Synthesis of (+)‐Obtusenyne

Abstract

An enantioselective synthesis of the halogenated medium-ring ether natural product (+)-obtusenyne is reported which uses the ring expansion of a seven-membered ketene acetal by means of a Claisen rearrangement to construct the core nine-membered oxygen heterocycle. The trans substituents across the ether linkage were established by using a transition-metal-catalyzed intramolecular hydrosilation reaction of an exo-cyclic enol ether. In addition, a formal synthesis of ent-obtusenyne from 2-deoxy-D-ribose is reported. A number of interesting points regarding the chemistry of medium-ring oxygen heterocycles are highlighted.

General Synthetic Approach for the Laurencia Family of Natural Products Empowered by a Potentially Biomimetic Ring Expansion

“…As such, an alternate construction was pursued next by forging the tetrahydropyran ring through a Tsuji–Trost-type reaction. Indeed, the requisite substrate was also readily prepared by a three-step opening sequence followed by a final acetate cleavage using LiAlH 4 . Upon exposure of the resultant product (i.e., 43 ) to PdCl 2 (CH 3 CN) 2 , the desired tetrahydropyran ring was indeed formed in 48% yield, but unfortunately the configuration of the vinyl side-chain was opposite that desired (based on NOE).…”

Progress in the Chemistry of Organic Natural Products 102

“…These can be roughly divided into four subgroups, namely: (1) those containing one tetrahydrofuran ring ; (2) those containing two isolated tetrahydrofuran rings (730)(731)(732)(733)(734)(735)(736)(737)(738); (3) those containing two fused tetrahydrofuran rings (739)(740)(741)(742)(743)(744)(745)(746)(747)(748)(749)(750)(751)(752)(753)(754)(755)(756)(757); and (4) maneonenes and isomaneonenes containing three tetrahydrofuran rings (758)(759)(760)(761)(762)(763)(764)(765)(766)(767)(768)(769). These can be roughly divided into four subgroups, namely: (1) those containing one tetrahydrofuran ring ; (2) those containing two isolated tetrahydrofuran rings (730)(731)(732)(733)(734)…”

“…Based on the same rationale, the proposed structure for 738 was also revised, albeit not yet confirmed by total synthesis [615]. Maneonenes (758)(759)(760)(761)(762)(763)(764)(765)(766) and isomaneonenes (767)(768)(769) contain three tetrahydrofuran rings and all feature a (E)-or (Z)-enyne terminus. The former can be further classified into 4,7:6,9-bisepoxy acetogenins featuring either a bromoallene functionality (739-746 and 749) or a bromopropargylic terminus (747 and 748) and to 7,10:9,12-bisepoxy acetogenins possessing a (E)-or (Z)-enyne moiety (750)(751)(752).…”

“…Acetogenins containing two fused tetrahydrofuran rings can be differentiated into those with either a 2,6-dioxabicyclo[3.3.0] octane (739)(740)(741)(742)(743)(744)(745)(746)(747)(748)(749)(750)(751)(752) or a 2,5-dioxabicyclo[2.2.1]heptane (753)(754)(755)(756)(757) substructure. The first members of these series, namely, (Z)-maneonenes A (758), B (762) and C (760), (E)-maneonene B (765), and isomaneonenes A (767) and B (768), were originally reported from a Hawaiian Laurencia nidifica population by the group of Erickson in 1976 [643,644,647]. All five 2,5-dioxabicyclo[2.2.1]heptane acetogenins exhibit a (E)-or (Z)-enyne terminus (753)(754)(755)(756)(757).…”

“…In all cases, they exhibit a Br substitution at C-13. Its first total synthesis was achieved in 1999 by the group of Murai [757], while three more synthetic protocols have also been reported [758][759][760]. Its structure was determined by single-crystal X-ray diffraction analysis.…”