Progress Toward the Synthesis of a Model Compound for Corydendramine A

Tiffani N. Gruber, Christopher J. NicholsDepartment of Chemistry & Biochemistry, California State University, Chico

Introduction Marine life has been a source of many compounds of interest to synthetic organic chemists. This particular investigation focuses on the progress towards the synthesis of a model compound for Corydendramine A, which is a natural product isolated from a marine hydroid, Corydendrium parasiticum. This compound is excreted by the hydroid as a defense mechanism against predatory fish however it is of importance to scientists due to the fact that is belongs to a class of compounds have shown to possess anti-bacterial/anti-fungal properties.

H

O

trans-CinnamaldehydeStarting Material 1

Horner-Emmons Reaction Reduction Mitsunobu Reaction Oxidation

Julia Coupling Reaction

Future WorkThe future work of this particular project would be to perform the Boc deprotection of the product which would yield the final compound. The Julia coupling reaction also needs to be performed in a more efficient manner. Additionally, the entire reaction scheme needs to be performed again using the trans,trans-2,6-Nonadienal (expensive) starting material in order to have completed the total synthesis of the model compound. It must be mentioned that a colleague has had performed a successful synthesis of the model compound using the nonadienal starting material (ORGN-683) However, such a synthesis was done under different conditions that what are presented in this poster. Nevertheless, the success of this synthetic scheme shows that both pathways could be performed to have a successful synthesis of the model compound for Corydendramine A.

AcknowledgmentsI would like to thank Dr. Nichols for being my mentor through this project as well as the California Science project for funding my research. Additionally, I would like to thank Dr. David Ball for his insight as well as Maddy McCrea-Henry for his guidance in the lab as well.

Two Starting Materials

Results & DiscussionOverall, the project was a success in verifying the steps of the synthetic scheme. However, the oxidation reaction and the Julia coupling proved to be the challenging aspects to this project. However, through perseverance and further research into various synthetic pathways, both reactions were finally accomplished. The structure of each intermediate was verified using 1H & 13C NMR as well as GCMS. Once the Julia coupling, which is the climax of the synthetic pathway, was accomplished, HPLC analysis was performed in order to deduce the E:Z ratio of the double bonds. The data obtained showed this ratio to be 3:2. In conclusion, the objective of the project was accomplished through the five step synthesis of the model compound using the trans-cinnamaldehyde as the starting material.

Abstract: Corydendramine A (1) was isolated from Corydendrium parasiticum in 2001 and has activity as a fish-feeding deterrent. A model compound (2) has been synthesized in 8 steps overall from 2-piperidinemethanol and trans-cinnamaldehyde, using a Julia coupling in the key step. HPLC analysis of the Julia coupling showed a 3:2 ratio of E to Z alkenes formed. Reasonable to good yields were obtained in each of the other synthetic steps.

References: 1.Mann, Carillon, Breyne, Duhayon, Hamon, Marquet. Eur. J. Org. Chem. 2002. 736-7442.. J.D. Kim. Tetrahedron 57 (2001), 8257-82663.Nakatani, Oshita, Ishigami, Watanabe, Kitahara. Tetrahedron 62 2006 160-1654.Xu, Cheng, Trudell. J. Org. Chem. 2003, 68, 5388-53915.Nakatani, Oshita, Ishigami, Watanabe, Kitahara. Tetrahedron 62 2006 160-165

NH

HO

Marine Hydroid Corydendrium parasiticum

SS

NO

O

1. H2O22. (NH4)6Mo7O24

32%

S

NSOO

1. H2O22. (NH4)6MO7O24

17%

[4]

O

1. Ph3P2. DIAD3. Benzene

1. Ph3P2. DIAD3. Benzene

S

NSH

2-mercaptabenzothiazole

S

NSH

2-mercaptabenzothiazole

92%

79%

SS

N

SN

S

[3]

H

O

OEt

O

H

O

OEt

O

1. NaH2. THF-20 C [1]

EtOPO(OEt)2

O

EtOPO(OEt)2

O

68%

88 %

+

1. NaH2. THF-20 C [1]

+

OH

1. Benzene2. DIBAL-H (20% toluene)3. HCl

0 C

1. Benzene2. DIBAL-H (20% toluene)3. HCl

0 C

88%

70%

OH

[2]

[2]

H

O

trans,trans-2,6-NonadienalStarting Material 2

NH

OBoc

1. 18-C-62. KHMDS

N

Boc

1. 18-C-62. KHMDS

NH

OBoc

NBoc

60%

0%

X

[5]

ExperimentalNothing is certain in science. Many times what is theoretically plausible does not transfer over to success in the lab. Thus for the purposes of this investigation, the synthetic pathway was tested using a more economical starting material, trans-cinnamaldehyde. The goal was to use this compound as the basis for the synthesis of the model compound for Corydendramine A. Once the synthetic scheme was tested, then the trans,trans-2,6-Nonadienal would be used as the starting material. The synthesis, using the trans-cinnamaldehyde was carried out through the Julia coupling step with relatively decent yields. Using the trans-trans-2,6-Nonadienal as the starting material was only carried out through the oxidation of the sulfoxide to the sulfone. The yield for this particular reaction was not very high however, production of the sulfone verified that the reaction did work. Overall, the synthesis pathway was shown to be a decent scheme for the synthesis of the model compound.

NH

Model Compound(2)

Corydendramine A

(1)