Synthesis of manoalide using a 1,2-metallate rearrangement

Article abstract of DOI:10.1039/a701936j

Manoalide, a marine antiinflammatory sesterterpenoid, has been synthesised using a 1,2-metallate rearrangement of a higher order cuprate and a Pd⁰-catalysed carbonylation of an iodo alkene to generate the central dihydropyranone ring.

Full text of DOI:10.1039/a701936j

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Synthesis of manoalide using a 1,2-metallate rearrangement
Agne`s Pommier and Philip J. Kocien´ski*
Department of Chemistry, University of Glasgow, Glasgow, UK G12 8QQ
Manoalide, a marine antiinflammatory sesterterpenoid, has
been synthesised using a 1,2-metallate rearrangement of a
higher order cuprate and a Pd0-catalysed carbonylation of
an iodo alkene to generate the central dihydropyranone
ring.
alcohol 5 in 90% yield. The Fischer carbene complex generated
by electrophilic cyclisation of 5 with (CO)5Mo·NEt3‡ was
converted in situ to the alkenylstannane 7 in the presence of
Bu3SnOTf according to the procedure of McDonald et al.3
(64% overall from 5). Transmetallation of the alkenylstannane
to the desired alkenyllithium 3 was plagued by competing
metallation at the 2-position of the furan ring and success was
only achieved after a protracted study of the reaction conditions.
Clean transmetallation was eventually accomplished with BusLi
Manoalide 1 is a sesterterpenoid metabolite isolated from the
Pacific sponge Luffariella variablis.1 As a potent inhibitor of
phospholipase A2, it has been evaluated in phase II clinical trials
for the treatment of psoriasis.2 We now report a short synthesis
of racemic manoalide from the homocuprate 2 and lithiated
dihydrofuran 3 (Scheme 1) which features the use of a
1,2-metallate rearrangement of a higher order cuprate and a Pd0-
catalysed carbonylation of an iodo alkene to generate the central
dihydropyranone ring.
2 +
3
i
2–
2Li+
SiEt3
O
The lithiated dihydrofuran 3 was prepared as shown in
Scheme 2. Addition of prop-2-ynylmagnesium bromide to
5-triethylsilyl-3-furaldehyde 4† gave the homoprop-2-ynylic
R
R
O
Cu
O
8
O
HO
O
1,2-metallate rearrangement
SiEt3
OH
2–
2Li+
R
O
Manoalide 1
O
Cu
SiEt3
O
9
+
CuLi
O
2
Li
ii
SiEt3
O
2
3
H
O
Scheme 1
I
SiEt3
O
SiEt3
O
i
90%
10 (72% from 7)
HO
O
iii
94%
4
5
SiEt3
O
ii
O
O
SiEt3
O
SiEt3
+
HNEt3
O
O
O
11
–
Bu3Sn
iii
(CO)5Mo
iv, v
56%
6
7 (64% from 5)
rac-Manoalide 1
3
Scheme 3 Reagents and conditions: i, add a solution of 3 in Et2O–pentane
to a solution of 2 in Et2O–Me2S (1:1) at 2 40 °C; ii, I2 (4 equiv.), 2 30 °C;
iii, Pd(PPh3)4, Pri2NEt, THF–MeOH, CO (2 atm), 60 °C, 24 h; iv, DIBAL-
H, CH2Cl2, 2 80 °C; v, O2, hn, rose bengal, MeOH, 2 80 °C
Scheme 2 Reagents and conditions: i, prop-2-ynylmagnesium bromide,
Et2O, 2 40 °C ? room temp.; ii, (CO)5Mo·NEt3, Bu3SnOTf, Et2O–Et3N,
room temp., 48 h; iii, BusLi, Et2O–pentane, 2 60 °C, 20 min
Chem. Commun., 1997
1139

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aldehyde; (ii) metallation of the resultant adduct with BusLi, and (iii)
addition of chlorotriethylsilane (ref. 15).
‡ The yellow complex (CO)5Mo·NEt3 is formed by irradiation of
hexacarbonylmolybdenum with intense visible light (Hg lamp) in diethyl
ether containing triethylamine at 0 °C.
§ For details of the preparation of cuprate 2 see ref. 6. The homoallylic iodo
alkane precursor to cuprate 2 was prepared in four steps (25% overall) from
b-ionone by analogy to the procedure described for the corresponding
homoallylic bromo alkane (ref. 10).
in a diethyl ether–pentane mixture at 2 60 °C for 20 min and the
lithium reagent 3 used immediately in the next step.
The key step in our synthesis involved a 1,2-metallate
rearrangement4 of the higher order cuprate 8 derived from
addition of alkenyllithium 3 to the lower order homocuprate 2§
which occurred with clean inversion of configuration to give the
alkenylcuprate 9 (Scheme 3). Attempts to carboxylate 9 with
CO2 in the presence of triethyl phosphite5—a ploy which had
been successful in our synthesis of the related terpenoid
luffariolide E6,7—failed to give any of the desired lactone 11.
We therefore quenched the alkenylcuprate 9 with iodine at
2 30 °C to give iodo alkene 10 in 72% overall yield from 7, and
then introduced the remaining carbon (94% yield) by Pd0-
catalysed carbonylation using a modification of conditions
previously described by Heck.8 Finally, reduction of the lactone
to the lactol with DIBAL-H (94%) and photooxidation of the
silylfuran (60%)9 gave manoalide, identical by high field NMR
spectroscopy (1H and 13C) and mass spectrometry with a sample
prepared previously and correlated with the natural product.10
The synthesis of racemic manoalide reported herein was
accomplished in a total of 12 steps (4% overall) from
commercially available b-ionone and 3-furaldehyde. The
discovery of conditions for transmetallating stannyldihydro-
furan 6 without competing metallation of the furan was a crucial
advance. Another tactical advance was the iodination of the
metallate rearrangement product 10 which provided a clean,
efficient and highly stereoselective route to the (Z)-iodo alkene
11, itself a useful precursor to a wide range of trisubstitued
alkenes. The overall yield of our synthesis compares favourably
with previous syntheses.10–14
References
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We thank the EPSRC for financial support, Dr Michael Garst
for NMR spectra of authentic manoalide and Rhonan Ford for
technical advice.
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Footnotes
* E-mail: p.kocienski@chem.gla.ac.uk
† 5-Triethylsilyl-3-furaldehyde was prepared in one pot from commercial
3-furaldehyde in 73% yield by (i) addition of lithium morpholide to the
Received in Liverpool, UK, 21st March 1997; Com. 7/01936J
1140
Chem. Commun., 1997