Exploration and determination of the redox properties of the pseudopterosin class of marine natural products

Article abstract of DOI:10.1016/j.tet.2009.09.021

We describe herein the redox chemistry of the pseudopterosin class of marine natural products. Known for their anti-inflammatory and wound healing properties, their chemistry has largely gone unexplored. Details of both voltammetric and preparative scale

Full text of DOI:10.1016/j.tet.2009.09.021

Tetrahedron 65 (2009) 10784–10790
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Exploration and determination of the redox properties of the pseudopterosin
class of marine natural products
*
Wei Zhong, R. Daniel Little
Department of Chemistry & Biochemistry, University of California, Santa Barbara, CA 93106, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2009
Received in revised form 20 August 2009
Accepted 7 September 2009
Available online 11 September 2009
We describe herein the redox chemistry of the pseudopterosin class of marine natural products. Known
for their anti-inflammatory and wound healing properties, their chemistry has largely gone unexplored.
Details of both voltammetric and preparative scale experiments are provided and speculation is provided
concerning the potential role of electron transfer chemistry in the expression of pseudopterosin
bioactivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Electron transfer
Redox
Oxidation
Pseudopterosins
Marine natural products
Voltammetry
Adenosine receptors
1. Introduction
H
H
The pseudopterosins constitute a class of diterpene glycosides
isolated from the marine octocoral Pseudopterogorgia elisabethae.1–3
They are structurally quite simple molecules, consisting of a tri-
cyclic hydrocarbon core possessing four stereocenters, and a sugar,
that is appended to a catechol subunit. Pseudopterosin A (PsA, 1a),
a potent inhibitor of phorbol myristate acetate (PMA)-induced
topical inflammation in mice,4 stabilizes cell membranes,5 prevents
the release of prostaglandins and leukotrienes from zymosan
stimulated murine macrophages, and inhibits degranulation of
human polymorphonuclear leukocytes6 and also inhibits phag-
osome formation in Tetrahymena cells.7 Its C-10 O-methyl ether, 1b,
offers a promising treatment for contact dermatitis,8 and displays
potent anti-inflammatory and wound healing properties.9 In ad-
dition to interest in their bioactivity profiles, the pseudopterosins
have attracted a significant amount of attention by those persons
expert in the art of organic synthesis.10
O
O
O
OH
OH
HO
OH
OR
OH
O
OH
OH
1a, PsA, R = H
1b, R = CH3
2, iso-PsE
(cyclic voltammetry) and preparative scale conditions, characterize
the products, examine the anti-inflammatory activity of one of the
products derived from iso-PsE (2), and speculate concerning the
role of redox chemistry in activation of adenosine receptors.11,12
2. Results and discussion
2.1. Cyclic voltammetry
Given the presence of the electron rich catechol subunit, it is
reasonable to speculate that redox chemistry might play a role in
the expression of pseudopterosin bioactivity. In this manuscript, we
detail for the first time, their redox behavior under both analytical
We began conservatively, electing to focus upon 4, a simplified
system that was designed to model the pseudopterosin framework.
It was constructed by treating tri-O-benzyl-D-glucal (3) with
DMDO, followed by ring opening of the resulting epoxide using 3,6-
dimethyl catechol in the presence of potassium carbonate and
18-crown-6. With 4 in hand, we examined its redox properties
voltammetrically.
* Corresponding author. Tel.: þ1 805 893 3693; fax: þ1 805 893 4120.
E-mail address: little@chem.ucsb.edu (R.D. Little).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.021

W. Zhong, R.D. Little / Tetrahedron 65 (2009) 10784–10790
10785
CH3
O
1. DMDO, acetone/DCM, 0 °C
OBn
OBn
–e
OBn
OBn
?
H3C
O
O
2. 3,6-dimethyl catechol, K2CO3
18-crown-6, acetone, reflux
HO
OH
OBn
OBn
(65%)
3
4
( compare with structures 1a, 1b, and 2 )
As Figure 1 shows, an irreversible wave appeared, displaying
a peak potential, Ep, of approximately þ1.6 V (Ag/AgNO3 reference
electrode, scan rate 100 mV/s). This value agrees well with those
reported in the literature for a variety of substituted catechols.13
That the voltammogram displayed an irreversible behavior in-
dicates that the intermediate formed in the oxidation step un-
dergoes a chemical transformation that removes it from the redox
equilibrium at a rate that exceeds that of the scan.14
Figure 2. Cyclic voltammogram for iso-PsE derivative, structure 5: glassy carbon an-
ode, Pt cathode, 500 mV/s scan rate, CH3CN solvent, 0.1 N (n-Bu)4NBF4 supporting
electrolyte.
PIDA and its trifluoroacetate analog, PIFA, prior to the dropwise
addition of the starting material.13,17,18 In the following discussion,
we abbreviate the reagent generated in the equilibrium with the
symbol PhIL2, with L referring to both acetate and trifluoroacetate.
Each substrate was transformed to a keto ketal wherein the C-20
hydroxyl group appended to the sugar cyclized onto the aromatic
framework, in one case transforming the model system 4 to
structure 6, and in the other converting the natural product derived
framework 5 into keto ketal 7a. In neither instance were we able to
detect the formation diastereomers at the newly formed stereo-
center (marked with a red asterisk in the products).
Figure 1. Cyclic voltammogram for model structure 4: glassy carbon anode, Pt cath-
ode, 100 mV/s scan rate, CH3CN solvent, 0.1 N (n-Bu)4NBF4 supporting electrolyte.
Encouraged by these results, we proceeded to investigate the
iso-PsE derived analog 5. It was constructed by treating iso-PsE (2)
with acetone dimethyl acetal and CSA. Like the model system 4,
structure 5 also displayed an irreversible redox curve (Epw1.5 V vs
Ag/AgNO3, scan rate 500 mV/s; note Fig. 2), thereby demonstrating
that the initially formed cation radical undergoes a follow-up re-
action at a rate that exceeds that of the reverse scan.15,16 Once again,
this begs the question: What is the nature of the transformation(s)
that occur after the initial oxidation?
The stereochemical assignments were made using NOE spec-
troscopy. For the keto ketal 6, irradiation of the
only to enhancement of the signal for the proton at the
(refer to structure 8 for labels). On the other hand, irradiation of the
methyl group positioned at the carbon led to enhancements of
-H (þ6.6%) as well as the H positioned at
a-methyl group led
b-position
d
both the signal for the
g
HO
OH
OH
CH3
HO
O
H
H
O
O
O
(CH3)2C(OMe)2,
O
O
CSA, CH2Cl2
CH3
OH
OH
(82%)
CH3
CH3
5
2, iso-PsE
–e (C/Pt)
?
5
CH3CN, n-Bu4NBF4
2.2. Preparative scale oxidation; product identification
C-20 of the sugar residue (þ4%). In addition, irradiation of the signal
corresponding to the anomeric H led only to enhancements of the
signals for the H’s positioned at carbons 30 and 50 on the sugar
subunit. Clearly, these observations are consistent with our struc-
tural assignment and not the alternative diastereomer.
To address this query each substrate, 4 and 5, was subjected to
a preparative scale oxidation. Phenyliodoso diacetate (PIDA) was
pretreated with TFA at 0 ꢀC to generate an equilibrium mixture of

10786
W. Zhong, R.D. Little / Tetrahedron 65 (2009) 10784–10790
CH3
O
2'
CH3
OBn
OBn
OBn
*
Ph L2, 0 °C
H3C
OBn
H3C
O
O
2'
O
OBn
O
HO
CH3NO2, CH2Cl2
OH
O
OBn
(64%)
4
6
acetate. For comparison, the same amount (50
dopterosin A (PsA, 1a) displayed inhibition at the 84% level and
mg/ear) of pseu-
H
H
O
afforded an ED50 of 8 mg/ear when a dose dependent evaluation was
performed.20 The ED50 for iso-PsE (2) is slightly larger, being 27
ear;12 the ED50 for 7b has not yet been measured.
mg/
CH3
OH
Me
2'
Ph L2, 0 °C
O
OR
OR
*
H3C
O
H3C
CH3NO2, CH2Cl2
(56%)
O
OH
OR
OR
O
O
2.4. Mechanism
7a, R = C(CH3)2
7b, R = H
5, R = C(CH3)2
What is the mechanism for the conversion of 4–6, and 5–7a?
Elegant studies have been conducted in both the electrochemical
and reagent promoted arenas. A recent review by Quideau and co-
workers summarizes their research involving each approach and
also provides an excellent summary of literature citations to the
work of others.13 In addition, we draw attention to the pioneering
electrochemical research from the laboratories of Miller,21 Swen-
ton,22 Yamamura,23 Nishiyama,24 Scha¨fer,25 Dryhurst,26 Hammer-
ich and Parker,27 and Nematollahi.28
+6.6%
+4%
H
γ
CH3
H
OBn
+4.2%
H
OBn
OBn
δ
β
O
O
α
O
H3C
O
8
When PhIL2 is utilized, literature precedence implicates the four
mechanistic options illustrated in Scheme 1. Three of the pathways
begin with a ligand exchange of trifluoroacetate/acetate/acetate for
ArO to afford structure 10. From there the paths diverge, one
leading to the pentadienyl cation 11 via the loss of PhI and tri-
fluoroacetate/acetate. Subsequent attack by R0OH and loss of
a proton leads to the product, keto ketal 12.29 Pathway two pro-
ceeds via attack by R0OH at the OR5-bearing carbon of 10 with
concomitant displacement of PhI and trifluoroacetate/acetate to
afford product 12. A third option suggests the equilibration of 10 via
a migration of iodine from oxygen to the adjacent carbon to afford
the structure 13.13a Attack of R0OH upon iodine leading to 14, fol-
lowed by a carbon to oxygen migration with loss of PhI, would
generate the product. Finally, for non-phenolic structures, i.e., those
where RsH in 9, a charge transfer (CT) complex is implicated by UV
spectroscopy; a subsequent single electron transfer (SET) affords
a cation radical whose existence is supported by its ESR spectrum
(note pathway 4).30
As anticipated, the analysis for structure 7a was more complex.
Once again, NOE experiments proved invaluable. We were also
guided by NMR chemical shift analysis resulting from a B3LYP/6–
31G(d) calculation carried out on structures 7a and 7c (Table 1).19
Irradiation of the signal for H-50 led to a 3.1% increase in the signal
corresponding to H-7, suggesting that they are on the same side of
the structure; in 7c, they are on opposite sides and an enhancement
would not be observed. In addition, irradiation of H-10 led to
a dramatic 13.6% increase in the signal corresponding to H-20 but no
effect on the signal for H-7. If the isolated material corresponded to
7c one would have anticipated seeing a change in the signal for H-7
since in that structure, they are positioned on the same side.
Table 1
Chemical shift data for selected protons and results of NOE experiments
H
H
Electrochemically, there are two reasonable pathways to con-
sider for transformations conducted under neutral or non-basic
conditions (note Scheme 2). Each begins with a one-electron oxi-
dation to afford cation radical 15, an event that generally occurs in
the potential range of þ1 to þ1.4 V.13 Capture of 15 by a nucleophile,
R0OH, followed by the sequential loss a proton, a second electron,
and a second proton leads to the product, 12. The second pathway
differs in the timing of the events, suggesting instead that the ini-
tially formed cation radical 15 undergoes the loss of a proton to
afford radical 17 at a rate that exceeds capture by R0OH, and that the
reaction with the latter is delayed until the penultimate stage of the
5 step sequence. Following this scenario, the radical 17 will undergo
oxidation at or below the potential needed for the first oxidation
step, and deliver the pentadienyl cation 11, an intermediate that is
common to both the PhIL2 and electrochemical routes (compare
Schemes 1 and 2). Subsequent capture by R0OH and proton loss
delivers the product. Using symbolism that is common to electro-
chemical parlance, the first pathway is illustrative of an ECPEP
pathway, while the second is representative of an EPECP path. In
each instance, the symbols ‘E’, ‘P’, and ‘C’ refer to an electrochemical
step, the loss (or addition) of a proton, and a chemical trans-
formation, respectively.
H7
1
7
Me
Me
O
O
O
O
H3C
O
H3C
O
O
2'
O
O
O
5'
H1'
O
7c
(not observed)
H5'
O
7a
Structure
Calculated/observed chemical shift (d) for proton listed below
0
0
0
H1
H7
H2
H5
7a
7c
3.38/3.03
2.71/d
4.34/4.58
4.31/d
3.95/4.14
4.21/d
6.15/6.04
6.15/d
d¼not observed; irradiation of H1 leads to a 13.6 enhancement of the signal for H2;
irradiation of H1 increases the signal for H7 by 3.1%.
2.3. A brief assessment of bioactivity
We wondered whether 7b, the keto ketal resulting from re-
moval of the isopropylidene group from 7a would display any of the
bioactivity that is characteristic of the pseudopterosins. Like other
pseudopterosins, 7b displayed 65% inhibition of mouse ear edema
that was induced by treatment of the ear with phorbol myristate

W. Zhong, R.D. Little / Tetrahedron 65 (2009) 10784–10790
10787
R3
R2
R1
R4
Intermediate common to Ph L2
and electrochemical pathways
(see also Scheme 2 & ref. 29)
OR5
O
11
– L,
1
–PhI
R'OH
R3
–H+
R3
O
R2
R1
R4
R3
R2
R1
R4
Ph L2
– L
R2
R1
R4
OR5
R'OH
2
OR5
OR5
OR'
OR
9
–PhI, – L
–H+
R = H
OI(OAc)Ph
12, the product
starting material
10
3
( O to C )~
( C to O )~
Ph L2
4
–PhI
–PhI
R ° H
R3
R3
CT-complex
R2
R1
R3
OR5
R2
R1
R4
R'OH
SET
OR5
– L, –H+
see reference 13
cation radical
O
O
L
Ph
13
OR'
Ph
14
Scheme 1. Mechanistic options when PhIL2 is used as an oxidant. Here and in Scheme 2, possible stereochemistry-determining steps are highlighted in red.13a,29
R3
R2
R1
R4
(a) –e
product 12
OR5
OR'
(b) –H+
(a) R'OH
(b) –H+
OH
16
R3
(a) R'OH
R2
R1
R4
OR5
–e
(b) –H+
9
OH
15
R3
R3
–H+
R2
R1
R4
R2
R1
R4
–e
OR5
OR5
O
O
17
11
Scheme 2. Electrochemical options: the ECPEP and EPECP pathways.
2.5. Origin of the stereoselectivity13,29
si-face is approached in the manner portrayed by structure 19.
Thus, subject to the condition that attack upon a pentadienyl
cation intermediate is stereochemically determining, we predict
that keto ketal 6 will be the preferred product derived from both
the PhIL2 and electrochemically promoted paths, and this is ob-
served.
Since pentadienyl cation 11 is common to both the PhIL2 and
the electrochemically promoted pathways shown in Schemes 1
and 2, we begin our discussion focusing upon this type of in-
termediate. In the transition structure for the model system 4,
Me
O
δ+
Me
rotation about
H
δ+
H
red bond
6
OBn
OBn
Me
O
O
OBn
OBn
OBn
( observed )
O
O
rotation about
red bond
O
O
O
Me
H
OBn
H
19
preferred si-face approach
18
re-face approach
attack upon the re-face suffers from an energy raising interaction
between the anomeric hydrogen and one of the two methyl
groups appended to the catechol framework, as exemplified by
structure 18. That interaction is replaced by a less demanding one
between the anomeric hydrogen and the carbonyl unit when the
An alternative hypothesis, one that is similar to the third pathway
shown in Scheme 1 and is consistent with a recent model put forth
by Quideau and co-workers.13,31 It capitalizes upon the chirality that is
present in the sugar portion of the starting material. As portrayed in
Scheme 3, the sequence begins with a reaction by the C-20 hydroxyl

10788
W. Zhong, R.D. Little / Tetrahedron 65 (2009) 10784–10790
CH3
O
Ar
Ar
OBn
OBn
OBn
OBn
OBn
CH2OBn
O
O
O
O
Ph L2
OBn
HO
H3C
O
O
OBn
details outlined
below
OBn
OH
O
Ph
O
L
4
20
6
CH3
CH3
CH3
OBn
OBn
H3C
O
O
O
OBn
OBn
OBn
O
O
O
O
O
O
OH
OBn
OBn
OBn
CH3
L
O
OBn
H3C
Ph
L
Ph
Ph
20b
20a
21
H
H
Me
O
Me
Ph
L
Ph L2
7a
5
H3C
O
H3C
O
O
Ph
O
OH
O
O
O
O
O
O
22
23
Scheme 3. Alternative mechanistic rationale.
group of the sugar with PhIL2 to form the
l
3-iodane structures 20a,b.
3. Concluding remarks
Intramolecular cyclization with displacement of the second tri-
fluoroacetate/acetate ligand leads to a cyclic structure represented
by 21. Migration of oxygen from iodine to carbon with the con-
comitant loss of iodobenzene, leads to the observed product, 6.
Application of the same line of reasoning to the iso-PsE derived
substrate 5 leads to the analysis shown in Scheme 3, and the pre-
diction that the observed product, 7a, ought to be preferred.
In conclusion, we have shown that pseudopterosin oxidation
leads to the formation of a keto ketal that is formed via intra-
molecular trapping by the hydroxyl group positioned at C-20 of the
pendant sugar. The keto ketal displays anti-inflammatory activity,
albeit to a lesser degree than the natural products. Accompanying
the cyclization is a conformational change that may trigger the
activation/deactivation of adenosine receptors with which the
pseudopterosins are known to interact. Additional experiments are
needed to address this hypothesis; they are currently underway.
2.6. Commentary regarding possible bio-relevance
We close our discussion with commentary regarding the possi-
ble relevance of the electron transfer chemistry discussed herein to
the bioactivity expressed by the pseudopterosins. Not long ago we
determined that the pseudopterosins target the adenosine class of
G-protein coupled receptors (GPCR).32 In general, their activation is
triggered bya conformational change that is induced by the guest, in
the present case, a pseudopterosin.32c We speculate that the con-
formational change that accompanies the cyclization of 24–25 could
trigger a conformational change in the receptor that sets in motion
a cascade of events that ultimately leads to the expression of
pseudopterosin bioactivity.33 That 24 could be formed via electron
transfer and acid–base reactions that are common in biological
systems, is in accord with this description and is an attractive fea-
ture of this proposal. The reversibility of each of step is another
attractive element since this provides a means of re-establishing the
receptor’s resting state.
4. Experimental section
4.1. General
4.1.1. Compound 4. To a solution of tri-O-benzyl glucal (0.28 g,
0.67 mmol) in dry DCM (10 mL) at 0 ꢀC was added freshly prepared
DMDO in acetone (9.6 mL, 0.07 mol/L) dropwise. The reaction
mixture was stirred at 0 ꢀC for 10 min and then flushed using dry
argon. The resulting white solid was dissolved in dry acetone
(4.5 mL) and then added to a refluxing solution of 3,6-dimethyl
catechol (372 mg, 2.69 mmol), K2CO3 (745 mg, 5.39 mmol) and
catalytic amount of 18-crown-6 (3 mg) in dry acetone (11.5 mL).
The reaction mixture was refluxed for 3 h, and then cooled to room
temperature. The solution was filtered through a pad of Celite, and
reversible
conformational change
H
H
CH3
OH
(a) –e
(b) –H
CH3
H
+
+
iso-PsE, 2
underside
approach
OH
OH
O
OH
2'
O
O
(c) +H
(d) +e
O
O
O
OH
O
24
25

W. Zhong, R.D. Little / Tetrahedron 65 (2009) 10784–10790
10789
then concentrated to dryness in vacuo. The residue was dissolved in
ethyl acetate (20 mL) and poured into 1 N HCl (20 mL). The aqueous
layer was extracted with ethyl acetate (2ꢁ10 mL). The combined
extracts were washed with brine (40 mL), dried over Na2SO4, fil-
tered and then concentrated to dryness in vacuo. The residue was
purified by column chromatography over silica gel (toluene/ace-
tone, 100:1, v/v) to afford aryl O-glycoside 4 (0.25 g, 0.44 mmol,
65%) as an orange oil. Rf 0.29 (hexane/ethyl acetate, 9:1, v/v). 1H
(m, 2H), 1.91–1.80 (m, 1H), 1.74–1.68 (m, 8H), 1.62–1.46 (m, 7H),
1.34–1.22 (m, 8H), 1.16 (d, 3H, J¼7.2), 1.00 (d, 3H, J¼5.2). 13C NMR
(CDCl3, 50 MHz):
d 198.1, 150.9, 141.6, 136.9, 132.6, 126.7, 124.7,
108.7, 98.4, 72.7, 71.8, 68.8, 63.2, 40.8, 38.1, 36.8, 30.3, 28.2, 27.3,
26.1, 25.6, 24.4, 21.0, 19.5, 17.6, 15.9, 9.9. ESI-MS: found 507.2731,
C29H40O6Naþ Calculated 507.2722.
4.1.5. Compound 7b. To a solution of iso-PsE (75 mg, 0.17 mmol) in
dry DCM (2 mL) was added p-methoxybenzaldehyde dimethyl ac-
etal (0.26 mL) and catalytic amount of CSA (8 mg). The reaction
mixture was stirred at room temperature for 24 h and then
NMR (CDCl3, 200 MHz):
d 7.57 (br, 1H), 7.27–7.09 (m, 15H), 6.76 (d,
1H, J¼7.8), 6.51 (d, 1H, J¼7.8), 4.87 (d, 1H, J¼11.4), 4.76 (d, 1H,
J¼10.8), 4.74 (d, 1H, J¼11.4), 4.54 (d, 1H, J¼10.8), 4.50–4.41 (m, 3H),
3.77–3.43 (m, 5H), 3.38–3.31 (m, 1H), 2.97 (br, 1H), 2.23 (s, 3H), 2.13
quenched by TEA (25 mL). The mixture was concentrated to dryness
(s, 3H). 13C NMR (CDCl3, 50 MHz):
d
147.6, 143.2, 138.2, 137.9, 137.7,
in vacuo. The residue was purified by column chromatography over
silica gel (hexane/ethyl acetate, 10/1, v/v) to afford PMB protected
iso-PsE (67 mg, 0.12 mmol, 71%) as a yellow oil. To a solution of
PIDA (59 mg, 0.18 mmol) in dry CH3NO2 (12 mL) at 0 ꢀC was added
129.2, 128.6, 128.4, 128.3, 127.9, 127.7, 126.9, 123.6, 120.7, 105.3, 84.4,
77.3, 75.3, 74.9, 74.2, 73.5, 68.3, 16.5, 15.8. ESI-MS: found 593.2523,
C35H38O7Naþ Calculated 593.2515.
TFA (23 mL, 0.3 mmol), followed by addition of a solution of PMB
4.1.2. Compound 6. To a solution of PIDA (0.24 g, 0.75 mmol) in dry
protected iso-PsE (67 mg, 0.12 mmol) in dry DCM (12 mL). The
resulting solution was stirred at 0 ꢀC for 30 min, and then quenched
by solid NaHCO3 (595 mg). The solution was filtered through a pad
of Celite, and then concentrated to dryness in vacuo. The residue
was purified by column chromatography over silica gel (hexane/
ethyl acetate/TEA, 95/5/0.5, v/v/v) to afford keto ketal (36 mg,
0.064 mmol, 54%) as a yellow solid. To a solution of PMB protected
keto ketal (36 mg, 0.064 mmol) in DCM/H2O (1.26 mL, 17/1, v/v)
was added DDQ (39 mg, 0.13 mmol) at room temperature. The re-
action mixture was stirred at room temperature for 4 h, and then
diluted with DCM (2 mL) followed by filtered through Celite. The
organic layer was washed with satd NaHCO3 (2 mL), dried over
Na2SO4, filtered and then concentrated to dryness in vacuo. To
a solution of the residue in DCM/MeOH (1.2 mL, 1:1, v/v) was added
NaOMe (pH¼8–10). The reaction mixture was stirred at room
temperature for 12 h, and then concentrated to dryness in vacuo.
The residue was purified by column chromatography over silica gel
(DCM/MeOH/TEA, 100/1/0.5, v/v/v) to afford compound 7b (18 mg,
0.04 mmol, 63%) as a yellow oil. Rf 0.32 (DCM/MeOH, 50:1, v/v). 1H
CH3NO2 (50 mL) at 0 ꢀC was added TFA (87
mL, 1.13 mmol), followed
by addition of a solution of compound 4 (284 mg, 0.5 mmol) in dry
DCM (50 mL). The resulting solution was stirred at 0 ꢀC for 30 min,
and then quenched by solid NaHCO3 (2.5 g). The solution was fil-
tered through a pad of Celite, and then concentrated to dryness in
vacuo. The residue was purified by column chromatography over
silica gel (hexane/ethyl acetate/TEA, 95/5/0.5, v/v/v) to afford
compound 6 (181 mg, 0.32 mmol, 64%) as a yellow oil. Rf 0.51
(hexane/ethyl acetate, 5:1, v/v). 1H NMR (CDCl3, 200 MHz):
d 7.28–
7.06 (m, 15H), 6.58 (d, 1H, J¼6.4), 5.92 (d, 1H, J¼6.4), 5.27 (d, 1H,
J¼7.2), 4.86 (d, 1H, J¼10.8), 4.82 (d, 1H, J¼11.6), 4.63 (d, 1H, J¼11.6),
4.59 (d,1H, J¼12.0), 4.45–4.39 (m, 2H), 4.01–3.93 (m,1H), 3.69–3.52
(m, 5H), 1.93 (s, 3H), 1.79 (s, 3H). 13C NMR (CDCl3, 50 MHz):
d 197.8,
144.1, 138.1, 137.9, 137.8, 137.3, 130.2, 128.3, 127.9, 127.8, 127.7, 127.6,
123.4, 100.3, 100.1, 94.4, 82.4, 81.6, 78.2, 77.4, 75.2, 73.4, 72.8, 68.4,
17.2, 14.7. ESI-MS: found 591.2368, C35H36O7Naþ Calculated
591.2359.
4.1.3. Compound 5. To a solution of iso-PsE (115 mg, 0.26 mmol) in
dry acetone (0.55 mL) was added 2,2-dimethoxypropane (0.55 mL)
and a catalytic amount of p-TsOH (5 mg). The reaction mixture was
stirred at room temperature for 14 h and then quenched using TEA
NMR (CDCl3, 200 MHz):
d
6.02 (d, 1H, J¼5.6), 5.06 (m, 1H), 4.53 (t,
1H, J¼4.8, 5.6), 4.24–3.97 (m, 2H), 3.96–3.71 (m, 4H), 3.61–3.47 (m,
2H), 2.78 (m, 1H), 2.13 (m, 1H), 1.78 (m, 2H), 1.70–1.41 (m, 9H), 1.38
(d, 1H, J¼6.6), 1.30–1.23 (m, 4H), 1.20 (d, 3H, J¼7.2), 1.00 (d, 3H,
(25
mL). The mixture was concentrated to dryness in vacuo. The
J¼6.0), 0.91 (m, 1H). 13C NMR (CDCl3, 100 MHz):
d 197.9, 151.7, 142.3,
residue was purified by column chromatography over silica gel
(hexane/ethyl acetate, 10/1, v/v) to afford compound 5 (102 mg,
0.21 mmol, 82%) as a white solid. Rf 0.48 (hexane/ethyl acetate, 5:1,
135.9, 132.5, 126.0, 124.6, 97.7, 77.2, 73.3, 69.0, 68.3, 64.7, 40.8, 38.1,
36.9, 30.4, 28.6, 28.5, 26.3, 25.7, 21.1, 19.7, 17.6, 16.4, 9.7. ESI-MS:
found 467.2419, C26H36O6Naþ Calculated 467.2410.
v/v). 1H NMR (CDCl3, 200 MHz):
d 8.11 (br, 1H), 5.15–5.08 (m, 2H),
4.69–4.58 (m, 1H), 4.50 (t, 1H, J¼6.2), 4.23 (dd, 1H, J¼2.2, 6.2), 4.09
(m, 1H), 3.65 (m, 1H), 3.47–3.37 (m, 2H), 2.24–1.97 (m, 6H), 1.76 (d,
3H, J¼1.2),1.69 (d, 3H, J¼1.2),1.65–1.54 (m, 4H),1.50 (s, 3H),1.39 (m,
6H),1.20 (d,1H, J¼7.2),1.06 (d,1H, J¼5.6). 13C NMR (CDCl3, 50 MHz):
Acknowledgements
We gratefully acknowledge the U.S. Army Medical Research
Program (Grant Number W81XWH-06-1-0089) for its support of
this research. The Supported Activity was also sponsored, in part, by
an educational donation provided by Amgen. The authors are
grateful to them.
We are appreciative of the efforts of Mr. Ian Pahk who synthe-
sized 3,6-dimethyl catechol, and Mr. Abdul Hackim for performing
the CV experiments on the resulting model system, 4.
d
145.3, 141.9, 135.2, 133.1, 129.8, 128.4, 121.5, 109.7, 101.9, 75.5, 75.3,
69.9, 65.4, 41.9, 39.4, 35.6, 30.4, 29.5, 27.7, 26.9, 25.8, 25.6, 23.6,
20.9, 17.6, 16.4, 10.8. ESI-MS: found 509.2886, C29H42O6Naþ Calcu-
lated 509.2879.
4.1.4. Compound 7a. To a solution of PIDA (86 mg, 0.27 mmol) in
dry CH3NO2 (18 mL) at 0 ꢀC was added TFA (31
m
L, 0.40 mmol),
followed by addition of
a solution of compound 5 (86 mg,
0.18 mmol) in dry DCM (18 mL). The resulting solution was stirred
at 0 ꢀC for 30 min, and then quenched by solid NaHCO3 (885 mg).
The solution was filtered through a pad of Celite, and then con-
centrated to dryness in vacuo. The residue was purified by column
chromatography over silica gel (hexane/ethyl acetate/TEA, 95/5/0.5,
v/v/v) to afford compound 7a (48 mg, 0.099 mmol, 56%) as a yellow
oil. Rf 0.48 (hexane/ethyl acetate/TEA, 10:1:0.05, v/v/v). 1H NMR
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