α-Silyl controlled asymmetric michael additions of acyclic and cyclic ketones to nitroalkenes

Article abstract of DOI:10.1055/s-1999-2715

Virtually enantiopure α-t-butyldimethylsilyl ketones (R)1 and (S)-5 are converted regioselectively to the corresponding trimethylsilyl enol ethers (R)-2 and (S,Z)-6. Subsequent asymmetric Michael addition to nitroalkenes in the presence of SnCl₄

Full text of DOI:10.1055/s-1999-2715

LETTER
747
α-Silyl Controlled Asymmetric Michael Additions of Acyclic and Cyclic
Ketones to Nitroalkenes
Dieter Enders*, Thomas Otten
Institut für Organische Chemie, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax Int. +49 (241) 8888-127; E-mail: Enders@RWTH-Aachen.de
Received 5 March 1999
Lewis acids in order to promote the 1,4-addition in dichlo-
romethane.7 Accordingly, a variety of Lewis acids were
screened, with AlCl3 and LiClO4 resulting in no product
formation, TiCl4 affording many by-products and
Abstract: Virtually enantiopure a-t-butyldimethylsilyl ketones (R)-
1 and (S)-5 are converted regioselectively to the corresponding tri-
methylsilyl enol ethers (R)-2 and (S,Z)-6. Subsequent asymmetric
Michael addition to nitroalkenes in the presence of SnCl4 affords the
1,4-adducts 3 and 7 in good yields and high diastereo- and enantio- BF3∑OEt2 causing partial removal of the a-silyl group.
meric excesses. Removal of the t-butyldimethylsilyl group with
n-Bu4NF, THF, NH4F/HF leads to the a,b-disubstituted g-nitro
ketones (S,R)-4 (de = 91-92 %, ee > 98 %) and (R,S)-8 (de > 96 %,
mation. After simple workup and isolation, the silyl nitro
ee > 98 %) in very good overall yields.
Best results were obtained by the use of SnCl4, with
Michael additions taking place with little by-product for-
ketones 3 were obtained in good yields and excellent dia-
stereo- and enantiomeric excesses (de,ee > 96 %). The ab-
solute configuration of crystalline 3a could be determined
Key words: asymmetric synthesis, Michael addition, a-silyl ke-
tones, nitroalkenes, nitro ketones
by X-ray structure analysis. The (R,S,R)-configuration ob-
tained indicates the expected trans orientation of the silyl
The Michael addition is one of the most important meth-
ods for C-C-bond formation in synthetic chemistry1 and a
great variety of asymmetric versions of this name reaction
have been developed in recent years.2
group and the introduced nitroalkane moiety at the six-
membered ring and is assumed for all compounds 3a-c.
The final step required the removal of the t-butyldimeth-
ylsilyl directing group with n-Bu4NF and NH4F/HF as a
buffer system, resulting in the formation of a,b-disubsti-
tuted g-nitro ketones 4 in very good yields. Desilylation
with n-Bu4NF alone caused epimerisation at the a-posi-
tion, which was dramatically reduced in the presence of
NH4F/HF. Nevertheless, partial epimerisation could not
be avoided. The very high diastereomeric excesses (de =
91-92 %) were determined by NMR and the excellent
enantiomeric excesses (ee > 98 %) by HPLC on chiral sta-
tionary phases (Table 1).
Nitroalkenes are of special interest as excellent Michael
acceptors due to their low tendency for 1,2-addition and
the strong anion-stabilizing effect of the nitro group.3 The
latter is an important functional group which can be trans-
formed into other functionalities, such as the carbonyl
group via Nef reaction or the amino group by reduction.4
We now wish to report a new efficient method for the dia-
stereo- and enantioselective synthesis of a,b-disubstituted
g-nitro ketones with high diastereomeric and enantio-
meric excesses via a-t-butyldimethylsilyl ketones, which
can be easily prepared based on the SAMP/RAMP-hydra-
zone methodology.5 The synthetic utility of the concept of
a-silyl ketone control in asymmetric synthesis has already
been demonstrated by us in various other applications.6
As is depicted in Scheme 1, initially the silyl ketone 1 was
converted regioselectively to the corresponding silyl enol
ether 2 by deprotonation with lithium diisopropylamide
and treatment with chlorotrimethylsilane. Deprotonation
at the stereogenic centre and thus racemisation did not oc-
cur, because the approach of the amide is hindered by the
bulky silyl group resulting in formation of the desired,
enantiomerically pure silyl enol ether in almost quantita-
tive yield (95%). Due to the cyclic structure of silyl ketone
1, the procedure leads to the (R)-configuration of 2, which
was used as nucleophile in the asymmetric Michael addi-
tion to nitroalkenes. It was found necessary to employ
Synlett 1999, No. 6, 747–749 ISSN 0936-5214 © Thieme Stuttgart · New York

748
D. Enders, T. Otten
LETTER
O
Ar
O
O
Ar
O
NO2
t-BuMe2Si
NO2
CH3
t-BuSiMe2
CH3
57 - 74 %
52 - 70 %
(S,R)-4
(R,S)-8
ee > 96 %
(S)-5
ee > 96 %
(R)-1
de = 91 - 92 %, ee > 98 %
de > 96 %, ee > 98 %
LDA, THF
TBAF, THF
81 - 90 %
LDA, THF / HMPA
TMSCl
TBAF, THF
80 - 89 %
95 %
95 %
TMSCl
NH4F / HF
NH4F / HF
NO2
NO2
OSiMe3
O
Ar
O
Ar
Ar
Me3SiO
Ar
t-BuMe2Si
t-BuMe2Si
NO2
CH2Cl2, SnCl4, - 70 ºC
NO2
CH3
CH2Cl2, SnCl4, - 70 ºC
74 - 87 %
t-BuSiMe2
t-BuSiMe2
CH3
68 - 83%
(R)-2
(R,S,R)-3
(S,Z)-6
(S,R,S)-7
de > 96 %, ee > 96 %
de > 96 %, ee > 96 %
Scheme 1
Scheme 2
Starting from acyclic ketones such as 5 (Scheme 2) for the
preparation of silyl enol ethers leads to the selectivity
problem of E/Z-geometry. Metalation with lithium diiso-
propylamide and treatment with chlorotrimethylsilane
generates both the E- and Z-silyl enol ethers. However, to
obtain high inductions in asymmetric reactions it is essen-
tial to employ stereochemically uniform enol ethers.
Thus, metalation in the presence of HMPA8 as a strong
cation solvating compound allowed regio- and stereose-
lective access to the pure (S,Z)-silyl enol ether 6 in excel-
lent yield (95%). Subsequent SnCl4 promoted asymmetric
Michael additions to nitroalkenes yielded the virtually
diastereo- and enantiomerically pure 1,4-adducts 7 (de, ee
> 96 %) in good yields (Scheme 2). The absolute config-
uration could be determined by X-ray structure analysis of
crystalline 7a as (S,R,S) indicating the all syn orientation.9
Removal of the t-butyldimethylsilyl group with n-Bu4NF
and NH4F/HF gave the a,b-disubstituted g-nitro ketones 8
in very good yields and high diastereo- and enantiomeric
excesses (de > 96 %, ee > 98 %).10 It is noteworthy that in
this case no epimerisation was observed as was in case of
nitroketones 4 (Table 2).
General procedures:
Synthesis of silyl enol ether (S,Z)-6: To a solution of 12
mmol diisopropylamine in 50 ml dry THF was added 12
mmol n-butyllithium (1.6 M in n-hexane) at 0 °C. After
stirring for 20 min 14 ml of HMPA were added and the
yellow solution was cooled to -80 °C. A solution of the
a-silyl ketone 5 (10 mmol) 5 in 10 ml dry THF was added
slowly and the reaction mixture was stirred at this temper-
ature for 30 min. After addition of 16 mmol Me3SiCl the
solution was allowed to warm to room temperature over
30 min. The mixture was quenched with a saturated solu-
tion of NaHCO3 (25 ml). The aqueous layer was separat-
ed, extracted with n-pentane and the combined organic
layers washed with brine, dried over Na2SO4 and concen-
trated in vacuo. To remove the residue of HMPA the
crude Z-silyl enol ether was dissolved in a little n-pentane
and eluated with n-pentane through a small column of
neutral Al2O3 and the solvent removed in vacuo. The ob-
tained silyl enol ether (3.3 g, 95%) was used for the prep-
aration of the Michael adducts.
Asymmetric Michael addition: A solution of 7.5 mmol
SnCl4 in dry CH2Cl2 (20 ml) was cooled to -70 °C. A so-
lution of 7.5 mmol nitroalkene in dry CH2Cl2 (5 ml) was
then added. After stirring for 10 min, the intensely co-
loured mixture was treated dropwise with a solution of the
silyl enol ether 6 in dry CH2Cl2 (5 ml) and stirred for 48
hours (24 hours for cyclic silyl enol ether 2) at -70 °C.
The reaction was quenched by pouring the reaction mix-
ture into a well stirred emulsion of diethyl ether and a sat-
urated NaHCO3 solution. The organic layer was separated
and the aqueous layer extracted with diethyl ether. The
combined organic phase was washed with brine, dried
(Na2SO4) und concentrated in vacuo. The crude product
was purified by flash chromatoghraphy (SiO2, Et2O/n-
pentane) and washing with n-pentane to afford 7.
Removal of the t-butyldimethylsilyl group: A solution of 5
mmol Michael adduct 7 in dry THF (50 ml) was cooled to
-50 °C. Then 100 mmol NH4F, 1 ml aqueous 48% HF und
Synlett 1999, No. 6, 747–749 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
α-Silyl Controlled Asymmetric Michael Additions of Acyclic and Cyclic Ketones to Nitroalkenes
749
Int. Ed. Engl. 1988, 27, 581. b) Enders, D.; Lohray, B. B. Helv.
Chim. Acta 1989, 72, 980. c) Lohray, B. B.; Zimbinski, R.
Tetrahedron Lett. 1990, 31, 7273. d) Enders, D.; Nakai, S.
Chem. Ber. 1991, 124, 219. e) Enders, D.; Ward, D.; Adam, J.;
Raabe, G. Angew.Chem. 1996, 108, 1059; Angew. Chem. Int.
Ed. Engl. 1996, 35, 981. f) Enders, D.; Prokopenko, O. F.;
Raabe, G.; Runsink, J. Synthesis 1996, 1095. g) Enders, D.;
Fey, P.; Schmitz, T.; Lohray, B. B.; Jandeleit, B J. Organomet.
Chem. 1996, 514, 227. h) Enders, D.; Potthoff, M.; Raabe, G.;
Runsink, J. Angew. Chem. 1997, 109, 2454; Angew. Chem.
Int. Ed. Engl. 1997, 36, 2362. i) Enders, D.; Klein, D.; Raabe,
G.; Runsink, J. Synlett 1997, 1271. j) Enders, D.; Hett, R.
Synlett 1998, 961.
5.5 mmol n-Bu4NF (1M in THF) were added and the so-
lution was allowed to warm. When only a very small res-
idue of starting material could be detected (TLC control)
it was hydrolyzed with a saturated NaHCO3 solution, ex-
tracted with diethyl ether, washed with brine, dried
(Na2SO4) and concentrated in vacuo. The crude product
was purified by flash chromatography (SiO2, Et2O/n-pen-
tane) to give 8.
In summary, an efficient asymmetric synthesis of cyclic
and acyclic a,b-disubstituted g-nitro ketones in good
overall yields and with excellent diastereo- and enantio-
meric excesses (de = 91 - > 96 %, ee > 98 %) has been de-
veloped employing 1,4-additions of a-silyl ketones to
nitroalkenes.
(7) a) Yoshikoshi, A.; Miyashita, M. Acc. Chem. Res. 1985, 18,
284. b) Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T.
Chem. Lett. 1994, 97. c) Bernardi, A.; Colombo, G.;
Scolastico, C. Tetrahedron Lett. 1996, 37, 8921.
(8) a) Ireland, R. E.; Müller, R. H.; Willard, A. K. J. Am. Chem.
Soc. 1976, 98, 2868. b) Davenport, K. G.; Eichenauer, H.;
Enders, D.; Newcomb, M.; Bergbreiter, D. E. J. Am. Chem.
Soc. 1979, 101, 5654. c) Fataftah, Z. A.; Kopka, I. E.; Rathke,
M. W. J. Am. Chem. Soc. 1980, 102, 3959.
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz prize) and the Fonds der Chemischen Industrie. We thank
Degussa AG, BASF AG, Bayer AG, former Hoechst AG and Wak-
ker Chemie for the donation of chemicals.
(9) Analytical data of compound 7a:
mp: 115 °C, [a]DRT: -92.5 (c = 1.10, CHCl3), IR (KBr): n =
1681 (C=O) cm-1. 1H-NMR (500 MHz, CDCl3): d = 0.06 (s,
3H, SiCH3), 0.18 (s, 3H, SiCH3), 0.79 (d, 3J = 7.0 Hz, 3H,
CH3CH), 1.02 (s, 9H, C(CH3)3), 2.41 (dq, 3J = 8.2 Hz, 3J = 7.0
Hz, 1H, CH3CH), 2.92 (dd, 2J = 13.4 Hz, 3J = 1.8 Hz, 1H, CH2-
Ph), 3.00 (dd, 3J = 12.2 Hz, 3J = 2.1 Hz, 1H, CHSi), 3.21 (dd,
2J = 13.4 Hz, 3J = 12.5 Hz, 1H, CH2-Ph), 3.33 (ddd, 3J = 9.5
Hz, 3J = 8.5 Hz, 3J = 5.5 Hz, 1H, CHPh), 3.73 (dd, 2J = 12.8
Hz, 3J = 9.8 Hz, 1H, CH2NO2), 3.85 (dd, 2J = 12.8 Hz, 3J = 5.5
Hz, 1H, CH2NO2), 6.68 (m, 2H, Ph), 7.16 (m, 3H, Ph), 7.18 -
7.26 (m, 3H, Ph), 7.31 (m, 2H, Ph). 13C-NMR (125 MHz,
CDCl3): d = - 6.3 (SiCH3), -4.7 (SiCH3), 14.8 (CH3CH), 18.3
(C(CH3)3), 27.1 (C(CH3)3), 34.9 (CH2-Ph), 46.1 (CHPh), 47.6
(CHSi), 49.8 (CH3CH), 77.4 (CH2NO2), 126.8 (CpPh),127.5
(CpPh),127.9 (CPh), 128.5 (CPh), 128.7 (CPh), 128.9 (CPh), 137.1
(CqPh), 141.9 (CqPh), 213.2 (C=O). MS (70eV): m/z (%): 368
(19.6, M+ - t-Bu), 307 (3.4), 281 (9.7), 247 (33.9), 207 (48.5),
163 (24.1), 149 (100), 131 (30.5), 91 (39.1), 69 (51.2), 57
(71.0).
References and Notes
(1) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis, Tetrahedron Organic Chemistry Series Vol. 9;
Baldwin, J. E.; Magnus, P. D., Eds.; Pergamon: Oxford, 1992.
(2) Reviews: a) Oare, D.A.; Heathcock, C.H. Top. Stereochem.
1989, 19, 227. b) Oare, D.A.; Heathcock, C.H. Top.
Stereochem. 1991, 20, 87. c) Rossiter, B. E.; Swingle, N. M.
Chem. Rev. 1992, 92, 771. d) Leonhard, J. Contemporary Org.
Synthesis 1994, 1, 387. e) Yamamoto, Y.; Pyne, S. G.;
Schinzer, D.; Feringa, B. L.; Jansen, J. F. G. A. In Houben-
Weyl, 4th ed., Vol. E21b; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E.; Eds.; Thieme: Stuttgart, 1995;
chapter 1.5.2 f) Leonhard, J.; Diez- Barra, E.; Merino, S. Eur.
J. Org. Chem. 1998, 2051.
(3) Examples of asymmetric Michael additions to nitroolefins:
a) Langer, W.; Seebach, D. Helv. Chim. Acta 1979, 62, 1710.
b) Blarer, S. J.; Schweizer, W. B.; Seebach, D. Helv. Chim.
Acta 1982, 65, 1637. c) Blarer, S. J.; Seebach, D. Chem. Ber.
1983, 116, 3086. d) Calderari, G.; Seebach, D. Helv. Chim.
Acta 1985, 68, 1592. e) Busch, K.; Groth, U. M.; Kühnle, W.;
Schöllkopf, U. Tetrahedron 1992, 48, 5607. f) Juaristi, E.;
Beck, A. K.; Hansen, J.; Matt, T.; Mukhopadhyay, T.; Simson,
M.; Seebach, D. Synthesis 1993, 1283. g) Schäfer, H.;
Seebach, D. Tetrahedron 1995, 51, 2305. h) Enders, D.; Syrig,
R.; Raabe, G.; Fernández, R.; Gasch, C.; Lassaletta, J.-M.;
Llera, J.-M. Synthesis 1996, 48 i) Enders, D.; Wiedemann, J.
Synthesis 1996, 1443. j) Enders, D.; Haertwig, A. ; Raabe, G.;
Runsink, J. Angew. Chem. 1996, 108, 2540; Angew. Chem.
Int. Ed. Engl. 1996, 35, 2388. k) Enders, D; Haertwig, A.;
Raabe, G.; Runsink, J. Eur. J. Org. Chem. 1998, 1771.
l) Enders, D.; Haertwig, A.; Runsink, J. Eur. J. Org. Chem.
1998, 1793.
C25H35NO3Si calc.C 70.55 H 8.29 N 3.29
(425.65)found 70.24 8.463.17
(10) Analytical data of compound 8a:
mp: 92 °C, [a]DRT: -6.5 (c = 1.00, CHCl3), IR (KBr): n = 1707
(C=O) cm-1. 1H-NMR (400 MHz, CDCl3): d = 0.90 (d, 3J =
7.2 Hz, 3H, CH3CH), 2.72-2.79 (m, 1H, CH2), 2.84-2.95 (m,
4H, 2CH2, CH-Ph), 3.65 (ddd, 3J = 9.4 Hz, 3J = 9.4 Hz, 3J =
4.9 Hz, 1H, CHPh), 4.45 (dd, 2J = 12.4 Hz, 3J = 4.9 Hz, 1H,
CH2NO2), 4.52 (dd, 2J = 12.4 Hz, 3J = 9.2 Hz, 1H, CH2NO2),
7.10 (m, 2H, Ph), 7.18 (m, 2H, Ph), 7.21 - 7.33 (m, 6H, Ph).
13C-NMR (100 MHz, CDCl3): d = 15.9 (CH3CH), 29.9 (CH2-
Ph), 43.6 (CH2CO), 45.9 (CH-Ph), 48.8 (CHCO), 78.1
(CH2NO2), 126.3 (CPh),127.9 (CPh), 128.0 (CPh), 128.4 (CPh),
128.6 (CPh), 129.0 (CPh), 137.5 (CqPh), 140.7 (CqPh), 212.0
(C=O). MS (70eV): m/z (%): 311 (M+), 177 (9.5), 159 (4.7),
133 (16.8), 131 (24.6), 105 (84.9), 91(100) 77 (14.3), 65 (8.3).
C19H21NO3 calc.C 73.29 H 6.80 N 4.50
(4) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979,
33, 1.
(311.38)found 73.25 6.98 4.42
(5) Enders, D.; Lohray, B. B.; Burkamp, F.; Bhushan, V.; Hett, R.
Liebigs Ann. 1996, 189 and literature cited therein.
(6) Asymmetric syntheses via a-silyl ketones: a) Enders, D.;
Lohray, B. B. Angew. Chem. 1988, 100, 594; Angew. Chem.
Article Identifier:
1437-2096,E;1999,0,06,0747,0749,ftx,en;G09099ST.pdf
Synlett 1999, No. 6, 747–749 ISSN 0936-5214 © Thieme Stuttgart · New York