Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A

Article abstract of DOI:10.1039/c1ob05335c

A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the

Full text of DOI:10.1039/c1ob05335c

Organic &
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Volume 9 | Number 16 | 21 August 2011 | Pages 5581–5880
ISSN 1477-0520
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Debendra K. Mohapatra,
J. S. Yadav et al.
Ring-closing metathesis (RCM) based
synthesis of the macrolactone core of
amphidinolactone A
1477-0520(2011)9:16;1-S

Organic &
Biomolecular
Chemistry
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COMMUNICATION
Ring-closing metathesis (RCM) based synthesis of the macrolactone core of
amphidinolactone A†
Debendra K. Mohapatra,*a Manas R. Pattanayak,a,b Pragna P. Das,a Tapas R. Pradhana and J. S. Yadav*a,c
Received 3rd March 2011, Accepted 11th May 2011
DOI: 10.1039/c1ob05335c
A convergent synthesis of the macrolactone core of am-
phidinolactone A has been achieved, in a 10 step linear
sequence with 32% overall yield, through a ring-closing
metathesis reaction as the macrolactonization step. The RCM
precursor was obtained by the union of acid and alcohol
fragments derived from (R)-epichlorohydrin and (R)-2,3-O-
isopropylidene glyceraldehyde, respectively.
control of the double bond geometry by the protecting groups dur-
ing the ring-closing metathesis reaction.5b,e In continuation of our
interest in exploring the substrate directed ring-closing metathesis
reaction for macrolide synthesis, we planned to synthesize initially
the macrolactone core of amphidinolactone A.
According to our retrosynthetic analysis of amphidinolactone
A (1) shown in Scheme 1, 3 could be achieved through ring-
closing metathesis reaction of 5 which in turn could be obtained
by esterification of acid 6 with alcohol 7. Acid fragment 6 and
alcohol fragment 7 could be obtained from (R)-epichlorohydrin
(8) and (R)-2,3-O-isopropylidene glyceraldehyde (9), respectively.
In 2007, Kobayashi et al. isolated amphidinolactone A (1), a
cytotoxic 13-membered macrolide, from symbiotic dinoflagellate
Amphidinium sp. (Y-25) separated from an Okinawa a marine acoel
flatworm Amphiscolops sp.1 The relative and absolute stereochem-
istry of amphidinolactone A (1) have been elucidated on the basis
of extensive spectral analysis followed by total synthesis.2 The
interesting biological profile as well as the structural complexity
of amphidinolactone A (1) (Fig. 1) has attracted the attention
of synthetic organic chemists worldwide. Recently, we reported a
concise and efficient total synthesis3 of amphidinolactone A via
stereoselective intramolecular Nozaki–Hiyama–Kishi reaction.
Fig. 1 Structure of amphidinolactone A (1).
Construction of lactone through the formation of C–C bond
and particularly by intramolecular ring-closing metathesis4 reac-
tion stands as a promising tool for the synthesis of macrolides and
heterocycles. The influence of protecting groups and the substrate-
specific nature of the ring-closing metathesis reaction have been
reported previously.5 During our studies on the total synthesis of
nonenolide and decarestrictine C1 and C2, we observed a complete
Scheme 1 Retrosynthetic analysis of amphidinolactone A (1).
Chiral epoxide 8 obtained through Jacobsen’s hydrolytic kinetic
resolution protocol,6 was taken as the starting material for the
synthesis of acid fragment 6. The epoxide 8 was treated with
lithium acetylide prepared from TBS-protected alkyne 10 using n-
BuLi in THF at -78 ◦C to afford 11 in 92% yield.7 The epoxidation
of the resulting chlorohydrin 11 proceeded smoothly with NaH in
THF at 0 ◦C to obtain 12 in 91% yield. Partial hydrogenation was
achieved with Lindlar catalyst8 to furnish the Z-olefin derivative 13
in 96% yield. One-carbon homologation9 with dimethyl sulfonium
methylide at -10 ◦C afforded the allylic alcohol 14 in 85%
yield. Protection of the secondary hydroxyl group as its PMB
aOrganic Chemistry Division-I, Indian Institute of Chemical Tech-
nology, CSIR, Hyderabad, India. E-mail: mohapatra@iict.res.in,
yadavpub@iict.res.in; Fax: +91-40-27160512; Tel: +91-40-27193128
bUniversity of Hyderabad, Hyderabad 500 0046, India
cKing Saud University, P.O. Box 2454, Riyadh 11451, Saudi Arabia
† Electronic supplementary information (ESI) available: Experimental
details and 1H and 13C NMR spectra. See DOI: 10.1039/c1ob05335c
5630 | Org. Biomol. Chem., 2011, 9, 5630–5632
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ether followed by desilylation with p-TsOH in MeOH at room
temperature gave the primary alcohol 15 in 81% yield over two
steps. Treatment of the resulting primary hydroxyl group with
TEMPO10 and BAIB furnished the corresponding aldehyde which
on further oxidation under Pinnick11 conditions furnished the acid
fragment 6 in 89% yield over two steps (Scheme 2).
isomer as the major product). The primary hydroxyl group of
17 was converted to the corresponding iodide with I2, TPP and
imidazole in THF and subsequent reductive elimination14 of iodine
with activated Zn dust in EtOH provided the allylic alcohol 18
in 85% yield over two steps. The resulting secondary hydroxyl
group was protected as its PMB ether to obtain 19 in 92%
yield. Deprotection of the isopropylidene group with p-TsOH in
MeOH15 at room temperature afforded diol 20 in 87% yield. The
primary hydroxyl group of diol 20 was selectively protected as
its TBDPS-ether by using TBDPS-Cl and imidazole in THF to
obtain the alcohol fragment 7 in 89% yield.
Our next target was to couple both the fragments and inves-
tigate the critical ring-closing metathesis reaction. As per our
earlier reports, we followed the Yamaguchi conditions16 for the
esterification reaction. In this case, the yield was only 30–35%.
However, a better result was achieved by uniting both the coupling
partners with EDCI and DMAP in CH2Cl2 to afford the triene
ester 4 in 90% yield (Scheme 4).17 This sets the stage for the
crucial RCM reaction. When ester 4 was refluxed with Grubbs’
II generation catalyst in CH2Cl2 under high dilution conditions
(0.001 M), the reaction did not proceed at all. The extent of bias if
any conferred by the protecting groups on the outcome of the ring-
closing metathesis reaction could not be predicted with certainty.
We envisaged that PMB-protecting groups around the reacting
centers might act as a temporary constraint to stop them from
coming close enough for the reaction to happen. This prediction
was also supported by computational analysis (Fig. 2) where the
di-PMB protected product 2 showed a minimum energy of 44.18
kcal mol-1 and its protection free counterpart 3 showed 24.71
kcal mol-1 as well as experimental studies. To further prove our
predictions, di-PMB protected ester 4 was treated with DDQ18
Scheme 2 Reagents and conditions: (a) n-BuLi, BF3·(OEt)2, 10, -78 ◦C,
1 h, 92%; (b) NaH, THF, 0 ◦C, 1 h, 91%; (c) H2, Pd/C on CaCO3,
quinoline, rt, 2 h, 96%; (d) Me3SI, n-BuLi, THF, -10 ◦C, 2 h, 85%
(e) PMB-Br, NaH, THF, 4 h, 91% (f) p-TsOH, MeOH, 0 ◦C–rt, 1 h,
89%; (g) (i) TEMPO, BAIB, CH2Cl2, 30 min, (ii) NaClO2, NaH2PO4,
2-methyl-2-butene, t-BuOH, H2O, 2 h, 89% (over two steps).
Synthesis of fragment 7 was commenced with two-carbon
homologation of the known aldehyde (R)-2,3-O-isopropylidene
glyceraldehyde (9)12 to give a,b-unsaturated ester in 85% yield
which was converted to the corresponding E-allylic alcohol
16 under standard reaction conditions (Scheme 3). Sharpless
asymmetric epoxidation13 of 16 with (-)-DET and TBHP afforded
2,3-epoxy alcohol 17 in 93% yield (94 : 6 ratio with the required
Scheme 3 Reagents and conditions: (a) Ph3P CHCO2Et, benzene, reflux,
2 h, 85%; (b) DIBAL-H, CH2Cl2, 0 ◦C, 30 min, 84%; (c) (-)-DET,
Ti(Oi-Pr)4, TBHP, CH2Cl2, -20 ◦C, 12 h, 93%; (d) (i) I2, PPh3, imidazole,
THF, 0 ◦C, 10 min; (ii) activated Zn, NaI, EtOH, reflux, 85% (for 2 steps);
(e) PMB-Br, NaH, THF, 5 h, 92%; (f) CSA, MeOH, 0 ◦C, 2 h, 87%; (g)
TBDPS-Cl, imidazole, THF, 3 h, 89%.
Scheme 4 Reagents and conditions: (a) EDCI, DMAP (cat), CH2Cl2, 0 ◦C,
5 h, 90%; (b) Grubbs’ II generation catalyst, CH2Cl2, reflux, no reaction; (c)
DDQ, CH2Cl2 : H2O (9 : 1), 0 ◦C, 93%; (d) Grubbs’ II generation catalyst,
CH2Cl2, reflux, 76%.
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Acknowledgements
M.R.P., P.P.D., and T.R.P. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the award of
research fellowships. D.K.M. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, for a research grant (P-
81-113) (INSA Young Scientist Award Scheme).
5632 | Org. Biomol. Chem., 2011, 9, 5630–5632
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The Royal Society of Chemistry 2011
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