Synthesis Study Of Pyrrolozoxazine Alkaloids

In recent years, bis-a-substituent pyrrolozoxazine alkaloids including pyrrole spiroketal alkaloids and pyrrolozoxazine alkaloids along with 5-hydroxymethyl-pyrrole-2-carbaldehyde alkaloids were reported. Pyrrole spiroketal alkaloids have been found in Astragalus A. tatarinowii rhizome, Acorus tatarinowii, Capparis spinosa and Bee-collected Brassica campestris pollen. Pyrrolozoxazine alkaloids were found in Morus alba, Capparis spinosa, Astragalus A. tatarinowii rhizome and fermentation broth of an endophytic actinomycetes. Pharmacological experiments showed that these alkaloids had anti-aging and cell protection activity. The low content of these alkaloids limits further anti-aging activity study. In this thesis, two pyrrole spiroketal alkaloids (pollenopyrroside A and capparisine B) and two analogues (2-52a and 2-52b) were synthesized by a total synthesis route. Six pyrrolozoxazine alkaloids and two 5-hydroxymethyl-pyrrole-2-carbaldehyde alkaloids were obtained via biosynthetic method.Three total synthesis routes of six-membered sugar ring pyrrole spiroketal alkaloids were designed. Pollenopyrroside A and capparisine B, two diastereoisomers of pyrrole spiroketal alkaloids were first synthesized by 14 steps including nucleophilic substitution, improved microwave-assisted bishydroxymethylation of pyrrole, acid-catalyzed spirocyclization and Barton-McCombie deoxygenation with total yields of 2.7% and 8.8%, respectively. Among the 14 steps, microwave-assisted bishydroxymethylation of pyrrole was reported for the first time. The stereochemistry of key intermindiate 2-39a and 2-39b was determined by NOESY analysis and computer simulation. In addition, the steric configuration of astragalines D was consistent with capparisine B based on the NMR comparision.Pyrrolozoxazine alkaloids 1-12?1-17 were synthesized with D-fructose and D-amino acids by 4 steps, including dehydration of D-fructose, reduction, peroxidation and one-pot reaction. The one-pot reaction is a combination of Maillard condensation and lactonization. A possible biosynthetic pathway of bis-a-substituent pyrrolidine alkaloids was proposed. Based on the proposed biosynthetic pathway, six pyrrolozoxazine alkaloids 1-12?1-17 were synthesized via biosynthetic method. In a mixture of acetic acid and triethylamine, condensation of D-fructose and D-amino acids at 80? for 8h produced pyrrolozoxazine alkaloids in the yield of 15%?21%. Replacing amino acids with tyramine or phenethylamine can afford pyrrolezanthine (1-18) or ganodine ? (1-19)-two 5-hydroxymethyl-pyrrole-2-carbaldehyde alkaloids in a yield of 42% or 39%.With AGE-mediated preadipocytes aging as senescence model, pyrrole spiroketal compounds were tested for their regulation of aging-related proteins. The results displayed pyrrole spiroketal alkaloids 2-42a and 2-42b, and analogue 2-52a can reduce p16 protein expression, indicating pyrrole spiroketal compounds have a certain antiaging activity. Pyrrole spiroketal pyrrole alkaloids and pyrrolozoxazine alkaloids were invesgated for their scavenging activity of singlet oxygen with ATTA-Eu3+lanthanide fluorescence probe. The results showed that these alkaloids have certain singlet oxygen scavenging ability. For example, singlet oxygen scavenging rate of alkaloid 1-17 was 73% in an incubation time of 20min.