Oxamidation of Unsaturated O-Alkyl Hydroxamates: Synthesis of the Madangamine Diazatricylic (ABC Rings) Skeleton

Abstract

A novel approach to the diazatricyclic madangamine ABC ring system and the synthesis of an advanced, differentially protected intermediate for the synthesis of madangamine D is reported. Central to the success of this approach is the iodine(III)-mediated intramolecular oxamidation of an unsaturated O-methyl hydroxamate, a π-N-type cyclization which proceeds in high yield and with complete regioselectivity to generate the 2-azabicyclo[3.3.1]nonane (morphan) system encompassing rings A and C.

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

“…In this work, we propose a regioselective approach to the synthesis of 2,3-dihydropyrroloquinazolin-5(1H)-ones 6 functionalized with a hydroxymethyl group by oxidative cyclization of hereto unknown 2-(buten-3-yl)quinazolin-4(3H)-ones 7 upon action of bis(trifluoroacetoxy)iodobenzene (PIFA) (see Scheme 1D). A part from the well-known applications of hypervalent iodine compounds for oxidative rearrangements, fragmentations, halogenations and hydroxylations [37,38], they were also involved in the synthesis of N-heterocycles [39,40] including from properly functionalized arenes and alkenes [41][42][43][44][45][46][47][48][49][50][51][52][53]. In the case of such substrates having oxygen-containing functional groups, PIFA attacked the double bond first [41][42][43].…”

“…In the case of such substrates having oxygen-containing functional groups, PIFA attacked the double bond first [41][42][43]. With unsaturated amides or hydroxamates, oxidation of the nitrogen atom to nitrenium intermediates occurred initially; further stabilization of these species resulted in the formation of hydroxylated lactams [44][45][46][47][48], azaspirocycles [49][50][51][52][53], or tricyclic nitrogen-containing heterocycles [44,53].…”

“…Two pathways seem to be possible for the oxidative heterocyclization of quinazolinones 7 (see Scheme 2 ). The first of them (pathway a) includes the formation of the nitrene cation 11 [ 41 – 42 44 – 45 53 ] under action of PIFA as an oxidant. A subsequent electrophilic attack at the double bond provides aziridinium cation 12 that undergoes selective ring opening with the trifluoroacetate anion to give intermediate 13 .…”

Alkene Difunctionalization Using Hypervalent Iodine Reagents: Progress and Developments in the Past Ten Years

“…Additionally, this nitrenium-mediated aminooxygenation was successfully applied to the synthesis of a series of polyhydroxylated indolizidine alkaloids 56 (Scheme 11b) [52,53]. The same protocol was recently used to synthesize madangamine D and other morphan-based natural products [54].…”

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E

“…Since their isolation, the madangamines have attracted significant attention from the synthetic community with numerous reported strategies to polycyclic core fragments. [11][12][13][14][15][16][17][18][19][20][21][22] However, there exist only two reports of total syntheses of members of the family and a single formal synthesis of madangamine A (Figure 1B). [23][24][25][26] In 2014, Amat reported the first asymmetric total synthesis of madangamine D, employing a stereoselective cyclocondensation of phenylglycinol to establish an enantio-enriched bicyclic (rings BC) scaffold.…”