syn-Diastereoselective glycolate aldol addition reactions of an N(3)-(p-methoxyphenoxy)acetyloxazolidine-2-thione

Article abstract of DOI:10.1016/j.tetasy.2016.11.001

An N₃-(p-methoxyphenoxy)acetyloxazolidine-2-thione has been synthesized and employed in glycolate asymmetric aldol addition reactions with aromatic and aliphatic aldehydes. It was determined that the titanium tetrachloride medicated aldol reaction afforded diastereoselectivities that ranged from 75:25 to 94:6 when the reaction was conducted at ?78?°C. The absolute stereochemistry of the aldol adducts was determined by¹H NMR spectroscopy and X-ray crystallography. The¹H NMR spectra of the aldol adducts contained a signal (the α-proton of the glycolate position of the aldol side chain) that was highly deshielded due to conformational restriction about the N(3)-(p-methoxyphenoxy)acetyl side chain and the oxazolidine-2-thione auxiliary.

Full text of DOI:10.1016/j.tetasy.2016.11.001

Tetrahedron: Asymmetry xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
syn-Diastereoselective glycolate aldol addition reactions of an
N(3)-(p-methoxyphenoxy)acetyloxazolidine-2-thione
Craig S. Haynes, Cassie A. Goodman, Juandah Bruce, Sarah C. Genin, Brad J. Austermuehle, Victor L. Leong,
⇑
Austin R. Leise, Robert Larson, Christopher G. Hamaker, Shawn R. Hitchcock
Department of Chemistry, Illinois State University, Normal, IL 61790-4160, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An N3-(p-methoxyphenoxy)acetyloxazolidine-2-thione has been synthesized and employed in glycolate
asymmetric aldol addition reactions with aromatic and aliphatic aldehydes. It was determined that the
titanium tetrachloride medicated aldol reaction afforded diastereoselectivities that ranged from 75:25
to 94:6 when the reaction was conducted at À78 °C. The absolute stereochemistry of the aldol adducts
was determined by 1H NMR spectroscopy and X-ray crystallography. The 1H NMR spectra of the aldol
Received 22 September 2016
Accepted 3 November 2016
Available online xxxx
adducts contained a signal (the a-proton of the glycolate position of the aldol side chain) that was highly
deshielded due to conformational restriction about the N(3)-(p-methoxyphenoxy)acetyl side chain and
the oxazolidine-2-thione auxiliary.
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
group would be useful in the Crimmins based oxazolidine-2-thione
based glycolate system. It is in this context that the application of
The chiral auxiliary guided asymmetric glycolate aldol addition
reaction has been proven to be a versatile reaction that has allowed
for the synthesis of a diverse array of natural products.1–3 The sem-
inal efforts of Evans et al.1a in this area employed an N(3)-p-
an N(3)-p-methoxyphenoxyacetyloxazolidinone in the asymmetric
glycolate aldol addition reaction, and the observation of a highly
deshielded a-proton of the glycolate system is described herein.
methoxybenzyloxyacetyl-oxazolidin-2-one auxiliary
1 in the
2. Results and discussion
synthesis of the polyether antibiotic X-206 (Chart 1).1a This work
would be followed by the works of Crimmins and Choy,2 Hulme
and Rosser,3 Davies et al.,4 and Roush Owens,5 and Seeberger.6
Crimmins et al. later employed oxazolidine-2-thiones as effective
chiral auxiliaries for aldol addition reactions7a–d and the glycolate
aldol reactions.7e–h Romea, Urpí et al.8 developed a highly stereos-
elective anti-aldol addition using a thiazolidine-2-thione system.
These glycolate systems have all been used to great success as well
as other chiral auxiliary systems.9–12
A key component of interest is the glycolate protecting group.
The benzyl group and the related p-methoxybenzyl group are the
most commonly used protecting groups for the glycolate side chain
(see Chart 1 references).13,14 In contrast, the p-methoxyphenoxy
group is a protecting group that has not been applied as often. It
is a robust protecting group that can be orthogonally removed in
the presence of a myriad of functional groups.15 We have previ-
ously used this protecting group in glycolate aldol addition reac-
tions with Ephedra based oxadiazinones.16 Based on this work,
we became interested in determining if the p-methoxyphenoxy
The oxazolidine-2-thione auxiliary 10 was prepared as
described by Crimmins et al. by reacting (S)-phenylalanine with
thiophosgene in dichloromethane in the presence of triethy-
lamine.17a This process was carried out on 15 g scale and the pro-
duct was purified by flash chromatography (92%). This compound
was then treated with p-methoxyphenoxyacetic acid by reaction
with EDC and catalytic DMAP17b to afford the N(3)-p-methoxy
phenoxyacetyloxazolidine-2-thione 11 in 69% yield after
chromatography and recrystallization (Scheme 1). Crystals
suitable for X-ray crystallographic diffraction were grown by the
slow diffusion of hexanes into an ethyl acetate solution of 11
(Scheme 1).
With the oxazoldine-2-thione in hand, we conducted a series of
titanium mediated glycolate aldol addition reactions using reaction
conditions modified from those described by Crimmins et al.18
Thus, the acylated thione 11 was dissolved in dichloromethane,
cooled to À78 °C, reacted with TiCl4, and subsequently treated with
triethylamine. The aldehyde was then added to this mixture to
afford the final aldol addition product after purification by flash
chromatography or recrystallization (Table 1). The absolute
⇑
Corresponding author. Tel.: 309 438 7854; fax: 309 438 5538.
E-mail address: hitchcock@ilstu.edu (S.R. Hitchcock).
http://dx.doi.org/10.1016/j.tetasy.2016.11.001
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
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2
C. S. Haynes et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
O
O
O
O
O
O
O
O
OPMB
O
OBn
OBn
O
N
O
N
O
N
N
O
1
2
3
4
Ph
CH3
Evans, 19891a
CH2Ph
CH2Ph
CH2Ph
Crimmins and Choy, 19972
Hulme and Rosser, 20023
Davies et al., 20044
S
O
O
O
O
S
O
O
OPiv
OPMB
S
N
OMOM
OBn
O
N
O
N
O
N
5
6
7
8
CH2Ph
Roush and Owen, 20055
Chart 1. Oxazolidinone, oxazolidine-2-thione, and thiazolidine-2-thione glycolates.
CH2Ph
CH2Ph
Seeberger et al., 20086
Crimmins et al., 20087
Romea, Urpi, et al., 20128
MeO
OCH2CO2H
O
O
S
S
H
(PMPOCH2CO2H)
HO
NH2
Cl2C=S, Et3N
CH2Cl2
O
N
O
N
OCH3
EDC, DMAP, CH2Cl2
CH2Ph
CH2Ph
CH2Ph
92%
69%
9
10
11
(S)-phenylalaninol
Scheme 1. Synthesis and X-ray crystal structure of oxazolidine-2-thione 11.
stereochemistry of the glycolate aldol adduct 12a was confirmed
by X-ray crystallographic analysis (Fig. 1).
chemistry of the product, the transition state model that was pro-
posed by Crimmins and McDougall was invoked (Scheme 3).
Over the course of analyzing the 500 MHz 1H NMR spectra of
Analysis of the 1H NMR spectrum of 12a revealed that the
3JHa/Hb coupling constant between the glycolytic protons Ha
and Hb was 4.65 Hz. This observation suggested a syn-configu-
ration for 12a,19 which was in agreement with the X-ray crys-
tal structure. By correlation, the syn-configuration was assigned
for analogues 12b–12i as evidenced by the coupling constants
listed in Table 1.
aldol adducts 12a–i, it was determined that the glycolic a-proton
was not in the expected region of the NMR spectrum near
6.0 ppm (Fig. 2). Crimmins and McDougall7h had prepared a syn-
glycolate oxazolidine-2-thione derivative 16 in which the glycolic
a
-proton appeared at a resonance of 6.04 ppm. A COSY 1H NMR
spectrum revealed that the signal in question appeared at
The cleavage of 12a with methanol and imidazole yielded the
methyl ester in 87% yield (Scheme 2). The specific rotation of the
7.24 ppm in aldol adduct 12a. The deviation of the chemical shift
of the
a
-proton from the expected value was attributed to the
-proton.
methyl ester was determined to be [
a]
24 = À28.6 (c 0.688, CHCl3).
presence of a deshielding region proximal to the a
D
This was in agreement with the literature value of the (2S,3R)-
The origin of the deshielding effect was unclear, but may be due
to the glycolytic proton being in the deshielding region of an aro-
matic system. A conformational evaluation of 12a provided some
enantiomer {[
a]
D
24 = À25.0 (c 0.35, CHCl3)} that had been previously
prepared by our group.16 Based on the observed (2S,3R)-stereo-
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C. S. Haynes et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
3
Table 1
Asymmetric glycolate aldol addition reaction with 11
OCH3
R
O
Ha
Hb
O
O
S
S
OH
TiCl4, TEA, RCHO
O
N
O
OCH3
O
N
CH2Cl2, -78 oC
12a-i
11
CH2Ph
CH2Ph
Entry
Aldehyde, RCHO
Adduct
Crude dra
3J(Ha–Hb) (Hz)
Yieldb (%)
1
2
3
4
5
6
7
8
9
C6H5A
12a
12b
12c
12d
12e
12f
12g
12h
12i
92:8
91:9
94:6
75:25
88:12
93:7
4.7
3.8
3.8
5.7
7.1
4.6
4.1
2.7
8.3
71
47
83
65
82
52
89
95
56
p-ClC6H4A
p-BrC6H4A
o-FC6H4A
m-NO2C6H4A
2-C10H7A
(E)-PhCH@CHA
(CH3)2CHCH2A
(CH3)3CA
94:6
91:9
62:38c
a
b
c
The crude diastereomeric ratios were determined by 1H NMR spectroscopy.
Isolated chemical yield of the dominant isomer (P95:5) after flash chromatography or recrystallization.
The trimethylacetaldehyde example failed to react at À78 °C. The reaction was carried out at À25 °C. Please see Section 4.
Figure 1. X-ray crystal structure of glycolate aldol adduct 12a.
OH
O
arrangement may well be present in the solution state due to
favorable dipole minimization. Based on this configurational
arrangement, the benzyl substituent of the oxazolidine-2-thione
is not suspected to be the origin of the deshielding effect; its prox-
imidazole, CH3OH
87%
Ph
MeO
12a
OPMP
13
imity to the deshielded
a-proton is not sufficient. The appendant
Scheme 2. Stereochemical determination.
phenyl ring of the N(3)-aldol side chain in 12a is not suspected
since all of the aldol adducts 12a–i share this deshielded proton,
regardless of the presence of an aryl group 12a–g or alkyl group
12h–i. Specifically, oxazolidine-2-thione 12i possesses a tert-butyl
insight into the unusual chemical shift value. The X-ray crystal
structure of 12a suggests that the N(3)-amide carbonyl and the
thiocarbonyl group share an anti-parallel arrangement. This same
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4
C. S. Haynes et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
OCH3
OCH3
OCH3
group at the end of the N(3)-aldol side chain, and the observed
chemical shift of this deshielded proton is 7.13 ppm (Fig. 2). Based
on these observations, it is proposed that the conformational
restriction about the oxazolidine-2-thione auxiliary and the aldol
side chain causes the aromatic ring of the p-methoxyphenoxy
group to orient in such a way that the glycolytic proton is
deshielded. This argument is supported by the fact that the
methanolysis of 12a to give 13 causes the glycolytic proton to
appear at 5.07 ppm in the cleaved ester.
H
H
H
O
O
O
OH
OH
5.07 ppm
OH
7.13ppm
S
S
7.24 ppm
O
N
O
CH3O
O
O
N
O
CH2Ph
CH2Ph
12i
a-proton of glycolate aldol adducts.
12a
13
3. Conclusion
Figure 2. Comparison of the
In conclusion, the p-methoxyphenoxy group has much potential
as a protecting group in glycolate chemistry as it can be removed
under conditions orthogonal to many alcohol protecting groups.
We have prepared an N(3)-p-methoxyphenoxyacetyloxazolidine-
2-thione and applied it to asymmetric glycolate aldol addition
reactions. The absolute stereochemistry was determined and con-
firmed through a combination of 1H NMR spectroscopy and X-ray
(m, 2H), 4.95–5.01 (m, 1H), 5.55 (q, J = 17.8 Hz, 2H), 6.83–6.89
(m, 2H), 6.91–6.95 (m, 2H), 7.21–7.24 (m, 2H), 7.28–7.37 (m,
3H). 13C NMR (125 MHz, CDCl3): d 37.54, 55.72, 59.90, 70.22,
71.65, 114.79, 116.04, 127.58, 129.12, 129.42, 134.90, 151.96,
154.51, 169.51, 184.85. IR (nujol mull): 1707, 1365, 1329, 1196,
754, 733, 700 cmÀ1. [
a] -
23 = +85.0 (c 1.02, CHCl3). ESI HRMS for C19
D
crystallography. It was determined that the
a-glycolytic proton
H
19NO4S: calcd (M+H+) 358.1121, found 358.1113.
of aldol adducts 12a–i was highly deshielded. The origin of the
deshielding is postulated to be due to the presence of the highly
deshielded glycolic
can be attributed to the presence of the p-methoxyphenoxy group.
a-proton in the aldol adducts, which in turn
4.3. General procedure for the asymmetric glycolate aldol
addition reaction
In a 250 mL, flame dried, nitrogen purged round bottom flask
equipped with a magnetic stirrer bar were placed the oxazolidin-
2-thione 11 (0.500 g, 1.40 mmol, 1 equiv), and CH2Cl2 (10 mL)
and cooled to À78 °C before the addition of TiCl4 (0.160 mL,
1.54 mmol). The reactants were allowed stir for 30 min. Then the
addition of TEA (0.50 mL, 3.50 mmol) then occurred and was
allowed to stir for one hour. The aldehyde (2.52 mmol) was then
added and allowed to stir for 6 h at À78 °C. The reaction was
quenched with brine (3 mL). The product was extracted by dilution
with CH2Cl2 (50 mL) with one treatment of 1 M HCl (30 mL) and
brine (30 mL). The crude product was purified by flash column
chromatography.
4. Experimental
4.1. General
All chemical reagents were used as purchased. All reaction vessels
were flame dried and purged under a nitrogen atmosphere. All NMR
spectra were recorded in CDCl3 and reported in parts per million (d
scale) with tetramethylsilane as an internal standard (d = 0 ppm,
1H) or deuterated chloroform as a standard (d = 77.0 ppm, 13C). Opti-
cal rotation data were collected ona JASCOP-1010digital polarimeter
operating at 589 nm in an 8 Â 100 mm cell. Melting points were
determined using a Laboratory Devices Mel-Temp apparatus and
are uncorrected.
4.3.1. (2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-
3-phenylpropanoyl]oxazolidine-2-thione 12a
4.2. (S)-4-Benzyl-3-[(p-methoxyphenoxy)acetyl]oxazolidine-2-
The title compound was purified by flash column chromatogra-
phy (hexanes:EtOAc, 75:25) to yield 0.583 g (1.26 mmol, 89%) of
white crystals. Large scale preparation (5 g): In a 1 L, flame dried,
nitrogen purged round bottom flask equipped with a magnetic stir-
rer bar were placed 11 (5.00 g, 1.40 mmol), and CH2Cl2 (140 mL)
and then cooled to À78 °C before the addition of TiCl4 (1.60 mL,
1.54 mmol). The reactants were allowed to stir for 45 min. The
addition of TEA (0.50 mL, 3.50 mmol) occurred and was allowed
to stir for 75 min. The benzaldehyde (2.60 mL, 2.36 mmol) was
then added and allowed to stir for 6 h at À78 °C. The reaction
was quenched with brine (5 mL). The product was extracted by
dilution with CH2Cl2 (80 mL) and treated with 1 M HCl (35 mL)
and brine (35 mL). The extracted crude product was then dried
(MgSO4). The crude product was determined to have a diastereos-
thione 11
In a 100 mL, flame dried, nitrogen purged round bottom flask
equipped with a magnetic stirrer bar (S)-4-benzyl-1,3-oxazo-
lidine-2-thione (15.0 g, 77.9 mmol), CH2Cl2 (312 mL), 1-ethyl-3-
(3-dimethylamino propyl)carbodiimide (EDC, 16.4 g, 85.5 mmol),
DMAP (2.38 g, 19.5 mmol), and p-methoxyphenoxyacetic acid
(14.2 g, 77.9 mmol) was added sequentially and stirred overnight.
The reaction was quenched, extracted and the solvents removed
in vacuo. The crude product was purified by flash column chro-
matography (hexanes:EtOAc, gradient: 80:20 to 65:35) to yield
19.3 g (69%) of the title compound as an off-white solid. Melting
point: 86–88 °C. 1H NMR (400 MHz, CDCl3): d 2.83 (dd, J = 10.0,
3.3 Hz, 1H), 3.33 (dd, J = 10.0, 3.3 Hz, 1H), 3.78 (s, 3H), 4.40–4.45
R
R
H
H
OPMP
H
OPMP
TiLn
H
OH
S
O
O
TiLn
O
S
H
S
S
O
OPMP
R
O
N
TiLn
N
O
O
N
O
O
O
N
OPMP
Bn
Bn
14
Bn
Bn
15
12
Scheme 3. Proposed transition state for the formation of the major diastereomer.
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C. S. Haynes et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
5
electivity of 92:8 by 1H NMR spectroscopy and was recrystallized
from hexanes and ethyl acetate to yield 4.60 g (9.94 mmol, 71%)
of white crystals of 12a in a ratio of P95:5 favoring the major
diastereomer. Melting point: 154–157 °C. 1H NMR (500 MHz,
CDCl3): d 2.78 (dd, J = 13.4, 9.9 Hz, 1H), 3.19 (dd, J = 13.4, 3.1 Hz,
1H), 3.77 (s, 3H), 3.89 (dd, J = 8.5, 7.3 Hz, 1H), 4.24 (dd, J = 8.9,
1.3 Hz, 1H), 4.62–4.66 (m, 1H), 5.27 (d. J = 4.7 Hz, 1H), 6.84 (d,
J = 9.4 Hz, 2H), 6.99 (d, J = 8.45 Hz, 2H), 7.15 (d, J = 6.15 Hz, 1H),
7.24 (d, J = 4.7 Hz, 1H), 7.33 (m, 8H), 7.55 (d, J = 7.5 Hz, 1H). 13C
NMR (125 MHz, CDCl3): d 3.4, 55.7, 61.0, 70.8, 75.5, 79.7, 114.8,
117.1, 126.7, 127.5, 128.3, 128.5, 129.0, 129.5, 134.8, 138.2,
151.2, 154.9, 170.8, 184.9. IR (nujol mull): 3550, 1720, 1231,
122–124 °C. 1H NMR (500 MHz, CDCl3): d 2.69 (dd, J = 10.2,
13.4 Hz, 1H), 3.11–3.16 (m, 2H), 3.68 (s, 3H), 3.93 (t, J = 8.0 Hz,
1H), 4.19 (d, J = 9.3 Hz, 1H), 4.65–4.69 (m, 1H), 5.44 (t, J = 5.7 Hz,
1H), 6.76 (d, J = 9.2 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.98–6.94 (m,
1H), 7.06–7.11 (m, 4H), 7.17–7.24 (m, 4H), 7.61 (t, J = 7.1 Hz, 1H).
13C NMR (125 MHz, CDCl3): d 37.3, 55.6, 61.2, 69.4 (d, JC–F
=
1.8 Hz), 78.7, 114.8, 114.9 (d, JC–F = 21.8 Hz), 116.8, 124.4
(d, JC–F = 2.6 Hz), 125.3 (d, JC–F = 12.7 Hz), 127.4, 128.9, 129.4
(d, JC–F = 3.64 Hz), 129.4, 130.1 (d, JC–F = 8.2 Hz), 134.8, 154.0,
154.77, 160.0 (d, JC–F = 247.1 Hz), 170.2, 184.7 ppm. IR (CHCl3):
3414, 2837, 1705, 1507, 1365 1329, 1108, 828, 702 cmÀ1. [
a]
=
24
D
+16 (c 1.00, CHCl3). ESI HRMS for C26H24FNO5S: calc’d (M+H+)
1062, 829, 742, 692 cmÀ1. [
a
]
D
23 = +148 (c 1.00, CHCl3). Melting
482.1439, found 482.1426.
point: 154–157 °C. ESI-HRMS for C26H25NO5S: calc’d (M+H+)
464.1526; found 464.1522.
4.3.5. (2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-
3-(m-nitrophenyl)propanoyl]oxazolidine-2-thione 12e
4.3.2. (2S,3R)-4-Benzyl-3-((p-chlorophenyl)-3-hydroxy-2-(p-
methoxyphenoxy)propanoyl)oxazolidine-2-thione 12b
The title compound was obtained as mixture of diastereomers
with a crude ratio of 88:12 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The title compound
was purified by flash column chromatography (hexanes:EtOAc,
75:25) to yield 0.586 g (1.15 mmol, 82%) in a ratio of P95:5 favor-
ing the major diastereomer as light yellow crystals. Melting point:
142–143 °C. 1H NMR (500 MHz, CDCl3): d 2.58 (dd, J = 13.4, 9.8 Hz,
1H), 3.13–3.17 (m, 2H), 3.66 (s, 3H), 4.22 (dd, J = 8.9, 7.5 Hz, 2H),
4.33 (dd, J = 9.4, 2.1 Hz, 1H), 4.84–4.84 (m, 1H), 5.41 (dd, J = 7.1,
2.9 Hz, 1H), 6.71–6.77, (m, 4H), 7.07 (d, J = 7.1 Hz, 1H), 7.17–7.26
(m, 4H), 7.48, (t, J = 15.8, 7.9 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 8.09
(dd, J = 5.1, 2.2 Hz, 1H), and 8.37–8.38 (m, 1H). 13C NMR
(125 MHz, CDCl3): d 37.4, 55.7, 60.9, 71.3, 73.0, 79.1, 114.9,
116.7, 121.6, 123.1, 127.7, 129.1, 129.3, 129.5, 132.4, 134.5,
141.6, 148.3, 150.8, 155.2, 169.6, 185.2 ppm. IR (CHCl3): 3404,
The title compound was obtained as mixture of diastereomers
with a crude ratio of 91:9 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The crude product
was purified by flash column chromatography (hexanes:EtOAc,
75:25) to yield 0.331 g (0.667 mmol, 48%) in a ratio of P95:5
favoring the major diastereomer. Melting point: 153–155 °C. 1H
NMR (500 MHz, CDCl3): d 2.77 (dd, J = 13.5, 9.9 Hz, 1H), 3.18 (dd,
J = 13.5, 3.15 Hz, 1H), 3.74 (s, 3H), 4.05 (dd, J = 8.9, 6.5 Hz, 1H),
4.31 (dd, J = 9.3, 1.7 Hz, 1H), 4.71–4.75 (m, 1H), 5.28 (d,
J = 3.8 Hz, 1H), 8.80 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H),
7.13 (d, J = 6.7 Hz, 1H), 7.18 (d, J = 3.8 Hz, 1 H), 7.26–7.33 (m,
7H), 7.48 (d, J = 8.7 Hz, 2H). 13C NMR (125 MHz, CDCl3): d 37.4,
55.7, 61.0, 71.0, 74.2, 79.5, 114.8, 115.0, 117.0, 127.6, 128.0,
128.5, 129.1, 129.5, 134.2, 134.7, 137.2, 151.0, 155.0, 170.3,
185.0. IR (CHCl3): 3478, 2837, 1702, 1506, 1368, 1328, 1092, 822,
2922, 1709, 1530, 1350, 1327, 1070, 827, 702 cmÀ1. [ 25 = +85 (c
a]
D
1.10, CHCl3). ESI HRMS for C26H24N2O7S: calc’d (M+H+) 498.1143,
found 498.1136.
703 cmÀ1. [ 24 = +124 (c 1.00, CHCl3). ESI HRMS for C26H24ClNO5-
a]
D
S: calc’d (M+H+) 498.1143, found 498.1136.
4.3.6. (2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-
3-(2-naphthyl)propanoyl]oxazolidine -2-thione 12f
4.3.3. (2S,3R)-4-Benzyl-3-[(p-bromophenyl)-3-hydroxy-2-(p-
methoxyphenoxy)propanoyl]oxazolidine-2-thione 12c
The title compound was obtained as mixture of diastereomers
with a crude ratio of 94:6 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The product was
purified by flash column chromatography (hexanes:EtOAc, 75:25)
to yield 0.625 g (1.16 mmol, 83%) in a ratio of P95:5 favoring
the major diastereomer as a tan powder. Melting point: 147–
150 °C. 1H NMR (500 MHz, CDCl3): d 2.77 (dd, J = 13.4, 9.8, 1H),
3.18 (dd, J = 13.4, 2.9 Hz, 1 H), 3.74 (s, 3H), 4.05 (dd, J = 16.4,
8.2 Hz, 1 H), 4.31(d, J = 9.2 Hz, 1 H), 4.73 (t, J = 8.2 Hz, 1H), 5.26
(d, J = 3.7 Hz, 1 H), 6.81(d, J = 8.8 Hz, 2H), 6.90 (d, J = 9.3 Hz, 2H),
7.13 (d, J = 6.7 Hz, 2 H), 7.18 (d, J = 3.65 Hz, 1H), 7.28 (m, 2H),
7.42 (d, J = 8.8 Hz, 2H), 7.48 ppm (d, J = 8.3 Hz, 2H). 13C NMR
(125 MHz, CDCl3): d 37.4, 55.8, 61.04, 71.0, 74.4, 79.48, 114.9,
117.0, 122.4, 127.6, 128.3, 129.1, 129.5, 131.5, 134.7, 137.7,
151.0, 155.1, 170.3, and 185.0 ppm. IR (CHCl3): 3451, 2957, 1708,
The title compound was obtained as mixture of diastereomers
with a crude ratio of 93:7 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The title compound
was purified by recrystallization from ethyl acetate and hexanes to
yield the title compound (0.723 mmol, 52%) in a ratio of P95:5
favoring the major diastereomer white crystals. Melting point:
160–162 °C. 1H NMR (500 MHz, CDCl3): d 2.66 (dd, J = 13.4,
9.8 Hz, 1H), 3.06 (dd, J = 13.4, 3.16 Hz, 1H), 3.10 (d, J = 6.3 Hz,
1H), 3.41 (dd, J = 8.9, 7.5 Hz, 1H), 3.66 (s, 3H), 4.01 (dd, J = 9.2,
1.6 Hz, 1H), 4.49–4.53 (m, 1H), 5.33–5.36 (m, 1H), 6.73 (d,
J = 9.2 Hz, 2H), 6.90 (d, J = 9.2 Hz, 2H), 7.16–7.22 (m, 3H), 7.25 (d,
J = 4.6 Hz, 1H), 7.38–7.41 (m, 2H), 7.73–7.77 (m, 3H), 7.86 (s, 1H)
ppm. 13C NMR (125 MHz, CDCl3): d 37.4, 55.7, 61.0, 10.6, 75.6,
79.8, 114.8, 117.1, 124.4, 125.7, 126.4, 126.4, 127.5, 127.7, 128.0,
128.2, 129.0, 129.4, 132.9, 133.3, 134.7, 135.8, 151.2, 154.9,
170.8, 184.9 ppm. IR (CHCl3): 3444, 2930, 1704, 1507, 1364,
1508, 1367, 1328, 1070, 829, 702 cmÀ1. [
a]
23 = +130 (c 1.00, CHCl3).
1328, 1108, 825, 702 cmÀ1. [ 23 = +166 (c 1.00, CHCl3). ESI HRMS
a]
D
D
ESI HRMS for
542.0632.
C
26H24BrNO5S: calc’d (M+H+) 542.0638, found
for C30H27NO5S: calc’d (M+H+) 514.1688, found 514.1689.
4.3.7. (2S,3R,E)-1-[(S)-4-Benzyl-(3-hydroxy-2-(p-methoxy-
phenoxy)-5-phenyl-4-pentenoyl)oxazolidine-2-thione 12g
The title compound was obtained as mixture of diastereomers
with a crude ratio of 94:6 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The title com-
pound was purified by flash column chromatography (hexanes:
EtOAc, 75:25) to yield 0.680 g (1.24 mmol, 89%) in a ratio of
P95:5 favoring the major diastereomer as white crystals. Melting
point: 128–130 °C. 1H NMR (500 MHz, CDCl3): d 2.69 (dd, J = 13.4,
4.3.4. (2S,3R)-4-Benzyl-3-[(o-fluorophenyl)-3-hydroxy-2-(p-
methoxyphenoxy)propanoyl]Oxazolidine-2-thione 12d
The title compound was obtained as mixture of diastereomers
with a crude ratio of 75:25 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The title compound
was purified by flash column chromatography (hexanes:EtOAc,
75:25) to yield 0469 g (0.975 mmol, 65%) in a ratio of P95:5
favoring the major diastereomer as white crystals. Melting point:
Please cite this article in press as: Haynes, C. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.001

6
C. S. Haynes et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
9.8 Hz, 1H), 3.08 (dd, J = 134, 3.1 Hz, 1H), 3.65 (s, 1H), 3.94 (dd,
J = 9.1, 7.5 Hz, 1H), 4.17 (dd, J = 9.3, 1.7 Hz, 1H), 4.70–4.75 (m,
1H), 4.79–4.81 (m, 1H), 6.36 (dd, J = 16.1, 7.1 Hz, 1H), 6.61 (d,
J = 15.9 Hz, 1H), 6.75 (d, J = 9.2 Hz, 2H), 6.90 (d, J = 9.1 Hz, 2H),
7.02–7.04 (m, 2H), 7.09 (d, J = 4.1 Hz, 1H), 7.13–7.15 (m, 1H),
7.16–7.21 (m, 5H), 7.27 (d, J = 7.3 Hz, 2H). 13C NMR (125 MHz,
CDCl3): d 37.5, 55.7, 60.9, 71.0, 74.2, 79.0, 114.9, 116.8, 126.4,
126.7, 127.5, 128.2, 128.7, 129.0, 129.5, 133.0, 134.8. 136.0,
151.4, 154.9, 170.4, 185.4 ppm. IR (CHCl3): 3417, 1710, 1507,
4.4. Methyl 3-hydroxy-2-(p-methoxyphenoxy)-3-phenyl-
propanoate 13
In a 500 mL, flame dried, nitrogen purged round bottom flask
equipped with a magnetic stirrer bar were added imidazole
(2.316 g, 34.0 mmol, 3 equiv), anhydrous methanol (30 mL) and
THF (20 mL). Compound 12a (4.602 g, 9.94 mmol, 1 equiv) was
then added and allowed to stir overnight. The MeOH was removed
via rotary evaporation and the crude product was then extracted
with CH2Cl2 (80 mL) and sequentially treated with 1 M HCl
(35 mL) and brine (35 mL). The solvent was removed by rotary
evaporation to yield a viscous oil. This product was then purified
by flash column chromatography (hexanes:EtOAc, 75:25) to yield
a viscous oil (2.613 g, 8.64 mmol, 87%). 1H NMR (500 MHz, CDCl3):
d 2.99 (s, 1H), 3.54 (s, 3H), 3.65 (s, 3H), 4.56 (d, J = 5.3 Hz, 1H), 5.07
(d, J = 5.3 Hz, 1H), 6.68–6.72 (m, 4H), 7.22–7.30 (m, 3H), 7.33–7.35
(m, 2H) ppm. 13C NMR: d 52.25, 55.64, 74.84, 83.10, 114.74, 117.14,
126.61, 128.41, 128.46, 138.74, 151.75, 155.03, 170.12 ppm. IR:
1366, 1328, 1071, 828, 702 cmÀ1. [ 24 = +205 (c 1.00, CHCl3).
a]
D
ESI HRMS (C28H27NO5S): calc’d (M+H+) 490.1689, found 490.1682.
4.3.8. (2S,3R)-4-Benzyl-3-[(3-hydroxy-2-(p-methoxyphenoxy)-
5-methylhexanoyl)]oxazolidine-2-thione 12h
The title compound was obtained as mixture of diastereomers
with a crude ratio of 91:9 ratio favoring the major syn-diastere-
omer as determined by 1H NMR spectroscopy. The title product
was purified by flash column chromatography (hexanes:EtOAc,
75:25) to yield 0.567 g (91%) in a ratio of P95:5 favoring the
major diastereomer as white crystals. Melting point: 49–51 °C.
1H NMR (400 MHz, CDCl3): 0.93 (d, J = 6.6 Hz, 3H), 0.97 (d,
J = 6.6 Hz, 3H), 1.47–1.54 (m, 1H), 1.73–1.92 (m, 2H), 2.12 (d,
J = 11.0 Hz, 1H), 2.79 (dd, J = 10.0, 3.3 Hz, 1H), 3.26 (dd,
J = 10.0 Hz, 3.1 Hz, 1H), 3.77 (s, 3H), 4.29–4.41 (m, 3H), 4.88–
4.94 (m, 1H), 6.84–6.88 (m, 3H), 6.90–6.94 (m, 2H), 7.15–7.17
(m, 2H), 7.27–7.33 (m, 2H). 13C NMR (100 MHz, CDCl3): d 22.0,
237, 24.6, 37.4, 43.2, 55.7, 60.9, 70.5, 71.2, 79.1, 114.9, 116.4,
127.5, 129.0, 129.5, 134.9, 151.5, 154.7, 170.6, 185.4. IR (neat):
3569, 2964, 1748, 1507, 1393, 1052, 828, 701 cmÀ1. [ 23 = +146
a]
D
(c 0.50, CHCl3).
Acknowledgements
The authors acknowledge Zachary Lawton and Prof. C. Mulligan
for their technical assistance in the collection of ESI-HRMS data.
Structural elucidations were made with assistance from high reso-
lution MS instrumentation acquired through support by the
National Science Foundation MRI Program under Grant No. CHE
1337497.
3420, 1729, 1474, 1444, 1366, 1326, 1038, 126, 752, 702 cmÀ1
.
[a]
23 = +9.4 (c 1.10, CHCl3). ESI HRMS for C24H29NO5S: calc’d
D
(M+H+) 444.1841, found 444.1845.
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2016.11.
001.
4.3.9. (2S,3R)-4-Benzyl-3-(3-hydroxy-2-(p-methoxyphenoxy)-
4,4-dimethylpentanoyl)oxazolidine-2-thione 12i
In a 250 mL, flame dried, nitrogen purged round bottom flask
equipped with a magnetic stirrer bar, oxazolidine-2-thione 11
(0.500 g, 1.40 mmol), and CH2Cl2 (10 mL) were cooled to À25 °C
before the addition of TiCl4 (0.160 mL, 1.54 mmol). The reactants
were allowed stir for 30 min and then the addition of di-isopropy-
lethylamine (0.61 mL, 3.5 mmol) followed. The mixture was stirred
for one hour after which N-methylpyrrolidinone (NMP) (0.13 mL
1.4 mmol) was added and the reaction was stirred for 30 min.
The trimethylacetaldehyde (2.1 mmol) was added and the reaction
stirred for 4 h at À25 °C. The reaction was quenched by the addi-
tion of brine (30 mL). The reaction mixture was diluted with CH2-
Cl2 (50 mL) and treated with 1 M HCl (30 mL), and the layers were
separated. The organic layer was subsequently treated with brine
(30 mL), dried (MgSO4), and the solvent was removed by rotary
evaporation. The title compound was obtained as mixture of
diastereomers with a crude ratio of 62:38 ratio favoring the major
syn-diastereomer as determined by 1H NMR spectroscopy. This
material was purified by flash column chromatography (hexanes:
EtOAc, 75:25) to yield 0.348 g (0.784 mmol, 56%) in a ratio of
P95:5 favoring the major diastereomer of a viscous oil. 1H NMR
(500 MHz, CDCl3): d 0.99 (s, 9H), 2.26 (d, J = 8.71 Hz, 1H), 2.62
(dd, J = 13.47 Hz, 9.80, 1H), 3.02 (dd, J = 13.4, 3.24 Hz, 1H), 3.73
(d, J = 8.3 Hz, 1H), 4.23–4.26 (m, 2H), 4.87–4.92 (m, 1H), 6.79 (d,
J = 9.1 Hz, 2H), 6.92 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 6.5 Hz, 2H),
7.13 (d, J = 8.3 Hz, 1H), 7.16–7.22 (m, 5H) ppm. 13C NMR
(125 MHz, CDCl3): d 26.6, 35.8, 37.7, 55.7, 607, 71.0, 74.9, 80.8,
114.9, 116.3, 127.5, 129.0, 129.4, 134.9, 150.4, 154.6, 173.7,
186.3 ppm. IR (CHCl3): 3499, 2965, 1704, 1507, 1367, 1324, 1045,
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D
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Please cite this article in press as: Haynes, C. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.001

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Please cite this article in press as: Haynes, C. S.; et al. Tetrahedron: Asymmetry (2016), http://dx.doi.org/10.1016/j.tetasy.2016.11.001