CHEM221 Organic Chemistry I

Introduction

Bacterial cultures is a good source of pyrrolizidine alkaloids with about 40 members being characterized from them (Robertson & Stevens, 2014, 2017). They were first recognized in 1997 by the Upjoh Company which described unidentified ‘antibiotic 354’ from fermentation of Streptomyces puniceus subsp. Doliceus (Dolak & DeBoer, 1980) where ¹H NMR spectroscopic technique was used for characterization. Since then the bacterial pyrrolizidines biosynthesis has been neglected and was addressed about 40 years later that is in 2015. From the study legonmycins A and B were produced from Streptomyces sp. MA37 as metabolites in a study done in Legon, Ghana (Huang et al., 2015) from four important genes(lgn A-D). Bacterial pyrrolizidines have been found to possess important biological activities. For example, cytotoxicity tests on quinohemamine, dibohemamines D–F, jenamidine A, and clazamycins have shown that they are cytotoxic against a various cancer cell lines. Also, NP25302 and bohemamine are capable of inhibiting HL-60 cell adhesion to Chinese hamster ovary cells that express intercellular adhesion molecule ICAM-1 (CD-54). Thus the interest of total synthesis of legonmycins.

Results and Discussion

The synthesis route was developed from simplification of Snider’s route (Snider & Duvall, 2005)  for the  synthesis of both legonmycins A and B with expectation to facilitate the C(7a)hydroxylation by targeting the tendency to enolize C(1-7a). The products were obtained through three main steps. The first step involved addition of a protecting group by adding 2-lithiopropionitrile to methyl N-Boc-Prolinate (15) α-cyanokenone (16) which was used in crude form. Under acidic conditions the protecting group that is Boc, was removed and in situ cyclization and pyrrolizidine derivative (17) occurred and was obtained two steps as seen in scheme 1.

Scheme 1:  Legonmycin Core Preparation.

This was followed by diacylation reaction whereby the reaction with isovaleryl chloride in acrylonitrile with pyridine which acted as HCl released scavenger. Solutions of diacylated product (18) was obtained with enough purity after the filtration. Activation of electron rich pyrrole (using generic electrophile X₂) was considered to be capable of hastening the cleavage of the ester. Also the extended iminium ion would be generated by the subsequent ejection of the activating reagent irrespective of the activation site which would produce legonmycin A directly. This is as shown in scheme 2 below.

Scheme 2: Hypothesis of diacylated pyrrolizidinone oxidative hydrolysis (R=iBu)

This concept was analyzed by conducting an NMR experiment where a solution of crude diacylated species 18 at -78^o in deuterated methanol was treated with iodine solution (1.0 equiv) sequentially in pyridine- d₅ (4.5 equiv) and methanol- d₄. The proton NMR spectrum showed loss of a triplet at 3.76ppm that arised from the enantiotopic protons of CH₂N pyrrole 18 and the appearance of new resonances at 3.21 (ddd,J=11.5, 9.0, 2.5 Hz, 1H) and 3.64 (dt,  J=11.5, 8.5 Hz, 1H) ppm that resembled those that were reported for the  diastereotopic protons of CH2N in legonmycin A. Mass spectrometry analysis of  the isolated material from NMR experiment showed m/z= 270.1892, which showed that the reported spectrum produced in methanol-d4  (Huang et al., 2015) is not that of legonmycin A  but it is for that of the C(7a)-OCD₃ derivative ( 21 ,  m/z for C₁₄H₂₀D₃N_2O [M + H]⁺ = 270.1892 as seen in scheme 3). A sample of the corresponding OCH₃ derivative 22 was obtained and it contained a small amounts of toluene whose source was from the chromatography solvent, by a similar reaction in (non-deuterated) methanol. The ¹³C NMR spectrum for the OCH₃ derivative corresponded closely to that obtained in this synthesis and was reported for legonmycin A in methanol-d4. Additional resonance occurred at 51.7 ppm for the OCH₃ carbon (3.12 ppm in the 1H NMR spectrum) and also a shift in the resonance C(7a).

Conclusion

Synthesis of legonmycins A and B was successfully carried out by three important steps. That is, diacylation of pyrrolizinone derivatives followed by activation of electrophile and hydrolysis of the electron rich pyrroles.

References

Dolak, L., & DeBoer, C. (1980). Clazamycin B is antibiotic 354. The Journal of antibiotics, 33(1), 83-84.

Huang, S., Tabudravu, J., Elsayed, S. S., Travert, J., Peace, D., Tong, M. H., . . . Ebel, R. (2015). Discovery of a single monooxygenase that catalyzes carbamate formation and ring contraction in the biosynthesis of the legonmycins. Angewandte Chemie International Edition, 54(43), 12697-12701.

Robertson, J., & Stevens, K. (2014). Pyrrolizidine alkaloids. Natural product reports, 31(12), 1721-1788.

Robertson, J., & Stevens, K. (2017). Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis. Natural product reports, 34(1), 62-89.

Snider, B. B., & Duvall, J. R. (2005). Synthesis of Jenamidines A1/A2. Organic letters, 7(20), 4519-4522.

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