Development of an approach to the synthesis of the plakortones

Article abstract of DOI:10.1016/S0040-4039(00)00464-0

A general synthesis of the plakortones has been developed by the synthesis of two key sections, with a focus on Pd(II)-promoted preparation of a cis-fused tetrahydrofuranolactone. The key intermediates were obtained in homochiral form starting from asymmetric epoxidation of an allylic alcohol. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00464-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3567–3571
Development of an approach to the synthesis of the plakortones
M. F. Semmelhack ∗ and Ponnusamy Shanmugam †
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA
Received 6 January 2000; revised 10 March 2000; accepted 16 March 2000
Abstract
A general synthesis of the plakortones has been developed by the synthesis of two key sections, with a focus
on Pd(II)-promoted preparation of a cis-fused tetrahydrofuranolactone. The key intermediates were obtained in
homochiral form starting from asymmetric epoxidation of an allylic alcohol. © 2000 Elsevier Science Ltd. All
rights reserved.
Palladium-promoted intramolecular alkoxycarbonylation of hydroxyalkenes (1) has been developed
as a route to bicyclic tetrahydrofuran lactones (2).1–5 The general process was first demonstrated in the
construction of a cyclohexane ring with cis fused lactone6 and later developed to control the relative
configuration of the 2,5-substituents around a tetrahydrofuran ring.7 Several families of natural products
incorporate this ring system and it is an interesting question whether the palladium methodology offers
efficient strategies for their construction. The plakortones (3–6) were identified in 1996 and show activity
as activators of the cardiac sarcoplasmic reticulum Ca+2-pumping ATPase and are of potential interest
as agents to increase calcium pumping in order to correct cardiac muscle relaxation abnormalities.8 The
1
structure is based on detailed H NMR studies and the configuration at C-40 in 3–6 is not defined, and
likewise for the configuration at C-20 in 5 and 6. A few other diverse structures show similar activity (e.g.,
gingerol9 for activation of cardiac SR Ca+2-ATPase and plakorin10 for skeletal muscle Ca+2-ATPase), but
no detailed SAR work has been published.
∗
†
Corresponding author. Tel: +1 609 258-5501; fax: +1 609 258-3409; e-mail: mfshack@princeton.edu (M. F. Semmelhack)
On deputation from Regional Research Laboratory (CSIR), Trivandrum-695019, India.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00464-0
tetl 16744

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Retrosynthetic analysis: We are prompted by a recent paper11 with similar ideas to report here our
progress in developing an approach to the plakortone structures. Key to the palladium methodology,
a retrosynthetic analysis is shown in Scheme 1. The key transforms are the alkene coupling (a; for
plakortones A and B; alternative C–C single bond couplings would be appropriate for plakortones C and
D), the palladium alkoxycarbonylation (b), the addition of a carbonyl anion equivalent to a homochiral
epoxide (c), and the enolate Claisen rearrangement (d). This analysis results in a short sequence, but
exposes obvious selectivity issues in the trisubstituted double bond preparation (a) and in creating
the second stereogenic center in intermediate 7. We report here the synthesis of homochiral lactone 8
(Y=CH2OH) and the sulfone, 9 (X=S02Ph).
Scheme 1.
The general conversion of 1 to 2 (R2, R3=H) has ample precedent,12 but the precursor 7 has two
quarternary centers, and the influence of such steric crowding was not previously tested. The simple
model 10, prepared from diacetone alcohol (2.5 mol equiv. of vinyl-MgBr; 71% yield) underwent the
desired conversion to give 11 in 87% yield. The Pd(II) was used here in small excess (1.5 mol equiv.)
which was convenient on this research scale, although procedures with catalytic Pd(II) and excess Cu(II)
as reoxidant are available.2,3,11 The formation of the cis-fused lactone is general with this methodology.
Molecular mechanics analysis13 suggests that the cis arrangement (11) is more stable than the trans by
10–15 kcal/mol.
Preparation of the bicyclic lactone: The synthesis of precursor 7 (P=t-butyldimethylsilyl, TBS) is
shown in Scheme 2. Following a known procedure,14 asymmetric epoxidation of the allylic alcohol 12
gave 13 in 97% yield and 85–90% ee; protection as the TBS ether (14, 86%) followed by displacement
with 2-ethyl-2-lithio-1,3-dithiane produced the hydroxy thioketal 15 (98%). The standard hydrolysis15
affords the β-hydroxyketone 16 in 96% yield. The simplest procedure for preparation of 7a is by

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addition of a vinyl organometallic nucleophile. However, the use of vinylmagnesium bromide led to
>80% enolization rather than addition. Several variations were tested; the most effective was to treat 16
with anhydrous CeCl3 prior to addition of vinylmagnesium bromide.16
Scheme 2. (a) See Ref. 13a, b; (b) see Ref. 13c; (c) anion prepared from nBuLi (1.15 mol equiv.) and 2-ethyl-1,3-dithiane (1
mol equiv.) in ether at 0°C, 1 h; then 14 (1 mol equiv. in THF), 0°C/5 h and 23°C/12 h; (d) yellow HgO (2.2 mol equiv.), HgCl2
(3 mol equiv.), MeOH, reflux, 18 h; (e) (i) mix CeCl3 (freshly dried, 1.1 mol equiv.), THF, vinyl-MgBr (2.5 mol equiv., 1 M in
THF), −78°C; (ii) add 16 (1 mol equiv.) in THF, −78°C; (iii) 0°C, 45 min; (iv) HOAc at −40°C; (f) see text and Ref. 16
The product mixture had three components: unreacted 16 attributed to enolization (20%), and a mixture
of diastereomeric diols, 7a and 17 (67% together after flash chromatography). 1H NMR spectral analysis
of the mixture indicated a ratio of 4:1 (using the signals due to the methine proton appearing at δ 6.8 and
6.9 ppm). Slow elution of the mixture through a silica gel column afforded the pure diol 7a (40%) along
with a mixture of 7a and 17 (2.5:1 ratio, 25%). Cyclization17 of 7a with Pd(OAc)2 (2 mol equiv.) in the
presence of CO (1.1 atm) in THF at 23°C gave a single bicyclic lactone (18) in 86% yield after column
chromatography. While 17 could not be obtained in pure form, a mixture (2.5:1) of 7a and 17 produced a
mixture of lactones, again inseparable, but whose 1H NMR spectral data were consistent with a mixture
of 18 and 19. The relative configurations of 18 were established to be the same as the natural product by
thorough NOE-difference studies (examples in Fig. 1 and Table 1).
Fig. 1. NOE enhancements with irradiation at Ha (δ 4.52) (500 MHz)
Synthesis of the side chain precursor, 9: The side chain unit is available in racemic form according to
Scheme 3, a process which should be readily adaptable to asymmetric synthesis through kinetic resolution
of the early intermediate, 20. Since the configuration of the stereogenic center in the side chain is not
established in the plakortones, it will be important to have access to both enantiomers of 20. Addition
of EtMgBr to E-2-pentenal18 gave 20 in 71% yield after fractional distillation. Based on the Johnson
protocol19 for the enolate Claisen rearrangement, an optimized procedure for converting 20 to 21 was

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Table 1
Comparison of the chemical shifts and NOE enhancements for bicyclic lactone 18 and the bicyclic
lactone portion of plakortone B8a
developed. A mixture of 20, trimethyl orthoacetate (5 mol equiv.), and propionic acid (0.12 mol equiv.)
was heated at 85°C while MeOH distilled through a short fractionating column. When the MeOH ceased
to distill (ca. 2 h), the solution was transferred to a sealed tube and heated at 145°C for 24 h. Isolation20
gave 21 as a mixture with the corresponding Z isomer (78% yield together; 85:15 based on integration
of the vinyl signals in the 1H NMR spectrum). Reduction of the mixture with LiAlH4 gave the alcohol
22, which, after column chromatography, was isolated as a single geometrical isomer (92% yield based
on the amount of 21 in the starting E/Z mixture). PCC oxidation21 gave the aldehyde 23 (76% yield).
Addition of MeMgBr led to the diastereomers represented by 24 (3:2 ratio, estimated by 1 H NMR; 95%
yield).
Scheme 3. Synthesis of the side chain unit. (a) EtMgBr (1 M in THF, 1.2 mol equiv.), 23°C; (b) see text; (c) LiAlH4 (2 mol
equiv.), ether, 0→23°C, 14 h; (d) pyridinium chlorochromate (1.4 mol equiv.), CH2Cl2, 23°C, 1.5 h; (e) MeMgBr (1 M sol. in
THF, 1.2 mol equiv., 0°C, 1.5 h); (f) PhSSPh (1.8 mol equiv.), pyridine (ca. 2 mol equiv.), (nBu)3P (1.5 mol equiv.), 23°C, 5.5
h; (g) PhSeSePh (0.9 mol equiv.), CH2Cl2:Et2O (1:7), 30% H2O2 (30 mol equiv.), 0°C, 1 h
Anticipating a Julia coupling22 to join the side chain to the furanolactone, the corresponding phenyl
thioether (25, 83% yield) and phenyl sulfone (26, 95% yield) were prepared by standard procedures.23
This work provides effective methodology for the formation of the non-racemic furanolactone portion
and a method for the side chain synthesis which should be readily adaptable to the preparation of each
enantiomer separately. The completion of an asymmetic synthesis of plakotone B is underway.
Acknowledgements
Financial support in the form of a grant from the Research Corporation is acknowledged. One of the
authors (P.S.) thanks DST (Goverment of India, New Delhi) for awarding a BOYSCAST fellowship.

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palladium(II) acetate (0.267 gm, 1.18 mmol). The flask was evacuated (0.1 torr) and the flask and balloon were filled with
argon. This process was repeated three times with argon. It was then repeated with carbon monoxide (CO) three times.
With the balloon filled with CO (ca. 1.1 atm), dry THF (5 mL) was added via syringe followed by a addition over 2 min
of a solution of the diol 7a (0.180 g, 0.593 mmol) in 3 mL of dry THF. The mixture was stirred at 23°C for 4 h and then
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hexane:EtOAc 5:1). 1H NMR (500 MHz, CDCl3): δ 4.5 (t, J=2.5 Hz, 1H), 3.5 (d, J=10.5 Hz, 1H), 3.4 (d, J=10.5 Hz, 1H),
2.6 (br s, 2H), 2.2 (abq, J=14 Hz, 2H), 1.8 (approx quintet, J=7 Hz, 1H), 1.7 (approx quintet, J=7 Hz, 1H), 1.55 (m, 2H; br
q), 1.0 (t, J=7.5 Hz, 3H), 0.9 (s overlapping t, 12H), 0.06 (s, 6H). 13C NMR (125 MHz, CDCl3): δ 176.4, 99.2, 88.4, 83.2,
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calcd: 329.2149; found: 329.2149.
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