4-Pentenoic acid

[591-80-0]  · C5H8O2  · (MW 100.12)

(reagent used for protection of amines and activation of certain alcohols1)

Physical Data: mp -22.5 °C; bp 83-84 °C/12 mmHg; d 0.981 g cm-3.

Solubility: soluble in alcohol, diethyl ether, and most organic solvents.

Form Supplied in: colorless liquid; widely available.

Purification: fractional distillation using a Vigreux column.

Handling, Storage, and Precautions: corrosive organic acid with an acrid odor. Use in a well-ventilated fume hood with gloves, eye protection, and protective clothing to avoid contact. Moderately toxic by ingestion. LD50 (rat, oral): 470 mg/kg.

Amides and Esters of 4-Pentenoic Acid

Amides and esters of 4-pentenoic acid will undergo ring-closure to form five-membered lactones in the presence of electrophiles. In the case of 4-pentenoic amides, this lactonization liberates the amine; hence, the 4-pentenoyl group serves as an amine-protecting group.1 In the case of 4-pentenoic esters the lactonization cleaves the alkyl ester bond. Hereby the 4-pentenoic ester can serve as a leaving group for the corresponding alcohol.2 This alcohol, however, has to be allylic or activated as a lactol for the lactonization to occur.

4-Pentenoic amides and esters can be prepared from the corresponding amine or alcohol by 1,3-dicyclohexylcarbodiimide coupling with 4-pentenoic acid.2,3 Alternative procedures involve reaction of the amine or the alcohol with 4-pentenoic anhydride or 4-pentenoyl chloride in the presence of a tertiary amine.1,4 Both 4-pentenoic anhydride and 4-pentenoyl chloride are commercially available, but can also be easily prepared from the parent acid.1,4 In addition, 4-pentenoyl chloride can be generated in situ by allowing 4-pentenoic acid to react with 1-amino-1-chloro-N,N,2-trimethyl-1-propene.5 In a special case, cyanomethyl 4-pentenoate has been used for enzymatic resolution of amines by forming the 4-pentenoic amide from only one of the enantiomers (1).6

Deprotection of 4-Pentenoic Amides

4-Pentenoic amides can be cleaved and the free amine regenerated by treatment with 3 equiv of iodine in THF-H2O mixture (2).1 The deprotection is usually complete within a few minutes and proceeds through an intermediate iminolactone which undergoes hydrolysis to the free amine and lactone. Although an oxidizing medium is used for the deprotection, a large variety of other oxidizable functionalities are stable to these conditions including allyl and para-methoxybenzyl ethers as well as alkyl sulfides.1 Most acid and base labile functional groups are also stable to the deprotection conditions.1 Even a 4-pentenyl glycoside is not affected by the pentenoyl deprotection (3).1 This has been used for preparation of 4-pentenyl 2-azido-2-deoxy-glucopyranosides which are useful glycosyl donors in oligosaccharide synthesis.7 Notably, the 4-pentenoyl group is orthogonal to several other amine-protecting groups including BOC and phthalimide which is very useful in synthetic strategies involving several amino groups.8

Deprotection of 4-pentenoic amides can also be achieved on solid phase.9 This has been exploited for preparation of oligonucleotides where the 4-pentenoyl group serves as a protective group for the amino group in adenine, cytosine, and guanine.10 The 4-pentenoyl protected nucleosides are coupled together on solid phase using the phosphoramidite or the H-phosphonate method.10 Before cleaving the oligonucleotide from the solid support the 4-pentenoyl groups are removed with 2% iodine in pyridine- MeOH.10

Besides applications in carbohydrate and nucleoside chemistry the 4-pentenoyl group can also be used for protection of amino acids.1,3 No epimerization of the amino acids is observed in the deprotections. In an interesting study valine benzyl ester was protected with the 4-pentenoyl group as well as derivatives containing alkyl substituents in the 2, 3, 4, or 5 positions (4).3 The purpose was to investigate the effect of alkyl substitution on the cleavage reaction. In the event, it turned out that the parent acid (R1 = R2 = R3 = R4 = H) was the best amine-protecting group.3

Ring-Closure of 4-Pentenoic Esters

Glycopyranoses which are protected at all positions except the anomeric center can be esterified with 4-pentenoic acid to form glycopyranosyl 4-pentenoates.11 These can be activated with electrophiles for glycosylations in the same way as the corresponding 4-pentenyl glycosides.12 Using iodonium di-sym-collidine perchlorate (IDCP) or N-iodosuccinimide/trifluoromethanesulfonic acid as the promoter the 4-pentenoate at the anomeric center undergoes the iodolactonization process and glycosylation of an added alcohol can be achieved (5).11

Glycosyl 4-pentenoates can also be prepared directly from 2-(trimethylsilyl)ethyl glycosides by treatment with 4-pentenoic anhydride and boron trifluoride etherate (6).13

The 4-pentenoic esters can also participate in another glycosylation reaction involving a Ferrier rearrangement under neutral conditions.2 In this case, the 3-hydroxy group in a glycal is esterified with 4-pentenoic acid. The glycal 3-pentenoate is then treated with IDCP and an alcohol to effect allylic rearrangement to the corresponding alkyl hex-2-enopyranoside (7).2

Finally, it should be noted that 4-pentenoic esters only undergo lactonization with electrophiles if they are attached at the anomeric center or at the 3-position in glycals. When the 4-pentenoic ester is placed at other positions in sugars, simple addition to the double bond will occur upon treatment with iodine and ROH.

Related Reagents.

Benzyl chloroformate; di-t-butyl dicarbonate; tetrachlorophthalic anhydride.

1. Madsen, R.; Roberts, C.; Fraser-Reid, B., J. Org. Chem. 1995, 60, 7920.
2. López, J. C.; Gómez, A. M.; Valverde, S.; Fraser-Reid, B., J. Org. Chem. 1995, 60, 3851.
3. Lodder, M.; Golovine, S.; Laikhter, A. L.; Karginov, V. A.; Hecht, S. M., J. Org. Chem. 1998, 63, 794.
4. Kudo, H.; Sanda, F.; Endo, T., Macromolecules 1999, 32, 8370.
5. Fürstner, A.; Langemann, K., J. Am. Chem. Soc. 1997, 119, 9130.
6. Takayama, S.; Moree, W. J.; Wong, C.-H., Tetrahedron Lett. 1996, 37, 6287.
7. Olsson, L.; Jia, Z. J.; Fraser-Reid, B., J. Org. Chem. 1998, 63, 3790.
8. Debenham, J.; Rodebaugh, R.; Fraser-Reid, B., Liebigs Ann./Recueil 1997, 791.
9. Carrington, S.; Renault, J.; Tomasi, S.; Corbel, J.-C.; Uriac, P.; Blagbrough, I. S., Chem. Commun. 1999, 1341.
10. (a) Iyer, R. P.; Yu, D.; Habus, I.; Ho, N.-H.; Johnson, S.; Devlin, T.; Jiang, Z.; Zhou, W.; Xie, J.; Agrawal, S., Tetrahedron 1997, 53, 2731. (b) Iyer, R. P.; Yu, D.; Jiang, Z.; Agrawal, S., Tetrahedron 1996, 52, 14419. (c) Iyer, R. P.; Yu, D.; Ho, N.-H.; Devlin, T.; Agrawal, S., J. Org. Chem. 1995, 60, 8132.
11. (a) López, J. C.; Fraser-Reid, B., J. Chem. Soc., Chem. Commun. 1991, 159. (b) Kunz, H.; Wernig, P.; Schultz, M., Synlett 1990, 631.
12. Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson, H.; Merritt, J. R.; Rao, C. S.; Roberts, C.; Madsen, R., Synlett 1992, 927.
13. Ellervik, U.; Magnusson, G., Acta Chem. Scand. 1993, 47, 826.

Robert Madsen & Bert Fraser-Reid

NPG Research Institute, Durham, North Carolina, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.