Synthesis of the C(1)-C(13) Fragment of Leiodermatolide via Hydrogen-Mediated C-C Bond Formation

Article abstract of DOI:10.1021/acs.orglett.7b03351

The C(1)-C(13) fragment of the antimitotic marine macrolide leiodermatolide is prepared in seven steps via hydrogenative and transfer-hydrogenative reductive C-C couplings. A hydrogen-mediated reductive coupling of acetylene with a Roche-type aldehyde is used to construct C(7)-C(13). A 2-propanol-mediated reductive coupling of allyl acetate with (E)-2-methylbut-2-enal at a low loading of iridium (1 mol %) is used to construct C(1)-C(6), which is converted to an allylsilane using Oestereich's copper-catalyzed allylic substitution of Si-Zn reagents. The union of the C(1)-C(6) and C(7)-C(13) fragments is achieved via stereoselective Sakurai allylation.

Full text of DOI:10.1021/acs.orglett.7b03351

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Letter
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Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Synthesis of the C(1)−C(13) Fragment of Leiodermatolide via
Hydrogen-Mediated C−C Bond Formation
James Roane,† Julian Wippich,† Stephen D. Ramgren, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The C(1)−C(13) fragment of the antimitotic
marine macrolide leiodermatolide is prepared in seven steps
via hydrogenative and transfer-hydrogenative reductive C−C
couplings. A hydrogen-mediated reductive coupling of
acetylene with a Roche-type aldehyde is used to construct
C(7)−C(13). A 2-propanol-mediated reductive coupling of
allyl acetate with (E)-2-methylbut-2-enal at a low loading of
iridium (1 mol %) is used to construct C(1)−C(6), which is
converted to an allylsilane using Oestereich’s copper-catalyzed allylic substitution of Si−Zn reagents. The union of the C(1)−
C(6) and C(7)−C(13) fragments is achieved via stereoselective Sakurai allylation.
s exemplified by vincristine, paclitaxel, docetaxel, ixabepi-
lone, eribulin, and the antibody−maytansinoid conjugate
Sakurai allylation enables union of the C(1)−C(6) and C(7)−
C(13) fragments.
A
Kadcyla, anticancer agents based on natural products that
perturb microtubule dynamics have found broad use in human
medicine.1 Leiodermatolide, a marine macrolide isolated in
2008 from crude extracts of a deep water lithistid sponge of the
genus Leiodermatium, was identified in connection with efforts
aimed at the discovery of antimitotic agents.2 Leiodermatolide
displays potent and selective antiproliferative activity against a
panel of human cancer cell lines by virtue of what appears to be
a unique mechanism for disruption of tubulin dynamics: while
causing irregular spindle formation in two different cancer cell
lines at nanomolar concentrations, purified tubulin was
unaffected even at significantly higher concentrations.2,3
Retrosynthetically, we envisioned a convergent route to
leiodermatolides A and B from Fragments A and B via
esterification and (Z)-selective ring-closing metathesis (RCM)
(Figure 1).9 The synthesis of Fragment A, the topic of this
report, would be realized through Sakurai reaction of allylsilane
6 and α,β-stereogenic chiral aldehyde 12.10 The requisite
allylsilane 6 appeared accessible from allyl alcohol 2 through
anti-Markovnikov Wacker oxidation11 and copper-catalyzed
allylic substitution.12 The allyl alcohol 2 could, in turn, be
prepared through 2-propanol-mediated reductive coupling of
allyl acetate with tiglic aldehyde 1.13 The α,β-stereogenic chiral
aldehyde 12 is prepared through hydrogen-mediated reductive
coupling of acetylene14 with “Roche-type” aldehyde 9. On the
basis of this plan, Fragment A, which incorporates six
stereogenic structural features, is accessible in seven steps
(LLS).
The synthesis of allylsilane 6 begins with the 2-propanol-
mediated reductive coupling of allyl acetate with tiglic aldehyde
1 (Scheme 1).13 This reaction was conducted on 40 mmol scale
using the iridium catalyst modified by (S)-BINAP at roughly 1
mol % loadings. The secondary homoallylic alcohol 2 was
obtained in 78% yield in highly enantiomerically enriched form
(92% ee). The cyclometalated π-allyliridium C,O-benzoate
catalyst, which was generated in situ from its components, was
recovered from the reaction mixture in 39% yield. Using 1 mol
% of the recovered catalyst, tiglic aldehyde 1 was converted to
allyl alcohol 2 on 10 mmol scale in 73% yield with comparable
levels of enantioselectivity (93% ee). Benzoylation of 2
followed by anti-Markovnikov Wacker oxidation of the terminal
olefin in the presence of the allylic benzoate provided the
The intriguing biological properties and scarcity of
leiodermatolide have motivated efforts toward its preparation
through de novo chemical synthesis. To date, total syntheses of
leiodermatolide have been reported by Furstner4 and Paterson.5
̈
Additionally, several leiodermatolide substructures were pre-
pared by Maier.6 Despite this progress, existing routes to
leiodermatolide are on the order of roughly 20 steps (LLS) or
more,4,5 warranting further work toward strategies that might
streamline its synthesis and broaden access to structural
analogues.
We have developed a suite of reductive C−C bond
formations mediated by elemental hydrogen7a or hydrogen
transfer from alcohols.7 Application of these methods to the
synthesis of type I polyketides has enabled routes significantly
more concise than previously possible.8 Given the challenges
posed by leiodermatolide, a campaign toward its preparation via
hydrogenative coupling was undertaken. Here, we describe our
initial approach to the C(1)−C(13) fragment, which exploits a
hydrogen-mediated reductive coupling of acetylene to assemble
the C(7)−C(13) fragment and a 2-propanol-mediated
reductive coupling of allyl acetate with (E)-2-methylbut-2-
enal to construct the C(1)−C(6) fragment. A stereoselective
Received: October 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03351
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Figure 1. Retrosynthetic analysis of leiodermatolides A and B highlighting construction of the C(1)−C(13) fragment via hydrogenative and transfer-
hydrogenative reductive coupling.
Scheme 1. Enantioselective Synthesis of Allylsilane 6 via 2-
Propanol-Mediated Reductive Coupling of Allyl Acetate with
Tiglic Aldehyde 1.
related copper-catalyzed allylic substitution using silylzinc
reagents provided superior yields and regioselectivities,
enabling formation of allylsilane 6 in 84% yield as a 14:1
mixture of regioisomers.12b
a
Construction of α,β-stereogenic chiral aldehyde 12 begins
with enantioselective benzoylation of diol 7 (Scheme 2).17
Although the yield in this reaction was modest, exceptionally
low loadings of the easily prepared diamine catalyst18 were
Scheme 2. Enantioselective Synthesis of α,β-Stereogenic
Chiral Aldehyde 12 via Hydrogen-Mediated Reductive
a
Coupling of Acetylene with “Roche-Type” Aldehyde 9
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary phase HPLC
analysis. See the Supporting Information for further experimental
details.
aldehyde 4. Pinnick oxidation15 delivered carboxylic acid 5,
which upon treatment with TMS-diazomethane16 provided the
corresponding methyl ester. Initial attempts to convert the
allylic benzoate (5-methyl ester) to the allylsilane 6 under
Fleming’s conditions, which utilize the cuprate generated from
stoichiometric quantities of silyl lithium reagent, cuprous
cyanide, and triphenylphosphine,12a provided allylsilane 6 in
modest yields and regioselectivities. Fortunately, Oestereich’s
a
Yields are of material isolated by silica gel chromatography.
Enantioselectivity was determined by chiral stationary-phase HPLC
analysis. See the Supporting Information for further experimental
details.
B
DOI: 10.1021/acs.orglett.7b03351
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Letter
required (0.5 mol %). Dess−Martin oxidation of the resulting
alcohol provided the “Roche-type” aldehyde 9.19 The hydrogen
mediated reductive coupling of acetylene14 to aldehyde 9 was
quite challenging due to branching at the α-position and the
relatively remote location of the σ-inductive benzoyloxy moiety.
Eventually, using a cationic rhodium catalyst modified by the
Roche ligand,20 conditions were identified that enabled
formation of the (Z)-butadienylated adduct 10 in 61% yield
as a 5:1 mixture of diastereomers. Protection of the allylic
hydroxyl as the TOM ether (iPr3SiOCH2)21 followed by
reductive removal of the benzoate and Dess−Martin oxidation
provided the α,β-stereogenic chiral aldehyde 12.
merger of our asymmetric allylation method with Oestereich’s
protocol12b for regio- and stereospecific formation of
allylsilanes should broaden access to chiral reagents of this
type. Additionally, the generality of the hydrogen-mediated
reductive coupling of acetylene with carbonyl compounds to
form enantiomerically enriched (Z)-butadienyl alcohols is
demonstrated. Future work will be devoted to the discovery
and development of related hydrogen-mediated reductive
couplings and their application to target oriented synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The diastereoselective Sakurai reaction of allylsilane 6 and
α,β-stereogenic chiral aldehyde 12 was initially explored under
conditions reported by Panek (Scheme 3).10 Standard
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03351.
Spectral data for all new compounds (1H NMR, 13C
NMR, IR, HRMS) (PDF)
Scheme 3. Sakurai Reaction of Allylsilane 6 and Aldehyde 12
To Assemble Fragment A, Which Incorporates C(1)−C(13)
a
of Leiodermatolides A and B
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mkrische@mail.utexas.edu.
ORCID
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
†J.R. and J.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Acknowledgment is made to the Robert A. Welch Foundation
(F-0038), the NIH-NIGMS (RO1-GM069445), and the UT
Austin Center for Green Chemistry and Catalysis for partial
support of this research. The Deutsche Forschungsgemein-
schaft (J.W.) and the American Cancer Society (S.R.) are
acknowledged postdoctoral fellowship support. Donggeon
Nam is acknowledged for skillful technical assistance.
a
Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details.
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