Enantioselective synthesis of β-amino sulfones by aza-Michael addition to alkenyl sulfones

Full text of DOI:10.1002/(sici)1521-3773(19990115)38:1/2<195::aid-anie195>3.0.co;2-6

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Enantiopure b-amino sulfones play an important role in
physiological processes.[3] Additionally, they readily undergo
electrophilic substitution in the a postion and have, for
instance, been used as intermediates in the synthesis of a-
amino acids,[4, 5] amino alcohols,[6] substituted uridines and
adenosines,[7] alkaloids,[8] b-lactams,[9] and nitrogen hetero-
cycles.[10, 11] As early as the 1960s Stirling and McDowell
investigated the kinetics of the intermolecular addition of
achiral amines to alkenyl sulfones.[12] Today, there exist
several procedures for intramolecular[6, 8, 13] and intermolecu-
lar[7, 10, 11, 14] aza-Michael additions to alkenyl sulfones. How-
ever, to our knowledge the enantioselective aza-Michael
addition with a nitrogen nucleophile bearing chirality infor-
mation, which may subsequently be cleaved, has not been
described. We now report the synthesis of the title compounds
by asymmetric conjugate addition with (S)-1-amino-2-me-
thoxymethylpyrrolidine (SAMP, (S)-1)[15] as a chiral ammonia
equivalent; this species has already been proven to be of great
value in asymmetric synthesis. As shown in Scheme 1,
2471.8(3) Š3, Z ˆ 4, 1calcd ˆ 1.469 gcm 3, R1 ˆ 0.048 based on F, wR2 ˆ
0.133 based on F 2. Maximum and minimum heights in the final
difference Fourier map are 0.578 and 0.378 eŠ 3. 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-101870. 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).
[10] a) C. Dupas, J.-P. Renard, J. Chem. Phys. 1974, 61, 3871; b) fitting was
attempted with the de Neef formula for ferromagnetic one-dimen-
sional systems with S ˆ 1 (A. Escuer, R. Vincente, M. S. El Fallah, X.
Solans, M. Font-Bardía, J. Chem. Soc. Dalton Trans. 1996, 1013), but
was unsuccessful.
[11] A. Escuer, R. Vicente, X. Solans, M. Font-Bardía, Inorg. Chem. 1994,
33, 6007.
[12] R. L. Carlin, Magnetochemistry, Springer, New York, 1986, p. 14.
[13] S. Mitra, A. K. Gregson, W. E. Hatfield, R. R. Weller, Inorg. Chem.
1983, 22, 1729.
Enantioselective Synthesis of b-Amino
Sulfones by aza-Michael Addition to
Alkenyl Sulfones**
Dieter Enders,* Stephan F. Müller, and Gerhard Raabe
Dedicated to Professor Elias J. Corey
on the occasion of his 70th birthday
The use of sulfones in organic synthesis has become
increasingly important in recent years. This has been due to
versatile synthetic transformations involving sulfones, for
example functionalization in the a position by electrophilic
substitution, replacement of the sulfone group with other
functional groups, and reductive cleavage of the sulfone
group. Furthermore, a,b-unsaturated sulfones are excellent
Michael acceptors and react with a number of carbon and
heteroatom nucleophiles, such as alcohols, thiols, and
amines.[1] The aza-Michael addition involving C N bond
formation has proven to be a particularly useful synthetic
tool.[2] The conjugate addition of an enantiopure ammonia
equivalent B, bearing a readily cleaved chiral auxiliary, to
alkenyl sulfones C should provide a novel enantioselective
access to synthetically valuable b-amino sulfones A.
Scheme 1. Enantioselective synthesis of b-amino sulfones by aza-Michael
addition on alkenyl sulfones. a) 1.5 equiv of nitrogen nucleophile (S)-1 or
(R,R,R)-2 per equiv of sulfone 3, Yb(OTf)3 (0.1 equiv), THF, room
temperature (RT) for 20 d (procedure A) or heating at reflux for 3 d
(procedure B); b) BH3 ´ THF (10.0 equiv, 1n in THF), THF, reflux, 5 h; HCl
(4n), RT, 2 h; c) Boc2O (10.0 equiv), Et3N, MeOH, RT, 2 d. OTf ˆ tri-
fluoromethanesulfonate.
R
*
SO2Ph
R
*
R2N-NH2
+
SO2Ph
NH2
A
B
C
conjugate addition of (S)-1 to (E)-alkenyl sulfones (E)-3a ± e
afforded Michael adducts (R,S)-4a ± e in the presence of
catalytic amounts of ytterbium trifluoromethanesulfonate
(Yb(OTf)3)[16] in moderate chemical yields and with moderate
to good diastereoselectivities. The epimers could be separated
by preparative HPLC to yield virtually diastereomerically
pure b-hydrazino sulfones (R,S)-4a ± e (de ˆ 93 to greater
than 96%, Table 1). The absolute configuration of the newly
formed stereogenic center of the major diastereomer was
determined by X-ray structural analysis of crystalline (R,S)-
4b (Figure 1).[17, 18]
[*] Prof. Dr. D. Enders, Dipl.-Chem. S. F. Müller, Dr. G. Raabe
Institut für Organische Chemie der Technischen Hochschule
Professor-Pirlet-Strasse 1, D-52074 Aachen (Germany)
Fax: (‡49)241-888-8127
E-mail: enders@rwth-aachen.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Leibniz prize and Sonderforschungsbereich 380) and by the Fonds
der Chemischen Industrie. We thank the Degussa AG, BASF AG,
Hoechst AG, Bayer AG, and Wacker Chemie for their donation of
chemicals.
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Table 1. Yields and diastereomeric excesses of b-hydrazino sulfones 4
prepared by conjugate addition of SAMP to (E)-alkenyl sulfones 3.
Reductive cleavage of the chiral auxiliary from b-hydrazino
sulfones (R,S)-4a ± e with BH3 ´ THF[23] in refluxing THF
afforded b-amino sulfones (R)-5a ± e without racemization.
Treatment with di-tert-butyldicarbonate (Boc2O) and triethyl-
amine in methanol gave the N-Boc-protected b-amino
sulfones 6 (ee ˆ 92 to greater than 96%) without prior
purification of the amines 5 (Table 3). After N N bond
cleavage the chiral auxiliary (S)-2-methoxymethyl-pyrroli-
dine could be recovered as the N-Boc derivative andÐafter
deprotection, nitrosation, and reductionÐreused as a chiral
ammonia equivalent.
Product
R[a]
Yield [%][b]
Method
de [%][c, d]
(R,S)-4a
(R,S)-4a
(R,S)-4b
(R,S)-4b
(R,S)-4c
(R,S)-4c
(R,S)-4d
(R,S)-4d
(R,S)-4e
(R,S)-4e
Et
Et
iPr
iPr
iBu
iBu
cHex[e]
cHex
BOM[f]
BOM
42
58
25
52
34
58
6
35
32
65
A
B
A
B
A
B
A
B
A
B
64 (ꢀ96)
40 (ꢀ96)
79 (ꢀ96)
43 (ꢀ96)
54 (93)
44 (93)
61 (ꢀ96)
50 (ꢀ96)
36 (ꢀ96)
30 (ꢀ96)
[a] 2-Aryl-substituted alkenyl sulfones are not suitable as Michael accept-
ors in the aza-analogous conjugate addition. [b] Yield of isolated 4. The
yield based on the conversion is usually 90 ± 95%. [c] The de values were
determined by 1H NMR spectroscopy (Varian Gemini 300-MHz spec-
trometer). [d] The numbers in parentheses refer to the de value after
resolution of the diastereomers by HPLC (SiO2, diethyl ether/pentane 3/1).
[e] cHex ˆ cyclohexyl. [f] BOM ˆ benzyloxymethyl.
Table 3. Yields, optical rotations, and enantiomeric excesses of N-Boc-
protected b-amino sulfones 6.
Product
R
Yield [%][a]
[a]2D5 (c, CHCl3) ee[b] [%]
(R)-6a
(R)-6b
(R)-6c
(R)-6d
(R)-6e
Et
iPr
iBu
cHex
BOM
60
42
73
58
82
2.1 (0.78)
12.9 (0.31)
‡ 7.1 (1.25)
8.1 (0.16)
ꢀ 96
ꢀ 96
92
ꢀ 96
9.7 (0.57)
ꢀ 96
[a] Yield determined over two steps. [b] The ee values were determined
from the de values of the corresponding Mosher amides by 1H NMR
spectroscopy (Varian Gemini 300-MHz spectrometer).[24]
Similarly, cleavage of the chiral auxiliary from b-hydrazino
sulfones (S,R,R,R)-4a ± f (Table 2) synthesized with (R,R,R)-2
proceeded without racemization.[25] By replacing SAMP by
RAMBO, both enantiomers of the title compounds could be
accessed.
In summary, the described asymmetric aza-Michael addi-
tion with C N bond formation opens up an efficient approach
to synthetically valuable and virtually enantiopure b-amino
sulfones.[26]
Figure 1. Structure of b-amino sulfone (R,S)-4b.[19]
Alternatively, (R,R,R)-2-amino-3-methoxymethyl-azabicy-
clo[3.3.1]octane (RAMBO, (R,R,R)-2), first synthesized as its
enantiomer SAMBO by Martens et al.,[20] can be employed as
the nitrogen nucleophile. This compound may be obtained by
a five-step reaction sequence[21] from the benzyl ester of
(R,R,R)-2-azabicyclo[3.3.0]octane-3-carboxylic acid, a precur-
sor to the angiotensin converting enzyme (ACE) inhibitor
Ramipril from the Hoechst AG.[22] With (R,R,R)-2 as a
nucleophile, considerably higher selectivities were obtained
than with (S)-1. The separation of the diastereomers by means
of HPLC was also feasible in this case (Table 2).
Experimental Section
4a ± f: The alkenyl sulfone 3a ± f (5.0 mmol) was added dropwise to a
solution of Yb(OTf)3 (0.31 g, 0.50 mmol) in THF (10 mL) under an
atmosphere of argon at room temperature. After the mixture was stirred
for 15 min, the nitrogen nucleophile (S)-1 or (R,R,R)-2 (7.5 mmol) was
added dropwise to the colorless to light yellow solution, and the mixture
was stirred for 20 d at room temperature (procedure A) or 3 d under reflux
(procedure B). The solution was then poured into pentane/diethyl ether
(2/1, 150 mL) and filtered through celite. The solvent was evaporated under
reduced pressure, and the residue was purified by column chromatography
or HPLC (SiO2, pentane/diethyl ether) to provide the major diastereomer.
Products 4a ± f were isolated as colorless oils, and (R,S)-4b was obtained in
crystalline form (m.p. 638C).
Table 2. Yields and diastereomeric excesses of b-hydrazino sulfones 4
prepared by conjugate addition of RAMBO to (E)-alkenyl sulfones 3
(procedure A).
Product
R[a]
Yield[%][b]
de [%][c,d]
(R)-5a ± e: The b-hydrazino sulfones (R,S)-4a ± e (Table 1) were dissolved
in THF (20 mL per mmol) under an atmosphere of argon. BH3 ´ THF
(10 equiv, 1.0n in THF) was added, and the reaction mixture was heated at
reflux for 5 h. After the mixtrure had cooled to room temperature,
hydrochloric acid (4n, 3 mL per mmol) was slowly added and the solution
was stirred for 2 h at room temperature. The solvent was evaporated under
reduced pressure, and the residue was treated with a saturated aqueous
solution of Na2CO3. The aqueous phase was extracted with dichloro-
methane/diethyl ether (3/1), and the combined organic layer was washed
with brine. After drying of the solution over Na2SO4 the solvent was
evaporated in vacuo. Without further purification, the crude product (R)-
5a ± e was subjected to reaction with Boc2O or with (R)-Mosherꢁs acid in
order to determine the enantiomeric excess of the amine.
(S,R,R,R)-4a
(S,R,R,R)-4b
(S,R,R,R)-4c
(S,R,R,R)-4d
(S,R,R,R)-4e
(S,R,R,R)-4 f
Et
iPr
iBu
cHex
BOM
nBu
46
21
32
29
29
45
82 (ꢀ96)
ꢀ 96
90 (ꢀ96)
94
90
86 (ꢀ96)
[a] 2-Aryl-substituted alkenyl sulfones are not suitable as Michael accept-
ors in the aza-analogous conjugate addition. [b] Yield of isolated 4. The
yield based on the conversion is usually 90 ± 95%. [c] The de values were
determined by 1H NMR spectroscopy (Varian Gemini 300-MHz spec-
trometer). [d] The numbers in parentheses refer to the de value after
resolution of the diastereomers by HPLC (SiO2, diethyl ether/pentane 3/1).
196
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(R)-6a ± e: The crude b-amino sulfones (R)-5a ± e were dissolved in
methanol (30 mL per mmol), and Boc2O (10 equiv) and triethylamine
(ca. 3 mL per mmol) were added at 08C. The reaction mixture was stirred
for 2 d. The solvent was evaporated under reduced pressure, and the
residue was diluted with diethyl ether. The mixture was washed with a
saturated aqueous solution of NH4Cl and then brine, and dried over
MgSO4. The solvent was evaporated, and the products were purified by
chromatography (SiO2, diethyl ether/pentane). The products (R)-6a ± e
were obtained as colorless solids.
the hydrogen positions could be localized, the remaining were calculated.
Reflections observed [I> 2s(I)]: 1826, parameters refined: 208; Rˆ
3
0.056, Rw ˆ 0.046; min./max. residual electron density 0.4/‡ 0.3e Š
.
The configuration at C8 was determined with respect to the known
configuration at C3. 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-102345. 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).
[18] S. R. Hall, H. D. Flack, J. M. Stewart, XTAL3.2 Reference Manual,
Universities of West Australia, Geneva, Maryland, Lamb, Perth, 1992.
[19] Software for preparing the ball-and-stick plot representation: Ball &
Stick Version 2.2, A. Falk, N. Müller, G. Schoppel, L. Webb, Linz
(Austria), Stafford (UK).
[20] a) J. Martens, S. Lübben, Liebigs Ann. Chem. 1990, 949 ± 952; b) J.
Wilken, C. Thorey, H. Gröger, D. Haase, W. Saak, S. Pohl, J. Muzart, J.
Martens, Liebigs Ann. Chem. 1997, 2133 ± 2146, and references
therein.
[21] Preparation analogous to that of SAMP (S)-1.[15]
[22] V. Teetz, R. Geiger, R. Henning, H. Urbach, Arzneim. Forsch. 1984,
34, 1399 ± 1401.
[23] a) H. Feuer, F. Brown, J. Org. Chem. 1970, 35, 1468 ± 1471; b) H.
Susuki, S Aoyagi, C. Kibayashi, J. Org. Chem. 1995, 60, 6114 ± 6122;
c) N. Yamazaki, H. Suzuki, S. Aoyagi, C. Kibayashi, Tetrahedron Lett.
1996, 37, 6161 ± 6164; d) D. Enders, R. Lochtmann, Synlett 1997, 355 ±
357.
[24] a) J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34, 2543 ±
2549; b) J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512 ±
519.
[25] The starting material for the synthesis of RAMBOÐ(R,R,R)-azabi-
cyclo[3.3.0]octane-3-carboxylic acid benzyl ester hydrochloride, which
was supplied by the Hoechst AG ± showed an ee value of 80%
(determined by 1H NMR spectroscopy from the de value of the
corresponding Mosher amide).
Received: July 16, 1998 [Z12157IE]
German version: Angew. Chem. 1999, 111, 212 ± 214
Keywords: aminations
´ asymmetric synthesis ´ chiral
auxiliaries ´ Michael additions ´ sulfones
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[26] All new compounds showed suitable spectroscopic data (IR, MS,
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A Novel High-Nuclearity Luminescent
Gold(i) ± Sulfido Complex**
Vivian Wing-Wah Yam,* Eddie Chung-Chin Cheng,
and Kung-Kai Cheung
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There has been growing interest in the study of CuI, AgI,
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these aggregates exhibit rich luminescence behavior.[2] Re-
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with their well-known ability to exhibit a variety of bridging
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[*] Prof. V. W.-W. Yam, E. C.-C. Cheng, Dr. K.-K. Cheung
Department of Chemistry
The University of Hong Kong
[16] S. Matsubara, M. Yoshioka, K. Utimoto, Chem. Lett. 1994, 827 ± 830.
[17] Crystal structure analysis of (R,S)-4b (C17H28O3N2S): orthorhombic,
Pokfulam Road, Hong Kong SAR (China)
Fax: (‡852)2857-1586
space group P212121 (no. 19), a ˆ 8.2728(4), b ˆ 10.3874(5), c ˆ
3
E-mail: wwyam@hkucc.hku.hk
22.205(1) Š, Vˆ 1908.14 Š3, Zˆ 4, Mcalcd ˆ 340.49, 1calcd ˆ 1.185 g cm
.
[**] V.W.-W.Y. acknowledges financial support from the Research Grants
Council and The University of Hong Kong. E.C.-C.C. acknowledges
the receipt of a postgraduate studentship administered by The
University of Hong Kong.
Crystals were obtained from dichloromethane/n-hexane, crystal dimen-
sions ca. 0.3Â 0.3Â 0.3 mm3, Enraf-Nonius CAD4 diffractometer, CuKa
radiation (graphite monochromator, lˆ 1.54179 Š. The structure was
solved with direct methods (Gensin, Gentan, from Xtal3.2).[18] Some of
Angew. Chem. Int. Ed. 1999, 38, No. 1/2
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1433-7851/99/3801-0197 $ 17.50+.50/0
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