An enantioselective synthetic pathway towards plakortones

Article abstract of DOI:10.1039/b205924j

An enantioselective synthesis of functionalized bicyclic lactones 2, 3 and 4, core structures of plakortones, are described; the configurations of 2,3 and 4 were confirmed by X-ray crystallographic analyses of their precursors 11, 19 and 24, respectively.

Full text of DOI:10.1039/b205924j

An enantioselective synthetic pathway towards plakortones†‡
Hing Ken Lee and Henry N. C. Wong*
Department of Chemistry, Institute of Chinese Medicine and Central Laboratory of the Institute of Molecular
Technology for Drug Discovery and Synthesis,§ The Chinese University of Hong Kong, Shatin, New
Territories, Hong Kong SAR, China. E-mail: hncwong@cuhk.edu.hk; Fax: (852)26035057;
Tel: (852)26096329
Received (in Cambridge, UK) 19th June 2002, Accepted 9th August 2002
First published as an Advance Article on the web 21st August 2002
An enantioselective synthesis of functionalized bicyclic
lactones 2, 3 and 4, core structures of plakortones, are
described; the configurations of 2, 3 and 4 were confirmed by
X-ray crystallographic analyses of their precursors 11, 19
and 24, respectively.
5 and its diastereomer 6 was previously reported.3 Since the
secondary hydroxy group of alcohols 5 and 6 was introduced
from enantiopure (+)-2,3-O-isopropylidene-
-glyceraldehyde,4
D
the absolute configuration of our synthesized compounds could
be accordingly established based on this stereogenic center.
With the chiral alcohols 5 and 6 in hand, two model studies
were attempted. As shown in Scheme 1, alcohol 5 was protected
as TMS ether 7 with TMSCl in a good yield (96%). A highly
Plakortones A–D (1a–d) were isolated in 1996 from the sponge
Plakortis halichondriodes.1a These compounds are cardiac
sacroplasmic reticulum Ca2+-pumping ATPase activators that
were found to be active at micromolar concentrations and
relevant to the correction of cardiac muscle relaxation abnor-
malities. Plakortones E and F (1e,f) were recently isolated.1b
Plakortones A–F (1a–f) consist of bicyclic lactone skeletons
whose relative structures are shown in Fig. 1.
Although three approaches were published recently2 con-
cerning the synthetic studies of plakortones, the absolute
configurations of these compounds have only been recently
established by Boukouvalas’s unpublished total synthesis.
Before we started this program, we were not aware of
plakortones’ absolute configurations, and therefore we report
herein enantioselective preparations of the functionalized
bicyclic lactones 2, 3 and 4. It is noteworthy that intermediate 4
is an enantiomer of the natural molecules as shown in Fig. 2.
This key approach will serve our overall program for the
realization of natural and non-natural forms of plakortones.
Our synthetic program required chiral alcohols 5 and 6 as
precursors. The highly diastereoselective preparation of alcohol
Fig. 1 The relative structures of plakortones A–F.
Fig. 2 The absolute structures of bicyclic lactones 2, 3 and 4.
Scheme 1 Reagents and conditions: i, TMSCl, imidazole, DMAP, DMF, rt,
30 min; ii, n-BuLi (2 equiv.), TMSCl (0.5 equiv.), THF, 278 °C, 5 min; iii,
40% peracetic acid (4 equiv.), NaOAc (4 equiv.), CH2Cl2, 0 °C 2 rt, 48 h;
iv, 80% aetic acid, rt, 24 h; v, Et3N (100 equiv.), toluene, reflux, 72 h; vi,
1 M HCl (aq), rt, 48 h; vii, TBDMSCl (1.5 equiv.), imidazole (3 equiv.),
DMAP, DMF, 0 °C, 1 h; viii, p-BrC6H4COCl (2 equiv.), pyridine (3 equiv.),
CH2Cl2, rt, 24 h; ix, 1 M HCl–THF (1+5, v/v), rt, 24 h; x, Dess–Martin
periodinane, CH2Cl2, rt, 2 h; xi, RhCl(PPh3)3, C6H6, reflux, 72 h.
† Dedicated to Professor Thomas C. W. Mak on the occasion of his 65th
birthday.
‡ Electronic supplementary information (ESI) available: selected analytical
data for compounds 2, 3 and 4 and crystal data of compounds 11, 19 and 24.
See http://www.rsc.org/suppdata/cc/b2/b205924j/
§ An area of Excellence of the University Grants Committee (Hong
Kong).
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CHEM. COMMUN., 2002, 2114–2115
This journal is © The Royal Society of Chemistry 2002

regiospecific silylation to form the 2-silylfuran 8 was realized
by addition of n-BuLi (2 equiv.) at 278 °C in THF, and was
followed by slowly addition of TMSCl (1 equiv.) in THF at 278
°C. After rapid quenching with water, 8 was obtained in 80%
yield.5 The 2,4-disubstituted furan 8 was converted to buteno-
lide 9 by the peracetic acid oxidation established by Kuwajima
and Urabe.6 The removal of the acetonide protection of 9 was
accomplished by its treatment with 80% acetic acid, furnishing
10 in 93% yield.7 The optimum condition for the intramolecular
Michael addition of butenolide 10 to generate the spiro
compounds with appropriate configurations was assessed by
changing the reaction temperature, solvent and bases. Even-
tually it was uncovered that triethylamine (100 equiv.) in
toluene with heating at reflux for 72 h was the most suitable
condition. The syn-spiro compound was always formed as the
major product with the syn:anti ratio of 2+1. However, these
diastereomeric mixtures are not readily separable by column
chromatography. In order to separate them more effectively,
butenolide 10 was subjected to an intramolecular Michael
addition,5b an acid-promoted transesterification,5b and a se-
lective protection of the primary hydroxy group of the bicyclic
lactone with TBDMSCl. In this way, the less polar protected
bicyclic lactone 11 was obtained in 45% yield, while the anti-
spiro diol 12 was obtained in 20% yield. Alcohol 11 was
protected by p-bromobenzoyl chloride (p-BrBzCl) to yield the
p-bromobenzoate ester 13. Removal of the TBDMSCl group
was achieved with 1 M HCl–THF (1+5, v/v), furnishing 14.
Oxidation of 14 with Dess–Martin periodinane8 led to an
aldehyde, which was reductively decarbonylated to bicyclic
lactone 2 by Wilkinson’s reagent9 immediately without further
purification, with retention of both geometrical and ster-
eochemical configuration. In a similar pathway, bicyclic lactone
3 was also realized from chiral alcohol 6 (Scheme 1). The
configurations of both 11 and 19 were confirmed by X-ray
crystallography.¶
Scheme 2 Reagents and conditions: i, 80% acetic acid, rt, 24 h; ii,
TBDMSCl, imidazole, DMAP, THF, rt, 30 min; iii, p-TsOH, DMP (2
equiv.), THF, reflux, 8 h, 80% in 3 steps; iv, 0.1 M TBAF in THF, 0 °C, 30
min; v, PDC, molecular sieves, CH2Cl2, rt, 2 h, vi, EtMgBr (2 equiv.), THF,
0 °C, 10 min; vii, PDC, molecular sieves, CH2Cl2, rt, 8 h, 68% in 3 steps;
viii, CH2NCHLi (1.5 equiv.), hexanes, 290 °C, 1 h; ix, TMSCl, imidazole,
DMAP, DMF, rt, 24 h; x, 40% peracetic acid (4 equiv.), NaOAc (4 equiv.),
CH2Cl2, 0 °C, rt, 48 h; xi, 80% acetic acid, rt, 24 h; xii, Et3N (100 equiv.),
toluene, reflux, 24 h; xiii, 1 M HCl (aq), rt, 48 h; xiv, TBDMSCl (1.5
equiv.), imidazole (3 equiv.), DMAP, DMF, 0 °C, 1 h; xv, OsO4 (0.1
equiv.), NMO, acetone–H2O (4+1, v/v), rt, 72 h; xvi, p-TsOH, DMP (2
equiv.), THF, rt, 8 h, xvii, NaH, imidazole, THF, 0 °C, 5 min, CS2 (5 equiv.),
0 °C, 10 min, MeI (5 equiv.), 0 °C, 10 min; xviii, nBu3SnH, AIBN, toluene,
reflux, 8 h; xix, 1 M HCl–THF (1+5, v/v), rt, 24 h; xx, Dess–Martin
periodinane, CH2Cl2, rt, 2 h; xxi, RhCl(PPh3)3, p-xylene, reflux, 72 h.; xxii,
80% acetic acid, rt; 24 h; xxiii, NaIO4, H2O, CH2Cl2, rt, 15 min.
Encouraged by the aforementioned results, the enantiose-
lective synthesis of aldehyde 4 from 16 was achieved and
depicted in Scheme 2. The removal of the TBDMS ether and
acetonide group of 16 provided a triol, which underwent a
regioselective TBDMS protection and was followed by an
acetonide protection, furnishing 22 (72% in 3 steps). The
selective deprotection of the TBDMS ether of 22 was achieved
by slow addition of 0.1 M TBAF in THF, leading to an alcohol,
which underwent PDC oxidation, EtMgBr addition and PDC
oxidation again, to provide ketone 23 (72% in 4 steps). Highly
diastereoselective addition of vinyllithium to 23 at 290 °C in
hexanes afforded exclusively the desired alcohol, which was
protected as the TMS ether immediately. Subsequently, the
TMS ether was then reacted with peracetic acid,6 which was
followed by treatment with 80% acetic acid, affording buteno-
lide 24 (60% in 4 steps).¶ The bicyclic lactone 25 was obtained
from 24 via Michael addition, acetonide deprotection, acid
promoted transesterification5b and selective TBDMS protection
(30% in 4 steps). The secondary hydroxyl group of 25 was
converted to a xanthate, which underwent osmium dihydroxyla-
tion,10 acetonide and Barton deoxygenation,11 affording 26
(73% in 4 steps). Finally, aldehyde 4 was accomplished from 26
in a sequence through TBDMS ether deprotection, Dess–Martin
periodinane8 oxidation, reductive decarbonylation,9 acetonide
deprotection and oxidative diol cleavage.12
In conclusion, we have demonstrated that the preparation of
2, 3 and 4, potential core skeletons of the plakortones, were
accomplished through enantioselective routes. Total synthesis
of plakortone A (1a) in both its natural and non-natural forms is
in progress.∑
We are grateful to Professor Thomas C.W. Mak for all X-ray
crystallographic analyses, and to Professor John Boukouvalas
for informing us the absolute configurations of plakortones.
This work was partially supported by a Direct Grant (Project ID
2060130), administered by the Chinese University of Hong
Kong, as well as by the Areas of Excellence Scheme established
under the University Grants Committee of the Hong Kong
Special Administrative Region, China (Project No. AoE/P-
10/01).
Notes and references
¶ CCDC 188284, 188285 and 188701. See http://www.rsc.org/suppdata/cc/
b2/b205924j/ for crystallographic data in CIF or other electronic format
∑ An article reporting the total synthesis and absolute stereochemistry of
plakortone D has recently appeared, see P. Y. Hayes and W. Kitching, J.
Am. Chem. Soc., 2002, 124, 9718.
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