Total synthesis of (±)-cephalosol via silyl enol ether acylation

Article abstract of DOI:10.1055/s-0029-1218647

An efficient total synthesis of (±)-cephalosol is reported. Key steps are the acylation of a silyl enol ether with monomethyl oxalyl chloride and the subsequent acid-mediated ring closure to the isocoumarin structure. A chemoselective allylation and the conversion of the olefin into a methyl acetate were applied to install the γ-lactone moiety. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1218647

PAPER
917
Total Synthesis of ( )-Cephalosol via Silyl Enol Ether Acylation
Total
S
ynthesis of
l
(
)-Cep
e
halosol xander Arlt, Ulrich Koert*
Fachbereich Chemie, Philipps Universität Marburg, Hans-Meerwein-Strasse, 35032 Marburg, Germany
Fax +49(6421)2825677; E-mail: koert@chemie.uni-marburg.de
Received 13 October 2009; revised 3 December 2009
HO
8
O
MeO
O
Abstract: An efficient total synthesis of ( )-cephalosol is reported.
Key steps are the acylation of a silyl enol ether with monomethyl
oxalyl chloride and the subsequent acid-mediated ring closure to the
isocoumarin structure. A chemoselective allylation and the conver-
sion of the olefin into a methyl acetate were applied to install the g-
lactone moiety.
7
7a
9
O
O
O
10
5a
11b
O
MeO
MeO
O
11a
11
3
2
5
OR
O
12
O
Key words: acylation, cephalosol, chemoselectivity, isocoumarins,
lactones
1
MeO
cephalosol
1
MeO
O
Cephalosol was isolated from Cephalosporium acremoni-
um IFB-E007, an endophytic fungal strain living in Tra-
chelospermun jasminoides, well known in Chinese herbal
medicine for the treatment of arthritis and other inflamma-
tory diseases.1 Its structure was determined by spectro-
scopic methods and the absolute configuration was
proposed by a computational approach. The unprecedent-
ed skeleton of cephalosol consists of an isocoumarin an-
nulated to an a,b unsaturated g-lactone bearing a
quaternary center (C3) with a methyl acetate side chain.
The antibiotic activity of the novel natural product (MIC
values mg mL–1: Escheria coli/3.8, Pseudomonas fluore-
scens/3.9, Trichophyton rubrum/7.8, Candida albicans/
1.95) was associated with the a,b unsaturated g-lactone
substructure. Here, we report our results on an efficient
synthesis of cephalosol.
O
OR
O
O
+
RO
MeO
OR
2
3
Scheme 1 Retrosynthetic analysis of cephalosol
Weinreb amide 6. Compared to the 82% yield for the
same acylation of the corresponding ethyl ester,6 a lower
yield of 60% was achieved for the formation of 7. Side re-
actions due to self condensation can occur more easily for
the methyl ester than for the ethyl ester.
HO
O
MeO
O
MeI
K2CO3
acetone
OH
OMe
Our synthetic plan relied on an introduction of the C1–C2
methyl ester side chain at the late stage of the synthesis
(Scheme 1). The ketone 1 could be a suitable precursor for
such a transformation. This should allow the simultaneous
introduction of a C1–C2 side-chain equivalent, the gener-
ation of the stereocenter, and the ring closure to the g-lac-
tone. Ketone 1 could be accessible from the reaction of
benzyl methyl ketone 2 with an oxalic acid derivative 3.
HO
MeO
MeO
79%
4
5
MeO
O
LDA
MeCON(OMe)Me (6)
OMe
O
THF, –78 °C
60%
Among the various methods for the synthesis of
isocoumarins2 there are only a few examples for the prep-
aration of 3-carboxyisocoumarins such as 1: a Wittig ap-
proach,3 the use of a-diazophosphonates,4 and a Claisen
approach of homophthalate with oxalate,5 which is related
to the proposed route 2 + 3 → 1.
Starting point of the synthesis was the preparation of the
ketone 7 (Scheme 2). Orsellinic acid (4) was converted in
one step into its dimethyl ether methyl ester 5. The latter
gave the ketone 7 via deprotonation and reaction with the
7
Scheme 2 Synthesis of the ketone 7
The acylation of the ketone 7 with dimethyl oxalate (9)
was examined next (Scheme 3). Different bases (NaH,
LDA) and various oxalic acid equivalents (9 and mono-
methyl oxalyl chloride 10) did not give the desired prod-
uct 11 but the isocoumarin 12. The intramolecular attack
of the enolate oxygen at the methyl ester dominated in all
cases over the intermolecular acylation reaction.
SYNTHESIS 2010, No. 6, pp 0917–0922
Advanced online publication: 12.01.2010
DOI: 10.1055/s-0029-1218647; Art ID: T19809SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0
In order to suppress the intramolecular side reaction by
lowering the nucleophilicity of the enolate equivalent and
by increasing the electrophilicity of the oxalate equiva-

918
A. Arlt, U. Koert
PAPER
MeO
O
MeO
MeO
O
MeO
O
CO2Me
O
OMe
O
OMe
LDA
O
TsOH (cat.)
toluene, reflux
O
MeO
MeO
MeO
MeO
OMe
O
72%
OMe
O
O
Li
O
O
11
MeO
14
7
8
O
MeO
O
O
R
O
O
O
OMe
O
MeO
MeO
9
R = OMe
O
O
10 R = Cl
MeO
MeO
MeO
MeO
O
CO2Me
O
15
16
O
Scheme 4 Cyclization of 11 to the isocoumarine 14
O
MeO
MeO
12
OMe
O
enolate formation of the strong chelator 11, which may
adopt a conformation unfavorable for the cyclization.
11
The completion of the cephalosol skeleton synthesis re-
quired the addition of a C2 unit to the keto group in 14.
Towards this goal two synthetic routes were examined
(Scheme 5). The shorter one included the addition of a
methyl acetate enolate 17 to obtain the tertiary alcohol 19,
which should cyclize to the desired g-lactone 20. The
presence of three carbonyl groups and two Michael accep-
tor positions in 14 complicated this reaction and no suit-
MeO
O
1. TMSCl
10, TiCl4
2. LiHMDS
OMe
2,6-(t-Bu)2C5H3N
THF, –50 °C
7
11
MeO
CH2Cl2
–30 °C
60%
98%
E/Z = 5.5:1
OTMS
13
Scheme 3 The intermolecular acylation 7 → 8 → 11
MeO
O
lent, the Lewis acid mediated reaction of the correspond-
ing silyl enol ether with the acid chloride 10 was
examined. The ketone 7 could be converted into the silyl
enol ether 13 by addition of LiHDMS to a mixture of
TMSCl and 7 at –50 °C.7 TiCl4 was found to be the most
suitable Lewis acid for the reaction of 13 with 10 to pro-
duce the 1,3-diketone 11. Because the diketone was
formed as titanium enolate,8 an excess of Lewis acid was
necessary, 6 equivalents proved to be the best choice. The
acid liberated in the titanium enolate formation protonated
some silyl enol ether 13 and converted it back into the ke-
tone 7. This side reaction could be suppressed by addition
of a base (1.1 equiv of 2,6-di-tert-butylpyridine9). Using
these optimized conditions a 60% yield of the desired 1,3-
diketone 11 was obtained.
O
O
MeO
RO
OMe
OMe
HO
17 R = M
18 R = TMS
O
OMe
MeO
19
MeO
O
MeO
O
O
O
O
O
MeO
O
OMe
O
O
14
20
MeO
The cyclization of the 1,3-diketone 11 to the isocoumarin
14 was achieved with catalytic amounts of TsOH in boil-
ing toluene (Scheme 4). In the mixture of side products
(19%), the regioisomeric cyclization product 15 was the
main constituent. The assignment of the two regioisomers
was possible by combined NMR techniques (HMBC,
HMQC, NOESY). Using one equivalent of TfOH instead
of TsOH for the cyclization gave 62% yield of the desired
product 14 with the g-lactone 16 as the main side product.
MeO
O
M
21
O
O
MeO
OMe
HO
22
Basic cyclization conditions did not deliver compound 14.
One possible explanation for this failure could be the easy
Scheme 5 Two possible strategies for the introduction of the methyl
acetate side chain
Synthesis 2010, No. 6, 917–922 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Cephalosol
919
able conditions for this reaction using a zinc/copper boron trichloride at the ortho carbonyl group16 the selec-
enolate could be found. The corresponding selective addi- tive conversion of the dimethyl ether 20 into the target
tion of the ketene acetal 18 to the desired carbonyl group compound ( )-cephalosol was possible in 88% yield. The
in 14 was also unsuccessful.
analytical and spectral data of synthetic cephalosol (mp,
NMR, IR) were identical to those reported.1
The reactivity of allylmetal reagents can be tuned by prop-
er choice of the metal. The addition of an allylmetal re- In conclusion, the first synthesis of ( )-cephalosol was ac-
agent 21 to 14 would lead to the homoallylic alcohol 22. complished in 10 steps from orsellinic acid with 5.8%
A subsequent oxidative cleavage of the double bond could overall yield. The total synthesis confirms the structural
deliver the required compound 20. We investigated the assignment of the natural product and opens synthetic ac-
addition of allylmagnesium, -tin, and -zinc reagents to the cess to derivatives with potential antibiotic applications.
ketone 14. No satisfying chemoselectivity was achieved
with allylmagnesium chloride,10 but considerable attack at
the ester groups was observed. The reactivity of tetraallyl-
tin/Ti(Oi-Pr)411 was too low to obtain any addition prod-
uct 22.
All nonaqueous reactions were carried out using flame-dried glass-
ware under argon. All solvents were distilled by rotary evaporation.
Solvents for nonaqueous reactions were dried as follows prior to
use: THF was dried with KOH and subsequently distilled from so-
dium/benzophenone; Et2O was distilled from K/Na alloy (K/Na,
4:1). All commercially available reagents and reactants were used
without purification, unless otherwise noted. Reactions were moni-
tored by TLC using Merck Silica Gel 60 F245 plates and visualized
Allylzinc chloride (3.3 equiv) exhibited at –20 °C the de-
sired reactivity12 and delivered without detection of the in-
termediate g-hydroxy ester 22 directly the g-lactone 23
(Scheme 6). The attempted asymmetric addition of an al- by fluorescence quenching under UV light. In addition, TLC plates
lylzinc reagent in the presence of a chiral bisoxazoline13
were stained using a KMnO4 stain. Chromatographic purification of
products was performed on Merck Silica Gel 60 (230–400 mesh)
was unsuccessful because no turnover was observed un-
using a forced flow of eluents. Concentration under reduced pres-
der these conditions even at higher temperature. The con-
sure was performed by rotary evaporation at 40 °C and appropriate
pressure. Yields refer to purified and spectroscopically pure prod-
version of the terminal alkene 23 into the methyl ester 20
was achieved using the standard reaction sequence of ox-
idative cleavage,14 Pinnick oxidation15 and methyl ester
formation.
ucts, unless otherwise noted. IR spectra were recorded on a Bruker
IFS 200 or a Nicolet Magna-IR 750 spectrometer. The absorption
bands are given in wave numbers (cm–1). NMR spectra were record-
ed on a Bruker ARX300, DRX400, or DRX500 spectrometer at
room temperature. Chemical shifts are reported in ppm with the sol-
vent resonance as internal standard. Mass spectra were recorded on
a Finnigan MAT TSQ 700 or MAT 95S spectrometer.
allylzinc chloride
Me2NAc, THF
–20 °C, 6 h
MeO
O
MeO
O
O
O
O
O
Methyl 2,4-Dimethoxy-6-methylbenzoate (5)
69%
MeO
MeO
O
To a suspension of K2CO3 (25.6 g, 185 mmol) in acetone (60 mL)
was added orsellinic acid (4; 4.96 g, 29.5 mmol). MeI (11.0 mL,
177 mmol) was added and the reaction mixture was refluxed for 7
h. After removal of the solvent and excess MeI in vacuo, H2O (120
mL) was added and the resulting solution was extracted with Et2O
(5 × 60 mL). The combined organic layers were washed with
NaHCO3 (50 mL) and brine (50 mL). Drying (Na2SO4) and subse-
quent evaporation of the solvent gave the crude product. Purifica-
tion by silica gel chromatography (pentane–Et2O, 3:1) delivered the
methyl ester 5 as a light yellow oil, which turned into a white solid
upon storage at 4 °C.
OMe
O
14
23
MeO
O
1. K2Os2O4, NaIO4
dioxane–H2O
2. NaClO2
O
O
t-BuOH–H2O
MeO
O
3. TMSCHN2
CH2Cl2–MeOH
48%
Yield: 3.91 g (79%); mp 41 °C; Rf = 0.27 (pentane–Et2O, 3:1).
O
IR (film): 2949, 2841, 1724, 1603, 1266, 1231, 1201, 1157, 1096,
1052, 831, 642, 611 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H, CH3), 3.79 (s, 3 H,
OCH3), 3.80 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 6.29–6.33 (m, 2
H, 3-H, 5-H).
13C NMR (75 MHz, CDCl3): d = 20.1 (CH3), 52.1 (OCH3), 55.5
(OCH3), 56.1 (OCH3), 96.4 (CH), 106.9 (CH), 116.6 (C-1), 138.4
(C-6), 158.4 (COCH3), 161.5 (COCH3), 168.8 (CO2CH3).
20
MeO
HO
O
O
BCl3
CH2Cl2, 0 °C
MeO
O
88%
O
O
HRMS (ESI): m/z [M + Na]+ calcd for C11H14O4 + Na: 233.0790;
found: 233.0784.
MeO
( )-Cephalosol
Scheme 6 Introduction of the methyl acetate side chain and comple-
tion of the synthesis
Methyl 2,4-Dimethoxy-6-(2-oxopropyl)benzoate (7)
To i-Pr2NH (3.9 mL, 28 mmol) in THF (56 mL) was added n-BuLi
(10.5 mL of a 2.5 M solution in hexanes, 26.3 mmol) at 0 °C. After
30 min, the LDA solution thus obtained was cooled to –78 °C and
transferred via a cannula to a solution of the ester 5 (5.00 g, 23.8
mmol) in THF (56 mL) at –78 °C. The reaction mixture was stirred
The final step of the synthesis required the selective cleav-
age of the C8 methyl ether. Using the precoordination of
Synthesis 2010, No. 6, 917–922 © Thieme Stuttgart · New York

920
A. Arlt, U. Koert
PAPER
for 5 min at –78 °C and then the Weinreb amide 6 (2.8 mL, 26
mmol) was added via a syringe. After 80 min at –78 °C, aq 2 M HCl
(60 mL) was added and the mixture was allowed to warm to r.t. The
mixture was extracted with CH2Cl2 (3 × 100 mL) and the combined
organic layers were dried (Na2SO4). After evaporation of the sol-
vents, the crude product was purified by silica gel chromatography
(pentane–Et2O, 1:2) to afford the ketone 7; as a yellow oil, which
solidified upon storage at 4 °C.
(2.00 g, 6.16 mmol) in CH2Cl2 (18 mL) during 75 min. The mixture
was stirred for 4 h at –30 °C. H2O (80 mL) was added and the mix-
ture was allowed to warm to r.t. The separated aqueous layer was
extracted with CH2Cl2 (3 × 40 mL) and the combined organic layers
were dried (Na2SO4). After evaporation of the solvents, a silica gel
chromatography (pentane–EtOAc–HCO2H, 8:4:0.3) gave the 1,3-
diketone 11 as a yellow oil, which upon storage at –20 °C became a
white solid.
Yield: 3.58 g (60%); mp 64 °C; Rf = 0.24 (pentane–Et2O, 1:2).
Yield: 1.23 g (60%); mp 81 °C; Rf = 0.36 (pentane–EtOAc–
HCO2H, 8:4:0.3).
IR (film): 2957, 2933, 2870, 1689, 1602, 1583, 1460, 1323, 1201,
1154, 831, 734, 643 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 3 H, CH3), 3.68 (s, 2 H,
CH2), 3.81 (s, 3 H, OCH3), 3.82 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3),
6.31 (d, J = 2.2 Hz, 1 H, CH), 6.41 (d, J = 2.2 Hz, 1 H, CH).
13C NMR (75 MHz, CDCl3): d = 29.4 (CH3), 49.2 (CH2), 52.2
(OCH3), 55.6 (OCH3), 56.2 (OCH3), 97.9 (CH), 107.6 (CH), 116.2
(C-1), 135.9 (C-6), 159.3 (COCH3), 162.0 (COCH3), 168.1
(CO2CH3), 205.5 (CH2COCH3).
IR (film): 2953, 2845, 1727, 1598, 1577, 1261, 1207, 1157, 1046,
1016, 833, 732, 673 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04 (s, 3 H, CH3), 3.63 (s, 3 H,
COHCO2CH3), 3.72 (s, 3 H, 1-CO2CH3), 3.80 (s, 3 H, 4-OCH3),
3.82 (s, 3 H, 6-OCH3), 6.32 (d, J = 2.2 Hz, 1 H, CH-3), 6.47 (d,
J = 2.2 Hz, 1 H, CH-5), 15.68 (s, 1 H, OH).
13C NMR (75 MHz, CDCl3): d = 25.9 (CH3), 52.1 (1-CO2CH3), 52.6
(COHCO2CH3), 55.6 (4-OCH3), 56.0 (6-OCH3), 98.5 (CH-5), 108.0
(CH-3), 113.4 (CHbenzyl), 117.3 (C-1), 135.4 (C-2), 158.7 (C-6),
161.7 (C-4), 162.4 (COHCO2CH3), 167.4 (1-CO2CH3), 169.3
(COH), 199.4 (COCH3).
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O5 + Na: 275.0895;
found: 275.0890.
Methyl 2,4-Dimethoxy-6-[2-(trimethylsiloxy)prop-1-enyl]ben-
zoate (13)
HRMS (ESI): m/z [M + Na]+ calcd for C16H18O8 + Na: 361.0899;
found: 361.0894.
To a solution of ketone 7 (3.55 g, 14.2 mmol) and TMSCl (3.6 mL,
28 mmol) at –50 °C was added LiHMDS (20.5 mL 0.9 M solution
in methylcyclohexane, 18.5 mmol) via a syringe during 30 min. The
reaction mixture was stirred for 1 h at –50 °C. A 9:1 mixture of sat.
aq NH4Cl/25% NH3 (30 mL) was added. The mixture was allowed
to warm to r.t. and treated with H2O (50 mL). The separated aque-
ous layer was extracted with Et2O (2 × 40 mL), the combined or-
ganic layers were dried (Na2SO4), and the solvents removed in
vacuo. After three-fold co-evaporation with toluene (30 mL) and 12
h drying in high vacuum, the silyl enol ether 13 was obtained. Anal-
6,8-Dimethoxy-3-methyl-1H-isochromen-1-one (12)
To the ketone 7 (185 mg, 733 mmol) in THF (5 mL) was added di-
methyl oxalate (1.15 mL, 0.69 mmol), followed by the dropwise ad-
dition of LiHMDS (0.69 mL of a 1 M solution in toluene,
0.69 mmol) at –50 °C. The reaction mixture was stirred for 2 h at
–50 °C and then treated with aq 2 M HCl (2 mL). The aqueous layer
was extracted with EtOAc (3 × 10 mL) and the combined organic
layers were dried (Na2SO4). Evaporation of the solvents gave a mix-
ture with isocoumarin 12 as the main component. An analytical
sample was purified by silica gel chromatography.
1
ysis of the H NMR spectrum showed a 5.5:1 E/Z mixture. The
crude product was used for the following acylation step without fur-
ther purification.
Rf = 0.25 (EtOAc–pentane, 1:1).
IR (film): 2846, 1715, 1667, 1596, 1568, 1212, 1160, 971, 692 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.20 (d, J = 0.9 Hz, 1 H, CH3),
3.87 (s, 3 H, OCH3), 3.94 (s, 3 H, OCH3), 6.08 (d, J = 0.9 Hz, 1 H,
CHbenzyl), 6.28 (d, J = 2.3 Hz, 1 H, CH), 6.40 (d, J = 2.3 Hz, 1 H,
CH).
Light yellow oil; yield: 4.51 g (98%); Rf = 0.68 (pentane–Et2O,
1:2).
IR (film): 2954, 1726, 1596, 1578, 1425, 1258, 1201, 1154, 1095,
839, 756, 688 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.17 [s, 9 H, Si(CH3)3-Z], 0.24 8s,
9 H, Si(CH3)3-E], 1.85 (d, J = 0.6 Hz, 3 H, CH3-E), 1.93–1.97 (m,
3 H, CH3-Z), 3.76 (s, 3 H, OCH3-Z), 3.78 (s, 3 H, OCH3-E), 3.79 (s,
3 H, OCH3-E), 3.84 (s, 3 H, OCH3-E), 3.87 (s, 3 H, OCH3-Z), 5.31–
5.34 (m, 1 H, CH-Z), 5.72–5.77 (m, 1 H, CH-E), 6.27 (d, J = 2.2 Hz,
1 H, CHarom-Z), 6.29–6.34 (m, 2 H, CHarom-E), 7.13 (d, J = 2.2 Hz,
1 H, CHarom-Z).
13C NMR (75 MHz, CDCl3): d = 19.6 (CH3), 55.7 (OCH3), 56.4
(OCH3), 98.3 (CHarom), 99.5 (CHarom), 103.0 (CC-3), 103.8 (CHben-
zyl), 142.6 (CC-4), 155.6 (C-3), 159.7 (C-1), 163.5 (COCH3), 165.5
(COCH3).
HRMS (ESI): m/z [M + H]+ calcd for C12H13O4: 221.0814; found:
221.0808.
13C NMR (75 MHz, CDCl3): d = 0.3 [Si(CH3)3-E], 0.9 [Si(CH3)3-Z],
19.7 (CH3-E), 24.3 (CH3-Z), 52.1 (OCH3-Z), 52.1 (OCH3-E), 55.4
(OCH3-E), 55.8 (OCH3-Z), 55.9 (OCH3-E), 96.2 (CHarom-E), 96.5
(CHarom-Z), 104.6 (CH-E), 104.7 (CH-Z), 106.5 (CH-Z), 106.7 (CH-
E), 115.3 (C-1-Z), 116.6 (C-1-E), 151.4 (CO-Z), 152.9 (CO-E),
157.5 (CO-Z), 157.8 (CO-E), 161.0 (CO-Z), 161.0 (CO-E), 168.5
(COSi-E), 169.1 (COSi-Z).
Cyclization of 11 with TsOH; Methyl 4-Acetyl-6,8-dimethoxy-
1-oxo-1H-isochromene-3-carboxylate (14) and 6,8-Dimethoxy-
4-(methyl-2-oxoacetate)-3-methyl-1-oxo-1H-isochromene (15)
To the 1,3 diketone 11 (386 mg, 1.14 mmol) in toluene (114 mL)
was added TsOH (33 mg) and the reaction mixture was refluxed for
90 min. After evaporation of the solvent, a silica gel chromatogra-
phy (pentane–acetone, 3:1 → 2:1) afforded the isocoumarin 14
(253 mg, 72%) and a mixture of side products with compound 15 as
the main component (66 mg, 19%).
HRMS (ESI): m/z [M + Na]+ calcd for C16H24O5Si + Na: 347.1291;
found: 347.1285.
Methyl (Z)-2-(2-Hydroxy-1-methoxy-1,4-dioxopent-2-en-3-yl)-
4,6-dimethoxybenzoate (11)
Isocoumarin 14
White powder; mp 185 °C; Rf = 0.33 (pentane–acetone, 2:1).
To a solution of monomethyl oxalyl chloride (1.2 mL, 13 mmol) in
CH2Cl2 (60 mL) were added successively TiCl4 (4.1 mL, 37 mmol)
and 2,6-di-tert-butylpyridine (1.5 mL, 6.7 mmol) at –30 °C. To the
dark red reaction mixture was added dropwise the silyl enol ether 13
IR (film): 1710, 1593, 1457, 1431, 1310, 1253, 1206, 1167, 1029,
730, 700, 577 cm–1.
Synthesis 2010, No. 6, 917–922 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Cephalosol
921
1H NMR (300 MHz, CDCl3): d = 2.58 (s, 3 H, CH3), 3.87 (s, 3 H, 6-
OCH3), 3.92 (s, 3 H, CO2CH3), 3.98 (s, 3 H, 8-OCH3), 6.27 (d,
J = 2.2 Hz, 1 H, H-5), 6.62 (d, J = 2.2 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 32.1 (CH3), 53.3 (CO2CH3), 56.0
(6-OCH3), 56.7 (8-OCH3), 100.7 (CH-5), 101.0 (CH-7), 104.7 (CC-
1), 126.5 (C-4), 137.0 (CC-4), 138.7 (C-3), 155.9 (C-1), 161.0
(CO2CH3), 164.1 (C-8), 166.0 (C-6), 199.9 (COCH3).
H2O (40 mL), the aqueous layer was extracted with CH2Cl2
(3 × 60 mL) and the combined organic layers were dried (Na2SO4).
After evaporation of the solvents in vacuo, a silica gel chromatog-
raphy (pentane–acetone, 3:1 → 2:1) gave the g-lactone 23; as a light
yellow solid.
Yield: 358 mg (69%); mp 189 °C; Rf = 0.17 (pentane–acetone, 3:1).
IR (film): 1764, 1594, 1565, 1456, 1383, 1208, 1167, 992, 970, 838,
754 cm–1.
HRMS (ESI): m/z [M + Na]+ calcd for C15H14O7 + Na: 329.0637,
found: 329.0632.
1H NMR (400 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 2.72 (dd,
J = 14.6, 7.1 Hz, 1 H, CH2allyl), 2.88 (dd, J = 14.6, 7.4 Hz, 1 H,
CH2allyl), 3.97 (s, 3 H, 8-OCH3), 4.00 (s, 3 H, 6-OCH3), 5.02 (d,
J = 16.1 Hz, 1 H, CH2), 5.03 (d, J = 11.0 Hz, 1 H, CH2), 5.49 (dddd,
J = 16.4, 11.7, 7.2, 7.2 Hz, 1 H, CHCH2allyl), 6.48 (d, J = 2.2 Hz, 1
H, H-9), 6.68 (d, J = 2.1 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 25.1 (CH3), 42.7 (CH2allyl), 56.1 (8-
OCH3), 56.7 (6-OCH3), 84.9 (C-1), 100.0 (CH-7), 100.9 (CH-9),
103.7 (CC-5), 120.9 (CH2), 129.9 (CHCH2allyl), 133.4 (Cbenzyl),
134.0 (Cq), 140.7 (Cq), 156.5 (C-5), 162.4 (C-3), 165.3 (C-6), 166.0
(C-8).
Regioisomer 15
Colorless oil; Rf = 0.41 (pentane–acetone, 2:1).
1H NMR (300 MHz, CDCl3): d = 2.29 (s, 3 H, CH3), 3.83 (s, 3 H, 8-
OCH3), 3.90 (s, 3 H, CO2CH3), 3.96 (s, 3 H, 6-OCH3), 6.44 (d,
J = 2.2 Hz, 1 H, H-5), 6.48 (d, J = 2.2 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 19.0 (CH3), 53.6 (CO2CH3), 55.8
(8-OCH3), 56.5 (6-OCH3), 98.4 (H-5), 99.0 (H-7), 102.1 (CC-1),
112.9 (C-4), 138.6 (CC-4), 156.8 (C-1), 161.1 (C-3), 163.2
(CO2CH3), 163.8 (C-6), 166.0 (C-8), 186.6 (COCO2CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H14O7 + Na: 329.0637;
HRMS (ESI): m/z [M + Na]+ calcd for C17H16O6 + Na: 339.0845;
found: 329.0632.
found: 339.0839.
Cyclization of 11 with TfOH; Methyl 4-Acetyl-6,8-dimethoxy-1-
oxo-1H-isochromene-3-carboxylate (14) and 1,6,8-Trimethoxy-
1-methyl-1H-furo[3,4-c]isochromene-3,5-dione (16)
Methyl 2-(6,8-Dimethoxy-1-methyl-3,5-dioxo-3,5-dihydro-1H-
furo[3,4-c]isochromen-1-yl)acetate (20)
Oxidative Alkene Cleavage: To the alkene 23 (150 mg, 474 mmol)
in dioxane–H2O (3:1, 8.4 mL) was added 2,6-lutidine (0.22 mL, 1.9
mmol) at 20 °C. To this solution were added K2OsO4·2 H2O
(7.0 mg, 19 mmol) and NaIO4 (406 mg, 1.90 mmol). The reaction
mixture was stirred for 26 h at 20 °C. Solids formed were filtered
off and H2O (5 mL) was added to the filtrate. After extraction with
CH2Cl2 (8 × 5 mL), the combined organic layers were washed with
H2O (5 mL), and dried (Na2SO4). Evaporation of the solvents in
vacuo gave the corresponding aldehyde (168 mg).
To the 1,3-diketone 11 1.56 g, 4.61 mmol) in CH2Cl2 (92 mL) was
added TfOH (0.41 mL, 4.6 mmol) at 0 °C. The reaction mixture
was stirred at 0 °C for 4.5 h and then treated with sat. aq NaHCO3
(25 mL). After addition of H2O (40 mL), the mixture was extracted
with CH2Cl2 (4 × 25 mL) and the combined organic layers were
dried (Na2SO4). After evaporation of the solvent, a silica gel chro-
matography (pentane–acetone, 3:1 → 2:1) afforded the isocou-
marin 14 (874 mg, 62%) and the g-lactone 16 (121 mg, 9%). The
analytical data of compound 14 corresponded to the data from the
TsOH-mediated cyclization (vide supra).
Oxidation of the Aldehyde: The aldehyde was dissolved in t-BuOH–
H2O (5:2, 7.5 mL). NaH2PO4·2 H2O (248 mg, 1.59 mmol) and 2-
methylbut-2-ene (0.51 mL, 4.8 mmol) were added at 20 °C. After 5
min, NaClO2 (286 mg, 3.16 mmol) was added and the reaction mix-
ture was stirred for 25 h at 20 °C. After the addition of aq 10%
Na2SO3 (10 mL) and aq 2 M HCl (6 mL), the mixture was extracted
with CH2Cl2 (5 × 20 mL), and the combined organic layers were
dried (Na2SO4). After evaporation of the solvents in vacuo the cor-
responding carboxylic acid (137 mg) was obtained.
16
White solid; mp 257 °C; Rf = 0.36 (pentane–acetone, 2:1).
IR (film): 2947, 1771, 1594, 1455, 1383, 1283, 1247, 1206, 1167,
990, 865 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.91 (s, 3 H, CH3), 3.21 (s, 3 H, 1-
OCH3), 3.97 (s, 3 H, 8-OCH3), 4.02 (s, 3 H, 6-OCH3), 6.63 (d,
J = 2.3 Hz, 1 H, H-9), 6.69 (d, J = 2.2 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 25.5 (CH3), 51.8 (1-OCH3), 56.2
(8-OCH3), 56.7 (6-OCH3), 99.9 (C-9), 101.2 (C-7), 103.5 (CC-5),
106.6 (C-1), 128.2 (Cbenzyl), 133.7 (CqCbenzyl), 142.4 (CqC-3), 156.3
(C-3), 160.8 (C-5), 165.0 (C-6), 166.6 (C-8).
Formation of the Methyl Ester: To the carboxylic acid in CH2Cl2–
MeOH (4:1, 1.8 mL) was added dropwise TMSCHN2 in Et2O
(0.25 mL, 2 M, 0.50 mmol) at 0 °C. After 5 min, H2O–AcOH (10:1,
10 mL) was added. H2O (6 mL) was added and the mixture was ex-
tracted with CH2Cl2 (8 × 10 mL) and the combined organic layers
were dried (Na2SO4). After evaporation of the solvents in vacuo, a
silica gel chromatography (CH2Cl2–acetone, 30:1 → 10:1) afforded
the methyl ester 20.
HRMS (ESI): m/z [M + Na]+ calcd for C15H14O7 + Na: 329.0637;
found: 329.0632.
White solid; yield: 79.1 mg (48% from 23); mp 202 °C; Rf = 0.55
(CH2Cl2–acetone, 10:1).
1-Allyl-6,8-dimethoxy-1-methyl-1H-furo[3,4-c]isochromene-
3,5-dione (23)
Allylzinc Chloride Solution in THF: A solution of ZnCl2 in THF
(13.6 mL, 0.5 M, 6.80 mmol) was diluted with THF (3.4 mL). To
this solution was added dropwise a THF solution of allylmagnesium
chloride (4.0 mL, 1.7 M, 6.8 mmol) at 20 °C. The reaction mixture
was stirred for 2 h at 20 °C. The allylzinc chloride solution thus ob-
tained (0.32 M) was used directly in the following reaction.
IR (film): 1760, 1596, 1564, 1456, 1384, 1253, 1204, 1163, 993,
967, 733 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.86 (s, 3 H, CH3), 3.01 (d,
J = 15.6 Hz, 1 H, CH2), 3.19 (d, J = 15.7 Hz, 1 H, CH2), 3.59 (s, 3
H, CO2CH3), 3.97 (s, 3 H, 8-OCH3), 4.02 (s, 3 H, 6-OCH3), 6.43 (d,
J = 2.2 Hz, 1 H, H-9), 6.67 (d, J = 2.2 Hz, 1 H, H-7).
Addition of Allylzinc Chloride to the Isocoumarin 14: To the isocou-
marin 14 (500 mg, 1.63 mmol) in N,N-dimethylacetamide (18 mL)
was added a THF solution of allylzinc chloride (17.0 mL, 0.32 M,
5.44 mmol) during 6 h at –20 °C. Half sat. aq NH4Cl (40 mL) was
added and the mixture was allowed to warm to r.t. After addition of
13C NMR (75 MHz, CDCl3): d = 25.7 (CH3), 42.5 (CH2), 52.3
(CO2CH3), 56.1 (8-OCH3), 56.7 (6-OCH3), 82.0 (C-1), 100.0 (C-7),
100.6 (C-9), 103.9 (CC-5), 132.8 (Cbenzyl), 133.9 (Cq), 140.9 (Cq),
156.4 (C-5), 162.0 (C-2), 165.4 (C-6), 166.0 (C-8), 168.2
(CO2CH3).
Synthesis 2010, No. 6, 917–922 © Thieme Stuttgart · New York

922
A. Arlt, U. Koert
PAPER
HRMS (ESI): m/z [M + H]+ calcd for C17H17O8: 349.0923; found:
349.0918.
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White solid; yield: 44 mg (88%); mp 202–203 °C (Lit.1 mp 206–
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IR (film): 3519, 1775, 1724, 1694, 1615, 1565, 1516, 1465, 1428,
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J = 16.0 Hz, 1 H, H-2), 3.19 (d, J = 16.0 Hz, 1 H, H-2), 3.60 (s, 3 H,
1-OCH3), 3.93 (s, 3 H, 10-OCH3), 6.44 (d, J = 2.1 Hz, 1 H, H-11),
6.69 (d, J = 2.1 Hz, 1 H, H-9), 11.29 (s, 1 H, 8-OH).
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OCH3), 56.9 (10-OCH3), 82.6 (C-3), 100.9 (C-7a), 103.3 (C-9),
103.8 (C-11), 131.7 (C-11a), 135.4 (C-11b), 140.3 (C-5a), 162.3
(C-5), 165.3 (C-7), 166.8 (C-8), 167.9 (C-10), 168.7 (C-1).
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HRMS (ESI): m/z [M + Na]+ calcd for C16H14O8 + Na: 357.0586;
found: 357.0581.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
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Acknowledgment
Generous support by the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie is gratefully acknowledged.
Synthesis 2010, No. 6, 917–922 © Thieme Stuttgart · New York