Synthetic transformations of higher terpenoids. XXVII.* synthesis of 7-hydroxylabdanoids and their transformations

Article abstract of DOI:10.1007/s10600-012-0215-3

Allylic oxidation of phlomisoic acid and its methyl ester by selenium dioxide occurred stereoselectively to form 7α-hydroxy derivatives of labdanoids, which were oxidized by active manganese dioxide to 7-ketofuranolabdanoids. Oximation of the last by hydr

Full text of DOI:10.1007/s10600-012-0215-3

Chemistry of Natural Compounds, Vol. 48, No. 2, May, 2012 [Russian original No. 2, March-April, 2012]
SYNTHETIC TRANSFORMATIONS OF HIGHER TERPENOIDS.
ꢀ
XXVII. SYNTHESIS OF 7-HYDROXYLABDANOIDS
AND THEIR TRANSFORMATIONS
Yu. V. Kharitonov, E. E. Shulꢁts, Yu. V. Gatilov,
I. Yu. Bagryanskaya, M. M. Shakirov,
and G. A. Tolstikov
UDC 547.913.6
Allylic oxidation of phlomisoic acid and its methyl ester by selenium dioxide occurred stereoselectively
to form 7ꢂ-hydroxy derivatives of labdanoids, which were oxidized by active manganese dioxide to
7-ketofuranolabdanoids. Oximation of the last by hydroxylamine hydrochloride in MeOH in the presence of
NaOAc gave pure (E)-ketooximes. Beckmann rearrangement of 7-ketooximes of phlomisoic acid and its
methyl ester occurred with formation of the corresponding octahydro-1H-benzoazepines.
Keywords: phlomisoic acid, synthesis, 7R-hydroxy-15,16-epoxy-8(9),13(16),14-labdatrien-18-oic acid,
7-ketolabdanoids, oximes, 5-furan-3-ylethylbenzoazepines, XSA.
Furan-containing labdanoids functionalized in ring B were isolated from extracts of plants that exhibit sedative and
uterotonic properties and are used in folk medicine for cardiovascular disorders [2]. 7-Keto- and 7-hydroxyfurolabdanoids
showed antibacterial [3], antifeedant [4], and cytotoxic activity [5]. The isolation of 8,9-secofuranolabdanoids that exhibited
cytotoxicity against human tumor cells was reported [6]. Promising inhibitors of N–O synthase were recently found among
labdanoids modified in ring B [7]. Therefore, it seemed interesting to synthesize modified labdanoids. Currently known
approaches are most often based on transformations of available natural metabolites [8, 9]. We proposed earlier methods for
preparing the plant diterpenoid phlomisoic acid (1) and its ester 2 from lambertianic acid, an available metabolite of Pinus
sibirica R. Major [10, 11]. Herein results from a study of the transformations of furanolabdanoids 1 and 2 in ring B are
reported.
Allylic oxidation of 1 and 2 by SeO in dioxane occurred stereoselectively to form 7ꢂ-hydroxy derivatives 3 and 4
2
(59 and 74% yields, respectively) (Scheme 1). This could be explained by attack of the reagent from the less hindered ꢂ-side.
An analogous stereochemical result was obtained upon oxidation by this reagent of other labdanoids, in particular (+)-coronarin
E [9].
O
13
O
O
20
11
O
1
9
O
15
17
B
SeO
2
O
HO
5
3
7
OH
H
H
O
RO C
2
RO C
2
19
18
1, 2
3, 4
5
1, 3: R = H; 2, 4: R = CH
3
ꢃꢃꢃꢃꢃꢃ
For No. XXVI, see Ref. [1].
Scheme 1
ꢀ
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, RussianAcademy of Sciences, 630090,
Novosibirsk, Prosp. Lavrentꢁeva, 9, fax: (383) 330 97 52, e-mail: schultz@nioch.nsc.ru. Translated from Khimiya Prirodnykh
Soedinenii, No. 2, March–April, 2012, pp. 225–231. Original article submitted July 31, 2011.
©
250
0009-3130/12/4802-0250 2012 Springer Science+Business Media, Inc.

TABLE 1. Parameters of H-Bonds for the Crystal Solvate of 3
°
°
X–H…Y bond
Í…X, A
X...Y, A
X-H...Y, ꢆ
O(1R)-H(1R)...O(4)
O(2)-H(2)...O(1R)
O(3)-H(3)...O(2)
2.02
1.92
1.86
2.806 (2)
2.732 (2)
2.662 (2)
161
168
164
O4
O3
C18
C3
C20
C19
C4
C5
C2
C1
C10
C6
O2
C11
C9
C7
C8
C16
C13
C14
C12
O1
C17
C15
Fig. 1. Molecular structure of 3 from an XSA. The EtOH solvate molecule is not shown.
The structure of 3 was established by an x-ray crystal structure analysis (XSA) (Fig. 1). The unit cell contained one
molecule of 3 and one EtOH molecule. The bond lengths and angles were similar within 3ꢄ of the mean-statistical values [12].
The cyclohexane ring had the chair conformation; the cyclohexene moiety, a half-chair conformation. The furan ring was
°
practically planar (mean-statistical deviation of atoms from the plane, 0.005 A ). Molecules of 3 in the crystal were linked
through H-bonds with EtOH solvate molecules and to each other into infinite 3D-frameworks (Table 1). The presence of H...ꢅ
°
°
interactions (distance from H to the furan-ring centroids H19B…Cg, 2.67 A ; H15…Cg, 2.92 A ) was also noteworthy. A
structure with a similar framework and an analogous configuration of the substituents, hispanolane 1,7,7ꢁ-borate (5) [14], was
found in the Cambridge Crystallographic Structure Database (CCSD) [13].
Oxidation of 3 and 4 by active manganese dioxide in CH Cl gave the corresponding unsaturated ketones 6 and 7 (49
2
2
and 69% yields, respectively) (Scheme 2). We studied the possibility of transforming the labdanoid ketones into benzoazepine
derivatives. Reaction of 6 or 7 with hydroxylamine hydrochloride in MeOH in the presence of NaOAc produced pure
(E)-oximes 8 and 9 (89 and 98% yields, respectively). Treatment of ketooxime 8 with thionylchloride in anhydrous dioxane
formed a mixture of isomeric lactams, derivatives of ocahydro-1H-benzo[d]azepine (10) and octahydro-1H-benzo[c]azepine
(11) in 30 and 8% yields, respectively. Beckmann rearrangement of oxime 9 under the described conditions gave derivative 12
in 20% yield. The formation of 10 and 11 upon rearrangement of (E)-oxime 8 was obviously related to partial isomerization
of 8 into the corresponding (Z)-oxime under the reaction conditions, which rearranged to form octahydro-1H-benzo[c]azepine
11. The formation of 12 upon rearrangement of the (E)-oxime of methyl ester 9 indicated that it isomerized readily into the
(Z)-oxime upon treatment with SOCl in dioxane and rearranged subsequently. An attempt to perform the Beckmann
2
rearrangement of the sulfonate of (E)-oxime 13 in acetic acid saturated with HCl was unsuccessful. Only starting 13 was
isolated. An attempt to perform the reaction in trifluoroacetic acid afforded the corresponding (E)-oxime 9.
The structure of 12 was established by an XSA. Two molecules of 12 and an EtOH solvate molecule were located in
the independent unit part of the crystallographic cell. Figure 2 shows the molecular structure of 12. The second molecule is
highly disordered. The six-membered ring had the chair conformation with axial carboxymethyl and C-5a methyls. The
conformation of seven-membered ring B in the disordered molecule was close to a boat with atoms N(22), C-29a, and C-21
°
deviating from the plane of the double bond by 0.910(7), 1.399(7), and 1.907(6) A, respectively. A similar conformation of a
seven-membered ring was noted in (4aS,6S,9aS)-6-methoxy-9-vinyl-1,2,3,4,4a,6,7,9a-octahydro-5H-benzo(7)annulen-5-one [15].
251

O6A
C35B
C35A
C36A
O6B
C34B
C15
O2
C34A
C33A
C32A
C36B
C16
C13
C11
C7
C26A
C27B
C6
C27A
C28A
C14
C33B
C26B
C31A
C32B
C31B
C28B
C37
C12
C8
C25B
C25A
O7
C5A
C17
C9
C5
C29
C25
C19
O3
C4
C39
C10
C9A
C29A
C38
C30
C24
C23
O5
C20
C21
C18
C3
O4
O8
C1
C40
O1
N2
N22
Fig. 2. General view of the crystallographically independent molecules of 12. The EtOH solvate molecule is not shown.
The conformation of ring B in the ordered molecule of 12 was distorted, i.e., atom C-9a also lay in the plane of the double
°
bond. The deviations of N(2) and C-1 from the plane of the double bond were 0.686(5) and 1.158(5) A. The two independent
molecules in the crystal formed pairs through two H-bonds N(2)–H…O(5) and N(22)–H…O(1) with parameters H…O 2.08
°
and 2.10, N…O 2.947(4) and 2.819(4) A and N–H…O 169 and 138°. The EtOH solvate molecule was also bonded to these
°
pairs through an H-bond O1…O1W 2.722(5) A .
13
O
O
11
20
O
O
17
5
15
a
b
7
7
c
5a
9a
3
O
3, 4
3
NH
8
+
9
9
1
O
N
NH
H
H
1
H
H
O
HO C
HO C
2
2
OH
RO C
RO C
2
2
19
18
6, 7
8, 9
10
11
6, 8: R = H; 7, 9: R = CH
3
O
O
d
c
9
9
O
N
NH
H
H
H CO C
3
2
OTs
H CO C
3
2
12
a. MnO ; b. NH OH4HCl, AcONa; c. SOCl ; d. TsCl, Py, DMAP
13
2
2
2
Scheme 2
The compositions and structures of the prepared compounds were confirmed by elemental analysis and mass, IR, UV
and NMR spectra. The axial orientation of the C-7 hydroxyl in 3 and 4 was confirmed by PMR spectra. Proton H-7 resonated
as a doublet with spin–spin coupling constant 2.2–2.3 Hz with the H-6a proton. Oximes 8 and 9 were formed as pure geometric
isomers. The C-6 protons in PMR spectra of 8 and 9 were shifted to weak field ( 2.77 and 3.46 ppm for 8) compared with the
location of the corresponding protons in the spectra of ketones 6 and 7 ( 2.74 and 2.96 ppm for 6). A comparison of the
13
chemical shifts in C NMR spectra of resonances for C-6 and C-8 and the corresponding starting carbonyl compounds
showed a significant strong-field shift for C-6 in 8 and 9 (ꢇ = 14.3–15.3 ppm) (the change of shift for C-8 was about
ꢇ 5.7 ppm). These results confirmed that the oxime had the (E)-configuration [16].
13
PMR and C NMR spectra of furan-substituted octahydro-1H-benzo[d]azepine 10 had characteristic differences
that enabled the structure to be unambiguously determined. The magnetically non-equivalent C-1 protons were situated at
13
stronger field than the corresponding protons in spectra of 11 and 12. Atom C-1 in the C NMR spectrum of 10 also had a
characteristic strong-field shift ( 28.82 ppm) compared with the locations of the C-1 resonances in 11 and 12 ( 36.36 and
36.68 ppm). Atoms C-4, C-5a, C-9a, and C-17 experienced analogous strong-field shifts. The singlet for C-5 was shifted to
weaker field 158.20 ppm than the corresponding C atom in isomers 11 and 12.
252

Thus, methods for preparing 7-hydroxy- and 7-ketolabdanoids were developed based on the available labdanoid
phlomisoic acid. The regioselectivity of the Beckmann rearrangement depended on the substituents in the bicyclic fragment
of the corresponding 7-ketooxime.
EXPERIMENTAL
1
NMR spectra were taken from CDCl solutions on Bruker AV-300 (operating frequency 300.13 for H and
3
13
1
13
75.47 MHz for C) and AV-600 (operating frequency 600.30 for H and 150.96 MHz for C) instruments. Resonances in
NMR spectra were assigned using various types of H–H and C–H shift correlation spectroscopy (COSY, COXH, COLOC).
Multiplicities of resonances in C NMR spectra were determined by standard methods of recording spectra with J-modulation
13
(JMOD). The atomic numbering of the diterpene framework given for the structures of 1, 2 (for 3–9), and 10 (for 10–12) was
13
used to describe the PMR and C NMR spectra of the new diterpenoid derivatives.
Mass spectra were obtained in a DFS Thermo Scientific high-resolution mass spectrometer (ionizing electron energy
20
70 eV, vaporizer temperature 230–280°C). Specific rotation [ꢂ] was measured at room temperature (20–23°C) in CHCl
D
3
solution on a PoLAAr3005 polarimeter. IR spectra were recorded in KBr pellets on a Vector-22 instrument. UV absorption
–4
spectra were recorded in EtOH (c 10 M) on an HP 8453 UV–Vis spectrometer. The XSA was performed on a Kappa Apex
II (Bruker) diffractometer with a two-coordinate CCD detector at room temperature (Mo Kꢂ-radiation, graphite monochromator,
ꢈ–ꢉ-scanning in the limit 2ꢊ = 54.4°).
The course of reactions and purity of products were monitored by TLC on Silufol UV-254 plates using CHCl :EtOH
3
(10:1) and petroleum ether:EtOAc (10:1). Spots were detected by spraying plates with aqueous H SO (10%) with subsequent
2
4
heating to 100°C or by illumination in UV light. Phlomisoic acid (1) was prepared from lambertianic acid according to the
literature method [11]; the methyl ester of 1 (2), as before [10].
(1S,4aS,7R,8aR)-7-Hydroxy-1,4a,6-trimethyl-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-
carboxylic Acid [7R-Hydroxy-15,16-epoxy-8(9),13(16),14-labdatrien-18-oicAcid] (3). Asolution of 1 (1.00 g, 3.16 mmol)
in dioxane under a stream of Ar was treated with SeO (0.42 g, 3.79 mmol), stirred for 13 h, diluted with H O (50 mL), and
2
2
extracted with CHCl (3 ꢋ 50 mL). The organic layer was washed with H O (3 ꢋ 50 mL) and dried over MgSO . The solvent
3
2
4
was evaporated in vacuo. The solid was chromatographed over silica gel (CHCl eluent). Crystallization from Et O afforded
3
2
20
–1
3 (0.62 g, 59%) as a white solid, mp 103–105°C, [ꢂ] +94.4° (c 1.1). IR spectrum (ꢌ, cm ): 3412, 2935, 2609, 1692, 1650,
D
1503, 1469, 1445, 1256, 1209, 1026, 874, 780, 600.
PMR spectrum ( , ppm, J/Hz): 0.84 (3H, s, H -20), 1.06 (1H, dt, J = 13.3, 4.1, H-3), 1.24 (1H, m, H-1), 1.26 (3H, s,
3
H -19), 1.52 (1H, dm, J = 13.0, 2.9, H-2), 1.73 (1H, dd, J = 11.7, 1.8, H-5), 1.75 (3H, s, H -17), 1.84, 1.87 (2H, m, H-1, 2), 1.91
3
3
(1H, m, H-6), 1.97 (1H, m, H-11), 2.16–2.77 (3H, m, H-3, 6, 11), 2.47 (2H, m, H-12), 3.47 (1H, m, OH), 3.50 (1H, d, J = 2.3,
H-7), 3.72 (1H, m, OH), 6.27 (1H, dd, J = 1.8, 0.9, H-14), 7.21 (1H, dd, J = 1.4, 0.9, H-16), 7.33 (1H, dd, J = 1.8, 1.4, H-15).
13
C NMR spectrum ( , ppm): 16.18 (q, C-20), 17.64 (q, C-17), 19.24 (t, C-2), 24.97 (t, C-12), 25.63 (t, C-6), 28.30 (q,
C-19), 28.82 (t, C-11), 36.38 (t, C-3), 37.04 (t, C-1), 40.21 (s, C-10), 43.26 (s, C-4), 46.71 (d, C-5), 70.30 (d, C-7), 110.60 (d,
C-14), 125.07 (s, C-13), 127.96 (s, C-8), 138.32 (d, C-16), 142.68 (d, C-15), 144.11 (s, C-9), 183.78 (s, C-18).
Mass spectrum (m/z, I , %): 314 (14), 253 (14), 250 (33), 237 (24), 233 (48), 232 (23), 217 (16), 191 (21), 188 (12),
rel
187 (79), 174 (17), 173 (100), 159 (32), 145 (39), 135 (27), 133 (31), 119 (49), 105 (36), 95 (44), 91 (44), 81 (80), 67 (27), 53
(32), 42 (27), 41 (40), 28 (30). C H O . [M] 332.1980.
20 28
4
(1S,4aS,7R,8aR)-Methyl-7-hydroxy-1,4a,6-trimethyl-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (4). A solution of 2 (1.00 g, 3.03 mmol) in dioxane under a stream of Ar was treated
with SeO (0.40 g, 3.63 mmol), stirred for 13 h, diluted with H O (50 mL), and extracted with CHCl (3 ꢋ 50 mL). The
2
2
3
organic layer was washed with H O (3 ꢋ 50 mL) and dried over MgSO . The solvent was evaporated in vacuo. The solid was
2
4
20
chromatographed over silica gel (petroleum ether:Et O eluent, 4:1) to afford 4 (0.76 g, 74%) as an oil, [ꢂ] +124.48° (c 2.1).
IR spectrum (ꢌ, cm ): 3391, 2948, 2873, 1724, 1651, 1501, 1466, 1443, 1380, 1234, 1198, 1161, 1143, 1054, 1026, 991, 874,
2
D
–1
779, 756, 600.
PMR spectrum ( , ppm, J/Hz): 0.71 (3H, s, H -20), 1.04 (1H, td, J = 13.5, 4.4, H-3), 1.20 (3H, s, H -19), 1.22 (1H, m,
3
3
H-1), 1.53 (1H, dm, J = 13.9, H-2), 1.62 (1H, dd, J = 13.0, 2.2, H-5), 1.77 (3H, s, H -17), 1.82–1.91 (2H, m, H-1, 2), 1.95 (1H,
3
dt, J = 14.4, 4.2, H-6), 2.05 (1H, td, J = 14.4, 2.0, H-6), 2.12 (1H, m, H-11), 2.22 (2H, m, H-3, 11), 2.43 (2H, m, H-12), 3.60
(3H, s, OCH ), 3.93 (1H, d, J = 2.2, H-7), 6.26 (1H, dd, J = 1.6, 1.0, H-14), 7.20 (1H, dd, J = 1.0, 0.8, H-16), 7.32 (1H, dd,
3
J = 1.6, 0.8, H-15).
253

13
C NMR spectrum ( , ppm): 15.99 (q, C-20), 17.67 (q, C-17), 19.33 (t, C-2), 25.01 (t, C-12), 28.13 (q, C-19), 28.84
(t, C-11), 30.14 (t, C-6), 36.46 (t, C-3), 37.38 (t, C-1), 40.03 (s, C-10), 43.37 (s, C-4), 46.73 (d, C-5), 51.13 (q, OCH ), 70.16
3
(d, C-7), 110.61 (d, C-14), 125.10 (s, C-13), 128.16 (s, C-8), 138.32 (d, C-16), 142.66 (d, C-15), 143.93 (s, C-9), 177.88 (s,
C-18).
Mass spectrum (m/z, I , %): 346 (6), 328 (18), 369 (18), 265 (21), 264 (100), 253 (17), 251 (47), 191 (96), 189 (19),
rel
187 (31), 173 (45), 149 (17), 145 (17), 135 (72), 133 (19), 123 (27), 121 (19), 119 (21), 109 (25), 108 (18), 107 (23), 105 (26),
85 (19), 83 (29), 81 (79), 79 (22), 67 (26), 57 (18), 55 (24), 53 (30), 43 (22), 41 (32). C H O . [M] 346.2136.
21 30
4
(1S,4aS,8aR)-1,4a,6-Trimethyl-7-oxo-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-
carboxylic Acid [7-Oxo-15,16-epoxy-8(9),13(16),14-labdatrien-18-oic Acid] (6). A solution of 3 (1.00 g, 3.01 mmol) in
CH Cl was stirred vigorously, treated with freshly prepared MnO (6.54 g, 75.20 mmol), and stirred for 24 h at room temperature.
2
2
2
The precipitate was filtered off and washed with CH Cl . The solvent was evaporated in vacuo. The solid was chromatographed
2
2
over silica gel (CHCl eluent). Ketone 6 (0.49 g, 49%) and starting 3 (0.50 g) eluted successively.
3
20
–1
Compound 6: [ꢂ] +119.36° (c 2.52). UV spectrum (ꢍ , nm, log ꢎ): 248 (3.89). IR spectrum (ꢌ, cm ): 3145,
D
max
2939, 2631, 1722, 1694, 1661, 1606, 1501, 1469, 1379, 1346, 1261, 1160, 1025, 874, 756, 600.
PMR spectrum ( , ppm, J/Hz): 1.01 (3H, s, H -20), 1.08 (1H, dt, J = 13.6, 4.3, H-3), 1.24 (3H, s, H -19), 1.38 (1H, dt,
3
3
J = 13.1, 3.6, H-1), 1.61 (1H, td, J = 14.1, 2.8, H-2), 1.79 (3H, s, H -17), 1.90 (1H, dd, J = 15.0, 3.2, H-5), 1.93 (1H, td, J = 14.1,
3
3.2, H-2), 1.99 (1H, dm, J = 12.6, H-1), 2.23 (1H, dm, J = 13.2, H-3), 2.38–2.45 (2H, m, H-11), 2.52 (2H, m, H-12), 2.74 (1H,
dd, J = 17.6, 3.2, H-6), 2.96 (1H, dd, J = 17.6, 15.0, H-6), 6.28 (1H, d, J = 1.6, H-14), 7.24 (1H, d, J = 1.0, H-16), 7.34 (1H, dd,
J = 1.0, 1.6, H-15).
13
C NMR spectrum ( , ppm): 11.10 (q, C-20), 15.48 (q, C-17), 18.61 (t, C-2), 23.71 (t, C-12), 27.48 (q, C-19), 30.06
(t, C-11), 35.50 (t, C-3), 35.98 (t, C-6), 36.54 (t, C-1), 41.04 (s, C-10), 43.03 (s, C-4), 50.23 (d, C-5), 110.08 (d, C-14), 123.91
(s, C-13), 130.36 (s, C-8), 138.16 (d, C-16), 142.60 (d, C-15), 165.19 (s, C-9), 182.25 (s, C-18), 199.81 (s, C-7).
C H O . [M] 330.1823.
20 26
4
(1S,4aS,8aR)-Methyl 1,4a,6-trimethyl-7-oxo-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-
carboxylate (7). A solution of 4 (1.00 g, 2.89 mmol) in CH Cl was stirred vigorously, treated with active MnO (6.54 g,
2
2
2
75.20 mmol), and stirred for 24 h. The solid was filtered off and washed with CH Cl . The solvent was evaporated in vacuo.
2
2
20
The solid was chromatographed over silica gel (petroleum ether:Et O eluent, 4:1) to afford 7 (0.69 g, 69%), [ꢂ] +127.45°
(c 1.96). UV spectrum (ꢍ , nm, log ꢎ): 203 (4.01), 246 (4.02). IR spectrum (ꢌ, cm ): 3424, 2958, 2939, 2860, 1722, 1659,
2
D
–1
max
1608, 1462, 1380, 1332, 1234, 1191, 1163, 1139, 1086, 1026, 870, 791.
PMR spectrum ( , ppm, J/Hz): 0.83 (3H, s, H -20), 0.99t (1H, m, J
= 13.5, H-3), 1.09 (3H, s, H -19), 1.30 (1H, m,
3
3
gem
H-1), 1.53 (1H, dm, J = 14.4, H-2), 1.71 (3H, s, H -17), 1.80 (1H, dd, J = 15.0, 3.2, H-5), 1.81 (1H, m, H-2), 1.91 (1H, m,
3
H-1), 2.16 (1H, m, H-3), 2.30–2.40 (2H, m, H-11), 2.43–2.45 (2H, m, H-12), 2.64 (1H, dd, J = 17.4, 3.2, H-6), 2.92 (1H, dd,
J = 17.6, 15.0, H-6), 3.56 (3H, s, OCH ), 6.21 (1H, d, J = 1.6, H-14), 7.22 (1H, d, J = 0.8, H-16), 7.30 (1H, dd, J = 1.6, 0.8,
3
H-15).
13
C NMR spectrum ( , ppm): 11.35 (q, C-20), 15.52 (q, C-17), 18.95 (t, C-2), 24.01 (t, C-12), 27.54 (q, C-19), 30.30
(t, C-11), 35.81 (t, C-3), 36.46 (t, C-6), 37.13 (t, C-1), 41.12 (s, C-10), 43.39 (s, C-4), 50.55 (d, C-5), 51.29 (q, OCH ), 110.39
3
(d, C-14), 124.23 (s, C-13), 130.35 (s, C-8), 138.42 (d, C-16), 142.82 (d, C-15), 164.85 (s, C-9), 176.81 (s, C-18), 199.38 (s,
C-7).
Mass spectrum (m/z, I , %): 344 (13), 286 (39), 326 (15), 251 (10), 250 (18), 190 (12), 189 (75), 177 (15), 176 (51),
rel
161 (11), 149 (10), 135 (25), 105 (11), 110 (10), 95 (11), 91 (13), 82 (15), 81 (100), 53 (14), 41 (13), 28 (17), 18 (38).
C H O . [M] 344.1986.
21 28
4
(1S,4aS,8aR,E)-7-Hydroxyimino-1,4a,6-trimethyl-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylic Acid (8). A solution of 6 (1.00 g, 3.03 mmol) in MeOH (20 mL) was treated with
hydroxylamine hydrochloride (0.38 g, 5.45 mmol) and NaOAc (1.37 g, 16.67 mmol), stirred for 5 h at room temperature, and
left overnight. The solvent was evaporated. The solid was treated with H O (40 mL) and extracted with CHCl (3 ꢋ 30 mL).
2
3
The organic layer was washed with H O (3 ꢋ 30 mL) and dried over MgSO . The solvent was evaporated in vacuo. The solid
2
4
was chromatographed over silica gel (CHCl eluent). Trituration of fractions containing the product in petroleum ether afforded
3
20
8 (0.93 g, 89%) as a white powder, mp 154–156°C, [ꢂ] +166.25° (c 2.08). UV spectrum (ꢍ , nm, log ꢎ): 243 (3.97).
IR spectrum (ꢌ, cm ): 3266, 2938, 2553, 1773, 1693, 1619, 1501, 1466, 1381, 1355, 1331, 1186, 1165, 1144, 1062, 1025,
D
max
–1
978, 943, 909, 874, 811, 780, 751.
254

PMR spectrum ( , ppm, J/Hz): 0.94 (3H, s, H -20), 1.07 (1H, m, H-3), 1.28 (3H, s, H -19), 1.32 (1H, m, H-1), 1.62
3
3
(1H, dd, J = 14.6, 2.8, H-5), 1.81 (1H, m, H-2), 1.84 (3H, s, H -17), 1.93 (1H, m, H-2), 2.00 (1H, m, H-1), 2.26 (1H, m, H-3),
3
2.34 (1H, m, H-1), 2.45–2.52 (4H, m, H-11, 12), 2.77 (1H, dd, J = 17.6, 14.6, H-6), 3.46 (1H, dd, J = 17.6, 2.8, H-6), 6.30 (1H,
dd, J = 1.6, 0.8, H-14), 7.28 (1H, d, J = 0.8, H-16), 7.35 (1H, dd, J = 1.6, 0.8, H-15).
13
C NMR spectrum ( , ppm): 13.32 (q, C-20), 16.68 (q, C-17), 19.33 (t, C-2), 21.68 (t, C-6), 25.17 (t, C-12), 28.21 (q,
C-19), 29.66 (t, C-11), 36.31 (t, C-3), 37.48 (t, C-1), 40.27 (s, C-10), 43.66 (s, C-4), 49.67 (d, C-5), 110.55 (d, C-14), 124.12
(s, C-13), 124.57 (s, C-8), 138.45 (d, C-16), 142.82 (d, C-15), 153.54 (s, C-9), 158.17 (s, C-7), 182.84 (s, C-18).
Mass spectrum (m/z, I , %): 345 (14), 328 (26), 315 (20), 314 (44), 264 (45), 251 (39), 250 (96), 248 (19), 234 (23),
rel
233 (57), 232 (76), 188 (24), 187 (62), 186 (37), 175 (28), 174 (21), 173 (73), 171 (23), 159 (31), 145 (38), 133 (27), 131 (22),
119 (40), 107 (24), 105 (35), 96 (23), 95 (48), 93 (23), 91 (40), 81 (100), 79 (22), 77 (24), 67 (25), 55 (21), 53 (34). C H O N.
20 27
4
[M] 345.1940.
(1S,4aS,8aR,E)-Methyl 7-Hydroxyimino-1,4a,6-trimethyl-5-[2-(furan-3-yl)ethyl]-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (9). A solution of 7 (1.00 g, 2.90 mmol) in MeOH (20 mL) was treated with
hydroxylamine hydrochloride (0.24 g, 3.48 mmol) and NaOAc (1.31 g, 15.96 mmol), stirred for 5 h at room temperature, and
left overnight. The solvent was evaporated. The solid was treated with H O (40 mL) and extracted with CHCl (3 ꢋ 30 mL).
2
3
The organic layer was washed with H O (3 ꢋ 30 mL) and dried over MgSO . The solvent was evaporated in vacuo. The solid
2
4
was chromatographed over silica gel (petroleum ether:Et O eluent, 4:1). Crystallization from petroleum ether afforded 9
2
20
(1.02 g, 98%) as a white powder, mp 131–133°C, [ꢂ] +134.50° (c 0.8). UV spectrum (ꢍ , nm, log ꢎ): 201 (4.1), 243
D
max
–1
(4.25). IR spectrum (ꢌ, cm ): 3248, 2943, 2854, 1724, 1626, 1502, 1462, 1439, 1379, 1356, 1236, 1196, 1143, 1026, 962,
904, 872, 779.
PMR spectrum ( , ppm, J/Hz): 0.81 (3H, s, H -20), 1.04 (1H, dt, J = 13.5, 3.8, H-3), 1.25 (3H, s, H -19), 1.33 (1H, dt,
3
3
J = 13.4, 3.5, H-1), 1.58 (2H, m, H-2, 5), 1.87 (3H, s, H -17), 1.92 (1H, m, H-2), 2.97 (1H, m, H-1), 2.23 (1H, m, H-3), 2.30
3
(1H, m, H-11), 2.41 (1H, m, H-11), 2.47–2.53 (2H, m, H-12), 2.69 (1H, dd, J = 17.7, 14.5, H-6), 3.43 (1H, dd, J = 17.7, 3.5,
H-6), 3.65 (3H, s, OCH ), 6.28 (1H, dd, J = 1.4, 0.9, H-14), 7.23 (1H, d, J = 0.9, H-16), 7.34 (1H, d, J = 1.4, 0.9, H-15).
3
13
C NMR spectrum ( , ppm): 13.09 (q, C-20), 16.29 (q, C-17), 19.28 (t, C-2), 21.18 (t, C-6), 25.17 (t, C-12), 27.92 (q,
C-19), 29.57 (t, C-11), 36.36 (t, C-3), 37.72 (t, C-1), 40.00 (s, C-10), 43.88 (s, C-4), 49.76 (d, C-5), 51.32 (q, OCH ), 110.56
3
(d, C-14), 124.53* (s, C-13), 124.67* (s, C-8), 138.43 (d, C-16), 142.80 (d, C-15), 152.06 (s, C-9), 157.97 (s, C-7), 177.36 (s,
C-18).
Mass spectrum (m/z, I , %): 359 (7), 342 (19), 278 (26), 265 (36), 264 (100), 246 (35), 218 (43), 204 (18), 200 (14),
rel
188 (10), 187 (11), 186 (52), 159 (12), 158 (11), 146 (13), 145 (11), 144 (14), 136 (11), 132 (10), 119 (10), 107 (14), 105 (16),
91 (21), 81 (73), 79 (14), 77 (14), 67 (11), 55 (13), 53 (38), 41 (22), 27 (11). C H NO . [M] 359.2087.
21 29
4
Beckmann Rearrangement of Oxime 8. A solution of 8 (0.50 g, 1.45 mmol) in anhydrous dioxane (20 mL) at 0°C
was treated dropwise with freshly distilled SOCl (2 mL), stirred for 10 min at 0°C and 1 h at room temperature, diluted with
2
H O (30 mL), and extracted with CHCl (3 ꢋ 40 mL). The organic layer was washed with H O (3 ꢋ 40 mL) and dried over
2
3
2
MgSO . The solvent was evaporated in vacuo. The solid was chromatographed over a column of silica gel (CHCl eluent).
4
3
Compounds 10 (0.15 g, 30%) and 11 (0.04 g, 8%) eluted successively. Crystallization of fraction 1 from petroleum ether
isolated (5aS,9S,9aR)-9-carboxy-4,5a,9-trimethyl-5-[2-(furan-3-yl)ethyl]-2-oxo-2,3,5a,6,7,8,9,9a-octahydro-1H-
–1
benzo[d]azepine (10) as a white powder, mp 202–205°C. UV spectrum (ꢍ , nm, log ꢎ): 220 (3.91). IR spectrum (ꢌ, cm ):
max
3433, 2959, 2938, 2858, 1693, 1614, 1468, 1443, 1221, 1165, 1146, 873, 819, 779, 721, 674.
PMR spectrum ( , ppm, J/Hz): 0.81 (3H, s, H -19), 1.13 (1H, dt, J = 13.5, 4.1, H-8), 1.39 (3H, s, H -20), 1.48 (1H, dt,
3
3
J = 13.5, 2.9, H-6), 1.63 (1H, m, H-7), 1.66 (1H, dd, J = 12.4, 3.2, H-9a), 1.99 (3H, s, H -17), 1.98 (1H, m, H-6), 2.17 (1H, td,
3
J = 13.5, 2.7, H-7), 2.32 (1H, m, H-8), 2.42–2.54 (4H, m, H-11, 12), 3.18 (1H, dd, J = 16.8, 3.2, H-1), 3.53 (1H, dd, J = 16.8,
12.4, H-1), 6.27 (1H, d, J = 1.6, H-14), 7.23 (1H, d, J = 0.8, H-16), 7.34 (1H, dd, J = 1.6, 0.8, H-15).
13
C NMR spectrum ( , ppm): 13.66 (q, C-17), 18.46 (q, C-20), 19.15 (t, C-7), 24.63 (t, C-12), 27.96 (q, C-19), 28.82
(t, C-1), 29.65 (t, C-11), 35.69 (t, C-6), 37.62 (t, C-8), 39.42 (s, C-5a), 44.93 (s, C-9), 46.85 (d, C-9a), 110.47 (d, C-14),
124.24* (s, C-13), 124.30* (s, C-4), 138.50 (d, C-16), 142.85 (d, C-15), 158.20 (s, C-5), 165.20 (s, C-2), 172.66 (s, C-18).
C H NO . [M] 345.1931.
20 27
4
(5aS,9S,9aR)-9-Carboxy-4,5a,9-trimethyl-5-[2-(furan-3-yl)ethyl]-3-oxo-2,3,5a,6,7,8,9,9a-octahydro-1H-
–1
benzo[c]azepine (11), oil. UV spectrum (ꢍ , nm, log ꢎ): 220 (3.90). IR spectrum (ꢌ, cm ): 3432, 2954, 2938, 2861, 1724,
max
1649, 1468, 1458, 1227, 1169, 1149, 734, 673.
255

PMR spectrum ( , ppm, J/Hz): 0.94 (1H, m, H-8), 1.24 (3H, s, H -19), 1.27 (3H, s, H -20), 1.37 (1H, m, H-6), 1.62–
3
3
1.74 (2H, m, H-7, 9a), 1.91 (3H, s, H -17), 1.90–2.08 (2H, m, H-6, 7), 2.24 (1H, m, H-8), 2.40–2.55 (4H, m, H-11, 12), 3.48
3
(1H, m, H-1), 3.94 (1H, dd, J = 14.7, 4.6, H-1), 6.31 (1H, d, J = 1.5, H-14), 7.27 (1H, d, J = 0.8, H-16), 7.38 (1H, dd, J = 1.5,
0.8, H-15).
13
C NMR spectrum ( , ppm): 15.57 (q, C-17), 19.81 (t, C-7), 21.93 (q, C-20), 25.28 (t, C-12), 30.17 (t, C-11), 30.22
(q, C-19), 36.36 (t, C-1), 39.16 (t, C-6), 40.39 (t, C-8), 42.32 (s, C-5a), 43.90 (s, C-9), 58.78 (d, C-9a), 110.74 (d, C-14),
124.43 (s, C-13), 127.87 (s, C-4), 138.71 (d, C-16), 143.05 (d, C-15), 152.17 (s, C-5), 177.87 (s, C-3), 182.28 (s, C-18).
C H NO . [M] 345.1937.
20 27
4
Beckmann Rearrangement of Oxime 9. A solution of 9 (0.50 g, 1.39 mmol) in anhydrous dioxane (20 mL) at 0°C
was treated dropwise with freshly distilled SOCl (2 mL), stirred for 9 h at room temperature, diluted with H O (30 mL), and
2
2
extracted with CHCl (3 ꢋ 40 mL). The organic layer was washed with H O (3 ꢋ 40 mL) and dried over MgSO . The solvent
3
2
4
was evaporated in vacuo. The solid was chromatographed over a column of silica gel (petroleum ether:Et O eluent) to afford
2
(5aS,9S,9aR)-9-methoxycarbonyl-4,5a,9-trimethyl-5-[2-(furan-3-yl)ethyl]-3-oxo-2,3,5a,6,7,8,9,9a-octahydro-1H-
–1
benzo[c]azepine (12) as an oil (0.10 g, 20%). UV spectrum (ꢍ , nm, log ꢎ): 220 (3.86). IR spectrum (ꢌ, cm ): 3421, 3290,
max
2890, 2945, 1755, 1724, 1649, 1468, 1382, 1363, 1232, 1203, 1153, 754.
PMR spectrum ( , ppm, J/Hz): 0.95 (1H, dt, J = 13.5, 4.1, H-8), 1.08 (3H, s, H -19), 1.21 (3H, s, H -20), 1.53 (2H, m,
3
3
H-6, 9a), 1.62 (1H, m, H-7), 1.72 (1H, m, H-6), 1.72 (1H, td, J = 13.2, 3.8, H-7), 1.94 (3H, s, H -17), 2.20 (1H, m, H-8), 2.35–
3
2.48 (4H, m, H-11, 12), 3.46 (1H, dd, J = 12.7, 4.2, H-1), 3.64 (3H, s, OCH ), 3.62 (1H, m, H-1), 6.26 (1H, d, J = 1.8, H-14),
3
6.47 (1H, br.s, NH), 7.21 (1H, d, J = 0.8, H-16), 7.32 (1H, dd, J = 1.8, 0.8, H-15).
13
C NMR spectrum ( , ppm): 16.83 (q, C-17), 19.39 (t, C-7), 20.88 (q, C-20), 24.95 (t, C-12), 29.03 (q, C-19), 30.60
(t, C-11), 36.68 (t, C-1), 38.54 (t, C-6), 39.96 (t, C-8), 43.40 (s, C-5a), 44.17 (s, C-9), 51.72 (q, OCH ), 58.18 (d, C-9a), 110.48
3
(d, C-14), 124.26 (s, C-13), 127.99 (s, C-4), 138.41 (d, C-16), 142.77 (d, C-15), 150.48 (s, C-5), 174.77 (s, C-3), 177.14 (s,
C-18).
Mass spectrum (m/z, I , %): 358 (36), 344 (32), 278 (33), 204 (23), 191 (100), 190 (89), 189 (34), 176 (35), 162 (28),
rel
161 (24), 121 (20), 119 (21), 105 (31), 91 (35), 85 (30), 83 (49), 81 (84), 79 (23), 77 (21), 67 (20), 55 (21), 53 (32), 41(29).
C H NO . [M] 358.2008.
21 22
4
(1S,4aS,8aR,E)-Methyl 1,4a,6-Trimethyl-5-[2-(furan-3-yl)ethyl]-7-[(tosyloxy)-imino]-1,2,3,4,4a,7,8,8a-
octahydronaphthalen-1-carboxylate (13). A solution of oxime 8 (1.00 g, 2.78 mmol) in Py (10 mL) was treated with tosyl
chloride (2.65 g, 13.91 mmol) and 4-dimethylaminopyridine (0.01 g, 0.08 mmol), stirred for 8 h at room temperature, left
overnight, treated with aqueous HCl (50 mL, 10%), and extracted with CHCl (3 ꢋ 30 mL). The organic layer was washed
3
with H O (3 ꢋ 30 mL) and dried over MgSO . The solvent was evaporated in vacuo. The residue afforded 13 (1.43 g, 100%)
2
4
as an oil
PMR spectrum ( , ppm, J/ Hz): 0.75 (3H, s, H -20), 1.00 (1H, dt, J = 13.4, 4.0, H-3), 1.21 (3H, s, H -19), 1.28 (1H,
3
3
dt, J = 13.2, 4.0, H-1), 1.52 (1H, dd, J = 13.3, 3.2, H-5), 1.56 (1H, m, H-2), 1.76 (3H, s, H -17), 1.83 (1H, dt, J = 14.0, 3.5,
3
H-2), 2.93 (1H, dt, J = 12.1, 3.1, H-1), 2.22 (1H, dt, J = 13.7, 3.1, H-3), 2.26–2.37 (2H, m, H-11), 2.41–2.48 (2H, m, H-12),
2.47 (3H, s, CH ), 2.67 (1H, dd, J = 18.0, 14.5, H-6), 3.29 (1H, dd, J = 18.0, 3.8, H-6), 3.65 (3H, s, OCH ), 6.26 (1H, dd,
3
3
J = 1.6, 1.0, H-14), 7.22 (1H, d, J = 1.0, H-16), 7.32 (2H, d, J = 8.6, H-3ꢁ, 5ꢁ), 7.33 (1H, dd, J = 1.6, 0.8, H-15), 7.39 (2H, d,
J = 8.6, H-2ꢁ, 6ꢁ).
13
C NMR spectrum ( , ppm): 12.74 (q, C-20), 17.02 (q, C-17), 19.06 (t, C-2), 21.51 (q, CH ), 22.54 (t, C-6), 24.69 (t,
3
C-12), 27.66 (q, C-19), 29.79 (t, C-11), 36.86 (t, C-3), 37.35 (t, C-1), 40.08 (s, C-10), 43.57 (s, C-4), 49.08 (d, C-5), 51.38 (q,
OCH ), 110.51 (d, C-14), 123.32* (s, C-13), 124.36* (s, C-8), 128.88 (d, C-2ꢁ, 6ꢁ), 129.30 (d, C-3ꢁ, 5ꢁ), 138.43 (d, C-16),
3
141.36 (s, C-4ꢁ), 142.93 (d, C-15), 146.93 (s, C-1ꢁ), 157.63 (s, C-9), 164.30 (s, C-7), 176.73 (s, C-18).
C H NO S. [M] 513.2178.
28 35
6
X-ray Crystal StructureAnalysis of 3. We used a crystal of the EtOH solvate (1:1 ratio) of size 0.20 ꢋ 0.030 ꢋ 0.40 mm.
°
° 3
The crystals were orthorhombic, a = 7.7228(3), b = 14.8159(6), c = 18.7926(8) A, V = 2150.3(2) A , space group P2 2 2 ,
1 1 1
3
–1
Z = 4, C H O + C H O, d = 1.169 g/cm , ꢏ = 0.081 mm . Intensities of 4755 independent reflections were measured.
20 28
4
2
6
calcd
Absorption corrections were applied using the SADABS program [17], which used multiple measurements of the same reflections
at different crystal orientations (transmission 0.59–0.74). The structure was solved by direct methods using the SHELXS-97
program [18]. Structure parameters were refined by anisotropic full-matrix least-squares methods using the SHELXL-97
program. Parameters of H atoms were calculated in each refinement cycle using coordinates of the corresponding non-
2
hydrogen atoms. The final structure refinement was made over all F to wR = 0.1392, S = 1.06, 252 refined parameters
2
256

(R = 0.0490 for 3872 F > 4ꢄ). A CIF file containing complete information on the structure was deposited in the CCDC, No.
729044, from where it can be obtained upon request at the internet site www.ccdc.cam.ac.uk/data_request/cif.
X-ray Crystal Structure Analysis of 12. The crystallographic data and parameters of the XSA for 12 are:
°
2(C H NO ) + C H O, MW 764.97, monoclinic system, space group P2 , a = 10.6647(8), b = 11.3857(8), c = 17.6343(14) A,
21 29
4
2
6
1
° 3
3
–1
ꢐ = 98.397(3)°, V = 2118.3(3) A , Z = 2, d
= 1.199 g/cm , ꢏ = 0.083 mm , scan range 2ꢊ < 51.3°, 14,238 measured
calcd
reflections, 6811 independent (R = 0.0409), 6053 reflections with I ꢑ 2ꢄ(I), 584 refined parameters, R [I ꢑ 2ꢄ(I)] = 0.0618,
int
1
wR = 0.1775 and GOF = 1.024 (over all reflections), absolute structure parameter (Flack) –0.1(14). The second
2
crystallographically independent molecule was disordered. The six-membered ring was disordered in the ratio 0.63(3):0.37(3).
The (furan-3-yl)ethyl substituent was disordered in the ratio 0.547(7):0.453(7). The EtOH solvate was also disordered. The
occupancy ratio of the CH groups was 0.82(2):0.18(2). The OH hydrogen atom of EtOH could not be located. A CIF file
2
containing complete information on the structure was deposited in the CCDC, No. 832262, from where it can be obtained upon
request at the internet site www.ccdc.cam.ac.uk/data_request/cif.
ACKNOWLEDGMENT
The work was supported financially by the Russian Foundation for Basic Research (Project No. 09-03-00183) and a
Grant to Leading Scientific School NSh 7005.2010.03.
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257