Studies towards enantioselective synthesis of mitomycins A and B series

Abstract

Abstract of thesis entitled STUDIES TOWARDS ENANTIOSELECTIVE SYNTHESIS OF MITOMYCINS A AND B SERIES Submitted by Sui Yi for the degree of Doctor of Philosophy at The University of Hong Kong in May 2017 Mitomycins are a large family of natural products with unique structures and they are well known for their antibiotic and antitumor activity (Figure 1). Since the absolute configurations of mitomycins affect their biological activities, it is important to develop chemical synthesis of enantioenriched mitomycins. However, only one enantioselective total synthesis of mitomycin K has been achieved by our group and no enantioselective syntheses of A and B series of mitomycins have been achieved. In this thesis, the study towards enantioselective synthesis of A and B series of mitomycins has been explored. Initially, the aziridine ring was constructed from amine 2.13, aldehyde 2.14, and diazo compound 2.12 in both racemic and enantioselective versions via Wulff enantioselective aziridination reaction (Scheme 1). Then, a model study for the C8a–C9 bond formation was investigated with reduced structural complexity and steric hindrance of coupling precursors (Scheme 2). Fragments 2.52 and 2.35 were coupled through an SN2 reaction under basic conditions, affording intermediate 2.53. Intramolecular α-arylation of silyl enol ether 2.55, obtained from 2.53 in 2 steps, constructed the requisite C8a–C9 bond. Further two manipulations delivered quinone 2.58, completing this model study. On the basis of this model study, substrates 2.61, 2.62 and 2.69 were investigated for the construction of C8a–C9 bond individually (Scheme 3). However, none of them succeeded since the labile β-oxyl ketone moiety impeded the construction C8a−C9 bond in the real system. In order to overcome this difficulty, the carbon chain between the terminal oxyl and the carbonyl groups was homologated by one carbon to avoid the problematic β-oxyl ketone moiety. With the extra carbon, C8a−C9 bond was constructed successfully, affording diastereomers (±)-3.2. After removal of a benzyl group, (±)-3.13a and (±)-3.13b were separated for divergent syntheses of A and B series of mitomycins (Scheme 4). Eight further transformations of (±)-3.13a gave 8-membered ring (±)-3.25a as a late stage intermediate for A series of mitomycins, while further 5 manipulations of (±)-3.13b gave the precursor of 8-membered ring (±)-3.23b as a late stage intermediate for B series of mitomycins (Scheme 5).

Figure 1 Structures of Mitomycins Scheme 1 Synthesis of Aziridine Segment 2.23

Scheme 2 Model Study on Construction of C8a−C9 Bond

Scheme 3 Trials of Construction of C8a−C9 Bond in Real System Scheme 4 Construction of the C8a−C9 Bond Scheme 5 Syntheses of Late Stage Intermediates of A and B Series of Mitomycins