Reduction of (+)-usninic acid and its pyrazole derivative by sodium borohydride

Article abstract of DOI:10.1007/s10600-011-9882-8

The reaction of (+)-usninic acid and its pyrazole derivative with sodium borohydride was studied. The reduction occurred stereoselectively at the endocyclic carbonyl group. Novel (+)-usninic acid derivatives that were reduction products of the carbonyls were obtained.

Full text of DOI:10.1007/s10600-011-9882-8

Chemistry of Natural Compounds, Vol. 47, No. 2, May, 2011 [Russian original No. 2, March-April, 2011]
REDUCTION OF (+)-USNINIC ACID AND ITS PYRAZOLE
DERIVATIVE BY SODIUM BOROHYDRIDE
*
D. N. Sokolov, O. A. Luzina, M. P. Polovinka,
UDC 547.992
and N. F. Salakhutdinov
The reaction of (+)-usninic acid and its pyrazole derivative with sodium borohydride was studied. The
reduction occurred stereoselectively at the endocyclic carbonyl group. Novel (+)-usninic acid derivatives
that were reduction products of the carbonyls were obtained.
Keywords: (+)-usninic acid, reduction, sodium borohydride.
The isolation and synthetic transformation of plant metabolites in order to increase their biological activity and/or
prepare new drugs is one of the leading areas in the chemistry of natural compounds. Usninic acid (1) is the principal
secondary metabolite of several lichens and exhibits various types of biological activity [1]. The reduction of 1 by H /Pd,
2
which quantitatively reduced the C –C double bond, was reported previously [2]. However, there is practically no information
4
4a
on the reduction of the carbonyls of 1 by metal hydride complexes. An example of the reduction of 1 by NaBH was described.
4
A small amount of the carbonyl (C =O) reduction product was isolated from the product mixture [3].
13
Herein we present results for the preparation of (+)-usninic acid (1) derivatives reduced at the carbonyls in order to
expand the repertoire of semi-synthetic natural dibenzofuran derivatives that hold promise of exhibiting high biological activity.
We reduced 1 with NaBH under various conditions. The reaction occurred exceedingly nonselectively in alcohols
4
(MeOH, EtOH, i-PrOH) at room temperature to form a multi-component product mixture (>20). The reaction did not occur if
benzene or hexane was used as the solvent. The most acceptable solvent was THF. Reduction of 1 in THF occurred at low
temperatures (–20°C). A mixture of products (~4:5) reduced at the C =O carbonyl (2) or two carbonyls (C =O and C =O) (3)
1
1
11
formed during the two-hour reaction in overall yield 57%. In addition, the reaction mixture contained starting 1. Increasing
the reaction time in order to increase the conversion of substrate complicated the reaction mixture owing to increased amounts
of minor products. Reduction of the C =O occurred stereoselectively. Compound 3 was apparently a mixture of stereoisomers
1
with clear predominance of one of them. Thus, reduction of the C =O carbonyl occurred less selectively. We assumed the
11
configuration of the C center in both compounds based on literature data for the reaction mechanism of carbonyls with
1
NaBH [4]. The mutual axial–axial location of protons on C and C was established using the spin–spin coupling constant
4
1
2
(SSCC) (10.5 Hz) and literature data for the SSCC in substituted cyclohexenones [5].
OH
O
O
OH
OH
OH
OH
OH
O
10
12
15
9
11
2
11
NaBH
11
4
9a
9b
1
1
1
+
3
-20ꢀC, THF
HO
7
HO
HO
O
O
OH
4a
4a
5a
O
O
4
O
13
14
13
O
O
O
3a
1
2
Reaction under analogous conditions of a pyrazole derivative of 1 (4) with NaBH produced 5 by reduction of C =O.
4
1
The reaction occurred stereoselectively in excellent (96%) yield at temperatures from –40 to 0°C. The yield of 5 decreased
slightly with the temperature increased to ambient. Increasing the temperature further to 50°C caused 5 to react with the
Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, 630090, Novosibirsk,
e-mail: dsokolov@nioch.nsc.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 188–190, March–April, 2011.
Original article submitted July 19, 2010.
©
0009-3130/11/4702-0203 2011 Springer Science+Business Media, Inc.
203

excess of NaBH to give the product from reduction of the C =O carbonyl (6) (a mixture of stereoisomers at the C center,
4
13
13
~2:3 according to PMR data).
12
11
OH
OH
OH
OH
OH
O
15
9b
9
NaBH
NaBH
4
N
N
4
N
9a
1
1
1
HO
HO
HO
HO
N
-20ꢀC, THF
N
50ꢀC, THF
N
3
7
4a
5a
Ph
O
Ph
Ph
O
O
13
14
13
13
O
O
5
4
6a,b
Thus, reduction of the carbonyls of 1 by NaBH occurred sequentially. The endocyclic carbonyl (C =O) was most
4
1
reactive. It was reduced stereoselectively. The C =O carbonyl was reduced only at elevated temperature and not
13
stereoselectively. This was shown using the reaction of a pyrazole derivative of 1 (4) with NaBH as an example.
4
EXPERIMENTAL
13
PMR and C NMR spectra were recorded on a Bruker DRX-500 spectrometer at operating frequency 500.13 MHz
( H) and 125.76 ( C); IR spectra, on a Vector 22 spectrometer; mass spectra (ionizing-electron energy 70 eV), in a DFS high-
1
13
resolution mass spectrometer. Melting points were measured on a Kofler block. Compound 1 ([ꢀ] +478°, c 0.1, CHCl ) was
D
3
isolated from a mixture of lichens of the genus Usnea by the literature method [6]. Compound 4 was synthesized by the
literature method [7]. We used commercially available NaBH . The reaction of 1 was monitored experimentally using PMR
4
spectra. Column chromatography used Merck silica gel (60–200 ꢁ). Atoms in the compounds were numbered based on the
commonly accepted numbering of usninic acid structures and did not always agree with the numbering of the atoms according
to the nomenclature name.
Reaction of 1 with NaBH . Asolution of 1 (1 mmol) in THF (20 mL) was cooled to –20°C, treated with a suspension
4
of NaBH (50 mg) in THF (5 mL), stirred at that temperature for 2 h, treated with dilute HCl solution until the pH was ~5,
4
brought to room temperature, treated with CH Cl (30 mL), washed with H O (2ꢂ), and dried over calcined MgSO . The
2
2
2
4
solvent was removed. The products were chromatographed over a column of silica gel (60–200 ꢁ) with elution by CHCl to
3
isolate starting 1 (30%) and a mixture of 2 and 3a, b in a 4:5 ratio according to PMR spectra in overall yield 57%. Compounds
2 and 3a, b were separated by repeated chromatography over a column of silica gel (60–200 ꢁ) with elution by CH Cl .
2
2
1,1ꢃ-{(1S,9bR)-1,7,9-Trihydroxy-8,9b-dimethyl-3-oxo-1,2,3,9b-tetrahydrodibenzo[b,d]furan-2,6-diyl}diethanone
–1
(2). Yield 12%, mp 97°C, [ꢀ] +346° (c 0.1, CHCl ). IR spectrum (KBr, ꢄ, cm ): 1043, 1158, 1290, 1625, 1718, 3211, 3411.
D
3
PMR spectrum (CDCl , ꢅ, ppm, J/Hz): 1.53 (3H, s, H-15), 2.04 (3H, s, H-10), 2.55 (3H, s, H-12), 2.65 (3H, s, H-14),
3
3.76 (1H, d, J = 10.5, H-2), 4.70 (1H, d, J = 10.5, H-1), 4.97 (1H, s, 1-OH), 5.79 (1H, s, H-4), 9.23 (1H, s, 9-OH), 13.29 (1H,
s, 7-OH).
13
C NMR spectrum (CDCl , ꢅ, ppm): 9.68 (C-10), 22.30 (C-15), 33.48 and 34.85 (C-12 and C-14), 51.37 (C-9b),
3
65.51 (C-1), 74.37 (C-2), 103.65 (C-6), 105.96 (C-4), 110.12 (C-8), 110.76 (C-9a), 157.53 (C-5a), 158.92 (C-9), 165.73 (C-7),
184.15 (C-4a), 192.83 (C-3), 202.91 (C-13), 208.83 (C-11).
+
Found: m/z 346.1050 [M] ; C H O ; calcd: MW = 346.1047.
18 18
7
(1S,9bR)-6-Acetyl-1,7,9-trihydroxy-2-(1-hydroxyethyl)-8,9b-dimethyl-1,2-dihydrodibenzo[b,d]furan-3(9bH)-
–1
one (3a, 3b) (3a:3b ratio ~10:1 according to PMR). Yield 12%, mp 92°C. IR spectrum (KBr, ꢄ, cm ): 1046, 1157, 1289,
1625, 3204, 3400.
PMR spectrum of 3a (CDCl , ꢅ, ppm, J/Hz): 1.23 (3H, d, J = 6, H-12), 1.54 (3H, s, H-15), 2.07 (3H, s, H-10), 2.67
3
(3H, s, H-14), 3.05 (1H, dd, J = 4.5, 10.5, H-2), 4.56 (1H, d, J = 10.5, H-1), 4.98 (1H, dq, J = 4.5, 6, H-11), 5.75 (1H, s, H-4),
5.92 (1H, s, 1-OH), 9.48 (1H, s, 9-OH), 13.31 (1H, s, 7-OH).
The following resonances in the PMR spectrum of 3b could be assigned: 1.26 (3H, d, J = 6, H-12), 1.53 (3H, s, H-15),
2.06 (3H, s, H-10), 2.68 (3H, s, H-14), 4.83 (1H, m), 5.85 (1H, s, H-4).
13
C NMR spectrum of 3a (CDCl , ꢅ, ppm): 7.02 (C-10), 18.57 and 19.70 (C-12 and C-15), 30.79 (C-14), 48.75 (C-
3
9b), 51.85 (C-2), 69.30 (C-11), 71.74 (C-1), 100.93 (C-6), 103.48 (C-4), 108.04 and 108.14 (C-8 and C-9a), 154.96 (C-5a),
156.51 (C-9), 162.85 (C-7), 181.99 (C-4a), 194.84 (C-3), 200.33 (C-13).
+
Found: m/z 348.1210 [M] ; C H O ; calcd: MW = 348.1204.
18 20
7
204

Reaction of 4 with NaBH . Asolution of 4 (1 mmol) in THF (20 mL) was cooled to –20°C, treated with a suspension
4
of NaBH (50 mg) in THF (5 mL), stirred at that temperature for 2 h, treated with dilute HCl solution until the pH was ~5,
4
brought to room temperature, treated with CH Cl (30 mL), washed with H O (2ꢂ), and dried over calcined MgSO . The
2
2
2
4
solvent was removed. The products were chromatographed over a column of silica gel (60–200 ꢁ) with elution by CHCl .
3
1-{(4S,4aR)-4,5,7-Trihydroxy-3,4a,6-trimethyl-1-phenyl-4,4a-dihydro-1H-benzofuro[3,2-f]indazol-8-
–1
yl)ethanone (5). Yield 96%, mp 155°C, [ꢀ] +152° (c 0.1, CHCl ). IR spectrum (KBr, ꢄ, cm ): 1068, 1288, 1369, 1441,
D
3
1627, 3188, 3392.
PMR spectrum (CDCl , ꢅ, ppm, J/Hz): 1.35 (3H, s, H-15), 2.03 (3H, s, H-10), 2.32 (3H, s, H-12), 2.61 (3H, s, H-14),
3
5.26 (1H, br.s, 1-OH), 5.33 (1H, d, J = 6, H-1), 5.87 (1H, s, H-4), 7.31–7.42 (5H, m, arom. H), 9.25 (1H, s, 9-OH), 13.31 (1H,
s, 7-OH).
13
C NMR spectrum (CDCl , ꢅ, ppm): 6.97 (C-10), 12.25 (C-12), 15.93 (C-15), 30.79 (C-14), 50.90 (C-9b), 74.30
3
(C-1), 88.99 (C-4), 101.03 (C-6), 106.56 (C-9a), 107.66 (C-8), 111.35 (C-2), 123.23, 127.39, 129.01 and 137.75 (2C, C, 2C,
and C, all arom.), 138.10 (C-3), 146.22 (C-11), 156.84 (C-9), 157.26 (C-5a), 162.58 (C-7), 167.26 (C-4a), 200.58 (C-13).
+
Found: m/z 418.1521 [M] ; C H O N ; calcd: MW = 418.1523.
24 22
5 2
Reaction of 5 with NaBH . A solution of 5 (1 mmol) in THF (20 mL) was treated with a suspension of NaBH
4
4
(50 mg) in THF (5 mL), heated to 50°C, stirred for 2 h, brought to room temperature, treated with dilute HCl solution under the
pH was ~5, treated with CH Cl (30 mL), washed with H O (2ꢂ), and dried over calcined MgSO . The solvent was removed.
2
2
2
4
The products were chromatographed over a column of silica gel (60–200 ꢁ) with elution by CHCl .
3
(4S,4aR)-8-(1-Hydroxyethyl)-3,4a,6-trimethyl-1-phenyl-4,4a-dihydro-1H-benzofuro[3,2-f]indazol-4,5,7-triol (6a
–1
and 6b) (6a:6b ratio ~2:3 according to PMR data). Yield 71%, mp 233°C. IR spectrum (KBr, ꢄ, cm ): 1041, 1067, 1174,
1440, 1504, 1627, 3271.
PMR spectrum of 6a (CDCl , ꢅ, ppm, J/Hz): 1.33 (3H, s, H-15), 1.47 (3H, d, J = 6, H-14), 2.04 (3H, s, H-10), 2.27
3
(3H, s, H-12), 4.00 (1H, br.s, 13-OH), 4.50 (1H, d, J = 7, 1-OH), 5.20 (1H, q, J = 6, H-13), 5.28 (1H, d, J = 7, H-1), 5.73 (1H,
s, H-4), 7.28–7.38 (5H, m, arom. H), 8.24 and 8.67 (1H and 1H, s and s, 7-OH and 9-OH).
13
C NMR spectrum (CDCl , ꢅ, ppm): 7.62 (C-10), 12.43 (C-12), 16.36 (C-15), 23.26 (C-14), 51.96 (C-9b), 65.78
3
(C-13), 74.85 (C-1), 88.07 (C-4), 104.39 (C-8), 107.00 (C-9a), 107.24 (C-6), 111.68 (C-2), 123.23, 127.35, 129.18 and 138.57
(2C, C, 2C, and C, all arom.), 138.45 (C-3), 146.74 (C-11), 150.14 (C-7), 152.05 (C-5a), 155.10 (C-9), 168.68 (C-4a).
+
Found: fragment ion (–H O) m/z 402.1570 [M] ; C H O N .
2
24 22 4 2
PMR spectrum of 6b (CDCl , ꢅ, ppm, J/Hz): 1.34 (3H, s, H-15) and 1.50 (3H, d, J = 6, H-14), 2.04 (3H, s, H-10), 2.32
3
(3H, s, H-12), 3.77 (1H, br.s, 13-OH), 4.54 (1H, d, J = 7, 1-OH), 5.24 (1H, q, J = 6, H-13), 5.30 (1H, d, J = 7, H-1), 5.76 (1H,
s, H-4), 7.28–7.38 (5H, m, arom. H), 8.30 and 8.64 (1H and 1H, s and s, 7-OH and 9-OH).
13
The following resonances in the C NMR spectrum of 6b could be assigned: 12.51 (C-12), 16.43 (C-15), 51.86
(C-9b), 66.06 (C-13), 88.00 (C-4), 107.36 (C-6), 111.62 (C-2), 146.59 (C-11), 150.24 (C-7), 152.12 (C-5a).
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