Synthesis of racemic frenolicin B and 5-epi-frenolicin B via intramolecular palladium-catalyzed aryloxycarbonylation

Article abstract of DOI:10.1055/s-1999-3482

A synthesis of the pyranonaphthoquinone antibiotic (±)-frenolicin B [(±)-1] is described. Key step is the intramolecular palladium-catalyzed aryloxycarbonylation of the 2-allyl-1-naphthol derivatives 8a,b to give the tricyclic γ-lactones 6a,b. Only the former (6a) is converted successfully into (±)-deoxyfrenolicin, the immediate precursor of (±)-1.

Full text of DOI:10.1055/s-1999-3482

PAPER
821
Synthesis of Racemic Frenolicin B and 5-epi-Frenolicin B via Intramolecular
Palladium-Catalyzed Aryloxycarbonylation
a
b
a
b
c,1
Pierre Contant, Martin Haess, Johann Riegl, Michelangelo Scalone,* Mike Visnick*
a
Vitamins Division, F. Hoffmann-La Roche AG, CH-4070, Basel, Switzerland
b
Pharmaceuticals Division, Process Research, F. Hoffmann-La Roche AG, CH-4070, Basel, Switzerland
F. Hoffmann-La Roche Inc. Nutley, New Jersey, 07110-1199, USA
c
E-Mail: michelangelo.scalone@roche.com; mike.visnick@wl.com
Received 14 October 1998; revised 4 December 1998
dimethoxy (a) and the acetonide (b) protecting group
were examined.
Abstract: A synthesis of the pyranonaphthoquinone antibiotic (±)-
frenolicin B [(±)-1] is described. Key step is the intramolecular pal-
ladium-catalyzed aryloxycarbonylation of the 2-allyl-1-naphthol
derivatives 8a,b to give the tricyclic g-lactones 6a,b. Only the
former (6a) is converted successfully into (±)-deoxyfrenolicin, the
immediate precursor of (±)-1.
Key words: rac-frenolicin B, rac-5-epi-frenolicin B, rac-deoxyfre-
nolicin, palladium-catalyzed aryloxycarbonylation
Frenolicin B (1), a metabolite of Streptomyces roseoful-
2
,3
vus, belongs to the pyranonaphthoquinone family of an-
tibiotics, other representatives of which are deoxy-
frenolicin (2), kalafungin (3) and isoeleutherin (4) (Figure
4
1
).
Scheme 1
The structure of 1 has been assigned by chemical correla-
tion as well as spectral comparison with other members of
11
this natural product class. To date, however, no crystal
1
2
structure of frenolicin B has been published. When a
sample of natural 113 was dissolved in hot methanol and
subsequently cooled to ambient temperature, crystals suit-
able for X-ray analysis were obtained. The view of a sin-
gle molecule of 1 confirms the original assignment with
regard to the relative stereochemistry of the C-3a, C-5 and
Figure 1. Representative pyranonaphthoquinone natural products
1
1
C-11b stereogenic centers (Figure 2). To assign the ab-
solute stereochemistry of 1 its optical rotary dispersion
spectrum was compared with that of isoeleutherin and
5
The interesting biological activity of 1 and 2 has led to
6
,7
the development of several syntheses. Our synthetic
strategy to racemic 1 is outlined in Scheme 1. Construc-
tion of the pyran ring system of racemic deoxyfrenolicin
14
kalafungin. The absolute stereochemistry for isoeleuth-
erin has previously been assigned as 2R and 10R through
15
a classical degradation study. The positive Cotton effect
2
,8
[
(±)-2], the immediate precursor of (±)-1, is achieved
observed for frenolicin B establishes its absolute stereo-
chemistry as 3aR, 5R, and 11bR.
from the hydroxy ester (±)-5, which can be prepared from
9
the tricyclic dihydronaphthofuran (±)-6. Key step for the
To initiate our synthesis, we prepared 8a and 8b from ju-
glone (7) as outlined in Scheme 2. O-Methylation of 7
with methyl iodide and silver oxide followed by reduction
of the intermediate 9 with sodium dithionite afforded the
hydroquinone intermediate 10. Subsequent O-allylation at
synthesis of 6 is the palladium- catalyzed aryloxycarbon-
1
0
ylation of the 2-allyl-1-naphthol derivative 8. In order to
remain flexible and circumvent instability problems in
any step of the synthesis, both series containing the
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

8
22
P. Contant et al.
PAPER
Table Palladium-Catalyzed Aryloxycarbonylation of 8a, 8b
En-
try
Sub-
strate
Con-
di-
%
Yield (%)b
Con-
ver-
sion
6
a,b
14a,b
15a,b
tionsa
1
2
3
4
8a
8a
8b
8b
A
B
A
B
95
100
95
38
31
40
0
0
0
20
0
12
0
6
Figure 2. X-ray crystallographic structure of 1
100
0
a
A: 200% Pd(OAc) /Et N/Me C(OMe) ; B: 10% PdCl /10% CuCl /
2
3
2
2
2
2
1
10% Chloranil.
Isolated yield.
b
C-1 and methylation of the phenolic group at C-4 afforded
the allyl ether 12, which was converted into 8a by Claisen
rearrangement in DMF. On the other hand, reduction of 7
with sodium dithionite followed by ketalization and O-al-
lylation at C-1 gave 13, which was converted into 8b by
Claisen rearrangement.
from 8b in 40% yield under a CO atmosphere only when
a two-fold amount of palladium(II) acetate was used (Ta-
ble, Entry 3). The addition of 2,2-dimethoxypropene and
triethylamine reduced the side reactions resulting from the
cleavage of the acetal group. As side products the β-hy-
dride elimination products 14b and 15b were isolated.
With palladium(II) in catalytic amounts only decomposi-
tion was observed (Table, Entry 4). On the other hand,
with 8a as substrate both catalytic and stoichiometric
amounts of palladium(II) afforded the desired product 6a,
albeit in moderate yield (Table, Entries 1 and 2). Remark-
ably, under catalytic conditions none of the β-hydride
elimination side products 14a and 15a were observed. Un-
fortunately, all attempts to increase the yield of 6a or 6b
by varying either the solvent, the substrate-to-palladium
ratio or the secondary oxidant remained unsuccessful.
We found that the oxidative ring opening of 6b to the 1,4-
naphthoquinone 5 by treatment with cerium(IV) ammoni-
um nitrate (CAN) according to a reported procedure18
gave capricious results with yields of 5 ranging from 20 to
5
9%. In contrast, the oxidative ring opening of 6a pro-
ceeded uneventfully to afford the methoxy-
naphthoquinone 16 in 76% yield (Scheme 3). The
subsequent reduction of 16 to the air sensitive hydro-
quinone 17 set the stage for the ensuing pyran ring annu-
lation.
Reagents and conditions: a) MeI/Ag O/CH Cl (ca 100%); b)
2
2
2
Na S O /EtOAc (99%); c) allyl bromide/K CO /acetone, reflux
2
2
4
2
3
(
88%); d) Me SO /40% aq NaOH (90%); e) DMF, 140°C (88%); f) i. The literature contains numerous reports describing the
2 4
Na S O /EtOAc, ii. Me C(OMe )/BF OEt ; g) allyl bromide/K CO / condensation of hydroquinones with aldehydes as a gen-
2
2
4
2
2
3•
2
2
3
acetone, reflux (52%); h) neat, 130°C (87%)
eral synthetic route to fused pyran rings. Most germane to
the present work is the study by Li and Ellison in which
they prepared the pyranonaphthoquinone nanaomycin A
by this route. Preliminary experiments in our laboratory
showed that condensation of 17 with butyraldehyde fol-
lowed by CAN-oxidation afforded the 1,3-cis diastere-
omer 22 as the product of kinetic control (Schemes 4 and
Scheme 2
19
Palladium-catalyzed aryloxycarbonylation reactions have
been already employed for the synthesis of naphthoquin-
1
6,17
one antibiotics.
We found that 6b could be obtained
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Frenolicin B and 5-epi-Frenolicin B
823
cessed further uneventfully. In sharp contrast to reports in
the literature,16 we observed that demethylation of 22 or
2
3 with boron tribromide at –78°C led to rapid equilibra-
tion of these pyran ring diastereomers. Fortunately, use of
the more moderate Lewis acid boron trichloride effected
smooth demethylation to the free naphthoquinones 24 and
2
5 without epimerization. Typically, 24 and 25 were pre-
pared from 17 save isolation of any intermediates
Scheme 4). The pure cis-ester 25 was isolated from the
(
kinetically controlled reaction in 47% overall yield by
fractional crystallization of the mixture of diastereomers
richer in 22. Similarly, the trans-ester 24 was isolated in
2
6% overall yield from the reaction mixture richer in 23
due to equilibration. Both compounds 24 and 25 were ob-
tained in >99% isomeric purity according to capillary gas
chromatographic analysis.
Scheme 3
To complete the synthesis of racemic frenolicin B, the
trans-ester 24 was saponified to afford racemic deoxyfre-
nolicin [(±)-2] (Scheme 6). Subsequent oxidative cycliza-
5
), the ratio between 22 and 23 being 5.2:1. On the other
hand, if the reaction mixture reached equilibrium, the
product consisted of a 1:3.5 mixture of 22 and 23.
tion in methanol/pyridine gave racemic frenolicin B [(±)-
1
1
], identical by 400 MHz H NMR to the material isolated
from natural sources. In a similar fashion the previously
unknown racemic 5-epi-frenolicin B [(±)-27] was pre-
pared from cis-ester 25. The reported procedure for the
23
conversion of (±)-1 to its 5-epi isomer (±)-27 could not
be reproduced.
Melting points were taken on a Buchi SMP-20 apparatus and are not
1
corrected. H NMR spectra were recorded on Bruker AC-250 and
AM-400 with TMS as internal standard. Chemical shifts are report-
ed for signal centers, J values are in Hz. IR spectra were obtained
on a Nicolet 170 SX FT IR spectrometer. MS spectra were obtained
either by electron ionization on an AEI MS9 instrument or by chem-
ical ionization on a VG 7070 F. Column chromatography, unless
otherwise noted, was performed on Merck 60 silica gel, 230–400
mesh, under flash chromatographic conditions. Analytical gas chro-
matographic analyses were performed on a Perkin-Elmer Per-
maphase PVMS/54 0.3 micron fused silica column (25 m with ID =
Reagents and conditions: Me(CH ) CHO/HCl, 25°C, 3 h; b) CAN/
2
2
0
.32 mm), or on a 5% OV 17 or GCQ (2 m with ID = 2.2 mm).
CH Cl (Æ 22/23 = 5.2:1); c) BCl /CH Cl ; d) fractional crystallizati-
2
2
3
2
2
on, hexane/EtOAc; e) Me(CH ) CHO/HCl, 25°C, 8 h; f) CAN/
2
2
5
-Methoxynaphthalene-1,4-diol (10)
CH Cl (Æ 22/23 = 1:3.5)
2
2
A mixture of 7 (50.0 g, 0.287 mol), MeI (80.0 g, 0.563 mol) and
Scheme 4
Ag O (55 g, 0.237 mol) in CH Cl (900 mL) was stirred under N
2
2
2
2
for 22 h at r.t. Additional MeI (34 g, 0.239 mol) and Ag O (55 g,
2
0
.237 mol) were then added and the mixture stirred for additional 3
h. Afterwards, the mixture was filtered through dicalite, the cake
Scheme 5. Pyran ring annulation leads initially to 19 with washed with CH Cl and the combined filtrates evaporated to give
A mechanism consistent with these results is shown in
2
2
the propyl and methoxycarbonylmethyl side chains in fa- 54.5 g (ca 100%) of 5-methoxy-1,4-naphthoquinone (9) as dark red
2
4,25
crystals; mp 184°C (Lit.
100 g, 0.531 mol) in EtOAc (6 L) was added to a solution of
Na S O (780 g 4.48 mol) in H O (8 L). The resulting biphasic so-
mp 189°C). A solution of this material
vorable pseudo equatorial relationships relative to one an-
other. Keto-enol tautomerization to 20 followed by
oxidation gives the 1,4-naphthoquinone 22. In contrast, if
(
2
2
4
2
lution was stirred vigorously for 0.5 h, the organic layer separated,
and the aqueous layer extracted with EtOAc (3 î 2 L). The com-
bined organic layers were washed with H O (3 î 2 L), dried
2
0 is allowed to equilibrate via a retro-Michael/Michael
2
0
addition at C1 or C3, the trans isomer 21 is expected to
2
prevail due to more severe circumstances of 1,3-allylic (Na SO ) and evaporated. The resulting solid was dried under high
2
4
2
1
strain in 20 versus 21. The practical separation of com- vacuum at r.t. for 48 h to afford 100g (99%) of 10 as a light-brown,
air sensitive solid; mp >100°C (dec).
pounds 22 and 23 by fractional crystallization or column
–
1
chromatography proved elusive due to their poor air and IR (KBr): ν = 1637, 1609, 1415,1049, 749 cm .
thermal stability.2 Experimentally this problem was
2
1
H NMR (DMSO-d ): δ = 4.00 (s, 3 H), 6.58 (d, J = 8.2 Hz, 1 H),
solved by direct conversion of 22 and 23 to the free naph- 6.73 (d, J = 8.2 Hz, 1 H), 6.93 (d, J = 7 Hz, 1 H), 7.31 (t, J = 7 Hz,
thoquinones 24 and 25, respectively, which could be pro- 1 H) 7.65 (d, J = 7 Hz, 1 H), 8.79 (s, 1 H), 9.40 (s, 1 H).
6
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

8
24
P. Contant et al.
PAPER
Scheme 5
Scheme 6
MS: m/z = 190 (M+).
IR (KBr): n = 3382, 1630, 1600, 1029, 756 cm .
–1
1
Anal. Calcd for C H O : C, 69.46; H, 5.30. Found: C, 69.08; H,
H NMR (CDCl ): δ = 4.03 (s, 3 H), 4.62 (m, 2 H), 5.29 (m, 1 H),
11
10
3
3
5
.39.
5.47 (m, 1 H), 6.15 (m, 1 H), 6.76 (s, 2 H), 6.80 (d, J = 6.8 Hz, 1 H),
7
.32 (dd, J = 6.8, 5.8 Hz, 1 H), 7.81 (d, J = 5.8 Hz, 1 H), 8.96 (s, 1
H).
4
-Allyloxy-8-methoxy-1-naphthol (11a)
A mixture of 10 (25 g, 0.131 mol), anhyd K CO (36.3 g, 0.263 mol)
MS: m/z = 230 (M+).
2
3
and allyl bromide (47.7 g, 0.394 mol) in acetone (500 mL) was re-
fluxed for 14 h. After filtering off the solids, the mother liquor was
evaporated to dryness to afford 32.8 g of a brown solid. Dissolution
of this solid in EtOAc (250 mL), washing this solution with brine,
drying (Na SO ) and concentration afforded crude 11a (30.1 g) as a
Anal. Calcd for C H O : C, 73.03; H, 6.13. Found: C, 73.32; H,
1
4
14
3
6
.36.
1
-Allyloxy-4,5-dimethoxynaphthalene (12)
2
4
To a solution of 11a (26.2 g, 0.114 mol) and dimethyl sulfate (14.5
g, 0.114 mol) in dioxane (750 mL) was added under N , at r.t. and
with vigorous stirring, 40% aq NaOH (440 mL, 4.40 mol) within 10
min. The mixture was stirred for additional 12 h at r.t., diluted with
dark beige crystalline material. Silica gel chromatography (hexane/
EtOAc, 9:1) yielded 11a (26.8 g, 88%) as a yellow crystalline com-
pound; mp 101–102°C.
2
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Frenolicin B and 5-epi-Frenolicin B
MS: m/z = 256 (M+).
825
H O (1.5 L), and the aqueous layer extracted with CH Cl (4 î 250
2
2
2
mL). The combined organic extracts were washed with brine (4 î
50 mL), dried (Na SO ) and concentrated to afford crude 12 (27.8
g) as a brown solid. Silica gel chromatography (10% EtOAc in hex-
Anal. Calcd for C H O : C, 74.98; H, 6.29. Found: C, 74.57; H,
1
6
16
3
2
2
4
6
.27.
ane) yielded 12 (24.9 g, 90%) as a beige crystalline compound; mp
Methyl rac-8,9-Dihydro-5,5-dimethylfuro[3’,2’:3,4]naph-
tho[1,8-de][1,3]dioxin-9-acetate (6b, Stoichiometric Conditions)
1
03°C.
–
1
IR (KBr); ν = 1593, 1280, 803, 756 cm .
A mixture of 8b (0.50 g, 1.95 mmol), Pd(OAc) (878 mg, 3.90
2
1
mmol), Et N (0.41 mL, 2.95 mmol), acetone dimethylacetal (0.36
H NMR (CDCl ): δ = 3.91 (s, 3 H), 3.97 (s, 3 H), 4.65 (m, 2 H),
3
3
mL, 3.90 mmol) in toluene/MeOH (1:1, 25 mL) was stirred at 35°C
for 30 min under 1.1 bar of CO atmosphere. The black palladium
precipitate was filtered and the filtrate concentrated on an evapora-
tor. Silica gel chromatography (5% hexane in EtOAc) of the dark
oily residue (0.86 g) afforded 6b (260 mg, 40%) as a light tan oil.
An analytical sample was obtained by crystallization from hexane
5
=
.32 (m, 1 H), 5.51 (m, 1 H), 6.16 (m, 1 H), 6.72 (s, 2 H), 6.75 (d, J
5.8 Hz, 1 H), 7.34 (t, J = 5.8 Hz, 1 H), 7.90 (d, J = 5.8 Hz, 1 H).
MS: m/z = 244 (M+).
Anal. Calcd for C H O : C, 73.75; H, 6.60. Found: C, 73.72; H,
6
15
16
3
.56.
9
affording 0.7 g of pure 6b as light tan crystals; mp 76–78°C (Lit.
bp 160–165°C/1 Torr).
2
-Allyl-4,5-dimethoxy-1-naphthol (8a)
A solution of 12 (6.95 g, 2.80 mmol) in DMF (10 mL) was heated
Anal. Calcd for C H O : C, 68.78; H 5.77, Found: C, 68.75; H,
5.77.
1
8
18
5
to 140°C for 4 h under N . Afterwards, DMF was removed in vacuo
2
at 70°C and the residue chromatographed on silica gel (10% EtOAc
in hexane) to afford 8a (6.10 g, 88%) as a beige crystalline com-
pound; mp 100–101°C.
Methyl rac-2,3-Dihydro-5,6-dimethoxynaphtho[1,2-b]furan-2-
acetate (6a, Catalytic Conditions)
–
1
IR (KBr): ν = 3301, 1587, 1513, 1237, 1204 cm .
A mixture of PdCl (349 mg, 1.96 mmol), CuCl (263 mg, 1.96
2
2
1
mmol) and chloranil (5.32 g, 21.6 mmol) in toluene/MeOH (9:1, 60
mL) was vigorously stirred at r.t. under 1.1 bar of CO atmosphere
for 30 min, whereby an abundant yellow-orange precipitate formed.
A solution of 8a (4.78 g, 19.6 mmol) in toluene/MeOH (9:1, 60 mL)
was rapidly added. The mixture turned red-brown within 5 min, was
stirred for 1 h, filtered through a short silica gel pad and evaporated
to dryness. The resulting dark brown residue (12.46 g) was dis-
H NMR (CDCl ): δ = 3.53 (m, 2 H), 3.91 (s, 3 H), 3.97 (s, 3 H),
3
5
1
7
.12 (br s, 1 H), 5.20 (m, 1 H), 5.26 (m, 1 H), 6.05 (m, 1 H), 6.62 (s,
H), 6.85 (d, J = 7.76 Hz, 1 H), 7.38 (dd, J = 7.76, 8.44 Hz, 1 H),
.70 (dd, J = 8.44, 1.0 Hz, 1 H).
MS: m/z = 244 (M+).
Anal. Calcd for C H O : C, 73.75; H, 6.60. Found: C, 73.75; H,
6
15
16
3
solved in toluene/Et O (1:1, 100 mL) and extracted with 0.1 N aq
.71.
2
NaOH solution (6 î 100 mL). The organic phase was dried
(
MgSO ) and evaporated to dryness. The dark oily residue (5.43 g)
4
6
5
-Allyloxy-2,2-dimethylnaphtho[1,8-de]-[1,3]-dioxin (13)
-Hydroxy-1,4-naphthoquinone (7) was reduced with aqueous so-
was chromatographed on silica gel (hexane/Et O, 2:1) affording 6a
(
by crystallization from MeOH at –18°C to give 6a as light tan crys-
tals; mp 115–116°C.
2
1.87 g, 31%) as a light tan solid. An analytical sample was obtained
dium dithionite and then ketalized with 2,2-dimethoxypropane ac-
cording to
dimethylnaphtho[1,8-de]-[1,3]-dioxin-6-ol (11b) as a yellow oil. A
solution of 11b (0.8 g, 3.7 mmol) in acetone (10 mL) was treated un-
der argon with allyl bromide (1.34 g, 11.0 mmol) and K CO (0.5 g,
9
a
published procedure
to afford 2,2-
–
1
IR (KBr): ν = 1723s, 1588m, 1262s, 1201 cm .
2
3
1
H NMR (CDCl ): δ = 2.83 (dd, J = 16.0, 6.9 Hz, 1 H), 2.97 (dd, J
3
3
.7 mmol). The mixture was refluxed for 24 h, after which time ad-
=
1
(
7
16.0, 6.8 Hz, 1 H) 3.08 (dd, J = 15.6, 6.4 Hz, 1 H), 3.57 (dd, J =
5.6, 8.8 Hz, 1H), 3.74 (s, 3 H), 3.90 (s, 3 H), 3.97 (s, 3 H), 5.32
dddd, J = 6.9, 6.4, 6.8, 8.8, 1 H), 6.78 (s, 1H), 6.85 (bd, J = 8.0, 1H);
.37 (dd, J = 7.8, 8.0, 1H); 7.50 (dd, J = 8.0, 1.0, 1H).
ditional allyl bromide (0.3 mL, 3.7 mmol) was added and reflux
continued for 12 h. Afterwards, the mixture was filtered through
Celite and concentrated. EtOAc (100 mL) was added and the solu-
tion washed with brine (20 mL). The organic layer was dried
MS: m/z = 302 (M+).
(Na SO ) and concentrated to give 0.7 g of a brown oil. Chromatog-
2 4
raphy on silica gel (2% EtOAc in hexane) afforded 13 (0.5 g, 52%)
as a light brown oil.
Anal. Calcd. for C H O : C, 67.54; H, 6.00. Found: C, 67.44; H,
1
7
18
5
6
.03.
–
1
IR (KBr): ν = 1610, 1417, 1025, 750 cm .
1
Methyl rac-2,3-Dihydro-5,6-dimethoxy-naphtho[1,2-b]furan-2-
acetate (6a, Stoichiometric Conditions)
H NMR (CDCl ): δ = 1.64 (s, 6 H), 4.66 (m, 1 H), 5.32 (m, 1 H),
.49 (m, 1 H), 6.17 (m, 1 H), 6.74 (s, 2 H), 6.90 (dd, J = 7.8, 1 Hz,
H), 7.8 (dd, J = 8.5, 1 Hz, 1 H).
3
5
1
A mixture of 8a (425 mg, 1.0 mmol), Pd(OAc) (576 mg, 2.52
2
mmol), Et N (0.21 mL, 1.5 mmol) in toluene/MeOH (1:1, 25 mL)
3
MS: m/z = 256 (M+).
was stirred at r.t. under 1.1 bar of CO atmosphere for 22 h. The mix-
ture was worked up and purified as above to afford 6a (114 mg,
Anal. Calcd for C H O : C, 74.98; H, 6.29. Found: C, 74.90; H,
16
16
3
3
8%) as light tan crystals; mp 115–116°C.
6
.44.
Methyl rac-1,4-Dihydro-b-hydroxy-5-methoxy-1,4-dioxo-2-
naphthalenebutyrate (16)
To a solution of 6a (90 mg, 0.30 mmol) in MeCN (1.5 mL) was add-
5
-Allyl-2,2-dimethylnaphtho[1,8-de][1,3]dioxin-6-ol (8b)
Neat 13 (5.2 g, 3.9 mmol) was heated at 130°C under argon for 5 h.
Chromatography of the residue on silica gel (5% EtOAc in hexane)
afforded 8b (4.7 g, 87%) as a colorless oil.
ed at r.t. under N a solution of CAN (406 mg, 0.75 mmol) in H O
2
2
(1.5 mL) dropwise over 2 min. The mixture was stirred for 5 min at
–
1
IR (KBr): ν = 3506, 1614, 1410, 1200, 754 cm .
r.t., diluted with brine (5 mL) and extracted with EtOAc (2 î 10
1
H NMR (CDCl ): δ = 1.63 (s, 6 H), 3.52 (m, 2 H), 5.13 (s, 1 H),
mL). The organic extracts were combined, dried (MgSO ), concen-
3
4
5
.20 (m, 1 H), 5.26 (m, 1 H), 6.1 (m, 1 H), 6.63 (s, 1 H), 6.81 (dd, J
trated and chromatographed on silica gel (EtOAc/hexane, 1:1) to af-
=
1
7.8, 1.0 Hz, 1 H), 7.40 (dd, J = 7.8, 8.7 Hz, 1 H), 7.63 (dd, J = 8.7,
Hz, 1 H).
ford 16 (68 mg, 76%) as a yellow crystalline compound.
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

8
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P. Contant et al.
PAPER
Crystallization from EtOAc/hexane gave an analytical sample; mp
Anal. Calcd for C H O : C, 66.27; H, 5.85. Found: C, 66.28; H,
5.91.
1
9
20
6
9
1
27°C (Lit. mp 130–132°C).
Anal. Calcd for C H O : C, 63.15; H, 5.30. Found: C, 62.95; H,
16
16
6
Methyl rac-trans-9-Hydroxy-5,10-dioxo-1-propyl-3,4,5,10-tet-
rahydro-1H-naphthol[2,3-c]pyran-3-acetate (24)
5
.34.
Anhyd HCl gas was gently bubbled through Et O (23 mL) for 10
min at r.t., then 17 (2.2 g, 7.18 mmol) and butyraldehyde (2.2 mL,
2
Methyl rac-ß-1,4,10-Trihydroxy-5-methoxy-2-naphthalenebu-
tyrate (17)
2
4.9 mmol) were added and the stirring was continued for 8 h at r.t.
To a solution of 16 (4.80 g, 16.0 mmol) in dioxane/Et O (1:1, 360
2
Analogous workup as above afforded the crude intermediate which
mL) was added 18% aq HCl (60 mL) followed by activated zinc (10
g) portionwise over a period of 30 min while maintaining the reac-
tion temperature between 0 and 8°C. The color of the mixture
changed from deep yellow to almost colorless during the zinc addi-
was reacted with CAN (13.2 g, 24 mmol) in H O (60 mL). After
2
workup a crude 3.5:1 mixture of 23 and 22 was obtained. Treatment
of this mixture with BCl and workup as above afforded pure 24
3
(
640 mg, 26%, > 99% pure by GC analysis) as yellow needles after
tion. Afterwards the mixture was extracted under N with EtOAc (3
2
26
crystallization (EtOAc/hexane); mp 135–136°C (Lit. mp 134–
36°C).
î 100 mL). The combined organic layers were washed with brine
1
and satd NaHCO solution, dried (MgSO ) and evaporated to afford
3
4
crude 17 (5.1 g) as a yellow solid. This solid was triturated with
Anal. Calcd for C H O : C, 66.27; H, 5.85. Found: C, 66.46; H,
19 20 6
Et O (3 î 30 mL) and dried at high vacuum, affording 17 (3.68g,
5.76.
2
7
5%) as a beige powder; mp > 150°C (dec).
–
1
rac-cis-9-Hydroxy-5,10-dioxo-1-propyl-3,4,5,10-tetrahydro-
H-naphtho[2,3-c]pyran-3-acetic Acid [(±)-26, rac-5-epi-Deoxy-
frenolicin]
IR (KBr): ν = 3376, 1715, 1619, 1171, 1062 cm .
1
1
H NMR (CDCl ): δ = 2.50 (m, 2 H), 2.76 (dd, J = 15, 2.6 Hz, 1 H),
3
3
.05 (dd, J = 15, 2.2 Hz, 1 H), 3.68 (s, 3 H), 4.03 (s, 3 H), 4.42 (br
s, 1 H), 4.46 (m, 1 H), 6.53 (s, 1 H), 6.76 (d, J = 7.6 Hz, 1 H), 7.30
dd, J = 8.8, 7.6 Hz, 1 H) 7.90 (dd, J = 8.8, 1.0 Hz, 1 H), 8.42 (s, 1
A solution of 25 (270 mg, 0.782 mmol) in THF/H O (3:1, 95 mL)
2
was treated at r.t. under N with LiOH◊H O (656 mg, 15.6 mmol)
2
2
(
and the resulting purple mixture was stirred at r.t. After 6 h, the so-
lution was acidified to pH 2–3 with 1 N aq HCl (20 mL). The aque-
ous phase was separated and extracted with EtOAc, the combined
H), 8.75 (s, 1 H).
MS: m/z = 306 (M+).
organic phases were washed with brine, dried (MgSO ) and concen-
trated to give crude (±)-26 (293 mg) as a brownish-yellow solid. An
analytical sample was prepared by crystallization from benzene and
4
Anal. Calcd for C H O : C, 62.74; H, 5.92. Found: C, 62.91; H,
16
18
6
5
.88.
subsequent washing of the red-brown crystals with cold Et O; mp
2
Methyl rac-cis-9-Hydroxy-5,10-dioxo-1-propyl-3,4,5,10-tet-
rahydro-1H-naphtho[2,3-c]pyran-3-acetate (25)
27
1
62–165°C (Lit. mp 167–183°C).
Anal. Calcd for C H O : C, 65.45; H, 5.49. Found: C, 65.62; H,
Anhyd HCl gas was gently bubbled through Et O (23 mL) for ca 5
18 18
6
2
5
.61.
min at r.t., then 17 (800 mg, 2.61 mmol) and butyraldehyde (0.80
mL, 9.07 mmol) were added all at once and the mixture stirred un-
der N at r.t. Within 10 min the initial grey suspension had devel-
rac-trans-9-Hydroxy-5,10-dioxo-1-propyl-3,4,5,10-tetrahydro-
1H-naphtho-[2,3-c]pyran-3-acetic Acid [(±)-2, rac-Deoxyfreno-
licin]
2
oped into a pink-red homogeneous solution. After 3 h the mixture
was poured into brine (20 mL) and extracted with EtOAc (3 î 40
mL). The combined extracts were washed with H O (20 mL), dried
The same procedure described above for the preparation of (±)-26
afforded (±)-2 from 24 as yellow crystals after recrystallization
2
(
MgSO ), filtered and evaporated to give 1.2 g of an oil which was
4
1
7
dissolved in MeCN (25 mL) and treated with a solution of CAN (5.0
from benzene/CHCl (3:1); mp 214–216°C (Lit. mp 200–204°C).
3
g, 9.1 mmol) in H O (25 mL). After 10 min at r.t. brine (20 mL) was
added and the mixture extracted with EtOAc. The organic layers
2
Anal. Calcd. for C H O : C, 65.45; H, 5.49. Found: C, 65.56; H,
1
8
18
6
5
.59.
were combined, dried (MgSO ) and evaporated to afford 1.4 g of a
4
yellow red oil containing a 5.2:1 mixture of 22 and 23. This oil was
dissolved in CH Cl (20 mL), cooled to –78°C and treated with a 1
rac-7-Hydroxy-5-propyl-3,3a,5,11b-tetrahydro-2H-furo[3,2-
b]naphthol[2,3-d]pyran-2,6,11(3H,5H)-trione [(±)-1, rac-Freno-
licin B]
2
2
M solution of BCl in CH Cl (4.0 mL, 4.0 mmol) dropwise over 15
3
2
2
min. After stirring at –78°C for 20 min, the mixture was slowly
warmed to 0°C (15–20 min) and poured into ice-cold 5% aq
NaHCO solution (50 mL). CH Cl (100 mL) was added and after
A solution of (±)-2 (65 mg, 0.197 mmol) in MeCN (3 mL), MeOH
(5 mL) and pyridine (0.25 mL) in a thick-walled glass tube was sat-
3
2
2
urated with oxygen during 10 min. Afterwards, the tube was sealed
and heated at 70°C for 2 h, after which time the mixture was re-
charged with oxygen and heated for an additional 2.5 h. Evapo-
ration of the solvent and chromatography of the residue on silica gel
stirring for 1 h at r.t. the aqueous phase was separated and extracted
with CH Cl (4 î 35 mL). The combined organic extracts were dried
2
2
(
MgSO ) and concentrated in vacuo to give a yellow oil (1.15 g).
4
Chromatography on silica gel (30% EtOAc in hexane) afforded a
.2:1 mixture of 25 and 24 (580 mg, GC analysis) as a yellow semi-
solid material. One crystallization from hexane/EtOAc gave pure 25
420 mg, 47%) as light yellow needles; mp 97–99°C.
(1:3 EtOAc/hexane) afforded (±)-1 (45 mg, 75%) as an orange-red
5
solid. Crystallization from MeOH gave an analytical sample as red
2
6
needles; mp >197°C (dec).
(
–
1
IR (KBr): ν = 3432, 2962, 1784, 1650, 1154 cm .
–
1
IR (KBr): ν = 3444, 1734, 1639, 1248, 754 cm .
1
H NMR (CDC1 ): δ = 1.03 (t, J = 7.3 Hz, 3 H), 1.68 (m, 4 H), 2.70
1
3
H NMR (CDCl ): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.41 (m, 2 H), 1.76
3
(d, J = 17.7 Hz, 1 H), 3.01 (dd, J = 17.7, 5.2 Hz, 1 H), 4.62 (dd, J =
(
m, 1 H), 2.05 (m, 1 H), 2.30 (dd, J = 18.5, 4.0 Hz, 1 H), 2.62 (dd,
J = 15.5, 5.5 Hz, 1 H), 2.75 (dd, J = 15.5, 7.5 Hz, 1 H), 2.85 (dt, J =
8.5, 2.6 Hz, 1 H), 3.72 (s, 3 H), 3.90 (m, 1 H), 4.82 (m, 1 H), 7.25
dd, J = 7.4, 2.4 Hz, 1 H), 7.61 (m, 2 H), 12.0 (s, 1 H).
5
.2, 3.1 Hz, 1 H), 4.90 (dd, J = 9.77, 3.5 Hz, 1 H), 5.25 (d, J = 3.1
Hz, 1 H), 7.28 (m, 1 H), 7.66 (m, 2 H), 11.85 (s, 1 H).
MS: m/z = 328 (M+).
1
(
MS: m/z = 344 (M+).
Anal. Calcd for C18
.59.
H O : C, 65.85; H, 4.91. Found C, 65.51, H,
16 6
4
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Racemic Frenolicin B and 5-epi-Frenolicin B
827
rac-7-Hydroxy-5a-propyl-3,3a,5,11b-tetrahydro-2H-furo[3,2-
b]naphtho[2,3-d]pyran-2,6,11(3H,5H)-trione [(±)-27, rac-5-epi-
Frenolicin B]
A solution of (±)-26 (82 mg, 0.248 mmol) in MeOH (80 mL) and
pyridine (0.05 mL) was brought to reflux while passing a gentle
stream of oxygen. After 12 h the solvent was evaporated in vacuo to
afford 170 mg of a reddish-brown solid. Chromatography on silica
gel (EtOAc/hexane, 3:1) gave (±)-27 (37.6 mg, 46%) as red crys-
tals; mp 155–156°C.
Acknowledgement
We would like to thank U. Hengartner for his enthusiastic support
of this work and for helpful discussions as well as Prof. Sir J. Bald-
win for the discussions on the mechanism. We are also indebted to
the colleagues of the Structural Analysis Department at F. Hoff-
mann- La Roche AG for solving the crystal structure of frenolicin B
(P. Schönholzer, M. Hennig), for IR spectra (A. Bubendorf), NMR
(W. Arnold), MS (W. Vetter, W. Meister) and elemental analyses
(St. Müller, G. Nein).
–
1
IR (KBr): ν = 3494, 1789, 1667, 1455, 1151 cm .
1
H NMR (CDCl ): δ = 0.91 (t, J = 7.3 Hz, 3 H), 1.40 (m, 2 H), 2.0
3
References
(m, 2 H), 2.72 (d, J = 17.8 Hz, 1 H), 2.90 (dd, J = 17.8, 4.0 Hz, 1 H),
4
.32 (dd, J = 5.0, 3.0 Hz, 1 H), 4.77 (m, 1 H), 5.28 (dd, J = 3, 1.0
(
1) Present address: Parke-Davis Pharmaceutical Research, Ann
Hz, 1 H), 7.31 (m, 1 H), 7.65 (m, 2 H), 11.75 (s, 1 H).
MS: m/z = 328 (M+).
Arbor, MI 48105, USA.
(2) Iwai, Y.; Kora, Y.; Takahashi, T.; Hayashi, J.; Awaya, R.;
Masuma, R.; Orwa, R.; Omura S. J. Antibiotics 1978, 31, 959.
3) Ellestad, G.A.; Whaley, H.A.; Patterson, E.L. J. Am. Chem.
Soc. 1966, 88, 4109.
4) U. Graefe, Biochemie der Antibiotika, Spektrum
Akademischer Verlag: Heidelberg, 1992.
5) a) Block, D.E.;. Herrmann, T.E; Hsieh, J.-H.; Mehta, N.S.;
Rai, V.R. EP Appl. No. 702086, F. Hoffmann- La Roche AG
Anal. Calcd for C H O : C, 65.85; H, 4.91. Found: C, 65.53; H,
18
16
6
(
(
(
4
.93.
Methyl rac-cis-9-Methoxy-5,10-dioxo-1-propyl-3,4,5,10-tet-
rahydro-1H-naphtho[2,3-c]pyran-3-acetate ((±)-22)
A mixture of (±)-25 (100 mg, 0.291 mmol), Ag O (350 mg, 1.52
2
mmol) and MeI (114 mg, 0.80 mmol) was stirred in CH Cl (10 mL)
2
2
(1996); Chem. Abstr. 1996, 124, 258686.
at reflux for 3.5 h. The silver salts were then removed by filtration
through dicalite and the filter cake thoroughly washed with EtOAc
b) Nagakawa, A., Fukamachi, N., Yamachi, K., Hayashi, M.,
Ohishi, S., Kobayashi, B., Omura, S. J. Antibiot. 1987, 40,
(30 mL). Rotary evaporation of the filtrates and chromatography of
1075.
the residue on silica gel (30% to 50% EtOAc/hexane) afforded
crude (±)-22, which was crystallized from EtOAc/hexane to afford
c) Utawale, G.G., EP Appl. No. 709036, F. Hoffmann- La
Roche AG (1996); Chem. Abstr. 1996, 125, 9150.
d) Eisenbeins, H.G.; Miller, R.W.; Schildknecht, E.G., EP
Appl. No. 580059, F. Hoffmann- La Roche AG (1994);
Chem.Abstr. 1994, 120,162492.
(
1
±)-22 (85 mg, 82%) as yellow-brown cubic crystals; mp 145–
46°C (Lit.17 mp 146–147°C).
Anal. Calcd for C H O : C, 67.03; H, 6.19. Found: C, 67.77; H,
20
22
6
6
.25.
(6) a) Ichihara, A.; Ubukata, M.; Oikawa, H.; Murakami, K.;
Sakamura, S. Tetrahedron Lett. 1980, 21, 4469.
Methyl rac-trans-9-Methoxy-5,10-dioxo-1-propyl-3,4,5,10-tet-
rahydro-1H-naphtho[2,3-c]pyran-3-acetate [(±)-23]
The same procedure described for the preparation of the cis-isomer
b) Semmelhack, M.F.; Bozell, J.; Keller, L.; Sato, T.; Spiess,
E.J.; Wulff, W.; Zask, A. Tetrahedron 1985, 41, 5803.
(7) After our work had been completed two asymmetric syntheses
of 1 have appeared:
(
1
±)-22 afforded (±)-23 from (±)-24 as a fluffy yellow solid; mp
29–130°C (Lit.16 mp 134–136°C).
Masquelin, T.; Hengartner, U.; Streith, J. Helv. Chim. Acta
1
997, 80, 43.
Kraus, G.A.; Li, J.; Gordon, M.S.; Jensen, J.H. J. Org. Chem.
995, 60, 1154.
Anal. Calcd for C H O : C, 67.03; H, 6.19. Found: C, 67.03; H,
20
22
6
6
.42.
1
(
8) Rai, V.R., F. Hoffmann-La Roche Inc., Nutley, New Jersey,
unpublished results.
9) Yoshii, E.; Kometani, E.; Nomura, K.; Takeuchi, Y.; Odake,
S.; Nagata, Y. Chem. Pharm. Bull. 1984, 32, 4779.
Crystal Structure of 128
Crystal data: C H O , yellow; dimensions: 0.20 î 0.25 î 0.40
1
8
16
6
(
3
–1
mm , M = 327.3 gmol , orthorhombic, space group P2 2 2 , a =
1
1 1
3
8
.3398 (11), b = 12.0683 (11), c = 15.764 (2) Å, V = 71586.6 (3) Å
(
10) Colquhoun, H.M.; Thompson, D.J.; Twigg, M.V.
Carbonylation, Direct Synthesis of Carbonyl Compounds,
Plenum: 1991.
–
1
,
Z = 4, D = 1.370 gcm , Mo-Kα radiation, λ = 0.71069 Å (graphite
c
–
1
monochromator), µ = 0.097 mm .
Data collection: The intensity data for the compound were collected
on an a Nicolet P3 diffractometer, using the ω-2θ scan technique at
(11) Ellestad, G.; Kunstmann, M. P.; Whaley, H. A.; Patterson, E.
L. J. Am. Chem. Soc. 1968, 90, 1325.
2
94K. 2209 reflections were measured, of which 2185 were inde-
(12) To the best of our knowledge the crystal structure of only one
other member of pyranonaphthoquinones, i.e. kalafungin, has
been determined: Duchamp, D.J., The crystal and molecular
structure of kalafungin, Amer. Cryst. Assoc. Abstr. Papers,
Summer Meeting. 82, 1968, cited in Hoeksema, H.; Krueger,
W.C., J. Antibiotics 1976, 29, 704. However, no data could be
found in accessible data bases. C. Hubschwerlen, F.
pendent reflections with θ in the range of 1–56.0°, 1115 reflections
having F > 5σ(F). The data were corrected for Lorenz and polari-
zation effects but not for absorption.
Structure Solution and Refinement: The structure was solved by di-
rect methods (SHELXTL PLUS ) and refined with the full-matrix
least-square procedures against F with anisotropic thermal param-
eters in the last cycles of refinement for all non-hydrogen atoms.
Hydrogen atoms were included at calculated positions with fixed
thermal parameters. The refinement converged at R = 0.0519 and Rw
2
9
2
Hoffmann-La Roche AG Basel, has completed a synthesis of
frenolicin B confirming the absolute stereochemistry of this
natural product. G. Moine, F. Hoffmann-La Roche AG Basel,
has synthesized the (4aR, 10aR)-dihydroxy analogue of
deoxyfrenolicin as its (–)-menthol ester and determined the
absolute stereochemistry by X-ray analysis. This work has not
been published externally to date.
=
0.0666 for reflections > 5σ. The difference Fourier synthesis on
the basis of the final structural model showed a maximum of 0.17
eÅ and a minimum of –0.19 eÅ .
–
1
–1
(13) Kindly provided by V.R. Ray, F. Hoffmann-La Roche Inc.,
Nutley, New Jersey.
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York

8
28
P. Contant et al.
PAPER
(23) Omura, S.; Tsuzudi, K.; Iwai, Y.; Kishi, M.; Watanabe, S.;
Shimizu, H. J. Antibiotics 1985, 38, 1447.
(24) Thomson, R.H.; Race, E.; Rowe, F.M. J. Chem. Soc. 1947,
350.
(25) Masquelin, T.; Hengartner,U.; Streith, J. Synthesis 1995, 780.
(26) Ichihara, A.; Ukubata, M.; Oikawa, H.; Murakami, K.;
Sakamura, S. Tetrahedron Lett. 1980, 21, 4469.
(27) Uno, H. J. Org. Chem. 1986, 51, 350.
(28) Further details on the crystal structure determination are
available on request from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge CB2 1EZ (UK).
(29) Scheldrick, G.M. SHELXTL PLUS, Siemens Analytical X-
ray Instruments, Inc., Madison, WI, 1990.
(
(
14) Hoeksema, H.; Krueger, W.C. J. Antibiotics 1976, 29, 704.
15) a) Schmid, H.; Ebnöther, A.; Meyer, T.M. Helv. Chim. Acta
1
950, 33, 1751.
b) Eisenhuth, W.; Schmid, H. Helv. Chim. Acta 1958, 41,
021.
2
(
(
(
16) Semmelhack, M.F.; Keller, L.; Sato, T.; Spiess, E.; Wulff, W.
J. Org. Chem. 1985, 50, 5566.
17) Semmelhack, M.F.; Zask, A. J. Am. Chem. Soc. 1983, 105,
034.
18) Kometani, T.; Takeuchi, Y.; Yoshii, E. J. Org. Chem. 1983,
8, 2632.
2
4
(
(
19) Li, T-T.; Ellison, R.H. J. Am. Chem. Soc. 1978, 100, 6263.
20) We thank one of the referees for pointing our attention on this
additional possibility.
(
(
21) Hoffmann, R.W. Chem. Rev. 1989, 89, 1841.
22) Pure 22 and 23 were prepared by O-methylation of 25 and 24,
respectively (cf. experimental part).
Article Identifier:
1437-210X,E;1999,0,05,0821,0828,ftx,en;Z07598SS.pdf
Synthesis 1999, No. 5, 821–828 ISSN 0039-7881 © Thieme Stuttgart · New York