Attempted Diels-Alder Reactions on Vindoline Derivatives

The Diels-Alder reaction of vindoline and methyl vinyl ketone resulted in a Friedel-Crafts reaction product. In the reaction between the ortho-quinone derivative of vindoline and N-phenylmaleimide, two anomalous products were obtained, a vindoline dimer, and a condensed vindoline derivative.

Vinblastine (1) has an antimicrotubule effect used for treating certain kinds of cancer, including Hodgkin's lymphoma, nonsmall-cell lung cancer, breast cancer, head and neck cancer and testicular cancer. Vincristine (2), the N-formyl derivative of vinblastine (1) can be used in various types of chemotherapy. Its main uses are in the treatment of non-Hodgkin's and Hodgkin's lymphoma, acute lymphoblastic leukaemia, and nephroblastoma.
In the course of the synthetic investigations of dimeric Vinca alkaloids, various methods have been elaborated to synthesize new derivatives of vinblastine (1) and vincristine (2) with improved therapeutic effect exhibiting a higher selectivity and a lower toxicity [3,4].
In our research project, we intended to investigate the Diels-Alder reaction of vindoline (4) and its newly synthesized ortho-quinone derivative [10].

Results and discussion
In spite of the fact that the C=C double bond in the 14,15-position of vindoline (4) is not a dienophilic electron deficient structural part, based on the analogy that acrolein also exhibits this type of reactivity [10], we carried out its Diels-Alder reaction with methyl vinyl ketone as a "diene" in an attempt to obtain compound 5. However, a Friedel-Crafts reaction was observed to take place (Scheme 1) affording the alkylated adduct (6) in good yield (57%).
Next, the ortho-quinone derivative of vindoline (7) was treated with N-phenylmaleimide in toluene in order to obtain adduct 8 via the usual cycloaddition reaction. However, instead of this adduct two by-products were isolated in low yields, a dimeric derivative (9) in a yield of 3%, and a vindoline condensed with N-phenylmaleimide (10) in a yield of 2% (Scheme 2).
In the course of the reaction, the expected adduct (8) 1 H-13 C, and long-range 1 H-13 C scalar spin-spin connectivities were established from 2D zTOCSY, gHSQCAD, and gHMBCAD experiments, respectively. All pulse sequences were applied by using the standard spectrometer software package. All experiments were performed at 298 K. HRMS and MS-MS analyses were performed on an LTQ FT Ultra (Thermo Fisher Scientific) system. The ionization method was ESI, operated in positive ion mode. The protonated molecular ion peaks were fragmented by CID at a normalized collision energy of 35%. For the CID experiment helium was used as the collision gas.

Scheme 2 Outcome of the reaction between the ortho-quinone derivative of vindoline and N-phenylmaleimide
The samples were dissolved in methanol. Data acquisition and analysis were accomplished with Xcalibur software version 2.0 (Thermo Fisher Scientific). TLC was carried out using Kieselgel 60F 254 (Merck) glass plates.