [c] Selectivity index=
ratio of HeLa ED50 versus T. brucei (BSF) ED50.
the unnatural (36R)-configured butenolide, displayed no ac-
tivity, the (8E)-alkenyl analogue 52 (Table 1, entry 11),
which shares the unnatural (36R)-configuration, was only 7-
fold less active than chamuvarinin and was more potent
than the corresponding (36S)-diastereomer 50 (Table 1,
entry 9).
ing the overall synthetic efficiency of our initial approach
(2.2% overall yield with 17 steps in the longest linear se-
quence), while also enabling the preparation of a series of
analogues for preliminary structure–activity relationship
(SAR) exploration of trypanocidal activity. The selective ac-
tivity displayed by analogues 48 and 49 towards the blood-
stream form of T. brucei demonstrates that subtle modifica-
tions of the central ether array can retain parasitic activity,
8316
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 8309 – 8320

Chamuvarinin and Structural Analogues
FULL PAPER
1H; H20), 3.64 (dt, J=5.6, 5.6 Hz, 1H; H23), 3.57–3.51 (m, 1H; H15), 3.47
(t, J=6.6 Hz, 2H; H9), 3.30–3.19 (m, 2H; H24, H28), 2.42 (d, J=5.1 Hz,
while being essentially inactive towards mammalian cell
lines. Studies are currently focused on elucidating the specif-
ic parasite protein target(s) of our acetogenin-like analogues
because unlike mammalian cells, which are dependent on
Complex I for mitochondrial respiration and sensitive to
acetogenin inhibition, the bloodstream form of T. brucei
lacks this multienzyme complex and relies solely on the Try-
panasome Alternative Oxidase, a cytochrome-independent
terminal oxidase that reduces oxygen to water by the trans-
fer of two electrons from ubiquinol. In conjunction, further
structural optimization of our lead compounds as potential
new chemotherapeutic agents for the treatment of African
sleeping sickness is underway and will be reported in due
course.
1H; OH), 1.97–1.76 (m, 4H; H17a, H18, H26a), 1.70–1.49 (m, 8H; H10, H17b
H22, H25a, H26b, H27a), 1.49–1.23 (m, 20H; H11–H14, H21, H29–H33), 1.23–
1.05 (m, 2H; H25b, H27b), 0.90–0.83 (m, 21H; H34, 2ꢂSiC(CH3)3), 0.06 (s,
,
AHCTUNGTRENNUNG
3H; SiCH3), 0.056 (s, 3H; SiCH3), 0.054 (s, 3H; SiCH3), 0.04 ppm (s, 3H;
SiCH3); 13C NMR (100 MHz, CDCl3): d=138.7, 128.4, 127.6, 127.5, 82.6,
82.2, 80.8, 78.1, 75.4, 74.5, 72.9, 72.0, 70.5, 36.4, 33.0, 31.9, 31.4, 31.0, 29.8,
29.5, 28.8, 28.5, 28.0, 26.2, 26.00, 25.97, 25.7, 25.6, 25.4, 25.3, 23.6, 22.7,
18.3, 18.2, 14.1, ꢀ4.1, ꢀ4.2, ꢀ4.6 ppm (2C); HRMS (ES+): m/z calcd for
C45H88O6Si2N: 794.6147 [M+NH4]+; found: 794.6145.
Compound 6: Et3N (176 mL, 1.27 mmol) and MsCl (70 mL, 0.91 mmol)
were added to a solution of alcohol 33 (141 mg, 0.181 mmol) in CH2Cl2
(9 mL) at 08C. After 1 h, saturated aqueous NH4Cl (5 mL) and CH2Cl2
(5 mL) were added. The organic compounds were extracted with CH2Cl2
(3ꢂ5 mL) and the combined organic extracts were washed with H2O
(10 mL) and brine (10 mL), dried (Na2SO4), filtered, and concentrated.
The crude mesylate was dissolved in THF (7 mL) and cooled to 08C with
stirring and TBAF (4.53 mL of a 1.0m solution in THF, 4.53 mmol) was
added. The reaction mixture was warmed to RT. After 22 h, the reaction
mixture was quenched with H2O (10 mL) and EtOAc (10 mL). The or-
ganic compounds were extracted with EtOAc (3ꢂ10 mL) and the com-
bined organic extracts were washed with brine (20 mL), dried (Na2SO4),
filtered, and concentrated. Purification by flash column chromatography
Experimental Section
General: See the Supporting Information for details of instrumentation,
purification of reagents and solvents, and chromatography. All non-aque-
ous reactions were performed under an atmosphere of argon with oven-
dried apparatus and standard techniques for handling air-sensitive mate-
rials. The Alamar BlueTM viability test[38] was utilized to establish ED50
values for all of the analogues, against cultured bloodstream (strain 427)
and procyclic (strain 29–13) T. brucei, as well as HeLa cells.
(20% EtOAc/hexanes) provided tetrahydrofuran alcohol
6 (86 mg,
90%), as a colorless oil. Rf =0.42 (50% EtOAc/hexanes); [a]2D0 =ꢀ1.8
(c=0.5 in CHCl3); IR (NaCl): n˜ =3453, 2928, 2856, 1454, 1357, 1172,
1
1092, 1070, 910, 733, 695 cmꢀ1; H NMR (500 MHz, CDCl3): d=7.36–7.32
(m, 4H; Ar-H), 7.31–7.28 (m, 1H; Ar-H), 4.51 (s, 2H; Ph-CH2), 3.93 (dt,
J=7.6, 6.2 Hz, 1H; H19), 3.89 (dt, J=6.8, 5.7 Hz, 1H; H23), 3.87–3.81 (m,
2H; H16, H20), 3.47 (t, J=6.6 Hz, 2H; H9), 3.41–3.34 (m, 1H; H15), 3.30
(ddd, J=10.1, 5.5, 1.8 Hz, 1H; H24), 3.31–3.27 (m, 1H; H28), 2.53 (brs,
Compound 32: nBuLi (0.48 mL, 0.67 mmol, 1.6m in hexane) was added
to a solution of alkyne 8 (230 mg, 0.68 mmol) in MTBE (3 mL) at 08C.
The reaction mixture was cooled to ꢀ1008C and after 10 min a solution
of aldehyde 7 (57.9 mg, 0.13 mmol) in MTBE (1 mL) was added through
a cannula. After 4 h, saturated aqueous NH4Cl (5 mL) and CH2Cl2
(5 mL) were added. The organic compounds were extracted with CH2Cl2
(3ꢂ5 mL), washed with brine (5 mL), dried (Na2SO4), filtered, and con-
centrated in vacuo. Purification by flash column chromatography (5%
EtOAc/hexanes) provided alkyne 32 (79.3 mg, 77%), as a colorless oil
(>95:5 d.r.). Rf =0.10 (5% EtOAc/hexanes); [a]2D0 = +6.1 (c=0.59 in
CHCl3); IR (NaCl): n˜ =3442, 2929, 2856, 1456, 1363, 1251, 1102, 836,
1H; OH), 2.01–1.91 (m, 2H; H17a, H18a), 1.87–1.79 (m, 3H; H21a, H22a
,
H
H
26a), 1.79–1.70 (m, 2H; H18b, H22b), 1.70–1.45 (m, 8H; H10, H14a, H17b
21b, H25a, H26b, H27a), 1.43–1.20 (m, 18H; H11–H13, H14b, H25b, H29–H33),
,
1.20–1.10 (app. dq, J=12.4, 3.8 Hz, 1H; H27b), 0.88 ppm (t, J=6.9 Hz,
3H; H34); 13C NMR (75 MHz, CDCl3): d=138.7, 128.3, 127.6, 127.5, 83.1,
82.1, 82.0, 81.5, 79.9, 77.9, 74.1, 72.9, 70.5, 36.5, 33.4, 31.9, 31.5, 29.7, 29.6,
29.4, 28.9, 28.4, 28.0, 27.4, 26.9, 26.2, 25.7, 25.6, 23.5, 22.7, 14.1 ppm;
HRMS (ES+): m/z calcd for C33H58O5N: 548.4304 [M+NH4]+; found:
548.4310.
776 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.38–7.32 (m, 4H; Ar-H),
;
7.31–7.28 (m, 1H; Ar-H), 4.51 (s, 2H; Ph-CH2) 4.49–4.45 (m, 1H; H20),
4.33 (dd, J=6.7, 1.6 Hz, 1H; H23), 4.16–4.09 (m, 1H; H19), 4.08–3.89 (m,
1H; H16), 3.68–3.52 (m, 1H; H15), 3.47 (t, J=6.6 Hz, 2H; H9), 3.31 (ddd,
J=11.2, 6.7, 1.9 Hz, 1H; H24), 3.28–3.18 (m, 1H; H28), 2.32 (d, J=6.0 Hz,
1H; OH), 2.03–1.74 (m, 5H; H17a, H18, H25a, H26a), 1.73–1.58 (m, 3H; H10,
H17b), 1.57–1.08 (m, 22H; H11–H14, H25b, H26b, H27, H29–H33), 0.97–0.82 (m,
Compound 37: NaHMDS (160 mL, 0.2m soln in THF, 32 mmol) was added
to a solution of sulfone 34 (18.4 mg, 25 mmol) in THF (4 mL) at ꢀ788C.
After 10 min, a solution of aldehyde 5 (29.0 mg, 148 mmol) in THF
(2 mL) was added dropwise through a cannula. The reaction mixture was
warmed to ꢀ208C. After 4 h, saturated aqueous NH4Cl (2 mL) was
added, and the reaction mixture was warmed to RT. The organic com-
pounds were extracted with EtOAc (3ꢂ5 mL) and the combined organic
extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated. Purification by flash column chromatography (15%
EtOAc/hexanes) provided 37 (7.2 mg, 41%), as a colorless oil. Rf =0.83
(20% EtOAc/hexanes); [a]2D0 = +10.6 (c=0.36 in CHCl3); IR (NaCl): n˜ =
21H; H34, 2ꢂSiCACHTUNGTRENNUNG(CH3)3), 0.13 (s, 3H; SiCH3), 0.12 (s, 3H; SiCH3), 0.08
(s, 3H; SiCH3), 0.06 ppm (s, 3H; SiCH3); 13C NMR (100 MHz, CDCl3):
d=138.7, 128.4, 127.6, 127.5, 85.2, 83.3, 83.0, 82.5, 82.2, 81.4, 80.70, 80.65,
77.8, 75.2, 74.8, 72.9, 70.5, 66.9, 65.7, 64.5, 36.5, 33.1, 32.9, 31.9, 31.4, 29.8,
29.5, 28.4, 27.9, 27.6, 26.8, 26.7, 26.2, 26.0, 25.8, 25.6, 25.4, 23.3, 22.7,
18.33, 18.28, 14.1, ꢀ4.1, ꢀ4.5, ꢀ4.6, ꢀ4.9 ppm; HRMS (ES+): m/z calcd
for C45H84O6Si2N: 790.5832 [M+NH4]+; found: 790.5832.
2929, 2856, 2361, 2342, 1760 cmꢀ1 1H NMR (400 MHz, CDCl3): d=6.98
;
Compound 33: A solution of alkyne 32 (5.9 mg, 7.6 mmol) and TsNHNH2
(85 mg, 0.46 mmol) in DME (1 mL) was heated at reflux. A solution of
NaOAc (62 mg, 0.46 mmol) in H2O (1 mL) was added to the reaction sol-
ution over a period of 4 h. After this time, the reaction solution was
cooled and diluted with H2O (5 mL) and EtOAc (5 mL). The organic
compounds were extracted with EtOAc (3ꢂ5 mL) and the combined or-
ganic extracts were washed with HCl (3m, 3ꢂ5 mL), a saturated solution
of NaHCO3 (15 mL), and brine (15 mL). The organic extracts were dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography (10% EtOAc/hexanes) provided alcohol 33
(3.70 mg, 62%), as a colorless oil. Rf =0.40 (15% EtOAc/hexanes);
[a]2D0 = +2.6 (c=1.1 in CHCl3); IR (NaCl): n˜ =3442, 2928, 1460, 1363,
(app. q, J=1.6 Hz, 1H; H35), 5.40–5.35 (m, 2H; H8, H9), 4.99 (ddq, J=
7.8, 6.8, 1.6 Hz, 1H; H36), 4.00–3.89 (m, 2H; H16, H19), 3.89–3.82 (m, 2H;
H20, H23), 3.65–3.59 (m, 1H; H15), 3.29 (ddd, J=9.6, 5.6, 1.9 Hz, 1H; H24),
3.26–3.18 (m, 1H; H28), 2.26 (ddt, J=8.0, 7.5, 1.7 Hz, 2H; H3), 2.02–1.93
(m, 4H; H7, H10), 1.93–1.77 (m, 5H; H17a, H18a, H21a, H22a, H26a), 1.77–1.63
(m, 4H; H17b, H18b, H21b, H22b), 1.59–1.06 (m, 29H; H4–H6, H11–H14, H25,
H
26b, H27a, H29–H33), 1.40 (d, J=6.8 Hz, 3H; H37), 1.14 (app. qd, J=11.3,
4.0 Hz, 1H; H27b), 0.91–0.84 (m, 12H; H34, SiC(CH3)3), 0.06 (s, 3H;
AHCTUNGTRENNUNG
SiCH3), 0.04 ppm (s, 3H; SiCH3); 13C NMR (125 MHz, CDCl3): d=
173.9, 148.9, 134.3, 130.6, 130.0, 82.3, 81.9, 81.8, 81.5, 80.1, 77.8, 77.4, 74.7,
36.5, 32.6, 32.4, 32.2, 31.9, 31.5, 29.7, 29.6, 29.5, 29.4, 29.3, 28.7, 28.3, 27.9,
27.5, 27.3, 27.2, 27.0, 26.7, 26.0, 25.8, 25.6, 25.1, 23.5, 22.6, 19.2, 18.2, 14.1,
ꢀ4.2, ꢀ4.6 ppm; HRMS (ES+): m/z calcd for C43H76O6SiNa: 739.5307
[M+Na]+; found: 739.5309.
1097, 835, 775 cmꢀ1 1H NMR (400 MHz, CDCl3): d=7.37–7.32 (m, 4H;
;
Ar-H), 7.31–7.28 (m, 1H; Ar-H), 4.51 (s, 2H; Ph-CH2), 3.90 (dt, J=8.4,
5.9 Hz, 1H; H16), 3.83 (app. td, J=7.1, 3.7 Hz, 1H; H19), 3.77–3.72 (m,
Chem. Eur. J. 2013, 19, 8309 – 8320
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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8317

G. J. Florence et al.
Chamuvarinin (1): A solution of alkene 37 (3.4 mg, 4.74 mmol) and
TsNHNH2 (53 mg, 284 mmol) in DME (0.5 mL) was heated to reflux.
NaOAc (39 mg, 284 mmol) in H2O (0.5 mL) was added to the reaction
solution over 3 h. The reaction mixture was cooled and diluted with H2O
(3 mL) and EtOAc (3 mL). The organic compounds were extracted with
EtOAc (3ꢂ5 mL) and the combined organic extracts were washed with
3n HCl (3ꢂ5 mL), NaHCO3 (10 mL), and brine (10 mL), dried
(Na2SO4), filtered, and concentrated. The crude residue was filtered
through a silica plug (20% EtOAc/hexanes), concentrated, and redis-
solved in MeOH (1.0 mL). A 3n solution of HCl (0.3 mL) was added to
the resulting solution at 08C. After 45 min of warming to RT, the reac-
tion mixture was quenched by the addition of saturated aqueous
NaHCO3 (3 mL). The organic compounds were extracted with CH2Cl2
(3ꢂ5 mL). The combined organic extracts were dried (Na2SO4), filtered,
and concentrated. Purification by flash column chromatography (35%
EtOAc/hexanes) provided chamuvarinin (1; 2.1 mg, 73%), as a colorless
oil. Rf =0.17 (20% EtOAc/hexanes); [a]2D0 = +9.9 (c=0.1 in CHCl3); IR
H17b, H18b), 1.59–1.50 (m, 2H; H4), 1.45–1.27 (m, 12H; H5, H6, H11–H14),
1.39 (d, J=6.8 Hz, 3H; H37), 0.88 (s, 9H; SiCACTHUNGTRNEUNG(CH3)3), 0.06 (s, 3H;
SiCH3), 0.04 ppm (s, 3H; SiCH3); 13C NMR (100 MHz, CDCl3): d=
173.8, 148.8, 134.2, 130.5, 130.0, 82.0, 79.4, 77.4, 75.0, 64.9, 32.9, 32.5, 32.4,
29.5, 29.3, 29.2, 28.6, 27.8, 27.7, 27.2, 25.9, 25.5, 25.1, 19.2, 18.2, ꢀ4.2,
ꢀ4.6 ppm; HRMS (ES+): m/z calcd for C29H56O5SiN: 526.3922
[M+NH4]+; found: 526.3920.
Compound 38: NaHCO3 (120 mg, 1.40 mmol) followed by Dess–Martin
periodinane (360 mg, 0.84 mmol) were added to a solution of alcohol 41
(140 mg, 0.28 mmol) in CH2Cl2 (4 mL) at 08C. The reaction mixture was
stirred at 08C for 30 min, followed by warming to RT over an additional
1 h. The reaction mixture was re-cooled to 08C prior to the addition of
cold hexane (5 mL) and cold toluene (5 mL). The resultant white suspen-
sion was concentrated in vacuo to remove CH2Cl2 and purification by
flash column chromatography (15% EtOAc/hexanes) provided aldehyde
38 (98.6 mg, 69%), as a colorless oil. Rf =0.55 (30% EtOAc/hexanes);
[a]2D0 = +30.7 (c=1.08 in CHCl3); IR (thin film): n˜ =2928, 2855, 1755,
(NaCl): n˜ =2926, 2855, 1721, 1438, 1171, 1120, 721 cmꢀ1
;
1H NMR
1
1736, 1080 cmꢀ1; H NMR (300 MHz, CDCl3): d=9.64 (d, J=2.0 Hz, 1H;
(400 MHz, CDCl3): d=6.98 (q, J=1.6 Hz, 1H; H35), 4.99 (qq, J=6.8,
1.7 Hz, 1H; H36), 3.93 (dt, J=7.9, 6.1 Hz, 1H; H19), 3.88 (dt, J=6.5,
5.6 Hz, 1H; H23), 3.85–3.79 (m, 2H; H16, H20), 3.40–3.33 (m, 1H; H15),
3.28 (ddd, J=11.2, 5.6, 1.9 Hz, 1H; H24), 3.26–3.19 (m, 1H; H28), 2.53
(brs, 1H; OH), 2.28–2.23 (m, 2H; H3), 2.02–1.89 (m, 2H; H17a, H18a),
1.87–1.78 (m, 3H; H21a, H22a, H26a), 1.78–1.69 (m, 2H; H18b, H22b), 1.69–
1.43 (m, 7H; H4, H17b, H21b, H25a, H26b, H27a), 1.42–1.34 (m, 4H; H14, H29),
1.40 (d, J=6.8 Hz, 3H; H37), 1.33–1.20 (m, 27H; H5–H13, H25b, H30–H33),
1.13 (qd, J=10.9, 4.1 Hz, 1H; H27b), 0.87 ppm (t, J=7.1 Hz, 3H; H34);
13C NMR (125 MHz, CDCl3): d=173.9, 148.8, 134.3, 83.1, 82.06, 82.02,
81.5, 79.9, 77.9, 77.4, 74.4, 36.5, 33.5, 31.9, 31.4, 29.8, 29.7, 29.6 (2C), 29.5,
29.4 (2C), 29.3, 29.2, 28.8, 28.3, 28.0, 27.4, 26.9, 25.7, 25.5, 25.2, 23.5, 22.6,
19.2, 14.1 ppm; HRMS (ES+): m/z calcd for C37H64O6Na: 627.4601
[M+Na]+; found: 627.4606.
H20), 6.98 (app. q, J=1.5 Hz, 1H; H35), 5.43–5.30 (m, 2H; H8, H9), 4.98
(qq, J=6.8, 1.8 Hz, 1H; H36), 4.28 (ddd, J=7.7, 6.9, 2.0 Hz, 1H; H19),
4.07–4.00 (m, 1H; H16), 3.61 (app. q, J=5.0 Hz, 1H; H15), 2.25 (ddt, J=
8.9, 7.5, 1.6 Hz, 2H; H3), 2.20–2.11 (m, 1H; H18a), 2.01–1.84 (m, 6H; H7,
H10, H17a, H18b), 1.81–1.69 (m, 1H; H17b), 1.59–1.46 (m, 3H; H4, H14a),
1.44–1.22 (m, 11H; H5, H6, H11–H13, H14b), 1.39 (d, J=6.8 Hz, 3H; H37),
0.87 (s, 9H; SiCACHTNUGTRNEN(UG CH3)3), 0.06 (s, 3H; SiCH3), 0.05 ppm (s, 3H; SiCH3);
13C NMR (100 MHz ,CDCl3): d=203.0, 173.8, 148.8, 134.2, 130.4, 130.0,
83.3, 83.0, 77.4, 74.5, 33.1, 32.5, 32.4, 29.5, 29.3, 29.2, 28.6, 27.5, 27.2, 26.9,
25.9, 25.4, 25.1, 19.2, 18.2, ꢀ4.3, ꢀ4.5 ppm; HRMS (ES+): m/z calcd for
C29H54O5SiN: 524.3766 [M+NH4]+; found: 524.3755.
Compound 42:
Method A: nBuLi (430 mL, 0.68 mmol, 1.6m in hexane) was added to a
solution of alkyne 8 (330 mg, 0.97 mmol) in THF (2 mL) at ꢀ788C. After
10 min, a solution of aldehyde 38 (98.6 mg, 0.19 mmol) in THF (1 mL)
was added through a cannula. After 1.5 h, saturated aqueous NH4Cl
(5 mL) and EtOAc (5 mL) were added. The organic compounds were ex-
tracted with EtOAc (3ꢂ5 mL), washed with brine (5 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography (5% EtOAc/hexanes) provided alkyne 42 as a
75:25 mixture of C20 diastereoisomers (92.7 mg, 56%), as a colorless oil.
Compound 40: NaHMDS (470 mL, 0.2m solution in THF, 94 mmol) was
added to a solution of sulfone 39 (41.4 mg, 63 mmol) in THF (3 mL) at
ꢀ788C. After 10 min, a solution of aldehyde 5 (48.9 mg, 250 mmol) in
THF (2 mL) was added dropwise through a cannula. The reaction mix-
ture was warmed to ꢀ208C. After 2.5 h, saturated aqueous NH4Cl
(2 mL) was added, and the reaction mixture was warmed to RT. The or-
ganic compounds were extracted with EtOAc (3ꢂ5 mL) and the com-
bined organic extracts were washed with brine (10 mL), dried (Na2SO4),
filtered, and concentrated. Purification by flash column chromatography
(15% EtOAc/hexanes) provided 40 (33.5 mg, 85%), as a colorless oil.
Rf =0.53 (15% acetone/hexanes); [a]2D0 = +19.5 (c=0.81 in CHCl3); IR
Method B: nBuLi (160 mL, 0.25 mmol, 1.6m in hexane) was added to a
solution of alkyne 8 (100 mg, 0.29 mmol) in MTBE (1 mL) at 08C. The
temperature was then lowered to ꢀ1008C and after 10 min a solution of
aldehyde 38 (30.2 mg, 59 mmol) in MTBE (1 mL) was added through a
cannula. After 4 h, saturated aqueous NH4Cl (5 mL) and CH2Cl2 (5 mL)
were added. The organic compounds were extracted with CH2Cl2 (3ꢂ
5 mL), washed with brine (5 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. Purification by flash column chromatography (5–10%
EtOAc/hexanes) provided alkyne 42 (14.6 mg, 29%), as a colorless oil (>
95:5 d.r.). Rf =0.53 (20% EtOAc/hexanes); [a]2D0 = +19.4 (c=0.84 in
(thin film): n˜ =2928, 2857, 1761, 1653, 1084 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d=6.98 (app. q, J=1.6 Hz, 1H; H35), 5.45–5.32 (m, 2H; H8, H9),
5.03–4.95 (qq, J=6.7, 1.7 Hz, 1H; H36), 4.03–3.89 (m, 2H; H16, H19), 3.66–
3.49 (m, 3H; H15,H20), 2.29–2.23 (ddt, J=8.6, 7.4, 1.6 Hz, 2H; H3), 2.04–
1.80 (m, 6H; H7, H10, H17a, H18a), 1.75–1.63 (m, 2H; H17b, H18b), 1.55–1.50
(m, 2H; H4), 1.46–1.25 (m, 12H; H5, H6, H11–H14), 1.40 (d, J=6.8 Hz,
3H; H37), 0.89–0.87 (m, 18H; 2ꢂSiCACHTUNGRTNEUNG(CH3)3), 0.06 (s, 3H; SiCH3), 0.049
CHCl3); IR (thin film): n˜ =3486, 2928, 2855, 1759, 1099 cmꢀ1 1H NMR
;
(s, 3H; SiCH3), 0.048 (s, 3H; SiCH3), 0.04 ppm (s, 3H; SiCH3); 13C NMR
(75 MHz, CDCl3): d=173.8, 148.8, 134.3, 130.6, 130.0, 82.0, 79.6, 77.2,
74.8, 66.0, 32.5, 32.4, 29.7, 29.6, 29.4, 29.2, 28.6, 28.5, 27.2, 26.0, 25.9, 25.8,
25.1, 19.2, 18.3, 18.2, ꢀ4.2, ꢀ4.6, ꢀ5.3 ppm; HRMS (ES+): m/z calcd for
C35H70O5Si2N: 640.4787 [M+NH4]+; found: 640.4784.
(300 MHz, CDCl3): d=6.98 (app. q, J=1.5 Hz, 1H; H35), 5.45–5.30 (m,
2H; H8, H9), 4.99 (qq, J=6.7, 1.6 Hz, 1H; H36), 4.48–4.43 (m, 1H; H20),
4.33–4.28 (m, 1H; H23), 4.15–4.08 (m, 1H; H19), 4.06–3.99 (m, 1H; H16),
3.58–3.51 (m, 1H; H15), 3.30 (ddd, J=11.1, 6.1, 1.8 Hz, 1H; H24), 3.25–
3.21 (m, 1H; H28), 2.27 (ddt, J=8.9, 7.6, 1.6 Hz, 2H; H3), 2.02–1.67 (m,
8H; H7, H10, H17, H18a, H25a), 1.58–1.49 (m, 3H; H4, H27a), 1.46–1.24 (m,
25H; H5, H6, H11–H14, H18b, H26, H29–H33), 1.40 (d, J=6.8 Hz, 3H; H37),
Compound 41: (ꢁ)-CSA (6.80 mg, 0.03 mmol) was added to a solution of
bis-tert-butyldimethylsilyl ether 40 (184 mg, 0.295 mmol) in MeOH/
CH2Cl2 (1:4, 3 mL) at 08C. After 1.5 h, saturated aqueous NaHCO3
(5 mL) and CH2Cl2 (5 mL) were added. The organic compounds were ex-
tracted with CH2Cl2 (3ꢂ10 mL) and the combined organic extracts were
dried (Na2SO4), filtered, and concentrated. Purification by flash column
chromatography (20% EtOAc/hexanes) provided alcohol 41 (94.5 mg,
63%), as a colorless oil. Rf =0.45 (35% EtOAc/hexanes); [a]2D0 = +16.2
1.21–1.11 (m, 2H; H25b, H27b), 0.91–0.85 (m, 21H; H34, 2ꢂSiCACHTUNGTRENNUNG(CH3)3),
0.12 (s, 3H; SiCH3), 0.10 (s, 3H; SiCH3), 0.06 (s, 3H; SiCH3), 0.05 ppm
(s, 3H; SiCH3); 13C NMR (75 MHz, CDCl3): d=173.7, 148.8, 134.2,
130.4, 130.0, 85.1, 83.2, 83.0, 81.4, 80.6 77.7, 77.3, 75.1, 66.8, 64.5, 36.4,
33.0, 32.5, 32.3, 31.8, 31.3, 29.5, 29.4, 29.2, 28.6, 27.8, 27.2, 26.8, 26.6, 25.9,
25.7, 25.4, 25.3, 25.1, 23.2, 22.6, 19.1, 18.23, 18.18, 14.0, ꢀ4.2, ꢀ4.6, ꢀ4.7,
ꢀ4.9 ppm; HRMS (ES+): m/z calcd for C49H92O7Si2N: 862.6407
[M+NH4]+; found: 862.6405.
(c=0.87 in CHCl3); IR (thin film): n˜ =3480, 2928, 2855, 1755, 1082 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=6.97 (q, J=1.5 Hz, 1H; H35), 5.42–5.29
(m, 2H; H8, H9), 4.98 (qq, J=6.8, 1.8 Hz, 1H; H36), 4.09–4.02 (m, 1H;
H19), 3.91 (dt, J=7.9, 6.3 Hz, 1H; H16), 3.64–3.61 (m, 1H; H20a), 3.58–3.54
(m, 1H; H15), 3.46 (dd, J=11.5, 6.0 Hz, 1H; H20b), 2.25 (ddt, J=8.9, 7.3,
1.7 Hz, 2H; H3), 2.02–1.86 (m, 6H; H7, H10, H17a, H18a), 1.73–1.61 (m, 2H;
Compound 43:
A solution of alkyne 42 (14.6 mg, 17 mmol) and
TsNHNH2 (193 mg, 1.04 mmol) in DME (1 mL) was heated to reflux.
NaOAc (141 mg, 1.04 mmol) in H2O (1 mL) was added to the reaction
8318
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 8309 – 8320

Chamuvarinin and Structural Analogues
FULL PAPER
solution over 3 h. The reaction mixture was cooled and diluted with H2O
(3 mL) and EtOAc (5 mL). The organic compounds were extracted with
EtOAc (3ꢂ5 mL) and the combined organic extracts were washed with
3n HCl (3ꢂ5 mL), NaHCO3 (10 mL), and brine (10 mL), dried
(Na2SO4), filtered, and concentrated. Purification by flash column chro-
matography (5–10% EtOAc/hexanes) provided alkane 43 (13.3 mg,
90%), as a colorless oil. Rf =0.57 (20% EtOAc/hexanes); [a]2D0 = +7.8
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(c=0.98 in CHCl3); IR (thin film): n˜ =3495, 2928, 2855, 1759, 1086 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=6.99 (app. q, J=1.5 Hz, 1H; H35), 4.99
(qq, J=6.8, 1.6 Hz, 1H; H36), 3.91 (dt, J=8.2, 6.3 Hz, 1H; H16), 3.84 (td,
J=7.1, 3.5 Hz, 1H; H19), 3.75–3.71 (m, 1H; H20), 3.64 (app. q, J=5.5 Hz,
1H; H23), 3.55–3.51 (m, 1H; H15), 3.28–3.20 (m, 2H; H24, H28), 2.27 (ddt,
J=8.9, 7.2, 1.7 Hz, 2H; H3), 1.95–1.78 (m, 4H; H17a, H18, H26a), 1.69–1.51
(m, 7H; H4, H17b, H22, H25a, H27a), 1.49–1.21 (m, 33H; H5–H14, H21, H26b
H29–H33), 1.40 (d, J=6.8 Hz, 3H; H37), 1.19–1.07 (m, 2H; H25b, H27b),
0.89–0.88 (m, 21H; H34, 2ꢂSiC(CH3)3), 0.07–0.05 ppm (m, 12H; 2ꢂ
,
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AHCTUNGTRENNUNG
SiCH3); 13C NMR (75 MHz, CDCl3): d=173.9, 148.8, 134.3, 82.5, 82.2,
80.8, 78.0, 77.4, 75.4, 74.5, 72.0, 36.4, 33.0, 31.8, 31.4, 29.8, 29.6, 29.52,
29.46, 29.3, 29.2, 28.8, 28.5, 28.0, 27.4, 26.00, 25.96, 25.7, 25.6, 25.4, 25.3,
25.2, 23.6, 22.6, 19.2, 18.3, 18.2, 14.1, ꢀ4.1, ꢀ4.2, ꢀ4.57, ꢀ4.59 ppm;
HRMS (ES+): m/z calcd for C49H94O7Si2Na: 873.6436 [M+Na]+; found:
873.6443.
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Compound 1: Et3N (11.0 mL, 78 mmol) and MsCl (4.30 mL, 56 mmol) were
added to a solution of alcohol 43 (9.50 mg, 11.0 mmol) in CH2Cl2 (1 mL)
at 08C. After 1.5 h, saturated aqueous NH4Cl (2 mL) and CH2Cl2 (5 mL)
were added. The organic compounds were extracted with CH2Cl2 (3ꢂ
5 mL) and the combined organic extracts were washed with H2O (5 mL)
and brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The crude mesylate was dissolved in CH2Cl2/MeOH (1:4, 2.5 mL), cooled
to 08C, and 3n HCl (0.3 mL) was added. After 2 h of warming to RT, the
reaction mixture was quenched by the addition of saturated aqueous
NaHCO3 (5 mL). The organic compounds were extracted with CH2Cl2
(3ꢂ5 mL). The combined organic extracts were washed with brine
(10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude
diol was dissolved in pyridine (1 mL) and heated to 658C. After 16 h,
H2O (2 mL) was added and the organic compounds were extracted with
CH2Cl2 (3ꢂ5 mL). The combined organic extracts were dried (Na2SO4)
and concentrated. Purification by flash column chromatography (10–25%
EtOAc/hexanes) afforded chamuvarinin 1 (3.8 mg, 57% over 3 steps), as
a colorless oil. Spectroscopic data were in full agreement with those of
the synthetic material prepared from compound 37.
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Acknowledgements
We thank the EPSRC (EP/F011458/1), the Royal Society (G.J.F.), EaSt-
Chem (V.R.R.), the Wellcome Trust (T.K.S.) and AstraZeneca for sup-
port; Dr. Dusan Uhrin (Edinburgh) and Dr. Tomas Lebl (St. Andrews)
for NMR spectra; Professor Erwan Poupon (Universitꢃ Paris Sud) for
copies of 1H and 13C NMR spectra of natural chamuvarinin; and the
EPSRC National Mass Spectrometry Service Centre, Swansea, UK.
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Received: December 20, 2012
Revised: March 14, 2013
Published online: April 29, 2013
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