Catalyst-controlled stereoselective combinatorial synthesis

Article abstract of DOI:10.1002/anie.200351129

Stereochemical diversity as a novel concept in combinatorial chemistry for the synthesis of nonpeptidic biologically active compounds is introduced. As an example, the combination of the hydrogenation of imines in the presence of either enantiomer of a ch

Full text of DOI:10.1002/anie.200351129

Communications
Combinatorial Synthesis
Catalyst-Controlled Stereoselective
Combinatorial Synthesis**
Lutz F. Tietze,* Nils Rackelmann, and
Govindasamy Sekar
Dedicated to Professor Ernst Schaumann
on the occasion of his 60th birthday
Combinatorial chemistry[1] is an important method for the
development of pharmaceuticals,[2] agrochemicals,[3] cata-
lysts,[4] and materials.[5] It can be performed either on a solid
phase or in solution and in some cases, the advantages of
solid- and liquid-phase synthesis may be combined, if the
products can be precipitated as salts.[6] The aim of combina-
torial chemistry is the preparation of a multitude of organic
compounds with constitutional diversity. Stereochemical
aspects have so far played only a minor role, although the
configuration of a molecule can have a considerable effect on
its biological activity; this applies to both the absolute as well
as the relative configuration.[7] Herein we present a method to
access stereochemical diversity of nonpeptidic active com-
pounds as a new combinatorial strategy.[8] By using enantio-
merically pure catalysts, several stereo-
genic centers are constructed in a cata-
lyst-controlled manner.[9] This general
concept is introduced with the example
of the synthesis of 12 stereoisomers of
the biologically highly active ipecacua-
nha alkaloid emetine (1), which contains
four stereogenic centers. The ruthenium
complexes (R,R)-5 and (S,S)-5 devel-
oped by Noyori and co-workers[10] were
used as catalysts. The key step of the
synthesis is the enantio- or diastereoselective hydrogenation
of imines, which can be prepared either by oxidation of a
secondary amine or by a Bischler–Napieralski reaction.
Oxidation of the racemic mixture of 2a and 4a with
potassium permanganate led to the imine 3 in very good
yields,[11] which was hydrogenated to the almost enantiomeri-
cally pure tetrahydroisoquinolines 2a and 4a by transfer
hydrogenation with formic acid in the presence of the
catalysts (R,R)-5 and (S,S)-5, respectively (Scheme 1).[12]
Protection of the secondary amino group in 2a and 4a with
benzyloxycarbonyl chloride, cleavage of the silyl group, and
subsequent oxidation of the primary alcohol yielded the
[*] Prof. Dr. L. F. Tietze, Dipl.-Chem. N. Rackelmann, Dr. G. Sekar
Institut für Organische Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
Fax: (+49)551-399-476
E-mail: ltietze@gwdg.de
[**] The investigations were supported by the Deutsche Forschungsge-
meinschaft (SFB 416) and the Fonds der Chemischen Industrie. We
thank BASF, Bayer, Degussa, Symrise, and Wacker Chemie for
providing us with chemicals.
4254
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200351129
Angew. Chem. Int. Ed. 2003, 42, 4254 –4257

Angewandte
Chemie
Scheme 1. Synthesis of benzoquinolidizines 10a–c and 11a–c: a) 3 (1 equiv), (R,R)-5 or (S,S)-5, respectively, (2.5 mol%), HCO2H/NEt3, DMF,
room temperature, 60 min, 93%, >95% ee; b) 2c or 4c (1.1 equiv), 6 (1 equiv), 7 (10 equiv), EDDA (1 mol%), benzene, 608C, ultrasound, 17 h,
86%; c) K2CO3 (0.5 equiv), MeOH; then Pd/C, H2, 77%. DMF=N,N-dimethylformamide, EDDA= ethylenediammonium diacetate, Bn=benzyl,
Cbz=benzyloxycarbonyl, TIPS=triisopropylsilyl, Ts=p-toluenesulfonyl, cymene=4-isopropyltoluene.
aldehydes 2c and 4c, respectively. A domino reaction[13] of 2c
with Meldrum acid (6) and the enol ether 7 in the presence of
catalytic amounts of ethylenediammonium diacetate
(EDDA) led to the formation of the lactone 8, which was
treated directly with methanol/potassium carbonate and then
hydrogenated with Pd/C as catalyst. In this sequence, cleavage
of the lactone 8 occurs first with the formation of a methyl
ester and an aldehyde, which after hydrogenolysis of the Cbz
protecting group reacts with the formed secondary amino
function to give an enamine. This enamine is hydrogenated
under the reaction conditions to form the benzoquinolizidine
framework of emetine (1). The mixture of the three
diastereomers 10a–c (1.5:1.0:1.8) can be separated chroma-
tographically.[14] The conversion of the enantiomeric alde-
hyde 4c under identical conditions afforded the diastereom-
ers 11a–c.
The condensation of the diastereomeric benzoquinolizi-
dines 10a–c with 2-(3,4-dimethoxyphenyl)ethylamine (12)
gave the corresponding amides, which were converted into
the imines 13a–c in a Bischler–Napieralski reaction in 60–
78% yield (Scheme 2). In a similar manner, the imines 14a–c
were prepared from 11a–c. Hydrogenation of 13a–c with
(S,S)-5 led to 15a–c, whereas the diastereomers 15d–f were
obtained in the presence of (R,R)-5.[15] Analogously, the
stereoisomers 16a–c and the corresponding diastereomers
16d–f were obtained from 14a–c with (S,S)-5 and (R,R)-5,
respectively. The yields in all hydrogenations were greater
than 71%, the diastereoselectivities were, however, slightly
different because of the presence of matched and mismatched
combinations: Thus, in the transfer hydrogenation of 13a with
(S,S)-5, selectivities > 98:2 were found (that is, the other
possible diastereomer could not be detected), whereas in the
worst case, in the reaction of 13a with (R,R)-5, a ratio of 91:9
was observed.
The concept of stereoselective combinatorial synthesis,
which is introduced by means of the synthesis of 12 stereo-
isomers of emetine (1), makes a large number of stereo-
isomers of a chiral compound accessible in a targeted manner.
The reactions introduced may be varied in many ways. Thus
we have also used 2-phenylethylamine, 2-(2-methoxyphenyl)-
ethylamine, 2-(2,5-dimethoxyphenyl)ethylamine, and a sero-
tonin derivative as amino components instead of 12. The
described strategy is generally applicable, and good results
can be expected if the enantiomeric catalysts or reagents
allow high stereochemical control, independent of the sub-
strate.
Received: February 7, 2003 [Z51129]
Keywords: asymmetric catalysis · combinatorial chemistry ·
.
domino reactions · hydrogenation · imines
Angew. Chem. Int. Ed. 2003, 42, 4254 –4257
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4255

Communications
Scheme 2. Stereoselective synthesis of 12 stereoisomers of 1 (15a–f and 16a–f): a) 10a–c or 11a–c, 12, AlMe3, reflux, 4.5 h, 60–78%; then POCl3,
benzene, reflux, 45 min, 60–82%; b) (R,R)-5 or (S,S)-5 (10 mol%), HCO2H/NEt3, DMF, room temperature, 60 min, 71–82%, d.r. 91:9 to >98:2.
Perspectives in Solid Phase Synthesis and Combinatorial Libra-
ries (Ed.: R. Epten), Mayflower Worldwide Ltd, Birmingham
(UK), 2001, p. 149 – 152.
[1] a) A. Kirschning, H. Monenschein, R. Wittenberg, Angew.
Chem. 2001, 113, 670 – 701; Angew. Chem. Int. Ed. 2001, 40,
650 – 679; b) S. Senkan, Angew. Chem. 2001, 113, 322 – 344;
Angew. Chem. Int. Ed. 2001, 40, 312 – 329; c) F. Balkenhohl, C.
von dem Bussche-Hünnefeld, A. Lansky, C. Zechel, Angew.
Chem. 1996, 108, 2436 – 2487; Angew. Chem. Int. Ed. Engl. 1996,
35, 2288 – 2337.
[2] a) J. Rademann, G. Jung, Science 2000, 287, 1947 – 1948; b) K. C.
Nicolaou, R. Hughes, S. Y. Cho, N. Winssinger, C. Smethurst, H.
Labischinski, R. Endermann, Angew. Chem. 2000, 112, 3473 –
3478; Angew. Chem. Int. Ed. 2000, 39, 3823 – 3828; c) P. N. Kaul,
Prog. Drug Res. 1998, 50, 9 – 105.
[3] W. A. Kleschick, L. N. Davis, M. R. Dick, J. R. Garlich, E. J.
Martin, N. Orr, S. C. Ng, D. J. Pernich, S. H. Unger, G. B.
Watson, R. N. Zuckermann, ACS Symp. Ser. 2001, 774, 205 – 213.
[4] a) M. T. Reetz, Angew. Chem. 2001, 113, 292 – 320; Angew.
Chem. Int. Ed. 2001, 40, 284 – 310; b) B. Jandeleit, D. Schaefer,
T. S. Powers, H. W. Turner, W. H. Weinberg, Angew. Chem. 1999,
63, 2494 – 2532; Angew. Chem. Int. Ed. 1999, 111, 2648 – 2689;
c) P. P. Pescarna, J. C. van der Waal, I. E. Maxwell, T. Masch-
meyer, Catal. Lett. 1999, 63, 1 – 11.
[9] Reagent-controlled reactions in which enantiomerically pure
auxiliaries are used are likewise possible.
[10] N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1996, 118, 4916 – 4917.
[11] A solution of a racemic mixture of 2a and 4a (27.6 g, 70.2 mmol)
in CH3CN (650 mL) was treated at À78C with KMnO4 (23.3 g,
147 mmol) in small portions over a period of 15 min and then
stirred for 70 min at À58C. The reaction mixture was diluted
with ice-cold Et2O (2.5 L), the organic phase was washed with
saturated NaCl solution until the solution was colorless, and
dried over Na2SO4. The solvent was removed under reduced
pressure to yield the dihydroisoquinoline 3 as a pale yellow oil,
which was used without further purification (24.7 g, 90%).
[12] A solution of dimeric dichloro(p-cymene)ruthenium(ii) (403 mg,
0.66 mmol),
1,2-(R,R)-N-tosyl-1,2-diphenylethylenediamine
(530 mg, 1.45 mmol), and NEt3 (0.37 mL, 2.63 mmol) in DMF
(6.1 mL) was stirred under argon for 60 min at 808C. The warm
solution was added to the dihydroisoquinoline
3 (21.5 g,
55 mmol) in DMF (103 mL) and the mixture was cooled to
08C. A mixture of HCO2H and NEt3 (5:2; 27.5 mL) was then
added dropwise, and the reaction mixture was stirred for 2 h at
258C. The reaction was worked up by the addition of a saturated
solution of K2CO3, the mixture was diluted with H2O, the
aqueous phase extracted with ethyl acetate, and the combined
organic phases dried over Na2SO4. After removal of the solvent
under reduced pressure, the brown crude product was purified
by chromatography on silica gel (AcOEt/NEt3, 100:1) to yield 2a
as a yellow oil (20.2 g, 93%, > 95% ee).
[5] a) W. F. Maier, Angew. Chem. 1999, 111, 1294 – 1296; Angew.
Chem. Int. Ed. 1999, 38, 1216 – 1218; b) E. W. McFarland, W. H.
Weinberg, Trends Biotechnol. 1999, 17, 107 – 115.
[6] L. F. Tietze, H. Evers, E. Töpken, Angew. Chem. 2001, 113, 903 –
905; Angew. Chem. Int. Ed. 2001, 40, 927 – 929.
[7] a) G. Ekatodromis, A. Borgeat, Curr. Top. Med. Chem. 2001, 1,
205 – 206; b) B. Testa, M. Reist, P.-A. Carrupt, Ann. Pharm. Fr.
2000, 58, 239 – 246; c) S. Schiffman, K. Sennewald, J. Gagnon,
Physiology and Behavior 1981, 27, 51 – 59; d) G. Blaschke, H. P.
Kraft, K. Fickentscher, F. Koehler, Arzneim.-Forsch. 1979, 29,
1640 – 1642.
[13] a) L. F. Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304 – 322; b) L.
F. Tietze, F. Haunert in Stimulating Concepts in Chemistry (Eds.
F. Vögtle, J. F. Stoddart, M. Shibasaki, Wiley-VCH, Weinheim,
[8] For a further approach to stereochemical combinatorial syn-
thesis, see: U. Müllenmeister, W.-D. Fessner in Innovation and
4256
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 4254 –4257

Angewandte
Chemie
2000, p. 39 – 64; c) L. F. Tietze, M. Lieb, Curr. Opin. Chem. Biol.
1998, 2, 363 – 371; d) L. F. Tietze, Chem. Rev. 1996, 96, 115 – 136;
e) L. F. Tietze, U. Beifuss, Angew. Chem. 1993, 105, 137 – 170;
Angew. Chem. Int. Ed. Engl. 1993, 32, 131 – 163.
[14] 10a: 1H NMR (300 MHz, C6D6, TMS): d = 0.82 (t, 3J(H,H) = 7.5
2
Hz, 3H; 13-H), 1.10 (m, 1H; 12-H), 1.26 (ddd, J(H,H) = 13.0
Hz, 3J(H,H) = 11.5, 11.5 Hz, 1H; 1-Hax), 1.34 (m, 1H; 3-H), 1.63
2
3
(m, 1H; 12-H), 1.94 (ddd, J(H,H) = 13.0 Hz, J(H,H) = 3.0, 3.0
Hz, 1H; 1-Heq), 2.00–2.32 (m, 6H; CH2CO2Me, 2-H; 4-Hax, 6-H,
7-H), 2.55 (ddd, 2J(H,H) = 11.5 Hz, 3J(H,H) = 5.5, 5.5 Hz, 1H; 6-
2
3
H), 2.77 (dd, J(H,H) = 11.5 Hz, J(H,H) = 3.5 Hz, 1H; 4-Heq),
2.90–3.10 (m, 2H, 7-H; 11b-H), 3.27 (s, 3H; OMe), 3.38 (s, 3H;
OMe), 6.31 (s, 1H; 8-H), 6.62 ppm (s, 1H; 11-H); 13C NMR (75
MHz, C6D6, TMS): d = 12.69 (C13), 18.13 (C12), 29.95 (C7),
34.10 (C1), 37.73 (C3), 38.24 (CH2CO2Me), 39.48 (C2), 50.95
(OMe), 53.39 (C4), 55.63 (OMe), 56.13 (OMe), 59.14 (C6), 63,71
(C11b), 110.0 (C8), 112.8 (C1), 127.5 (C11a), 130.8 (C7a), 148.5
(C10), 148.8 (C9), 172.7 ppm (C O); [a]2D0 = À57.9 (c = 0.60 in
=
CHCl3). 10b: 1H NMR (300 MHz, C6D6, TMS): d = 0.81 (t,
3J(H,H) = 7.5 Hz, 3H; 13-H), 1.00 (m, 1H; 12-H), 1.41–1.52 (m,
3H; 1-H, 12-H, 3-H), 1.80 (m, 1H; CH2CO2Me), 1.92 (dd,
2J(H,H) = 15.5 Hz, 3J(H,H) = 15.5 Hz; 1H, 4-Hax), 2.01 (dd,
2J(H,H) = 22.0 Hz, 3J(H,H) = 12.0 Hz; 1H, CH2CO2Me), 2.35–
2.48 (m, 4H; 1-H, 2-H, 6-H, 7-H), 2.77(m; 1H, 6-H), 2.93 (dd,
3
2J(H,H) = 15.5 Hz, J(H,H) = 5.5 Hz; 1H, 4-Heq), 3.10–3.14 (m,
2H; 7-H, 11b-H), 3.34 (s, 3H; OMe), 3.42 (s, 3H; OMe), 3.44 (s,
3H; OMe), 6.45, (s, 1H; 8-H), 6.77 ppm (s, 1H; 11-H); 13C NMR
(75 MHz, C6D6): d = 11.20 (C13), 23.75 (C12), 30.00 (C7), 38.85
(C1), 38.52 (C3), 38.24 (CH2CO2Me), 41.79 (C2), 50.93 (OMe),
52.77 (C4), 55.64 (OMe), 56.00 (OMe), 61.43 (C6), 63,00 (C11b),
110.1 (C8), 112.8 (C1), 127.4 (C11a), 130.8 (C7a), 148.5 (C10),
148.8 (C9), 172.9 ppm (C O); [a]2D0 = À22.0 (c = 1.04 in CHCl3).
=
10c: 1H NMR (300 MHz, C6D6, TMS): d = 0.88 (t, J = 7.5 Hz,
3H; 13-H), 1.26 (m, 1H; 3-H), 1.54–1.80 (m, 2H; 12-H), 1.88
(ddd, 2J(H,H) = 13.5 Hz, 3J(H,H) = 4.0, 4.0 Hz, 1H; 1-Heq), 2.04
(ddd, 2J(H,H) = 13.5 Hz, 3J(H,H) = 10.0, 4.5 Hz, 1H; 1-Hax) 2.22
(m, 1H; 2-H), 2.28–2.45 (m, 3H; CH2CO2Me, 7-H) 2.57 (t, J =
4.0 Hz, 2H; 4-H2), 2.53 (dd, 2J(H,H) = 12.5 Hz, 3J(H,H) = 4.0
2
3
Hz, 1H; 6-H), 2,71 (ddd, J(H,H) = 12.5 Hz, J(H,H) = 6.0, 1.0
2
3
Hz, 1H; 6-H), 3.04 (ddd, J(H,H) = 17.0 Hz, J(H,H) = 13.0, 6.5
Hz, 1H; 7-H), 3.43 (m, 1H; 11b-H), 3.39 (s, 3H; OMe), 3.44 (s,
3H; OMe), 6.43, (s, 1H; 8-H), 6.77 ppm (s, 1H; 11-H); 13C NMR
(75 MHz, C6D6): d = 12.32 (C13), 25.65 (C12), 28.44 (C7), 32.68
(C1), 33.72 (C2), 37.92 (CH2CO2Me), 40.76 (C3), 50.97 (OMe),
53.09 (C6), 54.35 (C4), 55.61 (OMe), 55.65 (OMe), 58.20 (C11b),
109.8 (C8), 112.8 (C11), 127.3 (C11a), 130.1 (C7a), 148.6 (C10),
148.7 (C9), 173.0 ppm (C O); [a]2D0 = À81.5 (c = 0.46 in CHCl3).
=
1
3
[15] 15d: H NMR (600 MHz, CDCl3, TMS): d = 0.97 (t, J(H,H) =
7.5 Hz, 3H; 13-H), 1.32–1.43 (m, 2H, 1-H; 12-H), 0.97 (t,
3J(H,H) = 7.5 Hz, 3H; 13-H), 1.58–1.67 (m, 2H, 1’-H; 3-H), 1.71
(m, 1H; 12-H), 1.83–1.93 (m, 2H; 1-H, 1’-H), 2.08 (m, 1H; 2-H),
2.32 (dd, 2J(H,H) = 11.5 Hz, 3J(H,H) = 1.5 Hz, 1H; 4-H), 2.42
2
3
(ddd, J(H,H) = 11.5 Hz, J(H,H) = 11.5, 3.5 Hz, 1H; 6-H), 2.55
(m, 1H; 7-H), 2.71 (m, 2H, 4’’-H; 7-H), 2.83 (ddd, 2J(H,H) =
3
11.5 Hz, J(H,H) = 6.5, 1.5 Hz, 1H; 6-H), 2.95–3.05 (m, 4H; 3’’-
H, 4-H, 4’’-H, 11b-H), 3.23 (m, 1H; 3’’-H), 3.78 (s, 3H; OMe),
3.80 (s, 3H; OMe), 3.82 (s, 3H; OMe), 3.83 (s, 3H; OMe), 3.96
(m, 1H; 1’’-H), 6.54, 6.55, 6.57, 6.61 ppm (s, 4H; 5’’-H, 8-H, 8’’-H,
11-H); 13C NMR (150 MHz, CDCl3): d = 12.56 (C13), 17.45
(C12), 29.30, 29.33 (C4’’, C7), 34.82 (C1), 36.61 (C2), 37.30 (C3),
39.83 (C1’), 40.62 (C3’’), 52.00 (C2’’), 52.95 (C6), 55.72, 55.85,
55.96 (OMe), 58.86 (C4), 63.34 (C11b) 107.8, 109.1, 111.4, 111.7
(C5’’, C8, C8’’, C11), 126.8, 127.0, 130.6, 131.8 (C4a’’, C7a’’, C8a,
C11a), 146.9, 147.1, 147.1, 147.2 ppm (C6’’, C7’’, C9, C10); [a]D20
À82.3 (c = 0.40 in CHCl3).
=
Angew. Chem. Int. Ed. 2003, 42, 4254 –4257
www.angewandte.org
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4257