Synthesis of N-methyl urocanates of hydroxyderivatives of isocembrol

Article abstract of DOI:10.1007/s10600-007-0065-6

Alcohols were prepared by stereospecific hydroxylation of isocembrol and were esterified into N-methylurocanates, proposed biomimetics of taxol.

Full text of DOI:10.1007/s10600-007-0065-6

Chemistry of Natural Compounds, Vol. 43, No. 2, 2007
SYNTHESIS OF -METHYL UROCANATES OF
N
HYDROXYDERIVATIVES OF ISOCEMBROL
F. A. Valeev,1 Sh. M. Salikhov,1 O. Yu. Krasnoslobodtseva,1
B. T. Sharipov,1 L. V. Spirikhin,1 and G. A. Tolstikov2
UDC 547.913.6
Alcohols were prepared by stereospecific hydroxylation of isocembrol and were esterified into
N
-methylurocanates, proposed biomimetics of taxol.
Keywords: isocembrol, diterpenoids, eleuthesoids, eleutherobin, sarcodictyin, urocanic acid
Urocanic [3-(4-imidazolyl)prop-2-enoic] acid exhibits multifaceted biological activityand is formed
as a result
in vivo
ofhistidine metabolism [1]. Its -methylderivative is the acid component in the diterpene esters eleutherobin and sarcodictyins,
N
metabolites of soft coral
sp. and
, which exhibit a taxol-like mechanism of cytotoxic activity
Sarcodictyon roseum
Eleutherobia
[2]. In creating a combinatorylibraryof sarcodictyins, it was discovered that removal ofthe -methylurocanic acid or replacing
N
its imidazole ring by oxazole, thiazole, or benzene sharply affected its cytotoxic activity [3]. Valdivones, eleuthesides that are
not -methylurocanate esters [4], have not been demonstrated to have similar properties. On the other hand, an eleuthesoid
N
containing a benzene ring instead of menthane retains its cytotoxic activity [5]. It may be that the biological properties of
eleutherobin and sarcodictyin are unique because they are also -methylurocanate esters, which makes it probable that other
N
accessible taxol biomimetics exist.
Therefore, cembrane derivatives, which are proposed biogenetic precursors of eleuthesides [6], are promising
diterpenoids for preparing -methylurocanates. One of these derivatives, isocembrol (1), was isolated from Siberian cedar resin
N
[7] and was studied for possible generation of the eleutheside carbon skeleton [8]. In contrast with this, we used hydroxy
derivatives of isocembrol directly as the alcohols of -methylurocanate esters.
N
We studied the possibility of introducing selectively a secondary hydroxyl into the molecule because esterification of
the tertiary alcohol of 1 is problematical due to steric hindrances and competing elimination.
18
HO
HO
HO
HO
OH
OH
O
3
7
9
5
15
17
16
2
3
3
2
1
19
+
13
11
1
2
3a
3b
20
HO
HO
OEt
OH
+
13
4
5
Scheme 1.
1) Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, fax (3472) 35 60 66, e-mail:
chemorg@anrb.ru; 2) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of
Sciences, fax (3832) 34 47 52, e-mail: gtolstik@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 119-
123, March-April, 2007. Original article submitted June 21, 2006.
0009-3130/07/4302-0143 ©2007 Springer Science+Business Media, Inc.
143

Reaction of1 and -butylhydroperoxide (TBHP) in benzene in the presence of catalytic amounts ofVO(acac) produced
t
2
regioselectively and stereospecifically epoxide 2. The stereochemistry of 2 was established based on spectral data. Thus, the
13
large SSCC J = 9.1 Hz in the PMR spectra indicated that the oxirane ring had the β-orientation. The C NMR spectra
1,2
exhibited signals for C-2 and C-3 at 62.8 and 57.4 ppm, respectively.
The oxirane ring was opened by reacting 2 with LiAlH in boiling THF or (i-Bu)2AlH in toluene at 75°C. In both
4
instances the reaction occurred regioselectively and stereospecifically to produce -alcohols 3a and 3b in 1:7 and 1:10 ratios,
respectively. The structures of the isolated regioisomers 3a and 3b were confirmed bytheir spectral properties. Thus, the PMR
spectrum of 3a has two SSCC for H-3 with the C-2 protons. The two-dimensional 90° H—H COSY spectrum showed chemical
shifts (CS) for the C-2 protons at 1.95 and 1.40 ppm. The proton with CS 1.95 ppm gave signals overlapping those of allylic
protons and its SSCC could not be observed. The proton with CS 1.40 ppm was well observed and had a trans-SSCC of
8.9 Hz with H-3 and a cis-SSCC of 3.2 Hz with the C-1 proton. Thus, the C-3 hydroxyl was oriented in the direction opposite
13
of the isopropyl. The C NMR spectrum recorded in the JMOD regime had the signal for C-3 at 73.8 ppm with a negative
amplitude, indicating that diol 3a was a secondary alcohol.
For regioisomer 3b, double resonance established vicinal constants of 6.4 and 5.7 Hz for H-2 with the C-3 protons.
The large J = 10.7 Hz indicated that they were trans-diaxial, from which the R-configuration for C-2 was deduced.
2,1
Allylic oxidation of isocembrol by SeO in boiling ethanol occurred regio- and stereospecifically. The reaction gave
2
30% yield of diol 4 (Scheme 1) and its esterification product 5 (35%).
The configuration of the new asymmetric center in 4 was established using PMR data. Thus, the signal for H-13
appeared at 3.74 ppm and gave a doublet—doublet signal with J
= 10.8 and J
= 1.7 Hz. The couplings were confirmed
13,14
14,1
by double resonance. Thus, the stereochemistry of C-3 was also S-type.
The picture was analogous in the PMR spectrum of 5 with the single difference that the signals for H-13 were slightly
shifted to 3.72 ppm with SSCC 10.6 and 4.3 Hz; H-14, 1.90 with SSCC 12.4, 10.7, and 1.6 Hz; and H-1, 2.48 with SSCC 9.4,
8.7, 5.3, and 1.6 Hz. The ethoxy quartet was observed at 3.22 ppm; the triplet, at 1.08 ppm. Thus, the structure of C-13
corresponded to the S-configuration also, as in 4.
The N-methylurocanic acid was prepared by Hofman degradation of histidine (6) [9] with subsequent N-methylation
of the methyl or ethyl ester of urocanic acid as before [10] and hydrolysis. The mixed anhydride 14 was synthesized as before
[11] according to Scheme 2.
_
CO R
2
CO
2
CO H
2
1
3
b, c
5
a
N(CH )
3 3
NH
2
+
HN
N
HN N
7
HN
N
7
6
8 - 10
CO Piv
CO R
2
2
d
e, f
CH
N
N
CH
N
3
N
3
11 - 13
14
8, 13: R = H; 9, 11: R = CH3; 10, 12: R = C2H5
b. c.
+
a.
d.
CH3I, KOH, CH3OH; 30% NaOH, boiled, 8 – 66%; MeOH or EtOH, H ;
e.
f.
CH3I, K2CO3, acetone; NaOH, THF-H2O; PivCl, THF
Scheme 2.
An attempt to esterify 3a by heating with N-methylurocanic acid in the presence of dicyclohexylcarbodiimide (DCC)
[12] was unsuccessful. Nevertheless, 3b and 4 were esterified into the urocanates 16 and 17 by this route in 25 and 31% yields,
respectively.
144

HO
HO
HO
R
R
3
7
9
5
2
1
13
13
11
R
16
17
15
O
5'
C
1'
3'
O
R =
N
N
7'
Urocanate 15 could be prepared in 71% yield by alcoholysis of pivaloyl-N-methylurocanate by diol 3a. Under these
conditions the esterification proceeded with incomplete conversion in 38% yield.
The spectral properties of urocanates 15, 16, and 17 confirmed their structures and were composites of the CS of C and
H atoms of N-methylurocanic acid and the corresponding diols with slight differences.
EXPERIMENTAL
13
1
PMR and C NMR spectra were recorded on a Bruker AM-300 spectrometer at working frequencies 300.13 ( H) and
13
75.47 MHz ( C). Published NMR spectra of 1 and its derivatives provided a basis for spectral identification of the products
[13, 14]. C NMR spectra were recorded with modulation of the C–H coupling constants, i.e., signals of CH – and CH groups
13
3
were readily distinguished from CH and quaternary C atoms. Spectra were also calculated using the ACD Labs program
2
package. Melting points were determined on an S 30A/G Kofler block (GDR). Analytical TLC used PTSKh-AF-A Sorbfil
plates (ZAO Sorbpolimer, Krasnodar). Optical rotation angles were measured on a Perkin—Elmer 3141 instrument.
(1S,2S,3S,4R)-2,3-Epoxycembra-7(E),11(E)-dien-4-ol (2). Amixtureof1(0.540g, 1.9mmol)andacatalyticamount
of VO(acac) in benzene (10 mL) at 5°C was stirred for 5 min and treated with TBHP (0.58 g, 1.9 mmol, 29%) in toluene. The
2
reaction mixture was brought to room temperature after 20 min. Three hours after the reaction was finished (TLC monitoring),
EtOAc (50 mL) was added. The mixture was washed with Na S O solution (3 × 10 mL) and water (2 × 10 mL) and dried over
2 2
5
MgSO . Solvent was removed in a rotaryevaporator. The solid was chromatographed over SiO (petroleum ether:EtOAc, 6:1)
4
2
20
to afford 2 (0.426 g, 75%), C H O , R 0.50 (petroleum ether:EtOAc, 3:1), mp 81-84°C, [α]
+233.3° (c 0.03, CHCl ).
3
f
20 34
2
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.94 (3H, d, J = 6.9, CH ), 0.98 (3H, d, J = 6.9, CH ), 1.28 (3H, s, CH ), 1.32
3
3
3
3
(1H, m, CH), 1.52 (3H, s, CH ), 1.64 (3H, s, CH ), 1.71 (2H, m, CH ), 1.90 (2H, m, CH ), 2.10 (5H, m, CH, CH ), 2.30 (4H,
3
3
2
2
2
m, CH ), 2.88 (1H, dd, J = 9.1, 2.4, H-2), 3.35 (1H, d, J = 2.4, H-3), 5.02 (1H, d, J = 10.1, H-7), 5.20 (1H, dd, J = 9.4, 4.4,
2
H-11).
13
C NMR spectrum (CDCl , δ, ppm): 13.9 (C-16), 14.4 (C-17), 18.0 (C-19), 20.3 (C-18), 22.1 (C-20), 22.8 (C-6), 23.9
3
(C-10), 24.3 (C-14), 30.0 (C-5), 36.4 (C-13), 39.4 (C-15), 39.7 (C-9), 44.1 (C-1), 57.4 (C-2), 62.8 (C-3), 69.8 (C-4), 126.0
(C-7), 126.8 (C-11), 133.0 (C-8), 133.6 (C-12).
(1S,3S,4R)-Cembra-7(E),11(E)-dien-3,4-diol (3a) and (1S,2R,4R)-Cembra-7(E),11(E)-dien-2,4-diol (3b).
Method A. A solution of LiAlH
2
(0.071 g, 1.879 mmol) in THF (30 mL) was treated with (0.575 g, 1.9 mmol) in
4
THF (5 mL) and refluxed for 4 h. After the reaction was finished (TLC monitoring), the mixture was brought to room
temperature. A solution of NaHCO was slowlyadded until hydrogen evolution stopped. The aqueous layer was extracted with
3
EtOAc (4 × 10 mL) and dried over MgSO . Solvent was removed in a rotaryevaporator. The solid was chromatographed over
4
SiO (petroleum ether:EtOAc, 5:1) to afford 3a (0.486 g, 84%) and 3b (0.069 g, 12%).
2
Method B. A solution of 2 (0.09 g, 0.294 mmol) in toluene (5 mL) was treated dropwise with (i-Bu) AlH in toluene
2
(0.5 mL, 0.7 mmol, 70%), heated at 75°C for 1 h, cooled to 0°C, and decomposed byadding successivelywater (5 mL) and HCl
(5 mL, 1 N). The aqueous layer was extracted with EtOAc (4 × 10 mL). The organic layer was dried over MgSO . Solvent
4
was removed in a rotary evaporator. The solid was chromatographed over SiO (petroleum ether:EtOAc, 5:1) to afford 3a
2
(0.081 g, 88%), C H O , and 3b (0.008 g, 8.5%), C H O .
20 36
2
20 36
2
20
3a. R 0.25 (petroleum ether:EtOAc, 3:1), [α]
+107.7° (c 0.015, CHCl ).
f
D
3
145

PMR spectrum (CDCl , δ, ppm, J/Hz): 1.85 (3H, d, J = 6.9, CH ), 1.90 (3H, d, J = 6.9, CH ), 1.10 (3H, s, CH ), 1.15-
3
3
3
3
3
1.30 (4H, m, CH ), 1.40 (1H, ddd, J = 10.7, J = 8.9, J = 3.2, H-2a), 1.40 (3H, s, CH ), 1.5 (2H, m, H-10a, H-6a), 1.8 (1H,
2
3,2
1,2
3
d, J = 6.9, 3.2, H-15), 1.9-2.0 (8H, m, CH ), 2.1 (2H, m, H-10b, H-6b), 3.53 (1H, dd, J = 8.9, 1.6, H-3), 4.9 (1H, td, J = 7.0, 1.1,
2
H-11), 5.18 (1H, t, J = 6.8, H-7).
13
C NMR spectrum (CDCl , δ, ppm): 15.1 (C-18), 15.5 (C-19), 18.2 (C-16), 20.7 (C-17), 22.76 (C-20), 23.1 (C-6),
3
24.6 (C-10), 27.1 (C-14), 30.2 (C-15), 32.62 (C-5), 36.2 (C-9), 39.5 (C-13), 39.7 (C-2), 40.2 (C-1), 73.8 (C-3), 75.4 (C-4), 124.4
(C-7), 127.0 (C-11), 134.2 (C-8), 135.1 (C-12).
20
3b. R 0.30 (petroleum ether:EtOAc, 3:1), [α]
-40.4° (c 0.02, CHCl ).
3
f
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.72 (3H, d, J = 6.9, CH ), 0.90 (3H, d, J = 6.9, CH ), 1.10 (3H, s, CH ), 1.30
3
3
3
3
(2H, m, CH ), 1.45 (1H, m, CH), 1.54 (1H, m, CH ), 1.62 (6H, s, CH , CH ), 1.67-1.70 (3H, m, CH, CH ), 1.80 (1H, m, H-1),
2
2
3
3
2
1.90-2.28 (6H, m, CH, CH ), 2.33 (1H, m, CH ), 2.50 (1H, m, CH ), 3.10 (1H, s, OH), 3.30 (1H, ddd, J = 10.7, 6.4, 5.7, H-2),
2
2
2
5.02 (1H, br.s, H-7), 5.07 (1H, br.s, H-11).
13
C NMRspectrum (CDCl , δ, ppm): 15.51 (CH ), 15.76 (CH ), 17.50 (CH ), 20.68 (CH ), 22.37 (CH ), 23.89 (C-6),
3
3
3
3
3
3
24.03 (C-10), 27.01 (C-15), 27.92 (C-14), 34.35 (C-5), 36.95 (C-9), 37.81 (C-13), 39.73 (C-1), 39.83 (C-3), 73.74 (C-4), 76.92
(C-2), 125.77 (C-11), 126.33 (C-7), 134.74 (C-8), 136.35 (C-12).
(1S,4R,13S)-Cembra-2(E),7(E),11(E)-trien-4,13-diol(4)and(1S,4R,13S)-Ethoxycembra-2(E),7(E),11(E)-trien-4-ol
(5). A solution of 1 (0.220 g, 0.759 mmol) in EtOH (80%, 15 mL) was boiled gently for 2 h and treated with SeO (0.084 g,
2
0.766 mmol) in EtOH (80%, 5 mL). After the reaction was finished (TLC monitoring), the mixture was brought to room
temperature and filtered to remove precipitated Se. The filtrate was evaporated. The solid was dissolved in EtOAc (25 mL),
washed with water (2 × 10 mL), and dried over MgSO . Solvent was removed in a rotary evaporator. The solid was
4
chromatographed over SiO (petroleum ether:EtOAc, 7:1) to afford 4 (0.062 g, 30%), C H O and 5 (0.071 g, 35%),
2
20 36 2
C H O .
20 36
2
20
4. R 0.22 (petroleum ether:EtOAc, 5:1), [α]
+56.1° (c 0.01, CHCl ).
3
f
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.85 (3H, d, J = 6.8, CH ), 0.88 (3H, d, J = 6.8, CH ), 0.90-1.18 (2H, m, CH,
3
3
3
CH ), 1.24 (3H, s, CH ), 1.24-1.43 (3H, m, CH, CH ), 1.48 (3H, s, CH ), 1.54 (3H, s, CH ), 1.65-1.90 (3H, m, CH ), 1.90 (1H,
2
3
2
3
3
2
ddd, J = 12.8, 10.8, 1.7, H-14), 2.15 (2H, m, CH ), 2.25 (1H, m, CH ), 2.35 (1H, dddd, J = 8.7, 8.6, 8.5, 1.7, H-1), 3.30 (1H,
2
2
br.s, OH), 3.74 (1H, dd, J = 10.8, 4.4, H-13), 5.10 (2H, m H-7, H-11), 5.12 (1H, dd, J = 15.7, 8.9, H-2), 5.52 (1H, dd, J = 15.7,
H-3).
13
4
C NMR spectrum (CDCl , δ, ppm): 9.19 (C-16), 14.89 (C-17), 19.57 (C -CH ), 19.95 (C-15), 22.15 (C-6), 23.25
3
8
3
12
(C-10), 27.88 (C -CH ), 33.00 (C -CH ), 35.14 (C-14), 38.64 (C-9), 42.79 (C-5), 45.73 (C-1), 72.30 (C-4), 77.57 (C-13),
3
3
128.77 (C-11), 128.89 (C-7), 129.10 (C-2), 131.75 (C-8), 134.35 (C-12), 137.62 (C-3).
20
5. R 0.30 (petroleum ether:EtOAc, 5:1), [α]
+40.5° (c 0.046, CHCl ).
3
f
D
PMR spectrum (CCl :C D , δ, ppm, J/Hz): 0.80 (3H, d, J = 6.9, CH ), 0.83 (3H, d, J = 6.9, CH ), 0.86 (1H, m, CH),
4
6
6
3
3
1.08 (3H, t, J = 7.0, CH ), 1.15 (3H, s, CH ), 1.16 (1H, m, CH), 1.25 (1H, m, CH ), 1.44 (2H, m, CH ), 1.48 (3H, s, CH ), 1.50
3
3
2
2
3
(3H, m, CH ) 1.9 (1H, ddd, J = 12.4, 10.6, 1.6, H-14), 2.15 (1H, m, CH ), 2.48 (1H, dddd, J = 9.4, 8.7, 5.3, 1.6, H-1), 3.22 (2H,
3
2
q, J = 6.9, CH ), 3.72 (1H, dd, J = 10.6, 4.3, H′′-13), 5.08 (1H, dd, J = 16.0, 5.3, H-2), 5.12 (2H, m, H-7, H-11), 5.33 (1H, d,
2
J = 16.0, H-3).
13
C NMR spectrum (CCl :C D , δ, ppm): 9.28 (CH ), 15.0 (C-19), 16.13 (C-16), 20.13 (C-6), 21.49 (C-10), 23.10
4
6
6
3
(C-18), 23.15 (C-20), 33.63 (C-14), 35.49 [C(CH ) ], 38.59 (C-9), 43.07 (C-5), 45.94 (C-1), 57.02 (CH O), 75.80 (C-4), 77.01
3 2
2
(C-13), 128.05 (C-11), 129.57 (C-7), 131.08 (C-8), 134.76 (C-12).
(E)-3-(1H-Imidazol-4-yl)-2-propenoic Acid (8). A solution of histidine (6, 2.0 g, 13 mmol) in methanol (5 mL) was
placed in a round-bottomed flask equipped with a reflux condenser and two dropping funnels, cooled to 0-5°C, stirred, and
treated simultaneously with KOH (2.0 g, 34 mmol, 25%) in methanol and CH I (2.0 mL, 34 mmol, 50%) in methanol. After
3
1 h when the pH of the reaction mixture was neutral, the mixture was brought to room temperature and treated with another
portion of KOH (1.0 g, 17 mmol, 25%) in methanol and CH I (1.2 mL, 17 mmol, 50%) in methanol. When the pH of the
3
solution again became neutral, methanol was removed in a rotary evaporator. The solid was dissolved in aqueous NaOH (30%)
and refluxed for 5 h. The mixture was neutralized by HCl (5 M) and evaporated. The solid was extracted with EtOH.
Recrystallization from EtOH afforded urocanic acid (8, 1.17 g, 66%), C H N O , R 0.40 (EtOH), mp 210-212°C.
f
6
6 2 2
PMR spectrum [(CD ) SO, δ, ppm, J/Hz]: 6.30 (1H, d, J = 15.6, H-2), 7.38 (1H, d, J = 15.6, H-3), 7.41 (1H, s, H-5),
3 2
7.75 (1H, s, H-7).
146

13
C NMR spectrum [(CD ) SO, δ, ppm]: 116.34 (C-2), 123.2 (C-7), 134.44 (C-3), 136.3 (C-4), 139.56 (C-5), 169.8
3 2
(C=O).
(E)-3-(1-Methyl-1H-imidazol-4-yl)-2-propenoic Acid (13). The ethyl ester 12 (0.720 g, 4.02 mmol) in THF:H O
2
(20 mL, 1:1) was treated with NaOH (0.164 g, 4.10 mmol) and stirred at room temperature for 24 h. The mixture was
neutralized with HCl (2.06 mL, 2 M, 4.12 mmoL). Solvent was removed in a rotary evaporator. The solid was
chromatographed over SiO (EtOH:EtOAc, 1:5) to afford 13 (0.546 g, 90%), C H N O , R 0.45 (EtOH), mp 235-237°C.
f
2
6 6 2 2
PMR spectrum (CD OD, δ, ppm): 3.35 (s, N–CH ), 4.90 (d, H-2), 5.90 (s, H-5), 5.97 (d, H-3), 6.23 (s, H-7).
3
3
13
C NMRspectrum (CD OD, δ, ppm): 34.26 (N–CH ), 118.41(C-2), 124.74(C-3), 136.29(C-7), 137.98(C-4), 140.80
3
3
(C-5), 171.45 (C=O).
(1S,3S,4R)-3-[1′′-Methyl-1′′H-imidazol-4′′-yl]-(E)-ethenylcarbonyloxy]-cembra-7(E),11(E)-dien-4-ol (15).
A
solution of 3a (0.115 g, 0.373 mmol) in CH Cl (1 mL) was treated with Et N (0.78 mL, 5.595 mmol) and 4-DMAP (0.045 g,
2
2
3
0.373 mmol). The solution was cooled to 0 C and treated with a solution of pivaloyl N-methylurocanate (15 mL, 3.112 mmol,
0.2 M) in CH Cl . The mixture was brought to room temperature and stirred for 5 d. After the reaction was finished (TLC
2
2
monitoring), the mixture was diluted with saturated NaHCO solution, extracted with CH Cl (3 × 10 mL), and dried over
3
2
2
MgSO . Solvent was removed in a rotary evaporator. The solid was chromatographed over SiO (EtOAc) to afford 15 (0.114
4
2
20
g, 71%), C H N O R 0.25 (EtOAc), [α]
+11.5° (c 0.066, CHCl ).
3
f
6
6
2
2
D
4
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.74 (3H, d, CH ), 0.83 (3H, d, CH ), 1.12 (3H, s, C -CH ), 1.15-1.30 (2H,
3
3
3
3
12
8
m, CH ), 1.45-1.60 (2H, m, CH ), 1.55 (3H, s, C -CH ), 1.60 (3H, s, C -CH ), 1.85 (1H, ddd, J = 14.2, 8.3, 5.6, H-2), 1.95-
2
2
3
3
2.30 (13H, m, CH, CH ), 2.5 (1H, br.s, OH), 3.68 (3H, s, N–CH ), 4.75 (1H, s, H-7′), 5.02 (1H, t, J = 7.0, H-7), 5.07 (1H,
2
3
dd, J = 8.3, 2.7, H-3), 5.38 (1H, t, J = 7.3, H-11), 6.58 (1H, d, J = 15.6, H-2′), 7.07 (1H, s, H-5′), 7.55 (1H, d, J = 15.6, H-3′).
13
19
17
16
20
C NMR spectrum (CDCl , δ, ppm): 14.78 (C -CH ), 14.88 (C -CH ), 16.92 (C -CH ), 21.11 (C -CH ), 21.77
3
3
3
3
3
18
(C-6), 24.08 (C -CH ), 24.17 (C-10), 25.67 (C-14), 29.0 (C-15), 33.54 (N–CH ), 35.60(C-9), 35.69(C-5), 38.87 (C-13), 39.24
3
3
(C-1), 39.31 (C-2), 75.21 (C-4), 78.15 (C-3), 116.13 (C-2′), 122.55 (C-3′), 124.83 (C-11), 126.56 (C-7), 133.73 (C-8), 134.33
(C-12), 136.36 (C-7′), 138.44 (C-4′), 139.13 (C-5′), 168.30 (C=O).
(1S,3S,4R)-2-[1′′-Methyl-1′′H-imidazol-4′′-yl]-(E)-ethenylcarbonyloxy]-cembra-7(E),11(E)-dien-4-ol (16).
A
solution of 3b (0.169 g, 0.548 mmol) in CHCl (50 mL) was treated with 13 (0.248 g, 1.644 mmol), DCC (0.451 g,
3
2.192 mmol), and 4-DMAP (0.334 g, 2.740 mmol). The mixture was heated on an oil bath at 65°C for 7 d, diluted with
saturated NH Cl solution, extracted with CH Cl (3 × 10 mL), and dried over MgSO . Solvent was removed in a rotary
4
2
2
4
evaporator. The solid was chromatographed over SiO (EtOAc) to afford 16 (0.060 g, 25%), C H N O , R 0.30 (EtOAc),
f
2
6 6 2 2
20
[α]
-2.20° (c 0.050, CHCl ).
3
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.78 (3H, d, J = 6.8, CH ), 0.88 (3H, d, J = 6.8, CH ), 1.21 (3H, s, CH ), 1.61
3
3
3
3
(3H, s, CH ), 1.62 (3H, s, CH ), 1.30 (2H, m, CH ), 1.48 (2H, m, CH ), 1.70 (2H, m, CH ), 1.80 (1H, m, CH), 1.93 (1H, ddt,
3
3
2
2
2
J = 8.7, 7.0, 3.6, H-1), 2.12 (6H, m, CH ), 2.30 (1H, ddd, CH ), 3.70 (3H, s, N–CH ), 4.95 (1H, J = 8.7, 5.7, 2.8, H-2), 5.05
2
2
3
(1H, dd, H-11), 5.26 (1H, m, H-7), 6.52 (1H, d, J = 15.6, H-11), 7.07 (1H, s, H-5′), 7.45 (1H, s, H-7′), 7.55 (1H, d, J = 15.7,
H-2′).
13
18
19
16
17
C NMR spectrum (CDCl , δ, ppm): 15.36 (C -CH ), 15.94 (C -CH ), 18.16 (C -CH ), 19.60 (C -CH ), 22.57
3
3
3
3
3
20
(C-6), 24.55 (C-10), 24.78 (C -CH ), 27.61 (C-14), 28.91 (C-15), 30.44 (C-5), 33.47 (N–CH ), 37.14 (C-9), 37.97 (C-13),
3
3
39.04 (C-3), 39.48 (C-1), 75.64 (C-4), 76.48 (C-2), 115.98 (C-2′), 122.54 (C-3′), 124.19 (C-11), 126.24 (C-7), 135.4 (C-8),
135.61 (C-12), 135.93 (C-7′), 138.40 (C-4′), 139.11 (C-5′), 167.32 (C=O).
(1S,3S,4R)-13-[1′′-Methyl-1′′H-imidazol-4′′-yl]-(E)-ethenylcarbonyloxy]-cembra-2(E),7(E),11(E)-trien-4-ol (17).
Method A. A solution of 4 (0.115 g, 0.373 mmol) in CH Cl (1 mL) was treated with Et N (0.78 mL, 5.595 mmol)
2
2
3
and 4-DMAP (0.045 g, 0.373 mmol), cooled to 0°C, and treated with pivaloyl N-methylurocanate (15 mL, 3.112 mmol, 0.2 M)
in CH Cl . The mixture was brought to room temperature and stirred for 5 d. After the reaction was finished (TLC
2
2
monitoring), the mixture was diluted with saturated NaHCO solution, extracted with CH Cl (3 × 10 mL), and dried over
3
2
2
MgSO . Solvent was removed in a rotary evaporator. The solid was chromatographed over SiO (EtOAc) to afford 17
4
2
(0.114 g, 71%).
Method B. A solution of 4 (0.238 g, 0.778 mmol) in CHCl (70 mL) was treated with 13 (0.352 g, 2.330 mmol), DCC
3
(0.640 g, 3.108 mmol), and 4-DMAP (0.474 g, 3.885 mmol). The mixture was heated on an oil bath at 65°C for 6 d, diluted
with saturated NH Cl solution, extracted with CH Cl (3 × 10 mL), and dried over MgSO . Solvent was removed in a rotary
4
2
2
4
147

evaporator. The solid was chromatographed over SiO (EtOAc) to afford 17 (0.131 g, 38%), C H N O , R 0.25 (EtOAc),
f
2
6 6 2 2
20
[α]
+11.5° (c 0.066, CHCl ).
3
D
PMR spectrum (CDCl , δ, ppm, J/Hz): 0.78 (3H, d, J = 6.8, CH ), 0.88 (3H, d, J = 6.8, CH ), 1.20-1.30 (3H, m, CH,
3
3
3
CH ), 1.45 (3H, m, CH ), 1.58 (3H, s, CH ), 1.60 (3H, s, CH ), 1.62 (2H, m, CH ), 1.70 (2H, m, CH ), 1.82 (1H, m, CH ), 1.95
2
3
3
3
2
2
2
2
3
(1H, ddd, J = 12.0, J = 10.9, 1.7, H-14), 2.0-2.20 (4H, m, CH ), 2.25 (1H, m, CH ), 2.50 (1H, dddd, J = 9.0, 8.3, 7.5, 1.7,
2
2
H-1), 3.70 (3H, s, N–CH ), 4.83 (1H, m, H-2), 5.13 (1H, m, J = 10.9, 4.7, H-13), 5.38 (1H, dd, J = 15.7, 8.3, H-2), 5.30 (1H,
3
m, H-7), 5.40 (1H, m, H-11), 6.65 (1H, d, J = 15.7, H-1′), 7.06 (1H, s, H-5′), 7.45 (1H, s, H-7′), 7.55 (1H, d, J = 15.7, H-2′).
13
20
19
16
17
C NMR spectrum (CDCl , δ, ppm): 10.05 (C -CH ), 12.65 (C -CH ), 19.35 (C -CH ), 19.78 (C -CH ), 21.98
3
3
3
3
3
18
(C-6), 23.71 (C-10), 27.67 (C -CH ), 32.61 (C-9), 33.08 (C-15), 33.30 (N–CH ), 37.97(C-14), 47.67(C-5), 45.20 (C-1), 72.09
3
3
(C-4), 79.43 (C-13), 116.31 (C-2′), 122.03 (C-2), 128.33 (C-7), 128.85 (C-11), 130.18 (C-12), 130.70 (C-3′), 131.31 (C-8),
135.48 (C-7′), 138.0 (C-3), 138.30 (C-4 ), 138.86 (C-5′), 166.54 (C=O).
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