Asymmetric synthesis of 2,4,5-trisubstituted Δ2- thiazolines

Article abstract of DOI:10.1002/chem.201301120

Δ²-Thiazolines are interesting heterocycles that display a wide variety of biological characteristics. They are also common in chiral ligands used for asymmetric syntheses and as synthetic intermediates. Herein, we present asymmetric routes to

Full text of DOI:10.1002/chem.201301120

DOI: 10.1002/chem.201301120
Asymmetric Synthesis of 2,4,5-Trisubstituted D2-Thiazolines
Christoffer Bengtsson,[a] Hanna Nelander,[b] and Fredrik Almqvist*[a, c, d]
Abstract: D2-Thiazolines are interesting heterocycles that display a wide variety of
biological characteristics. They are also common in chiral ligands used for asym-
metric syntheses and as synthetic intermediates. Herein, we present asymmetric
Keywords: acyl migration · asym-
metric synthesis · heterocycles · un-
natural amino acids · thiazolines
routes to 2,4,5-trisubstituted D2-thiazolines. These D2-thiazolines were synthesized
from readily accessible/commercially available a,b-unsaturated methyl esters
through a Sharpless asymmetric dihydroxylation and an O!N acyl migration reac-
tion as key steps. The final products were obtained in good yields with up to 97%
enantiomeric excess.
Introduction
D2-Thiazolines constitute a class of compounds with diverse
applications. They possess interesting properties as flavoring
agents[1] and pheromones,[2] are present in the structures of
many natural products (e.g., Pulicatin B[3] and micacoci-
din[4]), and are useful as chiral ligands in asymmetric synthe-
sis[5] (Figure 1). As ligands, they have proven successful in a
variety of reactions, including Pd-catalyzed allylic substitu-
tions,[5a,6] Diels–Alder reactions,[7] Friedel–Crafts alkylations
of indoles[8] and alkylzinc additions to aldehydes.[9] Many
ways to construct the D2-thiazoline heterocycles have been
developed, and they normally involve the use of a dehydrat-
ing reagent. Among the known methods are reactions with
triethylamine (TEA)/MsCl (Ms=mesityl),[5a,6] SOCl2/pyri-
dine,[10] the Lawesson reagent,[7b,11] the Burgess reagent,[4c,10]
Figure 1. Examples of D2-thiazoline-containing natural products and
chiral ligands.
the Hendrickson reagent,[12] TiCl4,[13] PCl5,[4a] P2S5,[14] diethy-
laminosulfur trifluoride (DAST),[15] [bis(2-methoxyethyl)a-
mino]sulfur trifluoride (Deoxo-Fluor),[9a,16] PPh3/diisopropyl
azodicharboxylate (DIAD),[17] 3-nitrophenylboronic acid,[18]
and Ru/tert-butyl hydroperoxide (TBHP).[19] These processes
normally lead to 2,4-disubstituted D2-thiazolines, with less
attention given to the asymmetric synthesis of their 2,4,5-tri-
substituted analogues.
[a] Dr. C. Bengtsson, Prof. Dr. F. Almqvist
Department of Chemistry
Umeꢁ University, 90187 Umeꢁ (Sweden)
Fax : (+46)907867655
E-mail: fredrik.almqvist@chem.umu.se
In our research group, we are interested in D2-thiazolines
as intermediates in the synthesis of thiazolo/thiazolino ring-
fused 2-pyridones,[20,21] which are constructed through a
ketene/imine cyclocondensation reaction between a D2-thia-
zoline and an acyl Meldrumꢀs acid derivative.[22] In the case
of 2-substituted thiazolino ring-fused 2-pyridones, only race-
mates have previously been synthesized (Figure 2), through
a conjugate addition reaction with a higher order cuprate
onto the corresponding a,b-unsaturated methyl esters.[20b]
The intriguing biological activity demonstrated by these
compounds as novel antibacterial agents[20c,23] encouraged us
to develop asymmetric synthetic pathways to the enantiom-
ers of these compounds. The previously developed cuprate
addition has proven hard to perform on a larger scale, and
[b] H. Nelander
AstraZeneca R&D Mçlndal
Medicinal Chemistry, 43183 Mçlndal (Sweden)
[c] Prof. Dr. F. Almqvist
Laboratories for Chemical Biology Umeꢁ
LCBU, Umeꢁ University, 90187 Umeꢁ (Sweden)
[d] Prof. Dr. F. Almqvist
Umeꢁ Center for Microbial Research
UCMR, Umeꢁ University, 90187 Umeꢁ (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301120.
ꢂ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original
work is properly cited and is not used for commercial purposes
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FULL PAPER
Figure 2. Previously synthesized racemic 2-substituted thiazolino ring-
fused 2-pyridones.
also required very fresh organolithium reagents to proceed
in satisfactory yields. Consequently, development of an
asymmetric version of that method was not an attractive
option. Initially, we also considered the Sharpless amino hy-
droxylation reaction in the synthesis of (ꢀ)-5. However, that
route would give the syn-diastereomer of (ꢀ)-5 when per-
formed on the commercially available trans-methyl cinna-
mate 1 and eventually give the cis-configured D2-thiazoline.
Additionally, this reaction is known to give mixtures of re-
gioisomers and, in some cases, poor conversions.[24]
Scheme 1. a) K2OsO4·2H2O, NMO, MeCN/acetone/H2O (1:1:1), RT,
81%; b) NsCl, TEA, CH2Cl2, 08C, 75%; c) NaN3, DMF, 408C, 70%;
d) i) SnCl2·2H2O, RT; ii) NaHCO3, Boc2O, 1,4-dioxane/H2O, RT, 93 %;
e) i) Ms2O, TEA, CH2Cl2; ii) KSAc, DMF, RT, 60%; f) i) K2CO3 or
NaOMe, MeOH; ii) TFA or HCl; iii) Imino ether, TEA, CH2Cl2.
We envisioned instead a synthetic pathway starting with a
Sharpless asymmetric dihydroxylation of commercially avail-
able methyl cinnamate, followed by the selective conversion
of the a-hydroxy group into an azide. Subsequently, this
azide could be reduced and protected in a two-step one-pot
reaction to give the tert-butoxycarbonyl (Boc)-protected
amino alcohol,[15b] and the remaining benzylic hydroxy
group could then be converted to a thiol through simple
functional-group interconversion (FGI). Finally, we envi-
sioned that deprotection followed by a thioamine/imino
ether condensation[22] would give the 5-substituted D2-thia-
zoline (Figure 3).
in pKa value between the a- and b-hydroxyl groups.[25] The
conversion of the Boc-protected amino alcohol (ꢀ)-5 into
the S-acyl/N-Boc-protected amino thiol (ꢀ)-6 went smoothly
with mesyl anhydride and potassium thioacetate in 60%
yield over two steps. Mesyl anhydride was used instead of
MsCl to prevent possible scrambling of the sterogenic
center due to displacement of the mesyl sulfonate by the nu-
cleophilic chloride ion. However, all attempts to deprotect
and then cyclize this compound with the imino ether to gen-
erate the 5-substituted D2-thiazoline (ꢀ)-7 failed to work
and afforded complex mixtures (Scheme 1).
Amido alcohols are known to be suitable precursors for
the synthesis of D2-thiazolines,[11] and consequently our next
method was to prepare the amido alcohol of (ꢀ)-5. Unfortu-
nately, neither Boc-deprotection followed by N,N,N’,N’-
tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate
(TBTU)/N,N-diisopropylethylamine
(DIPEA)-mediated
coupling nor direct coupling of the amine with acid chlor-
ide/TEA proved successful.
In our next attempt to synthesize the amido alcohols, we
envisioned making the ester of azido alcohol (ꢀ)-4, which
could then undergo a tandem azide reduction/O!N acyl
migration reaction. Of the esterification conditions exam-
ined for (ꢀ)-4 (TBTU/acid chloride or N,N-dicyclohexylcar-
bodiimide (DCC)/4-dimethylaminopyridine (DMAP; Steg-
lich conditions)), DCC/DMAP proved more effective.[26] To
our delight, the SnCl2·2H2O-induced azide reduction/O!N
acyl migration reaction worked well (Table 1) for all substi-
tuted (i.e., R¼H) acyl azido esters (ꢀ)-8 (Table 1, en-
tries 2–5), with the corresponding amido alcohols (ꢀ)-9 iso-
lated in 70–84% yields (Table 1). In addition, this synthetic
route remained efficient when performed on a gram scale.
An initial attempt to prepare the corresponding thiol
amide of (ꢀ)-9c was performed with 0.6 equivalents of the
Lawesson reagent (LR) in toluene at reflux (Table 2). Grati-
Figure 3. Retrosynthetic analysis of the 5-phenyl-substituted D2-thiazo-
lines.
Results and Discussion
To test our synthetic strategy, we initially performed the di-
hydroxylation reaction under racemic conditions. Commer-
cially available methyl cinnamate 1 was converted into the
corresponding Boc-protected amino alcohol (ꢀ)-5 via diol
(ꢀ)-2, nosylate (ꢀ)-3, and azide (ꢀ)-4 by following to pub-
lished procedures for the corresponding ethyl ester (Sche-
me 1).[15b] The excellent selectivity for the a-hydroxy group
in the nosylation reaction can be attributed to the difference
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F. Almqvist et al.
Table 1. Synthesis of (ꢀ)-9: a) RCH2COOH, DCC, DMAP, CH2Cl2, RT;
b) i) SnCl2·2H2O, RT; ii) NaHCO3, MeOH/H2O or 1,4-dioxane/H2O, RT.
sponding azido alcohols (ꢀ)-14 through K2OsO4·2H2O-cata-
lyzed dihydroxylation and selective a-hydroxy nosylation
((ꢀ)-13). The nosylates (ꢀ)-13 were then substituted with
NaN3 to give the corresponding azido alcohols (ꢀ)-14.
The azido alcohols (ꢀ)-14 were then reacted with cyclo-
propylacetic acid under Steglich esterification conditions to
furnish the azido esters (ꢀ)-15 in 75–94% yields (Table 4).
Entry
R
8
Yield
[%]
9
Yield
[%]
Table 4. Synthesis of (ꢀ)-17: a) Cyclopropylacetic acid, DCC, DMAP,
CH2Cl2, RT; b) i) SnCl2·2H2O, RT; ii) NaHCO3, MeOH/H2O; c) the Law-
esson reagent, toluene, reflux.
1
2
3
4
5
H
c-Pr
Ph
m-CF3Ph
2-thienyl
(ꢀ)-8a[a]
(ꢀ)-8b
(ꢀ)-8c
(ꢀ)-8d
(ꢀ)-8e
96
95
95
90
91
(ꢀ)-9a
–
(ꢀ)-9b[b]
(ꢀ)-9c[b]
(ꢀ)-9d[b]
(ꢀ)-9e[c]
71
70
80
84
[a] Ac2O/DMAP was used. [b] Use of 1,4-dioxane/H2O instead of
MeOH/H2O gave a lower yield [c] 1,4-Dioxane/H2O was used, MeOH/
H2O gave only a 50% yield.
Table 2. Synthesis of (ꢀ)-10: a) The Lawesson reagent (0.6 equiv), tol-
uene, reflux.
Entry
R
15
Yield 16
[%]
Yield 17
[%]
Yield
[%]
1
2
3
4
p-FPh
(ꢀ)-15a 85
(ꢀ)-16a 83
(ꢀ)-17a 71
Entry
R
9
10
Yield
[%]
m-MeOPh (ꢀ)-15b 94
(ꢀ)-16b 80
(ꢀ)-16c 77
(ꢀ)-16d 78
(ꢀ)-17b 80
(ꢀ)-17c 24
(ꢀ)-17d 65
Bn
(ꢀ)-15c 75
(ꢀ)-15d 81
2-thienyl
1
2
3
4
c-Pr
Ph
m-CF3Ph
2-thienyl
(ꢀ)-9b
(ꢀ)-9c
(ꢀ)-9d
(ꢀ)-9e
(ꢀ)-10a
(ꢀ)-10b
(ꢀ)-10c
(ꢀ)-10d
71
80
72
74
The azide reduction/O!N acyl migration reaction was ef-
fective for these azido esters, and the corresponding amido
alcohols (ꢀ)-16 were isolated in 77–83% yield (Table 4).
Treatment of aryl/heteroaryl-substituted amido alcohols
(ꢀ)-16a,b,d with LR proceeded efficiently to form the de-
sired D2-thiazolines (ꢀ)-17 (Table 4, entries 1, 2, and 4).
However, the reaction to form benzyl substituted (ꢀ)-17c,
which was only isolated in 24% yield (Table 4, entry 3), was
less effective.
fyingly, we observed only thiazoline formation, with (ꢀ)-10b
isolated in 80% yield.
To investigate the scope and limitations of this reaction, a
series of cinnamate analogues (11) were synthesized by the
Horner–Wadsworth–Emmons olefination reaction in excel-
lent yields and trans selectivities (Table 3). The cinnamate
analogues (11) were subsequently converted into the corre-
After establishing the synthetic route required to access
the target D2-thiazolines racemically, we prepared
the enantioselective synthesis. Methyl cinnamate
was first oxidized by Sharpless asymmetric dihy-
droxylation using commercially available AD a- or
b-mixes (Scheme 2). Treatment of the enatiomeri-
cally pure dihydroxy compounds (ꢁ)-2 and (+)-2
with NsCl and TEA followed by NaN3 displace-
ment gave the enantiomerically pure azido alcohols
(+)-4 and (ꢁ)-4, respectively (Scheme 2).
Table 3. Synthesis of (ꢀ)-14: a) NaH, THF, RT; b) K2OsO4·2H2O, N-methylmorpho-
line N-oxide (NMO), MeCN/acetone/H2O (1:1:1), RT; c) NsCl, TEA, CH2Cl2, 08C;
d) NaN3, DMF, 408C.
Azido alcohols (+)-4 and (ꢁ)-4 were converted
into the azido esters (ꢁ)-8b,e and (+)-8b,e, respec-
tively, by the Steglich esterification procedure. This
was followed by a SnCl2·2H2O-induced azide reduc-
tion/O!N acyl migration reaction to give amido al-
cohols (ꢁ)-9b,e and (+)-9b,e in 72–82% yield and
excellent enantiomeric excess (99%; Scheme 3).
After LR-induced ring-closure, the 5-phenyl-substi-
tuted D2-thiazolines (ꢁ)-10a,d and (+)-10a,d were
Entry
R
11
Yield 12
[%]
Yield 13
[%]
Yield 14
[%]
Yield
[%]
1
2
3
4
p-FPh
m-MeOPh 11b
Bn
2-thienyl
11a
98
96
(ꢀ)-12a 65
(ꢀ)-13a 63
(ꢀ)-14a 65
(ꢀ)-12b 75
(ꢀ)-12c 80
(ꢀ)-12d 73
(ꢀ)-13b 70
(ꢀ)-13c 62
(ꢀ)-13d 54
(ꢀ)-14b 82
(ꢀ)-14c 79
(ꢀ)-14d 78
11c[a] 62
11d
98
[a] The aldehyde was freshly distilled prior to use.
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2,4,5-Trisubstituted D2-Thiazolines
FULL PAPER
yses of compounds 18a,b have previously been reported by
our group.[20c,23]
Epimerization of the stereochemistry occurred in the
ring-closing reaction with LR (e.g., Scheme 3, (ꢁ)-9b,
99% ee!(ꢁ)-10a, 80% ee). A series of experiments to in-
vestigate the influence of LR stoichiometry on the reaction
yield and ee was therefore performed. Use of less LR result-
ed in a decreased yield and ee of the product (Table 5,
Table 5. Effect of varying the amount of the Lawesson reagent.
Scheme 2. a) AD-mix-b, MeSO2NH2, tBuOH/H2O (1:1), RT; b) AD-mix-
a, MeSO2NH2, tBuOH/H2O (1:1), RT; c) NsCl, TEA, CH2Cl2, 08C;
d) NaN3, DMF, 408C.
Entry
Amount LR
[equiv]
T
Yield
[%]
ee
N
[%][a]
isolated in 71–80% yields and 71–88% ee (Scheme 3).
1
2
3
4
0.5
0.6
0.6
1.0
reflux[b]
50
75
78
90
65
73
75
97
We used the enantiomerically enriched thiazolines
(+)-10a,d and (ꢁ)-10a,d to synthesize the previously men-
tioned biologically active 2-pyridones (Structures I and II,
Figure 2) by an acyl/ketene cyclocondensation reaction
with the acyl Meldrumꢀs acid derivative 19[22] (Scheme 4).
This gave the enantiomerically enriched 2-phenyl-substitut-
ed thiazolino ring-fused 2-pyridones (+)-18a,b and (ꢁ)-
18a,b in 80–85% yields and 70–88% ee (Scheme 4). Hydrol-
RT–reflux[c]
reflux[b]
reflux[b]
[a] Determined by chiral HPLC on a Whelk-O1 column. [b] The oil bath
was preheated before the reaction was started. [c] The reaction was
heated to reflux starting from RT; the reflux was then continued for 1 h.
entry 1). Conversely, increasing the amount of LR to
1 equivalent significantly improved both the yield (90%)
and the ee of the reaction (Table 5, entry 4). Reports on this
type of 2,4,5-trisubstituted D2-thiazoline containing an ester
substituent in the 4-position are scarce in the litera-
AHCTUNGTRENNUNG
ture.[11c,15a,17] To the best of our knowledge, this is the first
reported direct cyclization of amido alcohols to D2-thiazo-
lines containing an ester in the 4-position and an aryl/heter-
oaryl in the 5-position with LR.
In addition, these data support the proposed mechanism
for the formation of D2-thiazolines with LR published by
Nishio,[11b] in which the initial thiolation of the hydroxy com-
pound is known to occur with retention of configuration
(Scheme 5).[27] The resultant thiol amide can either undergo
a second thiolation reaction of the amide with another
equivalent of LR (to form the enantiomerically pure thiol
thio amide) or a syn-elimination facilitated by compound B
(Scheme 5). In the latter case, a Michael acceptor is formed
that can react further with a sulfur nucleophile (i.e., com-
pound C, Scheme 5) through conjugate addition and form
the racemic thiol amide. Conjugate addition reactions of
thiols to trisubstituted a,b-unsaturated carbonyl compounds
are known to precede in high diastereoselectivities with (E)-
olefins even at elevated temperatures.[28] This selectivity is
explained by the selective protonation of the enolate inter-
mediate (shown in the inset in Scheme 5) due to stereoelec-
tronic effects of the sulfur substituent.[28] The a,b-unsaturat-
ed ester formed may also undergo a thiolation reaction with
LR, and subsequent cyclization to the racemic trans-5-sub-
stituted 2-thiazoline. Although this 5-endo-trig cyclization is
disfavored for oxygen and nitrogen nucleophiles, it is known
Scheme 3. a) RCH2COOH, DCC, DMAP, CH2Cl2, RT; b) i) SnCl2·2H2O,
RT, 2 h; ii) NaHCO3, MeOH/H2O or 1,4-dioxane/H2O, RT, 18 h; c) the
Lawesson reagent, toluene, reflux; the ee was determined by chiral chro-
matography.
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F. Almqvist et al.
to proceed for sulfur-based nu-
cleophiles.[29] Carbocationic in-
termediates have also been re-
ported with LR and amido al-
cohols, but only in the presence
of the strongly cation-stabilizing
ferrocene group.[11c,30]
Conclusion
We have developed scalable
and robust synthetic pathways
to highly enantiomerically en-
riched 5-substituted D2-thiazo-
lines, which can be used in a
ketene/imine cyclocondensation
reaction to yield 2-substituted
ring-fused 2-pyridones. The ab-
solute stereochemistry was ini-
Scheme 4. a) Trifluoroacetic acid (TFA), 19, microwave irradiation, 1408C, 2 min, dichloroethene (DCE); the
ee was determined by chiral chromatography.
tially set through a Sharpless asymmetric dihydroxylation
of methyl cinnamate. The subsequent nosylation, NaN3
displacement, esterification, and azide reduction/O!N
acyl migration reactions all proceeded in good yields and
without detectable epimerization on a gram scale. The
final ring-closure of the amido alcohols proceeded in good
yields with only 0.6 equivalents of LR, albeit with some
epimerization. Increasing the amount of LR to 1 equiva-
lent in this reaction ameliorated this problem, and afford-
ed D2-thiazolines in excellent yield and stereochemical
purity. The established route proved effective in the syn-
thesis of aryl/heteroaryl 5-substituted D2-thiazolines and
provides facile access to interesting unnatural analogues
of cysteine and serine. Ultimately, this methodology also
opens up synthetic possibilities for making asymmetric 5-
substituted D2-thiazoline-containing ligands, as well as an-
alogues of D2-thiazoline based natural products.
Experimental Section
General: Unless stated otherwise, all reagents and solvents were used
as received from commercial suppliers. DMF and THF were dried in a
solvent drying system (THF drying agent: neutral alumina; DMF
drying agent: activated molecular sieves, also equipped with an isocya-
nate scrubber) and were collected fresh prior to every reaction. NaH
was prewashed with pentane, dried under vacuum, and stored in a des-
sicator. Preparatory HPLC was performed on a C18 reversed-phase
column (25 cmꢃ21.2 mm, 5 mm) with H2O/MeCN mixtures as the
eluent. Chiral chromatography was performed on either an (S,S)-
Whelk-O1 chiral column with hexane/CH2Cl2/alcohol as the eluents or
with supercritical fluid chromatography on a Chiralpak-AD or Lux C4
chiral column with CO2/MeOH mixtures as the eluents. Microwave re-
actions were performed in a microwave reactor; temperatures were
monitored with an IR probe. TLC was performed on silica gel and de-
tected with UV light. Column chromatography was employed on
normal phase silica gel (eluents given in brackets). Optical rotation
was measured with a polarimeter at 208C and 589 nm. IR was record-
1
Scheme 5. Possible mechanism for D2-thiazoline formation with the Law-
ed on a spectrometer equipped with an ATR device. H and 13C NMR
esson reagent.
spectra were recorded on a 400 MHz spectrometer at 298 K and cali-
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2,4,5-Trisubstituted D2-Thiazolines
FULL PAPER
brated by using the residual peak of the solvent as the internal standard
(CDCl3: CHCl3 dH =7.26 ppm, CDCl3 dC =77.16 ppm; [D6]DMSO:
[D5]DMSO dH =2.5 ppm, [D6]DMSO dC =39.5 ppm). HRMS was per-
formed by using a mass spectrometer with electrospray ionization (ES+);
sodium formate was used as the calibration chemical.
column chromatography on silica gel (heptane/EtOAc 95:5!80:20) to
give (ꢀ)-6 as a yellow noncrystalline solid (145 mg, 60%). 1H NMR
(400 MHz, CDCl3): d=7.34–7.22 (m, 5H), 5.27 (d, J=9.2 Hz, 1H), 5.00
(d, J=7.2 Hz, 1H), 4.75 (dd, J=9.2, 7.2 Hz, 1H), 3.59 (s, 3H), 2.33 (s,
3H), 1.41 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=194.0, 170.8,
155.2, 137.6, 128.8 (2C), 128.3 (2C), 128.2, 80.4, 58.2, 52.5, 50.4, 30.5,
28.4 ppm (3C); IR: n˜ =3368, 1747, 1718, 1498, 1164 cmꢁ1; HRMS (ES)
calcd for C17H23NNaO5S: 376.1195 [M+Na]+; found: 376.1196.
Representative procedures
(ꢀ)-(2S,3R)-2,3-Dihydroxy-3-phenylpropionic acid methyl ester ((ꢀ)-2):
Methyl cinnamate (30.83 mmol, 5 g), K2OsO4·2H2O (0.62 mmol, 228 mg),
and 4-methylmorpholine N-oxide (46.25 mmol, 5.42 g) were mixed in ace-
tone/MeCN/H2O (1:1:1, 140 mL) and the reaction was stirred at RT for
16 h. The volatile solvents were removed by evaporation and the remain-
ing mixture was diluted with saturated aqueous NaHCO3 and extracted
with EtOAc. The organic phase was dried (Na2SO4), filtered, and concen-
trated. The crude material was purified by column chromatography on
silica gel (heptane/EtOAc 80:20!50:50) to give (ꢀ)-2 as a colorless oil
(4.9 g, 81%). Spectral data agreed with published results.[31]
(ꢀ)-(2R,3R)-2-Azido-3-(2-cyclopropylacetoxy)-3-phenylpropionic
acid
methyl ester ((ꢀ)-8b): Compound (ꢀ)-4 (0.90 mmol, 200 mg), cyclopro-
pylacetic acid (1.18 mmol, 0.11 mL), and dicyclohexylcarbodiimide
(1.18 mmol, 242 mg) were mixed in CH2Cl2 (8 mL) and DMAP
(1.18 mmol, 144 mg) was added; the reaction was stirred at RT for 1 h.
The reaction mixture was diluted with CH2Cl2 and washed with 2%
aqueous KHSO4. The organic phase was dried (Na2SO4), filtered, and
concentrated. The crude material was purified by column chromatogra-
phy on silica gel (heptane/EtOAc 95:5!85:15) to give (ꢀ)-8b as a color-
less oil (258 mg, 95%). 1H NMR (400 MHz, CDCl3): d=7.41–7.32 (m,
5H), 6.16 (d, J=6.4 Hz, 1H), 4.35 (d, J=6.4 Hz, 1H), 3.76 (s, 3H), 2.28
(d, J=7.2 Hz, 2H), 1.11–0.98 (m, 1H), 0.59–0.51 (m, 2H), 0.20–0.13 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=171.5, 167.8, 135.4, 129.2,
128.7 (2C), 127.2 (2C), 74.5, 65.4, 52.8, 39.4, 6.8, 4.5 ppm (2C); IR: n˜ =
(ꢀ)-(2S,3R)-3-Hydroxy-2-(4-nitrobenzenesulfonyloxy)-3-phenylpropionic
acid methyl ester ((ꢀ)-3): Compound (ꢀ)-2 (26.25 mmol, 5.15 g) was dis-
solved in CH2Cl2 (250 mL) and cooled to 08C in an ice bath. 4-Nitroben-
zenesulfonyl chloride (26.25 mmol, 5.82 g) followed by TEA
(26.25 mmol, 3.66 mL) were added and the reaction was stirred at 08C
for 1 h. The reaction mixture was acidified and then washed with 1m
aqueous HCl (pHꢂ1), dried (Na2SO4), filtered, and concentrated. The
crude material was purified by column chromatography on silica gel
(heptane/EtOAc 90:10!60:40) to give (ꢀ)-3 as a colorless solid (7.5 g,
75%). Spectral data agreed with published results.[25]
2118, 1750 cmꢁ1
: HRMS (ES) calcd for C15H17N3NaO4: 326.1117
[M+Na]+; found: 326.1115.
(ꢀ)-(2R,3R)-2-(2-Cyclopropylacetylamino)-3-hydroxy-3-phenylpropionic
acid methyl ester ((ꢀ)-9b): SnCl2·2H2O (2.25 mmol, 508 mg) was dis-
solved in MeOH/H2O 1:4 (2.5 mL) and (ꢀ)-8b (0.45 mmol, 135 mg) dis-
solved in MeOH (2.5 mL) was added and the reaction was stirred at RT
for 2 h. NaHCO3 (9 mmol, 756 mg) was added in portions to the reaction
mixture and the reaction was stirred at RT for an additional 18 h. The re-
action mixture was filtered through Celite and the Celite was carefully
washed with EtOAc. The organic phase was washed with saturated
NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude material
was purified by column chromatography on silica gel (heptane/EtOAc
80:20!50:50) to give (ꢀ)-9b as a colorless noncrystalline solid (89 mg,
71%). 1H NMR (400 MHz, CDCl3): d=7.27–7.19 (m, 3H), 7.18–7.13 (m,
2H), 6.66–6.58 (m, 1H), 5.18 (d, J=3.6 Hz, 1H), 4.97–4.92 (m, 1H), 4.45
(brs, 1H), 3.65 (s, 3H), 2.07 (d, J=7.6 Hz, 1H), 0.86–0.76 (m, 1H), 0.52–
0.42 (m, 2H), 0.09–0.00 ppm (m, 2H): 13C NMR (100 MHz, CDCl3): d=
174.2, 170.1, 139.2, 128.3 (2C), 128.1, 126.0 (2C), 75.1, 59.1, 52.6, 41.0,
6.9, 4.6 ppm (split, 2C); IR: n˜ =3419, 1743, 1656, 1521 cmꢁ1: HRMS (ES)
calcd for C15H19NNaO4: 300.1212 [M+Na]+; found: 300.1211.
(ꢀ)-(2R,3R)-2-Azido-3-phenyl-3-hydroxypropionic acid methyl ester
((ꢀ)-4): Compound (ꢀ)-3 (7.55 mmol, 2.88 g) and NaN3 (45.3 mmol,
2.94 g) were mixed in dry DMF (13 mL) and the reaction was heated to
408C for 48 h. The reaction mixture was diluted with brine and extracted
with EtOAc, the organic phase was dried (Na2SO4), filtered, and concen-
trated. The crude material was purified by column chromatography on
silica gel (heptane/EtOAc 90:10!60:40) to give (ꢀ)-4 as a colorless non-
1
crystalline solid (1.17 g, 70%). H NMR (400 MHz, CDCl3): d=7.42–7.31
(m, 5H), 5.00 (d, J=7.2 Hz, 1H), 4.10 (d, J=7.2 Hz, 1H), 3.77 (s, 3H),
3.02 ppm (brs, 1H); 13C NMR (100 MHz, CDCl3): d=169.5, 139.0, 128.9,
128.7 (2C), 126.7 (2C), 74.2, 66.9, 52.9 ppm; IR: n˜ =3426, 2117,
1738 cmꢁ1; HRMS (ES) calcd for C10H11N3NaO3: 244.0698 [M+Na]+;
found: 224.0701.
(ꢀ)-(2R,3R)-2-tert-Butoxycarbonylamino-3-hydroxy-3-phenylpropionic
acid methyl ester ((ꢀ)-5): SnCl2·2H2O (22.6 mmol, 5.1 g) was dissolved in
1,4-dioxane/H2O (1:4, 20 mL) and (ꢀ)-4 (4.52 mmol, 1 g) dissolved in 1,4-
dioxane (20 mL) was added. The reaction was stirred at RT for 4 h.
NaHCO3 (4.6 mmol, 386 mg) was added, followed by Boc2O (0.35 mmol,
76 mg), and the reaction was stirred at RT for an additional 16 h. The re-
action mixture was filtered through Celite, and washed with EtOAc. The
organic phase was washed with saturated NaHCO3, dried (Na2SO4), fil-
tered, and concentrated. The crude material was purified by column
chromatography on silica gel (heptane/EtOAc 90:10!60:40) to give (ꢀ)-
5 as a colorless noncrystalline solid (1.24 g, 93%). 1H NMR (400 MHz,
CDCl3): d=7.39–7.24 (m, 5H), 5.34 (d, J=7.2 Hz, 1H), 5.18 (d, J=
2.8 Hz, 1H), 4.77–4.66 (m, 1H), 3.70 (s, 3H), 1.45 ppm (s, 9H); 13C NMR
(100 MHz, CDCl3): d=170.5, 156.4, 139.3, 128.4 (2C), 128.1, 126.1 (2C),
80.7, 75.1, 59.8, 52.5, 28.3 ppm (3C); IR: n˜ =3425, 1744, 1713, 1502,
1368 cmꢁ1; HRMS (ES) calcd for C15H21NNaO5: 318.1317 [M+Na]+;
found: 318.1318.
(ꢀ)-(4S,5S)-2-Cyclopropylmethyl-5-phenyl-4,5-dihydrothiazole-4-carboxyl-
ic acid methyl ester ((ꢀ)-10a): Compound (ꢀ)-9b (0.46 mmol, 126 mg)
and 0.6 (0.28 mmol, 113 mg) or 1 equivalent (0.46 mmol, 186 mg) of the
Lawesson reagent were mixed in toluene (3 mL) and the reaction was
heated at reflux with an oil bath for 1 h. The reaction mixture was diluted
with EtOAc and washed with saturated aqueous NaHCO3. The organic
phase was dried (Na2SO4), filtered, and concentrated. The crude material
was purified by column chromatography on silica gel (heptane/EtOAc
80:20!50:50) to give (ꢀ)-10a as a colorless oil (with 0.6 equivalents of
the Lawesson reagent: 90 mg, 71%; with 1 equivalent of the Lawesson
reagent: 114 mg, 90%). 1H NMR (400 MHz, CDCl3): d=7.26–7.13 (m,
5H), 5.21 (d, J=6.8 Hz, 1H), 5.05–5.01 (m, 1H), 3.68 (s, 3H), 2.45–2.40
(m, 2H), 1.00–0.88 (m, 1H), 0.53–0.45 (m, 2H), 0.20–0.12 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=174.9, 170.9, 140.6, 129.0 (2C), 128.2,
127.6 (2C), 85.9, 56.6, 52.9, 39.4, 9.4, 5.2, 5.1 ppm; IR: n˜ =1744, 1619,
1266 cmꢁ1; HRMS (ES) calcd for C15H17NNaO2S: 298.0878 [M+Na]+;
found: 298.0875.
(ꢀ)-(2S,3S)-3-Acetylsulfanyl-2-tert-butoxycarbonylamino-3-phenylpro-
pionic acid methyl ester ((ꢀ)-6): Compound (ꢀ)-5 (0.68 mmol, 200 mg)
was dissolved in CH2Cl2 (8 mL) and cooled to 08C in an ice bath. Ms2O
(0.75 mmol, 131 mg) followed by TEA (1.02 mmol, 0.14 mL) were added
and the reaction was stirred at 08C for 2 h. The reaction mixture was di-
luted with CH2Cl2 and washed with saturated aqueous NH4Cl. The organ-
ic phase was dried (Na2SO4), filtered, and concentrated. The crude mate-
rial was dissolved in dry DMF (8 mL) and potassium thioacetate
(3.4 mmol, 388 mg) was added; the reaction was stirred at RT for 15 h.
The reaction mixture was quenched with 1m aqueous HCl and acidified
to pHꢂ1, then extracted with EtOAc. The organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified by
trans-3-(3-Methoxyphenyl)acrylic acid methyl ester (11b): Trimethyl phos-
phonoacetate (8.20 mmol, 1.33 mL) was dissolved in dry THF (40 mL)
and NaH (9.02 mmol, 216 mg) was added; the reaction was stirred at RT
for 5 min before 3-methoxybenzaldehyde (4.10 mmol, 0.5 mL) was
added. The stirring continued at RT for a further 15 h. THF was evapo-
rated and the crude mixture was diluted with saturated aqueous
NaHCO3 and extracted with EtOAc. The organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified by
column chromatography on silica gel (heptane/EtOAc 95:5!70:30) to
Chem. Eur. J. 2013, 19, 9916 – 9922
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9921

F. Almqvist et al.
give 11b as a colorless oil (755 mg, 96%). Spectral data agreed with pub-
[9] a) P. Wipf, X. Wang, Org. Lett. 2002, 4, 1197–1200; b) Z. Gong, Q.
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A
Methyl cinnamate (12.32 mmol, 2 g), AD-mix-b (16.48 g) and methylsul-
fonamide (12.32 mmol, 1.17 g) were mixed in tBuOH/H2O (1:1, 40 mL)
and the reaction was stirred at RT for 18 h. The reaction mixture was di-
luted with water, extracted with EtOAc, and the combined organic
phases were dried (Na2SO4), filtered, and concentrated. The crude mate-
rial was purified by column chromatography on silica gel (heptane/
EtOAc 80:20!50:50) to give (ꢁ)-2 as a colorless solid (2 g, 83%).
[a]2D5 ꢃC =ꢁ10 (c=4.0 in CHCl3); spectral data agreed with published re-
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ACHTUNGTRENNUNG
Compound (ꢁ)-10d (0.23 mmol, 72 mg), 19 (0.58 mmol, 181 mg), and tri-
fluoroacetic acid (TFA, 0.23 mmol, 18 mL) were mixed in 1,2-dichloro-
ethane (1 mL) and the reaction was heated in a microwave oven at
1408C for 2 min. The reaction mixture was diluted with CH2Cl2 and
washed with saturated aqueous NaHCO3. The organic phase was dried
(Na2SO4), filtered, and concentrated. The crude material was purified by
column chromatography on silica gel (heptane/EtOAc 90:10!50:50) to
give (ꢁ)-18b as a yellow foam (97 mg, 83%). [a]2D5 ꢃC =ꢁ113 (c=2.0 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.88–7.82 (m, 1H), 7.79–7.69
(m, 2H), 7.49–7.43 (m 2H), 7.43–7.30 (m, 7H), 7.28–7.23 (m, 1H), 7.09–
7.05 (m, 2H), 5.82 (s, 1H), 5.60 (d, J=3.2 Hz, 1H), 5.00 (d, J=3.2 Hz,
1H), 4.19–4.07 (m, 2H), 3.84 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=168.2, 161.2, 155.6, 149.0, 138.4, 136.5, 134.0, 133.7, 131.9, 129.4 (2C),
129.3, 129.0, 128.8, 128.0, 127.9, 127.5 (2C), 126.8 (2C), 126.3, 125.8,
125.6, 123.9, 115.5, 108.1, 71.2, 53.5, 50.9, 37.0 ppm; IR: n˜ =1752, 1656,
1265 cmꢁ1; HRMS (ES) calcd for C30H23NNaO3S2: 532.1017 [M+Na]+;
found: 532.1020.
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Acknowledgements
We are grateful for financial support from the Swedish Research Council
(621-2010-4730), the Knut and Alice Wallenberg Foundation, VINNO-
VA, and the Kempe Foundation (SJCKMS). We also thank Dr. James
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Received: March 22, 2013
Published online: June 17, 2013
9922
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 9916 – 9922