A s y m m e t r i c C o n s t r u c t i o n o f t h e A z a s p i r o [ 5 . 6 ] d o d e c -9 -e n e S y s t e mAbstract: The asymmetric formation of azaspiro[5.6]dodec-9-ene system is described. The Diels-Alder reactions of an a-methylene caprolactam and diene in the presence of a Cu(II) and (S,S)-tBu-BOX complex afford the desired spirocyclic compounds with good exo-selectivity as well as excellent enantioselectivity. These exoadducts would be applicable to the synthesis of marine natural toxins including the corresponding cyclic imine moiety.Recently, a new class of marine toxins containing an azaspiro[5.6]dodec-9-ene moiety has been isolated from shellfish and dinoflagellate, such as pinnatoxins 1 and pteriatoxin 2 (Figure 1). The toxicological properties of these compounds seem to be attributed to the cyclic imine moiety, which would be biogenetically constructed by an intramolecular Diels-Alder reaction via exo-addition. Several groups have investigated the synthesis of these attractive target molecules. 3,4 Our strategy in the construction of the azaspirocyclic moiety is an asymmetric DielsAlder reaction of a-methylene caprolactam and diene utilizing chiral Lewis acid (Scheme 1). We selected (S,S)-tBuBOX/Cu complex reported by Evans 5 as a chiral Lewis acid in Diels-Alder reaction considering that carbamate lactam, such as 1, would be applicable to the asymmetric construction of a spirocyclic system due to the nature of its locked s-cis conformation. 6 Herein we describe the asymmetric formation of azaspiro[5.6]dodec-9-ene, which is supposed to be the common synthetic key intermediate for pinnatoxin and pteriatoxin, since the conversion of lactam to imine have been known well. 7The a-methylene caprolactam derivative was readily prepared by the following sequence (Scheme 2). N-CBZ protected e-caprolactam 2 was converted to the silyl ketene acetal 3, which was subjected to the reaction with Eschenmoser's salt and the subsequent treatment with MeI on heating to furnish a-methylene-lactam 4. 8 At first, the Diels-Alder reaction of 4 with cyclopentadiene in the presence of a Cu(II) and (S,S)-t-Bu-BOX complex was investigated (Scheme 3). The reaction of 4 and cyclopentadiene in the presence of (S,S)-t-BuBOX, Cu(OTf) 2 , and MS-3Å at 25 °C for 6 h afforded the corresponding spirocyclic adducts with good enantioselectivity. This result indicates that the a-methylene lactam could coordinate the copper/t-Bu-BOX complex to form the preferential intermediate. In other words, it could support the proposal of s-cis conformation of the dienophile in the activated complex. It should be noted that the slight exoselectivity (exo/endo = 1.6:1) was observed in this case. Roush and other groups have found that the Diels-Alder reaction of conformationally rigid cyclic cisoid dienophiles, such as a-methylene-lactone, with cyclopentadiene proceeds with exo-selectivity accounting for by Berson's dipole moment hypotheses. 9,10
A s y m m e t r i c C o n s t r u c t i o n o f t h e A z a s p i r o [ 5 . 5 ] u n d e c -8 -e n e S y s t e mAbstract: In the course of the synthetic studies on gymnodimine, a potent shellfish toxin, the asymmetric construction of the azaspirocyclic part was achieved by the (-)-siam×Cu(SbF 6 ) 2 complex catalyzed intermolecular Diels-Alder reaction in high exo-and enantioselectivities.Gymnodimine 1 is a potent marine toxin which was isolated from New Zealand oysters Tiostrea chilensis as well as the concurrent dinoflagellate Gymnodinium cf. mikimotoi. 1 The toxin includes a characteristic spirocyclic imine moiety which has been proposed to be biogenetically constructed by intramolecular Diels-Alder reaction of the triene part with the a,b-unsaturated ketone as the precursor of the cyclic imine part in an exo-cycloaddition. 1 On the other hand, the first total synthesis of pinnatoxin A 2 and its enantiomer, structurally reminiscent of 1, has been achieved by Kishi et al. 3 according to the proposed biogenesis. 2 We have studied aiming to the synthesis of 1, 4,5 the pathway of which involves asymmetric intermolecular exo-cyclic Diels-Alder reaction in the different manner from the Kishi procedure (Scheme 1). In this paper we present the efficient asymmetric construction of the 1-oxo-2-azaspiro[5.5]undec-8-ene part, which could be a key intermediate for the total synthesis of 1.In order to construct the requisite azaspirocyclic system, we developed asymmetric intermolecular Diels-Alder reaction reported by Ellman. 6 Asymmetric addition of various dienes to dienophilic a-methylene lactam 2, prepared from d-valerolactam, 7 in the presence of (-)-siam and Cu(SbF 6 ) 2 6 was investigated (Table). The reaction of isoprene 3 (1.0 equiv) with 2 (2.0 equiv) and (-)-siam·Cu(SbF 6 ) 2 (0.4 equiv) in the dark proceeded smoothly to afford a cycloadduct 4 (98% yield) with >99% ee (entry 1). In the case of cyclopentadiene 5, cycloadduct 6 was produced (99% yield) with >99% ee, and the ratio of exo/endo isomers amounted to 87:13 (entry 2). The reaction of further functionalized diene 7 afforded cycloadduct 8 (33% yield) with high exo/endo selectivity (~95/5) and high enantiomeric excess (94%), along with the regioisomer of 8 (29% yield) (entry 3). 8 The reaction with 9 9 having (2S)-5-oxotetrahydrofuran-2-yl group gave satisfactorily the desired cycloadduct 10 (89% yield) in 88% diastereomeric excess (entry 4). The respective structures of the cycloadducts 8 and 10 were determined by the NMR spectroscopic analysis of their derivatives according to the Kusumi procedure. 10 On the other hand, the attempted treatment of 9 (1.0 equiv) and 2 (1.0 equiv) under the modified conditions of the chiral reagents developed by Evans {Cu ++ [(S,S)-t-Bu-BOX](SbF 6 -) 2 (0.2 equiv) in CH 2 Cl 2 at 24 °C, 214 h} 11 led to no reaction, in contrast with the satisfactory results of 9 and a-methylene e-caprolactam. 12 Ellman described that the Cu(II) ligand complex exists as a unique M 2 L 4 helicate in solid state, while the complex coordinates p...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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