Synthesis of the originally proposed structure of palmerolide C

Article abstract of DOI:10.1002/chem.201203067

A stereoselective synthesis of the proposed structure of palmerolide C (1), a cytotoxic marine macrolide isolated from the Antarctic tunicate Synoicum adareanum, utilizes a convergent carbonyl-based coupling strategy to construct the C1-C24 carbon skeleton (see scheme). Compound 1 was shown to be a diastereomer of palmerolide C, and the structural revision of the natural product is proposed. Copyright

Full text of DOI:10.1002/chem.201203067

DOI: 10.1002/chem.201203067
Synthesis of the Originally Proposed Structure of Palmerolide C
[
a]
Gordon J. Florence* and Joanna Wlochal
In 2006, Baker and co-workers reported the isolation of
[1]
palmerolide A, the first member of a unique family of
polyketide-derived macrolides from the Antarctic tunicate
Synoicum adareanum collected in the shallow waters sur-
ACHTUNGTRENNUNG
[2,3]
rounding Anvers Island on the Antarctic Peninsula.
Sig-
nificant synthetic attention was drawn to palmerolide A (1,
Scheme 1) given its remarkable selectivity towards human
melanoma cancer cell lines (UACC-62 and Mi14 IC =24
5
0
and 76 nm, respectively), culminating in three total syntheses
[4,5]
and numerous synthetic studies to date.
Alongside pal-
merolide A, eight further palmerolides were co-isolated
[2]
from S. adraneum. Within this family of macrolides, pal-
merolide C (2) is a constitutional isomer of 1 that displays
similar activity towards the UACC-62 human melanoma cell
[
2a,6]
line (IC =110 nm).
Structurally, palmerolide C shares
50
[1c]
many features with 1, supporting a common biogenesis,
including the elaborate side chain appended at C20, contain-
ing an E,E-dienamide (C21–C24), whereas the 20-mem-
bered macrolide core retains the E,E-diene at C14–C17.
However, palmerolide C differs markedly within the C6–
C11 region, with an E alkene at C6 and a contiguous stereo-
triad spanning C8–C10. The absolute configuration of the
stereotriad was proposed as 8S, 9S, 10S on the basis of C8-
Mosher ester analysis and J-based configurational analysis,
[6]
as shown in 2. To date no total synthesis of palmerolide C
has been reported and herein we report our efforts towards
this goal, culminating in the synthesis of the initially pro-
posed structure 2 and a reassignment of the structure of pal-
merolide C based on our re-evaluation of available spectro-
[6,7]
scopic data.
As outlined in Scheme 1, our strategy towards 2 was reli-
ant on late-stage enamide installation and macrolactoniza-
tion with the assembly of the carbon skeleton arising from
[8]
the Julia–Kocienski olefination at C14–C15 between the
fully elaborated coupling partners aldehyde 3 (C1–C14) and
sulfone 4 (C15–C24), which we viewed advantageous in
terms of minimizing the number of post-coupling operations.
In turn, the synthesis of the two key coupling partners was
Scheme 1. Synthetic strategy for originally proposed structure of palmer-
olide C. Ar=1-phenyltetrazole, TBS=tert-butyldimethylsilyl, TES=tri-
AHCTUNGTRENNUNGe thylsilyl.
envisaged to arise from the application of suitable aldol-
based coupling strategies. The C1–C14 aldehyde 3 would be
reliant on an aldol/elimination/reduction sequence using
C1–C6 aldehyde 5 and C7–C14 methyl ketone 6. In turn the
C15–C24 subunit 4 would rely on an ambitious vinylogous
Mukaiyama aldol reaction reliant on Felkin–Anh induction
from the a-chiral iododiene aldehyde 7 to control the intro-
[
a] Dr. G. J. Florence, J. Wlochal
EaStCHEM School of Chemistry
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.201203067.
[9]
duction of the C19 stereocenter.
14250
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14250 – 14254

COMMUNICATION
Scheme 2. Synthesis of C1–C14 subunit 3: a) 30 mol% (S)-proline,
CHCl , RT, 5 days, 44% (96% ee); b) PMBTCA, La(OTf) , PhCH , 08C
to RT, 6 h (77%); c) p-TsOH·H O, MeOH, RT, 2 h (92%); d) i) H
THF/H O, 0 8C to RT, 12 h; ii) MeI, K CO
e) TBSOTf, 2,6-lutidine, CH Cl
À788C, 2 h (98%); f) i) thexylBH
THF, 08C, 1 h; ii) H
96%); g) TBSCl, ImH, CH
iPrMgCl, THF, À408C, 4 h (97%); i) MeMgBr, THF, 08C, 1 h (96%);
j) (COCl) , DMSO, CH Cl N, À788C to RT, 1 h (80%);
, À788C, 1 h; Et
k) (EtO) P(O)CH CO Et, LiCl, iPrNEt , MeCN, RT, 18 h (77%); l) CSA
10 mol%), CH Cl /MeOH (4:1), 08C, 1.5 h (98%); m) (COCl) , DMSO,
CH Cl N, À788C to RT, 1 h (87%). PMBTCA=para-
, À788C, 1 h; Et
methoxybenzyl trichloroacetimidate, OTf=trifluoromethanesulfonate, p-
TsOH·H O=para-tolunenesulfonic acid monohydrate, TBSOTf=tert-bu-
3
A
H
U
G
R
N
N
3
3
2
2
IO
6
2
,
,
2
2
3
, DMF, 08C, 2 h (64%);
2
2
,
2
O
2
(30% aq), NaOH (10 wt% aq), 08C, 20 min
Cl , RT, 10 h (92%); h) (MeO)NHMe·HCl,
(
2
2
Scheme 3. Synthesis of C15–C24 subunit 4: a) (EtO)
(CH )CO Et, Ba(OH) wet THF, 08C, 10 h (76%, E/Z=7:1);
b) DIBAL, CH Cl , CH Cl , 08C,
, À788C, 4 h (81%); c) DMP, NaHCO
1 h (90%); d) i) CrCl , CHI , THF, 1,4-dioxane, RT, 2 h; ii) TBAF, THF,
08C to RT, 1 h (90%, E/Z=19:1); e) DMP, NaHCO , CH Cl , 08C, 1 h
À958C, 2 h (70%, 6:1 d.r.);
, À788C, 2 h (96%); h) DIBAL, CH Cl
, THF,
, HMPA, MeOH,
8C to RT, 12 h (95%). Ar=1-phenyltetrazole, DIBAL=diisobutylalu-
2
P(O)CH-
2
2
2
3
A
H
U
T
E
N
N
3
2
2
,
2
2
2
2
(
2
2
2
2
2
3
2
2
2
2
3
2
3
3
2
2
(90%); f) BF
g) TESOTf, 2,6-lutidine, CH
3
·Et
2
O, CaH
2
,
CH
2 2
Cl ,
2
tyldimethylsilyl trifluoromethanesulfonate, thexyl=2,3-dimethyl-2-butyl,
TBSCl=tert-butyldimethylsilyl chloride, ImH=imidazole, CSA=(Æ)-
camphorsulfonic acid.
2
Cl
2
2
2
,
À788C, 2 h (81%); i) 1H-mercaptophenyltetrazole, DIAD, PPh
3
08C to RT, 1 h (80%); j) (NH Mo O, H
0
4
)
6
7
O
24·4H
2
2 2
O
minium hydride, TBAF=tetrabutylammonium fluoride, DMP=Dess–
Martin periodinane, TESOTf=triethylsilyl trifluoromethanesulfonate,
DIAD=diisopropyl azodicarboxylate, HMPA=hexamethylphosphor-
As shown in Scheme 2, the synthesis of the C1–C14 sub-
AHCTUNGTRENNUNGa mide.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
unit 3 began with Endersꢁ proline-catalyzed organocatalytic
cross aldol reaction of dioxanone 8 and aldehyde 9 to intro-
[10]
duce the anti-configured C8 and C9 stereocenters. Reac-
tion of 8 and 9 with 30 mol% (S)-proline in chloroform over
five days provided anti-aldol adduct 10 in 44% yield with
alkene. Reaction of 15 and triethyl 2-phosphonopropionate
under the conditions described by Paterson and co-workers
9
6% enantiomeric excess (ee). PMB ether formation and
(Ba(OH) in wet THF) provided the E-trisubstituted enoate
2
[14,15]
acetonide deprotection provided ketodiol 11 in 71% yield
over two steps. Regioselective oxidative cleavage of 11 with
periodic acid and methylation of the intermediate carboxylic
acid gave a-hydroxyester 12 (64%). Protection of the a-
hydroxyl as its TBS ether (98%) was followed by hydro-
16 (76%, E/Z=7:1).
DIBAL reduction and subsequent
reoxidation of the intermediate alcohol with Dess–Martin
periodinane gave aldehyde 17 in preparation for the installa-
tion of the sensitive C24-vinyl iodide. Initially, Takai olefina-
[11]
[16]
tion of 17 proved troublesome due to the propensity of
the intermediate to both isomerize and decompose upon iso-
lation. Gratifyingly, this issue was resolved by submitting
the crude reaction products directly to TBAF to give alcohol
18 in excellent yield and selectivity (90% over two steps, E/
Z=19:1). Dess–Martin periodinane oxidation of 18 provid-
ed aldehyde 7 in preparation for the vinylogous Mukaiyama
ACHTUNGTRENNUNGb oration with thexylborane to provide 13 (96%). TBS pro-
tection, conversion of the resulting ester to the Weinreb
amide and subsequent addition of MeMgBr provided effi-
cient access to the C7–C14 methyl ketone 6, (86% from 13)
in readiness for the aldol/elimination sequence to introduce
the C6–C7 alkene. The required C1–C6 aldehyde 5 was
readily prepared from mono-TBS-protected 1,4-butanediol
[12]
[9]
aldol reaction to introduce the C19-stereocenter. Treat-
14 in 53% yield over four steps.
ment of 7 and silyl ketene acetal 19 with BF ·Et O in
3
2
As outlined in Scheme 3, preparation of the C15–C24 sub-
CH Cl at À958C provided the desired g-adduct 21 preferen-
2
2
unit began with the homologation of the readily available a-
tially with good levels of Felkin–Anh induction (70%, d.r.=
[13]
[17]
chiral aldehyde 15
to install the C21 E-trisubstituted
6:1). Chromatographic separation provided 21 as a single
Chem. Eur. J. 2012, 18, 14250 – 14254
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14251

G. J. Florence and J. Wlochal
pure diastereomer, which was readily protected as its TES
ether 22 (TESOTf/2,6-lutidine, 96%). The resulting ester
was reduced with DIBAL to give alcohol 23. Treatment of
completed in two further steps involving selective primary
TBS ether deprotection at C14 with CSA in CH Cl /MeOH
2
2
(93%) and Dess–Martin oxidation (80%). Having establish-
ed access to 3, our attention turned to the final C14–C15
coupling to introduce the E,E-diene motif and the comple-
tion of the putative structure of palmerolide C. In practice,
treatment of sulfone 4 with NaHMDS in THF at À788C fol-
lowed by the addition of aldehyde 3 proceeded smoothly to
give the E,E-diene 28 in 78% yield (E/Z=6:1) completing
23 with 1H-mercaptophenyltetrazole under Mitsunobu con-
ditions (80%) gave sulfide 24. The use of HMPA as a co-
solvent with MeOH in the oxidation of 24 with H O and
2
2
ammonium molybdate proved critical in providing access to
[18]
sulfone 4 in 95% yield, in preparation for the C14–C15
Julia–Kocienski olefination.
[8]
With the key subunits in hand, attention turned to their
assembly beginning with the aldol/elimination coupling of 5
and 6 to install the C6–C7 alkene (Scheme 4). Thus, enoliza-
tion of 6 with c-Hex BCl/Et N and addition of aldehyde 5
the C1–C24 carbon skeleton. Selective deprotection of the
C19-TES ether with HF·pyridine/pyridine (88%) provided
29. At this stage the minor Z,E-diene from the coupling re-
action was separated by chromatography. Subsequent cleav-
age of the C1-ethyl ester with KOTMS provided the inter-
mediate seco-acid, which smoothly underwent macrolactoni-
zation under Yamaguchi conditions to provide the 20-mem-
2
3
followed by mild oxidative work-up provided aldol adduct
2
4 in 90% yield, as an inconsequential 1.6:1 mixture of dia-
[19,20]
stereomers.
Treatment of 24 with Martin sulfurane pro-
[24]
moted elimination to provide the E-enone 25 exclusively in
bered macrolide 30 in 71% yield over two steps. Removal
of the remaining TBS ethers at C8 and C9 was then effected
by treatment of 30 with TBAF in THF to give the advanced
precursor 31 (85%). Following extensive optimization of the
protocol developed by Nicolaou and Chen for palmerol-
[21]
95% yield.
Reduction of enone 25 under Luche condi-
tions (NaBH , CeCl , À788C) proceeded with high levels of
4
3
substrate control over the C7 stereocenter to give alcohol 26
[22,23]
in 94% yield.
Formation of the TBS ether at C7 (87%)
[
4b–e]
was then followed by oxidative cleavage of the C10-PMB
ether with DDQ (88%) and carbamate formation (72%) to
provide 27. The fully elaborated C1–C14 aldehyde 3 was
A
H
U
G
R
N
U
G
the installation of the terminal enamide by the
[25]
Buchwald Cu-catalyzed coupling of 31 and amide 32 with
CuI (2 equiv), K CO (5 equiv), and N,N’-dimethylethylene-
2
3
Scheme 4. Completion of the originally proposed structure of palmerolide C: a) i) Compound 6, cHex
À788C, 2 h; iii) H (30% aq), pH 7 buffer, MeOH, 08C, 0.5 h (90%); b) [C (CF O] (C
NaBH Cl
MeOH, À788C, 1 h (94%); d) TBSOTf, 2,6-lutidine, CH
f) Cl CC(O)NCO, CH Cl , 08C to RT 1 h; then Al , CH Cl , RT, 16 h (72%); g) CSA, CH
CH Cl
, 08C, 1 h (80%); i) NaHMDS, THF, À788C, 1 h (78%, E/Z=7:1); j) HF·pyr, pyr, THF, 08C, 1 h (88%); k) KOTMS, THF, 08C, 10 h; l) i) 2,4,6-tri-
chlorobenzoyl chloride, Et N, PhMe, RT, 1 h; ii) DMAP, RT, 15 h (71% from 29); m) TBAF, THF, 08C to RT, 2 h (85%); n) CuI, K CO , N,N’-dimeth-
ylethylenediamine, DMF, RT, 1 h (53%). cHex=cyclohexyl, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, NaHMDS=sodium bis(trimethylsilyl)-
amide, Ar=1-phenyltetrazole, HF·pyr=hydrogen fluoride pyridine complex, pyr=pyridine, KOTMS=potassium trimethylsilanolate, DMAP=4-N,N-di-
methylaminopyridine, DMF=N,N-dimethylformamide.
2
BCl, Et
3
N, Et
Cl
, À108C, 1 h (95%); c) CeCl
Cl pH 7 buffer, 08C, 1 h (88%);
/MeOH (6:1), 08C, 1 h (93%); h) DMP, NaHCO
2
O, À788C, 0.5 h; ii) compound 5,
2
O
2
6
H
5
C
A
H
U
G
R
N
U
G
3
)
2
2
S
A
H
U
G
R
N
U
G
6
H
5
)
2
, CH
2
2
3
·7H O,
2
4
,
2
2
,
À788C, 2 h (87%); e) DDQ, CH
Cl
2
2
,
3
2
2
2
O
3
2
2
2
2
3
,
2
2
3
2
3
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
14252
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 14250 – 14254

Synthesis of the Originally Proposed Structure of Palmerolide C
COMMUNICATION
diamine (3 equiv) in degassed DMF provided 2 in 53% iso-
lated yield completing the synthesis of the proposed struc-
ture of palmerolide C (2).
At this point, comparison of the H NMR spectroscopic
data of our synthetic material 2 with that reported for pal-
Acknowledgements
This work was supported by the EPSRC (EP/F011458/1), the Royal Soci-
ety (University Research Fellowship to GJF), and AstraZeneca. We
1
1
thank Professor Bill J. Baker for copies of H NMR spectra of natural
palmerolide C. We thank the EPSRC National Mass Spectrometry Serv-
ice Centre, Swansea, UK for mass spectroscopic analysis.
merolide C in both [D ]DMSO and [D ]MeCN did not
6
3
[26]
match.
There were distinct differences between the H8,
H9, and H10 resonances suggesting that at least one of the
three stereocenters within the C8–C10 stereotriad had been
incorrectly assigned. Based on the available spectroscopic
data, we undertook a re-evaluation of the original J-based
Keywords: macrolide · melanoma · natural products ·
structure elucidation · total synthesis
[6,27]
configurational analysis.
The initial assignment for pal-
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an anti relationship between H9–H10 as shown in Figure 1
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Figure 1. Reassignment of palmerolide C based on re-evaluation of J-
based configurational analysis data (Newman projections reproduced
from ref. [6]).
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and the revised structure of palmerolide C to be as depicted
in structure 33.
In summary, we have completed a highly stereocontrolled
synthesis of 2, the originally proposed structure of palmero-
lide C. The synthesis proceeds in 23 steps in the longest
linear sequence. The use of a fully functionalized C1–C14
subunit 3 and incorporating the E,E-iododiene in 4 enables
an efficient five-step endgame following the final key C14–
C15 bond construction. Further studies are currently under-
way to secure the unambiguous structural identity of pal-
merolide C.
4
4, 1012–1044.
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[
[
3
13] Aldehyde 15 was prepared in three steps from methyl (S)-3-hy-
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Chem. Eur. J. 2012, 18, 14250 – 14254
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14253

G. J. Florence and J. Wlochal
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[
[
[
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[
25] For full details of optimized conditions, see the Supporting Informa-
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[
Received: August 29, 2012
Published online: October 2, 2012
[
Please note: Minor changes have been made to this manuscript since its
publication in Chemistry—A European Journal Early View. The Editor.
[
14254
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