Azaspirocycle

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 total number of atoms in the azaspirocycle is optimally seven or eight, similar to the optimal requirements in the monocyclic guanethidine series. However, an additional factor with the azaspiro-alkanes is that the number of atoms in the heterocyclic ring should be as large as possible consistent with the previous condition. Compound (XXX) has a longer duration of action than guanethidine both in animals [221] and in man [224]. 

Some examples of the use of nitrogen nucleophiles as the key step in organic syntheses include the preparation of pyrroles (equation 58),201-202 a number of alkaloids203 207 includi ibogamine, catha-ranthine205-206 and perhydrohistrionicotoxin,207 amino sugars (equation 59), 5-amino-l,3-penta-dienes209 and 1-azaspirocycles.210... 

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. 

Penster, M. D. B., Patrick, B. O., Dake, G. R. Construction of Azaspirocyclic Ketones through a-Hydroxyiminium Ion or a-Siloxy Epoxide Semipinacol Rearrangements. Org. Lett. 2001, 3, 2109-2112. 

Metathetic ring closure. Catalyst 1. can be regarded as the standard workhorse for RCM and the scope of its applications continues to expand. Thus, its use in the elaboration of cyclic structures including azaspirocycles," 3-pyrrolines," and those containing phosphine oxides, phosphinates, dioxasilanes, - sulfonamides. l-(Dialkoxyboryl)vinylcycloalkenes are obtained from x-alken-l-ynyl boronates. ... 

On the other hand, the azaspirocyclization of A-acyl-A-alkoxynitrenium ions, which can be generated under mild conditions by the treatment of A-methoxyamides with iodine (III) reagents, constitutes a very efficient synthetic entry to l-azaspiro[4.5]decanediones. 

It is worth noting that Wardrop has also successfully explored the N-acylnitrenium route applied to a- and ( -substituted 3-(methoxyphenyl)-N-methoxypropionamides (e.g.39) [32], Using PIFA as the oxidant agent, a Tc-face selective azaspirocyclization was found, compound 40 being isolated with an excellent diastereoselectivity (Scheme 16). 

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. 

Recent approaches to the construction of l-azaspiro[4.5]decanes and related 1-azaspirocycles 06X3467. 

Pinnaic Acids and Halichlorine, Novel Marine Azaspirocycles. 167... 

An intramolecular aza-Piancatelli rearrangement that constructs a fully substituted carbon centre bearing a nitrogen atom and a spirocyclic ring system in a single operation has been catalysed by dysprosium (Ill)triflate. The azaspirocycles are formed exclusively as the irons diastereomer, consistent with a electrocyclization (Scheme 99). ... 

Iminium ions generated in situ can also serve as migration termini for semipinacol rearrangements. For instance, azaspirocyclic ketones are generated from appropriately-substituted A -tosyl enamides (48 49). The... 

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... 

SCHEME 15.10 Azaspirocyclic products from iV-benzylacetamide radicals. 

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,... 

Azaspirocyclic hexenones can be derived by sequential reaction of some cyclohexadienyltricarbonyliron complexes with benzylamine followed by oxidative removal of the Fe(CO)3 moiety. ... 

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