First total syntheses of (-)-macrosphelides J and K and elucidation of their absolute configuration

Article abstract of DOI:10.1039/b817693k

First total syntheses of (-)-macrosphelides J and K and their structural elucidation are described. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b817693k

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Chemical Communications
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Number 18 | 14 May 2009 | Pages 2413–2592
ISSN 1359-7345
COMMUNICATION
Young-Ger Suh et al.
FEATURE ARTICLE
First total syntheses of
(−)-macrosphelides J and K
and elucidation of their absolute
configuration
Hao Shen and Zuowei Xie
Constrained-geometry ruthenium
carboranyl complexes and their
unique chemical properties
1359-7345(2009)18;1-Z

COMMUNICATION
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First total syntheses of (À)-macrosphelides J and K and elucidation
of their absolute configurationw
Hwayoung Yun, Seung-Mann Paek, Jong-Wha Jung, Nam-Jung Kim, Seok-Ho Kim
and Young-Ger Suh*
Received (in Cambridge, UK) 8th October 2008, Accepted 1st December 2008
First published as an Advance Article on the web 15th January 2009
DOI: 10.1039/b817693k
First total syntheses of (–)-macrosphelides J and K and their
structural elucidation are described.
probably via incorporation of an alkoxy unit to the
g-keto-trans-a,b-unsaturated acid moiety of macrosphelide
B,6 which exhibits strong immunosuppressant activity equal
to that of rapamycin.7 Regarding the stereochemistry of C-12,
we assumed its configuration as shown in the structure of 1
(Scheme 1) on the basis of our preliminary molecular modeling
study. The molecular modeling study revealed a favorable
addition of the alkoxy unit to the g-keto-trans-a,b-unsaturated
acid moiety from the a-face. Thus, we have executed syntheses
of (À)-macrosphelides J (1) and K (2). We herein report the
first total syntheses of (À)-macrosphelides J and K and their
structural elucidation.
All thirteen macrosphelides including macrosphelide M,
isolated from a strain of Periconia byssoides separated from
the sea hare Aplysia kurodai in 2007,1 have been reported
during the past two decades.2 These natural macrolides are of
great interest both for their excellent biological activities such
as potent cell–cell adhesion inhibition2a,b,e and for their unique
structural features. In particular, some of these macrocyclic
polyketides are considered potential leads for the treatment of
various cancers, although their structures have not yet been
completely elucidated.3 These all prompted us to initiate
studies on the synthesis of macrosphelides, including
macrosphelides J and K (Fig. 1).4
Fig. 1 Structures of macrosphelides B, J and K.
(À)-Macrosphelides
J and K are structurally unique
Scheme 1 Retrosynthesis.
members of their class, and they were first isolated from
5
¯
the Microsphaeropsis sp. FO-5050 in 1999 by Omura et al.
Our retrosynthetic approach to the proposed structures of
macrosphelides J and K is outlined in Scheme 1. For the
syntheses of macrosphelides J and K, we initially applied the
strategy previously employed for the synthesis of macro-
sphelides A and B.4n However, our preliminary studies on
the synthesis of macrosphelides J and K revealed that our
previous intramolecular nitrile oxide–olefin cycloaddition
strategy could not provide the requisite stereochemistry for
the C-12 stereogenic center. Thus, we turned our attention
to the asymmetric intermolecular nitrile oxide–olefin cyclo-
addition to install the correct stereochemistry of C-12, as well
as a masked form of the labile g-keto-a-hydroxy acid moiety.
The revised strategy envisioned that both (À)-macro-
sphelides J and K could be effectively synthesized from the
common advanced intermediate 34q by a reductive N–O
cleavage of isoxazoline followed by O-alkylation. The key
macrocyclic isoxazoline 3 would be synthesized via a modular
assembly of the three fragments 4, 6 and 7. The 16-membered
macrocyclic skeleton of 3 can be conveniently constructed
by Yamaguchi macrolactonization of the corresponding
o-hydroxy acid. A stereoselective nitrile oxide cycloaddition
They consist of three core fragments, including a g-keto-trans-
a,b-unsaturated acid, which is commonly connected via an
ester linkage throughout the series. These macrolides also
contain five stereogenic centers, of which stereochemistries
have yet to be elucidated. Generally, the stereochemistries of
the three stereogenic centers corresponding to C-8, C-9 and
C-15 of (À)-macrosphelides J and K are known to be identical.
Thus, we assumed that the configurations of C-8, C-9 and
C-15 of (À)-macrosphelides J and K were also identical to
those of other macrosphelides. In addition, we anticipated the
configuration of C-3 to be as illustrated in Scheme 1. This
configuration was suspected because it has been proposed that
macrosphelides J and K are derived from macrosphelide B,3e
College of Pharmacy, Seoul National University, San 56-1,
Sillim-Dong, Gwanak-Gu, Seoul, 151-742, Korea.
E-mail: ygsuh@snu.ac.kr; Fax: +82-2-888-0649;
Tel: +82-2-880-7875
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all new compounds along
with copies of 1H and 13C NMR spectra. See DOI: 10.1039/b817693k
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2463–2465 | 2463

of 8 and 9 would allow to effectively prepare the labile g-keto-
a-hydroxy-ester moiety of 3 in a stable isoxazoline form.8a The
optically active g,d-dihydroxy-trans-a,b-unsaturated acid
moiety 4 could be provided via trans-vinylogous OBO ester
anion addition to the appropriate carbonyl system, which was
previously developed in our laboratory.9
At the stage of conversion of the isoxazoline 3 to the
b-hydroxy ketone 16 in the presence the labile hydroxyacrolate
moiety, we encountered serious problems upon attempt of
N–O bond cleavage of the isoxazoline. We could not obtain
the b-hydroxy ketone 16, though we tried a variety of
procedures for the reductive N–O bond cleavage such as
catalytic Raney-Ni hydrogenation,16a Zn in AcOH reduction,16b
SmI2 reduction,16c CuSO4 reduction,16d Mo(CO)6/H2O
reduction16e and Mo(CO)3(CH3CN)3/SiO2 reduction.16f
Hydrogenolysis of 3 in the presence of Pd/C gave the olefin
saturated product in 80% yield. However, we finally obtained
the desired b-hydroxy ketone 16 in 64% yield by using
Ti(Oi-Pr)4/EtMgBr (Scheme 4).16g
The synthetic procedure for the isoxazoline fragment 12 from
the (S)-2-(4-methoxybenzyloxy)propanal (10)10 is described in
Scheme 2. Exposure of the aldehyde 10 to hydroxylamine hydro-
chloride in the presence of sodium acetate afforded the aldoxime 8
as a [3 + 2] cycloaddition precursor in 96% yield.11 The pivotal
diastereoselective nitrile oxide–olefin cycloaddition of aldoxime 8
was performed with the acrylate 9,12 which was prepared on a
multi-gram scale from (1R)-(+)-2,10-camphorsultam. The
cycloaddition proceeded smoothly to produce the isoxazoline 7
in 78% yield and with high diastereoselectivity (410 : 1).8b
Ti-mediated transesterification of the isoxazoline 7 with allyl
alcohol gave the ester 11 in 84% yield and it gave the recovered
auxiliary in 90% yield.13 The alcohol 12 was finally obtained by
an oxidative cleavage of the PMB protected intermediate 11 in
90% yield.
Scheme 4 Completion of the synthesis.
For the O-alkylation of the alcohol 16, we also examined a
variety of alkylation conditions. Our initial attempts included
O-methylation under the conditions such as Me2SO4, Ag2O or
NaH or KOt-Bu or KHCO3/MeI, TMSCHN2 and O-ethylation
under the conditions of Ag2O or NaH or KOt-Bu or
KHCO3/EtI. However, each of these resulted in hydrolysis
of the ester linkages. Fortunately, the best result was achieved
upon treatment of 16 with alkyl trifluoromethanesulfonate
(ROTf) in the presence of 2,6-di-tert-butylpyridine (DTBP),
which gave the corresponding ethers 17 (R = Me) and
18 (R = Et) without the problematic isomerization or
epimerization.17 Finally, MEM-deprotection of 17 and 18 by
TFA treatment of the resulting alcohol afforded macrosphelides
J (1) and K (2). The synthetic macrosphelides J and K
exhibited all spectral data identical to those of the authentic
natural products.5,18
Scheme 2 Stereoselective synthesis of isoxazoline moiety.
Next, the alcohol 12 was coupled with (S)-3-(4-methoxy-
benzyloxy)butanoic acid (6)14 in the presence of the EDCI,
providing the ester 13 (Scheme 3). This ester was then
deprotected with DDQ to yield the free alcohol 5.
Similarly, coupling of the alcohol 5 and the optically active
g,d-dihydroxy-trans-a,b-unsaturated acid 44n in the presence
of EDCI provided the diester 14, which was then deprotected
by DDQ treatment to give the free alcohol 15. Finally,
sequential deallylation of 15 and macrolactonization of the
resulting o-hydroxy acid in a one-pot process by Pd(PPh3)4
and Yamaguchi lactonization, respectively, afforded the key
isoxazoline macrolide 3 in 60% yield.15
In summary, we have accomplished the first syntheses of
(À)-macrosphelides J (1) and K (2) from ethyl (S)-(À)-lactate in
15 steps. We also confirmed their structures, particularly the
stereochemistries of their five stereogenic centers. Considering that
the g-keto-trans-a,b-unsaturated acid moiety of macrosphelide B
possibly functions as a Michael acceptor of O-nucleophiles for
their biological activity as well as the structural similarity of
macrosphelides B and J or K, our syntheses of the proposed
structures on the basis of the mechanistic hypothesis are quite
important in terms of further studies on the macrosphelides. The
total synthesis of other macrosphelides employing this strategy, as
well as their biological evaluations, are in progress and these will
be published in due course.
This work was supported by the Center for Bioactive
Molecular Hybrids, Yonsei University and Seoul R&BD
Program.
Scheme 3 Preparation of common isoxazoline intermediate.
2464 | Chem. Commun., 2009, 2463–2465
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20
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2463–2465 | 2465