Synthesis of Guaipyridine Alkaloids Rupestine M and L by Cycloaddition/Cycloreversion of an Intermediate 1,4-Oxazinone

Abstract

A new method to prepare 1,4-oxazinone intermediates was developed based on aza-conjugate addition of β-amino alcohols to electron-deficient alkyne precursors. A tandem intramolecular cycloaddition/cycloreversion reaction sequence was evaluated, leading to the synthesis of the guaipyridine alkaloid natural products rupestine M and L. Starting from (–)-citronellal and thus a known configuration of the C5 stereocenter, a revised absolute configuration of natural rupestine L is suggested based on optical rotation.

Regioselective Formation of Pyridines by Cycloaddition/Cycloreversion of 1,4-Oxazinone Precursors with Bisalkyne Substrates

“…Oxazinone 6 and the symmetric TMS-bisalkyne 10a were reacted overnight in toluene at 110 °C (entry 1). We noticed that this thermal cycloaddition/cycloreversion reaction had a faster rate relative to other precursors previously explored 3 5 and the resulting product 11a was afforded in excellent yield (96%) as a single pyridine isomer. 8 In similar fashion, the bispropargyl ether 10b was also effective in the reaction sequence and gave pyridine 11b in 46% yield and as a 19:1 ratio of isomers (entry 2).…”

“…Cycloaddition reactivity of 6 was established with the terminal alkyne 7a (Scheme 1, entry 1). 5 Reaction with this alkyl-substituted terminal alkyne was poorly selective, giving a 1:1 ratio of the 2,3,5-pyridine 8a and the complementary 2,4,6-isomer 9a. In a target-directed synthesis of the 2,3,5-substituted guaipyridine alkaloid natural products, we successfully pursued a strategy based on intramolecular cycloaddition in part to avoid this regioselectivity.…”

“…In a target-directed synthesis of the 2,3,5-substituted guaipyridine alkaloid natural products, we successfully pursued a strategy based on intramolecular cycloaddition in part to avoid this regioselectivity. 5 Reaction of oxazinone 6 with butynoate 7b also afforded a modest ratio of isomeric pyridines; 8b and 9b were produced in a 2:1 ratio. These isomers were difficult to separate and only a 32% yield of the more abundant pyridine 8b could be cleanly isolated free of the isomeric pyridine (see the Supporting Information).…”

“…As part of a program to explore new methods to prepare 1,4-oxazinones, we recently developed a synthesis starting from dimethyl acetylenedicarboxylate (Scheme 1 ). 5 The sequence is direct, high-yielding, uses readily available materials, and can be performed on reasonable scale (>13 g) using a single recrystallization to isolate the intermediate lactone 5 . Acetate elimination and alkene isomerization on 5 gives oxazinone 6 .…”

“…In a target-directed synthesis of the 2,3,5-substituted guaipyridine alkaloid natural products, we successfully pursued a strategy based on intramolecular cycloaddition in part to avoid this regioselectivity. 5…”