Thiazole intermediates in synthesis

An enantioselective synthesis of both (R)- and (5)-a-alkylcysteines 144 and 147 is based on the phase-transfer catalytic alkylation of fert-butyl esters of 2-phenyl-2-thiazoline-4-carboxylic acid and 2-ort/ro-biphenyl-2-thiazoline-4-carboxylic acid, 142 and 145 06JOC8276 . Treatment of 142 and 145 with alkyl halides and potassium hydroxide in the presence of chiral catalysts 140 and 141 gives the alkylated products, which are hydrolyzed to (R)- and (S)-a-alkylcysteines 144 and 147, respectively, in high enantioselectivity. This method may have potential for the practical synthesis of chiral a-alkylcysteines. 

The stereoselective addition of the titanium enolate of A-acetyl-4-phenyl-l,3-thiazolidine-2-thione 153 to the cyclic A-acyl iminium ion 154 is utilized in the synthesis of (-)-stemoamide, a tricyclic alkaloid 06JOC3287 . The iminium ion addition product 155 undergoes magnesium bromide-catalyzed awtz-aldol reaction with cinnamaldehyde 156 to give adduct 157, which possesses the required stereochemistry of all chiral centers for the synthesis of (-)-stemoamide. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 06EJOC2851 . An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination 06OL1553 . A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 06OL4457 . 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is demonstrated in a recent enantioselective synthesis of solandelactones E and F 07OL3481 . Addition of aldehyde 132 to the enolate solution of /V-propionyl thiazolidinethione 131 

Highly diastereoselective acetate aldol additions using chlorotitanium enolates of mesityl-substituted JV-acetylthiazolidinethione 136 has been documented 07OL149 . These aldol reactions proceed in high yields and diastereoselectivities (94/6 to 98/2) for aliphatic, aromatic, and a,P-unsaturated aldehydes. Compound 136 also undergoes double diastereoselective aldol additions with chiral aldehyde 139 to give adduct 140 in high yields. 

The stereoselectivity of the Julia olefinations has been well documented, and as a rule of thumb, a-lithioalkyl benzothiazolyl sulfones deliver cz s-olcfins and a-lithiobenzyl benzothiazolyl sulfones trans-olefins 05SL289 . However, unexpected high cw-selectivity 

The utility of thiazolidinethione chiral auxiliaries in asymmetric aldol reactions is amply demonstrated in a recent enantioselective synthesis of apoptolidinone. This synthesis features three thiazolidinethione propionate aldol reactions for controlling the configuration of 6 of 12 stereogenio centers 05JA13810 . For example, addition of aldehyde 146 to the enolate solution of A -propionyl thiazolidinethione 145 produces aldol product 147 with excellent selectivity ( 98 2) for the Evans syn isomer. Compound 145 also undergoes diastereoselective aldol addition with bisaryl aldehyde 148 to give the Evans syn product 149, which is converted to eupomatilone-6 in 6 steps 05JOC9658 . 

Addition of the titanium enolate of Af-acetyl-4-isopropyl-l,3-thiazohdme-2-thione 150 to the A-acyl iminium ions from 151 furnishes the corresponding Mannich-type adducts 152 and 153 with good diastereoselectivity 05JOC4214 . A similar diastereoselective addition of the titanium enolate derived from Af-4-chlorobutyryl-l,3-thiazolidine-2-thione 154 to A -Boc-2-methoxypyrrohdine 155 has been used to provide 2-substituted pyrrolidine 156, a key intermediate in the synthesis of (+)-isoretronecanol 05TL2691 . 

The Ni(II) Tol-BINAP-catalyzed enantioselective orthoester alkylation of N-acylthiazolidinethiones 158 is carried out using 5 mol% of (5)-Ni(ll) Tol-BINAP 157 to provide 159 in good yields and with excellent enantioselectivities 05JA10506 . 

Exo- and enantioselective 1,3-dipolar cycloaddition of nitrones 161 with 3-(2-alkenoyl)-2-thiazolidinethiones 162 is carried out in the presence of a catalytic amount of binaphthyldiimine-Ni(II) complex, readily prepared in situ from dirmine 160 and Ni(C104)2 6H20 050L1431 . 

A new route to 3,4-disubstituted piperidines employs diastereoselective 1,4-addition of N-nicotinoyl thiazolidinethiones with aryl cuprates 05TL8673 . Treatment of the pyridinium salt, prepared from chiral nicotinic amide 165 and phenyl chloroformate, with 

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Rhodanines, as intermediates, in synthesis of amino adds peptides and purines, 167 Rhodaninic acid, see 2-Mercapto-4-hydroxy-thiazole Rhodanine Rhodanine, modes of preparation, 19 /V-phenyl, preparation, 19 /V-substituted, preparation, 20 structure of, 19... 

Pyrroloj2,1 -b) thiazole, formation of, 36 as intermediate for dyes, 36 in synthesis of chain-bridged thiazolocyanines, 58... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Care must be taken in the choice of organic solvent. Chloroform should never be used under the basic conditions due to the risk of the formation of isocyanides (see Chapter 7) and the use of carbon disulphide can lead to formation of dithiocarba-mates, e.g. dimethyl A -(ethoxycarbonylmethyl)iminodithiocarbonate is formed (35-39%), as the major product in high purity, in the liquiddiquid two-phase methyl-ation of ethyl glycinate in carbon disulphide [15]. The product is useful as an intermediate in the synthesis of thiazoles [15] and dihydrooxazoles [16]. 

Thiamin is synthesized in bacteria, fungi, and plants from 1-deoxyxylulose 5-phosphate (Eq. 25-21), which is also an intermediate in the nonmevalonate pathway of polyprenyl synthesis. However, thiamin diphosphate is a coenzyme for synthesis of this intermediate (p. 736), suggesting that an alternative pathway must also exist. Each of the two rings of thiamin is formed separately as the esters 4-amino-5-hydroxy-methylpyrimidine diphosphate and 4-methyl-5-((i-hydroxyethyl) thiazole monophosphate. These precursors are joined with displacement of pyrophosphate to form thiamin monophosphate.92b In eukaryotes this is hydrolyzed to thiamin, then converted to thiamin diphosphate by transfer of a diphospho group from ATP.92b c In bacteria thiamin monophosphate is converted to the diphosphate by ATP and thiamin monophosphate kinase.92b... 

The thiazole ring is assembled on the 5-carbon backbone of 1-deoxyxylulose 5-phosphate, which is also an intermediate in the alternative biosynthetic pathway for terpenes (Fig. 22-2) and in synthesis of vitamin B6 (Fig. 25-21). In E. coli the sulfur atom of the thiazole comes from cysteine and the nitrogen from tyrosine.374 The same is true for chloroplasts,375 whereas in yeast glycine appears to donate the nitrogen.372 The thiamin biosynthetic operon of E. coli contains six genes,372a 376 one of which (ThiS) encodes a protein that serves as a sulfur carrier from cysteine into the thiazole.374 The C-terminal glycine is converted into a thiocarboxylate ... 

Commercial thiamine dietary supplements are prepared by synthesis Pyrimidine + thiazole nuclei synthesized separately and then condensed also build on pyrimidine with acelaiiudiiie. Precursors in the biosynthesis of thiamine include thiazole and pyrimidine pyrophosphate, with thiamine phosphate as an intermediate. In plants, production sites arc found in grain and cereal germ. 

The thiazole 40 is available as it is an intermediate in the manufacture of vitamin B L and one patented synthesis uses the dichloro-compound 49 to make 41 by rather a different route.9... 

Organomercury derivatives of heterocycles in synthesis 85MI12. Organosilicon and organotin derivatives of thiazole and oxazole as intermediates in organic synthesis 88G211. 

The reaction of 2-aminothiazole and 2-aminobenzothiazole with 2-benzoyl-2-bromoacetate has been employed in the preparation of several fused imidazole systems <89JHC1875>. a-Bromo ketones attack the ring nitrogen of 2-aminothiazoles to give the salts (160). The same type of reaction takes place with ethylbromoacetate (Scheme 39). Basihcation of (160) affords the imines (I6I) which are intermediates in the synthesis of imidazo[2,l-h]thiazoles <89JCS(P1)643>. On the other hand, when an a-bromo aldehyde is made to react with 2-aminothiazoles, the salt (162) is formed directly leading to (163) after basification. 

The azido aldehyde 91 as intermediate for the synthesis of (+)-hydantocidin was synthesized from ribonolactone (Scheme 10). The a- or 3-anomers 87 and 88 were readily obtained (76-80%) through the addition of 2-lithiothiazole to the ribonolactone and subsequent acetylation. Their reaction with TMSNj afforded the a- and 3-azides 89 and 90 in a 1 3 ratio and 84% overall yield. The cleavage of the thiazole ring in the major isomer 90 by using either mercury(ll) or copper(ll) ion assisted hydrolysis in the final step afforded the aldehyde 91 (57%). 

The Hantzsch synthesis involves three intermediate steps. In the first, the halogen atom of the or-halo aldehyde or a-halo ketone is nucleophilically substituted. The resulting iS-alkyliminium salt 2 undergoes a proton transfer (2 -> 3) cyclization produces a salt of a 4-hydroxy-4,5-dihydrothiazole 4 which is converted into a 2,5-disubstituted thiazole 1 in protic solvents by an acid-catalysed elimination of water. 

Several examples of this widely practiced name reaction have been applied in drug discovery abound. For example in a study describing the design and synthesis of inhibitors of hepatitis C virus (HCV) NS5B polymerase, thiazole intermediate was constructed via the Gabriel reaction, ... 

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