Synthesis of the floresolide B hydroquinone lactone core using ring-closing metathesis

Article abstract of DOI:10.1016/j.tetlet.2005.09.023

The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach. Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the hydroquinone a

Full text of DOI:10.1016/j.tetlet.2005.09.023

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7793–7796
Synthesis of the floresolide B hydroquinone lactone core using
ring-closing metathesis
Timothy F. Briggs and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306, USA
Received 1 September 2005; revised 2 September 2005; accepted 6 September 2005
Available online 21 September 2005
Abstract—The hydroquinone lactone core of the floresolides was synthesized through a ring-closing metathesis (RCM) approach.
Optimal RCM efficiency was obtained at higher reaction concentration. An unexpected Lewis acid-promoted rearrangement of the
hydroquinone and other observations relevant to on-going total synthesis efforts are discussed.
Ó 2005 Elsevier Ltd. All rights reserved.
The floresolides1 are cytotoxic hydroquinone cyclo-
phanes that bear a structural relationship to the longi-
thorone family of prenylated quinones and hydro-
quinones.2 The longithorones and the floresolides are
both isolated from similar ascidian species found in shal-
low waters off the Flores Islands, which suggests a
possible biogenetic relationship as well. No synthetic
approaches to the floresolides have been reported.3
Our interest in the floresolides as synthetic targets stems
from the cyclophane, a motif found within the floreso-
lide tricyclic structure as well as the structure of other
natural products under current investigation in our
Laboratory.
manner, and when manifest within a cyclophane, the
methods available for controlled construction of this
functionality are limited considerably. We envision, for
the total synthesis, installing this remote alkene before
annealing the hydroquinone lactone, as the rigid bicyclic
lactone limits the conformational degrees of freedom
available to the system. As part of our end game strat-
egy, we aim to effect a ring-closing metathesis4 to pre-
pare the seven-membered lactone (Fig. 1).
Several potential problems face the proposed olefin
metathesis cyclization: (1) Trisubstituted electron-defi-
cient alkenes can be difficult to prepare by ring-closing
metathesis. (2) Pendant alkenes such as the isopropenyl
group must be inert to metathesis side reactions. (3)
Most significantly, the Z conformation of esters is on
the order of 8.5 kcal/mol lower in energy than the E con-
formation.5 The Z-ester places the chain termini at
The major synthetic challenge presented by the floreso-
lides is the ansa bridge, which features an isolated, tri-
substituted alkene. Isolated, trisubstituted alkenes are
often difficult to prepare in a regio- and stereo-specific
OH
OH
OH
O
O
O
O
O
O
O
floresolide A (1)
floresolide B (2)
3
Figure 1. Floresolides A and B and model lactone 3.
Keywords: Floresolide; Ring-closing metathesis; Synthesis.
*
Corresponding author. Tel.: +1 850 644 2333; fax: +1 850 644 8281; e-mail: gdudley@chem.fsu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.023

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T. F. Briggs, G. B. Dudley / Tetrahedron Letters 46 (2005) 7793–7796
impossibly separated regions of space (vide infra). This
unfavorable equilibrium must be overcome for cycliza-
tion to occur.6
Our synthetic sequence began with a Mitsunobu cou-
pling10 of phenol 411 and (E)-2-methyl-2-butenol (5).12
An aromatic Claisen rearrangement13 of 6 then provided
7, the 2,6-diallylated phenol. Acylation with methacry-
loyl chloride afforded 8, our substrate for the key
metathesis cyclization (Scheme 1).
Indeed, despite the ubiquity of olefin metathesis reac-
tions in synthesis, we could find no prior examples of
ring-closing metatheses to afford trisubstituted, a,b-
unsaturated lactones within either seven-, eight-, or
nine-membered rings.7–9 We are also concerned, consid-
Our initial attempts at cyclization using GrubbsÕ second-
generation catalyst (9, 5 mol %)14 confirmed the expected
synthetic hurdles but yielded encouraging results
(Scheme 2). We employed high dilution conditions
(0.004 mol/L) to thwart expected cross-metathesis
pathways. Nonetheless, pseudo-dimer15 11 (from cross-
metathesis of the allyl moiety) was the major pro-
duct, along with a low yield (<20%) of the desired lactone
(12).
ering FurstnerÕs findings,7c about possible olefin migra-
¨
tion in the aftermath of cyclization to afford the b,c-
unsaturated lactone.
For the sake of our studies and for instructive purposes
relating to future synthetic efforts, we deemed it critical
to establish precedent for our cyclization by investigat-
ing the synthesis of a model hydroquinone lactone sys-
tem (3). Lactone 3 is essentially a nor-prenyl analog of
floresolide B (2), in which five carbons of the ansa bridge
are omitted. The synthesis of 3 described herein
addresses the aforementioned concerns, expands the
scope of the RCM reaction, and provides key insight
for our on-going efforts directed toward the total synthe-
sis of floresolides A and B.
Note that the Ôthird alkeneÕ, the terminal disubstituted
propenyl moiety, remains intact throughout this
process. We hypothesize that acrylate 8 enters the cata-
lytic cycle exclusively by reaction at the terminal,
monosubstituted allyl group to generate alkylidene 10.
Cyclization onto the electron-deficient disubstituted
acrylate is slow, particularly considering that the
acrylate alkene is inaccessible in the (preferred) Z-ester
conformation (Z-10, Scheme 2).5 Therefore, revers-
ible intermolecular cross-coupling occurs even at
relatively high dilution. Pseudo-dimer 11 then reenters
the catalytic cyclic exclusively via 10, which in time
cyclizes onto the acrylate to afford lactone 12.16
OBn
OBn
DIAD, PPh3
THF, 72%
OH
HO
O
5
6
4
Guided by this hypothesis, we elected to forgo high dilu-
tion in favor of a higher catalyst concentration, which
we expected would increase the rate at which the system
reaches the thermodynamically preferred lactone (12).
Thus, 8 and 9 (10 mol %) were dissolved in a convenient
amount of methylene chloride (0.02 mol/L) and heated
at reflux for 20 h to provide lactone 12 as the sole iden-
tifiable product, isolated in 55% yield after recrystalliza-
tion (Scheme 3).17
methacryloyl
chloride, Et3N
DMAP, CH2Cl2
OBn
OBn
PhNEt2
reflux
85%
HO
O
90%
O
8
7
Scheme 1. Synthesis of the cyclization substrate.
Mes
N
N Mes
Cl
OBn
OBn
Ru
PCy3
Cl
Ph
O
O
9 5 mol%
8
O
CH2Cl2
O
[Ru]
[Ru]
E-10
Z-10
OBn
OBn
O
O
OBn
O
O
O
O
11
12
Scheme 2. Initial attempt at olefin metathesis.

T. F. Briggs, G. B. Dudley / Tetrahedron Letters 46 (2005) 7793–7796
7795
occurs best by embracing the kinetic detour through
cross-metathesis en route to the thermodynamically pre-
ferred cyclization product (12). We also identified and
circumvented the propensity of this system to rearrange
to naphthol 13. Armed with these key insights into the
hydroquinone lactone chemistry, we are now construct-
ing the ansa bridge to advance material suitable for the
total synthesis of the floresolides. Details of our
on-going efforts will be reported in due course.
OBn
OBn
9 (10 mol%), CH2Cl2, reflux
O
O
0.02M in 8, 20 h, 55%a
O
O
8
12
Scheme 3. Optimized cyclization conditions: aAverage yield of 12
following chromatographic purification and recrystallization (three
experiments).
Acknowledgments
This research was supported by an award from Research
Corporation and by the FSU Department of Chemistry
and Biochemistry. G.B.D. acknowledges an award from
the Oak Ridge Associated Universities and a grant from
the James and Ester King Biomedical Research Pro-
gram, Florida Department of Health. We thank all of
these agencies for their support. We thank Dr. Joseph
Vaughn and Dr. Thomas Gedris for assistance with
the NMR facilities, Dr. Umesh Goli for providing the
mass spectrometry data, and the Krafft Lab for the
use of their FT-IR instrument.
OBn
OBn
OH
O
1 equiv. AlCl3, CH2Cl2
O
0 oC, 30 min.
O
13a
12
Scheme 4. Lewis acid-promoted rearrangement of 12.
To complete our study we needed to cleave the benzyl
ether18 and reveal hydroquinone 3. We looked first at
Lewis acids rather than reducing agents out of concern
for the pendant alkenes present in 12. In doing so, we
observed an interesting rearrangement (albeit counter
to our synthetic goals) exemplified by the aluminum
chloride-promoted reaction outlined in Scheme 4.
Naphthol 13 was the only detectable product from this
experiment.19
Supplementary data
Experimental procedures and characterization data for
all compounds and a proposed mechanism for the trans-
formation 12!13. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2005.09.023.
BirkoferÕs hydrogenolysis20 was recently shown to
remove benzyl ethers selectively in the presence of other
potentially labile functionality.21 Consistent with prior
reports, a black, heterogeneous mixture of 12, palladium
acetate, triethylamine, and triethylsilane gave rise to
hydroquinone lactone 3 after workup with acetic acid.
Triethylamine is a necessary component for debenzyl-
ation; however, it also promotes isomerization of 12 to
the b,c-unsaturated lactone. For best results (in this
case), triethylamine must be included in molar ratios
equal to or less than that of the palladium catalyst. This
carefully optimized protocol affords the floresolide lac-
tone model system (3) in 73% yield as the sole isolated
product (Scheme 5).
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