Toward Leiodermatolide: Synthesis of the Core Structure

Article abstract of DOI:10.1021/acs.orglett.6b01355

The macrocyclic core (35) of the marine natural product leiodermatolide (1) was synthesized from two key fragments, vinyl iodide 23 (C1-C11 part) and vinyl stannane 31 (C12-C18 part). A Stille coupling led to conjugated Z,Z-diene 32. The derived seco acid 34 was cyclized using a Yamaguchi macrolactonization. Key steps in the assembly of vinyl iodide 23 were a Paterson aldol reaction, and a Kumada coupling on a triflate derivative to create the C4-C5 trisubstituted double bond. The two stereocenters in fragment 31 were established by a Marshall-Tamaru reaction. The longest linear sequence comprises 20 steps.

Full text of DOI:10.1021/acs.orglett.6b01355

Letter
pubs.acs.org/OrgLett
Toward Leiodermatolide: Synthesis of the Core Structure
Anita Reiss and Martin E. Maier*
Institut fur Organische Chemie, Eberhard Karls Universitat Tubingen, Auf der Morgenstelle 18, 72076 Tubingen, Germany
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* Supporting Information
ABSTRACT: The macrocyclic core (35) of the marine natural product leiodermatolide (1) was synthesized from two key
fragments, vinyl iodide 23 (C1−C11 part) and vinyl stannane 31 (C12−C18 part). A Stille coupling led to conjugated Z,Z-diene
32. The derived seco acid 34 was cyclized using a Yamaguchi macrolactonization. Key steps in the assembly of vinyl iodide 23
were a Paterson aldol reaction, and a Kumada coupling on a triflate derivative to create the C4−C5 trisubstituted double bond.
The two stereocenters in fragment 31 were established by a Marshall−Tamaru reaction. The longest linear sequence comprises
20 steps.
he macrolide (−)-leiodermatolide (1) was discovered by
structure was finally secured through the first total synthesis of
T
the Wright group in a screening program aimed at the
(−)-leiodermatolide by the Furstner group.5 In this elegant
̈
discovery of antimitotic agents from marine sponges (Figure 1).
synthesis, acid 2, prepared by aldol technology, was esterified
with enynol 3 followed by ring-closing alkyne metathesis.
Finally, the δ-lactone part was attached via a Suzuki coupling
(Scheme 1). Later, the Furstner group refined some steps of
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Scheme 1. Fragments and Order of Assembly in the Total
Syntheses of Leiodermatolide
Figure 1. Structure of (−)-leiodermatolide (1).
It was isolated from the listhed sponge Leiodermatium. Cells
treated with leiodermatolide showed abnormal spindle
formation, even though tubulin was not affected. The IC50
values for several cancer cell lines were in the low nanomolar
range. In a patent application from 2008 only the flat structure
(constitution) was reported.1 Later a tentative stereostructure
appeared on a webpage.2 However, in this structure C6 and C8
were inverted. In 2011 an almost complete structure assign-
ment was achieved through NMR spectroscopie analysis, NMR
shift calculations, and molecular modeling.3 However, the
relative configurations of the macrolactone part and the δ-
lactone remained open.
The structure of 1 is characterized by a 16-membered
macrolactone ring, with a diene-containing side chain with a δ-
lactone at its terminus. The macrolactone contains a conjugated
Z,Z-diene and one trisubstituted double bond. In addition,
there are eight stereocenters. Our group had contributed to the
chemistry of leiodermatolide with the synthesis of key
fragments and a macrolactonization approach to the macro-
lactone core, both based on the C6,C8-epimer.4 The exact
their first synthesis.6 In the total synthesis by Paterson et al. the
C17−C18 bond was early on established by a Heck coupling
between vinyl iodide 6 and δ-lactone 7.7 This was followed by
Stille coupling with stannane 5 to form the C11−C12 bond. A
Yamaguchi macrolactonization on a deprotected seco acid
essentially completed this route. Prior to their total synthesis,
Received: May 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01355
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Letter
the Paterson group had published a synthesis of an enantiomer
of the macrocyclic core featuring an (E)-(1-bromoprop-1-en-2-
yl) side chain at C15.8
Scheme 3. Synthesis of C1−C11 Fragment 23 via Aldol
Technology, Chain Extension via Grignard Reaction and
Kumada Coupling To Form the Trisubstituted Double Bond
Biological studies confirmed that the cell cycle stops at the
G2/M transition.6 In addition, leiodermatolide induces
formation of micronuclei, centrosome amplification, and tubuli
disruption.9 As a possible mode of action centrosome
declustering was suggested. However, defined protein targets
could not yet be identified. Testing of seven analogs that were
also prepared showed that the 9-carbamate can be replaced by
an acetate. The 7-OH has to be free for good activity.
Moreover, the C18−C19 dihydro analog was less active. The δ-
lactone in its correct configuration also seems to be crucial for
good potency.
The novel mode of action together with the challenging
structural features make leiodermatolide an interesting target
for further synthetic studies. According to our previous
retrosynthetic plan, leiodermatolide would be constructed
from three fragments, a C1−C11 part 8, the C12−C18 middle
piece 9, and a δ-lactone fragment 10 (Scheme 2).3 Here the
Scheme 2. Plan for the Synthesis of Leiodermatolide
Z,Z-diene would be established by a Stille coupling and ring
closure would be achieved by macrolactonization. Whether the
planned C18−C19 olefination, for example by Julia−Kocienski
olefination, was a good decision will have to be determined. In
this paper we describe the synthesis of the macrolactone core
according to this rough sketch. To introduce the stereocenters
at C8 and C9 in fragment 8, a boron-mediated aldol reaction
was envisoned.10 For chain extension, a C4 unit would be
added by Grignard addition to a C3 aldehyde. Based on our
previous studies the stereocenters on C14 and C15 would be
created by a Marshall−Tamaru reaction.11
The known aldehyde12 11 and chiral ketone13 12 were used
in a boron-mediated aldol reaction using (+)-Ipc2BOTf at −78
°C (Scheme 3).10 A similar aldol reaction was used by the
Paterson group to construct the stereotetrad of leiodermatolide
although with a different aldehyde as a precursor to a Z-
vinylstannane.8 The resulting β-hydroxyketone 13 was treated
with [NMe4][B(OAc)3H] in an anti selective reduction to give
anti diol 14 in good yield (86%) and a high diastereomeric ratio
of 16:1.14 The diol 14 was protected as a TBS ether, and after
cleaving the PMB ether with DDQ and oxidation of the
resulting alcohol with Dess-Martin periodinane (DMP) at 0 °C,
aldehyde 16 was obtained. Diol 14 was initially protected as
acetonide. However, during the oxidative cleavage of the PMB
ether and oxidation to the corresponding aldehyde, epimeriza-
tion at C9 to the 7,9-syn-isomer was observed (see Supporting
Information (SI)). For chain extension aldehyde 16 was treated
with the Grignard reagent 17.15 The resulting secondary
alcohol was directly oxidized with DMP to ketone 18 in good
yield (82% over two steps). For the formation of the
trisubstituted double bond at C4, ketone 18 was enolized
with KHDMS in THF at −80 °C and the enolate was trapped
with PhNTf2. The methyl group was introduced by a Kumada
coupling16 with MeMgBr in refluxing THF in the presence of
Pd(PPh3)4 which gave enyne 19 in 86% yield over two steps
1
and an E/Z ratio of 4:1 (determined by H NMR).
Exchange of the protecting group at C1 led to pivaloate 21.
For the iodination of the triple bond the TIPS group had to be
removed since the direct iodination17 (NIS, AgNO3, AgF,
MeCN) did not work in our hands. For the desilylation of 21,
TBAF·3H2O in THF at room temperature was used, but under
these conditions the TBS groups also were cleaved. The
resulting diol was then protected as acetal 22. After introducing
the iodine using I2 and DMAP in toluene at 50 °C,18 the triple
bond was reduced with NsNHNH2 to give the cis vinyl iodide
23 in 87% yield.19 The observed coupling constant J(10H/
3
11H) of 7.6 Hz indicated the required cis-double bond.
The other coupling partner, stannane 31, was prepared from
enoate20 24, which itself was obtained by a Horner−
Wadsworth−Emmons reaction (Scheme 4). Thus, the crude
ester 24 was directly reduced with DIBAL-H at −78 °C to the
corresponding alcohol which subsequently was protected as
B
DOI: 10.1021/acs.orglett.6b01355
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Scheme 4. Formation of Vinyl Stannane 31
Scheme 5. Formation of Core Structure 35
11.2 Hz), 12-H (δ = 6.28, dd, J = 11.2, 11.2 Hz), 13-H (δ =
5.32, dd, J = 10.6, 10.6 Hz) (see also SI).
In summary, we achieved the synthesis of core structure 35
of the natural product (−)-leiodermatolide in 20 steps based on
the known aldehyde 11 and ketone 12 in an overall yield of
1.3%. Further studies to complete the natural product are
ongoing in our group.
TBDPS ether 25 in 53% yield over three steps (including the
HWE reaction to form 24). The acetal function was then
cleaved using PPTS in wet acetone under reflux to provide
aldehyde21 26, required for the Marshall−Tamaru reaction, in
98% yield. The E/Z ratio for 26 was at least 9:1. With the (R)-
mesylate22 27, ZnEt2, and the catalyst system Pd(OAc)2/PPh3,
the secondary alcohol 28 could be obtained. It was protected as
TES-ether 29 by treating it with TESOTf and 2,6-lutidine at
−65 °C. The TMS group at C7 was replaced by iodine using
NIS and AgNO3 (0.2 equiv) in DMF at room temperature.23,24
The triple bond was reduced with dipotassium diazodicarbox-
ylate in MeOH at room temperature.4a The resulting Z-vinyl
iodide was converted to vinyl stannane 31 with tBuLi and
Bu3SnCl.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01355.
Experimental procedures, spectroscopic data, and images
1
of H and 13C NMR spectra for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
With the key fragments 23 and 31 in hand, a Stille coupling
was used to combine them. Thus, best result were obtained
using Pd(PPh3)4 as the catalyst and CuTC and [NMe4]-
[Ph2PO2] as additives providing diene 32 in an acceptable yield
of 60% (Scheme 5). To complete core structure 35, the
pivaloate was cleaved using DIBAL-H at −90 °C, followed by
oxidation of alcohol 33 under Stark conditions25 using TPAP
and NMO·H2O. Thereafter, the protecting groups were cleaved
under acidic conditions (AcOH, 1 N HCl) to provide seco acid
34. A final macrolactonization under Yamaguchi conditions led
to core structure 35 in good yield (71%). A comparison of the
13C NMR data of 35 with leiodermatolide (1) showed good
agreement for peaks that we could assign unambigously.
Chemical shift differences were seen for carbon atoms around
C9 which carries a carbamate function. The expected large
coupling constants seen for 15-H [3J(14H,15H) of 10.4 Hz]
and 7-H [3J(6H,7H) of 10.1 Hz] of 35 match well with the
stereochemistry and local conformation of the natural product.
The olefinic protons of the diene part show similar chemical
shifts and coupling constants as the reference compound 10-H
(δ = 5.59, dd, J = 10.4, 10.4 Hz), 11-H (δ = 6.44, dd, J = 11.2,
*E-mail: martin.e.maier@uni-tuebingen.de.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Deutsche Forschungsgemein-
schaft (Grant No. Ma 1012/25/1) and the state of Baden-
■
Wurttemberg. The authors would like to acknowledge
̈
networking contribution by the COST Action CM1407
“Challenging organic syntheses inspired by nature - from
natural products chemistry to drug discovery”.
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DOI: 10.1021/acs.orglett.6b01355
Org. Lett. XXXX, XXX, XXX−XXX