180973-24-4

Usage

Uses

Used in Pharmaceutical Research:
(3S,4E)-3-Hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid is used as a research compound for studying lipid metabolism due to its structural similarity to endogenous lipid molecules, which may provide insights into the regulation and dysregulation of lipid pathways.
Used in Drug Development:
(3S,4E)-3-Hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid is used as a potential therapeutic agent for developing drugs targeting thioesterases or other enzymes involved in fatty acid metabolism, which may have implications for treating metabolic disorders and other diseases related to lipid metabolism.
Used in Chemical Synthesis:
(3S,4E)-3-Hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid can be used as a building block or intermediate in the synthesis of more complex organic compounds, particularly those with biological activity or pharmaceutical potential.
Further research is needed to fully understand the properties and potential applications of (3S,4E)-3-Hydroxy-7-[(triphenylmethyl)thio]-4-heptenoic acid, as its biological activity and therapeutic potential are not yet fully established.

Synthetic route

(E)-(S)-3-Hydroxy-7-tritylsulfanyl-hept-4-enoic acid benzyl ester (180973-40-4) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
With lithium hydroxide In methanol; water	100%

(3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one (663918-95-4) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
With lithium hydroxide; water In tetrahydrofuran Cooling with ice;	96%
Stage #1: (3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one With water; lithium hydroxide In tetrahydrofuran at 0 - 20℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water pH=2;	86%
With lithium hydroxide monohydrate; water In tetrahydrofuran at 0 - 30℃; for 12h;	13 g

(E)-(S)-3-hydroxy-1-[(R)-4-isopropyl-5,5-diphenyl-2-oxo-oxazolidin-3-yl]-7-tritylthio-4-hepten-1-one (878630-47-8) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Stage #1: (E)-(S)-3-hydroxy-1-[(R)-4-isopropyl-5,5-diphenyl-2-oxo-oxazolidin-3-yl]-7-tritylthio-4-hepten-1-one With water; sodium hydroxide In tetrahydrofuran; methanol at 0℃; for 1h; Stage #2: With hydrogenchloride In water; ethyl acetate at 0℃;	92%
With sodium hydroxide	76%
With sodium hydroxide In methanol; water at 0 - 20℃; for 1h;	58%

(2E)-5-[(triphenylmethyl)thio]-2-pentenal (180973-22-2) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: BuLi / tetrahydrofuran / -78 °C 1.2: Cp2ZrCl2 / tetrahydrofuran / -78 - 20 °C 2.1: 76 percent / NaOH View Scheme
Multi-step reaction with 2 steps 1.1: SmI2 / tetrahydrofuran / -78 °C 1.2: tetrahydrofuran / -78 °C 2.1: 76 percent / NaOH View Scheme
Multi-step reaction with 2 steps 1: 99 percent / Ti(IV) complex with (S)-(-)-binaphthyl amino alcohol 2: 100 percent / LiOH / methanol; H2O View Scheme

triphenylmethanethiol (3695-77-0) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 78 percent / Cs2CO3 2: 91 percent / DIBAL 3: 74 percent / (COCl)2, DMSO, Et3N 4: 99 percent / Ti(IV) complex with (S)-(-)-binaphthyl amino alcohol 5: 100 percent / LiOH / methanol; H2O View Scheme
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 1 h / 25 °C / Inert atmosphere; Automated synthesizer 2.1: dmap / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere; Automated synthesizer 2.2: 2 h / -20 - 25 °C / Inert atmosphere; Automated synthesizer 2.3: -78 - 0 °C / Inert atmosphere; Automated synthesizer 3.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere; Automated synthesizer 3.2: 1 h / -78 - -30 °C / Inert atmosphere; Automated synthesizer 3.3: 1 h / -50 - 0 °C / Inert atmosphere; Automated synthesizer 4.1: water; sodium hydroxide / tetrahydrofuran; methanol / 1 h / 0 °C 4.2: 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 20 °C / Flow reactor 2.1: diisobutylaluminium hydride / toluene / -97 °C / Flow reactor 3.1: lithium hexamethyldisilazane / tetrahydrofuran / -40 °C / Flow reactor 3.2: 0.02 h / -78 °C / Flow reactor 4.1: sodium hydroxide / methanol; water / 1 h / 0 - 20 °C View Scheme

(E)-5-(tritylthio)-2-penten-1-ol (180973-37-9) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 74 percent / (COCl)2, DMSO, Et3N 2: 99 percent / Ti(IV) complex with (S)-(-)-binaphthyl amino alcohol 3: 100 percent / LiOH / methanol; H2O View Scheme
Multi-step reaction with 3 steps 1.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 2.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 2.2: 2 h / -78 °C 2.3: 0.5 h / -78 °C 3.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

(E)-5-Tritylsulfanyl-pent-2-enoic acid methyl ester (180973-36-8) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 91 percent / DIBAL 2: 74 percent / (COCl)2, DMSO, Et3N 3: 99 percent / Ti(IV) complex with (S)-(-)-binaphthyl amino alcohol 4: 100 percent / LiOH / methanol; H2O View Scheme

methyl (2E)-penta-2,4-dienoate (2409-87-2) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 78 percent / Cs2CO3 2: 91 percent / DIBAL 3: 74 percent / (COCl)2, DMSO, Et3N 4: 99 percent / Ti(IV) complex with (S)-(-)-binaphthyl amino alcohol 5: 100 percent / LiOH / methanol; H2O View Scheme

S-trityl 3-mercaptopropionaldehyde (150350-28-0) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dmap / N,N-dimethyl-formamide / 2 h / 100 °C / Inert atmosphere; Automated synthesizer 1.2: 2 h / -20 - 25 °C / Inert atmosphere; Automated synthesizer 1.3: -78 - 0 °C / Inert atmosphere; Automated synthesizer 2.1: n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere; Automated synthesizer 2.2: 1 h / -78 - -30 °C / Inert atmosphere; Automated synthesizer 2.3: 1 h / -50 - 0 °C / Inert atmosphere; Automated synthesizer 3.1: water; sodium hydroxide / tetrahydrofuran; methanol / 1 h / 0 °C 3.2: 0 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -97 °C / Flow reactor 3.1: lithium hexamethyldisilazane / tetrahydrofuran / -40 °C / Flow reactor 3.2: 0.02 h / -78 °C / Flow reactor 4.1: sodium hydroxide / methanol; water / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 0 - 20 °C / Inert atmosphere 2.1: diisobutylaluminium hydride / toluene / -97 °C / Flow reactor 3.1: lithium hexamethyldisilazane / tetrahydrofuran / -78 °C / Flow reactor 3.2: 0.02 h / Flow reactor 4.1: sodium hydroxide / methanol; water / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: triphenylphosphine / toluene; water / 6 h / 25 - 105 °C 1.2: 2 h / 0 - 5 °C 2.1: diisobutylaluminium hydride / toluene / 3 h / 0 - 5 °C / Inert atmosphere 3.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 4.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 4.2: 2 h / -78 °C 4.3: 0.5 h / -78 °C 5.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

ethyl (E)-5-(triphenylmethylthio)-2-pentenoate (1309766-86-6) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: diisobutylaluminium hydride / toluene / -97 °C / Flow reactor 2.1: lithium hexamethyldisilazane / tetrahydrofuran / -40 °C / Flow reactor 2.2: 0.02 h / -78 °C / Flow reactor 3.1: sodium hydroxide / methanol; water / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: diisobutylaluminium hydride / toluene / -97 °C / Flow reactor 2.1: lithium hexamethyldisilazane / tetrahydrofuran / -78 °C / Flow reactor 2.2: 0.02 h / Flow reactor 3.1: sodium hydroxide / methanol; water / 1 h / 0 - 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: diisobutylaluminium hydride / toluene / 3 h / 0 - 5 °C / Inert atmosphere 2.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 3.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 3.2: 2 h / -78 °C 3.3: 0.5 h / -78 °C 4.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

trityl chloride (76-83-5) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions

Yield

Multi-step reaction with 8 steps 1.1: toluene / 6 h / 25 - 30 °C 2.1: sodium tetrahydroborate / tetrahydrofuran / 0.17 h / 0 - 5 °C 2.2: 3 h / 0 - 30 °C 3.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2 h / -75 - -70 °C 3.2: 2 h / -75 - 5 °C 4.1: triphenylphosphine / toluene; water / 6 h / 25 - 105 °C 4.2: 2 h / 0 - 5 °C 5.1: diisobutylaluminium hydride / toluene / 3 h / 0 - 5 °C / Inert atmosphere 6.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 7.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 7.2: 2 h / -78 °C 7.3: 0.5 h / -78 °C 8.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

3-(tritylthio) propanoic acid (27144-18-9) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: sodium tetrahydroborate / tetrahydrofuran / 0.17 h / 0 - 5 °C 1.2: 3 h / 0 - 30 °C 2.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2 h / -75 - -70 °C 2.2: 2 h / -75 - 5 °C 3.1: triphenylphosphine / toluene; water / 6 h / 25 - 105 °C 3.2: 2 h / 0 - 5 °C 4.1: diisobutylaluminium hydride / toluene / 3 h / 0 - 5 °C / Inert atmosphere 5.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 6.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 6.2: 2 h / -78 °C 6.3: 0.5 h / -78 °C 7.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

3-(tritylthio)propan-1-ol (100360-56-3) → (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 2 h / -75 - -70 °C 1.2: 2 h / -75 - 5 °C 2.1: triphenylphosphine / toluene; water / 6 h / 25 - 105 °C 2.2: 2 h / 0 - 5 °C 3.1: diisobutylaluminium hydride / toluene / 3 h / 0 - 5 °C / Inert atmosphere 4.1: manganese(IV) oxide / dichloromethane / 8 h / 25 - 45 °C 5.1: titanium tetrachloride / dichloromethane / 0 - 5 °C 5.2: 2 h / -78 °C 5.3: 0.5 h / -78 °C 6.1: lithium hydroxide monohydrate; water / tetrahydrofuran / 12 h / 0 - 30 °C View Scheme

(S)-2-{(Z)-2-[(S)-2-((R)-2-Amino-3-methyl-butyrylamino)-3-tritylsulfanyl-propionylamino]-but-2-enoylamino}-3-methyl-butyric acid methyl ester (180973-32-4) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (5E,7S,11R,14S,17E,20S)-methyl 17-ethylidene-7-hydroxy-11,20-diisopropyl-9,12,15,18-tetraoxo-1,1,1-triphenyl-14-(tritylthiomethyl)-2-thia-10,13,16,19-tetraazahenicos-5-en-21-oate (180973-33-5)

Conditions	Yield
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine	95%

C52H49N5O7S (1196992-63-8) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → C63H63N5O7S2 (1196992-65-0)

Conditions	Yield
Stage #1: C52H49N5O7S With diethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;	95%

(R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-16-1) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-18-3)

Conditions

Yield

Stage #1: (R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester With diethylamine In acetonitrile at 20℃; for 1h; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃;

91%

[(1-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-76-3) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → [(1-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-77-4)

Conditions

Yield

Stage #1: [(1-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester With diethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;

87%

(R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-1-methyl-ethylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-05-8) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-1-methyl-ethylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-07-0)

Conditions

Yield

Stage #1: (R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-1-methyl-ethylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester With diethylamine In acetonitrile at 20℃; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃;

85%

2-(Trimethylsilyl)ethanol (2916-68-9) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (S,E)-2-(trimethylsilyl)ethyl 3-(((S)-2-amino-3-methylbutanoyl)oxy)-7-(tritylthio)hept-4-enoate (1043577-31-6)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane Cooling with ice;	80%
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 5℃; for 0.916667h;	2.5 g

[(1-{(S)-2-[(R)-3-(3-chloro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-69-4) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → [(1-{(S)-2-[(R)-3-(3-chloro-phenyl)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-72-9)

Conditions

Yield

Stage #1: [(1-{(S)-2-[(R)-3-(3-chloro-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester With diethylamine In dichloromethane; acetonitrile at 20℃; for 1.5h; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 20℃; for 16h; Inert atmosphere;

80%

(R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclobutylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-35-4) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclobutylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196992-37-6)

Conditions

Yield

Stage #1: (R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclobutylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester With diethylamine In acetonitrile at 20℃; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;

75%

(R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(1-hydroxy-2-methoxycarbonyl-ethyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester (1196991-91-9) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (R)-4-{(S)-1-[1-(1-hydroxy-2-methoxycarbonyl-ethyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-butyric acid tert-butyl ester (1196991-93-1)

Conditions

Yield

Stage #1: (R)-4-(9H-fluoren-9-ylmethoxycarbonylamino)-4-{(S)-1-[1-(1-hydroxy-2-methoxycarbonyl-ethyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester With diethylamine In dichloromethane; acetonitrile for 1.5h; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h; Inert atmosphere;

72%

(3S,4R)-4-[(S)-2-((R)-2-Amino-propionylamino)-3-tritylsulfanyl-propionylamino]-3-hydroxy-5-methyl-hexanoic acid allyl ester + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (3S,4R)-3-Hydroxy-4-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-5-methyl-hexanoic acid allyl ester (881845-29-0)

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine	65%

[(1-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-pyridin-4-yl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-82-1) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → [(1-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-3-pyridin-4-yl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-84-3)

Conditions

Yield

Stage #1: [(1-{(S)-2-[(R)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-pyridin-4-yl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester With diethylamine In acetonitrile at 20℃; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;

61%

C46H44N4O7S (1196992-56-9) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → [(1-{(S)-2-[2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-acetylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester (1196992-58-1)

Conditions	Yield
Stage #1: C46H44N4O7S With diethylamine In acetonitrile at 20℃; for 2h; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 20℃; for 16h; Inert atmosphere;	56%

((R)-2-{(S)-2-[2-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl ester (1196992-44-5) + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → ((R)-2-{(S)-2-[2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-2-methyl-propionylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl ester (1196992-46-7)

Conditions

Yield

Stage #1: ((R)-2-{(S)-2-[2-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-methyl-propionylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl ester With diethylamine In acetonitrile at 20℃; for 1.25h; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;

51%

[2-((S)-2-{[1-(9H-fluoren-9-ylmethoxycarbonylamino)-cyclopropanecarbonyl]-amino}-3-tritylsulfanyl-propionylamino)-3-methyl-butyrylamino]-acetic acid methyl ester + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → [2-((S)-2-{[1-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-cyclopropanecarbonyl]-amino}-3-tritylsulfanyl-propionylamino)-3-methyl-butyrylamino]-acetic acid methyl ester

Conditions

Yield

Stage #1: [2-((S)-2-{[1-(9H-fluoren-9-ylmethoxycarbonylamino)-cyclopropanecarbonyl]-amino}-3-tritylsulfanyl-propionylamino)-3-methyl-butyrylamino]-acetic acid methyl ester With diethylamine In acetonitrile at 20℃; Inert atmosphere; Stage #2: (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane; acetonitrile at 0 - 20℃; Inert atmosphere;

41%

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → spiruchostatin A

Conditions	Yield
Multi-step reaction with 4 steps 1: 65 percent / N,N-diisopropylethylamine; benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium PF6(1-) 2: 87 percent / morpholine / Pd(PPh3)4 / methanol 3: 67 percent / MNBA; DMAP / CH2Cl2 4: 100 percent / I2 / methanol; CH2Cl2 View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (3S,4R)-3-Hydroxy-4-[((E)-(4S,7R,11S)-11-hydroxy-7-methyl-6,9-dioxo-1,2-dithia-5,8-diaza-cyclopentadec-12-ene-4-carbonyl)-amino]-5-methyl-hexanoic acid

Conditions	Yield
Multi-step reaction with 3 steps 1: 65 percent / N,N-diisopropylethylamine; benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium PF6(1-) 2: 87 percent / morpholine / Pd(PPh3)4 / methanol 3: 100 percent / I2 / methanol; CH2Cl2 View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (2S,6R,9S,12R,13S)-13-Hydroxy-12-isopropyl-6-methyl-2-((E)-4-tritylsulfanyl-but-1-enyl)-9-tritylsulfanylmethyl-1-oxa-5,8,11-triaza-cyclopentadecane-4,7,10,15-tetraone (881845-68-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 65 percent / N,N-diisopropylethylamine; benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium PF6(1-) 2: 87 percent / morpholine / Pd(PPh3)4 / methanol 3: 67 percent / MNBA; DMAP / CH2Cl2 View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (3S,4R)-3-Hydroxy-4-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-5-methyl-hexanoic acid (878630-45-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 65 percent / N,N-diisopropylethylamine; benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium PF6(1-) 2: 87 percent / morpholine / Pd(PPh3)4 / methanol View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → romidepsin (128517-07-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: 95 percent / (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, DIEA 2: 98 percent / LiOH 3: EDCl, DMAP, TsOH 4: 84 percent / I2 / methanol; H2O View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (3S,9S,12R,16S)-6-eth-(Z)-ylidene-3,12-diisopropyl-16-((E)-4-tritylsulfanyl-but-1-enyl)-9-tritylsulfanylmethyl-1-oxa-4,7,10,13-tetraazacyclohexadecane-2,5,8,11,14-pentaone (180973-35-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: 95 percent / (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, DIEA 2: 98 percent / LiOH 3: EDCl, DMAP, TsOH View Scheme

(E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → (5E,7S,11R,14S,17E,20S)-17-ethylidene-7-hydroxy-11,20-diisopropyl-9,12,15,18-tetraoxo-1,1,1-triphenyl-14-(tritylthiomethyl)-2-thia-10,13,16,19-tetraazahenicos-5-en-21-oic acid (180973-34-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 95 percent / (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, DIEA 2: 98 percent / LiOH View Scheme

C51H51ClN3O5PolS + (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (180973-24-4) → C77H75ClN3O7PolS2

Conditions	Yield
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 24h;

Upstream product

• 3695-77-0 triphenylmethanethiol 
• 663918-95-4 (3S,4E)-3-hydroxy-1-((4R)-4-isopropyl-2-thioxothiazolidin-3-yl)-7-tritylsulfanyl-hept-4-en-1-one 
• 150350-28-0 S-trityl 3-mercaptopropionaldehyde 
• 1309766-86-6 ethyl (E)-5-(triphenylmethylthio)-2-pentenoate 
• 100360-56-3 3-(tritylthio)propan-1-ol 
• 27144-18-9 3-(tritylthio) propanoic acid 
• 76-83-5 trityl chloride 
• 2409-87-2 methyl (2E)-penta-2,4-dienoate 
• 180973-36-8 (E)-5-Tritylsulfanyl-pent-2-enoic acid methyl ester 
• 180973-37-9 (E)-5-(tritylthio)-2-penten-1-ol 
• 180973-22-2 (2E)-5-[(triphenylmethyl)thio]-2-pentenal 
• 878630-47-8 (E)-(S)-3-hydroxy-1-[(R)-4-isopropyl-5,5-diphenyl-2-oxo-oxazolidin-3-yl]-7-tritylthio-4-hepten-1-one 
• 180973-40-4 (E)-(S)-3-Hydroxy-7-tritylsulfanyl-hept-4-enoic acid benzyl ester 

Downstream Products

• 881845-29-0 (3S,4R)-3-Hydroxy-4-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-5-methyl-hexanoic acid allyl ester 
• 881845-68-7 (2S,6R,9S,12R,13S)-13-Hydroxy-12-isopropyl-6-methyl-2-((E)-4-tritylsulfanyl-but-1-enyl)-9-tritylsulfanylmethyl-1-oxa-5,8,11-triaza-cyclopentadecane-4,7,10,15-tetraone 
• 878630-45-6 (3S,4R)-3-Hydroxy-4-{(S)-2-[(R)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-5-methyl-hexanoic acid 
• 1043577-31-6 (S,E)-2-(trimethylsilyl)ethyl 3-(((S)-2-amino-3-methylbutanoyl)oxy)-7-(tritylthio)hept-4-enoate 
• 1309766-85-5 allyl (3S,4R,5S)-4-[(S)-2-{(R)-2-[(E)-(S)-3-hydroxy-7-(tritylthio)-4-heptenoylamino]propionylamino}-3-(tritylthio)propionylamino]-3-hydroxy-5-methylheptanoate 
• 1309766-89-9 (2S,6R,9S,12R,13S)-12-((S)-sec-butyl)-13-hydroxy-6-methyl-2-[(E)-4-tritylthio-1-butenyl]-9-tritylthiomethyl-1-oxa-5,8,11-triaza-cyclopentadecane-4,7,10,15-tetraone 
• 1089192-66-4 (S,E)-2-(trimethylsilyl)ethyl 3-(((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl) amino)-3-methylbutanoyl)oxy)-7-(tritylthio)hept-4-enoate 
• 1137735-74-0 (S,E)-2-(trimethylsilyl)ethyl 3-(((S)-2-amino-3-methylbutanoyl)oxy)-7-(tritylthio)hept-4-enoate 
• 1196992-58-1 [(1-{(S)-2-[2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-acetylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester 
• 1196992-72-9 [(1-{(S)-2-[(R)-3-(3-chloro-phenyl)-2-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester 
• 1196992-65-0 C₆₃H₆₃N₅O₇S₂ 
• 1196992-37-6 (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclobutylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester 
• 1196992-18-3 (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-cyclopropylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester 
• 1196992-07-0 (R)-4-((E)-(S)-3-hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-4-{(S)-1-[1-(methoxycarbonylmethyl-carbamoyl)-1-methyl-ethylcarbamoyl]-2-tritylsulfanyl-ethylcarbamoyl}-butyric acid tert-butyl ester 

Relevant academic research and scientific papers

AN IMPROVED PROCESS FOR THE PREPARATION OF (1S, 4S, 7Z, 10S, 16E, 21R)- 7-ETHYLIDENE-4,21-BIS(1-METHYLETHYL)-2-OXA-12,13-DITHIA-5, 8, 20, 23- TETRAAZABICYCLO[8.7.6]TRICOS-16-ENE-3, 6, 9, 19, 22-PENTONE

The present invention is relates to an improved process for the preparation (1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(1-methylethyl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabi-cyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone of formula I.

Study for diastereoselective aldol reaction in flow: synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid, a key component of cyclodepsipeptide HDAC inhibitors

Abstract Flow synthesis of (E)-(S)-3-hydroxy-7-tritylthio-4-heptenoic acid (5), a key component of cyclodepsipeptide histone deacetylase inhibitors was achieved. An efficient flow system for the synthesis of α, β-unsaturated ester 8 was established using a flow reactor column packed with polymer-supported 1,4-diazabicyclo[2.2.2]octane and a fast mixing accessible flow reactor (Comet X-01). Enal 9 was efficiently prepared by a partial reduction of the α, β-unsaturated ester 8 using diisobutylaluminium hydride in the flow system, and the continuous-flow diastereoselective aldol reaction was performed at low temperature, giving a good yield and diastereoselectivity of the desired aldol 10.

Depsipeptides and Their Therapeutic Use

A Compound of structure (IX) or (X) or a pharmaceutically acceptable salt thereof, wherein: X is —C(═O)N(R10)— or —CH(OPr3)—; R7, R9 and R10 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid; Pr1 and Pr2 are the same or different and represent hydrogen or a thiol protecting group; Pr3 is hydrogen or an alcohol protecting group; R1, R2, R5 and R6 are the same or different and represent hydrogen or an amino acid side chain moiety from either a natural or an unnatural amino acid, or R1 and R2 and/or R5 and R6, taken together with the carbon atom to which they are attached, form a spirocyclic moiety, with the proviso that: each of R1 and R2 is not hydrogen, or each of R5 and R6 is not hydrogen.

Total synthesis of spiruchostatin B aided by an automated synthesizer

The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs.

Macrolactamization versus macrolactonization: Total synthesis of FK228, the depsipeptide histone deacetylase inhibitor

(Chemical Equation Presented) The cyclic depsipeptide FK228 is the only natural product histone deacetylase (HDAC) inhibitor that has advanced to clinical trials as an anticancer agent. While currently obtained by fermentation, total synthesis is an attractive alternative that will facilitate the preparation of unnatural analogues. The previous total syntheses of FK228 featured macrocylization by ester bond formation from a seco-hydroxy acid. Such routes are operationally jeopardized by the steric hindrance of the carboxylic acid and the sensitivity of the allylic alcohol toward elimination. We report a strategically different approach whereby the ester bond is formed intermolecularly at an early stage and macrocyclization is efficiently achieved by amide bond formation.

A total synthesis of spiruchostatin A

We achieved the total synthesis of the histone deacetylase inhibitor spiruchostatin A, as the prelude to the preparation of a combinatorial library of its analogues. Two key reactions were an asymmetric acetate aldol reaction using a Zr-enolate and macrol