Unsaturated syn - And anti -1,2-amino alcohols by cyclization of allylic bis-trichloroacetimidates. Stereoselectivity dependence on substrate configuration

Article abstract of DOI:10.1021/jo502404y

Disubstituted allylic bis-imidates undergo Lewis acid catalyzed or spontaneous cyclization to oxazolines, which are precursors of unsaturated amino alcohols. Stereoselectivity of the cyclization is mainly determined by the substrate configuration. Highly

Full text of DOI:10.1021/jo502404y

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Article
Unsaturated syn- and anti-1,2-Amino Alcohols by
Cyclization of Allylic bis-Trichloroacetimidates.
Stereoselectivity Dependence on Substrate Configuration.
Liene Grigorjeva, Artis Kinens, and Aigars Jirgensons
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502404y • Publication Date (Web): 08 Dec 2014
Downloaded from http://pubs.acs.org on December 13, 2014
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The Journal of Organic Chemistry
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Unsaturated syn- and anti-1,2-Amino Alcohols by Cyclization of Allylic bis-
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Trichloroacetimidates. Stereoselectivity Dependence on Substrate Configuration.
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Liene Grigorjevaa, Artis Kinensb, Aigars Jirgensonsa*
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aLatvian Institute of Organic Synthesis, Aizkraukles 21, Riga LVꢀ1006, Latvia
bUniversity of Latvia, 19 Rainis Blvd., Riga LV1586, Latvia
*Corresponding author email: aigars@osi.lv
ABSTRACT: Disubstituted allylic bisꢀimidates undergo Lewis acid catalyzed or
spontaneous cyclization to oxazolines which are precursors of unsaturated amino
alcohols. Stereoselectivity of the cyclization is mainly determined by the substrate
configuration. Highly selective cis-oxazoline formation is achieved starting from antiꢀ
E-bisꢀimidates while transꢀoxazoline predominantly forms from antiꢀZ-bisꢀimidates.
Based on DFT calculations, the stereoselectivity trends can be explained by the
formation of the energetically most stable carbenium ion conformation followed by
the cyclization via most favorable bond rotations.
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Introduction
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The abundance of 1,2ꢀamino alcohol motif in pharmacologically active compounds
and natural products stimulates the development of more efficient methods for the
construction of this substructure.1 Efficient synthetic approach to unsaturated 1,2ꢀ
amino alcohols are particularly important because the double bond provides high
derivatization potential.2 Stereoselective synthesis of such compounds can be
efficiently achieved via allylic substitution catalyzed by Pd(0)3 or Pd(II)4 complexes.
Allylic substitution via activation of a leaving group by Lewis and Brønsted acid
catalysts, have been intensively studied in recent years,5 however, there are limited
examples for the synthesis of 1,2ꢀamino alcohols using this approach.6 Recently we
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reported
a
method for the cyclization of monoꢀsubstituted allylic bisꢀ
trichloroacetimidates 1 to oxazolines 2 (R1 = Alk, Ar; R2 = H; Scheme 1). 6aꢀf In this
reaction, one of the imidates serves as a leaving group while the other as Nꢀ
nucleophile. The allylic substitution is catalyzed by Lewis acids or occurs
spontaneously if substrate contains carbenium ion stabilizing group.
NH
R1
R1
+
R2
CCl3
R2
O
cat. LA
or spontaneous
cyclization
R1
NH
CCl3
R2
X-
N
O
O
N
O
O
NH
R1
R2
CCl3
CCl3
trans-2
CCl3
syn,anti-E,Z-
1
cis-2
A
Scheme 1. Cyclization of bisꢀtrichloroacetimidates 1 to oxazolines 2
The cyclization of disubstituted allylic bisꢀimidates 1 would be a useful route
towards unsaturated syn or anti amino alcohols if the reaction stereoselectivity and
regioselectivity could be controlled. In this report we present studies of the reaction
selectivity depending on the following parameters: a) bisꢀimidate 1 Eꢀ/Zꢀ
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configuration; b) syn/anti configuration of bisꢀimidate groups; c) substituents R1 and
R2; d) reaction conditions (solvent, Lewis acid).
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Results and discussion
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Isomeric diols 6 for bisꢀimidate synthesis 1 were prepared in a nonꢀstereoselective
manner starting from propargylic alcohol 3 and aldehyde 4 (Table 1).6aꢀd,7 The double
bond in addition products 5 was reduced to give diol isomers E-6 and Z-6 depending
on the reduction method. Syn-and anti- isomers for each double bond isomer E-6 and
Z-6 were separated using column chromatography.
Table 1. Synthesis of diols 6
entry
R1
R2
5, yield%
5a, 89
5b, 88
5c, 74
5d, 70
5e, 92
5f, 70
Eꢀ6, yield (%)a Zꢀ6, yield (%)a
1
2
3
4
5
6
nꢀPent nꢀPent
Eꢀ6a, 92
Eꢀ6b, 74
Eꢀ6c, 91
Eꢀ6d, 93
Eꢀ6e, 84
Eꢀ6f, 97
Zꢀ6a, 63
Zꢀ6b, 86
Zꢀ6c, 85
Zꢀ6d, 75
Zꢀ6e, 75
Zꢀ6f, 66
Ph
Ph
Ph
Ph
Ph
nꢀPent
iꢀPr
Bn
Ph
4ꢀMeOC6H4
aTotal yield for the mixture of syn and anti isomers
All four isomers of diol 6a (R1 = R2 = nꢀPent) were transformed to bisꢀimidates
syn-E-1a, antiꢀE-1a, syn-Z-1a, anti-Z-1a (Figure 1). These imidate isomers were
investigated as model compounds for oxazoline 2 formation with Lewis acid catalyst
AlCl3 or TMSOTf in the range of solvents (see Supporting information for results
with FeCl3 and BF3·Et2O). In most cases, bisꢀimidates syn-E-1, antiꢀE-1 gave
oxazoline cis-2a in the preference to trans-2a (Figure 1). The degree of selectivity
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was dependent on a substrate syn/anti configuration, Lewis acid catalyst and solvent.
The best cisꢀselectivity (>10:1) for oxazoline cisꢀ2a formation was achieved starting
from antiꢀEꢀ1a using multiꢀcoordinating Lewis acid catalyst (AlCl3) in CH2Cl2 or
toluene. The use of monoꢀcoordinating Lewis acid such as TMSOTf significantly
decreased cyclization selectivity for both, synꢀ Eꢀ1a and antiꢀEꢀ1a. In turn, Zꢀ
configured bisꢀimidates synꢀZꢀ1, antiꢀZꢀ1a predominantly gave oxazoline transꢀ2a
under all the conditions used. However, the highest transꢀselectivity was achieved
using monoꢀcoordinating Lewis acid TMSOTf in either THF, toluene or Et2O.
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AlCl3 catalyzed cyclization
TMSOTf catalyzed cyclization
Figure 1 Transꢀ and cisꢀselectivity for oxazoline 2a formation in LA catalyzed
cyclization of bisꢀimidates synꢀEꢀ1a, antiꢀEꢀ1a, synꢀZꢀ1a, antiꢀZ-1a
To explain the stereoselectivity trends for oxazoline cisꢀ2 and transꢀ2 formation,
potential reaction mechanism was hypothesized. Concerted stereospecific antiꢀSN2’ or
synꢀSN2’ mechanism can be excluded. If this was the case, either bisꢀimidate synꢀEꢀ1
or antiꢀEꢀ1 should provide oxazoline cisꢀ2 with Zꢀconfiguration of the double bond,8
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however, only formation of oxazoline Eꢀcisꢀ2 was observed. Next, SN1ꢀtype
mechanism was considered. According to this, coordination of 1 with Lewis acid
followed by dissociation of complexed imidate would provide carbenium ion A which
would then cyclize to oxazoline 2 (Scheme 1, Figure 2). However, it is difficult to
explain preferential formation of cisꢀ2 oxazoline which should be apparently
disfavored if diastereomeric transition states for the carbenium ion A cyclization are
considered. To get an insight of the reaction energy profile, DFT calculations were
performed. The calculations indicated that transition state energy ∆Gǂ value for
carbenium ion A (R1 = R2 = Me) cyclization approaches 0 and is lower compared to
bond rotation barriers (see Supporting Information). Based on these results we could
assume that, the stereoselectivity is determined by the conformation of the
intermediate carbenium ion A which undergoes cyclization via energetically preferred
bond rotations. According to the Hammond’s postulate,9 it can be assumed that
carbenium ion A with energetically most favored conformation is formed first. Using
the DFT method, the lowest energy conformation of carbenium ion A resulting from
each isomer of 1 was calculated (see Supporting Information). These calculations
suggested that from bisꢀimidates syn-E-1 and antiꢀE-1 carbenium ion E-,E-A is
generated in a conformation, which undergoes favorable C-O bond rotation (over H vs
R) to form oxazoline cis-2. In turn, imidates syn Zꢀ1 and antiꢀZꢀ1 led to carbenium ion
Eꢀ,ZꢀA which has prerequisite conformation for the cyclization to oxazoline transꢀEꢀ
2. Based on this stereoselectivity model, it can be considered that solvent and Lewis
acid catalyst and syn/anti configuration of a substrate 1 have an impact on distribution
between carbenium ion Eꢀ,E-A and E-,ZꢀA conformations.
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Figure 2. Stereoinduction model for cisꢀ2 and trans-2 oxazoline formation
Subsequently, we further investigated the scope of cyclization by employing
different substituted allylic bisꢀimidates 1b-e containing carbenium ion stabilizing
phenyl group (Table 2). These bisꢀimidates apeared to be quite labile and only
isomers of intermediate E-1c could be isolated and subjected to cyclization. In all
other cases, diols 6 were converted to imidates 1 which were transformed in situ to
oxazolines 2. As expected from ionization induced reaction mechanism,
regioselective cyclization of unsymetrically substituted substrates 1b-d was observed,
providing compounds 2b-d as the only regioisomers (Table 1, entries 1ꢀ10). Cisꢀ
/transꢀselectivity again showed remarkable dependency on a substrate configuration.
Imidates E-1b-e preferentially gave oxazolines cis-2b-e. Cisꢀselectivity was better for
antiꢀE-1b-e compared to syn-E-1b-e. Imidates anti-Z-1b-e gave exclusively
oxazolines trans-2b-e.
Since 4ꢀmethoxyphenyl group has better ability to stabilize carbenium ion
compared to phenyl group, spontaneous cyclization of all bisꢀimidate 1f isomers
prepared in situ from diols 6f led to regioselective formation of oxazoline 2f (Table
3). Low cisꢀ/transꢀselectivity for oxazoline 2f formation was observed starting from
bisꢀimidates synꢀEꢀ1f and antiꢀEꢀ1f. This could be explained by increased activation
energy for the cyclization of more stabilized carbenium ion intermediate A (Figure 2).
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In this case, slower cyclization leads to equilibration of unequivalent diastereomeric
transition states thus influencing cisꢀ/transꢀstereoselectivity for the product 2f
formation. Notably, bisꢀimidate antiꢀZꢀ1f gave oxazoline transꢀ2f as the only
detectable isomer.
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Table 2. Cyclization of bisꢀimidates 1 containing phenyl group
product,
yield (%)
2b, 73
2b, 76
2b, 70
2c, 96
2c, 93
2c, 80
2c, 90
2d, 92
2d, 94
2d, 93
2e, 88
2e, 90
2e, 92
cis-2/
trans-2a
30:1
1:0
0:1
5:2
6:1
1:33
0:1
1:1
6:1
entry
substrate
R
catalyst
time
solvent
1
2
3
4
5
6
7
8
syn-E-6b
anti-E-6b
anti-Z-6b
syn-E-1c
anti-E-1c
anti-Z-6c
anti-Z-6c
syn-E-6d
anti-E-6d
anti-Z-1d
syn-E-6e
anti-E-6e
anti-Z-6e
nꢀPent
ꢀ
ꢀ
ꢀ
6h
6 h
12 h
5 min toluene
5 min CH2Cl2
24 h
1 min CH2Cl2
2 min CH2Cl2
2 min CH2Cl2
1 min Et2O
2 min CH2Cl2
2 min CH2Cl2
1 min CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
iꢀPr
AlCl3
AlCl3
ꢀ
TMSOTf
AlCl3
AlCl3
TMSOTf
AlCl3
AlCl3
TMSOTf
CH2Cl2
Bn
Ph
9
10
11
12
13
0:1
3:2
3:1
0:1
a Cisꢀ/transꢀ ratio was determined using 1HꢀNMR.
Table 3. Cyclization of bisꢀimidate 1f containing 4ꢀmethoxyphenyl group
MeO
MeO
NH
CCl3
MeO
DBU (2 equiv)
O
MeO
Ph
Ph
OH
Ph
Ph
spontaneous
Cl3CCN (4 equiv)
N
O
N
O
+
O
NH
CCl3
syn,anti-E,Z-
CH2Cl2, 0 oC-rt
OH
CCl3
2f
CCl3
2f
syn,anti-E,Z-6f
1f
cis-
trans-
entry substrate
yield of 2f (%)
cisꢀ2f/transꢀ2fa
1
2
syn-E-6f
anti-E-6f
anti-Z-6f
93
90
89
1:1.5
1:3.3
0:1
3
a
Cisꢀ/transꢀ ratio was determined using 1HꢀNMR.
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Several oxazolines were isolated as pure isomers cisꢀ2 and transꢀ2 and
converted to Bocꢀprotected amino alcohols anti-7 and syn-7 in high overall yields
7
8
(Table 4).
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Table 4. NꢀBoc amino alcohols 7 from oxazolines 2
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entry
oxazoline, R
cis-2b, nꢀPent
trans-2b, nꢀPent
cis-2d, Bn
cis-2c, iꢀPr
trans-2c, iꢀPr
product, yield (%)
anti-7b, 80
syn-7b, 87
anti-7d, 89
anti-7c, 88
syn-7c, 83
1
2
3
4
5
6
7
cis-2e, Ph
trans-2e, Ph
anti-7e, 87
syn-7e, 90
In summary, we have demonstrated efficient method for the stereoselective
synthesis of amino alcohols via cyclization of disubstituted allylic bisꢀimidates.
Stereoselectivity of bisꢀimidate cyclization is determined by the substrate
configuration and can be enhanced by appropriate selection of Lewis acid and solvent.
Cisꢀoxazoline predominantly forms from allylic antiꢀEꢀbisꢀimidates using multiꢀ
coordinating Lewis acid catalyst (AlCl3) in nonꢀcoordinating solvents. Furthermore
the cis-selectivity for antiꢀEꢀbisꢀimidate cyclization is highly dependent on the
substitution pattern. Trans-oxazoline predominantly forms from allylic antiꢀZꢀbisꢀ
imidates using monoꢀcoordinating Lewis acid (TMSOTf) with a slight dependence on
the reaction solvent. In this case cyclization is highly transꢀselective independently of
the bisꢀimidate substituents.
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EXPERIMENTAL SECTION
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General information.
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Reagents and starting materials were obtained from commercial sources and used as
received. The solvents were purified and dried by standard procedures prior to use.
All reactions were performed under an inert atmosphere. Flash chromatography was
carried out using Merck Kieselgel (230 – 400 mesh) silica gel. Thin layer
chromatography was performed on silica gel and was visualized by staining with
KMnO4. NMR spectra were recorded on 400 MHz and 600 MHz spectrometers with
chemical shift values (δ) in ppm using the residual chloroform signal as internal
standard. Gas chromatographic analysis was performed on gas chromatographic
system with mass selective detector. Exact molecular masses (HRMS) were
determined on a hybrid quadrupole timeꢀofꢀflight mass spectrometer equipped with an
electrospray ion source.
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Diols 5 and 6 were prepared as described previously.6a Compounds 5a10, 5b,e11, antiꢀ
Eꢀ6a,10 synꢀEꢀ6a,10 antiꢀZꢀ6a,3cantiꢀEꢀ6c12, synꢀEꢀ6c12antiꢀEꢀ6e,13 synꢀEꢀ6e13 have
been previously described in literature. The stereochemistry of other diols 6 was
assigned by comparing the chemical shift differences in NMR spectra.
5-Methyl-1-phenylhex-2-yne-1,4-diol (5c). 1.21 g, 74%. Purified by flash
chromatography on silica gel using a mixture of light petroleum ether and EtOAc
1
(2:1, 1:1, 0:1) as an eluent. Colorless solid. HꢀNMR δH (400 MHz, CDCl3): 7.54 –
7.52 (m, 2H), 7.41 – 7.31 (m, 3H), 5.51 (s, 1H), 4.26 (d, J = 5.5 Hz, 1H), 2.35 (bs,
1H), 1.97 (bs, 1H), 1.91 (octet, J = 6.7 Hz, 1H), 1.02 (dd, J = 6.7 and 2.7 Hz, 3H),
1.00 (dd, J = 6.7 and 2.7 Hz, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 140.6, 128.6,
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128.4, 126.6, 86.5, 85.3, 67.9, 64.6, 34.5, 18.1, 17.5. GCꢀMS: m/z (EI): 204 (M)+.
Anal. calcd for C13H16O2: C, 76.44; H, 7.90; Found: C, 76.22; H, 7.97.
6
7
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9
1,5-Diphenylpent-2-yne-1,4-diol (5d). 1.42 g, 70%. Purified by flash chromatography
on silica gel using a mixture of light petroleum ether and EtOAc (2:1, 1:1, 0:1) as an
eluent. Colorless oil. (1HꢀNMR δH (400 MHz, CDCl3): 7.46 – 7.22 (m, 10H), 5.46 (s,
1H), 4.70 – 4.65 (m, 1H), 3.02 (dd, J = 6.7 and 2.4 Hz, 2H), 2.38 (bs, 1H) and 2.13
(bs, 1H). 13C{1H}NMR δC (100 MHz, CDCl3): 140.2, 136.3, 129.8, 129.0, 128.6,
128.4, 126.9, 126.6, 87.0, 85.5, 64.5, 63.2, 43.8. GCꢀMS: m/z (EI): 252 (M)+.
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1-(4-Methoxyphenyl)-4-phenylbut-2-yne-1,4-diol (5f). 1.50 g, 70%. Crystallized
1
from Et2O. Colorless solid. M.p. 119ꢀ120oC. HꢀNMR δH (400 MHz, CDCl3): 7.56 –
7.54 (m, 2H), 7.48 – 7.45 (m, 2H), 7.41 – 7.32 (m, 3H), 6.90 (d, J = 8.6 Hz, 2H), 5.56
(s, 1H), 5.51 (s, 1H), 3.81 (s, 3H), 2.29 (bs, 1H), 2.22 (bs, 1H). 13C{1H}NMR δC (100
MHz, CDCl3): 159.8, 140.6, 132.5, 128.7, 128.5, 128.1, 126.6, 114.0, 86.6, 86.3, 64.7,
64.3, 55.5. GCꢀMS: m/z (EI): 268 (M)+. Anal. calcd for C17H16O3: C, 76.10; H, 6.01;
Found: C, 75.61; H, 5.92.
(1S*,4R*,E)-1-Phenylnon-2-ene-1,4-diol (syn-E-6b). 1.51 g, 74% as a mixture with
diol anti-E-6b. Separated by flash chromatography on silica gel using a mixture of
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light petroleum ether and EtOAc (4:1, 1:1) as an eluent. Colorless oil. HꢀNMR δH
(400 MHz, CDCl3): 7.38 – 7.26 (m, 5H), 5.88 (dd, J = 15.7 and 5.9 Hz, 1H), 5.79 (dd,
J = 15.7 and 6.3 Hz, 1H), 5.22 (d, J = 5.9 Hz, 1H), 4.13 (q, J = 6.3 Hz, 1H), 2.09 (bs,
1H), 1.62 (bs, 1H), 1.57 – 1.22 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H). 13C{1H}NMR δC
(100 MHz, CDCl3): 142.8, 134.3, 132.7, 128.5, 127.7, 126.2, 74.5, 72.3, 37.2, 31.7,
25.1, 22.6, 14.0. GCꢀMS: m/z (EI): 233 (MꢀH)+.
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(1R*,4R*,E)-1-Phenylnon-2-ene-1,4-diol (anti-E-6b). 1.51 g, 74% as a mixture with
diol syn-E-6b. Separated by flash chromatography on silica gel using a mixture of
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light petroleum ether and EtOAc (4:1, 1:1) as an eluent. Colorless oil. HꢀNMR δH
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(400 MHz, CDCl3): 7.35 – 7.24 (m, 5H), 5.86 (dd, J = 15.5 and 5.7 Hz), 5.78 (dd, J =
15.5 and 6.1 Hz, 1H), 5.19 (d, J = 5.7 Hz, 1H), 4.11 (q, J = 6.1 Hz, 1H), 2.34 (bs, 1H),
1.82 (bs, 1H), 1.57 – 1.23 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H). 13C{1H}NMR δC (100
MHz, CDCl3): 142.8, 134.0, 132.6, 128.5, 127.7, 126.3, 74.4, 72.2, 37.1, 31.7, 25.0,
22.6, 14.0. GCꢀMS: m/z (EI): 233 (MꢀH)+.
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(1S*,4R*,Z)-1-Phenylnon-2-ene-1,4-diol (anti-Z-6b). 1.74 g, 86% as a mixture with
diol syn-Zꢀ6b. Separated by flash chromatography on silica gel using a mixture of
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light petroleum ether and EtOAc (4:1, 1:1) as an eluent. Colorless oil. HꢀNMR δH
(400 MHz, CDCl3): 7.41 – 7.25 (m, 5H), 5.72 (dd, J = 11.3 and 8.2 Hz, 1H), 5.57 –
5.51 (m, 2H), 4.54 (q, J = 7.0 Hz, 1H,), 2.26 (bs, 1H), 1.73 (bs, 1H), 1.67 – 1.24 (m,
8H), 0.89 (t, J = 7.0 Hz, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 142.9, 134.4,
133.9, 128.6, 127.6, 126.0, 69.6, 67.6, 37.1, 31.7, 25.0, 22.5, 13.9. GCꢀMS: m/z (EI):
233 (MꢀH)+.
(1S*,4R*,Z)-5-Methyl-1-phenylhex-2-ene-1,4-diol (anti-Z-6c). 405 mg, 85% as a
mixture with diol syn-E-6c. Separated by flash chromatography using a mixture of
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light petroleum ether and EtOAc (6:1, 1:1) as an eluent. Colorless oil. HꢀNMR δH
(400 MHz, CDCl3): 7.43 – 7.26 (m, 5H), 5.79 (dd, J = 11.3 and 8.2 Hz, 1H), 5.59 –
5.55 (m, 2H), 4.29 (dd, J = 8.6 and 7.0 Hz, 1H), 2.33 (bs, 1H), 1.77 (octet, J = 6.7 Hz,
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1H), 1.67 (bs, 1H), 1.01 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). C{1H}NMR
δC (100 MHz, CDCl3): 143.3, 134.5, 132.3, 128.7, 127.7, 126.0, 73.2, 70.4, 34.1, 18.2,
18.0. GCꢀMS: m/z (EI): 188 (MꢀH2O)+.
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(1S*,4R*,E)-1,5-Diphenylpent-2-ene-1,4-diol (syn-E-6d). 421 mg, 93% as a mixture
with diol anti-E-6d. Separated by flash chromatography using a mixture of light
petroleum ether and EtOAc (4:1, 1:1) as an eluent. Colorless crystals. M.p. 85 ꢀ 86°C.
1HꢀNMR δH (400 MHz, CDCl3): 7.35 – 7.15 (m, 10H), 5.80 – 5.75 (m, 2H), 5.14 –
5.11 (m, 1H), 4.35 – 4.29 (m, 1H), 2.89 (bs, 1H), 2.80 (d, J = 6.7 Hz, 2H), 2.43 (bs,
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1H). C{1H}NMR δC (100 MHz, CDCl3): 142.6, 137.5, 133.2, 133.1, 129.5, 128.39,
128.36, 127.5, 126.4, 126.1, 74.2, 72.8, 43.7. GCꢀMS: m/z (EI): 253 (MꢀH)+. Anal.
calcd. for C17H18O2·1/3 H2O: C, 78.43; H, 7.23; Found: C, 78.15; H, 7.02.
(1S*,4S*,E)-1,5-Diphenylpent-2-ene-1,4-diol (anti-E-6d). 421 mg, 93% as a mixture
with diol anti-E-6d. Separated by flash chromatography using a mixture of light
petroleum ether and EtOAc (4:1, 1:1) as an eluent. Colorless crystals. M.p. 109 ꢀ
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110°C. HꢀNMR δH (400 MHz, CDCl3): 7.36 – 7.18 (m, 10H), 5.89 – 5.82 (m, 2H),
5.18 (d, J = 3.1 Hz, 1H), 4.40 – 4.35 (m, 1H), 2.87 (dd, J = 13.7 and 5.9 Hz, 1H), 2.83
(dd, J = 13.7 and 7.8 Hz, 1H), 2.27 (bs, 1H), 1.93 (bs,1H). 13C{1H}NMR δC (100
MHz, CDCl3): 142.5, 137.6, 133.0, 132.8, 129.5, 128.48, 128.46, 127.7, 126.5, 126.3,
74.2, 72.8, 43.8. GCꢀMS: m/z (EI): 236 (MꢀH2O)+. Anal. calcd. for C17H18O2·1/6
H2O: C, 79.35; H, 7.18; Found: C, 79.67; H, 7.11.
(1S*,4R*,Z)-1,5-Diphenylpent-2-ene-1,4-diol (anti-Z-6d). 365 mg, 75% as a mixture
with diol syn-Z-6d. Separated by flash chromatography using a mixture of light
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petroleum ether and EtOAc (6:1, 1:1) as an eluent. Colorless oil. HꢀNMR δH (400
MHz, CDCl3): 7.38 – 7.22 (m, 10H), 5.64 (dd, J = 11.3 and 8.2 Hz, 1H), 5.56 (dd, J =
11.3 and 8.0 Hz, 1H), 5.25 (d, J = 8.2 Hz, 1H), 4.81 (q, J = 7.2 Hz, 1H), 3.00 (dd, J =
13.1 and 6.7 Hz, 1H), 2.83 (dd, J = 13.1 and 7.0 Hz, 1H), 2.22 (bs, 1H), 1.70 (bs, 1H).
13C{1H}NMR δC (100 MHz, CDCl3): 142.5, 137.5, 133.9, 132.6, 129.7, 128.6, 128.4,
127.5, 126.8, 125.8, 69.5, 67.0, 44.0. GCꢀMS: m/z (EI): 236 (MꢀH2O)+.
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(1S*,4S*,Z)-1,4-Diphenylbut-2-ene-1,4-diol (anti-Z-6e). 1.32 g, 87% as a mixture
with diol syn-Z-6e (see Table 1). Separated by flash chromatography using a mixture
of light petroleum ether and EtOAc (4:1, 0:1) as an eluent. Colorless oil. 1HꢀNMR δH
(400 MHz, CDCl3): 7.46 – 7.28 (m, 10H), 5.80 – 5.78 (m, 2H), 5.71 – 5.69 (m, 2H),
2.31 (bs, 2H). 13C{1H}NMR δC (100 MHz, CDCl3): 143.0, 133.5, 128.7, 127.8, 126.1,
70.4. GCꢀMS: m/z (EI): 222 (MꢀH2O)+.
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(1S*,4S*,E)-1-(4-Methoxyphenyl)-4-phenylbut-2-ene-1,4-diol (syn-E-6f). 980 mg,
97% crude product as a mixture with diol anti-E-6f. Separated by flash
chromatography on silica gel using a mixture of CH2Cl2 and MeOH (10:1) as an
eluent. Recrystallized from Et2O. Colorless solid. M.p. 106 ꢀ 107°C. 1HꢀNMR δH (400
MHz, CDCl3): 7.36 – 7.26 (m, 7H), 6.91 – 6.86 (m, 2H), 6.02 – 5.94 (m, 2H), 5.24 –
5.16 (m, 2H), 3.82 (s, 3H), 2.60 (bs, 1H) and 2.52 (bs, 1H). 13C{1H}NMR δC (100
MHz, CDCl3): 159.1, 142.6, 134.8, 133.3, 132.8, 128.5, 127.7, 127.6, 126.2, 113.9,
74.3, 73.8, 55.2. GCꢀMS: m/z (EI): 252 (MꢀH2O)+. Anal. calcd. for C17H18O3: C,
75.53; H, 6.71; Found: C, 75.31; H, 6.69.
(1R*,4S*,E)-1-(4-Methoxyphenyl)-4-phenylbut-2-ene-1,4-diol (anti-E-6f). 980 mg,
97%, crude product as a mixture with diol syn-E-6f. Separated by flash
chromatography on silica gel using a mixture of CH2Cl2 and MeOH (10:1) as an
eluent. Recrystallized from Et2O. Colorless solid. M.p. 137 ꢀ 138°C. 1HꢀNMR δH (400
MHz, CDCl3): 7.37 – 7.26 (m, 7H), 6.92 – 6.87 (m, 2H), 6.02 – 6.00 (m, 2H), 5.27 –
5.25 (m, 1H), 5.22 – 5.20 (m, 1H), 3.81 (s, 3H), 1.90 (d, J = 3.7 Hz, 1H), 1.84 (d, J =
3.7 Hz, 1H). 13C{1H}NMR δC (100 MHz, CDCl3): 159.3, 142.6, 134.8, 133.3, 132.8,
128.6, 127.8, 127.7, 126.3, 114.0, 74.4, 73.9, 55.3. GCꢀMS: m/z (EI): 269 (MꢀH)+.
Anal. calcd for C17H18O3·1/5 H2O: C, 74.54; H, 6.77; Found: C, 74.89; H, 6.62.
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(1S*,4S*,Z)-1-(4-Methoxyphenyl)-4-phenylbut-2-ene-1,4-diol (anti-Z-6f). 725 mg,
66% yield as a mixture with diol syn-Z-6f (see Table 1). Separated by flash
chromatography using a mixture of light petroleum ether and EtOAc (4:1, 0:1) as an
eluent. Oil. 1HꢀNMR δH (400 MHz, CDCl3): 7.45 – 7.26 (m, 7H), 6.92 – 6.87 (m, 2H),
5.82 – 5.74 (m, 2H), 5.67 (d, J = 7.0 Hz, 1H), 5.64 (d, J = 7.0 Hz, 1H), 3.81 (s, 3H),
2.27 (bs, 1H), 1.63 (bs, 1H). 13C{1H}NMR δC (100 MHz, CDCl3): 159.2, 143.1,
135.3, 133.7, 133.1, 128.7, 127.8, 127.4, 126.0, 114.1, 70.3, 70.1, 55.3. GCꢀMS: m/z
(EI): 252 (MꢀH2O)+.
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General procedure for the synthesis of bis-imidates 1.
To a solution of diol 3 (1.0 mmol) in CH2Cl2 (10 mL) 4 Å molecular sieves were
added. Reaction mixture was cooled to 0oC, DBU (2 mmol, 2 equiv.) was added.
o
Solution was stirred at 0 C for 30 minutes. Trichloroacetonitrile (4 mmol, 4 equiv.)
was added, and the reaction mixture was stirred at 0 oC temperature until TLC showed
complete conversion. Solvent was removed and the residue was purified by flash
column chromatography using mixture of light petroleum ether and EtOAc (8:1) as an
eluent to give bisꢀtrichloroacetimidate 1.
Bis-trichloroacetimidate syn-E-1a. Prepared according to the general procedure (436
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mg, 99%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.26 (s, 2H), 5.87 – 5.79
(m, 2H), 5.44 – 5.37 (m, 2H), 1.83 – 1.65 (m, 4H), 1.47 – 1.24 (m, 12H), 0.87 (t, J =
7.0 Hz, 6H). 13CꢀNMR δC (100 MHz, CDCl3): 161.8, 130.2, 91.9, 78.4, 34.0, 31.5,
24.5, 22.5, 14.0. HRMS (EIꢀTOF) m/z: Calcd for C16H27Cl3NO 354.1153; Found
354.1155 [MꢀCl3CC(=O)NH2)+H]+.
Bis-trichloroacetimidate anti-E-1a. Prepared according to the general procedure (413
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mg, 95%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.26 (s, 2H), 5.84 – 5.77
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(m, 2H), 5.41 – 5.36 (m, 2H), 1.85 – 1.64 (m, 4H), 1.46 – 1.24 (m, 12H), 0.87 (t, J =
7.0 Hz, 6H). 13C{1H}NMR δC (100 MHz, CDCl3): 161.7, 130.3, 91.9, 78.6, 34.1,
31.4, 24.5, 22.5, 13.9. HRMS (EIꢀTOF) m/z: Calcd for C16H27Cl3NO 354.1153;
Found 354.1155 [MꢀCl3CC(=O)NH2)+H]+
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Bis-trichloroacetimidate syn-Z-1a. Prepared according to the general procedure (2.20
g, yield 85%). Colorless oil. Two rotational isomers for syn-Z-1a was observed in 1Hꢀ
and 13CꢀNMR spectra. Their interꢀconversion with sufficiently high energy barrier
was confirmed by exchange peaks in 2D NMR NOESY spectra (see Supporting
Information). 1HꢀNMR δH (600 MHz, CDCl3, mixture of two rotamers ~ 1:1): 8.85 (s,
0.5H), 8.42 (s, 0.5H), 8.29 (s, 1H), 5.79 (q, J = 6.8 Hz, 1H), 5.63 (m, 1H), 5.53ꢀ5.61
(m, 1H), 5.33 (td, J = 9.0, 2.4 Hz, 0.5H), 5.27 (t, J = 6.9 Hz, 0.5H), 1.83ꢀ1.93 (m, 2H),
1.25 – 1.67 (m, 14H), 0.89ꢀ0.92 (m, 6H). 13C{1H}NMR δC (100 MHz, CDCl3, mixture
of two rotamers ~1:1): 162.8, 161.6, 159.7, 132.1, 131.0, 130.6, 93.0, 91.8, 91.4, 75.5,
75,1, 74.8, 36.0, 34.8, 34,2, 31.6, 31.3, 24.9, 24.6, 24.5, 22.51, 22.46, 13.9. Unstable
under the conditions of HRMS analysis.
Bis-trichloroacetimidate anti-Z-1a. Prepared according to the general procedure
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(624 mg, 71%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.23 (s, 2H), 5.89 –
5.79 (m, 2H), 5.57 – 5.51 (m, 2H), 1.84 – 1.75 (m, 2H), 1.69 – 1.61 (m, 2H), 1.51 –
1.22 (m, 12H), 0.87 (t, J = 7.0 Hz, 6H). 13C{1H}NMR δC (100 MHz, CDCl3): 161.8,
131.3, 91.9, 75.7, 34.3, 31.5, 24.6, 22.5, 14.0. Unstable under the conditions of
HRMS analysis.
Bis-trichloroacetimidate syn-E-1c. Prepared according to the general procedure (173
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mg, 78%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.38 (s, 1H), 8.26 (s, 1H),
7.42 – 7.28 (m, 5H), 6.42 (d, J = 5.7 Hz, 1H), 6.05 (ddd, J = 15.7, 5.9, 1.2 Hz, 1H),
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5.88 (ddd, J = 5.7, 6.3, 1.2 Hz, 1H), 5.25 (t, J = 6.1 Hz, 1H), 2.05 (m, 1H), 0.99 (d, J
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= 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). C{1H}NMR δC (100 MHz, CDCl3): 161.8,
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161.2, 138.3, 130.8, 129.2, 128.5, 128.2, 127.0, 91.9, 91.6, 82.6, 79.5, 32.2, 18.1,
17.8. Unstable under the conditions of HRMS analysis.
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Bis-trichloroacetimidate anti-E-1c. Prepared according to the general procedure (172
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mg, 86%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.37 (s, 1H), 8.24 (s, 1H),
7.24ꢀ7.41 (m, 5H), 6.42 (d, J = 5.7 Hz, 1H), 6.01 (ddd, J = 15.6, 5.9, 1.2 Hz, 1H),
5.87 (ddd, J = 15.6, 6.3, 1.2 Hz, 1H), 5.22 (t, J = 6.2 Hz, 1H), 1.99 ꢀ 2.08 (m, 1H),
0.97 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). 13C{1H}NMR δC (100 MHz,
CDCl3): 161.8, 161.2, 138.4, 130.8, 129.2, 128.5, 128.2, 126.8, 91.9, 91.6, 82.8, 79.5,
32.3, 17.9. Unstable under the conditions of HRMS analysis.
Bis-trichloroacetimidate anti-Z-1d. Prepared according to the general procedure (116
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mg, yield 93%). Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 8.40 (s, 1H), 8.27 (s,
1H), 7.48 (d, J = 7.4 Hz, 2H), 7.37 – 7.19 (m, 8H), 6.96 (d, J = 9.4 Hz, 1H), 6.27
(ddd, J = 9.0,7.2, 5.5 Hz, 1H), 5.79 (dd, J = 11.0, 9.0 Hz, 1H), 5.72 (dd, J = 11.0, 9.4
Hz, 1H), 3.14 – 3.10 (m, 2H). 13C{1H}NMR δC (100 MHz, CDCl3): 161.5, 161.2,
138.8, 136.7, 131.4, 130.8, 129.8, 128.4, 128.2, 128.0, 126.6, 126.4, 91.6, 91.5, 75.84,
75.80, 40.9. Unstable under the conditions of HRMS analysis.
Synthesis of oxazolines 2.
Method A (from bisꢀimidates 1). Molecular sieves (4 Å) and Lewis acid catalyst
(0.05 mmol, 10 molꢀ%) were added to a stirred solution of bisꢀimidate 1 (0.50 mmol)
in solvent (5 mL) at rt. After reaction was complete (TLC checking at the first minute
of the reaction), TEA (50 molꢀ%) was added, and reaction solvent was removed under
reduced pressure. The residue was purified by column chromatography on silica gel
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eluting with a mixture of light petroleum ether and ethyl acetate (8:1) to afford the
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oxazoline 2.
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Method B (from diol 3). To a solution of diol 3 (0.31 mmol) in solvent (5 mL) 4 Å
molecular sieves were added. Reaction mixture was cooled to 0 oC, DBU (9 µL, 0.06
mmol, 20 molꢀ%) was added, and solution was stirred at 0oC for 30 minutes. Then
trichloroacetonitrile (0.13 mL, 1.25 mmol, 4 equiv.) was added, the reaction mixture
was stirred until TLC showed complete conversion of starting material to bisꢀimidate
1(~20 min). Catalytic amount of Lewis acid (25 molꢀ%) was added and the mixture
was stirred until complete conversion of bisꢀimidate 1 to oxazoline 2. After reaction
was complete (TLC checking at the first minute of the reaction), TEA (50 molꢀ%)
was added, and solvent was removed under reduced pressure. The residue was
purified by column chromatography on silica gel using mixture of light petroleum
ether and EtOAc (8:1) as an eluent to afford the oxazoline 2.
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Method C (from diol 3). To a solution of diol 3 (1.0 mmol) in CH2Cl2 (10 mL) 4 Å
molecular sieves were added. Reaction mixture was cooled to 0oC, DBU (2 mmol, 2
o
equiv.) was added. Solution was stirred at 0 C for 30 minutes. Trichloroacetonitrile
o
(4 mmol, 4 equiv.) was added, and the reaction mixture was stirred at 0 C
temperature until TLC showed complete conversion to oxazoline 2. Solvent was
removed and the residue was purified by flash column chromatography using mixture
of light petroleum ether and EtOAc (8:1) as an eluent to afford oxazoline 2.
Oxazoline cis-2a. Prepared according to the method A (31ꢀ34 mg, the yield depended
on the Lewis acid catalyst and the reaction solvent, see SI). Colorless oil. 1HꢀNMR δH
(400 MHz, CDCl3): 5.75 (dt, J = 15.3, 7.0 Hz, 1H), 5.37 (dd, J = 15.3, 8.6 Hz, 1H),
4.86 (unresolved td, 1H,), 4.74 (t, J = 8.6 Hz, 1H), 2.14 – 2.00 (m, 2H), 1.75 – 1.46
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(m, 2H), 1.45 – 1.21 (m, 12H), 0.94 – 0.85 (m, 6H). 13C{1H}NMR δC (100 MHz,
CDCl3): 162.5, 136.4, 122.7, 87.8, 87.0, 70.7, 32.4, 31.5, 31.4, 30.2, 28.6, 25.6, 22.5,
22.4, 14.0, 13.9. GCꢀMS: m/z (EI): 354 [M]+. HRMS (EIꢀTOF) m/z: Calcd for
C16H27Cl3NO 354.1153; Found 354.1153 [M+H].+. See SI for 2DꢀNOESY spectra.
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Oxazoline trans-2a. Prepared according to the method A (30ꢀ67 mg, the yield
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depended on Lewis acid catalyst and the reaction solvent, see SI). Colorless oil. Hꢀ
NMR δH (400 MHz, CDCl3): 5.73 (dt, J = 15.3, 6.7 Hz, 1H), 5.42 (dd, J = 15.3, 7.8
Hz, 1H), 4.53 (dt, J = 7.4, 5.5 Hz, 1H), 4.33 (t, J = 7.4 Hz, 1H), 2.11 – 1.98 (m, 2H),
1.82 – 1.63 (m, 2H), 1.51 – 1.22 (m, 12H), 0.91 – 0.86 (m, 6H). 13C{1H}NMR δC
(100 MHz, CDCl3): 162.0, 135.0, 127.6, 89.7, 86.9, 73.9, 34.1, 32.3, 31.43, 31.37,
28.5, 24.2, 22.5, 22.4, 14.0, 13.9. GCꢀMS: m/z (EI): 354 [M]+. HRMS (EIꢀTOF) m/z:
Calcd for C16H27Cl3NO 354.1153; Found 354.1161 [M+H].+ See SI for 2DꢀNOESY
spectra.
Oxazoline cis-2b. Prepared according to the method C (Table 2), 380 mg, 76% from
anti-E-6b and 113 mg, 73% from syn-E-6b. Purified by flash chromatography.
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Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 7.40 (d, J = 7.4 Hz, 2H), 7.33 (t, J =
7.2 Hz, 2H), 7.28 – 7.24 (m, 1H), 6.67 (d, J = 15.9 Hz, 1H), 6.12 (dd, J = 15.7, 7.8
Hz, 1H), 5.01 – 4.95 (m, 2H), 1.80 – 1.26 (m, 8H), 0.87 (t, J = 7.0 Hz, 3H).
13C{1H}NMR δC (100 MHz, CDCl3): 162.9, 136.3, 134.1, 128.6, 128.0, 126.6, 123.4,
88.0, 87.3, 70.6, 31.5, 30.4, 25.7, 22.4, 13.9. GCꢀMS: m/z (EI): 360 [M]+. Calcd for
C17H21Cl3NO 360.0683; Found 360.0685 [M+H]+ See SI for 2DꢀNOESY spectra.
Oxazoline trans-2b. Prepared according to the method C (Table 2), 161 mg, 70%
1
from anti-Z-6b. Purified by flash chromatography. Colorless oil. HꢀNMR δH (400
MHz, CDCl3): 7.31 (d, J = 7.5 Hz, 2H), 7.24 (t, J = 7.5 Hz, 2H), 7.17 (t, J = 7.3 Hz,
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1H), 6.54 (d, J = 15.7 Hz, 1H), 6.08 ( dd, J = 15.7, 7.4 Hz, 1H), 4.59 (q, J = 7.4 Hz,
1H), 4.48 (m, 1H), 1.80 – 1.61 (m, 2H), 1.49 – 1.21 (m, 6H), 0.83 (t, J = 7.0 Hz, 3H).
13C{1H}NMR δC (100 MHz, CDCl3): 162.5, 136.1, 132.9, 128.6, 128.1, 127.0, 126.6,
89.7, 86.8, 73.8, 34.2, 31.4, 24.3, 22.4, 13.9. GCꢀMS: m/z (EI): 360 [M]+. HRMS (EIꢀ
TOF) m/z: Calcd for C17H21Cl3NO 360.0683; Found 360.0657 [M+H]+. See SI for
2DꢀNOESY spectra.
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Oxazoline cis-2c. Prepared according to the method A, 86 mg, 96% from syn-E-1c
and 96 mg, 93% from syn-E-1c in a mixture with isomer trans-2c (Table 2). Purified
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by flash chromatography. Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 7.39 – 7.24
(m, 5H), 6.66 (d, J = 15.7 Hz, 1H), 6.12 (dd, J = 15.7, 8.2 Hz, 1H), 4.93 (unresolved t,
1H), 4.57 (t, J = 8.6 Hz, 1H), 2.06 (m, 1H), 1.09 (d, J = 6.7 Hz, 3H), 0.97 (d, J = 6.7
Hz, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 163.2, 136.3, 134.5, 128.6, 128.1,
126.7, 123.0, 93.0, 87.0, 70.2, 28.8, 19.2, 19.0. GCꢀMS: m/z (EI): 331 [M]+. HRMS
(EIꢀTOF) m/z: Calcd for C15H17Cl3NO 332.0370; found 332.0343 [M+H]+. See SI for
2DꢀNOESY spectra.
Oxazoline trans-2c. Prepared according to method B, 208 mg, 90% from anti-Z-6c.
Prepared according to method C, 251 mg, 80% from anti-Z-6c. Purified by flash
chromatography. Colorless oil. 1HꢀNMR δH (400 MHz, CDCl3): 7.41 – 7.24 (m, 5H),
6.62 (d, J = 15.7 Hz, 1H), 6.16 (dd, J = 15.7, 7.4 Hz, 1H), 4.67 (unresolved t, 1H),
4.47 (t, J = 6.7 Hz, 1H), 2.04 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H), 1.03 (d, J = 6.7 Hz,
3H). 13C{1H}NMR δC (100 MHz, CDCl3): 162.5, 136.1, 132.7, 128.6, 128.1, 127.7,
126.6, 93.9, 86.8, 71.2, 32.1, 17.2, 17.1. GCꢀMS: m/z (EI): 331 [M]+. HRMS (EIꢀ
TOF) m/z: Calcd for C15H17Cl3NO 332.0370; Found 332.0344 [M+H]+. See SI for
2DꢀNOESY spectra.
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Oxazoline cis-2d. Prepared according to the method B, 111 mg, 94% from anti-E-6d
and 136 mg, 92% from syn-E-6d in a mixture with isomer trans-2d (Table 2). Purified
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by flash chromatography on silica gel. Colorless oil. HꢀNMR δH (400 MHz, CDCl3):
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7.42 – 7.23 (m, 10H), 6.72 (d, J = 15.7 Hz, 1H), 6.18 (dd, J = 15.7, 7.8 Hz, 1H), 5.23
(unresolved td, 1H), 5.07 (unresolved t, 1H), 3.05 (dd, J = 14.9, 9.4 Hz, 1H), 2.90
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(dd, J = 14.9, 4.3 Hz, 1H). C{1H}NMR δC (100 MHz, CDCl3): 162.7, 136.9, 136.1,
134.4, 129.2, 128.6, 128.5, 128.1, 126.8, 126.7, 123.2, 88.1, 86.8, 70.5, 36.9. GCꢀMS:
m/z (EI): 380 [M]+. HRMS (EIꢀTOF) m/z: Calcd for C19H17Cl3NO 380.0370; Found
380.0361 [M+H]+. See SI for 2DꢀNOESY spectra.
Oxazoline trans-2d. Prepared according to the method A (Table 2). 42 mg, 93% from
1
anti-Z-1d Purified by flash chromatography. Colorless oil. HꢀNMR δH (400 MHz,
CDCl3): 7.38 – 7.20 (m, 10H), 6.43 (d, J = 15.8 Hz, 1H), 6.05 (dd, J = 15.8, 7.4 Hz,
1H), 4.90 (unresolved ddd, 1H), 4.68 (t, J = 7.4 Hz, 1H), 3.22 (dd, J = 14.1, 6.8 Hz,
1H), 3.04 (dd, J = 14.1, 6.1 Hz, 1H). 13C{1H}NMR δC (100 MHz, CDCl3): 162.3,
136.0, 135.1, 132.9, 129.6, 128.8, 128.5, 128.1, 127.2, 126.61, 126.58, 89.6, 86.7,
72.9, 40.1. GCꢀMS: m/z (EI): 380 [M]+. HRMS (EIꢀTOF) m/z: Calcd for
C19H17Cl3NO 380.0370; Found 380.0370 [M+H]+. See SI for 2DꢀNOESY spectra.
Oxazoline cis-2e. Prepared according to the method B. 139 mg, 90% from anti-E-6e
and 308 mg, 88% from anti-E-6e as a mixture with oxazoline trans-2e (Table 2).
Purified by flash chromatography on silica gel. Colorless oil. 1HꢀNMR δH (400 MHz,
CDCl3): 7.38 – 7.14 (m, 8H), 7.05 – 7.03 (m, 2H), 6.55 (d, J = 15.8 Hz, 1H), 6.05 (d,
J = 10.2 Hz, 1H), 5.50 (dd, J = 15.8, 7.9 Hz, 1H), 5.30 (dd, J = 10.2, 7.9 Hz, 1H).
13C{1H}NMR δC (100 MHz, CDCl3): 162.6, 136.3, 135.2, 133.1, 128.6, 128.5, 128.3,
127.7, 126.5, 126.2, 124.9, 87.8, 86.7, 72.4. GCꢀMS: m/z (EI): 366 [M]+. HRMS (EIꢀ
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2DꢀNOESY spectra.
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Oxazoline trans-2e. Prepared according to the method B, 142 mg, 92% from anti-Z-
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6e (Table 2). Purified by flash chromatography on silica gel. Colorless oil. HꢀNMR
δH (400 MHz, CDCl3): 7.46 – 7.25 (m, 10H), 6.65 (d, J = 15.7 Hz, 1H), 6.31 (dd, J =
15.7, 7.8 Hz, 1H), 5.58 (d, J = 8.0 Hz, 1H), 4.88 (t, J = 7.8 Hz, 1H). 13C{1H}NMR δC
(100 MHz, CDCl3): 162.2, 138.4, 135.9, 133.6, 129.1, 129.0, 128.6, 128.2, 126.7,
126.3, 125.5, 90.3, 86.6, 77.5. GCꢀMS: m/z (EI): 366 [M]+. HRMS (EIꢀTOF) m/z:
Calcd for C18H15Cl3NO [M]+ 366.0214; Found 366.0218 [M+H]+. See SI for 2Dꢀ
NOESY spectra
Oxazoline cis-2f. Prepared according to the method C (Table 2), 272 mg, 93% from
syn-E-6f and 79 mg, 90% from anti-E-6f. Purified by flash chromatography. Colorless
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oil. HꢀNMR δH (400 MHz, CDCl3): 7.41 – 7.25 (m, 5H), 6.99 (d, J = 8.4 Hz, 2H),
6.74 (d, J = 8.4 Hz, 2H), 6.49 (d, J = 15.5 Hz, 1H), 6.05 (d, J = 10.0 Hz, 1H), 5.36
(dd, J = 15.5, 8.0 Hz, 1H), 5.28 (unresolved t, 1H), 3.75 (s, 3H). 13C{1H}NMR δC
(100 MHz, CDCl3): 162.5, 159.3, 135.4, 132.7, 129.1, 128.48, 128.45, 127.7, 126.3,
122.6, 113.8, 87.8, 86.7, 72.7, 55.2. GCꢀMS: m/z (EI): 395 [MꢀH]+. HRMS (EIꢀTOF)
m/z: Calcd for C19H17Cl3NO2 396.0319; Found 396.0317 [M+H]+. See SI for 2Dꢀ
NOESY spectra.
Oxazoline trans-2f. Prepared according to the method C (Table 2), 144 mg, 89% from
1
anti-Z-6f. Purified by flash chromatography. Colorless solid. M.p. 126 ꢀ 127°C. Hꢀ
NMR δH (400 MHz, CDCl3): 7.46 – 7.33 (m, 7H), 6.87 (d, J = 8.8 Hz, 2H), 6.57 (d, J
= 15.7 Hz, 1H), 6.15 (dd, J = 15.7, 7.7 Hz, 1H), 5.57 (d, J = 8.0 Hz, 1H), 4.84
(unresolved t, 1H), 3.82 (s, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 162.1, 159.7,
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138.5, 133.2, 129.1, 128.9, 128.7, 128.0, 125.6, 124.1, 114.0, 90.4, 86.6, 77.7, 55.3.
GCꢀMS: m/z (EI): 395 [MꢀH]+. Anal. Calcd, for C19H16Cl3NO2·1/3 H2O: C, 56.67; H,
4.17; N, 3.48; Found: C, 56.88; H, 4.11; N, 3.38. HRMS (EIꢀTOF) m/z: Calcd for
C19H17Cl3NO2 396.0319; Found 396.0307 [M+H]+. See SI for 2DꢀNOESY spectra.
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General procedure for the synthesis of amino alcohols 7.
To a solution of oxazoline 2 (1 mmol) in EtOH (2 mL) 6 M aq. HCl (2 mL) was
added and the reaction mixture was stirred at r.t. for 1–2 h, then refluxed for 10 h.
Resulting solution was cooled to r.t. and concentrated in vacuum. The residue was
dissolved in a mixture of saturated aq. NaHCO3 (10 mL) and EtOAc (10 mL). Boc2O
(1.2 mmol, 1.2 equiv.) was added to the resulting biphasic mixture and vigorous
stirring was continued overnight. Organic phase was separated and washed with water
and brine, dried with Na2SO4 and concentrated in vacuum. The residue was purified
by column chromatography on silica gel eluting with a mixture of hexane and ethyl
acetate (gradient 4:1 to 1:1) to afford product 7.
N-Boc protected amino alcohol syn-7b. Prepared according to the general procedure,
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305 mg, 87%. Colorless solid. M.p. 56 ꢀ 57°C. HꢀNMR δH (400 MHz, CDCl3): 7.39
– 7.21 (m, 5H), 6.58 (d, J = 15.7 Hz, 1H), 6.18 (dd, J = 15.7, 5.9 Hz, 1H), 5.00 (bs,
1H), 4.36 – 4.22 (m, 1H), 3.79 – 3.69 (m, 1H), 1.96 (bs, 1H), 1.59 – 1.41 (m, 2H),
1.46 (s, 9H), 1.41 – 1.24 (m, 6H), 0.89 (t, J = 7.0 Hz, 3H). 13C{1H}NMR δC (100
MHz, CDCl3): 155.9, 136.5, 131.3, 128.5, 128.3, 127.6, 126.4, 79.6, 73.7, 56.5, 33.7,
31.7, 28.4, 25.3, 22.5, 14.0. Anal. calcd for C20H31NO3·0.2 H2O: C, 71.27; H, 9.39; N,
4.16; Found: C, 71.04; H, 9.19; N, 4.04. HRMS (EIꢀTOF) m/z: Calcd for
C20H31NO3Na 356.2196; Found 356.2171 [M+Na]+.
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N-Boc protected amino alcohol anti-7b. Prepared according to the general procedure,
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7.22 (m, 5H), 6.59 (d, J = 16.0 Hz, 1H), 6.17 (dd, J = 16.0, 7.0 Hz, 1H), 5.10 (bs, 1H),
4.33 – 4.27 (m, 1H), 3.80 – 3.72 (m, 1H), 1.86 (bs, 1H), 1.57 – 1.22 (m, 8H), 1.45 (s,
9H), 0.88 (t, J = 7.0 Hz, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 155.5, 136.6,
133.0, 128.5, 127.7, 126.5, 124.9, 79.7, 74.3, 57.1, 34.1, 31.7, 28.4, 25.5, 22.5, 14.0.
Anal. calcd for C20H31NO3·0.25 H2O: C, 71.08; H, 9.39; N, 4.14; Found: C, 71.34; H,
9.26; N, 4.06. HRMS (EIꢀTOF) m/z: Calcd for C20H31NO3Na 356.2196; Found
356.2170 [M+Na]+.
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N-Boc protected amino alcohol syn-7c. Prepared yield according to the general
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procedure, 118 mg, 83%. Colorless oil. HꢀNMR δH (400 MHz, CDCl3): 7.39 (d, J =
7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.63 (d, J = 15.8 Hz,
1H), 6.21 (dd, J = 16.0, 7.4 Hz, 1H), 5.23 (bs, 1H), 4.49 – 4.40 (m, 1H), 3.37 – 3.31
(m, 1H), 1.87 (bs, 1H), 1.71 – 1.61 (m, 1H), 1.45 (s, 9H), 1.01 (d, J = 6.5 Hz, 3H),
0.97 (d, J = 6.5 Hz, 3H). 13C{1H}NMR δC (100 MHz, CDCl3): 155.9, 136.6, 131.1,
128.8, 128.5, 127.6, 126.4, 79.6, 79.0, 54.4, 30.5, 28.3, 19.2, 18.2. Oil. HRMS (EIꢀ
TOF) m/z: Calcd for C18H27NO3Na 328.1883; Found 328.1856 [M+Na]+.
N-Boc protected amino alcohol anti-7c. Prepared according to the general procedure,
42 mg, 88%. Colorless oil. 1HꢀNMR δH (400 MHz, CDCl3): 7.38 (d, J = 7.4 Hz, 2H),
7.31 (t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 16.0 Hz, 1H), 6.21 (dd, J
= 15.8, 7.4 Hz, 1H), 5.24 (bs, 1H), 4.49 – 4.39 (m, 1H), 3.39 – 3.35 (m, 1H), 1.86 (bs,
1H), 1.72 – 1.60 (m, 1H), 1.45 (s, 9H), 1.01 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz,
3H). 13C{1H}NMR δC (100 MHz, CDCl3): 155.2, 136.6, 132.9, 128.5, 127.7, 126.5,
124.7, 79.7, 79.5, 54.6, 31.4, 28.4, 19.0, 18.7. HRMS (EIꢀTOF) m/z: Calcd for
C18H27NO3Na 328.1883; Found 328.1857 [M+Na]+.
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N-Boc protected amino alcohol anti-7d. Prepared according to the general procedure,
33 mg, 89%. Colorlessn oil. 1HꢀNMR δH (400 MHz, CDCl3): 7.40 (d, J = 8.0 Hz,
2H), 7.34 – 7.20 (m, 8H), 6.62 (d, J = 15.8 Hz, 1H), 6.26 (dd, J = 16.0, 7.8 Hz, 1H),
5.18 (d, J = 8.2 Hz, 1H), 4.36 – 4.26 (m, 1H), 4.06 – 3.94 (m, 1H), 2.82 (dd, J = 13.7,
4.0 Hz, 1H), 2.69 (dd, J = 13.7, 9.2 Hz, 1H), 2.23 (bs, 1H), 1.44 (s, 9H).
13C{1H}NMR δC (100 MHz, CDCl3): 155.4, 137.8, 136.6, 133.4, 129.3, 128.64,
128.55, 127.8, 126.6, 126.5, 124.9, 79.7, 75.0, 57.1, 40.6, 28.4. HRMS (EIꢀTOF) m/z:
Calcd for C22H27NO3Na 376.1183; Found 376.1860 [M+Na]+.
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N-Boc protected amino alcohol syn-7e. Prepared according to the general procedure
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(149 mg, 90%) as an oil. HꢀNMR δH (400 MHz, CDCl3):7.39 – 7.22 (m, 10H), 6.54
(d, J = 16.0 Hz, 1H), 6.19 (dd, J = 16.0, 5.9 Hz, 1H), 4.95 (d, J = 7.4 Hz, 1H), 4.86 –
4.82 (m, 1H), 4.61 – 4.55 (m, 1H), 2.87 (bs, 1H), 1.38 (s, 9H). 13C{1H}NMR δC (100
MHz, CDCl3): 155.8, 140.7, 136.5, 131.7, 128.5, 128.3, 127.8, 127.7, 127.0, 126.5,
79.8, 76.1, 58.3, 28.3. HRMS (EIꢀTOF) m/z: Calcd for C21H25NO3Na 362.1727;
Found 362.1702 [M+Na]+.
N-Boc protected amino alcohol anti-7e. Prepared according to the general procedure
1
(64 mg, 87% yield) as an oil. HꢀNMR δH (400 MHz, CDCl3): 7.39 – 7.15 (m, 10H),
6.35 (d, J = 16.0 Hz, 1H), 5.97 (dd, J = 16.0, 5.7 Hz, 1H), 4.95 (d, J = 7.4 Hz, 1H),
4.91 – 4.82 (m, 1H), 4.59 – 4.46 (m, 1H), 2.97 (bs, 1H), 1.38 (s, 9H). 13C{1H}NMR
δC (100 MHz, CDCl3): 155.8, 146.7, 140.4, 136.5, 132.6, 128.5, 128.2, 127.7, 126.4,
126.3, 124.8, 80.0, 76.6, 58.5, 28.4. HRMS (EIꢀTOF) m/z: Calcd for C21H25NO3Na
362.1727; Found 362.1700 [M+Na]+.
DFT calculations of the reaction energy profile. All calculations were performed
using Gaussian 09.14 Geometry optimizations were performed without any restrains
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using density functional theory method B3LYP with 6ꢀ31++g(d,p) basis set (for all
atoms). For compounds that had multiple conformations lowestꢀenergy conformation
was found by comparing the structures optimized from different starting points.
Stationary points were verified to be real minima (zero imaginary frequency) or
transition states (one imaginary frequency) by performing frequency calculations at
the same level of theory. Thermochemical analysis was done at 298.15 K. Transition
states were located using either Berny or QST2 algorithm. Intrinsic reaction
coordinates (IRC) were calculated for the transition states to confirm that the saddle
point connected the correct reactant and product on the potential energy surface.
Singleꢀpoint energy calculations were performed on the stationary points using a
larger basis set 6ꢀ311++G(3df,2p). Thermal correction to Gibbs free energy from
lower level frequency calculations combined with singleꢀpoint energies was used to
describe reaction energetics.
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Supporting Information.
Full set of bisꢀimidate 1 cyclization results and DFT calculations. Copies of NMR
spectra of compounds 1-7. This material is available free of charge via the Internet at
http://pubs.acs.org/."
Corresponding author
Email: aigars@osi.lv
Acknowledgements
This work has been supported by the European Social Fund within the project
«Support for the implementation of doctoral studies at Riga Technical University».
Financial support from the European Regional Development Fond (grant number
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ERAF 2010/2DP/2.1.1.1.0./10/APIA/ VIAA/074) is gratefully acknowledged. We
thank A. Maleckis for assistance in manuscript preparation and Prof. E. Liepins for 2ꢀ
NMR investigations.
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