Stereoselective synthesis of γ,δ-unsaturated β-amino sulfones from ellman's N-tert-butylsulfinyl ketimines and methyl Phenyl sulfone

Article abstract of DOI:10.1055/s-0032-1317171

A practical and straightforward approach for the highly stereoselective synthesis of γ,δ-unsaturated β-amino sulfones by nucleophilic (phenylsulfonyl)methylation of N-tert-butylsulfinyl ketimines with methyl phenyl sulfone was achieved. With lithium bis(trimethylsilyl)amide as the base, the corresponding sulfone-stabilized carbanion derived from methyl phenyl sulfone can be transferred to (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines in very good yields and with high diastereoselectivities. Electron-withdrawing or electron-donating substituents on the aryl rings of (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines did not exert a significant effect on the outcome of the diastereoselective nucleophilic (phenylsulfonyl) methylation.

Full text of DOI:10.1055/s-0032-1317171

LETTER
▌2485
lSettteer reoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones from Ellman’s
N-tert-Butylsulfinyl Ketimines and Methyl Phenyl Sulfone
Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones
Hua Zhang,a,b Ya Li,b Fanghui Xu,b Xin Feng Ren,b Le Wang,b Pei Zhou,*c Zhihua Sun*b
a
School of Environment Science and Engineering, Shanghai Jiaotong University, Shanghai 200240, P. R. of China
b
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201600, P. R. of China
Fax +86(21)67791432; E-mail: sungaris@gmail.com
c
Key Laboratory of Urban Agriculture (South), School of Agriculture College and Biology, Ministry of Agriculture, Shanghai Jiaotong Uni-
versity, Shanghai 200240, P. R. of China
Fax +86(21)34205762; E-mail: zhoupei@sjtu.edu.cn
Received: 21.06.2012; Accepted after revision: 03.08.2012
separation of the corresponding diastereomeric products
Abstract: A practical and straightforward approach for the highly
was laborious. Recently, we developed a practical ap-
stereoselective synthesis of γ,δ-unsaturated β-amino sulfones by
proach for the highly stereoselective synthesis of β-amino
sulfones, based on nuleophilic (phenylsulfonyl) alkyla-
nucleophilic (phenylsulfonyl)methylation of N-tert-butylsulfinyl
ketimines with methyl phenyl sulfone was achieved. With lithium
bis(trimethylsilyl)amide as the base, the corresponding sulfone- tion of Ellman’s N-tert-butylsulfinyl aldimines with alkyl
phenyl sulfones.11 A remarkable feature of this reaction is
stabilized carbanion derived from methyl phenyl sulfone can be
transferred to (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines in
very good yields and with high diastereoselectivities. Electron-
ic, and heterocyclic imines alike with very high yields and
withdrawing or electron-donating substituents on the aryl rings of
that it can be applied to nonenolizable, enolizable, aromat-
excellent diastereoselectivities. However, although sig-
(S)-α,β-unsaturated N-tert-butylsulfinyl ketimines did not exert a
nificant progress has been made in the area of synthesis of
chiral β-amino sulfones, the asymmetric synthesis of
structure diverse β-amino sulfones, especially those with
the amino group adjacent to a chiral tertiary carbon center,
is yet to be developed.
significant effect on the outcome of the diastereoselective nucleo-
philic (phenylsulfonyl) methylation.
Key words: amines, ketimines, nucleophilic addition, β-amino sul-
fones
Ideally, we can envision that a straightforward (arylsulfo-
nyl)alkylation of chiral ketimines with alkylaryl sulfone
would provide a highly attractive route to the target struc-
tures. It should be mentioned that Shiau, Jain, and co-
workers recently developed a method to prepare racemic
β-amino sulfonate esters from N-tert-butanesulfinyl ket-
imines and ethoxysulfonylmethide in strong basic condi-
tions, and only low to moderate yields (15–42%) were
Chiral β-amino sulfones are prevalent as a common motif
in natural and unnatural products,1 and have been exten-
sively used as important building blocks in the design of
many enzyme inhibitors such as novel HIV protease
inhibitors2 and matrix metalloproteinase inhibitors.3 Be-
sides, β-amino sulfones are useful synthetic intermediates
as exemplified by their utility in the synthesis of allylic
amines, nonproteinogenic α-amino acids,4 amino alco-
hols,5 carbohydrate derivatives,6 and nitrogen hetero-
cycles,7 taking advantage of the varying chemical
reactivities of sulfones (so-called ‘chemical chameleon’)
such as electrophilic substitution in the α-position and re-
ductive cleavage of the sulfone group.8
Table 1 Optimization of Reaction Conditionsa
Entrya Base
Molar ratio Solvent Yield (%)b dr (%)c
(2a/1/base)
1
2
3
4
5
6
7
LiHMDS
1:1.2:1.3
CH2Cl2 83
CH2Cl2 32
CH2Cl2 25
CH2Cl2 trace
CH2Cl2 trace
95:5
94:6
92:8
–
Not surprisingly, the synthesis of β-amino sulfones have
attracted a lot of synthetic endeavors. The classic method
developed for their asymmetric synthesis involves a syn-
thetic sequence starting from natural amino acids.9 The
other straightforward approach was achieved via aza-
Michael addition of chiral amines to α,β-unsaturated sul-
fones.10 Also, the same process employing achiral amines
and optically active α,β-unsaturated sulfones as reactive
partners has also been described. However, in many cases
these reactions proceeded with low stereoselectivity, and
NaHMDS 1:1.2:1.3
KHMDS
LDA
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
1:1.2:1.3
n-Buli
–
LiHMDS
KHMDS
THF
THF
20
45
95:5
10:1
a In all cases, base was added to a mixture of 1 and 2a at –65 °C, and
the reactions were usually complete within 4 h.
b Yield of isolated analytically pure material.
c Diastereomeric ratios were determined by 1H NMR of the crude
reaction mixture.
SYNLETT 2012, 23, 2485–2490
Advanced online publication: 21.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317171; Art ID: ST-2012-W0535-L
© Georg Thieme Verlag Stuttgart · New York

2486
H. Zhang et al.
LETTER
obtained with the optimized reaction conditions (n-BuLi, tence of the high electronegativity of the fluorine atom(s),
–
THF, HMPA, –78 °C).12 In this paper, as part of our con- (phenylsulfonyl)difluoromethyl anion (PhSO2CF2 ) was
tinuing effort to develop structure-diverse β-amino sul- regarded as a relatively ‘hard’ nucleophile, and thus un-
fones, we wish to disclose the highly diastereoselective dergo 1,2-addition reactions with α,β-enones or α,β-unsat-
(phenylsulfonyl) methylation of α,β-unsaturated N-tert- urated ketimines. However, to the best our knowledge, the
butylsulfinyl ketimines, which has enabled us for the first addition reaction between methyl phenyl sulfone and α,β-
time to efficiently synthesize γ,δ-unsaturated β-amino sul- enones or α,β-unsaturated ketimines have not been dis-
fones containing chiral tertiary carbon centers through a closed. With these in mind, we initially prepared a variety
simple and reliable protocol. It is also worthy to point out of (S)-α,β-unsaturated N-tert-butylsulfinyl ketimines 2 by
that another significant structural feature of this kind of β- Ti(OEt)4-mediated condensation of (S)-N-tert-butylsul-
amino sulfones is the existence of allylic amine subunit, as finamide and the requisite α,β-unsaturated ketones, ac-
it is well-known that allyllic amines are widely applied in cording to the reported protocol.14 With these α,β-
medicinal chemistry and drug discovery since a variety of unsaturated ketimines 2 in hand, we next chose (S)-α,β-
synthetically and biologically important organic com- unsaturated N-tert-butylsulfinyl ketimine 2a as a model
pounds can be obtained through the functionalization of compound to test the nucleophilic (phenylsulfonyl) meth-
their double bond.
ylation with PhSO2Me (Scheme 1).
Although α,β-unsaturated ketimines have been widely Following initial deprotonation with lithium hexamethyl-
used as important intermediates in organic synthesis, in- disilazide (LiHMDS), PhSO2Me reacted with 2a to afford
stances of nucleophilic 1,2-addition of α,β-unsaturated the 1,2-addition product 3a (not 1,4-addition product)
ketimines are scarce. Recently, Hu and coworkers report- with very good yield (83%) and diastereoselectivity (dr =
ed nucleophilic 1,2-addition of the (phenylsulfonyl)di- 95:5). Several bases were then screened, and the results
fluoromethyl anion, generated in situ from PhSO2CF2H are summarized in Table 1 (Scheme 2). As shown, a
and a base, to α,β-unsaturated ketones and N-tert-butyl- significant drop in yield was observed when sodium
sulfinyl ketimines.13 It was believed that, due to the exis- hexamethyldisilazide (NaHMDS) or potassium hexa-
O
O
O
O
H2N
S
NaOH, H2O
+
H
Ti(OEt)4, THF
R1
R1
R2
R2
S
S
O
O
NH
N
CH2SO2Ph
PhSO2Me (1)
base, CH2Cl2
–65 °C
R2
R1
R2
R1
3
2
Scheme 1 Synthesis of γ,δ-unsaturated β-amino sulfones
Cl
S
S
base
CH2Cl2, –65 °C
O
O
Cl
CH2SO2Ph
NH
N
PhSO2Me
+
1
MeO
Cl
MeO
Cl
2a
3a
Scheme 2 Stereoselective synthesis of 3a
S
S
S
O
N
O
O
NH
NH
Ar
CH2SO2Ph
CH2SO2Ph
Ar
1, LiMHDS
CH2Cl2, –65 °C
+
Ar
Ar
Ar
Ar
2
3
3'
Scheme 3 Stereoselective synthesis of γ,δ-unsaturated β-amino sulfones
Synlett 2012, 23, 2485–2490
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones
2487
methyldisilazide (KHMDS) was used as base. Also, n- The absolute configuration of product 3a was determined
BuLi was not suitable for this reaction, probably due to its to be SS,S by its single-crystal X-ray structure (Figure 1),
high nucleophilicity toward ketimine 2a. Reactant molar and the configurations of others were assigned by analo-
ratios were also carefully examined to improve the prod- gy.22 The stereocontrol mode of the present diastereose-
uct yield using LiHMDS as the base, and the best yield of lective (phenylsulfonyl)methylation of ketimines can be
product 3a was obtained with a reactant molar ratio of predicted by envisaging a cyclic six-membered transition
2a/1/LiHMDS = 1:1.2:1.3. Having identified the optimal state (Figure 2) in which the bulky tert-butyl group pref-
reaction conditions, the scope of this nucleophilic 1,2-ad- erentially adopts an equatorial position, and the (phenyl-
–
dition reaction was investigated with various (S)-α,β-un- sulfonyl)methyl anion (PhSO2CH2 ) attack the Re face of
saturated ketimines (Table 2, Scheme 3).
the ketimine.15
Table 2 Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones
Entry
1
Ketimines 2
Products 3
Yield (%)a
83
dr (%)b
95:5
S
S
O
NH
Cl
O
N
Cl
CH2SO2Ph
MeO
MeO
Cl
Cl
2a
3a
2
87
92:8
S
S
O
NH
O
N
CH2SO2Ph
Cl
Cl
2b
3b
3
82
95:5
S
S
O
NH
Cl
O
N
Cl
CH2SO2Ph
Cl
Cl
3c
2c
4
5
6
85
86
81
93:7
92:8
92:8
S
S
S
S
S
S
O
N
N
N
O
NH
CH2SO2Ph
CH2SO2Ph
CH2SO2Ph
2d
3d
O
NH
O
2e
3e
O
NH
O
NO2
NO2
2f
3f
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2485–2490

2488
H. Zhang et al.
LETTER
Table 2 Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones (continued)
7
85
93:7
S
S
O
N
O
NH
CH2SO2Ph
Cl
OMe
Cl
OMe
2g
3g
8
83
98:2
S
S
O
N
O
NH
CH2SO2Ph
OMe
OMe
2h
3h
9
87
95:5
S
S
O
NH
O
N
CH2SO2Ph
2i
3i
10
81
96:4
S
S
O
N
O
NH
CH2SO2Ph
O2N
O2N
2j
3j
11
12
13
87
82
85
94:6
94:6
92:8
S
S
O
NH
O
N
CH2SO2Ph
MeO
MeO
2k
3k
S
S
O
NH
O
N
CH2SO2Ph
MeO
MeO
2l
3l
S
S
O
NH
O
N
CH2SO2Ph
Cl
Cl
3m
2m
Synlett 2012, 23, 2485–2490
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones
2489
Table 2 Stereoselective Synthesis of γ,δ-Unsaturated β-Amino Sulfones (continued)
14
82
97:3
S
S
O
N
O
NH
CH2SO2Ph
2n
3n
15
85
98:2
S
S
O
NH
O
N
CH2SO2Ph
MeO
MeO
3o
2o
a Isolated yield.
b Diastereomeric ratios were determined by 1H NMR of the crude reaction mixture
nyl)methylate (S)-2-methyl-N-(1-phenylethylidene)pro-
pane-2-sulfin amide with predeprotonated or in situ
generated (phenylsulfonyl)methyl anion failed, and we
assume that unwanted aza-enolization of the ketimines
occurred.16–20
In summary, we have developed the highly efficient syn-
thesis of γ,δ-unsaturated β-amino sulfones through diaste-
reoselective nucleophilic of (S)-α,β-unsaturated N-tert-
butylsulfinyl ketimines, with in situ generated
–
PhSO2CH2 anion and an appropriate base (LiHMDS).
The reaction afford the 1,2-addition products with good
diastereoselectivities and very good yields.21 Electron-
withdrawing or electron-donating substituents on the aryl
rings of (S)-α,β-unsaturated N-tert-butylsulfinyl ket-
imines did not exert a significant effect on the outcome of
the diastereoselective nucleophilic (phenylsulfonyl)meth-
ylation. Our further attempts to (phenylsulfonyl)methyla-
tion of (S)-2-methyl-N-(1,5-diphenylpenta-2,4-dien-
ylidene)propane-2-sulfinamide with predeprotonated or
in situ generated (phenylsulfonyl)methyl anion 3n suc-
ceeded.
Figure 1 Single-crystal X-ray structure of compound 3a
Ph
Nu
Ph
Acknowledgment
PhSO2H
2C
O
O
Li
Ph
N
N
We thank the Natural Science Foundation of China (No. 31071860)
for financial support. This work was also supported by the National
High-Tech Research and Development Plan (2012AA101405), the
Special Fund for Agroscientific Research in the Public Interest of
China (200903056).
t-Bu
S
CH=CHPh
••
Figure 2 Cyclic six-membered transition state
Supporting Information for this article is available online at
It has been rationalized that ‘hard’ nucleophiles usually
undergo 1,2-addition reaction with α,β-unsaturated ket-
imines, whereas ‘soft’ nucleophiles prefer attacking the
β-carbon atom of α,β-unsaturated ketimines. Our herein-
reported (phenylsulfonyl)methylation of α,β-unsaturated
ketimines afforded 1,2-addition products, indicating that
the (phenylsulfonyl)methyl anion is still a relatively hard
nucleophile. Our further attempts to (phenylsulfo-
http://www.thieme-connect.com/ejournals/toc/synlett.SupInpfioomgrattr
o
nSupprigI
o
tnnofrmat
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2485–2490

2490
H. Zhang et al.
LETTER
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(21) General Procedure for the Synthesis of Compounds 3
LiHMDS (1.3 equiv, 1.3 mL, 1.0 mol/L) was added to a
mixture of the (S)-α,β-unsaturated N-tert-butylsulfinyl
ketimines 2 (1 mmol) and methyl phenyl sulfone (1, 1.2
equiv, 1.2 mmol) in CH2Cl2 (5 mL) at –65 °C. Reaction
mixtures were stirred over 4 h. Then a half-saturated
NH4Cl/H2O solution (2 mL) was added at lower temperature,
and the quenched reaction mixture was extracted three times
with EtOAc. The combined organic layers were dried over
anhyd MgSO4. Evaporation of the solvent afforded the crude
product, which was subject to flash chromatography to give
the corresponding γ,δ-unsaturated β-amino sulfones 3.
Spectral Data of the Product 3a White solid; mp 157.5–
158.1 °C; [α]25 128.4 (c 0.61, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.77–7.76 (d, J = 8 Hz, 2 H), 7.75–6.80 (m, 10
H), 6.82–6.80 (d, J = 8 Hz, 1 H), 6.29–6.27 (d, J = 8 Hz, 1
H), 6.23 (s, 1 H), 4.39–4.35 (d, J = 14 Hz, 1 H), 4.13–4.09
(d, J = 14 Hz, 1 H), 3.80 (s, 3 H), 1.41 (s, 9 H). 13C NMR
(100 MHz, CDCl3): δ = 159.3, 140.7, 134.8, 134.2, 134.0,
133.3, 133.0, 131.4, 129.4, 129.1, 128.1, 128.0, 127.7,
127.2, 126.5, 113.7, 64.6, 63.3, 56.6, 55.2, 23.1. ESI-HRMS:
m/z calcd for C27H29Cl2NO4S2Na [M + Na]+: 588.08073;
found: 588.07789. Other spectral data can be found in the
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