Stereoselective allylation and reduction of N-tert-butanesulfinyl-α-keto aldimines

Article abstract of DOI:10.1016/j.tetasy.2017.08.010

A simple methodology for the synthesis of N-tert-butanesulfinyl-α-keto aldimines from both α-keto aldehydes and carboxylic esters has been developed. The addition of an in situ formed allyl indium reagent to these chiral imines was also studied. The addition took place in a sequential manner, first to the imine group with excellent diastereoselectivity and then to the carbonyl group with lower diastereoselectivity. Ruthenium-catalyzed ring closing metathesis of the resulting 5-aminoocta-1,7-dien-4-ol derivatives provided access to 6-aminocyclohex-3-enols. Reduction of the α-keto aldimines led to N-tert-butanesulfinyl-1,2-aminoalcohols as a 1:1 diastereomeric mixture.

Full text of DOI:10.1016/j.tetasy.2017.08.010

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective allylation and reduction of N-tert-butanesulfinyl-a-
keto aldimines
a,c,
Edgar Maciá a,b,c, Francisco Foubelo a,b,c, , Miguel Yus
⇑
⇑
a Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
b Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
c Centro de Innovación en Química Avanzada (ORFEO-CINQA), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple methodology for the synthesis of N-tert-butanesulfinyl-a-keto aldimines from both a-keto alde-
Received 28 July 2017
Accepted 8 August 2017
Available online xxxx
hydes and carboxylic esters has been developed. The addition of an in situ formed allyl indium reagent to
these chiral imines was also studied. The addition took place in a sequential manner, first to the imine
group with excellent diastereoselectivity and then to the carbonyl group with lower diastereoselectivity.
Ruthenium-catalyzed ring closing metathesis of the resulting 5-aminoocta-1,7-dien-4-ol derivatives pro-
Dedicated to the memory of Professor
Howard Flack
vided access to 6-aminocyclohex-3-enols. Reduction of the
1,2-aminoalcohols as a 1:1 diastereomeric mixture.
a
-keto aldimines led to N-tert-butanesulfinyl-
Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction
work in this area, we have described the stereoselective indium
promoted coupling of N-tert-butanesulfinyl imines with allylic bro-
mides7 and alcohols,8 also with trimethylsilylpropargyl bromide.9
The resulting homoallyl and homopropargyl amine derivatives,
respectively, were used as precursors in the synthesis of natural
products10 and other structurally diverse nitrogen-containing
compounds.11 More recently, the indium-mediated diastereoselec-
tive allylation of N-tert-butanesulfinyl imines derived from
The amine functionality is widely present in drugs and drug
candidates.1 More than 75% of these compounds are aminated
derivatives. This functionality is also abundant in natural products,
many of which display interesting biological activities, or are cata-
lysts and materials.2 Due to the fact that in most of these com-
pounds the nitrogen atom is bonded to a stereogenic center,
especially in naturally occurring products, the development of
new synthetic methodologies for their preparation in an efficient,
reliable and simple manner, is of great interest. The most useful
procedures involve the reduction of ketimines or the nucleophilic
addition of organometallic compounds to aldimines.3 The presence
of a electron withdrawing group on the nitrogen of the imine facil-
itates the nucleophilic addition and in many cases it behaves as a
protecting group of the resulting amine derivative. At this point,
it is worth mentioning that N-tert-butanesulfinyl imines have
found high applicability in synthesis,4 because they can be pre-
pared in large-scale processes from the corresponding carbonyl
compound and are commercially available in enantiomerically
pure form at reasonable prices as tert-butanesulfinamide.5 The
tert-butanesulfinyl group can be removed easily under acidic con-
ditions from these compounds to give free amines and, in addition,
useful synthetic procedures have been developed in order to recy-
cle the chiral tert-butanesulfinamide.6 Regarding our previous
a
-ketoesters was also studied.12 Continuing our interest in this
topic, we herein report our first approach to the indium-mediated
allylation and also the reduction of N-tert-butanesulfinyl imines
derived from
a-ketoaldimines. The nucleophilic addition to these
compounds with two potential electrophilic positions has not been
studied to date.
2. Results and discussion
Starting
a-keto aldimines 3a and 3b were prepared in high
yields by direct condensation of commercially available methylgly-
oxal 2a and phenylglyoxal 2b, respectively, with (S)-tert-butane-
sulfinamide 1, in the presence of CuSO4 in dichloromethane at
room temperature (Scheme 1A).13 The same reaction conditions
worked for the direct condensation of
and (S)-tert-butanesulfinamide 1 to produce
e, although in moderate yields. These -ketohemithioketals 6c-e
behave as -keto aldehyde surrogates and were prepared from
the corresponding ethyl esters 4 by reaction with dimsyl anion to
a
-ketohemithioketals 6c-e
a-keto aldimines 3c-
a
a
⇑
Corresponding authors. Fax: +34 965 909672.
E-mail addresses: foubelo@ua.es (F. Foubelo), yus@ua.es (M. Yus).
http://dx.doi.org/10.1016/j.tetasy.2017.08.010
0957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Maciá, E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.010

2
E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
t-Bu
S
O
N
O
O
S
CuSO4 (2.2 equiv)
CH2Cl2, 23 ºC, 24 h
R
R
+
A)
H
H
t-Bu
NH2
O
O
1
(S)-
2
3a
3b
(1.2 equiv)
[R = Me, 97%]
[R = Ph, 93%]
R
O
OEt
4
(1.2 equiv)
1. DMSO (1.4 equiv), MeLi (1.6 equiv)
THF, -78 to 23 ºC
R
Me
2. 12 M HCl (1 equiv), H2O (3 equiv)
DMSO (1 equiv), 23 ºC
O
S
5
t-Bu
SMe
OH
S
N
O
O
S
R
CuSO4 (2.2 equiv)
CH2Cl2, 23 ºC, 24 h
R
+
B)
H
t-Bu
NH2
O
O
(1.2 equiv)
6c [R = 4-BrC6H4, 96%]
6d
1
(S)-
3c [R = 4-BrC6H4, 60%]
3d
[R = 4-MeOC6H4, 74%]
6e [R = Me(CH2)8, 80%]
[R = 4-MeOC6H4, 69%]
3e [R = Me(CH2)8, 55%]
Scheme 1. Synthesis of N-tert-butanesulfinyl-a-keto aldimines 3.
give b-keto sulfoxide intermediates 5,14 which under controlled
acidic conditions led to compounds 6c-e (Scheme 1B).15
ture (Table 1, entry 3). The allylation at room temperature with
excess (3.0 equiv) of allyl bromide 7 exclusively produced com-
pound 10a, resulting from a double allylation (Table 1, entry 4).
Similar results to those obtained working at room temperature
were found at 60 °C (Table 1, entries 5 and 6). We observed that
the addition to the imine took place in an almost total diastereos-
elective manner [Re-face addition to imines with an (SS)-configura-
tion]. However, subsequent addition to the carbonyl was less
diastereoselective, leading to mixture of diastereoisomers in a
2:1 to 3:1 ratio.
We decided to study the indium-mediated allylation of these a-
keto aldimines 3 with allyl bromide 7, paying attention to the
chemo- and stereoselectivity of the process. For this reason, we
took the chiral imine 3a derived from methylglyoxal 2a as the
model compound for the optimization of the reaction conditions.
Thus, the reaction of imine 3a with 1.0 equiv of allyl bromide 7
and 1.5 equiv of indium metal in THF at 5 °C for 14 h led to a mix-
ture of monoallylated product 9a, along with a significant amount
of starting material 3a (Table 1, entry 1). When the reaction was
performed at the same temperature, but using 3.0 equiv of allyl
bromide 7 and 2.5 equiv of indium, a 1:1 mixture of starting imine
3a and homoallylalcohol 9a was obtained (Table 1, entry 2). When
the allylation reactions were performed at room temperature in
the presence of 1.0 and 3.0 equiv of allyl bromide 7, the results
were quite different. With 1.0 equiv of 7, the homoallylamine
derivative 8a was now the major component of the reaction mix-
We studied next the reaction of different N-tert-butanesulfinyl-
a-keto aldimines 3 with allyl bromide 7, by applying the optimized
conditions shown in Table 1, entry 4, in order to produce the reac-
tion products 10 resulting from the double allylation. Compounds
10 were obtained in moderate yields and with high diastereoselec-
tivity for aliphatic derivatives {10a (R = Me) and 10c [R = Me
(CH2)8]}, and as a mixture of stereoisomers as a consequence of
the lack of diastereoselectivity in the allylation step of the carbonyl
Table 1
Optimization of the allylation reaction conditionsa
t-Bu
t-Bu
t-Bu
t-Bu
S
S
S
S
reaction
N
O
HN
O
N
O
HN
O
conditions
Me
Me
Br
+
+
+
H
H
Me
9a
OH
Me
OH
10a
O
O
7
3a
8a
Entry
Reaction conditions
Ratiob
3a
8a
9ac
10a
1
2
3
4
5
6
7 (1 equiv), In (1.5 equiv), THF (2 mL), 5 °C, 14 h
7 (3 equiv), In (2.5 equiv), THF (2 mL), 5 °C, 14 h
7 (1 equiv), In (1.5 equiv), THF (2 mL), 23 °C, 6 h
7 (3 equiv), In (2.5 equiv), THF (2 mL), 23 °C, 6 h
7 (1 equiv), In (1.5 equiv), THF (2 mL), 60 °C, 6 h
7 (3 equiv), In (2.5 equiv), THF (2 mL), 60 °C, 6 h
85
50
10
0
0
0
0
0
65
0
64
0
15
50
25
0
30
0
0
0
0
100
6
100
a
b
c
Reactions were carried out with 0.5 mmol of 3a.
Ratio was determined from the 1H NMR spectrum of the crude reaction mixture.
Formed as a 2:1 to 3:1 mixture of diastereoisomers.
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E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
t-Bu
group for phenyl substituted compound 10b. The yields shown in
t-Bu
Scheme 2 refer to the isolated products after column chromatogra-
phy purification.
Double allylated amino alcohol derivatives 10 are interesting
building blocks. For instance, ring-closing metathesis of these
S
S
HN
O
N
O
NaBH4 (3 equiv)
MeOH, 0 ºC, 4 h
R
R
H
OH
12a [R = Me, 84%, 60:40 dr]
O
compounds by means
a Hoveyda–Grubbs second generation
3
ruthenium catalyst16 produced N-tert-butanesulfinyl-6-aminocy-
clohex-3-en-1-ol derivatives 11 (Scheme 3). Starting from diene
10a, compound 11a was isolated in 92% yield. The relative config-
uration of 11a was determined to be cis after NOESY experiments,
so we assumed that the addition to the carbonyl group in the
second allylation step leading to compounds 10 (Scheme 2), took
place preferentially to the Re-face. The ring-closing metathesis of
a 3:2 diastereomeric mixture of 10b led to aminocyclohexenol
derivatives 11b and 110b in 65% overall yield. These compounds
were easily separated after column chromatography and subse-
quently characterized as single isomers (Scheme 3).
12b
[R = Ph, 54%, 59:41 dr]
12c [R = 4-BrC6H4, 78%, 56:44 dr]
12d [R = 4-MeOC6H4, 89%, 57:43 dr]
12e
[R = Me(CH2)8, 56%, 54:46 dr]
Scheme 4. Reduction of N-tert-butanesulfinyl-a-keto aldimines 3.
octadienes led to the formation of the corresponding 3-aminocy-
clohex-2-enol derivatives. In addition, N-tert-butanesulfinyl-1,
2-aminoalcohols were also accessible by reduction of the
starting
a-keto aldimines, although as a c.a. 1:1 mixture of
diastereoisomers.
In addition, N-tert-butanesulfinyl-1,2-aminoalcohol derivatives
12 were also prepared by reduction of the a-keto aldimines 3 with
sodium borohydride in methanol. Unfortunately, an almost 1:1
mixture of diastereoisomers was obtained in all cases which could
not be easily separated (Scheme 4). These 1,2-aminoalcohol
derivatives could be of potential interest as chiral ligands in differ-
ent catalytic processes. Further studies regarding the use of more
selective reducing agents are currently in progress, along with
the chemoselective oxidation of compounds 12 leading to amino-
methyl ketone derivatives.
4. Experimental
4.1. General
(SS)-tert-Butanesulfinamide and its enantiomer were a gift of
Medalchemy (>99% ee by chiral HPLC on a Chiracel AS column,
90:10 n-hexane/i-PrOH, 1.2 mL/min, k = 222 nm). TLC was per-
formed on silica gel 60 F254, using aluminum plates and visualized
with phosphomolybdic acid (PMA) stain. Flash chromatography
was carried out on handpacked columns of silica gel 60 (230–400
mesh). Melting points are uncorrected. Optical rotations were
measured using a polarimeter with a thermally jacketted 5 cm cell
at approximately 20 °C and concentrations (c) are given in g/100
mL. Infrared analyses were performed with a spectrophotometer
equipped with an ATR component; wavenumbers are given in
cmꢀ1. Low-resolution mass spectra (EI) were obtained at 70 eV;
and fragment ions in m/z with relative intensities (%) in parenthe-
ses. High-resolution mass spectra (HRMS) were also carried out in
the electron impact mode (EI) at 70 eV and on an apparatus
3. Conclusion
In conclusion, 5-aminoocta-1,7-dien-4-ol derivatives with alkyl
or aryl substituents at the 4-position were prepared by double ally-
lation of N-tert-butanesulfinyl-a-keto aldimines promoted by
indium. The allylation of the imine group took place in an almost
diastereoselective manner, while the addition to the carbonyl
group was less stereoselective. This methodology made use of
indium metal which is nontoxic and does not require exclusion
of moisture or air. Ring closing metathesis of substituted
t-Bu
t-Bu
S
S
HN
R
O
N
O
In (1.5 equiv)
Br
R
+
H
THF, 23 ºC, 12 h
HO
O
3
7 (2.2 equiv)
10a [R = Me, 25%, single diastereoisomer]
10b [R = Ph, 40%, 3:2 diastereoisomeric mixture]
10e
[R = Me(CH2)8, 37%, single diastereoisomer]
Scheme 2. Double allylation of N-tert-butanesulfinyl-
a-keto aldimines 3.
t-Bu
t-Bu
S
HN
O
O
S
HN
O
HO
Me
Hoveyda-Grubbs II (5 mol%)
CH2Cl2, 40 ºC, 4 h
HO
Me
10a
11a (92%)
t-Bu
t-Bu
t-Bu
S
S
HN
HN
O
S
HN
O
HO
Ph
Ph
HO
Hoveyda-Grubbs II (5 mol%)
CH2Cl2, 40 ºC, 4 h
+
HO
Ph
10b
11b (36%)
11'b (29%)
Scheme 3. Synthesis of aminocyclohexenol derivatives 11.
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4
E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
equipped with a time of flight (TOF) analyzer and the samples were
ionized by ESI techniques and introduced through an ultra-high
pressure liquid chromatography (UPLC) model. 1H NMR spectra
were recorded at 300 or 400 MHz for 1H NMR and 75 or
100 MHz for 13C NMR, using CDCl3 as the solvent and TMS as inter-
nal standard (0.00 ppm). The data are being reported as: s = singlet,
d = doublet, t = triplet, q = quadruplet, h = septuplet, m = multiplet
or unresolved, br s = broad signal, coupling constant(s) in Hz, inte-
gration. 13C NMR spectra were recorded with 1H-decoupling at
100 MHz and referenced to CDCl3 at 77.16 ppm. DEPT-135 experi-
ments were performed to assign CH, CH2 and CH3.
80%) was obtained as a yellow oil; Rf 0.21 (hexane/EtOAc, 2:1);
IR (neat)
m
;
2939, 2910, 2805, 1692, 1435, 1375 1201, 1111, 1078,
922 cm–1
1H NMR (300 MHz, CDCl3) d 0.85 (3H, t, J = 6.9 Hz,
CH3), 1.22–1.28 (14H, m, 7 ꢁ CH2), 1.60–1.66 (2H, m, CH2), 2.65
(3H, s, CH3), 5.31 (1H, s, CH); 13C NMR (100 MHz, CDCl3) d 13.5
(CH3), 14.1 (CH3), 22.6 (CH2), 23.0 (CH2), 29.1 (CH2), 29.2 (CH2),
29.3 (CH2), 31.8 (CH2), 36.5 (CH2), 78.1 (CH), 206.7 (C); LRMS (EI)
m/z 185 (M+ꢀ47, 9%), 155 (25), 141 (34), 113 (100), 85 (66), 57
(46), 56 (20).
4.3. General procedure for the synthesis of N-tert-
butanesulfinyl-a-keto aldimines 3
4.2. General procedure for the synthesis of hemithioketals 6
To solution of
a
a
-keto aldehyde 2 or hemithioketal 6
To a solution of dimethyl sulfoxide (1.10 g, 1.0 mL, 14.0 mmol)
in THF (15 mL) was added dropwise a 1.6 M solution of methyl-
lithium in Et2O (6.0 mL, 9.6 mmol) at 0 °C. After 1 h at this temper-
ature, the corresponding ethyl ester 4 (7.0 mmol) was added, and
stirring was continued for 12 h at room temperature. To the reac-
tion mixture were successively added water (15 mL) and chloro-
form (15 mL). Then it was acidified to pH 2–3 with 1 M
hydrochloric acid and extracted with chloroform (3 ꢁ 10 mL).
The organic layer was dried over anhydrous magnesium sulfate
and evaporated (15 Torr). The resulting residue was the corre-
sponding b-ketosulfoxide 5, which was pure enough to be used
in the next step. Thus, to a solution of the corresponding b-ketosul-
foxide 5 (7.0 mmol) was successively added water (18 mL) and a
12 M hydrochloric solution (0.5 mL, 6.0 mmol) at room tempera-
ture and stirring was maintained for 24 h. When a solid was
formed, it was filtered off, washed with cold water and dried under
vacuum to give pure products 6c and 6d. For the aliphatic derivate,
the reaction mixture was extracted with ethyl acetate (3 ꢁ 10 mL).
The organic layer was dried over anhydrous magnesium sulfate
and evaporated (15 Torr) to give pure product 6e. Yields, physical
and spectroscopic data for these compounds follow.
(5.0 mmol), and (SS)-tert-butanesulfinamide 1 (0.665 g, 5.5 mmol)
in dry dichloromethane (15 mL) under argon was added anhydrous
copper(II) sulfate (1.760 g, 11.0 mmol) and the reaction mixture
was stirred at room temperature for 24 h. The solid was filtered
off, washed with ethyl acetate (3 ꢁ 10 mL) and the organic layer
was evaporated (15 Torr). The resulting residue was purified by
column chromatography (silica gel, hexane/ethyl acetate, 6/1) to
yield pure compounds 3. Yields, physical and spectroscopic data
for these compounds follow.
4.3.1. (SS,E)-N-(tert-Butanesulfinyl)-1-iminopropan-2-one 3a
The representative procedure was followed by using
a-keto
aldehyde 2a (0.360 g, 0.344 mL, 5.0 mmol). Purification by column
chromatography (hexane/AcOEt, 4:1) yielded 3a (0.213 g,
4.85 mmol, 97%) as a orange oil; Rf 0.76 (hexane/EtOAc, 2:1);
[a]
30 = +111.2 (c 0.45, CH2Cl2); IR (neat)
m
2970, 1705, 1364,
D
1240, 1090, 1030 cm–1
;
1H NMR (300 MHz, CDCl3) d 1.28 [9H, s,
(CH3)3], 2.50 (3H, s, CH3), 7.92 (1H, s, CH); 13C NMR (100 MHz,
CDCl3) d 22.7 (CH3), 25.4 (CH3), 58.7 (C), 160.6 (CH), 195.6 (C);
LRMS (EI) m/z 119 (M+ꢀ56, 100%), 57 (100), 43 (93); HRMS calcd
for C7H13NO2S: 175.0667; found: 175.0664.
4.2.1. 1-(4-Bromophenyl)-2-hydroxy-2-(methylthio)ethan-1-
one 6c
The representative procedure was followed by using ethyl ester
4c (1.60 g, 1.14 mL, 7.0 mmol). Compound 6c (1.754 g, 6.72 mmol,
96%) was obtained as a orange solid, mp 76–77 °C (hexane/CH2Cl2);
4.3.2. (SS,E)-N-(tert-Butanesulfinyl)-2-imino-1-phenylethan-1-
one 3b
The representative procedure was followed by using
a-keto
aldehyde 2b (0.67 g, 5.0 mmol). Purification by column chro-
matography (hexane/AcOEt, 4:1) yielded 3b (1.10 g, 4.65 mmol,
Rf 0.11 (hexane/EtOAc, 2:1); IR (neat)
m 2961, 1711, 1480, 1325,
93%) as a orange oil; Rf 0.65 (hexane/EtOAc, 2:1); [
(c 0.65, CH2Cl2); IR (neat) 2905, 1635, 1580, 1300, 1261,
1167, 1022 839 cm–1 1H NMR (300 MHz, CDCl3) d 1.30 [9H, s,
a]
30 = +88.2
D
1283, 1193, 1072, 854, 715 cm–1 1H NMR (300 MHz, CDCl3) d
;
m
1.98 (3H, s, CH3), 6.08 (1H, s, CH), 7.64 (2H, d, J = 8.7 Hz, 2 ꢁ CH),
7.91 (2H, d, J = 8.7 Hz, 2 ꢁ CH); 13C NMR (100 MHz, CDCl3) d 10.1
(CH3), 74.7 (CH), 129.6 (C), 130.4 (CH), 131.2 (C), 132.1 (CH),
192.8 (C); LRMS (EI) m/z 214 (M+ꢀ47, 22%), 212 (25), 184 (95),
182 (100), 156 (35), 154 (40); HRMS calcd for C8H6Br79O2 (M+-
ꢀCH3S): 212.9551; found: 212.9560.
;
(CH3)3], 7.50–7.66 (3H, m, 3 ꢁ CH), 8.15 (2H, d, J = 7.5 Hz,
2 ꢁ CH), 8.50 (1H, s, CH); 13C NMR (100 MHz, CDCl3) d 22.7
(CH3), 58.6 (C), 128.7 (CH), 130.1 (CH), 134.3 (C), 134.5 (CH),
161.0 (C), 188.1 (C); LRMS (EI) m/z 131 (M+ꢀ106, 80%), 105
(100), 77 (50), 51 (26); HRMS calcd for C8H5NO (M+ꢀC4H10SO):
131.0371; found: 131.0371.
4.2.2. 2-Hydroxy-1-(4-methoxyphenyl)-2-(methylthio)ethan-1-
one 6d
4.3.3. (SS,E)-1-(4-Bromophenyl)-N-(tert-butanesulfinyl)-2-imi-
noethan-1-one 3c
The representative procedure was followed by using ethyl ester
4d (1.26 g, 1.13 mL, 7.0 mmol). Compound 6d (1.01 g, 5.18 mmol,
74%) was obtained as a orange solid, mp 73–74 °C (hexane/CH2Cl2);
The representative procedure was followed by using
hemithioketal 6c (1.30 g, 5.0 mmol). Purification by column chro-
matography (hexane/AcOEt, 4:1) yielded 3c (0.945 g, 3.0 mmol,
Rf 0.09 (hexane/EtOAc, 2:1); IR (neat)
m 2940, 1713, 1480, 1330,
1320, 1281, 1160, 850 cm–1 1H NMR (300 MHz, CDCl3) d 2.00
;
60%) as a orange oil; Rf 0.85 (hexane/EtOAc, 2:1); [
0.70, CH2Cl2); IR (neat) 2961, 1662, 1584, 1365, 1280, 1093,
1078 cm–1 1H NMR (300 MHz, CDCl3) d 1.29 [9H, s, (CH3)3], 7.66
a]
30 = +42.7 (c
D
(3H, s, CH3), 3.89 (3H, s, CH3), 6.08 (1H, s, CH), 6.97 (2H, d,
J = 8.7 Hz, 2 ꢁ CH), 8.05 (2H, d, J = 8.7 Hz, 2 ꢁ CH); 13C NMR
(100 MHz, CDCl3) 11.5 (CH3), 55.6 (CH3), 77.2 (CH), 113.8 (CH),
114.3 (CH), 121.4 (C), 132.3 (CH), 133.4 (CH), 164.0 (C), 193.8
(C); LRMS (EI) m/z 165 (M+ꢀ47, 24%), 135 (100), 107 (60), 77 (34).
m
;
(2H, d, J = 8.7 Hz, 2 ꢁ CH), 8.04 (2H, d, J = 8.7 Hz, 2 ꢁ CH); 8.42
(1H, s, CH); 13C NMR (100 MHz, CDCl3) 22.7 (CH3), 55.8 (C), 129.9
(C), 131.6 (CH), 131.2 (CH), 132.2 (C), 160.6 (CH), 187.0 (C); LRMS
(EI) m/z 211 (M+ꢀ106, 92%), 209 (90), 185 (100), 183 (92), 157 (35),
155 (40), 75 (36); HRMS calcd for C8H4Br79NO (M+ꢀC4H10SO):
208.9476; found: 208.9473.
4.2.3. 1-Hydroxy-1-(methylthio)undecan-2-one 6e
The representative procedure was followed by using ethyl ester
4e (1.40 g, 1.62 mL, 7.0 mmol). Compound 6e (1.30 g, 5.60 mmol,
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E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4.3.4. (SS,E)-N-(tert-Butanesulfinyl)-2-imino-1-(4-methoxyphenyl)-
ethan-1-one 3d
(C), 119.7 (CH2), 131.9 (CH), 172.6 (CH); LRMS (EI) m/z 161
(M+ꢀ56, 15%), 146 (60), 120 (100), 91 (13), 57 (50); HRMS calcd
for C10H19NO2S: 217.1136; found: 217.1136.
The representative procedure was followed by using
hemithioketal 6d (1.06 g, 5.0 mmol). Purification by column chro-
matography (hexane/AcOEt, 4:1) yielded 3d (0.921 g, 3.45 mmol,
69%) as a yellow solid, mp 64–65 °C (hexane/CH2Cl2); Rf 0.60 (hex-
4.4.3. (SS,4S,5R)-5-Amino-N-(tert-butanesulfinyl)-4-methylocta-
1,7-dien-4-ol 10a
The representative procedure was followed by using a-keto
imine 3a (0.0875 g, 0.5 mmol). Purification by column chromatog-
ane/EtOAc, 2:1); [
a
]
D
30 = +48.7 (c 1.00, CH2Cl2); IR (neat)
m
2939,
1666, 1590, 1509, 1309, 1261, 1251, 1167, 1022 cm–1
;
1H NMR
(300 MHz, CDCl3) d 1.29 [9H, s, (CH3)3], 3.90 (3H, s, CH3), 6.99 (2H,
d, J = 9.0 Hz, 2 ꢁ CH), 8.16 (2H, d, J = 9.0 Hz, 2 ꢁ CH); 8.48 (1H, s,
CH); 13C NMR (100 MHz, CDCl3) 22.7 (CH3), 55.6 (CH3), 58.5 (C),
114.1 (CH), 127.6 (C), 131.5 (C), 132.6 (CH), 161.3 (CH), 186.4 (C);
LRMS (EI) m/z 161 (M+ꢀ106, 60%), 135 (100), 77 (15); HRMS calcd
for C9H7NO2 (M+ꢀC4H10SO): 161.0477; found: 161.0478.
raphy (hexane/AcOEt, 4:1) yielded 10a (0.032 g, 0.125 mmol, 25%)
as a yellow oil; Rf 0.21 (hexane/EtOAc, 2:1); [
CH2Cl2); IR (neat) 2892, 1652, 1614, 1475, 1402, 1274, 1167,
1095 cm–1 1H NMR (300 MHz, CDCl3) d 1.24 [9H, s, (CH3)3], 1.26
a]
30 = +18.1 (c 1.00,
D
m
;
(3H, s, CH3), 2.10–2.55 (4H, m, 2 ꢁ CH2), 3.21 (1H, dt, J = 10.5,
3.0 Hz, CH), 3.82 (1H, d, J = 5.1 Hz, NH), 4.01 (1H, br s, OH), 5.02–
5.31 (4H, m, 2 ꢁ CH2), 5.81–6.10 (2H, m, 2 ꢁ CH); 13C NMR
(100 MHz, CDCl3) d 22.9 (CH3), 26.1 (CH3), 37.1 (CH2), 42.1 (CH2),
56.4 (C), 68.0 (CH), 73.3 (C), 117.1 (CH2), 117.9 (CH2), 135.1 (CH),
135.7 (CH); LRMS (EI) m/z 203 (M+ꢀ56, 18%), 191 (9), 163 (100),
157 (50), 146 (95), 130 (97), 117 (41), 109 (18), 89 (92), 55 (37);
HRMS calcd for C9H17NO2S (M+ꢀC4H8): 203.0980; found: 203.0988.
4.3.5. (SS,E)-N-(tert-Butanesulfinyl)-1-iminoundecan-2-one 3e
The representative procedure was followed by using
hemithioketal 6e (1.16 g, 5.0 mmol). Purification by column chro-
matography (hexane/AcOEt, 4:1) yielded 3e (0.79 g, 2.75 mmol,
55%) as a yellow oil; Rf 0.94 (hexane/EtOAc, 2:1); [
(c 1.12, CH2Cl2); IR (neat) 2954, 2923, 2854, 1702, 1458, 1365,
a]
30 = +176.2
D
m
1094 cm–1; 1H NMR (300 MHz, CDCl3) d 0.88 (3H, t, J = 6.3 Hz, CH2-
CH3), 1.24–1.31 [21H, m, 6 ꢁ CH2 and (CH3)3], 1.66 (2H, m, CH2),
2.86 (2H, t, J = 7.5 Hz, CH2), 7.93 (1H, s, CH); 13C NMR (100 MHz,
CDCl3) d 14.8 (CH3), 22.6 (CH3), 22.8 (CH2), 23.5 (CH2), 29.1
(CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 31.8 (CH2), 38.0 (CH2),
58.6 (C), 160.5 (CH), 198.2 (C); LRMS (EI) m/z 181 (M+ꢀ106, 5%),
152 (19), 124 (56), 98 (90), 55 (100); HRMS calcd for C11H19NO (M-
4.4.4. (SS,4S⁄,5R)-5-Amino-N-(tert-butanesulfinyl)-4-pheny-
locta-1,7-dien-4-ol 10b
The representative procedure was followed by using
a-keto
imine 3b (0.120 g, 0.5 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 10b (0.042 g, 0.13 mmol, 26%) as a
yellow oil (58:42 mixture of diastereoisomers); Rf 0.34 (hexane/
EtOAc, 2:1); IR (neat)
m 2902, 1475, 1450, 1326, 1274, 1167,
1095 cm–1 1H NMR (300 MHz, CDCl3) d 1.18 and 1.21 [9H, 2 s,
;
+
ꢀC4H10SO): 181.1467; found: 181.1469.
(CH3)3], 1.84–1.90 (2H, m, CH2), 2.41–2.48 (2H, m, CH2), 2.83
(1H, d, J = 6.9 Hz, NH), 3.41–3.46 (1H, m, CH), 3.77 and 4.79 (1H,
2 br s, OH), 4.91–5.30 (4H, m, 2 ꢁ CH2), 5.50–5.86 (2H, m,
2 ꢁ CH), 7.30–7.53 (5H, m, 5 ꢁ CH); 13C NMR (100 MHz, CDCl3) d
22.8 (CH3), 22.9 (CH3), 36.0 (CH2), 37.0 (CH2), 41.2 (CH2), 43.4
(CH2), 56.6 (C), 56.7 (C), 66.3 (CH), 67.1 (CH), 77.0 (C), 77.4 (C),
117.1 (CH2), 117.2 (CH2), 118.6 (CH2), 119.3 (CH2), 126.7 (CH),
126.8 (CH), 127.2 (CH), 127.3 (CH), 128.1 (CH), 128.2 (CH), 133.5
(CH), 134.3 (CH), 135.4 (CH), 135.7 (CH), 142.2 (C), 142.9 (C); LRMS
(EI) m/z 265 (M+ꢀ56, 10%), 224 (19), 183 (100), 147 (50), 77 (24),
55 (47); HRMS calcd for C10H20NOS (M+ꢀC8H7O): 202.1266; found:
202.1259.
4.4. General procedure for the allylation of N-tert-
butanesulfinyl-
a
-keto aldimines 3. Synthesis of compounds 10
To a solution of the corresponding
a-keto imine 3 (0.5 mmol) in
THF (2 mL) was added the corresponding allylic bromide 4
(0.225 g, 0.161 mL, 1.5 mmol) and indium (0.143 g, 1.25 mmol).
The resulting suspension was stirred at 23 °C for 6 h and after that
quenched with brine (4.0 mL) and extracted with ethyl acetate
(3 ꢁ 10 mL). The organic layer was dried over anhydrous magne-
sium sulfate and evaporated (15 Torr). The resulting residue was
then purified by column chromatography (silica gel, hexane/ethyl
acetate) to yield pure compounds 10. Yields, physical and spectro-
scopic data for these compounds follow.
4.4.5. (SS,4R,5S)-5-Allyl-4-amino-N-(tert-butanesulfinyl)tetra-
dec-1-en-5-ol 10e
4.4.1. (SS,3R)-3-Amino-N-(tert-butanesulfinyl)hex-5-en-2-one
The representative procedure was followed by using a-keto
8a
imine 3e (0,143 g, 0.5 mmol). Purification by column chromatogra-
Yellow oil; RF 0.17 (hexane/AcOEt 2:1); [
CH2Cl2); IR (neat) 2950, 1713, 1639, 1457, 1386, 1364, 1041,
910 cm–1 1H NMR (300 MHz, CDCl3) d 1.26 [9H, s, (CH3)3], 2.25
(3H, s, CH3), 2.43–2.65 (2H, m, CH2), 4.14 (H, q, J = 5.0 Hz, CH),
4.56 (H, d, J = 5.0 Hz, NH), 5.10–5.16 (2H, m, CH2), 5.62–5.74 (1H,
m, CH); 13C NMR (100 MHz, CDCl3) d 22.7 (CH3), 27.2 (CH3), 37.2
(CH2), 56.0 (C), 62.5 (CH), 118.85 (CH2), 132.1 (CH), 205.9 (C);
LRMS (EI) m/z 174 (M+ꢀ43, 18%), 161 (28), 146 (13), 118 (100),
91 (24), 57 (37); HRMS calcd for C8H16NOS (M+ꢀC2H3O):
174.0953; found: 174.0953.
a]
30 = +20.3 (c 0.65,
D
phy (hexane/AcOEt, 4:1) yielded 10e (0.068 g, 0.185 mmol, 37%) as
m
a yellow oil; Rf 0.34 (hexane/EtOAc, 2:1); [
Cl2); IR (neat) 2920, 2903, 2865, 1665, 1644, 1252, 1235, 1083,
975 cm–1 1H NMR (300 MHz, CDCl3) d 0.88 (3H, t, J = 5.1 Hz,
a]
30 = +56.1 (c 1.12, CH2-
D
;
m
;
CH3), 1.24 [9H, s, (CH3)3], 1.26–1.34 (16H, m, 8 ꢁ CH2), 2.04–2.39
(4H, m, 2 ꢁ CH2), 3.29 (1H, td, J = 7.8, 1.8 Hz, CH), 3.88 (1H, d,
J = 1.8 Hz, NH), 5.04–5.15 (4H, m, 2 ꢁ CH2), 5.71–5.83 (1H, m,
CH), 5.99–6.12 (1H, m, CH); 13C NMR (100 MHz, CDCl3) d 14.1
(CH3), 22.6 (CH2), 22.7 (CH2), 22.9 (CH3), 29.3 (CH2), 29.5 (CH2),
29.6 (CH2), 30.2 (CH2), 31.9 (CH2), 37.1 (CH2), 38.9 (CH2), 41.8
(CH2), 56.3 (C), 66.1 (CH), 74.5 (C), 117.0 (CH2), 117.5 (CH2),
135.7 (CH), 136.1 (CH); LRMS (EI) m/z 315 (M+ꢀ56, 14%), 274
(35), 233 (28), 141 (60), 113 (100), 85 (60) 71 (55), 57 (47); HRMS
calcd for C17H33NO2S (M+ꢀC4H8): 315.2232; found: 315.2238.
4.4.2. (SS)-N-(tert-Butanesulfinyl)-1-imino-2-methylpent-4-en-
2-ol 9a
Yellow oil (diastereomeric mixture); RF 0.45 (hexane/AcOEt
2:1); IR (neat)
m ;
2970, 1683, 1452, 1312, 1201, 1049, 896 cm–1
1H NMR (300 MHz, CDCl3) d 1.21 and 1.22 [9H, 2s, (CH3)3], 1.37
and 1.39 (3H, 2s, CH3), 2.44–2.48 (2H, m, CH2), 3.31 (1H, br s,
OH), 5.10–5.20 (2H, m, CH2), 5.51–5.92 (1H, m, CH), 8.06 (1H, s,
CH); 13C NMR (100 MHz, CDCl3) d 14.1 (CH3) 21.8 (CH3), 22.7
(CH3), 23.1 (CH3), 44.5 (CH2), 44.6 (CH2), 56.8 (C), 74.9 (C), 75.1
4.5. General procedure for the ring-closing metathesis of
compounds 10. Synthesis of aminocyclohexenols 11
A mixture of the corresponding 1,7-octadiene 10 (0.25 mmol),
ruthenium Hoveyda–Grubbs catalyst (7 mg, 0.0225 mmol) in dry
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6
E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
dichloromethane (4.0 mL) was stirred at 40 °C under argon for 4 h.
Then the solvent was evaporated (15 Torr) and the resulting resi-
due was purified by column chromatography (silica gel, hexane/
AcOEt) to yield pure compounds 11. Yields, physical and spectro-
scopic data for these compounds follow.
acetate (3 ꢁ 15 mL). The organic layer was dried over anhydrous
magnesium sulfate and evaporated (15 Torr). The resulting residue
was then purified by column chromatography (silica gel, hexane/
ethyl acetate) to yield pure compounds 12. Yields, physical and
spectroscopic data for these compounds follow.
4.5.1. (SS,1S,6R)-6-Amino-N-(tert-butanesulfinyl)-1-methylcyclo-
hex-3-en-1-ol 11a
4.6.1. (SS)-1-Amino-N-(tert-butanesulfinyl)propan-2-ol 12a
The representative procedure was followed by using
a-keto
The representative procedure was followed by using 1,7-octadi-
ene 10a (0.065 g, 0.25 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 11a (0.053 g, 0.23 mmol, 92%), as
imine 3a (0.0875 g, 0.5 mmol). Purification by column chromatog-
raphy (hexane/AcOEt, 4:1) yielded 12a (0.075 g, 0.42 mmol, 84%)
as a yellow oil (60:40 mixture of diastereoisomers); Rf 0.09 (hex-
a brown oil; Rf 0.50 (hexane/EtOAc, 2:1); [
Cl2); IR (neat) 3002, 2958, 1493, 1470, 1302, 1274, 1115, 1095,
967 cm–1 1H NMR (300 MHz, CDCl3) d 1.22 [9H, s, (CH3)3], 1.26
a
]
D
30 = +58.1 (c 1.15, CH2-
ane/EtOAc, 2:1); IR (neat) m 2958, 1464, 1410, 1356, 1132, 1007;
m
1H NMR (300 MHz, CDCl3) d 1.14 and 1.20 (3H, 2d, J = 6.3 Hz,
CH3), 1.23 and 1.24 [9H, 2s, (CH3)3], 3.01–3.20 and 3.32–3.71
(2H, 2m, CH2), 3.83–3.86 and 4.01–4.04 (2H, 2m, CH, NH); 13C
NMR (100 MHz, CDCl3) d 18.8 (CH3), 20.3 (CH3), 22.1 (CH3), 22.6
(CH3) 54.2 (CH2), 55.4 (C), 55.9 (C), 67.7 (CH), 68.0 (CH2), 68.3
(CH); LRMS (EI) m/z 123 (M+ꢀ56, 100), 57 (43); HRMS calcd for C3-
H9NO2S [M+ꢀC4H8]: 123.0354; found: 123.0346.
;
(3H, s, CH3), 2.22–2.39 (4H, m, 2 ꢁ CH2), 3.31 (1H, m, CH), 3.84
(1H, d, J = 5.0 Hz, NH), 5.12 (1H, br s, OH), 5.40–5.70 (2H, m,
CH = CH); 13C NMR (100 MHz, CDCl3) d 22.6 (CH3), 25.7 (CH3),
31.6 (CH2), 36.8 (CH2), 55.6 (C), 59.7 (CH), 69.8 (C), 122.7 (CH),
125.5 (CH); LRMS (EI) m/z 175 (M+ꢀ56, 28%), 160 (40), 97 (15),
57 (100); HRMS calcd for C7H13NO2S (M+ꢀC4H8): 175.0667; found:
175.0664.
4.6.2. (SS)-2-Amino-N-(tert-butanesulfinyl)-1-phenylethan-1-ol
12b
4.5.2. (SS,1R,6R)-6-Amino-N-(tert-butanesulfinyl)-1-phenylcyclo-
hex-3-en-1-ol 11b
The representative procedure was followed by using a-keto
imine 3b (0.120 g, 0.5 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 12b (0.065 g, 0.27 mmol, 54%) as a
white solid (59:41 mixture of diastereoisomers), mp 101–102 °C
The representative procedure was followed by using 1,7-octadi-
ene 10b as 3:2 diastereomeric mixture (0.080 g, 0.25 mmol). Purifi-
cation by column chromatography (hexane/AcOEt, 4:1) yielded
11b (0.026 g, 0.09 mmol, 36%), as a yellow oil; Rf 0.23 (hexane/
(hexane/CH2Cl2); Rf 0.27 (hexane/EtOAc, 1:1); IR (neat)
m 2957,
2871, 1457, 1416, 1379, 1245, 1099 cm–1 1H NMR (300 MHz,
;
EtOAc, 2:1); [
a]
30 = ꢀ20.8 (c 0.67, CH2Cl2); IR (neat)
m
3354,
CDCl3) d 1.19 and 1.23 [9H, 2 s, (CH3)3], 3.31–3.36 and 3.84–3.92
(3H, 2m, CH2, NH), 4.24 and 4.55 (1H, 2 br s, OH), 4.73–4.77 and
4.90–4.94 (1H, 2m, CH), 7.20–7.50 (5H, m, CH); 13C NMR
(100 MHz, CDCl3) d 22.6 (CH3), 22.7 (CH3), 54.3 (CH2), 54.4 (CH2),
56.0 (C), 56.1 (C), 73.0 (CH), 73.9 (CH), 130.0 (CH), 126.1 (CH),
127.6 (CH), 127.8 (CH), 128.4 (CH), 128.5 (CH), 141.4 (C), 141.5
(C); LRMS (EI) m/z 185 (M+ꢀ56, 20%), 146 (35), 121 (68), 91 (85),
79 (100), 57 (74); HRMS calcd for C8H11NO2S (M+ꢀC4H8):
185.0510; found: 185.0494.
D
2979, 1646, 1447, 1364, 1267, 1035 cm–1
;
1H NMR (300 MHz,
CDCl3) d 1,19 [9H, s, (CH3)3], 1.66–1.73 (1H, m, CH), 2.25–2.40
(1H, m, CH), 2.65–2.78 (1H, m, CH) 2.80–2.94 (1H, m, CH), 3.31
(1H, d, J = 10.5 Hz, NH), 3.55–3.61 (1H, m, CH), 5.60–5.73 (1H, m,
CH), 5.85–6.00 (1H, m, CH) 7.29–7.40 (3H, m, CH), 7.48–7.55 (2H,
m, CH); 13C NMR (100 MHz, CDCl3) d 22.7 (CH3), 32.8 (CH2), 40.8
(CH2), 56.0 (C), 62.3 (CH), 73.7 (C), 124.8 (CH), 126.7 (CH), 127.4
(CH), 128.1 (CH), 128.7 (CH), 142.6 (C); LRMS (EI) m/z 219
(M+ꢀ74, 10%), 188 (21), 170 (18), 156 (86), 105 (100), 77 (30), 57
(31); HRMS calcd for C16H23NO2S: 293.1449; found: 293.1462.
4.6.3. (SS)-2-Amino-1-(4-bromophenyl)-N-(tert-butanesulfinyl)
ethan-1-ol 12c
4.5.3. (SS,1S,6R)-6-Amino-N-(tert-butanesulfinyl)-1-methylcyclo-
hex-3-en-1-ol 110b
The representative procedure was followed by using a-keto
imine 3c (0.158 g, 0.5 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 12c (0.124 g, 0.39 mmol, 78%) as a
white solid (56:44 mixture of diastereoisomers), mp 80–82 °C
The representative procedure was followed by using 1,7-octadi-
ene 10b as 3:2 diastereomeric mixture (0.080 g, 0.25 mmol). Purifi-
cation by column chromatography (hexane/AcOEt, 4:1) yielded
110b (0.021 g, 0.07 mmol, 29%), as a dark brown oil; Rf 0.15 (hex-
(hexane/CH2Cl2); Rf 0.08 (hexane/EtOAc, 2:1); IR (neat)
m 2952,
1450, 1422, 1325, 1245, 1113, 958, 658 cm–1 1H NMR (300 MHz,
;
ane/EtOAc, 2:1); [
a
]
D
30 = +47.8 (c 1.15, CH2Cl2); IR (neat)
m
3338,
CDCl3) d 1.20 and 1.24 [9H, 2 s, (CH3)3], 3.21–3.40 (2H, m, CH2),
3.61–3.92 (1H, m, NH), 4.72 and 4.91 (1H, 2 dd, J = 8.7, 3.3 Hz,
CH), 7.20–7.30 (2H, m, 2 ꢁ CH), 7.47 (2H, d, J = 8.3 Hz, 2 ꢁ CH);
13C NMR (100 MHz, CDCl3) d 22.6 (CH3), 22.7 (CH3), 54.4 (CH2),
54.5 (CH2), 56.1 (C), 56.2 (C), 72.4 (CH), 73.4 (CH), 121.4 (C),
121.6 (C), 127.7 (CH), 127.8 (CH), 131.5 (CH), 131.6 (CH), 140.2
(C), 140.5 (C); LRMS (EI) m/z 264 (M+ꢀ56, 15%), 262 (17%), 196
(38), 184 (92), 183 (30), 182 (100), 181 (33), 156 (41), 154 (45);
HRMS calcd for C8H10Br79NOS (M+ꢀC4H8): 262.9616; found:
262.9627.
2972, 2908, 1679, 1448, 1305, 1126, 1026 cm–1
;
1H NMR
(300 MHz, CDCl3) d 1.13 [9H, s, (CH3)3], 2.24–2.74 (4H, m, CH),
3.53 (1H, br s, OH), 3.65 (1H, d, J = 5.7 Hz, NH), 3.77 (1H, q,
J = 5.7 Hz, CH), 5.69 (1H, m, CH), 5.79 (1H, m, CH), 7.28–7.40 (3H,
m, CH), 7.48–7.53 (2H, m, CH); 13C NMR (100 MHz, CDCl3) d 22.6
(CH3), 30.0 (CH2), 38.2 (CH2), 56.6 (C), 57.9 (CH), 73.9 (C), 124.0
(CH), 125.4 (CH), 126.1 (CH), 128.1 (CH), 128.5 (CH), 144.3 (C);
LRMS (EI) m/z 219 (M+ꢀ74, 9%), 188 (7), 170 (18), 157 (13), 156
(100), 155 (12), 105 (40), 77 (15), 57 (13); HRMS calcd for C16H23
NO2S: 293.1449; found: 293.1438.
-
4.6.4. (SS)-2-Amino-N-(tert-butanesulfinyl)-1-(4-methoxyphenyl)-
4.6. General procedure for the reduction of N-tert-
butanesulfinyl- -keto aldimines 3. Synthesis of compounds 12
ethan-1-ol 12d
a
The representative procedure was followed by using a-keto
imine 3d (0.135 g, 0.5 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 12d (0.120 g, 0.45 mmol, 89%) as a
white solid (57:43 mixture of diastereoisomers), mp 76–77 °C
To a solution of the corresponding a-keto imine 3 (0.5 mmol) in
methanol (3 mL) was added sodium borohydride (57 mg, 1.5 mmol)
at 0 °C. The resulting suspension was stirred at the same tempera-
ture for 4 h, and after that quenched with an aqueous saturated
solution of ammonium chloride (10.0 mL) and extracted with ethyl
(hexane/CH2Cl2); Rf 0.05 (hexane/EtOAc, 2:1); IR (neat)
1470, 1459, 1358, 1330, 1200, 1135, 1032 cm–1 1H NMR
(300 MHz, CDCl3) d 1.20 and 1.24 [9H, s, (CH3)3], 3.31–3.42 (2H,
m 2950,
;
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E. Maciá et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
m, CH2), 3.80 (3H, s, CH3), 4.1 (1H, br s, OH), 4.70–4.74 and 4.87–
References
4.90 (1H, 2m, CH), 6.88 (2H, dd, J = 8.7, 1.5 Hz, 2 ꢁ CH), 7.23–7.31
(2H, m, CH); 13C NMR (100 MHz, CDCl3) d 22.6 (CH3), 22.7 (CH3),
54.3 (CH2), 54.4 (CH2), 55.3 (CH3), 55.9 (C), 56.0 (C), 72.6 (CH),
73.6 (CH), 113.9 (CH), 127.2 (CH) 127.3 (CH) 133.4 (C) 133.5 (C),
159.1 (C), 159.3 (C); LRMS (EI) m/z 165 (M+ꢀ106, 20%), 137 (86),
135 (100), 119 (90), 109 (80), 81 (84); HRMS calcd for C9H11NO2
(M+ꢀC4H10SO): 165.0790; found: 165.0782.
1. Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57, 10257.
2. For recent reviews, see: (a) Zhao, X.; Zhu, B.; Jiang, Z. Synlett 2015, 26, 2216; (b)
Fang, X.; Wang, C.-J. Chem. Commun. 2015, 1185; (c) Ishikawa, H.; Shiomi, S.
Org. Biomol. Chem. 2016, 14, 409.
3. For recent reviews, see: (a) Liu, Y.-L.; Zhou, J. Synthesis 2015, 47, 1210; (b)
Thaima, T.; Zamani, F.; Hyland, C. J. T.; Pyne, S. G. Synthesis 2017, 49, 1461; (c)
Cheng, M.-X.; Yang, S.-D. Synlett 2017, 28, 159.
4. For reviews, see: (a) Lin, G.-Q.; Xu, M.-H.; Zhong, Y.-W.; Sun, X.-W. Acc. Chem.
Res. 2008, 41, 831; (b) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. Chem.
Soc. Rev. 2009, 38, 1162; (c) Robak, M. A. T.; Herbage, M. A.; Ellman, J. A. Chem.
Rev. 2010, 110, 3600.
5. (a) Weix, D. J.; Ellman, J. A. Org. Lett. 2003, 5, 1317; (b) Weix, D. J.; Ellman, J. A.
Org. Synth. 2005, 82, 157.
4.6.5. (SS)-1-Amino-N-(tert-butanesulfinyl)dodecan-2-ol 12e
The representative procedure was followed by using
a-keto
imine 3e (0.143 g, 0.5 mmol). Purification by column chromatogra-
phy (hexane/AcOEt, 4:1) yielded 12e (0.081 g, 0.28 mmol, 56%) as a
yellow oil (54:46 mixture of diastereoisomers); Rf 0.13 (hexane/
6. (a) Wakayama, M.; Ellman, J. A. J. Org. Chem. 2009, 74, 2646; (b) Aggarwal, V. K.;
Barbero, N.; McGarrigle, E. M.; Mickle, G.; Navas, R.; Suárez, J. R.; Unthank, M.
G.; Yar, M. Tetrahedron Lett. 2009, 50, 3482.
EtOAc, 2:1); IR (neat)
m
2954, 2923, 2854, 1455, 1408, 1375,
;
7. (a) Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 2004, 15, 3823; (b) González-
Gómez, J. C.; Medjahdi, M.; Foubelo, F.; Yus, M. J. Org. Chem. 2010, 75, 6308; (c)
Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2012, 2543; For general
reviews on allylation of carbonyl compounds and imines, see: (d) Yus, M.;
González-Gómez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774; (e) Yus, M.;
González-Gómez, J. C.; Foubelo, F. Chem. Rev. 2013, 113, 5595.
8. Barros, O. S. R.; Sirvent, J. A.; Foubelo, F.; Yus, M. Chem. Commun. 2014, 50, 6898.
9. García-Muñoz, M. J.; Zacconi, F.; Foubelo, F.; Yus, M. Eur. J. Org. Chem. 2013,
1287.
10. See, for instance: (a) González-Gómez, J. C.; Foubelo, F.; Yus, M. Synlett 2008,
2777; (b) Medjahdi, M.; González-Gómez, J. C.; Foubelo, F.; Yus, M. Eur. J. Org.
Chem. 2011, 2230.
11. See, for instance: (a) Medjahdi, M.; González-Gómez, J. C.; Foubelo, F.; Yus, M. J.
Org. Chem. 2009, 74, 7859; (b) Sirvent, A.; Foubelo, F.; Yus, M. J. Org. Chem.
2014, 79, 1356.
1271, 1137, 1094, 985 cm–1
1H NMR (300 MHz, CDCl3) d 0.88
(3H, t, J = 6.6 Hz, CH3), 1.23 and 1.24 [9H, 2 s, (CH3)3], 1.24–1.32
(14H, m, 7 ꢁ CH2), 1.38–1.43 (2H, m, CH2), 2.91–3.10 and 3.15–
3.33 (2H, 2m, CH2), 3.58–3.66, 3.71–3.79, 3.80–3.92 (2H, 3m, NH,
CH); 13C NMR (100 MHz, CDCl3) d 14.1 (CH3), 22.6 (CH3), 22.7
(CH3), 25.6 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 31.9 (CH2)
34.4 (CH2), 34.6 (CH2), 52.5 (CH2), 52.9 (CH2), 55.8 (C). 56.1 (C),
70.8 (CH), 71.6 (CH); LRMS (EI) m/z 235 (M+ꢀ56, 16%), 155 (45),
141 (55), 113 (100), 85 (76), 71 (48), 57 (35), 56 (24); HRMS calcd
for C15H33NO2S: 291.2232; found: 291.2235.
12. Maciá, E.; Foubelo, F.; Yus, M. Tetrahedron 2016, 72, 6001.
13. Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64,
1278.
Acknowledgements
14. Alvarez Ibarra, C.; Cuervo Rodríguez, R.; Fernández Monreal, M. C.; García
Navarro, F. J.; Martín Tesorero, J. J. Org. Chem. 1989, 54, 5620.
15. (a) Becker, H. D.; Mikol, G. J.; Russell, G. A. J. Am. Chem. Soc. 1963, 85, 3410; (b)
Antoine, M.; Gerlach, M.; Günther, E.; Schuster, T.; Czech, M.; Seipelt, I.;
Marchand, P. Synthesis 2012, 44, 69.
We thank the continued financial support from our Ministerio
de Ciencia e Innovación (MCINN; CONSOLIDER INGENIO 2010-
CDS2007-00006, CTQ2011-24165), the Ministerio de Economía y
Competitividad (MINECO; projects CTQ2014-53695-P, CTQ2014-
51912-REDC, CTQ2016-81797-REDC), FEDER, the Generalitat
Valenciana (PROMETEO 2009/039, PROMETEOII/2014/017), and
the University of Alicante.
16. Benedetti, E.; Lomazzi, M.; Tibiletti, F.; Goddard, J.-P.; Fensterbank, L.; Malacria,
M.; Palmisano, G.; Penoni, A. Synthesis 2012, 44, 3523.
Please cite this article in press as: Maciá, E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.010