Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling

Article abstract of DOI:10.1016/j.tet.2020.131249

The stereoselective synthesis of highly functionalized aminohydroxythiols represents a synthetic challenge as the oxidation sensitivity and coordinating property of the thiol group interferes with many established synthetic methods. The SmI₂/Li

Full text of DOI:10.1016/j.tet.2020.131249

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols
via SmI2-mediated coupling
a
a
a
a
b
€
Carina Doler , Michael Friess , Florian Lackner , Hansjorg Weber , Roland C. Fischer ,
Rolf Breinbauer a
,
*
a Institute of Organic Chemistry, Graz University of Technology, A-8010, Graz, Austria
b Institute of Inorganic Chemistry, Graz University of Technology, A-8010, Graz, Austria
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of highly functionalized aminohydroxythiols represents a synthetic chal-
lenge as the oxidation sensitivity and coordinating property of the thiol group interferes with many
established synthetic methods. The SmI2/LiBr-mediated reductive coupling between Ellman N-sulfiny-
limines, containing thiol groups protected either as trityl thioether or dihydrothiazolidine, and aldehydes
enables the synthesis of chiral aminohydroxythiols in high enantio- and diastereoselectivity. The scope of
this reaction has been established for 18 examples and applied for the synthesis of a complex inter-
mediate needed for a biosynthesis study.
Received 17 March 2020
Received in revised form
27 April 2020
Accepted 28 April 2020
Available online xxx
Keywords:
Asymmetric synthesis
Ellman reagent
© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
Chiral auxiliary
Reductive coupling
Samarium diiodide
Sharpless aminohydroxylation
Single electron transfer
1. Introduction
In the course of a biosynthetic study [1] we faced the challenge
in synthesizing the highly functionalized chiral thiol-containing
1,2-aminoalcohol compound A (Fig. 1).
While there are excellent methods for the synthesis of chiral 1,2-
aminoalcohols available, such as nucleophilic addition at an
amino carbonyl or -hydroxy imine [2e14], ring opening reactions
of epoxide [14e21] or aziridine [14,22e29] precursors, as well as
the addition of both heteroatoms to -unsaturated double bonds
via Sharpless asymmetric aminohydroxylation [14,30e33], the
presence of a thiol group limits the applicability of these methods
as we found out when trying several of these methods as thiols (or
thioethers) are incompatible with oxidative conditions and coor-
dinate to metal reagents.
One of the first methods we considered for the synthesis of the
highly functionalized intermediate A was the Sharpless asymmetric
aminohydroxylation (SAA). To the best of our knowledge the SAA
had been attempted for sulfur containing heterocycles (thiophene)
a
-
Fig. 1. Intermediate A designed for a biosynthetic study.
a
[34,35], but not yet for thiol or thioether containing substrates.
These functional groups represent a special challenge due to their
oxidation sensitivity and metal coordinating properties. However,
with trityl protected substrate 3 an aminohydroxylation product 4
was generated in 42% yield (Scheme 1). Unfortunately, the pro-
duced amino-alcohol 4 showed a regiochemistry contrary to the
intended one. Apparently, in our reaction the regioselectivity of the
SAA was dominated by the trityl protecting group and therefore
opposite to the established rule about the regioselectivity of the
SAA [36,37]. Since this undesired regioselectivity of the SAA could
not be changed, we turned to a pinacol type C-C coupling of an
aldehyde with an imine [38], for which SmI2 [39,40] has proved as a
very powerful and chemoselective reagent whose activity and
a,b
* Corresponding author.
E-mail address: breinbauer@tugraz.at (R. Breinbauer).
https://doi.org/10.1016/j.tet.2020.131249
0040-4020/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

2
C. Doler et al. / Tetrahedron xxx (xxxx) xxx
Scheme 1. Illustration of failed SAA strategy and envisioned SmII-mediated cross coupling strategy (Success of the SAA-reaction was strongly depending on the thiol protection).
selectivity towards functional groups can be finetuned by the use of
appropriate additives and ligands [41e46]. The SmI2 reagent was
originally introduced by Kagan et al. [47]. Besides cross coupling
reactions SmI2 was also frequently used to perform various
reduction reactions [46]. Preparation of vicinal amino-alcohols via
SmII-mediated pinacol type reactions was achieved by coupling
different imine derivatives (i.e. nitrones) with aldehydes or ketones
[48e59]. The stereoselectivity of this SmII-mediated pinacol type
reaction could be significantly increased by coupling a N-tert-
butane sulfinimine derived from Ellman’s auxillary with carbonyl
moieties [38,51e56]. Various further examples for the utilization of
SmII-mediated cross couplings in synthetic strategies can be found
in the literature [40,57,58]. Employment of this strategy in the
synthesis of A was envisioned to be achieved by the SmII-mediated
coupling of a suitably protected tert-butylsulfinimine derivative of
cysteine with ethyl-6-oxohexanoate (Scheme 1).
1,2-aminoalcohol-thiols when using suitable protecting groups for
the mercapto moiety.
2. Results and discussion
In our synthetic strategy the use of (R)- or (S)-tert-butane sul-
finimine (“Ellman reagent” [59]) as chiral auxiliary at the imine
moiety allowed the stereoselective formation of a vicinal amino-
alcohol moiety next to an already existing chiral amine via a
pinacol-type cross coupling reaction. Therefore, within a short re-
action sequence highly functionalized small molecule in-
termediates could be synthesized in high enantio- and
diastereoselectivities when the thiol group was protected either as
a trityl thioether or dihydrothiazolidine thioaminal. To test the
SmII-induced coupling reaction on thiol protected aldimines we
started from both easily accessible compounds such as cysteine and
Here, we report that the SmII-mediated coupling between al-
dehydes and aldimines can be extended to the synthesis of chiral
methionine as well as the structurally more demanding
D-penicil-
lamine (Scheme 2). For the imine substrates both the trityl-Boc
Scheme 2. Synthesis of imine substrates (Boc-Trt-L-cysteine is commercially available; Syntheses of 13, 9 and 18 are described in the experimental section).
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
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C. Doler et al. / Tetrahedron xxx (xxxx) xxx
3
protecting group strategy as well as the thioaminal-Boc protecting
group strategy was used. The reduction of the protected chiral
amino acid compounds to the aldehyde was performed via our
recently developed protocol of in situ activation with 1,10-carbon-
yldiimidazole (CDI) followed by reduction with DIBAL-H [60]. For
the protected cysteine and methionine substrates the reduction to
the aldehyde was high yielding (92%e95%) and did not lead to any
racemization of those compounds. The protected D-penicillaminal
(19) could be isolated in 98% yield after the CDI mediated DIBAL-H
reduction of the carboxylic acid moiety. The aldehyde substrates
were converted to the respective imine substrates (compounds 6b,
15, 11, 20) via Ti(OiPr)4-mediated condensation with (S)-tert-butane
sulfinamide (Ellman-reagent) in 32%e96% yield after column
chromatography (Scheme 2).
sources did not lead to the desired increase in yield (entries 9e12).
Fortunately, through in situ formation of the much more reactive
“SmBr2“-species by addition of 16 eq LiBr, an increase in yield (73%)
and diastereoselectivity of the reaction (99:1) could be achieved
(entry 13). The observed positive effect of LiBr addition to the SmI2
reagent is in accordance to reported investigations concerning
SmII-mediated coupling reactions [63e70]. Therefore, the found
optimum reaction conditions were used to explore the substrate
scope of this reaction (Scheme 3).
The SmI2-LiBr induced reductive coupling was tested with 6
different aldehyde substrates furnishing 7a-7f in good to moderate
yields (Scheme 3). Aliphatic aldehydes (piv-, isobutyr- and iso-
valeraldehyde) gave slightly better yields than their aromatic
counterparts or penten-4-al bearing an unsaturated double bond.
The diastereomeric excess of the reaction was excellent for all
aldehyde substrates with the exception of the sterically less hin-
dered penten-4-al (dr 95:5). While the diastereoselectivity of the
reaction is mainly controlled by the absolute configuration of the
used Ellman reagent, it might also be influenced by the steric
hindrance of the aldehyde substrate, as observed for the SmI2-
mediated reductive coupling of non-thiol containing aldimines and
aliphatic aldehydes [38].
The SmII-mediated reductive coupling reaction was optimized
for the test reaction of 6b with isovaleraldehyde [38]. Under stan-
dard reaction conditions (entry 1) the desired product 7c could be
isolated in only 36% yield, but with excellent diastereomeric ratio
(dr) of 98:2 using 2.0 eq t-BuOH as proton source (Table 1). A slight
improvement of the reaction outcome could be observed, when the
aldehyde and aldimine substrate solutions were prepared sepa-
rately (each of them 0.16M) and added via syringe pump over a
period of 15 min to the SmI2*THF solution at ꢀ78 ꢁC (entry 3). In
this case 2.0 eq of the proton source were added to the aldimine
solution before the addition. The reaction was cleaner but no in-
crease in dr was recognized. However, due to the observed positive
effect also for the following screening reactions the substrate so-
lutions were added separately via syringe pump at a concentration
of 0.16M each.
The absolute configuration of the coupling products of the
reductive coupling reactions could be unambiguously proven by X-
ray spectroscopy for compound 7a (c.f. molecular structure shown
in Scheme 3, for crystallographic details see SI). According to this
data, the two newly formed stereogenic centres are introduced
with the (S)-N-tert-butane sulfinimines in (R,S)-configuration. This
is in accordance with the literature for this type of coupling re-
actions [38].
By increasing the reduction potential of SmII-metal a positive
influence on the reaction outcome could be noticed. The use of the
nontoxic HMPA surrogate tris-(N,N-tetramethylene)phosphoric
acid triamide (TPPO) [61,62] led to 53% yield accompanied by a drop
in dr from 98:2 to 95:5 (entries 5&6), which made this modification
less attractive. The use of more acidic alcohols as alternative proton
The substrate scope was further investigated by testing different
aldimines (6b, 11, 15, 20) in the established cross coupling reaction.
In substrate 11 the amino thiol group is protected as an N-Boc-2-
phenylthiazolidine leading to
a more rigid substrate when
compared to the S-trityl protected substrate 6b (Table 2). Coupling
Table 1
Reaction optimization conditions.
Entry
Isoveraldehyde
SmI2*THF
Substrate solution
Comments
Isolated yield
dr
1
2
3
4
5
6
7
8
1.50 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
3.00 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
1.50 eq
3.00 eq
3.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
3.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
2.00 eq
0.08M
0.08M
0.08M
0.50M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
0.08M
addition at once
aldehyde freshly distilled
36 %a
98:2
98:2
98:2
97:3
94:6
95:5
99:1
96:4
98:2
98:2
99:1
95:5
99:1
/
36 %a
40 %a,b
21%a,b
37%a,b
53%a,b
53%a,b
30%a,b
37%b
2 eq TPPO
8 eq TPPO
9
2 eq trifluoroethanol
2 eq phenol
2 eq HFIP
8 eq deionized H2O
16 eq LiBr
8 eq abs. MeOH
8 eq TPPO
10
11
12
13
14
15
16
37%b
43%b
19%b
73%b
no product formationb
47%a,b
64%b
97:3
99:1
16 eq LiBr
dr was determined via HPLC-MS.
c Isolated via preparative HPLC. HFIP: hexafluoroisopropanol.
a
Reaction conditions: 2.00 eq t-BuOH as proton source.
Reaction conditions: aldehyde/imine solutions were added separately via syringe pump.
b
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Scheme 3. SmI2-LiBr-mediated reductive coupling with substrate 6b.
compound 11 with sterically more demanding aldehyde substrates
such as pivaldehyde or 2-phenylacetaldehyde subsequently led to a
dramatic decrease of the dr (82:18 and 77:23 for compound 12a
and 12d respectively) of the reaction. Whereas the reductive cross
coupling with sterically less hindered aliphatic aldehyde substrates
proceeded in excellent dr’s of 98:2 for 12c and 12d, a minor
decrease of the dr for 3-phenylpropionaldehyde (dr 93:7; 12e) and
penten-4-al (95:5; 12f) was observed.
The SmI2-LiBr-mediated reductive cross coupling with the
aldimine compound 15 delivered products in quite consistent yield.
As sterically more demanding aldehyde substrates such as piv-
aldehyde showed a decrease in yield to 58% (Table 2), the also very
demanding 2-phenylacetaldehyde showed a yield in the same
range as obtained for the other aldehyde substrates. However, steric
effects seem to exert a strong influence on the diastereomeric
excess of the reaction. The dr of reactions with sterically more
demanding aldehydes was the highest (compound 16a and 16d),
whereas more flexible aldehydes show a decreased dr (compounds
16c, 16e and 16f).
The substrate screening revealed, that the level of diaster-
eoselectivity for this transformation is not only influenced by the
configuration of the N-tert-butane sulfinimine. Also, the steric bulk
of the aldehyde substrates slightly influences the stereo-selective
outcome of the reaction. For the
D-pencillimine substrate 20
nearly no product formation could be detected. This substrate is the
most sterically demanding imine substrate tested for the reductive
coupling reactions. Very likely the increased steric repulsion led to
the poor product formation for this imine substrate.
Finally, with the optimized reaction conditions for the SmII-
mediated reductive coupling reaction, the synthesis of target
compound A could be attempted (Scheme 4). For the synthesis of
intermediate A we started from commercially available N-Boc-S-
trityl-L-cysteine. After two reaction steps the corresponding imine
substrate 6a could be isolated in moderate yield of 48%. The SmI2-
LiBr-mediated reductive coupling reaction with the C5-aldehyde
compound 22 proceeded well in presence of 16 eq LiBr as additive.
Compound 23 could be isolated as single diastereomer in 67% yield.
For this coupling reaction a (R)-tert-butylsulfinylimine was used
as substrate contrary to the previous described screening reactions,
where (S)-tert-butylsulfinylimines were used. The steric inversion
of the auxiliary group changed the spatial arrangement of the
central 2,3-diamino-alcohol moiety formed by the cross coupling
reaction. This means that while the 1,2-aminoalcohol moiety was
still formed in trans fashion, its overall orientation relative to the
protected 3-amino group was inverted. The observed high dia-
stereoselectivity in the formation of 63 (dr ¼ 98:2), alongside with
the fact, that also in couplings with (S)-tert-butylsulfinylimines
many products could be formed with high diastereoselectivity
(Table 2), shows that the stereoselectivity of the SmI2-LiBr
The substrate screening revealed that for the flexible aldimine
substrates 6b and 15 dr’s are better for sterically demanding alde-
hyde substrates such as pivaldehyde or 2-phenylacetaldehyde. This
is in contrast to rigid aldimine substrate 11, which showed poor dr
for the reaction with sterically demanding aldehyde compounds.
For the SmI2-LiBr-mediated reductive coupling reaction with the
sterically very demanding and rigid aldimine substrate 20 derived
from D-penicillamine, the reaction led to the formation of many
side products and only little product formation could be indicated
with HPLC-MS. Compounds 21d and 21e could be isolated in poor
yield of 6% and 2% (Table 2).
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Table 2
Substrate screening of SmI2-LiBr-mediated reductive coupling reactions.
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
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Scheme 4. Synthesis of biosynthesis intermediate A.
mediated cross-coupling reaction is predominantely determined by
the sulfinylimine group. Thus the influence of the protected amino
group in a-position to the sulfinyl moiety of the imine substrate on
degassed solvents were used. For degassing, the solvent or reaction
mixture was first evacuated and then reflushed with protective gas.
This process was repeated several times, dependent on the solvent
volume. For work-up procedures with compounds sensitive to
oxidation, the solvents were degassed for 15 min in an ultrasonic
bath under nitrogen counter flow before use. In general, tempera-
tures were measured externally if not otherwise stated. When
working at a temperature of 0 ꢁC, an ice-water bath served as the
cooling medium. Lower temperatures were achieved by either us-
ing an acetone/dry ice cooling bath or a cryostatic temperature
regulator. Reactions, which were carried out at higher tempera-
tures than RT, were heated in a silicon oil bath on a heating plate
(RCT basic IKAMAG® safety control, 0e1500 rpm) equipped with an
external temperature controller. SmI2- or SmBr2-catalysed re-
actions were carried out under exclusion of light, and absolute THF
free of any stabilizer was used. For hydrogenation reactions special
safety conditions were necessary. During work-up the catalyst
filtration was carried out via an inverse filter funnel through a pad
of Celite under inert gas. After the product had been isolated, the
catalyst pad was rinsed with water and the used catalyst was then
stored under water. A description of the utilized analytical methods
can be found in the Supporting Information.
the selectivity of the coupling reaction via a matched/mismatched
relation seems to be rather low. In literature it is assumed that the
stereoselectivity of the SmI2-LiBr-mediated cross-coupling reaction
arises from a transition state which is avoiding an unfavourable
gauche interaction of the residues originating from the imine and
aldehyde substrate [38,71].
The removal of the chiral auxiliary of 23 under acidic condition
with 4M HCl delivered compound 24 in 90% yield. Treatment with
50% trifluoroacetic acid in DCM in presence of 2.0 eq Et3SiH led to
the removal of the Boc and Trt protecting groups to furnish inter-
mediate A in 94% isolated yield (27% overall yield after 5 reaction
steps starting from commercially available Boc-Trt-L-cysteine).
3. Conclusion
In summary, we have presented an efficient stereoselective ac-
cess to chiral 1,2-amino-alcohols containing thiol groups via the
SmI2-LiBr-mediated coupling of aldehydes with Ellman sulfinyli-
mines. Key element is the use of suitable protecting groups for the
thiol moiety which has to be protected either as S-trityl ether or
phenylthiazolidine. The scope of the reaction has been established
for 18 compounds (yields of 58e78%, dr up to 99:1). It shows broad
tolerance to various alkyl aldimine substrates but is less suitable for
aromatic aldimines. The presented methodology forms the 1,2-
amino-alcohol moiety in trans fashion. Thus, our method appears
to be complementary to a recently published photocatalytic
method for the preparation of syn-1,2-amino-alcohols [72]. It might
become a valuable tool for the synthesis of such highly function-
alized thiol containing small molecule intermediates, as we could
advantageously use it for the synthesis of intermediate A.
4.2. SAA strategy
4.2.1. Ethyl (R,E)-4-((tert-butoxycarbonyl)amino)-5-(tritylthio)
pent-2-enoate (3)
In an inert 100 mL round bottom flask 334 mg (0.75 mmol, 1.00
eq) 5 were dissolved in 7 mL ab. THF. 313 mg (0.90 mmol/1.2 eq)
ethyl 2-(triphenyl-l5-phosphaneylidene)acetate were added to
this clear colorless solution. The resulting yellowish mixture was
stirred at RT for 1 h. Complete conversion was indicated via TLC. For
work-up the solvent was removed under reduced pressure. The
crude product (yellowish oil) was purified via flash column chro-
matography [100 g silica, 16 ꢂ 4 cm, CH/EA ¼ 9/1, fraction: 1e30,
fraction size: 20 mL] to afford a clear colorless oil (246.1 mg,
0.48 mmol, 63%). HPLC-MS: tR ¼ 8.65 min (Naþ, Hþ adduct); TLC:
4. Experimental section
4.1. General information
Rf ¼ 0.5 (CH/EA ¼ 5/1); 1H NMR (300.36 MHz, CDCl3)
d 7.57e7.17
15.6 Hz, 4.8 Hz, 1H), 5.85 (d,
3
(m, 15H), 6.72 (dd, JHH
¼
Reactions carried out under inert conditions were performed
with standard Schlenk techniques under exclusion of oxygen. The
reaction vessel was evacuated, flame dried, and flushed with argon
or nitrogen gas for three times. Solvents were dried and/or
degassed with common methods and afterwards stored under inert
gas atmosphere (argon or N2) over molecular sieves (SI). The
addition of chemicals was conducted under argon or nitrogen
counter flow, which should exclude traces of moisture and oxygen.
All reactions were stirred with Teflon-coated magnetic stirring bars
unless otherwise stated. Oxidation sensitive reactions were
accomplished under argon or nitrogen atmosphere and absolute
3JHH ¼ 15.6 Hz, 1H,), 4.64 (s, 1H), 4.21 (q, 3JHH ¼ 7.1 Hz, 2H), 2.48 (s,
3
2H), 1.47 (s, 9H), 1.31 (t, JHH ¼ 7.1 Hz, 3H); 13C NMR (75.53 MHz,
CDCl3)
d 166.1, 154.9, 146.7, 144.5, 129. 7, 128.2, 127.0, 121.8, 80.0,
67.3, 60.6, 50.6, 36.4, 28.5, 14.4.
4.2.2. Ethyl-(4R)-2,4-bis((tert-butoxycarbonyl)amino)-3-hydroxy-
5-(tritylthio)pentanoate (4)
In a 5 mL glass vial 47.2 mg (0.40 mmol, 3.08 eq) tert-butyl
carbamate were dissolved in a mixture of 500
mL NaOH (0.4M) and
500 L 1-propanol. 44.5 L (0.39 mmol, 3 eq) freshly prepared tert-
m
m
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C. Doler et al. / Tetrahedron xxx (xxxx) xxx
7
BuOCl-solution (108) were added to this clear colorless solution
and it was stirred at rt for 5 min. Then a solution of 67.7 mg
1.00 eq) were dissolved in a mixture of 46 mL EtOH and 14 mL dist.
H2O (EtOH/dist. H2O ¼ 10/3). 2.5 mL (2.60 g, 24.5 mmol, 0.99 eq)
benzaldehyde were added to the clear colorless solution, giving a
cloudy suspension, which was stirred at rt overnight. Complete
conversion was detected via TLC. For work-up the white precipitate
was collected by filtration and washed with 40 mL ice cold Et2O.
The crude product was dried in high vacuum and used without
further purification in the next reaction step. 4.96 g (23.6 mmol,
96%) crude product could be obtained in form of off-white crystals.
TLC: Rf ¼ 0.42 (MeOH/DCM ¼ 3/1 þ1% NH3); 1H NMR (300.36 MHz,
(0.13 mmol, 1.00 eq) 19 and 6.6 mg (8.00
mmol, 5.80 mol%)
(DHQ)2AQN in 1 mL 1-propanol were added to the reaction mixture
giving a clear yellow solution. In a separate 2 mL glass vial 2.4 mg
(0.006 mmol, 5 mol %) K2OsO2(OH)4, were dissolved in 1 mL NaOH
(0.4M). The clear purple catalyst-solution was then added to the
reaction mixture giving a green-yellowish coloured mixture which
was stirred at rt for at least 1 h. TLC and HPLC-MS indicated full
conversion and for work-up 500 mg NaHSO3/Na2S2O3 (1/1) were
added. The aqueous phase was extracted with EtOAc (3 ꢂ 5 mL) and
the combined organic layers were dried over MgSO4. The solvent
was removed under reduced pressure resulting in an orange oil.
The crude product was purified via flash chromatography [10 g
silica, 7 ꢂ 1 cm; CH/EA ¼ 5/1 (fraction 1e68), fraction size: 6 mL) to
afford a clear oil (35.3 mg, 0.05 mmol, 41%). HPLC-MS: tR ¼ 8.45 min
(Naþ, Hþ adduct); TLC: Rf ¼ 0.11 (CH/EA ¼ 5/1); 1H NMR
DMSO)
d 7.73e7.12 (m, HAr, 5H), 5.67 (s, 1H), 5.50 (s, 1H), 4.24 (dd,
3
3JHH ¼ 6.8, 4.6 Hz, 1H), 3.96e3.84 (m, 1H), 3.36 (ddd, JHH ¼ 23.5,
10.0, 7.2 Hz, 2H), 3.21e3.03 (m, 2H); 13C NMR (75.53 MHz, DMSO)
d
173.0, 172.2, 141.2, 138.94, 128.5, 128.3, 128.2, 127.6, 127.3, 126.9,
71.8, 71.1, 65.4, 64.9, 38.4, 38.0.
4.3.4. (4R)-3-(tert-Butoxycarbonyl)-2-phenylthiazolidine-4-
carboxylic acid (9)
(300.36 MHz, CDCl3)
d 7.29 (m, 15H), 5.32 (s, 1H, NH), 4.71 (d,
3JHH ¼ 8.3 Hz, 1H, OH), 4.27 (d,3JHH ¼ 7.7 Hz, 1H), 4.16 (dt,
In a 100 mL round bottom flask 1.65 g (7.88 mmol, 1.00 eq) 8
were dissolved in 33 mL of a dioxane water mixture (1,4-dioxane:
dist. H2O: 0.1 M NaOH ¼ 2:1:1). The resulting off-white suspension
was cooled to 0 ꢁC in an ice bath. At this temperature 1.89 g
(8.67 mmol, 1.10 eq) Boc-anhydride were added. The mixture was
allowed to warm up to RT and stirred overnight. The reaction was
monitored via TLC. For work-up the 1,4-dioxane was removed un-
der reduced pressure. The remaining colorless suspension was
diluted with 20 mL 10% NaHSO3 solution and 20 mL EtOAc. The pH-
value of this mixture was adjusted to 2 via the addition of addi-
tional 4 mL HCl (6M). The two phases were separated and the
aqueous phase was extracted with EtOAc (5 ꢂ 20mL). The com-
bined organic phases were dried over MgSO4, filtrated in vacuum
and the solvent was removed under reduced pressure, giving
colorless crystals as crude product (2.39 g, 7.73 mmol, 98%). The
product was used without further purification in the next reaction
3JHH ¼ 19.6, 7.3 Hz, 2H), 3.90 (s, 1H), 3.42 (s, 1H), 2.56 (dd,
3JHH ¼ 12.5, 4.2 Hz, 1H), 2.41 (dd, JHH ¼ 12.5, 5.1 Hz, 1H), 1.42 (s,
3
18H), 1.25 (m, 3H); 13C NMR (75.53 MHz, CDCl3)
d 170.9, 156.4,
144.5, 129.6, 128.0, 126.8, 79.7, 73.7, 67.1, 61. 7, 55.9, 52.3, 33.4, 28.3,
14.1.
4.3. Reductive cross coupling strategy
4.3.1. General procedure for the DIBAL-H reduction of protected
amino acids
In an inert Schlenk flask 1.0 eq of the carboxylic acid substrate
was dissolved in dry DCM (6.5 mL/mmol substrate). The resulting
solution was cooled to 0 ꢁC in an ice bath.1.1 eq CDI were added and
the Schlenk flask was equipped with a bubbler. The resulting so-
lution was stirred for 1 h at 0 ꢁC and was then further cooled down
to ꢀ78 ꢁC in an acetone/dry ice bath. At this temperature 2.1 eq
DIBAL-H (1M in DCM) were added via syringe pump over 60 min.
After complete addition the reaction mixture was stirred at ꢀ78 ꢁC
for further 30 min. Complete conversion was detected via TLC and
HPLC-MS. For work-up the reaction mixture was quenched by the
addition of EtOAc (7.5 mL/mmol substrate) and (25% w/w) tartaric
acid (7.5 mL/mmol substrate). The aqueous phase was extracted
with EtOAc (2 ꢂ 3.75 mL/mmol substrate). The combined organic
layers were washed with 1M HCl (7.5 mL/mmol substrate), (10% w/
w) NaHCO3 (38.5 mL/mmol substrate), brine (38.5 mL/mmol sub-
strate) and dried over MgSO4. The solvent was removed under
reduced pressure to afford the crude product. The reaction and the
work-up were carried out under exclusion of light. In order to
prevent oxidation of the product all solvents had to be degassed for
30 min in an ultrasonic bath prior use in the work-up procedure.
The crude product was stored under inert conditions and exclusion
of light.
step. TLC: Rf
¼
0.42 (MeOH/DCM
¼
3/1
þ
1% NH3);
d 7.73e7.19 (m,
m.p. ¼ 174e176 ꢁC; 1H NMR (300.36 MHz, CDCl3)
5H), 5.96 (s, 1H), 4.90 (s, 1H), 3.36 (dd, J ¼ 23.5, 17.1 Hz, 2H), 1.45 (s,
9H); 13C NMR (75.53 MHz, CDCl3)
85.3, 66.9, 64.3, 28.1, 27.6.
d 173.4, 146.9, 128.5, 128.1, 126.7,
4.3.5. tert-Butyl-(4R)-4-formyl-2-phenylthiazolidine-3-carboxylate
(10)
2.09 g (6.76 mmol/1.0 eq) 9 were converted following general
procedure 4.3.1. As crude product a yellowish oil (1.61 g, 5.47 mmol,
81%) could be obtained. It was used without further purification in
the next reaction step. HPLC-MS: tR ¼ 8.66 min (Naþ, Hþ adduct);
TLC: Rf ¼ 0.39 (CH/EA ¼ 5/1); 1H NMR (300.36 MHz, CDCl3)
d 9.72
(s, 1H), 7.47e7.07 (m, 5H), 5.94 (s, 1H), 4.76 (s, 2H), 3.20 (m, 1H), 1.16
(m, 9H); 13C NMR (75.53 MHz, CDCl3)
128.3, 126.4, 82.0, 69.6, 66.3, 28.0, 21.0.
d 198.8, 171.2, 140.7, 128.5,
4.3.6. N-(tert-Butoxycarbonyl)-S-trityl- -homocysteine (13)
L
4.3.2. tert-Butyl (R)-(1-oxo-3-(tritylthio)propane-2-yl)carbamate
(5)
In a 100 mL three necked round bottom flask equipped with
Schlenk adapter and dry ice reflux condenser 3.00 g (12.00 mmol,
1.00 eq) L-Boc-methionine were dissolved in 25 mL liquid ammonia
at ꢀ78 ꢁC (dry ice/acetone cooling bath). 1.38 g (60.20 mmol, 5.00
eq) Na were added in portions to this clear colorless solution. The
reaction mixture turned dark blue and was allowed to reflux
at ꢀ40 ꢁC for 1 h. The reaction was monitored via HPLC-MS. After
complete conversion 2.51 g (46.9 mmol, 3.90 eq) NH4Cl were added
and the reaction mixture was allowed to warm up to rt overnight.
The next day the white residue was suspended in 50 mL DCM and
3.66 g (14.10 mmol, 1.17 eq) triphenylmethanol and 2.5 mL (5% v/v)
trifluoroacetic acid were added to the off-white suspension. The
reaction mixture was stirred for 2 h at rt and reaction conversion
600.7 mg (1.3 mmol/1.0 eq) Boc-Trt-L-cysteine were converted
following general procedure 4.3.1. As crude product a clear, sticky
oil (534 mg, 1.19 mmol, 92%) could be obtained. It was used without
further purification in the next reaction step. HPLC-MS:
tR ¼ 8.17 min (Naþ, Hþ adduct); TLC: Rf ¼ 0.42 (CH/EA ¼ 5/1); 1H
NMR (300.36 MHz, CDCl3)
d 9.18 (s, 1H), 7.46-7.22 (m, 15 H), 5.13-
4.97 (m, 1H), 2.71 (m, 2H), 1.43 (s, 9H); 13C NMR (75,53 MHz, CDCl3)
198.2, 155.4, 144.3, 129.6, 128.2, 127.1, 80.5, 77.0, 67.4, 31.5, 28.4.
d
4.3.3. (4R)-2-Phenylthiazolidine-4-carboxylic acid (8)
In a 100 mL round bottom flask 3.00 g -cysteine (24.60 mmol,
L
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

8
C. Doler et al. / Tetrahedron xxx (xxxx) xxx
was monitored via HPLC-MS. After complete conversion the reac-
tion mixture was quenched by the addition of 25 mL dist. H2O and
the aqueous phase was extracted with DCM (3 ꢂ 25 mL). The
combined organic phases were extracted with brine (1 ꢂ 20 mL)
and dried over MgSO4. After filtration the solvent was removed
under reduced pressure giving a colorless solid. The product was
purified via column chromatography [250 g silica gel, 13 ꢂ 3.5 cm,
CH/EE/AcOH ¼ 4/1/0.02, fraction 1e15, fraction size 150 mL] to
afford a colorless solid (3.00 g, 6.28 mmol, 52%). HPLC-MS:
tR ¼ 7.79 min (Naþ, Kþ adduct); TLC: Rf ¼ 0.31 (CH/EA ¼ 5/1);
2.89 mmol, 98%) could be obtained. It was used without further
purification in the next reaction step. HPLC-MS: tR ¼ 7.49 min (Naþ,
Kþ adduct); TLC: Rf ¼ 0.65 (CH/EA/AcOH ¼ 52/1/0.01).
4.3.11. General procedure for the synthesis of tert-butanesulfinyl
imines
In a round bottom flask the respective aldehydes (1.00 eq) and
the (R)-tert-butanesulfinamide or (S)-tert-butanesulfinamide (1.10
eq) were dissolved in abs. THF (0.5M) at rt. After the educts had
dissolved completely, Ti(OiPr)4 (1.50 eq) was added dropwise via
septum to the reaction mixture upon which the reaction mixture
turned bright yellow. This solution was stirred at rt for 3 h until
complete conversion was detected via TLC and HPLC-MS. For re-
action work-up the reaction mixture was filtrated through a pad of
Celite, which later was washed with DCM (3 ꢂ 10 mL). The solvent
of the filtrate was removed under reduced pressure giving the
crude product as yellowish oil. The product was further purified via
column chromatography.
m.p. ¼ 143e146 ꢁC; 1H NMR (300.36 MHz, CDCl3)
d 7.57e7.17 (m,
3
15H), 4.68 (d, JH,H ¼ 7.6 Hz, 1H), 2.48-2.21 (m, 2H), 1.99-1.54 (m,
2H), 1.49 (s, 9H); 13C-APT-NMR (75,53 MHz, CDCl3)
d 176.3, 155.5,
144.7, 129.6, 127.9, 126.8, 80.3, 67.2, 52.9, 31.9, 28.4, 20.7.
4.3.7. tert-Butyl (R)-(1-oxo-4-(tritylthio)butan-2-yl)carbamate
(14)
1 g (2.09 mmol/1.0 eq) 13 were converted following general
procedure 4.3.1. As crude product a clear, sticky oil (920 mg,
2.00 mmol, 95%) was obtained. It was used without further puri-
fication in the next reaction step. TLC: Rf ¼ 0.47 (CH/EA ¼ 4/1);1H
4.3.12. tert-Butyl ((R,E)-1-(((R)-tert-butylsulfinyl)imino)-3-
(tritylthio)propan-2-yl)carbamate (6a)
NMR (300.36 MHz, CDCl3)
d
9.40 (s 1H), 7.53-7.15 (m, 15H), 4.87 (d,
According to general procedure 4.3.11, 2.00 g (4.47 mmol, 1.00
eq) 5 and 596 mg (4.92 mmol, 1.10 eq) (R)-tert-butanesulfinamide
were dissolved in 9 mL THF. 1.98 mL (1.91 g, 6.70 mmol, 1.50 eq)
isopropyltitanate were added dropwise. Complete conversion was
detected via HPLC-MS. Column Chromatography [250 g SiO2, 6.5
cmx15 cm; CH/EA ¼ 9/1; fraction size 166 mL; fraction 15 to 30]
afforded 6a as yellowish oil (2.22 g, 4.03 mmol, 90%). HPLC-MS:
3JHH ¼ 11.6 Hz, NH, 1H), 4.13 (m, 1H), 2.46e2.17 (m, 2H), 1.89 (m,
1H), 1.55 (m, 1H), 1.42 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
155.5, 144.7, 129.7, 128.1, 126.9, 80.2, 59.2, 28.6, 28.4, 27.8.
d 199.0,
4.3.8. (4S)-5,5-Dimethyl-2-phenylthiazolidine-4-carboxylic acid
(17)
In a 100 mL round bottom flask 2.00 g (13.40 mmol, 1.00 eq)
D
-
tR
¼
8.56 min; TLC: Rf
¼
0.57 (CH/EA
¼
3/1); 1H NMR
3
penicillamine were dissolved in 40 mL H2O:EtOH (10/3). 1.37 mL
(1.42 g, 13.40 mmol, 1.00 eq) benzaldehyde were added to this clear
colorless solution and the mixture was stirred at rt overnight. Full
conversion was detected via TLC and the product was collected by
filtration and washed with ice cold Et2O (20 mL). The product was
dried in vacuo, giving a white powder (2.63 g, 11.1 mmol, 83%) as
crude product. The crude product was used without further puri-
fication in the next step. TLC: Rf ¼ 0.28 (DCM/MeOH/NH3 ¼ 3/1/
0.01); m.p. ¼ 165 ꢁC;
(300.36 MHz, CDCl3)
d
7.82 (d, JHH ¼ 23.6 Hz, 1H), 7.55-7.13 (m,
15H), 5.23-4.93 (m, 1H, NH), 4.56-4.18 (m, 1H), 2.55 (dd, 2JHH ¼ 36.8,
11.8 Hz, 2H), 1.48 (s, 9H), 1.21 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d
166.8, 155.5, 144.5, 144.4, 129.7, 129.6, 128.2, 128.2,127.1, 127.0,
80.2, 80.1, 67.1, 66.9, 57.7, 57.5, 55.6, 34.2, 28.4, 22.3.
4.3.13. tert-Butyl ((R,E)-1-(((S)-tert-butylsulfinyl)imino)-3-
(tritylthio)propan-2-yl)carbamate (6b)
According to general procedure 4.3.11, 200 mg (0.447 mmol,1.00
eq) 5 and 60 mg (0.492 mmol, 1.10 eq) (S)-tert-butanesulfinamide
4.3.9. (4S)-3-(tert-Butoxycarbonyl)-5,5-dimethyl-2-
were dissolved in 1 mL THF. 198 mL (191 mg, 0.670 mmol, 1.50 eq)
phenylthiazolidine-4-carboxylic acid (18)
isopropyltitanate were added dropwise. Complete conversion was
detected via HPLC-MS. Column chromatography [100 g SiO2; 4
cmx12 cm; CH/EA ¼ 9/1; fraction size 70 mL, fraction 6 to 12] gave
6b as yellowish oil (208 mg, 0.376 mmol, 85%). HPLC-MS:
In a 100 mL round bottom flask 2.63 g (12.60 mmol, 1.00 eq) 17
were dissolved in 42 mL Et2O/1M NaOH/H2O (2/1/1). 3.02 g
(13.9 mmol, 1.10 eq) Boc2O were added to this two phase colorless
solution and the reaction mixture was stirred at rt overnight. Full
conversion was detected via TLC and HPLC-MS. For reaction work-
up the reaction mixture was acidified to pH 2 with 1M HCl until a
white precipitate formed. The aqueous layer was extracted with
EtOAc (3 ꢂ 50 mL) and the combined organic layers were dried over
MgSO4. The drying reagent was filtered off and the solvent was
removed via rotary evaporator. The crude product was purified via
column chromatography [250 g SiO2, 6.5 cmx15 cm, CH/EA/
AcOH ¼ 4/1/0.001, 160 mL fraction size, fraction 6 to 15] to afford 18
as colorless powder (1.93 g, 5.72 mmol, 46%). HPLC-MS:
tR ¼ 6.69 min (Naþ, Kþ adduct); TLC: Rf ¼ 0.25 (CH/EA/AcOH ¼ 3/
tR ¼ 8.57 min (Hþ-, Naþ- adduct); TLC: Rf ¼ 0.57 (CH/EA ¼ 3/1);
3
1H NMR (300.36 MHz, CDCl3)
d
7.82 (d, JHH ¼ 23.6 Hz, 1H), 7.60-
6.91 (m, 15H), 5.26-5.00 (m, 1H, NH), 4.38 (dd, 3JHH ¼ 22.9, 15.7 Hz,
1H), 2.82-2.48 (m, 2H), 1.48 (s, 9H), 1.23 (s, 9H); 13C NMR
(75.53 MHz, CDCl3)
d 166.8, 155.7, 144.4, 129.6, 128.2, 127.0, 80.7,
67.1, 57.7, 55.6, 28.5, 22. 7, 22.3.
4.3.14. tert-Butyl (4R)-4-((E)-(((S)-tert butylsulfinyl)imino)
methyl)- 2-phenylthiazolidine-3-carboxylate (11)
According to general procedure 4.3.11, 902 mg (3.07 mmol, 1.00
eq) 10 and 410 mg (3.38 mmol, 1.10 eq) (S)-tert-butanesulfinamide
were dissolved in 6.20 mL THF. 1.37 mL (1.31 g, 4.61 mmol, 1.50 eq)
isopropyltitanate were added dropwise. Complete conversion was
detected via HPLC-MS. Column Chromatography [125 g SiO2, 4
cmx24 cm, CH/EA ¼ 9/1; fraction size 80 mL; fraction 9 to 19] gave
11 as yellowish foam (310 mg, 0.78 mmol, 96%). HPLC-MS:
tR ¼ 7.56 min (Hþ-, Naþ- adduct); TLC: Rf ¼ 0.23 (CH/EA ¼ 5/1);
1/0.1%); m.p. ¼ 215e217 ꢁC; 1H NMR (300.36 MHz, DMSO‑d6)
3
d
12.91 (s, 1H, OH), 7.74 (s, 2H), 7.30 (d, JHH ¼ 7.1 Hz, 3H), 6.03 (d,
3JHH ¼ 35.9 Hz, 1H), 4.32 (s, 1H), 1.57 (s, 3H), 1.32 (s, 4H), 1.30e1.15
(m, 3H), 1.04 (s, 5H); 13C NMR (75.53 MHz, DMSO‑d6)
d 171.0, 152.7,
141.2, 127.8, 127.2, 80.1, 72.8, 65.0, 51.3, 30.8, 27.6, 24.4.
4.3.10. tert-Butyl (4S)-4-formyl-5,5-dimethyl-2-phenylthiazolidine-
3-carboxylate (19)
1H NMR (300.36 MHz, CDCl3)
d 7.48e7.10 (m, 5 H), 5.92 (d,
3JHH ¼ 45.6 Hz, 1H), 5.23 (s, 1H), 3.65 (s, 1H), 3.40-3.01 (m, 2H), 1.14
1.00 g (2.97 mmol/1.0 eq) 18 were converted following general
(s, 18H); 13C NMR (75.53 MHz, CDCl3)
d 167.7, 153.6, 128.7, 128.5,
procedure 4.3.1. As crude product
a
colorless oil (930 mg,
128.0, 126.5, 81.7, 66.8, 65.3, 57.5, 28.2, 22.6, 22.3.
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

C. Doler et al. / Tetrahedron xxx (xxxx) xxx
9
3
4.3.15. tert-Butyl ((R,E)-1-(((S)-tert-butylsulfinyl)imino)-4-
(tritylthio)butan-2-yl)carbamate (15)
According to general procedure 4.3.11, 1.00 g (2.17 mmol, 1.00
eq) 14 and 289 mg (9.83 mmol, 1.10 eq) (S)-tert-butanesulfinamide
8.3 Hz, 1H), 3.89 (d, JHH ¼ 10.6 Hz, 2H, NH, OH), 3.31 (d,
3JHH ¼ 10.6 Hz, 1H), 3.15 (d, JHH ¼ 10.6 Hz, 1H), 2.85 (dd, J ¼ 12.0,
3
8.5 Hz, 1H), 2.48 (dd, J ¼ 12.1, 7.5 Hz, 1H), 1.50 (s, 9H), 1.28 (s, 9H),
0.98 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d 156.8,144.8,129.8,128.1,
were dissolved in 4.5 mL THF. 963
m
L (924 mg, 3.25 mmol, 1.50 eq)
126.8, 83.6, 80.5, 67.3, 60.8, 56.4, 49.5, 36.2, 35.5, 28.5, 27.2, 22.7.
HR-MS (ESI): MNaþ, found 661.3079. C36H50N2O4S2Na requires
661.3110.
isopropyltitanate were added dropwise. Complete conversion was
detected via TLC. Column chromatography [125 g SiO2; 4 cmx24
cm, CH/EE ¼ 9/1, CH/EE ¼ 4/1, fraction size 80 mL; fraction 12e24]
gave 15 as a yellowish foam (585 mg, 1.04 mmol, 48%). TLC:
Rf ¼ 0.33 (CH/EA ¼ 4/1); m.p. ¼ 62e65 ꢁC; 1H NMR (300.36 MHz,
4.3.19. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-5-methyl-1-(tritylthio)hexan-2-yl)carbamate (7b)
According to general procedure 4.3.16,126 mg (1.45 mmol, 16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
CDCl3)
d
7.83 (d, 3JHH ¼ 2.9 Hz, 1H), 7.52e7.27 (m, 15H), 4.76 (s, 1H,
NH), 4.42 (m, 1H), 2.45-2.23 (m, 2H), 1.82 (m, 1H), 1.50 (m, 1H), 1.46
(s, 9H), 1.20 (m, 9H); 13C NMR (75.53 MHz, CDCl3) ¼ 167.5, 155.1,
144.8, 129.7, 128.1, 126.9, 80.1, 67.14, 57.1, 54.4, 32.0, 28.4, 28.0, 22.5.
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 12
m
L (0.136 mmol,
1.50 eq, 9.80 mg) isobutyraldehyde were dissolved in 567
mL ab.
THF each. The educt-solutions were added via syringe pump to the
4.3.16. tert-Butyl (4S)-4-((E)-(((S)-tert- butylsulfinyl)imino)
SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min
methyl)-5,5-dimethyl-2-phenylthiazolidine-3-carboxylate (20)
According to general procedure 4.3.11 930 mg (2.89 mmol, 1.00
eq) 19 and 395 mg (3.26 mmol, 1.10 eq) (S)-tert-butanesulfinamide
were dissolved in 5.93 mL THF. 1.31 mL (1.26 g, 4.45 mmol, 1.50 eq)
isopropyltitanate were added dropwise. Complete conversion was
detected via TLC. Column chromatography [125 g SiO2, 5 cmx20 cm,
CH/EA ¼ 4/1, fraction size 80 mL, fraction 5 to 11] gave 20 as
colorless oil (402 mg, 0.945 mmol, 32%). HPLC-MS: tR ¼ 7.91 min
(38 mL/min). The crude product was purified via preparative HPLC
[method A] to afford 7b as clear, colorless oil (42.5 mg/0.068 mmol,
75%). HPLC-MS: tR ¼ 8.69 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.31
(CH/EA ¼ 3/1); [a]D20 -18.1ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
3
d
7.37 (m, 15H), 5.08 (d, JHH ¼ 8.7 Hz, 1H, NH-2), 3.76 (d,
3JHH ¼ 10.5 Hz, 1H, NH), 3.49 (dd, JHH ¼ 16.4, 8.7 Hz, 1H), 3.43 (d,
3
3JHH ¼ 8.8 Hz, 1H, OH), 3.14 (dd, JHH ¼ 10.5, 4.7 Hz, 1H), 3.00 (m,
3
1H), 2.73 (m, 2H), 1.82-1.65 (m, 1H), 1.48 (s, 9H), 1.29 (s, 9H), 1.00 (d,
(Naþ-, Kþ- adduct); TLC: Rf ¼ 0.25 (CH/EA ¼ 4/1); 1H NMR
2JHH ¼ 6.6 Hz, 3H), 0.86 (d, 2JHH ¼ 6.6 Hz, 3H); 13C NMR (75.53 MHz,
3
(300.36 MHz, CDCl3)
d
8.23 (d, JHH ¼ 4.3 Hz, 1H), 7.59 (m, 2H),
CDCl3) d 157.0, 144.8, 129.8, 128.1, 126.9, 80.5, 79.2, 67.5, 60.6, 56.5,
7.36e7.28 (m, 3H), 6.02 (s, 1H), 4.81 (s, 1H), 1.68 (s, 3H), 1.43 (s, 3H),
49.3, 35.7, 30.2, 28.5, 22.7, 20.1, 17.9. HR-MS (ESI): MNaþ, found
647.2957. C35H48N2O4S2Na requires 647.2953.
1.29 (s, 9H), 1.21 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d
166.2, 153.6,
140.4, 128.3, 127.9, 127.2, 81.3, 74.0, 66.8, 57.4, 53.0, 30.9, 28.1, 24.1,
22.7.
4.3.20. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-6-methyl-1-(tritylthio)heptan-2-yl)carbamate (7c)
According to general procedure 4.3.16,126 mg (1.45 mmol, 16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
4.3.17. General procedure for SmI2-LiBr-catalysed reactions
A dark blue SmI2-solution (2.00 eq, 0.04M in THF) in an inert
Schlenk flask was slowly cooled down to ꢀ78 ꢁC via an acetone/
dry-ice cooling bath. In the meantime, in an inert Schlenk flask
the respective imine (1.00 eq) was dissolved in abs. THF (0.16M) and
in a second inert Schlenk flask the respective aldehyde was dis-
solved in abs. THF (0.16M). 16 eq LiBr were added in one portion
at ꢀ78 ꢁC to the SmI2-solution and the reaction mixture was stirred
for 15 min at this temperature. Then both educt-solutions were
added simultaneously via syringe pump over a time period of
15 min to the SmBr2-THF-solution at ꢀ78 ꢁC. After the addition the
reaction mixture was stirred under exclusion of light for 2 h.
Complete conversion of the reaction was detected via TLC and
HPLC-MS. For work-up the reaction mixture was quenched by the
addition of sat. NaHSO3-solution upon which the dark blue reaction
mixture immediately turned yellow and the aqueous layer was
extracted with EtOAc (3x). The combined organic phases were
washed with brine and dried over MgSO4. The solvent was removed
under reduced pressure with a rotary evaporator. The crude prod-
uct was purified via preparative HPLC.
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 15
mL (0.136 mmol,
1.50 eq, 11.7 mg) isovaleraldehyde were dissolved in 567
mL ab. THF
each. The educt-solutions were added via syringe pump to the
SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min
(38 mL/min). The crude product was purified via preparative HPLC
[method A] to afford 7c as clear, colorless oil (31.3 mg, 0.049 mmol,
54%). HPLC-MS: tR ¼ 8.69 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.33
(CH/EA ¼ 3/1); [a]D20 -23.4ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
3
d
7.37 (m, 15H), 5.06 (d, JHH ¼ 8.7 Hz, 1H, NH), 3.74 (d,
3JHH ¼ 10.1 Hz, 1H, NH), 3.60-3.48 (m, 1H), 3.48-3.32 (3, 1H), 3.05-
2.92 (m, 1H), 2.69 (m, 2H), 1.87 (m, 1H), 1.48 (s, 9H), 1.41-1.32 (m,
1H),1.23 (s, 9H),1.22-1.18 (m,1H),1.01 (d, 3JHH ¼ 6.6 Hz, 3H), 0.91 (d,
3JHH ¼ 6.6 Hz, 3H); 13C NMR (75.53 MHz, CDCl3)
d 156.8, 144.7,
129.8, 128.1, 126.9, 80.5, 71.9, 67.5, 63.5, 56., 49.1, 43.2, 35.3, 28.4,
24.8, 23.8 (CH3, C-7), 22.8, 21.9. HR-MS (ESI): MNaþ, found
647.3104. C36H50N2O4S2Na requires 661.3110.
4.3.21. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-5-phenyl-1-(tritylthio)pentan-2-yl)carbamate (7d)
According to general procedure 4.3.16,126 mg (1.45 mmol, 16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
4.3.18. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-5,5-dimethyl-1-(tritylthio)hexan-2-yl)carbamate (7a)
According to general procedure 4.3.16, 126 mg (1.45 mmol,16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 16
m
L (0.136 mmol,
1.50 eq, 16.4 mg) phenylacetaldehyde were dissolved in 567
mL ab.
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 15
m
m
L (0.136 mmol,
L ab. THF each.
THF each. The educt-solutions were added via syringe pump to the
1.50 eq, 11.7 mg) pivaldehyde were dissolved in 567
SmI2-LiBr-solution in THF (0.04 M) at ꢀ78 ꢁC over a period of
The educt-solutions were added via syringe pump to the SmI2-LiBr-
15 min (38 mL/min). The crude product was purified via preparative
solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min (38
m
L/
HPLC [method A] to afford 7d as clear, colorless oil (41.5 mg,
min). The crude product was purified via preparative HPLC [method
A] to afford 7a as clear, colorless oil (42.9 mg, 0.067 mmol, 74%).
HPLC-MS: tR ¼ 8.97 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.35 (CH/
0.062 mmol, 68%). HPLC-MS: tR ¼ 8.69 min (Naþ-, Kþ- adduct); TLC:
Rf ¼ 0.33 (CH/EA ¼ 3/1); [a]2D0 -7.0ꢁ [CHCl3]; 1H NMR (300.36 MHz,
3
CDCl3)
d
7.21 (ddt, JHH ¼ 20.6, 18.8, 7.3 Hz, 20H), 4.87 (d,
EA ¼ 3/1); [a]2D0 þ23.1ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
d
7.37
3JHH ¼ 8.1 Hz, 1H, NH-2), 3.65 (d, 3JHH ¼ 9.9 Hz, 1H, NH), 3.58-3.35
(m, 2H, H-2), 2.97 (dd, 3JHH ¼ 8.4, 5.2 Hz, 1H), 2.69 (t, 3JHH ¼ 12.2 Hz,
3
3
(m, 15H), 5.55 (d, JHH ¼ 8.7 Hz, 1H, NH-2), 3.98 (dd, JHH ¼ 16.6,
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

10
C. Doler et al. / Tetrahedron xxx (xxxx) xxx
1H), 2.56 (m, 3H), 1.35 (s, 9H), 1.12 (s, 9H); 13C NMR (75.53 MHz,
CDCl3) 156.9, 144.7, 138.9, 129.8, 129.3, 128.5, 128.1, 126.9, 126.4,
82.3, 67.0, 62.5, 60.8, 56.3, 35.7, 35.5, 28.1, 27.4, 23.4. HR-MS (ESI):
MNaþ, found 507.2314. C24H40N2O4S2Na requires 507.2327.
d
80.6, 74.8, 67.5, 63.0, 56.6, 49.3, 40.4, 35.2, 28.4, 22.8. HR-MS (ESI):
MNaþ, found 695.2957. C39H48N2O4S2Na requires 695.2953.
4.3.25. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tert-butylsulfinyl)amino)-
2-hydroxy-3-methylbutyl)-2-phenylthiazolidine-3-carboxylate
(12b)
4.3.22. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-6-phenyl-1-(tritylthio)hexan-2-yl)carbamate (7e)
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
According to general procedure 4.3.16, 126 mg (1.45 mmol,16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 17
mL
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 18
m
L (0.136 mmol,
(0.189 mmol, 1.50 eq, 14 mg) isobutyraldehyde were dissolved in
1.50 eq, 18.3 mg) phenylpropionaldehyde were dissolved in
788 mL ab. THF each. The educt-solutions were added via syringe
567
m
L ab. THF each. The educt-solutions were added via syringe
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
period of 15 min (53 mL/min). The crude product was purified via
period of 15 min (38
mL/min). The crude product was purified via
preparative HPLC [method A] to afford 12b as clear, colorless oil
(41 mg, 0.087 mmol, 69%). HPLC-MS: tR ¼ 7.84 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.21 (CH/EA ¼ 3/1); [a]2D0 þ77.3ꢁ [CHCl3]; 1H NMR
preparative HPLC [method A] to afford 7e as clear, colorless oil
(41.7 mg, 0.061 mmol, 67%). HPLC-MS: tR ¼ 8.86 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.33 (CH/EA ¼ 3/1); [a]2D0 -6.7ꢁ [CHCl3]; 1H NMR
(300.36 MHz, CDCl3)
d 7.31-7.28 (m, 5H), 6.07 (s, 1H), 5.18 (s, 2H,
(300.36 MHz, CDCl3)
d
7.38 (ddd, 3JHH ¼ 31.4, 23.9, 7.2 Hz, 20H), 4.95
NH, OH), 5.08 (d, 3JHH ¼ 7.2 Hz, 1H), 3.49-3.30 (m, 4H), 2.13-2.02 (m,
3
3
(d, JHH ¼ 8.2 Hz, 1H, NH), 3.65 (d, JHH ¼ 8.2 Hz, 1H, NH), 3.61 (d,
1H), 1.24 (s, 9H), 1.12-1.00 (m, 12H), 0.94 (d, 3JHH ¼ 6.7 Hz, 3H); 13
C
3JHH ¼ 9.9 Hz, 1H, OH), 3.49 (q, JHH ¼ 8.2, 1H), 3.30 (m, 1H), 3.06
NMR (75.53 MHz, CDCl3) 156.6, 140.7, 128.7, 128.0, 125.4, 82.8, 76.0,
67.4, 62.5, 61.3, 56.3, 34.8, 28.0, 27.5, 23.3, 21.5, 14.7. HR-MS (ESI):
MNaþ, found 493.2158. C23H38N2O4S2Na requires 493.2171.
3
3
(dd, JHH ¼ 8.2, 4.5 Hz, 1H), 2.98-2.86 (m, 1H), 2.83-2.61 (m, 3H),
1.86-1.64 (m, 2H), 1.50 (s, 9H), 1.27 (s, 9H); 13C NMR (75.53 MHz,
CDCl3)
d 156.9, 144.7, 142.2, 129.8, 128.7, 128.4, 128.1, 126.9, 125.9,
80.6, 72.6, 67.6, 63.1, 56.6, 49.3, 35.9, 35.1, 32.3, 28.4, 22.8. HR-MS
4.3.26. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tert-butylsulfinyl)amino)-
2-hydroxy-4-methylpentyl)-2-phenylthiazolidine-3-carboxylate
(12c)
(ESI): MNaþ, found 709.3141. C40H50N2O4S2Na requires 709.3110.
4.3.23. tert-Butyl ((2R,3S,4R)-3-(((S)-tert-butylsulfinyl)amino)-4-
hydroxy-1-(tritylthio)oct-7-en-2-yl)carbamate (7f)
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
According to general procedure 4.3.16, 126 mg (1.45 mmol,16.00
eq) LiBr were added to 4.50 mL (0.182 mmol, 2.00 eq) SmI2-solution
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 20
mL
(0.189 mmol, 1.50 eq, 16 mg) isovaleraldehyde were dissolved in
at ꢀ78 ꢁC. 50 mg (0.091 mmol, 1.00 eq) 6b and 13
m
m
L (0.136 mmol,
L ab. THF each.
788 mL ab. THF each. The educt-solutions were added via syringe
1.50 eq, 11.5 mg) 4-pentenal were dissolved in 567
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
The educt-solutions were added via syringe pump to the SmI2-LiBr-
period of 15 min (53 mL/min). The crude product was purified via
solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min (38
m
L/
preparative HPLC [method A] to afford 12c as clear, colorless oil
(38 mg, 0.078 mmol, 63%). HPLC-MS: tR ¼ 8.08 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.19 (CH/EA ¼ 3/1); [a]2D0 þ47.3ꢁ [CHCl3]; 1H NMR
min). The crude product was purified via preparative HPLC [method
A] to afford 7f as colorless, clear oil (40 mg, 0.063 mmol, 69%).
HPLC-MS: tR ¼ 8.66 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.36 (CH/
(300.36 MHz, CDCl3)
d 7.39-7.28 (m, 5H), 6.10 (s, 1H), 5.27 (d,
EA ¼ 3/1); [a]2D0 -17.4ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
d
7.37
3JHH ¼ 3.0 Hz, 1H, NH), 5.09-4.99 (m, 1H), 4.79 (s, 1H, OH), 3.69 (s,
1H), 3.48-3.17 (m, 3H), 1.99-1.87 (m, 1H), 1.49-1.36 (m, 2H), 1.24 (s,
9H), 1.07 (s, 9H), 0.95 (d, 3JHH ¼ 6.5 Hz, 3H), 0.89 (d, 3JHH ¼ 6.5 Hz,
(m, 15H), 5.85 (m, 1H), 5.05 (m, 3H, NH), 3.69 (d, 3JHH ¼ 10.2 Hz, 1H,
NH), 3.61 (d, 3JHH ¼ 8.7 Hz, 1H, OH), 3.48 (m, 1H), 3.33 (m, 1H), 3.05
3
3
(dd, JHH ¼ 9.7, 4.6 Hz, 1H), 2.80 (dd, JHH ¼ 13.2, 8.1 Hz, 1H), 2.64
(dd, 3JHH ¼ 13.2, 7.4 Hz, 1H), 2.32 (m, 1H), 2.17 (m, 1H), 1.67-1.36 (m,
3H); 13C NMR (75.53 MHz, CDCl3)
d 156.6, 140.6, 128.7, 128.0, 125.7,
82.8, 70.1, 66.9, 65.7, 61.1, 56.6, 41.5, 34.4, 28.0, 24.6, 24.3, 23.4, 21.4.
HR-MS (ESI): MNaþ, found 507.2342. C24H40N2O4S2Na requires
507.2327.
11H), 1.27 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d 156.9, 144.7, 138.3,
129.8, 128.1, 126.9, 115.1, 80.6, 73.0, 67.6, 63.0, 56.6, 49.2, 35.2, 33.3,
30.3, 28.4, 22.8. HR-MS (ESI): MNaþ, found 659.2908.
C
36H48N2O4S2Na requires 659.2953.
4.3.27. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tert-butylsulfinyl)amino)-
2-hydroxy-3-phenylpropyl)-2-phenylthiazolidine-3-carboxylate
(12d)
4.3.24. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tert-butylsulfinyl)amino)-
2-hydroxy-3,3-dimethylbutyl)-2-phenylthiazolidine-3-carboxylate
(12a)
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 22
mL
(0.189 mmol, 1.50 eq, 23 mg) phenylacetaldehyde were dissolved in
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 21
m
L
788 mL ab. THF each. The educt-solutions were added via syringe
(0.189 mmol, 1.50 eq, 16 mg) pivaldehyde were dissolved in
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
788
mL ab. THF each. The educt-solutions were added via syringe
period of 15 min (53 mL/min). The crude product was purified via
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
preparative HPLC [method A] to afford 12d as clear, colorless oil
(39 mg, 0.075 mmol, 60%). HPLC-MS: tR ¼ 7.90 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.28 (CH/EA ¼ 3/1); [a]2D0 þ84.5ꢁ [CHCl3]; 1H
period of 15 min (53 mL/min). The crude product was purified via
preparative HPLC [method A] to afford 12a as clear, colorless oil (39,
0.08 mmol, 63%). HPLC-MS: tR ¼ 7.99 min (Naþ-, Kþ- adduct); TLC:
NMR (300.36 MHz, CDCl3) d 7.54-7.29 (m, 10H), 6.15 (s, 1H), 5.44 (d,
Rf ¼ 0.19 (CH/EA ¼ 3/1); [a]2D0 þ72.7ꢁ [CHCl3]; 1H NMR (300.36 MHz,
3JHH ¼ 3.6 Hz, 1H, NH), 5.18-5.05 (m, 1H), 4.82 (s, 1H, OH), 3.92 (s,
3
3
CDCl3)
d
7.55 (d, JHH ¼ 7.5 Hz, 2H), 7.45-7.30 (m, 3H), 6.10 (s, 1H),
1H), 3.57-3.42 (m, 2H), 3.33 (d, JHH ¼ 11.7 Hz, 1H), 3.21 (d,
5.09 (d, 3JHH ¼ 3.0 Hz, 1H, NH), 5.00 (q, 3JHH ¼ 9.0, 4.6 Hz, 1H), 4.15
(d, 3JHH ¼ 5.0 Hz, 1H, OH), 3.80 (q, 3JHH ¼ 8.2, 4.0 Hz, 1H), 3.59-3.47
3JHH ¼ 14.0, 1H), 2.67 (dd, 3JHH ¼ 14.0, 10.3 Hz, 1H), 1.23 (s, 9H), 1.17
(s, 9H); 13C NMR (75.53 MHz, CDCl3)
d 156.7, 140.5, 139.9, 129.4,
(m, 1H), 3.46-3.32 (m, 2H), 1.28 (s, 9H), 1.12 (s, 9H), 1.09 (s, 9H); 13
C
128.8, 128.4, 128.11, 126.2, 125.7, 82.9, 73.7, 67.1, 65.5, 61.2, 56.6,
NMR (75.53 MHz, CDCl3)
d 156.7, 140.7, 128.6, 127.9, 126.4, 82.7,
39.0, 34.6, 28.0, 23.4. HR-MS (ESI): MNaþ, found 541.2172.
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

C. Doler et al. / Tetrahedron xxx (xxxx) xxx
11
C27H38N2O4S2Na requires 541.2170.
4.3.31. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-6-methyl-1-(tritylthio)heptan-3-yl)carbamate (16b)
According to 4.3.16, 123 mg (1.42 mmol, 16.00 eq) LiBr were
4.3.28. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tert-butylsulfinyl)amino)-
2-hydroxy-4-phenylbutyl)-2-phenylthiazolidine-3-carboxylate
(12e)
added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution at ꢀ78 ꢁC.
50 mg (0.089 mmol, 1.00 eq) 15 and 12 mL (0.133 mmol, 1.50 eq,
9.6 mg) isobutyraldehyde were dissolved in 553 mL ab. THF each.
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
The educt-solutions were added via syringe pump to the SmI2-LiBr-
solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min (37
mL/
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 25
mL
min). The crude product was purified via preparative HPLC [method
A] to afford 16b as clear, colorless oil (32 mg, 0.05 mmol, 68%).
HPLC-MS: tR ¼ 8.78 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.30 (CH/
(0.189 mmol, 1.50 eq, 25 mg) phenylpropionaldehyde were dis-
solved in 788 mL ab. THF each. The educt-solutions were added via
syringe pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC
EA ¼ 3/1); [a]2D0 -5.4ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
d 7.34
3
over a period of 15 min (53
mL/min). The crude product was purified
(m, 15H), 5.16 (d, JHH ¼ 8.9 Hz, 1H, NH), 3.90 (m, 1H), 3.80 (d,
via preparative HPLC [method A] to afford 12e as clear, colorless oil
(50 mg, 0.094 mmol, 74%). HPLC-MS: tR ¼ 8.17 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.22 (CH/EA ¼ 3/1); [a]2D0 þ39.6ꢁ [CHCl3]; 1H
3JHH ¼ 9.9 Hz, 1H, NH), 3.57 (d, 3JHH ¼ 5.3 Hz, 1H, OH), 3.08 (m, 2H),
3
2.40-2.20 (m, 2H), 2.09 (m, 1H), 1.94 (dd, JHH ¼ 12.9, 6.3 Hz, 1H),
1.59 (m, 1H),1.49 (s, 9H), 1.28 (s, 9H), 1.05 (d, 3JHH ¼ 6.3 Hz, 3H), 0.92
NMR (300.36 MHz, CDCl3)
d
7.51-7.27 (m, 10H), 6.22 (s, 1H), 5.48 (s,
(d, 3JHH ¼ 12.9 Hz, 3H); 13C NMR (75.53 MHz, CDCl3)
d 157.5, 145.0,
1H, OH), 5.36 (t, 3JHH ¼ 6.8 Hz, 1H, NH), 5.25 (dd, 3JHH ¼ 6.4, 3.1 Hz,
1H), 3.67 (d, 3JHH ¼ 7.8 Hz, 1H), 3.61-3.34 (m, 3H), 3.14-2.94 (m, 2H),
2.29-2-22 (m, 1H), 1.99-1.180 (m, 1H), 1.37 (s, 9H), 1.17 (s, 9H); 13C
129.7, 128.0, 126.7, 80.4, 79.0, 66.8, 62.1, 56.5, 48.7, 33.6, 30.5, 29.0,
28.5, 22.7, 20.0, 17.9. HR-MS (ESI): MNaþ, found 661.3113.
C36H50N2O4S2Na requires 661.3110.
NMR (75.53 MHz, CDCl3)
d 156.4, 142.5, 140.5, 129.0, 128.6, 128.3,
127.9, 125.7, 125.2, 82.8, 69.9, 66.5, 65.3, 60.9, 56.6, 34., 33.4, 31.6,
28.0, 23.3. HR-MS (ESI): MNaþ, found 555.2344. C28H40N2O4S2Na
requires 555.2327.
4.3.32. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-7-methyl-1-(tritylthio)octan-3-yl)carbamate (16c)
According to general procedure 4.3.16,123 mg (1.42 mmol, 16.00
eq) LiBr were added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution
at ꢀ78 ꢁC. 50 mg (0.089 mmol, 1.00 eq) 15 and 14
mL (0.133 mmol,
4.3.29. tert-Butyl (4S)-4-((1S,2R)-1-(((S)-tertbutylsulfinyl)amino)-
2-hydroxyhex-5-en-1-yl)-2-phenylthiazolidine-3-carboxylate (12f)
According to general procedure 4.3.16,175 mg (2.02 mmol,16.00
eq) LiBr were added to 6.30 mL (0.252 mmol, 2.00 eq) SmI2-solu-
1.50 eq, 11.4 mg) isovaleraldehyde were dissolved in 553 mL ab. THF
each. The educt-solutions were added via syringe pump to the
SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min
(37 mL/min). The crude product was purified via preparative HPLC
tion at ꢀ78 ꢁC. 50 mg (0.126 mmol, 1.00 eq) 11 and 19
m
L
[method A] to afford 16c as clear, colorless oil (43 mg, 0.066 mmol,
(0.189 mmol, 1.50 eq, 16 mg) 4-pentenal were dissolved in
74%). HPLC-MS: tR ¼ 8.93 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.26
788
m
L ab. THF each. The educt-solutions were added via syringe
(CH/EA ¼ 3/1); [a]2D0 -7.8ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
3
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
d
7.51-7.31 (m, 15H), 5.12 (d, JHH ¼ 8.8 Hz, 1H, NH), 3.93 (m, 1H),
3
period of 15 min (53
mL/min). The crude product was purified via
3.75 (d, JHH ¼ 10.1 Hz, 2H, NH, OH), 3.46 (m, 1H), 2.83 (dd,
preparative HPLC [method A] to afford 12f as clear, colorless oil
(35 mg, 0.073 mmol, 66%). HPLC-MS: tR ¼ 7.83 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.23 (CH/EA ¼ 3/1); [a]2D0 þ45.5ꢁ [CHCl3]; 1H
3JHH ¼ 10.1, 4.9 Hz, 1H), 2.40-2.19 (m, 2H), 2.05-1.83 (m, 2H), 1.69-
3
1.56 (m, 1H), 1.51 (s, 9H), 1.31 (s, 11H), 1.02 (d, JHH ¼ 6.6 Hz, 3H),
0.97 (d, JHH ¼ 6.4 Hz, 3H); 13C NMR (75.53 MHz, CDCl3)
d 157.4,
3
NMR (300.36 MHz, CDCl3)
d
7.34-7.26 (m, 5H), 6.08 (s, 1H), 5.90-
145.0, 129.7, 128.0, 126.7, 80.5, 71.9, 66.8, 64.9, 56.6, 48.7, 43.4, 33.3,
28.9, 28.5, 24.9, 23.7, 22.8, 22.0. HR-MS (ESI): MNaþ, found
675.3273. C37H52N2O4S2Na requires 675.3266.
5.77 (m, 1H), 5.28 (d, 3JHH ¼ 3.4 Hz, 1H, NH), 5.07-4.96 (m, 1H, OH),
3.65 (s, 1H), 3.48-3.20 (m, 3H), 2.44-2.12 (m, 2H), 1.92-1.75 (m, 1H),
1.59-1.40 (m, 1H), 1.24 (s, 9H), 1.07 (s, 9H); 13C NMR (75.53 MHz,
CDCl3)
d
156.8,140.6,138.8,128.7, 128.1, 125.5,114.8, 82.9, 71.0, 66.9,
4.3.33. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-6-phenyl-1-(tritylthio)hexan-3-yl)carbamate (16d)
According to general procedure 4.3.16,123 mg (1.42 mmol, 16.00
eq) LiBr were added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution
65.3, 61.0, 56.5, 34.5, 31.4, 29.8, 28.0, 23.3. HR-MS (ESI): MNaþ,
found 505.2127. C24H38N2O4S2Na requires 505.2171.
at ꢀ78 ꢁC. 50 mg (0.089 mmol, 1.00 eq) 15 and 15
mL (0.133 mmol,
4.3.30. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-6,6-dimethyl-1-(tritylthio)heptan-3-yl)carbamate (16a)
According to general procedure 4.3.16, 123 mg (1.42 mmol,16.00
eq) LiBr were added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution
1.50 eq, 16 mg) isovaleraldehyde were dissolved in 553 mL ab. THF
each. The educt-solutions were added via syringe pump to the
SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min
(37 mL/min). The crude product was purified via preparative HPLC
at ꢀ78 ꢁC. 50 mg (0.089 mmol, 1.00 eq) 15 and 15
mL (0.133 mmol,
[method A] to afford 16d as clear, colorless oil (43 mg, 0.063 mmol,
1.50 eq,11.5 mg) pivaldehyde were dissolved in 553
mL ab. THF each.
70%). HPLC-MS: tR ¼ 8.75 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.22
The educt-solutions were added via syringe pump to the SmI2-LiBr-
(CH/EA ¼ 3/1); [a]2D0 -4.0ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
3
solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min (37
mL/
d
7.49-7.28 (m, 20H), 5.00 (d, JHH ¼ 8.4 Hz, 1H, NH), 4.02 (m, 1H),
3
min). The crude product was purified via preparative HPLC [method
A] to afford 16a as clear, colorless oil (34 mg, 0.051 mmol, 58%).
HPLC-MS: tR ¼ 9.12 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.46 (CH/
3.87 (dd, JHH ¼ 20.2, 9.2 Hz, 2H, OH,NH), 3.65 (m, 1H), 3.06-2.75
(m, 3H), 2.41-2.14 (m, 2H), 2.00 (m, 1H), 1.60 (m, 1H), 1.43 (s, 9H),
1.29 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d 157.5, 145.0, 138.7, 129.7,
EA ¼ 3/1); [a]2D0 þ1.7ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
d
7.34
129.4,128.6,128.0,126.7,126.5, 80.6, 74.8, 66.8, 64.1, 56.7, 48.9, 40.5,
(m, 15H), 5.48 (d, 3JHH ¼ 9.1 Hz, 1H, NH), 3.94 (m, 1 H, NH), 3.20 (bs,
33.0, 28.9, 28.5, 22.9. HR-MS (ESI): MNaþ, found 709.3146.
1H), 3.16 (bs, 1H), 2.38-2.10 (m, 3H, H-1), 1.49 (s, 10H), 1.29 (s, 9H),
C40H50N2O4S2Na requires 709.3110.
1.03 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d 157.4, 145.0, 129.7, 128.0,
126.7, 83.5, 80.4, 66.8, 62.3, 56.4, 48.8, 35.5, 34.2, 28.8, 28.6, 27.4,
22.7. HR-MS (ESI): MNaþ, found 675.3297. C37H52N2O4S2Na re-
quires 675.3266.
4.3.34. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-7-phenyl-1-(tritylthio)heptan-3-yl)carbamate (16e)
According to general procedure 4.3.16,123 mg (1.42 mmol, 16.00
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

12
C. Doler et al. / Tetrahedron xxx (xxxx) xxx
eq) LiBr were added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution
4.3.37. tert-Butyl (4S)-4-((1S)-1-(((S)-tert-butylsulfinyl)amino)-2-
hydroxy-4-phenylbutyl)-5,5-dimethyl-2-phenylthiazolidine-3-
carboxylate (21e)
at ꢀ78 ꢁC. 50 mg (0.089 mmol, 1.00 eq) 15 and 18
mL (0.133 mmol,
1.50 eq, 18 mg) phenylpropionaldehyde were dissolved in
553
m
L ab. THF each. The educt-solutions were added via syringe
According to general procedure 4.3.16, 147 mg (1.70 mmol, 16.00
eq) LiBr were added to 5.30 mL (0.212 mmol, 2.00 eq) SmI2-solution
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
period of 15 min (37
mL/min). The crude product was purified via
at ꢀ78 ꢁC. 45 mg (0.106 mmol, 1.00 eq) 20 and 21
mL (0.159 mmol,
preparative HPLC [method A] to afford 16e as clear colorless oil
(39 mg, 0.056 mmol, 62%). HPLC-MS: tR ¼ 8.89 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.23 (CH/EA ¼ 3/1); [a]2D0 -10.4ꢁ [CHCl3]; 1H NMR
1.50 eq, 21 mg) phenylpropionaldehyde were dissolved in
660 mL ab. THF each. The educt-solutions were added via syringe
pump to the SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a
(300.36 MHz, CDCl3)
d
7.50-7.28 (m, 15H), 4.99 (d, 3JHH ¼ 8.6 Hz, 1H,
period of 15 min (44 mL/min). The crude product was purified via
3
NH), 4.15 (d, JHH ¼ 7.7 Hz, 1H, OH), 3.98 (m, 1H), 3.58 (d,
preparative HPLC [method A] to afford 21e as clear, colorless oil
(1.3 mg, 0.002 mmol, 2%). HPLC-MS: tR ¼ 8.42 min (Naþ-, Kþ-
adduct); TLC: Rf ¼ 0.13 (CH/EA ¼ 4/1); 1H NMR (499.98 MHz, CDCl3)
3JHH ¼ 10.2 Hz, 1H, NH), 3.34 (m, 1H), 3.03-2.66 (m, 3H), 2.42-2.18
(m, 2H), 2.03-1.77 (m, 3H), 1.62 (m, 1H), 1.50 (s, 9H), 1.27 (s, 9H); 13
C
NMR (75.53 MHz, CDCl3)
d
157.5, 144.9, 142.1, 129.7, 128.7, 128.5,
d 7.35-7.15 (m, 10H), 6.28 (s, 1H, OH), 5.83 (s, 1H), 4.48 (s, 1H), 3.92
128.0, 126.7, 125.9, 80.6, 72.3, 66.8, 64.8, 56.7, 49.0, 35.9, 33.0, 32.3,
(d, 3JHH ¼ 8.3 Hz, 1H), 3.72 (t, 3JHH ¼ 8.2 Hz, 1H), 2.97-2.78 (m, 2H),
2.23 (d, 3JHH ¼ 21.7 Hz, 1H), 1.87 (q, 3JHH ¼ 13.7, 5.1 Hz, 1H), 1.68 (s,
3H),1.65 (s, 3H), 1.27 (s, 9H), 1.04 (s, 9 H). HR-MS (ESI): MNaþ, found
583.2134. C30H44N2O4S2Na requires 583.2640.
28.9, 28.5, 22.8. HR-MS (ESI): MNaþ, found 723.3251.
C
41H52N2O4S2Na requires 723.3266.
4.3.38. Ethyl 6-oxohexanoate (22)
4.3.35. tert-Butyl ((3S,4S,5R)-4-(((S)-tert-butylsulfinyl)amino)-5-
hydroxy-1-(tritylthio)non-8-en-3-yl)carbamate (16f)
In a 50 mL round bottom flask 2 mL (12.2 mmol, 1 eq) ethyl 6-
hydroxyhexanoate were dissolved in 12.5 mL DCM. 195.5 mg
(1.25 mmol, 10 mol%) TEMPO and 4.44 g (13.8 mmol, 1.1 eq) iodo-
benzenediacetate were added. The resulting orange solution was
stirred at rt overnight. Complete conversion was detected via TLC.
The reaction mixture was quenched by the addition of DCM (50 mL)
and Na2S2O3 (75 mL). The aqueous phase was extracted with DCM
(3 ꢂ 25 mL). The organic layers were washed with saturated
NaHCO3 solution (75 mL) and brine (75 mL). The organic phase was
dried over MgSO4 and the solvent was removed under reduced
pressure. The crude product, an orange liquid, was purified via flash
chromatography (200 g silica, 50 ꢂ 5 cm; CH/EA ¼ 6/1 (fraction
1e9), fraction size: 125 mL) to afford 22 as colorless liquid (1.68 g,
10.6 mmol, 88%). GC-MS: tr ¼ 4.43 min, m/z ¼ 130.0 (11%)
[Mþ ꢀ C2H5], 113.0 (55%) [Mþ ꢀ C2H5O], 101.0 (55%) [Mþ ꢀ C3H5O],
87.0 (32%) [Mþ-C4H7O], 73 (100%) [C3H5Oþ2 ], 57.0 (63%) [C3H5Oþ];
According to general procedure 4.3.16, 123 mg (1.42 mmol,16.00
eq) LiBr were added to 4.40 mL (0.177 mmol, 2.00 eq) SmI2-solution
at ꢀ78 ꢁC. 50 mg (0.089 mmol, 1.00 eq) 15 and 13
m
L (0.133 mmol,
1.50 eq, 11 mg) 4-pentenal were dissolved in 553
mL ab. THF each.
The educt-solutions were added via syringe pump to the SmI2-LiBr-
solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min (37
mL/
min). The crude product was purified via preparative HPLC [method
A] to afford 16f as clear, colorless oil (45 mg, 0.069 mmol, 78%).
HPLC-MS: tR ¼ 8.73 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.21 (CH/
EA ¼ 3/1); [a]2D0 -4.7ꢁ [CHCl3]; 1H NMR (300.36 MHz, CDCl3)
d 7.37
(m, 15H), 5.95-5.82 (m, 1H), 4.21e4.98 (m, 3H, NH), 3.96 (d,
3JHH ¼ 6.6 Hz, 2H, OH), 3.68 (d, 3JHH ¼ 10.3 Hz, NH), 3.39 (s, 1H), 2.88
(dd, 3JHH ¼ 9.9, 6.6 Hz, 1H), 2.36-2.22 (m, 4H), 1.97 (m, 1H), 1.78-1.58
(m, 3H), 1.50 (s, 9H), 1.30 (s, 9H); 13C NMR (75.53 MHz, CDCl3)
d
157.4, 144.9, 138.3, 129.7, 128.0, 126.7, 115.1, 80.5, 72.6, 66.7, 64.7,
TLC: Rf ¼ 0.28 (CH/EA ¼ 5/1); 1H NMR (300.36 MHz, CDCl3)
d 9.73
56.7, 48.9, 33.3, 33.0, 30.2, 28.9, 28.4, 22.8. HR-MS (ESI): MNaþ,
found 673.3142. C37H50N2O4S2Na requires 673.3110.
(s, 1H), 4.09 (q, 3JHH ¼ 7.1 Hz, 2H), 2.43 (m, 2H), 2.29 (m, 2H), 1.68-
1.60 (m, 4H), 1.22 (t, 3JHH ¼ 7.1 Hz, 3H); 13C NMR (75.53 MHz, CDCl3)
d
202.1, 173.3, 60.4, 43. 6, 34.4, 24. 5, 21.6, 14.3.
4.3.39. (7S,8R)-8-((tert-Butoxycarbonyl)amino)-7-(((R)-tert-
butylsulfinyl)amino)-6-hydroxy-9-(tritylthio)nonanoate (23)
According to general procedure 4.3.16, 2.20 g (4.00 mmol, 1.00
4.3.36. tert-Butyl (4S)-4-((1S)-1-(((S)-tert-butylsulfinyl)amino)-2-
hydroxy-3-phenylpropyl)-5,5-dimethyl-2-phenylthiazolidine-3-
carboxylate (21d)
eq) 6a, 948 mg (6.00 mmol, 1.50 eq) 22 and 750
mL (592 mg,
According to general procedure 4.3.16, 147 mg (1.70 mmol, 16.00
eq) LiBr were added to 5.30 mL (0.212 mmol, 2.00 eq) SmI2-solution
7.99 mmol, 2.00 eq) t-BuOH were dissolved in 50 mL ab. THF. The
educt-solution was added dropwise to 100 mL SmI2-solution in THF
(0.08M) at ꢀ78 ꢁC. The crude product was purified via flash chro-
matography [400 g SiO2; 21 cmx6 cm; CH/EE ¼ 3/1; fraction size:
250 mL; fraction: 12e34] to afford 23 as yellowish oil (1.02 g,
1.43 mmol, 86%). HPLC-MS-major diastereomer: tR ¼ 8.32 min
(Naþ-, Hþ- adduct); HPLC-MS-minor diastereomer: tR ¼ 8.48 min
(Naþ-, Hþ- adduct); TLC: Rf ¼ 0.23 (CH/EA ¼ 3/1); 1H-NMR-major
at ꢀ78 ꢁC. 45 mg (0.106 mmol, 1.00 eq) 20 and 19
mL (0.159 mmol,
1.50 eq, 19 mg) phenylacetaldehyde were dissolved in 660
m
L ab.
THF each. The educt-solutions were added via syringe pump to the
SmI2-LiBr-solution in THF (0.04M) at ꢀ78 ꢁC over a period of 15 min
(44 mL/min). The crude product was purified via preparative HPLC
[method A] to afford 21d as clear, colorless oil (3.2 mg, 0.006 mmol,
6%). HPLC-MS: tR ¼ 8.68 min (Naþ-, Kþ- adduct); TLC: Rf ¼ 0.15 (CH/
diastereomer (300.36 MHz, CDCl3)
d 7.49-7.04 (m, 15H), 5.90 (dd,
EA ¼ 4/1); 1H NMR-major diastereomer (499.98 MHz, CDCl3)
3JHH ¼ 8.40 Hz, 1H, NH), 4.06 (q, JHH ¼ 14.1, 7.1 Hz, 3H), 3.09 (m,
2H), 2.51 (dd, 3JHH ¼ 13.1, 4.5 Hz, 1H), 2.31 (dd, 3JHH ¼ 13.1, 6.8 Hz,
1H), 2.23 (dd, 3JHH ¼ 14.8, 7.3 Hz, 2H), 1.68-1.45 (m, 6H), 1.41 (s, 9H),
1.19 (t, 3JHH ¼ 6.6 Hz, 3H), 1.12 (s, 9H); 13C-NMR-major diastereomer
3
3
d
7.51-7.26 (m, 10H), 5.99 (s, 1H), 4.80 (d, JHH ¼ 10.0 Hz, 1H, OH),
3
3
4.57 (s, 1H, NH), 4.24 (d, JHH ¼ 7.3 Hz, 1H), 4.02 (t, JHH ¼ 9.5 Hz,
1H), 3.92-3.85 (m, 1H), 3.12 (s, 1H), 2.89 (s, 1H), 1.49 (s, 3H), 1.46 (s,
3H), 1.37 (s, 9H), 1.11 (s, 9H); 1H NMR-minor diastereomer
(75.53 MHz, CDCl3)
d 173.8, 156.0, 144.6, 129.8, 128.1, 126.9, 79.6,
(499.98 MHz, CDCl3)
d
7.51-7.26 (m, 10H), 5.99 (s, 1H), 5.04 (d,
72.7, 67.2, 66.0, 60.4, 56.4, 49.9, 34.3, 32.5, 28.6, 25.4, 25.1, 24.9, 23.1,
14.4.
3JHH ¼ 8.4 Hz, 1H, OH), 3.71 (d, JHH ¼ 10.3 Hz, 1H, NH), 3.53 (d,
3JHH ¼ 8.3 Hz, 1H), 3.41 (s, 1H), 2.98 (d, 3JHH ¼ 7.3 Hz, 1H), 2.73-2.60
(m, 2H), 1.64 (s, 9H), 1.49 (s, 3H), 1.25 (s, 9H), 0.98 (s, 3H), 0.89 (s,
3H). HR-MS (ESI): MNaþ, found 569.2485. C29H42N2O4S2Na requires
569.2484.
3
4.3.40. (7S,8R)-7,8-Diamino-6-hydroxy-9-mercaptononanoate
(intermediate A)
In a 1.50 mL glass vial 70 mg (0.10 mmol, 1.00 eq) 23 were
Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249

C. Doler et al. / Tetrahedron xxx (xxxx) xxx
13
2329e2342.
dissolved in 490 mL EtOH (clear yellowish solution). 49 mL 4M HCl-
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solution were added to the reaction mixture at rt. After 10 h com-
plete conversion was detected via HPLC-MS and the solvent was
removed under reduced pressure. The residue was dissolved in
1.50 mL DCM (clear yellowish solution) and 34 mg (0.29 mmol, 2.00
eq) triethylsilane were added. 1.50 mL trifluoroacetic acid were
added dropwise to this mixture giving an intense yellow solution
which turned slightly yellowish again after 5 min. This reaction
mixture was stirred for 2 h at rt. After complete conversion (indi-
cated via HPLC-MS) the solvent was removed under reduced
pressure in high vacuum with a cooling trap. The product was
purified via reversed phase column chromatography [10 g C18 silica
gel, 100% dist H2O with 0.01% HCOOH, fraction size: 100 mL; frac-
tion 9e15] to afford A as clear, colorless oil (23 mg, 0.09 mmol, 88%).
HPLC-MS-major diastereomer: tR ¼ 2.47 min (Naþ-, Hþ-, Kþ-
adduct); HPLC-MS-minor diastereomer: tR ¼ 2.61 min (Naþ-, Hþ-,
Kþ- adduct); 1H-NMR-diastereomeric mixture (300.36 MHz, D2O)
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d
4.07 (dd, 3JHH ¼ 14.3, 7.1 Hz, 4H), 4.03-3.95 (m, 1H), 3.88 (m, 1H),
3
3
3.83-3.67 (m, 3H), 3.60 (t, JHH ¼ 4.8 Hz, 1H), 3.15 (dd, JHH ¼ 15.1,
3.9 Hz, 1H), 2.95 (dd, 3JHH ¼ 14.6, 6.2 Hz, 2H), 2.76 (dd, 3JHH ¼ 15.1,
3
8.6 Hz, 1H), 2.33 (t, JHH ¼ 7.1 Hz, 4H), 1.64-1.39 (m, 10H), 1.32 (s,
2H), 1.16 (t, JHH ¼ 7.1 Hz, 6H); 13C-NMR-diastereomeric mixture
3
(75.53 MHz, D2O) d 177.0, 70.1, 69.5, 61.7, 55.0, 53.3, 52.8, 33.8, 33.7,
32.6, 32.1, 24.4, 23.9, 23.4, 23.0, 13.3.
Declaration of competing interest
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[40] M. Szostak, N.J. Fazakerley, D. Parmar, D. Procter, J. Chem. Rev. 114 (2014)
5959e6039.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
ꢀ
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Acknowledgments
Financial support by the Austrian Science Fund (FWF) (Project I-
1722 “ERA-Synbio”), NAWI Graz and BioTechMed Graz is gratefully
acknowledged. We thank Ing. Karin Bartl, (Graz University of
Technology) for measuring HR-MS spectra.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131249.
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Please cite this article as: C. Doler et al., Stereoselective synthesis of chiral thiol-containing 1,2-aminoalcohols via SmI2-mediated coupling,
Tetrahedron, https://doi.org/10.1016/j.tet.2020.131249