Concise synthesis of 2,4-disubstituted thiazoles from β-azido disulfides and carboxylic acids or anhydrides: Asymmetric synthesis of cystothiazole C

Article abstract of DOI:10.1039/c4ob01460j

A novel and efficient method for the one-pot synthesis of 2,4-disubstituted thiazoles from carboxylic acids or anhydrides is presented. Based on this new method, the total synthesis of the bis-2,4-disubstituted bis(thiazoles) natural product cystothiazole C is also presented. This journal is

Full text of DOI:10.1039/c4ob01460j

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Concise synthesis of 2,4-disubstituted thiazoles from
β-azido disulfides and carboxylic acids or anhydrides:
asymmetric synthesis of cystothiazole C†
Cite this: Org. Biomol. Chem., 2014,
12, 8453
Yi Liu,a,b Xue Sun,a,b Xing Zhang,a Jun Liu*a and Yuguo Du*a,b
Received 11th July 2014,
Accepted 27th August 2014
A novel and efficient method for the one-pot synthesis of 2,4-disubstituted thiazoles from carboxylic
acids or anhydrides is presented. Based on this new method, the total synthesis of the bis-2,4-disubsti-
tuted bis(thiazoles) natural product cystothiazole C is also presented.
DOI: 10.1039/c4ob01460j
www.rsc.org/obc
their easily available derivatives β-azido disulfides, should be
ideal building blocks. Recently, our group developed a novel
Introduction
2,4-Disubstituted thiazole is an important structural motif for phosphine-promoted one-pot four-step synthesis of 2,4-disub-
many natural products, such as cystothiazoles A & C (1–2),1 stituted thiazoline from β-azido disulfides and carboxylic
tristhiazole-containing cyclopeptide marthiapeptide A (3)2 and acids.8
thiopeptide thiocillin I.3 2,4-Disubstituted thiazole-containing
As shown in Scheme 1, treatment of β-azido disulfides 6a
derivatives also serve as useful building blocks in organic syn- and carboxylic acids 7 with triphenylphosphine in the pres-
thesis,4 play significant pharmaceutical roles in medicinal ence of EDCI and DIPEA obtained thiazolines 5 in good to
chemistry, and show antitumor, antithrombotic, antimicrobial, excellent yields. The formation of thiazoline can be explained
antiviral and other biological activities.5
by the initial disulfide bond cleavage and subsequent for-
The syntheses of 2,4-disubstituted thiazoles have been mation of the β-azido thiolester 8, which undergoes Staudinger
extensively studied in the last few decades, and significant reduction to form the phosphinimine (aza-ylide), followed by a
achievements in construction of 2,4-disubstituted thiazoles, ring closure through the intra-molecular aza-Wittig reaction. It
especially for the formation of poly-2,4-substituted thiazoles, is known that the thiazole is the aromatic form of thiazoline.
have been reported.4d,f Most of the current methodologies, The dehydrogenation of thiazoline can be conveniently
however, suffer from one or more limitations such as low employed for the preparation of the corresponding thiazole.4f
yield, multistep reactions, and the use of strong dehydrating These discoveries encouraged us to further explore an efficient
reagents, which limit their applicability to complex sub- method for making 2,4-disubstituted thiazole. The following
strates.6 Developing a novel efficient one-pot procedure to sections describe our efforts toward the one-pot synthesis of
prepare this heterocyclic system from easily available starting these thiazoles from carboxylic acid or anhydrides, and the
materials has remained to be of intense interest in organic application of this protocol to the total synthesis of cystothia-
chemistry and drug discovery.
zole C. To the best of our knowledge, no method has been
Biosynthetically, 2,4-disubstituted thiazole was possibly reported to prepare thiazoles directly from carboxylic acids or
formed from cysteine-containing peptides via sequential de- anhydrides in one pot.
hydration and oxidative dehydrogenation.7 For the chemical syn-
thesis of 2,4-disubstituted thiazoles, cysteine and cystine, or
Results and discussion
The direct oxidation of thiazoline with dehydrogenation
reagents has been used extensively for the construction of thia-
zoles and several efficient oxidants have been suggested.9
However, selection of oxidants and reaction conditions is
crucial for the transformation due to the instability of thiazo-
line under some strong oxidants, such as KMnO4, oxone, per-
acids and oxaziridines.4f We initially commenced our study by
treating reactants β-azido disulfide ester 6a and n-butyric acid
aState Key Laboratory of Environmental Chemistry and Eco-toxicology, Research
Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing
100085, China. E-mail: duyuguo@rcees.ac.cn, junliu@rcees.ac.cn;
Fax: +86-010-62923563
bSchool of Chemistry and Chemical Engineering, University of Chinese Academy of
Sciences, Beijing 100049, China
†Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for compounds 10a–10g, 10i–10m, 10o, 13, 15a, 15b, 16–19 and 2.
See DOI: 10.1039/c4ob01460j
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Scheme 1 Proposed mechanism for the thiazoline formation.
7a with activated manganese dioxide9i as the oxidation reagent cyclo[5.4.0]undecane (DBU) as oxidative dehydrogenation
in DCM.
reagent according to Williams’s procedure9c (entries 3–8). The
To our surprise, activated manganese dioxide was an in- amount of DBU and BrCCl3 was crucial to the transformation
appropriate reagent for this one-pot protocol and gave trace and the best result was obtained when the dosage of BrCCl3/
amounts of the target product (entry 1), which might be DBU was set at 8.0 eq./12.0 eq. furnishing the thiazole in good
ascribed to the using of the low boiling point solvent DCM.9h overall yield of 67% (entry 6). Several other brominating
Other dehydrogenation reagents were also investigated and are reagents, such as NBS or CBr4, were also examined, but were
summarized in Table 1. Attempts to utilize Singh’s copper salt found ineffective for this conversion (entries 9 and 10).
oxidation methodology10 in the one-pot protocol were also
Under the optimal reaction conditions, the reaction scopes
made, but no desired product was observed even at the elev- for reactions of two β-azido disulfide derivatives 6a–b and car-
ated reaction temperature (entry 2). Gratifyingly, we found that boxylic acids 7 bearing different substituents have been deter-
the desired thiazole could be achieved in one pot using bromo- mined. As shown in Table 2, both aromatic acids and aliphatic
trichloromethane (BrCCl3) in combination with 1,5-diazabi- acids could be efficiently incorporated into the thiazoles in
Table 1 Screening the oxidants under various conditionsa
Entry
Oxidantsb
Time
T (°C)
Yieldc (%)
1
2
3
4
5
6
7
8
MnO2
16 h
16 h
3 h
rt or reflux
rt or reflux
rt
rt
rt
rt
rt
rt
rt
rt
rt
reflux
reflux
rt
<5
4.0 eq. CuBr2/DBU/HMTA
3.0 eq. BrCCl3, 3.0 eq. DBU
8.0 eq. BrCCl3, 4.0 eq. DBU
8.0 eq. BrCCl3, 8.0 eq. DBU
8.0 eq. BrCCl3, 12.0 eq. DBU
10.0 eq. BrCCl3, 14.0 eq. DBU
10.0 eq. BrCCl3, 16.0 eq. DBU
8.0 eq. NBS, 12.0 eq. DBU
8.0 eq. CBr4, 12.0 eq. DBU
8.0 eq. BrCCl3
NDd
8
1 h
16
50
67
49
0.5 h
0.5 h
0.5 h
0.5 h
24 h
24 h
24 h
5 h
43
9
NDd
NDd
NDd
15e
40e
23e
10
11
12
13
14
8.0 eq. DBU, 8.0 eq. BrCCl3
12.0 eq. DBU, 8.0 eq. BrCCl3
12.0 eq. DBU, 8.0 eq. BrCCl3
5 h
48 h
a Unless otherwise noted, the acid (4.0 eq.), EDCI (4.0 eq.), DIPEA (8.0 eq.) in DCM were used at room temperature, 15 min later, dialkyl disulfide
6a and nBu3P (2.2 eq.) were added into the solution and stirred for 1 h at room temperature. PPh3 (8.0 eq.) was then added into the mixture and
refluxed for further 5 h and then oxidation reagents were added slowly into the reaction at room temperature. b HMTA: hexamethylenetetramine.
c Isolated yield. d No desired product. e Using DBU instead of DIPEA as the base in the reaction.
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Table 2 Thiazoles formation from carboxylic acidsa
a Unless otherwise noted, the acid (4.0 eq.), EDCI (4.0 eq.), DIPEA (8.0 eq.) in DCM were used at room temperature. 15 min later, β-azido disulfide
and nBu3P (2.2 eq.) were added into the solution and stirred for 1 h at room temperature. PPh3 (8.0 eq.) was then added into the mixture and
refluxed for further 5 h and then DBU (12.0 eq.)/BrCCl3 (8.0 eq.) were added slowly into the reaction mixture at room temperature. b 8.0 eq. DBU
and 6.0 eq. BrCCl3 was used. c 4.0 eq. EDCI, 8.0 eq. DIPEA, 1.2 eq. β-azido disulfide, 2.6 eq. nBu3P and 9.6 eq. PPh3 were used. d No desired
product.
good yields. Each of the aromatic carboxylic acid substrates, used as substrates. Various anhydrides and two β-azido disul-
containing either an electron-withdrawing or an electron- fides underwent smooth conversion to produce thiazoles in
donating substituent on the aromatic ring, was converted to excellent yields (from 66% to 74%). However, the bisthiazole
the corresponding thiazoles in good to excellent yields (56% to could not be efficiently synthesized under current conditions.
75%). The position (i.e., p-NO2 and o-I) and the number (i.e.,
The application of our one-pot formation of thiazole was
3,4,5-trimethoxy) of the substituent on the aromatic ring has immediately tested in a concise synthesis of bisthiazoles
little influence on the yields. Interestingly, we found that the cystothiazole C. Cystothiazoles A and C, isolated from the myxo-
desired bisthiazole could also be achieved in one pot using bacterium culture broth of Cystobacter fuscus in 1998, possess
p-phthalic acid as the substrate albeit in 17% yield.
a novel bis-2,4-disubstituted thiazole structure and a β-methoxy-
To test if the reaction conditions of the one-pot procedure acrylate moiety.1 Cystothiazole A (1) differs from cystothiazole
are mild enough, the optically pure L-lactic acid derivative was C (2) at C5 whereby a methoxy group is present rather than the
used and no detectable epimerization was observed at the free hydroxyl group (Fig. 1). Both cystothiazoles have shown
α-carbon of product 10j (see ESI†). The same reaction per- potent antifungal activity against a broad range of additional
formed with Weinreb amide 6b also gave good yield and fungi such as the phytopathogenic fungus Phytophthora capsics
benzoic acid was obtained in the highest yield of 75%.
(0.04 and 5 μg per disk, respectively) with no effect on bacterial
Anhydrides were also examined under these reaction con- growth. Their fungicidal activity appeared to be due to their
ditions (Table 3). To our delight, we observed that acetic anhy- ability to inhibit mitochondrial respiration by blocking elec-
dride could participate in the one-pot reaction with β-azido tron transfer between cytochrome
b
and cytochrome
disulfides in 73% yield. The coupling reagents EDCI was c. Although structurally related to the known α-methoxyacrylic
found unnecessary for the reaction when anhydrides were acid natural products myxothiazoles and melithiazoles,
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Table 3 Thiazoles formation from anhydridesa
a Unless otherwise noted, β-azido disulfide, anhydride (4.0 eq.) and DIPEA (8.0 eq.) in DCM were used at room temperature. nBu3P (2.2 eq.) was
added into the solution and stirred for 1 h at room temperature. PPh3 (8.0 eq.) was then added into the mixture and refluxed for further 5 h and
then DBU (12.0 eq.)/BrCCl3 (8.0 eq.) were added slowly into the reaction mixture at room temperature. b 4.0 eq. EDCI was used. c No desired
product. d 8.0 eq. DBU and 6.0 eq. BrCCl3 was used.
Fig. 1 The structures of cystothiazoles A (1) and C (2), marthiapeptide A (3).
cystothiazole A showed greater IC50 values when examined for yield over two steps, respectively. The key bisthiazole unit 15b
in vitro cytotoxicity using human colon carcinoma HCT-116 was achieved from commercially available isobutyric acid in
and human leukemia K562 cells, the resulting IC50 values were 38% yield and three synthetic steps. To the best of our knowl-
130 ng ml−1 and 110 ng ml−1, respectively.10 Owing to their edge, this is the shortest route towards bisthiazole fragment
novel structural scaffolds and potential biological activities, synthesis so far.
cystothiazoles A and C are remarkable synthetic targets for
chemists.11
To avoid the reductive cleavage of the thiazole ring, THF
was used as the solvent in the following reduction reaction.12
The synthesis of (+)-cystothiazole C (Scheme 2) began with Reduction of 15b with DIBAL-H to the corresponding aldehyde
the reaction of β-azido disulfide 6a and isobutyric acid 12 in and subsequent treatment with stable Wittig ylide (ethoxycar-
the presence of EDCI, DIPEA, nBu3P and PPh3, followed by oxi- bonylmethylene)triphenyl phosphorane at room temperature
dation with BrCCl3/DBU gave 13 in 74% overall yield. Removal delivered an easily separable mixture of E/Z isomers (3 : 1) in
of methyl ester from compound 13 with NaOH aqueous solu- 84% yield for two steps. The resulting (E)-α, β-unsaturated
tion in THF afforded the corresponding acid 14 in quantitative esters 16 was then treated with DIBAL-H in dry THF at −78 °C
yield. Without further purification, the crude acid was treated again to afford the corresponding allyl alcohol. The alcohol
with β-azido disulfides 6a or 6b in a one-pot protocol as was oxidized with Dess–Martin periodinane to afford aldehyde
described above, afforded the bisthiazole 15 in 48% or 52% 18 quantitatively.
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Scheme 2 Asymmetric synthesis of (+)-cystothiazole C.
According to Qu’s method,13 the (R)-BTHL (LiCl assisted yields via a one-pot disulfide cleavage/thiocarbonylation/intra-
BINOL-Ti species) catalyzed asymmetric vinylogous molecular Staudinger Reduction/aza-Wittig/oxidation reaction.
Mukaiyama aldol reaction between aldehyde and the Bras- The utility of the method was demonstrated by an efficient
sard’s diene14 was a good strategy for the formation of the total synthesis of (+)-cystothiazole C (9 steps, 7.3% overall yield
vicinal stereogenic centers and the β-methoxy acrylate moiety from isobutyric acid and β-azido disulfides) taking advantage
with excellent enantioselectivities. As expected, catalyzed with of the most convenient synthesis of the key bisthiazole frag-
20% (R)-BINOL/Ti(OiPr)4/LiCl/H2O complex, the aldehyde 18 ment (only 3 steps from isobutyric acid in 38% yield). Further
reacted smoothly with the known Brassard’s diene and applications of this strategy to the synthesis of related poly-
afforded the desired β-methoxy acrylate 19 in 52% yield. thiazole-containing natural products are currently under inves-
Finally, treatment of 19 with trifluoroacetic acid in CHCl3 furn- tigation in our laboratory.
ished the thermodynamically stable E isomer, (+)-cystothiazole
C in 67% yield. The physical data of the synthetic (+)-cystothia-
zole C were consistent with those of the natural product
{[α]D20 +147 ((c 0.2, CHCl3))}(lit.1 [α]D20 +145 (c 0.2, CHCl3)).
Based on our process, (+)-cystothiazole A could be easily
achieved by methylation of the secondary alcohol group of
(+)-cystothiazole C using Meerwein’s reagent.11h
Experimental
General
All reactions were performed under an argon atmosphere and
the solvents were dried according to the established pro-
cedures ahead of use. All reagents were purchased from com-
mercial sources. All reactions under standard conditions were
monitored by thin-layer chromatography (TLC) on gel F254
plates. Flash chromatography (FC) was performed using silica
Conclusions
In conclusion, we have developed a novel and efficient gel (200–300 meshes) according to the protocol of Still, Kahn,
approach for the synthesis of 2,4-disubstituted thiazoles and Mitra. Visualization was accomplished with UV light or
directly from carboxylic acids or anhydrides with β-azido disul- KMnO4 solution. Optical rotations were recorded on a polari-
fides for the first time. A variety of commonly used carboxylic meter. High-resolution mass spectrometry data were acquired
acids and anhydrides were transformed into thiazoles in good using a Q-TOF analyzer. Melting points were analyzed on a
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Melt-Temp II capillary melting point apparatus. The ee value δ: 13.6, 23.5, 35.5, 52.4, 127.1, 146.3, 162.0, 172.4; ESI-HRMS
was determined using chiral HPLC with the Chiralcel IA calcd for C8H11NNaO2S ([M + Na]+) 208.0403, found 208.0381.
column. 1H NMR, 13C NMR were measured on 400 MHz or
Methyl 2-phenylthiazole-4-carboxylate (10b). The title com-
100 MHz spectrometers (NMR in CDCl3 with TMS as an pound was prepared according to the typical procedure, as
internal standard). Chemical shifts (δ) are given in ppm rela- described above in 73% yield as a pale yellow solid; data are
tive to residual solvent (usually chloroform; δ 7.26 for 1H NMR consistent with a previously characterized compound.15 m.p.
or 77.23 for proton decoupled 13C NMR), and coupling con- 71–72 °C; 1H NMR (400 MHz) δ: 3.97 (s, 3H), 7.43–7.46 (m,
stants (J) in Hz. β-Azido disulfides 6 were prepared according 3H), 7.98–8.00 (m, 2H), 8.16 (s, 1H); 13C NMR (100 MHz) δ:
to our previous method.8
52.5, 127.0, 127.3, 129.0, 130.8, 132.7, 147.7, 161.9, 169.0;
ESI-HRMS calcd for C11H9NNaO2S ([M + Na]+) 242.0246, found
242.0224.
General procedure for the formation of thiazoles from
carboxylic acids
Methyl 2-methylthiazole-4-carboxylate (10c). The title com-
To a solution of acid 7 (1.0 mmol) in CH2Cl2 (5 ml) were pound was prepared according to the typical procedure, as
added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro- described above in 71% yield as a white solid; data are consist-
chloride (EDCI) (191.7 mg, 1.0 mmol) and N,N′-diisopropyl- ent with
a
previously characterized compound.9d m.p.
1
ethylamine (DIPEA) (258.4 mg, 2.0 mmol) at room 54–55 °C; H NMR (400 MHz) δ: 2.77 (s, 3H), 3.94 (s, 3H), 8.05
temperature. After stirring for 15 min, 6 (0.25 mmol) was (s, 1H); 13C NMR (100 MHz) δ: 19.3, 52.4, 127.4, 146.5, 161.8,
added into the solution and then Bu3P (111.3 mg, 0.55 mmol) 166.9; ESI-HRMS calcd for C6H7NNaO2S ([M + Na]+) 180.0090,
was added slowly into the mixture away from light. The reac- found 180.0078.
tion mixture was stirred at room temperature for another 1 h.
Methyl 2-(thiophen-2-yl)thiazole-4-carboxylate (10d). The
PPh3 (524.6 mg, 2.0 mmol) was added into the solution and title compound was prepared according to the typical pro-
heated to reflux for further 5 h. The solution was cooled to cedure, as described above in 35% yield as a yellow solid; m.p.
room temperature, and 1,8-diazabicycloundec-7-ene (DBU) 109–110 °C; 1H NMR (400 MHz) δ: 3.96 (s, 3H), 7.08–7.11
(456.6 mg, 3.0 mmol) was added. Bromotrichloromethane (m, 1H), 7.45 (dd, J = 0.8 Hz, J = 5.2 Hz, 1H), 7.59 (dd, J = 0.8
(396.5 mg, 2.0 mmol) was then introduced via a syringe over Hz, J = 3.6 Hz, 1H), 8.10 (s, 1H); 13C NMR (100 MHz) δ: 52.5,
3 min. The resulting mixture was stirred further for 30 min at 126.6, 127.7, 127.9, 128.8, 136.2, 147.3, 161.7, 162.5; ESI-HRMS
room temperature. The solvent was quenched with saturated calcd for C9H7NNaO2S2 ([M + Na]+) 247.9810, found 247.9843.
NH4Cl solution, and then extracted with EtOAc (20 ml × 3).
Methyl 2-(4-nitrophenyl)thiazole-4-carboxylate (10e). The
The combined organic layer was washed with brine and dried title compound was prepared according to the typical pro-
over anhydrous Na2SO4, concentrated in vacuo, and purified by cedure, as described above in 56% yield as a yellow solid; data
FC to give compound 10.
are consistent with a previously characterized compound.9g m.
p. 210–214 °C; 1H NMR (400 MHz) δ: 4.00 (s, 3H), 8.18–8.21
(m, 2H), 8.30–8.32 (m, 3H); 13C NMR (100 MHz) δ: 52.7, 124.4,
127.7, 128.8, 138.1, 148.6, 149.0, 161.5, 165.9; EI-HRMS calcd
General procedure for the formation of thiazoles from
anhydrides
β-Azido disulfide 6 (0.25 mmol) was dissolved in CH2Cl2 for C11H8N2O4S ([M]+) 264.0205, found 264.0209.
(5 ml). Then acetic anhydride 11 (1.0 mmol) and N,N′-diisopro- Methyl 2-(2-iodophenyl)thiazole-4-carboxylate (10f). The
pylethylamine (DIPEA) (258.5 mg, 2.0 mmol) were added into title compound was prepared according to the typical pro-
the solution at room temperature. After stirring for 5 min, cedure, as described above in 75% yield as a white solid; m.p.
nBu3P (111.3 mg, 0.55 mmol) was added slowly into the 63–64 °C; 1H NMR (400 MHz) δ: 3.96 (s, 3H), 7.11 (td, J =
mixture away from light. The reaction mixture was stirred at 1.6 Hz, J = 9.2 Hz, 1H), 7.41 (td, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.71
room temperature for another 0.5 h. PPh3 (524.6 mg, (dd, J = 1.6 Hz, J = 7.6 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 8.30 (s,
2.0 mmol) was added into the solution and heated to reflux for 1H); 13C NMR (100 MHz) δ: 52.4, 96.6, 128.2, 128.8, 131.2,
further 5 h. The solution was cooled to room temperature, and 131.4, 137.4, 140.3, 146.6, 161.9, 168.3; ESI-HRMS calcd for
the DBU (456.6 mg, 3.0 mmol) was added. Bromotrichloro- C11H8INNaO2S ([M + Na]+) 367.9213, found 367.9201.
methane (396.5 mg, 2.0 mmol) was then introduced into the
Methyl 2-(3,4,5-trimethoxyphenyl)thiazole-4-carboxylate (10g).
solution via a syringe over 3 min. The resulting mixture was The title compound was prepared according to the typical pro-
stirred further for 30 min at room temperature. The reaction cedure, as described above in 74% yield as a white solid; m.p.
was quenched with saturated NH4Cl solution, and then 110–112 °C; 1H NMR (400 MHz) δ: 3.86 (s, 3H), 3.91 (s, 6H),
extracted with EtOAc (20 ml × 3). The combined organic layer 3.93 (s, 3H), 7.17 (s, 2H), 8.12 (s, 1H); 13C NMR (100 MHz)
was washed with brine and dried over anhydrous Na2SO4, con- δ: 52.4, 56.4, 61.0, 104.3, 127.2, 128.2, 140.4, 147.5, 153.6,
centrated in vacuo, and purified by FC to give compound 10.
Methyl 2-propylthiazole-4-carboxylate (10a). The title com- 348.0303, found 348.0309.
161.8, 168.8; ESI-HRMS calcd for C14H15KNO5S ([M + K]+)
pound was prepared according to the typical procedure, as
Dimethyl 2,2′-(1,4-phenylene)dithiazole-4-carboxylate (10i).
described above in 67% yield as colorless oil; 1H NMR The title compound was prepared according to the typical pro-
(400 MHz) δ: 1.02 (t, J = 7.2 Hz, 3H), 1.80–1.87 (m, 2H), 3.04 (t, cedure, as described above in 17% yield as a white solid; m.p.
J = 7.2 Hz, 2H), 3.95 (s, 3H), 8.09 (s, 1H); 13C NMR (100 MHz) 160–161 °C; 1H NMR (400 MHz) δ: 4.00 (s, 3H), 8.11 (s, 2H),
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8.23 (s, 1H); 13C NMR (100 MHz) δ: 52.5, 127.5, 127.7, 134.6, into the mixture away from light. The reaction mixture was
148.0, 161.8, 167.7; ESI-HRMS calcd for C16H12N2NaO4S2 stirred at room temperature for another 0.5 h. PPh3 (13.1 g,
([M + Na]+) 383.0131, found 383.0111.
50.0 mmol) was added into the solution and heated to reflux
(S)-Methyl 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-4- for further 5 h. The solution was cooled to room temperature,
carboxylate (10j). The title compound was prepared according and then DBU (11.4 g, 75.0 mmol) was added. Bromotrichloro-
to the typical procedure, as described above in 54% yield as methane (9.9 g, 50.0 mmol) was then introduced via a syringe
colorless oil with 99.9% ee; [α]2D0 −121.5 (c 2.3, CHCl3); 1H over 10 min. After stirring at room temperature for 40 min the
NMR (400 MHz) δ: 1.13 (s, 9H), 1.41 (d, J = 6.4 Hz, 3H), 3.91 (s, reaction mixture was quenched with saturated NH4Cl solution,
3H), 5.23 (q, J = 6.4 Hz, 1H), 7.31–7.46 (m, 6H), 7.61 (d, J = and then extracted with EtOAc (50 ml × 3). The combined
6.8 Hz, 2H), 7.71 (d, J = 6.8 Hz, 2H), 8.12 (s, 1H); 13C NMR organic layer was washed with brine and dried over anhydrous
(100 MHz) δ: 19.3, 25.4, 26.9, 52.3, 70.6, 127.3, 127.7, 127.8, Na2SO4, concentrated in vacuo, and purified by FC (silica gel,
129.9, 130.0, 132.5, 133.4, 135.7, 135.8, 146.5, 162.0, 178.6; hexanes–EtOAc 3 : 1) to give compound 13 as a white solid
1
Enantiomeric excess was determined by HPLC with a Chiralcel (1.69 g, 73%). m.p. 112–114 °C; H NMR (400 MHz) δ: 1.41 (d,
IA column (99.5/0.5 hexane–2-propanol), 0.2 ml min−1; for our J = 6.8 Hz, 6H), 3.41 (sept, J = 6.8 Hz, 1H), 3.93 (s, 3H), 8.06 (s,
10j, tR = 49.5 min, for its enantiomer, tR = 46.9 min. ESI-HRMS 1H); 13C NMR (100 MHz) δ: 23.2, 33.6, 52.4, 126.6, 146.2,
calcd for C23H27KNO3SSi ([M + K]+) 464.1112, found 464.1115.
162.1, 179.1; ESI-HRMS calcd for C8H11NNaO2S ([M + Na]+)
N-Methoxy-N-methyl-2-propylthiazole-4-carboxamide (10k). 208.0403, found 208.0423.
The title compound was prepared according to the typical pro-
2′-Isopropyl-N-methoxy-N-methyl-2,4′-bithiazole-4-carboxa-
cedure, as described above in 61% yield as colorless oil; 1H mide (15b). To a solution of 13 (500 mg, 2.7 mmol) in MeOH
NMR (400 MHz) δ: 1.01 (t, J = 7.6 Hz, 3H), 1.79–1.88 (m, 2H), (15 ml) was added 1 N NaOH solution 5 ml under an ice-bath.
3.00 (t, J = 7.6 Hz, 2H), 3.43 (s, 3H), 3.77 (s, 3H), 7.88 (s, 1H); After stirring at 0 °C for 2 h, the mixture was diluted with
13C NMR (100 MHz) δ: 13.6, 23.2, 34.5, 35.4, 61.5, 124.2, 148.1, 15 ml H2O and the pH adjusted to 2.0 using 1 N HCl. The
163.2, 170.5; ESI-HRMS calcd for C9H14N2NaO2S ([M + Na]+) resulting solution was extracted with EtOAc 5 times. The
237.0668, found 237.0596.
organic layer was separated, washed with brine, dried
N-Methoxy-N-methyl-2-phenylthiazole-4-carboxamide (10l). (Na2SO4), filtered and concentrated in vacuo. The residue 14
The title compound was prepared according to the typical pro- was used for the next reaction without further purification.
cedure, as described above in 75% yield as colorless oil; data The acid 14 was dissolved in 35 ml CH2Cl2, 1-ethyl-3-(3-
are consistent with a previously characterized compound.16 1
H
dimethylaminopropyl)carbodiimide hydrochloride (EDCI)
NMR (400 MHz) δ: 3.49 (s, 3H), 3.88 (s, 3H), 7.44–7.45 (m, 3H), (517.6 mg, 2.7 mmol) and N,N′-diisopropylethylamine (DIPEA)
7.96–7.98 (m, 2H), 8.01 (s, 1H); 13C NMR (100 MHz) δ: 34.4, (697.9 mg, 5.4 mmol) at room temperature. After stirring for
61.7, 124.9, 126.7, 129.0, 130.4, 133.2, 149.7, 167.4; ESI-HRMS 15 min, 6b (529.2 mg, 1.4 mmol) was added into the solution
calcd for C12H12N2NaO2S ([M
271.0538.
+
Na]+) 271.0512, found and then Bu3P (622.2 mg, 3.1 mmol) was added slowly into the
mixture away from light. The reaction mixture was stirred at
Methyl 2-pentylthiazole-4-carboxylate (10m). The title com- room temperature for another 1 h. PPh3 (2.94 g, 11.3 mmol)
pound was prepared according to the typical procedure, as was added into the solution and heated to reflux for further
described above in 66% as colorless oil; 1H NMR (400 MHz) 5 h. The solution was cooled to room temperature, and then
δ: 0.87 (t, J = 7.2 Hz, 3H), 1.29–1.37 (m, 4H), 1.73–1.79 (m, 2H), DBU (2.56 g, 16.8 mmol) was added. Bromotrichloromethane
3.02 (t, J = 8.0 Hz, 2H), 3.91 (s, 3H), 8.04 (s, 1H); 13C NMR (2.24 g, 11.3 mmol) was then introduced via a syringe over
(100 MHz) δ: 13.8, 22.2, 29.7, 31.1, 33.5, 52.3, 127.0, 146.2, 10 min. After stirring at room temperature for further 40 min
161.9, 172.5; ESI-HRMS calcd for C10H15NNaO2S ([M + Na]+) the reaction mixture was quenched with saturated NH4Cl solu-
236.0715, found 236.0671.
tion, and then extracted with EtOAc (20 ml × 3). The combined
N-Methoxy-N-methyl-2-pentylthiazole-4-carboxamide (10o). organic layer was washed with brine and dried over anhydrous
The title compound was prepared according to the typical pro- Na2SO4, concentrated in vacuo, and purified by FC (silica gel,
cedure, as described above in 71% yield as colorless oil; 1H hexanes–EtOAc 1 : 1) to give compound 15b as colorless oil
1
NMR (400 MHz) δ: 0.88 (t, J = 7.2 Hz, 3H), 1.33–1.38 (m, 4H), (417.4 mg, 52% for two steps). H NMR (400 MHz) δ: 1.44 (d,
1.75–1.83 (m, 2H), 3.00 (t, J = 7.2 Hz, 2H), 3.41 (s, 3H), 3.75 (s, J = 7.2 Hz, 6H), 3.37 (sept, J = 7.2 Hz, 1H), 3.46 (s, 3H), 3.82 (s,
3H), 7.86 (s, 1H); 13C NMR (100 MHz) δ: 13.9, 22.3, 29.5, 31.2, 3H), 7.89 (s, 1H), 8.00 (s, 1H); 13C NMR (100 MHz) δ: 23.1,
33.4, 34.5, 61.4, 124.2, 148.1, 163.1, 170.7; ESI-HRMS calcd for 33.3, 34.3, 61.5, 115.4, 125.1, 148.2, 149.2, 162.3, 163.1, 178.8;
C11H18N2NaO2S ([M + Na]+) 265.0981, found 265.0979.
ESI-HRMS calcd for C12H15N3NaO2S2 ([M + Na]+) 320.0498,
Methyl 2-isopropylthiazole-4-carboxylate (13). To a solution found 320.0534.
of isobutyric acid 12 (2.2 g, 25.0 mmol) in CH2Cl2 (100 ml) was
Methyl 2′-isopropyl-2,4′-bithiazole-4-carboxylate (15a). Fol-
added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro- lowing the procedure described above, starting from methyl
chloride (EDCI) (4.8 g, 25.0 mmol) and N,N′-diisopropylethyl- 2-isopropylthiazole-4-carboxylate 13 (100.0 mg, 0.54 mmol)
amine (DIPEA) (6.5 g, 50.0 mmol) at room temperature. After and β-azido disulfide ester 6a (89.6 mg, 0.28 mmol), we
stirring for 15 min, 6a (2.0 g, 6.25 mmol) was added into the obtained the title product 15a as a white solid (70.2 mg, 48%
solution and then Bu3P (2.8 g, 13.7 mmol) was added slowly for two steps). m.p. 98–99 °C; 1H NMR (400 MHz) δ: 1.44
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(d, J = 6.8 Hz, 6H), 3.36 (sept, J = 6.8 Hz, 1H), 3.98 (s, 3H), 8.02 periodinane (319 mg, 0.75 mmol) was added into the solution
(s, 1H), 8.18 (s, 1H); 13C NMR (100 MHz) δ: 23.1, 33.3, 52.5, at 0 °C. After stirring at room temperature for 0.5 h, saturated
116.2, 127.9, 147.5, 147.7, 162.0, 163.9, 178.7; ESI-HRMS calcd aqueous NaHCO3 was added. The aqueous phase was extracted
for C11H12KN2O2S2 ([M + K]+) 306.9972, found 306.9967.
with EtOAc 3 times. Combined organic phases were dried
(E)-Ethyl 3-(2′-isopropyl-2,4′-bithiazol-4-yl)acrylate (16). To a (Na2SO4), filtered, and concentrated in vacuo. The reaction solu-
solution of 15b (100 mg, 0.34 mmol) in dry THF (15 ml) at tion was removed by reduced pressure. The crude yellow
−78 °C was added diisobutylaluminum hydride (1.0 M in mixture was purified by flash silica gel chromatography
hexanes, 1.68 ml, 1.68 mmol)) dropwise. The mixture was (hexanes–EtOAc 5 : 1) to give the title aldehyde 18 as a white
stirred at −78 °C for 1 h. The reaction was quenched with 20% solid (39.3 mg, 99%). Data are consistent with a previously
aqueous sodium-potassium tartrate (15 ml) and diluted with characterized compound.11a 1H NMR (400 MHz) δ: 1.45 (d, J =
EtOAc (15 ml). After being warmed to room temperature, the 6.8 Hz, 6H), 3.37 (sept, J = 6.8 Hz, 1H), 7.02 (dd, J = 7.6 Hz, J =
solution was stirred vigorously for 1 h. The organic phase was 15.6 Hz, 1H), 7.45 (d, J = 15.6 Hz, 1H), 7.58 (s, 1H), 7.92 (s, 1H),
separated, and the aqueous phase was re-extracted with EtOAc 9.74 (d, J = 7.6 Hz, 1H); 13C NMR (100 MHz) δ: 23.1, 33.4, 116.0,
3 times. The combined organic phases were dried (Na2SO4), fil- 123.4, 130.5, 143.6, 148.0, 152.2, 164.0, 179.0, 193.6; EI-HRMS
tered, and concentrated in vacuo. The crude residue was used calcd for C12H12N2OS2 ([M]+) 264.0391, found 264.0396.
for the next step without further purification. The crude
(2Z,4S,5R,6E)-Methyl 5-hydroxy-7-(2′-isopropyl-2,4′-bithiazol-
product was dissolved in dry CH2Cl2 (15 ml) and stirred at 4-yl)-3-methoxy-4-methylhepta-2,6-dienoate (19). Under a N2
room temperature and then ethyl (triphenylphosphoranyli- atmosphere in a dry bottle, a mixture of Ti(OiPr)4 (56.8 mg,
dene)acetate (586.3 mg, 1.68 mmol) in dry CH2Cl2 (10 ml) was 0.2 mmol) and (R)-BINOL (57.3 mg, 0.2 mmol) was stirred in
slowly added into the mixture. The resulting mixture was THF (16 ml) at room temperature for 20 min. Then to the
stirred for 1 h. Then the solvent was removed by reduced mixture was added H2O (3.6 mg, 0.2 mmol). After another
pressure. The crude product was estimated to be comprised of 20 min, anhydrous LiCl (8.6 mg, 0.2 mmol) kept in a Schlenk
1
a 3 : 1 ratio of E/Z olefin isomers by H NMR signal interpret- tube was quickly added bottle to bottle under a N2 atmosphere.
ation and was purified by flash silica gel chromatography After the mixture was stirred for 30 min, 4.8 ml of the catalyst
(hexanes–EtOAc 10 : 1) to give E isomer 16 as colorless oil solution was transferred to another bottle and the aldehyde 18
1
(65.7 mg, 63% for two steps). H NMR (400 MHz) δ: 1.34 (t, J = (80 mg, 0.3 mmol) and Brassard’s diene (324.5 mg 1.5 mmol)
7.2 Hz, 3H), 1.44 (d, J = 7.2 Hz, 6H), 3.37 (sept, J = 7.2 Hz, 1H), were added successively into the solution. After stirring for
4.27 (q, J = 7.2 Hz, 2H), 6.82 (d, J = 15.6 Hz, 1H), 7.42 (s, 1H), 36 h at room temperature, the reaction solution was cooled to
7.62 (d, J = 15.6 Hz, 1H), 7.89 (s, 1H); 13C NMR (100 MHz) 0 °C and quenched with 5 drops of 1 N HCl. After an
δ: 14.3, 23.1, 33.4, 60.5, 115.6, 120.8, 121.8, 136.3, 148.3, 152.5, additional 3 min, the mixture was neutralized with saturated
163.6, 167.2, 178.9; ESI-HRMS calcd for C14H16N2NaO2S2 NaHCO3. The aqueous phase was extracted with EtOAc 3
([M + Na]+) 331.0545, found 331.0561.
times. The combined organic phases were dried (Na2SO4), fil-
(E)-3-(2-(2-Isopropylthiazol-4-yl)thiazol-4-yl)acrylaldehyde (18). tered, and concentrated in vacuo. The reaction solution was
To a solution of 16 (50 mg, 0.162 mmol) in dry THF (10 ml) at removed by reduced pressure. The crude mixture was purified
−78 °C was added diisobutylaluminum hydride (1.0 M in by flash silica gel chromatography (hexanes–EtOAc 2 : 1) to give
hexanes, 0.81 ml, 0.81 mmol) dropwise. The mixture was the product 19 as colorless oil (64.2 mg, 52%). [α]2D0 +120 (c 0.1,
1
stirred at −78 °C for 1 h. The reaction mixture was quenched CHCl3); H NMR (400 MHz) δ: 1.18 (d, J = 7.2 Hz, 3H), 1.44 (d,
with aqueous 20% sodium-potassium tartrate (10 ml) and J = 6.8 Hz, 6H), 2.54–2.60 (m, 1H), 3.37 (sept, J = 6.8 Hz, 1H),
diluted with EtOAc (10 ml). After warming to room tempera- 3.67 (s, 3H), 3.97 (s, 3H), 4.50 (dd, J = 4.4 Hz, J = 4.4 Hz, 1H),
ture, the solution was stirred vigorously for 1 h. The phases 5.14 (s, 1H), 6.61–6.71 (m, 2H), 7.09 (s, 1H), 7.89 (s, 1H);
were separated, and the aqueous phase was re-extracted with 13C NMR (100 MHz) δ: 12.5, 23.2, 33.4, 40.5, 51.1, 55.7, 74.8,
EtOAc 3 times. The combined organic phases were dried 91.5, 115.0, 115.1, 123.4, 132.8, 148.7, 154.5, 162.6, 168.7,
(Na2SO4), filtered, and concentrated in vacuo. The reaction 176.9, 178.6; ESI-HRMS calcd for C19H24N2NaO4S2 ([M + Na]+)
solvent was removed by reduced pressure. The crude yellow 431.1075, found 431.1085.
mixture was purified by flash silica gel chromatography
(+)-Cystothiazole C (2). To a solution of aldol product 19
(hexanes–EtOAc 3 : 1) to give the title alcohol 17 as colorless oil (30 mg, 0.07 mmol) in 2 ml chloroform was added one drop of
(38.9 mg, 90%). Data are consistent with a previously charac- CF3COOH in ice bath. The reaction mixture was stirred in ice
terized compound.3 1H NMR (400 MHz) δ: 1.44 (d, J = 7.2 Hz, bath for 0.5 h and then the solvent was neutralized with satu-
6H), 3.37 (sept, J = 7.2 Hz, 1H), 4.37 (dd, J = 1.2 Hz, J = 5.2 Hz, rated NaHCO3. The mixture was extracted with EtOAc 3 times.
2H), 6.67 (d, J = 15.6 Hz, 1H), 6.79 (dt, J = 5.2 Hz, J = 15.6 Hz, Combined organic phases were dried (Na2SO4), filtered, and
1H), 7.09 (s, 1H), 7.87 (s, 1H); 13C NMR (100 MHz) δ: 23.1, concentrated in vacuo. The reaction solution was removed by
33.3, 63.2, 115.0, 115.5, 123.5, 131.8, 148.6, 154.2, 162.9, 178.7; reduced pressure. The crude mixture was purified by flash
ESI-HRMS calcd for C12H14N2NaOS2 ([M + Na]+) 289.0440, silica gel chromatography (hexanes–EtOAc 2 : 1) to give the
found 289.0438; To
0.15 mmol) in dry CH2Cl2 (7 ml) was added NaHCO3 (20 mg) consistent with
and the mixture was stirred at room temperature. Dess–Martin [α]2D0 +147 (c 0.2, CHCl3); 1H NMR (400 MHz) δ: 1.18 (d, J =
a
solution of the alcohol (40 mg, (+)-cystothiazole C as colorless oil (19.5 mg, 65%); data are
a
previously characterized compound.1
8460 | Org. Biomol. Chem., 2014, 12, 8453–8461
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7.2 Hz, 3H), 1.44 (d, J = 6.8 Hz, 6H), 2.92 (br, 1H), 3.37 (sept,
J = 6.8 Hz, 1H), 3.66 (s, 3H), 3.70 (s, 3H), 4.17 (dq, J = 4.4 Hz,
J = 6.8 Hz, 1H), 4.52 (dd, J = 4.4 Hz, J = 4.4 Hz, 1H), 5.09 (s,
1H), 6.61 (dd, J = 4.8 Hz, J = 16.0 Hz, 1H), 6.71 (d, J = 16.0 Hz,
1H), 7.06 (s, 1H), 7.86 (s, 1H); 13C NMR (100 MHz) δ: 12.4,
23.1, 33.3, 40.4, 51.1, 55.7, 74.8, 91.5, 114.9, 115.1, 123.4,
132.7, 148.7, 154.5, 162.6, 168.7, 176.9, 178.6; ESI-HRMS calcd
for C19H24N2NaO4S2 ([M + Na]+) 431.1075, found 431.1080.
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Acknowledgements
This work was supported by Strategic Priority Research
Program of the Chinese Academy of Sciences (grant no.
XDB14040201), NNSF of China (Projects 21202193, 21232002),
and the Postdoctoral Science Foundation (2013M541012). We
thank Ming Xiao and Min Li for high resolution mass spec-
trometry determination.
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