Useful chiral lactones derived from cis-bicyclo[3.3.0]octan-3,7-dione via asymmetric deprotonation

Leonard, John; Hewitt, J. D.; Ouali, Dehimi; Rahman, S. K.; Simpson, Stephen J.; Newton, Roger F.

doi:10.1016/s0957-4166(00)82377-0

Cited by 19 publications

(1 citation statement)

References 9 publications

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“…The N -Ts azoene Ts- 9 was selected because of the many methods available for the cleavage of N -Ts hydrazones with formation of the parent ketones. 44b, The sequence leading from ketone 4 to azoene Ts- 9 , which utilizes as a key step the facile 1,4-elimination of chlorohydrazones, is shown in Scheme . Enantioselective deprotonation of ketone 4 with lithium amide Li- 10 in the presence of 1 equiv of LiCl at −100 °C in THF and trapping of the intermediate lithium enolate 11 with ClSiMe 3 gave after a chromatographic purification enol ether 12 of 90% ee in 80% yield. 30b,f,g, Because of the ready hydrolysis of 12 on silica gel, chromatography has to be carried out as rapidly as possible. The chiral amine H- 10 could be recovered in 70% yield.…”

Section: Resultsmentioning

confidence: 99%

A New Strategy for the Enantioselective Synthesis of Carba-Prostacyclin Analogues Based on Organocopper Conjugate Addition to a Bicyclic Azoene and Its Application to the Synthesis of 13,14-Dinor-inter-p-phenylene Carbacyclin

Bergen

Gais

2002

J. Am. Chem. Soc.

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An enantioselective synthesis of E/Z-13,14-dinor-inter-p-phenylene carbacyclin (E/Z-2d) by a new strategy has been realized that holds the prospect of serving as a general route for carba-prostacyclin analogues. The key intermediate in this synthesis is the bicyclic azoene Ts-9, and the key step is the regio- and stereoselective conjugate addition of the chiral arylcopper compound Cu-8d/P-n-Bu3 to the azoene with formation of hydrazone 7d. Enantioselective synthesis of azoene Ts-9 of 95% ee from ketone 4 was accomplished in four and five steps, respectively. Thus, enantioselective deprotonation of bicyclic ketone 4 with chiral base Li-10 and trapping of lithium enolate 11 with ClSiMe3 gave enol ether 12, which was chlorinated with N-chlorosuccinimide (NCS) to afford chloro ketone 13. Alternatively, chloro ketone 13 was also prepared upon chlorination of 11 with NCS. Chloro ketone 13 was converted to chloro hydrazone 14, which upon treatment with a mild base furnished azoene Ts-9. Arylcopper compound 8d of 98% ee was obtained in two steps from alcohol 16, which was prepared by enantioselective reduction of ketone 17 with (-)-diisopinocampheylchloroborane. Carbacyclin derivative E/Z-2d was found to be essentially inactive as an inhibitor of ADP induced human platelet aggregation, having an IC50 of >10 micromol/L.

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Section: Resultsmentioning

confidence: 99%

A New Strategy for the Enantioselective Synthesis of Carba-Prostacyclin Analogues Based on Organocopper Conjugate Addition to a Bicyclic Azoene and Its Application to the Synthesis of 13,14-Dinor-inter-p-phenylene Carbacyclin

Bergen

Gais

2002

J. Am. Chem. Soc.

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Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

Vaulont

Gais²,

Reuter

et al. 1998

Eur. J. Org. Chem.

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Asymmetric total syntheses of 3‐oxacarbacyclin (4) and 3‐oxaisocarbacyclin (5) have been achieved by a new and common route. The key step of these syntheses is an enantioselective deprotonation of the prochiral ketone 25 with lithium (R,R)‐bis(phenylethyl)amide (12) in the presence of LiCl. Treatment of the thus formed enolate 26 with ClSiEt3 gave the enol ether 27 of 92% ee in 94% yield. Deprotonation of the analogous prochiral ketone 9 with 12 in the presence of LiCl followed by reaction of the enolate 13 with ClSiEt3 led to isolation of the silyl enol ether 8b of 92% ee in 95% yield. A study of the deprotonation of 9 with the chiral lithium amides 14−19 showed that 12 in combination with LiCl is the optimal base in terms of enantioselectivity and accessibility. The ω‐side chain in 4 and 5 was established by a Mukaiyama reaction of 27 with the unsaturated aldehyde 28, leading to ketone 39 of 90% de, in combination with a stereoselective Pd‐catalyzed allylic rearrangement of acetate 47 to the isomeric acetate 48 and a Mitsunobu reaction of the allylic alcohol 49. The key step in the construction of the α‐side chain in 4 is a Horner‐Wadsworth‐Emmons reaction of ketone 7c with the 8‐phenylnormenthol‐containing phosphonoacetate 56 which gave ester 60 of 90% de. Ester 60 was obtained diastereomerically pure by chromatography in 72% yield from 7c. Reduction of 60 furnished the allylic alcohol 62 which was converted to 4 in a standard fashion. It is at the stage of the α,β‐unsaturated ester 60 where divergence into synthesis of 5 was made. Selective isomerization of 60 to the β,γ‐unsaturated ester 66 of 97% ie in 91% yield was accomplished by deprotonation of 60 with 12 to enolate 65 and its subsequent regioselective protonation. By a similar reaction sequence the isomeric α,β‐unsaturated ester 61 was converted to the ß,γ‐unsaturated ester 69 of 97% ie in 88% yield. Reduction of 66 afforded the homoallylic alcohol 71 which was converted to 5 in a standard fashion.

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Asymmetric Synthesis of Isocarbacyclin Based on the Olefination-Isomerization-Coupling Process with Chiral Sulfoximines

et al. 1998

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Useful chiral lactones derived from cis-bicyclo[3.3.0]octan-3,7-dione via asymmetric deprotonation

Cited by 19 publications

References 9 publications

A New Strategy for the Enantioselective Synthesis of Carba-Prostacyclin Analogues Based on Organocopper Conjugate Addition to a Bicyclic Azoene and Its Application to the Synthesis of 13,14-Dinor-inter-p-phenylene Carbacyclin

A New Strategy for the Enantioselective Synthesis of Carba-Prostacyclin Analogues Based on Organocopper Conjugate Addition to a Bicyclic Azoene and Its Application to the Synthesis of 13,14-Dinor-inter-p-phenylene Carbacyclin

Asymmetric Synthesis of 3-Oxacarbacyclin and 3-Oxaisocarbacyclin by a Common Enantioselective Deprotonation Based Route

Asymmetric Synthesis of Isocarbacyclin Based on the Olefination-Isomerization-Coupling Process with Chiral Sulfoximines

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