Radical conjugate addition of aryl-tethered -alkoxyacrylates: Formal synthesis of (±)-Frenolicin B and (±)- epi -Frenolicin B

Article abstract of DOI:10.1055/s-0029-1217118

The radical conjugate addition of aromatic-tethered O-stannyl ketyl radicals to -alkoxyacrylates is demonstrated for the preparation of benzopyran - lactone-fused tricyclic systems. This method is then applied to the stereodivergent formal synthesis of th

Full text of DOI:10.1055/s-0029-1217118

PAPER
415
Radical Conjugate Addition of Aryl-Tethered b-Alkoxyacrylates:
Formal Synthesis of ( )-Frenolicin B and ( )-epi-Frenolicin B
F
ormal Synthesis
h
of
(
)-Freno
r
licin
B
a
nd ( )-
s
epi-Freno
t
licin
B
opher D. Donner*a,b
a
School of Chemistry, The University of Melbourne, Victoria 3010, Australia
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
Fax +61(3)93478189; E-mail: cdonner@unimelb.edu.au
b
Received 24 September 2009
Few examples of aryl-tethered ketyl radical conjugate ad-
dition reactions have been reported3,5 and notably, the
ketyl radical cyclisation to a b-alkoxyacrylate that in-
cludes an aryl tether appears to have been unexplored.
Given our ongoing interest in developing methodology
for the preparation of pyranoquinone natural products,6
we sought to explore the possibility of applying the radi-
cal conjugate addition approach towards these systems us-
ing an aryl-linked b-alkoxyacrylate as the cyclisation
substrate. Herein we describe the application of this ap-
proach to a formal synthesis of ( )-frenolicin B (1), a pyr-
anonaphthoquinone antibiotic first isolated from a strain
of Streptomyces roseofulvus,7 which exhibits excellent
anticoccidial activity8 and has recently been shown to be
a potent inhibitor of the serine/threonine kinase AKT
(AKT1 IC50 = 0.313 mM).9
Abstract: The radical conjugate addition of aromatic-tethered O-
stannyl ketyl radicals to b-alkoxyacrylates is demonstrated for the
preparation of benzopyran-g-lactone-fused tricyclic systems. This
method is then applied to the stereodivergent formal synthesis of the
kinase inhibitor ( )-frenolicin B and ( )-epi-frenolicin B.
Key words: radical conjugate addition, O-stannyl ketyl, frenolicin
B, pyranonaphthoquinone
Radical conjugate addition reactions have emerged as a
useful tool in synthetic organic chemistry with many vari-
ations on this general technique having been explored.1
Along with the advantages usually associated with radical
reactions (e.g., mild neutral conditions and compatibility
with unprotected functional groups), radical conjugate ad-
dition reactions display exclusive preference for 1,4- over
1,2-addition, in contrast to related anionic processes.
However, the reductive nature of most radical processes
has been seen as a shortcoming of this technique. To alle-
viate this deficiency, Enholm has demonstrated that ketyl
radicals, generated from the corresponding aldehyde (or
ketone), cyclise efficiently onto a,b-unsaturated esters to
generate products that retain an alcohol group at the site
of the initially formed radical.2 A variation on this general
process is the inclusion of a heteroatom into the tether,
giving access to tetrahydropyrans and tetrahydrofurans
(Scheme 1).3 Such a strategy has been employed regularly
towards the preparation of a variety of natural products
that incorporate cyclic ether motifs.1b,4
Both frenolicin B (1) and epi-frenolicin B (2) have previ-
ously been prepared by the regioselective Diels–Alder
reaction of 1-(trimethylsiloxy)butadiene with the pyra-
nobenzoquinones 3 and 4, respectively (Scheme 2).10 We
planned to prepare benzoquinone 3 and/or 4 by either
alkylation and oxidation of benzopyran 5, or more directly
by oxidation of 6. It was anticipated that the key g-lac-
tone-fused benzopyran tricyclic intermediates 5 and 6
may each be formed in a single step by an intramolecular
radical conjugate addition of the ketyl radical formed
from benzaldehydes 7 and 8, respectively.
R1 R2
R1 R2
OH
O
O
ref. 10
O
O
O
O
CO2R
CO2R
SnBu3
Bu3SnH
•
CHO
AIBN
PhH, 80 °C
O
O
O
O
O
n
n
O
O
n = 0, 1
frenolicin B (1) R1 = Pr, R2 = H
3 R1 = Pr, R2 = H
4 R1 = H, R2 = Pr
epi-frenolicin B (2) R1 = H, R2 = Pr
O
O
CO2R
OH
O
+
MeO
R
MeO
R
O
CO2Et
n
n
O
O
Scheme 1 Radical conjugate addition of O-stannyl ketyl radicals to
b-alkoxyacrylates3
CHO
O
MeO
MeO
O
5 R = H
6 R = Pr
7 R = H
8 R = Pr
SYNTHESIS 2010, No. 3, pp 0415–0420
Advanced online publication: 13.11.2009
DOI: 10.1055/s-0029-1217118; Art ID: P12909SS
x
x
.
x
x
.2
0
0
9
Scheme 2 Retrosynthetic analysis of frenolicin B (1) and epi-freno-
licin B (2)
© Georg Thieme Verlag Stuttgart · New York

416
C. D. Donner
PAPER
With the expectation of being able to introduce the propyl in only 15% yield. Although the ratio of cyclised products
group in 3 at a late stage via the reported diastereoselec- favours the trans-isomer 13, conversion of the trans-iso-
tive allylation of benzopyrans,11 the benzaldehyde 7 be- mer 13 into the required lactone 5 could be effected in
came the first target as a potential radical cyclisation moderate yield by heating 13 in N,N-dimethylformamide
substrate. Thus, the synthesis began with reduction of 4,7- with potassium carbonate.14
dimethoxyphthalide (9)12 using lithium aluminium hy-
At this point we anticipated being able to install the C5
alkyl group using conditions reported for the stereoselec-
dride in tetrahydrofuran to give the symmetrical diol 1013
in 93% yield (Scheme 3). Slow addition of ethyl propi-
tive allylation of benzopyrans using allyltriphenyltin and
olate to diol 10 in the presence of N-methylmorpholine
gave the alkoxyacrylate 11 in 80% yield, exclusively as
the E-isomer. A small amount of the dialkylated product
12 (8% yield) and unreacted diol 10 (10% yield) were also
obtained. Oxidation of benzyl alcohol 11 [TEMPO,
PhI(OAc)2] gave the corresponding benzaldehyde 7 in
78% yield.
2,3-dichloro-5,6-dicyano-1,4-benzoquinone.11 Unfortu-
nately, these conditions failed to give any of the anticipat-
ed product 14, with only recovery of starting material 5
being observed.
With access to the benzopyran 14, and hence potentially
frenolicin B (1), via a late-stage introduction of the C5
propyl group being unsuccessful, instead we resorted to
incorporating the required propyl group early in the syn-
thetic sequence. Beginning from 2,5-dimethoxybenzalde-
hyde (15) (Scheme 4), conversion into the acetal 16
proceeded smoothly upon treatment with propane-1,3-di-
ol.15 Metallation of the acetal followed by addition of bu-
tyraldehyde gave the ortho-substituted product 17 in 64%
yield as the predominant product with a minor amount of
the para-substituted isomer also formed (14% yield).
Alkylation of the sterically hindered secondary alcohol in
17 proceeded reluctantly with significant decomposition
of ethyl propiolate occurring before alkylation was com-
plete. The addition of further portions of ethyl propiolate
and N-methylmorpholine during the course of the reaction
allowed further conversion of alcohol 17 into the required
product 18. Although complete conversion of 17 into 18
was not effected, adequate quantities of the b-alkoxyacry-
late 18 could be obtained for further use. Hydrolysis of the
acetal in 18 proceeded by exposure to dilute hydrochloric
acid in acetone to give benzaldehyde 8 (90% yield) in
preparation for the radical cyclisation.
MeO
MeO
MeO
OH
O
CO2Et
O
a
b
c
O
MeO
OR
MeO
MeO
MeO
OH
9
10
11 R = H
12 R =
CO2Et
MeO
MeO
MeO
CO2Et
O
O
O
d
+
CHO
O
MeO
OH CO2Et MeO
e
O
7
13
5
MeO
MeO
f
5
O
1
O
O
14
Cyclisation of the ketyl radical derived from benzalde-
hyde 8 may lead to the formation of four possible (racem-
ic) diastereoisomeric products. Treatment of benz-
aldehyde 8 under the conditions described earlier led to
the isolation of three products. The major product (66%
yield) was identified as the lactone 19. The 1,3/3,4-cis/cis
relative stereochemistry in 19 was established from the
presence of NOE correlations between the H1/H3 and H3/
H4 methine protons on the pyran ring.16 The chromato-
graphically inseparable minor products from the radical
conjugate addition reaction (combined yield of 26%) were
shown to have a 3,4-trans-relationship by analysis of the
1H NMR spectrum, being consistent with epimeric struc-
tures 20. The preferential formation of 19 from the radical
conjugate addition of benzaldehyde 8 is in accord with the
known preference for b-alkoxyacrylates, as with related
hept-1-enyl radical systems, to give 1,3-cis-products via a
6-exo radical cyclisation process.17
Scheme 3 Reagents and conditions: (a) LiAlH4, THF, 0 °C, 1.5 h
(93%); (b) ethyl propiolate, NMM, CH2Cl2, 1.5 h (11 80%, 12 8%);
(c) TEMPO, PhI(OAc)2, CH2Cl2, 5 h (78%); (d) Bu3SnH, AIBN, ben-
zene, reflux, 5 h (13 46%, 5 13%, 11 15%); (e) K2CO3, 18-crown-6,
DMF, 100 °C, 12 h (66%); (f) Ph3SnCH2CH=CH2, DDQ, CH2Cl2.
With the cyclisation substrate prepared, the propensity of
7 to undergo an intramolecular radical conjugate addition
was explored. A solution of the aldehyde 7 (0.05 M in
benzene) and tributyltin hydride (1.5 equiv) was heated at
reflux with 2,2¢-azobis(isobutyronitrile) added in portions
over six hours. Under these conditions the cyclised prod-
uct 13 was isolated in 37% yield with the major product
being the benzyl alcohol 11 (51% yield), formed by com-
petitive reduction of the ketyl radical generated from alde-
hyde 7. Despite the concentration of tributyltin hydride
being lower than that originally described by Enholm,2
cyclisation could not compete efficiently with reduction.
However, at lower concentration (0.017 M) the cyclised
products 13 and 5 were formed in a 3.5:1 ratio (combined
yield of 59%) with the reduction product 11 being isolated
Completion of the formal synthesis of frenolicin B (1) and
epi-frenolicin B (2) was undertaken by the stereodiver-
gent conversion of 19 into the benzoquinones 3 and 4, as
outlined in Scheme 5. Firstly, oxidation of 19 using ceri-
Synthesis 2010, No. 3, 415–420 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of ( )-Frenolicin B and ( )-epi-Frenolicin B
417
MeO
MeO
MeO
MeO
MeO
O
O
OH
O
a
a
ref. 10
b
OH
O
O
O
O
CHO
MeO
O
O
O
O
O
MeO
O
O
15
16
17
4
epi-frenolicin B (2)
5
O
MeO
MeO
MeO
O
MeO
CO2Et
CO2Et
d
c
O
O
O
O
O
OH
O
O
19
O
CHO
ref. 10
5
b, c
O
O
3a
MeO
O
18
8
3
O
O
O
O
3
frenolicin B (1)
MeO
MeO
MeO
Scheme 5 Reagents and conditions: (a) CAN, MeCN, H2O, 20 min
(71%); (b) BBr3, CH2Cl2, –60 °C to r.t., 1 h; (c) CAN, MeCN, H2O, 5
min (69% 2 steps).
1
e
1
O
3
O
3
+
O
MeO
OH CO2Et
20
CHCl3 (d = 7.26 for 1H and 77.0 for 13C) was used as internal stan-
dard. IR spectra were recorded on a Perkin-Elmer Spectrum One
FT-IR spectrophotometer. GC-MS spectra were recorded on an Ag-
ilent 7890A GC system using a HP-5MS column (30 m, i.d. 0.25
mm, film thickness 0.25 mm) and 5975C MS system (EI, 70 eV).
GC heat program: 1005 → 2505, heating rate 5 °C min–1. The reten-
tion time (tR) and selected fragment ions as their mass/charge ratio
(m/z) are reported. HRMS (ESI) were recorded on a Thermo-Finni-
gan LTQ-FT ICR hybrid mass spectrometer. All moisture sensitive
reactions were performed under a dry N2 or argon atmosphere in
oven-dried or flame-dried glassware. Anhyd THF and CH2Cl2 were
pre-dried over activated alumina under argon. Benzene was distilled
from Na/benzophenone ketyl prior to use. TLC was performed on
pre-coated silica plates (Merck 60GF254) and compounds were visu-
alised at 254 nm and 365 nm or stained with 20% w/v phosphomo-
lybdic acid in EtOH. Flash column chromatography (silica gel,
Kieselgel 60, 230–400 mesh) was performed using the indicated
solvent system; PE = petroleum ether. Melting points were mea-
sured using a Bausch and Lomb hot-stage melting point apparatus
and are uncorrected.
O
19
Scheme
4
Reagents and conditions: (a) propane-1,3-diol,
(MeO)3CH, Bu4NBr3, 45 min (100%); (b) 1. BuLi, Et2O–hexane, 0
°C, 1.5 h; 2. PrCHO, 0 °C to r.t., 1.5 h (64%); (c) ethyl propiolate,
NMM, CH2Cl2, 22 h (75%); (d) 2 M HCl, acetone, 16 h (90%); (e)
Bu3SnH, AIBN, benzene, reflux, 3 h (19 66%, 20 26%).
um(IV) ammonium nitrate gave the benzoquinone 4 in
71% yield. The spectroscopic data for 4 was in agreement
with data reported by Kraus,10 thus confirming both the
structure and relative stereochemistry of the pyranoben-
zoquinone 4. Access to the natural product frenolicin B
(1) requires epimerisation of the C5 asymmetric centre in
19. This was achieved by exposure of 19 to boron tribro-
mide in dichloromethane leading to formation of a mix-
ture of products (due to partial cleavage of the methyl
ethers) that were subsequently treated with cerium(IV)
ammonium nitrate to give the pyranobenzoquinone 3 as
the exclusive product in 69% yield, with the spectroscopic
data for 3 being consistent with that previously reported.10
Since the benzoquinones 3 and 4 have previously been
converted into the pyranonaphthoquinones 1 and 2, re-
spectively, using a Diels–Alder/oxidation procedure,10
this constitutes a formal synthesis of both ( )-frenolicin B
(1) and ( )-epi-frenolicin B (2).
2,3-Bis(hydroxymethyl)-1,4-dimethoxybenzene (10)
To a soln of 4,7-dimethoxyphthalide12 (9, 460 mg, 2.37 mmol) in
THF (20 mL) at 0 °C was added LiAlH4 (200 mg, 5.27 mmol) in
portions over 10 min. Stirring was continued at 0 °C for a further 90
min at which time the reaction was quenched by the dropwise addi-
tion of sat. NH4Cl (20 mL). The resultant suspension was diluted
with CHCl3 (15 mL) and filtered through Celite and the filter cake
was washed with CHCl3 (10 mL); the filtrate was further extracted
with CHCl3 (3 × 5 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo to give 10 (436 mg,
93%) as a white crystalline solid; mp 139–140 °C [Lit.13 145 °C
(toluene–MeOH)]. 1H and 13C NMR data are in agreement with the
literature.13
In summary, the potential for aromatic-tethered ketyl rad-
icals to undergo cyclisation to b-alkoxyacrylates has been
demonstrated. The radical cyclisation of acrylate 8 occurs
with good diastereoselectivity to give the cis/cis-benzopy-
ran 19 as the major product, thus providing rapid access to
the epimeric pyranobenzoquinones 3 and 4 and complet-
ing a formal synthesis of both ( )-frenolicin B (1) and ( )-
epi-frenolicin B (2).
IR (neat): 3311, 2932, 1488, 1440, 1265, 1232, 1088, 987 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.75 (br s, 2 H), 3.82 (s, 6 H), 4.83
(s, 4 H), 6.84 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 56.2, 56.5, 111.1, 129.5, 151.9.
GC-MS: m/z (%) = 198.1 (M+, 49), 180.1 (100), 165.1 (47), 151.1
(47), 137.1 (40), 121.1 (36), 107.1 (20), 91.1 (29), 77.1 (33);
tR = 22.51 min.
1H and 13C NMR spectra were recorded using a Varian-500 spec-
trometer operating at 500 MHz and 125 MHz, respectively; residual
Synthesis 2010, No. 3, 415–420 © Thieme Stuttgart · New York

418
C. D. Donner
PAPER
Ethyl 2-[(3S*,4R*)-4-Hydroxy-5,8-dimethoxyisochroman-3-
HRMS: m/z [M + Na]+ calcd for C10H14NaO4: 221.0784; found:
221.0785.
yl]acetate (13) and (3aR*,9bR*)-6,9-Dimethoxy-3,3a,5,9b-tet-
rahydro-2H-furo[3,2-c]isochromen-2-one (5)
Ethyl (E)-3-[2-(Hydroxymethyl)-3,6-dimethoxybenzyl-
oxy]acrylate (11) and Diethyl (2E,2¢E)-3,3¢-(3,6-Dimethoxy-1,2-
phenylene)bis(methylene)bis(oxy)diacrylate (12)
A soln of 7 (100 mg, 0.34 mmol), Bu3SnH (148 mg, 0.51 mmol),
and AIBN (6 mg, 0.037 mmol) in benzene (20 mL) was flushed with
argon for 1 h after which the soln was heated at reflux for 5 h during
which further portions of AIBN (6 mg) were added after 1 h and 2
h of heating. After cooling and removal of the solvent in vacuo the
remaining residue was purified by column chromatography (gradi-
ent elution, EtOAc–PE, 1:2 to 1:1) to give, in order of elution, 13
(46 mg, 46%), 5 (11 mg, 13%), and reduction product 11 (15 mg,
15%).
To a suspension of 10 (400 mg, 2.02 mmol) in CH2Cl2 (10 mL) was
added NMM (225 mg, 2.22 mmol) followed by the addition of ethyl
propiolate (225 mL, 2.22 mmol) over 20 min and stirring was con-
tinued for a further 90 min. The soln was diluted 0.5 M HCl and ex-
tracted with CHCl3 (3 × 10 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo. Column
chromatography (gradient elution, EtOAc–PE, 1:1 to 4:1) gave, in
order of elution, 12 (60 mg, 8%), 11 (480 mg, 80%), and starting
diol 10 (40 mg, 10%).
trans-Product 13
Colourless oil.
IR (neat): 3461, 2927, 1735, 1486, 1257, 1164, 1055, 1026 cm–1.
Monoacrylate 11
Colourless solid.
1H NMR (500 MHz, CDCl3): d = 1.28 (t, J = 7.2 Hz, 3 H), 2.60 (dd,
J = 15.4, 9.0 Hz, 1 H), 2.95 (dd, J = 15.4, 3.4 Hz, 1 H), 3.75 (s, 3 H),
3.84 (s, 3 H), 4.00 (m, 1 H), 4.19 (m, 2 H), 4.62 (d, J = 16.0 Hz, 1
H), 4.72 (d, J = 8.3 Hz, 1 H), 4.82 (d, J = 16.0 Hz, 1 H), 6.68 (d,
J = 8.8 Hz, 1 H), 6.72 (d, J = 8.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.2, 38.1, 55.5, 55.7, 60.5, 64.2,
66.2, 75.3, 108.6, 108.8, 125.4, 125.5, 149.3, 151.6, 171.3.
GC-MS: m/z (%) = 296.1 (M+, 9), 278.1 (86), 250.1 (54), 206.1
(29), 205.1 (100), 191.1 (46), 180.1 (31), 179.1 (46), 165.1 (44),
91.1 (23); tR = 32.35 min.
HRMS: m/z [M + Na]+ calcd for C15H20NaO6: 319.1152; found:
319.1149.
IR (neat): 3451, 2941, 1701, 1619, 1484, 1258, 1124, 1091, 1008
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.27 (t, J = 7.2 Hz, 3 H), 2.37 (t,
J = 6.7 Hz, 1 H), 3.81 (s, 3 H), 3.85 (s, 3 H), 4.16 (q, J = 7.2 Hz, 2
H), 4.72 (d, J = 6.7 Hz, 2 H), 5.10 (s, 2 H), 5.36 (d, J = 12.7 Hz, 1
H), 6.85 (d, J = 9.0 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 7.67 (d, J =
12.7 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.4, 56.1, 56.3, 57.1, 59.7, 63.9,
97.3, 111.1, 112.4, 123.1, 130.5, 152.1, 152.2, 162.2, 167.8.
GC-MS: m/z (%) = 296.1 (M+, 3), 181.1 (100), 180.1 (58), 165.1
(28), 151.0 (34); tR = 33.50 min.
HRMS: m/z [M + Na]+ calcd for C15H20NaO6: 319.1152; found:
cis-Lactone 5
319.1153.
Colourless solid; mp 162–165 °C.
IR (neat): 2923, 1770, 1489, 1263, 1153, 1092, 1070, 1056, 964
cm–1.
Diacrylate 12
Colourless solid.
1H NMR (500 MHz, CDCl3): d = 2.72 (d, J = 17.5 Hz, 1 H), 2.90
(dd, J = 17.5, 4.9 Hz, 1 H), 3.79 (s, 3 H), 3.85 (s, 3 H), 4.34 (dd, J =
4.9, 2.8 Hz, 1 H), 4.47 (d, J = 16.1 Hz, 1 H), 4.98 (d, J = 16.1 Hz, 1
H), 5.33 (d, J = 2.8 Hz, 1 H), 6.78 (d, J = 8.9 Hz, 1 H), 6.84 (d, J =
8.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 37.6, 55.7, 56.1, 62.7, 71.8, 72.6,
109.0, 111.2, 117.7, 125.7, 148.8, 152.8, 175.1.
IR (neat): 2997, 1702, 1629, 1488, 1263, 1231, 1185, 1136, 1095,
1042 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 6 H), 3.82 (s,
6 H), 4.16 (q, J = 7.1 Hz, 4 H), 5.03 (s, 4 H), 5.33 (d, J = 12.4 Hz, 2
H), 6.93 (s, 2 H), 7.66 (d, J = 12.4 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 14.4, 56.3, 59.7, 63.9, 97.2,
112.9, 124.5, 152.3, 162.3, 167.8.
GC-MS: m/z (%) = 250.1 (M+, 100), 191.1 (21), 175.1 (20);
tR = 31.51 min.
HRMS: m/z [M + Na]+ calcd for C20H26NaO8: 417.1520; found:
417.1521.
HRMS: m/z [M + H]+ calcd for C13H15O5: 251.0914; found:
251.0913.
Ethyl (E)-3-(2-Formyl-3,6-dimethoxybenzyloxy)acrylate (7)
To a soln of 11 (450 mg, 1.52 mmol) in CH2Cl2 (10 mL) was added
PhI(OAc)2 (587 mg, 1.82 mmol) and TEMPO (24 mg, 0.15 mmol)
and the mixture was stirred at r.t. for 5 h. After removal of the sol-
vent in vacuo the remaining residue was purified by column chro-
matography (EtOAc–PE, 1:2) to give 7 (350 mg, 78%) as a
colourless crystalline solid; mp 96–97 °C.
(3aR*,9bR*)-6,9-Dimethoxy-3,3a,5,9b-tetrahydro-2H-furo[3,2-
c]isochromen-2-one (5)
From Ester 13: A soln of 13 (9 mg, 0.03 mmol), K2CO3 (60 mg),
and 18-crown-6 (1.8 mg, 6.8 mmol) in DMF (0.5 mL) was heated at
100 °C for 12 h. H2O (5 mL) was added and the mixture extracted
with EtOAc (3 × 5 mL). The combined organic extracts were
washed with H2O (3 × 5 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. Column chromatography (gradient elution, EtOAc–
PE, 1:2 to 1:1) gave 5 (5 mg, 66%) identical to the material de-
scribed above.
IR (neat): 2982, 1709, 1682, 1618, 1483, 1271, 1130, 1006 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H), 3.82 (s,
3 H), 3.87 (s, 3 H), 4.15 (q, J = 7.1 Hz, 2 H), 5.29 (s, 2 H), 5.29 (d,
J = 12.7 Hz, 1 H), 7.02 (d, J = 9.1 Hz, 1 H), 7.13 (d, J = 9.1 Hz, 1
H), 7.69 (d, J = 12.7 Hz, 1 H), 10.55 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.3, 56.3, 56.7, 59.6, 63.0, 96.7,
113.6, 117.9, 124.0, 124.4, 152.3, 156.9, 162.9, 168.0, 191.9.
GC-MS: m/z (%) = 294.1 (M+, 3), 179.1 (100); tR = 33.17 min.
HRMS: m/z [M + Na]+ calcd for C15H18NaO6: 317.0996; found:
2-(2,5-Dimethoxyphenyl)-1,3-dioxane (16)
To 2,5-dimethoxybenzaldehyde (15, 1.0 g, 6.00 mmol) in propane-
1,3-diol (1.75 mL, 24.1 mol) was added trimethyl orthoformate
(0.75 mL, 6.86 mmol) and Bu4NBr3 (26 mg, 0.05 mmol). The mix-
ture was stirred for 45 min at r.t. and then the reaction was quenched
with sat. NaHCO3 (5 mL) and H2O (20 mL). The mixture was ex-
tracted with EtOAc (3 × 10 mL) and the combined organic fractions
317.0996.
Synthesis 2010, No. 3, 415–420 © Thieme Stuttgart · New York

PAPER
Formal Synthesis of ( )-Frenolicin B and ( )-epi-Frenolicin B
419
were washed sequentially with 10% NaHCO3 (20 mL) and H2O
(3 × 20 mL), dried (MgSO4), and concentrated in vacuo to give 16
(1.35 g, 100%) as a colourless oil, which was used without further
purification.
ued for 22 h. The soln was diluted with brine (20 mL) and extracted
with CHCl3 (4 × 10 mL). The combined organic extracts were dried
(MgSO4), filtered, and concentrated in vacuo. Column chromatog-
raphy (gradient elution, EtOAc–PE, 1:3 to 1:1) gave, in order of elu-
tion, 18 (320 mg, 28%, 75% based on recovered 17) and starting
alcohol 17 (530 mg, 62%); colourless plates; mp 125–126 °C
(CH2Cl2–hexane).
IR (neat): 2955, 1501, 1277, 1214, 1147, 1091, 1044, 992 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.43 (m, 1 H), 2.25 (m, 1 H), 3.79
(s, 3 H), 3.80 (s, 3 H), 4.01 (m, 2 H), 4.25 (m, 2 H), 5.85 (s, 1 H),
6.81 (d, J = 8.9 Hz, 1 H), 6.85 (dd, J = 8.9, 3.1 Hz, 1 H), 7.20 (d,
J = 3.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 25.9, 55.8, 56.4, 67.6, 96.8,
111.9, 112.3, 115.9, 127.7, 150.6, 153.9.
GC-MS: m/z (%) = 224.2 (M+, 100), 223.2 (29), 193.1 (37), 166.1
(62), 165.1 (54), 151.1 (32), 138.1 (38), 123.1 (25), 87.1 (40);
tR = 22.37 min.
IR (neat): 2924, 1703, 1636, 1260, 1121, 1099, 1081, 1065, 986 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.96 (t, J = 7.4 Hz, 3 H), 1.21 (t,
J = 7.1 Hz, 3 H), 1.37 (m, 1 H), 1.46 (m, 1 H), 1.57 (m, 1 H), 1.76
(m, 1 H), 2.27 (m, 1 H), 2.36 (m, 1 H), 3.76 (s, 3 H), 3.77 (s, 3 H),
3.98 (m, 2 H), 4.08 (m, 2 H), 4.22 (dd, J = 11.2, 5.1 Hz, 1 H), 4.33
(dd, J = 11.4, 5.0 Hz, 1 H), 5.33 (d, J = 12.2 Hz, 1 H), 6.21 (m, 1 H),
6.23 (s, 1 H), 6.79 (d, J = 9.0 Hz, 1 H), 6.89 (d, J = 9.0 Hz, 1 H),
7.89 (d, J = 12.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.7, 14.3, 19.7, 26.0, 35.5, 56.3,
57.0, 59.2, 67.7, 67.8, 81.5, 96.7, 97.3, 111.7, 115.1, 125.7, 130.0,
150.8, 153.5, 164.4, 168.6.
GC-MS: m/z (%) = 394.2 (M+, 2), 279.1 (31), 221.1 (75), 205.1
(80), 203.1 (100), 191.1 (31); tR = 37.47 min.
HRMS: m/z [M + Na]+ calcd for C21H30NaO7: 417.1884; found:
417.1883.
1-[2-(1,3-Dioxan-2-yl)-3,6-dimethoxyphenyl]butan-1-ol (17)
and 1-[4-(1,3-Dioxan-2-yl)-2,5-dimethoxyphenyl]butan-1-ol
To a soln of 16 (1.35 g, 6.02 mmol) in Et2O (8 mL) and hexane (25
mL) maintained at 0 °C was added 2.2 M BuLi in hexane (5.5 mL,
12.1 mmol). The mixture was stirred for a further 1.5 h after which
butyraldehyde (1.2 mL, 13.3 mmol) was added dropwise and stir-
ring was continued at 0 °C for a further 30 min and then at r.t. for 1
h. H2O (30 mL) and sat. NH4Cl (20 mL) were added and the mixture
extracted with EtOAc (2 × 10 mL). The aqueous layer was further
acidified with 2 M HCl and extracted with CHCl3 (3 × 10 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo and the residual oil was purified by column chromatography
(gradient elution, EtOAc–PE, 1:2 to 1:1) to give, in order of elution,
recovered 16 (460 mg, 34%), 1-[4-(1,3-dioxan-2-yl)-2,5-dimeth-
oxyphenyl]butan-1-ol (165 mg, 9%, 14% based on recovered 16),
and 17 (755 mg, 42%, 64% based on recovered 16).
Ethyl (E)-3-[1-(2-Formyl-3,6-dimethoxyphenyl)butoxy]acry-
late (8)
To a soln of 18 (320 mg, 0.81 mmol) in acetone (5 mL) at 0 °C was
added 2 M HCl (0.5 mL). The soln was allowed to warm to r.t. and
stirred for 16 h. The soln was diluted with 5% NaHCO3 (5 mL) and
extracted with CHCl3 (4 × 5 mL). The combined organic extracts
were dried (MgSO4), filtered, and concentrated in vacuo. Column
chromatography (EtOAc–PE, 1:3) gave 8 (246 mg, 90%) as a co-
lourless oil.
ortho-Isomer 17
Colourless solid mp 66–67 °C.
IR (neat): 3557, 2956, 1483, 1464, 1403, 1254, 1228, 1079, 988 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.98 (t, J = 7.2 Hz, 3 H), 1.39 (m,
1 H), 1.50 (m, 1 H), 1.68 (m, 2 H), 1.95 (m, 1 H), 2.25 (m, 1 H), 3.75
(s, 3 H), 3.81 (s, 3 H), 3.93 (m, 2 H), 4.19 (dd, J = 11.3, 5.0 Hz, 1
H), 4.25 (dd, J = 11.5, 4.9 Hz, 1 H), 5.77 (dd, J = 10.0, 2.4 Hz, 1 H),
6.18 (s, 1 H), 6.71 (d, J = 9.1 Hz, 1 H), 6.84 (d, J = 9.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.9, 19.7, 25.8, 38.9, 55.6, 56.3,
67.7, 70.4, 97.4, 109.9, 112.6, 124.7, 134.3, 151.1, 152.6.
IR (neat): 2961, 1704, 1638, 1620, 1477, 1258, 1189, 1123, 1048,
951 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.92 (t, J = 7.5 Hz, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H), 1.33 (m, 1 H), 1.50 (m, 1 H), 1.78 (m, 1 H), 2.12
(m, 1 H), 3.80 (s, 3 H), 3.81 (s, 3 H), 4.07 (m, 2 H), 5.12 (d, J = 12.6
Hz, 1 H), 5.68 (dd, J = 8.8, 4.9 Hz, 1 H), 6.87 (d, J = 9.0 Hz, 1 H),
7.00 (d, J = 9.0 Hz, 1 H), 7.42 (d, J = 12.6 Hz, 1 H), 10.47 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.6, 14.3, 19.2, 37.4, 56.2, 56.5,
59.6, 78.3, 97.8, 111.9, 116.2, 125.8, 129.6, 151.0, 154.2, 161.6,
167.9, 193.6.
GC-MS: m/z (%) = 336.2 (M+, 1), 221.1 (100), 191.1 (33), 179.1
(26); tR = 33.55 min.
HRMS: m/z [M + Na]+ calcd for C18H24NaO6: 359.1465; found:
GC-MS: m/z (%) = 296.1 (M+, 2), 221.1 (27), 220.2 (75), 205.1
(100), 191.1 (62); tR = 29.76 min.
HRMS: m/z [M + Na]+ calcd for C16H24NaO5: 319.1516; found:
319.1516.
359.1465.
1-[4-(1,3-Dioxan-2-yl)-2,5-dimethoxyphenyl]butan-1-ol
Colourless oil.
IR (neat): 3405, 2957, 1464, 1403, 1204, 1092, 1040 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.4 Hz, 3 H), 1.33 (m,
1 H), 1.44 (m, 2 H), 1.70 (m, 2 H), 2.25 (m, 1 H), 3.82 (s, 3 H), 3.84
(s, 3 H), 4.01 (m, 2 H), 4.25 (m, 2 H), 4.87 (m, 1 H), 5.85 (s, 1 H),
6.89 (s, 1 H), 7.15 (s, 1 H).
GC-MS: m/z (%) = 296.1 (M+, 29), 278.1 (26), 253.2 (100), 195.0
(20), 87.0 (47); tR = 31.20 min.
(3aR*,5S*,9bR*)-6,9-Dimethoxy-5-propyl-3,3a,5,9b-tetrahy-
dro-2H-furo[3,2-c]isochromen-2-one (19)
A soln of 8 (85 mg, 0.25 mmol), Bu3SnH (92 mg, 0.32 mmol), and
AIBN (4 mg, 0.02 mmol) in benzene (16 mL) was flushed with ar-
gon for 1 h after which the soln was heated at reflux for 3 h. After
cooling and removal of the solvent in vacuo the remaining residue
was purified by column chromatography (EtOAc–PE, 1:3) to give,
in order of elution, a mixture of trans-epimers 20 (22 mg, 26%) as
a colourless oil and the cis-lactone 19 (49 mg, 66%).
cis-Lactone 19
Colourless solid, mp 102–103 °C (CH2Cl2–hexane).
Ethyl (E)-3-{1-[2-(1,3-Dioxan-2-yl)-3,6-dimethoxyphenyl]but-
oxy}acrylate (18)
To a soln of 17 (850 mg, 2.87 mmol) in CH2Cl2 (15 mL) was added
NMM (345 mL, 3.15 mmol) followed by ethyl propiolate (321 mL,
3.15 mmol). Further portions of NMM (345 mL) and ethyl propi-
olate (321 mL) were added after 2 h and 5 h and stirring was contin-
IR (neat): 2952, 1765, 1484, 1266, 1256, 1248, 1164, 1082, 976,
910 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.84 (t, J = 7.5 Hz, 3 H), 1.27 (m,
2 H), 1.96 (m, 2 H), 2.70 (d, J = 17.1 Hz, 1 H), 2.82 (dd, J = 17.1,
Synthesis 2010, No. 3, 415–420 © Thieme Stuttgart · New York

420
C. D. Donner
PAPER
4.3 Hz, 1 H), 3.78 (s, 3 H), 3.84 (s, 3 H), 4.26 (dd, J = 4.3, 2.3 Hz,
1 H), 4.83 (m, 1 H), 5.33 (d, J = 2.3 Hz, 1 H), 6.77 (d, J = 8.9 Hz, 1
H), 6.86 (d, J = 8.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.1, 17.8, 36.3, 38.3, 55.6, 56.1,
70.7, 72.6, 72.8, 108.8, 112.1, 118.4, 129.2, 149.7, 152.8, 175.9.
GC-MS: m/z (%) = 292.1 (M+, 10), 249.1 (100), 205.1 (28);
tR = 32.88 min.
HRMS: m/z [M + H]+ calcd for C16H21O5: 293.1384; found:
Acknowledgment
Financial support from the Australian Research Council through the
Centres of Excellence program is gratefully acknowledged. Profes-
sor Carl Schiesser, The University of Melbourne, is acknowledged
for useful discussions.
References
293.1383.
(1) For reviews, see: (a) Zhang, W. Tetrahedron 2001, 57,
7237. (b) Srikanth, G. S. C.; Castle, S. L. Tetrahedron 2005,
61, 10377.
(2) Enholm, E. J.; Prasad, G. Tetrahedron Lett. 1989, 30, 4939.
(3) Lee, E.; Tae, J. S.; Chong, Y. H.; Park, Y. C.; Yun, M.; Kim,
S. Tetrahedron Lett. 1994, 35, 129.
(3aR*,5S*,9bR*)-5-Propyl-3,3a,5,9b-tetrahydro-2H-furo[3,2-
c]isochromene-2,6,9-trione (4)
To 19 (19 mg, 65 mmol) in MeCN (0.5 mL) was added CAN (89 mg,
0.16 mmol) in H2O (0.2 mL). After stirring for 20 min the soln was
diluted with H2O (5 mL) and extracted with CHCl3 (4 × 3 mL). The
combined organic extracts were dried (MgSO4), filtered, and con-
centrated in vacuo. Column chromatography (EtOAc–CHCl3, 2:1)
gave 4 (12 mg, 71%) as a pale-yellow solid. The 1H and 13C NMR
data are in agreement with the literature.10b
(4) Selected recent examples include: (a) Satoh, M.; Koshino,
H.; Nakata, T. Org. Lett. 2008, 10, 1683. (b) Clark, J. S.;
Hayes, S. T.; Blake, A. J.; Gobbi, L. Tetrahedron Lett. 2007,
48, 2501. (c) Park, J.; Kim, B.; Kim, H.; Kim, S.; Kim, D.
Angew. Chem. Int. Ed. 2007, 46, 4726. (d) Clark, J. S.;
Hayes, S. T.; Wilson, C.; Gobbi, L. Angew. Chem. Int. Ed.
2007, 46, 437. (e) Kadota, I.; Abe, T.; Sato, Y.; Kabuto, C.;
Yamamoto, Y. Tetrahedron Lett. 2006, 47, 6545.
(5) (a) Tamiya, M.; Jäger, C.; Ohmori, K.; Suzuki, K. Synlett
2007, 780. (b) Bentley, J.; Nilsson, P. A.; Parsons, A. F.
J. Chem. Soc., Perkin Trans. 1 2002, 1461. (c) Monovich,
L. G.; Le Huérou, Y.; Rönn, M.; Molander, G. A. J. Am.
Chem. Soc. 2000, 122, 52.
(6) (a) Donner, C. D. Tetrahedron Lett. 2007, 48, 8888.
(b) Tewierik, L. M.; Dimitriadis, C.; Donner, C. D.; Gill, M.;
Willems, B. Org. Biomol. Chem. 2006, 4, 3311. (c)Donner,
C. D.; Gill, M. J. Chem. Soc., Perkin Trans. 1 2002, 938.
(7) Iwai, Y.; Kora, A.; Takahashi, Y.; Hayashi, T.; Awaya, J.;
Masuma, R.; Oiwa, R.; Omura, S. J. Antibiot. 1978, 31, 959.
(8) Omura, S.; Tsuzuki, K.; Iwai, Y.; Kishi, M.; Watanabe, S.;
Shimizu, H. J. Antibiot. 1985, 38, 1447.
IR (neat): 2932, 1769, 1655, 1146, 1088, 1044, 907 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.89 (t, J = 7.4 Hz, 3 H), 1.26 (m,
1 H), 1.42 (m, 1 H), 1.82 (m, 1 H), 1.94 (m, 1 H), 2.71 (d, J = 17.5
Hz, 1 H), 2.86 (dd, J = 17.5, 4.6 Hz, 1 H), 4.29 (dd, J = 4.6, 2.5 Hz,
1 H), 4.61 (m, 1 H), 5.11 (m, 1 H), 6.80 (d, J = 10.2 Hz, 1 H), 6.86
(d, J = 10.2 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.9, 18.1, 35.4, 37.2, 69.3, 70.9,
71.6, 133.4, 136.2, 137.2, 147.6, 174.3, 184.0, 185.8.
GC-MS: m/z (%) = 264.1 ([M + 2]+, 13), 221.1 (100), 177.1 (91),
175.1 (30); tR = 34.37 min.
GC-MS: m/z (%) = 264.1 ([M + 2]+, 7), 262.1 (M+, 8), 221.1 (57),
220.0 (66), 177.1 (33), 175.1 (100), 161.1 (40); tR = 29.43 min.
HRMS: m/z [M + H]+ calcd for C14H15O5: 263.0914; found:
263.0913.
(9) (a) Toral-Barza, L.; Zhang, W.-G.; Huang, X.; McDonald, L.
A.; Salaski, E. J.; Barbieri, L. R.; Ding, W.-D.;
(3aR*,5R*,9bR*)-5-Propyl-3,3a,5,9b-tetrahydro-2H-furo[3,2-
c]isochromene-2,6,9-trione (3)
Krishnamurthy, G.; Hu, Y. B.; Lucas, J.; Bernan, V. S.; Cai,
P.; Levin, J. I.; Mansour, T. S.; Gibbons, J. J.; Abraham, R.
T.; Yu, K. Mol. Cancer Ther. 2007, 6, 3028. (b) Salaski, E.
J.; Krishnamurthy, G.; Ding, W.-D.; Yu, K.; Insaf, S. S.; Eid,
C.; Shim, J.; Levin, J. I.; Tabei, K.; Toral-Barza, L.; Zhang,
W.-G.; McDonald, L. A.; Honores, E.; Hanna, C.;
Yamashita, A.; Johnson, B.; Li, Z.; Laakso, L.; Powell, D.;
Mansour, T. S. J. Med. Chem. 2009, 52, 2181.
To 19 (4.0 mg, 13.7 mmol) in CH2Cl2 (0.5 mL) at –60 °C was added
1 M BBr3 in CH2Cl2 (70 mL, 70 mmol). The soln was allowed to
warm to r.t. then stirred for a further 1 h. H2O (2 mL) was added and
the mixture stirred vigorously for 30 min and extracted with CHCl3
(3 × 3 mL). The combined organic extracts were dried (MgSO4), fil-
tered, and concentrated in vacuo. The residual oil was dissolved in
MeCN (0.5 mL), cooled to 0 °C and CAN (19 mg, 0.03 mmol) in
H2O (0.1 mL) was added. After stirring for 5 min the soln was di-
luted with brine (5 mL) and extracted with CHCl3 (3 × 2 mL). The
combined organic extracts were dried (MgSO4), filtered, and con-
centrated in vacuo. Column chromatography (EtOAc–CHCl3 2:1)
gave 3 (2.5 mg, 69%) as a pale yellow solid. The 1H and 13C NMR
data were in agreement with the literature.10b
(10) (a) Kraus, G. A.; Li, J.; Gordon, M. S.; Jensen, J. H. J. Am.
Chem. Soc. 1993, 115, 5859. (b) Kraus, G. A.; Li, J.;
Gordon, M. S.; Jensen, J. H. J. Org. Chem. 1995, 60, 1154.
(11) Xu, Y.-C.; Roy, C.; Lebeau, E. Tetrahedron Lett. 1993, 34,
8189.
(12) Magnus, P.; Eisenbeis, S. A.; Magnus, N. A. J. Chem. Soc.,
Chem. Commun. 1994, 1545.
(13) Jansen, R. J.; de Gelder, R.; Rowan, A. E.; Scheeren, H. W.;
Nolte, R. J. M. J. Org. Chem. 2001, 66, 2643.
(14) Tatsuta, K.; Suzuki, Y.; Toriumi, T.; Furuya, Y.; Hosokawa,
S. Tetrahedron Lett. 2007, 48, 8018.
IR (neat): 2930, 1781, 1659, 1197, 1150 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.92 (t, J = 7.4 Hz, 3 H), 1.63 (m,
4 H), 2.68 (d, J = 17.7 Hz, 1 H), 2.92 (dd, J = 17.7, 5.3 Hz, 1 H),
4.57 (dd, J = 5.3, 3.0 Hz, 1 H), 4.75 (m, 1 H), 5.09 (d, J = 3.0 Hz, 1
H), 6.81 (d, J = 10.3 Hz, 1 H), 6.86 (d, J = 10.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.5, 19.4, 33.6, 36.8, 66.2, 68.4,
69.6, 132.2, 136.5, 136.6, 146.9, 173.9, 184.3, 185.2.
GC-MS: m/z (%) = 264.1 ([M + 2]+, 14), 221.1 (100), 177.1 (75),
175.1 (27); tR = 35.09 min.
GC-MS: m/z (%) = 264.1 ([M + 2]+, 13), 262.1 (M+, 7), 221.1 (100),
220.0 (33), 177.1 (95), 175.1 (65); tR = 30.51 min.
HRMS: m/z [M + H]+ calcd for C14H15O5: 263.0914; found:
263.0914.
(15) Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem. 2002,
67, 5842.
(16) For ease of comparison in the discussion the same
numbering system is used for structures 19 and 20 in
Scheme 4. However, the IUPAC name and numbering for 19
are given in the experimental section and depicted in
Scheme 5.
(17) (a) Lee, E.; Tae, J. S.; Lee, C.; Park, C. M. Tetrahedron Lett.
1993, 34, 4831. (b) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim,
1996.
Synthesis 2010, No. 3, 415–420 © Thieme Stuttgart · New York