Spirocyclic piperidines

Reactivity of 23-unsaturaIed piperidines provides intcre.sling and efficient chemistry for the synthesis of more complex piperidines <01OL769>. Construction of 2-spirocyclic piperidines 104 and 105 was achieved via the semipinacol rearrangement of cyclobutyl (102) and cyclopentyl (103) substituted precursors <010L2109>. The products contain the structural features of natural products such as histrionicotoxin.halichlorine and fasicularin. 

Scheme 29 Formation of spirocyclic piperidines in the presence of acylating agents.

Spirocyclic piperidine amides as potent, nonpeptide inhibitors of human mast cell tryptase... 

The serine protease tryptase is released from mast cells at sites of inflammation. Thus, tryptase inhibitors have potential for treating inflammatory disorders, such as asthma, allergic rhinitis, and inflammatory bowel disease. We explored a series of spirocyclic piperidine amide derivatives (1) as tryptase inhibitors and identified 2 (JNJ-27390467) as a potent, selective inhibitor of human p-tryptase (Ki = 3.7 nM). This compound has -700-fold selectivity vs. inhibition of trypsin, and greater selectivity vs. inhibition of 12 other serine proteases. In pharmacokinetics studies in dogs and rats, 2 showed... 

Histrionicotoxin (HTXs) are a family of spirocyclic piperidine alkaloids that were isolated in 1971 from the Colombian frog Dendrobates histrionicus. HTX and its analogs have generated considerable pharmacological interest as... 

Stockman and coworkers [329] developed a straightforward synthesis of a tricyclic compound 2-636 which has some resemblance to the spirocyclic portion of the natural product halichlorine (2-637) [330]. On treatment of the symmetrical ketone 2-633, accessible in five steps from alcohol 2-632, with hydroxylamine hydrochloride the spiro piperidine 2-636 could be obtained in 62% yield (Scheme... 

The arylenamide photocyclisation protocol continues to provide convenient access to intermediates of interest in alkaloid synthesis. Spirocyclic 5-lactam (55) has been prepared from cycloalkylenamide (54) and irradiation of enones (56) yields the corresponding spiroketones (57). Analogous photocyclisations have led to nitro-substituted berbine derivatives. The piperidine arylenamides (59) are efficiently photocyclised to the corresponding benzo[b]quinolizine-6-ones (60), providing convenient access to benzoquinolizidine derivatives. In contrast,... 

The first total synthesis of racemic histrionicotoxin (58), the parent structure in a family of related spirocyclic alkaloids isolated from the skins of Dendrobates histrionicus, utilized the Eschenmoser reaction to generate the anchor of what would become the enyne group extending from the a-position of the piperidine nucleus. The spirothiolactam intemiediate (77) was condensed with ethyl 2-bromoace-toacetate in the presence of sodium bicarbonate to produce (78) in good yield (Scheme 18). Prior to further reaction on the vinylogous carbamate, the pendent allylic acetate was elalx>rated to the enyne (79). Subsequent deacylation and enyne protection yielded spirobicycle (80), which gave a 1 1 mixture of isomers upon reduction. The desired diastereomer (81) was isolated and subsequently converted to racemic histrionicotoxin (58). 

The cyclization of the substrate 200 led to the formation of the spirocyclic substituted pyrrolidine derivative 201 in good yield and with a reasonable diastereomeric excess. Under the same conditions, the benzylamine 202 underwent a reductive hthiation with LiDBB leading to the spirocyclic pyrroHdine 203 in moderate yield. As a working hypothesis for the selectivity, the authors proposed coordination between the lithium and nitrogen atoms during the carboHthiation of piperidine... 

Alkaloids from the water Hly genus Nuphar include monomeric (C15) sesqui-terpenoid piperidines and quinoHzidines, and dimeric (C30) thiospirane metabolites in which two quinohzidine moieties are linked by a spirocyclic tetrahydrothiophene ring. The terminus of the regular sesquiterpene backbone in all of these alkaloids has been elaborated into a 3-furyl ring. Only the simple monomeric alkaloids are germane to the current review. 

Recently, Chen et al. reported on a one-pot, three-component tandem reaction sequence to prepare piperidine containing spirocyclic oxindoles 345 using chiral orga-nocatalyst 341 (Scheme 40.75). 

These spirocyclic molecules are very attractive building blocks. As well as having a clearly defined 3-dimensional shape, a variety of functional group vectors on the spirocycle are available to interact with a binding pocket (Figure 18.19). In addition, these small molecules mimic monocyclic rings (such as morpholines and piperidines, for example) and the linear azaspiro[3.3]heptanes (Figure 18.20) have shown increased aqueous... 

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