Tricyclic ring systems, alkylative

The formal total synthesis of racemic guanacastepene (rac-187) from Snider and co-workers (Fig. 20) was submitted six months later than the completed synthesis of Danishefsky s group [116-118]. The shortest sequence developed by the Snider group utilized the sequential cuprate addition/enolate alkylation of 2-methylcyclopent-2-enone 90 previously exploited by Piers, Williams and Danishefsky (Schemes 15 and 31). As outlined in Figs. 19 and 20, the strategies of Danishefsky and Snider are closely related. Both rely on stepwise annulations to build up the tricyclic ring system. They differ only in respect to the particular reactions that converted the monocyclic starting material (90) via bicyclic hydroazulenes (207 vs 227) into the desired tricyclic 5-7-6-system (224). 

The key step employed a rhodium(l)-catalysed allenic Pauson-Khand reaction to generate the tricyclic ring system 276 from the allenyne 275. However, all attempts to introduced the missing methyl group by a 1,4-addition protocol failed to provide the completed neodolastane framework. Allenyne 275 was synthesized from the enone 274 by a multistep procedure. The quaternary atom was constructed by sequential enolate alkylations. 

As with the mitomycins, general routes to the synthesis of FR900482 and analogs have evolved. A very straightforward approach is the formation of the aziridine ring late in the synthesis using an intramolecular N-alkylation. A second is the incorporation of an intact monocyclic aziridine as part of the formation of the tricyclic ring system. 

In conclusion, Funk completed a synthesis of ( )-FR901483 in 22 steps and 2.4 % overall yield from the starting dioxanone, demonstrating that the easily accessible trifimctional arrays of 2-amidoacroleins can be exploited in the rapid assembly of tricyclic ring systems. Attention should also be drawn to the />-methoxy benzyl substituent introduced at C(6) by alkylation of a tricyclic lactam in an advanced stage of the synthesis. 

Of the carbocyclic sesquiterpenes found in Eremophila, the most elaborate are the tetracyclic enr-zizaenes (89,90,92,93). One possible sequence for the assembly of such a nucleus is given in Scheme 24. Cyclization of 2E,6Z-farnesyl pyrophosphate between the 1 and 6 position would generate the bisabolonium cation equivalent which, after a hydride shift, could further cyclize to a spiro carbocation. The tricyclic ring system can then be assembled by invoking alkylation of the cyclohexene double bond. The tertiary carbocation generated incorporates a bicyclo[3.2.1]octane system which can rearrange in two ways leading to the tricyclic sesquiterpenes metabolites found in Eremophila. 

The cedrene isoprenologues can also be generated from the carbocation (213).which, in this case, alkylates the Si-face of CIO in a lOZ-ene. The spiro-ring system produced displays the 1,4-cis- disubstituted cyclopentane ring. Further cyclization of this intermediate generates the tricyclic ring system of the 2-ep/-cedrene metabolites as shown in Scheme 52. 

Scheme 10.17 illustrates allylation by reaction of radical intermediates with allyl stannanes. The first entry uses a carbohydrate-derived xanthate as the radical source. The addition in this case is highly stereoselective because the shape of the bicyclic ring system provides a steric bias. In Entry 2, a primary phenylthiocar-bonate ester is used as the radical source. In Entry 3, the allyl group is introduced at a rather congested carbon. The reaction is completely stereoselective, presumably because of steric features of the tricyclic system. In Entry 4, a primary selenide serves as the radical source. Entry 5 involves a tandem alkylation-allylation with triethylboron generating the ethyl radical that initiates the reaction. This reaction was done in the presence of a Lewis acid, but lanthanide salts also give good results. 

Although 1,3,2-diazaphospholenium cations are usually prepared from neutral NHPs or 1,3,2-diazaphospholes via Lewis-acid induced substituent abstraction or A-alkylation, respectively (cf. Sect. 3.1.2), the group of Cowley was the first to describe a direct conversion of a-diimines into cationic heterocycles by means of a reaction that can be described as capture of a P(I) cation by diazabutadiene via [4+1] cycloaddition [31] (Scheme 4). The P(I) moiety is either generated by reduction of phosphorus trihalides with tin dichloride in the presence of the diimine [31] or, even more simply, by spontaneous disproportionation of phosphorus triiodide in the presence of the diimine [32], The reaction is of particular value as it provides a straightforward access to annulated heterocyclic ring systems. Thus, the tricyclic structure of 11 is readily assembled by addition of a P(I) moiety to an acenaphthene-diimine [31], and the pyrido-annulated cationic NHP 12 is generated by action of appropriate... 

The most efficient routes to the cationic oxazolo[3,2- ]pyridine ring system 351 rely on the method of Bradsher and Zinn <1967JHC66> involving the cyclocondensation of iV-phenacyl-2-pyridones 349 obtained by alkylation of readily available 2-pyridones 347 (Scheme 95). This method has been used by Babaev et al. to prepare a series of 6-nitro-oxazolo[3,2- ]pyridines 355 from 5-nitro-2-pyridone 352 in excellent yields <2003MOL460>. Similarly, tricyclic oxazolo[3,2- ]pyridines 359 have been prepared from the corresponding quinolin-2(177)-ones 356 <2003H(60)131>. 

A nitroalkane has also served as nucleophile in the cyclizadon as shown in Scheme 8E.32 to give the ergoline ring system in high diastereo- and enantioselecdvity. The initially obtained modest enanitoselectivity (66% ee) by using a catalyst derived from Pd2(dba)3 CHCl3 and (5, 5 )-chiraphos (2) was optimized to 95% ee by using a complex of (S)-BINAP (ent-4) and Pd(OAc)2 [169,170], The obtained tricyclic alkylation product provided an expeditious access to (-)-chanoclavine I. 

The most efficient route to the cationic oxazolo[3,2- ]pyridine ring system 69 relies on the cyclocondensation of N-phenacyl-2-pyridones 68 obtained by alkylation of 2-pyridones 67 (Scheme 41) <1967JHC66, CHEC-III(11.10.7.8) 479>. The use of this method is exemplified by the preparation of tricyclic oxazolo[3,2- ]pyridines 71 from the corresponding quinolin-2(l//)-ones 70 (Scheme 42) <2003H131>. 

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