Asymmetric synthesis of α-substituted β-amino sulfones by aza-Michael addition/α-alkylation

Article abstract of DOI:10.1055/s-1999-972952

The aza-Michael addition of (S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP) to alkenyl sulfones (E)-1, followed by reductive N-N bond cleavage with BH₃ · THF and N-benzylation yields N-benzyl-protected β-amino sulfones (R)-3 with high enantiomeric excesses (ee≥96%). Subsequent α- alkylation of (R)-3 with various electrophiles leads to α-alkyl-β-amino sulfones (R,R)-4a-e in excellent yields (88-97%) and finally high diastereomeric (de = 96-≥98%) and enantiomeric purity (ee≥96%). The absolute configuration was determined by X-ray structural analysis and confirmed by NMR spectroscopy (NOE-experiments).

Full text of DOI:10.1055/s-1999-972952

LETTER
741
Asymmetric Synthesis of a-Substituted b-Amino Sulfones by aza-Michael
Addition / a-Alkylation
Dieter Enders,* Stephan F. Müller, Gerhard Raabe
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Fax: +49 (241) 8888-127; E-mail: Enders@RWTH-Aachen.de
Received 18 February 1999
finally alkylated to afford the title compounds (Scheme 1,
Table 1).
Abstract: The aza-Michael addition of (S)-1-amino-2-methoxyme-
thyl-pyrrolidine (SAMP) to alkenyl sulfones (E)-1, followed by re-
ductive N-N bond cleavage with BH3⋅THF and N-benzylation
yields N-benzyl-protected b-amino sulfones (R)-3 with high enanti-
omeric excesses (ee ≥ 96 %). Subsequent a-alkylation of (R)-3 with
various electrophiles leads to a-alkyl-b-amino sulfones (R,R)-4a-e
in excellent yields (88-97 %) and finally high diastereomeric (de =
96 - ≥ 98 %) and enantiomeric purity (ee ≥ 96 %). The absolute con-
figuration was determined by X-ray structural analysis and con-
firmed by NMR spectroscopy (NOE-experiments).
Key words: asymmetric synthesis, Michael addition, a-alkylation,
amines, sulfones, alkenyl sulfones
Since sulfones are capable of undergoing a variety of syn-
thetically important transformations, their synthesis and
utility has recently received much attention.1 For instance,
sulfones allow a-functionalization, their replacement by
other functional groups, and removal by reductive cleav-
age. In addition, the ease of a-deprotonation allows sulf-
one anions to take part, for example, in cyclopropana-
tions,2 aldol-type reactions3 and a-alkylations,4 which
have been widely used in total synthesis of bioactive com-
pounds.
Scheme 1. Reagents and Conditions: a) Yb(OTf)3 (0.1 equiv), THF,
add 1 (1.0 equiv), add SAMP, (1.5 equiv), reflux, 3 d; b) BH3⋅THF (10
equiv, 1.0 M in THF), THF, reflux, 5 h; rt, HCl (4.0 M), 2 h; c) BnBr
(3.0 equiv), Na2CO3 (6.0 equiv), CH2Cl2/H2O (4:1), reflux, 2 d;
Cyclic and acyclic b-amino sulfones are known to under-
go electrophilic substitutions a to the sulfone group.5 d) LDA (1.3 equiv), TMEDA (1.3 equiv), –78 °C, add (R)-3, 4 h, R2X
(1.4 equiv, neat, 4a,b,e: MeI, 4c: EtI, 4d: BnBr) –78 °C → rt, 14 h.
However, to our knowledge the asymmetric synthesis of
acyclic a-substituted b-amino sulfones has not been de-
scribed. We have recently demonstrated the enantioselec-
tive synthesis of b-amino sulfones by aza-Michael
addition to alkenyl sulfones.6 Conjugate addition of (S)-1-
amino-2-methoxymethylpyrrolidine (SAMP)7 to (E)-alk-
enyl sulfones (E)-1a-c has been shown to afford Michael
adducts (R,S)-2a-c in the presence of catalytic amounts of
ytterbium trifluoromethanesulfonate (Yb(OTf)3) in mod-
erate yields and with moderate to good diastereoselectivi-
ties. The epimers could be separated by preparative HPLC
to yield virtually diastereomerically pure b-hydrazino sul-
fones.
We now wish to report an important extension of our pre-
vious protocol by a-alkylation to generate two neighbour-
ing stereogenic centres. In order to reach this goal, the
prozection of the b-amino function was changed. Thus,
after removal of the chiral auxiliary with excess
BH3⋅THF,8 subsequent N,N-dibenzylation9 allowed ac-
cess to N,N-dibenzyl-protected b-amino sulfones (R)-
3a-c in good yields (61 - 70 % over two steps), which were
Synlett 1999, No. 6, 741–743 ISSN 0936-5214 © Thieme Stuttgart · New York

742
D. Enders et al.
LETTER
In a typical experiment the N,N-dibenzyl-b-amino sulfone (R,R)-4a-e: The N,N-dibenzyl-b-amino sulfones (R)-3a-c
(R)-3 was metalated with LDA in the presence of TME- (5 mmol) were dissolved in THF (25 mL) and added to a
DA. The corresponding electrophile R2X (methyl iodide, solution of LDA (6.5 mmol) at –78 °C. TMEDA (6.5
ethyl iodide or benzyl bromide, respectively) was added mmol) was added, and the reaction mixture was stirred at
affording products (R,R)-4a-e after work-up and purifica- –78 °C for 4 h. The corresponding electrophile (7.0 mmol,
tion as colorless oils in excellent yields (88 - 97 %), good neat) was slowly added and the solution was stirred for 1
to high diastereomeric excesses (de = 64 - > 97 %) and ex- h at –78 °C and then overnight at room temperature. After
cellent enantiomeric excesses (ee ≥ 96 %). The major di- quenching with pH 7-buffer the aqueous phase was ex-
astereomer of each of the products (R,R)-4a-e could be tracted three times with diethyl ether. The combined or-
obtained practically diastereomerically pure (de ≥ 96 - ≥ ganic layer was washed with brine, dried over MgSO4,
98 %) after isolation of the main epimer by recrystalliza- and the solvent was removed under reduced pressure. The
tion ((R,R)-4a,c,d) or column chromatography ((R,R)-4e), products were purified by chromatography (SiO2, diethyl
respectively.
ether/pentane). Products (R,R)-4a-d were isolated in crys-
talline form and product (R,R)-4e was obtained as a co-
lourless oil.
The relative and absolute configuration of the newly
formed stereogenic centres of the major diastereomer is
based on the X-ray structural analysis of crystalline (R,R)-
4b.10 This result was confirmed by NOE-analysis of com-
pounds (R,R)-4b and (R,R)-4e.11
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz prize, Sonderforschungsbereich 380) and the Fonds der
Chemischen Industrie. We thank Degussa AG, BASF AG, Bayer
AG and former Hoechst AG for the donation of chemicals.
In summary, we have synthesized a-alkylated b-amino
sulfones 4 of high diastereo- and enantiomeric purity by
a-alkylation of N,N-dibenzyl-protected b-amino sulfones
3, readily available through aza-Michael addition. These
compounds are interesting synthetic intermediates for the
creation of enantiopure acyclic and cyclic carbon frame-
works with a nitrogen-bearing stereogenic centre and ap-
plications in the asymmetric synthesis of bioactive
compounds can be envisaged.
References and Notes
(1) a) Simpkins, N. S. In Sulphones in Organic Synthesis,
Tetrahedron Organic Chemistry Series, Vol. 10; Baldwin, J.
E.; Magnus, P. D., Eds; Pergamon: Oxford, 1993. b) Patai, S.;
Rappoport, Z.; Stirling, C. J. The Chemistry of Functional
Groups: The Chemistry of Sulphones and Sulphoxides; Wiley:
Chichester, 1988. c) Schank, K. In Houben-Weyl, 4th ed., Vol.
E11/2, p 1132. d) Durst T. In Comprehensive Organic
Chemistry, Vol. 3; Barton, D. H. R.; Ollis, W. D, Eds.;
Pergamon: Oxford, 1979, p 171. e) Simpkins, N. S.
Tetrahedron 1990, 46, 6951.
(2) a) Tanikaga, R.; Shibata, N.; Yoneda, T. J. Chem. Soc., Perkin
Trans. 1 1997, 2253. b) Campbell, R. V. M.; Crombie, L.;
Findley, D. A. R.; King, R. W.; Pattenden, G.; Whiting, D. A.
J. Chem. Soc., Perkin Trans. 1 1975, 897.
(3) For some recent examples see: a) Knight, D. W.; Sibley, A. W.
J. Chem. Soc., Perkin Trans. 1 1997, 2179. b) Hart, D. J.; Li,
J.; Wu, W.-L.; Kozikowski, A. P. J. Org. Chem. 1997, 62,
5023. c) Magnus, N.; Magnus, P. Tetrahedron Lett. 1997, 38,
3491. d) Solladié-Cavallo, A.; Roche, D.; Fischer, J.; De Cian,
A. J. Org. Chem. 1996, 61, 2690. e) Markó, I. E.; Murphy, F.;
Dolan, S. Tetrahedron Lett. 1996, 37, 2089.
(4) Recent examples: a) Tanimoto, H.; Oritani, T. Tetrahedron
1997, 53, 3527. b) Alonso, D. A.; Falvello, L. R.; Mancheno,
B.; Nájera, C.; Tomás, M. J. Org. Chem. 1996, 61, 5004.
c) Bonete, P.; Nájera, C. Tetrahedron 1996, 52, 4111.
d) Houston, T. A.; Koreeda, M. Synth. Commun. 1994, 24,
393. e) Pine, S. H.; Shen, G.; Bautista, J.; Sutton, Jr., C.;
Yamada, W.; Apodaca, L. J. Org. Chem. 1990, 55, 2234. f)
Isobe, M.; Obeyama, J.; Funabashi, Y.; Goto, T. Tetrahedron
Lett. 1988, 29, 4773. g) Larcheveque, M.; Sanner, C.
Tetrahedron 1988, 44, 6407. h) Eisch, J. J.; Behrooz, M.; Dua,
S. K. J. Organomet. Chem. 1985, 121. i) Eisch, J. J.; Galle, J.
E. J. Org. Chem. 1980, 45, 4534.
General Procedure for the Preparation of Compounds 3
and 4:12,13
(R)-3a-c: The b-hydrazino sulfones (R,S)-2a-c (10 mmol)
were dissolved in THF (100 mL) under an atmosphere of
argon. BH3⋅THF8 (100 mmol, 1.0 M in THF) was added,
and the rection mixture was heated at reflux for 5 h. After
cooling to room temperature the solution was slowly
quenched with HCl (4.0 M, 30 mL) and stirred for 2 h at
room temperature. The solvent was evaporated under re-
duced pressure, and the residue was carefully treated with
a saturated aqueous solution of Na2CO3. The aqueous
phase was extracted 3 times with diethyl ether/CH2Cl2
(3:1), and the combined organic layers were washed with
brine. After drying over Na2SO4 the solvent was removed
under reduced pressure. Without further purification, the
crude product was subjected to reaction with benzyl bro-
mide or with (R)-Mosher’s acid in order to determine the
enantiomeric excess of the amine.
To obtain the N,N-dibenzyl-b-amino sulfones (R)-3a-c,
the crude amines were dissolved in a mixture of CH2Cl2
and water (4:1, 100 mL), and Na2CO3 (60 mmol) and
BnBr (30 mmol) was added at room temperature.9 The re-
action mixture was heated under reflux for 2 d. After sep-
aration of the organic layer the aqueous phase was
extracted with CH2Cl2, and the combined organic layer
was washed with saturated aqueous solution of Na2CO3
and then brine. After drying over MgSO4 the solvent was
evaporated, and the products were purified by chromato-
graphy (SiO2, diethyl ether/pentane) to obtain (R)-3a-c as
colourless solids.
(5) a) Sasaki, N. A.; Dockner, M.; Chiaroni, A.; Riche, C.; Potier,
P. J. Org. Chem. 1997, 62, 765 and references cited therein.
b) Alonso, D. A.; Costa, A.; Mancheno, B.; Nájera, C.
Tetrahedron 1997, 53, 4791.
(6) Enders, D.; Müller, S. F.; Raabe, G. Angew. Chem. 1999, 111,
212; Angew. Chem., Int. Ed. Engl. 1999, 38, 195.
Synlett 1999, No. 6, 741–743 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of a-Substituted b-Amino Sulfones by aza-Michael Addition / a-Alkylation
743
(7) a) Enders, D. in Asymmetric Synthesis, Vol. 3; Morrison, J. D.,
Ed.; Academic: Orlando, 1984, p 275. b) Enders, D.; Fey, P.;
Kipphardt, H. Org. Synth. 1987, 65, 173; 183.
1346, 1305, 1239, 1193, 1148, 1086, 1025, 999, 972, 921,
876, 804, 751, 719, 690, 597, 570, 533 cm -1; Anal. calcd. for
C16H26N2O3S: C 58.87, H 8.03, N 8.58. Found: C 58.42, H:
7.62, N: 8.80.
(8) Enders, D.; Lochtman, R.; Meiers, M.; Müller, S. F.; Lazny,
R. Synlett 1998, 1182.
(9) Yamazaki, N.; Kibayashi, C. J. Am. Chem. Soc. 1989, 111,
1396.
(R)-3b: [a]2D5 = +40.28 (c 2.16, CHCl3); 1H NMR (300 MHz,
CDCl3): d 0.88 (t, 3H, J = 7.0 Hz, CH3), 1.65 (m, 2H,
CH3CH2), 2.96 (dd, 1H, J = 13.5, 8.2 Hz, CHHSO2Ph), 3.07
(m, 1H, CHCH2), 3.22 (d, 2H, J = 13.7 Hz, CHHPh), 3.49 (dd,
1H, J = 13.5, 2.2 Hz, CHHSO2Ph), 3.67 (d, 2H, J = 13.7 Hz,
CHHPh), 7.18-7.85 (m, 15H, Ph); 13C NMR (75 MHz,
CDCl3): d 11.3, 25.6, 53.3, 54.9, 56.1, 127.0, 128.0, 128.9,
129.2, 129.3, 139.0, 139.8; MS: m/z 393 (M+), 364, 302, 238,
196, 105, 91, 77; IR (KBr): 2972, 2923, 1602, 1494, 1380,
1359, 1301, 1199, 1146, 1083, 1028, 836, 791, 745, 698, 622,
589, 566, 548 cm-1; Anal. calcd. for C24H27NO2S: C 73.25; H
6.92; N 3.56. Found: C 72.83; H 6.98; N 3.41.
(10) Crystallographic data (excluding structure factors) for the
structure reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 115145. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB21EZ, UK (fax: (+44) 1223-336-033; e-
mail: deposit@ccdc.cam.ac.uk). b) Software for preparing the
ball-and-stick plot representation: Ball & Stick Version 2.2,
Falk, A.; Müller, N.; Schoppel, G.; Webb, L., Linz (Austria),
Stafford (UK).
(R,R)-4b: 1H NMR (500 MHz, CDCl3): d 0.89 (t, 3H, J = 7.2
Hz, CH3CH2), 1.24-1.38 (m, 1H, CH3CHH), 1.35 (d, 3H, J =
7.3 Hz, CH3CH), 1.54-1.66 (m, 1H, CH3CHH), 3.29 (d, 2H, J
= 13.4 Hz, CHHPh), 3.38 (dd, 1H, J = 11.6, 2.8 Hz, CH2CH),
3.52 (q, 1H, J = 7.3 Hz, CHSO2Ph), 3.79 (d, 1H, J = 13.4 Hz,
CHHPh), 7.17-8.80 (m, 15H, Ph); 13C NMR (125 MHz,
CDCl3): d 11.5, 11.6, 20.8, 53.4, 56.4, 58.1, 126.9, 128.0,
128.6, 128.9, 129.0, 133.5, 137.7, 139.4; MS: m/z 407 (M+),
378, 316, 238, 105, 91; IR (neat): 3062, 3028, 2873, 1601,
1494, 1448, 1304, 1240, 1146, 1085, 1027, 1001, 962, 912,
867, 848, 750, 699, 668, 625, 572, 551, 522 cm-1; Anal. calcd.
for C25H29NO2S: C 73.67, H 7.17, N 3.44. Found: C 73.47, H
7.09, N 3.40.
(11) 4b: NOE’s were observed between CH3CH2→CH3CH,
CH2Ph→CH3CH, CH2Ph→CH3CH and
SO2Phortho→CH3CHN.
4e: NOE’s were observed between CH2Ph→CH3CH,
CH3CH→CHN and SO2Phortho→CHN.
(12) Selected analytical and spectroscopic data of compounds 2, 3
and 4:
(R,S)-2b: [a]2D5 = –109.5 (c 1.0, CHCl3); 1H NMR (500 MHz,
C6D6): d 0.67 (t, 3H, J = 7.5 Hz, CH3CH2), 1.42-1.60 (m, 4H,
CHCH2CH2CH2 / CH3CHH / CHCHHCH2CH2), 1.65-1.74
(m, 1H, CH3CHH), 1.76-1.83 (m, 1H, CHCHHCH2CH2),
2.19-2.24 (m, 1H, CHHN), 2.62 (m, 1H, OCH2CHN), 2.92
(dd, 1H, J = 14.3, 3.1 Hz, CHHSO2Ph), 3.05 (dd, 1H, J = 14.3,
8.2 Hz, CHHSO2Ph), 3.18 (s, 3H, CH3O), 3.23-3.29 (m, 2H,
CHHN / CHHO), 3.34 (m, 1H, CHNH), 3.57 (dd, 1H, J = 9.16,
3.97 Hz, CHHO), 6.97-7.81 (m, 5H, Ph); 13C NMR (125 Hz,
C6D6): d 9.0, 21.3, 26.0, 27.0, 54.7, 56.6, 58.5, 58.8, 65.9,
75.6, 128.1, 129.2, 133.3, 140.8; MS: m/z 326 (M+), 281, 266,
214, 171, 155, 143, 141, 129, 125, 114, 111, 84; IR (neat):
3387, 3063, 2965, 2930, 2876, 2827, 1585, 1459, 1447, 1384,
(13) All new compounds showed suitable spectroscopic data (IR,
MS, NMR) and correct elemental analyses or high-resolution
mass spectra.
Article Identifier:
1437-2096,E;1999,0,06,0741,0743,ftx,en;G08199ST.pdf
Synlett 1999, No. 6, 741–743 ISSN 0936-5214 © Thieme Stuttgart · New York