Studies of hypolipidemic agents. 1. Synthesis and hypolipidemic activities of alkoxycinnamic acid derivatives

Watanabe, Toshio; Hayashi, Kimiaki; Yoshimatsu, Shigeki; Sakai, Kazuo; Takeyama, Shigeyuki; Takashima, Kohki

doi:10.1021/jm00175a010

Cited by 35 publications

(25 citation statements)

References 5 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously this final deprotection step was done under homogeneous acid (H 3 BO 3 ) catalyzed condition and yield was only 72%. 2) In conclusion, we have described a novel and efficient onepot method for the stereoselective synthesis of (E)-a-methylcinnamic acids directly from unmodified Baylis-Hillman adducts. The method is associated with several advantages including mild reaction conditions, application of inexpensive and easily available reagents, operational simplicity, high yields and excellent stereoselectivity.…”

mentioning

confidence: 99%

“…2,3) For example, 1-[p-(myristyloxy)-a-methylcinnamoyl]glycerol, 1 (LK-903) is very active hypocholesterolemic agent. 2) Its corresponding parent acid (E)-p-myristyloxy-a-methylcinnamic acid (2) also shows good hypolipidemic activity.…”

mentioning

confidence: 99%

“…The adduct 3i (prepared from 4-(myristyloxy) benzaldehyde and methyl acrylate in presence of DABCO) was treated with I 2 /NaBH 4 reagent system followed by hydrolysis with KOH/MeOH to afford the acid 2 in 75% yield which also exhibits potent hypolipidemic activity. 2) Previously, esterification of the acid (2) with 2,3-acetonide protected glycerol 6 (Chart 2) was carried out classically by converting the acid into corresponding acid chloride. 2) Under this classical condition, the yield of the ester 7 was only 70%.…”

mentioning

confidence: 99%

“…2) Previously, esterification of the acid (2) with 2,3-acetonide protected glycerol 6 (Chart 2) was carried out classically by converting the acid into corresponding acid chloride. 2) Under this classical condition, the yield of the ester 7 was only 70%. During the portion-wise addition of acetonide protected glycerol (6) to the acid chloride, the byproduct was HCl acid which might be causing the deprotection of the acid sensitive acetonide group lowering the yield of the ester.…”

mentioning

confidence: 99%

“…During the portion-wise addition of acetonide protected glycerol (6) to the acid chloride, the byproduct was HCl acid which might be causing the deprotection of the acid sensitive acetonide group lowering the yield of the ester. 2) To avoid this problem, we undertook a straightforward strategy involving the direct coupling of acid 2 and alcohol 6 for esterification applying a recently reported protocol using BOC 2 O and DMAP 31) as coupling reagents. Purification of the ester 7 is easier by this method since the byproducts, tBuOH and CO 2 are volatile which is a great advantage over the classical method.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Synthetic Applications of Baylis-Hillman Chemistry: An Efficient and Solely Stereoselective Synthesis of (E)-.ALPHA.-Methylcinnamic Acids and Potent Hypolipidemic Agent LK-903 from Unmodified Baylis-Hillman Adducts

Das

Banerjee

Chowdhury

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Thus, various pharmaceutically potent molecules contain amethylcinnamic acid moiety as the key structural unit. 2,3) For example, 1-[p-(myristyloxy)-a-methylcinnamoyl]glycerol, 1 (LK-903) is very active hypocholesterolemic agent. 2) Its corresponding parent acid (E)-p-myristyloxy-a-methylcinnamic acid (2) also shows good hypolipidemic activity. 2) Biological properties of these compounds mostly depend on the stereochemistry of the double bond of the cinnamic acid moiety. 2,3) Therefore, development of a simple and efficient method for the stereoselective synthesis of (E)-a-methylcinnamic acids and their derivatives is an interesting problem in organic synthesis. [4][5][6][7] As a part of our continued interest in synthetic applications of the Baylis-Hillman reaction, [8][9][10][11][12][13][14] we envisaged a simple synthesis of (E)-a-methylcinnamic acids directly from unmodified Baylis-Hillman adducts.The Baylis-Hillman reaction is a versatile and atom economic carbon-carbon bond forming reaction that provides poly-functional molecules known as Morita-Baylis-Hillman adducts. 15,16) These adducts have been employed for the stereoselective synthesis of various naturally occurring bioactive compounds [16][17][18][19] including several alkaloids, 20) terpenoids, 21,22) macrolides 23) and pheromones. 24,25) All of these molecules contain a stereodefined a,b-unsaturated carbonyl moiety as the central structural unit which have been well documented in the literature. 16) We herein, wish to report an efficient one-pot and solely stereoselective synthesis of (E)-a-methylcinnamic acids directly from unmodified Baylis-Hillman adducts. We observed that the treatment of Baylis-Hillman adduct, methyl-3-hydroxy-3-aryl-2-methylenepropanoates 3 with NaBH 4 in combination with molecular I 2 in tetrahydrofuran (THF) at room temperature, followed by hydrolysis with KOH/MeOH and crystallization afforded the corresponding (E)-a-methylcinnamic acids 5 in high yields via the formation of the intermediates 4 (Chart 1).Previously, a-methylcinnamic acids were not obtained directly from the unmodified Baylis-Hillman adducts. 26) One modified version (acetyl derivative) of the Baylis-Hillman adduct was used in that case 26) which required three steps to get the desired product starting from the adduct itself. Being intrigued with this fact, and after systematic literature survey, 16) it became clear that, synthesis of the desired trisubstituted olefin moiety directly from the unmodified Baylis-Hillman adducts is significantly challenging task compared to that from an activated version (acetyl or allyl bromide derivatives) of the adducts. 27) The present method is more advantageous and easily accessible to a-methylcinnamic acids as they have been accomplished directly from unmodified Baylis-Hillman adducts with sole (E)-stereoselectivity (Chart 1). Here, initially we treated 3b (Arϭ2-Cl-C 6 H 4 ) with NaBH 4 in presence of I 2 in THF at room temperature. The mode of addition of reagents was found to be important for achieving optimum yields....

show abstract

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Synthetic Applications of Baylis-Hillman Chemistry: An Efficient and Solely Stereoselective Synthesis of (E)-.ALPHA.-Methylcinnamic Acids and Potent Hypolipidemic Agent LK-903 from Unmodified Baylis-Hillman Adducts

Das

Banerjee

Chowdhury

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

show abstract

Phosphapalladacycle-Catalyzed Heck Reactions for Efficient Synthesis of Trisubstituted Olefins: Evidence for Palladium(0) Intermediates

Beller¹,

Riermeier

1998

Eur. J. Inorg. Chem.

101

View full text Add to dashboard Cite

Heck Reactions of Aryl Chlorides Catalyzed by Palladium/Tri‐tert‐butylphosphine: (E)‐2‐Methyl‐3‐Phenylacrylic Acid Butyl Ester and (E)‐4‐(2‐Phenylethenyl)benzonitrile

Littke

2005

Organic Syntheses

View full text Add to dashboard Cite

( E) ‐2‐Methyl‐3‐phenacrylic acid butyl ester Bis(tri‐ tert ‐butylphosphine)palladium ( E) ‐4‐(2‐Phenylethenyl)benzonitrile Tris(dibenzylideneacetone)palladium

show abstract

Studies of hypolipidemic agents. 1. Synthesis and hypolipidemic activities of alkoxycinnamic acid derivatives

Cited by 35 publications

References 5 publications

Synthetic Applications of Baylis-Hillman Chemistry: An Efficient and Solely Stereoselective Synthesis of (E)-.ALPHA.-Methylcinnamic Acids and Potent Hypolipidemic Agent LK-903 from Unmodified Baylis-Hillman Adducts

Synthetic Applications of Baylis-Hillman Chemistry: An Efficient and Solely Stereoselective Synthesis of (E)-.ALPHA.-Methylcinnamic Acids and Potent Hypolipidemic Agent LK-903 from Unmodified Baylis-Hillman Adducts

Phosphapalladacycle-Catalyzed Heck Reactions for Efficient Synthesis of Trisubstituted Olefins: Evidence for Palladium(0) Intermediates

Heck Reactions of Aryl Chlorides Catalyzed by Palladium/Tri‐tert‐butylphosphine: (E)‐2‐Methyl‐3‐Phenylacrylic Acid Butyl Ester and (E)‐4‐(2‐Phenylethenyl)benzonitrile

Contact Info

Product

Resources

About