Chemical Reactivity of Dihydropyrazine Derivatives. Cycloaddition Behavior toward Ketenes

Abstract

Dihydropyrazines (DHPs), which are derived from aminosugars, exhibit various properties such as specific DNA strand-breakage activity, [1][2][3] facile dimerization, [4][5][6] unique ESR spectral behavior, [7][8][9] in vitro, induction of apoptosis 10) and mutagenesis 11,12) in vivo. It is thought that all these phenomena originate from the two natural characteristics of DHPs, i.e., their high chemical reactivity and radical generation ability. [4][5][6][7][8][9] As exemplified in Chart 1, less substituted DHPs such as 5,6-dimethyl-2,3-dihydropyrazine exhibit high chemical reactivity and readily transform to dimeric heterocyclic compounds via aldol condensation or pericyclic ene reaction (Chart 1). 5,6) In order to clarify the inherent chemical reactivity of DHPs, we studied the cycloaddition behavior of DHPs as diazadienes or imines towards ketenes. The results are discussed in detail on the basis of molecular orbital (MO) calculations on the cycloaddition pathways and the single crystal X-ray analyses of the cycloadducts. Results and DiscussionFirst, reactions of relatively stable 2,3-diphenyl DHP derivatives (1a-c) 13) with ketenes (2a-c) were performed (Chart 2).The reaction of 1a with 2a provided the 1 : 1 adduct (3aa) and two stereoisomeric 1:2 adducts (anti 4aa and syn 4aa). The yields and product ratios for the reactions with 1a-c and 2a-c are summarized in Table 1. ; 4-22-1 Ikeda, Kumamoto 860-0082, Japan. Received April 9, 2009; accepted May 7, 2009; published online May 12, 2009 The cycloaddition behavior of dihydropyrazines toward ketenes was investigated using single-crystal X-ray structures of the cycloadducts and density functional theory (DFT) calculation data. The reaction proceeds via a stepwise pathway involving an orientation complex prior to formation of the betaine intermediate. This is followed by electrocyclization to afford the 1 : 1 and 1 : 2 adducts bearing b b-lactam ring(s).

Phenyl-Substituted Dihydropyrazines with DNA Strand-Breakage Activity

“…The chemical reactivity of DHPs with the component in vivo was considered to also be a factor in their bacterial toxicity, as shown with reactions of DHPs with ethylenediamine, [6][7][8] ketene 9) or thiourea.…”