Synthesis of Designed Structural Derivatives of Natural Products

Derivatives of natural products often give insight into the mechanism of action of a given natural product and, in Some cases, can even show greater or equivalent biological activity when compared to the parent compound. These derivatives can often be synthesized by simple alterations of the synthetic route to the natural product itself. This was the case for the derivatives of salinosporamide A as well as the derivatives of belactosin C, which were accessed using the same synthetic route as was used to access the natural product itself.

Synthesis of derivatives can also be used as a tool to confirm structural assignments, as is seen in the enantioselective synthesis of (+)-dihydroplakevulin, where the derivative was a known compound and comparisons between the known data and the experimental data confirmed the structural assignments of the new compounds that resulted from this methodology.

Further, the synthesis of des-methyl, des-amino pateamine A (DMDA-PatA), a simplified analogue of natural product pateamine A, displayed very similar biological activity as pateamine A itself and thus led to the discovery of a promising anticancer agent.

1) "Bioinspired Total Synthesis and Human Proteasome inhibitory Activity of (-)- Salinosporamide A, (-)-Homosalinosporamide A, and Derivatives Obtained via Organonucleophile Promoted Bis-Cyclizations" Nguyen, H.; Ma, G.; Fremgen,T.; Gladysheva, T. ; Romo, D. J. Org. Chem., 2011, 76, 2.


Biosynthetic considerations enabled a concise route to (-)-salinosporamide A, (-)- homosalinosporamide A, as well as its derivatives. In studying the byproducts generated, optimization of the key step, bis-cyclization of a β-keto tertiary amide, was completed enabling a gram scale synthesis of the bicyclic core. Enzymatic assays of derivatives, such as (-)-homosalinosporamide A showed inhibition of the 20S and 26S proteasome. The approach taken to synthesize these natural products raises questions regarding the way biosynthetic enzymes preserve the stereochemistry at C2 and further shows the possibility of dynamic kinetic resolution.

2) "Concise Total Synthesis of (+)-Salinosporamide A, (+)-Cinnabaramide A, and Derivatives via a Bis-cyclization Process: Implications for a Biosynthetic Pathway?" Ma, G.; Nguyen, H. Romo, D. Org. Lett., 2007, 9, 2143.


4-Alkylidene-3-lactones (hetero ketene dimers) and a-amino acids are useful precursors for total syntheses of the B-lactone-containing proteasome inhibitors salinosporamide A, cinnabaramide A, and derivatives. A key step is a nucleophile-promoted, bis-cyclization of keto acids that simultaneously generates the γ-lactam and β-lactone of these natural products. This reaction sequence may have implications for the biosynthesis of these natural products.

3) "Potent in Vitro and in Vivo Anticancer Activities of Des-methyl, Des-amino Pateamine A, a Synthetic Analogue of Marine Natural Product Pateamine A" Kuznetsv, G.; Xu, Q.; Rudolph-Owen, L.; TenDyke, K.; Liu, J.; Towle, M., Zhao, N.; Marsh, J.; Agoulnik, S.; Twine, N.; Parent, L.; Chen, Z.; Shie, J.; Jian, Y.; Zhang, H.; Du, H.; Boivin, R.; Wang, Y.; Romo, D.; Littlefield, B. Mol Cancer Ther., 2009, 8, 1250.


Des-methyl, des-amino pateamine A (DMDA-PatA) was shown to retain almost full in vitro potency in P-glycoprotein-overexpressing MES-SA/Dx5-RX1 human uterine sarcoma cells relative to the natural product pateamine A. This structurally simplified analogue was found to directly inhibit DNA polymerases α and γ in cell-free studies, making it a promising natural-product based anticancer agent.

4) "Total Synthesis of (-)-Belactosin C and Derivatives via Double Diastereoselective Tandem Mukaiyama Aldol Lactonizations” Cho, S. W. ; Romo, D. Org. Lett., 2007, 9, 1537.


The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonization (TMAL) process. One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide, whereas a second approach involved amide coupling of a dipeptide with a β-lactone carboxylic acid, obtained via the TMAL process employing a chiral silyl ketene acetal. Notable improvements in diastereoselectivity were achieved in a proximal double diastereoselective TMAL process.

5) “Bicyclic- and Tricyclic-3-Lactones via an Organonucleophile Bis-cyclization of KetoAcids: Enantioselective Synthesis of (+)-Dihydroplakevulin" Henry-Riyad, H.; Lee, C. S.; Purohit, V.; Romo, D. Org. Lett., 2006, 8, 4363.


We extended the scope of previous routes to bicyclic β-lactones into keto acid substrates, providing access to bicyclic and tricyclic β-lactones bearing tertiary carbinol centers and quaternary carbons. Application of this process to complete the synthesis of (+)-dihydroplakevulin, a known derivative of the DNA polymerase inhibitor plakevulin A, further demonstrated the utility of our method.