Total synthesis of the antimitotic marine macrolide (-)-leiodermatolide

Article abstract of DOI:10.1002/anie.201310164

Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we rep

Full text of DOI:10.1002/anie.201310164

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Angewandte
Communications
DOI: 10.1002/anie.201310164
Natural Product Synthesis
Total Synthesis of the Antimitotic Marine Macrolide
(ꢀ)-Leiodermatolide**
Ian Paterson,* Kenneth K.-H. Ng, Simon Williams, David C. Millican, and Stephen M. Dalby
Abstract: Leiodermatolide is an antimitotic macrolide isolated
from the marine sponge Leiodermatium sp. whose potentially
novel tubulin-targeting mechanism of action makes it an
exciting lead for anticancer drug discovery. In pursuit of
a sustainable supply, we report a highly stereocontrolled total
synthesis (3.2% yield) based on a convergent sequence of
palladium-mediated fragment assembly and macrolactoniza-
tion. Boron-mediated aldol reactions were used to configure
the three key fragments 2, 5, and 6 by employing the
appropriate enantiomer of the lactate-derived ketone 7.
T
ubulin-targeting compounds are perhaps the most validated
subset of clinically important anticancer agents, with natural
products and analogues representing the mainstay for current
chemotherapy,[1–3] recently supplemented by the approval of
the antibody–maytansinoid conjugate Kadcyla (trastuzumab
emtansine).[2] Leiodermatolide (1; Scheme 1) was isolated
(0.001% wet weight) by the Wright group in 2008 from the
lithistid sponge Leiodermatium sp. collected by submersible
off the Florida coastline.[4a] Leiodermatolide exhibits potent
antiproliferative activity against a panel of human cancer cell
lines (e.g. IC50 = 3.3 nm for A549 lung adenocarcinoma cells,
5.0 nm for PANC-1 pancreatic carcinoma cells), whilst show-
ing reduced toxicity to normal cells. This activity appears to
be mediated through the disruption of tubulin dynamics to
induce cell-cycle arrest in the G2/M phase and apoptosis.
Although the exact mechanism of action of leiodermatolide is
currently unknown, it is clearly distinct from that of other
tubulin-targeting drugs. Thus, leiodermatolide could serve as
a promising lead compound for the development of new
anticancer agents, provided a sustainable supply can be
generated by chemical synthesis.[5–7]
Scheme 1. Retrosynthetic analysis and key fragments for the synthesis
of leiodermatolide. Bz=benzoyl, PMB=para-methoxybenzyl,
TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl, TMS=tri-
methylsilyl.
[*] Prof. Dr. I. Paterson, K. K.-H. Ng, S. Williams, D. C. Millican,
Dr. S. M. Dalby
From a structural perspective, leiodermatolide features
a triply unsaturated 16-membered macrolactone appended at
C9 with a carbamate group and at C15 with an E,E-dienyl side
chain terminating in a d-lactone ring. This unique structure
incorporates a total of nine stereocenters. In association with
the Wright research group,[4b] we elucidated the relative
configuration of leiodermatolide by using a combination of
homo- and heteronuclear NMR spectroscopic analysis,
molecular modeling, and computational DP4 NMR predic-
tion.[8] The resulting assignment for the C1–C16 region was
further supported by our synthesis of a macrocyclic fragment
with a truncated side chain,[5] whereas an alternative stereo-
structure could be ruled out on the basis of synthetic studies
reported earlier.[6a] The full configuration of the isolated C1–
C16 and C20–C25 stereoclusters was only recently tied down
University Chemical Laboratory, University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
E-mail: ip100@cam.ac.uk
Homepage: http://www-paterson.ch.cam.ac.uk
[**] This research was supported by a SCAST postgraduate research
scholarship (K.K.-H.N.), the Todd-Raphael Fund (S.W.), and Clare
College, Cambridge (S.M.D.). We thank Dr. Amy Wright (HBOI,
Florida Atlantic University) for helpful discussions and the EPSRC
UK National Mass Spectrometry Facility at Swansea University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310164.
ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
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with the first total synthesis of (ꢀ)-leiodermatolide (1) by the
Fꢀrstner research group employing an elegant strategy based
on ring-closing alkyne metathesis.[7] We now report a highly
convergent total synthesis of (ꢀ)-leiodermatolide implement-
ing a complementary macrolactonization strategy that also
features the extensive application of our versatile lactate aldol
chemistry[9] along with a variety of palladium-mediated
coupling reactions.[10]
Building on the lessons learned from earlier synthetic
efforts directed towards the macrocyclic core,[5] Scheme 1
depicts the main retrosynthetic disconnections and key
fragments 2–6 devised for the synthesis of leiodermatolide.
The structure was initially simplified by disassembly of the
10Z,12Z-diene region and opening of the macrolactone ring
in 1 to reveal the C1–C11 vinyl stannane 2 and the C12–C25
vinyl iodide 3 containing the entire side chain for a planned
late-stage Stille coupling. The former fragment was then
envisaged to be available by elaboration of vinyl triflate 4
through a Suzuki-type methylation and an anti-selective aldol
reaction using (R)-7. The more elaborate fragment 3 would
arise in turn through stereocontrolled installation of the
16E,18E diene by a Heck coupling between vinyl iodide 5 and
the correctly configured allyl-substituted d-lactone 6, con-
structed using (S)- and (R)-7, respectively.
The synthesis of vinyl stannane 2 utilized Roche ester
derivative 8 as the source of the C6 methyl-bearing stereo-
center (Scheme 2).[11] The required 4E-configured trisubsti-
tuted alkene was first introduced via the corresponding
stereodefined vinyl triflate 4. In practice, controlled addition
of TBSO(CH2)4MgBr to 8 provided the required ketone
(88%), which was converted into 4 with high selectivity
(82%, > 20:1 Z/E) by treatment of the kinetically generated
lithium enolate (LiHMDS) with the Comins reagent.[12] After
screening various methods for methylation, Suzuki coupling
of 4 with trimethylboroxine[13] (cat. [Pd(PPh3)4], K2CO3) was
found to proceed well to afford the E alkene 9 (96%, > 20:1
E/Z). Following cleavage of the PMB ether (DDQ) and Dess–
Martin oxidation (69%), the resulting aldehyde 10 was
treated with the E dicyclohexylboron enolate derived from
(R)-7 (c-Hex2BCl, Et3N).[9] This matched aldol addition[14]
afforded the anti adduct 11 (96%, d.r. > 20:1) with a high
level of control over the C7/C8 stereocenters.
Next, 11 was converted into ynone 12 (67%) by
a sequence of silylation, (trimethylsilyl)acetylide addition,
basic methanolysis, and oxidative glycol cleavage.[15] The
Z iodoenone could then be conveniently accessed through
conjugate addition of NaI (AcOH, THF)[16] to 12 to afford 13
(8:1 Z/E, 81% yield of the isolated Z isomer). To set the C9
configuration, Evans–Saksena reduction[17] (Me4NBH(OAc)3,
MeCN, AcOH) of 13 proceeded well to give the 1,3-anti diol
14 (97%, d.r. > 20:1). Although preliminary studies were
discouraging,[5] a cyclic C7/C9 protecting group was selected;
thus, differentiation of the diol for regioselective carbamate
formation at C9 would be required in the final stages of the
synthesis. Accordingly, diol 14 was first converted into its
acetonide (Me2C(OMe)2, PPTS), and stannylation (tBuLi,
Bu3SnCl, 81%) then provided the C1–C11 fragment 2 (20%
yield over 14 steps) in readiness for installation of the
10Z,12Z diene of leiodermatolide.
Scheme 2. Preparation of vinyl stannane 2. Reagents and conditions:
a) TBSO(CH2)4MgBr, THF, ꢀ788C, 88%; b) LiHMDS, THF; Comins
reagent, ꢀ78!ꢀ208C, 82%; c) (MeBO)3, [Pd(PPh3)4] (10 mol%),
K2CO3, dioxane, 508C, 96% (>20:1 E/Z); d) DDQ, pH 7 buffer,
CH2Cl2, 84%; e) DMP, NaHCO3, CH2Cl2, 82%; f) (R)-7, c-Hex2BCl,
Et3N, Et2O, ꢀ78!ꢀ208C, 96% (d.r.>20:1); g) TMSCl, imid, CH2Cl2,
ꢁ
96%; h) LiC CTMS, THF, ꢀ788C; i) K2CO3, MeOH; j) NaIO4/SiO2,
CH2Cl2, 69% over 3 steps; k) NaI, AcOH, THF, 81% (8:1 Z/E);
l) Me4NBH(OAc)3, MeCN, AcOH (3:1), ꢀ308C, 97% (d.r.>20:1);
m) Me2C(OMe)2, PPTS, CH2Cl2, 99%; n) tBuLi, Bu3SnCl, Et2O, ꢀ788C,
81%. Comins reagent=2-(Tf2N)-5-Cl(C5H3N), DDQ=2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMP=Dess–Martin periodinane,
HMDS=hexamethyldisilazide, PPTS=pyridinium para-toluenesulfo-
nate.
The requisite Stille coupling partner 3 was prepared from
chiral intermediates 5 and 6 (Scheme 3). Vinyl iodide 5 was
readily secured by using a second boron-mediated aldol
reaction, this time between (S)-7[9] and aldehyde 15[18] to give
the anti adduct 16 (90%, d.r. > 20:1). Silylation (TBSOTf) of
16, selective reduction with LiAlH4 (d.r. > 20:1), and meth-
anolysis smoothly afforded diol 5 (91% over 3 steps).
Construction of the d-lactone fragment 6 required the
installation of three contiguous stereocenters, including the
axial C21 allyl group. The C22/C23 configuration was set by
a third boron-mediated aldol reaction, in this case between
(R)-7[9] again and propanal to generate ketone 17 (94%, d.r. >
20:1). Following silylation (TBSOTf),[19] the addition of H2C
=
CHCH2MgBr gave a 1,2-diol, which underwent oxidative
cleavage (NaIO4/SiO2)[15] to afford 18 (83%). The C21
tertiary alcohol stereocenter could then be configured with
good selectivity (d.r. 10:1) through the Mukaiyama aldol
addition[20] of silyl ketene acetal 19, mediated by BF3·OEt2 at
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Scheme 3. Preparation of vinyl iodide 3. Reagents and conditions:
a) (S)-7, c-Hex2BCl, Et3N, Et2O, ꢀ78!ꢀ208C, 90% (d.r. >20:1);
b) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ788C; c) LiAlH4, THF, ꢀ788C;
d) K2CO3, MeOH, 91% over 3 steps; e) c-Hex2BCl, Et3N, Et2O; EtCHO,
ꢀ78!ꢀ208C, 94% (d.r.>20:1); f) TBSOTf, 2,6-lutidine, CH2Cl2,
Scheme 4. Completion of leiodermatolide (1). Reagents and condi-
tions: a) [Pd(PPh3)4] (10 mol%), CuTC, Bu4NPh2PO2, DMF, 80%;
b) HF·py, pyridine, THF; c) TEMPO, PhI(OAc)2, CH2Cl2; d) NaClO2,
NaH2PO4, 2-methyl-2-butene, tBuOH, H2O, THF; e) TBAF, THF, 508C,
51% over 4 steps; f) TCBC, Et3N, THF; DMAP, PhMe, 80%; g) Dowex
50WX8, MeOH, 91%; h) TMS-imidazole, CH2Cl2; PPTS, MeOH;
Cl3CCONCO, CH2Cl2, ꢀ788C; Al2O3; PPTS, MeOH, 53%. DMAP=4-
dimethylaminopyridine, py=pyridine, TBAF=tetrabutylammonium
fluoride, TC=2-thiophenecarboxylate, TCBC=2,4,6-trichlorobenzoyl
chloride, TEMPO=2,2,6,6-tetramethylpiperidine 1-oxyl.
=
ꢀ788C, 98%; g) H2C CHCH2MgBr, THF, ꢀ788C; h) NaIO4, MeOH,
pH 7 buffer, 85% over 2 steps; i) 19, BF3·OEt2, CH2Cl2, ꢀ788C; j) 3m
HCl, THF, H2O, 82% over 2 steps (d.r. 10:1); k) TMSCl, imid, CH2Cl2,
97%; l) 5, Pd(OAc)2 (10 mol%), Ag2CO3, DMF, 808C, 73%; m) NaIO4/
SiO2, CH2Cl2; n) [ICH2PPh3]I, NaHMDS, THF, ꢀ788C, 62% over
2 steps. DMF=N,N-dimethylformamide.
ꢀ788C. Subsequent acid-mediated cyclization then provided
d-lactone 20 (82%, 2 steps).[21] In this situation, 1,2-induction
by Felkin–Anh control and 1,3-induction based on the Evans
polar model are mutually reinforcing.[22] The NMR spectro-
scopic data for 20 matched well with those for the d-lactone
ring of leiodermatolide, and the stereochemical assignment
was further confirmed by single-crystal X-ray crystallogra-
phy.[4b,23] Silylation (TMSCl) then afforded 6 (97%), in
readiness for the key Heck reaction. After some experimen-
tation, the exposure of 5 and 6 to Pd(OAc)2 (10 mol%) and
Ag2CO3 in DMF at 808C[24] generated adduct 21 (73%) with
exclusively the required 16E,18E geometry. Stork–Wittig
olefination[25] of the aldehyde arising from oxidative glycol
cleavage of 21 (NaIO4/SiO2)[15] provided the Z vinyl iodide 3
(62%, > 20:1 Z/E), thus completing the synthesis of this
fragment in 28% yield over 10 steps.
With an effective means of generating the two key
fragments 2 and 3 secured, their controlled linkage to
construct the full 25-carbon backbone of leiodermatolide
was now executed (Scheme 4). Accordingly, Stille cross-
coupling[26] of 2 and 3 under Fꢀrstner conditions[26a] smoothly
established the 10Z,12Z diene of 22 (80%). A sequence of
selective desilylation at C1 and C21 (HF·py, pyridine),
oxidation at C1, and desilylation at C15 (TBAF) then
provided the required seco acid 23 (51% overall). Gratify-
ingly, Yamaguchi macrolactonization[27] served to efficiently
close the 16-membered macrolactone. Acetonide cleavage
then gave 24 (73%), corresponding to the descarbamoyl
derivative of leiodermatolide. Notably, the order of steps
could be reversed, whereby acetonide cleavage was carried
out first on 23 to give the unprotected tetraol, which was then
macrolactonized to afford 24 with complete selectivity at
C15.[23]
Initially, we explored the introduction of the carbamate
functionality on triol 24 itself by treatment with Cl3CCONCO
(CH2Cl2, ꢀ788C),[28] but this reaction only afforded a disap-
pointing 4:1 mixture of the C7 and C9 carbamates,[23,29]
a result anticipated from earlier studies with a truncated
macrolide core.[5] To solve this problem, an effective sequence
of hydroxy-group differentiation was sought to overturn the
intrinsic substrate selectivity. Pleasingly, regiocontrolled sily-
lation at C7 (1-(trimethylsilyl)imidazole; PPTS, MeOH) gave
the corresponding C9/C21 diol, the treatment of which with
Cl3CCONCO and acidic workup exclusively afforded (ꢀ)-
20
leiodermatolide (1, 53%; ½aꢂD ¼ꢀ74.0 (c = 0.027, MeOH);
24
lit.:[4] ½aꢂD ¼ꢀ84.2 (c = 0.34, MeOH)). To our satisfaction, all
1H and 13C NMR spectroscopic data for this synthetic material
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[11] a) I. Paterson, G. J. Florence, K. Gerlach, J. P. Scott, J. Am.
correlated with those recorded for an authentic sample of
natural leiodermatolide.
Chem. Soc. 2001, 123, 9535; b) I. Paterson, E. A. Arnott,
Tetrahedron Lett. 1998, 39, 7185.
In conclusion, we have achieved a highly convergent total
synthesis of the antimitotic marine macrolide (ꢀ)-leioderma-
tolide (1) in 23 steps and 3.2% yield. This route features
a uniformly high level of stereocontrol relying on lactate aldol
chemistry,[9] combined with expedient fragment assembly
based on a variety of palladium-catalyzed coupling reactions
and an efficient macrolactonization step. It should be
amenable to the synthesis of useful quantities of this other-
wise scarce yet highly promising anticancer agent[30] for
further biological evaluation and should also enable struc-
ture–activity-relationship studies. Indeed, we have already
prepared the first novel leiodermatolide analogues in the
form of triol 24 and the regioisomeric C7 carbamate.[31]
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Received: November 22, 2013
[19] S. Crossman, M. V. Perkins, J. Org. Chem. 2006, 71, 117.
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[21] Intermediate 20 also featured in the synthesis by the Fꢀrstner
group (Ref. [7]), although it was prepared by an entirely
different route. They converted this compound into a vinyl
boronate by olefin metathesis and then employed a Suzuki cross-
coupling to construct the C17–C18 bond.
Published online: January 30, 2014
Keywords: aldol reaction · antitumor agents · cross-coupling ·
.
macrolides · total synthesis
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