The use of L-(+)-tartaric acid in the enantioselective synthesis of isoquinoline alkaloids

Article abstract of DOI:10.1016/S0040-4039(00)00072-1

L-(+)-Tartaric acid was used in an enantioselective synthesis of (S)-(- )-N-acetylcalycotomine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00072-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1963–1966
The use of L-(+)-tartaric acid in the enantioselective synthesis of
isoquinoline alkaloids
Marek Ziółkowski and Zbigniew Czarnocki ∗
Department of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland
Received 21 October 1999; accepted 11 January 2000
Abstract
L-(+)-Tartaric acid was used in an enantioselective synthesis of (S)-(−)-N-acetylcalycotomine. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: alkaloids; asymmetric synthesis; hydroxy acids; isoquinolines.
Natural tartaric acid ((2R,3R)-dihydroxybutanedioic acid) has been extensively used as a readily
available and effective chiral auxiliary.1,2 In the chemistry of isoquinolines it is still useful as illustrated
by the efficient synthesis of both enantiomers of novel tetracyclic isoquinoline derivatives.3 Dörnyei and
Szãntay4 were in fact the first in this area. In 1976 they described synthesis of compound 1, a novel
derivative of tartaric acid, that contained the isoquinoline moiety.
Enantiomer of compound 1 was then further elaborated5 into aldehyde 2, from which several isoquino-
line alkaloids were obtained (Scheme 1). We have shown that aldehyde 2 could be effectively transformed
into 1-benzyltetrahydroisoquinolines, protoberberines, aporphines as well as their homologs, thus being
a crucial derivative in the enantioselective synthesis of these types of alkaloids.5 However, in tartaric acid,
which is an efficient chiral inductor, only one asymmetric center was used, the second being sacrificed.
The idea of the more effective use of chirality in tartaric acid has focused our interest for a long time and
recently we were able to successfully accomplish this task. Also, the fact that the target compound 10
maintains the same C2 symmetry as the chiral substrate 4, seemed to be interesting.
Thus, reaction of L-(+)-diethyl tartarate 4 with 3,4-dimethoxyphenylethylamine 3 afforded diamide
5 in nearly quantitative yield. Protection of the hydroxyl groups in 5 by di-O-acetylation using acetic
anhydride in pyridine afforded ester-amide 6 in 96% isolated yield. Compound 6 was then subjected
to several experiments directed towards double Bischler–Napieralski cyclization, but despite prolonged
efforts and the use of many reagents and methods we were unable to obtain the desired product.
Eventually, we found that mild conditions, involving the use of PCl5 at 0°C afforded a very unstable
mono-imine derivative, which could not be properly characterized due to its decomposition. Immediate
∗
Corresponding author. Tel: +48 228220211; fax: +48 228225996; e-mail: czarnoz@alfa.chem.uw.edu.pl (Z. Czarnocki)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00072-1
tetl 16352

1964
Scheme 1.
reduction and N-acetylation of this mono-imine brought about the formation of stable amide 7. This
1
compound appeared to be diastereomerically pure (by H NMR),6 since the small amount of impurity
that contaminated amide 7 turned out to be a chlorination product (8) of the activated aromatic ring during
a Bischler–Napieralski process (Scheme 2).
Scheme 2. (a) PCl5, CH2Cl2. (b) NaBH4, EtOH. (c) (CH3CO)2O, pyH
Compound 7 was again subjected to the above three-step reaction sequence, finally giving the
desired derivative 9 in 61% yield (from 6). Again, it was found that this derivative was virtually
diastereomerically pure. After removal of both O-acetyl groups from 9, cleavage of the glycol system in
10 with sodium metaperiodate and, finally, reduction of the aldehyde 2 thus formed to the well known7,8
(S)-(−)-N-acetylcalycotomine 11, we accomplished the planned task (Scheme 3). The efficiency of the
chiral transfer in the whole sequence seems to be quite good since the yield of 11 was acceptable and
its enantiomeric purity (determined by 19F NMR of its Mosher’s acid ester9) turned out to be >98% ee.
We think, therefore that the above described approach may serve as an interesting alternative to existing
procedures.

1965
Scheme 3. (a) HCl, reflux. (b) NaIO4, EtOH/H2O. (c) NaBH4, EtOH/H2O
Acknowledgements
This work was supported by the National Committee for Research in the form of a Grant GR-1092/99.
References
1. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; Wiley-Interscience: New York, 1995; p.
940.
2. Inomata, K.; Ukaji, Y. Rev. Heteroatom. Chem. 1998, 18, 119–140.
3. Lee, J. Y.; Lee, Y. S.; Chung, B. Y.; Park, H. Tetrahedron 1997, 53, 2449–2458.
4. Dörnyei, G.; Szantay, Cs. Acta Chim. Acad. Sci. Hung. 1976, 89, 161–168.
5. Czarnocki, Z.; Suh, D.; MacLean, D. B.; Hultin, P.G.; Szarek,W. A. Can. J. Chem. 1991, 70, 1555–1561 and references cited
therein.
6. Preparation of monoamide 7: To a stirred and cooled to 0°C suspension of 3.9 g (18.7 mmol) of PCl5 in dry methylene
chloride (150 mL) a sample of 5.0 g (8.9 mmol) of acetylamide 6 was added in one portion. After 2 h of stirring at the same
temperature, the solution was poured slowly into a suspension of 7.8 g (93.5 mmol) sodium bicarbonate in 100 mL of water.
Extraction with chloroform, drying (MgSO4) and evaporation of the solvents gave the residue, which was dissolved in 50 mL
of ethanol and subjected to reduction with 2.0 g of NaBH4 added in four portions. After 2 h stirring at the same temperature,
ethanol was removed and 50 mL of chloroform and 50 mL of brine was added to the residue. The organic layer was separated
and water layer was then extracted with chloroform. Combined organic extracts after drying (MgSO4) were evaporated and
residue was dissolved in 50 mL of pyridine and treated with 15 mL of freshly distilled acetic anhydride for 12 h at room
temperature. The solvents were evaporated in vacuo and the residue was dissolved in 70 mL of chloroform. The organic
phase was washed with 3×50 mL of brine, dried (MgSO4) and concentrated under reduced presure. Column chromatography
on Al2O3(III) using hexanes/ethyl acetate 1:1 (v/v) allowed the separation of compounds 7 and 8. Data for amide 7: yield
74%, mp 196–197.5°C, [α]2D3 −48.9 (c 1.19, CHCl3). IR (KBr, cm−1): 3400; 2900; 1750; 1650; 1500; 1275; 1200. 1H NMR
(500 MHz, CDCl3, δ (ppm)): 6.81 (s, 1H, H-8); 6.68–6.74 (m, 2H, H-5 and H-9); 6.64 and 6.60 (two s, 1H each, H-50 and
H-80); 6.04 (t, 1H, J=5.9 Hz, NH); 5.67 (d, 1H, J=9.8 Hz, H-1a); 5.62 (dd, 1H, J1=9.8 Hz, J2=2.4 Hz, H-1a0); 5.26 (d, 1H,
J=2.4 Hz, H-10); 3.88, 3.86, 3.84 and 3.84 (four s, 3H each, 4×OCH3); 3.74 (dd, 2H, J1=5.4 Hz, J2=7.8 Hz, 2H-3); 3.58
(ddd, 1H, J1=6.8 Hz, J2=13.2 Hz, J3=6.4 Hz, H-3eq0); 3.37 (ddd, 1H, J1=5.9 Hz, J2=13.2 Hz, J3=6.4 Hz, H-3ax0); 2.95 (dt, 1H,
J1=5.4 Hz, J2=16.1 Hz, H-4eq); 2.66–2.76 (m, 2H, 2H-40); 2.86 (dt, 1H, J1=6.8.0 Hz, J2=16.1 Hz, H-4ax); 2.21 and 2.10 (two
s, 3H each, 2×OAc); 1.84 (s, 3H, NAc). 13C NMR (125 MHz, CDCl3, δ (ppm)): 170.43; 169.93; 168.42; 167.33; 149.18;
148.57; 147.79; 146.88; 130.94; 126.65; 124.82; 120.63; 112.00; 111.76; 111.36; 111.15; 72.21; 72.04; 56.05; 55.97; 55.92;
55.77; 50.20; 41.96; 40.43; 35.18; 27.68; 21.64; 20.97; 20.60. LSIMS (+) 8 kV (%): 587 (45) (M+H+); 527 (12); 467 (4);
262 (16); 246 (76); 234 (100); 192 (59); 107 (28); 81 (41). Data for compound 8: yield 10%, mp 180–182°C, [α]2D3 −44.1
(c 1.29, CHCl3). IR (KBr, cm−1): 3400; 2900; 1750; 1650; 1520; 1275; 1200; 1050. 1H NMR (500 MHz, CDCl3, δ (ppm)):
6.85 (s, 1H, H-8); 6.71, 6.65 and 6.60 (three s, 1H each, H-5, H-50 and H-80); 6.13 (t, 1H, J=5.5 Hz, NH); 5.69 (d, 1H, J=9.8
Hz, H-1a); 5.64 (dd, 1H, J1=9.8 Hz, J2=2.5 Hz, H-1a0); 5.26 (d, 1H, J=2.5 Hz, H-10); 3.88, 3.86, 3.84 and 3.84 (four s, 3H
each, 4×OCH3); 3.76 (dd, 2H, J1=5.5 Hz, J2=7.0 Hz, 2H-3); 3.56 (ddd, 1H, J1=7.0 Hz, J2=13.0 Hz, J3=6.5 Hz, H-3eq0); 3.43
(ddd, 1H, J1=7.5 Hz, J2=13.0 Hz, J3=6.5 Hz, H-3ax0); 2.99 (dt, 1H, J1=5.5 Hz, J2=21.5 Hz, H-4eq); 2.86 (dd, 2H, J1=7.5 Hz,
J2=6.5 Hz, 2H-40); 2.80 (dt, 1H, J1=7.0 Hz, J2=21.0 Hz, H-4ax); 2.25 and 2.10 (two s, 3H each, 2×OAc); 1.85 (s, 3H, NAc).
13C NMR (125 MHz, CDCl3, δ (ppm)): 170.41; 170.00; 168.44; 167.55; 149.58; 148.38; 148.01; 146.89; 127.77; 126.65;

1966
124.82; 124.66; 113.53; 112.55; 111.78; 111.16; 72.19; 72.10; 56.18; 56.16; 56.05; 55.78; 50.20; 41.96; 39.05; 33.00; 27.67;
21.64; 21.00; 20.56. LSIMS (+) 8 kV (%): 621 (82) (M+H)+; 460 (18); 234 (100).
7. All analytical data for 11 were in accordance with those already described.8
8. Czarnocki, Z.; Ziólkowski, M.; Leniewski, A.; Maurin, J. K. Enantiomer 1999, 4, 71–77 and references cited therein.
9. Determination of the enantiomeric composition of (S)-(−)-N-acetylcalycotomine 11: Oxalyl chloride (0.12 mL, 1.4 mmol)
was added to the solution (R)-(+)-MTPA (66 mg, 0.28 mmol) and DMF (0.022 mL, 0.28 mmol) in 12 mL of hexane. After 1 h
the mixture was filtered and concentrated in vacuo and the residue was used without further treatment. The solution of (S)-(−)-
N-acetylcalycotomine 11 (20mg, 0.08 mmol), 1 mL of triethylamine and a catalytic amount of 4-dimethylaminopyridine in 3
mL of dichloromethane was treated with Mosher’s acid chloride in 3 mL of dichloromethane. The mixture was then stirred
for 24 h at room temperature. The organic layer was washed with aqueous solution of tartaric acid (2%), sodium bicarbonate
and brine. The water layer was extracted with two portions of chloroform and the combined extracts were dried (MgSO4),
evaporated and the residue was filtered through a small pad of silica gel using CHCl3 as eluent. The 19F NMR spectra were
recorded at 471 MHz with C6F6 as external reference. In 19F NMR spectra, a pair of signals (due to the presence of stable
conformers) were observed at −71.18 and −71.54 ppm (S enantiomer) with relative intensities 1.00:2.32, R enantiomer was
not observed. Therefore, the enantiomeric purity of (S)-(−)-N-acetylcalycotomine 11 exceeds the value of 98% ee.