Spirocyclic amines, formation

More recently, the radical cyclization onto azide groups pioneered by Kim was applied in the construction of the B/E spirocyclic junction found in the [6.5.6.5] ABCE ring system of indole alkaloids such as strychnine, the clinically used anticancer agents vincristine and vinblastine and, in particular, aspidospermine87. In model system studies, cyclization of the iodoazide 24, prepared in 6 steps, in the presence of (TMS SiH, produced the N—Si (TMS>3 protected alkaloid 25, that after washing with dilute acid afforded the amine 26 in 95% yield from 24 (equation 58). The formation of the liable N—Si(TMS)3 bond was considered to arise from the reaction of the product amine 26 with the byproduct (TMS)3SiI. 

Tandem fragmentation-cyclization of bicyclic ketones connected to unsaturated side chains have been used to construct hi-, tri-, and spirocyclic ketones [334], Cossy et al. have shown that depending upon the substitution pattern, ketyl radical anions obtained from photochemically induced electron transfer from amines to cyclopropylketones lead either to the formation of 3-substituted cycloalkanones or to ring expanded products (Scheme 78) [335],... 

To probe this, model compounds were prepared and subjected to the reaction. Firstly, formation of the ABE ring system was modeled [14]. Diazotization of the amine 35 and reaction of the resulting diazonium salt afforded the spirocyclic product 36 in an acceptable 57% yield from the amine. This marked the first example where the radical-polar crossover reaction was terminated in an intramolecular manner. Modeling the ABCE tetracycle also worked well in preparing products 40 42. Importantly, the relative stereochemistry of 42, and by implication that of the other tetracycles, was verified by X-ray crystal structure analysis... 

The relative ease of the cyclization step from A to C may also be linked to the nucleophilic or coordinative ability of the heteroatom bound to the metal. The reaction of 7 with diphenylacetylene (Ph2C2) leads to the seven-membered derivatives 68 and 69 after prior isolation of the monoinsertion product 24, treatment with a silver salt, followed by the usual thermolytic conditions. This is another rare example of an intramolecular formation of a C-S bond within the coordination sphere of a transition metal and a novel, albeit limited to one alkyne, route to the rare family of dibenzo[bd] thiepins. With the closely related 8, which differs from 7 only by the tertiary amine unit in the metallacyclic framework instead of a thioether function, a carbocyclic product 71 is obtained (see under carbocycle reactions, next section). The formation of the seven-membered S-heterocycles is attributed to the good coordinative ability of the thioether group in 7. The S-atom remains close to the vinylic carbon function before the cyclization. With the poorly coordinating, readily displaced amine function in 8, the N-atom is detached from the metal and ultimately affords a spirocyclic product (see Scheme 18). 

The main stereoselective MBFTs for the synthesis of spirocyclic acetals or aminals involve the activation of a C-C triple bond to form an intermediate cyclic enol ether. The method disclosed above for the synthesis of a-heteroatom-substituted spirocen-ter (see Section 9.3.3, Scheme 9.18) [34] was next extended by the same authors to the synthesis of spiroacetals. They simply used salicyladehyde as starting aldehyde, but the transformation was not diastereoselective anymore [43]. This problem of stereoselectivity was recently solved by Gong and coworkers, who employed a gold(I)/chiral Brpnsted acid catalysis to do so [44], The chroman spiroacetals were obtained in excellent yields (67-97%) and with high stereoselectivities (up to 95% ee, up to 25 1 dr) (Scheme 9.24). This reaction resulted in the formation of three new single bonds and two stereogenic centers. 

Cu(I)-catalysis [Cul (5mol%) in the presence of NEtj (8mol%)] effects the formation of a spirocyclic vinylcyclopentadiene from a tungstaoctatetraene complex. Unfortunately, replacement of NEtj by chiral amines or diamines does not result in enantioselective spirocylization [98] stable copper(I) carbenes have been isolated and fully characterized [99,100]. A cross-coupling affording highly function-... 

---