Synthesis of 13-amino-14,15-dinorlabd-8(9)-ene from sclareol

Article abstract of DOI:10.1007/s11172-014-0703-7

13-Amino-14,15-dinorlabd-8(9)-ene was synthesized from sclareol in four steps in 47% total yield. 14,15-Dinorlabd-8(9)-en-13-one was an intermediate compound, reduction of its oxime with LiAlH₄ was a key step of this synthetic scheme.

Full text of DOI:10.1007/s11172-014-0703-7

Russian Chemical Bulletin, International Edition, Vol. 63, No. 9, pp. 2074—2076, September, 2014
2074
Synthesis of 13ꢀaminoꢀ14,15ꢀdinorlabdꢀ8(9)ꢀene from sclareol
K. I. Kuchkova, A. N. Aryku, E. S. Sekara, A. N. Barba, I. P. Dragalin, P. F. Vlad, and N. D. Ungur
Institute of Chemistry of the Moldova Academy of Sciences,
3 ul. Akademiei, MDꢀ2028 Kishinev, Republic of Moldova.
Fax: (373 2) 73 9954. Eꢀmail: aricu_aculina@yahoo.com
13ꢀAminoꢀ14,15ꢀdinorlabdꢀ8(9)ꢀene was synthesized from sclareol in four steps in 47%
total yield. 14,15ꢀDinorlabdꢀ8(9)ꢀenꢀ13ꢀone was an intermediate compound, reduction of its
oxime with LiAlH4 was a key step of this synthetic scheme.
Key words: sclareol, sclareol oxide, 14,15ꢀdinorlabdꢀ8(9)ꢀenꢀ13ꢀone, 13ꢀaminoꢀ14,15ꢀdiꢀ
norlabdꢀ8(9)ꢀene, selective dehydration, reduction.
In the search of new biologically active compounds and
the products significantly depends on the reaction temꢀ
perature and time (Table 1). When the reaction is carried
out in an ice—water bath for 10 min, sclareol oxide 5 is the
major reaction product. Even a shortꢀtime heating for
10 min at 60 C gives, besides unsaturated ketones 3 and 4
and sclareol oxide 5, two unidentified compounds, whose
fraction mounted to 32% in the products.
in continuation of our work on the synthesis of nitrogenꢀ
containing drimane sesquiterpenoids,1—4 in the present
paper we describe the use of sclareol 1 (Scheme 1) in the fourꢀ
step synthesis of 13ꢀaminoꢀ14,15ꢀdinorlabdꢀ8(9)ꢀene (7).
Hydroxy ketone 2 was obtained by oxidation of sclareꢀ
ol 1 using KMnO4 in acetone.5 Selective dehydration
of hydroxy ketone 2 with the formation of 14,15ꢀdinorꢀ
labdꢀ8(9)ꢀenꢀ13ꢀone (3) was carried out according to
the developed by us procedure6 upon treatment with
MeSO3SiMe3 in acetonitrile. As compared to the proceꢀ
dures described earlier,7,8 in our method the reaction proꢀ
ceeds with high degree of selectivity, at room temperature,
and much faster. It should be noted that composition of
A key step in the synthesis of compound 7 from sclareꢀ
ol 1 is the reduction (LiAlH4 in THF) of oxime 6 obtained
from ketone 3. Oxime 6 is formed as a mixture of Zꢀ and
1
Eꢀisomers (TLC, H, 13C, and 15N NMR spectral data),
which were separated by column chromatography. A mixꢀ
ture of both isomers of oxime 6 can be used for the reducꢀ
tion, since Zꢀisomer in solutions is known to easily conꢀ
Scheme 1
Reagents and conditions: a. KMnO4, acetone, 20 C, 5 h, 80%; b. MeSO3SiMe3, MeCN, 18 C, 10 min, 96%; c. NH2OH•HCl,
EtOH—Py (1 : 1), 20 C, 20 h, 99%; d. LiAlH4, THF, , 5 h, 62%.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 2074—2076, September, 2014.
1066ꢀ5285/14/6309ꢀ2074 © 2014 Springer Science+Business Media, Inc.

13ꢀAminoꢀ14,15ꢀdinorlabdꢀ8(9)ꢀene
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
2075
Table 1. Reaction of hydroxy ketone 2 with MeSO3SiMe3 in
MeCN
10 min at 18 C. Then, water (10 mL) and diethyl ether (30 mL)
were added, and the mixture was poured into a separatory funnel
and stirred. The aqueous layer was separated, the ethereal layer
was washed with an aqueous solution of NaHCO3 (3×3 mL) and
water (3×3 mL) and dried. The solvent was evaporated to obtain
14,15ꢀdinorlabdꢀ8(9)ꢀenꢀ13ꢀone (3) (0.18 g, 96%). Its structure
Entry
Reaction conditions
Y (%)
N (%)
Т/С
/min
3
4
5
1
was confirmed by elemental analysis, IR and H and 13C NMR
1
2
3
4
10
10
18
60
10
40
10
10
98
99
98
95
23
65
96
59
14
31
11
16
71
13
11
13
spectra, which were in full agreement with the literature data.
According to GCꢀMS analysis, the product contains the isomer
with the C(7)=C(8) double bond (4) (< 1%) and sclareol oxide 5
(~1%) as minor side products.
14,15ꢀDinorlabdꢀ8(9)ꢀenꢀ13ꢀone oxime (6). The compound
NH2OH•HCl (60 mg, 0.87 mmol) was added to a solution of
ketone 3 (0.18 g, 0.69 mmol) in EtOH (0.9 mL) and pyridine
(0.9 mL) and the mixture was stirred at 20 C for 20 h. Then, the
reaction mixture was diluted with water (20 mL) and extracted
with diethyl ether (3×20 mL). The extract was washed with 5%
aqueous HCl (5×5 mL), an aqueous NaHCO3 (2×5 mL), and
water (2×5 mL), dried. The ether was evaporated to obtain
a mixture of Zꢀ and Eꢀisomers of oxime 6 (188 mg, 99%) in
the ratio 1 : 2.2 (1H NMR spectral data). A dense liquid,
Y is the total yield of the reaction products, N is the percentage
of compounds 3—5 in the mixture of products (GCꢀMS data).
vert to Eꢀisomer.9,10 The 1H and 13C NMR spectra showed
that amine 7 was obtained as unseparable mixture of two
diastereomers.
In conclusion, we have developed an efficient scheme
for the synthesis of 13ꢀaminoꢀ14,15ꢀdinorlabdꢀ8(9)ꢀene
(7), which can be of interest as a compound with potential
biological activity, as well as an intermediate product,
which can be converted to derivatives at the amino group.
17
[]D +59.7 (c 1.27, CHCl3). Found (%): C, 77.75; H, 11.15;
N, 5.01. C18H31NO. Calculated (%): C, 77.92; H, 11.26; N, 5.05.
IR, /cm–1: 957 (N—O), 1665 (C=N), 3118, 3209 (OH). Colꢀ
umn chromatography on silica gel was used to isolate both isoꢀ
mers of oxime 6 in the individual state. Eꢀ and Zꢀisomers were
eluted from the column with 9 : 1 and 4 : 1 mixtures of light
petroleum—diethyl ether, respectively.
ZꢀIsomer (Zꢀ6). Dense liquid. Rf 0.41 (benzene—diethyl
ether, 3 : 1). 1H NMR, : 0.86 (s, 3 H, H(17)); 0.91 (s, 3 H,
H(16)); 0.97 (s, 3 H, H(18)); 1.13 (dd, 1 H, H(5), J = 12.5 Hz,
J = 2.4 Hz); 1.17—1.41 (m, 2 H, H(3)); 1.17—1.85 (m, 2 H,
H(1)); 1.42—1.66 (m, 4 H, H(2), H(6)); 1.65 (s, 3 H, H(15)); 1.91
(s, 3 H, H(14)); 2.0 (m, 2 H, H(7)); 2.10—2.20 (m, 2 H, H(11));
2.25 (m, 2 H, H(12)); 8.23 (br.s, 1 H, OH). 13C NMR, : 13.57
(C(14)); 19.10 (C(2)); 19.44 (C(15)); 20.01 (C(18)); 20.09 (C(6));
21.73 (C(17)); 23.51 (C(11)); 29.85 (C(12)); 33.35 (C(4), C(16));
33.69 (C(7)); 36.84 (C(1)); 39.08 C(10)); 41.82 (C(3)); 51.91
(C(5)); 126.97 (C(8)); 139.56 (C(9)); 159.18 (C(13)). 15N NMR,
: 339.5 (=N—OH).
EꢀIsomer (Eꢀ6). Dense liquid. Rf 0.61 (benzene—diethyl
ether, 3 : 1). 1H NMR, : 0.85 (s, 3 H, H(17)); 0.90 (s, 3 H,
H(16)); 0.96 (s, 3 H, H(18)); 1.13 (dd, 1 H, H(5), J = 12.5 Hz,
J = 2.4 Hz); 1.17—1.41 (m, 2 H, H(3)); 1.17—1.85 (m, 2 H,
H(1)); 1.42—1.66 (m, 4 H, H(2), H(6)); 1.60 (s, 3 H, H(15));
1.93 (s, 3 H, H(14)); 2.0 (m, 2 H, H(7)); 2.10—2.20 (m, 2 H,
H(11)); 2.25 (m, 2 H, H(12)); 8.15 (br.s, 1 H, OH). 13C NMR,
: 13.59 (C(14)); 19.05 (C(2), C(6)); 19.52 (C(15)); 20.08 (C(18));
21.71 (C(17)); 24.81 (C(11)); 33.33 (C(16)); 33.34 (C(4)); 33.66
(C(7)); 36.64 (C(12)); 37.01 (C(1)); 39.07 (C(10)); 41.79 (C(3));
51.90 (C(5)); 126.76 (C(8)); 139.48 (C(9)); 158.91 (C(13)).
15N NMR, : 336.6 (=N—OH).
4ꢀ[(4aS,8aS)ꢀ2,5,5,8aꢀTetramethylꢀ3,4,4a,5,6,7,8,8aꢀoctaꢀ
hydronaphthalenꢀ1ꢀyl]butanꢀ2ꢀamine (13ꢀaminoꢀ14,15ꢀdinorꢀ
labdꢀ8(9)ꢀene) (7). Lithium aluminumhydride (0.14 g, 3.69 mmol)
was added to a solution of oxime 6 (0.1 g, 0.36 mmol) in anꢀ
hydrous THF (10 mL) and the mixture was refluxed with stirring
for 5 h and cooled. Then, the reaction mixture was quenched
with water (20 mL), acidified with 10% aqueous HCl, and exꢀ
tracted with diethyl ether (3×10 mL). The aqueous layer was
neutralized with NaHCO3 and the liberated amine 7 was exꢀ
Experimental
1
H, 13C, and 15N NMR spectra were obtained on an Avance
III Bruker 400 spectrometer (400, 100, and 40 MHz, respectiveꢀ
ly) in CDCl3. Chemical shifts are given in  scale relative to the
1
signals of CHCl3 in H and 13C NMR spectra (signals at  7.24
and 77.00, respectively) and relative to MeNO2 in 15N NMR
spectra. Signals in the 13C NMR spectra were assigned using the
DEPТ, 1H/H COSYꢀ45, 1H/13C HMQC, and HMBC experiꢀ
ments, whereas the 1H/15N HMBC experiments was used for
the 15N NMR spectra. IR spectra were recorded on a Perkin
Elmer Spectrum 100 FTꢀIR spectrophotometer. Elemental
analysis was performed on a Vario EL III microanalyzer,
[]D were measured on a Рꢀ2000 polarimeter. Reaction progress
was monitored by TLC on Sorbfil plates (Russia), visualizaꢀ
tion in I2 vapors. Column chromatography was carried out on
L100/400 m silica gel. The composition of the products of the
dehydration reaction of 8ꢀhydroxyꢀ14,15ꢀdinorlabdanꢀ13ꢀone
(2) was determined on an AGILENT 7890A instrument with
a MSD 5975C VL quadrupole MS detector and an HРꢀ5MS
capillary column (30 m/0.25 m). The temperature of injector
was 250 C, ionization potential 70 eV. Conditions of analysis
were as follows: t1 = 70 C (2 min);  (70  200C) = 5 C min–1
1
;
1
 (200  300C) = 20 C min–1; t2 = 300 C (5 min). The flow
rate of helium: 1 mL min–1. Diethyl ether and ethyl acetate
extracts were dried with anhydrous MgSO4. Solvents were evapꢀ
orated from the extracts at reduced pressure. Before use in the
reduction with LiAlH4, THF was distilled over LiAlH4. For asꢀ
signment of signals in the NMR spectra, the atom numbering
scheme is given for structure 2 (see Scheme 1).
4ꢀ[(4aS,8aS)ꢀ2,5,5,8aꢀTetramethylꢀ3,4,4a,5,6,7,8,8aꢀocꢀ
tahydronaphthalenꢀ1ꢀyl]butanꢀ2ꢀone (14,15ꢀdinorlabdꢀ8(9)ꢀ
enꢀ13ꢀone) (3). The reagent MeSO3SiMe3 (0.56 mL, 0.6 g,
3.56 mmol) was added to a solution of hydroxy ketone 2 (0.2 g,
0.71 mmol) in acetonitrile (2 mL) and the mixture was stirred for

2076
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 9, September, 2014
Kuchkova et al.
tracted with diethyl ether (3×25 mL). The extract was washed
with water (3×5 mL) and dried. The ether was evaporated to
obtain the product (62 mg), which was purified on a column with
silica gel, eluting amine 7 with a mixture of CHCl3—MeOH
(95 : 5). The yield was 58 mg (62%) (unseparable mixture of
diastereomers in the ratio 1 : 0.8 according to the 1H NMR
2. K. I. Kuchkova, A. N. Arycu, P. F. Vlad, K. Deleanu,
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Ya. Lipkovskii, Yu. A. Simonov, V. Kh. Kravtsov, Chem.
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24, 697.
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17
data). Dense liquid. []D +70.3 (c 1.33, CHCl3). Rf 0.40
(CHCl3—MeOH, 1 : 1). Found (%): C, 81.90; H, 12.50; N, 5.15.
C18H33N. Calculated (%): C, 82.06; H, 12.62; N, 5.32. IR,
/cm–1: 1579, 3285, 3342 (NH2). 15N NMR, : 41.6 (NH2).
Major isomer. 1H NMR, : 0.80 (s, 3 H, H(17)); 0.88 (s, 3 H,
H(16)); 0.95 (s, 3 H, H(18)); 1.09 (d, 3 H, H(14), J = 6.2 Hz);
1.10 (m, 1 H, H(5)); 1.30—1.70 (signals overlap) (m, 2 H, NH2);
1.56 (s, 3 H, H(15)); 2.87 (m, 1 H, H(13)). 13C NMR, : 19.09
(C(2), C(6)); 19.52 (C(15)); 20.12 (C(18)); 21.71 (C(17)); 23.71
(C(14)); 24.90 (C(11)); 33.32 (C(16)); 33.34 (C(4)); 33.64 (C(7));
37.10 (C(1)); 39.02 (C(10)); 40.80 (C(12)); 41.83 (C(3)); 48.01
(C(13)); 51.92 (C(5)); 125.52 (C(8)); 140.44 (C(9)).
Minor isomer. 1H NMR, : 1.08 (d, 3 H, H(14), J = 6.2 Hz);
1.55 (s, 3 H, H(15)). Other signals are the same as those given for
the major isomer. 13C NMR, : 19.06 (C(2), C(6)); 19.54 (C(15));
20.12 (C(18)); 21.71 (C(17)); 23.83 (C(14)); 24.78 (C(11)); 33.32
(C(16)); 33.34 (C(4)); 33.64 (C(7)); 37.11 (C(1)); 39.02 (C(10));
40.80 (C(12)); 41.83 (C(3)); 47.95 (C(13)); 51.92 (C(5)); 125.55
(C(8)); 140.48 (C(9)).
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Received November 19, 2013;
in revised form April 10, 2014