Simple synthesis of new chiral oxindole derivative

Article abstract of DOI:10.1007/s11172-008-0204-7

A synthesis of chiral optically active 3-hydroxyoxindoles with 1,3-disubstituted 2,2-dimethyl-cyclobutane structural fragment by the Et ₂NH-catalyzed aldol reaction of indoline-2,3-diones with (-)-(1S,3S)-pinonic acid derivatives is described.

Full text of DOI:10.1007/s11172-008-0204-7

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1571—1574, July, 2008
1571
Simple synthesis of new chiral oxindole derivative
F. Z. Makaev, O. M. Radul, and A. P. Gudima
Institute of Chemistry, Academy of Sciences of Moldova Republic,
3 ul. Akademiei, MDꢀ2028 Kishinev, Moldova Republic.
Fax: (373 22) 739 954. Eꢀmail: flmacaev@cc.acad.md, ivanluka@moldnet.md
A synthesis of chiral optically active 3ꢀhydroxyoxindoles with 1,3ꢀdisubstituted 2,2ꢀdimethylꢀ
cyclobutane structural fragment by the Et2NHꢀcatalyzed aldol reaction of indolineꢀ2,3ꢀdiones with
(–)ꢀ(1S,3S)ꢀpinonic acid derivatives is described.
Key words: isatin, oxindoles, pinonic acid derivatives.
Chiral oxindoles display various physiological activiꢀ
ty.1—5 At the same time, cyclobutaneacetic acid derivaꢀ
tives are known as precursors of carbocyclic nucleosides
and of structural fragment of natural dipeptides.6,7 In this
connection, a synthesis of compounds combining the
pharmacophore groups indicated is of interest. Recentꢀ
ly,8 an enantioselective synthesis of (3S)ꢀ3ꢀhydroxyoxinꢀ
amide (1690 cm–1), and hydroxy (3370 cm–1) groups are
observed. In the H NMR spectrum, the singlet signals
1
for the gemꢀdimethyl group of the cyclobutane ring (δ 0.81
and 1.27), the ester group (δ 3.63), as well as two signals
for the ethyl group at δ 1.28 and 3.66 are the most characꢀ
teristic. The signal for the methylene group connecting
the oxindole and cyclobutanoyl fragments is registered at
δ 2.93. In the 13C NMR spectrum of compound 3a, two
signals at δ 17.23 and 30.04 belong to the gemꢀdimethyl
group. The difference of more than 12 ppm is caused by
the fact that one of the Me groups is sterically shielded by
the two cis substituents of the cyclobutane ring, whereas
the other one does not participate in the interaction with
them resulting in its signal being observed more upfield.
The stereochemistry of the sp3ꢀhybridized C(3´*) atom
formed and the chiral centers of 1,3ꢀdisubstituted 2,2ꢀdiꢀ
methylcyclobutane fragment of compound 3a are estabꢀ
lished on the basis of the Xꢀray analysis data.10
doles from isatin (1a
) and chiral vinyl ketenes cataꢀ
lyzed by TiCl4 has been described
.
In the present work, a simple synthesis of new 3ꢀhydrꢀ
oxyoxindole derivatives with gemꢀdimethylcyclobutane
structural fragment is suggested. It was found that
keeping at room temperature of equimolar amounts of
Nꢀethylisatin (1b),9 pinonic acid ester 2a, and Et2NH in
MеOH leads to aldol 3a (Scheme 1)*.
In the IR spectrum of compound 3a, the absorption
bands of the ester (1730 cmꢁ–1), ketone (1720 cm–1),
The synthesis of compounds 3b—f from compounds
1a—c (see Ref. 9) and 2a—c has been accomplished simꢀ
ilarly.11,12 It was found that the synthesis of alcohols 3e,f
* The numeration of atoms in Scheme 1 is given for discussion on
the structures and spectra of compounds synthesized and does not
obey the IUPAC rules.
Scheme 1
1: R1 = H (a), Et (b), CH2Ph (c); 2: R2 = CO2Me (a), CN (b), CONH2 (c), CO2H (d);
3, 4: R1 = Et, R2 = CO2Me (a); R1 = Et, R2 = CN (b); R1 = CH2Ph, R2 = CO2Me (c); R1 = H, R2 = CO2Me (d); R1 = H, R2 = CN (e);
R1 = H, R2 = CONH2 (f)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1540—1543, July, 2008.
1066ꢀ5285/08/5707ꢀ1571 © 2008 Springer Science+Business Media, Inc.

1572
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Makaev et al.
(C(5)); 42.5 (C(6)); 50.7 (COOMe); 53.5 (C(3)); 172.4 (COOMe);
206.5 (C(2)). Found (%): C, 66.53; H, 9.09. C11H18O3. Calculated
(%): C, 66.64; H, 9.15.
Methyl (–)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(1ꢀethylꢀ3ꢀhydroxyꢀ2ꢀoxoꢀ
2,3ꢀdihydroꢀ1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetate
(3a). A mixture of isatin 1b (0.875 g, 5 mmol), ester 2a (0.99 g,
5 mmol), and Et2NH (0.37 g, 5 mmol) in MеOH (10 mL) was
stirred for 6 h at room temperature. Water (20 mL) was added and
the mixture was extracted with CHCl3 (3×50 mL). A combined
extract was dried with Na2SO4. The solvent was evaporated,
requires stirring of the reagents for 96 h, whereas an
increase in the reaction time in the preparation of comꢀ
pound 3a from 6 to 24 h leads to a decrease in the yield
from 71 to 48%. The latter fact is caused, apparently, by
the retro aldol reaction. Attempts to reach complete conꢀ
version in the syntheses under consideration were unsucꢀ
cessful (TLC data).
The mother liquor left after crystallization of product
3a consists of a mixture of compounds, the three of which
were successfully isolated by column chromatography.
The first and the second fractions were the starting comꢀ
pounds 1b and 2a, respectively. The most polar fraction
(20%) is a mixture of compounds 3a and 4a (1 : 7). Chroꢀ
matography of the mother liquors left after crystallizaꢀ
tion of indoles 3b—f gives the starting isatins 1a—c, meꢀ
thyl ketones 2a—c, and a mixture of diastereoisomeric
alcohols 3b—d and 4b—d, respectively. In the case of
synthesis of compound 3b, α,βꢀunsaturated ketone 5 was
also isolated. It should be noted that the mother liquors
left after crystallization of alcohols 3e,f were unseparable
mixtures of compounds. All the attempts to obtain
the condensation product of compound 1 with pinonic
acid 2d under conditions indicated above were unꢀ
successful.
the residue (1.9 g) was recrystallized from EtOH. The yield was 1.33 g
20
(71%), m.p. 124—125 °C (from ethanol), [α]
–27.9 (c 1.22,
D
MeOH). IR, ν/cm–1: 1690 (CON); 1720 (C=O); 1730 (COOMе);
3370 (OH). H NMR (CDCl3), δ: 0.81, 1.27 (both s, 3 H each,
1
C(6)Mе2); 1.28 (t, 3 H, CH2Mе, J = 7.3 Hz); 1.86—2.29 (m, 5 H,
C(4)H2, C(9)H2, C(5)H); 2.82, 2.93 (both d, 1 H each, ABꢀsystem,
C(1)H2, J = 14.1 Hz, J = 31.1 Hz); 2.86 (t, 1 H, C(3)H, J = 8.4 Hz);
2.75—3.02 (m, 3 H, C(3)H, C(1)H2); 3.66 (q, 2 H, CH2Mе,
J = 7.3 Hz); 3.63 (s, 3 H, COOMе); 4.38 (br.s, 1 H, OH); 6.81—7.43
(m, 4 H, C(4´)H, C(5´)H, C(6´)H, C(7´)H). 13C NMR (CDCl3),
δ: 12.21 (CH2Mе); 17.23 (C(8)); 22.54 (C(4)); 22.55 (C(CH2Mе));
30.04 (C(7)); 34.60 (C(9)); 37.79 (C(5)); 43.81 (C(6)); 48.94
(C(1)); 51.37 (COOMе); 53.94 (C(3)); 73.84 (C(3´)); 108.59
(C(7´)); 121.07 (C(9´)); 122.58 (C(5´)); 123.82 (C(4´)); 129.96
(C(6´)); 142.63 (C(8´)); 172.99 (COOMе); 175.92 (C(2´)); 207.34
(C(2)). Found (%): C, 67.30; H, 7.01; N, 3.32. C21H27NO5.
Calculated (%): C, 67.54; H, 7.29; N, 3.75.
To sum up, a simple synthesis of chiral optically acꢀ
tive 3ꢀhydroxyoxindoles from isatins and (–)ꢀpinonic
acid derivatives has been suggested.
The mother liquor (0.55 g) left after crystallization of alcohol 3a
was subjected to column chromatography on SiO2 (15 g) (eluent,
CHCl3) to obtain a pale yellow mixture of alcohols 3a and 4a (1 : 7).
The yield was 0.37 g (20%). 1H NMR of predominant isomer 4a
(CDCl3), δ: 0.57 (t, 3 H, CH2Mе, J = 7.25 Hz); 0.86, 1.18 (both s,
3 H each, C(6)Mе2); 1.71—2.28 (m, 5 H, C(4)H2, C(9)H2, C(5)H);
2.80, 2.96 (both d, 1 H each, ABꢀsystem, C(1)H2, J = 14.1 Hz,
J = 31.1 Hz); 2.86 (t, 1 H, C(3)H, J = 8.4 Hz); 2.75—3.02 (m, 3 H,
C(3)H, C(1)H2); 3.64 (q, CH2Mе, J = 7.3 Hz); 3.51 (s, 3 H,
COOMе); 4.50 (br.s, 1 H, OH); 6.71—7.33 (m, 4 H, C(4´)H,
C(5´)H, C(6´)H, C(7´)H). 13C NMR of predominant isomer 4a
(CDCl3), δ: 11.80 (CH2Mе); 16.72 (C(8)); 21.92 (C(4)); 22.13
(C(CH2Mе)); 29.61 (C(7)); 34.20 (C(9)); 41.58 (C(5)); 43.32
(C(6)); 49.83 (C(1)); 51.87 (COOMе); 52.60 (C(3)); 72.93 (C(3´));
108.19 (C(7´)); 121.01 (C(9´)); 122.12 (C(5´)); 123.29 (C(4´));
129.75 (C(6´)); 142.65 (C(8´)); 172.64 (COOMе); 176.03 (C(2´));
206.77 (C(2)). Found (%): C, 67.70; H, 7.41; N, 3.57. C21H27NO5.
Calculated (%): C, 67.54; H, 7.29; N, 3.75.
Experimental
Specific rotation was determined on a Jasco Pꢀ2000 automatic
polarimeter. Melting points were measured on a Boetius apparatus.
IR spectra were recorded on a Specord 75 spectrophotometer in
Nujol, 1H and 13C NMR spectra were recorded on a Bruker ACꢀE
200 (200.13 and 50.32 MHz) and Bruker ACꢀ80 (80 and 20 MHz)
spectrometers for 2—3% solutions in CDCl3 or DMSOꢀd6 with
Me4Si as the internal standard. Silica gel L40/100, 100/160 μ
(CzSSR) and 40/63μ (Fluka) was used for column chromatograꢀ
phy. Silufol and Alufol (Czechoslovakia) plates were used for TLC,
a 5% solution of phosphomolybdic acid in EtOH followed by
heating or acidified 2% aqueous KMnO4 were used for visualization
of compounds.
(+)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(1ꢀEthylꢀ3ꢀhydroxyꢀ2ꢀoxoꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetonitrile
(3b) was synthesized similarly to compound 3a. The yield was 58%,
(–)ꢀαꢀPinene from Fluka was used, nD20 1.466, [α] 20 –58.48
D
(c 0.046, CHCl3). Keto nitrile 2b was obtained according to the
20
known method,12 [α]
–131.16 (c 1.02, CHCl3). Keto amide 2c
m.p. 176—177 °C (from ethanol), [α] 20 +64.06 (c 1.32, MeOH).
D
D
was synthesized according to the described method,12 [α]
–
3.58
IR, ν/cm–1: 1660 (CON); 1715 (C=O); 2240 (CN); 3380 (OH).
1H NMR (CDCl3), δ: 0.88, 1.35 (both s, 3 H each, C(6)Mе2); 1.27
(t, 3 H, CH2Me, J = 9.2 Hz); 1.61—2.27 (m, 5 H, C(4)H2, C(9)H2,
C(5)H); 2.86, 2.97 (both d, 1 H each, ABꢀsystem, C(1)H2, J =
11.2 Hz, J = 14.5 Hz); 2.84 (t, 1 H, C(3)H, J = 5.6 Hz); 3.61—3.88
(q, 2 H, CH2Me, J = 6.5 Hz); 4.39 (s, 1 H, OH); 6.81—7.44 (m, 4 H,
C(4´)H, C(5´)H, C(6´)H, C(7´)H). 13C NMR (CDCl3), δ: 12.26
(N—CH2Me); 16.92 (C(8)); 17.33 (C(9)); 22.52 C(7)); 29.99
(N—CH2Me); 30.00 (C(4)); 34.74 (C(5)); 43.56 (C(6)); 48.99
(C(3)); 49.72 (C(1)); 53.67 (C(9)); 73.95 (C(3´)); 108.70 (C(7´));
117.62 (CN); 120.05 (C(4´)); 122.77 (C(9´)); 123.90 (C(6´));
129.93 (C(8´)); 175.86 (C(2´)); 205.56 (C(2)). Found (%):
20
D
(c 0.19, CHCl3). Keto acid 2d was obtained according to the deꢀ
20
scribed method,13 [α]
–82.79 (c 1.22, CHCl3). The synthesis
D
of compounds 1b,c was described earlier.9
Methyl 2ꢀ[(1S,3S)ꢀ3ꢀacetylꢀ2,2ꢀdimethylcyclobutyl]acetate
(2a) was obtained by methylation of acid 2d with diazomethane. The
16
yield was 73%, pale yellow oil, [α]
–50.97 (c 1.01, CHCl3). IR,
D
ν/cm–1: 1715 (COMe); 1735 (COOMe). H NMR (CDCl3), δ:
0.81, 1.28 (both s, 3 H each, C(6)Mе2); 1.79—2.27 (m, 5 H,
C(4)H2, C(9)H2, C(5)H); 2.01 (s, 3 H, MeCO); 2.86 (t, 1 H,
C(3)H, J = 8.5 Hz); 3.60 (s, 3 H, COOMe). 13C NMR (CDCl3), δ:
16.6 (C(8)); 22.4 (C(7), C(4)); 29.5 (C(1)); 34.2 (C(9)); 37.5
1

New chiral oxindole derivatives
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1573
C, 70.70; H, 7.00; N, 8.34. C20H24N2O3. Calculated (%): C, 70.56;
H, 7.11; N, 8.23.
(+)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(3ꢀHydroxyꢀ2ꢀoxoꢀ2,3ꢀdihydroꢀ
1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetonitrile (3e)
was synthesized similarly to compound 3a. The yield was 55%, m.p.
Column chromatography on SiO2 (eluent, CHCl3) of the mother
liquor (0.55 g) left after crystallization of alcohol 3b gave an oily
mixture of alcohols 3b and 4b (1 : 4) crystallizing on standing. The
163—164 °C (from ethanol), [α] 20 +66 (c1.0, MeOH). IR, ν/cm–1
:
D
1690, 3440 (CONH); 1720 (C=O); 2245 (CN); 3375 (OH).
yield was 15%, m.p. 127—139 °C, [α] 20 +10.89 (c 1.32, MeOH).
1H NMR (CDCl3), δ: 0.86, 1.32 (both s, 3 H each, C(6)Mе2);
1.62—2.22 (m, 5 H, C(4)H2, C(9)H2, C(5)H); 2.88, 2.98
(both d, 1 H each, ABꢀsystem, C(1)H2, J = 10.7 Hz, J = 27.7 Hz);
2.92 (t, 1 H, C(3)H, J = 8.6 Hz); 4.61 (s, 1 H, OH); 6.81—7.49
(m, 4 H, C(4´)H, C(5´)H, C(6´)H, C(7´)H); 8.73 (s, 1 H, NH).
13C NMR (CDCl3), δ: 16.97 (C(8)); 17.45 (C(4)); 22.58 (C(7),
C(9)); 38.05 (C(5)); 43.70 (C(6)); 49.05 (C(1)); 54.20 (C(3));
74.40 (C(3´)); 110.62 (C(7´)); 118.35 (CN); 122.95 (C(5´));
124.12 (C(4´)); 128.27 (C(9´)); 130.05 (C(6´)); 140.81
(C(8´)); 178.70 (C(2´)); 207.06 (C(2)). Found (%): C, 69.57;
H, 6.34; N, 9.10. C18H20N2O3. Calculated (%): C, 69.21; H, 6.45;
N, 8.96.
D
1H NMR of predominant isomer 4b (CDCl3), δ: 0.73, 1.33 (both s,
3 H each, C(6)Mе2); 0.86 (t, 3 H, CH2Me, J = 10.2 Hz); 1.70—2.41
(m, 5 H, C(4)H2, C(9)H2, C(5)H); 2.55, 3.01 (both d, 1 H each,
ABꢀsystem, C(1)H2, J = 11.9 Hz, J = 16.1 Hz); 2.84 (t, 1 H, C(3)H,
J = 5.6 Hz); 3.75 (q, 2 H, CH2Me, J = 7.2 Hz); 4.49 (s, 1 H, OH);
6.60—7.42 (m, 4 H, C(4´)H, C(5´)H, C(6´)H, C(7´)H). Found (%):
C, 70.68; H, 6.86; N, 8.14. C20H24N2O3. Calculated (%): C, 70.56;
H, 7.11; N, 8.23.
Methyl (–)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(1ꢀbenzylꢀ3ꢀhydroxyꢀ2ꢀ
oxoꢀ2,3ꢀdihydroꢀ1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}ꢀ
acetate (3c) was synthesized similarly to compound 3a. The yield
was 70%, m.p. 152—153 °C (from ethanol), [α] 20 –44.89 (c 1.59,
(–)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(3ꢀHydroxyꢀ2ꢀoxoꢀ2,3ꢀdihydroꢀ
1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetamide (3f) was
synthesized similarly to compound 3a. The yield was 51%, m.p.
D
MeOH). IR, ν/cm–1: 1695 (CON); 1715 (C=O); 1735 (COOMe);
1
3375 (OH). H NMR (CDCl3), δ: 0.82, 1.27 (both s, 3 H each,
C(6)Mе2); 1.81—2.29 (m, 5 H, C(4)H2, C(9)H2, C(5)H); 2.89,
2.99 (both d, 1 H each, ABꢀsystem, C(1)H2, J = 11.6 Hz, J = 24.3 Hz);
2.92 (t, 1 H, C(3)H, J = 8.4 Hz); 3.64 (s, 3 H, COOMe); 4.48
(s, 1 H, OH); 4.88 (s, 2 H, N—CH2—Ph); 6.24—7.41 (m, 9 H,
C(4´)H, C(5´)H, C(6´)H, C(7´)H, N—CH2—Ph). Found (%):
C, 72.00; H, 6.39; N, 3.32. C26H29NO5. Calculated (%): C, 71.70;
H, 6.71; N, 3.22.
205—207 °C (from ethanol), [α] 20 –28.46 (c 1.23, MeOH). IR,
D
ν/cm–1: 1680, 3440 (CONH); 1700 (CONH2); 1715 (C=O); 3290
1
(OH). H NMR (DMSOꢀd6), δ: 0.70, 1.25 (both s, 3 H each,
C(6)Mе2); 1.49—2.12 (m, 5 H, C(4)H2, C(9)H2, C(5)H);
2.72—3.21 (m, 3 H, C(3)H, C(1)H2); 4.08 (s, 1 H, OH), 6.00
(s, 2 H, CONH2); 6.75—7.27 (m, 4 H, C(4´)H, C(5´)H,
C(6´)H, C(7´)H); 10.21 (s, 1 H, NH). Found (%): C, 66.48;
H, 7.39; N, 8.09. C18H22N2O4. Calculated (%): C, 65.44; H, 6.71;
N, 8.48.
Column chromatography on SiO2 (eluent, CHCl3) of the mother
liquor left after crystallization of alcohol 3c gave yellow oil cryꢀ
20
stallizing on standing. The yield was 17%, m.p. 131—149 °C, [α]
(+)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(1ꢀEthylꢀ2ꢀoxoꢀ2,3ꢀdihydroꢀ1Hꢀ3ꢀ
indolylidene)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetonitrile (5). The
product was obtained by chromatography of the mother liquor left
after crystallization of alcohol 3b. The yield was 13%, m.p. 162—164 °C
D
–42.59 (c 0.72, MeOH). 1H NMR of predominant isomer 4c
(CDCl3), δ: 0.82, 1.27 (both s, 3 H each, C(6)Mе2); 1.86—2.42
(m, 5 H, C(4)H2, C(9)H2, C(5)H); 2.79, 2.88 (both d, 1 H each,
ABꢀsystem, C(1)H2, J = 16.9 Hz, J = 28.9 Hz); 2.91 (t, 1 H,
C(3)H, J = 8.6 Hz); 3.63 (s, 3 H, COOMe); 4.37 (s, 1 H, OH);
4.89 (s, 2 H, N—CH2—Ph); 6.63—7.39 (m, 9 H, C(4´)H,
C(5´)H, C(6´)H, C(7´)H, N—CH2—Ph). Found (%): C, 71.55;
H, 6.85; N, 3.19. C26H29NO5. Calculated (%): C, 71.70; H, 6.71;
N, 3.22.
(from ethanol), [α] 20 +6.68 (c0.16, MeOH). IR, ν/cm–1
: 1660, 1685
D
1
(C=O); 2240 (CN). H NMR (CDCl3), δ: 0.81, 1.33 (both s,
3 H each, C(6)Mе2); 1.15 (t, 3 H, CH2Me, J = 7.2 Hz); 1.87—2.81
(m, 5 H, C(4)H2, C(9)H2, C(5)H); 3.39 (t, 1 H, C(3)H, J = 5.7 Hz);
3.74 (q, 2 H, CH2Me, J = 7.2 Hz); 6.95—8.39 (m, 5 H,
C(1)H, C(4´)H, C(5´)H, C(6´)H, C(7´)H). Found (%): C, 74.59;
H, 6.67; N, 8.81. C20H22N2O2. Calculated (%): C, 74.51; H, 6.88;
N, 8.69.
Methyl (–)ꢀ2ꢀ(1S,3S)ꢀ{3ꢀ[2ꢀ(3S)ꢀ(3ꢀhydroxyꢀ2ꢀoxoꢀ2,3ꢀdiꢀ
hydroꢀ1Hꢀ3ꢀindolyl)acetyl]ꢀ2,2ꢀdimethylcyclobutyl}acetate (3d)
was synthesized similarly to compound 3a. The yield was 48%, m.p.
76 °C (from ethanol), [α] 20 –49.11 (c 0.68, MeOH). IR, ν/cm–1
:
This work was financially supported by the Academy
of Sciences of Moldova Republic and Belorussian Founꢀ
dation for Basic Research (Joint Project ASMꢀFCFBꢀ
08.820.05.15BF).
D
1
1685, 3445 (CONH); 1730 (COOMe); 3370 (OH). H NMR
(CDCl3), δ: 0.78, 1.24 (both s, 3 H each, C(6)Mе2); 1.75—2.50
(m, 5 H, C(4)H2, C(9)H2, C(5)H); 2.79, 2.86 (both d, 1 H each,
ABꢀsystem, C(1)H2, J = 17.2 Hz, J = 29.3 Hz); 2.84 (t, 1 H, C(3)H,
J = 8.5 Hz); 3.62 (s, 3 H, COOMe); 4.76 (s, 1 H, OH); 6.81—7.36
(m, 4 H, C(4´)H, C(5´)H, C(6´)H, C(7´)H); 8.85 (br.s, NH).
Found (%): C, 65.87; H, 6.89; N, 3.82. C19H23NO5. Calculatꢀ
ed (%): C, 66.07; H, 6.71; N, 4.06.
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3, 75.
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Column chromatography on SiO2 (eluent, CHCl3) of the mother
liquor left after crystallization of alcohol 3d gave a mixture
of alcohols 3d and 4d. The yield was 10%, yellow oil, [α] 20 –38.71
D
(c 0.88, MeOH). 1H NMR of predominant isomer 4d (CDCl3),
δ: 0.87, 1.24 (both s, 3 H each, C(6)Mе2); 1.75—2.50 (m, 7 H,
C(1)H2, C(4)H2, C(9)H2, C(5)H); 2.81 (t, 1 H, C(3)H, J = 8.3 Hz);
3.09 (br.s, 1 H, OH); 3.61 (s, 3 H, COOMe); 6.81—7.31 (m, 4 H,
C(4´)H, C(5´)H, C(6´)H, C(7´)H); 8.67 (br.s, NH). Found (%):
C, 66.30; H, 6.65; N, 4.18. C19H23NO5. Calculated (%): C, 66.07;
H, 6.71; N, 4.06.

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Received April 12, 2006;
in revised form April 14, 2008