Synthesis of the C1-C10 Fragment of Madeirolide A

Article abstract of DOI:10.1021/acs.orglett.6b00777

The synthesis of a fully elaborated C1-C10 fragment of madeirolide A has been achieved via a strategy based on a series of stereospecific processes. The concise synthetic route also features an iridium-catalyzed visible light induced radical cyclization for construction of the THP ring and a palladium-catalyzed glycosylation for formation of the α-cineruloside linkage.

Full text of DOI:10.1021/acs.orglett.6b00777

Letter
pubs.acs.org/OrgLett
Synthesis of the C1−C10 Fragment of Madeirolide A
Sunghyun Hwang, Inhwan Baek, and Chulbom Lee*
Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea
S
* Supporting Information
ABSTRACT: The synthesis of a fully elaborated C1−C10
fragment of madeirolide A has been achieved via a strategy
based on a series of stereospecific processes. The concise
synthetic route also features an iridium-catalyzed visible light
induced radical cyclization for construction of the THP ring
and a palladium-catalyzed glycosylation for formation of the α-
cineruloside linkage.
adeirolides are a family of glycosylated macrolides
isolated by Wright and Winder from a Leiodermatium
however, is incommensurate with their antitumor activity
profiles: whereas mandelalides exhibited nanomolar cytotoxicity
against tumor cell lines, no appreciable antiproliferative activity
was detected from madeirolides. Given the difficulties
associated with detailed bioassays of madeirolides due to the
scarcity of the sponge isolates, along with the interesting issues
regarding their stereostructure, biogenetic origin, and biological
profile, we embarked on a total synthesis investigation of
madeirolides that could enable full-scale biological evaluations.5
Reported here is the first account of our endeavor
accomplishing the synthesis of the fully functionalized C1−
C10 fragment of madeirolide A.
M
species harvested from the deep sea off the coast of Madeira,
Portugal (Figure 1).1 Both congeners A (1) and B (2) were
Our synthesis strategy arose from the notion that the lactone
and (E,Z)-diene linkages could serve as staging points for
macrocyclization (Scheme 1).3,6 In this plan targeting a
penultimate intermediate (e.g., 1′), it was anticipated that
both the C1 ester and the C10−C13 moiety, in the form of a
diene or an enyne, would also lend themselves to strategic
junctures at which the elaborated fragments 4 and 5 could be
conjoined in a convergent manner with flexibility to probe the
relative stereochemistry with regard to each domain. An
additional element of consideration in the design of the
synthesis plan was the prospect of assembling the oxacyclic
subunits by way of catalytic methods developed in our
laboratory. In particular, the 2,6-cis-THP skeleton of 5 was
envisioned to be built through a free radical-mediated
cyclization of iodide 6 under visible light induced photoredox
conditions,7,8 while the α-cinerulose 5,1′-glycosidic linkage
would be established with control of anomeric configuration via
the palladium-catalyzed glycosylation9 with pyranone 7.10 With
this disconnection relying on the two catalytic events for the
critical bond formations, the synthesis problem presented by
the aglycon of 5 was essentially reduced to the stereoselective
preparation of the C4−C10 subunit 8 possessing four
stereocenters, which in turn could be derived from the aldol
Figure 1. Madeirolides and mandelalide A.
shown to possess inhibitory activity against the fungal pathogen
Candida albicans with fungicidal MIC values of 12.5 and 25 μg/
mL, respectively. Structurally, madeirolides belong to a group of
macrolides that feature one or multiple bicyclic ether units
embedded within a stereochemically decorated macrolactone
scaffold. Differing in the pentasubstituted tetrahydropyran and
glycone domains, these sponge-derived polyketides bear
considerable structural resemblance to the mandelalide family
of macrolides isolated from a species of Lissoclinum ascidian.2
Indeed, madeirolide A (1) and the recently revised structure of
mandelalide A (3) share a nearly identical substructure
encompassing 20 carbon atoms of the 24-membered macro-
lactone backbone.3 Since these secondary metabolites originate
from marine invertebrates yet of distinctive phyla, it remains a
possibility that a common microbial symbiont may be involved
in their biogenesis.4 The remarkable structural homology,
Received: March 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00777
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Letter
Scheme 1. Retrosynthetic Analysis of Madeirolide A
Scheme 2. Synthesis of C4−C10 Lactone 18
adduct 9 through a sequence involving stereospecific [3,3]
sigmatropic rearrangement and alkene hydroxylation reactions.
Based on a synthetic roadmap aimed at establishing all of the
stereocenters in the C1−C10 chain of madeirolide A via a series
of diastereoselective processes, our synthesis started with the
known Abiko−Masamune anti-aldol product 12 derived from
crotonaldehyde (Scheme 2).11 Following reductive detachment
of the chiral auxiliary, the resulting diol 13 was silylated
selectively at the primary hydroxyl group to give TBDPS ether
14, which was then condensed with acid 15 to give the allylic
ester 9. The Ireland−Claisen rearrangement of 9 took place
smoothly with excellent stereoselectivity to provide acid 16 as a
single stereoisomer, thus transferring the chirality of the allylic
center to the stereochemistry of C5 and C6 centers with
concomitant two-carbon chain elongation.12 In order to install
the C7 hydroxyl group via a π-facial selective alkene addition
reaction, acid 16 was subjected to a sequence of iodolactoniza-
tion and deiodination reactions. While literature precedents
suggested the halolactonization of γ,δ-unstaturated acids with
an intervening substitution at the α and/or β position such as
16 to be straightforward,13 the strong dependence of the
stereochemical outcome on the solvent as well as temperature
was noted.14 After considerable experimentation, it was found
that the desired iodide 17 could be obtained in excellent yield
(85% over two steps) and diastereoselectivity (dr = 9:1) by
performing the reaction at −40 °C using acetonitrile as the
solvent. The iodide was then subjected to reductive
deiodination to provide lactone 18. In this radical-mediated
hydrodeiodination, visible light photocatalytic conditions gave
higher yields of 18 than traditional organosilane and organotin-
based methods.15 However, the established catalytic systems,
such as [Ir(ppy)2 (dtbbpy)]PF6/DIPEA7 and fac-Ir(ppy)3/
Hantzsch ester/Bu3N,16 did not fare well. A brief survey of
various conditions for hydrodehalogenation revealed the
combination of [Ir(ppy)2 (dtbbpy)]PF6 catalyst and both
DIPEA and Hantzsch ester as the reductants to be optimal,
affording lactone 18 in 81% yield.
Having prepared the C4−C10 sector 18 equipped with four
stereocenters, we then set out to advance it to β-alkoxyacrylate
6 en route to tetrahydropyran aglycon 22 (Scheme 3). For the
installation of a β-alkoxyacrylate group at the C7 hydroxyl,
lactone 18 was first reduced to diol 8a and monosilylated to
TBS ether 8b (TBSCl, imidazole, DCM, 90%). Our initial
attempts at employing well-established protocols for the
Michael reaction with propiolates,17 however, met with little
success, indicating that steric congestion around the C7 alcohol
essentially was prohibitive. Despite screening a wide variety of
conditions, 21b could be produced only in unsustainable yield
(ca. 5%) from reactions run at elevated temperatures for
prolonged reaction times (>48 h). Thus, an alternative
approach was sought in which the requisite β-alkoxyacrylate
would arise from the selective elimination of cyclic acetal 20,
which could be accessed from diol 8a via transacetalization with
dimethyl acetal 19. Gratifyingly, when a diastereomeric mixture
of cyclic acetal 20 (dr = 1.7:1) was treated with LHMDS at −78
°C, selective ring-opening elimination occurred smoothly to
furnish acrylate 21a as an E-isomer exclusively.18 The ensuing
primary alcohol was then converted to iodide 6 poised for a free
radical mediated cyclization.19 In the presence of the iridium
B
DOI: 10.1021/acs.orglett.6b00777
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Letter
Scheme 3. Synthesis of C1−C10 Aglycon 22
Scheme 4. Completion of the C1−C10 Glycoside 5
rearrangement, iodolactonization, and radical cyclization,
establishing all of the stereocenters along the C1−C10 chain
with high stereocontrol. Notably, the 2,6-cis-tetrahydropyran
and α-cinerulose glycosidic linkage were constructed with
complete stereospecificity by taking advantage of the iridium-
catalyzed reductive cyclization and palladium-catalyzed glyco-
sylation, respectively. The demonstrated efficiency of visible
light photoredox catalysis holds promise for this chemistry in
further applications to the synthesis of other THF and THP
oxacycle subunits present in the madeirolides. Our campaign
for the preparation of the remaining northern fragment, as well
as the total synthesis of madeirolide A, is in progress, and the
results will be reported in due course.
catalyst in conjunction with DIPEA, irradiation of 6 with a 2 W
blue LED (λmax = 454 nm) strip led to clean reductive
cyclization giving rise to the targeted tetrahydropyran 22 in
70% yield with complete 2,6-cis-selectivity.
With the THP aglycon 22 in hand, our synthesis
investigation entered the final assembly stage, in which
attachment of the cinerulose saccharide unit was carried out
through stereoselective formation of an α-glycosidic linkage
(Scheme 4). After the C5 hydroxyl was unmasked by removal
of the benzyl group (20% Pd(OH)2/C, H2, 91%) from 22, the
resultant alcohol 23 was subjected to a glycosylation with
pyranone 7.20 Coupling of 23 and 7 by the glycosylation
method, making use of a palladium-catalyzed O-allylation,10
furnished 24 in 89% yield as a single anomer. Finally,
hydrogenation of the C2′−C3′ alkene in the saccharide
generated the fully elaborated C1−C10 fragment 5.
The spectroscopic signatures of the glyco C1−C10 fragment
5 matched well those of the corresponding sector in
madeirolide A. Specifically, a high degree of homology was
noted in the 1H and 13C NMR signals from the C1−C7 as well
as the C1′−C6′ regions. In addition, chemical correlation was
also conducted by converting methyl ester 22 to thioester 25, a
key intermediate in the related synthesis reported by the
Paterson group.5 All spectroscopic data of thioester 25
corresponded to the reported values in all aspects, indicating
the identity of the structure.21
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.6b00777.
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: chulbom@snu.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The present study has procured a stereoselective and robust
synthetic entry to a fully adorned C1−C10 fragment of
madeirolide A. Starting from a readily available aldol product,
our concise route provides the key intermediate through a
series of diastereoselective processes that include Claisen
Support for this research was provided by the Basic Science
R e s e a r c h P r o g r a m ( 2 0 1 3 R 1 A 1 A 2 0 1 8 7 3 0 ,
2013R1A2A2A010170) of the National Research Foundation
(NRF) funded by the Ministry of Science, ICT & Future
Planning of Korea.
C
DOI: 10.1021/acs.orglett.6b00777
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Letter
acrylate product 21a from both epimers of acetal 20 is believed to be a
consequence of elimination of the primary (C4), in preference to the
secondary (C7) alkoxide leaving group via the transition state that
minimizes the A1,3 strain while leading to a more stable product. For a
detailed mechanistic scheme, see the Supporting Information. For a
related example, see: Caballero, M.; Garcia-Valverde, M.; Pedrosa, R.;
Vicente, M. Tetrahedron: Asymmetry 1996, 7, 219.
(19) (a) Araki, Y.; Endo, T.; Arai, Y.; Tanji, M.; Ishido, Y.
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(21) For the comparison of spectroscopic data and the details of
chemical correlation studies, see the Supporting Information.
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