New bifunctional carbohydrate-like thiourea derivatives–design and first application in organocatalysis

Article abstract of DOI:10.1080/00397911.2018.1468465

From easily available aminopyran and aminooxepane derivatives and 2,5-bis(trifluoromethyl)phenyl isothiocyanate the corresponding thiourea derivatives were prepared. One compound was further modified by introducing a tertiary amino group. The four catalys

Full text of DOI:10.1080/00397911.2018.1468465

Synthetic Communications
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Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
New bifunctional carbohydrate-like thiourea
derivatives – design and first application in
organocatalysis
Lutz Adam, Luise Schefzig, Tommaso Pecchioli, Reinhold Zimmer & Hans-
Ulrich Reissig
To cite this article: Lutz Adam, Luise Schefzig, Tommaso Pecchioli, Reinhold Zimmer & Hans-
Ulrich Reissig (2018): New bifunctional carbohydrate-like thiourea derivatives – design and first
application in organocatalysis, Synthetic Communications, DOI: 10.1080/00397911.2018.1468465
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https://doi.org/10.1080/00397911.2018.1468465
New bifunctional carbohydrate-like thiourea derivatives –
design and first application in organocatalysis
Lutz Adam, Luise Schefzig, Tommaso Pecchioli, Reinhold Zimmer, and
Hans-Ulrich Reissig
€
€
Institut fur Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, Berlin, Germany
ABSTRACT
ARTICLE HISTORY
Received 22 January 2018
From easily available aminopyran and aminooxepane derivatives and
2,5-bis(trifluoromethyl)phenyl isothiocyanate the corresponding thio-
urea derivatives were prepared. One compound was further modified
by introducing a tertiary amino group. The four catalysts were then
examined as catalysts in a Michael addition of acetylacetone to
b-nitrostyrene. A 1:1 mixture of one of these thioureas with an (S)-
prolinol derivative was also tested as catalyst, but no synergetic
effect was found. The best yield achieved was 88% and the highest
ee amounted to 39%. In a preliminary experiment, the aldol reaction
of acetone with isatin was investigated. One catalyst provided the
expected aldol product in low yield, but in excellent enantioselectiv-
ity.
KEYWORDS
Conjugate addition;
organocatalyst; oxepane;
pyran; thiourea
GRAPHICAL ABSTRACT
The asymmetric organocatalysis with its various activation modes has become a funda-
mental strategy in creation of stereo-defined molecules including the construction of
complex biomolecules and natural products.[1] One of the most efficient and widely
used class of organocatalysts are bifunctional thiourea derivatives. Since the first investi-
gation of bifunctional thiourea and its derivatives introduced by Jorgensen, Takemoto,
Schreiner and other, much attention has been found on the application of this organoca-
talytic system.[2] Among the various functionalized thiourea catalysts bearing at least
one chiral moiety, growing attention has been paid more recently to carbohydrate-
substituted thiourea derivatives.[3] In 2014, one of the first reports emerged on employ-
ing bifunctional thiourea catalysts, such as 1, having a carbohydrate unit (Figure 1). It
€
€
Institut fur Chemie und Biochemie, Freie Universitat
CONTACT Reinhold Zimmer
Berlin, Takustrasse 3, D-14195 Berlin, Germany.
rzimmer@chemie.fu-berlin.de
Supplemental data for this article can be accessed on the Publisher’s website.
Dedicated to the memory of Dr. Maurice Taszarek.
ß 2018 Taylor & Francis

2
L. ADAM ET AL.
Figure 1. Selected examples of literature known carbohydrate-substituted thiourea derivatives and
catalyst type 6 investigated in this study.
ꢀ
was applied by Agoston and Fu€gedi to the conjugate addition of acetylacetone to
b-nitrostyrene.[4] After this study, further thiourea catalysts bearing a carbohydrate moi-
ety, for example 2–5, have been designed as suitable hydrogen-bonding organocatalysts
and were tested in various asymmetric reactions, including decarboxylative Mannich
reactions, Michael additions, aza-Henry reaction and additions of malonates to
imines.[5–12] Stimulated by these results, we were interested to replace the carbohydrate
unit by a stereodefined carbohydrate-mimetic moiety that are rapidly accessible by
our established approach via 1,2-oxazines,[13] creating thiourea derivatives of type 6.
Moreover, the newly designed catalysts of type 6 should be tested in typical organocata-
lytic processes.
In the course of our research, we have constantly reported on the preparation of
enantiopure 3,6-dihydro-2H-1,2-oxazines[14] and their application as synthetically useful
chiral building blocks.[14–16] A serendipitous but important discovery during these stud-
ies was the Lewis-acid promoted rearrangement of 4-(2-trimethylsilyl)ethoxy-substituted
3,6-dihydro-2H-1,2-oxazines such as 7, 10 or 12 (Scheme 1). Our study herein
commenced with the selection of the amino-substituted pyran and oxepane derivatives

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3
Scheme 1. Syntheses of amino-substituted pyran and oxepane derivatives.
9, 11 and 13, previously synthesized in short reaction sequences from corresponding
enantiopure compounds 7, 10 and 12. The Lewis-acid induced rearrangement of
2H-1,2-oxazine 7 using TMSOTf as promoter afforded the bicyclic ketone 8 in good
yield. The plausible mechanism of this rearrangement was already discussed in details in
former reports.[17] After subsequent stereoselective reduction of ketone 8 with NaBH4 in
ethanol followed by hydrogenolysis of the corresponding alcohol intermediate with
palladium on charcoal the aminopyran derivative 9 was obtained in excellent yield. A
similar reaction sequence starting form precursor 10 was applied to the preparation of
aminopyran 11 containing an anomeric center.[18] Similarly, to the synthesis of 9, the
desired aminooxepane 13 was achieved in a five-step reaction sequence starting from
3,6-dihydro-2H-1,2-oxazine 12.[19]
Having the required primary amine precursors in hand, we adopted an operative
simple procedure to prepare the desired chiral thioureas 15–17.[4] The reaction of
amino-substituted pyran derivative 9 with an excess of 2,5-bis(trifluoromethyl)phenyl
isothiocyanate 14 (1.5 equiv) in methanol afforded after a short reaction time (1.5 h) the
thiourea derivative 15 in 46% yield (Scheme 2, conditions a). The moderate yield was
probably caused by the formation of the side product 18, an adduct of 14 and methanol.
A better yield of 15 was achieved by running the reaction in isopropanol (conditions b).
The additions of aminopyran 11 and aminooxepane 13 to 14 gave the expected thiour-
eas 16 and 17, respectively, in moderate to very good yields. The obtained thioureas
bear additional free hydroxyl groups that might be valuable due to additional hydrogen
bonding in a cooperative catalytic process.[3,20] Moreover, the installation of a basic moi-
ety, for example a tertiary amino group, in our designed catalysts 15–17 could add-
itional activate nucleophiles in the reactions.[2d]

4
L. ADAM ET AL.
Scheme 2. Additions of aminopyrans 9 and 11 and of aminooxepane 13 to isothiocyanate 14 leading
to bifunctional thioureas 15–17. Reagents and conditions: a) MeOH, 0 ꢀC, 1.5 h. b) iPrOH, 0 ꢀC, 1.5 h.
In order to address the role of an additional tertiary amino group in the organocata-
lyst, we prepared the bifunctional thiourea derivative 22 bearing a pyrrolidinyl moiety.
Starting from bicyclic ketone 8 (Scheme 3) mesylation of the primary alcohol function
gave the corresponding mesylate intermediate that was treated with an excess of pyrroli-
dine (5 equiv) in 1,4-dioxane at 100 ꢀC (17 h) leading to compound 19 in 52% yield (over
two steps). Surprisingly, only under these fairly harsh conditions, we were able to intro-
duce the cyclic amine without problems. When the reaction was performed using typic-
ally milder conditions (room temperature, shorter reaction time), the substitution failed
and only starting material was recovered. The subsequent steps were achieved according
to established protocols. The stereoselective reduction of ketone 19 using sodium borohy-
dride gave the alcohol 20 as a single diastereomer that was then subjected to a palla-
dium-catalyzed hydrogenolysis to afford the pyran derivative 21 in excellent yield.

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5
Scheme 3. Synthesis of thiourea derivative 22 bearing a tertiary amino group. Reagents and condi-
tions: (a) MsCl, NEt3, CH2Cl2, 0 ꢀC, 4 h; (b) pyrrolidine, 1,4-dioxane, 100 ꢀC, 17 h; (c) NaBH4, EtOH, 0 ꢀC
to room temp, 3 h; (d) H2, Pd/C, iPrOH, room temp., 3.5 d; (e) isothiocyanate 14, iPrOH, 0 ꢀC to room
temp., 17 h.
Scheme 4. Michael addition of acetylacetone (24) to b-nitrostyrene (23).
Table 1 Michael addition of acetylacetone (24) to b-nitrostyrene (23) in
the presence of thiourea catalysts.
Entry Catalyst
Solvent
CH2Cl2
CH2Cl2, MeOH
CH2Cl2, MeOH
Time (h) Yield (%)a
[a]D
Ee (%)b
1
2
3
4
5
6
15
16
17
159
159
93
59
13
56
66
50
88
þ60
þ12
þ5.2
ꢁ9.1
þ8.3
þ26
39
9
3
17 þ 26 CH2Cl2, MeOH
48
ꢁ5
26
22
CH2Cl2, MeOH
CH2Cl2
48
4
69
15
aYields after chromatography.
bDetermined by HPLC analysis using a chiral column (see experimen-
tal section).

6
L. ADAM ET AL.
Finally, applying the optimized conditions with isopropanol as solvent, the addition of 21
and isothiocyanate 14 furnished the desired thiourea derivative 22 in 77% yield.
In a preliminary study, the thiourea derivatives 15–17 and 22 were evaluated as
organocatalysts in a typical Michael addition of acetylacetone (24) to b-nitrostyrene (23)
that furnished adduct 25 (Scheme 4, Table 1). The conjugate addition reaction was
carried out with 10 mol-% of catalyst 15 at room temperature in dichloromethane to
afford 25 in 59% yield and with an enantiomeric excess of 39% (Table 1, entry 1). Under
the same conditions, catalysts 16 and 17 were also tested (Table 1, entries 2 and 3).
Both catalysts showed dramatically reduced enantioselectivities (3–9% ee). At this point,
we encountered solubility problems and solvent screening identified that the addition of
methanol (10 vol-%) was necessary. The use of this protic solvent may cause the lower
enantioselectivities by interfering with the hydrogen bonds.
The self-assembly of several components, in particular of two chiral compounds, to
deliver a highly active catalytic species, is an attractive method in stereoselective synthe-
sis.[21] We therefore performed the Michael addition under the influence of a 1:1 mix-
ture of thiourea 17 and prolinol derivative (S)-26 (entry 4).[22] This result has to be
compared with that of thiourea derivative 17 only (entry 3) and of (S)-26 (entry 5). The
catalyst system of 17 and (S)-26 afforded product 25 in a slightly improved yield of
66%, but all reactions gave disappointingly low enantioselectivities with ee values
between 3 and ꢁ5%, close to the analytical error. In consequence, a desired synergetic
effect caused by the chosen catalyst system was not observed. Nevertheless, it is remark-
able that the reaction time with the catalyst mixture of entry 4 was significantly shorter
than that of entry 3 (48 h instead of 93 h).
Next, we tested thiourea compound 22 bearing a tertiary amino group at the pyran
moiety (Table 1, entry 6). The use of this catalyst resulted in the formation of 25 with
the best yield of 88% in a reasonable reaction time, albeit in a lower ee of only 15%
compared with the catalyst 15.
The enantiomeric excesses of product 25 were established by HLPC using chiral col-
umn (chiralpak IA) and the absolute configuration was determined by comparison of
the optical rotation value with those reported in the literature.[23] It was found that in
almost all cases the (þ)-enantiomer (S)-25 was preferentially formed.
After these disillusioning low stereoselectivities obtained in Michael additions to 25,
we briefly examined a second asymmetric carbon-carbon bond forming reaction with
our bifunctional thiourea derivatives. For this purpose, we choose the enantioselective
aldol reaction of isatin 27 with acetone.[5,24] The aldol reactions were performed using
1-2 mol-% of catalysts 15–17 in the presence of 10 mol-% of pyrrolidine at 4 ꢀC in
dichloromethane (Scheme 5). Monitoring the reaction by TLC indicated complete
Scheme 5. Aldol reaction of isatin (27) with acetone catalyzed by 17.

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SYNTHETIC COMMUNICATIONSV
7
conversion of 27 after 74 hours in all cases. Unfortunately, the chromatographic separ-
ation of the polar aldol product 28 and the employed catalyst turned out to be very dif-
ficult. Only in the case of the aldol reaction with catalyst 17, we were able to isolate
pure 28 in moderate 28% yield (additional material of 28 was still in mixed fractions).
The measured optical rotation of product 28 was in the same range as that reported in
the literature[25] and it indicates an excellent enantioselectivity in the range of >95% ee
for this sample.[26] An unambiguous confirmation of this ee value by chiral HPLC so far
failed. Although this transformation looks very promising, detailed investigations are
required for its optimization.
In summary, starting from easily available aminopyran and aminooxepane derivatives
9, 11, 13 and 21 and 2,5-bis(trifluoromethyl)phenyl isothiocyanate 14, we have prepared
the bifunctional thioureas 15–17 and 22 bearing a carbohydrate-like moiety. These new
potential organocatalysts were tested for the first time in the Michael addition of 24 to
23 leading to the addition product 25 in up to 88% yield. The moderate enantioselectiv-
ity observed in the conjugate addition induced by catalyst 15 certainly needs improve-
ment. A further option is the application of other asymmetric transformations as briefly
demonstrated by the applied aldol reaction of 27 with acetone that provided a sample of
28 with excellent ee.
Experimental
General methods
Reactions were generally performed under argon in flame-dried flasks. Solvents and
reagents were added by syringes. Solvents were dried using standard procedures.
Reagents were purchased and were used as received without further purification unless
stated. Reactions were monitored by thin-layer chromatography (TLC). Products were
purified by flash chromatography (FLC) on silica gel (32–63 lm). Unless otherwise
stated, yields refer to chromatographically homogeneous and spectroscopically pure
materials (1H-NMR spectroscopy). NMR spectra were recorded with JEOL (ECX 400,
Eclipse 500) instruments. Chemical shifts are reported relative to TMS (1H:
d ¼ 0.00 ppm) and CDCl3 (13C: d ¼ 77.0 ppm). Integrals are in accordance with assign-
ments; coupling constants are given in Hz. Multiplicity is indicated as follows: s (sing-
let), d (doublet), t (triplet), m (multiplet), mc (centered multiplet), dd (doublet of
doublet), br s (broad singlet). MS and HRMS analyses were performed with a Varian
Ionspec QFT-7 instrument (ESI-FT ICRMS). Elemental analyses were carried out
with a Vario EL Elemental Analyzer. Optical rotations ([a]D) were determined with
Perkin–Elmer 141 or Perkin–Elmer 241 polarimeters at the temperatures given. Melting
points were measured with a Reichert apparatus (Thermovar) and are uncorrected.
The starting materials 9,[17] 11,[18] 13,[19] and the prolinol derivative 26[27] were
prepared according to literature procedures.
General Procedure 1, syntheses of thiourea derivatives
The corresponding aminopyran or aminooxepane derivative (1.0 equivalent) and isothio-
cyanate 14 (1.0 equivalent) were dissolved in methanol or isopropanol (2-8 mL/mmol
substrate) at 0 ꢀC. After stirring the mixture for 1.5 h at this temperature, the solvent

8
L. ADAM ET AL.
was removed under reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (CH2Cl2/MeOH, 15:1) to give the corresponding thiourea product.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(2S,3R,4S,5S)-4-hydroxy-2,5-bis(hydroxyl-methyl)-
6,6-dimethyltetrahydro-2H-pyran-3-yl]thiourea (15)
According to the general procedure 1, pyran derivative 9 (282 mg, 1.38 mmol), and iso-
thiocyanate 14 (374 mg, 1.38 mmol) in methanol (7 mL) were used. The crude product
was purified by column chromatography to give 15 (305 mg, 46%) as colorless crystals,
mp. 83–86 ꢀC, and 18 (160 mg, 38%) as colorless wax. Product 15: [aD20] þ 45.0 (c 0.5,
MeOH). 1 H NMR (CD3OD, 500 MHz): d ¼ 1.27, 1.46 (2 s, 3 H each, Me), 1.78 (q,
J ¼ 5.3 Hz, 1 H, 500-H), 3.56 (dd, J ¼ 11.6, 7.1 Hz, 1 H, 200-CH2), 3.66-3.72 (m, 2 H, 200-
CH2, 500-CH2), 3.75 (dd, J ¼ 11.1, 5.7 Hz, 1 H, 500-CH2), 4.05 (t, J ¼ 4.7 Hz, 1 H, 400-H),
4.19-4.25 (m, 1 H, 200-H), 4.63-4.66 (m, 1 H, 300-H), 7.63 (s, 1 H, 40-H), 8.21 ppm (s, 2 H,
13
20-H). C NMR (CD3OD, 125.8 MHz): d ¼ 26.5, 27.6 (2 q, Me), 49.4 (d, C-500), 58.0 (d,
C 300), 62.8 (t, 200-CH2), 63.2 (t, 500-CH2), 70.8 (d, C-200), 72.6 (d, C-400), 75.8 (s, C-600),
1
2
117.8 (d, C-40), 123.7 (d, C-20), 124.7 (q, JCF ¼ 271.9 Hz, CF3), 132.6 (q, JCF ¼ 32.9 Hz,
C-30), 141.5 (s, C-10), 182.8 ppm (s, C-2). 19 F NMR (CD3OD, 376 MHz): d ¼ ꢁ60.4 ppm
(s, CF3). IR (ATR): m ¼ 3500-3100 (OH, NH), 3100-2895 (¼C-H, C-H), 1275 cmꢁ1
(C ¼ S). HRMS (ESI-TOF) calcd for C18H23F6N2O5S [M þ H]þ: 477.1277, found:
477.1325. Elemental analysis calc (%) for C18H22F6N2O5S (476.4): C 45.38, H 4.65, N
5.88, S 6.73; found: C 45.38, H 4.66, N 5.92, S 7.24. Product 18: 1 H NMR (CD3OD,
400 MHz): d ¼ 4.07 (s, 3 H, OMe), 7.69 (s, 1 H, 4-H), 8.30 ppm (br s, 2 H, 2-H).
13 C NMR (CD3OD, 125.8 MHz): d ¼ 56.4 (q, OMe), 117.0 (d, C-4), 121.1 (d, C-2), 123.3
1
2
(q, JCF ¼ 277.2 Hz, CF3), 131.7 (q, JCF ¼ 37.4 Hz, C-30), 189.5 ppm (s, C ¼ S); the signal
of C-10 could not be detected. IR (ATR): m ¼ 3300-3200 (N-H), 3100-2900 (¼C-H,
C-H), 1280 cmꢁ1 (C ¼ S). Elemental analysis calc (%) for C10H7F6NOS (303.2): C 39.61,
H 2.33, N 4.62, S 10.57; found: C 39.64, H 2.54, N 4.69, S 10.04.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(2S,3S,4R,5S,6S)-3,5-dihydroxy-2,6-bis-(hydroxy-
methyl)-7,7-dimethyloxepan-4-yl]thiourea (17)
According to the general procedure 1, oxepane derivative 13 (353 mg, 1.50 mmol), and
isothiocyanate 14 (407 mg, 1.50 mmol) in methanol (8 mL) were used. The crude prod-
uct was purified by column chromatography to give 17 (605 mg, 80%) as pale pink solid,
1
mp. 165 ꢀC, [aD20] -20.5 (c 0.7, MeOH). H NMR (CD3OD, 500 MHz, 300 K): d ¼ 1.35
(2 s, 3 H each, Me), 2.00-2.08 (m, 1 H, 600-H), 3.53–3.72 (m, 5 H, 200-H, 200-CH2, 600-CH2),
3.85 (dd, J ¼ 7.8, 2.9 Hz, 1 H, 500-H), 3.95 (mc, 1 H, 300-H), 4.58–4.70 (m, 1 H, 400-H), 7.56
(s, 1 H, 40-H), 8.07 ppm (s, 2 H, 20-H). 13 C NMR (CD3OD, 125.8 MHz, 300 K): d ¼ 21.2,
00
00
00
00
ꢂ
31.6 (2 q, Me), 59.8 (d, C-6 ), 63.6 (t, 2 -CH2, 6 -CH2), 67.7 (d, C-4 ), 73.7, 74.9 (2 d,
1
C-200, C-500), 77.4 (s, C-700), 118.1 (d, C-40), 124.4 (d, C-20), 124.7 (q, JCF ¼ 273.5 Hz,
2
0
0
ꢂ
CF3), 132.8 (q, JCF ¼ 40.9 Hz, C-3 ), 143.0 (s, C-1 ), 184.2 ppm (s, C-2); intensity of the
peak corresponds to two C atoms. 19 F NMR (CD3OD, 376 MHz): d ¼ ꢁ64.3 ppm (s,
CF3). IR (ATR): m ¼ 3500–3100 (O-H, N-H), 3100–2850 (¼C-H, C-H), 1275 cmꢁ1
(C ¼ S). HRMS (ESI–TOF): calcd for C19H25F6N2O5S [M þ H]þ: 507.1400, found:
507.1383. Elemental analysis calc (%) for C19H24F6N2O5S (506.5): C 45.06, H 4.78, N
5.53, S 6.33; found: C 45.00, H 4.79, N 5.46, S 6.48.

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9
Michael addition of acetylacetone to b-nitrostyrene
To a solution of b-nitrostyrene 23 (30 mg, 0.20 mmmol) in dichloromethane (1 mL) or
dichloromethane/methanol (1 mL/0.1 mL), the corresponding organocatalyst (0.20 mmol)
was added under argon atmosphere at room temperature. The solution was stirred for
5 min, then acetylacetone 24 (24 lL, 0.23 mmol) was added and stirring was continued
for the time indicated in Table 1 of the main text. The solution concentrated under
reduced pressure and the crude product was purified by column chromatography on
silica gel (hexane/ethyl acetate, 3:1) to give the product 25. The ratio of the formed
enantiomers was determined by chiral HPLC (chiralpak IA, 4.6x250 mm; 5%
isopropanol/hexane; flow 1 mL/min, 25 bar; UV 215 nm, RI).
1
[aD20] þ 60 (c 0.59, CH2Cl2); 39% ee. H NMR (CDCl3, 400 MHz): d ¼ 1.91, 2.25 (2 s,
3 H each, Me), 4.19 (ddd, J ¼ 10.9, 8.1, 6.4 Hz, 1 H, PhCH), 4.57 (d, J ¼ 10.9 Hz, 1 H,
COCH), 4.68–4.75 (m, 2 H, CH2), 7.11-7.63 ppm (m, 5 H, Ph). The NMR data are in
accordance to those reported in the literature.[4]
Acknowledgments
Generous support of this work by the Deutsche Forschungsgemeinschaft and Bayer HealthCare is
most gratefully acknowledged.
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[13] (a) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-Harrasi, A.; Fisera, L.; Hlobilova, I.;
Zahn, G.; Reissig, H.-U. Stereodivergent Syntheses of Highly Substituted Enantiopure
4-Alkoxy-3,6-Dihydro-2H-1,2-Oxazines by Addition of Lithiated Alkoxyallenes to
Carbohydrate-Derived Aldonitrones. Eur. J. Org. Chem 2005, 1003–1019. (b) Schade, W.;
Reissig, H.-U. A New Diastereoselective Synthesis of Enantiomerically Pure 1,2-Oxazine
Derivatives by Addition of Lithiated Methoxyallene to Chiral Nitrones. Synlett. 1999, 632–634.
[14] Reviews: (a) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Sugars, Alkaloids and
Heteroaromatics: Exploring Heterocyclic Chemistry with Alkoxyallenes. Acc. Chem. Res.
2009, 42, 45–56. (b) Pfrengle, F.; Reissig, H.-U. Amino Sugars and Their Mimetics via 1,2-
Oxazines. Chem. Soc. Rev. 2010, 39, 549–557.
[15] For recent contributions on functionalization of 1,2-oxazines, see: (a) Moinizadeh, N.;
Klemme, R.; Kansy, M.; Zimmer, R.; Reissig, H.-U. Convenient Syntheses of Enantiopure
1,2-Oxazin-4-yl Nonaflates and Phosphates and Their Palladium-Catalyzed Cross
Couplings. Synthesis. 2013, 45, 2752–2762. (b) Medveckꢀy, M.; Linder, I.; Schefzig, L.;
Reissig, H.-U.; Zimmer, R. Iodination of Carbohydrate-Derived 1,2-Oxazines to
Enantiopure 5-Iodo-3,6-Dihydro-2H-1,2-Oxazines and Subsequent Palladium-Catalyzed
Cross-Coupling Reactions. Beilstein J. Org. Chem. 2016, 12, 2898–2905. (c) Dekaris, V.;
Reissig, H.-U. Stereocontrolled Synthesis of Enantiopure Polyhydroxylated Azetidines via
1,2-Oxazines. Synlett. 2010, 42–46. (d) Al-Harrasi, A.; Fischer, S.; Zimmer, R.; Reissig, H.-
U. Ring Enlargement of Carbohydrate-Derived 1,2-Oxazines to Enantiopure 5-Bromo-1,2-
Oxazepines and Subsequent Palladium-Catalyzed Reactions. Synthesis. 2010, 304–314. (e)
Dekaris, V.; Pulz, R.; Al-Harrasi, A.; Lentz, D.; Reissig, H.-U. Stereoselective Syntheses of
Aza, Amino and Imino Sugar Derivatives by Hydroboration of 3,6-Dihydro-2H-1,2-
ꢀ
Oxazines as Key Reaction. Eur. J. Org. Chem. 2011, 3210–3219. (f) Jasinski, M.; Moreno-
Clavijo, E.; Reissig, H.-U. Synthesis of a Series of Enantiopure Polyhydroxylated Bicyclic
N-Heterocycles from an L-Erythrose-Derived Nitrone and Alkoxyallenes. Eur. J. Org.
Chem. 2014, 442–454. (g) Pecchioli, T.; Cardona, F.; Reissig, H.-U.; Zimmer, R.; Goti, A.
Stereodivergent Synthesis of (-)-Hyacinthacine B4, Purported (þ)-Hyacinthacine C5 and Its
C-5 Epimer – Expanding the Scope of Additions of Lithiated Alkoxyallenes to Cyclic
Nitrones. J. Org. Chem. 2017, 82, 5835–5844.
ꢀ
[16] (a) Bouche, L.; Reissig, H.-U. Synthesis of Novel Carbohydrate Mimetics via 1,2-Oxazines.
ꢀ
Pure Appl. Chem. 2012, 84, 23–36. (b) Bouche, L.; Reissig, H.-U. Synthesis of Di- and
Trivalent Carbohydrate Mimetics with Oxepane Substructure by Employing Copper-
Catalyzed [3 þ 2] Cycloadditions of Alkynes with Azidooxepanes. Eur. J. Org. Chem. 2014,
3697–3703. (c) Kandziora, M.; Reissig, H.-U. Synthesis of Rigid p-Terphenyl-Linked
Carbohydrate Mimetics. Beilstein. J. Org. Chem. 2014, 10, 1749–1758. (d) Kandziora, M.;
Reissig, H.-U. Preparation of Multivalent Carbohydrate Mimetics Based on Enantiopure
1,2-Oxazines by Sonogashira Coupling and Subsequent Reductive Ring-Opening. Eur. J.

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SYNTHETIC COMMUNICATIONSV
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Org. Chem. 2015, 370–377. (e) Kandziora, M.; Mucha, E.; Zucker, S. P.; Reissig, H.-U.
Syntheses of Mono- and Divalent C-Aminoglycosides Using 1,2-Oxazine Chemistry and
Olefin Metathesis. Synlett. 2015, 26, 367–374. (f) Dernedde, J.; Enders, S.; Reissig, H.-U.;
Roskamp, M.; Schlecht, S.; Yekta, S. Inhibition of Selectin Binding by Colloidal Gold with
Functionalized Shells. Chem. Commun. 2009, 932–934. (g) Roskamp, M.; Enders, S.;
Pfrengle, F.; Yekta, S.; Dekaris, V.; Dernedde, J.; Reissig, H.-U.; Schlecht, S. Multivalent
Interaction and Selectivities in Selectin Binding of Functionalized Gold Colloids Decorated
with Carbohydrate Mimetics. Org. Biomol. Chem. 2011, 9, 7448–7456. (h) Salta, J.; Reissig,
H.-U. Synthesis of Divalent Carbohydrate Mimetics by Reductive Amination with
Enantiopure 1,2-Oxazines as Precursors. Synthesis. 2015, 47, 1893–1899. (i) Salta, J.;
Dernedde, J.; Reissig, H.-U. Synthesis of Multivalent Carbohydrate Mimetics with
Aminopolyol End Groups and Their Evaluation as L-Selectin Inhibitors. Beilstein. J. Org.
Chem. 2015, 11, 638–646.
[17] Al-Harrasi, A.; Pfrengle, F.; Prisyazhnyuk, V.; Yekta, S.; Koos, P.; Reissig, H.-U.
Enantiopure Aminopyrans by a Lewis Acid Promoted Rearrangement of 1,2-Oxazines:
Versatile Building Blocks for Oligosaccharide and Sugar Amino Acid Mimetics. Chem.
Eur. J. 2009, 15, 11632–11641.
[18] Pfrengle, F.; Reissig, H.-U. Internally Protected Amino Sugar Equivalents from
Enantiopure 1,2-Oxazines: Synthesis of Variably Configured Carbohydrates with
C-Branched Amino Sugar Units. Chem. Eur. J. 2010, 16, 11915–11925.
ꢀ
[19] Bouche, L.; Kandziora, M.; Reissig, H.-U. Synthesis of New Enantiopure
Poly(Hydroxy)Aminooxepanes as Building Blocks for Multivalent Carbohydrate Mimetics.
Beilstein J. Org. Chem. 2014, 10, 213–223.
[20] For asymmetric catalysis employing thiourea catalysts having free hydroxyl groups, see: (a)
Ghosh, D.; Gupta, N.; Abdi, S. H. R.; Nandi, S.; Khan, N. U. H.; Kureshy, R. I.; Bajaj,
H. C. Organocatalyzed Enantioselective Allylation of Isatins by Using a Chiral Amino
Alcohol Derived Squaramide as Catalyst. Eur. J. Org. Chem. 2015, 2801–2806. (b) Ren, X.;
He, C.; Feng, Y.; Chai, Y.; Yao, W.; Chen, W.; Zhang, S. Novel Ferrocene-Based
Bifunctional Amine-Thioureas for Asymmetric Michael Addition of Acetylacetone to
ꢀ
Nitroolefins. Org. Biomol. Chem. 2015, 13, 5054–5060. (c) Concepcion Gimeno, M.;
Herrera, R. P. Hydrogen Bonding Networks in Chiral Thiourea Organocatalysts: Evidence
on the Importance of the Aminoindanol Moiety. Cryst. Growth Des. 2016, 16, 5091–5099.
ꢀ
(d) Izaga, A.; Herrera, R. P.; Concepcion Gimeno, M. Gold(I)-Mediated Thiourea
Organocatalyst Activation: A Synergic Effect for Asymmetric Catalysis. ChemCatChem.
2017, 9, 1313–1321. (e) ref 12.
[21] For reviews on asymmetric activation, see: (a) Mikami, K.; Terada, M.; Korenaga, T.;
Matsumoto, Y.; Ueki, M.; Angelaud, R. Asymmetric Activation. Angew. Chem. 2000, 112,
3676–3701. Angew. Chem. Int. Ed, 2000, 39, 3532–3556. (b) Piovesana, S.; Scarpino
Schietroma, D. M.; Bella, M. Multiple Catalysis with Two Chiral Units: An Additional
Dimension for Asymmetric Synthesis. Angew. Chem. 2011, 123, 6340–6357. Angew. Chem.
Int. Ed. 2011, 50, 6216–6232.
[22] In a previous contribution, we reported the successful application of prolinol derivative
(S)-26 in combination with a polymer-supported BINOL-titanium catalyst employed in a
Mukaiyama aldol reaction leading to aldol product in high yield and with excellent enan-
tioselectivity: Zimmer, R.; Dekaris, V.; Knauer, M.; Schefzig, L.; Reissig, H.-U. Synthesis of
Poly(Ethylene Glycol)-Supported (R)-BINOL Derivatives and Their First Application in
Enantioselective Mukaiyama Aldol Reactions. Synth. Commun. 2009, 39, 1012–1026.
ꢀ
ꢀ
[23] Alma¸si, D.; Alonso, D. A.; Gomez-Bengoa, E.; Najera, C. Chiral 2-Aminobenzimidazoles as
Recoverable Organocatalysts for the Addition of 1,3-Dicarbonyl Compounds to
Nitroalkenes. J. Org. Chem. 2009, 74, 6163–6168.
[24] For a related thiourea-catalyzed aldol reaction see: Guo, Q.; Bhanushali, M.; Zhao, C.-G.
Quinidine Thiourea-Catalyzed Aldol Reaction of Unactivated Ketones: Highly
Enantioselective Synthesis of 3-Alkyl-3-Hydroxy-Indolin-2-Ones. Angew. Chem. 2010, 122,
9650–9654. Angew. Chem. Int. Ed. 2010, 49, 9460–9464.

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[25] Allu, S.; Molleti, N.; Panem, R.; Singh, V. K. Enantioselective Organocatalytic Aldol
Reaction of Unactivated Ketones with Isatins. Tetrahedron Lett. 2011, 52, 4080–4083.
[26] The ee value was estimate by comparison of the measured [a]D ¼ þ34 with this found in
the literature (ref 24) [a]D ¼ þ27.3 (89% ee).
[27] Boeckman, Jr, R. K.; Biegasiewicz, K. F.; Tusch, D. J.; Miller, J. R. Organocatalytic
Enantioselective Alpha-Hydroxymethylation of Aldehydes: Mechanistic Aspects and
Optimization. J. Org. Chem. 2015, 46, 4030–4045.