Total Synthesis of (-)-Basiliskamide A and NMR Studies on the Conversion of Basiliskamide A to Basiliskamide B

The polyketides basiliskamides A (1) and B (2) were isolated from the marine bacterium PNG-276 from the coast of Papua New Guinea (Figure 1). These antifungal polyketides show potent in vitro activity against Candida albicans and Aspergillus fumigatus, as well as at least 4-fold less cytotoxicity for normal human fibroblast cells when compared to amphotericin B. The relative configurations of basiliskamides A (1) and B (2) were proposed by Andersen and co-workers and the absolute configurations have been confirmed by total synthesis. We have recently concluded the total synthesis of basiliskamide B. As the natural supply of basiliskamide A is restricted, and attracted by its potent cytotoxicity, we initiated a project directed towards an efficient and flexible total synthesis, in order to provide further material for more extensive biological studies, along with access to novel analogs. Results and Discussion


Introduction
The polyketides basiliskamides A (1) and B (2) were isolated from the marine bacterium PNG-276 from the coast of Papua New Guinea (Figure 1). 1,2These antifungal polyketides show potent in vitro activity against Candida albicans and Aspergillus fumigatus, 1 as well as at least 4-fold less cytotoxicity for normal human fibroblast cells when compared to amphotericin B. 1,3 The relative configurations of basiliskamides A (1) and B (2) were proposed by Andersen and co-workers 1 and the absolute configurations have been confirmed by total synthesis. 4e have recently concluded the total synthesis of basiliskamide B. 5 As the natural supply of basiliskamide A is restricted, and attracted by its potent cytotoxicity, we initiated a project directed towards an efficient and flexible total synthesis, in order to provide further material for more extensive biological studies, along with access to novel analogs. 6

Results and Discussion
Our approach for the preparation of (-)-basiliskamide A (1) began with the synthesis of vinyl iodide 4, prepared in 7 steps and 19.1% overall yield from ethylketone 3 (Scheme 1). 5,7he next step involved a Stille cross-coupling reaction between Z-vinylstannane 5 8 and E-vinyl iodide 4 (Scheme 2).This was accomplished by treatment of 4 and 5 in DMF with catalytic amounts of Pd(MeCN) 2 Cl 2 at 50 o C, providing 6 in 60% yield after purification by silica-gel column chromatography.At this point only four synthetic operations remained to conclude the total synthesis of (-)-basiliskamide A. Removal of the isopropylidene acetal protecting group in 6 with 80% AcOH provided diol 7. Selective protection of the less hindered oxygen with TES chloride in the presence of pyridine gave alcohol 8 (67% yield, 2 steps). 9Treatment of secondary alcohol 8 with E-cinnamoyl chloride in the presence of DMAP and Et 3 N gave ester 9, which, after treatment with HF in acetonitrile, provided (-)-basiliskamide A in 42% for the four-step sequence.
The spectroscopic and physical data ( 1 H and 13 C NMR, IR, [a] D , R f ) for synthetic (-)-basiliskamide A were identical in all respects with the published data for the natural product. 1,4

NMR studies
At this point, we decided to investigate the possibility of basiliskamide B being produced by cinnamoyl side chain migration from basiliskamide A. To this end, we did an NMR study to verify whether the conversion of basiliskamide A to basiliskamide B in mild acidic CDCl 3 solution was possible or not (Scheme 3).This conversion would occur through migration of the cinnamoyl side chain from the more hindered oxygen at C9 in basiliskamide A to the less hindered oxygen at C7.
In the 1 H NMR spectrum of basiliskamide A (1), the signal at d 3.63 ppm (dt, J 3.5 and 10.0 Hz) is attributed to the hydrogen H7.In the 1 H NMR spectrum of basiliskamide B the signal at d 3.35 ppm (dd, J 2.5 and 9.5 Hz) refers to the hydrogen H9 (Figure 2).
After 24 h, the 1 H NMR spectrum of basiliskamide A (1) shows a new signal at d 3.35 ppm, which corresponds to the hydrogen H9 of basiliskamide B (Figure 3).After 20 days, we can observe that the signal at d 3.35 ppm increases leading to a 1.00:0.45ratio of basiliskamide A ( 1) and basiliskamide B (2), respectively.This clearly shows that the migration of the cinnamoyl side chain is occurring and that it is possible that basiliskamide B is an artifact of basiliskamide A. 10

Conclusions
In summary, a highly convergent and efficient total synthesis of (-)-basiliskamide A has been accomplished.The synthesis required 15 steps from ethylketone 3 and produced the desired product in 3.2% overall yield.This approach compares very well with the published routes to (-)-basiliskamide A 4 and the synthetic strategy presented here is, in principle, readily applicable for the preparation of additional analogues.

Figure 3 .
Figure 3. Partial 1 H NMR spectrum (CDCl 3 , 500 MHz) showing the migration of the cinnamoyl side chain after 24 h and after 20 days.