A C2-chiral bis(amidinium) catalyst for a Diels-Alder reaction constituting the key step of the Quinkert-Dane estrone synthesis

Article abstract of DOI:10.1002/ejoc.200200635

A novel C₂-chiral bis(amidinium) salt 12 has been synthesised from 5-(tert-butyl)isophthalic acid. The hydrogenbond-mediated association of dienophiles 3a and 3b with the chiral host molecule 12 accelerates the Diels-Alder reactions with diene 2 by more than three orders of magnitude. In addition, enantioselective formation of the desired adducts is observed under catalysis with 12. Good ratios of 4a(b) + ent-4a(b)/5a(b) + ent-5a(b) from 1:10 to 1:22 were found in all reactions. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200200635

FULL PAPER
A C2-Chiral Bis(amidinium) Catalyst for a Diels؊Alder Reaction Constituting
the Key Step of the Quinkert؊Dane Estrone Synthesis
Svetlana B. Tsogoeva,*[a] Gerd Dürner,[b] Michael Bolte,[b] and Michael W. Göbel*[b]
Keywords: Cycloaddition / Asymmetric catalysis / Chirality / Hydrogen bond
A novel C2-chiral bis(amidinium) salt 12 has been syn-
thesised from 5-(tert-butyl)isophthalic acid. The hydrogen-
bond-mediated association of dienophiles 3a and 3b with the
chiral host molecule 12 accelerates the Diels−Alder reactions
observed under catalysis with 12. Good ratios of 4a(b) + ent-
4a(b)/5a(b) + ent-5a(b) from 1:10 to 1:22 were found in all re-
actions.
with diene 2 by more than three orders of magnitude. In ad- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
dition, enantioselective formation of the desired adducts is Germany, 2003)
(ϩ)-Estrone 1 and related 19-nor steroids form a promi- that TiIV complexes may completely reverse the ratio of
nent group of targets for organic synthesis.[1] Up to now, a rac-4a and rac-5a.[4,5] Using TADDOLϪTiIV complexes,
considerable number of useful synthetic strategies have been enantioselectivities of adduct 5a of up to 93% were
proposed. Dane’s early suggestion to assemble the steroidal obtained in the chirogenic cycloaddition step.[5]
skeleton in a DielsϪAlder reaction of diene 2 and the un-
A conceivable alternative strategy for promoting asym-
saturated diketone 3a as dienophile is certainly among metric DielsϪAlder reactions involves the use of hydrogen
them.[2] Upon closer examination, however, the reaction of bonding to position and to activate the dienophile within a
2 and 3a turned out to produce mainly the wrong adduct, chiral environment.[6] Thus, soluble amidinium salts have
rac-4a, accompanied by small amounts of the useful inter- been shown to accelerate the cycloaddition of compounds
mediate rac-5a (Scheme 1).[3]
2 and 3a by more than two orders of magnitude.[7]
As in other cases of DielsϪAlder reactions, the ratio of
Furthermore, the ratio of constitutional isomers is shifted
constitutional isomers in the cycloaddition of diene 2 and in favour of adduct 5a.[7,8] In the presence of axially chiral
dienophiles of type 3 is sensitive to the presence of Lewis amidinium ions, 5a could be obtained with considerable en-
acids. Thus, it has been shown by Quinkert and co-workers antioselectivity.[8] In this case no transition metal is involved
Scheme 1
in the catalysis. This is a clear advantage for pharmaceutical
intermediates with stringent restrictions on residual heavy
[a]
Institut für Organische Chemie der Georg-August-Universität
Göttingen
metal content. The lengthy synthesis of axially chiral amid-
Tammannstraße 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-(0)551/399660
E-mail: stsogoe@gwdg.de
ines[9] and the limited enantioselectivity, on the other hand,
restrict the practical value of this method.
[b]
Institut für Organische Chemie und Chemische Biologie der
Goethe-Universität Frankfurt,
An interesting class of tris(amidines) was recently intro-
duced by Kraft.[10] Carboxylic acid salts of these com-
Marie-Curie-Straße 11, 60439 Frankfurt am Main, Germany
Fax: (internat.) ϩ 49-(0)69/79829464
Eur. J. Org. Chem. 2003, 1661Ϫ1664
DOI: 10.1002/ejoc.200200635
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1661

S. B. Tsogoeva, G. Dürner, M. Bolte, M. W. Göbel
FULL PAPER
pounds are characterised by hydrogen bonds between both
anionic oxygen atoms and the NϪH donors of two flanking
amidinium groups. Based on this structural motif and the
work of Buddrus,[11] we have now prepared the novel C2-
symmetric chiral bis(amidinium) salt 12 anticipating that
diketones of type 3 may bind in the same way as the car-
boxylates in Kraft’s complexes.
To warrant good substrate affinity of the catalyst by hy-
drogen bonding, nonpolar solvents and low temperatures
are required, conditions that severely restrict the solubility
of the salts. A maximum of lipophilic groups was therefore
incorporated into the target structure 12. Tetrakis[3,5-bis-
(trifluoromethyl)phenyl]borate has been shown in previous
studies to reduce unwanted ion-pair interactions to a very
low level.[7]
The bis(amidinium) salt 12 was prepared from 5-(tert-
butyl)isophthalic acid (6) (Scheme 2). Reaction of 6 with
PCl5, followed by NH3, afforded diamide 8. Imidic acid es-
ter 9 was obtained after treatment with triethyloxonium
tetrafluoroborate, and could be converted into amidine 10
with (R,R)-(ϩ)-1,2-diphenyl-1,2-ethanediamine. The route
for generating catalyst 12 involves formation of picrate 11
followed by anion exchange with Naϩ[BArЈ4]Ϫ.
Figure 1. Molecular structure of 11
The kinetic effects induced by the dicationic catalyst 12
surpassed by far the effects of monoamidinium salts. At ϩ5
The three-dimensional structure of the picrate 11 was de- °C, a rate increase of more than 3000-fold was found. Good
termined by X-ray crystallographic analysis (Figure 1).[12]
total yields and favourable ratios of constitutional isomers
To measure the rates, yields and product ratios in the [4a(b) ϩ ent-4a(b)]/[5a(b) ϩ ent-5a(b)] of Ͼ 1:10 were seen
DielsϪAlder reactions of 2 and 3a or 3b, our previously in all reactions (Table 1).
reported methods have been applied.[7,8] Solutions of diene
At 5 °C, the enantioselectivity in the cycloaddition with
(45 m), dienophile (30 m), catalyst 12 (30 m) and 2- dienophile 3a did not reach satisfactory levels (Ϫ14%).
methoxy-6-methylnaphthalene (10 m) as an internal However, the ee improved to Ϫ25% at Ϫ16 °C and finally
standard were kept in dry CH2Cl2 at the temperature given reached Ϫ47% at Ϫ70 °C. At the same time, the consti-
in Table 1. Rates based on the disappearance of diene 2 tutional selectivity rose from 1:10 to 1:22 with 80% total
were obtained from repeated HPLC analyses of the reaction yield of cycloadducts. Catalyst 12 thus compares favourably
mixture. Between one and several days was needed for com- with axially chiral amidinium salts. In the corresponding
plete consumption of diene 2. After water-induced tauto- reaction with ethyl-substituted diketone 3b, only the wrong
merization of the initially formed diketones, the combined isomer 4b was formed with interesting stereoselectivity
yield and ratio of the keto-enols (4 ϩ ent-4) and (5 ϩ ent- (Ϫ48%).
5) was quantified. HPLC analysis on chiral columns finally
In summary, we have established a short synthetic route
determined the enantiomeric excess.
towards C2-symmetric bis(amidinium) salt 12. As a catalyst
Scheme 2. (a) PCl5; (b) NH3, CH2Cl2, room temp.; (c) Et3OBF4, CH2Cl2, room temp.; (d) HCl, EtOH, room temp.; (e) (R,R)-(ϩ)-1,2-
diphenyl-1,2-ethanediamine, EtOH, reflux; (f) picric acid, MeOH; (g) Dowex 1 ϫ 8 ClϪ form, MeOH; (h) NaTFPB·2H2O, CH2Cl2/MeOH
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Eur. J. Org. Chem. 2003, 1661Ϫ1664

A C2-Chiral Bis(amidinium) Catalyst for a DielsϪAlder Reaction
FULL PAPER
Table 1. DielsϪAlder experiments with diketones 3a and 3b
Dienophile T [°C] Yield, (%)[a] [4a(b) ϩ ent-4a(b)]/[5a(b) ϩ ent-5a(b)][a] ee (%)[b]
k [mϪ1·sϪ1 [c]
]
4a(b) ϩ ent-4a(b) 5a(b) ϩ ent-5a(b)
3a[d] [8]
3a
ϩ7
ϩ5
Ϫ16
Ϫ70
Ϫ22
Ͻ3
80
78
80
quant.
1:Ͻ 0.1
1:13
1:10
1:22
1:11
0
Ϫ21
Ϫ40
Ϫ15
Ϫ48
0
Ϫ14
Ϫ25
Ϫ47
Ϫ7
Ͻ4 ϫ 10Ϫ8
1.3 ϫ 10Ϫ4
4.8 ϫ 10Ϫ5
slow
3a
3a
3b
1.0 ϫ 10Ϫ5
[a] Yields were determined by reverse-phase HPLC (Merck Purospher 100 RP-18). [b] All enantiomeric excesses were determined by HPLC
on a chiral phase column (Daicel OJ-R 150 ϫ 4 mm). A negative ee stands for an excess of ent-5a or ent-5b (slower running enantiomer);
in the case of 4a(b) and ent-4a(b) it means an excess of the enantiomer with the longer retention time (the absolute configuration has
[c]
not been determined experimentally). Second-order rate constants are based on the decrease of the diene concentration. Since glass
[d]
surfaces influence rates and product distributions, all reactions were run in polyethylene vials.
The reaction was carried out in the
absence of catalyst 12.
in 25 mL of EtOH was treated with 3 mL of 1  HCl and stirred
for 10 min at room temperature. Removal of the solvent in vacuo
afforded 550 mg (quant.) of hydrochloride 9 as a colourless solid,
in a DielsϪAlder reaction forming the skeleton of estrone
and norgestrel, 12 is clearly superior to axially chiral
monoamidinium salts as far as rates and constitutional
selectivity are concerned.
Although the enantioselectivities achieved are still too
low to be of practical use, substituting the phenyl group in
the diamino building block by sterically more demanding
groups is a promising strategy for future optimisation.
1
m.p. 174Ϫ175 °C. H NMR (250 MHz, [D6]DMSO): δ ϭ 8.32 (s,
1 H), 8.20 (s, 2 H), 7.07Ϫ7.48 (m, NH2ϩClϪ), 4.35 (q, J ϭ 7.1 Hz,
4 H), 1.36 (s and t, 15 H, J ϭ 7.1 Hz) ppm. C16H26Cl2N2O2 (349.3):
calcd. C 55.02, H 7.50, N 8.02; found C 54.93, H 7.39, N 8.19.
Imidazole 10: A solution of (ϩ)-(1R,2R)-diphenylethylenediamine
(226.9 mg, 1.069 mmol) and hydrochloride 9 (186 mg, 0.536 mmol)
in anhydrous EtOH (2.8 mL) was stirred for 1 h at room temp. and
for 4 h at reflux. After evaporation of the solvent at reduced pres-
sure, the residue was dissolved in CH2Cl2 (27 mL) and the solution
was extracted with 5% aq Na2CO3 (25 mL). The organic phase was
dried (Na2SO4) and the solvent was evaporated at reduced pressure.
Further purification by flash chromatography (EtOAc/hexane,
10:1) gave 10 (158 mg, 51%) as a colourless solid, m.p. 135Ϫ140
°C. IR (NaCl, film): ν˜ ϭ 3375, 3168, 3061, 3028, 2963, 2868, 2369,
1947, 1870, 1802, 1718, 1670, 1623, 1576, 1492, 1452, 1419, 1364,
Experimental Section
General: Solvents were distilled before use: CH2Cl2 (P4O10), EtOH
(Na), MeCN (CaH2). HPLC column: Merck LiChrospher 100 RP-
18 (5 µm), 125 ϫ 4 mm; Daicel OJ-R, 150 ϫ 4 mm. Melting points
(uncorrected): hot plate microscope. 1H NMR spectra were re-
corded at 250 and 400 MHz; chemical shifts (δ) are given in ppm,
and J in Hz.
1275, 1204, 1154, 1028, 1009, 894, 851, 758 cmϪ1 1H NMR
.
5-tert-Butyl-1,3-benzenedicarboxamide (8): Compound 6 (2.5 g,
11.25 mmol, 1 equiv.) was mixed with PCl5 (7 g 33.74 mmol; 3
equiv.) and heated until a slightly yellow liquid containing 7 was
formed. This was added dropwise to vigorously stirred CH2Cl2
(350 mL), saturated with NH3. The reaction mixture was stirred at
room temp. overnight. The precipitate was filtered, washed with
water and dried. Recrystallisation from methanol gave 2.39 g (97%)
of amide 8 as colourless crystals, m.p. 246Ϫ248 °C. 1H NMR
(250 MHz, DMSO): δ ϭ 8.19 (t, J ϭ 1.5 Hz, 1 H), 8.03 (s, 2 NH),
8.00 (d, J ϭ 1.5 Hz, 2 H), 7.38 (s, 2NH), 1.32 (s, 9 H) ppm.
C12H16N2O2 (220.27): calcd. C 65.43, H 7.32, N 12.72; found C
65.66, H 7.35, N 12.76.
([D6]DMSO): δ ϭ 8.55 (s, 1 H), 8.15 (s, 2 H), 8.00 (s, 2 NH), 7.3
(m, 20 H), 4.95 (d, 2 H), 4.70 (d, 2 H), 1.35 (s, 9 H) ppm. ESI-MS:
m/z ϭ 575.5 [M ϩ H]ϩ.
Bis(amidinium) Picrate 11: A solution of 183 mg of 40% picric acid
(0.48 mmol, 2 equiv.) in 1.5 mL of methanol was added to a solu-
tion of 10 (140 mg, 0.24 mmol, 1 equiv.) in 1 mL of methanol. The
addition of 0.5 mL of water led to the formation of a yellow pre-
cipitate. Crystals of 11 suitable for X-ray structure analysis were
grown from acetone and diethyl ether by slow evaporation of the
solvent at ϩ5 °C; m.p. 162Ϫ164 °C (m.p. 145Ϫ149 °C from MeOH
and H2O). 1H NMR (400 MHz, CDCl3): δ ϭ 9.54 (s, 1 H), 8.61 (s,
2 H), 8.45 (s, 4 H), 7.11Ϫ7.26 (m, 20Harom), 5.16 (s, 4 H), 1.29 (s,
Diethyl 5-tert-Butyl-1,3-benzenedicarboximidate, Salt with Hydro-
chloric Acid (9): A mixture of amide 8 (500 mg, 2.26 mmol), 9 H) ppm. 1H NMR (400 MHz, [D6]DMSO): δ ϭ 8.58 (s, 4 H),
triethyloxonium tetrafluoroborate (1.24 g, 6.52 mmol) and dry 8.57 (s, 1 H), 8.50 (s, 2 H), 7.50 (m, 20 H), 5.46 (s, 4 H), 1.42 (s, 9
CH2Cl2 (4 mL) was stirred at room temp. under argon for 20 h. To
the resulting precipitate was added 40 mL of CH2Cl2 and 50 mL
H) ppm. C52H46N10O15 (1050.98) (11·H2O; from MeOH and H2O):
calcd. C 59.43, H 4.41, N 13.33; found C 59.31, H 4.67, N 13.39.
of sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and The single-crystal structure of the bis(amidinium) picrate (11·Et2O)
the solvent was evaporated at reduced pressure. Flash chromatogra- was determined at 173 K with a Siemens-SMART-CCD three-cir-
phy (silica gel; hexane/EtOAc, 1:2) gave the imidic acid ester as a cle diffractometer. The structure was solved by direct methods.
colourless oil (440 mg, 70%). IR (NaCl, film): ν˜ ϭ 3418, 3173,
CCDC-192449 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
2962, 2606, 2345, 1718, 1702, 1677, 1654, 1624, 1589, 1560, 1438,
1399, 1364, 1295, 1248, 1164, 1028 cmϪ1 1H NMR (250 MHz, www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
.
[D6]DMSO): δ ϭ 9.00 (s, 2NH), 8.06 (m, 1 H), 7.95 (d, J ϭ 1.5 Hz, Crystallographic Data Centre, 12 Union Road, Cambridge
2 H), 4.25 (q, J ϭ 7.1 Hz, 4 H), 1.32 (t, J ϭ 7.1 Hz, 6 H), 1.31 (s,
CB2 1EZ, UK; Fax: (internat.)
ϩ 44-1223/336-033; E-mail:
9 H) ppm. A solution of the imidic acid ester (440 mg, 1.59 mmol)
deposit@ccdc.cam.ac.uk]. The single-crystal structure of a related
Eur. J. Org. Chem. 2003, 1661Ϫ1664
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1663

S. B. Tsogoeva, G. Dürner, M. Bolte, M. W. Göbel
FULL PAPER
chloroform solvate (11·2CHCl3) was also determined (CCDC-
[2] [2a]
E. Dane, J. Schmitt, Justus Liebigs Ann. Chem. 1938, 536,
[2b]
196Ϫ203.
E. Dane, J. Schmitt, Justus Liebigs Ann. Chem.
192448).
1939, 537, 246Ϫ249.
G. Singh, J. Am. Chem. Soc. 1956, 78, 6109Ϫ6115.
[3]
[4] [4a]
Bis(amidinium) Tetrakis(aryl)borate 12: Picrate 11 (98 mg,
0.095 mmol) was dissolved in 10 mL of methanol and filtered
through Dowex 1 ϫ 8 ClϪ form (200Ϫ400 mesh). The solvent was
removed in vacuo. The corresponding residue was dissolved
in CH2Cl2 (3 mL) and treated with a solution of tetrakis(3,5-
G. Quinkert, M. Del Grosso, A. Bucher, J. W. Bats, G.
[4b]
Dürner, Tetrahedron Lett. 1991, 32, 3357Ϫ3360.
G. Quink-
ert, M. Del Grosso, A. Bucher, M. Bauch, W. Döring, J. W.
Bats, G. Dürner, Tetrahedron Lett. 1992, 33, 3617Ϫ3620.
G. Quinkert, M. Del Grosso, A. Döring, W. Döring, R. I.
Schenkel, M. Bauch, G. T. Dambacher, J. W. Bats, G. Zimmer-
mann, G. Dürner, Helv. Chim. Acta 1995, 78, 1345Ϫ1391.
[5]
[6]
bistrifluoromethylphenyl)borate
(NaTFPB·2H2O;
190.5 mg,
0.206 mmol; 2.1 equiv.) in 5 mL of MeOH. After stirring the clear
solution at room temperature for 30 min, the solvent was removed
in vacuo and the residue treated with CH2Cl2. The suspension was
washed twice with H2O and the organic layer dried with Na2SO4.
Removal of the solvent in vacuo afforded 217.5 mg (99.5%) of 12
as a colourless solid with m.p. 45Ϫ48 °C. 1H NMR (400 MHz,
[D6]DMSO): δ ϭ 8.62 (s, 1 H), 8.50 (s, 2 H), 7.75 (s, 8 H), 7.63 (s,
16 H), 7.50 (m, 20 H), 5.45 (s, 4 H), 1.42 (s, 9 H) ppm.
C104H64B2F48N4 (2303.19): calcd. C 54.23, H 2.80, N 2.43; found
C 54.24, H 2.96, N 2.50.
For recent examples of DielsϪAlder reactions catalysed by
[6a]
achiral hydrogen bond donors see:
P. R. Schreiner, A.
[6b]
Wittkopp, Org. Lett. 2002, 4, 217Ϫ220.
Y. Huang, V. H.
Rawal,, J. Am. Chem. Soc. 2002, 124, 9662Ϫ9663.
T. Schuster, M. Kurz, M. W. Göbel, J. Org. Chem. 2000, 65,
1697Ϫ1701.
T. Schuster, M. Bauch, G. Dürner, M. W. Göbel, Org. Lett.
2000, 2, 179Ϫ181.
[7]
[8]
[9]
T. Schuster, M. W. Göbel, Synlett 1999, 966Ϫ968.
[10] [10a]
[10b]
A. Kraft, R. Fröhlich, Chem. Commun. 1998, 1085Ϫ1086.
A. Kraft, A. Reichert, Tetrahedron 1999, 55, 3923Ϫ3930.
A. Kraft, J. Chem. Soc., Perkin Trans. 1 1999, 705Ϫ714.
[10c]
Acknowledgments
Financial support by the DFG is gratefully acknowledged.
[11]
C. Dauwe, J. Buddrus, Synthesis 1995, 171Ϫ172.
[12]
Crystal data for (11·Et2O): C56H54N10O15, M ϭ 1107.09,
monoclinic, space group C2, a ϭ 17.9670(10), b ϭ 13.3150(10),
3
[1] [1a]
˚
˚
c ϭ 13.7960(10) A, β ϭ 122.910(10)°, V ϭ 2770.8(3) A , Z ϭ
G. Quinkert, H. Stark, Angew. Chem. 1983, 95, 651Ϫ669.
2, Dx ϭ 1.327 Mg·mϪ3, Mo-Kα radiation, λ ϭ 0.71073 A, Cell
[1b] L. F. Tietze, T. Nöbel, M. Spescha, J. Am. Chem. Soc. 1998,
120, 8971Ϫ8977.
˚
[1c]
parameters from 4887 reflections, θ ϭ 1.76Ϫ25.03°, µ ϭ 0.098
mmϪ1, T ϭ 173 (2) K, crystal size 0.58 ϫ 0.32 ϫ 0.12 mm.
Received November 17, 2002
L. F. Tietze, G. Schneider, J. Wolfling, A.
Fecher, T. Nöbel, S. Petersen, I. Schuberth, C. Wulff, Chemis-
try. 2000, 6, 3755Ϫ3760.
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Eur. J. Org. Chem. 2003, 1661Ϫ1664