General and stereoselective aminoxylation of biradical titanium(iv) enolates with TEMPO: A detailed study on the effect of the chiral auxiliary

Article abstract of DOI:10.1039/c8ob01074a

A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.

Full text of DOI:10.1039/c8ob01074a

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10.1039/C8OB01074A.
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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C8OB01074A
Organic & Biomolecular Chemistry
ARTICLE
General and stereoselective aminoxylation of biradical
titanium(IV) enolates with TEMPO: a detailed study on the effect
of the chiral auxiliary
Received 00th January 20xx,
Accepted 00th January 20xx
Stuart C. D. Kennington,a Alejandro Gómez-Palomino,a Ernest Salomó,a Pedro Romea,*a Fèlix
Urpí,*a and Mercè Font-Bardiab
DOI: 10.1039/x0xx00000x
www.rsc.org/
A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(IV) enolates with
TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single
diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and
stereoselective
oxidation.
variety of oxidizing agents like N-sulfonyloxaziridines,
peroxides, or transition metals.2,3 Aside from these methods,
the emergence of organocatalytic procedures represented a
major step forward in the asymmetric synthesis of α-hydroxy
carbonylic compounds. Thereby, initial reports on the
enantioselective preparation of aminoxylated adducts through
addition of aldehydes and activated ketones to nitrosobenzene
catalyzed by chiral amines4 were soon enlarged by the SOMO
activation mode concept.5 This broadly referred to the
oxidation of chiral enamines, which provided a cation radical
that underwent highly enantioselective reactions. Thus, it
presently stands as a milestone in asymmetric transformations
involving radical or electronically excited species.5,6
Mirroring such achievements, the recognition of the biradical
character of titanium(IV) enolates7 laid the foundations for
their use in SOMO-like transformations without the need for a
stoichiometric oxidizing reagent. Zakarian proved the
feasibility of such a new approach by developing a new
photoredox alkylation of titanium(IV) enolates from chiral N-
acyl oxazolidinones catalyzed by a ruthenium complex.8 In this
context, the commercially available and persistent radical
TEMPO was an appealing reagent to trap chiral titanium(IV)
biradical enolates and stereoselectively afford the
aminoxylated derivatives. TEMPO had been used as precursor
of electrophilic reagents for the stereoselective construction of
carbon-oxygen bonds.9 In contrast, its use in radical like
reactions was scarce and restricted to non-stereoselective
transformations10 until Zakarian11 and our group12
independently developed the asymmetric oxidation of
titanium(IV) enolates of a wide range of chiral N-acyl
oxazolidinones with TEMPO, which provides the corresponding
Introduction
The widespread presence of α-hydroxy carbonylic and
carboxylic structures in biologically active natural products has
fostered the development of increasingly efficient
transformations involving either the asymmetric construction
of carbon–carbon or carbon–oxygen bonds from metal
enolates to access these structures (Scheme 1).1
O
OMe
O
OH
HO
HO
HO
O
OMe
MeO
OH
Peloruside A
M
R
M
O
O
O
R
R
OH
R
R
OH
Cα oxidation
Cα alkylation
Scheme 1 Reactivity of the Cα position of enolates
Particularly, the stereoselective Cα-oxidation of carbonyl
bonds has received lasting attention, resulting in a number of
procedures based on the treatment of metal enolates with a
aminoxylated
adducts
with
good
yields
and
diastereoselectivities (Scheme 2).
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Journal Name
O
O
Herein, we describe a detailed study of the aminoxylation of
DOI: 10.1039/C8OB01074A
titanium(IV) enolates derived from a wide array of chiral auxiliaries
possessing different oxygen and sulphur patterns and several side
chains as well as a further analysis of the scope of the reaction and
the final removal of the chiral scaffold.
O
O
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1) TiCl4, i-Pr2NEt
R
R
N
O
N
O
N
2) TEMPO
O
Bn
Bn
Scheme 2 Stereoselective aminoxylation of titanium(IV) enolates with TEMPO
O
S
S
We have also reported theoretical insights of this TEMPO-mediated
oxidation reinforcing the proof of the valence tautomerism and the
resulting biradical character of titanium(IV) enolates from N-acyl
oxazolidinones as well as offering a concise explanation of the
entire mechanism.13 Essentially, the process hinges on the radical
attack of a first molecule of TEMPO to the Cα position of the
biradical form of the titanium(IV) enolate (Scheme 3). This is then
followed by a fast oxidation of the resultant titanium(III) complex by
a second molecule of TEMPO. Thereby, the high stereocontrol
achieved by such transformations may be explained through a
chelated titanium(IV) enolate in which the C4-benzyl group favours
the approach of the oxidizing agent to the less sterically hindered π-
face of the biradical enolate.
O
NH
R
O
NH
R
S
NH
R
oxazolidinones
oxazolidinethiones
thiazolidinethiones
Fig. 1 Five membered cyclic chiral auxiliaries
Results and Discussion
Chiral auxiliary screening.
Taking advantage of our own studies on the aminoxylation of
titanium(IV) enolates from N-acyl oxazolidinones with TEMPO,12,13
we initially investigated the influence of chiral auxiliaries 1–6 with
various combinations of oxygen and sulphur heteroatoms exo and
endo to the heterocycle and bulky groups at C4 (Figure 2).22–24 By
choosing such a wide range of chiral substrates we envisaged to
fully understand the effect both the heteroatoms and the groups at
C4 and therefore to find the most effective scaffold for this type of
reaction.
Cl4
IVTi
Cl4
IIITi
Valence
tautomerism
N
O
O
O
O
O
R
R
O
N
O
N
Ph
Ph
Cl4
IIITi
Cl4
IVTi
N
O
O
Isopropyl series
O
O
O
R
R
N
O
S
S
O
N
O
N
O
O
Ph
O
NH
O
NH
S
NH
N
Ph
4
4
4
i-Pr
i-Pr
i-Pr
1
2
3
O
O
H3O
R
O
N
tert-Butyl series
O
O
S
S
N
Bn
O
NH
O
NH
S
NH
4
4
4
t-Bu
t-Bu
t-Bu
Scheme 3. Mechanism for the stereoselective aminoxylation of titanium(IV) enolates
from chiral N-acyl oxazolidinones with TEMPO
4
5
6
Fig. 2 C4 Substituted five membered cyclic chiral auxiliaries
Thus, considering the key role played by chiral scaffolds in
stereoselective reactions,14,15 we decided to assess its influence on
such oxidations with the aim of identifying other chiral auxiliaries
which may able to produce a single diastereomer and be easily
removed from the resultant aminoxylated adduct leaving
enantiopure synthons. Particularly, we focused our attention on
chiral oxazolidinones developed by Evans16,17 and related five
membered heterocycles with a long tradition within stereoselective
synthesis (Figure 1).18–21
To best analyse the isolated effects of such parameters we
conducted the aminoxylation of N-propanoyl derivatives 1a–6a
(Scheme 4), easily prepared from chiral auxiliaries 1–6, under the
same conditions, more specifically the optimised conditions
reported in our previous report.12 The results of this preliminary
examination summarised in Scheme 3 showed a clear trend.
Indeed, substitution of the exocyclic oxygen by sulphur both in the
isopropyl and the tert-butyl series produced a significant
2 | J. Name., 2012, 00, 1-3
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ARTICLE
X
X
X
O
O
1) n-BuLi
1) TiCl4, i-Pr2NEt, CH2Cl2
Y
NH
R
Y
N
Y
N
2) EtCOCl
2) TEMPO
O
N
R
R
X, Y: O, S
R: i-Pr, t- Bu
1 – 6
1a – 6a
7a – 12a
O
S
S
O
S
S
O
O
O
O
O
O
O
N
O
N
S
N
O
N
O
N
S
N
OTEMP
OTEMP
OTEMP
OTEMP
OTEMP
OTEMP
i-Pr
i-Pr
i-Pr
t-Bu
t-Bu
t-Bu
7a
8a
9a
10a
11a
12a
dr 78:22 (85%)a
dr 93:7 (85%)a
dr 91:9 (87%)a
dr 91:9 (77%)a
dr > 97:3 83%b
dr > 97:3 70%b
a Isolated overall yield. b Isolated yield of the major diastereomer
Scheme 4 Stereoselective aminoxylation of titanium(IV) enolates from N-propanoyl C4-substituted chiral auxiliaries 1a–6a with TEMPO
improvement of the diastereoselectivity. Moreover, the bulky tert- Thus, N-propanoyl derivatives 13a–16a, easily prepared from chiral
butyl group turned out to be crucial to obtain a single diastereomer; auxiliaries 13–16, were submitted to the previous experimental
in all cases moving from isopropyl to tert-butyl as the C4 group conditions. The results summarised in Scheme 5 proved the benefit
induced
a significant increase in the diastereomeric ratio. of installing two groups at C5. Indeed, the results from N-propanoyl
Particularly, tert-butyl N-propanoyl oxazolidinethione 5a (X: S, Y: O, C4 benzyl oxazolidinones 13a (X: O, R: H) and 14a (X: O, R: Me)
R: t-Bu) and thiazolidinethione 6a (X, Y: S, R: t-Bu) were the most clearly showed that the diastereoselectivity is greatly increased by
appropriate platforms to carry out a completely stereocontrolled attaching two geminal methyl groups at C5. Furthermore, the
oxidation in high yields.
placement of two phenyl groups at this position was also
advantageous for the isopropyl oxazolidinethione 15a (X: S, R: Ph,
R1: i-Pr) since just a single diastereomer 19a was obtained albeit in a
moderate yield (compare 8a and 19a in Scheme 4 and 5
Having identified the crucial role of the exocyclic heteroatom and
the C4 alkyl group, we next evaluated the consequences of placing
geminal groups at the C5 position. As we had already described the
aminoxylation using chiral auxiliary 14,12 in which the oxazolidinone
possesses a geminal dimethyl moiety at C5, we next evaluated the
outcome of parallel reactions from oxazolidinones and
oxazolidinethiones 13–16 shown in Figure 3.25
respectively).
Finally,
N-propanoyl
5,5-disubstituted
oxazolidinethione 16a (X: S, R, R1: Ph) demonstrates that a C4
substituent larger than Ph group is required to obtain a single
diastereomer (compare 19a and 20a in Scheme 5).
All together, these results indicate that only three of the ten
different chiral auxiliaries evaluated (oxazolidinethiones 5 and 15,
and thiazolidinethione 6) give complete control of the newly
created stereocentre (see 11a and 12a in Scheme 4 and 19a in
Scheme 5). Among all the scaffolds, the tert-butyl oxazolidinethione
5 emerges as the most appropriate choice. Certainly, it provides
marginally lower yields than the SuperQuat auxiliary 14, but it offers
the advantage of giving complete stereocontrol and it is also
significantly easier to synthesise starting from readily available tert-
O
O
S
S
O
NH
4
O
NH
4
O
NH
4
O
NH
4
5
5
5
5
Ph
Ph
Ph
Bn
Bn
i-Pr
Ph
Ph
13
14
15
16
Fig. 3 C4 and C5 Substituted chiral auxiliaries
leucine.§
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ARTICLE
X
X
X
O
O
1) n-BuLi
1) TiCl4, i-Pr2NEt, CH2Cl2
O
R
NH
R1
O
N
O
N
2) EtCOCl
2) TEMPO
O
R
R
S
N
R1
13a – 16a
R1
R
R
R
X: O, S
R: H, Me, Ph
R1: Bn, i-Pr, Ph
13 – 16
17a – 20a
O
O
S
O
O
O
O
O
N
O
N
O
N
O
N
OTEMP
OTEMP
OTEMP
OTEMP
Ph
Ph
Bn
17a
dr 78:22 (93%)a
Bn
18a
dr 94:6 93%b
i-Pr
Ph
Ph
Ph
19a
20a
dr > 97:3 55%b
dr 91:9 56%b
a Isolated overall yield. b Isolated yield of the major diastereomer
Scheme 5 Stereoselective aminoxylation of titanium(IV) enolates from N-propanoyl C4 and C5-substituted chiral auxiliaries 13a–16a with TEMPO
simple propyl chain and also a more complex example. Initially, we
employed NaBH4 to obtain the corresponding alcohols 21a and 21b.
In the case of 11a the reaction took two hours at 0 °C and yielded
85% of the enantiopure alcohol 21a. Moving to the more hindered
adduct 11b the reaction required a longer time and at room
temperature but also gave an excellent 92% yield of the desired
alcohol 21b. Carboxylic acids 22a and 22b were next obtained
through common treatment with lithium hydroperoxide in good
yields. Methanol was then used to displace the auxiliary and leave
an ester. Adducts 11a and 11b performed in a similar manner. Both
gave excellent yields of methyl esters 23a and 23b respectively with
11b taking longer to complete the reaction. Changing methanol for
Scope of the Aminoxylation Reaction
Since the screening process led us to a new chiral auxiliary, we next
reexamined the scope of the radical aminoxylation with TEMPO
using this new scaffold. To do this, we varied the acyl group
attached to the chiral heterocycle intending to test the impact of
sterically hindered R groups as well as others containing various
common functional groups. The results summarised in Scheme 6
demonstrated that the simple treatment of titanium(IV) enolates
from a wide array of N-acyl tert-butyl oxazolidinethiones (5a–g)
with TEMPO afforded a single diastereomer 11 for all the substrates
with the exception of α-phenyl derivative 11e, which was obtained
as an equimolecular mixture of two diastereomers in 90% overall
yield. Presumably, the higher acidity of the Cα position in N-(2-
phenylacetyl) oxazolidinethione 5e precludes its use,26 in contrast
to the high stereocontrol achieved with a parallel reaction from
oxazolidinone SuperQuat 14. Importantly, the steric bulk of R nor
the presence of a terminal double bond or an ester had a significant
influence on the yield. All together, these results highlight the
excellent chemo- and diastereoselectivity of the radical-mediated
direct oxidation with TEMPO, which permits the obtainment of a
single stereoisomer in high yields using straightforward and mild
experimental conditions.
In turn, we took advantage of crystalline properties of adduct 11b
to confirm the configuration of the α stereocentre by X-ray analysis
(Figure 4).‡
Removal of the chiral auxiliary
We finally proceeded to investigate the removal of the chiral
auxiliary from adducts 11a and 11b (Scheme 7) using both the most
Fig. 4 ORTEP X-ray structure of adduct 11b (ellipsoid contour probability: 50%).
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ARTICLE
S
S
S
O
O
1) n-BuLi
1) TiCl4, i-Pr2NEt, CH2Cl2
R
R
O
NH
t-Bu
O
N
O
N
2) RCH2COCl
2) TEMPO, 0 °C, 1 h
O
N
t-Bu
5a–g
t-Bu
11a–g
5
S
S
S
S
O
O
O
O
O
N
O
N
Ph
OTEMP
O
N
O
N
OTEMP
OTEMP
OTEMP
t-Bu
11a
83%a
t-Bu
11b
81%a
t-Bu
11c
80%a
t-Bu
11d
78%a
S
S
S
O
O
O
CO2Me
O
N
O
N
O
N
OTEMP
OTEMP
OTEMP
t-Bu
11e
dr 1:1 90%b
t-Bu
11f
90%a
t-Bu
11g
93%a
a Isolated yield of diastereomerically pure adduct 11. b Overall isolated yield.
Scheme 6 Stereoselective aminoxylation of titanium(IV) enolates from (S) N-acyl-4-tert-butyl-1,3-oxazolidine-2-thiones 5 with TEMPO
HO
HO
Ph
O
O
OTEMP
21a
OTEMP
21b
HO
HO
Ph
OTEMP
22a
OTEMP
LiOOH
THF/H2O, 0°C
3 h
LiOOH
THF/H2O, 0°C
84%
NaBH4
THF/H2O
0 °C, 2 h
NaBH4
THF/H2O
rt, 20 h
22b
92%
0.5 h
76%
69%
S
S
O
O
O
MeOH, DMAP
rt, 20 h
MeOH, DMAP
rt, 72 h
O
MeO
O
N
O
N
Ph
OTEMP
MeO
Ph
86%
89%
OTEMP
23a
OTEMP
OTEMP
t-Bu
t-Bu
23b
11a
11b
morpholine, DMAP
THF, rt, 24 h
92%
morpholine, DMAP
THF, rt, 12 h
C12H25SH
C12H25SH
n-BuLi
THF
95%
n-BuLi
THF
rt, 6 h
93%
89%
O
O
rt, 14 h
N
O
Ph
N
O
O
OTEMP
O
OTEMP
24a
24b
C12H25
S
C12H25
S
Ph
OTEMP
OTEMP
25a
25b
Scheme 7 Removal of the chiral auxiliary from α-aminoxylated adducts
morpholine allowed us to form amides 24a and 24b, again in recovery of the auxiliary was excellent in all cases, with the
excellent yields. Finally, displacement of the chiral auxiliary with a minimum amount being 78% and an average recovery of 89% over
thiol to form thioesters 25a and 25b also proceeded smoothly and the ten different reactions.
both derivatives were isolated in excellent yields. Remarkably, the
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Journal Name
extracted with CH2Cl2 (3 × 100 mL) and the organiVciewlaAyretircsle Ownelirnee
DOI: 10.1039/C8OB01074A
dried (MgSO4), and concentrated. The resulting solid was purified
Conclusions
In summary, we have comprehensively investigated the role of the
chiral auxiliary on the outcome, both in terms of yield and
stereocontrol, of the α-aminoxylation of the titanium(IV) enolates
from a number of N-acylated imide-like derivatives with TEMPO.
The 4-tert-butyl-1,3-oxazolidine-2-thione auxiliary has been
identified as the most appropriate to carry out this reaction since it
combines all the favoured characteristics and gives complete
control of the newly formed stereocentre with an excellent yield for
a wide range of N-acylated 4-tert-butyl-1,3-oxazolidine-2-thiones.
Compared to previous studies that used SuperQuat, this is more
selective, with a comparable yield and is also much easier to
synthesise from commercially available tert-leucinol. Finally,
straighforward conversion of α-OTEMP adducts affords enantiopure
intermediates in excellent yields and with a high recovery of the
chiral auxiliary.
by column chromatography (CH2Cl2) to give 5.50 g (34.5 mmol, 77%
yield) of heterocycle 5 as a white solid. Mp: 155–156 °C [lit.27 Mp:
155.1–155.3 °C]. Rf = 0.65 (CH2Cl2). [α]D20 = –11.0 (c 1.0, CHCl3) [lit.27
20
[α]D = –11.6 (c 0.92, CHCl3)]. IR (ATR): 3183, 2997, 2960, 1534,
1
1183 cm–1. H NMR (400 MHz, CDCl3): δ 8.43 (br s, 1H), 4.62 (t, J =
9.5 Hz, 1H), 4.46 (dd, J = 9.5, 6.3 Hz, 1H), 3.81 (dd, J = 9.5, 6.3 Hz,
1H), 0.94 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ 189.6, 71.8, 65.8,
33.6, 20.0. HRMS (+ESI): m/z calcd. for C7H14NOS [M+H]+: 160.0791;
found: 160.0793.
Acylation of 5: Synthesis of (S)-4-tert-butyl-N-propanoyl-1,3-
oxazolidine-2-thione (5a)
A 1.6 M solution of n-BuLi in hexanes (2.1 mL, 3.3 mmol) was added
dropwise to a solution of 5 (478 mg, 3.0 mmol) in THF (4 mL) at –78
°C under N2. The reaction mixture was stirred for 10 min and then
propanoyl chloride (0.34 mL, 3.9 mmol) was carefully added
dropwise. The resulting solution was stirred for 5 min at –78 °C and
then allowed to warm to room temperature and stirred for further
1.5 h. The reaction mixture was cooled with an ice-water bath and
quenched with sat NH4Cl (2 mL) and water (5 mL). This mixture was
extracted with CH2Cl2 (3 × 20 mL), the combined organic extracts
were dried (MgSO4), filtered, and concentrated. The crude reaction
mixture was purified by column chromatography (50:50
CH2Cl2/Hexanes) to afford 595 mg (2.8 mmol, 92% yield) of N-
propanoyl oxazolidinethione 5a as a colourless oil. Rf =0.4 (50:50
Experimental section
General experimental remarks
Unless otherwise stated, reactions were conducted in oven-dried
glassware under an inert atmosphere of nitrogen with anhydrous
solvents. The solvents and reagents were dried and purified, when
necessary, according to standard procedures. All commercial
reagents were used as received. Analytical thin-layer
chromatographies (TLC) were carried out on Merck silica gel 60
F254 plates and analyzed by UV (254 nm) and stained with
phosphomolybdic acid. Rf values are approximate. Column
chromatography were carried out under low pressure (flash)
conditions and performed on SDS silica gel 60 (35-70 μm). Melting
points are uncorrected. Specific rotations ([α]) were determined at
589 nm and at 20 °C. IR spectra (Attenuated Total Reflectance, ATR)
20
CH2Cl2/Hexanes). [α]D = +152.2 (c 1.1, CHCl3). IR (ATR): 2967,
1708, 1479, 1402, 1362, 1267, 1179, 1048 cm–1. 1H NMR (400 MHz,
CDCl3): δ 4.78 (dd, J = 7.5, 1.7 Hz, 1H), 4.45 (dd, J = 9.5, 1.7 Hz, 1H),
4.34 (dd, J = 9.5, 7.5 Hz, 1H), 3.38 (dq, J = 18.1, 7.2 Hz, 1H), 3.29 (dq,
J = 18.1, 7.2 Hz, 1H), 1.21 (t, J= 7.2 Hz, 3H), 0.94 (s, 9H). 13C NMR
(100.6b MHz, CDCl3): δ 187.0, 174.9, 69.2, 65.1, 36.1, 31.1, 25.8,
8.9. HRMS (+ESI): m/z calcd. for C10H18NO2S [M+H]+: 216.1053;
found: 216.1058.
were recorded on
a Nicolet 6700 FT-IR Thermo Scientific
spectrometer and only the more representative frequencies (ν) are
reported. 1H NMR (400 MHz) and 13C NMR (100.6 MHz) spectra
were recorded on a Varian Mercury 400 spectrometer. Chemical
shifts (δ) are quoted in ppm and referenced to internal TMS (δ 0.00
General aminoxylation procedure
1
for H NMR) or CDCl3 (δ 77.0 for 13C NMR); data are reported as
Neat TiCl4 (121 µL, 1.1 mmol, 1.1 equiv) was added dropwise to a
solution of the acylated chiral auxiliary (1 mmol, 1 equiv) in CH2Cl2
(4 mL) at 0 °C under N2 and the resultant mixture was stirred for 5
min. Then, i-Pr2NEt (192 µL, 1.1 mmol, 1.1 equiv) was added and
the mixture was further stirred for 30 min. A solution of TEMPO
(328 mg, 2.1 mmol, 2.1 equiv) in CH2Cl2 (0.5 mL + 0.5 mL) was
added via cannula and the reaction mixture was stirred for 1 h,
quenched with sat NH4Cl (2 mL), and stirred vigorously for 10 min. It
was then diluted in water (20 mL) and extracted with CH2Cl2 (3 × 20
mL). The organic layer was washed with brine (50 mL), dried
(MgSO4), and concentrated to yield the crude product. Column
chromatography was then conducted to yield the isolated product.
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
broad (and their corresponding combinations) with coupling
constants measured in Hz; when necessary, 2D techniques (COSY
and HSQC) were also used to assist with structure elucidation. High
resolution mass spectra (HRMS) were obtained with an Agilent
1100 spectrometer by the Unitat d'Espectrometria de Masses,
Universitat de Barcelona.
Synthesis of (S)-4-tert-butyl-1,3-oxazolidine-2-thione (5)
Neat CS2 (8.4 mL, 135 mmol) was added to a solution of tert-
leucinol (5.27 g, 45 mmol) in EtOH (10 mL) at room temperature
under N2. Then, a 2.6 M solution of KOH (26 mL, 67.5 mmol) in 1:1
EtOH/H2O was added and the resulting mixture was heated at
reflux for two days. The volatiles were removed and the residue
was carefully acidified with 2 M HCl until pH 2. The mixture was
(S)-4-tert-Butyl-N-[(S)-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)propanoyl]-1,3-oxazolidine-2-thione (11a). Starting from (S)
4-tert-butyl-N-propanoyl-1,3-oxazolidine-2-thione (5a, 215 mg, 1.0
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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ARTICLE
mmol) diastereomerically pure adduct 11a (308 mg, 0.83 mmol,
83% yield) was isolated as a white solid after chromatographic
purification (60:40 CH2Cl2/Hexanes). Mp: 130–131 °C. Rf = 0.3
(60:40 CH2Cl2/Hexanes). [α]D20 = +84.0 (c 1.0, CHCl3). IR (ATR): 2970,
187.0, 172.7, 83.1, 69.1 (×2), 66.1, 64.9, 59.7, 42.3, 4V0ie.1w,A3rt6ic.l0e O(×nl2in)e,
25.9, 25.7, 17.1, 14.6, 6.8, 4.3, 4.2, 1.4. HRDMOSI:(1E0S.1I)0:3m9//Cz8OcaBl0cd10.7f4oAr
C21H37N2O3S [M+H]+: 397.2519; found: 397.2524.
1
2926, 1717, 1178, 1357, 1138, 943, 800, 601 cm–1. H NMR (400
(S)-4-tert-Butyl-N-[(S)-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)-5-
hexenoyl]-1,3-oxazolidine-2-thione (11f). Starting from (S) 4-tert-
butyl-N-(5-hexenoyl)-1,3-oxazolidine-2-thione (5f, 255 mg, 1.0
mmol) diastereomerically pure adduct 11f (368 mg, 0.90 mmol, 90%
MHz, CDCl3): δ 6.57 (q, J = 6.8 Hz, 1H), 4.66 (dd, J = 7.4, 1.4 Hz, 1H),
4.45 (dd, J = 9.5, 1.4 Hz, 1H), 4.28 (dd, J = 9.5, 7.4 Hz, 1H), 1.50–1.15
(m, 18H), 1.41 (d, J = 6.8 Hz, 3H), 0.98 (s, 9H). 13C NMR (100.6 MHz,
CDCl3): δ 186.9, 175.3, 79.4, 69.2, 66.0, 59.6, 40.2, 36.1, 34.0, 26.0,
20.2, 19.3, 17.1. HRMS (ESI): m/z calcd. for C19H35N2O3S [M+H]+:
371.2363; found: 371.2359.
yield) was isolated as
a
white solid after chromatographic
20
purification. Mp: 94–95 °C. Rf = 0.8 (CH2Cl2). [α]D = +96.9 (c 1.0,
CHCl3). IR (ATR): 2966, 2922, 2862, 1716, 1475, 1360, 1327, 1297,
1179, 1134 cm–1. 1H NMR (400 MHz, CDCl3): δ 6.66 (dd, J = 7.0, 3.2
Hz, 1H), 5.83–5.71 (m, 1H), 5.02–4.96 (m, 1H), 4.98–4.91 (m, 1H),
4.63 (dd, J = 7.3, 1.3 Hz, 1H), 4.45 (dd, J = 9.5, 1.3 Hz, 1H), 4.26 (dd, J
= 9.5, 7.3 Hz, 1H), 2.23–2.11 (m, 2H), 2.02–1.90 (m, 1H), 1.89–1.78
(m, 1H), 1.47 (br s, 6H), 1.18 (s, 6H), 1.16 (s, 6H), 0.99 (s, 9H). 13C
NMR (100.6 MHz, CDCl3): δ 186.9, 173.7, 137.9, 114.7, 81.2, 69.2,
66.5, 40.3, 36.2, 31.1, 27.4, 26.1, 17.1. HRMS (ESI): m/z calcd. for
C22H39N2O3S [M+H]+: 411.2676; found: 411.2680.
(S)-4-tert-Butyl-N-[(S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)propanoyl]-1,3-oxazolidine-2-thione (11b). Starting from (S)
4-tert-butyl-N-(3-phenylpropanoyl)-1,3-oxazolidine-2-thione
(5b,
291 mg, 1.0 mmol) diastereomerically pure adduct 11b (361 mg,
0.81 mmol, 81% yield) was isolated as a white solid after
chromatographic purification (CH2Cl2). Mp: 138–139 °C. Rf = 0.8
20
(CH2Cl2). [α]D = +87.0 (c 1.0, CHCl3). IR (ATR): 2962, 2922, 2862,
1713, 1479, 1368, 1349, 1308, 1182, 1149 cm–1. 1H NMR (400 MHz,
CDCl3): δ 7.29–7.15 (m, 5H), 7.00 (dd, J = 10.7, 6.0 Hz, 1H), 3.97–
3.91 (m, 2H), 3.47 (dd, J = 12.6, 6.0 Hz, 1H), 2.92–2.85 (m, 2H),
1.57–1.13 (m, 18H), 0.85 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ
187.3, 175.1, 135.3, 129.6, 128.4, 126.9, 80.8, 68.7, 66.7, 59.9, 40.4,
40.2, 35.9, 34.1, 33.5, 26.1, 20.2, 20.1, 17.2. HRMS (ESI): m/z calcd.
for C24H39N2O3S [M+H]+: 447.2676; found: 447.2682.
(S)-4-tert-Butyl-N-[(S)-5-methoxy-2-(2,2,6,6-tetramethylpiperidin-
1-yloxy)-5-oxopentanoyl]-1,3-oxazolidine-2-thione (11g). Starting
from
(S)
4-tert-butyl-N-(5-methoxy-5-oxopentanoyl)-1,3-
oxazolidine-2-thione (5g, 287 mg, 1.0 mmol) diastereomerically
pure adduct 11g (413 mg, 0.93 mmol, 93% yield) was isolated as a
white solid after chromatographic purification (95:5 CH2Cl2/EtOAc).
20
Mp: 104–105 °C. Rf = 0.4 (CH2Cl2). [α]D = +102.5 (c 1.0, CHCl3). IR
(ATR): 2929, 1731, 1713, 1360, 1320, 1297, 1167, 1142, 934 cm–1.
1H NMR (400 MHz, CDCl3): δ 6.71 (dd, J = 6.1, 2.3 Hz, 1H), 4.54–4.48
(m, 1H), 4.50–4.45 (m, 1H), 4.45–4.40 (m, 1H), 3.61 (s, 3H), 2.61–
2.51 (m, 1H), 2.41–2.30 (m, 2H), 2.20–2.10 (m, 1H), 1.47 (s, 6H),
1.17 (s, 6H), 1.15 (s, 6H), 0.96 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ
187.3, 173.9, 173.1, 80.1, 69.3, 66.4, 51.4, 40.0, 35.8, 26.4, 25.9,
25.6, 16.9. HRMS (ESI): m/z calcd. for C22H39N2O5S [M+H]+:
443.2574; found: 443.2576.
(S)-4-tert-Butyl-N-[(S)-3-methyl-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)butanoyl]-1,3-oxazolidine-2-thione (11c). Starting from (S) 4-
tert-butyl-N-(3-methylbutanoyl)-1,3-oxazolidine-2-thione (5c, 243
mg, 1.0 mmol) diastereomerically pure adduct 11c (320 mg, 0.80
mmol, 80% yield) was isolated as
a
white solid after
chromatographic purification (CH2Cl2). Mp: 111–112 °C. Rf = 0.7
20
(CH2Cl2). [α]D = +97.0 (c 1.0, CHCl3). IR (ATR): 2962, 2929, 1698,
1
1468, 1349, 1301, 1171, 1145 cm–1. H NMR (400 MHz, CDCl3): δ
6.75 (d, J = 5.4 Hz, 1H), 4.62 (dd, J = 7.3, 1.3 Hz, 1H), 4.44 (dd, J =
9.5, 1.3 Hz, 1H), 4.21 (dd, J = 9.5, 7.3 Hz, 1H), 2.49–2.36 (m, 1H),
1.63–1.09 (m, 18H), 1.02 (d, J = 6.7 Hz, 3H), 0.99 (s, 9H), 0.90 (d, J =
7.1 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 187.6, 173.0, 82.3, 69.2,
66.7, 59.8, 40.4, 36.2, 34.2, 31.7, 26.2, 25.8, 22.4, 22.3, 20.3, 17.9,
17.1, 16.8. HRMS (ESI): m/z calcd. for C21H39N2O3S [M+H]+:
399.2676; found: 399.2679.
Removal of the chiral auxiliary
(S)-2-(2,2,6,6-Tetramethylpiperidin-1-yloxy)-1-propanol (21a).
A
solution of 11a (74 mg, 0.20 mmol) in THF (1.5 mL) was added to a
solution of NaBH4 (31 mg, 0.8 mmol, 4 equiv) in 40:1 THF/H2O (1.4
mL) at 0 °C under N2 and the resultant mixture was stirred at room
temperature for 2 h. The mixture was then diluted with Et2O (20
mL), washed with 1 M NaOH (3 × 20 mL), water (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4), and concentrated.
The crude was purified by column chromatography (90:10
Hexanes/EtOAc) to give 36 mg (0.17 mmol, 84% yield) of pure
alcohol 21a as a colourless oil. The aqueous phase was acidified and
extracted with CH2Cl2 (3 × 20 mL) to recover 34 mg (90%) of pure
(S)-4-tert-Butyl-N-[(S)-2-cyclopropyl-2-(2,2,6,6-
tetramethylpiperidin-1-yloxy)acetyl]-1,3-oxazolidine-2-thione
(11d). Starting from (S) 4-tert-butyl-N-(2-cyclopropylacetyl)-1,3-
oxazolidine-2-thione (5d, 241 mg, 1.0 mmol) diastereomerically
pure adduct 11d (308 mg, 0.78 mmol, 78% yield) was isolated as a
white solid after chromatographic purification (95:5 CH2Cl2/EtOAc).
20
auxiliary 5. Rf = 0.2 (90:10 Hexanes/EtOAc). [α]D = –35.6 (c 1.0,
20
Mp: 107–108 °C. Rf = 0.4 (CH2Cl2). [α]D = +112.1 (c 1.0, CHCl3). IR
CHCl3). IR (ATR): 3376 (br), 2972, 2928, 1453, 1375, 1162, 1131,
1043 cm–1. 1H NMR (400 MHz, CDCl3): δ 5.53 (s br, 1H), 4.38 (dqd, J
= 9.3, 6.3, 2.2 Hz, 1H), 3.90 (dd, J = 11.9, 9.3 Hz, 1H), 3.57 (dd, J =
11.9, 2.2 Hz, 1H), 1.60–1.25 (m, 6H), 1.32 (s, 3H), 1.30 (s, 3H), 1.15
(s, 3H), 1.11 (s, 3H), 1.01 (d, J = 6.3 Hz, 3H). 13C NMR (100.6 MHz,
(ATR): 2958, 2925, 1716, 1483, 1353, 1316, 1182, 1138, 949 cm–1.
1H NMR (400 MHz, CDCl3): δ 6.64 (d, J = 8.4 Hz, 1H), 4.64 (dd, J =
7.4, 1.4 Hz, 1H), 4.46 (dd, J = 9.5, 1.4 Hz, 1H), 4.26 (dd, J = 9.5, 7.4
Hz, 1H), 1.47–1.15 (m, 19H), 0.97 (s, 9H), 0.71–0.56 (m, 2H), 0.54–
0.45 (m, 1H), 0.29–0.21 (m, 1H). 13C NMR (100.6 MHz, CDCl3): δ
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J. Name., 2013, 00, 1-3 | 7
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Journal Name
CDCl3): δ 76.8, 69.3, 61.1, 59.9, 40.2, 39.9, 34.5, 32.6, 20.4, 20.3, of pure auxiliary 5 and 42 mg (0.14 mmol, 69% yieldV)ieowf AcraticrbleoOxnylilniec
20
17.2, 16.0. HRMS (ESI): m/z calcd. C12H26NO2 [M+H]+: 216.1958; acid 22b as a colourless oil. Rf = 0.4 (65:35 CH2Cl2/EtOAc). [α]D = –
DOI: 10.1039/C8OB01074A
found: 216.1964.
68.5 (c 1.0, CHCl3). IR (ATR): 2971, 2927, 2870, 1717, 1454, 1372,
1233, 1131, 1027, 751, 694 cm–1. 1H NMR (400 MHz, CDCl3): δ 7.33–
7.20 (m, 5H), 4.69 (dd, J = 8.5, 3.4 Hz, 1H), 3.46 (dd, J = 14.6, 8.5 Hz,
1H), 3.14 (dd, J = 14.6, 3.4 Hz, 1H), 1.68–1.59 (m, 5H), 1.50–1.44 (m,
1H), 1.28 (s, 3H), 1.18 (s, 3H), 1.12 (s, 3H), 1.09 (s, 3H). 13C NMR
(100.6 MHz, CDCl3): δ 173.1, 137.6, 129.6, 128.2, 126.5, 80.5, 63.1,
62.8, 39.3, 39.2, 37.6, 31.2, 29.9, 21.0, 20.8, 16.3. HRMS (ESI): m/z
calcd. for C18H28NO3 [M+H]+: 306.2064; found: 306.2070.
(S)-3-Phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy-1-propanol
(21b). A solution of 11b (58 mg, 0.13 mmol) in THF (1.5 mL) was
added to a solution of NaBH4 (31 mg, 0.8 mmol, 6.15 equiv) in 40:1
THF/H2O (1.4 mL) at 0 °C under N2 and the resultant mixture was
stirred at room temperature for 20 h. The mixture was then diluted
with Et2O (20 mL), washed with 1 M NaOH (3 × 20 mL), water (20
mL), and brine (20 mL). The organic layer was dried (MgSO4) and
concentrated. The crude was purified by column chromatography
(95:5 CH2Cl2/EtOAc) to give 35 mg (0.12 mmol, 92% yield) of pure
Methyl (S)-2-[(2,2,6,6-tetramethylpiperidin-1-yl)oxy]propanoate
(23a). A solution of 11a (74 mg, 0.20 mmol) and DMAP (11 mg, 80
alcohol 21b as colourless oil. The aqueous layer was acidified and µmol) in methanol (5 mL) was stirred for 20 h at room temperature
under N2. The volatiles were removed and the resultant residue was
extracted with CH2Cl2 (3 × 20 mL) to recover 20 mg (95%) of pure
auxiliary 5. Rf = 0.5 (95:5 CH2Cl2/EtOAc). [α]D20 = –62.1 (c 1.0, CHCl3). diluted in Et2O (20 mL), washed with 1 M NaOH (3 × 20 mL), water
IR (ATR): 3303 (br), 2923, 1451, 1359, 1131, 1027, 694 cm–1. H (20 mL), and brine (20 mL). The organic layer was dried (MgSO4) and
1
NMR (400 MHz, CDCl3): δ 7.30–7.18 (m, 5H), 5.67 (br s, 1H), 4.47 concentrated. The crude was purified by column chromatography
(dddd, J = 9.4, 7.2, 5.5, 2.0 Hz, 1H), 3.97 (dd, J = 11.9, 9.4 Hz, 1H), (90:10 Hexanes/EtOAc) to give 42 mg (0.17 mmol, 86% yield) of
3.65 (dd, J = 11.9, 2.0 Hz, 1H), 2.72 (dd, J = 13.7, 7.2 Hz, 1H), 2.59 pure ester 23a as a colourless oil. The aqueous layer was acidified
(dd, J = 13.7, 5.5 Hz, 1H), 1.58–1.42 (m, 6H), 1.47 (s, 3H), 1.30 (s,
3H), 1.12 (s, 3H), 0.98 (s, 3H). 13C NMR (100.6 MHz, CDCl3): δ 138.3,
129.4, 128.1, 126.1, 81.2, 67.8, 61.5, 60.0, 40.3, 39.9, 37.6, 34.5,
32.4, 29.7, 20.6, 20.2, 17.1. HRMS (ESI): m/z calcd. for C18H30NO2
[M+H]+: 292.2271; found: 292.2278.
and extracted with CH2Cl2 (3 × 20 mL) to recover 28 mg (88%) of
pure auxiliary 5. Rf = 0.4 (90:10 Hexanes/EtOAc). [α]D = –56.3 (c
20
1.0, CHCl3). IR (ATR): 2931, 1741, 1452, 1374, 1361, 1262, 1243,
1197, 1131, 1078, 973, 941, 788 cm–1. 1H NMR (400 MHz, CDCl3): δ
4.34 (q, J = 6.9 Hz, 1H), 3.71 (s, 3H), 1.49–1.38 (m, 6H), 1.40 (d, J =
6.9 Hz, 3H), 1.18 (br s, 3H), 1.12 (br s, 6H), 1.02 (br s, 3H). 13C NMR
(100.6 MHz, CDCl3): δ 174.5, 81.6, 60.1, 59.5, 51.4, 40.3, 40.1, 33.6,
32.9, 20.2, 20.0, 18.1, 17.1. HRMS (ESI): m/z calcd. for C13H26NO3
[M+H]+: 244.1907; found: 244.1901.
(S)-2-[(2,2,6,6-Tetramethylpiperidin-1-yl)oxy]propanoic acid (22a).
A mixture of 11a (74 mg, 0.20 mmol), 30% H2O2 (90 µL, 0.8 mmol, 4
equiv), and LiOH (10 mg, 0.42 mmol, 2 equiv) in 3:1 THF/H2O (4 mL)
was stirred at 0 °C for 30 min. A sat solution of Na2S2O3 (2 mL) was
added and the volatiles were removed in vacuo. The solution was Methyl
(S)-3-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-
acidified with 2 M HCl and the aqueous layer was extracted with yloxy)propanoate (23b). A solution of 11b (89 mg, 0.2 mmol) and
EtOAc (3 × 10 mL). The combined organic extracts were dried DMAP (11 mg, 80 µmol) in methanol (5 mL) was stirred for 72 h at
(MgSO4) and concentrated. The crude was purified by column room temperature under N2. The volatiles were removed and the
chromatography (from CH2Cl2 to 65:35 CH2Cl2/EtOAc) to give 27 mg resultant residue was diluted in Et2O (20 mL), washed with 1 M
(84%) of pure auxiliary 5 and 35 mg (0.15 mmol, 76% yield) of
carboxylic acid 22a as a colourless oil. Rf = 0.3 (65:35 CH2Cl2/EtOAc).
[α]D20 = – 39.8 (c 1.0, CHCl3). IR (ATR): 2974, 2927, 2873, 1720, 1454,
NaOH (3 × 20 mL), water (20 mL), and brine (20 mL). The organic
layer was dried (MgSO4) and concentrated. The crude was purified
by column chromatography (50:50 CH2Cl2/Hexanes) to give 57 mg
(0.18 mmol, 89% yield) of pure ester 23b as a colourless oil. The
aqueous layer was acidified and extracted with CH2Cl2 (3 × 20 mL)
to recover 30 mg (94%) of pure auxiliary 5. Rf = 0.5 (50:50
CH2Cl2/Hexanes). [α]D20 = –17.1 (c 1.0, CHCl3). IR (ATR): 2946, 2911,
1
1372, 1359, 1239, 1128, 1077, 935, 783 cm–1. H NMR (400 MHz,
CDCl3): δ 4.55 (q, J = 6.7 Hz, 1H), 1.73–1.63 (m, 5H), 1.54–1.48 (m,
1H), 1.50 (d, J = 6.7 Hz, 3H), 1.35 (s, 3H), 1.30 (s, 3H), 1.26 (s, 3H),
1.24 (s, 3H). 13C NMR (100.6 MHz, CDCl3): δ 174.3, 62.9, 62.5, 39.2,
39.0, 30.9, 30.1, 29.7, 20.9 (×2), 17.0, 16.4. HRMS (ESI): m/z calcd.
for C12H24NO3 [M+H]+: 230.1751; found: 230.1759.
1
1736, 1366, 1166, 1043, 694 cm–1. H NMR (400 MHz, CDCl3): δ
7.28–7.13 (m, 5H), 4.45 (dd, J = 10.2, 5.5 Hz, 1H), 3.50 (s, 3H), 3.25
(dd, J = 13.2, 5.5 Hz, 1H), 2.99 (dd, J = 13.2, 10.2 Hz, 1H), 1.49–0.99
(m, 18H). 13C NMR (100.6 MHz, CDCl3): δ 173.1, 136.0, 129.4, 128.3,
126.6, 86.6, 60.6, 59.5, 51.1, 40.3, 40.2, 38.5, 33.5, 32.9, 20.3, 20.1,
17.1. HRMS (ESI): m/z calcd. for C19H30NO3 [M+H]+: 320.2220;
found: 320.2225.
(S)-3-Phenyl-2-(2,2,6,6-tetramethylpiperidin-1-yloxy)propanoic
acid (22b). A mixture of 11b (89 mg, 0.20 mmol), 30% H2O2 (90 µL,
0.8 mmol, 4 equiv), and LiOH (11 mg, 0.42 mmol, 2 equiv) in 3:1
THF/H2O (4 mL) was stirred at 0 °C for 3 h. A sat solution of Na2S2O3
(2 mL) was added and the volatiles were removed in vacuo. The
solution was acidified with 2 M HCl and the aqueous layer was N-[2(S)-(2,2,6,6-Tetramethylpiperidin-1-
yloxy)propanoyl]morpholine (24a). A solution of 11a (74 mg, 0.20
mmol), morpholine (69 µL, 0.78 mmol, 3.9 equiv), and DMAP (14
mg, 0.1 mmol) in THF (2 mL) was stirred for 12 h at room
extracted with EtOAc (3 × 10 mL). The combined organic extracts
were dried (MgSO4) and concentrated. The crude was purified by
column chromatography (65:35 CH2Cl2/EtOAc) to give 25 mg (78%)
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
temperature under N2. The volatiles were then removed and the S-Dodecyl
ARTICLE
(S)-[3-phenyl-2-(2,2,6,6-tetramethylpiperidin-1-
View Article Online
DOI: 10.1039/C8OB01074A
residue was purified by column chromatography (from CH2Cl2 to yloxy)]propanethioate (25b). A 1.6 M solution of n-BuLi in hexanes
90:10 CH2Cl2/EtOAc) to afford 57 mg (0.19 mmol, 95% yield) of pure
(38 µL, 60 µmol) was added to a solution of dodecanethiol (145 µL,
0.6 mmol) in THF (2 mL) at 0 °C under N2 and the resultant solution
was stirred for 15 min. Then, a solution of 11b (89 mg, 0.20 mmol)
in THF (2 × 0.75 mL) was added and the reaction mixture was
stirred at room temperature for 14 h. It was diluted with Et2O (20
mL), washed with 1 M NaOH (3 × 20 mL), water (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4) and concentrated. The
crude was purified by column chromatography (80:20
Hexanes/CH2Cl2) to give 87 mg (0.18 mmol, 89% yield) of pure
thioester 25b as a colourless oil. The aqueous layer was acidified
amide 24a as a white solid and 31 mg (97%) of chiral auxiliary 5.
20
Mp: 57–58 °C. Rf = 0.3 (90:10 CH2Cl2/EtOAc). [α]D = –3.0 (c 1.0,
CHCl3). IR (ATR): 2949, 2851, 1644, 1464, 1429, 1233, 1109, 568 cm–
1. 1H NMR (400 MHz, CDCl3): δ 4.61 (q, J = 7.1 Hz, 1H), 3.77–3.53 (m,
8H), 1.60–1.05 (m, 18H), 1.44 (d, J = 7.1 Hz, 3H). 13C NMR (100.6
MHz, CDCl3): δ 172.3, 83.0, 66.9, 66.6, 59.6, 46.1, 42.1, 40.2, 40.1,
33.9, 33.2, 29.7, 20.6, 20.3, 18.5, 17.0. HRMS (ESI): m/z calcd. for
C16H31N2O3 [M+H]+: 299.2329; found: 299.2334.
N-[(S)-[3-Phenyl-2-(2,2,6,6-tetramethylpiperidin-1-
and extracted with CH2Cl2 (3 × 20 mL) to recover 28 mg (88%) of
yloxy)propanoyl]morpholine (24b). A solution of 11b (89 mg, 0.20
mmol), morpholine (69 µL, 0.78 mmol, 3.9 equiv), and DMAP (14
mg, 0.1 mmol 0.5 equiv) in THF (2 mL) was stirred for 24 h at room
temperature under N2. The volatiles were then removed and the
residue was purified by column chromatography (from CH2Cl2 to
80:20 CH2Cl2/EtOAc) to afford 69 mg (0.18 mmol, 92% yield) of pure
amide 24b as a white solid and 26 mg (81%) of chiral auxiliary 5.
Mp: 148–149 °C. Rf = 0.7 (90:10 CH2Cl2/EtOAc). [α]D20 = –4.7 (c 1.0,
20
pure chiral auxiliary 5. Rf = 0.4 (80:20 Hexanes/CH2Cl2). [α]D
=
+21.1 (c 1.0, CHCl3). IR (ATR): 2921, 2850, 1686, 1451, 1362, 1130,
1
934, 696 cm–1. H NMR (400 MHz, CDCl3): δ 7.26–7.16 (m, 5H), 4.53
(dd, J = 9.2, 5.1 Hz, 1H), 3.30 (dd, J = 13.5, 5.1 Hz, 1H), 3.01 (dd, J =
13.5, 9.2 Hz, 1H), 2.74 (t, J = 7.3 Hz, 2H), 1.54–0.85 (m, 40H), 0.88 (t,
J = 6.7 Hz, 3H). 13C NMR (100.6 MHz, CDCl3): δ 201.1, 136.4, 129.7,
128.2, 126.5, 91.4, 40.5, 38.8, 31.9, 29.7, 29.6 (× 2), 29.5, 29.4, 29.1,
28.8, 28.4, 22.7, 20.3, 20.2, 17.1, 14.1. HRMS (ESI): m/z calcd. for
C30H52NO2S [M+H]+: 490.3713, found: 490.3715.
1
CHCl3). IR (ATR): 2930, 1632, 1448, 1239, 1109, 1024, 701 cm–1. H
NMR (400 MHz, CDCl3): δ 7.28–7.17 (m, 5H), 4.73 (dd, J = 11.0, 4.6
Hz, 1H), 3.64–3.53 (m, 2H), 3.39 (ddd, J = 11.5, 5.5, 3.1 Hz, 1H),
3.32–3.21 (m, 4H), 3.10 (dd, J = 12.5, 11.0 Hz, 1H) 3.05–3.00 (m,
1H), 2.74 (ddd, J = 11.5, 7.8, 2.9 Hz, 1H), 1.62–1.02 (m, 18H). 13C
NMR (100.6 MHz, CDCl3): δ 171.1, 136.5, 129.7, 128.4, 126.7, 82.6,
66.5, 66.1, 60.4, 59.5, 46.0, 41.7 40.5, 40.3, 39.0, 33.9, 33.3 20.4,
20.2, 17.1. HRMS (ESI): m/z calcd. for C22H35N2O3 [M+H]+: 375.2642;
found: 375.2651.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank to Professor Antoni Riera by his kind donation of
enantiomerically pure (R) 2-amino-1,1,2-triphenyl-1-ethanol to
prepare chiral auxiliary 16. Financial support from the Spanish
Ministerio de Economía y Competitividad (Grant No. CTQ2015-
65759-P) and the Generalitat de Catalunya (2017SGR 271) as
well as doctorate studentships to S. C. D. K. (Generalitat de
Catalunya) and A. G.-P. (APIF, Universitat de Barcelona) are
acknowledged.
S-Dodecyl
(S)-2-(2,2,6,6-tetramethylpiperidin-1-
yloxy)propanethioate (25a). A 1.6 M solution of n-BuLi in hexanes
(38 µL, 60 µmol) was added to a solution of dodecanethiol (145 µL,
0.6 mmol) in THF (2 mL) at 0 °C under N2 and the resultant solution
was stirred for 15 min. Then, a solution of 11a (74 mg, 0.20 mmol)
in THF (2 × 0.75 mL) was added and the reaction mixture was
stirred at room temperature for 6 h. It was diluted with Et2O (20
mL), washed with 1 M NaOH (3 × 20 mL), water (20 mL), and brine
(20 mL). The organic layer was dried (MgSO4) and concentrated. The
crude was purified by column chromatography (70:30
Hexanes/CH2Cl2) to give 77 mg (0.19 mmol, 93% yield) of pure
thioester 25a as a colourless oil. The aqueous layer was acidified
and extracted with CH2Cl2 (3 × 20 mL) to recover 30 mg (94%) of
pure chiral auxiliary 5. Rf = 0.2 (70:30 Hexanes/CH2Cl2). [α]D20 = –5.8
(c 1.0, CHCl3). IR (ATR): 2922, 2852, 1681, 1453, 1361, 1132, 957,
922, 573 cm–1. 1H NMR (400 MHz, CDCl3): δ 4.42 (q, J = 6.9 Hz, 1H),
2.85 (t, J = 7.4 Hz, 2H), 1.67–0.99 (m, 41H), 0.88 (t, J = 6.9 Hz, 3H).
13C NMR (100.6 MHz, CDCl3): δ 203.4, 87.1, 60.5, 59.5, 40.3, 34.4,
33.5, 31.9, 29.6 (× 3), 29.5, 29.4, 29.3, 29.1, 28.9, 28.1, 22.7, 20.3,
19.4, 17.1, 14.1. HRMS (ESI): m/z calcd. for C24H48NO2S [M+H]+:
414.3400; found: 414.3390.
Notes and references
‡ Crystallographic data for adduct 11b has been deposited at the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 1835692. A copy of the data can be
obtained free of charge on application to CCDC (E-mail:
deposit@ccdc.cam.ac.uk).
§ See Experimental Section
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DOI: 10.1039/C8OB01074A
S
O
S
O
1) TiCl4, i-Pr2NEt
R
R
N
O
N
O
N
O
2)
t-Bu
t-Bu
N
O
80–90%
Single diastereomer
Highly stereoselective
radical-like aminoxylation
Reactions of Ti(IV) enolates from N-acyl-4-tert-butyl-1,3-oxazolidine-2-thiones
with TEMPO afford a single diastereomer of aminoxylated adducts in high yields