Diastereo- and enantioselective synthesis of syn-2,3-disubstituted 1,4-diketones via oxidative coupling of metalated hydrazones

Article abstract of DOI:10.1055/s-1998-1562

An efficient diastereo- and enantioselective synthesis of syn-2,3-disubstituted 1,4-diketones 4 is described. Key step of the procedure is the oxidative coupling of the metalated SAMP/RAMP-hydrazones 2 with iodine, followed by oxidative cleavage of the dimerized bishydrazones 3 with ozone and subsequent separation of the minor meso-isomer by chromatography. The d,l-isomers of the title 1,4-diketones 4 are obtained in good overall yields (20-64%) and high diastereo- and enantiomeric excesses (de ≥ 98%, ee = 80 - ≥95%).

Full text of DOI:10.1055/s-1998-1562

January 1998
SYNLETT
43
Diastereo- and Enantioselective Synthesis of syn-2,3-Disubstituted 1,4-Diketones via Oxidative
Coupling of Metalated Hydrazones
Dieter Enders*, Peter Müller and Daniela Klein
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: (int.)+241 8888 127; E-mail: Enders@RWTH-Aachen.de
Received 16 October 1997
Abstract: An efficient diastereo- and enantioselective synthesis of syn-
2,3-disubstituted 1,4-diketones 4 is described. Key step of the procedure
is the oxidative coupling of the metalated SAMP/RAMP-hydrazones 2
with iodine, followed by oxidative cleavage of the dimerized
bishydrazones 3 with ozone and subsequent separation of the minor
meso-isomer by chromatography. The d,l-isomers of the title 1,4-
diketones 4 are obtained in good overall yields (20 - 64%) and high
diastereo- and enantiomeric excesses (de ≥ 98%, ee = 80 − ≥95%).
1
1,4-Diketones constitute an important class of compounds , for instance
2
as precursors of cyclopentanoids and five-membered heteroaromatics .
3
Although numerous synthetic routes to 1,4-diketones are known , there
are only a few asymmetric syntheses of the title compounds published
4
so far , and the direct approach via auxiliary controlled oxidative
coupling has very recently been reported only for the related 1,4-
5-7
dicarboxylic acid derivatives . The latter reports prompt us to disclose
8
our own early results on the asymmetric synthesis of 1,4-diketones via
oxidative coupling of metalated SAMP/RAMP-hydrazones with iodine
and subsequent removal of the auxiliary by ozonolysis.
As is shown in Scheme 1, symmetrical and unsymmetrical acyclic and
cyclic ketones 1 are converted into their corresponding SAMP-
9-11
12
hydrazones , followed by metalation with t-BuOK/n-BuLi in ether
at −78°C. The resulting azaenolates are trapped with a solution of iodine
in THF at the same temperature and, after aqueous work up, the light
sensitive bishydrazones 3 are used in the next step without further
purification (d/l:meso up to 86:14). Oxidative cleavage with ozone and
flash chromatography affords the 2,3-disubstituted 1,4-diketones 4. The
minor meso-isomer is easily separated by further chromatography
(MPLC) and the syn-configured title diketones 4a-e are isolated in
Scheme 1
diastereomerically pure form (de
≥ 98%), in good to excellent
enantiomeric excesses (ee = 80 - ≥95%) and in good overall yields (20 -
1
1
64%). In the case of sterically demanding groups R (e.g.: 4d, R =t-Bu)
only low overall yields were obtained, even employing KDA as base
13
(see Table 1)
.
The (S,S)-configuration of the 1,4-diketones 4 shown is based on the
9
stereochemical outcome of our previous results employing SAMP-
hydrazones, but not yet confirmed. However, as shown in the case of 4d
the (R,R)-enantiomers are accessible in the same way by using RAMP
instead of SAMP as the chiral auxiliary. The diastereomeric excesses of
13
the diketones were determined by C NMR spectroscopy, and the
1
enantiomeric excesses were measured by H NMR shift experiments
with Eu(hfc) .
3
In a futher experiment trifluoromethyl iodide was used instead of iodine
as dimerization reagent. Subsequent ozonolysis of the crude product 3a
and purification by flash chromatography gave the 2,3-disubstituted 1,4-
diketone 4a with an overall yield of 11%, a d/l:meso ratio of 67:33 and
an enantiomeric excess of 83%. This example shows that
trifluoromethyl iodide can be used as reagent for the oxidative coupling
In summary a novel diastereo- and enantioselective synthesis of syn-2,3-
disubstituted 1,4-diketones via oxidative coupling of metalated SAMP-
hydrazones with good overall yields of up to 64% and with high
3i,6,7
3p,q,6,7
besides the well known reagents like iodine
, Cu(II)-salts
,
diastereo- and enantiomeric excesses (de ≥ 98%, ee = 80 - ≥ 95%) has
3j
3b,6
14
Ce(IV)-salts and TiCl
. In comparison with iodine, trifluoromethyl
been developed
.
4
iodide leads to similar diastereo- and enantiomeric excesses, but in a
much lower yield.

44
LETTERS
SYNLETT
Acknowledgements. This work was supported by Deutsche
Forschungsgemeinschaft (Leibniz prize) and the Fonds der Chemischen
Industrie. We thank Degussa AG, BASF AG, Bayer AG and Hoechst
AG for the donation of chemicals.
(9) Enders, D. in Asymmetric Synthesis, Vol. 3; Morrison, J.D., Ed.;
Academic Press: Orlando, 1984; p 275.
(10) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth. 1987, 65, 173, 183.
(11) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933.
(12) Schlosser, M. J. Organomet. Chem. 1967, 8, 9.
References and Notes
(13) Synthesis of 2,3-disubstituted 1,4-bishydrazones 3a-e via
oxidative coupling with iodine: SAMP-hydrazones 2 (11 mmol)
(1) Reviews: a) Rio, G.; Lecas-Nawrocka, A. Bull. Soc. Chim. Fr.
1976, 317. b) Nimgirawath, S.; Ritchie, E.; Taylor, W.C. Aust. J.
Chem. 1976, 29, 339. c) Miyakoshi, T. Org. Prep. Proc. Int. 1989,
21, 659.
12
are added to a suspension of t-BuOK/n-BuLi (11 mmol) in dry
Et O (50 mL) at −78°C. After 2h a solution of iodine (10 mmol) in
2
dry THF (10 mL) is added dropwise to the reaction mixture via
(2) Reviews: a) Ellison, R.A. Synthesis 1973, 397. b) Ho, T.L. Synth.
Commun. 1974, 265. c) Trost, B.M. Chem. Soc. Rev. 1982, 11,
141. d) Piancatelli, G.; D'Auria, M.; D'Onofrio, F. Synthesis 1994,
867.
cannula. After warming to room temperature overnight the
reaction mixture is worked up (aqu. NH Cl-solution/Et O/
4
2
NaSO ). The crude products could be used in the next step
4
without further purification.
Synthesis of 1,4-bishydrazone 3a via oxidative coupling with
trifluoromethyl iodide: SAMP-Hydrazone 2a (1 mmol) is added to
a solution of LDA (1.1 mmol) in dry THF (5 mL) at 0°C. After 4h
the reaction mixture is cooled to −78°C and added dropwise to a
−78°C cold solution of trifluoromethyl iodide (1.12 mmol) in dry
THF (5 mL) via cannula. After warming to room temperature the
(3) For some typical recent examples see: a) Trehan, I.R.; Singh, L.;
Arora, A.K.; Singh, V.; Kad, G.L. Ind. J. Chem. B 1996, 35, 708.
b) Kel'in, A.V.; Kulinkovich, O.G. Synthesis 1996, 330.
c) Echavarren, A.M.; Perez, M.; Castano, A.M.; Cuerva, J.M.
J. Org. Chem. 1994, 59, 4179. d) Wedler, C.; Schick, H. Synthesis
1992, 543. e) Fujii, T.; Hirao, T.; Ohshiro, Y. Tetrahedron Lett.
1992, 33, 5823. f) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40,
407. g) Zefirov, N.S.; Samsoniya, N.S.; Kutateladze, T.G.;
Zhdankin, V.V. Zh. Org. Khim. 1991, 27, 220. h) Miyashita, M.;
Awen, B.Z.E.; Yoshikoshi, A. Synthesis 1990, 563. i) Shatzmiller,
S.; Lidor, R.; Shalom, E; Menaske, N.; Bahar, E. Isr. J. Chem.
1989, 29, 187. j) Baciocchi, E.; Cash, A.; Ruzziconi, R.
Tetrahedron Lett. 1989, 30, 3707. k) Ahlbrecht, H.; von Daacke,
A. Synthesis 1987, 24 and earlier work cited therein. l) Hosomi,
A.; Shirahata, A.; Araki, Y.; Sakurai, H. J. Org. Chem. 1981, 46,
4631. m) Mayring, L.; Severin, T. Chem. Ber. 1981, 114, 3863.
n) Seuron, N.; Wartski, L.; Seyden-Penne, J. Tetrahedron Lett.
1981, 22, 2175. o) Frazier, R.H.; Harlow, R.L. J. Org. Chem.
1980, 45, 5408. p) Kobayashi, Y.; Taguchi, T.; Tokuno, E.
Tetrahedron Lett. 1977, 3741. q) Ito, Y.; Konoike, T.; Harada, T.;
Saegusa, T. J. Am. Chem. Soc. 1977, 99, 1487.
reaction mixture is worked up (aqu. NH Cl-solution/Et O/
4
2
Na SO ). The crude product can be used in the next step without
2
4
further purification.
Synthesis of 2,3-disubstituted 1,4-diketones 4a-e: Ozonolysis of
hydrazones 3 (5 mmol) dissolved in CH Cl (100 mL) at −78°C
2
2
was controlled by TLC. Subsequently the reaction mixture is
warmed to room temperature under an argon stream. The crude
products 4 are concentrated in vacuo and purified by flash
chromatography (SiO , Et O/pentane 1:1). The pure d/l-isomers
2
2
of 4 are obtained after MPLC chromatography (Lichroprep
50cm, 40mm, Si 60, corn size 15-25µm, ether/petroleum ether 1:1,
15ml/min).
(S,S)-4,5-Dimethyloctane-3,6-dione-bis-SAMP-hydrazone 3a:
1
1
yellow oil. IR (CHCl ) 1625 cm− (C=N). H NMR (300 MHz,
3
CDCl ): δ = 1.05 (d, J = 6.9 Hz, 6H, CH CH), 1.10 (t, J = 7.4 Hz,
3
3
6H, CH CH ), 1.59-1.62 (m, 2H), 1.75-1.85 (m, 4H), 1.90-2.04
3
2
(4) a) Döpp, D.; Pies, M. J. Chem. Soc. Chem. Commun. 1987, 1734.
b) Enders, D.; Mannes, D.; Raabe, G. Synlett 1992, 837.
c) Enders, D. in Stereoselective Synthesis, Ottow, E.; Schöllkopf,
K.; Schulz, B.-G., Eds.; Springer: Berlin, 1994; p 63. d) Enders,
D.; Kirchhoff, J.; Mannes, D.; Raabe, G. Synthesis 1995, 659.
(m, 6H), 2.31-2.44 (m, 4H), 2.80-2.82 (m, 2H), 2.99-3.17 (m, 6H),
13
3.33 (s, 6H, OCH ); C NMR (75 MHz, CDCl ): δ = 11.00
3
3
(CH CH ), 17.79 (CHCH ), 22.20 (CH ), 24.87 (CH ) 27.39
2
3
3
2
2
(CH ), 41.01 (CHCH ) 54.59 (NCH ), 59.11 (OCH ), 66.04
2
3
2
3
+
(NCH), 76.54 (OCH ), 174.93 (C=N). MS, m/z: 393.9 (M ),
265.0 (M −C H N O). HRMS Calcd. for
2
(5) Porter, N.A.; Su, Q.; Harp, J.J.; Rosenstein, I.J.; McPhail, A.T.
+
C
H
N O :
6
13
2
22 42
4
2
Tetrahedron Lett. 1993, 34, 4457.
394.33035, found: 394.33035.
(S,S)-4,5-Dimethyl-3,6-octanedione 4a: colourless oil. C NMR
13
(6) Kise, N.; Tokioka, K.; Aoyama, Y. J. Org. Chem. 1995, 60, 1100.
(7) a) Langer, T.; Illich, M.; Helmchen, G. Tetrahedron Lett. 1995,
36, 4409. b) Langer, T.; Illich, M.; Helmchen, G. Synlett 1996,
1137.
(75 MHz, CDCl ): δ = 7.70 (CH CH ), 14.34 (CHCH ), 34.59
3
2
3
3
(CH ), 47.80 (CH), 215.15 (C=O). All other spectroscopic data
2
15
were in agreement with those reported in the literature
.
(8) Müller, P. diploma work, University of Bonn, 1986. b) Müller, P.
dissertation, Technical University of Aachen, 1989.
(14) All new compounds gave correct elemental analyses and suitable
spectroscopic data (IR, NMR, MS).
For the oxidative coupling of dimethylhydrazones see: a) Corey,
E.J.; Enders, D. Tetrahedron Lett. 1976, 29, 11. b) Corey, E.J.;
Enders, D. Chem. Ber. 1978, 11, 1362.
(15) Koch, D.; Schäfer, H.; Steckhan, E. Chem. Ber. 1974, 107, 3640.