Use of the Oxazole-Olefin Diels-Alder Reaction in the Total Synthesis of the Monoterpene Alkaloids (-)-Plectrodorine and (+)-Oxerine

Abstract

Oxazoles have been shown to behave as dependable azadiene components in Diels-Alder reactions.1) Since Kondrat'eva reported the first example of a Diels-Alder reaction of an oxazole with an olefin to produce a pyridine in 1957, 2,3) this methodology has become a valuable tool for the preparation of highly substituted pyridines, such as pyridoxine and its analogues. Despite an early recognition of the practical value of the oxazole-olefin Diels-Alder reaction, there are few reports applying this cycloaddition intramolecularly to the synthesis of pyridine-containing natural products. [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] In the present study, we sought to explore the feasibility of intramolecular oxazole-olefin Diels-Alder reaction for an efficient construction of two monoterpene alkaloids possessing the cyclopenta[c]pyridine ring system. [20][21][22][23] Plectrodorine (1), selected as the first target for the monoterpene alkaloids, was isolated as a racemate together with isoplectrodorine (2) from the aerial parts of Plectronia odorata (Rubiaceae) by Koch and co-workers.24) The structure and relative stereochemistry of 1 were elucidated through a combination of spectral analysis and chemical transformation. The Koch group 25) then described the isolation of oxerine from the aerial parts of Oxera morieri (Verbenaceae) and proposed its absolute stereochemistry to be (5R,7S)-3 by partial synthesis of oxerine from harpagide of known absolute configuration. 26) We chose (5R,7S)-3 as the second target to demonstrate the versatility of our synthetic strategy, although racemic synthesis of oxerine has been accomplished by several research groups. [27][28][29][30] A brief account of the results reported here has been published in a preliminary form. 31)For the construction of the cyclopenta[c]pyridine skeleton via the intramolecular Diels-Alder reaction of oxazoles, we planned to employ the oxazole-olefin 4. The introduction of suitable olefinic dienophiles to the oxazole aldehyde 5 would provide 4, whereas the oxazole ring of 5 was envisaged to arise from the addition of a-lithiated methyl isocyanide to the g-butyrolactone 6 according to the procedure of Jacobi. 32,33) The requisite g-butyrolactone 6 was readily obtained from Seebach's dioxolanone 7. 34,35) Thus, reduction of 7 with BH 3 · Me 2 S followed by alkaline hydrolysis and acid-promoted lactone formation afforded 6 in 73% yield. The absolute configuration of 6 was further substantiated by the identity of specific rotation of the benzoate 8, derived from 6, with the data reported in the literature. 36) After protection of the tertiary hydroxy group in 6 with tert-butyldimethylsilyl triflate (TBDMSOTf) to afford the lactone 9, the formation of an oxazole ring was carried out by treatment of 9 with 2.5 eq of a-lithiated methyl isocyanide in THF at Ϫ78°C for 3 h followed by addition of AcOH, a slight modification of the Jacobi method, 32,33) giving the alcohol 10 in 66% yield. With a view to introducing an olefinic dienophile, the alcohol 10 was...

Intramolecular Diels–Alder Reactions of Oxazoles, Imidazoles, and Thiazoles

“…55 In 2006, Ohba and co-workers reported the total syntheses of (-)-plectrodorine and (+)-oxerine with an approach to the cyclopenta-[c]pyridine core of these target molecules that employed the IMDA of oxazole-olefins (Scheme 18). 56…”

Convenient Formal Synthesis of (+)-Grandisol through Lewis Acid Promoted Enantioselective Pinacolic Rearrangement

“…Reduction of acid 4 using borane dimethylsulfide complex 6 directly afforded without basic treatment 7 the pure a-hydroxylactone 5 8 according to the mechanism depicted in the Scheme 3. Attempts to perform the intermolecular cyclopropanation reaction 9 on the lactone 5 did not lead to the expected cyclopropanol 6, but returned the lactone practically unchanged, only the isopropyl ester 7 was isolated in very low yield (10%) possibly resulting from the nucleophilic attack of isopropyl anion on the lactone function.…”

“…To overcome this problem, the hydroxyl group of the lactone 5 was protected as a silyl ether giving the a-(silyloxy)lactone 8 8 which successfully underwent the intermolecular cyclopropanation reaction using excess of ethylmagnesium bromide in the presence of titanium tetraisopropoxide. The cyclopropanol 9 was isolated as an enantiomerically pure product in 88% yield (Scheme 5) and the structure was confirmed by X-ray crystal-structure analysis (Figure 1).…”

Estudio experimental y teórico del Oxazol y sus derivados en la reacción de cicloadición [4+2] Diels-Alder

“…Las reacciones Diels-Alder de oxazoles 1 y alquenos 2, seguida por la deshidratación de los cicloaductos 3 para producir piridinas sustituidas 4, son de los procesos más interesantes que se han presentado en química orgánica desde su descubrimiento en 1957 por Kondrat'eva, debido a su versatilidad e importancia al obtener diversos productos naturales como la vitamina B 6 y análogos, con demanda electrónica normal, ver Esquema 1. [1][2][3][4][5][6][7][8][9][10] Esquema 1.…”

“…Hoy en día, las reacciones Diels-Alder se han utilizado como un procedimiento muy valioso en síntesis, debido a que permite la preparación de piridinas altamente sustituidas [6][7][8][9][10] que difícilmente se pueden obtener a través de otras rutas. Ver Figura 1.…”