A synthesis of the pseudopterosin A-F aglycone

Article abstract of DOI:10.1055/s-0032-1316643

The synthesis of the pseudopterosin A-F aglycone from 3-methylcatechol features (a) the use of asymmetric Ireland-Claisen and aryl Claisen rearrangements to install three of the four stereocentres present in the molecule and (b) an A→AB→ABC annulation strategy using ring-closing metathesis and cationic cyclisation reactions as the key steps.

Full text of DOI:10.1055/s-0032-1316643

PAPER
▌2779
paper
A Synthesis of the Pseudopterosin A–F Aglycone
A Synthesis of the Pseudopterosin A–F Aglycone
John P. Cooksey,* Philip J. Kocieński,* Arndt W. Schmidt, Thomas N. Snaddon, Colin A. Kilner
School of Chemistry and Institute of Process Research and Development, University of Leeds, Leeds LS2 9JT, UK
Fax +44(113)3436401; E-mail: p.j.kocienski@leeds.ac.uk; E-mail: j.p.cooksey@leeds.ac.uk
Received: 24.04.2012; Accepted: 13.06.2012
ed on the synthesis of aglycones 1 and 3 (Scheme 1).9 In
addition, several fragment syntheses have been report-
ed.6b,10 We now describe the synthesis of the pseudopter-
osin A–F aglycone 1, in which three of the six C–C bond-
Abstract: The synthesis of the pseudopterosin A–F aglycone from
3-methylcatechol features (a) the use of asymmetric Ireland–
Claisen and aryl Claisen rearrangements to install three of the four
stereocentres present in the molecule and (b) an A→AB→ABC an-
nulation strategy using ring-closing metathesis and cationic cyclisa- forming steps in the strategy depicted in Scheme 1 are re-
tion reactions as the key steps.
sponsible for the creation of the four stereogenic centres
at C1, C3, C4 and C7. The stereogenic centre at C1 is
formed by a substrate-controlled cationic cyclisation,11
which was used in previous syntheses of the pseudoptero-
sins.9d,e,g–i Installation of the stereogenic centres at C3 and
C4 was accomplished by a reagent-controlled enantio-
and diastereoselective Ireland–Claisen rearrangement.12
Finally, the stereogenic centre at C7 was constructed by a
substrate-controlled aryl Claisen rearrangement.13
Key words: total synthesis, terpenoids, ring closure, rearrange-
ment, metathesis, pericyclic reaction
In the early 1980s, as part of a routine screening program,
Fenical and co-workers identified the presence of several
anti-microbial and cytotoxic metabolites in extracts of the
Caribbean sea whip Pseudopterogorgia elisabethae.1 The
first four members of the pseudopterosin family of marine
metabolites (pseudopterosins A–D) were subsequently
isolated and their structures were established through
comprehensive spectroscopic investigations and X-ray
crystallography (Figure 1). Pseudopterosin A exhibited
potent anti-inflammatory and analgesic activities and
stimulated the search for more family members; as a re-
sult, a further 32 pseudopterosins have now been identi-
fied.2 A notable feature of the pseudopterosin family is the
simple means by which structural variation is achieved;
all 36 members of the pseudopterosin family can be de-
rived from just three diastereoisomeric amphilectane di-
terpene aglycones and five monosaccharides (D- and L-
xylose, D- and L-arabinose and L-fucose) with further
variation being derived from the regiochemistry of glyco-
sidation and the extent and position of acetylation. The
structural diversity of the pseudopterosins is exemplified
by the structures presented in Figure 1.
Our synthesis began with the preparation of the cinnamyl
propionate ester 5 (Scheme 2). Phenol 714 was converted
into the aryl iodide 13 over six conventional steps.15 The
allyl ester side-chain was subsequently appended via a li-
gand-free Heck reaction16 with allyl propionate to give the
desired Ireland–Claisen precursor 5 in 76% yield. Initial
efforts to append the allyl ester side-chain by using the
OR2
OR2
R1O
O
OR3
R1O
O
OR3
O
O
OH
OH
H
B
A
H
C
The pseudopterosins display antibacterial, antiviral and
antimalarial activity as well as cytotoxicity3 but it is their
anti-inflammatory activity1,3b,d,4 that holds most promise
of practical application. Their anti-inflammatory activity
is unusual in that the release of pro-inflammatory media-
tors is blocked without inhibition of the eicosanoid
pathway4e,5 and recent work by Little and co-workers has
begun to unravel the complex mechanisms through which
they act.6
The commercial potential of the pseudopterosins7 stimu-
lated a number of research groups to investigate their syn-
thesis. Pseudopterosins A8 and E8b have succumbed to
total synthesis; however, most effort has been concentrat-
pseudopterosin A–D
pseudopterosin G–J
A: R1 = H, R2 = H, R3 = H
B: R1 = Ac, R2 = H, R3 = H
C: R1 = H, R2 = Ac, R3 = H
D: R1 = H, R2 = H, R3 = Ac
R
R
R
R
1 = H, R2 = H, R3 = H
1 = Ac, R2 = H, R3 = H
1 = H, R2 = Ac, R3 = H
1 = H, R2 = H, R3 = Ac
G:
H:
I:
J:
OH
OH
OH
HO
O
OH
O
O
HO
OH
OH
O
H
H
SYNTHESIS 2012, 44, 2779–2785
Advanced online publication: 08.08.2012
pseudopterosin E
pseudopterosin K
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316643; Art ID: SS-2012-N0380-OP
© Georg Thieme Verlag Stuttgart · New York
Figure 1 Structural diversity of pseudopterosins

2780
J. P. Cooksey et al.
PAPER
procedure developed by Jeffery17 [allyl alcohol or allyl
propionate (3.0 equiv), Pd(OAc)2 (5 mol%), PPh3 (10
mol%), AgOAc (1.0 equiv), DMF, 65 °C, 5 h] suffered
from lower yield (~50%) and the formation of several la-
bile by-products.
OH
OH
RCM
OH
OH
7
4
H
12
H
1
3
cationic
cyclisation
Installation of the C3 and C4 stereocentres in the required
syn-relationship was accomplished by using Corey’s en-
antio- and diastereoselective variant of the Ireland–
Claisen rearrangement (Scheme 2).12 Treating compound
5 with 1.5 equivalents of the chiral Lewis acid 16 (pre-
pared in situ from the bis-sulfonamide 1518) and triethyl-
amine (3.0 equiv) in toluene at –78 °C, gave carboxylic
acid 17 in 91% yield after aqueous workup.19 Analysis of
alkylation
1
2
pseudopterosin A–F,
iso-E and Z aglycone
pseudopterosin K and L
aglycone
OH
aryl Claisen
rearrangement
OH
OMe
OH
H
1
OMe
the crude product by H NMR spectroscopy (500 MHz)
H
revealed a single major diastereoisomer (dr ≥ 97:3), the
syn-stereochemistry of which was assigned based upon
literature precedent.12 The bis-sulfonamide 15 was easily
recovered by using column chromatography and recryst-
allisation (CH2Cl2–petrol) in 78% yield. Reduction of car-
boxylic acid 17 to alcohol 18 was accomplished in 84%
yield by treating 17 with ethyl chloroformate followed by
reaction of the intermediate acyl carbonate in situ with
sodium borohydride using the procedure developed by
Gallagher and co-workers.20 The enantiomeric ratio of the
Ireland–Claisen rearrangement was assigned as ≥97:3 on
the basis of 1H and 19F NMR spectroscopic analysis of the
corresponding (R)- and (S)-Mosher ester derivatives.21 Fi-
nally, conventional TBDPS protection of compound 18
gave silyl ether 19 in 89% yield.
Ireland–Claisen
rearrangement
4
3
pseudopterosin G–J
and M-Y aglycone
O
OPiv
Heck reaction
O
O
5
Scheme 1
We next attempted to introduce the C7 stereogenic centre
by a reprise of the reagent-controlled asymmetric aryl
Claisen rearrangement of crotyl ether 20 (Scheme 3) using
catalyst 16 and its less reactive bis(p-toluenesulfonamide)
analogue.22 However, the reaction was capricious and re-
sulted in poor yield (55% at best) and poor diastereoselec-
tivity (dr = 2:1). The most common outcome of the
reaction was dealkylation of the crotyl chain. In order to
derive benefit from misfortune, we removed the crotyl
group by treating 19 with boron tribromide at –78 °C and
the resultant phenol 21 was used immediately in an asym-
metric Tsuji–Trost O-alkylation.23 This reaction provided
the desired (R)-pent-3-en-2-yl ether 24 in 95% yield and
dr ≥97:3. The stereochemistry of the reaction was tenta-
tively assigned on the basis of literature precedent.24
Compound 24 was converted into the O-methylated deriv-
ative 26 in 82% yield over two conventional steps. At-
tempts to induce the key aryl Claisen rearrangement by
heating 26 with [Eu(fod)3] (1 mol%) at 50 °C in CHCl3 –
conditions described by Trost and Toste24 – resulted in no
reaction, whereas increasing the reaction temperature
(1,2-dichloroethane, 80 °C) gave a mixture of recovered
starting material and the by-product phenol 27, resulting
from dealkylation of the pent-3-en-2-yl side-chain. The
desired aryl Claisen rearrangement was eventually
achieved by using the conditions developed by Batey and
co-workers.25 Thus, heating compound 26 in the presence
of [Eu(fod)3] (5 mol%) in toluene at 120 °C in a sealed
tube gave phenol 28 in 72% yield and a dr of 5:1. The ste-
reochemistry of the reaction was again assigned on the ba-
sis of literature precedent,24 and the dr of the reaction was
ascertained by 1H NMR spectroscopy of the crude product
by integration of the signals corresponding to C7-H
[δ = 3.96 ppm (1 H, quint, J = 6.9 Hz) for the major iso-
mer and δ = 4.17–4.10 ppm (1 H, m) for the minor iso-
mer]. The phenol 27 was also isolated in 25% yield, which
could be recycled by submission to the Tsuji–Trost O-
alkylation reaction conditions to give the aryl Claisen pre-
cursor 26 in 95% yield and dr ≥97:3. Finally, O-methyla-
tion of phenol 28 and TBDPS-deprotection gave the
alcohol 4 in 87% yield.
With the C3, C4 and C7 stereocentres in place, comple-
tion of the synthesis required first construction of ring B
via a ring-closing metathesis26 and then construction of
ring C via a cationic cyclisation11 with concomitant instal-
lation of the remaining C1 stereocentre. Ring-closing
metathesis26 of alcohol 4 was accomplished by using 5
mol% Grubbs 2nd generation catalyst27 followed by cata-
lytic hydrogenation using platinum on activated carbon to
give alcohol 31 in 92% yield over two steps (Scheme 4).
Unfortunately, partial epimerisation at C7 occurred dur-
ing the ring-closing metathesis and the dr worsened from
5:1 to 3:1. Various methods to inhibit this epimerisation,
such as (a) the use of methyl tert-butyl ether as solvent,28
(b) the use of acetic acid as an additive,29 and (c) the use
of other ring-closing metathesis catalysts (the Grubbs 1st
generation catalyst30 and the Hoveyda–Grubbs 2nd gener-
Synthesis 2012, 44, 2779–2785
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Synthesis of the Pseudopterosin A–F Aglycone
2781
ation catalyst31) were to no avail. The dr of the product
was assigned by using 1H NMR spectroscopy of the crude
product by integration of the signals corresponding to
C12-H [δ = 6.73 ppm (1 H, s) for the major isomer and
δ = 6.81 ppm (1 H, s) for the minor isomer]. Compound
31 could be isolated as a single diastereoisomer after pu-
rification by repeated column chromatography using TLC
silica or, more conveniently, by recrystallisation from pet-
rol (mp 74–75 °C). Spectroscopic data (1H and 13C NMR,
IR, MS and [α]D) for compound 31 were in accordance
with those reported by Majdalani and Schmalz.9e A more
practical approach to enhance the diastereoisomeric puri-
ty involved O-brosylation of the 3:1 diastereoisomeric
mixture of compound 31 by using standard methods to
give the brosylate 32 in 98% yield and dr = 3:1. Com-
pound 32 could then be isolated as a single diastereoiso-
mer (mp 82–83 °C) in 64% yield by recrystallisation from
petrol, and its absolute stereochemistry was confirmed by
X-ray crystallography (Figure 2). The X-ray structure also
confirmed the predicted stereochemistry of both Claisen
rearrangements.
Figure 2 X-ray crystal structure of brosylate 32
OMe
OTs
OTs
TsCl (1.0 equiv)
Et3N (1.5 equiv)
MOMCl (1.5 equiv)
DIPEA (1.25 equiv)
OTs
OH
ICl (1.1 equiv)
OH
OH
O
OH
CH2Cl2, 0 °C → r.t., 18 h
77% (403 mmol scale)
AcOH, 70 °C, 16 h
78% (287 mmol scale)
CH2Cl2, 0 °C → r.t., 18 h
99% (60.2 mmol scale)
I
I
7
8
9
6
mp 53–54 °C
mp 92–93 °C
mp 120–122 °C
NaOH (10 equiv)
H2O–EtOH, reflux, 5 h
89%
OH
PivCl (1.2 equiv)
Et3N (2.4 equiv)
DMAP (5 mol%)
OMe
OMe
O
O
OH
O
AcCl (0.5 equiv)
MeOH–CH2Cl2 (5:1)
(1.2 equiv)
DIAD (1.2 equiv)
10
OPiv
OH
O
O
PPh3 (1.2 equiv)
CH2Cl2, r.t., 1.5 h
99%
0 °C → r.t., 24 h
I
I
THF, 0 °C → r.t., 18 h
79%
I
I
98%
13
12
11
10
mp 40–41 °C
mp 91–93 °C
O
O
O
O
1. ClCO2Et (1.1 equiv)
Et3N (1.1 equiv)
THF, 0 °C, 1 h
OPiv
16 (1.5 equiv)
Et3N (3.0 equiv)
OPiv
14 (2.0 equiv)
H
PhMe, –78 °C → r.t., 14 h
91% (8.75 mmol scale)
dr ≥ 97:3, er ≥ 97:3
Pd(OAc)2 (5 mol%)
Ag2CO3 (0.6 equiv)
PhH, reflux, 24 h
76%
2. NaBH4 (2.5 equiv)
THF–H2O, 0 °C → r.t., 2 h
84% ( 7.99 mmol scale)
4
O
3
CO2H
O
5
17
catalyst preparation
(Ar = 3,5-(CF3)2C6H3)
TBDPSCl (1.05 equiv)
imidazole (1.3 equiv)
DMAP (5 mol%)
SO2Ar
NH
O
O
SO2Ar
Ph
Ph
Ph
OPiv
OPiv
N
BBr3 (2.0 equiv)
CH2Cl2, r.t., 2 h
B
Br
H
H
CH2Cl2, r.t., 18 h
89%
N
NH
Ph
SO2Ar
16
SO2Ar
OTBDPS
OH
15
mp 152–153 °C
19
18
Scheme 2
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2779–2785

2782
J. P. Cooksey et al.
PAPER
The synthesis of the pseudopterosin A–F aglycone was pound 34 with ethylaluminium dichloride according to
completed in four steps, as shown in Scheme 4. Alkyla- precedent,9d,e,g–i were unsuccessful. Instead, a product
tion of brosylate 32 with the lithiated sulfone 33 gave an arising from reduction of the sulfone 34 was isolated, the
1
inseparable 1:1 mixture of diastereoisomeric sulfones 34 structure of which (35) was assigned by H NMR spec-
in 99% yield. The dr of the reaction was assigned on the troscopy and HRMS analysis. However, by treating com-
basis of 1H NMR spectroscopy of the crude product by in- pound 34 with methylaluminium dichloride (1.5 equiv) in
tegration of the signals corresponding to C12-H [δ = 6.61 dichloromethane at –78 °C for 15 min, pseudopterosins
ppm (1 H, s) and δ = 6.52 ppm (1 H, s)]. Attempts to per-
form the cationic cyclisation reaction11 by treating com-
N
N
Mes
Cl
Cl
Mes
dr = 5:1
H
OH
O
Ru
PCy3
OMe
OH
OMe
Ph
OPiv
OR
OMe
OMe
BBr3 (1.1 equiv)
Grubbs II (5 mol%)
H
H
H
CH2Cl2, –78 °C, 30 min
CH2Cl2, r.t., 3 h
99%
OTBDPS
21
OTBDPS
OH
19 R = Piv
20 R = H
4
30
H2 (1 bar), 5% Pt/C
cyclohexane, r.t., 16 h
93%
OTroc
22 (1.05 equiv)
Pd2dba3⋅CHCl3 (1 mol%)
(R,R)-23 (3 mol%)
O
O
dr = 3:1
dr = 3:1
NH HN
OMe
OMe
Br
SO2Cl
OMe
OMe
CH2Cl2, r.t., 18 h
95%, (dr ≥ 97:3)
(1.5 equiv)
PPh2 Ph2P
H
H
(R,R)-23
Et3N (2.0 equiv)
DMAP (5 mol%)
CH2Cl2, 0 °C → r.t., 18 h
OBs
OH
98%
O
O
32
31
OH
OPiv
LiAlH4 (2.0 equiv)
64% crystallise from petrol
H
H
THF, 0 °C → r.t., 1 h
OMe
dr 97:3
H
85%
SO2Tol
OTBDPS
25
OTBDPS
24
OMe
OMe
Li
OMe
H
33 (4.0 equiv)
Me2SO4 12.0 equiv)
96% K2CO3 (3.0 equiv)
acetone, r.t., 4 d
THF–HMPA (4:1)
–78 °C → r.t., 20 h
99%
dr = 1:1
OBs
TolO2S
34
OH
O
OMe
32
Eu(fod)3 (5 mol%)
OMe
mp 82–83 °C
(X-ray)
H
MeAlCl2 (1.5 equiv)
CH2Cl2, –78 °C, 15 min
H
PhMe, 120 °C, 22 h
(sealed tube)
OTBDPS
27 (25%)
OTBDPS
26
OMe
OMe
OMe
OMe
mp 48–49 °C
H
H
+
Me2SO4
(12.0 equiv)
K2CO3
dr = 5:1
dr = 5:1
OH
OMe
OMe
dr = 15:1
OMe
(3.0 equiv)
H
H
acetone, r.t., 4 d
99%
35
36
OTBDPS
28 (72%)
OTBDPS
crystallise from MeOH
91% from 34
29
TBAF⋅3H2O (1.1 equiv)
THF, r.t., 20 h
OH
OMe
92%
OH
OMe
dr = 5:1
H
H
LiSEt (10 equiv)
OMe
OMe
DMF, reflux, 3 h
98%
dr ≥ 97:3
H
OH
1
36
4
mp 58–59 °C
Scheme 3
Scheme 4
Synthesis 2012, 44, 2779–2785
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Synthesis of the Pseudopterosin A–F Aglycone
2783
resulting yellow/brown solution stirred at –78 °C for 2 min. Trieth-
ylamine (3.7 mL, 26.3 mmol, 3.0 equiv), freshly distilled from
CaH2, was added dropwise to the reaction mixture at –78 °C, again
at a rate sufficient to keep the internal reaction temperature ≤ –75
°C. The resulting yellow solution was stirred at –78 °C for 2 h and
then allowed to warm to r.t. slowly over 20 h. The reaction was
quenched with 2 M HCl (150 mL) and the resulting biphasic mix-
ture stirred vigorously at r.t. for 30 min. The layers were separated
and the aqueous layer extracted with CH2Cl2 (2 × 150 mL). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated in vacuo. The residual pale yellow/brown solid was purified
by column chromatography on silica gel eluting with petrol–Et2O
(2:1→1:1) to give the title compound 17 [Rf (petrol–Et2O, 2:1) =
0.14; yield: 2.99 g, 7.99 mmol, 91%; dr ≥97:3 and er ≥97:3] as
a pale yellow oil that solidifies on storage at ca. –20 °C. Recov-
ered N,N′-[(1S,2S)-1,2-diphenylethane-1,2-diyl]bis[3,5-bis(trifluo-
romethyl)benzenesulfonamide] 15 [Rf (petrol–Et2O, 2:1) = 0.57;
yield: 7.77 g, 10.2 mmol, 78%] was obtained as a white solid after
A–F aglycone dimethyl ether 36 was isolated as a 15:1
mixture of diastereoisomers. The dr of the reaction was
1
assigned on the basis of H NMR spectroscopy of the
crude product by integration of the signals corresponding
to C14-H [δ = 5.13 ppm (1 H, dhept, J = 9.0, 1.5 Hz) for
the major isomer and δ = 4.96 ppm (1 H, br d, J = 9.2 Hz)
for the minor isomer]. Compound 36 was isolated in 91%
yield as a single diastereoisomer (mp 58–59 °C) after re-
crystallisation from methanol, and its spectroscopic and
physical data (1H and 13C NMR, IR, MS, mp and [α]D)
were in accordance with those reported by Majdalani and
Schmalz.9e Finally, demethylation of 36 using lithium
thioethoxide (LiSEt)9e gave the pseudopterosin A–F agly-
cone 1 in 98% yield, the spectroscopic and physical data
(1H and 13C NMR, IR, MS, mp and [α]D) of which were in
accordance with those reported by Corey and Lazerwith.9f
1
crystallisation from CH2Cl2–petrol. H NMR spectroscopy of the
crude product revealed a single diastereoisomer. The er of the reac-
tion was assigned using 1H and 19F NMR spectroscopy of the corre-
sponding (R)- and (S)-Mosher ester derivatives.
The synthesis of pseudopterosins A–F aglycone from
commercial 3-methylcatechol has been completed in 23
steps. The synthesis features highly enantio- and diastereo-
selective Ireland–Claisen and aryl Claisen rearrangements
to introduce the C3, C4 and C7 stereocentres, an annula-
tion strategy based on ring-closing metathesis, and cation-
ic cyclisation reactions as the key steps. The synthesis
required only six C–C bond-forming steps (average yield
88%) but it was adversely affected by the number of pro-
tecting group operations (11) required to manipulate and
stabilize the catechol moiety. Therefore, our synthesis,
like most of those reported to date, is too long to provide
a viable alternative to extraction of the natural product
that currently satisfies commercial demand.32 Recent re-
ports of the isolation of pseudopterosins from renewable
sources such as algal symbionts33 and clonal bacteria
strains34 derived from Pseudopterogorgia elisabethae of-
fer exciting new opportunities.
[α]D +17.0 (c 0.5, CHCl3).
IR (neat): 3800–2200 (br s), 3357 (s), 3263 (s), 3079 (m), 2975 (s),
2935 (s), 2876 (s), 1753 (s), 1711 (s), 1637 (w), 1612 (m), 1596 (s),
1494 (s), 1474 (s), 1459 (s) cm−1.
1H NMR (500 MHz, CDCl3): δ = 6.64 (1 H, d, J = 1.8 Hz, C8H),
6.62 (1 H, app t, J = 2.7, 1.8 Hz, C12H), 5.92–5.82 (1 H, m, C5H),
5.82–5.74 (1 H, m, C3′H), 5.66–5.57 (1 H, m, C2′H), 5.14–5.08
(2 H, m, C5′H2), 4.40–4.37 (2 H, m, C1′H2), 3.49 (1 H, td, J = 9.1,
2.3 Hz, C4H), 2.85–2.77 (1 H, m, C3H), 2.11 (3 H, d, J = 2.7 Hz,
C20H3), 1.72 (3 H, dd, J = 6.5, 1.2 Hz, C4′H3), 1.36 [9 H, s,
C2′′(CH3)3], 1.21 (3 H, d, J = 7.0 Hz, C18H3).
13C NMR (75 MHz, CDCl3): δ = 181.1 (C2), 176.1 (C1′′), 150.1
(C9), 139.5 (C10), 137.8 (C5H), 137.5 (C13), 131.1 (C11), 129.9
(C2′H), 126.0 (C3′H), 121.6 (C8H), 116.9 (C5′H2), 110.9 (C12H),
69.4 (C1′H2), 52.6 (C4H), 44.6 (C3H), 39.0 [C2′′(CH3)3], 27.2
[C2′′(CH3)3], 17.6 (C4′CH3), 15.8 (C20H3), 15.0 (C18H3).
LRMS (ES+): m/z (%) = 397 (100) [M + Na+], 349 (40).
HRMS (ES+): m/z [M + Na+] calcd for C22H30NaO5: 397.1985;
found: 397.1975.
For general information and full experimental details for all com-
pounds see the Supporting Information.
3-{(3R,4R)-5-[(tert-Butyldiphenylsilyl)oxy]-4-methylpent-1-en-
3-yl}-6-methoxy-5-methyl-2-[(S,E)-pent-3-en-2-yl]phenol (28)
Compound 26 (1.31 g, 2.42 mmol, 1.0 equiv) and europium(III)
tris(1,1,1,2,2,3,3-heptafluoro-7,7-dimethyl-4,6-octanedionate)
[Eu(fod)3] (125 mg, 121 μmol, 5 mol%) in PhMe (8 mL) was heated
at 120 °C in a sealed tube for 22 h. The reaction mixture was con-
centrated in vacuo to give a pale yellow oil that was purified by col-
umn chromatography on silica gel eluting with petrol–Et2O (10:1)
to give the title compound 28 [Rf (petrol–Et2O, 10:1) = 0.4; yield:
945 mg, 1.74 mmol, 72%; dr = 5:1] as a colourless oil and phenol
27 [Rf (petrol–Et2O, 10:1) = 0.1; yield: 287 mg, 605 μmol, 25%] as
a colourless oil. The dr of the reaction was assigned using 1H NMR
spectroscopy of the crude product by integration of the signals cor-
responding to C7H [δ = 3.96 (1 H, quint, J = 6.9 Hz) for the major
isomer and δ = 4.17–4.10 (1 H, m) for the minor isomer].
(2R,3R)-3-[3-[(E)-But-2-enyloxy]-5-methyl-4-(pivaloyloxy)phe-
nyl]-2-methylpent-4-enoic Acid (17)
A flame-dried one-necked flask equipped with a tap was charged
with N,N′-[(1S,2S)-1,2-diphenylethane-1,2-diyl]bis[3,5-bis(trifluo-
romethyl)benzenesulfonamide] (15) (10.0 g, 13.1 mmol, 1.5 equiv)
and CH2Cl2 (200 mL). Freshly distilled boron tribromide (1.66 mL,
17.5 mmol, 2.0 equiv) was added dropwise to the colourless solu-
tion at r.t. and the resulting pale orange solution stirred at r.t. for 2
h. The reaction mixture was concentrated in vacuo to give an off-
white solid that was heated in vacuo at 60 °C for 15 min to remove
the excess boron tribromide. The off-white solid was washed twice
using the following process: the flask was back-filled with N2,
CH2Cl2 (100 mL) added and the solution concentrated in vacuo to
give an off-white solid that again was heated under vacuo at 60 °C
for 15 min. The flask was back-filled with N2, PhMe (160 mL) add-
ed and the resulting pale yellow/brown suspension heated gently
(ca. 60 °C) until complete dissolution occurred, affording a pale yel-
low/brown solution of catalyst 16 that was transferred via a cannula
to a 3-necked flask equipped with a thermometer and addition fun-
nel required for the next step.
Compound 28
IR (neat): 3515 (m), 3072 (m), 2959 (s), 2931 (s), 2858 (s), 1634
(w), 1615 (w), 1589 (w), 1489 (m), 1454 (m), 1427 (m), 1412 (m),
1389 (w), 1361 (w), 1302 (w), 1220 (m), 1111 (s) cm−1.
1H NMR (500 MHz, CDCl3): δ = 7.64–7.56 (4 H, m, ArH), 7.43–
7.30 (6 H, m, ArH), 6.51 (1 H, s, C12H), 6.03 (1 H, dt, J = 16.9, 9.8
Hz, C5H), 5.90 (1 H, ddq, J = 15.4, 5.7, 1.7 Hz, C6H), 5.85 (1 H, s,
OH), 5.49 (1 H, ddq, J = 15.5, 6.5, 1.7 Hz, C6′H), 5.09 (1 H, dd, J =
10.0, 2.1 Hz, C5′H-cis), 5.09 (1 H, dd, J = 16.9, 2.1 Hz, C5′H-
Compound 5 (3.28 g, 8.75 mmol, 1.0 equiv) in PhMe (15 mL + 10
mL rinse) was added dropwise via an addition funnel to the previ-
ously prepared solution of catalyst 16 in PhMe at –78 °C, at a rate
sufficient to keep the internal reaction temperature ≤ –75 °C and the
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2779–2785

2784
J. P. Cooksey et al.
PAPER
(2) (a) Berrue, F.; Kerr, R. G. Nat. Prod. Rep. 2009, 26, 681.
trans), 3.96 (1 H, quint, J = 6.9 Hz, C7H), 3.76 (3 H, s, OCH3),
3.78–3.75 (1 H, m, C4H), 3.45 (1 H, dd, J = 9.9, 6.8 Hz, C2HAHB),
3.39 (1 H, dd, J = 9.9, 6.2 Hz, C2HAHB), 2.21 (3 H, s, C20H3), 2.06
(1 H, quint, J = 6.7 Hz, C3H), 1.61 (3 H, d, J = 6.4 Hz, C6′′H3), 1.35
(3 H, d, J = 7.0 Hz, C19H3), 1.04 [9 H, s, SiC(CH3)3], 0.91 (3 H, d,
J = 6.8 Hz, C18H3).
13C NMR (75 MHz, CDCl3): δ = 147.9 (C9), 144.2 (C10), 138.9
(C5H), 137.4 (C13), 135.7 (2C, CArH), 135.6 (2C, CArH), 135.2
(C6H), 134.0 (CAr), 133.9 (CAr), 129.7 (CArH), 129.6 (CArH), 127.8
(C8), 127.7 (2C, CArH), 127.6 (2C, CArH), 127.6 (C11), 124.5
(C6′H), 121.3 (C12H), 116.7 (C5′H2), 67.3 (C2H2), 60.5 (OCH3),
46.6 (C4H), 40.6 (C3H), 35.3 (C7H), 27.0 [SiC(CH3)3], 19.4
[SiC(CH3)3], 18.8 (C19H3), 18.1 (C6′′H3), 16.1 (C20H3), 13.5
(C18H3).
(b) Rodríguez, A. D. Tetrahedron 1995, 51, 4571.
(3) (a) Ata, A.; Win, H. Y.; Holt, D.; Holloway, P.; Segstro, E.
P.; Jayatilake, G. S. Helv. Chim. Acta 2004, 87, 1090.
(b) Rodríguez, I. I.; Shi, Y.-P.; García, O. J.; Rodríguez, A.
D.; Mayer, A. M. S.; Sánchez, J. A.; Ortega-Barria, E.;
González, J. J. Nat. Prod. 2004, 67, 1672. (c) Ettouati, W.
S.; Jacobs, R. S. Mol. Pharmacol. 1987, 31, 500. (d) Correa,
H.; Aristizabal, F.; Duque, C.; Kerr, R. Marine Drugs 2011,
9, 334.
(4) (a) Roussis, V.; Wu, Z.; Fenical, W.; Strobel, S. A.; Van D,
G. D.; Clardy, J. J. Org. Chem. 1990, 55, 4916. (b) Mayer,
A. M. S.; Jacobson, P. B.; Fenical, W.; Jacobs, R. S.; Glaser,
K. B. Life Sci. 1998, 62, PL401. (c) Ata, A.; Kerr, R. G.;
Moya, C. E.; Jacobs, R. S. Tetrahedron 2003, 59, 4215.
(d) Moya, C. E.; Jacobs, R. S. Comp. Biochem. Physiol.,
Part C: Toxicol. Pharmacol. 2006, 143, 436. (e) Correa, H.;
Valenzuela, A. L.; Ospina, L. F.; Duque, C. J. Inflamm.
(London) 2009, 6, 5. (f) Dayan, N.; Grove, G.; Sivalenka, R.
IFSCC Mag. 2009, 12, 17.
(5) (a) Coleman, A. C.; Kerr, R. G. Tetrahedron 2000, 56, 9569.
(b) Hoarau, C.; Day, D.; Moya, C.; Wu, G.; Hackim, A.;
Jacobs, R. S.; Little, R. D. Tetrahedron Lett. 2008, 49, 4604.
(6) (a) Zhong, W.; Little, R. D. Tetrahedron 2009, 65, 10784.
(b) Zhong, W.; Moya, C.; Jacobs, R. S.; Little, R. D. J. Org.
Chem. 2008, 73, 7011.
(7) See for example: (a) Fenical, W. H.; Jacobs, R. S. US
5,624,911, 1997. (b) Haimes, H. H.; Jimenez, P. A. US
5,597,808, 1997. (c) Jacobs, R. S.; Kerr, R. G. US 7,060,686,
2006. (d) Jacobs, R. S.; Mydlarz, L. D.; Moya, C. US
2005/0026897, 2005.
HRMS (ES+): m/z [M + Na+] calcd for C35H46NaO3Si: 565.3108;
found: 565.3110.
Compound 27
[α]D +67.2 (c 0.5, CHCl3).
IR (neat): 3521 (s), 3134 (w), 3071 (m), 3049 (s), 3014 (s), 2959 (s),
2931 (s), 2857 (s), 2737 (w), 1636 (w), 1590 (m), 1487 (s), 1472 (s),
1462 (s), 1427 (s), 1389 (m), 1361 (m), 1305 (m), 1264 (m), 1223
(m) cm−1.
1H NMR (500 MHz, CDCl3): δ = 7.64 (2 H, dd, J = 8.0, 1.4 Hz,
ArH), 7.57 (2 H, dd, J = 7.9, 1.3 Hz, ArH), 7.43–7.31 (6 H, m,
ArH), 6.65 (1 H, d, J = 2.1 Hz, C8H), 6.52 (1 H, d, J = 2.0 Hz,
C12H), 5.94 (1 H, dt, J = 16.9, 9.8 Hz, C5H), 5.56 (1 H, s, OH),
5.11–5.02 (2 H, m, C5′H2), 3.77 (3 H, s, OCH3), 3.45 (1 H, dd, J =
9.9, 4.6 Hz, C2HAHB), 3.39 (1 H, dd, J = 10.0, 5.4 Hz, C2HAHB),
3.28 (1 H, t, J = 9.0 Hz, C4H), 2.25 (3 H, s, C20H3), 1.96 (1 H, app
hept, C3H), 1.06 [9 H, s, SiC(CH3)3], 1.03 (3 H, d, J = 6.8 Hz,
C18H3).
13C NMR (75 MHz, CDCl3): δ = 148.7 (C9), 143.7 (C10), 140.2
(C13), 140.01 (C5H), 135.8 (2C, CArH), 135.7 (2C, CArH), 134.1
(CAr), 133.9 (CAr), 130.5 (C11), 129.6 (CArH), 129.5 (CArH), 127.7
(2C, CArH), 127.6 (2C, CArH), 122.2 (C12H), 115.7 (C5′H2), 112.4
(C8H), 66.6 (C2H2), 60.8 (OCH3), 52.3 (C4H), 40.4 (C3H), 27.1
[SiC(CH3)3], 19.5 [SiC(CH3)3], 16.1 (C20H3), 15.0 (C18H3).
(8) (a) Broka, C. A.; Chan, S.; Peterson, B. J. Org. Chem. 1988,
53, 1584. (b) Corey, E. J.; Carpino, P. J. Am. Chem. Soc.
1989, 111, 5472.
(9) (a) Ganguly, A. K.; McCombie, S. W.; Cox, B.; Lin, S.;
McPhail, A. T. Pure Appl. Chem. 1990, 62, 1289.
(b) McCombie, S. W.; Cox, B.; Ganguly, A. K. Tetrahedron
Lett. 1991, 32, 2087. (c) Buszek, K. R.; Bixby, D. L.
Tetrahedron Lett. 1995, 36, 9129. (d) Gill, S.; Kocieński, P.;
Kohler, A.; Pontiroli, A.; Qun, L. Chem. Commun. 1996,
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(f) Corey, E. J.; Lazerwith, S. E. J. Am. Chem. Soc. 1998,
120, 12777. (g) LeBrazidec, J.-Y.; Kocieński, P. J.;
Connolly, J. D.; Muir, K. W. J. Chem. Soc., Perkin Trans. 1
1998, 2475. (h) Chow, R.; Kocieński, P. J.; Kuhl, A.;
LeBrazidec, J.-Y.; Muir, K.; Fish, P. J. Chem. Soc., Perkin
Trans. 1 2001, 2344. (i) Kocieński, P. J.; Pontiroli, A.; Qun,
L. J. Chem. Soc., Perkin Trans. 1 2001, 2356. (j) Harrowven,
D. C.; Tyte, M. J. Tetrahedron Lett. 2004, 45, 2089.
(k) Mans, D. J.; Cox, G. A.; RajanBabu, T. V. J. Am. Chem.
Soc. 2011, 133, 5776.
(10) (a) Corey, E. J.; Carpino, P. Tetrahedron Lett. 1990, 31,
3857. (b) Kozikowski, A. P.; Wu, J. P. Synlett 1991, 465.
(c) Jung, M. E.; Siedem, C. S. J. Am. Chem. Soc. 1993, 115,
3822. (d) McCombie, S. W.; Ortiz, C.; Cox, B.; Ganguly, A.
K. Synlett 1993, 541. (e) Harrowven, D. C.; Dennison, S. T.;
Howes, P. Tetrahedron Lett. 1994, 35, 4243. (f) Schmalz,
H.-G.; Schwarz, A.; Dürner, G. Tetrahedron Lett. 1994, 35,
6861. (g) Schmalz, H.-G.; Majdalani, A.; Geller, T.;
Hollander, J.; Bats, J. W. Tetrahedron Lett. 1995, 36, 4777.
(h) Eklund, L.; Sarvary, I.; Frejd, T. J. Chem. Soc., Perkin
Trans. 1 1996, 303. (i) Schmalz, H.-G.; Siegel, S.; Schwarz,
A. Tetrahedron Lett. 1996, 37, 2947. (j) Harrowven, D. C.;
Sibley, G. E. M. Tetrahedron Lett. 1999, 40, 8299.
(k) Benoit-Marquie, F.; Csaky, A. G.; Esteban, G.; Martinez,
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HRMS (ES+): m/z [M + H+] calcd for C30H39O3Si: 475.2663; found:
475.2673.
Anal. Calcd for C30H38O3Si; C, 75.90; H, 8.07. Found: C, 75.60; H,
8.30.
Acknowledgment
We thank Professor Hans-Günther Schmalz of the University of
Cologne for 1H and 13C NMR spectra for compounds 25 and 30.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
Primary Data for this article are available online at
http://www.thieme-connect.com/ejournals/toc/synthesis and can be
cited using the following DOI:
m
irDyaraPtir
m
Dyr
1
at 0.4125/pd0035th.mPiryDaraZtahenl1
01Chemyrsti
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© Georg Thieme Verlag Stuttgart · New York

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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2779–2785