Asymmetric synthesis of α-substituted β-amino sulfones by aza-Michael addition to alkenyl sulfones and subsequent α-alkylation

Article abstract of DOI:10.1002/(sici)1099-0690(200003)2000:6<879::aid-ejoc879>3.0.co;2-e

The aza-Michael addition of enantiopure 1-aminopyrrolidines to (E)- alkenyl sulfones in the presence of a catalytic amount of ytterbium trifluoromethanesulfonate [Yb(OTf)₃] yields β-hydrazino sulfones in moderate to good yields and with diastereoselectivities of up to 98%. The latter undergo reductive N-N bond cleavage with BH₃ · THF and, after N- protection with Boc₂O or benzyl bromide, afford N-protected β-amino sulfones with moderate to high enantiomeric excesses (ee = 42 to ≥96%) without racemization. Subsequent α-alkylation of the N,N-dibenzyl protected β-amino sulfones with various electrophiles yields α-alkyl-β-amino sulfones in excellent yields (88-97%) with high diastereomeric (de ≥96 to ≥98%) and enantiomeric purity (ee = 94 to ≥96%). The absolute configuration of the new stereogenic centre was determined by X-ray structural analysis and confirmed by NMR spectroscopy (NOE experiments). Possible reaction mechanisms for the conjugate addition and α-alkylation are presented.

Full text of DOI:10.1002/(sici)1099-0690(200003)2000:6<879::aid-ejoc879>3.0.co;2-e

FULL PAPER
Asymmetric Synthesis of α-Substituted β-Amino Sulfones by Aza-Michael
Addition to Alkenyl Sulfones and Subsequent α-Alkylation
Dieter Enders,*[a] Stephan Frank Müller,[a] Gerhard Raabe,[a] and Jan Runsink[a]
Keywords: Asymmetric synthesis / Michael addition / Sulfones / α-Alkylation / Amines
The aza-Michael addition of enantiopure 1-aminopyrrolidi-
nes to (E)-alkenyl sulfones in the presence of a catalytic
amount of ytterbium trifluoromethanesulfonate [Yb(OTf)3]
yields β-hydrazino sulfones in moderate to good yields and
with diastereoselectivities of up to 98%. The latter undergo
reductive N–N bond cleavage with BH3 THF and, after N-
protection with Boc2O or benzyl bromide, afford N-protected
alkylation of the N,N-dibenzyl protected β-amino sulfones
with various electrophiles yields α-alkyl-β-amino sulfones in
excellent yields (88–97%) with high diastereomeric (de Ն96
to Ն98%) and enantiomeric purity (ee = 94 to Ն96%). The
absolute configuration of the new stereogenic centre was de-
termined by X-ray structural analysis and confirmed by NMR
spectroscopy (NOE experiments). Possible reaction mecha-
β-amino sulfones with moderate to high enantiomeric exces- nisms for the conjugate addition and α-alkylation are pre-
ses (ee = 42 to Ն96%) without racemization. Subsequent α-
sented.
Introduction
fones.[16] Currently, there exist several procedures for intra-
molecular[7,9,17] and intermolecular[8,11,12,18] aza-Michael
additions to alkenyl sulfones.
The variety of synthetic transformations which may be
carried out using sulfones makes them a very valuable and
versatile functional group for organic synthesis. Amongst
these transformations are the easy α-substitution by elec-
trophiles, and the ability of α,β-unsaturated sulfones to un-
dergo efficient conjugate addition reactions with a wide
range of carbon and heteroatom nucleophiles.[1] In particu-
lar, the aza-Michael addition is noteworthy as a widely used
method for CϪN bond formation.[2]
The aim of this project was to develop a stereoselective
route to the title compounds A by the conjugate addition
of an enantiopure ammonia equivalent C to the alkenyl sul-
fones D followed by reductive cleavage of the chiral auxili-
ary and α-alkylation of the resulting β-amino sulfones B.
Results and Discussion
We now wish to report the intermolecular asymmetric
aza-Michael addition of a variety of nitrogen nucleophiles
1–6 to (E)-1-butenyl phenyl sulfone 8 in the presence of
catalytic amounts of ytterbium trifluoromethanesulfonate
[Yb(OTf)3][19] which result in the formation of β-hydrazino
sulfones 15–18, 20, and 27 (Scheme 1, Table 1).
Enantiopure β-amino sulfones play an important role in
physiological processes.[3] In addition, they readily undergo
electrophilic substitution in the α-position[4] and have, for
instance, been used as intermediates in the synthesis of α-
amino acids,[5,6] amino alcohols,[7] substituted uridines and
adenosines,[8] alkaloids,[9] β-lactams,[10] and nitrogen
heterocycles.[11,12] The ease of deprotonation allows sulfone
anions to participate, for example, in cyclopropanations,[13]
aldol-type reactions,[14] and α-alkylations[15] and demon-
strates their importance in organic synthesis. As early as the
1960’s Stirling and McDowell investigated the kinetics of
the intermolecular addition of achiral amines to alkenyl sul-
Scheme 1. Aza-Michael addition of various 1-aminopyrrolidines to
alkenyl sulfone 8
[a]
The nitrogen nucleophiles utilised in this study, (S)-1-am-
ino-2-(hydroxymethyl)pyrrolidine[20] (SAHP, (S)-1), (S)-1-
amino-2-(methoxymethyl)pyrrolidine[21] [SAMP, (S)-2], (S)-
1-amino-2-(1Ј-methoxy-1Ј-methylethyl)pyrrolidine[22]
Institut für Organische Chemie, Rheinisch-Westfälische
Technische Hochschule Aachen,
Professor-Pirlet-Straße 1, D-52074 Aachen, Germany
Fax: (internat.) ϩ 49-(0)241/888-8127
E-mail: Enders@RWTH-Aachen.de
Eur. J. Org. Chem. 2000, 879Ϫ892
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0306Ϫ0879 $ 17.50ϩ.50/0
879

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
Table 1. Aza-Michael addition of various 1-aminopyrrolidines to
alkenyl sulfone 8
Table 2. Aza-Michael addition of SAMP [(S)-2] to (E)-alkenyl sul-
fones 7–14
Nucleophile no.
Product Config.[a] Yield de
Sulfone
(E)
R[a]
Product
(R,S)-
Method
Yield[b]
[%]
de[c][d]
[%]
[%]
[%]
SAHP
(S)-1
15
20
16
17
(R,S)
(R,S)
(R,S)
(R,S)
57
42
82
71
51
7
Me
19
20
20
21
21
22
22
23
23
24
24
25
25
26
26
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
85
42
58
25
52
29
52
34
58
31
60
6
41 (Ն 98)
64 (Ն 96)
40 (Ն 96)
79 (Ն 96)
43 (Ն 96)
68
SAMP
SADP
(S)-2
(S)-3
(S)-4
64 (Ն 96)[b]
8
Et
68
8
Et
SAEP
RAMBO
SADMP
74
9
iPr
(R,R,R)-5 27
(S,R,R,S)-6 18
(S,R,R,R) 46
82 (Ն 96)[b]
9
iPr
[c]
–
46
71
10
10
11
11
12
12
13
13
14
14
nPr
nPr
43
[a]
The absolute configuration of the new stereogenic centre of the
major diastereomer was determined by X-ray structural analysis of
iBu
54 (93)
iBu
44 (93)
crystalline (R,S)-21 on the assumption that the addition mechan-
nBu
nBu
cHex[e]
cHex
Bom[f]
Bom
52 (86)
[b]
ism is the same in all cases. –
In the cases of 20 and 27 both
40 (86)
[c]
epimers were separated by HPLC. – The absolute configuration
has not been determined.
61 (Ն 96)
50 (Ն 96)
36 (Ն 96)
30 (Ն 96)
35
32
65
[a]
[SADP, (S)-3], (S)-1-amino-2-(1Ј-ethyl-1Ј-methoxypropyl)-
pyrrolidine[22] [SAEP, (S)-4], (R,R,R)-2-amino-3-methoxy-
methyl-2-azabicyclo[3.3.0]octane[23] [RAMBO, (R,R,R)-5]
2-Aryl-substituted alkenyl sulfones are not suitable as Michael
acceptors for this conjugate addition. – [b] Yield of isolated product.
[c]
The yield based on the conversion is usually 90Ϫ95%. – The de
values were determined by H- and 13C-NMR spectroscopy. Ϫ
1
[d]
and
(2S,3R,4R,5S)-1-amino-3,4-dimethoxy-2,5-bis(me-
The numbers in parentheses refer to the de value after separation
[e]
thoxymethyl)pyrrolidine[24]
[SADMP, (S,R,R,S)-6]
of the diastereomers by HPLC (SiO2, diethyl ether/pentane). –
[f]
cHex ϭ cyclohexyl. Ϫ Bom ϭ benzyloxymethyl.
(Scheme 1) are differently substituted 1-aminopyrrolidines,
which constitute chiral equivalents of ammonia by reduct-
ive cleavage of the hydrazine NϪN bond.
Figure 1. X-ray structure of the β-hydrazino sulfone (R,S)-21
ure 1)[27,28,29] on the assumption that the reaction pathway
was the same in all cases.
Scheme 2. Aza-Michael addition of SAMP [(S)-2] to alkenyl sul-
fones
RAMBO [(R,R,R)-5], first synthesised as its enantiomer
As shown in Scheme 1, β-hydrazino sulfones were pre- SAMBO by Martens et al.,[23] was also employed as a chiral
pared in moderate to good yields and with moderate to high nitrogen nucleophile in the conjugate addition to several al-
diastereoselectivities. In two cases the epimers were separ- kenyl sulfones.[26] (R,R,R)-5 may be obtained by a five-step
ated by preparative HPLC to yield diastereomerically pure reaction sequence[30] from the benzyl ester of (R,R,R)-2-az-
Michael adducts (20 and 27). In order to demonstrate the abicyclo[3.3.0]octane-3-carboxylic acid, a precursor to the
general applicability of this method, several (E)-alkenyl sul- angiotensin converting enzyme (ACE) inhibitor Ramipril
fones (7–14) were synthesised by Horner olefination[25] and (from the former Hoechst AG[31]). With RAMBO as a nu-
subsequently used in the conjugate addition with SAMP cleophile considerably higher diastereoselectivities were ob-
((S)-2) as chiral nucleophile. As shown in Scheme 2, the β- tained than with SAMP. The separation of the diastereo-
hydrazino sulfones 19–26 were obtained in variable yields mers by HPLC was also feasible in these cases (Scheme 3,
and with moderate to high diastereoselectivities[26] (de ϭ 43 Table 3).
Ϫ Ն98%).
A possible mechanism for the conjugate addition of
In almost every case, the epimers were separated by pre- SAMP to (E)-alkenyl sulfones in the presence of Yb(OTf)3
parative HPLC to yield virtually diastereomerically pure is shown in Figure 2. If we assume complexation of the ox-
Michael adducts (Table 2). It is noteworthy that the chem- ophilic ytterbium by the oxygen atom of the methoxymethyl
ical yields based on the conversion are usually 90–95% and group of the incoming nitrogen nucleophile SAMP [(S)-2]
the isolated starting material can be reused after purifica- and the oxygen atoms of the sulfone group, then there are
tion.
two possible faces from which the addition can occur. At-
The absolute configuration of the newly formed ste- tack from the Si-face (mechanism A) would result in strong
reogenic centres of the major diastereomers was deduced by steric interactions between the nucleophile and the substitu-
an X-ray structural analysis of crystalline (R,S)-20 (Fig- ent R of the alkenyl sulfone, whereas the addition from the
880
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
FULL PAPER
Table 3. Aza-Michael Addition of RAMBO [(R,R,R)-5] to (E)-alk- butyldicarbonate (Boc2O) or benzyl bromide gave the N-
enyl sulfones 8–14
Boc (34Ϫ40) or N,N-dibenzyl (41Ϫ45) protected β-amino
sulfones, respectively, in moderate to good yields without
Sulfone
R[a]
Product
Yield[b]
[%]
de[c][d]
any prior purification of the crude amines (Scheme 4,
Table 4). After NϪN bond cleavage, the chiral auxiliary (S)-
2-(methoxymethyl)pyrrolidine could be recovered as its N-
Boc or N-benzyl derivative and – after deprotection, nitro-
sation, and reduction – reused in asymmetric synthesis.
(E)-
(S,R,R,R)-
[%]
8
9
10
11
12
13
14
Et
iPr
nPr
iBu
nBu
cHex
Bom
27
28
29
30
31
32
33
46
21
40
32
45
29
29
82 (Ն 96)
96
86 (Ն 96)
90 (Ն 96)
86 (Ն 96)
94
90
[a]
2-Aryl-substituted alkenyl sulfones are not suitable as Michael
[b]
acceptors for this conjugate addition. Ϫ Yield of isolated prod-
[c]
uct. The yield based on the conversion is usually 90Ϫ95%. Ϫ
The de values were determined by 1H- and 13C-NMR spectroscopy.
Ϫ
[d] The numbers in parentheses refer to the de value after separa-
tion of the diastereomers by HPLC (SiO2, diethyl ether/pentane).
Scheme 3. Aza-Michael addition of RAMBO [(R,R,R)-6] to alk-
enyl sulfones
Scheme 4. Asymmetric synthesis of N-protected β-amino sulfones
Table 4. Reductive NϪN bond cleavage with BH3 THF followed
by N-protection of the resulting β-amino sulfone
Hydrazine
(S,R)-
R
Protecting
group(s)
Product
(R)-
Yield[a]
[%]
ee[b]
[%]
19
20
20
21
21
22
23
23
24
25
26
26
Me
Et
Bn2
Boc
Bn2
Boc
Bn2
Boc
Boc
Bn2
Boc
Boc
Boc
Bn2
41
34
42
35
43
36
37
44
38
39
40
45
40
60
78
42
43
82
73
74
54
58
82
61
Ն 96
Ն 96
Ն 96
Ն 96
Ն 96
42
Et
iPr
iPr
Figure 2. Postulated transition states for the conjugate addition of
1-aminopyrrolidines to alkenyl sulfones in the presence of
Yb(OTf)3
nPr
iBu
iBu
nBu
cHex
Bom
Bom
92
94
84
Ն 96
Ն 96
Ն 96
Re-face is sterically favoured and leads to the (R)-config-
uration at the newly formed stereogenic centre. The config-
uration of the stereogenic centre in 2-position of RAMBO
[(R,R,R)-5] bearing the methoxymethyl group has the op-
posite configuration to SAMP, which explains the opposite
stereochemical outcome of the conjugate addition of this
nucleophile to (E)-alkenyl sulfones [(S) versus (R)]. The in-
crease in the diastereoselectivities of the Michael adducts
[a]
Yield determined over two steps (NϪN bond cleavage and N-
[b]
protection). – The ee values were determined from the de values
of the corresponding Mosher amides by H NMR spectroscopy.
1
Similarly, cleavage of the chiral auxiliary from β-hy-
synthesised with RAMBO as nucleophile may be due to a drazino sulfones (S,R,R,R)-27Ϫ33 proceeded without race-
stronger steric interaction of the bicyclic pyrrolidine ring mization.[34] By replacing SAMP with RAMBO both en-
with the R-group of the alkenyl sulfone.
antiomers are accessible.
Reductive cleavage of the chiral auxiliary from β-hy-
An important extension of the outlined protocol is the α-
drazino sulfones (R,S)-19Ϫ26 with BH3 THF[32] in re- alkylation of β-amino sulfones to generate two neigh-
fluxing THF afforded β-amino sulfones without racemiz- bouring stereogenic centres. In order to achieve this goal it
ation as shown by the de value of their corresponding was necessary to incorporate a protected β-amino sulfone
Mosher amides[33] (MTPA amides). Treatment with di-tert- that could selectively deprotonated at the α-carbon atom.
Eur. J. Org. Chem. 2000, 879Ϫ892
881

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
firmed by NOE-analysis of compounds (R,R)-47 and
(R,R)-53 (Figure 4).
Scheme 5. Asymmetric synthesis of α-alkylated β-amino sulfones
Table 5. Asymmetric synthesis of α-alkylated β-amino sulfones
(R,R)-46Ϫ53
Hydrazine R1
(R)-
R2X
Product Yield de[a][b]
ee[c]
[%]
(R,R)
[%]
[%]
41
42
42
42
43
44
44
45
Me
Et
MeI
MeI
EtI
46
47
48
91
95
97
88
93
93
88
97
70 (Ն 98) Ն 96
Ͼ97 Ն 96
Et
68 (Ͼ 97) Ն 96
64 (Ͼ 97) Ն 96
50 (Ն 96) Ն 96
90 (Ն 96) 94
Et
BnBr 49
iPr
iBu
iBu
MeI
MeI
EtI
50
51
52
53
Figure 4. NOE analyses of compounds (R,R)-47 and (R,R)-53
50 (Ն 96) 94
68 (Ն 96) Ն 96
Bom MeI
A possible transition state in the α-alkylation of N,N-di-
benzyl protected β-amino sulfones is presented in Figure 5.
If we assume a planar configuration of the carbanion after
deprotonation with LDA and a coordinative bond between
the lithium cation and the oxygen atoms of the sulfone
group and the nitrogen atom of the dibenzylamino group,
there are two possible faces from which the electrophile
(Eϩ) may approach. Owing to steric interactions between
the incoming electrophile and the substituent R, the Si-face
is hindered and the addition from the Re-face is favoured
and will therefore lead to the (R)-configuration at the newly
formed stereogenic centre. The stereochemical outcome of
the alkylation is consistent with the postulated mechanism.
[a]
Determined by GC analysis (46) and NMR spectroscopy
[b]
(47Ϫ53). Ϫ
The numbers in parentheses refer to the de value
after isolation of the major diastereomer by recrystallization
(46,48,49,51,52), HPLC (50), or column chromatography (53). Ϫ [c]
Based on the de values of the corresponding Mosher amides (NMR
spectroscopy) of the free amines assuming no overall racemization
under subsequent reaction conditions as confirmed by chiral
HPLC of compounds 47 and 49 (Chiralpak OD), 51 (Chiralcel
OD2), and 52 and 53 ((S,S)-Whelk 01).
Therefore, N,N-dibenzyl be protected β-amino sulfones (R)-
41Ϫ45 were metallated with LDA in the presence of
TMEDA and alkylated with various electrophiles
(Scheme 5, Table 5). Products (R,R)-46Ϫ53 were obtained
in excellent yields (88Ϫ97%), with medium to high diastere-
omeric and high enantiomeric excesses (de ϭ 50 to Ͼ97%,
ee ϭ 94 to Ն96%).[35]
The major diastereomer of each of the products was ob-
tained practically pure after isolation of the main epimer
by recrystallization (46,48,49,51,52), HPLC (50), or column
chromatography (53). The relative and absolute configura-
tion of the newly formed stereogenic centres of the major
diastereomers is based on the X-ray structural analysis of
crystalline (R,R)-47 (Figure 3). [27,28,29] This result was con-
Figure 5. Postulated transition states for the α-alkylation of N,N-
dibenzyl protected β-amino sulfones
Conclusion
In summary, we have synthesised a variety of virtually
diastereo- and enantiopure α-alkylated β-amino sulfones.
The described asymmetric aza-Michael addition followed
by reductive NϪN bond cleavage and subsequent α-al-
kylation opens up an efficient approach to biologically in-
Figure 3. X-ray structure of the α-alkylated β-amino sulfone
(R,R)-47
882
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
FULL PAPER
(2R,2ЈS)-2-[(2Ј-(1ЈЈ-Methoxy-1ЈЈ-methylethyl)pyrrolidin-1Ј-yl)-
amino]butyl Phenyl Sulfone (16): Prepared by method GP 1 from
(E)-1-butenyl phenyl sulfone 8 and SADP (S)-3 in the presence of
Yb(OTf)3 in THF. The β-hydrazino sulfone 16 was obtained as a
teresting and synthetically valuable N-protected α-alkylated
β-amino sulfones which can act as intermediates for the cre-
ation of acyclic and cyclic carbon frameworks with a nitro-
gen-bearing stereogenic centre. Application to the asymmet-
ric synthesis of bioactive compounds can be envisaged.
colourless oil (5.81 g, 82% yield; method A, de ϭ 68%). – [α]D20
ϭ
Ϫ13.9 (c ϭ 0.80, CHCl3). – IR (CHCl3): ν˜ ϭ 3373 (w), 3064 (w),
2973 (s), 2937 (s), 2880 (m), 2828 (m), 1715 (w), 1676 (w), 1586
(w), 1462 (s), 1448 (s), 1382 (m), 1365 (m), 1306 (s), 1237 (m), 1148
(s), 1086 (s), 999 (w), 934 (w), 875 (w), 804 (w), 752 (s), 720 (m),
690 (s) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ 0.71 (t, 3J ϭ
7.39 Hz, 3 H, CH3CH2), 1.05, 1.18 (2 s, 6 H, (CH3)2COCH3), 1.21–
2.09 (m, 6 H, CH3CH2, CHCH2CH2CH2), 2.43–2.54 (m, 1 H,
CHHN), 2.70–2.78 (dd, 3J1 ϭ 9.23 Hz, 3J2 ϭ 6.21 Hz, 1 H,
(CH3)2CCHN), 2.92 (dd, 2J ϭ 14.27 Hz, 3J ϭ 4.20 Hz, 1 H,
CHHSO2Ph), 3.05 (s, 3 H, OCH3), 3.06–3.17 (m, 2 H, CHHSO2Ph,
CHHN), 3.31–3.47 (m, 2 H, CHNH, NH), 6.88–7.01 (m, 3 H, m-,
p-Ar-H), 7.77–7.91 (m, 2 H, o-Ar-H). – 13C NMR (75 MHz, C6D6):
δ ϭ 9.54 (CH3CH2), 21.55, 22.14 [(CH3)2C], 22.90, 25.47, 26.12
(CH3CH2, CH2CH2CH), 48.89 (OCH3), 55.25 (CHNH), 58.45,
58.79 (CH2S, CH2N), 73.95 (CCHN), 77.60 (COCH3), 128.31,
129.16, 133.10 (Ar-C), 141.26 (ipso-Ar-C). – MS (EI, 70 eV): m/z
(%) ϭ 354 (0.4) [Mϩ], 336 (12), 318 (7), 295 (15), 281 (15), 279
(38), 153 (10), 143 (23), 141 (9), 139 (8), 138 (6), 137 (9), 126 (6),
125 (13), 123 (5), 122(14), 121 (8), 111 (13), 110 (8), 109 (6), 99
(18), 97 (6), 94 (5), 85 (6), 84 (7), 83 (17), 82 (5), 81 (6), 79 (5), 78
(7), 77 (37), 74 (5), 73 (100), 71 (6), 70 (14), 69 (16), 68 (7), 67 (6),
59 (5), 57 (8), 56 (10), 55 (36), 54 (5), 53 (5), 51 (11). –
C18H30N2O3S (354.514): calcd. C 60.98, H 8.53, N 7.90; found: C
61.19, H 8.67, N 7.89.
Experimental Section
General: All solvents were dried and purified prior to use. – All
reactions were carried out under an atmosphere of dry argon. –
Column Chromatography: Merck silica gel 60, 0.040–0.063 mm
(230–400 mesh). – Optical rotation values: Perkin–Elmer P 241;
solvents Merck Uvasol quality. – IR: Perkin–Elmer FT/IR 1750. –
NMR: Varian VXR 300, Gemini 300, Inova 400 and Unity 500,
TMS as internal standard. – MS: Finnigan MAT 212 and Finnigan
SSQ 7000 (70 eV). – Microanalyses: Elementar vario EL. High-
resolution MS: Finnigan MAT, MAT 95. – Melting points (uncor-
rected): Büchi 510. – THF was dried by distillation from K/benzo-
phenone under Ar. SAHP,[20] SAMP,[21] SADP,[22] SAEP,[22]
RAMBO,[23] and SADMP[24] were prepared according to the pub-
lished procedures.
General Procedure for the Synthesis of the β-Hydrazino Sulfones
(15–33, GP 1): In a typical experiment the (E)-1-alkenyl sulfone
7–14 (20 mmol) was added dropwise to a solution of ytterbium
trifluoromethanesulfonate [Yb(OTf)3] (0.62 g, 2 mmol) in THF
(40 mL) under an atmosphere of argon at room temperature and
the mixture stirred for 15 min. The corresponding nitrogen nucle-
ophile 1–6 (30 mmol) was added dropwise to the colourless to light
yellow solution, and the mixture then stirred for 20 d at room tem-
perature (method A) or heated 3 d under reflux (method B). The
solution was then poured into pentane/Et2O (2:1, 400 mL) and fil-
tered through Celite . The solvent was evaporated under reduced
pressure, and the residue purified by column chromatography or –
to provide the major diastereomer – by HPLC (SiO2, pentane/Et2O
mixtures). The air-sensitive products were isolated as colourless
oils. Compound (2R/2ЈS)-21 was recrystallized from CH2Cl2/n-hex-
ane in order to determine the absolute configuration of the new
stereogenic centre.
(2R,2ЈS)-2-[(2Ј-(1ЈЈ-Ethyl-1ЈЈ-methoxypropyl)pyrrolidin-1Ј-yl)-
amino]butyl Phenyl Sulfone (17): Prepared by method GP 1 from
(E)-1-butenyl phenyl sulfone 8 and SAEP (S)-4 in the presence of
Yb(OTf)3 in THF.
The β-hydrazino sulfone 17 was obtained as a colourless oil (5.43 g,
71% yield; method A, de ϭ 74%). – [α]2D0 ϭ Ϫ8.7 (c ϭ 1.02,
CHCl3). – IR (CHCl3): ν˜ ϭ 3389 (w), 3064 (w), 2969 (s), 2938 (s),
2879 (s), 2827 (m), 1711 (w), 1677 (w), 1626 (w), 1586 (w), 1460
(s), 1448 (s), 1381 (m), 1350 (m), 1307 (s), 1237 (m), 1148 (s), 1086
(s), 1026 (m), 999 (w), 922 (m), 881 (w), 835(w), 807 (w), 751 (s),
1
718 (m), 690 (s), 598 (s) cm–1. – H NMR (300 MHz, C6D6): δ ϭ
0.68 (t, 3J ϭ 7.39 Hz, 3 H, CH3CH2CH), 0.79–2.02 (m, 17 H,
(CH3CH2)2C, CHCH2CH2CHH, CH3CH2CH), 2.44–3.43 (m, 9 H,
CHCH2CH2CHH, CH3O, CHNH, OCCHN, CH2SO2Ph), 6.92–
7.03 (m, 3 H, m-, p-Ar-H), 7.76–7.92 (m, 2 H, o-Ar-H). – 13C NMR
(75 MHz, C6D6): δ ϭ 8.58, 8.88, 9.50 (3 ϫ CH3CH2), 23.19, 24.79,
25.22, 25.68, 27.26 (3 ϫ CH3CH2, CH2CH2CHN), 49.84 (CHNH),
55.15 (COCH3), 57.86, 58.74 (CH2S, CH2N), 72.43 (CHCCO),
79.93 (COCH3), 127.86, 129.01, 133.18 (Ar-C), 141.04 (ipso-Ar-
C). – MS (EI, 70 eV): m/z (%) ϭ 382 (1) [Mϩ], 283 (6), 282 (18),
281 (100), 279 (15), 266 (10), 143 (8), 125 (5), 111 (5), 99 (18), 97
(6), 94 (5), 85 (8), 84 (8), 83 (5), 77 (11), 70 (12), 69 (8), 68 (5), 59
(7), 57 (6), 56 (5), 55 (13), 45 (5). – C20H34N2O3S (382.568): calcd.
C 62.79, H 8.96, N 7.32; found: C 63.06, H 8.55, N 6.82.
(2R,2ЈS)-2-[(2Ј-(Hydroxymethyl)pyrrolidin-1Ј-yl)amino]-
butyl Phenyl Sulfone (15): Prepared by method GP 1 from (E)-1-
butenyl phenyl sulfone 8 and SAHP (S)-1 in the presence of
Yb(OTf)3 in THF. The β-hydrazino sulfone 15 was obtained as a
colourless oil (3.56 g, 57% yield; method A, de ϭ 51%). Ϫ [α]D20
ϭ
Ϫ93.5 (c ϭ 0.93, CHCl3). – IR (CHCl3): ν˜ ϭ 3384 (m), 3065 (w),
2965 (s), 2876 (s), 1586 (w), 1480 (m), 1461 (s), 1448 (s), 1399 (m),
1385 (m), 1305 (s), 1239 (m), 1199 (m), 1182 (m), 1148 (s), 1086
(s), 1039 (s), 1001 (m), 805, (w), 753 (m), 720 (m), 690 (s), 667 (w),
1
597 (s), 569 (s), 536 (s) cm–1. – H NMR (300 MHz, C6D6): δ ϭ
0.62 (t, 3J ϭ 7.42 Hz, 3 H, CH3CH2), 1.09–1.92 (m, 7 H, CH3CH2,
CHCH2CH2CH2, CHHN), 2.07–3.10 (m,
4
H, CHHN,
OCH2CHN, CH2SO2Ph), 3.22–4.60 (m, 5 H, CH2O, CHNH, NH,
OH), 6.96–7.13 (m, 3 H, m-, p-Ar-H), 7.75–7.92 (m, 2 H, o-Ar-
H). – 13C NMR (75 MHz, C6D6): δ ϭ 9.05 (CH3CH2), 21.03
2-[(3Ј,4Ј-Dimethoxy-2Ј,5Ј-bis(methoxymethyl)pyrrolidin-1Ј-yl)-
amino]butyl Phenyl Sulfone (18): Prepared by method GP 1 from
(CH2CH2N), 24.67 (CH3CH2), 26.03 (CH2CHCH2OH), 54.17 (E)-1-butenyl phenyl sulfone 8 and SADMP (S,R,R,S)-6 in the
(CHNH), 55.96 (CH2N), 58.04 (CH2S), 66.38 (CHCH2OH), 66.48 presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 18 was ob-
(CH2OH), 128.16, 129.31, 133.48 (Ar-C), 140.43 (ipso-Ar-C). – MS
tained as a colourless oil (3.96 g, 46% yield; method A, de ϭ
(EI, 70 eV): m/z (%) ϭ 312 (11) [Mϩ], 282 (17), 281 (100), 266 (9),
71%). – [α]2D0 ϭ Ϫ8.7 (c ϭ 1.02, CHCl3). – IR (CHCl3): ν˜ ϭ 3284
143 (8), 125 (6), 115 (51), 111 (8), 100 (3), 85 (34), 84 (11), 77 (25), (w), 3064 (w), 2978 (s), 2928 (s), 2894 (s), 2827 (s), 1586 (w), 1460
70 (25), 68 (10), 57 (8), 56 (6), 55 (11). – C15H24O3N2S (312.332): (s), 1448 (s), 1384 (m), 1364 (m), 1306 (s), 1236 (m), 1197 (s), 1149
calcd. C 57.67, H 7.74, N 8.97; found: C 57.80, H 7.76, N 8.94.
(s), 1107 (s), 1026 (m), 999 (m), 955 (m), 923 (m), 874 (w), 851 (w),
Eur. J. Org. Chem. 2000, 879Ϫ892
883

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
806 (w), 755 (s), 720 (m), 690 (s), 667 (w), 600 (m), 574 (m), 532 NMR (125 MHz, C6D6): δ ϭ 9.01 (CH3CH2), 21.30 (CH2CH2N),
(m) cm–1. – 1H NMR (500 MHz, C6D6): δ ϭ 0.75 (t, 3J ϭ 7.38 Hz, 25.97 (CH3CH2), 27.00 (CH2CHN), 54.72 (CHNH), 56.62 (CH2N),
3 H, CH3CH2), 1.45–1.63 (m, 1 H, CH3CHH), 1.71–1.88 (m, 1 H,
CH3CHH), 2.91 (dd, 2J 13.93 Hz, 3J
4.70 Hz,
CHHSO2Ph), 3.08–3.29 (m, 16 H, CHHSO2Ph, 4 ϫ CH3O,
58.54 (CH2S), 58.78 (OCH3), 65.89 (CHN), 75.61 (CH2O), 128.11,
H, 129.22, 133.26 (Ar-C), 140.82 (ipso-Ar-C). – MS (EI, 70 eV): m/z
(%) ϭ 326 (11) [Mϩ], 283 (8), 282 (16), 281 (100), 266 (5), 143 (18),
ϭ
ϭ
1
CHNH, 2 ϫ CHN), 3.44–3.79 (m, 6 H, CHOCH3, CH2OCH3), 141 (2), 139 (7), 129 (38), 111 (8), 97 (10), 85 (15), 84 (23), 83 (10),
3.87 (br. s, 1 H, NH), 6.95–7.08 (m, 3 H, m-, p-Ar-H), 7.79–7.83 77 (13), 71 (14), 70 (39), 69 (8), 68 (21), 56 (10), 55 (15). –
(m, 2 H, o-Ar-H). – 13C NMR (125 MHz, C6D6): δ ϭ 9.67 C16H26N2O3S (326.460): calcd. C 58.87, H 8.03, N 8.58; found: C
(CH3CH2), 25.19 (CH3CH2), 53.58 (CHNH), 58.45, 58.70, (4 ϫ 58.42, H 7.62, N 8.80.
OCH3), 58.84 (CHS), 61.69 (2
ϫ CHCHN), 69.22 (2 ϫ
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]-3-
methylbutyl Phenyl Sulfone (21): Prepared by method GP 1 from
(E)-3-methyl-1-butenyl phenyl sulfone 9 and SAMP (S)-2 in the
presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 21 was ob-
tained as a colourless solid [1.70 g, 25% yield; method A, de ϭ 79%
(Ն 96% after HPLC) or 3.54 g, 52% yield; method B, de ϭ 43%
(Ն 96% after HPLC)]. 21 was obtained in crystalline form after
recrystallization of the major diastereoisomer from CH2Cl2/n-hex-
ane. – M.p. 63 °C. – [α]2D0 ϭ –161.5 (c ϭ 0.27, CHCl3) – IR (CHCl3):
ν˜ ϭ 3063 (w), 2960 (s), 2930 (s), 2874 (s), 2825 (s), 1586 (w), 1461
(s), 1447 (s), 1389 (s), 1371 (m), 1305 (s), 1241 (m), 1194 (s), 1145
(s), 1087 (s), 1025 (w), 999 (m), 967 (m), 919 (m), 877 (m), 854 (m),
788 (m), 752 (s), 718 (m), 690 (s), 599 (s), 582 (s), 545 (m)
CH2OCH3), 84.79 (2 ϫ CHCHN), 129.22, 133.16 (Ar-C), 141.38
(ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 431 (5), 430 (20) [Mϩ],
387 (7), 386 (21), 385 (100), 233 (32), 143 (10), 140 (6), 125 (9), 110
(7), 101 (23), 85 (5), 77 (17), 75 (5), 71 (22), 55 (11), 45 (17). –
C20H34N2O6S (430.566): calcd. C 55.79, H 7.96, N 6.51; found: C
55.72, H 8.14, N 6.34.
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]propyl
Phenyl Sulfone (19): Prepared by method GP 1 from (E)-1-propenyl
phenyl sulfone 7 and SAMP (S)-2 in the presence of Yb(OTf)3 in
THF. The β-hydrazino sulfone 19 was obtained as a colourless oil
[5.31 g, 85% yield; method B, de ϭ 41% (Ն 98% after HPLC)]. –
Major diastereoisomer: [α]2D0 ϭ –61.1 (c ϭ 2.66, CHCl3) – IR
(CHCl3): ν˜ ϭ 3063 (w), 2969 (m), 2927 (m), 2876 (m), 2826 (m),
1
3
cm–1. – H NMR (300 MHz, C6D6): δ ϭ 0.54 [d, J ϭ 7.05 Hz, 3
1585 (w), 1479 (m), 1447 (m), 1396 (m), 1368 (m), 1305 (s), 1253 H, CH3(CH3)CH], 0.73 [d, 3J ϭ 6.72 Hz, 3 H, CH3(CH3)CH],
(m), 1197 (m), 1147 (s), 1087 (s), 1025 (w), 999 (w), 958 (w), 920 1.42–1.91 (m, 4 H, CHCH2CH2CH2), 2.25 (q, J ϭ 8.73 Hz, 1 H,
3
(w), 897 (m), 843 (m), 752 (m), 720 (m), 690 (s), 600 (m), 574 (m),
CHHNH), 2.41 [sepd, 3J1 ϭ 2.86 Hz, 3J2 ϭ 7.05 Hz, 1 H,
535 (s) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ 1.07 (d, 3J ϭ (CH3)2CH], 2.69–2.74 (m, 1 H, OCH2CHN), 2.78 (dd, 2J ϭ
6.38 Hz, 3 H, CH3CH), 1.33–1.59 (m, 4 H, CHCH2CH2CH2), 2.17 14.44 Hz, 3J ϭ 9.40 Hz, 1 H, CHHSO2Ph), 2.89 (dd, 2J ϭ
(q, 3J ϭ 8.73 Hz, 1 H, CHCH2CH2CHH), 2.61 (m, 1 H, 14.44 Hz, 3J ϭ 2.02 Hz, 1 H, CHHSO2Ph), 3.21 (s, 3 H, CH3O),
CHCH2CH2CH2), 2.76 (dd, 2J ϭ 14.10 Hz, 3J ϭ 4.37 Hz, 1 H, 3.22–3.44 (m, 1 H, CHNH), 3.65 (dd, J ϭ 9.06 Hz, 3J ϭ 3.70 Hz,
2
CHHSO2Ph), 3.09–3.54 (m, 8 H, CHCH2CH2CHH, CHHSO2Ph,
1 H, CHHO), 6.88–7.01 (m, 3 H, m-, p-Ar-H), 7.75–7.82 (m, 2 H,
CH2OCH3, CHNH), 6.90–7.07 (m, 3 H, m-, p-Ar-H), 7.78–7.81 o-Ar-H). – 13C NMR (75 MHz, C6D6): δ ϭ 15.19, 18.53 (2 ϫ CH3),
(m, 2 H, o-Ar-H). – 13C NMR (125 MHz, C6D6): δ ϭ 20.28 21.28, 26.97 (CH2CH2CHN), 27.94 [(CH3)2CH], 56.97, 56.03
(CH3CH), 21.33, 27.02 (CH2CH2CHN), 49.29 (CHNH), 56.91,
61.11 (CH2S, CH2N), 58.77 (OCH3), 65.97 (CHN), 75.72 (CH2O), (CH2O), 128.13, 129.19, 133.25 (Ar-C), 140.48 (ipso-Ar-C). – MS
128.10, 129.16, 133.16 (Ar-C), 141.03 (ipso-Ar-C). – MS (EI,
(EI, 70 eV): m/z (%) ϭ 340 (9) [Mϩ], 297 (6), 296 (17), 295 (100),
70 eV): m/z (%) ϭ 312 (11) [Mϩ], 268 (17), 267 (100), 169 (7), 141 294 (2), 155 (10), 143 (5), 130 (2), 129 (26), 125 (2), 111 (8), 97 (6),
(9), 129 (32), 125 (43), 123 (13), 97 (15), 94 (11), 85 (25), 84 (16), 85 (5), 84 (6), 71 (5), 70 (9), 69 (5), 68 (4), 55 (3), 45 (4). –
77 (19), 71 (18), 70 (18), 68 (14), 57 (10), 56 (19), 45 (18) cm–1. – C17H28N2O3S (340.487): calcd. C 59.97, H 8.29, N 8.23; found: C
(CH2S, CH2N), 58.02, 58.83 (CHNH, OCH3), 65.74 (CHN), 75.56
C15H24N2O3S (312.433): calcd. C 57.67, H 7.82, N 8.97; found: C
57.77, H 7.86, N 9.08.
60.32, H 8.59, N 8.30.
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]-
pentyl Phenyl Sulfone (22): Prepared by method GP 1 from (E)-
1-pentenyl phenyl sulfone 10 and SAMP (S)-2 in the presence of
Yb(OTf)3 in THF. The β-hydrazino sulfone 22 was obtained as a
colourless oil (1.97 g, 29% yield; method A, de ϭ 68% or 3.54 g,
52% yield; method B, de ϭ 43%). – IR (CHCl3): ν˜ ϭ 3063 (w),
2959 (s), 2930 (s), 2873 (s), 2826 (s), 1723 (w), 1586 (w), 1448 (s),
1383 (m), 1306 (s), 1241 (m), 1186 (m), 1147 (s), 1087 (s), 1000 (w),
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]-
butyl Phenyl Sulfone (20): Prepared by method GP 1 from (E)-1-
butenyl phenyl sulfone 8 and SAMP (S)-2 in the presence of
Yb(OTf)3 in THF. The β-hydrazino sulfone 20 was obtained as a
colourless oil (2.74 g, 42% yield; method A, de ϭ 64% (Ն 96% after
HPLC) or 3.79 g, 58% yield; method B, de ϭ 40% (Ն 96% after
HPLC)). – Major diastereoisomer: [α]2D0 ϭ –109.5 (c ϭ 1.00,
CHCl3) – IR (CHCl3): ν˜ ϭ 3063 (w), 2965 (m), 2930 (m), 2876 (m), 967 (m), 921 (m), 860 (m), 791 (m), 753 (s), 721 (m), 690 (s), 601
2827 (m), 1585 (w), 1459 (m), 1447 (s), 1384 (w), 1346 (w), 1305 (m), 574 (s), 535 (s) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ 0.76–
(s), 1239 (w), 1193 (m), 1148 (s), 1086 (s), 1025 (w), 999 (w), 972 1.84 (m, 11 H, CH3CH2CH2, CHCH2CH2CH2), 2.21 (q, J ϭ
(w), 921 (w), 876 (w), 804 (w), 751 (m), 719 (w), 690 (m), 597 (m), 8.72 Hz, 1 H, CHHN), 2.59–2.7 (m, 1 H, OCH2CHN), 2.90 (dd,
1
570 (m), 533 (m) cm–1. – H NMR (500 MHz, C6D6): δ ϭ 0.67 (t,
2J ϭ 11.43 Hz, 3J ϭ 3.35 Hz, 1 H, CHHSO2Ph), 3.04 (dd, 2J ϭ
11.43 Hz, J ϭ 6.22 Hz, 1 H, CHHSO2Ph), 3.18 (s, 3 H, CH3O),
3J ϭ 7.48 Hz, 3 H, CH3CH2), 1.42–1.60 (m, 4 H, CHCH2CH2CH2,
3
CH3CHH, CHCHHCH2CH2), 1.65–1.74 (m, 1 H, CH3CHH), 3.20–3.41 (m, 3 H, CHHO, CHHN, CHNH), 3.58 (dd, 2J ϭ
1.76–1.83 (m, 1 H, CHCHHCH2CH2), 2.19–2.24 (m, 1 H, CHHN),
2.62 (m, 1 H, OCH2CHN), 2.92 (dd, 2J ϭ 14.34 Hz, 3J ϭ 3.05 Hz, H), 7.77–7.84 (m, 2 H, o-Ar-H). – 13C NMR (125 MHz, C6D6):
1 H, CHHSO2Ph), 3.05 (dd, 2J ϭ 14.34 Hz, 3J ϭ 8.24 Hz, 1 H,
14.23 (CH3CH2), 18.26 (CH3CH2), 21.31, 26.96
8.73 Hz, 3J ϭ 4.03 Hz, 1 H, CHHO), 6.89–7.02 (m, 3 H, m-, p-Ar-
δ
ϭ
CHHSO2Ph), 3.09 (br. s, 1 H, NH), 3.18 (s, 3 H, CH3O), 3.23–3.29 (CH2CH2CHN), 35.57 (CH3CH2CH2), 53.48 (CHNH), 56.71,
2
(m, 2 H, CHHN, CHHO), 3.34 (m, 1 H, CHNH), 3.57 (dd, J ϭ 59.02 (CH2S, CH2N), 56.96 (CHN), 58.77 (OCH3), 75.52 (CH2O),
3
9.16 Hz, J ϭ 3.97 Hz, 1 H, CHHO), 6.97–701 (m, 2 H, m-Ar-H), 128.36, 129.17, 133.18 (Ar-C), 140.90 (ipso-Ar-C). – MS (EI,
7.01–7.05 (m, 1 H, p-Ar-H), 7.79–7.81 (m, 2 H, o-Ar-H). – 13C 70 eV): m/z (%) ϭ 340 (8) [Mϩ], 297 (7), 296 (19), 295 (100), 143
884
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
FULL PAPER
(9), 129 (31), 125 (7), 111 (6), 97 (8), 85 (7), 84 (11), 83 (5), 77 (15), (2R,2ЈS)-2-Cyclohexyl-2-[(2Ј-(methoxymethyl)pyrrolidin-1Ј-
71 (11), 70 (13), 69 (7), 68 (6), 55 (8), 45 (8). – C17H28N2O3S
yl)amino]ethyl Phenyl Sulfone (25): Prepared by method GP 1 from
(340.487): calcd. C 59.97, H 8.29, N 8.23; found: C 59.84, H 8.42, (E)-2-cyclohexyl-1-ethenyl phenyl sulfone 13 and SAMP (S)-2 in
N 8.23.
the presence of Yb(OTf)3 in THF. Theβ-hydrazino sulfone 25 was
obtained as a colourless oil [0.46 g, 6% yield; method A, de ϭ 61%
(Ն 96% after HPLC) or 2.66 g, 35% yield; method B, de ϭ 50%
(Ն 96% after HPLC)]. – Major diastereoisomer: [α]2D0 ϭ –134.1 (c ϭ
0.29, CHCl3) – IR (CHCl3): ν˜ ϭ 3065 (w), 2925 (s), 2852 (s), 2669
(w), 1586 (w), 1498 (m), 1448 (s), 1385 (m), 1344 (m), 1307 (m),
1249 (m), 1230 (m), 1198 (m), 1181 (m), 1150 (s), 1117 (s), 1087
(s), 1025 (w), 999 (w), 957 (m), 937 (m), 923 (m), 890 (m), 840 (w),
806 (m), 788 (m), 754 (s), 723 (m), 690 (s), 666 (m), 633 (m), 567
(m), 543 (m) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ 0.94–2.15
(m, 15 H, (CH2)5CH, NCHCH2CH2CH2), 2.27 (q, J ϭ 8.73 Hz, 1
H, CHHN), 2.64–2.74 (m, 1 H, OCH2CHN), 2.87 (dd, 2J ϭ
14.44 Hz, 3J ϭ 9.74 Hz, 1 H, CHHSO2Ph), 3.01 (dd, 2J ϭ
14.44 Hz, 3J ϭ 1.34 Hz, 1 H, CHHSO2Ph), 3.22 (s, 3 H, CH3O),
3.23–3.46 (m, 3 H, CHHO, CHHN, CHN), 3.60 (dd, 2J ϭ 9.07 Hz,
3J ϭ 3.69 Hz, 1 H, CHHO), 6.99–7.11 (m, 3 H, m-, p-Ar-H), 7.81–
7.85 (m, 2 H, o-Ar-H). – 13C NMR (125 MHz, C6D6): δ ϭ 21.31,
26.46, 26.66, 26.79, 27.09, 29.64, 32.50 [(CH2)5CH,
CH2CH2CHN)], 38.73 [(CH2)5CH)], 56.06, 56.08 (CH2S, CH2N),
57.82, 58.86 (CHNH, OCH3), 65.79 (CHN), 75.34 (CH2O), 128.03,
129.26, 133.38 (Ar-C), 140.43 (ipso-Ar-C). – MS (EI, 70 eV): m/z
(%) ϭ 380 (11) [Mϩ], 337 (7), 336 (20), 335 (100), 155 (11), 129
(40), 111 (10), 109 (6), 97 (9), 85 (9), 84 (6), 83 (6), 77 (7), 71 (8),
70 (13), 68 (5), 67 (7), 55 (11), 45 (6). – C20H32N2O3S (380.450):
calcd. C 63.12, H 8.48, N 7.36; found: C 63.22, H 8.47, N 7.67.
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]-4-
methylpentyl Phenyl Sulfone (23): Prepared by method GP 1 from
(E)-4-methyl-1-pentenyl phenyl sulfone 11 and SAMP (S)-2 in the
presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 23 was ob-
tained as a colourless oil [2.41 g, 34% yield; method A, de ϭ 54%
(93% after HPLC) or 4.11 g, 58% yield; method B, de ϭ 44% (93%
after HPLC)]. – Major diastereoisomer: [α]2D0 ϭ –99.2 (c ϭ 1.09,
CHCl3) – IR (CHCl3): ν˜ ϭ 3064 (m), 2956 (s), 2930 (s), 2872 (s),
2827 (s), 1586 (w), 1467 (s), 1448 (s), 1386 (m), 1367 (m), 1306 (s),
1261 (m), 1234 (m), 1183 (s), 1147 (s), 1099 (s), 1087 (s), 1025 (m),
999 (m), 957 (m), 920 (m), 854 (m), 784 (m), 752 (s), 721 (m), 690
(s), 602 (s), 575 (s), 535 (s) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ
0.71 [d, 3J ϭ 6.38 Hz, 3 H, CH3(CH3)CH], 0.86 [d, 3J ϭ 6.38 Hz, 3
H, CH3(CH3)CH], 1.20–1.85 (m,
7
H, (CH3)2CHCH2,
CHCH2CH2CH2), 2.25 (q, J ϭ 8.40 Hz, 1 H, CHHN), 2.60 (m, 1
H, OCH2CH), 2.95 (dd, 2J ϭ 14.44 Hz, 3J ϭ 3.36 Hz, 1 H,
CHHSO2Ph), 3.12 (dd, 2J ϭ 14.43 Hz, 3J ϭ 6.71 Hz, 1 H,
CHHSO2Ph), 3.18 (s, 3 H, CH3O), 3.19–3.46 (m, 3 H, CHNH,
CHHO, CHHN), 3.56 (dd, 2J ϭ 9.06 Hz, 3J ϭ 4.03 Hz, 1 H,
CHHO), 6.91–7.03 (m, 3 H, m-, p-Ar-H), 7.79–7.84 (m, 2 H, o-Ar-
H).
– δ ϭ 21.38, 26.98
13C NMR (125 MHz, C6D6):
(CH2CH2CHN), 22.22, 23.40, 24.86 [(CH3)2CH], 42.90
[(CH3)2CHCH2], 52.04 (CHNH), 56.93, 59.41 (CH2S, CH2N),
58.78 (OCH3), 66.05 (CHN), 75.48 (CH2O), 128.19, 129.17, 133,19
(Ar-C), 140.85 (ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 354 (11)
[Mϩ], 311 (6), 310 (17), 309 (100), 129 (44), 111 (8), 97 (12), 85 (8),
84 (10), 83 (8), 77 (16), 71 (9), 70 (17), 68 (7), 55 (8), 45 (10). –
C18H30N2O3S (354.512): calcd. C 60.98, H 8.53, N 7.90; found: C
60.90, H 8.55, N 7.89.
(2R,2ЈS)-3-Benzyloxy-2-[(2Ј-(methoxymethyl)pyrrolidin-1Ј-
yl)amino]propyl Phenyl Sulfone (26): Prepared by method GP 1
from (E)-3-benzyloxy-1-propenyl phenyl sulfone 14 and SAMP (S)-
2 in the presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 26
was obtained as a colourless oil [2.68 g, 32% yield; method A, de ϭ
36% (Ն 96% after HPLC) or 5.44 g, 65% yield; method B, de ϭ
30% (Ն 96% after HPLC)]. – Major diastereoisomer: [α]2D0 ϭ –90.4
(c ϭ 0.72, CHCl3) – IR (CHCl3): ν˜ ϭ 3063 (m), 3029 (m), 2969 (s),
2922 (s), 2873 (s), 1586 (w), 1495 (m), 1449 (s), 1399 (m), 1364 (m),
1305 (s), 1260 (m), 1237 (m), 1188 (s), 1147 (s), 1088 (s), 1027 (m),
1001 (m), 919 (m), 848 (m), 791 (m), 752 (s), 723 (m), 692 (s), 600
(m), 575 (s), 531 (m) cm–1. – 1H NMR (300 MHz, C6D6): δ ϭ 1.36–
1.82 (m, 4 H, CHCH2CH2CH2), 2.22 (q, J ϭ 8.39 Hz, 1 H,
CHHN), 2.58–2.67 (m, 1 H, CH3OCH2CHN), 3.15 (s, 3 H, CH3O),
3.17–3.79 (m, 8 H, OCH2CHCH2, CH2OCH3, CHCH2SO2Ph,
CHHN), 4.22 (s, 2 H, PhCH2O), 6.83–7.78 (m, 10 H, Ar-H). – 13C
NMR (125 MHz, C6D6): δ ϭ 21.32, 26.76 (CH2CH2CHN), 53.94
(CHNH), 56.74, 57.17 (CH2S, CH2N), 58.76 (CHN), 65.89
(OCH3), 71.44, 73.23 (CH2OCH2), 75.14 (CH2OCH3), 127.72,
128.04, 128.12, 128.37, 129.13, 133.10 (Ar-C), 138.80, 140.85 (ipso-
Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 418 (16) [Mϩ], 375 (7), 374
(20), 373 (100), 155 (12), 129 (15), 111 (8), 97 (5), 91 (31), 85 (15),
84 (7), 77 (5), 71 (5), 70 (7). – C22H30N2O4S (418.557): calcd. C
63.13, H 7.22, N 6.69; found: C 63.10, H 7.61, N 7.07.
(2R,2ЈS)-2-[(2Ј-(Methoxymethyl)pyrrolidin-1Ј-yl)amino]-
hexyl Phenyl Sulfone (24): Prepared by method GP 1 from (E)-1-
hexenyl phenyl sulfone 12 and SAMP (S)-2 in the presence of
Yb(OTf)3 in THF. The β-hydrazino sulfone 24 was obtained as a
colourless oil (2.20 g, 31% yield; method A, de ϭ 52% (86% after
HPLC) or 4.25 g, 60% yield; method B, de ϭ 40% (86% after
HPLC)). – Major diastereoisomer: [α]2D0 ϭ –99.7 (c ϭ 0.60,
CHCl3) – IR (CHCl3): ν˜ ϭ 3064 (m), 2957 (s), 2929 (s), 2873 (s),
2826 (s), 2280 (w), 1586 (m), 1479 (s), 1462 (s), 1448 (s), 1381 (s),
1305 (s), 1244 (s), 1185 (s), 1142 (s), 1087 (s), 1025 (m), 999 (m),
971 (m), 918 (s), 894 (m), 843 (s), 813 (m), 782 (m), 753 (s), 720
(m), 690 (s), 603 (s), 578 (s), 543 (s), 503 (s) cm–1. – 1H NMR
(300 MHz, C6D6): δ ϭ 0.82 (t, 3J ϭ 7.39 Hz, 3 H, CH3CH2), 0.85–
1.86 (m, 10 H, CH3CH2CH2CH2, NHCHCH2CH2CH2), 2.24 (q,
J ϭ 8.40 Hz, 1 H, CHHN), 2.62–2.71 (m, 1 H, OCH2CHN), 2.92
(dd, 2J ϭ 14.44 Hz, 3J ϭ 3.19 Hz, 1 H, CHHSO2Ph), 3.08 (dd,
2J ϭ 14.44 Hz, 3J ϭ 8.22 Hz, 1 H, CHHSO2Ph), 3.19 (s, 3 H,
CH3O), 3.20–3.46 (m, 3 H, CHNH, CHHO, CHHN), 3.58 (dd,
2J ϭ 9.06 Hz, J ϭ 4.03 Hz, 1 H, CHHO), 7.77–7.81 (m, 3 H, m-,
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
3
p-Ar-H), 7.88–7.93 (m, 2 H, o-Ar-H). – 13C NMR (125 MHz, 2Ј-yl)amino]butyl Phenyl Sulfone (27): Prepared by method GP 1
C6D6): δ ϭ 14.23 (CH3CH2), 21.32, 23.09, 26.94, 27.14, 33.14
(CH3CH2CH2CH2, CH2CH2CHN), 53.60 (CHNH), 56.70, 59.03 presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 27 was ob-
(CH2S, CH2N), 58.78 (OCH3), 65.94 (CHN), 75.53 (CH2O), tained as a colourless oil [3.37 g, 46% yield; method A, de ϭ 82%
from (E)-1-butenyl phenyl sulfone 8 and RAMBO (R,R,R)-5 in the
127.72, 128.36, 133.17 (Ar-C), 142.22 (ipso-Ar-C). – MS (EI, (Ն 96% after HPLC)]. – Major diastereoisomer: IR (CHCl3): ν˜ ϭ
70 eV): m/z (%) ϭ 354 (9) [Mϩ], 311 (6), 309 (100), 143 (5), 129 3256 (w), 3064 (w), 2939 (s), 2863 (s), 1586 (w), 1479 (m), 1460 (s),
(10), 125 (3), 111 (5), 97 (7), 85 (5), 84 (7), 77 (7), 70 (8), 55 (6). – 1447 (s), 1399 (m), 1382 (w), 1348 (w), 1306 (s), 1236 (m), 1196
C18H30N2O3S (354.512): calcd. C 60.98, H 8.53, N 7.90; found: C
60.81, H 8.57, N 7.75.
(m), 1149 (s), 1116 (s), 1087 (s) 1025 (w), 999 (w), 974 (m), 931
(m), 909 (m), 846 (w), 804 (w), 753 (s), 720 (m), 690 (s), 668 (w),
Eur. J. Org. Chem. 2000, 879Ϫ892
885

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
599 (s), 575 (s), 542 (m), 531 (s) cm–1. – 1H NMR (300 MHz, CHHSO2Ph), 3.02–3.08 (m, 1 H, CH2CHCHN), 3.16 (s, 3 H,
2
C6D6): δ ϭ 0.68 (t, 3J ϭ 7.39 Hz, 3 H, CH3CH2), 0.99–2.06 (m, CH3O), 3.17 (dd, J ϭ 14.34 Hz, 3J ϭ 7.33 Hz, 1 H, CHHSO2Ph),
10 H, CH2CH2CH2, CH3CH2, CHCH2CHN), 2.21–2.35 (m, 1 H,
3.19 (dd, 2J ϭ 8.85 Hz, 3J ϭ 6.26 Hz, 1 H, CHHO), 3.50 (dd, 2J ϭ
CHCHN), 2.61–2.76 (m, 1 H, OCH2CHN), 2.90–2.99 (dd, 2J ϭ 8.85 Hz, 3J ϭ 4.58 Hz, 1 H, CHHO), 3.53–3.58 (m, 1 H,
14.60 Hz, 3J ϭ 3.86 Hz, 1 H, CHHSO2Ph), 3.00–3.53 (m, 9 H, CHCH2SO2Ph), 6.94–7.02 (m, 3 H, m-, p-Ar-H), 7.83–7.90 (m, 2
CH2OCH3, NH, CHNH, CHHSO2Ph/CH2CH2CH2CHN), 6.94– H, o-Ar-H). – 13C NMR (125 MHz, C6D6): δ ϭ 14.26 (CH3CH2),
7.13 (m, 3 H, m-, p-Ar-H), 7.82–7.90 (m, 2 H, o-Ar-H). – 13C NMR 18.29 (CH3CH2), 24.54 (CH2CH2CHN), 33.25, 34.52, 34.92, 35.65
(75 MHz, C6D6): δ ϭ 9.08 (CH3CH2), 24.56 (CH2CH2CH), 25.32 (CH3CH2CH2, CH2CH2CH2CHCH2), 39.27 (CHCHN), 52.91
(CH3CH2), 33.22, 34.62, 35.66 (CH2CH2CH2CHCH2), 39.34 (CHNH), 58.72 (OCH3), 59.35 (CH2S), 68.47 (CH2CHN), 75.62
(CHCHN), 54.33 (CH3CH2), 58.74 (OCH3), 58.93 (CH2S), 68.43,
75.74 (CHCH2O), 75.80 (CHCHN), 128.19, 129.23, 133.29 (Ar-C), (ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 380 (12) [Mϩ], 337 (7),
140.84 (ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 366 (8) [Mϩ], 322
336 (24), 335 (100), 169 (51), 143 (7), 137 (13), 125 (15), 124 (17),
(CH2O), 75.78 (CHCHN), 127.78, 127.97, 133.13 (Ar-C), 140.82
(21), 321 (100), 179 (8), 169 (36), 125 (47), 111 (29), 109 (23), 97 123 (13), 110 (19), 109 (15), 108 (34), 95 (15), 85 (15), 83 (14), 82
(38), 95 (30), 85 (24), 83 (32), 81 (34), 77 (23), 71 (40), 69 (41), 67 (13), 81 (31), 79 (13), 78 (11), 77 (52), 74 (27), 71 (21), 70 (17), 69
(36), 57 (64), 55 (62) 45 (9). – C19H30N2O3S (366.525): calcd. C
62.26, H 8.25, N 7.64; found: C 62.07, H 7.98, N 8.13.
(27), 68 (10), 67 (58), 65 (10), 59 (51), 57 (36), 55 (32). –
C20H32N2O3S (380.552): calcd. C 63.12, H 8.48, N 7.36; found: C
63.56, H 8.62, N 7.83.
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]-3-methylbutyl Phenyl Sulfone (28): Prepared by
method GP 1 from (E)-3-methyl-1-butenyl phenyl sulfone 9 and
RAMBO (R,R,R)-5 in the presence of Yb(OTf)3 in THF. The β-
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]-4-methylpentyl Phenyl Sulfone (30): Prepared by
method GP 1 from (E)-3-methyl-1-pentenyl phenyl sulfone 11 and
hydrazino sulfone 28 was obtained as a colourless oil (1.60 g, 21% RAMBO (R,R,R)-5 in the presence of Yb(OTf)3 in THF. The β-
yield; method A, de Ն 96%). – IR (CHCl3): ν˜ ϭ 3388 (w), 3064
(w), 2954 (s), 2863 (s), 1586 (w), 1460 (s), 1448 (s), 1350 (m), 1305
(s), 1237 (m), 1199 (m), 1144 (s), 1115 (s), 1087 (s) 1025 (w), 996
hydrazino sulfone 30 was obtained as a colourless oil [2.53 g, 32%
yield; method A, de ϭ 90% (Ն 96% after HPLC)]. – Major diaster-
eoisomer: IR (CHCl3): ν˜ ϭ 3265 (w), 3062 (w), 2948 (s), 2864 (s),
(w), 963 (m), 942 (m), 905 (m), 842 (w), 752 (s), 718 (m), 690 (s), 1585 (w), 1469 (s), 1448 (s), 1403 (w), 1383 (w), 1361 (w), 1303 (s),
668 (w), 599 (s), 568 (m), 542 (m), 533 (m) cm–1. – 1H NMR 1237 (m), 1188 (m), 1141 (s), 1107 (s), 1089 (s) 1027 (w), 997 (w),
3
(500 MHz, C6D6): δ ϭ 0.55 [d, J ϭ 7.14 Hz, 3 H, CH3(CH3)CH], 948 (m), 896 (m), 850 (m), 810 (m), 753 (s), 689 (s), 577 (s), 541
1
0.79 [d, 3J ϭ 6.87 Hz, 3 H, CH3(CH3)CH], 1.12–1.85 [m, 8 H,
(s), 499 (s), 479 (s) cm–1. – H NMR (500 MHz, C6D6): δ ϭ 0.70
(CH3)2CH, CH2CH2CH2, CHCHHCH], 2.07 (ddd, 2J ϭ 12.09 Hz, (t, J ϭ 6.71 Hz, 3 H, CH3(CH3)CH), 0.85 (t, J ϭ 6.41 Hz, 3 H,
3J1 ϭ 9.07 Hz, 3J2 ϭ 5.49 Hz, 1 H, CHCHHCH), 2.29–2.54 (m,
CH3(CH3)CH), 1.08–1.44 (m, 7 H, NCHCHHCHHCH2CHCHH,
2 H, OCH2CHN, CH2CHCHN), 2.73–2.97 (m, 3 H, CH2SO2Ph, (CH3)2CHCHH), 1.50–1.72 (m, 1 H, CH2CHHCH2), 1.76–1.85 (m,
3
3
2
3
CH2CHCHN), 3.21 (s, 3 H, CH3O), 3.31 (dd, J ϭ 8.79 Hz, J ϭ
2 H, NCHCHHCH2CH2, (CH3)2CHCHH), 2.01–2.07 (m, 1 H,
3
3
6.87 Hz, 1 H, CHHO), 3.52 (dt, J1 ϭ 14.83 Hz, J2 ϭ 2.47 Hz, 1 NCHCHCHH), 2.24–2.32 (m, 1 H, CH2CHCHN), 2.66–2.73 (m,
H, CHCH2SO2Ph), 3.65 (dd, 2J ϭ 8.79 Hz, 3J ϭ 3.58 Hz, 1 H, 1 H, OCH2CHN), 2.95 (dd, 2J ϭ 14.65 Hz, 3J ϭ 3.52 Hz, 1 H,
CHHO), 6.95–7.06 (m, 3 H, m-, p-Ar-H), 7.79–7.88 (m, 2 H, o-Ar- CHHSO2Ph), 3.03–3.11 (m, 1 H, CH2CHCHN), 3.12–3.17 (m, 1
H). – 13C NMR (75 MHz, C6D6): δ ϭ 15.24, 18.40 (2 ϫ CH3), H, CHHSO2Ph), 3.18 (s, 3 H, CH3O), 3.21 (dd, 2J ϭ 8.85 Hz, 3J ϭ
24.87 (CH2CH2CH), 26.76 [(CH3)2CH], 32.82, 35.58, 35.68
6.41 Hz, 1 H, CHHO), 3.53–3.60 (m, 2 H, CHHO, CHCH2SO2Ph),
(CH2CH2CH2CHCH2), 40.19 (CHCHN), 55.41 (CH2S), 57.29, 3.70 (br. s, 1 H, NH), 6.95–7.03 (m, 3 H, m-, p-Ar-H), 7.82–7.86
58.84 (CHNH, OCH3), 68.27 (CH2CHN), 75.73 (CH2O), 75.99 (m, 2 H, o-Ar-H). – 13C NMR (125 MHz, C6D6): δ ϭ 22.20, 23.72
(CHCHN), 128.04, 129.23, 135.35 (Ar-C), 140.40 (ipso-Ar-C). – (2
ϫ CH3), 24.53 (CH2CH2CH), 24.79 [(CH3)2CH], 33.30
MS (EI, 70 eV): m/z (%) ϭ 380 (9) [Mϩ], 337 (6), 336 (17), 335 (CH2CHCH2CHN), 34.46 (CH2CH2CHN), 35.72 (CHCH2CHN),
(81), 195 (5), 169 (24), 151 (7), 143 (7), 125 (54), 123 (7), 110 (11),
97 (8), 83 (10), 81 (14), 80 (11), 79 (13), 78 (16), 77 (52), 71 (15),
39.31 (CHCHN), 42.44 [(CH3)2CHCH2], 51.46 (CHNH), 58.77
(OCH3), 59.72 (CH2S), 68.53 (CHCH2O), 75.57 (CH2O), 75.97
70 (16), 69 (100), 68 (17), 67 (50), 65 (10), 51 (34), 45 (38). – (CHCHN), 128.31, 129.25, 133.29 (Ar-C), 140.78 (ipso-Ar-C). –
C20H32N2O3S (380.552): calcd. C 63.12, H 8.48, N 7.36; found: C MS (EI, 70 eV): m/z (%) ϭ 394 (11) [Mϩ], 351 (7), 350 (23), 349
62.67, H 8.42, N 7.23.
(100), 169 (41), 137 (5), 125 (7), 108 (5), 83 (6), 81 (9), 79 (8), 78
(5), 77 (15), 71 (7), 67 (18), 57 (6), 55 (10). – C21H34N2O3S
(394.579): calcd. C 63.92, H 8.69, N 7.10; found: C 63.65, H 8.70,
N 7.37.
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]pentyl Phenyl Sulfone (29): Prepared method GP 1 from
(E)-1-pentenyl phenyl sulfone 10 and RAMBO (R,R,R)-5 in the
presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 29 was ob-
tained as a colourless oil [3.04 g, 40% yield; method A, de ϭ 86%
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]hexyl Phenyl Sulfone (31): Prepared by method GP 1
(Ն 96% after HPLC)]. – Major diastereoisomer: IR (CHCl3): ν˜ ϭ from (E)-1-hexenyl phenyl sulfone 12 and RAMBO (R,R,R)-5 in
3386 (w), 3064 (w), 2956 (s), 2866 (s), 1727 (w), 1586 (w), 1460 (s), the presence of Yb(OTf)3 in THF. The β-hydrazino sulfone 31 was
1447 (s), 1380 (w), 1350 (w), 1307 (s), 1235 (m), 1195 (m), 1145 (s),
obtained as a colourless oil [3.55 g, 45% yield; method A, de ϭ
1116 (s), 1087 (s) 1024 (w), 999 (w), 950 (m), 932 (m), 902 (m), 875 86% (Ն 96% after HPLC)]. – Major diastereoisomer: IR (CHCl3):
(w), 861 (w), 790 (m), 753 (s), 721 (m), 690 (s), 625 (m), 600 (s), ν˜ ϭ 3376 (w), 3064 (w), 2954 (s), 2862 (s), 1722 (w), 1586 (w), 1447
1
575 (s), 532 (s) cm–1. – H NMR (500 MHz, C6D6): δ ϭ 0.78 (d, (s), 1384 (w), 1350 (m), 1306 (s), 1237 (m), 1197 (m), 1148 (s), 1117
3J ϭ 7.32 Hz, 3 H, CH3CH2), 0.97–1.81 (m, 11 H, CH3CH2CH2, (s), 1087 (s) 1025 (w), 999 (w), 949 (m), 929 (m), 876 (w), 842 (w),
CH2CH2CH2, CHCHHCH), 2.01 (ddd, 2J ϭ 14.95 Hz, 3J1
9.46 Hz, 3J2 ϭ 5.49 Hz, 1 H, CHCHHCH), 2.27 (quind, 3J1
ϭ
807 (m), 753 (s), 721 (m), 690 (s), 668 (m), 601 (s), 575 (s), 531 (s)
1
3
ϭ
cm–1. – H NMR (300 MHz, C6D6): δ ϭ 0.82 (d, J ϭ 7.39 Hz, 3
9.85 Hz, 3J2 ϭ 2.44 Hz, 1 H, CH2CHCHN), 2.66–2.72 (m, 1 H, H, CH3CH2), 0.95–1.86 (m, 13 H, CH3CH2CH2CH2,
OCH2CHN), 2.94 (dd, 2J ϭ 14.04 Hz, 3J ϭ 4.07 Hz, 1 H,
CH2CH2CH2CHN, CHCHHCH), 2.01 (ddd, J ϭ 14.78 Hz, 3J1 ϭ
2
886
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
9.40 Hz, 3J2 ϭ 5.38 Hz, 1 H, CHCHHCH), 2.28 (quind, 3J1
FULL PAPER
ϭ
H, CH3O), 3.15 (dd, 2J ϭ 9.07 Hz, 3J ϭ 6.38 Hz, 1 H, CHHOCH3),
8.73 Hz, 3J2 ϭ 2.29 Hz, 1 H, CH2CHCHN), 2.67–2.73 (m, 1 H, 3.25 (dd, 2J ϭ 14.44 Hz, 3J ϭ 7.72 Hz, 1 H, CHHSO2Ph), 3.41 (dd,
OCH2CHN), 2.98 (dd, 2J ϭ 14.44 Hz, 3J ϭ 4.37 Hz, 1 H,
CHHSO2Ph), 3.02–3.09 (m, 1 H, CH2CHCHN), 3.15–3.39 (m, 5
2J ϭ 14.44 Hz, J ϭ 4.03 Hz, 1 H, CHHSO2Ph), 3.45–3.52 (m, 2
3
H, CHHOCH3, CHCHHOCH2), 3.72 (dd, 2J ϭ 9.73 Hz, 3J ϭ
H, CH3O, CHHSO2Ph, CHHO), 3.49 (dd, 2J ϭ 9.06 Hz, 3J ϭ 5.03 Hz, 1 H, CHCHHOCH2), 3.85–3.94 (m, 1 H, CHCH2SO2Ph),
2
2
4.70 Hz, 1 H, CHHO), 3.50–3.59 (m, 1 H, CHCH2SO2Ph), 6.97–
4.22 (d, J ϭ 11.75 Hz, 1 H, CHHPh), 4.29 (d, J ϭ 12.08 Hz, 1
7.09 (m, 3 H, m- p-Ar-H), 7.81–7.87 (m, 2 H, o-Ar-H). – 13C NMR H, CHHPh), 6.92–7.26 (m, 8 H, CH2-Ar-H, SO2-m-, p-Ar-H),
(75 MHz, C6D6): δ ϭ 14.21 (CH3CH2), 23.03 (CH3CH2), 24.51
(CH2CH2CH2CHN), 27.19 (CH3CH2CH2), 33.25, 34.51, 35.63,
7.81–7.88 (m, 2 H, SO2-o-Ar-H). – 13C NMR (125 MHz, C6D6):
δ
ϭ
24.54 (CH2CH2CH), 33.98, 34.54, 35.48
35.65 (CH3CH2CH2CH2, CH2CH2CH2CHCH2), 39.25 (CHCHN), (CH2CH2CH2CHCH2), 39.25 (CHCHN), 53.88 (CHNH), 57.49
53.09 (CHNH), 58.72 (OCH3), 59.37 (CH2S), 68.46 (CHCH2O), (CH2S), 58.74 (OCH3), 68.34 (NCHCH2O), 71.04 (NHCHCH2O),
75.64 (CH2O), 75.78 (CHCHN), 127.69, 129.21, 133.25 (Ar-C), 73.06 (PhCH2O), 75.18 (OCH2), 75.81 (CHCHN), 127.69, 127.80,
140.82 (ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 394 (12) [Mϩ], 128.50, 128.57, 129.20, 133.26 (Ar-C), 138.76, 140.58 (ipso-Ar-C). –
349 (100), 169 (37), 151 (5), 125 (6), 110 (5), 81 (6), 77 (9), 67 (10),
55 (6). – C21H34N2O3S (394.579): calcd. C 63.92, H 8.69, N 7.10;
found: C 63.92, H 8.74, N 7.25.
MS (EI, 70 eV): m/z (%) ϭ 458 (39) [Mϩ], 415 (27), 414 (65), 413
(100), 195 (21), 170 (6), 169 (48), 125 (17), 110 (8), 92 (8), 91 (67),
79 (12), 77 (12), 71 (9), 67 (20), 45 (7). – C25H34N2O4S (458.622):
calcd. C 65.47, H 7.47, N 6.11; found: C 65.31, H 7.48, N 6.61.
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]-2-cyclohexylethyl Phenyl Sulfone (32): Prepared by
method GP 1 from (E)-2-cyclohexyl-1-ethenyl phenyl sulfone 13
and RAMBO (R,R,R)-5 in the presence of Yb(OTf)3 in THF. The
β-hydrazino sulfone 32 was obtained as a colourless oil (2.44 g,
29% yield; method A, de ϭ 94%). – IR (CHCl3): ν˜ ϭ 3375 (w),
3064 (w), 2927 (m), 2855 (s), 1728 (w), 1586 (w), 1448 (s), 1385 (w),
1348 (m), 1307 (s), 1248 (m), 1233 (m), 1198 (m), 1148 (s), 1120
(s), 1088 (s) 1025 (w), 999 (w), 955 (w), 931 (w), 909 (m), 888 (w),
840 (w), 804 (w), 754 (s), 723 (m), 690 (s), 667 (w), 631 (m), 567
General Procedure for the Synthesis of N-Protected β-Amino Sul-
fones (34–45) by Reductive N–N Bond Cleavage with BH3 THF and
Subsequent N-Protection of the Free Amine (GP 2): In a typical
experiment the β-hydrazino sulfone 19–26 (10 mmol) was dissolved
in THF (50 mL) under an atmosphere of argon. BH3 THF[32]
(100 mL, 1.0  in THF) was added, and the reaction mixture
heated under reflux for 5 h. The solution was cooled to room tem-
perature, hydrochloric acid (30 mL, 4.0 ) slowly (!) added and
the solution stirred for 2 h at room temperature. The solvent was
evaporated under reduced pressure, and the residue treated with
saturated aqueous Na2CO3 solution. The aqueous phase was ex-
tracted with CH2Cl2/Et2O (3:1), and the combined organic layer
washed with brine. The organic phase was dried with Na2SO4 and
the solvent evaporated in vacuo to yield a colourless oil. Without
further purification, the crude β-amino sulfone was treated with
Boc2O or benzyl bromide.
1
(m), 543 (s), 533 (s), 457 (w) cm–1. – H NMR (300 MHz, C6D6):
δ ϭ 0.37–2.44 [m, 21 H, (CH2)5CHCH, CH2CH2CH2, CHCH2CH,
2
CH2CHCHNNH], 2.75–2.86 (m, 1 H, OCH2CHN), 2.91 (dd, J ϭ
14.56 Hz, 3J ϭ 8.79 Hz, 1 H, CHHSO2Ph), 2.99 (dd, 2J ϭ
14.56 Hz, 3J ϭ 2.47 Hz, 1 H, CHHSO2Ph), 3.22 (s, 3 H, CH3O),
3.36 (dd, 2J ϭ 8.79 Hz, 3J ϭ 6.87 Hz, 1 H, CHHO), 3.52 (dt, 3J1 ϭ
8.79 Hz, 3J2 ϭ 2.47 Hz, 1 H, CHCH2SO2Ph), 3.64 (dd, 2J ϭ
8.79 Hz, 3J ϭ 3.85 Hz, 1 H, CHHO), 6.92–7.07 (m, 3 H, m-, p-Ar-
H), 7.79–7.87 (m, 2 H, o-aryl-H). – 13C NMR (75 MHz, C6D6):
Conversion to the N-Boc-Protected β-Amino Sulfone: The crude β-
amino sulfone was dissolved in methanol (300 mL) and Boc2O
(100 mmol) and triethyl amine (3 mL) added at 0 °C. The reaction
mixture was stirred for 2 d at room temperature. The solvent was
evaporated under reduced pressure, and the residue diluted with
Et2O. The mixture was washed with saturated aqueous NH4Cl so-
lution and then brine, dried with MgSO4 and concentrated under
reduced pressure. After purification by column chromatography
(SiO2, pentane/Et2O-mixtures), the products 34–40 were obtained
as colourless oils.
δ
ϭ 24.94, 26.61, 26.67, 26.88, 27.08 [(CH2)5CH], 29.42
(CH2CH2CHN), 32.89, 35.53, 35.68 (CH2CH2CH2CHCH2CH),
37.70, 40.14 [(CH2)5CH, CHCHN], 56.57 (CH2S), 57.19, 58.90
(CHNH, OCH3), 68.57 (CHCH2O), 75.64 (CH2O), 76.05
(CHCHN), 128.05, 128.24, 133.29 (Ar-C), 140.59 (ipso-Ar-C). –
MS (EI, 70 eV): m/z (%) ϭ 420 (3) [Mϩ], 376 (5), 170 (6), 169 (16),
126 (9), 125 (98), 110 (14), 109 (84), 108 (21), 93 (15), 91 (33), 81
(17), 80 (12), 79 (29), 78 (12), 77 (35), 68 (11), 67 (100), 65 (13), 59
(18), 57 (20), 55 (31), 53 (14), 51 (19), 45 (9). – C23H36N2O3S
(420.617): calcd. C 65.68, H 8.63, N 6.66; found: C 65.78, H 8.50,
N 6.84.
Conversion to the N,N-Dibenzyl-Protected β-Amino Sulfone: The
crude β-amino sulfone was dissolved in a mixture of CH2Cl2/H2O
(4:1, 100 mL) and solid Na2CO3 (60 mmol) and benzyl bromide
(30 mmol) added at room temperature. The reaction mixture was
heated under reflux for 1Ϫ3 d (monitored by TLC). The organic
layer was separated, the aqueous phase extracted twice with
CH2Cl2, and the combined organic phases washed with a saturated
aqueous Na2CO3 solution and then brine. The organic solution was
dried with MgSO4, the solvent evaporated, and the products puri-
fied by chromatography (SiO2, pentane/Et2O mixtures) to yield
compounds 41Ϫ45 as colourless solids.
(2S,2ЈR,4ЈR,5ЈR)-2-[(2Ј-Aza-3Ј-methoxymethylbicyclo[3.3.0]octan-
2Ј-yl)amino]-3-benzyloxypropyl Phenyl Sulfone (33): Prepared by
method GP 1 from (E)-3-benzyloxy-1-propenyl phenyl sulfone 14
and RAMBO (R,R,R)-5 in the presence of Yb(OTf)3 in THF. The
β-hydrazino sulfone 33 was obtained as a colourless oil (2.66 g,
29% yield; method A, de ϭ 90%). – IR (CHCl3): ν˜ ϭ 3529 (w),
3261 (w), 3087 (w), 3063 (w), 3030 (w), 2938 (m), 2863 (s), 1586
(w), 1496 (m), 1478 (m), 1448 (s), 1397 (w), 1364 (w), 1343 (m),
1306 (s), 1235 (m), 1198 (m), 1148 (s), 1118 (s), 1086 (s) 1028 (w),
1000 (w), 975 (w), 950 (w), 929 (w), 902 (m), 880 (w), 819 (w), 792 (R)-2-(tert-Butoxycarbonylamino)butyl Phenyl Sulfone (34): Pre-
(w), 752 (s), 723 (m), 698 (s), 690 (s), 668 (w), 647 (w), 601(s), 574 pared by method GP 2 by cleavage of hydrazine 20 with BH3 THF
(s), 546 (m), 532 (s) cm–1. – 1H NMR (500 MHz, C6D6): δ ϭ 1.04– and subsequent protection of the resulting crude amine with
1.82 (m, 7 H, CH2CH2CH2, CHCHHCH), 2.00 (ddd, 2J ϭ Boc2O. Compound 34 was obtained as a colourless solid (1.88 g,
3
3
12.09 Hz, J1 ϭ 9.40 Hz, J2 ϭ 5.37 Hz, 1 H, CHCHHCH), 2.24 60%, 2 steps). – M.p. 107 °C. – [α]2D0 ϭ –2.1 (c ϭ 0.78, CHCl3) –
(quind, 3J1 ϭ 8.39 Hz, 3J2 ϭ 2.35 Hz, 1 H, CH2CHCHN), 2.61– IR (KBr) ν˜ ϭ 3386 (s), 3062 (w), 3011 (m), 2965 (m), 2932 (m),
2.68 (m, 1 H, OCH2CHN), 3.06 (m, 1 H, CH2CHCHN), 3.14 (s, 3 2875 (m), 1689 (s), 1654 (w), 1586 (w), 1520 (s), 1482 (w), 1453
Eur. J. Org. Chem. 2000, 879Ϫ892
887

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
(m), 1391 (m), 1367 (m), 1318 (m), 1297 (s), 1251 (s), 1285 (s), 1242 with Boc2O. Compound 37 was obtained as a colourless solid
(s), 1170 (s), 1151 (s), 1112 (m), 1082 (s), 1052 (m), 1029 (w), 1015
(2.49 g, 73%, 2 steps). – M.p. 89 °C. – [α]2D0 ϭ ϩ7.1 (c ϭ 1.25,
(w), 987 (m), 933 (w), 747 (m), 694 (m), 621 (m), 573 (s), 548 (m), CHCl3) – IR (KBr): ν˜ ϭ 3387 (s), 3067 (w), 2974 (s), 2962 (s), 2928
530 (s) cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 0.91 (t, 3J ϭ
(s), 2898 (s), 2872 (s), 1689 (s), 1586 (m), 1516 (s), 1451 (s), 1402
7.39 Hz, 3 H, CH3CH2), 1.41 [s, 9 H, C(CH3)3], 1.64–181 (m, 2 H, (s), 1391 (s), 1366 (s), 1326 (s), 1304 (s), 1291 (s), 1246 (s), 1230 (s),
CH3CH2), 3.25 (dd, 2J
ϭ
14.44 Hz, 3J
ϭ
4.37 Hz,
1
H,
1169 (s), 1144 (s), 1110 (m), 1085 (s), 1046 (m), 1024 (s), 999 (m),
CHHSO2Ph), 3.45 (dd, 2J ϭ 14.44 Hz, 3J ϭ 7.05 Hz, 1 H, 938 (w), 922 (w), 878 (m), 862 (m), 846 (w), 781 (s), 754 (s), 693
1
CHHSO2Ph), 3.80–3.92 (m, 1 H, CHNH), 4.92 (br. s, 1 H, NH),
(s), 622 (m), 592 (s), 552 (s), 530 (s) cm–1. – H NMR (300 MHz,
7.54–7.67 (m, 3 H, m-, p-Ar-H), 7.01–7.94 (m, 2 H, o-Ar-H). – 13C CDCl3): δ ϭ 0.88 [d, J ϭ 6.05 Hz, 6 H, (CH3)2CH], 1.40 [s, 9 H,
3
NMR (75 MHz, CDCl3): δ ϭ 10.26 (CH3CH2), 27.52 (CH3CH2),
C(CH3)3], 1.45–1.75 [m, 3 H, (CH3)2CHCH2], 3.26 (dd, 2J ϭ
28.33 [(CH3)3C], 48.72 (CHNH), 59.16 (CH2S), 79.57 [(CH3)3C], 14.10 Hz, 3J ϭ 3.36 Hz, 1 H, CHHSO2Ph), 3.38–3.52 (m, 1 H,
127.89, 129.35, 133.76 (Ar-C), 140.01 (ipso-Ar-C), 155.03
CHHSO2Ph), 3.94–4.08 (m, 1 H, CHNH), 4.88 (br. s, 1 H, NH),
(NHCO). – MS (CI, isobutane): m/z (%) ϭ 314 (17) [Mϩϩ1], 260 7.54–7.69 (m, 3 H, m-, p-Ar-H), 7.91–7.97 (m, 2 H, o-Ar-H). –
(5), 259 (12), 258 (100), 214 (15). – C15H23NO4S (313.418): calcd. 13C NMR (75 MHz, CDCl3): δ ϭ 21.87, 22.73 [(CH3)2CH], 24.78
C 57.48, H 7.40, N 4.47; found: C 57.45, H 7.31, N 4.28.
[(CH3)2CH], 28.32 [(CH3)3C], 43.23 [(CH3)2CHCH2], 45.68
(CHNH), 59.69 (CH2S), 79.56 [(CH3)3C], 127.86, 129.33, 133.73
(Ar-C), 140.15 (ipso-Ar-C), 154.90 (NHCO). – MS (CI, isobutane):
m/z (%) ϭ 342 (19) [Mϩϩ1], 288 (6), 287 (15), 286 (100), 242 (23),
146 (4), 143 (6). – C17H27NO4S (341.472): calcd. C 59.80, H 7.97,
N 4.10; found: C 59.60, H 8.21, N 3.95.
(R)-2-(tert-Butoxycarbonylamino)-3-methylbutyl Phenyl Sulfone
(35): Prepared by method GP 2 by cleavage of hydrazine 21 with
BH3 T HF and subsequent protection of the resulting crude amine
with Boc2O. Compound 35 was obtained as a colourless solid
(1.38 g, 42%, 2 steps). – M.p. 94 °C. – [α]2D0 ϭ –12.9 (c ϭ 0.31,
CHCl3) – IR (KBr): ν˜ ϭ 3389 (s), 3070 (w), 2971 (s), 2931 (s), 2875
(m), 1585 (m), 1516 (s), 1452 (s), 1390 (s), 1369 (s), 1310 (s), 1297
(s), 1247 (s), 1169 (s), 1147 (s), 1105 (m), 1083 (s), 1041 (m), 1018
(s), 998 (m), 957 (w), 938 (w), 876 (m), 844 (w), 783 (m), 754 (s),
695 (s), 621 (m), 574 (s), 527 (s) cm–1. – 1H NMR (300 MHz,
(R)-2-(tert-Butoxycarbonylamino)hexyl Phenyl Sulfone (38): Pre-
pared by method GP 2 by cleavage of hydrazine 24 with BH3 THF
and subsequent protection of the resulting crude amine with
Boc2O. Compound 38 was obtained as a colourless solid (1.84 g,
54%, 2 steps). – M.p. 101 °C. – [α]2D0 ϭ ϩ10.3 (c ϭ 0.88, CHCl3) –
IR (KBr): ν˜ ϭ 3387 (s), 3065 (m), 2980 (s), 2957 (s), 2934 (s), 2870
(m), 1692 (s), 1519 (s), 1482 (m), 1449 (s), 1390 (s), 1366 (s), 1293
(s), 1251 (s), 1172 (s), 1149 (s), 1103 (m), 1086 (s), 1037 (m), 1022
(s), 933 (w), 874 (m), 785 (s), 747 (s), 690 (s), 622 (m), 575 (s), 530
(s) cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 0.86 (t, 3J ϭ 6.72 Hz,
3 H, CH3CH2), 1.23–1.35 (m, 4 H, CH3CH2CH2), 1.41 [s, 9 H,
C(CH3)3], 1.60–1.78 (m, 2 H, CH3CH2CH2CH2), 3.24 (dd, 2J ϭ
14.44 Hz, 3J ϭ 4.54 Hz, 1 H, CHHSO2Ph), 3.44 (dd, 2J ϭ
14.44 Hz, 3J ϭ 5.54 Hz, 1 H, CHHSO2Ph), 3.85–3.99 (m, 1 H,
CHNH), 4.90 (br. s, 1 H, NH), 7.53–7.68 (m, 3 H, m-, p-Ar-H),
7.91–7.95 (m, 2 H, o-Ar-H). – 13C NMR (75 MHz, CDCl3): δ ϭ
13.92 (CH3CH2), 22.24 (CH3CH2), 27.98 (CH3CH2CH2), 28.33
[(CH3)3C], 34.08 (CH3CH2CH2CH2), 47.39 (CHNH), 59.46
(CH2S), 81.41 [(CH3)3C], 127.88, 129.34, 133.74 (Ar-C), 140.11
(ipso-Ar-C), 154.97 (NHCO). – MS (EI, 70 eV): m/z (%) ϭ 341
(0.2) [Mϩ], 285 (17), 242 (5), 228 (5), 186 (5), 185 (10), 184 (100),
157 (5), 144 (9), 143 (20), 141 (7), 130 (5), 125 (6), 100 (5), 99 (12),
93 (5), 86 (15), 83 (6), 77 (16), 58 (9), 57 (83), 55 (8). – C17H27NO4S
(341.472): calcd. C 59.80, H 7.97, N 4.10; found: C 59.67, H 8.33,
N 4.00.
3
CDCl3): δ ϭ 0.88 [2 d, J ϭ 6.72 Hz, 6 H, C(CH3)2CH], 1.42 [s, 9
H, C(CH3)3], 1.92–2.10 [m, 1 H, (CH3)2CH], 3.22–3.40 (m, 2 H,
CH2SO2Ph), 3.65–3.88 (m, 1 H, CHNH), 4.75 (br. s, 1 H, NH),
7.54–7.70 (m, 3 H, m-, p-Ar-H), 7.89–7.94 (m, 2 H, o-Ar-H). –
13C NMR (75 MHz, CDCl3): δ ϭ 17.95, 18.86 [(CH3)2CH], 28.34
[(CH3)3C], 31.92 [(CH3)2CH], 52.13 (CHNH), 57.58 (CH2S), 79.40
[(CH3)3C], 128.06, 129.33, 133.77 (Ar-C), 138.20 (ipso-Ar-C),
155.16 (NHCO). – MS (CI, isobutane): m/z (%) ϭ 328 (14)
[Mϩϩ1], 272 (100), 254 (12), 228 (48), 143 (6), 132 (13), 131 (6). –
C16H25NO4S (327.445): calcd. C 58.69, H 7.70, N 4.28; found: C
58.87, H 7.53, N 4.03.
(R)-2-(tert-Butoxycarbonylamino)pentyl Phenyl Sulfone (36): Pre-
pared by method GP 2 by cleavage of hydrazine 22 with BH3 THF
and subsequent protection of the resulting crude amine with
Boc2O. Compound 34 was obtained as a colourless solid (2.69 g,
82%, 2 steps). – M.p. 98 °C. – IR (KBr): ν˜ ϭ 3384 (s), 2976 (m),
2932 (m), 2871 (w), 1689 (s), 1519 (s), 1450 (m), 1391 (m), 1365
(m), 1304 (s), 1289 (s), 1264 (m), 1230 (m), 1169 (s), 1150 (s), 1085
(m), 1053 (w), 1013 (m), 879 (w), 854 (w), 785 (m), 756 (m), 743
1
(m), 690 (m), 611 (w), 587 (m), 548 (m), 530 (m) cm–1. – H NMR
(400 MHz, CDCl3): δ ϭ 0.89 (t, 3J ϭ 7.29 Hz, 3 H, CH3CH2),
1.21–1.50 (m, 2 H, CH3CH2), 1.40 [s, 9 H, C(CH3)3], 1.62–1.76 (m,
(R)-2-(tert-Butoxycarbonylamino)-2-cyclohexylethyl Phenyl Sulfone
(39): Prepared by method GP 2 by cleavage of hydrazine 25 with
BH3 THF and subsequent protection of the resulting crude amine
with Boc2O. Compound 39 was obtained as a colourless solid
(2.13 g, 58%, 2 steps). – M.p. 135 °C. – [α]2D0 ϭ –8.1 (c ϭ 0.16,
CHCl3) – IR (KBr): ν˜ ϭ 3363 (s), 3063 (m), 2979 (s), 2931 (s), 2851
(s), 1689 (s), 1587 (m), 1525 (s), 1478 (m), 1449 (s), 1386 (s), 1368
(s), 1347 (s), 1308 (s), 1247 (s), 1171 (s), 1149 (s), 1122 (s), 1085 (s),
1055 (m), 1039 (m), 1018 (s), 962 (m), 936 (w), 893 (w), 873 (m),
845 (w), 807 (w), 779 (m), 743 (s), 720 (m), 691 (s), 641 (w) cm–1. –
1H NMR (300 MHz, CDCl3): δ ϭ 0.86–1.78 [kB, 20 H, (CH2)5CH,
C(CH3)3], 3.20–3.42 (m, 2 H, CH2SO2Ph), 3.70–3.88 (m, 1 H,
CHNH), 7.51–7.69 (m, 3 H, m-, p-Ar-H), 7.85–7.94 (m, 2 H, o-Ar-
H). – 13C NMR (75 MHz, CDCl3): δ ϭ 25.85, 26.12, 29.56
[(CH2)5CH], 28.37 [(CH3)3C], 41.39 [(CH2)5CH], 51.80 (CHNH),
2
3
2 H, CH3CH2CH2), 3.26 (dd, J ϭ 14.29 Hz, J ϭ 3.85 Hz, 1 H,
CHHSO2Ph), 3.38–3.48 (m, 1 H, CHHSO2Ph), 3.89–3.99 (m, 1 H,
CHNH), 4.88 (br. s 1 H, NH), 7.54–7.68 (m, 3 H, m-, p-Ar-H),
7.90–7.97 (m, 2 H, o-Ar-H). – 13C NMR (100 MHz, CDCl3): δ ϭ
13.62 (CH3CH2), 19.13 (CH3CH2), 28.34 [(CH3)3C], 36.43
(CH3CH2CH2), 47.21 (CHNH), 59.43 (CH2S), 79.64 [(CH3)3C],
127.88, 129.35, 133.75 (Ar-C), 140.14 (ipso-Ar-C), 154.97
(NHCO). – MS (EI, 70 eV): m/z (%) ϭ 327 (1) [Mϩ], 284 (14), 271
(10), 228 (13), 186 (6), 185 (15), 184 (100), 143 (18), 141 (6), 130
(5), 129 (6), 125 (5), 77 (12), 72 (10), 69 (6), 58 (7), 57 (60). –
C16H25NO4S (327.445): calcd. C 58.69, H 7.70, N 4.28; found: C
58.61, H 7.63, N 4.16.
(R)-2-(tert-Butoxycarbonylamino)-4-methylpentyl Phenyl Sulfone
(37): Prepared by method GP 2 by cleavage of hydrazine 23 with 57.52 (CH2S), 80.05 [(CH3)3C], 128.04, 129.34, 133.75 (Ar-C),
BH3 THF and subsequent protection of the resulting crude amine
888
140.00 (ipso-Ar-C), 155.10 (NHCO). – MS (CI, isobutane): m/z
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
FULL PAPER
(%) ϭ 368 (50) [Mϩϩ1], 314 (6), 313 (15), 312 (100), 228 (27), 172
CHHSO2Ph), 3.67 (d, 2J ϭ 13.74 Hz, 2 H, CHHPh), 7.18–7.85 (m,
(53), 143 (11), 113 (8), 112 (7), 99 (5). – C19H29NO4S (367.510): 15 H, Ar-H). – 13C NMR (75 MHz, CDCl3): δ ϭ 11.30 (CH3CH2),
calcd. C 62.10, H 7.95, N 3.81; found: C 61.81, H 8.60, N 3.60.
25.60 (CH3CH2), 53.32 (NCH2), 54.90 (CHN), 56.05 (CH2S),
127.02, 128.02, 128.19, 128.92, 129.32, 129.34 (Ar-C), 138.95,
139.84 (ipso-Ar-C). – MS (CI, isobutane): m/z (%) ϭ 394 (100)
[Mϩϩ1], 304 (4), 254 (2), 162 (2). – C24H27NO2S (393.550): calcd.
C 73.25, H 6.92, N 3.56; found: C 72.83, H 6.98, N 3.41.
(R)-3-Benzyloxy-2-(tert-Butoxycarbonylamino)propyl Phenyl Sul-
fone (40): Prepared by method GP 2 by cleavage of hydrazine 26
with BH3 THF and subsequent protection of the resulting crude
amine with Boc2O. Compound 40 was obtained as a colourless
solid (3.33 g, 82%, 2 steps). – M.p. 97 °C. – [α]2D0 ϭ –9.7 (c ϭ 0.57,
(R)-2-Dibenzylamino-3-methylbutyl Phenyl Sulfone (43): Prepared
CHCl3) – IR (KBr): ν˜ ϭ 3384 (s), 3062 (m), 2979 (s), 2918 (s), 2868 by method GP 2 by cleavage of hydrazine 21 with BH3 THF and
(m), 2761 (w), 1685 (m), 1585 (m), 1522 (s), 1473 (m), 1449 (s), subsequent protection of the resulting crude amine with benzyl
1392 (s), 1366 (s), 1327 (s), 1294 (s), 1285 (s), 1248 (s), 1206 (m), bromide. Compound 43 was obtained as a colourless solid (1.75 g,
1172 (s), 1151 (s), 1120 (m), 1084 (s), 1053 (s), 1027 (s), 999 (m), 43%, 2 steps). – M.p. 112 °C. – [α]2D0 ϭ ϩ31.0 (c ϭ 1.05, CHCl3) –
965 (m), 938 (w), 868 (m), 850 (m), 789 (s), 752 (s), 732 (s), 694 (s),
IR (CHCl3): ν˜ ϭ 3085 (w), 3062 (m), 3028 (m), 2961 (m), 2931 (m),
640 (s), 608 (m), 583 (m), 558 (s), 530 (s) cm–1. – 1H NMR 2873 (m), 2839 (w), 2803 (w), 1585 (w), 1494 (m), 1466 (m), 1447
3
(300 MHz, CDCl3): δ ϭ 1.40 [s, 9 H, C(CH3)3], 3.45 (br. d, J ϭ (s), 1402 (w), 1386 (m), 1364 (m), 1307 (s), 1255 (m), 1205 (m),
2
3
6.05 Hz, 2 H, CH2SO2Ph), 3.56 (dd, J ϭ 9.34 Hz, J ϭ 4.95 Hz,
1150 (s), 1087 (s), 1070 (m), 1028 (m), 999 (m), 974 (m), 924 (w),
1 H, OCHHCH), 3.69 (dd, 2J ϭ 9.34 Hz, 3J ϭ 3.71 Hz, 1 H, 690 (s), 668 (w), 647 (w), 632 (w), 614 (w), 588 (s), 572 (m), 558
OCHHCH), 4.11–4.23 (m, 1 H, CHNH), 4.46 (s, 2 H, PhCH2O), (m), 523 (w), 486 (w), 465 (w) cm–1. – 1H NMR (400 MHz, CDCl3):
5.05–5.25 (br. s, 1 H, CHNH), 7.22–7.96 (m, 10 H, Ar-H). – 13C
δ ϭ 0.78 (d, 3J ϭ 6.87 Hz, 3 H, CH3(CH3)CH), 0.95 [d, 3J ϭ
NMR (75 MHz, CDCl3): δ ϭ 28.89 [(CH3)3C], 46.52 (CHNH), 6.60 Hz, 3 H, CH3(CH3)CH], 1.81–1.93 [m, 1 H, (CH3)2CH], 3.08–
57.13 (CH2S), 71.60, 73.90 (CH2OCH2), 80.30 [(CH3)3C], 128.36, 3.15 (m, 2 H, CH2SO2Ph), 3.43–3.50 (m, 1 H, CHN), 3.47 (d, 2J ϭ
128.50, 128.56, 129.07, 129.28, 129.94, 134.41, 138.19 (Ar-C), 13.47 Hz, 2 H, CHHPh), 3.69 (d, 2J ϭ 13.47 Hz, 2 H, CHHPh),
155.30 (NHCO). – MS (CI, isobutane): m/z (%) ϭ 406 (31) 7.20–7.88 (m, 15 H, Ar-H). – 13C NMR (100 MHz, CDCl3): δ ϭ
[Mϩϩ1], 352 (6), 351 (18), 350 (100), 307 (6), 306 (33), 266 (5), 210
19.91, 20.09 [(CH3)2CH], 31.59 [(CH3)2CH], 54.65 (NCH2), 54.79
(9), 143 (15). – C21H27NO5S (405.515): calcd. C 62.20, H 6.71, N (CH2S), 58.34 (CHN), 127.00, 127.88, 128.16, 129.19, 129.32,
3.45; found: C 62.07, H 6.83, N 3.23.
133.52 (Ar-C), 139.21, 140.38 (ipso-Ar-C). – MS (EI, 70 eV): m/z
(%) ϭ 407 (1) [Mϩ], 367 (2), 366 (8), 365 (17), 364 (100), 252 (2),
238 (2), 223 (2), 222 (3), 181 (9), 132 (8), 129 (2), 105 (3), 104 (2),
92 (6), 91 (70), 78 (2), 77 (5), 65 (5), 51 (2). – C25H29NO2S
(407.575): calcd. C 73.67, H 7.12, N 3.44; found: C 73.43, H 7.34,
N 3.34.
(R)-2-Dibenzylaminopropyl Phenyl Sulfone (41): Prepared by
method GP 2 by cleavage of hydrazine 19 with BH3 THF and
subsequent protection of the resulting crude amine with benzyl
bromide. Compound 41 was obtained as a colourless oil (1.52 g,
40%, 2 steps). – [α]2D0 ϭ –10.5 (c ϭ 2.16, CHCl3) – IR (CHCl3): ν˜ ϭ
3400 (m), 3085 (m), 3062 (m), 3029 (m), 3004 (m), 2971 (m), 2923
(R)-2-Dibenzylamino-4-methylpentyl Phenyl Sulfone (44): Prepared
(m), 2876 (m), 2806 (m), 1954 (w), 1877 (w), 1812 (w), 1603 (w), by method GP 2 by cleavage of hydrazine 23 with BH3 THF and
1586 (w), 1495 (s), 1453 (s), 1400 (m), 1375 (m), 1305 (s), 1260 (m), subsequent protection of the resulting crude amine with benzyl
1207 (m), 1149 (s), 1084 (s), 1024 (s), 911 (w), 841 (w), 797 (w), bromide. Compound 42 was obtained as a colourless oil (3.12 g,
746 (s), 699 (s), 625 (m), 595 (m), 587 (m), 570 (s), 545 (m),
74%, 2 steps). – [α]2D0 ϭ ϩ22.9 (c ϭ 4.97, CHCl3) – IR (KBr): ν˜ ϭ
1
3
cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 1.30 (d, J ϭ 6.59 Hz, 3085 (w), 3063 (m), 3029 (m), 2952 (s), 2922 (s), 2867 (m), 2838
3 H, CH3), 3.07 (dd, 2J ϭ 13.73 Hz, 3J ϭ 9.06 Hz, 1 H, (m), 2812 (m), 1603 (w), 1586 (w), 1495 (m), 1468 (m), 1447 (s),
2
CHHSO2Ph), 3.23–3.34 (m, 1 H, CHN), 3.39 (d, J ϭ 14.01 Hz, 2 1407 (m), 1384 (m), 1384 (m), 1364 (m), 1323 (s), 1303 (s), 1276
H, CHHPh), 3.47 (dd, 2J ϭ 13.73 Hz, 3J ϭ 2.74 Hz, 1 H,
CHHSO2Ph), 3.56 (d, 2J ϭ 14.01 Hz, 2 H, CHHPh), 7.16–7.80 (kB,
(m), 1247 (m), 1208 (w), 1189 (m), 1147 (s), 1117 (m), 1085 (s),
1075 (m), 1047 (w), 1028 (m), 986 (m), 959 (m), 921 (w), 907 (w),
15 H, Ar-H). – 13C NMR (75 MHz, CDCl3): δ ϭ 16.49 (CH3CH), 854 (m), 828 (w), 802 (w), 783 (m), 747 (s), 732 (s), 719 (s), 699 (s),
48.88 (CH3CH), 53.50 (NCH2), 59.34 (CH2S), 126.99, 127.03, 687 (s) cm–1. – 1H NMR (400 MHz, CDCl3): δ ϭ 0.36 [d, 3J ϭ
128.28, 128.53, 129.23, 133.49 (Ar-C), 139.00, 139.52 (ipso-Ar-C). –
MS (EI, 70 eV): m/z (%) ϭ 379 (2) [Mϩ], 364 (9), 288 (18), 225 CH3(CH3)CH], 1.24–1.32 [m, 1 H, (CH3)2CHCHH], 1.57–1.65 [m,
6.60 Hz, 3 H, CH3(CH3)CH], 0.79 [d, 3J ϭ 6.60 Hz, 3 H,
(17), 224 (100), 181 (15), 146 (10), 105 (6), 91 (85). – C23H25NO2S:
calcd. 379.1606; found 379.1606 (HRMS).
1 H, (CH3)2CHCHH], 1.77–1.88 [m, 1 H, (CH3)2CH], 2.93 (dd,
3
2J ϭ 14.02 Hz, J ϭ 8.52 Hz, 1 H, CHHSO2Ph), 3.11–3.17 (m, 1
2
2
H, CHN), 3.17 (d, J ϭ 13.47 Hz, 2 H, CHHPh), 3.51 (dd, J ϭ
14.02 Hz, 3J ϭ 2.20 Hz, 1 H, CHHSO2Ph), 3.65 (d, 2J ϭ 13.47 Hz,
2 H, CHHPh), 7.16–7.84 (m, 15 H, Ar-H). – 13C NMR (100 MHz,
CDCl3): δ ϭ 20.79, 23.62 [(CH3)2CH], 24.00 [(CH3)2CH], 41.69
[(CH3)2CHCH2] 50.93 (CHN), 53.31 (NCH2), 55.84 (CH2S),
127.04, 127.97, 128.06, 129.12, 129.36 (Ar-H), 139.00, 139.62 (ipso-
Ar-H). – MS (EI, 70 eV): m/z (%) ϭ 421 (3) [Mϩ], 366 (7), 365
(21), 364 (82), 330 (16), 267 (11), 266 (53), 196 (6), 121 (12), 132
(9), 106 (6), 92 (9), 91 (100), 77 (5), 65 (5), 57 (3). – C26H31NO2S
(421.604): calcd. C 74.07, H 7.41, N 3.32; found: C 73.86, H 7.361,
N 3.33.
(R)-2-Dibenzylaminobutyl Phenyl Sulfone (42): Prepared by method
GP 2 by cleavage of hydrazine 20 with BH3 THF and subsequent
protection of the resulting crude amine with benzyl bromide. Com-
pound 42 was obtained as a colourless solid (3.07 g, 78%, 2 steps). –
M.p. 124 °C. – [α]2D0 ϭ ϩ40.3 (c ϭ 2.16, CHCl3) – IR (KBr): ν˜ ϭ
2972 (s), 2949 (w), 2923 (s), 2866 (w), 2832 (w), 1958 (w), 1809 (w),
1602 (s), 1494 (s), 1448 (w), 1401 (w), 1380 (s), 1359 (s), 1316 (w),
1301 (s), 1249 (w), 1199 (s), 1146 (s), 1083 (s), 1028 (s), 985 (w),
965 (w), 953 (w), 928 (w), 907 (w), 856 (w), 836 (s), 791 (s), 745 (s),
727 (w), 698 (s), 687 (w), 622 (s), 589 (s), 566 (s), 548 (m), 526 (w),
495 (w), 468 (m) cm–1. – 1H NMR (300 MHz, CDCl3): δ ϭ 0.88
(t, 3J ϭ 7.00 Hz, 3 H, CH3CH2), 1.52–1.78 (m, 2 H, CH3CH2),
(R)-2-Dibenzylamino-3-benzyloxypropyl Phenyl Sulfone (45): Pre-
2.96 (dd, 2J ϭ 13.54 Hz, 3J ϭ 8.24 Hz, 1 H, CHHSO2Ph), 3.02– pared by method GP 2 by cleavage of hydrazine 26 with BH3 THF
3.11 (m, 1 H, CHCH2SO2Ph), 3.22 (d, 2J ϭ 13.74 Hz, 2 H,
CHHPh), 3.49 (dd, 2J 13.54 Hz, 3J
2.20 Hz,
and subsequent protection of the resulting crude amine with benzyl
H, bromide. Compound 45 was obtained as a colourless solid (2.96 g,
ϭ
ϭ
1
Eur. J. Org. Chem. 2000, 879Ϫ892
889

D. Enders, S. F. Müller, G. Raabe, J. Runsink
FULL PAPER
61%, 2 steps). – [α]2D0 ϭ Ϫ30.2 (c ϭ 1.39, CHCl3) – IR (film): ν˜ ϭ
2933 (w), 2873 (w), 2801 (w), 2732 (w), 2605 (w), 2336 (w), 1952
3753 (w), 3524 (w), 3394 (w), 3167 (w), 3086 (m), 3062 (s), 3029 (w), 1899 (w), 1814 (w), 1729 (w), 1601 (s), 1494 (s), 1448 (s), 1361
(s), 3005 (m), 2925 (s), 2860 (s), 2806 (m), 2721 (w), 1603 (m), 1586 (w), 1304 (s), 1240 (m), 1218 (w), 1146 (s), 1102 (w), 1085 (s), 1027
(m), 1545 (w), 1495 (s), 1448 (s), 1364 (s), 1306 (s), 1254 (m), 1205
(s), 1001 (s), 962 (s), 912 (s), 867 (s), 848 (m), 825 (w), 750 (s), 699
(m), 1150 (s), 1105 (s), 1087 (s), 1074 (s), 1028 (s), 1001 (m), 974 (s), 668 (s), 625 (s), 594 (w), 572 (s), 551 (s), 522 (s), 487 (w), 464
(m), 910 (m), 860 (m), 798 (m), 748 (s), 720 (s), 699 (s), 672 (w), (w) cm–1. – 1H NMR (500 MHz, CDCl3): δ ϭ 0.89 (t, 3J ϭ 7.17 Hz,
1
622 (m), 588 (m) cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 3.33– 3 H, CH3CH2), 1.24–1.38 (m, 1 H, CH3CHH), 1.35 (d, 3J ϭ
3.78 (m, 5 H, CH2CHCH2SO2Ph), 3.52 (d, 2J ϭ 14.29 Hz, 2 H,
7.33 Hz, 3 H, CH3CH), 1.54–1.66 (m, 1 H, CH3CHH), 3.29 (d,
CHHPh), 3.74 (d, 2J ϭ 13.74 Hz, 2 H, CHHPh), 4.39 (s, 2 H, 2J ϭ 13.42 Hz, 2 H, CHHPh), 3.38 (dd, 3J1 ϭ 11.60 Hz, 3J2
ϭ
CH2O), 7.15–7.79 (20 H, Ar-H). – 13C NMR (75 MHz, CDCl3): 2.75 Hz, 1 H, CHCHSO2Ph), 3.52 (q, 3J ϭ 7.32 Hz, 1 H,
δ ϭ 52.88 (CHN), 54.04 (CH2S), 54.73 (NCH2), 70.57, 73.09 CHSO2Ph), 3.79 (d, J ϭ 13.42 Hz, 1 H, CHHPh), 7.17–7.24 (m,
2
(CH2OCH2), 127.00, 127.56, 127.59, 127.83, 128.34, 128.53, 128.74,
2 H, CH2-p-Ar-H), 7.24–7.31 (m, 8 H, CH2-m-Ar-H, CH2-o-Ar-
H), 7.46–7.52 (m, 2 H, SO2-m-Ar-H), 7.57–7.62 (m, 1 H, SO2-p-
129.22, 133.48 (Ar-C), 138.07, 139.23, 139.67 (ipso-Ar-C). – MS
(CI, isobutane): m/z (%) ϭ 487 (31) [Mϩϩ1], 486 (100) [Mϩ], 419 Ar-H), 7.76–7.80 (m, 2 H, SO2-o-Ar-H). – 13C NMR (125 MHz,
(3), 396 (3), 364 (6), 346 (36), 332 (6), 291 (4), 254 (11), 198 (10),
CDCl3): δ ϭ 11.52 (CH3CH2), 11.58 (CH3CH), 20.76 (CH3CH2),
143 (16), 107 (11). – C22H22NO2S (Mϩ Ϫ C8H9O): calcd. 364.1371; 53.38 (NCH2), 56.43 (CHN), 58.10 (CHS), 126.87, 128.00, 128.63,
found 364.1370 (HRMS).
128.88, 128.98, 133.48 (Ar-C), 137.73, 139.25 (ipso-Ar-C). – MS
(CI, isobutane): m/z (%) ϭ 408 (100) [Mϩϩ1], 268 (6), 266 (6), 238
(4). – C25H29NO2S (407.577): calcd. C 73.67, H 7.17, N 3.44;
found: C 73.47, H 7.09, N 3.40.
General Procedure for the Synthesis of N,N-Dibenzyl-Protected α-
Alkylated β-Amino Sulfones (46–53, GP 3): In a typical experiment
the N,N-dibenzyl-protected β-amino sulfone 41Ϫ45 (5 mmol) was
dissolved in THF (25 mL) and added dropwise to a solution of
LDA (6.5 mmol) in THF (10 mL) at –78 °C under an atmosphere
of argon. Tetramethylethylendiamine (TMEDA) (6.5 mmol) was
added, and the reaction mixture stirred at –78 °C for 4 h. The cor-
responding electrophile (7.0 mmol, MeI: 46,47,50,51,53, EtI: 48,52,
BnBr: 49) was slowly added (neat) and the solution stirred for 1 h
at –78 °C and then overnight at room temperature. After quenching
with pH-7-buffer, the aqueous phase was extracted three times with
Et2O. The combined organic phases were washed with brine, dried
with MgSO4, and the solvent removed under reduced pressure.
Purification by column chromatography (SiO2, pentane/Et2O mix-
tures) afforded products 46Ϫ53 as colourless oils.
(R,R)-2-Dibenzylamino-1-ethylbutyl Phenyl Sulfone (48): The N,N-
dibenzyl-protected β-amino sulfone 42 was metallated with LDA
and allowed to react with iodoethane by the method described in
GP 3 to yield product 48 as a colourless oil [2.04 g, 97%, de ϭ 68%
(Ͼ97% after recryst. from CH2Cl2/n-hexane)]. – Major diastereo-
isomer: M.p. 108 °C. – [α]D20 ϭ ϩ19.9 (c ϭ 1.23, CHCl3) – IR (film):
ν˜ ϭ 3085 (m), 3062 (m), 3029 (m), 2965 (s), 2934 (s), 2876 (m),
2801 (m), 2254 (w), 1602 (w), 1585 (w), 1494 (m), 1449 (s), 1377
(m), 1363 (m), 1303 (s), 1255 (m), 2111 (m), 1145 (s), 1085 (s), 1045
(m), 1028 (m), 963 (s), 911 (w), 865 (w), 824 (w), 730 (s), 699 (s),
624 (s), 609 (m), 587 (m), 574 (s), 551 (m), 526 (m), 466 (w)
1
3
cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 0.83 (t, J ϭ 7.19 Hz, 3
3
H, CH3), 0.98 (t, J ϭ 7.41 Hz, 3 H, CH3), 1.16–1.96 (m, 4 H, 2
(R,R)-2-Dibenzylamino-1-methylpropyl Phenyl Sulfone (46): The
N,N-dibenzyl-protected β-amino sulfone 41 was metallated with
LDA and allowed to react with iodomethane by the method de-
scribed in GP 3 to yield product 46 as a colourless oil (1.42 g, 91%,
de ϭ 70% (Ն 98% after recryst. from CH2Cl2/n-hexane)). – Major
diastereoisomer: M.p. 112 °C. – [α]2D0 ϭ –1.4 (c ϭ 1.43, CHCl3) –
IR (CHCl3): ν˜ ϭ 3528 (w), 3388 (m), 3085 (m), 3062 (m), 3027 (m),
2927 (m), 2940 (m), 2880 (m), 2831 (m), 2831 (m), 2803 (m), 1603
(w), 1585 (w), 1494 (m), 1447 (s), 1383 (m), 1362 (m), 1304 (s),
1235 (m), 1219 (m), 1147 (s), 1084 (s), 1075 (s), 1050 (m), 1027 (m),
1000 (m), 970 (w), 944 (w), 909 (w), 875 (w), 841 (w), 819 (w), 751
(s), 732 (s), 699 (s), 668 (w), 626 (m), 597 (m), 588 (m), 574 (m),
551 (m), 530 (m), 506 (w), 465 (w) cm–1. – 1H NMR (300 MHz,
CDCl3): δ ϭ 1.19 (d, 3J ϭ 7.14 Hz, 3 H, CH3), 1.36 (d, 3J ϭ
ϫ CH3CH2), 3.19–3.26 (m, 2 H, CHCHSO2Ph), 2.28 (d, 2J ϭ
13.74 Hz, 2 H, CHHPh), 3.78 (d, 2J ϭ 13.46 Hz, 2 H, CHHPh),
7.18–7.80 (m, 15 H, Ar-H). – 13C NMR (75 MHz, CDCl3): δ ϭ
11.92, 13.41 (2 ϫ CH3CH2), 18.80, 20.91 (2 ϫ CH3CH2), 53.48
(NCH2), 58.44 (CHN), 65.77 (CHS), 126.89, 128.89, 128.07,
129.01, 129.13, 133.54 (Ar-C), 138.72, 139.33 (ipso-Ar-C). – MS
(CI, isobutane): m/z (%) ϭ 422 (100) [Mϩϩ1], 296 (7), 283 (10),
280 (18), 268 (5), 192 (2), 190 (8). – C24H27NO2S (421.037): calcd.
C 73.25, H 6.92, N 3.56; found: C 73.18, H 6.65, N 3.54.
(R,R)-2-Dibenzylamino-1-benzylbutyl Phenyl Sulfone (49): The
N,N-dibenzyl-protected β-amino sulfone 42 was metallated with
LDA and allowed to react with benzyl bromide by the method
described in GP 3 to yield product 49 as a colourless oil [2.13 g,
88%, de ϭ 64% (Ͼ 97% after recryst. from CH2Cl2/n-hexane)]. –
Major diastereoisomer: M.p. 133 °C. – [α]2D0 ϭ ϩ45.8 (c ϭ 3.00,
CHCl3) – IR (film): ν˜ ϭ 3534 (m), 3165 (w), 3085 (s), 3062 (s),
3029 (s), 3005 (s), 2966 (s), 2932 (s), 2874 (s), 2833 (s), 2801 (s),
2729 (m), 2606 (w), 2253 (w), 1953 (w), 1889 (w), 1811 (w), 1603
(s), 1586 (m), 1495 (s), 1451 (s), 13.65 (s), 1303 (s), 1253 (s), 1207
(s), 1144 (s), 1084 (s), 1046 (s), 1028 (s), 1000 (m), 972 (s), 911 (s),
872 (m), 826 (w), 734 (s), 698 (s), 647 (w), 624 (s), 612 (s), 584 (s),
3
3
7.14 Hz, 3 H, CH3), 3.43 (dq, J1 ϭ 7.14 Hz, J2 ϭ 2.21 Hz, 1 H,
2
3
CH3CHN), 3.48 (d, J ϭ 13.73 Hz, 2 H, CHHPh), 3.62 (dq, J1 ϭ
3
2
7.14 Hz, J2 ϭ 1.92 Hz, 1 H, CHSO2Ph), 3.65 (d, J ϭ 14.01 Hz,
2 H, CHHPh), 7.41–7.74 (m, 15 H, Ar-H). – 13C NMR (75 MHz,
CDCl3): δ ϭ 10.13, 12.73 (2 ϫ CH3), 51.19 (CHN), 54.15 (NCH2),
60.78 (CHS), 126.96, 128.57, 128.23, 128.50, 129.07, 133.44 (Ar-
C), 137.97, 139.44 (ipso-Ar-C). – MS (EI, 70 eV): m/z (%) ϭ 393
(1, Mϩ), 236 (6), 225 (18), 224 (100), 181 (8), 91 (65), 65 (5). –
C24H27NO2S (393.550): calcd. C 73.25, H 6.92, N 3.56; found: C
73.18, H 6.65, N 3.54.
1
553 (s), 532 (m) cm–1. – H NMR (300 MHz, CDCl3): δ ϭ 0.98 (t,
3J ϭ 7.14 Hz, 3 H, CH3), 1.53–1.68 (m, 1 H, CH3CHH), 1.72–87
2
3
(R,R)-2-Dibenzylamino-1-methylbutyl Phenyl Sulfone (47): The
(m, 1 H, CH3CHH), 3.15 (dd, J ϭ 15.66 Hz, J ϭ 4.67 Hz, 1 H,
N,N-dibenzyl-protected β-amino sulfone 42 was metallated with PhCHHCH), 3.26 (dd, 2J ϭ 15.93 Hz, 3J ϭ 7.30 Hz, 1 H,
LDA and allowed to react with iodomethane by the method de-
scribed in GP 3 to yield product 47 as a colourless solid (1.94 g,
95%, de ϭ 70%). – M.p. 105 °C. – [α]2D0 ϭ ϩ54.7 (c ϭ 1.30,
CHCl3) – IR (CHCl3): ν˜ ϭ 3085 (w), 3062 (m), 3028 (s), 2962 (w),
PhCHHCH), 3.34 (d, 2J ϭ 13.73 Hz, 2 H, NCHHPh), 3.56–3.85
2
(m, 2 H, CHCHSO2Ph), 3.72 (d, J ϭ 13.74 Hz, 2 H, NCHHPh),
6.68–7.60 (m, 20 H, Ar-H). – 13C NMR (75 MHz, CDCl3): δ ϭ
12.16 (CH3), 21.70 (CH3CH2), 31.25 (CHCH2), 54.18 (NCH2),
890
Eur. J. Org. Chem. 2000, 879Ϫ892

Asymmetric Synthesis of α-Substituted β-Amino Sulfones
FULL PAPER
58.58 (CHN), 65.42 (CHS), 126.47, 126.98, 128.17, 128.41, 128.46,
(w), 1813 (w), 1703 (w), 1639 (w), 1601 (m), 1585 (m), 1546 (w),
128.64, 128.88, 128.94, 133.94 (Ar-C), 138.26, 139.20, 133.39 (ipso- 1495 (m), 1448 (s), 1381 (m), 1368 (s), 1347 (m), 1305 (s), 1282 (s),
Ar-C). – MS (CI, isobutane): m/z (%) ϭ 484 (100) [Mϩϩ1], 394 1209 (m), 1146 (s), 1085 (s), 1026 (m), 1000 (m), 967 (s), 917 (m),
(20), 342 (5), 287 (7), 247 (7), 238 (16). – C31H33NO2S, (483.675):
calcd. C 76.98, H 6.88, N 2.90; found: C 76.76, H 6.93, N 2.82.
856 (m), 830 (w), 748 (s), 727 (s), 696 (s), 626 (s), 610 (m), 573 (s),
536 (s), 494 (m), 469 (w) cm–1. – 1H NMR (400 MHz, CDCl3): δ ϭ
3
3
0.38 [d, J ϭ 6.32 Hz, 3 H, CH3(CH3)CH], 0.86 [d, J ϭ 6.59 Hz,
(R,R)-2-Dibenzylamino-1,3-dimethylbutyl Phenyl Sulfone (50): The
N,N-dibenzyl-protected β-amino sulfone 43 was metallated with
LDA and allowed to react with iodomethane by the method de-
scribed in GP 3 to yield product 50 as a colourless oil [1.96 g, 93%,
de ϭ 50% (Ն 96% after HPLC)]. – Major diastereoisomer: M.p.
134 °C. – [α]2D0 ϭ ϩ117.7 (c ϭ 0.30, CHCl3) – IR (KBr): ν˜ ϭ 3404
(w), 3063 (m), 3028 (m), 2993 (m), 2959 (m), 2926 (m), 2788 (m),
2704 (w), 1602 (w), 1585 (w), 1495 (m), 1448 (s), 1384 (m), 1384
(m), 1362 (m), 1304 (s), 1237 (m), 1207 (w), 1144 (s), 1087 (s), 1071
(m), 1044 (w), 1027 (m), 1009 (m), 970 (m), 910 (w), 861 (m), 844
(w), 805 (w), 766 (m), 754 (s), 736 (s), 701 (s), 692 (s), 497 (w),
466 (w) cm–1. – 1H NMR (500 MHz, CDCl3): δ ϭ 0.92 [d, 3J ϭ
6.60 Hz, 3 H, CH3(CH3)CH], 1.10 [d, 3J ϭ 6.60 Hz, 3 H,
CH3(CH3)CH], 0.93–1.08 [m, 1 H, (CH3)2CH], 0.96 (t, 3J ϭ
7.29 Hz,
3 H, CH3CH2), 1.56–1.95 [m, 4 H, CH3CH2,
(CH3)2CHCH2], 3.21–3.27 (m, 3 H, CHHPh, CHSO2Ph), 3.40 (d,
3J ϭ 10.17 Hz, 1 H, CHN), 3.77 (d, 2J ϭ 13.20 Hz, 2 H, CHHPh),
7.16–7.86 (m, 15 H, Ar-H). – 13C NMR (100 MHz, CDCl3): δ ϭ
13.42 (CH3CH2), 18.59 (CH3CH2), 20.72, 24.19 [(CH3)2CH], 24.31
[(CH3)2CH], 37.05 [(CH3)2CHCH2], 53.49 (NCH2), 54.04 (CHN),
65.39 (CHS), 127.01, 128.12, 128.95, 129.18, 129.26, 133.57 (Ar-
C), 139.20, 139.43 (ipso-Ar-C). – MS (CI, isobutane): m/z (%) ϭ
450 (100) [Mϩϩ1], 360 (9), 311 (5), 310 (22), 309 (7), 308 (23), 266
(10), 218 (8), 143 (32). – C28H35NO2S (449.655): calcd. C 74.79, H
7.85, N 3.12; found: C 74.49, H 7.85, N 3.06.
3
CH3(CH3)CH], 1.39 (d, J ϭ 7.14 Hz, 3 H, CH3CHSO2Ph), 1.82–
(R,R)-2-Dibenzylamino-3-benzyloxy-1-methylpropyl Phenyl Sulfone
2.01 [m, 1 H, (CH3)2CH], 3.29 (d, J ϭ 13.16 Hz, 2 H, CHHPh), (53): The N,N-dibenzyl-protected β-amino sulfone 45 was
3.37 (d, J ϭ 9.61 Hz, 1 H, CHCHSO2Ph), 3.51 (q, J ϭ 7.23 Hz, metallated with LDA and allowed to react with iodomethane by
2
3
3
2
1 H, CHCHSO2Ph), 3.91 (d, J ϭ 13.46 Hz, 2 H, CHHPh), 7.20–
the method described in GP 3 to yield product 53 as a colourless
oil [2.42 g, 97%, de ϭ 68% (Ն 96% after column chromato-
7.98 (m, 15 H, Ar-H). – 13C NMR (125 MHz, CDCl3): δ ϭ 12.01
(CH3CH), 21.29, 21.31 [(CH3)2CH], 27.11 [(CH3)2CH], 53.88 graphy)]. – Major diastereoisomer: – [α]2D0ϭ –12.1 (c ϭ 1.16,
(NCH2), 59.10, 60.28 (CHCHS), 127.03, 128.08, 128.10, 129.03,
CHCl3) – IR (CHCl3): ν
˜ ϭ 3535 (w), 3085 (m), 3063 (m), 3028 (s),
129.20, 133.41 (Ar-C), 139.15, 139.59 (ipso-Ar-C) – MS (CI, isobut-
2928 (m), 2862 (m), 2805 (m), 1603 (w), 1586 (w), 1495 (m), 1450
ane): m/z (%) ϭ 422 (100) [Mϩϩ1], 296 (9), 282 (15), 281 (8), 280 (s), 1364 (m), 1305 (s), 1253 (m), 1218 (m), 1147 (s), 1107 (s), 1085
(30), 190 (21). – C26H31NO2S (421.604): calcd. C 74.07, H 7.41, N (s), 1028 (m), 1000 (m), 910 (w), 872 (w), 800 (w), 752 (s), 699 (s),
3.32; found: C 73.70, H 7.53, N 3.29.
668 (m), 624 (m), 593 (m), 571 (w), 538 (w) cm–1. – 1H NMR
(400 MHz, CDCl3): δ ϭ 1.31 (d, 3J ϭ 7.43 Hz, 3 H, CH3CH), 3.45
(R,R)-2-Dibenzylamino-1,4-dimethylpentyl Phenyl Sulfone (51): The
N,N-dibenzyl-protected β-amino sulfone 44 was metallated with
LDA and allowed to react with iodomethane by the method de-
scribed in GP 3 to yield product 51 as a colourless oil [1.96 g, 93%,
de ϭ 90% (Ն 96% after recryst. from CH2Cl2/n-hexane)]. – Major
diastereoisomer: M.p. 128 °C. – [α]2D0 ϭ ϩ40.6 (c ϭ 1.40, CHCl3) –
IR (KBr): ν˜ ϭ 3083 (w), 3059 (m), 3027 (m), 3001 (w), 2959 (s),
2942 (s), 2926 (s), 2905 (s), 2866 (m), 2833 (m), 2817 (m), 2796 (m),
2712 (w), 1602 (w), 1585 (w), 1495 (m), 1471 (m), 1447 (s), 1401
(w), 1383 (m), 1366 (m), 1341 (m), 1305 (s), 1295 (s), 1270 (m),
1234 (m), 1207 (m), 1163 (s), 1150 (s), 1080 (s), 1020 (s), 970 (m),
860 (m), 825 (m), 765 (m), 750 (s), 740 (s), 700 (s), 630 (s), 600 (s),
3
3
(qd, J1 ϭ 7.42 Hz, J2 ϭ 2.75 Hz, 1 H, CH3CH), 3.66–3.89 (m, 7
2
H, OCH2CH, NCH2Ph), 4.42 (d, J ϭ 12.10 Hz, 1 H, OCHHPh),
4.48 (d, J ϭ 11.82 Hz, 1 H, OCHHPh), 7.17–7.87 (m, 20 H, Ar-
2
H). – 13C NMR (100 MHz, CDCl3): δ ϭ 10.80 (CH3), 55.11
(NCH2), 55.71, 60.57 (CHCHS), 68.21, 72.96 (CH2OCH2), 126.92,
127.53, 127.58, 128.62, 128.13, 128.58, 128.83, 129.02, 133.42 (Ar-
C), 138.07, 138.29, 139.56 (ipso-Ar-C). – MS (CI, isobutane): m/z
(%) ϭ 500 (100) [Mϩϩ1], 408 (5), 394 (32), 360 (20), 358 (11), 289
(7), 198 (7), 143 (17). – C23H24NO2S (Mϩ Ϫ C8H9O): calcd.
378.1528; found 378.1528 (HRMS).
1
570 (s), 560 (s), 530 (m) cm–1. – H NMR (400 MHz, CDCl3): δ ϭ
Acknowledgments
3
3
0.35 [d, J ϭ 6.60 Hz, 3 H, CH3(CH3)CH], 0.87 [d, J ϭ 6.87 Hz,
3 H, CH3(CH3)CH], 0.90–1.99 [m, 3 H, (CH3)2CHCH2], 1.38 (d,
Our work has been generously supported by the Deutsche For-
schungsgemeinschaft (Leibniz award, Sonderforschungsbereich
380) and the Fonds der Chemischen Industrie. We thank Bayer
AG, BASF AG, Degussa-Hüls AG and former Hoechst AG for the
donation of chemicals.
3J ϭ 7.42 Hz, 3 H, CH3CHSO2Ph), 3.27 (d, J ϭ 13.19 Hz, 2 H,
2
CHHPh), 3.52–3.59 (m, 2 H, CHCHSO2Ph), 3.78 (d, 2J ϭ
13.20 Hz, 2 H, CHHPh), 7.17–7.85 (m, 15 H, Ar-H). – 13C NMR
(100 MHz, CDCl3): δ ϭ 11.11 (CH3CH), 20.50, 23.94 [(CH3)2CH],
24.26 [(CH3)2CH], 37.00 [(CH3)2CHCH2], 52.21 (CHS), 53.45
(NCH2), 58.00 (CHN), 127.00, 128.11, 128.62, 129,01, 129.21,
130.99 (Ar-C), 137.97, 139.39 (ipso-Ar-C). – MS (CI, isobutane):
m/z (%) ϭ 436 (100) [Mϩϩ1], 346 (6), 296 (18), 295 (5), 294 (5),
266 (12), 204 (4), 190 (9), 143 (7). – C27H33NO2S (435.628): calcd.
C 74.44, H 7.64, N 3.22; found: C 74.20, H 7.36, N 3.11.
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