Synthesis and reactivity of (+)-16-deoxo-15-oxoisosteviol

Article abstract of DOI:10.1055/s-2008-1072533

The synthesis of optically pure (-)-isosteviol derivatives with a keto function shifted to position 15 and its insertive esterification are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072533

PAPER
1443
Synthesis and Reactivity of (+)-16-Deoxo-15-oxoisosteviol
S
ynthesis and Reactivi
a
ty of (+)-16
r
-Deoxo-
t
15-oxo
i
isoste
v
n
iol Bomkamp,a Katharina Gottfried,a Olga Kataeva,b Siegfried R. Waldvogel*a
a
b
Received 26 November 2007; revised 21 January 2008
Me
O
Abstract: The synthesis of optically pure (–)-isosteviol derivatives
with a keto function shifted to position 15 and its insertive esterifi-
cation are described.
Me
H
SeO2, xylene,
∆, 2 d, 85%
O
3
2
H
Key words: terpenoids, chiral pool, esters, carbocycles, rearrange-
ments
Me
CO2Me
Me
O
Stevioside and rebauside F, which are both glycosides of
the same aglycon, can be easily isolated from stevia plants
and are used as alternative sweeteners.1 Upon treatment
with strong mineral acids, these readily available com-
mercial mixtures provide (–)-isosteviol (1) in large quan-
tities.2 1 represents a unique diterpenoid skeleton with a
keto and carbonyl group pointing in almost the same di-
rection (Figure 1), and its co-crystallization with various
organic compounds was studied intensively.3 Recently,
we exploited the high optical purity and the specific ar-
rangement of functional groups for the construction of
enantiomerically pure receptor structures based on triphe-
nylene ketals.4 In order to facilitate selective and optimal
binding of guests, a more centred and therefore less open
arrangement of the hydrogen bonding donors is crucial.5
Since the host/guest interaction is almost insulated from
the outer sphere, no self-aggregation phenomena are ob-
served.6 In order to close up the geometry of the (–)-iso-
steviol-based receptor, a shifting of the keto group from
position 16 into the adjacent location 15 was envisioned.
Standard protocols known from simple terpenoids, e.g.
camphor,7 were tested on the 16-oxobeyerane skeleton.
H2NNH2,
CH2Cl2, 2 d,
r.t., 54%
Me
H
N
N
R
H
H2NNHTs,
or CH2Cl2, 2 d,
r.t., 90%
H
Me
CO2Me
4 R = H
5 R = Ts
Me
NaBH3CN,
p-TsOH, DMF,
sulfolane,
Me
H
5
O
12 h, 110 °C,
68%
H
Me
6
CO2Me
Me
Me
H
NaCN, DMF,
∆, 14 h, 91%
O
H
CO2H
Me
7
Scheme 1 Sequence for shifting the oxo moiety
required blocking of the carboxy moiety, which was per-
formed by methylation of the carboxylate providing 2 in
good yield.8
In this paper we report the efficient translocation of the
keto function onto position 15. Furthermore, a novel in-
sertive esterification is described. The synthetic pathway
The installation of the a-keto group was achieved in a
Riley oxidation8,9 using selenium dioxide (Scheme 1).
The 15,16-diketo compound 3 was obtained as orange co-
loured crystals in 85% yield, whose analytical data
matched a structural analogue of the beyerane series.8 Ini-
tially, a Wolff–Kishner reduction was envisioned for the
removal of the of the 16-oxo functionality.10 The conver-
sion with hydrazine occurred selectively on the less hin-
dered keto group. With hydrazine hydrate, moderate
yields of 54% could be obtained, however, despite intense
studies, no reaction conditions could be found for its con-
version into 6. Therefore, a more reactive hydrazine deriv-
ative was prepared. Gratifyingly, the installation of the N-
tosyl hydrazone to give 5, could be performed in very
good yield (90%). The subsequent reductive step turned
Me
Me
O
16
H
15
4
3
H
CO2R
Me
1 R = H (–)-isosteviol
2 R = Me
Figure 1 Diterpenes from the beyerane series
SYNTHESIS 2008, No. 9, pp 1443–1447
Advanced online publication: 27.03.2008
DOI: 10.1055/s-2008-1072533; Art ID: T18607SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
8

1444
M. Bomkamp et al.
PAPER
Me
O
Me
Me
H
Me
H
OH
OH
H+
+
H
6
– H2O
O
O
H
O
Me
Me
O
O
8
+
Me
H
MeO
O
TfOH, P4O10
catechol, toluene,
,
6
∆
Me
Me
H
H
9
O
Scheme 3 Mechanistic rationale for ester formation
Me
O
O
OMe
desiccants did not succeed. Most probably, phosphorous
pentoxide induces the formation of triflic anhydride.
9
The molecular structure of this ester was proven by X-ray
crystal structure analysis of suitable single crystals. The
conformation of 9 is shown in Figure 2. As expected, the
shift of the keto group to the adjacent position respective
to isosteviol, does not affect the rigid skeleton of the mol-
ecule. The carbonyl group of the exocyclic substituent in
position 4 eclipses the C3–C4 bond of the skeleton, which
is the most favourable orientation since there are no hy-
drogen bonds, as for example in case of the methyl ester
of isosteviol15 or more bulky ester derivatives.16 Isosteviol
derivatives are known for the recognition of aromatic
compounds and this behaviour is expressed in the molec-
ular packing of compound 9 (Figure 3), with 2-methoxy-
phenoxy substituents being located between the lipophilic
polycyclic skeletons of the molecule. This clearly indi-
cates the dominating role of CH–p interactions in the crys-
tal packing.17 For 1 itself, two orientations of the
carboxylic group are observed in the crystal: one with the
carbonyl bond in ecliptic orientation to the C3–C4 bond of
the skeleton, and a second with the C–OH bond in such an
ecliptic position leading to the formation of hydrogen
bonded dimers. In molecular complexes of isosteviol with
aromatic compounds a different hydrogen bond pattern
dictates the eclipsed orientation of the hydroxyl group.3
Scheme 2 Insertive esterification
out to be challenging; simple treatment with sodium boro-
hydride in alcohol at low temperature11 led to complete
decomposition. Switching to cyanoborohydride under
acidic conditions at elevated temperatures as developed
by Reißig et al.,12 gave access to the desired compound
but in low yield (27%). Significant reduction of the excess
of cyanoborohydride reagent, however, resulted in 68%
isolated yield of 6. The methyl ester was deprotected by a
dealkylative cleavage using sodium cyanide in DMF,
which gave 7 in 91% yield. For the construction of recep-
tor geometries involving triphenylene ketals, the corre-
sponding catechol ketals had to be made – these were then
to be oxidatively trimerized.5,13
The sterically demanding environment of the translocated
keto function caused problems in the formation of the
benzodioxole moiety via ketalization. Employing typical
solvents for such transformations, e.g. toluene, chloroben-
zene or 1,2-dichlorobenzene in combination with strong
acids such as toluenesulfonic acid, methanesulfonic acid
or triflic acid, did not show any conversion even under
drastic conditions (Scheme 2).14 When phosphorous pent-
oxide was present in a mixture of catechol, triflic acid, tol-
uene and 6, an unusual reactivity was initiated. Despite
intense optimization studies, the yield did not exceed a
modest 22%, since prolonged reaction times promoted de-
composition. It turned out that the product of the reaction,
9 (an ester of guaiacol), was formed by an insertive ester-
ification (Scheme 2). This curious and unprecedented for-
mation of the ester might be a consequence of steric
demand on that particular keto function. After the cate-
chol was added to the ester moiety and water removed, the
carbocation is stabilized by methyl transfer onto the adja-
cent phenolic hydroxy group, providing 9 (Scheme 3).
The insertive esterification reaction seems to be a rather
limited transformation because of the harsh reaction con-
ditions. The unusual reaction pathway is attributed to the
steric demand around the functional groups in 6. Other
In conclusion, the 16-keto functionality on the beyerane
scaffold derived from (–)-isosteviol, can be efficiently
shifted to the adjacent position 15 in an overall yield of
52% starting from 2. The sequence involves a selenium
Figure 2 Molecular structure of 9
Synthesis 2008, No. 9, 1443–1447 © Thieme Stuttgart · New York

PAPER
Synthesis and Reactivity of (+)-16-Deoxo-15-oxoisosteviol
1445
Anal. Calcd for C21H30O4: C, 72.80; H, 8.73. Found: C, 72.51; H,
8.85.
(+)-Methyl ent-16-(1,1-Diazendiyl)beyeran-15-on-19-oate (4)
To a solution of 3 (1.0 g, 3 mmol) in CH2Cl2 (150 mL) at r.t., hydra-
zine hydrate (220 mg, 4 mmol) was added and the resulting solution
was stirred at r.t. for 24 h. The mixture was concentrated in vacuo
and the crude product was purified by column chromatography (cy-
clohexane–EtOAc, 95:5).
25
Yield: 560 mg (54%); yellow glassy solid; [a]D +0.7 (c 1.00,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.51 (s, 3 H, CH3), 0.82 (dt,
J = 13.2, 4.0 Hz, 1 H), 0.98 (dd, J = 13.5, 4.1 Hz, 1 H), 1.04–1.14
(m, 2 H), 1.06 (s, 3 H, CH3), 1.16 (s, 3 H, CH3), 1.32 (dd, J = 13.4,
4.4 Hz, 2 H), 1.39–1.51 (m, 3 H), 1.57–1.83 (m, 7 H), 2.15–2.25 (m,
2 H), 3.66 (s, 3 H).
Figure 3 Crystal packing of 9 with wrapped arene moieties
13C NMR (100 MHz, CDCl3): d = 11.6, 19.1, 21.1, 23.2, 26.9, 28.8,
34.2, 38.2, 38.5, 39.3, 39.7, 40.1, 43.8, 49.5, 51.3, 51.2, 56.5, 57.7,
145.6, 177.9, 208.0.
dioxide oxidation, formation of N-tosyl hydrazone and
subsequent reductive removal using sodium cyanoboro-
hydride. Upon ketalization with strong acidic media and
catechol, the first example of an insertive esterification
was found. The shifting of the keto group produces a
much more convergent arrangement of functionalities on
the beyerane skeleton.
MS (EI, 70 eV): m/z (%) = 360.2 (65) [M]+, 332.2 (100).
HRMS: m/z [M] calcd for C21H32N2O3: 360.2413; found: 360.2418.
(–)-Methyl ent-16-[2-(4-Methylphenylsulfonyl)-1,1-diazene-
diyl]beyeran-15-on-19-oate (5)
To a solution of diketone 3 (9.0 g, 26 mmol) in CH2Cl2 (100 mL) at
r.t., p-tosyl hydrazine (4.8 g, 26 mmol) was added and the resulting
solution was stirred at r.t. for 48 h. The mixture was concentrated in
vacuo and the crude product was purified by column chromatogra-
phy (cyclohexane–EtOAc, 75:25).
All reagents used were of analytical grades. Solvents were dried if
necessary by standard methods. Column chromatography was per-
formed on silica gel (particle size 63–200 mm; Merck, Darmstadt,
Germany) using cyclohexane–EtOAc as eluent. Melting points
were determined on an SMP3 melting point apparatus (Stuart Sci-
entific, Watford Herts, UK) and are uncorrected. Micro analyses
were performed using a Vario EL III (Elementar-Analysensysteme,
20
Yield: 12.0 g (90%); yellow glassy solid; [a]D –7.9 (c 1.00,
CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.63 (s, 3 H, CH3), 0.87 (dt,
J = 13.2, 4.2 Hz, 1 H), 1.00 (dd, J = 13.4, 4.1 Hz, 1 H), 1.08–1.16
(m, 2 H), 1.09 (s, 3 H, CH3), 1.19 (s, 3 H, CH3), 1.24–1.45 (m, 4 H),
1.54–1.62 (m, 2 H), 1.68–1.88 (m, 6 H), 2.16–2.32 (m, 2 H), 2.40
(s, 3 H), 3.66 (s, 3 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.78 (d, J = 8.2 Hz,
2 H), 12.08 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 11.4, 18.9, 20.8, 20.9, 21.5, 22.5,
28.7, 33.6, 37.9, 38.6, 39.6, 39.9, 40.8, 43.7, 50.5, 51.3, 51.5, 56.2,
58.3, 127.6, 129.5, 135.6, 144.0, 152.7, 177.6, 209.8.
1
Hanau, Germany). H NMR spectra were recorded at 25 °C on
Bruker DPX 300 or DPX 400 instruments (Analytische Messtech-
nik, Karlsruhe, Germany). Chemical shifts (d) are reported in parts
per million (ppm) relative to TMS as internal standard or traces of
CHCl3 in the deuterated solvent. Mass spectra were obtained on a
MAT8200, MAT95XL (Finnigan, Bremen, Germany), MS50 (Kra-
tos, Manchester, England) or FT-ICR (Bruker APEX IV) employ-
ing EI, ESI. Optical rotations were measured using a Jasco P-1020
apparatus (path length 100 mm).
MS (EI, 70 eV): m/z (%) = 514.3 (60) [M]+, 332.2 (100).
HRMS: m/z [M + H+] calcd for C28H39N2O5S: 515.2574; found:
515.2574.
(–)-Methyl ent-15,16-Beyerandion-19-oate (3)
A suspension of (–)-isosteviol methyl ester (10.1 g, 30 mmol) and
selenium dioxide (4.4 g, 54 mmol) in xylene (150 mL) was stirred
under reflux for 48 h. The inorganic solid was filtered off with the
aid of Celite™. The filter cake was extensively rinsed with CH2Cl2
and the filtrate was concentrated in vacuum. The crude product was
purified by column chromatography (cyclohexane–EtOAc, 95:5).
(+)-Methyl ent-15-Oxobeyeran-19-oate (6)
To a solution of 5 (5.0 g, 9.7 mmol) in DMF–sulfolane (1:1, 30 mL),
sodium cyanoborohydride (3.1 g, 49 mmol) and PTSA (3.7 g, 19.5
mmol) were added and the resulting mixture was stirred under re-
flux for 48 h. After cooling of the solution to r.t., it was brought to
pH 8 with sat. NH4Cl. After extraction with MTBE (5 × 110 mL),
the combined organic layers were washed with H2O (5 × 100 mL)
and brine (2 × 100 mL), dried over MgSO4 and subsequently con-
centrated under reduced pressure. The crude product was purified
by column chromatography (cyclohexane–EtOAc, 95:5).
25
Yield: 9.0 g (85%); orange crystalline solid; mp 190 °C; [a]D
–173.9 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.53 (s, 3 H, CH3), 0.86 (dt,
J = 13.1, 4.1 Hz, 1 H), 0.99 (dd, J = 13.5, 4.1 Hz, 1 H), 1.11 (s, 3 H,
CH3), 1.14 (dd, J = 12.7, 2.0 Hz, 1 H), 1.19 (s, 3 H, CH3), 1.18–1.31
(m, 2 H), 1.37–1.44 (m, 1 H), 1.53–1.64 (m, 3 H), 1.71–1.85 (m,
4 H), 1.87–1.94 (m, 2 H), 1.96–2.01 (m, 1 H), 2.14–2.19 (m, 1 H),
2.24–2.35 (m, 1 H), 3.64 (s, 3 H, OCH3).
13C NMR (100 MHz, CDCl3): d = 11.4, 18.9, 20.1, 20.8, 21.4, 28.7,
34.1, 37.9, 38.7, 39.7, 39.8, 43.7, 46.9, 47.3, 50.5, 51.3, 56.2, 59.6,
177.6, 208.8, 210.1.
25
Yield: 2.2 g (68%); colourless crystalline solid; mp 152 °C; [a]D
+22.5 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.71 (s, 3 H, CH3), 0.84 (dt,
J = 13.1, 4.2 Hz, 1 H), 0.95–1.53 (m, 9 H), 1.05 (s, 3 H, CH3), 1.17
(s, 3 H, CH3), 1.60–1.94 (m, 7 H), 2.07–2.27 (m, 3 H), 3.64 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 11.6, 19.1, 20.8, 21.0, 27.1, 28.8,
33.7, 34.7, 38.2, 38.4, 38.6, 40.2, 43.8, 51.17, 51.22, 52.6, 54.4,
56.5, 57.0, 178.0, 222.3.
MS (EI, 70 eV): m/z (%) = 346.2 (25) [M]+, 318.2 (6), 290.2 (100),
276.2 (18), 231.2 (55), 180.1 (37).
Synthesis 2008, No. 9, 1443–1447 © Thieme Stuttgart · New York

1446
M. Bomkamp et al.
PAPER
MS (EI, 70 eV): m/z (%) = 332.3 (47) [M]+, 314.2 (36), 300.2 (100),
273.2 (24), 255.2 (58).
tion Denzo,19 structure solution SHELXS-97,20 structure refinement
by full-matrix least-squares against F2 using SHELXL-97.21
Anal. Calcd for C21H32O3: C, 75.86; H, 9.70. Found: C, 75.54; H,
9.81.
Crystal data for 9: Empirical formula C27H36O4; M = 424.56;
a = 9.0044(3) Å, b = 12.5039(3) Å, c = 20.8612(6) Å;
V = 2348.8(1) Å3; D (calculated) = 1.201 g cm–3, m = 0.624 mm–1;
empirical absorption correction (0.835 £ T £ 0.912), Z = 4; crystal
system = orthorhombic; space group P212121 (No. 19); T = 223 K;
w and j scans, 19749 reflections collected ( h, k, l), [(sinq)/
l] = 0.60 Å–1, 4112 independent (Rint = 0.064) and 3666 observed
reflections [I ≥ 2s(I)]; 284 refined parameters, R = 0.047, wR2 =
0.114; max. residual electron density 0.16 (–0.16) e Å–3; hydrogen
atoms calculated and refined as riding atoms. CCDC 667062 con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html or from the Cambridge Crystallographic Data Cen-
tre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk.
(+)-ent-15-Oxobeyeran-19-oic Acid (7)
To a solution of 6 (440 mg, 1.3 mmol) in DMF (30 mL), NaCN (190
mg, 4 mmol) was added and the resulting mixture was stirred under
reflux for 24 h. The mixture was fractionated with MTBE (100 mL)
and acidic FeSO4 solution [made from HCl (1 M, 50 mL) and
FeSO4·7H2O (1.5 g)]. The organic layer was washed with H2O
(5 × 100 mL), brine (100 mL), dried (Na2SO4) and concentrated un-
der reduced pressure. The crude product was purified by column
chromatography (cyclohexane–EtOAc, 80:20).
Yield: 383 mg (91%); colourless crystalline solid; mp 221 °C;
[a]D25 +34.1 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.71 (s, 3 H, CH3), 0.80–0.88 (m,
1 H), 0.95–1.03 (m, 1 H), 1.05 (s, 3 H, CH3), 1.07–1.20 (m, 3 H),
1.24 (s, 3 H, CH3), 1.25–1.54 (m, 5 H), 1.60–1.65 (m, 1 H), 1.71–
1.95 (m, 6 H), 2.08–2.16 (m, 2 H), 2.24–2.35 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 11.8, 19.0, 20.8, 23.8, 27.1, 29.1,
33.6, 34.7, 37.8, 38.6, 38.6, 40.2, 43.6, 51.1, 52.6, 54.4, 56.5, 57.0,
183.6, 222.4.
Acknowledgment
The authors are grateful to Dr. Roland Fröhlich for using X-ray fa-
cilities at the University of Münster. Financial support by the SFB
624 (DFG) and by the University of Bonn is highly appreciated.
MS (EI, 70 eV): m/z (%) = 318.2 (96) [M]+, 300.2 (100), 274.2 (20),
255.2 (45).
References
(1) Starraat, A. N.; Kirby, C. W.; Pocs, R.; Brandle, J. E.
Phytochemistry 2002, 59, 367.
Anal. Calcd for C20H30O3: C, 75.43; H, 9.50. Found: C, 75.04; H,
9.33.
(2) (a) Mosettig, E.; Nes, W. R. J. Org. Chem. 1955, 20, 884.
(b) Mosettig, E.; Beglinger, U.; Dolder, F.; Lichti, H.; Quitt,
P.; Waters, J. A. J. Am. Chem. Soc. 1963, 85, 2305.
(3) Alfonsov, V. A.; Bakaleynik, G. A.; Gubaidullin, A. T.;
Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Litvinov,
I. A.; Strobykina, I. Yu.; Andreeva, O. V.; Korochkina, M.
G. Mendeleev Commun. 1999, 6, 227.
(–)-(2-Methoxyphenyl)-ent-15-oxobeyeran-19-oate (9)
Under an inert atmosphere 6 (270 mg, 0.8 mmol) and catechol (200
mg, 1.8 mmol) were added to a suspension of P4O10 (50 mg) in tol-
uene (20 mL). The suspension was heated to reflux, whereupon
TfOH (90 mg, 0.6 mmol) was added. The resulting mixture was
stirred under reflux for 30 min after which ice (20 g) was added. The
suspension was fractionated with MTBE (30 mL) and aq NaOH
(20%, 30 mL). The aqueous layer was extracted with MTBE (2 × 30
mL) and the combined organic layers were washed with H2O
(2 × 30 mL) and brine (30 mL). After drying (MgSO4), the solution
was concentrated under reduced pressure and the crude product was
purified by column chromatography (cyclohexane–EtOAc, 98:2).
(4) Bomkamp, M.; Artiukhov, A.; Kataeva, O.; Waldvogel, S.
R. Synthesis 2007, 1107.
(5) (a) Waldvogel, S. R.; Fröhlich, R.; Schalley, C. A. Angew.
Chem. Int. Ed. 2000, 39, 2472. (b) Bomkamp, M.; Siering,
C.; Landrock, K.; Stephan, H.; Fröhlich, R.; Waldvogel, S.
R. Chem. Eur. J. 2007, 13, 3724.
(6) (a) Schopohl, M. C.; Siering, C.; Kataeva, O.; Waldvogel, S.
R. Angew. Chem. Int. Ed. 2003, 42, 2620. (b) Schophol, M.
C.; Faust, A.; Mirk, D.; Fröhlich, R.; Kataeva, O.;
Waldvogel, S. R. Eur. J. Org. Chem. 2005, 2987.
(7) Fabris, F.; Zambrini, L.; Rosso, E.; De Lucchi, O. Eur. J.
Org. Chem. 2004, 15, 3313.
(8) Coates, M. C. J. Org. Chem. 1987, 52, 2065.
(9) Rabjohn, N. Org. React. 1976, 24, 261.
(10) Cram, D. J.; Sahyun, M. R. V. J. Am. Chem. Soc. 1962, 84,
1734.
25
Yield: 80 mg (22%); colourless crystalline solid; mp 139 °C; [a]D
–14.4 (c 1.00, CHCl3).
1H NMR (400 MHz, CDCl3): d = 0.87 (s, 3 H, CH3), 0.91 (dt,
J = 13.1, 4.2 Hz, 1 H), 1.07 (s, 3 H, CH3), 1.09 (dd, J = 13.5, 4.1 Hz,
1 H), 1.15–1.26 (m, 3 H), 1.30–1.67 (m, 9 H), 1.40 (s, 3 H), 1.75–
1.97 (m, 3 H), 2.14 (dd, J = 18.6, 4.1 Hz, 1 H), 2.28–2.31 (m, 1 H),
2.50 (ddd, J = 26.6, 13.7, 3.7 Hz, 1 H), 3.83 (s, 3 H), 6.90–6.96 (m,
2 H), 7.02 (dd, J = 7.8, 1.6 Hz, 1 H), 7.16 (ddd, J = 8.2, 7.4, 1.7 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 12.2, 19.1, 21.0, 21.1, 27.2, 29.1,
33.9, 34.8, 38.5, 38.7, 38.8, 41.0, 44.3, 51.3, 52.8, 54.5, 55.8, 56.7,
57.1, 112.4, 120.7, 122.9, 126.5, 140.0, 151.55, 175.7, 222.3.
(11) Caglioti, L. Tetrahedron 1966, 22, 487.
(12) Frey, B.; Schnaubelt, J.; Reißig, H.-U. Eur. J. Org. Chem.
1999, 1385.
(13) (a) Waldvogel, S. R.; Mirk, D. Tetrahedron Lett. 2000, 41,
4769. (b) Waldvogel, S. R.; Mirk, D.; Herbrüggen, J. GDCh-
Monographie 2001, 23, 233.
Anal. Calcd for C27H36O4: C, 76.38; H, 8.55. Found: C, 76.70; H,
8.71.
(14) Tested reaction conditions for the synthesis of 8: (+)-
Methyl-ent-15-oxobeyeran-19-oate (6) was dissolved in
toluene, chlorobenzene or 1,2-dichlorobenzene and, after
addition of catechol and a catalytic amount of a Brønsted
acid, the mixture was heated under reflux applying a Dean–
Stark trap. Even under very harsh conditions such as TsOH
in boiling 1,2-dichlorobenzene (180 °C) or TfOH in boiling
toluene, no product formation was observed.
X-ray Crystal Structure Determination
Crystallization resulted from slow solvent diffusion from a solution
of 9 in CH2Cl2 and MeOH, which was covered with n-heptane. The
data set for 9 was collected with a Nonius Kappa CCD diffractome-
ter equipped with fine-focus Cu Ka radiation sealed tube
(l = 1.54178 Å). Programs used: data collection COLLECT (Non-
ius B.V., 1998), data reduction Denzo-SMN,18 absorption correc-
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