Asymmetric synthesis of β-amino-cyclohexyl sulfonates via aza Michael addition

Article abstract of DOI:10.1055/s-2002-19766

The Lewis acid catalyzed asymmetric synthesis of β-amino-cyclohexyl sulfonates via aza-Michael addition is reported. As key step the addition of (S)-1-amino-2-methoxymethyl-pyrrolidine (SAMP) or (R,R,R)-2-amino-3-methoxymethyl-2-azabicyclo[3.3.0]-octane (RAMBO) to alkenyl-cyclohexyl sulfonates is applied, to give β-hydrazino sulfonates in moderate to good yields and diastereomeric excesses (yield = 41-85%, de = 55-90%). The epimers are separated by preparative HPLC, followed by reductive N-N bond cleavage with BH₃·THF and protection of the resulting amines with CbzCl to afford NCbz-protected-β-amino-cyclohexyl sulfonates in moderate to good yields (38-68%, 2 steps) and enantiomeric excesses (ee) of ≥96%.

Full text of DOI:10.1055/s-2002-19766

304
LETTER
Asymmetric Synthesis of -Amino-cyclohexyl Sulfonates via aza Michael
Addition
A
symmetric Synth
i
esis of
e
-Amino-c
t
yclohex
e
yl Sulfona
r
te
s
Enders,* Stefan Wallert
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 29 October 2001
CbzHN
O
O
O O
Abstract: The Lewis acid catalyzed asymmetric synthesis of
-
*
+
R2N-NH2
S
S
amino-cyclohexyl sulfonates via aza-Michael addition is reported.
As key step the addition of (S)-1-amino-2-methoxymethyl-pyrroli-
dine (SAMP) or (R,R,R)-2-amino-3-methoxymethyl-2-azabicyc-
lo[3.3.0]-octane (RAMBO) to alkenyl-cyclohexyl sulfonates is
applied, to give -hydrazino sulfonates in moderate to good yields
and diastereomeric excesses (yield = 41–85%, de = 55–90%). The
epimers are separated by preparative HPLC, followed by reductive
N–N bond cleavage with BH3 THF and protection of the resulting
amines with CbzCl to afford NCbz-protected- -amino-cyclohexyl
sulfonates in moderate to good yields (38–68%, 2 steps) and enan-
tiomeric excesses (ee) of 96%.
*
R
OCy
R
OCy
3 steps
(S)-1, (R,R,R)-2
6
3
ee ≥ 96%
43-68%
(2 steps)
c
a
41-85%
*
R2N
NH2
NH
*
O
O
O
O
b
S
S
*
R
OCy
R
OCy
5
4
Key words: asymmetric synthesis, Michael addition, sulfonates,
hydrazines, Lewis acid
de = 44-90%
(de ≥ 96% after HPLC)
The synthesis of unnatural amino acids is still of great im-
portance, since these compounds can be utilized for exam-
ple in the preparation of new peptides with a high
potential for biological activities. In recent years 2-substi-
tuted taurines were used in the synthesis of -amino sul-
fonopeptides.1 White et al. designed -sulfonopeptides as
inhibitors of D-alanyl-D-alanine transpeptidases contain-
ing a taurine instead of a penultimate amino acid.2 Fur-
thermore, Liskamp et al. synthesized oligopeptido
sulfonamides on solid phase in order to analyze their
three-dimensional structure and biological activity.3
OCH3
OCH3
*
R2N-NH2 =
N
N
NH2
NH2
(S)-1 (SAMP)
(R,R,R)-2 (RAMBO)
Scheme Reagents and conditions: a) ZnBr2 (0.2 equiv), MeOH, add
3, add (S)-1 or (R,R,R)-2 (3.0 equiv), r.t., 7–14 d. b) BH3 THF (10
equiv, 1.0 M in THF), THF, reflux, 5 h; r.t., add MeOH, reflux, 1 h.
c) CbzCl (3.0 equiv), Na2CO3 (6.0 equiv), CH2Cl2–H2O (4:1), reflux,
1–3 d.
We now wish to report the 1,4-addition of (S)-1-amino-2-
methoxymethyl-pyrrolidine (SAMP, (S)-1)8 to (E)-alke-
nyl-cyclohexyl sulfonates 3. As shown in the Scheme,
(S)-1 could be added to 3 in the presence of catalytic
amounts of zinc bromide (ZnBr2) in moderate to good
yields and moderate diastereomeric excesses (Table 1).
After work up, the epimers could be separated by pre-
parative HPLC to yield virtually diastereomerically pure
-hydrazino-cyclohexyl sulfonates 4. The absolute con-
figuration was determined by NMR spectroscopy (NOE-
experiments).9
In addition to the peptides, the -amino-sulfonates them-
selves are of great interest. The best known -amino-sul-
fonic acid is taurine, but there are also other interesting
derivatives like 2-amino-2-phenylethanesulfonic acid4
as a potential GABAB receptor antagonist or flavo-
cristamide5 A and B, which have inhibitory activity
against DNA polymerase .
The Michael reaction can provide an efficient access to
the desired taurine derivatives. The first published aza-
Michael addition to alkenyl-sulfonates is dated to 1970,
when Dumaitre et al. reacted primary and secondary
amines with ethene-sulfonates.6 During the following
years, considerable attention towards the aza-Michael ad-
dition to alkenyl-sulfonates7 has been shown, but to our
knowledge enantioselective 1,4-additions with enan-
tiopure nitrogen-nucleophiles have not been described.
Further investigations led us to (R,R,R)-2-amino-3-
methoxymethyl-2-azabicyclo[3.3.0]octane
[RAMBO,
(R,R,R)-2], which was used as a chiral auxiliary in the aza-
Michael addition to alkenyl-sulfones.10 The enantiomer
SAMBO was first synthesized by Martens et al.11 Start-
ing from (R,R,R)-2-azabicyclo[3.3.0]octane-3-carboxylic
acid benzyl ester, a side product in the synthesis of the
ACE-inhibitors ramipril of the former Hoechst AG,12
(R,R,R)-2 was produced in a 5 step synthesis. The use
of RAMBO instead of SAMP had a significant effect on
the diastereomeric excesses, which increased from de =
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0304,0306,ftx,en;G31701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Asymmetric Synthesis of -Amino-cyclohexyl Sulfonates
305
Table 1 Aza-Michael Addition of SAMP [(S)-1] to 1-(E)-Alkenyl-
Cyclohexyl Sulfonates 3
Table 3 Synthesis of N-Cbz-Protected Amines 6.
6
R
Yielda (%)
eeb (%)
96
4
R
Yield (%)
dea (%)
(R)–6a
(R)–6b
(R)–6c
(R)–6d
(R)–6e
(S)–6a
(S)–6b
(S)–6c
(S)–6d
(S)–6e
(S)–6f
Me
68
53
43
52
53
56
53
38
57
56
63
(R,S)–4a
(R,S)–4b
(R,S)–4c
(R,S)–4d
(R,S)–4e
Me
78
74
73
41
66
44 ( 96)
55 ( 96)
58 ( 96)
80 ( 96)
60 ( 96)
Et
96
Et
n-Pr
i-Pr
96
n-Pr
i-Pr
Ph(CH2)2
96
Ph(CH2)2
Me
96
96
a Determined by 13C NMR spectroscopy; in brackets: after HPLC on
chiral stationary phase (Daicel AD).
Et
96
n-Pr
i-Pr
96
50–60% up to de = 80–90% (Table 2). As in the case of
SAMP, the epimers 4 could be separated by preparative
HPLC and the configuration of the new stereogenic center
was determined by NMR-spectroscopy (NOE-experi-
ments).9
96
Ph(CH2)2
n-Bu
96
96
a Over 2 steps.
b Determined by HPLC on chiral stationary phase (Daicel AD).
Table 2 Aza-Michael Addition of RAMBO [(R,R,R)-2] to 1-(E)-
Alkenyl Cyclohexyl Sulfonates 3
4
R
Yield (%)
dea (%)
References
(S,R,R,R)–4f
(S,R,R,R)–4g
(S,R,R,R)–4h
(S,R,R,R)–4i
(S,R,R,R)–4j
(S,R,R,R)–4k
Me
77
85
62
44
63
65
64 ( 96)
77 ( 96)
82 ( 96)
90 ( 96)
78 ( 96)
80 ( 96)
(1) (a) Gennari, C.; Gude, M.; Potenza, D.; Piarrulli, U. Chem.
Eur. J. 1998, 4, 1924. (b) Gude, M.; Piarulli, U.; Potenza,
D.; Salom, B.; Gennari, C. Tetrahedron Lett. 1996, 37,
8589. (c) Liskamp, R. M. J.; Moree, W. J.; van Gent, L. C.;
van der Marel, G. A. Tetrahedron 1993, 49, 1133.
(d) Liskamp, R. M. J.; Moree, W. J.; van der Marel, G. A. J.
Org. Chem. 1995, 60, 5157.
(2) (a) White, E. H.; Paik, S. Tetrahedron Lett. 1996, 4663.
(b) White, E. H.; Paik, S. Tetrahedron 1996, 5303.
(3) Liskamp, R. M. J.; Monnee, M. C. F.; Marijine, M. F.;
Brouwer, A. J. Tetrahedron Lett. 2000, 41, 7991.
(4) Abbenante, G.; Hughes, R.; Prager, R. H. Aust. J. Chem.
1997, 50, 523.
Et
n-Pr
i-Pr
Ph(CH2)2
n-Bu
a Determined by 13C NMR spectroscopy, in brackets: after HPLC on
chiral stationary phase (Daicel AD).
(5) Kobayashi, J.; Mikami, S.; Shigemori, H.; Takao, T.;
Shimonoishi, Y.; Izuta, S.; Yoshida, S. Tetrahedron 1995,
38, 10487.
(6) Berre, A.; Etienne, A.; Dumaitre, B. Bull. Soc. Chim. Fr.
1970, 946.
In the following step the chiral auxiliary of 4 was removed
by a racemization free reductive N–N bond cleavage uti-
lizing BH3 THF.13 The resulting crude amines 5 were not
purified, but directly protected with CbzCl to yield N-
Cbz-protected- -amino-cyclohexyl sulfonates 6 in mod-
erate to good yields and high enantiomeric excesses
(Table 3).
(7) (a) Meyle, E.; Keller, E.; Otto, H. H. Liebigs Ann. Chem.
1985, 802. (b) Wilken, J.; Thorey, C.; Gröger, H.; Haase, D.;
Saak, W.; Pohl, S.; Muzart, J.; Martens, J. Liebigs Ann.
Chem. 1997, 2133. (c) King, J. F.; Loosmore, S. M.; Aslam,
M.; Lock, J. D.; McGarrity, M. J. J. Am. Chem. Soc. 1982,
104, 7108. (d) Berre, A.; Delacroix, A.; Gressin, J. C.;
Masson, J. C. Bull. Soc. Chim. Fr. 1976, 1845.
(e) Liskamp, R. M. J.; Ameijde, J. Tetrahedron Lett. 2000,
41, 1103. (f) Makara, G. M.; Ma, Y. Tetrahedron Lett. 2001,
42, 4123.
(8) (a) Enders, D. In Asymmetric Synthesis, Vol. 3; Morrison, J.
D., Ed.; Academic Press: Orlando, 1984, 275. (b) Enders,
D.; Fey, P.; Kipphardt, H. Org Synth. 1987, 65, 173.
(c) Enders, D.; Fey, P.; Kipphardt, H. Org Synth. 1987, 65,
183.
In summary, we have developed a novel method for the
asymmetric synthesis of -amino-cyclohexyl sulfonates.
The reaction sequence starts with an aza-Michael-addi-
tion of SAMP or RAMBO to 1-(E)-alkenyl cyclohexyl
sulfonates, followed by N–N-bond cleavage of the gener-
ated hydrazines utilizing BH3 THF and Cbz protection of
the resulting amines.14–16
Acknowledgement
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 380) and the Fonds der Chemischen Industrie. We thank De-
gussa AG, BASF AG, Bayer AG and Aventis Pharma for the dona-
tion of chemicals.
(9) (R,S)-4d: NOE’s were observed between: CHN NCH2,
CHCH3 (a) CH2CH3, CH-Cy CH2SO2. (S,R,R,R)-4j:
NOE’s were observed between: CHCH3 CH2CH3,
CHCH3 (a) CH2CH3, CH-Cy NH, CHNH
NCHCH2CH2.
Synlett 2002, No. 2, 304–306 ISSN 0936-5214 © Thieme Stuttgart · New York

306
D. Enders, S. Wallert
LETTER
= 14.3, 5.5 Hz, 2 H, NCHCH, CHHSO2), 3.3 (m, 2 H,
(10) Enders, D.; Müller, S.; Raabe, G. Angew. Chem. Int. Ed.
1999, 38, 195; Angew. Chem. 1999, 111, 212.
(11) Martens, J.; Lübben, S. Liebigs Ann. Chem. 1990, 949.
(12) Teetz, V.; Geiger, R.; Henning, R.; Urbach, H. Arzneim.
Forsch. 1984, 34, 1399.
CHHSO2, CHHOCH3), 3.3 (s, 3 H, OCH3), 3.5 (m, 2 H,
CHHOCH3, CHNH), 4.7 (sep, J = 4.3 Hz, 1 H, CH-Cy); 13
NMR (100 MHz, CDCl3): = 14.60, 18.61, 23.84, 24.50,
25.23, 33.16, 33.42, 33.89, 35.10, 35.72, 38.93, 54.01,
C
(13) Enders, D.; Lochtmann, R.; Meiers, M.; Müller, S. F.;
Lazny, R. Synlett 1998, 1182.
55.00, 59.23, 68.81, 75.58, 75.91, 81.24; MS (EI) m/z 402,
320, 277, 276, 275, 169, 67; IR (CHCl3): 3260, 2938, 2863,
2371, 1649, 1451, 1348, 1265, 1240, 1195, 1168, 1119,
1033, 1004, 937, 870, 833, 792, 737, 702, 643, 603, 564,
531, 490, 463 cm–1; Anal. Calcd. for: C20H38N2O4S: C,
59.70; H, 9.45; N, 6.97. Found: C, 59.50; H, 9.64; N, 7.16.
Analytical data of compound (R,S)-4e: [ ]D24 = –55.7 (1.0,
CHCl3); 1H NMR (400 MHz, CDCl3): = 1.1–2.1 (m, 16 H,
NCH2CH2CH2, CH2-Cy, CH2CH2Ar), 2.3 (q, J = 8.70 Hz, 1
H, CHHN), 2.6–2.8 (m, 3 H, OCH2CHN, CH2CH2Ar), 2.9
(s, 1 H, NH), 3.1 (dd, J = 14.56, 4.12 Hz, 1 H, CHHSO2), 3.2
(dd, J = 14.43, 7.50 Hz, 1 H, CHHSO2), 3.3 (s, 3 H, OCH3),
3.3–3.5 (m, 3 H, CHNH, CHHO, CHHN), 3.5 (dd, J = 9.06,
4.12 Hz, 1 H, CHHO), 4.7 (sep, J = 4.3 Hz, 1 H, CH-Cy),
(14) General procedure for the preparation of compounds 4–6.
Synthesis of -hydrazino-cyclohexyl sulfonates 4a–k:
ZnBr2 (0.2 equiv) was dissolved in dry MeOH (1 mL/mmol
3) under argon atmosphere. The sulfonate 3 was added to the
mixture and the solution was stirred for 10 min at room
temperature. Then 3 equiv (S)-1 or (R,R,R)-2 was added and
the reaction mixture was stirred for 7–14 d at room
temperature. The solution was poured into a mixture of n-
pentane and diethyl ether (2:1, 30 mL/mmol 3) to precipitate
the Lewis acid. After filtration through Celite® the crude
product was purified by column chromatography (SiO2, n-
pentane–diethyl ether) to afford 4 as colorless oils.
Synthesis of -amino-cyclohexyl sulfonates 5:
7.2–7.3 (m, 5 H, CH-Ar); 13C NMR (100 MHz, CDCl3):
21.24, 23.69, 25.07, 26.39, 31.45, 32.95, 33.02, 34.53,
54.36, 54.43, 57.16, 59.26, 66.15, 75.04, 81.39, 126.14,
128.59, 128.62, 141.90; MS (EI) m/z 424, 342, 299, 298,
=
The -hydrazino-sulfonates 4a–k were dissolved in dry THF
(10 mL/mmol 4) under argon atmosphere. BH3 THF (10
equiv, 1.0 M in THF) was added and the reaction mixture
was refluxed for 5 h. After cooling to r.t. the solution was
slowly quenched with MeOH (3 mL/mmol 4). The solvents
were carefully evaporated and the mixture was treated again
with MeOH (30 mL/mmol 4). The solution was refluxed for
30 min after which the solvent was removed under reduced
pressure and the crude amines were used in the next reaction
step without further purification.
297, 129, 91, 70; IR (CHCl3): 3639, 3281, 3085, 3061, 3026,
2937, 2862, 2312, 1947, 1805, 1724, 1603, 1583, 1496,
1454, 1344, 1265, 1169, 1118, 1031, 1003, 935, 870, 829,
747, 700, 644, 595, 533, 489, 457 cm-1; Anal. Calcd. for:
C22H36N2O4S: C, 62.26; H, 8.49; N, 6.60. Found: C, 62.33;
H, 8.80; N, 6.69.
Analytical data of compound (R,S)-6k: 1H NMR (300 MHz,
CDCl3): = 0.9 (t, J = 7.2 Hz, 3 H, CH3), 1.2–2.0 (m, 14 H,
CH2-Cy, CH2CH2CH3), 3.3 (dd, J = 14.43, 4.21 Hz, 1 H,
CHHSO2), 3.4 (dd, J = 14.42, 5.60 Hz, 1 H, CHHSO2), 4.1
(m, 1 H, CHNH), 4.7 (sep, J = 4.12 Hz, 1 H, CH–Cy), 5.1 (s,
Synthesis of Cbz-protected amines 6:
The crude product 5 was dissolved in a mixture of CH2Cl2
and H2O (4:1, 10 mL/mmol 4). Na2CO3 (6 equiv) and CbzCl
(3 equiv) were added at r.t. The reaction mixture was
refluxed for 1–3 d. After separation of the organic layer the
aqueous phase was extracted with CH2Cl2 (3 20 mL). The
combined organic layers were washed with saturated
aqueous Na2CO3 solution and brine. After drying over
MgSO4 the solvent was evaporated and the products were
purified by column chromatography (SiO2, n-pentane–Et2O)
to afford 6 as colorless solids.
2 H, OCH2), 5.2 (s, 1 H, NH), 7.3–7.4 (m, 5 H, H-Ar); 13
C
NMR (75 MHz, CDCl3): = 23.71, 25.06, 32.51, 32.94,
32.99, 35.29, 47.78, 55.12, 67.16, 82.05, 126.47, 128.34,
128.48, 128.82, 128.67, 136.53, 140.86, 155.89; IR (KBr):
3854, 3839, 3751, 3676, 3362, 3030, 2936, 2863, 2344,
1691, 1533, 1498, 1454, 1409, 1384, 1328, 1294, 1247,
1214, 1170, 1127, 1049, 1010, 930, 905, 874, 832, 776, 742,
728, 699, 614, 585, 559, 528, 493, 458 cm-1; Anal. Calcd.
for: C24H31NO5S: C, 64.72; H, 7.00; N, 3.15. Found: C,
64.63; H, 7.44; N, 3.06.
(15) Selected analytical and spectroscopic data of compounds 4
24
and 6. Analytical data of compound (S,R,R,R)-4h: [ ]D
=
+17.7 (1.0, CHCl3); 1H NMR (400 MHz, CDCl3): = 0.9 (t,
J = 7.4 Hz, 3 H, CH2CH3); 1.1–2.1 (m, 22 H, CH2CH2CH2,
CH2CH2CH3, CHCH2CH, CH2-Cy), 2.4 (q, J = 8.79 Hz, 1 H,
NCHCH), 2.7 (sex, J = 5.40 Hz, 1 H, NCHCH2O), 3.1 (dd, J
(16) All new compounds showed suitable spectroscopic data
(NMR, MS, IR) and correct elemental analyses.
Synlett 2002, No. 2, 304–306 ISSN 0936-5214 © Thieme Stuttgart · New York