Enantiopure trifluoromethylated β3,3-amino acids: Synthesis by asymmetric reformatsky reaction with stable analogues of trifluoromethyl N-tert-butanesulfinylketoimines and incorporation into α/β-peptides

Article abstract of DOI:10.1021/jo302549v

Addition of a Reformatsky reagent to α-aryl(alkyl) α-trifluoromethyl N-tert-butanesulfinyl hemiaminals, bench-stable surrogates of trifluoromethyl ketoimines, provided β-alkyl(aryl) β-trifluoromethyl β-amino acids derivatives in good yields and high diastereoselectivities. The N-tert-butanesulfinyl β^3,3-amino esters were further utilized as versatile intermediates for the elaboration of heterodi- and -tripeptides.

Full text of DOI:10.1021/jo302549v

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Article
Enantiopure trifluoromethylated beta3,3-amino acids: Synthesis by
asymmetric Reformatsky reaction with stable analogues of trifluoromethyl
N-tert-butanesulfinyl ketoimines and incorporation into alpha/beta-peptides.
Fabienne GRELLEPOIS
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302549v • Publication Date (Web): 28 Dec 2012
Downloaded from http://pubs.acs.org on January 2, 2013
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Enantiopure trifluoromethylated
β
3,3ꢀamino acids: Synthesis
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by asymmetric Reformatsky reaction with stable analogues of
trifluoromethyl Nꢀtertꢀbutanesulfinyl ketoimines and
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incorporation into α/βꢀpeptides.
Fabienne Grellepois*
Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS
UMR 7312, UFR des Sciences Exactes et Naturelles, BP 1039, 51687 Reims Cedex 2, France
fabienne.grellepois@univ-reims.fr
t-Bu
t-Bu
O
O
O
CF3
R
S
S
Br
HN
O
O
NH O
PGHN
OCH3
OR'
N
N
F3C
R
OEt
H
H
R
OR'
O
CF3
Zn, CuCl
Me-THF, 0°C
dr up to >99:1
yield up to 87%
Addition of a Reformatsky reagent to αꢀaryl(alkyl) αꢀtrifluoromethyl Nꢀtertꢀbutanesulfinyl
hemiaminals, bench stable surrogates of trifluoromethyl ketoimines, provided ꢀalkyl(aryl)
trifluoromethyl ꢀamino acids derivatives in good yields and high diastereoselectivities. The
β
βꢀ
β
Nꢀtertꢀbutanesulfinyl β3,3ꢀamino esters were further utilized as versatile intermediates for the
elaboration of heteroꢀdiꢀ and tripeptides.
Introduction
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Enantiopure
β
ꢀamino acids are very attractive building blocks for the synthesis of
peptidomimetics and many others bioactive compounds.1 They are in particular the subunits
ꢀ2 and ꢀpeptides3 which have received a great deal of attention due to their unique
folding properties and their specific biological activities.2,3 Despite this tremendous interest in
ꢀamino acids1b,4 and considering the beneficial effects of the substitution of hydrogen by
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of
β
α/β
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β
fluorine,5 very little is known about the synthesis and the biological properties of their
fluorinated and fluoroalkylated analogues.6
Amongst the various substitution patterns of fluoroalkylated
βꢀamino acids, enantiopure βꢀ
trifluoromethyl
β
ꢀamino acids (β3ꢀamino acids7) have been extensively studied. Numerous
diastereoselective8 and enantioselective9 syntheses of (R)ꢀ or (S)ꢀ3ꢀaminoꢀ4,4,4ꢀ
trifluorobutanoic acid derivatives have been reported to date. These compounds have been
incorporated into partially modified retropeptides leading to a nine membered
βꢀturn like
conformation and into peptidomimetics having MMP inhibitory activities.10 Despite the
promising studies showing new secondary structures provided by
βꢀpeptides containing chiral
gemꢀdisubstituted
β
ꢀamino acids in nonfluorinated series,11 enantiopure geminally
disubstituted βꢀtrifluoromethyl βꢀamino acids derivatives (βꢀalkyl(aryl) βꢀtrifluoromethyl βꢀ
amino acids) have been scarcely reported. Only one derivative belonging to this subclass of
β3,3ꢀamino acids, an Nꢀacetyl
β
ꢀmethyl β ꢀtrifluoromethyl β ꢀamino ester, has been described
to date.8i Its synthesis involved the highly stereoselective addition of 2ꢀ(pꢀtolylsulfinyl)ꢀ
benzylic carbanion to a trifluoromethylated imine and phenyl ring oxidation into a carboxylic
acid function as key steps. This approach is consequently limited to βꢀalkyl substituents and
required numerous steps to obtain the target building block. The development of a short,
efficient and general synthesis of enantiopure βꢀtrifluoromethyl βꢀamino acids containing a
quaternary stereogenic center in the βꢀposition is still missing and constitutes a challenge for
organic chemists.
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Since its first report 15 years ago,12 chiral Nꢀtertꢀbutanesulfinamides developped by Ellman
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have been increasingly used for the preparation of a wide range of chiral monoꢀ and polyꢀ
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functionalized amines derivatives, including variously substituted β
ꢀamino acids.13 While the
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1,2ꢀaddition of ester enolate14 with tertꢀbutanesulfinyl ketoimines is the favored reaction for
the synthesis of a variety of nonracemic Nꢀprotected β3,3ꢀamino esters, the use of the
Reformatsky reagent appeared to be more suitable when the target building block is required
on a large scale.15 In spite of the obvious interesting properties of Ellman’s chiral auxiliary
such as the availability of both enantiomers and the mild conditions required for its
cleavage,13 only a few publications deal with the applications of trifluoromethylꢀsubstituted
Nꢀtertꢀbutanesulfinyl ketoimines.16 The presence of the activating substituent on the nitrogen
atom makes the aliphatic and aromatic trifluoromethyl Nꢀtertꢀbutanesulfinyl ketoimines
significantly more electrophilic than their Nꢀalkyl or Nꢀaryl analogues. They have to be
generated and isolated quickly prior to use16a since they are unstable at room temperature and
easily hydrolyzed or decomposed during workꢀup or purification on silica gel. Only
trifluoromethyl α,βꢀunsatured Nꢀtertꢀbutanesulfinyl ketoimines are quite stable.16b,d
According to the authors, the conjugative stabilizing effect of the CꢀC double bond on the Cꢀ
N double bond might explain this higher stability.
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In this paper, we wish to disclose our results for the oneꢀstep synthesis of various enantiopure
Nꢀtertꢀbutanesulfinyl trifluoromethyl β3,3ꢀamino esters from bench stable analogues of
aliphatic and aromatic trifluoromethyl Nꢀtertꢀbutanesulfinyl ketoimines. We also report the
coupling of one of the target buildingꢀblocks with natural
αꢀamino acid derivatives to
elaborate an original α/β/αꢀtripeptide.
Results and Discussion
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The low hydrostability of aliphatic and aromatic trifluoromethyl Nꢀtertꢀbutanesulfinyl
ketoimines significantly diminishs their potential synthetic value and thus our initial efforts
focused on developing bench stable surrogates.
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As perfluoroalkyl groups adjacent to imines are known to increase their reactivity towards
nucleophiles and to have a stabilizing effect for the obtained quaternary species, hemiaminals
appeared to be the most convenient precursors for our work.17,18
2,2,2ꢀTrifluoroacetophenone 1a reacted with
a
slight excess of (S)ꢀ2ꢀmethylꢀ2ꢀ
propanesulfinamide (S)ꢀ2 (1.2 equivalents) in the presence of Ti(OEt)4 (2 equivalents) in
hexane at room temperature for 4 days to give the hemiaminal 3a (Table 1, entry 1).
Hemiaminal 3a was isolated in 75% yield as a mixture of two diasteroisomers. The separation
of both diastereomers and the unequivocal assignment of their stereochemistry were irrelevant
for the pursuit of our study (vide infra). Monitoring of the reaction by 19F NMR indicated that
the ketone 1a was slowly converted into the corresponding ketoimine (small signal, broad
singlet at ꢀ70.8 ppm) which was then rapidly converted into hemiaminal 3a. Although this
transformation was extremely slow, hemiaminal 3a was easily isolated and purified by
chromatography on silica gel and found to be highly stable.19 These conditions were then
applied to variously substituted trifluoromethylketones 1b-h (Table 1). They were effective
for most electron rich and electron poor aromatic ketones 1b,c-e,f and aliphatic ketones 1g,h
(the isolated yields ranged from 64ꢀ76%) (entries 2, 5ꢀ8). 4ꢀNitrophenyl hemiaminal 3c was
isolated in only 45% yield due to the formation of many trifluoromethylated byꢀproducts
during the course of the reaction (entry 3). The limitation of this approach was observed for
the ketone 1d which didn’t lead to the corresponding hemiaminal as the condensation stopped
at the ketoimine stage (Table 1, entry 4 and Scheme 1). Ketoimine 4 was isolated in 67%
yield and was stable enough to be stored several days in the freezer (around 5% of
decomposition into ketone 1d was detected by 19F NMR after 4 days in the freezer). The
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bulky methoxy group close to the imine function seemed to prevent nucleophilic addition.
Finally, it should be noted that a small amount of enamine 5 was also formed when the
reaction was performed with 1,1,1ꢀtrifluorobutanꢀ2ꢀone 1h (Scheme 2). The Z geometry of the
enamine 5 was determined by an heteronuclear nOe experiment.
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Table 1. Synthesis of hemiaminals 3a-g.
entry
R
time hemiꢀ yield
1
(%)
aminal
1
2
3
4
5
6
7
8
Ph
4 d
3 d
3 d
6 d
6 d
4 d
4 d
2 d
75
76
45
ꢀ
1a
1b
1c
1d
3a
3b
3c
4ꢀFC6H4
4ꢀNO2C6H4
2ꢀMeOC6H4
a
-
1e 3ꢀMeOC6H4
3d
3e
3f
64
69
70
65b
4ꢀMeOC6H4
1f
1g
1h
Me
Et
3g
a
only ketimine 4 was formed and isolated, see
b
Scheme 1. 6% of enamine 5 was also isolated,
see Scheme 2.
Scheme 1. Synthesis of imine 4 from ketone 1d.
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Scheme 2. Reaction of ketone 1h with Ellman’s chiral auxiliary (S)-2 in the presence of
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Ti(OEt)4.
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To carry out the synthesis of β3,3ꢀamino acids, we first explored the effect of solvent and
temperature on the diastereoselectivity and yield of the addition process of Reformatsky
reagent. This reaction being tolerant to a large range of solvents,20 addition of organozinc
reagent to 3a was explored in DME, Et2O, THF, 2ꢀMeꢀTHF, CH2Cl2, DMF and MeCN (Table
2). The Reformatsky reagent was formed in situ by reacting ethyl bromoacetate (2.5
equivalents) in the presence of a large excess of Zn (10 equivalents) and CuCl (1 equivalent)
30 min at room temperature and 45 min at 50°C (or at reflux in Et2O or CH2Cl2). The reaction
was successful at room temperature in Et2O, THF and 2ꢀMeꢀTHF but not in DME (entries 1ꢀ
4). The facial stereoselectivity of the addition was better in 2ꢀMeꢀTHF than THF and Et2O
(86:14 instead of 78:22 and 80:20, entries 2ꢀ4). In 2ꢀMeꢀTHF, decreasing the temperature
from room temperature to 0°C had a slightly beneficial effect on the diastereoselectivity
(88:12 instead of 86:14) and on the yield of βꢀamino acids 6a and 6’a (respectively 69 and
77%, entries 4ꢀ5). Starting from a diastereoisomeric pure sample of 3a led to the same
diastereomeric ratio (entry 6) as that obtained from a mixture (entry 5). This strongly implies
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that the addition of the reagent occurred on the intermediate ketoimine and thus the separation
of both diastereoisomers of hemiaminals 3a-g was unnecessary for this reaction. The
stereoselectivity could not be improved by lowering the temperature as the addition was
inhibited at ꢀ10°C (entry 7). Changing the solvent to CH2Cl2 gave no improvement in
stereoselectivity (53:47, entry 8). Finally, in polar aprotic solvents such as DMF and MeCN
the reaction failed (entries 9ꢀ10). Based on these results, using 2ꢀMeꢀTHF21 at 0°C appeared
to be the best conditions for the synthesis of the target β3,3ꢀaminoꢀacids 6 and 6’.
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Table 2. Optimisation of Reformatsky reagent additions to N-sulfinyl hemiaminal 3a.
t-Bu
t-Bu
O
S
S
Br
O
NH
O
HN
O
OEt
F3C
Ph
OEt
CF3
OEt
Ph
Zn, CuCl
solvent, T°C
3a
(SS,S) + (SS,R)
6a
6'a
dr (6a:6’a)a yield (%)b
entry solvent T°C
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2
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4
DME
Et2O
THF
rt
rt
rt
ꢀc
ꢀc
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70
69
77
79
ꢀc
80:20
78:22
86:14
88:12
88:12
ꢀc
2ꢀMeꢀTHF rt
5d 2ꢀMeꢀTHF 0°C
6e 2ꢀMeꢀTHF 0°C
2ꢀMeꢀTHF ꢀ10°C
7
CH2Cl2
DMF
rt
rt
rt
53:47
ꢀc
63
ꢀc
8
9
10
MeCN
ꢀc
ꢀc
a
diastereomeric ratios 6a:6’a determined by 19F
b
NMR of the crude mixture. isolated yield after
silica gel purification. The two diastereoisomers
6a and 6’a were not separated. No addition
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d
observed. reaction performed with the mixture
e
of two diastereoisomers of hemiaminal 3a.
reaction performed on the major diastereoisomer
of hemiaminal 3a.
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The addition of various simple Reformatsky reagents to the aromatic and aliphatic
hemiaminals 3a-g was thus explored under these optimized conditions. Results are collected
in Table 3. For aromatic derivatives (entries 1ꢀ10), the diastereomeric ratio ranges from
moderate to very high (82:18 to 96:4). Notably, switching from ethyl bromoacetate to the
more sterically encumbered tertꢀbutyl bromoacetate always improved the facial
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stereoselectivity. Except for βꢀ4ꢀfluorophenyl βꢀtrifluoromethyl βꢀamino ethyl ester 6d/6’d
(entries 4), the major diastereomers could be separated by silica gel chromatrography. In most
cases, a small amount of pure minor diastereomer was also isolated (entries 1ꢀ3, 5ꢀ6, 8ꢀ9). The
reaction of methyl and ethyl hemiaminal 3f-g with methyl, ethyl or tertꢀbutyl bromoacetate
gave the corresponding β3,3ꢀamino esters 6k-o with excellent stereoselectivity (>99:1)
regardless the bromoacetate used (entries 11ꢀ15).
Table 3. Synthesis of trifluoromethyl β3,3-amino esters.
dr (6:6’)a
product 6 yield (%) product 6’ yield (%)
entry hemiaminal
R
R’
Ph
Ph
Ph
Et
88:12
87:13
93:7
59
9
1
2
3
4
3a
3a
3a
3b
6a
6b
6c
6’a
6’b
6’c
Bn
58
11
3
tꢀBu
65
4ꢀFC6H4
Et
86:14
6d/ 6’d 77b
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4ꢀFC6H4
4ꢀNO2C6H4
3ꢀMeOC6H4
3ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMeOC6H4
Me
tꢀBu
tꢀBu
Et
93:7
96:4
67
79
64
70
57
71
86
79
68
85
87
2
3
5
6
3b
3c
3d
3d
3e
3e
3f
6e
6f
6’e
6’f
90:10
93:7
7
6g
6h
6i
tꢀBu
Et
2
9
8
6’h
6’i
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82:18
90:10
>99:1c
>99:1c
>99:1c
>99:1c
>99:1c
9
tꢀBu
Me
Et
10
11
12
13
14
15
6j
6k
6l
Me
3f
Me
tꢀBu
Et
3f
6m
6n
6o
Et
3g
Et
tꢀBu
3g
diastereomeric ratios 6a: 6’a determined by 19F NMR of the crude mixture. the two
a
b
diastereomers 6d and 6’d could not be separated by silica gel purification. c the minor isomer
was not detected by 19F NMR of the crude reaction mixture.
These conditions were also applied to the imine 4 using ethyl bromoacetate. Only a small
conversion of imine into amino ester 6p was observed which might be due to the steric
hindrance around the electrophilic carbon of the imine function (16% of conversion according
19
to the F NMR of the crude reaction mixture) (Scheme 3). However, the diastereoselectivity
of the addition was excellent (dr >99:1).
Scheme 3. Reformatsky reaction of imine 4 with ethyl bromoacetate.
t-Bu
t-Bu
O
S
S
N
O
Br
O
NH
O
OEt
F3C
CF3
OEt
Zn, CuCl
2-Me-THF, 0°C
OMe
OMe
4
conv = 16%
dr > 99:1
6p (14%)
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The absolute configuration of the amino ester 6h was determined by Xꢀray crystallography
(figure 1).22 The absolute configurations of other amino esters 6 and 6’ were assigned by
analogy.
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S
S
O
NH
O
F3C
O
S
6h
O
Figure 1. Structure of compound 6h from single crystal X-ray data.
The observed diastereoselectivity (vide supra) for the addition of the Reformatsky reagent is
consistent with a ZimmermanꢀTraxlerꢀtype sixꢀmembered transition state TS-1 with
coordination of the sulfinyl oxygen of the intermediate imine to zinc (Scheme 4).13,15,16b,c,e,20
In this sixꢀmembered chair transition state, the trifluoromethyl group prefers to occupy the
equatorial position rather than the axial one due to steric hindrance (its Van der Waals radius
lies between those of iPr and tBu) and to the electrostatic repulsion between the
trifluoromethyl group and the lone pair of the sulfur atom.5b,16b,c,e,23
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Scheme 4. Rationalization of the observed diastereoselectivity.
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Because application of
βꢀtrifluoromethyl βꢀamino acids in peptide design is still in the early
stages of development,6c,10 we then focused on the elaboration of heteroꢀdiꢀ and tripeptides
containing βꢀtrifluoromethyl βꢀmethyl amino acid 7.
β3,3 Amino acid 7 was prepared by basic hydrolysis of methyl, ethyl or tertꢀbutyl amino esters
6k-m in very good yields (78%ꢀ99%) (Table 4).
Table 4. Preparation of trifluoromethyl β3,3-amino acid 7.
t-Bu
t-Bu
1. LiOH,H2O
solvent
S
S
O
NH
O
O
NH
O
T°C
F3C
F3C
OR
OH
2. HCl, H2O
6k-m
7
R
solvent
T°C yield 7 (%)
6
Me MeOH:H2O (3:1)
Et EtOH:H2O (3:1)
rt
rt
99
92
6k
6l
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tꢀBu THF:H2O (1:1) reflux
78
6m
5
6
7
8
The coupling at the Cꢀtermini of the Nꢀprotected β3,3 amino acid 7 with
Lꢀalanine methyl ester
9
hydrochloride or ꢀphenylalanine ethyl ester hydrochloride was achieved using a conventional
L
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procedure24 (EDCI, HOBT, DIEA, DMF) (Scheme 5). NꢀProtected dipeptides 8a-b were
obtained in excellent yield (93ꢀ96%). Removal of the sulfinyl protecting group of dipeptides
8a-b was easily performed by reaction with HCl (2N in Et2O) in an alcoholic solvent.14b,15
After basic aqueous workꢀup, dipeptides 9a-b were isolated in respectively 82 and 78% yield.
Scheme 5.
Access to
C
-coupling of β3,3 amino acid 7 with alanine and phenylalanine amino esters:
β
/α
-dipeptides 9a-b.
To prove that these new trifluoromethyl β3,3ꢀamino acid derivatives were also suitable for
incorporation into peptide via their Nꢀtermini, coupling of the ꢀpeptide 9a was then
β/α
investigated. Because of the low nucleophilicity and steric hindrance of amine adjacent to the
electron withdrawing and bulky trifluoromethyl group, specific activating methods (amino
acid bromide25 or chloride,26 highly electrophilic mixed anhydride27) have been developed for
the Nꢀterminal coupling of αꢀtrifluoromethylated αꢀamino acids. Based on these results, we
performed the reaction of dipeptide 9a with freshly prepared Fmoc alanine acid chloride26,28 in
the presence of DIEA in CH2Cl2. Under these coupling conditions, the heterotripeptide 10 was
obtained and isolated in very good yield (87%). Attempts to perform the reaction with the
more stable Fmoc alanine acid fluoride29 failed.
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Scheme 6. -coupling of dipeptide 9a with
N
N-Fmoc L-alanine acid chloride: Access to the
7
8
original α/β/α-tripeptide 10.
9
O
CF3
10
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OCH3
H2N
N
H
O
9a
Cl
FmocHN
O
DIEA, CH2Cl2, rt
O
O
CF3
FmocHN
OCH3
N
N
H
H
O
10 (87%)
Conclusion
In conclusion, the asymmetric synthesis of βꢀalkyl(aryl) βꢀtrifluoromethyl βꢀamino esters has
been described via an highly stereoselective iminoꢀReformatsky reaction with bench stable
trifluoromethyl Nꢀtertꢀbutanesulfinyl ketoimine surrogates. This approach is the first efficient
and general preparation of
stereocenter adjacent to the amine function. The versatility of these Nꢀtertꢀbutanesulfinyl
alkyl(aryl) ꢀtrifluoromethyl ꢀamino esters was further proved by their incorporation into
peptides. Cꢀ as well as Nꢀterminal coupling with natural ꢀamino acid derivatives was
βꢀtrifluoromethyl βꢀamino acid derivatives containing a quaternary
β
ꢀ
β
β
α
successfully performed. We expect that the reported synthesis will find utility in the synthesis
of new peptidomimetics and foldamers.
Experimental section
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nꢀHexane and DME (monoglyme) were distilled from CaH2. THF, Et2O and MeCN were
dried using a Pure Solv solvent drying system over aluminium oxide under an Argon
atmosphere. CH2Cl2 (extraꢀdry, water < 0,003%), DMF (extraꢀdry, water < 0,005%) and 2ꢀ
MeꢀTHF (extraꢀdry, water < 0,005%, on molecular sieves) were purchased from Acros
Organics. Ti(OEt)4 and DIEA were distilled prior to use. Zn was activated by stirring with a
2% HCl solution and successive washing with distilled H2O, 95% EtOH, and Et2O.30 Zn was
then dried thoroughly in a vacuum oven at 70°C for at least 24h15 (activated Zn can be stored
under these conditions for 10 days). Thin–layer chromatography using precoated aluminium
backed plates (Merck Kieselgel 60F254) were visualized by UV light and/or by
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phosphomolybdic acid. Silicagel 40ꢀ63
ꢀm (MachereyꢀNagel GmbH & Co KG) was used for
flash chromatography. Silicagel 15ꢀ40
ꢀm (Merck) was used for the separation of
diastereomers 6 and 6’. NMR spectra were recorded in CDCl3 with 250 MHz, 500 MHz, or
) are reported in ppm relative to TMS for 1H and
600 MHz spectrometers. Chemicals shifts (
δ
13C NMR spectra and to CFCl3 for 19F NMR spectra. In the 13C NMR data, reported signal
multiplicities are related to CꢀF coupling. The following abbreviations are used to indicate the
multiplicities: s (singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), m (multiplet). Diastereomeric ratios (dr) were determined by 19F NMR. HRMS were
recorded on an ESIꢀQꢀTOF mass spectrometer using an electrospray source in positive mode.
Melting points (mp) were determined on a Tottoli apparatus and were uncorrected. Optical
rotations were measured at room temperature (c.a. 20 °C).
General procedure for the reaction of ketones 1a-h with (S)-tert-butanesulfinamide (S)-2
in the presence of Ti(OEt)4.
A solution of trifluoromethyl ketone 1, (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (1.2 equiv) and
Ti(OEt)4 (2 equiv) in nꢀhexane was stirred at room temperature under Ar for 2ꢀ6 days . The
reaction mixture was then quenched with H2O and after 5 min of stirring was filtered on a pad
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of celite (Et2O). The organic layer of the filtrate was extracted, washed with brine, dried
(MgSO4) and concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (petroleum ether:Et2O).
9
(SS)-N-(1-ethoxy-2,2,2-trifluoro-1-phenylethyl)-tert-butylsulfinamide 3a. Following the
general procedure, 2,2,2ꢀtrifluoroacetophenone 1a (5.0 g, 28.7 mmol) reacted with (S)ꢀtertꢀ
butanesulfinamide (S)ꢀ2 (4.2 g, 34.5 mmol) and Ti(OEt)4 (12.0 mL, 57.4 mmol) in nꢀhexane
(70 mL) for 4 days. Purification on silica gel (petroleum ether:Et2O 1:1 to 2:3) afforded
hemiaminal 3a (7.0 g, 75%, dr = 74:26) as a colorless oil. IR (film) νmax 1079, 1100, 1175,
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58
59
60
2982 cmꢀ1; NMR 19F (235 MHz, CDCl3)
1H (250 MHz, CDCl3)
δ ꢀ78.5 (s, CF3, major), ꢀ78.9 (s, CF3, minor); NMR
δ
1.25ꢀ1.37 (m, 12H, minor and major), 3.44 (m, 1H, minor), 3.76 (m,
1H, major), 3.88 (m, 1H, minor and major), 4.38 (s, 1H, minor), 4.62 (s, 1H, major), 7.35ꢀ
7.70 (5H, minor and major); NMR 13C (62.9 MHz, CDCl3)
δ
14.6 (minor), 14.9 (major), 22.2
(minor), 22.5 (major), 57.1 (minor), 57.3 (major), 59.2 (minor), 60.2 (major), 86.8 (q, J = 30.5
Hz, minor), 89.4 (q, J = 29.0 Hz, major), 122.7 (q, J = 290.0 Hz, minor), 123.2 (q, J = 290.0
Hz, major), 127.6 (minor), 127.8 (major), 128.7 (minor), 129.0 (major), 129.6 (major), 129.9
(minor), 133.1 (major), 134.1 (minor). HRMS (ESI+): m/z calcd for C14H20F3NaNO2S
[M+Na]+ 346.1065, found 346.1079.
(SS)-N-(1-ethoxy-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-tert-butylsulfinamide
3b.
Following the general procedure, 2,2,2,4’ꢀtetrafluoroacetophenone 1b (2.15 g, 11.2 mmol)
reacted with (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (1.63 g, 13.4 mmol) and Ti(OEt)4 (4.7 mL, 22.4
mmol) in nꢀhexane (30 mL) for 3 days. Purification on silica gel (petroleum ether:Et2O 1:1 to
2:3) afforded hemiaminal 3b (2.9 g, 76%, dr = 64:36) as a yellow oil. IR (film) νmax 1089,
1161, 1183, 2983 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
ꢀ78.3 (s, CF3, major), ꢀ78.9 (s, CF3,
1
minor), ꢀ111.1 (m, CF, minor), ꢀ112.1 (m, CF, major); NMR H (250 MHz, CDCl3)
δ 1.29ꢀ
1.37 (m, 12Η, minor and major), 3.39 (m, 1H, minor), 3.73 (m, 1H, major), 3.90 (m, 1H,
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minor and major), 4.26 (s, 1H, minor), 4.65 (s, 1H, major), 7.10 (ddd, J = 4.0 Hz, J = 8.5 Hz,
J = 16.0 Hz, 2H, minor and major), 7.46 (m, 1H, minor), 7.52 (dd, J = 5.5 Hz, J = 9.0 Hz, 1H,
major), 7.65 (dd, J = 5.5 Hz, J = 8.5 Hz, 1H, minor and major); NMR 13C (62.9 MHz, CDCl3)
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δ
14.3 (minor), 14.7 (major), 21.9 (minor), 22.2 (major), 56.9 (minor), 57.0 (major), 59.0
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(minor), 60.1 (major), 88.9 (q, J = 29.0 Hz, minor), 89.6 (q, J = 30.0 Hz, major), 114.6 (d, J =
21.5 Hz, minor and major), 115.1 (d, J = 22.5 Hz, minor), 115.5 (d, J = 22.0 Hz, major),
122.5 (q, J = 290.0 Hz, minor), 123.0 (q, J = 296.0 Hz, major), 129.1 (d, J = 3.0 Hz, major),
129.8 (d, J = 8.5 Hz, major), 130.3 (d, J = 3.0 Hz, minor), 130.4 (d, J = 9.0 Hz, minor), 131.0
(d, J = 8.5 Hz, minor and major), 163.3 (d, J = 250.0 Hz, major), 163.4 (d, J = 250.0 Hz,
minor). HRMS (ESI+): m/z calcd for C14H19F4NaNO2S [M+Na]+ 364.0970, found 364.0954.
(SS)-N-(1-ethoxy-2,2,2-trifluoro-1-(4-nitrophenyl)ethyl)-tert-butylsulfinamide
3c.
Following the general procedure, 4’ꢀnitroꢀ2,2,2ꢀtrifluoroacetophenone 1c (1.82 g, 8.3 mmol)
reacted with (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (1.21 g, 10.0 mmol) and Ti(OEt)4 (3.5 mL, 16.6
mmol) in nꢀhexane (40 mL) for 3 days. Purification on silica gel (petroleum ether:Et2O 2:1 to
1:3) afforded hemiaminal 3c (1.40 g, 45%, dr = 71:29) as a yellow oil. IR (film) νmax 1092,
1183, 1351, 1528 cmꢀ1; NMR 19F (235 MHz, CDCl3)
minor); NMR 1H (250 MHz, CDCl3)
δ ꢀ77.3 (s, CF3, major), ꢀ78.1 (s, CF3,
δ
1.24 (s, 9H, major), 1.27 (s, 9H, minor), 1.29 (m, 3H,
minor and major), 3.34 (m, 1H, minor), 3.71 (m, 1H, major), 3.92 (m, 1H, minor and major),
4.51 (s, 1H, minor), 4.83 (s, 1H, major), 7.71 (d, J = 8.5 Hz, 2H, minor), 7.84 (d, J = 8.5 Hz,
2H, major), 8.16 (d, J = 9.0 Hz, 2H, major), 8.21 (d, J = 10.0 Hz, 2H, minor); NMR 13C (62.9
MHz, CDCl3)
δ 14.6 (minor), 14.9 (major), 22.2 (minor), 22.5 (major), 57.5 (minor), 57.7
(major), 59.7 (minor), 60.6 (major), 88.8 (q, J = 29.0 Hz, major), 89.7 (q, J = 30.0 Hz, minor),
122.3 (q, J = 288.0 Hz, minor), 122.7 (q, J = 289.0 Hz, major), 122.9 (major), 123.7 (minor),
129.3 (minor), 130.4 (major), 140.7 (major), 141.0 (minor), 148.6 (major), 148.8 (minor).
HRMS (ESI+): m/z calcd for C14H19F3NaN2O4S [M+Na]+ 391.0915, found 391.0910.
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(SS)-N-(1-ethoxy-2,2,2-trifluoro-1-(3-methoxyphenyl)ethyl)-tert-butylsulfinamide
3d.
4
5
6
7
8
Following the general procedure, 3’ꢀmethoxyꢀ2,2,2ꢀtrifluoroacetophenone 1e (1.29 g, 6.3
mmol) reacted with (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (917 mg, 7.6 mmol) and Ti(OEt)4 (2.65
mL, 12.6 mmol) in nꢀhexane (30 mL) for 6 days. Purification on silica gel (petroleum
ether:Et2O 3:2 to 1:2) afforded hemiaminal 3d (1.42 g, 64%, dr = 57:43) as a yellow oil. IR
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60
(film)
ν
max 1089, 1104, 1162, 1183, 1264, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ78.3 (s,
1
CF3, major), ꢀ78.8 (s, CF3, minor); NMR H (250 MHz, CDCl3)
δ 0.80ꢀ1.43 (m, 12H, minor
and major), 3.46 (m, 1H, minor), 3.75 (m, 1H, major), 3.82 (d, J = 1.0 Hz, 3H, minor), 3.83
(s, 3H, major), 3.88 (m, 1H, minor and major), 4.36 (s, 1H, minor), 4.60 (s, 1H major), 6.94ꢀ
7.40 (m, 4H, minor and major); NMR 13C (62.9 MHz, CDCl3)
δ 14.9 (minor), 15.2 (major),
22.4 (minor), 22.8 (major), 55.4 (minor), 55.5 (major), 57.4 (minor), 57.6 (major), 59.5
(major), 60.5 (minor), 89.5 (q, J = 29.0 Hz, major), 89.9 (q, J = 29.5 Hz, minor), 114.2
(minor), 115.0 (major), 115.2 (major), 115.5 (minor), 119.8 (minor), 121.6 (major), 122.8 (q,
J = 287.0 Hz, minor), 123.3 (q, J = 291.0 Hz, major), 129.0 (minor), 130.0 (major), 134.7
(major), 135.9 (minor), 159.4 (major), 160.0 (minor). HRMS (ESI+): m/z calcd for
C15H22F3NaNO3S [M+Na]+ 376.1170, found 376.1158.
(SS)-N-(1-ethoxy-2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)-tert-butylsulfinamide
3e.
Following the general procedure, 4’ꢀmethoxyꢀ2,2,2ꢀtrifluoroacetophenone 1f (808 mg, 3.96
mmol) reacted with (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (576 mg, 4.75 mmol) and Ti(OEt)4 (1.66
mL, 7.92 mmol) in nꢀhexane (20 mL) for 4 days. Purification on silica gel (petroleum
ether:Et2O 3:2 to 1:2) afforded hemiaminal 3e (966 mg, 69%, dr = 62:38) as a yellow oil. IR
(film)
ν
max 1091, 1173, 1258, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
ꢀ78.8 (s, CF3, major),
ꢀ79.0 (s, CF3, minor); NMR 1H (250 MHz, CDCl3)
δ
1.18 (t, J = 7.5 Hz, 3H, minor), 1.28 (s,
9H, major), 1.30 (s, 9H, minor), 1.31 (m, 3H, major), 3.44 (m, 1H, minor and major), 3.73 (m,
1H, minor), 3.80 (s, 3H, minor and major), 3.84 (m, 1H, major), 4.31 (s, 1H, minor), 4.58 (s,
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1H, major), 6.90 (m, 2H, minor and major), 7.42 (d, J = 9.0 Hz, 2H, minor), 7.54 (d, J = 9.0
4
5
6
Hz, 2H, major); NMR 13C (62.9 MHz, CDCl3)
δ 14.8 (minor), 15.1 (major), 22.4 (minor),
7
8
9
22.7 (major), 55.3 (major), 55.4 (minor), 57.2 (minor), 57.4 (major), 59.2 (minor), 60.3
(major), 89.5 (q, J = 29.0 Hz, major), 89.8 (q, J = 30.0 Hz, minor), 113.3 (major), 114.2
(minor), 122.9 (q, J = 287.0 Hz, minor), 123.3 (q, J = 290.5 Hz, major), 125.7 (minor), 126.0
(major), 129.1 (minor), 130.6 (major), 160.0 (major), 160.9 (minor). HRMS (ESI+): m/z calcd
for C15H22F3NaNO3S [M+Na]+ 376.1170, found 376.1161.
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(SS)-(+)-N-(2-ethoxy-1,1,1-trifluoropropan-2-yl)-tert-butylsulfinamide 3f. Following the
general procedure, 1,1,1ꢀtrifluoroacetone 1g (5.0 g, 44.5 mmol) reacted with (S)ꢀtertꢀ
butanesulfinamide (S)ꢀ2 (6.5 g, 53.4 mmol) and Ti(OEt)4 (18.6 mL, 89.0 mmol) in nꢀhexane
(80 mL) for 4 days. Purification on silica gel (petroleum ether:Et2O 1:1) afforded hemiaminal
20
D
3f (8.1 g, 70%, dr = 100:0) as a white solid. mp 52ꢀ53°C; [
α]
+73 (c 1.04, CHCl3); IR
(film) νmax 939, 1062, 1131, 1169, 2984 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ84.8 (s, CF3);
1
NMR H (250 MHz, CDCl3)
δ 1.21 (t, J = 7.5 Hz, 3H), 1.23 (s, 3H), 1.67 (s, 3H), 3.59 (m,
1H), 3.71 (td, J = 7.5 Hz, J = 14.5 Hz, 1H), 3.90 (s, 1H); NMR 13C (62.9 MHz, CDCl3)
δ
15.2, 16.4, 22.4, 56.6, 58.4, 87.8 (q, J = 30.0 Hz), 123.5 (q, J = 123.5 Hz). HRMS (ESI+): m/z
calcd for C9H19F3NO2S [M+H]+ 262.1089, found 262.1087.
(SS)-N-(2-ethoxy-1,1,1-trifluorobutan-2-yl)-tert-butylsulfinamide 3g and (SS,Z)-2-methyl-N-
(1,1,1-trifluorobut-2-en-2-yl)propane-2-sulfinamide
5. Following the general procedure,
1,1,1ꢀtrifluoroꢀ2ꢀbutanone 1h (588 mg, 4.67 mmol) reacted with (S)ꢀtertꢀbutanesulfinamide
(S)ꢀ2 (679 mg, 5.60 mmol) and Ti(OEt)4 (1.95 mL, 9.34 mmol) in nꢀhexane (8 mL) for 2
days. Purification on silica gel (petroleum ether:Et2O 1:1 to 1:2) afforded hemiaminal 3g (835
mg, 65%, dr = 9:91) as a white solid followed by enamine 5 (64 mg, 6%) as a beige solid. 3g:
IR (film)
ν
max 963, 1060, 1132, 1155, 1181, 2902, 2986 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ
1
73.6 (s, CF3, minor), ꢀ79.6 (s, CF3, major); NMR H (250 MHz, CDCl3)
δ major 0.93 (t, J =
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7.5 Hz, CH3), 1.10 (t, J = 7.0 Hz, CH3), 1.11 (s, 9H), 1.88 (dq, J = 7.5 Hz, J = 14.5 Hz, 1H),
4
5
6
2.13 (m, 1H), 3.51 (m, 2H), 3.90 (s, 1H); NMR 13C (62.9 MHz, CDCl3)
δ major 7.3, 15.0,
7
8
22.3, 24.4, 56.5, 58.0, 89.2 (q, J = 28.5 Hz), 123.5 (q, J = 288.0 Hz). HRMS (ESI+): m/z calcd
9
for C10H20F3NaNO2S [M+Na]+ 298.1065, found 298.1055. 5: mp 107ꢀ108°C; [
α]
+45 (c
20
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59
60
1.01, CHCl3); IR (film) νmax 1052, 1125, 1179, 1261, 1276, 3125 cmꢀ1; NMR 19F (235 MHz,
ꢀ70.1 (s, CF3); NMR 1H (500 MHz, CDCl3)
4.5 Hz, 3H), 4.65 (s, 1H), 6.18 (q, J = 7.5 Hz, 1H); NMR 13C (125.8 MHz, CDCl3)
CDCl3)
δ
δ 1.28 (s, 3H), 1.88 (qd, J = 2.0 Hz, J =
δ
12.5,
22.4, 57.3, 121.6 (q, J = 273.0 Hz), 125.6, 128.4 (q, J = 32.5 Hz). HRMS (ESI+): m/z calcd for
C8H15F3NOS [M+H]+ 230.0826, found 230.0820.
(S)-2-methyl-N-(2,2,2-trifluoro-1-(2-methoxyphenyl)ethylidene)propane-2-sulfinamide
4.
Following the general procedure, 2’ꢀmethoxyꢀ2,2,2ꢀtrifluoroacetophenone 1d (1.1 g, 5.39
mmol) reacted with (S)ꢀtertꢀbutanesulfinamide (S)ꢀ2 (784 mg, 6.47 mmol) and Ti(OEt)4 (2.25
mL, 10.68 mmol) in nꢀhexane (20 mL) for 6 days. Purification on silica gel (petroleum
ether:Et2O 2:1 containing 0.1% of Et3N) afforded imine 4 (1.1 g, 67%) as a yellow oil. IR
(film) νmax 1105, 1141, 1199, 1258, 1492, 1600, 1638, 2966 cmꢀ1; NMR 19F (235 MHz,
CDCl3)
2H), 7.21 (d, J = 7.5 Hz, 1H), 7.38 (m, 1H); NMR 13C (62.9 MHz, CDCl3)
δ δ 1.22 (s, 9H), 3.83 (s, 3H), 6.91 (m,
ꢀ71.4 (br s, CF3); NMR 1H (250 MHz, CDCl3)
δ
22.9, 55.6, 59.0,
110.7, 119.0 (q, J = 283.5 Hz), 120.0, 128.2, 132.4, 156.6 (2 quaternary carbons not detected).
HRMS (ESI+): m/z calcd for C13H16F3NaNO2S [M+Na]+ 330.0752, found 330.0741.
General procedure for the Reformatsky reaction.
A threeꢀnecked flask containing activated Zn (10 equiv) and CuCl (1 equiv) was heated under
Ar with a heat gun for 5 min. The flask was allowed to cool to rt, 2ꢀMeꢀTHF was added
(formation of a black slurry) and the suspension was heated to reflux under vigorous stirring
for 30 min under Ar. The heating bath was then removed, alkyl bromoacetate (2.5 equiv) was
added dropwise (caution: exothermic reaction) while maintaining the vigorous stirring and the
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reaction was stirred for an additional 30 min at room temperature and 45 min at 50°C. The
reaction was then cooled to 0°C, a solution of hemiaminal 3 or imine 4 in 2ꢀMeꢀTHF was
added and the resulting reaction mixture was stirred at 0°C under Ar (reaction monitored by
19F NMR). The reaction mixture was filtered on a pad of celite (Et2O). The filtrate was
washed with diluted HCl 2%, a saturated aqueous solution of NaHCO3 and brine. The organic
layer was dried (Na2SO4), concentrated under reduced pressure and the residue was purified
by chromatography on silica gel (petroleum ether:EtOAc).
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(SS,S)-(+)-Ethyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6a
and (SS,R)-Ethyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6’a
.
Following the general procedure, a solution of hemiaminal 3a (358 mg, 1.11 mmol) in 2ꢀMeꢀ
THF (15 mL) was added to a suspension of activated Zn (723 mg, 11.1 mmol), CuCl (110
mg, 1.11 mmol) and ethyl bromoacetate (308
reaction mixture was stirred 6h at 0°C. Purification of the residue (dr 6a: 6’a = 88:12) on
silica gel (petroleum ether:EtOAc 6:1 to 4:1) afforded ꢀamino ester 6’a (35 mg, 9%) as a
ꢀL, 2.78 mmol) in 2ꢀMeꢀTHF (5 mL). The
β
colorless oil, an intermediate fraction containing 6’a and 6a (38 mg, 9%), and βꢀamino ester
20
6a (240 mg, 59%) as a colorless oil. 6a: [
α]
+80 (c 0.85, CHCl3); IR (film) νmax 1077,
D
1160, 1178, 1260, 1276, 1729, 2986 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ75.0 (s, CF3);
1
NMR H (500 MHz, CDCl3)
δ 1.25 (t, J = 7.0 Hz, 3H), 1.29 (s, 9H), 3.24 (d, J = 16.0 Hz,
1H), 3.38 (d, J = 16.0 Hz, 1H), 4.18 (m, 2H), 6.26 (s, 1H), 7.41 (m, 3H), 7.59 (m, 2H); NMR
13C (125.8 MHz, CDCl3)
286.5 Hz), 128.5, 128.8, 129.5, 133.6, 170.5. HRMS (ESI+): m/z calcd for C16H22F3NaNO3S
[M+Na]+ 388.1170, found 388.1172. 6’a: IR (film)
3006 cmꢀ1; NMR 19F (235 MHz, CDCl3) ꢀ73.1 (s, CF3); NMR 1H (500 MHz, CDCl3)
δ 1.18
δ
14.1, 22.8, 39.1, 57.0, 61.5, 65.0 (q, J = 27.5 Hz), 125.3 (q, J =
ν
max 1078, 1180, 1260, 1276, 1734, 2988,
δ
(t, J = 7.0 Hz, 3H), 1.33 (s, 9H), 3.42 (d, J = 17.5 Hz, 1H), 3.61 (d, J = 17.5 Hz, 1H), 4.09 (q,
13
J = 7.0 Hz, 2H), 5.14 (s, 1H), 7.39 (m, 3H), 7.52 (d, J = 7.0 Hz, 2H); NMR C (125.8 MHz,
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CDCl3)
δ
14.1, 22.7, 38.4, 57.4, 61.3, 64.9 (q, J = 27.0 Hz), 124.9 (q, J = 286.0 Hz), 127.1,
128.7, 129.2, 136.9, 169.6. HRMS (ESI+): m/z calcd for C16H22F3NaNO3S [M+Na]+
388.1170, found 388.1166.
5
6
7
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9
(SS,S)-(+)-Benzyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6b
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and (SS,R)-Benzyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6’b
.
Following the general procedure, a solution of hemiaminal 3a (321 mg, 0.99 mmol) in 2ꢀ
MeꢀTHF (15 mL) was added to a suspension of activated Zn (649 mg, 9.92 mmol), CuCl
(98 mg, 0.99 mmol) and benzyl bromoacetate (389
The reaction mixture was stirred 3h at 0°C. Purification of the residue (dr 6b: 6’b = 87:13)
on silica gel (petroleum ether:EtOAc 6:1 to 2:1) afforded ꢀamino ester 6’b (47 mg, 11%)
ꢀL, 2.48 mmol) in 2ꢀMeꢀTHF (5 mL).
β
as a beige oil, an intermediate fraction containing 6’b and 6b (61 mg, 14%), and βꢀamino
20
ester 6b (245 mg, 58%) as a beige oil. 6b: [
α
]
+83 (c 0.97, CHCl3); IR (film) νmax
D
1076, 1173, 1260, 1276, 1732, 2962, 2983 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ75.0 (s,
1
CF3); NMR H (500 MHz, CDCl3)
δ 1.28 (s, 9H), 3.33 (d, J = 16.0 Hz, 1H), 3.49 (d, J =
16.0 Hz, 1H), 5.16 (s, 2H), 6.20 (s, 1H), 7.34 (m, 5H), 7.40 (m, 3H), 7.60 (m, 2H); NMR
13C (125.8 MHz, CDCl3)
δ
22.6, 39.0, 56.9, 64.9 (q, J = 27.5 Hz), 67.1, 125.2 (q, J =
286.5 Hz), 128.36, 128.39, 128.5, 128.6, 129.4, 133.4, 135.0, 170.0. HRMS (ESI+): m/z
calcd for C21H24F3NaNO3S [M+Na]+ 450.1327, found 450.1317. 6’b: IR (film) νmax 1078,
1160, 1178, 1259, 1275, 1736, 2980 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ73.2 (s, CF3);
1
NMR H (500 MHz, CDCl3)
δ 1.31 (s, 9H), 3.49 (d, J = 17.5 Hz, 1H), 3.71 (d, J = 17.5
Hz, 1H), 4.99 (d, J = 12.0 Hz, 1H), 5.07 (s, 1H), 5.12 (d, J = 12.0 Hz, 1H), 7.21 (dd, J =
3.0 Hz, J = 6.5 Hz, 2H), 7.32 (m, 3H), 7.36 (m, 3H), 7.49 (m, 2H); NMR 13C (125.8 MHz,
CDCl3)
δ 22.6, 38.4, 57.4, 64.9 (q, J = 27.0 Hz), 67.1, 124.9 (q, J = 286.0 Hz), 127.1,
128.5, 128.8, 129.2, 135.2, 136.8, 169.3. HRMS (ESI+): m/z calcd for C21H24F3NaNO3S
[M+Na]+ 450.1327, found 450.1312.
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(SS,S)-(+)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6c
4
5
6
and (SS,R)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-phenylbutanoate 6’c
.
7
8
Following the general procedure, a solution of hemiaminal 3a (306 mg, 0.95 mmol) in 2ꢀMeꢀ
9
THF (15 mL) was added to a suspension of activated Zn (618 mg, 9.45 mmol), CuCl (94 mg,
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60
0.95 mmol) and tertꢀbutyl bromoacetate (347
reaction mixture was stirred 5h at 0°C. Purification of the residue (dr 6c: 6’c = 93:7) on silica
gel (petroleum ether:EtOAc 6:1 to 4:1) afforded ꢀamino ester 6’c (13 mg, 3%) as a colorless
ꢀL, 2.36 mmol) in 2ꢀMeꢀTHF (5 mL). The
β
oil, an intermediate fraction containing 6’c and 6c (15 mg, 4%), and βꢀamino ester 6c (241
20
D
mg, 65%) as a beige oil. 6c: [
α]
+70 (c 1.08, CHCl3); IR (film) νmax 1078, 1155, 1260,
1
1276, 1368, 1723, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
ꢀ74.3 (s, CF3); NMR H (500
MHz, CDCl3)
δ 1.27 (s, 9H), 1.40 (s, 9H), 3.08 (d, J = 15.5 Hz, 1H), 3.26 (d, J = 15.5 Hz,
1H), 6.24 (s, 1H), 7.38 (m, 3H), 7.60 (d, J = 7.5 Hz, 2H); NMR 13C (125.8 MHz, CDCl3)
δ
22.8, 27.9, 40.6, 57.0, 65.3 (q, J = 27.0 Hz), 82.4, 125.4 (q, J = 286.5 Hz), 128.4, 128.7,
129.3, 134.1, 169.4. HRMS (ESI+): m/z calcd for C18H26F3NaNO3S [M+Na]+ 416.1483, found
416.1471. 6’c: IR (film) νmax 1077, 1263, 1275, 1726, 2928, 2984 cmꢀ1; NMR 19F (235 MHz,
1
CDCl3)
δ
ꢀ72.9 (s, CF3); NMR H (250 MHz, CDCl3)
δ
1.33 (s, 9H), 3.32 (d, J = 17.0 Hz,
1H), 3.52 (d, J = 17.0 Hz, 1H), 5.12 (s, 1H), 7.39 (m, 3H), 7.53 (m, 2H). HRMS (ESI+): m/z
calcd for C18H26F3NaNO3S [M+Na]+ 416.1483, found 416.1482.
(SS,S)-Ethyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-fluorophenyl)butanoate
6d
and
(SS,R)-Ethyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-
fluorophenyl)butanoate 6’d. Following the general procedure, a solution of hemiaminal 3b
(403 mg, 1.18 mmol) in 2ꢀMeꢀTHF (15 mL) was added to a suspension of activated Zn
(772 mg, 11.8 mmol), CuCl (117 mg, 1.18 mmol) and ethyl bromoacetate (327 ꢀL, 2.95
mmol) in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred 5h30 at 0°C. Purification of
the residue (dr 6d: 6’d = 86:14) on silica gel (petroleum ether:EtOAc 6:1 to 4:1) afforded
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an unseparable mixture of
IR (film)
β
ꢀamino esters 6d and 6’d (348 mg, 77%) as a pale yellow oil.
ν
max 1078, 1169, 1515, 1729, 2983 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ73.3 (s,
7
8
9
CF3, minor), ꢀ75.2 (s, CF3, major), ꢀ112.2 (m, CF, major), ꢀ112.9 (m, CF, minor); NMR
1H (500 MHz, CDCl3)
δ
1.16 (t, J = 7.0 Hz, 3H, minor), 1.22 (t, J = 7.0 Hz, 3H, major),
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1.26 (s, 9H, major), 1.29 (s, 9H, minor), 3.18 (d, J = 16.0 Hz, 1H, major), 3.33 (d, J =
16.0 Hz, 1H, major), 3.36 (d, J = 17.5 Hz, 1H, minor), 3.59 (d, J = 17.5 Hz, 1H, minor),
4.06 (m, 2H, minor), 4.15 (m, 2H, major), 5.10 (s, 1H, minor), 6.25 (s, 1H, major), 7.04 (t,
J = 9.0 Hz, 2H, minor), 7.07 (t, J = 8.5 Hz, 2H, major), 7.47 (dd, J = 5.0 Hz, J = 9.0 Hz,
2H, minor), 7.56 (dd, J = 5.0 Hz, 8.5 Hz, 2H, major); NMR 13C (125.8 MHz, CDCl3)
δ
14.0 (minor and major), 22.5 (minor), 22.7 (major), 38.2 (minor), 39.1 (major), 57.0
(major), 57.3 (minor), 61.3 (minor), 61.5 (major), 64.5 (q, J = 27.5 Hz, minor), 64.6 (q, J
= 27.5 Hz, major), 115.4 (d, J = 22.0 Hz, major), 115.6 (d, J = 21.5 Hz, minor), 124.7 (q,
J = 285.5 Hz, minor), 125.1 (q, J = 286.0 Hz, major), 129.0 (d, J = 8.5 Hz, minor), 129.3
(d, J = 3.5 Hz, major), 130.8 (d, J = 8.5 Hz, major), 132.7 (d, J = 3.5 Hz, minor), 162.9 (d,
J = 249.5 Hz, minor), 163.1 (d, J = 250.0 Hz, major), 169.4 (minor), 170.2 (major).
HRMS (ESI+): m/z calcd for C16H21F4NaNO3S [M+Na]+ 406.1076, found 406.1080.
(SS,S)-(+)-tert-Butyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-
fluorophenyl)butanoate 6e and (SS,R)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-
trifluoro-3-(4-fluorophenyl)butanoate 6’e. Following the general procedure, a solution of
hemiaminal 3b (378 mg, 1.11 mmol) in 2ꢀMeꢀTHF (15 mL) was added to a suspension of
activated Zn (724 mg, 11.1 mmol), CuCl (110 mg, 1.11 mmol) and tertꢀbutyl
bromoacetate (409
ꢀL, 2.79 mmol) in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred
5h30 at 0°C. Purification of the residue (dr 6e: 6’e = 93:7) on silica gel (petroleum
ether:EtOAc 6:1 to 4:1) afforded
β
ꢀamino ester 6’e (8 mg, 2%) as a colorless oil and βꢀ
20
amino ester 6e (305 mg, 67%) as a colorless oil. 6e: [
α]
+75 (c 0.99, CHCl3); IR (film)
D
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νmax 1079, 1157, 1242, 1369, 1515, 1723, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ74.4
(s, CF3), ꢀ112.6 (m, CF); NMR 1H (500 MHz, CDCl3)
δ 1.27 (s, 9H), 1.40 (s, 9H), 3.05 (d,
5
6
7
8
9
J = 15.5 Hz, 1H), 3.22 (d, J = 15.5 Hz, 1H), 6.26 (s, 1H), 7.08 (t, J = 8.5 Hz, 2H), 7.60
(dd, J = 5.0 Hz, 8.5 Hz, 2H); NMR 13C (125.8 MHz, CDCl3)
δ
22.8, 28.0, 40.7, 57.1, 65.1
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(q, J = 27.5 Hz), 82.7, 115.4 (d, J = 21.5 Hz), 125.3 (q, J = 286.5 Hz), 130.0 (d, J = 3.5
Hz), 130.9 (d, J = 8.5 Hz), 163.1 (d, J = 250.0 Hz), 169.3. HRMS (ESI+): m/z calcd for
C18H25F4NaNO3S [M+Na]+ 434.1389, found 434.1380. 6’e: IR (film) νmax 1079, 1158,
1241, 1253, 1512, 1772, 2980 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ ꢀ73.1 (s, CF3), ꢀ113.1
1
(m, CF); NMR H (250 MHz, CDCl3)
δ 1.32 (s, 9H), 1.34 (s, 9H), 3.29 (d, J = 17.0 Hz,
1H), 3.53 (d, J = 17.0 Hz, 1H), 5.11 (s, 1H), 7.08 (t, J = 7.0 Hz, 2H), 7.51 (dd, J = 5.0 Hz,
J = 8.5 Hz, 2H). HRMS (ESI+): m/z calcd for C18H25F4NaNO3S [M+Na]+ 434.1389, found
434.1390.
(SS,S)-(+)-tert-Butyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-
nitrophenyl)butanoate 6f and (SS,R)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-
trifluoro-3-(4-nitrophenyl)butanoate 6’f. Following the general procedure, a solution of
hemiaminal 3c (247 mg, 0.67 mmol) in 2ꢀMeꢀTHF (8 mL) was added to a suspension of
activated Zn (439 mg, 6.71 mmol), CuCl (66 mg, 0.67 mmol) and tertꢀbutyl bromoacetate
(246
ꢀL, 1.68 mmol) in 2ꢀMeꢀTHF (3 mL). The reaction mixture was stirred 6h at 0°C.
Purification of the residue (dr 6f: 6’f = 96:4) on silica gel (petroleum ether:EtOAc 6:1 to
4:1) afforded
β
ꢀamino ester 6’f (9 mg, 3%) as a colorless oil and βꢀamino ester 6f (233
20
mg, 79%) as a colorless oil. 6f: [
α
]
+49 (c 1.10, CHCl3); IR (film) νmax 1078, 1159,
ꢀ73.6 (s, CF3); NMR 1H (500
D
1351, 1526, 1722, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
MHz, CDCl3)
δ 1.28 (s, 9H), 1.39 (s, 9H), 3.08 (d, J = 16.0 Hz, 1H), 3.25 (d, J = 16.0 Hz,
1H), 6.26 (s, 1H), 7.85 (d, J = 9.0 Hz, 2H), 8.24 (d, J = 16.0 Hz, 2H); NMR 13C (125.8
MHz, CDCl3)
δ
22.7, 27.9, 40.7, 57.6, 65.7 (q, J = 27.5 Hz), 83.2, 123.4, 124.9 (q, J =
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287.0 Hz), 130.1, 141.6, 148.2, 168.8. HRMS (ESI+): m/z calcd for C18H25F3NaN2O5S
4
5
6
[M+Na]+ 461.1334, found 461.1339. 6’f: IR (film) νmax 1080, 1161, 1351, 1527, 1723,
7
8
1
2980 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
ꢀ72.6 (s, CF3); NMR H (250 MHz, CDCl3)
9
δ
1.33 (s, 9H), 1.36 (s, 9H), 3.36 (d, J = 17.5 Hz, 1H), 3.61 (d, J = 17.5 Hz, 1H), 5.16 (s,
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1H), 7.74 (d, J = 9.0 Hz, 2H), 8.26 (d, J = 9.0 Hz, 2H). HRMS (ESI+): m/z calcd for
C18H25F3NaN2O5S [M+Na]+ 461.1334, found 461.1351.
(SS,S)-(+)-Ethyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(3-
methoxyphenyl)butanoate 6g. Following the general procedure, a solution of hemiaminal
3d (226 mg, 0.64 mmol) in 2ꢀMeꢀTHF (10 mL) was added to a suspension of activated Zn
(418 mg, 6.40 mmol), CuCl (63 mg, 0.64 mmol) and ethyl bromoacetate (177
ꢀL, 1.60
mmol) in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred 4h30 at 0°C. Purification of
the residue (dr 6g:6’g = 90:10) on silica gel (petroleum ether:EtOAc 6:1 to 4:1) afforded
20
β
ꢀamino ester 6g (163 mg, 64%) as a colorless oil. [
α
]
+80 (c 1.28, CHCl3); IR (film)
D
νmax 1078, 1178, 1258, 1393, 1435, 1587, 1605, 1728, 2962, 2981 cmꢀ1; NMR 19F (235
1
MHz, CDCl3)
δ
ꢀ74.7 (s, CF3); NMR H (500 MHz, CDCl3)
δ
1.25 (t, J = 7.0 Hz, 3H),
1.29 (s, 9H), 3.19 (d, J = 16.0 Hz, 1H), 3.36 (d, J = 16.0 Hz, 1H), 3.82 (s, 3H), 4.18 (m,
2H), 6.22 (s, 1H), 6.93 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H),
7.31 (t, J = 8.0 Hz, 1H); NMR 13C (125.8 MHz, CDCl3)
δ 14.1, 22.9, 39.4, 55.5, 57.1,
61.5, 65.2 (q, J = 27.5 Hz), 114.9, 115.3, 120.8, 125.3 (q, J = 286.5 Hz), 129.4, 135.2,
159.6, 170.4. HRMS (ESI+): m/z calcd for C17H24F3NaNO4S [M+Na]+ 418.1276, found
418.1286.
(SS,S)-(+)-tert-Butyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(3-
methoxyphenyl)butanoate 6h and (SS,S)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-
trifluoro-3-(3-methoxyphenyl)butanoate 6’h. Following the general procedure, a solution
of hemiaminal 3d (299 mg, 0.85 mmol) in 2ꢀMeꢀTHF (10 mL) was added to a suspension
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of activated Zn (553 mg, 8.46 mmol), CuCl (84 mg, 0.85 mmol) and tertꢀbutyl
4
5
6
bromoacetate (310
ꢀL, 2.11 mmol) in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred
7
8
21h at 0°C. Purification of the residue (dr 6h: 6’h = 93:7) on silica gel (petroleum
9
ether:EtOAc 6:1 to 4:1) afforded
β
ꢀamino ester 6’h (9 mg, 2%) as a colorless oil and βꢀ
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17
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59
60
20
amino ester 6h (252 mg, 70%) as a white solid. 6h: mp 95ꢀ97°C; [
α
]
+60 (c 1.14,
D
CHCl3); IR (film) νmax 1078, 1155? 1176, 1259, 1368, 1722, 2980 cmꢀ1; NMR 19F (235
1
MHz, CDCl3)
δ
ꢀ73.9 (s, CF3); NMR H (500 MHz, CDCl3)
δ
1.28 (s, 9H), 1.40 (s, 9H),
3.04 (d, J = 15.5 Hz, 1H), 3.24 (d, J = 15.5 Hz, 1H), 3.81 (s, 3H), 6.19 (s, 1H), 6.91 (dd, J
= 2.0 Hz, J = 8.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.23 (s, 1H), 7.29 (t, J = 8.0 Hz, 1H);
NMR 13C (125.8 MHz, CDCl3)
δ 22.9, 28.0, 40.9, 55.5, 57.2, 65.6 (q, J = 27.0 Hz), 82.5,
114.8, 115.1, 120.7, 125.4 (q, J = 286.5 Hz), 129.3, 135.8, 159.5, 169.4. HRMS (ESI+):
m/z calcd for C19H28F3NaNO4S [M+Na]+ 446.1589, found 446.1608. An analytical sample
of 6h was crystallized from Et2O. 6’h: IR (film) νmax 1154, 1259, 1275, 1725, 2978 cmꢀ1;
1
NMR 19F (235 MHz, CDCl3)
δ
ꢀ72.8 (s, CF3); NMR H (250 MHz, CDCl3)
δ
1.32 (s, 9H),
1.34 (s, 9H), 3.28 (d, J = 17.0 Hz), 3.51 (d, J = 17.0 Hz), 3.80 (s, 3H), 5.13 (s, 1H), 6.90
(m, 1H), 7.08 (m, 2H), 7.34 (m, 1H). (ESI+): m/z calcd for C19H28F3NaNO4S [M+Na]+
446.1589, found 446.1582.
(SS,S)-(+)-Ethyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-
methoxyphenyl)butanoate 6i and (SS,R)-Ethyl N-(tert-butanesulfinyl)-3-amino-4,4,4-
trifluoro-3-(4-methoxyphenyl)butanoate 6’i. Following the general procedure, a solution
of hemiaminal 3e (211 mg, 0.60 mmol) in 2ꢀMeꢀTHF (10 mL) was added to a suspension
of activated Zn (391 mg, 5.98 mmol), CuCl (59 mg, 0.60 mmol) and ethyl bromoacetate
(166
ꢀL, 1.50 mmol) in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred 4h30 at 0°C.
Purification of the residue (dr 6i: 6’i = 82:18) on silica gel (petroleum ether:EtOAc 6:1 to
4:1) afforded
β
ꢀamino ester 6’i (21 mg, 9%) as an offꢀwhite solid, an intermediate fraction
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4
containing 6’i and 6i (4 mg, 2%), and
β
ꢀamino ester 6i (135 mg, 57%) as a colorless oil.
20
5
6
6i: [
α
]
+100 (c 1.21, CHCl3); IR (film) νmax 1077, 1161, 1518, 1728, 2963, 2981, 3245
D
7
8
cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ δ 1.24 (t,
ꢀ75.4 (s, CF3); NMR 1H (500 MHz, CDCl3)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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59
60
J = 7.0 Hz, 3H), 1.27 (s, 9H), 3.20 (d, J = 16.0 Hz, 1H), 3.34 (d, J = 16.0 Hz, 1H), 3.79 (s,
3H), 4.17 (m, 2H), 6.26 (s, 1H), 6.90 (d, J = 9.0 Hz, 2H), 7.48 (d, J = 9.0 Hz, 2H); NMR
13C (125.8 MHz, CDCl3)
δ 14.0, 22.8, 39.1, 55.3, 56.8, 61.4, 64.4 (q, J = 27.5 Hz), 113.7,
125.1, 125.4 (q, J = 286.0 Hz), 130.2, 160.2, 170.6. HRMS (ESI+): m/z calcd for
C17H24F3NaNO4S [M+Na]+ 418.1276, found 418.1281. 6’i: mp 123ꢀ124°C; IR (film) νmax
1077, 1158, 1180, 1257, 1515, 1732, 2963, 2981 cmꢀ1; NMR 19F (235 MHz, CDCl3)
73.4 (s, CF3); NMR 1H (600 MHz, CDCl3)
δ ꢀ
δ
1.20 (t, J = 7.0 Hz, 3H), 1.32 (s, 9H), 3.37 (d,
J = 17.0 Hz, 1H), 3.57 (d, J = 17.0 Hz, 1H), 3.80 (s, 3H), 4.10 (q, J = 7.0 Hz, 2H), 5.11 (s,
1H), 6.90 (d, J = 9.0 Hz, 2H), 7.42 (d, J = 9.0 Hz, 2H); NMR 13C (151.0 MHz, CDCl3)
δ
14.1, 22.7, 38.3, 55.4, 57.3, 61.3, 64.5 (q, J = 27.0 Hz), 114.0, 125.0 (q, J = 286.0 Hz),
128.4, 128.7, 160.0, 169.6. HRMS (ESI+): m/z calcd for C17H25F3NO4S [M+H]+ 396.1456,
found 396.1448.
(SS,S)-(+)-tert-Butyl
N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-(4-
methoxyphenyl)butanoate 6j. Following the general procedure, a solution of hemiaminal 3e
(321 mg, 0.91 mmol) in 2ꢀMeꢀTHF (10 mL) was added to a suspension of activated Zn (594
mg, 9.08 mmol), CuCl (90 mg, 0.91 mmol) and tertꢀbutyl bromoacetate (333
ꢀL, 2.27 mmol)
in 2ꢀMeꢀTHF (5 mL). The reaction mixture was stirred 21h at 0°C. Purification of the residue
(dr 6j: 6’j = 90:10) on silica gel (petroleum ether:EtOAc 6:1 to 4:1) afforded βꢀamino ester 6j
20
D
(274 mg, 71%) as a white solid. mp 112ꢀ114°C; [
α]
+84 (c 1.01, CHCl3); IR (film) νmax
1077, 1154, 1260, 1518, 1723, 2979 cmꢀ1; NMR 19F (235 MHz, CDCl3)
NMR 1H (500 MHz, CDCl3)
δ ꢀ74.7 (s, CF3);
δ
1.25 (s, 9H), 1.41 (s, 9H), 3.05 (d, J = 15.5 Hz, 1H), 3.22 (d, J
= 15.5 Hz, 1H), 3.78 (s, 3H), 6.27 (s , 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 9.0 Hz, 2H);
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NMR 13C (125.8 MHz, CDCl3)
δ 22.8, 27.9, 40.5, 55.2, 56.8, 64.8 (q, J = 27.5 Hz), 82.3,
113.6, 127.0 (q, J = 286.5 Hz), 125.6, 130.1, 160.1, 169.6. HRMS (ESI+): m/z calcd for
C19H28F3NaNO4S [M+Na]+ 446.1589, found 446.1576.
5
6
7
8
9
(SS,R)-(+)-Methyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-methylbutanoate 6k. .
Following the general procedure, a solution of hemiaminal 3f (677 mg, 2.59 mmol) in 2ꢀMeꢀ
THF (20 mL) was added to a suspension of activated Zn (1.69 g, 25.9 mmol), CuCl (256 mg,
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60
2.59 mmol) and methyl bromoacetate (615
ꢀL, 6.48 mmol) in 2ꢀMeꢀTHF (10 mL). The
reaction mixture was stirred 4h at 0°C. Purification of the residue (dr 6k: 6’k > 99:1) on silica
gel (petroleum ether:EtOAc 4:1 to 3:2) afforded
βꢀamino ester 6k (648 mg, 86%) as a
20
D
colorless oil. [
α]
+76 (c 0.97, CHCl3); IR (film) νmax 1071, 1170, 1728, 2931, 3265 cmꢀ1;
1
NMR 19F (235 MHz, CDCl3)
δ
ꢀ81.0 (s, CF3); NMR H (500 MHz, CDCl3)
δ
1.13 (s, 9H),
1.56 (s, 3H), 2.59 (d, J = 15.5 Hz, 1H), 2.66 (d, J = 15.5 Hz, 1H), 3.60 (s, 3H), 5.51 (s, 1H);
NMR 13C (125.8 MHz, CDCl3)
δ
19.3, 22.4, 40.1, 52.1, 56.3, 58.9 (q, J = 28.0 Hz), 125.6 (q,
J = 285.0 Hz), 170.4. HRMS (ESI+): m/z calcd for C10H18F3NaNO3S [M+Na]+ 312.0857,
found 312.0865.
(SS,R)-(+)-Ethyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-methylbutanoate 6l
.
Following the general procedure, a solution of hemiaminal 3f (838 mg, 3.21 mmol) in 2ꢀ
MeꢀTHF (25 mL) was added to a suspension of activated Zn (2.10 g, 32.1 mmol), CuCl
(318 mg, 3.21 mmol) and ethyl bromoacetate (889
ꢀL, 8.02 mmol) in 2ꢀMeꢀTHF (15 mL).
The reaction mixture was stirred 4h30 at 0°C. Purification of the residue (dr 6l: 6’l > 99:1)
on silica gel (petroleum ether:EtOAc 4:1 to 2:1) afforded
20 +71 (c 1.03, CHCl3); IR (film)
βꢀamino ester 6l (766 mg, 79%)
as a colorless oil. [
α
]
ν
max 1077, 1170, 1724, 2984, 3263
D
cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
ꢀ80.9 (s, CF3); NMR 1H (500 MHz, CDCl3)
δ 1.10 (s,
9H), 1.12 (t, J = 7.0 Hz, 3H), 1.53 (s, 3H), 2.55 (d, J = 15.0 Hz, 1H), 2.61 (d, J = 15.0 Hz,
1H), 4.04 (q, J = 7.0 Hz, 2H), 5.55 (s, 1H); NMR 13C (125.8 MHz, CDCl3)
δ 13.8, 19.2,
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22.4, 40.3, 56.2, 58.9 (q, J = 28.0 Hz), 61.3, 125.6 (q, J = 285.0 Hz), 169.9. HRMS
(ESI+): m/z calcd for C11H21F3NO3S [M+H]+ 304.1194, found 304.1199.
6
7
8
9
(SS,R)-(+)-tert-Butyl N-(tert-butanesulfinyl)-3-amino-4,4,4-trifluoro-3-methylbutanoate
6m. Following the general procedure, a solution of hemiaminal 3f (545 mg, 2.09 mmol) in
2ꢀMeꢀTHF (20 mL) was added to a suspension of activated Zn (1.37 g, 20.9 mmol), CuCl
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59
60
(207 mg, 2.09 mmol) and tertꢀbutyl bromoacetate (765
ꢀL, 5.21 mmol) in 2ꢀMeꢀTHF (10
mL). The reaction mixture was stirred 20h at 0°C. Purification of the residue (dr 6m:6’m
> 99:1) on silica gel (petroleum ether:EtOAc 6:1 to 4:1) afforded βꢀamino ester 6m (454
20
mg, 68%) as a white solid. mp 39ꢀ40°C; [
α
]
+66 (c 1.10, CHCl3); IR (film) νmax 1070,
ꢀ80.6 (s, CF3); NMR 1H (500
D
1157, 1717, 2871, 3252 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
MHz, CDCl3)
δ 1.24 (s, 9H), 1.45 (s, 9H), 1.65 (s, 3H), 2.57 (d, J = 15.0 Hz, 1H), 2.62 (d,
J = 15.0 Hz, 1H), 5.66 (s, 1H); NMR 13C (125.8 MHz, CDCl3)
δ
19.6, 22.7, 28.0, 41.7,
56.5, 59.1 (q, J = 28.0 Hz), 82.8, 126.0 (q, J = 285.0 Hz), 169.3. HRMS (ESI+): m/z calcd
for C13H24F3NaNO3S [M+Na]+ 354.1327, found 354.1321.
(SS,R)-(+)-Ethyl N-(tert-butanesulfinyl)-3-amino-3-(trifluoromethyl)pentanoate 6n
.
Following the general procedure, a solution of hemiaminal 3g (179 mg, 0.58 mmol) in 2ꢀ
MeꢀTHF (8 mL) was added to a suspension of activated Zn (377 mg, 5.76 mmol), CuCl
(57 mg, 0.58 mmol) and ethyl bromoacetate (159
ꢀL, 1.44 mmol) in 2ꢀMeꢀTHF (3 mL).
The reaction mixture was stirred 4h at 0°C. Purification of the residue (dr 6n:6’n > 99:1)
on silica gel (petroleum ether:EtOAc 6:1 to 2:1) afforded βꢀamino ester 6n (159 mg, 85%)
20
as a colorless oil. [
α
]
+45 (c 1.12, CHCl3); IR (film) νmax 1079, 1171, 1723, 2960,
ꢀ77.3 (s, CF3); NMR 1H (500 MHz,
D
2983, 3259, 3313 cmꢀ1; NMR 19F (235 MHz, CDCl3)
δ
CDCl3)
δ 1.09 (t, J = 7.5 Hz, 3H), 1.21 (s, 9H), 1.24 (t, J = 7.0 Hz, 3H), 2.01 (quint, J =
7.5 Hz, 1H), 2.18 (quint, J = 7.5 Hz, 1H), 2.63 (d, J = 15.0 Hz, 1H), 2.68 (d, J = 15.0 Hz),
4.15 (q, J = 7.0 Hz, 2H), 5.67 (s, 1H); NMR 13C (125.8 MHz, CDCl3)
δ 7.8, 14.0, 22.6,
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