Azaspirocycles synthesis

Azaspirocyclic ketoaziridines 304 (X = Cl or OTBS), potential intermediates for the total synthesis of antitumor alkaloid cephalotaxine 305, have been prepared in 26% (X = Cl) and 76% (X = OTBS) yields, respectively, via an lAOC reaction of azide 303 (Eq. 34) [80]. 

The molecular complexities of these architecturally novel alkaloids have prompted intense studies to elaborate new and efficient methods and strategies for the synthesis of these products. Hence, several stereocontrol approaches have been developed to successfully construct the azaspirocyclic core of pinnaic acids and halichlorine, providing access to the formal total synthesis and highly stereoselectivity of these molecules (Christie et al. 2004 Zhang et al. 2005 Andrade and Martin 2005 Clive et al. 2005 and references cited therein). In particular, Danishefsky s research group has reported the first total synthesis of halichlorine (Trauner et al. 1999), supporting the previous conclusions regarding the structure of this alkaloid (Kuramoto et al. 1996 Arimoto et al. 1998), and has... 

Zhang, H.L., Zhao, G., Ding, Y, and Wu, B. 2005. An efficient and enantioselective approach to the azaspirocyclic core of alkaloids formal synthesis of halichlorine and pinnaic acid. J Org Chem 70, 4954-4961. 

The synthesis of racemic desmethylamino FR901483 was reported by Snider in 1998 [9] (3.1.1). Three years later, using the A-alkoxy-A-acylnitrenium ion methodology for the azaspirocyclization step (3.2.1), Wardrop published a formal synthesis of desmethylamino FR901483 [10] having reached the advanced intermediate 15 previously reported in Snider s pioneering work (Scheme 8). 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

In Chap. 10, Russel presents Oxindoles and SpirocycMc Variations Strategies for C3 Functionalization of indoles and the role this emerging strategy plays both in the asymmetric introduction of C3 quaternary centers and in the synthesis of oxindoles and myriad-related natural products, including oxaspirocycles and azaspirocycles. 

Intramolecular amination with allylic acetates is used for the synthesis of cyclic alkaloids (Scheme This protocol can be applied to a synthesis of 21-membered cyclic amine skeleton of the spermidine alkaloid and l-azaspirocycles.f 3-Methylenepyrolidines are provided by the nucleophilic addition of allylzinc reagents to imines and subsequent Pd-catalyzed intramolecular allyIation.[" i... 

Six-membered Rings.—A reaction, which may be especially suited to natural product synthesis, provides a facile route to 1-azaspirocycles. Cyclization via a 7T- allyl palladium complex occurs in almost quantitative yield in some cases,... 

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