Stereoselective synthesis of (1R,5S)-4-[(E)-alkylidene]-1,8,8-trimethyl-2- oxabicyclo[3.2.1]octan-3-ones

Article abstract of DOI:10.1055/s-2005-861862

Various (1R,5S)-4-[(E)-alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1] octan-3-ones were prepared, stereoselectively, via coupling of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1] octan-3-one with Grignard reagents, potass

Full text of DOI:10.1055/s-2005-861862

PAPER
1087
Stereoselective Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxa-
bicyclo[3.2.1]octan-3-ones
S
ynthesis of (1
R
,5
r
S
)-4-[(
E
)
o
-Alkylidene]
š
-1, 8,8-trimethyl
G
-2-oxabicyclo[3.2
r
o3-ones šelj, David Bevk, Renata Jakše, Anton Meden, Simon Rečnik, Branko Stanovnik, Jurij Svete*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Fax +386(1)2419220; E-mail: jurij.svete@uni-lj.si
Received 3 November 2004; revised 3 January 2005
In continuation of our work in this field we now report a
Abstract: Various (1R,5S)-4-[(E)-alkylidene]-1,8,8-trimethyl-2-
oxabicyclo[3.2.1]octan-3-ones were prepared, stereoselectively, via
coupling of (1R,5S)-4-[(E)-(dimethylamino)methylidene]-1,8,8-tri-
methyl-2-oxabicyclo[3.2.1]octan-3-one with Grignard reagents,
potassium cyanide, and 2-methyl-1H-indole.
stereoselective synthesis of (1R,5S)-4-[(E)-alkylidene]-
1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5 by
coupling of (1R,5S)-4-[(E)-(dimethylamino)methyli-
dene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one (2)
with Grignard reagents, potassium cyanide, and 2-methyl-
1H-indole.
Key words: Grignard reactions, chiral pool, coupling, terpenoids,
enaminones
Enaminone 2 was prepared in two steps from (+)-camphor
(1) according to literature procedures (Scheme 1).8
(+)-Camphor (1) and its derivatives, belong to the most
frequently employed types of ex-chiral pool starting ma-
terials utilized as building blocks, ligands in various
asymmetric reagents and/or catalysts, resolving agents,
and shift reagents in NMR spectroscopy. The interest in
the chemistry of camphor (1) and related terpenoids is as-
sociated with its availability as well as with the diversity
of its transformations.1
Me2N
4'
H
4
5
6
7
3
i, ii
8
O
Ref. 8
O 2
O
1
1
2
2-Substituted alkyl 3-(dimethylamino)prop-2-enoates and
related enaminones are a group of reagents and building
blocks, which can be used as versatile reagents for the
preparation of a variety of dehydroalanine derivatives,
heterocyclic systems, fuctionalized heterocycles, natural
products, and their analogs.2 Recently, 3-(dimethylami-
no)prop-2-enoates have also found use in combinatorial
synthesis.3
Scheme 1 (i) AcOOH, HOAc, NaOAc, r.t.; (ii) t-BuOCH(NMe2)2,
decaline, reflux, chromatographic separation.8
Treatment of 2 with Grignard reagents in THF at –78 °C
to r.t. afforded the corresponding dimethylamine substitu-
tion products 3a–l. In the reactions of 2 with n-alkyl-,
ethynyl-, benzyl-, and arylmagnesium halides, the E-iso-
mers of the substitution products 3a,b,d,h–l were ob-
tained, stereoselectively, in 21–83% yields. However,
treatment of 2 with i-propyl-, i-butyl-, (RS)-s-butyl-, and
cyclopentylmagnesium halides led to mixtures of the ma-
jor E-isomers 3c,e–g and the minor Z-isomers 3¢c,e–g.
Compound 3c was isolated and characterized as a 98:2
mixture of 3c and 3¢c, respectively, while isomeric mix-
tures 3/3¢e–g were separated by medium pressure liquid
chromatography (MPLC) to afford isomerically pure ma-
jor E-isomers 3e–g in 59–78% yields and the minor Z-iso-
mers 3¢e–g in 2–11% yields. In contrast to reactions with
Grignard reagents, transformations of 2 with KCN and 2-
methylindole were carried out under acidic conditions to
give (1R,5S)-4-[(E)-cyanomethylidene]-1,8,8-trimethyl-
2-oxabicyclo[3.2.1]octan-3-one (4) and (1R,5S)-4-[(E)-
(2-methyl-1H-indol-3-yl)methylidene]-1,8,8-trimethyl-2-
oxabicyclo[3.2.1]octan-3-one (5) in 49% and 31% yield,
respectively (Scheme 2).
Acid-catalyzed substitution of the dimethylamino group
in 3-(dimethylamino)propenoates with O-, C-, and N-nu-
cleophiles represents a general synthetic method for b-de-
rivatisation of a,b-unsaturated carbonyl compounds.2,3
Since the pioneering work of Benary,4 coupling of vinyl-
ogous amides with Grignard reagents5 and organolithium
compounds6 has been used for the conversion of amino-
methylidene compounds into the alkylidene derivatives.
Recently, our studies in the field of 3-dimethylaminopro-
penate chemistry were extended towards the preparation
and utilization of (+)-camphor (1) derived enaminones.
In connection with this, we reported the stereoselec-
tive synthesis of 1,2,4-triazolo[4,3–x]azinyl-1,7,7-tri-
methylbicyclo[2.2.1]heptan-2-ones7 and N-substituted
(1R,5S)-4-aminomethylidene-1,8,8-trimethyl-2-oxabicy-
clo[3.2.1]octan-3-ones from the corresponding camphor-
derived enaminones.8
Structures of compounds 3–5 were determined by spec-
troscopic (IR, H NMR, 13C NMR, MS, and HRMS)
methods and by elemental analyses. Compounds 3a,c,e–i,
3¢g, and 5 were not isolated in analytically pure form.
1
SYNTHESIS 2005, No. 7, pp 1087–1094
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-861862; Art ID: T13104SS
x
x
.
x
x
.2
0
0
5
© Georg Thieme Verlag Stuttgart · New York

1088
U. Grošelj et al.
PAPER
R
constants (3JC–H) between the methylidene proton (HC4¢)
and the carbonyl carbon atom (O=C3), measured from the
antiphase splitting of cross peaks in the HMBC spectrum.
Generally, the magnitude of coupling constant, 3JC–H, for
nuclei with cis-configuration around the C=C double
bond is smaller (2–6 Hz) than that for trans-oriented nu-
clei (8–12 Hz).2,7–10 In compound 4, the magnitude of cou-
pling constant (3JC–H = 6.2 Hz) showed the E-
configuration around the exocyclic C=C double bond.
However, in compound 5 the magnitude of coupling con-
stant, 3JC–H = 7.6 Hz, could not be used as a reliable crite-
rion for unambiguous determination of configuration
around the C=C double bond (Figure 1).
H
O
O
3a–l
i
Me2N
NC
O
H
H
ii
O
O
O
Structures of compounds 3a, 3l, 4, and 5 were determined
by X-ray diffraction (Figures 2– 5).
iii
4
2
HN
Me
H
O
O
5
Scheme 2 (i) RMgX, THF, –78 °C to r.t., chromatography; (ii)
KCN, HOAc, r.t.; (iii) 2-methyl-1H-indole, MeOH, H2SO4 (1 equiv),
reflux.
Figure 2 ORTEP view of compound 3a.
Their identities were confirmed by 13C NMR and EI-
HRMS. Minor isomer 3¢c was not isolated and was char-
acterized only by 1H NMR. Due to very small amounts of
the isolated minor isomers 3¢e,f, compound 3¢e was char-
acterized by 1H NMR and IR, while 3¢f was characterized
by 1H NMR, IR, EI-MS, and EI-HRMS.
The configuration around the exocyclic C=C double bond
in compounds 3a–l were established by NOESY spectros-
copy. In the minor isomers 3¢e–g, NOE between HC4¢ and
HC5 was in agreement with the Z-configuration, while no
NOE between HC4¢ and HC5 was observed in the major
E-isomers 3a–l. (Figure 1).
NOE
R
Figure 3 ORTEP view of compound 3l.
H
H
4'
H
5
R
O
4
O
C
The configurations around the exocyclic C=C double
bond in compounds 3a–g and 3¢c,e–g, derived from alkyl-
magnesium halides, were correlated with chemical shifts
d for HC4¢ and HC5. In the case of the E-isomers 3a–g,
signals for HC5 appeared at lower field (2.77–2.79 ppm)
than in the case of the Z-isomers 3¢c,e–g (2.35–2.41 ppm).
Signals for HC4¢ exhibited an even stronger dependence
of chemical shift on the configuration, since typical chem-
ical shifts for the HC4¢ protons of the E-isomers 3a–g
were 6.62–6.91 ppm and, in the case of the Z-isomers
3¢c,e–g, 5.61–5.88 ppm (Table 1).
6
7
3
8
O
O
2
1
Compound 4: 3JC–H = 6.2 Hz
Compound 5: 3JC–H = 7.6 Hz
Compounds 3'e–g
Figure 1 Structure determination by NOESY and HMBC spectros-
copy.
In the case of compounds 4 and 5, the configuration
around the exocyclic C=C double bond was studied by
HMBC spectroscopy on the basis of long-range coupling
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

PAPER
Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones
1089
Table 1 Correlation between the Chemical Shifts (d) of HC4¢ and
HC5 Protons and Configuration around the Exocyclic C=C Double
Bond in Compounds 3a–g and 3¢c,e–g
Compound
d (ppm)
HC4¢
E or Z
HC5
2.79
2.77
2.78
2.77
2.78
2.79
2.79
2.35
2.41
2.38
2.37
3a
3b
3c
6.91
6.83
6.66
6.84
6.86
6.62
6.76
5.66
5.88
5.61
5.77
E
E
E
E
E
E
E
Z
Z
Z
Z
3d
3e
3f
Figure 4 ORTEP view of compound 4.
3g
3¢c
3¢e
3¢f
3¢g
(Fluka, silica gel 60, 0.04–0.06 mm). Medium pressure liquid chro-
matography (MPLC) was performed with a Büchi isocratic system
with detection on silica gel (Merck, silica gel 60, 0.015–0.035 mm);
column dimensions (dry filled): 15 × 460 mm; back pressure: 10–
15 bar; detection: UV 254 nm; sample amount: 100–150 mg of iso-
meric mixture per run. The Z/E ratios of isomers were determined
by 1H NMR.
MeMgBr (3M in Et2O), EtMgBr (1M in THF), i-PrMgCl, 2M in
Et2O, n-BuMgCl (2M in THF), i-BuMgCl (2M in Et2O), sec-
BuMgCl (2M in Et2O), C5H11MgCl (2M in THF), C2HMgBr (0.5M
in THF), PhMgBr (1M in Et2O), 4-Me-C6H4MgBr (1M in Et2O), 4-
F-C6H4MgBr (2M in Et2O), and 2-methylindole are commercially
available (Fluka AG). (1R,5S)-4-[(E)-(dimethylamino)meth-
ylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-one (2) was
prepared according to the procedure described in the literature.6
Figure 5 ORTEP view of compound 5.
In addition to previous reports,5 especially in connection
with the work of Young and co-workers in the field of L-
pyroglutamic acid derived enaminones,5d the results of
this study prove, that coupling of N,N-dimethyl enamino
lactones with Grignard reagents can be successfully em-
ployed for introduction of alkylidene residues to active
methylene compounds. Besides the most commonly used
aldol-type condensations and Wittig-type olefinations,
this two step approach represents an alternative methodol-
ogy for the preparation of various b-substituted a,b-unsat-
urated acid derivatives.
(1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-
3-ones 3a–l; General Procedure
A soln of 2 (0.223 g, 1 mmol) in anhyd THF (83 mL) was cooled to
–78 °C under argon and a soln of Grignard reagent in THF or Et2O
(6 mmol) was added slowly over a period of 5 min. The mixture was
stirred at –78 °C for 1 h, warmed up to r.t. and stirred at r.t. for ad-
ditional 24 h. Sat. aq NH4Cl (10 mL) was added, the mixture was
stirred at r.t. for 1 h, poured into brine (20 mL), and the product was
extracted with CH2Cl2 (3 × 70 mL). The organic phases were com-
bined, dried over anhyd Na2SO4, filtered, and the filtrate was evap-
orated in vacuo. The residue was purified by column
chromatography (CC, EtOAc–hexanes) followed by medium pres-
sure liquid chromatography (MPLC, EtOAc–hexanes). Fractions
containing the product were combined and evaporated in vacuo to
give 3. Experimental, analytical, and spectral data for compounds
3a–l are given in Tables 2–4.
Melting points were determined on a Kofler micro hot stage. The 1H
NMR spectra were obtained on a Bruker Avance DPX 300 at 300
1
MHz for H and 75.5 MHz for 13C nucleus, using DMSO-d6 and
CDCl3 as solvents and with TMS as the internal standard. Mass
spectra were recorded on an AutoSpecQ spectrometer, IR spectra
on a Perkin-Elmer Spectrum BX FTIR spectrophotometer. Mi-
croanalyses were performed on a Perkin-Elmer CHN Analyser
2400. Column chromatography (CC) was performed on silica gel
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Table 2 Experimental Data for (1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5
Compound
R
E:Z
Yield (%)
71
Mp (°C)
Mobile phase (chromatographic method)
1:4 (CC)a
3a
3b
3c
3d
3e
3¢e
3f
Me
100:0
100:0
98:2
80–83 (hexane)
Et
83
68–74
1:4 (CC)a
i-Pr
68
Oil
1:2 (CC),a 1:15 (MPLC)a
1:5 (CC),a 1:6 (MPLC)a
1:2 (CC),a 1:15 (MPLC)a
n-Bu
100:0
100:0
0:100
100:0
0:100
100:0
0:100
100:0
100:0
100:0
100:0
100:0
100:0
100:0
68
Oil
i-Bu
59
Oil
i-Bu
2
Oil
(RS)-s-Bu
(RS)-s-Bu
Cyclopentyl
Cyclopentyl
Ethynyl
PhCH2
Ph
66
Oil
1:2 (CC)a, 1:15 (MPLC)a
1:3 (CC),a 1:15 (MPLC)a
3¢f
3g
3¢g
3h
3i
7
Oil
78
75–78 (heptane)
11
Oil
35
Oil
1:4 (CC)a
67
Oil
1:2 (CC),a 1:6 (MPLC)a
1:5 (CC)a
3j
27
101–102 (hexane)
93–95 (hexane)
118–123
3k
3l
4-Methylphenyl
4-Fluorophenyl
–
21
1:5 (CC),a 1:10 (MPLC)a
100:1 (CC),b 1:8 (MPLC)a
–
64
4
49
147–150
5
–
31
215–222 (CH2Cl2–hexane) –
a EtOAc–hexanes.
b CHCl3–MeOH.
Table 3 Analytical, MS, and IR Data for (1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5
20
Compounda
EI-MS (m/z)
EI-HRMS (m/z)
IR (cm–1)
[a]D
3a
194 (M+)
Calcd, 194.130680;
found, 194.130120
2970, 1713 (CO), 1646, 1381, 1315, 1299, 1268, +35.2 (c 0.128, CH2Cl2)
1207, 1167, 1142, 1040
3ba
3c
208 (M+)
Calcd, 208.146330;
found, 208.146950
2975, 1709 (CO), 1643, 1460, 1384, 1299, 1261, +56.3 (c 0.318, CH2Cl2)
1207, 1169, 1146, 1050
222 (M+)
Calcd, 222.161980;
found, 222.162350
2963, 1717 (CO), 1645, 1466, 1298, 1260, 1204, +45.6 (c 0.272, CH2Cl2)
1158, 1143, 1053, 964
3da
3e
236 (M+)
Calcd, 236.177630;
found, 236.177807
2960, 1715 (CO), 1654, 1466, 1394, 1379, 1298, +50.3 (c 0.286, CHCl3)
1269, 1202, 1165, 1144, 1056, 1031
236 (M+)
Calcd, 236.177630;
found, 236.178520
2958, 1718 (CO), 1646, 1466, 1379, 1300, 1283, +53.1 (c 0.162, CH2Cl2)
1202, 1165, 1144, 1034
3¢e
2957, 1717 (CO), 1641, 1466, 1379, 1248, 1221,
1203, 1162, 1137, 1064
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones
1091
Table 3 Analytical, MS, and IR Data for (1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5 (continued)
Compounda
EI-MS (m/z)
EI-HRMS (m/z)
IR (cm–1)
[a]D
20
3f
236 (M+)
Calcd, 236.177630;
found, 236.178360
2962, 1719 (CO), 1646, 1460, 1377, 1298, 1269, +45.6 (c 0.182, CH2Cl2)
1203, 1161, 1143, 1055
3¢f
3g
3¢g
3h
3i
236 (M+)
Calcd, 236.177630;
found, 236.177220
2962, 1717 (CO), 1641, 1462, 1377, 1317, 1246,
1203, 1136, 1063, 1018
248 (M+)
Calcd, 248.177630;
found, 248.178350
2957, 2861, 1710 (CO), 1641, 1464, 1448, 1393, +49.3 (c 0.134, CHCl3)
1372, 1315, 1299, 1258, 1207, 1173, 1145,
1106, 1052, 951
248 (M+)
Calcd, 248.177630;
found, 248.176690
2954, 2868, 1719 (CO), 1638, 1466, 1450, 1393, +29.4 (c 0.034, CHCl3)
1380, 1248, 1203, 1161, 1137, 1063, 955
204 (M+)
Calcd, 204.115030;
found, 204.115650
2974, 2099 (C≡C), 1710 (CO), 1612, 1467,
1395, 1379, 1301, 1267, 1248, 1202, 1167,
1146, 1068, 1013
+79.6 (c 0.093, CH2Cl2)
270 (M+)
2943, 1713 (CO), 1641, 1495, 1468, 1453, 1395, +50.0 (c 0.212, CHCl3)
Calcd, 270.161980;
found, 270.162055
1380, 1300, 1267, 1202, 1168, 1144, 1035
3ja
3ka
3la
2970, 1703 (CO), 1622, 1445, 1379, 1296, 1271, +358.0 (c 0.188, CH2Cl2)
1202, 1142, 1058, 936
2967, 1708 (CO), 1627, 1513, 1379, 1300, 1270, +395.8 (c 0.118, CHCl3)
1206, 1167, 1143, 1060
274 (M+)
Calcd, 274.136908;
found, 274.137550
2974, 1700 (CO), 1628, 1599, 1506, 1384, 1274, +328.9 (c 0.228, CHCl3)
1224, 1207, 1143, 1059
4a
5a
205 (M+)
Calcd, 205.110279;
found, 205.110850
2969, 2223 (CN), 1716 (CO), 1397, 1321, 1300, +47.2 (c 0.284, CH2Cl2)
1267, 1175, 1149, 1063
309 (M+)
Calcd, 309.172879;
found, 309.173860
3243, 2981, 1677 (CO), 1594, 1459, 1319, 1270, +193.8 (c 0.258, CH2Cl2)
1240, 1146, 1063
a CHN analysis: C 0.4%; H 0.4%; N 0.2%.
Table 4 NMR Data for (1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5
Compound
1H NMR (d)
13C NMR (d)
3a
0.95, 1.02, 1.32 (9 H, 3 s, 3 × CH3), 1.44–1.53 (1 H, m, CHH), 1.79 13.6, 18.4, 18.9, 23.9, 28.1, 37.3, 44.6, 46.5,
(3 H, d, J = 7.2 Hz, CH3C4¢), 1.98–2.20 (3 H, m, 3 H, CH2, CHH), 92.5, 134.7, 136.8, 167.5
2.79 (1 H, d, J = 6.0 Hz, HC5), 6.91 (1 H, dq, J = 0.7, 7.2 Hz, HC4¢)
3b
3c
0.95, 1.01 (6 H, 2 s, 2 × CH3), 1.05 (3 H, t, J = 7.5 Hz, CH3CH2),
1.32 (3 H, s, CH3), 1.44–1.54 (1 H, m, CHH), 1.97–2.25 (5 H, m,
CH2, CHH, CH2CH3), 2.77 (1 H, d, J = 6.0 Hz, HC5), 6.83 (1 H, t,
J = 7.9 Hz, HC4¢)
13.6, 18.5, 18.9, 21.3, 23.9, 28.4, 37.3, 44.5,
46.8, 92.6, 133.2, 143.6, 167.6
0.95, 1.02 (6 H, 2 s, 2 × CH3), 1.028, 1.031 [6 H, 2 d, J = 6.7 Hz,
(CH3)2CH], 1.31 (3 H, s, CH3), 1.45–1.58 (1 H, m, CHH), 1.98–2.22 44.1, 46.6, 92.2, 131.2, 148.2, 167.4
(3 H, m, CH2, CHH), 2.54–2.71 [1 H, m, CH(CH3)2], 2.78 (1 H, d,
18.1, 18.4, 22.0, 22.3, 23.5, 26.9, 28.1, 36.9,
J = 6.0 Hz, HC5), 6.66 (1 H, d, J = 10.2 Hz, H–C4¢)
3¢c
2.35 (1 H, d, J = 6.0 Hz, HC5), 5.66 (1 H, d, J = 9.4 Hz, HC4¢)
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

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Table 4 NMR Data for (1R,5S)-4-Alkylidene-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones 3–5 (continued)
Compound
1H NMR (d)
13C NMR (d)
3d
0.91 [3 H, t, J = 7.2 Hz, H3C(CH2)3], 0.94, 1.02, 1.32 (9 H, 3 s, 3 × 13.8, 18.1, 18.4, 22.3, 23.5, 27.2, 27.9, 30.7,
CH3), 1.28–1.53 (5 H, m, 2 × CH2, CHH), 1.97–2.23 (5 H, m, 2 ×
CH2, CHH), 2.77 (1 H, d, J = 6.0 Hz, HC5), 6.84 (1 H, t, J = 7.5 Hz,
HC4¢)
36.9, 44.1, 46.4, 92.1, 133.2, 142.0, 167.2
3e
0.93, 0.94 [6 H, 2d, J = 6.7 Hz, (CH3)2CH], 0.95, 1.01, 1.32 (9 H, 3 18.1, 18.4, 22.4, 22.6, 23.5, 27.7, 28.2, 36.6,
s, 3 × CH3), 1.44–1.53 (1 H, m, CHH), 1.70–1.85 [1 H, m,
CH(CH3)2], 1.97–2.21 (5 H, m, 2 × CH2, CHH), 2.78 (1 H, d, J = 6.0
Hz, HC5), 6.86 (1 H, t, J = 7.5 Hz, HC4¢)
36.8, 44.2, 46.4, 92.2, 133.7, 140.9, 167.1
3¢e
0.91, 0.93 [6 H, 2 d, J = 6.8 Hz, (CH3)2CH], 0.95, 0.98, 1.29 (9 H,
3 s, 3 × CH3), 1.50–1.63 (1 H, m, CHH), 1.65–1.76 [1 H, m,
CH(CH3)2], 1.92–2.20 (3 H, m, of CH2, CHH), 2.41 (1 H, d, J = 6.4
Hz, HC5), 2.47–5.57 (1 H, m, CHH), 2.63–2.73 (1 H, m, CHH),
5.88 (1 H, t, J = 7.2 Hz, H–C4¢)
3f
0.82–0.88 (3 H, m), 0.94–0.96 (3 H, m), 0.99–1.02 (6 H, m), 1.26– 11.90, 12.04, 18.00, 18.10, 18.31, 18.34, 19.81,
1.55 (3 H, m), 1.32 (3 H, s, CH3), 1.98–2.23 (3 H, m), 2.30–2.48 (1 20.03, 23.41, 23.44, 27.82, 28.17, 29.30, 29.56,
H, m), 2.79 (1 H, m), 6.62 (1 H, d, J = 10.6 Hz, H–C4¢)
33.87, 33.95, 36.84, 44.08, 44.10, 46.52, 46.62,
92.10, 92.20, 132.02, 132.14, 147.31, 147.32,
167.28, 167.33
3¢f
3g
0.81–0.89 (3 H, m), 0.94–0.99 (9 H, m), 1.15–1.45 (2 H, m), 1.29 (3 11.71, 11.92, 18.14, 18.21, 18.22, 18.41, 20.04,
H, s, CH3), 1.49–1.61 (1 H, m), 1.92–2.21 (3 H, m), 2.38 (1 H, d,
J = 6.0 Hz, HC5), 3.47–3.64 (1 H, m), 5.61 (1 H, t, J = 10.2 Hz,
HC4¢)
20.08, 23.43, 23.47, 28.24, 28.82, 30.02, 30.26,
33.65, 33.96, 37.03, 44.03, 44.08, 54.64, 54.73,
92.44, 92.59, 131.18, 131.22, 151.42, 151.77,
165.75, 165.82
0.95, 1.01, 1.31 (9 H, 3 s, 3 × CH3), 1.32–1.43 (2 H, m), 1.45–1.55 18.1, 18.4, 23.5, 25.4, 25.5, 28.2, 33.1, 33.3,
(1 H, m), 1.57–1.65 (2 H, m), 1.66–1.88 (4 H, m), 1.97–2.21 (3 H, 36.9, 38.3, 44.1, 46.7, 92.1, 131.8, 146.8, 167.4
m), 2.63–2.77 (1 H, m), 2.79 (1 H, d, J = 5.7 Hz, HC5), 6.76 (1 H,
d, J = 10.2 Hz, HC4¢)
3¢g
3h
3i
0.95, 0.98 (6 H, 2 s, 2 × CH3), 1.14–1.23 (2 H, m), 1.29 (3 H, s,
18.2, 18.3, 23.5, 25.5, 25.6, 28.5, 33.4, 33.7,
CH3), 1.49–1.70 (5 H, m), 1.84–2.19 (5 H, m), 2.37 (1 H, d, J = 6.0 37.0, 38.9, 44.1, 54.5, 92.5, 130.6, 150.9, 165.9
Hz, HC5), 3.74–3.88 (1 H, m), 5.77 (1 H, d, J = 9.4 Hz, HC4¢)
0.97, 1.04, 1.34 (9 H, 3 s, 3 × CH3), 1.51–1.60, 2.01–2.29 (4 H, 2 m, 18.4, 18.7, 23.7, 27.6, 37.0, 45.2, 49.5, 79.7,
2 × CH2), 3.15 (1 H, d, J = 6.0 Hz, HC5), 3.51 (1 H, d, J = 2.6 Hz, 89.7, 94.1, 117.3, 146.4, 166.1
HC∫C), 6.61 (1 H, d, J = 2.6 Hz, H–C4¢)
0.98, 1.04, 1.33 (9 H, 3 s, 3 × CH3), 1.48–1.56, 2.00–2.24 (4 H, 2 m, 18.1, 18.4, 23.4, 27.7, 33.6, 36.8, 44.3, 46.5,
2 × CH2), 2.92 (1 H, d, J = 5.7 Hz, HC5), 3.43–3.59 (2 H, m,
CH2Ph), 7.00 (1 H, dt, J = 0.8, 7.9, HC4¢), 7.15–7.32 (5 H, m, Ph)
92.3, 126.4, 128.4, 128.6, 133.8, 138.4, 139.2,
166.8
3j
0.99, 1.00, 1.35 (9 H, 3 s, 3 × CH3), 1.73–1.82, 2.06–2.37 (4 H, 2 m, 18.4, 18.9, 23.9, 28.4, 37.2, 45.0, 47.4, 93.5,
2 × CH2), 3.11 (1 H, d, J = 6.4 Hz, HC5), 7.32–7.44 (5 H, m, Ph),
7.76 (1 H, s, HC4¢)
129.0, 129.1, 130.0, 134.1, 135.4, 138.7, 168.2
3k
3l
0.96, 0.99, 1.35 (9 H, 3 s, 3 × CH3), 1.73–1.82, 2.04–2.35 (4 H, 2 m, 17.9, 18.4, 21.3, 23.4, 27.9, 36.8, 44.5, 46.9,
2 × CH2), 2.38 (3 H, s, CH3), 3.11 (1 H, d, J = 6.4 Hz, HC5), 7.19– 92.8, 129.2, 129.6, 132.1, 132.8, 138.2, 138.9,
7.27 (4 H, m, Ar), 7.73 (1 H, s, HC4¢)
167.8
0.96, 1.00, 1.35 (9 H, 3 s, 3 × CH3), 1.71–1.79, 2.04–2.37 (4 H, 2 m, 18.4, 18.9, 23.9, 28.2, 37.2, 45.0, 47.3, 93.1,
2 × CH2), 3.05 (1 H, d, J = 6.0 Hz, HC5), 7.06–7.13 (2 H, m, Ar),
7.30–7.36 (2 H, m, Ar), 7.70 (1 H, s, H–C4¢)
116.1 (JF–C(7¢) = 21.7 Hz), 131.5 (JF–C(5¢) = 3.2
Hz), 131.8 (JF–C(6¢) = 8.2 Hz), 134.0, 137.1, 163.1
(JF–C(8¢) = 249.9 Hz), 167.5
4
5
0.99, 1.08, 1.38 (9 H, 3 s, 3 × CH3), 1.55–1.64, 2.08–2.41 (4 H, 2 m, 18.4, 18.6, 23.6, 27.2, 36.7, 46.0, 50.9, 95.5,
2 × CH2), 3.19 (1 H, d, J = 6.8 Hz, HC5), 6.34 (1 H, s, HC4¢) 105.6, 115.5, 154.6, 163.5
0.95, 0.99, 1.34 (9 H, 3 s, 3 × CH3), 1.81–1.90, 2.01–2.12, and 2.21– 13.2, 18.5, 18.8, 24.0, 28.8, 37.3, 44.9, 48.4,
2.38 (4 H, 3 m, 2 × CH2), 2.41 (3 H, s, Me), 3.07 (1 H, d, J = 6.4 Hz, 93.6, 109.3, 111.3, 120.0, 120.6, 122.1, 127.4,
HC5), 7.09–7.18 (2 H, m, Ar), 7.31–7.34 (1 H, m, Ar), 7.49–7.52 (1 131.6, 132.8, 136.0, 137.1, 168.9
H, m, Ar), 7.81 (1 H, s, HC4¢), 8.70 (1 H, br s, NH)
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

PAPER
Synthesis of (1R,5S)-4-[(E)-Alkylidene]-1,8,8-trimethyl-2-oxabicyclo[3.2.1]octan-3-ones
1093
(1R,5S)-4-[(E)-Cyanomethylidene]-1,8,8-trimethyl-2-oxabicy-
clo[3.2.1]octan-3-one (4)
Crystal data are given in Table 5. Bond lengths and angles are omit-
ted as they are all within expected ranges and the details can be
found in the deposited material.17
KCN (0.130 g, 2 mmol) was added to a soln of 2 (0.223 g, 1 mmol)
in HOAc (100%, 3 mL) and the mixture was stirred at r.t. for 5 d.
Volatile components were evaporated in vacuo and CH2Cl2 (20 mL)
was added to the residue. The so formed suspension was filtered, the
undissolved material was washed with CH2Cl2 (50 mL), and the fil-
trate was evaporated in vacuo. The residue was purified by CC
(EtOAc–hexanes, 1:10). Fractions containing the product were
combined and evaporated in vacuo to give 4. Experimental, analyt-
ical, and spectral data for compound 4 are given in Tables 2–4.
Acknowledgment
The financial support from the Ministry of Education, Science, and
Sport, Slovenia through grants P0-0502-0103, P1-0179, and J1-
6689-0103-04 is gratefully acknowledged.
We acknowledge with thanks the financial support from the phar-
maceutical companies Krka d.d. (Novo mesto, Slovenia) and Lek
d.d. (Ljubljana, Slovenia).
The authors wish to express their gratitude to the Alexander von
Humboldt Foundation, Germany, for the donation of a Büchi medi-
um pressure liquid chromatograph.
Crystallographic data were collected on the Kappa CCD Nonius dif-
fractometer in the Laboratory of Inorganic Chemistry, Faculty of
Chemistry and chemical Technology, University of Ljubljana,
Slovenia. We acknowledge with thanks the financial contribution of
the Ministry of Science and technology, Republic of Slovenia
through grant Packet X-2000 and PS-511-102, which thus made the
purchase of the apparatus possible.
(1R,5S)-4-[(E)-(2-Methyl-1H-indol-3-yl)methylidene]-1,8,8-tri-
methyl-2-oxabicyclo[3.2.1]octan-3-one (5).
A soln of H2SO4 acid in anhyd MeOH (1 M, 0.5 mL, 0.5 mmol) was
added to the soln of 2 (0.223 g, 1 mmol) and 2-methyl-1H-indole
(0.131 g, 1 mmol) in anhyd MeOH (3 mL) and the mixture was
heated under reflux for 5 h. Volatile components were evaporated
in vacuo and the residue was purified by CC (EtOAc–hexanes, 1:2).
Fractions containing the product were combined and evaporated in
vacuo to give 5. Experimental, analytical, and spectral data for com-
pound 5 are given in Tables 2–4.
X-Ray Structure Analysis
Single crystal X-ray diffraction data of compounds 3a, 3l, 4, and 5
were collected at r.t. on a Nonius Kappa CCD diffractometer (Mo-
Ka radiation) using the Nonius Collect Software.11 DENZO and
SCALEPACK12 were used for indexing and scaling of the data. The
structures were solved by means of SIR97.13 Refinement was done
using Xtal3.414 program package and the crystallographic plots
were prepared by ORTEP III.15 Crystal structures were refined on F
values using the full-matrix least-squares procedure. The non-hy-
drogen atoms were refined anisotropically in all cases. The posi-
tions of hydrogen atoms were geometrically calculated and their
positional and isotropic atomic displacement parameters were not
refined. Absorption correction was not necessary. Regina16 weight-
ing scheme was used in all cases.
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Copound
Formula
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Sp. group
a (Å)
3a
3l
4
5
C12H18O2
monoclinic
P21
C17H19FO2
monoclinic
P21
C12H15NO2
orthorhombic
C2221
C20H23NO2
monoclinic
P21
8.0442(2)
13.2697(3)
10.6110(3)
93.6516(10)
1130.36(5)
2
10.9342(2)
11.9219(2)
11.9019(2)
107.7885(10)
1477.31(5)
2
7.54390(10)
11.5398(2)
25.5523(5)
90
11.2229(2)
11.5846(2)
13.3444(3)
104.8836(9)
1676.74(6)
2
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c (Å)
b (o)
Vol. (Å3)
Za
2224.46(7)
8
Z¢b
4
4
8
4
c
Rw
0.041
0.032
0.039
0.040
a Z: Multiplicity of the space group.
b Z¢: Number of molecules in the unit cell.
c Rw given for ‘observed’ reflections (I > 2s(I)).
Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York

1094
U. Grošelj et al.
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Synthesis 2005, No. 7, 1087–1094 © Thieme Stuttgart · New York